A Phase 1b, Open-label, Single-arm, Dose-selection, Proof-of-concept Study to Assess the Safety and Efficacy of a Novel HSP90 Inhibitor (CUDC-305) in the Treatment of Moderate to Severe Plaque Psoriasis
Phase: PHASE1
Conditions: Psoriasis Vulgaris
Sponsor: Aarhus University Hospital

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A PHASE 1b, OPEN-LABEL, SINGLE-ARM, DOSE-SELECTION, 
PROOF-OF-CONCEPT STUDY TO ASSESS THE SAFETY AND 
EFFICACY OF A NOVEL HSP90 INHIBITOR (CUDC-305) IN THE 
TREATMENT OF MODERATE TO SEVERE PLAQUE PSORIASIS  
 
 
 
 
 
PROTOCOL CUDC 305 
 
 
FINAL 
 
 
 
VERSION 4.0 
 22 June 2018 
 
 
 
 
 
 
 
Sponsor: 
 
 
Dr. Anne Bregnhøj 
 
 
 
 
Department of Dermatology 
 
 
 
 
Aarhus University Hospital 
 
 
 
 
P.P. Orums Gade 11 
 
 
 
 
DK-8000 Aarhus C 
 
 
 
 
Denmark  

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TABLE OF CONTENTS 
TABLE OF CONTENTS ................................................................................................................ 2 
SIGNATURE PAGE ...................................................................................................................... 5 
PRINCIPAL/QUALIFIED INVESTIGATOR SIGNATURE PAGE ............................................ 6 
LIST OF ABBREVIATIONS ......................................................................................................... 7 
SUMMARY .................................................................................................................................... 9 
1 
BACKGROUND .................................................................................................................. 15 
2 
STUDY OBJECTIVES ......................................................................................................... 17 
2.1 
Primary Objective ......................................................................................................... 17 
2.2 
Secondary Objectives .................................................................................................... 17 
3 
STUDY ENDPOINTS .......................................................................................................... 18 
3.1 
Primary Endpoint .......................................................................................................... 18 
3.2 
Secondary Endpoints .................................................................................................... 18 
4 
STUDY DESIGN.................................................................................................................. 19 
5 
STUDY POPULATION ....................................................................................................... 20 
5.1 
Inclusion Criteria .......................................................................................................... 20 
5.2 
Exclusion Criteria ......................................................................................................... 21 
5.3 
Discontinuations ........................................................................................................... 22 
6 
TREATMENT ...................................................................................................................... 24 
6.1 
Treatment Administration ............................................................................................. 24 
6.2 
Study Treatment ............................................................................................................ 24 
6.2.1 Description ................................................................................................................ 24 
6.2.2 Storage Conditions ................................................................................................... 24 
6.2.3 Study Product Dispensing and Return ...................................................................... 24 
6.2.4 Study Product Accountability ................................................................................... 24 
6.2.5 Rationale for Selection and Timing of Doses in the Study ........................................ 25 
6.2.6 Method of Assignment to Treatment Dose ................................................................ 25 
6.2.7 Safety Monitoring Rules ............................................................................................ 25 
6.2.8 Breaking of Study Blinding ....................................................................................... 25 
6.2.9 Assessment of Treatment Adherence ......................................................................... 25 
6.3 
Concomitant Therapy.................................................................................................... 26 
6.3.1 Permitted Therapies .................................................................................................. 26 
6.3.2 Prohibited Therapies or Procedures ........................................................................ 26 
7 
SCHEDULE OF EVENTS ................................................................................................... 28 
8 
STUDY ASSESSMENTS .................................................................................................... 31 

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8.1 
Efficacy Assessments .................................................................................................... 31 
8.1.1 Psoriasis Area and Severity Index ............................................................................ 31 
8.1.2 Physician’s Global Assessment ................................................................................. 31 
8.1.3 Body Surface Area .................................................................................................... 31 
8.1.4 Pruritus Numeric Rating Scale ................................................................................. 32 
8.2 
Quality-of-Life Assessments ........................................................................................ 32 
8.2.1 Dermatology Life Quality Index Questionnaire ....................................................... 32 
8.3 
Safety Assessments ....................................................................................................... 32 
8.3.1 Vital Signs ................................................................................................................. 32 
8.3.2 Physical Examination ............................................................................................... 32 
8.3.3 Clinical Laboratory Tests ......................................................................................... 33 
8.3.4 Electrocardiogram .................................................................................................... 34 
8.3.5 Chest X-Ray .............................................................................................................. 34 
8.4 
Other Assessments ........................................................................................................ 35 
8.4.1 Skin Biopsies ............................................................................................................. 35 
8.4.2 Medical Photography ................................................................................................ 35 
8.4.3 Blood Collection for Genetic Testing and PBMC IsolationFejl! Bogmærke er ikke 
defineret. 
8.4.4 Status of Psoriatic Arthritis ...................................................................................... 35 
9 
ADVERSE EVENTS ............................................................................................................ 36 
9.1 
Adverse Event Causality ............................................................................................... 36 
9.2 
Adverse Event Severity................................................................................................. 37 
9.3 
Serious Adverse Events ................................................................................................ 37 
9.3.1 SAE Reporting ........................................................................................................... 38 
9.4 
Pregnancy Reporting ..................................................................................................... 38 
10 SAMPLE SIZE AND STATISTICAL METHODS  ............................................................ 40 
10.1 
Determination of Sample Size ...................................................................................... 40 
10.2 
Statistical and Analytical Plans ..................................................................................... 40 
10.2.1 
Subject Disposition ............................................................................................... 40 
10.2.2 
Efficacy Analysis ................................................................................................... 40 
10.2.3 
Safety Analysis ...................................................................................................... 41 
10.2.4 
Interim Analysis .................................................................................................... 41 
11 DATA QUALITY ASSURANCE/SITE MONITORING .................................................... 42 
12 DATA COLLECTION AND RETENTION ........................................................................ 42 
13 CONFIDENTIALITY OF TRIAL DOCUMENTS AND SUBJECT RECORDS ............... 42 
14 INVESTIGATOR’S FILES AND RETENTION OF DOCUMENTS ................................. 42 
15 ETHICS................................................................................................................................. 43 
15.1 
Local Regulations/Declaration of Helsinki ................................................................... 43 

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15.2 
Ethical Review .............................................................................................................. 43 
15.3 
Informed Consent.......................................................................................................... 43 
16 PUBLICATION POLICY .................................................................................................... 44 
17 REFERENCES ..................................................................................................................... 45 
APPENDIX A: Psoriasis Area and Severity Index....................................................................... 47 
APPENDIX B: Numeric Rating Scale .......................................................................................... 48 
APPENDIX C: Dermatology Life Quality Index ......................................................................... 49 
 
 
 

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SIGNATURE PAGE 
The signatures below constitute the approval of this protocol and the attachments and provide the 
necessary assurances that this trial will be conducted according to local legal and regulatory 
requirements, and International Council for Harmonisation guidelines. 
 
 
Sponsor: 
 
 
Name (printed) 
 
Title 
 
 
Signature 
 
 
 Date (DD-MMM-YYYY) 
Director Scientific Affairs – 
Innovaderm: 
 
Name (printed) 
 
Title 
 
 
Signature 
 
 
 Date (DD-MMM-YYYY) 
 
Study Statistician: 
 
 
Name (printed) 
 
Title 
 
 
Signature 
 
 
 
 Date (DD-MMM-YYYY) 
 
 
 
 
 

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PRINCIPAL/QUALIFIED INVESTIGATOR SIGNATURE PAGE 
 
 
 
 
Investigator Name: 
 
 
 
 
Signature: 
 
Date: 
 
 
 
 
 
 
(DD-MMM-YYYY) 
 
Institution Name: 
 
 
 
 
 
By my signature, I agree to personally supervise the conduct of this study at my study site and to ensure 
its conduct is in compliance with the protocol, informed consent, Institutional Review 
Board/Independent Ethics Committee procedures, instructions from Innovaderm Research 
representatives, the Declaration of Helsinki, International Council for Harmonisation (ICH) Good 
Clinical Practice (GCP) Guidelines, and local regulations governing the conduct of clinical studies. 
 
 
 

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LIST OF ABBREVIATIONS 
 
AE 
adverse event 
ALT 
alanine aminotransferase 
anti-HBc  
anti–hepatitis B core antibodies 
AST 
aspartate aminotransferase 
ATP 
adenosine triphosphate 
ATPase 
adenosine triphosphatase 
β-hCG 
β-human chorionic gonadotropin 
BCG 
Bacillus Calmette–Guérin 
BMI 
body mass index 
Bpm 
beats per minute 
BSA 
body surface area 
BUN 
blood urea nitrogen 
CK 
creatine kinase 
CRF 
case report form 
CYP450 
cytochrome P450 
DLQI 
Dermatology Life Quality Index 
ECG 
electrocardiogram 
ET 
early termination (visit) 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyltransferase 
HBsAg 
hepatitis B surface antigens 
HBV  
hepatitis B virus 
HCT 
hematocrit 
HCV 
hepatitis C virus 
Hgb 
hemoglobin 
HIV  
human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICH 
International Council for Harmonisation 
IL 
interleukin 
IRB 
institutional review board 
ITT 
intent-to-treat (population) 
LDH 
lactate dehydrogenase 
LMW 
low molecular weight 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MPV 
mean platelet volume 
MTD 
maximum tolerated dose 
NRS 
Numeric Rating Scale  
NSAID 
nonsteroidal anti-inflammatory drug 
PASI 
Psoriasis Area and Severity Index 

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PBMC 
peripheral blood mononuclear cell  
PGA 
Physician’s Global Assessment 
PK 
pharmacokinetics 
PP 
per-protocol (population) 
PPD 
purified protein derivative  
RBC 
red blood cell (count) 
REB 
research ethics board 
RT-PCR 
reverse transcription polymerase chain reaction 
SAE 
serious adverse event 
SAF 
safety (population) 
TB 
tuberculosis 
TEAE 
treatment-emergent adverse events  
TNF 
tumor necrosis factor 
ULN 
Upper Limit of Normal 
WBC 
white blood cell (count) 
 
 
 

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SUMMARY 
 
Title: 
A Phase 1b, open-label, singlecenter, single-arm, dose-selection, proof-of-
concept study to assess the safety and efficacy of a novel HSP90 inhibitor 
(CUDC-305) in the treatment of moderate to severe plaque psoriasis 
  
Phase: 
1b 
 
Population: 
Approximately  12 and not exceeding 16 male or female subjects aged 18 
years or older with moderate to severe plaque psoriasis will be included in 
this study. 
 
Number of Sites: 
One center in Denmark will participate in this study.  
 
Study Duration: 
Subject participation will be approximately 20 weeks, involving a 4-week 
screening phase, a 12-week treatment phase, and a 4-week observational 
follow-up phase to assess for psoriasis relapse and flare.  
 
Objectives:   
 
Primary:  
 To determine the optimal efficacious dose-range of CUDC-305 in the treatment of moderate 
to severe plaque psoriasis in a Phase 1b proof-of-concept study 
 
Secondary:   
 
 To evaluate the safety and tolerability of CUDC-305 in the treatment of moderate to severe 
plaque psoriasis 
 To investigate changes in skin and blood biomarkers 
 
Endpoints: 
 
Primary Efficacy Endpoint:  
 Change from baseline in Psoriasis Area and Severity Index (PASI) score at Week 12 
Secondary Efficacy Endpoints:   
 
 Proportion of subjects with Physician’s Global Assessment (PGA) of clear or almost clear at 
Weeks 2, 4, 8, 12, and 16 
 Change and percent change from baseline in body surface area (BSA) covered with plaque 
psoriasis at Weeks 2, 4, 8, 12, and 16 
 Change and percent change from baseline in BSA multiplied by the PGA at Weeks 2, 4, 8, 
12, and 16 

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 Proportion of subjects achieving 50%, 75%, and 90% reduction from baseline in PASI at 
Weeks 2, 4, 8, 12, and 16 
 Change and percent change from baseline in PASI scores at Weeks 2, 4, 8, and 16 
 Percent change from baseline in PASI scores at Week 12 
 Change from baseline in pruritus Numeric Rating Scale (NRS) at Weeks 2, 4, 8, 12, and 16 
 Change from baseline in the Dermatology Life Quality Index (DLQI) total score at Weeks 4, 
8, 12, and 16 
 Change from baseline in skin and blood biomarkers at Weeks 4, 8, and 12 
Secondary Safety Endpoints: 
 Incidence of treatment-emergent adverse events (TEAEs)  
 Incidence of related TEAEs 
Overall Study Design: 
 
This is a 12-week treatment, singlecenter, open-label, single-arm, dose-selection, proof-of-concept 
study to determine a dosage of CUDC-305 that is tolerable and demonstrates preliminary efficacy 
for use in future efficacy Phase 2 trials. 
 
Eligible subjects will be sequentially assigned to one of the four cohorts (approximately n =  4 per 
cohort) receiving ascending or descending doses of CUDC-305. The first cohort will be 
administered a starting oral dose of 250 mg/d for 12 weeks, which is believed to be the target 
effective dose for treatment of psoriasis. The dose regimen to be administered to the subsequent 
cohort will be decided after reviewing the safety and efficacy data of the first four subjects 
completing the treatment period (12 weeks) in the current cohort. A safety meeting will take place 
to review the available data prior to deciding the next dose and then initiating dosing of the 
subsequent cohort. The doses that will be evaluated in this study range between 100 mg and 1000 
mg and may include: 100 mg, 250 mg, 500 mg, 800 mg, or 1000 mg orally once daily.  
 
The sponsor and principal investigator(s) will jointly evaluate the safety and tolerability of CUDC-
305 at the safety meeting, and intolerability will be determined by taking into account all 
information from adverse events (AEs), vital signs, physical examination findings, laboratory 
abnormalities, and electrocardiogram (ECG) findings. The study may be stopped permanently or 
interrupted at any time for safety reasons.  
 
PASI, PGA, BSA, pruritus NRS, and DLQI will be performed to assess efficacy. Safety will be 
assessed with the vital signs, physical examination, clinical laboratory tests, ECG, and collection 
of AEs. 
 
Skin biopsies will be collected from nonlesional and lesional skin for immunohistochemistry and 
gene expression analysis.  
 
 
Medical photographs of the target lesion will also be performed at each study visit (except the 
screening visit). 

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Inclusion Criteria: 
 
Subjects will be eligible to be enrolled in the study if they meet all of the following criteria at the 
screening and baseline (Day 0) visits, unless specified otherwise: 
 
1. Men or women aged 18 years or older at the time of consent.  
2. Subject has a history of plaque psoriasis for at least 6 months prior to the screening visit. 
3. Subject has stable psoriasis conditions for at least 3 months before screening, according to 
subject. 
4. Subject has plaque psoriasis covering ≥3% of his total BSA at baseline (Day 0). 
5. Subject has a PASI score of ≥6 at baseline (Day 0). 
6. Subject has a PGA score of ≥3 at baseline (Day 0). 
7. Subject has a body mass index (BMI) ≤40 kg/m2. 
8. Subject is a candidate for phototherapy or systemic treatement of psoriasis (either naïve or 
has a history of previous treatment).  
9. Subjects (women and men) involved in any sexual intercourse that could lead to pregnancy 
must agree to use an effective contraceptive method from at least 4 weeks before baseline 
(Day 0) until at least 4 weeks after the last study product administration for the duration of 
the study. Effective contraceptive methods are: systemic hormonal contraceptives (oral 
contraceptive, patch, vaginal ring, injectables, or implants), intrauterine devices, 
vasectomy, or barrier methods of contraception in conjunction with spermicide. Hormonal 
contraceptives must be on a stable dose for at least 4 weeks before baseline (Day 0).  
Note: Women of nonchildbearing potential are as follows:  
- 
Women who have had surgical sterilization (hysterectomy, bilateral oophorectomy, 
bilateral salpingectomy, or bilateral tubal ligation) 
- 
Women ≥60 years of age 
- 
Women >40 and <60 years of age who have had a cessation of menses for at least 
12 months and a follicle-stimulating hormone (FSH) test confirming 
nonchildbearing potential (FSH ≥40 mIU/mL) or cessation of menses for at least 
24 months without FSH levels confirmed 
10. Women of childbearing potential must have a negative serum pregnancy test at screening 
and negative urine pregnancy test at baseline (Day 0). 
11. Subject must have negative tuberculosis (TB) infection tests. Subject will be evaluated for 
latent TB infection with a purified protein derivative (PPD) test, T-spot test or a 
Quantiferon Gold test, and with a chest x-ray, if one has not been performed in the last 
6 months. Subject who demonstrates evidence of latent TB infection (either PPD greater 
than or equal to 5 mm of induration or positive Quantiferon Gold or T-spot test, irrespective 
of Bacillus Calmette–Guérin (BCG) vaccination status and negative chest x-ray findings 
for active TB, or suspicious chest x-ray findings) will not be allowed to participate in the 
study. 

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12. Subject must be willing to participate and must be capable of giving informed consent, and 
the consent must be obtained prior to any study-related procedures. 
Exclusion Criteria: 
 
Subjects will not be eligible for participation in the study if they meet any of the following criteria 
at the screening and baseline (Day 0) visits, unless specified otherwise: 
 
1. Female subject who is breastfeeding, pregnant, or who is planning a pregnancy during the 
study. 
2. Subject has evidence of erythrodermic, pustular, predominantly guttate psoriasis, or 
drug-induced psoriasis. 
3. Subject has a history of skin disease or presence of skin condition that, in the opinion of 
the investigator, would interfere with the study assessments. 
4. Subject is known to have immune deficiency or is immunocompromised. 
5. Subject has a history of cancer or lymphoproliferative disease within 5 years prior to 
baseline (Day 0). Subjects with successfully treated non-metastatic cutaneous squamous 
cell or basal cell carcinoma and/or localized carcinoma in situ of the cervix are not to be 
excluded. 
6. Subject has had a major surgery within 8 weeks prior to baseline (Day 0) or has a surgery 
planned during the study. 
7. Subject has any clinically significant medical condition or physical/laboratory/ECG/vital 
signs abnormality that would, in the opinion of the investigator, put the subject at undue 
risk or interfere with interpretation of study results. 
8. Subject has alanine aminotransferase (ALT) or aspartate aminotransferase (AST) values 
≥ 2 times the upper limit of normal (ULN) at screening. 
9. Subject has absolute neutrophil count ≤1,5 X 109/L or platelet count ≤100 X 109/L at 
screening. 
10. Subject has history of clinically significant anemia or hemoglobin (Hgb) value ≤ 10 g/dL 
at screening. 
11. Subject has a creatinine clearance ≤ 60 ml/min at screening (calculated with Cockcroft-
Gault formula) 
12. Subject with positive results for hepatitis B surface antigens (HBsAg), anti-hepatitis B core 
antibodies (anti-HBc), hepatitis C virus (HCV), or human immunodeficiency virus (HIV).  
13. Subject has a known or suspected allergy to CUDC-305 or any component of the 
investigational product. 
14. Subject has a history of clinically significant drug or alcohol abuse in the last year prior to 
baseline visit (Day 0). 

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15. Subject is currently receiving an investigational product or device or has received one 
within 4 weeks prior to baseline visit (Day 0). 
16. Subject has used biologics medication 12 weeks prior to baseline visit (Day 0), or 
5 half-lives (whichever is longer).  
17. Subject has used any systemic treatment for psoriasis (including corticosteroids, oral 
retinoids, immunosuppressive medication, methotrexate, cyclosporine, or apremilast) 
within 4 weeks prior to baseline visit (Day 0). 
18. Subject has used any topical medication to treat psoriasis (including corticosteroids; 
retinoids; vitamin D analogues, such as calcipotriol; or tar) within 2 weeks prior to baseline 
visit (Day 0). 
19. Subject had any UVB phototherapy (including tanning beds) or excimer laser within 
2 weeks prior to baseline visit (Day 0). 
20. Subject had PUVA treatment within 4 weeks prior to baseline visit (Day 0). 
21. Subject has received a live attenuated vaccine within 4 weeks prior to baseline visit (Day 0) 
or plan to receive a live attenuated vaccine during the study and up to 1 month after the last 
study drug administration.Subject had excessive sun exposure within 2 weeks prior to 
baseline visit (Day 0), or is planning a trip to a sunny climate, or is not willing to minimize 
natural and artificial sunlight exposure during the study. Use of sunscreen products and 
protective apparel are recommended for other circumstances when exposure cannot be 
avoided. Sunscreen must not be applied on the clinic visit days before the visit. 
22. Subject has a history of an allergic reaction or significant sensitivity to lidocaine or other 
local anesthetics. 
23. Subject has a history of hypertrophic scarring or keloid formation in scars or suture sites. 
24. Subject is taking anticoagulant medication, such as heparin, low molecular weight 
(LMW)-heparin, warfarin, antiplatelets (nonsteroidal anti-inflammatory drugs [NSAIDs] 
and low-dose aspirin that is equal or lower than 81 mg will not be considered antiplatelets), 
or has a contraindication to skin biopsies. 
Statistical Analysis: 
 
Because of the nature and design of the study, the statistical analysis will be mainly descriptive.  
 
Descriptive summaries of demographics, baseline characteristics, and subject disposition will be 
presented by dose regimen and overall. Continuous variables will be summarized by dose regimen 
and overall in tables and will include the number of subjects, mean, standard deviation, median, 
minimum, maximum, and range. Categorical variables will be presented by dose regimen and 
overall in tables as frequencies and percentages.  
 
No formal sample size calculations were conducted.  Four subjects will be enrolled into each 
cohort, for a total of  a maximum of 16 subjects. This sample size was selected to allow sufficient 
characterization of the drug’s safety profile over the planned doses range and to allow for 

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preliminary efficacy assessment of CUDC-305 in subjects with moderate to severe plaque 
psoriasis.  
 

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1 
BACKGROUND 
Psoriasis is a chronic inflammatory skin disease characterized by immune dysregulation of 
unknown etiology affecting over 25 million individuals worldwide (1, 2). Psoriasis can become 
debilitating and severely impact quality of life, well-being and personal interactions (3, 4). An 
estimated 25% of patients suffer moderate to severe disease forms that require systemic therapy 
with immune suppressants and ultraviolet phototherapy (5, 6). Despite advances in the 
development of targeted biologics including TNF, IL-12/23 and IL-17 inhibitors, most psoriasis 
patients remain inadequately treated and dissatisfied with the therapy they are receiving (7, 8). 
Due to the risk of serious adverse side effects associated with these therapies, patients are often 
required to alternate between various therapeutic modalities as a precautionary measure.  There 
is a pressing need for the clinical development of effective, safe, easy to use, and affordable 
psoriasis therapeutics that target the upstream proteomic mediators of the disease.  
 
Human psoriatic lesions display a profound upregulation of HSP90 as compared to normal skin 
which is thought to be partially associated with IL-17 production (9, 10). CUDC-305 (previously 
called Debio 0932) is a novel small molecule HSP90 inhibitor which displays promising 
pharmacological properties for  drug development in psoriasis such as good oral bioavailability, 
potent HSP90 inhibition, accumulation in the skin (as demonstrated in preclinical models), no 
ocular toxicity, a good safety profile (demonstrated in a Phase 1 oncology dose escalation study), 
a pharmacokinetic profile (high first-past metabolism) that permits rapid flexibility in terms of 
dose-control/ therapy discontinuation, and targeting of multiple upstream mediators of 
inflammatory pathways. Clinical investigation in psoriasis is supported by evaluation of anti-
psoriatic potential in human epidermal keratinocyte and monocytic cell lines showing that 
HSP90 inhibition with CUDC-305 is highly effective in inhibiting proliferation in keratinocytes 
and monocytes, and reducing the secretion of inflammatory cytokines in activated monocytes 
and T-cells.   
 
In clinically relevant animal models of psoriasis, oral delivery of CUDC-305 resulted in 
clinically significant alleviation of psoriasis, reduced epidermal thickness, and dramatic 
reduction in levels of TNFα and IL-17, pro-inflammatory cytokines linked to the persistence of 
psoriasis (11). Clinical safety of CUDC-305 has been validated in a CUDC-305 Phase 1 trial for 
oncology indication.  Interestingly during that study, a patient with severe psoriasis covering 
more than 40% of the skin surface showed complete remission  after 43 days of treatment with 
800 mg CUDC-305 daily (11). These serendipitous clinical findings in association with 
supporting preclinical data in three different murine clinical investigations support the clinical 
investigation of the safety and efficacy of CUDC-305 in the treatment of moderate to severe 
plaque psoriasis.  
 
The clinic lack of activity on pharmacodynamic markers, the lack of clear relationship between 
dose/exposure or toxicity/signs of activity, a high intra- and inter patient variability, lower than 
expected plasma levels based on pharmacological models and a poor oral availability despite a 
good absorption due to extensive metabolism were referenced in the Declaration of the End of 
Trial Form as reasons for the discontinuation of the trial: A Phase I-II evaluation of the safety and 
efficacy of the oral HSP90 inhibitor Debio-0932 in combination with standard of care in first- and 

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second-line therapy of patients with Stage IIIb or IV Non-small Cell Lung Cancer - the HALO 
study (HSP90 inhibition And Lung cancer Outcomes), during Part A.  It is important to highlight 
that this study was completed in patients with advanced cancers, specifically Stage IIIb and IV 
Non-small Cell Lung Cancer (NSCLC), where CUDC-305 administration was being evaluated in 
combination with cisplatin/pemetrexed and cisplatin/gemcitabine (naive Stage IIIb and IV NSCLC 
patients) or with docetaxel (previously treated Stage IIIb and IV NSCLC).  The proposed trial is 
designed as a dose-ranging trial in order to explore dose and define the maximum tolerated dose 
and viable Phase 2 doses in patients with moderate to severe psoriasis (the target population); a 
unique population that is quite disparate from that of previous trials.  Furthermore, discontinuation 
of the referenced Phase 2 studies were not based on safety concerns and that all safety observations 
from these studies  “were consistent with the previously observed side effects.”  Finally, preclinical 
studies found that CUDC-305 accumulated in dermal tissues versus plasma(11). In a xenograft 
mouse model of psoriasis daily dosing of CUDC-305 lead to plasma levels of ~2uM and skin levels 
of ~24 pmol/mg of wet tissue 30 minutes post-dosing on the final treatment day, representing a 
concentration in skin that exceeds the IC50 (~0.1 μM) of CUDC-305 for HSP90α/β (based on the 
assumption that 1mg of tissue equals 1 ml of biological fluid and taking in to account the 6% 
unbound plasma fraction of CUDC-305). This suggests that concerns with reduced efficacy being 
associated with poor oral bioavailability may be less relevant in dermal indications, such as 
psoriasis.  

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2 
STUDY OBJECTIVES 
2.1 Primary Objective 
The primary objective is as follows: 
 To determine the optimal efficacious dose-range of CUDC-305 in the treatment of moderate 
to severe plaque psoriasis in a Phase 1b proof-of-concept study 
2.2 Secondary Objectives 
The secondary objectives are as follows: 
 To evaluate the safety and tolerability of CUDC-305 in the treatment of moderate to severe 
plaque psoriasis 
 To investigate changes in skin and blood biomarkers 

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3 
STUDY ENDPOINTS 
3.1 Primary Endpoint 
The primary efficacy endpoint is as follows: 
 
 Change from baseline in Psoriasis Area and Severity Index (PASI) score at Week 12 
3.2 Secondary Endpoints 
The secondary endpoints are as follows: 
 
Efficacy Endpoints   
 
 Proportion of subjects with Physician’s Global Assessment (PGA) of clear or almost clear at 
Weeks 2, 4, 8, 12, and 16 
 Change and percent change from baseline in body surface area (BSA) covered with plaque 
psoriasis at Weeks 2, 4, 8, 12, and 16 
 Change and percent change from baseline in BSA multiplied by the PGA at Weeks 2, 4, 8, 
12, and 16 
 Proportion of subjects achieving 50%, 75%, and 90% reduction from baseline in PASI at 
Weeks 2, 4, 8, 12, and 16 
 Change and percent change from baseline in PASI scores at Weeks 2, 4, 8, and 16 
 Percent change from baseline in PASI scores at Week 12 
 Change from baseline in pruritus Numeric Rating Scale (NRS) at Weeks 2, 4, 8, 12, and 16 
 Change from baseline in the Dermatology Life Quality Index (DLQI) total score at Weeks 4, 
8, 12, and 16 
 Change from baseline in skin and blood biomarkers at Weeks 4, 8, and 12 
Safety Endpoints  
 Incidence of treatment-emergent adverse events (TEAEs)  
 Incidence of related TEAEs 
 
 

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4 
STUDY DESIGN  
This is a 12-week treatment,  singlecenter, open-label, single-arm, dose-selection, 
proof-of-concept study to determine a dosage of CUDC-305 that is tolerable and demonstrates 
preliminary efficacy for use in future efficacy Phase 2 trials. 
 
Eligible subjects will be sequentially assigned to one of the four cohorts (approximately n =  4 per 
cohort) receiving ascending or descending doses of CUDC-305. The first cohort will be 
administered a starting oral dose of 250 mg/d for 12 weeks, which is believed to be the target 
effective dose for treatment of psoriasis. The dose regimen to be administered to the subsequent 
cohort will be decided after reviewing the safety and efficacy data of the first four subjects 
completing the treatment period (12 weeks) in the current cohort. A safety meeting will take place 
to review the available data prior to deciding the next dose and then initiating dosing of the 
subsequent cohort. The doses that will be evaluated in this study range between 100 mg and 1000 
mg and may include: 100 mg, 250 mg, 500 mg, 800 mg, or 1000 mg orally once daily.  
 
 
The sponsor and principal investigator(s) will jointly evaluate the safety and tolerability of CUDC-
305 at the safety meeting, and intolerability will be determined by taking into account all 
information from adverse events (AEs), vital signs, physical examination findings, laboratory 
abnormalities, and electrocardiogram (ECG) findings. The study may be stopped permanently or 
interrupted at any time for safety reasons.  
 
PASI, PGA, BSA, pruritus NRS, and DLQI will be performed to assess efficacy. Safety will be 
assessed with the vital signs, physical examination, clinical laboratory tests, ECG, and collection 
of AEs. 
 
Skin biopsies will be collected from nonlesional and lesional skin for immunohistochemistry and 
gene expression analysis.  
 
 
Medical photographs of the target lesion will also be performed at each study visit (except the 
screening visit). 
 
A schedule of events is presented in Section 7. 
 

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5 
STUDY POPULATION  
This study will include approximately  16 subjects with moderate to severe plaque psoriasis. 
Subjects will be men or women, aged 18 years or older.  
 
Subjects who are discontinued after taking the first dose of study product will not be replaced. 
5.1 Inclusion Criteria 
Subjects will be eligible to be enrolled in the study if they meet all of the following criteria at the 
screening and baseline (Day 0) visits, unless specified otherwise: 
 
1. Men or women aged 18 years or older at the time of consent.  
2. Subject has a history of plaque psoriasis for at least 6 months prior to the screening visit. 
3. Subject has stable psoriasis conditions for at least 3 months before screening, according to 
subject. 
4. Subject has plaque psoriasis covering ≥3% of his total BSA at baseline (Day 0). 
5. Subject has a PASI score of ≥6 at baseline (Day 0). 
6. Subject has a PGA score of ≥3 at baseline (Day 0). 
7. Subject has a body mass index (BMI) ≤40 kg/m2. 
8. Subject is a candidate for phototherapy or systemic treatement of psoriasis (either naïve or 
has a history of previous treatment).  
9. Subjects (women and men) involved in any sexual intercourse that could lead to pregnancy 
must agree to use an effective contraceptive method from at least 4 weeks before baseline 
(Day 0) until at least 4 weeks after the last study product administration for the duration of 
the study. Effective contraceptive methods are: systemic hormonal contraceptives (oral 
contraceptive, patch, vaginal ring, injectables, or implants), intrauterine devices, 
vasectomy, or barrier methods of contraception in conjunction with spermicide. Hormonal 
contraceptives must be on a stable dose for at least 4 weeks before baseline (Day 0).  
Note: Women of nonchildbearing potential are as follows:  
- 
Women who have had surgical sterilization (hysterectomy, bilateral oophorectomy, 
bilateral salpingectomy, or bilateral tubal ligation) 
- 
Women ≥60 years of age 
- 
Women >40 and <60 years of age who have had a cessation of menses for at least 
12 months and a follicle-stimulating hormone (FSH) test confirming 
nonchildbearing potential (FSH ≥40 mIU/mL) or cessation of menses for at least 
24 months without FSH levels confirmed 
10. Women of childbearing potential must have a negative serum pregnancy test at screening 
and negative urine pregnancy test at baseline (Day 0). 

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11. Subject must have negative tuberculosis (TB) infection tests. Subject will be evaluated for 
latent TB infection with a purified protein derivative (PPD) test, T-spot test or a 
Quantiferon Gold test, and with a chest x-ray, if one has not been performed in the last 
6 months. Subject who demonstrates evidence of latent TB infection (either PPD greater 
than or equal to 5 mm of induration or positive Quantiferon Gold or T-spot test, irrespective 
of Bacillus Calmette–Guérin (BCG) vaccination status and negative chest x-ray findings 
for active TB, or suspicious chest x-ray findings) will not be allowed to participate in the 
study. 
12. Subject must be willing to participate and must be capable of giving informed consent, and 
the consent must be obtained prior to any study-related procedures. 
5.2 Exclusion Criteria 
Subjects will not be eligible for participation in the study if they meet any of the following criteria 
at the screening and baseline (Day 0) visits, unless specified otherwise: 
 
1. Female subject who is breastfeeding, pregnant, or who is planning a pregnancy during the 
study. 
2. Subject has evidence of erythrodermic, pustular, predominantly guttate psoriasis, or 
drug-induced psoriasis. 
3. Subject has a history of skin disease or presence of skin condition that, in the opinion of 
the investigator, would interfere with the study assessments. 
4. Subject is known to have immune deficiency or is immunocompromised. 
5. Subject has a history of cancer or lymphoproliferative disease within 5 years prior to 
baseline (Day 0). Subjects with successfully treated non-metastatic cutaneous squamous 
cell or basal cell carcinoma and/or localized carcinoma in situ of the cervix are not to be 
excluded. 
6. Subject has had a major surgery within 8 weeks prior to baseline (Day 0) or has a surgery 
planned during the study. 
7. Subject has any clinically significant medical condition or physical/laboratory/ECG/vital 
signs abnormality that would, in the opinion of the investigator, put the subject at undue 
risk or interfere with interpretation of study results. 
8. Subject has alanine aminotransferase (ALT) or aspartate aminotransferase (AST) values 
≥ 2 times the upper limit of normal (ULN) at screening. 
9. Subject has absolute neutrophil count ≤1,5 X 109/L or platelet count ≤100 X 109/L at 
screening. 
10. Subject has history of clinically significant anemia or hemoglobin (Hgb) value ≤ 10 g/dL 
at screening. 
11. Subject has a creatinine clearance ≤ 60 ml/min at screening (calculated with Cockcroft-
Gault formula) 

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12. Subject with positive results for hepatitis B surface antigens (HBsAg), anti-hepatitis B core 
antibodies (anti-HBc), hepatitis C virus (HCV), or human immunodeficiency virus (HIV).  
13. Subject has a known or suspected allergy to CUDC-305 or any component of the 
investigational product. 
14. Subject has a history of clinically significant drug or alcohol abuse in the last year prior to 
baseline visit (Day 0). 
15. Subject is currently receiving an investigational product or device or has received one 
within 4 weeks prior to baseline visit (Day 0). 
16. Subject has used biologics medication 12 weeks prior to baseline visit (Day 0), or 
5 half-lives (whichever is longer).  
17. Subject has used any systemic treatment for psoriasis (including corticosteroids, oral 
retinoids, immunosuppressive medication, methotrexate, cyclosporine, or apremilast) 
within 4 weeks prior to baseline visit (Day 0). 
18. Subject has used any topical medication to treat psoriasis (including corticosteroids; 
retinoids; vitamin D analogues, such as calcipotriol; or tar) within 2 weeks prior to baseline 
visit (Day 0). 
19. Subject had any UVB phototherapy (including tanning beds) or excimer laser within 
2 weeks prior to baseline visit (Day 0). 
20. Subject had PUVA treatment within 4 weeks prior to baseline visit (Day 0). 
21. Subject has received a live attenuated vaccine within 4 weeks prior to baseline visit (Day 0) 
or plan to receive a live attenuated vaccine during the study and up to 1 month after the last 
study drug administration.Subject had excessive sun exposure within 2 weeks prior to 
baseline visit (Day 0), or is planning a trip to a sunny climate, or is not willing to minimize 
natural and artificial sunlight exposure during the study. Use of sunscreen products and 
protective apparel are recommended for other circumstances when exposure cannot be 
avoided. Sunscreen must not be applied on the clinic visit days before the visit. 
22. Subject has a history of an allergic reaction or significant sensitivity to lidocaine or other 
local anesthetics. 
23. Subject has a history of hypertrophic scarring or keloid formation in scars or suture sites. 
24. Subject is taking anticoagulant medication, such as heparin, low molecular weight 
(LMW)-heparin, warfarin, antiplatelets (nonsteroidal anti-inflammatory drugs [NSAIDs] 
and low-dose aspirin that is equal or lower than 81 mg will not be considered antiplatelets), 
or has a contraindication to skin biopsies. 
5.3 Discontinuations 
Subjects have the right to withdraw from the study at any time for any reason without penalty. The 
investigator also has the right to withdraw subjects from the study if he or she feels it is in the best 
interest of the subject or if the subject is uncooperative or noncompliant.  
 

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Should a subject decide to withdraw, all efforts will be made to complete and report the 
observations as thoroughly as possible, particularly the follow-up examination. 
 
The investigator or one of his or her staff members should contact the subject to determine as 
completely as possible the reason for the withdrawal. A complete final evaluation at the time of 
the subject’s withdrawal should be made with an explanation of why the subject is withdrawing 
from the study. If the reason for removal of a subject is an AE or an abnormal laboratory test result, 
the principal specific event or test will be recorded. The criteria for enrollment must be followed 
explicitly. Subjects who discontinue the study after taking his or her first dose will be asked, if 
they agree, to come for a last assessment (early termination visit). Subjects who discontinue will 
not be replaced. 
 
Reasons for discontinuation include the following: 
 
The investigator decides that the subject should be withdrawn. If this decision is made because 
of a serious adverse event (SAE), the study product is to be discontinued immediately and 
appropriate measures are to be taken. The investigator will notify the sponsor immediately. 
 
The attending physician requests that the subject be withdrawn from the study. 
 
The subject, for any reason, requires treatment with another therapeutic agent that has been 
demonstrated to be effective for treatment of the study indication. In this case, discontinuation 
from the study occurs immediately upon introduction of the new agent. 
 
The subject is lost to follow-up. In this case, a reasonable attempt to contact the subject and 
ascertain his or her status must be made, and these attempts must be documented. 
 
The sponsor or regulatory authorities, for any reason, stop the study. In this case, all subjects 
will be discontinued from the study and notified of the reasons for the discontinuation. 
 
The subject has become pregnant at any time during the study.  
 
Other: the subject may withdraw from the study for any other reason, including withdrawal of 
consent. 

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6 
TREATMENT 
6.1 Treatment Administration 
Subjects who fulfill all of the inclusion criteria and none of the exclusion criteria will be accepted 
into the study. Each subject should read and sign an informed consent form prior to any screening 
procedures being performed. This study involves the investigational study product CUDC-305 
(also known as Debio 0932) administered orally once daily early in the morning for 12 weeks at 
approximately the same time (± 1 hour) every day. Various doses, starting at 250 mg and ranging 
between 100 mg to 1000 mg, will be administered in each cohort to determine the dose to be used 
in future efficacy Phase 2 trials in psoriasis.  
6.2 Study Treatment 
6.2.1 Description 
CUDC-305 is formulated as a round red coated tablet for daily oral administration containing 
various amounts of the active compound.  
6.2.2 Storage Conditions  
The study product will be provided by Regranion to the investigator. It will be kept on site in a 
secure, temperature-controlled place between 15°C and 30°C and will only be supplied to subjects 
in the trial under the supervision of the investigator. Room temperature on site will be monitored 
and recorded.  
6.2.3 Study Product Dispensing and Return 
The study product will be dispensed by the study site during the treatment period to the subject at 
each study visit (except at the Week 1 visit). Subjects are to return all study product (used and 
unused) to the study site at the Week 1, 2, 4, 6, 8, 10, and 12 visits. The number of capsules will 
be counted prior to dispensing and upon return, and the counts will be recorded in the source 
documents and case report form (CRF). Each subject is to be instructed on the importance of 
returning study product at the next study visit. If a subject does not return study product, he or she 
will be instructed to return it as soon as possible. 
6.2.4 Study Product Accountability  
The investigator is responsible for maintaining accurate records of the study product received 
initially and of the study product dispensed/used. After verification of the product accountability 
by the sponsor or designee, used product will be stored safely until destruction/return. Any study 
product accidentally or deliberately destroyed, or returned to the sponsor or designee will be 
accounted for. Any discrepancies between amounts dispensed and returned will be explained. 
 

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All study product accountability forms and treatment logs must be retained in the investigator’s 
study file. Product inventory and accountability records will be maintained as per Good Clinical 
Practice (GCP) and International Council for Harmonisation (ICH) guidelines. These records must 
be available for inspection at any time by the sponsor, its designees, or by regulatory agencies. 
6.2.5 Rationale for Selection and Timing of Doses in the Study 
The goal of this trial is to explore dose and define the recommended dose for future Phase 2 studies 
in psoriasis. Based on previously completed Phase 1 safety and pharmacokinetic analyses, the 
maximum tolerated dose (MTD) of CUDC-305 was determined to be 1,000 mg/d, thus defining 
the upper limit of this Phase 1b trial. The starting dose for this study will be 250 mg/d which 
corresponds to 1/4 of the MTD of the previous Phase 1 clinical study and is based on the NOAEL 
of the 28-day toxicity studies and cardiovascular assessment study in dogs. The doses that will be 
evaluated in this study range between 100 mg and 1000 mg and may include: 100 mg, 250 mg, 
500 mg, 800 mg, or 1000 mg orally once daily.  
6.2.6 Method of Assignment to Treatment Dose 
Eligible subjects will be sequentially assigned to one of the four cohorts (approximately n =  4 per 
cohort) receiving ascending or descending doses of CUDC-305. The first cohort will be 
administered a starting oral dose of 250 mg/d which is believed to be the target effective dose for 
treatment of psoriasis. The dose regimen to be administered to the subsequent cohort will be 
decided after reviewing the safety and efficacy data of the first four subjects completing the 
treatment period (12 weeks) in the previous cohort. The dose regimen of the subsequent cohort 
could be higher or lower, according the safety and efficacy data of the previous cohort. A safety 
meeting will take place to review the available data prior to deciding the next dose and then 
initiating dosing of the subsequent cohort. The study may be stopped permanently or interrupted 
at any time for safety reasons following review of study data.  
6.2.7 Safety Monitoring Rules 
If a severe AE or SAE is reported in any dose cohort, the study may be suspended pending review 
of the safety data or unless the investigator determines that the event is unrelated to the study 
product.  
The sponsor, in consultation with the investigator(s), may decide to stop or modify the dose 
escalation at any time for safety reasons following review of study data.  
6.2.8 Breaking of Study Blinding 
This is an open-label study, therefore no unblinding procedure is planned for this study. 
6.2.9 Assessment of Treatment Adherence 
Subject adherence to treatment with CUDC-305 will be assessed at each visit. Adherence to 
treatment will be assessed by direct questioning, review of the subject’s dosing diary, and by 

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maintaining adequate product dispensing records. Any deviation from the prescribed dosage 
regimen will be recorded in the source document and CRF. 
 
If there is a discrepancy between the subject dosing diary entries and the capsule count, assessment 
of treatment adherence will be based on the latter. 
 
Subjects who are significantly non-adherent to treatment will be counseled and could be 
discontinued from the study, at the discretion of the Investigator.  
6.3 Concomitant Therapy 
All medications (including over-the-counter drugs, vitamins, and antacids) taken within 4 weeks 
prior to screening and throughout the study must be recorded.  
 
Medication entries may be captured as generic or trade names. Trade names should be used for 
combination drugs. Entries will include the dose, unit, frequency of administration, route of 
administration, start date, discontinuation date, and indication. If the medication is discontinued or 
the dosage is changed, these details must be recorded. 
6.3.1 Permitted Therapies 
6.3.1.1 Emollients 
 
Subjects can apply a bland emollient of their choice, except emollients containing salicylic acid, 
on their skin including on psoriasis lesions during the entire duration of the study. Emollient must 
not be applied on the clinic visit days before the visit. 
 
Every effort should be made to keep the same emollient throughout the study. The complete 
commercial name of the selected emollient(s) will be recorded in the source document and the 
CRF. No other products may be applied to the lesions during the study.  
6.3.2 Prohibited Therapies or Procedures 
The following therapies are prohibited: 
 Use of biologics medication 12 weeks prior to baseline visit (Day 0), or 5 half-lives (whichever 
is longer) and throughout the study 
 Use of any systemic treatment for psoriasis (including corticosteroids, oral retinoids, 
immunosuppressive medication, methotrexate, cyclosporine, or apremilast) within 4 weeks 
prior to baseline visit (Day 0) and throughout the study 
 Use of any topical medication or topical medical devices to treat psoriasis (including 
corticosteroids; retinoids; vitamin D analogues, such as calcipotriol; or tar) within 2 weeks 
prior to baseline visit (Day 0) and throughout the study 
 Use of anticoagulant medication (e.g., heparin, LMW-heparin, warfarin, antiplatelets [NSAIDs 
and low-dose aspirin that is equal or lower than 81 mg will not be considered antiplatelets])  

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 Use of UVB phototherapy (including tanning beds) or excimer laser within 2 weeks prior to 
baseline visit (Day 0) 
 Use of PUVA treatment within 4 weeks prior to baseline visit (Day 0) 
 Excessive sun exposure within 2 weeks prior to baseline visit (Day 0), or planning a trip to a 
sunny climate, or is not willing to minimize natural and artificial sunlight exposure during the 
study. Use of sunscreen products and protective apparel are recommended when exposure 
cannot be avoided. Sunscreen must not be applied on the clinic visit days before the visit. 

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7 
SCHEDULE OF EVENTS 
The screening evaluation will only be performed after the subject has agreed to participate and has 
signed and dated the informed consent form. No treatment or trial-related procedures will be 
initiated before the informed consent is signed. The baseline (Day 0) visit must be performed, at 
the latest, 30 days after the screening visit. 
 
The screening evaluation will be performed according to the inclusion and exclusion criteria. If 
the subject fulfills all inclusion criteria and no exclusion criteria, he or she may be included in the 
study.  
 
Table 1 provides a description of the procedures to be performed at each visit. 

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Table 1: Schedule of Events  
 
Screening Baseline
/Day 0 
 
 
 
 
 
 
End of 
Treatment/ 
ET 
Follow-up 
Visit 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 
Week 
–4 
0 
1 
2 
4 
6 
8 
10 
12 
16 
 Day  
Window (days) 
–30 to –1 
Days 
0 
7  
1 Day 
14  
1 Day 
28  
2 Days 
42  
2 Days 
56  
2 Days 
70  
2 Days 
84  
2 Days 
112 
4 Days 
Informed consent  
X 
 
 
 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
 
 
Medical and surgical history, 
including smoking status and 
psoriatic arthritis evaluation1 
X 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
Pregnancy test2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
X 
 
 
X 
 
X 
 
X 
X3 
ECG 
X 
 
 
 
 
 
 
 
X 
X3 
Weight, height and BMI4 
X 
X 
 
 
 
 
 
 
X 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry and hematology laboratory 
panel 
X 
X 
 
 
X 
 
X 
 
X 
X3 
Serology (HBV, HCV, HIV) 
X 
 
 
 
 
 
 
 
 
 
Chest x-ray5 
X 
 
 
 
 
 
 
 
 
 
PPD, T-spot test or Quantiferon Gold5 
X 
 
 
 
 
 
 
 
 
 
PASI 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PGA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BSA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pruritus NRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
DLQI questionnaire 
 
X 
 
 
X 
 
X 
 
X 
X 
Psoriatic arthritis evaluation  
 
 
 
 
X 
 
X 
 
X 
X 
Identification of target lesion 
 
X 
 
 
 
 
 
 
 
 

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Screening Baseline
/Day 0 
 
 
 
 
 
 
End of 
Treatment/ 
ET 
Follow-up 
Visit 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 
Week 
–4 
0 
1 
2 
4 
6 
8 
10 
12 
16 
 Day  
Window (days) 
–30 to –1 
Days 
0 
7  
1 Day 
14  
1 Day 
28  
2 Days 
42  
2 Days 
56  
2 Days 
70  
2 Days 
84  
2 Days 
112 
4 Days 
Medical photographs of target lesion 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Collection of skin biopsies6 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study product administration on site 
 
X 
 
 
 
 
 
 
 
 
Study product dispensing 
 
X 
 
X 
X 
X 
X 
X 
 
 
Collect study product/study product 
accountability 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Subject dosing dairy 
distribution/collection/review 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events evaluation 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BMI = body mass index; BSA = body surface area; DLQI = Dermatology Life Quality Index; ECG = electrocardiogram; ET = early termination (visit); HBV = 
hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; NRS = Numeric Rating Scale; PASI = Psoriasis Area and Severity Index; 
PBMC = peripheral blood mononuclear cell; PGA = Physician’s Global Assessment; PPD = purified protein derivative. 
Note:  
1 Smoking status: never smoked, past smoker, active smoker. For past smoker and active smoker, record the number of years, number of cigarettes per day, 
and when applicable year stopped. 
2 Women of childbearing potential only; serum pregnancy test at the screening visit and urine pregnancy test at the other visits. 
3 Only if clinically significant changes are detected at Week 12. 
4 Height will be measured at screening visit only, and BMI will be calculated at screening and baseline (Day 0) visits. 
5 If one has not been performed in the last 6 months. 
6 Skin biopsies on nonlesional skin at baseline and on the target lesion at baseline, Week 4, Week 8, and Week 12 for gene expression and 
immunohistochemistry staining. 

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8 
STUDY ASSESSMENTS 
8.1 Efficacy Assessments 
Clinical evaluations of psoriasis will be performed by an experienced and qualified dermatologist 
(board certified or equivalent) or other suitably qualified and experienced designee. To assure 
consistency and reduce variability, the same assessor should perform all assessments on a given 
subject whenever possible. 
8.1.1 Psoriasis Area and Severity Index  
The Psoriasis Area and Severity Index (PASI) is a scale from 0 to 72 that is regularly used in 
plaque psoriasis studies (12, 13). Refer to APPENDIX A for a complete description of this scale. 
The PASI will be evaluated at the visits specified in Section 7. To be eligible for this study, subjects 
must have a PASI of ≥ 6 at baseline (Day 0). 
8.1.2 Physician’s Global Assessment  
The Physician’s Global Assessment (PGA) of disease severity will be assessed at the visits 
specified in Section 7. The PGA is a global assessment of the current state of the disease. It is a 
5-point morphological assessment of overall disease severity; assessment will be determined 
according to the following categories: 0 (clear), 1 (almost clear), 2 (mild), 3 (moderate), and 
4 (severe)(14).  To be eligible for this study, subjects must have a PGA score of ≥ 3 at the baseline 
(Day 0) visit. The PGA should be performed at arm’s length distance from the subject. A detailed 
description of PGA scores is provided in Table 2. 
Table 2: Physician’s Global Assessment of Disease Severity in Psoriasis 
Score 
Grade 
Description 
0 
Clear 
No signs of psoriasis, postinflammatory hyperpigmentation may be present 
1 
Almost clear 
No thickening, normal to pink coloration, no to minimal focal scaling 
2 
Mild 
Just detectable to mild thickening; pink to light red coloration; predominantly fine 
scaling 
3 
Moderate 
Clearly distinguishable to moderate thickening; moderate scaling 
4 
Severe 
Severe thickening with hard edges; bight to deep dark red coloration; severe/coarse 
scaling covering almost all or all lesions 
8.1.3 Body Surface Area  
The overall BSA affected by psoriasis will be evaluated (from 0% to 100%) at the visits specified 
in Section 7. One subject’s palm represents 1% of his/her total BSA. To be eligible, subjects must 
have a BSA of ≥ 3% at baseline (Day 0). 

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8.1.4 Pruritus Numeric Rating Scale  
The intensity of pruritus will be recorded at the visits specified in Section 7 using a Pruritus 
Numeric Rating Scale (15). This will be evaluated by asking subjects to assign a numerical score 
representing the current intensity of their symptoms over the last 24h on a scale from 0 to 10, with 
0 for having no symptoms and 10 having worst imaginable symptoms. The NRS of pruritus is 
provided in APPENDIX B. 
8.2 Quality-of-Life Assessments 
8.2.1 Dermatology Life Quality Index Questionnaire  
The Dermatology Life Quality Index (DLQI) is a simple 10-question validated questionnaire that 
has been used in more than 40 different skin conditions. Its use has been described in more than 
1,000 publications, including many multinational studies. The DLQI is the most frequently used 
instrument in studies of randomized controlled trials in dermatology. It will be completed at the 
visits specified in Section 7. The questionnaire is provided in APPENDIX C. 
8.3 Safety Assessments 
8.3.1 Vital Signs 
The following vital signs will be recorded at every visit with the subject in a seated position, after 
having sat calmly for at least 5 minutes: systolic and diastolic blood pressure (mmHg), pulse 
(bpm), and body temperature (°C). 
 
Weight (kg) and height (cm) will be collected to calculate the Body Mass Index (BMI) which will 
be recorded at the screening and baseline (Day 0) visits. The height will only be recorded once at 
the screening visit and the same value will be used for BMI calculation at baseline (Day 0). The 
weight will be recorded at screening, baseline (Day 0), and at the Week 12 visit (end of treatment 
visit). 
 
If deemed appropriate by the investigator, clinically significant findings in the vital signs will 
exclude a subject from study participation. Any abnormal finding related to vital signs that the 
investigator considers to be clinically significant must be recorded as an AE if this abnormality 
was not present at the baseline (Day 0) visit or is assessed as having worsened since baseline (Day 
0). Any change in health between the informed consent form and the first study drug administration 
will be recorded as medical history. 
8.3.2 Physical Examination 
The following sites/systems will be included in the physical examination to be performed at the 
visits specified in Section 7. In case clinically significant findings are detected at Week 12, the 
physical examination may be repeated at Week 16. Each system will be scored as normal/abnormal 

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(nonclinically significant or clinically significant). Pertinent details must be recorded for any 
clinically significant findings.  
 General appearance 
 Dermatological (except psoriasis) 
 Head, eyes, ears, nose, throat (HEENT) 
 Respiratory 
 Cardiovascular 
 Abdominal 
 Neurological 
 Musculoskeletal 
 Lymphatic  
 
If deemed appropriate by the investigator, clinically significant findings in the physical 
examination will exclude a subject from study participation. Any significant change will be 
reported as an AE if this abnormality was not present at the baseline (Day 0) visit or is assessed as 
having worsened since baseline (Day 0). Any change in health between the informed consent form 
and the first study drug administration will be recorded as medical history.  
8.3.3 Clinical Laboratory Tests 
Laboratory tests will be performed at the visits specified in Section 7. In case clinically significant 
findings are detected at Week 12, the corresponding laboratory test may be repeated at Week 16. 
The tests will include hematology with differential and a standard chemistry panel (chemistry 
includes liver function tests). A serum pregnancy test will be performed at screening, and a urine 
pregnancy test will be performed at all the other study visits for women of childbearing potential. 
In addition, serology testing (HBV, HCV, HIV) and tuberculosis test (PPD, T-spot test or 
Quantiferon Gold, if one has not been performed in the last 6 months) will be performed at the 
screening visit only.  
 
All routine laboratory tests will be analyzed at the local laboratory of each trial site.  
 
The specific tests in these panels are listed in Table 3: 
 

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Table 3: Clinical Laboratory Testing  
 
Laboratory Testing 
Tests Included 
Hematology 
HCT, Hgb, MCH, MCHC, MCV, MPV, platelets, RBC, WBC and differentials (neutrophils, 
lymphocytes, monocytes, eosinophils and basophils relative and absolute). 
Serum chemistry 
Albumin, alkaline phosphatase, ALT, AST, chloride, CK, creatinine (enzymatic), GGT, glucose 
random, HbA1c, LDH, potassium, sodium, total bilirubin, urea (BUN), uric acid, cholesterol, 
triglycerides 
Pregnancy test 
β-hCG in serum for females of childbearing potential at screening only and urine pregnancy 
test at the other visits. 
Laboratory tests required at 
screening only 
FSH levels for women greater than 40 and less than 60 years of age who have had a cessation 
of menses for at least 12 months but less than 24 months. 
Tuberculosis test (PPD, T-spot test or Quantiferon Gold), and serology (HBV [HBsAg, anti-
HBc], HCV, HIV) 
ALT = alanine aminotransferase; anti-HBc = anti–hepatitis B core antibodies; AST = aspartate aminotransferase; β-hCG = β-
human chorionic gonadotropin; BUN = blood urea nitrogen; CK = creatine kinase; FSH = follicle-stimulating hormone; 
GGT = gamma-glutamyltransferase; HBsAg = hepatitis B surface antigens; HBV = hepatitis B virus; HCT = hematocrit; 
HCV = hepatitis C virus; Hgb = hemoglobin; HIV = human immunodeficiency virus; LDH = lactate dehydrogenase; MCH = mean 
corpuscular hemoglobin; MCHC= mean corpuscular hemoglobin concentration; MCV = mean corpuscular volume; MPV = mean 
platelet volume; PPD = purified protein derivative; RBC = red blood cell (count); WBC = white blood cell (count). 
 
If deemed appropriate by the investigator and in accordance with the exclusion criteria described 
in Section 5.2, clinically significant findings in clinical laboratory testing will exclude a subject 
from study participation. Any significant change will be reported as an AE if this abnormality was 
not present at the baseline (Day 0) visit or is assessed as having worsened since baseline (Day 0). 
Any change in health between the informed consent form and the first study drug administration 
will be recorded as medical history. 
8.3.4 Electrocardiogram 
Twelve-lead ECGs will be performed as a safety assessment at the visits specified in Section 7. In 
case clinically significant findings are detected at Week 12, the ECG may be repeated at Week 16. 
Clinically significant findings in the ECG will exclude a subject from study participation (as 
deemed appropriate by the investigator). Any significant change will be reported as an AE if this 
abnormality was not present at baseline (Day 0) visit or is assessed as having worsened since 
baseline (Day 0).  
8.3.5 Chest X-Ray 
In addition to PPD, T-spot test or Quantiferon Gold, a chest x-ray will be performed at screening 
only (if one has not been performed in the last 6 months) to assess the presence of tuberculosis.  

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8.4 Other Assessments  
Refer to the study manual for detailed instructions on tube labeling, sample collection, processing, 
storage, shipping, and laboratories in charge of the analyses below. 
8.4.1 Skin Biopsies 
All subjects will have two 4.0-mm skin biopsy taken from a nonlesional area at the baseline 
(Day 0) visit and two 4.0-mm biopsy taken from the target lesion at baseline (Day 0), Week 4, 
Week 8, and Week 12 visits, for a total of 10 biopsies.   
 
The first half will be used for immunohistochemistry staining and will be proceed in OCT.  
 
The second half will be processed in RNAlater and used for gene expression analysis using reverse 
transcription polymerase chain reaction (RT-PCR). 
 
The skin will be cleaned, disinfected, and anesthetized before skin biopsies are performed. Sterile 
gauze will be used to absorb any bleeding. The biopsy sites will be cauterized and sutured if 
necessary. 
8.4.2 Medical Photography  
Medical photographs of another lesion than the target lesions will be performed at baseline (Day 0) 
and at all subsequent visits (if no other lesions are present on the body, photographs could be 
performed on a biopsied lesion). Care will be taken to use the same camera, the same 
magnification, and the same settings for each photograph at each visit in order to obtain 
comparable pictures. Medical photography will be taken using a blue background. 
 
Photographs will be identified as follows: study number, subject number, subject initials, visit 
name, and date. Photographs will be kept as electronic files on site and will be transmitted to the 
sponsor for review.  
8.4.3 Status of Psoriatic Arthritis 
Subjects suffering from psoriatic arthritis (as reported in the subject’s medical history at screening) 
will be asked at the visits specified in Section 7 if their condition has improved, remained stable, 
or worsened) since the screening visit. 

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9 
ADVERSE EVENTS 
An AE is any untoward medical occurrence in a subject administered a pharmaceutical product, 
without regard to the possibility of a causal relationship with this treatment.  
 
Investigators are responsible for monitoring the safety of subjects who are participating in this 
study and for alerting the sponsor of any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the subject. The investigator is responsible for appropriate 
medical care of subjects during the study. 
 
The investigator remains responsible for following through with an appropriate health care option 
for all AEs that are serious or that caused the subject to discontinue before completing the study. 
The subject should be followed until the event is resolved or stable. Follow-up frequency is left to 
the discretion of the investigator. 
 
Safety will be evaluated by collecting information on AEs and by accessing data from vital signs, 
ECGs, physical examinations, and laboratory results.  
 
Prior to subject enrollment, study site personnel will note the occurrence and nature of each 
subject’s medical condition(s) in the appropriate section of the source document and CRF. During 
the study, site personnel will again note any change in the condition(s) and the occurrence and 
nature of any AEs.  
 
If a subject exp  eriences an AE at any time after the first dose of the study product, the event will 
be recorded as an AE in the source document and CRF.  
9.1 Adverse Event Causality 
The investigator will establish causality of the AE to the experimental treatment. The investigator 
should take into account the subject’s history, most recent physical examination findings, and 
concomitant medications.  
 
The following definitions will be used to determine causality of an AE:  
 
 
Not related: Temporal relationship of the onset of the AE, relative to the experimental 
treatment, is not reasonable, or another cause can explain the occurrence of the AE. 
 
Related: Temporal relationship of the onset of the AE, relative to the experimental 
treatment, is reasonable, follows a known response pattern to the treatment, and an 
alternative cause is unlikely. 
 

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9.2 Adverse Event Severity 
The intensity of an AE is an estimate of the relative severity of the event made by the investigator 
based on his or her clinical experience and familiarity with the literature. The following definitions 
are to be used to rate the severity of an AE: 
 
Mild: The symptom is barely noticeable to the subject and does not influence performance 
of daily activities. Treatment is not ordinarily indicated. 
 
Moderate: The symptom is sufficiently severe to make the subject uncomfortable, and 
performance of daily activities is influenced. Treatment may be necessary. 
 
Severe: The symptom causes severe discomfort, and daily activities are significantly 
impaired or prevented. Treatment may be necessary. 
9.3 Serious Adverse Events 
If a subject experiences an SAE at any time after the first study product administration, the event 
will be recorded as an SAE in the source document and CRF.  
A serious adverse event or reaction is any untoward medical occurrence that, at any dose: 
 
Results in death 
 
Is life-threatening 
 
Requires in-patient hospitalization or prolongation of existing hospitalization 
 
Results in persistent or significant disability/incapacity 
 
Is a congenital anomaly/birth defect 
NOTE: The term “life-threatening” in the definition of “serious” refers to an event in which 
the subject was at risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death if it were more severe. 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately life-
threatening or result in death or hospitalization, but may jeopardize the subject or may require 
intervention to prevent one of the other outcomes listed in the definition above. These should also 
usually be considered serious. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias, or convulsions that do not result in hospitalization; or 
development of drug dependency or drug abuse. 

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9.3.1 SAE Reporting 
All SAEs, related to the experimental treatment or not, occurring during the course of the study 
must be reported on an SAE form to the sponsor within 24 hours of the knowledge of the 
occurrence. (This refers to any AE that meets one or more of the aforementioned serious criteria.) 
The SAE reporting period ends at the Follow-up visit (Week 16).  
 
Reporting should be done by sending the completed SAE Report Form to the following e-mail 
address (faxing can also be done as a second option in case e-mailing is not possible).  
 
Contact name:  
Dr.  Anne Bregnhøj 
 
 
 
Department of Dermatology, Aarhus University Hospital 
 
 
 
P.P. Orumsgade 11, DK-8000 Aarhus C 
 
 
 
Denmark 
E-mail: annebreg@rm.dk 
Phone: +45 21835720  
Fax: +45 78461824 
 
 
The sponsor will evaluate all SAEs as soon as the reports are received and will assess the 
expectedness of each SAE in relation to the study treatment. For each SAE received, the sponsor 
will make a determination as to whether the criteria for expedited reporting to relevant regulatory 
authorities have been met. The sponsor or designee will manage the expedited reporting of relevant 
safety information to concerned regulatory agencies in accordance with local laws and regulations. 
9.4 Pregnancy Reporting 
If a female subject or a female partner of a male subject becomes pregnant during the study, the 
subject should inform the study site as soon as possible. Upon confirmation of the pregnancy, the 
female subject will be discontinued from the study. The investigator must complete a 
study-specific pregnancy form upon confirmation of a pregnancy and send it to the sponsor within 
24 hours of confirmation of the pregnancy (contact information to be used is the same as for SAE 
reporting). Posttreatment follow-up should be done to ensure subject safety. Pregnancy is not itself 
an AE or SAE; however, maternal/fetal complications or abnormalities will be recorded as AEs or 
SAEs, as appropriate. The investigator will follow the pregnancy until completion or until 
pregnancy termination and, in the case of a live-born offspring, to 1 month of age in that infant. 
The investigator will notify the sponsor of the outcome as a follow-up to the initial pregnancy 
form. All pregnancies should be reported to the sponsor and ethics committee.  
 
9.5  Suspected Unexpected Serious Adverse Reactions 
If a subject experience a SUSAR at any time after the first study product administration, the event 
will be recorded as a SUSAR in the source document and CRF.  
 
 

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SUSARs meets the same criteria as SARs, but are not expected to occur according to the reference 
safety informations in the Investigator´s Brochure.   
9.5.1 SUSAR Reporting 
All SUSARs occurring during the course of the study must be reported on a SUSAR form to the 
sponsor within 24 hours of the knowledge of the occurrence. 
 
Reporting should be done by sending the completed SUSAR Report Form to the following e-mail 
address (faxing can also be done as a second option in case e-mailing is not possible).  
 
Contact name:  
Dr.  Anne Bregnhøj 
 
 
 
Department of Dermatology, Aarhus University Hospital 
 
 
 
P.P. Orumsgade 11, DK-8000 Aarhus C 
 
 
 
Denmark 
E-mail: annebreg@rm.dk 
Phone: +45 21835720 
Fax: +45 78461824 
 
 
Sponsor must ensure that all relevant information about SUSARs, which is fatal or life threatening, 
is recorded and reported to Danish Medicines Agency and the Ethical Committee no later that 7 
days after sponsor has been informed about such a serious reaction. No later than 8 days after 
initial reporting sponsor must inform the Danish Medicines Agency and the Ethical Committee 
about follow-up information and action taken. 
 
Any other SUSARs must be reported to Danish Medicines Agency and the Ethical Committee no 
later that 15 days after sponsor has been informed about them.   
 
SUSAR´s from non-EU/EEA countries shall not be reported to the Danish Medicines Agency. 
 

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10 
SAMPLE SIZE AND STATISTICAL METHODS  
10.1 Determination of Sample Size 
No formal sample size calculations were conducted. Six subjects will be enrolled into each cohort, 
for a total of maximum 16  subjects. This sample size was selected to allow sufficient 
characterization of the drug’s safety profile over the planned doses range and to allow for 
preliminary efficacy assessments of CUDC-305 in subjects with moderate to severe plaque 
psoriasis.  
10.2 Statistical and Analytical Plans 
Because of the nature and design of the study, the statistical analysis will be mainly descriptive.  
 
Descriptive summaries of demographics, baseline characteristics, and subject disposition will be 
presented by dose regimen and overall. Continuous variables will be summarized by dose regimen 
and overall in tables and will include the number of subjects, mean, standard deviation, median, 
minimum, maximum, and range. Categorical variables will be presented by dose regimen and 
overall in tables as frequencies and percentages. 
 
Even if not sample size calculation was performed we bring a power analysis for the primary 
endpoint: PASI at week 12. A non parametric Wilcoxon signed-rank test will allow us to determine 
that Change in PASI is significant different form 0 with 80% power and 95% confidence level if 
the observed effect size is greater or equal to 1.23 standard deviation.  
10.2.1 Subject Disposition 
Efficacy will be evaluated on the basis of the intent-to-treat (ITT) population. A supportive 
analysis will also be conducted on the per-protocol (PP) population. 
 
The intent-to-treat (ITT) population will include all subjects who received at least one dose of the 
study product. 
 
The per-protocol (PP) population will include all subjects who received at least one dose of the 
study product with no significant protocol deviations.  
 
The safety population (SAF) will be defined as all subjects who received at least one dose of the 
study product.  
10.2.2 Efficacy Analysis 
The primary and secondary efficacy analyses will be summarized and presented descriptively. No 
statistical comparison per se will be performed. However, comparison between the different doses 
tested may be performed.  

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10.2.3 Safety Analysis 
Safety analysis will be summarized and presented descriptively by evaluating the incidence of 
TEAEs and drug-related TEAEs.  
10.2.4 Interim Analysis 
No formal interim analysis of the study endpoints is planned for this study. However, reviews of 
available safety data and preliminary efficacy data to guide decisions regarding the subsequent 
cohorts (dose decision) will be conducted by the sponsor and/or investigator(s) on an ongoing 
basis. Because this is an open-label study, the unblinding is not to be taken into consideration for 
the safety meetings. 
 
Beyond the mainly descriptive analysis by using regular measures of central tendency and 
measures of dispersion, the continuous endpoints as Changes and Percentages of Changes can 
be assessed and tested with a mixed-  effect model (Fixed-factors: treatment and time, random 
intercept for each patient). The least square mean and standard error of the mean will be exposed 
on proper plots and tables.  Proportion of subjects at each time point for efficacy and safety 
endpoints can be compared by using contingency tables and Fisher exact test. 
 

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11 
DATA QUALITY ASSURANCE/SITE MONITORING 
During the study, monitoring visits will be performed at regular intervals. The monitoring visits 
will be conducted to ensure protocol adherence, quality of data, accuracy of entries on the CRFs, 
product accountability, compliance with regulatory requirements, and continued adequacy of the 
investigational site and its facilities.  
 
The site may be audited or monitored or both by a quality assurance officer named by the sponsor, 
and regulatory authorities may wish to perform on-site audits. The investigator will be given notice 
before an audit occurs and will be expected to cooperate with any audit and provide assistance and 
documentation (including source data) as requested. 
 
12 
DATA COLLECTION AND RETENTION 
The investigator must maintain source documents for each subject in the study. These source 
documents will consist of case and visit notes (clinical medical records) containing demographic 
and medical information and the results of any tests or assessments. Subject data will be transcribed 
by site personnel into a paper CRF. All information on the CRFs must be traceable to these source 
documents in the subject’s file. The data collected will be entered in a database system thereafter. 
Data listings will be reviewed, and manual queries will be generated and sent to the site if 
necessary. 
 
13 
CONFIDENTIALITY OF TRIAL DOCUMENTS AND 
SUBJECT RECORDS  
The investigator must assure that the subjects’ anonymity will be maintained and that subjects’ 
identities are protected from unauthorized parties. On CRFs or other documents submitted to the 
sponsor, subjects should not be identified by their names, but by an identification code. The 
investigator should keep a subject enrolment log relating codes with the names of subjects. The 
investigator should maintain in strict confidence documents not for submission to the sponsor (e.g., 
subjects’ written consent forms). 
 
14 
INVESTIGATOR’S FILES AND RETENTION OF 
DOCUMENTS 
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should be 
classified into two separate categories:  Investigator Study File and subject clinical source 
documents. 
The records should be retained by the investigator according to ICH, local regulations, or as 
specified in the Clinical Trial Agreement, whichever retention period is longer.  
 

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15 
ETHICS 
15.1 Local Regulations/Declaration of Helsinki 
This study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki (2008) and that are consistent with Good Clinical Practice ICH Tripartite 
Guideline (July 2002) and the applicable laws and regulations of the country in which the research 
is conducted, whichever affords the greater protection to the individual.   
15.2 Ethical Review  
It is the understanding of the sponsor that this protocol (and any amendments) as well as 
appropriate consent procedures, will be reviewed and approved by a research ethics 
board/institutional review board (REB/IRB). This board must operate in accordance with the 
current federal regulations. For sites with a local ethics committee, a letter or certification of 
approval will be sent by the investigator to the sponsor (or contract research organization) prior to 
initiation of the study, and also whenever subsequent modifications to the protocol are made.   
15.3 Informed Consent  
It is the responsibility of the investigator, or a person designated by the investigator (if acceptable 
by local regulation), to obtain written informed consent from each individual participating in this 
study, after adequate explanation of the aims, methods, objectives, and potential hazards of the 
study. It must also be explained to the subjects that they are completely free to refuse to enter the 
study or to withdraw from it at any time for any reason.   
 
If new safety information results in significant changes in the risk/benefit assessment, or if any 
new information becomes available that may affect the willingness of a subject to continue to 
participate, the consent form should, if necessary, be reviewed and updated by the REB/IRB. All 
subjects (including those already being treated) should be informed of the new information, given 
a copy of the revised form, and asked to give their consent to continue in the study. 
15.4 Risk: Benefit 
Psoriasis is a serious chronic disease associated with significant morbidity and impairment. The 
disease is usually not life threatening and does not induce irreversible injury to skin or other organs, 
with the exception of psoriatic arthritis. Psoriasis is however, considered to be a systemic 
inflammatory disease, and patients with psoriasis have an increased risk of comorbidities related 
to the metabolic syndrome, including adiposity, arterial hypertension and abnormalities in lipid 
and glucose metabolism (Reich K, JEADV 2012). This leads to an increased risk of cardiovascular 
complications among patients with psoriasis compared to controls. A recent study has shown that 
treatment with potent anti-inflammatory drug (biologics) in patients with severe psoriasis was 
associated with reduced coronary artery disease progression monitored by CT scans compared 
with a control group (Hjuler KF, JAMA Dermatol 2016).  
Currently used immunosuppressants and antimetabolites are associated with potentially serious 
side effects include life-threatening infections and neoplasms.  Reports indicate that although 
dermatologists are aware of the national treatment guidelines for psoriasis(16), less than 50% of 

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patients with moderate-to-severe psoriasis receive systemic treatment(17). This deficiency has 
been linked to elevated safety concerns(17). Indeed, due to the risk of serious adverse side effects 
associated with these therapies patients are often required to alternate between various therapeutic 
modalities as a precautionary measure. Recent publications indicate that oral therapeutics, 
particularly those without immunosuppressive side-effects, remain a critical unmet need for 
patients that are unwilling or unable to use injectable treatments(18).  Thus, while current 
guidelines recommend systemic treatment with immunomodulatory biologics(5), in order to 
achieve adequate disease control in patients with moderate-to-severe psoriasis, efficacious oral 
psoriasis therapeutics with a strong safety profile that also have a pharmacokinetic profile that 
permits the management of spontaneously arising adverse effects. The goal of therapy is to bring 
disease under control by using the least toxic therapy, where drugs associated with risk of serious 
irreversible toxicity or mortality should be reserved for patients with severe, recalcitrant psoriasis.  
Potentially serious although reversible gastrointestinal toxicities could be associated with CUDC-
305. Although not evident in human studies, preclinical animal data also suggest a potential for an 
increased QTc intervals in the heart following CUDC-305 and treated patients will be required to 
undergo mandatory cardiac monitoring.  In vitro studies suggest that high doses of CUDC-305 
may have off-target effects on opioid receptors. Quality of life and study product accountability 
will be closely monitored. To further mitigate risk during study enrollment all available safety and 
efficacy data will be reviewed by the principal investigator (PI) or delegate and the sponsor’s 
medical monitor before subsequent cohorts are dosed. A safety meeting will take place to review 
the available data prior to deciding the next dose and then initiating dosing of the subsequent 
cohort. The study may be stopped permanently or interrupted at any time for safety reasons 
following review of study data. If any subject from the sentinel cohort experiences a severe or 
clinically significant adverse event (AE) that is considered possibly drug-related, then dosing of 
the remaining cohorts with higher doses will not be conducted. Dose escalation can only proceed 
if all parties (PI or delegate and the sponsor’s medical monitor) agree that it is safe to do so and 
will be documented in the form of a signed dose decision document. Participants will be closely 
monitored at all times during the study by experienced medical, nursing and clinical staff. In the 
event of an unexpected AE or medical emergency the participant will be transferred to a hospital 
for further management this will be implemented without delay. Phase I clinical studies support a 
favorable toxicity profile of CUDC-305 and the overall risk:benefit, considering all aspects 
detailed above, is considered to be acceptable to support commencing the study in patients with 
moderate to severe psoriasis.  
 
 
16 
PUBLICATION POLICY  
The publication policy will be addressed in the Research and Financial Agreement, and all details 
outlined in the agreement will apply to this protocol. The trial will be registered on 
ClinicalTrials.Gov prior to the first subject being dosed. 
 

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Confidential and proprietary. Permission should be obtained before any reproduction. 
17 
REFERENCES 
 
1. 
Lowes MA, Suarez-Farinas M, Krueger JG. Immunology of psoriasis. Annual review of 
immunology. 2014;32:227-55. 
2. 
Rachakonda TD, Schupp CW, Armstrong AW. Psoriasis prevalence among adults in the 
United States. Journal of the American Academy of Dermatology. 2014;70(3):512-6. 
3. 
Pfohler C, Muller CS, Vogt T. Psoriasis vulgaris and psoriasis pustulosa - epidemiology, 
quality of life, comorbidities and treatment. Current rheumatology reviews. 2013;9(1):2-7. 
4. 
Stern RS, Nijsten T, Feldman SR, Margolis DJ, Rolstad T. Psoriasis is common, carries a 
substantial burden even when not extensive, and is associated with widespread treatment 
dissatisfaction. The journal of investigative dermatology Symposium proceedings / the Society for 
Investigative Dermatology, Inc [and] European Society for Dermatological Research. 
2004;9(2):136-9. 
5. 
Pathirana D, Ormerod AD, Saiag P, Smith C, Spuls PI, Nast A, et al. European S3-
guidelines on the systemic treatment of psoriasis vulgaris. Journal of the European Academy of 
Dermatology and Venereology : JEADV. 2009;23 Suppl 2:1-70. 
6. 
Menter A, Gottlieb A, Feldman SR, Van Voorhees AS, Leonardi CL, Gordon KB, et al. 
Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 1. Overview of 
psoriasis and guidelines of care for the treatment of psoriasis with biologics. Journal of the 
American Academy of Dermatology. 2008;58(5):826-50. 
7. 
Horn EJ, Fox KM, Patel V, Chiou CF, Dann F, Lebwohl M. Are patients with psoriasis 
undertreated? Results of National Psoriasis Foundation survey. Journal of the American Academy 
of Dermatology. 2007;57(6):957-62. 
8. 
Armstrong AW, Robertson AD, Wu J, Schupp C, Lebwohl MG. Undertreatment, treatment 
trends, and treatment dissatisfaction among patients with psoriasis and psoriatic arthritis in the 
United States: findings from the National Psoriasis Foundation surveys, 2003-2011. JAMA 
dermatology. 2013;149(10):1180-5. 
9. 
Kumar P, Kolls JK. Act1-hsp90 heats up TH17 inflammation. Nature immunology. 
2013;14(1):16-7. 
10. 
Kakeda M, Arock M, Schlapbach C, Yawalkar N. Increased expression of heat shock 
protein 90 in keratinocytes and mast cells in patients with psoriasis. Journal of the American 
Academy of Dermatology. 2014;70(4):683-90 e1. 
11. 
Stenderup K, Rosada C, Gavillet B, Vuagniaux G, Dam TN. Debio 0932, a new oral Hsp90 
inhibitor, alleviates psoriasis in a xenograft transplantation model. Acta dermato-venereologica. 
2014;94(6):672-6. 
12. 
Fredriksson T, Pettersson U. Severe psoriasis--oral therapy with a new retinoid. 
Dermatologica. 1978;157(4):238-44. 
13. 
Marks R, Barton SP, Shuttleworth D, Finlay AY. Assessment of disease progress in 
psoriasis. Archives of dermatology. 1989;125(2):235-40. 
14. 
Langley RG, Feldman SR, Nyirady J, van de Kerkhof P, Papavassilis C. The 5-point 
Investigator's Global Assessment (IGA) Scale: A modified tool for evaluating plaque psoriasis 
severity in clinical trials. J Dermatolog Treat. 2015;26(1):23-31. 
15. 
Phan NQ, Blome C, Fritz F, Gerss J, Reich A, Ebata T, et al. Assessment of pruritus 
intensity: prospective study on validity and reliability of the visual analogue scale, numerical rating 
scale and verbal rating scale in 471 patients with chronic pruritus. Acta dermato-venereologica. 
2012;92(5):502-7. 
16. 
Nast A, Mrowietz U, Kragballe K, Puig L, Reich K, Warren RB, et al. National and 
multinational guidelines in Europe: results from an online survey on awareness of different 

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Confidential and proprietary. Permission should be obtained before any reproduction. 
national 
and 
European 
psoriasis 
guidelines. 
Archives 
of 
dermatological 
research. 
2013;305(7):637-43. 
17. 
Nast A, Mrowietz U, Kragballe K, de Jong EM, Puig L, Reich K, et al. Barriers to the 
prescription of systemic therapies for moderate-to-severe psoriasis--a multinational cross-
sectional study. Archives of dermatological research. 2013;305(10):899-907. 
18. 
Mahmood T, Zaghi D, Menter A. Emerging oral drugs for psoriasis. Expert opinion on 
emerging drugs. 2015;20(2):209-20. 
 
 
 

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Confidential and proprietary. Permission should be obtained before any reproduction. 
APPENDIX A: Psoriasis Area and Severity Index 
 
PASI Scoring 
 
Four anatomic sites – head, upper extremities, trunk and lower extremities – are assessed for 
erythema, induration (infiltration, plaque thickness), and desquamation (scaling) as seen on the 
day of the examination. The severity of each sign is assessed using a 5-point scale: 
 0 = No symptoms 
 1 = Slight 
 2 = Moderate 
 3 = Marked 
 4 = Very marked 
 
The area affected by psoriasis within a given anatomic site is estimated as a percentage of the total 
area of that anatomic site and assigned a numerical value according to the degree of psoriatic 
involvement as follows: 
 0 = no involvement 
 1 =  10% 
 2 = 10 to  30% 
 3 = 30 to  50% 
 4 = 50 to  70% 
 5 = 70 to  90% 
 6 = 90 to 100% 
 
Assignments for the following body regions are as follows: 
 Neck: include with the head 
 Buttocks: include with the lower extremities 
 Axillae: include with the trunk 
 Genitals: include with the trunk 
 The inguinal canal separates the trunk and legs anteriorly 
 
The PASI score for each body region is obtained by using the formula 
 
PASI = 0.1 (Eh + Ih + Dh) Ah + 0.2 (Eu + Iu + Du) Au + 0.3 (Et + It + Dt) At + 0.4 (El + Il + Dl) Al 
 
Where E, I, D, and A denote erythema, induration, desquamation, and area, respectively, and h, u, 
t, and l denote head, upper extremities, trunk, and lower extremities, respectively.  
 

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APPENDIX B: Numeric Rating Scale  
 
 
Numeric Rating Scale (NRS) 
 
 
 
0 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
8 
 
9 
 
10 
 
 
 
 
No itch 
Worst imaginable itch 
 
 
 
 
 

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Confidential and proprietary. Permission should be obtained before any reproduction. 
APPENDIX C: Dermatology Life Quality Index  
 
Subject ID #: ___ ___ - ___ ___ ___  
 
Subject Initials: ___ ___ ___ 
 
Visit Day: ___________ 
 
Visit Date (dd-mmm-yyyy):______________ 
The aim of this questionnaire is to measure how much your skin problem has affected your life OVER 
THE LAST WEEK.  Please check one box for each question. 
 
1. Over the last week, how itchy, sore, painful or stinging has your 
skin been? 
Very much 
A lot 
A little 
Not at all 
 
 
 
 
2. Over the last week, how embarrassed or self conscious have you 
been because of your skin? 
Very much 
A lot 
A little 
Not at all 
 
 
 
 
 
3. Over the last week, how much has your skin interfered with you 
going shopping or looking after your home or yard? 
Very much 
A lot 
A little 
Not at all 
 
 
 
 
 
 
 
Not relevant  
4. Over the last week, how much has your skin influenced the 
clothes you wear? 
Very much 
A lot 
A little 
Not at all 
 
 
 
 
 
 
 
Not relevant  
5. Over the last week, how much has your skin affected any social 
or leisure activities?  
 
 
Very much 
A lot 
A little 
Not at all 
 
 
 
 
 
 
 
Not relevant  
6. Over the last week, how much has your skin made it difficult for 
you to do any sport? 
 
Very much 
A lot 
A little 
Not at all 
 
 
 
 
 
 
 
Not relevant  
7. Over the last week, has your skin prevented you from working or 
studying? 
yes 
no 
 
 
 
 
Not relevant  
If "No", over the last week how much has your skin been a 
problem at work or studying? 
A lot 
A little 
Not at all  
 
 
 
 
 
 

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8. Over the last week, how much has your  
skin 
created 
problems with your partner or any of your close friends or 
relatives?  
 
Very much 
A lot 
A little 
Not at all 
 
 
 
 
 
 
 
Not relevant  
9. Over the last week, how much has your  
skin 
caused 
any 
sexual difficulties?  
Very much 
A lot 
A little 
Not at all 
 
 
 
 
 
 
 
Not relevant  
10. Over the last week, how much of a problem has the treatment for 
your skin been, for example by making your home messy, or by 
taking up time? 
Very much 
A lot 
A little 
Not at all 
 
 
 
 
 
 
 
Not relevant  
©AY Finlay, GK Khan, April 1992 www.dermatology.org.uk. 
 
Please check you have answered EVERY question. Thank you.