Meda Pharmaceuticals

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1 MP03-33 Nasal Spray Page 1 of 9 Meda Pharmaceuticals Active-Controlled Trial of the Safety and Tolerability of MP03-33 in Patients with Chronic Allergic or Nonallergic Rhinitis (MP432) FINAL CLINICAL STUDY REPORT Date of Version: 11 January 2009 IND Number: 69,785 Name of Product: MP03-33 Phase of Development: III Date of First Observation: 24 July 2006 Date of Last Observation: 28 December 2007 Indication Studied: Chronic allergic or nonallergic rhinitis Study Design: A randomized, open-label, active-controlled, parallel-group study in subjects with chronic allergic or nonallergic rhinitis for 1-year duration Sponsor s Contact: Meda Pharmaceuticals 265 Davidson Avenue, Suite 300 Somerset, NJ Date of Report: 11 Jan 2009 This study was performed in accordance with Good Clinical Practice, including the archiving of essential documents.

2 MP03-33 Nasal Spray Page 2 of 9 2 SYNOPSIS NAME OF COMPANY: Meda Pharmaceuticals INDIVIDUAL STUDY SYNOPSIS Page 1 of 3 NAME OF FINISHED PRODUCT: MP03-33 Astelin Nasal Spray NAME OF ACTIVE INGREDIENT: Azelastine hydrochloride INDIVIDUAL STUDY TABLE REFERRING TO PART OF THE DOSSIER Volume: Page: (FOR NATIONAL AUTHORITY USE ONLY) Title of Study: Active-Controlled Trial of the Safety and Tolerability of MP03-33 in Patients With Chronic Allergic or Nonallergic Rhinitis Investigators: A list of study investigators is provided in Appendix Study Sites: Of 48 sites from 5 countries (Australia, Bulgaria, France, Slovakia, and United Kingdom) chosen for this study, 3 sites (Sites 105, 311, and 501) did not screen any subjects Publication (Reference): None Studied Period: Date of First Enrollment: 24 July 2006; Phase of Development: III Date of Last Completed: 28 December Objectives: The objective of this study was to evaluate the safety and tolerability of MP03-33 (a new formulation of azelastine hydrochloride nasal spray) with chronic use over a 1-year period in subjects with chronic allergic or nonallergic rhinitis. Commercially available azelastine hydrochloride nasal spray (Astelin ) served as an active control. Methodology: This was a randomized, open-label, active-controlled, parallel-group study in subjects with chronic allergic or nonallergic rhinitis. Qualified subjects were randomized to treatment with MP03-33 nasal spray 2 sprays per nostril twice daily (bid) or Astelin nasal spray 2 sprays per nostril bid. Safety and tolerability assessments were made at Months 1, 3, 6, 9, and 12. Monthly phone contact was maintained with the subjects at Months 2, 4, 5, 7, 8 10, and 11 during the 12-month evaluation period. As specified in the protocol, an interim analysis was performed when 559 subjects (281 in the MP03-33 treatment group and 278 in the Astelin treatment group) completed their 6-month visit. Number of Subjects: Of the 862 randomized subjects, 858 subjects were analyzed for safety (428 were from the MP03-33 group and 430 from the Astelin group). Diagnosis and Main Criteria for Inclusion: Male and female subjects 12 years of age and older with a history of chronic rhinitis symptoms due to allergic or nonallergic perennial rhinitis or nonallergic vasomotor rhinitis who were likely to benefit from therapy with azelastine hydrochloride nasal spray were considered for entry into the study. Subjects with a seasonal allergic component also were included, provided that they had significant symptoms outside of the allergy season during the year. Subjects on a stable dose of immunotherapy were included. Test Product, Dose, Mode of Administration, and Batch Number(s): MP03-33: Mode of Administration: Topical/intranasal spray Dose: 1.1 mg, total daily dose Regimen: 2 sprays per nostril bid (morning and evening) Batch Numbers: c and c Duration of Treatment: 1 year

3 MP03-33 Nasal Spray Page 3 of 9 NAME OF COMPANY: Meda Pharmaceuticals INDIVIDUAL STUDY SYNOPSIS Page 2 of 3 NAME OF FINISHED PRODUCT: MP03-33 Astelin Nasal Spray NAME OF ACTIVE INGREDIENT: Azelastine hydrochloride INDIVIDUAL STUDY TABLE REFERRING TO PART OF THE DOSSIER Volume: Page: (FOR NATIONAL AUTHORITY USE ONLY) Reference Therapy, Dose, Mode of Administration, and Batch Number(s): Astelin Nasal Spray (commercial formulation): Mode of Administration: Topical/intranasal spray Dose: 1.1 mg, total daily dose Regimen: 2 sprays per nostril bid (morning and evening) Batch Numbers: DF008992, 2940 Criteria for Evaluation: Efficacy: Change from baseline to each clinical visit up to 12 months in the Mini-Rhinoconjunctivitis Quality-of-Life Questionnaire (Mini-RQLQ) for subjects 18 years and older. Safety: Frequency of subject-reported adverse events (AEs), examination of the long-term effect of MP03-33 by direct visual examination with specific attention to possible nasal irritation, and focused examination of the head and neck. Statistical Methods: The sample size was based on International Conference on Harmonization (ICH) guideline E1: The Extent of Population Exposure to Assess Clinical Safety for Drugs Intended for Long-Term Treatment of Non-Life-Threatening Conditions that requires treatment of 300 subjects for 6 months and 100 subjects for 1 year. Based on an estimated attrition rate of 25% at the 6-month time point, and of 50% by the 1-year time point, 400 subjects per group represented an adequate sample size to ensure an adequate safety database. Change from baseline to each clinical visit up to 12 months (1, 3, 6, 9, and 12 months) for overall score and individual domain was summarized by treatment group for Mini-RQLQ results. Number and percentage of subjects considered as treatment- and diary-compliant at each clinic visit and over all clinic visits up to 12 months were calculated and summarized by treatment group. The incidence of AEs was summarized by body system, preferred term overall and by maximum severity and relationship to study drug. An additional summary table was produced which displayed the number and percentage of subjects with TEAEs by decreasing order of (preferred term) frequency. Subgroup summaries of TEAEs by age (subjects 12 to < 18 and adults 65 years of age), race, and gender were also produced. A summary of the incidence of TEAEs by type of rhinitis diagnosis (PAR versus nonallergic/vasomotor rhinitis) was also performed on the request by FDA. Vital signs results were also summarized and listed. Direct visual examination of the nasal mucosa and a focused head and neck examination were performed at screening, randomization, and at Months 1, 3, 6, 9, and 12 clinic visits. The direct visual examination of nasal mucosa was performed with specific attention to nasal irritation (mucosal erythema/discharge, edema, mucosal crusting, mucosal bleeding, epistaxis, erosion, mucosal ulceration, and septal perforation). The focused head and neck examination was performed with specific attention to conjunctiva, erythematous tympanic membrane (TM), and lymphadenopathy. SUMMARY OF RESULTS Efficacy Results: The least squares (LS) mean change from baseline at Month 12 for all individual domains of the Mini-RQLQ and the overall Mini-RQLQ score were significantly (P<.001) improved from baseline in both the MP03-33 and Astelin treatment groups. The results at Months 1, 3, 6, and 9 were similar to those for Month 12. An analysis of Mini-RQLQ results by rhinitis diagnosis showed that subjects with both PAR and non-allergic rhinitis had statistically and clinically significant improvements from baseline that persisted throughout the study. The improved RQLQ scores provide supportive evidence that subjects were compliant and that rhinitis symptoms were responsive to therapy in this 1-year study.

4 MP03-33 Nasal Spray Page 4 of 9 NAME OF COMPANY: Meda Pharmaceuticals INDIVIDUAL STUDY SYNOPSIS Page 3 of 3 NAME OF FINISHED PRODUCT: MP03-33 Astelin Nasal Spray NAME OF ACTIVE INGREDIENT: Azelastine hydrochloride INDIVIDUAL STUDY TABLE REFERRING TO PART OF THE DOSSIER Volume: Page: (FOR NATIONAL AUTHORITY USE ONLY) Safety Results: MP03-33 and Astelin were well tolerated during this study. The side effect profile was similar in both treatment groups, with a similar incidence of subjects with TEAEs and treatment-related TEAEs. TEAEs occurring in 5% of subjects in both treatment groups included headache, nasopharyngitis, epistaxis, and dysgeusia (taste-related complaints). In the MP03-33 group, pharyngolaryngeal pain was an additional TEAE occurring in 5% of subjects. The incidence of TEAEs was higher in the subjects with nonallergic rhinitis. No deaths or SAEs related to study drug were reported in either treatment group during the 1-year study period; 5.1% of subjects in the MP03-33 group and 4.0% of subjects in the Astelin group discontinued the study due to an AE. There were no reports of severe epistaxis or ulceration in either treatment group, and only 1 subject in each treatment group reported severe pain. Conclusions: MP03-33 and Astelin were both safe and well tolerated during this study of 1-year duration in subjects with allergic or nonallergic rhinitis. There was no evidence of increased nasal irritation with the new formulation compared to Astelin. There were no reports of severe epistaxis or ulceration in either treatment group, and only 1 subject in each treatment group reported severe pain. In addition, quality of life, as measured by the Mini-RQLQ, was significantly improved from baseline to 12 Months in both treatment groups. Date of Final Report: 11 January 2009

5 MP03-33 Nasal Spray Page 5 of 9 SUPPLEMENTARY INFORMATION TO SYNOPSIS NAME OF COMPANY: Germany: Meda Pharma GmbH & Co. KG NAME OF FINISHED PRODUCT: MP03-33 / Allergodil Nasenspray Substantial amendments (protocol amendments and premature interruption and/or discontinuation): No.* Date issued In force Modifications 1 11 May 2006 Upon approval by IRB/EC 2 02 January 2007 Upon approval by IRB/EC Protocol Amendment 1 included additional details on study procedures. Protocol Amendment 2 included a change in visit windows for specific visits and additional data to be recorded. * In addition, there were some country and site specific amendments. Number of Subjects planned: It was planned to randomize and analyze 800 subjects, i.e. 400 subjects per treatment group. Publication (reference): Berger WE. Pharmacokinetic characteristics and safety and tolerability of a reformulated azelastine hydrochloride nasal spray in patients with chronic rhinitis. Expert Opin Drug Metab Toxicol Jan;5(1): Names of Investigators and Site List: cf. next pages 11 January 2009 Supplementary information to CSR Synopsis

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