Bluebird bio receives FDA approval for first gene therapy treatment for beta-thalassemia

Zyntelgo^® (betibeglogene autotemcel), by bluebird bio, has been approved by the Food and Drug Administration (FDA) for treatment of transfusion-dependent beta-thalassemia (TDT) treatment. Zyntelgo is a one-time gene therapy that adds functional copies of a modified form of the beta-globin gene into a patient’s own hematopoietic stem cells.¹ It may increase hemoglobin to normal or near-normal levels and eliminate the need for chronic red blood cell (RBC) transfusions and iron management therapies. The clinical benefits are expected to last for the patient’s lifetime.

Name:                ZYNTEGLO (betibeglogene autotemcel)
Manufacturer: bluebird bio Inc.
Indication:         For treatment of adult and pediatric patients with beta-thalassemia who require regular red blood cell (RBC) transfusions

Condition overview

Beta-thalassemia (BT) is an inherited blood disorder that causes a reduction of normal hemoglobin and red blood cells in the blood, leading to insufficient delivery of oxygen in the body. The reduced levels of red blood cells can lead to a number of health issues including dizziness, weakness, fatigue, bone abnormalities and more serious complications.

In clinical practice, patients are managed and classified by their transfusion needs.

• Non-transfusion-dependent beta-thalassemia requires no transfusions or occasional transfusions due to specific circumstances.
• Transfusion-dependent beta-thalassemia is the most severe form of the disease, characterized by severe anemia, and requires lifelong, regular blood transfusions to maintain Hb levels. There are estimated to be 1,000 to 1,300 people in the U.S. living with TDT.

Current treatment options:^2,3

• Medications: Reblozyl (luspatercept-aamt) – this is an erythroid maturation agent for the treatment of anemia in TDT. It is administered once every three weeks subcutaneously by a health care professional. A randomized, double-blind, placebo-controlled trial found luspatercept-aamt decreases transfusion burden in individuals with TDT compared with placebo (21.4% versus 4.5% receiving placebo achieved at least a 33% reduction in transfusion burden from baseline during weeks 13-24.) Transfusions and iron chelation are still required for most patients taking luspatercept-aamt.
• Blood transfusions and iron chelation therapy: Patients with TDT require lifelong regular red blood cell (RBC) transfusions to relieve anemia and prolong survival. Without regular transfusions, individuals often die in early childhood. With multiple blood transfusions throughout a lifetime, iron from transfused blood accumulates in the body tissues. The resulting iron overload impacts the function of many organs. Nearly 70% of TDT deaths are associated with cardiac complications due to iron overload. Iron chelation therapy is effective in improving survival, decreasing risk of heart failure, and decreasing morbidities from iron overload.
• Allogenic hematopoietic stem cell transplant (Allo-HSCT): Allo-HSCT is an established treatment considered potentially curative in TDT. However, treatment is generally limited to children with a matched donor, typically a sibling, due to suboptimal clinical outcomes for adolescents and adults.
  • The best outcomes are seen in TDT children with a related human leukocyte antigen (HLA)-matched sibling donor (MSD);only 25-30% of those with TDT.² Thalassemia patients less than 14 years old with an MSD have a cure rate of over 90% with a 4% risk of mortality.³ Cure rates decrease in older patients, those with extensive iron toxicity, and those without a matched donor.

New drug overview

Zyntelgo is a one-time gene therapy that adds functional copies of a modified form of the beta-globin gene to a patient’s own hematopoietic stem cells.²

Treatment with Zyntelgo may increase hemoglobin to normal or near-normal levels and eliminate the need for chronic red blood cell (RBC) transfusions and iron management therapies. The clinical benefits are expected to last for the patient’s lifetime.

The patient’s hematopoietic stem cells are removed, and then enriched to create the product. Patients undergo full myeloablation with busulfan to eliminate existing bone marrow containing the globin mutation. The product is supplied frozen as a suspension in cryopreservation solution. Zyntelgo is administered via a single intravenous infusion where it is grafted into the bone marrow where it reconstitutes the hematopoietic system. Zyntelgo pricing will be $2.8 million for the one-time treatment.⁴

Efficacy ^{1-3, 8-10}

The safety and effectiveness of Zynteglo were established in two multicenter clinical studies that included adult and pediatric patients with beta-thalassemia requiring regular transfusions. Effectiveness was established based on achievement of transfusion independence (TI). This is attained when the patient maintains a pre-determined level of hemoglobin without needing any red blood cell transfusions for at least 12 months. Of 41 patients receiving Zynteglo, 89% achieved transfusion independence. TI was maintained through the most recent follow-up (four years for Phase 3 patients, and seven years for the Phase 1/2 patients).

Most patients stopped transfusions within one month of beti-cel infusion.

Safety²

Survival remains 100% with no reports of graft versus host disease, hematologic malignancy, or vector-related complications. The most common drug product-related adverse events included: thrombocytopenia (4.8%) and abdominal pain (7.9%).

ICER Evidence Report³

The Institute for Clinical and Economic Review (ICER) published a report in June 2022 that concluded that Zynteglo provides net health benefits to patients with TDT. Given the high annual costs of standard care, Zynteglo meets commonly accepted value thresholds if paid through an outcomes-based contract for patients with  sustained transfusion independence. Because of the questions about the durability of the clinical benefit, ICER stated that the evidence demonstrates that betibeglogene autotemcel is superior overall to the current standard of care, but the magnitude of that overall net health benefit is less certain.⁴

Bluebird bio has stated that pricing will be consistent with an outcome-based payment plan for those who achieve and maintain transfusion independence.

FDA Cellular, Tissue, and Gene Therapies Advisory Committee (ADCOM) Vote¹¹

FDA’s ADCOM met in June 2022 to review Zynteglo. For the question “Do the benefits of beti-cel outweigh the risks for the treatment of subjects with TDT?” the committee’s vote was unanimously in favor: 13 (yes) to 0 (no).

Pipeline¹²

A Phase 3 trial for Vertex Pharmaceuticals’ CTX001, an investigational and curative CRISPR/Cas9-based gene therapy for transfusion-dependent beta-thalassemia, is ongoing.  Vertex anticipates filing for FDA approval in the first quarter of 2023.

References

1. FDA Approves First Cell-Based Gene Therapy to Treat Adult and Pediatric Patients with Beta-thalassemia Who Require Regular Blood Transfusions. Accessed at: https://www.fda.gov/news-events/press-announcements/fda-approves-first-cell-based-gene-therapy-treat-adult-and-pediatric-patients-beta-thalassemia-who
2. Advisory committee Betibeglogene autotemcel briefing document. BLA 125717. Accessed in June 2022 at: Cellular, Tissue, and Gene Therapies Advisory Committee June 9, 2022- June 10, 2022 Meeting Briefing Document- Sponsor- 125717 (fda.gov)
3. Betibeglogene autotemcel for beta thalassemia: effectiveness and value. Evidence report. June 2, 2022. Accessed in June 20 22: ICER_Beta-Thalassemia_Evidence-Report_060222-1.pdf
4. Disease State Background: Beta Thalassemia: https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=848
5. BlueBird Bio Press Release: https://investor.bluebirdbio.com/news-releases/news-release-details/long-term-data-bluebird-biosbetibeglogene-autotemcel-beti-cel#:~:text=Beti%2Dcel%20is%20a%20one,)%20stem%20cells%20(HSCs).
6. Angelucci E, Benz EJJ, eds. Hematopoietic cell transplantation for transfusion-dependent thalassemia. UpToDate; 2021.
7. Anurathapan U, Hongeng S, Pakakasama S, et al. Hematopoietic stem cell transplantation for severe thalassemia patients from haploidentical donors using a novel conditioning regimen. Biology Blood and Marrow Transp 2020; 26 (6): 106-112.
8. Locatelli F, Thompson AA, Kwiatkowski JL, Porter JB, et al. Betibeglogene Autotemcel Gene Therapy for Non -β0/β0 Genotype βThalassemia. N Engl J Med. 2022 Feb 3;386(5):415-427. doi: 10.1056/NEJMoa2113206. Epub 2021 Dec 11. PMID: 34891223.
9. Thompson AA, Walters MC, Kwiatkowski J, Rasko JEJ, et al. Gene Therapy in Patients with Transfusion-Dependent β-Thalassemia. N Engl J Med. 2018 Apr 19;378(16):1479-1493. doi: 10.1056/NEJMoa1705342. PMID: 29669226.
10. Kwiatkowski JL, Locatelli F, Walters MC, et al. Improvement in Health-Related Quality of Life Following Treatment with Betibeglogene Autotemcel in Patients with Transfusion-Dependent βThalassemia Enrolled in Phase 3 Studies. Blood. 2021;138:3085.
11. Biospace.com FDA advisory committee unanimously supports beti-cel gene therapy for people with beta-thalassemia who require regular red blood cell transfusions. Accessed in June 2022 at: FDA Advisory Committee Unanimously Supports beti-cel Gene Therapy for People with beta-thalassemia Who Require Regular Red Blood Cell Transfusions | BioSpace
12. https://www.vrtx.com/research-development/pipeline/