FDA approves first cell-based gene therapies for sickle cell disease
For the first time, the FDA has approved two cell-based gene therapies for treating the rare but potentially fatal sickle cell disease. One is also the first approved therapy to utilize the CRISPR/Cas9 gene editing technology, signifying innovative advancement in the fields of gene therapy and regenerative medicine.
Sickle cell disease (SCD) is a group of inherited blood disorders that affect hemoglobin, the oxygen-carrying protein in red blood cells. In someone with SCD, the hemoglobin is mutated, causing the red blood cells to become hard, sticky and C-shaped – resembling a sickle. The sickle cells die prematurely, which causes a shortage of red blood cells, and because of their physical characteristics, they’re prone to lodge in small blood vessels, clogging them and depriving the tissues and organs of oxygen. This can cause severe pain and organ damage (vaso-occlusive crisis) and may lead to life-threatening disabilities and/or death.
Current treatments for SCD are focused on preventing and treating the pain and other complications of vaso-occlusive crises such as vision loss, stroke, and anemia. But now, in a first, the FDA has improved the outlook for people with SCD by approving two cell-based gene therapies, Casgevy and Lyfgenia, as treatments for the disease.
“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,” said Nicole Verdun, director of the Office of Therapeutic Products within the FDA’s Center for Biologics Evaluation and Research. “Gene therapy holds the promise of delivering more targeted and effective treatments, especially for individuals with rare disease where the current treatment options are limited.”
Casgevy and Lyfgenia are approved to treat patients 12 and older with SCD. Both are made from the patient’s own blood-cell-producing (hematopoietic) stem cells, which are modified and given back to the patient as a one-time, single-dose infusion. Prior to the infusion, patients are given high-dose chemotherapy to remove cells from the bone marrow so they can be replaced with the modified cells.
Lyfgenia uses a lentiviral gene delivery vehicle or vector to treat patients with a history of vaso-occlusive crises. Lentiviruses are RNA viruses derived from the human immunodeficiency virus (HIV) that have been modified to be incapable of producing virus once infected into the host cell. The patient’s hematopoietic stem cells are genetically modified to produce a gene-therapy-derived hemoglobin, HbAT87Q, that functions like hemoglobin A, which is the hemoglobin produced by someone without SCD. Red blood cells containing HbAT87Q are less likely to sickle and impede blood flow.
In addition to being one of the first two FDA-approved gene therapies, Casgevy is the first approved therapy that utilizes the gene editing technology CRISPR/Cas9. After modifying the patient’s hematopoietic stem cells using CRISPR/Cas9 to produce increased amounts of fetal hemoglobin (HbF), they are transplanted back into the patient, where they attach and multiply within the bone marrow. The increase in HbF facilitates oxygen delivery and prevents the sickling of red blood cells.
Both therapies had undergone clinical trials to evaluate their safety and efficacy. With Casgevy, 93.5% of patients were free from severe vaso-occlusive crisis episodes for at least 12 consecutive months during the two-year follow-up period. The most common side effects were low platelet and white blood cell counts, mouth sores, nausea and vomiting, musculoskeletal pain, abdominal pain, headache and itching.
And with Lyfgenia, 88% of patients had complete resolution of vaso-occlusive events between six and 18 months after receiving the treatment. The most common side effects included stomatitis (sores on the lips, mouth and throat), low levels of platelets, and white and red blood cells, consistent with chemotherapy and underlying disease. Blood cancer has occurred in patients treated with Lyfgenia, so a black box warning is included in the label with information regarding this risk.
Applications for both Casgevy and Lyfgenia received Priority Review, Orphan Drug, Fast Track and Regenerative Medicine Advanced Therapy designations. This means that, among other things, the FDA considered it appropriate to approve the therapies to “fill an unmet medical need” and “get important new drugs to the patient earlier” to “treat, modify, reverse, or cure a serious or life-threatening disease or condition.” An ‘orphan drug’ is defined as a drug intended to treat a condition affecting fewer than 200,000 people in the US – SCD affects approximately 100,000 – or one which will not be profitable within seven years of its approval.