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Phase IIa clinical results for novel HIV-1 maturation inhibitor (GSK'254) released

Once-daily monotherapy with the next-generation HIV-1 maturation inhibitor GSK364054 (GSK'254) was found to be safe, effective and well-tolerated in adults not receiving treatment for HIV infection, according to the results of a global phase IIa double-blind, randomized, placebo-controlled trial published in Clinical Infectious Diseases.

Results from previous trials suggest that GSK'254 monotherapy is safe and effective in otherwise healthy HIV-infected adults, and that GSK'254 does not cause drug interactions in combination with dolutegravir or tenofovir alafenamide/emtricitabine. In this Phase IIa proof-of-concept trial, researchers aim to evaluate the antiviral efficacy, tolerability and pharmacokinetics of GSK'254 in treatment-naïve HIV-infected adults.

In the first part of the trial, patients received 10 or 200 mg doses of GSK'254 or placebo for 10 days. Eligible patients were between 18 and 65 years of age, had HIV infection, weighed greater than or equal to 50 kg (men) or 45 kg (women), and had a BMI between 18.5 and 31.0 kg/m2. In addition, all patients were not receiving antiretroviral therapy (ART), had a plasma HIV RNA viral load greater than or equal to 5000 copies/mL, and had a CD4+ T cell count greater than or equal to 350 cells/mm3. On day 11, researchers conducted an interim analysis and found that patients taking GSK'254 200 mg developed post-treatment resistance. Because of this resistance, Part 2 of the trial changed the duration of GSK'254 monotherapy from 10 days to 7 days. Patients included in Part 2 received 40, 80 or 140 mg doses of GSK'254 or placebo once daily for 7 days, followed by combination antiretroviral therapy on day 8. The primary endpoint is the maximum change in plasma HIV RNA from the time of baseline testing, the change from the time of baseline testing to day 11 (Part 1), and the change from the time of baseline testing to day 8 (Part 2).

Of the 34 patients finally analyzed, the mean age was 31.8 years and 94% were male; none failed at follow-up. The largest decreases in plasma HIV RNA from baseline levels occurred in patients in the 200 mg and 140 mg dose groups, with maximum mean decreases of 2.0 and 1.5 log10, respectively. Notably, a 42.7 mg dose of GSK'254 was estimated to result in a maximum 50% decrease in plasma HIV RNA from baseline levels (95% confidence interval, 7.6-77.8).

In Part 1 and Part 2 of the trial, the median time to reach the HIV-1 RNA nadir was 11.5 days and 8 days for patients, respectively. In Part 1, while a decrease in plasma HIV RNA from baseline levels of more than 1.5 log10 was observed in patients receiving GSK'254 200 mg, the change in plasma HIV RNA remained close to baseline levels in patients receiving the 10 mg dose. Treatment resistance was observed in four patients receiving GSK'245 200 mg on day 11, and no resistance was observed on days 8, 9, or 10.

In the second part, there was a value greater than 1.5 log10 A decrease in plasma HIV RNA from baseline levels was observed in 3 patients taking GSK'254 140 mg and 1 patient taking GSK'254 40 mg. No treatment resistance was observed after 7 days of monotherapy.

Overall, 22 patients (65%) treated with GSK'254 reported adverse events, with headache and oropharyngeal pain being the most common. Although one patient reported two serious adverse events, including cardiomyopathy and anal abscess, the investigators noted that neither event was related to GSK'254 treatment. Of note, 14 abnormal laboratory findings of potential clinical importance were observed in 14 patients, including decreased neutrophils (n=6) and white blood cell count (n=3) and increased white blood cell count (n=2) and chloride concentration (n=2). In addition, heart rate and blood pressure were elevated in four patients.

This study was limited by the small sample size and the inclusion of only 2 women, so the results may not be generalizable to other patient populations. "Overall, the results of this study support the clinical development of GSK'254 and provide informed dosing options for the ongoing Phase IIb study evaluating GSK'254 in combination with 2 nucleoside reverse transcriptase inhibitors," the researchers concluded.

What is a maturation inhibitor?

Maturation is one of the final steps in the life cycle of the AIDS virus (HIV) and involves the processing of viral proteins required for HIV to become infectious. HIV maturation inhibitors are promising new molecules that are still being studied for their ability to prevent these protein processes. Researchers expect to be able to prevent HIV from infecting other cells in the body through the use of maturation inhibitors.

In a simplified version of the HIV life cycle, HIV first binds and fuses the cell membrane of the host cell in order to inject the viral content into the cell. The HIV genome is then reverse transcribed, converting from ribonucleic acid (RNA) to deoxyribonucleic acid (DNA), and the viral DNA is integrated into the host cell's genome. At this point, the virus may remain latent for a period of time or immediately begin to produce viral products such as new viral RNA or proteins for subsequent assembly and release of infectious viral particles.

An important step in the HIV maturation process is the processing of the gag protein. gag is actually a protein, meaning that it is initially produced as a long thread of different proteins and is later cleaved into functional parts. gag proteins must be cleaved into small pieces by HIV protease to produce structural proteins (important for the assembly of infectious HIV viral particles). The role of the maturation inhibitor is to keep the gag processing inhibited by binding the gag polyprotein and preventing HIV protease cleavage, and to cause the virus particle to be unable to infect other host cells.

The development of novel HIV inhibitors is important because HIV treatment often includes different types of drugs to combat as many stages of the HIV virus life cycle as possible. In addition, HIV can mutate during exposure to drugs, leading to drug resistance and the creation of HIV strains resistant to entire classes of drugs. Therefore, the introduction of new drugs such as maturation inhibitors can provide an effective treatment for patients who have exhausted all their medications.

Reference source.

Spinner CD, Felizarta F, Rizzardini G, et al. 第二阶段a对下一代成熟抑制剂GSK3640254的抗病毒效果、安全性、耐受性和药代动力学的概念验证评估。Clin Infect Dis. 2022年1月6日在线发表。 Doi:10.1093/cid/ciab1065

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Phase IIa clinical results for novel HIV-1 maturation inhibitor (GSK'254) releasedPhase IIa clinical results for novel HIV-1 maturation inhibitor (GSK'254) released

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