Gene Editing

Verve Therapeutics’ PCSK9 Pivot

Verve Therapeutics’ stock price and gene editing momentum both took major dips last week, after the company announced that it paused its Heart-1 trial evaluating its VERVE-101 PCSK9 gene therapy, and revealed that it will now prioritize the development of its VERVE-102 therapy.

  • Verve is developing investigational CRISPR-based gene editing therapies intended to allow long-term LDL-C reductions by permanently altering the PCSK9 gene.
  • Like other CRISPR gene editing techniques, Verve’s therapies have been viewed with optimism that they might lead to permanent cholesterol improvements from just one treatment, and concerns that they could lead to similarly-permanent unintended consequences.

The Heart-1 Phase 1b trial dosed 13 patients with heterozygous familial hypercholesterolemia with various levels of VERVE-101, finding that the gene editing therapy did indeed allow up to 73% LDL-C reductions (46% average) with reductions lasting up to nine months.  

However, one out of six participants who received a 0.45 mg/kg dose of VERVE-101 experienced a Grade 3 transient increase in serum alanine aminotransferase (a liver enzyme) and a Grade 3 thrombocytopenia (a drop in blood platelet count).

  • These patients were asymptomatic, the lab changes ended up being reversible, and Verve was impressively transparent about the whole process.
  • However, it comes just a few months after Verve revealed that two out of ten earlier Heart-1 patients went on to have severe cardiac events (MI after one day, cardiac arrest after 5 weeks) and several participants recorded increases in liver transaminases.

Verve will work with regulators to define a path forward for VERVE-101, but appears to be pivoting its focus to its VERVE-102 therapy. In fact, VERVE-102’s Heart-2 clinical trial is already scheduled for this quarter.

What makes Verve Therapeutics so sure that VERVE-102 will be better? They believe that VERVE-101’s lipid nanoparticle technology, which is responsible for delivering its gene editor to patients’ livers, was responsible for the abnormal lab results.

The Takeaway

Permanently reducing cholesterol through one-time gene editing is pretty darn futuristic, so it’s  understandable that Verve Therapeutics’ R&D pathway will include its share of challenges. Whether VERVE-102 will provide the same LDL-C benefits and none of the challenges of VERVE-101 remains to be seen, but there’s little doubt that Verve remains extremely committed to its vision for PCSK9 gene editing.

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