Development of TAK1 Compounds for Neonatal Onset Multisystem Inflammatory Disease

DESCRIPTION (provided by applicant): Cryopyrin-associated periodic syndromes (CAPS) are a family of rare autoinflammatory diseases of which neonatal-onset multisystem inflammatory disease (NOMID) is the most severe phenotype. NOMID is characterized by NLRP3 activating mutations resulting in excessive interleukin- 1?IL-1?and IL-18 production associated with recurrent fever, rash, skeletal lesions, chronic meningitis, seizures, deafness and mental impairment. Consistent with IL-1? central role in these disorders, protein-based anti-IL-1drugs such as anakinra have demonstrated efficacy in the treatment of NOMID. Unfortunately, these drugs suffer from high price, the requirement for parenteral administration, the potential for development of resistance and the lack of efficacy against skeletal lesions. These shortcomings provide a strong rationale for the development of a safe, more effective and affordable oral inhibitor of IL-1?o treat this disease. IL-1?iosynthesis is regulated by p38 an JNK mitogen-activ