Clinical Trial Updates

Clinical trial update (April 2017)

Luspatercept (ACE-536):
• A novel agent that increases haemoglobin by promoting erythropoiesis (differentiation and maturation of late-stage erythrocyte precursors).
• Phase 2 data in adults with β-thalassaemia shows sustained increase in haemoglobin levels with reduction of transfusion requirement and improvement in quality of life. An improvement in iron overload was also noted. The drug was well tolerated with mild to moderate side effects such muscle and joint pains.
• A recently concluded Phase 2 trial addressed the efficacy and safety of luspatercept in adults with NTDT. In this group of patients haemoglobin levels, the liver iron was decreased and quality of life improved
• An ongoing Phase 3 trial (BELIEVE) evaluates the efficacy and safety of luspatercept in patients with transfusion-dependent β-thalassemia. This trial started in 2016 and is ongoing in many sites across the world. It involves patients/volunteers (up to 300 will take part) who are over 18 years old, and who fulfil certain criteria, such as being free of hepatitis, or diabetes or have major organ damage. Psychiatric illness is also a reason for exclusion from the trial. It is hoped that the trials will be concluded by late 2018 and early 2109

LentiGlobin BB305 Drug Product (DP)
• A novel lentiviral vector for gene therapy
• Early data from the ongoing Phase 1/2 Hgb-204 and Hgb-205 trails in β-thalassaemia major and severe sickle cell disease shows that autologous hematopoietic stem cell transplantation using LentiGlobin® DP lentiviral vector encoding the human β-globin gene results in sustained production of therapeutic haemoglobin A leading to clinical and biochemical amelioration along with transfusion discontinuation, with an acceptable safety profile. In these trials myeloablation (destruction of the patient’s bone marrow by drugs, in order to make ‘room’ for the growth of the treated marrow cells) was used. According to the genetic characteristics of the patients, some have become transfusion free in less thatn 12 months after the treatment, while the more severe thalassaemia caseshave reduced their transfusion requirements by 60%
• A number of ongoing Phase 1, 2 and 3 trials evaluate the safety and efficacy of LentiGlobin DP gene therapy in β-thalassaemia major and/or severe sickle cell disease.

• An agent that regulates hemoglobin gene expression, approved and used for the treatment of other haematological conditions, such as myelofibrosis and resistant to hydroxyurea polycythemia vera. Ruxolitinib, belongs to a group of drugs that have been shown to reduce ineffective erythropoiesis.
• A Phase 2 trial (TRUTH) in transfusion-dependent β-thalassemia with splenomegaly, showed that ruxolitinib therapy resulted in slight improvement in pre-transfusion haemoglobin levels and survival of transfused red cells with a noticeable reduction in spleen size, rendering the drug a promising alternative to splenectomy.
Aydinok Y, Karakas Z, Cassinerio E, et al in Blood 2016, 1`28:852

• A novel blood processing system to enhance safety of blood transfusions in terms of blood-borne infections and perhaps transfusion reactions,
• A US Phase 3 trial showed that INTERCEPT red cells were non-inferior to control red cells in terms of myocardial infarction, renal failure or death.
• A similar EU Phase 3 trial is ongoing. The treatment has been shown to not increase destruction (haemolysis) of the red cells.
Wlitshire M, Meli A, Schott MA et al. Transfus Med. 2016. 26(3): 208-14

• A calcium channel blocker that prevents entrance of iron into cells, used for the treatment of hypertension and coronary artery disease.
• A recently published randomized trial showed that addition of amlodipine to standard iron chelation therapy in thalassemia major patients with cardiac siderosis, amlodipine combined with chelation therapy reduced cardiac iron more effectively than chelation therapy alone.
• An ongoing randomized trial (CANALI) evaluates the efficacy and safety of adding amlodipine on top of deferasirox on cardiac iron in transfusion-dependent thalassaemia patients with moderate cardiac iron overload (MRI T2* 10-20 ms).

• A new for the treatment of vaso-occlusive events in sickle cell disease (antibody against the adhesion molecule P-selectin)
• A recently published Phse 2 trial showed that Crizanlizumab reduced significantly pain crises with a low incidence of adverse events.
https://www.ncbi.nlm.nih.gov/pubmed/27959701 Ataga KI, Kutlar A, Kanter J, Liles D, et al N Engl J Med 2017 376(5): 429-439