Merck's Big Week: HIV Approval and Landmark 3-Country Approval for Keytruda

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The U.S. Food and Drug Administration (FDA) approved Merck & Co.’s supplemental New Drug Applications (sNDAs) for Pifeltro (doravirine) in combination with other antiretroviral medicines and Delstrigo (doravine/lamivudine/tenofovir disoproxil fumarate) for HIV-1 patients who are switching from a stable antiretroviral regimen and whose virus is suppressed, meaning HIV-1 RNA is less than 50 copies per mL.

Pifeltro is a non-nucleoside reverse transcriptase inhibitor (NNRTI) indicated in combination with antiretroviral drugs for HIV-1 infection in adults with no previous antiretroviral treatment history. Delstrigo is a three-drug combination approved for HIV-1 infection in adults with no antiretroviral treatment history. Doravine is a non-NNRTI and lamivudine and tenofovir disoproxil fumarate are nucleoside analogue reverse transcriptase inhibitors.

The sNDAs for both Pifeltro and Delstrigo are based on the Phase III DRIVE-SHIFT clinical trial. The trial met its primary endpoint of non-inferior efficacy based on the proportion of patients who switched to Delstrigo and had plasma HIV-1 RNA levels less than 50 copies/mL at Week 48 compared to the same parameters on their baseline regimen with the same criteria at Week 24.

“Thanks to developments in HIV science, more treatment options are becoming available to address the medical needs of people living with HIV,” said Princy Kumar, Chief, Division of Infectious Diseases and Tropical Medicine at MedStar Georgetown University Hospital and Professor of Medicine and Microbiology, Georgetown University School of Medicine, Washington, DC. “The expanded indications offer certain people with HIV-1 infection, and their doctors, the choice to switch their current antiretroviral therapy to Delstrigo and Pifeltro in combination with other antiretroviral agents.”

Delstrigo and Pifeltro were first approved by the FDA in August 2018 for adults with no previous antiretroviral treatment.

It’s been a big week for Merck. In particular, the company had the unusual case of having its checkpoint inhibitor Keytruda (pembrolizumab) approved simultaneously in three countries for advanced endometrial carcinoma.

Daina Graybosh, an analyst with SVB Leerink, wrote in a note to clients that this was a “groundbreaking early-approval.”

The approval was for Keytruda plus Lenvima, Eisai’s oral kinase inhibitor, for patients with advanced endometrial carcinoma that is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), who have disease progression after previous systemic therapy and who are not candidates for curative surgery or radiation. It’s the first U.S. approval for the combination and the first time any anti-PD-1 checkpoint inhibitor has been approved in combination with a kinase inhibitor for advanced endometrial carcinoma in the U.S.

It was also approved by regulators in Australia and Canada. The trial was approved on a Phase II single-arm trial that reported an objective response rate (ORR) of 38.3%.

“We did not expect approval from the single-arm data,” Graybosch wrote. A single-arm trial doesn’t have a placebo control and is not randomized.

The approval came under a new FDA pilot program, Project Orbis. Orbis is a new, international partnership between the FDA’s Oncology Center of Excellence, the Australian Therapeutic Good Administration, and Health Canada. Project Orbis is designed to increase collaboration among international regulatory organizations that will provide patients with earlier access to new cancer therapies that are available in other countries where regulatory submission might be slower.

“We are pleased to be working alongside our Australian and Canadian colleagues to help make potentially life-changing treatments available to patients as quickly as possible while still ensuring the FDA’s high standards of safety and effectiveness,” said Acting FDA Commissioner Ned Sharpless. “As Project Orbis expands, we look forward to welcoming additional international partners to collaborate with us in this important initiative as we work to help further serve the global patient community.”

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