First Example in Respiratory Area

							First Example in Respiratory Area

 Steroid Nasal Spray  Seasonal Allergic Rhinitis, Age12 yr  Randomized, Double-Blind, Parallel-Group  5-21 Days of Screening Followed by 2 Weeks of
Treatment  Placebo, 50mcg, 100mcg, 200mcg, 400mcg,  ~ 125 Patients/Treatment.

ICSA2007 Symposium, 6/5/07 Panel Session Shuyen Ho

Primary Efficacy & Key Safety Endpoints

 Mean change from baseline over the entire
treatment period in daily, reflective total nasal symptom scores (rTNSS)

 Adverse events  24-hour urinary cortisol excretion

ICSA2007 Symposium, 6/5/07 Panel Session Shuyen Ho

Primary Efficacy Endpoint
Mean Change in Daily rTNSS over Treatment Period
0 -1 -2 -3 -4 -5 placebo 50mcg 100mcg 200mcg 400mcg

0

1

2

3

4

5

6

7

8

9

10 11 12 13 14 99

Day
ICSA2007 Symposium, 6/5/07 Panel Session Shuyen Ho

Primary Efficacy Endpoint
Mean Change in Daily rTNSS over Entire Treatment Period
0

-1 placebo 50mcg 100mcg 200mcg 400mcg

-2

-3

-4

ICSA2007 Symposium, 6/5/07 Panel Session Shuyen Ho

Onset of Action
Mean Change in AM Pre-dose iTNSS
0 -0.5 -1 -1.5 -2 -2.5 -3 -3.5 placebo 50mcg 100mcg 200mcg 400mcg

0

4

8

12

24

48

72

Hour
ICSA2007 Symposium, 6/5/07 Panel Session Shuyen Ho

“Important” Efficacy Endpoint
Mean changes in AM pre-dose iTOSS over Entire Treatment Period
0

-1

-2

placebo 50mcg 100mcg 200mcg 400mcg

-3

ICSA2007 Symposium, 6/5/07 Panel Session Shuyen Ho

Adverse Events during Treatment Period
Placebo Rate > 3% Epistaxis Headache Withdrawal Drug Related 11 ( 9) 5 ( 4) 6 ( 5) 1 (<1) 14 (11) 50ug 11 ( 9) 4 ( 3) 7( 6) 1 (<1) 17 (13) 100ug 15 (12) 10 ( 8) 7 ( 6) 1 (<1) 14 (11) 200ug 13 (10) 11 ( 9) 2 ( 2) 4 (3) 14 (11) 400ug 13 (10) 9 ( 7) 4 ( 3) 1 (<1) 17(13)

ICSA2007 Symposium, 6/5/07 Panel Session Shuyen Ho

24-hour Urinary Cortisol Excretion
Change from Baseline to Week 2 (UC pop)

ICSA2007 Symposium, 6/5/07 Panel Session Shuyen Ho

Dose Selection
 Which dose would you choose?  Why?

ICSA2007 Symposium, 6/5/07 Panel Session Shuyen Ho

Discussion
 Flat Dose Response Pattern for steroids, once a particular  

does starts to work, all higher doses work? Why not study more lower doses, e.g. 25 mcg, or even 12.5 mcg? Why not use active control (market leader) to better asses relative efficacy and safety? Why not wait until the final formulation and final device are developed?

ICSA2007 Symposium, 6/5/07 Panel Session Shuyen Ho

Second Example in Respiratory Area
 A Novel Compound  COPD (Chronic Obstructive Pulmonary Disease) –
Smoker’s Lung  Randomized, Double-Blind, Parallel-Group, >40 yrs  2 Weeks Run-in Followed by 4 Weeks of Treatment  Placebo, 5mg, 10mg, 15mg.  ~105 Patients/Treatment

ICSA2007 Symposium, 6/5/07 Panel Session Shuyen Ho

One of the Primary Efficacy Endpoints
Change from baseline in trough FEV1 at Endpoint – Measured in AM prior to dosing

ICSA2007 Symposium, 6/5/07 Panel Session Shuyen Ho

Phase II Study Results
Dose 5mg 10mg 15mg

FEV1 (Trt – Plb) (Endpoint at 4 wks)

60ml

10ml

140ml

ICSA2007 Symposium, 6/5/07 Panel Session Shuyen Ho

Phase III Study Results
Study
FEV1 (15mg-Plb) (Average Over Time)

1
40ml

2
20ml

3
30ml

4
30ml

FEV1 (15mg-Plb) (Endpoint at 24 wks)

80ml

40ml

30ml

40ml

ICSA2007 Symposium, 6/5/07 Panel Session Shuyen Ho

Discussion
 A successful phase II does ranging study does not
guarantee phase III successes – Duh!

 Is it Preventable?  If you say yes, then how?

ICSA2007 Symposium, 6/5/07 Panel Session Shuyen Ho