Document 3 PEP005 (ingenol mebutate) Gel 0000 2.7.4 Summary of Clinical Safety CONFIDENTIAL PEP005 (ingenol mebutate) Gel 2.7.4 Summary of Clinical Safety for Actinic Keratosis LEO Pharma A/S Clinical Development 29 May 2011 THIS DOCUMENT CONTAINS TRADE SECRETS, OR COMMERCIAL OR FINANCIAL INFORMATION, PRIVILEGED OR CONFIDENTIAL, DELIVERED IN CONFIDENCE AND RELIANCE THAT SUCH INFORMATION WILL NOT BE COPIED OR MADE AVAILABLE TO ANY THIRD PARTY WITHOUT THE WRITTEN CONSENT OF LEO PHARMA A/S - LEO PHARMACEUTICAL PRODUCTS LTD. A/S 00255345v 2.0 PEP005 (ingenol mebutate) Gel 0000 2.7.4 Summary of Clinical Safety PEP005 (ingenol mebutate) Gel Page 2 of 168 2.7.4 Summary of Clinical Safety for Actinic Keratosis 29 May 2011 Module 2 Summary of Clinical Safety TABLE OF CONTENTS TABLE OF CONTENTS ......................................................................................................... 2 TABLE OF TABLES ............................................................................................................... 5 TABLE OF FIGURES ............................................................................................................. 8 TABLE OF ATTACHMENTS ............................................................................................... 9 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................... 10 1 EXPOSURE TO THE DRUG ............................................................................................ 12 1.1 OVERALL SAFETY EVAULATION PLAN AND NARRATIVES OF SAFETY STUDIES .......................................................................................................................... 13 1.1.1 Studies in the PEP005 Gel Development Program ......................................................... 13 1.1.2 Development Plan for PEP005 Gel in Actinic Keratosis ................................................ 15 1.1.3 Summary of All Investigations Pertinent to Safety ......................................................... 16 1.1.3.1 Tabular Summaries of Clinical Studies ........................................................................ 16 1.1.4 Methods and Definitions ................................................................................................. 28 1.1.5 Analysis Populations ....................................................................................................... 28 1.1.5.1 Adverse Events ............................................................................................................. 30 1.1.5.2 Serious Adverse Events ................................................................................................ 30 1.1.5.3 Local Skin Responses ................................................................................................... 31 1.1.5.4 Pigmentation and Scarring ........................................................................................... 32 1.2 OVERALL EXTENT OF EXPOSURE ............................................................................. 33 1.2.1 Disposition ...................................................................................................................... 33 1.2.2 Extent of Exposure .......................................................................................................... 35 1.3 DEMOGRAPHIC AND OTHER CHARACTERISTICS OF STUDY POPULATION ... 39 2 ADVERSE EVENTS ........................................................................................................... 44 2.1 ANALYSIS OF ADVERSE EVENTS .............................................................................. 44 2.1.1 Common Adverse Events ................................................................................................ 46 2.1.1.1 Treatment-related Adverse Events ............................................................................... 49 2.1.1.2 Adverse Events by Severity ......................................................................................... 51 2.1.1.3 Treatment-related Severe Adverse Events ................................................................... 53 2.1.1.4 Analysis of Adverse Events across PEP005 Gel Concentration .................................. 54 2.1.1.5 Effects of Dosing Regimen and Treatment Location ................................................... 57 2.1.1.6 Effect of Multiple Treatments of PEP005 Gel ............................................................. 57 THIS DOCUMENT CONTAINS TRADE SECRETS, OR COMMERCIAL OR FINANCIAL INFORMATION, PRIVILEGED OR CONFIDENTIAL, DELIVERED IN CONFIDENCE AND RELIANCE THAT SUCH INFORMATION WILL NOT BE COPIED OR MADE AVAILABLE TO ANY THIRD PARTY WITHOUT THE WRITTEN CONSENT OF LEO PHARMA A/S - LEO PHARMACEUTICAL PRODUCTS LTD. A/S 00255345v 2.0 PEP005 (ingenol mebutate) Gel 0000 2.7.4 Summary of Clinical Safety PEP005 (ingenol mebutate) Gel Page 3 of 168 2.7.4 Summary of Clinical Safety for Actinic Keratosis 29 May 2011 2.1.1.7 Combined Adverse Events and Local Skin Responses ................................................ 58 2.1.2 Deaths .............................................................................................................................. 61 2.1.3 Other Serious Adverse Events ......................................................................................... 61 2.1.3.1 Serious Adverse Events Reported in Studies Evaluating Field Application of Study Medication for Treatment of AK Lesions ............................................................... 62 2.1.3.1.1 Squamous Cell Carcinoma Reported during Studies Evaluating Field Application of Study Medication for Treatment of AK Lesions ...................................... 66 2.1.3.2 Serious Adverse Events in Lesion-specific and Non-AK Studies ............................... 67 2.1.3.3 Serious Adverse Events from Ongoing Studies ........................................................... 69 2.1.4 Other Significant Adverse Events ................................................................................... 69 2.1.4.1 Adverse Events Leading to Discontinuation ................................................................ 69 2.1.4.1.1 Adverse Events Leading to Discontinuation from the Study .................................... 70 2.1.4.1.2 Adverse Events Leading to Discontinuation of Treatment ....................................... 73 2.1.5 Analysis of Adverse Events by Organ System or Syndrome .......................................... 76 2.1.5.1 Infections and Infestations ........................................................................................... 76 2.1.5.2 Neoplasms .................................................................................................................... 79 2.1.5.3 Eye Disorders ............................................................................................................... 80 2.1.5.4 Cardiac Disorders ......................................................................................................... 81 2.1.6 Long-term Adverse Effects ............................................................................................. 82 2.1.6.1 Study Patients ............................................................................................................... 82 2.1.6.2 Safety through 12 Months of Follow-up ...................................................................... 84 2.2 NARRATIVES ................................................................................................................... 85 3 CLINICAL LABORATORY EVALUATIONS ............................................................... 86 4 VITAL SIGNS, PHYSICAL FINDINGS, AND OTHER OBSERVATIONS RELATED TO SAFETY ................................................................................................ 87 4.1 VITAL SIGNS ................................................................................................................... 87 4.2 ELECTROCARDIOGRAM RESULTS ............................................................................ 88 4.2.1 ECG Intervals .................................................................................................................. 88 4.2.2 ECG Abnormalities Reported as Adverse Events ........................................................... 91 4.2.3 Cardiac Safety Testing .................................................................................................... 94 4.3 LOCAL SKIN RESPONSE ............................................................................................... 94 4.3.1 Composite LSR Scores .................................................................................................... 94 4.3.1.1 Evaluation of Treatment Regimen and Mean Maximum LSR Composite Score ........ 97 4.3.1.2 Evaluation of Multiple Treatments of PEP005 Gel on Maximum LSR Composite Scores ................................................................................................................................ 97 THIS DOCUMENT CONTAINS TRADE SECRETS, OR COMMERCIAL OR FINANCIAL INFORMATION, PRIVILEGED OR CONFIDENTIAL, DELIVERED IN CONFIDENCE AND RELIANCE THAT SUCH INFORMATION WILL NOT BE COPIED OR MADE AVAILABLE TO ANY THIRD PARTY WITHOUT THE WRITTEN CONSENT OF LEO PHARMA A/S - LEO PHARMACEUTICAL PRODUCTS LTD. A/S 00255345v 2.0 PEP005 (ingenol mebutate) Gel 0000 2.7.4 Summary of Clinical Safety PEP005 (ingenol mebutate) Gel Page 4 of 168 2.7.4 Summary of Clinical Safety for Actinic Keratosis 29 May 2011 4.3.2 Individual Local Skin Responses ...................................................................................