# Presentation: 727579

## SB 207499 (Ariflo®, cilomilast)GlaxoSmithKlineNew 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

## 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**

## 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.**

## Preclinical Considerations

**Virgil Whitehurst, Ph.D.**
**Pharmacologist**

## 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

**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**

**Characterization of **
**Toxicological Profile**

## Arteritis (multi-organs), including the mesentery
Testicular Degeneration
Adrenal Cortex Hypertrophy
Myocardial Necrosis
GI Disturbances

**Testicular Degeneration**
**Adrenal Cortex Hypertrophy**
**Myocardial Necrosis**
**GI Disturbances**

**Toxic Effects of **
**Cilomilast in Animals**

## 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. 

**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. **

**Arteritis**

## Cilomilast Induced Arteritis

| 
Species | Effect
Dose
(mg/kg) | AUC
(mcg.h
/mL) | 
NOAEL
(mg/kg) | AUC
(mcg.h
/mL) | Margin of Safety**  |
| --- | --- | --- | --- | --- | --- |
| Rat | ≥ 30 * | ≥ 12 | 20 | 4 | 0.2 x |
| Mouse | 200 | 424 | 100 | 157  | 7 x |
| Monkey | _ | _ | 10*** | 88 | 4 x |
|  * deaths occurred @ 40 mg/kg; ** based on human AUC of 22 mcg.h/ml; *** Highest dose tested |  |  |  |  |  |

**Cilomilast Induced Arteritis**

## 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.

- 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.

**Summary – Cilomilast (1)**

## Therefore, the data provide no margin of safety for arteritis compared to the proposed clinical dose regimen 
Arteritis is a significant safety concern

- Arteritis is a significant safety concern

**Summary – Cilomilast (2)**

## Slide 11

## NDA 21-573
Ariflo Immediate Release Tablets
Study 032: Dose-Response

CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS REVIEW

Sandra Suarez-Sharp, Ph.D.

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

## Mean (SEM) change from baseline in trough pre-bronchodilator FEV1 by week and treatment group 

- Mean (SEM) change from baseline in trough pre-bronchodilator FEV1 by week and treatment group

**Study 032: Multiple Administration of Oral Cilomilast (5, 10 and 15mg Twice Daily) for 6 Weeks to Patients with COPD**

## Cilomilast Trough Concentration as a 

**Cilomilast trough concentration (ng/mL)**

- 0

- 5

- 10

- 15

- 5

- 10

- 15

- 5

- 10

- 15

- 5

- 10

- 15

- 0

- 1000

- 2000

- 3000

**WEEK 1**

**WEEK 2**

**WEEK 4**

**WEEK 6**

**Cilomilast Trough Concentration as a **
**Function of Dose and Visit**

## Baseline FEV1 as a Function of Dose

- 0

- 5

- 10

- 15

**Dose (mg)**

- 0

- 1

- 2

- 3

- 4

**Baseline FEV****1**** (L)**

| Dose (mg) | Mean (SD) | Median |
| --- | --- | --- |
| 0 | 1.38 (0.53) | 1.28 |
| 5 | 1.32 (0.39) | 1.25 |
| 10 | 1.41 (0.49) | 1.32 |
| 15 | 1.35 (0.45) | 1.26 |

**Baseline FEV****1**** (L)**

**Baseline FEV****1**** as a Function of Dose**

## Change from Baseline in FEV1 after

- -0.05

- 0

- 0.05

- 0.1

- 0.15

- 0.2

- 1

- 2

- 4

- 6

**Week**

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

**Change from Baseline in FEV****1**** after**
**Baseline Adjustment**

## Change from Baseline in FEV1-Cilomilast Trough Concentration Relationship

- 0

- 1000

- 2000

- 3000

- 0

- 1000

- 2000

- 3000

- -1.2

- -0.4

- 0.4

- 1.2

- 2.0

**WEEK 1**

**WEEK 2**

**WEEK 4**

**WEEK 6**

**Cilomilast trough concentration (ng/mL)**

- Change from baseline in FEV1 (L)

**Change from Baseline in FEV****1****-Cilomilast Trough Concentration Relationship**

## Adverse Experiences (GIT) Occurring in more than 5%

**Percentage AE**

- 0

- 5

- 10

- 15

- 0

- 5

- 10

- 15

- 0

- 5

- 10

- 15

- 0

- 5

- 10

- 15

- 0

- 2

- 4

- 6

- 8

- 10

- 12

**Abd Pain**

**Diarrhea**

**Nausea**

**Vomiting**

**Adverse Experiences (GIT) Occurring in more than 5%**
**of Patients in Any Treatment Group (% of Patients)**

## Cilomilast Trough Concentration in Patients Experiencing

-        3

-       34

-     4567

-        3

-       34

-     4567

-        3

-       34

-     4567

-        3

-       34

-     4567

- Visit

- 0

- 500

- 1000

- 1500

- 2000

**ABDOMINAL PAIN**

**Cilomilast trough concentration (ng/mL)**

**5**

**10**

**        ****15**

- Visit

**NO AEs**

- 4

- 5

- 6

- 7

- 4

- 5

- 6

- 7

- 4

- 5

- 6

- 7

**Cilomilast Trough Concentration in Patients Experiencing**
**GIT Side Effects vs. No AEs**

## 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. 

- 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.

**CONCLUSIONS**

## 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.

- the variability of the data
- No correlation between Cilomilast trough concentrations and side effects.

**CONCLUSIONS, cont.**

## He Sun, Ph.D.
Emmanuel O. Fadiran, Ph.D.
Henry Malinowski, Ph.D.

- Emmanuel O. Fadiran, Ph.D.
- Henry Malinowski, Ph.D.

**ACKNOWLEDGEMENTS**

## Slide 23

## Ariflo®Glaxo Smith KlineNDA 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

## Hochberg Procedure
Repeated Measures Analyses
Endpoint Analyses
Sample Size Discussion
Sponsor’s Delta

- Repeated Measures Analyses
- Endpoint Analyses
- Sample Size Discussion
- Sponsor’s Delta

**Topics**

- 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?

**Hochberg Procedure**

## 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)

## 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

- 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

**Endpoint Analyses**

## 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     

-  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

**Sample Size**

##    90 % Power
   Choice of 0.025 Significance Level 

-    Choice of 0.025 Significance Level

**Why Significance with Smaller**
**Delta?**

## Slide 31

## Ariflo Immediate Release Tablets
NDA 21-573
Clinical Considerations

- NDA 21-573
- Clinical Considerations

- Pulmonary and Allergy Drugs Advisory Committee Meeting
*Gaithersburg*, *Maryland*
*September 5, *2003

- Raymond Anthracite, M.D.
- Medical Officer

## 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**

## 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**

## 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)**

## 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**

## 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**

## 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)**

## 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**

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

| Demographic
Characteristics | Placebo
(N = 1091) | SB 207499
(N = 1792) |
| --- | --- | --- |
| Sex:	Male (%)
	Female (%) | 784 (71.9)
307 (28.1) | 1274 (71.1)
518 (28.9) |
| Race:	Caucasian (%)
	Black (%) | 1047 (96.0)
28 (2.6) | 1718 (95.9)
45 (2.5) |
| Age:		Mean (SD) | 64.2 (8.8) | 64.3 (8.6) |
| FEV1 (% pred) Mean (SD) | 49.99 (11.74) | 49.69 (11.80) |
| Reversibility (%) Mean (SD) | 6.72 (7.83) | 6.52 (7.95) |
| Smoking History (pack-years) 		Mean (SD) | 52.5 (29.9) | 51.1 (28.5) |
| Completed Study | 827 (75.8) | 1265 (70.6) |

## Study 039

## Study 042

## Study 091

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

## Study 156

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

|  | 039
(N = 585) |  | 042
(N = 659) |  | 091
(N = 665) |  | 156
(N = 741) |  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Treatment | BL1 | MC2 | BL | MC | BL | MC | BL | MC |
| Placebo | 1.42 | -0.03 | 1.36 | -0.00 | 1.44 | -0.03 | 1.38 | -0.02 |
| SB 207499 | 1.34 | 0.01 | 1.38 | 0.03 | 1.45 | 0.00 | 1.36 | 0.01 |
| Difference3 | 0.04 |  | 0.03 |  | 0.03 |  | 0.02 |  |
| Stat. Signif. | Yes |  | No |  | No |  | Yes |  |
| 1 = BaseLine		2 = Mean Change (from baseline)
3 = Difference between treatments in MC adjusted for center and week. |  |  |  |  |  |  |  |  |

## Study 039

## Study 042

## Study 091

## Study 156

## ISE – Total SGRQ At Baseline, Mean Change From Baseline, Difference Between Treatments,  Statistical Significance & MID4

|  | 039
(N = 491) |  | 042
(N = 565) |  | 091
(N = 566) |  | 156
(N = 641) |  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Treatment | BL1 | MC2 | BL | MC | BL | MC | BL | MC |
| Placebo | 44.8 | 0.4 | 45.9 | -4.9 | 42.1 | -2.3 | 43.2 | -1.3 |
| SB 207499 | 45.1 | -3.7 | 43.8 | -4.2 | 42.7 | -2.7 | 44.4 | -3.2 |
| Difference3 | -4.1 |  | 0.7 |  | -0.4 |  | -1.9 |  |
| Stat. Signif. | Yes |  | No |  | No |  | Yes |  |
| MID4 | Yes |  | No |  | No |  | No |  |
| 1 = BaseLine		2 = Mean Change (from baseline)
3 = Difference adjusted for country and week.
4 = Minimum Important Difference (> 4.0) |  |  |  |  |  |  |  |  |

## Secondary Efficacy Endpoints(mean change from baseline)

**Trough FVC (L)**
**Post-exercise (6-Minute Walk) breathlessness by modified Borg Scale (11-point, 0-10 scale)**
**Summary Diary COPD symptom score (11-point, 0-10 scale)**
**6-minute walk (meters)**
**Percent of patients COPD exacerbation-free through 24 weeks (% of patients in treatment group)**

## Modified Borg Breathlessness Scale

| 0 | nothing at all |
| --- | --- |
| 1 | very, very slight (just noticeable) |
| 2 | very slight |
| 3 | moderate |
| 4 | somewhat severe |
| 5 | severe |
| 6 |  |
| 7 | very severe |
| 8 |  |
| 9 | very, very severe (almost maximal) |
| 10 | maximal |

## ISE – Post-Exercise Breathlessness, Mean Change From Baseline In Pivotal Efficacy Trials

**039**

**042**

**091**

**156**

## ISE – Efficacy Trials Summary

**FEV1**
- 24-week trials
- 25-30% drop outs
- placebo decline in 3 trials occurred over first few weeks & did not occur at all in the 4th
- 2 of 4 pivotal trials statistically significant
**SGRQ**
- 1 of 4 pivotal trials statistically significant & Minimally Importantly Different
**Secondary Endpoints**
- 1 of 5 endpoints show some support for SB 207499

## ISE – Efficacy Trials Summary (cont.)

**Has SB 207499 shown a magnitude and consistency of efficacy that is sufficient to approve SB 207499 for the indication, “...maintenance of lung function (FEV1)...?”**

## Integrated Safety Outline

**Includes:**
**Asthma & COPD Controlled Trials**
**COPD Controlled Trials**
**COPD Uncontrolled Long-Term Extensions (LTEs) for safety**
**AEs, SAEs, AE Withdrawals & Deaths**
**Emphasis On:**
**Gastro-Intestinal AEs (GIAEs)**
**Adequacy Of Evaluation For Mesenteric Arteritis**

## ISS - Screening Demographics:  Asthma & COPD Patients  In All Controlled Studies

| 
Characteristic | Placebo
n = 1802 | SB 15mg
n = 2475 | Total SB
n = 3350 |
| --- | --- | --- | --- |
| Gender:  male  N (%) | 1229 (68) | 1720 (70) | 2259 (67) |
| Race:  Caucasian  N (%) | 1734 (96) | 2373 (96) | 3220 (96) |
| Age (yrs):  Mean (SD) | 61 (12) | 62 (11) | 59 (13) |
| Smoke (pack-years):  Mean (SD) | 50 (30) | 50 (29) | 48 (29) |
| FEV1 % pred. (L):  Mean (SD) | 53 (13) | 52 (13) | 53 (13) |

## ISS – Disposition: Asthma & COPD Patients  In All Controlled Studies

| 
Reason For Withdrawal | Placebo
n = 1802 | SB 15mg1
n = 2475 | Tot SB1
n = 3350 |
| --- | --- | --- | --- |
| Total Withdrawn | 343 (19) | 640 (26) | 781 (23) |
| adverse event | 169 (9) | 403 (16) | 463 (14) |
| 	COPD exacerbation2 | 51 (3) | 50 (2) | 53 (2) |
| 	not COPD exacerbation | 118 (7) | 353 (14) | 410 (12) |
| 		Gastrointestinal3 | 29 (2) | 342 (14) | 364 (11) |
| protocol deviation | 55 (3) | 64 (3) | 98 (3) |
| lost to follow-up | 38 (2) | 45 (2) | 60 (2) |
| other | 64 (4) | 105 (4) | 135 (4) |
| 1 twice daily	2 does not include asthma patients
3 nausea, abdominal pain, diarrhea, vomiting & dyspepsia |  |  |  |

## ISS – N (%) Of Adverse Events (Where % In 15 mg Twice Daily SB 2074999 > PBO):  All Controlled Asthma & COPD Trials

| Adverse Event | 0 mg
(n=1802) | 2.5 mg
(n=72) | 5 mg
(n=366) | 10 mg
(n=437) | 15 mg
(n=2475) |
| --- | --- | --- | --- | --- | --- |
| NAUSEA | 76 (4) | 2 (3) | 17 (5) | 3 (8) | 361 (15) |
| DIARRHEA | 110 (6) | 4 (6) | 11 (3) | 15 (3) | 325 (13) |
| ABD PAIN | 97 (5) | 1 (1) | 4 (1) | 16 (4) | 256 (10) |
| headache | 109 (6) | 7 (10) | 24 (7) | 32 (7) | 198 (8) |
| DYSPEPSIA | 38 (2) | 0 | 8 (2) | 7 (2) | 167 (7) |
| VOMITING | 22 (1) | 1 (1) | 5 (1) | 11 (3) | 133 (5) |

## ISS – Deaths In All Controlled Asthma & COPD Trials

| PLACEBO | SB 207499 |
| --- | --- |
| Run-In:
72yM suicide |  |
| Double-Blind:
75yF MI
	 | Double-Blind:
63yM MI	73YM MI
71yF MI	67yM AAA
70yM CVA	
72yM cerebral aneurysm	          |
| Post-Therapy:
74yM CHF	75yM CHF
58yM CHF	57yF MI
77yM aneurysm | Post-Therapy:
63yM MI	79yM Resp Fail
80yM CHF	74yF MI |

## ISS – N (%) Of SAEs Where % In SB 15 mg > PBO:  All Controlled Asthma & COPD Trials

| Serious
AE | 0 mg1
(n=1802) | 2.5 mg1
(n=72) | 5 mg1
(n=366) | 10 mg1
(n=437) | 15 mg1
(n=2475) |
| --- | --- | --- | --- | --- | --- |
| TOTAL | 110 (6) | 1 (1) | 7 (2) | 8 (2) | 127 (5) |
| CV disorder | 1 (<1) | 0 | 0 | 0 | 6 (<1) |
| aneurysm | 2 (<1) | 0 | 0 | 0 | 5 (<1) |
| abdominal pain | 0 | 0 | 0 | 0 | 4 (<1) |
| vasc. disorder | 1 (<1) | 0 | 0 | 0 | 4 (<1) |
| urinary retent. | 0 | 0 | 0 | 0 | 3 (<1) |
| alcohol intol. | 0 | 0 | 0 | 0 | 2 (<1) |
| myalgia | 0 | 0 | 0 | 0 | 2 (<1) |

## ISS – N (%) Of W/Ds Due To AEs Where % In Twice Daily SB 15 mg > PBO:  All Controlled Asthma & COPD Trials

| Serious
AE | 0 mg
(n=1802) | 2.5 mg
(n=72) | 5 mg
(n=366) | 10 mg
(n=437) | 15 mg
(n=2475) |
| --- | --- | --- | --- | --- | --- |
| TOTAL | 161 (9) | 3 (4) | 25 (7) | 31 (7) | 388 (16) |
| NAUSEA | 8 (<1) | 0 | 0 | 8 (2) | 114 (5) |
| ABD. PAIN | 9 (1) | 0 | 2 (1) | 3 (1) | 89 (4) |
| DIARRHEA | 7 (<1) | 0 | 1 (<1) | 4 (1) | 82 (3) |
| VOMITING | 3 (<1) | 0 | 0 | 3 (1) | 32 (1) |
| DYSPEPSIA | 2 (<1) | 0 | 0 | 1 (<1) | 25 (1) |
| dizziness | 2 (<1) | 0 | 0 | 2 (1) | 21 (1) |
| headache | 2 (<1) | 0 | 0 | 1 (<1) | 19 (1) |

## ISS – Development Of “GIAEs Of Concern”

**Pre-Clinical Arteritis**
- mostly mesenteric
- seen in two species
- no safety margin between animals & humans
- Early in development, GSK had tried to identify biomarkers for arteritis, unsuccessfully

## ISS – Development Of “GIAEs Of Concern”

**GIAEs**
- thought to be centrally mediated for PDE inhibitors
- also, may reflect mesenteric arteritis with SB 207499
- were severe enough to cause premature patient termination from clinical studies
- account for majority of the early terminators in SB 207499 groups
**Continued drug development required a plan for evaluating patients for arteritis**

## ISS –Development Of “GIAEs Of Concern”

**Prospective Evaluation**
- single out cases with GIAEs for thorough evaluation
- search for a pre-fatal and possibly monitorable manifestation (fecal blood loss)
- establish a database of colonoscopies from which human safety could be inferred
**Justification**
- colonoscopy becoming standard of care for adeno-carcinoma surveillance in asymptomatic adults > 50
- certainly, symptomatic individuals in the same age range with GI blood loss would be candidates for the same procedure

## ISS –Development Of “GIAEs Of Concern”

**All Pivotal Controlled Studies (039, 042, 091, 156)**
**Both Uncontrolled Studies (040, 041)**
**Cardiac Safety Study (168)**
**Mechanism-Of-Action Studies (076, 110, 111)**
**“****GIAE Of Concern” Defined As:**
- GI symptoms that cause patient concern, e.g.
- bloody or black stools
- pain, cramps, diarrhea, vomiting
**AND/OR**... interfere with patient’s daytime activities or sleep

## ISS – Protocol-Specified Initial Evaluation Of “GIAEs Of Concern”

**WITHIN 24 HOURS, A PHYSICIAN EVALUATION WILL INCLUDE EXAMINATION AND...**
**Fecal Occult Blood** (FOB) to signal need for further clinical evaluation
- patient to use previously provided FOB test, **OR...**
- digital rectal exam with FOB testing on exam
**Orthostatic Vital Signs** to signal acute volume depletion from blood loss or fluid third-spacing

## ISS – Protocol-Specified Follow-Up Evaluation Of “GIAEs Of Concern”

**Pivotal Studies 039, 156, Cardiac Safety Study 168, Mechanism of Action 110, 111 and LTE Study 041 required DAILY monitoring by...**
- clinical examination
- FOB
- Orthostatic VS
- ...until resolution or definitive diagnosis
**Pivotal Study 156, Cardiac Safety study 168 LTEs 040 and 041 were amended to require a complete colonoscopy within 2 weeks of...**
- melena
- FOB-positive stools

## ISS – GIAEs Of Concern In All Phase III Controlled COPD Trials

| 
GI Adverse Event
Of Concern | Placebo
(N = 1326)
n (%) | SB 207499 15 mg
(N = 2119)
n (%) |
| --- | --- | --- |
| Total | 56 (4) | 264 (13) |
| abdominal pain | 30 (2) | 119 (6) |
| diarrhea | 23 (2) | 108 (5) |
| nausea | 8 (1) | 90 (4) |
| vomiting | 6 (1) | 60 (3) |
| dyspepsia | 4 (<1) | 34 (2) |
| melena | 9 (1) | 21 (1) |
| flatulence | 2 (<1) | 18 (1) |
| GE reflux | 0 | 10 (1) |

## ISS – Implementation Of Planned FOB Monitoring Of GIAEs Of Concern And Follow-Up In All Phase III Controlled COPD Trials

| 
Implementation Of Planned Monitoring | Placebo 
(N = 56)
n (%) | SB 207499 15 mg
(N = 264)
n (%) |
| --- | --- | --- |
| FOB any time after GIAEOC | 46 (82) | 237 (90) |
| FOB-positive test | 6 (11) | 18 (7) |
| FOB test within 14 days | 31 (55) | 154 (58) |
| FOB-positive test | 6 (11) | 15 (6) |
| GIAEOC+(FOB+)+CScope | 2 (4) | 4 (2) |

## ISS – Colonoscopies In Patients With A GIAEOC And Positive FOB From All Phase III Controlled COPD Trials

**Placebo-Treated:**
**156.457.14400 – diverticulae, polyps, IH**
**168.625.18447 – diverticulae, polyps**
**SB 207499-Treated:**
**156.490.16423 – diverticulae**
**156.505.15358 – vilotubular adenomas**
**156.509.22706 – diverticulae, polyps, IH**
**168.648.18699 – diverticulae, IH**

## ISS - N (%) Of COPD Patients With On-Therapy FOB Results In Phase III Controlled COPD Trials

|  |  |  | Double-Blind Period |  |
| --- | --- | --- | --- | --- |
| 
Treatment | Patients Tested | 
Baseline | Negative 
n (%)* | Positive
n (%)* |
|  | 955 | negative | 939 (98.3) | 16 (1.7) |
| Placebo | 3 | positive | 3 (100) | 0 |
|  | 12 | missing | 12 (100) | 0 |
|  | 1488 | negative | 1455 (97.8) | 33 (2.2) |
| SB 207499 | 6 | positive | 5 (83.3) | 1 (16.7) |
|  | 10 | missing | 10 (100) | 0 |
| * Percentages are calculated on the row totals for each treatment |  |  |  |  |

## ISS – Baseline FOB-Negative Phase III COPD Patients Who Became Positive During Treatment In Phase III Controlled COPD Trials

| Set/Subset | Placebo | SB 207499 |
| --- | --- | --- |
| Total Patients | 16 | 33 |
| # FOB-positive stool samples | 31 | 67 |
| # patients with > 1 GIAE of concern | 7 | 15 |
| # patients receiving colonoscopy | 2* | 3* |
| * The results of these examinations were previously presented. |  |  |

## Demographics & Disposition In Uncontrolled Trials (040, 041)

|  | Prior Treatment |  |
| --- | --- | --- |
| Demographic
Characteristics | Placebo
(N = 383) | SB 207499
(N = 695) |
| Sex:	Male (%)
	Female (%) | 305 (79.6)
78 (20.4) | 534 (76.8)
161 (23.2) |
| Race:	Caucasian (%)
	Black (%) | 374 (97.7)
2 (0.5) | 670 (96.4)
12 (1.7) |
| Age:		Mean (SD) | 64.0 (8.9) | 63.4 (9.0) |
| FEV1 (% pred) Mean (SD) | 49.94 (11.69) | 49.43 (11.83) |
| Smoking History (pack-years) 		Mean (SD) | 48.4 (25.9) | 50.3 (28.0) |

## ISS – Dispositions In Uncontrolled Trials

|  | Prior Treatment |  |  |
| --- | --- | --- | --- |
| Reason For Withdrawal | Placebo
n = 383 | SB 15mg
n = 695 | Tot SB
n = 1078 |
| Total Withdrawn | 177 (46) | 263 (38) | 440 (41) |
| adverse event | 93 (24) | 104 (15) | 197 (18) |
| 	COPD exacerbation1 | 6 (2) | 11 (2) | 17 (2) |
| 	not COPD exacerbation | 87 (23) | 93 (13) | 180 (17) |
| 		Gastrointestinal2 | 74 (19) | 27 (4) | 111 (10) |
| protocol deviation | 8 (2) | 6 (1) | 14 (1) |
| lost to follow-up | 5 (1) | 11 (2) | 16 (2) |
| other | 71 (19) | 142 (20) | 213 (20) |
| 1 does not include asthma patients
2 nausea, abdominal pain, diarrhea, vomiting & dyspepsia |  |  |  |

## ISS – Treatment Exposure In Uncontrolled Trials, Including Controlled Feeder Studies

| Exposed
(days) | SB 207499
n = 1078 |
| --- | --- |
| > 90 | 1003 |
| >180 | 973 |
| >360 | 865 |
| >540 | 774 |

## ISS – N (%) Of Patients With AEs in Uncontrolled Trials

| Adverse Event | Total SB 207499
n = 1078 |
| --- | --- |
| Total | 1009 (94) |
| chronic obstructive airways disease | 653 (61) |
| upper respiratory tract infection | 187 (17) |
| DIARRHEA | 175 (16) |
| ABDOMINAL PAIN | 173 (16) |
| injury | 142 (13) |
| NAUSEA | 140 (13) |
| headache | 120 (11) |
| back pain | 117 (11) |
| DYSPEPSIA | 114 (11) |

## ISS – On-Therapy Deaths In Uncontrolled Trials

| 66yM COPD
59yM CHF
56yM bronchopneumonia
74yM hanging
77yM heart failure
75yM MI
70yM probable MI
68yM MI
68yM ischemic colitis |
| --- |

## ISS – Post-Therapy Deaths In Uncontrolled Trials

| 66yF COPD
66yM pneumonia
69yM respiratory insufficiency
84yM COPD
73yM cardiac arrest
76yM circulatory failure
71yM cardiac arrest
71yM neoplasm NOS | 63yM cardiac arrest
69yM cardiac arrest
56yM sudden death
51yF malignant neoplasm
75yM pneumonia
74yM MI
74yM cardiac arrest
73yM COPD |
| --- | --- |

## ISS – N (%) Of Patients With SAEs In Uncontrolled Trials

| SAEs | Total
n = 1078 |
| --- | --- |
| Total | 273 (25) |
| chronic obstructive pulmonary disease | 85 (8) |
| pneumonia | 34 (3) |
| injury | 20 (2) |
| chest pain | 13 (1) |
| angina pectoris | 10 (1) |
| pulmonary carcinoma | 10 (1) |
| myocardial infarction | 9 (1) |
| neoplasm | 9 (1) |

## ISS – N (%) Of Patients Withdrawing Due To AEs From Uncontrolled Trials

| AE Causing Withdrawal | Total
n = 1078 |
| --- | --- |
| Total | 177 (16) |
| ABDOMINAL PAIN | 36 (3) |
| NAUSEA | 26 (2) |
| DIARRHEA | 23 (2) |
| chronic obstructive pulmonary disease | 17 (2) |
| VOMITING | 12 (1) |
| lung cancer | 9 (1) |
| headache | 5 (1) |
| myocardial infarction | 5 (1) |

## ISS – GIAEs Of Concern In  Uncontrolled COPD Trials

| GIAE Of Concern | Total (N = 1078)
n (%) |
| --- | --- |
| Total | 141 (13) |
| abdominal pain | 65 (6) |
| diarrhea | 47 (4) |
| nausea | 30 (3) |
| vomiting | 18 (2) |
| dyspepsia | 10 (1) |
| melena | 10 (1) |
| gastritis | 6 (1) |
| constipation | 4 (<1) |

## ISS – Implementation Of Planned FOB Monitoring Of GIAEs Of Concern And Follow-Up In Uncontrolled COPD Trials

| Implementation Of Planned Monitoring | Total (N = 141)
n (%) |
| --- | --- |
| FOB any time after GIAEOC | 128 (91) |
| FOB-positive test | 9 (6) |
| FOB test within 14 days | 68 (48) |
| FOB-positive test | 8 (6) |
| GIAEOC+(FOB+)+CScope | 4 (3) |

## ISS – Colonoscopies From Patients In Uncontrolled Studies 040 & 041

**On-Treatment:**
**040.148.9866 – polyps**
**040.226.7371 – diverticulae**
**041.020.05598 – hemorrhoids**
**041.038.05057 – hemorrhoids**
**Post-Treatment:**
**041.064.06001 – normal**

## ISS - Conclusion

**GIAEs**
**...****were a feature of treatment with SB 207499**
**...****were of sufficient severity to cause most of the withdrawals in patients treated with SB 207499**
**GIAEs Of Concern (GIAEOC)**
**only 50-60% of patients with GIAEOC were tested for FOB within 2 weeks**
**FOB+ patients with GIAEOC were not all evaluated for ischemic colitis by colonoscopy**

## ISS – Conclusion (cont.)

**Database of colonoscopy patients with **GIAEOC and FOB+
**SB 207499 - Treated**
- Controlled Trials:
**4 patients**
- Uncontrolled Trials (includes 1 post-therapy patient):
**5 patients**
**Placebo – Treated**
**2 patients**

## Overall Summary

**Efficacy (FEV1)**
**24-week trials with 25-30% drop outs**
**where a placebo decline was seen, it occurred over first few weeks**
**2 of 4 pivotal trials statistically significant**
**support for efficacy of SB 207499 from:**
**1 of 4 trials of the co-primary endpoint**
**1 of 5 secondary endpoints**

## Overall Summary (cont.)

**Safety**
**preclinical findings of mesenteric arteritis**
**prominent dose-related GI AEs and withdrawals due to them**
**limited safety database of colonoscopies in FOB+ patients with GIAEOCs**
**Controlled & Uncontrolled SB 207499**
**9 patients**
**Placebo Patients**
**2 patients**

## Advisory Committee Questions

**Has cilomilast, at a dose of 15 mg twice daily, shown a magnitude and consistency of efficacy that is sufficient to support approval for the maintenance of lung function (FEV1) in patients with COPD?**
**Is the safety database, aside from the concern about vasculitis, for cilomilast for the maintenance of lung function (FEV1) in patients with COPD sufficient to support approval?**
**Do you feel that the concern about mesenteric arteritis has been adequately studied to be dismissed as a safety concern in humans?**
**Do the efficacy and safety data provide substantial and convincing evidence that support the approval of cilomilast at a dose of 15 mg twice daily for the maintenance of lung function (FEV1) in patients with COPD?**

## Slide 91

## Advisory Committee Questions

**Has cilomilast, at a dose of 15 mg twice daily, shown a magnitude and consistency of efficacy that is sufficient to support approval for the maintenance of lung function (FEV1) in patients with COPD?**
**If not, what further efficacy data should be obtained?**

## Advisory Committee Questions

**Is the safety database for cilomilast, aside from the concern about vasculitis, for the maintenance of lung function (FEV1) in patients with COPD sufficient to support approval?**
**If not, what further safety data should be obtained?**

## Advisory Committee Questions

**Do you feel that the concern about mesenteric arteritis has been adequately studied to be dismissed as a safety concern in humans?**
**If not, what further data should be obtained?**

## Advisory Committee Questions

**Do the efficacy and safety data provide substantial and convincing evidence that support the approval of cilomilast at a dose of 15 mg twice daily for the maintenance of lung function (FEV1) in patients with COPD?**

## Slide 96