Clinical Study Report – Part 1 of Trial LP0084-1013

Safety and efficacy of escalating doses of two LEO 43204 formulations

applied once daily for two consecutive days on full face or approximately

250 cm2 (40 in2) on the chest in subjects with actinic keratosis

Part 1: A phase 1, multicentre, randomised, open-label, parallel group,

dose escalation, 8-week trial

LEO Pharma A/S LP0084-1013

Clinical Development and Safety 20-Aug-2015

EudraCT Number: NA

eDoc-00551654 - Version 1.0

LP0084-1013 20-Aug-2015 Page 2 of 54

Clinical Study Report Statement

Approval Statement, Sponsor

The following persons have approved this Clinical Study Report on behalf of

LEO Pharma A/S using electronic signatures:

Biostatistics

Medical Department

Approval Statement, Investigator

The international co-ordinating investigator approves the Clinical Study Report by manually

signing the International Co-ordinating Investigator Clinical Study Report Approval Form,

which is a separate document adjoined to this report.

The following person has approved this Clinical Study Report:

Dr. Gary Goldenberg

International co-ordinating investigator

PPDPPD

PPDPPD

LP0084-1013 20-Aug-2015 Page 3 of 54

Compliance with Good Clinical Practice

This clinical trial was performed in compliance with GCP, including the archiving of essential

documents.

This clinical study report, presenting part 1 of the trial, is together with the LP0084-1013

main clinical study report designed to comply with the standards issued by the International

Conference on Harmonisation (ICH) (E3 Structure and Content of Clinical Study Reports and

clarified in the ICH E3 Q&A document 07-Jun-2012; E6 Good Clinical Practice; E9

Statistical Principles for Clinical Trials and M4 Common Technical Document) (1, 2, 3, 4, 5).

Public Registration of the Clinical Trial

The trial was registered at ClinicalTrials.gov on 12-Aug-2013, trial registration number:

NCT01922050. The results are disclosed in accordance with applicable national regulations

and LEO procedures.

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Table of Contents

Clinical Study Report Statement ................................................................................................ 2

Compliance with Good Clinical Practice ................................................................................... 3

Table of Contents ....................................................................................................................... 4

List of Tables .............................................................................................................................. 5

List of Figures ............................................................................................................................ 6

List of Appendices...................................................................................................................... 7

List of Abbreviations.................................................................................................................. 8

1 Introduction ........................................................................................................................... 9

1.1 Frequency and Timing of Measurements ........................................................................ 10

2 Trial Objectives and Response Criteria/Endpoints – Part 1 ................................................ 11

2.1 Primary Objectives .......................................................................................................... 11

2.2 Secondary Objectives ...................................................................................................... 11

2.3 Primary Response Criterion ............................................................................................ 11

2.4 Other Evaluations ............................................................................................................ 11

2.4.1 Evaluation of (Serious) Adverse Events...................................................................... 11

2.4.2 Evaluation of Laboratory Data .................................................................................... 11

2.4.3 Evaluation of Other Observations ............................................................................... 11

3 Trial Population – Part 1...................................................................................................... 13

3.1 Overview ......................................................................................................................... 13

3.2 Disposition of Subjects.................................................................................................... 13

3.3 Trial Analysis Set ............................................................................................................ 13

3.4 Demographics and Other Baseline Characteristics ......................................................... 14

4 Exposure and Treatment Compliance– Part 1 ..................................................................... 22

5 Safety Evaluation – Part 1 ................................................................................................... 23

5.1 Adverse Events................................................................................................................ 23

5.1.1 Brief Summary of Adverse Events .............................................................................. 23

5.1.2 Display of Adverse Events .......................................................................................... 23

5.1.3 Analysis of Adverse Events......................................................................................... 25

5.2 Deaths, other Serious Adverse Events, and other Significant Adverse Events ............... 31

5.2.1 Serious Adverse Events ............................................................................................... 31

5.2.2 Other Significant Adverse Events ............................................................................... 31

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5.3 Local Skin Responses...................................................................................................... 31

5.3.1 Dose-limiting Toxicities .............................................................................................. 32

5.4 Vital Signs, Physical Findings and other Observations Related to Safety ...................... 37

5.4.1 Vital Signs and Physical Findings ............................................................................... 37

5.4.2 ECG Assessments........................................................................................................ 37

5.5 Clinical Laboratory Evaluation ....................................................................................... 37

6 Overall Conclusions of Part 1.............................................................................................. 38

7 References ........................................................................................................................... 39

8 Narratives – Part 1 ............................................................................................................... 40

8.1 Serious Adverse Events ................................................................................................... 40

8.2 Other Significant Adverse Events ................................................................................... 42

9 End-of-Text Tables and Figures........................................................................................... 45

End-of-Text Listings

End-of-Text Listings have been moved to Appendix 2.7. Note that the numbering of the

listings is as described in the statistical analysis plan update (SAPU).

List of Tables

Table 1 Schedule of trial procedures............................................................................. 10

Table 2 Age overall and by cohort (gel): evaluable subjects analysis set ..................... 15

Table 3 Sex, race, ethnicity and skin type overall and by cohort (gel): evaluable subjects analysis set.......................................................................................... 16

Table 4 Duration of AK overall and by cohort (gel): evaluable subjects analysis set .. 17

Table 5 AK treatment history overall and by cohort (gel): evaluable subjects analysis set ..................................................................................................................... 18

Table 6 Skin disease history overall and by cohort (gel): evaluable subjects analysis set.......................................................................................................................... 19

Table 7 AK count at baseline overall and by cohort (gel): evaluable subjects analysis set ..................................................................................................................... 21

Table 8 Overall summary of adverse events by cohort: safety analysis set .................. 24

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Table 9 Adverse events by SOC and preferred term (gel): safety analysis set ............. 26

Table 10 Number of subjects with Administration Site Reactions by intensity (gel): safety analysis set ............................................................................................. 30

Table 11 DLTs by cohort (gel): safety subjects analysis set............................................ 36

Table 12 Age overall and by cohort (cream): evaluable subjects analysis set ................ 45

Table 13 Sex, race, ethnicity and skin type overall and by cohort (cream): evaluable subjects analysis set.......................................................................................... 46

Table 14 Duration of AK overall and by cohort (cream): evaluable subjects analysis set.......................................................................................................................... 47

Table 15 AK treatment history overall and by cohort (cream): evaluable subjects analysis set........................................................................................................ 47

Table 16 Skin disease history overall and by cohort (cream): evaluable subjects analysis set ..................................................................................................................... 48

Table 17 AK count at baseline overall and by cohort (cream): evaluable subjects analysis set........................................................................................................ 49

Table 18 Overall summary of adverse events (cream): safety analysis set..................... 49

Table 19 Adverse events by SOC and preferred term (cream): safety analysis set ........ 50

Table 20 DLTs by cohort (cream): safety subjects analysis set....................................... 52

Table 21 Number of subjects with Administration Site Reactions by intensity (cream): safety analysis set ............................................................................................. 53

List of Figures

Figure 1 Maximum composite LSR score during Week 1 by cohort: safety analysis set (gel): safety analysis set ................................................................................... 32

Figure 2 Dose Escalation Rules ...................................................................................... 33

Figure 3 Maximum composite LSR score during Week 1 by cohort: safety analysis set (cream): safety analysis set .............................................................................. 54

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List of Appendices

Listings

Appendix No Appendix Title Status

1.6 Listing of Subjects receiving Investigational Product from Specific Batches - Part 1

Enclosed

1.7 Randomisation Scheme and Codes - Part 1 Enclosed

2.1 Discontinued Subjects – Part 1 Enclosed

2.2 Protocol Deviations – Part 1 Enclosed

2.3 Trial Analysis Sets – Part 1 Enclosed

2.4 Demographic Data – Part 1 Enclosed

2.5 Compliance and/or Investigational Product Concentration Data – Part 1

Enclosed

2.6 Efficacy Data – Part 1 Enclosed

2.7 Safety Data – Part 1 Enclosed

2.8 Listing of Laboratory Values by Subject – Part 1 Enclosed

Additional Related Reports (not part of appendices)

Report title Status

LP0084-1013 main clinical study report

Enclosed

ECG Safety Report Enclosed

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List of Abbreviations

ADR Adverse drug reaction

AK Actinic keratosis

AE Adverse event

BCC Basal cell carcinoma

CRF Case report form

CRO Contract research organisation

DLT Dose limiting toxicity

EoT End-of-text

GCP Good Clinical Practice

ICH International Conference on Harmonisation

IP Investigational product

LLT Lowest level term

LSR Local skin response

MedDRA Medical Dictionary for Regulatory Activities

MTD Maximum tolerated dose

PT Preferred term

QTcF QT interval corrected according to Fridericia

SAE Serious adverse event

SAPU Statistical analysis plan update

SCC Squamous cell carcinoma

SOC System Organ Class

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1 Introduction

Trial LP0084-1013 was a seamless phase 1/2 clinical trial constituting 2 parts: a phase 1 open

label, dose escalation part and a phase 2 randomised double-blind, vehicle-controlled part.

The trial is reported in two interdependent clinical study reports each presenting one part of

the trial. This report describes the results of Part 1 of the trial, identifying the maximum

tolerated dose (MTD) with a focus on safety and tolerability of LEO 43204 gel and cream

formulations and undertaken in a dose escalation manner. The cream formulation was

discontinued after cohort 4 (0.012%) due to CMC development issues which did not affect the

quality of the investigational medicinal product in this trial and therefore have no

consequences for the analysis and interpretation of the collected data.

All tables and figures in Part 1 are presented in-text (gel) or end-of-text (cream) in this CSR

Part 1 document.

The LP0084-1013 main clinical study report contains the introduction, information on ethics,

objectives, trial administrative structure, investigational plan, and statistical methods for the

whole of the trial. Also, the results from Part 2 of the trial (dose selection) are reported here

and finally, the trial in full is evaluated in the discussion.

The clinical study report synopsis exists as a separately approved document and includes both

Part 1 and Part 2 results.

The schedule of all trial procedures for all trial visits for Part 1 is presented in Table 1.

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1.1 Frequency and Timing of Measurements

Table 1 Schedule of trial procedures

Part 1: 2-day Application Dose Escalation

Visit Number 1 2 3 4 5 6 7Unscheduled1

/ Early Term

Visit

(window)

Within 35 days prior to Day 1

Day 1

Day 2

Day 3

Day 8 Week 2 Week 8 N/A

None None None ±1 day ±2 days ±7 days

Informed consent X

In-/exclusion criteria X X2

Medical/surgical history3

X X2

Concurrent diagnosis X X2

Skin diseases X X2

AK treatment history X X2

Fitzpatrick skin type X

Demographics X

Height and weight X

Concomitant medications, treatments, procedures

X X X X X X X

Physical exam X X X X

Vital signs X X X X X X X

Laboratory X X4 X X

ECG X X X X X

Urine pregnancy test5 X X X X

Identify treatment area

X X2

Randomisation X

AK assessment X X

Apply trial medication

X X

LSR X X X X X X X

Adverse events X X X X X X X

1) For unscheduled visits, only assessments that are required as judged by the investigator was to be conducted2) Re-check3) Relevant medical/surgical history within 12 months prior to Visit 14) Performed before study medication application. Not required if screening visit performed within the last 14 days5) Only subjects of childbearing potential

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2 Trial Objectives and Response Criteria/Endpoints – Part 1

2.1 Primary Objectives

To identify MTD levels of LEO 43204 gel and cream, respectively, after once daily

treatment for 2 consecutive days

Dose escalation beyond cohort 4 continued with gel formulation only due to CMC

development issues with the cream formulation, which did not affect the quality of the

investigational medicinal product in this trial and therefore have no consequences for the

analysis and interpretation of the collected data. Consequently, the MTD of LEO 43204 cream

could not be identified (see Section 5.8 of the LP0084-1013 main clinical study report).

2.2 Secondary Objectives

To evaluate safety of LEO 43204 gel and cream, respectively, after once daily treatment

for 2 consecutive days

Dose escalation beyond cohort 4 continued with gel formulation only (see Section 2.1 and

LP0084-1013 main clinical study report, Section 5.8).

2.3 Primary Response Criterion

Dose limiting toxicity based on LSRs up to and including Day 8

2.4 Other Evaluations

2.4.1 Evaluation of (Serious) Adverse Events

Incidence of AEs and SAEs

Incidence of AEs and LSRs leading to discontinuation of the trial medication

Incidence and severity of LSRs

Any adverse drug reactions (ADRs) reported

Changes in vital signs, ECGs, and blood laboratory parameters that are out of normal

range and clinically relevant

Reason for withdrawal

2.4.2 Evaluation of Laboratory Data

Abnormal haematology and biochemistry laboratory values

2.4.3 Evaluation of Other Observations

Change from baseline to Week 2 in ECG assessments

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The ECG evaluation is erroneously defined in the clinical study protocol and was updated to

reflect the actual ECG assessments (see Section 5.8 of the LP0084-1013 main clinical study

report).

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3 Trial Population – Part 1

3.1 Overview

This report describes the results from Part 1 of the trial. Part 2 results are described in

LP0084-1013 main clinical study report.

3.2 Disposition of Subjects

A total of 86 subjects were enrolled in the trial, 6 were screening failures, 2 were excluded as

recruitment goals for all cohorts were met, 1 was a voluntary withdrawal, and thus 77 subjects

were included in Part 1. All 77 subjects completed all visits. In the group administered

LEO 43204 in gel formulation 3 subjects were included in the 0.0015% cohort, 3 subjects in

the 0.003% cohort, 6 in the 0.006% cohort, 6 in the 0.012% cohort, 17 in the 0.018% cohort,

and 18 in the 0.025% cohort. Out of the group administered LEO 43204 in cream formulation

3 subjects were included in the 0.0015% cohort, 3 subjects in the 0.003% cohort, 6 in the

0.006% cohort, and 12 in the 0.012% cohort. A listing of discontinued subjects can be found

in Appendix 2.1 (Part 1), Listings 1-1 and 1-2.

The first subject was enrolled on 09-Oct-2013 and the last subject´s last visit was on

03-Jul-2014. The last subject had scheduled last visit 23-May-2014 and the visit 03-Jul-2014

was a follow-up visit.

The individual visit dates are listed in Appendix 2.4 (Part 1), Listing 4-4 (Part 1).

3.3 Protocol Deviations

A listing of the protocol deviations during the trial conduct is in Appendix 2.2 (Part 1), Listing

2-1. All comments made in the comment field in the CRF are in Appendix 2.2 (Part 1), Listing

2 2. The log of protocol deviations was also reviewed to ascertain protocol deviations.

One subject (Subject Number ) had a major protocol deviation: the subject did not

receive the second dose of investigational product due to AE.

All other protocol deviations were considered minor and are not discussed further in the text.

3.4 Trial Analysis Set

The ‘evaluable subjects analysis set’ was defined as all subjects who received at least one

application of trial medication and had LSRs recorded at all visits up to and including Day 8,

or had experienced a DLT at one or more visits up to and including Day 8. The safety analysis

PPI

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set was defined as all subjects who received at least one application of trial medication and

had safety information available post treatment.

Of the 86 enrolled subjects 77 subjects were included in the trial of whom all were included in

the evaluable subjects analysis set and safety analysis set.

Listings of the trial analysis sets and reasons for exclusion from the trial analysis sets (screen

failures) are in Appendix 2.3 (Part 1), Listings 3-1 and 3-2, respectively.

3.5 Demographics and Other Baseline Characteristics

Results are presented for the LEO 43204 gel formulation cohorts with cream formulation

results for cohort 1 to 4 as end-of-text for information.

The median age at baseline was 69.0 years for all cohorts in total for both gel (Table 2) and

cream treatment groups (Table 12). All subjects in both treatment groups were white and most

subjects were men, non-Hispanic or Latino with Fitzpatrick skin type II (Table 3 and Table

13). The median duration of AK was 6.0 years for the group treated with gel and 5.0 years in

the group treated with cream (Table 4 and Table 14). Most subjects in both treatment groups

had a history of AK treatment and the most common AK treatment was cryo/liquid nitrogen

and 5-fluorouracil (Table 5 and Table 15). About half of the subjects in both treatment groups

had a history of skin disease. The most common skin disease history was seborrhoeic

keratosis for the gel treatment group and photodermatitis for the cream treatment group (Table

6 and Table 16). Median number of AKs at baseline was 10.0 for the group treated with gel

and 12.0 for the group treated with cream (Table 7, Table 17, and Appendix 2.6 [Part 1]).

There were some differences between cohorts, as would be expected with groups of such

small sizes, but these are not expected to influence the interpretation of the results with regard

to MTD.

Listings of demographic and baseline data are in Appendix 2.4 (Part 1).

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Table 2 Age overall and by cohort (gel): evaluable subjects analysis set

Total(n=53)

Gel 0.0015(n=3)

Gel 0.003(n=3)

Gel 0.006(n=6)

Gel 0.012(n=6)

Gel 0.018(n=17)

Gel 0.025(n=18)

Age (years) Median 69.0 80.0 70.0 68.5 75.5 63.0 71.5Minimum 48 56 48 51 59 57 48Maximum 91 85 70 91 91 76 87Number 53 3 3 6 6 17 18

20APR15:08:46:16 LP0084 1013 t01_age_gel.doc

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Table 3 Sex, race, ethnicity and skin type overall and by cohort (gel): evaluable subjects analysis set

Total(n=53)

n1

Gel 0.0015(n=3)

n1

Gel 0.003(n=3)

n1

Gel 0.006(n=6)

n1

Gel 0.012(n=6)

n1

Gel 0.018(n=17)

n1

Gel 0.025(n=18)

n1

SexMale 33 2 2 2 4 11 12Female 20 1 1 4 2 6 6Total 53 3 3 6 6 17 18

RaceWhite 53 3 3 6 6 17 18Total 53 3 3 6 6 17 18

EthnicityNot Hispanic or Latino 51 3 3 6 5 17 17Hispanic or Latino 2 0 0 0 1 0 1Total 53 3 3 6 6 17 18

Skin classificationType I 4 1 0 0 0 0 3Type II 37 0 2 6 5 12 12Type III 11 2 1 0 1 5 2Type V 1 0 0 0 0 0 1Total 53 3 3 6 6 17 18

24APR15:15:07:22 LP0084 1013 t03 sex race etc gel.doc

1) n=Number of subjects.

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Table 4 Duration of AK overall and by cohort (gel): evaluable subjects analysis set

Total(n=53)

Gel 0.0015(n=3)

Gel 0.003(n=3)

Gel 0.006(n=6)

Gel 0.012(n=6)

Gel 0.018(n=17)

Gel 0.025(n=18)

Duration of AK (years) Median 6.0 11.0 2.0 6.5 6.0 4.0 9.5Minimum 0 9 0 0 2 0 1Maximum 42 27 5 29 26 26 42Number 53 3 3 6 6 17 18

20APR15:08:47:37 LP0084 1013 t05 ak dur gel.doc

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Table 5 AK treatment history overall and by cohort (gel): evaluable subjects analysis set

AK treatments

Total(n=53)

n1

Gel 0.0015(n=3)

n1

Gel 0.003(n=3)

n1

Gel 0.006(n=6)

n1

Gel 0.012(n=6)

n1

Gel 0.018(n=17)

n1

Gel 0.025(n=18)

n1

Cryo/liquid nitrogen 41 3 3 4 5 11 15Surgical excision/curettage 12 0 0 2 2 1 7Dermabrasion 2 0 0 0 1 0 1Medium or greater depth chemical peel

1 0 0 0 0 0 1

Laser resurfacing 0 0 0 0 0 0 05-Fluorouracil 16 1 1 2 2 3 7Imiquimod 3 1 0 0 0 1 1Diclofenac 6 0 0 0 1 4 1Photodynamic therapy 7 1 0 0 0 1 5Retinoids 3 0 0 0 0 1 2Ingenol mebutate gel trunk and extremities

1 0 0 0 0 1 0

Other 1 0 0 0 0 0 1

Total number of previous treatments

93 6 4 8 11 23 41

Total number of previously treated subjects

43 3 3 4 5 12 16

24APR15:15:11:32 LP0084 1013 t07 akhist gel.doc

1) n=Number of subjects.

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Table 6 Skin disease history overall and by cohort (gel): evaluable subjects analysis set

Total(n=53)

Gel 0.0015(n=3)

Gel 0.003(n=3)

Gel 0.006(n=6)

Gel 0.012(n=6)

Gel 0.018(n=17)

Gel 0.025(n=18)

Preferred term1 n3 n3 n3 n3 n3 n3 n3

Seborrhoeic keratosis 16 1 1 1 3 5 5 Squamous cell carcinoma of skin 14 2 0 1 3 2 6 Basal cell carcinoma 12 1 1 2 1 0 7 Lentigo 7 1 0 1 0 2 3 Dry skin 5 0 0 0 1 1 3

Photodermatosis 5 1 1 1 0 2 0 Rosacea 5 2 0 0 0 2 1 Melanocytic naevus 4 0 0 1 1 0 2 Onychomycosis 4 1 1 0 1 0 1 Alopecia 3 1 1 0 0 0 1

Seborrhoeic dermatitis 3 0 0 0 1 1 1 Acne 2 0 0 0 0 1 1 Actinic elastosis 2 0 0 0 1 0 1 Actinic keratosis 2 0 0 0 0 1 1 Neurofibroma 2 0 0 1 1 0 0

Pruritus 2 1 0 0 0 0 1 Solar dermatitis 2 0 0 0 0 0 2 Tinea pedis 2 0 0 0 0 1 1 Acrochordon 1 0 0 0 1 0 0 Campbell de morgan spots 1 0 0 1 0 0 0

Dermatitis 1 0 0 0 0 0 1 Dysplastic naevus 1 0 0 0 0 1 0 Eczema 1 0 0 0 1 0 0 Fibrous histiocytoma 1 0 0 0 0 0 1 Haemangioma of skin 1 0 0 0 0 1 0

Herpes zoster 1 0 0 0 1 0 0 Idiopathic guttate hypomelanosis 1 0 0 0 0 1 0 Keloid scar 1 0 0 0 1 0 0 Lichenoid keratosis 1 0 0 0 1 0 0 Nasopharyngeal cancer 1 0 0 0 1 0 0

24APR15:15:35:51 LP0084 1013 t09 dishist gel.doc Continued...

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Table 6 Skin disease history overall and by cohort (gel): evaluable subjects analysis set, continued

Total(n=53)

Gel 0.0015(n=3)

Gel 0.003(n=3)

Gel 0.006(n=6)

Gel 0.012(n=6)

Gel 0.018(n=17)

Gel 0.025(n=18)

Preferred term1 n3 n3 n3 n3 n3 n3 n3

Neoplasm 1 0 0 0 0 0 1 Notalgia paraesthetica 1 0 0 0 0 0 1 Oral herpes 1 0 0 0 0 0 1 Pilonidal cyst 1 1 0 0 0 0 0 Plastic surgery to the face 1 1 0 0 0 0 0

Porokeratosis 1 0 0 0 0 0 1 Psoriasis 1 0 1 0 0 0 0 Purpura 1 0 0 0 0 1 0 Sebaceous hyperplasia 1 0 0 0 0 0 1 Skin cancer 1 0 0 0 0 0 1

Skin graft 1 1 0 0 0 0 0 Skin papilloma 1 0 0 0 0 0 1 Solar lentigo 1 0 0 0 1 0 0 Stasis dermatitis 1 0 0 0 0 0 1 Tinea cruris 1 0 0 0 1 0 0

Urticaria 1 0 0 0 0 0 1 Varicose vein 1 0 0 0 0 0 1

Total number of diagnoses2 121 14 6 9 21 22 49

Total number of subjects 30 2 2 2 4 6 14

(*ESC*)n 24APR15:15:35:51 LP0084 1013 t09 dishist gel.doc

1) Classification according to MedDRA version 15.1.2) Different diagnoses within the same preferred term and involving

the same subject have been counted as one. A subject could appear in multiple classes.3) n=Number of subjects.

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Table 7 AK count at baseline overall and by cohort (gel): evaluable subjects analysis set

Total(n=53)

Gel 0.0015(n=3)

Gel 0.003(n=3)

Gel 0.006(n=6)

Gel 0.012(n=6)

Gel 0.018(n=17)

Gel 0.025(n=18)

Number of AK lesions Median 10.0 13.0 12.0 8.0 12.0 10.0 10.0Minimum 5 12 8 5 5 5 5Maximum 20 13 13 19 17 20 20Number 53 3 3 6 6 17 18

20APR15:08:49:57 LP0084 1013 t11 aklesions gel.doc

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4 Exposure and Treatment Compliance– Part 1

All 77 subjects received first administration of medication and 71 subjects received the

second administration (>90%). Out of the 6 subjects not applying the second dose 4 subjects

were in the gel formulation cohorts (3 in the 0.025% cohort and 1 in the 0.018% cohort) and 2

subjects were in the cream formulation cohorts (both in the 0.012% cohort).

A listing is provided in Appendix 2.5 (Part 1), Listing 5-1.

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5 Safety Evaluation – Part 1

Note that the primary response criterion for Part 1 was dose-limiting toxicity (DLT) up to and

including Day 8, and that this information is presented in Section 5.3.1.

Results are presented for the LEO 43204 gel formulation cohorts with cream formulation

results for cohort 1 to 4 as end-of-text for information.

5.1 Adverse Events

5.1.1 Brief Summary of Adverse Events

An overview summary of AEs is presented in Table 8 (gel) and Table 18 (cream). All cohorts

for both gel and cream had subjects with AEs and most AEs were related to treatment.

Approximately half of the subjects had administration site reactions (MedDRA high level

group term) and relatively few AEs were of severe intensity (Table 10 and Table 21). There

were no deaths, 2 subjects had SAEs (squamous cell carcinoma (SCC) of skin inside

treatment area and breast cancer, both had gel treatment), and 5 subjects had discontinued

treatment due to AEs (see Section 5.2).

5.1.2 Display of Adverse Events

An overall summary of the AEs is showed in Table 8 (gel) and Table 18 (cream).

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Table 8 Overall summary of adverse events by cohort: safety analysis set

Gel 0.0015(n=3)

Gel 0.003(n=3)

Gel 0.006(n=6)

Gel 0.012(n=6)

Gel 0.018(n=17)

Gel 0.025(n=18)

Adverse event category AE1,2 n3 AE1,2 n3 AE1,2 n3 AE1,2 n3 AE1,2 n3 AE1,2 n3

All adverse events 7 3 3 1 9 5 14 5 19 11 17 11 Severe adverse events 0 0 0 0 0 0 0 0 1 1 0 0 Related adverse events 3 2 3 1 6 4 10 5 11 5 15 11 AEs leading to withdrawal from trial

0 0 0 0 0 0 0 0 0 0 0 0

SAEs 0 0 0 0 1 1 0 0 1 1 0 0 AEs leading to death 0 0 0 0 0 0 0 0 0 0 0 0

26MAR15:12:32:10 LP0084 1013 t01 summary gel.doc

1) AE=Number of adverse events.2) Different adverse events within the same preferred term and system organ class

and involving the same subject have been counted as one.3) n=Number of subjects.

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5.1.3 Analysis of Adverse Events

The most commonly reported AEs among all cohorts were within the primary SOC ‘general

disorders and administration site conditions’ and the most commonly reported AEs by SOC

and preferred term for the gel cohorts were application site pain and application site pruritus

(Table 9 and Table 19). The cream cohorts had generally few AEs with application site pain as

the most commonly reported AE among the 4 cohorts (Table 19).

Adverse events in the ‘eye disorders’ SOC were reported for 5 subjects in the gel cohorts (2 in

the 0.025% cohort, 1 in the 0.0015% cohort, 1 in the 0.012% cohort, and 1 in the 0.018%

cohort) and 2 subjects in the cream cohorts (both in the 0.012% cohort) (Table 9 and Table

19).

One subject in the 0.018% gel cohort had herpes simplex (not related to treatment) and no

subjects in Part 1 reported insomnia (Table 9, Table 19, Appendix 2.7 [Part 1], Listing 7-1).

Approximately half of the subjects had administration site reactions (MedDRA high level

group term) and most administration site reactions were of mild or moderate intensity.

Administration site reactions of severe intensity were reported for 2 subjects in the cream

cohorts and none in the gel cohorts (Table 10, gel and Table 21, cream).

Listings are available in Appendix 2.7 (Part 1), Listings 7-1, 7-2, and 7-3.

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Table 9 Adverse events by SOC and preferred term (gel): safety analysis set

Gel 0.0015(n=3)

Gel 0.003(n=3)

Gel 0.006(n=6)

Gel 0.012(n=6)

Gel 0.018(n=17)

Gel 0.025(n=18)

System Organ Class (SOC)Preferred Term1 n2 % n2 % n2 % n2 % n2 % n2 %

General disorders and administration site conditionsApplication site pain 1 33.3 1 33.3 2 33.3 3 50.0 3 17.6 8 44.4Application site pruritus 1 33.3 1 33.3 2 33.3 4 66.7 2 11.8 1 5.6Application site erythema 0 0.0 0 0.0 2 33.3 1 16.7 2 11.8 1 5.6Application site discolouration 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 1 5.6Application site discomfort 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 1 5.6Application site exfoliation 0 0.0 0 0.0 0 0.0 0 0.0 1 5.9 0 0.0Application site oedema 0 0.0 0 0.0 0 0.0 0 0.0 1 5.9 0 0.0Application site photosensitivityreaction

0 0.0 0 0.0 0 0.0 0 0.0 1 5.9 0 0.0

SOC total 2 66.7 1 33.3 4 66.7 5 83.3 5 29.4 10 55.6 Eye disordersEye irritation 0 0.0 0 0.0 0 0.0 1 16.7 1 5.9 0 0.0Dry eye 1 33.3 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0Eyelid oedema 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 1 5.6Periorbital oedema 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 1 5.6Scintillating scotoma 1 33.3 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0SOC total 1 33.3 0 0.0 0 0.0 1 16.7 1 5.9 2 11.1

27APR15:11:26:24 LP0084 1013 t03 ae soc pt gel.doc Continued...

LP0084-1013 20-Aug-2015 Page 27 of 54

Table 9 Adverse events by SOC and preferred term (gel): safety analysis set, continued

Gel 0.0015(n=3)

Gel 0.003(n=3)

Gel 0.006(n=6)

Gel 0.012(n=6)

Gel 0.018(n=17)

Gel 0.025(n=18)

System Organ Class (SOC)Preferred Term1 n2 % n2 % n2 % n2 % n2 % n2 %

Infections and infestationsHerpes simplex 0 0.0 0 0.0 0 0.0 0 0.0 1 5.9 0 0.0Nasopharyngitis 0 0.0 0 0.0 0 0.0 1 16.7 0 0.0 0 0.0Upper respiratory tract infection 0 0.0 0 0.0 0 0.0 0 0.0 1 5.9 0 0.0Viral infection 0 0.0 0 0.0 0 0.0 0 0.0 1 5.9 0 0.0Viral upper respiratory tractinfection

0 0.0 0 0.0 1 16.7 0 0.0 0 0.0 0 0.0

SOC total 0 0.0 0 0.0 1 16.7 1 16.7 3 17.6 0 0.0 Nervous system disordersHeadache 0 0.0 1 33.3 0 0.0 0 0.0 2 11.8 1 5.6Sciatica 0 0.0 0 0.0 1 16.7 0 0.0 0 0.0 0 0.0SOC total 0 0.0 1 33.3 1 16.7 0 0.0 2 11.8 1 5.6

Gastrointestinal disordersCheilitis 1 33.3 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0Glossodynia 0 0.0 0 0.0 0 0.0 1 16.7 0 0.0 0 0.0Nausea 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 1 5.6SOC total 1 33.3 0 0.0 0 0.0 1 16.7 0 0.0 1 5.6

Neoplasms benign, malignant and unspecified (incl cysts andpolyps)Basal cell carcinoma 1 33.3 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0

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LP0084-1013 20-Aug-2015 Page 28 of 54

Table 9 Adverse events by SOC and preferred term (gel): safety analysis set, continued

Gel 0.0015(n=3)

Gel 0.003(n=3)

Gel 0.006(n=6)

Gel 0.012(n=6)

Gel 0.018(n=17)

Gel 0.025(n=18)

System Organ Class (SOC)Preferred Term1 n2 % n2 % n2 % n2 % n2 % n2 %

Neoplasms benign, malignant and unspecified (incl cysts andpolyps)Breast cancer 0 0.0 0 0.0 0 0.0 0 0.0 1 5.9 0 0.0Squamous cell carcinoma of skin 0 0.0 0 0.0 1 16.7 0 0.0 0 0.0 0 0.0SOC total 1 33.3 0 0.0 1 16.7 0 0.0 1 5.9 0 0.0

Renal and urinary disordersHaematuria 0 0.0 0 0.0 0 0.0 1 16.7 0 0.0 0 0.0Polyuria 1 33.3 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0SOC total 1 33.3 0 0.0 0 0.0 1 16.7 0 0.0 0 0.0

Blood and lymphatic system disordersLymphadenopathy 0 0.0 0 0.0 0 0.0 1 16.7 0 0.0 0 0.0SOC total 0 0.0 0 0.0 0 0.0 1 16.7 0 0.0 0 0.0

InvestigationsHepatic enzyme increased 0 0.0 0 0.0 0 0.0 0 0.0 1 5.9 0 0.0SOC total 0 0.0 0 0.0 0 0.0 0 0.0 1 5.9 0 0.0

Respiratory, thoracic and mediastinal disordersSinus congestion 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 1 5.6SOC total 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 1 5.6

Skin and subcutaneous tissue disordersRash 0 0.0 0 0.0 0 0.0 1 16.7 0 0.0 0 0.0SOC total 0 0.0 0 0.0 0 0.0 1 16.7 0 0.0 0 0.0

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Table 9 Adverse events by SOC and preferred term (gel): safety analysis set, continued

Gel 0.0015(n=3)

Gel 0.003(n=3)

Gel 0.006(n=6)

Gel 0.012(n=6)

Gel 0.018(n=17)

Gel 0.025(n=18)

System Organ Class (SOC)Preferred Term1 n2 % n2 % n2 % n2 % n2 % n2 %

Vascular disordersHypertension 0 0.0 0 0.0 0 0.0 0 0.0 1 5.9 0 0.0SOC total 0 0.0 0 0.0 0 0.0 0 0.0 1 5.9 0 0.0

Total number of adverseevents3

7 3 9 14 19 17

Total number of subjects 3 100.0 1 33.3 5 83.3 5 83.3 11 64.7 11 61.1

27APR15:11:26:24 LP0084 1013 t03 ae soc pt gel.doc

1) Classification according to MedDRA version 15.1.2) n=Number of subjects.3) Different adverse events within the same preferred term and system organ class and involving the same subject

have been counted as one. A single subject could appear in multiple classes.

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Table 10 Number of subjects with Administration Site Reactions by intensity (gel): safety analysis set

Gel 0.0015(n=3)

Gel 0.003(n=3)

Gel 0.006(n=6)

Gel 0.012(n=6)

Gel 0.018(n=17)

Gel 0.025(n=18)

Intensity n1 n1 n1 n1 n1 n1

Severe 0 0 0 0 0 0Moderate 1 1 3 4 3 8Mild 1 0 1 1 2 2Total 2 1 4 5 5 10

20APR15:12:00:44 LP0084 1013 t07_Adm_reac_gel.doc

1) n=Number of subjects.

LP0084-1013 20-Aug-2015 Page 31 of 54

5.2 Deaths, other Serious Adverse Events, and other Significant Adverse

Events

Narratives of SAEs and other significant adverse events are provided end-of-text, Section 8.

No deaths were reported.

5.2.1 Serious Adverse Events

Two subjects had 1 SAE each: SCC of skin (inside treatment area) and breast cancer (non-

cutaneous). Both were assessed as not related to treatment and the treatment was gel for both

subjects.

Subject Number had an SAE (basal cell carcinoma) that was downgraded to AE (AK)

and is thus not reported as an SAE.

For end-of-text narratives, see Section 8.1.

5.2.2 Other Significant Adverse Events

Five subjects (3 in the gel cohorts and 2 in the cream cohorts) discontinued treatment with

investigational product due to AEs after the first application but remained in the trial

(Appendix 2.7 [Part 1], Listing 0-3). Out of these, 1 subject (Subject Number ) had

application site pain, conjunctival hyperaemia, and application site discomfort; 2 subjects

(Subject Numbers and ) had application site pain only; 1 subject (Subject Number

) had eyelid oedema, and 1 subject (Subject Number ) had application site erythema

and application site discolouration (Appendix 2.7 [Part 1], Listings 7-1 and 0-3). Note that the

AE form in the CRF for Part 1 did not contain a specific field to record that the reported AE

lead to discontinuation from treatment. All AEs leading to discontinuation from treatment are

thus based on the investigator comments in the CRF (Appendix 2.7 [Part 1], Listing 0-3). For

Subject Numbers and the AEs leading to discontinuation from treatment were not

specified in the investigator comments and each narrative thus contains all AEs reported

during Day 1 and 2.

For end-of-text narratives, see Section 8.2.

5.3 Local Skin Responses

Figure 1 (gel) and Figure 3 (cream) illustrate the tendency towards an increase in maximum

composite LSR score with increasing dose, from 7 (0.0015% cohort) to 17 (0.025% cohort)

for gel and from 6 (0.0015% cohort) to 13 (0.012% cohort) for cream. Individual LSR

measurements are in Appendix 2.7 (Part 1), Listing 7-4.

PPI

PPI

PPI PPIPPI PPI

PPI PPI

LP0084-1013 20-Aug-2015 Page 32 of 54

Figure 1 Maximum composite LSR score during Week 1 by cohort: safety analysis set (gel): safety analysis set

5.3.1 Dose-limiting Toxicities

The objective of Part 1 was to identify MTD levels of LEO 43204 gel and cream, after once

daily treatment for 2 consecutive days. The MTD was defined as the highest dose level with

less than 4 out of 12 subjects (cohorts 1 to 4) or less than 6 out of 18 subjects (cohorts 5 and

6) experiencing a DLT. The number of subjects in each cohort depended on the number of

observed DLTs; however, the MTD was always to be confirmed in a cohort of 12 or 18

subjects. LEO 43204 formulated as cream was originally part of the trial objectives but testing

was discontinued after cohort 4 (0.012%) due to CMC development issues with the cream

formulation, which did not affect the quality of the investigational medicinal product in this

trial and therefore have no consequences for the analysis and interpretation of the collected

data (detailed description in Section 8.3 of the clinical study protocol). Therefore, tables and

figures for the cream formulation are presented end-of-text. The dose escalation rules are

presented in Figure 2, an overview of DLTs in Table 11 (gel) and Table 20 (cream), and

individual DLT measurements in Appendix 2.7 (Part 1), Listing 7-4.

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Figure 2 Dose Escalation Rules

Cohorts 1 to 3

LEO 43204 in gel or cream formulation was administered to subjects in cohort 1 (0.0015%) to

cohort 3 (0.006%) with no DLTs.

Cohort 4

LEO 43204, 0.012% was administered in gel or cream formulation. Two subjects receiving

the cream formulation had DLTs and no DLTs were reported for the gel formulation. Hence, 6

additional subjects were treated with LEO 43204 cream, 0.012% (according to protocol) and

1 DLT was observed. Out of the 3 subjects with DLTs 2 subjects did not get the second

administration of treatment (see Section 5.2.2 and Appendix 2.7 [Part 1], Listing 0-3). One of

LP0084-1013 20-Aug-2015 Page 34 of 54

the subjects with discontinued treatment (Subject Number ) also had LSR component

‘swelling’ of grade 4 (Appendix 2.7 [Part 1], Listing 0-4).

Sponsor’s decision to discontinue dose-escalation with the cream formulation was not based

on the results in the first 4 cohorts, but due to CMC development problems, as described in

the first paragraph of Section 5.3.1. The gel cohort was moved forward to the next dose level.

Due to high variability in LSRs in the first 4 cohorts it was decided from cohort 5 and

onwards to increase the number of subjects per cohort from 6 (with a possible extra 6) to 9

(with a possible extra 9) to reduce variability. Thus, the MTD was defined as the dose with an

occurrence of less than 6 DLTs among 18 subjects instead of less than 4 DLTs among 12

subjects.

Cohort 5

LEO 43204, 0.018% was administered in gel formulation only, due to the sponsor’s decision

to discontinue treatment with the cream formulation (see first paragraph of Section 5.3.1). No

DLTs were reported. One subject did not receive the second treatment administration, as

decided by the investigator, due to LSRs that did not meet the DLT criteria (see Appendix 2.7

[Part 1], Listing 0-4).

Cohort 6

In cohort 6 (0.025%) 2 of the first 9 subjects had DLTs and 2 subjects did not receive the

second treatment administration but did not meet the DLT criteria: 1 subject refused treatment

due to bilateral eyelid oedema and 1 subject had a application site erythema and did not

receive second dose as per investigator decision (see Section 5.2.2). As 2 subjects had DLTs

and 2 subjects did not receive the second dose it was decided to extend the cohort with 9

additional subjects to gain more confidence with the 0.025% dose before further dose

escalation. In this extended cohort, 4 more subjects had DLTs, i.e. 6 subjects in total for the 18

subjects in the cohort. In addition, 1 subject did not receive the second dose due to application

site pain, but it was decided that the subject was to remain in the trial (Appendix 2.7 [Part 1],

Listing 0-3). Thus, the dose escalation was stopped at this point in accordance with the

predefined stopping criteria and the MTD was confirmed at the 0.018% dose by extending

cohort 5 with an additional 8 subjects. According to the clinical study protocol 9 subjects were

to be included in this extended cohort, but the last subject was not included as none of the first

8 subjects had a DLT. As none of the subjects in the extended cohort 5 had DLTs the MTD

was 0.018%.

Doses to be used in Part 2

It was decided to move forward with the MTD dose (0.018%) and 2 doses below in Part 2.

PPI

LP0084-1013 20-Aug-2015 Page 35 of 54

Hence, the doses to be used in Part 2 were the following: 0.018%, 0.012%, 0.006%, and

vehicle.

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Table 11 DLTs by cohort (gel): safety subjects analysis set

Gel 0.0015(n=3)

Gel 0.003(n=3)

Gel 0.006(n=6)

Gel 0.012(n=6)

Gel 0.018(n=17)

Gel 0.025(n=18)

Did subject experience a DLT? n1 % n1 % n1 % n1 % n1 % n1 %

No 3 100.0 3 100.0 6 100.0 6 100.0 17 100.0 12 66.7Yes 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 6 33.3Total 3 100.0 3 100.0 6 100.0 6 100.0 17 100.0 18 100.0

21MAY15:09:53:40 LP0084 1013 t05 dlt gel.doc

1) n=Number of subjects.

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5.4 Vital Signs, Physical Findings and other Observations Related to Safety

5.4.1 Vital Signs and Physical Findings

Vital sign monitoring showed no findings of concern. Listings are in Appendix 2.8 (Part 1),

Listing 8-3.

5.4.2 ECG Assessments

The ECG assessments were analysed by a central CRO and the results evaluation and

conclusion is presented in a separate ECG Safety Report. The ECG analysis assessed the

change in ECG recordings from baseline to Day 1, Day 3, and Week 2, respectively, for all

dose cohorts and formulations. A listing with individual ECG measurements is in

Appendix 2.8 (Part 1), Listing 8-4.

A small increase in QTcF was noted on Day 3 in the 3 higher dose groups receiving the gel

formulation of LEO 43204. It should be noted that group sizes were rather small and there

was no obvious relationship to the dose administered regarding this effect. Furthermore, no

evidence for an effect of LEO 43204 on QTcF was observed after application of the cream

formulation.

5.5 Clinical Laboratory Evaluation

One subject (Subject Number ) in the LEO 43204 gel, 0.018% group had severe elevated

hepatic enzymes that were non-related to medication and the event was recovered/resolved.

No other subjects had abnormal laboratory measurements of concern and thus, clinical

laboratory evaluations showed no findings of concern. Haematology and biochemistry

parameters are available in Appendix 2.8 (Part 1), Listings 8-1 and 8-2 and Appendix 2.7

(Part 1), Listing 7-1).

PPI

LP0084-1013 20-Aug-2015 Page 38 of 54

6 Overall Conclusions of Part 1

The trial population consisted of primarily old men with fair skin. The median duration of

AK was 5 to 6 years (gel and cream), most subjects had a history of AK treatment and the

most common AK treatments were cryo/liquid nitrogen and 5-fluorouracil (Section 3.5)

The maximum post-baseline composite LSR score had a tendency towards an increased

score with increasing dose for both gel and cream cohorts (Section 5.3)

Based on pre-defined criteria, the MTD of LEO 43204 gel formulation in the 2-day

treatment regimen was 0.018%. As per protocol, the MTD dose (0.018%) and 2 lower

dose levels (0.006% and 0.012%) were taken forward into Part 2 of the trial (Section

5.3.1)

There were no deaths; 2 subjects had 1 SAE each: SCC of skin and breast cancer; and 5

subjects discontinued treatment due to AEs (Section 5.2)

All cohorts for both gel and cream had subjects with AEs, most AEs were related to

treatment, approximately half of the subjects had administration site reactions, and

relatively few AEs were of severe intensity (Section 5.1.3)

Vital signs and laboratory monitoring showed no evidence of safety concern (Sections 5.4

and 5.5)

ECG monitoring showed no association between LEO 43204 treatment and evidence of

cardiac effects (Section 5.4.2)

LP0084-1013 20-Aug-2015 Page 39 of 54

7 References

1. ICH E3. Structure and Content of Clinical Study Reports. November 1995

2. ICH E3 (R1). ICH E3 Guideline: Structure and Content of Clinical Study Reports

Questions and Answers. July 2012

3. ICH E6 (R1). Guideline for Good Clinical Practice. June 1996

4. ICH E9. Statistical Principles for Clinical Trials. February 1998

5. M4E(R1). The Common Technical Document for the Registration of Pharmaceuticals

for Human Use Efficacy. September 2002

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8 Narratives – Part 1

8.1 Serious Adverse Events

Narratives for 2 SAEs are reported below. The SAE of subject number was changed

from BCC to SCC, as confirmed by biopsy after SAE reconciliation had been performed.

Subject Number ; Squamous Cell Carcinoma of Skin (moderate)

This case concerns a . Treatment with LEO 43204 gel, 0.006% once daily

topically was started on and stopped on , as per protocol. The

treatment was administered on the full face.

Medical history included from in ,

in , and in , and

in .

Current medical conditions included on

, on

, starting in , starting in ,

starting in , starting on ,

starting in , and starting in .

Concomitant medication included since for

, , since for , and

, since for

.

The subject had a lesion that could be possible basal cell carcinoma within the treatment area

at Visit 7 on , 49 days after the last dose of the investigational

product. At Baseline the lesion appeared to be actinic keratosis. During the treatment period

the lesion eroded and continued to enlarge. The subject was advised to have a biopsy by the

dermatologist and was examined at the primary dermatologist's office on . The

physician assistant did a shave biopsy of the right forehead to rule out basal cell carcinoma.

The histological diagnosis was that of well differentiated, transected squamous cell

carcinoma. The subject was scheduled for follow up with the primary dermatologist's office.

Treatment with investigational product was completed according to protocol.

At the time of reporting the outcome of the event squamous cell carcinoma was

not resolved and the subject was awaiting Moh's surgery.

PPI

PPI

60-70 year-old

Day 1 Day 2

PPI PPIPPI PPI PPI

PPI PPIPPI PPI PPI PPI

PPI PPI PPIPPI

PPI PPI PPI PPI PPIDay -21 PPI PPI PPI PPI PPI PPI PPIDay -550 PPI PPI PPI PPI PPI PPI

PPI PPI PPI Day -22 PPI PPI PPI PPIPPI PPI PPI PPI

PPI PPI PPI PPIPPI PPI PPI PPI PPI PPI PPIPPI PPI PPI PPI PPI PPI PPI PPI PPIPPI

Day 50

PPI

Day 54

PPD

PPD

LP0084-1013 20-Aug-2015 Page 41 of 54

Causality as per investigator: not related. The non-trial related cause was provided as

excessive UV radiation exposure.

Causality as per sponsor: not related.

Subject Number ; Breast Cancer (mild)

This case concerns a . Treatment with LEO 43204 gel, 0.018% once daily

topically was started on and ended on according to protocol. The

treatment was administered on the full face.

The subject's medical history included ,

, , , , ,

, , and

.

Concomitant medication included , , for ;

, for ; ,

; , for ; ,

for ; , for

and , and , for .

The subject was diagnosed with right breast invasive ductal carcinoma on , 13

days after first dose of investigational product. The subject did not receive treatment for

invasive ductal carcinoma.

On the subject underwent right needle-directed lumpectomy x2 with right

sentinel lymph node mapping and biopsy. Lymph node was sent for frozen sectioning. The

lymph node was noted to be negative and the two wide local excision specimens were also

noted to be with evidence of clip in the central portion. The pathologist confirmed that the

gross margins were clear. No complications during procedure.

The following tests were performed: right ultrasound core biopsy was performed on

.

At the time of reporting, the event was ongoing, and the final event outcome was reported as

not recovered.

Causality as per investigator: not related

Causality as per sponsor: not related

70-80 year-old

PPI

Day 1 Day 2

PPI PPI PPI PPI PPIPPI PPI PPI PPI PPI PPI PPIPPI PPI PPI PPI PPI PPI PPI PPI

PPI PPI PPI

PPI PPI PPI PPIPPI PPI PPI PPI PPI PPIPPI PPI PPI PPI PPI PPI PPIPPI PPI PPI PPI PPI PPI PPI PPIPPI PPI PPI PPI PPI PPI PPI

Day 14

Day 79

Day 14

PPD

PPD

LP0084-1013 20-Aug-2015 Page 42 of 54

8.2 Other Significant Adverse Events

Discontinuation from Treatment due to Adverse Event

Note that the CRF did not contain a specific section to report AEs leading to discontinuation

from treatment. The narratives below are based on the investigator comments in the CRF, and

for Subject Numbers and the AEs leading to discontinuation from treatment were

not specified and each narrative thus contains all AEs reported during Day 1 and 2. For

listings, see Appendix 2.4 [Part 1], Appendix 2.5 [Part 1], Appendix 2.6 [Part 1], and

Appendix 2.7 [Part 1].

Subject ; Application Site Pain, Conjunctival Hyperaemia, and Application Site

Discomfort (all moderate)

This case concerns a . The subject was treated with LEO 43204 cream,

0.012%, once . The treatment was administered on full face.

The subject discontinued treatment after the first treatment due to AEs. The AE terms of the

AEs leading to discontinuation of treatment were not defined in the investigator comment in

the CRF and this narrative thus contains all AEs reported during Day 1 and 2. Application site

pain (LLT application site burning) started , and both conjunctival hyperaemia

and application site discomforted started , and could have impacted the decision

to discontinue treatment. The stop dates of the events were , , and

, respectively.

The outcome of all events was recovered/resolved.

Causality as per investigator: probable for all events.

Subject ; Application Site Pain (moderate)

This case concerns a . The subject was treated with LEO 43204 gel, 0.025%,

once . The treatment was administered on full face.

The subject discontinued treatment due to intense exzematous reaction according to the

investigator comment. Application site pain (LLT application site burning) was the only AE

reported for this subject, with start and stop date .

The outcome of the event was recovered/resolved.

Causality as per investigator: probable.

PPI PPI

PPI

40-50 year-old

Day 1

Day 1Day 2

Day 6 Day 8Day 6

PPI

>60-year-oldDay 1

Day 1

LP0084-1013 20-Aug-2015 Page 43 of 54

Subject ; Application Site Pain (severe)

This case concerns a . The subject was treated with LEO 43204 cream,

0.012%, once . The treatment was administered on full face.

The subject discontinued treatment due to burning pain and swelling (involving eyelids and

lips) according to the investigator comment. Application site pain (LLT application site

burning) was the only AE related to the investigator comment, and had start date

. The stop date of the event was .

The outcome of the event was recovered/resolved.

Causality as per investigator: probable.

Subject ; Eyelid Oedema (moderate)

This case concerns a . The subject was treated with LEO 43204 gel, 0.025%,

once . The treatment was administered on full face.

The subject discontinued treatment due to bilateral eyelid oedema according to the

investigator comment. The only AE reported for the subject was eyelid oedema with start date

and stop date .

The outcome of the event was recovered/resolved.

Causality as per investigator: probable.

Subject ; Application Site Erythema and Application Site Discolouration (both

moderate)

This case concerns an . The subject was treated with LEO 43204 gel,

0.025%, once . The treatment was administered on full face.

The subject discontinued treatment due to side effects, according to the investigator comment.

The AE terms of the AEs leading to discontinuation of treatment were not defined in the

investigator comment in the CRF and this narrative thus contains all AEs reported during

Day 1 and 2. Application site erythema and application site discolouration both started

and stopped , and could have impacted the decision to discontinue

treatment.

The outcome of both events was recovered/resolved.

PPI

PPI

50-60 year-oldDay 1

Day 1 Day 6

<80 year-oldDay 1

Day 15Day 1

PPI

80-90 year-oldDay 1

Day 1 Day 15

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Causality as per investigator: possible for both events.

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9 End-of-Text Tables and Figures

Table 12 Age overall and by cohort (cream): evaluable subjects analysis set

Total(n=24)

Cream 0.0015(n=3)

Cream 0.003(n=3)

Cream 0.006(n=6)

Cream 0.012(n=12)

Age (years) Median 69.0 63.0 77.0 55.0 69.0Minimum 40 63 71 52 40Maximum 82 72 82 78 82Number 24 3 3 6 12

20APR15:08:46:46 LP0084 1013 t02 age cream.doc

LP0084-1013 20-Aug-2015 Page 46 of 54

Table 13 Sex, race, ethnicity and skin type overall and by cohort (cream): evaluable subjects analysis set

Total(n=24)

n1

Cream 0.0015(n=3)

n1

Cream 0.003(n=3)

n1

Cream 0.006(n=6)

n1

Cream 0.012(n=12)

n1

SexMale 18 3 3 5 7Female 6 0 0 1 5Total 24 3 3 6 12

RaceWhite 24 3 3 6 12Total 24 3 3 6 12

EthnicityNot Hispanic or Latino 22 3 3 6 10Hispanic or Latino 2 0 0 0 2Total 24 3 3 6 12

Skin classificationType I 5 0 1 0 4Type II 11 2 2 5 2Type III 8 1 0 1 6Total 24 3 3 6 12

24APR15:15:08:32 LP0084 1013 t04 sex race etc cream.doc

1) n=Number of subjects.

LP0084-1013 20-Aug-2015 Page 47 of 54

Table 14 Duration of AK overall and by cohort (cream): evaluable subjects analysis set

Total(n=24)

Cream 0.0015(n=3)

Cream 0.003(n=3)

Cream 0.006(n=6)

Cream 0.012(n=12)

Duration of AK (years) Median 5.0 6.0 7.0 5.0 3.0Minimum 0 3 1 0 0Maximum 26 10 18 11 26Number 24 3 3 6 12

20APR15:08:47:42 LP0084 1013 t06 ak dur cream.doc

Table 15 AK treatment history overall and by cohort (cream): evaluable subjects analysis set

AK treatments

Total(n=24)

n1

Cream 0.0015(n=3)

n1

Cream 0.003(n=3)

n1

Cream 0.006(n=6)

n1

Cream 0.012(n=12)

n1

Cryo/liquid nitrogen 19 3 3 5 8Surgical excision/curettage 2 0 0 0 2Dermabrasion 0 0 0 0 0Medium or greater depth chemical peel 0 0 0 0 0Laser resurfacing 0 0 0 0 05-Fluorouracil 5 1 0 1 3Imiquimod 3 0 1 0 2Diclofenac 3 0 0 0 3Photodynamic therapy 3 1 0 1 1Retinoids 0 0 0 0 0Ingenol mebutate gel trunk and extremities 0 0 0 0 0Other 1 0 0 1 0

Total number of previous treatments 36 5 4 8 19

Total number of previously treated subjects

19 3 3 5 8

24APR15:15:26:33 LP0084 1013 t08 akhist cream.doc

1) n=Number of subjects.

LP0084-1013 20-Aug-2015 Page 48 of 54

Table 16 Skin disease history overall and by cohort (cream): evaluable subjects analysis set

Total(n=24)

Cream 0.0015(n=3)

Cream 0.003(n=3)

Cream 0.006(n=6)

Cream 0.012(n=12)

Preferred term1 n3 n3 n3 n3 n3

Photodermatosis 5 0 1 2 2 Basal cell carcinoma 4 1 0 0 3 Onychomycosis 4 0 1 1 2 Seborrhoeic keratosis 4 1 0 0 3 Malignant melanoma 3 0 1 0 2

Rosacea 3 0 0 1 2 Lentigo 2 1 0 0 1 Melanocytic naevus 2 1 0 0 1 Squamous cell carcinoma of skin 2 0 0 0 2 Tinea pedis 2 0 1 0 1

Acne 1 0 0 0 1 Actinic elastosis 1 0 0 0 1 Actinic keratosis 1 0 0 1 0 Alopecia 1 0 1 0 0 Dermatitis 1 0 0 0 1

Dermatitis contact 1 0 0 0 1 Excoriation 1 0 0 0 1 Lichen planus 1 0 0 0 1 Lichenoid keratosis 1 0 0 0 1 Neurodermatitis 1 0 0 0 1

Pruritus 1 0 0 0 1 Psoriasis 1 1 0 0 0 Purpura senile 1 0 0 0 1 Scar 1 0 0 0 1 Seborrhoea 1 0 0 0 1

Skin atrophy 1 1 0 0 0 Solar lentigo 1 0 0 0 1 Stasis dermatitis 1 0 1 0 0 Sunburn 1 0 0 1 0 Synovial cyst 1 0 0 0 1

Total number of diagnoses2 51 6 6 6 33

Total number of subjects 10 1 1 2 6

24APR15:15:37:30 LP0084 1013 t10 dishist cream.doc

1) Classification according to MedDRA version 15.1.2) Different diagnoses within the same preferred term and involving

the same subject have been counted as one. A subject could appear in multiple classes.3) n=Number of subjects.

LP0084-1013 20-Aug-2015 Page 49 of 54

Table 17 AK count at baseline overall and by cohort (cream): evaluable subjects analysis set

Total(n=24)

Cream 0.0015(n=3)

Cream 0.003(n=3)

Cream 0.006(n=6)

Cream 0.012(n=12)

Number of AK lesions Median 12.0 12.0 11.0 11.5 12.0Minimum 6 9 10 10 6Maximum 17 17 16 15 15Number 24 3 3 6 12

20APR15:08:50:02 LP0084 1013 t12 aklesions cream.doc

Table 18 Overall summary of adverse events (cream): safety analysis set

Cream 0.0015(n=3)

Cream 0.003(n=3)

Cream 0.006(n=6)

Cream 0.012(n=12)

Adverse event category AE1,2 n3 AE1,2 n3 AE1,2 n3 AE1,2 n3

All adverse events 1 1 1 1 3 2 20 8 Severe adverse events 0 0 0 0 0 0 2 2 Related adverse events 1 1 1 1 1 1 18 8 AEs leading to withdrawal from trial 0 0 0 0 0 0 0 0 SAEs 0 0 0 0 0 0 0 0 AEs leading to death 0 0 0 0 0 0 0 0

26MAR15:12:32:16 LP0084 1013 t02 summary cream.doc

1) AE=Number of adverse events.2) Different adverse events within the same preferred term and system organ class

and involving the same subject have been counted as one.3) n=Number of subjects.

LP0084-1013 20-Aug-2015 Page 50 of 54

Table 19 Adverse events by SOC and preferred term (cream): safety analysis set

Cream 0.0015(n=3)

Cream 0.003(n=3)

Cream 0.006(n=6)

Cream 0.012(n=12)

System Organ Class (SOC)Preferred Term1 n2 % n2 % n2 % n2 %

General disorders and administration site conditionsApplication site pain 0 0.0 1 33.3 0 0.0 5 41.7Application site erythema 0 0.0 0 0.0 1 16.7 3 25.0Application site pruritus 0 0.0 0 0.0 0 0.0 4 33.3Application site discomfort 0 0.0 0 0.0 0 0.0 1 8.3Application site warmth 0 0.0 0 0.0 0 0.0 1 8.3SOC total 0 0.0 1 33.3 1 16.7 8 66.7

Eye disordersConjunctival hyperaemia 0 0.0 0 0.0 0 0.0 1 8.3Periorbital oedema 0 0.0 0 0.0 0 0.0 1 8.3SOC total 0 0.0 0 0.0 0 0.0 2 16.7

Infections and infestationsUrinary tract infection 0 0.0 0 0.0 1 16.7 0 0.0Viral upper respiratory tractinfection

0 0.0 0 0.0 0 0.0 1 8.3

SOC total 0 0.0 0 0.0 1 16.7 1 8.3 Musculoskeletal and connective tissue disordersPain in extremity 0 0.0 0 0.0 0 0.0 1 8.3Spinal column stenosis 0 0.0 0 0.0 1 16.7 0 0.0

27APR15:11:27:39 LP0084 1013 t04 ae soc pt cream.doc Continued...

LP0084-1013 20-Aug-2015 Page 51 of 54

Table 19 Adverse events by SOC and preferred term (cream): safety analysis set, continued

Cream 0.0015(n=3)

Cream 0.003(n=3)

Cream 0.006(n=6)

Cream 0.012(n=12)

System Organ Class (SOC)Preferred Term1 n2 % n2 % n2 % n2 %

Musculoskeletal and connective tissue disordersSOC total 0 0.0 0 0.0 1 16.7 1 8.3

Gastrointestinal disordersCheilitis 0 0.0 0 0.0 0 0.0 1 8.3SOC total 0 0.0 0 0.0 0 0.0 1 8.3

Renal and urinary disordersRenal colic 0 0.0 0 0.0 0 0.0 1 8.3SOC total 0 0.0 0 0.0 0 0.0 1 8.3

Vascular disordersFlushing 1 33.3 0 0.0 0 0.0 0 0.0SOC total 1 33.3 0 0.0 0 0.0 0 0.0

Total number of adverseevents3

1 1 3 20

Total number of subjects 1 33.3 1 33.3 2 33.3 8 66.7

27APR15:11:27:39 LP0084 1013 t04 ae soc pt cream.doc

1) Classification according to MedDRA version 15.1.2) n=Number of subjects.3) Different adverse events within the same preferred term and system organ class and involving the same subject

have been counted as one. A single subject could appear in multiple classes.

LP0084-1013 20-Aug-2015 Page 52 of 54

Table 20 DLTs by cohort (cream): safety subjects analysis set

Cream 0.0015(n=3)

Cream 0.003(n=3)

Cream 0.006(n=6)

Cream 0.012(n=12)

Did subject experience a DLT? n1 % n1 % n1 % n1 %

No 3 100.0 3 100.0 6 100.0 9 75.0Yes 0 0.0 0 0.0 0 0.0 3 25.0Total 3 100.0 3 100.0 6 100.0 12 100.0

21MAY15:09:54:16 LP0084 1013 t06 dlt cream.doc

1) n=Number of subjects.

LP0084-1013 20-Aug-2015 Page 53 of 54

Table 21 Number of subjects with Administration Site Reactions by intensity (cream): safety analysis set

Cream 0.0015(n=3)

Cream 0.003(n=3)

Cream 0.006(n=6)

Cream 0.012(n=12)

Intensity n1 n1 n1 n1

Severe 0 0 0 2Moderate 0 0 1 5Mild 0 1 0 1Total 0 1 1 8

20APR15:12:00:24 LP0084 1013 t08_Adm_reac_cream.doc

1) n=Number of subjects.

LP0084-1013 20-Aug-2015 Page 54 of 54

Figure 3 Maximum composite LSR score during Week 1 by cohort (cream): safety analysis set

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LP0084-1013 Clinical Study Report Part 1 20-Aug-2015

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25-Aug-2015 22:47 GMT+0

Biostatistics Approval 27-Aug-2015 08:40 GMT+0

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