Abstract Background and Aims Ontamalimab, a fully-human monoclonal antibody targeting MAdCAM-1, induced remission in patients with moderate-to-severe ulcerative colitis [UC] in the TURANDOT study. We aimed to assess long-term safety, tolerability, and efficacy of ontamalimab in TURANDOT II. Methods TURANDOT II was a phase 2, multicentre, open-label [OL] study in patients with moderate-to-severe UC who completed TURANDOT on placebo or ontamalimab (NCT01771809). Patients were randomised to 75 mg or 225 mg ontamalimab every 4 weeks for 72 weeks [OL1]. The dosage could be increased to 225 mg from Week 8 at the investigator’s discretion. All patients then received 75 mg every 4 weeks for 72 weeks [OL2], followed by 6-month safety follow-up. The primary objective was safety, measured by adverse events [AEs], serious AEs [SAEs], and AEs leading to withdrawal. Mucosal healing [MH; centrally read endoscopy] was assessed. Results Of 330 patients, 180 completed OL1; 94 escalated to 225 mg; 127 completed OL2. Overall, 36.1% experienced drug-related AEs. The most common SAE [10.0%] was worsening/ongoing UC; 5.5% of patients had serious infections, the most common being gastroenteritis [0.9%]. One death and four cancers [all unrelated to ontamalimab] occurred. No PML [progressive multifocal leukoencephalopathy]/lymphoproliferative disorders occurred. Geometric mean high-sensitivity C-reactive protein [hsCRP] and faecal calprotectin decreased across OL1 in both dose groups. The proportion of patients assigned to placebo in TURANDOT achieving MH increased from 8.8% [6/68] at baseline to 35.3% at Week 16 [24/68; non-responder imputation]. The corresponding increase in the ontamalimab group was from 23.3% [61/262] to 26.7% [70/262]. Conclusions Ontamalimab was well tolerated up to 144 weeks in patients with moderate-to-severe UC, with good safety and efficacy.

INTRODUCTION: Ontamalimab (SHP647), a human monoclonal IgG 2 antibody, targets mucosal addressin cell adhesion molecule-1 (MAdCAM-1), to reduce lymphocyte homing to the gastrointestinal (GI) tract. In the TURANDOT II trial, ontamalimab was well-tolerated and clinical benefit was seen up to 144 wks in patients with ulcerative colitis (UC). Here we report long-term mucosal healing, response and remission in a subset of patients in TURANDOT II. METHODS: TURANDOT II (NCT01771809) is a phase 2, 2-part open-label (OL) extension study of ontamalimab in patients with UC who received placebo or ontamalimab 7.5, 22.5, 75 or 225 mg in the feeder study (TURANDOT). At TURANDOT II baseline (TURANDOT wk 12), patients were randomized to ontamalimab 75 or 225 mg every 4 wks for 72 wks (OL1). In cases of clinical exacerbation or no response, escalation from 75 to 225 mg was permitted from wk 8. In OL2, patients received 75 mg every 4 wks for 72 wks. Endoscopies were carried out at wk 16, and a subset of patients undergoing routine cancer surveillance had at least one follow-up endoscopy between wks 40 and 72 of OL1: all endoscopies were centrally-read. Mucosal healing (Mayo endoscopy subscore ≤1), clinical remission (total Mayo score ≤2, no subscore >1) and clinical response (≥3-point decrease in total Mayo score from TURANDOT baseline, ≥30% change; ≥1-point decrease in or ≤1 rectal bleed absolute score) were measured. RESULTS: Of 330 patients in TURANDOT II, 101 had follow-up endoscopies (Table 1), 25.7% (n = 26) of whom had mucosal healing at TURANDOT II baseline. At wk 16, 43.6% (n = 44) had mucosal healing, and 33 of these patients (75%) maintained mucosal healing up to wk 40–72. Of 65 responders in TURANDOT, 37 (56.9%) had mucosal healing at both wk 16 and wk 40–72. Of 36 non-responders, 7 (19.4%) and 9 (25%) achieved mucosal healing at wk 16 and wk 40–72, respectively (Figure 1). Of the responders, 58 (89.2%) maintained response and 27 (41.5%) were in remission at wk 16; at wk 40–72, 53 (81.5%) maintained response and 33 (50.8%) were in remission. Of non-responders, 22 (61.1%) achieved response and 5 (13.9%) achieved remission by wk 16; by wk 40–72, 17 (47.2%) had responded and 8 (22.2%) were in remission. Overall, the mean Mayo endoscopic subscore of 2 (SD, 0.1) was maintained to wk 40–72. CONCLUSION: Mucosal healing, response and remission persisted in a subset of patients who continued ontamalimab treatment up to 72 wks and underwent surveillance endoscopies between wks 40 and 72.

BACKGROUND: Treatment of ulcerative colitis (UC) aims to induce and maintain both endoscopic and symptomatic remission. While assessment of endoscopic remission is limited by timing of endoscopy, symptomatic remission can be assessed at any clinical visit, thus potentially allowing a more granular assessment of the time to onset of efficacy of a therapeutic agent. Ontamalimab (SHP647), a monoclonal IgG 2 antibody against mucosal addressin cell adhesion molecule-1, can induce endoscopic remission in patients with moderate-to-severe UC after 12 weeks of treatment (1), but its effects on symptomatic remission at earlier timepoints remain unexplored. We aimed to determine rates of clinical and symptomatic remission in patients with UC during ontamalimab induction treatment. METHODS: Two phase 2 studies (TURANDOT, NCT01620255 and TURANDOT II, NCT01771809) were conducted. Patients who completed TURANDOT, a 12-week, double-blind, placebo-controlled trial of ontamalimab (7.5, 22.5, 75 and 225 mg s.c. every 4 weeks [Q4W]), who had discontinued immunosuppressants could enter TURANDOT II, the open-label extension study. TURANDOT II consisted of two open-label periods followed by a 24-week follow-up period. At baseline (TURANDOT week 12), patients were randomized to ontamalimab 75 or 225 mg s.c. Q4W for 72 weeks. Dose escalation from 75 to 225 mg was permitted between weeks 8 and 72 in cases of clinical exacerbation or no response. Partial Mayo scores (PMS), assessed in both trials, were used to determine proportions of patients with clinical remission (PMS of ≤2 with no individual subscore >1 and a rectal bleeding [RB] subscore of ≤1) and symptomatic remission (an RB subscore of 0 and stool frequency subscore of ≤1). RESULTS: In total, 357 patients received placebo (n = 73) or ontamalimab (7.5 mg, n = 71; 22.5 mg, n = 72; 75 mg, n = 71; 225 mg, n = 70) in TURANDOT. At week 4, the proportions of patients with clinical remission were greater in the treated groups than the placebo group, particularly the 22.5 mg (difference vs placebo [90%CI] 11.2% [0.4, 21.9]) and 75 mg groups (10.3% [–0.5, 20.9]). The proportions with clinical remission at week 8 were 19.2%, 19.7%, 36.1%, 32.4% and 34.3%, and by week 12 were 16.4%, 23.9%, 40.3%, 36.6% and 25.7%, in the placebo, 7.5, 22.5, 75 and 225 mg groups, respectively. A total of 330 patients completed TURANDOT and were randomized and treated in TURANDOT II. All patients received open-label ontamalimab (75 mg, n = 164; 225 mg, n = 166) in TURANDOT II; 68 had previously received placebo, and 262 had received ontamalimab in TURANDOT. In patients who previously received placebo, there was a rapid increase in the proportion with clinical remission from baseline (75 mg, 24.2%; 225 mg, 11.4%) to week 4 (48.5%; 42.9%), week 8 (51.5%; 42.9%) and week 12 (63.6%; 57.1%). Similar patterns were observed in the results for symptomatic remission both in TURANDOT and TURANDOT II. CONCLUSION(S): The ability of ontamalimab to induce clinical and symptomatic remission is rapid and robust, as shown initially in patients in TURANDOT (particularly at doses of 22.5 and 75 mg, with differences versus placebo as early as week 4) and confirmed in those who received ontamalimab for the first time in TURANDOT II.

SHP647, a fully human IgG2 monoclonal antibody, binds to human mucosal addressin cell adhesion molecule-1 (MAdCAM-1) thus reducing lymphocyte homing to the gastrointestinal tract. Results from the Phase 2, extension study TURANDOT II (NCT01771809) showed that SHP647 was well tolerated for up to 144 weeks and resulted in continued clinical benefit in patients with moderate-to-severe ulcerative colitis (UC). This analysis from the TURANDOT II trial reports biomarker and pharmacokinetic (PK) data from the first 72 weeks of the study. TURANDOT II was a Phase 2, multi-centre, 2-part open-label (OL) study of SHP647 in patients with moderate-to-severe UC who completed TURANDOT on placebo or SHP647 7.5, 22.5, 75, or 225 mg s.c. every 4 weeks. At TURANDOT II baseline, patients were randomised to SHP647 75 or 225 mg s.c. every 4 weeks for 72 weeks (OL part 1). Dose escalation from 75 to 225 mg was permitted at the investigator’s discretion at any time from 8 to 72 weeks in the event of clinical exacerbation or no treatment response. In OL part 2, all patients received 75 mg every 4 weeks for a further 72 weeks. In OL part 1, high-sensitivity C-reactive protein (hsCRP) and faecal calprotectin (FCP) were analysed every 4 weeks until Week 24, and then at 32 and 72 weeks. Soluble MAdCAM-1 levels were measured at Weeks 0 and 16, and plasma SHP647 concentrations were measured every 4 weeks. No biomarker or PK data were collected in OL part 2. Of the 330 patients treated, 329 were included in the pharmacodynamic population (SHP647 75 mg, n = 163; SHP647 225 mg, n = 166). Two patients in the 225 mg dose group were not included in the PK population. FCP and hsCRP levels reduced consistently over the 72 weeks of OL part 1 in both dose groups (Figures 1 and 2). Mean plasma concentrations of SHP647 increased dose-dependently. Geometric mean soluble MAdCAM-1 concentrations were lower in both dose groups at Week 16 vs. baseline, with changes of –74%, –86%, and –81% in the 75 mg, 225 mg, and total groups, respectively. Figure 1. Geometric mean faecal calprotectin levels from TURANDOT II baseline (Week 12 of TURANDOT) to Week 72. Abstract OP51 – Figure 2. Geometric mean hsCRP levels over time from TURANDOT II baseline (Week 12 of TURANDOT) to Week 72. This analysis of data from the TURANDOT II study shows that SHP647 treatment is associated with a reduction in biomarkers specific to its mode of action, as well as long-term reductions in inflammatory biomarkers.

IL-22 was first detected in responders to UST at Week 4, the earliest time point in our assessment, and continued to improve through Week 8.A trend of normalization of MMPs, IL-10, and NGAL was observed in UST responders; this trend was weaker or absent in UST non-responders and PBO-treated patients.TNF was elevated in UC prior to treatment and was not normalized by UST induction therapy.Conclusions: Transcriptomic and protein analyses in this subset of patients from the phase 3 UC induction study demonstrated the suppression of IL-12 (IFNg) and Il-23 (IL-17A) pathways and normalization of the UC disease gene expression profile in response to UST.These results provide insight into the molecular mechanisms of UST efficacy.Reference: 1

Background & Aims Nonalcoholic steatohepatitis (NASH) is a chronic and severe form of nonalcoholic fatty liver disease that can progress to cirrhosis and hepatocellular carcinoma and is a risk factor for cardiovascular disease. Although NASH has no approved treatments, obeticholic acid (OCA), a synthetic bile acid and farnesoid X receptor (FXR) agonist, was shown to improve histological features of NASH and fibrosis. Considering that FXR activation influences plasma lipoprotein concentrations, the Combination OCA aNd sTatins for monitoRing Of Lipids (CONTROL) study evaluated how statins can regulate lipoprotein metabolism with OCA treatment in patients with NASH. Methods This randomized, double-blind, placebo-controlled, phase 2 study began with a 5-week screening/statin washout; 84 patients with NASH were randomly assigned (1:1:1:1) to receive placebo or 5 mg, 10 mg or 25 mg OCA once daily during the 16-week double-blind phase. Concurrent once daily atorvastatin (10 mg/days) was initiated at Week 4 with subsequent titration. Enrolled patients had biopsy-confirmed diagnosis of NASH with no evidence of hepatic decompensation. Plasma was collected to analyse lipoprotein parameters. Results At Week 4, all OCA groups had an increase from baseline in mean low-density lipoprotein cholesterol (LDLc) and mean LDL particle concentration (LDLpc), mostly owing to large, less atherogenic LDLc particles. Atorvastatin 10 mg decreased LDLc and LDLpc levels below baseline in all OCA groups by Week 8; higher doses did not provide additional clinical benefits. Conclusions The CONTROL study showed that OCA-induced increases in LDLc in patients with NASH were mitigated with atorvastatin. The combination of OCA and atorvastatin was generally safe and well tolerated (NCT02633956).

SHP647, a fully human IgG2 monoclonal antibody, binds to MAdCAM-1, reducing lymphocyte homing to the GI tract. In the TURANDOT II trial, SHP647 was well-tolerated and clinical benefit was seen up to 144 weeks in patients with moderate-to-severe ulcerative colitis (UC). This analysis reports efficacy by dose in TURANDOT II, and by prior treatment and response in the TURANDOT induction study. TURANDOT II (NCT01771809) is a Phase 2, multi-centre, two-part, open-label (OL) study of SHP647 in patients with moderate-to-severe UC who completed TURANDOT on placebo or SHP647 7.5, 22.5, 75, or 225 mg sc every 4 weeks. At TURANDOT II baseline, patients were randomised to SHP647 75 or 225 mg sc every 4 weeks for 72 weeks (OL1). Dose escalation from 75 to 225 mg was permitted at the investigator’s discretion from Week 8 to Week 72 in the case of clinical exacerbation or no response. In OL2, all patients received 75 mg every 4 weeks for 72 weeks. Mucosal healing (Mayo endoscopy subscore ≤1), clinical remission (total Mayo score ≤2 with no individual subscore >1, rectal bleed subscore ≤1) and response (based on total Mayo score) were assessed at Week 16 (centrally read endoscopy). Long-term efficacy was assessed by clinical response and remission (partial Mayo score) up to 144 weeks. In total, 330 patients were randomised and treated (SHP647 in TURANDOT, n = 262; placebo in TURANDOT, n = 68). Mucosal healing increased from 20.3% at TURANDOT II baseline (67/330) to 28.5% (94/330) at Week 16 (Figure 1a). Overall, 67 patients (20.3%) were in remission at Week 16, compared with 38 (11.5%) at baseline. Of those not in remission at the end of TURANDOT, 14.0% (41/292) had achieved remission by Week 16 of TURANDOT II—23 of these had been on SHP647 in TURANDOT (23/262; 8.8%) and 18 had been on placebo (18/68; 26.5%). Of patients with clinical response at the end of TURANDOT, 79% maintained response at Week 16; of non-responders in TURANDOT, 38% achieved response by Week 16. Figure 1b shows long-term clinical remission by partial Mayo score; clinical response showed a similar trend. Overall, the mean partial Mayo score improved from 3.8 (SD, 2.29) at TURANDOT II baseline to 1.0 (1.31) at Week 144 in patients who remained in the study (n = 127). The mean change from TURANDOT baseline to Week 144 was –4.7 (1.73). Figure 1. (a) Proportion of patients with mucosal healing at Week 16, overall and by dose and treatment arm in TURANDOT; (b) proportion of patients in clinical remission (partial Mayo score) over time. The 75 mg treatment group includes patients who escalated from SHP647 75 mg to SHP647 225 mg, as well as those who did not escalate. The 225 mg treatment group includes only patients who were assigned to receive SHP647 225 mg at the beginning of OL part 1. Patients who were missing results for the endpoint were imputed as not meeting the endpoint. Clinical remission is defined as the partial Mayo score of 2 points or lower with no individual subscore exceeding 1 point and rectal bleed subscore of 0 or 1. OL, open label. Clinical response and remission in the induction study continued in the extension study, persisting over the long term in most patients who reached these thresholds. The observed clinical benefit supports continued study of SHP647 in Phase 3 trials.

ObjectiveNeutralising pro-inflammatory interleukin-6 (IL-6) may effectively treat Crohn’s disease (CD). Effects of PF-04236921, an anti-IL-6 antibody, in adults with CD are reported.DesignParallel-group, dose-ranging, double-blind trial with 4-week screening and 12-week treatment periods. After induction, patients entered 28-week follow-up or 48-week open-label extension (OLE) with 28-week follow-up. Adults with confirmed CD and inadequate response to anti-tumour necrosis factor (TNF) therapy were included. Induction study: 249 patients randomised 1:1:1:1 to placebo, PF-04236921 10, 50 or 200 mg by subcutaneous injection on days 1 and 28. OLE study: PF-04236921 50 mg every 8 weeks up to six doses followed by 28-week follow-up.Results247 patients were randomised and received treatment in the induction study. The 200 mg dose was discontinued due to safety findings in another study (NCT01405196) and was not included in the primary efficacy analysis. Crohn’s Disease Activity Index (CDAI)-70 response rates with PF-04236921 50 mg were significantly greater than placebo at weeks 8 (49.3% vs 30.6%, P<0.05) and 12 (47.4% vs 28.6%, P<0.05) and met the primary end point. Week 12 CDAI remission rates with PF-04236921 50 mg and placebo were 27.4% and 10.9%, respectively (16.5% difference; P<0.05). 191 subjects received treatment in the OLE. Common treatment-emergent and serious adverse events in both studies included worsening CD, abdominal pain and nasopharyngitis.ConclusionsPF-04236921 50 mg induced clinical response and remission in refractory patients with moderate-to-severe CD following failure of anti-TNF therapy. GI abscess and perforation were observed, a specific focus of attention during future clinical development.Trial registration numberNCT01287897 and NCT01345318.

Background PF-00547659 is a fully human monoclonal antibody that binds to human mucosal addressin cell adhesion molecule-1 (MAdCAM-1) to selectively reduce lymphocyte homing to the intestinal tract. We aimed to assess the efficacy and safety of PF-00547659 in patients with moderate to severe ulcerative colitis.Methods This phase 2, randomised, double-blind, placebo-controlled clinical trial recruited patients aged 18-65 years from 105 centres in 21 countries, with a history (>= 3 months) of active ulcerative colitis extending more than 15 cm beyond the anal verge (with a total Mayo score >= 6 and a Mayo endoscopic subscore >= 2) who had failed or were intolerant to at least one conventional therapy. Patients were stratified by previous anti-TNF alpha treatment, and randomly assigned by a computer-generated randomisation schedule to receive a subcutaneous injection of 7.5 mg, 22.5 mg, 75 mg, or 225 mg PF-00547659 or placebo at baseline, then every 4 weeks. Patients, investigators, and sponsors were blinded to the treatment. The primary endpoint was the proportion of patients achieving remission (total Mayo score <= 2 with no individual subscore >1 and rectal bleeding subscore <= 1) at week 12. The efficacy analysis included all patients who received at least one dose of the randomised treatment; the safety analysis was done according to treatment received. All p values were one-sided and multiplicity-adjusted. This study is registered with ClinicalTrials.gov, number NCT01620255.Findings Between Nov 2, 2012, and Feb 4, 2016, we screened 587 patients; 357 were eligible and randomly assigned to receive placebo (n=73) or PF-00547659 at doses of 7.5 mg (n=71), 22.5 mg (n=72), 75 mg (n=71), or 225 mg (n=70). Remission rates at week 12 were significantly greater in three of four active-treatment groups than in the placebo group (2.7% [two of 73]): 7.5 mg (11.3% [eight of 71]), 22.5 mg (16.7% [12 of 72]), 75 mg (15.5% [11 of 71]), and 225 mg (5.7% [four of 70]). These rates corresponded to a stratum-adjusted (anti-TNF alpha-naive and anti-TNF alpha-experienced) risk difference versus placebo of 8.0% for 7.5 mg (90% CI 1.9 to 14, p=0.0425), 12.8% for 22.5 mg (5.6 to 19.9, p=0.0099), 11.8% for 75 mg (4.8 to 18.8, p=0.0119), and 2.6% for 225 mg (-1.2 to 6.4, p=0.1803). Four of 73 (5.5%) patients had a serious adverse event in the placebo group, ten of 71 (14.1%) in the 7.5 mg group, one of 70 (1.4%) in the 22.5 mg group, three of 73 (4.1%) in the 75 mg group, and three of 70 (4.3%) in the 225 mg group. No safety signal was observed for the study drug.Interpretation PF-00547659 was safe and well tolerated in this patient population, and better than placebo for induction of remission in patients with moderate to severe ulcerative colitis. The greatest clinical effects were observed with the 22.5 mg and 75 mg doses.

Monteleone G, Neurath MF, Ardizzone S, et al. Mongersen, an oral SMAD7 antisense oligonucleotide, and Crohn’s disease. N Engl J Med 2015;372:1104–1113. The efficacy of currently available drugs for the treatment of Crohn's disease remains suboptimal. Novel drugs targeting the major inflammatory pathways involved in Crohn's disease are needed. In patients with Crohn's disease, the activity of the immunosuppressive cytokine transforming growth factor (TGF)-β1 is abnormally decreased owing to increased levels of the intracellular protein SMAD7 (J Clin Invest 2001;108:601–609). Mongersen is a novel oligonucleotide that hybridizes to human SMAD7 messenger RNA. It has been developed in a modified-release tablet with a pH-dependent coating. This formulation facilitates release of the active drug primarily into the terminal ileum and right colon. The current study was conducted to further investigate the efficacy and safety of Mongersen for the treatment of active Crohn’s disease in adults (N Engl J Med 2015;372:1104–1113). This multicenter, randomized, double-blind, placebo-controlled phase II study assessed 166 patients aged 18–75 years with moderate-to-severe Crohn's disease. Patients had inflammatory lesions in the terminal ileum, right colon, or both, and had steroid-dependent or glucocorticoid-resistant disease. Patients were randomized to receive one of three doses of Mongersen (10, 40, or 160 mg/d) or placebo for 2 weeks, followed by evaluations at days 15, 28, and 84. A total of 160 patients (96.4%) completed the 2 weeks of treatment and the day 28 follow-up, and 138 patients (83.1%) completed the day 84 follow-up. The percentage of patients who were in clinical remission at day 15 (defined as a Crohn’s Disease Activity Index score of <150) and remained in remission for ≥2 weeks (primary endpoint) was significantly higher in the 160 mg (65%) and 40 mg Mongersen groups (55%) than in the 10-mg group (12%; P < .001) or the placebo group (10%; P < .001). Furthermore, at day 28, the proportions of patients with a ≥100-point decrease in Crohn’s Disease Activity Index score was significantly higher in the 160-mg group (72%), 40-mg group (58%), and 10-mg group (37%) than in the placebo group (17%). Additionally, at day 84, the percentage of patients with glucocorticoid-free remission was significantly greater in the 160-mg group than in the placebo group (67% vs 11%). In patients with baseline elevations in C-reactive protein (CRP), the rates of remission in the 160-mg and 40-mg groups were significantly greater than with placebo. However, among patients with an increased CRP at baseline, neither placebo nor Mongersen treatment significantly reduced median CRP level at days 15, 28, or 84. It is also worth noting the significant decreases in mean concentrations of interleukin-8 and tumor necrosis factor (TNF) in plasma with Mongersen 40 mg or 160 mg at days 15 and 28. Nine serious adverse events were reported in 6 patients, most of which were hospitalizations for complications or symptoms of Crohn’s disease. Overall, the authors conclude that the data from this phase II study support the efficacy of Mongersen and better define the adverse event profile, and also support proceeding to phase III studies. These findings also support earlier work showing that SMAD7 has a role in the gut inflammation involved in Crohn's disease. This is the first clinical trial of a non-TNF inhibitor with such high clinical response and remission rates since the publication of the landmark paper by Targan et al (N Engl J Med 1997;337:1029–1035) almost 20 years ago, showing a clinical response at 4 weeks in 81% of patients with Crohn’s disease given cA2 5 mg/kg. However, we must be careful not to draw definite conclusions from these phase II trial results. There can be a disconnect between clinical symptoms and mucosal lesions (Gut 2014;63:88–95). We therefore need to assess objective signs of inflammation such as CRP, fecal calprotectin, and/or endoscopy findings in Crohn’s patients treated with Mongersen in addition to assessing clinical symptoms. Mongersen treatment did not decrease median CRP levels significantly in this study, a finding also reported for vedolizumab (N Engl J Med 2013;369:711–721). This lack of effect on CRP levels may be explained by the gut specificity of this antiadhesion molecule. The gut inflammation associated with Crohn’s disease is characterized by abnormal decreases in the activity of the immunosuppressive cytokine TGF-β. In a phase I clinical trial (Mol Ther 2012;20:870–876), treatment with Mongersen reduced the percentage of inflammatory cytokine-expressing CCR9-positive T cells in the blood. Interestingly, in the current phase II trial, Mongersen reduced mean plasma concentrations of interleukin-8 and TNF-α. Hence, Mongersen should theoretically decrease both intestinal inflammation and the concentration of serum proinflammatory markers; the direct impact of Mongersen on CRP levels as well as its potential for gut specificity requires further investigation. Mucosal healing has emerged as a major therapeutic goal in Crohn’s disease in both clinical practice and clinical trials (J Crohns Colitis 2011;5:477–483). A combination of endpoints, comprising patient-reported outcomes and objective evaluation of inflammation by endoscopy, is now recommended by the US Food and Drug Administration (Gastroenterology 2015;148:37–51.e1). The lack of data on mucosal healing in the current trial limits our interpretation of the true efficacy of this new drug, although this is currently being investigated in a proof-of-concept study. Importantly, in this phase II trial, a persistent effect was observed at day 84, which is part of the induction period for Crohn’s disease medications. Data at 6 months and 1 year are needed to assess the maintenance effect of Mongersen and the optimal maintenance regimen is yet to be determined. Higher therapeutic monoclonal antibody concentrations have been associated with greater efficacy in inflammatory bowel disease (Inflamm Bowel Dis 2014;20:1288–1295), yet a phase I (Mol Ther 2012;20:870–876) pharmacokinetic analysis revealed that Mongersen was detectable in the plasma of one participant at a level only marginally above the lower limit of quantification. However, Mongersen was not measurable for the remaining patients (Mol Ther 2012;20:870–876), and data about this were not presented in the trial by Monteleone et al (J Clin Invest 2001;108:601–609). Ongoing Mongersen maintenance trials will explore the rates of loss of response and drug persistence. Moreover, the possible synergistic or additive effects of other immunosuppressive drugs, such as thiopurines, methotrexate, and biologics, on Mongersen efficacy remain unknown. In the phase II trial, a minority of patients received concomitant glucocorticoids (17%–32% of randomized patients) and/or immunomodulators (15%–29% of randomized patients). Last but not least, all drugs with proven efficacy have side effects. In the Mongersen trial, most adverse events were related to complications and symptoms of Crohn’s disease. However, phase II studies are underpowered to assess the safety profile of drugs. This aspect will need to be addressed in phase III trials and then in postmarketing studies if Mongersen is approved for the treatment of Crohn’s disease. TGF-β1 has well-established profibrogenic effects. Given its mechanism of action, Mongersen carries a theoretical risk of intestinal strictures, relatively frequent in Crohn’s disease (Gastroenterology 2010;139:1147–1155). Among the 14 patients who completed the 6-month phase I trial in Crohn’s disease and received oral Mongersen once daily for 7 days (Aliment Pharmacol Ther 2012;36:850–857), none developed small bowel strictures (assessed using small intestine contrast ultrasonography) or experienced obstructive symptoms during the study period. These results suggest that Mongersen is not associated with the formation of small bowel strictures in Crohn’s disease; long-term data in a large cohort of patients are needed to confirm these preliminary findings. Mongersen was developed in a proprietary modified-release tablet designed to deliver the active substance primarily into the lumen of the terminal ileum and right colon. Despite the advent of biologics (anti-TNF agents, vedolizumab), we are still facing significant unmet medical need in Crohn’s disease. An orally administered drug with a very favorable risk–benefit ratio such as Mongersen may change the landscape of Crohn’s disease management. The excellent data generated so far, if confirmed in future registration trials, suggest that Mongersen could be the beginning of a therapeutic revolution for Crohn’s disease.