Mongersen

Izzo R, et al. Digestive and Liver Disease, 2016, 48(2), e68-e69.

Mongersen has emerged as a targeted therapeutic for Crohn's disease (CD) by modulating Smad7 expression and restoring Transforming Growth Factor Beta 1 (TGF-β1) signaling. Smad7, a key inhibitor of TGF-β1 activity, is highly expressed in CD and contributes to inflammation and tissue damage. Mongersen-mediated Smad7 knockdown reduces inflammation by reactivating endogenous TGF-β1 signaling, thus attenuating inflammatory responses.
In a study using a chronic colitis-driven intestinal fibrosis mouse model, Mongersen demonstrated dual efficacy in mitigating both inflammation and fibrosis. BALB/c mice received weekly rectal doses of trinitrobenzene sulfonic acid (TNBS) to induce colitis and collagen deposition. Starting at week 4, Mongersen was administered orally every 48 hours until week 7. Histological analysis and molecular assays revealed that TNBS-induced chronic colitis increased Smad7 expression, reduced phosphorylated Smad2/3 (p-Smad2/3) levels, and elevated TGF-β1 RNA transcripts, alongside extensive collagen I deposition in the colon.
Mongersen treatment significantly reversed these pathological changes. By inhibiting Smad7, the agent restored Smad2/3 phosphorylation, reduced TGF-β1 RNA expression, and curtailed collagen deposition. Notably, this intervention ameliorated chronic inflammation and fibrosis without exacerbating TGF-β1-driven fibrogenesis, a potential concern given the pro-fibrotic nature of TGF-β1.

Feagan BG, et al. Gastroenterology, 2018, 154(1), 61-64.e6.

Mongersen (GED-0301) is an antisense oligodeoxynucleotide specifically designed to bind and degrade Smad7 mRNA, a critical regulator in Crohn's disease (CD). Smad7 overexpression in CD inhibits Transforming Growth Factor Beta (TGF-β) signaling, contributing to the inflammatory environment in the intestinal mucosa. Mongersen restores TGF-β activity, reducing inflammation and improving disease outcomes.
In clinical trials involving 63 CD patients, Mongersen was administered orally at a dose of 160 mg/day for durations of 4, 8, or 12 weeks. Endoscopic evaluations at week 12 revealed significant improvement in 37% of participants. Additionally, remission rates, defined as a Crohn's Disease Activity Index (CDAI) score below 150, were observed in 32% of patients after 4 weeks, 35% after 8 weeks, and 48% after 12 weeks of treatment. Corresponding reductions in CDAI scores were -124, -112, and -133 points, demonstrating a substantial decrease in clinical disease activity.
Preclinical models further elucidate Mongersen's mechanism of action. In a mouse model of chronic colitis, Mongersen reduced Smad7 expression, restored Smad2/3 phosphorylation, and diminished collagen deposition, effectively attenuating both inflammation and colitis-driven fibrosis. Importantly, no safety concerns emerged during these studies, highlighting Mongersen's clinical tolerability.