Regulatory Decision Summary for Pifeltro

The purpose of this Supplemental New Drug Submission (SNDS) was to expand the indication for Pifeltro (doravirine) for the treatment of human immunodeficiency virus 1 (HIV-1) infection to pediatric patients weighing at least 35 kg without past or present evidence of viral resistance to doravirine. Upon review, an indication for the treatment of HIV-1 infection in pediatric patients 12 years and older and weighing at least 35 kg without past or present evidence of viral resistance to doravirine was authorized.

Pifeltro (doravirine) is currently indicated, in combination with other antiretroviral medicinal products, for the treatment of HIV-1 in adults without past or present evidence of viral resistance to doravirine. The expansion of the indication for Pifeltro to HIV-1-infected adolescent patients was supported by the interim (Week 24) data from an ongoing 96-week phase I/II, open-label study P027 (IMPAACT 2014). This study aims to evaluate the pharmacokinetics (PK), safety, and tolerability of doravirine as a single agent or as a fixed-dose combination with lamivudine and tenofovir disoproxil fumarate (Delstrigo; a complete antiretroviral regimen for the treatment of HIV-1) in HIV-1-infected patients 12 years of age and older and weighing at least 35 kg.

Study P027 includes two cohorts that were enrolled in a staggered fashion. In cohort 1, 9 patients 12 years and older and weighing at least 35 kg were enrolled to evaluate the PK and safety of a single oral dose of doravirine added to background antiretroviral regimen. Once doravirine dose was confirmed in cohort 1 (i.e., 100 mg once daily), 45 patients were enrolled in cohort 2 to evaluate the PK, safety and efficacy of doravirine administered as Delstrigo; this cohort included 43 virologically suppressed patients that switched to once daily Delstrigo from their current antiretroviral regimen and 2 treatment-naïve patients that initiated once daily Delstrigo. In cohort 2, a semi-intensive PK sampling was performed for 10 patients at Week 1 and sparse PK sampling was done for all 45 patients at Week 4. The PK analysis in cohort 2 demonstrated that the steady-state exposure of doravirine in adolescents was comparable to its known exposure in adults.

Delstrigo was well tolerated in study P027 and there were no discontinuations due to adverse events. Four patients (44.4%) in cohort 1 and all patients in cohort 2 reported adverse events. There were no drug-related adverse events, serious adverse events, or adverse events that were Grade 3 or greater in severity in cohort 1. In cohort 2, grade 3 adverse events were reported for 9 patients (20.0%), none of which was related to the study drug; 1 treatment-naïve patient (2.2%) had a drug-related adverse event of dizziness (grade 1 in severity). The most frequently reported adverse events (20%) were decreased glomerular filtration rate (42.2%), increased alanine transaminase (40.0%), increased aspartate transaminase (26.7%), increased blood creatinine (26.7%), and decreased carbon dioxide (20.0%); most of these adverse events were grade 1 in severity. There were no clinically important laboratory findings. Overall, the safety profile of doravirine in adolescents at Week 24 in study P027 was similar to its known safety profile in adults. As study P027 is ongoing, a long-term safety data for adolescent patients will be available in the future.

The efficacy assessment of doravirine administered as Delstrigo was conducted in cohort 2. After switching to Delstrigo from their current antiretroviral regimen, 95% (41/43) of virologically suppressed patients remained suppressed (HIV-1 RNA <50 copies/mL) at Week 24. One of the two treatment-naïve patients achieved HIV-1 RNA <50 copies/mL by Week 12 and maintained it through Week 24. The other treatment-naïve patient met the protocol-defined virologic failure criteria (defined as 2 consecutive plasma HIV-1 RNA test results 200 copies/mL at or after Week 24) and was evaluated for the development of resistance; no emergence of genotypic or phenotypic resistance to doravirine, lamivudine, or tenofovir (the active metabolite of tenofovir disoproxil fumarate) was detected. For virologically suppressed patients, a small increase from baseline in CD4 cell count was observed at Week 24, i.e., mean change (95% confidence interval [CI]) of 79.0 (12.7, 145.3) cells/mm³.

In summary, based on the review of submitted evidence, Health Canada considers that the benefit-harm-uncertainty profile of Pifeltro is favorable when used in combination with other antiretroviral medicinal products for the treatment of HIV-1 infection in pediatric patients 12 years of age and older and weighing at least 35 kg. The efficacy and safety of Pifeltro have not been established in pediatric patients younger than 12 years of age and weighing less than 35 kg and therefore, Health Canada has not authorized an indication in this patient population.

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