Crohn's Disease Forum » Treatment » New Drug Pipeline: Celgene GED-0301

10-16-2014, 11:28 AM   #1
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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:
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.
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 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.
And here's the full Phase I results:

Last edited by xeridea; 10-20-2014 at 09:08 AM.
10-16-2014, 11:33 AM   #2
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Interesting but why put out a press release about the announcement. This isn't the release of a new iPhone what's the secret? Maybe to generate investor buzz and enthusiasm to raise the stock in anticipation.

Look forward to results!
10-20-2014, 09:13 AM   #3
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Here are the Phase II results. Not stellar but on par with or better than some current therapies. Holds promise as steroid alternative with less side-effects.

Crohn’s disease (CD)-related inflammation is characterized by defective activity of the immunosuppressive cytokine transforming growth factor (TGF)-β1, due to high Smad7 (an inhibitor of TGF-β1) signalling. The effects of an oral, topically active Smad7 antisense oligonucleotide, Mongersen, were evaluated in a phase II study in patients with active CD.

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 CD (CD 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 <150 at Day 15 and maintained for ≥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<0.0001 for both). No significant difference in clinical remission was seen for 10 mg/day (12.2%) vs. 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 vs. placebo (16.7%; p=0.039, p=0.0001 and p<0.0001, respectively). The rates of adverse events (AEs) and serious AEs (SAEs) were similar across groups. Nine SAEs occurred in 6 patients (placebo, n=1; Mongersen 10 mg, n=3; 40 mg, n=1; 160 mg, n=1). Most SAEs consisted of hospital admissions for CD-associated complications or symptoms, and included: pyrexia and cough (placebo); abdominal pain (n=2), CD 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).

Induction therapy with orally administered, topically active Mongersen for CD 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 (EUDRACT NUMBER 2011-002640-27).
10-20-2014, 09:17 AM   #4
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Thanks for posting. Nice to see a new approach working and with a faster response time than the current lineup.
12-25-2014, 01:52 AM   #5
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Guys - I have a question on this. It says in xeridea's post that the medicine is released only in the lumen of the terminal ileum and right colon.

So - what does this mean for those of us who's Crohn's is not in the terminal ileum or right colon? Mine is at its worst in the left colon. Does that mean this med wouldn't be for me? Also, anyone know if everyone in the clinical trial had inflammation mainly in the terminal ileum and right colon?

Thanks Guys!
01-17-2015, 02:55 PM   #6
Join Date: Jan 2015
hi pmitra,

i ask myself the same since i read about that new medicine for the first time.
My sons crohns is located throughout his gut.
It would be a shame if it would fail for him only because of the formulation.

But i guess that celgene will reformulate the drug after approvement of the actual formulation.
I am optimistic.
As far as i know there are several drugs which already release througout the gut. (Ferrings Pentasa for example, SGX-203..)

Does anybody else with biotech knowledge has any more information on that? Is it that hard to topically target the whole gut?? Will Celgene conduct phase 3 with the actual formulation or can they change it before phase 3??

Thank you all

04-30-2015, 09:01 AM   #7
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Just read about this drug. Phase 2 findings published in the New England Journal of Medicine.

Nice to see development of new treatment options.
Surgery Oct 12, 2010

Crohns Medicines:
Started Humira June 22nd, 2011
Increased to weekly injections on November 1st, 2016
Due to the insurance company, Humira ended on January 31, 2017.
Started Entyvio February 9th, 2017
Loperamide 3 capsules twice a day
Vitamin B6, B12, Folic Acid
Vitamin D3 10000 I.U.
Nature Made Multivitamin

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