An FDA Cellular, Tissue, and Gene Therapies Advisory Committee (AdComm) discussion was generally favorable towards Vertex Pharmaceuticals and CRISPR Therapeutics’ autologous gene-edited cell therapy exagamglogene autotemcel (exa-cel), an investigational treatment for sickle cell disease (SCD) and transfusion-dependent β-thalassemia (TDT), ahead of ahead of its Prescription Drug User Fee Act action date for SCD, which is slated for December 8, 2023.1
The committee spoke on the question: “Please discuss the Applicant's off-target analysis (eg, in silico and cellular methods) and provide recommendations for additional studies, if needed, to assess the risk of off-target editing for exa-cel?” During the discussion, the members of the AdComm were generally of the opinion that the off-target analyses conducted by Vertex were reasonably robust, and that in light of the positive efficacy data demonstrating transformative potential for a patient population with very great unmet need, further risk analyses prior to approval are unlikely to be necessary.
“We want to be careful to not let the perfect be the enemy of the good,” Gil I. Wolfe, MD, the professor and chairman of Neurology at the University at Buffalo, said during the discussion. “Right now, I feel that you can do a lot of in-depth analysis with regard to cellular analysis and in silico analysis... But at some point you have to just try things out in patients and at this point I think there’s a huge unmet need in patients with SCD and it’s important we think about how we can advance therapies that could potentially help them. I certainly think that this is one of them.”
As such, the discussion shifted mainly to whether additional postmarketing research on the potential risks posed by the therapy could be worthwhile. Among the suggestions put forth by the members were monitoring edits in real time, use of whole genome sequencing and long-range sequencing, prescreening for the presence of the CPS1 variant in patients, and further investigation of off-target editing in treated patients who are known to have the CPS1 variant and following up with outcomes for these patients.
“I think most of us agree that the benefits outweigh the risks; these patients are quite sick and this is a very good therapy,” Joseph Wu, MD, PhD, the director of the Stanford Cardiovascular Institute, said. “I think the question for us on the biology side is: What is the frequency of these off-target effects? Unless you do whole genome sequencing, you wouldn’t know. It’s very inexpensive, it costs less than $1,000... Do it on 20 of your patients and see what the data looks like. This is information that can be further fed into their artificial intelligence machine learning in silico model to help improve the whole process and this could also help improve the whole field. I just don’t understand why there’s the hesitation of doing it.”
- The FDA's Cellular, Tissue, and Gene Therapies Advisory Committee discussed Vertex and CRISPR's exa-cel for Sickle Cell Disease and found Vertex's off-target analyses to be robust.
- The committee suggested further postmarketing research to monitor edits in real time, use whole genome sequencing, and prescreen for specific variants in patients. This data will be crucial to understanding long-term safety.
- The FDA's concerns centered around the in silico and cellular analysis, highlighting discrepancies in data, small sample sizes, and the need for more comprehensive empirical testing to ensure off-target editing risks are well-understood prior to approval.
Prior to the discussion portion, Vertex’s argument in favor of approval of the biologics license application (BLA) for exa-cel in SCD was made based on efficacy and safety data from the phase 1/2/3 CLIMB-121 clinical trial (NCT03745287), which was conducted exclusively in patients with SCD, and the phase 3 long-term follow-up study CLIMB-131 (NCT04208529), which includes both patients with SCD and patients with TDT. In terms of efficacy, the company reported that among 30 evaluable patients with SCD, 29 (97%) achieved the primary end point of freedom from vaso-occlusive crises (VOCs) for at least 12 consecutive months. Furthermore, among the 30 patients, all 30 (100%) achieved a key secondary end point for freedom from inpatient hospitalization for VOCs for at least 12 consecutive months. It was noted that 6 adolescent patients achieved both of these end points. The patient who did not achieve the primary end point was also an adolescent patient.
In terms of safety, exa-cel was reported to be generally safe and well-tolerated in the clinical trials with a safety profile consistent with what would be anticipated in patients receiving myeloablative busulfan conditioning and hemopoietic stem cell transplantation. The only risk specific to exa-cel identified in the clinical safety data was delayed platelet engraftment.
Because long-term safety was the focus of the AdComm meeting, the company also built on its argument with a package of nonclinical safety data, which included in silico and cellular analyses, regarding the risk of off-target editing from exa-cel. The key findings of this group of nonclinical studies, as summarized in the company’s presentation, were that on-target edits are limited to the erythroid-specific enhancer, that editing did not impact the distribution and persistence of cells post transplant, and that there was no evidence of chromosomal abnormalities and no evidence of off-target editing. Furthermore, the company noted that in a GLP mouse toxicity study, there was no evidence of exa-cel having tumorigenicity.
The FDA’s response to Vertex found common ground with the company on the clinical efficacy and safety results, with concerns mainly focused on the nonclinical data package and the long-term safety risks related to the potential for off-target editing. Specific concerns were raised with the in silico and heterogeneity analysis presented by the company. Some of the concerns highlighted in the FDA’s summary of the issues were the different number and subset of nucleotide variations that were identified in the 2 in silico studies as contributing to off-target loci, the database used containing only a small amount of sequencing data from exa-cel's target population, the fact that the majority of off-target loci arising from variants were not empirically tested, and the fact that only a small subset of in silico nominated loci were experimentally tested. The agency also raised concerns with the cellular off-target editing analysis of exa-cel presented by the company, pointing out the small sample size and the use of a limited number of samples from patients with SCD alongside samples from healthy donors. The agency noted that off-target loci identified by the cellular analysis did not overlap with the 171 off-target loci nominated with the in silico analyses and that it is unclear whether analyses using healthy donor cells would be informative for the risks in the target population for exa-cel.
Notably, several days prior to the AdComm meeting, staff reviewers at the FDA had called for consideration of the need for further clinical study in relation to the concerns of off-target editing and the small sample size used in the lab analysis.2 Although, no concerns were raised about the therapy's efficacy.
“There seems to be a lot of uncertainty and a lot of unknowns about what these off-target changes might mean; that was repeated over and over this morning,” Lisa Lee, PhD, the associate vice president for scholarly integrity and research compliance at Virginia Tech, added during the discussion. “Given the theoretical possibilities, are those unknowns more harmful than not allowing this to go forward?... Given what people are dealing with right now, and given that the evidence for the efficacy of this treatment is overwhelming, I really wonder what would we not be able to tolerate with respect to the unknowns?”
1. 76th Cellular, Tissue, and Gene Therapies Advisory Committee (CTGTAC) Meeting. October 31, 2023. https://www.fda.gov/advisory-committees/advisory-committee-calendar/cellular-tissue-and-gene-therapies-advisory-committee-october-31-2023-meeting-announcement-10312023
2. 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/