- Joined
- Jul 11, 2014
- Messages
- 337
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
Stage
hase 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.
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
Stage
hase 2b trials planned for latter half of 2014An 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.
Last edited:
