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Our Take: Vertex, CRISPR Therapeutics gain first-ever approval of CRISPR-based gene-edited therapy

Nov 20, 2023

Editor’s note: Due to the Thanksgiving holiday, Our Take will return on December 4.

Marking “a historic day in science and medicine,” the U.K.’s Medicines and Healthcare products Regulatory Agency (MHRA) granted conditional marketing authorization on Wednesday to a treatment referred to as exa-cel, the first CRISPR-based gene-edited therapy ever to be approved by a regulatory agency. 

Boston-based Vertex Pharmaceuticals and CRISPR Therapeutics, headquartered in Zug, Switzerland, collaborated on developing the therapy, which will be marketed as Casgevy in Britain and is authorized for the treatment of two rare, inherited blood disorders — sickle cell disease and transfusion-dependent beta thalassemia — in patients ages 12 and older. 

Sickle cell disease is a chronic, debilitating disorder that causes excruciating bouts of pain. It can also cause strokes and organ damage. The need for regular blood transfusions often begins in early childhood, and the median life expectancy of individuals with sickle cell disease in the U.S. is 42 to 47 years, according to the American Society of Hematology.

Beta thalassemia major, the most severe form of the disease, can delay growth; cause enlargement of the spleen, liver, and heart; and cause bones to become brittle and deformed. Individuals with this disorder can experience heart failure in their teens or early 20s, and most die before the age of 30. 

The FDA is reviewing Vertex’s IND applications for exa-cel, which is short for exagamglogene autotemcel, in both disorders. A decision on the sickle cell disease indication is expected by Dec. 8, and the deadline for the beta thalassemia decision is March 30. 

Exa-cel was developed using technology for which Jennifer Doudna and Emmanuelle Charpentier won a Nobel Prize in 2020: the CRISPR/Cas 9 genetic scissors. The technology allows researchers to change DNA quickly and with extremely high precision. 

“Today is a historic day in science and medicine: This authorization of Casgevy in Great Britain is the first regulatory authorization of a CRISPR-based therapy in the world,” said Dr. Reshma Kewalramani, CEO of Vertex, in the companies’ announcement of the MHRA authorization. 

“I hope this represents the first of many applications of this Nobel Prize-winning technology to benefit eligible patients with serious disease,” said Samarth Kulkarni, CEO of CRISPR Therapeutics. 

Patients who undergo treatment with exa-cel have stem cells removed from their bone marrow so that a gene in the cells can be edited in a laboratory. The patients receive a conditioning treatment to prepare their bone marrow, and then billions of the modified cells are infused back into the patients. The treated cells produce fetal hemoglobin, which restores normal red blood cell function. Patients may spend a month or longer in the hospital during treatment.

The studies used to support the regulatory applications are ongoing, to enroll additional patients and to assess the longer-term effects of treatment. Thus far, the efficacy results have been impressive, and no significant safety concerns have been identified. 

In the clinical trial evaluating exa-cel in sickle cell disease, 30 patients had been enrolled long enough to be included in the primary efficacy analysis. Of that group, 29 were free from severe pain crises for at least 12 months after completing treatment. 

In the clinical trial evaluating exa-cel in beta thalassemia, 42 patients were eligible for inclusion in the primary efficacy analysis. Of those patients, 39 did not require a red blood cell transfusion for at least 12 months after completing treatment. In the other three patients, the need for transfusions was reduced by more than 70%.

Although exa-cel is not considered a cure, the hope is that a single treatment will provide freedom from symptoms for life. Vertex and CRISPR Therapeutics plan to follow the patients in the clinical trials for 15 years to find out how long the therapy works. 

The FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee convened a  panel of 14 experts on Oct. 31 to discuss exa-cel’s risk-benefit profile. Specifically, according to the briefing document, the panel was tasked with evaluating whether Vertex’s analysis of off-target mutations following the gene-editing process provided an adequate safety assessment. 

Off-target mutations are a major safety concern with CRISPR-based gene editing because they can cause adverse outcomes, such as cancer. 

Genetic Engineering & Biotechnology News published an article that included various remarks by various members of the panel, noting that a comment by Scot Wolfe, an expert in genome editing at the University of Massachusetts Chan Medical School, summed up the committee’s overall point of view:

“We want to be careful not to let the perfect be the enemy of the good.”  

Our Take: Vertex has not said what it will charge for exa-cel, but the treatment could cost as much as $2 million per patient, according to NPR. 

Like other expensive gene therapies, exa-cel’s price could place the therapy out of reach for most patients, but we expect that Vertex offer the therapy under some sort of risk-sharing or value-based agreement in the UK and for commercial payers in the US, if approved by the FDA.

Melissa Creary, an assistant professor at the University of Michigan’s School of Public Health, has more than 20 years of experience working with the sickle cell community. She told NPR that she’s concerned exa-cel “will be a very highly lauded technology that people will not be able to use.” She said she believes those who need the therapy the most won’t be able to afford it. 

But Dr. Lewis Hsu, a professor at the University of Illinois Chicago and chief medical director of the Sickle Cell Disease Association of America, noted that even with such a high price tag exa-cel could still be cost-effective in light of the current cost of caring for patients with sickle cell disease over their lifetime. 

“There is a return on investment to the health care system,” Dr. Hsu told NPR.

The New York Times reported that lifelong care for patients with sickle cell disease is “enormously expensive, costing the health care system an estimated $3 billion a year.”

What else you need to know
Amazon’s One Medical will be a primary care provider for employers in the Health Transformation Alliance, an organization comprising nearly 60 large companies such as American Express, JPMorgan Chase, Marriott, and Walgreens. HTA’s member companies combine their resources to drive better health outcomes for employees and their dependents while also addressing the cost of care. HTA members’ self-insured health plans cover more than 4 million employees and their dependents in the U.S., according to the organization, and HTA member companies spend more than $27 billion annually on health care. Robert Andrews, CEO of Health Transformation Alliance, said in an interview with Fierce Healthcare that One Medical will be the largest primary care provider in HTA’s network at this point and will be paid on a capitated basis. “We want to set a precedent where value-based care is the rule, and not the exception,” he said. 

In separate news, One Medical members in the greater Seattle area will have access to more than 2,000 specialists in Virginia Mason Franciscan Health’s network as a result of a new collaboration between the two organizations. (Virginia Mason Franciscan Health is part of CommonSpirit Health.) One Medical is also partnering with Edison, N.J.-based Hackensack Meridian Health to expand access to primary care and connect patients to specialty care provided through Hackensack Meridian Health’s network. The two organizations said in a press release they plan to open multiple locations in New Jersey in the next several years.

Express Scripts will offer a new cost-based pharmacy network option in early 2024 called the Express Scripts ClearNetwork, which will be similar to the pricing model Mark Cuban Cost Plus Drugs uses. Express Scripts, the pharmacy benefit manager that is part of Cigna’s Evernorth Health Services subsidiary, said in a news release that employers, health plans, and other clients will pay “a straightforward estimated acquisition cost for individual medications, in addition to a small markup for pharmacy dispensing and service costs.” The estimated acquisition cost will be based on the lowest of several third-party industry benchmarks, according to Express Scripts. The markup will include a flat fee paid to dispensing pharmacies and another fee, not to exceed 15% of the drug’s cost, which will be shared with participating pharmacies “to ensure a reasonable profit” and cover Express Scripts’ claims management and network services.  

Two plaintiffs filed a proposed class-action lawsuit against UnitedHealthcare, UnitedHealth Group, and naviHealth in which they allege the defendants used an artificial intelligence-powered algorithm that wrongfully denied post-acute care, resulting in the deaths of two Medicare Advantage plan members. The dispute centers on UnitedHealthcare’s alleged use of an AI model developed by naviHealth, called nH Predict, to establish post-acute care coverage criteria for MA plan members. The plaintiffs said in the court document the defendants continue to use the “flawed” AI model despite knowing it “has a 90% error rate,” which they based on the percentage of denials allegedly overturned on appeal. The plaintiffs said the defendants know that only a small minority of plan members will appeal denied claims and will instead pay out-of-pocket or forgo the rest of their prescribed care. In a statement sent to news outlets, a spokesperson for UnitedHealth denied that the naviHealth tool is used to make coverage determinations and said the lawsuit “has no merit.” UnitedHealth Group’s Optum acquired naviHealth in 2020.

Novo Nordisk will invest more than $6 billion to expand its existing manufacturing facilities in Kalundborg, Denmark. The vast majority of the investment will be used to increase the drugmaker’s capacity to manufacture active pharmaceutical ingredients, according to a press release. The new API facility will be designed to manufacture multiple products, including GLP-1 products such as Ozempic and Wegovy. Novo Nordisk said the construction projects would be completed gradually from late 2025 through 2029, and the company expects to add 800 new jobs in the facilities when they are ready to begin production. 

Dr. Janet Woodcock will retire from the FDA early next year, bringing a nearly 40-year career with the agency to a close. Dr. Woodcock, who currently serves as principal deputy commissioner, led the FDA as acting commissioner from January 2021 until February 2022, while the agency was responsible for reviewing COVID-19 vaccines and treatments. Before that, she led the FDA’s pharmaceutical division in two separate stints, each at least a decade long, Reuters reported. 

Reforming Pharmacy Benefit Managers — A Review of Bipartisan Legislation. NEJM, 11.3.23 (registration required)

What else we’re reading 
The Biggest Ideas in the Universe: Space, Time, and Motion, by Sean Carroll. Einstein’s Twin Paradox, Schrodinger’s Cat, black holes, and parallel universes: these concepts have fascinated me since I was a kid, notwithstanding the fact that I barely survived high school physics. Over the years I’ve read dozens of popular books about the nature of the universe by Carl Sagan, Brian Greene, Michio Kaku, and even Bill Bryson.

In my mid-30s I developed a similar fascination for popular neuroscience, if there is such a term, having read a diverse set of authors including Michael Gazzaniga, Steven Johnson, Gerald Edelman, Helen Fisher, and of course, Oliver Sacks. (In fact, I nearly pursued my PhD in economics at Claremont Graduate University, due to my interest in neuroeconomics. Instead, I ended up at Dartmouth, and here I am writing about health care.)

What makes The Biggest Ideas in the Universe different from other pop physics books is that Carroll is trying to bridge the gap between studying actual theoretical physics concepts, which would require a facility with advanced mathematics, and the pop science books that attempt to describe these concepts without any math at all. He points out that there is a difference between understanding a mathematical equation in physics, which anyone who’s taken high school algebra can do, and solving math problems in quantum mechanics.

I’m less than 100 pages in and it’s a slog. Carroll’s writing is excellent; it’s the math that’s getting me down. I dispute his claim that all you need is high-school algebra to understand the equations. It wasn’t that long ago that I was studying PhD-level statistics, and at times, I’m struggling. But I intend to push on. Because I always felt that reading about physics without understanding how, for instance, the Twin Paradox works mathematically, is sort of cheating. Put differently, because so many of these ideas defy common sense, knowing the proof behind the concept might make the conclusions easier to understand. 

We’ll see. The Thanksgiving holiday is coming and I’ll have plenty of time to finish The Biggest Ideas in the Universe. It’s better than arguing with my uncles about the political topics of the day — inflation, education, foreign policy — which if we were smart, we’d admit we know nothing about and watch the football game instead.
 – JM

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