MSD/Merck stop once-weekly NNRTI MK-8507: islatravir studies continue with closer monitoring
30 November 2021. Related: Antiretrovirals.
On 18 November 2021, a press release from MSD/Merck included top line concerns about an investigational NNRTI currently being studied with islatravir as a component of once-weekly oral ART.
The statement reports decreases in total lymphocyte and CD4 counts in participants receiving MK-8507 + islatravir that were dose-related to the NNRTI and were sufficient for dosing to be stopped.
The press release notes that the company are confident in the profile of islatravir and that both treatment and prevention studies with this compound are continuing.
However it also reports that a review of other ongoing studies reported small and non-significant mean changes in total lymphocyte counts. This included a decrease in HIV negative people using once-monthly islatravir as PrEP at 60 mg and 120 mg that was dose-dependent, but that remained within the normal range.
It also included small mean CD4 decreases in two phase 3 switch studies (ILLUMINATE A nd B) – using daily dual ART with doravirine and islatravir (0.75 mg) – both of which are continuing.
The development of MK-8507 is now on hold.
This is very disappointing news.
It shows the difficulties in drug development even after promising compounds have cleared in vitro, animal studies and phase 1 studies.
A conference call with community advocates shortly after the press release included additional details on these early findings. This included the significance of the mean dose-related reductions in both total lymphocytes and CD4 T cells in the highest dose (400 mg) MK-8507 group. Mean reductions of 17%, 26% and 30% in total lymphocytes and 11%, 23% and 30% in CD4 T cells were seen in the 100 mg, 200 mg and 400 mg MK-8507 groups.
It also included details of reductions in total lymphocyte counts in ongoing islatravir studies.
For example, mean reductions of 21% and 36% were seen in the phase 2 PrEP studies in HIV negative people, at the 60 mg and 120 mg arms monthly dose respectively (vs +4% increase in the placebo group).
While mean reductions are still within the normal range, and no individuals went below this range, this might require new entry criteria for these studies.
Although the mean CD4 reductions at week-48 in ongoing treatment experienced phase 3 studies using daily islatravir with doravirine are small, larger CD4 reductions have been experienced by a minority of participants.
The company emphasised that these signals are being taken seriously and that participant safety remains central to continued research with all investigational compounds.
No increase in side effects have been reported. Increasing monitoring will be added to all studies in discussion with investigators.
Merck press release. Merck provides update on phase 2 clinical trial of once-weekly investigational combination of MK-8507 and islatravir for the treatment of people living with HIV-1. (18 November 2021).
This report was first posted on 19 November 2021, with updated comments and a changed in the title on 24 November 2021.