Presentation from Dr. Todd Zion

SmartCells, Inc. An Introduction to SmartInsulinTM Todd C. Zion, Ph.D. Co-founder, President & CEO April 6th, 2009 e-mail: todd.zion@smartinsulin.com Phone: 978.927.4246 Web: www.smartinsulin.com 1 SmartCells, Inc.

Imagine a “Smart” Insulin Calculate Insulin Dose  SmartInsulinTM Food Food Measure Blood Glucose Blood Glucose • Once-a-day injection • No hypoglycemia • Near-perfect glucose control • Significantly fewer finger-sticks • Minimal dietary restrictions 2 SmartCells, Inc.

SmartCells, Inc. and the SmartInsulinTM Mission • Founded in August 2003 – Exclusive licensee from M.I.T. – Based on founder’s 5+ years of Ph.D. research • World-class collaborators to complement 12 full-time employees – Management includes founder, M.I.T. Ph.D.’s, and biotech executives – Collaborators from M.G.H., Joslin, former Lilly/Novo experts • $4.2M+ in private investment; $6.3M+ in public grant funds Corporate Headquarters in Beverly, MA (25 miles north of Boston) For more information, please visit www.smartinsulin.com 3 SmartCells, Inc.

Insulin and Type 1 Diabetes • Insulin saves lives, BUT with… – Life-threatening bouts of hypoglycemia – Poor glucose control and long-term complications – Frequent finger sticks and counting carbs – Constant vigilance • Insulin lowers blood glucose levels no matter what – Too much: Hypoglycemia – Too little: Hyperglycemia and ketoacidosis • Effective control requires glucose-responsive delivery 4 SmartCells, Inc.

-cell glucose-stimulated insulin release Saturated maximum above 400 mg/dl Rapid increase between 100 and 400 mg/dl Negligible below 100 mg/dl http://journals.prous.com/journals/dot/20033904/html/dt390287/images/Langin_f1.gif Cerasi, E., Q. Rev. Biophys. 8 (1975) 1-41. • Provide the missing -cells: regeneration or transplantation • Mimic the -cell function 5 SmartCells, Inc.

The artificial pancreas approach Assume the insulin molecule cannot be changed Better accuracy, redun dancy, biocompa Renard, E., Curr. Opin. Pharmacol. 2 (2002) 708-716. tibility Better algorithms and device integration • SmartCells makes the insulin molecule glucose-responsive • Eliminates the need for cells, pumps, sensors and algorithms 6 SmartCells, Inc.

Glucose-responsive SmartInsulin technology Insulin Key: Insulin Glycosylated insulin-polymer conjugate (IPC) Insulin Glucose Multivalent glucose-binding molecule (GBM) Conceptual particle surface boundary 1. IPC and GBM combine to form insoluble network 2. Free glucose molecules displace the IPC from the GBM 3. The matrix erodes from the surface inward 4. The released IPC lowers glucose levels in the body 5. The matrix stops eroding until the next glucose challenge 7 SmartCells, Inc.

SmartInsulin subcutaneous injection Dispersion in 10 ml Withdrawal into 31G multi-dose vial subcutaneous insulin syringe 8 SmartCells, Inc.

Pancreas-like performance in rats SmartInsulin Pancreas 8000 500 800 500 Insulin Insulin Serum Rat Insulin Conc. (pM) 7000 700 Glucose Glucose 400 400 Serum IPC Conc. (pM) 6000 Glucose (mg/dl) 600 Glucose (mg/dl) 5000 300 300 IP glucose 500 IP glucose 4000 400 200 200 3000 300 2000 100 100 200 1000 0 0 100 0 0 100 200 300 400 0 100 200 300 400 Time (min) Time (min) • Glucose-stimulated release mimics pancreas • Glucose stimulated to basal release ~ 4x-5x 9 SmartCells, Inc.

No hypoglycemia over 4x dose increase 600 600 NO FEEDING NO FEEDING Diabetics Diabetics Normals Normals 500 500 10 U/kg 5 U/kg Glucose (mg/dl) Glucose (mg/dl) 400 400 300 300 200 200 100 100 0 0 0 200 400 600 0 200 400 600 Time (min) Time (min) 600 NO FEEDING Diabetics Normals 500 • Substantially improved therapeutic Glucose (mg/dl) 20 U/kg 400 window vs. conventional insulin 300 • Minimal risk of dangerous 200 overdose 100 0 10 0 200 400 600 SmartCells, Inc. Time (min)

Safety summary in preclinical models • No signs of injection site irritation • No risk of hypoglycemia over broad range of doses • No excessive body weight gain or loss due to repeated dosing • No signs of organ abnormalities due to repeated dosing • No signs of toxicity or cell abnormalities after repeated dosing • No signs of anti-insulin antibody formation 11 SmartCells, Inc.

JDRF partnership summary • Industry Discovery & Development Partnership – Metabolic Control – Dr. Aaron Kowalski • Initiated in August 2008 • Year 1: Pre-clinical formulation optimization in Type 1 models – Successful completion of Q1-Q3 milestones – End of Year 1: Success in large animal, human-representative models • Year 2: Manufacturing and Safety Studies to Support Clinical Trial – End of Year 2: Human Clinical Trials 12 SmartCells, Inc.

Path to Proof-of-Concept Human Clinical Trial Q2 ‘09 Q3 ‘09 Q4 ‘09 Q1 ’10 Q2 ’10 Serum half- Animal life in rats, cats and Studies pigs Single dose ADME 14 Complete Toxicology Safety day tox Contract Study Safety Phase 1a Antigenicity CROs reporting Studies pharmacol Receptor Clinical binding Qualify Trial Contract Clinical Stability test suppliers Manufacturi CMO batches Fill Select assays CMC Optimize and finish ng Produce 1st reporting process Stability test batch Design Phase Request pre- Hold Pre-IND Submit IND 1 Regulatory Contract IND meeting meeting Active IND CRO 13 SmartCells, Inc.

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Presentation from Dr. Todd Zion

by JDRF New England Chapter on Apr 20, 2009

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