‘A watershed moment for the field of gene therapy’: bluebird bio’s gene therapy Zynteglo receives FDA approval

By Rachel Arthur

- Last updated on GMT


Related tags bluebird bio Gene therapy Zynteglo FDA approval Fda Us

The U.S. Food and Drug Administration (FDA) has approved bluebird bio’s Zynteglo (betibeglogene autotemcel), also known as beti-cel: a one-time gene therapy custom-designed to treat the underlying genetic cause of beta thalassemia in adult and pediatric patients who require regular red blood cell (RBC) transfusions.

After nearly 10 years of development, the therapy is the first of its kind and will offer patients an alternative to regular red blood cell transfusions and iron chelation. It also becomes the most expensive drug in the world, with a $2.8m price tag.

“The FDA approval of Zynteglo offers people with beta-thalassemia the possibility of freedom from burdensome regular red blood cell transfusions and iron chelation, and unlocks new possibilities in their daily lives,”​ said Andrew Obenshain, chief executive officer, bluebird bio. “After more than a decade of research and clinical development, and through the perseverance of clinicians, patients, and their families, the approval of Zynteglo marks a watershed moment for the field of gene therapy.

“As the first ex-vivo lentiviral vector gene therapy approved in the US for the treatment of people with beta-thalassemia, we are ushering in a new era in which gene therapy has the potential to transform existing treatment paradigms for diseases that currently carry a lifelong burden of care.”

While Zynteglo was given the green light in Europe in 2019, the company has since taken the drug off the market as part of its withdrawal from the region after failing to reach agreements with governments over coverage, turning its attention to the US instead.

The approval of Zynteglo in the US provides a critical boost for bluebird bio: which warned earlier this year that the future of the company could be at stake​ over its financial position: with the approval of key therapies such as Zynteglo becoming all the more important (it is now waiting for a decision on elivaldogene autotemcel (eli-cel) for cerebral adrenoleukodystrophy, which was unanimously endorsed by an FDA committee in June at the same time as Zynteglo with a PDUFA goal date set for September 16).

Treatment options

Zynteglo works by adding functional copies of a modified form of the beta-globin gene (βA-T87Q-​globin gene) into a patient’s own hematopoietic (blood) stem cells (HSCs) to allow them to make normal to near normal levels of total hemoglobin without regular RBC transfusions.

Beta-thalassemia is a rare, genetic blood disease caused by mutations in the beta-globin gene and characterized by significantly reduced or absent adult hemoglobin production.

Patients with the most severe form experience severe anemia and lifelong dependence on regular red blood cell transfusions, a lengthy process undertaken every 2-5 weeks.

The median age of death of patients with transfusion-dependent beta‑thalassemia in the US who died during the last decade was 37 years. bluebird bio estimates that there are approximately 1,300-1,500 individuals with transfusion-dependent beta-thalassemia in the US.

The functional beta-globin gene is added into a patient’s cells outside of the body (ex-vivo​), and then infused into the patient.

Though Zynteglo is designed to be administered to the patient once, the treatment process is comprised of several steps that may take place over the course of several months.

Zynteglo will be available only at Qualified Treatment Centers (QTCs), selected based on their experience in stem cell transplantation, cell and gene therapy and beta-thalessemia - due to the complex nature of the therapy.

Specialized training will also be delivered to staff.

‘Setting the standard’ for one-time gene therapies

The high upfront cost of gene therapies has created barriers to their adoption and coverage by payers. bluebird bio has set the cost of the therapy in the US at $2.8m, ‘in recognition of its robust and sustained clinical benefit demonstrated in clinical studies and its potential to alleviate a lifetime of health care costs associated with regular RBC transfusions and iron management’.

But the company makes the comparison with the current standard of care: where patients require RBC transfusions every two to five weeks and may lose decades of life relative to the general population. The lifetime cost of medical care for a patient can reach up to $6.4m, it says: and the average total health care cost per patient comes in at 23 times higher than the general population.

In an effort to address payer concerns, bluebird bio has set out details of its US commercial infrastructure to support rapid access to the drug, saying it can ‘set the standard’ for what a one-time therapy can deliver.

This includes one upfront payment that can be paired with an outcomes-based agreement. As part of this agreement, bluebird will reimburse contracted commercial and government payers up to 80% of the cost of the therapy if a patient fails to achieve and maintain transfusion independence up to two years following infusion (all patients in Phase 3 studies for the therapy who achieved transfusion independence remained transfusion free).

bluebird bio says this outcome measure is recognized by payers and providers as ‘clinically meaningful’ and straightforward to track through claims data.

New England health care company Point32Health says bluebird bio’s commitment to refund up to 80% of treatment cost ‘meaningfully reduces’ the risk associated with upfront payment, and will enable implementation of an outcomes-based agreement ‘at a scale and magnitude not previously seen in the US’.

Bluebird bio estimates around 70-75% of patients with transfusion-dependent beta-thalassemia are covered by commercial insurance, and the company is currently in late-stage negotiations with commercial payers including national Pharmacy Benefit Managers (PBMs) with the potential to represent dozens of plans. It is also engaging with state Medicaid agencies representing approximately 80% of publicly insured thalassemia patients.

Novartis’ Zolgensma gene therapy – approved in 2019 and with a similar $2.1m price tag – now operates under similar outcome-based measures with payers able to recoup a significant portion​ of the price if health outcomes are not met.

Clinical data supporting approval of Zynteglo

bluebird bio has the 'longest and most robust clinical program' in transfusion-dependent beta‑thalassemia (TDT) in the field of gene therapy, according to the company.

The approval of Zynteglo is based on data from bluebird bio’s Phase 3 studies HGB-207 (Northstar-2) and HGB-212 (Northstar-3), and the long-term follow-up study LTF-303.

The single-arm, open-label, 24-month Phase 3 studies of ZYNTEGLO included 41 patients aged 4 to 34 years with both non-β0/β0 and β0/β0 genotypes, with longest follow up out to 4 years. Eighty-nine percent (32/36) of evaluable patients across ages and genotypes achieved transfusion independence (TI), which is defined as no longer needing red blood cell transfusions for at least 12 months while maintaining a weighted average total hemoglobin of at least 9 g/dL. Results in these patients were durable as of last follow-up.

The most common non-laboratory adverse reactions (≥20%) were mucositis, febrile neutropenia, vomiting, pyrexia, alopecia, epistaxis, abdominal pain, musculoskeletal pain, cough, headache, diarrhea, rash, constipation, nausea, decreased appetite, pigmentation disorder, and pruritus. The most common Grade 3 or 4 laboratory abnormalities (>50%) include neutropenia, thrombocytopenia, leukopenia, anemia, and lymphopenia.

Enrollment is complete and all patients have been treated in the Phase 3 Northstar-2 (HGB-207) and Northstar-3 (HGB-212) studies evaluating ZYNTEGLO. Follow-up in HGB-212 is ongoing. bluebird bio is also conducting a long-term follow-up study, LTF-303, to monitor safety and efficacy for patients with TDT who have participated in bluebird bio-sponsored clinical studies of lentiviral vector (LVV) gene therapy through 15 years post-treatment.

Across all studies, all patients who achieved transfusion independence have remained transfusion-free.

Zynteglo was reviewed by the FDA under Priority Review, and the company received a Priority Review voucher upon approval. Zynteglo was previously granted Orphan Drug designation and Breakthrough Therapy designation.

New option for patients

Two experts are among those welcoming the approval of the drug in the US.

“Transfusion-dependent beta-thalassemia is associated with an intense treatment burden and significant health risks related to regular red blood transfusions and iron management,”​ said Alexis A. Thompson, MD, MPH, Chief of the Division of Hematology, Children's Hospital of Philadelphia. “As a clinician and an investigator in the Zynteglo clinical development program, I celebrate the therapeutic potential of this treatment for patients and its implications for the field of gene therapy, all made possible through the incredible courage of patients and families who participated in the clinical trials.”

Meanwhile, Craig Butler, National Executive Director, Cooley’s Anemia Foundation, said: "The Cooley’s Anemia Foundation applauds the FDA’s approval of Zynteglo for people with beta‑thalassemia who require regular red blood cell transfusions. The availability of a one-time gene therapy which offers the possibility of transfusion independence opens up new and exciting opportunities for those who are medically eligible to receive this treatment option.

“While advances in treatment have been of enormous benefit to those with beta-thalassemia, a potentially curative therapy may offer a true life-changing experience.”

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