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Thursday, 31 July, 2025
HomeHIV/AidsOptimism as phase 3 trials launch for new monthly anti-HIV pill

Optimism as phase 3 trials launch for new monthly anti-HIV pill

An HIV prevention pill that could provide a month of protection per tablet has been approved to proceed to pivotal trials to test its efficacy, writes Elri Voigt writes in Spotlight, describing new findings on the pill, presented at the International Aids Conference in Rwanda last week.

There are several antiretroviral formulations proven to prevent HIV infection: a daily pill, two different jabs offering protection for two and six months respectively, and the vaginal ring that has to be replaced monthly.

In a few years, a long-acting pill may join the ranks, if it works.

The pill, for now called MK-8527, has the potential to prevent HIV infection for up to a month in its current formulation. It is a nucleoside reverse transcriptase translocation inhibitor (NRTTI), meaning it disrupts a specific step in the cycle by which the virus makes copies of itself.

The pill is now moving on to pivotal phase three trials, after promising results from a smaller phase two study presented at the International Aids Society (IAS) conference in Kigali, Rwanda.

The phase two study, conducted in trial sites in South Africa, the United States and Israel, showed that MK-8527 was well tolerated and had a safety profile similar to a placebo. It also showed the levels of the antiretroviral were at the required levels in the bodies of study participants, although the study was not designed to determine whether it is effective.

Whether MK-8527 actually prevents HIV infection will now be tested in two large phase three studies across multiple countries, including South Africa.

In these studies, the efficacy of the pill will be compared to a daily HIV prevention pill already available in South Africa’s public sector. The daily pill contains the ARV drugs tenofovir disaproxil fumarate and emtricitabine.

Latest findings

The phase two study looked at three different doses of the monthly pill – 3mg, 6mg and 12mg – as well as a placebo. The 350 participants, about one third of whom were from South Africa, were given one pill (either an active pill or placebo) every month for six months and monitored for at least two months. None acquired HIV during the study.

The researchers enrolled adults who were at a low risk of being exposed to HIV: they excluded pregnant and breastfeeding women, and anyone who had previously used MK-8527 or a similar ARV drug called Islatravir, said Dr Kenneth Mayer, a Professor of Medicine at Harvard Medical School, who presented the findings in Kigali last week.

The levels of the antiretroviral in participants’ blood were measured on day one and two, on the last day of taking the pill, and again at the first follow-up visit after stopping the pill. Based on these results, Mayer said there doesn’t appear to be a build-up of drug in the body that might prove toxic over time.

This supports evaluating the use of a monthly pill over a longer time period (than the six months in the study), he said “without concern that increasing drug levels will cause toxicity after a longer period of monthly administration”.

About 20 participants across the three active pill arms were monitored more closely to measure the levels of MK-8527 triphosphate in their blood at each study visit. Results showed that the 6mg and 12mg doses kept levels at “above the threshold of protection” for just more than 28 days.

There is likely to be “a cushion of forgiveness” of about one week, said Mayer. This means that for the two higher doses, a person might still be protected against HIV, even if they take the monthly pill a few days late.

Apart from staying in the body for a long time, it also seems that the drug works very quickly. Mayer told delegates that modelling, informed by measurements of how the drug is taken up in the body, suggests the pill could offer protection against HIV infection potentially as soon as an hour after taking it.

How safe is it?

Since HIV prevention medicines are offered to healthy people, or at least people who do not have HIV, the safety of these drugs is particularly closely watched. This is because the risk/benefit trade-off is different than for people who have HIV and who might be willing to accept more side effects if it means the medicines keep them alive and healthy.

The most common side effects in the phase two study were headache, nausea and fatigue. The rates of these side effects were similar between participants who got the antiretroviral pills and those who got the placebo.

When looking specifically at the study drug related side effects, Mayer said most were classified as a grade one or two. Around 5% of the side effects across all the study arms were grade three, seen as more serious.

One concerning event in the 3mg arm was a spontaneous abortion at six weeks into a pregnancy. Mayer said this was seen as a serious adverse event. Although he didn’t have all of the details, he understood that the participant had previously experienced pregnancy losses, but most, if not all, were induced.

“She did not have any other medical conditions associated with adverse pregnancy outcomes, so we had to consider the event related to the study medication, out of an abundance of caution, since this was a safety trial,” he told Spotlight.

Participants had their CD4 levels (an indicator of immune system health) and lymphocyte (a type of white blood cell) counts checked at each study visit. A significant drop in either or both indicators would lead to the drug being stopped. Mayer said CD4 and lymphocyte counts were specifically monitored because the monthly pill has the same mechanism of action as another drug called Islatravir, which in high doses resulted in a decrease in both these counts.

“MK-8527 is chemically different (from Islatravir), but since they both inhibit these steps in the virus life cycle, it was important to monitor these parameters during the safety trial,” Mayer said. “Fortunately, we did not see a significant trend affecting these clinical lab values.”

Only two participants dropped out of the study due to side effects in the two higher dose groups. One person from the 12mg arm had hypoaesthesia – a loss of sensation or numbness – while another person in the 6mg arm left because their CD4 and/or lymphocyte count dropped to levels that met the study’s rules for stopping the pill.

Another study participant’s counts also dropped to levels that meant they should stop taking the pill, said Mayer but this was only detected as they were completing the trial, so the medication didn’t have to be stopped. For both participants whose CD4 and lymphocyte counts had dropped, the levels returned to normal a few weeks after they stopped taking the drug.

In the next few years, the larger phase three studies should provide much more extensive and detailed data on the safety and side effect profile of MK-8527.

Is there a place for a monthly pill?

At last year’s Aids 2024 conference, delegates celebrated the success of the PURPOSE 1 and 2 trials that showed remarkable protection offered by lenacapavir, the long-acting HIV prevention jab, which in June, was approved for use by the US Food and Drug Administration for HIV prevention.

It has not yet been registered by the South African Health Products Regulatory Authority.

While most of the focus in HIV circles is still on lenacapavir, experts told Spotlight that even though MK-8527 may potentially only protect against HIV for about a month at a time, it could still be a useful option for HIV prevention.

“There is a real place for a long-acting, non-injectable PrEP (pre-exposure prophylaxis). And we believe there really is a role for a monthly pill – they are small, (and) easy to take,” said Professor Linda-Gail Bekker, CEO of the Desmond Tutu Health Foundation and Director of the Desmond Tutu HIV Centre.

“There is potential for giving all 12 pills in one go or three pills in one go or any variation,” she added.

“I think the world will divide into people who prefer to take pills, as opposed to those who prefer to take injectables. And for those who prefer to take pills, obviously being able to do so infrequently and/or take away just three pills and be able to cover a whole three months could be game changing,” she added.

This potential future option, provided it works, comes with financial upheaval with the sudden termination of research funding and aid by the United States. Bekker hopes a pill for prevention may be an affordable and accessible option.

“In keeping with other antiretroviral pills, there is huge hope that this would be easy to make … by generic companies, therefore very affordable, if not more so than other PrEP agents now,” she said.

“Injectables have tended to be far more expensive, being more difficult to make. So, there is … hope that this will really increase availability and accessibility once shown to be effective.”

Mitchell Warren, executive director of the Aids Vaccine Advocacy Coalition (Avac), said a monthly pill for prevention will not replace but add to the existing basket of HIV prevention options.

“It may help people who have a hard time adhering to daily pill-taking, it will help people who don't want to get an injection,” he said. “It (MK-8527) is just 12 pills a year, that's a remarkable advance.”

Next steps – the phase three trials

Merck, which is developing the pill, said that MK-8527 will be evaluated at clinical trials sites across the globe in two large phase three studies called EXPrESSIVE-10 and EXPrESSIVE-11. Starting later this year, they will determine the safety and tolerability of the pill, and whether it works as well as or better than the standard of care – the daily HIV prevention pill containing tenofovir disoproxil fumarate and emtricitabine – at preventing HIV.

EXPrESSIVE-11 aims to enrol about 4 390 people. It will include cisgender men, transgender women and men, or gender nonbinary persons aged 16 and older. This study will evaluate an 11 mg dose of MK-8527 and follow participants for at least two years – at sites across 16 countries, including South Africa, the United States, Brazil, France, and Kenya.

EXPrESSIVE-10 will also evaluate an 11mg dose of MK-8527 and follow participants for at least two years, enrolling about 4 580 adolescent girls and women, 16 and older, in sites across SA, Uganda and Kenya.

“If MK-8527 is found to be comparable or superior to daily oral PrEP, it could offer people a simple way to protect themselves, without requiring daily medication or injections,” said Mayer.

Warren said the EXPrESSIVE studies are similar to the PURPOSE studies for lenacapavir and show that the research field is becoming more inclusive by involving people who are often left out of studies, like 16- and 17-year-olds, as well as transgender men and non-binary people.

Warren added that, like the PURPOSE studies, if a woman falls pregnant during the study, she will have the option to give consent again and continue. This allows researchers to collect data on pregnant and breastfeeding women too.

The Desmond Tutu HIV Centre, which provided two trial sites during the earlier phase two study, will provide trial sites for both EXPrESSIVE-10 and EXPrESSIVE-11, said Bekker.

While results from the phase three studies are at least two years away, Merck would like to try to roll out the product as soon as possible if it is successful.

“We are pursuing very optimistic and aggressive timelines,” said Dr Rebecca Plank, a scientist in clinical research at Merck.

Spotlight article – IAS2025: Findings give hope for monthly HIV prevention pill (Creative Commons Licence)

 

See more from MedicalBrief archives:

 

Almost 40% of the world’s anti-HIV pill users live in South Africa

 

HIV prevention pill uptake in SA climbs to 1m users

 

HIV drug trial success triumph for Professor Bekker

 

 

 

 

 

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