Impact of patient characteristics on the clinical efficacy of mongersen (GED-0301), an oral Smad7 antisense oligonucleotide, in active Crohn’s disease

Significance Statement

Crohn’s disease (CD) is a chronic condition characterized by segmental, transmural inflammation, which, although most common in the terminal ileum and right colon, can affect any part of the alimentary tract. In addition to the commonly observed signs and symptoms of Crohn’s disease, local complications as well as manifestations outside the digestive tract can also occur as a result of Crohn’s disease -associated inflammation, underscoring the importance of effective treatment options.

Subgroup analyses from prospective, randomised, controlled trials in patients with active Crohn’s disease have shown that patient demographics and disease characteristics such as disease duration and treatment history can impact clinical outcomes. Our retrospective study further evaluated the impact of patient baseline clinical and disease characteristics on the efficacy of mongersen, an oral, locally active Smad7 antisense oligonucleotide that targets Smad7 in the ileum and colon. In addition to the impact of human serum C-reactive protein (hsCRP) values, disease duration, and disease activity at baseline on mongersen over 10 weeks, our analysis also looked at how sex, body mass index, smoking status, history of Crohn’s disease-related intestinal resection, steroid status, and immunosuppressant use at baseline impacted treatment efficacy.

Our results showed that patients with Crohn’s Disease Activity Index (CDAI) scores ≤260 at baseline had significantly higher clinical remission rates (defined as a CDAI <150) with mongersen 40 mg/day and 160 mg/day treatment, whereas patients with CDAI scores >260 at baseline achieved clinical remission most frequently with the highest mongersen dose (160 mg/day), suggesting that greater disease activity can impact clinical benefit. Baseline disease characteristics such as hsCRP (<3 mg/L or ≥3 mg/L) and disease duration (<5 or ≥5 years) did not appear to significantly impact efficacy of mongersen treatment in our study.

About the author

Giovanni Monteleone received his medical degree from the University Magna Graecia of Catanzaro (Italy) and completed his internship, residency, and a fellowship in gastroenterology at the same university. He joined the faculty at the University of Rome Tor Vergata in 2003, becoming an Assistant Professor of Gastroenterology, then Professor of Gastroenterology. He is the Head of Gastroenterology Unit at the Policlinico Tor Vergata in Rome. Dr. Monteleone’s basic research is mostly focused on mechanisms involved in the control of mucosal immune homeostasis and inflammatory signals that sustain and amplify pathological processes in the gastrointestinal tract. In particular, he is interested in understanding how immune cells and non-immune cells cross-talk in the gastrointestinal mucosa and which molecules mediate such an interplay. So far, these studies have contributed to delineate novel pathways of intestinal mucosal damage and paved the way for the development of anti-inflammatory compounds, which are now ready to move into the clinic. Dr. Monteleone is also interested in the immune-inflammatory networks involved in the colitis-associated colon carcinogenesis. He is author of >300 peer-reviewed articles, books, and book chapters, and serves as an editorial board member or a reviewer for several journals.

Journal Reference

Aliment Pharmacol Ther. 2016 ;43(6):717-24.

Monteleone G¹, Di Sabatino A², Ardizzone S³, Pallone F¹, Usiskin K⁴, Zhan X⁴, Rossiter G⁴, Neurath MF⁵.

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Department of Systems Medicine, University of Tor Vergata, Rome, Italy.
First Department of Internal Medicine, St. Matteo Hospital Foundation, University of Pavia, Pavia, Italy.
Department of Surgery, “L. Sacco” University Hospital, Milan, Italy.
Celgene Corporation, Warren, NJ, USA.
Department of Medicine, University of Erlangen-Nürnberg, Erlangen, Germany.

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Abstract

BACKGROUND:

In a phase 2 study, mongersen, an oral antisense oligonucleotide targeting Smad7, was effective in inducing clinical remission in approximately 60% of patients with active Crohn’s disease (CD).

AIM:

In a post hoc analysis to evaluate those patient disease characteristics that may have influenced the efficacy and safety of mongersen therapy.

METHODS:

Patients with steroid-dependent/resistant, active Crohn’s disease were randomised to mongersen 10, 40 or 160 mg/day or placebo for 2 weeks; patients were followed for 10 weeks. Clinical remission [Crohn’s Disease Activity Index (CDAI) score <150] and clinical response (CDAI score reduction ≥100 points) were assessed at weeks 2, 4 and 12 for these subgroups: disease duration <5/≥5 years, human serum C-reactive protein (hsCRP) <3/≥3 mg/L, and CDAI at baseline ≤260/>260. Additional patient baseline and disease characteristics were explored.

RESULTS:

Clinical remission and response rates were significantly higher in patients receiving mongersen 40 and 160 mg/day but not 10 mg/day vs. placebo and independent of disease duration and hsCRP. Patients with baseline CDAI ≤260 had significantly higher remission rates with 40 and 160 mg/day. In patients with baseline CDAI >260, remission rates were statistically greater with 160 mg/day and numerically better with 40 mg/day vs. placebo. Adverse event rates were similar across treatment groups. Mongersen was safe and well tolerated.

CONCLUSIONS:

Patients with higher CDAI scores achieved clinical remission most frequently with the highest mongersen dose. Disease duration and baseline human serum C-reactive protein did not appear to significantly impact efficacy of mongersen in this study (EudraCT Number: 2011-002640-27.).

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