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Beta Thalassemia Requires Specialized Management for Patients, Payors and Pharmacists

Dr. Billings, PharmD, BCGP, and Dr. Mahler, PhD, of IPD Analytics discuss specialized treatment with Beta Thalassemia at AMCP 2023.


By Marie Rosenthal, MS |

Patients with transfusion-dependent beta thalassemia (beta thal) have a high disease burden that requires specialized care. Although there are curative therapies for the disease, they are expensive, and may not be available for all patients. But then, they might not be appropriate for all patients either, explained Jennifer Billings, PharmD, BCGP, director of clinical pharmacy at IPD Analytics, a syndicated healthcare and drug intelligence consulting company.

“There is still a need for additional curative and supportive treatments,” Dr. Billings said at AMCP 2023.

Beta thal is a rare, genetic hematologic disorder characterized by ineffective erythropoiesis. There are two classifications: non-transfusion dependent and transfusion dependent.

Symptoms of non–transfusion-dependent beta thal typically appear in early childhood or later, and patients suffer mild to moderate anemia. Symptoms of transfusion-dependent disease usually appear by 24 months, and patients suffer severe, life-threatening cases of anemia, according to Julia Mahler, PharmD, clinical pharmacist with IPD Analytics.

Beta thal is more common in North Africa, the Middle East, India, and Central and Southeast Asia, with about one child in 100,000 births worldwide developing beta thal. In the United States, cases are higher where immigrants from these countries settle. The CDC estimates there are about 2,000 patients in the United States.

This autosomal recessive genetic disease is characterized by mutations in the hemoglobin beta (HBB) gene. β0 mutations are correlated with the absence of beta-globin production. β+ is correlated with reduced beta-globin production. However, both genotypes can be transfusion dependent or non-transfusion dependent, according to Dr. Mahler.

Patients see an expansion of bone marrow, extramedullary hematopoiesis, hypercoagulability, increased iron absorption and anemia. “And with that we will see the classic symptoms of anemia: impaired development, exercise intolerance, poor perfusion, poor quality of life, and fatigue,” Dr. Mahler said. The anemia is treated with red blood cell (RBC) transfusions, which are going to lead to iron overload.

“So, these patients are really battling iron overload,” she added.

“The takeaway is that beta thalassemia is more complex than just the classic symptoms of anemia that we would see. And because of that, it’s going to require specialized care with multiple specialists. And because this disease does start in early childhood, we’re going to need to make sure that we have an adequate transition from pediatric specialists into adult specialists,” Dr. Mahler said.

The median age of death in beta thal patients is about 45 years, most often from heart failure due to the iron overload in the heart, according to Dr. Mahler.

Evolving Treatments Bring Higher Costs

While the costs of transfusions themselves are not too steep (approximately $22,500 per year), healthcare costs over a lifetime can add up to approximately $2 million. But the treatment landscape is changing, and those changes will increase costs, both pharmacists said.

Non–transfusion-dependent patients require periodic RBC transfusions, chelation therapy, if needed, and supportive care with an agent such as hydroxyurea. Patients also will need monitoring for complications of disease and iron overload.

Treatment and monitoring are similar for those with transfusion-dependent disease, except the RBC transfusions occur regularly (typically every two to five weeks), chelation therapy is more frequent and supportive care can include luspatercept-aamt (Reblozyl, Bristol Myers Squibb).

Luspatercept-aamt, which was approved in 2019, is indicated for the treatment of anemia in adults with beta thal who require regular RBC transfusions. In clinical trials, about 21.4% of beta thal patients achieved the primary end point of reducing transfusion burden by about one-third versus 4.5% of placebo patients. The wholesale acquisition cost (WAC) of luspatercept-aamt is about $189,995 per year, depending on the patients’ weight and how often they require transfusions.

“We see luspatercept as more of a supportive care treatment because it reduces the need for transfusion and, therefore, chelation therapy, but it doesn’t eliminate the need for these treatments,” Dr. Mahler explained, adding that it is not indicated for non–transfusion-dependent patients. Moreover, the drug is only indicated for adults, but “the need for supportive care is also in the pediatric population.”

Mitapivat (Pyrukynd, Agios), approved for adults with pyruvate kinase deficiency (PKD), is seeking a beta thal indication. Mitapivat is an oral pyruvate kinase R activator that aims to increase hemoglobin levels. It is in phase 3 trials, and approval for the new indication is expected in 2025.

“We could see [mitapivat] competing with hydroxyurea in non–transfusion-dependent patients and then luspatercept in the transfusion-dependent patients,” Dr. Mahler said. Because mitapivat adds a novel mechanism of action in the beta thal space, she added, these agents could be used in combination.

Hematopoietic stem cell transplants (HSCTs) are curative for either type of beta thal, and transfusion-dependent patients might also qualify for a gene therapy with betibeglogene autotemcel (beti-cel; Zynteglo, bluebird bio). HSCT with a human leukocyte antigen (HLA)-matched sibling donor is the standard of care, but “the decision to pursue a transplant is complex, patient-specific and should be made with a thalassemia specialist in a high-volume transplant center,” Dr. Mahler said.

If an HLA-matched sibling donor cannot be found, she added, a partial mismatched related or matched unrelated donor can be used as an alternative.

HSCT requires myeloablation therapy, which carries a high risk for toxicity. “We see the best outcomes in kids younger than 7 and those who don’t have any organ toxicity from iron overload,” she said.

There are complications, such as graft-versus-host-disease, and the myeloablation also carries risks for potentially fatal infections.

“There is also a risk for infertility with these myeloablative conditioning treatments, which is important because this is a pediatric disease where parents are making decisions on behalf of what’s best for their children,” Dr. Mahler said. “If I have a 9-year-old daughter with beta thalassemia, she’s a great candidate for transplant. But I also may want to wait a few years until she hits puberty, and I’m able to use effective fertility preservation methods before she undergoes an HSCT.

“But the longer I wait, the more at risk she is for having that organ toxicity, which does affect the transplant outcomes,” she added. “These decisions are really complex and especially with the mortality risk need to be made with the family.”

Gene Therapy Promising but Expensive

The most expensive curative treatment is gene therapy, which requires myeloablative conditioning, but does not require a suitable donor.

Approved in 2022, beti-cel, the first gene therapy for beta thal, uses a lentiviral vector gene addition. It is indicated for both children and adults with transfusion-dependent disease.

In clinical trials, 32 of 36 (89%) patients met the primary endpoint of transfusion independence, defined as not requiring RBC transfusions for at least 12 months while maintaining an average hemoglobin level of 9 g/dL, which is within the goal range.

Long-term data showed up to seven years of treatment effect, “which is promising,” Dr. Mahler said. However, its $2.8 million price tag for a one-time treatment in addition to the costs of administration and hospitalization put this product out of reach for some patients. However, the manufacturer does offer an outcomes-based agreement that would reimburse contracted payors up to 80% of the cost if the patient fails to achieve and maintain transfusion independence for two years after treatment.

“This is a promising treatment option, and we see it as an alternative for patients who could qualify for transplant but can’t find a matched donor,” Dr. Mahler said, adding that fewer than 25% of patients have a suitable matched donor.

Another gene therapy, exagamglogene autotemcel, which uses CRISPR technology, could see approval by the end of the year.

Variety of Payor Strategies

About 75% of patients with transfusion-dependent beta thal are commercially insured, according to Dr. Billings. Because of beta thal patients’ shortened life span, Medicare is unlikely to cover many of these patients, so the remaining 25% are likely covered by Medicaid.

Payors are leveraging different strategies for these newer products, according to Dr. Billings. Some payors are covering luspatercept under the pharmacy benefit; others under the medical benefit, while beti-cel is covered under the medical benefit.

Payors can help lower the cost of luspatercept by encouraging the use of clinically appropriate, low-cost care settings (nonhospital outpatient vs. hospital outpatient).

Some are adding clinical criteria from clinical trials rather than just from the FDA indication for these more expensive treatments.

Payors have many factors to consider when assessing the cost benefit of gene therapies, including outcomes data, durability of effect, toxicities, patient acceptability and whether the patient might someday need to repeat therapy.

“You have a $2.8 million price tag with additional up-front hospital and other treatment costs. ICER had estimated those costs to exceed about $100,000,” Dr. Billings said.

“And I think I’d be remiss if I didn’t talk about sequential treatment with more than one therapy. Beti-cel is supposed to be a one-time therapy. However, if a patient does receive beti-cel and does not achieve transfusion independence or still suffers complications from the disease, will we see that patient subsequently administered another product that comes to the market?” she asked.

“I think these are questions that we just don’t have the answers to, but it’s definitely something that I think are on the minds of payors.”

Innovative Payment Models: Early Days

Innovative contracting and payment models, such as reinsurance programs, likely will become another strategy to ensure access and manage these high costs therapies, according to Dr. Billings.

“I think a lot of i’s need to be dotted and t’s need to be crossed when it comes to these types of agreements,” Dr. Billings warned. “But first and foremost, they require an outcome that can be easily identified, measured and tracked in claims data.”

Fortunately, transfusion independence, as an outcome, lends itself nicely to outcomes-based contracts.

“So the devil is in the details when it comes to some of these outcomes-based agreements and their terms. And you need to have a clear definition of the outcome and a clear definition of treatment failure. Is that one transfusion? Is that two transfusions over a certain time? If someone’s in a car accident and requires a transfusion, how is that addressed in the agreement?”

And who is going to be responsible for monitoring and following the patient? What happens if the person changes commercial insurers?

“For payors, key considerations include the quality of the safety, efficacy and outcomes data, as well as availability of treatment alternatives,” Dr. Billings said. “As more potentially curative therapies enter the market, these innovative management and contracting strategies are really going to be important to ensuring access to these potential lifesaving therapies for patients.”


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