Shares in Celgene Corp have risen steadily following promising mid-stage data of its closely-watched Crohn’s disease drug mongersen.
|Company||Nogra Pharma Ltd.|
|Description||Antisense oligonucleotide targeting SMAD family member 7 (MADH7; SMAD7)|
|Molecular Target||SMAD family member 7 (MADH7) (SMAD7)|
|Mechanism of Action|
|Therapeutic Modality||Nucleic acid: Linear RNA: Antisense|
|Latest Stage of Development||Phase II|
|Standard Indication||Crohn’s disease|
|Indication Details||Treat moderate to severe Crohn’s disease|
Mongersen (GED-0301) from Celgene Corp. (NASDAQ:CELG) produced clinical remission rates as high as 65.1% in a Phase II trial in 166 patients with moderate to severe Crohn’s disease, according to an abstract published in advance of the United European Gastroenterology’s meeting in Vienna.
In the trial, 55% of patients receiving 40 mg/day of mongersen and 65.1% of those receiving 160 mg/day achieved clinical remission compared with 9.5% of placebo patients (p<0.0001 for both). A cohort receiving 10 mg/day achieved a clinical remission rate of 12.2%, which was not significantly better than placebo.
The study’s primary outcomes were clinical remission, defined by a CDAI score less than 150 at day 15 and maintained for more than two weeks, and safety. Mongersen was well-tolerated, and toxicities associated with systemically active antisense therapies were not observed.
The study’s secondary endpoint is clinical response, defined as a CDAI score reduction of 100 points at day 28. Those rates were dose-dependent: 36.6%, 57.5% and 72.1% for the low, medium and high doses compared with 16.7% for placebo.
Celgene said it plans to start Phase III testing of mongersen shortly. The company paid $710 million up front to obtain exclusive, worldwide rights to the antisense oligonucleotide targeting SMAD family member 7 (MADH7; SMAD7) from Nogra Pharma Ltd. (Dublin, Ireland) in April. Nogra is eligible for $1.9 billion in milestones, plus tiered single-digit royalties.
GED-0301, an antisense oligonucleotide targeting the SMAD7 gene, is in phase II clinical trials at Nogra Pharma for the oral treatment of moderate to severe Crohn’s disease.
生物技术公司新基（Celgene）从爱尔兰制药商Nogra制药手中获得了一种处于后期临床开发的克罗恩病（Crohn’s disease）药物GED-0301。GED-0301是一种口服反义药物，靶向于Smad7信使RNA（mRNA），该药开发用于中度至重度克罗恩病 的治疗。反义药物是一种合成的核酸拷贝，旨在结合导致疾病的基因的mRNA，关闭基因的表达；口服；【Celgene签署$26亿协议获克罗恩病反义药物 GED-0301】http://www.hfoom.com/product/20140425/8311.html
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract suffered by approximately one million patients in the United States. The two most common forms of IBD are Crohn’s disease (CD) and ulcerative colitis (UC). Although CD can affect the entire gastrointestinal tract, it primarily affects the ilieum (the distal or lower portion of the small intestine) and the large intestine. UC primarily affects the colon and the rectum. Current treatment for both CD and UC include aminosalicylates (e.g., 5- aminosalicylic acid, sulfasalazine and mesalamine), antibiotics (e.g., ciprofloxacin and metronidazole), corticosteroids (e.g., budesonide or prednisone), immunosuppressants (e.g., azathioprine or methotrexate) and tumor necrosis factor (TNF) antagonists (e.g., infliximab (Remicade®)). Patient response to these therapies varies with disease severity and it can vary over cycles of active inflammation and remission. Moreover, many of the current therapies for IBD are associated with undesirable side effects.
Although the etiologies of CD and UC are unknown, both are considered inflammatory diseases of the intestinal mucosa. 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.
Recent studies have focused on SMAD7 as a target for treating patients suffering from IBD.
Such therapies include anti-SMAD7 antisense therapies. As such, there is a need for methods based on predictive biomarkers that can be used to identify patients that are likely (or unlikely) to respond to treatment with anti- SMAD7 therapies.
Phosphorothioate antisense oligonucleotide targeting human mothers against decapentaplegic homolog 7 (SMAD7) gene, whose sequence is 5′-GTCGCCCCTTCTCCCCGCAGC-3′, wherein ‘C’ at postions 3 and 16 is 5-methyl 2′-deoxycytidine 5′-monophosphate
5*-GTCGCCCCTTCTCCCCGCAGC-3* (SEQ ID NO: 3).
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