Once-weekly antiretrovirals on the horizon

Two antiretrovirals with the potential for once-weekly oral dosing were unveiled at the Conference on Retroviruses and Opportunistic Infections (CROI 2024) in Denver on Monday.

The new agents have undergone phase I studies, which establish appropriate dosing and weed out drugs which have serious side effects. Before becoming available for prescription, drugs go through two further phases of testing to establish their efficacy, dosing and safety. During these stages of development many products fall by the wayside either because unexpected problems arise or the commercial priorities of the pharmaceutical company change.

It can take three to five years for new agents to complete these phases of testing, so the antiretrovirals presented this week are unlikely to change patterns of antiretroviral treatment in the near future. But they do offer a clear indication of the direction that pharmaceutical companies are heading in the antiretroviral drugs market – less frequent dosing, for both treatment and PrEP (regular medication to prevent HIV).

MK-8527

MK-8527, a new nucleoside reverse transcriptase translocation inhibitor being developed by Merck, is the same type of antiretroviral as islatravir. Merck had hoped that islatravir could be developed as a weekly or monthly antiretroviral but at the higher doses needed for long-acting dosing, islatravir caused loss of lymphocytes (white blood cells). Merck is now developing MK-8527 as a once-weekly drug for treatment and as a monthly drug for PrEP.

Professor Russ Carstens of Merck & Co presented results of two phase 1 safety and efficacy studies in 37 previously untreated people with HIV without resistance to nucleoside or nucleotide reverse transcriptase inhibitors. The studies tested the virological efficacy of five doses (0.25mg, 0.5mg, 1mg, 3mg or 10mg) seven days after the administration of a single dose. Viral load reductions ranged from -0.80log at the dose of 0.25mg, -1.39log at the dose of 0.5mg and -1.21log at 1mg to -1.66log at 3mg and -1.39log at 10mg.

Two studies in people without HIV tested the pharmacokinetics of single doses and multiple doses. In Trial A, 34 people received single ascending doses from 0.5mg to 200mg. The study showed that doses of 5mg and above resulted in intracellular concentrations that were above the threshold for antiviral activity against wild-type HIV-1. A comparison of dosing in the fasted state and after a high-fat meal showed that although a high-fat meal reduced plasma concentrations, it resulted in 58% higher intracellular concentrations of MK-8527 triphosphate over the seven-day period after dosing.

In Trial B, four groups of eight people without HIV were randomised to receive three doses of MK-8527 at one-week intervals or a placebo, each group receiving a higher dose, 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 profile supports once-weekly dosing, and possibly dosing at longer intervals.

Drug-related adverse events were mild or moderate and occurred in 14% of participants in Trial A and 34% in Trial B. No dose-related changes in laboratory tests such as cholesterol, liver enzymes or kidney function were observed. The doses selected for development are not expected to have lymphocyte toxicity based on pre-clinical tests used previously to analyse how islatravir caused lymphocyte loss, Professor Carstens told a question-and-answer session.

GS-1720

GS-1720 is a once-weekly integrase inhibitor taken orally. GS-1720 might be combined with lenacapavir, a long-acting HIV capsid inhibitor already approved as Sunlenca. Gilead Sciences has several other long-acting drugs in early development, including a second oral capsid inhibitor (GS-4182) and an oral NNRTI (GS-5894) that is suitable for once-weekly dosing.

At CROI 2024, Dr Carl Fichtenbaum of the University of Cincinnati presented results of a phase 1b safety and efficacy study in people with HIV and a phase 1a safety and pharmacokinetic study in people without HIV.

In the phase 1a study, ascending doses up to 1350mg were assessed for tolerability and the pharmacokinetic half-life (the time it takes drug concentrations to fall by half from peak levels) in eight people. The study found that after a single dose of 450mg, it took a median of 9.4 days for the drug concentration to fall by half, supporting once-weekly dosing.

The phase 1b study tested four single doses of GS-1720 (30mg, 150mg, 450mg, 900mg) for safety and antiviral activity in people with HIV. Each dose was tested in seven participants. People were eligible to join the study if they had a viral load between 5000 and 500,000 and were previously untreated or off treatment for at least 12 weeks and without any previous experience of integrase inhibitor treatment.

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

Study participants had a median age of 33 years, 23 out of 28 were previously untreated and the median baseline viral load was 4.9 log ₁₀ copies/ml.

Viral load reductions at day 11 ranged from -1.74log (30mg dose) and -2.18log (150mg) to -2.44log at the 450mg dose and -2.37log at the 900mg dose. All participants who received doses of 450mg or 900mg experienced viral load reductions of at least -1.5log.

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

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

On Wednesday, results were also presented for a weekly dual therapy combination that is slightly further ahead in the clinical trials process. Islatravir and lenacapavir are each taken as a pill every seven days in this small phase II study.