April 23, 2024

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Breakthrough in HIV Treatment: Promising Once-Weekly Oral Drugs Unveiled at CROI 2024

Breakthrough in HIV Treatment: Promising Once-Weekly Oral Drugs Unveiled at CROI 2024

Breakthrough in HIV Treatment: Promising Once-Weekly Oral Drugs Unveiled at CROI 2024

Two Long-Acting HIV Oral Drugs, Once a Week, Worth Looking Forward To!

At the Conference on Retroviruses and Opportunistic Infections (CROI 2024) held in Denver on March 3, two antiretroviral drugs with the potential for once-a-week oral dosing were announced.

The new drugs have undergone Phase I studies to determine the appropriate dosage and eliminate drugs with serious side effects. Before they can be prescribed, the drugs will need to undergo testing in two additional stages to determine their efficacy, dosage, and safety. Many products are set aside during these development stages, either due to unexpected issues or changes in pharmaceutical company priorities.

It may take three to five years to complete these testing stages, so the antiretroviral drugs introduced this week are unlikely to change the pattern of antiretroviral therapy in the near future. However, they do clearly indicate the direction of pharmaceutical companies in the development of antiretroviral drugs – reducing the dosing frequency for treatment and PrEP (routine drugs for preventing HIV).

Breakthrough in HIV Treatment: Promising Once-Weekly Oral Drugs Unveiled at CROI 2024

MK-8527 Type

MK-8527 is a new nucleoside reverse transcriptase translocation inhibitor being developed by Merck, similar to islatravir. Merck had hoped islatravir could be developed as a once-a-week or once-a-month antiretroviral drug, but at the higher doses required for long-acting, islatravir resulted in the loss of lymphocytes (white blood cells). Merck is currently developing MK-8527 as a once-weekly treatment and once-monthly PrEP drug.

Professor Russ Carstens of Merck presented the results of two Phase I safety and efficacy studies involving 37 previously untreated HIV-infected individuals with no resistance to nucleoside or nucleotide reverse transcriptase inhibitors. These studies tested the virological efficacy of five doses (0.25mg, 0.5mg, 1mg, 3mg, or 10mg) given once daily for seven days after a single dose. The range of viral load reductions was from -0.80 log at the 0.25mg dose to -1.39 log at the 0.5mg and 1mg doses to -1.66 log at the 1mg dose and -1.39 log at the 10mg dose.

Two studies in non-HIV populations tested single and multiple doses. In Study A, 34 people received single escalating doses from 0.5mg to 200mg. The study showed that doses of 5mg and above resulted in intracellular concentrations higher than the antiviral activity threshold against wild-type HIV-1. Comparisons of fasting and high-fat meal doses showed that while a high-fat meal reduced plasma concentrations, it led to a 58% increase in intracellular concentrations of MK-8527 triphosphate seven days after dosing.

In Study B, four groups of eight non-HIV-infected individuals were randomly assigned to receive three doses of MK-8527 or placebo, with each group receiving a higher dose, ranging from 5mg to 40mg. After the third dose, the half-life of MK-8527 ranged from 216 to 291 hours, depending on the dose, leading Merck researchers to conclude that the pharmacokinetic characteristics support once-weekly dosing and possibly longer dosing intervals.

Drug-related adverse events were mild to moderate, with rates of 14% in Study A and 34% in Study B, and no dose-related changes were observed in laboratory tests, such as cholesterol, liver enzymes, or kidney function. During the Q&A session, Professor Carstens said that based on preclinical tests previously used to analyze how islatravir caused lymphocyte loss, the selected dose for development is not expected to have lymphocyte toxicity.

GS-1720 Type

GS-1720 is a once-weekly integrase inhibitor for oral use. GS-1720 may be used in combination with lenacapavir, a long-acting HIV capsid inhibitor approved as Sunlenca. Gilead Sciences also has several other long-acting drugs in early development, including a second oral capsid inhibitor (GS-4182) and an oral NNRTI (GS-5894) suitable for once-weekly dosing.

At CROI 2024, Dr. Carl Fichtenbaum of the University of Cincinnati presented the results of Phase 1b safety and efficacy studies in HIV-infected individuals and Phase 1a safety and pharmacokinetic studies in non-HIV-infected individuals.

In the 1a study, the tolerability and pharmacokinetic half-life (the time for drug concentration to decrease by half from peak levels) of escalating doses up to 1350 mg in 8 people were evaluated. The study found that after a single dose of 450mg, the median time for drug concentration to decrease by half was 9.4 days, supporting once-weekly dosing.

The 1b study tested the safety and antiviral activity of four single doses of GS-1720 (30mg, 150mg, 450mg, 900mg) in HIV-infected individuals. Each dose was tested in seven participants. Participants were eligible if they had viral loads between 5000 and 500,000, were previously untreated or had discontinued treatment for at least 12 weeks, and had no previous experience with integrase inhibitors.

The study measured changes in viral load from baseline to day 11 after dosing.

The median age of the participants was 33 years, with 23 of the 28 participants never having received treatment before. The median baseline viral load was 4.9 log10 copies/mL.

The range of viral load reduction on day 11 was -1.74 log (30mg dose) and -2.18 log (150mg) to -2.44 log (450mg dose) and -2.37 log (900mg dose). All participants receiving the 450mg or 900mg dose had viral load reductions of at least -1.5 log.

Resistance testing in the 30mg and 900mg cohorts showed no evidence of integrase inhibitor-resistant mutations in viral isolates on day 11. One case of viral rebound without resistance occurred in the 30mg cohort. Resistance testing in the 150mg and 450mg cohorts is ongoing.

No serious drug-related adverse events (Grade 3 or higher) were reported. Two participants receiving 30mg and 150mg doses experienced Grade 3 laboratory events (one case of elevated creatinine and two cases of decreased creatinine clearance).

On Wednesday, the results of a once-weekly dual therapy combination were also announced, slightly ahead in clinical trials. In this small Phase II study, Islatravir and lenacapavir were taken once a week in pill form.

Breakthrough in HIV Treatment: Promising Once-Weekly Oral Drugs Unveiled at CROI 2024

Carstens RP et al. Single dose administration of MK-8527, a novel nRTTI, in adults with HIV-1. Conference on Retroviruses and Opportunistic Infections, Denver, abstract 115, 2024.
Gillespie G et al. Safety and pharmacokinetics of MK-8527, a novel nRTTI, in adults without HIV. Conference on Retroviruses and Opportunistic Infections, Denver, abstract 129, 2024.
Fichtenbaum CJ et al. Antiviral activity, safety, and pharmacokinetics of GS-1720: a novel weekly oral InSTI. Conference on Retroviruses and Opportunistic Infections, Denver, abstract 116, 2024.

(source:internet, reference only)

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