Emtricitabine/Tenofovir Disoproxil Fumarate

Merck is betting that its once-monthly pill will provide an alternative to Gilead\'s twice-yearly lenacapavir injection, which has been hailed as a scientific breakthrough.\n Even with the HIV prevention waters now dominated by Gilead Science’s Yeztugo (lenacapavir), Merck & Co. is not afraid to swim deeper in. The New Jersey pharma is teaming up with the Gates Foundation to launch a pair of phase 3 trials of its once-monthly, oral pre-exposure prophylaxis (PrEP) prospect.The EXPrESSIVE-10 trial will begin enrolling women and girls across 31 sites in Kenya, South Africa and Uganda within the next few months, Merck said in a July 14 release. Another trial, EXPrESSIVE-11, will start enrolling sexually active people from 16 countries in August. Both trials aim to enroll around 4,400 people and will test whether Merck’s MK-8527 reduces the incidence of HIV compared to Gilead’s daily PrEP pill Truvada (emtricitabine/tenofovir).The Gates Foundation is providing grant funding to the International Clinical Research Center (ICRC) at the University of Washington and the University of Alabama at Birmingham to support EXPrESSIVE-10, according to the release, with the money going towards a community advisory group, patient recruitment and retention materials, while also supporting ICRC’s partnership with the trial sites.The nonprofit is also providing funds for a community advisory group, patient recruitment and retention materials for EXPrESSIVE-11. MK-8527 inhibits the reverse transcriptase enzyme that HIV uses to replicate, according to the release. The Big Pharma recently wrapped up a phase 2 trial of the asset, which revealed similar rates of adverse events between the treatment and placebo arms. The company plans to share more data from the study at the AIDS Society Conference on HIV Science in Rwanda on July 16.The public health world has been abuzz about Gilead’s twice-yearly lenacapavir injection, which was approved as Yeztugo on June 19 and has been hailed as a scientific breakthrough. An HIV physician told Mizuho Securities that she expects most of her patients to switch to Yeztugo within the next year, with the pharma projecting a peak sales potential of $8 billion per year for the drug. For MK-8527, Merck is betting that there will be a robust market of people seeking PrEP who prefer oral meds to needles.“Scientific advances against HIV have brought us further than ever imagined and are ushering in a new era in HIV prevention,” Trevor Mundel, Ph.D., president of global health at the Gates Foundation, said in the release. “With only 18% of global PrEP need currently met, there is a clear and urgent need for options like MK-8527 that may offer the ability to prevent infection. These phase 3 trials are a key step toward translating progress into longer-acting options that could help turn the tide on HIV.”The World Health Organization updated its HIV prevention guidelines on July 14 to recommend Yeztugo, with Director-General Tedros Adhanom Ghebreyesus, Ph.D., calling lenacapavir the “next best thing” in the absence of an HIV vaccine.

KIGALI, RWANDA — Three years after a safety disappointment halted earlier plans for a once-monthly HIV PrEP candidate, Merck is back in the late stages of development with a next-generation effort. The New Jersey company said Monday that it plans to move into Phase 3 next month with a once-monthly oral prevention tool for HIV, known as MK-8527. While current PrEP pills must be taken every day, MK-8527’s monthly dosing schedule would represent a significant advance for oral HIV preventatives. The drug is a nucleoside reverse transcriptase translocation inhibitor, or NRTTI. It’s an improved, follow-up version to Merck’s other NRTTI, islatravir, which the pharmaceutical maker scrapped for development as an HIV prophylactic after safety issues. MK-8527 didn’t have those same concerns, according to Phase 2 data presented Monday at the biennial International AIDS Society conference on HIV Science, taking place in Kigali, Rwanda. “We’re not seeing an issue with lymphocytes and CD4 cells” with MK-8527, Luisa Stamm, associate VP and section head for HIV at Merck, said in an interview with Endpoints News . There were “no clinically meaningful changes” in lab tests, including total lymphocyte and CD4 T-cell counts, the company said. A total of 350 people at low risk for HIV were enrolled in the placebo-controlled study , including 51.4% white individuals, 41.4% Black participants and 2.3% Asian enrollees. About 94% of participants received all six monthly doses. “The top-level, bottom-line is that it was safe and well tolerated,” Ken Mayer, presenting author of the study, said in an interview with Endpoints on the sidelines of IAS. While Merck scrapped development of islatravir for PrEP in 2022, it carried forward with the drug as an HIV treatment. The company modified the dosing regimen and ran new clinical trials, and the FDA accepted a new application for a two-drug regimen of islatravir and doravirine as a once-daily, oral treatment for adults with HIV-1. An approval decision is slated for April 28, 2026, Merck said last week. Like islatravir, MK-8527 is also an NRTTI. “It inhibits both transcription and translocation, so that’s why it’s particularly potent. One molecule inhibits two steps of the virus life cycle,” Mayer said. The long period between doses has to do with how the body metabolizes the drug. “It’s converted to its active form intracellularly, and that triphosphate has a very long half-life, which enables this monthly dosing,” Stamm said. “Half-life is about 10 days, so that really allows us to predict with that low 11 mg dose that we’ll be above that target efficacy threshold.” Next month, Merck plans to dose the first participant in a 4,390-person Phase 3 trial in people at risk for HIV. The EXPrESSIVE-11 trial will include people in more than 15 countries and will test MK-8527 against daily Truvada, also known generically as emtricitabine/tenofovir disoproxil fumarate, or FTC/DTF. “When we think about globally, FTC/TDF is the most accessible standard of care, so we thought that was the first good reason” for making it the comparator, Stamm said. The second main reason, she said, was that Merck wanted to do a direct comparison to another oral drug, rather than long-acting injectables, which have shown strong results in preventing PrEP. The US federal trials database lists an estimated study completion of October 2027, but Stamm cautioned that the trial will be event-driven, rather than time-driven. Later this fall, Merck also plans to begin a separate Phase 3 of MK-8527 in conjunction with the Gates Foundation, which is one of the largest funders of HIV work globally and has been a partner of Merck on other programs, including islatravir. That Phase 3 trial, called EXPrESSIVE-10, will include women and adolescent girls in Kenya, South Africa, and Uganda. For the sub-Saharan Africa study, the Gates Foundation will provide grant funding to the International Clinical Research Center within the University of Washington Department of Global Health and in partnership with the University of Alabama at Birmingham. The move into late-stage testing with MK-8527 could be a pivotal moment for preventing new acquisitions of HIV. Despite the availability of daily oral PrEP pills and long-acting injectables, the world is well behind global organizations’ targets for PrEP uptake. The United Nations had a goal of getting at least 21.2 million annual PrEP users in 2025. Nine million initiations have been made, the AIDS Vaccine Advocacy Coalition (AVAC) said in a June report . “We know from the contraception literature that the more clinical options you offer people, the larger the number of people who will be accessing at least one option. People cycle through things,” Mayer said. If successful, Merck’s tablet would provide a potentially easier-to-access tool than the two approved long-acting injectables. GSK’s ViiV Healthcare markets a once-every-two-month PrEP injectable called Apretude, and Gilead secured FDA approval for a twice-yearly shot, called Yeztugo, this summer. For nearly a decade, daily pills were the only PrEP option prior to the approval of the injectable Apretude in late 2021. A tablet could come with fewer manufacturing challenges, and would be easier to take than an injection. But questions remain as to what requirements would be put in place for HIV testing frequency and how many of the monthly tablets people would be able to get from the pharmacy at one time. “There are a lot of ways that we could make it a lot easier for people and make it appealing, and there are a lot of ways that the crazy system in the US could make it very difficult,” Mayer said. As Merck runs its Phase 3 trials, a key question will be access and cost, should the tablet pass muster. “We could be on the verge of an HIV prevention revolution that reduces new infections towards epidemic control—if the world comes together again to overcome monopolies, drive down prices, and ensure everyone who could benefit has access to these new, highly effective prevention tools,” Winnie Byanyima, UNAIDS executive director, said in an annual report released last week. Byanyima appears to have directly pointed to Merck’s MK-8527 in her remarks, referring to the potential of monthly tablets potentially becoming a “reality” to prevent HIV “within the next few years.” Price has also been an issue. Advocates have criticized the price of ViiV’s Apretude and Gilead’s Yeztugo. ViiV has a generic manufacturing licensing agreement via the Medicines Patent Pool, or MPP, a United Nations-backed organization that helps countries secure access to critical medicines. Gilead has a pact with six generic manufacturers, but not by way of MPP. Merck is already pondering how MK-8527 could be rolled out. “It’s not too early to be planning for this. We’ve been thinking about it a lot, also looking at what others are doing,” Stamm said. Merck has a history of working with governments and organizations like the Gates Foundation for “ensuring broad and sustainable accessibility,” Stamm said. As an example, she pointed to Merck’s voluntary licensing agreement with MPP for the investigational antiviral molnupiravir during the Covid-19 pandemic. “There we were really successful, through voluntary licensing, to get supply available for high- and middle-income countries essentially at the same time,” Stamm said. “I think we’ll take the same approach, is our early thoughts here, when we’re thinking about 8527.”