木瓜直播

Treatment with an HIV maturation inhibitor known as GSK3640254 -- or the catchy name of GSK'254 for short -- appeared to dramatically lower viral load in a proof-of-concept phase IIa clinical trial, researchers reported.

In a 7-day trial that tested multiple doses of GSK'254, viral loads were reduced by a factor of 50 with a dose of 140 mg and by a factor of 100 with a 200-mg dose, according to Christoph Spinner, MD, of Technical University of Munich, who presented the findings at the .

Phase III trials will test GSK'254 at doses of 100, 150, and 200 mg in once-daily dosing, Spinner said, in combination with two nucleoside reverse transcriptase inhibitors in treatment-naïve individuals.

In the current trial, five groups of six patients with HIV infection received doses ranging from 10 mg to 200 mg once daily, and another group of four patients were given placebo as a control arm. About 65% of the patients given the active treatment experienced some adverse event, and nine experienced what researchers considered treatment related adverse effects -- mainly gastrointestinal events at Grade 1 or Grade 2. "No adverse events led to discontinuation of treatment, and there were no deaths in the study," Spinner said in his oral presentation.

Maturation inhibitors are a class of antiretroviral medicines that target the late stage of the HIV viral life cycle, he explained. In particular, they block enzyme activity necessary to complete replication, resulting in the formation of immature virus particles.

Because this uses a different mechanism of action than current antiretrovirals, they could be a new option for individuals showing resistance to existing agents, Spinner suggested.

Maturation inhibitors have been advanced before, but they have failed due to development of resistance. And that problem reared its head again with GSK'254.

The two-part phase IIa study was adaptive in design. In part one, participants received GSK'254 at 10 or 200 mg, or placebo for 10 days. A planned interim analysis showed treatment-emergent resistance-associated mutations in the 200 mg arm after dosing was complete. As a result, in part two, participants received GSK'254 at doses of 40, 80, or 140 mg, or placebo, for a shortened period of 7 days. The primary endpoint was the maximum change in plasma HIV-1 RNA during parts one and two while secondary endpoints measured safety, tolerability, and pharmacokinetic parameters.

Joseph P. McGowan, MD, medical director at Northwell Health HIV Service Line Program, Manhasset, New York, told 木瓜直播, "This study reports on a second-generation maturation inhibitor. The first generation (beviramat) was dropped during development due to high rates of pre-existing inherent resistance (natural polymorphisms) that affected up to 50% of viral strains.

"The newer agents lack that baseline resistance. They work at a step that is complementary to the protease inhibitors at the final stage of viral maturation when the long polypeptide strand consisting of the virus' structural and enzymatic components must be cleaved into their active form," he explained.

McGowan, who was not involved in the study, noted that the study showed a positive dose-response relationship. But at the same time, the findings related to resistance were concerning.

"Unfortunately, if dosing was extended beyond 7 days, resistance mutations were rapidly selected in [four] of the six patients at the highest dose, with a quarter selecting phenotypically resistant virus. This would suggest that the drug has a low barrier to resistance and would function best if combined with at least two other active drugs, unless one had a high resistance barrier (such as a second-generation integrase inhibitor)."

Still, he agreed that "the drug was well tolerated and should advance to later phase study."

Spinner noted that troublesome resistance has always been the bane of HIV therapy. "Because of HIV's tendency to develop resistance to treatment over time, there is a need to improve the number of treatment options available for people living with HIV," he said. "The antiviral, safety, and tolerability findings observed in this proof-of-concept study show the potential of this maturation inhibitor and warrant its continued study as an effective new treatment option for people living with HIV."