FDA Approves Exa-cel, Vertex and CRISPR Therapeutics’ Gene Therapy, for Sickle Cell Disease

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The FDA’s decision was based on data from the CLIMB-121 and CLIMB-131 clinical trials, making it the first CRISPR-based gene therapy to be approved in the US.

Tim Hunt, JD, the CEO of the Alliance for Regenerative Medicine

Tim Hunt, JD

The FDA has approved Vertex Pharmaceuticals' and CRISPR Therapeutics’ autologous gene-edited cell therapy exagamglogene autotemcel (exa-cel), marketed under the name Casgevy, for the treatment of severe sickle cell disease (SCD) in patients aged 12 years and older with recurrent vaso-occlusive crises.1 It is the first CRISPR-based gene therapy to be approved in the United States.

The FDA’s decision was based on results from the phase 1/2/3 CLIMB-121 clinical trial (NCT03745287), which was conducted exclusively in patients with SCD, and the phase 3 long-term follow-up study CLIMB-131 (NCT04208529), which includes both patients with SCD and patients with transfusion-dependent β-thalassemia (TDT).

Alongside today's approval of exa-cel, the FDA also approved bluebird bio's lovotibeglogene autotemcel (lovo-cel), marketed as Lyfgenia.1 A gene-edited cell therapy modified with the use of a lentiviral vector, lovo-cel was approved for the treatment for SCD in patients aged 12 years and older who have a history of vaso-occlusive events.

"Today’s FDA approval of Casgevy for severe SCD marks a seminal moment in the history of biotechnology and human health,” Tim Hunt, JD, the CEO of the Alliance for Regenerative Medicine, told CGTLive. “As the first gene-editing medicine approved in the US, Casgevy represents a durable and potentially curative treatment option for a population that has been overlooked for far too long—and one that is the largest to date for a gene therapy. Importantly, today’s milestone will also pave the way for a coming wave of next-generation gene-editing treatments for a range of diseases, from other rare disorders to cancers.”

Among 31 evaluable patients with SCD treated in CLIMB-121 and CLIMB-131, 29 patients (93.5%) achieved the primary end point of freedom from vaso-occlusive crises (VOCs) for at least 12 consecutive months during a 24-month follow-up period.1 Furthermore, among the 30 patients, 100% achieved a key secondary end point for freedom from inpatient hospitalization for VOCs for at least 12 consecutive months, according to data considered current in October 2023.2 Six adolescent patients achieved both of these end points and the patient who did not achieve the primary end point was also an adolescent patient.

READ MORE: Coverage of the American Society of Hematology (ASH) 2023 Annual Meeting

In terms of safety, the adverse event (AE) profile of exa-cel displayed similarity to that of autologous stem cell transplant.3 The most common AEs experienced by patients treated with exa-cel were low levels of platelets and white blood cells, mouth sores, nausea, musculoskeletal pain, abdominal pain, vomiting, febrile neutropenia, headaches, and itching.1 Fatigue, fever, and increased risk of infection were also reported.3

Nicole Verdun, MD, the director of the Office of Therapeutic Products within the FDA’s Center for Biologics Evaluation and Research

Nicole Verdun, MD

“Sickle cell disease is a rare, debilitating and life-threatening blood disorder with significant unmet need, and we are excited to advance the field especially for individuals whose lives have been severely disrupted by the disease by approving two cell-based gene therapies today,” Nicole Verdun, MD, the director of the Office of Therapeutic Products within the FDA’s Center for Biologics Evaluation and Research, said in a statement.1 “Gene therapy holds the promise of delivering more targeted and effective treatments, especially for individuals with rare diseases where the current treatment options are limited.”

Vertex and CRISPR Therapeutics originally completed their rolling submission of 2 separate biologics license applications (BLAs) for exa-cel for SCD and TDT indications in April 2023.4 Upon acceptance of the BLAs by the FDA in June 2023, the SCD BLA was granted priority review status while the TDT BLA was set for standard review with a still-upcoming Prescription Drug User Fee Act target action date of March 30, 2024.5

More recently, on October 31, 2023, the FDA Cellular, Tissue, and Gene Therapies Advisory Committee (AdComm) held a meeting to discuss the risk of off-target editing for exa-cel.2 The members of the AdComm were generally of the opinion that the off-target analyses conducted by Vertex were reasonably robust, and the talk shifted mainly to whether additional postmarketing research on the potential risks posed by the therapy could be worthwhile.

"The dual approvals for 2 distinct gene therapies for severe SCD are groundbreaking," Hunt added. "A patient population that has been overlooked for far too long now has 2 durable, and potentially curative, treatment options. These 2 therapies represent the fourth and fifth FDA approvals of gene therapies targeting rare genetic diseases in 2023, doubling the number of such therapies on the market from just 1 year ago. These milestones will propel future advancements for gene therapy across many different disease states.”

Shortly before today’s decision, on November 16, 2023, the United Kingdom’s Medicines and Healthcare products Regulatory Agency approved exa-cel for the treatment of both SCD and TDT in patients aged 12 years and older.3 It was the first CRISPR-based gene therapy to be approved in the UK.

“The approval of the first gene therapies for SCD represents a tremendous step forward for the SCD community, which has been historically overlooked and underfunded. While these new gene therapies are potentially life-changing for individuals living with SCD, they must be accessible to be effective," American Society of Hematology president Robert A. Brodsky, MD, said in a statement. "ASH remains committed to improving the availability of innovative treatments for blood disorders such as gene therapies for SCD and providing resources to clinicians to help implement these evolving therapies. People with SCD need more – they need comprehensive care.”

"This is really an exciting time to be in the field," Akshay Sharma, MBBS, assistant member, bone marrow transplant department, St. Jude Children’s Research Hospital, told CGTLive™ regarding the approvals of both exa-cel and lovo-cel. "Many people don't know, but SCD was one of the first genetic diseases whose molecular basis was identified more than 50 years ago. Primarily because of the population that it affects—in the US, it's African Americans and in the rest of the world it's individuals of African and South Asian origin—it has been a neglected disease. From from where I stand as a provider who takes care of patients with SCD it's a really exciting time to be in the field."

"Having said that, though, I am a little bit skeptical, because of the price tag for these therapies, which is $2 million to $3 million," Sharma continued. "How many patients will actually be able to afford these therapies in the short term? And that's within the US. The major burden of SCD in the world is in Sub-Saharan Africa and Southeast Asia. How are individuals in those countries going to ever be able to afford these therapies? I think that remains a question mark. So from a global perspective, I think all this data is really exciting, but what we really need to now work towards and where the real work now begins is to make these therapies accessible and affordable for people who actually need them. Because if there's a therapy which works really well, but most people can't access it, then that's not an effective therapy."

REFERENCES
1. FDA Approves First Gene Therapies to Treat Patients with Sickle Cell Disease. News release. FDA. December 7, 2023. Accessed December 7, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapies-treat-patients-sickle-cell-disease
2. 76th Cellular, Tissue, and Gene Therapies Advisory Committee (CTGTAC) Meeting. October 31, 2023. https://www.fda.gov/advisory-committees/advisory-committee-calendar/cellular-tissue-and-gene-therapies-advisory-committee-october-31-2023-meeting-announcement-10312023
3. MHRA authorises world-first gene therapy that aims to cure sickle-cell disease and transfusion-dependent β-thalassemia. News release. MHRA. November 16, 2023. Accessed December 7, 2023. https://www.gov.uk/government/news/mhra-authorises-world-first-gene-therapy-that-aims-to-cure-sickle-cell-disease-and-transfusion-dependent-thalassemia
4. Vertex and CRISPR Therapeutics Complete Submission of Rolling Biologics License Applications (BLAs) to the US FDA for exa-cel for the Treatment of Sickle Cell Disease and Transfusion-Dependent Beta Thalassemia. News release. Vertex Pharmaceuticals Inc; CRISPR Therapeutics. April 3, 2023. Accessed December 7, 2023. https://www.businesswire.com/news/home/20230402005036/en/
5. FDA accepts Biologics License Applications for exagamglogeneautotemcel (exa-cel) for severe sickle cell disease and transfusion-dependent Beta thalassemia. News release. Vertex Pharmaceuticals. June 8, 2023. Accessed December 7, 2023. https://investors.vrtx.com/news-releases/news-release-details/fda-accepts-biologics-license-applications-exagamglogene
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