FDA advisory meeting on exa-cel completed ahead of decision on use

Approval decision on SCD gene editing therapy expected in early December

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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An advisory committee to the U.S. Food and Drug Administration (FDA) has completed its meeting on exa-cel — formally exagamglogene autotemcel — ahead of the agency’s approval decision on the gene editing therapy, expected next month.

The meeting was scheduled as part of the FDA’s review of exa-cel, which is up for potential approval as a treatment for  sickle cell disease (SCD) and transfusion-dependent beta thalassemia. A decision on its use in SCD is expected from the FDA in early December.

CRISPR Therapeutics, which is developing exa-cel in partnership with Vertex Pharmaceuticals, did not provide details on the contents of the meeting, held by the FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee. The company stated in a press release only that the meeting had been completed.

According to briefing documents released by the FDA ahead of the meeting, a major focus of the discussion was on potential safety issues associated with exa-cel.

The regulatory agency did grant priority review to the therapy for SCD, setting a Dec. 8 date for a decision on its approval.

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SCD is caused by mutations that lead to the production of an abnormal form of hemoglobin — the protein that red blood cells use to carry oxygen through the bloodstream. Abnormal hemoglobin tends to clump inside red blood cells, deforming them into the sickle-like shape that gives the disease its name, and ultimately causing SCD symptoms.

The inherited disease specifically affects the adult form of hemoglobin. An alternative form of the protein, called fetal hemoglobin or HbF — which is more effective at transporting oxygen than its adult counterpart — is made during fetal development, but its production usually stops in the first months of life. Exa-cel aims to boost the production of HbF, thus lessening hemoglobin clumping and red blood cell sickling.

The therapy involves collecting a patient’s hematopoietic stem and progenitor cells. These are specialized cells in the bone marrow that are responsible for giving rise to new blood cells. Using a gene editing tool called CRISPR/Cas-9, scientists then modify these cells in a laboratory to disrupt the activity of a gene called BCL11A.

The BCL11A gene normally helps to turn off the production of HbF; by disabling this gene, exa-cel aims to increase HbF production. The modified stem cells are then returned to the patient by a stem cell transplant.

In a Phase 2/3 clinical trial called CLIMB–121 (NCT03745287), 29 of 30 evaluated patients treated with exa-cel were free from painful vaso-occlusive crises (VOCs) a year after receiving treatment. All but one of these patients remained free of VOCs over a mean period of nearly two years. 

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Advisory committee focus was on genetic diversity in analysis

The main focus of the advisory committee meeting, according to the FDA’s briefing documents, was assessing the possibility that exa-cel might cause changes in genes other than BCL11A that have a similar genetic sequence. Such off-target genetic changes could potentially cause health problems for patients.

To account for this possibility, exa-cel’s developers had conducted analyses in which they screened reference genomes looking for other areas of the genetic code with a similar sequence that might be accidentally targeted. This analysis identified some sites with similar sequences, but none were considered of major concern according to the developers.

The FDA, however, has raised questions about whether this analysis fully captured the genetic diversity of people with SCD. Specifically, the agency noted that the disease predominantly affects people of African descent, and the reference genomes used may not have been diverse enough to reflect the full genetic diversity of the African diaspora.

Given the limited amount of sequencing data from the intended population, it is not clear how comprehensively the variants in the target population were assessed.

In particular, the agency noted that the reference genomes contained very little information from people living in certain regions of Africa. This raises the possibility that there could be other off-target sites in these populations that were missed by the developers’ screen.

“Given the limited amount of sequencing data from the intended population, it is not clear how comprehensively the variants in the target population were assessed,” the briefing documents state.

The documents also note that, at present, only a few dozen people have been treated with exa-cel, and only a handful of patients were specifically tested for off-target genetic changes. The limited data may make it impossible to definitively draw conclusions about the therapy’s safety in broader populations.

To address the potential safety issues associated with exa-cel, its developers have proposed the launch of a new study to collect long-term safety data, if the therapy is approved. Those studies could last as long as 15 years. The developers also have proposed routine monitoring for all treated patients.

These plans “are under review at this time,” according to the briefing documents.