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Islatravir returns to clinical trials

In late 2021, the pharmaceutical company Merck announced that it had suspended many clinical trials with the experimental anti-HIV drug islatravir. This suspension arose because interim data analyses from clinical trials had found that some people who were given relatively large doses of this drug (0.75 mg and 2.25 mg per day) developed lower-than-normal levels of a certain group of cells in their blood.

The cells in question are called lymphocytes (T-cells, B-cells and natural killer cells). These cells are needed to contain infections and tumours and regulate the immune system. Fortunately, none of the people who took relatively high doses of islatravir and who developed low lymphocyte levels became ill.

The reductions in lymphocyte levels occurred during the first year of use of high-dose islatravir and then stabilized. That is, no further decreases occurred while people were taking high-dose islatravir. This is reassuring and suggests that no permanent injury occurred. Furthermore, once people stopped taking high-dose islatravir or were switched to a lower dose (0.25 mg per day), recovery of lymphocyte levels gradually ensued. In some people this recovery took longer than six months. Researchers are continuing to monitor all people who took high-dose islatravir.

A safer, lower dose of islatravir

Scientists at Merck have since undertaken in-depth analyses of different doses of islatravir in lab experiments with cells and animals and other experiments with people. Their analyses suggest that using a lower dose of islatravir (0.25 mg per day) is likely much safer. So far, no decrease in lymphocyte levels have been found in people who have used this lower dose.  The 0.25 mg per day dose will be used in several clinical trials that are planned to start in the first half of 2023.

In some trials Merck will be testing a combination of low-dose islatravir with another anti-HIV drug called doravirine (Pifeltro). This latter drug is already approved for HIV treatment. The approach with reduced-dose islatravir for clinical trials has been approved by regulatory authorities in the U.S. (the Food and Drug Administration) and other high-income countries. Merck will test low-dose islatravir in the following populations:

  • people with HIV who have not previously taken treatment
  • people with HIV who are taking treatment and have a suppressed viral load and who will change to an islatravir-based regimen

Merck is cooperating with another company called Gilead Sciences to develop a combination of islatravir + lenacapavir (the latter is made by Gilead). Both companies will test a combination of two drugs: lenacapavir (mentioned in detail later in this issue of TreatmentUpdate) and low-dose islatravir.

PrEP

Merck was testing islatravir taken once monthly for its ability to reduce the risk of HIV infection. Using drugs to reduce the risk of getting HIV is called pre-exposure prophylaxis (PrEP). However, due to previously mentioned issues with high-dose islatravir, this trial was halted. Merck does not plan to resume testing once-monthly islatravir with a lower dose of this drug.

Islatravir as a model for new drugs

Islatravir belongs to a new class of drugs called HIV reverse transcriptase translocation inhibitors (RT translocation inhibitors). This class of drugs interferes with the functioning of a vital viral enzyme called RT, which is needed to help HIV infect cells. Translocation inhibitors also interfere with HIV’s ability to take over a cell and hijack its functions. It is possible that translocation inhibitors have other actions against HIV that are less well understood. Islatravir is a model of the first translocation inhibitor to enter clinical trials.

A new drug

Merck has also developed another experimental anti-HIV drug with the code name MK-8527. It is also a translocation inhibitor acting against RT. It is likely that this drug has potential for long-acting therapy. However, at this time, the focus of the study of MK-8527 is safety and to determine how long the drug remains in the body.

—Sean R. Hosein

REFERENCES:

  1. Merck. Merck to initiate new phase 3 clinical program with lower dose of daily oral islatravir in combination with doravirine for treatment of people with HIV-1 infection. Press release. 20 September 2022.
  2. Auger A, Beilhartz GL, Zhu S, et al. Impact of primer-induced conformational dynamics of HIV-1 reverse transcriptase on polymerase translocation and inhibition. Journal of Biological Chemistry. 2011 Aug 26;286(34):29575-83.