Gilead Sciences has new data showing COVID drug Veklury maintained efficacy despite changes in a coronavirus structure it targets, just as the company explores expedited ways to launch a pivotal trial for an investigational oral antiviral.
Compared with the original SARS-CoV-2 virus, Veklury (remdesivir) showed no major shifts in its ability to tackle coronaviruses with substitutions in the RNA-dependent RNA polymerase (RdRp), according to data presented at IDWeek 2022. Also known as nsp12, RdRp is a protein key in the replication of RNA viruses like SARS-CoV-2.
Coronaviruses with RdRp mutations isolated from patients in the phase 3 ACTT-1 trial—which got Veklury its FDA approval—showed up to about a 3.4-fold decrease in their susceptibility to Veklury compared with the original virus, the data showed. The fold change was measured by increases in half-maximal effective concentration of the drug, or EC50, and investigators called the difference “low.” ACTT-1 was conducted in 2020, before the delta and omicron variants were identified.
What’s more, the RdRp substitutions didn’t seem to affect clinical outcomes. Among Veklury takers who were eligible for this analysis, 67% of patients with the mutations recovered from COVID, compared with 58% of those without the mutations.
Because Veklury targets RdRp, theoretically the drug might not work as well if the protein underwent major structural changes, Anu Osinusi, Gilead’s vice president of clinical research for hepatitis, respiratory and emerging viruses, explained in an interview with Fierce Pharma.
The new data were consistent with other analyses Gilead has done, Osinusi said, and they continue to “bolster the story that there is a high barrier to resistance developing against remdesivir in patients.”
The results were better than findings from a recent Science Translational Medicine study. In that study, in which several Gilead scientists participated, researchers reported multiple pathways, including combinations of RdRp substitutions, that could give the coronavirus varying degrees of resistance to Veklury.
Introducing one specific combo of substitutions resulted in 38-fold Veklury resistance but also a viral replication defect, the study found. However, as the researchers noted, the substitutions selected from lab dishes merely described possible pathways to Veklury-resistant mutations, and that they were either rare or simply not detected in the more than 6 million publicly available RdRp sequences with or without Veklury treatment.
Watching for mutants has become a main theme in the fight against COVID. Antibody drugs like Regeneron’s REGEN-COV have lost their emergency use authorizations because of reduced activity against omicron. Most SARS-CoV-2 variants identified show mutations on the spike protein on the surface of the virus, making neutralizing antibody therapies that target the protein ineffective.
“To date, we haven’t really seen any major genetic changes in any of the variants of concern, or even variants of interest, that have emerged that would significantly alter that viral RNA polymerase that is targeted by Veklury,” Osinusi said.
Still, as COVID cases drop, Veklury sales declined 46% year-over-year in the second quarter to $445 million despite an expanded FDA approval for non-hospitalized patients in January. Veklury’s recent decrease also has Pfizer’s more convenient oral antiviral Paxlovid to thank. But the Pfizer therapy has its own problem, including potentially dangerous drug-drug interactions and reported fast COVID rebound. That’s why Gilead is working on its own oral COVID drug.
Gilead is moving a remdesivir prodrug coded GS-5245 “with full speed” potentially across the disease spectrum, Osinusi said. As the COVID treatment landscape is changing, the company is collaborating with global health authorities to launch a phase 3 global clinical trial that will “prioritize sites that can move quickly with clinical trial enrollment,” a Gilead spokesperson told Fierce Pharma. The California drugmaker previously disclosed a phase 1 trial for GS-5245 in January.
The proposed phase 3 trial will be randomized and double-blinded, pitting GS-5245 against placebo in non-hospitalized COVID patients who are at high risk of progression to hospitalization. Investigators will measure the rate of COVID-related hospitalization and all-cause death by day 29 as the trial’s primary endpoint, according to Gilead. The trial hasn’t started enrolling, pending endorsement from regulatory authorities, the spokesperson said.
Veklury remains a standard of care for COVID, “but we also recognize the limitations of it being an intravenous agent,” Osinusi said. “There is a need for having additional oral antiviral agents because that’s really when you’re going to be able to meet the needs of the broader population.”