New and Emerging Therapies in IBD Sarah Streett MD, AGAF Clinical Associate Professor of Medicine Stanford University
New and Emerging Therapies in IBD I have no relevant financial disclosures.
IBD is a Great Medical Mystery Ulcerative colitis and Crohn s disease remain incompletely understood. They are systemic processes, with manifestations that can spill over from the GI tract to involve the skin, eyes, joints, hepatobiliary system. They typically affect people in the their youth or their prime. They are on the rise world wide, both in first and developing countries. Are they autoimmune disorders, infectious diseases, environmental?
Genetic Susceptibility Over 160 susceptibility loci have been identified as conferring an increased risk of IBD. These are diverse disorders. The genes whose function are Genetics known impact the GI immune system. IBD is distinct in each individual. The Crohn s/uc paradigm may become outdated.
Epigenetics Which genes we inherit is only part of the story. Only half of the time do both identical twins both develop Crohn s disease. Epigenetics, the study of the way in which the expression of heritable traits is modified by environmental influences or other mechanisms, without a change to the DNA sequence, has increasingly come into focus. Environmental factors such as diet, exposure to antibiotics or other chemicals can modify the potential for a gene to cause a disease.
GI Immune System The digestive tract is our largest immunologically active surface. Alterations in immune pathways, Immune system from genetic or acquired origin, may alter the local response. Genetics The gut immune system is highly complex, and dynamic. There is increasing evidence that the gut immune system regulates our systemic immune system.
Microbiome The gut microflora outnumber our own cells by a factor of 10 to 1, and microbial DNA outnumbers human DNA by 100 to 1. The gut microbiota can be thought of as a microbial organ, which actively participates in many processes that benefit us: Immune system Digestion and energy capture from food. Defense against intestinal pathogens. Genetics Local and systemic immune response modulation and tolerance. Microbiome Synthesis of vitamins and other substances such as butyrate and SCFA which are essential.
Role of the Microbiome Perturbation of the microbiome has been implicated in the development of obesity, metabolic syndrome, fatty liver, as well as in IBD. Multiple factors impact the composition of our microbiome; Parental characteristics, mode of delivery, early antibiotic exposure. Diet composition has been estimated to affect 50-60% of microbiome composition- Western diet (animal protein, refined carbs, low fiber and food additives) is associated with decreased microbial diversity, as well as altered composition of bacterial phyla (lower numbers of bacteria from the phylum Bacteroidetes, greater numbers of Firmicutes) Food additives may play a role- emulsifiers cause IBD in mouse models of colitis. Goldszmid, R Nature Immunology 13, 932 938 (2012)
Convergence of Evidence We have a convergence of evidence in the fields of genetics/epigenetics, immunology, and a rapidly growing understanding of the microbiome. Immune system Severine Vermeer described: The current hypothesis in IBD is that the disease results from a faulty immune recognition, tolerance, and defense against the commensal microbiota and dietary antigens present in Westernized diets and in a genetically susceptible host. Genetics Microbiome Environmen t
Principles of Therapy: 1. IBD is chronic, and progressive. 2. Treating early has benefit. 3. Everyone s disease, and response to therapy is different. 4. Combinations of medications are often the most effective. 5. It is important to monitor the disease objectively, not rely on symptoms. 6. Risks of treatment should be weighed against the risks of untreated disease progression. 7. When you find a therapy that works, continue it. 8. Steroids for a prolonged period are deleterious and indicate that alternate therapy is needed. 9. Narcotics are contraindicated, mask symptoms and worsen outcomes.
Goals of Therapy 1- Relieve symptoms 2- Clinical remission 3- Steroid free remission 4- Mucosal healing 5- Histologic healing
Treatment Phases 1. Induction- people are often the sickest, and most motivated. This is a high risk time. 2. Maintenance- once remission has been achieved, compliance becomes a common issue. 3. Episodic treatment leads to irreversible organ damage, and flares may not respond to treatment that worked before. 4. Chronic inflammation is a risk for cancer.
Mainstay IBD Therapy: 5-ASA or Sulfasalazine- Can be effective for mild colitis. Beneficial to combine w topicals. Steroids remain important as induction agents, but should never be given for prolonged courses. Immunomodulators 6-MP/Imuran and Mtx have better efficacy in UC- Biologics- anti-tnf
Risk Assessment: Top down therapy concept- Evolved to a paradigm of patent risk assessment, and top vs. accelerated step up therapy. High risk features: Young age Severe disease Extensive disease (pan-colitis, small bowel/ugi CDz) Fistulizing, stenosing, or rectal Crohn s Need for more than one course of steroids
Anti-integrin Therapies: Vedolizumab Etrolizumab- Anti-integrin therapies Alicaforsen Anti IL 12/23: Usteminumab JAK-STAT Inhibitors: Tofacitinib- Other mechanisms of action: Mongersen- Antisense Smad7 Ozanimod- S1P Receptor New and Emerging Therapies
Anti-Integrin Therapies Family of medications that are antibodies that bind to integrin receptors. Integrins are expressed on white blood cells and allow them to dock along the blood vessel in order to migrate into different tissues. Blocking integrins can decrease inflammation by preventing white cells from entering into the intestine.
Vedolizumab Vedolizumab was FDA approved in 2014 for the treatment of both Crohn s and UC. Humanized (IgG1) mab against alpha-4-beta-7 integrin, that interferes only with the alpha-4-beta- 7/MAdCAM-1 interaction. Alpha-4-beta-7 is expressed selectively in the GI tract. First GI specific IBD therapy, appears in have an excellent safety profile. Colombel et al, GUT, Feb 2016
Vedolizumab:
Etrolizumab: Humanized monoclonal antibody against both alpha 4 beta7 and alpha e beta7. Alpha e beta 7 action blocks white cell retention in the epithelium through binging with e cadherin, potentially given it greater effectiveness. It is in Phase III trials now for UC and Crohn s.
Alicaforsen Anti-adhesion therapy which blocks an activated leukocyte receptor on endothelial cells. It is a small molecule intracellular treatment which targets mrna to decrease production of ICAM-1. We are starting a clinical trial at SUH first in people who have had colectomy with IAPP, and have chronic pouchitis.
Ustekinumab Approved by the FDA in 2009 for the treatment of psoriasis. Fully human IgG1 antibody that binds to interleukins 12 and 23 by the p40 subunit. IL 12 and IL 23 are proinflammatory cytokines, and induce differentiation of Th1 and Th17 t cells, which are instigators in IBD pathogenesis. Genetic changes in the genes encoding IL 23 have been found in people with IBD.
Ustekinumab: Uniti phase III trial showed effectiveness in moderate/severe Crohn s disease, for both induction and maintenance of short term remission. No malignancies, opportunistic infections, cases of tuberculosis or major adverse cardiovascular events were observed in patients treated with Stelara. However TB and other opportunistic infections, skin cancers, and a rare neurologic condition have occurred in the psoriasis population. Small increase in cardiovascular issues was not found to be statistically significant, but continues to be monitored. Expect this to be available for Crohn s late this year.
Tofacitinib: Janus kinases (Jaks) & signal transducers, and activators of transcription (Stats) are intracellular signaling molecules that mediate the signal of initial ligand-receptor binding to modulation of gene expression. FDA approved as Xeljanz for the treatment of rheumatoid arthritis 2012. Tofacitinib is a pan-jak inhibitor that preferentially binds to Jak1 and 3, diminishing the downstream effects of several IBD-associated cytokines. This is a small molecule therapy, taken orally. It works at an earlier stage in the inflammatory process.
Tofacitinib: Phase II data for UC was promising, and currently Phase III OCTAVE trials are underway. Initial results for the Induction in moderate to severe UC were favorable at 8 weeks, with good safety profile Crohn s Phase II data was mixed potentially due to very high placebo response, but Phase III also underway. Potential safety issues being monitored are suppressed white cell counts, cholesterol elevations, TB reactivation, and potential increase risk of intestinal perforation and malignancies.
Mongersen Small molecule and acts inside the cell to interfere with a suppressor of antiinflammation genes. Binding (and degrading) target mrna with antisense molecules allows specific inhibition this involved pathway. Targets early events in intestinal inflammatory to reset the mucosal immune system homeostasis. Phase II study in Crohn s disease resulted in a clinical response that was sustained over three months. Safety monitoring needed for kidney issues, increased risk of fibrosis. Vanhove et al, CLINICAL PHARMACOLOGY & THERAPEUTICS ANUARY 2016
Ozanimod Small molecule, taken orally Induces internalization of a receptor on memory T cell lymphocytes that facilitates their exit from lymph nodes into the circulation. Phase II study in UC showed improved mucosal healing at 8 weeks. Phase II study for Crohn s underway.
Emerging Therapies: IBD is unique in different people, as are responses to treatments. Significant progress is being made to develop targeted treatments to halt the disease process. The goal of therapy should be steroid free disease remission. Personalization of therapy is the future.