IMO-8400, a toll-like receptor 7, 8, and 9 antagonist, demonstrates clinical activity in a phase 2a, randomized, placebo-controlled trial in patients with moderate-to-severe plaque psoriasis
Background Aberrant toll-like receptors (TLRs) 7, 8, and 9 activation by self-nucleic acids is implicated in immune-mediated inflammatory diseases (IMIDs) such as psoriasis. In preclinical IMID models, blocking TLR-activation reduced disease severity. IMO-8400 is a first-in-class, oligonucleotide-based antagonist of TLRs 7, 8, and 9. We evaluated the short-term safety and proof-of-concept for efficacy of IMO-8400 in a first-in-patient phase 2 trial. Methods Forty-six psoriasis patients were randomly assigned to IMO-8400 in four dose levels or placebo for 12 weeks. Post-treatment follow-up was seven weeks. Primary outcome was incidence of adverse events. Secondary, exploratory outcomes included changes in psoriasis area and severity index (PASI). Results IMO-8400 across all dose levels did not cause any serious or severe adverse events. The most common treatment-related adverse events were dose-dependent injection-site reactions. All IMO-8400 groups showed clinical improvement, but a clear dose-response relationship and statistically significant differences with placebo were not observed (P = 0.26). Eleven (38%) of 29 subjects on IMO-8400 achieved ≥ 50% PASI-reduction, compared to 1 (11%) of 9 subjects on placebo. Five (17%) and 2 (7%) IMO-8400-treated subjects achieved PASI-75 and PASI-90, respectively, compared to none on placebo. Conclusions Short-term IMO-8400-treatment was well tolerated and reduced psoriasis severity. These findings warrant further investigation of endosomal TLR-antagonism as a therapeutic approach in psoriasis and other TLR-mediated IMIDs. Trial registration EudraCT 2013-000164-28 and Clinicaltrials.gov NCT01899729.
|Keywords||Drug-development, Endosomal toll-like receptors, Human beta-defensin-2, Immune-mediated inflammatory diseases, Oligonucleotide antagonist, Type 1 interferon signaling pathway|
|Persistent URL||dx.doi.org/10.1016/j.clim.2016.09.015, hdl.handle.net/1765/94623|
Balak, D.M.W, van Doorn, M.B.A, Arbeit, R.D. (Robert D.), Rijneveld, R. (Rianne), Klaassen, E. (Erica), Sullivan, T. (Tim), … Rissmann, R. (Robert). (2017). IMO-8400, a toll-like receptor 7, 8, and 9 antagonist, demonstrates clinical activity in a phase 2a, randomized, placebo-controlled trial in patients with moderate-to-severe plaque psoriasis. Clinical Immunology, 174, 63–72. doi:10.1016/j.clim.2016.09.015