SmartCells is developing SmartInsulin, a glucose-responsive insulin designed to mimic the pancreas' natural insulin release in response to blood glucose levels. SmartInsulin is formed by conjugating insulin to a glucose-binding molecule so that it releases insulin in response to glucose. In animal studies, SmartInsulin demonstrated glucose-responsive insulin release and maintained blood glucose levels within a normal range without hypoglycemia, even at doses 4 times higher than standard insulin. SmartCells has received funding from private investors and grants and is partnering with JDRF to complete preclinical development and safety studies in preparation for a first-in-human clinical trial planned for Q1 2010.

1. 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
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SmartCells, Inc.

2. 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
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SmartCells, Inc.

3. 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
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SmartCells, Inc.

4. 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
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SmartCells, Inc.

5. -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
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SmartCells, Inc.

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

7. 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
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SmartCells, Inc.

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

9. 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
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SmartCells, Inc.

10. 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)

11. 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
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SmartCells, Inc.

12. 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
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SmartCells, Inc.

13. Path to Proof-of-Concept Human Clinical Trial
Q2 ‘09 Q3 ‘09 Q4 ‘09 Q1 ’10 Q2 ’10
Serum half-
Animal life in rats,
Studies cats and 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
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SmartCells, Inc.