ITK TXK Inhibitors as Oral Immunotherapeutic Drugs for Psoriasis

Psoriasis is a devastating autoimmune disease that manifests itself in the form of patchy inflammatory skin lesions that can appear anywhere throughout the body resulting in tremendous physical pain and discomfort This chronic disease can also cause arthritic joints and have a profound impact on a patient s psychological well being In psoriatic lesions the detection of increased numbers of T cells and elevated levels of IL and IFNg have implicated Th and Th cell subsets in disease pathogenesis Interleukin inducible T cell kinase ITK and TXK also known as Resting Lymphocyte Kinase or RLK are members of the Tec kinase family downstream of the T cell receptor and are involved in survival and activation of Th and Th cells respectively Selectively blocking ITK TXK will result in a more broad inhibition of Th and Th cells as opposed to the mechanistic actions of approved clinical therapies which target either the upstream differentiator cytokines IL IL or the effector cytokine IL produced by activated Th cells In this SBIR Phase application we propose to develop the first ITK TXK inhibitor drug candidate for the treatment of psoriasis We have developed an innovative kinase drug discovery platform KINect that exploits our proprietary kinase inhibitor library in the context of structure based drug design SBDD to rapidly identify and develop active drug like chemical cores into drug candidates Using this approach and our own ITK crystal structure we utilized our extensive drug development experience to identify a set of potent selective covalent and proprietary lead ITK TXK inhibitor compounds that block Th Th cell activation The advantage of our ITK TXK inhibitor approach over that of ibrutinib a pan Tec kinase inhibitor used to treat B cell malignancies is that we spare inhibition of the Tec family kinase member Bruton s tyrosine kinase BTK and avoid the associated increased risk of infection and bleeding We propose to further develop ITK TXK drug candidates to test the central hypothesis of this project that orally available inhibitors of ITK TXK kinases will be effective immunotherapeutics that downregulate Th and Th activation in psoriatic lesions and demonstrate efficacy in psoriasis The proposed research focuses on the following specific aims Identify ITK TXK selective inhibitors with appropriate PK properties that modulate Th and Th cell activation and! Determine efficacy of ITK TXK selective inhibitors in pre clinical in vivo models of T cell activation and psoriasis SBIR Phase studies will focus on generating preclinical in vivo efficacy data as well as pharmaceutical pharmacokinetic and safety data advancing the program to IND and initiation of human Phase clinical evaluation in psoriasis patients We anticipate a co development partnership license following Phase clinical studies with a deal value of andgt $ M Given the need for new psoriasis therapies the development of an effective ITK TXK inhibitor drug will address a key unmet need and have a major medical impact Project Narrative Psoriasis is a debilitating and highly prevalent autoimmune disease found in more than of U S population which similarly affects males and females alike and people of diverse ethnic backgrounds To overcome this unmet medical need Confluence Life Sciences Inc will develop proprietary safe and highly efficacious orally available small molecule inhibitors of ITK TXK two kinases responsible for T cell differentiation and receptor activation to be used as an immunotherapeutic treatment for patients who suffer from this disease