The U.S. Food and Drug Administration (FDA) made history on December 9th, 2023 by approving the first two cutting-edge gene therapies for sickle cell disease (SCD) – a debilitating, lifelong inherited blood disorder that affects over 100,000 Americans.
One of the newly approved treatments, CRISPR Therapeutics’ CasgevyTM (exa-cel), represents the first ever FDA-approved therapy utilizing CRISPR gene editing technology. The other, Bluebird Bio’s LYFGENIA® (betibeglogene autotemcel), delivers functional gene copies into cells via a viral vector. Both treatments work by introducing a modified and functional copy of the hemoglobin beta (HBB) gene in order to induce production of healthy hemoglobin and thereby reduce sickling of red blood cells, which causes the symptoms of SCD.
Hailed by many as marking a new era of precision genetic medicine, these approvals provide real hope to sickle cell patients who have waited decades for more effective therapies.
Highly Anticipated Milestone Culminates Years of Research
The quest to find a genetic cure for sickle cell disease has been years in the making, with this week’s FDA decision representing a major regulatory milestone.
While current standard-of-care focuses on managing SCD symptoms, these newly approved treatments target the underlying genetic root cause of the disease – a mutation in the HBB gene which causes abnormal sickling of red blood cells, leading to anemia, severe pain, organ damage, and early death. By adding functional gene copies, the therapies aim to restore normal hemoglobin production and prevent sickling complications.
Researchers have been exploring gene therapy and gene editing approaches to sickle cell treatment for over two decades. Early successes with viral vector gene therapy in small trials and animal models built momentum, even amid setbacks with insertional oncogenesis side effects. Meanwhile CRISPR’s dramatic rise as a precise and efficient gene editing technology opened new possibilities.
Phase 3 trials over the past few years have shown extremely promising results from both Casgevy and LYFGENIA, with up to 80% of treated patients showing complete elimination of vaso-occlusive crises (debilitating pain episodes), reduced transfusions, and improved quality of life – leading to overwhelming positive votes in favor by FDA’s advisory committees.
Genetically Targeted Treatments Usher in Precision Medicine
Unlike conventional pharmaceutical approaches which only address symptoms, these pioneering genetic therapies offer more precise, disease-modifying solutions by fixing the root biological cause.
The approval of Casgevy and LYFGENIA are early examples of a wave of emerging genetically targeted treatments that promise to usher in an era of precision medicine – where therapy is tailored to a patient’s exact genetic profile.
Sickle cell has laid the foundations for this revolution not only because of its clear genetic cause, but also thanks to decades of dedicated work by researchers and patient advocates. Especially critical has been the collection of real-world evidence and patient-focused endpoint data – championed by Sickle Cell Disease Association of America (SCDAA) and partners – that convinced regulators of the immense value to patients.
Patient groups hope these first approvals blaze a trail for other rare disease communities on the long road to developing precisison genetic medicines.
First CRISPR Therapy Approval Makes History
While both gene editing and gene therapy have been discussed for sickle cell treatment over the past 20 years, the Casgevy approval represents the first ever green light for a working CRISPR medicine.
CRISPR’s ability to directly edit genes piqued researchers’ interest several years ago. But moving from promise to reality has required tackling formidable challenges like delivering gene editors effectively to blood stem cells and minimizing off-target effects.
Years of clever CRISPR engineering and testing by CRISPR Therapeutics, together with gene therapy expertise from partner Vertex, have now paid off spectacularly – placing them firmly in the history books.
Moreover, their CRISPR-based approach avoids relying on viruses, addressing earlier concerns around viral vector gene therapy safety. Regulators will however still require stringent post-approval monitoring for cancer risk from both products.
Competitive Landscape Heats Up
FDA approval kicks off a high-stakes battle for market share between would-be rivals Bluebird Bio and CRISPR Therapeutics.
Both aim to reach as many eligible US sickle cell patients as possible with these likely one-time curative therapies. But achieving reimbursement from payers may prove the next challenge.
LYFGENIA is priced at US$2.8 million, making it one of the most expensive treatments ever. Meanwhile Casgevy comes in a little lower at $2.5 million over 5 years. These head-turning price tags clearly limit accessibility, but manufacturers argue this fairly reflects potentially lifetime savings from avoided hospitalizations.
Globally, securing access in less wealthy nations where sickle cell is most prevalent will require creative affordability solutions like installment payment models.
Outlook: Cautious Optimism
Patients, doctors and investors greeted the news with joy, tempered by some words of caution around lasting benefits and safety issues requiring long term study:
Durability remains a open question, given these treatments are newly approved following just 2 years of trial evidence so far. Continued production of gene-therapy derived hemoglobin will likely be critical to avoid sickling symptoms returning over a patient’s lifetime.
Though safety has been extensively studied, therapies require extracting and genetically modifying a patient’s blood stem cells. Monitoring is needed for side effects like insertional oncogenesis and clonal expansion. Broader ecosystem impacts from releasing increasing numbers of genetically edited human cells also require ongoing evaluation.
Nonetheless, doctors hailed the approvals as offering “hope on the horizon” for long-suffering patients. If the early benefits hold up, the treatments constitute life-changing – or even life-saving – advances for individuals affected by sickling complications.
Gene therapy and gene editing communities also see reason for optimism that these first historic approvals blaze a trail towards tackling other rare genetic disorders in dire need of treatment options.
|CRISPR Therapeutics / Vertex
|$2.5 million (over 5 years)
|CRISPR-based gene editing approach
|LYFGENIA® (betibeglogene autotemcel)
|$2.8 million (one-time)
|Gene therapy using viral vector
What Comes Next?
In the wake of the pivotal FDA gene therapy decisions, all eyes turn to the critical questions of who gets access, how quickly, and what comes next on the horizon:
Access and Affordability
With sky-high price tags, debates around access and affordability will likely come to the forefront. This includes pushing for public and private insurance coverage in the US, as well as exploring creative global access models. Patient advocacy will be key.
Real-World Evidence Gathering
Careful evidence gathering in real-world use will reveal the durability and safety of these treatments over patients’ lifetimes. This data will shape confidence and decision making for regulators, doctors and manufacturers.
Both gene therapy products are initially approved for adults and pediatric patients 12 years and older. Gaining approval for younger children will be an important next milestone.
Ongoing efforts by manufacturers to improve the therapies will continue , including making the procedures safer and even finding ways to reduce reliance on chemotherapy during pre-treatment conditioning.
Researchers are already discussing expanding the application of genetic approaches like those just approved for sickle cell to tackle related hemoglobin disorders like beta thalassemia. Further down the line, the technology could be tailored to address other monogenic diseases.
So while last week’s FDA decision provides cause for celebration, in many ways this breakthrough moment marks just the end of the beginning. The hard work now lies in ensuring patient access, evidencing real-world impact, refining these life-changing medicines and charting the future path for genetic precision therapies.
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