Beta thalassemia carries a high disease burden, and while some therapies are available, patients still face a persistent unmet need for curative and supportive treatments, said speakers at AMCP 2023.

Beta thalassemia is a rare, inherited blood disease that causes reduced or absent hemoglobin production and ineffective erythropoiesis, said Julia Mahler, PharmD, clinical pharmacist, IPD Analytics. 

Non-transfusion dependent beta thalassemia, also called beta thalassemia intermedia, is associated with mild-to-moderate anemia. Symptoms typically appear in early childhood or later. 

Patients with transfusion dependent beta thalassemia, also known as beta thalassemia major or Cooley’s anemia, typically develop severe, life-threatening anemia by age 2, Dr Mahler said.

Beta thalassemia impacts approximately 1 in 100,000 births worldwide, largely affecting people from Mediterranean countries, North Africa, the Middle East, India, Central Asia, and Southeast Asia. The incidence in the United States is difficult to determine due to immigration patterns, Dr Mahler said, but the Centers for Disease Control and Prevention estimate there are 1500 people living with transfusion dependent beta thalassemia in America.

Patients with beta thalassemia can develop multi-organ complications such as heart failure, liver disease, bone disease, and vascular disease, Dr Mahler said. Patients often must seek care from multiple specialists, may need to travel for red blood cell transfusions, and may not always have access to centers of excellence for their disease.

“With this complex disease comes a high disease burden. There is definitely a quality-of-life issue with these patients,” Dr Mahler said.

Recently Approved Therapies

The treatment paradigm varies depending on the type of beta thalassemia a patient has, Dr Mahler said.

Patients with non-transfusion dependent beta thalassemia typically have periodic red blood cell transfusions, whereas those with transfusion dependent disease require regular transfusions, Dr Mahler said.

Iron chelation therapy is used on an as-needed basis in patients with non-transfusion dependent disease, but is a component of standard care for patients with more severe disease who receive regular transfusions.

“Iron overload is, unfortunately, a hallmark and a really important complication. The body has no way of naturally excreting excess iron, so it’s going to build up in the heart, the liver, and endocrine organs. This is the cause of death in these patients,” Dr Mahler said.

She advised the effects of “iron overload are either partially or completely irreversible, so we really need to prevent these complications through iron chelation therapy.”

Supportive care for non-transfusion dependent beta thalassemia is hydroxyurea, while curative therapy involves stem cell transplants. 

Stem cell transplants are considered a standard of care. However, patients undergoing stem cell transplants are at risk of non-engraftment/graft failure and graft vs host disease, which can be fatal, Dr Mahler said. Patients receiving stem cell transplants also require myeloablative therapy, which carries risks of infertility, infections, and heightened mortality.

“This is a pediatric disease, where it’s parents making decisions on behalf of what’s best for their kids,” Dr Mahler said. “These decisions are really complex and, especially with the mortality risk, need to be made with the family.”

Patients with transfusion-dependent beta thalassemia typically receive luspatercept-aamt as supportive care, while curative care may involve stem cell transplants or betibeglogene autotemcel (beti-cel). 

Luspatercept-aamt is an erythroid maturation agent which received approval in 2019 and is indicated for adult patients with beta thalassemia who require regular transfusions. With an annual wholesale acquisition price of $189,995, luspatercept reduces the burden of transfusions and supportive treatments but does not eliminate the need for these treatments, Dr Mahler said.

Beti-cel, a lentiviral vector gene therapy, was approved in 2022 for adult and pediatric patients who require regular transfusions. Long-term trials showed beti-cel’s effect lasted up to 7 years. Beti-cel’s annual wholesale acquisition cost is $2.8 million for a one-time treatment.

Several challenges complicate patient access to therapies, Dr Mahler said. Patients may not have access to certain therapies or a matched donor for stem cell transplants. The costs of these agents may contribute to financial toxicity, and there is a lack of data supporting the use of curative therapies in older patients, Dr Mahler said.

Additionally, currently available therapies may not be as effective as therapies still in development, she said.

Therapies in the Pipeline

Mitapivat is an oral pyruvate kinase R activator intended to be used as supportive care to improve hemoglobin in patients with beta thalassemia, Dr Mahler said. Mitapivat is currently being studied in the phase 3 trials ENERGIZE and ENERGIZE-T, and its approval is anticipated in 2025. Mitapavit could cost between $200,000 and $400,000 annually, depending on trial efficacy results and the size of the patient population for which this agent receives approval.

Exagamglogene autotemcel (exa-cel) is a CRISPR-Cas9 therapy currently being studied in a single-arm, open-label phase 1/2/3 study. If exa-cel qualifies for priority review, it could be approved as early as Q4 of 2023. Pricing would likely be similar to beti-cel, Dr Mahler said.

In addition to hemoglobin response, Dr Mahler advocated for stakeholders to consider quality of life measures such as fatigue when determining the value of a new therapy, as this may impact medication adherence.

“Hemoglobin response is definitely important, but if we want patients to take [a medication], we’re going to want to make sure it’s making them feel better,” Dr Mahler said.

Payer Contracting for Beta Thalassemia Therapies

For beta thalassemia treatments, coverage policies often align with a drug’s FDA-approved indication but can also include criteria from clinical trials, said Jennifer Billings, PharmD, BCGP, director of clinical pharmacy, IPD Analytics.

Dr Billings reviewed the coverage policies of 6 commercial and public payers during the session. The least restrictive criteria included an FDA-approved indication and minimal prescriber documentation. By comparison, moderately restrictive criteria also involved warnings and precautions and additional prescriber documentation, and the most restrictive plans required patients to meet clinical trial inclusion criteria, Dr Billings said.

“This does vary from payer to payer. It varies by drug. But in general, those are the three categories,” Dr Billings said.

Beyond costs, study outcomes, and durability of effect, payers may also consider patient acceptability of therapies, treatment-related toxicities, and the potential need for sequential treatments with more than 1 therapy, Dr Billings said.

Regarding contracting and payment models, Dr Billings emphasized the importance of clearly defining what constitutes a treatment failure, with specific time periods and number of transfusions, as well as how providers must measure patient outcomes.

Given the high costs associated with some beta thalassemia therapies, “the devil is really in the details when it comes to some of these outcomes-based agreements and terms that are agreed upon,” Dr Billings said. 

The Centers for Medicare & Medicaid Services are engaged in efforts to expand the use of innovative contracts and improve access to cell and gene therapies, but in the meantime, unmet need persists for patients with beta thalassemia, Dr Billings said.

“The good news is that the discussions are still going on. Hopefully we’ll be able to move the needle in the right direction,” Dr Billings said.