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Investigational

Cabotegravir  Audio icon

Other Names: 744 LA, CAB, GSK-1265744, GSK1265744, GSK744, GSK744 LA, GSK744 LAP, S-265744, S/GSK1265744, cabotegravir LA, cabotegravir sodium
Drug Class: Integrase Inhibitors
Molecular Formula: C19 H17 F2 N3 O5
Registry Number: 1051375-10-0 (CAS)
Chemical Name: (3S,11aR)-N-((2,4-difluorophenyl)methyl)-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo(3,2-a)pyrido(1,2-d)pyrazine-8-carboxamide
Company: ViiV Healthcare
Phase of Development: IIb
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Chemical Image:
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cabotegravir
cabotegravir
Molecular Weight: 405.3553
(Compound details obtained from ChemIDplus Advanced,1 NIAID Therapeutics Database,2 and ViiV Healthcare website3)
Patent Version Content

Pharmacology


Mechanism of Action: HIV-1 integrase strand transfer inhibitor. Cabotegravir (also known as S/GSK1265744) prevents viral DNA integration into the host genome and is being developed for both HIV treatment and prevention.4,5

Half-life (T½): 21 to 50 days (long-acting parenteral [LAP] nanosuspension administered via intramuscular [IM] or subcutaneous [SC] injection); 40 hours (oral dosing).6

Metabolism/Elimination: Cabotegravir is primarily metabolized via glucuronidation by UGT1A1 (main pathway) and UGT1A9 (minor pathway). Cytochrome P450 (CYP)-mediated metabolism is expected to have a minimal role in cabotegravir metabolism.7 Following a single oral radiolabeled dose of cabotegravir 30 mg, 58.5% of the administered dose was recovered in feces and 26.8% was recovered in urine. Cabotegravir is eliminated in feces primarily as unchanged drug and in urine as a glucuronide metabolite (M1).8

Resistance: In vitro, cabotegravir has exhibited activity against raltegravir-resistant isolates.9

Exposure of MT-2 cells infected with HIV-1 IIIB to increasing concentrations of cabotegravir for up to 112 days did not produce highly resistant mutants. Among 25 site-directed molecular clones containing single INSTI resistance substitutions, the majority remained fully susceptible to cabotegravir. However, the Q148K and Q148R mutants resulted in a moderate loss of efficacy for cabotegravir, with a 5.6-fold change (FC) with Q148K and a 5.1-FC with Q148R. Among 24 double or multiple integrase mutants, the following six had a FC >10 and were considered highly resistant to cabotegravir: E138A/Q148R, E138K/Q148K, E138K/Q148R, G140C/Q148R, G140S/Q148R, and Q148R/N155H. Cabotegravir cross-resistance to raltegravir and elvitegravir is limited. When tested against mutant viruses resistant to approved NRTIs, NNRTIs, and PIs, cabotegravir demonstrated efficacy with a potency similar to that against wild-type virus.10,11

In vitro analysis was performed on the susceptibility of recombinant viruses with patient-derived integrase from various clades of HIV-1 to cabotegravir. Fifty percent and 90% inhibitory concentrations (IC50 and IC90) of cabotegravir against each virus was comparable to cabotegravir’s activity against the wild-type control. No virus exhibited significant resistance to cabotegravir. Cabotegravir demonstrated a modest reduction in activity against two common integrase resistant viruses with the mutations G140S plus Q148H or E92Q plus N155H. These viruses, however, had significant resistance to raltegravir.12

In the Phase IIb LATTE study (NCT01641809), protocol-defined virologic failure was reported in seven total participants (three participants receiving oral CAB and four participants receiving efavirenz) during the 24-week induction phase of the study. During the induction phase, no treatment-emergent resistance was detected. During the 72-week maintenance phase of the study, five total participants experienced protocol-defined virologic failure: two in the CAB 10-mg group, one in the CAB 30-mg group, and two in the efavirenz group. Treatment-emergent resistance was detected in three participants, with two participants developing only NNRTI resistance mutations and one participant (who had low CAB and rilpivirine exposures) developing both an NNRTI (E138Q) and INI (Q148R) mutation.13


Dosing in Clinical Trials



Study Identifiers: LAI116482 (LATTE)14; NCT0164180915
Phase: IIb
Study Purpose: Dose-ranging efficacy study of oral CAB to select oral dose and evaluate oral CAB plus rilpivirine as a two-drug antiretroviral therapy (ART) regimen for suppressive maintenance therapy
Study Population: HIV-infected, treatment–naive adults
Dosing:
  • Induction phase: Oral CAB 10, 30, or 60 mg once daily versus efavirenz 600 mg once daily, each given in combination with two background nucleoside reverse transcriptase inhibitors (NRTIs). The induction phase lasted through Week 24.
  • Maintenance phase: Those participants successfully completing the induction phase continued their randomized dose of oral CAB, but discontinued the background NRTIs and added rilpivirine 25 mg. The comparator arm continued with efavirenz 600 mg plus the background NRTIs. The maintenance phase lasted through Week 96.
  • Open-Label phase: Participants receiving oral CAB plus rilpivirine in the maintenance phase could enroll to continue treatment on the same regimen beyond Week 96.13-16
(See references cited above for information on study results.)


Study Identifier: LATTE 217; NCT0212035218
Phase: IIb
Study Purpose: Safety and efficacy study to evaluate the antiviral activity, tolerability, and safety of two intramuscular (IM) dosing regimens of the long-acting injectables CAB LA plus rilpivirine LA (also known as TMC278 LA) and to compare the IM dosing regimens to oral CAB plus abacavir/lamivudine (ABC/3TC)
Study Population: HIV-infected, treatment-naive adults
Dosing:
  • Induction phase: Once-daily regimen of oral CAB 30 mg plus ABC/3TC 600/300 mg for 20 weeks. In the last 4 weeks of the induction phase, participants will also receive oral rilpivirine 25 mg once daily. (Participants who qualify will continue on to the maintenance phase of the study.)
  • Maintenance phase: Following induction, qualifying participants will be randomized to one of three treatment arms for maintenance therapy. All doses of CAB LA and rilpivirine LA will be given IM.
    • A loading dose of CAB LA 800 mg plus rilpivirine LA 600 mg will be given on Day 1. Starting at Week 4, participants will receive a regimen of CAB LA 400 mg plus rilpivirine LA 600 mg administered every 4 weeks over 96 weeks.
    • A loading dose of CAB LA 800 mg plus rilpivirine LA 900 mg will be given on Day 1. A second loading dose of CAB LA 600 mg will be given at Week 4. Starting at Week 8, participants will receive a regimen of CAB LA 600mg plus rilpivirine LA 900 mg administered every 8 weeks over 96 weeks.
    • Oral CAB 30 mg plus ABC/3TC for 96 weeks (or 104 weeks if continuing on through extension phase).
  • Extension phase: For long-term collection of efficacy and safety data.
There will also be a long-term follow-up period for participants who withdraw from the study and have received at least one dose of CAB LA and/or rilpivirine LA.17,18

Two Phase IIa studies of CAB LA will be undertaken to develop the safety and pharmacokinetic profile of CAB LA for pre-exposure prophylaxis (PrEP). The ECLAIR study will investigate CAB LA in HIV-uninfected men at risk of acquiring HIV, and HPTN 077 will examine CAB LA in HIV-uninfected women and men.17,19-21 In addition, the Phase II CAPRISA 014 study will help to establish the safety and acceptability of CAB LA in at-risk HIV-uninfected women.22


Adverse Events


In the Week 96 analysis of the LATTE study (NCT01641809) involving 243 treatment-naive participants (n = 181 CAB; n = 62 EFV), drug-related adverse events (AEs) ≥ Grade 2 occurred in 14% of participants in the oral CAB arm and in 19% of participants in the EFV arm, overall. Drug-related adverse events ≥ Grade 2 occurring during the 72-week maintenance phase were reported in 4% of oral CAB participants and 4% of EFV participants. Serious adverse events (SAEs) occurred in 10% of participants receiving oral CAB and 6% of participants receiving EFV, with none of the SAEs in the oral CAB groups deemed drug-related and one of the SAEs in the EFV group considered drug-related. Three percent of oral CAB participants versus 15% of EFV participants withdrew from the study because of an AE (with most withdrawals occurring prior to the maintenance phase). Headache was more common with oral CAB treatment than with EFV treatment. Grade 3-4 laboratory abnormalities occurred in 26% of participants assigned to oral CAB versus 37% of participants assigned to EFV, most commonly due to elevated CPK. Elevations in ALT (any grade) occurred in 20% of oral CAB participants and 21% of EFV participants.13,23

Safety data from eight Phase I or IIa clinical studies of oral CAB and CAB LA were evaluated in a meta-analysis. One hundred eighty-seven healthy and HIV-infected participants received oral CAB ranging from 5 mg to 50 mg for up to 14 days. Ninety-eight healthy participants received IM or SC CAB LA in single or repeat doses up to 800 mg. No drug-related serious AEs occurred. The most common AEs not related to an injection site reaction (ISR) were headache (22%) and nausea (5%). ISRs related to CAB LA were predominately mild (93%) and Grade 1. No Grade 3 ISR AEs were reported. The most frequent ISRs related to the IM and SC long-acting injectables were pain (71% for IM; 24% for SC), erythema (9% for IM; 23% for SC), and nodules (7% for IM; 23% for SC). All ISRs were self-limited, and there were no study withdrawals because of an ISR.24


Drug Interactions


Oral CAB does not affect the pharmacokinetics of midazolam in human study participants, indicating that cabotegravir is neither a CYP inhibitor nor inducer. In vitro, cabotegravir does not inhibit UGT enzymes, except UGT1A3. (Cabotegraivr, however, is predicted to have no clinically significant effect on UGT1A3 substrates.) Cabotegravir does not inhibit hepatic, intestinal, or renal drug transporters, except for organic anion transporters 1 and 3 (OAT1/3). Drug-drug interactions are possible between cabotegravir and sensitive OAT1/3 substrates having a narrow therapeutic index (such as methotrexate).7,25

Co-administration of oral CAB with an oral contraceptive containing levonorgestrel (LNG) and ethinyl estradiol (EE) did not affect the pharmacokinetics of LNG or EE, suggesting oral CAB can be administered in combination with LNG- and EE-containing oral contraceptives without clinically significant interactions.26

There are no apparent pharmacokinetic interactions between oral CAB and etravirine or between oral CAB and rilpivirine.27,28


References


  1. United States National Library of Medicine. ChemIDplus Advanced. Available at: http://chem.sis.nlm.nih.gov/chemidplus/rn/1051375-10-0. Last accessed on October 1, 2015.
  2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. Available at: http://chemdb.niaid.nih.gov/DrugDevelopmentHIV.aspx. Last accessed on October 1, 2015.
  3. ViiV Healthcare website. Medicines in development. Available at: https://www.viivhealthcare.com/our-medicines/medicines-in-development.aspx. Last accessed on October 1, 2015.
  4. Karmon SL, Markowitz M. Next-generation integrase inhibitors : where to after raltegravir? Drugs. 2013 Mar;73(3):213-28. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23413196. Last accessed on October 1, 2015.
  5. Ford SL, Margolis D, Chen S, Gould E, Spreen W. Plasma and tissue GSK1265744 pharmacokinetics following long-acting parenteral administration in healthy male and female subjects. Abstract presented at: 14th International Workshop on Clinical Pharmacology of HIV Therapy; April 22-24, 2013; Amsterdam, The Netherlands. Abstract O_02. Available at: http://regist2.virology-education.com/abstractbook/2013_3.pdf. Last accessed on October 1, 2015.
  6. Spreen W, Ford SL, Chen S, et al. Pharmacokinetics, safety and tolerability of the HIV integrase inhibitor S/GSK1265744 long acting parenteral nanosuspension following single dose administration to healthy adults. Abstract presented at: 19th International AIDS Conference; July 22-27, 2012; Washington DC. Abstract TUPE040. Available at: http://pag.aids2012.org/abstracts.aspx?aid=10191. Last accessed on October 1, 2015.
  7. Reese M, Ford S, Bowers G, et al. In vitro drug interaction profile of the HIV integrase inhibitor, GSK1265744, and demonstrated lack of clinical interaction with midazolam. Abstract presented at: 15th International Workshop on Clinical Pharmacology of HIV & Hepatitis Therapy; May 19-21, 2014; Washington, DC. Abstract P_20. Available at: http://regist2.virology-education.com/abstractbook/2014_4.pdf. Last accessed on October 1, 2015.
  8. Culp A, Bowers G, Gould E, et al. Metabolism, Excretion, and Mass Balance of the HIV Integrase Inhibitor, Cabotegravir (GSK1265744) in Humans. 54th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); September 5-9, 2014; Washington, DC. Levin: Conference Reports for National AIDS Treatment Advocacy Project (NATAP); 2014. Available at: http://www.natap.org/2014/ICAAC/ICAAC_41.htm. Last accessed on October 1, 2015.
  9. Underwood M, St Clair M, Johns B, Sato A, Fujiwara T, Spreen W. S/GSK1265744: a next generation integrase inhibitor (INI) with activity against raltegravir-resistant clinical isolates. Abstract presented at: 18th International AIDS Conference; July 18-23, 2010; Vienna, Austria. Abstract MOAA0103. Available at: http://pag.aids2010.org/Abstracts.aspx?AID=14960. Last accessed on October 1, 2015.
  10. Yoshinaga T, Kobayashi M, Seki T, et al. Antiviral Characteristics Of S/GSK1265744, An HIV Integrase Inhibitor (INI) Dosed By Oral Or Long-acting Parenteral Injection. Abstract presented at: 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); September 9-12, 2012; San Francisco, CA. Abstract H-550. Available at: http://www.abstractsonline.com/Plan/ViewAbstract.aspx?sKey=e1c18d5b-830f-4b4e-8671-35bcfb20eed5&cKey=3ecd6397-c9eb-4793-94f5-fde7784fe6ab&mKey=%7b6B114A1D-85A4-4054-A83B-04D8B9B8749F%7d. Last accessed on October 1, 2015.
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  14. Margolis D, Brinson C, Eron J, et al. 744 and Rilpivirine as Two-Drug Oral Maintenance Therapy: LAI116482 (LATTE) Week 48 Results. Abstract presented at: 21st Conference on Retroviruses and Opportunistic Infections (CROI); March 3-6, 2014; Boston, MA. Abstract 91LB. Available at: http://croi2014.org/sites/default/files/uploads/CROI2014_Final_Abstracts.pdf. Last accessed on October 1, 2015.
  15. ViiV Healthcare. A Phase IIb, Dose Ranging Study of Oral GSK1265744 in Combination With Nucleoside Reverse Transcriptase Inhibitors for Induction of Human Immunodeficiency Virus -1 (HIV-1) Virologic Suppression Followed by an Evaluation of Maintenance of Virologic Suppression When Oral GSK1265744 is Combined With Oral Rilpivirine in HIV-1 Infected, Antiretroviral Therapy Naive Adult Subjects. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on June 28, 2012. NLM Identifier: NCT01641809. Available at: http://www.clinicaltrials.gov/ct2/show/NCT01641809. Last accessed on October 1, 2015.
  16. Margolis DA, Brinson CC, Smith GH, et al. Cabotegravir plus rilpivirine, once a day, after induction with cabotegravir plus nucleoside reverse transcriptase inhibitors in antiretroviral-naive adults with HIV-1 infection (LATTE): a randomised, phase 2b, dose-ranging trial. Lancet Infect Dis. 2015 Jul 17. [Epub ahead of print]. Available at: http://www.ncbi.nlm.nih.gov/pubmed/26201299. Last accessed on October 1, 2015.
  17. Spreen B. Nanoformulations: Update from ViiV Healthcare. Slides presented at: 16th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy; May 26-28, 2015; Washington, DC. Available at: http://regist2.virology-education.com/2015/16HIVHEP/10_Spreen.pdf. Last accessed on October 1, 2015.
  18. ViiV Healthcare. A Phase IIb Study Evaluating a Long-Acting Intramuscular Regimen of GSK1265744 Plus TMC278 For The Maintenance of Virologic Suppression Following an Induction of Virologic Suppression on an Oral Regimen of GSK1265744 Plus Abacavir/Lamivudine in HIV-1 Infected, Antiretroviral Therapy-Naive Adult Subjects. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on April 17, 2014. NLM Identifier: NCT02120352. Available at: http://www.clinicaltrials.gov/ct2/show/NCT02120352. Last accessed on October 1, 2015.
  19. ViiV Healthcare. A Phase IIa Study to Evaluate the Safety, Tolerability and Acceptability of Long Acting Injections of the HIV Integrase Inhibitor, GSK1265744, in HIV Uninfected Men (ECLAIR). In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on February 27, 2014. NLM Identifier: NCT02076178. Available at: http://www.clinicaltrials.gov/ct2/show/NCT02076178. Last accessed on October 1, 2015.
  20. National Institute of Allergy and Infectious Diseases (NIAID). A Phase IIa Study to Evaluate the Safety, Tolerability and Pharmacokinetics of the Investigational Injectable HIV Integrase Inhibitor, GSK1265744, in HIV-uninfected Men and Women. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on June 27, 2014. NLM Identifier: NCT02178800. Available at: http://www.clinicaltrials.gov/ct2/show/NCT02178800. Last accessed on Last accessed on October 1, 2015.
  21. Hankins C. Pre-Exposure Prophylaxis: state-of-the-art and roll-out. Slides presented at: 8th International Workshop on HIV Treatment, Pathogenesis and Prevention Research in Resource-Poor Settings (INTEREST); May 5-9, 2014; Lusaka, Zambia. Available at: http://regist2.virology-education.com/2014/8INTEREST/16_Hankins.pdf. Last accessed on Last accessed on October 1, 2015.
  22. Centre for the AIDS Programme of Research in South Africa. Phase II Trial to Assess the Safety and Acceptability of the Long-acting Injectable HIV Integrase Inhibitor, Cabotegravir (GSK1265744), in HIV Uninfected Women in KwaZulu-Natal, South Africa. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on May 27, 2015. NLM Identifier: NCT02462772. Available at: https://clinicaltrials.gov/ct2/show/NCT02462772. Last accessed on Last accessed on October 1, 2015.
  23. Margolis DA, Brinson CC, Smith GH, et al. Cabotegravir and Rilpivirine As 2-Drug Oral Maintenance Therapy: LATTE W96 Results. Abstract presented at: 22nd Conference on Retroviruses and Opportunistic Infections (CROI); February 23-26, 2015; Seattle, WA. Abstract 554LB. Available at: http://www.croiconference.org/sessions/cabotegravir-and-rilpivirine-2-drug-oral-maintenance-therapy-latte-w96-results. Last accessed on Last accessed on October 1, 2015.
  24. Lou Y, Gould E, Chen S, et al. Meta-Analysis of Safety Data from 8 Clinical Studies with GSK1265744, an HIV Integrase Inhibitor, Dosed Orally or as Injection of Long-Acting Parenteral Nanosuspension. Abstract presented at: 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); September 11, 2013; Denver, CO. Abstract H-672. Available at: http://www.abstractsonline.com/Plan/ViewAbstract.aspx?mID=3283&sKey=5ef1a3c2-e263-412a-b6ef-497a54ca5c4a&cKey=d23b3828-ee96-4e5d-9f7d-e384b4edaa1f&mKey=7dd36e88-52c3-4ff1-a5df-1d00766558b8. Last accessed on October 1, 2015.
  25. Reese M, Ford S, Bowers G, et al. In Vitro Drug Interaction Profile of the HIV Integrase Inhibitor, GSK1265744, and Demonstrated Lack of Clinical Interaction with Midazolam. 15th International Workshop on Clinical Pharmacology of HIV & Hepatitis Therapy; May 19-21, 2014; Washington, DC. Levin: Conference Reports for National AIDS Treatment Advocacy Project (NATAP); 2014. Available at: http://www.natap.org/2014/Pharm/Pharm_09.htm. Last accessed on October 1, 2015.
  26. Trezza C, Ford SL, Gould E, et al. Lack of Effect of Oral Cabotegravir on the Pharmacokinetics of a Levonorgestrel/Ethinyl Estradiol Containing Oral Contraceptive in Healthy Adult Females. Abstract presented at: 16th International Workshop on Clinical Pharmacology of HIV & Heptatitis Therapy; May 26-28, 2015; Washington, DC. Abstract 82. Available at: http://regist2.virology-education.com/abstractbook/2015_4.pdf. Last accessed on October 1, 2015.
  27. Ford SL, Gould E, Chen S, et al. Effects of Etravirine on the Pharmacokinetics of the Integrase Inhibitor S/GSK1265744. Antimicrob Agents Chemother. 2013 Jan;57(1):277-80. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3535890/. Last accessed on Last accessed on October 1, 2015.
  28. Ford SL, Gould E, Chen S, et al. Lack of Pharmacokinetic (PK) Interaction between Rilpivirine and the Integrase Inhibitors Dolutegravir and S/GSK1265744. Abstract presented at: 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); September 9-12, 2012; San Francisco, CA. Abstract A-1249. Available at: http://www.abstractsonline.com/Plan/ViewAbstract.aspx?sKey=a96a704b-ee24-44df-8955-f1688acf7663&cKey=e28b4ccf-4d66-40ce-8e3e-fa596b9d2eae&mKey=%7b6B114A1D-85A4-4054-A83B-04D8B9B8749F%7d.Last accessed on October 1, 2015.


Last Reviewed: October 1, 2015

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