The Impact of Orphan Drug Legislation on the Beta Thalassemia Treatment Landscape

Orphan drug designation incentives have helped boost enthusiasm for researching and developing drugs for beta thalassemia, a new review concludes.

Drugs for beta thalassemia are eligible for orphan drug designation (ODD) in the United States and European Union, and a review published in Drug Discovery Today concluded that this type of legislation has helped facilitate development of better treatments for the rare blood disease.

The review encompassed all beta-thalassemia drugs that have been granted ODD by the FDA or the European Medicines Agency (EMA).

Beta thalassemia, a group of autosomal recessive blood disorders, is considered a rare disease in the United States and European Union, although it is one of the most prevalent blood disorders globally and is not uncommon in many countries. Patients are generally stratified by transfusion dependency status: Those who are transfusion dependent (TDT) need blood transfusions regularly, while patients with non–transfusion-dependent thalassemia only need blood transfusions occasionally or never. For patients with TDT beta thalassemia, iron chelation therapy is needed to prevent iron overload.

Beta thalassemia’s rare status in the United States and European Union makes drugs intended to treat it eligible for ODD, with the FDA and EMA having the power to grant the status to new drugs, previously unlicensed drugs, or new uses of an already licensed drug intended to treat rare and severe diseases. The ODD policies aim to give drug makers incentive to invest in rare disease treatments.

There have been 28 ODDs for beta thalassemia since 2001, when both the United States and European Union programs were active. The FDA program began in 1983, while the EMA legislation has been active since 2000. Twenty-two ODDs were granted by the FDA and 18 by the EMA; 12 were granted by both agencies. At the time of the review, 10 of the 28 ODDs were discontinued—1 in preclinical research, 3 in phase 1 trials, and 8 in phase 2 trials. Since the start of ODD legislation, varied therapeutic approaches addressing different pathophysiological targets have been proposed.

Iron homeostasis is one area in which ODD may have affected the treatment landscape. Deferoxamine mesylate was the longtime standard iron chelation therapy, until 2 oral drugs that were granted ODD—deferiprone in the United States and deferasirox by both agencies—mostly replaced deferoxamine. In patients with TDT, traditional iron chelation remains crucial, but new avenues have been explored and granted ODDs in the time since orphan drug legislation has been active.

“Although the importance of iron chelation was already clear, new drugs to confront iron overload and to deliberately address other features of the disease have become available only over the past 30 years, after orphan drug legislations were passed,” the authors wrote.

Although the most commonly used fetal hemoglobin enhancing drug, hydroxyurea, has not been granted ODD for beta thalassemia, several agents focused on hemoglobin regulation are being explored. A similar trend is occurring with treatment strategies for ineffective erythropoiesis, another characteristic of beta thalassemia. While mitigating alpha and non-alpha chain imbalance is the logical approach, the review authors highlight alternatives such as activin II receptor traps, heme biosynthesis inhibition, and pyruvate kinase activation. Gene therapy for beta thalassemia has also been explored in the era of ODD legislation, with 4 each receiving ODD from the FDA and the EMA, 3 of which were granted ODD from both entities.

“Recently, the prospects for a definitive treatment of beta thalassemia through allogeneic bone marrow transplantation or gene therapy have taken center stage,” the authors wrote. “These prospects should not detract from the importance to also continue unrelenting efforts to ameliorate treatment protocols for the large proportion of patients who, for a variety of reasons, cannot currently access bone marrow transplantation or gene therapy.”

Overall, the success rate of orphan drug regulations for beta thalassemia is 6 licensed drugs related to 4 active pharmaceutical ingredients: the gene therapy BB-305, erythroid maturation agent luspatercept, and 2 formulations each of deferiprone and deferasirox. As for predicting the potential for successful ODD development, an individual company’s specific expertise in certain molecules or methodology seemed to play a major role.

The review found that small- and medium-size companies and public institutions were less likely to take advantage of orphan drug legislation incentives than expected. The drugs targeting beta thalassemia and ineffective erythropoiesis were largely developed by big companies, with a few exceptions. But overall, the authors conclude that ODD legislation has helped boost enthusiasm for researching and developing drugs for rare conditions.

“Considering ODDs in general, advances in genetics and pathophysiology, incentives from orphan legislations, and accelerated regulatory pathways have stimulated research efforts in the area of rare diseases, increasing the likelihood of successfully bringing new drugs to patients,” the authors wrote.


Costa E, Domenica Cappellini M, Rivella S, et al. Emergent treatments for β-thalassemia and orphan drug legislations. Drug Discov Today. Published online September 1, 2022. doi:10.1016/j.drudis.2022.103342