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Harnessing the Inflammatory Reflex: Using Neuromodulation as a Novel Approach to Treat Chronic Inflammatory Diseases R Zitnik, Y Levine, M Faltys, T Arnold SetPoint Medical Corporation, Valencia, California 12/7/12 North American Neuromodulation Society Meeting 2012 1 Inflammatory Disorders Have Significant Morbidity and Mortality- Medical Need Remains High Inflammatory Bowel Disease: Crohn’s and Ulcerative Colitis • • • • Rheumatoid Arthritis Psoriasis, Ankylosing Spondylitis, Psoriatic Arthritis, Lupus Common disorders- up to 2% of population Affects young and middle aged adults Severe, “life-impacting” symptoms Systemic inflammation associated with highly elevated cardiovascular mortality risk 12/7/12 North American Neuromodulation Society Meeting 2012 2 Current Drugs and Biologics are an Important Advance- Yet Have Major Drawbacks • Lack of efficacy in 1/3 (RA) to 2/3 (Crohn’s) • Rare but serious safety issues: Infection, TB, CHF, cancer risk, MS, PML, hypercholesterolemia • $30 billion in annual sales with per patient cost of $25-35K/year Goal is to improve the treatment of these diseases using neuromodulation 12/7/12 North American Neuromodulation Society Meeting 2012 3 CNS Regulates the Immune System via the “Inflammatory Reflex” • Afferent vagus and CNS sense inflammatory mediators (should this read: CNS senses inflammation via the afferent vagus) • Efferent vagus signals resident T cells and macrophages in the spleen and GI tract • Pro-inflammatory cytokine production reduced • Circulating immune cells traversing the spleen are altered: • Reduced capacity to express inflammatory mediators and adhesion molecules as cells move into diseased tissue In inflammatory diseases, activity of pathway is decreased Tracey, Cell 2012 Rosas-Ballina, Science 2011 12/7/12 North American Neuromodulation Society Meeting 2012 4 Stimulating this Reflex Using Neuromodulation will Reduce Inflammation and Improve Clinical Disease Rheumatoid Arthritis Inflammatory Bowel Disease Andersson U, Tracey K. Ann Rev Immunol 2012; 30:313 12/7/12 North American Neuromodulation Society Meeting 2012 5 VNS Lead for Rodent Inflammation Models 12/7/12 North American Neuromodulation Society Meeting 2012 6 Joint Swelling Was Reduced in Standard CollagenInduced Arthritis Model •Bolder BioPATH, Inc. •n=4/Normal Controls •n=12/disease control •n=9/ stimulation group •*p≤0.05 t-test to Disease Controls 12/7/12 North American Neuromodulation Society Meeting 2012 7 Importantly, Structural Damage to the Joint was Also Reduced •Bolder BioPATH, Inc. •n=12/disease control •n=9/ stimulation group •*p≤0.05 t-test to Disease Controls * * 12/7/12 * North American Neuromodulation Society Meeting 2012 * 8 Clinical Study of Neuromodulation in Rheumatoid Arthritis “Methotrexate Failure” Population • Active RA despite treatment with first line agent methotrexate • Patients would otherwise have been candidates for a TNF antagonist Standard RA clinical endpoints: • DAS28 (Tender and Swollen Joint score, CRP, Patient VAS) • ACR 20/50/70 Response Rate • EULAR Response and Remission Rate Commercially purchased VNS devices were used for the study 12/7/12 North American Neuromodulation Society Meeting 2012 9 Individual Patient DAS Scores Show Rapid and Marked Improvement in 6 of the 8 Subjects EULAR Remission 12/7/12 North American Neuromodulation Society Meeting 2012 10 Clinical Response Rates are Comparable to Those Seen with Biologics 12/7/12 North American Neuromodulation Society Meeting 2012 11 Future Studies Will Utilize SetPoint’s Proprietary Neuromodulation Platform Surgical Implant MicroRegulator Patient Charger 12/7/12 Pod Prescription Pad North American Neuromodulation Society Meeting 2012 12 Summary and Conclusions • Inflammatory diseases are a $30B market with significant unmet need • Using neuromodulation to drive the inflammatory reflex has a sound biological foundation: Use in clinic is supported by strong preclinical evidence • This is the first demonstration that an implantable neuromodulation device improves clinical manifestations of RA: • Significant and clinically meaningful improvement in signs and symptoms • Response rates were comparable to those with current biologic agents • Further larger controlled studies in RA and other chronic inflammatory diseases are warranted. • Our microregulator offers significant advantages over current vagal nerve stimulation devices SetPoint intends to offer a novel therapy that will significantly increases patient QOL, while bending per-patient cost curves down by more than 60% 12/7/12 North American Neuromodulation Society Meeting 2012 13