SCD is an autosomal recessive disorder affecting millions of people worldwide. Although life expectancy has increased over the last 20 years, acute and chronic complications still result in comorbidities, high social burden and premature death at around 40 years. Approximately 1.1% of couples worldwide are at risk of having a child with a hemoglobin disorder (sickle cell disease or thalassemia), and 2.3 conceptions per 1,000 are affected by sickle cell disease. Estimates suggest that each year, around 300,000 children are born with sickle cell disease, and this number could reach 400,000 by 2050. Sickle cell disease affects over 100,000 children and adults in the United States. In France, approximately 26,000 patients are affected (50% children, 50% adults).
The disease extends far beyond episodic pain crises. Chronic hemolysis, vaso-occlusion, and endothelial dysfunction lead to progressive organ damage affecting the brain (silent infarcts, overt stroke), kidneys, lungs (pulmonary hypertension, acute chest syndrome), and spleen. This cumulative damage reduces life expectancy by 20-30 years even in high-income settings, and patients often develop complications that current therapies cannot reverse.
Mast cells, a major target of masitinib, appear to play a critical role in severe forms of SCD and its complications, such as vaso-occlusive crises (VOC), acute chest syndrome (ACS), and pain. Masitinib has demonstrated a survival benefit in an SCD mouse model: all control SCD mice experienced VOC and 83% died in the first 3 hours, whereas SCD mice pretreated with masitinib for 4 days experienced no VOCs and no death. Furthermore, lung histology and immunohistochemistry showed that masitinib protects against acute lung injury and mast cell infiltration in an SCD mouse model.
Masitinib clinical development in SCD is being conducted as part of the SICKMAST collaborative program, funded with 9.2 million euros, which aims to demonstrate in a phase 2 clinical trial the efficacy of masitinib in the treatment of acute and chronic complications of SCD in patients identified based on biomarkers. The Assistance Publique-Hôpitaux de Paris (AP-HP) is the sponsor of this phase 2 study, designed in two steps:
- Part 1 : Identification and validation biomarkers highlighting the role of mast cells and basophils in orchestrating acute and chronic complications of sickle cell disease
- Part 2 : Demonstrating in a phase 2 clinical trial the efficacy of masitinib in the treatment of acute and chronic complications of sickle cell disease in patients identified based on biomarkers
