Soluble Adenylyl Cyclase (sAC) Inhibitors for Psoriasis

Background & Unmet Need

• Inflammatory diseases of the skin, including psoriasis and atopic dermatitis, affect millions of people every year
• These diseases cause significant morbidity and increase the risk of other diseases such as diabetes, heart disease, and depression
• Whereas biologics and other systemic therapies are effective for patients with severe disease, those with mild to moderate disease are limited to topical anti-inflammatories
• However, corticosteroids, the most effective topicals, have significant skin and systemic side effects
• Soluble adenylyl cyclase (sAC) is an important source of the second messenger cAMP, which is critical for the activation of T cells during the inflammatory response
• Unmet Need: Broadly effective non-steroidal anti-inflammatory for topical treatment of psoriasis

Technology Overview

• The Technology: sAC inhibitors that prevent the induction of Th17-mediated psoriasis when topically administered
• The Discovery: Th17 cell polarization and growth were prevented by loss of sAC activity
• Based on previous high throughput screening studies that identified LRE1 as an allosteric inhibitor of sAC, TDI chemists developed a series of potent analogs with <100 nM EC50 and attractive PK characteristics
• PoC Data: In a 7-day murine imiquimod (IMQ) induced psoriasis model, topically administered TDI-11861 (EC50=1 nM) showed comparable efficacy to steroid control clobetasol but without induction of weight loss
• Safety: No overt toxicity was observed in in vivo studies, and TDI-11861 showed no significant activity against >310 kinases or 47 other well-known targets

Technology Applications

• Treatment and prevention of psoriasis and related inflammatory skin diseases
• Combination therapy with topical steroids or systemic biologics
• The sAC inhibitor compounds are also actively being developed for contraception and ocular hypotony

Technology Advantages

• No overt toxicity was noted in in vivo studies, despite high dosages
• Demonstrated efficacy via topical administration
• Comparable efficacy to topical steroids but with superior safety profile