WO2021207230A1 - Methods of treating cytokine release syndrome using a pi3k inhibitor - Google Patents

Methods of treating cytokine release syndrome using a pi3k inhibitor Download PDF

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Publication number
WO2021207230A1
WO2021207230A1 PCT/US2021/026000 US2021026000W WO2021207230A1 WO 2021207230 A1 WO2021207230 A1 WO 2021207230A1 US 2021026000 W US2021026000 W US 2021026000W WO 2021207230 A1 WO2021207230 A1 WO 2021207230A1
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coronavirus
inhibitor
pi3k inhibitor
infection
acid
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PCT/US2021/026000
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French (fr)
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John DIPERSIO
Sarah OELSNER
Jonathan A. Pachter
Daniel W. PATERSON
Brian M. STUGLIK
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Verastem, Inc.
Washington University
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Publication of WO2021207230A1 publication Critical patent/WO2021207230A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2887—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against CD20
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention relates to use of a PI3K inhibitor in the treatment of a cytokine release syndrome, such as a cytokine release syndrome associated with a viral infection, use of a PI3K inhibitor in the treatment of an acute respiratory distress syndrome, such as an acute respiratory distress syndrome characterized by cytokine release syndrome, and kits comprising a PI3K inhibitor for said uses.
  • a cytokine release syndrome such as a cytokine release syndrome associated with a viral infection
  • an acute respiratory distress syndrome such as an acute respiratory distress syndrome characterized by cytokine release syndrome
  • kits comprising a PI3K inhibitor for said uses.
  • the immune system functions to protect the body against harmful antigens. Regulation of the immune system is essential for an organism’s well being. Immune system disorders can lead to hyperactivity or hypoactivity of the immune system. In cases of immune system hyperactivity, the body attacks and damages its own tissues. In cases of immune system hypoactivity, also known as immune deficiency, the body’s ability to fight foreign antigens is diminished, which often leads to a increased vulnerability to infections. [0004] Infectious diseases, such as those caused by viral infection, continue to present a significant public health risk. According to the U.S. Center for Disease Control and Prevention, the Ebolavirus outbreak of 2014 resulted in approximately 29,000 new cases, of which over 11,000 resulted in death.
  • Described herein is a method of treating cytokine release syndrome through administering a PI3K inhibitor to a patient in need thereof. Also described is a method of treating a patient in acute respiratory distress through administration of a PI3K inhibitor. Kits for such treatment are also described.
  • a PI3K inhibitor is a PI3K5 inhibitor, a RI3Kg inhibitor, or a dual RI3Kd/g inhibitor.
  • the PI3K inhibitor is selected from the group consisting of duvelisib, tenalisib, idelalisib, copanlisib, IPI-549, CAL-130, BKM 120, GDC-0941, PX-866, GDC-0032, BAY 80-6946, BEZ235, BYL719, BGT-226, GDC-0980, GSK 2126458, PF-05212384, XL765, AS604850, AS252424, or XL147, or a combination thereof.
  • the PI3K inhibitor is duvelisib.
  • wherein the PI3K inhibitor is IPI-549.
  • the PI3K inhibitor is idelalisib.
  • the infection is a viral infection.
  • the infection is associated with a virus selected from the group consisting of a coronavirus, a papillomavirus, a pneumovirus, a picornavirus, an influenza virus, an adenovirus, a cytomegalovirus, a polyomavirus, a poxvirus, a flavivirus, an alphavirus, an ebolavirus, a herpesvirus, a morbillivirus, an enterovirus, an orthopneumovirus, a lentivirus, and a hepatovirus.
  • the infection is associated with an influenza virus.
  • the infection is associated with an ebolavirus. In some embodiments, wherein the infection is associated with a coronavirus.
  • the coronavirus is selected from the group consisting of: 229E alpha coronavirus, NL63 alpha coronavirus, OC43 beta coronavirus, HKU1 beta coronavirus, Middle East Respiratory Syndrome coronavirus (MERS-CoV), severe acute respiratory syndrome coronavirus (SARS-CoV), and SARS-CoV2 (COVID-19).
  • the coronavirus is SARS-CoV2. In some embodiments, coronavirus is SARS-CoV.
  • the method further comprises administering a composition comprising an antiviral agent.
  • the antiviral agent is selected from the group consisting of abacavir, acyclovir, adefovir, amantadine, amprenavir, atazanavir, cidofovir, danoprevir, darunavir, delavirdine, didanosine, docosanol, double- stranded RNA activated caspase oligomerizer (DRACO), efavirenz, elvitegravir, emtricitabine, enfuvirtide, entecavir, etravirine, famciclovir, foscamet, fomivirsen, ganciclovir, ibacitabine, indinavir, interferon-a inhibitor, idoxuridine, lamivudine, lopinavir, maraviroc, MK-2048, n
  • a method of treating an acute respiratory distress syndrome comprising administering to a patient in need thereof a therapeutically effective amount of a composition comprising a PI3K inhibitor.
  • the PI3K inhibitor is a PI3K5 inhibitor, a RI3Kg inhibitor, or a dual RI3Kd/g inhibitor.
  • the PI3K inhibitor is selected from the group consisting of duvelisib, tenalisib, idelalisib, copanlisib, IPI-549, CAL-130, BKM 120, GDC-0941, PX-866, GDC-0032, BAY 80-6946, BEZ235, BYL719, BGT-226, GDC-0980, GSK 2126458, PF- 05212384, XL765, AS604850, AS252424, or XL147, or a combination thereof.
  • the PI3K inhibitor is duvelisib.
  • the PI3K inhibitor is IPI-549.
  • the PI3K inhibitor is idelalisib. In some embodiments, the PI3K inhibitor is administered to a patient prophylactically. In certain embodiments, the patient displays elevated ferritin levels, decreased platelet count, elevated erythrocyte sedimentation rate, and/or has an H-Score indicative of hyperinflammation. In some embodiments, the PI3K inhibitor is administered to a patient with symptoms. In certain embodiments, the symptoms comprise acute respiratory distress.
  • the acute respiratory distress syndrome is associated with a disease or disorder selected from the group consisting of an infectious disease or disorder, graft-versus-host disease, organ trauma, tissue trauma, pancreatitis, haemophagocytic lymphohistiocytosis, sepsis, and systemic inflammatory response syndrome.
  • the infectious disease or disorder is associated with a viral infection or a bacterial infection.
  • the viral infection is associated with a virus selected from the group consisting of a coronavirus, a papillomavirus, a pneumovirus, a picomavirus, an influenza virus, an adenovirus, a cytomegalovirus, a polyomavirus, a poxvirus, a flavivirus, an alphavirus, an ebolavirus, a herpesvirus, a morbillivirus, an enterovirus, an orthopneumovirus, a lentivirus, and a hepatovirus.
  • the viral infection is associated with an influenza virus.
  • the viral infection is associated with an ebolavirus.
  • the viral infection is associated with a coronavirus.
  • the coronavirus is selected from the group consisting of: 229E alpha coronavirus, NL63 alpha coronavirus, OC43 beta coronavirus, HKU1 beta coronavirus, Middle East Respiratory Syndrome coronavirus (MERS-CoV), severe acute respiratory syndrome coronavirus (SARS-CoV), and SARS- CoV2 (COVID-19).
  • the coronavirus is SARS-CoV2.
  • the method further comprises administering a composition comprising an antiviral agent.
  • the antiviral agent is selected from the group consisting of abacavir, acyclovir, adefovir, amantadine, amprenavir, atazanavir, cidofovir, danoprevir, darunavir, delavirdine, didanosine, docosanol, double-stranded RNA activated caspase oligomerizer (DRACO), efavirenz, elvitegravir, emtricitabine, enfuvirtide, entecavir, etravirine, famciclovir, foscamet, fomivirsen, ganciclovir, ibacitabine, indinavir, interferon-a inhibitor, idoxuridine, lamivudine, lopinavir, maraviroc, MK-2048, nelf
  • the bacterial infection is associated with a bacteria selected from the group consisting of: Chlamydia pneumoniae , Vibrio cholerae , Streptococcus pneumoniae , Mycoplasma pneumoniae , Haemophilus influenzae , Legionella pneumophila , Salmonella enterica , Salmonella bongori, Escherichia coli , Helicobacter pylori , Neisseria gonorrhoeae , Neisseria meningitidis , Staphylococcus aureus , Acinetobacter baumannii , Burkholderia cepacian , Clostridium difficile , Clostridium sordellii , an Enterobacteriaceae, Enterococcus faecalis , Klebsiella pneumoniae , Morganella morganii, Mycobacterium abscessus , Mycobacterium tuberculosis , a Norovirus,
  • the method further comprises administering a composition comprising an antibacterial agent.
  • the antibacterial agent is selected from the group consisting of doxycycline, vancomycin, metronidazole, gentamicin, colistin, fidaxomicin, telavancin, oritavancin, dalbavancin, daptomycin, cephalexin, cefuroxime, cefadroxil, cefazolin, cephalothin, cefaclor, cefamandole, cefoxitin, cefprozil, ceftobiprole, cipro, Levaquin, floxin, tequin, avelox, norflox, tetracycline, minocycline, oxytetracycline, amoxicillin, ampicillin, penicillin V, dicloxacillin, carbenicillin, methicillin, ertapenem, doripenem, imipenem/cil
  • the acute respiratory distress syndrome is characterized by cytokine release syndrome.
  • the method further comprises administering a composition comprising a cytokine inhibitor.
  • the cytokine inhibitor is selected from the group consisting of an IL-6 antagonist, an IL-1 antagonist, a soluble tumor necrosis factor receptor, an IL-1 receptor agonist, and a TGF-bI latency-associated peptide.
  • the IL-6 antagonist is tocilizumab, sarilumab, or siltuximab.
  • the composition comprising the PI3K inhibitor is administered orally. In some embodiments, the composition comprising the PI3K inhibitor is administered parenterally. In some embodiments, the PI3K inhibitor is administered to a patient prophylactically. In certain embodiments, the patient displays elevated ferritin levels, decreased platelet count, elevated erythrocyte sedimentation rate, and/or has an H-Score indicative of hyperinfl animation. In some embodiments, the PI3K inhibitor is administered to a patient with symptoms. In certain embodiments, the symptoms comprise acute respiratory distress. In some embodiments, the PI3K inhibitor is administered at a therapeutically effective amount to reduce pro-inflammatory cytokines in a patient in need thereof.
  • the PI3K inhibitor is administered at a therapeutically effective amount to reduce cytokine levels in a patient in need thereof, wherein the cytokines are selected from the group consisting of TNF ⁇ , IL-10, CCL3, and CCL4.
  • the PI3K inhibitor is administered at a therapeutically effective amount to reduce TNFa levels in a patient in need thereof.
  • the PI3K inhibitor is administered at a therapeutically effective amount to reduce IL-10 levels in a patient in need thereof.
  • the PI3K inhibitor is administered at a therapeutically effective amount to reduce CCL3 levels in a patient in need thereof.
  • the PI3K inhibitor is administered at a therapeutically effective amount to reduce CCL4 levels in a patient in need thereof.
  • the kit further comprises a composition comprising a cytokine inhibitor.
  • the cytokine inhibitor is selected from the group consisting of an IL-6 antagonist, an IL-1 antagonist, a soluble tumor necrosis factor receptor, an IL-1 receptor agonist, and a TGF-bI latency-associated peptide.
  • the IL-6 antagonist is tocilizumab, sarilumab, or siltuximab.
  • the cytokine release syndrome is associated with a coronavirus infection.
  • the coronavirus infection is associated with a coronavirus selected from the group consisting of: 229E alpha coronavirus, NL63 alpha coronavirus, OC43 beta coronavirus, HKU 1 beta coronavirus, Middle East Respiratory Syndrome coronavirus (MERS-CoV), severe acute respiratory syndrome coronavirus (SARS- CoV), and SARS-CoV2 (COVID-19).
  • the coronavirus infection is associated with SARS-CoV2 (COVID-19).
  • the kit further comprises an antiviral agent.
  • the antiviral agent is selected from the group consisting of abacavir, acyclovir, adefovir, amantadine, amprenavir, atazanavir, cidofovir, danoprevir, darunavir, delavirdine, didanosine, docosanol, double-stranded RNA activated caspase oligomerizer (DRACO), efavirenz, elvitegravir, emtricitabine, enfuvirtide, entecavir, etravirine, famciclovir, foscarnet, fomivirsen, ganciclovir, ibacitabine, indinavir, interferon-a inhibitor, idoxuridine, lamivudine, lopinavir, maraviroc, MK-2048, nelfmavir, nevi
  • DPACO caspase oligo
  • FIG. 1 shows cytokine levels for patients with heme malignancies treated with a PI3K inhibitor.
  • FIG. 1A shows relative cytokine expression levels at Cycle 2, Day 1 of 28- day cycles compared to baseline for chronic lymphocytic leukemia/ small lymphocytic leukemia (CLL/SLL) treated with duvelisib or Ofatumumab.
  • FIG. IB shows relative cytokine expression levels at Cycle 1, Day 15 and Cycle 2, Day 1 of 28-day cycles for indolent Non-Hodgkins lymphoma (iNHL) treated with duvelisib. Cytokine levels were determined using a Luminex multiplex immunoassay.
  • the present disclosure provides a method of using a PI3K inhibitor in the treatment of a cytokine release syndrome, for example, a cytokine release syndrome associated with a viral infection.
  • the present disclosure also provides a method of using a PI3K inhibitor in the treatment of an acute respiratory syndrome, for example, an acute respiratory syndrome characterized by cytokine release syndrome.
  • an acute respiratory syndrome for example, an acute respiratory syndrome characterized by cytokine release syndrome.
  • a PI3K inhibitor of the present disclosure is used in a method of treating a cytokine release syndrome, such as those associated with an infection.
  • the cytokine release syndrome is the result of an infection by a pathogen, e.g., a bacterium, a virus, a fungus, a protozoan (e.g, an amoeba), an alga, or a prion.
  • a pathogen e.g., a bacterium, a virus, a fungus, a protozoan (e.g, an amoeba), an alga, or a prion.
  • Intracellular pathogens include facultative intracellular parasites, which are capable of living and reproducing either inside or outside host cells, and obligate intracellular parasites, which cannot reproduce outside their host cell.
  • the intracellular pathogen is dormant, latent, or symbiotic within a cell, but can cause a disease or disorder at a later stage of the pathogen’s life cycle.
  • An infection by the intracellular pathogen can be acute or chronic.
  • the disease or disorder mediated by an intracellular pathogen is a chronic infection.
  • the disease or disorder mediated by an intracellular pathogen is an acute infection.
  • the cytokine release syndrome is associated with a viral infection.
  • the virus is selected from the group consisting of a retrovirus (e.g, human immunodeficiency virus (HIV), simian immunodeficiency virus (SIV), human T-cell lymphotropic virus (HTLV)-l, HTLV-2, HTLV-3, HTLV-4), Ebola virus, hepatitis A virus, hepatitis B virus, hepatitis C virus, a herpes simplex virus (HSV)
  • HIV human immunodeficiency virus
  • SIV simian immunodeficiency virus
  • HTLV human T-cell lymphotropic virus
  • HSV herpes simplex virus
  • HSV-1, HSV-2, varicella zoster virus, cytomegalovirus an adenovirus, an orthomyxovirus (e.g, influenza virus A, influenza virus B, influenza virus C, influenza virus D, thogotovirus), a flavivirus (e.g., dengue virus, Zika virus), West Nile virus, Rift Valley fever virus, an arenavirus, Crimean-Congo hemorrhagic fever virus, an echovirus, a rhinovirus, coxsackie virus, a coronavirus (e.g, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)), a respiratory syncytial virus, a mumps virus, a rotavirus, measles virus, rubella virus, a parvovirus (e.g, an adeno-associated virus), a vaccinia virus, a variola virus, a molluscum virus, bovine leukemia virus, a poliovirus
  • the virus is a novel virus not previously characterized (e.g, a novel coronavirus).
  • a PI3K inhibitor described herein is used for treating cytokine release syndrome associated with a viral infection, e.g, a cytokine release syndrome associated with a viral infection selected from the group consisting of acquired immune deficiency syndrome (AIDS), HTLV-1 associated myelopathy/tropical spastic paraparesis, Ebola virus disease, hepatitis A, hepatitis B, hepatitis C, herpes, herpes zoster, acute varicella, mononucleosis, respiratory infections, pneumonia, influenza, dengue fever, encephalitis (e.g, Japanese encephalitis), West Nile fever, Rift Valley fever, Crimean-Congo hemorrhagic fever, Kyasanur Forest disease, Yellow fever, Zika fever, aseptic meningitis, SARS, myocarditis, common cold, lung infections, molloscum contagiosum, enzootic bovine leucosis, coron
  • AIDS acquired immune defic
  • a PI3K inhibitor described herein is used for treating cytokine release syndrome associated with an ebolavirus. In some embodiments, a PI3K inhibitor described herein is used for treating cytokine release syndrome associated with SARS. In some embodiments, a PI3K inhibitor described herein is used for treating cytokine release syndrome associated with COVID-19.
  • the virus associated with the infection is an RNA virus (having a genome that is composed of RNA).
  • RNA viruses may be single-stranded RNA (ssRNA) or double-stranded RNA (dsRNA).
  • ssRNA single-stranded RNA
  • dsRNA double-stranded RNA
  • RNA viruses have high mutation rates compared to DNA viruses, as RNA polymerase lacks proofreading capability (see Steinhauer DA, Holland JJ (1987). "Rapid evolution of RNA viruses”. Annu. Rev. Microbiol. 41: 409- 33).
  • RNA viruses include, without limitation, bunyaviruses (e.g, hantavirus), coronaviruses (e.g, MERS-CoV, SARS-CoV, SARS-CoV-2), flaviviruses (e.g, yellow fever virus, west nile virus, dengue virus), hepatitis viruses (e.g, hepatitis A virus, hepatitis C virus, hepatitis E virus), influenza viruses (e.g, influenza virus type A, influenza vims type B, influenza vims type C), measles vims, mumps vims, norovimses ( e.g ., Norwalk vims), poliovims, respiratory syncytial vims (RSV), retrovimses (e.g.
  • bunyaviruses e.g, hantavirus
  • coronaviruses e.g, MERS-CoV, SARS-CoV, SARS-CoV-2
  • the RNA vims is an influenza vims, e.g., influenza A.
  • the RNA vims is RSV.
  • the RNA vims is MERS-CoV.
  • the RNA vims is SARS-CoV.
  • the RNA vims is SARS-CoV2.
  • the RNA vims is ZIKA.
  • RNA vimses are classified by the type of genome (double-stranded, negative (-), or positive (+) single-stranded). Double-stranded RNA vimses contain a number of different RNA molecules, each coding for one or more viral proteins. Positive-sense ssRNA vimses utilize their genome directly as mRNA; ribosomes within the host cell translate mRNA into a single protein that is then modified to form the various proteins needed for viral replication. One such protein is RNA-dependent RNA polymerase (RNA replicase), which copies the viral RNA in order to form a double-stranded, replicative form.
  • RNA replicase RNA-dependent RNA polymerase
  • Negative-sense ssRNA vimses have their genome copied by an RNA replicase enzyme to produce positive-sense RNA for replication. Therefore, the vims comprises an RNA replicase enzyme. The resultant positive-sense RNA then acts as viral mRNA and is translated by the host ribosomes.
  • the vims is a dsRNA vims. In some embodiments, the vims is a negative ssRNA vims. In some embodiments, the vims is a positive ssRNA vims. In some embodiments, the positive ssRNA vims is a coronavims.
  • SARS-CoV2 also sometimes referred to as the novel coronavims of 2019 or 2019-nCoV, is a positive-sense single-stranded RNA vims.
  • SARS-CoV2 has four stmctural proteins, known as the S (spike), E (envelope), M (membrane), and N (nucleocapsid) proteins.
  • the N protein holds the RNA genome; together, the S, E, and M proteins form the viral envelope.
  • Spike allows the vims to attach to the membrane of a host cell, such as the ACE2 receptor in human cells (Kmse R.L. (2020), Therapeutic strategies in an outbreak scenario to treat the novel coronavims originating in Wuhan, China (version 2).
  • SARS-CoV2 is the highly contagious, causative viral agent of coronavims disease 2019 (COVID19), a global pandemic.
  • COVID19 coronavims disease 2019
  • the cytokine release syndrome being treated is associated with SARS-CoV2 (COVTD19).
  • the vims associated with the infection is a DNA vims (having a genome that is composed of DNA)
  • Exemplary DNA vimses include, without limitation, parvoviruses (e.g., adeno-associated vimses), adenoviruses, asfarvi ruses, herpesviruses (e.g., herpes simplex vims 1 and 2 (HSV-1 and HSV-2), epstein-barr virus sEBV), cytomegalovirus (CMV)), papillomoviruses (e.g., HPV),polyomaviruses (e.g, simian vacuolating vims 40 (SV40)), and poxviruses (e.g., vaccinia viru , cowpox vims, smallpox virus, fowl pox virus, sheeppox virus, myxoma vims).
  • parvoviruses e.g., a
  • the DNA vims is an adenovirus, e.g., AdV5. In certain embodiments, the DNA vims is an enterovims, e.g, EV71. In certain embodiments, the DNA vims is a herpesvims, e.g. , HSV- 1
  • the infection is systemic.
  • the infection is localized, e.g, to an organ or, e.g, to a tissue.
  • infection is localized to an organ including but not limited to the eye, the ear, the inner ear, the lungs, trachea, bronchus, bronchioli, the liver, the gall bladder, the bile duct, the kidney, the bladder, the testis, the cervix, the ovary, the utems, the skin, or the brain.
  • the infection is localized to the lungs.
  • the infection is chronic.
  • chronic refers to an infection that persists for an extended period of time, or recurs.
  • the infection is acute.
  • acute refers to an infection that is of short duration.
  • viral count is determined using a plaque assay.
  • viral count is determined using a focus forming assay (FFA).
  • viral count is determined using an endpoint dilution assay.
  • viral count is determined using an enzyme-linked immunosorbent assay (ELISA).
  • ELISA enzyme-linked immunosorbent assay
  • TRPS Tunable resistive pulse sensing
  • viral replication is determined by quantifying the amount or percentage of host cell death, e.g.
  • viral count is determined by measuring viral titer or multiplicity of infection (MOI) or by performing a plaque assay, a focus forming assay, and endpoint dilution assay, a viral protein quantification assay (for example, a hemagglutination assay, a bicinchoninic acid assay (BCA), or a single radial immunodiffusion assay (SRID) assay), transmission electron microscopy analysis, a tunable resistive pulse sensing (TRPS) assay, a flow cytometry assay, a quantitative PCR (qPCR) assay, or an Enzyme-linked immunosorbent assay (ELISA).
  • viral replication is determined by quantification of viral nucleic acid (for example, viral DNA or viral
  • viral transmission is quantified using epidemiological modeling (see, e.g., GrawF. et al, (2016) Modeling Viral Spread. AnnuRev Virol , 3(1)).
  • viral transmission is assessed in vitro , e.g, in cell culture, e.g, using microscopy, e.g. , using transmission electron microscopy (TEM).
  • TEM transmission electron microscopy
  • viral assembly is determined using statistical modeling (see, e.g, Clement N et al. , (2016) Viral Capsid Assembly: A Quantified Uncertainty Approach. J Comp Biol , 25(1)).
  • viral assembly is determined using biochemical techniques to determine capsid complex formation, e.g. , co-immunoprecipitation, e.g. , western blotting.
  • viral assembly is determined by flow cytometry for detection of colocalized viral protein (see, e.g, Stoffel, C.L. et al. (2005).
  • Viral genes encode elements necessary for the process of viral infection, a multi- step process, including, for example, attachment to the host cell, penetration, deenvelopment, viral gene transcription cascade, viral protein expression, viral genome replication, viral packaging and assembly, envelopment, transport and maturation, release and egress, and host cell-to-cell transmission
  • b genes are those genes corresponding to early steps of viral infection, e.g. , viral genome replication
  • g genes are those genes corresponding to late steps of viral infection, e.g. , egress. Methods to quantify viral gene expression are known in the art.
  • viral gene expression is determined using reverse transcriptase and quantitative polymerase chain reaction (RT-qPCR).
  • RNA sequencing RNA-Seq
  • viral DNA is quantified using a Sourthern blot.
  • b gene expression is quantified.
  • g gene expression is quantified.
  • b gene expression and g gene expression are quantified.
  • expression of the entire viral genome is quantified.
  • viral release is determined by biochemical assay, e.g, western blotting, e.g, metabolic labeling (see, e.g, Yadav etal, (2012). “A facile quantitative assay for viral particle genesis reveals cooperativity in virion assembly and saturation of an antiviral protein.” Virology. 429(2): 155-162).
  • viral release is determined by ELISA.
  • viral release is determined using electron microscopy, e.g, transmission electron microscopy (TEM).
  • TEM transmission electron microscopy
  • viral release is determined by infectivity measurements for the detection of virions in a sample, e.g. , serum.
  • viral release is determined by quantification of viral DNA or viral RNA in serum in vivo or culture supernatant in vitro.
  • the cytokine release syndrome is associated with a bacterial infection.
  • cytokine release syndrome is associated with a bacteria selected from from the group consisting of Chlamydia (e.g, C. trachomatis ), Escherichia coli (e.g., enteropathogenic E. coli, enterohemmorhagic E. coli, uropathogenic E. coli, enteroinvasive E. coli), Helicobacter pylori, Mycobacterium (e.g.,M. tuberculosis, M. leprae, M. lepromatosis), Listeria (e.g, L.
  • Shigella e.g., S.flexneri
  • Staphylococcus e.g, S. aureus
  • Streptococcus e.g, S. pyogenes
  • Streptomyces Pneumococcus, Meningococcus, Gonococcus
  • Klebsiella e.g, K. pneumoniae
  • Proteus Serratia, Pseudomonas (e.g, P. aeruginosa), Legionella, Acinetobacter (e.g, A. baumannii), Corynebacterium (e.g, C. diphtheria), Coxiella (e.g, C.
  • Burnetii Bacillus (e.g., B. anthricis ), Bacteroides, Bordetella, Enterococcus (e.g, E. faecalis), Francisella (e.g, F. tularensis), Haemophilus influenza, Neisseria (e.g, N. meningitides, N. gonorrhoeae), Rickettsia, Salmonella (e.g., S. typhimurium), Vibrio cholerae, Clostridium (e.g, C. tetan, C. botulinum), Yersinia (e.g., Y. pestis), Borrielia (e.g, B. burgdorferi), Brucella, Burkholderia, Campylobacter, and Mycoplasma.
  • Bacillus e.g., B. anthricis
  • Bacteroides Bacteroides
  • Bordetella Enterococcus (
  • a PI3K inhibitor described herein is used for treating cytokine release syndrome associated with a bacterial infection, e.g, a cytokine release syndrome associated with, for example, an intracellular bacterial infection.
  • Methods described herein can be used to treat, for example, a bacterial disease or disorder selected from the group consisting of chlamydia, tuberculosis, peptic ulcers, leprosy, listeriosis, sialadenitis, bacteria-caused diarrhea or food poisoning, strep throat, scarlet fever, impetigo, cellulitis, pneumonia, meningitis, bacterial endocarditis, diverticulitis, disseminated gonococcemia, septic arthritis, gonococcal ophthalmia neonatorum, urinary tract infections, soft tissue infections, spondyloarthropathies (e.g, ankylosing spondylitis), legionellosis (e.g, Legionnaires’ disease,
  • the cytokine release syndrome is associated with a fungal infection.
  • the fungus is selected from the group consisting of Candida (e.g., C. albicans , C. krusei , C. glabrata, C. tropicalis ), Cryptococcus (e.g. , C. neoformans , C. gattii ), Aspergillus (e.g, A. fumigatus, A. niger ), Mucorales ( e.g.,M . mucor, M. absidia,M. rhizopus), Sporothrix (e.g. , S.
  • Candida e.g., C. albicans , C. krusei , C. glabrata, C. tropicalis
  • Cryptococcus e.g. , C. neoformans , C. gattii
  • Aspergillus e.g, A. fumigatus, A. niger
  • schenkii Blastomyces (e.g, B. dermatitidis), Paracoccidioides (e.g, P. brasiliensis ), Coccidioides (e.g, C. immitis ), Histoplasma (e.g, H. capsulatum), Acremonium, Basidiobolus (e.g, B. ranarum), Cladophialophora (e.g., C. bantiana ), Cunninghamella (e.g, C. bertholletiae), Epidermophyton, Exophiala, Exserohilum, Fonsecaea (e.g., F. pedrosoi), Hortaea (e.g., H.
  • Lacazia e.g., L. loboi
  • Leptosphaeria e.g., L. maculans
  • Madurella e.g.,M. mycetomatis
  • Malassezia Microsporum, Mucor, Neotestudina, Onychocola, Phial ophora
  • Piedraia Pneumocystis (e.g, P. jirovecii), Pseudallescheria (e.g, P. boydii ), Pyrenochaeta, Rhizomucor, Scedosporium, Scytalidium, Sporothrix, Trichophyton, Trichosporon, and Zygomycete.
  • a PI3K inhibitor described herein is used for treating a cytokine release syndrome associated with an intracellular fungal infection, e.g, a cytokine release syndrome associated with an intracellular fungal infection selected from the group consisting of candidiasis, cryptococcosis, aspergillosis, mucormycosis, sporotrichosis, blastomycosis, paracoccidioidomycosis, coccidioidomycosis, histoplasmosis, eumycetoma, onychomycosis, hyalohyphomycosis, subcutaneous zygomycosis, cerebral abscesses, phaeohyphomycosis, chromoblastomycosis, mycetoma, pulmonary mucormycosis, tinea corporis, tinea capitis, tinea cruris, tinea pedis, tinea unguium, tinea nigr
  • the cytokine release syndrome is associated with an intracellular protozoan infection.
  • the protozoan is an amoeba.
  • the amoeba is selected from the group consisting of Apicomplexans (Plasmodium (e.g., P. n ⁇ nac, R. falciparum, P. ovale, P.
  • Trypanosoma e.g, Trypanosoma brucei, Trypanosoma cruzi
  • Leishmania e.g., Leishmania donovani
  • a PI3K inhibitor described herein is used for treating a disease or disorder caused by an intracellular amoebal infection, e.g ., a cytokine release syndrome associated with an amoebal infection selected from the group consisting of babesiosis, malaria, cryptosporidiosis, cyclosporiasis, cystoisosporiasis, toxoplasmosis, trypanosomiasis, Chagas disease, and leishmaniasis.
  • a cytokine release syndrome associated with an amoebal infection selected from the group consisting of babesiosis, malaria, cryptosporidiosis, cyclosporiasis, cystoisosporiasis, toxoplasmosis, trypanosomiasis, Chagas disease, and leishmaniasis.
  • the cytokine release syndrome is associated with an alga.
  • the alga is a Prototheca.
  • a PI3K inhibitor described herein is used for treating a cytokine release syndrome associated with an intracellular algal infection, e.g. , protothecosis.
  • the cytokine release syndrome is associated with a prion.
  • a PI3K inhibitor described herein is used for treating cytokine release syndrome associated with caused an intracellular prion infection, e.g. , a cytokine release syndrome associated with a prion infection selected from the group consisting of Creutzf el dt- Jakob disease, variant Creutzfeldt-Jakob disease, Gerstmann-Straussler- Scheinker syndrome, fatal familial insomnia, and kuru.
  • cytokine release is studied in vitro , e.g. , in cell culture.
  • in vitro cytokine release is quantified from the cell culture supernatant.
  • cytokine release is studied in vivo , e.g. , in an animal model.
  • in vivo cytokine release is quantified from a bodily fluid, e.g. , whole blood, serum, plasma, or lymph.
  • the animal model is a murine model.
  • the animal model is a non-human primate.
  • cytokine release is studied in a human patient.
  • cytokine release is assessed through quantification of cytokine expression levels.
  • cytokine expression levels are quantified using an enzyme-linked immunosorbent assay (ELISA).
  • cytokine expression levels are quantified using a multiplex immunoassay, e.g., Luminex.
  • cytokine expression levels are quantified using a cytokine array.
  • cytokine expression levels are quantified using a Western Blot.
  • cytokine expression levels are quantified using mass spectrometry.
  • cytokine release is assayed through monitoring changes in the immune system.
  • FACS fluorescence activated cell sorting
  • transcriptomic profiling e.g ., by RNA-sequencing (RNA Seq)
  • blood smears complete blood count
  • hematocrit e.g ., hematocrit
  • symptoms of a disease or disorder are indicative of changes in the immune system.
  • a decrease in symptoms of a disease or disorder, such as fever, pneumonia, shortness of breath, and low blood oxygen levels are indicative of changes in the immune system.
  • the invention also provides for methods of treating acute respiratory distress syndrome with a PI3K inhibitor described herein.
  • Acute respiratory distress syndrome is a disorder characterized by poor blood oxygenation, fluid infiltration into the lungs, and acuity of onset (Diamond et al. (2020).
  • Acute Respiratory Distress Syndrome (ARDS).
  • StatPearls [Internet], Treasure Island (FL): StatPearls Publishing).
  • ARDS onset occurs within 7 days of the causal event.
  • ARDS is clinically defined by the ratio of the patient's oxygen levels in arterial blood (Pa02) to the oxygen in the inspired air (Fi02).
  • ARDS is defined as patients exhibiting a Pa02/Fi02 ratio of less than 300.
  • ARDS has high morbidity and mortality.
  • Clinical ARDS is further described, for example, in Fan et al. (2016).
  • Acute Respiratory Distress Syndrome Advances in Diagnosis and Treatment. JAMA. 319 (7): 698-710.
  • Risk factors for ARDS include, without limitation, an infectious disease or disorder (e.g., a viral infection, e.g, a bacterial infection), graft-versus-host disease, organ trauma, tissue trauma, haemophagocytic lymphohistiocytosis, sepsis, systemic inflammatory response syndrome, drowning, drug overdose, fat embolism, inhalation of toxic fumes, and pancreatitis.
  • the risk factor for ARDS is an infectious disease or disorder, e.g, a virus, e.g, a coronavirus, e.g, SARS-CoV2.
  • the risk factor for ARDS is an infectious disease or disorder, e.g, a virus, e.g, a ebolavirus. In some embodiments, the risk factor for ARDS is an infectious disease or disorder, e.g, a bacteria, e.g., Streptococcus pneumoniae. In some embodiments, ARDS is associated with cytokine release syndrome. In a particular embodiment, ARDS is associated with cytokine release syndrome associated with SARS-Cov2 (COVID19). In some embodiments, ARDS is associated with mortality associated with SARS-Cov2 (COVID19).
  • Existing therapies for patients with ARDS comprise supportive and/or palliative care, including, without limitation, reducing shunt fraction, increasing oxygen delivery, decreasing oxygen consumption, and avoiding further injury to affected tissues and organs.
  • a patient with ARDS is placed on a mechanical ventilator.
  • a patient on a mechanical ventilator is administered a PI3K inhibitor as described herein.
  • a patient on a mechanical ventilator is administered a PI3K inhibitor as described herein intravenously.
  • PI3K inhibitors that can be used in the kits and methods provided herein include, but are not limited to, those described in, e.g., WO 09/088990, WO2011/008302, WO 2010/036380, WO 2010/006086, WO 09/114870, WO 05/113556, and US 2011/0046165, the entirety of each incorporated herein by reference.
  • Additional PI3K inhibitors that can be used in the compositions and methods provided herein include, but are not limited to, AMG-319, GSK 2126458 (2,4-Difluoro-N- ⁇ 2-(methyloxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3- pyridinyl ⁇ benzenesulfonamide), GSK 1059615 (5Z-[[4-(4-pyridinyl)-6- quinolinyl]methylene]-2,4-thiazolidinedione), GDC-0032 (4-[5,6-dihydro-2-[3-m ethyl -1-(1- methylethyl)-lH- 1 ,2,4-triazol-5-yl]imidazo[l,2-d] [l,4]benzoxazepin-9-yl]-a,a-dimethyl- IH-Pyrazole- 1 -acetamide), GDC-09
  • a PI3K inhibitor is a compound that inhibits one or more PI3K isoforms, e.g., alpha, beta, delta, or gamma isoform.
  • a PI3K inhibitor is a compound that inhibits one or more PI3K isoforms with an IC50 of less than about 1000 nM, less than about 900 nM, less than about 800 nM, less than about 700 nM, less than about 600 nM, less than about 500 nM, less than about 400 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 75 nM, less than about 50 nM, less than about 25 nM, less than about 20 nM, less than about 15 nM, less than about 10 nM, less than about 10 nM, less than about 5 nM, or less than about 1 nM.
  • the PI3K inhibitor is a compound that inhibits alpha, beta, delta and gamma isoforms of PI3K. In another embodiment, the PI3K inhibitor is a compound that inhibits beta, delta, and gamma isoforms of PI3K. In another embodiment, the PI3K inhibitor is a compound that inhibits the delta and gamma isoforms of PI3K.
  • the PI3K inhibitor is a PI3K isoform selective inhibitor. In some embodiments, the PI3K inhibitor is a PI3K alpha selective inhibitor. In another embodiment, the PI3K inhibitor is a PI3K beta selective inhibitor.
  • the PI3K inhibitor is a PI3K gamma selective inhibitor.
  • the PI3K gamma selective inhibitor selectively inhibits PI3K gamma isoform over PI3K delta isoform.
  • the PI3K gamma selective inhibitor has a delta/gamma selectivity ratio of greater than 1, greater than about 5, greater than about 10, greater than about 50, greater than about 100, greater than about 200, greater than about 400, greater than about 600, greater than about 800, greater than about 1000, greater than about 1500, greater than about 2000, greater than about 5000, greater than about 10,000, or greater than about 20,000.
  • the PI3K gamma selective inhibitor has a delta/gamma selectivity ratio in the range of from greater than 1 to about 5, from about 5 to about 10, from about 10 to about 50, from about 50 to about 850, or greater than about 850.
  • the delta/gamma selectivity ratio is determined by dividing the inhibitor's IC50 against PI3K delta isoform by the inhibitor's IC50 against PI3K gamma isoform.
  • the PI3K inhibitor is a PI3K gamma selective inhibitor.
  • the PI3K gamma selective inhibitor selectively inhibits PI3K gamma isoform over PI3K alpha isoform.
  • the PI3K gamma selective inhibitor has an alpha/gamma selectivity ratio of greater than 1, greater than about 5, greater than about 10, greater than about 50, greater than about 100, greater than about 200, greater than about 400, greater than about 600, greater than about 800, greater than about 1000, greater than about 1500, greater than about 2000, greater than about 5000, greater than about 10,000, or greater than about 20,000.
  • the PI3K gamma selective inhibitor has an alpha/gamma selectivity ratio in the range of from greater than 1 to about 5, from about 5 to about 10, from about 10 to about 50, from about 50 to about 850, or greater than about 850. In some embodiments, the alpha/gamma selectivity ratio is determined by dividing the inhibitor's IC50 against PI3K alpha isoform by the inhibitor's IC50 against PI3K gamma isoform.
  • the PI3K inhibitor is a PI3K gamma selective inhibitor.
  • the PI3K gamma selective inhibitor selectively inhibits PI3K gamma isoform over PI3K beta isoform.
  • the PI3K gamma selective inhibitor has a beta/gamma selectivity ratio of greater than 1, greater than about 5, greater than about 10, greater than about 50, greater than about 100, greater than about 200, greater than about 400, greater than about 600, greater than about 800, greater than about 1000, greater than about 1500, greater than about 2000, greater than about 5000, greater than about 10,000, or greater than about 20,000.
  • the PI3K gamma selective inhibitor has a beta/gamma selectivity ratio in the range of from greater than 1 to about 5, from about 5 to about 10, from about 10 to about 50, from about 50 to about 850, or greater than about 850.
  • the beta/gamma selectivity ratio is determined by dividing the inhibitor's IC50 against PI3K beta isoform by the inhibitor's IC50 against PI3K gamma isoform.
  • the PI3K inhibitor is selective for both gamma and delta isoforms, as determined by IC50 from whole blood assays for both PI3K-delta and PI3K- gamma at clinically achievable plasma exposures.
  • the PI3K gamma and delta selective inhibitor selectively inhibits PI3K gamma and delta isoforms over PI3K beta isoform.
  • the PI3K gamma and delta selective inhibitor has a beta/delta selectivity ratio of greater than 1, greater than about 5, greater than about 10, greater than about 50, greater than about 100, greater than about 200, greater than about 400, greater than about 600, greater than about 800, greater than about 1000, greater than about 1500, greater than about 2000, greater than about 5000, greater than about 10,000, or greater than about 20,000 and a beta/gamma selectivity ratio of greater than 1, greater than about 5, greater than about 10, greater than about 50, greater than about 100, greater than about 200, greater than about 400, greater than about 600, greater than about 800, greater than about 1000, greater than about 1500, greater than about 2000, greater than about 5000, greater than about 10,000, or greater than about 20,000.
  • the PI3K gamma and delta selective inhibitor has a beta/delta selectivity ratio in the range of from greater than 1 to about 5, from about 5 to about 10, from about 10 to about 50, from about 50 to about 850, or greater than about 850 and a beta/gamma selectivity ratio in the range of from greater than 1 to about 5, from about 5 to about 10, from about 10 to about 50, from about 50 to about 850, or greater than about 850.
  • the beta/delta selectivity ratio is determined by dividing the inhibitor's IC 50 against PI3K beta isoform by the inhibitor's IC 50 against PI3K delta isoform and the beta/gamma selectivity ratio is determined by dividing the inhibitor's IC 50 against PI3K beta isoform by the inhibitor's IC 50 against PI3K gamma isoform.
  • PI3K gamma inhibitors that can be used in the compositions and methods provided herein include, but are not limited to, IPI-549 (2-amino-N-[(lS)-l-[8-[2-(l-methylpyrazol-4- yl)ethynyl]-l-oxo-2-phenylisoquinolin-3-yl]ethyl]pyrazolo[l,5-a]pyrimidine-3-carboxamide), CZC24832 (5-(2-Amino-8-fluoro-[l,2,4]triazolo[l,5-a]pyridin-6-yl)-N-tert-butylpyridine-3- sulfonamide), AS252424 (5-[l-[5-(4-Fluoro-2-hydroxy-phenyl)-furan-2-yl]-meth-(Z)- ylidene]-thiazolidine-2,4-dione), or AS252424
  • the PI3K inhibitor is a PI3K delta/gamma dual inhibitor.
  • the PI3K delta/gamma dual inhibitor has an IC50 value against PI3K alpha that is at least 5X, 10X, 20X, 50X, 100X, 200X, 500X, or 1000X higher than its IC50 values against delta and gamma.
  • the PI3K inhibitor may be administered daily, every other day, three times a week, twice a week, weekly, or bi-weekly.
  • the dosing schedule can include a "drug holiday," e.g., the drug may be administered for two weeks on, one week off, or three weeks on, one week off, or four weeks on, one week off, etc., or continuously, without a drug holiday.
  • the inhibitor may be administered orally, intravenously, intraperitoneally, topically, transdermally, intramuscularly, subcutaneously, intranasally, sublingually, or by any other route.
  • a PI3K inhibitor described herein may be administered in multiple doses. Dosing may be about once, twice, three times, four times, five times, six times, or more than six times per day. Dosing may be about once a month, about once every two weeks, about once a week, or about once every other day. In some cases, continuous dosing is achieved and maintained as long as necessary.
  • a PI3K inhibitor described herein may be administrated prophylactically. In some embodiments, a PI3K inhibitor described herein may be administered when a patient displays sympytoms. In some embodiments, a PI3K inhibitor described herein may be administered prophylactically and to a patient with symptoms.
  • symptoms of a disease or disorder comprise fever, cough, sore throat, runny nose, congestion, headache, malaise, diarrhea, nausea, vomiting, hyperinflammation, rash, pneumonia, chest pain, swollen lymph nodes, decreased appetite, shortness of breath, low blood oxygen levels, seizures, and death.
  • symptoms of a disease or disorder comprise acute respiratory distress syndrome, fever, pneumonia, shortness of breath, and low blood oxygen levels. In certain embodiments, symptoms of a disease or disorder comprise acute respiratory distress syndrome.
  • a COVID19 patient with markers of hyperinflammation is prophylactically administered a PI3K disclosed herein.
  • the markers of hyperinflammation comprise elevated ferritin, decreased platelet counts, and elevated erythrocyte sedimentation rate.
  • the H-Score is used to diagnose hyperinflammation (Cron & Chatham (2020). Don’t Forget the Host: COVID-19 Cytokine Storm. The Rheumatologist).
  • the H-Score (also referred to as HScore) is described in, for example, Fardet et al. (2014). Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome. Arthritis & Rheumatology. 66(9):2613- 2620.
  • doses of a PI3K inhibitor described herein will range from about 0.0001 mg to about 100 mg per day, or about 0.001 mg to about 100 mg per day, or about 0.01 mg to about 100 mg per day, or about 0.1 mg to about 100 mg per day, or about 0.0001 mg to about 500 mg per day, or about 0.001 mg to about 500 mg per day, or about 0.01 mg to 1000 mg, or about 0.01 mg to about 500 mg per day, or about 0.1 mg to about 500 mg per day, or about 1 mg to 50 mg per day, or about 5 mg to 40 mg per day.
  • An exemplar ⁇ ' dosage is about 10 to 30 mg per day.
  • Methods of treatment of the present invention can be used as a monotherapy or in combination with one or more other therapies (e.g. , anti-infective agents, e.g. a cytokine inhibitor) that can be used to treat a disease or disorder, for example, an infection.
  • therapies e.g. , anti-infective agents, e.g. a cytokine inhibitor
  • the term “combination,” as used herein, is understood to mean that two or more different treatments are delivered to the subject during the course of the subject’s affliction with the disorder, such that the effects of the treatments on the patient overlap at a point in time. In certain embodiments, the delivery of one treatment is still occurring when the delivery of the second begins, so that there is overlap in terms of administration.
  • the delivery of one treatment ends before the delivery of the other treatment begins.
  • the treatment is more effective because of combined administration.
  • the second treatment is more effective, e.g., an equivalent effect is seen with less of the second treatment, or the second treatment reduces symptoms to a greater extent, than would be seen if the second treatment were administered in the absence of the first treatment, or the analogous situation is seen with the first treatment.
  • delivery is such that the reduction in a symptom, or other parameter related to the disorder is greater than what would be observed with one treatment delivered in the absence of the other.
  • the effect of the two treatments can be partially additive, wholly additive, or greater than additive.
  • the delivery can be such that an effect of the first treatment delivered is still detectable when the second is delivered.
  • the subject has received, is receiving, or is scheduled to receive one or more other therapies suitable for use in treating the disease or disorder.
  • the method of treatment of the present invention further comprises administering to the subject one or more other therapies suitable for use in treating a disease or disorder, for example, an infection.
  • the one or more other therapies comprise an agent that ameliorates one or more symptoms of infection with an intracellular pathogen.
  • the one or more other therapies comprise surgical removal of an infected tissue.
  • the one or more other therapies comprise an immunosuppressive agent, e.g. , a cytokine inhibitor, e.g. , an IL-6 inhibitory antibody.
  • the one or more other therapies comprise an anti-inflammatory composition.
  • a method of use disclosed herein can be used in combination with an agent, for example, an anti-infective agent that ameliorates one or more symptoms of a disease or disorder associated with an intracellular pathogen.
  • an agent for example, an anti-infective agent that ameliorates one or more symptoms of a disease or disorder associated with an intracellular pathogen.
  • a method of use disclosed herein can be used in combination with an antiviral agent.
  • the anti -infective agent inhibits or reduces the viability, proliferation, infectivity, and/or virulence of the intracellular pathogen.
  • Intracellular pathogens may evade immune surveillance and challenge by residing in a latent state.
  • the anti-infective agent reverses the latency of the intracellular pathogen such that the infection can be recognized by the host’s immune system.
  • the intracellular pathogen is a virus
  • the anti-infective agent is an antiviral agent.
  • antiviral agents that can be used in the combination include but are not limited to abacavir, acyclovir, adefovir, amprenavir, atazanavir, cidofovir, darunavir, delavirdine, didanosine, docosanol, efavirenz, elvitegravir, emtricitabine, enfuvirtide, entecavir, etravirine, famciclovir, foscamet, fomivirsen, ganciclovir, indinavir, idoxuridine, lamivudine, lopinavir, maraviroc, MK-2048, nelfmavir, nevirapine, penciclovir, raltegravir, rilpivirine, ritonavir, saquinavir, stavudine, tenofovir trifluridine, valaciclovir, valganciclovir
  • exemplary anti-HIV agents that can be used in the combination include, but are not limited to, nucleoside/nucleotide reverse transcriptase inhibitors (e.g ., lamivudine, abacavir, zidovudine, stavudine, didanosine, emtricitabine, and tenofovir), non-nucleoside reverse transcriptase inhibitors (e.g., delavirdine, efavirenz, etravirine, and nevirapine), protease inhibitors (e.g.
  • nucleoside/nucleotide reverse transcriptase inhibitors e.g ., lamivudine, abacavir, zidovudine, stavudine, didanosine, emtricitabine, and tenofovir
  • non-nucleoside reverse transcriptase inhibitors e.g., delavirdine, efavirenz
  • the vims is SARS-CoV2, and the combination therapy comprises hydroxychloroquine. In certain embodiments, the vims is SARS-CoV2, and the combination therapy comprises an antiviral agent.
  • the intracellular pathogen is a bacterium
  • the anti- infective agent is an anti -bacterial agent.
  • Exemplary anti -bacterial agents that can be used in the combination include but are not limited to vancomycin, metronidazole, gentamicin, colistin, fidaxomicin, telavancin, oritavancin, dalbavancin, daptomycin, cephalexin, cefuroxime, cefadroxil, cefazolin, cephalothin, cefaclor, cefamandole, cefoxitin, cefprozil, ceftobiprole, cipro, Levaquin, floxin, tequin, avelox, norflox, tetracycline, minocycline, oxytetracycline, doxycycline, amoxicillin, ampicillin, penicillin V, dicloxacillin, carbenicillin, methicillin,
  • the intracellular pathogen is a fungus
  • the anti- infective agent is an anti-fungal agent.
  • anti-fungal agents that can be used in the combination include but are not limited to natamycin, rimocidin, filipin, nystatin, amphotericin B, candicin, and hamycin, miconazole, ketoconazole, clotrimazole, econazole, omoconazole, bifonazole, butoconazole, fenticonazole, isoconazole, oxiconazole, sertaconazole, sulconazole, tioconazole, fluconazole, itraconazole, isavuconazole, ravuconazole, posaconazole, voriconazole, terconazole, and albaconazole, abafungin, terbinafme, naftifme, butena
  • the intracellular pathogen is a protozoan
  • the anti- infective agent is an anti -protozoal agent.
  • Exemplary anti -protozoal agents that can be used in the combination include but are not limited to quinine (optionally in combination with clindamycin), chloroquine, amodiaquine, artemisinin and its derivatives ( e.g ., artemether, artesunate, dihydroartemisinin, arteether), doxy cy cline, pyrimethamine, mefloquine, halofantrine, hydroxychloroquine, eflomithine, nitazoxanide, omidazole, paromomycin, pentamidine, primaquine, pyrimethamine, proguanil (optionally in combination with atovaquone), sulfonamides (e.g., sulfadoxine, sulfamethoxypyrida), quinine (option
  • the intracellular pathogen is a Plasmodium (e.g, P. vivax, P. falciparum, P. ovale, P. malariae), and the anti -infective agent is an anti-malarial agent.
  • Plasmodium e.g, P. vivax, P. falciparum, P. ovale, P. malariae
  • the anti -infective agent is an anti-malarial agent.
  • anti-malarial agents that can be used in the combination include but are not limited to quinine (optionally in combination with clindamycin), chloroquine, amodiaquine, artemisinin and its derivatives (e.g, artemether, artesunate, dihydroartemisinin, arteether), doxycycline, halofantrine, mefloquine, primaquine, proguanil (optionally in combination with atovaquone), sulfonamides (e.g, sulfadoxine, sulfamethoxypyridazine), tafenoquine. It is understood that many of these anti-malarial agents can be used in combination especially for treating severe and/or acute infections.
  • the intracellular pathogen is an alga
  • the anti- infective agent is an anti-algal agent.
  • Exemplary anti-algal agents that can be used in the combination include but are not limited to ketoconazole, itraconazole, fluconazole, and voriconazole.
  • the intracellular pathogen is a prion
  • the anti- infective agent is an anti-prion agent.
  • anti-prion agents that can be used in the combination include but are not limited to pentosan polysulfate, quinacrine, thioflavine, amphotericin B, tetracyclines, tricyclic antidepressants (e.g, desipramine), and lithium chloride.
  • an additional class of agents that may be used as part of a combination therapy in treating a cytokine release syndrome are immunosuppressive agents, e.g ., cytokine inhibitors, calcineurin inhibitors, mTOR inhibitors, or steroids:
  • the immunosuppressive agents comprise calineurin inhibitors, e.g, tacrolimus and cyclosporine.
  • the immunosuppressive agents comprise mTOR inhibitors, e.g. , sirolimus.
  • the immunosuppressive agents comprise steroids, e.g. , prednisone.
  • the immunosuppressive agents comprise cytokine inhibitors, e.g.
  • the cytokine inhibitor comprises an inhibitory antibody. In certain embodiments, the cytokine inhibitor comprises an inhibitory antibody against IL-6. In certain embodiments, the cytokine inhibitor comprises tocilizumab, sarilumab, or siltuximab. In certain embodiments, the immunosuppressive agent, e.g. , the cytokine inhibitor, e.g. tocilizumab, sarilumab, or siltuximab, is administrered intravenously.
  • Appropriate therapies can be selected according to diagnosis of the specific infection. Wherein the subject is infected with a plurality of pathogens (e.g, a plurality of intracellular pathogens, e.g, a plurality of viral infections), two or more appropriate therapies for treating these infections may be used in combination with a PI3K inhibitor disclosed herein.
  • a plurality of pathogens e.g, a plurality of intracellular pathogens, e.g, a plurality of viral infections
  • two or more appropriate therapies for treating these infections may be used in combination with a PI3K inhibitor disclosed herein.
  • compositions that contain a therapeutically effective amount of a PI3K described herein.
  • the composition can be formulated for use in a variety of drug delivery systems.
  • One or more physiologically acceptable excipients or carriers can also be included in the composition for proper formulation.
  • Suitable formulations for use in the present disclosure are found in Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, Pa., 17th ed., 1985. For a brief review of methods for drug delivery, see, e.g, Langer (Science 249:1527-1533, 1990).
  • a PBK inhibitor is administered orally.
  • a PI3K inhibitor e.g ⁇ ., duvelisib, tenalisib, or IPI-549
  • a pharmaceutical excipient suitable for ora! administration e.g., a compound, e.g., a PI3K inhibitor as disclosed herein, and a pharmaceutical excipient suitable for ora! administration.
  • the pharmaceutical composition can be a liquid pharmaceutical composition suitable for oral consumption.
  • Pharmaceutical compositions suitable for oral administration can be presented as discrete dosage forms, such as capsules, cachets, or tablets, or liquids or aerosol sprays each containing a predetermined amount of an active ingredient as a powder or in granules, a solution, or a suspension in an aqueous or non- aqueous liquid, an oil -in-water emulsion, or a water-in-oil liquid emulsion.
  • Such dosage forms can be prepared by any of the methods of pharmacy, but all methods include the step of bringing the active ingredient into association with the carrier, which constitutes one or more ingredients.
  • the pharmaceutical compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
  • a tablet can be prepared by compression or molding, optionally with one or more accessory' ingredients.
  • Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with an excipient such as, but not limited to, a binder, a lubricant, an inert diluent, and/or a surface active or dispersing agent.
  • Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the present disclosure further encompasses anhydrous pharmaceutical compositions and dosage forms comprising an active ingredient, since water can facilitate the degradation of some compounds.
  • water can be added (e.g., about 5% water) in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf-life or the stability of formulations overtime.
  • Anhydrous pharmaceutical compositions and dosage forms can be prepared using anhydrous or low moisture containing ingredients and low ' moisture or low humidity conditions.
  • compositions and dosage forms which contain lactose can be made anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected.
  • An anhydrous pharmaceutical composition can be prepared and stored such that its anhydrous nature is maintained.
  • anhydrous pharmaceutical compositions can be packaged using materials known to prevent exposure to water such that they can be included in suitable formulary' kits. Examples of suitable packaging include, without limitation, hermetically sealed foils, plastic or the like, unit dose containers, blister packs, and strip packs.
  • an active ingredient can be combined in an intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier can take a wide variety of forms depending on the form of preparation desired for administration.
  • any of the usual pharmaceutical media can be employed as carriers, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like in the case of oral liquid preparations (i.e., suspensions, solutions, and elixirs) or aerosols; or carriers such as starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents can be used in the case of oral solid preparations, in some embodiments without employing the use of lactose.
  • suitable carriers include powders, capsules, and tablets, with the solid oral preparations.
  • tablets can be coated by standard aqueous or nonaqueous
  • the pharmaceutical composition may comprise a binder.
  • Binders suitable for use in pharmaceutical compositions and dosage forms include, without limitation, com starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre - gelatinized starch, hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixtures thereof.
  • the pharmaceutical composition may comprise a filler.
  • suitable fillers for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre -gelatinized starch, and mixtures thereof.
  • the pharmaceutical composition may comprise a disintegrant.
  • Disintegrants can be used in the pharmaceutical compositions as provided herein to provide tablets that disintegrate when exposed to an aqueous environment. Too much of a disintegrant can produce tablets which can disintegrate in the bottle. Too little can be insufficient for disintegration to occur and can thus alter the rate and extent of release of the active ingredient(s) from the dosage form. Thus, a sufficient amount of disintegrant that is neither too little nor too much to detrimentally alter the release of the active ingredient(s) can be used to form the dosage forms of the compounds disclosed herein. The amount of disintegrant used can vary' based upon the type of formulation and mode of administration, and can be readily discernible to those of ordinary' skill in the art.
  • Disintegrants that can be used to form pharmaceutical compositions and dosage forms include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre -gelatinized starch, other starches, clays, other algins, other celluloses, gums or mixtures thereof.
  • lubricants which can be used to form pharmaceutical compositions and dosage forms include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethylaureate, agar, or mixtures thereof.
  • Additional lubricants include, for example, a syloid silica gel, a coagulated aerosol of synthetic silica, or mixtures thereof.
  • a lubricant can optionally be added, in an amount of less than about 1 weight percent of the pharmaceutical composition.
  • the active ingredient therein can be combined with various sweetening or flavoring agents, coloring matter or dyes and, for example, emulsifying and/or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.
  • the tablets can be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.
  • formulations for oral use can also be presented as hard gelatin capsules w'herein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules w'herein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
  • a surfactant may be used.
  • Surfactants useful to form pharmaceutical compositions and dosage forms include, without limitation, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof, i.e., a mixture of hydrophilic surfactants can be employed, a mixture of lipophilic surfactants can be employed, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant can be employed.
  • a suitable hydrophilic surfactant can generally have an HLB value of at least about 10, while suitable lipophilic surfactants can generally have an HLB value of or less than about 10.
  • An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of non-ionic amphiphilic compounds is the hydrophilic - lipophilic balance ("HLB" value).
  • HLB hydrophilic - lipophilic balance
  • Hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable.
  • lipophilic ⁇ i.e., hydrophobic) surfactants are compounds having an HLB value equal to or less than about 10.
  • an HLB value of a surfactant is merely a rough guide generally used to enable formulation of industrial, pharmaceutical and cosmetic emulsions.
  • Hydrophilic surfactants can be either ionic or non-ionic.
  • suitable ionic surfactants include, without limitation, alkyl ammonium salts; fusidic acid salts; faty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; lecithins and hydrogenated lecithins; iysolecithins and hydrogenated lysolecithins; phospholipids and derivatives thereof; iysophosphoiipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di-
  • ionic surfactants include, without limitation: lecithins, iysolecithin, phospholipids, lysophosphoiipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and diglycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof.
  • ionic surfactants can be the ionized forms of lecithin, iy solecithin, phosphatidylcholine, phosphatidylethanol amine, phosphatidylglycerol , phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanol amine, PVP-phosphatidyllthanolamine, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono/ di acetyl ated tartaric acid esters of mono/diglycerides, citric acid esters of mono/di glycerides, cho
  • hydrophilic non-ionic surfactants can include, without limitation, alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogol glycerides; polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers, polyoxyalkylene alkylphenols such as polyethylene glycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esters such as polyethylene glycol fatty acids monoesters and polyethylene glycol fatty acids diesters; polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of a polyol with at.
  • polyol can be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a saccharide.
  • hydrophilic-non-ionic surfactants appropriate for use include, without limitation, PEG- 10 laurate, PEG-12 laurate, PEG-20 Iaurate, PEG-32 iaurate, PEG-32 dilaurate, PEG- 12 oleate, PEG- 15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG -32 oleate, PEG-200 oleate, PEG-400 oleate, PEG- 15 stearate, PEG-32 di stearate, PEG- 40 stearate, PEG- 100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl Iaurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG- 20 glyceryl oleate, PEG-30
  • suitable lipophilic surfactants include, without limitation: fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acids esters; propylene glycol faty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxy ethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- and di-glycerides; hydrophobic transesterification products of a polyol with at least one member of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; oil-soluble vitamins/vitamin derivatives; and mixtures thereof.
  • non-limiting examples of lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or are hydrophobic transesterification products of a polyol with at least one member of vegetable oils, hydrogenated vegetable oils, and triglycerides.
  • the pharmaceutical composition can include a solubilizer to ensure good solubilization and/or dissolution of a compound as provided herein and to minimize precipitation of the compound. This can be especially important for pharmaceutical compositions for non-oral use, e.g., pharmaceutical compositions for injection.
  • a solubilizer can also be added to increase the solubility of the hydrophilic drug and/or other components, such as surfactants, or to maintain the pharmaceutical composition as a stable or homogeneous solution or dispersion.
  • solubilizers include, but are not limited to, the following: alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediois and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinyla!cohol, hydroxypropyl metbylcellulose and other cellulose derivatives, cyelodextrins and cyclodextrin derivatives; ethers of polyethylene glycols having an average molecular weight of about 200 to about 6000, sucH as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG; amides and other nitrogen-containing compounds such as 2-pyrrolidone, 2 ⁇ piperidone, e
  • mixtures of solubilizers can also be used.
  • examples include, but not limited to, triacetin, tri ethyl citrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methyl pyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethylene glycol 200-100, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide.
  • solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol and propylene glycol.
  • mixtures of solubilizers can also be used, the amount of solubilizer that can be included is not limited.
  • the amount of a given solubilizer can be limited to a bioacceptable amount, which can be readily determined by one of skill in the art.
  • the solubilizer can be in a weight ratio of about 10%, 25%, 50%, 100%, or up to about 200% by weight, based on the combined weight of the drug, and other excipients.
  • solubilizer can also be used, such as about 5%, 2%, 1% or even less.
  • the solubilizer can be present in an amount of about 1% to about 100%, more typically about 5% to about. 25% by weight.
  • the pharmaceutical composition can further comprise one or more pharmaceutically acceptable additives and excipients.
  • additives and excipients include, without limitation, detackifiers, anti-foaming agents, buffering agents, polymers, antioxidants, preservatives, chelating agents, viscorn odulators, tonicifiers, tlavorants, colorants, oils, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.
  • exemplary preservatives can include, without limitation, antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives.
  • exemplary-’ antioxidants include, but are not limited to, alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxy toluene, monothiogly cero! , potassium metabi sulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabi sulfite, and sodium sulfite.
  • Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA), citric acid monohydrate, disodium edetate, dipotassium edetate, edetic acid, fumaric acid, malic acid, phosphoric acid, sodium edetate, tartaric acid, and trisodium edetate.
  • EDTA ethylenediaminetetraacetic acid
  • citric acid monohydrate disodium edetate
  • dipotassium edetate dipotassium edetate
  • edetic acid fumaric acid, malic acid
  • phosphoric acid sodium edetate
  • tartaric acid tartaric acid
  • trisodium edetate trisodium edetate.
  • Exemplary' antimicrobial preservatives include, but are not limited to, benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridmiunm chloride, chi orhexi dine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxy ethanol, phenyl ethyl alcohol, phenylmercuric nitrate, propylene glycol, andthimerosal.
  • Exemplary' antifungal preservatives include, but are not limited to, butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.
  • Exemplary alcohol preservatives include, but are not limited to, ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.
  • Exemplary' acidic preservatives include, but are not limited to, vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.
  • preservatives include, but are not limited to, tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxy ani sol (BHA), butylated hydroxytoluened (BHT), ethyienediamine, sodium iauryl sulfate (SLS), sodium lauryl ether sulfate (SEES), sodium bisulfite, sodium metabi sulfite, potassium sulfite, potassium metabi sulfite, Glydant Plus, Phenonip, methylparaben, Germ all 1 15, Germaben II, Neolone, Kathon, and Euxyl.
  • the preservative is an anti-oxidant.
  • the preservative is a chelating agent.
  • exemplary ’ oils include, without limitation, almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myri state, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sas
  • Exemplary' oils include, without limitation, butyl stearate, caprylic triglyceride, capric triglyceride, cyciomethicone, diethyl sebacate, dimethicone 360, isopropyl myri state, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and combinations thereof.
  • an acid or a base can be incorporated into the pharmaceutical composition to facilitate processing, to enhance stability, or for other reasons.
  • pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethyl enediamine, triethanolamine, triethylamine, triisopropanolamine, trimethyl amine, tris(hydroxymethyl)aminom ethane (TRIS) and the like.
  • bases that are salts of a pharmaceutically acceptable acid, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, faty acids, formic acid, fumaric acid, gluconic acid, hydroquinosuifonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, para-bromophenyl sulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluene sulfonic acid, uric acid, and the like.
  • a pharmaceutically acceptable acid such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid,
  • Salts of polyprotie acids such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate can also be used.
  • the cation can be any convenient and pharmaceutically acceptable cation, such as ammonium, alkali metals, alkaline earth metals, and the like. Examples can include, without limitation, sodium, potassium, lithium, magnesium, calcium and ammonium.
  • suitable acids are pharmaceutically acceptable organic or inorganic acids.
  • suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, and the like.
  • suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosuifonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluene sulfonic acid, uric acid and the like.
  • a PI3K inhibitor of the present disclosure is formulated for parenteral delivery, e.g ., intravenous delivery.
  • An intravenous drug delivery formulation of the present disclosure may be contained in a bag, a pen, or a syringe.
  • the bag may be connected to a channel comprising a tube and/or a needle.
  • the formulation may be a lyophilized formulation or a liquid formulation.
  • the formulation may freeze-dried (lyophilized) and contained in about 12-60 vials.
  • the formulation may be freeze-dried and 45 mg of the freeze-dried formulation may be contained in one vial.
  • the about 40 mg - about 100 mg of freeze-dried formulation may be contained in one vial.
  • a freeze-dried formulation from vials e.g. , 12, 27, or 45 vials, are combined to obtain a therapeutic dose of the PI3K inhibitor in the intravenous drug formulation.
  • the formulation may be a liquid formulation and stored as about 250 mg/vial to about 1000 mg/vial.
  • the formulation may be a liquid formulation and stored as about 600 mg/vial.
  • the formulation may be a liquid formulation and stored as about 250 mg/vial.
  • the PI3K inhibitor could exist in a liquid aqueous pharmaceutical formulation including a therapeutically effective amount of the PI3K inhibitor in a buffered solution forming a formulation.
  • compositions may be sterilized by conventional sterilization techniques, or may be sterile filtered.
  • the resulting aqueous solutions may be packaged for use as-is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration.
  • the pH of the preparations typically will be between 3 and 11, more preferably between 5 and 9 or between 6 and 8, and most preferably between 7 and 8, such as 7 to 7.5.
  • the resulting compositions in solid form may be packaged in multiple single dose units, each containing a fixed amount of the above-mentioned agent or agents.
  • the composition in solid form can also be packaged in a container for a flexible quantity.
  • the present disclosure provides a formulation with an extended shelf life including a PI3K inhibitor of the present disclosure, in combination with one or more of mannitol, citric acid monohydrate, sodium citrate, disodium phosphate dihydrate, sodium dihydrogen phosphate dihydrate, sodium chloride, polysorbate 80, water, and sodium hydroxide.
  • an aqueous formulation is prepared including the PI3K inhibitor of the present disclosure in a pH-buffered solution.
  • the buffer may have a pH ranging from about 4 to about 8, e.g ., from about 4.5 to about 6.0, or from about 4.8 to about 5.5, or may have a pH of about 5.0 to about 5.2.
  • Ranges intermediate to the above recited pH's are also intended to be part of this disclosure. For example, ranges of values using a combination of any of the above recited values as upper and/or lower limits are intended to be included.
  • buffers that will control the pH within this range include acetate (e.g, sodium acetate), succinate (such as sodium succinate), gluconate, histidine, citrate and other organic acid buffers.
  • the formulation includes a buffer system which contains citrate and phosphate to maintain the pH in a range of about 4 to about 8.
  • the pH range may be from about 4.5 to about 6.0, or from about pH 4.8 to about 5.5, or in a pH range of about 5.0 to about 5.2.
  • the buffer system includes citric acid monohydrate, sodium citrate, disodium phosphate dihydrate, and/or sodium dihydrogen phosphate dihydrate.
  • the buffer system includes about 1.3 mg/mL of citric acid (e.g, 1.305 mg/mL), about 0.3 mg/mL of sodium citrate (e.g, 0.305 mg/mL), about 1.5 mg/mL of disodium phosphate dihydrate (e.g, 1.53 mg/mL), about 0.9 mg/mL of sodium dihydrogen phosphate dihydrate (e.g, 0.86 mg/mL), and about 6.2 mg/mL of sodium chloride (e.g, 6.165 mg/mL).
  • citric acid e.g, 1.305 mg/mL
  • sodium citrate e.g, 0.305 mg/mL
  • disodium phosphate dihydrate e.g, 1.53 mg/mL
  • 0.9 mg/mL of sodium dihydrogen phosphate dihydrate e.g, 0.86 mg/mL
  • sodium chloride e.g, 6.165 mg/mL
  • the buffer system includes about 1 to about 1.5 mg/mL of citric acid, about 0.25 to about 0.5 mg/mL of sodium citrate, about 1.25 to about 1.75 mg/mL of disodium phosphate dihydrate, about 0.7 to about 1.1 mg/mL of sodium dihydrogen phosphate dihydrate, and about 6.0 to about 6.4 mg/mL of sodium chloride.
  • the pH of the formulation is adjusted with sodium hydroxide.
  • a polyol which acts as a tonicifier, may also be included in the formulation.
  • the polyol is added to the formulation in an amount which may vary with respect to the desired isotonicity of the formulation.
  • the aqueous formulation may be isotonic.
  • the amount of polyol added may also be altered with respect to the molecular weight of the polyol. For example, a lower amount of a monosaccharide (e.g, mannitol) may be added, compared to a disaccharide (such as trehalose).
  • the polyol which may be used in the formulation as a tonicity agent is mannitol.
  • the mannitol concentration may be about 5 to about 20 mg/mL. In certain embodiments, the concentration of mannitol may be about 7.5 to about 15 mg/mL. In certain embodiments, the concentration of mannitol may be about 10 to about 14 mg/mL. In certain embodiments, the concentration of mannitol may be about 12 mg/mL. In certain embodiments, the polyol sorbitol may be included in the formulation.
  • a detergent or surfactant may also be added to the formulation.
  • exemplary detergents include nonionic detergents such as polysorbates (e.g ., polysorbates 20, 80 etc.) or poloxamers (e.g., poloxamer 188). The amount of detergent added can minimize the formation of particulates in the formulation and/or reduce adsorption.
  • the formulation may include a surfactant which is a polysorbate.
  • the formulation may contain the detergent polysorbate 80 or Tween 80.
  • Tween 80 is a term used to describe polyoxyethylene (20) sorbitanmonooleate (see Fiedler, Lexikon der Hifsstoffe, Editio Cantor Verlag Aulendorf, 4th ed., 1996).
  • the formulation may contain between about 0.1 mg/mL and about 10 mg/mL of polysorbate 80, or between about 0.5 mg/mL and about 5 mg/mL. In certain embodiments, about 0.1% polysorbate 80 may be added in the formulation.
  • a composition described herein is formulated as a liquid formulation.
  • the liquid formulation may be presented at a 10 mg/mL concentration in either a USP / Ph Eur type I 50R vial closed with a rubber stopper and sealed with an aluminum crimp seal closure.
  • the stopper may be made of elastomer complying with USP and Ph Eur.
  • the liquid formulation may be diluted with 0.9% saline solution.
  • a composition described herein may be prepared as a 10 mg/mL concentration solution in combination with a sugar at stabilizing levels.
  • the liquid formulation may be prepared in an aqueous carrier.
  • a stabilizer may be added in an amount no greater than that which may result in a viscosity undesirable or unsuitable for intravenous administration.
  • the sugar may be di saccharides, e.g, sucrose.
  • the liquid formulation may also include one or more of a buffering agent, a surfactant, and a preservative.
  • the pH of the liquid formulation may be set by addition of a pharmaceutically acceptable acid and/or base.
  • the pharmaceutically acceptable acid may be hydrochloric acid.
  • the base may be sodium hydroxide.
  • compositions described herein can include an aqueous carrier.
  • Aqueous carriers of interest herein are pharmaceutically acceptable (safe and non-toxic for administration to a human) and are useful for the preparation of a liquid formulation.
  • Illustrative carriers include sterile water for injection (SWFI), bacteriostatic water for injection (BWFI), a pH buffered solution (e.g ., phosphate-buffered saline), sterile saline solution, Ringer's solution, and dextrose solution.
  • a preservative may be optionally added to the formulations described herein to reduce bacterial action.
  • the addition of a preservative may, for example, facilitate the production of a multi-use (multiple-dose) formulation.
  • Intravenous (IV) formulations may be the preferred administration route in particular instances, such as when a patient is in the hospital receiving all drugs via the IV route.
  • the liquid formulation is diluted with 0.9% Sodium Chloride solution before administration.
  • the diluted drug product for injection is isotonic and suitable for administration by intravenous infusion.
  • a salt or buffer component may be added in an amount of 10 mM - 200 mM.
  • the salts and/or buffers are pharmaceutically acceptable and are derived from various known acids (inorganic and organic) with “base forming” metals or amines.
  • the buffer may be phosphate buffer.
  • the buffer may be glycinate, carbonate, or citrate buffers, in which case, sodium, potassium or ammonium ions can serve as counterion.
  • the lyophilized drug product may be constituted with an aqueous carrier.
  • the aqueous carrier of interest herein is one which is pharmaceutically acceptable (safe and non-toxic for administration to a human) and is useful for the preparation of a liquid formulation.
  • Illustrative carriers include sterile water for injection (SWFI), bacteriostatic water for injection (BWFI), a pH buffered solution (e.g., phosphate- buffered saline), sterile saline solution, Ringer's solution, and dextrose solution.
  • PI3K inhibitors of the present disclosure can exist in a lyophilized formulation including the PI3K inhibitor and a lyoprotectant.
  • the lyoprotectant may be sugar, e.g, di saccharides.
  • the lyoprotectant may be sucrose or maltose.
  • the lyophilized formulation may also include one or more of a buffering agent, a surfactant, a bulking agent, and/or a preservative.
  • the amount of sucrose or maltose useful for stabilization of the lyophilized drug product may be in a weight ratio of at least 1 :2 PI3K inhibitor to sucrose or maltose.
  • the PI3K inhibitor to sucrose or maltose weight ratio may be of from 1 :2 to 1:5.
  • the pH of the formulation, prior to lyophilization may be set by addition of a pharmaceutically acceptable acid and/or base.
  • the pharmaceutically acceptable acid may be hydrochloric acid.
  • the pharmaceutically acceptable base may be sodium hydroxide.
  • the pH of the solution containing the PI3K inhibitor of the present disclosure may be adjusted between 6 to 8.
  • the pH range for the lyophilized drug product may be from 7 to 8.
  • a “bulking agent” may be added.
  • a “bulking agent” is a compound which adds mass to a lyophilized mixture and contributes to the physical structure of the lyophilized cake (e.g ., facilitates the production of an essentially uniform lyophilized cake which maintains an open pore structure).
  • Illustrative bulking agents include mannitol, glycine, polyethylene glycol and sorbitol. Lyophilized formulations of the present invention may contain such bulking agents.
  • a lyophilized drug product described herein is reconstituted with either Sterile Water for Injection, USP (SWFI) or 0.9% Sodium Chloride Injection, USP. During reconstitution, the lyophilized powder dissolves into a solution.
  • SWFI Sterile Water for Injection
  • USP 0.9% Sodium Chloride Injection
  • a lyophilized composition described herein is constituted to about 4.5 mL water for injection and diluted with 0.9% saline solution (sodium chloride solution).
  • a PI3K inhibitor of the present disclosure is administered topically and can be formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams, and ointments.
  • Such pharmaceutical compositions can contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
  • delivery of a PI3K inhibitor as disclosed herein is via an inhalation route.
  • Inhalation may be mediated through an oral and/or nasal cavity.
  • inhalation is with the aid of a nebulizer or an inhaler (e.g., a metered dose inhaler or a dry powder inhaler).
  • delivery is through inhalation of a liquid mist.
  • delivery is through inhalation of a solid.
  • the solid is nanosized and formulated in combination with nanoparticles, nanodiamonds, or nanocarbons, or packaged in liposomes or liposome-based packages.
  • kits comprising a PI3K inhibitor.
  • the kits may be used for the treatment, prevention, and/or diagnosis of a disease or disorder, such as a cytokine release syndrome, as described herein.
  • the kit comprises a container and a label or package insert on or associated with the container.
  • Suitable containers include, for example, bottles, vials, syringes, and IV solution bags.
  • the containers may be formed from a variety of materials, such as glass or plastic.
  • the container holds a composition that is by itself, or when combined with another composition, effective for treating, preventing and/or diagnosing a disease or disorder.
  • the container may have a sterile access port. For example, if the container is an intravenous solution bag or a vial, it may have a port that can be pierced by a needle.
  • At least one active agent in the composition is a PI3K inhibitor provided herein.
  • the label or package insert indicates that the composition is used for treating the selected condition.
  • the kit comprises (a) a first container with a first composition contained therein, wherein the first composition comprises a PI3K inhibitor provided herein; and (b) a second container with a second composition contained therein, wherein the second composition comprises a further therapeutic agent.
  • the further therapeutic agent is an immunosuppressive therapeutic agent, e.g ., a cytokine inhibitor.
  • the further therapeutic agent is an IL-6 antagonist, an IL-1 antagonist, a soluble tumor necrosis factor receptor, an IL-1 receptor agonist, and a TGF-bI latency-associated peptide, e.g. , tocilizumab, sarilumab, or siltuximab.
  • the further therapeutic agent is an antiviral therapeutic agent.
  • the kit in said embodiments can further comprise a package insert indicating that the compositions can be used to treat a particular condition, e.g, a viral infection, e.g. , COVID- 19.
  • the kit may further comprise a second (or third) container comprising a pharmaceutically acceptable excipient.
  • the kit comprises a first container comprising a PI3K inhibitor described herein and a pharmaceutically acceptable excipient.
  • the excipient is a buffer.
  • the kit may further include other materials desirable from a commercial and user standpoint, including, without limitation, filters, needles, and syringes.
  • PI3K refers to phosphoinositide 3-kinase, also called phosphatidylinositol 3-kinases in the art.
  • the class 1 isoforms are RI3Ka, RI3Kb, PI3K5, and RI3Kg.
  • PI3Ka and PBKalpha are used interchangably
  • RI3Kb and PBKbeta are used interachangably
  • PI3K5 and PBKdelta are used interchangably
  • RI3Kg and PBKgamma are used interchangably.
  • a “dual RI3Kd/g inhibitor”, as used herein, refers to a PI3K inhibitor that can reach the IC50 from whole blood assays for both PBK-delta and PBK-gamma at clinically achievable plasma exposures.
  • cytokine release syndrome refers to an acute overreaction of the immune system also known in the art as a “cytokine storm” or “cytokine storm syndrome”; such an immune response is a systemic inflammatory response syndrome that can result from an infectious disease or disorder.
  • Cytokine release syndrome pathology is associated with inflammation that begins at a local site and spreads throughout the body, for example, via systemic circulation. Cytokine release syndrome pathology resulting from viral infection is associated with acute lung injury and acute respiratory distress syndrome. Cytokine release syndrome pathology is described, for example, in Tisonick et al ., (2012) “Into the Eye of the Cytokine Storm,” Microbiol. Mol. Biol. Rev., 76(1): 16-32.
  • a "pharmaceutically acceptable form” of a disclosed compound includes, but is not limited to, pharmaceutically acceptable salts, hydrates, solvates, isomers, prodrugs, and isotopicaily labeled derivatives of disclosed compounds.
  • a "pharmaceutically acceptable form” includes, but is not limited to, pharmaceutically acceptable salts, isomers, prodrugs and isotopicaily labeled derivatives of disclosed compounds.
  • the pharmaceutically acceptable form is a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salt refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of subjects without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describes pharmaceutically acceptable salts in detail in j Pharmaceutical Sciences (1977) 66: 1-19.
  • Pharmaceutically acceptable salts of the compounds provided herein include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesuifonate, besylate, benzoate, hi sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cydopentanepropionate, digluconate, dodecyl sulfate, ethane sulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemi sulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethane sulfonate, iactobionate, lactate, laurate, lauryl sulfate, malate, maieate, malonate, methanesulfonate, 2-naphthalene sulfonate, nicotinate, nitrate, oleate, o
  • organic acids from which salts may be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-to!uenesulfonic acid, salicylic acid, and the like.
  • Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
  • Organic bases from which salts may be derived include, for example, primary, secondary, and tertiary ' amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, such as isopropyl amine, trimethylamine, drethylamine, triethylamine, tripropylamine, and ethanolamine.
  • the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.
  • the pharmaceutically acceptable form is a solvate (e.g, a hydrate).
  • solvate refers to compounds that further include a stoichiometric or non-stoichrometric amount of solvent bound by non-covalent intermolecular forces.
  • the solvate may be of a disclosed compound or a pharmaceutically acceptable salt thereof. Where the solvent is water, the solvate is a "hydrate”.
  • Pharmaceutically acceptable solvates and hydrates are complexes that, for example, can include 1 to about 100, or 1 to about 10, or one to about 2, about 3 or about 4, solvent or water molecules. It will be understood that the term "compound” as used herein encompasses the compound and solvates of the compound, as well as mixtures thereof.
  • the pharmaceutically acceptable form is a prodrug.
  • prodrug refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable form of the compound.
  • a prodrug may be inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis (e.g., hydrolysis in blood).
  • a prodrug has improved physical and/or delivery properties over the parent compound.
  • Prodrugs are typically designed to enhance pharmaceutically and/or pharmacokineticaliy based properties associated with the parent compound.
  • the prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design, of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam).
  • a discussion of prodrugs is provided in Higuchi, T., et al, "Pro-drugs as Novel Delivery Systems," A.C. S. Symposium Series, Vol. 14, Chp 1, pp 1-12 and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated in full by reference herein.
  • Exemplary advantages of a prodrug can include, but are not limited to, its physical properties, such as enhanced water solubility for parenteral administration at physiological pH compared to the parent compound, or it enhances absorption from the digestive tract, or it can enhance drug stability for long-term storage.
  • prodrug is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a subject.
  • Prodrugs of an active compound, as described herein may be prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound.
  • Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively.
  • prodrugs examples include, but are not limited to, acetate, formate and benzoate derivatives of an alcohol or acetamide, formamide and benzamide derivatives of an amine functional group in the active compound and the like.
  • Other examples of prodrugs include compounds that comprise -NO, -NO2, - QNQ, or -ONO2 moieties.
  • Prodrugs can typically be prepared using well-known methods, such as those described in Burger 's Medicinal Chemistry and Drug Discovery, 172-178, 949- 82 (Manfred E. Wolff ed., 5 th ed., 1995), and Design of Prodrugs (H. Bundgard ed., Elsevier, New York, 1985).
  • a prodrug can comprise a pharmaceutically acceptable ester formed by the replacement, of the hydrogen atom of the acid group with a group such as (C 1 -C 8 )alkyi, (C 2 -C 12 )alkanoyloxymethyl, 1- (alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1 -m ethyl -1 ⁇ (alkanoyloxy )-ethyl having from 5 to 10 carbon atoms, alkoxy carbonyloxymethyl having from 3 to 6 carbon atoms, 1- (aikoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1 -methyl- 1- (alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyi)aminomethyl having from 3 to 9 carbon atoms, l
  • a prodrug may be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (C 1 -C 6 )alkanoyloxymethyl, 1- ((C 1 -C 6 )alkanoyloxy)ethy 1 , l-methyl -1 -(( C 1 -C 6 )alkanoyloxy)ethyl ((C 1 - C 6 )alkoxycarbonyioxymethyl, N-(C 1 -C 6 )alkoxycarbonylaminomethyl, succinoyl, (C 1 - C 6 )alkanoyl, a-amino(C 1 -C 4 )alkanoyl, arylacyl and a-a minoacyl, or a-aminoacyl -a- aminoacyl, where each a-aminoacyl group is independently selected from naturally occurring
  • a prodrug may be formed by the replacement of a hydrogen atom in the amine group with a group such as R-carbonyl, RO-carbonyl, NRR'- carbonyl where R and R' are each independently (C 1 -C 10 )alkyl,(C 3 -C 5 )cycloalkyl, benzyl, a natural a-aminoacyl or natural a-aminoacyl-natural a-aminoacyl, -C(OH)C(O)OY 1 wherein Y 1 is H, (Ci-C 6 )alkyl or benzyl, -C(OY 2 )Y 3 wherein Y 2 is (C 1 -C 4 ) alkyl and Y 3 is (C 1 .- C 6 )alkyl, carboxy(C 1 -C 6 )alkyl, amino(C 1 -C
  • the pharmaceutically acceptable form is an isomer.
  • “Isomers” are different compounds that have the same molecular formula.
  • “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space.
  • the term “isomer” includes any and all geometric isomers and stereoisomers.
  • “isomers” include geometric double bond cis- and tram- isomers, also termed E- and Z- i somers; R- and 5-enantiomers; diastereomers, (d)-isomers and (/)-isomers, racemic mixtures thereof; and other mixtures thereof, as falling within the scope of this disclosure.
  • Enantiomers are a pair of stereoisomers that are non-superimposable mirror images of each other.
  • a 1: 1 mixture of a pair of enantiomers is a "racemic” mixture.
  • the term “( ⁇ )” is used to designate a racemic mixture where appropriate.
  • “Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.
  • the absolute stereochemistry '’ is specified according to the Cahn-ingold-Prelog R ⁇ S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S.
  • Resolved compounds whose absolute configuration is unknown may be designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line.
  • Certain of the compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry', as (R)- or (S)-.
  • the present chemical entities, pharmaceutical compositions and methods are meant to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures.
  • Optically active (R)- and (S)- i somers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry', and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.
  • Enantiomeric purity refers to the relative amounts, expressed as a percentage, of the presence of a specific enantiomer relative to the other enantiomer. For example, if a compound, winch can potentially have an (R)- or an (S)- isomeric configuration, is present as a racemic mixture, the enantiomeric purity is about 50% with respect to either the (R)- or (S)- isomer, if that compound has one isomeric form predominant over the other, for example, 80% (S)- and 20% (R)-, the enantiomeric purity of the compound with respect to the (S)-isomeric form is 80%,
  • the enantiomeric purity of a compound may be determined in a number of ways known in the art, including but not limited to chromatography using a chiral support, polarimetric measurement of the rotation of polarized light, nuclear magnetic resonance spectroscopy using chiral shift reagents which include but are not limited to lanthan
  • the pharmaceutically acceptable form is a tautomer.
  • tautomer is a type of isomer that includes two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a double bond, or a triple bond to a single bond, or vice versa).
  • Tautomerization includes prototropic or proton-shift tautomerization, which is considered a subset of acid-base chemistry.
  • Prototropic tautomerization or “proton-shift tautomerization” involves the migration of a proton accompanied by changes in bond order.
  • Tautomerizations i.e., the reaction providing a tautomeric pair
  • exemplary' tautomerizations include, but are not limited to, keto-enol; amide-imide; lactam-lactim; enamine-imine; and enamine-(a different) enamine tautomerizations.
  • keto-enol tautomerization is the interconversion of pentane-2, 4-di one and 4-hydroxypent-3- en-2-one tautomers.
  • Another example of tautomerization is phenol-keto tautomerization.
  • a specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4(lH)-one tautomers.
  • “Pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions as disclosed herein is contemplated. Supplementary active ingredients can also be incorporated into the pharmaceutical compositions.
  • the term “disease or disorder” means any pathological condition, including but not limited to a cytokine release syndrome, e.g, a cytokine release syndrome caused by a pathogen.
  • the disease or disorder is a cytokine release syndrome caused by a virus, e.g. , a coronavirus, e.g. , SARS-CoV2.
  • a disease or disorder associated with a specific pathogen or type of pathogen is a disease or disorder caused by the specific pathogen or type of pathogen.
  • a virus disease or disorder can be associated with a specific virus, for example, SARS-CoV2, or a specific group of viruses, for example, a specific genus of viruses, for example, coronaviruses.
  • a bacterial disease or disorder can be associated with a specific bacteria or a specific group of bacteria;
  • a fungal disease or disorder can be associated with a specific fungus or a specific group of fungus; and an amoeba disease or disorder can be associated with a specific amoeba or a specific group of amoeba.
  • the disease or disorder is an acute respiratory distress syndrome characterized by cytokine release syndrome, e.g. an acute respiratory distress syndrome associated with a pathogen, e.g, an acute respiratory distress syndrome not associated with a pathogen.
  • infection means the invasion and proliferation of pathogens, e.g, viruses, that are not normally present within the host, e.g, a patient.
  • An infection may cause no symptoms and be subclinical, or it may cause symptoms and be clinically apparent.
  • An infection may remain localized, or it may spread, for example, through the blood or lymphatic vessels, to become systemic.
  • prophylactic refers to a medication or a treatment designed and used to prevent a disease or disorder from occurring.
  • provention refers to a medication or a treatment designed and used to prevent a disease or disorder from occurring.
  • the term “treat”, “treatment”, “treating” and the like are used herein to generally mean obtaining a desired pharmacological and/or physiological effect.
  • the effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or may be therapeutic in terms of partially or completely curing a disease and/or adverse effect attributed to the disease.
  • treatment covers any treatment of a disease in a mammal, particularly a human, and includes: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e. preventing the disease from increasing in severity or scope; (c) relieving the disease, i.e. causing partial or complete amelioration of the disease; or (d) preventing relapse of the disease, i.e. preventing the disease from returning to an active state following previous successful treatment of symptoms of the disease or treatment of the disease.
  • “Individual,” “patient,” or “subject” are used interchangeably herein, and include any animal, e.g. mammals, e.g. mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
  • the PI3K inhibitor compounds and compositions thereof disclosed herein can be administered to a mammal, such as a human.
  • the PI3K inhibitor compounds disclosed herein can be administered to other mammals, such as an animal in need of veterinary treatment, e.g., domestic animals (e.g, dogs, cats, and the like), farm animals (e.g, cows, sheep, pigs, horses, and the like) and laboratory animals (e.g, rats, mice, guinea pigs, and the like).
  • veterinary treatment e.g., domestic animals (e.g, dogs, cats, and the like), farm animals (e.g, cows, sheep, pigs, horses, and the like) and laboratory animals (e.g, rats, mice, guinea pigs, and the like).
  • a patient may be an individual diagnosed with a high risk of developing a disease or disorder, for example, an infectious disease or disorder (e.g, an immunocompromised individual, a healthcare professional), someone who has been diagnosed with a disease or disorder, for example, an infectious disease or disorder, someone who previously suffered from a disease or disorder, for example, an infectious disease or disorder, or an individual evaluated for symptoms or indications of a disease or disorder, for example, an infectious disease or disorder.
  • an infectious disease or disorder e.g, an immunocompromised individual, a healthcare professional
  • someone who has been diagnosed with a disease or disorder for example, an infectious disease or disorder, someone who previously suffered from a disease or disorder, for example, an infectious disease or disorder, or an individual evaluated for symptoms or indications of a disease or disorder, for example, an infectious disease or disorder.
  • patient in need refers to a patient suffering from any of the symptoms or manifestations of a disease or disorder, for example, an infectious disease or disorder, a patient who may suffer from any of the symptoms or manifestations of a disease or disorder, for example, an infectious disease or disorder, or any patient who might benefit from a method of the disclosure for treating or preventing a disease or disorder, for example, an infectious disease or disorder.
  • a patient in need may include a patient who is diagnosed with a risk of developing a disease or disorder (for example, an infectious disease or disorder), a patient who has suffered from a disease or disorder (for example, an infectious disease or disorder) in the past, or a patient who has previously been treated for a disease or disorder (for example, an infectious disease or disorder).
  • a disease or disorder for example, an infectious disease or disorder
  • a patient who has suffered from a disease or disorder for example, an infectious disease or disorder
  • a patient who has previously been treated for a disease or disorder for example, an infectious disease or disorder
  • composition means a composition comprising at least one compound, e.g, a PI3K inhibitor disclosed herein, formulated together with one or more pharmaceutically acceptable carriers.
  • the term “therapeutically effective amount” refers to the amount of an agent, for example, a PI3K inhibitor described herein, that is sufficient to at least partially treat a condition when administered to a patient.
  • the therapeutically effective amount will vary depending on the severity of the condition, the route of administration of the component, and the age, weight, etc. of the patient being treated.
  • an effective amount of a disclosed a PI3K inhibitor is the amount of the a PI3K inhibitor necessary to treat a disease or disorder, for example, an infectious disease or disorder in a patient such that administration of the agent prevents the disease or disorder from occurring in a subject, prevents the disease or disorder progression, or relieves or completely ameliorates some or all associated symptoms of the disease or disorder, e.g, causes clearance of the infection.
  • administering refers to administration by any suitable route, for example, oral administration, administration as a suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intracranial, intranasal, or subcutaneous administration, or the implantation of a slow-release device, e.g ., a mini -osmotic pump, to a subject.
  • Administration is by any route, including parenteral and transmucosal (e.g, buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal).
  • Parenteral administration includes, without limitation, intravenous, intramuscular, intra-arterial, intradermal, subcutaneous, intraperitoneal, intraventricular, intrathecal, and intracranial delivery. In some embodiments, parenteral administration is intravenous. In some embodiments, parenteral administration is subcutaneous. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc.
  • co-administer it is meant that a compound or composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies (e.g, an antiviral agent).
  • additional therapies e.g, an antiviral agent.
  • the compounds or compositions described herein can be administered alone or can be co-administered to the patient.
  • Co-administration is meant to include simultaneous or sequential administration of the compound or composition individually or in combination (more than one compound or agent).
  • the preparations can also be combined, when desired, with other active substances (e.g. to reduce metabolic degradation or to provide an additional therapeutic for disease prevention or treatment).
  • Example 1 Treatment of Heme Malignancies with duvelisib modulates cytokine levels
  • PI3K inhibitor duvelisib or CD-20 targeting antibody Ofatumumab were administered to patients with chronic lymphocytic leukemia/ small lymphocytic leukemia (CLL/SLL) in the DUO clinical trial.
  • Duvelisib was administered to orally at 25 mg, twice daily (BID), to 160 patients.
  • Ofatumumab was administered intravenously to 159 patients according to the following dosage schedule: 300 mg on Day 1, 2000 mg weekly for 7-weeks, then 2000 mg monthly for four months. Serum samples were taken at Day 0 (as baseline) and Cycle 2, Day 1, of 28-day cycles.
  • Cytokine and chemokine levels were assessed using the Luminex multiplex immunoassay platform (Invitrogen) and quantified using the Luminex MAGPIX Instrument System (Invitrogen) according to the manufacturer’s instructions.
  • Non-Hodgkins lymphoma in the DYNAMO clinical trial. Serum samples were taken at Cycle 1, Day 15 and Cycle 2, Day 1, of 28-day cycles. Cytokine and chemokine levels were assessed using the Luminex multiplex immunoassay platform (Invitrogen) and quantified using the Luminex MAGPIX Instrument System (Invitrogen) according to the manufacturer’s instructions.
  • the CLL-treatment group displayed significant changes in a number of cytokine levels following duvelisib treatment. Surprisngly, CCL3, CCL4, CCL17, IL12, IL10, TNF-a, CCL19, and CXCL13 all demonstrated particularly significant reduction upon treatment.
  • the iNHL-treatment group displayed significant changes in a number of cytokine levels following duvelisib treatment, with CCL3, CCL4, CCL17, IL12, ILIO, TNF-a, CCL19, and CXCL13 showing significant reduction.

Abstract

Described herein is a method of using a PI3K inhibitor in the treatment of a cytokine release syndrome, such as a cytokine release syndrome associated with a viral infection, use of a PI3K inhibitor in the treatment of an acute respiratory distress syndrome, such as an acute respiratory distress syndrome characterized by cytokine release syndrome, and kits comprising a PI3K inhibitor for said uses.

Description

METHODS OF TREATING CYTOKINE RELEASE SYNDROME USING A PI3K
INHIBITOR
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63/005,969 filed on April 6, 2020, and U.S. Provisional Patent Application No. 63/023,379 filed May 12, 2020, the entire content of which is incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The invention relates to use of a PI3K inhibitor in the treatment of a cytokine release syndrome, such as a cytokine release syndrome associated with a viral infection, use of a PI3K inhibitor in the treatment of an acute respiratory distress syndrome, such as an acute respiratory distress syndrome characterized by cytokine release syndrome, and kits comprising a PI3K inhibitor for said uses.
BACKGROUND
[0003] The immune system functions to protect the body against harmful antigens. Regulation of the immune system is essential for an organism’s well being. Immune system disorders can lead to hyperactivity or hypoactivity of the immune system. In cases of immune system hyperactivity, the body attacks and damages its own tissues. In cases of immune system hypoactivity, also known as immune deficiency, the body’s ability to fight foreign antigens is diminished, which often leads to a increased vulnerability to infections. [0004] Infectious diseases, such as those caused by viral infection, continue to present a significant public health risk. According to the U.S. Center for Disease Control and Prevention, the Ebolavirus outbreak of 2014 resulted in approximately 29,000 new cases, of which over 11,000 resulted in death. According to the World Health Organization, as of 1 April 2020, the coronavirus pandemic of 2019 to 2020 caused by the virus SARS-CoV-2 (COVID-19), resulted in more than 912,000 cases and almost 46,000 deaths. For both viruses, cytokine release syndrome, an immune system hyperactivity characterized by a rapid induction of proinflammatory cytokines, contributed significantly to the mortality rates of those infected (Mehta etal. (2020) COVID-19: Consider Cytokine Storm Syndromes and Immunosuppression. Lancet. 395 (10229): 1033-1034). COVED- 19 infection results in severe acute respiratory distress syndrome (ARDS) in 15-20% of patients due to virally- driven hyperinflammation (Tian, S. et al. (2020)).
[0005] Accordingly, there remains a critical need for new and effective treatments for modulating the immune system in cases of immune system disorders, such as those resulting from a viral infection.
SUMMARY
[0006] Described herein is a method of treating cytokine release syndrome through administering a PI3K inhibitor to a patient in need thereof. Also described is a method of treating a patient in acute respiratory distress through administration of a PI3K inhibitor. Kits for such treatment are also described.
[0007] Accordingly, in one aspect, described herein is method of treating cytokine release syndrome induced by an infection, wherein the method comprises administering to a patient in need thereof a therapeutically effective amount of a composition comprising a PI3K inhibitor. In some embodiments, the PI3K inhibitor is a PI3K5 inhibitor, a RI3Kg inhibitor, or a dual RI3Kd/g inhibitor. In some embodiments, the PI3K inhibitor is selected from the group consisting of duvelisib, tenalisib, idelalisib, copanlisib, IPI-549, CAL-130, BKM 120, GDC-0941, PX-866, GDC-0032, BAY 80-6946, BEZ235, BYL719, BGT-226, GDC-0980, GSK 2126458, PF-05212384, XL765, AS604850, AS252424, or XL147, or a combination thereof. In certain embodiments, the PI3K inhibitor is duvelisib. In certain embodiments, wherein the PI3K inhibitor is IPI-549. In certain embodiments, the PI3K inhibitor is idelalisib.
[0008] In some embodiments, the infection is a viral infection. In some embodiments, wherein the infection is associated with a virus selected from the group consisting of a coronavirus, a papillomavirus, a pneumovirus, a picornavirus, an influenza virus, an adenovirus, a cytomegalovirus, a polyomavirus, a poxvirus, a flavivirus, an alphavirus, an ebolavirus, a herpesvirus, a morbillivirus, an enterovirus, an orthopneumovirus, a lentivirus, and a hepatovirus. In some embodiments, wherein the infection is associated with an influenza virus. In some embodiments, wherein the infection is associated with an ebolavirus. In some embodiments, wherein the infection is associated with a coronavirus. In some embodiments, the coronavirus is selected from the group consisting of: 229E alpha coronavirus, NL63 alpha coronavirus, OC43 beta coronavirus, HKU1 beta coronavirus, Middle East Respiratory Syndrome coronavirus (MERS-CoV), severe acute respiratory syndrome coronavirus (SARS-CoV), and SARS-CoV2 (COVID-19). In some embodiments, the coronavirus is SARS-CoV2. In some embodiments, coronavirus is SARS-CoV.
[0009] In some embodiments, the method further comprises administering a composition comprising an antiviral agent. In certain embodiments, the antiviral agent is selected from the group consisting of abacavir, acyclovir, adefovir, amantadine, amprenavir, atazanavir, cidofovir, danoprevir, darunavir, delavirdine, didanosine, docosanol, double- stranded RNA activated caspase oligomerizer (DRACO), efavirenz, elvitegravir, emtricitabine, enfuvirtide, entecavir, etravirine, famciclovir, foscamet, fomivirsen, ganciclovir, ibacitabine, indinavir, interferon-a inhibitor, idoxuridine, lamivudine, lopinavir, maraviroc, MK-2048, nelfmavir, nevirapine, oseltamivir, penciclovir, peramivir, pleconaril, raltegravir, remdesivir, rilpivirine, rifampin, rimantidine, ritonavir, saquinavir, stavudine, tenofovir trifluridine, valaciclovir, valganciclovir, vidarabine, tipranavir, zalcitabine, zanamivir, and zidovudine.
[0010] In another aspect, described herein is a method of treating an acute respiratory distress syndrome, wherein the method comprises administering to a patient in need thereof a therapeutically effective amount of a composition comprising a PI3K inhibitor. In some embodiments, the PI3K inhibitor is a PI3K5 inhibitor, a RI3Kg inhibitor, or a dual RI3Kd/g inhibitor.
[0011] In some embodiments, the PI3K inhibitor is selected from the group consisting of duvelisib, tenalisib, idelalisib, copanlisib, IPI-549, CAL-130, BKM 120, GDC-0941, PX-866, GDC-0032, BAY 80-6946, BEZ235, BYL719, BGT-226, GDC-0980, GSK 2126458, PF- 05212384, XL765, AS604850, AS252424, or XL147, or a combination thereof. In certain embodiments, the PI3K inhibitor is duvelisib. In certain embodiments, the PI3K inhibitor is IPI-549. In certain embodiments, the PI3K inhibitor is idelalisib. In some embodiments, the PI3K inhibitor is administered to a patient prophylactically. In certain embodiments, the patient displays elevated ferritin levels, decreased platelet count, elevated erythrocyte sedimentation rate, and/or has an H-Score indicative of hyperinflammation. In some embodiments, the PI3K inhibitor is administered to a patient with symptoms. In certain embodiments, the symptoms comprise acute respiratory distress.
[0012] In some embodiments, the acute respiratory distress syndrome is associated with a disease or disorder selected from the group consisting of an infectious disease or disorder, graft-versus-host disease, organ trauma, tissue trauma, pancreatitis, haemophagocytic lymphohistiocytosis, sepsis, and systemic inflammatory response syndrome. In some embodiments, the infectious disease or disorder is associated with a viral infection or a bacterial infection. In some embodiments, the viral infection is associated with a virus selected from the group consisting of a coronavirus, a papillomavirus, a pneumovirus, a picomavirus, an influenza virus, an adenovirus, a cytomegalovirus, a polyomavirus, a poxvirus, a flavivirus, an alphavirus, an ebolavirus, a herpesvirus, a morbillivirus, an enterovirus, an orthopneumovirus, a lentivirus, and a hepatovirus. In certain embodiments, the viral infection is associated with an influenza virus. In certain embodiments, the viral infection is associated with an ebolavirus. In certain embodiments, the viral infection is associated with a coronavirus. In certain embodiments, the coronavirus is selected from the group consisting of: 229E alpha coronavirus, NL63 alpha coronavirus, OC43 beta coronavirus, HKU1 beta coronavirus, Middle East Respiratory Syndrome coronavirus (MERS-CoV), severe acute respiratory syndrome coronavirus (SARS-CoV), and SARS- CoV2 (COVID-19). In certain embodiments, the coronavirus is SARS-CoV2.
[0013] In some embodiments, the method further comprises administering a composition comprising an antiviral agent. In some embodiments, the antiviral agent is selected from the group consisting of abacavir, acyclovir, adefovir, amantadine, amprenavir, atazanavir, cidofovir, danoprevir, darunavir, delavirdine, didanosine, docosanol, double-stranded RNA activated caspase oligomerizer (DRACO), efavirenz, elvitegravir, emtricitabine, enfuvirtide, entecavir, etravirine, famciclovir, foscamet, fomivirsen, ganciclovir, ibacitabine, indinavir, interferon-a inhibitor, idoxuridine, lamivudine, lopinavir, maraviroc, MK-2048, nelfmavir, nevirapine, oseltamivir, penciclovir, peramivir, pleconaril, raltegravir, remdesivir, rilpivirine, rifampin, rimantidine, ritonavir, saquinavir, stavudine, tenofovir trifluridine, valaciclovir, valganciclovir, vidarabine, tipranavir, zalcitabine, zanamivir, and zidovudine.
[0014] In some embodiments, the bacterial infection is associated with a bacteria selected from the group consisting of: Chlamydia pneumoniae , Vibrio cholerae , Streptococcus pneumoniae , Mycoplasma pneumoniae , Haemophilus influenzae , Legionella pneumophila , Salmonella enterica , Salmonella bongori, Escherichia coli , Helicobacter pylori , Neisseria gonorrhoeae , Neisseria meningitidis , Staphylococcus aureus , Acinetobacter baumannii , Burkholderia cepacian , Clostridium difficile , Clostridium sordellii , an Enterobacteriaceae, Enterococcus faecalis , Klebsiella pneumoniae , Morganella morganii, Mycobacterium abscessus , Mycobacterium tuberculosis , a Norovirus, Psuedomonas aeruginosa , and Stenotrophomonas maltophilia. In some embodiments, the bacteria is Streptococcus pneumoniae. In some embodiments, the bacteria is Klebsiella pneumoniae.
[0015] In some embodiments, the method further comprises administering a composition comprising an antibacterial agent. In some embodiments, the antibacterial agent is selected from the group consisting of doxycycline, vancomycin, metronidazole, gentamicin, colistin, fidaxomicin, telavancin, oritavancin, dalbavancin, daptomycin, cephalexin, cefuroxime, cefadroxil, cefazolin, cephalothin, cefaclor, cefamandole, cefoxitin, cefprozil, ceftobiprole, cipro, Levaquin, floxin, tequin, avelox, norflox, tetracycline, minocycline, oxytetracycline, amoxicillin, ampicillin, penicillin V, dicloxacillin, carbenicillin, methicillin, ertapenem, doripenem, imipenem/cilastatin, meropenem, amikacin, kanamycin, neomycin, netilmicin, tobramycin, paromomycin, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefoxotin, and streptomycin.
[0016] In some embodiments, the acute respiratory distress syndrome is characterized by cytokine release syndrome. In some embodiments, the method further comprises administering a composition comprising a cytokine inhibitor. In some embodiments, the cytokine inhibitor is selected from the group consisting of an IL-6 antagonist, an IL-1 antagonist, a soluble tumor necrosis factor receptor, an IL-1 receptor agonist, and a TGF-bI latency-associated peptide. In certain embodiments, the IL-6 antagonist is tocilizumab, sarilumab, or siltuximab.
[0017] In some embodiments, the composition comprising the PI3K inhibitor is administered orally. In some embodiments, the composition comprising the PI3K inhibitor is administered parenterally. In some embodiments, the PI3K inhibitor is administered to a patient prophylactically. In certain embodiments, the patient displays elevated ferritin levels, decreased platelet count, elevated erythrocyte sedimentation rate, and/or has an H-Score indicative of hyperinfl animation. In some embodiments, the PI3K inhibitor is administered to a patient with symptoms. In certain embodiments, the symptoms comprise acute respiratory distress. In some embodiments, the PI3K inhibitor is administered at a therapeutically effective amount to reduce pro-inflammatory cytokines in a patient in need thereof. In some embodiments, the PI3K inhibitor is administered at a therapeutically effective amount to reduce cytokine levels in a patient in need thereof, wherein the cytokines are selected from the group consisting of TNFα, IL-10, CCL3, and CCL4. In certain embodiments, the PI3K inhibitor is administered at a therapeutically effective amount to reduce TNFa levels in a patient in need thereof. In certain embodiments, the PI3K inhibitor is administered at a therapeutically effective amount to reduce IL-10 levels in a patient in need thereof. In certain embodiments, the PI3K inhibitor is administered at a therapeutically effective amount to reduce CCL3 levels in a patient in need thereof. In certain embodiments, the PI3K inhibitor is administered at a therapeutically effective amount to reduce CCL4 levels in a patient in need thereof. [0018] In another aspect, described herein is a kit comprising: a dual RI3Kd/g inhibitor; and detailed instructions for treating cytokine release syndrome in a patient in need thereof. In some embodiments, the kit further comprises a composition comprising a cytokine inhibitor. In some embodiments, the cytokine inhibitor is selected from the group consisting of an IL-6 antagonist, an IL-1 antagonist, a soluble tumor necrosis factor receptor, an IL-1 receptor agonist, and a TGF-bI latency-associated peptide. In certain embodiments, the IL-6 antagonist is tocilizumab, sarilumab, or siltuximab.
[0019] In some embodiments, the cytokine release syndrome is associated with a coronavirus infection. In some embodiments, the coronavirus infection is associated with a coronavirus selected from the group consisting of: 229E alpha coronavirus, NL63 alpha coronavirus, OC43 beta coronavirus, HKU 1 beta coronavirus, Middle East Respiratory Syndrome coronavirus (MERS-CoV), severe acute respiratory syndrome coronavirus (SARS- CoV), and SARS-CoV2 (COVID-19). In certain embodiments, the coronavirus infection is associated with SARS-CoV2 (COVID-19).
[0020] In some embodiments, the kit further comprises an antiviral agent. In some embodiments, the antiviral agent is selected from the group consisting of abacavir, acyclovir, adefovir, amantadine, amprenavir, atazanavir, cidofovir, danoprevir, darunavir, delavirdine, didanosine, docosanol, double-stranded RNA activated caspase oligomerizer (DRACO), efavirenz, elvitegravir, emtricitabine, enfuvirtide, entecavir, etravirine, famciclovir, foscarnet, fomivirsen, ganciclovir, ibacitabine, indinavir, interferon-a inhibitor, idoxuridine, lamivudine, lopinavir, maraviroc, MK-2048, nelfmavir, nevirapine, oseltamivir, penciclovir, peramivir, pleconaril, raltegravir, remdesivir, rilpivirine, rifampin, rimantidine, ritonavir, saquinavir, stavudine, tenofovir trifluridine, valaciclovir, valganciclovir, vidarabine, tipranavir, zalcitabine, zanamivir, and zidovudine. In some embodiments, the dual RI3Kd/g inhibitor is duvelisib.
BRIEF DESCRIPTION OF THE DRAWINGS
[0021] FIG. 1 shows cytokine levels for patients with heme malignancies treated with a PI3K inhibitor. FIG. 1A shows relative cytokine expression levels at Cycle 2, Day 1 of 28- day cycles compared to baseline for chronic lymphocytic leukemia/ small lymphocytic leukemia (CLL/SLL) treated with duvelisib or Ofatumumab. FIG. IB shows relative cytokine expression levels at Cycle 1, Day 15 and Cycle 2, Day 1 of 28-day cycles for indolent Non-Hodgkins lymphoma (iNHL) treated with duvelisib. Cytokine levels were determined using a Luminex multiplex immunoassay.
DETAILED DESCRIPTION
[0022] The present disclosure provides a method of using a PI3K inhibitor in the treatment of a cytokine release syndrome, for example, a cytokine release syndrome associated with a viral infection. The present disclosure also provides a method of using a PI3K inhibitor in the treatment of an acute respiratory syndrome, for example, an acute respiratory syndrome characterized by cytokine release syndrome. Various aspects of the invention are set forth below in sections; however, aspects of the invention described in one particular section are not to be limited to any particular section.
I. THERAPEUTIC APPLICATIONS
[0023] As disclosed herein, a PI3K inhibitor of the present disclosure is used in a method of treating a cytokine release syndrome, such as those associated with an infection. In certain embodiments, the cytokine release syndrome is the result of an infection by a pathogen, e.g., a bacterium, a virus, a fungus, a protozoan (e.g, an amoeba), an alga, or a prion. Intracellular pathogens include facultative intracellular parasites, which are capable of living and reproducing either inside or outside host cells, and obligate intracellular parasites, which cannot reproduce outside their host cell. In certain embodiments, the intracellular pathogen is dormant, latent, or symbiotic within a cell, but can cause a disease or disorder at a later stage of the pathogen’s life cycle. An infection by the intracellular pathogen can be acute or chronic. In certain embodiments, the disease or disorder mediated by an intracellular pathogen is a chronic infection. In certain embodiments, the disease or disorder mediated by an intracellular pathogen is an acute infection.
Treatment of cytokine release syndrome associated with viral infections
[0024] In certain embodiments, the cytokine release syndrome is associated with a viral infection. In certain embodiments, the virus is selected from the group consisting of a retrovirus (e.g, human immunodeficiency virus (HIV), simian immunodeficiency virus (SIV), human T-cell lymphotropic virus (HTLV)-l, HTLV-2, HTLV-3, HTLV-4), Ebola virus, hepatitis A virus, hepatitis B virus, hepatitis C virus, a herpes simplex virus (HSV)
(e.g, HSV-1, HSV-2, varicella zoster virus, cytomegalovirus), an adenovirus, an orthomyxovirus (e.g, influenza virus A, influenza virus B, influenza virus C, influenza virus D, thogotovirus), a flavivirus (e.g., dengue virus, Zika virus), West Nile virus, Rift Valley fever virus, an arenavirus, Crimean-Congo hemorrhagic fever virus, an echovirus, a rhinovirus, coxsackie virus, a coronavirus (e.g, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)), a respiratory syncytial virus, a mumps virus, a rotavirus, measles virus, rubella virus, a parvovirus (e.g, an adeno-associated virus), a vaccinia virus, a variola virus, a molluscum virus, bovine leukemia virus, a poliovirus, a rabies virus, a polyomavirus (e.g, JC virus, BK virus), an alphavirus, and a rubivirus (e.g, rubella virus).
In some embodiments, the virus is a novel virus not previously characterized (e.g, a novel coronavirus).
[0025] In certain embodiments, a PI3K inhibitor described herein is used for treating cytokine release syndrome associated with a viral infection, e.g, a cytokine release syndrome associated with a viral infection selected from the group consisting of acquired immune deficiency syndrome (AIDS), HTLV-1 associated myelopathy/tropical spastic paraparesis, Ebola virus disease, hepatitis A, hepatitis B, hepatitis C, herpes, herpes zoster, acute varicella, mononucleosis, respiratory infections, pneumonia, influenza, dengue fever, encephalitis (e.g, Japanese encephalitis), West Nile fever, Rift Valley fever, Crimean-Congo hemorrhagic fever, Kyasanur Forest disease, Yellow fever, Zika fever, aseptic meningitis, SARS, myocarditis, common cold, lung infections, molloscum contagiosum, enzootic bovine leucosis, coronavirus disease 2019 (COVID-19), mumps, gastroenteritis, measles, rubella, slapped-cheek disease, smallpox, warts (e.g, genital warts), molluscum contagiosum, polio, rabies, and pityriasis rosea. In some embodiments, a PI3K inhibitor described herein is used for treating cytokine release syndrome associated with an ebolavirus. In some embodiments, a PI3K inhibitor described herein is used for treating cytokine release syndrome associated with SARS. In some embodiments, a PI3K inhibitor described herein is used for treating cytokine release syndrome associated with COVID-19.
[0026] In some embodiments, the virus associated with the infection is an RNA virus (having a genome that is composed of RNA). RNA viruses may be single-stranded RNA (ssRNA) or double-stranded RNA (dsRNA). RNA viruses have high mutation rates compared to DNA viruses, as RNA polymerase lacks proofreading capability (see Steinhauer DA, Holland JJ (1987). "Rapid evolution of RNA viruses". Annu. Rev. Microbiol. 41: 409- 33). Exemplary RNA viruses include, without limitation, bunyaviruses (e.g, hantavirus), coronaviruses (e.g, MERS-CoV, SARS-CoV, SARS-CoV-2), flaviviruses (e.g, yellow fever virus, west nile virus, dengue virus), hepatitis viruses (e.g, hepatitis A virus, hepatitis C virus, hepatitis E virus), influenza viruses (e.g, influenza virus type A, influenza vims type B, influenza vims type C), measles vims, mumps vims, norovimses ( e.g ., Norwalk vims), poliovims, respiratory syncytial vims (RSV), retrovimses (e.g. , human immunodeficiency virus-1 (HIV-1)) and torovimses. In some embodiments, the RNA vims is an influenza vims, e.g., influenza A. In some embodiments, the RNA vims is RSV. In some embodiments, the RNA vims is MERS-CoV. In some embodiments, the RNA vims is SARS-CoV. In some embodiments, the RNA vims is SARS-CoV2. In some embodiments, the RNA vims is ZIKA.
[0027] RNA vimses are classified by the type of genome (double-stranded, negative (-), or positive (+) single-stranded). Double-stranded RNA vimses contain a number of different RNA molecules, each coding for one or more viral proteins. Positive-sense ssRNA vimses utilize their genome directly as mRNA; ribosomes within the host cell translate mRNA into a single protein that is then modified to form the various proteins needed for viral replication. One such protein is RNA-dependent RNA polymerase (RNA replicase), which copies the viral RNA in order to form a double-stranded, replicative form. Negative-sense ssRNA vimses have their genome copied by an RNA replicase enzyme to produce positive-sense RNA for replication. Therefore, the vims comprises an RNA replicase enzyme. The resultant positive-sense RNA then acts as viral mRNA and is translated by the host ribosomes. In some embodiments, the vims is a dsRNA vims. In some embodiments, the vims is a negative ssRNA vims. In some embodiments, the vims is a positive ssRNA vims. In some embodiments, the positive ssRNA vims is a coronavims.
[0028] SARS-CoV2, also sometimes referred to as the novel coronavims of 2019 or 2019-nCoV, is a positive-sense single-stranded RNA vims. SARS-CoV2 has four stmctural proteins, known as the S (spike), E (envelope), M (membrane), and N (nucleocapsid) proteins. The N protein holds the RNA genome; together, the S, E, and M proteins form the viral envelope. Spike allows the vims to attach to the membrane of a host cell, such as the ACE2 receptor in human cells (Kmse R.L. (2020), Therapeutic strategies in an outbreak scenario to treat the novel coronavims originating in Wuhan, China (version 2). FlOOOResearch, 9:72). SARS-CoV2 is the highly contagious, causative viral agent of coronavims disease 2019 (COVID19), a global pandemic. In some embodiments, the cytokine release syndrome being treated is associated with SARS-CoV2 (COVTD19).
[0029] In some embodiments, the vims associated with the infection is a DNA vims (having a genome that is composed of DNA), Exemplary DNA vimses include, without limitation, parvoviruses (e.g., adeno-associated vimses), adenoviruses, asfarvi ruses, herpesviruses (e.g., herpes simplex vims 1 and 2 (HSV-1 and HSV-2), epstein-barr virus sEBV), cytomegalovirus (CMV)), papillomoviruses (e.g., HPV),polyomaviruses (e.g, simian vacuolating vims 40 (SV40)), and poxviruses (e.g., vaccinia viru , cowpox vims, smallpox virus, fowl pox virus, sheeppox virus, myxoma vims). In certain embodiments, the DNA vims is an adenovirus, e.g., AdV5. In certain embodiments, the DNA vims is an enterovims, e.g, EV71. In certain embodiments, the DNA vims is a herpesvims, e.g. , HSV- 1
[0030] In some embodiments, the infection is systemic. In some embodiments, the infection is localized, e.g, to an organ or, e.g, to a tissue. In some embodiments, infection is localized to an organ including but not limited to the eye, the ear, the inner ear, the lungs, trachea, bronchus, bronchioli, the liver, the gall bladder, the bile duct, the kidney, the bladder, the testis, the cervix, the ovary, the utems, the skin, or the brain. In certain embodiments, the infection is localized to the lungs.
[0031] In some embodiments, the infection is chronic. As used herein, “chronic” refers to an infection that persists for an extended period of time, or recurs. In some embodiments, the infection is acute. As used herein, “acute” refers to an infection that is of short duration.
Assays for the study of viruses
[0032] Methods to quantify viral replication are known in the art. In some embodiments, viral count is determined using a plaque assay. In some embodiments, viral count is determined using a focus forming assay (FFA). In some embodiments, viral count is determined using an endpoint dilution assay. In some embodiments, viral count is determined using an enzyme-linked immunosorbent assay (ELISA). In some embodiments, viral count is determined using Tunable resistive pulse sensing (TRPS) to detect individual virus particles. In some embodiments, viral replication is determined by quantifying the amount or percentage of host cell death, e.g. , in vitro , for example, using propidium iodide (PI) to identify dead cells, quantifying the amount of morphologically rounded cells, or by immunofluorescence microscopy for apoptotic markers. In some embodiments, viral count is determined by measuring viral titer or multiplicity of infection (MOI) or by performing a plaque assay, a focus forming assay, and endpoint dilution assay, a viral protein quantification assay (for example, a hemagglutination assay, a bicinchoninic acid assay (BCA), or a single radial immunodiffusion assay (SRID) assay), transmission electron microscopy analysis, a tunable resistive pulse sensing (TRPS) assay, a flow cytometry assay, a quantitative PCR (qPCR) assay, or an Enzyme-linked immunosorbent assay (ELISA). In some embodiments, viral replication is determined by quantification of viral nucleic acid (for example, viral DNA or viral RNA) content.
[0033] Methods to quantify viral transmission are known in the art. In some embodiments, viral transmission is quantified using epidemiological modeling (see, e.g., GrawF. et al, (2016) Modeling Viral Spread. AnnuRev Virol , 3(1)). In some embodiments, viral transmission is assessed in vitro , e.g, in cell culture, e.g, using microscopy, e.g. , using transmission electron microscopy (TEM).
[0034] Methods to quantify viral assembly are known in the art. In some embodiments, viral assembly is determined using statistical modeling (see, e.g, Clement N et al. , (2018) Viral Capsid Assembly: A Quantified Uncertainty Approach. J Comp Biol , 25(1)). In some embodiments, viral assembly is determined using biochemical techniques to determine capsid complex formation, e.g. , co-immunoprecipitation, e.g. , western blotting. In some embodiments, viral assembly is determined by flow cytometry for detection of colocalized viral protein (see, e.g, Stoffel, C.L. et al. (2005). "Rapid Determination of Bacu!ovims Titer by a Dual Channel Virus Counter" American Biotechnology· Laboratory . 37 (22): 24-25). [0035] Viral genes encode elements necessary for the process of viral infection, a multi- step process, including, for example, attachment to the host cell, penetration, deenvelopment, viral gene transcription cascade, viral protein expression, viral genome replication, viral packaging and assembly, envelopment, transport and maturation, release and egress, and host cell-to-cell transmission, b genes are those genes corresponding to early steps of viral infection, e.g. , viral genome replication, g genes are those genes corresponding to late steps of viral infection, e.g. , egress. Methods to quantify viral gene expression are known in the art. In some embodiments, viral gene expression is determined using reverse transcriptase and quantitative polymerase chain reaction (RT-qPCR). In some embodiments, RNA sequencing (RNA-Seq) is used to determine viral gene expression. In some embodiments, viral DNA is quantified using a Sourthern blot. In some embodiments, b gene expression is quantified. In some embodiments, g gene expression is quantified. In some embodiments, b gene expression and g gene expression are quantified. In some embodiments, expression of the entire viral genome is quantified.
[0036] Methods to quantify virus release are known in the art. In some embodiments, viral release is determined by biochemical assay, e.g, western blotting, e.g, metabolic labeling (see, e.g, Yadav etal, (2012). “A facile quantitative assay for viral particle genesis reveals cooperativity in virion assembly and saturation of an antiviral protein.” Virology. 429(2): 155-162). In some embodiments, viral release is determined by ELISA. In some embodiments, viral release is determined using electron microscopy, e.g, transmission electron microscopy (TEM). In some embodiments, viral release is determined by infectivity measurements for the detection of virions in a sample, e.g. , serum. In some embodiments, viral release is determined by quantification of viral DNA or viral RNA in serum in vivo or culture supernatant in vitro.
Treatment of cytokine release syndrome associated with other pathogen infections
[0037] In certain embodiments, the cytokine release syndrome is associated with a bacterial infection. In certain embodiments, cytokine release syndrome is associated with a bacteria selected from from the group consisting of Chlamydia (e.g, C. trachomatis ), Escherichia coli (e.g., enteropathogenic E. coli, enterohemmorhagic E. coli, uropathogenic E. coli, enteroinvasive E. coli), Helicobacter pylori, Mycobacterium (e.g.,M. tuberculosis, M. leprae, M. lepromatosis), Listeria (e.g, L. monocytogenes), Shigella (e.g., S.flexneri), Staphylococcus (e.g, S. aureus), Streptococcus (e.g, S. pyogenes), Streptomyces, Pneumococcus, Meningococcus, Gonococcus, Klebsiella (e.g, K. pneumoniae), Proteus, Serratia, Pseudomonas (e.g, P. aeruginosa), Legionella, Acinetobacter (e.g, A. baumannii), Corynebacterium (e.g, C. diphtheria), Coxiella (e.g, C. burnetii), Bacillus (e.g., B. anthricis ), Bacteroides, Bordetella, Enterococcus (e.g, E. faecalis), Francisella (e.g, F. tularensis), Haemophilus influenza, Neisseria (e.g, N. meningitides, N. gonorrhoeae), Rickettsia, Salmonella (e.g., S. typhimurium), Vibrio cholerae, Clostridium (e.g, C. tetan, C. botulinum), Yersinia (e.g., Y. pestis), Borrielia (e.g, B. burgdorferi), Brucella, Burkholderia, Campylobacter, and Mycoplasma.
[0038] In certain embodiments, a PI3K inhibitor described herein is used for treating cytokine release syndrome associated with a bacterial infection, e.g, a cytokine release syndrome associated with, for example, an intracellular bacterial infection. Methods described herein can be used to treat, for example, a bacterial disease or disorder selected from the group consisting of chlamydia, tuberculosis, peptic ulcers, leprosy, listeriosis, sialadenitis, bacteria-caused diarrhea or food poisoning, strep throat, scarlet fever, impetigo, cellulitis, pneumonia, meningitis, bacterial endocarditis, diverticulitis, disseminated gonococcemia, septic arthritis, gonococcal ophthalmia neonatorum, urinary tract infections, soft tissue infections, spondyloarthropathies (e.g, ankylosing spondylitis), legionellosis (e.g, Legionnaires’ disease, Pontiac fever), diphtheria, salmonellosis, anthrax, cholera, tetanus, botulism, fasciitis, gas gangrene, plaque, Lyme disease, brucellosis, melioidosis, Q fever, tularemia, gonorrhea, typhus, mycoplasma pneumonia, gastroenteritis, and walking pneumonia.
[0039] In certain embodiments, the cytokine release syndrome is associated with a fungal infection. In certain embodiments, the fungus is selected from the group consisting of Candida (e.g., C. albicans , C. krusei , C. glabrata, C. tropicalis ), Cryptococcus (e.g. , C. neoformans , C. gattii ), Aspergillus (e.g, A. fumigatus, A. niger ), Mucorales ( e.g.,M . mucor, M. absidia,M. rhizopus), Sporothrix (e.g. , S. schenkii), Blastomyces (e.g, B. dermatitidis), Paracoccidioides (e.g, P. brasiliensis ), Coccidioides (e.g, C. immitis ), Histoplasma (e.g, H. capsulatum), Acremonium, Basidiobolus (e.g, B. ranarum), Cladophialophora (e.g., C. bantiana ), Cunninghamella (e.g, C. bertholletiae), Epidermophyton, Exophiala, Exserohilum, Fonsecaea (e.g., F. pedrosoi), Hortaea (e.g., H. werneckii), Lacazia (e.g., L. loboi), Leptosphaeria (e.g, L. maculans), Madurella (e.g.,M. mycetomatis), Malassezia, Microsporum, Mucor, Neotestudina, Onychocola, Phial ophora, Piedraia, Pneumocystis (e.g, P. jirovecii), Pseudallescheria (e.g, P. boydii ), Pyrenochaeta, Rhizomucor, Scedosporium, Scytalidium, Sporothrix, Trichophyton, Trichosporon, and Zygomycete.
[0040] In certain embodiments, a PI3K inhibitor described herein is used for treating a cytokine release syndrome associated with an intracellular fungal infection, e.g, a cytokine release syndrome associated with an intracellular fungal infection selected from the group consisting of candidiasis, cryptococcosis, aspergillosis, mucormycosis, sporotrichosis, blastomycosis, paracoccidioidomycosis, coccidioidomycosis, histoplasmosis, eumycetoma, onychomycosis, hyalohyphomycosis, subcutaneous zygomycosis, cerebral abscesses, phaeohyphomycosis, chromoblastomycosis, mycetoma, pulmonary mucormycosis, tinea corporis, tinea capitis, tinea cruris, tinea pedis, tinea unguium, tinea nigra, Lobo's disease, blackleg disease, mycetoma, pityriasis versicolor, malassezia folliculitis, steroid acne, seborrhoeic dermatitis, neonatal cephalic pustulosis, mucormycosis, maduromycosis, black piedra, pneumocystis pneumonia, pseudallescheriasis, scedosporiosis, sporotrichosis, and zygomycosis.
[0041] In certain embodiments, the cytokine release syndrome is associated with an intracellular protozoan infection. In some embodiments, the protozoan is an amoeba. In certain embodiments, the amoeba is selected from the group consisting of Apicomplexans (Plasmodium (e.g., P. nίnac, R. falciparum, P. ovale, P. malariae, Toxoplasma gondii, Cryptosporidium parvum, Babesia microti, Cyclospora cayetanensis, Cystoisospora belli), Trypanosoma (e.g, Trypanosoma brucei, Trypanosoma cruzi), and Leishmania (e.g., Leishmania donovani). [0042] In certain embodiments, a PI3K inhibitor described herein is used for treating a disease or disorder caused by an intracellular amoebal infection, e.g ., a cytokine release syndrome associated with an amoebal infection selected from the group consisting of babesiosis, malaria, cryptosporidiosis, cyclosporiasis, cystoisosporiasis, toxoplasmosis, trypanosomiasis, Chagas disease, and leishmaniasis.
[0043] In certain embodiments, the cytokine release syndrome is associated with an alga. In certain embodiments, the alga is a Prototheca. In certain embodiments, a PI3K inhibitor described herein is used for treating a cytokine release syndrome associated with an intracellular algal infection, e.g. , protothecosis.
[0044] In certain embodiments, the cytokine release syndrome is associated with a prion. In certain embodiments, a PI3K inhibitor described herein is used for treating cytokine release syndrome associated with caused an intracellular prion infection, e.g. , a cytokine release syndrome associated with a prion infection selected from the group consisting of Creutzf el dt- Jakob disease, variant Creutzfeldt-Jakob disease, Gerstmann-Straussler- Scheinker syndrome, fatal familial insomnia, and kuru.
Assays for the study of cytokine release
[0045] Methods for the study of cytokines are known in the art. In some embodiments, pro-inflammatory cytokines known in the art as chemokines are studied. Examples of chemokines include, without limitation, CXCL-8, CCL2, CCL3, CCL4, CCL5, CCL11, and CXCL10. In some embodiments, cytokine release is studied in vitro , e.g. , in cell culture. In certain embodiments, in vitro cytokine release is quantified from the cell culture supernatant. In some embodiments, cytokine release is studied in vivo , e.g. , in an animal model. In certain embodiments, in vivo cytokine release is quantified from a bodily fluid, e.g. , whole blood, serum, plasma, or lymph. In certain embodiments, the animal model is a murine model. In certain embodiments, the animal model is a non-human primate. In certain embodiments, cytokine release is studied in a human patient.
[0046] In some embodiments cytokine release is assessed through quantification of cytokine expression levels. In some embodiments, cytokine expression levels are quantified using an enzyme-linked immunosorbent assay (ELISA). In some embodiments, cytokine expression levels are quantified using a multiplex immunoassay, e.g., Luminex. In some embodiments, cytokine expression levels are quantified using a cytokine array. In some embodiments, cytokine expression levels are quantified using a Western Blot. In some embodiments, cytokine expression levels are quantified using mass spectrometry. [0047] In some embodiments, cytokine release is assayed through monitoring changes in the immune system. Methods of studying the immune system are known in the art, and include, without limitation: fluorescence activated cell sorting (FACS), transcriptomic profiling ( e.g ., by RNA-sequencing (RNA Seq)), blood smears, complete blood count, and hematocrit.
[0048] In certain embodiments, symptoms of a disease or disorder, such as fever, pneumonia, shortness of breath, and low blood oxygen levels, are indicative of changes in the immune system. In certain embodiments, a decrease in symptoms of a disease or disorder, such as fever, pneumonia, shortness of breath, and low blood oxygen levels, i.e., a decrease in symptoms following treatment with a PI3K inhibitor disclosed herein, are indicative of changes in the immune system.
Treatment of acute respiratory distress syndrome
[0049] The invention also provides for methods of treating acute respiratory distress syndrome with a PI3K inhibitor described herein.
[0050] Acute respiratory distress syndrome is a disorder characterized by poor blood oxygenation, fluid infiltration into the lungs, and acuity of onset (Diamond et al. (2020). Acute Respiratory Distress Syndrome (ARDS). StatPearls [Internet], Treasure Island (FL): StatPearls Publishing). ARDS onset occurs within 7 days of the causal event. ARDS is clinically defined by the ratio of the patient's oxygen levels in arterial blood (Pa02) to the oxygen in the inspired air (Fi02). ARDS is defined as patients exhibiting a Pa02/Fi02 ratio of less than 300. ARDS has high morbidity and mortality. Clinical ARDS is further described, for example, in Fan et al. (2018). Acute Respiratory Distress Syndrome: Advances in Diagnosis and Treatment. JAMA. 319 (7): 698-710.
[0051] Risk factors for ARDS include, without limitation, an infectious disease or disorder (e.g., a viral infection, e.g, a bacterial infection), graft-versus-host disease, organ trauma, tissue trauma, haemophagocytic lymphohistiocytosis, sepsis, systemic inflammatory response syndrome, drowning, drug overdose, fat embolism, inhalation of toxic fumes, and pancreatitis. In some embodiments, the risk factor for ARDS is an infectious disease or disorder, e.g, a virus, e.g, a coronavirus, e.g, SARS-CoV2. In some embodiments, the risk factor for ARDS is an infectious disease or disorder, e.g, a virus, e.g, a ebolavirus. In some embodiments, the risk factor for ARDS is an infectious disease or disorder, e.g, a bacteria, e.g., Streptococcus pneumoniae. In some embodiments, ARDS is associated with cytokine release syndrome. In a particular embodiment, ARDS is associated with cytokine release syndrome associated with SARS-Cov2 (COVID19). In some embodiments, ARDS is associated with mortality associated with SARS-Cov2 (COVID19).
[0052] Existing therapies for patients with ARDS comprise supportive and/or palliative care, including, without limitation, reducing shunt fraction, increasing oxygen delivery, decreasing oxygen consumption, and avoiding further injury to affected tissues and organs.
In some embodiments, a patient with ARDS is placed on a mechanical ventilator. In certain embodiments, a patient on a mechanical ventilator is administered a PI3K inhibitor as described herein. In certain embodiments, a patient on a mechanical ventilator is administered a PI3K inhibitor as described herein intravenously.
II. PI3K INHIBITORS
[0053] PI3K inhibitors that can be used in the kits and methods provided herein include, but are not limited to, those described in, e.g., WO 09/088990, WO2011/008302, WO 2010/036380, WO 2010/006086, WO 09/114870, WO 05/113556, and US 2011/0046165, the entirety of each incorporated herein by reference. Additional PI3K inhibitors that can be used in the compositions and methods provided herein include, but are not limited to, AMG-319, GSK 2126458 (2,4-Difluoro-N-{2-(methyloxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3- pyridinyl}benzenesulfonamide), GSK 1059615 (5Z-[[4-(4-pyridinyl)-6- quinolinyl]methylene]-2,4-thiazolidinedione), GDC-0032 (4-[5,6-dihydro-2-[3-m ethyl -1-(1- methylethyl)-lH- 1 ,2,4-triazol-5-yl]imidazo[l,2-d] [l,4]benzoxazepin-9-yl]-a,a-dimethyl- IH-Pyrazole- 1 -acetamide), GDC-0980 ((S)-l-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4- morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-l-yl)-2-hydroxypropan-l-one), GDC-0941 (2-(lH-indazol-4-yl)-6-((4-(methylsulfonyl)piperazin-l-yl)methyl)-4- morpholinothieno[3,2-d]pyrimidine), XL147 (N-(3-(benzo[c] [l,2,5]thiadiazol-5- ylamino)quinoxalin-2-yl)-4-methylbenzenesulfonamide), XL499, XL765 (SAR245409, N-[4- [[[3-[(3,5-dimethoxyphenyl)amino]-2-quinoxalinyl]amino]sulfonyl]phenyl]-3-methoxy-4- methyl-benzamide), PF-4691502 (2-amino-6-(6-methoxypyridin-3-yl)-4-methyl-8-[(lR,4R)- 4-(2-hydroxyethoxy)cyclohexyl]-7H,8H-pyrido[2,3-d]pyrimidin-7-one), BKM 120 (buparlisib, 5-(2,6-dimorpholinopyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-amine),
Idel alisib (CAL-101, GS 1101, (S)-2-(l-(9H-purin-6-ylamino)propyl)-5-fluoro-3- phenylquinazolin-4(3H)-one), CAL 263, SF1126 (3-[[2-[[5-
[[amino(azaniumyl)methylidene]amino]-2-[[4-oxo-4-[4-(4-oxo-8-phenylchromen-2- yl)morpholin-4-ium-4-yl]oxybutanoyl]amino]pentanoyl]amino]acetyl]amino]-4-(l- carboxylatopropylamino)-4-oxobutanoate), PX-866 (sonolisib, [(3aR,6E,9S,9aR,10R, 1 laS)- 6-[[bis(prop-2-enyl)amino]methylidene]-5-hydroxy-9-(methoxymethyl)-9a, 1 la-dimethyl- 1, 4, 7-trioxo-2, 3, 3a, 9, 10, ll-hexahydroindeno[4,5-h]isochromen-10-yl] acetate), BEZ235 (2- methyl-2-(4-(3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydroimidazo[4,5-c]quinolin-l- yl)phenyl)propanenitrile), GS9820 (CAL- 120, (S)-2-(l-((9H-purin-6-yl)amino)ethyl)-6- fluoro-3-phenylquinazolin-4(3H)-one), BYL719 ((2S)-1 ,2-Pyrrolidinedicarboxamide, Nl-[4- methyl-5 - [2-(2,2,2-trifluoro-l,l-dimethylethyl)-4-pyridinyl]-2-thiazolyl]), RP6503, tenalisib (RP6530, (S)-2-(l-((7H-purin-6-yl)amino)propyl)-3-(3-fluorophenyl)-4H-chromen-4-one), TGR1202 (((S)-2-(l-(4-amino-3-(3 -fluoro-4-isopropoxyphenyl)-lH-pyrazolo [3,4- d]pyrimidin-l-yl)ethyl)-6-fluoro-3 -(3-fluorophenyl)-4H-chromen-4-one)), INK1117 (MLN- 1117), BAY 80-6946 (2-amino-N-(7-methoxy-8-(3-morpholinopropoxy)-2,3- dihydroimidazo[l,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide), IC87114 (2-((6-amino- 9H-purin-9-yl)methyl)-5-methyl-3-o-tolylquinazolin-4(3H)-one), Palomid 529 (3-(4- methoxybenzyloxy)-8-(l-hydroxyethyl)-2-methoxy-6H-benzo[c]chromen-6-one), ZSTK474 (2-(difluoromethyl)- 1 -(4,6-dimorpholino- 1 ,3 ,5 -triazin-2-yl)- IH-benzo [djimidazole), PWT33597, TG 100-115 (6, 7-Bis(3-hydroxyphenyl)pteridine-2, 4-diamine), GNE-477 (5-[7- methyl-4-(morpholin-4-yl)-6-[(4-methylsulfonylpiperazin- l-yl)methyl]thieno[3,2- d]pyrimidin-2-yl]pyrimidin-2 -amine), CUDC-907 (N-hydroxy-2-(((2-(6-me lhoxypyri din-3 - yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)pyrimidine-5- carboxamide), AEZS-136, BGT-226 (8-(6-methoxypyridin-3-yl)-3-methyl-l-(4-(piperazin-l- yl)-3-(trifluoromemyl)phenyl)-lH-imidazo[4,5-c]quinolin-2(3H)-one maleic acid), PF- 05212384 (1 -(4-(4-(dimethylamino)piperidine- 1 -carbonyl)phenyl)-3 -(4-(4,6-dimorpholino- l,3,5-triazin-2-yl)phenyl)urea), LY3023414, PI-103 (3-[4-(4- morpholinyl)pyrido[3’,2’:4,5]furo[3,2-d]pyrimidin-2-yl]-phenol), INCB040093, CAL- 130 ((S)-2-(l-((2-amino-9H-purin-6-yl)amino)ethyl)-5-methyl-3-(o-tolyl)quinazolin-4(3H)-one), LY294002 (2-Morpholin-4-yl-8-phenylchromen-4-one), wortmannin, AS252424 (5-[l-[5-(4- Fluoro-2-hydroxy-phenyl)-furan-2-yl]-meth-(Z)-ylidene]-thiazolidine-2,4-dione), IPI-549 (2- amino-N-[(lS)-l-[8-[2-(l-methylpyrazol-4-yl)ethynyl]-l-oxo-2-phenylisoquinolin-3- yl]ethyl]pyrazolo[l,5-a]pyrimidine-3-carboxamide), CZC24832 (5-(2-Amino-8-fluoro- [l,2,4]triazolo[l,5-a]pyridin-6-yl)-N-tert-butylpyridine-3-sulfonamide), duvelisib (INK-1197, IPI-145, CopiktraTM, (S)-3-(l-((9H-purin-6-yl)amino)ethyl)-8-chloro-2-phenylisoquinolin- l(2H)-one), or AS-604850 (5-(2,2-Difluoro-benzo[l,3]dioxol-5-ylmethylene)-thiazolidine- 2,4-dione).
[0054] In some embodiments, a PI3K inhibitor is a compound that inhibits one or more PI3K isoforms, e.g., alpha, beta, delta, or gamma isoform. In some embodiments, a PI3K inhibitor is a compound that inhibits one or more PI3K isoforms with an IC50 of less than about 1000 nM, less than about 900 nM, less than about 800 nM, less than about 700 nM, less than about 600 nM, less than about 500 nM, less than about 400 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 75 nM, less than about 50 nM, less than about 25 nM, less than about 20 nM, less than about 15 nM, less than about 10 nM, less than about 10 nM, less than about 5 nM, or less than about 1 nM.
[0055] In some embodiments, the PI3K inhibitor is a compound that inhibits alpha, beta, delta and gamma isoforms of PI3K. In another embodiment, the PI3K inhibitor is a compound that inhibits beta, delta, and gamma isoforms of PI3K. In another embodiment, the PI3K inhibitor is a compound that inhibits the delta and gamma isoforms of PI3K.
[0056] In some embodiments, the PI3K inhibitor is a PI3K isoform selective inhibitor. In some embodiments, the PI3K inhibitor is a PI3K alpha selective inhibitor. In another embodiment, the PI3K inhibitor is a PI3K beta selective inhibitor.
[0057] In some embodiments, the PI3K inhibitor is a PI3K gamma selective inhibitor. In some embodiments, the PI3K gamma selective inhibitor selectively inhibits PI3K gamma isoform over PI3K delta isoform. In some embodiments, the PI3K gamma selective inhibitor has a delta/gamma selectivity ratio of greater than 1, greater than about 5, greater than about 10, greater than about 50, greater than about 100, greater than about 200, greater than about 400, greater than about 600, greater than about 800, greater than about 1000, greater than about 1500, greater than about 2000, greater than about 5000, greater than about 10,000, or greater than about 20,000. In some embodiments, the PI3K gamma selective inhibitor has a delta/gamma selectivity ratio in the range of from greater than 1 to about 5, from about 5 to about 10, from about 10 to about 50, from about 50 to about 850, or greater than about 850.
In some embodiments, the delta/gamma selectivity ratio is determined by dividing the inhibitor's IC50 against PI3K delta isoform by the inhibitor's IC50 against PI3K gamma isoform.
[0058] In some embodiments, the PI3K inhibitor is a PI3K gamma selective inhibitor. In some embodiments, the PI3K gamma selective inhibitor selectively inhibits PI3K gamma isoform over PI3K alpha isoform. In some embodiments, the PI3K gamma selective inhibitor has an alpha/gamma selectivity ratio of greater than 1, greater than about 5, greater than about 10, greater than about 50, greater than about 100, greater than about 200, greater than about 400, greater than about 600, greater than about 800, greater than about 1000, greater than about 1500, greater than about 2000, greater than about 5000, greater than about 10,000, or greater than about 20,000. In some embodiments, the PI3K gamma selective inhibitor has an alpha/gamma selectivity ratio in the range of from greater than 1 to about 5, from about 5 to about 10, from about 10 to about 50, from about 50 to about 850, or greater than about 850. In some embodiments, the alpha/gamma selectivity ratio is determined by dividing the inhibitor's IC50 against PI3K alpha isoform by the inhibitor's IC50 against PI3K gamma isoform.
[0059] In some embodiments, the PI3K inhibitor is a PI3K gamma selective inhibitor. In some embodiments, the PI3K gamma selective inhibitor selectively inhibits PI3K gamma isoform over PI3K beta isoform. In some embodiments, the PI3K gamma selective inhibitor has a beta/gamma selectivity ratio of greater than 1, greater than about 5, greater than about 10, greater than about 50, greater than about 100, greater than about 200, greater than about 400, greater than about 600, greater than about 800, greater than about 1000, greater than about 1500, greater than about 2000, greater than about 5000, greater than about 10,000, or greater than about 20,000. In some embodiments, the PI3K gamma selective inhibitor has a beta/gamma selectivity ratio in the range of from greater than 1 to about 5, from about 5 to about 10, from about 10 to about 50, from about 50 to about 850, or greater than about 850.
In some embodiments, the beta/gamma selectivity ratio is determined by dividing the inhibitor's IC50 against PI3K beta isoform by the inhibitor's IC50 against PI3K gamma isoform.
[0060] In some embodiments, the PI3K inhibitor is selective for both gamma and delta isoforms, as determined by IC50 from whole blood assays for both PI3K-delta and PI3K- gamma at clinically achievable plasma exposures. In some embodiments, the PI3K gamma and delta selective inhibitor selectively inhibits PI3K gamma and delta isoforms over PI3K beta isoform. In some embodiments, the PI3K gamma and delta selective inhibitor has a beta/delta selectivity ratio of greater than 1, greater than about 5, greater than about 10, greater than about 50, greater than about 100, greater than about 200, greater than about 400, greater than about 600, greater than about 800, greater than about 1000, greater than about 1500, greater than about 2000, greater than about 5000, greater than about 10,000, or greater than about 20,000 and a beta/gamma selectivity ratio of greater than 1, greater than about 5, greater than about 10, greater than about 50, greater than about 100, greater than about 200, greater than about 400, greater than about 600, greater than about 800, greater than about 1000, greater than about 1500, greater than about 2000, greater than about 5000, greater than about 10,000, or greater than about 20,000. In some embodiments, the PI3K gamma and delta selective inhibitor has a beta/delta selectivity ratio in the range of from greater than 1 to about 5, from about 5 to about 10, from about 10 to about 50, from about 50 to about 850, or greater than about 850 and a beta/gamma selectivity ratio in the range of from greater than 1 to about 5, from about 5 to about 10, from about 10 to about 50, from about 50 to about 850, or greater than about 850. In some embodiments, the beta/delta selectivity ratio is determined by dividing the inhibitor's IC50 against PI3K beta isoform by the inhibitor's IC50 against PI3K delta isoform and the beta/gamma selectivity ratio is determined by dividing the inhibitor's IC50 against PI3K beta isoform by the inhibitor's IC50 against PI3K gamma isoform.
[0061] PI3K gamma inhibitors that can be used in the compositions and methods provided herein include, but are not limited to, IPI-549 (2-amino-N-[(lS)-l-[8-[2-(l-methylpyrazol-4- yl)ethynyl]-l-oxo-2-phenylisoquinolin-3-yl]ethyl]pyrazolo[l,5-a]pyrimidine-3-carboxamide), CZC24832 (5-(2-Amino-8-fluoro-[l,2,4]triazolo[l,5-a]pyridin-6-yl)-N-tert-butylpyridine-3- sulfonamide), AS252424 (5-[l-[5-(4-Fluoro-2-hydroxy-phenyl)-furan-2-yl]-meth-(Z)- ylidene]-thiazolidine-2,4-dione), or AS-604850 (5-(2,2-Difluoro-benzo[l,3]dioxol-5- ylmethylene)-thiazolidine-2,4-dione. In some embodiments, the PI3K gamma inhibitor is IPI- 549.
[0062] In some embodiments, the PI3K inhibitor is a PI3K delta/gamma dual inhibitor. In some embodiments, the PI3K delta/gamma dual inhibitor has an IC50 value against PI3K alpha that is at least 5X, 10X, 20X, 50X, 100X, 200X, 500X, or 1000X higher than its IC50 values against delta and gamma.
[0063] In some embodiments, the PI3K inhibitor may be administered daily, every other day, three times a week, twice a week, weekly, or bi-weekly. The dosing schedule can include a "drug holiday," e.g., the drug may be administered for two weeks on, one week off, or three weeks on, one week off, or four weeks on, one week off, etc., or continuously, without a drug holiday. The inhibitor may be administered orally, intravenously, intraperitoneally, topically, transdermally, intramuscularly, subcutaneously, intranasally, sublingually, or by any other route.
[0064] In some embodiments, a PI3K inhibitor described herein may be administered in multiple doses. Dosing may be about once, twice, three times, four times, five times, six times, or more than six times per day. Dosing may be about once a month, about once every two weeks, about once a week, or about once every other day. In some cases, continuous dosing is achieved and maintained as long as necessary.
[0065] In some embodiments, a PI3K inhibitor described herein may be administrated prophylactically. In some embodiments, a PI3K inhibitor described herein may be administered when a patient displays sympytoms. In some embodiments, a PI3K inhibitor described herein may be administered prophylactically and to a patient with symptoms. In certain embodiments, symptoms of a disease or disorder comprise fever, cough, sore throat, runny nose, congestion, headache, malaise, diarrhea, nausea, vomiting, hyperinflammation, rash, pneumonia, chest pain, swollen lymph nodes, decreased appetite, shortness of breath, low blood oxygen levels, seizures, and death. In certain embodiments, symptoms of a disease or disorder comprise acute respiratory distress syndrome, fever, pneumonia, shortness of breath, and low blood oxygen levels. In certain embodiments, symptoms of a disease or disorder comprise acute respiratory distress syndrome.
[0066] In some embodiments, a COVID19 patient with markers of hyperinflammation is prophylactically administered a PI3K disclosed herein. In certain embodiments, the markers of hyperinflammation comprise elevated ferritin, decreased platelet counts, and elevated erythrocyte sedimentation rate. In some embodiments, the H-Score is used to diagnose hyperinflammation (Cron & Chatham (2020). Don’t Forget the Host: COVID-19 Cytokine Storm. The Rheumatologist). The H-Score (also referred to as HScore) is described in, for example, Fardet et al. (2014). Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome. Arthritis & Rheumatology. 66(9):2613- 2620.
[0067] Generally, doses of a PI3K inhibitor described herein, will range from about 0.0001 mg to about 100 mg per day, or about 0.001 mg to about 100 mg per day, or about 0.01 mg to about 100 mg per day, or about 0.1 mg to about 100 mg per day, or about 0.0001 mg to about 500 mg per day, or about 0.001 mg to about 500 mg per day, or about 0.01 mg to 1000 mg, or about 0.01 mg to about 500 mg per day, or about 0.1 mg to about 500 mg per day, or about 1 mg to 50 mg per day, or about 5 mg to 40 mg per day. An exemplar}' dosage is about 10 to 30 mg per day.
III. COMBINATION THERAPIES
[0068] Methods of treatment of the present invention can be used as a monotherapy or in combination with one or more other therapies ( e.g. , anti-infective agents, e.g. a cytokine inhibitor) that can be used to treat a disease or disorder, for example, an infection. The term “combination,” as used herein, is understood to mean that two or more different treatments are delivered to the subject during the course of the subject’s affliction with the disorder, such that the effects of the treatments on the patient overlap at a point in time. In certain embodiments, the delivery of one treatment is still occurring when the delivery of the second begins, so that there is overlap in terms of administration. This is sometimes referred to herein as “simultaneous” or “concurrent delivery.” In other embodiments, the delivery of one treatment ends before the delivery of the other treatment begins. In certain embodiments of either case, the treatment is more effective because of combined administration. For example, the second treatment is more effective, e.g., an equivalent effect is seen with less of the second treatment, or the second treatment reduces symptoms to a greater extent, than would be seen if the second treatment were administered in the absence of the first treatment, or the analogous situation is seen with the first treatment. In certain embodiments, delivery is such that the reduction in a symptom, or other parameter related to the disorder is greater than what would be observed with one treatment delivered in the absence of the other. The effect of the two treatments can be partially additive, wholly additive, or greater than additive. The delivery can be such that an effect of the first treatment delivered is still detectable when the second is delivered.
[0069] Accordingly, in certain embodiments, the subject has received, is receiving, or is scheduled to receive one or more other therapies suitable for use in treating the disease or disorder. In certain embodiments, the method of treatment of the present invention further comprises administering to the subject one or more other therapies suitable for use in treating a disease or disorder, for example, an infection. In certain embodiments, the one or more other therapies comprise an agent that ameliorates one or more symptoms of infection with an intracellular pathogen. In certain embodiments, the one or more other therapies comprise surgical removal of an infected tissue. In certain embodiments, the one or more other therapies comprise an immunosuppressive agent, e.g. , a cytokine inhibitor, e.g. , an IL-6 inhibitory antibody. In certain embodiments, the one or more other therapies comprise an anti-inflammatory composition.
[0070] It is understood that a method of use disclosed herein can be used in combination with an agent, for example, an anti-infective agent that ameliorates one or more symptoms of a disease or disorder associated with an intracellular pathogen. For example, a method of use disclosed herein can be used in combination with an antiviral agent.
[0071] Therapies suitable for treating infections by intracellular pathogens are generally known in the art and are reviewed, for example, by Kamaruzzaman el al. (2017) Br. J. Pharmacol. 174(14): 2225-36 and De Clercq et al. (2016) Clin. Microbiol. Rev. 29(3): 695- 747. In certain embodiments, the anti -infective agent inhibits or reduces the viability, proliferation, infectivity, and/or virulence of the intracellular pathogen. Intracellular pathogens may evade immune surveillance and challenge by residing in a latent state. Accordingly, in certain embodiments, the anti-infective agent reverses the latency of the intracellular pathogen such that the infection can be recognized by the host’s immune system. [0072] In certain embodiments, the intracellular pathogen is a virus, and the anti-infective agent is an antiviral agent. Exemplary antiviral agents that can be used in the combination include but are not limited to abacavir, acyclovir, adefovir, amprenavir, atazanavir, cidofovir, darunavir, delavirdine, didanosine, docosanol, efavirenz, elvitegravir, emtricitabine, enfuvirtide, entecavir, etravirine, famciclovir, foscamet, fomivirsen, ganciclovir, indinavir, idoxuridine, lamivudine, lopinavir, maraviroc, MK-2048, nelfmavir, nevirapine, penciclovir, raltegravir, rilpivirine, ritonavir, saquinavir, stavudine, tenofovir trifluridine, valaciclovir, valganciclovir, vidarabine, ibacitabine, amantadine, oseltamivir, rimantidine, tipranavir, zalcitabine, zanamivir, peramivir, danoprevir, remdesivir, and zidovudine. In particular, where the intracellular pathogen is an HIV, exemplary anti-HIV agents that can be used in the combination include, but are not limited to, nucleoside/nucleotide reverse transcriptase inhibitors ( e.g ., lamivudine, abacavir, zidovudine, stavudine, didanosine, emtricitabine, and tenofovir), non-nucleoside reverse transcriptase inhibitors (e.g., delavirdine, efavirenz, etravirine, and nevirapine), protease inhibitors (e.g. , amprenavir, fosamprenavir, atazanavir, darunavir, indinavir, lopinavir, ritonavir, nelfmavir, saquinavir, and tipranavir), fusion or entry inhibitors (e.g, enfuvirtide and maraviroc), integrase inhibitors (e.g, raltegravir and cabotegravir), and latency -reversing agents (e.g, HD AC inhibitors (e.g, vorinostat) and TLR7 agonists (e.g, GS-9620, e.g, as described in U.S. Patent Publication No. US20160008374A1)). In certain embodiments, the vims is SARS-CoV2, and the combination therapy comprises hydroxychloroquine. In certain embodiments, the vims is SARS-CoV2, and the combination therapy comprises an antiviral agent.
[0073] In certain embodiments, the intracellular pathogen is a bacterium, and the anti- infective agent is an anti -bacterial agent. Exemplary anti -bacterial agents that can be used in the combination include but are not limited to vancomycin, metronidazole, gentamicin, colistin, fidaxomicin, telavancin, oritavancin, dalbavancin, daptomycin, cephalexin, cefuroxime, cefadroxil, cefazolin, cephalothin, cefaclor, cefamandole, cefoxitin, cefprozil, ceftobiprole, cipro, Levaquin, floxin, tequin, avelox, norflox, tetracycline, minocycline, oxytetracycline, doxycycline, amoxicillin, ampicillin, penicillin V, dicloxacillin, carbenicillin, methicillin, ertapenem, doripenem, imipenem/cilastatin, meropenem, amikacin, kanamycin, neomycin, netilmicin, tobramycin, paromomycin, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefoxotin, and streptomycin.
[0074] In certain embodiments, the intracellular pathogen is a fungus, and the anti- infective agent is an anti-fungal agent. Exemplary anti-fungal agents that can be used in the combination include but are not limited to natamycin, rimocidin, filipin, nystatin, amphotericin B, candicin, and hamycin, miconazole, ketoconazole, clotrimazole, econazole, omoconazole, bifonazole, butoconazole, fenticonazole, isoconazole, oxiconazole, sertaconazole, sulconazole, tioconazole, fluconazole, itraconazole, isavuconazole, ravuconazole, posaconazole, voriconazole, terconazole, and albaconazole, abafungin, terbinafme, naftifme, butenafine, anidulafungin, caspofungin, micafungin, polygodial, benzoic acid, ciclopirox, tolnaftate, undecylenic acid, flucytosine or 5-fluorocytosine, griseofulvin, and haloprogin.
[0075] In certain embodiments, the intracellular pathogen is a protozoan, and the anti- infective agent is an anti -protozoal agent. Exemplary anti -protozoal agents that can be used in the combination include but are not limited to quinine (optionally in combination with clindamycin), chloroquine, amodiaquine, artemisinin and its derivatives ( e.g ., artemether, artesunate, dihydroartemisinin, arteether), doxy cy cline, pyrimethamine, mefloquine, halofantrine, hydroxychloroquine, eflomithine, nitazoxanide, omidazole, paromomycin, pentamidine, primaquine, pyrimethamine, proguanil (optionally in combination with atovaquone), sulfonamides (e.g., sulfadoxine, sulfamethoxypyridazine), tafenoquine, and tinidazole. In specific embodiments, the intracellular pathogen is a Plasmodium (e.g, P. vivax, P. falciparum, P. ovale, P. malariae), and the anti -infective agent is an anti-malarial agent. Exemplary anti-malarial agents that can be used in the combination include but are not limited to quinine (optionally in combination with clindamycin), chloroquine, amodiaquine, artemisinin and its derivatives (e.g, artemether, artesunate, dihydroartemisinin, arteether), doxycycline, halofantrine, mefloquine, primaquine, proguanil (optionally in combination with atovaquone), sulfonamides (e.g, sulfadoxine, sulfamethoxypyridazine), tafenoquine. It is understood that many of these anti-malarial agents can be used in combination especially for treating severe and/or acute infections.
[0076] In certain embodiments, the intracellular pathogen is an alga, and the anti- infective agent is an anti-algal agent. Exemplary anti-algal agents that can be used in the combination include but are not limited to ketoconazole, itraconazole, fluconazole, and voriconazole.
[0077] In certain embodiments, the intracellular pathogen is a prion, and the anti- infective agent is an anti-prion agent. Exemplary anti-prion agents that can be used in the combination include but are not limited to pentosan polysulfate, quinacrine, thioflavine, amphotericin B, tetracyclines, tricyclic antidepressants (e.g, desipramine), and lithium chloride. [0078] An additional class of agents that may be used as part of a combination therapy in treating a cytokine release syndrome are immunosuppressive agents, e.g ., cytokine inhibitors, calcineurin inhibitors, mTOR inhibitors, or steroids: In some embodiments, the immunosuppressive agents comprise calineurin inhibitors, e.g, tacrolimus and cyclosporine. In some embodiments, the immunosuppressive agents comprise mTOR inhibitors, e.g. , sirolimus. In some embodiments, the immunosuppressive agents comprise steroids, e.g. , prednisone. In some embodiments, the immunosuppressive agents comprise cytokine inhibitors, e.g. , an IL-6 antagonist, an IL-1 antagonist, a soluble tumor necrosis factor receptor, an IL-1 receptor agonist, and a TGF-bI latency-associated peptide. In certain embodiments, the cytokine inhibitor comprises an inhibitory antibody. In certain embodiments, the cytokine inhibitor comprises an inhibitory antibody against IL-6. In certain embodiments, the cytokine inhibitor comprises tocilizumab, sarilumab, or siltuximab. In certain embodiments, the immunosuppressive agent, e.g. , the cytokine inhibitor, e.g. tocilizumab, sarilumab, or siltuximab, is administrered intravenously.
[0079] Appropriate therapies can be selected according to diagnosis of the specific infection. Wherein the subject is infected with a plurality of pathogens (e.g, a plurality of intracellular pathogens, e.g, a plurality of viral infections), two or more appropriate therapies for treating these infections may be used in combination with a PI3K inhibitor disclosed herein.
IV. PHARMACEUTICAL COMPOSITIONS AND METHODS OF DELIVERY
[0080] The present disclosure also contemplates pharmaceutical compositions that contain a therapeutically effective amount of a PI3K described herein. The composition can be formulated for use in a variety of drug delivery systems. One or more physiologically acceptable excipients or carriers can also be included in the composition for proper formulation. Suitable formulations for use in the present disclosure are found in Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, Pa., 17th ed., 1985. For a brief review of methods for drug delivery, see, e.g, Langer (Science 249:1527-1533, 1990).
Enteral administration
[0081] In some embodiments of the methods described herein, a PBK inhibitor is administered orally. In certain embodiments of the compositions described herein, a PI3K inhibitor (e.g·., duvelisib, tenalisib, or IPI-549) is formulated for oral administration. Some embodiments pertaining to such methods and compositions include the following. [0082] In some embodiments, provided herein are pharmaceutical compositions for oral administration containing a compound, e.g., a PI3K inhibitor as disclosed herein, and a pharmaceutical excipient suitable for ora! administration.
[0083] In some embodiments, the pharmaceutical composition can be a liquid pharmaceutical composition suitable for oral consumption. Pharmaceutical compositions suitable for oral administration can be presented as discrete dosage forms, such as capsules, cachets, or tablets, or liquids or aerosol sprays each containing a predetermined amount of an active ingredient as a powder or in granules, a solution, or a suspension in an aqueous or non- aqueous liquid, an oil -in-water emulsion, or a water-in-oil liquid emulsion. Such dosage forms can be prepared by any of the methods of pharmacy, but all methods include the step of bringing the active ingredient into association with the carrier, which constitutes one or more ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet can be prepared by compression or molding, optionally with one or more accessory' ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with an excipient such as, but not limited to, a binder, a lubricant, an inert diluent, and/or a surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. [0084] The present disclosure further encompasses anhydrous pharmaceutical compositions and dosage forms comprising an active ingredient, since water can facilitate the degradation of some compounds. For example, water can be added (e.g., about 5% water) in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf-life or the stability of formulations overtime. Anhydrous pharmaceutical compositions and dosage forms can be prepared using anhydrous or low moisture containing ingredients and low' moisture or low humidity conditions. For example, pharmaceutical compositions and dosage forms which contain lactose can be made anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected. An anhydrous pharmaceutical composition can be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous pharmaceutical compositions can be packaged using materials known to prevent exposure to water such that they can be included in suitable formulary' kits. Examples of suitable packaging include, without limitation, hermetically sealed foils, plastic or the like, unit dose containers, blister packs, and strip packs.
[0085] in some embodiments, an active ingredient can be combined in an intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the form of preparation desired for administration. In preparing the pharmaceutical compositions for an oral dosage form, any of the usual pharmaceutical media can be employed as carriers, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like in the case of oral liquid preparations (i.e., suspensions, solutions, and elixirs) or aerosols; or carriers such as starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents can be used in the case of oral solid preparations, in some embodiments without employing the use of lactose. For example, suitable carriers include powders, capsules, and tablets, with the solid oral preparations. In some embodiments, tablets can be coated by standard aqueous or nonaqueous techniques.
[0086] In some embodiments, the pharmaceutical composition may comprise a binder. Binders suitable for use in pharmaceutical compositions and dosage forms include, without limitation, com starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre - gelatinized starch, hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixtures thereof.
[0087] In some embodiments, the pharmaceutical composition may comprise a filler. Examples of suitable fillers for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre -gelatinized starch, and mixtures thereof.
[0088] In some embodiments, the pharmaceutical composition may comprise a disintegrant. Disintegrants can be used in the pharmaceutical compositions as provided herein to provide tablets that disintegrate when exposed to an aqueous environment. Too much of a disintegrant can produce tablets which can disintegrate in the bottle. Too little can be insufficient for disintegration to occur and can thus alter the rate and extent of release of the active ingredient(s) from the dosage form. Thus, a sufficient amount of disintegrant that is neither too little nor too much to detrimentally alter the release of the active ingredient(s) can be used to form the dosage forms of the compounds disclosed herein. The amount of disintegrant used can vary' based upon the type of formulation and mode of administration, and can be readily discernible to those of ordinary' skill in the art. About 0.5 to about 15 weight percent of disintegrant, or about 1 to about 5 weight percent of disintegrant, can be used in the pharmaceutical composition. Disintegrants that can be used to form pharmaceutical compositions and dosage forms include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre -gelatinized starch, other starches, clays, other algins, other celluloses, gums or mixtures thereof.
[0089] in some embodiments, lubricants which can be used to form pharmaceutical compositions and dosage forms include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethylaureate, agar, or mixtures thereof. Additional lubricants include, for example, a syloid silica gel, a coagulated aerosol of synthetic silica, or mixtures thereof. A lubricant can optionally be added, in an amount of less than about 1 weight percent of the pharmaceutical composition.
[0090] In some embodiments, When aqueous suspensions and/or elixirs are desired for oral administration, the active ingredient therein can be combined with various sweetening or flavoring agents, coloring matter or dyes and, for example, emulsifying and/or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.
[0091] In some embodiments, the tablets can be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed. In some embodiments, formulations for oral use can also be presented as hard gelatin capsules w'herein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules w'herein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil. [0092] In some embodiments, a surfactant may be used. Surfactants useful to form pharmaceutical compositions and dosage forms include, without limitation, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof, i.e., a mixture of hydrophilic surfactants can be employed, a mixture of lipophilic surfactants can be employed, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant can be employed.
[0093] In some embodiments, a suitable hydrophilic surfactant can generally have an HLB value of at least about 10, while suitable lipophilic surfactants can generally have an HLB value of or less than about 10. An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of non-ionic amphiphilic compounds is the hydrophilic - lipophilic balance ("HLB" value). Surfactants with lower HLB values are more lipophilic or hydrophobic, and have greater solubility in oils, while surfactants with higher HLB values are more hydrophilic, and have greater solubility in aqueous solutions. Hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable. Similarly, lipophilic {i.e., hydrophobic) surfactants are compounds having an HLB value equal to or less than about 10. However, an HLB value of a surfactant is merely a rough guide generally used to enable formulation of industrial, pharmaceutical and cosmetic emulsions.
[0094] Hydrophilic surfactants can be either ionic or non-ionic. In some embodiments, suitable ionic surfactants include, without limitation, alkyl ammonium salts; fusidic acid salts; faty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; lecithins and hydrogenated lecithins; iysolecithins and hydrogenated lysolecithins; phospholipids and derivatives thereof; iysophosphoiipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof.
[0095] In some embodiments, ionic surfactants include, without limitation: lecithins, iysolecithin, phospholipids, lysophosphoiipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and diglycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof. [0096] In some embodiments, ionic surfactants can be the ionized forms of lecithin, iy solecithin, phosphatidylcholine, phosphatidylethanol amine, phosphatidylglycerol , phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanol amine, PVP-phosphatidyllthanolamine, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono/ di acetyl ated tartaric acid esters of mono/diglycerides, citric acid esters of mono/di glycerides, cholylsarcosine, caproate, caprylate, caprate, iaurate, myri state, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate, lauroyl carnitines, palmitoyl carnitines, myristoyl carnitines, and salts and mixtures thereof.
[0097] in some embodiments, hydrophilic non-ionic surfactants can include, without limitation, alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogol glycerides; polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers, polyoxyalkylene alkylphenols such as polyethylene glycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esters such as polyethylene glycol fatty acids monoesters and polyethylene glycol fatty acids diesters; polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of a polyol with at. least one member of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene sterols, derivatives, and analogues thereof, polyoxyethylated vitamins and derivatives thereof; polyoxyethylene -polyoxypropylene block copolymers; and mixtures thereof; polyethylene glycol sorbitan fatty acid esters and hydrophilic transesterification products of a polyol with at least one member of triglycerides, vegetable oils, and hydrogenated vegetable oils. The polyol can be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a saccharide.
[0098] In some embodiments, other hydrophilic-non-ionic surfactants appropriate for use include, without limitation, PEG- 10 laurate, PEG-12 laurate, PEG-20 Iaurate, PEG-32 iaurate, PEG-32 dilaurate, PEG- 12 oleate, PEG- 15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG -32 oleate, PEG-200 oleate, PEG-400 oleate, PEG- 15 stearate, PEG-32 di stearate, PEG- 40 stearate, PEG- 100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl Iaurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG- 20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyceryl iaurate, PEG-40 glyceryl Iaurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6 caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides, polyglyceryl- 10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30 soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 Lauryl ether, POE- 10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG- 100 succinate, PEG-24 cholesterol, polyglyceryl-10 oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopaLmitate, PEG 10-100 nonyl phenol series, PEG 15-100 octyl phenol series, and poloxamers.
[0099] In some embodiments, suitable lipophilic surfactants include, without limitation: fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acids esters; propylene glycol faty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxy ethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- and di-glycerides; hydrophobic transesterification products of a polyol with at least one member of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; oil-soluble vitamins/vitamin derivatives; and mixtures thereof. Within this group, non-limiting examples of lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or are hydrophobic transesterification products of a polyol with at least one member of vegetable oils, hydrogenated vegetable oils, and triglycerides.
[0100] In some embodiments, the pharmaceutical composition can include a solubilizer to ensure good solubilization and/or dissolution of a compound as provided herein and to minimize precipitation of the compound. This can be especially important for pharmaceutical compositions for non-oral use, e.g., pharmaceutical compositions for injection. A solubilizer can also be added to increase the solubility of the hydrophilic drug and/or other components, such as surfactants, or to maintain the pharmaceutical composition as a stable or homogeneous solution or dispersion. Examples of suitable solubilizers include, but are not limited to, the following: alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediois and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinyla!cohol, hydroxypropyl metbylcellulose and other cellulose derivatives, cyelodextrins and cyclodextrin derivatives; ethers of polyethylene glycols having an average molecular weight of about 200 to about 6000, sucH as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG; amides and other nitrogen-containing compounds such as 2-pyrrolidone, 2~piperidone, e-caprolactam, N-alkylpyrrolidone, N- hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaproiactam, dim ethyl acetamide and polyvinylpyrrolidone; esters such as ethyl propionate, tributylcitrate, acetyl tri ethyl citrate, acetyl tributyl citrate, tri ethyl citrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, e-caprolactone and isomers thereof, d-valerolactone and isomers thereof, b-butyrolactone and isomers thereof, and other solubilizers known in the art, such as dimethyl acetamide, dimethyl isosorbide, N-methyl pyrrolidones, monooctanoin, di ethylene glycol monoethyl ether, and water.
[0101] In some embodiments, mixtures of solubilizers can also be used. Examples include, but not limited to, triacetin, tri ethyl citrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methyl pyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethylene glycol 200-100, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide. In some embodiments, solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol and propylene glycol.
[0102] In some embodiments, mixtures of solubilizers can also be used, the amount of solubilizer that can be included is not limited. The amount of a given solubilizer can be limited to a bioacceptable amount, which can be readily determined by one of skill in the art. In some embodiments, it can be advantageous to include amounts of solubilizers far in excess of bioacceptable amounts, for example to maximize the concentration of the drug, with excess solubilizer removed prior to providing the pharmaceutical composition to a subject using conventional techniques, such as distillation or evaporation. Thus, if present the solubilizer can be in a weight ratio of about 10%, 25%, 50%, 100%, or up to about 200% by weight, based on the combined weight of the drug, and other excipients. If desired, very small amounts of solubilizer can also be used, such as about 5%, 2%, 1% or even less. Typically, the solubilizer can be present in an amount of about 1% to about 100%, more typically about 5% to about. 25% by weight.
[0103] In some embodiments, the pharmaceutical composition can further comprise one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, without limitation, detackifiers, anti-foaming agents, buffering agents, polymers, antioxidants, preservatives, chelating agents, viscorn odulators, tonicifiers, tlavorants, colorants, oils, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof. [0104] In some embodiments, exemplary preservatives can include, without limitation, antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives. Exemplar)-’ antioxidants include, but are not limited to, alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxy toluene, monothiogly cero! , potassium metabi sulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabi sulfite, and sodium sulfite. Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA), citric acid monohydrate, disodium edetate, dipotassium edetate, edetic acid, fumaric acid, malic acid, phosphoric acid, sodium edetate, tartaric acid, and trisodium edetate. Exemplary' antimicrobial preservatives include, but are not limited to, benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridmiunm chloride, chi orhexi dine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxy ethanol, phenyl ethyl alcohol, phenylmercuric nitrate, propylene glycol, andthimerosal. Exemplary' antifungal preservatives include, but are not limited to, butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid. Exemplary alcohol preservatives include, but are not limited to, ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol. Exemplary' acidic preservatives include, but are not limited to, vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid. Other preservatives include, but are not limited to, tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxy ani sol (BHA), butylated hydroxytoluened (BHT), ethyienediamine, sodium iauryl sulfate (SLS), sodium lauryl ether sulfate (SEES), sodium bisulfite, sodium metabi sulfite, potassium sulfite, potassium metabi sulfite, Glydant Plus, Phenonip, methylparaben, Germ all 1 15, Germaben II, Neolone, Kathon, and Euxyl. In certain embodiments, the preservative is an anti-oxidant. In certain embodiments, the preservative is a chelating agent.
[0105] In some embodiments, exemplary’ oils include, without limitation, almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myri state, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Exemplary' oils include, without limitation, butyl stearate, caprylic triglyceride, capric triglyceride, cyciomethicone, diethyl sebacate, dimethicone 360, isopropyl myri state, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and combinations thereof.
[0106] In some embodiments, an acid or a base can be incorporated into the pharmaceutical composition to facilitate processing, to enhance stability, or for other reasons. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethyl enediamine, triethanolamine, triethylamine, triisopropanolamine, trimethyl amine, tris(hydroxymethyl)aminom ethane (TRIS) and the like. Also suitable are bases that are salts of a pharmaceutically acceptable acid, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, faty acids, formic acid, fumaric acid, gluconic acid, hydroquinosuifonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, para-bromophenyl sulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluene sulfonic acid, uric acid, and the like. Salts of polyprotie acids, such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate can also be used. When the base is a salt, the cation can be any convenient and pharmaceutically acceptable cation, such as ammonium, alkali metals, alkaline earth metals, and the like. Examples can include, without limitation, sodium, potassium, lithium, magnesium, calcium and ammonium.
[0107] In some embodiments, suitable acids are pharmaceutically acceptable organic or inorganic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, and the like. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosuifonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluene sulfonic acid, uric acid and the like.
Parenteral delivery
[0108] In some embodiments, a PI3K inhibitor of the present disclosure is formulated for parenteral delivery, e.g ., intravenous delivery. An intravenous drug delivery formulation of the present disclosure may be contained in a bag, a pen, or a syringe. In certain embodiments, the bag may be connected to a channel comprising a tube and/or a needle. In certain embodiments, the formulation may be a lyophilized formulation or a liquid formulation. In certain embodiments, the formulation may freeze-dried (lyophilized) and contained in about 12-60 vials. In certain embodiments, the formulation may be freeze-dried and 45 mg of the freeze-dried formulation may be contained in one vial. In certain embodiments, the about 40 mg - about 100 mg of freeze-dried formulation may be contained in one vial. In certain embodiments, a freeze-dried formulation from vials, e.g. , 12, 27, or 45 vials, are combined to obtain a therapeutic dose of the PI3K inhibitor in the intravenous drug formulation. In certain embodiments, the formulation may be a liquid formulation and stored as about 250 mg/vial to about 1000 mg/vial. In certain embodiments, the formulation may be a liquid formulation and stored as about 600 mg/vial. In certain embodiments, the formulation may be a liquid formulation and stored as about 250 mg/vial. The PI3K inhibitor could exist in a liquid aqueous pharmaceutical formulation including a therapeutically effective amount of the PI3K inhibitor in a buffered solution forming a formulation.
[0109] These compositions may be sterilized by conventional sterilization techniques, or may be sterile filtered. The resulting aqueous solutions may be packaged for use as-is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The pH of the preparations typically will be between 3 and 11, more preferably between 5 and 9 or between 6 and 8, and most preferably between 7 and 8, such as 7 to 7.5. The resulting compositions in solid form may be packaged in multiple single dose units, each containing a fixed amount of the above-mentioned agent or agents. The composition in solid form can also be packaged in a container for a flexible quantity.
[0110] In certain embodiments, the present disclosure provides a formulation with an extended shelf life including a PI3K inhibitor of the present disclosure, in combination with one or more of mannitol, citric acid monohydrate, sodium citrate, disodium phosphate dihydrate, sodium dihydrogen phosphate dihydrate, sodium chloride, polysorbate 80, water, and sodium hydroxide. [0111] In certain embodiments, an aqueous formulation is prepared including the PI3K inhibitor of the present disclosure in a pH-buffered solution. The buffer may have a pH ranging from about 4 to about 8, e.g ., from about 4.5 to about 6.0, or from about 4.8 to about 5.5, or may have a pH of about 5.0 to about 5.2. Ranges intermediate to the above recited pH's are also intended to be part of this disclosure. For example, ranges of values using a combination of any of the above recited values as upper and/or lower limits are intended to be included. Examples of buffers that will control the pH within this range include acetate (e.g, sodium acetate), succinate (such as sodium succinate), gluconate, histidine, citrate and other organic acid buffers.
[0112] In certain embodiments, the formulation includes a buffer system which contains citrate and phosphate to maintain the pH in a range of about 4 to about 8. In certain embodiments the pH range may be from about 4.5 to about 6.0, or from about pH 4.8 to about 5.5, or in a pH range of about 5.0 to about 5.2. In certain embodiments, the buffer system includes citric acid monohydrate, sodium citrate, disodium phosphate dihydrate, and/or sodium dihydrogen phosphate dihydrate. In certain embodiments, the buffer system includes about 1.3 mg/mL of citric acid (e.g, 1.305 mg/mL), about 0.3 mg/mL of sodium citrate (e.g, 0.305 mg/mL), about 1.5 mg/mL of disodium phosphate dihydrate (e.g, 1.53 mg/mL), about 0.9 mg/mL of sodium dihydrogen phosphate dihydrate (e.g, 0.86 mg/mL), and about 6.2 mg/mL of sodium chloride (e.g, 6.165 mg/mL). In certain embodiments, the buffer system includes about 1 to about 1.5 mg/mL of citric acid, about 0.25 to about 0.5 mg/mL of sodium citrate, about 1.25 to about 1.75 mg/mL of disodium phosphate dihydrate, about 0.7 to about 1.1 mg/mL of sodium dihydrogen phosphate dihydrate, and about 6.0 to about 6.4 mg/mL of sodium chloride. In certain embodiments, the pH of the formulation is adjusted with sodium hydroxide.
[0113] A polyol, which acts as a tonicifier, may also be included in the formulation. The polyol is added to the formulation in an amount which may vary with respect to the desired isotonicity of the formulation. In certain embodiments, the aqueous formulation may be isotonic. The amount of polyol added may also be altered with respect to the molecular weight of the polyol. For example, a lower amount of a monosaccharide (e.g, mannitol) may be added, compared to a disaccharide (such as trehalose). In certain embodiments, the polyol which may be used in the formulation as a tonicity agent is mannitol. In certain embodiments, the mannitol concentration may be about 5 to about 20 mg/mL. In certain embodiments, the concentration of mannitol may be about 7.5 to about 15 mg/mL. In certain embodiments, the concentration of mannitol may be about 10 to about 14 mg/mL. In certain embodiments, the concentration of mannitol may be about 12 mg/mL. In certain embodiments, the polyol sorbitol may be included in the formulation.
[0114] A detergent or surfactant may also be added to the formulation. Exemplary detergents include nonionic detergents such as polysorbates ( e.g ., polysorbates 20, 80 etc.) or poloxamers (e.g., poloxamer 188). The amount of detergent added can minimize the formation of particulates in the formulation and/or reduce adsorption. In certain embodiments, the formulation may include a surfactant which is a polysorbate. In certain embodiments, the formulation may contain the detergent polysorbate 80 or Tween 80.
Tween 80 is a term used to describe polyoxyethylene (20) sorbitanmonooleate (see Fiedler, Lexikon der Hifsstoffe, Editio Cantor Verlag Aulendorf, 4th ed., 1996). In certain embodiments, the formulation may contain between about 0.1 mg/mL and about 10 mg/mL of polysorbate 80, or between about 0.5 mg/mL and about 5 mg/mL. In certain embodiments, about 0.1% polysorbate 80 may be added in the formulation.
[0115] In embodiments, a composition described herein is formulated as a liquid formulation. The liquid formulation may be presented at a 10 mg/mL concentration in either a USP / Ph Eur type I 50R vial closed with a rubber stopper and sealed with an aluminum crimp seal closure. The stopper may be made of elastomer complying with USP and Ph Eur. In certain embodiments, the liquid formulation may be diluted with 0.9% saline solution.
In certain embodiments, a composition described herein may be prepared as a 10 mg/mL concentration solution in combination with a sugar at stabilizing levels. In certain embodiments the liquid formulation may be prepared in an aqueous carrier. In certain embodiments, a stabilizer may be added in an amount no greater than that which may result in a viscosity undesirable or unsuitable for intravenous administration. In certain embodiments, the sugar may be di saccharides, e.g, sucrose. In certain embodiments, the liquid formulation may also include one or more of a buffering agent, a surfactant, and a preservative.
[0116] In certain embodiments, the pH of the liquid formulation may be set by addition of a pharmaceutically acceptable acid and/or base. In certain embodiments, the pharmaceutically acceptable acid may be hydrochloric acid. In certain embodiments, the base may be sodium hydroxide.
[0117] Compositions described herein can include an aqueous carrier. Aqueous carriers of interest herein are pharmaceutically acceptable (safe and non-toxic for administration to a human) and are useful for the preparation of a liquid formulation. Illustrative carriers include sterile water for injection (SWFI), bacteriostatic water for injection (BWFI), a pH buffered solution ( e.g ., phosphate-buffered saline), sterile saline solution, Ringer's solution, and dextrose solution.
[0118] A preservative may be optionally added to the formulations described herein to reduce bacterial action. The addition of a preservative may, for example, facilitate the production of a multi-use (multiple-dose) formulation.
[0119] Intravenous (IV) formulations may be the preferred administration route in particular instances, such as when a patient is in the hospital receiving all drugs via the IV route. In certain embodiments, the liquid formulation is diluted with 0.9% Sodium Chloride solution before administration. In certain embodiments, the diluted drug product for injection is isotonic and suitable for administration by intravenous infusion.
[0120] In certain embodiments, a salt or buffer component may be added in an amount of 10 mM - 200 mM. The salts and/or buffers are pharmaceutically acceptable and are derived from various known acids (inorganic and organic) with “base forming” metals or amines. In certain embodiments, the buffer may be phosphate buffer. In certain embodiments, the buffer may be glycinate, carbonate, or citrate buffers, in which case, sodium, potassium or ammonium ions can serve as counterion.
[0121] In certain embodiments, the lyophilized drug product may be constituted with an aqueous carrier. The aqueous carrier of interest herein is one which is pharmaceutically acceptable (safe and non-toxic for administration to a human) and is useful for the preparation of a liquid formulation. Illustrative carriers include sterile water for injection (SWFI), bacteriostatic water for injection (BWFI), a pH buffered solution (e.g., phosphate- buffered saline), sterile saline solution, Ringer's solution, and dextrose solution.
[0122] PI3K inhibitors of the present disclosure can exist in a lyophilized formulation including the PI3K inhibitor and a lyoprotectant. The lyoprotectant may be sugar, e.g, di saccharides. In certain embodiments, the lyoprotectant may be sucrose or maltose. The lyophilized formulation may also include one or more of a buffering agent, a surfactant, a bulking agent, and/or a preservative. The amount of sucrose or maltose useful for stabilization of the lyophilized drug product may be in a weight ratio of at least 1 :2 PI3K inhibitor to sucrose or maltose. In certain embodiments, the PI3K inhibitor to sucrose or maltose weight ratio may be of from 1 :2 to 1:5.
[0123] In certain embodiments, the pH of the formulation, prior to lyophilization, may be set by addition of a pharmaceutically acceptable acid and/or base. In certain embodiments the pharmaceutically acceptable acid may be hydrochloric acid. In certain embodiments, the pharmaceutically acceptable base may be sodium hydroxide. Before lyophilization, the pH of the solution containing the PI3K inhibitor of the present disclosure may be adjusted between 6 to 8. In certain embodiments, the pH range for the lyophilized drug product may be from 7 to 8.
[0124] In certain embodiments, a “bulking agent” may be added. A “bulking agent” is a compound which adds mass to a lyophilized mixture and contributes to the physical structure of the lyophilized cake ( e.g ., facilitates the production of an essentially uniform lyophilized cake which maintains an open pore structure). Illustrative bulking agents include mannitol, glycine, polyethylene glycol and sorbitol. Lyophilized formulations of the present invention may contain such bulking agents.
[0125] In certain embodiments, a lyophilized drug product described herein is reconstituted with either Sterile Water for Injection, USP (SWFI) or 0.9% Sodium Chloride Injection, USP. During reconstitution, the lyophilized powder dissolves into a solution.
In certain embodiments, a lyophilized composition described herein is constituted to about 4.5 mL water for injection and diluted with 0.9% saline solution (sodium chloride solution). [0126] In some embodiments, a PI3K inhibitor of the present disclosure is administered topically and can be formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams, and ointments. Such pharmaceutical compositions can contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
[0127] In some embodiments, delivery of a PI3K inhibitor as disclosed herein is via an inhalation route. Inhalation may be mediated through an oral and/or nasal cavity. In some embodiments, inhalation is with the aid of a nebulizer or an inhaler (e.g., a metered dose inhaler or a dry powder inhaler). In certain embodiments, delivery is through inhalation of a liquid mist. In certain embodiments, delivery is through inhalation of a solid. In certain embodiments, the solid is nanosized and formulated in combination with nanoparticles, nanodiamonds, or nanocarbons, or packaged in liposomes or liposome-based packages.
Kits
[0128] Also provided herein are kits comprising a PI3K inhibitor. The kits may be used for the treatment, prevention, and/or diagnosis of a disease or disorder, such as a cytokine release syndrome, as described herein.
[0129] In some embodiments, the kit comprises a container and a label or package insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, and IV solution bags. The containers may be formed from a variety of materials, such as glass or plastic. The container holds a composition that is by itself, or when combined with another composition, effective for treating, preventing and/or diagnosing a disease or disorder. The container may have a sterile access port. For example, if the container is an intravenous solution bag or a vial, it may have a port that can be pierced by a needle. At least one active agent in the composition is a PI3K inhibitor provided herein. The label or package insert indicates that the composition is used for treating the selected condition.
[0130] In some embodiments, the kit comprises (a) a first container with a first composition contained therein, wherein the first composition comprises a PI3K inhibitor provided herein; and (b) a second container with a second composition contained therein, wherein the second composition comprises a further therapeutic agent. In some embodiments, the further therapeutic agent is an immunosuppressive therapeutic agent, e.g ., a cytokine inhibitor. In some embodiments, the further therapeutic agent is an IL-6 antagonist, an IL-1 antagonist, a soluble tumor necrosis factor receptor, an IL-1 receptor agonist, and a TGF-bI latency-associated peptide, e.g. , tocilizumab, sarilumab, or siltuximab.
[0131] In some embodiments, the further therapeutic agent is an antiviral therapeutic agent. The kit in said embodiments can further comprise a package insert indicating that the compositions can be used to treat a particular condition, e.g, a viral infection, e.g. , COVID- 19.
[0132] Alternatively, or additionally, the kit may further comprise a second (or third) container comprising a pharmaceutically acceptable excipient. In some embodiments, the kit comprises a first container comprising a PI3K inhibitor described herein and a pharmaceutically acceptable excipient. In some aspects, the excipient is a buffer. The kit may further include other materials desirable from a commercial and user standpoint, including, without limitation, filters, needles, and syringes.
V. DEFINITIONS
[0133] The terms “a” and “an” as used herein mean “one or more” and include the plural unless the context is inappropriate. The term "about" when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of +20% or in some instances +10%, or in some instances +5%, or in some instances +1%, or in some instances +0.1% from the specified value, as such variations are appropriate to perform the disclosed methods. [0134] As used herein, “PI3K” refers to phosphoinositide 3-kinase, also called phosphatidylinositol 3-kinases in the art. The class 1 isoforms are RI3Ka, RI3Kb, PI3K5, and RI3Kg. As used herein, PI3Ka and PBKalpha are used interchangably, RI3Kb and PBKbeta are used interachangably, PI3K5 and PBKdelta are used interchangably, and RI3Kg and PBKgamma are used interchangably.
[0135] A “dual RI3Kd/g inhibitor”, as used herein, refers to a PI3K inhibitor that can reach the IC50 from whole blood assays for both PBK-delta and PBK-gamma at clinically achievable plasma exposures.
[0136] As used herein, “cytokine release syndrome” refers to an acute overreaction of the immune system also known in the art as a “cytokine storm” or “cytokine storm syndrome”; such an immune response is a systemic inflammatory response syndrome that can result from an infectious disease or disorder. Cytokine release syndrome pathology is associated with inflammation that begins at a local site and spreads throughout the body, for example, via systemic circulation. Cytokine release syndrome pathology resulting from viral infection is associated with acute lung injury and acute respiratory distress syndrome. Cytokine release syndrome pathology is described, for example, in Tisonick et al ., (2012) “Into the Eye of the Cytokine Storm,” Microbiol. Mol. Biol. Rev., 76(1): 16-32.
[0137] As used herein, a "pharmaceutically acceptable form" of a disclosed compound includes, but is not limited to, pharmaceutically acceptable salts, hydrates, solvates, isomers, prodrugs, and isotopicaily labeled derivatives of disclosed compounds. In some embodiments, a "pharmaceutically acceptable form" includes, but is not limited to, pharmaceutically acceptable salts, isomers, prodrugs and isotopicaily labeled derivatives of disclosed compounds.
[0138] In some embodiments, the pharmaceutically acceptable form is a pharmaceutically acceptable salt. As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of subjects without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describes pharmaceutically acceptable salts in detail in j Pharmaceutical Sciences (1977) 66: 1-19. Pharmaceutically acceptable salts of the compounds provided herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesuifonate, besylate, benzoate, hi sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cydopentanepropionate, digluconate, dodecyl sulfate, ethane sulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemi sulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethane sulfonate, iactobionate, lactate, laurate, lauryl sulfate, malate, maieate, malonate, methanesulfonate, 2-naphthalene sulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3- phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluene sulfonate, undecanoate, valerate salts, and the like. In some embodiments, organic acids from which salts may be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-to!uenesulfonic acid, salicylic acid, and the like.
[0139] Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate. Organic bases from which salts may be derived include, for example, primary, secondary, and tertiary' amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, such as isopropyl amine, trimethylamine, drethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.
[0140] In some embodiments, the pharmaceutically acceptable form is a solvate (e.g, a hydrate). As used herein, the term "solvate" refers to compounds that further include a stoichiometric or non-stoichrometric amount of solvent bound by non-covalent intermolecular forces. The solvate may be of a disclosed compound or a pharmaceutically acceptable salt thereof. Where the solvent is water, the solvate is a "hydrate". Pharmaceutically acceptable solvates and hydrates are complexes that, for example, can include 1 to about 100, or 1 to about 10, or one to about 2, about 3 or about 4, solvent or water molecules. It will be understood that the term "compound" as used herein encompasses the compound and solvates of the compound, as well as mixtures thereof.
[0141] In some embodiments, the pharmaceutically acceptable form is a prodrug. As used herein, the term "prodrug" refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable form of the compound. A prodrug may be inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis (e.g., hydrolysis in blood). In certain cases, a prodrug has improved physical and/or delivery properties over the parent compound. Prodrugs are typically designed to enhance pharmaceutically and/or pharmacokineticaliy based properties associated with the parent compound. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design, of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam). A discussion of prodrugs is provided in Higuchi, T., et al, "Pro-drugs as Novel Delivery Systems," A.C. S. Symposium Series, Vol. 14, Chp 1, pp 1-12 and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated in full by reference herein. Exemplary advantages of a prodrug can include, but are not limited to, its physical properties, such as enhanced water solubility for parenteral administration at physiological pH compared to the parent compound, or it enhances absorption from the digestive tract, or it can enhance drug stability for long-term storage.
[0142] The term "prodrug" is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a subject. Prodrugs of an active compound, as described herein, may be prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound. Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of an alcohol or acetamide, formamide and benzamide derivatives of an amine functional group in the active compound and the like. Other examples of prodrugs include compounds that comprise -NO, -NO2, - QNQ, or -ONO2 moieties. Prodrugs can typically be prepared using well-known methods, such as those described in Burger 's Medicinal Chemistry and Drug Discovery, 172-178, 949- 82 (Manfred E. Wolff ed., 5 th ed., 1995), and Design of Prodrugs (H. Bundgard ed., Elsevier, New York, 1985).
[0143] For example, if a disclosed compound or a pharmaceutically acceptable form of the compound contains a carboxylic acid functional group, a prodrug can comprise a pharmaceutically acceptable ester formed by the replacement, of the hydrogen atom of the acid group with a group such as (C1-C8)alkyi, (C2-C12)alkanoyloxymethyl, 1- (alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1 -m ethyl -1 ~(alkanoyloxy )-ethyl having from 5 to 10 carbon atoms, alkoxy carbonyloxymethyl having from 3 to 6 carbon atoms, 1- (aikoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1 -methyl- 1- (alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyi)aminomethyl having from 3 to 9 carbon atoms, l-(N-(a!koxycarbonyi)amino)ethyl having from 4 to 10 carbon atoms, 3-phthaiidyl, 4-crotonolactonyl, gamma-butyrolacton-4-y 1 , di-N,N-(C1- C2)alkylamino(C2-C3)aikyi (such as β-dimethyiaminoethyl), carbarnoyl-(C1-C2)aikyl, N,N- di(C1-C2)alkylcarbamoyl-(C1-C2)alkyl and piperidino- pyrrolidino- or morpholino (C2-C3)alkyl.
[0144] Similarly, if a disclosed compound or a pharmaceutically acceptable form of the compound contains an alcohol functional group, a prodrug may be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (C1-C6)alkanoyloxymethyl, 1- ((C1-C6)alkanoyloxy)ethy 1 , l-methyl -1 -(( C1-C6)alkanoyloxy)ethyl ((C1 - C6)alkoxycarbonyioxymethyl, N-(C1-C6)alkoxycarbonylaminomethyl, succinoyl, (C1- C6)alkanoyl, a-amino(C1-C4)alkanoyl, arylacyl and a-a minoacyl, or a-aminoacyl -a- aminoacyl, where each a-aminoacyl group is independently selected from naturally occurring 1. -ami no acids, P( O)(( O H)2, -P(O)(O(C1-C6)aikyl)2., and glycosyl (the radical resulting from the removal of a hydroxyl group of the hemi acetal form of a carbohydrate).
[0145] If a disclosed compound or a pharmaceutically acceptable form of the compound incorporates an amine functional group, a prodrug may be formed by the replacement of a hydrogen atom in the amine group with a group such as R-carbonyl, RO-carbonyl, NRR'- carbonyl where R and R' are each independently (C1-C10)alkyl,(C3-C5)cycloalkyl, benzyl, a natural a-aminoacyl or natural a-aminoacyl-natural a-aminoacyl, -C(OH)C(O)OY1 wherein Y1 is H, (Ci-C6)alkyl or benzyl, -C(OY2)Y3 wherein Y2 is (C1-C4) alkyl and Y3 is (C1.- C6)alkyl, carboxy(C1-C6)alkyl, amino(C1-C4)alkyl or mono-N-or di-N,N-(C1- C6)aikylaminoalkyl, ~C(Y4)Y5 wherein Y4 is H or methyl and Y5 is mono-N- or di-N,N~(C1~ C6)alkylamino, morpholino, piperidin-l-yl or pyrrolidin-l-yl. [0146] In some embodiments, the pharmaceutically acceptable form is an isomer. “Isomers" are different compounds that have the same molecular formula. "Stereoisomers" are isomers that differ only in the way the atoms are arranged in space. As used herein, the term "isomer" includes any and all geometric isomers and stereoisomers. For example, "isomers" include geometric double bond cis- and tram- isomers, also termed E- and Z- i somers; R- and 5-enantiomers; diastereomers, (d)-isomers and (/)-isomers, racemic mixtures thereof; and other mixtures thereof, as falling within the scope of this disclosure.
[0147] "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1: 1 mixture of a pair of enantiomers is a "racemic" mixture. The term "(±)" is used to designate a racemic mixture where appropriate. "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. The absolute stereochemistry'’ is specified according to the Cahn-ingold-Prelog R~ S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S. Resolved compounds whose absolute configuration is unknown may be designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line. Certain of the compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry', as (R)- or (S)-. The present chemical entities, pharmaceutical compositions and methods are meant to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures. Optically active (R)- and (S)- i somers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry', and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.
[0148] "Enantiomeric purity" as used herein refers to the relative amounts, expressed as a percentage, of the presence of a specific enantiomer relative to the other enantiomer. For example, if a compound, winch can potentially have an (R)- or an (S)- isomeric configuration, is present as a racemic mixture, the enantiomeric purity is about 50% with respect to either the (R)- or (S)- isomer, if that compound has one isomeric form predominant over the other, for example, 80% (S)- and 20% (R)-, the enantiomeric purity of the compound with respect to the (S)-isomeric form is 80%, The enantiomeric purity of a compound may be determined in a number of ways known in the art, including but not limited to chromatography using a chiral support, polarimetric measurement of the rotation of polarized light, nuclear magnetic resonance spectroscopy using chiral shift reagents which include but are not limited to lanthanide containing chiral complexes or the Pirkie alcohol, or derivatization of a compounds using a chiral compound such as Mosher's acid followed by chromatography or nuclear magnetic resonance spectroscopy.
[0149] In some embodiments, the pharmaceutically acceptable form is a tautomer. As used herein, the term "tautomer" is a type of isomer that includes two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a double bond, or a triple bond to a single bond, or vice versa). "Tautomerization" includes prototropic or proton-shift tautomerization, which is considered a subset of acid-base chemistry. "Prototropic tautomerization" or "proton-shift tautomerization" involves the migration of a proton accompanied by changes in bond order. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Where tautomerization is possible (e.g., in solution), a chemical equilibrium of tautomers may be reached. Tautomerizations (i.e., the reaction providing a tautomeric pair) may be catalyzed by acid or base, or can occur without the action or presence of an external agent. Exemplary' tautomerizations include, but are not limited to, keto-enol; amide-imide; lactam-lactim; enamine-imine; and enamine-(a different) enamine tautomerizations. A specific example of keto-enol tautomerization is the interconversion of pentane-2, 4-di one and 4-hydroxypent-3- en-2-one tautomers. Another example of tautomerization is phenol-keto tautomerization. A specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4(lH)-one tautomers.
[0150] "Pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions as disclosed herein is contemplated. Supplementary active ingredients can also be incorporated into the pharmaceutical compositions.
[0151] As used herein, the term “disease or disorder” means any pathological condition, including but not limited to a cytokine release syndrome, e.g, a cytokine release syndrome caused by a pathogen. In some embodiments, the disease or disorder is a cytokine release syndrome caused by a virus, e.g. , a coronavirus, e.g., SARS-CoV2. In particular embodiments, a disease or disorder associated with a specific pathogen or type of pathogen is a disease or disorder caused by the specific pathogen or type of pathogen. For example, a virus disease or disorder can be associated with a specific virus, for example, SARS-CoV2, or a specific group of viruses, for example, a specific genus of viruses, for example, coronaviruses. Similarly, a bacterial disease or disorder can be associated with a specific bacteria or a specific group of bacteria; a fungal disease or disorder can be associated with a specific fungus or a specific group of fungus; and an amoeba disease or disorder can be associated with a specific amoeba or a specific group of amoeba. In some embodiments, the disease or disorder is an acute respiratory distress syndrome characterized by cytokine release syndrome, e.g. an acute respiratory distress syndrome associated with a pathogen, e.g, an acute respiratory distress syndrome not associated with a pathogen.
[0152] As used herein, the term “infection” means the invasion and proliferation of pathogens, e.g, viruses, that are not normally present within the host, e.g, a patient. An infection may cause no symptoms and be subclinical, or it may cause symptoms and be clinically apparent. An infection may remain localized, or it may spread, for example, through the blood or lymphatic vessels, to become systemic.
[0153] As used herein, the term “prophylactic” refers to a medication or a treatment designed and used to prevent a disease or disorder from occurring. As used herein, the terms “prophylactic” and “prevention” are used interchangeably.
[0154] As used herein, the term "treat", "treatment", "treating" and the like are used herein to generally mean obtaining a desired pharmacological and/or physiological effect.
The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or may be therapeutic in terms of partially or completely curing a disease and/or adverse effect attributed to the disease. The term "treatment" as used herein covers any treatment of a disease in a mammal, particularly a human, and includes: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e. preventing the disease from increasing in severity or scope; (c) relieving the disease, i.e. causing partial or complete amelioration of the disease; or (d) preventing relapse of the disease, i.e. preventing the disease from returning to an active state following previous successful treatment of symptoms of the disease or treatment of the disease.
[0155] “Individual,” “patient,” or “subject” are used interchangeably herein, and include any animal, e.g. mammals, e.g. mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans. The PI3K inhibitor compounds and compositions thereof disclosed herein can be administered to a mammal, such as a human. The PI3K inhibitor compounds disclosed herein can be administered to other mammals, such as an animal in need of veterinary treatment, e.g., domestic animals (e.g, dogs, cats, and the like), farm animals (e.g, cows, sheep, pigs, horses, and the like) and laboratory animals (e.g, rats, mice, guinea pigs, and the like). A patient may be an individual diagnosed with a high risk of developing a disease or disorder, for example, an infectious disease or disorder (e.g, an immunocompromised individual, a healthcare professional), someone who has been diagnosed with a disease or disorder, for example, an infectious disease or disorder, someone who previously suffered from a disease or disorder, for example, an infectious disease or disorder, or an individual evaluated for symptoms or indications of a disease or disorder, for example, an infectious disease or disorder.
[0156] The term “patient in need,” as used herein, refers to a patient suffering from any of the symptoms or manifestations of a disease or disorder, for example, an infectious disease or disorder, a patient who may suffer from any of the symptoms or manifestations of a disease or disorder, for example, an infectious disease or disorder, or any patient who might benefit from a method of the disclosure for treating or preventing a disease or disorder, for example, an infectious disease or disorder. A patient in need may include a patient who is diagnosed with a risk of developing a disease or disorder (for example, an infectious disease or disorder), a patient who has suffered from a disease or disorder (for example, an infectious disease or disorder) in the past, or a patient who has previously been treated for a disease or disorder (for example, an infectious disease or disorder).
[0157] As used herein, the term “pharmaceutically acceptable composition” means a composition comprising at least one compound, e.g, a PI3K inhibitor disclosed herein, formulated together with one or more pharmaceutically acceptable carriers.
[0158] As used herein, the term “therapeutically effective amount” , “effective amount”, or a “pharmaceutically effective amount,” as used herein, refers to the amount of an agent, for example, a PI3K inhibitor described herein, that is sufficient to at least partially treat a condition when administered to a patient. The therapeutically effective amount will vary depending on the severity of the condition, the route of administration of the component, and the age, weight, etc. of the patient being treated. Accordingly, an effective amount of a disclosed a PI3K inhibitor is the amount of the a PI3K inhibitor necessary to treat a disease or disorder, for example, an infectious disease or disorder in a patient such that administration of the agent prevents the disease or disorder from occurring in a subject, prevents the disease or disorder progression, or relieves or completely ameliorates some or all associated symptoms of the disease or disorder, e.g, causes clearance of the infection. [0159] As used herein, the term “administering” refers to administration by any suitable route, for example, oral administration, administration as a suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intracranial, intranasal, or subcutaneous administration, or the implantation of a slow-release device, e.g ., a mini -osmotic pump, to a subject. Administration is by any route, including parenteral and transmucosal (e.g, buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, without limitation, intravenous, intramuscular, intra-arterial, intradermal, subcutaneous, intraperitoneal, intraventricular, intrathecal, and intracranial delivery. In some embodiments, parenteral administration is intravenous. In some embodiments, parenteral administration is subcutaneous. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc.
[0160] By "co-administer" it is meant that a compound or composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies (e.g, an antiviral agent). The compounds or compositions described herein can be administered alone or can be co-administered to the patient. Co-administration is meant to include simultaneous or sequential administration of the compound or composition individually or in combination (more than one compound or agent). Thus, the preparations can also be combined, when desired, with other active substances (e.g. to reduce metabolic degradation or to provide an additional therapeutic for disease prevention or treatment).
[0161] The description above describes multiple aspects and embodiments of the invention. The patent application specifically contemplates all combinations and permutations of the aspects and embodiments.
EXAMPLES
[0162] The invention now being generally described, will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and is not intended to limit the invention.
Example 1 - Treatment of Heme Malignancies with duvelisib modulates cytokine levels [0163] PI3K inhibitor duvelisib or CD-20 targeting antibody Ofatumumab were administered to patients with chronic lymphocytic leukemia/ small lymphocytic leukemia (CLL/SLL) in the DUO clinical trial. Duvelisib was administered to orally at 25 mg, twice daily (BID), to 160 patients. Ofatumumab was administered intravenously to 159 patients according to the following dosage schedule: 300 mg on Day 1, 2000 mg weekly for 7-weeks, then 2000 mg monthly for four months. Serum samples were taken at Day 0 (as baseline) and Cycle 2, Day 1, of 28-day cycles. Cytokine and chemokine levels were assessed using the Luminex multiplex immunoassay platform (Invitrogen) and quantified using the Luminex MAGPIX Instrument System (Invitrogen) according to the manufacturer’s instructions.
[0164] 25 mg duvelisib twice daily (BID) was administered to 129 patients with indolent
Non-Hodgkins lymphoma (iNHL) in the DYNAMO clinical trial. Serum samples were taken at Cycle 1, Day 15 and Cycle 2, Day 1, of 28-day cycles. Cytokine and chemokine levels were assessed using the Luminex multiplex immunoassay platform (Invitrogen) and quantified using the Luminex MAGPIX Instrument System (Invitrogen) according to the manufacturer’s instructions.
[0165] As shown in FIG. 1A, the CLL-treatment group displayed significant changes in a number of cytokine levels following duvelisib treatment. Surprisngly, CCL3, CCL4, CCL17, IL12, IL10, TNF-a, CCL19, and CXCL13 all demonstrated particularly significant reduction upon treatment. Similarly, as shown in FIG. IB, the iNHL-treatment group displayed significant changes in a number of cytokine levels following duvelisib treatment, with CCL3, CCL4, CCL17, IL12, ILIO, TNF-a, CCL19, and CXCL13 showing significant reduction. These data demonstrate that treatment with a PI3K inhibitor, such as duvelisib, can modulate cytokine levels.
INCORPORATION BY REFERENCE
[0166] Unless stated to the contrary, the entire disclosure of each of the patent documents and scientific articles referred to herein is incorporated by reference for all purposes.
EQUIVALENTS
[0167] The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting the invention described herein.
Scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims

WHAT IS CLAIMED IS:
1. A method of treating cytokine release syndrome induced by an infection, wherein the method comprises administering to a patient in need thereof a therapeutically effective amount of a composition comprising a PI3K inhibitor.
2. The method of claim 1, wherein the PI3K inhibitor is a PI3Kδ inhibitor, a RI3Kg inhibitor, or a dual RI3Kd/g inhibitor.
3. The method of claim 1 or 2, wherein the PI3K inhibitor is selected from the group consisting of duvelisib, tenalisib, idelalisib, copanlisib, IPI-549, CAL-130, BKM 120, GDC-0941, PX-866, GDC-0032, BAY 80-6946, BEZ235, BYL719, BGT-226, GDC- 0980, GSK 2126458, PF-05212384, XL765, AS604850, AS252424, or XL 147, or a combination thereof.
4. The method of any one of claims 1-3, wherein the PI3K inhibitor is duvelisib.
5. The method of any one of claims 1-3, wherein the PI3K inhibitor is IPI-549.
6. The method of any one of claims 1-3, wherein the PI3K inhibitor is idelalisib.
7. The method of any one of claims 1-6, wherein the PI3K inhibitor is administered to a patient prophylactically.
8. The method of claim 7, wherein the patient displays elevated ferritin levels, decreased platelet count, elevated erythrocyte sedimentation rate, and/or has an H-Score indicative of hyperinfl animation.
9. The method of any one of claims 1-6, wherein the PI3K inhibitor is administered to a patient with symptoms.
10. The method of claim 9, wherein the symptoms comprise acute respiratory distress.
11. The method of any one of claims 1-10, wherein the infection is a viral infection.
12. The method of any one of claims 1-11, wherein the infection is associated with a virus selected from the group consisting of a coronavirus, a papillomavirus, a pneumovirus, a picomavirus, an influenza virus, an adenovirus, a cytomegalovirus, a polyomavirus, a poxvirus, a flavivirus, an alphavirus, an ebolavirus, a herpesvirus, a morbillivirus, an enterovirus, an orthopneumovirus, a lentivirus, and a hepatovirus.
13. The method of any one of claims 1-12, wherein the infection is associated with an influenza virus.
14. The method of any one of claims 1-12, wherein the infection is associated with an ebolavirus.
15. The method of any one of claims 1-12, wherein the infection is associated with a coronavirus.
16. The method of claim 15, wherein the coronavirus is selected from the group consisting of: 229E alpha coronavirus, NL63 alpha coronavirus, OC43 beta coronavirus, HKU1 beta coronavirus, Middle East Respiratory Syndrome coronavirus (MERS-CoV), severe acute respiratory syndrome coronavirus (SARS-CoV), and SARS-CoV2 (COVID- 19).
17. The method of claim 16, wherein the coronavirus is SARS-CoV2.
18. The method of claim 16, wherein the coronavirus is SARS-CoV.
19. The method of any one of claims 1-18, further comprising administering a composition comprising an antiviral agent.
20. The method of claim 19, wherein the antiviral agent is selected from the group consisting of abacavir, acyclovir, adefovir, amantadine, amprenavir, atazanavir, cidofovir, danoprevir, darunavir, delavirdine, didanosine, docosanol, double-stranded RNA activated caspase oligomerizer (DRACO), efavirenz, elvitegravir, emtricitabine, enfuvirtide, entecavir, etravirine, famciclovir, foscamet, fomivirsen, ganciclovir, ibacitabine, indinavir, interferon-a inhibitor, idoxuridine, lamivudine, lopinavir, maraviroc, MK-2048, nelfmavir, nevirapine, oseltamivir, penciclovir, peramivir, pleconaril, raltegravir, remdesivir, rilpivirine, rifampin, rimantidine, ritonavir, saquinavir, stavudine, tenofovir trifluridine, valaciclovir, valganciclovir, vidarabine, tipranavir, zalcitabine, zanamivir, and zidovudine.
21. A method of treating an acute respiratory distress syndrome, wherein the method comprises administering to a patient in need thereof a therapeutically effective amount of a composition comprising a PI3K inhibitor.
22. The method of claim 21, wherein the PI3K inhibitor is a PI3K6 inhibitor, a RI3Kg inhibitor, or a dual RI3Kd/g inhibitor.
23. The method of claim 21 or 22, wherein the PI3K inhibitor is selected from the group consisting of duvelisib, tenalisib, idelalisib, copanlisib, IPI-549, CAL-130, BKM 120, GDC-0941, PX-866, GDC-0032, BAY 80-6946, BEZ235, BYL719, BGT-226, GDC- 0980, GSK 2126458, PF-05212384, XL765, AS604850, AS252424, or XL 147, or a combination thereof.
24. The method of any one of claims 21-23, wherein the PI3K inhibitor is duvelisib.
25. The method of any one of claims 21-23, wherein the PI3K inhibitor is IPI-549.
26. The method of any one of claims 21-23, wherein the PI3K inhibitor is idelalisib.
27. The method of any one of claims 21-26, wherein the acute respiratory distress syndrome is associated with a disease or disorder selected from the group consisting of an infectious disease or disorder, graft-versus-host disease, organ trauma, tissue trauma, pancreatitis, haemophagocytic lymphohistiocytosis, sepsis, and systemic inflammatory response syndrome.
28. The method of claim 27, wherein the infectious disease or disorder is associated with a viral infection or a bacterial infection.
29. The method of claim 28, wherein the viral infection is associated with a virus selected from the group consisting of a coronavirus, a papillomavirus, a pneumovirus, a picomavirus, an influenza virus, an adenovirus, a cytomegalovirus, a polyomavirus, a poxvirus, a flavivirus, an alphavirus, an ebolavirus, a herpesvirus, a morbillivirus, an enterovirus, an orthopneumovirus, a lentivirus, and a hepatovirus.
30. The method of claim 28 or 29, wherein the viral infection is associated with an influenza virus.
31. The method of claim 28 or 29, wherein the viral infection is associated with an ebolavirus.
32. The method of claim 28 or 29, wherein the viral infection is associated with a coronavirus.
33. The method of claim 32, wherein the coronavirus is selected from the group consisting of: 229E alpha coronavirus, NL63 alpha coronavirus, OC43 beta coronavirus, HKU1 beta coronavirus, Middle East Respiratory Syndrome coronavirus (MERS-CoV), severe acute respiratory syndrome coronavirus (SARS-CoV), and SARS-CoV2 (COVID- 19).
34. The method of claim 32 or 33, wherein the coronavirus is SARS-CoV2.
35. The method of claim 32 or 33, wherein the coronavirus is SARS-CoV.
36. The method of any one of claims 27-35, further comprising administering a composition comprising an antiviral agent.
37. The method of claim 36, wherein the antiviral agent is selected from the group consisting of abacavir, acyclovir, adefovir, amantadine, amprenavir, atazanavir, cidofovir, danoprevir, darunavir, delavirdine, didanosine, docosanol, double-stranded RNA activated caspase oligomerizer (DRACO), efavirenz, elvitegravir, emtricitabine, enfuvirtide, entecavir, etravirine, famciclovir, foscamet, fomivirsen, ganciclovir, ibacitabine, indinavir, interferon-a inhibitor, idoxuridine, lamivudine, lopinavir, maraviroc, MK-2048, nelfmavir, nevirapine, oseltamivir, penciclovir, peramivir, pleconaril, raltegravir, remdesivir, rilpivirine, rifampin, rimantidine, ritonavir, saquinavir, stavudine, tenofovir trifluridine, valaciclovir, valganciclovir, vidarabine, tipranavir, zalcitabine, zanamivir, and zidovudine.
38. The method of claim 28, wherein the bacterial infection is associated with a bacteria selected from the group consisting of: Chlamydia pneumoniae, Vibrio cholerae, Streptococcus pneumoniae, Mycoplasma pneumoniae, Haemophilus influenzae, Legionella pneumophila, Salmonella enterica, Salmonella bongori, Escherichia coli, Helicobacter pylori, Neisseria gonorrhoeae, Neisseria meningitidis, Staphylococcus aureus, Acinetobacter baumannii, Burkholderia cepacian, Clostridium difficile, Clostridium sordellii, an Enter obacteriaceae, Enterococcus faecalis, Klebsiella pneumoniae, Morganella morganii, Mycobacterium abscessus, Mycobacterium tuberculosis, a Norovirus, Psuedomonas aeruginosa, and Stenotrophomonas maltophilia.
39. The method of claim 38, wherein the bacteria is Streptococcus pneumoniae.
40. The method of claim 38, wherein the bacteria is Klebsiella pneumoniae.
41. The method of any one of claims 27-28 or 38-40, further comprising administering a composition comprising an antibacterial agent.
42. The method of claim 41, wherein the antibacterial agent is selected from the group consisting of doxycycline, vancomycin, metronidazole, gentamicin, colistin, fidaxomicin, telavancin, oritavancin, dalbavancin, daptomycin, cephalexin, cefuroxime, cefadroxil, cefazolin, cephalothin, cefaclor, cefamandole, cefoxitin, cefprozil, ceftobiprole, cipro, Levaquin, floxin, tequin, avelox, norflox, tetracycline, minocycline, oxytetracycline, amoxicillin, ampicillin, penicillin V, dicloxacillin, carbenicillin, methicillin, ertapenem, doripenem, imipenem/cilastatin, meropenem, amikacin, kanamycin, neomycin, netilmicin, tobramycin, paromomycin, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefoxotin, and streptomycin.
43. The method of any one of claims 21-42, wherein the acute respiratory distress syndrome is characterized by cytokine release syndrome.
44. The method of any one of claims 21-43, further comprising administering a composition comprising a cytokine inhibitor.
45. The method of claim 44, wherein the cytokine inhibitor is selected from the group consisting of an IL-6 antagonist, an IL-1 antagonist, a soluble tumor necrosis factor receptor, an IL-1 receptor agonist, and a TGF-bI latency-associated peptide.
46. The method of claim 45, wherein the IL-6 antagonist is tocilizumab, sarilumab, or siltuximab.
47. The method of any one of claims 21-46, wherein the PI3K inhibitor is administered to a patient prophylactically.
48. The method of claim 47, wherein the patient displays elevated ferritin levels, decreased platelet count, elevated erythrocyte sedimentation rate, and/or has an H-Score indicative of hyperinflammation.
49. The method of any one of claims 21-46, wherein the PI3K inhibitor is administered to a patient with symptoms.
50. The method of claim 49, wherein the symptoms comprise acute respiratory distress.
51. The method of any one of claims 1-46, wherein the composition comprising the PI3K inhibitor is administered orally.
52. The method of any one of claims 1-46, wherein the composition comprising the PI3K inhibitor is administered parenterally.
53. The method of any one of claims 1-52, wherein the PI3K inhibitor is administered at a therapeutically effective amount to reduce pro-inflammatory cytokine levels in a patient in need thereof.
54. The method of any one of claims 1-53, wherein the PI3K inhibitor is administered at a therapeutically effective amount to reduce cytokine levels in a patient in need thereof, wherein the cytokines are selected from the group consisting of TNFa, IL-10, CCL3, and CCL4.
55. A kit comprising: a dual RI3Kd/g inhibitor; and detailed instructions for treating cytokine release syndrome in a patient in need thereof.
56. The kit of claim 55, further comprising a composition comprising a cytokine inhibitor.
57. The kit of claim 56, wherein the cytokine inhibitor is selected from the group consisting of an IL-6 antagonist, an IL-1 antagonist, a soluble tumor necrosis factor receptor, an IL-1 receptor agonist, and a TGF-bI latency-associated peptide.
58. The kit of claim 57, wherein the IL-6 antagonist is tocilizumab, sarilumab, or siltuximab.
59. The kit of any one of claims 55-58, wherein the cytokine release syndrome is associated with a coronavirus infection.
60. The kit of claim 59, wherein the coronavirus infection is associated with a coronavirus selected from the group consisting of: 229E alpha coronavirus, NL63 alpha coronavirus, OC43 beta coronavirus, HKU1 beta coronavirus, Middle East Respiratory Syndrome coronavirus (MERS-CoV), severe acute respiratory syndrome coronavirus (SARS-CoV), and SARS-CoV2 (COVID-19).
61. The kit of claim 59 or 60, wherein the coronavirus infection is associated with SARS- CoV2 (COVID-19).
62. The kit of any one of claims 55-61, further comprising an antiviral agent.
63. The kit of claim 62, wherein the antiviral agent is selected from the group consisting of abacavir, acyclovir, adefovir, amantadine, amprenavir, atazanavir, cidofovir, danoprevir, darunavir, delavirdine, didanosine, docosanol, double-stranded RNA activated caspase oligomerizer (DRACO), efavirenz, elvitegravir, emtricitabine, enfuvirtide, entecavir, etravirine, famciclovir, foscamet, fomivirsen, ganciclovir, ibacitabine, indinavir, interferon-a inhibitor, idoxuridine, lamivudine, lopinavir, maraviroc, MK-2048, nelfmavir, nevirapine, oseltamivir, penciclovir, peramivir, pleconaril, raltegravir, remdesivir, rilpivirine, rifampin, rimantidine, ritonavir, saquinavir, stavudine, tenofovir trifluridine, valaciclovir, valganciclovir, vidarabine, tipranavir, zalcitabine, zanamivir, and zidovudine.
64. The kit of any one of claims 55-63, wherein the dual RI3Kd/g inhibitor is duvelisib.
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