Gilead’s HIV Combo Trials Paused by FDA, Lenacapavir PrEP Decision Unaffected

Highlights

• FDA has placed a clinical hold on five Gilead HIV combo trials due to safety concerns involving immune cell counts.
• The trials include WONDERS-1 and WONDERS-2, which compare the combo with Biktarvy.
• The hold does not affect lenacapavir's separate FDA review for PrEP, with a decision expected on June 19.
• Gilead reaffirms confidence in the combo therapy and broader HIV pipeline.
• Lenacapavir is a key part of Gilead’s future HIV strategy, supported by strong Phase III efficacy data.
• Analysts anticipate lenacapavir could generate $6.5 billion in peak sales for PrEP.
• Gilead is exploring Q6M injectable regimens as a long-term game changer in HIV treatment.

Clinical Trials Paused Over Safety Signal

The U.S. Food and Drug Administration (FDA) has placed a clinical hold on five ongoing trials for Gilead Sciences' investigational weekly HIV combination therapy, citing a safety concern. The affected trials include two Phase II/III studies—WONDERS-1 and WONDERS-2—and three Phase I studies.

According to Gilead, the hold was issued following the identification of “decreases in CD4+ T cell and absolute lymphocyte counts... in a subset of patients who received both drugs,” which could indicate a weakened immune system in patients with HIV.

The experimental regimen includes the integrase strand transfer inhibitor GS-1720 and the capsid inhibitor GS-4182. While the company did not explicitly mention lenacapavir in its statement, analysts from Jefferies clarified that GS-4182 is a pro-drug of lenacapavir, which is already approved under the brand name Sunlenca for treatment-experienced HIV patients and is under separate FDA review for use as pre-exposure prophylaxis (PrEP).

Impact on Lenacapavir and Gilead’s Pipeline

Despite the clinical pause, industry analysts expect no delay in the FDA’s upcoming decision on lenacapavir for PrEP, scheduled for June 19. “While it might increase some investor uncertainty into the all-important June 19 PDUFA for [lenacapavir] for PrEP, we see no major read-through and expect an on-time and clean FDA approval,” Jefferies stated.

Gilead emphasized that the pause affects only the trials involving the specific combo therapy and “does not impact any other assets in its HIV pipeline.” The company affirmed its confidence in the combination therapy and stated its commitment to working with regulators to resolve the issue.

Jefferies echoed this sentiment, noting that broader concerns from the FDA would likely have led to a halt on other formulations and integrase inhibitors currently under development by Gilead.

WONDERS Trials and Market Response

The WONDERS-1 trial is comparing the experimental combo against Gilead’s blockbuster HIV medication Biktarvy in patients who are virologically suppressed. WONDERS-2, on the other hand, is evaluating the combo in treatment-naive patients, again with Biktarvy as a comparator.

Following the announcement, Gilead’s stock saw a 2% drop to $110.75 as of 10:50 a.m. ET on Tuesday, reflecting market unease despite assurances from analysts and the company.

Lenacapavir’s Pivotal Role in Gilead’s HIV Strategy

Gilead is pinning significant hopes on lenacapavir as a cornerstone for its future HIV portfolio. The company is seeking FDA approval for a twice-yearly injectable version of the drug for PrEP. Data from the Phase III PURPOSE 1 and PURPOSE 2 studies support the application, with PURPOSE 1 showing 100% efficacy in cisgender women and PURPOSE 2 demonstrating a 96% reduction in HIV incidence among a diverse population, including transgender and nonbinary individuals.

The company aims to build on its $13.4 billion sales of Biktarvy in 2024 and is targeting the launch of nine new HIV drugs by 2033. BMO Capital Markets projects potential peak sales of $6.5 billion for lenacapavir in the PrEP indication.

Long-Term Vision: A Shift to Q6M Regimens

While the current hold raises questions about Gilead’s near-term plans, Jefferies is more focused on the company's long-term strategy involving other integrase inhibitors—GS-1219 and GS-3242—in combination with lenacapavir. These investigational drugs are designed for administration once every six months (Q6M), which could revolutionize HIV treatment.

“This would be the real game changer and value proposition for Gilead if they are able to swap the $15B Biktarvy market onto long-acting Q6M injectable in the later half of the decade,” Jefferies concluded.

Industry Context

The safety signals observed in Gilead’s combo trials are not without precedent in the HIV therapeutic landscape. For example, Merck’s Isentress faced a similar clinical hold in 2007 after CD4+ T cell reductions were noted. A combination of Isentress and lenacapavir was also placed on hold but was eventually released in 2022 using reduced dosages.