Andecaliximab [Anti-matrix Metalloproteinase-9] Induction Therapy for Ulcerative Colitis: A Randomised, Double-Blind, Placebo-Controlled, Phase 2/3 Study in Patients With Moderate to Severe Disease

Abstract

Background and AimsMatrix metalloproteinase-9 [MMP9] is implicated in the pathogenesis of ulcerative colitis [UC] via disruption of intestinal barrier integrity and function. A phase 2/3 combined trial was designed to examine the efficacy, safety, and pharmacokinetics of the anti-MMP9 antibody, andecaliximab [formerly GS-5745], in patients with moderately to severely active UC.MethodsPatients were randomised [1:1:1] to receive placebo, 150 mg andecaliximab every 2 weeks [Q2W], or 150 mg andecaliximab weekly [QW], via subcutaneous administration. The primary endpoint was endoscopy/bleeding/stool [EBS]-defined clinical remission [endoscopic subscore of 0 or 1, rectal bleeding subscore of 0, and at least a 1-point decrease from baseline in stool frequency to achieve a subscore of 0 or 1] at Week 8. The phase 2/3 trial met prespecified futility criteria and was terminated before completion. This study describes results from the 8-week induction phase.ResultsNeither 150 mg andecaliximab Q2W or QW resulted in a significant increase vs placebo in the proportion of patients achieving EBS clinical remission at Week 8. Remission rates [95% confidence intervals] were 7.3% [2.0%–17.6%], 7.4% [2.1%–17.9%], and 1.8% [0.0%–9.6%] in the placebo, andecaliximab Q2W, and andecaliximab QW groups, respectively. Similarly, Mayo Clinic Score response, endoscopic response, and mucosal [histological] healing did not differ among groups. Rates of adverse events were comparable among andecaliximab and placebo.ConclusionsEight weeks of induction treatment with 150 mg andecaliximab in patients with UC did not induce clinical remission or response. Andecaliximab was well tolerated and pharmacokinetic properties were consistent with those previously reported.

Genetic drug target validation using Mendelian randomisation

“…We also found evidence through cis-MR of a causative role for MMP9 in CD and IBD. Recent phase 2 trials failed to demonstrate efficacy of andecaliximab, a monoclonal antibody targeting MMP9 in either UC or CD 33,34 (Fig. 6).…”

Chemotherapy-induced peripheral neuropathy—part 2: focus on the prevention of oxaliplatin-induced neurotoxicity

“…Hence, it was suggested that MMP9 mAb has therapeutic potential for the treatment of CIPN. Importantly, a humanized MMP9 antibody (andecaliximab) has reached advanced clinical trials for the treatment of colitis (ClinicalTrials.gov: NCT02405442) [139,140] and alimentary tract cancer (ClinicalTrials.gov: NCT01803282) [141,142]; hence, it may also be repurposed for CIPN [143].…”

Mechanisms of Action of Novel Drugs Targeting Angiogenesis-Promoting Matrix Metalloproteinases

“…A randomized placebo controlled phase 1b single and multiple ascending dose-ranging clinical trial on 72 patients diagnosed with moderately to severely active ulcerative colitis (UC) showed that GS-5745 was safe, well-tolerated, and could be used as a potential therapeutic agent for UC (77). A phase 2/3 UC study with 165 patients treated over 8 weeks further indicated that GS-5745 was well-tolerated (78). A phase 1b trial investigating the safety, pharmacokinetics, and disease-related outcomes for 15 rheumatoid arthritis patients (ClinicalTrials.gov Identifier NCT02176876) demonstrated that GS-5745 was safe, with adverse events that were only grade 1 or 2 in severity and no indication of MSS (79).…”