FDA Approves First Gene Therapies to Treat Patients with Sickle Cell Disease

Rare Daily Staff

The U.S. Food and Drug Administration approved the first two cell-based gene therapies for treatment of the rare blood disorder sickle cell disease including the first approved treatment to utilize CRISPR/Cas9 genome editing technology, which the agency hailed as a sign of an innovative advancement in the field of gene therapy.

The agency approved Vertex and CRISPR Therapeutics Casgevy and Bluebird Bio’s Lyfgenia. Both products are made from the patients’ own blood stem cells, which are modified, and are given back as a one-time, single-dose infusion as part of a hematopoietic stem cell transplant. Prior to treatment, a patients’ own stem cells are collected, and then the patient must undergo high-dose chemotherapy, a process that removes cells from the bone marrow so they can be replaced with the modified cells in Casgevy and Lyfgenia.

SCD is an inherited blood disorder that affects the red blood cells, which are essential for carrying oxygen to all organs and tissues of the body. SCD causes severe pain, organ damage and shortened life span due to misshapen or “sickled” blood cells. People with SCD can experience painful blood vessel blockages, also known as vaso-occlusive crises (VOCs), that can lead to acute chest syndrome, stroke, jaundice, and symptoms of heart failure. Individuals may also experience anemia, which can result in end-organ damage and premature death. VOCs are the hallmark of SCD, often resulting in severe and debilitating pain. Current standard treatment options for SCD are largely symptomatic treatments and do not adequately address the burden of disease or alleviate the need for chronic care. Most often, treatment is focused on relieving pain, minimizing organ damage, maintaining hydration, and addressing fevers, requiring medication and sometimes monthly blood transfusions and frequent hospital visits.

The only cure for SCD today is a stem cell transplant from a matched donor, but this option is only available to a small fraction of people living with SCD. SCD requires lifelong treatment and significant use of health care resources, and ultimately results in reduced life expectancy and reduced lifetime earnings and productivity. In the U.K., the mean age of death for people living with SCD is around 40.

“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,” said Nicole Verdun, director of the Office of Therapeutic Products within the FDA’s Center for Biologics Evaluation and Research.

Casgevy, a cell-based gene therapy, uses CRISPR/Cas9, a type of genome editing technology. Patients’ hematopoietic stem cells are modified by genome editing using the technology. CRISPR/Cas9 can be directed to cut DNA in targeted areas, enabling the ability to accurately edit (remove, add, or replace) DNA where it was cut. The modified blood stem cells are transplanted back into the patient where they engraft (attach and multiply) within the bone marrow and increase the production of fetal hemoglobin (HbF), a type of hemoglobin that facilitates oxygen delivery. In patients with sickle cell disease, increased levels of HbF prevent the sickling of red blood cells.

The safety and effectiveness of Casgevy were evaluated in an ongoing single-arm, multi-center trial in adult and adolescent patients with SCD. Patients had a history of at least two protocol-defined severe VOCs during each of the two years prior to screening. The primary efficacy outcome was freedom from severe VOC episodes for at least 12 consecutive months during the 24-month follow-up period. A total of 44 patients were treated with Casgevy. Of the 31 patients with sufficient follow-up time to be evaluable, 29 (93.5 percent) achieved this outcome. All treated patients achieved successful engraftment with no patients experiencing graft failure or graft rejection.

The most common side effects were low levels of platelets and white blood cells, mouth sores, nausea, musculoskeletal pain, abdominal pain, vomiting, febrile neutropenia (fever and low white blood cell count), headache, and itching.

Lyfgenia is a cell-based gene therapy. Lyfgenia uses a lentiviral vector for genetic modification and is approved for the treatment of patients 12 years of age and older with sickle cell disease and a history of vaso-occlusive events. With Lyfgenia, the patient’s blood stem cells are genetically modified to produce HbAT87Q, a gene-therapy derived hemoglobin that functions similarly to hemoglobin A, which is the normal adult hemoglobin produced in persons not affected by sickle cell disease. Red blood cells containing HbAT87Q have a lower risk of sickling and occluding blood flow. These modified stem cells are then delivered to the patient.

Patients who received Casgevy or Lyfgenia will be followed in a long-term study to evaluate each product’s safety and effectiveness.

Both the Casgevy and Lyfgenia applications received Priority Review, Orphan Drug, Fast Track and Regenerative Medicine Advanced Therapy designations.

The safety and effectiveness of Lyfgenia is based on the analysis of data from a single-arm, 24-month multicenter study in patients with sickle cell disease and history of VOEs between the ages of 12- and 50- years old. Effectiveness was evaluated based on complete resolution of VOEs (VOE-CR) between 6 and 18 months after infusion with Lyfgenia. Twenty-eight (88 percent) of 32 patients achieved VOE-CR during this time period.

The most common side effects included stomatitis (mouth sores of the lips, mouth, and throat), low levels of platelets, white blood cells, and red blood cells, and febrile neutropenia (fever and low white blood cell count), consistent with chemotherapy and underlying disease.

Hematologic malignancy (blood cancer) has occurred in patients treated with Lyfgenia. A black box warning is included in the label for Lyfgenia with information regarding this risk. Patients receiving this product should have lifelong monitoring for these malignancies.

“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, director of the FDA’s Center for Biologics Evaluation and Research. “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.”