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CRISPR therapy for sickle cell approved by FDA in gene editing milestone

CRISPR

Developed by Vertex Pharmaceuticals and CRISPR Therapeutics, Casgevy is the first medicine based on the Nobel Prize-winning technology to be cleared in the U.S.

The Food and Drug Administration on Friday approved a gene editing treatment for the blood disease sickle cell, following a few weeks behind regulators in the U.K. to clear the world’s first medicine built from the Nobel Prize-winning technology CRISPR.

Called Casgevy, the treatment can free people with severe sickle cell from the excruciating pain crises that are a hallmark of the disease. Researchers expect that benefit to last many years, if not a lifetime, as Casgevy works by permanently — and precisely — changing the DNA of a patient’s own stem cells.

Its approval in the U.S. and U.K. caps a decade of remarkable scientific progress translating CRISPR from academic breakthrough to new medicine. The editing tool, often likened to “genetic scissors,” has proven both flexible and powerful, and drugmakers have been busy adapting it into treatments for an array of inherited diseases.

Developed by Vertex Pharmaceuticals and CRISPR Therapeutics, Casgevy is the first from that pipeline to reach the market. It’s approved in the U.S. to treat adults and adolescents 12 years of age or older who have recurrent pain crises from sickle cell, a long overlooked disease that predominantly affects people of African ancestry.

Also on Friday, the FDA cleared another genetic medicine for sickle cell, called Lyfgenia and developed by Bluebird bio. It’s for people 12 years of age or older who have a history of pain crises from the disease.

“These approvals represent an important medical advance with the use of innovative cell-based gene therapies to target potentially devastating diseases and improve public health,” Peter Marks, head of the FDA’s Center for Biologics Evaluation and Research, said in a statement

Casgevy is created from a patient’s stem cells, which are collected and shipped to a manufacturing facility where they are edited using CRISPR. A snip to DNA at just the right spot allows those cells, once reinfused, to produce a fetal form of the oxygen-carrying protein hemoglobin, which is damaged in people with sickle cell.

The CRISPR edit creates a genetic detour of sorts around the problem caused by the sickle cell mutation. Fetal hemoglobin-containing red blood cells don’t sickle as easily, alleviating the pain crises that result from sickled cells piling up and jamming blood vessels.

In testing, all but one of the 30 study participants who have been followed for at least 16 months post treatment remained free of pain crises for at least one full year, according to the most recently updated results. Twenty-seven haven’t had any crises, and participants have been able to stay out of the hospital as a result.

“If you use crises and hospitalization as a surrogate of disease severity, we are definitely winning that part of the battle,” Haydar Frangoul, a director of pediatric hematology at the Sarah Cannon Research Institute who helped run the Casgevy trial, said in an interview earlier this year.

Victoria Gray, the first person with sickle cell treated in Casgevy’s clinical trial, said that, as a result of her therapy, she no longer needs to receive blood transfusions.

“That was a routine I no longer have to do. My blood counts remain stable and I don’t experience pain from sickle cell,” she said. “This time of year I would always be in the hospital because of the temperature. Chills would send me into crisis. I don’t experience that any more.”

Lyfgenia works slightly differently than Casgevy. Rather than CRISPR, Bluebird uses a benign virus to insert an engineered gene that encodes for functional hemoglobin into patients’ stem cells. This has the same effect of reducing red blood cell sickling. Testing showed Lyfgenia can also eliminate sickle cell crises. 

Sickled red blood cells are identified by arrows in this microscope image comparison of unedited and edited cells.
Sickled cells are identified by arrows in this comparison of erythroid cells derived from the bone marrow of mice transplanted with unedited stem cells (left) and CRISPR edited stem cells (right).Retrieved from National Library of Medicine/PMC.

The treatments have drawbacks, however. Patients who receive either therapy must undergo a preparatory chemotherapy regimen that can cause painful mouth sores, low blood cell counts and organ damage. The side effects can be severe enough that older people or those whose organs are already heavily damaged from sickle cell may not be able to tolerate it.

Called busulfan, the chemotherapy can also cause infertility, complicating the choice of treatment for people who plan to have children. Vertex has set up a program offering fertility support to patients who are commercially insured, but the company said it cannot do the same for people on Medicaid or Medicare due to federal restrictions.

In theory, wayward gene edits by CRISPR could also cause cancer, a concern expert FDA advisers debated in an Oct. 31 meeting. They ultimately judged Vertex had accumulated enough evidence to prove Casgevy is safe.

“At the moment, these concerns are still theoretical, but, obviously, it’s something which patients are very aware of when we talk with them,” said Markus Mapara, director of blood and marrow transplantation at Columbia University and a trial investigator, in a September interview.

Testing of Lyfgenia, meanwhile, was temporarily halted due to reports of blood cancer in one participant and persistent anemia, a warning sign for malignancy, in another. The FDA added a black box warning, its strongest, to Lyfgenia’s labeling to reflect this risk. Testing by Bluebird implicated the patients’ disease and underlying genetics, rather than the therapy, but there are concerns about the safety of the virus Bluebird uses to modify patient stem cells. 

These hurdles and concerns may slow uptake. Vertex estimates there are about 25,000 people in the U.S. and Europe who are eligible for Casgevy. For those who do proceed with treatment, the process takes many months, involving the step-by-step coordination of testing, cell collection, manufacturing and preconditioning.

“What’s the turnaround going to be like?” said Stephan Grupp, a transplant specialist at Children’s Hospital of Philadelphia and a Casgevy trial investigator. “Execution is everything. It’s one thing to have good clinical data, but better execution beats slightly better data.”

Other companies have run into hurdles commercializing complex cell and gene therapies in the past. Bristol Myers Squibb couldn’t make enough of its CAR-T treatment Abecma early on in that drug’s launch, while Bluebird bio hit reimbursement issues in Europe for its beta thalassemia drug Zynteglo.

With Casgevy, Vertex will have to convince insurers of the treatment’s value despite a price tag expected to be millions of dollars. 

Stuart Arbuckle, the company’s chief operating officer, has said Vertex will explore linking payment to patient options. But that will be complicated in sickle cell as many patients in the U.S. are covered by Medicaid, which is limited by budget and price reporting rules.

“Most healthcare systems are essentially set up to think about and pay for chronic medicines for chronic conditions,” Arbuckle said at a recent event hosted by BioPharma Dive. “Clearly these types of one-time treatments really challenge that paradigm.”

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Tamia Sumpter

Tamia is a driven senior undergraduate Bioengineering student currently enrolled at Clemson University. With a strong foundation in her field, she has honed her skills through hands-on experience in research and development at Eli Lilly & Company. During her time in the ADME department, Tamia contributed significantly by working on siRNAs and their applications in finding In Vitro-In Vivo Correlation (IVIVC). Looking ahead, Tamia has set her sights on a promising career in law. She aspires to specialize in Intellectual Property Law, with a particular focus on serving as in-house counsel for leading medical device or pharmaceutical companies. Her enthusiasm for this role is palpable as she prepares to embark on her legal journey! She is also a proud member of the Omicron Phi chapter of Delta Sigma Theta Sorority, Inc., PEER Mentor for Clemson PEER/WiSE, and currently serves as the President of Clemson Bioengineering Organization (CBO). With her unique blend of scientific knowledge and legal interests, Tamia is poised to make a meaningful impact in the healthcare and life sciences industries.