Regulatory Decision Summary for Apretude

This New Drug Submission (NDS) was filed to obtain market authorization for Apretude for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 infection in at-risk individuals weighing at least 35 kg. Upon review, an indication for at-risk adults and adolescents aged 12 years and older and weighing at least 35 kg for PrEP to reduce the risk of sexually acquired HIV-1 infection was authorized.

This NDS was filed and approved under the Priority Review Policy. The sponsor consented to information sharing between Health Canada and health technology assessment organizations as part of an aligned review pathway.

The indication for Apretude in at-risk adults and adolescents aged 12 years and older and weighing at least 35 kg for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 infection was supported primarily by the safety and efficacy results from 2 randomized, international, multicenter, double-blind Phase 3 trials, HPTN 083 and HPTN 084. HPTN 083 was conducted in men and transgender women who have sex with men and have evidence of high-risk behavior for HIV-1 infection, and HPTN 084 in cisgender women at risk of acquiring HIV-1. In both trials, participants randomized to receive Apretude initiated oral lead-in dosing with one 30 mg cabotegravir tablet and placebo daily, for up to 5 weeks, followed by Apretude 3 mL (600 mg) intramuscular (IM) injection at months 1, 2 and every 2 months thereafter and a daily placebo tablet. Participants randomized to receive the active comparator Truvada initiated oral Truvada and placebo for up to 5 weeks, followed by oral Truvada daily and placebo IM injection at months 1, 2 and every 2 months thereafter.

In HPTN 083, a non-inferiority study, 4,570 cisgender men and transgender women who have sex with men were randomized 1:1 to receive either Apretude (n = 2,283) or Truvada (n = 2,287). Of these, 4,566 participants were treated with Apretude (n = 2,281) or Truvada (n = 2,285) as blinded study medication up to Week 153. Four participants were randomized but did not receive study drug (2 participants each in the Apretude and Truvada groups). The primary endpoint was the rate of incident HIV infections among participants randomised to Apretude compared to Truvada (corrected for early stopping). The primary analysis demonstrated the superiority of Apretude compared to Truvada with a 66% reduction in the risk of acquiring incident HIV infection resulting in a hazard ratio (95% CI) of 0.34 (0.18, 0.62); further testing revealed one of the infections on Apretude to be prevalent then yielding a 69% reduction in the risk of incident infection relative to Truvada. At a pre-planned interim review of trial data, a multinational Data and Safety Monitoring Board (MDSMB) recommended that the blinded phase of HPTN 083 be stopped due to the demonstration of superior efficacy of Apretude when compared to Truvada and that participants randomized to the active Truvada group be offered Apretude.

In HPTN 084, a superiority study, 3,224 cisgender women were randomized 1:1 and received either Apretude (n = 1,614) or Truvada (n = 1,610) as blinded study medication up to Week 153. The primary endpoint was the rate of incident HIV infections among participants randomized to Apretude compared to Truvada (corrected for early stopping). The primary analysis demonstrated the superiority of Apretude compared to Truvada with an 88% reduction in the risk of acquiring incident HIV-1 infection resulting in a hazard ratio (95% CI) of 0.12 (0.05, 0.31); further testing revealed 1 of the infections on Apretude to be prevalent then yielding a 90% reduction in the risk of HIV-1 incident infection relative to Truvada. The MDSMB recommended early termination of the blinded, randomized portion of HPTN 084 after an interim analysis indicated that pre-specified stopping criteria had been met, i.e. the superiority of Apretude compared with Truvada.

The most common adverse drugs reactions in HPTN 083 and HPTN 084 were injection site reactions (82% and 38%, respectively). Adverse events (all causality) leading to discontinuation and occurring in ≥1% of participants were increased alanine aminotransferase with Apretude and Truvada, and injection site pain with Apretude in HPTN 083, and increased alanine aminotransferase (<1%) with Apretude and Truvada in HPTN 084.

The use of Apretude in adolescents aged 12 years and older and weighing at least 35 kg is supported by the interim safety and pharmacokinetic data from an ongoing Phase 1/2 open-label, non-comparative study MOCHA in which oral and injectable cabotegravir or oral and injectable rilpivirine, each as a single agent, was administered in combination with other antiretroviral agents to HIV-1 infected adolescents; the pharmacokinetic data from two open-label Phase 2b safety studies HPTN 083-1 and HPTN 084-01 in adolescents aged 12 years and older and weighing at least 35 kg receiving Apretude that was consistent with the MOCHA study; and the safety and efficacy data from Phase 3 studies HPTN 083 and HPTN 084 in adults.

The main identified risks with Apretude include development of resistance with use in undiagnosed HIV-1 infection, hepatotoxicity, drug-drug interactions, long-acting properties of Apretude, hypersensitivity reactions and depressive disorders. All these risks are described in the Apretude Product Monograph along with adequate risk mitigation recommendations and will be monitored post-market as per the Risk Management Plan.

In summary, based on the data submitted in this New Drug Submission (NDS), the overall benefit-harm-uncertainty profile of Apretude is considered favorable in at-risk adults and adolescents aged 12 years and older and weighing at least 35 kg for PrEP to reduce the risk of sexually acquired HIV-1 infection.

For further details about Apretude, please refer to the PM, approved by Health Canada and available through the Drug Product Database.