Merck Resumes Trials on HIV Hopeful, But Drops PrEP Bid For Now

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After enduring nine months of clinical holds, Merck is restarting the Phase III clinical program for islatravir, its candidate for people with HIV-1 infection, the company announced Tuesday.

The pharma giant is launching three Phase III studies, all assessing islatravir together with its approved HIV-1 drug Pifeltro (doravirine). Two trials will look at the potential of the combo in virologically suppressed HIV-1 patients, while the other will assess its performance in patients who had not yet been treated. Crucially, all three trials will use a lower dose of islatravir than what was used during the previous clinical program.

Designed as a once-daily oral treatment, islatravir is an investigational nucleoside reverse transcriptase translocation inhibitor (NRTTI) that stops the infection by blocking a key enzyme HIV-1 needs to integrate into the host’s DNA. 

The compound interferes with the virus’ replication through many different mechanisms and demonstrates strong antiviral activity against HIV variants that have evolved resistance against common drugs.

In early, mid-stage and even later studies, islatravir performed promisingly, leading to high rates of durable virological suppression. The company even saw success with testing islatravir as pre-exposure prophylaxis (PrEP) against HIV-1.

However, late last year, patients treated with islatravir in a Phase II trial met a worrying decline in lymphocyte and CD4+ T-cell counts, which made them susceptible to infections. 

Not long after, the U.S. FDA slapped clinical holds on all of the candidate’s investigational new drug applications. This included its oral and implantable PrEP formulations, as well as its injectable form and once-daily oral combo with Pifeltro for the treatment of HIV-1. All told, 13 islatravir trials were suspended.

A Revitalized Program 

The renewed Phase III clinical program, which the FDA has greenlit, hinges on a lower dose of islatravir, combined with 100 mg of Pifeltro. 

Patients previously treated with the higher 0.75-mg islatravir dose can transition into a study that dispenses lower doses of the candidate. Studies seeking to re-assess islatravir at its previous dosing regimen will remain on hold.

“Based on our internal evaluations, lower doses of islatravir were identified that we anticipate will have comparable effects on lymphocyte and CD4+T-cell count as other standard of care antiretroviral regimens,” a Merck spokesperson told BioSpace. “The FDA reviewed the comprehensive data that we provided and agreed that we can proceed with lower doses of islatravir.”

Alongside the new Phase III program is a Phase II clinical trial testing out the lowered-dose islatravir used in combination with Gilead’s lenacapavir in virologically suppressed adults living with HIV-1. The islatravir-lenacapavir combo, designed to be taken orally once per week, remains investigational. Its safety and efficacy have yet to be established.

Merck is also planning a Phase Ib study for another NRTTI candidate, MK-8527, also for the treatment of adults with HIV-1.

Despite the release of its clinical holds and the revival of its HIV-1 program, Merck has decided to drop the investigation and development of islatravir as a once-a-month oral PrEP pill. 

Pharmacokinetic studies could not find an ideal lower dose that would yield sufficient preventive efficacy without triggering a worrying drop in lymphocyte counts.  

“Merck continues to believe in the potential of the nucleoside reverse transcriptase translocation inhibitor (NRTTI) mechanism and is evaluating additional compounds with the goal of helping to address unmet needs in HIV prevention,” the spokesperson added.