Gilead Sciences Terminates HIV Drug Trial After FDA Maintains Safety Hold
Key Insights
Gilead Sciences has completely terminated its Phase II/III WONDERS-2 trial testing experimental HIV (search) drugs GS-1720 and GS-4182 after the FDA refused to lift a clinical hold imposed due to safety concerns.
The trial suspension occurred after some participants experienced decreases in CD4+ T-cell counts and white blood cell counts, though these levels later returned to normal in the smaller study.
The company continues developing other HIV (search) treatments, including long-acting regimens based on lenacapavir, which recently became the first FDA-approved twice-yearly pre-exposure prophylaxis drug.
Gilead Sciences has permanently terminated its Phase II/III WONDERS-2 clinical trial testing experimental HIV (search) drugs after the U.S. Food and Drug Administration refused to lift a safety hold on the studies. The decision marks a significant setback for the pharmaceutical giant's efforts to develop once-weekly oral HIV treatments.
The terminated WONDERS-2 study enrolled 73 patients and was testing a combination of two experimental drugs – GS-1720 and GS-4182 – as a first-line treatment for people starting HIV (search) therapy. GS-1720 is a novel long-acting integrase (search) inhibitor designed for weekly dosing, while GS-4182 is a tablet formulation of lenacapavir, which Gilead already markets under the brand name Sunlenca.
Safety Concerns Prompt Trial Suspension
Both WONDERS studies were suspended in June 2025 after safety concerns emerged. Some participants receiving the drug combination experienced decreases in CD4+ T-cell counts, a key indicator of immune function in HIV (search) patients, as well as drops in total white blood cell counts and absolute lymphocyte counts.
"It is not yet clear which drug is associated with the white blood cell declines," according to reports. This side effect is not typical of integrase (search) inhibitors and has not been observed in people using lenacapavir for HIV (search) treatment or twice-yearly pre-exposure prophylaxis.
Despite the fact that blood counts in WONDERS-2 participants later returned to normal levels, the FDA maintained its clinical hold. CD4 and lymphocyte counts have since returned to baseline levels or are within normal ranges for all WONDERS-2 participants.
Broader Impact on Gilead's HIV Pipeline
While Gilead has terminated WONDERS-2, the larger WONDERS-1 study remains paused. This trial was evaluating the once-weekly GS-1720 plus GS-4182 combination as a switch option for approximately 675 people currently on treatment with viral suppression. Three Phase I studies testing the drugs are also still on hold.
The company is currently transitioning WONDERS-2 participants to standard care. "We continue to work closely with study investigators to ensure a smooth transition for participants to standard of care HIV (search) treatment options," a Gilead spokesperson stated.
Continued Development of Lenacapavir-Based Treatments
Despite this setback, Gilead continues developing other HIV (search) drugs, including long-acting regimens based on lenacapavir. The drug has achieved significant regulatory success, with the World Health Organization including it in recommendations for HIV treatment and prevention last year.
Lenacapavir became the first FDA-approved drug for pre-exposure prophylaxis that requires administration only twice a year, representing a major advancement in HIV (search) prevention. The drug is marketed as Sunlenca for treatment and Yeztugo (search) for pre-exposure prophylaxis.
Historical Context for Similar Setbacks
This is not the first time CD4 cell and lymphocyte decreases have affected long-acting oral antiretroviral development. In 2021, the FDA placed a clinical hold on Merck (search)'s islatravir after similar blood count declines in study participants. However, further analysis determined the doses were too high, leading to resumed studies with lower doses and eventual approval of a combination pill containing doravirine and low-dose islatravir (Idvynso (search)) last month.
The precedent suggests that while this represents a significant setback for GS-1720 and GS-4182, it may not necessarily mark the end of development for these experimental drugs.