Verve shows base editing works in humans in first clinical data—and is punished by investors

Verve Therapeutics has published the first data on an in vivo base editing program in humans, giving the world an early look at the effects of a cholesterol-busting candidate that could become part of Eli Lilly’s stable of heart disease drugs. But investors pummeled the stock amid potential safety concerns. 

Lilly recently paid Beam Therapeutics $200 million upfront to acquire the right to opt in to a set of Verve candidates, including the in vivo base editing asset VERVE-101. The therapy is designed to  permanently turn off the PCSK9 gene in the liver and thereby reduce levels of LDL cholesterol, a lipoprotein that drives the buildup of plaque and raises the risk of heart attack and stroke.

Verve used the American Heart Association Scientific Sessions conference in Philadelphia to provide the first clinical evidence that the treatment works as hoped. In the open-label phase 1b trial, 10 people with heterozygous familial hypercholesterolemia (HeFH) had received a single dose of VERVE-101 and been assessed for safety as of Oct. 16. Efficacy data were available for nine patients. 

Six patients received sub-therapeutic doses, 0.1 mg/kg and 0.3 mg/kg. At the potentially therapeutic doses, the two patients treated with 0.45 mg/kg of VERVE-101 had a time-averaged LDL-C reduction of 39% and 48%. The patient treated with 0.6 mg/kg had a time-averaged LDL-C reduction of 55% that was durable for 180 days, with more follow up to come.

“This result is within our base-case scenario … with Leqvio showing roughly 40% LDL-C reduction in less severe HeFH patient population and our KOL diligence suggesting something north of 45% LDL-C knockdown would be a win,” analysts at William Blair wrote in a note to investors this morning. “We find the dose-dependent LDL-C reductions compelling.” 

While praising aspects of the data set, the analysts have questions about the relationship between LDL-C reductions and PCSK9 inhibition. The two patients treated with 0.45 mg/kg had a time-averaged blood PCSK9 protein reduction of 59% and 84%. The reduction in the patient treated at the higher dose was 47%, meaning they had a bigger fall in LDL-C but a smaller drop in PCSK9 than the 0.45-mg/kg patients.

Verve management “cautioned on drawing conclusions from a single patient,” according to the analysts, but also highlighted nonhuman primate data that may explain the finding. Overall, Verve’s animal tests found a correlation of PCSK9 reduction and LDL-C lowering, but the link wasn’t seen in every individual. The analysts said more clinical data are needed “to give a less variable picture.”

On the safety front, Verve saw treatment-related adverse events, such as asymptomatic increases in liver transaminases, at the two higher doses, but the profile was clean enough for the trial to continue without changes to the protocol. The data, which Verve generated in New Zealand and the U.K., recently helped persuade the FDA to lift a clinical hold on VERVE-101. Verve plans to open U.S. sites next year.

Yet, while Verve has appeased the FDA, it appears that investors are proving harder to persuade. Verve’s share price fell 37% to $9.85 in premarket trading, potentially because of the safety profile seen in the clinical trial. One patient had a grade 3 heart attack the day after receiving 0.45 mg/kg of VERVE-101. The proximity of the event to dosing meant the heart attack was considered potentially related to treatment.

Analysts at William Blair said they “could see the timing of the [myocardial infarction] as concerning,” but they accepted the high burden of disease at baseline, including a history of cardiac arrest and recurrent in-stent restenosis, as factors in the case. 

“To address this moving forward, Verve will be enrolling less severe patients and including CT angiograms as part of the phase 1 study to try to reduce enrollment of patients likely to experience unrelated [cardiovascular] complications,” the analysts wrote.