Regulatory Decision Summary for Sunlenca

Heavily treatment-experienced (HTE) and multi-drug resistant (MDR) patients represent a small, often marginalized, subpopulation of the overall HIV community. These patients have very few remaining therapeutic options and often are on highly individualized anti-retroviral agents (ARV) combinations that may lack the efficacy, safety and tolerability profiles of regimens used in earlier lines of therapy. These patients remain at increased risk of advanced immunodeficiency and increased risk of morbidity and mortality.

The pivotal Phase 2/3 study, GS-US-4625 provides sufficient data on the safety and efficacy of Sunlenca (lenacapavir). Study GS-US-4625 followed a multi-stage approach with a short-term functional monotherapy phase with a placebo comparator, followed by a single-arm assessment of the durability of the antiviral effect and safety through Week 52. This ongoing 2-cohort study was conducted in patients infected with MDR HIV-1 in either a randomized cohort (Cohort 1) or a non-randomized cohort (Cohort 2). The primary endpoint was to evaluate the proportion of participants in Cohort 1 achieving a reduction in HIV-1 RNA of ≥ 0.5 log10 copies/mL from baseline at the end of the Functional Monotherapy Period. Overall, between Cohorts 1 and 2, 72 participants were enrolled and included in the full analysis set. Baseline characteristics were reflective of a HTE population with advanced HIV, however notably, there were baseline differences in regards to baseline HIV-1 count and baseline CD-4 counts.

Lenacapavir met the study’s primary endpoint, with a significantly greater proportion of participants who received lenacapavir (87.5%) having a reduction in HIV-1 RNA of ≥ 0.5 log10 copies/mL from baseline compared to those who received placebo (16.7%) (p < 0.0001). Post hoc analysis of the primary efficacy endpoint with adjustment for baseline HIV-1 RNA using rank analysis of covariance confirmed the difference between the groups remained statistically significant (p = 0.0003). The durability of the antiviral effect of lenacapavir + optimized background regimen (OBR) was demonstrated in Cohorts 1 and 2 at 26 weeks, with HIV-1 RNA < 50 and < 200 copies/mL in 80.6% (58 of 72 participants) and 87.5% (63 of 72 participants), respectively. High rates of virologic suppression were maintained through Week 52 with HIV-1 RNA < 50 and < 200 copies/mL of 77.8% (35 of 45 participants) and 82.2% (37 of 45 participants). There were clinically meaningful increases in CD4 cell count from baseline to week 26 and week 52. Overall, these results suggest that lenacapavir has long-term efficacy. The percentage of participants who experienced virologic failure through the Week 52 analysis was 11.1% (8 of 72). The virologic profiles of these 8 participants suggested they were at high risk of developing lenacapavir resistance due to lack of fully active ARV in the OBR (n = 4) or due to inadequate adherence to OBR (n = 4). As a consequence, lenacapavir may have been the only active ARV at the time of virologic failure. No cross resistance between lenacapavir and other ARVs was demonstrated.

The assessment of the long-term safety of lenacapavir in study GS-US-4625 is limited by the uncontrolled study design, small patient population and complex comorbidities with concomitant medications of the study population. The median duration on study was 376 days (53 weeks) (range 90-646). Despite these limitations, lenacapavir was generally safe and well tolerated. Adverse events (AEs) that occurred were consistent with those expected in people with advanced HIV/AIDS or with the subcutaneous administration of a drug product. 93% of patients experienced a treatment emergent adverse event (TEAE). The majority of these events were Grade 1 or Grade 2 and resolved without discontinuation or interruption of study medication. Adverse reactions determined to be related to the drug by the study investigator occurred in 48 patients (66.7%). Common adverse reactions were injection site reactions (ISRs) (63%) and nausea (4%). Serious adverse events occurred in 8 patients (11.1%). None were considered related to the study drug. 12.5% of treated participants experienced an emergent Grade 3 or Grade 4 elevation in serum creatinine, however these findings were confounded by advanced HIV and other comorbidities of the participants as well as concomitant medications including therapies used in prophylaxis against opportunistic infections. 45 participants (62.5%) experienced a study drug-related ISR. The 3 most commonly reported were injection site pain (37.5%, 27 of 72 participants), injection site swelling (33.3%, 24 participants), and injection site erythema (27.8%, 20 participants).

Overall, the safety profile of lenacapavir is considered acceptable given the significant risks associated with unsuppressed viral load in the patient population. The major limitations of the safety database for lenacapavir include the small study numbers and the limited long-term follow-up, with limited safety data available beyond 52 weeks of treatment. Therefore, rare adverse drug reactions associated with long exposure, long latency and cumulative effects are not well characterised. Most observed adverse events were tolerable and self-limited and can be adequately managed through labelling and pharmacovigilance.

A Risk Management Plan (RMP) for Sunleca was submitted by Gilead Sciences Canada, Inc. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will put in place to minimize risks associated with the product.

On the basis of the information reviewed, Sunlenca (lenacapavir) presents an acceptable safety profile in consideration of the intended population and the indication. Based on the benefit-harm-uncertainty profile of the product, it is recommended that Sunlenca (lenacapavir) be granted authorization.