The Promise of Novel Therapies for β Thalassemia Syndromes

In the past two decades, thalassemia has “graduated” from being a predominantly pediatric disease to a predominantly adult disease. While the thalassemia syndromes are heterogeneous, including homozygous or compound heterozygous β-globin defects, the pathophysiology is primarily related to ineffective erythropoiesis and systemic iron overload with tissue iron deposition. The major advances that have led to this dramatic improvement in life expectancy and reduction in morbidity for transfusion-dependent and non–transfusion-dependent patients include enhanced safety of the blood supply, the advent of oral chelators, the ability to noninvasively quantify tissue iron by MRI, and advances in stem cell transplantation (SCT). It is likely that even without curative treatment, children born after the year 2000 could have near normal life expectancy on regular transfusion if they chelate optimally. Additionally, in the near future, additional advances in therapy are anticipated, including optimization of gene therapy and the use of agents that leverage molecular targets.

Stringent testing of blood products has reduced the risk of transmission of viruses such as hepatitis C and HIV, which had previously wreaked havoc on this population, and now includes newer agents such as West Nile virus and severe acute respiratory syndrome. However, parasitic infections remain a potential concern, particularly malaria, Lyme disease, and babesiosis, for which testing is less comprehensive.

The approval of not one but two oral chelators, deferasirox and deferiprone, is another key development that had a major impact on reduction in morbidity. These are agents with a longer half-life than deferoxamine, and with the convenience of oral administration, have improved compliance significantly with less iron-related cardiac and endocrine dysfunction. The ability to combine chelators offers options for dose reduction for toxicity as well as intensification when required. Until recently, deferasirox was only available as dispersible tablets, and apart from the inconvenient mode of administration, the inactive ingredients also caused gastrointestinal intolerance. The introduction of the tablet form and granule formulation for children will eliminate some of these disadvantages, and likely improve compliance.

Previous reliance on the serum ferritin to guide chelation often resulted in over- or underchelation since serum ferritin does not reflect total body iron reliably. MRI technology has enabled more accurate quantification of iron in the liver and heart (standard), as well as pituitary and pancreas, allowing superior monitoring and tailored chelation regimens. This is now the recommended standard of care for monitoring iron overload, both in transfusion-dependent and non–transfusion-dependent patients.

Finally, advances in allogeneic hematopoietic stem cell transplantation (allo-HSCT) have resulted in better curative outcomes, with reduced toxicity and fewer long-term adverse effects. Despite these advances, there remain some unmet needs for this population. Currently, the mainstay of treatment is regular transfusion (for transfusion-dependent patients), regular monitoring for iron overload, and iron chelation therapy when indicated (for both transfusion-dependent and non-transfusion dependent patients). While allo-HSCT is curative, this option has the best results when the donor is a matched sibling. Only approximately 20 percent of patients have such a donor, and for the remainder of patients, a curative option was a significant need. Novel treatments are now in advanced stages of clinical trials and offer the promise of a cure for a much larger proportion of patients with thalassemia.

Gene Therapy

The development of a gene therapy strategy to “cure” thalassemia has been ongoing for three decades, but only recently have these efforts been moved into the clinic. Advanced lentiglobin gene transfer technology has been developed, and clinical trials are ongoing. Results from the Bluebird Bio phase I-II trials (HGB-204 and HGB-205) in 22 transfusion-dependent thalassemia patients after a median of 26 months of follow-up were recently reported.¹  Patients’ stem cells were collected after stimulation with plerixafor, then transduced ex vivo with the lentiglobin vector and reinfused after myeloablative conditioning with busulfan as a single agent. Of the 13 patients with non-β⁰/β⁰ genotypes, all but one were able to achieve transfusion independence. Hemoglobin production attributed to the transduced gene ranged from 3.4 to 10 g/dL, with total hemoglobin levels in the 8.2 to 13.7 g/dL range. In the remaining nine patients with β⁰/β⁰ genotypes, the median annualized transfusion volume was reduced by almost 75 percent, and three patients were able to come off regular transfusions altogether. In patients with at least 8 g/dL of hemoglobin from the transduced gene, the vector copy number was 0.6 or greater per transduced cell. The treatment as a whole was associated with only the usual adverse events which would otherwise be expected during autologous SCT. The vector had numerous integration sites, and no clonal dominance was noted. The company then refined the manufacturing process for the vector, and preliminary results from the phase III study (HGB-207) reported at the 2017 ASH Annual Meeting showed further improvements in vector copy numbers and consequently, increased hemoglobin production.²  While the duration of follow-up at the time of the report was still relatively short, the results were encouraging, and greater transfusion reduction or independence may be anticipated in subsequent reports.

Additional phase I/II trials using a lentiviral vector-based gene therapy are currently underway in Italy. Preclinical work has shown encouraging results for other novel strategies including gene editing. Targets for gene editing are diverse, including the BCL 11A locus and the b-globin gene locus itself. Techniques used to disrupt BCL 11A, thus resulting in continued expression of the g-globin gene and production of fetal hemoglobin, include zinc finger nucleases and the use of CRISPR/Cas9.

Activin Trap Agents to Promote Effective Erythropoiesis

Intramedullary hemolysis and ineffective erythropoiesis as a result of imbalanced α and β globin-chain production is a central part of the mechanism of disease in thalassemia. This results in accumulation of GDF11-producing cells. GDF11, a transforming growth factor β ligand, inhibits differentiation of the erythroid precursors, worsening ineffective erythropoiesis and thus anemia. Novel strategies to trap/bind GDF11 and thus promote more effective erythropoiesis led to the development of two such activin traps, luspatercept (ACE-536) and sotatercept (ACE-011). Luspatercept consists of the extracellular of activin IIb linked to the human IgG1 Fc domain and prevents binding of GDF11 to its receptor. The drug, which is administered subcutaneously every three weeks, has been in clinical trials for the past three years. Phase II trials were conducted in transfusion-dependent and non–transfusion-dependent thalassemia patients.³  There was significant reduction in transfusion requirements in almost all transfusion-dependent patients (genotypes were not required for entry into the study), greater tham 33 percent reduction in 83 percent of patients and more than 50 percent reduction in 67 percent, with several patients achieving transfusion independence. In the non–transfusion-dependent patients, there was a significant increase in hemoglobin levels, more than 1 g/dL in 78 percent, and greater than 1.5 g/dL in 56 percent of patients. In both populations, the drug was well tolerated in all patients, with very few adverse events related to the drug. The phase III double-blind, randomized, placebo-controlled, international multicenter trial (BELIEVE) of luspatercept has been completed recently, and results are expected to be published soon.