RT x HIV-1 protease

Katherine Welles After enduring nine months of clinical holds, Merck announced that it is restarting the Phase III clinical program for islatravir, its candidate for people with HIV-1 infection. Katherine Welles/Getty Images After enduring nine months of clinical holds, Merck is restarting the Phase III clinical program for islatravir, its candidate for people with HIV-1 infection, the company announced Tuesday. The pharma giant is launching three Phase III studies, all assessing islatravir together with its approved HIV-1 drug Pifeltro (doravirine). Two trials will look at the potential of the combo in virologically suppressed HIV-1 patients, while the other will assess its performance in patients who had not yet been treated. Crucially, all three trials will use a lower dose of islatravir than what was used during the previous clinical program. Designed as a once-daily oral treatment, islatravir is an investigational nucleoside reverse transcriptase translocation inhibitor (NRTTI) that stops the infection by blocking a key enzyme HIV-1 needs to integrate into the host’s DNA. The compound interferes with the virus’ replication through many different mechanisms and demonstrates strong antiviral activity against HIV variants that have evolved resistance against common drugs. In early , mid-stage and even later studies, islatravir performed promisingly, leading to high rates of durable virological suppression. The company even saw success with testing islatravir as pre-exposure prophylaxis (PrEP) against HIV-1. However, late last year, patients treated with islatravir in a Phase II trial met a worrying decline in lymphocyte and CD4+ T-cell counts, which made them susceptible to infections. Not long after, the U.S. FDA slapped clinical holds on all of the candidate’s investigational new drug applications. This included its oral and implantable PrEP formulations, as well as its injectable form and once-daily oral combo with Pifeltro for the treatment of HIV-1. All told, 13 islatravir trials were suspended . A Revitalized Program The renewed Phase III clinical program, which the FDA has greenlit, hinges on a lower dose of islatravir, combined with 100 mg of Pifeltro. Patients previously treated with the higher 0.75-mg islatravir dose can transition into a study that dispenses lower doses of the candidate. Studies seeking to re-assess islatravir at its previous dosing regimen will remain on hold. “Based on our internal evaluations, lower doses of islatravir were identified that we anticipate will have comparable effects on lymphocyte and CD4+T-cell count as other standard of care antiretroviral regimens,” a Merck spokesperson told BioSpace . “The FDA reviewed the comprehensive data that we provided and agreed that we can proceed with lower doses of islatravir.” Alongside the new Phase III program is a Phase II clinical trial testing out the lowered-dose islatravir used in combination with Gilead’s lenacapavir in virologically suppressed adults living with HIV-1. The islatravir-lenacapavir combo, designed to be taken orally once per week, remains investigational. Its safety and efficacy have yet to be established. Merck is also planning a Phase Ib study for another NRTTI candidate, MK-8527, also for the treatment of adults with HIV-1. Despite the release of its clinical holds and the revival of its HIV-1 program, Merck has decided to drop the investigation and development of islatravir as a once-a-month oral PrEP pill. Pharmacokinetic studies could not find an ideal lower dose that would yield sufficient preventive efficacy without triggering a worrying drop in lymphocyte counts. “Merck continues to believe in the potential of the nucleoside reverse transcriptase translocation inhibitor (NRTTI) mechanism and is evaluating additional compounds with the goal of helping to address unmet needs in HIV prevention,” the spokesperson added.

Courtesy of Kena Betancur/Getty Images As of now, six studies related to islatravir are on full clinical hold, while seven are on partial clinical hold. Here are more updates on the development of this drug. Recently FDA announced a pause in various trials of the HIV-1 drug islatravir. (Kena Betancur/Getty Images) On Monday , Merck & Co. announced that the U.S. Food and Drug Administration had placed holds on several clinical trials for the oral and implant formulations of investigation drug islatravir (MK-8591) for HIV-1 pre-exposure prophylaxis (PrEP), the injectable formulation of islatravir for HIV-1 treatment and prophylaxis and the oral doravirine/islatravir (DOR/ISL) HIV-1 once-daily treatment. As of now, six studies related to islatravir are on full clinical hold, while seven are on partial clinical hold. Islatravir is an inhibitor of nucleoside reverse transcriptase translocation designed to be administered once every month to patients at increased risk of or suffering from Human Immunodeficiency Virus (HIV) infection. Why Did FDA Decided to Pause the Trials of Islatravir? The FDA’s move is based on observations of a drop in T-cell counts in some participants receiving the drug. T-cells are critical to proper functioning of the immune system, which helps the body fight infections upon encountering pathogens. Studies showed a decline in total lymphocyte and CD4+ T-cell counts across different company-sponsored trials of islatravir at varying dose levels. There was a dose-dependent reduction in lymphocyte counts in a Phase II study of patients at low risk of HIV-1 infection, though this did not cause clinical adversities. In another two Phase III trials studying islatravir in HIV-1 virologically suppressed patients, a small treatment-related mean reduction in CD4+ T-cell counts was noted. Addressing the issue, Dr. Joan Butterton, vice president, infectious diseases, global clinical development at Merck Research Laboratories said, “We are grateful to the participants and the study investigators for their ongoing contributions to this research. Merck continues to investigate the potential of islatravir and nucleoside reverse transcriptase translocation inhibitors and remains committed to helping to address unmet needs in HIV treatment and prevention.” On November 18, Merck announced that it had paused its Phase II IMAGINE-DR trial of a combination of MK-8507, a non-nucleoside reverse transcriptase inhibitor, and islatravir. Then, on November 23, Gilead Sciences and Merck jointly announced they were pausing a Phase II trial of islatravir and lenacapavir in patients who are virologically suppressed on antiretroviral therapy. This was followed by Merck’s decision, reported last week, to pause enrollment in two Phase III trials of islatravir (MK-8591) The company said the temporary enrolment pause would enable it to conduct further analyses of the two Phase III trials, along with other ongoing studies. Based on the recommendation of the islatravir External Data Monitoring Committee (eDMC), Merck was supposed to implement additional monitoring measures, including more frequent assessments of total lymphocyte and CD4+ T-cell counts. However, now owing to the FDA clinical hold, participants who were receiving the drug, in any formulation, as part of the studies, will stop receiving it henceforth. No new studies related to the drug can be initiated while FDA’s clinical holds are in place, Merck said.

Pictured: Gilead sign in front of tree_JOSH EDELSO If approved, lenacapavir would be offered to HIV patients who have been heavily treated for the disease and have multi-drug-resistant HIV. JOSH EDELSON/AFP via Getty Images Gilead Sciences is aiming to win regulatory approval for the first HIV-1 treatment administered twice per year. On Monday, the company submitted a New Drug Application to the U.S. Food and Drug Administration (FDA) for lenacapavir, an investigational, long-acting HIV-1 capsid inhibitor. If approved, lenacapavir would be offered to HIV patients who have been heavily treated for the disease and have multi-drug-resistant HIV. The NDA is supported by data from the Phase II/III CAPELLA study assessing a subcutaneous formulation of the experimental drug. In the Phase II/III study, lenacapavir hit its primary endpoint by demonstrating an 88% efficacy in reducing the viral load of at least 0.5 log10 copies/mL from baseline compared to placebo. Additionally, those who received lenacapavir achieved a statistically significantly greater mean decrease in viral load than those on placebo. Gilead Sciences, which has three of the top four best-selling HIV drugs on the market, is planning to present complete data from the CAPELLA study at the International AIDS Society (IAS) Conference on HIV Science next month. Lenacapavir was generally well-tolerated. There were no serious adverse events related to the drug observed during the 14-day dosing period. The NDA comes weeks after the world marked the grim milestone of HIV’s 40th anniversary . Since it first raised its head, the virus has taken the lives of more than 35 million people across the globe. According to HIV data from the United Nations, in 2019, the most recent year with complete data, 1.7 million people were infected with HIV, and 690,000 died of AIDS-related causes. Currently, about 1.1 million Americans are living with HIV infection. It is estimated that 38,000 Americans are diagnosed with the infection each year, down significantly from peak infections. Gilead Sciences’ lenacapavir is a novel investigational capsid inhibitor that interrupts the activity of HIV capsid, a protein that surrounds and protects the virus’ genetic material and essential enzymes. In in vitro studies, lenacapavir interrupts multiple distinct stages of the viral lifecycle, potentially preventing the virus from becoming infectious and gaining access to uninfected cells. The FDA granted Breakthrough Therapy Designation to lenacapavir in 2019. Chief Medical Officer Merdad Parsey called lenacapavir a vital breakthrough innovation for HIV-1 patients who are multi-drug resistant and have few treatment options. The NDA filing moves the company one step closer to providing an “innovative treatment option that helps to address barriers to achieving viral suppression and meet the unmet needs of people living with multi-drug resistant HIV,” Parsey said in a statement. Gilead plans to submit marketing authorization applications for lenacapavir to the European Medicines Agency and other regulatory agencies in the coming months. Lenacapavir is being developed in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients. Earlier this year , Gilead Sciences and Merck teamed up to pair lenacapavir with Merck’s investigational nucleoside reverse transcriptase translocation inhibitor, islatravir. Both investigational drugs are potentially first-in-class medicines. It is thought the combination of the two medications could provide a new option of less frequent dosing for HIV patients.