# List of all Past, Current and Future Treatments for IBD



## xeridea

Here is a list of various past, present and future drugs and therapies for Crohn's Disease. If you know of a drug that is not included please post its name and any information you have and I will add it to the list.

*Abrilumab (AMG-181)*
Phase II/III trials still underway. Some forum members participated in some of the trials but did not report good results.

http://www.crohnsforum.com/showthread.php?t=51014

*ABS-11*
http://atlanticbiosci.com/home
Works on FOXP3 protein within regulatory T cells to control their activity and role in mediating inflammatory response and restoring balance between Regulatory and Effector T Cells.

*Adalimumab*
Humira (name derived from "human monoclonal antibody in rheumatoid arthritis") .  It binds to tumor necrosis factor-alpha (TNFα), preventing it from activating TNF receptors. TNFα inactivation has proven to be important in down regulating the inflammatory reactions associated with autoimmune diseases.

*ABT-494*
Abbvie
Status: Early Phase II.
A JAK1 Inhibitor. JAK inhibitors work on blocking activity of certain interleukin and T cells.

*Alequel*
http://www.enzo.com/therapeutics/pipeline/immune-regulation/alequel-
An oral therapy that is based on an autologous protein extracted from the (patient’s) colon to alter the antigen immune response. 

*AMG-139*
AMG 139 is a human anti-IL-23 antibody currently in a phase 2 trial for treating Crohn's disease. 

*Ampion*
http://ampiopharma.com/pipeline/ampion/
A low molecular weight fraction of human serum albumin (HSA). Currently in trials for treating osteoarthritis of the knee, but undergoing pre-clinical studies for Crohn’s.

*AMX-256* 
Anti-S100A9 Monoclonal Antibody.

Protein S100-A9 also known as migration inhibitory factor-related protein 14 (MRP-14) or calgranulin-B is a protein that in humans is encoded by the S100A9 gene. One of a class of S100 proteins, it works in concert with MRP-8, broadly regulates vascular inflammation and contributes to the biological response to vascular injury by promoting leukocyte recruitment. MRP-8/14 also regulates vascular insults by controlling neutrophil and macrophage accumulation,macrophage cytokine production, and SMC proliferation. The S100A9/A8 pair are also known as Calprotectin, an their levels are a well know measure of inflammation activity, particularly RA. AMX-256 would bind to this protein and reduce its signaling effects in the inflammatory process. 

Quinoline-3-Carboxamides, another drug currently under heavy research for autoimmune diseases, also binds to the S100-A9 and other S100 class proteins to neutralize them.

*APD-334*
_sphingosine 1-phosphate subtype 1 agonist_
APD334, an orally available agonist of the S1P1 receptor, is an internally discovered investigational drug candidate intended for the potential treatment of a number of conditions related to autoimmune diseases, including multiple sclerosis, psoriasis and rheumatoid arthritis. S1P1 receptors have been demonstrated to be involved in the modulation of several biological responses, including lymphocyte trafficking from lymph nodes to the peripheral blood. By isolating lymphocytes in lymph nodes, fewer immune cells are available in the circulating blood to effect tissue damage. We have optimized APD334 as a potent and selective small molecule S1P1 receptor agonist that reduces the severity of disease in preclinical autoimmune disease models.

http://www.arenapharm.com/apd334

*Apremilast*
(Otezla) is an orally available small molecule inhibitor of phosphodiesterase 4 (PDE4). Apremilast specifically inhibits PDE4 and inhibits spontaneous production of TNF-alpha from human rheumatoid synovial cells. It has anti-inflammatory activity. Currently approved for plaque psoriasis, being investigated for other chronic inflammatory diseases such as AS, RA, etc.

*Atrosab*
http://www.baliopharm.com/de/atrosab.html
Atrosab is a humanized monoclonal antibody that specifically blocks the pro-inflammatory TNF receptor 1 (TNFR1), without interacting with the TNF receptor 2 (TNFR2). As TNFR2 is known to play an important role for the defense of viral and bacterial infections, compounds not interacting with the TNFR2 are expected to have a significant improved safety profile, especially in respect to the occurrence of infections. Possible indications for ATROSAB include rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, plaque psoriasis, and inflammatory bowel disease (M. Crohn and colitis ulcerosa). Furthermore, as TNFR2 is also mediating remyelination whereas TNFR1 is involved as a signaling pathway in demyelination. ATROSAB is also expected to be effective in neuro-inflammatory and neuro-degenerative diseases like multiple sclerosis or M. Parkinson.

*AZ-17*
http://www.allozyne.com/wp-content/uploads/2013/12/Stenderup-AZ17-poster-2013.pdf
A bispecific Th17 antagonist that inhibits the differentiation and effector function of human Th17 cells in vivo. Drug is in early trial stages for treating MS but will likely be assessed for other inflammatory diseases.

*Bertilimumab*
Bertilimumab is a human monoclonal antibody that binds to eotaxin-1, an important regulator of overall eosinophil function. Currently in Phase II trials.

*BI-655066*
Though primarily targeting psoriasis, this IL-23 p19 antagonist monoclonal antibody is being studied for treating Crohn’s and a Phase II trial is recruiting patients.

*BL-5040*
http://www.biolinerx.com/uploaded/BL-7040 (Overview Mechanism of Action) (Leah) (final).pdf
BL-5040 is a novel drug candidate that utilizes a mutated version of leptin acting as an antagonist with anti-inflammatory properties. Leptin is a hormone that has an important role in regulating inflammation immunity, as well as appetite control. BL-5040 binds tightly to the leptin receptor and thus blocks the binding of leptin. It has been shown that BL-5040 can block inflammation in animal models without discernible side-effects. BioLineRx will be developing BL-5040 to treat inflammatory bowel diseases (IBD) such as colitis and Crohn's disease.

*Budesonide ER*
Entocort & similar. A synthetic steroid of the glucocorticoid family. It is released from granules in the ileum of the small intestine and the right (proximal) colon, where the inflammation of Crohn's disease occurs. Budesonide acts directly by contact with the ileum and colon. Budesonide that is absorbed into the body travels first to the liver where it is broken-down and eliminated from the body. This prevents the majority of the absorbed drug from being distributed to the rest of the body. As a result, budesonide causes fewer severe side effects throughout the body than other corticosteroids. 

*CALY-001*
http://www.calypsobiotech.com/site/en/
A monoclonal antibody against an undisclosed target to treat fistulizing Crohn's disease. The company expects it will be able to treat the disease's underlying inflammation as well as its fibrotic complications.

 
*Cenplacel-L*
Human placenta-derived adherent cells (PDAC cells) are a culture expanded, undifferentiated mesenchymal-like population derived from full-term placental tissue, with immunomodulatory and anti-inflammatory properties. PDA-001 (cenplacel-L), an intravenous formulation of PDAC cells, is in clinical development for the treatment of autoimmune and inflammatory diseases. To elucidate the mechanisms underlying the immunoregulatory properties of PDAC cells, we investigated their effects on immune cell populations, including T cells and dendritic cells (DC) in vitro and in vivo. PDAC cells suppressed T-cell proliferation in an OT-II T-cell adoptive transfer model, reduced the severity of myelin oligodendrocyte glycoprotein peptide-induced experimental autoimmune encephalomyelitis and ameliorated inflammation in a delayed type hypersensitivity response model. In vitro, PDAC cells suppressed T-cell proliferation and inhibited Th1 and Th17 differentiation. Analysis of tissues derived from PDAC cell-treated animals revealed diminished CD86 expression on splenic DC, suggesting that they can also modulate DC populations. Furthermore, PDAC cells modulate the differentiation and maturation of mouse bone marrow-derived DC. Similarly, human DC differentiated from CD14+monocytes in the presence of PDAC cells acquired a tolerogenic phenotype. These tolerogenic DC failed to induce allogeneic T-cell proliferation and differentiation toward Th1, but skewed T-cell differentiation toward Th2. Inhibition of cyclo-oxygenase-2 activity resulted in a significant, but not complete, abrogation of PDAC cells’ effects on DC phenotype and function, implying a role for prostaglandin E2 in PDAC-mediated immunomodulation. This study identifies modulation of DC differentiation toward immune tolerance as a key mechanism underlying the immunomodulatory activities of PDAC cells.
This drug is in early stage development by Celgene.

*Crohn's Map Vaccine*
This is a pre-trial vaccine against the MAP bacteria, which is implicated as one possible cause of Crohn's. There's a small but robust crowdfunding effort to get the MAP test and vaccine developed primarily by Prof. John Hermon-Taylor of King's College London to trial. A new test is being developed because MAP is hard to detect using current lab methods. The vaccine is a T-Cell vaccine. It has already been trialed in cattle and is in production at Oxford's Biotechnology lab in anticipation of the impending human trials.

*Cx601*
http://www.tigenix.com/
Cx601 is a suspension of allogeneic expanded adipose-derived stem cells (eASCs) delivered locally through intra-lesional injection. Cx601 is being developed for the treatment of perianal fistulas in Crohn's disease patients. 
Currently in Phase III trials in Europe with expected trials in US to follow. Target to European market in 2017 if it meets regulatory approvals.

August 7, 2015: TiGenix obtains FDA's endorsement through Special Protocol Assessment for its Cx601 Phase III registration trial in the US. This allows the Phase III trial to commence in the U.S. mid 2016, with plans to recruit about 224 participants. Results of current European trial are expected next quarter.

August 24, 2015: TiGenix announces Cx601 meets primary endpoint in Phase III trial, with more than 50% of patients with complex perianal fistulas, previously unresponsive to other treatment options including anti-TNF, achieving combined remission at 24 weeks.

*Cyclosporine*
This is an immunosuppressant drug widely used in organ transplantation to prevent rejection. It reduces the activity of the immune system by interfering with the activity and growth of T cells.

Typically used for UC but also for fistulizing Crohn’s. It acts faster than Azathioprine or 6-mercaptopurine.

*Dalazatide*
Kineta
Kineta released positive Phase 1b study results (safety) for a Kv1.3 channel blocker Dalazatide. This drug blocks an activation channel of effector memory T-cells that cause inflammation and tissue damage in a range of auto-immune diseases. As a selective agent it doesn't suppress the entire immune system.

*Dendritic Cell Therapy for Crohn's Disease*
The gut mucosa undergoes continuous antigenic exposure from food antigens, commensal flora derived ligands, and pathogens. This constant stimulation results in controlled inflammatory responses that are effectively suppressed by multiple factors. This tight regulation, necessary to maintain intestinal homeostasis, is affected during inflammatory bowel diseases (IBD) resulting in altered immune responses to harmless microorganisms. Dendritic cells (DCs) are sentinels of immunity, located in peripheral and lymphoid tissues, which are essential for homeostasis of T cell-dependent immune responses. The expression of a particular set of pathogen recognition receptors allows DCs to initiate immune responses. However, in the absence of danger signals, different DC subsets can induce active tolerance by inducing regulatory T cells (Treg), inhibiting inflammatory T helper cell responses, or both. Interestingly, several protocols to generate clinical grade tolerogenic DC (tol-DCs) in vitro have been described, opening the possibility to restore the intestinal homeostasis to bacterial flora by cellular therapy.

*DLX-105*
http://www.delenex.com/en/Home/
Though developed for plaque psoriasis, this is an anti-TNFα drug being trialed for treatment of fistulas by injection at the local site.

*E-6011*
http://www.eisai.com/
Humanized monoclonal antibody targeted for fractalkine which plays an important role for immune reactions such as infiltration by inflammatory cells.

Fractalkine is a large cytokine protein, and is a chemoattractant of T Cells and monocytes, and when cell-bound, promotes strong adhesion of leukocytes to activated endotheleal cells.

*Eldelumab*
This is a humanized monoclonal antibody to Interferon Gamma Inducible Protein 10 (IP-10). It works by neutralizing the IP-10 mediated calcium influx, leukocyte migration, and upregulation of CXCL-10 responsive genes.

IP-10 is a chemokine ligand of the CXC family, and is involved in recruitment of T Cells to inflamed tissues, and is also involved in proliferation and migration of epithelial and endothelial cells and aptosis of islet beta cells.

*ES-210*
http://ebsi.com/
A bispecific protein that blocks the costimulatory receptor CD86 while delivering the immunosuppressive cytokine IL-10 to CD86-expressing antigen presenting cells.

*FE-999301*
IL-6 antagonist. IL-6 is a pleiotropic cytokine, and its dysregulation is involved in many diseases including chronic inflammatory and autoimmune disorders, coronary artery and neurologic disease, and in cancer. Innovative therapeutic strategies that block the biologic functions of IL-6 are being developed and are emerging in the clinic. The best responses with IL-6 and IL-6R antibodies were seen in rheumatoid arthritis, systemic juvenile idiopathic arthritis, and CD, conditions that are known to be driven by IL-6. 

*FFP-102*
http://www.ffpharma.com/2014/
Humanized anti-CD40 monoclonal antibody. Anti-CD40 antibody is a negative allosteric modulator of the CD40 pathway. It functions as a reversible switch for B cell activation and inhibits immune responses more “upstream” than for example cytokine inhibitors like TNF and IL-23 blockers. 

*Filgotinib*
Galapagos
Filgotinib (GLPG0634) is an orally-available, selective inhibitor of JAK1 (Janus kinase 1) for the treatment of rheumatoid arthritis and potentially other inflammatory diseases. Filgotinib (GLPG0634) dose-dependently inhibited Th1 and Th2 differentiation and to a lesser extent the differentiation of Th17 cells in vitro. GLPG0634 was well exposed in rodents upon oral dosing, and exposure levels correlated with repression of Mx2 expression in leukocytes. The JAK1 selective inhibitor GLPG0634 (Filgotinib) is a promising novel therapeutic with potential for oral treatment of rheumatoid arthritis and possibly other immune-inflammatory diseases. Filgotinib (GLPG0634) is currently in a Phase 2 study in Crohn's disease.

Edit 8/6/2015: FITZROY Phase 2 recruitment for CD complete with last patient being randomized into study. A Phase 2B study of the same drug for RA will have its 24-week data released this month. AbbVie (Humira) has the rights to pick up licensing on this drug.

Prior Phase I dosage and safety trials listed here.

*Furestem-CD*
http://www.kangstem.com/front/
Stem cell therapy. Currently recruiting Phase 2 study patients. This is intended to be a “curative” therapy.

*GFT-505*
http://www.genfit.com/pipeline/tgftx5/
Originally targeting nonalcoholic steatohepatitis of the liver leading to cirrhosis, discovered to also be protective of the intestines against fibrosis. 
Fibrotic diseases are characterized by the proliferation and activation of specialized fibrosis-producing cells: fibroblasts/myofibroblasts. In vitro data show that GFT505 inhibits both proliferation induced by PDGF (Platelet-Derived Growth Factor) and activation induced by TGF (Transforming Growth Factor) in liver fibroblasts (hepatic stellate cells). Complementary in vitrostudies show that GFT505 acts as an inhibitor of a group of structurally related Receptor Tyrosine Kinases (RTKs) known to be involved in fibrotic mechanisms.

Based on our knowledge of the anti-inflammatory and anti-fibrotic properties of GFT505 in hepatic diseases, we have shown that GFT505 protects the intestine from inflammatory injury and reduces associated fibrosis in a model of colitis induced in mice by DSS (dextran sodium sulfate). 

*Inflectra*
http://www.hospira.com/en/

Class: Anti-TNFα mAB
Stage: Approved

This is a Remicade (Infliximab) biosimilar released in Europe early 2015. It purports to have the same profile as Remicade but at a reduced cost.

It is scheduled for Advisory review by FDA March 17, 2015, albeit for RA. But if that goes through approval for other conditions might soon follow.

On the business side, Hospira is apparently a takeover target by Pfizer.

*IBI-303*
http://www.innoventbio.com/en/about.aspx?key=product&type=IBI303
Anti-TNFα mAB. Marketed as low-cost alternative to other humanized mAB (Humira), seems only available to Chinese market.
IBI303 is a fully human monoclonal antibody binding to TNF-α preventing it from activating TNF receptors. IBI303 will be used to treat Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis, Crohn’s disease and other autoimmune diseases.

IBI303 has potential to provide Chinese autoimmune disease patients with high quality and low cost biological medicine.

*Infliximab (Remicade)*
http://www.remicade.com/
Anti-TNFα mAB.  Can reduce signs and symptoms and induce and maintain remission in patients with moderately to severely active Crohn’s disease who haven't responded well to other therapies

*INV-88*
http://www.innovimmune.com/inv88program.php
We have advanced our promising small molecule-based cytokine inhibitor portfolio INV-88, a novel class of proprietary oral small molecule NMEs (New Molecular Entity) that have been discovered by Innovimmune scientists. The INV-88 platform consists of several structurally-distinct lead scaffolds that inhibit human macrophage migration inhibitory factor [MIF], a cytokine which is critically implicated in the pathogenesis of several autoimmune and immunoinflammatory diseases. This important discovery by Innovimmune of a novel oral immunomodulatory drug is of significant advancement in the development of future treatments for these disorders with high unmet medical needs and due to the current limited available oral-based therapies for patients suffering from these debilitating diseases. The unique MOA of targeting MIF has been target validated in preclinical animal disease models and thus its preclinical Proof of Concept established in Rheumatoid Arthritis, Multiple Sclerosis, Alzheimer’s Disease, Type 1 and Type 2 Diabetes, Obesity, Lupus, Asthma, Crohn’s Disease, and Ulcerative Colitis. High priority INV-88 lead compound candidates have advanced to final Discovery stage, with several back-up scaffolds concurrently in development. The INV-88 lead candidates have been designed with highly favorable physico-chemical and ADMET properties that would translate into next-generation immunomodulatory therapies with a higher potency, better efficacy, superior safety profile and a wider therapeutic index providing better patient treatments.

*JKB-122*
http://www.jenkenbio.com/products.shtml
JKB-122 is a weak and competitive antagonist to TLR4 (toll-like receptor 4), a type 1 transmembrane protein that is a key mediator of the release of proinflammatory cytokines and inflammatory responses and a member of TLRs which are mainstays of the innate immune system and best known for their role in host defenses against infections. Lipopolysaccharide (LPS), an endotoxin, is a specific agonist for TLR4 and patients infected with chronic HCV infection display more than a 10-fold-increase in serum levels of endotoxins and an increased expression of TLR4. In addition, TLR4 is expressed in two key liver cell types involved in hepatic fibrosis: hepatic stellate cells and Kupffer cells. JKB-122 has been shown to exhibit antifibrotic activity in bile-duct ligated rats which further supports that a TLR4 antagonist is of potential in treating liver fibrosis.

This is an off-patent drug that is being repurposed against CD.

*KRP-203*
http://www.kyorin-pharm.co.jp/
Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid that is enriched in the blood and lymph, and functions in innate and adaptive immunity. S1P signaling regulates inflammation via its impact on the trafficking, differentiation, and effector functions of bone marrow-derived immune cells. S1P also activates nuclear factor kappa B and signal transducer and activator of transcription 3 inflammatory pathways. S1P is generated by the ubiquitously expressed lipid kinase, sphingosine kinase (SphK)1 and its tissue-restricted homolog, SphK2. S1P is irreversibly degraded by S1P lyase, which is highly expressed in enterocytes. Recent studies targeting S1P metabolism and signaling have shown promise in preclinical models of IBD and have shed light on the mechanisms by which S1P signaling impacts IBD. The evidence suggests that targeting S1P signaling and metabolism may represent a novel strategy in treating IBD and it may reduce colon cancer risk by interrupting the progression from inflammation to carcinogenesis.
Novartis may have worldwide distribution rights and enrolling patients for open label phase I study.

*Larazotide acetate*
Study showed that larazotide acetate is the first pharmacologic agent to prevent changes in blood mononuclear cell populations (specifically T-reg cells and B Cells) and other markers of immunological change associated with active celiac disease. This data suggests that larazotide acetate offers potential as a future treatment of celiac disease. Results from a second poster presented at ACG showed that larazotide acetate also inhibited the effect of inflammatory cytokines, including tumor necrosis factor (TNF-alpha) and interleukin (IL-4) on intestinal epithelial permeability, in vitro, further suggesting that the product offers potential as a future treatment for inflammatory bowel disease (IBD).
This drug may help in addressing the gut permeability issues some associate with IBD.

*LBP-001*
http://www.gt-biologics.com/live-biotherapeutics.php
Coined Live Biotherapeutics (LBPs) by the manufacturer, they are studying and developing specific bacterial species for restoring a healthy microbiota in CD patients, and the seem to have a special interest in pediatric Crohn’s.
The lead drug is Theatenix, comprised of Bacteroides thetaiotaomicron, which is an obligate anaerobe, a major endosymbiont of the human gut. Bacteroides thetaiotaomicron is a major component of the adult intestine and has been used as a useful model for the study of human-bacterial symbiosis. Its metabolic function for humans is to degrade plant polysacharides, a very essential capability for the human gut. Additionally, it is very important during the postnatal transition between mother's milk and a diet heavily consisting of plant starches. It has been found to stimulate angiogenesis (growth of new blood vessels from pre-existing vessels) within the gut, due to a microbial signal via bacterial sensing Paneth cells. B. thetaiotaomicron benefits its host by providing sufficient absorptive ability for nutrients the microbe helps process. Another postnatal developmental process within the gut mediated by Bacteroides thetaiotaomicron is the formation of the intestinal mucosal barrier, which helps protect the host against pathogenic invasion via the regulation of the expression of species-specific protein antibiotics. (13)
The environment sensing regulatory apparatus present in B. thetaiotaomicron allows for adaptive food seeking, which stabilizes food webs, and subsequently leads to the longevity of communities. (13) This ability to adaptively 'forage' is an area of biotechnical interest. 

*Leukothera*
http://www.actinobac.com/Actinobac/Technology.html
Leukotoxin (LtxA) is a protein toxin that is secreted from the oral bacterium, Aggregatibacter actinomycetemcomitans. LtxA targets specifically the β(2) integrin, leukocyte function antigen-1 (LFA-1) on white blood cells (WBCs) and causes cell death. LtxA preferentially targets activated WBCs and is being developed as a therapeutic agent for the treatment of WBC diseases such as hematologic malignancies and autoimmune/inflammatory diseases. 
Lodonal (Low Dose Naltrexone) / Naltrexone
http://www.tnibiotech.com/
LDN can bind to opioid receptors on immune cells and also stimulate the production of both endogenous met-enkephalin and beta-endorphin, resulting in increased number of T cells and NK cells that destroy infectious organisms and cancer cells. LDN can also rebalance the immune system in patients with autoimmune diseases, leading to decreased tissue inflammation, repair of damaged tissue and decreased symptoms.

*LYC-30937*
Lycera

Class: ATPase Modulator. 
Development Stage: Pre-clinical

This is a small molecule drug targeted toward the gut that acts selectively on chronically activated lymphocytes (T-Cells).

From the product overview:

The lead program in this portfolio originates from the emerging field of immune metabolism, a field of biology focused on how energy is made and utilized in both normal and disease causing immune cells. Metabolism in cells produces adenosine triphosphate (ATP) through various intracellular processes which can change based on the state of cells. Unlike normal cells, differences in the way disease-causing immune cells make ATP leads to metabolic abnormalities that sensitize them to modulation of the mitochondrial F1F0-ATPase. Lycera has developed proprietary compounds that modulate the F1F0-ATPase, resulting in selective cell death and depletion of chronically activated disease-causing immune cells while sparing normal immune cells that fight infection. ATPase modulators are unique first-in-class drugs with the potential to treat a broad spectrum of conditions. Such drugs are expected to have significant advantages over existing products, including broad efficacy and fewer side effects, particularly unwanted immune suppression.

March 28, 2015 Update: Lycera achieved another milestone on their collaboration agreement with Merck, indicating the drug is continuing to show promise on its way toward clinical trials.

May 5, 2015 Update: Lycera announced initiation of Phase I study. This is study of the drug in healthy populations to assess its safety. 

*Mannosides*
https://www.biovaria.org/past-event...estinal-inflammations-such-as-crohns-disease/
University of Nantes Angers Le Mans researchers have used mannosides to directly target adherent-invasive Escherichia coli, which cause intestinal inflammation in Crohn's disease. The team is planning to test this alternative to standard-of-care TNF-lowering therapies in a mouse model for chronic CD.
The method is a new way of inhibiting E. coli-induced gastrointestinal inflammations such as certain forms of Crohn´s disease (CD). A new family of compounds has therefore been developed to block adhesin FimH on type-1 fimbriae of E. coli. The anti-adhesive compounds are hydrophilic mannoside derivatives. The compounds are terminated by alkyl chains or cyclic moities grafted to the mannosides by triazole or peptide linkages. The compounds were shown to strongly interact with the FimH adhesin and to prevent/abolish adhesion of Adherent Invasive E. coli (AIEC) to intestinal epithelial cells in vitro. Oral administration of the most potent compounds to mice (model of CD) in a curative protocole, was shown to strongly decrease the level of AIEC in the gut, ileum and feces, compared to untreated mice. This decrease was associated to a strong reduction of the inflammatory syndromes, reaching the level of non-infected mice. The compounds were shown to be non-toxic. Altogether these results highlight the strong potential of the antiadhesive compounds in CD treatment.
What is intriguing here is that they are specifically calling out AIEC as an underlying cause for some cases of Crohn’s.

Mercaptopurine (Purinethol, 6-MP)
6-MP is an immunomodulator and suppresses the immune system. Although the exact mechanism of how 6-MP works is not known, it is felt that by inhibiting the immune system, this drug suppresses the "overactive" immune reaction that is responsible for such disorders as Crohn's disease and Ulcerative Colitis. 

*Mesalamine* (Pentasa, Lialda, Asacol, Delzicol, Claversal, Rowasa)
These are a class of 5-aminosalicylic acid (5-ASA) drugs designed to release in the terminal ileum on a time release basis.
It is believed UC and CD casue excessive production of chemicals such as prostaglandins, that produce inflammation in the colon. Prostaglandins are produced by the enzymes, cyclooxygenase and lipoxygenase. These enzymes are over-active in individuals with ulcerative colitis. Mesalamine may work by blocking the activity of cyclooxygenase and lipoxygenase, thereby, reducing the production of prostaglandins. Reduced production of prostaglandins decreases inflammation in the colon and the symptoms associated with ulcerative colitis. 

The different brands vary based on their release mechanism and location they target. Some examples include:

Colazal (balsalazide)

Azulfidine

*Metronidazole*(Flagyl)
Metronidazole is an antibiotic effective against anaerobic bacteria and certain parasites. Metronidazole selectively blocks some of the functions within the bacterial cells and the parasites resulting in their death.

*MLN-3126*
This is a selective antagonist of CCR9, a chemokine receptor known to be important in the migration of inflammatory cells into the gastrointestinal tract.
There is some information on early trials in 2008 but sparse new information may indicate this drug is not under active development. 

*MP-196*
http://www.effimune.com/pipeline/other-products-in-the-pipeline/
Until recently, Th1 cells and IL-12 were thought to be the major drivers of T cell-mediated autoimmune inflammatory diseases. This conclusion was based on gene ablation of p40 (a subunit of IL-12 shared with IL-23) or use of neutralizing antibodies against p40. When the IL-12-specific subunit, p35, was directly targeted it became clear that IL-12 was not only required for inflammation (1, 2). Actually, Th17 cells and IL-23, a p40/p19 heterodimeric cytokine, are the crucial factors required to drive these diseases (3, 4). Th17 cells have now been implicated in several inflammatory disorders, including arthritis, inflammatory bowel disease, psoriasis, uveitis, and multiple sclerosis (5-9). The Th1 and Th17 pathways appear mutually exclusive since the IL-23/IL-17 pathway is strongly regulated by the IL-12/IFN-γ cytokines (Figure 1 and refs 10-11).
IL-23 is produced by sentinel DCs and macrophages within a few hours after exposure to endogenous danger signals or microbial products. This in turn triggers rapid IL- 17 responses from tissue-resident T cells. Other haematopoietic cells, including dendritic cells and macrophages, however, also express the IL-23 receptor and are responsive to IL-23. Therefore the functions of IL-23 extend beyond Th17 cells. Indeed IL-23 triggers a T-cell independent release of TNF-α and IL-1β from myeloid cells. In mice, the induction of a T cell-independent colonic inflammation is dependent on production of IL-23 but not IL-12, clearly defining a role for IL-23 actions on innate immune cells (12, 13). Importantly, the IL-23/IL-17 axis has a limited role in long term protection against microbial infection, in contrast with IL-12-responsive cells that induce IFN-γ, granzymes, FasL, and a set of chemokines (e.g., MIG, IP-10) that promote antigen-specific cellular immunity against invading pathogens.
For these reasons, EFFIMUNE developed MP196, a novel monoclonal antibody targeting selectively IL-23. MP196 is a drug candidate to neutralize autoimmune inflammation without precluding protective responses mediated by the IL-12/IFN-γ axis that are mediating protection to pathogens.

*Mongersen* (GED-0301)
http://ir.celgene.com/releasedetail.cfm?releaseid=876931
GED-0301 is an antisense oligonucleotide that targets the messenger RNA (mRNA) for Smad7, thereby reducing Smad7 protein levels. In patients with Crohn's disease, abnormally high levels of Smad7 interfere with TGF-β1 anti-inflammatory pathways in the gut, leading to increased inflammation. The distinct formulation of the tablet is designed to release GED-0301 into the far end of the small intestine (the terminal ileum) and near the end of the colon (right colon), where it is thought to act locally to reduce Smad7 levels.
II trials have shown 65% remission rate compared to 12% in placebo group. Entering Phase III trials by end of 2014.

3/19/2015: Phase II results update.

5/19/2015: CD-001 Endoscopic Study

Celgene is currently doing a more rigorous study they termed CD-001 that uses a more rigorous endoscopic assessment as opposed to CDAI scores to gauge efficacy. Divided into five phases, (screening, induction, observation, extension and follow-up), 48 patients will participate in this study that is designed to last 97 weeks. Endoscopic response and durability of response will be measured during the first three phases, and that can last up to 69 weeks. These are blinded phases so no data will be released until the last patient completes that 3rd phase, so 2017 we'll see these preliminary results.

On other fronts, a larger phase III trial of 2,000 patients will start enrollment soon.

*MT-1303*
Sphingosine-1-phosphate receptor modulator
The oral sphingosine 1-phosphate (S1P) receptor (S1PR) modulator has been shown to be effective in the treatment of patients with relapsing multiple sclerosis (MS). The drug binds with high affinity to 4 of the 5 G-protein-coupled S1P receptors (S1P(1-5)). After binding, the receptors are internalized, degraded, and thus functionally antagonized. Under physiologic conditions, S1P(1) mediates the egress of lymphocytes from secondary lymphoid organs to the peripheral circulation. Functional antagonism of S1P(1) results in a reduction in peripheral lymphocyte counts by inhibiting egress of lymphocytes, including potentially encephalitogenic T cells and their naïve progenitors that would otherwise be present within the circulation. Despite the reduction of lymphocyte counts, patients with MS have been shown to have few infections and related complications and were able to mount antigen-specific immune responses in vaccination studies.

10-Sep-2015: Biogen just inked a deal for worldwide licensing rights to this drug from Mitsubishi Tanabe. It is looking at accelerating a current Phase II trial for Crohn's to Phase III.

*NAT-100*
http://www.natcure.com/
Class: neutraceutical
Stage: Pre-clinical
The company is doing research studies to identify the active compound in the bark of the Millettia laurentii, commonly known as Wenge or Awong, is a member of the Leguminosae Family of trees. They have also identified Pseudotsuga pinaceae with similar capabilities. The active compound has been shown to have strong anti-inflammatory properties by exerting strong inhibitory effects on leukocytes and cytokines. The company has patented the application of these natural compounds for treatment of inflammatory diseases.

*NI-0401 (foralumab)*
http://www.novimmune.com/
Class: Biological / mAB
Stage: Stalled at Phase 1 / 2 trials.
This is an anti-CD3 antibody that seems to have failed trial endpoints.

*NN-8555*
http://novonordisk.com
Class: Biological / Anti-NKG2A mAB.
Stage: Suspended.
This is a first-in-class humanized IgG4 antibody. NKG2A is a checkpoint receptor that inhibits anti-cancer functions of cytotoxic NK and T lymphocytes. 
Novonordisk discontinued further development of this drug as a treatment for CD following an interim analysis of an on-going double-blinded randomized placebo controlled phase 2a trial. Their analysis showed that the drug did not meet their criteria for desired effect.
This drug may have been licensed by another company and may re-appear as different branding.

*NN-8828*
http://novonordisk.com
Class: Biological / Anti-IL21 mAB
Stage:Suspended
Novonordisk has scaled back on inflammatory diseases research. They may be licensing their products in this area to other companies.

*Ova-Treg / OvaSave*
http://txcell.com/index.php/en/products-112/ovasaver?task=view
Stagehase 2b trials planned for latter half of 2014
An antigen-specific type 1 regulatory T (Ag-Treg) cell based immunotherapy. The Ag-Treg cells utilized in Ovasave are isolated from whole blood of the patient, activated by the specific antigen, ovalbumin. The cloned Ag-Treg cells are expanded ex vivo before their reinjection into that same patient. The injected Ag-Treg cells home to sites of inflammation and are activated locally by the specific food antigen, ovalbumin, where they will exert anti-inflammatory effects on the host cells.

Dec 5, 2014 Update: Trial has recruited first patient for Phase IIb trial. This therapy targets severe (refractory) patients. See http://www.txcell.com/images/stories/pdf/PR_EN_TxCell_CATS29_start.pdf for further info.

March 25, 2015: TxCell granted US Patent for their Ovasave technology. Upon successful completion of the ongoing phase 2b trials they will transfer technology to Ferring to take to phase 3 trials and eventual commercialization.

June 30, 2015: FDA accepted TxCell's IND (Investigational New Drug) application to allow expansion of trials to the U.S.

July 29, 2015: TxCell was granted Fast Track Designation by the FDA on their lead product Ovasave. This facilitates the review and approval process. Ovasave is an antigen specific autologous T regulatory somatic cell therapy in development for the treatment of Inflammatory Bowel Disease that is currently in phase IIb trials in Europe.

August 6, 2015: TxCell appoints MaSTherCell for the manufacturing of Ovasave from Q2 2016. This will allow them to ramp up for their CAS29 Phase 2 study in CD, and eventually, provide commercial capacity should therapy be approved.

*PF-00547659*
http://www.pfizer.com/
Class: Biologic / MAdCAM mAB
The adhesion molecule mucosal addressin cell adhesion molecule (MAdCAM) plays an essential role in the recruitment of lymphocytes to specialized high endothelial venules of the gastrointestinal tract and in their excessive tissue extravasation observed in inflammatory conditions, such as Crohn's disease. 
PF-00547659 has potential utility in the treatment of inflammatory conditions by blocking tissue homing of activated α4β7+ leukocytes. The characterization of a rodent cross-reacting antibody as a surrogate for PF-00547659 in the search for potential pharmacological biomarkers and the determination of efficacious doses was effective in addressing the restricted orthologous cross-reactivity of PF-00547659 and the challenges this poses with respect to efficacy and safety testing.

*PF-04236921*
http://www.pfizer.com/
Class: Biologic / IL-6 mAB
Stage: Phase 2 trials underway.
IL-6 antibody.

*PH-46A*
http://www.trinotherapeutics.com/
Class: Nutraceutical 
State: Pre Phase 1
The indane skeleton is found naturally and in several therapeutic molecules in medicinal chemistry. During our work on the anti-inflammatory activity of naturally occurring and synthetic indanes, we have synthesized a novel indane scaffold that has been optimized for both anti-inflammatory activity and bioavailability. We have evaluated our lead molecule, PH46A, in in vivo models of inflammatory bowel disease (IBD), an area of considerable unmet clinical need; current therapies are often unable to control the course of the disease. The compound significantly reduced histological damage and serum amyloid A (SAA) levels in IL-10–/– colitis mice, was efficacious in the 5% dextran sulfate sodium (DSS) colitis model, and compared favorably with prednisolone in this model and supports its potential use to treat acute exacerbations of the disease. Further, the graded response to the compound may also lend itself to be used at a lower dose to maintain periods of remission.

*Prochymal*
http://www.osiris.com/prod_crohns.php
Class: mesenchymal stem cell therapy
Stage: Enrolling Phase 3 Trials
Stem cells are able to divide and renew themselves. They can be induced to become tissue and organ specific cells.  Because of these characteristics, stem cells act as an internal repair system and can replace diseased and damaged tissues.  Stem cell therapy works in IBD by serving as repair systems for specific inflammatory responses.

*PRX-106*
http://www.protalix.com/development-pipeline/prx-106-autoimmune.asp
Protalix is developing an oral Anti-TNF (PRX-106) for Inflammatory Bowel Disease. Oral Anti-TNF represents a novel mode of administering a recombinant anti-TNF protein. 

It looks like Phase 1 safety trials in 2015 and if that proved out, moving to stage 2 trials in 2016.

From press release: The Company plans to initiate clinical efficacy trials of Oral Anti-TNF for the treatment of Inflammatory Bowel Disease (IBD) in a non-IND setting during 2015. Upon reviewing the proof of concept (POC) data, expected in early 2016, the Company intends to collaborate with a well-suited partner for further development. 

*PRS-190*
http://www.pieris.com/
Class: Biologic / Th17 antagonist
Stage: Preclinical
A highly specific and potent bispecific antagonist targeting IL-17 and IL-23, two key members of the Th17 family of cytokines involved in autoimmunity and hyper-inflammation.

*PTG-100*
Protagonist Therapeutics
An orally administered α4β7 Integrin Specific Antagonist. This is the same target as Entivyo (Vedolizumab), but with the advantage that can be taken as a pill rather than via infusion. Currently in pre-clinical phase, with early trials scheduled for 2016.

*QBECO SSI*
Class: Vaccine
Stage: Phase II
http://www.qucrohnstrial.com/
Qu Biologics’ scientific team is exploring the treatment of Crohn’s disease and other immune-related diseases by focusing on the underlying source of the chronic inflammation: a deficiency in innate immune system function. Qu Biologics’ working hypothesis is that Crohn’s disease and other immune-related diseases are caused by an inability of a particular type of white blood cell, the macrophage, to effectively clear damaged or infected cells. If damaged or infected cells are not efficiently removed by macrophages, they become necrotic and release their contents into the surrounding tissue and/or blood vessels. The body then responds by generating an adaptive immune response against these cellular components, resulting in chronic inflammation in the affected tissue(s). Qu Biologics has demonstrated in animal models that SSIs, derived from inactivated bacterial preparations, initiate an immune response in the organ/tissue in which the bacterial species commonly causes infection. Based on this preliminary data in animals, it is believed possible that an SSI derived from a bacteria commonly found in the gut may stimulate an immune response in the colon and gastrointestinal tract, potentially resulting in marked recruitment of new macrophages to the colon which could clear the self-antigen that is triggering the chronic inflammatory response. - See more at: http://www.qucrohnstrial.com/ssi-intro/how-ssi-may-work/#sthash.woB3rZWj.dpuf
Update: March 31, 2015. U.S. patent granted for use of E.Coli to treat Crohn's.

*remestemcel-L (Prochymal)*
Class: Stem Cell Therapy
Stage: Phase III
http://www.mesoblast.com/products/immunologic-inflammatory/crohns-disease
Highly purified, immunoselected Mesenchymal Precursor Cells (MPCs) that help regulate T-cell mediated inflammatory responses by inhibiting T-cell prolieferation and also down-regulating the pro-inflammatory cytokine TNF-alpha and interferon gamma. More critically, mesenchymal lineage stem cells have been shown to be capable of effective down-regulation of Th17 cells, reduction in IL-17 levels, and induction of FoxP3 regulatory T cells.

*Remsima (Infliximab Biosimilar)*
http://www.celltrion.com/en/BIO/bio01.asp?menu_num=1
Class: Biologic, TNF-α mAb
Stage: Biosimilar for Remicade
First biosimilar to Remicade. Going through new FDA 351(k) regulatory pathway for approval. One manufacturer Celltrion, also challenging Jansen Patents in court hoping to get drug on market before 2018 patent expiry. Amgen also on board for developing this biosimilar, in addition to a biosimilar to Humira.

*Rifaximin ER*
Class: Antibiotic
Stage: Approved
Rifaximin ER, is an extended release antibiotic that is not readily absorbed in the blood when taken orally, so it works primarily in the gut. Because bacterial load is greater in the colon than in the small intestine, studies suggest that it works better in colonic CD rather than illeal CD. Also because of it’s poor absorption it works better against luminal bacteria than those that have infiltrated the mucosa.

*RNAi Oligonucleotide / Antisense *
Class: Gene therapy (genetic engineering/gene splicing)
Stage: Various ongoing trials.
Antisense oligonucleotides can regulate gene expression in living cells. It is based on some discoveries in the ‘70s that expression of specific gene product could be inhibited using short complimentary DNA sequences. Research in this area remained sparse until the early ‘90s when methods for DNA sequencing and synthesis of oligonucleotides improved. 
This is a broad field and holds promise for treating various and rare genetic diseases. 
There’s currently a lot of research going on in antisense therapies with promise of a whole new generation of therapies. See Mongersen (GED-0301), for example.

*RPC1063*
Class: Lymphocyte Trafficking agent
State: Phase 2 
Receptos 
This drug has the same mechanism as Tsybari and Entyvio, but instead of being injectable, is an oral lymphocyte trafficking agent. 

July 14, 2015 Update: Celgene announced an all cash $7.2B offer to purchase Receptos. 

*RHB-104*
Class: Antibiotics
Stage: Phase III trials.
http://www.redhillbio.com/product-pipeline/rhb-104/
This is an Anti-MAP (mycobacterium avium subsp. paratuberculosis) triple anti-biotic formulation consisting of a proprietary blend of clarithromycin, rifabutin, and clofazimine developed by Dr. Thomas Borody. 

Update 6/16/2015: UK Medicines and Healthcare Products Regulatory Agency (MHRA) has accepted RedHill's Clinical Trial Application (CTA) to initiate a second Phase III study of RHB-104 for Crohn's disease (the MAP EU study). This expands the first Phase III already in progress in US, Israel and NZ.

*SAR-252067*
Class: Biologic, TNF-α mAb
Stage: Phase I
http://www.kyowa-kirin.com/
This is another TNF-alpha human monoclonal antibody, specifically against the ligand superfamily member 14 (TNFRSF14; LIGHT; CD258). This protein may function as a costimulatory factor for the activation of lymphoid cells and as a deterrent to infection by herpesvirus. This protein has been shown to stimulate the proliferation of T cells, and trigger apoptosis of various tumor cells. This protein is also reported to prevent tumor necrosis factor alpha mediated apoptosis in primary hepatocyte. Two alternatively spliced transcript variant encoding distinct isoforms have been reported.

*SelK-2*
Class: Biologic, anti-PSGL-1
Stage: Investigational
http://www.selexys.com/
This is a humanized mAB gainst p selectin glycoprotein ligand-1. PSGL-1 is a glycoprotein found on endothelial cells that binds to P-selectin (P stands for platelet), which is one of a family of selectins that includes E-selectin (endothelial) and L-selectin (leukocyte). White blood cells normally do not interact with the endothelium of blood vessels. However,inflammation causes the expression of cell adhesion molecules (CAM) such as P-selectin on the surface of the blood vessel wall. White blood cells present in flowing blood can interact with CAM. The first step in this interaction process is carried out by PSGL-1 interacting with P-selectin and/or E-selectin on endothelial cells and adherent platelets. This interaction results in "rolling" of the white blood cell on the endothelial cell surface followed by stable adhesion and transmigration of the white blood cell into the inflamed tissue.

*SGM-1019*
http://www.secondgenome.com/
Class: Bacterial Inhibitor
Stage: Phase 1 Trials

SGM-1019 is an oral small molecule drug that inhibits a target that Second Genome researchers discovered to be a key driver of inflammatory bowel disease when modulated by changes in the microbiome.

Essentially, Second Genome believes they have identified a possible bacteria or other organism/agent (target) that may underlie Crohn's, and this drug specifically targets that bacteria. They are being very hush-hush about what that bacteria is (actually, they are not even calling it a bacteria in their press release).

July 15, 2015: Phasae I Trial Complete. Per company web site, "_the double blind, placebo controlled, single ascending oral dose trial in healthy subjects. SGM-1019 achieved targeted exposure levels and was well tolerated with no significant adverse events._"

*SGX-203*
Class: Corticosteroid
Stage: Development
http://www.soligenix.com/prod_thera_crohn.shtml
SGX-203 is an oral beclomethasone 17,21-dipropionate, a highly potent, topically active corticosteroid that has local effect on inflamed tissue. SGX203 is specifically formulated for oral administration as a single product consisting of two tablets. One tablet releases BDP in the upper gastrointestinal (GI) tract and the other tablet releases BDP in the lower GI tract. It is being developed for pediatric CD to make available a corticosteroid option with less toxicity than the current standard therapy prednisone. 

Small Molecule to Agonize OP3 Receptor for Inflammatory Bowel Diseases
Small Molecules to Inhibit RIP2 for Crohn's Disease and Polyarthritis

April 16, 2015: FDA authorizes Phase 3 trials for SGX-203. Plan to commence second half of 2015 with initial results out early 2017. 

*SQ-641*
Class: Antibiotic
Stage: Preclinical
http://www.sequella.com/
A semi-synthetic capuramycin class anti-biotic targeting the bacterial translocase-1 enzyme. Since humans don’t have this enzyme it’s an attractive target for treating mycobacterial infections. This therapy would target MAP but is also effective against C. Diff.

*STNM-01*
Class: Gene (RNAi) Therapy
Stage: Preclinical
http://www.stelic.com/cn21/pg111.html
A therapy targeting CHST15, a glycogene overexpressed at sites of fibrosis at stricture sites. 
STNM01 has been shown to selectively cleave CHST15 mRNA, which blocks expression of the CHST15 protein at sites of injury, and reverse the excessive accumulation of over-activated fibroblasts in this physiological state. This leads to the reduction of excessive collagen deposit and of intestinal stricture without affecting normal tissue structure.

*SYN-1002*
Class: Analgesic Peptide
Stage: Phase 1b
http://www.cllpharma.com/peptides-us.html
This drug is being studied for analgesic and anti-inflammatory action.

*Thalomid (thalidomide)*
Class: Immunomodulator
Status: Approved (Special Restricted Distribution)
http://www.thalomid.com
Possible mechanisms include anti-angiogenic and oxidative stress-inducing effects. It also inhibits TNF-α, IL-6, IL-10 and IL-12 production, modulates the production of IFN-γ and enhances the production of IL-2, IL-4 and IL-5 by immune cells. It increases lymphocyte count, costimulates T cells and modulates natural killer cell cytotoxicity. It also inhibits NF-κB and COX-2 activity.

There is one placebo controlled double blind study which showed about 50% remission rates at 8 weeks for refractory pediatric CD.

This drug is restricted because women of child-bearing capacity should not be exposed to it due to teratogenic actions (causes birth defects). 

Aug 19, 2015: A small scale placebo controlled trial of this drug showed 83.3% remission in cases of UC. 



*TNF-Kinoid*
Class: TNF Antibody
Stage: Phase I/II Trials
http://neovacs.fr/home/
Unlike anti-TNF mAB such as Remicade and Humira which require ongoing administration, TNF-Kinoid is a ant-TNF therapeutic vaccine. That is the patient will produce TNF antibodies themselves. The trial regiment was to receive 3 inoculations at days 0, 7, and 28, with a maintenance dose at 6 months. This is a vaccine, so the dosages will be the same or less as you get in a flu shot. 

*Tofacitinib (Xeljanz)*
Class: JAK Inhibitor
Stage: Approved for RA in trials for CD

It is an inhibitor of the enzyme janus kinase 3 (JAK3), which means that it interferes with the JAK-STAT signaling pathway, which transmits extracellular information into the cell nucleus, influencing DNA transcription. Recently it has been shown in a murine model of established arthritis that tofacitinib rapidly improved disease by inhibiting the production of inflammatory mediators and suppressing STAT1-dependent genes in joint tissue. This efficacy in this disease model correlated with the inhibition of both JAK1 and 3 signaling pathways, suggesting that tofacitinib may exert therapeutic benefit via pathways that are not exclusive to inhibition of JAK3.

*TRK-170*
Class: Small Molecule Drug
Stage: Phase II trials
http://www.toray.us/
TRK-170 is a small molecule alpha-4-beta-1 and alpha-4-beta-7 integrin antagonist.

Ustekinumab (Stelara/CNTO 1275)
Class: Biologic / mAB
Stage: Approved for plaque psoriasis
http://www.stelarainfo.com/
Interferes with the triggering of the body's inflammatory response through the suppression of certain cytokines. Specifically, CNTO 1275 blocks interleukin IL-12 and IL-23which help activate certain T-cells. It binds to the p-40 subunit of both IL-12 and IL-23 so that they subsequently cannot bind to their receptors. [14]

*VBY-036*
Class: Molecular Therapy
Stage: Preclinical
http://www.virobayinc.com/VBY-036.php
It is believed that Cathepsin S is a critical enzyme in the modulation of the immune system and the development of autoimmune diseases. In pre-clinical mouse models, it has been shown that VBY-036, a Cathepsin S inhibitor, can reduce inflammatory activity in the bowel, especially the large intestine. Trials are scheduled for 2015 with results expected in 2016.

*VE-202*
Class: Probiotic
State: Preclinical
http://www.vedantabio.com/
This is a formulation of about a dozen strains of the Clostridia bacteria (the good variety, not C. Diff) which Vedanta scientists have discovered helps recruit regulatory T-Cells to the gut to quell the inflammatory processes.

*1/21/2015 Update*: Here's a great National Geographic article describing some of the background on this development. It includes a link to the Nature article titled "Treg Induction by Rationally Selected Mixture of Clostridia Strains from the Human Microbiota." which was done by Kenya Honda et. al. Mr. Honda later went on to found Vedanta Bioscicences.

Here are the 17 strains they specifically identified in this study. Clostridium asparagiforme, Anaerotruncus colihominis, Clostridiaceae JC13, Clostridium bolteae, Clostridiales 1_7_47FAA, Lachnospiraceae 7 1 58FAA, Clostridium scindens, Clostridium 7 3 54FAA, Ruminococcus sp. ID8, Clostridium indolis, Eubacterium fissicatena, Clostridium ramosum, Lachnospiraceae 3_1_57FAA, Clostridium sp. 14774, Lachnospiraceae 3_1_57FAA, Blautia producta, Clostridium hathewayi. 

The study not only identified this group of bacteria, which only work in a symbiotic fashion to elicit the Treg response (they do not in isolation produce results), but also developed a platform for identifying other groups of bacteria which may target different parts of the immune system. And being that they are derived from human source, it's not a foreign drug that are usually held to a much higher scrutiny because their effect on the body is unknown. So trial clearances might be a lot easier.

*Vedolizumab (Entivyo)*
Class: mAB
Stage: Approved
https://www.entyvio.com/
It binds to integrin alpha-4-beta-7 (LPAM-1, lymphocyte Peyer's patch adhesion molecule 1). Blocking the this integrin results in gut-selective anti-inflammatory activity. Entyvio works by binding to white blood cells directed to the intestines, and thereby preventing these white blood cells from entering the intestinal walls and consequently reducing the inflammatory process caused by these cytokines.

*Vercimon (Traficet-EN)*
Class: Small Molecule Drug
Stage: Phase III
http://www.chemocentryx.com/product/CCR9.html
Vercirnon is intended to control the inflammatory response underlying IBD by targeting the chemokine receptor known as CCR9. In adults, CCR9 is found primarily on a population of T cells, a subset of the body's inflammatory cells that migrate selectively to the digestive tract. It is believed that when CCR9's ligand, CCL25 (also known as TECK), is over-expressed, the migration of T cells to the small and large intestine causes persistent inflammation that may result in Crohn's disease or ulcerative colitis, the two forms of IBD. Vercirnon is designed to prevent the migration of inflammatory cells to the digestive tract by blocking the function of CCR9. By interrupting CCR9 signaling, we believe vercirnon may hasten the elimination of inflammatory T cells from the intestines, thus potentially speeding recovery by reducing the longevity of flare-ups associated with IBD.

*VGX-1027*
Class: Small Molecule Drug
Stage: Phase I
http://www.inovio.com/technology/other-technologies/antiinflammatory-drugs/
A novel inhibitor of pro-inflammatory responses including TNF-alpha, this drug has demonstrated preclinical efficacy against Crohn’s disease and colitis, rheumatoid arthritis (RA), and Type 1 diabetes (T1D).

*Vidofludimus*
Class: Small Molecule Compound
Stage: Phase 1b
http://www.4sc.de/product-pipeline/clinical/vidofludimus
Vidofludimus is an orally administered small-molecule compound. The therapeutic efficacy of vidofludimus is based on a dual principle. First, the compound suppresses the formation of pro-inflammatory autologous messenger substances. Second, the compound blocks the enzyme DHODH (dihydroorotate dehydrogenase). This has the effect of inhibiting cell growth for activated immune cells in human blood - cells which play an important role in the development and further progression of autoimmune diseases. Trials to date have shown an 88.5% response rate for IBD.


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## nogutsnoglory

Great thread idea, thanks!


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## FrozenGirl

Great one! One minor point, in the AMG 185 thread you linked to they say AMG 181. No clue if that makes a difference, but great post. We all appreciate this!


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## rollinstone

great thread, we should sticky it


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## Farmwife

:thumright:Thanks :thumleft:


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## Mommabear

Wow! Thank you for doing this!!!


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## Tesscorm

Thank you so much for putting this together!!


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## DustyKat

xerida, thank you so much for taking the time and effort to compile this list. :thumleft: 

Do you want your updates to be incorporated into the first post? 

Dusty.


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## Jay Woodman

@xeridea Thanks for the list! I had no idea it was so extensive : )


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## xeridea

DustyKat said:


> xerida, thank you so much for taking the time and effort to compile this list. :thumleft:
> 
> Do you want your updates to be incorporated into the first post?
> 
> Dusty.


Hi DustyKat. I was thinking along the same lines, and that once I got to Z, to consolidate all of the entries into the first post. I'm glad to do that starting now if you think that makes more sense. I've probably got two, maybe three more updates to finish my list.


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## DustyKat

Whichever is easier for you is fine. 

Just let me know if you trouble editing the first post, as in access.


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## Carolyn

My daughter has taken THALOMID® (thalidomide).


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## xeridea

TxCell announces start of phase IIb clinical trial with Ovasave® for refractory Crohn’s disease.

This personalize T-reg therapy is for the severe cases of CD that are refractory to other treatments. It's a multi-center trial in Europe (Austria, Belgium, France, Germany, Italy and United Kingdom). See OvaSave in top post for a brief description of procedure.

See http://www.txcell.com/images/stories/pdf/PR_EN_TxCell_CATS29_start.pdf


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## Mommabear

Can someone comment on this possibility. Is this promising? I still believe and hope to see the day that the Crohn's MAP Vaccine works, but just in case ... 

http://neovacs.fr/wp-content/uploads/pr-8-12-10.pdf


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## xeridea

Arena Pharmaceuticals just released promising results from its phase 1b (safety) trial on its APD334 drug that targets the sphingosine 1-phosphate subtype 1 (S1P1) receptor. This is a lymphocyte lowering drug, and these class of drugs have shown promising results in phase 2 and 3 trials against psoriasis, MS and UC. APD334 is a small molecule drug (not biologic).

The phase 1b results were released yesterday which caused a bump in their stock price, and the company now plans to move quickly to bring the drug to phase 2 trials for CD.

There is more info on this drug in the top post, or the link below for the finance news trying to explain the company's 70% stock spike yesterday.

http://finance.yahoo.com/news/arena-pharmaceuticals-reports-positive-results-130000029.html


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## Crohn2357

*Isis Pharmaceuticals Announces Collaboration With Janssen to Discover and Develop RNA-Targeted Therapeutics for Autoimmune Diseases in the GI Tract*
http://ir.isispharm.com/phoenix.zhtml?c=222170&p=irol-newsArticle&id=2002820
*Isis Pharmaceuticals Announces Results of Alicaforsen Phase 3 Clinical Trials in Patients With Crohn's Disease*
http://ir.isispharm.com/phoenix.zhtml?c=222170&p=irol-newsArticle&id=1289685&highlight=

*Discussion:*
http://www.healingwell.com/community/default.aspx?f=38&m=3290188&g=3290207#m3290207


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## xeridea

Crohn2357 said:


> *Isis Pharmaceuticals Announces Collaboration With Janssen to Discover and Develop RNA-Targeted Therapeutics for Autoimmune Diseases in the GI Tract*
> http://ir.isispharm.com/phoenix.zhtml?c=222170&p=irol-newsArticle&id=2002820
> *Isis Pharmaceuticals Announces Results of Alicaforsen Phase 3 Clinical Trials in Patients With Crohn's Disease*
> http://ir.isispharm.com/phoenix.zhtml?c=222170&p=irol-newsArticle&id=1289685&highlight=
> 
> *Discussion:*
> http://www.healingwell.com/community/default.aspx?f=38&m=3290188&g=3290207#m3290207


It's discouraging they didn't see good results in CD in this Phase III trial. This seems contradictory to Celgene's initial results with Morgersen in that drug's phase II trials. 

On the flip side, they did see positive outcomes in UC so still pushing the IBD envelope forward.


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## Crohn2357

Yes, overall, it seems competition for ibd drug market is increasing.  I think that is the most important part.


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## xeridea

Protalix is developing an oral Anti-TNF (PRX-106) drug for Inflammatory Bowel Disease. Oral Anti-TNF represents a novel mode of administering a recombinant anti-TNF protein. 

It looks like Phase 1 safety trials in 2015 and on good results, to partner with a deeper pocket company to advance the drug to later stage trials.

From press release: The Company plans to initiate clinical efficacy trials of Oral Anti-TNF for the treatment of Inflammatory Bowel Disease (IBD) in a non-IND setting during 2015. Upon reviewing the proof of concept (POC) data, expected in early 2016, the Company intends to collaborate with a well-suited partner for further development.


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## Axelfl3333

An article in the daily mail mentioned Vedolizumab has been approved by NICE from April for treatment of crohns and ulcerative colitis.NICE is the clinical body in the UK which approves new drugs.


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## xeridea

Microbiome related development on drug that inhibits a "target" (possibly bacteria) that company believes may cause disruptions in gut that lead to CD. The press release is intentionally vague, my guess because they want to protect some proprietary information for the time being.

SGM-1019 is an oral small molecule drug that inhibits a target that Second Genome researchers discovered to be a key driver of inflammatory bowel disease when modulated by changes in the microbiome.

Here is the press release.


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## xeridea

Another microbiome company, Vedanta Biosciences, just inked a licensing deal with Janssen/J&J (the folks who bring us Remicade) to take its VE-202 drug into further development. This is essentially a probiotic formulation of a dozen or so strains of the Clostridium bacteria (not C. Diff though) that has been demonstrated to recruit regulatory T cells to the intestines. Treg cells are CD4+ T cells in charge of suppressing potentially deleterious activities of Th cells (Th cells control adaptive immunity against pathogens and cancer by activating other immune cells).


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## Crohn2357

http://www.healingwell.com/community/default.aspx?f=38&m=3299376
http://www.healingwell.com/community/default.aspx?f=17&m=3299379

I hope it is ok for you xeridea. Thanks for this work.


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## xeridea

*1/21/2015 Update to my Vedanta post above*: Here's a great National Geographic article describing some of the background on this development. It includes a link to the Nature article titled "Treg Induction by Rationally Selected Mixture of Clostridia Strains from the Human Microbiota." which was done by Kenya Honda et. al. Mr. Honda later went on to found Vedanta Bioscicences.

Here are the 17 strains they specifically identified in this study. Clostridium asparagiforme, Anaerotruncus colihominis, Clostridiaceae JC13, Clostridium bolteae, Clostridiales 1_7_47FAA, Lachnospiraceae 7 1 58FAA, Clostridium scindens, Clostridium 7 3 54FAA, Ruminococcus sp. ID8, Clostridium indolis, Eubacterium fissicatena, Clostridium ramosum, Lachnospiraceae 3_1_57FAA, Clostridium sp. 14774, Lachnospiraceae 3_1_57FAA, Blautia producta, Clostridium hathewayi. 

The study not only identified this group of bacteria, which only work in a symbiotic fashion to elicit the Treg response (they do not in isolation produce results), but also developed a platform for identifying other groups of bacteria which may target different parts of the immune system. And being that these bacteria are derived directly from human source, and not a foreign or novel compound whose safety profile is unknown, clearance to trials may be much faster.


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## xeridea

This is a follow up study on MS patients who received HSCT (a kind of stem cell therapy), and reports that after 2 years 80% of the patients were relapse free (in CD parlance, sustained remission) without any maintenance medication. Remarkably greater than half also had reversal of damage done by their disease. 

I mention this here because the study lead, Dr. Burt out of Northwestern University, is also investigating HSCT for Crohn's and other "autoimmune" diseases. Regardless, it provides another platform for re-booting the immune system.

http://www.healthline.com/health-ne...rst-ms-treatment-reverses-disability-012215#1


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## xeridea

*Inflectra*
http://www.hospira.com/en/
Class: Anti-TNFα mAB
Stage: Approved

This is a Remicade (Infliximab) biosimilar approved in Europe. It purports to have the same profile as Remicade but at a reduced cost.

Not yet available in the U.S., though it is scheduled for Advisory review by FDA March 17, 2015, albeit for RA. But if that goes through approval for other conditions might soon follow. 

On the business side, Hospira is a likely Pfizer takeover target.


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## xeridea

Company that may re-emerge out of sale of its cancer treatment technology could bring some novel therapies for inflammatory diseases.

This is not Crohn's related but may indicate a possible future treatment. Brystol-Meyers Squib shelled out big bucks (potentially $1.2 billion) to acquire some novel cancer treatment drug (one-a-day pill) from Flexus. Though all of the cancer technologies are sold, the company has kept its T cell research rights, and will focus on the regulatory T cells. These are the cells that help cool down inflammation and may play a role in Crohn's.

What struck me as interesting is that they were able to develop the cancer treatment in a very short period, so maybe they'll have a similar streak on their reg T cell efforts.


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## Crohn2357

http://medicalxpress.com/news/2015-03-drug-crohn-disease-early.html


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## xeridea

Crohn2357 said:


> http://medicalxpress.com/news/2015-03-drug-crohn-disease-early.html


Just published (3/19/2015) reports in New England Journal of Medicine on Celgene's GED-0301 continue to show very promising results. The drug is currently in Phase II trials but the results are promising enough that the company believes it can advance it to Phase III.

_65 percent of patients treated with GED-0301 160 mg once daily for two weeks achieved clinical remission at both day 15 and day 28, versus 10 percent of patients on placebo

72 and 67 percent of patients treated with 160 mg once daily were in clinical remission at day 28 and at day 84, respectively

Overall rates of adverse events and serious adverse events were similar across treatment groups, including placebo_

Here's the Press Release. The drug is listed in the master list above under "Mongersen".


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## irishgal

This is a great reference! I was wondering if the AMAT (anti map antibiotic therapy) could be added to your list. Maybe I missed it. I've tried a bunch of the meds listed, and nothing worked except AMAT. Also, LDN (low dose naltrexone) is another up and coming med that has some early validity.


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## xeridea

irishgal said:


> This is a great reference! I was wondering if the AMAT (anti map antibiotic therapy) could be added to your list. Maybe I missed it. I've tried a bunch of the meds listed, and nothing worked except AMAT. Also, LDN (low dose naltrexone) is another up and coming med that has some early validity.


RedHill's RHB-104 is listed for anti-MAP. I'll add what I know about LDN and it's mechanism of action.


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## xeridea

Celgene is upping its stake in the IBD market. They just announced a  $7.2B offer to purchase Receptos of San Diego, CA. Receptos' candidate drug RPC1063 operates on same targets as Entivyo and is showing statistically significant clinical and mucousal improvements. The current trials are for UC but Phase II trials are being initiated for CD.

What's promising with this drug is orally administered and has very good safety profile based on Phase I/II/III trial results.


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## teeny5

Hi Xeridea I currently take Colazal (balsalazide) and previously have taken Azulfidine (sulfasalazine) both are 5-ASAs

Both are mentioned here:

http://health.usnews.com/health-conditions/digestive-disorders/crohns-disease/treatment

Colazal - http://reference.medscape.com/drug/colazal-giazo-balsalazide-342075#10

Azulfidine - http://reference.medscape.com/drug/azulfidine-sulfasalazine-343280#10


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## xeridea

*PTG-100*
Protagonist Therapeutics
An orally administered α4β7 Integrin Specific Antagonist. This is the same target as Entivyo (Vedolizumab), but with the advantage that can be taken as a pill rather than via infusion. Currently in pre-clinical phase, with early trials scheduled for 2016.


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## xeridea

teeny5 said:


> Hi Xeridea I currently take Colazal (balsalazide) and previously have taken Azulfidine (sulfasalazine) both are 5-ASAs
> 
> Both are mentioned here:
> 
> http://health.usnews.com/health-conditions/digestive-disorders/crohns-disease/treatment
> 
> Colazal - http://reference.medscape.com/drug/colazal-giazo-balsalazide-342075#10
> 
> Azulfidine - http://reference.medscape.com/drug/azulfidine-sulfasalazine-343280#10


Thanks teeny, I have added these two under mesalamine in the master list.


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## xeridea

TxCell was granted Fast Track Designation by the FDA on their lead product Ovasave. This facilitates the review and approval process. Ovasave is an antigen specific autologous T regulatory somatic cell therapy in development for the treatment of Inflammatory Bowel Disease that is currently in phase IIb trials in Europe.

http://www.txcell.com/images/CP/2015/TxCell_PR_FastTrack_150727_EN_def.pdf


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## rollinstone

Anyone able to get the results of their phase 2a trial? Can't seem to find it online


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## xeridea

rollinstone said:


> Anyone able to get the results of their phase 2a trial? Can't seem to find it online


Here is an abstract of the Phase 1/II (a?) study. It was an open label study that looked at CDAI and CD16 monocyte reductions as response indication.


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## Crohn2357

Galapagos Announces Last Patient Has Been Randomized in Crohn’s Disease Study With Filgotinib

http://ibdnewstoday.com/2015/08/07/...t-randomized-crohns-disease-study-filgotinib/



> The company is expecting to announce the study’s primary endpoint results after 10 weeks of treatment in December, and 20-week treatment results during the first trimester of 2016.


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## egaleeye

FMT (Fecal  microbiota Transplants) wasn't on your list!


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## xeridea

Re: Refractory Perianal Fistulizing CD.

TiGenix announces achieving primary endpoint of their Phase III trial for treatment of complex perianal fistulas using a single injection of their Cx601 allogeneic expanded adipose-derived stem cells.

More than 50% of subjects achieved combined remission at week 24. A larger number of patients had their fistulas close by week 6. They report clinically significant results to patients refractory to all current therapies.

http://www.tigenix.com/en/download/...RoTo5qQ5U3RyU6FaVTYZWwrvKWoZaAoZTI2bQTok7QA==


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## xeridea

egaleeye said:


> FMT (Fecal  microbiota Transplants) wasn't on your list!


I'd gladly post any information you may have on this. Will you point me to any companies or trials that I can reference in the list?


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## MarkB

irishgal said:


> This is a great reference! I was wondering if the AMAT (anti map antibiotic therapy) could be added to your list. Maybe I missed it. I've tried a bunch of the meds listed, and nothing worked except AMAT. Also, LDN (low dose naltrexone) is another up and coming med that has some early validity.


Good point. Most of the treatments treat symptoms only. Anti-MAP treats the likely cause of many cases of Crohn's.  There's a 16-minute educational video that provides a great job introduction to the topic. 

Search for "Crohn's Controversy: Cause, Vaccine and Anti-MAP Therapy" on youtube.


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## xeridea

MarkB said:


> Good point. Most of the treatments treat symptoms only. Anti-MAP treats the likely cause of many cases of Crohn's.  There's a 16-minute educational video that provides a great job introduction to the topic.
> 
> Search for "Crohn's Controversy: Causie, Vaccine and Anti-MAP Therapy" on youtube.


The list includes RHB-104 anti-MAP therapy currently in phase 3 trials. We should see data on trial results by next summer. 

Like many others I hope research in this area proves out.


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## MarkB

Indeed!  I would point out that there are numerous studies in the medical literature showing that the anti-MAP regimen developed by Dr. Thomas Borody has been successful in many Crohn's patients. These are not controlled clinical trials, but rather case studies. This is all explained well in the video I referenced.  Based on all the reading I've done, I would tell a Crohn's sufferer who has tried everything else & still suffering, educate yourself on MAP now. There are ways to get on the anti-MAP regimen now, but it will take some research & legwork on your part. You probably won't get your gastroenterologist to prescribe it just yet (until the clinical trials are complete). But there are doctors out there who will work with you, and who will work with your gastroenterologist, and prescribe anti-MAP drugs. The case studies published to date are quite promising, and show considerable success in getting Crohn's into remission.


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## xeridea

S1P receptor modulators continue to make noise in the pharmasphere. Celgene's recent $7 Billion acquisition of Receptos, and yesterday, Biogen picked up worldwide rights to Mitsubishi Tanabe's MT-1303 in a multi-million dollar deal.

S1P modulation sounds like a gentler form of immunomodulation by the likes of AZA, 6MP and MTX, but seemingly, without some of the inherent increased risks of infections that those drugs bring.

*Sphingosine-1-phosphate receptor and its modulation*

The oral sphingosine 1-phosphate (S1P) receptor (S1PR) modulator has been shown to be effective in the treatment of inflammatory conditions such as MS, UC and CD. The drug binds with high affinity to 4 of the 5 G-protein-coupled S1P receptors (S1P(1-5)). After binding, the receptors are internalized, degraded, and thus functionally antagonized. Under physiologic conditions, S1P(1) mediates the egress of lymphocytes from secondary lymphoid organs to the peripheral circulation. Functional antagonism of S1P(1) results in a reduction in peripheral lymphocyte counts by inhibiting egress of lymphocytes, including potentially encephalitogenic T cells and their naïve progenitors that would otherwise be present within the circulation. Despite the reduction of lymphocyte counts, patients with MS have been shown to have few infections and related complications and were able to mount antigen-specific immune responses in vaccination studies.

10-Sep-2015: Biogen just inked a deal for worldwide licensing rights to this drug from Mitsubishi Tanabe. It is looking at accelerating a current Phase II trial for Crohn's to Phase III.


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## MarkB

The group developing the Crohn's MAP vaccine has posted a nice summary of the literature on the anti-MAP therapy that has been used since the 1990s & is currently used by a small group of Crohn's experts.  Lot of stuff there, including some papers from medical journals. I'd make sure you page all the way down to the Patient Information Leaflet on pages 61-63 of the file. 

http://crohnsmapvaccine.com/pdfs/map-info-pack-low-res.pdf


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## recmlc

fyi


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## xeridea

MarkB said:


> The group developing the Crohn's MAP vaccine has posted a nice summary of the literature on the anti-MAP therapy that has been used since the 1990s & is currently used by a small group of Crohn's experts.  Lot of stuff there, including some papers from medical journals. I'd make sure you page all the way down to the Patient Information Leaflet on pages 61-63 of the file.
> 
> http://crohnsmapvaccine.com/pdfs/map-info-pack-low-res.pdf


I have added CMV to the list.


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## MarkB

xeridea said:


> I have added CMV to the list.


Xeridea, Thank you for your maintenance of this excellent resource. 

I suggest it may be worth adding info on the AMAT (anti-MAP microbial therapy).  I know you have a link to the RedHill Biopharma clinical trial currently underway. But it's worth noting that some version of AMAT has been around for some time now, and is being practiced by a few physicians. These groups report greater success than some of the 'approved' drugs that are treating inflammation (rather than the likely underlying cause: MAP).  

Of the studies in the the link that the CMV group posted, I'd start with 3rd page of the document -- the paper by Chamberlin, Borody & Campbell (Expert Rev. Clin. Immunol. 7(6), 751–760 (2011)). For AMAT, see especially the material starting on page 754 of that paper (or page 6 of the CMV group's big pdf file).


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## xeridea

Galapagos' Filgotinib meets phase 2 primary endpoint. This is a once daily 200mg JAK1 inhibitor intended for moderate to severe CD who are non-responsive or failed anti-TNF drugs. The preliminary results showed statistically significant reduction of CDAI scores, normalization of CRP levels, and no effect on liver based on tested parameters. It also has a relatively good safety profile also being tested for RA.


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## Forristicat

I never knew there were so many.


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## xeridea

Enterome recently entered into agreements with Takeda (Entivyo) and Janssen (Remicade) to develop/market a new Crohn's treatment, that I'm assuming is based on their FimH antagonist platform. This is targeting AIEC, but from a different angle than Qu. Here's a video that describes the platform:

https://www.youtube.com/watch?v=aTeZZ7ydmfM


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## xeridea

Nestle expanding its footprint in the IBD microbiome space by investing $120 million in Seres for rights to their platform outside of North America. Seres is developing microbiome based therapies for C. Diff and IBD (CD/UC).


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## xeridea

Forum software doesn't let me edit the original post anymore, so here's an update on Xeljanz CD trials.

*Summary:*

The researchers concluded that clinical response or remission occurred in greater proportions of the treatment groups, but the results were not statistically significant.

*For the induction phase:*

Forty-three percent of the 10 mg group achieved clinical remission at week 8 — the primary endpoint — compared with 43.5% in the 5 mg group and 36.7% of the placebo group. However, researchers did not observe statistical significance in this comparison. Comparable results were observed in patients with and without previous TNFi exposure.

*For the maintenance Phase:*

In the maintenance trial, researchers randomly assigned 126 tofacitinib responders from the induction study 5 mg tofacitinib (n = 43), 10 mg tofacitinib (n = 43) or placebo (n = 42) twice daily for 26 weeks. In the 5 mg group, 39.5% achieved clinical response or remission, compared with 55.8% of the 10 mg group and 38.1% of the placebo group; however, although numerically higher in the 10 mg group, the results did not reach statistical significance. C-reactive protein and fecal calprotectin levels were significantly lower at week 26 for the 10 mg group (P < .0001) and fecal calprotectin was significantly lower for the 5 mg group vs. placebo (P < .05).


_*Tofacitinib (Xeljanz)*
Class: JAK Inhibitor
Stage: Approved for RA in trials for CD

It is an inhibitor of the enzyme janus kinase 3 (JAK3), which means that it interferes with the JAK-STAT signaling pathway, which transmits extracellular information into the cell nucleus, influencing DNA transcription. Recently it has been shown in a murine model of established arthritis that tofacitinib rapidly improved disease by inhibiting the production of inflammatory mediators and suppressing STAT1-dependent genes in joint tissue. This efficacy in this disease model correlated with the inhibition of both JAK1 and 3 signaling pathways, suggesting that tofacitinib may exert therapeutic benefit via pathways that are not exclusive to inhibition of JAK3._


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## FrozenGirl

Thanks for update. Interesting numbers, I do wonder why the placebo rate was so high. Further studies might be interesting to see if a statistically significant benefits comes out.


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## Charlotte.

Just came across this thread, thank you so much for the summary and research! That looks very promising what is on the way!


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## xeridea

Enterome is gaining more traction on the AIEC (Adherent Invasive E. Coli) front by securing an exclusive worldwide license of Vertex Pharmaceuticals small molecule FimH antagonists. FimH is a cell surface adhesion protein that allows the pathogenic E. Coli to stick to the gut wall and penetrate it, which leads to inflammation.

They will embark on their first clinical trial of one of these drugs, EB8108, later this year.

Looks like the AIEC race is on...


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## aypues

CCFA Patient Education Symposium - San Diego, from last weekend. Upcoming treatments.


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## xeridea

At the Digestive Disease Week conference in San Diego this week, a couple speakers presented findings showing early signals about the safety profile of Entyvio (vedolizumab: α4β7 integrin receptor antagonist) that may be different than anti-TNF-α drugs. Entyvio was approved in 2014 for treating UC/CD so the safety profile is still comparatively new, and collected mostly out of clinical trials, whereas the anti-TNF drugs have a much longer history of use dating back to the late 90's and have much more data reported from the field.

As one speaker put it, _"Further analysis of the long-term real-world safety of vedolizumab should be conducted before conclusive claims of vedolizumab's safety can be made,"_

The comparison numbers are Entyvio vs. anti-TNF-α.


 1.8% central nervous system hemorrhages and cerebrovascular accidents, vs. 0.4% in anti-TNF-α group.
 more pulmonary thrombotic and embolic conditions, 1% vs. 0.4% 
 pulmonary edema (0.6% vs. 0.1%)
 case of autoimmune hepatitis, optic neuritis, meningitis in patients who had previous predisposing conditions.

This is based on data from the FDA Adverse Event database and clinical experience from a doctor at Mayo.


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## xeridea

An update on BI-655066 (from the master list in the top post here). 

Now being referred to in a more traditional name for a biologic, risankizumab, in a randomized and blinded, placebo controlled Phase IIa (dose discovery) trial showed favorable results vs. placebo with fairly good safety signals and showing effectiveness in a refractory patient population.

“This was conducted in a very refractory patient population; 94% of patients had actually received TNF-blocker therapy and had failed or were intolerant to those drugs,” Feagan said. “At week 12 what we saw in the pooled group — the 200 mg and 600 mg [groups] taken together— was [the] overall rate of remission was approximately 30% vs. 15% [with placebo], which was statistically significant. But perhaps more importantly, the high dose of the drug ... was approximately 36%, and there was a dose-response curve where the low dose was intermediate between placebo and the high dose. So, a very clear proof-of-concept, with dose-linearity of response ... about as good as you can get in a phase 2 study.”

This drug is being developed by Germany's Boehringer-Ingelheim and should now start moving into phase III trials.


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## FrozenGirl

Thanks go the updates xeridea.  Also risankizumab sounds very promising given the result within TNF failure group. It sounds like a higher dose might give an even better response, if they could get to the 40-50 percent remission rate it could be a blockbuster drug.


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## xeridea

4D Pharma has re-started their Phase 1 trial of Thetanix for Pediatric Crohn's Disease. Thetanix is based on bacteroides thetaiotaomicron, a major symbiont of the adult human gut. It helps with digestion of many complex starches for which we don't have the enzymes, helps in the formation of the mucus layer and promotes the generation of new blood vessels in the gut.


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## Scared1

Hi xeridea, when you say we "don't have the enzymes" what do you mean? I am just curious - is this because of the immune disposition of Crohn's patients?


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## xeridea

Re: Refractory Perianal Fistulas

Takeda has licensed European riights to Ti-Genix's Cx601 treatment. They will further develop and commercialize the treatment. Takeda is the Japanese company that produces Entivyo.

The Cx601 treatment is wrapping up Phase III trials in Europe and expected to be approved there in 2017.


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## xeridea

Seres reports disappointing interim results on its SER-109 "poo;-in-a-pill" drug for recurrent CDI. There was no statistically significant difference between the drug and placebo. They're trying to figure out why this doesn't align with earlier, much more promising results.

http://finance.yahoo.com/news/seres-therapeutics-announces-interim-results-110000711.html


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## xeridea

4D Pharma announced that they have initiated Phase 1 trial of Thetanix for Pediatric Crohn's Disease. Phase 1 trials are for figuring out the proper/safe dosing levels of a drug.

Here is an excerpt from the top-post for Thetanix, where it was referred to by its pre-clinical development name LBP-001:

_Thetanix, comprised of Bacteroides thetaiotaomicron, an obligate anaerobe, is a major endosymbiont of the human gut. Bacteroides thetaiotaomicron is a major component of the adult intestine and has been used as a useful model for the study of human-bacterial symbiosis. Its metabolic function for humans is to degrade plant polysacharides, a very essential capability for the human gut. Additionally, it is very important during the postnatal transition between mother's milk and a diet heavily consisting of plant starches. It has been found to stimulate angiogenesis (growth of new blood vessels from pre-existing vessels) within the gut, due to a microbial signal via bacterial sensing Paneth cells. B. thetaiotaomicron benefits its host by providing sufficient absorptive ability for nutrients the microbe helps process. Another postnatal developmental process within the gut mediated by Bacteroides thetaiotaomicron is the formation of the intestinal mucosal barrier, which helps protect the host against pathogenic invasion via the regulation of the expression of species-specific protein antibiotics. The environment sensing regulatory apparatus present in B. thetaiotaomicron allows for adaptive food seeking, which stabilizes food webs, and subsequently leads to the longevity of communities._


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## xeridea

Celgene today announced interim topline results from their CD001 GED-0301 (mongersen) oral antisense therapy. 

This preliminary evaluation had a proportion of patients showing 25% or more endoscopic improvement, suggesting that mucosal healing is underway and that the drug is correctly targeting the underlying cause of Crohn's. 

This is an assessment at the first 12 weeks of the Phase 1b study, a period where patients have been taking daily doses of the drug. The next leg, lasting 52 weeks, will continue to monitor these patients and includes further endoscopic evaluation. Final study results are expected in 2017. They are also ramping up for the start of the Phase II study.

More specific data on this preliminary leg will be presented later this year at a scientific meeting.


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## Crohn2357

http://ibdnewstoday.com/2016/09/16/...ts-of-ged-0301-in-active-crohns-disease-study 

“These data support the notion that GED-0301, a potential first-in-class oral antisense therapy, *may target an underlying cause of Crohn’s disease, rather than simply improving symptoms.*”

GED-0301 takes an unusual approach to treating Crohn’s, using antisense technology to target a key intracellular signaling protein thought to be involved in intestinal inflammation and the pathogenesis of the disease. It is orally administered and designed to act locally."

How? Forgive my ignorance, but I can't see a fundamental difference of action between this and humira.


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## xeridea

Aerpio has begun Phase 1a safety and tolerability study of AKB-4924. This is a small molecule, HIF-1α (hypoxia inducible factor 1 alpha) stabilizing agent. HIF-1α is critical for the regulation of innate immune responses and maintenance of epithelial barrier function, particularly in the gut. AKB-4924 is being developed as a once-daily, orally administered therapy for IBD.

In multiple in vivo preclinical models of IBD, AKB-4924 has been shown to markedly reduce disease activity, with decreased levels of inflammation and preservation of mucosal integrity. 

HIF is a master regulator in the control of gene expression in response to changes in tissue oxygen levels. Though HIF is commonly associated with changes in vascular growth, it is also critical for the regulation of innate immune responses and maintenance of epithelial barrier, particularly in the gut and skin.


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## MarkB

I gleaned this news from the anti-MAP therapy RHB-104 from the 'MAP Vaccine Ready for Human Trials' thread, posted by Scared1.  Big news for folks tracking treatments of Crohn's. 



> On the contrary - very good news if you tuned into their webcast (I did). By increasing their length of the trial - they are able to show greater efficiency because they have a larger sample size, and they are introducing an early stop process for very success results as an option. The interim results are very good and a new paper was published:
> 
> "A single capsule formulation of RHB-104 demonstrates higher anti-microbial growth potency for effective treatment of Crohn’s disease associated with Mycobacterium avium subspecies paratuberculosis"


Additional notes: 
I added the link to the above paper. See also RedHill Biopharma's Crohn's page  and their 6 October 2016 announcement. 

Antimicrobial (anti-MAP) therapy is different from the vaccine, but both developing therapies target MAP (mycobacterium avium paratuburculosis). There is much evidence supporting MAP as a cause of Crohn's, although this remains controversial and is ignored by most gastroenterologists and CCFA.  If you are not familiar with this topic, good starting places are Phil Nicholson's Crohn's Controversy video, and the Core Literature packet downloadable from Dr. John Hermon-Taylor's group.


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## xeridea

Celgene released some additional positive data from their Phase 1b trial of GED-0301 (mongersen). Of note is the endoscopic improvements that were observed.

From this source:

Clinical improvement was seen by week 2, and clinical response (CDAI decrease ≥100) and remission (CDAI <150) rates were highest in the 12-week treatment group at 67 and 48 percent respectively, at week 12. The mean CDAI reduction from baseline at week 12 in the 12-week treatment group was 133 points. Of the patients with evaluable endoscopies at week 12 (n=52), 37 percent had an endoscopic response (≥25 percent reduction in SES-CD score from baseline), with no meaningful difference across treatment groups. In addition, of those patients with greater endoscopic disease activity at baseline (SES-CD score of >12; n=16), 63 percent exhibited a reduction ≥25 percent in SES-CD score and 31 percent had a reduction of ≥50 percent.


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## Seuxin

I will be probably involved in the GED-03-01 ( Mongersen) in a few week...


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## xeridea

xeridea said:


> Enterome is gaining more traction on the AIEC (Adherent Invasive E. Coli) front by securing an exclusive worldwide license of Vertex Pharmaceuticals small molecule FimH antagonists. FimH is a cell surface adhesion protein that allows the pathogenic E. Coli to stick to the gut wall and penetrate it, which leads to inflammation.
> 
> They will embark on their first clinical trial of one of these drugs, EB8108, later this year.
> 
> Looks like the AIEC race is on...


...and it was announced yesterday the kickoff of their Phase 1 trial.


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## DB in PVE

I would like to see dietary treatment included in this list because it's very effective and not all treatment has to be pharmaceutical.  I have a link to a short video from Dr. Micheal Greger summarizing the research on this but am not able to post it here because I'm a fairly new member.  But the study showed that the group assigned to a vegetarian diet achieved a higher and more sustained remission rate than any study ever documented.  That's pretty powerful.  The video can be found on the Nutrition Facts website.


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## jlvk

I don't know if this is silly question, but does anyone go without Humiera or TNF blockers and just treat during "flare ups" ? Im on prednisone right now for the inflammation they found, as well as antibiotics for an abscess that was caused by the disease. I'm very newly diagnosed and don't know whole lot about the condition but I figured there may be different severeties and I'm wondering if it is possible to go without the injections. Also trying to weigh the risk of taking/ not taking the injections (if it is at all possible).


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## Guerrero

Not everyone are on biologics it depends on your condition. A good GI should assess what's the best therapy for you.
Biologics have to be taken for long term period without quitting it to avoid building antibodies, while steroid for short term period to avoid many side effects.
Dont hesitate to ask question should you need further info


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## jlvk

This is extremely helpful! Thank you, I really want to make sure it's necessary before I committed into it.. this makes me very hopeful.


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## DB in PVE

It may be helpful to review this outstanding resource for understanding the published medical studies regarding Crohn's disease and diet (ie, clinical nutrition).  I have learned so much here.  I have healed my own GI issues by making changes to a whole food plant-based diet.  Most physicians have not been trained in nutrition and don't have time to keep up with all the medical journals so this is an important resource and they synthesize it down to easy to understand videos.

I am not yet a frequent-enough poster to be allowed to post a direct link, sorry. 
 Just go to the nutritionfacts dot org website and search on the word Crohn and it will all come up.  

DB


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## Lynda Lynda

Wow !


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