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Whether the investigational sickle cell disease therapy exagamglogene autotemcel (exa-cel) has adequately proven that it won't produce off-target genetic changes was questioned by FDA reviewers ahead of an advisory committee meeting.

The gene-editing CRISPR technology underpinning exa-cel -- a product of a partnership between Vertex Pharmaceuticals and CRISPR Therapeutics -- is the first of its kind to come before the agency for an approval decision. Exa-cel has demonstrated positive results in patients with transfusion-dependent beta-thalassemia and severe sickle cell disease.

However, in released in advance of the Cellular, Tissue, and Gene Therapies Advisory Committee meeting on Tuesday, the FDA reviewers expressed concern about whether the gene-editing therapy will make unwanted changes to patients' DNA.

FDA staff pointed out that exa-cel is produced from patient hematopoietic stem and progenitor cells (HSPCs) using CRISPR/Cas9 genome editing to reactivate fetal hemoglobin (HbF), and that genome editing has the potential to produce unintended genomic alterations or off-target editing.

In its , Vertex said extensive off-target assessment in CD34-positive samples from both healthy donors and sickle cell disease patients "revealed no detectable off-target edits or evidence of chromosomal abnormalities following treatment with exa-cel."

FDA staff noted that in the evaluation of off-target editing for exa-cel in the target population, Vertex Pharmaceuticals and CRISPR Therapeutics used both in silico and cell-based assays.

"However, the limited amount of sequencing data present in the reference database for the in silico analysis may not adequately capture variants in this population," the agency's reviewers wrote. "For the cellular off-target analysis, the applicant used HSPCs from a small number of healthy donors, transfusion-dependent beta-thalassemia, and SCD [sickle cell disease] donors. Additionally, the healthy donor cells may not adequately capture off-target editing in exa-cel due to potential differences in the chromatin landscape in SCD donor cells."

The advisory committee will discuss the off-target analysis performed by Vertex and CRISPR Therapeutics and provide recommendations about any additional studies that should be performed to inform the risk of off-target editing in patients who receive exa-cel.

While expressing concerns about the off-target effects of exa-cel, FDA staffers appeared to be convinced the therapy is effective.

In the pivotal clinical study (), 29 of 30 evaluable patients (96.7%) achieved the primary efficacy endpoint of the absence of severe vaso-occlusive crises (VOCs) for at least 12 consecutive months. Of those 29 patients, 28 remained free of VOCs for a mean duration of 22.3 months, with a maximum of 45.5 months.

Vertex called the magnitude of this effect "transformational," considering that the patients in this analysis had a mean of almost four VOCs per year in the 2 years prior to screening.

All 30 evaluable subjects met the key secondary endpoint of freedom from inpatient hospitalization for severe VOCs for at least 12 consecutive months. In addition, all six adolescents included in the primary efficacy analysis achieved absence of severe VOCs for at least 12 consecutive months.

These endpoints were supported by hematologic parameters and evidence of allelic editing in the bone marrow and peripheral blood. After exa-cel infusion, HbF increased rapidly, with the mean HbF greater than 40% by month 6. Individual patient HbF levels were stable through the duration of follow-up.

FDA staff noted that while this data provide evidence of exa-cel's efficacy, it comes from a single primary study that was uncontrolled and small.

"Such single-arm studies are subject to various biases that can limit confidence in the magnitude of the treatment effect," they wrote. "However, given the strongly positive results, FDA does not believe that the study design limitations call the efficacy of exa-cel into question."

While the FDA is not required to follow the advice of its advisory committees, it typically does. The agency is expected to decide by December 8 on whether to grant exa-cell an indication in sickle cell disease.

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