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

Investors punished Verve Therapeutics (VERV) this week—but analysts were far more forgiving—after it voluntarily paused an early-stage clinical trial of one of its lead programs, VERVE-101, after one patient showed an elevated level of a liver enzyme and a low platelet count.

After consulting with the trial’s independent data and safety monitoring board, Verve paused enrollment in the Phase Ib Heart-1 trial (NCT05398029). The pause followed investigators reporting a grade 3 drug-induced transient elevation of serum alanine aminotransferase (ALT) and grade 3 drug-induced thrombocytopenia, a serious adverse event, in one of 13 patients dosed to date—the sixth participant enrolled in the 0.45 mg/kg dose cohort, the second highest of four doses studied.

The sixth participant did not experience any bleeding or other symptoms related to the health abnormalities, which according to Verve were fully resolved “within a few days.” By contrast, the first five participants showed time-averaged low-density lipoprotein cholesterol (LDL-C) reductions of 21% to 73% (averaging 46%) as of the data cut-off date of March 18. LDL-C reductions have lasted up to 270 days in the two patients with the longest follow-up in the 0.45 mg/kg or 0.6 mg/kg cohorts.

Heart-1 is designed to assess VERVE-101 in patients with heterozygous familial hypercholesterolemia (HeFH), established atherosclerotic cardiovascular disease, and uncontrolled hypercholesterolemia. The trial’s endpoints include safety and tolerability, as well as changes in blood PCSK9 protein and LDL-C levels.

Verve dosed the trial’s first patient in 2022, making history by advancing the first base edited therapy into the clinic. Investigators treated patients with VERVE-101 at single doses of 0.1 mg/kg, 0.3 mg/kg, 0.45 mg/kg, and 0.6 mg/kg.

Last November, Verve presented the trial’s first human proof-of-concept data for VERVE-101 at the American Heart Association Scientific Sessions 2023. One month after treatment, HeFH patients showed dose-dependent reductions of disease-causing LDL-C.

After pausing the Heart-1 trial, Verve pivoted its development effort toward VERVE-102, another HeFH treatment candidate that is designed to target PCSK9. VERVE-102 will be studied in patients with HeFH or premature coronary artery disease in the Phase Ib Heart-2 trial (NCT06164730), set to start in the second quarter. Verve has regulatory clearances for Heart-2 from the U.K. and Canada.

VERVE-102 uses the same base editor and guide RNA for PCSK9 but a different LNP delivery system than VERVE-101.

Unlike VERVE-101, VERVE-102 includes a different ionizable lipid that was originally licensed from Novartis (NVS), and incorporates a GalNAc liver-targeting ligand, which Verve says have been well tolerated in third-party clinical trials of gene editing product candidates. By incorporating GalNAc, the LNP in VERVE-102 is designed to enable the treatment to access liver cells using either the asialoglycoprotein receptor or the low-density lipoprotein receptor.

Two biggest questions

“The two biggest questions on the news in our view are 1) whether the safety concern is due to the lipid nanoparticle (LNP) primarily thus limiting read-through to the base editing platform and 2) the degree of read-through to other clinical programs in the in vivo gene-editing space,” Myles R. Minter, PhD, an analyst covering biotechnology companies for William Blair, wrote Tuesday in a research note.

Minter’s first question arose from comments made by Verve’s co-founder and CEO in announcing the pause: “At potentially therapeutic dose levels of VERVE-101, we have observed certain asymptomatic laboratory abnormalities, which we believe are attributable to the LNP delivery system,” Sekar Kathiresan, MD, said in a statement.

“The safety of patients in our clinical trials is of the utmost importance. We plan to further investigate the laboratory abnormalities observed in the Heart-1 clinical trial in order to inform the next steps for VERVE-101,” Kathiresan promised.

Those next steps, he said, include talks with regulators toward a path forward for VERVE-101. The drug’s IND application and clinical trial applications remain active, and the safety events have been reported to the FDA and the New Zealand Medicines and Medical Devices Safety Authority (Medsafe).

VERVE-101 uses LNP technology licensed from privately held Acuitas Therapeutics, and according to Minter may incorporate an ionizable lipid shown to induce transient liver enzyme elevations in mouse and nonhuman-primate models in a dose-dependent manner.

“We note that changes in liver enzymes correlated with increased doses but less so with changes in PCSK9 and LDL-C levels, suggesting this signal is related LNP load rather than on-target mechanistic effects,” Minter wrote. “Although downplayed by several gene-editing players today, we cannot avoid the possibility that drug payload can also impact safety given the adenosine base editor is encoded by mRNA and is longer than cas9, albeit we do believe LNP-related safety is the primary player here.”

“Elevated ALT levels have been seen only at the higher dose of the first zinc finger nuclease mRNA pairs and notably lower than those observed in the other reports with differing payloads, Minter added.

As for his second question looking at impact beyond Verve, Minter had a ready answer: “(We) ultimately believe that there is minimal read-through across the gene editing space here from the VERVE-101 setback.”

Minter reiterated William Blair’s “Outperform” rating on Verve stock.

Gene editing shares tumble

Investors appeared to disagree, sending Verve shares tumbling 35% on Tuesday, from $12.79 to $8.32, before bargain hunters snapped up the stock the following day. The mini surge sent shares climbing back 5% Wednesday, to $8.71, but ended all but flat today, dipping 0.34% as shares closed at $8.68.

Verve wasn’t the only gene editing therapy developer to see stock losses following news of the enrollment pause:

  • CRISPR Therapeutics (CRSP), which with Vertex Pharmaceuticals (VRTX) made history in January by scoring the FDA’s first CRISPR-based gene-editing therapy approval for Casgevy™ (exagamglogene autotemcel), fell 5% from $68.18 to $65.03 Tuesday, then another 1% to $64.60 Wednesday.
  • Intellia Therapeutics (NTLA) dropped 8% from $27.22 to $25.10 Tuesday, then another 0.5% to $24.98 Wednesday.
  • Beam Therapeutics (BEAM) shrunk 6.5% from $32.66 to $30.55 Tuesday, then another 3% to $29.68 Wednesday.

Beam’s decline was, and should be, of keen interest to Verve shareholders. Beam held opt-in rights to four base editing programs being developed by Verve until October 2023, when Beam sold those rights to Eli Lilly (LLY) for $250 million upfront ($200 million cash and a $50 million equity investment), plus up to $350 million tied to achieving clinical, regulatory, and alliance milestones.

The opt-in rights, now held by Lilly, include co-developing and co-commercializing four Verve base editing programs focused on three cardiovascular disease targets—PCSK9ANGPTL3, and an undisclosed third “liver-mediated” target. Lilly can opt-in to share 33% of worldwide development expenses, and jointly commercialize and share profits and expenses related to commercialization in the U.S. on a 50/50 basis. Verve still holds all product rights for the PCSK9 and ANGPTL3 programs outside the U.S., and retains control of the development and commercialization of all products covered by the collaboration.

Mani Foroohar, MD, senior managing director, Genetic Medicines and a senior research analyst at Leerink Partners, commented in a research note that when Beam launches its Phase I trial of BEAM-302 in alpha-1 antitrypsin (AAT) deficiency later in the first half of this year, it will use a dose range that includes cohorts of 0.25 mg/kg to 0.75 mg/kg—a range that includes the dosage at which Verve saw toxicity.

LNP Differences

However, in correspondence with Leerink Partners, Foroohar wrote, Beam executives noted several differences between their LNPs and Verve’s—including ionizable lipid, formulation, manufacturing process and absence of the GalNAc ligand seen in VERVE-102.

“These LNPs may be dissimilar enough to make an apples-to-apples dose comparison overly simplistic,” Foroohar concluded.

At deadline, only Foroohar and a second analyst responded negatively to the trial pause.

Foroohar trimmed his firm’s 12-month price target on Beam shares 4%, from $28 to $27 based on an expected delay in the company receiving potential milestone payments from Lilly. He retained Leerink’s “Market Perform” rating on the stock.

In a research note on Tuesday, Foroohar observed that in addition to the delayed payments to BEAM, Verve’s pivot to VERVE-102 “heightens investor focus on safety into initial BEAM-302 data (potentially in 2025), alongside near-term focus on residual commercial opportunity in SCD.”

Dae Gon Ha, PhD, a director and equity research analyst covering biotechnology for Stifel, lowered his firm’s price target on Verve shares 29%, from $56 to $40. Ha cited the one-year delay in Verve’s market entry projection for VERVE-101 to 2028 in the U.S. and 2029 in Europe.

However, Ha maintained a “Buy” rating on the stock.

“Our review of various sources suggest that this may be an unfortunate n=1 observation (vs. fundamental issue with the program/approach),” Ha wrote Tuesday in a research note. “We tried to identify any causal link from LDL-c (or PCSK9), VERVE-101 preclinical observations, or any others but failed to land at a definitive conclusion.”

“We recognize that the PR highlighted the observations as ‘drug-induced,’” Ha added. “But contrary to the stock reaction, we are reluctant to throw in the towel on the program,” Ha added.

Leaders & laggards

  • Acorda Therapeutics (ACOR) shares cratered 74% from $13.47 to $2.50 on Tuesday, the first trading day after the company said it agreed to be acquired by privately held Merz Therapeutics for $185 million. Under the deal, Acorda and affiliates agreed to file for Chapter 11 bankruptcy in U.S. Bankruptcy Court for the Southern District of New York. Acorda listed $266.2 million in liabilities and only $108.5 million in assets. Merz has agreed to serve as the “stalking horse” bidder in a court-supervised sales process, during which the Frankfurt, Germany-based company plans to purchase substantially all of Acorda’s assets. Pearl River, NY-based Acorda disclosed Wednesday that the Nasdaq Stock Market will suspend trading in and delist the company’s common stock effective April 12. Upon delisting, Acorda shares are expected to trade on the Pink Market or Open Market, the lowest of three over-the-counter stock trading tiers overseen by the OTC Markets Group.
  • Eiger BioPharmaceuticals (EIGR) shares plunged 72% from $5.01 to $1.39 on Monday, after the company and its direct subsidiaries filed for Chapter 11 bankruptcy in U.S. Bankruptcy Court for the Northern District of Texas in Dallas. Eiger listed $53.1 million in liabilities and only $38.8 million in assets. Palo Alto, CA-based Eiger has agreed to sell its marketed progeria drug Zokinvy®(lonafarnib) to Sentynl Therapeutics for $26 million. Solana Beach, CA-based Sentynl has agreed to serve as the “stalking horse” bidder in a court-supervised sale of Zokinvy. “The company intends to sell substantially all of its assets during the bankruptcy case and to facilitate an orderly wind down of its operations,” Eiger stated.
  • Tracon Pharmaceuticals (TCON) shares plummeted 48% from 42 cents to 22 cents on Wednesday, after the company said the independent data monitoring committee of its Phase II ENVASARC pivotal trial (NCT04480502) recommended continuing the study as planned. Tracon disclosed the study had achieved an 11% objective response rate (ORR) by investigator review and a 5.5% confirmed ORR via blinded independent central review based on four patients. The trial completed enrollment in March with 82 evaluable patients in cohort C of treatment with single agent envafolimab at 600 mg subcutaneous every three weeks. The committee reviewed interim safety and efficacy data from 73 cohort C patients able to complete two on-treatment scans (a minimum of 12 weeks of treatment). Final data are expected in the third quarter.
  • Vanda Pharmaceuticals (VNDA) shares jumped 29% from $3.91 to $5.05 on Wednesday, the first trading day after the FDA approved the company’s Fanapt®(iloperidone) tablets for the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults. Fanapt® is an atypical antipsychotic agent first approved in 2009 for the acute treatment of patients with schizophrenia. Fanapt’s latest approval was based on data from an approximately 400-patient pivotal study showing that patients treated with the drug showed a larger, highly statistically significant (p=0.000008) improvement over placebo patients in the Young Mania Rating Scale (YMRS) following four weeks of treatment.
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