Whether the investigational sickle cell disease therapy exagamglogene autotemcel (exa-cel) has adequately proven it won’t produce off-target genetic changes was questioned by FDA reviewers before an advisory committee meeting last week.
This came as the gene-editing CRISPR technology underpinning exa-cel – a product of a partnership between Vertex Pharmaceuticals and CRISPR Therapeutics – was the first of its kind to go 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.
In briefing documents released in advance of the Cellular, Tissue, and Gene Therapies Advisory Committee meeting, the FDA reviewers expressed concern about whether the therapy would 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 foetal haemoglobin (HbF), and that genome editing has the potential to produce unintended genomic alterations or off-target editing, reports MedPage Today.
In its briefing document, 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.”
While expressing concerns about the off-target effects of exa-cel, FDA staffers appeared to be convinced the therapy is effective.
The compelling efficacy data, along with emotional testimony provided by 10 self-described sickle cell “warriors” during an open public hearing, seemed to leave panellists pondering how much more can be done to mitigate the potential risks of off-target editing.
“We ought to be careful to not let perfect be the enemy of the good,” said Scot Wolfe, PhD, of the UMass Chan Medical School in Massachusetts.
“You can do a lot of in-depth analysis … prior to the introduction to the patient, and you want to do as good a job as you possibly can, but at some point you just have to try things out on the patient.
“There is a huge unmet need for individuals with sickle cell disease, and it’s important we think about how we can advance therapies that can potentially help them. I certainly think this is one of them.”
“Each individual planet has several million genetic variants in their genome,” said Alexis Komor, PhD, of the University of California San Diego.
“The perfect off-target analysis would be to sequence the patient, use that as a reference genome, and then individually validate every single off-target. Do we have the technology to do that? Probably, but is that reasonable to expect?
“Given the benefits of this treatment – or this cure – and what these patients are dealing with without having this treatment, I think the benefits far outweigh the risks.”
In the pivotal clinical study (CLIMB-121), 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 this “transformational”, considering that the patients in this analysis had a mean of almost four VOCs per year in the two years before screening.
All 30 evaluable subjects met the key secondary endpoint of freedom from inpatient hospitalisation 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 haematologic 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 these 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.”
The agency is expected to decide by 8 December whether to grant exa-cell an indication in sickle cell disease.
MedPage Today article – FDA Reviewers Question Safety of Sickle Cell Gene Therapy (Open access)
MedPage Today article – Potential Cure for Sickle Cell Clears Hurdle for Approval (Open access)
See more from MedicalBrief archives:
Gene therapy: A game changer for those with sickle-cell disease
Call for guidelines and ethical boundaries in genetic editing therapies
Sickle cell disease 11 times more deadly than thought – global study