The FDA late last week set for December a groundbreaking decision on whether to grant its first-ever approval for a CRISPR-Cas9 gene-edited therapy—but the milestone so far doesn’t seem to be wowing investors judging from the flat stock prices of the companies involved.

Shares of CRISPR Therapeutics (CRSP) and Vertex Pharmaceuticals (VRTX) haven’t budged much since Thursday evening, when the companies announced that the FDA had accepted their Biologics License Applications (BLAs) seeking approval for exagamglogene autotemcel (exa-cel) in both severe sickle cell disease (SCD) and transfusion-dependent beta thalassemia (TDT).

CRISPR shares dipped 2% on Friday, the first trading day after the announcement, from $62.59 to $61.24 as of 2:21 p.m. ET. Vertex shares did slightly better, rising 0.5% from $332.58 to $334.11. The companies continued along their respective trajectories on Monday, with CRISPR dipping further to $59.97 as of 1:25 p.m., and Vertex crawling up to $336.85 as of 2:22 p.m.

The FDA split its BLA decisions on exa-cel by granting Priority Review in SCD, but a longer standard review for the therapy in TDT. As a result, the agency assigned Prescription Drug User Fee Act (PDUFA) target action dates of December 8 for the SCD application, but will hold off till March 30, 2024 for deciding the BLA in TDT.

As explained by Baird and a second analyst, Maury Raycroft, PhD, of Jefferies, the FDA set a slower BLA review for exa-cel in TDT because that indication has already seen a relatively new therapy enter the market—the Bluebird Bio (BLUE) first-in-class, one-time ex-vivo lentiviral vector cell-based gene therapy Zynteglo® (betibeglogene autotemcel or “beti-cel”). Zynteglo received agency approval in August 2022 as the first cell-based gene therapy for the treatment of adults and children with beta-thalassemia who require regular red blood cell transfusions.

Bluebird is likely to factor into the FDA’s decision on exa-cel for another reason: The company is awaiting word from the FDA on a BLA announced April 24 for another SCD treatment, lovotibeglogene autotemcel (lovo-cel), a one-time gene therapy indicated for sickle cell patients ages 12 and older who have a history of vaso-occlusive events.

Bluebird is expected to hear within two weeks about the status of its BLA for lovo-cel, formerly called LentiGlobin® or bb1111.

A likely reason for the seeming indifference of investors was posited by Jack K. Allen, CFA, senior research analyst with Baird. In a research note, he wrote that investors were holding off judgment till this week, after CRISPR and Vertex present updated data on exa-cel at the Annual European Hematological Association (EHA) Congress from clinical studies.

“This data update could have key read-throughs to the potential the competitive dynamics between exa-cel and lovo-cel (though we expect the clinical profiles of these assets to be more similar than different),” Allen wrote.

In advance of EHA, Vertex and CRISPR issued a press release containing select data from both pivotal trials for exa-cel in patients, one in SCD, the other in TDT. Both pivotal trials met primary and key secondary endpoints at pre-specified interim analyses, the companies said.

The companies shared data on 83 patients dosed with exa-cel and followed up for up to 43.7 months. The 83 included 48 TDT patients studied in CLIMB-111 (NCT03655678) and 35 SCD patients assessed in CLIMB-121 (NCT03745287). Patients in both trials were among patients studied in an ongoing long-term (up to 15 years), open-label trial, called CLIMB-131 (NCT04208529).

Of the 35 SCD patients, 17 patients were evaluable for the primary and key secondary endpoint. Sixteen of the 17 (94%) achieved the primary endpoint of freedom from vaso-occlusive crises (VOCs) for at least 12 consecutive months. The mean duration of being VOC-free was 18.7 months, with one patient achieving 36.5 months.

All 17 achieved the key secondary endpoint of being free from hospitalizations related to VOCs for at least 12 consecutive months (HF12). The one HF12 patient who did not achieve VF12 had “a complex set of comorbidities, including a history of chronic pain,” Vertex and CRISPR explained. And one of the VF12 patients had a VOC 22.8 months after exa-cel infusion resulting from a parvovirus infection. The patient fully recovered from the infection and has since been VOC-free, the companies reported.

Of the 48 TDT patients, 27 were evaluable—of which 24 (88.9%) achieved the primary endpoint of transfusion-independence for at least 12 consecutive months (TI12) and the secondary endpoint of transfusion-independence for at least six consecutive months. The mean duration of transfusion-independence was 20.5 months with a maximum of 40.7 months.

Among the patients who did not achieve TI12, one has since stopped transfusions and has been transfusion-free for 2.9 months. The other two patients had substantial reductions of 80% and 96% in transfusion volume from baseline.

“Importantly, there are signs of durability w/ permanent editing, as proportion of edited BCL11A alleles was noted to be stable over time in bone marrow and peripheral blood,” Raycroft observed.

One question left unanswered by the FDA is whether the agency will convene an advisory committee meeting for a recommendation on exa-cel.

“Given they are a first-in-class therapy, a potential adcom would not be unusual for FDA to consider,” Raycroft said, sharing a response received from CRISPR.

Leaders & laggards

  • Akoya Biosciences (AKYA) shares fell 5% on Thursday, from $5.56 to $5.28, after the company disclosed in a regulatory filing that it had carried out a reduction in force that cost the jobs of Chief People Officer Marilee Moy and Chief Medical Officer Ehab El-Gabry, MD. “The terminations were not the result of any disagreement between the Company and Ms. Moy or El-Gabry,” Akoya stated. El-Gabry joined Akoya last year. Separately, Akoya announced Thursday that it had priced a $43.5 million common stock offering consisting of seven million shares at $5 a share. Akoya has granted the underwriters a 30-day option to purchase up to an additional 1.305 million shares at the public offering price.
  • Chinook Therapeutics (KDNY) shares surged 58% on Monday, from $23.99 to $37.97 as of 2:40 p.m. ET, after the company announced that it agreed to be acquired by Novartis for up to $3.5 billion—of which $3.2 billion would be paid upfront, with the rest to consist of a contingent value right (CVR) payment of up to $300 million tied to achieving regulatory milestones for lead program atrasentan, an oral endothelin A receptor antagonist (ERA) that is in ongoing Phase III development for Immunoglobulin A Nephropathy (IgAN).
Previous articleCancer Risk Link to Fat Accumulation and Distribution May Depend on Sex
Next articleCharles River Signs Two Gene Therapy Manufacturing Agreements