Virus World

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.

After false starts, drugs that manipulate the code of life are finally changing lives. The idea for gene therapy—a type of DNA-based medicine that inserts a healthy gene into cells to replace a mutated, disease-causing variant—was first published in 1972. After decades of disputed results, treatment failures and some deaths in experimental trials, the first gene therapy drug, for a type of skin cancer, was approved in China in 2003. The rest of the world was not easily convinced of the benefits, however, and it was not until 2017 that the U.S. approved one of these medicines. Since then, the pace of approvals has accelerated quickly. At least nine gene therapies have been approved for certain kinds of cancer, some viral infections and a few inherited disorders. A related drug type interferes with faulty genes by using stretches of DNA or RNA to hinder their workings. After nearly half a century, the concept of genetic medicine has become a reality.

GENE INSERTION

These treatments use a harmless virus to carry a good gene into cells, where the virus inserts it into the existing genome, canceling the effects of harmful mutations in another gene.

GENDICINE: China’s regulatory agency approved the world’s first commercially available gene therapy in 2003 to treat head and neck squamous cell carcinoma, a form of skin cancer. Gendicine is a virus engineered to carry a gene that has instructions for making a tumor-fighting protein. The virus introduces the gene into tumor cells, causing them to increase the expression of tumor-suppressing genes and immune response factors.The drug is still awaiting FDA approval.

GLYBERA: The first gene therapy to be approved in the European Union treated lipoprotein lipase deficiency (LPLD), a rare inherited disorder that can cause severe pancreatitis. The drug inserted the gene for lipoprotein lipase into muscle cells. But because LPLD occurs in so few patients, the drug was unprofitable. By 2017 its manufacturer declined to renew its marketing authorization; Glybera is no longer on the market.

IMLYGIC: The drug was approved in China, the U.S. and the E.U. to treat melanoma in patients who have recurring skin lesions following initial surgery. Imlygic is a modified genetic therapy inserted directly into tumors with a viral vector, where the gene replicates and produces a protein that stimulates an immune response to kill cancer cells.

KYMRIAH: Developed for patients with B cell lymphoblastic leukemia, a type of cancer that affects white blood cells in children and young adults, Kymriah was approved by the FDA in 2017 and the E.U. in 2018. It works by introducing a new gene into a patient’s own T cells that enables them to find and kill cancer cells.

LUXTURNA: The drug was approved by the FDA in 2017 and in the E.U. in 2018 to treat patients with a rare form of inherited blindness called biallelic RPE65 mutation-associated retinal dystrophy. The disease affects between 1,000 and 2,000 patients in the U.S. who have a mutation in both copies of a particular gene, RPE65. Luxturna delivers a normal copy of RPE65 to patients’ retinal cells, allowing them to make a protein necessary for converting light to electrical signals and restoring their vision.

STRIMVELIS: About 15 patients are diagnosed in Europe every year with severe immunodeficiency from a rare inherited condition called adenosine deaminase deficiency (ADA-SCID). These patients’ bodies cannot make the ADA enzyme, which is vital for healthy white blood cells. Strimvelis, approved in the E.U. in 2016, works by introducing the gene responsible for producing ADA into stem cells taken from the patient’s own marrow. The cells are then reintroduced into the patient’s bloodstream, where they are transported to the bone marrow and begin producing normal white blood cells that can produce ADA. 

YESCARTA: Developed to treat a cancer called large B cell lymphoma, Yescarta was approved by the FDA in 2017 and in the E.U. in 2018. It is in clinical trials in China. Large B cell lymphoma affects white blood cells called lymphocytes. The treatment, part of an approach known as CAR-T cell therapy, uses a virus to insert a gene that codes for proteins called chimeric antigen receptors (CARs) into a patient’s T cells. When these cells are reintroduced into the patient’s body, the CARs allow them to attach to and kill cancer cells in the bloodstream.

ZOLGENSMA: In May 2019 the FDA approved Zolgensma for children younger than two years with spinal muscular atrophy, a neuromuscular disorder that affects about one in 10,000 people worldwide. It is one of the leading genetic causes of infant mortality. Zolgensma delivers a healthy copy of the human SMN gene to a patient’s motor neurons in a single treatment.

ZYNTEGLO: Granted approval in the E.U. in May 2019, Zynteglo treats a blood disorder called beta thalassemia that reduces a patient’s ability to produce hemoglobin, the protein in red blood cells that contains iron, leading to life-threatening anemia. The therapy has been approved for individuals 12 years and older who require regular blood transfusions. It employs a virus to introduce healthy copies of the gene for making hemoglobin into stem cells taken from the patient.The cells are then reintroduced into the bloodstream and transported to the bone marrow, where they begin producing healthy red blood cells that can manufacture hemoglobin.....

Published in Nature (4 December 2019):

https://doi.org/10.1038/d41586-019-03716-9