Regulatory Decision Summary for Biktarvy

The purpose of this Supplement to a New Drug Submission (SNDS) was to expand the current indication for Biktarvy (bictegravir/emtricitabine/tenofovir alafenamide) to include individuals with human immunodeficiency virus-1 (HIV-1) infection who have emtricitabine resistance substitutions (M184V/I) in their reverse transcriptase (RT).

The proposed update to the current indication for Biktarvy removes the current restriction on use in patients with HIV-1 who have resistance-associated substitutions to emtricitabine while retaining the requirements that there be no known resistance to bictegravir or tenofovir. This SNDS included data to support the use of Biktarvy in people with HIV-1 with M184V/I resistance substitutions in their reverse transcriptase (RT), the most clinically meaningful substitutions confirming resistance to emtricitabine.

To support the proposed change, the sponsor submitted a primary clinical study Study GS-US-380-4030, which evaluated the safety and efficacy of Biktarvy in HIV-1-infected patients with preexisting M184V/I resistance mutations. Additional supporting data were also submitted from other clinical trials, including GS-US-380-4580 and GS-US-380-1474 (pediatric patients), along with integrated analyses of pooled safety and efficacy data in virologically suppressed patients, both with and without preexisting M184V/I substitutions. To assess baseline M184V/I prevalence, virologic analyses were conducted in adult Phase 3 studies and pediatric Phase 2/3 Biktegravir studies using available RT genotyping data. Composite baseline genotypes, derived from historical and/or retrospective proviral DNA genotyping, identified participants with emtricitabine resistance.

The primary study was a Phase 3, randomized, double-blind, multicenter, active-controlled trial GS-US-380-4030 conducted in virologically suppressed adults, including those with known or suspected pre-existing M184V/1 resistance mutations. This study demonstrated that preexisting resistance at baseline, including M184V/I, had no effect on virologic response to Biktarvy through Week 48, based on the United States Food and Drug Administration (FDA)-defined Snapshot Algorithm, or through the end of the blinded treatment phase of the study. Among those with preexisting M184V/I, 89.4% in the Biktarvy group (42 of 47 participants) had HIV-1 RNA < 50 copies/mL at Week 48. There were no statistically significant differences in the proportions of participants in the Biktarvy group with and without M184V/I who had HIV-1 RNA < 50 copies/mL or ≥ 50 copies/mL at Week 48. Five of 47 (10.6%) participants with preexisting M184V/I in the Biktarvy group had no virologic data at Week 48, but had HIV-1 RNA < 50 copies/mL at their last on-treatment visit prior to Week 48. An integrated analysis of pooled data showed that among 142 subjects with pre-existing M184V/I resistance-associated mutations (RAMs) and 222 participants with any primary nucleotide reverse transcriptase inhibitor (NRTI) RAMs, there was no evidence of increased virologic failure (either as a failure of suppression or through suppression to < 50 copies/mL at Week 48 by the FDA defined Snapshot Algorithm; with these as either primary or secondary endpoints in the various studies). Among virologically suppressed pediatric participants in Study GS-US-380-1474, preexisting M184V/I was detected in 11 of 95 (11.6%) participants with composite baseline genotypic data who switched to Biktarvy. High levels of virologic suppression through 48 weeks of Biktarvy treatment and the absence of treatment-emergent resistance support the efficacy of Biktarvy in adolescents and children with suppressed HIV-1 harboring M184V/I.

Identified data limitations included the relatively low number of subjects with M184V/I mutations at baseline and the absence of studies specifically designed to assess efficacy in this population. Most subjects with NRTI resistance were identified through historical genotyping rather than targeted recruitment. As a result, the conclusions are based on pooled data across different studies. Also given that these studies were largely conducted in virologically suppressed patients with no restriction on virological failure (particularly in the context of NRTI mutations), it remains unclear how a history of virological failure might affect outcomes. The sponsor noted that although participants were not screened for prior virologic failure, studies GS-US-380-4030 and GS-US-380-4580 included individuals with historical antiretroviral (ARV) resistance and suspected past virologic failure, without any observed impact on virologic outcomes. Furthermore, the International AIDS Society guidelines recommend using two NRTIs plus a third agent with high resistance barrier in cases of NRTI resistance, with Biktarvy meeting those criteria. Overall, the pooled analysis showed no evidence of virologic failure in these subjects supporting the proposed changes to the indication.

The safety profile from the submitted studies was consistent with what has been previously observed for Biktarvy. The drug-related adverse event of constipation was added to the Less Common Adverse Events section of the Product Monograph as it occurred in these studies in greater than 2% of subjects and was not previously included.

Overall, the benefit-harm-uncertainty profile was favourable for Biktarvy for the approved indication when used under the conditions of use recommended in the approved Product Monograph. Therefore, a Notice of Compliance (NOC) was recommended.

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