CROI 2021: Once-daily GSK254 maturation inhibitor as treatment for HIV multidrug resistance

CROI 2021 included several studies on an investigational second-generation maturation inhibitor GSK3640254 (GSK254) that is active against natural polymorphisms that limited efficacy of the first compounds in this class.

Maturation inhibitors work at a late stage of the viral life cycle blocking the final protease cleaving and assembly and resulting in immature and noninfectious virions

Christoph Spinner presented results from a phase 2a two-stage dose-finding study in 34 treatment-naïve participants (n=6 per dose and n=2 placebo in each stage). Oral dosing was once-daily and given with a moderate fat meal.

Mean age was 31, 94% were men and mean baseline viral load range from about 15,000 to 65,000.

In stage 1, participants were randomised to either 10 mg of 200 mg for ten days. In part two, doses were 40 mg, 80 mg or 140 mg for seven days. Follow-up in stage 1 continued without treatment from days 11 to 17, with ART started on day 18. In stage 2, ART was started on day 8.

Changes in viral load were roughly proportional to dose, with mean changes in plasma viral load ranging from −2.0 to 0.2 log copies/mL. The greatest mean reductions of –2.0 and –1.5 log were greatest in the 200 mg and 140 mg groups, respectively.

However, 4/6 participants in the 200 mg arm in stage 1 developed drug resistance at day 11 with A364A/V partial mixed variant which by day 21 had developed into the full mutation in 1/4 with 132-fold phonotypic resistance. No resistance was seen in the 10 mg arm. but these results promped the reduction to 7 days monotherapy in stage 2 (and where no drug resistance was reported).

Tolerability was good with all adverse events at grade 1 or 2 and no dose signal. The only two serious events (anal abscess and congestive cardiomyopathy) were not judged related to the study drug.

A second study, GSK254 retained activity against a panel of clade B and C viruses with site directed mutations in gag (including V362I, V370A, Δ370, or R286K/V370A) that had limited activity of earlier maturation compounds, but showed a significant loss of sensitivity to A364V.

Median EC50 values were 1.4 nM (range: 0.48 to 6.9 nM) and 1.4 nM (range: 0.85 to 1.9 nM) for Subtype B and C respectively and the study also reported in vitro studies clarifying the mechanism of action.

The phase 2b study, also in treatment naïve, is planned to use 100 mg, 150 mg and 200 mg with 2 NRTIs.

comment

As with all drugs in new classes, maturation inhibitors would be active against resistance to other drug classes. GSK254 shows good antiviral activity.

The early cases of drug resistance though show a lower genetic barrier to drug resistance than PIs and NNTRIs and this will make it essential to be used in combination with other active drugs.