OP015 Multicentre clinical trial with topical administration of the Toll-Like receptor 9 agonist DIMS0150 shows evidence for efficacy in moderate to severe Ulcerative Colitis
R. Atreya*1, S. Bloom2, F. Scaldaferri3, V. Gerardi3, A. Karlsson4, T. Knittel4, J. Kowalski4, M. Lukas5, R. Lofberg6, R. Petryka7, G. Rydzewska8, R. Schnabel9, U. Seidler10, S. Nancey11, M. Neurath12, C. Hawkey13
1University of Erlangen-Nuremberg, Department of Medicine 1, Erlangen, Germany, 2University College London Hospital, Gastroenterology, London, United Kingdom, 3Catholic University of Rome, Internal Medicine/Gastroenterology Division, Rome, Italy, 4InDex Pharmaceuticals, Clinical Research, Stockholm, Sweden, 5Clinical Centre Isacre Lighthouse, IBD Clinical & Research Centre, Prague, Czech Republic, 6Karolinska Institute and Sophiahemmet, Gastro Center, Stockholm, Sweden, 7NZOZ Vivamed, Gastroenterology, Warsaw, Poland, 8Central Clinical Hospital Ministry of Interior in Warsaw, Department of Gastroenterology, Warsaw, Poland, 9Pannonia Maganorvosi Centrum, Gastroenterology, Budapest, Hungary, 10MHH, Dept. of Gastroenterology, Hepatology and Endocrinology, Hanover, Germany, 11Lyon-Sud Hospital, Gastroenterology, Pierre-Benite, France, 12University of Erlangen-Nuremberg, Gastroenterology, Erlangen, Germany, 13University of Nottingham, Nottingham Digestive Diseases Centre, Nottingham, United Kingdom
The Toll like receptor 9 agonist DIMS0150 was evaluated for its efficacy and safety as add-on therapy in patients with moderate to severe ulcerative colitis, refractory to conventional therapy.
The efficacy of DIMS0150 (orphan drug designation in Europe) was evaluated in a randomized, double blind, placebo-controlled, multicentre phase III trial in 131 patients with moderate to severe active ulcerative colitis who at enrolment were on concomitant corticosteroid medication. Patients were randomly assigned to receive two single doses of DIMS0150 (30 mg) or placebo (in a 2:1 ratio) administered topically through endoscopy to the inflamed mucosa at baseline and after 4 weeks. The primary endpoint was clinical remission at week 12, defined as a Clinical Activity Index (CAI)≤4. Secondary efficacy endpoints were clinical remission at week 4, clinical remission with mucosal healing (CAI)≤4 and endoscopic Mayo score of 0 or 1) at week 4, mucosal healing at week 4 and symptomatic remission (absence of blood in stool and number of weekly stools < 35) at week 4 and 8. The patients were followed for one year after administration of the first dose to evaluate long-term efficacy and safety.
In the intention-to-treat population, 44.4% (36/81) of DIMS0150 treated patients vs 46.5% (20/44) for placebo treated patients (p=0.91) achieved clinical remission at week 12 (primary endpoint). At week 4 28.4% (per protocol (PP): 26.5%) of DIMS0150 treated patients achieved clinical remission vs. 20.9% (PP: 12.9%) for placebo (p=0.28 [PP: p=0.10]). The proportion of patients in clinical remission with mucosal healing at week 4 was 21.0% in the DIMS0150 group vs 4.7% in the placebo group (p=0.02). The rate of mucosal healing at week 4 was 34.6% for DIMS0150 and 18.6% for placebo (p=0.09). Significantly more patients treated with DIMS0150 achieved symptomatic remission than recipients of placebo at week 4 (32.1% vs 14.0%, p = 0.02) and week 8 (44.4% vs. 27.9%, p = 0.06 [PP: 45.6% vs 22.6%, p=0.03]). A total of 13.8% SAEs were reported across both treatment groups with 18.6% of patients in the placebo group and 11.5% patients in the Kappaproct group reporting serious AEs, supporting the previously observed safety profile of DIMS0150.
Despite not meeting the primary endpoint, the results of this phase III trial suggest that topical administration of the TLR-9 agonist DIMS0150 is able to induce remission in ulcerative colitis patients, as judged by objective clinical and endoscopic measures. Therefore, the concept of TLR-9 activation is a promising and well-tolerated novel therapeutic option for refractory ulcerative colitis patients, warranting further clinical trials.