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ARTICLE

Mongersen (GED-0301) for Active Crohn's Disease

Results of a Phase 3 Study

Sands, Bruce E. MD1; Feagan, Brian G. MD2; Sandborn, William J. MD3; Schreiber, Stefan MD, PhD4; Peyrin-Biroulet, Laurent MD, PhD5; Frédéric Colombel, Jean MD1; Rossiter, Guillermo MD6; Usiskin, Keith MD6; Ather, Shabana MPH6; Zhan, Xiaojiang PhD, MS6; D'Haens, Geert MD, PhD7

Author Information
The American Journal of Gastroenterology: May 2020 - Volume 115 - Issue 5 - p 738-745
doi: 10.14309/ajg.0000000000000493

Abstract

INTRODUCTION

Crohn's disease (CD) is a chronic, relapsing, systemic inflammatory disease that progressively damages the bowel and may become disabling (1). The inflammation associated with CD has been linked to the dysregulation of multiple interconnected immune pathways (1). An overexpression of Smad7, a key regulator of transforming growth factor (TGF)-β1, has been found in the inflamed intestinal mucosa of patients with CD (2).

GED-0301 (mongersen) is an antisense oligodeoxynucleotide that is complementary to the sequence of the messenger RNA transcript of Smad7 (3). Orally administered GED-0301 is formulated as a gastro-resistant, delayed-release, pH-dependent tablet designed to deliver the active substance in the distal small intestine with negligible systemic exposure.

GED-0301 was shown to improve colitis induced by trinitrobenzene sulfonic acid or oxazalone in animal models in preclinical studies (4) and was reported to improve the symptoms of CD in early-phase studies (2,3,5). In functional studies using mucosal samples from patients with CD, blocking Smad7 with GED-0301 restored TGF-β1 signaling and thereby decreased proinflammatory cytokine production (2). In a phase 2, placebo-controlled study, a significantly higher proportion of patients with active CD achieved clinical remission with GED-0301 at the160-mg (65%) and 40-mg (55%) doses vs placebo (10%; P < 0.001 for each dose vs placebo) (5). In addition, a phase 1b blinded, non–placebo-controlled study in 63 patients demonstrated decreases in CD Activity Index (CDAI) scores (mean changes ranging from −112 to −133 points). A total of 48% (10/21) of patients achieved clinical remission, and 37% (19/52) of patients with evaluable endoscopy achieved ≥25% reduction from baseline in the endoscopy score at week 12 (3). A total of 15% (8/52) of patients achieved ≥50% reduction in the endoscopy score from baseline to week 12 (3). Here, we report the results of a phase 3 study to assess further the efficacy and safety of GED-0301 in patients with active CD.

METHODS

Study design

This phase 3, multicenter, randomized, double-blind, placebo-controlled study was conducted across 34 countries in Asia Pacific, Eastern Europe, North America, and Western Europe. The efficacy and safety of 3 oral treatment regimens for GED-0301 compared with placebo were evaluated in patients with active CD (Figure 1). Patients were randomized (1:1:1:1) to receive (i) placebo once daily through week 52; (ii) GED-0301 160 mg once daily for 12 weeks, followed by GED-0301 40 mg once daily through week 52; (iii) GED-0301 160 mg once daily for 12 weeks, followed by placebo once daily for 4 weeks and then alternating GED-0301 40 mg once daily for 4 weeks and placebo once daily for 4 weeks through week 52; or (iv) GED-0301 160 mg once daily for 12 weeks, followed by placebo once daily for 4 weeks and then alternating GED-0301 160 mg once daily for 4 weeks and placebo once daily for 4 weeks through week 52. This study was performed in accordance with the ethical principles of the Declaration of Helsinki and is consistent with International Conference on Harmonisation/Good Clinical Practice and applicable regulatory requirements. The clinical study protocol and amendment were approved by Independent Ethics Committees.

Figure 1
Figure 1:
Study design. IP, investigational product; q.d., once daily; R, randomization.

Patients were stratified by baseline concomitant use of corticosteroids (yes/no), concomitant use of immunosuppressants (i.e., azathioprine, 6-mercaptopurine, or methotrexate) (yes/no), and previous exposure to biologics (i.e., infliximab, adalimumab, certolizumab, or vedolizumab) (yes/no) through an interactive response technology system.

Patients who had a CDAI score of ≥180 and did not achieve or maintain a reduction of ≥70 points in the CDAI score from baseline for 2 consecutive study visits at least 14 days apart between the week 12 and week 52 visits met the criteria for early escape and could (i) continue in the study at the discretion of the investigator based on the totality of the clinical data, (ii) enter the long-term active-treatment study (GED-0301-CD-004), or (iii) discontinue the study.

Patient population

This phase 3 study included men and women aged 18 years and older diagnosed with CD at least 3 months before screening; patients were required to have active CD at the time of screening, defined as a CDAI score of ≥220 and ≤450 and a 7-day average daily stool frequency ≥3.5 or abdominal pain score ≥1.5 at screening. In addition, patients underwent a baseline ileocolonoscopy and were required to have a total Simple Endoscopic Score for Crohn's Disease (SES-CD) of ≥6 (or an ileum segmental SES-CD of ≥4 if they had only ileal disease, targeted to be no more than approximately 20% of the population) at screening and therapeutic failure or intolerance to at least one of the following: budesonide, systemic corticosteroids, immunosuppressants, or biologics for the treatment of CD. The total number of patients with previous exposure to biologics (no more than 3 were allowed per protocol) was targeted to comprise approximately 35% of the study population.

Patients were excluded if they had a diagnosis of ulcerative colitis or indeterminate or ischemic colitis; surgical resection within the past 6 months or intra-abdominal surgery within the past 3 months; or presence of symptomatic fibrotic or obstructive strictures. A prespecified period for patients who discontinued previous treatment for CD was required before screening.

Medications for CD permitted during the study included stable doses of aminosalicylates, corticosteroids (prednisone ≤20 mg/day or equivalent and budesonide ≤9 mg/day), or immunosuppressants (azathioprine, 6-mercaptopurine, or methotrexate). Although not mandatory, a corticosteroid-tapering schedule was allowed after week 12 as per the protocol, to be managed by the investigator.

Efficacy and safety assessments

Efficacy assessments included clinical, endoscopic, and patient-reported outcomes, including CDAI, frequency of liquid/soft stools and abdominal pain, and ileocolonoscopy for centrally read SES-CD. Patients recorded daily CD activity in an electronic diary device; entries could not be modified once entered. Diary data were used for calculation of CDAI and patient-reported outcome efficacy parameters. Recorded information included number of liquid/soft stools per 24 hours, abdominal pain/cramps, general well-being, fever >100 °F, and use of antidiarrheal medications.

The primary endpoint was the proportion of patients achieving clinical remission, defined as a CDAI score of <150 at week 12. Prespecified secondary endpoints included the proportion of patients achieving clinical remission (CDAI score of <150) at week 52; the proportion of patients with endoscopic response (ER)-50, defined as a ≥50% reduction from baseline to week 52 in the centrally read SES-CD; the proportion of patients who had a clinical response, defined as a decrease from baseline in the CDAI score of ≥100 points, at week 12; and the proportion of patients with ER-25, defined as ≥25% reduction from baseline to week 12 in the centrally read SES-CD. Exploratory efficacy endpoints included the proportion of patients who had a clinical response (decrease in the CDAI score of ≥100 points) at each time point through week 52 and the proportion of patients with ER-50 at week 12. In addition, changes in high-sensitivity C-reactive protein (hsCRP) and fecal calprotectin (FCP) at week 12 were assessed as exploratory biomarker endpoints. Subgroup analyses of the primary endpoint were also conducted to assess treatment effect by baseline demographics, disease characteristics, and medication use.

Safety assessments included collection of adverse events (AEs) and discontinuations due to AEs, as well as clinical laboratory testing, vital signs, physical examination, and electrocardiogram findings.

Statistical analyses

Efficacy endpoints were based on the intent-to-treat population, which included all patients who were randomized and received at least 1 dose of study medication. Missing data for the primary endpoint and other binary efficacy endpoints were handled using the nonresponder imputation method. Because the study was terminated early, the denominator for all binary efficacy endpoints at the time point under consideration included patients who had either completed that time point (determined by the presence of a record for the time point in the clinical database of patient visits) or discontinued at any time due to reasons other than “study terminated by sponsor,” instead of all patients included in the intent-to-treat population.

Because all patients randomized to a GED-0301 treatment group received GED-0301 160 mg once daily for the first 12 weeks, treatment comparisons for endpoints at week 12 were made between the pooled GED-0301 total group and placebo. For endpoints at week 52, treatment comparisons were made between each of the 3 individual GED-0301 treatment groups and placebo. Binary efficacy endpoints were analyzed by the Cochran-Mantel-Haenszel test stratified by the randomization stratification factors. Stratified treatment differences in proportions were calculated as the weighted average of the treatment differences across the strata using the Cochran-Mantel-Haenszel weights. We estimated a sample size of 1,064 (GED-0301 160 mg once-daily group: n = 798; placebo group: n = 266) would yield 99% power to detect a 14% difference (36% vs 22%) between GED-0301 160 mg once daily and placebo in the proportion of patients achieving the primary endpoint of the CDAI score of <150 at week 12, based on a 2-sided significance level of 0.05.

Cumulative and interval-blinded AEs, serious AEs, discontinuations due to AEs, and abnormal laboratory findings were reviewed by the sponsor's internal safety management team on a regular basis. An external, independent data monitoring committee (DMC) was empaneled before the start of the phase 3 program to oversee the safety and efficacy of the clinical studies and ensure an acceptable benefit to risk ratio. The DMC review of unblinded data and statistical analyses of the futility of this study to meet its primary and key objectives led to a recommendation by the DMC to terminate this study early. After this recommendation, this study was terminated by the sponsor on October 19, 2017.

RESULTS

Patients

A total of 701 patients were randomized and received at least 1 dose of study medication and were included in the intent-to-treat and safety populations. Planned enrollment for the study was 1,064 patients; however, based on a recommendation by the DMC, the study was prematurely halted because of lack of clinical benefit. A total of 78.6% (551/701) of patients completed week 12 and 5.8% (41/701) of patients completed week 52. A total of 8.3% (58/701) of patients were discontinued before week 12 because of study termination by the sponsor (Figure 2). During weeks 0–12, the most frequent reasons for discontinuation other than study termination by the sponsor were AEs, lack of efficacy, and withdrawal by patient. More AEs led to discontinuation before week 12 in the active treatment groups vs the placebo group.

Figure 2
Figure 2:
Patient disposition through week 52 (safety population). aIncludes pregnancy, withdrawal by patient, lost to follow-up, protocol violation, noncompliance, and other. One additional death (not shown here) occurred in a patient after discontinuation due to AE. A total of 8.3% (58/701) of patients were discontinued before week 12 because of study termination by sponsor. AE, adverse event.

Baseline patient demographics and disease characteristics were comparable across treatment arms (Table 1). In the overall population, 49.4% of patients were female, and the mean age was 38.5 years; mean duration of CD was 9.5 years. In accordance with the predefined target, 20.5% of patients had disease in the ileum only, while 33.4% had disease in the colon only, and 46.1% had disease located in both the ileum and colon. In addition, 55.3% of patients exhibited extraintestinal manifestations, with peripheral arthropathy being the most common (37.8%). The mean CDAI score at baseline was 304.7 (range: 133–511), and the mean SES-CD at baseline was 14.2 (range: 3–45).

Table 1
Table 1:
Baseline patient demographics and disease characteristics

Efficacy

Primary endpoint.

Achievement of clinical remission, defined as the CDAI score of <150, at week 12 was similar between the GED-0301 total group (160 mg once daily, pooled across all 3 dose regimen groups) and placebo (22.8% vs 25.0%; P = 0.6210) (Figure 3). Analyses of treatment effect by subgroup did not reveal any significant differences in this endpoint based on baseline patient demographics, clinical characteristics, or medication use, including previous exposure to biologic agents (see Figure, Supplementary Digital Content 1, http://links.lww.com/AJG/B341).

Figure 3
Figure 3:
Proportion of patients achieving clinical remission, defined as a CDAI score of <150, at week 12 (intent-to-treat population, nonresponder imputation). Bars represent SE. CDAI, Crohn's Disease Activity Index.

Secondary endpoints.

At the time of study termination, the proportions of patients who achieved clinical remission at week 52 were similar among the individual GED-0301 treatment groups and placebo (see Table, Supplementary Digital Content 1, http://links.lww.com/AJG/B341). Likewise, similar proportions of patients receiving placebo had an ER-50 at week 52 compared with the GED-0301 treatment groups, although the patient numbers were very small in all groups (see Table, Supplementary Digital Content 1, http://links.lww.com/AJG/B341).

A greater proportion of patients in the placebo group compared with the GED-0301 total group had a clinical response (decrease from baseline in the CDAI score of ≥100 points) at week 12 (44.4% vs 33.3%) (Figure 4). Similar proportions of patients in the GED-0301 total group and the placebo group had an ER-25 at week 12 (Figure 5a).

Figure 4
Figure 4:
Proportion of patients achieving clinical response, defined as a decrease from baseline in the CDAI score of ≥100, at week 12 (intent-to-treat population, nonresponder imputation). Bars represent SE. CDAI, Crohn's Disease Activity Index.
Figure 5
Figure 5:
Endoscopic response at week 12: SES-CD reduction by (a) ≥ 25% and (b) ≥50% (intent-to-treat population, nonresponder imputation). Bars represent SE. SES-CD, Simple Endoscopic Score for Crohn's Disease.

Exploratory endpoints.

The proportion of patients achieving an ER-50 at week 12 was greater in the placebo group compared with the GED-0301 total group (18.1% vs 10.1%) (Figure 5b). At the time of study termination, the proportions of patients who achieved clinical response at week 52 were similar among the GED-0301 treatment groups and placebo (see Table, Supplementary Digital Content 1, http://links.lww.com/AJG/B341).

Biomarker assessments

Overall, markers of inflammation, such as hsCRP and FCP, did not suggest a difference between placebo and GED-0301, consistent with the clinical and endoscopic assessments.

Safety

During weeks 0–12, 60.7% of patients in the GED-0301 total group and 57.5% in the placebo group reported treatment-emergent adverse events (TEAEs) (Table 2). The most frequently reported TEAEs (≥5% in placebo or GED-0301 total group) were arthralgia, exacerbation of CD, abdominal pain, viral upper respiratory tract infection, and pyrexia. Arthralgia and pyrexia occurred more frequently in the GED-0301 total group than in the placebo group. Incidence of serious TEAEs was 9.3% in the GED-0301 total group and 6.3% in the placebo group (Table 3). An increased frequency was observed in TEAEs related to underlying CD. Two deaths occurred in the GED-0301 total group due to small intestinal obstruction and pneumonia; neither death was suspected by the investigator to be treatment-related (Table 2).

Table 2
Table 2:
TEAEs during weeks 0–12
Table 3
Table 3:
Serious TEAEsa in ≥2 patients during weeks 0–12

Over the entire study (weeks 0–52), 70.2% of the GED-0301 total group and 71.3% of the placebo group reported a TEAE. The most frequently reported TEAEs (≥5% in any treatment group) were arthralgia, exacerbation of CD, abdominal pain, upper respiratory tract infection, pyrexia, headache, nausea, and diarrhea. Serious TEAEs were reported by 8.6%–15.9% of patients across GED-0301 treatment groups, with CD being the most commonly reported serious TEAE; 9.2% of the placebo group reported serious TEAEs during weeks 0–52. No meaningful safety signals were identified; AEs and serious AEs in the gastrointestinal system were predominant and consistent with the presence of active CD in the study population.

DISCUSSION

In this large phase 3, randomized, double-blind, placebo-controlled trial, GED-0301 (mongersen), an oral antisense oligodeoxynucleotide directed against Smad7, was not effective in patients with active CD. With nearly 70% of the planned enrollment of 1,064 patients randomized into the trial, the independent external DMC recommended terminating the study early based on review of the efficacy and safety data. This analysis demonstrated futility based on a low likelihood of achieving the primary outcome of clinical remission with continued enrollment. Secondary outcomes, including clinical response and ER, showed the same pattern. These results were unexpected, given the promising results with GED-0301 in a placebo-controlled phase 2 study. In that study, 55% of patients assigned to GED-0301 40 mg and 65% assigned to GED-0301 160 mg achieved clinical remission at day 15 compared with 10% of those assigned to placebo (5). Therefore, we sought to understand the factors that may have contributed to the lack of efficacy observed with GED-0301 in our study.

First, we confirmed that study material contained active drug. The sponsor retrieved representative study drug kits from sites worldwide in the trial. All retrieved kits were tested for identity of investigational product (active GED-0301 or placebo) and were found to be 100% accurate. In addition, release specifications for dissolution and purity of GED-0301 were met for drug substance and product manufacturing and were consistent with earlier clinical trials.

We also considered whether differences in the study population might have accounted for lack of efficacy in this study. GED-0301 is formulated to release and deliver in the distal small intestine. The phase 2 study did not require endoscopy for enrollment and excluded patients with a history of disease involving the transverse or left colon (5), in contrast to this study, which included patients with active ulceration observed in the terminal ileum and/or colon on ileocolonoscopy regardless of the location, provided that a minimum SES-CD of ≥6, or ≥4 for those with disease of the ileum only, was found at screening. As we did not directly assay the drug concentration in tissue in this study, we were unable to determine whether inadequate tissue concentrations in the distal colon may have accounted for the lack of efficacy. There was a numerically greater, but not significant, number of patients with clinical remission treated with GED-0301 vs placebo who had right-sided disease, although not of the magnitude seen in the previous phase 2 trial. Moreover, this was not accompanied by mucosal improvement in the endoscopic scores observed in the ileum or colon. Consistent with these assessments, we also did not observe a difference in markers of inflammation, such as hsCRP and FCP, between placebo and GED-0301. Although the phase 2 study showed strong differentiation between GED-0301 and placebo in clinical endpoints in patients with CD, it did not assess ER (5).

In addition, our study included approximately 50% of patients with previous exposure to biologic agents. Generally, studies with other agents have demonstrated lower rates of response and remission with study treatment among patients with previous exposure to biologic agents, as well as lower placebo rates for these outcomes (6). However, in this study, outcomes among biologic-naive patients assigned to GED-0301 were similar to outcomes with placebo, too. Further subset analyses explored subgroups defined by baseline characteristics, including body weight, age, gender, previous surgery, previous and concomitant corticosteroids, and immunomodulators, as well as baseline disease activity, endoscopic activity, and biomarkers. Benefit with GED-0301 was not apparent in any of these subgroups.

A limitation of the study was the lack of mucosal biopsies to assess histologic changes or tissue concentration of GED-0301.

In conclusion, GED-0301 was not effective for the treatment of active CD. We were unable to determine whether the observed lack of efficacy was due to inadequate colonic or ileal tissue concentration, the intended pharmacodynamic action, or the patient population.

CONFLICTS OF INTEREST

Guarantor of the article: Bruce E. Sands, MD.

Specific author contributions: B.E.S. was involved in the study concept and design, acquisition of data, analysis and interpretation of data, and development of the manuscript. B.G.F., W.J.S., S.S, L.P.-B., J.F.C., and G.D.'H. were involved in the acquisition of data, analysis and interpretation of data, and development of the manuscript. G.R., K.U., S.A., and X.Z. were involved in the analysis and interpretation of data and development of the manuscript. All authors approved the final submitted draft of the manuscript.

Financial support: This study was sponsored by Celgene Corporation (Summit, NJ). The named authors, which included Celgene Corporation employees, were involved in the study design; in the collection, analysis, and interpretation of data; in writing the report; and in the decision to submit the article for publication. Kristin Carlin, RPh, MBA, of Peloton Advantage, LLC, an OPEN Health company (Parsippany, NJ) provided editorial support, which was in accordance with Good Publication Practice (GPP3) guidelines and funded by Celgene Corporation (Summit, NJ). The authors, however, directed and are fully responsible for all content and editorial decisions for this manuscript.

Potential competing interests: B.E.S. has received personal fees for consulting from AbbVie, Akros Pharma, Allergan, Amgen, Arena Pharmaceuticals, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, EnGene, Forward Pharma, Immune Pharmaceuticals, Ironwood Pharmaceuticals, Lycera, Lyndra, Receptos, Shire, Synergy Pharmaceuticals, Target PharmaSolutions, Theravance Biopharma R&D, TiGenix, TopiVert Pharma, and Salix; grants, personal fees, and nonfinancial support from Celgene Corporation, Janssen, Pfizer, and Takeda; and personal fees and nonfinancial support from 4D Pharma, Capella Bioscience, Ferring, Gilead, Hoffmann-La Roche, Lilly, MedImmune, Oppilan Pharmaceuticals, Otsuka, Palatin Technologies, Prometheus Laboratories, Protagonist Therapeutics, Rheos Medicines, Seres Therapeutics, UCB Pharma, and Vivelix Pharmaceuticals. B.G.F. has received grant/research support from AbbVie, Amgen, AstraZeneca/MedImmune, Atlantic Pharmaceuticals, Boehringer Ingelheim, Celgene Corporation, Celltech, Genentech/Hoffmann-La Roche, Gilead, GlaxoSmithKline, Janssen, Pfizer, Receptos/Celgene International, Sanofi, Santarus, Takeda, Tillotts Pharma, and UCB Pharma; has served as a consultant for Abbott/AbbVie, Actogenix, Akros, Albireo Pharma, Allergan, Amgen, AstraZeneca, Avaxia Biologics, Avir Pharma, Axcan, Baxter, Biogen Idec, Boehringer Ingelheim, Bristol-Myers Squibb, Calypso Biotech, Celgene Corporation, Centocor, Elan/Biogen, EnGene, Ferring, GiCare Pharma, Gilead, Given Imaging, GlaxoSmithKline, Inception IBD, Ironwood Pharma, Janssen Biotech, J&J/Janssen, Kyowa Kakko Kirin, Lexicon, Lilly, Lycera BioTech, Merck, Mesoblast Pharma, Millennium, Nektar, Novo Nordisk, Pfizer, Prometheus, Protagonist, Receptos, Roche/Genentech, Salix, Serono, Shire, Sigmoid Pharma, Synergy Pharma, Takeda, Teva, TiGenix, Tillotts Pharma, UCB Pharma, Vertex, VHsquared, Warner-Chilcott, Wyeth, Zealand Pharma, and Zyngenia; and has served as a speaker for Abbott/AbbVie, Amgen, AstraZeneca, Avaxia Biologics, Bristol Myers Squibb, Celgene Corporation, Centocor, Elan/Biogen, Ferring, J&J/Janssen, Merck, Novartis, Novo Nordisk, Pfizer, Prometheus, Protagonist, Salix, Takeda, Teva, TiGenix, Tillots Pharma, and UCB Pharma. W.J.S. reports research grants from AbbVie, Amgen, Atlantic Healthcare Limited, Celgene Corporation/Receptos, Eli Lilly, Genentech, Gilead, Janssen, and Takeda; consulting fees from AbbVie, Allergan, Amgen, Arena Pharmaceuticals, Avexegen Therapeutics, BeiGene, Boehringer Ingelheim, Celgene Corporation, Celltrion, Conatus, Cosmo, Eli Lilly, Escalier Biosciences, Ferring, Forbion, Genentech, Gilead, Gossamer Bio, Incyte, Janssen, Kyowa Kirin Pharmaceutical Research, Landos Biopharma, Oppilan Pharma, Otsuka, Pfizer, Precision IBD, Progenity, Prometheus, Reistone, Ritter Pharmaceuticals, Robarts Clinical Trials (owned by Health Academic Research Trust, HART), Series Therapeutics, Shire, Sienna Biopharmaceuticals, Sigmoid Biotechnologies, Sterna Biologicals, Sublimity Therapeutics, Takeda, Theravance Biopharma, Tigenix, Tillotts Pharma, UCB Pharma, Ventyx Biosciences, Vimalan Biosciences, and Vivelix Pharmaceuticals; and stocks or stock options in BeiGene, Escalier Biosciences, Gossamer Bio, Oppilan Pharma, Precision IBD, Progenity, Ritter Pharmaceuticals, Ventyx Biosciences, and Vimalan Biosciences. S.S. reports personal fees from AbbVie, Arena, Bristol-Myers Squibb, Biogen, Celgene Corporation, Celltrion, Falk, Fresenius, Gilead, IMAB, Janssen, Merck Sharp & Dohme, Mylan, Pfizer, Protagonist, Provention Bio, Takeda, and Theravance. L.P.-B. has received honoraria from AbbVie, Allergan, Alma, Amgen, Arena, Biogen, Boehringer Ingelheim, Celgene Corporation, Celltrion, Enterome, Ferring, Genentech, Gilead, Hikma, Index Pharmaceuticals, Janssen, Merck Sharp & Dohme, Nestle, Pfizer, Pharmacosmos, Roche, Samsung Bioepis, Sandoz, Stema, Takeda, and Tillots; grant/research support from AbbVie, Merck Sharp & Dohme, and Takeda; and stock options in CTMA. J.F.C. has served as a consultant, advisory board member, and speaker for AbbVie, Bristol-Myers Squibb, Ferring, Genentech, Guiliani, Given Imaging, Merck, Millennium, Pfizer, Prometheus, Sanofi, Schering Plough, Takeda, Teva, and UCB Pharma. G.R. was an employee of Celgene Corporation at the time of the study conduct. K.U., S.A., and X.Z. are employees of Celgene Corporation. G.D.'H. is a consultant for AbbVie, Ablynx, Allergan, Alphabiomics, Amakem, Amgen, AM Pharma, Arena, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene Corporation/Receptos, Celltrion, Echo Pharmaceuticals, Eli Lilly, Engene, Ferring, Dr. Falk Pharma, Galapagos, Genentech/Roche, Gilead, GlaxoSmithKline, Gossamerbio, Hospira/Pfizer, Immunic, Johnson & Johnson, Kintai Therapeutics, Medtronics, Merck Sharp & Dohme, Millennium/Takeda, Mitsubishi Pharma, Mundipharma, Nextbiotics, Pfizer, Prodigest, Progenity, Prometheus /Nestle, Protagonist, Robarts Clinical Trials, Samsung Bioepis, Sandoz, Seres/Nestle, Setpoint, Shire, Teva, Tigenix, Tillotts, Topivert, Versant, and Vifor.

Data sharing: Celgene is committed to responsible and transparent sharing of clinical trial data with patients, healthcare practitioners, and independent researchers for the purpose of improving scientific and medical knowledge as well as fostering innovative treatment approaches. For more information, please visit: https://www.celgene.com/research-development/clinical-trials/clinical-trials-data-sharing/.

Clinical trial registration:ClinicalTrials.gov identifier: NCT02596893.

Study Highlights

WHAT IS KNOWN

  • ✓ GED-0301 is an orally administered antisense oligodeoxynucleotide to Smad 7 that is overexpressed in intestinal mucosa in CD.
  • ✓ Two preliminary studies supported the clinical benefit of GED-0301 in patients with active CD.
  • ✓ In a placebo-controlled study, significantly higher proportions of patients achieved clinical remission with GED-0301 vs placebo.

WHAT IS NEW HERE

  • ✓ This phase 3 study failed to demonstrate a clinical benefit for GED-0301 vs placebo.
  • ✓ Proportions of patients achieving clinical remission at week 12 were similar between GED-0301 160 mg and placebo.
  • ✓ Clinical response (≥100-point decrease in the CDAI score), endoscopic findings, and inflammatory biomarkers did not show benefit.

REFERENCES

1. Torres J, Mehandru S, Colombel JF, et al. Crohn's disease. Lancet 2016;389:1741–55.
2. Monteleone G, Kumberova A, Croft NM, et al. Blocking Smad7 restores TGF-β1 signaling in chronic inflammatory bowel disease. J Clin Invest 2001;108:601–9.
3. Feagan BG, Sands BE, Rossiter G, et al. Effects of mongersen (GED-0301) on endoscopic and clinical outcomes in patients with active Crohn's disease. Gastroenterology 2018;154:61–4.
4. Boirivant M, Pallone F, Di Giacinto C, et al. Inhibition of Smad7 with a specific antisense oligonucleotide facilitates TGF-β1-mediated suppression of colitis. Gastroenterology 2006;131:1786–98.
5. Monteleone G, Neurath MF, Ardizzone S, et al. Mongersen, an oral SMAD7 antisense oligonucleotide, and Crohn's disease. N Engl J Med 2015;372:1104–13.
6. Sands BE, Sandborn WJ, Van Assche G, et al. Vedolizumab as induction and maintenance therapy for Crohn's disease in patients naive to or who have failed tumor necrosis factor antagonist therapy. Inflamm Bowel Dis 2017;23:97–106.

Supplemental Digital Content

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