A historic moment in pharmaceuticals will happen next week: an FDA advisory committee is set to review the first-ever CRISPR gene editing-based therapy, Vertex Pharmaceuticals and CRISPR Therapeutics’ exa-cel for sickle cell disease (SCD).
But what would be even more industry changing would be securing the first such approval. Before they can do that, Vertex and CRISPR Tx will need to convince the FDA that the therapy, also known as exagamglogene autotemcel, does not cause off-target effects.
The FDA has asked the Cellular, Tissue, and Gene Therapies Advisory Committee to discuss just one question: the applicants’ off-target analysis and any recommendations for additional studies, if needed, to assess the off-target risk for exa-cel.
Vertex and CRISPR Tx are seeking approval of exa-cel for patients with SCD who are 12 years or older and have recurrent vaso-occlusive crises (VOCs).
To support their case, the companies submitted data from in silico and cellular assays. The first uses gRNA sequence information to scan the human reference genome to find potential off-target editing. But since this method only uses the reference genome, the FDA is concerned that edits specific to an SCD patient may be missed.
To try and make up for this missing information, Vertex and CRISPR Tx performed additional searches and identified 50 potential locations that could be altered. The analysis was conducted using the 1,000 genomes project database, which features whole genome sequencing for 2,504 people. But once those data were cut down into individuals of the target population, there were just 61 datasets that applied.
“The small target sample size in this database may not be sufficient for the safety assessment as it may not adequately capture variants in this population across the United States,” the FDA wrote in its briefing documents.
The FDA recommended a potentially more diverse data tool called CRISPRme that allows for the study of potential off-target effects with gene editing. A recent study on the tool used the same gene that exa-cel edits, finding a few off-target effects present in African ancestry samples.
For the cellular assays, the FDA also noted the small number of samples used by Vertex and CRISPR Tx.
“It is unclear whether the analysis using this limited sample size will provide for an adequate understanding of the potential risk of off-target editing,” the agency said.
To defend the off-target effect analysis, Vertex highlighted the many side effects of existing SCD therapies and the lack of treatment options for the VOCs that occur. There are currently no treatments available to prevent these crises, and Vertex and CRISPR Tx hope to offer one with exa-cel.
To treat the condition, patients with severe disease often have to undergo allogeneic hematopoietic stem cell transplant. This is a potentially curative approach but is not always an option for the majority of patients, Vertex said. The treatment requires a suitable stem cell donor, typically a sibling donor, which is typically only available in about 18% of cases. Risks of the procedure include graft failure, graft-versus-host disease (GVHD), severe infection, hematologic malignancy, bleeding events and death.
The safety profile of exa-cel was consistent with hematopoietic stem cell transplant, with “a highly positive benefit-risk for treatment of severe SCD patients,” Vertex said. Patients are sufficiently monitored post-treatment. Individuals who were enrolled in the phase 1/2/3 trial that underpinned the application are being followed for 15 years. The companies also plan to conduct a long-term post-marketing study following patients who have received the commercial product for 15 years.
Vertex said there were no off-target effects identified in preclinical studies and the therapy was designed using a highly specific guide sequence that has no off-target effects. Exa-cel precisely edits the site of the naturally occurring genetic variant that is associated with SCD severity.
Analysts from William Blair noted that the FDA’s focus was on the possible off-target effects of exa-cel, but did not question the efficacy or even safety. RBC Capital Markets called the AdComm query "pretty benign."
The key question, therefore, is whether the FDA will ask for more studies to elucidate potential off-target effects, and if so, whether Vertex and CRISPR Tx must do that before approval, according to William Blair. The companies have the additional post-marketing study already planned.
“Importantly, the FDA stated it does not believe the study design limitations, including the single-arm design, small sample size, or duration of long-term follow-up, call into question the efficacy of exa-cel,” William Blair analysts wrote in a Friday morning note. “We view today’s AdComm briefing documents as a near-best-case scenario for CRISPR/Vertex.”
Since exa-cel is the first CRISPR-based therapy to go through the FDA approval process, William Blair had been worried that the regulator’s issues would focus on the safety profile or the mechanism of action.
“In our view, the data generated to date by the CLIMB studies in TDT and SCD have demonstrated compelling efficacy with a tolerable safety profile and no clinical evidence of off-target editing, and we believe Vertex/CRISPR’s proposal of routine pharmacovigilance and post-marketing safety monitoring for exa-cel will be sufficient to address any additional off-target editing concerns,” William Blair said.
Ultimately, the firm believes the AdComm meeting “will be supportive of exa-cel’s therapeutic profile and will be a catalyst for the stock.”
RBC also thinks the favor is tipped towards approval, but still questioned how much market uptake will occur while the companies conduct such a long-term study. A key opinion leader (KOL) similarly saw the likely outcome to be positive but predicted that there will be much debate about possible blood cancers that can potentially follow treatment with exa-cel.
Vertex said there have been no reports of hematological malignancies in patients treated with exa-cel to date.
Another challenge for commercial uptake will be building out the infrastructure. The KOL noted that about 150-200 allogeneic hematopoietic stem cell transplants occur in the U.S. each year and questioned whether the manufacturing capabilities will be in place to support exa-cel.