Investigational drugs in phase I and phase II clinical trials for thalassemia

ABSTRACT

Introduction: Regular transfusion and iron chelation are the current treatment of severe forms of thalassemia. As a consequence of this demanding supportive treatment, there are several unmet therapeutic needs. Due to a deeper understanding in the pathophysiology of thalassemia, new therapeutic strategies have been developed that are now in pre-clinical and clinical trials.

Areas covered: Activin receptor ligand traps (luspatercept and sotatercept), drugs targeting ineffective erythropoiesis, showed encouraging results in Phase I and II clinical trials. A phase III clinical trial is currently ongoing. Ruxolitinib, a Jak2 inhibitor, has been tested to limit stress erythropoiesis in a phase II clinical trial. In addition, improvement in iron chelation has been developed. Moreover, several trials of gene therapy are currently active in different countries with different lentiviral vectors.

Expert opinion: The most promising molecules are the activin receptor ligand traps. Together with gene therapy these could be an alternative to bone marrow transplant, aiming towards a curative strategy. The main limit to gene therapy seems to be the conditioning regimen, thus an in vivo gene therapy would be more suitable. At pre-clinical level gene editing is showing extremely encouraging results.

KEYWORDS:

• Thalassemia
• Activin receptor ligand trap
• Jak2 inhibitor
• deferasirox
• gene therapy
• gene editing

Article highlights

• In the era of targeted drugs there is a potential for the discovery new molecules that might change the natural history of β-thalassemia

• The Activin receptor ligand trap Luspatercept, currently in Phase III clinical trial, is the most promising molecule that targets ineffective erythropoiesis

• The Jak2 inhibitor Ruxolitinib, borrowed from a disease with apparently opposite features compared to thalassemia, might be considered for patients candidate to splenectomy

• The fascinating gene therapy is now experimented in several clinical trials with a potential indication for patients in need for curative option

This box summarizes key points contained in the article.

Declaration of interest

M. D. Cappellini is a member of the advisory board for Novartis, Celgene and Sanofi-Genzyme. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was not funded.