Phase of Development: Cabotegravir is in Phase III development for both HIV treatment and HIV prevention.

Patent Version Content

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. It is being developed for both HIV treatment and HIV prevention.3-5

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 half-life of CAB was 18 days after the first injection and 40 days after the third injection. Seventeen percent of participants had detectable levels of CAB in plasma that persisted 52 weeks after their last injection.7,8

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.9 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]).10

Resistance: CAB has been described to have an in vitro resistance profile distinct from that of raltegravir (RAL) and elvitegravir (EVG) and similar to that of dolutegravir (DTG). Resistance to CAB has been observed in vitro. For example, moderate reductions in CAB activity have occurred with mutants containing Q148K, Q148R, G140S/Q148H, and E92Q/N155H, while high level resistance to CAB has occurred with E138A/Q148R, E138K/Q148K, E138K/Q148R, G140C/Q148R, G140S/Q148R, and Q148R/N155H.11-14 Mutants containing L74F/V75I plus Y143C, N155H, or G140S/Q148H have also exhibited high in vitro resistance to second-generation INSTIs, including CAB.15

In a Phase IIb study (LATTE; NCT01641809), protocol-defined virologic failure (PDVF) occurred in 7 participants (3 CAB; 4 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, 5 participants (2 CAB 10 mg; 1 CAB 30 mg; 2 EFV) experienced PDVF. Treatment-emergent resistance was detected in 3 participants receiving CAB 10 mg, with 2 participants developing only NNRTI-resistance mutations and 1 participant (who had low CAB and rilpivirine [RPV] exposures) developing both an NNRTI (E138Q) and INSTI (Q148R) mutation.16,17 During the open-label phase of the study, in which CAB participants had the option to continue on CAB 30 mg plus RPV, 3 participants had PDVF, and treatment-emergent resistance was detected in 2 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 as a PDVF.18

In another Phase IIb study (LATTE-2; NCT02120352), analysis through Week 96 found that 3 participants (2 IM CAB Q8W; 1 oral CAB) met PDVF criteria. No treatment-emergent resistance was detected in the participant in the oral dosing group. One of the participants in the 8-week group had emergent NNRTI-resistance mutations (K103N, E138G, and K238T) and INSTI-resistance mutations (Q148R), which reduced susceptibility to RPV and CAB. The other participant in the 8-week group developed a mixed integrase mutation, R269R/G, that did not reduce CAB susceptibility.19

Induction phase: Participants will receive oral CAB 10, 30, or 60 mg once daily versus EFV 600 mg once daily, each given in combination with 2 background NRTIs. The induction phase will last through Week 24.

Maintenance phase: Those participants successfully completing the induction phase will continue their randomized dose of oral CAB, but they will discontinue the background NRTIs and add RPV 25 mg. The comparator arm will continue with EFV 600 mg plus the background NRTIs. The maintenance phase will last through Week 96.

Induction phase: Participants will receive a 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 RPV 25 mg once daily. (Participants with HIV-1 RNA <50 copies/mL will continue on to the maintenance phase of the study.)

Maintenance phase: Following induction, qualifying participants will be randomized to 1 of the 3 treatment arms below for maintenance therapy. All doses of CAB LA and RPV LA will be given IM.

Additional studies evaluating CAB LA for HIV treatment are currently ongoing, including the following 2 Phase III trials:

FLAIR (NCT02938520), an open-label study evaluating the safety and efficacy of CAB LA plus RPV LA administered every 4 weeks for the maintenance of virologc suppression after a switch from an oral DTG-based regimen in adults who are treatment-naive.27

ATLAS (NCT02951052), an open-label switch study evaluating the safety and efficacy of switching to CAB LA plus RPV LA administered every 4 weeks from an ARV regimen containing 2 NRTIs plus an INI, NNRTI, or PI in adults who are virologically suppressed.28

Cabotegravir for HIV prevention

Study Identifiers: ECLAIR; NCT02076178Sponsor: ViiV HealthcarePhase: IIaStatus: 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.Dosing:

Study Identifiers: HPTN 077; NCT02178800Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)Phase: IIaStatus: This study is ongoing, but not recruiting participants.Study Purpose: The purpose of this study is to evaluate the safety, tolerability, and pharmacokinetics of CAB LA.Study Population: Participants are men and women without HIV who are at low risk of acquiring HIV.Dosing: Participants will be enrolled to either Cohort 1 or 2, and within each cohort, participants will be randomized to either CAB or placebo.

Oral phase: Participants in each cohort will receive either oral CAB 30 mg or placebo once daily for 4 weeks. (There will be a 1-week washout period between the end of the oral phase and the beginning of the injection phase.)

Injection phase: Following a 1-week washout period, participants will then receive the following:

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

HPTN 083 (NCT02720094), a Phase IIb/III trial that will compare CAB LA to oral tenofovir DF/emtricitabine in terms of safety and effectiveness as PrEP. Participants do not have HIV and include men who are cisgender and women who are transgender, both of whom have sex with men and are at high risk of acquiring HIV infection. This study is currently recruiting participants.36

HPTN 084 (NCT03164564), a Phase III trial that will compare CAB LA to oral tenofovir DF/emtricitabine in terms of safety and effectiveness as PrEP in women who do not have HIV and who are at risk for acquiring HIV. This study is not yet open for participant recruitment.37

Adverse Events

LATTE Study (NCT01641809)
A Week 96 analysis of the LATTE study, which involved 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, overall. 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. Headache was more common with oral CAB than with EFV.16,17,38

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 1 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, most commonly due to elevated CPK, occurred in 26% of participants assigned to oral CAB versus 37% of participants assigned to EFV. Elevations in ALT (any grade) occurred in 20% of oral CAB participants and 21% of EFV participants.16,38

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.18

LATTE-2 Study (NCT02120352)
The LATTE-2 study enrolled 309 participants, with 286 participants randomized to maintenance therapy (n = 115 IM CAB Q4W; n = 115 IM CAB Q8W; n = 56 oral CAB). Analysis at Week 96 found that, in the maintenance-exposed population, AEs occurred in 100% of participants in the 4-week and 8-week 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 2 participants (in the 8-week group) withdrew from the study because of an ISR.19

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 phase, SAEs occurred in 10% of participants in each of the IM groups and 13% of participants in the oral dosing group. None of the SAEs reported during the maintenance phase were drug-related. Eleven (4%) participants withdrew from the study because of an AE during the maintenance phase. Treatment-emergent laboratory abnormailites (Grade 3 or higher) during the maintenance period occurred in 28% of participants in the 4-week group, 18% of participants in the 8-week group, and 21% of participants in the oral dosing group. Possible drug-induced liver injury occurred in 2 participants who met predefined liver chemistry criteria for stopping treatment, and in both cases, abnormalities in liver chemistry resolved after treatment was discontinued.19

ECLAIR Study (NCT02076178)
In the 41-week ECLAIR study, which involved a total of 126 treated participants (n = 105 CAB; n = 21 placebo), 18 participants withdrew from CAB during the study. Five participants withdrew during oral therapy, 6 after oral therapy but prior to injections, and 7 during the injection period. During the injection phase, 4 out of 94 participants receiving CAB LA withdrew from the study because of injection intolerability. During the oral phase, 7 participants withdrew because of CAB-related AEs, which included 3 events of neutropenia, 3 events of increased blood CPK, and 1 event of fatigue. One participant receiving CAB LA experienced an SAE (appendicitis).7,29,30,32

Overall, 62% of placebo participants and 80% of CAB participants experienced a Grade 2 to 4 AE. During the injection phase, Grade 2 to 4 AEs (occurring in >5% of participants in the CAB LA arm) were reported in 80% of participants receiving CAB LA versus 48% of participants receiving placebo. The most common Grade 2 to 4 AE in the CAB LA group was injection site pain, followed by pyrexia, injection site pruritus, and injection site swelling. 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.29,30,32

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 1 injection, and 75% of participants completed all injections. Twelve (7.9%) participants receiving CAB and 1 (2.1%) participant receiving placebo discontinued treatment because of an AE. ISRs accounted for only 1 discontinuation, which occurred in a CAB participant. ISRs, the majority of which were mild, occurred frequently in participants receiving CAB. During the injection phase, injection site pain and headache occurred significantly more frequently with CAB than with placebo.34,35,39

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).9,40

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.41

There are no apparent pharmacokinetic interactions between oral CAB and etravirine or between oral CAB and RPV.42,43

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. Coadministration of RIF with CAB LA is also not recommended until further study is completed.44

References

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National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. Available at: https://chemdb.niaid.nih.gov/DrugDevelopmentHIV.aspx. Last accessed on September 13, 2017.

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. HIV AIDS (Auckl). 2016 Oct 14;8:157-164. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5074732/. Last accessed on September 13, 2017.

ViiV Healthcare website. Medicines in development. Available at: https://www.viivhealthcare.com/our-medicines/medicines-in-development.aspx. Last accessed on September 13, 2017.

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 September 13, 2017.

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 September 13, 2017

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 September 13, 2017.