Today, the US Food and Drug Administration (FDA) approved two gene-editing treatments for patients aged 12 years or older with severe sickle cell disease.
These "milestone treatments" mark the first cell-based gene therapies for this debilitating and potentially life-threatening blood disorder that affects about 100,000 people in the US.
One therapy — exagamglogene autotemcel or exa-cel (Casgevy) from Vertex Pharmaceuticals and Crispr Therapeutics — is the first to use the gene-editing tool CRISPR. The other — lovotibeglogene autotemcel or lovo-cel (Lyfgenia) from bluebird bio — uses a different gene-editing tool called a lentiviral vector.
"The approval of the first gene therapies for [sickle cell disease] represents a tremendous step forward for the [sickle cell] community, which has been historically overlooked and underfunded," said Robert A. Brodsky, of Johns Hopkins University School of Medicine, in a statement from the American Society of Hematology, following the approval.
"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," added Nicole Verdun, MD, of the FDA's Center for Biologics Evaluation and Research, in an agency press release.
Sickle cell disease involves a mutation in hemoglobin, a protein in red blood cells that provides oxygen to tissues. The mutation leads red blood cells to develop a crescent or sickle shape, which can restrict blood flow and cause severe pain and organ damage, known as vaso-occlusive events or crises.
Treatment options prior to these approvals primarily included red blood transfusions and hydroxyurea alongside pain management. The only potential curative option has been allogeneic hematopoietic stem cell transplantation, but that comes with significant risks and most patients don't have an appropriate donor.
Exa-cel
Exa-cel uses CRISPR gene-editing technology. Before the infusion, patients undergo myeloablative conditioning, which removes cells from the bone marrow. These cells are genetically modified to produce fetal hemoglobin. Patients then receive an infusion of the edited cells, which can help restore normal hemoglobin production.
The FDA approval was based on data from the pivotal CLIMB SCD-121 trial. In an October advisory committee meeting, the FDA highlighted trial data demonstrating that 29 of 31 patients reached the trial's primary endpoint: freedom from severe vaso-occlusive crises over a 12-month period. In addition, 28 of these patients remained free of vaso-occlusive crises for almost 2 years.
The committee noted that one of the 31 patients died about 9 months after receiving an exa-cel infusion.
The cell-based gene therapy also increased both fetal and total hemoglobin, with total hemoglobin levels increasing to > 11 g/dL by month 3 and remaining at that level afterward. No patients experienced graft failure or rejection.
The most common side effects included low platelets and white blood cell counts, mouth sores, nausea, musculoskeletal pain, vomiting, and febrile neutropenia.
Exa-cel could "provide a one-time functional cure" for patients with severe sickle cell disease, according to Franco Locatelli, MD, of Sapienza University of Rome, who presented initial findings last year.
While the current approval is for patients with infusion-dependent sickle cell disease, exa-cel is also being evaluated in patients with another blood disorder, beta-thalassemia.
Lovo-cel
Lovo-cel, a cell-based gene therapy, uses a different technology — a lentiviral vector, or gene delivery vehicle — that can also genetically modify a patient's blood stem cells.
Like exa-cel, lovo-cel is a one-time, single-dose infusion that contains the patient's modified cells. Before the infusion, patients undergo myeloablative conditioning. The patient's stem cells are then genetically modified to allow them to produce the most common form of hemoglobin, HbA
This approval was based on data from a single-arm, 24-month study in patients aged 12-50 years who had sickle cell disease and a history of vaso-occlusive events.
Overall, 88% of patients (28 of 32) achieved complete resolution of vaso-occlusive events 6-18 months after the infusion.
The most common side effects included stomatitis; febrile neutropenia; and low platelet, white blood cell, and red blood cell counts.
The FDA noted that hematologic cancer has occurred in patients treated with lovo-cel, and the label includes a black-box warning about the risk.
Brodsky noted, however, that "while these new gene therapies are potentially life-changing for individuals living with [sickle cell disease], they must be accessible to be effective."
Access is a potential concern. Exa-cel and lovo-cel could cost about $2 million.
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