24 November 2021 - - The US Food and Drug Administration has accepted the Biologics License Application for betibeglogene autotemcel (beti-cel) for priority review, US-based gene therapy company bluebird bio, Inc. (NASDAQ: BLUE) said.

Beti-cel is a gene therapy for adult, adolescent and pediatric patients with β-thalassemia across all genotypes who require regular red blood cell transfusions.

If approved, beti-cel will be the first one-time treatment that addresses the underlying genetic cause of disease for patients living with β-thalassemia in the US--offering an alternative to regular RBC transfusions and iron chelation therapy.

The agency has set a Prescription Drug User Fee Act (PDUFA) goal date of May 20, 2022.

The BLA for beti-cel is based on data from bluebird bio's Phase 3 studies HGB-207 (Northstar-2) and HGB-212 (Northstar-3), the Phase 1/2 HGB-204 (Northstar) and HGB-205 studies, and the long-term follow-up study LTF-303.

Together, these studies represent more than 220 patient-years of experience with beti-cel.

As of March 9, 2021, the results include a total of 63 pediatric, adolescent and adult patients, including long-term efficacy and safety results in two patients with more than seven years follow-up.

Additional data through August 2021 will be presented at the 63rd American Society of Hematology annual meeting and Exposition, taking place December 11-14, 2021.

The FDA previously granted beti-cel Orphan Drug status and Breakthrough Therapy designation.

β-thalassemia is a severe genetic disease for those requiring regular red blood cell transfusions, caused by mutations in the β-globin gene, which may cause significantly reduced adult hemoglobin.

This can result in severe anemia and lifelong dependence on RBC transfusions.

Patients who require regular RBC transfusions to maintain adequate Hb levels typically undergo the 4-7-hour process every 3-4 weeks.

While transfusions temporarily relieve symptoms associated with severe anemia, including fatigue, weakness, and shortness of breath, they do not address the underlying genetic cause of β-thalassemia and can lead to unavoidable iron overload and serious complications, including progressive multi-organ damage and organ failure.

Iron overload resulting from β-thalassemia or ongoing RBC transfusions requires chronic treatment with chelation therapy; even with chelation therapy, some patients remain significantly iron overloaded, and only 63% of patients are adherent, due in part to tolerability issues.

Despite advances in treatment and improved transfusion techniques, people with β-thalassemia who require regular transfusions have an increased risk for morbidity and mortality.

betibeglogene autotemcel (beti-cel) (pronounced BEH tee cell) is a one-time gene therapy custom-designed to treat the underlying cause of β-thalassemia in patients who require regular red blood cell transfusions.

Beti-cel adds functional copies of a modified form of the β-globin gene (βA-T87Q-globin gene) into a patient's own hematopoietic (blood) stem cells in order to correct the deficiency of adult hemoglobin that is the hallmark of β-thalassemia.

Once a patient has the βA-T87Q-globin gene, they have the potential to produce beti-cel-derived adult hemoglobin (HbAT87Q) at levels that may eliminate the need for transfusions.

In Phase 3 beti-cel studies, 89% (32/36) of evaluable patients across all ages and genotypes, including pediatric patients as young as four years of age and those with the most severe (β0/β0) genotypes, achieved transfusion independence, which is defined as no longer needing RBC transfusions for at least 12 months while maintaining a weighted average Hb of at least 9 g/dL.

beti-cel is manufactured using the BB305 lentiviral vector, a third-generation, self-inactivating LVV that has been studied for more than a decade across multiple therapeutic areas.

Adverse reactions considered related to beti-cel were uncommon and consisted primarily of non-serious infusion-related reactions that occurred on the day of infusion (e.g. abdominal pain, hot flush, dyspnea, tachycardia and non-cardiac chest pain) and cytopenias (e.g. thrombocytopenia, leukopenia and neutropenia).

Pain in extremity shortly after treatment was also documented, the company said.

One of these adverse events was a serious adverse event of thrombocytopenia considered possibly related to beti-cel and has resolved.

The majority of AEs and SAEs in the beti-cel clinical development program were unrelated to beti-cel and consistent with the known side effects of HSC collection and busulfan conditioning regimen (including several SAEs of veno-occlusive disease that resolved with treatment).

The Phase 3 Northstar-2 (HGB-207) and Northstar-3 (HGB-212) studies evaluating beti-cel are ongoing; enrollment is complete, and all patients have been treated.

bluebird bio is also conducting a long-term follow-up study, LTF-303, to monitor safety and efficacy for people who have participated in bluebird bio-sponsored beti-cel clinical studies through 15 years post-treatment.