At the Kahn Center, we evaluate in detail essentially all known risk factors for premature coronary artery disease (CAD) with extensive histories, physical exams, and lab testing. In appropriate patients, we recommend changes in diet and fitness, and may turn to supplments and prescription medicatioins to lower cholesterol levels.
The idea that gene editing could turn off cholesterol production to a meaningful degree might be appealing to some patients and is patterned after the observation that some people are born with gene variatns that reduce LDL-Cholesterol levels there whole life and lower there risk of CAD. Persons carrying loss-of-function variants of proprotein convertase subtilisin–kexin type 9 (PCSK9) are an example of that natural experiment.
VERVE-102 is an investigational base-editing therapy designed to durably inactivate
PCSK9 in the liver. A
new report on the early outcomes of this approach has generated headlines and conversations worldwide.
STUDY
In a phase 1, open-label, single-ascending-dose study, the researchers administered one intravenous infusion of VERVE-102 at one of six doses (ranging from 0.3 to 1.0 mg of total RNA per kilogram of body weight [mg per kilogram]) to adults with heterozygous familial hypercholesterolemia or premature coronary artery disease.
VERVE-102 consists of a messenger RNA encoding an adenine base-editor protein and a guide RNA targeting PCSK9, which are encapsulated in a lipid nanoparticle incorporating N-acetylgalactosamine. The objectives were to assess safety and changes in blood PCSK9 protein and LDL cholesterol levels.
RESULTS
A total of 35 participants across the six dose cohorts received VERVE-102 and had at least 28 days of follow-up. No dose-limiting toxic effects occurred. Mild-to-moderate infusion-related reactions and transient elevations in alanine aminotransferase levels were observed. Aspiration pneumonitis occurred in a participant with gastroesophageal reflux disease.
Dose-dependent mean reductions in the PCSK9 level ranged from 51% at the 0.3-mg-per-kilogram dose to 88% at the 1.0-mg-per-kilogram dose.
Corresponding reductions in the LDL-cholesterol level ranged from 9% at the 0.3-mg-per-kilogram dose to 62% at the 1.0-mg-per-kilogram dose, with an absolute reduction of 78 mg per deciliter at the highest dose.
Reductions appeared to be durable throughout follow-up, which was at least 1 year in 15 participants.
CONCLUSIONS
One dose of VERVE-102 led to dose-dependent, substantial, and sustained reductions in PCSK9 and LDL cholesterol levels in a small number of study participants in a phase 1 study.
If permitted by the FDA, the nexts step is a phase 2 study usually involved a few hundred participants. Finally, a large phase 3 study with thousands of patients studied in a double blind and randomized structured study is the final step before drug approval. This could be 5-10 years away in a typical drug development timeline.
Patients were calling the Kahn Center asking about getting this therapy but the interest is understandable but very premature. Large scale studies are needed for safety testing and outcome analysis like rates of heart attacks, strokes, and deaths.
Similar to the ongoing trials of drugs to lower Lipoprotein(a), these studies are very expensive and challenging and go on for years.
“[This study] is early clinical evidence that we can give protection to people who weren’t born with it,” says Dr. Sek Kathiresan, senior vice president at Eli Lilly Co. and CEO of Verve Therapeutics. “We still have a lot to learn. But if it holds up, we think it would mean an entirely new way to treat high cholesterol with one infusion for lifelong cholesterol-lowering.”
If it proves safe and effective in later clinical trials and eventually gets approved, the gene therapy could replace regular injections or daily pills because the liver cells that the therapy targets turn over every 200 to 300 days. Once the cells have been edited by VERVE-102, they produce more cells with the same genetic change, therefore sustaining the effect of the altered PCSK9—potentially over a lifetime.
