Drug information

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Pronounce:
Other Names:
CAB, CAB LA, cabotegravir LA, cabotegravir sodium, cabotegravir long-acting injectable, cabotegravir extended-release injectable suspension
Drug Class:
Integrase Strand Transfer Inhibitor (INSTIs)
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

Chemical Class:
Carbamoyl pyridone
Organization:
ViiV Healthcare
Phase of Development:

Cabotegravir is in Phase 3 development for HIV prevention. On May 4, 2021, the manufacturers of cabotegravir announced that they have begun a rolling submission of a New Drug Application (NDA) with the US Food and Drug Administration (FDA) for approval of long-acting, injectable cabotegravir for HIV prevention.

FDA-approved Products for HIV Treatment: Cabenuva, a two-drug regimen consisting of cabotegravir and rilpivirine extended-release injectable suspensions is FDA-approved for HIV treatment. Additionally, an oral tablet formulation of cabotegravir (brand name: Vocabria) is FDA-approved for use with oral rilpivirine for short-term HIV treatment.

Chemical Image: (Click to enlarge)

cabotegravir

Molecular Weight: 405.3553

(Compound details obtained from ChemIDplus Advanced,1 NIAID Therapeutics Database,2 HIV/AIDS (Auckland, N.Z.) article,3 HIV Treatment Bulletin article,4 ClinicalTrials.gov,5 and ViiV Healthcare press release6)

Pharmacology

Pharmacology

Mechanism of Action: HIV-1 integrase strand transfer inhibitor (INSTI). Cabotegravir (CAB), an analog of dolutegravir, prevents viral DNA integration into the host genome and inhibits HIV replication. CAB is FDA-approved for HIV treatment and is currently in Phase 3 development for HIV prevention.2,3,5,6

Half-life (T½): The mean elimination half-life of CAB is 5.6 to 11.5 weeks (extended-release injectable formulation) and 41 hours (oral formulation).5,6

The pharmacokinetic (PK) tail phase associated with CAB LA was assessed in both the ECLAIR (NCT02076178) and HPTN 077 (NCT02178800) HIV prevention trials. In the ECLAIR study, where CAB LA 800 mg was administered IM every 12 weeks to men without HIV, 17 percent of participants had plasma CAB was detectable at 52 weeks post injection. In the HPTN 077 study, male and female participants received CAB LA 800 mg IM every 12 weeks or 600 mg IM every 8 weeks. The apparent terminal phase plasma half-life of CAB was 33% longer for females than for males and was significantly longer for participants with a higher BMI. The median time for plasma CAB to drop below detectable levels was 42.7 weeks in males and 66.3 weeks in females. At 76 weeks post final injection, 58% of females and 87% of males had plasma CAB concentrations below detectable levels.7-11

Metabolism/Elimination: CAB is primarily metabolized by UGT1A1 (main pathway) and UGT1A9 (minor pathway). Following a single oral radiolabeled dose of CAB, 27% of the administered dose was recovered in urine (0% as unchanged drug) and 59% was recovered in feces (47% as unchanged drug).5

Resistance: Treatment-emergent resistance to CAB has been reported in Phase 2 and 3 clinical trials evaluating CAB plus rilpivirine (RPV) for HIV treatment. Information on HIV resistance mutations associated with CAB is described in the FDA-approved Full Prescribing Information for Cabenuva and Vocabria.5,6

In the Phase 2b/3 HPTN 083 prevention trial (NCT02720094) evaluating CAB LA versus tenofovir DF/emtricitabine (Truvada) in cisgender men and transgender women who have sex with men, 12 incident HIV infections and 4 baseline HIV infections occurred in the CAB arm, and 39 incident infections and 3 baseline infections occurred in the Truvada arm. Of the 12 incident infections that occurred in the CAB group, five had no recent CAB exposure, three occurred during oral lead-in, and four occurred in participants who had received on-time CAB injections and had adequate CAB plasma concentrations. Among the 16 infections in the CAB arm, five participants had integrase resistance-associated mutations (RAMs) detected – Q148R or Q148K and accessory mutations, or R263K – and one of these participants also developed an NNRTI RAM. One participant was reported to have NNRTI RAMs only and another participant had both NNRTI and NRTI RAMs. Investigators noted three cases of HIV infection and one case of escape viremia that occurred during the PK tail-phase, each with no evidence of INSTI resistance.12–14


In the Phase 3 HPTN 084 prevention trial (NCT03164564) evaluating CAB LA versus Truvada in women, there were 3 incident HIV infections and 1 baseline infection in the CAB arm, and 36 incident infections in the Truvada arm. Among the three incident infections that occurred in the CAB arm, two had not received injections and had no recent dosing with CAB. The third case of incident infection occurred in a participant who had delayed injection visits. No major INSTI RAMs were detected with CAB.3,15

Select Clinical Trials

Select Clinical Trials

Cabotegravir for HIV Prevention

Study Identifiers: ECLAIR; NCT02076178
Sponsor: ViiV Healthcare
Phase: 2a
Status: This study has been completed.
Study Purpose: The ECLAIR study evaluated the safety, tolerability, and acceptability of CAB LA for pre-exposure prophylaxis (PrEP).
Study Population:

  • Participants were men without HIV who were not at high risk of acquiring HIV.7,16

Selected Study Results:


Study Identifiers: HPTN 077; NCT02178800
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Phase: 2a
Status: This study has been completed.
Study Purpose: The purpose of this study was to evaluate the safety, tolerability, and pharmacokinetics of CAB LA.
Study Population:

  • Participants were men and women without HIV who are at low risk of acquiring HIV.9,17

Selected Study Results:


Study Identifiers: HPTN 083; NCT02720094
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Phase: 2b/3
Status: This study is ongoing, but not recruiting participants.
Study Purpose: The purpose of this study is to compare the safety and efficacy of CAB LA to oral tenofovir DF/emtricitabine (Truvada) for PrEP.
Study Population:

  • Participants do not have HIV and are in general good health.
  • Participants are cisgender men and transgender women who have sex with men and are at high risk of acquiring HIV.12

Selected Study Results:


Study Identifiers: HPTN 083-01 (a sub-study of HPTN 083); NCT04692077
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Phase: 2
Status: This study is currently recruiting participants
Study Purpose: The purpose of this open-label study is to evaluate the safety and acceptability of CAB LA in adolescent males.
Study Population:

  • Participants do not have HIV and are in general good health.
  • Participants are adolescents (up to 17 years of age) who are assigned male at birth (includes men who have sex with men, transgender women, and gender nonconforming people).18


Study Identifiers: HPTN 084; NCT03164564
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Phase: 3
Status: This study is currently recruiting participants.
Study Purpose: The purpose of this study is to compare the safety and efficacy of CAB LA to oral Truvada for PrEP.
Study Population:

  • Participants are women who are sexually active and do not have HIV but who are at risk of acquiring HIV.3

Selected Study Results:


Study Identifiers: HPTN 084-01 (a sub-study of HPTN 084); NCT04824131
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Phase: 2
Status: This study is currently recruiting participants
Study Purpose: The purpose of this open-label study is to evaluate the safety and acceptability of CAB LA in adolescent females.
Study Population:

  • Participants do not have HIV and are in general good health.
  • Participants are adolescents (up to 17 years of age) who are assigned female at birth.19

Adverse Events

Adverse Events


ECLAIR (NCT02076178)
In the 41-week ECLAIR study, 106 participants were randomly assigned to CAB and 21 participants were randomly assigned to placebo. Nineteen participants withdrew from the CAB group: one before treatment, 11 during or after oral therapy but prior to injections, and seven during the injection period. Of the seven CAB participants who withdrew during the injection phase, four withdrew because of injection intolerability.20

Overall, AEs occurred at a similar rate in both the CAB and placebo groups (CAB 96%; placebo 90%). However, Grade 2 or higher AEs occurred more frequently with CAB (80% of participants) than with placebo (48% of participants), mainly because of injection site pain. During the oral dosing phase, treatment-related AEs, most of which were Grade 1 to 2, occurred in 36% of CAB participants versus 14% of placebo participants. No SAEs occurred during oral dosing. During the injection period, 93% of CAB participants versus 57% of placebo participants reported an injection site reaction (ISR). The majority of CAB participants had ISRs that were Grade 1 (80%) or 2 (56%), while 19% of CAB participants experienced Grade 3 ISRs. Ninety-two percent of the ISRs that occurred in the CAB group were cases of injection-site pain, lasting an average duration of 5.4 days. Other ISRs occurring in the CAB group included mild pruritus, nodules/bumps, warmth to touch, bruising, and induration.20


HPTN 077 (NCT02178800)
The HPTN 077 study enrolled 110 participants into Cohort 1 (800 mg every 12 weeks) and 90 participants into Cohort 2 (600 mg every 8 weeks), with a total of 151 participants who received CAB and 48 who received placebo. Ten participants discontinued CAB because of drug-related AEs: two during oral therapy and eight during the injection phase. Reasons for CAB discontinuation included one gastrointestinal event, three rash/urticaria events, and six neurologic events. Four SAEs were reported among CAB participants: vertigo, transient weakness, laryngitis (unrelated), and acute kidney injury (unrelated).17

During the injection phase, Grade 2 or higher AEs occurred in 91% of participants in the CAB group versus 88% of participants in the placebo group. The most common Grade 2 or higher AE was decreased creatinine clearance, occurring with similar frequency in each arm. ISRs were the only Grade 2 or higher AEs that were significantly more common with CAB than placebo. Among participants receiving CAB, ISRs (mostly Grade 1 to 2) occurred in 92% of participants in Cohort 1 and 88% of participants in Cohort 2. There was only one participant who discontinued CAB due to an ISR. Two CAB participants (one in each cohort) had a Grade 3 ISR, although neither event resulted in product discontinuation.17


HPTN 083 (NCT02720094)
In the HPTN 083 trial, the primary safety analysis of results from the blinded phase of the study included 4,562 participants (2,280 CAB; 2,282 Truvada) and found no safety concerns. The frequency of Grade 2 or higher AEs, Grade 3 or higher AEs, and SAEs was similar between both arms. ISRs occurred in 81.4% of participants receiving CAB LA versus 31.3% of participants receiving placebo injections. The majority of ISRs with CAB LA were Grade 1 or 2 in intensity, occurred less frequently over time, and were associated with pain (60.8%) or tenderness (23.7%). Only 2.4% of CAB LA participants discontinued treatment because of an injection-related AE.21


HPTN 084 (NCT03164564)
In the HPTN 084 trial, 3,224 participants were randomized to receive either CAB LA plus placebo or oral Truvada plus placebo. Results from the blinded phase of the trial found that injection site reactions occurred more frequently with CAB LA (32%) than with placebo injections (9%). The majority of ISRs were mild, related to pain, and generally occurred more frequently with the first injection compared with later injections. No participants discontinued treatment because of an ISR. Besides differences in ISRs, there were few other notable differences in Grade 2 or higher AEs between the CAB LA and Truvada groups.3,22

Additional AEs known to be associated with CAB are described in the FDA-approved Full Prescribing Information for Cabenuva and Vocabria.5,6

Drug Interactions

Drug Interactions

CAB is primarily metabolized by UGT1A1, with minor contributions from UGT1A9. Drugs that are potent UGT1A1 or UGT1A9 inducers are predicted to decrease plasma concentrations of CAB and coadministration of these drugs with CAB is contraindicated.6

In vitro studies demonstrate that CAB inhibits renal drug transporters OAT1 and OAT3 and physiologically based pharmacokinetic (PBPK) modeling suggests that CAB may increase the exposure of drugs that are OAT1/3 substrates up to approximately 80%.6

Specific drug-drug interactions associated with CAB are described in the FDA-approved Full Prescribing Information for Cabenuva and Vocabria.5,6

References

References

  1. United States National Library of Medicine. ChemIDplus Advanced: cabotegravir. https://chem.nlm.nih.gov/chemidplus/rn/1051375-10-0. Accessed August 14, 2021
  2. Whitfield T, Torkington A, van Halsema C. Profile of cabotegravir and its potential in the treatment and prevention of HIV-1 infection: evidence to date. HIVAIDS Auckl NZ. 2016;8:157-164.
  3. National Institute of Allergy and Infectious Diseases (NIAID). A Phase 3 double blind safety and efficacy study of long-acting injectable cabotegravir compared to daily oral TDF/FTC for pre-exposure prophylaxis in HIV-uninfected women. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on May 22, 2017. NLM Identifier: NCT03164564. https://clinicaltrials.gov/ct2/show/NCT03164564. Accessed August 14, 2021
  4. ViiV Healthcare: Press release, dated May 4, 2021. ViiV Healthcare initiates rolling submission of new drug application with US FDA for long-acting cabotegravir for prevention of HIV. https://viivhealthcare.com/en-us/us-news/us-articles/2021/viiv-healthcare-initiates-rolling/. Accessed August 14, 2021
  5. ViiV Healthcare Company. Cabenuva: full prescribing information, January 2021. DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1698baf3-f895-4c42-a1b1-e9ee3f20da36. Accessed August 14, 2021
  6. ViiV Healthcare Company. Vocabria: full prescribing information, January 2021. DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=66d450fb-cca4-476c-b0c7-c0730e3e4cf3. Accessed August 14, 2021
  7. 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. https://clinicaltrials.gov/ct2/show/NCT02076178. Accessed August 14, 2021
  8. Ford S, Stancil B, Markowitz M, more authors. ECLAIR study of cabotegravir LA injections: characterization of safety and PK during the “PK tail” phase. Abstract presented at: HIV Research for Prevention (HIVR4P); October 17-21, 2016; Chicago, IL. Abstract OA12.06LB. https://www.liebertpub.com/doi/pdf/10.1089/aid.2016.5000.abstracts. Accessed August 14, 2021
  9. 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. https://clinicaltrials.gov/ct2/show/NCT02178800. Accessed August 14, 2021
  10. Landovitz R. Tail-phase safety, tolerability and pharmacokinetics of long-acting injectable cabotegravir in HIV-uninfected individuals: HPTN 077 final results. Webcast presented at: HIV Research for Prevention (HIVR4P); October 21-25, 2018; Madrid, Spain. http://webcasts.hivr4p.org/console/player/40424?mediaType=slideVideo&. Accessed August 14, 2021
  11. Landovitz RJ, Li S, Eron JJ, et al. Tail-phase safety, tolerability, and pharmacokinetics of long-acting injectable cabotegravir in HIV-uninfected adults: a secondary analysis of the HPTN 077 trial. Lancet HIV. 2020;7(7):e472-e481. doi:10.1016/S2352-3018(20)30106-5
  12. National Institute of Allergy and Infectious Diseases (NIAID). A Phase 2b/3 double blind safety and efficacy study of injectable cabotegravir compared to daily oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC), for pre-exposure prophylaxis in HIV-uninfected cisgender men and transgender women who have sex with men. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 21, 2016. NLM Identifier: NCT02720094. https://clinicaltrials.gov/ct2/show/NCT02720094. Accessed August 14, 2021
  13. Marzinke M, Grinsztejn B, Fogel J, et al. Laboratory analysis of HIV infections in HPTN 083: injectable CAB for PrEP. Abstract presented at: Conference on Retroviruses and Opportunistic Infections (CROI); March 6-10, 2021; Virtual. Abstract 153. https://www.croiconference.org/abstract/laboratory-analysis-of-hiv-infections-in-hptn-083-injectable-cab-for-prep/. Accessed August 14, 2021
  14. Marzinke M, Grinsztejn B, Fogel J, et al. Laboratory analysis of HIV infections in HPTN 083: injectable CAB for PrEP. Webcast presented at: Conference on Retroviruses and Opportunistic Infections (CROI); March 6-10, 2021; Virtual. http://www.croiwebcasts.org/console/player/48236?mediaType=slideVideo&. Accessed August 14, 2021
  15. Marzinke MA, Delany-Moretlwe S, Agyei Y, et al. Long-acting injectable PrEP in women: laboratory analysis of HIV infections in HPTN 084. Poster presented at: International AIDS Society (IAS) Conference on HIV Science; July 18-21, 2021; Virtual. https://www.hptn.org/sites/default/files/inline-files/210708 HPTN 084 Poster final.pdf. Accessed August 14, 2021
  16. Markowitz M, Frank I, Grant RM, et al. Safety and tolerability of long-acting cabotegravir injections in HIV-uninfected men (ECLAIR): a multicentre, double-blind, randomised, placebo-controlled, phase 2a trial. Lancet HIV. 2017;4(8):e331-e340.
  17. Landovitz R, Li S, Grinsztejn B, et al. Safety, tolerability, and pharmacokinetics of long-acting injectable cabotegravir in low-risk HIV-uninfected women and men HPTN 077. Slides presented at: International AIDS Society (IAS) Conference on HIV Science; July 23-26, 2017; Paris, France. http://programme.ias2017.org/PAGMaterial/PPT/2899_91/IAS2017_Landovitz_Final_072417.pptx. Accessed August 14, 2021
  18. National Institute of Allergy and Infectious Diseases (NIAID). Safety, tolerability and acceptability of long-acting cabotegravir (CAB LA) for the prevention of HIV among adolescent males - a sub-study of HPTN 083. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on January 6, 2021. NLM Identifier: NCT04692077. https://www.clinicaltrials.gov/ct2/show/NCT04692077. Accessed August 14, 2021
  19. National Institute of Allergy and Infectious Diseases (NIAID). Safety, tolerability and acceptability of long-acting cabotegravir (CAB LA) for the prevention of HIV among adolescent females - a sub-study of HPTN 084. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on December 22, 2020. NLM Identifier: NCT04824131. https://www.clinicaltrials.gov/ct2/show/NCT04824131. Accessed August 14, 2021
  20. Murray M, Markowitz M, Frank I, et al. Satisfaction and acceptability of cabotegravir long-acting injectable suspension for prevention of HIV: Patient perspectives from the ECLAIR trial. HIV clinical trials. 2018;19:1-10. doi:10.1080/15284336.2018.1511346
  21. Landovitz RJ, Donnell D, Clement ME, et al. Cabotegravir for HIV prevention in cisgender men and transgender women. N Engl J Med. 2021;385(7):595-608. doi:10.1056/NEJMoa2101016
  22. Delany-Moretlwe S, Hughes JP, Bock P, et al. Long acting injectable cabotegravir is safe and effective in preventing HIV infection in cisgender women: results from HPTN 084. HIV Research for Prevention (HIVR4P); January 27-28 and February 3-4, 2021. Conference Reports for National AIDS Treatment Advocacy Project (NATAP); 2021. https://www.natap.org/2021/HIVR4P/HIVR4P_11.htm. Accessed August 14, 2021

Last Reviewed: August 14, 2021