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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.”