- A novel agent that increases haemoglobin by promoting erythropoiesis. More specifically it promotes the differentiation and maturation of late-stage erythrocyte precursors by acting as a ligand trap for members of the TGF-β superfamily, the increased signaling of which inhibits erythrocyte maturation. This mechanism of action is distinct from that of erythropoiesis-stimulating agents (ESAs), which stimulate the proliferation of early-stage erythrocyte precursors.
- Two phase 2 dose-escalation trials in patients with transfusion dependent (TD) and non-transfusion dependent (NTD) β-thalassaemia patients showed that luspatercept, administered subcutaneously, induced a sustained increase in hemoglobin levels with reduction of transfusion requirement and improvement in quality of life.These trials included a base study on 64 patients (31 TD and 33 NTD) for 3 months, followed by an extension study on 51 patients (24 TD and 27 NTD) for up to 5 years. The trials documented an increase in mean haemoglobin levels of 1.0 g/dL or higher in 62% and 78% of patients; the median duration of this increase was 13.5 months. There was a reduction of transfusion requirements in TD patients of 33% or higher in 71% and 83% of patients, respectively; the median duration of this reduction was 6.3 months. In addition, there was an improvement in quality of life and a reduction in liver iron concentration. The drug was well tolerated and no serious adverse events were detected. The most frequent related adverse events included bone pain, myalgia, headache, musculoskeletal pain, arthralgia and injection site pain.
- An ongoing randomized, placebo-controlled phase 3 trial (BELIEVE) evaluates the efficacy and safety of luspatercept in 300 patients with TD β-thalassaemia. The patients are receiving luspatercept at a dose of 1mg/kg subcutaneously, titrated up to 1.25 mg/kg, every 3 weeks. The primary efficacy endpoint is the proportion of patients with a reduction in transfusion burden of 33% of higher. The trial is soon expected to reach full enrolment and results are expected by mid 2018.
- Another phase 2 trial (BEYOND) on NTD -thalassemia is expected to start by end 2017.
- A novel agent that increases haemoglobin by promoting erythropoiesis, with the same mechanism of action with luspatercept (differentiation and maturation of late-stage erythrocyte precursors)
- Early phase 2 data in β-thalassaemia shows sustained increase in haemoglobin levels.
- An ongoing phase 2 dose-finding trial evaluates the safety and tolerability of sotatercept in adults with TD and NDT β-thalassaemia.
LentiGlobin gene therapy
- LentiGlobin gene therapy consists of autologous CD34+ cells transduced with the BB305 lentiviral vector.
- Early data from the ongoing Phase 1/2 HGB-204 and HGB-205 trails in TD β-thalassaemia and severe sickle cell disease shows that autologous hematopoietic stem cell transplantation using LentiGlobin 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 in some of the cases, with an acceptable safety profile.
- 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.
- The phase 1/2 study [Northstar (HGB-204)] evaluated LentiGlobin gene therapy in 18 TD thalassaemia patients. All patients with non-β0/β0 genotypes in this trial stopped transfusions for at least 12 months (median hemoglobin 11.2 g/dL). There was a reduction of 60% or higher in transfusions in patients with a β0/β0 genotype. The safety profile was consistent with autologous HCT.
- The ongoing phase 2 study HGB-205 study evaluates the safety and efficacy of LentiGlobin gene therapy in patients with severe haemoglobinopathies, including TD thalassaemia and severe sickle cell disease (SCD). As of September 2016, 1 patient with severe SCD (male; 13 year-old) and 4 patients with TD thalassaemia (2 male, 2 female, 16−19 year-old) have received LentiGlobin.
The patient with severe SCD who was transfusion dependent before his enrollement in the study, experienced no clinical symptoms or complications of SCD in the 21 months since treatment A that time, his haemoglobin was 13.1 g/dL, with 50% HbS.
Of the 4 patients with TD thalassaemia, 3 have β0/βE genotypes and 1 β0/β0. Two of the β0/βE patients have been without transfusions for 33 and 30 months, with haemoglobin levels of 10.9 and 13.5 g/dL, respectively. The third patient with a β0/βE genotype has 12 months of follow-up and has not required transfusions, with an haemoglobin of 11.3 g/dL. The patient with the β0/β0 genotype has also been free of transfusions for 12 months, with an haemoglobin of 8.3 g/dL.
Since September 2016, 2 more patients with severe SCD have received LentiGlobin DP.
- The ongoing phase 3 trial [Northstar-2 (HGB-207)] evaluates the safety and efficacy of LentiGlobin gene therapy in TD β-thalassemia in 15 patients with non-β0/β0 genotypes, aged 12-50 years. As of March 2017, two 20-year-old female patients with β0/βE genotypes have been treated.
- An agent that inhibits the expression of the JAK2 gene, which is responsible for the regulation of the production and maturation of red cells. Ruxolitinib is used for the treatment of other haematological conditions, such as myelofibrosis and resistant to hydroxyurea polycythemia vera.
- A Phase 2 trial (TRUTH) in 30 transfusion-dependent β-thalassemia with splenomegaly showed that ruxolitinib therapy for 30 weeks resulted in slight improvement in pre-transfusion haemoglobin levels with a noticeable reduction in spleen size, rendering the drug a promising alternative to splenectomy.
- A novel blood processing system to enhance safety of blood transfusions in terms o blood-borne infections and perhaps transfusion reactions,
- The data from the recent Phase 3 study met the European criteria for red blood cell components for transfusion and demonstrated sufficient hemoglobin content and in vitro quality compared to untreated red cells. It is believed that the successful results from this study, combined with data from the prior Phase 3 study, support the safety and efficacy of the INTERCEPT RBC system.
- A similar EU Phase 3 trial is ongoing.
- A calcium channel blocker, used for the treatment of hypertension and coronary artery disease, that may prevent iron entry into cardiomyocytes.
- A randomized, placebo-controlled trial in 62 thalassemia major patients, the addition of amlodipine (at 5 mg/day) to standard iron chelation therapy for 12 months reduced myocardial iron concentration as estimated by MRI T2* 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 randomized, placebo-controlled phase 2 trial in 198 patients with sickle cell disease who received crizanlizumab, administered intravenously 14 times over a period of 52 weeks, showed a significant reduction of pain crises with a low incidence of adverse events.