advancing lexicon’s late-stage pipeline - jefferies · advancing lexicon’s late-stage pipeline...

© 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


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


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


-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**)


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

** ** ** **

**

*

*


-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


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


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


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

-


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)


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


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


p -value 0.29

eGFR<45 mL/min/1.73m2


p -value 0.08


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


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


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 -


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


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


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


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


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


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


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


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


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


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


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


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


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


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


Telotristat Etiprate Phase 2 Open-Label Study: Bowel Movement Frequency

-43.5% change from BL at Wks 11-12


-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


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


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


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: 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


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

NASDAQ: LXRX

www.lexpharma.com

advancing lexicon’s late-stage pipeline - jefferies · advancing lexicon’s late-stage pipeline...

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