BACKGROUND

1st Gene Editing AdCom

On 10/31/23 an FDA AdCom met to discuss the safety of VRTX/CRSP’s exa-cel (CTX001) to reduce or eliminate the painful and debilitating vaso-occlusive crises (VOC) for patients with sickle cell disease (SCD). As the first FDA AdCom for a cell therapy that involves gene editing, the AdCom provides helpful insights into the FDA’s review of gene editing and even other autologous gene therapies for rare inherited diseases.

What is Exa-cel?

Exa-cel is a cell therapy that uses CRISPR/Cas9 to edit the patient’s own (autologous) hematopoietic stem cells (HSCs) outside their body (ex vivo) to produce high levels of fetal hemoglobin in red blood cells after the gene edited HSCs are delivered back to the patient.

Exa-cel is Very Effective

The FDA characterized the clinical efficacy results of exa-cel to reduce VOCs in SCD patients as "strongly positive".

• See FIG. 9 below from the FDA’s exa-cel AdCom briefing document.

3 Insights Into FDA’s Review of Gene Editing & Other Autologous Cell Therapies

1. For gene editing safety, FDA is mainly concerned with off-target alterations

a. It was the reason for the VRTX/CRSP AdCom

"The FDA is convening this [AdCom] to discuss the Applicant’s analysis of off-target alterations following editing of patient [HSPCs] with [CRISPR/Cas9], and whether it provides an adequate safety assessment." ^1

2. FDA is OK with a single, small, uncontrolled primary registrational study, for a rare disease, if magnitude of the efficacy is highly positive

"However, given the strongly positive results, FDA does not believe that the study design limitations call the efficacy of exa-cel into question." ^1

3. The AdCom members who are gene editing KOLs likely will be the key AdCom members for off-target safety issues

a. For the exa-cel AdCom the genome editing KOLs were relied on heavily

i. Those KOLs were Scot Wolfe, PhD (UMass) & Alexis Komor, PhD (UCSD)

Footnotes

^1 All quotes from the FDA Briefing Document from BLA#125787/0