U.K.’s MHRA Authorizes First CRISPR/Cas9 Gene-Edited Therapy for SCD, TDT

Rare Daily Staff

The United Kingdom’s Medicines and Healthcare Products Regulatory Agency has granted conditional marketing authorization for Casgevy, CRISPR Therapeutics’ and Vertex Pharmaceuticals’ CRISPR/Cas9 gene-edited therapy for the treatment of sickle cell disease and transfusion-dependent beta thalassemia.

Casgevy has been authorized for the treatment of eligible patients 12 years of age and older with sickle cell disease (SCD) with recurrent vaso-occlusive crises or transfusion-dependent beta thalassemia (TDT), for whom a human leukocyte antigen matched related hematopoietic stem cell donor is not available. There are an estimated 2,000 patients eligible for Casgevy in the United Kingdom.

“Today is a historic day in science and medicine: this authorization of Casgevy in Great Britain is the first regulatory authorization of a CRISPR-based therapy in the world,” said Reshma Kewalramani, president and CEO of Vertex.

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.

Beta thalassemia 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. A lack of red blood cells, also known as anemia, is the primary manifestation of beta thalassemia. Because of this anemia, people living with beta thalassemia may experience fatigue and shortness of breath, and infants may develop failure to thrive, jaundice and feeding problems. Complications of beta thalassemia can also include an enlarged spleen, liver and/or heart; misshapen bones; and delayed puberty. Treatment for beta thalassemia is personalized and depends on the severity of disease that each person experiences.

Many people have to get regular blood transfusions to deliver healthy donated blood to their body. This requires many hospital visits and can also lead to an unhealthy buildup of iron. Today, stem cell transplant from a matched donor is a curative option but is only available to a small fraction of people living with beta thalassemia. Beta thalassemia requires lifelong treatment and significant use of health care resources, and ultimately results in reduced life expectancy, decreased quality of life, and reduced lifetime earnings and productivity. In the U.K., the mean age of death for people living with TDT is around 55.

Casgevy is a genetically modified autologous CD34+ cell enriched population that contains human hematopoietic stem and progenitor cells edited ex vivo by CRISPR/Cas9 at the erythroid-specific enhancer region of the BCL11A gene.

In two global clinical trials of Casgevy in SCD and TDT, the trials met their respective primary outcome of becoming free from severe VOCs or transfusion independent for at least 12 consecutive months. Once achieved, these benefits are potentially expected to be life-long. The safety profile of 97 SCD and TDT patients treated to date with Casgevy in these ongoing studies is generally consistent with myeloablative conditioning with busulfan and hematopoietic stem cell transplant.

In the U.K., exa-cel was granted an Innovation Passport under the Innovative Licensing and Access Pathway from the MHRA, and Vertex is already working closely with national health authorities to secure access for eligible patients as quickly as possible.

Exa-cel is also under review by the European Medicines Agency, the Saudi Food and Drug Authority, and the U.S. Food and Drug Administration. The FDA has granted Priority Review for SCD and Standard Review for TDT. The agency is expected to act on the application for SCD by December 8 and the TDT application by March 30, 2024.

Photo: Reshma Kewalramani, president and CEO of Vertex