GSK's First-in-Class HIV-1 Maturation Inhibitor GSK3640254 Shows Positive Proof-of-Concept in Phase IIa Study

On March 9, ViiV Healthcare, a subsidiary of GSK, announced positive data from the Phase IIa proof-of-concept study of GSK3640254, demonstrating a favorable dose–antiviral effect relationship, with the 140 mg and 200 mg dose groups showing significant reductions in plasma HIV-1 RNA viral load. Detailed data will be presented at the Conference on Retroviruses and Opportunistic Infections (CROI 2021).

GSK3640254 is an HIV-1 maturation inhibitor, a class of antiretroviral agents targeting the late stage of the HIV-1 life cycle. It blocks HIV-1 replication by inhibiting the activity of key enzymes at this stage, leading to the formation of immature viral particles. Due to its distinct mechanism of action compared with currently available antiretroviral drugs, GSK3640254 has the potential to provide a new therapeutic option for individuals with resistance to other anti-HIV-1 treatments.

This Phase IIa study employed an adaptive design comprising two stages to evaluate the antiviral activity, safety, and tolerability of once-daily GSK3640254 in 34 treatment-naïve adults with HIV-1 infection. In Stage 1, participants received GSK3640254 at doses of 10 mg or 200 mg, or placebo, for 10 days. Prespecified interim analysis results revealed the emergence of treatment-related resistance mutations in the 200 mg group following completion of dosing. In Stage 2, participants received GSK3640254 at doses of 40 mg, 80 mg, or 140 mg, or placebo, for 7 days. The primary endpoint was the maximum change in plasma HIV-1 RNA load from baseline in Stages 1 and 2. Secondary endpoints included safety, tolerability, and pharmacokinetic parameters.

The results showed that at the end of the study, the maximum mean changes in viral load in the 140 mg and 200 mg groups were -1.5 log10 and -2.0 log10 copies/mL, respectively. Throughout the study, GSK3640254 was well tolerated, with no discontinuations due to adverse events and no reported deaths. A total of 22 subjects (65%) reported adverse events, the most common being headache (n=4).

Kimberly Smith, Head of Research and Development at ViiV Healthcare, stated, “Treatment failure with antiretroviral therapy is very common among patients with HIV-1 infection over their lifetime; therefore, there is a need for drugs with novel mechanisms of action to combat the epidemic of this infectious disease. Previously, there were no drugs targeting the maturation stage of the HIV-1 virus, so maturation inhibitors have the potential to help meet critical clinical needs, particularly for patients who have developed resistance following prior treatment.”

BMS also announced positive data from a Phase IIa proof-of-concept study of BMS-955176, a maturation inhibitor co-developed with ViiV Healthcare, in July 2015. However, as BMS shifted its business focus away from the antiviral field, the project has seen no progress for a long time, and its current development status is unclear. There are a few other maturation inhibitors globally, but they have all been terminated. Currently, GSK is the only player remaining in this target area.

ViiV Healthcare has initiated a Phase IIb study of GSK3640254 to evaluate the efficacy, safety, and tolerability of this maturation inhibitor as part of combination therapy in treatment-naïve adults with HIV-1 infection.