Mongersen (GED-0301) is an antisense oligodeoxynucleotide that is complementary to the sequence of the messenger RNA transcript of Smad7. It is formulated as a gastro-resistant, delayed-release, pH-dependent tablet designed to deliver the active substance in the distal gastrointestinal tract with negligible systemic exposure. Clinical efficacy has been demonstrated in a phase 2 study.1 The intent of this phase 1b study is to examine endoscopic improvement and clinical benefit with 3 different mongersen treatment regimens in subjects with Crohn's disease (CD).Methods:
Subjects with active CD (Crohn's Disease Activity Index [CDAI] score of 220 to 450, total simple endoscopic score for CD [SES-CD] of ≥7, or ileal disease SES-CD of ≥4) were randomized to 4, 8, or 12 weeks of mongersen 160 mg daily, followed by an observation period without study drug. Endoscopic and clinical assessments are reported through week 12. Endoscopic assessments at baseline and week 12 were centrally read. Daily electronic diary records were used to collect CD symptoms, including abdominal pain (AP; 4-point scale) and soft/loose stool frequency (SF); clinical evaluation occurred at monthly visits.Results:
A total of 63 subjects were enrolled. At baseline, mean age was 41.5 years, mean SES-CD was 11.2, and mean CDAI score was 294. Mean average daily AP and SF scores were 1.8 and 5.4, respectively. Mean CD duration was 11.6 years, with 46% having had prior exposure to tumor necrosis factor (TNF)-α therapy; 46% of subjects had involvement distal to the mid-transverse colon. A total of 52 subjects had evaluable endoscopies at week 12. Of these subjects, 37% had an endoscopic response, defined as ≥25% reduction in SES-CD from baseline to week 12, with no meaningful difference across treatment groups. Of the subjects with greater endoscopic disease activity at baseline (SES-CD >12), 63% had a reduction ≥25%. Clinical remission, as defined by AP and SF scores of ≤1 and ≤3, respectively, was seen in all treatment groups. Improvement of individual components for AP and SF was seen by week 2 and maintained or increased through week 12. The highest clinical remission rates (43% at week 12) were seen in the 12-weeks treatment group. Similar patterns were seen when clinical remission was defined using CDAI criteria (score <150). Further analysis of clinical improvement showed benefit among subjects who had greater baseline disease severity based on SES-CD (>12) and CDAI score (>300), as well as among TNF-α exposed subjects. The adverse event (AE) and serious AE rates were low and similar across treatment groups. Mongersen was generally safe and well tolerated with no new safety signals emerging.Conclusions:
Oral mongersen resulted in meaningful endoscopic and clinical improvement at an early time point (12 weeks) for subjects with active CD.