A new small molecule DHODH-inhibitor [KIO-100 (PP-001)] targeting activated T cells for intraocular treatment of uveitis — A phase I clinical trial

• Published in: Frontiers in medicine 2022-10, Vol.9, p.1023224-1023224
• Main Authors: Thurau, Stephan, Deuter, Christoph M. E., Heiligenhaus, Arnd, Pleyer, Uwe, Van Calster, Joachim, Barisani-Asenbauer, Talin, Obermayr, Franz, Sperl, Stefan, Seda-Zehetner, Romana, Wildner, Gerhild
• Format: Article
• Language: English
• Subjects: clinical phase 1 trial; experimental autoimmune uveitis; humans; intravitreal therapy; Medicine; rat; uveitis
• ISSN: 2296-858X; 2296-858X
• DOI: 10.3389/fmed.2022.1023224

Uveitis is a T cell-mediated, intraocular inflammatory disease and one of the main causes of blindness in industrialized countries. There is a high unmet need for new immunomodulatory, steroid-sparing therapies, since only ciclosporin A and a single TNF-α-blocker are approved for non-infectious uveitis. A new small molecule inhibitor of dihydroorotate dehydrogenase (DHODH), an enzyme pivotal for de novo synthesis of pyrimidines, has a high potency for suppressing T and B cells and has already proven highly effective for treating uveitis in experimental rat models. Systemic and intraocular application of KIO-100 (PP-001) (previously called PP-001, now KIO-100) could efficiently suppress rat uveitis in a preventive as well as therapeutic mode. Here we describe the outcome of the first clinical phase 1 trial comparing three different doses of a single intraocular injection of KIO-100 (PP-001) in patients with non-infectious posterior segment uveitis. No toxic side effects on intraocular tissues or other adverse events were observed, while intraocular inflammation decreased, and visual acuity significantly improved. Macular edema, a sight-threatening complication in uveitis, showed regression 2 weeks after intraocular KIO-100 (PP-001) injection in some patients, indicating that this novel small molecule has a high potential as a new intraocular therapy for uveitis.