More problems for Gilead Sciences

Five clinical trials placed on hold due to safety concerns

This will be a quick post—I want to alert you to the latest regarding everyone’s favorite pharmaceutical company, Gilead Sciences. In between dealing with litigation regarding the Truvada disaster, they have been busy promoting their twice yearly injection for PrEP, lenacapavir, which we will see was developed for purposes unrelated to PrEP. Additionally, they’ve run into problems involving “safety concerns” relating to both an integrase strand inhibitor and the capsid inhibitor that is marketed as lenacapavir, and have had to pause no fewer than five clinical trials. As always, emphasis is mine throughout.

Gilead’s HIV Combo on Hold, With No Impact on FDA’s Pending Lenacapavir Decision

Five clinical trials for Gilead’s investigational weekly HIV combo pill have been placed on hold by the FDA after a safety signal emerged. While the combo includes a version of Gilead’s lenacapavir, which is approved as Sunleca [sic] for twice-yearly treatment of people with multi-drug-resistant HIV and currently under FDA review for the prevention of HIV, Jefferies analysts said the pause will not affect the looming decision date.

Gilead announced the clinical hold Tuesday morning, explaining in a release that two Phase II/III trials named WONDERS-1 and -2 had been paused, plus three Phase I studies. The combination therapy features the integrase strand transfer inhibitor GS-1720 and/or the capsid inhibitor GS-4182. While Gilead did not mention lenacapavir in the release, Jefferies analysts explained that GS-4182 is a pro-drug formulation of the investigational therapy, which is separately under review for HIV pre-exposure prophylaxis (PrEP).

What could this safety signal have been? Here we go:

Gilead said that the hold was placed after decreases in CD4+ T cell and absolute lymphocyte counts were identified in a subset of patients who received both drugs. This can be a signal of a weakened immune system in patients with HIV.

This can be a signal of a weakened immune system? I thought the entire definition of AIDS (well, one of the definitions) is an immune system that has shown dramatic decreases in CD4+ cell counts. Also, recall the shocking fact that 10-40% of virally suppressed patients fail to mount a substantive T cell increase. In other words, are these patients simply immunological non-responders, or are there even more problems with these medications?

The Phase II/III WONDERS-1 trial is comparing the combo with Gilead’s approved HIV medicine Biktarvy in people with HIV who are taking medication to suppress the virus. The Phase II/III WONDERS-2 study similarly features Biktarvy as the comparator but has enrolled patients with HIV who are treatment-naive.

The company underscored its faith in the combo therapy and pledged to work with regulators to resolve the hold. Gilead also stressed that the hold does not impact any other assets in its HIV pipeline.

Jefferies agreed with this assessment, noting that had the FDA been concerned, it would have stalled more of Gilead’s formulations and integrase inhibitors currently under development.

Other assets in the pipeline? It really is all about the money, isn’t it?

Gilead is seeking approval of lenacapavir as a twice-yearly injection for PrEP for HIV. The FDA’s decision, due June 19, has been eagerly anticipated by analysts, patients and Gilead, which is gearing up for a massive launch. The company is looking to the drug to build on its HIV empire, which is anchored by Biktarvy—a drug that recorded sales of $13.4 billion in 2024. BMO predicts peak sales of $6.5 billion for the PrEP indication. More broadly, Gilead is aiming to launch nine new HIV drugs by 2033.

This is insane, people. No wonder Gilead is launching nine new “anti-HIV” drugs in the next eight years, in addition to the thirty plus already on the market. They must be in a cold sweat about the potential ten billion dollar payout for the Truvada lawsuits. Are they hoping to monopolize the market entirely?

Gilead backed lenacapavir’s latest application with data from the Phase III PURPOSE 1 and PURPOSE 2 studies. PURPOSE 1, which focused on cisgender women, demonstrated 100% efficacy in preventing HIV infection. PURPOSE 2 enrolled a more diverse population of cisgender men, transgender men, transgender women and nonbinary individuals who have sex with partners assigned male at birth. Results showed that twice-yearly lenacapavir cut HIV incidence by 96%.

I’m really curious to see how long it takes for lenacapavir to fall apart entirely. Also, the language being used here is so tortured. “Cisgender men, transgender men, transgender women and nonbinary individuals who have sex with partners assigned male at birth?” This is another tacit admission that whatever “HIV” positivity indicates, it can not be a bidirectionally sexually transmitted pathogen—if the PURPOSE trials tell us anything, it is that even under the mainstream paradigm, women do not transmit “HIV.” I can’t wait for the day when I never hear the term “cisgender” again.

Jefferies said this indication is very different from what the combo has been aimed at addressing in the now-stalled trials. It’s also unclear if the lenacapavir pro-drug is even the issue at this point.

The prodrug, GS 4182, is an inactive component that is converted to the active drug in the body, and it is the capsid inhibitor that is called lenacapavir and is marketed as Sunlenca. A look at Sunlenca’s website is quite revealing—it is intended for “heavily treatment-experienced (HTE) adults” who are experiencing “HIV-1 treatment failures.” So Sunlenca is intended as a treatment add-on for “HIV” positive patients that have experienced treatment failure—how exactly does it function as a preventative, anyway? I’m not against repurposing drugs as a rule, but how is a drug that was specifically developed for “HIV” positive patients that have experienced treatment failure going to prevent “HIV?” It remains unclear.

Also, note that right on the front page is a warning about IRIS. We’re giving this to not only “HIV” positive but “HIV” negative individuals as PrEP. Heaven help us.

Other companies in the HIV space have had similar safety signals arise. Merck, for example, had trials of Isentress, launched in 2007, placed on hold by the FDA after CD4 T cell count reductions were observed. A combo of Isentress and Gilead’s lenacapavir for HIV treatment was also placed on hold several years ago but was ultimately released in 2022 using lower doses of Merck’s drug.

The trick is to minimize toxicity by keeping the dose as low as possible. That reminds me of the line that some researcher said to Celia Farber years ago about AZT—“Of course we knew it was toxic. Why do you think we lowered the dose?”

Altogether, Jefferies is not too worried about the clinical hold. The firm places more weight on Phase I data for lenacapavir in combination with the injectable integrase inhibitors GS-1219 and GS-3242. Gilead intends to pick one of those medicines to move forward in a combo regimen with lenacapavir by the end of the year. The drugs are administered as a single dose at the first month and sixth month (Q6M).

“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 wrote.

The future certainly seems to be long-acting injectables, for “HIV” positive and negative alike. Regardless, I wonder how much publicity these “safety signals” will get. Once the issue has been resolved—if it gets resolved—how do we know that the safety of the drug has improved at all? And why on earth are we going full steam ahead on lenacapavir despite the “safety signal” regarding its very own prodrug. Granted, the authors do state that “It’s also unclear if the lenacapavir pro-drug is even the issue at this point.” I’m assuming that’s insurance so that whatever happens, lenacapavir won’t be blamed. That would affect Gilead’s bottom line too much, and we all know that just can’t be allowed to happen.

As always, let me know what you think in the comments.