WO2018051250A1 - Combinaison comprenant du ténofovir alafénamide, du bictégravir et du 3tc - Google Patents

Combinaison comprenant du ténofovir alafénamide, du bictégravir et du 3tc Download PDF

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Publication number
WO2018051250A1
WO2018051250A1 PCT/IB2017/055537 IB2017055537W WO2018051250A1 WO 2018051250 A1 WO2018051250 A1 WO 2018051250A1 IB 2017055537 W IB2017055537 W IB 2017055537W WO 2018051250 A1 WO2018051250 A1 WO 2018051250A1
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pharmaceutically acceptable
acceptable salt
bictegravir
hiv
tenofovir alafenamide
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PCT/IB2017/055537
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English (en)
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Michael ABOUD
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Viiv Healthcare Company
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    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV

Definitions

  • Human immunodeficiency virus infection and related diseases are a major public health problem worldwide.
  • Human immunodeficiency virus type 1 (HIV-1) encodes three enzymes that are required for viral replication: reverse transcriptase, protease, and integrase.
  • reverse transcriptase a enzyme that is required for viral replication
  • protease a enzyme that is required for viral replication
  • integrase integrase
  • drugs targeting reverse transcriptase and protease are in wide use and have shown effectiveness, particularly when employed in combination, toxicity and development of resistant strains have limited their usefulness (Palella, et ai, N. Engl. J. Med. (1998) 338:853-860; Richman, Nature (2001) 410:995-1001).
  • a goal of antiretroviral therapy is to achieve viral suppression in the HIV-infected human.
  • Treatment guidelines published by the United States Department of Health and Human Services provide that achievement of viral suppression requires the use of combination therapies, i.e., several drugs from at least two or more drug classes.
  • ANTIRETROVIRAL GUIDELINES FOR ADULTS AND ADOLESCENTS GUIDELINES FOR THE USE OF ANTIRETROVIRAL AGENTS IN HIV- 1 -INFECTED ADULTS AND ADOLESCENTS. Department of Health and Human Services. Available at
  • the present inventors have identified a combination of therapeutic agents, uses thereof, and associated methods of treatment with advantages over previously known agents and combinations.
  • this invention provides a combination comprising tenofovir alafenamide, or a pharmaceutically acceptable salt thereof; bictegravir, or a pharmaceutically acceptable salt thereof; and 3TC, or a pharmaceutically acceptable salt thereof.
  • this invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the combination of tenofovir alafenamide, or a pharmaceutically acceptable salt thereof; bictegravir, or a pharmaceutically acceptable salt thereof; and 3TC, or a pharmaceutically acceptable salt thereof, in association with one or more therapeutically acceptable carriers therefor.
  • this invention provides a combination of tenofovir alafenamide, or a pharmaceutically acceptable salt thereof; bictegravir, or a pharmaceutically acceptable salt thereof; and 3TC, or a pharmaceutically acceptable salt thereof, for use in medical therapy.
  • a further embodiment of this invention provides a method for treating human immunodeficiency virus (HIV) in a human, comprising administering to the human a therapeutically effective amount of tenofovir alafenamide, or a pharmaceutically acceptable salt thereof; a therapeutically effective amount of bictegravir, or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of 3TC, or a pharmaceutically acceptable salt thereof.
  • HAV human immunodeficiency virus
  • tenofovir alafenamide, or a pharmaceutically acceptable salt thereof; bictegravir, or a pharmaceutically acceptable salt thereof; and 3TC, or a pharmaceutically acceptable salt thereof are co-administered in separate dosage forms.
  • tenofovir alafenamide, or a pharmaceutically acceptable salt thereof; bictegravir, or a pharmaceutically acceptable salt thereof; and 3TC, or a pharmaceutically acceptable salt thereof are co-administered in a single dosage form.
  • this invention provides a method for preventing human immunodeficiency virus (HIV) in a human, comprising administering to the human a therapeutically effective amount of tenofovir alafenamide, or a pharmaceutically acceptable salt thereof; a therapeutically effective amount of bictegravir, or a pharmaceutically acceptable salt thereof; and atherapeutically effective amount of 3TC, or a pharmaceutically acceptable salt thereof.
  • HAV human immunodeficiency virus
  • this invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of tenofovir alafenamide, or a pharmaceutically acceptable salt thereof; a therapeutically effective amount of bictegravir, or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of 3TC, or a pharmaceutically acceptable salt thereof, in
  • this invention provides a kit comprising:
  • composition comprising tenofovir alafenamide, or a pharmaceutically acceptable salt thereof;
  • composition comprising bictegravir, or a pharmaceutically
  • composition comprising 3TC, or a pharmaceutically acceptable
  • One embodiment of the invention provides a method for treating HIV infection in a human comprising administering to the human a therapeutically effective amount tenofovir alafenamide, or a pharmaceutically acceptable salt thereof; bictegravir, or a pharmaceutically acceptable salt thereof; and 3TC, or a pharmaceutically acceptable salt thereof.
  • Another embodiment of the invention provides a method for preventing HIV infection in a human comprising administering to the human a therapeutically effective amount of tenofovir alafenamide, or a pharmaceutically acceptable salt thereof; a
  • bictegravir or a pharmaceutically acceptable salt thereof
  • 3TC or a pharmaceutically acceptable salt thereof
  • tenofovir alafenamide, or a pharmaceutically acceptable salt thereof; bictegravir, or a pharmaceutically acceptable salt thereof; and 3TC, or a pharmaceutically acceptable salt thereof are co-administered in separate dosage forms.
  • tenofovir alafenamide, or a pharmaceutically acceptable salt thereof; bictegravir, or a pharmaceutically acceptable salt thereof; and 3TC, or a pharmaceutically acceptable salt thereof are co-administered in a single dosage form.
  • tenofovir alafenamide, or a pharmaceutically acceptable salt thereof, and 3TC, or a pharmaceutically acceptable salt thereof are administered orally, and bictegravir, or a pharmaceutically acceptable salt thereof, is administered orally or parenterally.
  • bictegravir is administered orally to assess the safety and tolerability, and if no or low issue in safety and tolerability is found (called "oral-lead method"), then bitegravir is administered intramuscularly or subcutaeneously, but tenofovir alafenamide, or a pharmaceutically acceptable salt thereof, and 3TC, or a pharmaceutically acceptable salt thereof, are orally administered.
  • tenofovir alafenamide, or a pharmaceutically acceptable salt thereof; bictegravir, or a pharmaceutically acceptable salt thereof; and 3TC, or a pharmaceutically acceptable salt thereof are all administered orally.
  • tenofovir alafenamide, or a pharmaceutically acceptable salt thereof; bictegravir, or a pharmaceutically acceptable salt thereof; and 3TC, or a pharmaceutically acceptable salt thereof are all administered parenterally in a long- acting intravenous formulation, either together or separately.
  • compositions comprising tenofovir alafenamide, or a pharmaceutically acceptable salt thereof; bictegravir, or a pharmaceutically acceptable salt thereof; and 3TC, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient are provided.
  • compositions consisting essentially of tenofovir alafenamide, or a pharmaceutically acceptable salt thereof; bictegravir, or a pharmaceutically acceptable salt thereof; and 3TC, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient are provided.
  • compositions consisting of tenofovir alafenamide, or a pharmaceutically acceptable salt thereof; bictegravir, or a pharmaceutically acceptable salt thereof; and 3TC, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients are provided.
  • combinations comprising tenofovir alafenamide, or a pharmaceutically acceptable salt thereof; bictegravir, or a pharmaceutically acceptable salt thereof; and 3TC, or a pharmaceutically acceptable salt thereof, are provided.
  • combinations consisting essentially of tenofovir alafenamide, or a pharmaceutically acceptable salt thereof; bictegravir, or a pharmaceutically acceptable salt thereof; and 3TC, or a pharmaceutically acceptable salt thereof, are provided.
  • combinations consisting of tenofovir alafenamide, or a pharmaceutically acceptable salt thereof; bictegravir, or a pharmaceutically acceptable salt thereof; and 3TC, or a pharmaceutically acceptable salt thereof; and one or more pharmaceutically acceptable carriers, diluents or excipients are provided.
  • Another embodiment provides further administration of at least one antiretroviral compound.
  • a method for treating or preventing an HIV infection in a human comprising administering to the human a therapeutically effective amount of tenofovir alafenamide, or a pharmaceutically acceptable salt thereof; a therapeutically effective amount of bictegravir, or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of 3TC, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.
  • one or more e.g., one, two, three, one or two, or one to three
  • One embodiment of the invention provides a method for treating HIV infection in a human comprising administering to the human a therapeutically effective amount of tenofovir alafenamide, or a pharmaceutically acceptable salt thereof; a therapeutically effective amount of bictegravir, or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of 3TC, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents that are suitable for treating an HIV infection.
  • the present disclosure provides a method for preventing an HIV infection, comprising administering to a human a therapeutically effective amount of tenofovir alafenamide, or a pharmaceutically acceptable salt thereof; a therapeutically effective amount of bictegravir, or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of 3TC, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents that are suitable for preventing an HIV infection.
  • the present disclosure provides a method for preventing an HIV infection, comprising administering to a human a therapeutically effective amount of tenofovir alafenamide, or a pharmaceutically acceptable salt thereof; a therapeutically effective amount of bictegravir, or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of 3TC, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents that are suitable for treating an HIV infection.
  • compositions comprising tenofovir alafenamide, or a pharmaceutically acceptable salt thereof; bictegravir, or a pharmaceutically acceptable salt thereof; and 3TC, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, one to two, or one to three) additional therapeutic agents, and a therapeutically acceptable carrier, diluent or excipient are provided.
  • One embodiment of the invention provides a method for treating or preventing HIV infection in a human comprising administering to the human a therapeutically effective amount of tenofovir alafenamide, or a pharmaceutically acceptable salt thereof; a therapeutically effective amount of bictegravir, or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of 3TC, or a pharmaceutically acceptable salt thereof.
  • kits comprising tenofovir alafenamide, or a
  • kits comprise tenofovir alafenamide in a syringe dosage or tablet dosage form, bictegravir in a syringe dosage or tablet dosage form, and 3TC in a syringe dosage or tablet dosage form.
  • a combination including tenofovir alafenamide, or a pharmaceutically acceptable salt thereof;
  • the additional therapeutic agent may be an anti-HIV agent.
  • the additional therapeutic agent is chosen from: HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, MK8591 (EFdA); HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors (e.g., CCR5 inhibitors, gp41 inhibitors (i.e., fusion inhibitors) and CD4 attachment inhibitors, such as combinectin), CXCR4 inhibitors, gpl20 inhibitors, G6PD and NADH-oxidase inhibitors, HIV vaccines, latency reversing agents (e.g., histone deacetylase inhibitors, proteasome inhibitors, protein kinase
  • latency reversing agents e.g., histone deacetylase
  • the additional therapeutic is chosen from: HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, pharmacokinetic enhancers, and combinations thereof.
  • tenofovir alafenamide, or a pharmaceutically acceptable salt thereof; bictegravir, or a pharmaceutically acceptable salt thereof; and 3TC, or a pharmaceutically acceptable salt thereof are formulated as a tablet that may optionally contain one or more other compounds useful for treating HIV.
  • the tablet can contain another active ingredient for treating HIV, such as HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, pharmacokinetic enhancers, and combinations thereof.
  • such tablets are suitable for once daily dosing.
  • the additional therapeutic agent may be chosen from one or more of:
  • Combination drugs chosen from: ATRIPLA ® (efavirenz+tenofovir disoproxil fumarate+emtricitabine ), COMPLERA ® (EVIPLERA ® , rilpivirine+tenofovir disoproxil fumarate+emtricitabine ), STRIBILD ® (elvitegravir+cobicistat+tenofovir disoproxil fumarate+emtricitabine), lamivudine+nevirapine+zidovu dine, atazanavir
  • TRIZIVIR ® abacavir sulfate+zidovudine+ lamivudine, ABC+AZT+3TC
  • TRUVADA ® tenofovir disoproxil fumarate+emtricitabine
  • TDF+FTC tenofovir+ lamivudine, atazanavir+cobicistat, doravirine+lamivudine+ tenofovir disoproxil fumarate, doravirine+lamivudine+tenofovir disoproxil and lamivudine+tenofovir disoproxil fumarate;
  • HIV protease inhibitors chosen from: amprenavir, atazanavir, fosamprenavir, fosam- prenavir calcium, indinavir, indinavir sulfate, lopinavir, ritonavir, nelfinavir, nelfinavir mesylate, saquinavir, saquinavir mesylate, tipranavir, brecanavir, darunavir, DG-17, TMB-657 (PPL-100), TMC-310911, and TMB-657;
  • HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase chosen from: delavirdine, delavirdine mesylate, nevirapine, (+), etravirine, dapivirine, doravirine, efavirenz, KM023, VM-1500, lentinan, AIC-292, EFdA (4'-Ethynyl-2- Fluoro-2'-Deoxyadenosine, or otherwise known as MK-8591), ENDURANT ® (rilpivirine), lentinan, AIC-292, and KM-023;
  • HIV nucleoside or nucleotide inhibitors of reverse transcriptase chosen from: VIDEX ® and VIDEX ® EC (didanosine, ddl), zidovudine, emtricitabine, didanosine, stavudine, zalcitabine, lamivudine, censavudine, abacavir, abacavir sulfate, amdoxovir, elvucitabine, alovudine, phosphazid, fozivudine tidoxil, apricitabine, amdoxovir, KP- 1461, fosalvudinetidoxil, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifUmarate, adefovir, adefovir dipivoxil, and festinavir, and MK8591 (EFd
  • HIV non-catalytic site or allosteric, integrase inhibitors (NCINI) chosen from: CX-05168, CX-05045 and CX-14442; the compound disclosed in Example 195 of WO 2016/005878 (ViiV Healthcare Company ® ) having the stucture:
  • HIV gp41 inhibitors chosen from: enfuvirtide, sifuvirtide and albuvirtide;
  • HIV entry inhibitors such as cenicriviroc
  • HIV gpl20 inhibitors chosen from: Radha-108 (Receptol) and BMS-663068;
  • CCR5 inhibitors chosen from: aplaviroc,vicriviroc,maraviroc, cenicriviroc, PRO- 140, Adaptavir (RAP-101), nifeviroc (TD-0232), TD-0680, TBR-220 (TAK- 220) and vMIP (Haimipu);
  • CD4 attachment inhibitors such as ibalizumab and combinectin
  • CXCR4 inhibitors chosen from: plerixafor, ALT-1188, vMIP and Haimipu;
  • Pharmacokinetic enhancers or boosting agents chosen from: cobicistat (TYBOST ® ), ritonavir (NORVIR ® ), and SPI-452;
  • Immune-based therapies chosen from: derma Vir, interleukin-7, lexgenleucel- T (VRX-496), plaquenil (hydroxychloroquine), proleukin (aldesleukin, IL-2), interferon alfa, interferonalfa-2b, interferon alfa-ti3 , pegylated interferon alfa, interferon gamma, hydroxyurea, mycophenolate mofetil (MP A) and its ester derivative mycophenolate mofetil (MMF), WF-10, ribavirin, IL-2, IL-2 XL, IL-12, polymer polyethyleneimine (PEI), Gepon, VGV- 1, MOR-22, toll-like receptors modulators (tlrl, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlrlO, tlrl 1,
  • HIV vaccines chosen from: peptide vaccines, recombinant subunit protein vac- cines, live vector vaccines, DNA vaccines, virus-like particle vaccines
  • HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins such as DARTs ® , Duo-bodies ® , Bites ® , XmAbs®, TandAbs ® , Fab derivatives
  • BMS-936559, TMB-360 and those targeting HIV gpl20 or gp41 are chosen from: bavituximab, UB-421, C2F5, C2G12, C4E10, C2F5+C2G12+ C4E10, 3-BNC- 117, KD-247, PGT145, PGT121, MDX010 (ipilimumab), VRCOl, VRC01-LS, A32, 7B2, N6, 10E8, VRC-07-523 and VRC07;
  • latency-reversing agents chosen from: histone deacetylase inhibitors such as Romidepsin, vorinostat, panobinostat; proteasome inhibitors, such as VELCADE ® ; protein kinase C (PKC) activators such as Indolactam, prostratin, ingenol B and DAG-lactones, lonomycin, GSK-343, PMA, SAIIA, BRIM inhibitors, IL-15, JQ1, amphotericin B, and disulfram;
  • histone deacetylase inhibitors such as Romidepsin, vorinostat, panobinostat
  • proteasome inhibitors such as VELCADE ®
  • PLC protein kinase C activators
  • Indolactam prostratin, ingenol B and DAG-lactones, lonomycin, GSK-343, PMA, SAIIA, BRIM inhibitors, IL-15, JQ1, amphotericin B
  • NCp7 inhibitors such as azodicarbonamide
  • P13K inhibitors chosen from: idelalisib, AZD-8186, buparlisib, CLR-457, pictilisib,neratinib,rigosertib,rigosertib sodium, EN-3342, TGR- 1202, alpelisib, duvelisib, UCB-5857, taselisib, XL-765, gedatolisib, VS-5584, copanlisib, CAI orotate, perifosine, RG-7666, GSK-2636771, DS-7423, panulisib, GSK- 2269557, GSK-2126458, CUDC-907, PQR-309, INCB-040093, pilaralisib, BAY-1082439, puquitinib mesylate, S
  • 2013/006738 (Gilead Sciences ® ), US 2013/0165489 (University of Pennsylvania ® ), US20140221380 (Japan Tobacco ® ), US20140221378 (Japan Tobacco ® ), WO 2013/006792 (Pharma Resources ® ), WO 2009/ 062285 (Boehringer Ingelheim ® ), WO 2010/130034 (Boehringer Ingelheim ® ), WO 2013/091096A1 (Boehringer Ingelheim), WO 2013/159064 (Gilead Sciences), WO 2012/ 145728 (Gilead Sciences ® ), W02012/003497 (Gilead Sciences ® ), W02014/100323 (Gilead Sciences ® ), W02012/ 145728 (Gilead Sciences ® ), W02013/159064 (Gilead Sciences ® ) and WO
  • (21) other drugs for treating HIV chosen from: REP 9, cytolin, CYT-107, alisporivir, BanLec, MK-8507, AG-1105, TR-452, MK-8591, REP 9. NOV-205, IND-02, metenkefalin, PGN-007, Acemannan, Gamimune, SCY-635, prolastin, 1,5- dicaffeoylquinic acid, BIT-225, RPI-MN, VSSP, Hlviral, IM0-3100, SB-728-T, RPI- MN, VIR-576, HGTV-43, MK-1376, rHIV7-shl-TAR-CCR5RZ, MazF gene therapy, BlockAide, ABX-464, SCY- 635, naltrexone, AAV-eCD4-Ig gene therapy, TEV-90110, TEV-90112, deferiprone, and PA-1050040 (PA-040).
  • tenofovir alafenamide, or a pharmaceutically acceptable salt thereof; bictegravir, or a pharmaceutically acceptable salt thereof; and 3TC, or a pharmaceutically acceptable salt thereof are combined with one, two, three, four or more additional therapeutic agents.
  • the one, two, three, four or more additional therapeutic agents can be different therapeutic agents selected from the same class of therapeutic agents, and/or they can be selected from different classes of therapeutic agents.
  • tenofovir alafenamide, or a pharmaceutically acceptable salt thereof; bictegravir, or a pharmaceutically acceptable salt thereof; and 3TC, or a pharmaceutically acceptable salt thereof are combined with one, two, three, four or more additional therapeutic agents selected from raltegravir, TRUVADA ® (tenofovir disoproxil fumarate+emtricitabine, TDF+FTC), maraviroc, enfuvirtide, EPZICOM ® (KIVEXA ® , abacavir sulfete+lamivu- dine, ABC+3TC), TRIZIVffi.
  • TRUVADA ® tenofovir disoproxil fumarate+emtricitabine, TDF+FTC
  • maraviroc enfuvirtide
  • EPZICOM ® KIVEXA ®
  • abacavir sulfete+lamivu- dine ABC+3TC
  • tenofovir alafenamide, or a pharmaceutically acceptable salt thereof; bictegravir, or a pharmaceutically acceptable salt thereof; and 3TC, or a pharmaceutically acceptable salt thereof are administered with ritonavir.
  • the components of the composition are administered as a simultaneous or sequential regimen. When administered sequentially, either combination may be administered in two or more administrations.
  • tenofovir alafenamide, or a pharmaceutically acceptable salt thereof; bictegravir, or a pharmaceutically acceptable salt thereof; and 3TC, or a pharmaceutically acceptable salt thereof are combined with one or more additional therapeutic agents, in a unitary dosage form for simultaneous administration to a human, for example as a solid dosage form for oral administration.
  • Co-administration of tenofovir alafenamide, or a pharmaceutically acceptable salt thereof; bictegravir, or a pharmaceutically acceptable salt thereof; and 3TC, or a pharmaceutically acceptable salt thereof, with one or more additional therapeutic agents generally refers to simultaneous or sequential administration of a compound disclosed herein and one or more additional therapeutic agents, such that therapeutically effective amounts of the compound disclosed herein and one or more additional therapeutic agents are both present in the body of the human.
  • Co-administration includes administration of unit dosages of tenofovir alafenamide, or a pharmaceutically acceptable salt thereof; bictegravir, or a pharmaceutically acceptable salt thereof; and 3TC, or a pharmaceutically acceptable salt thereof, before or after administration of unit dosages of one or more additional therapeutic agents, for example, administration of tenofovir alafenamide, or a pharmaceutically acceptable salt thereof; bictegravir, or a pharmaceutically acceptable salt thereof; and 3TC, or a pharmaceutically acceptable salt thereof, within seconds, minutes, or hours of the administration of one or more additional therapeutic agents.
  • a unit dose of tenofovir alafenamide, or a pharmaceutically acceptable salt thereof; bictegravir, or a pharmaceutically acceptable salt thereof; and 3TC, or a pharmaceutically acceptable salt thereof is administered first, followed within seconds or minutes by administration of a unit dose of one or more additional therapeutic agents.
  • a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of tenofovir alafenamide, or a pharmaceutically acceptable salt thereof;
  • a unit dose of tenofovir alafenamide, or a pharmaceutically acceptable salt thereof; bictegravir, or a pharmaceutically acceptable salt thereof; and 3TC, or a pharmaceutically acceptable salt thereof is administered first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of one or more additional therapeutic agents.
  • a unit dose of one or more additional therapeutic agents is administered first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of tenofovir alafenamide, or a pharmaceutically acceptable salt thereof;
  • the bictegravir is administered to the patient at about 50mg, once, twice or three times a day. In another embodiment, bictegravir is administered to the patient in about 20-200mg, once, twice or three times a day.
  • bictegravir is administered to the patient at about 5 mg to 100 mg, at about 25 mg to 75 mg, at about 35 mg to 65 mg, or about 45 mg to 55 mg, once or twice per day.
  • tenofovir alafenamide is administered to the patient at about 1 mg, about 5 mg, about 1 Omg, about 15mg, about 20 mg, about 25 mg dose, about 30 mg, about 35 mg, about 40 mg, about 45 mg or about 50 mg once, twice or three times a day.
  • tenofovir alafenamide is administered to the patient at about 1 mg to 50 mg or at about 5 mg to 25 mg once per day.
  • tenofovir alafenamide is administered to the patient at about 5 mg, once per day. In another embodi- ment, tenofovir alafenamide is administered to the patient at about 1 Omg, once per day. In another embodiment, tenofovir alafenamide is administered to the patient at about 25 mg, once per day.
  • 3TC is administered 25-300 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, or 300 mg, once, twice, or three times a day.
  • a single dosage form containing tenofovir alafenamide, bictegravir and 3TC contains 25mg of tenofovir alafenamide, 50mg of bictegravir, and 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, or 300 mg of 3TC.
  • this invention relates to a combination comprising tenofovir alafenamide, or a pharmaceutically acceptable salt thereof; bictegravir, or a pharmaceutically acceptable salt thereof; and 3TC, or a pharmaceutically acceptable salt thereof .
  • this invention relates to the above combination for use in medical therapy.
  • this invention relates to the above combination for use in the treatment of HIV.
  • this invention relates to pharmaceutical composition
  • a combination comprising tenofovir alafenamide, or a pharmaceutically acceptable salt thereof; bictegravir, or a pharmaceutically acceptable salt thereof; and 3TC, or a pharmaceutically acceptable salt thereof.
  • this invention relates to pharmaceutical composition
  • a combination comprising tenofovir alafenamide, or a pharmaceutically acceptable salt thereof; bictegravir, or a pharmaceutically acceptable salt thereof; and 3TC, or a pharmaceutically acceptable salt thereof in association with one or more pharmaceutically acceptable carriers therefor.
  • the present invention provides for the use of tenofovir alafenamide, or a pharmaceutically acceptable salt thereof; bictegravir, or a pharmaceutically acceptable salt thereof; and 3TC, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of HIV.
  • Bictegravir has structural formula I, and a method of making is described in 1189,216,996.
  • 3TC (lamivudine) has structural formula II.
  • Tenofovir alafenamide has chemical structure of formula III, and a method of making is described in EP1301519B1.
  • co-administer refers to administration of two or more agents within a 24-hour period of each other, for example, as part of a clinical treatment regimen. In other embodiments, “co-administer” refers to administration of two or more agents within 2 hours of each other. In other embodiments, “co-administer” refers to administration of two or more agents within 30 minutes of each other. In other embodiments, “co-administer” refers to administration of two or more agents within 15 minutes of each other. In other embodiments, “co-administer” refers to administration at the same time, either as part of a single formulation or as multiple formulations that are administered by the same or different routes.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound that is pharmaceutically acceptable and that possesses (or can be converted to a form that possesses) the desired pharmacological activity of the parent compound.
  • “pharmaceutically acceptable salts” of the compounds disclosed herein include salts derived from an appropriate base, such as an alkali metal (for example, sodium), an alkaline earth metal (for example, magnesium), ammonium and NX 4 + (wherein X is C1-C4 alkyl).
  • Pharmaceutically acceptable salts of a nitrogen atom or an amino group include, for example, salts of organic carboxylic acids such as acetic, benzoic, camphorsulfonic, citric, glucoheptonic, gluconic, lactic, fumaric, tartaric, maleic, malonic, malic, mandelic, isethionic, lactobionic, succinic, 2-napththalenesulfonic, oleic, palmitic, propionic, stearic, and trimethylacetic acids; organic sulfonic acids, such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids; and inorganic acids, such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric and sulfamic acids.
  • organic carboxylic acids such as acetic, benzoic, camphorsulfonic, citric, glucohepton
  • Pharmaceutically acceptable salts of a compound of a hydroxy group include the anion of said compound in combination with a suitable cation, such as Na + and NX4 + (wherein X is independently selected from H or a C1-C4 alkyl group).
  • Pharmaceutically acceptable salts also include salts formed when an acidic proton present in the parent compound is replaced by either a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as diethanolamine, triethanolamine, N- methylglucamine and the like. Also included in this definition are ammonium and substituted or quaternized ammonium salts.
  • salts of active ingredients of the compounds disclosed herein will typically be pharmaceutically acceptable, i.e., they will be salts derived from a physiologically acceptable acid or base.
  • salts of acids or bases that are not pharmaceutically acceptable may also find use, for example, in the preparation or purification of tenofovir alafenamide or another compound of the invention. All salts, whether or not derived from a physiologically acceptable acid or base, are within the scope of the present invention.
  • Metal salts typically are prepared by reacting the metal hydroxide with a compound of this invention.
  • metal salts that are prepared in this way are salts containing Li + , Na + , and K ⁇ .
  • a less soluble metal salt can be precipitated from the solution of a more soluble salt by addition of the suitable metal compound.
  • compositions herein comprise compounds disclosed herein in their un-ionized, as well as zwitterionic form, and combinations with
  • a zwitterionic compound is encompassed herein by referring to a compound that is known to form zwitterions, even if it is not explicitly named in its zwitterionic form.
  • Terms such as zwitterion, zwitterions, and their synonyms zwitterionic compound(s) are standard IUPAC-endorsed names that are well known and part of standard sets of defined scientific names.
  • the name zwitterion is assigned the name identification, CHEBI:27369, by the Chemical Entities of Biological Interest (ChEBI) dictionary of molecular entities. (See, for example, its on-line version at http://www.ebi.ac.uk/chebi/initdo).
  • a zwitterion or zwitterionic compound is a neutral compound that has formal unit charges of opposite sign. Sometimes these compounds are referred to by the term “inner salts”. Other sources refer to these compounds as “dipolar ions", although the latter term is regarded by still other sources as a misnomer.
  • aminoethanoic acid the amino acid glycine
  • H2NCH2COOH the amino acid glycine
  • Zwitterions, zwitterionic compounds, inner salts and dipolar ions in the known and well established meanings of these terms are within the scope of this invention, as would in any case be so appreciated by those of ordinary skill in the art. Because there is no need to name each and every embodiment that would be recognized by those of ordinary skill in the art, no structures of the zwitterionic compounds that are associated with the compounds of this invention are given explicitly herein. They are, however, part of the embodiments of this invention. No further examples in this regard are provided herein because these interactions and transformations in a given medium are known by any one of ordinary skill in the art.
  • “Therapeutically effective amount” refers to that amount of the compound being administered lhat will prevent a condition, or will reduce to some extent one or more of the symptoms of the disorder being treated.
  • Pharmaceutical compositions suitable for use herein include compositions wherein the active ingredients are contained in an amount sufficient to achieve the intended purpose. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
  • Preferred tenofovir alafenamide salt form is monofumarate and hemifumarate. Methods for preparing tenofovir alafenamide monofumarate is disclosed in US7,390,791. Methods for preparing tenofovir alafenamide hemifumarate is disclosed in US9.296.769
  • treatment refers to inhibition, reduction, elimination or alleviation of a disease.
  • prevention refers to reducing the risk of infection or exhibiting signs or symptoms of such infection in a human at high risk ho has not been pre- treated.
  • Retroviruses are RNA viruses and are generally classified into the alpharetrovirus, betaretrovirus, deltaretrovirus, epsilonretrovirus, garnmaretrovirus, lentivirus, and spumavirus families.
  • retroviruses include, but are not limited to, human immunodeficiency virus (HIV).
  • the active agents of the disclosed combination therapy may be administered to a human in any conventional manner. While it is possible for the active agents to be administered as compounds, they are preferably administered as a pharmaceutical composition that can include contact with an acid or base, either in an ionic salt form or in contact with the base or acid (i.e., co-formers) without sharing ions.
  • the salt, acid or base co-former, carrier, or diluent should be acceptable, in the sense of being compatible with the other ingredients and not deleterious to the recipient thereof.
  • carriers or diluents for oral administration include, but are not limited to: cornstarch, lactose, magnesium stearate, talc, microcrystalline cellulose, stearic acid, povidone, crospovidone, dibasic calcium phosphate, sodium starch glycolate, hydroxypropyl cellulose (e.g., low substituted hydroxypropyl cellulose),
  • hydroxypropylmethyl cellulose e.g., hydroxypropylmethyl cellulose 2910
  • sodium lauTyl sulfate sodium lauTyl sulfate
  • mannitol sodium stearyl fumarate
  • talc sodium lauTyl sulfate
  • salts and acid or base co-formers include fumarate, hemifumarate, sodium, and hydrochloride.
  • compositions may be prepared by any suitable method, such as those methods well known in the art of pharmacy, for example, methods such as those described in Gennaro, et al., REMINGTON'S PHARMACEUTICAL SCIENCES (18th ed., Mack Publishing Co., 1990), especially "Part 8: Pharmaceutical Preparations and their Manufacture".
  • suitable methods include the step ofbringing into association the compounds with the carrier or diluents and, optionally, one or more accessory ingredients.
  • accessory ingredients include, but are not limited to: fillers, binders, excipients, disintegrants, lubricants, colorants, flavoring agents, sweeteners, preservatives (e.g., antimicrobial preservatives), suspending agents, thickening agents, emulsifying agents, and/or wetting agents.
  • preservatives e.g., antimicrobial preservatives
  • suspending agents thickening agents, emulsifying agents, and/or wetting agents.
  • each compound to be administered ranges from about 0.001 to 100 mg per kg of body weight, such total dose being given at one time or in divided doses.
  • Each compound will be administered as a formulation in association with one or more pharmaceutically acceptable excipients.
  • both compounds will be combined and administered as a formulation in association with one or more pharmaceutically acceptable excipients.
  • the choice of excipient will, to a large extent, depend upon factors such as the particular mode of
  • compositions and methods for their preparation may be found, for example, in REMINGTON'S PHARMACEUTICAL SCIENCES (19th Edition, Mack Publishing Company, 1995).
  • Example 1 HIV Cell Line Assay The HIV cell line experiments taught by Kobayashi, et al., Antimicrobial Agents and Chemotherapy, 55: 814-815 (2011) are followed to test the antiviral abilities of the disclosed and claimed combination of tenofovir alafenamide, bictegravir, and 3TC, as compared with the antiviral abilities of each compound alone.
  • Example 2 Cells and viruses
  • Cells of MT-4 a human T-cell leukemia virus type 1 (HTLV-l)-transformed human T-cell line, are maintained as described previously [12].
  • 293T cells are maintained in Dulbecco's modified Eagle medium (DMEM)-F-12 medium containing 10% fetal bovine serum (FBS).
  • DMEM Dulbecco's modified Eagle medium
  • FBS fetal bovine serum
  • Peripheral blood mononuclear cells are derived from whole blood samples obtained from HIV-negative donors. PBMCs are separated from whole blood by density gradient centrifugation with Ficoll-Paque
  • HTV-1 strain IIIB is derived from cell-free supernatants of cultures of the chronically infected cell line, H93B (H9/HTL V-IHB).
  • HTV-1 strain Ba-L is purchased from Advanced Biotechnologies Inc. ® (Columbia,
  • Plasmid pGJ3-Luci containing a replication-defective HIV lentiviral vector expressing luciferase [21] is licensed from Christian Jassoy (University of Leipzig), and is used to create stocks of a vesicular stomatitis virus glycoprotein G (VSV-G)-pseudotyped self- inactivating pseudo-HIV (PHTV) lentiviral vector by cotransfection, along with plasmid pVSV-G (Clontech ® ) into CIP4 cells (a derivative of the 293T human renal epithelial cell line that expresses macrophage scavenger receptor SRA-I to improve adherence to plastic) and harvesting of the cell-free supernatant.
  • VSV-G vesicular stomatitis virus glycoprotein G
  • PHTV pseudo-HIV
  • Example 3 Antiviral assay in MT-4 cells
  • the MT-4 cells generated in Example II grow exponentially at a density of 5 X 10 5 or 6 X 105/ml are infected with HIV-1 strain .TUB at a viral multiplicity of infection of 0.001 or a 50% tissue culture infective dose of 4 to 10. The cells are then aliquoted to 96-well plates in the presence of varying concentrations of compounds.
  • antiviral activity is determined by a cell viability assay that either measures bioluminescence with a CellTiter-Glo ® luminescent reagent (Promega Corporation ® , Madison, WI) or measured absorbance at 560 and 690 nm using the yellow tetrazolium MTT reagent [3-(4,5- dimethyl-2-thiazolyl)-2,5- diphenyltetrazolium bromide].
  • Example 4 Pseudo-HIV assay.
  • the antiviral activities of tenofovir alafenamide alone, bictegravir alone, 3TC alone, as well as the combination of tenofovir alafenamide, bictegravir, and 3TC are measured in a single-round assay using a self-inactivating PHTV lentiviral vector.
  • Example 5 Antiviral assay in PBMCs.
  • PBMCs 4 X 10 5 /well
  • IHV-1 strain, Ba-L IHV-1 strain
  • An aliquot of the Ba-L-compound mixture is then transferred to the PBMC- compound mixture and is incubated for 7 days. After this incubation, supernatants are assayed for reverse transcriptase (RT) activity by incorporation of [methyl-3H]dTTP to measure viral replication, as previously described [15].
  • RT reverse transcriptase
  • Example 6 Effects of human serum and serum proteins.
  • HSA human serum albumin
  • AAG aj-acid glycoprotein
  • HS human serum
  • the protein- adjusted half-maximal effective concentration (PA-EC 50 ) is estimated by multiplying the EC 50 in PBMCs by the fold shift value.
  • the same experiment is conducted using the combination of tenofovir alafenamide, bictegravir, and 3TC.
  • Example 7 Combination antiviral activity assay in MT-4 cells.
  • the in vitro combination activity relationships of: (1) tenofovir alafenamide alone; (2) bictegravir alone; (3) 3TC alone; (4) and combination of tenofovir alafenamide, bictegravir, and 3TC; are determined as previously described [39].
  • Multiple concentrations of the compounds are tested in checkerboard dilution fashion in the presence and absence of dilutions of approved anti-IIIV drugs, adefovir, or ribavirin.
  • the assay used HIV-1 ULB-infected MT-4 cells, and the interaction of the compound combination is analyzed by dose wise additivity-based calculations to quantify deviation from dose wise additivity at the 50% level.
  • anti-hepatitis B virus anti-HBV
  • anti-HCV agents adefovir and ribavirin on: (1) tenofovir alafenamide alone; (2) the compound of formula II alone; and (3) tenofovir alafenamide and the compound of formula II are examined using linear regression, as described previously [41].
  • the CCR5 inhibitor, maraviroc is evaluated in a checkerboard dilution format using MAGI-CCR5 cells with the Gal Screen reagent (Tropix ® , Bedford, MA) for chemiluminescent endpoints, and data are analyzed as described by Prichard and Shipman [37] by using the MacSynergy II ® program. Synergy volumes in the range of -50 to 50 define additivity; ⁇ -50, antagonism; and >50, synergy.

Abstract

L'invention concerne des méthodes de traitement du VIH chez l'homme au moyen de combinaisons de ténofovir alafénamide et de bictégravir, et de 3TC, ainsi que des compositions contenant de tels composés.
PCT/IB2017/055537 2016-09-14 2017-09-13 Combinaison comprenant du ténofovir alafénamide, du bictégravir et du 3tc WO2018051250A1 (fr)

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JP2020529461A (ja) * 2017-08-09 2020-10-08 ヴィーブ ヘルスケア カンパニー 組み合わせ並びにその使用及び治療
EP3664896A4 (fr) * 2017-08-09 2021-06-09 VIIV Healthcare Company Combinaisons, utilisations et traitements correspondants

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