Regulatory Decision Summary for Dovato

Dovato is a fixed-dose combination of dolutegravir (DTG) (integrase strand-transfer inhibitor [INSTI]) and lamivudine (3TC) (non-nucleoside reverse transcriptase inhibitor [NRTI]), which are already approved in Canada either as single entities or in combination products. The recommended treatment regimen of Dovato is a single tablet to be taken once daily without regard to food.

The overall benefit-risk profile of Dovato is considered favorable when used as a complete regimen for the treatment of human immunodeficiency virus-1 (HIV-1) infection in adults and adolescents ≥12 years of age and ≥40 kg body weight, without evidence of viral resistance to DTG or 3TC.

The safety and efficacy of Dovato is supported by two identical active-controlled, double-blind, non-inferiority Phase III studies, GEMINI-1 and GEMINI-2, in HIV-1-infected adults without prior exposure to antiretroviral therapy. The primary efficacy endpoint in these trials was the proportion of patients with plasma HIV-1 RNA <50 copies/mL (i.e. virologic suppression) at Week 48 using the Food and Drug Administration (FDA) Snapshot method. In both trials, patients received DTG and 3TC as single entities and a comparative bioavailability study was conducted to bridge these data to Dovato (i.e. the fixed-dose combination).

At study Week 48, DTG+3TC was non-inferior to the standard of care, three-drug antiretroviral regimen consisting of DTG+2 NRTIs (emtricitabine and tenofovir disoproxil fumarate). In the pooled analysis of GEMINI trials, 91% of patients treated with DTG+3TC achieved virologic suppression compared to 93% of patients treated with the control regimen, resulting in a treatment difference (95% CI) of -1.7% (-4.4%, 1.1%). The immunologic response measured by an increase in CD4+T cells from baseline to Week 48 was also similar between DTG+3TC and the control regimen. Virologic failure rates at Week 48 were similar between DTG+3TC and the control regimen, i.e. 9% vs. 7%. There was no evidence of treatment-emergent genotypic or phenotypic resistance to DTG or 3TC in GEMINI trials.

DTG and 3TC have established safety profiles and considerable post-market experience. The Week 48 safety data from GEMINI trials were generally consistent with findings from prior clinical trials with DTG and/or 3TC, and there were no new safety concerns. In the pooled analysis, the most common adverse events that occurred in ≥2% of patients treated with DTG+3TC were headache, diarrhea, insomnia and nausea. Discontinuation rate due to adverse events was 2% in both treatment groups. The most common adverse events leading to discontinuation were psychiatric disorders (<1% of patients in both treatment groups). There were no treatment-related deaths.

There are no direct clinical data with Dovato in HIV-1-infected adolescents 12 years of age and older and weighting at least 40 kg. The safety and efficacy of Dovato in adolescents are supported by the clinical data from prior adolescent studies of DTG or 3TC as single agents in combination with other antiretroviral drugs and by GEMINI trials with DTG+3TC in adults.

The main risks associated with Dovato include acute exacerbations of hepatitis B and emergence of 3TC-resistant hepatitis B virus (HBV) in HIV-1/HBV co-infected patients; hepatotoxicity; lactic acidosis/severe hepatomegaly with steatosis; hypersensitivity reactions; immune reconstitution inflammatory syndrome and use in pregnancy. These risks are manageable through appropriate warnings and cautionary statements in the Dovato Product Monograph and through the Risk Management Plan (RMP) to be implemented by the sponsor.

Based on the data submitted, it is considered that the anticipated benefits of Dovato outweigh the potential risks under the conditions of use described in the Dovato Product Monograph at this time.