Raja Atreya, MD1, Laurent Peyrin-Biroulet, MD2, Andrii Klymenko, MD3, Monica Augustyn, MD4, Igor Bakulin, MD5, Dusan Slankamenac, MD6, Pal Miheller, MD7, Antonio Gasbarrini, MD8, Xavier Hébuterne, MD9, Karin Arnesson10, Thomas Knittel, MD10, Jan Kowalski10, Markus F. Neurath, MD1, William J. Sandborn, MD, FACG11, Walter Reinisch, MD12; 1University of Erlangen-Nürnberg, Erlangen, Bayern, Germany; 2Nancy University Hospital, Nancy, Lorraine, France; 3Zaporizhzhia Medical University, Zaporizhzhi, Zaporiz'ka Oblast', Ukraine; 4Centrum Medyczne Plejady, Krakow, Malopolskie, Poland; 5Mechnikov North-Western State Medical University, Saint Petersburg, Saint Petersburg City, Russia; 6General Hospital Zrenjanin, Zrenjanin, Vojvodina, Serbia; 7Semmelweis University, Budapest, Budapest, Hungary; 8Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Lazio, Italy; 9CHU de Nice and University Côte d’Azur, Nice, Provence-Alpes-Cote d'Azur, France; 10InDex Pharmaceuticals, Solna, Stockholms Lan, Sweden; 11University of California San Diego, La Jolla, CA; 12Medical University of Vienna, Vienna, Wien, Austria
Introduction: Cobitolimod is a topically administered DNA-based oligonucleotide that binds Toll-like receptor 9 (TLR9), triggering an anti-inflammatory mucosal response. We assessed the efficacy and safety of different dose regimens of cobitolimod in patients with moderate-to-severe left-sided ulcerative colitis (UC). Methods: The CONDUCT trial was a multicenter, randomised, placebo-controlled dose-ranging phase 2b study in 12 European countries in patients with left-sided, moderate-to-severe UC. Overall, 211 patients were randomised and received enemas of cobitolimod 31 mg (n=40), 125 mg (n=43), or 250 mg (n=42) at weeks 0 and 3, cobitolimod 125 mg at weeks 0, 1, 2, and 3 (n=42), or placebo (n=44) in a double blinded fashion. The primary efficacy endpoint was proportion of patients in clinical remission at week 6 defined by the 3-component Mayo score. A number of secondary endpoints were analysed at week 6, including symptomatic remission and endoscopic improvement. Results: Significantly more patients achieved clinical remission at week 6 in the cobitolimod 2x250 mg group than with placebo (21.4% [nine] versus 6.8% [three]; odds ratio [OR] 3.8 [80% CI 1.53–9.47]; one-sided p=0.0247 using non-responder imputation for missing data). Other dose groups showed no significant difference in clinical remission versus placebo: 2x31 mg (12.5% [five]; p=0.18); 2x125 mg (4.7% [two]; p=0.66); and 4x125 mg (9.5% [four]; p=0.33). The secondary endpoints clinical remission defined by the full Mayo Score and symptomatic remission were also statistically significant in the cobitolimod 2x250 mg group, whereas endoscopic improvement and normalization of elevated fecal calprotectin levels were numerically in favor of the cobitolimod 2x250 mg group compared to placebo. Adverse events occurred in 47.7% (21) of patients in the placebo group (4.5%  with serious events), 25.0% (10) in the cobitolimod 2x31 mg (5.0%  serious), 39.5% (17) in the 2x125 mg (none serious), 35.7% (15) in the 4x125 mg (4.8%  serious), and 42.9% (18) in the 2x250 mg (9.5%  serious) group with worsening of ulcerative colitis representing 8 out of 10 SAEs. Discussion: The CONDUCT study demonstrates that topical administration of 2x250mg of the TLR9 agonist cobitolimod is effective to induce clinical remission and no specific safety signals were detected. The concept of TLR9 activation is a promising novel therapeutic option in UC patients and is planned to be confirmed in an upcoming phase III program.
*one-sided p-value<0.10, based on Cochran Mantel-Haenszel test, adjusted for stratification factors. Clinical remission was defined as the 3-component Mayo score i) rectal bleeding subscore of 0, ii) stool frequency subscore of 0 or 1 (with at least one point decrease from baseline), and iii) centrally read endoscopy score of 0 or 1. Clinical remission, full Mayo score was defined as i) rectal bleeding subscore of 0, ii) stool frequency subscore of 0 or 1 (with at least one point decrease from baseline), iii) centrally read endoscopy score of 0 or 1 and iiii) physician’s global assessment score of 0 or 1. Symptomatic remission was defined as the 2 component Mayo subscores rectal bleeding of 0, ii) stool frequency of 0 or 1 (with at least one point decrease from baseline). Endoscopic improvement defined as the Mayo endoscopic subscore of 0 or 1. Clinical response was defined as a three point and ≥30% decrease from baseline in the sum of the full Mayo score.