WO2020223154A1 - Procédés d'amélioration de la réponse immunitaire - Google Patents

Procédés d'amélioration de la réponse immunitaire Download PDF

Info

Publication number
WO2020223154A1
WO2020223154A1 PCT/US2020/030060 US2020030060W WO2020223154A1 WO 2020223154 A1 WO2020223154 A1 WO 2020223154A1 US 2020030060 W US2020030060 W US 2020030060W WO 2020223154 A1 WO2020223154 A1 WO 2020223154A1
Authority
WO
WIPO (PCT)
Prior art keywords
patient
dosage form
bez235
pharmaceutically acceptable
acceptable salt
Prior art date
Application number
PCT/US2020/030060
Other languages
English (en)
Inventor
Joan Mannick
Chen SCHOR
William Marshall
Samuel BOOS
Abdellah Sentissi
Original Assignee
resTORbio, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by resTORbio, Inc. filed Critical resTORbio, Inc.
Publication of WO2020223154A1 publication Critical patent/WO2020223154A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system

Definitions

  • the present invention relates to catalytic mTOR inhibitors, or pharmaceutically acceptable salts thereof, for the treatment or prevention of a disease, disorder or condition, and pharmaceutical compositions thereof.
  • Senescence is the gradual functional decline of biological organisms. As an organism ages, cells divide less frequently leading to decreased cell populations. As critical cell populations dwindle, biological systems lose function, increasing the risk of disease such as cancer and infections. The rate of senescence is not constant for all organisms or members of a given species. Changes in energy homeostasis, such as caloric restriction, can alter the rate of senescence.
  • mTOR Mammalian Target of Rapamycin
  • mTOR is an evolutionarily conserved serine/threonine kinase that plays a central role in integrating environmental cues in the form of growth factors, amino acids, and energy. Additionally, mTOR plays a critical role in the maintenance of cellular homeostasis by regulation autophagy, the process whereby cells transport intracellular constituents such as proteins, lipids, and organelles, to the lysosome for degradation and recycling. Studies have shown the vital link mTOR provides between cellular function and metabolism and that dysregulation plays an important role in various diseases, such as, for example, cancer and neurodegenerative disorders, infectious, cardiovascular, pulmonary, hepatic, metabolic and inflammatory diseases.
  • FIG. 1 shows the steps of the manufacturing process for a described capsule formulation.
  • FIG. 2 shows the dissolution of formulation containing capsules that have been stored for two (2) weeks under the indicated conditions.
  • FIG. 3 shows the dissolution of formulation containing capsules that have been stored for three (3) weeks under the indicated conditions.
  • FIG. 4 shows the dissolution of formulation containing capsules that have been stored for four (4) weeks under the indicated conditions.
  • FIG. 5 shows the dissolution of formulation containing capsules that have been stored for up to six (6) months under the indicated conditions.
  • FIG. 6 shows the dissolution of formulation containing capsules that have been stored for up to six (6) months under the indicated conditions.
  • FIG. 7 shows the steps of the manufacturing process for a described tablet formulation.
  • the present invention provides a method of treating or preventing clinically symptomatic respiratory illness in a subject, comprising administering to the subject a catalytic mTOR inhibitor, or pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating or preventing clinically symptomatic respiratory illness in a subject, comprising administering to the subject a low dose of BEZ235, or pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating or preventing respiratory illness due to infection in a subject, comprising administering to the subject a catalytic mTOR inhibitor, or pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating or preventing respiratory illness due to infection in a subject, comprising administering to the subject a low dose of BEZ235, or pharmaceutically acceptable salt thereof.
  • the present invention provides a method comprising the step of administering a catalytic mTOR inhibitor or a pharmaceutically acceptable salt thereof, wherein the patient experiences fewer clinically symptomatic respiratory illnesses than a patient not administered a catalytic mTOR inhibitor or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method comprising the step of administering a low dose of BEZ235 or a pharmaceutically acceptable salt thereof, wherein the patient experiences fewer clinically symptomatic respiratory illnesses than a patient not administered BEZ235 or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method comprising the step of administering a catalytic mTOR inhibitor or a pharmaceutically acceptable salt thereof, wherein the patient experiences fewer respiratory illnesses due to infection than a patient not administered a catalytic mTOR inhibitor or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method comprising the step of administering a low dose of BEZ235 or a pharmaceutically acceptable salt thereof, wherein the patient experiences fewer respiratory illnesses due to infection than a patient not administered BEZ235 or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating an age- related condition, comprising administering to a subject in need thereof an effective amount of a catalytic mTOR inhibitor, or a pharmaceutically acceptable salt thereof, to treat said age-related condition.
  • the subject is suffering from, or susceptible to, a respiratory illness.
  • the present invention provides a method of treating an age- related condition, comprising administering to a subject in need thereof an effective amount of BEZ235, or a pharmaceutically acceptable salt thereof, to treat said age-related condition.
  • the subject is suffering from, or susceptible to, a respiratory illness.
  • the present invention provides a commercial package comprising a catalytic mTOR inhibitor, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of clinically symptomatic respiratory illnesses, as described below and herein.
  • the present invention provides a commercial package comprising BEZ235, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of clinically symptomatic respiratory illnesses, as described below and herein.
  • the invention provides a commercial package comprising a catalytic mTOR inhibitor, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of respiratory illnesses due to infection, as described below and herein.
  • the invention provides a commercial package comprising BEZ235, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of respiratory illnesses due to infection, as described below and herein.
  • the present invention provides pharmaceutical formulations (e.g., solid dosage forms) that are useful for the oral administration of BEZ235 or a pharmaceutically acceptable salt thereof to a subject in need thereof.
  • pharmaceutical formulations e.g., solid dosage forms
  • “combination” or“pharmaceutical combination” is defined to refer to either a fixed combination in one dosage unit form, a non-fixed combination or a kit of parts for a combined administration of a catalytic mTOR inhibitor or pharmaceutically acceptable salt thereof, e.g., BEZ235, or pharmaceutically acceptable salt thereof, with another therapeutic agent, wherein the catalytic mTOR inhibitor or pharmaceutically acceptable salt thereof, e.g., BEZ235, or pharmaceutically acceptable salt thereof, may be administered independently at the same time or separately with within time intervals that allow that the combination partners show a cooperative, e.g., synergistic, effect.
  • a catalytic mTOR inhibitor or pharmaceutically acceptable salt thereof e.g., BEZ235, or pharmaceutically acceptable salt thereof
  • the phrase“fixed combination” means that the active ingredients or therapeutic agents, e.g. BEZ235 and another therapeutic agent, are administered to a patient simultaneously in the form of a single entity or dosage form.
  • non-fixed combination means that the active ingredients or therapeutic agents, e.g. BEZ235 and another therapeutic agent, are both administered to a patient as separate entities or dosage forms either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the subject, e.g., a mammal or human, in need thereof.
  • active ingredients or therapeutic agents e.g. BEZ235 and another therapeutic agent
  • phrases“pharmaceutical composition” is defined herein to refer to a mixture or solution containing at least one therapeutic agent to be administered to a subject, e.g., a mammal or human, in order to treat a particular disease or condition affecting the subject thereof.
  • phrases “pharmaceutically acceptable” is defined herein to refer to those compounds, biologic agents, materials, compositions and/or dosage forms, which are, within the scope of sound medical judgment, suitable for contact with the tissues a subject, e.g., a mammal or human, without excessive toxicity, irritation allergic response and other problem complications commensurate with a reasonable benefit/risk ratio.
  • the phrase“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 humans and lower animals 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, S. M. Berge et ah, describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66(1): 1-19 (1977), incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts include salts of an amino group (or other basic 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, benzenesulfonate, benzoate, besylate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamo
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (Ci-4alkyl)4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counter ions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.
  • phrase“combined administration” as used herein are defined to encompass the administration of the selected therapeutic agents to a single subject, e.g., a mammal or human, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.
  • the term“treating” or“treatment” as used herein comprises relieving, reducing or alleviating at least one symptom in a subject or affecting a delay of progression of a disease, condition and/or disorder.
  • treatment can be the diminishment of one or several symptoms of a disorder or complete eradication of a disorder.
  • the term“treat” also denotes to arrest, delay the onset (i.e., the period prior to clinical manifestation of a disease) and/or reduce the risk of developing or worsening a disease, condition, and/or disorder.
  • the term“jointly therapeutically active” or“joint therapeutic effect” as used herein means that the therapeutic agents may be given separately (in a chronologically staggered manner, for example in a sequence-specific manner) such that the warm-blooded animal (for example, human) to be treated, still shows an interaction, such as a synergistic interaction (joint therapeutic effect). Whether this is the case can be determined by, inter alia, following the blood levels, showing that both therapeutic agents are present in the blood of the human to be treated at least during certain time intervals.
  • a therapeutically effective amount of a compound of the present invention refers to an amount of the compound of the present invention that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc.
  • synergistic effect refers to action of two agents producing an effect, for example, promoting and/or enhancing an immune response in a subject, which is greater than the simple addition of the effects of each drug administered by themselves.
  • a synergistic effect can be calculated, for example, using suitable methods such as the Sigmoid- Emax equation (Holford, N. H. G. and Scheiner, L. B., Clin. Pharmacokinet. 6: 429-453 (1981)), the equation of Loewe additivity (Loewe, S. and Muischnek, H., Arch. Exp. Pathol Pharmacol. 114: 313-326 (1926)) and the median-effect equation (Chou, T. C.
  • the term“subject” or“patient” as used herein includes animals, which are capable of promoting and/or enhancing an immune response and/or having an age-related condition.
  • subjects include mammals, e.g., humans, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats and transgenic non-human animals.
  • the subject is a human, e.g., a human suffering from, at risk of suffering from, or potentially capable of suffering from an age-related condition.
  • the subject is a human, e.g., a human suffering from, at risk of suffering from, or potentially capable of suffering from respiratory illness.
  • the term“about” or“approximately” shall have the meaning of within 10%, for example within 5%, of a given value or range.
  • the term“about” in connection with a particular drug dose shall have the meaning of a drug dose in the range of plus/minus 10%, for instance plus/minus 5%, plus/minus 2.5%, plus/minus 1%, of the nominal drug dose.
  • a nominal drug dose of about 100 mg active ingredient may contain from 90 to 110 mg, from 95 to 105 mg, from 97.5 to 102.5 mg, or from 99 to 101 mg active ingredient per dose.
  • the term“promote” or“enhance” in the context of an immune response refers to an increase in immune response, such as an increase in the ability of immune cells to target and/or kill cancer cells, to target and/or kill pathogens and pathogen infected cells, and protective immunity following vaccination, among others.
  • protective immunity refers to the presence of sufficient immune response (such as antibody titers) to protect against subsequent infection by a pathogen expressing the same antigen or protection against a new pathogen.
  • immunosenescence refers to a decrease in immune function resulting in impaired immune response, e.g., to cancer, vaccination, infectious pathogens, among others. It involves both the host’s capacity to respond to infections and the development of long-term immune memory, especially by vaccination. This immune deficiency is ubiquitous and found in both long- and short-lived species as a function of their age relative to life expectancy rather than chronological time. It is considered a major contributory factor to the increased frequency of morbidity and mortality among the elderly. Immunosenescence is not a random deteriorative phenomenon, rather it appears to inversely repeat an evolutionary pattern and most of the parameters affected by immunosenescence appear to be under genetic control. Immunosenescence can also be sometimes envisaged as the result of the continuous challenge of the unavoidable exposure to a variety of antigens such as viruses and bacteria.
  • Immunosenescence is a multifactorial condition leading to many pathologically significant health problems, e.g., in the aged population.
  • Age-dependent biological changes such as a decline in function of hematopoietic stem cells, an increase in PD1+ lymphocytes, a decline in the function of phagocytes, macrophages, dendritic cells, monocytes, T cells, B cells and NK cells, and a decline in innate, cell-mediated or humoral immunity contribute to the onset of immunosenescence.
  • immunosenescence can be measured in an individual by measuring telomere length in immune cells (See, e.g., US 5,741,677).
  • Immunosenescence can also be determined by documenting in an individual a lower than normal number of naive CD4 and/or CD8 T cells, a decrease in early pro-B cells and pre-B cells, a decrease in T and B cell repertoire, an increase in the number of PD 1 -expressing T cells, e.g., a lower than normal number of PD-1 negative T cells, an increase in CD8+CD28neg T cells, an increase in CD57+ and/or KLRG1+ CD8+ T cells, an increase in the number of LAG-3 -positive T cells, a change in T cell surface glycoproteins, a change in antibody glycosylation, a change the glycosylation of proteins expressed intracellularly or on the surface of immune cells, an increase in ICOS, CTLA-4, Tim-3 and/or LAG-3 expressing CD4 T cells, or decreased response to vaccination in a subjects they age.
  • PD 1 -expressing T cells e.g., a lower than normal number of PD-1 negative T
  • the term“impaired immune response” refers to a state in which a subject does not have an appropriate immune response, e.g., to cancer, vaccination, pathogen infection, among others.
  • a subject having an impaired immune response is predicted not to get protective antibody titer levels following prophylactic vaccination, or in which a subject does not have a decrease in cell-mediated immunity or disease burden after therapeutic vaccination.
  • a subject can also have an impaired immune response if the subject has an impaired expression of innate immune response genes.
  • a subject can also have an impaired immune response if the subject is a member of a population known to have decreased immune function or that has a history of decreased immune function such as the elderly, subjects undergoing chemotherapy treatment, asplenic subjects, immunocompromised subjects, or subjects having HIV/AIDS.
  • Methods described herein allow for the treatment of an impaired immune response by administration of a low, immune enhancing, dose of an mTOR inhibitor.
  • the term“low, immune enhancing dose” when used in conjunction with a catalytic mTOR inhibitor refers to a dose of mTOR inhibitor that partially, but not fully, inhibits mTOR activity, e.g., as measured by the inhibition of P70 S6 kinase activity. Methods for evaluating mTOR activity, e.g., by inhibition of P70 S6 kinase, are discussed herein. The dose is insufficient to result in complete immune suppression but is sufficient to enhance the immune response.
  • the low, immune enhancing dose of mTOR inhibitor results in a decrease in the number or percentage of PD-1 positive T cells and/or an increase in the number or percentage of PD-1 negative T cells, or an increase in the ratio of PD-1 negative T cells/PD- 1 positive T cells. In an embodiment, the low, immune enhancing dose of mTOR inhibitor results in an increase in the number of naive T cells. In an embodiment, the low, immune enhancing dose of mTOR inhibitor results in one or more of the following:
  • CD127high, CD27+, and BCL2 e.g., on memory T cells, e.g., memory T cell precursors;
  • KLRG1 or CD57 a decrease in the expression of KLRG1 or CD57, e.g., on naive or memory T cells, e.g., memory T cell precursors;
  • an increase in the number of memory T cell precursors e.g., cells with any one or combination of the following characteristics: increased CD62Lhigh, increased CD127high, increased CD27+, decreased KLRG1, and increased BCL2;
  • any of the changes described above occurs, e.g., at least transiently, e.g., as compared to a non-treated subject.
  • a dose of an mTOR inhibitor is associated with, or provides, mTOR inhibition of at least 5 but no more than 90%, at least 10 but no more than 90%, at least 15 but no more than 90%, at least 20 but no more than 90%, at least 30 but no more than 90%, at least 40 but no more than 90%, at least 50 but no more than 90%, at least 60 but no more than 90%, or at least 70 but no more than 90%.
  • a dose of an mTOR inhibitor is associated with, or provides, mTOR inhibition of at least 5 but no more than 80%, at least 10 but no more than 80%, at least 15 but no more than 80%, at least 20 but no more than 80%, at least 30 but no more than 80%, at least 40 but no more than 80%, at least 50 but no more than 80%, or at least 60 but no more than 80%.
  • a dose of an mTOR inhibitor is associated with, or provides, mTOR inhibition of at least 5 but no more than 70%, at least 10 but no more than 70%, at least 15 but no more than 70%, at least 20 but no more than 70%, at least 30 but no more than 70%, at least 40 but no more than 70%, or at least 50 but no more than 70%.
  • a dose of an mTOR inhibitor is associated with, or provides, mTOR inhibition of at least 5 but no more than 60%, at least 10 but no more than 60%, at least 15 but no more than 60%, at least 20 but no more than 60%, at least 30 but no more than 60%, or at least 40 but no more than 60%.
  • a dose of an mTOR inhibitor is associated with, or provides, mTOR inhibition of at least 5 but no more than 50%, at least 10 but no more than 50%, at least 15 but no more than 50%, at least 20 but no more than 50%, at least 30 but no more than 50%, or at least 40 but no more than 50%.
  • a dose of an mTOR inhibitor is associated with, or provides, mTOR inhibition of at least 5 but no more than 40%, at least 10 but no more than 40%, at least 15 but no more than 40%, at least 20 but no more than 40%, at least 30 but no more than 40%, or at least 35 but no more than 40%.
  • a dose of an mTOR inhibitor is associated with, or provides, mTOR inhibition of at least 5 but no more than 30%, at least 10 but no more than 30%, at least 15 but no more than 30%, at least 20 but no more than 30%, or at least 25 but no more than 30%.
  • a dose of an mTOR inhibitor is associated with, or provides, mTOR inhibition of at least 1, 2, 3, 4 or 5 but no more than 20%, at least 1, 2, 3, 4 or 5 but no more than 30%, at least 1, 2, 3, 4 or 5 but no more than 35, at least 1, 2, 3, 4 or 5 but no more than 40%, or at least 1, 2, 3, 4 or 5 but no more than 45%.
  • a dose of an mTOR inhibitor is associated with, or provides, mTOR inhibition of at least 1, 2, 3, 4 or 5 but no more than 90%.
  • the extent of mTOR inhibition can be expressed as the extent of P70 S6K inhibition, e.g., the extent of mTOR inhibition can be determined by the level of decrease in P70 S6K activity, e.g., by the decrease in phosphorylation of a P70 S6K substrate.
  • the level of mTOR inhibition can be evaluated by a method described herein, e.g. by the Boulay assay.
  • the term“promote” or“enhance” in the context of an immune response refers to an increase in immune response, such as an increase in the ability of immune cells to target and/or kill cancer cells, to target and/or kill pathogens and pathogen infected cells, and protective immunity following vaccination, among others.
  • protective immunity refers to the presence of sufficient immune response (such as antibody titers) to protect against subsequent infection by a pathogen expressing the same antigen.
  • the phrase“mTOR-mediated disease, disorder, or condition” refers to a disease, disorder, or condition that is characterized by abnormal mTOR activity or mTOR activity that, when modulated, leads to the amelioration of other abnormal biological processes.
  • an mTOR- mediated disease, disorder, or condition may be completely or partially mediated by modulating mTOR.
  • an mTOR-mediated disease, disorder, or condition is one in which inhibition of mTOR results in some effect on the underlying disease, disorder, or condition e.g., administration of an mTOR inhibitor results in some improvement in at least some of the subjects being treated.
  • autophagy-related disease, disorder, or condition refers to a disease, disorder, or condition that is characterized by abnormal activity in a lysosomal degradation pathway or a disease, disorder, or condition in which modulation of autophagy leads to the amelioration of one of more symptoms and/or one or more abnormal biological processes associates with the disease, disorder, or condition.
  • An autophagy-related disease, disorder, or condition may be completely or partially mediated by modulating autophagy.
  • age-related disease, disorder, or condition refers to any disease, disorder, or condition whose incidence in a population or severity in an individual correlates with the progression of age. More specifically, an age-related disease is a disease, disorder, or condition whose incidence is at least 1.5 fold higher among human individuals greater than 60 years of age relative to human individuals between the ages of 20-30 and in a selected population of greater than 100,000 individuals.
  • the invention relates to the treatment of conditions including, but not limited to immunosenescence (including associated respiratory tract infections, urinary tract infections, viral infections, and bacterial infections), sarcopenia, muscle wasting, tendon stiffness, tendon injury, tendonitis, Achilles rupture, adhesive capsulitis of shoulder, plantar fasciitis, polymyalgia rheumatica, rotator cuff tear, spinal stenosis, tennis elbow, Dupuytren's contractures, restless leg syndrome, osteoporosis, osteoarthritis, rheumatoid arthritis, autoimmune disease, polymyositis, gout, dementia, Huntington's disease, Alzheimer's disease, brain atrophy, aging-related mobility disability (e.g., frailty), cognitive decline, age related dementia, memory impairment, Lewy body dementia, frontotemporal dementia, Parkinson's disease, mild cognitive impairment, vascular dementia, stroke, transient ischemic attack, trigeminal neuralgia,
  • RTB101 refers to the monotosylate salt of BEZ235 unless otherwise indicated.
  • Other pharmaceutically acceptable salt forms are known in the art and contemplated herein (see, e.g., U.S. Pat. App. Pub. 12/514,976, which is incorporated herein by reference in its entirety).
  • the terms“inhibit”,“inhibition”, or“inhibiting,” in the context of a condition, symptom, disorder, or disease refer to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.
  • the term“mg/kg/day” refers to mg of compound per kg bodyweight of subject per day.
  • mTOR Inhibitors refers to a compound or ligand, or a pharmaceutically acceptable salt thereof, which inhibits the mTOR kinase in a cell.
  • An inhibitor may block or reduce the activity of mTOR by forming a reversible or irreversible covalent bond between the inhibitor and mTOR or through formation of a noncovalently bound complex. Such inhibition may be manifest only in particular cell types or may be contingent on a particular biological event.
  • inhibitor or“inhibition” with respect to mTOR also refers to altering the function of mTOR by decreasing the probability that a complex forms between mTOR and a natural substrate. In some embodiments, inhibition of mTOR may be assessed using the methods described in WO 1994/09010.
  • an mTOR inhibitor is a catalytic inhibitor.
  • Catalytic, ATP-competitive mTOR inhibitors have been found to target the mTOR kinase domain directly and target both mTORCl and mTORC2. These are more complete inhibitors of mTORCl than, for instance, allosteric mTOR inhibitors such as rapamycin, because they modulate rapamycin-resistant mTORCl outputs such as 4EBP1-T37/46 phosphorylation and cap-dependent translation.
  • BEZ235 is a catalytic mTOR inhibitor, having the chemical name 2-methyl-2-[4-(3- methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-l-yl)-phenyl]-propionitrile and the following chemical structure:
  • BEZ235 may also be used in its monotosylate salt form. Unless indicated otherwise, RTB101 refers to the monotosylate salt form of BEZ235. The synthesis of BEZ235 is described in W02006/122806, the contents of which are hereby incorporated by reference.
  • BEZ235 As a catalytic mTOR inhibitor, BEZ235 is capable of shutting down the complete function of mTORCl complex, including both the rapamycin sensitive (phosphorylation of P70 S6K, and subsequently phosphorylation of P70 S6) and rapamycin insensitive (phosphorylation of 4EBP1) functions.
  • BEZ235 has a differential effect according to the drug concentration used, whereby mTORCl inhibition predominates at a very low concentration (less than or equal to 10 nmol/L), mTORCl and mTORC2 inhibition predominates at low concentration (less than 200 nmol/L) but dual PI3K/ mTOR inhibition at relatively higher concentrations (approximately 500 nmol/L).
  • Exemplary catalytic mTOR inhibitors, and pharmaceutically acceptable salts thereof, for use in the present invention include, but are not limited to, AZD2014 (a.k.a. vistusertib; see WO2009/153579), AZD8055 (see WO2009/153579), XL388 (see US2010/0305093), MLN0128 (a.k.a. INK128 and sapanisertib; see WO2010/051043), DS3078, GDC0980 (a.k.a. apitolisib; see W02008/070740), GSK-2126458 (a.k.a.
  • VCD-597 see WO2010/110685
  • ME-344 see W02010/106211
  • WYE-132 see W02010/106211
  • WYE-132 see W02010/106211
  • EXEL-3885 see W02010/106211
  • EXEL-4431 see W02010/106211
  • AR-mTOR-26 see NV-128, VS-507, BN-107, BN-108, WAY-600, WYE-687, WYE- 354, KU0063794, PP242 (a.k.a. torkinib), PP30, CZ415, INK1069, EXEL-2044, EXEL-7518, SB2158, SB2280, and AR-mTOR-1.
  • a catalytic mTOR inhibitor, or pharmaceutically acceptable salt thereof, for use in the present invention is any of the below-depicted compounds.
  • the invention provides BEZ235 or a pharmaceutically acceptable salt thereof, for the enhancement or promotion of an immune response in a subject.
  • BEZ235 is in the form of the monotosylate salt.
  • BEZ235 is administered in a dosage range from 1 - 20 mg, e.g., 10 mg.
  • BEZ235 is in an immediate release dosage form. In some embodiments, BEZ235 is administered once per week. In some embodiments, BEZ235 is administered once per day.
  • BEZ235 is administered once per day in an amount of about 8-12 mg. In some embodiments, BEZ235 is administered once per day in an amount of about 10 mg. In some such embodiments, BEZ235 is in the form of the monotosylate salt.
  • the invention provides a pharmaceutical composition comprising BEZ235, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
  • the present invention provides methods of treating or preventing clinically symptomatic respiratory illness in a subject.
  • a subject with clinically symptomatic respiratory illness includes, for instance, a subject with symptoms consistent with a respiratory tract infection based on pre-specified diagnostic criteria, as defined and described further below and herein.
  • a clinically symptomatic respiratory illness is a respiratory tract infection, as described further below and herein.
  • the present invention provides a method comprising the step of administering a catalytic mTOR inhibitor, or a pharmaceutically acceptable salt thereof, wherein the patient experiences fewer clinically symptomatic respiratory illnesses than a patient not administered a catalytic mTOR inhibitor or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method comprising the step of administering a low dose of BEZ235 or a pharmaceutically acceptable salt thereof, wherein the patient experiences fewer clinically symptomatic respiratory illnesses than a patient not administered BEZ235 or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method comprising the step of administering a catalytic mTOR inhibitor or a pharmaceutically acceptable salt thereof, wherein the patient experiences fewer symptoms associated with a clinically symptomatic respiratory illness than a patient not administered a catalytic mTOR inhibitor or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method comprising the step of administering a low dose of BEZ235 or a pharmaceutically acceptable salt thereof, wherein the patient experiences fewer symptoms associated with a clinically symptomatic respiratory illness than a patient not administered BEZ235 or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method comprising the step of administering a catalytic mTOR inhibitor or a pharmaceutically acceptable salt thereof, wherein the patient experiences a decreased time to alleviation of symptoms associated with a clinically symptomatic respiratory illness than a patient not administered a catalytic mTOR inhibitor or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method comprising the step of administering a low dose of BEZ235 or a pharmaceutically acceptable salt thereof, wherein the patient experiences a decreased time to alleviation of symptoms associated with a clinically symptomatic respiratory illness than a patient not administered BEZ235 or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method comprising the step of administering a catalytic mTOR inhibitor or a pharmaceutically acceptable salt thereof to a patient, wherein the patient experiences a decrease in the severity of symptoms associated with a clinically symptomatic respiratory illness than a patient not administered a catalytic mTOR inhibitor or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method comprising the step of administering a low dose of BEZ235 or a pharmaceutically acceptable salt thereof to a patient, wherein the patient experiences a decrease in the severity of symptoms associated with a clinically symptomatic respiratory illness than a patient not administered BEZ235 or a pharmaceutically acceptable salt thereof.
  • symptoms of the clinically symptomatic respiratory illness include, but are not limited to, one or more of cough, sore throat, hoarseness of voice, nasal congestion (e.g., stuffy nose), runny nose/sneezing, headache, feverishness/chills, body aches (e.g., muscle or joint pain), lack of energy, loss of appetite, and issues with balance.
  • at least one, two, three, or four symptoms is/are at least moderate in severity.
  • at least one symptom is at least moderate in severity.
  • at least two symptoms are at least moderate in severity.
  • symptoms of the clinically symptomatic respiratory illness include, but are not limited to, one or more of cough, sore throat, hoarseness of voice, nasal congestion (e.g., stuffy nose), runny nose, sneezing, headache, feverishness/chills, body aches (e.g., muscle or joint pain), lack of energy, loss of appetite, and issues with balance.
  • at least one symptom is at least at least moderate in severity.
  • at least two symptoms are at least moderate in severity.
  • the patient has at least two symptoms selected from cough, sore throat, hoarseness of voice, nasal congestion (e.g., stuffy nose), runny nose/sneezing, headache, feverishness/chills, body aches (e.g., muscle or joint pain), lack of energy, loss of appetite, and issues with balance.
  • at least one symptom is at least moderate in severity.
  • at least two symptoms are at least moderate in severity.
  • the patient has at least two symptoms selected from cough, sore throat, hoarseness of voice, nasal congestion (e.g., stuffy nose), runny nose, sneezing, headache, feverishness/chills, body aches (e.g., muscle or joint pain), lack of energy, loss of appetite, and issues with balance.
  • at least one symptom is at least moderate in severity.
  • at least two symptoms are at least moderate in severity.
  • the patient has at least three symptoms selected from cough, sore throat, hoarseness of voice, nasal congestion (e.g., stuffy nose), runny nose/sneezing, headache, feverishness/chills, body aches (e.g., muscle or joint pain), lack of energy, loss of appetite, and issues with balance.
  • at least one symptom is at least moderate in severity.
  • at least two symptoms are at least moderate in severity.
  • the patient has at least three symptoms selected from cough, sore throat, hoarseness of voice, nasal congestion (e.g., stuffy nose), runny nose, sneezing, headache, feverishness/chills, body aches (e.g., muscle or joint pain), lack of energy, loss of appetite, and issues with balance.
  • at least one symptom is at least moderate in severity.
  • at least two symptoms are at least moderate in severity.
  • the present invention provides methods of treating or preventing clinically symptomatic respiratory illness in a patient, wherein the clinically symptomatic respiratory illness is characterized by the presence of at least two or three of the symptoms described above.
  • at least one symptom is at least moderate in severity.
  • at least two symptoms are at least moderate in severity.
  • the patient is an elderly patient.
  • a patient is identified as having a clinically symptomatic respiratory illness when the patient has at least two symptoms selected from cough, sore throat, hoarseness of voice, nasal congestion (e.g., stuffy nose), and runny nose/sneezing.
  • the present invention provides methods of treating or preventing clinically symptomatic respiratory illness in a patient comprising the step of administering a low dose of BEZ235 or a pharmaceutically acceptable salt thereof, wherein the clinically symptomatic respiratory illness is characterized by the presence of at least two symptoms selected from cough, sore throat, hoarseness of voice, nasal congestion (e.g., stuffy nose), and runny nose/sneezing.
  • the patient is an elderly patient.
  • at least one symptom is at least moderate in severity.
  • at least two symptoms are at least moderate in severity.
  • a patient is identified as having a clinically symptomatic respiratory illness when the patient has at least two symptoms selected from cough, sore throat, hoarseness of voice, nasal congestion (e.g., stuffy nose), runny nose, and sneezing.
  • the present invention provides methods of treating or preventing clinically symptomatic respiratory illness in a patient comprising the step of administering a low dose of BEZ235 or a pharmaceutically acceptable salt thereof, wherein the clinically symptomatic respiratory illness is characterized by the presence of at least two symptoms selected from cough, sore throat, hoarseness of voice, nasal congestion (e.g., stuffy nose), runny nose, and sneezing.
  • the patient is an elderly patient.
  • at least one symptom is at least moderate in severity.
  • at least two symptoms are at least moderate in severity.
  • a patient is identified as having a clinically symptomatic respiratory illness when the patient has at least one symptom selected from cough, sore throat, hoarseness of voice, nasal congestion (e.g., stuffy nose), and runny nose/ sneezing, and at least one symptom selected from headache, feverishness/chills, body aches (e.g., muscle or joint pain), lack of energy, loss of appetite, or issues with balance.
  • at least one symptom is at least moderate in severity.
  • at least two symptoms are at least moderate in severity.
  • the present invention provides methods of treating or preventing clinically symptomatic respiratory illness in a patient comprising the step of administering a low dose of BEZ235 or a pharmaceutically acceptable salt thereof, wherein the clinically symptomatic respiratory illness is characterized by the presence of at least one symptom selected from cough, sore throat, hoarseness of voice, nasal congestion (e.g., stuffy nose), and runny nose/sneezing, and at least one symptom selected from headache, feverishness/chills, body aches (e.g., muscle or joint pain), lack of energy, loss of appetite, or issues with balance.
  • at least one symptom is at least moderate in severity.
  • at least two symptoms are at least moderate in severity.
  • the patient is an elderly patient.
  • a patient is identified as having a clinically symptomatic respiratory illness when the patient has at least one symptom selected from cough, sore throat, hoarseness of voice, nasal congestion (e.g., stuffy nose), runny nose, and sneezing, and at least one symptom selected from headache, feverishness/chills, body aches (e.g., muscle or joint pain), lack of energy, loss of appetite, or issues with balance.
  • at least one symptom is at least moderate in severity.
  • at least two symptoms are at least moderate in severity.
  • the present invention provides methods of treating or preventing clinically symptomatic respiratory illness in a patient comprising the step of administering a low dose of BEZ235 or a pharmaceutically acceptable salt thereof, wherein the clinically symptomatic respiratory illness is characterized by the presence of at least one symptom selected from cough, sore throat, hoarseness of voice, nasal congestion (e.g., stuffy nose), runny nose, and sneezing, and at least one symptom selected from headache, feverishness/chills, body aches (e.g., muscle or joint pain), lack of energy, loss of appetite, or issues with balance.
  • at least one symptom is at least moderate in severity.
  • at least two symptoms are at least moderate in severity.
  • the patient is an elderly patient.
  • a patient is identified as having a clinically symptomatic respiratory illness when the patient has at least one symptom selected from cough, sore throat, hoarseness of voice, nasal congestion (e.g., stuffy nose), and runny nose/ sneezing, and at least one symptom selected from headache, feverishness/chills, and loss of appetite.
  • at least one symptom is at least moderate in severity.
  • at least two symptoms are at least moderate in severity.
  • the present invention provides methods of treating or preventing clinically symptomatic respiratory illness in a patient comprising the step of administering a low dose of BEZ235 or a pharmaceutically acceptable salt thereof, wherein the clinically symptomatic respiratory illness is characterized by the presence of at least one symptom selected from cough, sore throat, hoarseness of voice, nasal congestion (e.g., stuffy nose), and runny nose/ sneezing, and at least one symptom selected from headache, feverishness/chills, and loss of appetite.
  • at least one symptom is at least moderate in severity.
  • at least two symptoms are at least moderate in severity.
  • the patient is an elderly patient.
  • a patient is identified as having a clinically symptomatic respiratory illness when the patient has at least one symptom selected from cough, sore throat, hoarseness of voice, nasal congestion (e.g., stuffy nose), runny nose, and sneezing, and at least one symptom selected from headache, feverishness/chills, and loss of appetite.
  • at least one symptom is at least moderate in severity.
  • at least two symptoms are at least moderate in severity.
  • the present invention provides methods of treating or preventing clinically symptomatic respiratory illness in a patient comprising the step of administering a low dose of BEZ235 or a pharmaceutically acceptable salt thereof, wherein the clinically symptomatic respiratory illness is characterized by the presence of at least one symptom selected from cough, sore throat, hoarseness of voice, nasal congestion (e.g., stuffy nose), runny nose, and sneezing, and at least one symptom selected from headache, feverishness/chills, and loss of appetite.
  • at least one symptom is at least moderate in severity.
  • at least two symptoms are at least moderate in severity.
  • the patient is an elderly patient.
  • a patient is identified as having a clinically symptomatic respiratory illness when the patient has at least one symptom selected from cough, sore throat, hoarseness of voice, nasal congestion (e.g., stuffy nose), and runny nose/ sneezing, and at least one symptom selected from headache and feverishness/chills.
  • at least one symptom is at least moderate in severity.
  • at least two symptoms are at least moderate in severity.
  • the present invention provides methods of treating or preventing clinically symptomatic respiratory illness in a patient comprising the step of administering a low dose of BEZ235 or a pharmaceutically acceptable salt thereof, wherein the clinically symptomatic respiratory illness is characterized by the presence of at least one symptom selected from cough, sore throat, hoarseness of voice, nasal congestion (e.g., stuffy nose), and runny nose/sneezing, and at least one symptom selected from headache and feverishness/chills.
  • at least one symptom is at least moderate in severity.
  • at least two symptoms are at least moderate in severity.
  • the patient is an elderly patient.
  • a patient is identified as having a clinically symptomatic respiratory illness when the patient has at least one symptom selected from cough, sore throat, hoarseness of voice, nasal congestion (e.g., stuffy nose), runny nose, and sneezing, and at least one symptom selected from headache and feverishness/chills.
  • at least one symptom is at least moderate in severity.
  • at least two symptoms are at least moderate in severity.
  • the present invention provides methods of treating or preventing clinically symptomatic respiratory illness in a patient comprising the step of administering a low dose of BEZ235 or a pharmaceutically acceptable salt thereof, wherein the clinically symptomatic respiratory illness is characterized by the presence of at least one symptom selected from cough, sore throat, hoarseness of voice, nasal congestion (e.g., stuffy nose), runny nose, and sneezing, and at least one symptom selected from headache and feverishness/chills.
  • at least one symptom is at least moderate in severity.
  • at least two symptoms are at least moderate in severity.
  • the patient is an elderly patient.
  • a patient is identified as having a clinically symptomatic respiratory illness when the patient has at least one symptom selected from cough, sore throat, hoarseness of voice, nasal congestion (e.g., stuffy nose), and runny nose/ sneezing, and at least one symptom selected from headache, feverishness/chills, body aches (e.g., muscle or joint pain), lack of energy, and loss of appetite.
  • at least one symptom is at least moderate in severity.
  • at least two symptoms are at least moderate in severity.
  • the present invention provides methods of treating or preventing clinically symptomatic respiratory illness in a patient comprising the step of administering a low dose of BEZ235 or a pharmaceutically acceptable salt thereof, wherein the clinically symptomatic respiratory illness is characterized by the presence of at least one symptom selected from cough, sore throat, hoarseness of voice, nasal congestion (e.g., stuffy nose), and runny nose/sneezing, and at least one symptom selected from headache, feverishness/chills, body aches (e.g., muscle or joint pain), lack of energy, and loss of appetite.
  • at least one symptom is at least moderate in severity.
  • at least two symptoms are at least moderate in severity.
  • the patient is an elderly patient.
  • a patient is identified as having a clinically symptomatic respiratory illness when the patient has at least one symptom selected from cough, sore throat, hoarseness of voice, nasal congestion (e.g., stuffy nose), runny nose, and sneezing, and at least one symptom selected from headache, feverishness/chills, body aches (e.g., muscle or joint pain), lack of energy, and loss of appetite.
  • at least one symptom is at least moderate in severity.
  • at least two symptoms are at least moderate in severity.
  • the present invention provides methods of treating or preventing clinically symptomatic respiratory illness in a patient comprising the step of administering a low dose of BEZ235 or a pharmaceutically acceptable salt thereof, wherein the clinically symptomatic respiratory illness is characterized by the presence of at least one symptom selected from cough, sore throat, hoarseness of voice, nasal congestion (e.g., stuffy nose), runny nose, and sneezing, and at least one symptom selected from headache, feverishness/chills, body aches (e.g., muscle or joint pain), lack of energy, and loss of appetite.
  • at least one symptom is at least moderate in severity.
  • at least two symptoms are at least moderate in severity.
  • the patient is an elderly patient.
  • the present invention provides methods of treating or preventing clinically symptomatic respiratory illness in an elderly patient comprising the step of administering a low dose of BEZ235 or a pharmaceutically acceptable salt thereof, wherein: the clinically symptomatic respiratory illness is characterized by the presence of at least two symptoms selected from cough, sore throat, hoarseness of voice, nasal congestion (e.g., stuffy nose), and runny nose/sneezing; or
  • the clinically symptomatic respiratory illness is characterized by the presence of at least one symptom selected from cough, sore throat, hoarseness of voice, nasal congestion (e.g., stuffy nose), and runny nose/sneezing, and at least one symptom selected from headache, feverishness/chills, and loss of appetite; or
  • the clinically symptomatic respiratory illness is characterized by the presence of at least one symptom selected from cough, sore throat, hoarseness of voice, nasal congestion (e.g., stuffy nose), and runny nose/ sneezing, and at least one symptom selected from headache and feverishness/chills; or the clinically symptomatic respiratory illness is characterized by the presence of at least one symptom selected from cough, sore throat, hoarseness of voice, nasal congestion (e.g., stuffy nose), and runny nose/sneezing, and at least one symptom selected from headache, feverishness/chills, body aches (e.g., muscle or joint pain), lack of energy, and loss of appetite.
  • At least one symptom is at least moderate in severity. In some such embodiments, at least two symptoms are at least moderate in severity. In some such embodiments, a patient experiences fewer clinically symptomatic respiratory illnesses than a patient not administered BEZ235 or a pharmaceutically acceptable salt thereof.
  • the present invention provides methods of treating or preventing clinically symptomatic respiratory illness in an elderly patient comprising the step of administering a low dose of BEZ235 or a pharmaceutically acceptable salt thereof, wherein: the clinically symptomatic respiratory illness is characterized by the presence of at least two symptoms selected from cough, sore throat, hoarseness of voice, nasal congestion (e.g., stuffy nose), runny nose, and sneezing; or
  • the clinically symptomatic respiratory illness is characterized by the presence of at least one symptom selected from cough, sore throat, hoarseness of voice, nasal congestion (e.g., stuffy nose), runny nose, and sneezing, and at least one symptom selected from headache, feverishness/chills, and loss of appetite; or
  • the clinically symptomatic respiratory illness is characterized by the presence of at least one symptom selected from cough, sore throat, hoarseness of voice, nasal congestion (e.g., stuffy nose), runny nose, and sneezing, and at least one symptom selected from headache and feverishness/chills; or
  • the clinically symptomatic respiratory illness is characterized by the presence of at least one symptom selected from cough, sore throat, hoarseness of voice, nasal congestion (e.g., stuffy nose), runny nose, and sneezing, and at least one symptom selected from headache, feverishness/chills, body aches (e.g., muscle or joint pain), lack of energy, and loss of appetite.
  • at least one symptom is at least moderate in severity.
  • at least two symptoms are at least moderate in severity.
  • a clinically symptomatic respiratory illness is characterized by the presence of at least two symptoms outlined in Table 1 A or Table IB, below, wherein the presence of an“X” in a cell indicates that a particular symptom is present, and the absence of an “X’ indicates that a symptom may or may not be present.
  • at least one symptom is at least moderate in severity.
  • at least two symptoms are at least moderate in severity.
  • the present invention provides a method comprising the step of administering a low dose of BEZ235 or a pharmaceutically acceptable salt thereof, wherein the patient experiences fewer respiratory illnesses due to infection than a patient not administered BEZ235 or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method comprising the step of administering a low dose of BEZ235 or a pharmaceutically acceptable salt thereof, wherein the patient experiences fewer symptoms associated with a respiratory illness due to infection than a patient not administered BEZ235 or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method comprising the step of administering a low dose of BEZ235 or a pharmaceutically acceptable salt thereof, wherein the patient experiences a decreased time to alleviation of symptoms associated with respiratory illness due to infection than a patient not administered BEZ235 or a pharmaceutically acceptable salt thereof.
  • provided methods described above and herein comprise the administration of about 10 mg of BEZ235 or a pharmaceutically acceptable salt thereof (e.g., BEZ235 in the form of the monotosylate salt, referred to herein as RTB101), wherein administration occurs once daily. In some such embodiments, administration occurs orally and once daily. In some such embodiments, administration occurs orally and once daily for about 16 weeks.
  • the patient’s innate immunity is enhanced.
  • antigen-specific immunity is not enhanced.
  • At least one interferon-inducing gene is upregulated.
  • the clinically symptomatic respiratory illness is a respiratory tract infection.
  • the respiratory tract infection is associated with a viral pathogen.
  • viral pathogens include, but are not limited to, coronaviruses, human metapneumovirus (hMPV), human rhinovirus (HRV)/enterovirus, adenovirus, influenza A and B virus, parainfluenza viruses, and respiratory syncytial virus (RSV).
  • the patient is elderly, i.e., the patient is at least 65 years old.
  • the patient is at least 75 years old. [00128] In some embodiments, the patient is at least 85 years old.
  • the patient is immunocompromised.
  • the patient has an impaired immune response.
  • the patient is immunosenescent.
  • the patient is asthmatic.
  • the patient suffers from or is susceptible to a viral infection.
  • the patient suffers from or is susceptible to a respiratory illness, for instance, a respiratory tract infection (RTI).
  • a respiratory tract infection for instance, a respiratory tract infection (RTI).
  • the patient is a non-smoker. In some embodiments, the patient is a non-smoker with no prior history of smoking. In some embodiments, the patient is a previous smoker having smoked no more than 10 cigarette packs a year. In some embodiments, the patient is a previous smoker having smoked no more than 9, 8, 7, 6, 5, 4, 3, 2, or 1 cigarette packs a year. In some embodiments, the patient is a previous smoker who stopped smoking at least one year prior to treatment. In some embodiments, the patient is a previous smoker who stopped smoking at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 years prior to treatment.
  • the patient does not have a household member who smokes one or more packs of cigarettes per day. In some embodiments the patient does not have a household member who smokes.
  • the patient has no medical history of any clinically significant lung disease, exclusive of asthma.
  • the subject has no medical history of, e.g., chronic obstructive pulmonary disease (COPD), emphysema, interstitial pulmonary fibrosis (IPF), bronchiectasis, etc.
  • COPD chronic obstructive pulmonary disease
  • emphysema emphysema
  • IPF interstitial pulmonary fibrosis
  • bronchiectasis bronchiectasis
  • the subject resides in a nursing home facility.
  • the subject is residing in an assisted living facility.
  • the subject resides in a skilled nursing facility.
  • the subject resides in a rehabilitation facility.
  • the subject requires assistance with one or more activity of daily living.
  • ADL Activities of daily living
  • An individual’s ability to perform ADLs is important for determining what type of long-term care (e.g., nursing-home care or home care) and coverage the individual needs (i.e., Medicare, Medicaid or long-term care insurance).
  • ADLs activities of daily living: the things we normally do in daily living including any daily activity we perform for self-care such as cooking, feeding, bathing, dressing, grooming, work, homemaking, and leisure.
  • the ability or inability to perform ADLs can be used as a very practical measure of ability/disability in many disorders.
  • the subject has mobility disability.
  • Mobility disability or mobility impairment refers to the impaired ability of a person to use one or more of his/her extremities, or a decrease in strength needed to walk, grasp, or lift objects.
  • the use of a wheelchair, crutches, or a walker may be utilized to aid in mobility.
  • Mobility impairment may be caused by a number of factors, such as aging-related sarcopenia, disease, an accident, or a congenital disorder and may be the result from muscular, neuro-muscular or orthopedic impairments.
  • the low dose of BEZ235 or a pharmaceutically acceptable salt thereof is administered to the patient for up to about 3 consecutive weeks; up to about 4 consecutive weeks; up to about 5 consecutive weeks; about 6 consecutive weeks; up to about 8 consecutive weeks; up to about 10 consecutive weeks; up to about 12 consecutive weeks; up to about 16 consecutive weeks; up to about 20 consecutive weeks; up to about 6 consecutive months; up to about 1 year; or as part of long-term treatment (indefinitely).
  • the patient continues to experience fewer clinically symptomatic respiratory illnesses from about 1 day until about 1 year after the administration of BEZ235, or a pharmaceutically acceptable salt thereof.
  • the patient continues to experience fewer clinically symptomatic respiratory illnesses for at least 1 month and until about 1 year after the administration of BEZ235, or a pharmaceutically acceptable salt thereof.
  • the patient continues to experience fewer clinically symptomatic respiratory illnesses for at least 3 months and until about 1 year after the administration of BEZ235 or a pharmaceutically acceptable salt thereof. [00150] In some embodiments, the patient continues to experience fewer clinically symptomatic respiratory illnesses for at least 6 months after the administration of BEZ235 or a pharmaceutically acceptable salt thereof.
  • the patient is administered the low dose of BEZ235 or a pharmaceutically acceptable salt thereof as a monotherapy.
  • the pharmacokinetic AUC variability of patients receiving the low dose of BEZ235, or a pharmaceutically acceptable salt thereof is lower than a patient receiving a higher dose of BEZ235 or a pharmaceutically acceptable salt thereof.
  • BEZ235 or a pharmaceutically acceptable salt thereof is the monotosylate salt.
  • the method comprises the administration of 1 - 50 mg of BEZ235 or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises the administration of 1 - 25 mg of BEZ235 or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises the administration of 5 - 20 mg of BEZ235 or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises the administration of 6 - 18 mg of BEZ235 or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises the administration of 6 - 16 mg of BEZ235 or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises the administration of 6 - 14 mg of BEZ235 or a pharmaceutically acceptable salt thereof.
  • the method comprises the administration of 8 - 14 mg of BEZ235 or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises the administration of 8 - 12 mg of BEZ235 or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises the administration of 9 - 11 mg of BEZ235 or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises the administration of about 10 mg of BEZ235 or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of upregulating at least one interferon-inducing gene (ISG), comprising administering a low dose of BEZ235 or a pharmaceutically acceptable salt thereof, to a patient.
  • ISG interferon-inducing gene
  • the present invention provides a method of upregulating at least one protein involved in extracellular matrix remodeling, comprising administering a low dose BEZ235 or a pharmaceutically acceptable salt thereof, to a patient.
  • the protein involved in extracellular matrix remodeling is significantly upregulated following treatment for at least 1 day, about 1 week, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, or about 6 months.
  • the pharmaceutical composition may contain from about 0.1% to about 99.9%, for example from about 1% to about 60%, of the active ingredient(s).
  • compositions comprising a disclosed compound or combination, including fixed combinations or non-fixed combinations, for enteral or parenteral administration are, for example, those in unit dosage forms, such as sugar-coated tablets, tablets, capsules or suppositories, or ampoules. If not indicated otherwise, these are prepared in a manner known in the art, for example by means of various conventional mixing, comminution, granulating, sugar- coating, dissolving, lyophilizing processes, or fabrication techniques readily apparent to those skilled in the art. It will be appreciated that the unit content of a combination partner contained in an individual dose of each dosage form need not in itself constitute an effective amount since the necessary effective amount may be reached by administration of a plurality of dosage units. It will be further appreciated that the unit content of a combination partner for parenteral administration may contain a higher dosage amount of the combination partner which is diluted to the effective dosage amount before administration.
  • a unit dosage form containing the combination of agents or individual agents of the combination of agents may be in the form of micro-tablets enclosed inside a capsule, e.g., a gelatin capsule.
  • a gelatin capsule as is employed in pharmaceutical formulations can be used, such as the hard gelatin capsule known as CAPSUGELTM, available from Pfizer.
  • the unit dosage forms of the present invention may optionally further comprise additional conventional carriers or excipients used for pharmaceuticals.
  • additional conventional carriers or excipients used for pharmaceuticals include, but are not limited to, disintegrants, binders, lubricants, glidants, stabilizers, and fillers, diluents, colorants, flavors, and preservatives.
  • disintegrants include, but are not limited to, disintegrants, binders, lubricants, glidants, stabilizers, and fillers, diluents, colorants, flavors, and preservatives.
  • One of ordinary skill in the art may select one or more of the aforementioned carriers with respect to the particular desired properties of the dosage form by routine experimentation and without any undue burden.
  • the amount of each carrier used may vary within ranges conventional in the art.
  • the following references which are all hereby incorporated by reference disclose techniques and excipients used to formulate oral dosage forms.
  • These optional additional conventional carriers may be incorporated into the oral dosage form either by incorporating the one or more conventional carriers into the initial mixture before or during melt granulation or by combining the one or more conventional carriers with the granules in the oral dosage form.
  • the combined mixture may be further blended, e.g., through a V-blender, and subsequently compressed or molded into a tablet, for example a monolithic tablet, encapsulated by a capsule, or filled into a sachet.
  • Examples of pharmaceutically acceptable disintegrants include, but are not limited to, starches; clays; celluloses; alginates; gums; cross-linked polymers, e.g., cross-linked polyvinyl pyrrolidone or crospovidone, e.g., POLYPLASDONE XLTM from International Specialty Products (Wayne, NJ); cross-linked sodium carboxymethylcellulose or croscarmellose sodium, e.g., AC-DI-SOLTM from FMC; and cross-linked calcium carboxymethylcellulose; soy polysaccharides; and guar gum.
  • the disintegrant may be present in an amount from about 0% to about 10% by weight of the composition. In one embodiment, the disintegrant is present in an amount from about 0.1% to about 5% by weight of composition.
  • binders examples include, but are not limited to, starches; celluloses and derivatives thereof, for example, microcrystalline cellulose, e.g., AVICEL PHTM from FMC (Philadelphia, PA), hydroxypropyl cellulose hydroxylethyl cellulose and hydroxylpropylmethyl cellulose METHOCELTM from Dow Chemical Corp. (Midland, MI); sucrose; dextrose; corn syrup; polysaccharides; and gelatin.
  • the binder may be present in an amount from about 0% to about 50%, e.g., 2-20% by weight of the composition.
  • Examples of pharmaceutically acceptable lubricants and pharmaceutically acceptable glidants include, but are not limited to, colloidal silica, magnesium trisilicate, starches, talc, tribasic calcium phosphate, magnesium stearate, aluminum stearate, calcium stearate, magnesium carbonate, magnesium oxide, polyethylene glycol, powdered cellulose and microcrystalline cellulose.
  • the lubricant may be present in an amount from about 0% to about 10% by weight of the composition. In one embodiment, the lubricant may be present in an amount from about 0.1% to about 1.5% by weight of composition.
  • the glidant may be present in an amount from about 0.1% to about 10% by weight.
  • Examples of pharmaceutically acceptable fillers and pharmaceutically acceptable diluents include, but are not limited to, confectioner’s sugar, compressible sugar, dextrates, dextrin, dextrose, lactose, mannitol, microcrystalline cellulose, powdered cellulose, sorbitol, sucrose and talc.
  • the filler and/or diluent e.g., may be present in an amount from about 0% to about 80% by weight of the composition.
  • the effective dosage of a therapeutic agent may vary depending on the particular therapeutic agent or pharmaceutical composition employed, the mode of administration, the condition being treated, and the severity of the condition being treated. Thus, the dosage regimen is selected in accordance with a variety of factors including the route of administration and the renal and hepatic function of the patient. A clinician or physician of ordinary skill can readily determine and prescribe the effective amount of the single active ingredients required to alleviate, counter or arrest the progress of the condition.
  • packaged pharmaceutical products may contain one or more dosage forms that contain the combination of compounds, and one or more dosage forms that contain one of the combinations of therapeutic agent(s), but not the other therapeutic agent(s) of the combination.
  • BEZ235 or a pharmaceutically acceptable salt thereof for example its p-toluenesulfonate salt
  • the dosage of BEZ235 or a pharmaceutically acceptable salt thereof, such as its p- toluenesulfonate salt is administered, for example orally, at a dosage of about 10 mg daily to an adult person, such as a person aged 65 years or older.
  • the dosage of BEZ235 or a pharmaceutically acceptable salt thereof is from about 2 mg to about 19 mg, about 3 mg to about 17 mg, about 4 mg to about 16 mg, about 5 mg to about 15 mg, about 6 mg to about 14 mg, about 7 mg to about 13 mg, about 8 mg to about 12 mg, or about 9 mg to about 11 mg.
  • the dose of BEZ235 or a pharmaceutically acceptable salt thereof is about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg.
  • BEZ235 is administered orally as its p-toluenesulfonate salt (referred to herein as RTB101).
  • BEZ235 or a pharmaceutically acceptable salt thereof is administered twice per day, once per day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every two weeks, once every three weeks, once every four weeks, once a month, once every two months, once every three months, once every four months, once every six months, or once per year.
  • the optimal dosage for uses described above and herein can be determined empirically for each individual using known methods and will depend upon a variety of factors, including, though not limited to, the degree of advancement of the disease; the age, body weight, general health, gender and diet of the individual; the time and route of administration; and other medications the individual is taking.
  • the amount of therapeutic agent that may be combined with the carrier materials to produce a single dosage form will vary depending upon the individual treated and the particular mode of administration.
  • the unit dosage forms containing the combination of therapeutic agents as described herein will contain the amounts of each agent of the combination that are typically administered when the therapeutic agents are administered alone.
  • Frequency of dosage may vary depending on the therapeutic agent used and the particular condition to be treated. In general, the use of the minimum dosage that is sufficient to provide effective therapy is preferred. Patients may generally be monitored for therapeutic effectiveness using assays suitable for the condition being treated, which will be familiar to those of ordinary skill in the art.
  • the present invention provides a method of treating or preventing clinically symptomatic respiratory illness in a subject comprising administering to subject in need thereof BEZ235, or a pharmaceutically acceptable salt thereof, in an amount which is therapeutically effective at treating or preventing clinically symptomatic respiratory illness in a subject.
  • the present invention provides a method of treating or preventing respiratory illness due to infection in a subject comprising administering to subject in need thereof BEZ235, or a pharmaceutically acceptable salt thereof, in an amount which is therapeutically effective at treating or preventing respiratory illness due to infection in a subject.
  • the present invention provides a method of treating an age- related condition in a subject, comprising administering to a subject in need thereof BEZ235, or a pharmaceutically acceptable salt thereof, in an amount which is therapeutically effective to treat an age-related condition, such as respiratory tract infection.
  • the present invention provides a method of promoting and/or enhancing an immune response in a subject comprising administering to subject in need thereof BEZ235, or a pharmaceutically acceptable salt thereof in an amount which is therapeutically effective at promoting and/or enhancing an immune response in a subject, such as an innate immune response.
  • the present invention provides the use of BEZ235, or a pharmaceutically acceptable salt thereof for the treatment or prevention of clinically symptomatic respiratory illness and/or for the preparation of a medicament for the treatment or prevention of clinically symptomatic respiratory illness.
  • the present invention provides the use of BEZ235, or a pharmaceutically acceptable salt thereof for the treatment or prevention of respiratory illness due to infection and/or for the preparation of a medicament for the treatment or prevention of respiratory illness due to infection.
  • the present invention provides the use of BEZ235, or a pharmaceutically acceptable salt thereof for the treatment of an age-related condition and/or for the preparation of a medicament for the treatment of an age-related condition, such as respiratory tract infection.
  • the present invention provides a commercial package comprising BEZ235, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of clinically symptomatic respiratory illness.
  • the present invention provides a commercial package comprising BEZ235, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of respiratory illness due to infection.
  • the present invention provides a commercial package comprising BEZ235, or a pharmaceutically acceptable salt thereof, in the enhancement and/or promotion of an immune response, such as an innate immune response.
  • the present invention provides a commercial package comprising BEZ235, or a pharmaceutically acceptable salt thereof, and instructions for use in the treatment or prevention of clinically symptomatic respiratory illness.
  • the present invention provides a commercial package comprising BEZ235, or a pharmaceutically acceptable salt thereof, and instructions for use in the treatment or prevention of respiratory illness due to infection.
  • the methods provided herein can be used to treat or prevent an infection by a pathogen in a subject.
  • the subject is immunodeficient.
  • the subject is immunosenescent.
  • the subject is elderly.
  • the pathogen is a viral pathogen, e.g., a viral pathogen e.g.
  • HIV meningitis causing viruses, encephalitis causing viruses
  • the infection is a viral infection, such as a chronic viral infection.
  • a chronic viral infection is selected from Hepatitis A, Hepatitis B, Hepatitis C, Epstein-Barr Virus, HIV, Cytomegalovirus, Herpes Simplex Virus 1, Herpes Simplex Vims 2, Human Papillomavirus, Adenovirus, and Kaposi’s Sarcoma- Associated Herpesvirus.
  • a chronic viral infection comprises HIV.
  • a viral infection comprises a viral respiratory tract infection.
  • the viral respiratory tract infection is an upper viral respiratory tract infection.
  • the viral respiratory tract infection is a lower viral respiratory tract infection.
  • the viral respiratory tract infection is caused by a rhinovirus, coronavirus, influenza vims, respiratory syncytial vims (RSV), adenovims, metapneumovims, enterovims, bocavims paramyxovims, and/or parainfluenza vims.
  • a viral respiratory tract infection is pneumonia.
  • a viral respiratory tract infection includes a lung abscess.
  • a viral respiratory tract infection includes bronchitis.
  • the pathogen is a bacterial pathogen, e.g., a bacterial pathogen selected from Meningococcus, Haemophilus, Pneumococcus, Staphylococcus, Streptococcus, Neisseria, Moraxella, Escherichia coli, Klebsiella, Pseudomonas, Enterobacter, Proteus, Serratia, Legionella, Salmonella, Shigella, Acinetobacer, Listeria, Chlamydia, and Mycobacterium, among others.
  • a bacterial pathogen selected from Meningococcus, Haemophilus, Pneumococcus, Staphylococcus, Streptococcus, Neisseria, Moraxella, Escherichia coli, Klebsiella, Pseudomonas, Enterobacter, Proteus, Serratia, Legionella, Salmonella, Shigella, Acinetobacer, Listeria, Chlamydi
  • the pathogen is a parasitic pathogen, e.g., Toxoplasma, Leishmania and malaria, T. cruzii, Helminth, e.g., Schistosoma.
  • a parasitic pathogen e.g., Toxoplasma, Leishmania and malaria, T. cruzii, Helminth, e.g., Schistosoma.
  • the pathogen is a yeast or fungal pathogen, e.g., Candida, Cryptococcus, Coccidioides, Blastomyces, aspergillus, or mucormycetes.
  • the methods provided herein can be used to treat senescence in a subject.
  • senescence is meant to include all types of aging.
  • senescence comprises immunodeficiency, for example immunosenescence.
  • Immunosenescence includes reduced immune response to infection with age and results from thymic involution in T-cell lineages, resulting in decreased T cell production and export (see e.g., Shimatani, K et al. (2009) PNAS 106 (37): 15807-15812).
  • senescence comprises cellular senescence, in which a cell no longer divides.
  • age-related immunosenescence comprises decreased production of naive lymphocytes by hematopoietic stem cells (Chen, Science Signalling, ra75, 2009).
  • telomeres are correlated with the progressive shortening of telomeres that occurs with each cell division or the intracellular expression of pi 6.
  • senescence comprises an age-related decrease in the function of neutrophils, lymphocytes, NK cells, macrophages and/or dendritic cells (see e.g. Boraschi D et al. (2013) Sci Transl Med 5(185):ps8; Kumar R and Burns EA. (2008) Expert Rev. Vaccines 7(4): 467-479.
  • the present invention provides pharmaceutical formulations that are useful for the oral administration of BEZ235, or pharmaceutically acceptable salt thereof, to a subject in need thereof.
  • the present invention provides pharmaceutical formulations that are useful for the oral administration of RTB101 to a subject in need thereof.
  • RTB101 refers to the monotosylate salt unless otherwise indicated. It will be appreciated that 10 mg of RTB101 freebase (i.e., BEZ235) corresponds to about 13.67 mg RTB101 (i.e., monotosylate salt form of BEZ235).
  • the formulation is orally administered in a solid dosage form.
  • the formulation comprises one or more crystalline forms of RTB101 as described and defined in U.S. Pat. No. 8,436, 177, which is incorporated herein by reference in its entirety.
  • the formulation further comprises one or more pharmaceutically acceptable excipients or carriers.
  • the pharmaceutically acceptable excipients and carriers are selected from fillers, binders, diluents, disintegrants, glidants, and lubricants.
  • the pharmaceutically acceptable excipients and carriers are selected from fillers, binders, diluents, disintegrants, glidants, and lubricants.
  • formulations of the present invention are amenable to a wide range of doses of RTB101 and may be used for the production of RTB101 solid dosage forms comprising between about 5 and about 100 mg RTB101 (freebase; about 6.83 mg to about 136.6 mg monotosylate salt).
  • the present invention provides a solid dosage form comprising an intra-granular phase and an extra-granular phase.
  • intra-granular phase refers to that phase that is formed by a granulation process, wherein one or more ingredients (e.g., powder ingredients) are combined into multiparticle entities by compression or use of a binding agent (i.e., a granule).
  • extra-granular phase refers to that phase of a formulation that is added to the intra-granular phase, but does not go through the same granulation process.
  • the present invention provides a solid dosage form comprising an intra-granular phase, an extra-granular phase, and a film coating.
  • film coating refers to a matte, semi-glossy, or glossy finish on the surface of the solid dosage form that may be pigmented or not pigmented.
  • the present invention provides a solid dosage form comprising an intra-granular phase and an extra-granular phase, wherein the intra-granular phase comprises between about 30% to about 99.9% (w/w) of the solid dosage form and the extra-granular phase comprises between about 0.1% to about 70% (w/w) of the solid dosage form.
  • the intra-granular phase comprises between about 85% to about 98.5% (w/w) and the extra-granular phase comprises between about 1.5% to about 15% (w/w) of the solid dosage form.
  • the intra-granular phase comprises between about 90% to about 98.5% (w/w) and the extra-granular phase comprises between about 1.5% to about 10% (w/w) of the solid dosage form.
  • the present invention provides a solid dosage form comprising an intra-granular phase, an extra-granular phase, and a film coating, wherein the intra-granular phase comprises between about 30% to about 99.8% (w/w) of the solid dosage form, the extra- granular phase comprises between about 0.1% to about 69.9% (w/w) of the solid dosage form, and the film coating comprises between about 0.1% to 5% (w/w) of the solid dosage form.
  • the present invention provides a solid dosage form comprising an intra-granular phase and an extra-granular phase, wherein the intra-granular phase comprises between about 80% to about 97.5% (w/w) of the solid dosage form, the extra-granular phase comprises between about 1.5% to about 15% (w/w) of the solid dosage form, and the film coating comprises between about 1% to 5% (w/w) of the solid dosage form.
  • the present invention provides a solid dosage form comprising an intra-granular phase, an extra-granular phase, and a film coating, wherein the intra-granular phase comprises between about 86% to about 95% (w/w) of the solid dosage form, the extra- granular phase comprises between about 2.5% to about 10% (w/w) of the solid dosage form, and the film coating comprises between about 2.5% to 4% (w/w) of the solid dosage form.
  • the present invention provides a solid dosage form comprising an intra-granular phase and an extra-granular phase, wherein the intra-granular phase comprises about 98.5% (w/w) of the solid dosage form and the extra-granular phase comprises about 1.5% (w/w) of the solid dosage form.
  • the present invention provides a solid dosage form comprising an intra-granular phase and an extra-granular phase, wherein the intra-granular phase comprises about 95% (w/w) of the solid dosage form and the extra-granular phase comprises about 5% (w/w) of the solid dosage form.
  • the present invention provides a solid dosage form comprising an intra-granular phase an extra-granular phase, and a film coating, wherein the intra-granular phase comprises about 92% (w/w) of the solid dosage form, the extra-granular phase comprises about 5% (w/w) of the solid dosage form, and the film coating comprises about 3% (w/w) of the solid dosage form.
  • the intra granular phase comprises: a) RTB 101 , or a pharmaceutically acceptable salt thereof;
  • the extra granular phase comprises:
  • the extra granular phase comprises:
  • the present invention provides a capsule or table which comprises a provided solid dosage form. In some embodiments, the present invention provides a capsule. In some embodiments, the present invention provides a tablet.
  • the formulation comprises one or more fillers.
  • the filler is selected from ammonium aliginate, calcium carbonate, calcium lactate, calcium phosphate, calcium silicate, calcium sulfate, cellulose acetate, compressible sugar (e.g., lactose, glucose, and sucrose), corn starch, dextrates, erythritol, ethyl cellulose, glyceryl palmitostearate, isomalt, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, medium-chain triglycerides, microcrystalline cellulose, pre-gel atinized starch, polydextrose, polymethacrylates, silicic acid, simethicone, sodium alginate, sodium chloride, sorbitol, starch, sugar spheres, sulfobutylether b-cyclodextrin, talc, tragacanth, trehalose, and xylito
  • the filler is microcrystalline cellulose.
  • the filler is lactose.
  • the filler is starch.
  • the filler is a combination of starch and lactose.
  • the filler is a combination of lactose and microcrystalline cellulose.
  • the formulation comprises one or more binders.
  • the binder is selected from acacia gum, agar, alginic acid, calcium carbonate, calcium lactate, carbomers (e.g., acrylic acid polymer, carboxy polymethylene, polyacrylic acid, carboxyvinyl polymer), carboxymethylcellulose sodium, carrageenan, cellulose acetate phthalate, ceratonia, chitosan, copovidone, com starch, cottonseed oil, dextrates, dextrin, dextrose, ethylcellulose, gelatin, glyceryl behenate, guar gum, hydrogenated vegetable oil type I, hydroxyethylcellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hypromellose, inulin, lactose, magnesium aluminum silicate, maltodextrin, maltose, methylcellulose, microcrystalline cellulose, pecation of cellulose sodium acacia gum
  • the binder is hydroxypropyl cellulose.
  • the binder is methylcellulose.
  • the binder is hydroxypropyl methylcellulose (HPMC).
  • the binder is povidone (e.g., Kollidon K30).
  • the formulation comprises one or more disintegrants.
  • the disintegrant is selected from alginic acid, calcium alginate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, cellulose, chitosan, colloidal silicon dioxide, com starch, croscarmellose sodium, crospovidone, docusate sodium, glycine, guar gum, hydroxypropyl cellulose, magnesium aluminum silicate, methylcellulose, microcrystalline cellulose, pre-gelatinized starch, polacrilin potassium, povidone, silicates, sodium aliginate, sodium carbonate, and sodium starch glycolate.
  • the disintegrant is crospovidone.
  • the formulation comprises one or more surfactants.
  • the surfactant is selected from polyoxyethylene (20) sorbitan monolaurate (e.g., Tween-20), polyoxyethylene (20) sorbitan monooleate (e.g., Tween-80), sodium laurel sulfate, and sodium dodecyl sulfate.
  • the formulation comprises one or more pore formers.
  • the pore former is selected from hydroxypropylcellulose, hydroxypropylmethylcellulose, polyethyleneglycol, poloaxamer 188, povidone (e.g., Kollidon K25/K30), or sugar (e.g., glucose, mannose, fructose, and sucrose).
  • the formulation comprises one or more glidants.
  • the glidant is selected from calcium phosphate, cellulose, colloidal silicon dioxide, magnesium oxide, magnesium silicate, magnesium stearate, magnesium trisilicate, and talc.
  • the glidant is colloidal silicon dioxide.
  • the formulation comprises one or more lubricants.
  • the lubricant is selected from calcium stearate, glycerin monosterate, glyceryl behenate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, light mineral oil, myristic acid, poloxamer, polyethylene glycol, sodium benzoate, sodium chloride, sodium lauryl sulfate, sodium stearyl fumarate, solid polyethylene glycols, stearic acid, and talc.
  • the lubricant is magnesium stearate.
  • the formulation comprises one or more film coating agents.
  • the film coating comprises a poly(vinyl alcohol) base.
  • the film coating includes a coloring agent or pigment.
  • the film coating is Opadry II ®. In some embodiments, the film coating is Opadry II ® yellow.
  • formulation ingredients may serve multiple purposes within a formulation. Accordingly, a person of ordinary skill would recognize that certain formulation components may be classified according to multiple functions (e.g., a component may be both a filler and a binder).
  • a formulation of the present invention is prepared by granulation.
  • a granulation liquid is used.
  • the granulation liquid is water.
  • granules are passed through a 2 mm screen. In some embodiments, granules are passed through a 1 mm screen. In some embodiments, granules are passed through a 0.8 mm screen. In some embodiments, the granules are passed through a 0.5 mm screen.
  • granules have a particle size of between about 1 pm and about 100 pm, according to laser light diffraction. In some embodiments, granules have a particle size of between about 10 pm and about 90 pm. In some embodiments, granules have a particle size of between about 20 pm and about 80 pm. In some embodiments, granules have a particle size of between about 30 pm and about 70 pm. In some embodiments, granules have a particle size of between about 40 pm and about 60 pm. [00240] In some embodiments, the granule geometric mean particle size, according to laser light diffraction, is between about 10 pm and about 90 pm.
  • the granule geometric mean particle size is about 10 pm. In some embodiments, the granule geometric mean particle size is about 15 pm. In some embodiments, the granule geometric mean particle size is about 20 pm. In some embodiments, the granule geometric mean particle size is about 25 pm. In some embodiments, the granule geometric mean particle size is about 30 pm. In some embodiments, the granule geometric mean particle size is about 35 pm. In some embodiments, the granule geometric mean particle size is about 40 pm. In some embodiments, the granule geometric mean particle size is about 45 pm. In some embodiments, the granule geometric mean particle size is about 50 pm. In some embodiments, the granule geometric mean particle size is about 55 pm.
  • the granule geometric mean particle size is about 60 pm. In some embodiments, the granule geometric mean particle size is about 65 pm. In some embodiments, the granule geometric mean particle size is about 70 pm. In some embodiments, the granule geometric mean particle size is about 75 pm. In some embodiments, the granule geometric mean particle size is about 80 pm. In some embodiments, the granule geometric mean particle size is about 85 pm. In some embodiments, the granule geometric mean particle size is about 90 pm.
  • about five percent (5%) of the granules have a particle size of less than or equal to about 50 pm, according to laser light diffraction. In some embodiments, about ten percent (10%) of the granules have a particle size of less than or equal to about 50 pm. In some embodiments, about fifteen percent (15%) of the granules have a particle size of less than or equal to about 50 pm. In some embodiments, about twenty percent (20%) of the granules have a particle size of less than or equal to about 50 pm. In some embodiments, about twenty- five percent (25%) of the granules have a particle size of less than or equal to about 50 pm.
  • about thirty percent (30%) of the granules have a particle size of less than or equal to about 50 pm. In some embodiments, about thirty-five percent (35%) of the granules have a particle size of less than or equal to about 50 pm. In some embodiments, about forty percent (40%) of the granules have a particle size of less than or equal to about 50 pm. In some embodiments, about forty -five percent (45%) of the granules have a particle size of less than or equal to about 50 pm. In some embodiments, about fifty percent (50%) of the granules have a particle size of less than or equal to about 50 pm.
  • about fifty -five percent (55%) of the granules have a particle size of less than or equal to about 50 pm. In some embodiments, about sixty percent (60%) of the granules have a particle size of less than or equal to about 50 pm. In some embodiments, about sixty-five percent (65%) of the granules have a particle size of less than or equal to about 50 pm. In some embodiments, about seventy percent (70%) of the granules have a particle size of less than or equal to about 50 pm. In some embodiments, about seventy-five percent (75%) of the granules have a particle size of less than or equal to about 50 pm.
  • about eighty percent (80%) of the granules have a particle size of less than or equal to about 50 pm. In some embodiments, about eighty-five percent (85%) of the granules have a particle size of less than or equal to about 50 pm. In some embodiments, about ninety percent (90%) of the granules have a particle size of less than or equal to about 50 pm. In some embodiments, about ninety-five percent (95%) of the granules have a particle size of less than or equal to about 50 pm.
  • about five percent (5%) of the granules have a particle size of less than or equal to about 10 pm, according to laser light diffraction. In some embodiments, about ten percent (10%) of the granules have a particle size of less than or equal to about 10 pm. In some embodiments, about fifteen percent (15%) of the granules have a particle size of less than or equal to about 10 pm. In some embodiments, about twenty percent (20%) of the granules have a particle size of less than or equal to about 10 pm. In some embodiments, about twenty- five percent (25%) of the granules have a particle size of less than or equal to about 10 pm.
  • about thirty percent (30%) of the granules have a particle size of less than or equal to about 10 pm. In some embodiments, about thirty-five percent (35%) of the granules have a particle size of less than or equal to about 10 pm. In some embodiments, about forty percent (40%) of the granules have a particle size of less than or equal to about 10 pm. In some embodiments, about forty -five percent (45%) of the granules have a particle size of less than or equal to about 10 pm. In some embodiments, about fifty percent (50%) of the granules have a particle size of less than or equal to about 10 pm.
  • about fifty -five percent (55%) of the granules have a particle size of less than or equal to about 10 pm. In some embodiments, about sixty percent (60%) of the granules have a particle size of less than or equal to about 10 pm. In some embodiments, about sixty-five percent (65%) of the granules have a particle size of less than or equal to about 10 pm. In some embodiments, about seventy percent (70%) of the granules have a particle size of less than or equal to about 10 pm. In some embodiments, about seventy-five percent (75%) of the granules have a particle size of less than or equal to about 10 pm.
  • about eighty percent (80%) of the granules have a particle size of less than or equal to about 10 pm. In some embodiments, about eighty-five percent (85%) of the granules have a particle size of less than or equal to about 10 pm. In some embodiments, about ninety percent (90%) of the granules have a particle size of less than or equal to about 10 pm. In some embodiments, about ninety-five percent (95%) of the granules have a particle size of less than or equal to about 10 pm.
  • the present invention provides a solid dosage form comprising about 0.1% to about 50% (w/w) RTB101. In some embodiments, the solid dosage form comprises about 1% to about 40% (w/w) RTB101. In some embodiments, the solid dosage form comprises about 2% to about 35% (w/w) RTB101. In some embodiments, the solid dosage form comprises about 3% to about 30% (w/w) RTB101. In some embodiments, the solid dosage form comprises about 4% to about 25% (w/w) RTB101. In some embodiments, the solid dosage form comprises about 5% to about 20% (w/w) RTB101. In some embodiments, the solid dosage form comprises about 6% to about 15% (w/w) RTB101.
  • the present invention provides a solid dosage form comprising about 0.1% (w/w) RTB101.
  • the solid dosage form comprises about 1% (w/w) RTB101.
  • the solid dosage form comprises about 2% (w/w) RTB101.
  • the solid dosage form comprises about 3% (w/w) RTB101.
  • the solid dosage form comprises about 4% (w/w) RTB101.
  • the solid dosage form comprises about 5% (w/w) RTB101.
  • the solid dosage form comprises about 6% (w/w) RTB101.
  • the solid dosage form comprises about 7% (w/w) RTB101.
  • the solid dosage form comprises about 8% (w/w) RTB101. In some embodiments, the solid dosage form comprises about 9% (w/w) RTB101. In some embodiments, the solid dosage form comprises about 10% (w/w) RTB101. In some embodiments, the solid dosage form comprises about 11% (w/w) RTB101. In some embodiments, the solid dosage form comprises about 12% (w/w) RTB101. In some embodiments, the solid dosage form comprises about 13% (w/w) RTB101. In some embodiments, the solid dosage form comprises about 14% (w/w) RTB101. In some embodiments, the solid dosage form comprises about 15% (w/w) RTB101.
  • the solid dosage form comprises about 16% (w/w) RTB101. In some embodiments, the solid dosage form comprises about 17% (w/w) RTB101. In some embodiments, the solid dosage form comprises about 18% (w/w) RTB101. In some embodiments, the solid dosage form comprises about 19% (w/w) RTB101. In some embodiments, the solid dosage form comprises about 20% (w/w) RTB101. In some embodiments, the solid dosage form comprises about 25% (w/w) RTB101. In some embodiments, the solid dosage form comprises about 30% (w/w) RTB101. In some embodiments, the solid dosage form comprises about 35% (w/w) RTB101.
  • the solid dosage form comprises about 40% (w/w) RTB101. In some embodiments, the solid dosage form comprises about 45% (w/w) RTB101. In some embodiments, the solid dosage form comprises about 50% (w/w) RTB101.
  • the present invention provides a solid dosage form comprising one (1) filler.
  • the solid dosage form comprises two (2) fillers.
  • the solid dosage form comprises three (3) fillers.
  • the present invention provides a solid dosage form comprising about 50 to about 99.9% (w/w) filler. In some embodiments, the solid dosage form comprises about 55% to about 95% (w/w) filler. In some embodiments, the solid dosage form comprises about 60% to about 90% (w/w) filler. In some embodiments, the solid dosage form comprises about 65% to about 85% (w/w) filler. In some embodiments, the solid dosage form comprises about 70% to about 80% (w/w) filler.
  • the present invention provides a solid dosage form comprising about 50% (w/w) filler. In some embodiments, the solid dosage form comprises about 55% (w/w) filler. In some embodiments, the solid dosage form comprises about 60% (w/w) filler. In some embodiments, the solid dosage form comprises about 65% (w/w) filler. In some embodiments, the solid dosage form comprises about 70% (w/w) filler. In some embodiments, the solid dosage form comprises about 75% (w/w) filler. In some embodiments, the solid dosage form comprises about 80% (w/w) filler. In some embodiments, the solid dosage form comprises about 85% (w/w) filler. In some embodiments, the solid dosage form comprises about 90% (w/w) filler. In some embodiments, the solid dosage form comprises about 95% (w/w) filler. In some embodiments, the solid dosage form comprises about 99.9% (w/w) filler.
  • the present invention provides a solid dosage form comprising about 0.1% to about 10% (w/w) disintegrant. In some embodiments, the solid dosage form comprises about 0.5% to about 9% (w/w) disintegrant. In some embodiments, the solid dosage form comprises about 1% to about 8% (w/w) disintegrant. In some embodiments, the solid dosage form comprises about 1.5% to about 7% (w/w) disintegrant. In some embodiments, the solid dosage form comprises about 2% to about 6% (w/w) disintegrant. In some embodiments, the solid dosage form comprises about 2.5% to about 5% (w/w) disintegrant. In some embodiments, the solid dosage form comprises about 3% to about 4% (w/w) disintegrant.
  • the present invention provides a solid dosage form comprising about 0.1% (w/w) disintegrant.
  • the solid dosage form comprises about 1% (w/w) disintegrant.
  • the solid dosage form comprises about 2% (w/w) disintegrant.
  • the solid dosage form comprises about 3% (w/w) disintegrant.
  • the solid dosage form comprises about 4% (w/w) disintegrant.
  • the solid dosage form comprises about 5% (w/w) disintegrant.
  • the solid dosage form comprises about 6% (w/w) disintegrant.
  • the solid dosage form comprises about 7% (w/w) disintegrant.
  • the solid dosage form comprises about 8% (w/w) disintegrant. In some embodiments, the solid dosage form comprises about 9% (w/w) disintegrant. In some embodiments, the solid dosage form comprises about 10% (w/w) disintegrant.
  • the present invention provides a solid dosage form comprising about 0.1% to about 10% (w/w) binder. In some embodiments, the solid dosage form comprises about 1% to about 9% (w/w) binder. In some embodiments, the solid dosage form comprises about 2% to about 8% (w/w) binder. In some embodiments, the solid dosage form comprises about 3% to about 7% (w/w) binder. In some embodiments, the solid dosage form comprises about 4% to about 6% (w/w) binder.
  • the present invention provides a solid dosage form comprising about 0.1% (w/w) binder. In some embodiments, the solid dosage form comprises about 0.5% (w/w) binder. In some embodiments, the solid dosage form comprises about 1% (w/w) binder. In some embodiments, the solid dosage form comprises about 1.5% (w/w) binder. In some embodiments, the solid dosage form comprises about 2% (w/w) binder. In some embodiments, the solid dosage form comprises about 2.5% (w/w) binder. In some embodiments, the solid dosage form comprises about 3% (w/w) binder. In some embodiments, the solid dosage form comprises about 3.5% (w/w) binder.
  • the solid dosage form comprises about 4% (w/w) binder. In some embodiments, the solid dosage form comprises about 4.5% (w/w) binder. In some embodiments, the solid dosage form comprises about 5% (w/w) binder. In some embodiments, the solid dosage form comprises about 5.5% (w/w) binder. In some embodiments, the solid dosage form comprises about 6% (w/w) binder. In some embodiments, the solid dosage form comprises about 6.5% (w/w) binder. In some embodiments, the solid dosage form comprises about 7% (w/w) binder. In some embodiments, the solid dosage form comprises about 7.5% (w/w) binder. In some embodiments, the solid dosage form comprises about 8% (w/w) binder.
  • the solid dosage form comprises about 8.5% (w/w) binder. In some embodiments, the solid dosage form comprises about 9% (w/w) binder. In some embodiments, the solid dosage form comprises about 9.5% (w/w) binder. In some embodiments, the solid dosage form comprises about 10% (w/w) binder.
  • the present invention provides a solid dosage form comprising about 0.1% to 3% glidant.
  • the solid dosage form comprises about 0.25% to about 2.75% (w/w) glidant.
  • the solid dosage form comprises about 0.5% to about 2.5% (w/w) glidant.
  • the solid dosage form comprises about 0.75% to about 2.25% (w/w) glidant.
  • the solid dosage form comprises about 1% to about 2% (w/w) glidant.
  • the solid dosage form comprises about 1.25% to about 1.75% (w/w) glidant.
  • the present invention provides a solid dosage form comprising about 0.1% (w/w) glidant.
  • the solid dosage form comprises about 0.25% (w/w) glidant.
  • the solid dosage form comprises about 0.5% (w/w) glidant.
  • the solid dosage form comprises about 0.75% (w/w) glidant.
  • the solid dosage form comprises about 1% (w/w) glidant.
  • the solid dosage form comprises about 1.25% (w/w) glidant.
  • the solid dosage form comprises about 1.5% (w/w) glidant.
  • the solid dosage form comprises about 1.75% (w/w) glidant. In some embodiments, the solid dosage form comprises about 2% (w/w) glidant. In some embodiments, the solid dosage form comprises about 2.25% (w/w) glidant. In some embodiments, the solid dosage form comprises about 2.5% (w/w) glidant. In some embodiments, the solid dosage form comprises about 2.75% (w/w) glidant. In some embodiments, the solid dosage form comprises about 3% (w/w) glidant.
  • the present invention provides a solid dosage form comprising about 0.1% to about 3% lubricant.
  • the solid dosage form comprises about 0.25% to about 2.75% (w/w) lubricant.
  • the solid dosage form comprises about 0.5% to about 2.5% (w/w) lubricant.
  • the solid dosage form comprises about 0.75% to about 2.25% (w/w) lubricant.
  • the solid dosage form comprises about 1% to about 2 % (w/w) lubricant.
  • the solid dosage form comprises about 1.25% to about 1.75% (w/w) lubricant.
  • the present invention provides a solid dosage form comprising about 0.1% (w/w) lubricant.
  • the solid dosage form comprises about 0.25% (w/w) lubricant.
  • the solid dosage form comprises about 0.5% (w/w) lubricant.
  • the solid dosage form comprises about 0.75% (w/w) lubricant.
  • the solid dosage form comprises about 1% (w/w) lubricant.
  • the solid dosage form comprises about 1.25% (w/w) lubricant.
  • the solid dosage form comprises about 1.5% (w/w) lubricant.
  • the solid dosage form comprises about 1.75% (w/w) lubricant. In some embodiments, the solid dosage form comprises about 2% (w/w) lubricant. In some embodiments, the solid dosage form comprises about 2.25% (w/w) lubricant. In some embodiments, the solid dosage form comprises about 2.5% (w/w) lubricant. In some embodiments, the solid dosage form comprises about 2.75% (w/w) lubricant. In some embodiments, the solid dosage form comprises about 3% (w/w) lubricant.
  • the present invention provides a solid dosage form comprising about 0.1% to about 5% film coating. In some embodiments, the solid dosage form comprises about 1% to about 5% (w/w) film coating. In some embodiments, the present invention provides a solid dosage form comprising about 1% to about 5% film coat. In some embodiments, the solid dosage form comprises about 2.5% to about 4% (w/w) film coat.
  • the present invention provides a solid dosage form comprising about 0.1% (w/w) film coating. In some embodiments, the present invention provides a solid dosage form comprising about 0.5% (w/w) film coating. In some embodiments, the present invention provides a solid dosage form comprising about 1.5% (w/w) film coating. In some embodiments, the present invention provides a solid dosage form comprising about 2% (w/w) film coating. In some embodiments, the present invention provides a solid dosage form comprising about 2.5% (w/w) film coating. In some embodiments, the present invention provides a solid dosage form comprising about 3% (w/w) film coating.
  • the present invention provides a solid dosage form comprising about 3.5% (w/w) film coating. In some embodiments, the present invention provides a solid dosage form comprising about 4% (w/w) film coating. In some embodiments, the present invention provides a solid dosage form comprising about 4.5% (w/w) film coating. In some embodiments, the present invention provides a solid dosage form comprising about 5% (w/w) film coating.
  • the present invention provides a pharmaceutical formulation comprising about 0.1% to about 50% (w/w) RTB101, about 50% to about 99.9% (w/w) filler, about 0.1% to about 10% (w/w) disintegrant, about 0.1% to about 10% (w/w) binder, about 0.1% to about 3% (w/w) glidant, and about 0.1% to about 3% (w/w) lubricant.
  • the present invention provides a pharmaceutical formulation comprising about 6 to about 15% (w/w) RTB 101, about 65% to about 85% (w/w) filler, about 2% to about 6% (w/w) disintegrant, about 2% to about 4% (w/w) binder, about 0.5% to about 2.5% (w/w) glidant, and about 1% to about 2% (w/w) lubricant.
  • the present invention provides a pharmaceutical formulation comprising about 6% to about 15% (w/w) RTB 101, about 65% to about 85% (w/w) lactose and starch, about 2% to about 6% (w/w) crospovidone, about 2% to about 4% (w/w) povidone (e.g., Kollidon K30), and about 0.5% to about 2.5% (w/w) colloidal silicon dioxide, and about 1.25% to about 1.75% (w/w) magnesium stearate.
  • a pharmaceutical formulation comprising about 6% to about 15% (w/w) RTB 101, about 65% to about 85% (w/w) lactose and starch, about 2% to about 6% (w/w) crospovidone, about 2% to about 4% (w/w) povidone (e.g., Kollidon K30), and about 0.5% to about 2.5% (w/w) colloidal silicon dioxide, and about 1.25% to about 1.75% (w/w) magnesium stea
  • the present invention provides a pharmaceutical formulation comprising about 6% to about 15% (w/w) RTB101, about 64.9% to about 84.9% (w/w) lactose, about 0.1% to about 20% (w/w) starch, about 2% to about 6% (w/w) crospovidone, about 2% to about 4% (w/w) povidone, and about 0.5% to about 2.5% (w/w) colloidal silicon dioxide, and about 1.25% to about 1.75% (w/w) magnesium stearate.
  • the present invention provides a pharmaceutical formulation comprising about 14% (w/w) RTB101, about 66% (w/w) lactose, about 13% (w/w) starch, about 2% (w/w) crospovidone, about 3% (w/w) povidone, about 0.5% (w/w) colloidal silicon dioxide, and about 1.5% (w/w) magnesium stearate.
  • the present invention provides a pharmaceutical formulation comprising about 0.1% to about 50% (w/w) RTB101, about 50% to about 99.9% (w/w) filler, about 0.1% to about 10% (w/w) disintegrant, about 0.1% to about 10% (w/w) binder, about 0.1% to about 3% (w/w) glidant, about 0.1% to about 3% (w/w) lubricant, and about 0.1% (w/w) to about 5% (w/w) film coating.
  • the present invention provides a pharmaceutical formulation comprising about 5 to about 20% (w/w) RTB 101, about 65% to about 85% (w/w) filler, about 2% to about 6% (w/w) disintegrant, about 1% to about 9% (w/w) binder, about 0.75% to about 2.25% (w/w) glidant, about 1% to about 2% (w/w) lubricant, and about 2.5% (w/w) to about 4% (w/w) film coating.
  • the present invention provides a pharmaceutical formulation comprising about 5 to about 20% (w/w) RTB101, about 65% to about 85% (w/w) lactose (e.g., Pharmatose 200M) and microcrystalline cellulose (e.g., Avicel PHI 12), about 2% to about 6% (w/w) crospovidone (e.g., Polyplasdone Ultra), about 1% to about 9% (w/w) hydroxypropyl methyl cellulose (e.g., E3 Premium LV), about 1% to about 2% (w/w) colloidal silicon dioxide (e.g., Aerosil 200), about 1% to about 2% (w/w) magnesium stearate (e.g., Ligamed-MF-2V), and about 2.5% (w/w) to about 4% (w/w) poly(vinyl alcohol) based film coating (e.g., Opadry II ® yellow).
  • lactose e.g., Pharmatose 200M
  • the present invention provides a pharmaceutical formulation comprising about 5 to about 20% (w/w) RTB101, about 45% to about 55% (w/w) lactose, about 20% (w/w) to about 30% (w/w) microcrystalline cellulose, about 2% to about 6% (w/w) crospovidone, about 1% to about 9% (w/w) hydroxypropyl methyl cellulose, about 1% to about 2% (w/w) colloidal silicon dioxide, about 1% to about 2% (w/w) magnesium stearate, and about 2.5% (w/w) to about 4% (w/w) poly(vinyl alcohol) based film coating.
  • the present invention provides a pharmaceutical formulation comprising about 16.5% (w/w) RTB101, about 49.9% (w/w) lactose, about 21.8% (w/w) microcrystalline cellulose, about 4.8% (w/w) crospovidone, about 1.5% (w/w) hydroxypropyl methyl cellulose, about 1% (w/w) colloidal silicon dioxide, about 1.5% (w/w) magnesium stearate, and about 3% (w/w) poly(vinyl alcohol) based film coating.
  • the pharmaceutical compositions provided herein can be provided in a unit-dosage form or multiple-dosage form.
  • a unit-dosage form refers to physically discrete unit suitable for administration to a human and animal subject, and packaged individually as is known in the art. Each unit-dose contains a predetermined quantity of an active ingredient(s) sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carriers or excipients. Examples of a unit-dosage form include an individually packaged tablet or capsule. A unit-dosage form may be administered in fractions or multiples thereof.
  • a multiple-dosage form is a plurality of identical unit-dosage forms packaged in a single container to be administered in segregated unit-dosage form.
  • the unit dosage form may vary according to a variety of factors such as underlying disease states, the individual's condition, weight, sex and age and the mode of administration.
  • co-administration or sequential administration of other active agents may be desirable.
  • the active agents can be administered concurrently, or they each can be administered at separately staggered times.
  • the dosage amount may be adjusted when combined with other active agents, such as when there is synergy.
  • the present invention provides a unit-dosage form comprising about 0.1 mg to about lOO mg RTBlOl .
  • the unit-dosage form comprises about 7 mg to about 34 mg RTB101.
  • the unit-dosage form comprises about 7 mg RTB101.
  • the unit-dosage form comprises about 14 mg RTB101.
  • the unit-dosage-form comprises about 34 mg RTB101.
  • RTB101 incorporated into a provided composition will vary depending on whether the freebase or a salt form is utilized. By way of example, it will be appreciated that about 10 mg of RTB101 freebase corresponds to about 13.67 mg RTB101 monotosylate salt.
  • the present invention provides a unit-dosage form comprising about 39.5 mg to about 199.5 mg filler. In some embodiments, the unit-dosage form comprises about 39.5 mg filler. In some embodiments, the unit-dosage form comprises about 80 mg filler. In some embodiments, the unit-dosage form comprises about 199.5 mg filler. [00273] In some embodiments, the present invention provides a unit-dosage form comprising about 29.5 mg to about 148 mg filler. In some embodiments, the unit-dosage form comprises about 29.5 mg filler. In some embodiments, the unit-dosage form comprises about 59 mg filler. In some embodiments, the unit-dosage form comprises about 148 mg filler.
  • the present invention provides a unit-dosage form comprising about 1 mg to about 5 mg disintegrant. In some embodiments, the unit-dosage form comprises about 1 mg disintegrant. In some embodiments, the unit-dosage form comprises about 2 mg disintegrant. In some embodiments, the unit-dosage form comprises about 5 mg disintegrant.
  • the present invention provides a unit-dosage form comprising about 2.0 mg to about 10 mg disintegrant. In some embodiments, the unit-dosage form comprises about 2.0 mg disintegrant. In some embodiments, the unit-dosage form comprises about 4 mg disintegrant. In some embodiments, the unit-dosage form comprises about 10 mg disintegrant
  • the present invention provides a unit-dosage form comprising about 1.5 mg to about 7.5 mg binder. In some embodiments, the unit-dosage form comprises about 1.5 mg binder. In some embodiments, the unit-dosage form comprises about 3 mg binder. In some embodiments, the unit-dosage form comprises about 7.5 mg binder.
  • the present invention provides a unit-dosage form comprising about 0.6 mg to about 3.0 mg binder. In some embodiments, the unit-dosage form comprises about 0.6 mg binder. In some embodiments, the unit-dosage form comprises about 1.2 mg binder. In some embodiments, the unit-dosage form comprises about 3.0 mg binder.
  • the present invention provides a unit-dosage form comprising about 0.25 mg to about 1.25 mg glidant. In some embodiments, the unit-dosage form comprises about 0.25 mg glidant. In some embodiments, the unit-dosage form comprises about 0.5 mg glidant. In some embodiments, the unit-dosage form comprises about 1.25 mg glidant.
  • the present invention provides a unit-dosage form comprising about 0.4 mg to about 2.0 mg glidant. In some embodiments, the unit-dosage form comprises about 0.4 mg glidant. In some embodiments, the unit-dosage form comprises about 0.8 mg glidant. In some embodiments, the unit-dosage form comprises about 2.0 mg glidant.
  • the present invention provides a unit-dosage form comprising about 0.5 mg to about 2.5 mg lubricant. In some embodiments, the unit-dosage form comprises about 0.5 mg lubricant. In some embodiments, the unit-dosage form comprises about 1 mg lubricant. In some embodiments, the unit-dosage form comprises about 2.5 mg lubricant.
  • the present invention provides a unit-dosage form comprising about 0.6 mg to about 3.0 mg lubricant. In some embodiments, the unit-dosage form comprises about 0.6 mg lubricant. In some embodiments, the unit-dosage form comprises about 1.2 mg lubricant. In some embodiments, the unit-dosage form comprises about 3.0 mg lubricant.
  • the present invention provides a unit-dosage form comprising about 1.2 mg to about 6.0 mg film coating. In some embodiments, the unit-dosage form comprises about 1.2 mg film coating. In some embodiments, the unit-dosage form comprises about 2.4 mg film coating. In some embodiments, the unit-dosage form comprises about 6.0 mg film coating.
  • the present invention provides a unit-dosage form comprising about 7 mg to about 34 mg RTB101, about 39.5 mg to about 199.5 mg filler, about 1 mg to about 5 mg disintegrant, about 1.5 mg to about 7.5 mg binder, about 0.25 mg to about 1.25 mg glidant, and about 0.5 mg to about 2.5 mg lubricant.
  • the present invention provides a unit-dosage form comprising about 7 mg to about 34 mg RTB101, about 39.5 mg to about 199.5 mg lactose and starch, about 1 mg to about 5 mg crospovidone, about 1.5 mg to about 7.5 mg povidone, about 0.25 mg to about 1.25 mg colloidal silicon dioxide, and about 0.5 mg to about 2.5 mg magnesium stearate.
  • the present invention provides a unit-dosage form comprising about 7 mg to about 34 mg RTB101, about 33 mg to about 167 mg lactose, about 6.5 to about 32.5 mg starch, about 1 mg to about 5 mg crospovidone, about 1.5 mg to about 7.5 mg povidone, about 0.25 mg to about 1.25 mg colloidal silicon dioxide, and about 0.5 mg to about 2.5 mg magnesium stearate.
  • the present invention provides a unit-dosage form comprising about 7 mg RTB101, about 33 mg lactose, about 6.5 mg starch, about 1 mg crospovidone, about 1.5 mg povidone, about 0.25 mg colloidal silicon dioxide, and about 0.5 mg magnesium stearate.
  • the present invention provides a unit-dosage form comprising about 14 mg RTB101, about 67 mg lactose, about 13 mg starch, about 2 mg crospovidone, about 3 mg povidone, about 0.5 mg colloidal silicon dioxide, and about 1 mg magnesium stearate.
  • the present invention provides a unit-dosage form comprising about 34 mg RTB101, about 167 mg lactose, about 32.5 mg starch, about 5 mg crospovidone, about 7.5 mg povidone, about 1.25 mg colloidal silicon dioxide, and about 2.5 mg magnesium stearate.
  • the present invention provides a unit-dosage form comprising about 7 mg to about 34 mg RTB101, about 29.5 mg to about 148 mg filler, about 2 mg to about 10 mg disintegrant, about 0.6 mg to about 3.0 mg binder, about 0.4 mg to about 2.0 mg glidant, about 0.6 mg to about 3.0 mg lubricant, and, optionally, about 1.2 mg to about 6.0 mg film coating.
  • the present invention provides a unit-dosage form comprising about 7 mg to about 34 mg RTB 101, about 29.5 mg to about 148 mg lactose (e.g., Pharmatose 200M) and microcrystalline cellulose (e.g., Avicel PHI 12), about 2 mg to about 10 mg crospovidone (e.g., polyplasdone ultra), about 0.6 mg to about 3.0 mg hydroxypropyl methyl cellulose (e.g., E3 Premium LV), about 0.4 mg to about 2.0 mg colloidal silicone dioxide (e.g., Aerosil 200), about 0.6 mg to about 3.0 mg magnesium stearate (e.g., ligamed-MF-2V), and, optionally, about 1.2 mg to about 6.0 mg poly(vinyl alcohol) based film coating (e.g., Opadry II® Yellow).
  • lactose e.g., Pharmatose 200M
  • microcrystalline cellulose e.g., Avicel PHI 12
  • the present invention provides a unit-dosage form comprising about 7 mg to about 34 mg RTB101, about 20.5 mg to about 103 mg lactose; about 9.0 to about 45 mg microcrystalline cellulose, about 2 mg to about 10 mg, about 0.6 mg to about 3.0 mg hydroxypropyl methyl cellulose, about 0.4 mg to about 2.0 mg colloidal silicone, about 0.6 mg to about 3.0 mg magnesisum stearate, and, optionally, about 1.2 mg to about 6.0 mg poly(vinyl alcohol) based film coating.
  • the present invention provides a unit-dosage form comprising about 7 mg RTB101, about 20.5 mg lactose, about 9.0 mg microcrystalline cellulose, about 2 mg crospovidone, about 0.6 mg hydroxypropyl methyl cellulose, about 0.4 mg colloidal silicone dioxide, about 0.6 mg magnesium stearate, and, optionally, about 1.2 mg poly(vinyl alcohol) based film coating.
  • the present invention provides a unit-dosage form comprising about 14 mg RTB101, about 41 mg lactose, about 18 mg microcrystalline cellulose, about 4 mg crospovidone, about 1.2 mg hydroxypropyl methyl cellulose, about 0.8 mg colloidal silicone dioxide, about 1.2 mg magnesisum stearate, and, optionally, about 2.4 mg poly(vinyl alcohol) based film coating.
  • the present invention provides a unit-dosage form comprising about 34 mg RTB101, about 103 mg lactose, about 45 mg microcrystalline cellulose, about 10 mg crospovidone, about 3 mg hydroxypropyl methyl cellulose, about 2 mg colloidal silicone dioxide, about 3 mg magnesium stearate, and, optionally, about 6 mg poly(vinyl alcohol) based film coating.
  • the present invention provides methods of making the above described formulations and methods of treating or preventing an mTOR related disease, disorder, or condition including cancer, inflammatory conditions, immunological conditions, neurodegenerative diseases, diabetes, obesity, neurological disorders, autophagy-related diseases, age-related diseases, and/or cardiovascular conditions, in a subject in need thereof, comprising administering an above described formulation, alone or in combination with one or more additional therapeutic agents.
  • Exemplary of such inflammatory conditions include, but are not limited to: psoriasis, asthma and allergic rhinitis, bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, inflammatory bowel disease, irritable bowel syndrome, Crohn's disease, mucous colitis, ulcerative colitis, and obesity.
  • Exemplary of such immunological conditions include, but are not limited to: rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, multiple sclerosis, lupus, inflammatory bowel disease, ulcerative colitis, Crohn's disease, myasthenia gravis, Graves’ disease, encephalomyelitis, Type II diabetes, dermatomyositis, and transplant rejection (e.g., in the treatment of recipients of heart, lung, combined heart-lung, liver, kidney, pancreatic, skin, or corneal transplants; or graft-versus-host disease).
  • transplant rejection e.g., in the treatment of recipients of heart, lung, combined heart-lung, liver, kidney, pancreatic, skin, or corneal transplants; or graft-versus-host disease.
  • neurodegenerative disorders include, but are not limited to: Huntington's disease, Alzheimer's disease, Parkinson's disease, dementias caused by tau mutations, spinocerebellar ataxia type 3, motor neuron disease caused by SOD1 mutations, neuronal ceroid lipofucinoses/Batten disease (pediatric neurodegeneration), and HIV-associated encephalitis.
  • cardiovascular diseases include, but are not limited to: restenosis, Wolf-Parkinson-White Syndrome, stroke, myocardial infarction or ischemic damage to the heart, lung, gut, kidney, liver, pancreas, spleen or brain.
  • Age-related or age-associated diseases, disorders, and conditions are any disease, disorder, or condition that occurs with increasing frequency with increasing senescence.
  • Age- related diseases may affect any tissue, organ, or system of the body. Examples of age-related diseases include: cardiovascular diseases, pulmonary diseases, neurodegenerative diseases, muscular degenerative diseases, bone turnover or resorption disorders, proliferative disorders, immunosenescence disorders, and metabolic diseases.
  • age-related diseases include, but are not limited to: immunosenescence (including associated respiratory tract infections, urinary tract infections, viral infections, and bacterial infections), sarcopenia, muscle wasting, tendon stiffness, tendon injury, tendonitis, Achilles rupture, adhesive capsulitis of shoulder, plantar fasciitis, polymyalgia rheumatica, rotator cuff tear, spinal stenosis, tennis elbow, Dupuytren's contractures, restless leg syndrome, osteoporosis, osteoarthritis, rheumatoid arthritis, autoimmune disease, polymyositis, gout, dementia, Huntington's disease, Alzheimer's disease, brain atrophy, aging-related mobility disability (e.g., frailty), cognitive decline, age related dementia, memory impairment, Lewy body dementia, frontotemporal dementia, Parkinson's disease, mild cognitive impairment, vascular dementia, stroke, transient ischemic attack, trigeminal neuralgia,
  • immunosenescence
  • Exemplary such autophagy-related diseases, disorders, or conditions include, but are not limited to, cancer, Amyotrophic Lateral Sclerosis (ALS), Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, static encephalopathy of childhood with neurodegeneration in adulthood (SEND A), bacterial infections, viral infections, Tuberculosis, Crohn’s disease, systemic lupus erythematosus, cardiovascular diseases, metabolic diseases (e.g., Paget’s disease, insulin resistance and diabetes), pulmonary diseases (e.g., COPD, cystic fibrosis, asthma, emphysema, idiopathic pulmonary fibrosis), Vici syndrome, and diseases, disorders, or conditions associated with alpha-1 antitrypsin (AAT) deficiency (e.g., cirrhosis, hepatitis, hepatomegaly, jaundice, and liver failure).
  • AAT alpha-1 antitrypsin
  • the pharmaceutical formulation administered in an amount capable of selectively inhibiting TORC1.
  • the present invention provides a method for the treatment or prevention of an age-related disease, disorder, or condition, or an autophagy-related disease, disorder, or condition, in a subject in need thereof, comprising administering to the subject an effective amount of a pharmaceutical formulation comprising described herein, wherein the formulation is administered at a dosage sufficient to inhibit the mTORCl pathway without substantially inhibiting the mTORC2 pathway.
  • the present invention provides a method for treating or preventing an age-related disease, disorder, or condition, or an autophagy-related disease, disorder, or condition in a subject in need thereof, comprising administering to the subject an effective amount of a pharmaceutical formulation described herein, wherein the RTB101 is administered at a dose of about 5 mg/day (freebase; about 6.84 mg monotoyslate salt). In some embodiments the RTB101 is administered at a dose of about 10 mg/day (freebase; about 13.67 mg monotosylate salt). In some embodiments, the RTB101 is administered at a dose of about 25 mg/day (freebase; about 34.18 mg monotosylate salt).
  • the present invention provides a method for the treatment or prevention of an age related disease, disorder, or condition, or an autophagy-related disease, disorder, or condition, in a subject in need thereof, comprising administering to the subject an effective amount of pharmaceutical formulation described herein, wherein the formulation is administered daily.
  • the pharmaceutical formulation is administered daily in one or more divided doses.
  • the formulation is administered once per day (qua diem; QD).
  • the formulation is administered twice per day (bis in die; BID).
  • the formulation is administered thrice per day (ter in die; TID).
  • the formulation is administered four times per day (quater in die; QID).
  • the formulation is administered every four (4) hours (quaque four hours; q4h).
  • a provided method is any of those described above and herein, wherein the age-related disease, disorder, or condition, or an autophagy-related disease, disorder, or condition, is respiratory tract infections (RTIs), urinary tract infections (UTIs), viral infections, bacterial infections, Huntington’s disease, Parkinson’s disease, ALS, Alzheimer’s disease, or liver failure associated with AAT deficiency.
  • RTIs respiratory tract infections
  • UTIs urinary tract infections
  • viral infections bacterial infections
  • Huntington’s disease Parkinson’s disease
  • ALS Alzheimer’s disease
  • Alzheimer’s disease or liver failure associated with AAT deficiency.
  • a provided method comprises steps of administering to a subject suffering from or susceptible to an age-related disease, disorder, or condition an effective amount of a pharmaceutical formulation described herein, such that the severity or incidence of one or more symptoms of the age-related disease, disorder, or condition is reduced, or its onset is delayed.
  • the present invention provides a pharmaceutical formulation comprising RTB101 for use in the treatment or prevention of an age-related disease, disorder, or condition according to any of the methods described above and herein.
  • the present invention provides a unit dosage form comprising a provided composition comprising RTB101 as described herein.
  • the unit dosage form comprises about 10 mg of RTB101 (freebase; about 13.67 mg monotosylate salt).
  • the present invention provides a pharmaceutical formulation comprising RTB 101 for use in the manufacture of a medicament for the treatment or prevention of an age-related disease, disorder, or condition according to any of the methods described above and herein.
  • the present invention provides a pharmaceutical formulation comprising RTB101 for the treatment or prevention of an age-related disease, disorder, or condition according to any of the methods described above and herein, further comprising at least one substance related to RTB101 selected from 2-methyl-2-(4-(3-methyl-2-oxo-8- (quinolin-3-yl)-2,3-dihydro-lH-imidazo[4,5-c]quinolin-l-yl)phenyl)propanamide; 2 -methyl-2 - (4-(2-oxo-8-(quinolin-3 -yl)-2, 3 -dihydro- 1 H-imidazo[4, 5 -c] quinolin- 1 - yl)phenyl)propanenitrile; 2-(4-(8-bromo-3-methyl-2-oxo-2,3-dihydro-lH-imidazo[4,5- c]quinolin-l-yl)phenyl)-2-methylpropyl
  • the pharmaceutical formulation further comprises less than about 0.2% of 2-methyl-2-(4-(3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydro-lH-imidazo[4,5- c]quinolin- 1 -yl)phenyl)propanamide.
  • the formulation further comprises less than about 0.05% of each of one or more related substances selected from 2-methyl-2-(4-(2-oxo-8-(quinolin-3-yl)- 2,3-dihydro-lH-imidazo[4,5-c]quinolin-l-yl)phenyl)propanenitrile; 2-(4-(8-bromo-3 -methyl-2 - oxo-2, 3-dihydro-lH-imidazo[4,5-c]quinolin-l-yl)phenyl)-2-methylpropanenitrile; l-(4- isopropylphenyl)-3-methyl-8-(quinolin-3-yl)-lH-imidazo[4,5-c]quinolin-2(3H)-one; and 2-(4- (3,5-dimethyl-2,4-dioxo-8-(quinolin-3-yl)-2,3,4,5-tetrahydro-lH-imidazo
  • the formulation further comprises about 2.0% or less of total substances related to RTB101.
  • An individual pharmaceutical composition comprising a catalytic mTOR inhibitor (e.g., RTB101) may be provided as a hard gelatin capsule for oral administration comprising about 5, about 10, or about 25 mg of the catalytic mTOR inhibitor (freebase).
  • the excipients may be: lactose, crospovidone, polyvinyl pyrrolidone K30, starch, colloidal silicone dioxide, and magnesium stearate.
  • the 5, 10, and 25 mg (freebase) containing capsules may use a size 4 to a size 0 capsule shell, or larger.
  • An individual pharmaceutical composition comprising a catalytic mTOR inhibitor may be provided as a tablet for oral administration comprising about 5, about 10, or about 25 mg of the catalytic mTOR inhibitor (freebase).
  • the excipients may be: lactose, crospovidone, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicone dioxide, and magnesium stearate.
  • the 5, 10, and 25 mg (freebase) containing tablets may optionally be coated with a film coating.
  • compositions and dosage forms that comprise one or more agents that reduce the rate by which the compound of the present invention as an active ingredient will decompose.
  • agents which are referred to herein as "stabilizers.”
  • nM nanomolar
  • nm nanometer
  • Example 1 Gelatin Capsules Containing 10 mg RTB101 (freebase)
  • Drug load is adjusted to allow for the filling of size 4 capsules (approx. 38 mg; gelatin with about 2% Ti02 as opacifier).
  • An exemplar pharmaceutical formulation is provided in Table 1, below.
  • Step 1 Granulation
  • lactose monohydrate, 200 mesh, starch 1500, crospovidone XL, and RTB101 (BEZ235) drug substance were weighed, sieved (1000-pm screen), and then charged into a high shear mixer in the order stated. The ingredients were mixed at 250 revolutions per minute (rpm) for three (3) minutes. In a separate stainless steel container purified water and polyvinylpyrrolidone K30 were combined (range: 150-1000 rpm) for ninety (90) minutes to obtain the granulation solution. The granulation solution was added to the pre blend (50-80 grams/minute) at 250 rpm for 2-4 minutes. Water was used to rinse the granulation solution container and was added to the granulation.
  • the mass was mixed at 250 rpm for three (3) to five (5) minutes until granules were formed. If lumps or agglomerates were greater than 5 mm, the wet granules were sieved (2000-pm screen). The wet granules were transferred to the fluid bed dryer and dried until the loss on drying (LOD) was less than 3% at 105 °C.
  • the RTB101 dry granules were stored in sealed aluminum bags in high density polyethylene (HDPE) containers until further processing.
  • HDPE high density polyethylene
  • Step 2 Combining and Milling of Inner-Phase Granule Sublots
  • the RTB101 capsule blend is filled into hard gelatin capsules (e.g., size 4, pink opaque hard gelatin capsules or 2-tone blue top/white body capsules, optionally marked with “RTB101” and/or“10 mg”) with a capsule filler machine.
  • the RTBlOl capsule blend was filled into Size 4, pink, opaque, hard gelatin capsules using a capsule filler machine.
  • Empty capsule shells (100 capsules) were weighed to ensure that the average weight was within specification. Capsule shells and RTB101 capsule blend were charged into the capsule filler machine and in- process weight checks were performed to ensure appropriate machine settings.
  • in-process tests included weight of 20 capsules, uniformity of weight, closed length, disintegration, LOD, and a visual check of 125 capsules. Disintegration, LOD, and closed length were verified three (3) times daily (start, middle, and end of day). Weight uniformity, weight of 20 capsules, and the visual check occurred every thirty (30) minutes. If the production quantity was not sufficiently large, a visual check was performed on 100% of capsules. The weight of each capsule was verified with an automated weight control system. Capsules were de-dusted and run through the metal detector. Samples were taken for release testing. Capsule specifications are summarized in Table 2, below. Table 2. RTB101 10 mg Capsule Specifications
  • Step 5 Packaging
  • Table 3 summarizes the initial (i.e., not subject to storage conditions) content uniformity and blend uniformity of formulation containing capsules.
  • Capsules were filled with the formulation described in Example 1, above. Control samples were evaluated immediately for appearance, solubility and stability. Additional samples were stored at various temperatures and relative humidity (RH), such as those shown in Table 4, to assess the physical and chemical stability of the active pharmaceutical ingredient and the formulation.
  • RH relative humidity
  • FIG. 2 shows the dissolution of formulation containing capsules that have been stored for two (2) weeks under conditions A, B, and C, as compared to capsules that were tested immediately without storage. It can be seen that each stored test condition capsule dissolved at a rate comparable to the capsules that were tested immediately without storage.
  • FIG. 3 shows the dissolution of formulation containing capsules that have been stored for three (3) weeks under conditions A, B, C, D, and E, as compared to capsules that were tested immediately without storage. It can be seen that stored test condition capsules dissolved at rates comparable to the capsules that were tested immediately without storage with the exception of the capsules under condition E. This deviation is likely due to capsule polymerization.
  • FIG. 4 shows the dissolution of formulation containing capsules that have been stored for four (4) weeks under conditions A, B, and C, as compared to capsules that were tested immediately without storage. It can be seen that each stored test condition capsule dissolved at a rate comparable to the capsules that were tested immediately without storage.
  • FIG. 5 shows the dissolution of formulation containing capsules that have been stored for up to six (6) months under conditions A and B, with thirty (30) capsules per container, as compared to capsules that were tested immediately without storage. It can be seen that each stored test condition capsule dissolved at a rate comparable to the capsules that were tested immediately without storage.
  • FIG. 6 shows the dissolution of formulation containing capsules that have been stored for up to six (6) months under conditions A and B, with one-hundred twenty (120) capsules per container, as compared to capsules that were tested immediately without storage. It can be seen that each stored test condition capsule dissolved at a rate comparable to the capsules that were tested immediately without storage.
  • Results for visual evaluation and stability of a four (4) week stability study are summarized in Table 5.
  • Results for visual evaluation, stability, and dissolution of a longer duration stability study are summarized in Table 6.
  • “I.U.” indicates an individual unknown substance.
  • Information pertaining to related substances is summarized in Table 7, below.
  • Information relating to potential genotoxic impurities is summarized in Table 8, below.
  • RTB101 specification are summarized in Table 9, below. Table 5.
  • the impurity 507-07 is specified and its level is controlled at a limit of ⁇ 0.2% (w/w). All other impurities are unspecified. Each unspecified impurity is controlled at a limit of ⁇ 0.1% (w/w), and their sum is controlled to be not greater than 0.5% (w/w).
  • A1 is used as the starting material for the synthesis of the BEZ235 p-toluenesulfonate drug substance.
  • the amount of A1 was found to be ⁇ 0.5 ppm which, assuming the intended clinical trial dose of 10 mg of BEZ235 p-toluenesulfonate per day, would correspond to ⁇ 0.005 pg/day. This level is below the threshold of toxicological concern (TTC) of 1.5 pg/day per the ICH Guideline M7: Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk (May 2015).
  • A3 is used as a starting material for the synthesis of the BEZ235 p-toluenesulfonate drug substance.
  • the amount of A3 was found to be ⁇ 0.5 ppm which would correspond to ⁇ 0.005 pg/day. This level is below the TTC of 1.5 pg/day.
  • A4 is the first isolated intermediate in the synthesis of the drug substance.
  • the amount of intermediate A4 was demonstrated to be ⁇ 1.5 ppm (0.015 pg/day) which is also below the TTC of 1.5 pg/day.
  • A5 is a non-isolated intermediate after the nitro group reduction of A4.
  • the amount of A5 was found to be ⁇ 0.5 ppm which would correspond to ⁇ 0.005 pg/day. This level is below the TTC of 1.5 pg/day.
  • A8 (dimethylsulfate or alternatively methyl iodide) is used as a reagent during synthesis.
  • the amount of intermediates A8 was found to be ⁇ 1 ppm (0.01 pg/day) which is below the TTC of 1.5 pg/day.
  • A10 (3-quinoline boronic acid) is soluble in DMF/sodium bicarbonate (NaFlCCh
  • the amount of intermediate A10 was found to be ⁇ 1 ppm (0.01 pg/day) which is below the TTC of 1.5 pg/day.
  • Methyl tosylate, or other genotoxic tosylate derivatives were evaluated in early drug substance clinical lots.
  • a batch analysis report indicated a methyl tosylate level at ⁇ 20 ppm for this process impurity (i.e., meeting the ⁇ 20 ppm specification and no tosylate degradants were reported).
  • This ⁇ 20 ppm value corresponds to ⁇ 0.2 pg/day for the intended clinical trial dose of 10 mg of BEZ235 p-toluenesulfonate per day. This level is at least 7.5 times lower than the TTC value of 1.5 pg per day.
  • A2 is a non-isolated intermediate in the synthesis of the drug substance.
  • Triphenylphosphine oxide TPPO
  • TPPO Triphenylphosphine oxide
  • II bis-triphenylphosphine-palladium di chloride
  • the drug substance is tested for the presence of heavy metals (Copper [Cu], Iron [Fe], Nickel [Ni], Lead [Pb], Palladium [Pd], and Zinc [Zn]) using inductively coupled plasma - optical emission spectroscopy methodology and requirements are set for sum and individual of these metals.
  • heavy metals Copper [Cu], Iron [Fe], Nickel [Ni], Lead [Pb], Palladium [Pd], and Zinc [Zn]
  • the solvents used in the synthesis of BEZ235 p-toluenesulfonate and potentially present in the drug substance include:
  • RTB101 To optimize the dose of RTB101 administered to a patient it is desirable to have a formulation that provides good manufacturing characteristics and stability, in addition to being amenable for various dosages of active ingredient.
  • the 5 mg formulation resulted in reduced flowability of the RTB101 containing composition and associated aggregation and clumping.
  • the formulation of the present invention is amenable to a wide range of doses of RTB101 and may be used for the production of RTB101 solid dosage forms comprising between about 5 and about 100 mgRTBlOl (freebase; about 6.83 mg to about 136.6 mg monotosylate salt).
  • RTB101 solid dosage forms comprising between about 5 and about 100 mgRTBlOl (freebase; about 6.83 mg to about 136.6 mg monotosylate salt).
  • the 5 mg composition refers to 5 mg RTB101 freebase
  • the 10 mg composition refers to 10 mg RTB101 freebase.
  • the mass of RTB101 is the mass of the monotosylate salt.
  • Example 4 Tablets Containing 10 mg RTB 101 (freebase)
  • Formulation compositions of the present invention were compressed into tables using 5.5 mm round shaped punches. Tablets were then optionally coated with film coating agent to yield uncoated“core tablets” and“coated tablets.” Exemplar pharmaceutical formulations are provided in Table 11, below. A representative manufacturing process for the tablets is summarized in FIG. 7.
  • Step 1 Sieving Dry Intragranule Ingredients
  • Binder solution was formed by dissolving hydroxypropyl methyl cellulose in purified water. The binder solution was then added to the sieved, mixed dry ingredients until good granules formed. The granules were then dried with a target LOD of 1-2% (w/w). The dried granules were milled until a uniform granule size was obtained.
  • Crospovidone and colloidal silicon dioxide were sifted through a #30 mesh sieve. Magnesium stearate was separately sieved through a #60 mesh sieve. Crospovidone and colloidal silicon dioxide were mixed with the dry milled granules in the blender. The material was lubricated with the sieved magnesium stearate. The blending was conducted prelubrication for 15 min at 15 RMP and then for 5 min at 15 RPM. Rapid mix granulator parameters are summarized in Table 12, below.
  • Core tablets were optionally coated. Purified water was tarred and stirred to create a vortex. Opadry II Yellow (85F32004) was added slowly while the stirring was adjusted to maintain the vortex, if necessary. Stirring was continued until a homogenous dispersion was obtained.
  • Step 5 Packing
  • Core tablets and coated tablets were evaluated for stability in a substantially similar manner as that described for capsules in Example 2, above. Control samples were evaluated immediately for appearance, solubility, and stability. Additional samples were stored at various temperatures and relative humidity (RH), such as those shown in Table 4, above, to assess the physical and chemical stability of the active pharmaceutical ingredient and the formulation.
  • RH relative humidity
  • HDPE bottles containing either 30 or 120 (core or coated) were stored for one (1) month, three (3) months, and six (6) months at 25 °C/60% RH or 40 °C/60% RH (conditions A and B, respectively, from Table 4, above). Results are summarized in Tables 14, 15, 16, and 16, below. Impurities listed in the test parameters are found in Table 7, above.
  • RTB101 To optimize the dose of RTB101 administered to a patient it is desirable to have a formulation that provides good manufacturing characteristics and stability, in addition to being amenable for various dosages of active ingredient.
  • different unit dosage forms e.g., capsule versus tablet
  • the 10 mg composition refers to 10 mg RTB101 freebase.
  • the mass of RTB101 is the mass of the monotosylate salt.
  • Example 7 BEZ235 may decrease or prevent symptomatic respiratory illness in elderly subjects.
  • Aging is regulated in part by a discrete set of cellular signaling pathways including the mechanistic target of rapamycin (mTOR) pathway (Lopez-Otin et al., 2013). Inhibition of the mTOR pathway has extended lifespan in every species studied to date and improved the function of multiple aging organ systems in old mice including the immune, neurologic and cardiovascular systems (Johnson et al., 2013). These data raise the possibility that drugs that target the mTOR pathway will have therapeutic benefit in aging-related conditions in humans.
  • One of the aging-related conditions that improves in old mice treated with mTOR inhibitors is immunosenescence, which is the decline in both innate and adaptive immune function that occurs during aging.
  • RTIs respiratory tract infections
  • rapamycin rejuvenated hematopoietic stem cell function
  • increased naive lymphocyte production enhanced the immune response to influenza vaccination, and increased lifespan
  • the mTOR inhibitor RTB101 has been shown to protect mice from a lethal influenza virus challenge (Smallwood et al., 2017).
  • RTIs Decreasing the incidence of RTIs is a large unmet medical need in people age 65 and above who are also the fastest growing population globally (United Nations, 2005). RTIs are the fourth leading cause of hospitalization in people age 65 and over, and the second leading cause of hospitalization in people age 85 and over (Pfunter et al., 2013). Even upper RTIs, which are usually mild in younger adults, can cause significant morbidity in the elderly.
  • RTB101 is being developed to improve immune function and reduce the incidence of respiratory infections in elderly patients.
  • RTB 101 prevents clinically symptomatic respiratory illness in elderly subjects >65 years of age.
  • Subjects with clinically symptomatic respiratory illness are defined as subjects with symptoms consistent with an RTI based on pre specified diagnostic criteria.
  • RTB101 Rate of hospitalizations associated compared to placebo on the rate of with RTIs beginning at least 3 days hospitalizations associated with after the start of study drug treatment respiratory tract infections (RTIs) through Week 16
  • the study will be comprised of up to a 4-week Screening Period; a 16-week Primary Analysis Period (for evaluating efficacy and safety) during which time subjects meeting study eligibility criteria will be randomized 1 : 1 to receive RTB101 10 mg or matching placebo once daily through the Week 16 Visit; a 4-week Short-term Follow-up Period (for evaluating safety and efficacy through the Week 20 Visit); and a 28-week Long-term Follow-up Period (for evaluating safety through Week 48 by follow-up questionnaire).
  • Screening may occur prior to investigational product being available at the study site. During the Screening visit (maximum 4 weeks prior to Baseline/randomization), the study will be explained in detail to subjects and they will be asked to provide informed consent for participation. Subjects will be then assessed for eligibility to participate in the trial based on inclusion/exclusion criteria. The following assessments will be performed at this visit: Mini Mental Status Exam (MMSE); a review of subject demography and medical history (including current medical [including cardiac] conditions, prior and current medications); a complete physical exam (including height, weight, and vital signs [temperature, respiratory rate, heart rate and blood pressure]); and an electrocardiogram (ECG).
  • MMSE Mini Mental Status Exam
  • ECG electrocardiogram
  • a chest X-ray will be performed unless the subject has had a chest X-ray within the past 3 months and the film (or digital copy) and results of that CXR are available.
  • Blood and urine will be collected for the following tests: hematology, chemistry, urinalysis, serum cotinine, and HIV and hepatitis virus (B and C) screening.
  • Baseline Visit At the Baseline visit, a review of any changes to the subject’s medical (including cardiac) condition or current medications/other therapies will be performed. Subjects will then undergo clinical evaluation, including a targeted physical exam. This should include measurements of weight and vital signs, including orthostatic blood pressure, and an exam of the lungs, heart, oral cavity, and skin. The Clinical Frailty Scale score of each subject will also be determined. An ECG will be performed for Baseline safety assessment. Subjects will also have blood and urine samples obtained for Baseline safety assessments. In addition, blood samples will be obtained for biomarker analyses, including RNA expression and soluble biomarkers. Consent for Optional Blood Storage for Future Use and Consent for Optional Pharmacogenetic Analysis will be obtained at the Baseline Visit.
  • a single blood sample will also be obtained at the Baseline Visit in those subjects who sign the option Pharmacogenetic Analysis consent form for the purposes of possible future Pharmacogenomic analysis.
  • a mid turbinate nasal swab specimen will be collected. All subjects will complete the Health-Related Quality of Life Questionnaire (EQ-5D-5L) and report any respiratory illness symptoms the Baseline visit.
  • Randomization will be stratified based on the following factors that may influence the incidence or severity of clinically symptomatic respiratory illness and the response to RTB101 treatment:
  • Subjects will be given their first dose of study drug at the study site and trained on recording study assessment information, including: -Study drug dosing information, to be completed daily through the Week 16 study visit;
  • Subjects will be sent home with study drug. Subjects will be instructed to take their study drug each day with breakfast. Subjects will also be instructed to maintain the above- described records daily. Adverse events will be monitored and reported from the time of study drug administration at the Baseline Visit through Week 20.
  • Subject Contact/Follow up The Study Investigator and Study Coordinator will contact subjects who report at least one respiratory symptom (runny nose/sneezing, stuffy nose, sore throat, hoarseness, or cough) on two consecutive days and instruct the subjects to come to the study site within 48 hours for evaluation and for collection of a nasopharyngeal swab during the Clinically Symptomatic Respiratory Illness (Unscheduled) Visit (see below). Runny nose and sneezing are considered one symptom. Subjects who are unable to come to the study site may also have the nasopharyngeal swab (and, if indicated, a sputum specimen and RIDT) obtained during a home visit by trained personnel.
  • respiratory symptom runny nose/sneezing, stuffy nose, sore throat, hoarseness, or cough
  • Symptomatic Respiratory Illness Unscheduled Visits At the Clinically Symptomatic Respiratory Illness Unscheduled Visit, Study Investigators will evaluate the subject and perform a targeted physical exam based on the symptoms reported by the subj ect and including vital signs and temperature. Any medications used to treat the clinically symptomatic respiratory illness, including antibiotics and any change to current medications, will be recorded. In addition, a nasopharyngeal swab will be obtained. Subjects who have a productive cough that is changed from baseline should have a sputum specimen obtained for gram stain and culture. If clinically indicated, blood and urine samples needed to clinically evaluate the subject may be obtained at this visit.
  • Subjects who have influenza-like illness signs and symptoms should have a rapid influenza antigen diagnostic test (RIDT) done.
  • Subjects with influenza-like illness who have influenza detected by RIDT or nasopharyngeal swab PCR should receive anti-influenza treatment per local standard of care, unless contraindicated, and/or other appropriate medical care.
  • the nasopharyngeal swab and, if indicated, a sputum specimen and RIDT should be obtained at a home visit by trained personnel.
  • Appropriate medical care (including referral to their healthcare provider or to a hospital, if indicated) should be provided for all clinically symptomatic respiratory illness episodes (including anti-influenza treatment, if indicated, in subjects diagnosed with influenza) per local standard of care.
  • Study drug treatment can be continued in subjects who require antibiotics or anti -influenza medication for treatment of an RTI.
  • Weeks 2-12 Visits Provided the study drug continues to be well tolerated, subjects will be treated with study drug for 16 weeks, during which time they will return to the clinic every 2 weeks (visits Week 2, 4, 6, and 8) for the first 8 weeks, and then every 4 weeks (visit Week 12 and 16) for the final 8 weeks.
  • the subject will have clinical evaluations, including a targeted physical exam, which will include measurements of weight, blood pressure, heart rate, respiratory rate, and temperature, and an exam of the lungs, heart, oral cavity, and skin.
  • a review of any changes to medical (including cardiac) conditions and medications/other therapies will also be performed.
  • subjects will be queried by site staff regarding any visits to the ER, urgent care clinics, and any admission to a skilled nursing facility or hospital that may have occurred since their last study visit.
  • Subjects will also have a mid-turbinate swab taken at each visit regardless of whether the subject reports respiratory illness symptoms. If subject presents with respiratory illness symptoms at this visit they may also have a nasopharyngeal swab, RIDT and sputum sample (if applicable) obtained as part of an unscheduled visit assessment. Blood and urine specimens will be collected at each visit for safety monitoring. An ECG will be performed at Week 4, 8 and 12 visits for safety monitoring.
  • Study drug will be dispensed at Day 0, Week 4, Week 8 and Week 12 visits (however, in the case of lost or damaged study drug, study drug can be dispensed at any study site visit). The subjects should bring their remaining study drug to each study visit. At Study Visits Week 4 and Week 12, subjects participating in the PK assessments should be instructed to not take their study drug dose at home (it will be administered at the site). At Weeks 4, 8, and 12, subj ects will return study drug and will be dispensed new bottles. At Week 2 and 6, subjects will bring their drug supply to the study site to allow site personnel to perform a pill count; however, no new study drug will be dispensed at these visits.
  • Week 16 Visit Subjects will take their last dose of study drug at home and come to the study site to undergo a clinical evaluation, including a review of any changes to medical (including cardiac) conditions and medications/other therapies, and a complete physical exam, which will include measurements of weight and vital signs. An ECG will also be performed for safety monitoring. In addition, subjects will have blood and urine samples obtained for safety labs. Blood samples will also be obtained for RNA expression and soluble serum biomarker assessments. In addition, a mid-turbinate nasal swab will be obtained. Subjects will be queried by site staff regarding any visits to ER, urgent care clinics, any admission to a skilled nursing facility or hospital that may have occurred since their last study visit. All subjects will complete the EQ-5D-5L questionnaire at the Week 16 visit. All study drugs (RTB101 and placebo) should be returned to the study site.
  • RTB101 and placebo should be returned to the study site.
  • Short-term follow-up Period (Week 20): All subjects will return to the study site 4 weeks after their last dose of study drug for a Week 20 (Short-term Follow-up Period) visit. At the Week 20 visit, subjects will undergo a complete physical exam, which will include measurements of weight and vital signs. A review of any changes to medical (including cardiac) conditions and medications or other therapies will also be performed. Blood and urine will be collected for safety lab evaluation.
  • Subjects who develop medically important laboratory abnormalities or medically important AEs should be referred for appropriate medical care, as per the local standard of medical care. If at the time of the completion of the Week 20 visit, all adverse events that are unresolved should be captured as“ongoing” in the database; however, they should continue to be followed until resolution or judged to be permanent by the Investigator.
  • Respiratory Illness Symptoms questionnaire daily in order to rapidly and accurately capture the occurrence of symptoms consistent with an RTI and to enable collection of nasopharyngeal swabs within 48 hours of symptom confirmation when viral detection rates are highest (Ginocchio et al., 2011).
  • Sixteen weeks of treatment is considered a sufficient duration to achieve a clinically meaningful reduction in clinically symptomatic respiratory illness during winter cold and flu season when there is a peak in the circulation of multiple respiratory viruses.
  • PK samples will be obtained in approximately 400 subjects (200 in each treatment group) at weeks 4, 8, and 12 to enable characterization of PK after the study drug has reached steady state levels.
  • Study Population Prevention of clinically symptomatic respiratory illness is particularly important in people age 65 and older in whom RTIs are a leading cause of hospitalization.
  • Data from the Phase 2b trial RTB-BEZ235-202 suggests that RTB101 10 mg given once daily for 16 weeks during winter cold and flu season was safe and reduced the incidence of laboratory-confirmed RTIs in people age > 65.
  • data from the RTB- BEZ235-202 study suggests that RTB101 had no benefit in elderly subjects who were current smokers or had a medical history of COPD. Therefore, the Phase 3 study will enroll subjects who are age > 65 and who are not current smokers and do not have COPD. A Mini Mental Status Exam will be done at screening to ensure that subjects enrolled in the trial have the cognitive ability to understand the informed consent.
  • RTI-related morbidity and mortality defined as age > 85 or age >65 and ⁇ 85 years with a medical history of asthma or congestive heart failure. Enhancing immune function and reducing the incidence of clinically symptomatic respiratory illness is of particular clinical relevance in these subgroups.
  • RTIs are the second leading cause of hospitalization in people age > 85 (Pfunter et al., 2013), the most common cause of asthma exacerbations (Nicholson et al., 1993), and the underlying cause of 16% of hospital admissions in patients with congestive heart failure (Chin and Goldman, 1997).
  • Enrolling 35% of subjects from these subgroups is representative of the target > 65 year old population since -10% of those >65 have asthma (Gillman et al., 2012), 12% are >85 (U.S. Census 2010) and -10% of individuals > 60 have congestive heart failure ( Komanduri S et al., 2017).
  • the primary endpoint of the study is the percentage of subjects who experience at least one clinically symptomatic respiratory illness beginning at least 3 days after the start of study drug treatment through Week 16.
  • Clinically symptomatic respiratory illness is defined as respiratory illness symptoms that are consistent with a RTI based on pre specified diagnostic criteria and includes multiple types of RTIs (such as common cold, bronchitis, influenza-like illness, and pneumonia) caused by multiple different pathogens. Decreasing the incidence of clinically symptomatic respiratory illnesses is medically important in the elderly. Even respiratory illnesses such as upper RTIs that are normally mild in younger adults cause significant morbidity in the elderly (Nicholson et al., 1997) and significantly increase the risk of cardiovascular events (Musher et. al., 2019).
  • the clinical criteria that will be used in the Phase 3 trial to diagnose clinically symptomatic respiratory illnesses capture RTI events that were also captured in the Phase 2b (RTB-BEZ235-202) trial. Pre-specified clinical criteria will be used to diagnose clinically symptomatic respiratory illnesses to make sure that diagnosis is consistent across sites.
  • Secondary endpoints will include the incidence of clinically symptomatic respiratory illnesses associated with laboratory-confirmed pathogen(s). Assessment of clinically symptomatic respiratory illness that is associated with an infectious pathogen will allow assessment of the treatment effect of RTB101 on respiratory illness that is confirmed to be infectious in etiology. The incidence of clinically symptomatic respiratory illnesses associated with specific viruses (e.g., coronaviruses, hMPV, HRV/enterovirus, adenovirus, influenza A and B virus, parainfluenza viruses, and RSV) will also be assessed as a secondary endpoint to determine if RTB101 has consistent benefit across different viral infections, and to demonstrate no enhancement of any viral infection.
  • viruses e.g., coronaviruses, hMPV, HRV/enterovirus, adenovirus, influenza A and B virus, parainfluenza viruses, and RSV
  • Another secondary endpoint will be rate of clinically symptomatic respiratory illness because subjects may experience more than one respiratory illness during the 16-week treatment period, and RTB101 may decrease not just the percentage of subjects with clinically symptomatic respiratory illness but also the rate of clinically symptomatic respiratory illnesses. Additional secondary endpoints will determine if RTB101 decreases not only the incidence but also the severity and duration of respiratory illness symptoms. Decreasing the severity and duration of respiratory illness symptoms is a clinically important endpoint and will provide further evidence of the clinical benefit of RTBlOl .
  • An exploratory endpoint will be the rate of viral respiratory infection, irrespective of whether the infection is symptomatic, to better assess the antiviral effects of RTB101.
  • healthcare resource utilization will be assessed because an important benefit of decreasing the incidence of clinically symptomatic respiratory illness may be a decrease in healthcare resource utilization by elderly subjects. Since decreasing the incidence of clinically symptomatic respiratory illness may improve the quality of life of elderly subjects, an additional exploratory endpoint will be health related quality of life in all subjects assessed with the EQ-5D-5L questionnaire.
  • the incidence of clinically symptomatic respiratory illness in subjects with a medical history of asthma or who are D 85 years of age will be assessed as exploratory endpoints because these subpopulations had the greatest reduction on the incidence of laboratory confirmed RTIs after treatment with 10 mg RTB101 once daily as compared with placebo in the previous Phase 2b (RTB-BEZ235-202) trial.
  • the incidence of asthma exacerbations in subjects with a medical history of asthma will also be assessed since RTIs are common causes of asthma exacerbations.
  • Another exploratory endpoint will be the incidence of clinically symptomatic respiratory illness and the incidence of symptomatic respiratory illness associated with laboratory-confirmed pathogen(s) through Week 20 to assess if the efficacy of RTB101 persists for 4 weeks after subjects discontinue study drug.
  • RNA expression and soluble serum biomarkers and pharmacogenomics (also known as pharmacogenetics) (Note: pharmacogenomics will only be assessed in those subjects who sign a separate consent form to allow collection of a pharmacogenomic (also known as pharmacogenetic) sample) will be assessed as exploratory endpoints to assess the effects of RTB101 on relevant immunologic markers and to potentially assess the impact of mTOR pathway polymorphisms in a pharmacogenomic analysis.
  • Rationale for Choice of Comparator A placebo will be used as a comparator since there is no available drug known to reduce the incidence of clinically symptomatic respiratory illness in the elderly.
  • the placebo arm will provide data about baseline AE and clinically symptomatic respiratory illness incidence in the elderly to which responses in subjects receiving RTB101 can be compared.
  • the study population will be comprised of elderly individuals > 65 years of age without unstable underlying medical conditions defined as conditions that require acute medical intervention or ongoing adjustments of concomitant medications (as determined by medical history, ECG and laboratory tests at Screening, and physical examination, ECG and vital signs at Screening and Baseline). The goal is to randomize approximately 1066 subjects during winter cold and flu season.
  • the Investigator must ensure that all patients being considered for the study meet the following eligibility criteria. No additional criteria should be applied by the Investigator so that the study population will be representative of all eligible subjects. Subject selection is to be established by checking through inclusion/exclusion criteria at Screening and Baseline. A relevant record (e.g., checklist) of the eligibility criteria must be stored with the source documentation at the study site. Deviation from any entry criterion excludes a subject from enrollment into the study.
  • Subjects must be >65 years of age. 4. Subjects should require no or minimal assistance with self-care and activities of daily living. Subjects in assisted-living or long-term care residential facilities that provide minimal assistance are eligible.
  • Sexually active male subjects with a partner of child-bearing potential must be willing to wear a condom while on study drug and for 1 week after stopping study drug and should not father a child in this period.
  • a condom is required to be used also by vasectomized men with a partner of child-bearing potential to prevent delivery of the drug via seminal fluid.
  • Subjects must weigh at least 40 kg.
  • Subject must be able to communicate well with the Investigator, and to understand and comply with the daily reporting requirements.
  • lung diseases other than asthma (e.g., chronic obstructive pulmonary disease (COPD), emphysema, interstitial pulmonary fibrosis (IPF), bronchiectasis, etc.).
  • COPD chronic obstructive pulmonary disease
  • IPF interstitial pulmonary fibrosis
  • bronchiectasis bronchiectasis
  • Subjects with a Mini Mental Status Examination (MMSE) score ⁇ 24 at Screening 4. Subjects with current evidence of a serious and/or unstable medical disorder including cardiovascular, respiratory, gastrointestinal, renal (including subjects with an estimated glomerular filtration rate (eGFR) as estimated by the modified diet in renal disease (MDRD) GFR equation ⁇ 50 mL/min/1.73m2), or hematologic disorders.
  • MMSE Mini Mental Status Examination
  • Subjects with a history of systemic autoimmune diseases e.g., lupus, inflammatory bowel disease, rheumatoid arthritis, etc.
  • immunosuppressive therapy such as my cophenol ate, tacrolimus, cyclosporine, azathioprine, infliximab
  • prednisone >10 mg daily e.g., inhaled corticosteroids and the acute use of higher doses of prednisone to treat conditions such as exacerbation of asthma or other acute conditions are allowed.
  • WBC white blood cell
  • Subjects with any conditions affecting absorption, distribution, or metabolism of the study drug e.g., inflammatory bowel disease, gastric or duodenal ulcers, hepatic disease.
  • ALT, AST, alkaline phosphatase or serum bilirubin must not exceed 1.5 x upper limit of normal (ULN) in subjects who do not have a history of Gilbert's syndrome. If the subject has a history of Gilbert’s syndrome, direct and indirect reacting bilirubin should be differentiated, and the direct bilirubin must be less than 1.5 x ULN.
  • HBV Hepatitis B
  • HCV Hepatitis C
  • Subjects who previously received treatment with RTB101 in another clinical study e.g., CBEZ235Y2201, RTB-BEZ235-202, or RTB-101-203.
  • Treatment Arms Subjects enrolled in the study will be randomized in a 1 : 1 ratio to one of the following 2 treatment arms.
  • Treatment Assignment and Randomization At the Baseline visit, all eligible subjects will be randomized via the IXRS to one of the treatment arms.
  • Randomization will be stratified based on the following factors that may influence the incidence and severity of RTIs and the response to treatment:
  • Study drug will be administered orally by the subject at home with breakfast. Exceptions will be at the Baseline Visit, when the study drug will be administered to all subjects at the study site, and at the Week 4 and 12 visits, when the study drug will be administered (with a light meal) at the site to those subjects identified per the IXRS randomization for PK assessments.
  • mTOR is a key modulator of ageing and age-related disease. Nature 493, 338-345, doi: 10.1038/naturel l861.
  • NVP-BEZ235 a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer Res; 68:8022-30.

Landscapes

  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne des procédés de traitement ou de prévention d'une maladie, d'un trouble ou d'une affection chez un patient, comprenant l'administration au patient d'une quantité d'un inhibiteur de mTOR catalytique, ou d'un sel pharmaceutiquement acceptable de celui-ci. La présente invention concerne également des formulations pharmaceutiques d'un inhibiteur de mTOR catalytique, ou d'un sel pharmaceutiquement acceptable de celui-ci.
PCT/US2020/030060 2019-05-01 2020-04-27 Procédés d'amélioration de la réponse immunitaire WO2020223154A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201962841650P 2019-05-01 2019-05-01
US62/841,650 2019-05-01
US201962844550P 2019-05-07 2019-05-07
US62/844,550 2019-05-07

Publications (1)

Publication Number Publication Date
WO2020223154A1 true WO2020223154A1 (fr) 2020-11-05

Family

ID=73029150

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2020/030060 WO2020223154A1 (fr) 2019-05-01 2020-04-27 Procédés d'amélioration de la réponse immunitaire

Country Status (1)

Country Link
WO (1) WO2020223154A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016001208A1 (fr) * 2014-06-30 2016-01-07 Galenicum Health S.L. Compositions pharmaceutiques stables sous forme de comprimés à libération immédiate
US20180161319A1 (en) * 2016-11-23 2018-06-14 Novartis Ag Methods of enhancing immune response

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016001208A1 (fr) * 2014-06-30 2016-01-07 Galenicum Health S.L. Compositions pharmaceutiques stables sous forme de comprimés à libération immédiate
US20180161319A1 (en) * 2016-11-23 2018-06-14 Novartis Ag Methods of enhancing immune response

Similar Documents

Publication Publication Date Title
JP6675313B2 (ja) 組合せ医薬
AU2003229705B2 (en) High drug load tablet
JP6480420B2 (ja) コルヒチンの徐放性製剤およびその使用方法
JP5819328B2 (ja) ラキニモドとメトトレキセートとの組合せによる関節リウマチの治療
TWI556840B (zh) 治療用組成物
JP2017165740A (ja) ラキニモドを使用したループス腎炎の治療
CN105899232A (zh) 用于增强免疫应答的mTOR抑制剂
US20220288048A1 (en) Pimavanserin for treating schizophrenia or for treating psychosis secondary to neurodegenerative disorders or depressive disorder
US8758815B2 (en) Pharmaceutical compositions comprising a combination of metformin and sitagliptin
JP2013522219A (ja) アルコール耐性腸溶性医薬組成物
KR102319078B1 (ko) 궤양성 대장염의 치료용 의약 조성물
JP2019526571A (ja) 認知症の処置
US20190358240A1 (en) Hiv treatment formulation of atazanavir and cobicistat
JP2022031345A (ja) Ｓｔ－２４６（テコビリマット一水和物）懸濁製剤
WO2017048457A1 (fr) Combinaison de laquinimod et de pridopidine pour le traitement de la sclérose en plaques
AU2014224238A1 (en) Formulations of organic compounds
JP2020500930A (ja) エベロリムス、ダクトリシブまたは両方で免疫応答を増強する方法
TW202245788A (zh) Irak4降解劑及其用途
WO2020223154A1 (fr) Procédés d'amélioration de la réponse immunitaire
TWI830703B (zh) 組合物及其用途和治療
TW201020240A (en) Compositions comprising 4-(2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)acetamido)-3-chlorobenzoic acid and pharmaceutically acceptable salts thereof, and methods for preparing and using same
CA3113468A1 (fr) Formes posologiques unitaires de grapiprant
UA113858C2 (uk) Лікарський засіб піоглітазону з уповільненим вивільненням
CN115867272A (zh) 肠道选择性jak3抑制剂的给药
JP2004504343A (ja) 非便秘性の男性ｉｂｓ患者の治療のためのシランセトロン含有医薬品

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20798223

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC

122 Ep: pct application non-entry in european phase

Ref document number: 20798223

Country of ref document: EP

Kind code of ref document: A1