Drugs

Cabotegravir

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 Chemical Class: Carbamoyl pyridone Organization: ViiV Healthcare Phase of Development: Cabotegravir is in Phase III development for both HIV treatment and HIV prevention. Patients who do not qualify for or are unable to participate in the Phase III clinical studies of cabotegravir for HIV treatment may be able to obtain the drug through an expanded access (also called compassionate use) treatment program. For details on the program, go to ClinicalTrials.gov (NCT03462810).

Chemical Image:

(Click to enlarge)
cabotegravir

cabotegravir

Molecular Weight: 405.3553

(Compound details obtained from ChemIDplus Advanced,1 NIAID Therapeutics Database,2 HIV/AIDS (Auckland, N.Z.) article,3  ViiV Healthcare website,4 and ClinicalTrials.gov5)

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 being developed for both HIV treatment and HIV prevention.3,4,6

Half-life (T½): In a study of CAB LA (long-acting parenteral [LAP] nanosuspension) administered via intramuscular (IM) or subcutaneous (SC) injection, the mean apparent terminal phase half-life ranged from 21 to 50 days. Following oral dosing, the CAB half-life was 40 hours.7

Administration of CAB LA can result in prolonged measurable levels of CAB in plasma. In a Phase IIa HIV prevention trial (ECLAIR; NCT02076178) that investigated CAB LA 800 mg administered via IM injection every 12 weeks to men without HIV, the apparent terminal plasma half-life of CAB was 18 days after the first injection and 40 days after the third injection. In 17 percent of participants, plasma CAB was detectable at 52 weeks post injection.8,9

Metabolism/Elimination: CAB is primarily metabolized by UGT1A1 (main pathway) and UGT1A9 (minor pathway). CYP-mediated metabolism is expected to have a minimal role in CAB metabolism.10 Following a single oral radiolabeled dose of CAB 30 mg, 58.5% of the administered dose was recovered in feces (primarily as unchanged drug) and 26.8% was recovered in urine (as a glucuronide metabolite [M1]).11

Resistance: In a Phase IIb study (LATTE; NCT01641809), virologic failure (VF) occurred in seven participants (three CAB; four efavirenz [EFV]) during the 24-week induction phase of the study. No treatment-emergent resistance was detected in any participants during the induction phase. During the 72-week maintenance phase, five participants (two CAB 10 mg; one CAB 30 mg; two EFV) experienced VF. Treatment-emergent resistance was detected in three participants receiving CAB 10 mg, with two participants developing only NNRTI-resistance mutations and one participant (who had low CAB and rilpivirine [RPV] exposures) developing both an NNRTI (E138Q) and an INSTI (Q148R) mutation.12,13 During the open-label phase of the study, in which CAB participants had the option to continue on CAB 30 mg plus RPV, three participants had VF, and treatment-emergent resistance was detected in two of these participants. One participant had a non-primary INSTI mutation (V151V/I), and the other participant had emergent NNRTI resistance mutations (K101E and M230M/L). Emergent NNRTI resistance mutations (E138K and V108V/I) were also detected in a participant who was not counted among participants with VF.14

In another Phase IIb study (LATTE-2; NCT02120352), analysis through Week 96 found that three participants (two IM CAB Q8W; one oral CAB) met the criteria for VF. No treatment-emergent resistance was detected in the participant in the oral CAB dosing group. One of the participants in the 8-week IM CAB group had emergent NNRTI-resistance mutations (K103N, E138G, and K238T) and an INSTI-resistance mutation (Q148R), which reduced susceptibility to raltegravir (RAL), elvitegravir (EVG), and CAB. The other participant in the 8-week group developed a mixed integrase mutation, R269R/G, that did not reduce CAB susceptibility.15

Data through Week 48 of the Phase III ATLAS trial (NCT02951052) demonstrated that VF was infrequent across both study arms. Three participants in the CAB LA plus RPV LA (long-acting rilpivirine injection) group had confirmed VF. At the time of failure, one participant had the E138A reverse-transcriptase (RT) resistance-associated mutation (RAM) and one participant had both the E138K plus V108I RT RAMs. Both of these participants, however, had pre-existing NNRTI mutations at baseline. The E138E/K RT mutation and the N155H INSTI mutation were identified in a third participant at the time of failure.16

In the Phase III FLAIR trial (NCT02938520), Week 48 results also demonstrated a low rate of VF in both study arms. Four participants in the CAB LA plus RPV LA group had confirmed VF. Three of the four participants had treatment-emergent NNRTI and INSTI resistance with the following RAMs: E138E/A/K/T plus Q148R in one participant, K101E plus G140R in another participant, and E138K plus Q148R in a third participant. All three participants were noted to have HIV-1 subtype A1. One other participant with VF had received oral dosing and did not have resistance testing.17


Select Clinical Trials


Cabotegravir for HIV treatment

Study Identifiers: 1) LAI116482 (LATTE); NCT01641809 and 2) POLAR; NCT03639311
Sponsor: ViiV Healthcare
Phase: IIb
Status: LATTE is ongoing, but not recruiting participants. The POLAR trial is not yet open for participant recruitment.
Study Purpose: 1) The LATTE study is a dose-ranging efficacy study designed to select an oral dose of CAB and then evaluate CAB plus RPV as a two-drug oral ART regimen for suppressive maintenance therapy. 2) The POLAR trial is an open-label rollover study that will assess the safety and efficacy of CAB LA plus RPV LA in participants from the LATTE study.
Study Population: Participants in the LATTE study are treatment–naive adults with HIV who have HIV RNA ≥1,000 copies/mL at screening and CD4 counts ≥200 cells/mm3.

During the 24-week induction phase of the LATTE study, participants will receive either oral CAB or the control drug efavirenz (EFV), both with background NRTIs. In the subsequent 72-week maintenance phase, participants will be randomized to receive either a two-drug regimen of CAB plus RPV or to continue receiving EFV with the background NRTIs.12-14,18

Selected Study Results:

Study Identifiers: LATTE-2; NCT02120352
Sponsor: ViiV Healthcare
Phase: IIb
Status: This study is ongoing, but not recruiting participants.
Study Purpose: LATTE-2 is an open-label safety and efficacy study to (1) evaluate the antiviral activity, tolerability, and safety of two IM dosing regimens of the long-acting injectables CAB LA plus RPV LA relative to oral CAB plus abacavir/lamivudine (ABC/3TC) as maintenance therapy, and (2) select an IM regimen of CAB LA plus RPV LA to evaluate in Phase III trials.
Study Population: Participants are treatment-naive adults with HIV with HIV RNA ≥1,000 copies/mL at screening and CD4 counts ≥200 cells/mm3During the 20-week induction phase of the study, participants will receive oral CAB plus ABC/3TC. In the subsequent maintenance phase, participants will be randomized to one of three groups to receive CAB LA plus RPV LA IM for either 4 weeks (IM CAB Q4W) or 8 weeks (IM CAB Q8W), or to continue receiving oral CAB plus ABC/3TC daily (oral CAB).19,20

Selected Study Results

 

Study Identifiers: ATLAS; NCT02951052
Sponsor: ViiV Healthcare
Phase: III
Status: This study is ongoing, but not recruiting participants.
Study Purpose: The purpose of this open-label study is to evaluate the safety and efficacy of switching adults with HIV from a current suppressive ART regimen to CAB LA plus RPV.
Study Population: Participants are adults with HIV who have been on a stable ART regimen consisting of two NRTIs plus an INSTI, NNRTI, or PI for at least 6 months prior to screening. Participants have HIV RNA <50 copies/mL in the 12 months prior to and at screening.21
Selected Study Results:


Study Identifiers: FLAIR; NCT02938520
Sponsor: ViiV Healthcare
Phase: III
Status: This study is ongoing, but not recruiting participants.
Study Purpose: The purpose of this open-label trial is to evaluate the safety and efficacy of CAB LA plus RPV LA for the maintenance of virologic suppression following a switch from abacavir/dolutegravir/lamivudine (ABC/DTG/3TC) in treatment-naive adults.
Study Population: Participants are treatment-naive adults with HIV who have HIV RNA ≥1000 copies/mL. Participants must not have any primary resistance to NNRTIs (with the exception of K103N) and have no known INSTI resistance.22
Selected Study Results:

 

Additional studies evaluating CAB LA for HIV treatment are currently ongoing, including the following Phase III trials: 

  • ATLAS-2M (NCT03299049), an open-label study evaluating the safety and efficacy of CAB LA plus RPV LA administered every 8 weeks or every 4 weeks in adults with HIV who are virologically suppressed.23
  • ACTG A5359 (NCT03635788), an open label study comparing the safety, efficacy, and durability of CAB LA plus RPV LA versus standard of care (SOC) oral ART in adults with a history of sub-optimal adherence and control of their HIV infection.24

Cabotegravir for HIV prevention

Study Identifiers: ECLAIR; NCT02076178
Sponsor: ViiV Healthcare
Phase: IIa
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 at low risk of acquiring HIV. Participants received either oral CAB or placebo during the oral phase of the study and IM injections of either CAB LA or placebo during the subsequent injection phase.8,25

Selected Study Results:

Study Identifiers: HPTN 077; NCT02178800
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Phase: IIa
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. Participants received either oral CAB (30 mg) or placebo during the oral phase of the study, followed by CAB LA (600 mg or 800 mg) by injection during the injection phase.26,27


Selected Study Results:

 

Additional studies will be investigating CAB LA for HIV prevention. These include:

  • HPTN 083 (NCT02720094), a Phase IIb/III trial that will compare the safety and effectiveness of CAB LA to oral tenofovir DF/emtricitabine for PrEP. Participants are cisgender men and transgender women without HIV infection who have sex with men and are at high risk of acquiring HIV. This study is currently recruiting participants.28
  • HPTN 084 (NCT03164564), a Phase III trial that will compare the safety and effectiveness of CAB LA to oral tenofovir DF/emtricitabine for PrEP in women who do not have HIV but are at risk for acquiring HIV. This study is currently recruiting participants.29


Adverse Events


LATTE Study (NCT01641809)

A Week 96 analysis of the LATTE study, which included 243 treatment-naive participants (n = 181 CAB; n = 62 EFV), showed that drug-related adverse events (AEs) ≥ Grade 2 occurred in 14% of participants on oral CAB and in 19% of participants on EFV. Drug-related AEs ≥ Grade 2 occurring during the 72-week maintenance phase were reported in 4% of oral CAB participants and 4% of EFV participants. Twenty-six Grade 2-4 CAB-related events were reported: insomnia (n=3), depression (n=2), nausea (n=5), fatigue (n=3), and headache (n=5).12,13,30

Serious adverse events (SAEs) occurred in 10% of participants receiving oral CAB and 6% of participants receiving EFV. None of the SAEs in the oral CAB groups were drug-related and one SAE in the EFV group was considered drug-related. Three percent of oral CAB participants versus 15% of EFV participants withdrew from the study because of an AE. Most withdrawals occurred prior to the maintenance phase. Grade 3-4 laboratory abnormalities, mostly elevated CPK, occurred in 26% of oral CAB participants versus 37% of EFV participants. Elevations in ALT (any grade) occurred in 20% of oral CAB participants and 21% of EFV participants.12,30

In an analysis of Week 144 data from participants exposed to CAB during the maintenance phase and open-label phases, investigators reported that oral CAB was generally well tolerated and results continued to support the study of CAB.14

LATTE-2 Study (NCT02120352)

The LATTE-2 study enrolled 309 participants, with 286 participants randomized to the maintenance period (n = 115 IM CAB Q4W; n = 115 IM CAB Q8W; n = 56 oral CAB). Analysis at Week 96 found that during the maintenance period, AEs occurred in 100% of participants in the 4-week and 8-week IM groups and 96% of participants in the oral dosing group. The most common injection site reaction (ISR) and the most frequently reported AE in the IM groups was injection site pain. The majority of ISRs were mild or moderate in severity and were transient. Only two participants (both in the 8-week IM group) withdrew from the study because of an ISR.15

The most frequently reported AEs overall (excluding ISRs) were nasopharyngitis, diarrhea, and headache. The most common treatment-related AE (excluding ISRs) was nausea. During the maintenance period, SAEs occurred in 10% of participants in each of the IM groups and 13% of participants in the oral dosing group; none of the reported SAEs were drug-related. Eleven (4%) participants withdrew from the study because of an AE during the maintenance phase. Treatment-emergent laboratory abnormalities (Grade 3 or higher) occurred in 28% of participants in the 4-week IM group, 18% of participants in the 8-week IM group, and 21% of participants in the oral dosing group during the maintenance period. Possible drug-induced liver injury occurred in two participants receiving oral CAB who met predefined liver chemistry criteria for stopping treatment, and in both cases, abnormalities in liver chemistry resolved after treatment was discontinued.15

ATLAS (NCT02951052)

In the Phase III ATLAS trial, 308 participants were randomized in each treatment arm to either continue on their current oral ART regimen or switch to CAB LA plus RPV LA (after a lead-in with oral CAB plus RPV). Week 48 results found that 86% of participants in the LA group versus 71% of participants in the oral ART group experienced an AE (excluding ISRs). Drug-related AEs (excluding ISRs) occurred in 29% of participants in the LA group and 3% of participants in the oral ART group, with fatigue, pyrexia, headache, and nausea each occurring in 4% of LA participants and zero oral ART participants. The majority of the drug-related AEs that occurred in the LA group were mild or moderate. Only 3% of participants in the LA group withdrew from the study because of an AE. There were no reports of drug-related SAEs in the LA group.16

ISRs were commonly reported throughout the study, but the majority of ISRs were Grade 1 or 2 in intensity and resolved within seven days. Four participants withdrew from the study because of ISRs. The most common ISR among participants receiving CAB LA plus RPV LA was injection-site pain, occurring in 75% of participants.16,31

FLAIR (NCT02938520)

The Phase III FLAIR trial randomized 283 participants per treatment arm to either continue with oral ART (DTG/ABC/3TC) or switch to CAB LA plus RPV LA (after a lead-in with oral CAB plus RPV). Data from Week 48 showed that AEs (excluding ISRs) were reported in 87% of participants in the LA group and 80% of participants in the oral ART group. Drug-related AEs occurred in 28% of participants receiving CAB LA plus RPV LA versus 10% of participants receiving oral ART. Headache (5% LA group; 1% oral ART group) and pyrexia (3% LA group; 1% oral ART group) were the most common drug-related AEs (excluding ISRs). Most of the drug-related AEs that occurred in the LA arm were mild or moderate in intensity. Only 3% of participants in the LA arm withdrew from the study because of an AE. One drug-related SAE was reported in the LA arm—right knee monoarthritis.17

In the FLAIR trial, ISRs were common; injection-site pain was the most frequently reported ISR, and led to the withdrawal of two participants. Two additional participants withdrew from the study because of injection intolerability. The incidence of ISRs decreased over time, and most ISRs were Grade 1 or 2 and lasted for a median of three days.17,32

ECLAIR (NCT02076178)

The 41-week ECLAIR study included 126 treated participants (n = 105 CAB LA; n = 21 placebo). Eighteen participants withdrew from CAB LA during the study: five during oral therapy, six after oral therapy but prior to injections, and seven during the injection period. During the oral phase, seven participants withdrew because of CAB-related AEs, which included three events each of neutropenia and increased blood CPK, and one event of fatigue. During the injection phase, four out of 94 participants receiving CAB LA withdrew from the study because of injection intolerability. One participant receiving CAB LA experienced an SAE (appendicitis).8,25,33,34

Overall, 62% of placebo participants and 80% of CAB LA participants experienced a Grade 2 to 4 AE. During the injection phase, Grade 2 to 4 AEs were reported in 80% of participants receiving CAB LA versus 48% of participants receiving placebo. (Reported AEs include only those experienced by at least 5% of participants in the CAB LA arm) The most common Grade 2 to 4 AE in the CAB LA group was injection site pain (55 participants), followed by pyrexia (seven participants) and injection site pruritus and injection site swelling (six participants each). An analysis of ISRs occurring during the injection phase of the study found that 57% of participants in the placebo group experienced ISRs, whereas 93% of participants in the CAB LA group experienced ISRs. The majority of ISRs were Grade 1 or 2 in severity. Grade 2 to 4 drug-related lab abnormalities occurred in 13% of CAB participants versus 5% of placebo participants.25,33,34

HPTN 077 (NCT02178800)

The HPTN 077 study enrolled 199 participants (n = 110 Cohort 1; n = 89 Cohort 2), with 151 participants receiving CAB and 48 receiving placebo. Week 41 data showed that 94% of participants completed the oral phase, 89% of participants received at least one injection, and 75% of participants received all injections. Twelve (7.9%) participants receiving CAB and one (2.1%) participant receiving placebo discontinued treatment because of an AE. The only discontinuation due to an ISR was by a CAB participant. ISRs, which were mostly mild, occurred frequently in participants receiving CAB. During the injection phase, injection site pain and headache occurred more frequently with CAB than with placebo.26,27,35


Drug Interactions


Oral CAB does not affect the pharmacokinetics of midazolam in human study participants, indicating that CAB is neither a CYP inhibitor nor inducer. In vitro, CAB does not inhibit UGT enzymes, except UGT1A3. CAB, however, is predicted to have no clinically significant effect on UGT1A3 substrates. CAB does not inhibit hepatic, intestinal, or renal drug transporters (Pgp, BCRP, BSEP, MRP2, OCT1, OATP1B1, OAT1B3, MATE1, MATE2-K, MRP4, OCT2), except for OAT1 and OAT3 (OAT1/3). Drug-drug interactions are possible between CAB and sensitive OAT1/3 substrates having a narrow therapeutic index (such as methotrexate).10,36

Coadministration of oral CAB with an oral contraceptive containing levonorgestrel (LNG) and ethinyl estradiol (EE) did not affect the pharmacokinetics of LNG or EE, suggesting CAB can be administered in combination with LNG- and EE-containing oral contraceptives without clinically significant interactions.37

There are no apparent pharmacokinetic interactions between oral CAB and etravirine or between oral CAB and RPV.38,39

Coadministration of steady-state rifampin (RIF) 600 mg with a single-dose of oral CAB 30 mg increased CAB oral clearance by 2.4-fold and decreased CAB AUC(0-∞) by 59% compared to CAB administered alone. The coadministration of RIF with oral CAB 30 mg once daily is not recommended. The impact of RIF on the long-acting IM formulations of CAB and RPV was evaluated in an in silico study. Results indicated that coadministration of RIF 600 mg with CAB LA and RPV LA would likely lead to suboptimal concentrations of both CAB and RPV.40,41


References


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  22. ViiV Healthcare. A Phase III, randomized, multicenter, parallel-group, open-label study evaluating the efficacy, safety, and tolerability of long-acting intramuscular cabotegravir and rilpivirine for maintenance of virologic suppression following switch from an integrase inhibitor single tablet regimen in HIV-1 infected antiretroviral therapy naive adult participants. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on September 15, 2016. NLM Identifier: NCT02938520. https://clinicaltrials.gov/ct2/show/NCT02938520. Accessed March 20, 2019.
  23. ViiV Healthcare. A Phase IIIb, randomized, multicenter, parallel-group, non-inferiority, open-label study evaluating the efficacy, safety, and tolerability of long-acting cabotegravir plus long-acting rilpivirine administered every 8 weeks or every 4 weeks in HIV-1-infected adults who are virologically suppressed. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on October 2, 2017. NLM Identifier: NCT03299049. https://clinicaltrials.gov/ct2/show/NCT03299049. Accessed March 20, 2019.
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Last Reviewed: March 20, 2019