A gene editing milestone: The FDA approves CASGEVY, the first CRISPR-based therapy


Still a relatively new technology, CRISPR has been heralded in recent years as having the potential to tackle a range of diseases. And now, it has finally proved its worth. In a world first, the U.S. Food and Drug Administration (FDA) has approved CASGEVY – the CRISPR-based gene therapy developed by Vertex Pharmaceuticals and CRISPR Therapeutics for the treatment of sickle cell disease and beta-thalassemiajust weeks after it was approved by the Medicines and Healthcare products Regulatory Agency (MHRA) in the U.K.

Sickle cell disease and beta-thalassemia are both genetic conditions that affect hemoglobin. Sickle-cell disease can cause debilitating pain and life-threatening infections, and people with beta-thalassemia often require blood transfusions every few weeks of their lives. 

Previously, the only permanent treatment option for the two blood conditions was a bone marrow transplant. However, this needs to come from a closely matched donor and carries with it a risk of rejection. 

But, now, CASGEVY would mean that a curative, one-time treatment for patients is available.

So, how did the decision to approve CASGEVY come about? We take a closer look at the details of its U.K. and U.S. approval in this article.

How does CASGEVY work?

Both sickle cell disease and beta-thalassemia are caused by errors in the genes that encode hemoglobin, which helps red blood cells carry oxygen around the body. CASGEVY essentially works by turning on a gene called fetal hemoglobin, which people have as a fetus, as well as when they are born. 

“It’s known that fetal hemoglobin can essentially make it so that you have no symptoms if you have sickle cell disease or beta-thalassemia because babies who are born with sickle cell disease and beta-thalassemia have no symptoms until after the fetal hemoglobin turns off,” David Altshuler, chief scientific officer (CSO) of Vertex Pharmaceuticals, told Labiotech in a previous article about how gene therapy could offer promise for treating sickle cell disease. 

He continued to explain: “And there’s a small number of people with a very rare genetic mutation called hereditary inherited persistence of fetal hemoglobin; it never turns off. And, if it never turns off, people with sickle cell disease and beta-thalassemia will never get sick.”

BCL11A is the specific gene targeted by the CASGEVY CRISPR therapy, as it usually prevents the production of fetal hemoglobin in adults. Therefore, by disrupting this gene, CASGEVY allows for the production of fetal hemoglobin, which does not carry the same abnormalities as adult hemoglobin in people with sickle-cell disease or beta-thalassemia.

CASGEVY is administered by taking blood-producing stem cells from the bone marrow of people with sickle cell disease or beta-thalassemia, before using CRISPR/Cas9 to edit the genes encoding hemoglobin. Once the Cas9 enzyme – which acts as ‘molecular scissors’ – reaches BCL11A, it cuts both DNA strands, disabling the gene. The modified stem cells are then infused back into the patient, giving rise to red blood cells containing fetal hemoglobin, relieving symptoms by boosting the oxygen supply to tissues.

The U.K.’s decision to approve CASGEVY

CASGEVY has officially been authorized by the MHRA for the treatment of patients 12 years of age and older with sickle cell disease with recurrent vaso-occlusive crises or transfusion-dependent beta-thalassemia who cannot be matched with a stem cell donor. There are an estimated 2,000 patients eligible for CASGEVY in the U.K., according to Vertex’s press release

The approval from the MHRA came after some impressive clinical trial results testing CASGEVY in patients with sickle cell disease and beta-thalassemia. 

In the ongoing clinical trial for sickle cell disease, 45 patients have already received CASGEVY, with only 29 patients having been in the trial long enough to be eligible for the primary efficacy interim analysis. But, of these eligible patients, 28 (97%) were free of severe pain crises for at least 12 months after treatment.  

Meanwhile, in the clinical trial for transfusion-dependent beta-thalassemia, which is also ongoing, 54 patients have received CASGEVY. Only 42 patients have been in the trial long enough to be eligible for the primary efficacy interim analysis but, of these, 39 (93%) did not need a red blood cell transfusion for at least 12 months after treatment. The remaining three had more than a 70% reduction in the need for red cell transfusions. 

As these trials are still ongoing, further results will become available soon. 

Following the U.K.’s lead: the FDA also grants CASGEVY approval

After its MHRA approval, the next big question for CASGEVY was whether the FDA would follow the U.K.’s lead and approve the CRISPR-based therapy. According to the New York Times, a panel of experts said at the end of last month that CASGEVY was safe enough for clinical use, which ultimately set the stage for likely approval from the agency. 

And on December 8, the FDA made its decision, granting a historic approval to CASGEVY for the treatment of sickle cell disease.

However, the use of the therapy for the treatment of transfusion-dependant beta-thalassemia in the U.S. remains investigational. Vertex has submitted a biologics license application (BLA) to the FDA for the potential use of CASGEVY for patients 12 years and older with transfusion-dependant beta-thalassemia, and has been assigned a prescription drug user fee act (PDUFA) target action date of March 30, 2024.

Looking ahead: what does the future now hold for CASGEVY?

It is worth noting that some questions are currently circling about whether the U.K.’s National Health Service (NHS) and U.S. insurance companies will pay for CASGEVY, which, according to an SEC filing, will cost $2.2 million per patient.

Meanwhile, another issue that could potentially cloud CASGEVY’s approval is the fact that most people with sickle cell disease live in Africa, which does not have many medical facilities that can offer the complex care needed to deliver this type of treatment. 

But, now that it has been approved by the MHRA and the FDA, there is no denying that CASGEVY does hold the potential to change the lives of people with sickle cell disease and beta-thalassemia. 

“For years, people with sickle cell and transfusion-dependent beta-thalassemia have restricted their lives managing their diseases with limited new treatment options,” said Ludovic Fenaux, head of International at Vertex in a comment to Labiotech. “People in the U.K. with these diseases still die decades earlier than the general population. This approval gives hope for a life free from debilitating pain or monthly blood transfusions for eligible patients.”

And, perhaps just as importantly, CASGEVY could also open the door for other CRISPR-based therapies to be approved in the near future, potentially helping to treat a number of diseases that have historically been difficult to find a cure for.

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