Potential for once-monthly oral PrEP using MK-8527

Another conference highlight included results from a large pharmacokinetic study of MK-8527 which is a follow-on NRTTI to islatravir that is being studied in a once-monthly oral formulation as PrEP. [1]

This was a phase 2 double-blind, multicentre study that randomised 350 adults (2:2:2:1) at low risk of HIV to one of three doses of MK-8527 (3, 6, or 12 mg) or matched placebo, given monthly for six months. This was an international study with sites in Israel, South Africa and the US. Safety follow-up continued for a further 8 weeks.

Baseline characteristics included median age 28 years, 58% women, and 51% white, 41% Black/African American, 2.3% Asian.

Results

Overall, 328/360 (93%) received all six doses and pharmacokinetics were generally dose-proportional.

Tolerability and side effects were good in all arms, with no significant differences in the active vs placebo groups. This included no differences between arms in changes in total lymphocyte and CD4 count, although this did lead to one discontinuation in the 6 mg arm (grade 1, reduced by 36% but with a CD4 nadir of 313 cells/mm3, resolved after discontinuation).

PK results (Tmax and AUC) were dose-proportional with no evidence of the intracellular accumulation of the active triphosphate that led to the discontinuation of islatravir for monthly PrEP. Both the 6 mg and 12 mg doses produced drug exposure above the predicted levels needed for protection, including in PBMCs that persist for a further week, indicating window for dosing. Predicted protective levels were also achieved quickly, perhaps within an hour of dosing.

Importantly, these data support further development and two large international phase 3 studies in people at higher risk of HIV are planned to open later in 2025.

EXPRESSIVE 10 will enrol 4580 adolescent girls and young women in Kenya, South Africa and Uganda and EXPRESSIVE 11 will enrol 4390 gay and bisexual men, transgender and non-binary people in Argentina, Brazil, Chile, Columbia, Dominican Republic, France, Guatemala, Kenya, Malaysia, Peru, The Philippines, South Africa, Switzerland, Thailand, USA and Vietnam.

These preliminary results are very promising, as previous preclinical and early studies with islatravir indicated similar pharmacokinetics that would support monthly oral dosing that would support both PrEP and PEP.

If effective in phase 3 studies, once-monthly oral PrEP could easily be as highly acceptable as six-monthly injections.

Oral NRTTIs are much easier to manufacture and distribute than injectable drugs, which would also help with generic formulations and global distribution. A foil strip with 12 small tablets would be innocuous and would cover a year of treatment, perhaps with a 7-day window for monthly dosing.

Single tablets, especially if effective as PEP, could easily broaden to over-the-counter access, with minimal safety risks in ways that would be much more difficult with injections.