Landmark Approval: First CRISPR Therapy Approved by FDA

Today, the US Food and Drug Administration (FDA) approved exagamglogene autotemcel (exa‑cel), the first CRISPR-based gene therapy for the treatment of sickle cell disease (SCD). Exa‑cel was co-developed by Vertex Pharmaceuticals and CRISPR Therapeutics. This is a landmark approval that paves the way not only for better outcomes for patients with SCD, but for many diseases that require a gene-editing therapeutic approach. Vertex has filed for approval of exa-cel in a second therapeutic indication – beta thalassemia – and FDA will decide whether to approve it by March 30, 2024. Exa‑cel recently received approval in the United Kingdom for the treatment of SCD and transfusion-dependent beta thalassemia.

In a previous blog post, we highlighted a number of CRISPR-based therapies in development, including exa-cel, and the promising future of this technology. What began in 2012 with the discovery of CRISPR/Cas9 gene editing by Emmanuelle Charpentier (Max Planck Unit for the Science of Pathogens, Berlin, Germany) and Jennifer Doudna (University of California, Berkeley, USA) translated into a flurry of clinical research and resulted in an FDA advisory committee meeting in October 2023 to discuss potential safety concerns and the benefit/risk profile of exa-cel.

Cellular, Tissue, and Gene Therapies Advisory Committee (CTGTAC) Meeting Outcome

On October 31, 2023, the CTGTAC met to discuss the clinical benefit of exa-cel for the treatment of SCD and analyses to identify and quantify the potential risk of off-target genome editing. There was no voting question at this meeting; the committee was asked to discuss the sponsor’s off-target analysis and provide recommendations for additional studies (if needed) to assess the risk of off-target editing.

There were two guest speakers before the applicants presented: Dr. Fyodor Urnov (University of California, Berkeley) presented a very comprehensive historical review of three decades of genetic editing research and Dr. Daniel E. Bauer (Boston Children’s Hospital) reviewed the potential off-target effects of existing genetic editing technology. They then fielded questions from the committee about off-target effects and what they might mean clinically for patients. One committee member asked, “theoretically, is it catastrophic?” The discussion highlighted the fact that there remains a measure of uncertainty regarding the potential clinical consequences of off-target effects – it’s possible that they could do nothing, but truly the only way to know is long-term follow-up of treated patients.

In their sponsor presentation, Vertex Pharmaceuticals highlighted the fact that exa-cel demonstrated “transformative efficacy, a strong safety profile, and a highly positive benefit-risk for patients with SCD.” Vertex also reiterated that there were no off-target effects observed in the clinical trials, the fact that the patients’ stem cells are only transiently exposed to the Casp9 complex, and that exa-cel was generally safe and well tolerated. Questions from the committee were generally focused on off-target effects, long-term treatment effects, the need for re-treatment, and potential off-target effects if the patient was to subsequently receive a different genetic therapy. The Sponsor responded that exa-cel is intended to be a one-time treatment without any anticipated need for re-treatment and assured the panel that the cells only see the Casp9 briefly and only when the cells are outside the body.

Although the committee did feel that additional studies should be undertaken to explore the potential off-target effects of gene editing, they generally agreed that the “benefits far outweigh the risks,” even if those risks are not fully understood at this time, and the “evidence for the efficacy is overwhelming.” Ultimately, the only way to truly understand the long-term risks is to treat patients and continue following them for many years (currently, a 15-year registry has been submitted as a proposed postmarketing safety study).

Patient Perspectives

Powerful patient accounts of feeling “reborn” and life-changing treatment are surfacing and were shared during the open public hearing at the meeting, although they are tempered by descriptions of the arduous treatment process requiring long hospital stays, chemotherapy, and time away from work and family. The cost of treatment may also be a barrier to access.

However, the FDA’s approval of exagamglogene autotemcel (exa-cel), the first CRISPR-based gene therapy, signals a significant advancement in the use of gene editing to treat disease. This approval will positively impact research in many therapeutic areas and the lives of many future patients who may receive CRISPR-based treatments.

Jackie Orabone, PhD, helps clients prepare for FDA Advisory Committee meetings by combining her scientific expertise and research knowledge in immunology with medical communications agency experience. Connect with Jackie on LinkedIn.