Periodic Reporting for period 1 - ENHANCIDO (Commercialization of catalytic enhancers targeting IDO1 for multiple sclerosis)
Berichtszeitraum: 2020-09-01 bis 2022-08-31
Current clinical management of MS distinguishes between relapse-remitting MS (RRMS) and primary progressive MS (PPMS) and involves expensive and ineffective treatments with mild to extremely severe side effects with an inverse correlation between efficacy and safety. As such, there is a clear need for novel efficacious cost-effective solutions for the treatment of MS.
The ENHANCIDO project was granted in order to assess the commercial viability of novel, orally administered, effective, and safe small molecules that induce immune tolerance to alter the previously inexorable course of the disease. These first-in-class molecules work as positive allosteric modulators (PAMs) of the immunoregulatory enzyme indoleamine 2,3 dioxygenase 1 (IDO1). Within ENHANCIDO, we assessed whether IDO1 PAMs are feasible as breakthrough treatments for RRMS.
After two consecutive rounds of molecule optimization, we selected VIS329.25 as optimized IDO1 PAM. This candidate molecule showed a good pharmacodynamic and pharmacokinetic profile in vitro. In vivo, VIS329.25 exerted protective effects in an experimental model of acute MS. Moreover, its therapeutic effect is completely abrogated in genetically-modified mice that do not express IDO1 enzyme, suggesting the requirement of IDO1 target for the in vivo effect of VIS329.25. When administered in the relapsing-remitting MS model, representing 85% of the MS cases, the compound did not prove efficacy although no significant adverse effects could be detected.
An extensive market and competitor analysis outlined the commercial viability of IDO1 PAMs as first-in-class molecules in the treatment of autoimmune/inflammatory diseases such as MS and inflammatory bowel disease (IBD). The development of small compounds, acting as positive modulators of the immunoregulatory IDO1 enzyme and thus promoting therapeutic effects, retains their competitive advantage over biologics, such as oral intake and cheap synthesis/manufacturing costs. As allosteric modulators, their activity is also controlled by substrate availability, reducing the possibility of excessive activation and thereby resulting in limited off-target effects.
Thus, despite the setbacks in technical validation of in vivo performance, the concept remains commercially feasible and future technical development activities will be needed to identify and develop a strong drug candidate for the treatment of MS and other inflammatory diseases such as IBD.