The FDA just approved the first CRISPR gene-editing drug in the U.S. Here’s what you need to know

On Friday, the U.S. Food and Drug Administration (FDA) approved a pair of gene therapies for the painful and potentially fatal blood disorder, sickle cell disease (SCD)–including the first-ever CRISPR gene-editing treatment. The gene-editing treatment from Vertex Pharmaceuticals and partner CRISPR Therapeutics is called Exa-cel and marketed as Casgevy. Regulators also gave the green light to Bluebird Bio’s lovo-cel (marketed as Lyfgenia), which uses a different type of technology to replace the damaged gene that causes sickle cells to form. Both treatments are now approved for patients 12 years and older, and an estimated 100,000 people in the U.S., mostly Black Americans, have the inherited blood disorder SCD, according to the Centers for Disease Control and Prevention (CDC).

It’s a historic moment for the biotechnologies, especially for CRISPR gene-editing, the technology that led to scientists Jennifer Doudna and Emmanuelle Charpentier winning the 2020 Nobel Prize in Chemistry as founders of the technique. The very same technology is being tested for multiple other uses for global human maladies, including diseases ranging from HIV to heart disease and cancer, as well as use in agriculture and livestock. Casgevy was previously approved by U.K. regulators in November. 

Here’s what you need to know about Friday’s landmark FDA approvals, from the disease they treat to safety concerns and cost.

What is sickle cell disease (SCD) and how is it currently treated?

Sickle cell disease is an inherited blood disorder in which red blood cells become crescent-shaped and prevent the transportation of the oxygen critical for life throughout the body.  

It originates in the bone marrow due to a genetic kink that inhibits the production of healthy hemoglobin and is associated with devastating, lifelong, and potentially fatal health consequences, including stroke, increased risk of infections, painful episodes classified as “vaso-occlusive crises” that require emergency medical attention, liver problems, heart problems, and eye problems, according to the National Institutes of Health (NIH). 

There are an estimated 100,000 people in the U.S., 15,000 in the U.K., and 20 million worldwide living with SCD, with most being people of color; additionally, one in 365 Black or African American babies in the U.S. are born with the disease every year. It is most common in African, Asian, South American, and Indo-Caribbean nations, and the World Health Organization (WHO) estimates that approximately 5% of the global population suffers from hemoglobin disorders such as SCD, including 300,000 children born each year with such afflictions.

Current treatment for sickle cell disease is by and large based on managing the condition, especially when painful crises occur, and patients must have routine follow-up care, stay up to date on vaccinations due to increased infection risk, be administered IV fluids, have regular blood transfusions, and take a variety of prescription and over-the-counter medicines to help dull its symptoms. 

The only thing approaching a long-lasting cure for sickle cell disease is a bone marrow transplant, an intensive procedure requiring chemotherapy to kill off faulty bone marrow stem cells before being replaced with donor or healthy hemoglobin-producing stem cells that are re-infused into your body. 

What does a CRISPR gene-editing therapy like Casgevy do? How does a gene therapy like Lyfgenia work?

Casgevy and Lyfgenia aren’t traditional drugs, per se—they’re a process of treatment that tackles the offending hemoglobin-wrecking genes that cause sickle cell disease at the genetic level. Like stem cell transplants, they involve an intensive process in which patients must be conditioned for treatment with chemotherapy to kill off aberrant blood-producing stem cells before receiving healthy modified ones. Unlike transplants, however, the purpose of these treatments isn’t to just replace damaged hemoglobin-producing cells with healthy donor cells (either from someone else or from the patient), but to fix the gene outright.

Vertex and CRISPR’s Casgevy uses something called the CRISPR-Cas9 method invented by scientists including Nobel laureates Doudna and Charpentier using an “ex vivo,” or outside-the-body, approach. It involves taking stem cells, cultivating them in a lab, using a form of molecular scissors to slice and dice the offending DNA regions that lead to the malformed hemoglobin at the root of sickle cell disease, and then re-infusing them into a patient over the course of a month with continuous medical attention. It spurs the production of a type of healthy fetal hemoglobin, giving hope that its effects will last a lifetime.

Bluebird’s Lyfgenia utilizes a similar approach but with a more traditional form of gene therapy, one in which a virus is used as a shuttle to deliver a copy of healthy, adult hemoglobin-producing gene to bone marrow cells that is also meant to be a lasting treatment.

Are the new CRISPR gene-editing and Bluebird’s gene therapy treatments effective? Are they safe?

Both Casgevy and Lyfgenia have produced similar, and impressive, clinical trial results with few safety concerns. But that’s not to to say they haven’t shown any negative effects—and as new treatments, the companies will have to monitor their effects over the course of more than a decade to truly measure their lasting power and safety.

For Casgevy, regulators cited data showing that 29 of 30 patients had achieved the study’s main goal, which was to see patients free from those painful crisis events requiring hospitalization for at least one year. Some patients were able to live free of such crises for more than 45 months. Data had shown similar results for Lyfgenia.

“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,” said Dr. Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research (CBER), in a statement announcing the approvals.

That’s not to say the procedures involved in Casgevy’s and Lyfgenia’s administration don’t have some painful effects. The conditioning, chemotherapy stage of the treatment, as well as the monthlong reinfusion of healthy cells, can be painful and cause stomach problems. In children, especially, that can be a burden for them and their families—and chemotherapy conditioning comes with a risk of infertility, and even the potential to contract leukemia. Two patients in Bluebird’s Lyfgenia trial died of leukemia, though that was most likely not caused by the gene therapy, but by chemotherapy.

The companies say they have been making efforts to improve and soften the conditioning process. And sickle cell disease patient-advocacy groups, and patients and their families, still hailed the landmark approvals.

“We’re enthusiastic at the Sickle Cell Disease Association of America about the FDA’s approval of this therapy, which could change the lives of people and families affected by sickle cell disease,” said Regina Hartfield, president and CEO of the Sickle Cell Disease Association of America, in a statement. “As the national advocacy organization for people with sickle cell, we’re strongly supportive of the new potentially curative option for treatment and excited for the future.”

How much will the new sickle cell gene therapies cost?

One critical question will be the cost for the treatments—both the list price, and what patients will have to pay out of pocket. Given the demographics of SCD in America, and the disease’s disabling effect, many patients are covered under government programs such as Medicaid and Medicare, according to government data. 

For those with private insurance, and the uninsured, available evidence shows that costs for genetic treatments can prove gargantuan, with list prices averaging anywhere from $1 million to $2 million, according to one analysis by the price watchdog group Institute for Clinical and Economic Review (ICER).  Although this full price isn’t expected to come out of a patient’s pocket after insurance and other financial arrangements, such as patient assistance programs, it can still prove a tremendously hefty tab, with some experts saying out of pocket costs can reach upwards of $40,000. 

Companies justify that massive price tag with the hope of a lifelong cure, rather than a life riddled with debilitating pain and hospital visits for managing the condition and its widespread health effects. Another driver is complexity. Treatments like Casgevy and Lyfgenia are highly personalized, with each patient serving as the source for the genes to be repaired— meaning every single infusion of these products entails a laborious and complex manufacturing process on top of the intensive nature of preparing for and receiving the treatments. 

Over the coming months and years, we’ll learn what the financial reality will look like for patients. But the approval of a CRISPR gene-editing treatment alongside a new gene therapy for sickle cell disease is undeniably historic. And it’s just the beginning. Vertex and CRISPR’s Casgevy, for instance, is also largely expected to be approved by the FDA for the treatment of another inherited blood disorder, beta thalassemia, by the end of spring 2024.