FDA Approves Expanded Indications for 2 HIV Therapies

The US Food and Drug Administration (FDA) has approved 2 supplemental New Drug Applications (sNDA) for doravirine (Pifeltro) and doravirine/lamivudine/tenofovir disoproxil fumarate (Delstrigo). The approval allows treatment-experienced adults living with HIV, who are virally suppressed and have no prior history of treatment failure, to switch to either of the treatment options. The approval was granted to Merck.

Doravirine is a 100 mg, once-daily, non-nucleoside reverse transcriptase inhibitor (NNRTI), and doravirine/lamivudine/tenofovir disoproxil fumarate is a once-daily fixed-dose combination tablet of 100 mg doravirine, 3TC/300 mg lamivudine, and TDF/300 mg tenofovir disoproxil fumarate. Both were first approved by the FDA in August 2018 for adult patients with no documentation of past antiretroviral therapy.

The FDA’s decision was based on the results of the DRIVE-SHIFT study. The phase 3 trial evaluated a switch to doravirine/lamivudine/tenofovir disoproxil fumarate compared to continuing a baseline regimen of 2 nucleoside reverse transcriptase inhibitors, plus a boosted protease inhibitor, boosted elvitegravir, or NNRTI.

The study met its primary endpoint, demonstrating non-inferior efficacy. This was measured by the proportion of participants who switched therapy and had plasma HIV-1 RNA levels <50 copies/mL through week 48, compared to participants who continued their baseline regimen and had HIV-1RNA levels <50 copies/mL at week 24.

The most common adverse reactions observed with doravirine/lamivudine/tenofovir disoproxil fumarate in clinical studies were dizziness (7%), nausea (5%), and abnormal dreams (5%). The most common adverse reactions with doravirine were nausea (7%), dizziness (7%), headache (6%), fatigue (6%), diarrhea (5%), abdominal pain (5%), and abnormal dreams (5%).

In the DRIVE-SHIFT clinical trial, there were 6 participants of 447 total in the immediate switch group and 2 participants of 209 total in the delayed switch group who met the protocol-defined virologic failure criteria (HIV-1 RNA ≥50 copies/mL). Two of the 6 virologic failures in the immediate switch group had available resistance data and neither developed detectable genotypic or phenotypic resistance to doravirine, lamivudine, or tenofovir disoproxil fumarate during treatment with doravirine/lamivudine/tenofovir disoproxil fumarate. “One of the 2 virologic failures in the delayed switch group had available resistance data and developed the RT M184M/I substitution and phenotypic resistance to emtricitabine and lamivudine during treatment with their baseline regimen,” the press release indicates.

In both doravirine treatment arms of the 2 DRIVE-AHEAD and DRIVE-FORWARD studies, 11 of 747 total participants showed the emergence of doravirine-associated resistance substitutions (among the 28 participants with HIV-1 RNA >400 copies per mL at virologic failure or early study discontinuation and having resistance data). Of these 11 participants, 7 showed both genotypic and phenotypic resistance to doravirine, with at least a 100-fold reduction in susceptibility to doravirine. The other 4 participants had substitutions that were associated with less than 2-fold reduction in susceptibility to doravirine.

“Cross-resistance has been observed among NNRTIs, including doravirine. Treatment-emergent doravirine resistance-associated substitutions can confer cross-resistance to efavirenz, rilpivirine, nevirapine and etravirine,” Merck notes.

“Today’s approvals provide doravirine treatment options for people living with HIV-1 who are virally suppressed, reflecting Merck’s continued commitment to research and development of HIV treatments,” said George Hanna, MD, vice president and therapeutic area head of infectious diseases, Global Clinical Development, Merck Research Laboratories, in the announcement. “We are thankful to the researchers and HIV community for their collaboration that made this possible.”