FDA Staff Call for Further Study Considerations for Exa-Cel Ahead of Decision in Sickle Cell


The therapy’s PDUFA date is scheduled for December 8, 2023, and an Advisory Committee is set to meet on October 31, 2023, to discuss the treatment’s potential approval for sickle cell disease.

Staff reviewers at the FDA have asked the agency’s advisory committee (AdComm) to make considerations for the need for additional clinical studies of Vertex Pharmaceuticals and CRISPR Therapeutics gene-editing therapy exagamglogene autotemcel (exa-cel), an investigational treatment for sickle cell disease (SCD) and transfusion-dependent β-thalassemia (TDT).1

First reported by Reuters, the news comes just a short time ahead of the pending Presciption Drug User Fee Action (PDUFA) date for the treatment’s biologics license application (BLAs), which the agency accepted for review in June 2023.2 The agency had granted the BLA a priority review designation for SCD with a PDUFA target action date of December 8, 2023, and standard peview for TDT with a PDUFA target action date of March 30, 2024.

Currently, there is a meeting of the FDA’s Cellular, Tissue, and Gene Therapies AdComm to discuss this treatment scheduled for this week on Tuesday, October 31, 2023.3

The request for further study appears to be centered around postmarketing evaluation after the potential approval of the therapy, according to Reuters. Per the report, the FDA's staff pointed to the concerns about off-target genomic alterations, as well as the small sample size utilized in the lab analysis, which the agency staff suggested may not adequately allow for safety assessment—mainly because of a lack of real-world translatability, considering the diverse US patient population with sickle cell. Notably, no concerns have been raised about the therapy's efficacy.

Key Takeaways

  1. The FDA's staff has requested additional clinical studies for Vertex Pharmaceuticals and CRISPR Therapeutics' gene-editing therapy, exagamglogene autotemcel (exa-cel), intended for sickle cell disease (SCD) and transfusion-dependent β-thalassemia (TDT) treatment. The request is primarily focused on postmarketing evaluation and concerns about off-target genomic alterations.
  2. The treatment's biologics license application (BLA) is under review by the FDA, with a priority designation for SCD and a standard review for TDT. A meeting of the FDA's Cellular, Tissue, and Gene Therapies Advisory Committee is scheduled for October 31, 2023, to discuss the therapy.
  3. Exa-cel's BLAs are supported by data from phase 3 clinical trials, which demonstrated its efficacy, particularly in achieving freedom from vaso-occlusive crises and improving patient-reported outcomes. No concerns have been raised about the therapy's effectiveness.

Exa-cel’s BLAs are supported by data from 2 ongoing phase 3 clinical trials—CLIMB-111 (NCT03655678) in TDT and CLIMB-121 (NCT03745287) in SCD—as well as a long-term follow-up study—CLIMB-131 (NCT04208529)—that includes patients with both disorders. Updated data from the studies was presented at the European Hematology Association (EHA) 2023 Congress, held June 8-11, both virtually and in Frankfurt, Germany.4

Those data showed that of 17 patients evaluable patients, 16 (94.1%) achieved the primary endpoint of freedom from vaso-occlusive crises (VOCs) for at least 12 consecutive months (95% CI, 71.3-99.9; P = .0001). Patients had a mean duration of 18.7 months VOC-free, ranging up to36.5 months. All patients achieved the key secondary endpoint of being free from hospitalizations related to VOCs for at least 12 consecutive months (95% CI, 80.5-100.0; P <.0001). Fetal hemoglobin of 30% to 40% was maintained throughout the study and patients also had clinically significant improvements in patient-reported outcomes.

READ MORE: Vertex Doses First Patient in Phase 1/2 Trial of VX-264 in Type 1 Diabetes

In June, a spokesperson from Vertex told CGTLive, “We deliberately chose CRISPR/Cas9 gene editing as our approach specifically because of its ability to deliver precise, permanent edits at a single desired location, without evidence of off-target effects. And we are very pleased with the strength of our data for exa-cel—efficacy, safety and durability of response—and we believe the data presented at EHA established a differentiated profile in SCD.”

Additionally, in July 2023, the Institute for Clinical and Economic Review (ICER) published a finalized version of its evidence report assessing the cost effectiveness of gene therapy for SCD, namely exa-cel and another investigational product, lovotibeglogene autotemcel (lovo-cel, bluebird bio).5 The report, an updated version of a May 2023 draft,6 included revisions and was reviewed at a virtual public meeting of the California Technology Assessment Forum on July 27, 2023.

Although much of the report remains the same as the earlier iteration, ICER did update the calculated health-benefit price benchmark for lovo-cel and exa-cel to be between $1.35M to $2.05M. The report was a collaborative project with patients, clinicians, and caregivers providing commentary about quality of life, safety, access, and outcomes with standard-of-care (SOC) and gene therapy for SCD, as well as health economists, payers, and manufacturers, to compare cost-effectiveness. SOC for SCD consists of supportive care, hydroxyurea, and blood transfusions in some patients.

David Rind, MD, the chief medical officer at ICER, said in a statement at the time,7 “From the earliest days of gene therapy, patients, families, and clinicians have imagined that someday it might be possible to address the underlying genetics of SCD to achieve a cure. These first 2 genetic therapies, using different technologies and altering different genetic targets may mean that day has nearly arrived. However, the need for autologous bone marrow transplantation with these therapies means they come with important potential risks, and the first CRISPR therapy necessarily has even greater uncertainties about longer-term risks and durability of benefit than a lentiviral gene therapy.”

1. Roy S. UPDATE 3-US FDA advisers to determine need for more studies of Vertex/CRISPR gene therapy. Reuters. October 27, 2023. Accessed October 27, 2023. https://www.reuters.com/business/healthcare-pharmaceuticals/us-fda-advisers-consider-need-more-studies-vertexcrispr-gene-therapy-2023-10-27/
2. FDA accepts Biologics License Applications for exagamglogeneautotemcel (exa-cel) for severe sickle cell disease and transfusion-dependent Beta thalassemia. News release. Vertex Pharmaceuticals. June 8, 2023. Accessed October 27, 2023. https://investors.vrtx.com/news-releases/news-release-details/fda-accepts-biologics-license-applications-exagamglogene
3. FDA. Cellular, Tissue, and Gene Therapies Advisory Committee October 31, 2023 Meeting Announcement. Accessed October 27, 2023. https://www.fda.gov/advisory-committees/advisory-committee-calendar/cellular-tissue-and-gene-therapies-advisory-committee-october-31-2023-meeting-announcement-10312023
4. Positive Results From Pivotal Trials of exa-cel for Transfusion-Dependent Beta Thalassemia and Severe Sickle Cell Disease Presented at the 2023 Annual European Hematology Association (EHA) Congress. News release. Vertex Pharmaceuticals. June 9, 2023. Accessed October 27, 2023. https://investors.vrtx.com/news-releases/news-release-details/positive-results-pivotal-trials-exa-cel-transfusion-dependent
5. ICER. Gene Therapies for Sickle Cell Disease Evidence Report. July 13, 2023. Accessed October 27, 2023. https://icer.org/wp-content/uploads/2022/11/ICER_SCD_revisedreport_071323.pdf
6. Gene therapies for sickle cell disease. Draft Evidence Report. ICER. April 12, 2023. Accessed July 14,2023. https://icer.org/wp-content/uploads/2023/04/SCD_FOR-PUBLICATION.pdf
7. ICER publishes evidence report on gene therapies for sickle cell disease. News release. ICER. July 13, 2023. Accessed October 27, 2023. https://icer.org/news-insights/press-releases/icer-publishes-evidence-report-on-gene-therapies-for-sickle-cell-disease/
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