slides re: A Phase 3 Study of Denufosol for Cystic Fibrosis TIGER-1 Results

A Phase 3 Study of Denufosol for

Cystic Fibrosis:

TIGER-1 Results

Lead PI TIGER-1

Frank Accurso, MD

Professor of Pediatrics

Cystic Fibrosis Center Director

The Children’s Hospital

University of Colorado Denver

Transport of

Generate

Ions to

Epithelial

Rehydration

Exhibit 99.2

Cystic Fibrosis Therapies

Significant need for agent that addresses basic defect of ion transport prior to onset

of infection and inflammation:

Antibiotic

Mucus

Regulation

Anti-

Inflammatory

Gene

Therapy,

Potentiator

/Corrector

Lung

structural

damage

CFTR defect

Thickened

airway

secretions

Bacterial

colonization

Irreversible

inflammation

Lung Transplant

Inefficient

ion transport

Inefficient

ion transport

Ion

Transport

Restoration

denufosol

P2Y

Receptor Activation

Inhaled P2Y

receptor agonists increase mucosal hydration and the natural mechanism

of mucociliary clearance in the lung

sodium absorption

chloride ion and fluid secretion

cilia beat frequency

mucin

secretion from goblet cells

surfactant release from type II alveolar cells

TIGER-1 Clinical Study Design

CF patients

5 years with FEV

75% predicted

Standard of care allowed

352 CF patients randomized at 62 treatment centers

denufosol 60 mg

TID (n=314)

period

treatment period

24-week safety

extension period

1-week post-treatment

follow-up

placebo TID (n=174)

Placebo-controlled 24-week

Screening

denufosol 60 mg TID (n=178)

Demographic and Background

Characteristics (Intent to Treat Population: ITT*)

89%

95%

Pancreatic enzymes

82%

79%

Bronchodilators

39%

40%

Chronic macrolides

37%

38%

Chronic inhaled antibiotics

77%

Dornase

alfa

42%

48%

+ status

81%

84%

FEF

25%-75%

% Predicted

93%

92%

FEV

% Predicted

54%

49%

% Males

38 (21%)

33 (19%)

19 n (%)

59 (33%)

64 (37%)

12-18, n (%)

81 (46%)

77 (44%)

5-11, n (%)

14.3

14.9

Mean age, yrs

Denufosol (n=178)

Placebo (n=174)

*ITT=All patients randomized

Disposition by Treatment Group

5 (3%)

2 (1%)

Discontinued from placebo-controlled

phase due to an AE, n (%)

19 (11%)

18 (10%)

Discontinued early: placebo-controlled

phase, n (%)

159 (89%)

156 (90%)

Completed through Week 24, n (%)

178 (100%)

174 (100%)

Intent-to-treat population, n (%)

178

174

Randomized, n

Denufosol

Placebo

Primary Efficacy Results –

Placebo–Controlled (ITT)

Placebo

Denufosol

Met primary efficacy

endpoint: change in

FEV

from baseline to

endpoint*

45 mL treatment effect

(p = 0.047)

“Real world”

design

Broader population

Patients on multiple

therapies that improve

FEV

*Endpoint is the Week 24 value or the last observation carried

forward for patients who withdrew early.

-40

-20

100

120

140

Mean Change from Baseline FEV

CFB=Change from Baseline

ITT Population

Placebo

Denufosol

Treatment Week

-40

-20

100

120

140

Mean Change from Baseline FEV

CFB=Change from Baseline

ITT Population

Placebo

Denufosol

Treatment Week

-40

-20

100

120

140

Mean Change from Baseline FEV

CFB=Change from Baseline

ITT Population

Treatment Week

Placebo

Denufosol

Placebo Switched to

Denufosol

denufosol-only, open-label phase

Placebo

Denufosol

Mean Change from Baseline FEF

25%-75%

-100

-80

-60

-40

-20

100

120

140

160

CFB=Change from Baseline

ITT Population

Treatment Week

Placebo

Denufosol

Mean Change from Baseline FEF

25%-75%

-100

-80

-60

-40

-20

100

120

140

160

CFB=Change from Baseline

ITT Population

Treatment Week

Placebo

Denufosol

Placebo Switched to

Denufosol

Mean Change from Baseline FEF

25%-75%

-100

-80

-60

-40

-20

100

120

140

160

denufosol-only, open-label phase

CFB=Change from Baseline

ITT Population

Treatment Week

100

120

140

160

180

Effect of Denufosol in ITT Population and

Patients

110% Predicted

ITT

p-value = 0.047

(n=352)

100

120

140

160

180

110% Predicted

p-value = 0.015

(n=329)

112

ITT

p-value = 0.072

(n=352)

110% Predicted

p-value = 0.025

(n=329)

FEV

FEF

25%-75%

Secondary Efficacy Endpoint:

Pulmonary Exacerbation

Incidence as expected in this patient

population (i.e. low)

No significant difference between groups

May be confounded by denufosol’s

pharmacology

Longer treatment time may be needed

Pulmonary

Exacerbations

(Fuchs’

Criteria)

During Placebo–Controlled Phase

100

Placebo

Denufosol 60 mg

Log rank statistic = 2.379

p-value = 0.123

Time (Weeks)

ITT Population

Hospitalizations/Missed School and Work

During Placebo–Controlled Phase

3.6 (7.7)

13 (7.3%)

Denufosol

(n=178)

0.610

3.4 (7.9)

Mean Days of

CF-Related

Missed School or

Work (SD)

0.843

14 (8.0%)

Hospitalizations/

ER visits for

respiratory

complaint, n (%)

P-value

Placebo

(n=174)

ITT Population

Cystic Fibrosis Questionnaire –

Respiratory Subscale

-3.08 (15.43)

-1.48 (16.74)

CFB Week 24

81.4 (14.56)

(n=173)

Mean (SD)

Denufosol

79.3 (15.98)

Baseline

(n=162)

Mean (SD)

CFQ -

Respiratory

Placebo

ITT Population

High Level of Compliance with TID Dosing

Compliance during the placebo-controlled phase

~90% of patients were compliant

Comparable between denufosol and placebo

Average number of daily doses = 2.7

Excellent patient retention throughout study

352 patients were randomized

~90% completed the 24-week placebo-controlled phase

~99% of those who completed the placebo-controlled

phase elected to continue into the open-label extension

Most Common AEs (

10% in any group)

20 (11%)*

43 (25%)

Headache

36 (20%)

27 (15%)

Pyrexia

61 (34%)

51 (29%)

Pulmonary exacerbation

15 (8%)

23 (13%)

Pseudomonas infection

17 (10%)*

31 (18%)

Sinusitis

29 (16%)

30 (17%)

Productive cough

18 (10%)*

31 (18%)

Rhinorrhea

34 (19%)

32 (18%)

Pharyngolaryngeal pain

26 (15%)

34 (19%)

Nasal congestion

96 (54%)

103 (59%)

Cough

165 (93%)

169 (97%)

Any AE, n (%)

Denufosol (n=177)

Placebo (n=175)

*p-value <0.05 vs placebo

Safety Population

No Difference in Growth Between Groups

45.3

44.5

Baseline

0.922

1.01

1.03

CFB at 6 months

19.8

0.03

147.5

1.90

Denufosol

(n=177)

0.769

19.3

0.07

BMI, kg/m

Baseline

CFB at 6 months

Weight, kg

0.871

148.1

1.83

Height, cm

Baseline

CFB at 6 months

P-value

Placebo

(n=175)

Mean Change from Baseline (CFB)

Safety Population

Safety Overview

Safety

and

tolerability

profile

favorable

Relatively few SAEs and withdrawals due to AEs

AE profile

Comparable between treatment groups

SAEs comparable between treatment groups

Placebo: 14 (8%)

Denufosol: 16 (9%)

No evidence of systemic adverse effects (labs, vital

signs)

Minimal to no systemic absorption following dosing

No significant effect on growth (height/weight/BMI)

TIGER-1 Summary

Large multicenter, randomized, double-blind,

placebo-controlled trial

Used with other therapies

No significant interactions with concomitant medications

Significant

improvement

FEV

Comparable exacerbation rates

Well-tolerated

Good adherence to TID regimen

Placebo

Denufosol

Primary Efficacy Results –

Placebo–Controlled (ITT)

Endpoint is the Week 24 value or the last observation carried forward

for patients who withdrew early.

-150

-100

-50

100

= 41 mL

p-value = 0.101

Subgroup:

FEV

Patients

Who

Did

NOT

Experience an Exacerbation (Fuchs’

Criteria)

n=141 (81%)

n=131 (74%)

Placebo

Denufosol

-150

-100

-50

100

Subgroup: FEV

in Patients Who Did Experience

an Exacerbation (Fuchs’

Criteria)

n=33 (19%)

n=47 (26%)

= 101 mL

p-value = 0.062

Placebo

Denufosol

TIGER-2 Study Design

Current Status

~100 sites in North America, Australia and New Zealand

As of October 17, 133 patients randomized at 41 sites

TIGER-2 Study Design

Primary

outcome:

FEV

48 weeks; placebo-controlled

Planned sample size n=~450

Open-label extension to follow

Acknowledgements

Cystic Fibrosis Foundation

CFFT Therapeutics Development Network

CFFT Data Monitoring Committee

TIGER-1 Principal Investigators and

Research Coordinators