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How much will the FDA clinical hold imposed on Verve Therapeutics’ lead pipeline candidate VERVE-101—the first in vivo base editing therapy to reach the clinic—lead to investor skittishness about the broader CRISPR genome editing field, let alone base editing?

VERVE-101, a treatment for Heterozygous Familial Hypercholesterolemia (HeFH), has been placed on clinical hold for reasons the FDA will spell out in the formal letter that Verve expects to receive this month.

Verve’s acknowledgement of the clinical hold on Monday sparked a stock selloff that sent the company’s shares plummeting 37% early this week from $31.29. Verve saw its shares tumble 30% on Monday, to $21.75; fall another 5% on Tuesday to $20.58; then skid another 4% on Wednesday, to $19.71.

“Given the negative recent updates from this space, we believe that investors could become increasingly cautious about the FDA’s interest in allowing for in vivo CRISPR-based gene editing programs to progress into U.S.-based studies,” Jack K. Allen, senior research analyst with Baird, wrote Tuesday in a research note.

Besides Verve’s clinical hold, Allen observed, another reason for such caution was the death last month of Terry Horgan, the 27-year-old brother of Cure Rare Disease founder and CEO Rich Horgan, and a participant in the CRD Phase I TMH-001 clinical trial (NCT05514249) of CRD-TMH-001, a CRISPR gene-editing therapeutic designed to treat a rare mutation of Duchenne muscular dystrophy (DMD). Terry Horgan was the first and sole patient to have been dosed with the treatment in the trial, led by Brenda Wong, MD, at the University of Massachusetts Chan Medical School.

“The loss of Terry is heartbreaking, and he will be remembered as a hero. He was a medical pioneer whose courage and unflinching determination has paved the way for increased focus and attention on funding and developing new therapies for patients with rare and ultra-rare conditions,” Cure Rare Disease said in a statement.

Added Allen: “It’s interesting to see Verve’s program be placed on hold as many hold the belief that base editing, which only requires a single strand break, could be safer as compared to Intellia’s traditional CRISPR approach, which involves a double-strand break.”

Both VERVE-101 and Intellia’s products utilize lipid nanoparticle-based (LNP) delivery, he noted.

Contrast with Intellia

Allen contrasted Verve’s approach with that of Intellia’s NTLA-2002, which the company said recently was slated for a Phase II trial to be launched in the first half of 2023, to be followed near-term by a pivotal study of Intellia’s other lead in vivo CRISPR gene-edited therapy NTLA-2001, which the company is co-developing with Regeneron Pharmaceuticals.

“Both of these upcoming studies are slated to include U.S. sites, and hence we believe that the FDA’s view of novel CRISPR-based programs will be a key focus in the coming months as Intellia looks to file INDs and get these studies up and running,” Allen added.

In September, the companies trumpeted initial positive data for NTLA-2001, an in vivo CRISPR/Cas9 genome editing therapy in development as a single-dose treatment for transthyretin (ATTR) amyloidosis. The data showed that at 28 days after treatment, mean serum transthyretin (TTR) reductions were 93% at the 0.7 mg/kg dose and 92% at the 1.0 mg/kg dose.

Intellia shares early this week slid 5%, from $50.94 to $48.30 on Wednesday.

Allen acknowledged that CRD-TMH-001, which uses an AAV delivery approach, was not very similar to Intellia’s candidates—but added: “We note the death of a patient in another CRISPR study could lead regulators to take a cautious view of this space and may adversely impact investor sentiment.”

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 Therapeutics as well since that company on Monday also announced a regulatory delay.

In releasing third-quarter results, 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. Instead, Beam added, it will prioritize the BEACON trial (NCT05456880), designed to assess the company’s lead base editing candidate BEAM-101, being developed to treat sickle cell disease.

“A frustrating development in 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.”

BEAM shares sank 11% on Monday, from $42.80 to $37.91, then inched up 1% to $38.39 before dipping 1% to $37.88

Bankruptcy scenario flattens Clovis

Clovis Oncology (CLVS) shares cratered 72% in early trading Wednesday, from $0.98 to $0.2781, after the company acknowledged the strong possibility that it may file for Chapter 11 bankruptcy protection from creditors.

“A potential bankruptcy filing in the very near term looks increasingly probable as a way to preserve the value of our business and assets for the benefit of our stakeholders,” Clovis stated Wednesday in its latest Form 10-Q quarterly filing, which covers the third quarter of 2022.

Clovis also cited “continuing challenges we face” in raising additional capital, without elaborating. The company seeks to rebuild its cash and cash equivalents, which have plunged 59% over the past nine months to $58.32 million as of September 30, from $143.428 million as of December 31, 2021.

Based on our current cash and cash equivalents, together with current estimates for revenues to be generated by sales of Rubraca®, we must raise additional capital in the near term in order to fund our operating plan and to continue as a going concern beyond January 2023,” Clovis added.

Clovis is reeling in part from slumping sales of its marketed ovarian cancer drug Rubraca (rucaparib) due to competition from newer treatments with similar indications as well as fewer diagnoses of cancer over the past two years as lockdowns during the pandemic kept many patients at home while healthcare practices refocused on treating patients with COVID-19.

Rubraca finished 2021 with $148.757 million in global net product revenues, down nearly 11% from $164.522 million a year earlier. U.S. product revenues accounted for the year-over-year slump, falling 21% last year, to $115.7 million from $146.3 million in 2020. Outside the U.S., by contrast, Rubraca net product revenues nearly doubled, rising 82% to $33.1 million in 2021 from $18.2 million.

The slump in sales has raised uncertainty over the market potential of Rubraca which has hampered recent efforts to raise capital, Clovis stated.

Clovis is also blaming a regulatory factor for teetering on the edge of bankruptcy.

Over recent months, the FDA has shifted its review of poly (ADP-ribose) polymerase (PARP) inhibitors like Rubraca to overall survival (OS) data—a change that according to Clovis “has created uncertainty with respect to the timing, likelihood, and scope of an approval” for the supplemental NDA filed by company with the FDA for Rubraca as a first-line maintenance treatment for women with advanced ovarian cancer regardless of biomarker status who have responded to first-line platinum-based chemotherapy.

The regulatory shift also “may result in uncertainty” for the company’s Type II variation filing for a similar indication with the European Medicines Agency, “which we had been planning on to finally level the competitive landscape with our two competitors that have existing and established labels in the first-line maintenance treatment indication setting,” Clovis stated.

Those two PARP inhibitor competitors are the AstraZeneca/Merck & Co. co-developed Lynparza® (olaparib), and GlaxoSmithKline (GSK)’s Zejula® (niraparib).

Both products generate more for their companies than Rubraca does for Clovis. GSK reported £338 million ($385 million) in Zejula revenues during the first nine months of 2022. Lynparza finished the first half of 2022 with $1.291 billion in sales for AstraZeneca and $541 million in profits for Merck. (AstraZeneca is set to report Q3 results Thursday, for which Merck has recorded an additional $284 million in quarterly profits).

GSK is seeking FDA advice on whether to withdraw from its label its second-line maintenance indication in ovarian cancer based on final OS data from the trial that supported approval for Zejula in that indication. The FDA had scheduled a meeting of its Oncology Drugs Advisory Committee (ODAC) for this month, only to cancel that meeting, indicating that it was no longer necessary.

“While neither the FDA nor GSK have publicly stated the reason for the cancelation of the meeting, if the outcome of discussions between the FDA and GSK is a withdrawal or narrowing of that indication, we cannot assure you that the FDA would not seek to similarly limit our second line maintenance indication in ovarian cancer,” Clovis cautioned. “As a substantial portion of our Rubraca revenue is attributable to that indication, we would expect that a limiting of our second line maintenance indication could result in a significant impact on our revenue, although the timing and magnitude of such impact is not currently ascertainable.”

“This new regulatory framework has created an uncertain commercial landscape for Rubraca (and to a certain extent, other PARP inhibitors) and has impacted the perceived market opportunity and revenue potential for Rubraca (and to a certain extent, other PARP inhibitors.”

Clinical hold sinks Inhibikase shares

Inhibikase Therapeutics (IKT) shares plummeted 41% on Monday, from $0.7724 to $0.3174, after the company acknowledged that the FDA had placed a clinical hold on the company’s Phase IIa 201 trial (NCT05424276) assessing its lead candidate IkT-148009 in untreated Parkinson’s disease (PD), and the company’s program evaluating IkT-148009 in multiple systems atrophy (MSA).

Inhibikase did not detail what led to the clinical hold, only saying that it expected to receive an official clinical hold letter from the FDA within 30 days of the agency’s notification to the company.

“We have not seen any serious adverse events in the ongoing 201 trial and we remain committed to our mission to improve the lives of patients suffering from devastating neurodegenerative diseases,” Milton H. Werner, PhD, Inhibikase’s’ president and CEO, said in a statement. “Given the safety, tolerability, and pharmacokinetics data observed in clinical trials with IkT-148009 to date, we are actively working with the FDA to understand the agency’s concerns and to resolve them as soon as possible.”

IkT-148009 is a selective c-Abl kinase inhibitor designed to inhibit not only c-Abl but the Abl2/Arg enzyme as well, without inhibiting other members of the Abl-kinase family, such as c-Kit or PDGFRa/b. According to Inhibikase, IkT-148009 has nearly 25 times the potency of Novartis’ anticancer agent Gleevec® (imatinib) against wild-type c-Abl in enzyme inhibition assays.

Shares of Inhibikase rebounded 9% as of midday Tuesday, to $0.4981.

Ipsen’s Phase III win is a triple play for Merrimack

Merrimack Pharmaceuticals (MACK) saw its shares more than triple on Wednesday, rocketing 213% from an even $4 to $12.51, after licensee Ipsen announced that it intended to file a supplemental New Drug Application with the FDA for Onivyde in combination with a chemotherapy regimen for the treatment of patients with previously untreated metastatic pancreatic ductal adenocarcinoma (mPDAC).

Ipsen licensed Onivyde and several global oncology assets from Merrimack in 2017 for up to $1.025 billion—$575 million in cash and up to another $450 million in regulatory milestones. The potential $450 million consists of $225 million if the drug achieves FDA approval in first-line pancreatic cancer, $150 million for FDA approval in small cell lung cancer, and $75 million for FDA approval in any third indication.

Ipsen said its decision followed the combination of Onivyde® (irinotecan liposome injection) and 5 fluorouracil/leucovorin and oxaliplatin (also called the NALIRIFOX regimen) meeting the primary endpoint of the Phase III NAPOLI 3 trial (NCT04083235). Onivyde plus chemo demonstrated clinically meaningful and statistically significant improvement in overall survival compared to nab-paclitaxel plus gemcitabine in 770 previously untreated patients with mPDAC.

Onivyde plus chemo also met the key secondary efficacy outcome of progression-free survival (PFS) by showing significant improvement over the comparator arm, Ipsen added.

Ipsen did not detail NAPOLI 3’s results, saying that they will be presented at an unspecified “upcoming medical conference.”

Viatris acquisition lifts Oyster Point

Oyster Point Pharma (OYST) shares jumped 39% on Monday, from $8.35 to $11.57, after the developer of drugs for ophthalmic disease announced that Viatris (VTRS) had agreed to acquire the company. Viatris shares that day rose 13%, from $9.70 to $10.97.

The Oyster Point deal is one of two acquisitions totaling between $700 million and $750 million announced Monday by Viatris, the company formed in 2020 through the merger of Mylan and Pfizer’s Upjohn division. The other acquisition was Famy Life Sciences, a privately-held *drug developer in specialties that include oncology, dermatology—and ophthalmology.

By snapping up both companies, Viatris reasons it has the underpinnings of a leading ophthalmology franchise that would add Oyster Point’s marketed dry eye disease treatment Tyrvaya® (varenicline solution) and Famy’s Phase III-ready pipeline to Viatris’ global commercial footprint, supply chain, as well as R&D and regulatory capabilities.

While the value of each individual acquisition was not disclosed, Viatris and Oyster Point did say that Viatris was acquiring Oyster Point for $11 per share cash, plus one non-tradeable contingent value right (CVR) of up to an additional $2 per share, tied to Oyster Point achieving unspecified metrics based on full year 2022 performance.

Based on the 26,831,485 shares of common stock disclosed by Oyster Point in its last Form 10-Q quarterly filing on August 5, the value of the deal would range from $295.146 million, up to $348.809 million if Oyster Point performed well enough for Viatris shareholders to earn the additional CVR payout.

Viatris said it aims to close the acquisition of Oyster Point in Q1 2023, subject to customary closing conditions that include regulatory approvals and tender acceptance of more than 50% of Oyster Point shares.

Viatris reasons that by 2028, Oyster Point and Famy could add at least $1 billion in sales; Viatris is projecting 2022 total revenues of between $16.2 billion and $167.7 billion.

In the days after the announcement, Oyster Point shares finished flat, barely rising 0.17% to $11.59 on Tuesday and dipping nearly 1% on Wednesday to $11.52. Viatris saw its shares inch up 1% to $11.10 on Tuesday and slide 2% to $10.83 on Wednesday.

Veru plunges after FDA panel rebuff

Veru (VERU) shares plunged 59% at the start of trading Thursday morning, from $15.01 to $6.20, then rose to $6.59 10 minutes later (still down 56%) after the FDA’s Pulmonary-Allergy Drugs Advisory Committee concluded Wednesday in an 8-5 vote that the known and potential benefits of the company’s sabizabulin oral capsule (also called VERU-111) do not outweigh the treatment’s potential risks when used for treatment of adult patients hospitalized with COVID-19 at high risk of acute respiratory distress syndrome (ARDS).

The FDA does not have to abide by the recommendations of this or other advisory panels, though the agency usually does.

“We look forward to continuing to work with the FDA as we continue our efforts to ensure that this product is available to patients in a timely manner,” stated Mitchell Steiner, MD, Veru’s chairman, president, and CEO.

Earlier this week, by contrast, shares leaped 40% on Monday, from $10.35 to $14.44, and climbed another 4% on Tuesday to $15.01 based on apparent confidence from investors that the FDA would authorize emergency use of sabizabulin to treat SARS-CoV-2 infection in hospitalized patients with moderate to severe COVID-19 infection and who are at high risk of ARDS.

That confidence came despite several concerns highlighted by FDA staffers in a briefing document to the committee.

Veru supported its EUA application with data from the Phase III Study V3011902 (NCT04842747), in which 134 of 204 patients received the drug for up to 21 days. The trial, also called Study 902, showed that sabizabulin met the primary endpoint of all-cause mortality 60 days after treatment: 78.4% of patients treated with sabizabulin remained alive compared to 58.6% of patients randomized 2:1 between the drug and placebo.

While acknowledging the trial met its primary endpoint, FDA staffers questioned the small size of the patient population, and raised concerns that included:

  • A high placebo group mortality rate of 39.7%.
  • Potential for unblinding events with enteral tube administration
  • Baseline imbalances in standard of care therapies
  • Differences in hospitalization duration prior to trial enrollment
  • Uncertain effects of goals of care decisions on all-cause mortality
  • Negative studies with other microtubule disruptors in COVID-19
  • Uncertainty in identification of a clinically relevant patient population

“Based on our review, none of these uncertainties or imbalances alone invalidate the mortality benefit observed in Study 902, but all of these issues together in a small trial which is more vulnerable to imbalances raise questions about the results,” the FDA staffers asserted.

“We propose that there is equipoise in conducting a trial similar to Study 902, to address the uncertainties in the mortality data as well as to expand the safety database.”

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