Regulatory Decision Summary for Rukobia

Review decision

The Regulatory Decision Summary explains Health Canada’s decision for the product seeking market authorization. The Regulatory Decision Summary includes the purpose of the submission and the reason for the decision.


Product type:

Drug

Medicinal ingredient(s):

fostemsavir tromethamine

Therapeutic area:

Antivirals for Systemic Use

Type of submission:

Priority New Drug Submission (New Active Substance)

Control number:

250213
What was the purpose of this submission?

 

The purpose of this New Drug Submission (NDS) – New Active Substance (NAS) was to seek market authorization for Rukobia (fostemsavir extended-release tablets) in the treatment of human immunodeficiency virus type 1 (HIV-1) infection in heavily treatment-experienced (HTE) adults. Upon review, the indication for the treatment of HIV-1 infection in HTE adults with multidrug-resistant HIV-1 infection for whom it is otherwise not possible to construct a suppressive anti-viral regimen due to resistance, intolerance or safety considerations was authorized.

This NDS was filed and authorized under the Priority Review Policy.

 

Why was the decision issued?

 

The authorized indication for Rukobia is supported by 96-week safety and efficacy data from a Phase 3, partially-randomized, international, double-blind, placebo-controlled BRIGHTE trial. This trial was conducted in 371 heavily treatment-experienced patients with multi-class HIV-1 resistance. All patients were required to have a viral load ≥400 copies/mL and ≤2 classes of antiretroviral medications remaining at baseline due to resistance, intolerability, contraindication, or other safety concerns. Patients were enrolled in either a randomized or non-randomized cohort. Within the randomized cohort (n = 272), patients had 1, but no more than 2, fully active and available antiretroviral agent(s) at screening which could be combined as part of an efficacious background regimen. Randomized patients received either blinded Rukobia 600 mg twice daily (n = 203) or placebo (n = 69) in addition to their current failing regimen for 8 days of functional monotherapy. Beyond Day 8, randomized patients received open-label Rukobia 600 mg twice daily plus an investigator-selected optimized background therapy (OBT). This cohort provided the primary evidence of efficacy for Rukobia. In the non-randomized cohort (n = 99), patients had no fully active and approved antiretroviral agents available at screening. Non-randomized patients were treated with open-label Rukobia 600 mg twice daily plus OBT from Day 1 onward.

In the randomized cohort, the baseline characteristics were well balanced between the Rukobia and placebo group. The primary endpoint analysis, based on the adjusted mean decline in HIV-1 RNA from Day 1 at Day 8 in the randomized cohort, demonstrated superiority of Rukobia to placebo (0.79 vs. 0.17 log10 copies/mL decline, respectively; p <0.0001, Intent-to-Treat-Exposed [ITT-E] population). At Day 8, 65% (131/203) and 46% (93/203) of patients who received Rukobia had a reduction in viral load from baseline >0.5 log10 copies/mL and >1 log10 copies/mL, respectively, compared with 19% (13/69) and 10% (7/69) of patients, respectively, in the placebo group. In addition, HIV-1 RNA <40 copies/mL was achieved in 53%, 54% and 60% of patients at Weeks 24, 48, and 96, respectively ((ITT-E, Snapshot algorithm). At these time points, the proportion of patients with HIV-1 RNA <200 copies/mL was 68%, 69%, and 64% of patients at Weeks 24, 48, and 96, respectively. At these time points, the proportion of patients with HIV-1 RNA <400 copies/mL was 75%, 70%, and 64%, respectively (ITT-E, Snapshot algorithm).

In the nonrandomized cohort, HIV-1 RNA <40 copies/mL was achieved in 37% of patients at Week 24, 38% at Week 48, and 37% at Week 96. At each of these respective time points, the proportion of patients with HIV-1 RNA <200 copies/mL was 42%, 43% and 39%, and the proportion of patients with HIV-1 RNA <400 copies/mL was 44%, 44% and 40%, respectively (ITT-E, Snapshot algorithm).

A total of 370 patients (271 randomized and 99 non-randomized) received at least 1 dose of Rukobia 600 mg twice daily in the BRIGHTE trial and Rukobia was generally well tolerated. Overall, most (81%) of the adverse reactions reported with Rukobia were mild or moderate in severity. The proportion of patients who discontinued treatment with Rukobia due to an adverse event was 7% at week 96 analysis (randomized: 5% and non-randomized: 12%). The most common adverse events leading to discontinuation were related to infections (3% of patients receiving Rukobia). Serious drug reactions occurred in 3% of patients and included 3 cases of severe immune reconstitution inflammatory syndrome. Adverse reactions (all grades) reported in ≥2% of patients in the Week 96 analysis included nausea (9%), diarrhea (5%), fatigue, headache, rash (3% each), abdominal pain, vomiting, dyspepsia, immune reconstitution inflammatory syndrome, somnolence and dizziness (2% each).

The potential risks associated with the use of Rukobia include QTc interval prolongation, increased incidence of hepatic transaminase elevations in patients co-infected with hepatitis B and/or C, or immune reconstitution inflammatory syndrome (IRIS). These risks are manageable through the inclusion of appropriate warnings and cautionary statements in the Rukobia Product Monograph and through a Risk Management Plan (RMP).

Based on the review of above evidence, it is considered that the benefit-harm-uncertainty profile of Rukobia is favourable in the treatment of HIV-1 infection in HTE adults with multidrug-resistant HIV-1 for whom it is otherwise not possible to construct a suppressive antiretroviral (ART) regimen due to resistance, intolerance or safety considerations.

 

Decision issued

Approved; issued a Notice of Compliance in accordance with the Food and Drug Regulations.