Background: Mongersen (GED-0301), an antisense oligodeoxynucleotide complementary to the sequence of Smad7 mRNA, is being evaluated for the treatment (tx) of patients (pts) with active Crohn's disease (CD) (Monteleone et al. N Engl J Med 2015;372:1104–13). It is formulated as a gastro-resistant, delayed-release, pH-dependent tablet that delivers active substance to the distal GI tract with negligible systemic exposure. We explored the correlation between clinical and endoscopic indices in a phase 1b study.
Methods: Pts with active CD (CD Activity Index score [CDAI] = 220–450, total simple endoscopic score for CD [SES-CD] ≥7, or ileal disease SES-CD ≥4) were randomised to 4, 8, or 12 wks of oral mongersen 160 mg daily, followed by an observation period without study drug. Centrally read endoscopic assessments were performed at baseline (BL) and Wk 12. Daily electronic diary records were used to collect CD symptoms; a clinical evaluation, including CDAI determination, occurred at monthly visits through Wk 12.
Results: 63 pts were enrolled; at BL, mean age was 41.5 yrs, mean SES-CD was 11.2, mean CDAI was 294, and mean CD duration was 11.6 yrs; 46% had prior TNF-α exposure, and 33% had prior CD surgery. Improvement in clinical outcomes occurred as early as wk 2 in the 4-, 8-, and 12-wk tx groups: clinical response (CDAI decrease ≥100), 21%, 26%, and 29%; clinical remission (CDAI <150), 16%, 17%, and 19%; and mean change from BL in CDAI, −77.9, −77.2, and −78.6. These improvements were maintained across all 3 tx groups over 12 wks of tx, with the highest rates observed in the 12-wk tx group: clinical response, 53%, 44%, and 67%; clinical remission, 32%, 35%, and 48%; and mean change from BL CDAI, −124, −113, and −133. In all, 52 pts had evaluable endoscopies at Wk 12; of these, 37% had endoscopic response (≥25% reduction in SES-CD from BL to Wk 12), with no meaningful difference across tx groups. Among pts with SES-CD >12, 63% had ≥25% and 31% had ≥50% reduction in CDAI. Change in SES-CD (adjusted for BL CDAI, SES-CD, and tx group) showed a moderate correlation with change in CDAI (r=0.37; p=0.01). SES-CD was developed in pts with intact GI anatomy. Examining this relationship in the 32 pts without prior CD surgery showed an improved correlation (r=0.48; p=0.01). Adverse event (AE) rates and serious AE rates were low and similar across tx groups. Mongersen was generally safe and well tolerated.
Conclusions: Mongersen showed clinical and endoscopic improvements at Wk 12 for pts with active CD. A moderate correlation was seen between clinical and endoscopic benefit. This correlation improved when the analysis was confined to pts without prior CD surgery. No new safety signals were identified.