Looking to leapfrog antibodies and RNAi, Sekar Kathiresan says gene editing approach to cut PCSK9 looks durable
JP Morgan isn’t typically a data conference. But there are always exceptions for data that could make or break a company, piquing the interest of potential investors and partners alike.
Data, for instance, like what Sekar Kathiresan is bringing to the virtual conference, showing that a one-time treatment with Verve Therapeutics’ base editor can keep PCSK9 levels low — thereby lowering LDL cholesterol, aka the bad kind — out to 6 months. In non-human primates.
The two takeaway figures are 61% LDL cholesterol reduction and 89% cut in average blood PCSK9 protein level. That’s the same level of reduction for PCSK9 as the treatment registered at 2 weeks, when the researchers documented a 59% drop in LDL-C.
“What you are seeing is durable lowering of cholesterol and consistent lowering of LDL cholesterol 6 months after administration of the gene editing treatment,” Kathiresan told Endpoints News in a preview.
While preclinical, the results mark a significant step for the in vivo use of the next-generation gene editing tool known as base editing. Whereas the first generation of CRISPR gene editing molecules would snip the DNA sequence and let it repair on its own, base editing works by converting one letter on the genome to another.
In this case the construct, VERVE-101, made a single change from A to G in the genetic sequence of the PCSK9 gene in the liver, with an aim to inactivate the gene for good.
As liver cells turn over roughly every 200 days, Kathiresan added, 6-month durability data offer reasonable confidence that the changes are there to stay.
“The fundamental problem with coronary heart disease is cumulative exposure to LDL over time, OK? And the fundamental treatment is to lower that cumulative exposure as much as possible,” said the CEO, who left behind an academic career and a directorship at Mass General’s Center for Genomic Medicine to steer the biotech. “The way to think about this is kind of the area under the curve analysis, you know? You want to keep the LDL down and consistently down for as long a period as possible.”
VERVE-101 rides on the pharmacologic validation offered by monoclonal antibodies and siRNA therapies that target PCSK9 but does away with the need for chronic treatment. Each of which he sees presenting its own compliance issues that could lead to insufficient protection.
With toxicology studies underway, Verve expects to dose its first patient some time in 2022. By targeting the initial clinical indication of heterozygous familial hypercholesterolemia, the company will be developing “a genetic treatment for a genetic disease” before turning to “garden variety coronary heart disease.”
PCSK9 will just be a start. Kathiresan has identified seven other genes that, as he’s discovered over years of studies in population genetics, harbor protective mutations — one of them being ANGPTL3, for which Verve has also presented 2-week preclinical data. All eight targets fall into one of three pathways: LDL-C, triglycerides or lipoprotein(a).
“Each of those pathways are kind of complementary in terms of risk for a patient,” he said. “So a medicine targeting each of those pathways should be additive in terms of benefit.”