FDA OKs First Gene Therapies For Sickle Cell Disease

The U.S. Food and Drug Administration has approved Casgevy and Lyfgenia, the first cell-based gene therapies to treat sickle cell disease.

Sickle cell disease is a group of inherited blood disorders affecting approximately 100,000 people in the United States, primarily African Americans.

People with the condition have a mutation in hemoglobin, a protein that delivers oxygen to the body’s tissues.

The mutation causes red blood cells to develop a crescent or "sickle" shape. As a result, these cells restrict the flow in blood vessels and limit oxygen delivery to the tissues.

This causes severe pain and organ damage called vaso-occlusive events (VOEs) or vaso-occlusive crises (VOCs), the recurrence of which may lead to life-threatening disabilities and/or early death.

Both products, Casgevy and Lyfgenia, are made from the patients’ own modified blood stem cells. Before the treatment, a patient’s own stem cells are collected, while the patient must undergo high-dose chemotherapy to remove cells from the bone marrow so they can be replaced with the modified cells. The modified cells are given back as a one-time, single-dose infusion as part of a blood stem cell transplant.

A CRISPR/Cas9-based Casgevy

Casgevy, a cell-based gene therapy, is approved in patients 12 years and older with recurrent VOCs. It is the first FDA-approved therapy using CRISPR/Cas9, a type of genome editing technology that can be directed to cut DNA in targeted areas, enabling the accurate editing of DNA where it was cut.

The modified blood stem cells are transplanted back into the patient, where they attach and multiply within the bone marrow and increase the production of fetal hemoglobin (HbF), a type of hemoglobin that delivers oxygen to the tissues. In patients with sickle cell disease, increased levels of HbF prevent the sickling of red blood cells.

Forty-four patients were treated with Casgevy in the clinical trial. Of the 31 patients with sufficient follow-up time, 29 (93.5%) achieved freedom from severe VOC episodes for at least 12 consecutive months.

The most common side effects were low levels of platelets and white blood cells, mouth sores, nausea, musculoskeletal pain, abdominal pain, and vomiting, among others.

Black box warning for Lyfgenia

A cell-based gene therapy, Lyfgenia, is approved for treating patients between the ages of 12 and 50 with sickle cell disease and a history of VOEs.

The therapy allows genetic modification of the patient’s blood stem cells to produce HbAT87Q. This gene-therapy-derived hemoglobin functions similarly to the normal adult hemoglobin produced in people without the condition. Red blood cells containing HbAT87Q have a lower risk of sickling and occluding blood flow.

In the 24-month clinical trial, 28 (88%) of 32 patients achieved a complete resolution of VOEs.

The most common side effects included stomatitis, low levels of platelets, white blood cells, red blood cells, and febrile neutropenia, which is fever and low white blood cell count. These side effects are consistent with chemotherapy and sickle cell disease.

As blood cancer has occurred in patients treated with Lyfgenia, the therapy contains a black box warning with information regarding the possible risk.

Who is eligible for the therapies?

The FDA’s approval of Casgevy and Lyfgenia is a milestone in treating sickle cell disease. However, people with a recurring viral infection or significant organ damage may not be able to receive gene therapy, according to the Sickle Cell Disease Association of America.

Moreover, the therapies involve chemotherapy, which may lead to infertility or secondary cancer, temporary weakening of the immune system, and temporary hair loss.

Gene therapies are expensive, and it is unclear how insurance companies will handle them. Vertex Pharmaceuticals said Casgevy would cost $2.2 million in the U.S., while Bluebird Bio set a list price of $3.1 million for Lyfgenia.

Jennifer Doudna, Ph.D., who was awarded the Nobel Prize in 2020 for discovering CRISPR/Cas9, said on the X that the FDA’s approval of Casgevy marks "an extraordinary day" for sickle cell disease patients and the field of CRISPR medicine.

She said, "It is personally meaningful to me that the first CRISPR therapy helps patients with sickle cell disease, who were long neglected by the medical establishment."

Gene editing therapies Casgevy and Lyfgenia may revolutionize the treatment of sickle cell disease. And although they carry certain health risks, for many people, the benefits outweigh the dangers.


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