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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 sodium
Drug Class: Integrase Inhibitors
Molecular Formula: C19 H17 F2 N3 O5
Registry Number: 1051375-10-0 (CAS)
Company: ViiV Healthcare
Phase of Development: IIb
Chemical Image:
Click image to enlarge
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 

Resistance: In vitro, cabotegravir has exhibited activity against raltegravir-resistant isolates.8 

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. Eight site-directed molecular clones containing single raltegravir mutations exhibited less than a 2-fold change (FC) in cabotegravir susceptibility (except Q148K/R, which demonstrated a 5.6/5.1 FC, respectively). Fifteen site-directed molecular clones containing 14 double mutations exhibited less than a 12 FC. Cross-resistance to raltegravir and elvitegravir is limited.9

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.10

Virologic failure with treatment-emergent integrase inhibitor (INI) mutation (Q148R)  and non-nucleoside reverse transcriptase inhibitor (NNRTI) mutation (E138Q) has been reported in one patient receiving once-daily oral cabotegravir (CAB) 10 mg plus rilpivirine (RPV) in a Phase IIb study. This patient, however, had very low drug concentrations of both oral CAB and RPV.11
 


Dosing in Clinical Trials


Study Identifiers: LAI116482 (LATTE)11; NCT0164180912
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 in combination with two background nucleoside reverse transcriptase inhibitors (NRTIs)
  • Maintenance phase: Those participants successfully completing the induction phase will continue their randomized dose of oral CAB, but will discontinue the background NRTIs and add rilpivirine 25 mg. The comparator arm will continue with efavirenz 600 mg plus the background NRTIs.11,12 
(See references cited above for information on study results.)

Study Identifier: NCT0212035213
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 GSK744 LA plus 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.
  • Maintenance phase: Following initial IM loading doses of GSK744 LA plus TMC278 LA (and a second GSK744 LA loading dose given alone for only Arm 1), participants will receive either an IM regimen of GSK744 LA 400 mg plus TMC278 LA 600mg administered every 4 weeks over 96 weeks (Arm 1) or an IM regimen of GSK744 LA 600mg plus TMC278 LA 900 mg administered every 8 weeks over 96 weeks (Arm 2). The comparator arm (Arm 3) will continue with a regimen of oral CAB 30 mg plus ABC/3TC for 96 weeks.
  • Extension phase: For long-term collection of efficacy and safety data13

Two Phase IIa studies of GSK744 LA will be undertaken to develop the safety profile of the long-acting injectable for pre-exposure prophylaxis (PrEP). The ECLAIR study will investigate GSK744 LA in HIV-uninfected men at risk of acquiring HIV, and HPTN 077 will examine GSK744 LA in HIV-uninfected women and men.14-16
 


Adverse Events


In the Week 48 analysis of the LATTE study involving 243 treatment-naive patients, drug-related adverse events ≥ Grade 2 occurred in 14% of participants in the oral CAB arm and in 19% of participants in the EFV arm. Drug-related adverse events ≥ Grade 2 were uncommon during the maintenance phase, occurring in 4% of participants in both the oral CAB and EFV study arms. Serious adverse events occurring in the oral CAB arm were all unrelated to oral CAB treatment. Three percent of oral CAB participants and 13% of EFV participants withdrew from the study because of an adverse event. Headache, mostly Grade 1 and 2, was more common with oral CAB treatment (22%) than with EFV treatment (11%). Treatment-emergent laboratory abnormalities ≥ Grade 3 were reported in 21% of oral CAB participants and in 31% of EFV participants. Alanine aminotransferase (ALT) elevations of any grade were seen in 17% of oral CAB participants and in 21% of EFV participants.11,17

Safety data from eight Phase I or IIa clinical studies of oral CAB and the long-acting injectable formulation, GSK744 LA, were evaluated in a meta-analysis. One hundred eighty-seven healthy and HIV-infected participants received oral CAB 5 mg to 50 mg for up to 14 days. Ninety-eight healthy participants received IM or SC GSK744 LA in single or repeat doses up to 800 mg. No drug-related serious adverse events occurred. The most common adverse events not related to an injection site reaction (ISR) were headache (22%) and nausea (5%). ISRs related to GSK744 LA were predominately mild (93%) and Grade 1. No Grade 3 ISR adverse events 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.18
 


Drug Interactions


Cabotegravir 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).7,19 


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 July 30, 2014.
  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 July 30, 2014.
  3. ViiV Healthcare website. Medicines in development. Available at: https://www.viivhealthcare.com/our-medicines/medicines-in-development.aspx. Last accessed on July 30, 2014.
  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 July 30, 2014.
  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 July 30, 2014.
  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 July 30, 2014.
  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 July 30, 2014.
  8. 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 July 30, 2014.
  9. 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 July 30, 2014.
  10. Karmon SL, Mohri H, Spreen W, Hong Z, Ho D, Markowitz M. GSK1265744 Demonstrates Robust in Vitro Activity Against Various Clades of HIV-1. 21st Conference on Retroviruses and Opportunistic Infections (CROI); March 3-6, 2014; Boston, MA. Levin: Conference Reports for National AIDS Treatment Advocacy Project (NATAP); 2014. Available at: http://www.natap.org/2014/CROI/croi_193.htm. Last accessed on July 30, 2014.
  11. 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 July 30, 2014.
  12. 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 July 30, 2014.
  13. 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 July 30, 2014.
  14. 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 July 30, 2014.
  15. 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 July 30, 2014.
  16. 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 July 30, 2014.
  17. Margolis DA, Brinson CC, Eron JJ, et al. 744 and Rilpivirine as TwoDrug Oral Maintenance Therapy: LAI116482 (LATTE) Week 48 Results. 21st Conference on Retroviruses and Opportunistic Infections (CROI); March 3-6, 2014; Boston, MA. Levin: Conference Reports for National AIDS Treatment Advocacy Project (NATAP); 2014. Available at: http://www.natap.org/2014/CROI/croi_27.htm. Last accessed on July 30, 2014.
  18. 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 July 30, 2014.
  19. 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 July 30, 2014.
  20. 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 July 30, 2014.
  21. 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 July 30, 2014.
     


Last Reviewed: July 30, 2014

Last Updated: July 30, 2014


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