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The FDA has approved the world’s first medicine based on CRISPR gene-editing technology, a groundbreaking treatment for sickle cell disease that delivers a potential cure for people born with the chronic and life-shortening blood disorder. The new medicine, called Casgevy, is made by Vertex Pharmaceuticals and CRISPR Therapeutics. Its authorization is a scientific triumph for the technology that can efficiently and precisely repair DNA mutations — ushering in a new era of genetic medicines for inherited diseases. In a clinical trial, Casgevy was shown to eliminate recurrent episodes of debilitating pain caused by sickle cell, which afflicts approximately 100,000 people in the U.S., a vast majority of whom are Black.

The therapy, whose scientific name is exa-cel, is described as a potential cure because the genetic fix enabled by CRISPR is designed to last a lifetime, although confirmation will require years of follow-up. The FDA decision comes three weeks after regulators in the U.K. were the first to clear the drug. Approval in the European Union is expected next year. The FDA is also expected to rule on exa-cel as a treatment for beta thalassemia, another inherited blood disorder, by March 30. The FDA on Friday also approved another sickle cell treatment, a gene therapy from Bluebird Bio called Lyfgenia. Patients will now have the option of two cutting-edge therapies that provide potentially curative benefits....

FDA Approvl letters (Dec.08, 2023):

https://www.fda.gov/media/174618/download 

https://www.fda.gov/media/174617/download 

Bluebird bio’s blood disorder gene therapy has flown the nest early in the U.S. | Ahead of a much awaited FDA decision deadline Friday, the agency endorsed bluebird bio's gene therapy Zynteglo. It'll carry a $2.8 million price tag and is the first gene therapy for this rare disease. Bluebird bio’s blood disorder gene therapy has flown the nest early in the U.S. Wednesday, the FDA approved the company’s one-time beta thalassemia treatment Zynteglo, also known as betibeglogene autotemcel (beti-cel), two days ahead of the regulator’s approval action date of Aug. 19.  The green light is “monumental” for both patients and the company itself, Tom Klima, Bluebird’s chief commercial officer, said in an interview. Bluebird has endured its share of “bumps and bruises over the last year-and-a-half or so,” but things have been looking up since a positive FDA advisory committee meeting earlier this summer, he added. While bluebird’s approval prospects looked hazy at the start of the year, the clouds parted in June after an FDA expert panel unanimously endorsed the gene therapy. At the meeting, one member claimed the med could be “life-changing” for patients currently fettered by blood transfusions. The approval clears the drug for kids and adults with beta thalassemia who require regular red blood cell transfusions, the FDA said in a release. Beta thalassemia, a type of inherited blood disorder, causes a reduction of normal hemoglobin and red blood cells in the blood. That in turn leads to insufficient oxygen delivery in the body.

The disorder can cause dizziness, weakness, fatigue and bone abnormalities, plus more serious complications, the FDA pointed out. Transfusion-dependent beta thalassemia is the more severe form of the condition and typically forces patients to undergo lifelong red blood cell transfusions. Transfusions can lead to health complications of their own, including problems in the heart, liver and other organs from an excess build-up of iron in the body.  Regarding launch plans, bluebird aims to bring its first wave of qualified treatment centers online by September, Klima said. Meanwhile, bluebird plans to start collecting patients' cells by 2022’s fourth quarter, with the aim to kick off treatment of its first patients in early 2023, he added. As a one-time bespoke treatment, each Zynteglo dose is created by genetically modifying a patient’s own bone marrow stem cells. Specifically, the patient’s cells are modified to produce functional beta-globin, which is a component of hemoglobin. Across two clinical studies looking at adults and kids with transfusion-dependent beta thalassemia, 89% of the 41 patients on Zynteglo achieved transfusion independence, the FDA said.  Bluebird’s med won’t come cheap. Zynteglo will roll out at a price of $2.8 million per patient, Klima told Fierce Pharma, adding that the company feels that price tag “reflects the value of a one-time treatment in the U.S.” The list price doesn’t include the cost of hospitalization required for patients receiving the therapy, Stat News noted.

While bluebird celebrates the approval, insurers are no doubt taking notice. In launching the drug stateside, bluebird will have to do what it couldn't in Europe: Convince payers of Zynteglo's value.

Bluebird is finalizing contracts with commercial payers now, Klima said. The company's access strategy revolves around a "one-time upfront payment," with the option of a "rebate" for patients who don't achieve transfusion independence, which could help patients recoup up to 80% of the one-time treatment cost, the CCO explained. The upfront payment and rebate scheme is a "clear positive for [bluebird] and the broader field of gene therapy," RBC Capital Markets analysts wrote to clients Wednesday. However, the RBC team said there's still uncertainty surrounding bluebird's stock, given the "relatively small commercial opportunity" for Zynteglo, especially considering the turbulent experience the drug's had in Europe. Zynteglo won European approval back in 2019, where it was priced at almost 1.58 million euros (about $1.8 million at the time). However, the company later pulled the drug off the market because it couldn’t reach reimbursement deals with officials in various markets. In April, bluebird clipped 30% of its staff. With its U.S. approval, meanwhile, Zynteglo is now looking at a potential market of roughly 1,000 to 1,500 transfusion-dependent beta thalassemia patients.

Editor's note: This story has been updated with comments from Tom Klima, bluebird bio's chief commercial officer, as well as commentary from RBC Capital Markets analysts.

The therapy, called Skysona and cleared to treat cerebral adrenoleukodystrophy, is the product of more than a decade of work by Bluebird. It will cost $3 million.  The Food and Drug Administration on Friday granted accelerated approval to a personalized gene therapy for an ultra-rare childhood brain disease, called cerebral adrenoleukodystrophy or CALD. Built from a patient’s own stem cells, the therapy is the first medicine to be made available in the U.S. for CALD, which affects young boys and typically results in severe disability or death. It was developed by the biotechnology company Bluebird bio and will be sold as Skysona. Its approval is Bluebird’s second in four weeks, following an Aug. 17 FDA decision on another gene therapy from the company for the blood disorder beta thalassemia.  The back-to-back clearances come despite FDA concerns over the risk of the treatments causing cancer. Experts convened by the agency in June to vet the two therapies voted unanimously in favor of both, agreeing their benefits outweigh their potential side effects. Both CALD and severe beta thalassemia are uncommon, although CALD is far rarer. It’s one of a small cluster of diseases that were featured in the 1992 film Lorenzo’s Oil about a boy with adrenoleukodystrophy and his parents’ hunt for a cure. The buildup of harmful fatty acids in the brain and nervous system causes CALD, which leads to learning and behavioral problems before progressing to more severe neurological damage. In the U.S., an estimated 50 boys are born each year who will go on to develop CALD. Bluebird expects to treat about 10 annually. Meant to be a one-time infusion, Skysona will cost $3 million. The price tag makes the therapy one of the most expensive ever launched on a single-use basis, exceeding the $2.8 million cost of Bluebird’s other gene therapy. 

‘The most expeditious way’

Skysona is for children aged four to 17 years old who are in the early stages of the disease. The accelerated approval granted by the FDA means Bluebird must confirm its therapy’s benefit through further testing. The company expects to use data from long-term follow-up study, as well as from commercially treated patients, it said in a Friday statement. Bluebird was seeking full approval of Skysona, but agreed to a conditional clearance after talking with the FDA about some of the agency’s concerns. “Through the course of the review after the [June meeting], we discussed this would probably be the most expeditious way to get the therapy to patients,” said Bluebird CEO Andrew Obenshain in an interview Saturday. The FDA’s approval does not limit Skysona’s use based on the availability of a “matched” sibling donor for a stem cell transplant, which Bluebird previously proposed for the therapy’s labeling. These transplants can in some cases slow or stop the disease’s progression. The vast majority of boys with CALD don’t have such a sibling, and transplants from unmatched or unrelated donors carry significant safety risks. Skysona offers an alternative that promises years of benefit by replacing the defective gene responsible for CALD. In the main trial testing Skysona, 29 of 32 treated patients reached two years without dying or developing a major functional disability, meeting the study’s main goal. Further study showed that benefit was maintained through five years in most patients who had been followed for that long. (Another trial involving 35 patients is ongoing.) However, the FDA raised a number of issues about how that data was analyzed as well as the magnitude of benefit in patients for whom transplants are available. Additionally, three patients given Skysona developed a type of bone marrow cancer many months later. In two, the cancer was directly linked to treatment, likely caused by the modified virus used to create Skysona. FDA staff have indicated they think it’s possible more cases will develop over time. At the June meeting, advisers were tasked with weighing that risk and ultimately concluded it could be managed with sufficiently strong monitoring. The cancer, called myelodysplastic syndrome, can evolve into leukemia, but is treatable. Two of the three patients were in remission as of June.

“In general, families look at things as treatable versus untreatable,” said Amy Waldman, medical director of the Leukodystrophy Center at Children’s Hospital of Philadelphia, in an interview ahead of Friday’s approval. “I have had a family say to me, “You know you’re in trouble when you wish your child had a brain tumor.” The FDA’s labeling for Skysona carries what’s known as a “black-box” warning, the agency’s strictest, for the risk of blood cancers, including myelodysplastic syndrome. Doctors are advised to monitor patients closely via blood testing at least every six months and through genetic sequencing of cells annually for 15 years after treatment. At the June meeting, advisers agreed the tradeoff between Skysona’s benefits and its potential risks is clearest in patients who don’t have a matched, related donor for stem cell transplant. For patients with donors who match but are unrelated, the choice between Skysona and transplant is more complex. “Just because someone is matched doesn’t mean they are a perfect donor,” Christine Duncan, a physician at Boston Children’s Hospital who helped run one of the Skysona trials, said in an interview ahead of the FDA’s decision. “For children who have a matched unrelated donor, it’s a different risk-benefit analysis. But it’s one I’m hoping we’ll be able to have with patients.” Parents and family members of CALD patients who spoke in June described the uncertainty of waiting for a transplant match, as well as their fears of transplant-related side effects, which can include a serious complication known as graft-versus-host disease.  “This is a disease where time equals brain,” Bradford Zakes, the father of a boy who died of CALD, said then. “Having access to an alternative therapy that can be deployed quickly, without delay, would simply be a game changer in the lives of young boys born with this devastating disease.” Duncan, as well as others at the June meeting, also noted that children who are Black or Hispanic are less likely to find a donor match through national registries.

Commercial plans

Bluebird expects Skysona to be available by the end of the year, and is planning to work with a “limited number” of centers that are experienced in treating CALD and in stem cell transplantation, including Boston Children’s Hospital and CHOP. The company is not putting in place “outcomes-based” coverage agreements with insurers for Skysona as it did with its other gene therapy, for which it’s offering to reimburse part of the cost if patients don’t continue to benefit. “This is such an ultra-rare disease that these insurers are likely to see only one patient — most likely to see zero — the entire time,” said Obenshain. “Neither Bluebird nor the payers want to go through the complexity of a contract for a patient population so small.” Skysona’s clearance in the U.S. comes a little more than one year after it was approved in Europe. But Bluebird had trouble securing reimbursement and later withdrew the therapy from the market amid a broader wind down of its business there. Few patients were ever treated. While the two gene therapy approvals are a boost, Bluebird remains in financial difficulty. The company is running out of money and has warned it may face insolvency in the future. Its new products could bring in needed revenue, as could the sale of special regulatory vouchers awarded to Bluebird by the FDA. The vouchers can be used to speed drug reviews and have commanded prices of around $100 million each.

Editor’s note: This story has been updated with comments from Bluebird bio’s CEO.

Bluebird bio's treatment for a rare blood disorder received backing from advisers to the U.S. Food and Drug Administration on Friday, in a vote of confidence in gene therapies and bolstering the company beset by regulatory setbacks.  The decision comes less than 24 hours after the same committee in a surprise move endorsed approval of bluebird's other gene therapy, eli-cel, for a rare neurological disease despite concerns that the treatment may cause cancer.  The panel of 13 outside experts on Friday voted unanimously for beti-cel as a one-time gene therapy to treat Beta-thalassemia patients dependent on blood transfusions. The FDA is expected to decide on beti-cel's fate by Aug. 19 and eli-cel's by Sept. 16. The agency is not required to follow its advisers' recommendation, although it usually does. If the FDA approves the therapies, bluebird expects to launch both the products by this year. 

"Our expectation is that the product should be treating first patients by early fourth quarter," Chief Executive Officer Andrew Obenshain told Reuters. Panel member Jeannette Yen Lee said the therapy's efficacy data was "outstanding", adding that "the opportunity to be transplant-independent is really life changing for the patient." "We've personally watched friends and family participate in gene therapy trials and be cured of this painful disease. They no longer need blood transfusions," said Sarah Baqueri-Connolly, parent of a Beta-thalassemia patient who passed away in 2015.  "The therapy gives patients and their families hope, a hope that we didn't have." The back-to-back positive decisions are a big boost for bluebird, which had in March flagged "going concern" doubts following regulatory setbacks. “Hopefully, with approval will come some priority review vouchers for these products that will provide some non dilutive funding. And we'll also look at other ways of raising funding," CEO Obenshain said.

Company's Press Release (June 10, 2022):

https://investor.bluebirdbio.com/news-releases/news-release-details/fda-advisory-committee-unanimously-supports-beti-cel-gene