1. No category

May 2015
Forward Looking Statements
This presentation contains forward-looking statements within the
meaning of the Private Securities Litigation Reform Act of 1995. Such
statements include, but are not limited to, statements about the future
expectations, plans and prospects of the development of Islet Sciences
Inc.’ s products. These forward-looking statements about future
expectations, plans and prospects of the development of the Company's
products are subject to a number of risks, uncertainties and assumptions,
including those identified under “Risk Factors” in the Company’s most
recently filed Annual Report on Form 10-K, Quarterly Report on Form 10Q and in other filings the Company periodically makes with the SEC.
Actual results may differ materially from those contemplated by these
forward-looking statements. The Company does not undertake to update
any of these forward-looking statements to reflect a change in its views or
events or circumstances that occur after the date of this presentation.
2
Corporate Snapshot
Biotech company developing new medicines and technologies for the
treatment of metabolic disease
Treatment
De-risked Late-Stage Pipeline in High-Value
Indications – NASH/NAFLD & T2DM
Best-in-Class SGLT2 Inhibitor
Metabolic
Disease
Small Molecule Immune/Inflammatory
Modulators
Novel Beta-Cell Loss Diagnostic
Early
Diagnosis
Strong Intellectual Property
3
Development Pipeline
Therapeutic
Product Candidates
Lead
Preclinical
Phase 1
Phase 2a Phase 2b Phase 3
T2DM
Remo Biphasic
Status / Anticipated Milestones
- Two pha s e 2b s tudi es compl eted
- 2b s tudy for T2DM i ni tia ted
- Ini tia tion of 2b s tudy for NASH 2H 2015
NASH
- Precl i ni ca l pa cka ge compl ete
T1DM
ISLT-2669
Inflammation
ISLT-P
T1DM
- Fi rs t s peci es s a fety/effi ca cy s tudy compl eted
- Precl i ni ca l devel opment ongoi ng
- T2DM, NASH, Immune di s orders
- Fi rs t s peci es s a fety/effi ca cy s tudy compl eted.
- Status under revi ew
- Precl i ni ca l ongoi ng
IL-12 Inhibitor Library
Diagnostic
Product Candidates
Discovery
Validation
T2DM
Completed
Launch
Status / Anticipated Milestones
- As s a y devel opment compl eted
- T1DM CLIA va l i da tion a nd l a unch pl a nni ng
- T2DM va l i da tion pl a nni ng
T1DM
ISLT-B dx
CLIA/510k Approval
Territory Rights
Gl oba l outs i de of
Ja pa n, Korea ,
Ta i wa n, Chi na ,
La tin Ameri ca .
Pendi ng l i cens e
effectivenes s .
ISLT/Gl oba l
ISLT/Gl oba l
ISLT/Gl oba l
Territory Rights
ISLT Gl oba l
Planned
4
High-Need Target Indications:
Diabetes
>50% of Americans will have diabetes or be prediabetic by 2022
$5.7 billion3
Addressable U.S. Market
Today1
Addressable U.S. market
20222
86M
110M
29M
55M
$0 in 2013
1 Source: National Diabetes Statistics Report, 2014
ADA website
Source: American Diabetes Association, 2011 National Diabetes Fact Sheet, Jan. 26, 2011
3 Datamonitor Healthcare
2
5
High-Need Target Indications:
NASH/NAFLD
≥ 30% of U.S. population has nonalcoholic fatty liver disease (NAFLD)
> 12% of U.S. population have more serious Non-alcoholic Steatohepatitis (NASH)
$35+ billion4
Currently there are no approved therapies for NASH
Addressable U.S. Market
Today1
93M
25M
Addressable U.S. market
20252
102M
29M
$600MM in 20103
1 Chalasani et
al. AASLD Practice Guidelines. 2012
J and Torok N. NASH and the metabolic syndrome. 2008
3,4 Deutche Bank
2Jiang
6
Remogliflozin Etabonate
Selective once-daily SGLT2 inhibitor with best-in-class potential
Type 2 Diabetes – Phase 2b




Best-in-class lowering of HbA1c, plasma glucose, and weight
Low incidence of GFI
No increase in LDLc
No dose adjustment expected for patients with renal impairment
NASH/NAFLD – Phase 2b





Clinical evidence: robust increases in insulin sensitivity and reductions in ALT/AST
Preclinical results: dose-dependent decrease in liver triglycerides, weight and ALT/AST
Reduction in pro-inflammatory cytokines
Significant anti-oxidant activity
Plan to initiate phase 2b for NASH in 2015
>20 clinical trials completed and >800
subjects have received remogliflozin
etabonate with no drug-related SAEs:
Phase 1
Phase 2a
Phase 2b
17
3
2
7
Remogliflozin
Only Differentiated SGLT2 Inhibitor
SGLT2 is a well validated target for type 2 diabetes
 Three approved drugs in United States
 Little positive differentiation (share same basic chemical structure)
 Current class profile: Moderately efficacious, increases in LDLc, increases in GFI, dose
adjustment required with CKD
Remogliflozin
Dapagliflozin
(Farxiga)
Canagliflozin
(Invokana)
Empagliflozin
(Jardiance)
Ertugliflozin
Company
Islet/BHV
AZN
JNJ
LLY
PFE/MRK
Stage
Phase 2b
Approved
Approved
Approved
Phase 3
O-aryl glucoside
C-aryl glucoside
C-aryl glucoside
C-aryl glucoside
C-aryl glucoside
Chemistry
Nighttime SGLT2 inhibition can lead to:
 Increases in LDL Cholesterol (LDLc)
 Increased genital fungal infections (GFI)
 Nocturia / polyuria
 Changes in bone metabolism
Remogliflozin’s shorter half-life + Biphasic formulation enables overnight
drug-holiday and best in class once-daily target product profile
8
Remogliflozin
Competitive Landscape – SGLT2
Biphasic
Remogliflozin
+
HbA1c Lowering
Weight Loss
Renal Impairment
Nighttime Inhibition
Genital Fungal Infections
Change in LDLc
Cardiovascular Risk
Anti-oxidant/NASH
=
+
+
+
+
+
+
+
Dapagliflozin
Canagliflozin
Empagliflozin
=
=
=
=
=
=
=
=
=
=
=
=
=
=
=
=
=
=
=
Superior
Class Comparative
Inferior
9
Remogliflozin Clinical Development
Phase 1
Biopharm/PK
KG219017 Single dose PK/PD
KG2105217 Bioenhanced formulations
KGW111057 Modified release PK
KG2105259 Regional GI absorption
KG2105264 Mass balance
KG2105253 Renal impairment PK/PD
BHV 10020 Biphasic release formulation PD/PK
Phase 2a
KG2104940 12 day (proof of
concept)
Phase 2b
KG2105255 12 wk BID
KG2110375 12 wk QD
KG2110243 14 day Metformin
study
KGW108201 8 week echo/MRI
study in obese non-T2DM
Pharmacodynamic/Safety
KG2109799 High dose-escalation
KGI107465 T1DM with insulin PK/PD
KG2107489 QTc study
Drug interaction Studies
KG2108197 Ketoconazole DDI
KG2107494 Oral contraceptive DDI
KG2105251 Diuretic DDI
KG2105246 3 day PK metformin DDI
KGW111083 Bupropion DDI
Japan
KGT-1101 Single dose
KGT-1102 Repeat dose






Approx ~850 subjects dosed with remo
Doses up to 4g/day
Duration up to 12 weeks
No drug related SAE’s/Few mild AE’s
Preclinical package complete including 2 year carc
Synthetic route optimized
Remogliflozin
HbA1c Reduction
-2
0
4
8
12
0.4
0.2
Observed BID reductions
in HbA1c:
0
-0.2
1% - 1.4%
-0.4
-0.6
-0.8
-1
Placebo
Remo 100mg
-1.2
Difference between BID and QD attributable to PK and effect
on evening post prandial glucose
-2
0
4
8
12
0.4
0.2
0
Observed QD reductions
in HbA1c:
0.5% - 0.8%
-0.2
-0.4
-0.6
-0.8
-1
Placebo
Remo 250mg
11
Remogliflozin
Weight Loss
-2
0
2
4
8
12
1.5
1
0.5
Observed BID reductions
in weight:
0
-0.5
1.8% - 4.0%
-1
-1.5
-2
-2.5
Placebo
Remo 100mg
-3
Difference between BID and QD attributable to PK and effect
on evening post prandial glucose
-2
0
2
4
8
12
1
0.5
0
-0.5
Observed QD reductions
in weight:
1.5% - 2.5%
-1
-1.5
-2
-2.5
Placebo
Remo 250mg
-3
-3.5
12
Remogliflozin
Differentiation: Genital Fungal Infections
 Literature indicates excess bladder volume and hyperglycemia responsible for GFI
 By correlation, overnight SGLT2 inhibition leads to elevated urine glucose and increased
bladder volume
 Daytime not a concern due to regular urination (pressure relief) and fluid intake (UGE dilution)
 Risk factors that combine to create increased GFI incidence are high UGE (>80 g/24 hr) and
hemoconcentration (as indicated by elevated hematocrit)
Remo QD
Remo BID
Dapagliflozin
(Farxiga)
Canagliflozin
(Invokana)
Empagliflozin
(Jardiance)
Ertugliflozin
GFI (%)
1.9
2.8
8.4
11.4
6.4
NA
Nighttime
inhibition
No
Yes
Yes
Yes
Yes
Yes
0.5 - 0.8
1.0 – 1.4
0.7 - 0.9
0.7 - 0.9
0.4 – 0.6
0.6 – 0.8
HbA1c
Lowering (%)
Difference attributable to nighttime inhibition of SGLT2
13
Remogliflozin
Differentiation: LDL Cholesterol
Empagliflozin
Canagliflozin
 Drug On-Board overnight correlates with
increases in LDLc
Dapagliflozin
Remogliflozin BID
 Drug Off-Board overnight correlates with
no increase in LDLc
Remogliflozin QD
10 mg
25 mg
4.6%
6.5%
100mg
300mg
4.5%
8.0%
2.5mg
5mg
10mg
5.0%
3.1%
9.5%
50mg
100mg
250mg
500mg
1000mg
6.5%
4.9%
13.2%
11.9%
9.3%
100mg
250mg
500mg
1000mg
-8.9%
-1.5%
3.7%
-0.1%
Type 2 diabetics commonly show an elevation in plasma triglycerides (with little or no change in
LDLc and HDLc concentrations) as reflected by either increased total triglycerides or VLDL
concentrations
TG/VLDL are mobilized for energy during low glucose periods (e.g. sleep)
With glucose elimination (e.g. with SGLT2 inhibition during sleep) greater amounts of TG/VLDL are
mobilized.
This leads to small increases of LDLc concentration as VLDL transitions to LDLc
14
Remogliflozin
Differentiation: Renal Impairment
Accumulation
D UGE
Remogliflozin
Mild
Moderate
+10%
+10%
0%
0%
Dapagliflozin
Mild
Moderate
+39%
+100%
-42%
-80%
Canagliflozin
Mild
Moderate
+15%
+29%
-13%
-33%
Empagliflozin
Mild
Moderate
+18%
+20%
NA
>44% of diabetics over 20 y/o
>61% of diabetics over 65 y/o
have impaired renal function
 Diabetics are at increased risk of
developing chronic kidney disease
 Renal Impairment: kidneys are damaged with reduced filtration rates
 Can cause waste to build up, leading to cardiovascular disease, anemia, and bone disease
Remogliflozin not expected to require dose adjustment
in patients with mild to moderate renal impairment
15
Remogliflozin
Rationale for Biphasic Formulation
• Best-in-class side effect profile (QD) due to absence of during sleep period
• Best-in-class efficacy (BID) due to increased effect on evening post-prandial glucose
Combined single dose of instant release and delayed release provide
exposure during the day/evening but not during the overnight period, thereby
combining the positive effects of QD and BID dosing in single formulation.
Remo
UGE Amount
Wake
Sleep
Dinner
Lunch
Breakfast
Delayed Release
Wake
Sleep
Dinner
Lunch
Breakfast
Instant Release
16
Remogliflozin
Biphasic Achieves Ideal PK/PD Profile
Results of randomized, crossover study in healthy volunteers
• Formulation was well-tolerated with few AEs and no significant safety signals
• UGE extended well into dinner, but not substantially during sleep
Median Plasma Concentration vs. Time
Median UGE vs. Time
17
Remogliflozin
Progression of NASH
Obesity
Insulin Resistance
Normal
Inflammation
Oxidative Stress
NAFLD
NASH
Fibrosis
Cirrhosis/HCC
18
The major pathological events leading to NASH:
Obesity
Oxidative Stress
Insulin
Resistance
Insulin Resistance
Inflammation
Obesity
Dyslipidemia
NAFLD
(Steatosis)
Pro-Inflammatory
Pathways
Cytokines\Chemokines
Oxidative Stress
Hepatocellular
injury
NASH
(Steatohepatitis)
Remogliflozin
NASH/NAFLD
Remogliflozin effectively addresses major pathological events leading to NASH in
one molecule:
Obesity
Insulin Resistance
Oxidative Stress
Inflammation
 Unique intrinsic anti-oxidant activity
 Reduces oxidative stress
Serum TBARS
TROLOX (umoles/g)
250
200
Canagliflozin
150
Dapagliflozin
100
Remogliflozin
50
0
Serum TBARS (nmol/ml)
TROLOX Assay
20
15
10
5
0
SGLT2 Inhibitor
1
Normal
2
NAFLD
3
4
NAFLD
+
NAFLD
+
Remo 0.01% Remo 0.03%
20
Remogliflozin
NASH/NAFLD
Remogliflozin effectively addresses major pathological events leading to NASH in
one molecule:
Obesity
Insulin Resistance
Oxidative Stress
Inflammation
Significant Improvement in Postprandial Glucose Disposal
OGTT Population (N)
Placebo=
10
50mg bid=
11
100mg bid= 13
250mg bid= 9
500mg bid= 13
1000mg bid= 14
Pio 30mg=
11
21
Remogliflozin
NASH/NAFLD
Remogliflozin effectively addresses major pathological events leading to NASH in
one molecule:
Obesity
Insulin Resistance
Oxidative Stress
Inflammation
HOMA Insulin Sensitivity (%)
Remo 50 mg BID
HOMA β-Cell Function (%)
Δ (%) vs. Placebo
(95% CI)
Δ (%) vs. Placebo
(95% CI)
2.7 (-15.3, 24.6)
26.2 (6.3, 49.8))
22.9 (1.4, 48.9)
20.8 (1.9, 43.3)
19.1 (-2.0, 44.7)
29.4 (8.9, 53.8))
25.5 (3.8, 51.6)
36.8 (15.6, 61.9)
28.3 (5.7, 55.5)
46.3 (23.3, 73.6))
9.5 (-9.7, 32.7)
41.6 (19.5, 67.9)
(N=37*)
Remo 100 mg BID
(N=38*)
Remo 250 mg BID
(N=36*)
Remo 500 mg BID
(N=40*)
Remo 1000 mg BID
(N=37*)
Pioglitazone 30 mg
(N=38*)
Treatment Ratio (%)
Treatment Ratio (%)
Significant Increases in Insulin Sensitivity and Beta Cell Function
Remogliflozin
NASH/NAFLD
Remogliflozin effectively addresses major pathological events leading to NASH in
one molecule:
Obesity
Insulin Resistance
Oxidative Stress
Inflammation
 Improved Liver Function
 Reduced Inflammation in the Liver
140
120
% Control
100
80
60
MCP-1
40
20
0
Normal Untreated
Remo
0.1%
Remo
0.3%
ALT Reduction
p-value=0.049*
NAFLD
*Using a repeated measure analysis of all doses
23
Remogliflozin
Competitive Landscape NASH
Gilead
Islet Sciences
Intercept
Genfit
Regado
Galmed
Class
SGLT2 Inhibitor
FXR agonist
Anti-lysyl oxidase
FXR agonist
PPARα/δ agonist
CCR2/CCR5
antagonist
SCD1 inhibitor
Mechanism
Insulin sensitizer
Anti-obesity
Anti-oxidant
Transcript. regulator
Lipid metabolism
LOXL2 inhibitor
Transcript. regulator
Lipid metabolism
Transcript. regulator
Lipid metabolism
Init. Phase 2b
2Q 2015
Phase 3 enroll
2H 2015
Comp. Phase 2b
May 2019
NA
Comp. Phase 2
Mar 2015
NA
Comp. Phase 2b
Nov 2016
Obesity
Improved
No change
No Change
NA
Improved*
NA
NA
Steatosis
Improved*
Improved
NA
Improved*
Improved*
No Change
Improved
Oxidative Stress
Improved*
NA
No Change
NA
Improved*
NA
NA
Insulin Sensitivity
Improved
Improved
NA
Improved*
Improved*
NA
NA
Inflammation
Improved*
Improved
NA
NA
Improved*
Improved*
NA
LFT
Improved
Improved
NA
NA
Improved*
Improved*
No Change
NA
Improved
NA
NA
NA
Improved*
NA
Development
NAS Score
Anti-inflammatory Lipid metabolism
Anti-fibrotic activity unknown in humans for all programs.
* Pre-clinical
data unknown for all compounds
Anti-fibrotic activity
in humans
*Pre-clinical
24
IL-12 Antagonists
Immune/Inflammation Modulating Drugs
Protects against Beta Cell Death
•
•
•
•
•
•
First-in-class series of compounds
Antagonists of IL-12 targeting STAT4
pathway.
Immune- and inflammation modulating.
Preserves insulin producing beta cell
function by preventing cytokine-induced
destruction.
Displays anti-fibrotic activity in rodent model
of NASH.
Current lead candidate ISLT-2669
demonstrates longer half-life and superior
oral bioavailability.
Reduces Fibrosis in NASH
25
Intellectual Property Summary
Program
Remo
Biphasic
ISLT-2669
ISLT- P
ISLT-Bdx
26
Patent
ID Number
Status
Glucopyranosyloxypyrazole derivatives, medicinal
compositions containing the same and intermediates
in the production thereof
US 6,972,283; 7,056,892; 7,115,575; Issued
Glucopyranosyloxypyrazole Derivativees and Use
Thereof in Medicines
US 7,084,123; 7,393,838; 7,465,713 Issued
Progression Inhibitor For Disease Attributed To
Abnormal Accumulation Of Liver Fat
US 8,951,976
Issued
Process For Production Of Glucopyranosyloxypyrazole
Derivative
US 8,022,192
Issued
Combination immediate/delayed release delivery
system for short half-life pharmaceuticals
PCT/US2011/043143
Pending
Lisofylline analogs and methods for use
US 8,481,580
Issued
Lisofylline analogs and methods for use
US 8,987,321
Issued
Ex Vivo Maturation of Islet Cells
W02103/049693
Pending
Compositions And Methods For
Detecting Hypo-Methylated DNA In Body Fluids
PCT/US2014/020431
Pending
Compositions and Methods of Diagnosing
Diseases and Disorders associated with b cell death
WO2012/178007
Pending
Management Team
James Green, MBA
CEO
•
•
•
•
Steve Delmar, CPA
CFO
 35+ years of financial and operational executive leadership
 CFO at Integrity Management Consulting, ACE*COMM (NASDAQ), and
Microlog (NASDAQ)
 Director of Business Operations at Computer Sciences Corp.
 B.S. Accounting Clemson University
 R&D and business development at GlaxoSmithKline
 Focus on metabolic disease drug development
 Founder of Zen-bio, Artecel Sciences, and BHV Pharma
 Author of numerous peer-reviewed manuscripts and 17 issued patents
 Postdoctoral fellowship Harvard Medical School
 Ph.D. Duke University; B.S. University of Memphis
William Wilkison, Ph.D.
COO
Business development and finance at GlaxoSmithKline
Advisory experience at Ernst & Young, Citigroup, Bank of America
Founder BHV Pharma
MBA University of Pittsburgh; BBA University of North Florida
27
Scientific Advisors
Arun Sanyal, M.D.
Christian Mende, M.D.
Manal Abdelmalek, M.D.
James Snapper, M.D.
Masayuki Isaji, Ph.D.
 Charles Caravati Professor and chair, Division of Gastroenterology,
Hepatology and Nutrition, VCU
 Principal Investigator on FLINT study,
 Advisor to FDA for NASH detection and therapy
 Consultant to Intercept, Genfit
 Clinical Professor of Medicine at University of California, San Diego
 Fellow of the American College of Physicians, the American Society of
Hypertension, Nutrition and Nephrology
 Clinical consultant for Invokana (JNJ)
 Professor of Medicine at Duke University Medical Center, Division of
Gastroenterology
 Residency and Fellowship, Mayo Clinic
 PI on FLINT and PIVENS study
 Professor, Department of Medicine, Duke University Medical Center
 Residency Brigham and Women’s Hospital
 MD Harvard Medical
 Previous Head of Translational Research at GlaxoWellcome (GSK)
 Head of R&D and Board Member at Kissei Pharmaceuticals
 Champion for Remogliflozin as NASH treatment
 Inventor on multiple remogliflozin patents
28