New Treatment Options Are on the Horizon for β-Thalassemia

Pharmacy Times Oncology Edition, August 2022, Volume 4, Issue 4

Gene therapies in late-stage development may soon provide hope for a cure.

ß-thalassemia is a genetic disorder causing reduced production of hemoglobin, resulting in anemia.1,2 Symptoms can vary widely depending on whether an individual has β-thalassemia minor, intermedia, or major. In the most severe form, patients with β-thalassemia major, also known as Cooley anemia, become symptomatic in their early years of life.3

β-Thalassemia is highly prevalent in the Mediterranean, Middle East, Africa, South Asia, and India but historically has been a rare disease in the United States.1 However, immigration to the United States from affected regions during the past 50 years has led to a 7.5% increase in prevalence of the disease in the US population.4 It is now estimated that approximately 1000 individuals in the United States have β-thalassemia major.3

Treatment Landscape Today
β-Thalassemia has limited treatment options, with the disease mainly managed with red blood cell transfusions at regular intervals, generally every 2 to 4 weeks, and chelation therapy with a product such as deferoxamine (Desferal; Novartis) or deferasirox to remove excess iron from the bloodstream.1 Without transfusions and chelation therapy, patients with β-thalassemia may experience symptoms such as chronic fatigue, cardiac and liver disease, and pain.3 The only curative treatment for β-thalassemia major is a stem cell transplant.1,5

In late 2019, luspatercept-aamt (Reblozyl; Bristol Myers Squibb) became the first drug approved for treatment of anemia in adult patients with β thalassemia who require regular red blood cell transfusions.6-8 The approval of luspatercept-aamt was supported by the BELIEVE trial (NCT02604433), a phase 3 multicenter, randomized, double-blind, placebo-controlled trial enrolling 336 adult patients with β-thalassemia requiring routine red blood cell transfusions. Trial participants were randomized 2:1 to either luspatercept- aamt 1 mg/kg subcutaneously every 3 weeks with dose increases of 1.25 mg/ kg as permitted, or placebo subcutaneous injections every 3 weeks. All patients were permitted to remain on best supportive care, such as transfusions, chelating agents, antibiotics, antivirals, antifungals, and nutritional support. The primary end point of 33% reduction or more from baseline in transfusion burden from weeks 13 to 24 was met, with 21.4% of patients in the luspaterceptaamt arm achieving this compared with 4.5% of patients in the placebo arm.9

The most common adverse effects (AEs) associated with luspatercept-aamt include headache, bone pain, arthralgia, fatigue, cough, abdominal pain, diarrhea, nausea, trouble breathing, and dizziness. Additionally, thromboembolic events and hypertension have been associated with luspatercept-aamt treatment.8 According to the Thalassaemia International Federation’s 2021 guidelines for the management of transfusion-dependent
β-thalassemia, luspatercept-aamt could be beneficial for reducing iron chelation therapy as a result of reduced transfusion burden, and may be best positioned as a treatment option for patients living in areas with poor access to blood transfusions, as well as those who were transfusion independent but now require transfusions.5

Gene Therapy Offers Promise
Although luspatercept-aamt has been a great advancement in the treatment of transfusion-dependent β-thalassemia, a need remains for therapies that can eliminate the need for transfusions and cure the disease. The known genetic origins of β-thalassemia make it an excellent candidate for gene therapy, and 2 gene therapies in late-stage development may soon provide hope for a cure.

Betibeglogene autotemcel (Zynteglo; bluebird bio) is a 1-time ex vivo gene therapy for adults, adolescents, and pediatric patients with all genotypes (β 0 β0 and non-β0/β0) of transfusion-dependent β-thalassemia.10,11 Treatment with betibeglogene autotemcel involves extraction of the patient’s stem cells, introduction of functional copies of a modified form of the β-globin gene (βA[T87Q]-globin gene) into the stem cells via a BB305 lentiviral vector, and infusion of the modified cells into the patient. With a functioning β A(T87Q) globin gene, the patient should then be able to produce their own functional gene therapy–derived adult hemoglobin and no longer need red blood cell transfusions.11

Currently, betibeglogene autotemcel is approved in the European Union, United Kingdom, Iceland, Liechtenstein, and Norway for patients 12 years and older with transfusion-dependent β-thalassemia who are eligible for stem cell transplant but do not have an available donor.11-13 Further, bluebird bio has submitted a biologics license application (BLA) to the FDA, supported by data from phase 1/2 and phase 3 trials.11,14

In the phase 3 NorthStar-2 trial (NCT02906202) investigating betibeglogene autotemcel, 23 adult and pediatric patients with non-β 0/β0 genotypes were treated with betibeglogene autotemcel. In total, there were 22 patients who were eligible for evaluation, and 20 of them achieved transfusion independence, including 6 of 7 patients under age 12 years.15 The FDA also granted priority review of the BLA submission, and the expected action date is August 19, 2022, which gives a delay of 3 months from the original date of May 20, 2022, to allow the FDA time to review additional clinical data.16

CTX001 is a gene therapy in phase 3 clinical trials, codeveloped by CRISPR Therapeutics and partner Vertex. Like betibeglogene autotemcel, it is a 1-time ex vivo treatment but targets an increase in production of fetal hemoglobin via CRISPR/Cas9 editing of the BCL11A gene in the patient’s cells.17 Interim data from 10 adult and pediatric patients with varying genotypes enrolled in the VX21-CTX001-141 trial (NCT05356195) demonstrated increased hemoglobin and fetal hemoglobin after administration of CTX001. During the trial, all 10 patients were able to stop transfusions within 2 months of treatment.18 CRISPR Therapeutics and Vertex plan to submit a BLA to the FDA in late 2022.19

Potential Limitations of Gene Therapy for β-Thalassemia
Gene therapy is not without risk or safety concerns. There have been reports of myeloid malignancies following treatment with betibeglogene autotemcel for sickle cell disease, although the gene therapy has not been directly implicated in causing the malignancies.5 Even though patients with sickle cell disease and transfusion-dependent β-thalassemia have increased risk of developing myeloid malignancies irrespective of treatment with gene therapy, this remains an area of concern.5 Durability of effect is also an unknown.

In addition to safety concerns, cost may be a barrier to accessing gene therapy for patients with β-thalassemia. Betibeglogene autotemcel is priced at the equivalent of $1.8 million in Europe, and bluebird bio withdrew its approval in Germany after failing to agree on pricing with health authorities there.20

The Role of the Specialty Pharmacy
Despite potential limitations, the possibility of not 1 but 2 gene therapies for β-thalassemia being available in the United States in the near future is an exciting advancement for patients and their families. Specialty pharmacists currently help patients with β-thalassemia manage their treatment with luspatercept-aamt and chelation therapy, assisting with medication education, AE management, proper dosing, and accessing co-pay assistance.

As gene therapies for β-thalassemia come to market and patients’ needs for luspaterceptaamt or chelation therapy diminish, specialty pharmacy still has an opportunity to play a key role in the care continuum of the patient. Pharmacists’ expertise in medication education may be essential when providing patients initial counseling on all aspects of their gene therapy. Specialty pharmacies also have infrastructure that could be useful for the dispensing of gene therapy to a medical center for administration, and clinical management programs could be used to track long-term outcomes information that will be important to payers and manufacturers.

1. Beta thalassemia. National Organization for Rare Disorders. Updated 2018. Accessed March 30, 2022.
2. What is thalassemia? CDC. Updated April 29, 2022. Accessed July 20, 2022.
3. Thalassemia. Boston Children’s Hospital. Accessed March 30, 2022.
4. Sayani FA, Kwiatkowski JL. Increasing prevalence of thalassemia in America: implications for primary care. Ann Med. 2015;47(7):592-604. doi:10.3109/07853890.2015.1091942
5. Cappellini MD, Cohen A, Porter J, Taher A, Viprakasit V, eds. Guidelines
for the Management of Transfusion Dependent Thalassaemia (TDT). 3rd ed.
Nicosia (CY): Thalassaemia International Federation; 2014.
6. FDA approves first therapy to treat patients with rare blood disorder. News release. FDA. November 8, 2019. Accessed April 1, 2022. fda approves-first therapy-treat-patients-rare-blood-disorder
7. FDA Approves Reblozyl (luspatercept-aamt) for the treatment of anemia in adults with beta thalassemia who require regular red blood cell transfusions. News release. Celgene. November 8, 2019. Accessed March 30, 2022. FDA Approves-REBLOZYL-luspatercept-aamt-for-the-Treatment-of-Anemiain- Adults-With-Beta-Thalassemia-Who-Require-Regular-Red-Blood-Cell- Transfusions/default.aspx
8. Label: Reblozyl-luspatercept injection, powder, lyophilized, for solution. DailyMed. Updated October 29, 2021. Accessed March 30, 2022.
9. Reblozyl (luspatercept-aamt). Accessed March 31, 2022. https://www.
10. Pipeline. bluebird bio. Accessed March 31, 2022. https://www.bluebirdbio. com/our-science/pipeline
11. bluebird bio submits biologics license application (BLA) to FDA for betibeglogene autotemcel (beti-cel) gene therapy for patients with β thalassemia who require regular red blood cell transfusi ons. News release. bluebird bio. September 21, 2021. Accessed March 31, 2022. autotemcel-beti-cel-Gene-Therapy-for-Patients-With-%CE%B2-thalassemia-Who-Require-Regular-Red-Blood-Cell-Transfusions
12. Our therapies. bluebird bio. Accessed March 31, 2022.
13. Zynteglo. European Medicines Agency. March 25, 2019. Accessed March 31, 2022.
14. Our clinical trials. bluebird bio. Accessed March 31, 2022.
15. Locatelli F, Thompson AA, Kwiatkowski JL, et al. Betibeglogene autotemcel gene therapy for non–β 0/β0 genotype β-thalassemia. N Engl J Med. 2022;386(5):415-427. doi:10.1056/NEJMoa2113206
16. bluebird provides update on FDA review timelines for betibeglogene autotemcel (beti-cel) for beta-thalassemia and elivaldogene autotemcel (elicel) for cerebral adrenoleukodystrophy (CALD). News release. bluebird bio. January 18, 2022. Accessed March 31, 2022.
17. Hemoglobinopathies. CRISPR Therapeutics. Accessed April 1, 2022.
18. Locatelli F, Ailinca-Luchian S, Bobruff Y, et al. CTX001 for transfusiondependent Β-thalassemia: safety and ef ficacy results from the ongoing CLIMBTHAL-111 study of autologous CRISPR-CAS9-modified CD34+ hematopoietic stem and progenitor cells. Presented at: EHA 2021 Virtual Congress; 2021; virtual. Accessed April 1, 2022.
19. CRISPR Therapeutics provides business update and reports fourth quarter and full year 2021 financial results. News release. CRISPR Therapeutics. February 15, 2022. Accessed April 1, 2022.
20. Pagliarulo N. Bluebird to withdraw gene therapy from Germany after dispute over price. BioPharma Dive. April 20, 2021. Accessed April 1, 2022.

About the Author
Adrienne Brennan, PharmD, CSP, is a clinical program manager at AllianceRx Walgreens Pharmacy in Pittsburgh, Pennsylvania.

Editor's Note: Following the publication of this article in Pharmacy Times Oncology Edition, betibeglogene autotemcel (Zynteglo; bluebird bio, Inc) received FDA approval on August 17, 2022.