In Crohn disease, elevated levels of SMAD7 lead to decreased levels of the immunosuppressive transforming growth factor-β1 (TGFβ1). Celgene's mongersen, a 21-base single-strand oligonucleotide that binds SMAD7 mRNA to reduce its translation, may be able to normalize these levels, with impressive clinical effect, suggest new Phase II data. In the 166-patient trial, 65% of the patients who received the highest dose of mongersen achieved remission after 15 days of treatment, compared with 10% of the patients in the placebo group (New Engl. J.Med. 372, 1104–1113; 2015).

These results are “unprecedented” compared with the anti-inflammatory standards of care — including infliximab, adalimumab and vedolizumab — for moderate-to-severe active Crohn disease, comments Séverine Vermeire, a gastroenterologist at the University Hospitals Leuven in Belgium, in an editorial (New Engl. J. Med. 372, 1166–1167; 2015). The trial data also suggest that whereas symptoms usually recur rapidly after withdrawal of traditional anti-inflammatory drugs, the effects of mongersen seemed durable. But narrow inclusion criteria and a lack of congruence between clinical remission and biological remission (as measured by C-reactive protein) cloud interpretation of the results, Vermeire adds. “The impressive clinical effects of mongersen beg for follow-up studies to confirm that we have indeed entered a new phase of Crohn's disease treatment,” she concludes.

Celgene plans to initiate Phase III studies of the drug in Crohn disease in the second half of 2015. It is also set to start testing mongersen in a Phase II trial in ulcerative colitis. Around 30 other drugs for Crohn disease are also in clinical development, but none of these targets SMAD7.