At the end of 2021, clinical trials of two promising agents screeched to a halt, disappointing many who were excited about the prospects for long-acting HIV treatment and prevention with islatravir and injectable lenacapavir. This is why we do clinical trials, though, and they did their jobs correctly. Shout out also to independent Data Monitoring Committees.
On November 16, Merck stopped its study of once weekly oral islatravir and MK-8507, an investigational long-acting NNRTI, because the external Data Monitoring Committee (eDMC) detected a decrease in total lymphocytes and T cell counts with the combination. At the time, the changes seemed to be related to the dose of MK-8507. The next week, Merck and Gilead temporarily paused enrollment into the much-anticipated trial of once-weekly oral islatravir and lenacapavir. On December 6, at the recommendation of its eDMC, Merck paused enrollment in its two IMPOWER trials of once-monthly oral islatravir for PrEP. Just a week later, the FDA placed a partial clinical hold on seven oral islatravir/doravirine trials (no new enrollment, but existing participants continue to get medication) and a complete hold on six other islatravir treatment and prevention trials, including oral, injectable, and implant formulations. At the same time, Merck and Gilead also stopped dosing in a study of oral islatravir and lenacapavir. This may not portend the death of islatravir, but it is too soon to tell.
Lenacapavir, Gilead’s first-in-class capsid inhibitor, was being studied for treatment and prevention via subcutaneous injection every 6 months. Obviously, it needed a suitable partner for treatment, and islatravir appeared to be an excellent choice. Gilead quickly submitted a New Drug Application for lenacapavir based on promising 26-week results of the phase 2/3 CAPELLA trial in heavily treatment-experienced patients with multidrug resistant virus. As with the pivotal trial of fostemsavir, the primary endpoint was change in HIV RNA after 14 days of functional monotherapy, followed by optimization of the background therapy (OBT) and open label lenacapavir. There was also a separate nonrandomized cohort who started LEN and OBT from Day 1. These data were presented last July at the IAS Conference. The combination of injectable lenacapavir and an injectable version of islatravir was on the horizon until the FDA hold on islatravir stopped the phase I trial of the injectable formulation.
For an even worse end to 2021, on December 21, Gilead announced that the FDA had placed a clinical hold on injectable lenacapavir in all ongoing studies for treatment and prevention, due to concerns about the safety of the borosilicate glass vials. Both enrollment and dosing were stopped in 10 ongoing trials. If there is good news here, it is that there was no concern expressed about lenacapavir itself, so one hopes that Gilead will quickly solve this problem and continue on with the trials. However, if problems with islatravir are not solved, it will also be a setback for lenacapavir and LEN will be looking for another date to the prom.
Still in the pipeline are ViiV’s maturation inhibitor GSK-3640254 (called GSK-254); albuvirtide, a fusion inhibitor being developed by Frontier Biotechnologies; and a host of broadly neutralizing antibodies (bnAbs) being studied alone and in combinations for treatment, prevention, and cure. It’s clear that 2022 will be an interesting year in HIV drug development. Get your popcorn!