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© 2014 Lexicon Pharmaceuticals, Inc. Slide 0 Discovering Breakthrough Treatments for Human Disease
Advancing Lexicon’s Late-Stage Pipeline
Jeffrey L. Wade
Executive Vice President, Corporate Development and Chief Financial Officer
Jefferies 2014 Global Healthcare Conference
June 3, 2014
© 2014 Lexicon Pharmaceuticals, Inc. Slide 1
This presentation contains “forward-looking statements,” including
statements about Lexicon’s plans for the development of its drug
candidates and assessment of their therapeutic and commercial potential,
the timing of regulatory filings and of completion and initiation of ongoing
and future clinical trials of Lexicon’s drug candidates, and Lexicon’s drug
discovery and research programs, growth and future operating results,
future capital needs, strategic alliances, and intellectual property, as well as
other matters that are not historical facts or information. These forward-
looking statements are based on management’s current assumptions and
expectations and involve risks, uncertainties and other important factors
that may cause Lexicon’s actual results to be materially different from any
future results expressed or implied by such forward-looking statements.
Information identifying such important factors is contained in our reports
filed with the Securities and Exchange Commission. Lexicon undertakes no
obligation to update or revise any such forward-looking statements,
whether as a result of new information, future events or otherwise.
Forward-looking Statements
© 2014 Lexicon Pharmaceuticals, Inc. Slide 2
LX4211: First-in-Class Dual SGLT1/SGLT2 Inhibitor for Type 2 Diabetes
• SGLT1 is the primary transporter for absorption of glucose and galactose in the GI tract
• Reduction of glucose absorption in the proximal intestines leads to more glucose being delivered distally
• L cells respond by releasing GLP-1 and PYY
• SGLT2 is expressed in the kidney where it
reabsorbs 90% of filtered glucose
• Enhancing glucose excretion in the kidney will
enhance glycemic control
• This mechanism is independent of insulin and
may be pancreas-sparing
SGLT1 SGLT1
SGLT2
© 2014 Lexicon Pharmaceuticals, Inc. Slide 3
LX4211 is the First-in-Class Dual Inhibitor of SGLT1 and SGLT2 in Clinical Development
Compound Company SGLT1 SGLT2 Stage
Dapagliflozin BMS/AZ No Yes NDA approved
Canagliflozin Mitsubishi/JNJ No Yes NDA approved
Empagliflozin BI/Lilly No Yes NDA filed
LX4211 Lexicon Yes Yes Phase 3-ready
Ipragliflozin Kotobuki/Astellas No Yes Discontinued in U.S./E.U.; Phase 3 Japan
Tofogliflozin Chugai No Yes Discontinued by Roche; returned to Chugai (Ph3 Japan)
Ertugliflozin Pfizer/Merck No Yes Phase 3 starting
Luseogliflozin Taisho No Yes Phase 2
LIK066 Novartis Yes Yes Phase 2 withdrawn prior to enrollment
GSK-1614235 Kissei/Dainippon/GSK Yes No Phase 1
© 2014 Lexicon Pharmaceuticals, Inc. Slide 4
-1
-0.9
-0.8
-0.7
-0.6
-0.5
-0.4
-0.3
-0.2
-0.1
0
baseline week 4 week 8 week 12
ch
ange f
rom
basline (%
)
Change from Baseline in A1C
75 mg 200 mg 200 mg bid 400 mg PBO
LX4211 Produced Substantial Dose-Dependent Decreases in HbA1c on Background Metformin Therapy
(-.09)
* *p<0.001
(-.52**)
(-.79**)
(-.95 **)
(-.43**)
© 2014 Lexicon Pharmaceuticals, Inc. Slide 5
0
5
10
15
20
25
30
35
40
45
75 mg 200 mg 200 mg
bid
400 mg placebo
Uri
nary
glu
cose /
cre
ati
nin
e (g
/g)
Week 12 Urine Glucose to Urine
Creatinine Ratio
75 mg 200 mg 200 mg bid 400 mg placebo
37.28** 37.25**
Dose-Dependent Reduction in HbA1c from 200 to 400 mg Achieved without Additional Urinary Glucose Excretion
6.47
39.64**
3.75
*p<0.05, ** p<0.001
0
10
20
30
40
50
60
70
80
75mg 200mg 200mg BID 400mg placebo
g/2
4 h
r
Mean Urinary Glucose Excretion
(table 14.2.16.3)
Baseline Day 1 Week 12
** ** ** **
**
*
*
© 2014 Lexicon Pharmaceuticals, Inc. Slide 6
-7
-6
-5
-4
-3
-2
-1
0
mm
Hg
Change from Baseline to Week 12 in SBP
400 mg PBO
LX4211 Produced Significant Reductions in Systolic Blood Pressure
* p<0.05, ** p<0.001
-6.0**
-3.9* -4.5*
-0.1 -0.3
75 mg 200 mg 200 mg BID
© 2014 Lexicon Pharmaceuticals, Inc. Slide 7
LX4211 Reduced Systolic Blood Pressure the Most in Patients with High Baseline Systolic Blood Pressure
-60
-40
-20
0
20
40
60
80 100 120 140 160 180
Change in S
BP f
rom
Baseline (m
mH
g)
Baseline Systolic Blood Pressure (mmHg)
400 mg QD LX4211
(n=59)
• Large SBP change in patients with elevated SBP ₋14 mmHg reduction vs. placebo (p=0.002) when baseline SBP ≥130 mmHg
• Minimal SBP change in patients with normal BP ₋1 mmHg reduction vs. placebo (p=0.6) when baseline SBP <130 mmHg
-60
-40
-20
0
20
40
60
80 100 120 140 160 180
Change in S
BP f
rom
Baseline (m
mH
g)
Baseline Systolic Blood Pressure (mmHg)
Placebo
(n=60)
400 mg LX4211 Placebo
© 2014 Lexicon Pharmaceuticals, Inc. Slide 8
LX4211 Study in T2DM Patients with Renal Impairment
• Medical need:
- Up to 40% of patients with type 2 diabetes eventually will suffer from kidney failure1
- Many current medications, including metformin, are contraindicated in T2DM patients with moderate to severe renal impairment
• Rationale:
- SGLT1 inhibition in the gastrointestinal tract could provide benefit through its unique mechanism of action
• Opportunity:
- Position LX4211 for Phase 3 development in an important area of unmet medical need
- Provide perspective on the magnitude of the SGLT1 effect of LX4211
- Reinforce differentiation relative to selective SGLT2 inhibitors
• Selective SGLT2 inhibitors have demonstrated limited benefit in patients with compromised renal function
1. National Kidney Foundation, http://www.kidney.org/atoz/content/diabetes.cfm
© 2014 Lexicon Pharmaceuticals, Inc. Slide 9
LX4211.107: Study in T2DM Patients with Moderate to Severe Renal Impairment
• 30 patients with eGFR < 60 mL/min/1.73m2 randomized 1:1
• 7 days of dosing, 400 mg of LX4211 or placebo
• 50% of patients had eGFR < 45 mL/min/1.73m2
• Primary objective:
‒ Effect of LX4211 on postprandial glucose
• Secondary objectives: - Safety and tolerability - Pharmacodynamic effects of LX4211 on fasting plasma glucose
and GLP-1 (total and active) - The single-dose and multiple-dose pharmacokinetic effects of
LX4211 in this patient population
-
© 2014 Lexicon Pharmaceuticals, Inc. Slide 10
Glucose After a Standard Meal: Day -1 vs. Day 7
100
120
140
160
180
200
220
240
-1 0 1 2 3 4
Day -1 Day 7
100
120
140
160
180
200
220
240
-1 0 1 2 3 4
Day -1 Day 7
LX4211 n=16
Placebo n=15
Hours Hours
Glu
cose (m
g/d
l)
Glu
cose (m
g/d
l)
© 2014 Lexicon Pharmaceuticals, Inc. Slide 11
Glucose in Patients with eGFR < 45 mL/min/1.73 m2
LX4211 n=6
Placebo n=9
100
120
140
160
180
200
220
240
-1 0 1 2 3 4
Day -1 Day 7
Hours Hours
Glu
cose (m
g/d
l)
Glu
cose (m
g/d
l)
100
120
140
160
180
200
220
240
-1 0 1 2 3 4
Day -1 Day 7
© 2014 Lexicon Pharmaceuticals, Inc. Slide 12
LX4211.107 Fasting Plasma Glucose
Change in FPG mg/dL
All Patients
LX4211 vs. placebo -20
p -value 0.056
eGFR 45-59 mL/min/1.73m2
LX4211 vs. placebo -17
p -value 0.29
eGFR<45 mL/min/1.73m2
LX4211 vs. placebo -27
p -value 0.08
© 2014 Lexicon Pharmaceuticals, Inc. Slide 13
Total GLP-1 After a Standard Meal: Day -1 vs. Day 7
LX4211 n=16
Placebo n=15
Hours Hours
Tota
l G
LP-1, p
mol/
L
Tota
l G
LP-1, p
mol/
L
5
10
15
20
-1 0 1 2 3 4
Day -1 Day 7
5
10
15
20
-1 0 1 2 3 4
Day -1 Day 7
© 2014 Lexicon Pharmaceuticals, Inc. Slide 14
Active GLP-1 After a Standard Meal: Day -1 vs. Day 7
LX4211 n=16
Placebo n=15
Hours Hours
Acti
ve G
LP-1, p
mol/
L
Acti
ve G
LP-1, p
mol/
L
0
1
2
3
4
5
6
-1 0 1 2 3 4
Day -1 Day 7
0
1
2
3
4
5
6
-1 0 1 2 3 4
Day -1 Day 7
© 2014 Lexicon Pharmaceuticals, Inc. Slide 15
LX4211.107 Urinary Glucose Excretion Data
LX4211 Placebo
Mean Change from baseline in UGE (g/24 hrs)
33.6 -1
p (LX4211 vs. placebo) <0.001 -
LX4211 Placebo
eGFR≥45 ml/min/1.73m2 (N=16)
42 -2
p (LX4211 vs. placebo) <0.001 -
eGFR<45 ml/min/1.73m2 (N=15)
21 0
p (LX4211 vs. placebo) 0.001 -
© 2014 Lexicon Pharmaceuticals, Inc. Slide 16
Conclusions from Study of LX4211 in Patients with Renal Impairment
• LX4211 improved glycemic control in subjects with type 2 diabetes and renal impairment
- Post-prandial glucose (PPG) reduction was large and robust
• Benefits clear in population with eGFR<45 ml/min - GLP-1 elevations highlight SGLT1 effect
• Benefits obtained with low urinary glucose excretion
• Top-line safety and PK support LX4211 400 mg qd dose
• Significant opportunity to differentiate LX4211 in patients
with renal impairment during Phase 3
© 2014 Lexicon Pharmaceuticals, Inc. Slide 17
Recent LX4211 Clinical Trial Updates
Definitive QT Study Completed • Required study, part of cardiovascular safety profile • 64 healthy volunteers randomized to single doses of LX4211 400
mg, 2000 mg, placebo, or moxifloxacin in crossover fashion • Study results met FDA guidance for supporting CV safety
Additional Multiple Ascending Dose Study Completed • Phase 1 study evaluating safety and tolerability of 800 mg dose • 25 subjects randomized 2:2:1 to 10 days of treatment with LX4211
400 mg, LX4211 800 mg, or placebo • Study results showed adequate safety and pharmacokinetic data to
support use of LX4211 400 mg in Phase 3 clinical development
© 2014 Lexicon Pharmaceuticals, Inc. Slide 18
Type 1 Diabetes: An Area of High Unmet Medical Need
• Substantial and growing patient population ‒ More than one million patients in the U.S. ‒ Incidence rate in children, where most T1DM is first diagnosed, is
growing at 3% annually
• Key area of unmet medical need: Therapies that achieve euglycemia ‒ Reduction of glucose variability ‒ More effective and less difficult management of glucose control
• Substantial majority of T1DM patients are not achieving HbA1c
targets ‒ More than 50% have HbA1c >8% ‒ Up to 80% of T1DM patients in some age cohorts are above target
• Significant percentage of T1DM patients experience severe
hypoglycemic events ‒ Increases with age and duration of diabetes
© 2014 Lexicon Pharmaceuticals, Inc. Slide 19
LX4211 Type 1 Diabetes Proof of Concept Study
• Open-label Pioneer Group of 3 subjects on insulin pump to allow for initial assessment of safety and establishment of initial insulin dose reduction for Expansion Group
• Expansion Group of approximately 30 subjects on either
continuous subcutaneous insulin infusion (CSII, insulin pump) or multiple dose injection
• 7 sites in the United States
• Dose= 400mg taken before breakfast, 28 days of treatment
© 2014 Lexicon Pharmaceuticals, Inc. Slide 20
Patient Population: Key Inclusion Criteria
• Adult subjects 18 to 55 years old (inclusive) with T1DM, currently on either continuous subcutaneous insulin infusion (CSII, insulin pump) or multiple dose insulin injection (MDI)
• Screening with the following laboratory values: - HbA1c value ≥7.0% to ≤9.0% - FPG ≤270 mg/dL - Body mass index (BMI) ≤32 kg/m2 - Fasting C-peptide ≤0.7 ng/L - Triglycerides ≤1000 mg/dL
© 2014 Lexicon Pharmaceuticals, Inc. Slide 21
LX4211 Type 1 DM Proof of Concept Endpoints
• Primary goal: to establish safety and mechanistic proof-of-concept - First co-administration of LX4211 with insulin
• Primary Endpoint
- To assess the effect of LX4211 on the total amount of bolus insulin required
• Secondary Objectives (partial list)
- To assess multiple parameters of glycemic control - To assess the effect of LX4211 on basal and total insulin use - To assess other metabolic, pharmacodynamic and
pharmacokinetic parameters
© 2014 Lexicon Pharmaceuticals, Inc. Slide 22
Baseline Characteristics
Characteristic PL SD LX SD
Patients enrolled 17 16
Age Range (y) 21-57 11.8 21-55 12.1
Median Age (y) 34.0 45.5
Male / Female 8/9 8/8
Mean (range) Years Diabetes Duration 19.5 (4-40) 9.2 21.8 (3-42) 13.8
Mean Weight (kg) 76.8 15.5 78.4 14.8
Mean BMI (kg/m2) 26.2 3.1 27.1 3.1
MDI / CSII 5/12 6/10
Mean Total Daily Insulin Units/Kg 45.9/76.8=0.6 47.0/78.4=0.6
Mean Daily Insulin IU: Bolus/Total 0.44 0.43
Mean FPG (mg/dL) 160.2 71.5 170.3 62.4
Mean HbA1c 7.9 0.5 7.9 0.5
Systolic BP (mmHg) 119.8 7.0 118.1 9.2
Diastolic BP (mmHg) 75.6 7.6 70.8 7.1
All randomized patients completed the study
© 2014 Lexicon Pharmaceuticals, Inc. Slide 23
LX4211 Met Primary Endpoint, Significantly Reducing Bolus Insulin Use
-35
-30
-25
-20
-15
-10
-5
0
Bolus Insulin
Change f
rom
baseline (%
)
Placebo LX4211
-32
* * p= 0.007 relative to placebo
-6.4
© 2014 Lexicon Pharmaceuticals, Inc. Slide 24
LX4211 Produced a Significant Reduction in HbA1c at Four Weeks
-0.6
-0.5
-0.4
-0.3
-0.2
-0.1
0
HbA1c
HbA1c
Change f
rom
baseline (%
)
Placebo LX4211
* p= 0.002 relative to placebo
-0.55 *
-0.06
© 2014 Lexicon Pharmaceuticals, Inc. Slide 25
LX4211 Improved Glycemic Control as Measured by Continuous Glucose Monitoring
8.5
35.6 55.9
5.8
40.2 54
7.9
35.7 56.4
6.7
25
68.2
< 70 mg/dl
70 – 180 mg/dl
> 180 mg/dl
Blood Glucose Placebo
LX4211
Baseline Treatment
p=0.003
p=0.002
© 2014 Lexicon Pharmaceuticals, Inc. Slide 26
LX4211 Produced a Significant Reduction in Body Weight at Four Weeks
-2
-1.5
-1
-0.5
0
0.5
1
Body Weight
Body Weight
Bod
y w
eig
ht
(kg)
Placebo LX4211
* p= 0.005 relative to placebo
-1.72
*
+0.50
© 2014 Lexicon Pharmaceuticals, Inc. Slide 27
LX4211 Achieved Positive Proof-of-Concept in Type 1 Diabetes, Progressing into Late-Stage Development
• LX4211 met primary endpoint by lowering bolus insulin by 32%
• LX4211 improved glycemic control:
- Lowered A1C by 0.55% in four weeks - Less hyperglycemia, CGM time > 180 mg/dL range - More CGM time in 70-180mg/dL range - No increase in hypoglycemia - Less glycemic variability by multiple measures
• LX4211 decreased body weight
• LX4211 was well tolerated
• Lexicon is committed to progressing LX4211 into Phase 3
development in T1DM - Phase 3 planning ongoing
© 2014 Lexicon Pharmaceuticals, Inc. Slide 28
LX4211 Strategy for Late Stage Development and Commercialization
• Unique dual mechanism of action through inhibition of both SGLT1 and SGLT2 with favorable safety profile
• Phase 3 program in broad population of patients with diabetes - Alone or in combination other agents to treat type 2 diabetes - Diabetics with renal impairment - Type 1 diabetes
• Mechanistic synergy with DPP-4 inhibitors with potential for
combination products
• Potential to demonstrate cardiovascular benefit
© 2014 Lexicon Pharmaceuticals, Inc. Slide 29
Telotristat Etiprate: A Peripherally-Acting Serotonin Synthesis Inhibitor
• Telotristat etiprate (LX1606), a novel, orally-
delivered inhibitor of tryptophan hydroxylase
(TPH) that reduces serotonin production
- Absorbed into peripheral circulation
- Does not cross the blood-brain barrier
• Serotonin is a key mediator of
gastrointestinal motility, pain and
inflammation
• High serotonin implicated in carcinoid heart
disease and cardiac valve damage
Carcinoid syndrome results
from metastatic carcinoid
tumor, a life-threatening
neuroendocrine tumor that
produces large amounts of
serotonin; associated with
diarrhea, flushing, pain, and
valvular disease and
pulmonary hypertension
© 2014 Lexicon Pharmaceuticals, Inc. Slide 30
Telotristat Etiprate Phase 2 Open-Label Study: Bowel Movement Frequency
-43.5% change from BL at Wks 11-12
© 2014 Lexicon Pharmaceuticals, Inc. Slide 31
-80
-70
-60
-50
-40
-30
-20
-10
0
Individual patient responses
*1 patient excluded – no Week 12 data
% C
ha
ng
e in
BM
Fre
qu
en
cy
Percent Change in BM Frequency/Patient at Week 12* Last dose
500 500 500 350 500 500 500 500 500 500 500 500 150 500
Telotristat Etiprate Phase 2 Open-Label Study: Individual Patient Bowel Movement Frequency Response at Week 12
© 2014 Lexicon Pharmaceuticals, Inc. Slide 32
Assessment of U.S. Carcinoid Market and Telotristat Etiprate’s Opportunity
U.S. Carcinoid Treatment Flow
Market Assessment
Treated with Octreotide (13.4K, 98%)
Octreotide Adequately Controlled (7.4K, 55%)
Octreotide Not Adequately Controlled
(6.0K, 45%)
Carcinoid Functioning Tumors
(13.7K, 22%)
Carcinoid Non Functioning Tumors
(47.8K, 78%)
New Patients – Treatment Naive (Incidence)
1.6K
Sources: EPI Research, NET Claims data from IMS, primary research with 45 oncologists, August 2013
Note: Segment sizes in 2012
Telotristat etiprate blocks the
production of serotonin and is planned to be positioned as an essential add-on therapy to somatostatin analogs (SSA) during a patient’s journey with a functioning carcinoid tumor
Serotonin is a key
driver of functioning carcinoid tumors, and its overproduction results in the consequences of carcinoid syndrome
© 2014 Lexicon Pharmaceuticals, Inc. Slide 33
Most Carcinoid Patients are Eventually Not Adequately Controlled on Octreotide
% controlled % not controlled
79% of patients are eventually not adequately controlled on
octreotide
Octreotide fails to adequately control carcinoid syndrome within
36 months for 71% of patients
The current treatment paradigm for these patients includes: • Titration to higher doses of octreotide beyond label recommendations • Increase in frequency of immediate release octreotide injections
0 to 6
14%
6 to 12
12%
12 to 24
24% 24 to 36
21%
> 36
29%
No new therapy options exist for patients not adequately controlled
Note: values above represent time in months
Source: Primary research with 45 oncologists, August 2013
© 2014 Lexicon Pharmaceuticals, Inc. Slide 34
Telotristat Etiprate Phase 3 Study Overview: TELESTAR
• Phase 3, randomized, placebo-controlled, double-blind study
• Sample size: 105 subjects (at minimum)
• Double-blind treatment period: 12 weeks
• Open-label extension and follow-up period: 36 weeks
Objectives
• Primary: To confirm that at least 1 or more doses of telotristat etiprate compared to placebo is effective in reducing the change from baseline in the number of daily bowel movements (BMs) over the 12-week double-blind portion (treatment period) of the trial in patients inadequately controlled on somatostatin analog therapy
• Secondary: To examine changes in
- Urinary 5-HIAA levels
- Flushing episodes
- Abdominal pain
© 2014 Lexicon Pharmaceuticals, Inc. Slide 35
2014: Advancing Lexicon’s Late-Stage Pipeline
• Telotristat etiprate (LX1032) for carcinoid syndrome - Pivotal Phase 3 study TELESTAR enrolling well - Companion study TELECAST in progress - Commercial preparations underway
• LX4211 for diabetes
- Phase 3-ready in type 2 diabetes - Phase 3 planning underway for type 1 diabetes
• Meeting with FDA pending
© 2014 Lexicon Pharmaceuticals, Inc. Slide 36
Strong Financial Position Supports Business Model
• Cash and investments of $98 million at March 31, 2014
• Commercialize products independently and in collaboration with partners in sustainable business model
- Global licensing for large, primary care indications
- Form regional partnerships or commercialize independently for select indications
© 2014 Lexicon Pharmaceuticals, Inc. Slide 37 Discovering Breakthrough Treatments for Human Disease
Breakthrough Treatments for Human Disease
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