Heterozygous familial hypercholesterolemia (HeFH) can be difficult to control on available standard-of-care cholesterol-lowering medications. Therapeutic interventions are needed to reduce high LDL cholesterol levels and improve health and quality-of-life for people with HeFH. This is especially important as high LDL cholesterol can lead to plaques forming in arteries, blocking blood flow and raising the risk of significant and serious complications. According to Tristan Manalac on BioSpace, clinical-stage biotechnology company Verve Therapeutics is looking to transform the treatment landscape with VERVE-101.

Unpacking the Clinical Trial Data

Recently, Verve Therapeutics shared findings from the Phase 1b heart-1 study, which evaluated VERVE-101 for HeFH, at the American Heart Association (AHA)’s 2023 Scientific Sessions, which took place in early November 2023. Ten enrolled participants received intravenously administered VERVE-101 doses ranging from 0.1mg/kg to 0.6mg/kg, though one participant is not enrolled in the efficacy analysis given the treatment cutoff date. Findings from the study, which you can find in full here, include:

• From a pharmacodynamic perspective, a single VERVE-101 infusion reduced blood PCSK9 protein levels. PCSK9 protein expression has been linked to higher LDL cholesterol.
• Participants treated with 0.45mg/kg doses had an average PCK39 reduction of 59% and 84% respectively, with the participant receiving 0.6mg/kg seeing a reduction of 47%.
• Additionally, those treated with the 0.45mg/kg dose saw average LDL cholesterol reductions of 39% and 48% respectively, with the participant receiving 0.6mg/kg seeing a reduction of 55%.
• No treatment-related adverse events were noticed in lower doses. In those receiving higher doses, reactions included infusion-site reactions and asymptomatic increases in bilirubin levels.
• Serious adverse events occurred in two patients: one who had a fatal heart attack (unrelated to treatment) and one who had a grade 3 myocardial infarction (possibly related to treatment) and non-sustained ventricular tachycardia (unrelated to treatment).

Moving forward, the company plans to continue additional studies and cohorts for VERVE-101.

About Heterozygous Familial Hypercholesterolemia (HeFH)

There are two forms (heterozygous and homozygous) of familial hypercholesterolemia (FH), a rare and inherited form of extremely high low-density lipoprotein (LDL) cholesterol. FH is often resistant to standard cholesterol treatments. Because HeFH is inherited in an autosomal dominant pattern, someone only needs to inherit one defective gene to have this condition. People with HeFH cannot metabolize cholesterol through the liver. Those affected often have high LDL cholesterol levels from birth, with untreated children having a LDL cholesterol level above 160mg/dL and untreated adults having levels above 190mg/dL. Without treatment, people with HeFH may develop:

• Xanthomas: firm nodules from cholesterol buildup, often on the Achilles tendons or tendons on the top of the hand
• Corneal Arcus: a white, blue, or opaque ring around the cornea
• Premature coronary artery disease
  • Note: People with FH who are not treated have a 10-20x increased risk for developing coronary artery disease.
  • Due to: Atherosclerosis
  • Symptoms/Manifestations: Chest pain or discomfort. Heart attack. Sudden death.
• Cerebrovascular disease
  • May lead to a stroke or transient ischemic attack
• Peripheral vascular disease
  • Could cause pain that is worsened by activity and improved with rest, or severe lasting pain
• Aortic aneurysm

Treatment typically includes statins, alongside other cholesterol-lowering medications, as well as dietary and lifestyle changes.