Crohn’s disease-related inflammation is characterized by defective activity of the immunosuppressive cytokine transforming growth factor ( TGF )-beta1, due to high Smad7, an inhibitor of TGF-beta1, signalling.
The effects of an oral, topically active Smad7 antisense oligonucleotide, Mongersen, were evaluated in a phase II study in patients with active Crohn’s disease.
In a double-blind, placebo-controlled trial, the efficacy of Mongersen as induction therapy was evaluated in steroid-dependent or steroid-resistant patients ( utilizing ECCO consensus definition ) with active Crohn’s disease ( Crohn’s disease activity index [ CDAI ] score 220-400 ).
Patients were randomized to Mongersen 10, 40 or 160 mg/day or placebo for 2 weeks.
The primary outcomes were clinical remission ( CDAI score less than 150 at Day 15 and maintained for greater than or equal to 2 weeks ) and safety.
Secondary endpoints included clinical response ( CDAI score reduction of 100 points ) at Day 28.
Clinical remission was achieved by significantly greater proportions of patients receiving Mongersen 40 ( 55.0% ) and 160 mg/day ( 65.1% ) compared with placebo ( 9.5%; p less than 0.0001 for both ).
No significant difference in clinical remission was seen for 10 mg/day ( 12.2% ) versus placebo.
The rate of clinical response was significantly greater among patients receiving 10 ( 36.6% ), 40 ( 57.5% ) or 160 mg/day ( 72.1% ) of Mongersen versus placebo ( 16.7%; p=0.039, p=0.0001 and p less than 0.0001, respectively ).
The rates of adverse events and serious adverse reactions were similar across groups. Nine severe adverse effects occurred in 6 patients ( placebo, n=1; Mongersen 10 mg, n=3; 40 mg, n=1; 160 mg, n=1 ).
Most severe adverse events consisted of hospital admissions for Crohn’s disease-associated complications or symptoms, and included: pyrexia and cough ( placebo ); abdominal pain ( n=2 ), Crohn’s disease worsening and pyrexia ( Mongersen 10 mg ); seton placement for perianal fistula and surgery for hemorrhoid thrombosis ( Mongersen 40 mg ); and thermal burn ( Mongersen 160 mg ).
In conclusion, induction therapy with orally administered, topically active Mongersen for Crohn’s disease was well tolerated; toxicities previously reported with systemically active antisense agents were not observed. Mongersen treatment resulted in significant improvements in clinical remission and response rates within 4 weeks of initiation of treatment. ( Xagena )
Source: UEG ( United European Gastroenterology ) Week, 2014