# Presentation: 796582

## ARIFLO® (cilomilast) Tablets, 15 mg

**September 5, 2003**

**NDA 21-573****Pulmonary - Allergy Drugs Advisory Committee Meeting**

## ARIFLO® (cilomilast)Tablets, 15 mg

**David Wheadon, M.D.**
**Senior Vice President **
**Regulatory Affairs **
**GlaxoSmithKline**

## Chronic ObstructivePulmonary Disease

**Emphysema**

**Chronic Bronchitis**

## Impact of COPD in the US

**Affects an estimated 24 million Americans****1**
**Annual cost $32.1 billion in 2002****2**
**$18 billion in direct healthcare costs**
**$14.1 billion in indirect morbidity and mortality  costs**
**The fourth leading cause of ****death****3**
**123,974 deaths in 2001**

**1.  Mannino DM, *****et al.***** *****MMWR***** 2002; 51(No. SS06):1-16.**
**2.  NHLBI, *****Morbidity and Mortality Chartbook on Cardiovascular, Lung and Blood Diseases, 2002.***** **
**3.  CDC, *****National Vital Statistics Reports*****, Vol. 51, No. 5, March 14, 2003.**

## COPD Mortality is Increasing

**Pastor PN, *****et al.***** *****National Center for Health Statistics*****, 2002**

**COPD Mortality is Increasing**

**Percent change in age-adjusted death rates in the****US over 10 years (1990-2000)**

## Prognosis in Chronic Obstructive Pulmonary Disease

**Anthonisen N, *****Am Rev Respir Dis***** 1986; 133(1):14-20**

## Unmet Medical Need

**Limited treatment options**
**Only bronchodilators are approved for COPD **
**Address only bronchoconstriction **
**Smoking cessation is the only intervention known to reduce the rate of decline of FEV****1**

## COPD is a Complex Disease

## Ariflo:Second Generation PDE4 Inhibitor

**Highly Selective PDE4 inhibitor**
**100% bioavailability **
**Low plasma variability**
**Low potential for drug interactions**
**Improved safety profile**
**Tablet administered orally twice a day **
**Ariflo is an important new option for the treatment of COPD**

## Theophylline:Non-Selective PDE Inhibitor

**Pharmacological activity**
**Methylxanthine**
**Non-selective PDE inhibitor**
**Adverse effects may be related to PDE3 inhibition**
**Effects on other pharmacological pathways****(i.e., adenosine receptor antagonism)**
**Unpredictable pharmacokinetic profile**
**Drug and food interactions **
**Wide blood level variation (i.e., elderly, smokers)**
**Need for blood level monitoring**

## Phase III Development Program

**	****Study/Region****	****Duration**
**2 Pivotal NA****	****24 weeks**
**2 Pivotal EU****	****24 weeks**
**1 Cardiovascular Safety NA****	****12 weeks**
**1 Induced sputum NA****	****12 weeks**
**1 Lung biopsy EU****	****12 weeks**
**1 Lung volume NA****	****12 weeks**
**1 Open-Label Extension NA****	****12-36 months**
**1 Open-Label Extension EU****	****12-36 months**

**Exposure to Ariflo from above studies represents nearly 3,000 patient years**** **

## Poorly Reversible Population Studied in Ariflo Clinical Studies

## Proposed Indication

**ARIFLO****®**** is indicated for the maintenance of lung function (FEV****1****) in patients with chronic obstructive pulmonary disease (COPD) who are poorly responsive to albuterol (increase in FEV****1**** of **_**<**_**15% or **_**<**_** 200 mL).***** ***

## Order of GSK Presentation

**Rationale for the Use of Ariflo in COPD**

**Dr. Katharine Knobil**

**Order of GSK Presentation**

**Dr. David Wheadon**

**Conclusion and Q&A**

**Dr. Katharine Knobil**

**Efficacy Data from Ariflo Clinical Program**

**Dr. Kathy Rickard**

**Safety of Ariflo**

**Dr. Frank Sciurba**

**Assessment of Outcome in COPD**

## Slide 15

## Rationale for theUse of Ariflo in COPD

**Katharine Knobil, M.D.**
**Senior Director **
**Respiratory Clinical Development and Medical Affairs**
**GlaxoSmithKline**

## COPD is a Complex Disease

## Inflammatory Cells in COPD

**Adapted from Retamales I, *****et al.***** *****Am J Respir Crit Care Med*****  2001; 164:469-473.**
**Calhoun WJ, et al. *****Am J Respir Crit Care Med***** 2001; 165:730b-731b.**

*****

- *

*****

***p<0.01 vs control and mild**

## Airway CD8+ T-cellCorrelation with Airflow Limitation

**Adapted from Saetta M, *****et al. Am J Respir Crit Care Med***** 1998; 157:822-826 **

## A New Target for Treating COPDCells Expressing PDE4

## A Novel Approach to Treating COPD: PDE4 Inhibitors

**ATP**

**Adenyl cyclase**

**A Novel Approach to Treating COPD: ****PDE4 Inhibitors**

## Cilomilast Attenuates Fibroblast Activity

***In vitro*****, cilomilast inhibited:**
**Release of MMP-1 and MMP-9 from fibroblasts**
**Activation of  MMP-1 and MMP-9 **
**Degradation of collagen by fibroblasts**
**Suggests potential of PDE4 inhibitors to affect remodeling**

**Kohyama T, *****et al. Am J Respir Cell Mol Biol***** 2002; 27:487-494. **

**Alveolar Wall Destruction**

## Cilomilast Attenuates Release of  Chemoattractants for Human Neutrophils

**Adapted from Profita M, *****et al.****** ******Thorax***** 2003; 58:573-579**

**Bronchial Epithelial Cells**

**Sputum Cells**

**Neutrophils per high power field**

**400**

**0**

**Baseline**

**Cilomilast****(1 ********M)**

**100**

**300**

**200**

**400**

**0**

**Baseline**

**Cilomilast****(1 ********M)**

**100**

**300**

**200**

**P<0.006**

**P<0.008**

**Cells obtained from patients with COPD by bronchoscopy and sputum induction**

## Study 076: Ariflo Decreased Macrophages in Bronchial Biopsies

## Study 076: Ariflo Decreased CD-8+ Lymphocytes in Bronchial Biopsies

## Potential Therapeutic Benefits of Ariflo

**Potential Therapeutic Benefits of Ariflo**

## Slide 27

## Ariflo Clinical Development Program

**Katharine Knobil, M.D****.**
**Senior Director **
**Respiratory Clinical Development and Medical Affairs**
**GlaxoSmithKline**

**Efficacy Data**

## Phase III Development Plan Pivotal Studies

**Study****	****Abbreviated Title****	****Loc****	****Patients****	****Study Duration**
**039****	****Pivotal Phase III****	****NA****	****647****	****24 weeks**
**156****	****Pivotal Phase III ****	****NA****	****825****	****24 weeks**
**091****	****Pivotal Phase III ****	****EU****	****711****	****24 weeks**
**042****	****Pivotal Phase III ****	****EU****	****700****	****24 weeks**

## Phase III Development Plan Supporting Studies

**Phase III Development Plan Supporting Studies**

**Study****	****Abbreviated Title****	****Loc****	****Patients****	****Study Duration**
**110****	****Induced Sputum ****	****NA****	****65****	****12 weeks**
**076****	****Lung Biopsy ****	****EU****	****59****	****12 weeks**
**168****	****Cardiovascular Safety ****	****NA****	****282****	****12 weeks**
**041****	****Long-term Safety ****	****NA****	****355****	****up to 3 years**
**040****	****Long-term Safety ****	****EU****	****723****	****up to 3 years**
**111****	****Static Lung Volumes ****	****NA****	****156****	****12 weeks**

## Study Design: Pivotal Studies

**4 weeks**

**24 weeks**

**Ariflo 15mg BID **

**PRN****albuterol**

**Placebo BID **

**Placebo****Run-in**

## Key Inclusion Criteria

**COPD diagnosis**
**40-80 years old**
_**>**_** 10 pack year history of smoking**
**Symptoms***

***except NA Study 156**

## Key Inclusion Criteria

**Lung Function **
**FEV****1**** (post albuterol): 30 - 70% predicted**
**FEV****1****/FVC (pre albuterol): **_**<**_**70% predicted**
**Poorly reversible to albuterol**
_**<**_** 15% or **_**<**_** 200ml**

## Response to Albuterol in COPD Clinical Development Programs

**1. COMBIVENT Inhalation Aerosol Study Group, *****Chest***** 1994; 105:1411-1419. 2. Mahler D, *****et al. Chest***** 1999; 115:957-965. 3. Rennard S, *****et al. Am J Respir Crit Care Med***** 2001; 163:1087-1092. 4. Mahler D, *****et al. Am J Respir Crit Care Med***** 2002; 166:1084-1091. 5. Hanania NA, *****et al. Chest***** 2003 *****In Press.***

## Key Exclusion Criteria

**Clinical diagnosis of asthma**
**FEV****1**** variability >20% from Screening to Baseline**
**Exacerbation or oral steroid administration during run-in period**

## Efficacy AssessmentsCo-Primary Endpoints 

**Change from baseline in FEV****1 **** **
**Measured in AM prior to the next dose (trough)**
**Change from baseline in total score of the St. George’s Respiratory Questionnaire (SGRQ)  **
** ****A health-related quality of life instrument**

## Efficacy Assessments Secondary Endpoints

**Change from baseline in FVC**
**COPD Exacerbations**
**Post exercise breathlessness****(Borg scale)**
**Summary symptom score **
**Not collected in NA study 156**
**6-Minute walk**

## Baseline Characteristics

**	****            ****NA****	****	****               EU**
**	****039 ****	****156 ****	****042****	****091****	****n=647****	****n=825****	****n=700****	****n=711**
**Age****	****65.3****	****64.5****	****64.6****	****62.8**
**Female (%)****	****38****	****41****	****20****	****14**
**Race % (W/B)****	****93/3****	****93/6****	****99/0****	****98/0**
**Active smokers (%)****	****45****	****46****	****43****	****38**
**FEV****1**** (% Predicted)****	****49.7****	****50.2****	****49.0****	****50.3**
******2 reversibility (% ********)****	****7.3****	****8.6****	****5.1****	****5.0**
**DLCO (% Predicted)****	****58.5****	****55.3****	****70.8****	****70.0**
**Chronic Bronchitis (%)****	****61.5****	****37.5****	****80.1****	****89.6**

## Ariflo Maintains FEV1NA Study 039

**Ariflo Maintains FEV****1****NA Study 039**

## Ariflo: Consistent Treatment Effect

**P<0.001**

**Ariflo: Consistent Treatment Effect**

## Decline in Lung Function in Long-term COPD Studies

## Health-Related Quality of LifeSt. George’s Respiratory Questionnaire

**Disease-specific (respiratory disease)**
**Measures the impact of COPD on quality of life**
**Components of SGRQ**
**Symptoms **
**Activity **
**Impact **
**Decrease in score indicates improvement in QOL **
**Change of -4.0 is a clinically meaningful improvement**

## Ariflo Significantly ImprovesQuality of Life

## Change From Baseline In Total SGRQ Scores Averaged Over 24 Weeks

## Ariflo Pivotal ResultsSecondary Endpoints

**Ariflo Pivotal Results****Secondary Endpoints**

**Study****	****039****	****156****	****091****	****042**
**Measure****	****NA****	****NA****	****EU****	****EU****	**
**FVC****	**** ******** ****	**** ******** ****	**** ****T**** ****	**** ****T**
**6-minute Walk****	**** ****—**** ****	**** ****— ****	**** ****—**** ****	**** ****—**
**Symptom Score****	**** ****—**** ****	**** N/A****	**** ******** ****	**** ****—**** **
**Post-exercise ****	**** ******** ****	**** ****T ****	**** ****T**** ****	****T**** ****Breathlessness**
**COPD Exacerbations****	**** ******** ****	**** ****—**** ****	**** ******** ****	**** ****—**

****** ****= P <0.05 versus placebo**
**— ****= P >0.2 versus placebo**
**T = 0.05 **_**<**_** P **_**<**_** 0.2 in favor of Ariflo**

## Percent of Patients Exacerbation-Free

## Supporting Studies

## Long Term Extension Studies

**Evaluate long term safety and tolerability**
**Further evaluate FEV****1**** over time**
**Open-Label Extension of the pivotal studies**
**Subjects from NA Study 039 were eligible to enter Study 041**
**Subjects from EU Studies 042 and 091 were eligible to enter Study 040**
**Concomitant COPD medication use allowed **

## Long-Term Extension NA Study 041: FEV1

**Long-Term Extension ****NA Study 041: FEV****1**

**Week**

**EP**

**Study 039**

## Long-Term Extension EU Study 040: FEV1

**Week**

**Studies 042, 091**

**Study 040**

## Physiology of Hyperinflation

**	**

**Patient with COPD**

**Normal Chest X-ray**

**Physiology of Hyperinflation**

## Physiology of Hyperinflation

**Physiology of Hyperinflation**

## Study 111: Static Lung Volumes

**4 weeks**

**12 weeks**

**Ariflo 15mg BID (n=79) **

**PRN****albuterol**

**Placebo BID (n=77)**

**Placebo****Run-in**

## Change From Baseline In Pre-albuterol  Volume Of Trapped Gas (D)

**Difference from placebo = -180 ml (week 12), -140 ml (EP)**

**D = TLC****box**** – TLC****he**

## Ariflo Reduces Residual Volume 

## Ariflo Reduces Functional Residual Capacity 

## Can Ariflo be Compared to Theophylline?

**No comparable studies of similar design**
**Small numbers of patients (8 to 60 patients)****1**
**Short duration (1 day to 8 weeks)**
**Criteria for reversibility vary between studies**
**Non-selective PDE inhibitor**
**Primarily bronchodilator effect**
**Predominantly due to inhibition of PDE3****2**
**Weak activity at PDE4****3**

**1****Ram FSF, *****et al. Cochrane Database of Systematic Reviews***** 2003.**
**2 ****Theolair****®**** Prescribing Information**
**3****Howell, *****et al. J Pharmacol. Exp. Ther.***** 1993; 264: 609-615.**

## Can Ariflo be Compared to Theophylline?

**ZuWallack RL, *****et al. Chest***** 2001; 119:1661-1670.**
**Data on file, *****GlaxoSmithKline (SLGA4020/21).***

**Change from Baseline in FEV****1**** (L)**

## Efficacy SummaryCo-Primary Endpoints

**FEV****1****:**
**Maintenance of FEV****1**** over 24 weeks with statistically significant benefit over placebo in both NA pivotal studies**
**Magnitude of effect consistent across NA and EU studies**
**SGRQ:**** **
**Significant improvement in health-related quality of life versus placebo in both NA studies**
**Consistent improvement from baseline in Ariflo groups across NA and EU studies**

## Efficacy SummarySupporting Data 

**Decrease in relative risk of moderate to severe exacerbations in Studies 039 and 091**
**Maintenance of FEV****1**** observed in the long term studies for up to 84 weeks **
**Substantial reduction in hyperinflation**

## Efficacy Conclusions

**COPD is a complex and progressive disease**
**Poorly reversible population**
**Difficult to treat, more rapid decline in FEV****1**
**Ariflo targets inflammation specific to COPD**
**Efficacy data support proposed indication**

## Slide 62

## Safety of Ariflo

**Kathy Rickard, M.D.**
**Vice President **
**Respiratory Clinical Development and Medical Affairs**
**GlaxoSmithKline**

## Safety Overview

**Phase I & II studies**
**Over 50 studies including clinical pharmacology and dose ranging**
**Phase III studies**
**Adverse events**
**Gastrointestinal Safety **
**Cardiovascular Safety **
**Long term safety up to 3 years**

## Safety Exposure 

**3,445 patients in all Phase III COPD studies  **
**2,119 Ariflo; 1,326 placebo**
**2,883 patients in the pivotal 24-week COPD studies**
**1,792 Ariflo; 1,091 placebo**
**Over 1,000 patients in long-term extension studies**
**Nearly 3,000 patient-years of exposure to Ariflo**

## COPD 24-week Studies: AEs

**	****                               ****All Randomized Patients**
**	****Placebo ****	****Ariflo**
**	****n=1091****	****n=1792**
**Adverse Experience* ****	****%****	****%**
**Total****	****76.9****	****78.3**
**COPD ****	****36.2****	****30.4**
**Nausea****	****5.0****	****15.7**
**Diarrhea****	****7.9****	****14.4**
**Abdominal Pain****	****7.1****	****11.7**
**Upper Respiratory Tract infection****	****10.3****	****8.8**
**Headache****	****7.0****	****8.2**
**Dyspepsia****	****2.5****	****6.8**
**Vomiting****	****1.6****	****6.1**
**Injury****	****5.0****	****5.4**
**Coughing****	****5.3****	****3.5**

**COPD 24-week Studies: AEs**

*** Includes adverse experiences reported for **_**>**_**5% of patients in either of the treatment groups**

## COPD 24-week Studies:Withdrawal Due to AEs

**COPD 24-week Studies:****Withdrawal Due to AEs**

**                               ****	****                             ****All Randomized Patients**
**	****Placebo ****	****Ariflo**
**Adverse Experience*****	****n=1091****	****n=1792**
**	****%****	****%**
**Total****	****11.7****	****17.5**
**Nausea****	****0.5****	****5.1**
**Abdominal Pain****	****0.7****	****4.3**
**Diarrhea****	****0.6****	****3.6**
**COPD****	****3.8****	****2.2**
**Vomiting****	****0.3****	****1.4**
**Dyspepsia ****	****0.1****	****1.0**
**Dizziness****	****0.2****	****0.9**
**Headache****	****0.1****	****0.9**
**Flatulence****	****0.1****	****0.5****	**

*** Includes adverse experiences reported for **_**>**_**0.5% of patients in either of the treatment groups**

## Rationale for Extensive GI Monitoring

**Class-related GI adverse events**
**Medial necrosis in rat mesenteric arteries seen at **_**>**_**30mg/kg/day **
**Not observed in primates**
**No intestinal ischemia observed   **
**Medial necrosis also seen with theophylline and caffeine in rodents**
**No association of mesenteric ischemia  over decades of use in humans**

**Collins JJ, *****et al. Fundam Appl Toxicol***** 1988; 11:472-484. **
**Johansson S, *****Acta Pathol Microbiol Scand***** 1981; 89:185-191.**

## Extensive GI Safety Monitoring 

**Physical exams**
**Laboratory assessments**
**Orthostatic vital signs**
**Fecal occult blood tests**
**GI adverse events of concern**
**Any GI adverse event that interfered with patient’s daily activities**

## Extensive GI Safety Monitoring 

**Patients who completed study:**
**6  fecal occult blood tests**
**10 sets of laboratory evaluations**
**13 sets of vital signs**
**4 sets of orthostatic vital signs**

## COPD 24-week Studies:GIAEs of Concern

**	****                               ****All Randomized Patients**
**	****Placebo ****	****Ariflo**
**Adverse Experience*****	****n=1091****	****n=1792**
**(Preferred term)****	****%****	****%**
**Total****	****4.8****	****12.9**
**Abdominal Pain****	****2.6****	****5.9**
**Diarrhea****	****2.1****	****5.2**
**Nausea****	****0.6****	****4.3**
**Vomiting****	****0.5****	****2.9**
**Dyspepsia****	****0.3****	****1.6**
**Melena****	****0.8****	****0.9**
**Flatulence****	****0.2****	****0.9**

*** Includes adverse experiences reported for **_**>**_**0.5% of patients in either of the treatment groups**

## Cumulative Incidence of GI Adverse Events of Concern in Pivotal Studies

## Fecal Occult Blood Testing in the Pivotal Studies

**                               ****	****                        ****All Randomized Patients**
**	****Placebo ****	****Ariflo**
**	****n=1091****	****n=1792**
** ****	****	****Total **
**     ****# Tested****	****788****	****1256**
**     ****# Positive n (%)****	****12 (1.5%)****	****27 (2.2%)**
**GIAEs of Concern****	**** n=52 ****	****n=231**
**     ****# Tested****	****42****	****205**
**     ****# Positive n (%)****	****5 (11.9%)****	****16 (7.8%)**

## Reports of  Bowel Ischemia in the Clinical Program

**	****Placebo****	****Ariflo**
**Pivotal Trials****	**
**# Cases****	****2****	****0**
**Person-Years Exposed****	****444****	****683**
**Incidence Rate per 1000 py****	****4.5****	****0****	**
**Long Term Extension****	**
**# Cases****	****Not Applicable****	****3**
**Person-Years Exposed****	****...****	****1800**
**Incidence Rate per 1000 py****	****...****	****1.7**
**Total**
**# Cases****	****2****	****3**
**Person-Years Exposed****	****444****	****2483**
**Incidence Rate per 1000 py****	****4.5****	****1.2**
**py=person years**

## Incidence of Serious Adverse Events in Pivotal Studies

**                               ****	****                               ****All Randomized Patients**
**	****Placebo ****	****Ariflo**
**	****n=1091****	****n=1792**
**Serious Adverse Event: n (%)**
**Total****	****96 (8.8%) ****	****104 (5.8%)**
**Gastrointestinal body system ****	****12 (1.1%)****	**** 10 (0.6%)**
**Cardiovascular body system*             28 (2.6%)****	**** 20 (1.1%)**
**Respiratory body system****	****31 (2.8%)****	**** 30 (1.7%)**

***Includes events reported for cardiovascular general, heart rate and rhythm, and myocardial, endocardial, pericardial valve body systems.**

## GI Safety SummaryNo Evidence of Bowel Ischemia

**Mesenteric vasculopathy occurred only in rodents**
**No evidence of bowel ischemia in animals, including rats**
**Extensive GI safety monitoring demonstrated no serious GI effects**
**Incidence of bowel ischemia was comparable between Ariflo and placebo**

## Extensive Cardiovascular Safety Monitoring 

**CV safety issues with non-selective PDE inhibitors**
**Myocardial necrosis at high, lethal doses (**_**>**_**80mg/kg/day) in rat toxicity studies**
**CV Safety (vital signs, ECGs, Holters)**

**Whitehurst VE, *****et al. Toxicology***** 1996; 100:113-121.**

## Extensive Cardiovascular Safety Monitoring

**>70,000 ECGs **
**>68,000 ECGs in patients with COPD**
**>6,000 ECGs at C****max**
**>1,000 Holters**
**24-hour Holter monitoring in over 400 patients **

## Extensive ECG Monitoring Revealed No Safety Issues with Ariflo

***>5% of patients in any treatment group**

**	****                         ****All Randomized Patients**
**	****Placebo % ****	****Ariflo %**
**New Onset ECG Abnormalities* ****	****n=1091****	****n=1792**
**Sinus Bradycardia****	****13.6****	****14.4**
**Q-T Interval Increased****	****12.4****	****12.3**
**T-wave Abnormal NOS****	****13.0****	****9.5**
**Premature Atrial Contractions NOS****	****10.3****	****9.0**
**Intraventicular Block NOS****	****6.2****	****8.1**
**S-T Changes Nonspecific****	****9.4****	****8.1**
**Poor R-wave Progression****	****9.0****	****7.6**
**Sinus Tachycardia****	****5.8****	****6.0**
**PVCs NOS****	****2.8****	****5.7**
**Sinus Arrhythmia****	****7.1****	****5.6**
**Left Atrial Hypertrophy (P mitrale)****	****5.8****	****4.9**
**PVCs Unifocal****	****7.2****	****4.6**

## QTc Interval Similar Between Treatment Groups

**	****                               **
**	****                                      ****All Randomized Patients**
**	****             ****Placebo ****	****Ariflo**
**	****           ****n=1091****	****n=1792****	**** ****Mean QTc* (msec)**
**  ****Baseline****	****           424****	****425**
**  ****Change from Baseline at EP****	****          0.1****	****-0.4**
**QTc* Increases from baseline at any time-point****	**
** ****Patients with 30-60msec change******	****          144 (18.6%)****	****212 (17.3%)**
** ****Patients with >60msec change*****	*****                 23 (3.0%)****	**** 21 (1.7%)**

***Bazett’s correction**
****in patients with a normal QTc at Baseline**

## New Onset Cardiac Events:24-Hour Holter Monitoring

**  ****	****                                                        ****New Onset n (%)**
**Cardiac Event ****	****	****Placebo****	****Ariflo  **
**     ****	**
**Atrial Fibrillation****	****	****0****	****2 (0.7)**
**Atrial Flutter****	****	****0****	****1 (0.4)**
**First Degree AV Block****	****	****5 (3.6)****	****6 (2.2)**
**Mobitz Type 1****	****	****0****	****2 (0.7)**
**Mobitz Type 2****	****	****2 (1.4)****	****1 (0.4)**
**Sinus Bradycardia****	****	****12 (12.2)****	****29 (15.1)**
**Sinus Pause****	****	****6 (4.3)****	****4 (1.5)**
**Supraventricular Tachycardia****	****	****29 (46.8)****	****65 (45.5)**
**Non-Sustained VT****	****	****11 (8.3)****	****23 (8.7)**

## Incidence of Serious Adverse Events in Pivotal Studies

**                               ****	****                               ****All Randomized Patients**
**	****Placebo ****	****Ariflo**
**	****n=1091****	****n=1792**
**Serious Adverse Event: n (%)****	****	**
**Total****	****96 (8.8%) ****	****104 (5.8%)**
**Gastrointestinal body system ****	****12 (1.1%)****	****10 (0.6%)**
**Cardiovascular body system*     ****	****28 (2.6%)****	****20 (1.1%)**** **
**Respiratory body system****	****31 (2.8%)****	****30 (1.7%)**

***Includes events reported for cardiovascular general, heart rate and rhythm, and myocardial, endocardial, pericardial valve body systems.**

## Serious Adverse Events with Fatal Outcome in the Pivotal Studies

**	****Placebo****	****Ariflo**
**	****n=1091****	****n=1792**
**Fatal SAEs* ****	****5 (0.5%)****	****7 (0.4%)**

***None were considered related to treatment.**

## Safety Data from Long Term Extension Studies

**Greater than 1,000 patients for up to 3 years**
**Over 25,000 ECGs performed**
**Safety data similar to pivotal trials**
**No cardiovascular safety issues identified**
**No gastrointestinal safety issues identified**

## Additional Safety AssessmentsClinical Pharmacology Studies

**Male reproductive**
**Neuroendocrine**
**Drug-drug interactions**

## Male Reproductive System

**Nonclinical studies with Ariflo showed testicular degeneration in rats and rabbits, but not in mice or primates**
**Ariflo 15mg BID or placebo was administered to 100 healthy, young male subjects for 12 weeks**
**No evidence of a clinically significant effect on sperm number, motility, or morphology in humans**

## Neuroendocrine System

**Adrenocortical hypertrophy in rats**
**Stimulation of the HPA-axis is well-recognized response of rats to PDE inhibitors **
**Mammary tumors at high dose in mice associated with pseudopregnancy **
**No evidence of an effect on prolactin, ACTH, serum or urinary cortisol levels in humans**

**Kumari M, *****et al. Brit J Pharmacol***** 1997; 121:459-468.**
**Law LW, *****Proc Soc Exp Biol Med***** 1941; 48:486-487.**

## Interaction Studies

**No evidence of interactions:**
**Albuterol, ipratropium, theophylline, prednisolone, warfarin, and digoxin**
**Smoking**
**No effect on bioavailability with magnesium-aluminum-dimethicone antacid or food**
**Potential for increased GI intolerance **
**Co-administration with erythromycin **
**Severe hepatic impairment**
**Severe renal impairment**

## Ariflo Safety Conclusions

**Extensive safety data with exposure to Ariflo up to 3 years**
**For patients with GI adverse events, most occurred early and were mild to moderate in intensity**
**Serious AEs, including GI, were infrequent and similar between treatment groups**
**No evidence of an increased risk of cardiovascular events**

## Slide 90

## Assessment of Outcome in COPD

**Frank Sciurba, MD**
**Associate Professor of Medicine**
**Division of Pulmonary, Allergy and Critical Care Medicine University of Pittsburgh**** **

## The Face of Chronic Obstructive Pulmonary Disease (COPD)

**Emphysema**

**Chronic**** Bronchitis**

## Health Care Utilization and Mortality Due to Exacerbations

**Connors AF, *****et al.***** *****Am J Respir Crit Care Med*****. 1996;154:959-967**

**Health Care Utilization and ****Mortality Due to Exacerbations**

## No single parameter in patients with COPD is sufficient to be considered the gold standard to assess outcome.

**No single parameter in patients ****with COPD is sufficient to be considered the gold standard to assess outcome.**

***— ******A. Fishman, 1994***

## Clinical Research in COPD:Needs and Opportunities

**NHLBI Workshop Summary**
**What measures of disease status are useful indices therapeutic benefit?**
**What can be done to promote the development and testing of novel agents for the treatment of COPD? efforts that may reduce these barriers ...exploration of alternative outcome measures”**

**Croxton TL, *****et al.***** *****Am J Respir Crit Care Med *****2003; 167:1142.**

## FEV1: Advantages

**On average reflects function and prognosis**
**Reproducible measure**
**Responsiveness to various therapies well established**

## Prognosis in Chronic Obstructive Pulmonary Disease

**Anthonisen N, *****Am Rev Respir Dis***** 1986; 133(1):14-20**

## FEV1: Limitations

**Marked **_**individual**_** variation in symptoms and disability independent of FEV****1**
**Symptomatic and functional response to therapy may be independent of FEV****1**
**May not reflect changes in important disease activity which could lead to long term functional decline or frequency of exacerbations**

## Correlation of Quality of Life Scores (SGRQ*) with FEV1 in Patients with COPD

***Higher scores =  worse quality of life**
**Adapted with permission from Jones PW. *****Chest***** 1995; 107(suppl): 187S-193S.**

**Correlation of Quality of Life Scores (SGRQ*) with FEV****1**** in Patients with COPD**

## Spirometric Changes with Increasing Degrees of Obstruction

**Spirometric Changes with Increasing Degrees of Obstruction**

## Slide 101

## Hyperinflation in Emphysema

## Lung and Chest Wall Forces at End-Expiration in COPD vs. Normal

## Slide 104

## Dynamic Lung Volume Regulation During Exertion in COPD Compared to Normal

**O’Donnell. *****Chest***** 2000; 117:42S-47S.**

## Bronchodilator Responses in Patients with “Irreversible” Emphysema

**Change from Baseline post-albuterol  (L)**

***p<0.05**
**O’Donnell, DE. *****Eur Resp J***** 2001; 18:914-920.**

## Number of Inflammatory Cellsper m2 of Lung Surface Area

**	****	****Air Space****	****	****	****Tissue**
**	****Control****	****Mild****	****Severe****	****Control****	****Mild****	****Severe**
**Neutrophils****	****20****	****50****	****300*****	****24****	****29****	****140* ****(x10****8****/m****2****)**
**Macrophages****	****270****	****330****	****4000*****	****4.5****	****4.4****	****71*****(x10****8****/m****2****)**
**CD8+****	****40****	****46****	****1400*****	****31****	****34****	****250*****(x10****8****/m****2****)**

***Different from Control and Mild (p <0.01) **

**Retamales I, *****et al.***** *****Am J Respir Crit Care Med*****  2001; 164:469-473.**

**Calhoun WJ,***** et al. Am J Respir Crit Care Med *****2001;***** *****165:730b-731b.**

## The Cigarette Burns Out But the Inflammation Rages On

***- S. Shapiro***

***The Cigarette Burns Out But the Inflammation Rages On***

## Smoking Cessation: Anti-inflammatory Model

**Smoking Cessation: Anti-inflammatory Model**

## Ariflo Maintains FEV1NA Study 039

**Ariflo Maintains FEV****1****NA Study 039**

## Ariflo Reduces Residual Volume 

## Study 076:Ariflo Decreased Inflammatory Cells in Bronchial Biopsies

## Conclusions

**Clinically relevant outcomes of novel anti-inflammatory agents for COPD**
**Stabilization of FEV****1**
**Reduction in lung hyperinflation**
**Airway inflammation**
**FEV****1**** **
**Useful measure of severity and outcome in COPD**
**May not reflect other clinically important measures of lung hyperinflation and inflammatory activity**

## Slide 114

## Summary Remarks

**David Wheadon, M.D.**
**Senior Vice President**** **
**Regulatory Affairs **
**GlaxoSmithKline**

## COPD Mortality is Increasing

**Mannino DM *****et al.***** *****MMWR, *****2002: 51(SS06);1-16.   **
**Pastor PN *****et al. National Center for Health Statistics*****, 2002.**

**Percent change in age-adjusted death rates in the****US over 10 years (1990-2000)**

## Potential Therapeutic Benefits of Ariflo

**Potential Therapeutic Benefits of Ariflo**

## Ariflo:A New Treatment Option for COPD

**Achieved co-primary endpoints in both North American studies**
**No serious safety issues**
**Lack of interactions**
**Oral treatment may improve compliance**

## External Experts

**Loren Laine, M.D.**
**Chief, GI Section**
**L.A. County – U.S.C. Medical Center**
**Professor of Medicine**
**University of Southern California Medical School**

**Christina Wang, M.D.**
**Program Director**
**General Clinical Research Center**
**Harbor-UCLA Medical Center****Professor of Medicine**
**David Geffen UCLA****School of Medicine**

**Jeremy N. Ruskin, M.D.**
**Director, Cardiac Arrhythmia Service**
**Massachusetts General Hospital**
**Associate Professor of Medicine**
**Harvard Medical School**

**Gary Koch, Ph.D.**
**Professor of Biostatistics****University of North Carolina**

## Slide 120