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FDA Advisory Panel Finds Vertex's Off-Target Data Convincing for Approval

Normal red blood cells and sickle cells flow inside in artery

NEW YORK – Advisers to the US Food and Drug Administration on Tuesday were persuaded by data submitted by Vertex Pharmaceuticals that its investigational CRISPR-Cas9-based therapy benefits patients with severe sickle cell disease (SCD), though they emphasized the need for continued long-term monitoring after treatment.

The FDA convened its Cellular, Tissue, and Gene Therapies Advisory Committee to discuss whether Vertex has adequately analyzed mutations caused by the gene-editing therapy exagamglogene autotemcel (exa-cel) that may lead to off-target effects and heighten safety risks for patients. Off-target mutations are changes that occur if the Cas9 enzyme in the gene-editing therapy binds to genomic sites that, while similar to the guide RNA sequence, are not the intended target.

The FDA did not present questions for advisory committee members to vote on but asked members to provide feedback on whether the off-target analysis that Vertex submitted as part of its biologics license application (BLA) for exa-cel was sufficient.

"Exa-cel has been studied for treatment of sickle cell disease with severe vaso-occlusive crises and has shown efficacy," Nicole Verdun, director of the Office of Therapeutic Products at the FDA's Center for Biologics Evaluation and Research, said at the meeting. "We are here to discuss, specifically, the study and analysis of potential off-target genome editing with exa-cel."

Vertex is seeking FDA approval for two indications, but Tuesday's meeting focused on its application for SCD, an inherited condition in which red blood cells become misshapen, causing pain, anemia, and stroke, and damaging patients' organs. The condition affects about 70,000 patients in the US and is prevalent among individuals of African and Mediterranean ancestry.

If approved, exa-cel would be the first CRISPR gene-editing therapy to be marketed in the US.

Exa-cel uses CRISPR-Cas9 to edit patients' own CD34-positive hematopoietic stem and progenitor cells (HSPCs) ex vivo to alter the BCL11A gene. That genetic change is designed to reactivate high levels of fetal hemoglobin in red blood cells once infused back into the body. Hemoglobin is a protein that carries oxygen and is lacking or dysfunctional in patients with SCD.

The therapy is designed as a one-time, curative infusion.

"There's a huge unmet need for individuals with sickle cell disease," said Scot Wolfe, a professor in the molecular, cell, and cancer biology department at UMass Chan Medical School, and one of the committee members at the meeting Tuesday. "It's important we think about how we can advance therapies that could potentially help them."

There are available drugs approved to treat SCD already on the market; however, most are not curative, and patients must take them throughout their lives. The one curative option is allogeneic hematopoietic stem cell transplantation (HSCT), which is not accessible to most patients since it requires a suitable donor.

Vertex in its BLA said it found no detectable off-target mutations following exa-cel treatment through two analyses using in silico methods and cellular assays.

But in a briefing document released last week ahead of the advisory panel's meeting, FDA staff reviewers questioned the firm's analysis methods, raising concerns about small sample sizes. The cellular assay assessment, for example, included HSPCs from three healthy individuals, three individuals with SCD, and three with transfusion-dependent beta-thalassemia, another indication for which Vertex is seeking exa-cel's approval in a separate BLA.

The panel of independent experts convened Tuesday, however, felt that while there are opportunities for additional research to build evidence on the possibility of off-target effects, the analyses from Vertex were robust overall and that the benefits of making exa-cel available to patients outweighed the risks.

"Given the benefits of this cure and what these patients are dealing with without having this treatment, I think the benefits far outweigh the risks here," said Alexis Komor, an assistant professor in the chemistry and biochemistry department at 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 [variant] — is that reasonable?"

At some point, therapeutics need to move forward into patient care despite uncertainty, Wolfe added. "We want to be careful to not let the perfect be the enemy of the good," he said. 

Vertex has submitted plans to the FDA for post-marketing safety studies, should exa-cel be approved. That includes a proposed 15-year registry-based study to follow and compare patients treated with a commercial exa-cel product against outcomes from those who received allogenic HSCT, in addition to routine post-marketing surveillance.

Advisers at the meeting suggested that Vertex also conduct molecular analyses of patients after exa-cel infusion to monitor outcomes of on-target and possible off-target variants. "I really think it's worthwhile to follow these edits in real time," said John Tisdale, branch chief of the cellular and molecular therapeutics branch at the National Institutes of Health's National Heart, Lung, and Blood Institute.

About a dozen patients and family members spoke in favor of exa-cel during the portion of the meeting when committee members and the FDA heard from the public. Some of the participants had received the therapy as part of a clinical trial, and attested to the benefits they experienced, while others expressed hope that this therapy would be available to them in the future.

"Before this treatment, my entire childhood, and most of my adult life, was plagued with severe pain, fatigue, numerous hospital stays, and the fear of dying," said 38-year-old Victoria Gray, the first sickle cell patient to receive exa-cel as part of Vertex's clinical trial. Before getting exa-cel, she was taking three types of opioids to manage pain, which weren't very effective, and had regular blood transfusions. After exa-cel, she no longer has to use those therapies.

According to data Vertex submitted as part of its BLA, all patients eligible for analysis in its pivotal Phase I/II/III trial expressed increased fetal hemoglobin within three months of infusion, and 29 out of 30 patients on exa-cel didn't experience any severe vaso-occlusive crises, painful events that are a hallmark of SCD, for at least 12 months after treatment.

The single-arm study is ongoing, so not all patients enrolled have been on the therapy long enough to be included in analysis yet.

Originally developed by CRISPR Therapeutics, exa-cel is being developed and commercialized by Vertex as part of a global agreement the companies struck in 2017 and amended in 2021. Under the terms of the collaboration, Vertex splits program costs and profits 60-40 with CRISPR Therapeutics.

The nonprofit Institute for Clinical and Economic Review, which evaluates the value of healthcare interventions, in July said exa-cel and one of its competitors, Bluebird Bio's lovotibeglogene autotemcel (lovo-cel), could be reasonably priced as high as $2.05 million per infusion. Lovo-cel is an investigational SCD gene therapy under priority review at the FDA.

The FDA is expected to issue a decision on Vertex's exa-cel application in SCD, which it also granted priority review, by Dec. 8. The FDA is also evaluating exa-cel as a treatment for transfusion-dependent beta-thalassemia through the standard review process and expects to decide on that indication by March 30, 2024.