IDNews Uncertain Future for 2 Long-Acting HIV Therapies BY GINA SHAW
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he approvals have been put on hold for two major new long-acting HIV therapies, lenacapavir (LEN, Gilead) and islatravir (ISL, Merck)—for two very different reasons, and likely with very different long-term results. On March 3, 2022, the FDA issued a complete response letter for the New Drug Application for LEN, an investigational, longacting treatment for people with multidrug-resistant HIV infection that is administered subcutaneously every six months. The FDA cited issues with chemistry manufacturing and controls for the drug, specifically that the medication is not compatible with the proposed borosilicate glass vial, which contains boron trioxide to prevent cracking. The ongoing CAPELLA trial had been suspended in December 2021 because of these concerns. The most recent clinical data on LEN, presented at CROI 2022 in February, indicated that LEN, in combination with other antiretrovirals, achieved high rates of virologic suppression and clinically meaningful increases in CD4 counts in people living with HIV whose virus was no longer effectively responding to their current therapy (poster H03). There were no drug-related serious adverse events (AEs) in the study, and the most common AEs were mild to moderate injection site reactions (63%), nausea and diarrhea (13% each), and COVID-19 (11%). Gilead’s chief medical officer, Merdad Parsey, MD, PhD, said in a statement that the company will work with the FDA to identify a solution to the problem. “Gilead intends to provide FDA with a comprehensive plan and corresponding data to use a different vial type,” he said. “We look forward to discussing this further with FDA over the coming months so that we can make this investigational new therapy available to people living with multidrug-resistant HIV as soon as possible.” The vial compatibility issue is unlikely to present a longterm hurdle for LEN, said Melissa Badowski, PharmD, MPH, a clinical associate professor in the Section of Infectious Diseases Pharmacotherapy for the University of Illinois at Chicago College of Pharmacy and founding chair of the American College of Clinical Pharmacy’s HIV Practice and Research Network. “It’s reminiscent of the delay with Cabenuva [cabotegravir-rilpivirine, ViiV Healthcare], when the FDA rejected the application in December 2019 relating to chemistry and manufacturing controls, and then it took about a year for them to come back and get approval,” she told Infectious Disease Special Edition. “They just need to identify a different vial, and I think that will be very easy to navigate for them. The data look pretty good otherwise, so hopefully there will be no additional hiccups.”
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A Different Story The situation is different with Merck’s ISL, which also halted trials in December 2021. Islatravir, a first-in-class nucleoside reverse transcriptase translocation inhibitor with multiple mechanisms of action, was being investigated both in HIV prevention and treatment. But after small decreases in CD4 counts were identified in the ILLUMINATE SWITCH and IMAGINE-DR treatment trials, and dose-dependent decreases in total lymphocyte counts were found in the IMPOWER phase 2 prevention trials, Merck paused enrollment studies. On Dec. 13, 2021, the company announced that the FDA had placed a full clinical hold on five trials of oral and implant formulations of ISL for prevention and a study of injectable ISL, as well as a partial clinical hold on seven trials of oncedaily ISL plus doravirine for HIV treatment. (The partial hold means that participants in the trials will still continue to receive the medication with more frequent CD4 monitoring, but no new participants will be enrolled.) “Obviously, we want the CD4 count to go up, not down,” Dr. Badowski said. “Even though the CD4 decline was only in some patients, it was enough to cause a signal that halted enrollment. “It’s still too early to know if this drug will move forward or not, if they can identify what led to the CD4 decline. This is disappointing, but it’s actually a good thing to see that the issue has been identified. This is why clinical trials are done.” Despite these setbacks, Dr. Badowski said, the injectable long-acting HIV treatment and prevention realm is poised to explode. “There are a lot of patients who would like to go on a longeracting injectable,” she said. “It’s much more discreet when you don’t have to have bottles of HIV medication with you in your bag. I think this is going to be a very important option for patients to have. “In January 2021, we had the approval of the first long-acting injectable for treatment, cabotegravir-rilpivirine, but that is for virologically suppressed patients who are taking medications and doing well already. We need to have options in the future to help those who are more treatment-experienced as well as those who are treatment-naive and looking for discreet ■ dosing options.” Dr. Badowski reported no relevant financial disclosures.
