CLINICAL STUDY REPORT VERSION: 2.0 DATE: 04 MAR 2009

2.0 SYNOPSIS

Name of Sponsor: Chiesi Pharmaceuticals Inc. Total Number of (For Regulatory Authority Use Only) Name of Finished Product: Carmoterol Volumes: Name of Active Ingredient: Carmoterol hydrochloride Total Number of Pages: Title of Study: A randomized, controlled, 14-treatment day, multi-center study to determine the optimal efficacious and safe dose of CHF 4226 in a metered dose inhaler in treating patients with Chronic Obstructive Pulmonary Disease (COPD)

Investigators: The principal investigator was Barry Make, MD, National Jewish Medical & Research Center, Denver, Colorado, USA. All other investigators who participated in the trial are listed in Section 16.1.4

Study Center(s): This was a multi-center study conducted at 50 sites in 6 countries on 3 continents. A complete list of the study centers is provided in Section 16.1.4.

Publication (Reference): none to date Study Period: Phase of Development: Date of first patient enrolled: 16 Oct 06 Phase 2b Date of last patient completed: 26 Jun 2007

Objectives:

The primary objective was to identify the optimal once-daily dose of CHF 4226 to be further developed for the treatment of patients with COPD. The secondary objectives were to compare the efficacy of three different dosage strengths of CHF 4226 with placebo, and salmeterol 50μg b.i.d., and to monitor for safety and tolerability.

Methodology:

This was a randomized, double-blind placebo- and open-label, active-treatment controlled, parallel-group clinical trial. The study consisted of three periods: 1) a run-in period of 14-21 days duration, 2) a treatment period of 14 days duration, and 3) a post-treatment follow-up period of 7 days. There were two separate subgroups of approximately 50 patients each. One subgroup had 24 hour Holter monitoring on Day -1 and Day 13. The second subgroup performed 24-hour spirometry testing on Day 14.

Number of Patients (Planned and Analyzed):

Planned Enrollment: Approximately 300 patients Actual Enrollment: 278 patients Randomized: 278 were randomized. Of these patients, 1 (0.4%) withdrew consent prior to treatment. Safety Set: 277 patients Evaluated for Effectiveness: There were 274 patients in the modified intent-to-treat (MITT) dataset and 255 patients in the per protocol (PP) dataset (2 additional patients excluded from this dataset for Visit 4 only) Spirometry Subgroup: 54 patients evaluated for Safety, 53 for effectiveness Holter Subgroup: 60 patients Terminated Early: 10 patients

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CLINICAL STUDY REPORT VERSION: 2.0 DATE: 04 MAR 2009

SYNOPSIS (continued)

Name of Sponsor: Chiesi Pharmaceuticals Inc. Total Number of (For Regulatory Authority Use Only) Name of Finished Product: Carmoterol Volumes: Name of Active Ingredient: Carmoterol hydrochloride Total Number of Pages: Diagnosis and Main Criteria for Inclusion:

Patients were eligible for enrollment (at Visit 1) into the run-in period if they met all the following criteria: − Signed an Institutional Review Board-/Ethics Committee-approved Informed Consent form − Male or non-pregnant female between the ages of 40 – 75 years, inclusive − Current or past smoking history of at least 15 pack-years − Clinical diagnosis of COPD in accordance with the recommendations of the National Heart Lung and Blood Institute/World Health Organization (NHLBI/WHO) Global Initiative for Chronic Obstructive Lung Disease (GOLD)

− Met the following requirements after a forced expiratory volume at 1 second (FEV1) albuterol reversibility test (i.e., 30 minutes following 200μg (metered dose) albuterol/salbutamol pMDI): ƒ FEV1 is at least 0.9L ƒ FEV1 of 40% – 70%, inclusive, of patient’s predicted normal value ƒ ∆FEV1 > 4% of patient’s predicted normal value o If ∆FEV1 < 4% of patient’s predicted normal value, then this requirement must have been met after retesting during the run-in period, at least 24 hours prior to Day -1 ƒ FEV1/forced vital capacity (FVC) < 70%

If a patient met any one of the following exclusion criteria, he/she was NOT to be enrolled into the study: − History of asthma, allergic rhinitis, or atopy − Blood eosinophil count > 500/μL − COPD exacerbation or a lower respiratory tract infection within 8 weeks prior to screening, or during the run-in period, that resulted in the use of an antibiotic, or oral or parenteral corticosteroids − On an inhaled corticosteroid that was initiated, or the effective dose was changed, within 4 weeks prior to screening or during the run-in period − Uncontrolled cardiovascular (e.g., uncontrolled hypertension), respiratory, hematologic, immunologic, renal, neurologic, hepatic, endocrine (e.g., uncontrolled diabetes mellitus) or other disease, or any condition that might, in the judgment of the Investigator, placed the patient at undue risk or potentially compromised the results or interpretation of the study − History of coronary artery disease, cerebrovascular disease, cardiac arrhythmias − Concomitant disease of poor prognosis (e.g., cancer) − Serum potassium value ≤ 3.5 mEq/L or > 5.5mEq/L and/or a fasting serum glucose value ≥ 140 mg/dL − Abnormal QTc Fridericia interval value in the Screening Visit electrocardiogram (ECG) test (i.e., > 450 msec in males or > 470 msec in females) − Developed Cor Pulmonale − Long term oxygen therapy, i.e., ≥ 16 hours/24-hour period, every day

− Known intolerance/hypersensitivity to β2-adrenergic agonists, propellant gases/excipients − Treatment with a tricyclic antidepressant or a monoamine oxidase inhibitor (MAOI) − Receipt of a live-attenuated virus vaccination within two weeks prior to screening or during the run-in

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CLINICAL STUDY REPORT VERSION: 2.0 DATE: 04 MAR 2009

SYNOPSIS (continued)

Name of Sponsor: Chiesi Pharmaceuticals Inc. Total Number of (For Regulatory Authority Use Only) Name of Finished Product: Carmoterol Volumes: Name of Active Ingredient: Carmoterol hydrochloride Total Number of Pages:

− Pregnant or lactating female, or female at risk of pregnancy (i.e., not using an adequate contraceptive method) − Mentally or legally incapacitated − Participated in another investigational study within 30 days prior to screening − Alcohol or other substance abuse − Potentially non-compliant or unable to perform required outcome measurements of the protocol

These exclusion criteria above were reviewed at Visit 1 and again at Visit 2. In addition, the following criteria were reviewed at V2, prior to randomization, and at VH1, if applicable.

− Patient failed to meet FEV1 eligibility criteria after retest − Patient had taken any non-permitted medication during the run-in period − Patient had taken rescue albuterol in the 8 hours immediately prior to V2, in which case V2 was re-scheduled

Test Product, Dose and Mode of Administration, Batch Numbers:

Treatment A: CHF 4226 1μg once a day, in the morning (1 puff of CHF 4226 1μg + 1 puff of placebo pMDI)

Treatment B: CHF 4226 2μg once a day, in the morning (1 puff of CHF 4226 1μg + 1 puff of CHF 4226 1μg)

Treatment C: CHF 4226 4μg once a day, in the morning (1 puff of CHF 4226 2μg + 1 puff of CHF 4226 2μg)

Treatment D: Placebo once a day, in the morning (1 puff of placebo pMDI + 1 puff of placebo pMDI)

NOTE: Treatments A, B, C & D were double-blind

Batch numbers: – Placebo, - 1μg, - 2μg

Reference Therapy, Dose and Mode of Administration, Batch Numbers:

Treatment E: Salmeterol 50μg b.i.d., in the morning and in the evening (1 blister of Serevent® Diskus®/Accuhaler® BID)

Batch numbers: (supplied to United States (US) sites); (supplied to rest of world (ROW) sites)

NOTE: Treatment E was open-label

Criteria for Evaluation:

Primary Efficacy Variable: FEV1 change from predose (mean of -1 hour and -10 minutes on Day 1) to trough (mean of 23 and 24 hours) on Day 14, after 13 days of dosing

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CLINICAL STUDY REPORT VERSION: 2.0 DATE: 04 MAR 2009

SYNOPSIS (continued)

Name of Sponsor: Chiesi Pharmaceuticals Inc. Total Number of (For Regulatory Authority Use Only) Name of Finished Product: Carmoterol Volumes: Name of Active Ingredient: Carmoterol hydrochloride Total Number of Pages:

Secondary Efficacy Variables:

− FEV1 at 10 and 30 min, 1, 2, and 3 hrs; peak FEV1

− ΔFEV1 (absolute and %) at 10 and 30 minutes, 1, 2, and 3 hours

− FEV1 AUC 0-24 hours after 14 days of dosing (24-hr spirometry subgroup)

− FEV1 AUC 0-12 hours after 14 days of dosing (24-hr spirometry subgroup)

− FEV1 AUC 12-24 hours after 14 days of dosing (24-hr spirometry subgroup) − FVC at 10 and 30 min, 1, 2, and 3 hrs; peak FVC − ΔFVC (absolute and %) at 10 and 30 minutes, 1, 2, and 3 hours − FVC AUC 0-24 hours after 14 days of dosing (24-hr spirometry subgroup) − FVC AUC 0-12 hours after 14 days of dosing (24-hr spirometry subgroup) − FVC AUC 12-24 hours after 14 days of dosing (24-hr spirometry subgroup) − Albuterol rescue use

Safety:

Adverse events (AEs), laboratory parameters, ECG results with QTc interval, vital signs (heart rate and blood pressure)

Statistical Methods:

The primary efficacy endpoint was evaluated using an analysis of covariance that included the effects of treatment, country, and predose FEV1. The primary hypothesis was evaluated using a test of linear trend among the placebo and three CHF 4226 doses, which tested the hypothesis that CHF 4226 was not effective vs. the alternative that it was effective. If this test was found to be significant then each CHF 4226 dose was compared with the Placebo Group. This same methodology was used for testing secondary efficacy variables. Change from predose to 30 minutes postdose in QTc was analyzed by a one-way analysis of variance. A one-sided upper 95% confidence bound was placed on the difference from placebo.

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CLINICAL STUDY REPORT VERSION: 2.0 DATE: 04 MAR 2009

SYNOPSIS (continued)

Name of Sponsor: Chiesi Pharmaceuticals Inc. Total Number of (For Regulatory Authority Use Only) Name of Finished Product: Carmoterol Volumes: Name of Active Ingredient: Carmoterol hydrochloride Total Number of Pages: Summary – Conclusions

Efficacy Results:

The primary efficacy analyses demonstrated that CHF 4226 treatment once-daily was effective in increasing trough FEV1 following 13 days of dosing. The CHF 4226 2 and 4μg treatments resulted in statistically significant improvements over placebo in trough FEV1 values.

Figure 2-1. Mean Change from Baseline in Trough FEV1 on Day 14, MITT

0.12 p=0.003

0.1 p=0.010

p=0.038 0.08

p=0.092 0.06

0.04 Mean Change Placebo -subtracted Change

Liters 0.02

0 Placebo 1μg 2μg 4μg 50μg b.i.d. Carmoterol Carmoterol Carmoterol Salmeterol -0.02

-0.04

-0.06 Source: Section 14.2, Tables 2.1b, 2.15, 2.19

The mean change in trough FEV1 from predose to Day 2, after 1 day of dosing, increased as the CHF 4226 dosage strengths increased from 0μg (placebo) to 4μg. Only the CHF 4226 4μg treatment resulted in a statistically significant increase in trough FEV1 following 1 day of dosing (p = 0 .024). Taken together with the primary efficacy data, CHF 4226 treatment resulted in a placebo-subtracted increase in trough FEV1 after one 1 day of dosing with this increase still present following 13 days of dosing.

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