Emerging Medical Therapies in Inflammatory Bowel Disease

Emerging Medical Therapies in Inflammatory Bowel Disease - 2017 Nir Modiano, MD, PhD Assistant Professor of Medicine Division of Gastroenterology & Hepatology Director, Inflammatory Bowel Disease Program

Disclosures I have been a Consultant for: Takeda 23andme

Learning Objectives We will review: New & emerging medication options in Crohn s disease and Ulcerative Colitis Mechanisms under investigation Status of clinical trials

Treatment of IBD: A Rapid Evolution Vedolizumab Ustekinumab 1979 1980 1993 1994 1995 1998 2005 Sulfasalazine, Steroids Antibiotics, Mercaptopurine Budesonide 5-ASA Methotrexate (Mesalamine) Infliximab Secondgeneration TNF biologics 2014 2016?? After Rutgeerts, Rev Gastroenterol Disord 2004; 4 (Suppl 3): S3 S9

New & Emerging Medical Therapies Recently FDA Approved 2 new classes: Ustekinumab (anti-il12/23) Crohn s Vedolizumab (anti-α 4 β 7 ) Crohn s and UC Advanced Pipeline Trials Include: Mongersen (SMAD7) Ozanimod (S1P1-R) Tofacitinib (JAK1+3 antagonist) Etrolizumab (Interleukin blocker)

Emerging Therapies in IBD: *** *** From: Mehmet Coskun, Severine Vermeire, and Ole Haagen Nielsen, Trends in Pharma Sciences 2017.

Emerging Therapies in IBD: Biologics vs. Small Molecules Two Major Types of New Drugs: Small Molecules - Made using organic chemistry, often cheaper - Usually oral, daily meds - Can be made generic Biologics - Made in Cell Culture Line, a bioreactor (expensive) - Typically are antibodies that bind to a protein in the body - Must be given IV or as a shot - Long half life means weeks between doses - Cannot make generic but can make biosimilar

Clinical Trial Phases Preclinical Trials Phase I Phase II Phase III FDA Approval? Phase IV Lab and Animal Studies Small study In healthy Human Volunteers Initial Safety Assessment Medium Size Study In Patients Is it Effective? Large Study In Patients Is it truly Effective and Reasonably Safe? Large Studies Of Real Patients

* CD trial at OHSU * UC trial at OHSU From: Mehmet Coskun, Severine Vermeire, and Ole Haagen Nielsen, Trends in Pharma Sciences 2017.

Outline 1. IL12/23 Pathway Biologics 2. Jak Pathway Small Molecules 3. SMAD7 Antisense Oligonucleotide (Mongersen) 4. Integrin Blockers block white cells from reaching gut 5. S1P1 Receptor Blockers block white cells from exiting lymph nodes

Outline 1. IL12/23 Pathway Biologics. 2. Jak Pathway Small Molecules 3. SMAD7 Antisense Oligonucleotide (Mongersen) 4. Integrin Blockers block white cells from reaching gut 5. S1P1 Receptor Blockers block white cells from exiting lymph nodes

Ustekinumab Biologic agent (Fully humanized mab) Now approved for Plaque Psoriasis, Psoriatic arthritis, Crohn s Targets IL12b (p40) subunit of IL12/IL23 This cytokine pathway affects T-Cell differentiation GWAS (genetic studies) implicate IL12/IL23 with Crohn s IL12/23 implicated in colitis animal model

Ustekinumab and CD4 T-Cell Differentiation P40 =IL12B Th1 Response INF-γ Th17 response IL-17,21,22,26 From Benson et al; Nature Biotech 29(7), 2011

IL-12/23 as Therapeutic Targets in IBD: Ustekinumab From Benson et al; Nature Biotech 29(7), 2011

Ustekinumab Crohn s Phase III Data From Feagan et al., NEJM 2016 2 parallel Phase III trials -UNITI-1 had patients with more severe Crohn s who had already tried TNF biologics, -UNITI-2 had milder Crohn s and fewer patients had Already tried TNF biologics.

IL23 Therapies In Phase III data for Crohn s, and in 5 year data in Psoriasis patients, there was no signal for increased serious adverse events vs. placebo though it does modulate the immune system IL-23 is now thought to be the major driver of Ustekinumab efficacy Multiple biologics are in Phase II development targeting the p19 subunit specific to IL-23 Ustekinumab is currently in Phase III trials for UC

Outline 1. IL12/23 Pathway Biologics 2. Jak Pathway Small Molecules. 3. SMAD7 Antisense Oligonucleotide (Mongersen) 4. Integrin Blockers block white cells from reaching gut 5. S1P1 Receptor Blockers block white cells from exiting lymph nodes

Emerging Therapies in IBD: JAK Pathway From Choi et al., Clinic Rev Allerg Immunol 2015 IL-12, IL-23, and other interleukins bind to a cell surface receptor and mediate their intracellular effects in part through Janus Kinase (JAK) molecules. Could we develop a small molecule that can enter cells and block JAK function?

Emerging Therapies in IBD: Tofacitinib Phase II study in UC met endpoints for clinical response and remission JAK Inhibitor modulates multiple cytokines involved in lymphocyte activation, function, and proliferation Approved for RA. Adverse: Infections, neutropenia, lymphoma, skin cancer (NMSC), increase in cholesterol Similar molecule, Filgotinib, also in Phase III for UC and CD Completed Phase III promising data emerging will be filing for FDA review! Sandborn et al.; NEJM 2012

Emerging Therapies in IBD: Promoting TGF-β1 TGF-β1activates a receptor on the cell surface that promotes anti-inflammatory properties x If we could block SMAD7, Then TGF-β1 s anti- Inflammatory actions can kick in SMAD7 Blocks TGF-β1signaling Through SMAD2 activation! If we can inhibit the inhibitor of an inhibitor of inflammation The net result would be less inflammation! SMAD7 is very active in IBD

Antisense DNA Therapy? - Mongersen A radically new concept in IBD treatment developed by an Italian company, and now sold to Celgene Mongersen is an oral Smad7 antisense oligonucleotide * How does Antisense DNA Work? * DNA is transcribed to mrna from which a protein is made (mrna is a copy to the original blueprint for making a specific protein) Antisense DNA is designed to match and bind to the mrna, preventing translation into the protein, and targeting the mrna for degradation.

Antisense DNA Therapy? Mongersen is an oral Smad7 antisense oligonucleotide. Locally active in gut with negligible systemic absorption. Phase II trial in active Crohn s disease (by CDAI) suggests it may work! AE s similar to placebo Now in Phase III for Crohn s Met primary endpoint of clinical remission at day 15 (based on CDAI) Monteleone G. et al., NEJM 2015

Antisense DNA Therapy? Mongersen trial surprises: 1. Very quick dramatic effect 2. Response maintained at 12 weeks but treatment was only first 2 weeks! -May promote immune tolerance? 3. Clinical remission did not depend on baseline CRP, nor did treatment lower CRP. This is puzzling. - Medications effective in IBD usually work better for symptoms when CRP is higher, indicating true inflammation. Monteleone G. et al., NEJM 2015 Monteleone G. et al. [Italy] #826 DDW 2015

Intergrin / Anti-Adhesion Mechanisms 1. These are biologics that block the handshake when a white blood cell traveling through the bloodstream reaches the gut. 2. First was Natalizumab Effective in Crohn s, but also blocked the white cells from entering the brain. This meant that it worked for Multiple Sclerosis too BUT is associated with a serious brain infection called PML (progressive multifocal leukoencephalopathy) 3. Vedolizumab was designed to be specific for the gut NO PML. - Blocks α 4 β 7 located on circulating B and T lymphocytes which interacts specifically with MAdCAM-1 on intestinal vascular endothelium 4. Vedolizumab now approved for Crohn s and UC. - Advantages: Favorable risk profile, no systemic immunosuppression - Disadvantages: Takes 3-4 months to work, when it works. 5. Other gut-specific treatments are in development: - Etrolizumab and Anti-MAdCAM-1

Anti-MadCAM Study in UC Figure from Lobaton T. et al, AP&T 2014 Phase II trial of a novel biologic in Moderate-Severe UC Target is MadCAM-1 on high endothelial venules, which bind to α4β7 integrin on subsets of WBC s. Similar mechanism to Vedolizumab Does not affect brain immunity. Reinisch W. et al., #901a DDW 2015

Anti-MadCAM Turandot Study in UC Met primary and secondary endpoints; noted dose response peaks in bell shape Calprotectin drop with drug but not placebo Safety profile appears similar to placebo Proceeding to Phase III with 22.5 mg dose (28% mucosal healing seen with this dose) Reinisch W. et al., #901a DDW 2015

Ozanimod/Receptos (S1P1R Modulator) TOUCHSTONE Study Phase II Randomized DB PC trial of oral S1P1 Receptor Modulator in moderate-severe UC Ozanimod induces S1P1R internalization subset of autoreactive lymphocytes are retained in lymph nodes (note drop in lymphocyte count) Sandborn WJ, et. al. NEJM 2016 and Sandborn WJ, et. al. #445 DDW 2015

Ozanimod/Receptos (S1P1R Modulator) Phase II Study 197 patients, divided 1:1:1 Met efficacy endpoints at week 8 with dose response seen. No notable cardiac, ophthlamologic, or infectious AE s; did note drop in lymphocyte counts Sandborn WJ, et. al. NEJM 2016 Sandborn WJ, et. al. #445 DDW 2015

Sandborn WJ, et. al. NEJM 2016 Ozanimod/Receptos (S1P1R Modulator) Touchstone Study Maintenance Possible bradycardia and liver test changes NOTE: Fingolimod works by same mechanism (approved for MS) - Has had some side effects including slow heart rate, macular edema, and uncommon serious infections.

Emerging Therapies in IBD: Conclusions Therapeutic options have been rapidly growing in IBD Many new therapies, including oral therapies, are advancing in clinical trials Mechanisms generally involve blocking pro-inflammation pathways OR blocking white blood cells from getting out of the lymph nodes and into the gut. Future studies needed to: Compare efficacy of treatments (in a class and between classes) Identify ahead of time who will respond to what class of treatment!

Emerging Therapies in IBD: Clinical Trials at OHSU We are currently enrolling for two investigational new drug studies in IBD: 1. Ozanimod (S1P1R blocker, oral small molecule) for Moderate to Severe Ulcerative Colitis. 2. Mongersen (SMAD7 Antisense Therapy) for Crohn s Disease.

OHSU IBD Program Judy Collins, MD Kian Keyashian, MD Nir Modiano, MD, PhD Rebecca Matro, MD OHSU Colorectal Surgeons: Dan Herzig, MD Liana Tsikitis, MD Kim Lu, MD Stephanie Hill, RN Jullane Hohnstein, MA