Regulatory Decision Summary for Vocabria/Cabenuva

Vocabria and Cabenuva represent one treatment regimen for HIV-1 infection in virologically supressed patients. Vocabria is indicated, in combination with Edurant (rilpivirine tablets), as an oral lead-in to assess the tolerability of cabotegravir prior to administration of Cabenuva and as oral bridging therapy for patients who will miss planned Cabenuva injection. Cabenuva is indicated as a complete regimen to replace the current antiretroviral regimen. Vocabria is recommended to be administered for approximately one month (at least 28 days) prior to the initiation of Cabenuva. The recommended initial injection doses of Cabenuva are a single 3 mL (600 mg) intramuscular injection of cabotegravir and a single 3 mL (900 mg) intramuscular injection of rilpivirine. One month following the initiation injections, the recommended continuation injection doses of Cabenuva are a single 2 mL (400 mg) injection of cabotegravir and a single 2 mL (600 mg) injection of rilpivirine administered once monthly.

The indications for Vocabria and Cabenuva are supported by the safety and efficacy data from two Phase 3 randomized, multicenter, active-controlled, parallel-arm, open-label, non-inferiority trials, Flair (201584) and Atlas (201585). In Flair, HIV-1-infected, antiretroviral treatment-naive patients (n = 629) received a standard of care antiretroviral regimen for 20 weeks. Patients who were virologically suppressed (HIV-1 RNA < 50 copies/mL, n = 566) were then randomized to receive the Vocabria and Cabenuva regimen (oral lead-in + injections) or to remain on the standard of care regimen. In Atlas, HIV-1-infected, virologically-suppressed patients (HIV-1 RNA < 50 copies/mL for at least 6 months, n = 616) were randomized to receive the Vocabria and Cabenuva regimen (oral lead-in + injections) or to remain on their current antiretroviral regimen.

The primary endpoint of Flair and Atlas trials was the proportion of patients with plasma HIV-1 RNA ≥ 50 copies/mL at Week 48. In a pooled analysis, Cabenuva was non-inferior to the control antiretroviral regimens with 1.9% and 1.7% of patients having plasma HIV-1 RNA ≥ 50 copies/mL at Week 48, respectively. Furthermore, in the pooled analysis, Cabenuva was non-inferior to the control antiretroviral regimens on the proportion of subjects having plasma HIV-1 RNA < 50 copies/mL (93.1% and 94.4%, respectively) at Week 48. Treatment differences across baseline characteristics in Flair and Atlas (CD4 + count, gender, age, race, BMI, baseline 3rd agent treatment class) were comparable. No clinically relevant change from baseline in CD4 + cell counts was observed in either trial.

The most common adverse reactions in the pooled analysis of Flair and Atlas trials were injection site reactions (84%), pyrexia (8%), fatigue (5%) and headache (5%). The severity of injection site reactions was generally mild (Grade 1, 75% of patients) or moderate (Grade 2, 36% of patients). Four percent (4%) of patients experienced severe (Grade 3) injection site reactions and there were no Grade 4 injection site reactions. The median duration of all injection site reactions events was 3 days. Adverse events leading to discontinuation and occurring in more than 1 patient were injection site reactions, hepatitis A, acute hepatitis B, headache, and diarrhea, which occurred with an incidence of ≤ 1%.

The main risks and uncertainties associated with the Vocabria and Cabenuva treatment at this time are related to long-acting properties of Cabenuva. Residual concentrations of cabotegravir and rilpivirine injections may remain in the systemic circulation of patients for prolonged periods (up to 12 months or longer). Therefore, the Product Monograph recommends that it is important to carefully select patients who agree to the required monthly injection dosing schedule because non-adherence to monthly injections could lead to loss of virologic response and development of resistance. In addition, cases of hepatotoxicity have been reported in patients receiving cabotegravir with or without known pre-existing hepatic disease or other identifiable risk factors. Therefore, the Product Monograph recommends monitoring of liver chemistries. Moreover, the Risk Management Plan for Vocabria and Cabenuva includes drug resistance as an important identified risk, and hypersensitivity reactions and medication errors as important potential risks. The identified and potential risks will be monitored post-market.

Based on the data submitted, Health Canada considers that the overall benefit-harm-uncertainty profile of Vocabria and Cabenuva is positive when used under conditions described in the Vocabria and Cabenuva Product Monograph at this time.

For more information on Health Canadas decision, please view the Summary Basis of Decision.