Groundbreaking? Game-changing? Transformational? Historic?
None of the buzzwords sound adequate to describe Friday’s FDA approval of Vertex Pharmaceuticals and CRISPR Therapeutics’ Casgevy (exa-cel) to treat sickle cell disease (SCD).
The therapy is a long-awaited potential cure for the debilitating and life-threatening disease which affects more than 100,000 in the United States, most of them Black. It’s also the first medicine using the revolutionary CRISPR gene-editing system, which earned its inventors a Nobel Prize in 2020 and holds tantalizing potential to cure diseases for which there is no treatment.
Friday, in surprising timing, the FDA approved a second gene therapy for SCD, bluebird bio’s Lyfgenia (lovo-cel), which was due for a decision Dec. 20. Both approvals are for people 12 and older.
The FDA has signed off on roughly two dozen cell or gene therapies, beginning with Novartis’ Kymriah in 2017, but none have the potential impact of Casgevy and Lyfgenia.
“(Sickle cell) is not a rare genetic disease that no one’s ever heard of,” Julie Gerberding, president and CEO of the Foundation for the National Institutes of Health, said in an interview on Monday. “The applicability to a larger population is really, I think, part of what makes this so exciting. Although it’s also sort of the 0.5 version of where we can go in terms of really having a population-level impact.”
In October, an FDA advisory committee signed off on the safety of exa-cel, quelling concerns about off-target effects of CRISPR editing and clearing its path to approval. Then, three weeks ago, experts in the U.K. authorized Casgevy for SCD and another similar blood disorder, transfusion-dependent beta thalassemia (TDT).
While Vertex and CRISPR will charge $2.2 million for Casgevy, according to an SEC filing, bluebird has said it will price Lyfgenia at $3.1 million, raising questions about coverage and accessability. Most gene therapies are priced at more than $1 million and the treatments can run all the way up to $3.5 million for the world’s costliest drug—CSL Behring and uniQure’s hemophilia B treatment Hemgenix.
Earlier this year, the Institute for Clinical and Economic Review (ICER) assessed that both Vertex and bluebird’s therapies would meet cost-effectiveness thresholds if priced between $1.35 million and $2.05 million.
SCD causes blood cells to fold into crescent shapes, which makes them more likely to collect in blood vessels, depriving the muscles of oxygen. Patients undergo blood transfusions but still live with the constant threat of strokes and episodes of searing pain. The disorder also leaves patients susceptible to a host of other complications such as anemia, jaundice, infections, gallstones and organ damage.
Some patients can undergo bone marrow transplants that can cure the disease, but that requires a donor—a full brother or sister—and a variety of medicines to ensure that the body adapts to the new cells.
As for exa-cel, interim data reported in June showed that of 15 of 16 sickle cell patients treated (94%) did not have the debilitating pain episodes—also known as vaso-occlusive crises—for at least 12 consecutive months, which was the primary endpoint measured. The benefits are expected to be lifelong, Vertex and CRISPR have said.
Another trial with exa-cel in TDT patients showed that 89% achieved the primary endpoint of transfusion independence for at least 12 consecutive months. The FDA is scheduled to make a decision on exa-cel in that indication by March 30 of next year.
With the treatment, bone marrow stem cells are taken from patients and CRISPR is used to modify the marrow before the cells are reinfused by way of a stem cell transplant. The therapy allows the production of fetal hemoglobin, replacing the defective hemoglobin of people with the diseases.
Lasting up to a year, the process is laborious for patients and requires a hospital stay of a month or more as patients are treated and monitored after reinfusion.

‘Not at the end of the road’

While hailing exa-cel as a significant breakthrough in finding a cure for SCD, experts agree that there’s a long way to go to simplify its administration and ensure its safety and reliability.
During the FDA advisory committee meeting in October, Daniel Bauer, Ph.D., of the Boston Children’s Cancer and Blood Disorders Center, presented research that showed that CRISPR can cause unanticipated mutations but emphasized that the benefits of exa-cel outweigh the risks.
“We’re not at the end of the road,” Bauer told reporters during a Zoom session on Tuesday. “This is an important milestone but it’s still a very challenging therapy to deliver that requires collection of stem cells and ex-vivo manipulation and treatment with chemotherapy to ablate the blood system.”
While most researchers were going in a different direction a decade ago, Bauer and Stuart Orkin, M.D., of the Harvard Stem Cell Institute, were employing CRISPR to lay the groundwork for the development of exa-cel, with their efforts funded by the Doris Duke Foundation.
A decade later, Bauer and Orkin are thrilled with the development of the treatment. Orkin called the trial results—showing 94% of patients symptom free—“spectacular” and “well above the threshold of clinical benefit.”
The forefathers of exa-cel steer clear of calling it a cure, however. Even the earliest trial patients aren’t far enough removed from treatment to be declared free of SCD and the potential long-term side effects of the therapy, Bauer said.
“(Cure is) an exciting term but it’s a hard-to-define term,” Bauer said. “I think we would all agree that it takes a long time of observation to say that someone’s been cured.”

https://www.fiercepharma.com/pharma/vertex-crispr-score-landmark-fda-approval-sickle-cell-disease-gene-therapy