SB 207499 (Ariflo ® , cilomilast) GlaxoSmithKline New Drug Application 21-573

1. SB 207499 (Ariflo®, cilomilast)GlaxoSmithKlineNew Drug Application 21-573 Pulmonary - Allergy Drugs Advisory Committee Meeting Holiday Inn Gaithersburg, Maryland 5 September, 2003 Pulmonary and Allergy Drug Products Advisory Committee Meeting September 5, 2003

2. The Drug & Development Program • SB 207499 (phosphodiesterase IV inhibitor) • new molecular entity • first drug in its class • twice daily oral dosing • Indication: “…maintenance of lung function (FEV1) in patients with Chronic Obstructive Pulmonary Disease (COPD) who are poorly responsive to albuterol.” • Multi-national development program • Europe, Australia, Japan, New Zealand, North America, South Africa

3. Presenters • Preclinical Pharmacology-Toxicology • Virgil Whitehurst, Ph.D. • Dose-Finding • Sandra Suarez, Ph.D • Statistics • James Gebert, Ph.D. • Efficacy & Safety • Raymond Anthracite, M.D.

4. Preclinical Considerations Virgil Whitehurst, Ph.D. Pharmacologist

5. Characterization of Toxicological Profile • Identify target organs of toxicity • Identify the no-observed-adverse-effect-level (NOAEL) in animals • Determine severity, reversibility and monitorability of the toxicity • Determine the margin of safety, a ratio based on exposure (e.g., AUC) comparison between animal (NOAEL in the sensitive species) and human

6. Toxic Effects of Cilomilast in Animals • Arteritis (multi-organs), including the mesentery • Testicular Degeneration • Adrenal Cortex Hypertrophy • Myocardial Necrosis • GI Disturbances

7. Arteritis • Arteritis appears to be a class effect of PDE-4 inhibitors (rolipram and others). Other PDE inhibitors, such as theophylline, also induce arteritis. • Arteritis is irreversible in animals. • Arteritis induced by cilomilast occurs in animals at an AUC that is only a fraction of the expected human AUC.

8. Cilomilast Induced Arteritis

9. Summary – Cilomilast (1) • Cilomilast induced arteritis and death in rats. • The severity of the toxicity in rats increases over a narrow range of exposure. • Human exposure at the proposed clinical dose is higher than the toxic dose in the rat.

10. Summary – Cilomilast (2) • Therefore, the data provide no margin of safety for arteritis compared to the proposed clinical dose regimen • Arteritis is a significant safety concern

12. NDA 21-573 Ariflo Immediate Release Tablets Study 032: Dose-Response CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS REVIEW Sandra Suarez-Sharp, Ph.D.

13. N Dose baseline Week 6 0 106 91 5 109 95 10 102 85 15 107 90 * * * * * * Study 032: Multiple Administration of Oral Cilomilast (5, 10 and 15mg Twice Daily) for 6 Weeks to Patients with COPD Mean (SEM) change from baseline in trough pre-bronchodilator FEV1 by week and treatment group * p<0.02

14. Cilomilast Trough Concentration as a Function of Dose and Visit WEEK 1 WEEK 2 WEEK 4 WEEK 6 3000 Cilomilast trough concentration (ng/mL) 2000 1000 0 0 5 10 15 5 10 15 5 10 15 5 10 15 Dose (mg)

15. Baseline FEV1 as a Function of Dose 4 Baseline FEV1 (L) 3 2 Baseline FEV1 (L) 1 0 0 5 10 15 Dose (mg)

16. 0 mg 5 mg 10 mg 15 mg Change from Baseline in FEV1 after Baseline Adjustment 0.2 0.15 0.1 Change from baseline in FEV1 (L) 0.05 0 1 2 4 6 -0.05 Week

17. 2.0 1.2 0.4 -0.4 -1.2 Change from Baseline in FEV1-Cilomilast Trough Concentration Relationship 0 1000 2000 3000 WEEK 4 WEEK 6 Change from baseline in FEV1 (L) WEEK 1 WEEK 2 2.0 1.2 0.4 -0.4 -1.2 0 1000 2000 3000 Cilomilast trough concentration (ng/mL)

18. Adverse Experiences (GIT) Occurring in more than 5% of Patients in Any Treatment Group (% of Patients) Abd Pain Diarrhea Nausea Vomiting 12 10 8 Percentage AE 6 4 2 0 0 5 10 15 0 5 10 15 0 5 10 15 0 5 10 15 Dose (mg)

19. NAUSEA VOMITING D: 0 0 5 5 10 10 15 15 0 5 10 15 3 5 6 3 5 6 3 5 6 3 5 6 3 6 46 456 3 6 46 456 3 6 46 456 3 6 46 456 Visit Visit Cilomilast Trough Concentration in Patients Experiencing GIT Side Effects vs. No AEs NO AEs ABDOMINAL PAIN 5 10 15 2000 1500 Cilomilast trough concentration (ng/mL) 1000 500 0 3 34 4567 3 34 4567 3 34 4567 3 34 4567 4 5 6 7 4 5 6 7 4 5 6 7 Visit Visit

20. CONCLUSIONS • Dose-response relationship was not fully addressed by the sponsor. Data from Study 032 is not robust enough and 10 mg dose was not tested in Phase III clinical trials. • The lack of concentration-response relationship may be due to: • large degree of variability in the Cilomilast plasma trough concentrations (CV>60%) • Unbalanced data • A higher incidence of side effects (such as nausea, abdominal pain, diarrhea) was observed with increasing doses of Cilomilast.

21. CONCLUSIONS, cont. • Plasma concentrations increased proportionally to dose, however no clear correlation between trough concentrations of Cilomilast and some adverse events (AEs) was observed, most likely due to: • the variability of the data • No correlation between Cilomilast trough concentrations and side effects.

22. ACKNOWLEDGEMENTS • He Sun, Ph.D. • Emmanuel O. Fadiran, Ph.D. • Henry Malinowski, Ph.D.

24. Ariflo®Glaxo Smith KlineNDA 21573 Pulmonary and Allergy Drugs Advisory Committee Meeting Gaithersburg, Maryland September 5, 2003 Statistical Reviewer: James Gebert Pulmonary and Allergy Drug Products Advisory Committee Meeting September 5, 2003

25. Topics • Hochberg Procedure • Repeated Measures Analyses • Endpoint Analyses • Sample Size Discussion • Sponsor’s Delta

26. Hochberg Procedure • Modified Bonferroni procedure • Both endpoints significant if both p-values <0.05. • One endpoint significant if p<0.025. • Statistical significance not clinical significance • 95 % confidence limits on treatment difference no longer appropriate • May be inappropriate in regulatory setting because of risk benefit considerations. Both may need to be significant. • What if different endpoints significant in two different studies? How do you write label?

27. Repeated Measures Analyses • Compares treatments over 24 weeks of treatment • No imputation of missing visit data • Underweighs dropouts • Overweighs earlier visits • Needs more assumptions (must specify correlation structure of visits)

28. Endpoint Analyses • Little or no weight to earlier visits • All patients including dropouts given equal weight • No imputation of missing visit data • Equivalent to last visit analysis after doing LOCF • Usually larger delta but larger variability

29. Sample Size • Chosen to have 90% power • 3 of 4 studies used 2:1 weighting • Alpha level was chosen to be 0.025 for both endpoints • Delta=120 ml for FEV1 • Delta=4 for SGRQ Total Score • May give statistical significance not clinical significance • Large sample size can show significance even if true delta is smaller than assumed delta • Large sample size gives better estimate of true delta

30. Why Significance with Smaller Delta? • 90 % Power • Choice of 0.025 Significance Level

32. Raymond Anthracite, M.D. Medical Officer Ariflo Immediate Release Tablets NDA 21-573 Clinical Considerations Pulmonary and Allergy Drugs Advisory Committee Meeting Gaithersburg, Maryland September 5, 2003

33. Background • 4 Pre-Clinical Toxicities • Mesenteric Arteritis • the most serious animal toxicity • found in 2 species • Remaining 3 will not be addressed • Dose Selection – we agree that the dose selected was appropriate for development • Statistics – we agree with appropriateness of the analyses chosen

34. Efficacy & Safety Outline • EFFICACY • 4 Pivotal Trials • Co-Primary Endpoints • Trough FEV1 • SGRQ • Secondary Endpoints • SAFETY • AEs, SAEs, AE Withdrawals & Deaths • Emphasis On: • Gastro-Intestinal AEs (GIAEs) • Adequacy Of Evaluation For Mesenteric Arteritis

35. Phase II - III Clinical Trials • Asthma Studies – 4 (n=1069) • COPD Studies – 12 (n=5162+) • adequate & well-controlled (pivotal) – 4 (n=2883) • long-term, uncontrolled safety – 2 (n=1069+) • supportive – 6 (n=1210) • mechanism of action – 3 (n=280) • dose finding – 2 (n=648) • cardiology safety – 1 (n=282)

36. Phase III Pivotal Efficacy Trials • multi-national, multi-center, randomized, double-blind, placebo-controlled, parallel-group • 4-week single-blind placebo run-in period • 24-week double-blind treatment period • COPD patients 40-80 years of age (COPD criteria of ATS & ERS) • current and/or former smoking history > 10 pack-years

37. Phase III Pivotal Efficacy Trials (cont.) • pre-albuterol FEV1/FVC < 0.70 at screening • post-albuterol FEV1: • 30 - 70% of predicted normal, inclusive • “poorly responsive to albuterol” = “fixed airway obstruction” = post-albuterol FEV1: • < 15% increase over baseline, OR • < 200 mL increase over baseline

38. Phase III Pivotal Efficacy Trials (cont.)Similarities & Differences • 4 had the same co-primary efficacy endpoints and statistical analysis (039, 042, 091, 156) • FEV1 & SGRQ difference between treatments in mean change from baseline, each at p < 0.025 • 3 had the same randomization strategy (2:1, SB 207499 to PBO) & all 5 secondary efficacy endpoints (039, 042, 091) • 1:1 randomization (156) • COPD Symptom Score moved from diary to visit and excluded “breathlessness” (156) • 6-Minute Walk demoted to tertiary endpoint (156)

39. Phase III Pivotal Efficacy Trials (cont.)Similarities & Differences • Albuterol or salbutamol responsiveness: • 180 mcg by MDI with spacer (039, 156) • 400 (360) mcg by MDI with spacer (042, 091) • Pharmacokinetic sampling (039, 091, 156) • 2-week, double-blind run-out (091) • SB 207499 patients re-randomized (1:1) to placebo or SB 207499 • placebo patients continued taking placebo

40. Demographics & Disposition Of Phase III Pivotal COPD Trials (039, 042, 091, 156)

41. Study 039

42. Study 042

43. Study 091

44. ISE – MEAN TROUGH FEV1 (L) AT WEEK 24 AND AFTER 2-WEEK RUN-OUT

45. Study 156

46. ISE – Trough FEV1, Mean Change From Baseline, Difference Between Treatments & Statistical Significance

47. Study 039

48. Study 042

49. Study 091

50. Study 156