2024-01-18| R&DTrials & Approvals

Groundbreaking CRISPR/Cas9-based Genome Editing Therapy Secured the Second FDA Approval

by Richard Chau
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CASGEVY™ (exagamglogene autotemcel, exa-cel), a single-dose genome editing therapy co-developed by Vertex Pharmaceuticals and CRISPR Therapeutics, received successive regulatory approvals in the U.K. and the U.S. in November and December of 2023 for treating patients aged 12 years or older with sickle cell disease (SCD). On January 16, the U.S. FDA announced the second approval for the CRISPR/Cas9-based therapy, expanding its indications to cover the treatment of transfusion-dependent β-thalassemia (TDT) in patients 12 years of age or older.

Related article: FDA Approves A CRISPR-Based Therapy for Sickle Cell Disease

CRISPR/Cas9-based Therapy Helps TDT Patients Free From Life-long Blood Transfusions

Thalassemias are a group of autosomal recessive inherited blood disorders. Patients carry abnormal hemoglobin genes which results in the production of abnormal hemoglobin. This gives rise to red blood cells with smaller size, reduced oxygen-carrying capacity, and high susceptibility to damage, which in turn leads to chronic hemolytic anemia.

Thalassaemias are generally considered incurable and can be categorized into two main types, alpha (α) and beta (β), according to the globin chains affected, and the severity of clinical symptoms depends on how many of the four genes for alpha globin or two genes for beta globin are missing. The mildest cases can be asymptomatic requiring no treatment, while the most severe cases (e.g. TDT) require radical interventions for survival, including life-long regular blood transfusions and iron chelation therapy (which prevent iron overload in the body due to either the disease itself or from frequent blood transfusions).

The treatment of TDT with CASGEVY is based on the modification of the BCL11A gene by ex vivo genome editing of the patient’s hematopoietic stem cells using the novel CRISPR/Cas9 technology. In normal humans, this gene is activated after birth to suppress the production of fetal hemoglobin (HbF). By silencing the BCL11A gene and transplanting the genetically modified hematopoietic stem cells back into the patient’s bone marrow, the production of HbF can be restarted. This can partially compensate for the deficiency in normal hemoglobin production, improving the oxygen-carrying capacity of red blood cells, and alleviating the symptoms of anemia, thereby freeing TDT patients from the predicament of requiring regular blood transfusions for the rest of their lives.

Vertex and CRISPR Therapeutics Poised to Stay at the Forefront of the Market

Back in November 2023, CASGEVY received approval from the UK’s Medicines and Healthcare Products Regulatory Agency (MHRA) for the treatment of TDT patients aged 12 years or older (in parallel with the aforementioned approval for the treatment of SCD). The U.S. FDA followed suit by granting a second approval for CASGEVY, well ahead of the PDUFA date (March 30). Besides, the European Medicines Agency (EMA) has also indicated that its Committee for Medicinal Products for Human Use (CHMP) has given a positive opinion on CASGEVY, implying that approval at the EU level is on the horizon.

It is worth mentioning that, according to GlobalData’s analysis, about 88% of CRISPR-based genome editing therapies are still in the early stage of development (before entering Phase 1 clinical trial), and only a limited number of therapies have entered Phase 2 clinical trial or above. Given this, Vertex and CRISPR Therapeutics, which already have two regulatory approvals in the U.K. and two in the U.S., are unlikely to face challenges from competitors in the next few years, and will be able to stay at the forefront of the relevant therapeutic areas for some time.

Vertex to Enhance Global Support for More Patients

According to Vertex’s business updates released in early January, CASGEVY is currently being promoted for further expansion of its indications to include SCD or TDT patients between the ages of 5 and 11 years of age, and patient enrollment has been completed for two global Phase 3 clinical trials. 

Concerning patient affordability, Vertex recently signed a partnership with the Synergie Medication Collective, a medication contracting organization of the Blue Cross Blue Shield Association (a health insurance federation comprising 34 independent companies), to provide reimbursement for patients who use CASGEVY, which costs up to $2.2 million (in the U.S.), making the treatment more affordable to a wider range of patients.

In terms of regulatory approvals and patient support, apart from the above-mentioned regions, CASGEVY obtained approval in Saudi Arabia on January 9, and is currently under review in countries such as Switzerland and Bahrain, plus an upcoming submission in Canada in the first half of 2024. Therefore, one can expect an increasing number of countries where the treatment will be approved for use. In addition, Vertex and CRISPR Therapeutics currently have a total of 12 authorized treatment centers (ATCs) in the U.S. and Europe, with the ultimate goal of establishing 50 ATCs in the U.S. and 25 in Europe to benefit more patients.

CEO of CRISPR Therapeutics Expressed Optimism for BD in Genome Editing Technology

Speaking at the 42nd J.P. Morgan Healthcare Conference (JPM 2024) in San Francisco last week (January 8-11), Dr. Samarth Kulkarni, CEO of CRISPR Therapeutics, mentioned that while the support system for CASGEVY is maturing in the United States, he has noticed that the innovative treatment also has tremendous potential overseas. He particularly noted that there is a huge unmet need for patients with severe sickle-cell disease and thalassemia in Asia, the Middle East and parts of Europe. 

Dr. Kulkarni also praised the partnership with Vertex Pharmaceuticals and pointed out that there is still a lot of room for future business development in genome editing technology, and he participated in a number of meetings during JPM 2024 to explore new partnerships.

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