Researchers in and outside Verve Therapeutics (VERV) could hardly contain their glee Sunday as the company presented its first human proof-of-concept data for its CRISPR-based VERVE-101—the first base editing therapy to reach the clinic—in patients with heterozygous familial hypercholesterolemia (HeFH) at the American Heart Association Scientific Sessions 2023 (#AHA23).

The data showed that one month after treatment with VERVE-101, HeFH patients showed dose-dependent reductions of disease-causing low-density lipoprotein or “bad” cholesterol (LDL-C). Two patients treated with 0.45 mg/kg of VERVE-101 had a time-averaged blood PCSK9 protein reduction of 59% and 84%, and a time-averaged LDL-C reduction of 39% and 48%. The sole patient treated with 0.6 mg/kg showed a time-averaged blood PCSK9 protein reduction of 47% and a time-averaged LDL-C reduction of 55%, a reduction that held 180 days after treatment.

“Can we precisely rewrite the genetic code—make a single DNA spelling change—in the liver of a human being for clinical effect? YES!” Sekar Kathiresan, MD, Verve’s co-founder and CEO, who led the trial, exclaimed on X, formerly Twitter.

“IT WORKS!” Verve co-founder Kiran Musunuru, MD, PhD, professor of cardiovascular medicine and genetics, Perelman School of Medicine at the University of Pennsylvania, exclaimed in a thread posted on X.

But the data also included some less positive news: One 0.45 mg/kg patient suffered a grade 3 heart attack a day after treatment—an event considered potentially related to treatment. Verve said the event followed unstable chest pain symptoms before dosing that had not been reported to investigators. Coronary angiography taken after the event showed critical left main equivalent coronary artery disease.

The same patient also experienced a form of arrhythmia, non-sustained ventricular tachycardia (Grade 2), more than four weeks after dosing, which was determined to be unrelated to treatment.

One patient dosed in the 0.3 mg/kg cohort had a fatal cardiac arrest approximately five weeks after treatment due to underlying ischemic heart disease, which was determined not to be related to treatment by the trial’s investigator and independent data and safety monitoring board (DSMB).

Roller coaster ride

Yet the severe adverse events were enough, however, to take investors on a roller coaster ride. Soon as the opening bell rang on Monday, investors started unloading Verve shares, a selloff that caused the company’s stock price to plummet 40% on Monday, from $15.70 to $9.29—not the usual reaction to news that’s mostly positive, to the point of making genome editing history.

“To all looking to explain stock price dynamics (cacophonics is more like it) in gene editing biotech—ask yourselves: What does The Street know that the CSO of @EliLillyandCo doesn’t about @VerveTx technology and data?” Fyodor Urnov, PhD, director of technology & translation at the Innovative Genomics Institute, fumed on X on Monday.

VERVE-101 is among PCSK9-targeting Verve therapies for which Eli Lilly last month agreed to acquire opt-in rights held by Beam Therapeutics to Verve-developed base editing therapies through an up-to-$600 million collaboration ($250 million upfront). VERVE-101 consists of an adenine base editor messenger RNA that Verve has licensed from Beam.

Fortunately for Verve, the bearish sentiment didn’t last long. Verve shares recovered Tuesday, fishing the day rising 16% to $10.77, then climbed another 7% on Wednesday, to $11.49.

Even better for Verve, most analysts didn’t echo the investors in heading for the proverbial exits. As of Wednesday, not a single analyst lowered their 12-month price targets or ratings on Verve shares.

Eun Yang, PhD, equity analyst with Jefferies, provided some needed context in a research note Sunday when she noted that the 55% LDL-C reduction shown by the sole 0.6 mg/kg-dosed patient was comparable to those of three marketed therapies during their Phase III trials: Novartis’ small interfering RNA (siRNA) therapy Leqvio® (inclisiran); Regeneron Pharmaceuticals/Sanofi’s human monoclonal antibody Praluent® (alirocumab); and Amgen’s Repatha®.

Novartis has cited LDL-C lowering of up to 52% vs. placebo in patients with heart disease or at increased risk of heart disease who received two initial doses of Leqevio over a year, and who were unable to reach their LDL-C target despite statin therapy. Praluent, which also targets PCSK9, cites a study showing a 54% LDL-C reduction, while Repatha last year showed a 58% LDL-C reduction at week 260.

Verve’s explanation of the heart attack patient’s cardiovascular history satisfied analysts at RBC Capital Markets and William Blair.

“On the stock, we would not be surprised to see some volatility, but we remain buyers given impressive (effectiveness),” RBC Capital Markets analyst Luca Issi wrote in an investor note, as reported by Investor’s Business Daily.

William Blair biotechnology analyst Myles R. Minter, PhD, and research associate Sarah Schram, PhD, wrote in a research note that the heart attack patient’s case was disclosed to the FDA before it agreed last month to lift its clinical hold which blocked enrollment of patients in the U.S.: “Upon review, the agency still granted IND clearance so we are actually not overly concerned about this MI [myocardial infarction] currently given apparent regulatory comfort.”

Sticking with Verve

Also sticking with Verve (mostly) is Catherine D. (Cathie) Wood, the chief investment officer and portfolio manager of ARK Investment Management’s electronic transfer funds (ETFs). Two of those ETFs—ARK Genomic Revolution ETF (ARKG) and ARK Innovation ETF (ARKK)—include Verve among their portfolio companies.

While Wall Street investors were selling off Verve shares en masse Monday, Wood merely trimmed the ARK ETFs’ stakes in the company. ARKK sold just 0.1% (3,000) of the 2.652 million shares it held that day in Verve, while ARKG sold 0.4% (12,000) of its 2.98 million Verve shares. On Tuesday, the ETFs retained their holdings in Verve.

ARKG’s ownership stake in Verve now stands at 4.66% and a “weight” of 3.14%, the 13th highest percentage of portfolio among the 39 companies in which the fund holds shares. ARKK owns a 4.15% stake in Verve, whose weight of 0.61% places it 28th of the fund’s 33 portfolio companies.

VERVE-101 is a single-course treatment designed to treat HeFH by inactivating the PCSK9 gene in the liver to durably lower blood LDL-C. VERVE-101 consists of an adenine base editor messenger RNA that Verve has licensed from Beam, as well as an optimized guide RNA targeting the PCSK9 gene packaged in an engineered lipid nanoparticle.

As a result, Verve’s news had the effect of denting Beam’s shares on Monday, when they dipped 1% from $22.16 to $21.94. But as investors regained confidence in Verve and its historic research, Beam’s shares also rebounded Tuesday, climbing 12% to $24.55, and again on Wednesday, increasing another 2% to $25.15.

De-risking Beam

“Given the substantial reductions in PCSK9 and dose-dependent reductions in LDL-C, we believe that the initial data establishes clinical proof-of-concept and de-risks Beam’s base-editing technology,” William Blair’s Minter and analyst Sami Corwin, PhD, and colleagues wrote Monday in a research note. Blair reaffirmed its “Outperform” rating on Verve stock.

Despite selling its rights to Lilly, Beam may yet benefit from Verve’s development of VERVE-101 and other therapies, Minter and Schram predicted.

“Ultimately, we view [VERVE-101] data as a pivotal and encouraging milestone for Beam and the broader gene-editing space,” Minter and Schram opined in a Monday research note. “We anticipate Verve Therapeutics will be the first to treat a patient in vivo in the U.S. with Beam’s base-editing technology, which could also provide a tailwind for Beam as it advances its internal candidates.”

Beam is expected to submit IND applications for two in-vivo programs in early 2024—BEAM-301, a liver-targeting lipid nanoparticle (LNP) formulation of base editing reagents designed to correct the R83C mutation; and BEAM-302 is a liver-targeting LNP formulation of base editing reagents designed to correct the PiZ allele, as a second Jefferies analyst, Michael Yee, noted on Sunday.

However, while Beam expects to apply to conduct clinical trials for BEAM-302 outside the U.S., the company only explicitly committed to filing an IND “subsequently during early development.”

“We think the VERV data which triggered LLY $250M opt-in combined with the regulatory tailwinds (FDA cleared IND for VERV in the U.S.) should de-risk the regulatory path and help [Beam’s] enrollment,” Yee wrote.

Leaders & laggards

  • BioCardia (BCDA) shares nearly tripled, rocketing 168% from 40 cents to $1.07 on Tuesday, after the FDA approved Phase III trial plans for its CardiAMP™ autologous cell therapy to treat ischemic heart failure. Under the CardiAMP Heart Failure II study protocol, the primary efficacy endpoint is a hierarchical composite assessment consisting of all-cause death, the cardiac death equivalents of heart transplant and left ventricular assist device (LVAD) implantation, heart failure hospitalizations, worsening heart failure events treated as an outpatient, and change in quality-of-life, with a follow-up duration ranging from 12–24 months. BioCardia is conducting the CardiAMP Heart Failure trial (NCT02438306), which has completed enrollment and is expected to release final data analyses later this quarter.
  • BioXcel Therapeutics (BTAI) shares slid 23%, from $5.51 to $4.22, on Tuesday after the company acceded to the FDA’s recommendation to conduct an additional Phase III trial in the TRANQUILITY program, evaluating BXCL501 for acute treatment of agitation associated with Alzheimer’s dementia. The new trial is expected to enroll approximately 100 patients aged 65 years and older with mild, moderate, or severe dementia who will self-administer 60 mcg of BXCL501 or placebo whenever agitation episodes occur over four weeks. BioXcel also agreed to amend strategic financing agreements with Oaktree Capital Management and Qatar Investment Authority, under revised key financial terms that BioXcel said would increase its potential to access additional tranches of capital.
  • Chemomab (CMMB) shares leaped 31%, from 61 cents to 80 cents, after the FDA granted its Fast Track designation to CM-101 for the treatment of adults with primary sclerosing cholangitis (PSC). The designation came two days after the company presented data at the American Association for the Study of Liver Diseases (AASLD) The Liver Meeting® 2023 showing that treatment with CM-101 resulted in anti-fibrotic and anti-inflammatory activity in patients with liver fibrosis. Chemomab also presented data showing that CM-101’s target, the soluble protein CCL24, was associated with key inflammatory and fibrotic pathways implicated in the liver damage characterizing PSC. CM-101 is in a Phase II trial (NCT04595825) that is moving toward completion of enrollment, with a topline data readout expected in the second half of 2024.
  • Scisparc (SPRC) shares surged 48% Wednesday, from $4.36 to $6.46, after the company trumpeted as a ”major breakthrough” positive topline results from its 18-patient, open-label Phase IIa trial concluding that SCI-110 provided a safe and effective solution for alleviating agitation in elderly Alzheimer’s disease (AD) patients. When measured by the Cohen Mansfield Agitation Inventory (CMAI), SCI-110 treatment led to a significant 23% reduction in agitation symptoms. Moreover, patients treated with SCI-110 were free of delirium, oversedation, hypotension, or falls, demonstrating its potential safety and suitability for elderly patients. The investigator-initiated trial was conducted at the Sophie & Abraham Stuchynski Israeli Alzheimer’s Medical Center (IMCA).
  • Talis Biomedical (TLIS) shares zoomed 31.5% on Tuesday, from $5.40 to $7.10, after the company said it will chop its workforce approximately 90% and consolidate operations to a single site in Chicago. The job cuts are part of an effort to explore strategic alternatives with the goal of maximizing shareholder value. Talis’ board named a special committee of independent, disinterested directors to consider alternatives that include equity or debt financing alternatives, an acquisition, merger, reverse merger, divestiture of assets, licensing or other strategic transactions. Despite what it called progress developing the Talis One® sample-to-answer molecular testing platform, Talis said current market conditions required the move. Talis added that it will implement additional cost-saving measures to lower cash spending or “burn.”

Alex Philippidis is Senior Business Editor of GEN.

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