BMCC-2022-C11

Novel γ-globinHbF Inducer for Treatment of Sickle Cell Disease (SCD) and β–thalassemia

BMCC

AS-28 is a potent and orally active compound which can induce γ-globin expression in hydroxyurea (HU) non-responsive erythroid cells and ameliorate pathogenic symptoms in SCD mouse model.

未定中標題
BMCC Targeted indication

SCD and β-thalassemia

BMCC Status

Pre-clinical studies

BMCC Key features
  • Better γ-globin induction efficacy than HU.
  • Can induce γ-globin in HU non-responsive cells.
  • Can increase HbF and decrease sickle cell percentage in SCD mice.
  • Trend to increase the RBC number and hemoglobin amount in SCD mice.
BMCC Market
  • SCD and β–thalassemia are the most common monogenic mutation diseases in the world. Traditional treatments include blood transfusion and bone marrow transplantation. However, both of these approaches have disadvantages for patients.
  • Pharmacotherapy is another strategy to treat the patients. Hydroxyurea (HU) was the only HbF inducer approved by US-FDA in the past twenty years for treatment of SCD. However, many side effects of HU have been reported, including myelosuppression, reproductive toxicity, etc. and 25% of the patients were un-responsive to HU treatment. Recently, three new drugs: L-glutamine (reduction in frequency of vaso-occlusive crisis, VOC), Crizanlizumab (reduction in frequency of VOC) and Voxelotor (HbS polymerization inhibitor) were approved by US-FDA to treat the SCD. However, the mechanism of L-glutamine is largely unclear and the clinical benefit is mainly to reduce the risk of short-term and long-term complications; Crizanlizumab needs IV infusion and it also can only reduce the complication rates; Voxelotor can inhibit the HbS polymerization (one cause of SCD). However, the result of phase III clinical trial showed that 40 % of patients did not have the response of increased hemoglobin levels (N Engl J Med 2019, 381, 509-519). These deficiencies plus the high cost and limited availabilities of some of these compounds have implemented the barrier of their uses in clinical practice.
  • Our team focuses on the identification and development of better HbF-inducing compounds including AS-28, because HbF not only can inhibit HbS polymerization in SCD, but it also can substitute for the insufficient HbA in β-thalassemia.
  • AS-28 shows better HbF-inducing efficacy than HU does in erythroid cells including that from non-responders to HU. Thus, AS-28 could be a superior next-generation HbF inducer to treat SCD and β-thalassemia.

MODE OF ACTION

AS-28 is an inducer of γ-globin/HbF for prevention of HbS polymerization and substitution for insufficient HbA.

EXPERIMENTAL RESULTS

in vitro efficacy

AS-28 can efficiently induce γ-globin expression under non-toxic concentration and in HU non-responsive erythroid cells.

in vivo efficacy

AS-28 can decrease the sickle cell percentage in SCD mice.