North American Neuromodulation Society Meeting 2012

 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

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North American Neuromodulation Society Meeting 2012

Rheumatoid ArthritisInflammatory Bowel Disease: Crohn’s and Ulcerative Colitis

Psoriasis, Ankylosing Spondylitis, Psoriatic Arthritis, Lupus

Inflammatory Disorders Have Significant Morbidity and Mortality- Medical Need Remains High

• 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

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North American Neuromodulation Society Meeting 2012

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

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Goal is to improve the treatment of these diseases using neuromodulation

North American Neuromodulation Society Meeting 2012

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

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Tracey, Cell 2012

Rosas-Ballina, Science 2011

In inflammatory diseases, activity of pathway is

decreased

North American Neuromodulation Society Meeting 2012

Stimulating this Reflex Using Neuromodulation will Reduce Inflammation and Improve Clinical Disease

Andersson U, Tracey K.

Ann Rev Immunol 2012; 30:313

Rheumatoid Arthritis Inflammatory Bowel Disease

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North American Neuromodulation Society Meeting 2012

VNS Lead for Rodent Inflammation Models

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North American Neuromodulation Society Meeting 2012

•Bolder BioPATH, Inc.•n=4/Normal Controls•n=12/disease control•n=9/ stimulation group•*p≤0.05 t-test to Disease Controls

Joint Swelling Was Reduced in Standard Collagen-Induced Arthritis Model

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North American Neuromodulation Society Meeting 2012

•Bolder BioPATH, Inc.•n=12/disease control•n=9/ stimulation group•*p≤0.05 t-test to Disease Controls

*

**

*

Importantly, Structural Damage to the Joint was Also Reduced

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North American Neuromodulation Society Meeting 2012

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 antagonistStandard RA clinical endpoints:•DAS28 (Tender and Swollen Joint score, CRP, Patient VAS)•ACR 20/50/70 Response Rate•EULAR Response and Remission RateCommercially purchased VNS devices were used for the study

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North American Neuromodulation Society Meeting 2012

Individual Patient DAS Scores Show Rapid and Marked Improvement in 6 of the 8 Subjects

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EULAR Remission

North American Neuromodulation Society Meeting 2012

Clinical Response Rates are Comparable to Those Seen with Biologics

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North American Neuromodulation Society Meeting 2012

Future Studies Will Utilize SetPoint’s Proprietary Neuromodulation Platform

MicroRegulator Pod

Patient Charger Prescription Pad

Surgical Implant

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North American Neuromodulation Society Meeting 2012

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%

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