INT131 - InteKrin Therapeutics, Inc.

InteKrin
THERAPEUTICS
Company Focus
Diabetes, Obesity, and Metabolic Disease
Lead Product
INT131
Safe Insulin Sensitizer
Phase 3 Ready
1
INT131: Best in Class Drug in $5 - $6 Billion Category
InteKrin
THERAPEUTICS

Selectively modulates the target of Actos® & Avandia®

Strong Phase 2a and Phase 2b data demonstrate:

High dose TZD efficacy

Less weight gain

No edema

Bone marker data suggesting lack of TZD fracture risk
congestive heart failure risk

Far superior preclinical safety to Actos® or Avandia®

Initiating Phase 3 activity, EOP2 March 10, 2010
2
InteKrin
Highlights of INT131 Story

THERAPEUTICS
® and
®
Actos
Actos®
and Avandia
Avandia®
Safety Is the Issue with the TZDs,
Actos® and Avandia®
Efficacy
Fluid Retention
Weight Gain
Effect
Dose

INT131 Is a Non-TZD Insulin Sensitizer
with Superior Safety
$3,500

Safety Sells. There Is a Large Market
$3,000
$2,500
Japan
EU
US
$2,000
for a Safe Insulin Sensitizer
$1,500
$1,000
$500
$0
3
Diabetes Is a Growing Global Epidemic
InteKrin
THERAPEUTICS
4
Large and Growing Cost of Diabetes in the U.S.
InteKrin
THERAPEUTICS
Huang ES, Basu A, Capretta JC, et al. Federal cost estimates: a look at how a clinically driven projection
model for diabetes could inform budget estimates and decisions. Health Affairs 2009; 28:w978–w990
5
Large and Growing Cost of Diabetes in the U.S.
InteKrin
THERAPEUTICS
~ $10B Per Year Spending Increase
2008–2024
Huang ES, Basu A, Capretta JC, et al. Federal cost estimates: a look at how a clinically driven projection
model for diabetes could inform budget estimates and decisions. Health Affairs 2009; 28:w978–w990
6
Insulin Resistance Is Central to Metabolic Disease
Type 2
Diabetes
THERAPEUTICS
“Insulin sensitizers will always
be essential”
Robert Henry, MD, UCSD
Fatty
Liver
Glucose
Intolerance
InteKrin
PCOS
Dyslipidemia
Insulin
Resistance
Obesity
Neuro
Disease

24 Million in US with Type 2
Diabetes

57 Million in US with Pre-Diabetes
Cancer
Hypertension
Cardiovascular
Disease
“An insulin sensitizer is the best hope for a
diabetes drug with CV advantage.”
Richard Nesto, MD, Chairman Lahey Clinic
7
Three Mechanisms of Type 2 Diabetes Oral Treatment
Inhibit
Inhibit
Gluconeogenesis
Gluconeogenesis
Increase
Increase
Insulin
Insulin Production
Production
InteKrin
THERAPEUTICS
Decrease
Decrease
Insulin
Insulin Resistance
Resistance
 Glucose Uptake
 Gluconeogenesis
Metformin
Sulfonylureas
DPP-4 Inhibitors
Complementary Mechanisms of Action
TZDs
TZDs
®,,
Actos
Actos®
®
Avandia
Avandia®
SPARRM:
INT131
Decreasing Insulin Resistance Addresses
Underlying Disease Progression
8
InteKrin
TZD Safety and Side Effect Issues Are Linked
® and
®
Actos
Actos®
and Avandia
Avandia®
THERAPEUTICS
Fluid
Fluid Retention
Retention
Congestive Heart Failure
Effect
Efficacy
Fluid Retention
Adiposity Increase
Dose
Weight
Weight Gain
Gain
Bone
Bone Fracture
Fracture
ADOPT Study
9
Black Boxes, Warning Letters and Negative Press
InteKrin
THERAPEUTICS
10
InteKrin
Highlights of INT131 Story

THERAPEUTICS
® and
®
Actos
Actos®
and Avandia
Avandia®
Safety is the Issue with the TZDs,
Actos and Avandia.
Efficacy
Fluid Retention
Weight Gain
Effect
Dose

INT131 Is a Non-TZD Insulin Sensitizer
with Superior Safety

Safety Sells. There is a Large Market
$3,500
$3,000
$2,500
Japan
EU
US
$2,000
for a Safe Insulin Sensitizer.
$1,500
$1,000
$500
$0
11
Unique Scaffold and Binding Pocket Interactions
InteKrin
THERAPEUTICS
Cl O O
S
NH
Cl
Avandia®
Cl
Cl
O
N
INT131

Specifically designed to address TZD safety issues

10-Year comprehensive scientific development program
12
Phase 2a: 1 mg Efficacy Comparable to High Dose TZD
InteKrin
THERAPEUTICS
INT131-004:
INT131-004: 4
4 Week
Week Phase
Phase 2a
2a POC
POC Study
Study in
in Subjects
Subjects with
with Type
Type 2
2 DM
DM
Avandia
Avandia®®
88 mgs
mgs
Efficacy
Efficacy
13
InteKrin
Phase 2b Study Design
THERAPEUTICS
INT131-007
 Randomized, double blind
 Placebo controlled
 24 week treatment
Primary endpoint
 Change in HbA1c from baseline
 Secondary parameters: Edema,
bone markers, weight gain
366 Patients
6 Treatment Groups

HbA1c 7.5 to 10 (mean 8.3)

Stable on SFU or Met+SFU
Visit
1
2
3
Week -2
-1
0
2-Week
Screening/Lead-in
Period
4
2

4 INT131 dose groups

0.5, 1, 2, and 3 mg
45 mg Actos® and Placebo
5
6
7
8
9
6
12
18
24
26
24-Week
Treatment Period
2-Week
Follow-up
Period
14
Phase 2b Shows Excellent Efficacy Dose Response
InteKrin
THERAPEUTICS
HbA1c at 24 Weeks, Time Course
Treatment Duration (weeks)
0.0
0
5
10
15
20
25
HbA1c CFB (%, mean)
-0.2
-0.4
-0.6
-0.8
placebo
INT 0.5
-1.0
INT 1
INT 2
-1.2
INT 3
Actos 45
-1.4
Per Protocol Population
15
InteKrin
Phase 2b Weight Gain Differentiation
Weight gain for 45 mgs
Actos® ~ 3.6 kg

As predicted

Estimated at 1 year
~6 kg

Weight gain for 1 mg
INT131 ~1.2 kg


Appears to plateau by
18 - 24 weeks
Estimated at 1 year
~1.5 -2 kg
5.5
5
Placebo
INT131 1 mg
Actos 45 mg
4.5
4
Weight CFB (kg, mean)

THERAPEUTICS
3.5
3
2.5
2
1.5
1
0.5
0
0
5
10
15
20
25
-0.5
Treatment Duration (weeks)
Per Protocol Population
16
1 mg INT131 Selected for Phase 3


InteKrin
THERAPEUTICS
Favorable profile vs. maximal dose TZDs

Efficacy slightly less than 45 mgs Actos®, equal 8 mgs Avandia®

Superior safety and tolerability in a safety-centric market
Development Advantages

Fastest and most efficient path to market

High predictability for Phase 3 performance

Profile demonstrated in two different patient populations
17
Significant Bone Fracture Risk with TZDs at All Doses
Stratification Group
InteKrin
THERAPEUTICS
Adjusted Odds Ratio (95% CI)
Gender
Males
Females
2.50 (0.84 – 7.41)
2.56 (1.43 – 4.58)
Age
Patients <70 years
Patients >70 years
2.96 (1.40 – 6.25)
2.57 ( 1.33 – 5.40)
TZD Agent
Actos
Avandia
2.59 (0.96 – 7.01)
2.38 (1.39 – 4.09)
TZD Dose Level
Avandia 4 mgs, Actos 15 mg
Avandia 8 mg, Actos 30 mg
2.13 ( 1.15 – 3.96)
2.98 ( 1.42 – 6.26)
Incidence of fracture in 4 year raised from ~3.5% to ~9%
18
INT131 Is Not Predicted To Share TZD Fracture Risk
CTX % Change from Baseline at 24 Weeks
InteKrin
THERAPEUTICS
Osteocalcin % Change from Baseline at 24 Weeks
20.0
60
17.5
Osteocalcin (% CFB +/- SE)
CTX (% CFB +/- SE)
50
40
30
20
10
15.0
12.5
10.0
7.5
5.0
2.5
0.0
0
placebo
placebo
INT131 1 mg
Actos 45 mg
Bone Degradation Marker
INT131 1 mg
Actos 45 mg
-2.5
Bone Formation Marker

TZD biology provides mechanistic explanation

INT131 is differentiated from Actos® bone effects
19
Edema / Fluid are Significant Safety Issue in Diabetes



InteKrin
THERAPEUTICS
Edema / Fluid Retention Risks

Patients have existing microvasculature disease

Complications → impaired wound healing, amputations

Associated with risk and diagnosis of congestive heart failure
TZDs increase incidence and severity of edema and CHF

Use is contraindicated for Class III and IV CHF patients

Increase vascular permeability, worse with common con-meds

Edema incidence and severity will increase 3x – 4x
TZD use cost both private payers and government

Exploding costs for any CHF case

Amputations: Expensive care, hospital stays, complications

Need for medical attention, physician calls, physical therapy
20
Objective Edema Score Quantifies Peripheral Edema


InteKrin
THERAPEUTICS
Prospective edema evaluation

Three locations evaluated for pitting edema

Simple +/- pitting investigator rating

Investigators trained for consistency
Method attributes

Avoids subjective shortcomings of previous methods

Simple and quantifiable

Clinically relevant to the physician

Relevant to the patient
21
SPPARM Behavior: Excellent Edema Safety Margins

20
Predicted findings
Negative control
Actos® 45 mg


Predicted findings

Positive control
feet
Edema at specified site (% pts)

ankles
15
20
mid-pretibial
all 3 sites
10
5
0
placebo INT131
0.5 mg
Edema Observed at Baseline
Edema at specified site (% pts)
THERAPEUTICS
Edema Incidence at 24 Weeks, Change from Baseline
Placebo

InteKrin
INT131
1 mg
INT131
2 mg
INT131
3 mg
Actos
45 mg
-5
feet
ankles
15
m id-pretibial
all 3 sites

10
5
0
placebo INT131
0.5 mg
INT131
1 mg
INT131
2 mg
INT131
3 mg
Actos
45 mg
INT131

Minimal change from baseline

Superior at all doses
Safety Population
22
INT131 Superior in Terms of Edema Severity


“1” → Edema seen in
any single location
“2” → Edema seen in
any two locations
“3” → Edema seen in
all three locations
THERAPEUTICS
Edema Score = Severity Rating x Incidence
25
Edema Score (Change from Baseline)

InteKrin
20
Week 12
Week 24
15
10
5
0
Placebo INT131 INT131 INT131 INT131
0.5 mg 1 mg
2 mg
3 mg
Actos
45 mg
-5
Safety Population
23
InteKrin
INT131 Preclinical Safety Far Superior to TZDs
THERAPEUTICS

Chronic studies demonstrate safety at high exposure multiples

Additional special assessments, Draft Guidance for PPAR ligands

Lack of typical PPAR toxicities in all chronic studies
PPAR ligand
Rat Toxicity Studies
Safety Margin
(Rat: human)
Actos®
(TZD full agonist)
Avandia®
(TZD full agonist)
INT131
(SPPARM)
Cardiac hypertrophy
 Thoracic cavity fluid accumulation
 Plasma volume expansion (Hb, RBC)
 Lung congestion/ increased weight
 Cardiac death

None of the above, or other, PPAR
full agonist toxicities
4.6 (male)
5.4 (male)
> 420 (male)
24
Carcinogenicity Studies Successfully Completed


InteKrin
THERAPEUTICS
2-year rodent carcinogenicity studies address a critical class risk

Dual agonists have shown multi-species, multi-tissue findings

Entire PPAR class put on hold in 2004 for carcinogenicity concerns
INT131 showed no carcinogenicity in rat or mouse

No effects at exposures 125-560 fold over clinical exposures

Highest doses were not carcinogenic and lacked PPAR toxicities
“INT131 displayed an unprecedented preclinical safety profile at exposure
multiples far greater than other PPAR agonists tested to date.”
- Jeri El-Hage PhD, former FDA Lead Toxicologist
25
Highlights of INT131 Story

InteKrin
THERAPEUTICS
® and
®
Actos
Actos®
and Avandia
Avandia®
Safety is the Issue with the TZDs,
Actos and Avandia
Efficacy
Fluid Retention
Weight Gain
Effect
Dose

INT131 Is a Non-TZD Insulin Sensitizer
with Superior Safety

Safety Sells. There Is a Large Market
$3,500
$3,000
$2,500
Japan
EU
US
$2,000
for a Safe Insulin Sensitizer
$1,500
$1,000
$500
$0
26
INT131 Product Profile: Superior Safety
InteKrin
THERAPEUTICS

Comparable glucose lowering efficacy to maximal dose TZDs

Superior Safety and Tolerability

No edema, no clinically relevant hematocrit drop,

Absence of typical TZD bone fracture risk

Typical weight gain reduced 60% - 75%
CHF

Neutral to beneficial lipid profile

Single tablet once daily

Excellent combination potential with complementary agents

Beta cell preservation provides delay of disease progression
27
Januvia®: Safety Sells Against Generics
Insulin Secretagogue Market:
• Good efficacy
• Long track record
• Safety/ tolerability issues:
hypoglycemia, weight gain
Januvia®
• Premium price
• Modest efficacy
• Weight neutral
• Excellent safety profile
700
600
(Worldwide Sales - $millions)
• Low cost generic
THERAPEUTICS
Current Sales: >$3B Annual Run Rate
Safety First
Sulfonylureas
InteKrin
500
400
300
200
100
0
Q406 Q107 Q207 Q307 Q407 Q108 Q208 Q308 Q408 Q109 Q209
Successful Single Dose
Strategy
28
INT131 Safety Profile Allows for Single Dose
Total Sales: $5 - $6 Billion
InteKrin
THERAPEUTICS
Actos 15
Actos 30
Actos 45
Avandia 2
% Insulin Sensitizer
Avandia 4
Scripts,
Avandia 8
IMS Data
Actos 15 combos
Actos 30 combos
Avandia 2 combos

Simple messages:

“1 dose, 1 mg”

“No Fat, Fluid, or Fracture”

Same dose for combination products

Single dose consolidates a fragmented market
Avandia 4 combos
29
Safety Drives Pharmacoeconomic Decisions by Payers
InteKrin
THERAPEUTICS

Survey results project Tier 2 formulary position

Edema/fluid/CHF issues are very costly

Bone fracture issues are costly

Payer and physician liability is costly

Outcomes and cost data collected during Phase 3,
including during CV safety study
30
InteKrin
Management Team
THERAPEUTICS
Denny Lanfear
President and CEO
Linda Higgins, PhD
Chief Operating
Officer
Alex DePaoli, MD
Chief Medical
Officer
Geoff Parker
Chief Business
Officer
Tim Franson, MD
Acting Senior VP
Regulatory Affairs
31
InteKrin
Board of Directors and Investors

David Lowe, PhD

Jim Healy, MD, PhD

Sam Wertheimer, PhD

David Brand

Marty Freed, MD

Barry Selick, PhD

Denny Lanfear
THERAPEUTICS
InteKrin
THERAPEUTICS

Lowell Sears, Chairman
32
InteKrin
Highlights of INT131 Story

THERAPEUTICS
® and
®
Actos
Actos®
and Avandia
Avandia®
Safety Is the Issue with the TZDs,
Actos® and Avandia®
Efficacy
Fluid Retention
Weight Gain
Effect
Dose

INT131 Is a Non-TZD Insulin Sensitizer
with Superior Safety
$3,500
$3,000

Safety Sells. There Is a Large Market
$2,500
Japan
EU
US
$2,000
$1,500
for a Safe Insulin Sensitizer
$1,000
$500
$0
33
InteKrin
THERAPEUTICS
Company Focus
Diabetes, Obesity, and Metabolic Disease
Lead Product
INT131
Safe Insulin Sensitizer
Phase 3 Ready
34