Today, the US Food and Drug Administration (FDA) has approved two gene-editing treatments for patients 12 and older with severe sickle cell disease.
These “milestone treatments” mark the first cell-based gene therapies to treat this debilitating and potentially life-threatening blood disorder that affects about 100,000 people in the US.
The two therapies are exagamglogene autotemcel or exa-cel (Casgevy, Vertex Pharmaceuticals and Crispr Therapeutics) and lovotibeglogene autotemcel or lovo-cel (Lyfgenia, bluebird bio).
“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 uses CRISPR gene-editing technology. Before treatment, a patient’s stem cells are collected, and patients undergo myeloablative conditioning — high-dose chemotherapy. This process removes cells from the bone marrow, which can then be modified to allow cells to produce fetal hemoglobin. Patients then receive an infusion of these edited cells to promote normal hemoglobin production.
The FDA approval was based on data from the pivotal CLIMB SCD-121 trial. In an October advisory committee meeting, t he FDA highlighted trial data demonstrating that 29 of 31 patients reached the trial’s primary endpoint: freedom from severe vaso-occlusive crises — in which sickled red blood cells block blood flow to tissues and cause extreme pain — over a 12-month period. In addition, 28 of these patients remained free of these crises for almost 2 years, with the longest duration lasting almost 4 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 more than11 g/dL by month 3 and maintained at that level after. No patients experienced graft failure or rejection.
The most common side effects included low levels of platelets and white blood cells, 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-cell, 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 receiving the infusion, patients also undergo myeloablative conditioning. The patient’s stem cells are genetically modified to produce the most common form of hemoglobin, HbA.
This approval was based on data from a single-arm, 24-month study in patients, ages 12 to 50, with sickle cell disease and history of vaso-occlusive events.
Overall, 88% of patients (28 of 32) achieved complete resolution of vaso-occlusive events between 6 and 18 months following the infusion.
The most common side effects included stomatitis, febrile neutropenia as well as low levels of platelets, white blood cells, and red blood cells.
The FDA noted that hematologic malignancy has occurred in patients treated with lovo-cel, and the label includes a black box warning about the risk.
Source link : https://www.medscape.com/viewarticle/fda-oks-first-two-gene-editing-therapies-sickle-cell-disease-2023a1000uqp?src=rss
Publish date : 2023-12-08 18:06:19
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