Development of a novel, targeted small molecule inhibitor of the nucleoside salvage pathway through IND enabling studies and translational mouse models for acute disseminated encephalomyelitis (ADEM)

PROJECT SUMMARY Acute disseminated encephalomyelitis (ADEM) is an autoimmune disease that can present with fever and ataxia as well as loss of consciousness and coma. ADEM largely affects children and is strongly associated with a prior infection or immunization. ADEM is driven by T and B lymphocytes aberrantly activated against myelin antigens. There is no FDA-approved therapy for the treatment of ADEM, and most cases of ADEM are treated with corticosteroids. Corticosteroids have significant side effects including behavioral changes, hypotension, and tachycardia and are incompletely effective at treating the disease. ADEM is a rare disease but is associated with significant morbidity and mortality. Up to 50% of treated ADEM patients fail to fully recover from the disease, and ADEM has a 5 – 12% mortality rate. Our company, Trethera, is developing a small molecule drug, TRE-515, that has the potential to selectively block lymphocyte proliferation in ADEM by inhibiting deoxycytidine kinase (dCK), a key enzyme in the deoxyribonucleoside salvage pathway. Our preliminary studies show in the MOG35-55 experimental autoimmune encephalomyelitis (EAE) mouse model of ADEM that (i) immune cells activate dCK during disease, (ii) TRE-515 blocks dCK activity in immune cells, (iii) prophylactic or therapeutic TRE-515 treatments block clinical symptoms, (iv) TRE-515 treatments lead to fewer immune cell infiltrates in the central nervous system, (v) TRE-515 blocks B and T cell proliferation without affecting other immune cell types including innate immune cells or regulatory T and B cells, (vi) TRE-515 increases plasma deoxycytidine levels suggesting a potential biomarker for the early evaluation of drug-target engagement, (vii) TRE-515 blocks T cell proliferation in culture, and (viii) TRE-515 treatments and dCK knockout are not associated with significant toxicities. In support of and validating these studies, the FDA recently awarded TRE-515 Orphan Drug Designation (ODD) for the treatment of ADEM. This is the first and only time the FDA has awarded an ODD for the treatment of ADEM. Additionally, in Phase I clinical trials for solid tumors, TRE-515 treatments are associated with mild side effects and show evidence of efficacy. Collectively, these data strongly suggest that TRE-515 could be an important new therapy for ADEM. However, the MOG35-55 EAE model in which we have so far evaluated TRE- 515 is not driven by B cells despite the role of B cells in driving ADEM. In the proposed project, we will conduct critical preclinical studies to evaluate the effect of TRE-515 in an advanced PLP139-151 EAE model driven by both B and CD4 T cells. Additionally, to-date all our toxicology studies have been in adult animals but juvenile toxicity studies are required before we can treat children with ADEM. We will conduct juvenile toxicology studies in mice to enable us to test TRE-515 in the childhood population in which ADEM predominates. This work will be critical for moving TRE-515 into the clinical for ADEM patients.