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- Jul 11, 2014
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New Drug Pipeline: Celgene Mongersen (GED-0301)
This is about a new class of molecular therapy drug in the pipeline for moderate to severe CD. It's not another anti-TNF drug nor other systemic immuno-modulator/suppressant. Instead it targets the mucosal immune system. Only Phase I results (15 patients) have been published so far (see link below) and those showed 80% clinical remission rate based on mean CDAI scores (because ethics panel did not allow scope work for that particular study). Phase II results (166 patients) will be announced this weekend which will hopefully include scope results.
Here's the business side summary:
Here's some technical info on mechanism of action:
Additional technical info from the Phase I study:
And here's the full Phase I results:
This is about a new class of molecular therapy drug in the pipeline for moderate to severe CD. It's not another anti-TNF drug nor other systemic immuno-modulator/suppressant. Instead it targets the mucosal immune system. Only Phase I results (15 patients) have been published so far (see link below) and those showed 80% clinical remission rate based on mean CDAI scores (because ethics panel did not allow scope work for that particular study). Phase II results (166 patients) will be announced this weekend which will hopefully include scope results.
Here's the business side summary:
Celgene will be announcing phase II clinical trial results this weekend (Oct. 18) at United Gastroenterology Week in Vienna for a first-in-class drug for treatment of moderate to severe Crohn's. Celgene licensed this drug from Irish developer Nogra in April in a deal worth up to $2.6 billion. At that time only open label Phase I results on 15 patients were complete but Celgene got access to preliminary Phase II results of 166 patients. Apparently these were promising enough to be wroth the 10 figure bet. I think Phase III trials will be starting later this year.
"GED-0301 is a first-in-class oral antisense DNA oligonucleotide targeting Smad7 mRNA indicated for moderate-to-severe Crohn's. Celgene said it entered into its deal with Nogra following completion of a multicenter Phase II trial assessing the efficacy of three doses of GED-0301 in 166 patients with active Crohn's disease. Results from the 166-patient Phase II trial have been submitted for publication to “a major medical journal” and will be presented at an undisclosed upcoming medical congress by year’s end.
"GED-0301 is a first-in-class oral antisense DNA oligonucleotide targeting Smad7 mRNA indicated for moderate-to-severe Crohn's. Celgene said it entered into its deal with Nogra following completion of a multicenter Phase II trial assessing the efficacy of three doses of GED-0301 in 166 patients with active Crohn's disease. Results from the 166-patient Phase II trial have been submitted for publication to “a major medical journal” and will be presented at an undisclosed upcoming medical congress by year’s end.
Here's some technical info on mechanism of action:
Recent studies have demonstrated that TGF-β 1 acts as a potent immunoregulator able to control mucosal intestinal inflammation. TGF-βΙ binds a heterodimeric transmembrane serine/threonine kinase receptor containing two subunits, TGF-βΙ Rl and TGF-βΙ R2. Upon ligand binding, the TGF-βΙ Rl receptor is phosphorylated by the constitutively active TGF-βΙ R2 receptor and signal is propagated to the nucleus by proteins belonging to the SMAD family. Activated TGF-β Ι Rl directly phosphorylates SMAD2 and SMAD3 proteins, which then interact with SMAD4. The complex of SMAD2/SMAD3/SMAD4 translocates to the nucleus and modulates the transcription of certain genes.
Additional studies have demonstrated that another SMAD protein, SMAD7, also plays a role in inflammation. SMAD7, an intracellular protein, has been shown to interfere with binding of SMAD2/SMAD3 to the TGF-βΙ Rl preventing phosphorylation and activation of these proteins. Further, increased expression of SMAD7 protein is associated with an inhibition of TGF-βΙ mediated-signaling. Mucosal samples from IBD patients are characterized by high levels of SMAD7 and reduced levels of phosphorylated-SMAD3 indicating that TGF-βΙ -mediated signaling is compromised in these patients.
Additional studies have demonstrated that another SMAD protein, SMAD7, also plays a role in inflammation. SMAD7, an intracellular protein, has been shown to interfere with binding of SMAD2/SMAD3 to the TGF-βΙ Rl preventing phosphorylation and activation of these proteins. Further, increased expression of SMAD7 protein is associated with an inhibition of TGF-βΙ mediated-signaling. Mucosal samples from IBD patients are characterized by high levels of SMAD7 and reduced levels of phosphorylated-SMAD3 indicating that TGF-βΙ -mediated signaling is compromised in these patients.
Additional technical info from the Phase I study:
Novel therapeutic compounds have been predicated on the hypothesis that CD results from an exaggerated immune response, occurring in genetically susceptible individuals, and directed against components of the bacterial flora.8 Such hyperimmune reactivity is in part dependent on the inability of the mucosal immune system to mount an effective counter-regulatory response.9,10 For example, in CD, there is a defective activity of the suppressive cytokine transforming growth factor (TGF)-β1, due to high levels of Smad7, an intracellular protein that binds to the TGF-β1 receptor and prevents TGF-β1-driven signalling.11,12 Both T cells and non-T cells express high levels of Smad7 in CD tissue, and knockdown of Smad7 with a specific antisense oligonucleotide restores TGF-β1 activity, with the downstream effect of inhibiting inflammatory cytokine production.11
To inhibit Smad7 in the gut, we developed an antisense oligonucleotide-containing pharmaceutical compound, herein termed GED0301. Details of the Smad7 antisense oligonucleotide have been previously described.11 Briefly, GED0301 is a synthetic single-stranded DNA oligonucleotide in which the internucleotide linkages are modified to O,O-linked phosphorothioates to increase oligonucleotide stability. The oligonucleotide antisense matches the region 107–128 of the human Smad7 complementary DNA sequence and contains two CpG motifs which are chemically modified to avoid immunostimulatory effects. GED0301 is formulated as a solid oral dosage form. The formulation is protected by an external tablet coating made of pH (6.6–7.2)-dependent metacrylic acid polymers, which allow the antisense to transit through the stomach and proximal small intestine, and to be released only in the lumen of the terminal ileum and right colon. Preclinical studies confirmed that orally administered GED0301 reaches the gut, where it is taken up by epithelial and lamina propria cells and that a single administration of the oligonucleotide antisense reduced the mucosal expression of Smad7, enhanced TGF-β1-associated Smad2/3 phosphorylation and attenuated experimental colitis(ref. 13 and data not shown). Altogether, these data support the concept that Smad7 constitutes a molecular target for direct therapeutic interventions in CD.
To inhibit Smad7 in the gut, we developed an antisense oligonucleotide-containing pharmaceutical compound, herein termed GED0301. Details of the Smad7 antisense oligonucleotide have been previously described.11 Briefly, GED0301 is a synthetic single-stranded DNA oligonucleotide in which the internucleotide linkages are modified to O,O-linked phosphorothioates to increase oligonucleotide stability. The oligonucleotide antisense matches the region 107–128 of the human Smad7 complementary DNA sequence and contains two CpG motifs which are chemically modified to avoid immunostimulatory effects. GED0301 is formulated as a solid oral dosage form. The formulation is protected by an external tablet coating made of pH (6.6–7.2)-dependent metacrylic acid polymers, which allow the antisense to transit through the stomach and proximal small intestine, and to be released only in the lumen of the terminal ileum and right colon. Preclinical studies confirmed that orally administered GED0301 reaches the gut, where it is taken up by epithelial and lamina propria cells and that a single administration of the oligonucleotide antisense reduced the mucosal expression of Smad7, enhanced TGF-β1-associated Smad2/3 phosphorylation and attenuated experimental colitis(ref. 13 and data not shown). Altogether, these data support the concept that Smad7 constitutes a molecular target for direct therapeutic interventions in CD.
And here's the full Phase I results:
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