Milestone Gene Therapies for Sickle Cell Disease Greenlit by FDA

The FDA approved two cell-based gene therapies, exagamglogene autotemcel (Casgevy) and lovotibeglogene autotemcel (Lyfgenia), for sickle cell disease (SCD), the agency announced.

Marking the first FDA-approved therapy utilizing CRISPR/Cas9 technology, Casgevy is approved for the treatment of sickle cell disease in patients 12 years of age and older with recurrent vaso-occlusive crises (VOCs).

Lyfgenia, which uses a lentiviral vector for genetic modification, is approved for the treatment of patients 12 years of age and older with sickle cell disease and a history of vaso-occlusive events.

“These approvals represent an important medical advance with the use of innovative cell-based gene therapies to target potentially devastating diseases and improve public health,” said Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research (CBER), in a press release. “Today’s actions follow rigorous evaluations of the scientific and clinical data needed to support approval, reflecting the FDA’s commitment to facilitating development of safe and effective treatments for conditions with severe impacts on human health.”

Casgevy is given to increase the production of fetal hemoglobin, which prevents the sickling of red blood cells.

With Lyfgenia, the patient’s blood stem cells are genetically modified to produce a gene-therapy derived hemoglobin that functions similarly to hemoglobin A.

FDA approval for Casgevy was based on the pivotal clinical study CLIMB-121 in which 29 of 30 recipients achieved absence of severe VOCs for at least 12 consecutive months. The treatment has not been associated with excess severe adverse events.

Lyfgenia’s approval was based on the phase I/II HGB-206 study that showed that 6-18 months post-treatment, 30 of 32 patients had severe vaso-occlusive events resolved, with 28 of them having no more vaso-occlusive events at all.

Of the 100,000 Americans with sickle cell disease, the roughly 20% who have more frequent vaso-occlusive crises — namely, those in the hospital at least a few times a year — are the ones who stand to benefit from these newly approved gene therapies, Marks clarified during a media briefing.

Both treatments are administered as one-time infusions. They are made from the patients’ own blood stem cells, which are modified and returned to the patient in a hematopoietic stem cell transplant.

“Sickle cell disease is a rare, debilitating and life-threatening blood disorder with significant unmet need, and we are excited to advance the field especially for individuals whose lives have been severely disrupted by the disease by approving two cell-based gene therapies today,” said Nicole Verdun, MD, also at FDA’s CBER, in a statement.

“Gene therapy holds the promise of delivering more targeted and effective treatments, especially for individuals with rare diseases where the current treatment options are limited,” Verdun continued.

Unlike the CRISPR/Cas9 product, Lyfgenia carries a black box warning on its label about hematologic malignancy due to the death of two trial participants who developed acute myeloid leukemia, Verdun said during the briefing.

Whether there is an excess malignancy risk unique to Lyfgenia remains unclear without more follow-up. Verdun said the drug sponsors have agreed to long-term follow-up of 15 years plus lifetime monitoring for malignancy.

Marks stressed that the totality of all side effects that patients may encounter — from the gene therapies themselves, their conditioning regimens, or additional care to get people off their current medications — will have to be considered.

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