First Patient Dosed in Trial of “Gene Editing” Medicine

A novel therapy in early development aims to permanently turn off the PCSK9 gene in the liver and lower cholesterol with a one-time treatment. It is being developed for a genetic form of high cholesterol.

Verve Therapeutics has begun a phase 1b clinical trial, heart-1, of VERVE-101, which is a novel “gene editing” medicine. This one-time, in vivo therapy is designed to permanently turn off the PCSK9 gene in the liver to reduce low-density lipoprotein cholesterol (LDL-C). VERVE-101 is being developed initially as a treatment for patients with heterozygous familial hypercholesterolemia (HeFH), a life-threatening subtype of atherosclerotic cardiovascular disease.

The trial is taking place in New Zealand, and company officials said in a press release they are planning to file in the second half of this year an investigational new drug (IND) application to begin clinical development programs in the United States, as well as a first clinical trial application for development in the United Kingdom.

Verve expects to report initial clinical data from the VERVE-101 phase 1 clinical trial in 2023.

“With the current standard of care treatment for HeFH, less than 20% of patients achieve LDL-C goal levels due to the limitations of the chronic model, which requires rigorous patient adherence, regular healthcare access, and extensive health care infrastructure. VERVE-101 has the potential to change the way cardiovascular disease is cared for by lowering LDL-C as low as possible for as long as possible after a single treatment,” Andrew Bellinger, M.D., Ph.D., chief scientific and medical officer of Verve, said in a press release.

VERVE-101 consists of an adenine base editor messenger RNA (licensed from Beam Therapeutics) and an optimized guide RNA targeting the PCSK9 gene packaged in a lipid nanoparticle. By making a single A-to-G change in the DNA genetic sequence of PCSK9, VERVE-101 aims to inactivate the target gene.

The base editing in VERVE-101 is different from the CRISPR/cas9 approach pioneered by CRISPR Therapeutics and for which Jennifer Dounda and Emmanuelle Charpentier earned the 2020 Nobel Prize in Chemistry. In this approach, CRISPR/Cas9, a combination of the Cas9 enzyme and a guide RNA, cuts DNA and the natural DNA repair process takes over. CRISPR Therapeutics is using this type of gene editing tool to develop an ex vivo therapy — which removes cells from the body and the treated cells are then placed back into the body — for blood disorders, including sickle cell disease.

And while CRISPR/Cas9 acts like a scissors, Verve’s technology acts like an eraser. The therapy developed by Verve is able to erase and rewrite one letter of the genome at a time. VERVE-101 uses proprietary lipid nanoparticles to deliver the therapy — in this case, adenine base editor messenger RNA and a guide RNA that target the PCSK9 gene — directly to the cells without having to remove them from the body.

In May 2022, Verve Therapeutics released data from a study in non-human primates that had been followed for one year. This study demonstrated potent and durable editing of the PCSK9 gene and reductions of LDL-C, and the therapy was well-tolerated.