The U.S. Food and Drug Administration (FDA) made history on December 9th, 2023 by approving the first ever gene editing therapy to treat sickle cell disease. Known as exa-cel, the one-time treatment from Vertex Pharmaceuticals and CRISPR Therapeutics is the first therapy approved in the U.S. to use CRISPR gene editing technology to treat a genetic disorder by editing a patient’s stem cells.
The approval marks a major medical advancement that has the potential to functionally cure sickle cell disease, a painful and debilitating inherited blood disorder that impacts over 100,000 people in the U.S. and millions worldwide. Exa-cel targets the underlying genetic cause of the disease and experts suggest it could eliminate the need for regular blood transfusions for those treated.
Highlights of the Exa-Cel Gene Editing Treatment
- Exa-cel is the first ever FDA approved gene editing therapy to treat a genetic disease
- It uses CRISPR gene editing technology to functionally cure sickle cell disease by editing stem cells
- Sickle cell disease is an inherited blood disorder that causes pain, organ damage, strokes, and early death
- Over 100,000 people in the U.S. and millions globally suffer from sickle cell disease
- Exa-cel is a one-time stem cell transplant that could eliminate the need for blood transfusions
- Experts hail approval as ushering in a new era of genomic medicine
How Exa-Cel Works to Treat Sickle Cell Disease
Exa-cel works by using CRISPR gene editing technology to correct the genetic mutation that causes sickle cell disease. The therapy involves harvesting stem cells from a patient’s own blood, then using CRISPR to precisely edit the DNA in those stem cells to switch on the production of fetal hemoglobin.
The edited stem cells are then infused back into the patient in a one-time transplant. Once in the body, the genetically corrected stem cells take over blood cell production from the patient’s original mutated cells. This effectively provides a “functional cure” by eliminating or drastically reducing symptoms of sickle cell disease.
Highlights of How Exa-Cel Gene Editing Treatment Works
1. Patient stem cells harvested from blood
2. CRISPR used to precisely edit DNA in stem cells
3. Edited stem cells produce fetal hemoglobin
4. Cells infused back into patient in one-time transplant
5. Edited stem cells take over blood cell production
6. Functional cure achieved - symptoms eliminated
Experts suggest exa-cel could essentially replace the need for regular painful blood transfusions for sickle cell patients. It also has the potential to greatly reduce organ damage and pain crises caused by the disease. By providing a lasting fix rather than just managing symptoms, many are calling exa-cel a “functional cure” for sickle cell disease.
Exa-Cel Approval Culmination of Yearslong Journey
The FDA approval of exa-cel caps off a 30-year quest to develop a genetic fix for sickle cell disease. Early gene therapy experiments in the 1990s aiming to switch production of fetal hemoglobin on ran into major roadblocks.
It was the advent of more precise CRISPR gene editing in 2012 that revived efforts to genetically correct sickle cell disease. Researchers at Vertex and CRISPR Therapeutics began collaborating on an experimental CRISPR sickle cell treatment in 2015.
After successful early trials, the companies began a Phase 3 clinical study called CLIMB-111 in 2019 comparing exa-cel to standard care. Results published in 2021 showed that after 2 years, 94% of treated patients were crisis-free compared to only 6% on standard care.
With strong evidence of safety and efficacy from the CLIMB trials, Vertex submitted exa-cel to the FDA for approval in March 2022. Following priority review, the agency granted approval on December 9th, 2023 – opening up the treatment to all eligible sickle cell disease patients in the U.S.
First Ever CRISPR Therapy Approval Ushers in New Era
The makers of exa-cel suggest its approval marks the start of a “new era in genomic medicine.” It is the first ever FDA approved treatment to use CRISPR gene editing and pioneers an entirely new class of precision genetic medicines.
Experts say it could lay the groundwork for developing gene editing treatments for thousands of other genetic conditions in the future. The fact the therapy provides lasting correction after a single treatment is also groundbreaking.
Patient advocacy groups celebrated the approval as finally bringing hope to an underserved community in desperate need of better treatment options beyond pain management.
With exa-cel’s approval, the U.S. now leads the globe in authorizing a CRISPR therapy. However, access barriers around cost and limited treatment centers could mean only a fraction of U.S. sickle cell patients initially benefit.
Who Can Get the New Sickle Cell Gene Therapy?
The FDA granted approval of exa-cel for sickle cell disease patients ages 16-50 with at least 2 painful crises in the past two years. Those with a graft vs host disease history are excluded.
Vertex estimates there are about 16,000 sickle cell patients in the U.S. eligible for exa-cel based on those criteria. However, treatment capacity will be limited initially until more qualified treatment centers and medical personnel are trained to deliver the complex one-time stem cell transplant.
Only about 100 patients are expected to get exa-cel in the first year. Vertex hopes to expand treatment reach to 500-1,000 patients per year over the next 2-3 years by certifying more major transplant centers able to perform the procedure.
Concerns Exist Around Cost and Equal Access
A key question surrounding exa-cel is whether patients outside of top tier care centers will be able to access “the cure” as production scales up. There are only about 150 established stem cell transplant centers in the U.S.
Vertex has yet to announce a price for the ultra personalized therapy. But as a potentially curative gene therapy, estimates suggest it could cost over $2-3 million per patient. Even half that price tag would likely make it the world’s most expensive medication.
High costs mean state Medicaid programs and smaller health systems may struggle to cover exa-cel for their sickest patients. Sickle cell disease disproportionately impacts Black Americans and the under/uninsured.
Advocacy groups warn patient access must be equitable across income and racial lines as additional treatment centers are certified. They are pressuring Vertex to responsibly price exa-cel so those most vulnerable to sickle cell disease are not left behind.
What Are Potential Long Term Risks of Gene Editing Therapy?
While exa-cel’s approval offers new hope, the gene edited stem cell transplant does carry significant risks in exchange for potential lasting benefit. About 1 in 5 patients suffer serious side effects like infections leading to extended hospitalization.
Rare cases resulted in severe anemia, bleeding, and respiratory failure – highlighting it is not universally curative. There is also some concern CRISPR may miss the target gene or make unintended edits capable of eventually causing cancer.
Patients will need lifelong follow up exams to monitor for delayed side effects. Ongoing global studies tracking the first exa-cel recipients from initial trials will be key to quantifying very long term safety.
Despite known risks, many patients describe emerging from pain crises as “rebirth” so great is their renewed lease on life. With proper informed consent, 93% of trial participants said they would go through the treatment again.
What Comes Next After Exa-Cel Approval?
Vertex and CRISPR Therapeutics are wasting no time advancing a next generation CRISPR sickle cell therapy meant to improve efficacy and limit side effects. Early data already shows promising results.
They are also exploring whether gene editing could benefit the much larger beta thalassemia patient group struggling with severe anemia requiring transfusions. Beyond sickle cell disease, the partners envision CRISPR cures for diseases like diabetes and ALS.
Meanwhile, competitor bluebird bio gained FDA approval concurrently for a similar gene therapy called Zynteglo. And Sangamo Therapeutics, Graphite Bio, and Generation Bio are hot on their heels – ensuring momentum in the nascent field of genetic cures.
Far from the end, experts call CRISPR’s arrival on the medical scene just the beginning. The pace of advancement from proof of concept to cure has been unusually swift. Approval of exa-cel now ushers in a paradigm shift toward precision genetic medicines.
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