Eli Lilly is laying the groundwork for a phase 2 trial of the lipid-lowering gene editor it acquired from Verve Therapeutics, with the candidate now showing strong and consistent cholesterol reductions after a higher dosing regimen.
Lilly today shared that its one-time base editor VERVE-102, meant to permanently turn off the cholesterol-producing PCSK9 gene, slashed cholesterol by 62% in patients given the highest dose of one milligram per kilogram of body mass. This drop was sustained for up to 18 months, as were cholesterol reductions at lower dose levels previously reported by Verve.
The analysis includes 35 patients enrolled so far in the phase 1b Heart-2 study, which focuses on those with inherited, genetically controlled high cholesterol or premature coronary artery disease (CAD).
Dosing in the trial is still ongoing, Scott Vafai, M.D., Verve’s chief medical officer, told Fierce Biotech, but he would not comment on whether any higher doses will be tested. Verve is a wholly owned subsidiary of Lilly.
“We're really excited to share what we think are really encouraging results, demonstrating the potential for one-time treatment to durably lower LDL cholesterol,” Vafai said.
So far, VERVE-102’s efficacy compares well with existing PCSK9 inhibitors like Amgen’s Repatha, Vafai said. Those drugs typically showed cholesterol reductions between 50% and 60% in their pivotal trials.
“Anything above 50% LDL-C lowering that was maintained with a good safety profile is kind of the bar you want to be at,” Myles Minter, Ph.D., a healthcare analyst with William Blair who covered Verve before its acquisition by Lilly, told Fierce. VERVE-102’s 62% score at its highest dose clears that bar.
Elevated cholesterol is an undisputed driver of cardiovascular disease, the world’s leading cause of death. But it can be tough for patients to stay on top of their cholesterol levels with existing medications like statins and PCSK9 inhibitors, Vafai told Fierce.
“These treatments are effective at lowering LDL, but the real-world efficacy is limited due to high discontinuation rates,” the Verve exec said. “We know that up to half of patients are not taking these therapies after one year, and I've seen this in my own clinical experience.”
VERVE-102 packages a base editor, which flips a single letter of DNA without breaking the molecule’s iconic double helix, inside a lipid nanoparticle that targets the liver. Verve’s first attempt to tackle PCSK9 with a base editor fumbled after liver toxicity emerged; so far, VERVE-102 has avoided a similar fate by switching to a different nanoparticle delivery system that includes a sugar called N-Acetylgalactosamine, or GalNac.
GalNac “provides an additional way” for the nanoparticle to get inside of liver cells, Vafai explained. “The overall formulation of the lipid nanoparticle changed, and we're really excited by the safety profile that we're seeing.”
VERVE-102’s LDL-lowering so far seems stable and durable, with none of the cycling that can be seen when taking PCSK9 inhibitors. On those medicines, William Blair’s Minter explained to Fierce that cholesterol levels can creep back up between doses.
“Your LDL-C is starting to revert back to normal before you get another hit,” Minter said, and “every moment of LDL-C exposure matters for your lifetime risk of a cardiac event.”
But one key question remains for VERVE-102 and competing cardiovascular gene editors, Minter said—which patients will they ultimately serve. A one-time edit to your genome may make sense for a younger patient with heterozygous familial hypercholesterolemia (HeFH), he told Fierce, the genetic disease that Verve is focusing on in its trial.
“You've got an otherwise healthy individual that's got decades of life ahead of them,” he said, who may go from “running around on the sporting field” to having their first cardiac arrest and “staring down the barrel of this lifelong LDL-C control.”
For such a patient, a one-and-done treatment, even if it comes with some risks, may be appealing. For an older patient with elevated cholesterol, though, or someone with high LDL-C but no history of heart attack or stroke, the calculus may be different.
A 65-year-old “looking for something that tops me up over a statin” would likely go with an established PCSK9-inhibiting medicine, Minter said. “Probably not going to get a base editor at 65.”
Asked about the ultimate patient population that Verve is targeting with its lead editor, Vafai stayed tight-lipped.
“Right now we focus on patients with heterozygous FH and premature CAD,” he told Fierce. There may be a chance to expand the patient pool down the line, he said, “but that will require discussion with regulators and us moving further along in the clinical development process.”
Lilly hopes to begin enrolling a phase 2 study of VERVE-102 by the end of this year. The Big Pharma is hardly the only company pursuing gene editing for cardiovascular diseases. Mammoth Biosciences, CRISPR Therapeutics and Scribe Therapeutics, to name a few, are pursuing in vivo gene editing for various cardio targets.
But Vafai thinks Verve’s base editing approach stands supreme to the CRISPR-based methods others are using, which involves breaking the DNA double helix and making larger changes to the genome. Tweaking just a single letter in the code minimizes the chance of “unintended changes,” he said.
The ultimate goal of VERVE-102, Vafai told Fierce, is to mimic the low cholesterol enjoyed by people born with a non-functional PCSK9 gene.
“These individuals have lifelong low LDL cholesterol, and this translates into remarkable protection from cardiovascular events,” he said. “We started this journey really inspired by human genetics.”