Sekar Kathiresan, MD, Verve Therapeutics co-founder and CEO

Verve Therapeutics said Monday that the FDA has placed on clinical hold its Investigational New Drug application for a trial of its lead pipeline candidate VERVE-101, the first in vivo base editing therapy to reach the clinic as a potential treatment for Heterozygous Familial Hypercholesterolemia (HeFH).

Verve, a developer of gene editing therapies for cardiovascular disease, did not detail what led to the clinical hold, only saying that it expected to receive a formal letter with questions from the FDA within 30 days of the agency’s notification to the company, which occurred Friday.

“Verve plans to provide updates pending engagement with the FDA and intends to work closely with the FDA to resolve the hold as promptly as possible in order to initiate dosing in the U.S.,” the company stated.

VERVE-101 is a single-course gene editing treatment designed to reduce the low-density lipoprotein cholesterol (LDL-C) that drives HeFH, a subtype of atherosclerotic cardiovascular disease. VERVE-101 consists of an adenine base editor messenger RNA that Verve has licensed from another base editing therapy developer, Beam Therapeutics, as well as an optimized guide RNA targeting the PCSK9 gene packaged in an engineered lipid nanoparticle.

By making a single A-to-G change in the DNA genetic sequence of PCSK9, VERVE-101 aims to inactivate that target gene. Verve reasons that inactivation of the PCSK9 gene has previously been shown to up-regulate LDLR expression, leading to lower LDL-C levels and thus reducing the risk for atherosclerotic cardiovascular disease (ASCVD)—of which HeFH is a subtype.

Investors responded to the clinical hold announcement with a stock selloff that sent Verve’s shares tumbling 27% in trading as of midday Monday, to $22.85 from Friday’s closing price of $31.29.

Impact seen on Beam Therapeutics

Mani Foroohar, MD, senior managing director, genetic medicines and a senior research analyst with SVB Securities, opined that Verve’s regulatory setback will also sour investors on Beam as well since that company has also announced a regulatory delay.

In releasing third-quarter results today, Beam said it will not submit this year a previously-planned IND application for BEAM-102, its base editing program designed to treat sickle cell disease by directly editing the causative HbS point mutation to create the naturally occurring normal human hemoglobin variant, HbG-Makassar.

Beam said it was skipping the IND this year—the company said in August it was “on track” for the second half of 2022—in order to optimize its Makassar approach, alongside its HbF upregulation approach, for future ex vivo and in vivo hematopoietic stem cell (HSC) candidates.

Those candidates will emerge, according to Beam, in its Wave 2 ex vivo HSC development strategy, designed to enable an improved, reduced-toxicity conditioning regimen for patients undergoing HSC transplantation; and Wave 3 development, focused on in vivo delivery of base editors directly to HSCs.

Beam Therapeutics CEO John Evans

Beam added that it was instead prioritizing the BEACON trial (NCT05456880), designed to assess the company’s lead base editing candidate BEAM-101, being developed to treat sickle cell disease.

BEAM-101 is designed to produce base edits designed to potentially alleviate the effects of sickle cell disease by mimicking genetic variants seen in individuals who have hereditary persistence of fetal hemoglobin.

“We are laser-focused on screening and site activation efforts to enroll our first sickle cell patient by year-end,” Beam CEO John Evans stated.

“Frustrating development”

“A frustrating development on its own right, this misstep by VERV management (who took a highly promotional tone into this disclosure) will also predispose investors to consider the disclosed reasoning for the delay in BEACON with skepticism,” Foroohar wrote in a research note.

“As a result, we are not surprised to see BEAM shares trading down sharply in early trading,” Foroohar added.

Beam shares fell about 12% as of midday Monday, from $42.80 to $37.76.

In July, Verve dosed the first patient with VERVE-101 in the Phase Ib heart-1 trial (NCT05398029), designed to assess the safety and tolerability of VERVE-101 with additional analyses for pharmacokinetics and reductions in blood PCSK9 protein and LDL-C.

Verve said today it had completed dosing of VERVE-101 in the first dose cohort of the dose-escalation portion of the heart-1 trial, which was well tolerated in all three patients. No treatment-related adverse events reported to date, and all adverse events observed have been Grade 1 in nature, Verve said.

The company added that the trial’s independent Data Safety Monitoring Board (DSMB) had reviewed safety data from the first cohort and recommended dose escalation to the planned second dose level, which is expected to begin soon. Verve plans to report initial safety and pharmacodynamic data for all dose cohorts of the dose-escalation portion of the heart-1 study in the second half of 2023 at an unspecified medical meeting.

The heart-1 trial is designed to enroll approximately 40 adults and includes a single ascending dose portion, followed by an expansion single-dose cohort where additional participants will receive the selected potentially therapeutic dose.

To date, enrollment efforts have been ongoing in New Zealand and the U.K.—but not in the U.S.

“Comprehensive” package

“We prepared a comprehensive regulatory package for VERVE-101, a first-in-class in vivo liver base editing program, that we submitted to the FDA in October,” Sekar Kathiresan, MD, Verve’s co-founder and CEO, said in a statement. “We anticipate receiving details from the FDA in the next month, and are committed to working closely with the Agency to address their questions, so that we may open enrollment for patients with HeFH in the U.S.”

Verve said it had not included clinical data from heart-1 in the IND package it submitted to the FDA.

On October 31, Beam trumpeted the publication in the American Heart Association journal Circulation of positive preclinical data for VERVE-101 from a study conducted in non-human primates. The study showed that four NHPs dosed with 0.75 mg/kg of the base editing therapy showed a mean reduction in blood PCSK9 protein of 67% and LDL-C reduction of 49% from baseline a year after treatment. NHPs that received the 1.5 mg/kg dose showed a mean reduction in PCSK9 protein of 83% and LDL-C reduction of 69% from baseline following evaluation up to 476 days post-treatment.

Verve disclosed the clinical hold within its release of third-quarter financial results. The company ended Q3 with a net loss of $45.19 million, more than double its $22.749 million net loss for the three months ending September 30, 2021.

For the first nine months of this year, Verve reported a net loss of $116.302 million, up 31% from its net loss of $88.977 million for January–September 2021.

Verve signaled it was well capitalized to weather a short-term setback by reporting cash, cash equivalents, and marketable securities of $550.710 million—a long enough financial “runway” to last into the second half of 2025, and up 53% from $360.442 million.

On Twitter, one investor expressed skepticism about how Verve can satisfy the FDA in demonstrating the safety of VERVE-101.

“The question to ask for $VERV is not ‘will they get off hold?,’ but ‘what kind of safety database would they need for FDA approval?’ Would 10,000 patients followed for 10 years do it? Idk…,” tweeted “Sheep of Wall Street,” an “MD/MBA investor.”

Another market watcher saw an opportunity in Verve shares going forward.

“I know a hold by the FDA is very scary, but at $20, this vulture capitalist will be picking at the stock,” tweeted “Biotech2k”, a “fan of #Biotech, #Tech and #Crypto.” “It’s not my favorite company with the challenges it faces in PCSK9, but at $20, it will be priced for the risk and the reward will be worth it.”

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