Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Effects of EP262 in Subjects With Chronic Spontaneous Urticaria (CALM-CSU)
Phase: PHASE2
Conditions: Chronic Spontaneous Urticaria
Sponsor: Escient Pharmaceuticals, Inc

Official Title: 
Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate the Effects of EP262 in Subjects with Chronic Spontaneous Urticaria 
NCT Number: 
NCT06077773 
Document Date: 
EP-262-201 Protocol, Amendment 4.0 (26 July 2024) 
 
 
 

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Confidential Document 
All information contained within this protocol is confidential. It may not be 
reproduced, copied, or disseminated in any manner without the prior written consent 
of Escient. 
 
1. 
TITLE PAGE 
 
 
Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study 
to Evaluate the Effects of EP262 in Subjects with Chronic Spontaneous 
Urticaria 
 
Study Acronym: 
CALM-CSU 
Protocol Number: 
EP-262-201 
EU CT Number: 
2023-504799-94 
IND Number: 
161897 
Protocol Version Number: 
Amendment 4.0 
Issue Date: 
26 July 2024 
Drug Development Phase: 
Phase 2 
Sponsor: 
Escient Pharmaceuticals, Inc., an Incyte company (Escient) 
10578 Science Center Drive, Suite 250 
San Diego, CA 92121 USA 
Phone/Fax: +1 (858) 617-8220 
 
, MD 
 Inflammation and Autoimmunity 
Incyte Corporation 
Phone: 
 
 
 
 

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Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study 
to Evaluate the Effects of EP262 in Subjects with Chronic Spontaneous 
Urticaria 
 
Study Acronym: 
CALM-CSU 
Protocol Number: 
EP-262-201 
EU CT Number: 
2023-504799-94 
Protocol Version Number: 
Amendment 4.0 
Issue Date: 
26 July 2024 
Sponsor Statement 
This protocol was subject to critical review and has been approved by the following individuals: 
 
 
26-Jul-2024 | 12:05 EDT 
 
, MD 
Date 
, Inflammation and Autoimmunity 
Incyte Corporation 
 
 
26-Jul-2024 | 09:19 PDT 
 
, PhD 
Date 
 Clinical Development 
Escient Pharmaceuticals, Inc., an Incyte company 
 
 
26-Jul-2024 | 18:53 PDT 
 
, MS 
Date 
, Biometrics and Data Analytics 
Escient Pharmaceuticals, Inc., an Incyte company 

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Investigator’s Agreement 
I have read the protocol for EP-262-201 and agree to conduct the study as outlined. I agree to 
maintain the confidentiality of all information received or developed in connection with this 
protocol. 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
Date 

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PROTOCOL HISTORY 
 
Document 
Amendment Type 
Date 
Amendment 4.0 
Global 
26 July 2024 
Amendment 3.1 
Country-specific (Canada) 
05 April 2024 
Amendment 3.0 
Global 
05 April 2024 
Amendment 2.1 (Obsoleted) 
Country-specific (Canada) 
11 March 2024 
Amendment 2.0 
Global 
11 March 2024 
Amendment 1.1 
Country-specific (Canada) 
23 January 2024 
Amendment 1.0 
Global 
29 November 2023 
Amendment 0.1 
Country-specific (Canada) 
31 August 2023 
Original Protocol 
Not applicable 
09 May 2023 

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2. 
Synopsis 
 
Name of Sponsor/Company: 
Escient Pharmaceuticals, Inc., an Incyte company (Escient) 
Name of Investigational Product: 
EP262 oral capsules 
Study Number: 
EP-262-201 
Phase of Development: 
Phase 2 
Title of Study: 
Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Effects of 
EP262 in Subjects with Chronic Spontaneous Urticaria 
Study Center(s): 
Multi-center within North America and Europe 
Objectives 
Endpoints 
Primary Objective 
To evaluate the efficacy of EP262 compared to 
placebo in subjects with chronic spontaneous 
urticaria (CSU) 
• Change from baseline to Visit 4 (Week 6) in 
the sum of the daily Urticaria Activity Score 
(UAS) over a 7-day period (UAS7) 
Secondary Objectives 
To evaluate the safety and tolerability of EP262 
compared to placebo in subjects with CSU 
• Type, frequency, and severity of treatment- 
emergent adverse events (TEAEs) 
• Change from baseline in vital signs, 
electrocardiograms (ECGs), and clinical 
laboratory parameters 
To evaluate the efficacy of EP262 compared to 
placebo in subjects with CSU as assessed by the 
following: 
• Pruritus severity 
• Hive severity 
• Change from baseline to Visit 4 (Week 6) in 
the sum of the daily Itch Severity Score (ISS) 
over a 7-day period (ISS7) 
• Change from baseline to Visit 4 (Week 6) in 
the sum of the daily Hive Severity Score 
(HSS) over a 7-day period (HSS7) 

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Exploratory Objectives 

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Methodology: 
Study EP-262-201 is a Phase 2 randomized, double-blind, placebo-controlled study to evaluate the 
efficacy, safety, and tolerability of EP262 over 6 weeks in subjects with CSU. The study will be 
conducted in 2 parts: Part 1 will assess 50 mg and 150 mg doses of EP262 and Part 2 will assess a 
25 mg dose of EP262 to further characterize the therapeutic dose range. Part 2 will begin after the last 
subject is randomized into Part 1. Part 1 and Part 2 are identical in terms of their visit structure, 
procedures conducted, and the populations being studied. The primary difference between the 2 parts 
is the EP262 dose levels being assessed. 
Each part includes a Screening Period of at least 2 weeks and up to 30 days to assess subject eligibility 
that includes collection of the daily UAS score; a 6-week Double-Blind Treatment Period; and a 
4-week Safety Follow-Up Period after administration of the last dose of study drug (EP262 or placebo) 
for a total study duration of up to approximately 14 weeks for each subject. In Part 1, approximately 
114 subjects will be randomized in a 1:1:1 ratio to receive a 150 mg dose of EP262, 50 mg dose of 
EP262, or placebo orally (PO), once daily (QD) during the 6-week Double-Blind Treatment Period. In 
Part 2 of the study, approximately 40 subjects will be randomized in a 3:1 ratio to receive either a 
25 mg dose of EP262 or placebo PO, QD, during the 6-week Double-Blind Treatment Period. 
Enrollment of subjects with prior omalizumab use will be limited to 15 subjects in Part 1 and 
5 subjects in Part 2. 
EP-262-201 Study Design 
Screening 
Double-Blind 
Safety 
Period 
Treatment Period 
Follow-Up Period 
 
Part 1 
Part 2a 
 
Screening 
Enroll/Randomize 
Follow-Up 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5b 
Day -30 to Day -14 
Day 1 
Week 3 
Week 6 
Week 10 
PO = oral; QD = once daily. 
a Part 2 will begin after the last subject is randomized into Part 1. 
b Any subject who completes the Double-Blind Treatment Period or discontinues study drug (EP262 or placebo) 
early will have a Safety Follow-Up Visit approximately 4 weeks (±3 days) after the last dose of study drug. 
Screening Period 
The Screening Period will consist of 1 study visit (Visit 1). During this period, subjects will undergo 
assessments to determine study eligibility per inclusion and exclusion criteria and must remain on their 
prescreening background therapy. Visit 1 (Day -30 to Day -14 [inclusive]) may be conducted over 
more than 1 day but must be completed between Day -30 and Day -14 (inclusive). 
Double-Blind Treatment Period 
The Double-Blind Treatment Period will consist of 3 study visits (Visits 2, 3, and 4 [Day 1, Week 3, 
and Week 6]). During this period, all subjects who meet eligibility requirements will be enrolled into 
the study and will be randomized on Visit 2 (Day 1) to receive double-blind, QD, PO doses of EP262 
50 mg EP262 PO QD 
150 mg EP262 PO QD 
Placebo PO QD 
25 mg EP262 PO QD 
Placebo PO QD 

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or placebo for 6 weeks. In Part 1, subjects will be randomized in a 1:1:1 ratio to receive a 150 mg dose 
of EP262, 50 mg dose of EP262, or placebo PO, QD. In Part 2, subjects will be randomized in a 3:1 
ratio to receive either a 25 mg dose of EP262 or placebo PO, QD. Randomization will be conducted 
centrally via an Interactive Web Response System (IWRS) and stratified based on prior use of 
omalizumab (yes/no). QD PO dosing of study drug should occur after at least a 4 hour fast and 
administered at approximately the same time of day. Subjects should refrain from eating for at least 
2 hours postdose. The time and date of all dose administrations will be recorded in a daily diary. The 
first dose of study drug will be administered at the clinical site on Visit 2 (Day 1) after all baseline 
study procedures are completed. Visit 2 (Day 1) will not have a visit window; all other visits in the 
Double-Blind Treatment Period will have a visit window of ±3 days. Subjects who discontinue from 
treatment early should have the Early Treatment Termination Visit conducted as soon as possible after 
the last dose of study drug, ideally within 2 days after the last dose of study drug. Throughout the 
treatment period, subjects must remain on their prescreening background therapy, although rescue 
medication may be taken as needed. 
Safety Follow-Up Period 
Any subject who completes the Double-Blind Treatment Period or discontinues study drug (EP262 or 
placebo) early will have a Safety Follow-Up Visit approximately 4 weeks (±3 days) after the last dose 
of study drug. 
Number of Subjects (Planned): 
Approximately 154 subjects with CSU will be randomized into this study. Approximately 114 subjects 
will be randomized in Part 1 and approximately 40 subjects will be randomized in Part 2. Enrollment 
of subjects with prior omalizumab use will be limited to 20 subjects (15 subjects in Part 1 and 
5 subjects in Part 2). 
Main Criteria for Inclusion and Exclusion: 
Subjects who have an exclusionary result during the Screening Period (between Visit 1 and Visit 2) 
may have that assessment repeated once at the discretion of the Investigator within the screening 
window and be enrolled if a repeat assessment is within the indicated range as specified below for 
participating in the study. 
Inclusion Criteria 
To be eligible for study participation, all subjects must meet all of the following inclusion criteria: 
1. Male or female subject, aged 18 to 80 years, inclusive, at the time of consent 
2. Diagnosis of CSU (presence of urticaria on most days of the week, for a duration of 6 weeks or 
longer, at any time before Screening) for ≥6 months 
3. Must be on daily stable doses of H1 antihistamine (H1AH) consistent with standard of care for 
CSU starting at least 3 consecutive days immediately prior to the Screening Visit and willing to 
remain on stable doses through the Safety Follow-Up Visit 
4. Current H1AH treatment up to 4 times the approved dose per local treatment guidelines 
5. UAS7 ≥16 during the 7 days prior to randomization (Day 1) (data from at least 4 of the 7 days are 
required to be considered an acceptable profile) 
6. If female, must have a negative serum pregnancy test at Screening, be willing to not donate eggs 
from Screening until 12 weeks after the last dose of study drug, and: 
a. Is surgically sterile; or 
b. Has been amenorrhoeic for ≥1 year without an alternative medical cause; or 

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c. If of childbearing potential1, must agree to use 2 forms of contraception, which includes at 
least 1 form of highly effective and 1 effective method2 of contraception from Screening 
until 12 weeks after the last dose of study drug. The following methods can achieve a 
failure rate of less than 1% per year when used consistently and correctly and are 
considered highly effective birth control methods: 
• 
Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation 
• 
Progestogen only hormonal contraception associated with inhibition of ovulation 
• 
Intrauterine device 
• 
Intrauterine hormone releasing system 
• 
Bilateral tubal occlusion 
• 
Vasectomized partner who has received a medical assessment of surgical success 
• 
Sexual abstinence (complete sexual abstinence defined as refraining from heterosexual 
intercourse for the entire period of risk associated with study drug), the reliability of 
which needs to be evaluated in relation to the duration of the clinical study and the 
preferred and usual lifestyle of the subject 
7. If male and is not confirmed surgically sterile, must be willing to not donate sperm and must agree 
to use a barrier method of contraception (eg, condom with spermicide) during intercourse and at 
least 1 other acceptable contraceptive measure for his female partner(s) (eg, hormonal 
contraceptives, intrauterine device, female surgical sterilization, abstinence) from Screening 
through 12 weeks after the last dose of study drug 
8. Must be able to communicate well with the Investigator, understand and comply with the 
requirements of the study, and understand and provide written consent 
Exclusion Criteria 
All subjects meeting any of the following criteria will be excluded from this study: 
1. Clearly defined underlying etiology for chronic urticarias other than CSU, including diseases with 
possible symptoms of urticaria or angioedema (eg, urticarial vasculitis, urticaria pigmentosa, 
erythema multiforme, mastocytosis, mast cell activation syndrome, hereditary or acquired 
angioedema, lymphoma, leukemia, generalized cancer) 
2. Chronic urticaria with clearly defined predominant or sole trigger (chronic inducible urticaria) 
including urticaria factitia (symptomatic dermographism), cold, heat, solar, pressure, delayed 
pressure, aquagenic, cholinergic, or contact urticaria 
3. Other active skin diseases associated with chronic pruritus that might confound the study 
evaluations and results (eg, atopic dermatitis [AD], bullous pemphigoid, prurigo nodularis, 
dermatitis herpetiformis) 
4. Use of the following prohibited treatments: 
a. Drugs that are agonists at the mas-related G protein-coupled receptor X2 (MRGPRX2), 
including icatibant, opioids (eg, codeine, morphine), vancomycin, clomipramine, or 
 
 
1 Women of childbearing potential are defined as those who are fertile, following menarche and until becoming 
postmenopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without 
an alternative medical cause. 
2 Effective methods of contraception include barrier methods of contraception (eg, male condom, female condom, 
cervical cap or diaphragm, and contraceptive sponge). 

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nondepolarizing neuromuscular blocking agents (eg, atracurium, rocuronium, vecuronium, 
cisatracurium, mivacurium) within 14 days before Screening 
b. Monoclonal antibodies (eg, omalizumab, dupilumab, tezepelumab) within 4 months or 
5 half-lives (whichever is longer) before Screening 
c. Immunosuppressant drugs, including systemic corticosteroids, hydroxychloroquine, 
methotrexate, mycophenolate, cyclosporine, or cyclophosphamide within 30 days before 
Screening 
d. Current or anticipated use of corticosteroids, or uncontrolled disease states, such as 
asthma, psoriasis, or inflammatory bowel disease, where flares are commonly treated with 
oral or parenteral corticosteroids 
e. Drugs that inhibit uridine 5’-diphospho-glucuronosyltransferase 1A1 (UGT1A1)
 
 
 
f. 
 
g. 
 
 
5. Active malignancy or history of malignancy of any organ system (other than localized squamous 
cell or basal cell carcinoma of the skin that have been excised or resolved), treated or untreated, 
within the past 5 years from Screening 
6. Evidence of clinically significant cardiac, neurologic, psychiatric, pulmonary, renal, hepatic, 
endocrine (including uncontrolled diabetes mellitus), metabolic, or gastrointestinal disease that, in 
the Investigator’s opinion, would compromise the safety of the subject, interfere with the 
interpretation of the study results, or otherwise preclude subject participation 
7. Screening 12-lead ECG that demonstrates clinically relevant abnormalities that may affect subject 
safety 
8. Any clinically significant abnormalities on screening laboratory tests that, in the opinion of the 
Investigator, precludes participation in the study. The following abnormalities will specifically be 
considered exclusionary: 
a. Bilirubin >upper limit of normal (ULN) and/or any known condition that results in 
abnormal bilirubin elevations or fluctuations (eg, Gilbert’s, Dubin-Johnson, Rotor 
syndrome) 
b. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >1.5× ULN 
9. Other co-morbidities that would introduce additional risk factors or interfere with study procedures 
based on clinically significant physical examination, vital sign, standard 12-lead ECG, chemistry, 
hematology, urinalysis, or coagulation results at Screening as deemed by the Investigator 
10. Positive result for human immunodeficiency virus (HIV) or presence of actively replicating viral 
hepatitis due to hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at Screening 
11. Significant history of abuse of drugs, solvents, or alcohol within the past year 
12. Participation in any clinical study with an investigational or approved drug/device within 30 days 
or 5 half-lives (whichever is longer) before Screening or is planning to participate in another 
clinical study while enrolled in this study 
13. History of known or suspected hypersensitivity to any component of study drug 
14. Female who is pregnant, nursing, or intends to become pregnant during the study 
15. Had a major surgery within 8 weeks prior to Day 1 or has a major surgery planned during the 
study 

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16. Is directly affiliated with the study at the clinical site or is an immediate family member (spouse, 
parent, child, or sibling; biological or legally adopted) of personnel directly affiliated with the 
study at the clinical site 
17. Is employed by Incyte Corporation or its wholly owned subsidiary, Escient, (that is an employee, 
temporary contract worker, or designee responsible for the conduct of the study) or is an 
immediate family member of an employee of Incyte Corporation or Escient 
18. Subject is, in the opinion of the Investigator, not suitable to participate in the study 
19. Subject is performing mandatory military service, deprived of liberty and/or due to a judicial 
decision, cannot take part in clinical studies, or is in a residential care institution 
Study Drug Materials and Management: 
Study Drug 
In Part 1, capsules containing 25 mg of EP262, 75 mg of EP262, or placebo will be supplied in bottles 
in a manner to ensure the study blind. Each subject will take 2 capsules per dose. 
In Part 2, capsules containing 25 mg of EP262 or placebo will be supplied in bottles in a manner to 
ensure the study blind. Each subject will take 1 capsule per dose. 
Study Drug Packaging and Labeling 
Study drug will be packaged into bottles labeled with a unique number and supplied to clinical sites in 
a blinded manner. 
Study Drug Storage 
The study drug capsules should be stored at controlled room temperature, 15°C to 25°C (59°F to 
77°F), with excursions up to 30°C (86°F). 
Study Drug Administration 
Each study drug dose is to be administered PO as intact capsules (swallowed whole, not split, opened, 
or chewed) and taken with approximately 240 mL (8 fluid ounces) of water on an empty stomach. 
Subjects will be instructed to take the study drug at approximately the same time of the day after a fast 
of at least 4 hours. Subjects should refrain from eating for at least 2 hours postdose. On the days of 
clinic visits, the time of study drug administration may differ depending on the scheduled visit time. 
The first dose of study drug will be administered at the clinical site on Visit 2 (Day 1) after all baseline 
study procedures are completed. 
Study Drug Dispensing and Accountability 
Subjects will record self-administration of study drug daily in a dosing diary that will be reviewed at 
each clinical site visit during the Double-Blind Treatment Period by site staff. 
Subjects should be instructed to retain the study drug, including the study drug bottle, even if empty, 
and to return it and any remaining study drug to the clinical site at their next visit. The site staff should 
perform study drug accountability and, if applicable, follow-up with the subject to retrieve any 
remaining study drug that has not been returned. 
Key Study Procedures and Efficacy, Safety, Pharmacokinetic, Pharmacodynamic, and Baseline 
Characterization Assessments: 
At specific visits outlined in the Schedule of Assessments (Appendix A), subjects will undergo 
efficacy, safety, pharmacokinetic (PK), PD, and baseline characterization assessments. 

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Key Study Procedures 
Fasting Requirements 
Subjects should fast for at least 8 hours before study visits that require a blood sample for assessment 
of clinical chemistry. Water is acceptable in the morning of clinic visits to ensure the subject is 
hydrated for laboratory sample collection. Subjects should fast at least 4 hours before administration of 
each dose of study drug and refrain from eating for at least 2 hours postdose. Each dose of study drug 
is to be taken with approximately 240 mL (8 fluid ounces) of water on an empty stomach. 
Discontinuation of Study Drug 
For subjects who terminate treatment with study drug early, regardless of the reason, every effort will 
be made to complete the early treatment termination evaluations as soon as possible after the last dose 
of study drug, ideally within 2 days after the last dose of study drug. 
Whenever possible, subjects should remain in the study and complete the remaining study visits and 
assessments even when study drug has been discontinued. Subjects who discontinue study drug for any 
reason and continue with the study visits as planned through Visit 4 (Week 6) (participating only in 
efficacy and safety, but not PK measures) will participate in the Safety Follow-Up Visit if the last dose 
of study drug was administered less than 4 weeks before Visit 4 (Week 6) to ensure that at least 
4 weeks of follow-up data are collected for all randomized subjects. 
If a subject discontinues study drug and chooses not to complete all the remaining study visits, the 
subject should have the Early Treatment Termination Visit conducted as soon as possible after the last 
dose of study drug, ideally within 2 days after the last dose of study drug, and a Safety Follow-Up 
Visit approximately 4 weeks (±3 days) after the last dose of study drug if at least 4 weeks of follow-up 
data have not already been collected. If a subject fails to attend the Safety Follow-Up Visit and has not 
withdrawn consent, all reasonable efforts will be made to contact the subject to ensure that he/she is in 
satisfactory health. All contacts and contact attempts must be documented in the subject’s medical 
record. 
Rescue Medications 
In addition to their daily background therapy, for the duration of the study (Screening, Double-Blind 
Treatment, and Safety Follow-Up Periods), if symptoms worsen, all subjects will be able to use a 
second generation H1AH that is different from background therapy as rescue medication as needed. 
The choice of H1AH and dosage will be determined by the Investigator; however, discussion with the 
subject prior to initiation of any rescue medication is encouraged. Once a rescue medication has been 
selected, switching to a different rescue medication during the study is not permitted. Use of rescue 
medication must be documented. 
Efficacy Assessments 
The primary efficacy evaluation is based on the UAS, a patient-reported assessment of disease activity. 
Secondary efficacy evaluations include assessments of itching (ISS) and hives (HSS), both of which 
comprise the UAS. Exploratory efficacy evaluations include
 
. All 
efficacy assessments will be performed as indicated in the Schedule of Assessments (Appendix A). 
Examples of the patient-reported assessments are provided in the appendices but are not to be 
distributed to subjects for completion. Subjects will be trained on completion of all patient-reported 
assessments using the study-issued electronic device or application (app). 
Urticaria Activity Score Over a 7-Day Period (UAS7) 
The UAS is a CSU-specific, 24-hour self-evaluation, patient-reported outcome measure (Zuberbier 
2022). It is based on the assessment of key CSU symptoms: intensity of itch and number of wheals. 
The UAS scale for both itch and wheal assessment are recorded as a score from 0 to 3 (Total = 0 to 

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6), with 0 representing no itch/hives to 3 representing intense itch/hives (ie, Itch – interferes with 
normal daily activity or sleep; Hives – More than 50 wheals). Daily UAS scores are summed over 
7 consecutive days to derive the UAS7, with higher scores indicating greater disease severity. Well- 
controlled urticaria is defined as a UAS7 score ≤6. The
 
 
 
Subjects will be instructed to complete the UAS daily, in the morning before dosing (as applicable), 
and at approximately the same time of day, beginning at the Screening Visit to the Safety Follow-Up 
Visit. The questionnaire will be completed during the Screening Visit. For all other days that 
coincide with a study visit (for Visit 2 and beyond), the UAS is to be completed in the morning 
before the study visit. 
The UAS scores from Day -7 through Day -1 will be summed to determine subject eligibility for 
continued participation regarding disease activity. The UAS scores from Day -6 through Day 1 will 
be summed to serve as the baseline UAS7 score. The 7 daily UAS scores prior to Visit 4 (Week 6) 
will be summed for primary endpoint analyses. Data from at least 4 of the 7 days for each week are 
required to be considered an acceptable profile. An example of the UAS7 is included in Appendix C. 

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Safety Assessments 
Safety evaluations, including adverse events (AEs), concomitant medications, medical history, vital 
signs, physical examinations, standard 12-lead ECGs, and laboratory evaluations of safety will be 
performed as indicated in the Schedule of Assessments (Appendix A). 
Adverse Event Collection 
AEs will be documented from the signing of the Informed Consent Form (ICF) until the end of study 
participation. 
Pharmacokinetic Assessments 
Blood sampling will be collected predose (as applicable) at Visits 2, 3, 4, and 5 (Day 1, Week 3, 
Week 6, and Safety Follow-Up Visit) to analyze trough EP262 concentrations. The EP262 metabolite 
profile may also be analyzed from these trough samples. 
Pharmacodynamic Assessments 

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Baseline Characterization 
Statistical Methods: 
The primary efficacy endpoint is the change from baseline in UAS7 at Visit 4 (Week 6), defined as the 
sum of the daily UAS over the 7 days prior to the timepoint of interest. If a subject has at least 
4 completed daily scores on the UAS (both domains) over the 7 days prior to the timepoint of interest, 
the UAS7 will be defined as the average of the available daily scores, multiplied by 7. If a subject has 
fewer than 4 completed daily scores on the UAS over the 7 days prior to the timepoint of interest, then 
the UAS7 will be considered missing for that timepoint. 
Efficacy analyses will compare placebo and each EP262 dose separately. Subjects who receive placebo 
in Parts 1 and 2 will be pooled for analysis. Additional analysis comparing placebo and all EP262 
doses combined may be performed as appropriate. Statistical testing will be performed as 2-sided test 
with statistical significance level of 0.10, with no adjustment for multiplicity. 
The primary endpoint will be analyzed using a mixed effects model for repeated measures based on the 
data from each week up to Week 6. The model will include treatment, week, and treatment by week 
interaction as fixed effects. Additional model covariates will include baseline UAS7 score and 
randomization strata. The treatment effect will be the contrast between EP262 and placebo least- 
squares (LS) means. 
The primary analysis of the primary endpoint of change from baseline in UAS7 will include all 
observed data (weekly UAS7 considered non-missing) with no data imputations, under the assumption 
of missing at random. Sensitivity analysis using an alternative model and/or data imputation method 
will be performed. 
Additional statistical analysis details will be specified in the Statistical Analysis Plan (SAP). 

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Sample Size Considerations: 
The study will enroll approximately 154 subjects. 
In Part 1, approximately 114 subjects will be randomized in a 1:1:1 ratio to receive 50 mg EP262, 
150 mg EP262, or placebo. 
In Part 2, approximately 40 subjects will be randomized in a 3:1 ratio to receive 25 mg of EP262 or 
placebo. 
Overall, approximately 30, 38, 38, and 48 subjects will be randomized to receive 25 mg EP262, 50 mg 
EP262, 150 mg EP262, and placebo, respectively, across both parts of the study. 
For Part 1, a sample size of 34 subjects per treatment group will provide 80% power to detect an 
8-point difference in the UAS7 change from baseline at Visit 4 (Week 6), assuming a standard 
deviation of 13 points, and a 2-sided alpha of 10%. 
For Part 2, a sample size of 27 subjects receiving 25 mg of EP262 and 43 subjects receiving placebo 
pooled from both parts of the study will provide 80% power to detect an 8-point difference in the 
UAS7 change from baseline at Visit 4 (Week 6) between EP262 25 mg and placebo, with the same 
assumption of 13-point standard deviation and 2-sided alpha of 10%. 
With an estimated early withdrawal rate of approximately 10%, the planned enrollment of 38 subjects 
per treatment group (50 mg EP262, 150 mg EP262, and placebo) in Part 1 and 40 subjects (30 subjects 
in 25 mg EP262 and 10 subjects in placebo) in Part 2 will ensure adequate sample size to complete the 
6-week treatment period. 

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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................ 1 
2. 
SYNOPSIS .................................................................................................................... 5 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ................ 17 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............................. 22 
5. 
INTRODUCTION....................................................................................................... 25 
5.1. 
Role of the MRGPRX2 Receptor in the Pathogenesis of Chronic 
Spontaneous Urticaria .................................................................................................................... 25 
5.2. 
EP262 and Study Rationale ......................................................................................... 25 
5.3. 
EP262 Dose Rationale ................................................................................................ 26 
5.4. 
Summary of Benefits and Risks .................................................................................. 28 
5.4.1. 
Benefit Summary ........................................................................................................ 28 
5.4.2. 
Risk Summary ............................................................................................................. 28 
5.4.3. 
Mitigation Strategy ..................................................................................................... 29 
5.4.4. 
Overall Benefit:Risk Conclusion ................................................................................ 29 
6. 
TRIAL OBJECTIVES AND PURPOSE .................................................................... 29 
7. 
INVESTIGATIONAL PLAN ..................................................................................... 31 
7.1. 
Overall Study Design .................................................................................................. 31 
7.1.1. 
Screening Period ......................................................................................................... 32 
7.1.2. 
Double-Blind Treatment Period .................................................................................. 32 
7.1.3. 
Safety Follow-Up Period ............................................................................................ 33 
7.2. 
Start of Study .............................................................................................................. 33 
7.3. 
End of Study ............................................................................................................... 33 
7.4. 
Number of Subjects ..................................................................................................... 33 
7.5. 
Dose Adjustment Criteria ............................................................................................ 33 
7.6. 
Criteria for Study Termination .................................................................................... 34 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS .............................................. 34 
8.1. 
Subject Inclusion Criteria ............................................................................................ 34 
8.2. 
Subject Exclusion Criteria .......................................................................................... 35 
8.3. 
Study Restrictions ....................................................................................................... 37 
8.4. 
Concomitant Medications ........................................................................................... 38 

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8.5. 
Auxiliary Medicinal Products ..................................................................................... 38 
8.5.1. 
Background Therapy ................................................................................................... 38 
8.5.2. 
Rescue Medications .................................................................................................... 38 
8.5.3. 
Permitted Medications ................................................................................................ 38 
8.6. 
Removal of Subjects from Therapy or Assessment .................................................... 39 
8.6.1. 
Discontinuation of Study Drug ................................................................................... 39 
8.6.2. 
Discontinuation from the Study .................................................................................. 40 
9. 
TREATMENT OF SUBJECTS .................................................................................. 40 
9.1. 
Treatment Assignment ................................................................................................ 40 
9.2. 
Treatment Compliance ................................................................................................ 40 
9.3. 
Randomization and Blinding ...................................................................................... 40 
9.3.1. 
Randomization ............................................................................................................ 40 
9.3.2. 
Blinding ....................................................................................................................... 41 
9.3.2.1. 
Emergency Unblinding ............................................................................................... 41 
9.3.2.2. 
Unblinding for Regulatory Reporting ......................................................................... 41 
9.4. 
Study Visits ................................................................................................................. 41 
9.4.1. 
Screening Period ......................................................................................................... 42 
9.4.1.1. 
Visit 1 (Day -30 to Day -14 [inclusive]) ..................................................................... 42 
9.4.2. 
Double-Blind Treatment Period .................................................................................. 43 
9.4.2.1. 
Visit 2 (Day 1) – Enrollment and Randomization ....................................................... 43 
9.4.2.2. 
Visit 3 (Week 3) .......................................................................................................... 43 
9.4.2.3. 
Visit 4 (Week 6) .......................................................................................................... 44 
9.4.3. 
Safety Follow-Up Period ............................................................................................ 44 
9.4.3.1. 
Visit 5 (Week 10) ........................................................................................................ 44 
9.4.4. 
Early Treatment Termination Visit ............................................................................. 45 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ............................................ 45 
10.1. 
Study Drug .................................................................................................................. 45 
10.2. 
Study Drug Packaging and Labeling .......................................................................... 45 
10.3. 
Study Drug Storage ..................................................................................................... 46 
10.4. 
Study Drug Administration ......................................................................................... 46 
10.4.1. 
Instructions for Missed Dose(s) .................................................................................. 46 
10.5. 
Study Drug Dispensing and Accountability ................................................................ 46 
10.6. 
Study Drug Handling and Disposal ............................................................................ 46 

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10.7. 
Product Quality Complaints ........................................................................................ 47 
11. 
EFFICACY ASSESSMENTS ..................................................................................... 47 
12. 
SAFETY ASSESSMENTS ......................................................................................... 49 
12.1. 
Adverse Events ........................................................................................................... 49 
12.1.1. 
Definition of an Adverse Event ................................................................................... 49 
12.1.2. 
Determining Severity of Adverse Events .................................................................... 50 
12.1.3. 
Determining Causality of Adverse Events .................................................................. 50 
12.1.4. 
Recording Adverse Events .......................................................................................... 51 
12.1.4.1. 
Special Instructions for Recording Adverse Events in the eCRF ............................... 51 
12.2. 
Serious Adverse Events .............................................................................................. 52 
12.2.1. 
Definition of a Serious Adverse Event ........................................................................ 52 
12.2.2. 
Reporting Serious Adverse Events ............................................................................. 52 
12.2.3. 
Pregnancy .................................................................................................................... 53 
12.3. 
Medical History........................................................................................................... 53 
12.4. 
Vital Signs ................................................................................................................... 53 
12.5. 
Body Weight and Height ............................................................................................ 54 
12.6. 
Physical Examinations ................................................................................................ 54 
12.7. 
Standard 12-Lead Electrocardiograms ........................................................................ 54 
12.8. 
Laboratory Evaluations of Safety ............................................................................... 54 
12.9. 
Other Laboratory Evaluations ..................................................................................... 55 
12.10. 
Subject Safety Guidelines ........................................................................................... 55 
12.10.1. 
Potential Side Effects .................................................................................................. 55 
12.10.2. 
Overdose ..................................................................................................................... 55 
12.10.3. 
Management of Liver Test Abnormalities .................................................................. 55 
13. 
PHARMACOKINETICS ASSESSMENTS ............................................................... 56 
14. 
PHARMACODYNAMIC ASSESSMENTS .............................................................. 56 
15. 
BASELINE CHARACTERIZATION ........................................................................ 57 
16. 
STATISTICS .............................................................................................................. 57 

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16.1. 
Analysis Sets ............................................................................................................... 57 
16.2. 
Estimand ..................................................................................................................... 58 
16.3. 
Endpoints .................................................................................................................... 58 
16.3.1. 
Primary Efficacy Endpoint .......................................................................................... 58 
16.3.2. 
Secondary Efficacy Endpoints .................................................................................... 58 
16.3.3. 
Exploratory Endpoints ................................................................................................ 58 
16.4. 
Sample Size Considerations ........................................................................................ 59 
16.5. 
Subject Disposition ..................................................................................................... 60 
16.6. 
Demographics and Baseline Characteristics ............................................................... 60 
16.7. 
Study Drug Usage and Compliance ............................................................................ 60 
16.8. 
Efficacy and Pharmacodynamic Analysis ................................................................... 60 
16.8.1. 
Primary Efficacy Analysis .......................................................................................... 60 
16.8.2. 
Additional Efficacy and Pharmacodynamic Analyses ................................................ 61 
16.8.3. 
Primary and Sensitivity Analyses to Address Missing Data in the Primary 
Analysis .......................................................................................................................................... 61 
16.9. 
Safety Analysis ........................................................................................................... 61 
16.10. 
Pharmacokinetic Analysis ........................................................................................... 61 
16.11. 
Subgroup Analyses ..................................................................................................... 62 
16.12. 
Multiple Comparison/Multiplicity ............................................................................... 62 
16.13. 
Interim Analysis .......................................................................................................... 62 
17. 
QUALITY CONTROL AND DATA MANAGEMENT ............................................ 62 
17.1. 
Data Quality Assurance............................................................................................... 62 
17.2. 
Data Management ....................................................................................................... 62 
17.3. 
Monitoring .................................................................................................................. 63 
17.4. 
Confidentiality and Auditing ...................................................................................... 63 
17.5. 
Case Report Forms ...................................................................................................... 63 
17.6. 
Source Documents ...................................................................................................... 64 
17.7. 
Records Retention ....................................................................................................... 64 
17.8. 
Informed Consent ........................................................................................................ 64 
17.9. 
Ethical Conduct of the Study ...................................................................................... 65 
17.10. 
Institutional Review Board/Independent Ethics Committee ....................................... 65 
18. 
STUDY MANAGEMENT .......................................................................................... 65 
18.1. 
Protocol Deviations ..................................................................................................... 65 

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18.2. 
Publications ................................................................................................................ 66 
18.3. 
Change in Clinical Site Staff ...................................................................................... 66 
19. 
LIST OF REFERENCES ........................................................................................... 67 
APPENDIX A. 
SCHEDULE OF ASSESSMENTS ................................................................... 70 
APPENDIX B. 
COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS .......... 74 
APPENDIX H. 
SUMMARY OF CHANGES BY AMENDMENT .......................................... 81 
LIST OF FIGURES 
Figure 1: 
EP-262-201 Study Design .......................................................................................... 32 
LIST OF TABLES 
Table 1: 
Abbreviations and Specialist Terms .......................................................................... 22 

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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 1: 
Abbreviations and Specialist Terms 
 
Abbreviation or Specialist Term 
Explanation 
AAS 
Angioedema Activity Score 
 
 
AD 
atopic dermatitis 
AE 
adverse event 
 
 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
app 
application 
AST 
aspartate aminotransferase 
ATC 
Anatomic Therapeutic Chemistry 
BCRP 
breast cancer resistance protein 
CFR 
Code of Federal Regulations 
Cmax 
maximum observed concentration 
CONSORT 
Consolidated Standards of Reporting Trials 
CRO 
Contract Research Organization 
CSU 
chronic spontaneous urticaria 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
CU 
chronic urticaria 
CU-Q2oL 
Chronic Urticaria Quality of Life questionnaire 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EU 
European Union 
FAS 
Full Analysis Set 
FcεR1 
high affinity IgE receptor 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 

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Abbreviation or Specialist Term 
Explanation 
GM-CSF 
granulocyte macrophage colony-stimulating factor 
H1AH 
H1 antihistamine 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HEENT 
head, eyes, ears, nose, throat 
HIV 
human immunodeficiency virus 
HRQoL 
health-related quality of life 
HSS 
Hive Severity Score 
 
 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IgE 
immunoglobulin E 
IgG 
immunoglobulin G 
IL 
interleukin 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
ISS 
Itch Severity Score 
 
 
IWRS 
Interactive Web Response System 
LS 
least-squares 
MATE 
multidrug and toxin extrusion 
MedDRA 
Medical Dictionary for Regulatory Activities 
 
 
MRGPR 
mas-related G protein-coupled receptor 
NOAEL 
no-observed-adverse-effect-level 
OATP 
organic anion transporting polypeptide 
P-gp 
P-glycoprotein 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
PO 
oral 
PP 
Per Protocol 

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Abbreviation or Specialist Term 
Explanation 
PQC 
product quality complaint 
QC 
quality control 
QD 
once daily 
RAE 
recurrent angioedema 
SAE 
serious adverse event 
SAER 
Serious Adverse Event Report 
SAP 
Statistical Analysis Plan 
SOP 
standard operating procedure 
t1/2 
half-life 
TEAE 
treatment-emergent adverse event 
Th2 
type 2 T helper cells 
Tmax 
time to reach maximum observed concentration 
TNF-α 
tumor necrosis factor-alpha 
TPO 
thyroid peroxidase 
UAS 
Urticaria Activity Score 
 
 
UCT 
Urticaria Control Test 
 
 
UGT1A1 
uridine 5’-diphospho-glucuronosyltransferase 1A1 
ULN 
upper limit of normal 
US 
United States 
WHO 
World Health Organization 

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5. 
INTRODUCTION 
5.1. 
Role of the MRGPRX2 Receptor in the Pathogenesis of Chronic 
Spontaneous Urticaria 
Chronic spontaneous urticaria (CSU; also known as chronic idiopathic urticaria) is a condition 
characterized by the development of systemic itchy red hives (wheals) and/or deep tissue 
swelling (angioedema) for periods of at least 6 weeks (Zuberbier 2022) with no specific eliciting 
factor. The hives and angioedema associated with CSU are directly attributable to the 
degranulation of mast cells, which can be triggered by many different stimuli. 
The mas-related G protein-coupled receptor (MRGPR) family is comprised of 8 human Class A 
rhodopsin-like G-protein coupled receptors (MRGPRX1-X4 and D-G) that can sense noxious 
stimuli and appear to have a role in innate immunity. MRGPRX2 is predominantly expressed in 
mast cells and has been shown to induce degranulation upon binding to a wide variety of 
agonists (Subramanian 2016, Corbiere 2021). MRGPRX2 has been shown to mediate 
immunoglobulin E (IgE)-independent activation of mast cells, including degranulation and 
regulation of inflammatory processes. Activation of MRGPRX2 triggers release of 
proinflammatory mediators and a multicellular signaling cascade that likely plays a key role in 
multiple human diseases involving clinically relevant mast cell activation, including CSU 
(Babina 2020, Thapaliya 2021). 
There are several lines of evidence to support a role of MRGPRX2 and IgE-independent mast 
cell activation in the etiology of CSU. First, many patients with CSU remain inadequately 
controlled even when receiving antihistamine, with or without concomitant anti-IgE treatment. 
Second, serum from patients with CSU has been reported to degranulate mast cells lacking the 
high affinity IgE receptor (FcεR1) to a much larger extent than serum from healthy control 
subjects (Bossi 2011), whereas loss of MRGPRX2 reduces degranulation stimulated by CSU 
patient serum (Quan 2022). Third, patients with CSU have been reported to have elevated 
plasma/serum levels of substance P, an agonist of MRGPRX2 (Metz 2014, Zheng 2016), and a 
greater number of MRGPRX2 positive mast cells in skin biopsies (Fujisawa 2014). Finally, and 
in keeping with the aforementioned findings, patients with CSU have been reported to show 
enhanced skin reactivity to intradermally injected MRGPRX2 drug ligands (Shtessel 2021). 
Overall, these data provide strong support for the potential therapeutic benefit of MRGPRX2 
antagonism in the treatment of CSU and warrant further investigation as a novel, IgE- 
independent, mast cell-specific treatment approach. 
5.2. 
EP262 and Study Rationale 
EP262 is a potent small-molecule antagonist of the human MRGPRX2 receptor under 
development as an orally (PO) administered therapy for CSU. 
Preliminary results from Study EP-262-101, a first-in-human randomized, Phase 1 clinical study 
of single and multiple daily PO doses of EP262 or placebo in 64 healthy subjects, have provided 
information on the safety, tolerability, and pharmacokinetics (PK) of EP262. Study EP-262-101 
also included an initial food effect evaluation. Thirty healthy subjects received a single 50, 150, 
400, 800, or 1200 mg dose of EP262. Eighteen subjects received 50, 150, or 300 mg as a 
multiple dose regimen over 7 days. 

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All doses evaluated were well tolerated with no dose-limiting adverse events (AEs), early 
terminations due to AEs, severe AEs, or serious AEs (SAEs) reported. No adverse trends in 
safety laboratory measures, vital signs, or electrocardiogram (ECG) parameters have been 
observed. EP262 concentrations increased with increasing single doses in an approximately 
linear manner and modeling of single dose data predicted multiple dose concentrations. The time 
to reach the maximum EP262 observed concentration (Tmax) was achieved on average at 
approximately 3.2 hours postdose with a half-life (t1/2) of approximately 121 hours for the 
150 mg dose, driven by an extended terminal elimination phase. EP262 concentrations were 
approximately 2-fold higher when administered with a high-fat meal than when administered in 
the fasted state. The absence of safety signals, in conjunction with favorable PK profiles, 
supports further investigation of EP262 in subjects with CSU in this clinical study. 
Study EP-262-201 will evaluate the efficacy, safety, and tolerability of EP262 over 6 weeks of 
treatment in subjects with CSU. A 6-week treatment duration is deemed adequate based on the 
anticipated rapid onset of action of EP262 to directly block activation of MRGPRX2 and is 
consistent with the treatment duration at which efficacy has been demonstrated for other 
approved and investigational agents. 
The primary efficacy measure will be the change from baseline to Week 6 in patient-reported 
disease activity, as assessed by the Urticaria Activity Score (UAS) over a 7-day period (UAS7), 
a widely used CSU-specific patient reported outcome measure. Secondary 
 
efficacy measures for this study include the Itch Severity Score (ISS) over a 7-day period (ISS7) 
and the Hive Severity Score (HSS) over a 7-day period (HSS7), which are the components of the 
UAS7; 
 
 
tudy EP-262-201 
will also assess the safety and tolerability of EP262. Collectively, the results will guide further 
development of EP262, including the design of subsequent confirmatory studies. 
The study will be randomized to ensure random allocation of subjects to treatment arms and to 
reduce bias. Because efficacy assessments have a high degree of subjectivity, the study will be 
double-blinded. In addition, a placebo-controlled design will be used to control for confounding 
factors, such as potential Investigator bias, and to ensure that the statistical procedures can be 
appropriately applied. 
5.3. 
EP262 Dose Rationale 
The 150 mg and 50 mg EP262 dose levels to be evaluated in Part 1 of Study EP-262-201 were 
selected based on a variety of factors to explore efficacy without adversely impacting safety, 
including results from nonclinical pharmacology studies, nonclinical toxicology studies, and 
preliminary results from Study EP-262-101, a Phase 1 first-in-human clinical study in healthy 
subjects. 
In vivo results from a transgenic, human MRGPRX2 knock-in mouse model of acute mast cell 
degranulation demonstrated complete inhibition of vascular permeability by all MRGPRX2 
agonists tested at EP262 plasma concentrations of approximately 
 nM. This was further 
supported by results from nonclinical studies in a chronic disease mouse model of atopic 
dermatitis (AD) induced by cutaneous co-exposure to house dust mite extracts and 

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Staphylococcus aureus Enterotoxin Type B. In the transgenic MRGPRX2 mouse model of AD, 
treatment produced reductions in disease score, transepidermal water loss, and levels of type 2 
T helper cells (Th2) cytokines. Based on several studies in this model evaluating different doses, 
trough EP262 concentrations of at least 
 nM were required to yield full attenuation of 
disease and inflammatory activity. Lower trough concentrations of EP262 did not result in robust 
disease improvement. Given that MRGPRX2 is activated by numerous agonists and that it is not 
known which agonist(s) may be the key factors involved in the pathophysiology of chronic 
urticaria, it is important to select a dose that completely inhibits the multiple agonists tested. 
Thus, it was assumed that EP262 trough concentrations of 
 nM or higher will likely be 
necessary for maximum clinical efficacy. 
Consequently, Part 1 of Study EP-262-201 was designed to assess 2 dose levels: 
• A dose level of 150 mg, which maximizes the likelihood of observing an impact on 
pharmacodynamics (PD)/efficacy while falling within exposures that are anticipated to be 
safe and well tolerated. During the course of the 6-week treatment period, the 150 mg 
dose is predicted to result in the following: 
• EP262 trough concentrations that exceed the full pharmacologic activity threshold 
(
 nM) while remaining within the range of concentrations achieved in the 
multiple-dose portion of Study EP-262-101 
• EP262 concentrations that are well tolerated with no undue safety signals based on 
Study EP-262-101 results at doses 
 mg 
• EP262 exposure that remains below the exposures associated with the no-observed- 
adverse-effect-level (NOAEL) in definitive 42-day toxicology studies 
• A lower dose level of 50 mg that will target EP262 trough concentrations between 
 and 
 nM, which may result in partial pharmacologic activity and will enable 
dose and exposure response analyses to help better characterize the therapeutic dose 
range 
 
The PK profile of EP262 in subjects with CSU is anticipated to be similar to that in healthy 
subjects. To further ensure similar circulating concentrations of EP262 between these two 
populations, subjects with conditions that may alter PK, such as clinically significant hepatic or 
renal impairment, are excluded from participating in this study.
 
 

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5.4. 
Summary of Benefits and Risks 
5.4.1. 
Benefit Summary 
While it is currently uncertain whether patients with CSU will benefit from treatment in this 
study, nonclinical in vitro and in vivo data, as well as scientific publications implicating 
MRGPRX2 as a mediator of mast cell degranulation and associated inflammation (Kapp 1991, 
Morita 1995, Nakamura 2013, Azimi 2017, Nattkemper 2018, Green 2019, Meixiong 2019, 
Serhan 2019, Ogasawara 2020, Wang 2020, Youngblood 2020, Corbiere 2021), provide 
compelling support that EP262 has the potential to be an effective treatment for patients with 
CSU. 
5.4.2. 
Risk Summary 
The doses evaluated in study EP-262-101 were well tolerated with no dose limiting AEs, early 
terminations due to AEs, severe AEs, or SAEs reported. Additionally, no adverse trends in safety 
laboratory measures, vital signs, or ECGs were observed. 

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5.4.3. 
Mitigation Strategy 
For this initial clinical proof-of-concept study, subjects with clinically significant co-morbidities 
such as hepatic, renal, or cardiovascular disease will be excluded. 
 
Routine safety measures have been incorporated into the protocol, including AE reviews, vital 
sign and 12-lead ECG assessments, and laboratory evaluations, including monitoring of bilirubin 
and management of liver test abnormalities (Section 12.10.3). 
5.4.4. 
Overall Benefit:Risk Conclusion 
Overall, the clinical and nonclinical experience to date with EP262 suggests minimal risk to 
subjects participating in Study EP-262-201. Importantly, there is a clear unmet need for novel 
treatment options for CSU. Current clinical guidelines recommend second-generation 
H1 antihistamines (H1AH) as first-line treatment, with the option to increase dosing (Bernstein 
2014, Zuberbier 2022), and omalizumab, an anti-IgE monoclonal antibody, or cyclosporine as 
second-line options for patients who do not adequately respond to antihistamines alone. 
Nonetheless, nearly 60% of patients continue to experience hives despite treatment with 
antihistamines, and almost 30% of omalizumab-treated patients report uncontrolled disease, 
particularly those with moderate-to-severe disease or low serum levels of IgE at baseline (Folci 
2018, Maurer 2019, Maurer 2020, Fok 2021). If determined to be effective, EP262 may 
ultimately have the potential to offer a much-needed novel treatment option for patients suffering 
from CSU. 
 
6. 
TRIAL OBJECTIVES AND PURPOSE 
 
Objectives 
Endpoints 
Primary Objective 
To evaluate the efficacy of EP262 compared to 
placebo in subjects with chronic spontaneous 
urticaria (CSU) 
• Change from baseline to Visit 4 (Week 6) in the 
sum of the daily UAS over a 7-day period 
(UAS7) 

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Secondary Objectives 
To evaluate the safety and tolerability of EP262 
compared to placebo in subjects with CSU 
• Type, frequency, and severity of treatment- 
emergent AEs (TEAEs) 
• Change from baseline in vital signs, ECGs, and 
clinical laboratory parameters 
To evaluate the efficacy of EP262 compared to 
placebo in subjects with CSU as assessed by the 
following: 
• Pruritus severity 
• Hive severity 
• Change from baseline to Visit 4 (Week 6) in the 
sum of the daily ISS over a 7-day period (ISS7) 
• Change from baseline to Visit 4 (Week 6) in the 
sum of the daily HSS over a 7-day period 
(HSS7) 
Exploratory Objectives 

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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
Study EP-262-201 is a Phase 2 randomized, double-blind, placebo-controlled study to evaluate 
the efficacy, safety, and tolerability of EP262 over 6 weeks in subjects with CSU. The study will 
be conducted in 2 parts: Part 1 will assess 50 mg and 150 mg doses of EP262 and Part 2 will 
assess a 25 mg dose of EP262 to further characterize the therapeutic dose range. Part 2 will begin 
after the last subject is randomized into Part 1. Part 1 and Part 2 are identical in terms of their 
visit structure, procedures conducted, and the populations being studied. The primary difference 
between the 2 parts is the EP262 dose levels being assessed. Designated Sponsor (or designee) 
personnel will have access to unblinded individual subject treatment assignments as described in 
Section 9.3.2. 
Each part includes a Screening Period of at least 2 weeks and up to 30 days to assess subject 
eligibility that includes collection of the daily UAS score; a 6-week Double-Blind Treatment 
Period; and a 4-week Safety Follow-Up Period after administration of the last dose of study drug 

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(EP262 or placebo) for a total study duration of up to approximately 14 weeks for each subject 
(Figure 1). In Part 1, approximately 114 subjects will be randomized in a 1:1:1 ratio to receive a 
150 mg dose of EP262, 50 mg dose of EP262, or placebo PO, once daily (QD) during the 6-week 
Double-Blind Treatment Period. In Part 2 of the study, approximately 40 subjects will be 
randomized in a 3:1 ratio to receive either a 25 mg dose of EP262 or placebo PO, QD, during the 
6-week Double-Blind Treatment Period. Enrollment of subjects with prior omalizumab use will 
be limited to 15 subjects in Part 1 and 5 subjects in Part 2. 
Figure 1: 
EP-262-201 Study Design 
Screening 
Period 
Double-Blind 
Treatment Period 
Safety 
Follow-Up Period 
 
 
 
Part 1 
 
 
 
 
Part 2a 
 
 
Screening 
Visit 1 
Day -30 to Day -14 
Enroll/Randomize 
Visit 2 
Day 1 
 
Visit 3 
Week 3 
 
Visit 4 
Week 6 
Follow-Up 
Visit 5b 
Week 10 
 
PO = oral; QD = once daily. 
a Part 2 will begin after the last subject is randomized into Part 1. 
b Any subject who completes the Double-Blind Treatment Period or discontinues study drug (EP262 or placebo) 
early will have a Safety Follow-Up Visit approximately 4 weeks (±3 days) after the last dose of study drug. 
 
7.1.1. 
Screening Period 
The Screening Period will consist of 1 study visit (Visit 1). During this period, subjects will 
undergo assessments to determine study eligibility per inclusion and exclusion criteria and must 
remain on their prescreening background therapy. Visit 1 (Day -30 to Day -14 [inclusive]) may 
be conducted over more than 1 day but must be completed between Day -30 and Day -14 
(inclusive). 
7.1.2. 
Double-Blind Treatment Period 
The Double-Blind Treatment Period will consist of 3 study visits (Visits 2, 3, and 4 [Day 1, 
Week 3, and Week 6]). During this period, all subjects who meet eligibility requirements will be 
enrolled into the study and will be randomized on Visit 2 (Day 1) to receive double-blind, QD, 
PO doses of EP262 or placebo for 6 weeks. In Part 1, subjects will be randomized in a 1:1:1 ratio 
to receive a 150 mg dose of EP262, 50 mg dose of EP262, or placebo PO, QD. In Part 2, subjects 
will be randomized in a 3:1 ratio to receive either a 25 mg dose of EP262 or placebo PO, QD. 
Randomization will be conducted centrally via an Interactive Web Response System (IWRS) and 
stratified based on prior use of omalizumab (yes/no). QD PO dosing of study drug should occur 
after at least a 4 hour fast and administered at approximately the same time of day. Subjects 
should refrain from eating for at least 2 hours postdose. The time and date of all dose 
50 mg EP262 PO QD 
150 mg EP262 PO QD 
Placebo PO QD 
25 mg EP262 PO QD 
Placebo PO QD 

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administrations will be recorded in a daily diary. The first dose of study drug will be 
administered at the clinical site on Visit 2 (Day 1) after all baseline study procedures are 
completed. Visit 2 (Day 1) will not have a visit window; all other visits in the Double-Blind 
Treatment Period will have a visit window of ±3 days. Subjects who discontinue from treatment 
early should have the Early Treatment Termination Visit conducted as soon as possible after the 
last dose of study drug, ideally within 2 days after the last dose of study drug. Throughout the 
treatment period, subjects must remain on their prescreening background therapy, although 
rescue medication may be taken as needed. 
7.1.3. 
Safety Follow-Up Period 
Any subject who completes the Double-Blind Treatment Period or discontinues study drug 
(EP262 or placebo) early will have a Safety Follow-Up Visit approximately 4 weeks (±3 days) 
after the last dose of study drug. 
7.2. 
Start of Study 
A subject is considered to have started the study when the subject signs his/her first informed 
consent to participate in the clinical study. 
The start of the study is the date of when the first subject signs his/her first informed consent to 
participate in the clinical study. 
7.3. 
End of Study 
A subject is considered to have completed the study if he/she has completed all phases of the 
study, including the last study visit (ie, the Safety Follow-Up Visit [Visit 5]). 
The end of the study is defined as the date of the last study visit of the last subject in the study 
globally. The end of study may result from the completion of the study according to the protocol 
or due to early termination by the Sponsor or at the request of a regulatory agency, Institutional 
Review Board (IRB), or Independent Ethics Committee (IEC) (Section 7.6). 
7.4. 
Number of Subjects 
Approximately 154 subjects with CSU will be randomized into this study. Approximately 
114 subjects will be randomized in Part 1 and approximately 40 subjects will be randomized in 
Part 2. Enrollment of subjects with prior omalizumab use will be limited to 20 subjects 
(15 subjects in Part 1 and 5 subjects in Part 2). 
7.5. 
Dose Adjustment Criteria 
The dosage for study drug should be maintained constant during the study. However, dosing of 
study drug may be interrupted or discontinued due to safety findings. Refer to Section 8.6 for 
guidance on mandatory discontinuation of study drug due to safety findings. 

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7.6. 
Criteria for Study Termination 
The Sponsor reserves the right to terminate the study at a clinical site at any time for any reason 
at the sole discretion of the Sponsor. Potential reasons for closure of a clinical site include but are 
not limited to: 
• Good Clinical Practice (GCP) noncompliance 
• Poor study data quality 
The entire study will be terminated by the Sponsor should new information become available 
resulting in a clearly negative benefit/risk balance. The entire study may also be terminated by 
the Sponsor for other reasons or at the request of a regulatory agency, IRB, or IEC. If instructed 
by the Sponsor or designee, the Investigator must implement the termination of the study in a 
timeframe to ensure subject safety and well-being. Refer to Section 8.6.2 (Discontinuation from 
the Study) for instructions for subjects whose participation from the study is discontinued. 
The Investigator and/or Sponsor (or designee) must notify the IRB/IEC of discontinuation of a 
site or the study and the reason for doing so. 
 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
Subjects who have an exclusionary result during the Screening Period (between Visit 1 and 
Visit 2) may have that assessment repeated once at the discretion of the Investigator within the 
screening window and be enrolled if a repeat assessment is within the indicated range as 
specified below for participating in the study. 
8.1. 
Subject Inclusion Criteria 
To be eligible for study participation, all subjects must meet all of the following inclusion 
criteria: 
1. Male or female subject, aged 18 to 80 years, inclusive, at the time of consent 
2. Diagnosis of CSU (presence of urticaria on most days of the week, for a duration of 
6 weeks or longer, at any time before Screening) for ≥6 months 
3. Must be on daily stable doses of H1AH consistent with standard of care for CSU starting 
at least 3 consecutive days immediately prior to the Screening Visit and willing to remain 
on stable doses through the Safety Follow-Up Visit 
4. Current H1AH treatment up to 4 times the approved dose per local treatment guidelines 
5. UAS7 ≥16 during the 7 days prior to randomization (Day 1) (data from at least 4 of the 
7 days are required to be considered an acceptable profile) 
6. If female, must have a negative serum pregnancy test at Screening, be willing to not 
donate eggs from Screening until 12 weeks after the last dose of study drug, and: 
a. Is surgically sterile; or 
b. Has been amenorrhoeic for ≥1 year without an alternative medical cause; or 

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c. If of childbearing potential3, must agree to use 2 forms of contraception, which 
includes at least 1 form of highly effective and 1 effective method4 of contraception 
from Screening until 12 weeks after the last dose of study drug. The following 
methods can achieve a failure rate of less than 1% per year when used consistently 
and correctly and are considered highly effective birth control methods: 
• Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation 
• Progestogen only hormonal contraception associated with inhibition of ovulation 
• Intrauterine device 
• Intrauterine hormone releasing system 
• Bilateral tubal occlusion 
• Vasectomized partner who has received a medical assessment of surgical success 
• Sexual abstinence (complete sexual abstinence defined as refraining from 
heterosexual intercourse for the entire period of risk associated with study drug), 
the reliability of which needs to be evaluated in relation to the duration of the 
clinical study and the preferred and usual lifestyle of the subject 
7. If male and is not confirmed surgically sterile, must be willing to not donate sperm and 
must agree to use a barrier method of contraception (eg, condom with spermicide) during 
intercourse and at least 1 other acceptable contraceptive measure for his female partner(s) 
(eg, hormonal contraceptives, intrauterine device, female surgical sterilization, 
abstinence) from Screening through 12 weeks after the last dose of study drug 
8. Must be able to communicate well with the Investigator, understand and comply with the 
requirements of the study, and understand and provide written consent 
8.2. 
Subject Exclusion Criteria 
All subjects meeting any of the following criteria will be excluded from this study: 
1. Clearly defined underlying etiology for chronic urticarias other than CSU, including 
diseases with possible symptoms of urticaria or angioedema (eg, urticarial vasculitis, 
urticaria pigmentosa, erythema multiforme, mastocytosis, mast cell activation syndrome, 
hereditary or acquired angioedema, lymphoma, leukemia, generalized cancer) 
2. Chronic urticaria with clearly defined predominant or sole trigger (chronic inducible 
urticaria) including urticaria factitia (symptomatic dermographism), cold, heat, solar, 
pressure, delayed pressure, aquagenic, cholinergic, or contact urticaria 
 
 
 
 
3 Women of childbearing potential are defined as those who are fertile, following menarche and until becoming 
postmenopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without 
an alternative medical cause. 
4 Effective methods of contraception include barrier methods of contraception (eg, male condom, female condom, 
cervical cap or diaphragm, and contraceptive sponge). 

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3. Other active skin diseases associated with chronic pruritus that might confound the study 
evaluations and results (eg, AD, bullous pemphigoid, prurigo nodularis, dermatitis 
herpetiformis) 
4. Use of the following prohibited treatments: 
a. Drugs that are agonists at the MRGPRX2 receptor, including icatibant, opioids 
(eg, codeine, morphine), vancomycin, clomipramine, or nondepolarizing 
neuromuscular blocking agents (eg, atracurium, rocuronium, vecuronium, 
cisatracurium, mivacurium) within 14 days before Screening 
b. Monoclonal antibodies (eg, omalizumab, dupilumab, tezepelumab) within 4 months 
or 5 half-lives (whichever is longer) before Screening 
c. Immunosuppressant drugs, including systemic corticosteroids, hydroxychloroquine, 
methotrexate, mycophenolate, cyclosporine, or cyclophosphamide within 30 days 
before Screening 
d. Current or anticipated use of corticosteroids, or uncontrolled disease states, such as 
asthma, psoriasis, or inflammatory bowel disease, where flares are commonly treated 
with oral or parenteral corticosteroids 
e. 
f. 
g. 
5. Active malignancy or history of malignancy of any organ system (other than localized 
squamous cell or basal cell carcinoma of the skin that have been excised or resolved), 
treated or untreated, within the past 5 years from Screening 
6. Evidence of clinically significant cardiac, neurologic, psychiatric, pulmonary, renal, 
hepatic, endocrine (including uncontrolled diabetes mellitus), metabolic, or 
gastrointestinal disease that, in the Investigator’s opinion, would compromise the safety 
of the subject, interfere with the interpretation of the study results, or otherwise preclude 
subject participation 
7. Screening 12-lead ECG that demonstrates clinically relevant abnormalities that may 
affect subject safety 
8. Any clinically significant abnormalities on screening laboratory tests that, in the opinion 
of the Investigator, precludes participation in the study. The following abnormalities will 
specifically be considered exclusionary: 
a. Bilirubin >upper limit of normal (ULN) and/or any known condition that results in 
abnormal bilirubin elevations or fluctuations (eg, Gilbert’s, Dubin-Johnson, Rotor 
syndrome) 
b. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >1.5× ULN 
9. Other co-morbidities that would introduce additional risk factors or interfere with study 
procedures based on clinically significant physical examination, vital sign, standard 

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12-lead ECG, chemistry, hematology, urinalysis, or coagulation results at Screening as 
deemed by the Investigator 
10. Positive result for human immunodeficiency virus (HIV) or presence of actively 
replicating viral hepatitis due to hepatitis B virus (HBV) or hepatitis C virus (HCV) 
infection at Screening 
11. Significant history of abuse of drugs, solvents, or alcohol within the past year 
12. Participation in any clinical study with an investigational or approved drug/device within 
30 days or 5 half-lives (whichever is longer) before Screening or is planning to 
participate in another clinical study while enrolled in this study 
13. History of known or suspected hypersensitivity to any component of study drug 
14. Female who is pregnant, nursing, or intends to become pregnant during the study 
15. Had a major surgery within 8 weeks prior to Day 1 or has a major surgery planned during 
the study 
16. Is directly affiliated with the study at the clinical site or is an immediate family member 
(spouse, parent, child, or sibling; biological or legally adopted) of personnel directly 
affiliated with the study at the clinical site 
17. Is employed by Incyte Corporation or its wholly owned subsidiary, Escient, (that is an 
employee, temporary contract worker, or designee responsible for the conduct of the 
study) or is an immediate family member of an employee of Incyte Corporation or 
Escient 
18. Subject is, in the opinion of the Investigator, not suitable to participate in the study 
19. Subject is performing mandatory military service, deprived of liberty and/or due to a 
judicial decision, cannot take part in clinical studies, or is in a residential care institution 
8.3. 
Study Restrictions 
Unless stated otherwise, subjects must adhere to the following restrictions from Screening until 
the end of the study unless subject safety is compromised: 
• Do not use any drugs of abuse (cannabinoids [eg, oil, recreation smoking] are not 
restricted). 
• Do not use any investigational drugs/devices. 
• Maintain current dose and regimen of all prescribed medication, unless changed in 
consultation with the Medical Monitor. 
• Do not start new medications, including prescription medications and antihistamines 
(besides protocol-defined rescue therapy), during the Double-Blind Treatment Period 
unless deemed necessary by a healthcare provider. 
• 
 
 

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8.4. 
Concomitant Medications 
Subjects are to follow the medication restrictions outlined in the inclusion and exclusion criteria 
(Section 8.1 and Section 8.2) and subject restrictions (Section 8.3) during the study. 
The Investigator should contact the Medical Monitor with any questions about concomitant 
medication use or timing of administration. In instances where a medication is initiated prior to 
discussion with the Medical Monitor, the Investigator must notify the Medical Monitor as soon 
as he/she is aware of the use of the new medication to discuss the subject’s concomitant 
treatment and any impact to participation in the study. 
All medications taken within 14 days before Screening and details of concomitant medications 
from Screening through the end of study participation should be recorded. In addition, all 
medications taken to treat CSU beginning from the date of diagnosis should also be recorded. 
8.5. 
Auxiliary Medicinal Products 
All auxiliary medicinal products to be used in this clinical study are authorized and will be used 
in accordance with their marketing authorizations. 
8.5.1. 
Background Therapy 
All subjects must be on daily stable doses of H1AH that is consistent with standard of care for 
CSU starting at least 3 consecutive days immediately prior to the Screening Visit and willing to 
remain on stable doses through the Safety Follow-Up Visit. 
8.5.2. 
Rescue Medications 
In addition to their daily background therapy, for the duration of the study (Screening, Double- 
Blind Treatment, and Safety Follow-Up Periods), if symptoms worsen, all subjects will be able 
to use a second generation H1AH that is different from background therapy as rescue medication 
as needed. The choice of H1AH and dosage will be determined by the Investigator; however, 
discussion with the subject prior to initiation of any rescue medication is encouraged. Once a 
rescue medication has been selected, switching to a different rescue medication during the study 
is not permitted. Use of rescue medication must be documented. 
8.5.3. 
Permitted Medications 
Allowed second generation H1AH include bilastine, cetirizine, desloratadine, ebastine, 
fexofenadine, levocetirizine, loratadine, and rupatadine. Additional H1AH not listed above may 
be permitted at the discretion of the Medical Monitor. 

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8.6. 
Removal of Subjects from Therapy or Assessment 
If a subject discontinues study drug and/or is withdrawn from the study, the reason will be 
recorded on the electronic case report form (eCRF) page and the Sponsor will be notified within 
24 to 48 hours. 
8.6.1. 
Discontinuation of Study Drug 
Discontinuation of study drug for a subject occurs when the study drug is stopped earlier than the 
protocol planned treatment duration. Discontinuation of study drug is mandatory in the following 
instances: 
• AEs for which continued exposure to study drug would be detrimental, including AEs 
that are Common Technical Criteria for Adverse Events (CTCAE) Grade 4 or higher 
(Section 12.1.2) 
• Abnormal liver laboratory results meeting the threshold for discontinuation as listed 
in Section 12.10.3 
• Withdrawal of consent 
• Lost to follow-up 
• Protocol deviation that results in a significant risk to the subject’s safety 
• Investigator decision 
• Sponsor decision 
• Pregnancy during the study (Section 12.2.3) 
• Any circumstance that results in a negative benefit:risk balance 
For subjects who terminate treatment with study drug early, regardless of the reason, every effort 
will be made to complete the early treatment termination evaluations as soon as possible after the 
last dose of study drug, ideally within 2 days after the last dose of study drug. 
Whenever possible, subjects should remain in the study and complete the remaining study visits 
and assessments even when study drug has been discontinued. Subjects who discontinue study 
drug for any reason and continue with the study visits as planned through Visit 4 (Week 6) 
(participating only in efficacy and safety, but not PK measures) will participate in the Safety 
Follow-Up Visit if the last dose of study drug was administered less than 4 weeks before Visit 4 
(Week 6) to ensure that at least 4 weeks of follow-up data are collected for all randomized 
subjects. 
If a subject discontinues study drug and chooses not to complete all the remaining study visits, 
the subject should have the Early Treatment Termination Visit conducted as soon as possible 
after the last dose of study drug, ideally within 2 days after the last dose of study drug, and a 
Safety Follow-Up Visit approximately 4 weeks (±3 days) after the last dose of study drug if at 
least 4 weeks of follow-up data have not already been collected. If a subject fails to attend the 
Safety Follow-Up Visit and has not withdrawn consent, all reasonable efforts will be made to 
contact the subject to ensure that he/she is in satisfactory health. All contacts and contact 
attempts must be documented in the subject’s medical record. 

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8.6.2. 
Discontinuation from the Study 
Discontinuation from the study is mandatory for the following reasons: 
• Death 
• Withdrawal of consent 
• Lost to follow-up 
• Termination of the study by the Sponsor or at the request of a regulatory agency or an 
IRB or IEC (Section 7.6) 
• Other 
A subject may elect to discontinue study participation at any time for any reason without 
prejudice to their future medical care by the physician or at the institution. If a subject withdraws 
consent, no further evaluation should be performed, and no additional data should be collected. 
The Sponsor may retain and continue to use any data collected before such withdrawal of 
consent. The Investigator should make a reasonable attempt to document the specific reason why 
consent was withdrawn. 
 
9. 
TREATMENT OF SUBJECTS 
9.1. 
Treatment Assignment 
In Part 1, approximately 114 subjects will be randomized in a 1:1:1 ratio to receive a 50 mg dose 
of EP262, 150 mg dose of EP262, or placebo PO, QD during the 6-week Double-Blind 
Treatment Period. In Part 2 of the study, approximately 40 subjects will be randomized in a 
3:1 ratio to receive either a 25 mg dose of EP262 or placebo PO, QD, during the 6-week Double- 
Blind Treatment Period. 
9.2. 
Treatment Compliance 
The Investigator should assess the subject’s compliance with dosing of study drug by counting 
returned study drug capsules and reviewing the subject’s dosing diary as indicated in the 
Schedule of Assessments (Appendix A). 
If the Investigator has concerns about a subject’s dosing compliance, the Investigator should 
discuss this with the subject, assess the reasons for noncompliance and the likelihood that the 
subject will remain noncompliant, and notify the Sponsor accordingly. 
9.3. 
Randomization and Blinding 
9.3.1. 
Randomization 
Beginning at Visit 2 (Day 1), subjects will be randomized in a 1:1:1 ratio to receive a 50 mg dose 
of EP262, 150 mg dose of EP262, or placebo PO, QD for Part 1 or a 3:1 ratio to receive either a 
25 mg dose of EP262 or placebo for Part 2 for 6 weeks during the Double-Blind Treatment 
Period. Randomization will be conducted centrally via an IWRS and stratified based on prior use 
of omalizumab (yes/no). Separate randomization lists will be utilized for each part of the study. 

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The master randomization lists will be kept secured until the study blind is broken as specified in 
the study-specific blinding and unblinding plan. 
Subjects who withdraw for any reason without completing all screening evaluations successfully 
will be considered “screening failures”. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure subjects, to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements, and to respond to queries from 
regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any SAEs. 
9.3.2. 
Blinding 
The Sponsor, Medical Monitor, Contract Research Organization (CRO) staff, Investigators, site 
staff, and subjects will be blinded to subject’s assigned treatment until the database is locked 
except for CRO or vendor staff involved in the analysis of PK samples or safety reporting to 
regulatory agencies. Procedures for emergency unblinding and unblinding for regulatory 
reporting are described in Section 9.3.2.1 and Section 9.3.2.2, respectively. 
9.3.2.1. 
Emergency Unblinding 
If an emergency unblinding during the Double-Blind Treatment Period is required, the subject’s 
treatment assignment may be unblinded through IWRS by the Investigator. If a treatment 
assignment is unblinded, the subject will be discontinued from randomized treatment. 
Blinding codes should only be broken in emergency situations for reasons of subject safety and 
when knowledge of the treatment assignment will impact the clinical management of the subject. 
Every reasonable attempt should be made to complete the post-treatment evaluation procedures 
prior to unblinding as knowledge of the treatment arm could influence subject assessment. 
In all emergency cases, the reasons and rationale for unblinding will be documented in writing 
and maintained in the study file. 
9.3.2.2. 
Unblinding for Regulatory Reporting 
Access to randomization codes and corresponding treatment assignment will be made available 
through the IWRS system to the appropriate individual(s) responsible for unblinding suspected 
unexpected serious adverse reactions for reporting to the Regulatory Authorities. 
9.4. 
Study Visits 
Subjects should fast for at least 8 hours before study visits that require a blood sample for 
assessment of clinical chemistry. Water is acceptable in the morning of clinic visits to ensure the 
subject is hydrated for laboratory sample collection. Subjects should fast at least 4 hours before 
administration of each dose of study drug and refrain from eating for at least 2 hours postdose. 
Each dose of study drug is to be taken with approximately 240 mL (8 fluid ounces) of water on 
an empty stomach. 
Study procedures are listed for each visit in the following sections and summarized in the 
Schedule of Assessments (Appendix A). Further details regarding efficacy, safety, PK, PD, and 
baseline characterization assessments are located in Sections 11, 12, 13, 14, and 15, respectively. 

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9.4.1. 
Screening Period 
9.4.1.1. 
Visit 1 (Day -30 to Day -14 [inclusive]) 
During the Screening Period, subjects will undergo assessments to determine their study 
eligibility. Subjects will be screened and should meet all inclusion criteria and none of the 
exclusion criteria to be enrolled in the study. Any questions regarding eligibility may be 
discussed with the Medical Monitor. 
The following assessments may be conducted over more than 1 day but must be completed 
between Day -30 and Day -14 (inclusive): 
• Completion of informed consent before performance of any study procedures or 
assessments 
• Medical history, including CSU disease history 
• Height 
• Body weight 
• Vital signs 
• Physical examination 
• Standard 12-lead ECG 
• Assessment of baseline concomitant medications, including all medications taken to 
treat CSU beginning from the date of diagnosis, any prior use of omalizumab, and all 
medications taken within 14 days before Screening 
• AE assessment 
• Blood and/or urine sample collection for screening and safety laboratory assessments 
• Eligibility check 
• Electronic device/app training 
• 
 
Subjects will be instructed to complete the UAS and 
 daily, in the morning before dosing (as 
applicable), and at approximately the same time of day, from the Screening Visit to the Safety 
Follow-Up Visit and the 
weekly, in the morning before dosing (as applicable), and at 
approximately the same time of day, from Day 1 to the Safety Follow-Up Visit using the study- 
issued electronic device or app. The questionnaires will be completed during the Screening Visit. 
For all other days that coincide with a study visit (for Visit 2 and beyond), the questionnaires are 
to be completed in the morning before the visit, unless specified otherwise. 
Screening results will be reviewed by the Investigator to determine the subject’s eligibility. 
Subjects who have an exclusionary result during the Screening Period (between Visit 1 and 
Visit 2) may have that assessment repeated once at the discretion of the Investigator within the 
screening window and be enrolled if a repeat assessment is within the indicated range as 
specified in Section 8 for participating in the study. Subjects who are confirmed to be eligible 

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will be asked to return to the site for Visit 2 (Day 1) to be enrolled and randomized into the 
study. 
9.4.2. 
Double-Blind Treatment Period 
9.4.2.1. 
Visit 2 (Day 1) – Enrollment and Randomization 
Subjects who continue to meet study eligibility requirements will be enrolled and randomized 
during Visit 2 (Day 1). 
The following assessments will be performed during Visit 2 (Day 1): 
• Complete 
 
• Confirm that the UAS and 
 were completed daily from the last visit through the 
morning of Visit 2 (Day 1) 
• Vital signs 
• Standard 12-lead ECG 
• Concomitant medication usage assessment 
• AE assessment 
• Eligibility check 
• Blood and/or urine sample collection for PD, safety, PK, and baseline 
characterization laboratory assessments 
• Randomization to study drug treatment assignment via IWRS: 
− Part 1: 50 mg EP262, 150 mg EP262, or placebo in a 1:1:1 ratio 
− Part 2: 25 mg EP262 or placebo in a 3:1 ratio 
• Dispense study drug 
• Upon completion of the assessments listed above, study drug is to be administered PO 
as intact capsules (swallowed whole, not split, opened, or chewed) and taken with 
approximately 240 mL (8 fluid ounces) of water on an empty stomach 
9.4.2.2. 
Visit 3 (Week 3) 
The following assessments will be performed during Visit 3 (Week 3): 
• Complete 
 
• Confirm that the UAS and 
were completed daily from the last visit through the 
morning of Visit 3 (Week 3) 
• Confirm that the 
 was completed weekly from the last visit through Visit 3 
(Week 3) 
• Collect study drug 
• Assess study drug accountability and compliance 

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• Vital signs 
• Concomitant medication usage assessment 
• AE assessment 
• Blood and/or urine sample collection for PD, safety, and PK laboratory assessments 
• Dispense study drug 
• Upon completion of the assessments listed above, study drug is to be administered PO 
as intact capsules (swallowed whole, not split, opened, or chewed) and taken with 
approximately 240 mL (8 fluid ounces) of water on an empty stomach 
9.4.2.3. 
Visit 4 (Week 6) 
The following assessments will be performed during Visit 4 (Week 6): 
• Complete 
 
• Confirm that the UAS and 
 were completed daily from the last visit through the 
morning of Visit 4 (Week 6) 
• Confirm that the 
 was completed weekly from the last visit through Week 5 
• Collect study drug 
• Assess study drug accountability and compliance 
• Body weight 
• Vital signs 
• Standard 12-lead ECG 
• Concomitant medication usage assessment 
• AE assessment 
• Blood and/or urine sample collection for PD, safety, and PK laboratory assessments 
9.4.3. 
Safety Follow-Up Period 
9.4.3.1. 
Visit 5 (Week 10) 
The following assessments will be performed during the Safety Follow-Up Visit, approximately 
4 weeks after the last dose of study drug: 
• Complete the 
 
• Confirm that the UAS and 
 were completed daily from the last visit through the 
morning of Visit 5 (Week 10) 
• Confirm that the 
was completed weekly from the last visit through Week 9 
• Body weight 
• Vital signs 

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• Standard 12-lead ECG 
• Concomitant medication usage assessment 
• AE assessment 
• Blood and/or urine sample collection for PD, safety, and PK laboratory assessments 
9.4.4. 
Early Treatment Termination Visit 
Subjects who discontinue from treatment early should have the Early Treatment Termination 
Visit conducted as soon as possible after the last dose of study drug, ideally within 2 days after 
the last dose of study drug. The following assessments will be performed during the Early 
Treatment Termination Visit: 
• Complete 
 
• Confirm that the UAS and 
 were completed daily from the last visit through the 
morning of the Early Treatment Termination Visit 
• Confirm that the 
was completed weekly from the last visit through the Early 
Treatment Termination Visit 
• Collect study drug 
• Assess study drug accountability and compliance 
• Body weight 
• Vital signs 
• Standard 12-lead ECG 
• Concomitant medication usage assessment 
• AE assessment 
• Blood and/or urine sample collection for PD, safety, and PK laboratory assessments 
 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Study Drug 
In Part 1, capsules containing 25 mg of EP262, 75 mg of EP262, or placebo will be supplied in 
bottles in a manner to ensure the study blind. Each subject will take 2 capsules per dose. 
 
 
10.2. 
Study Drug Packaging and Labeling 
Study drug will be packaged into bottles labeled with a unique number and supplied to clinical 
sites in a blinded manner. 

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10.3. 
Study Drug Storage 
The study drug capsules should be stored at controlled room temperature, 15°C to 25°C (59°F to 
77°F), with excursions up to 30°C (86°F). 
10.4. 
Study Drug Administration 
Each study drug dose is to be administered PO as intact capsules (swallowed whole, not split, 
opened, or chewed) and taken with approximately 240 mL (8 fluid ounces) of water on an empty 
stomach. Subjects will be instructed to take the study drug at approximately the same time of the 
day after a fast of at least 4 hours. Subjects should refrain from eating for at least 2 hours 
postdose. On the days of clinic visits, the time of study drug administration may differ depending 
on the scheduled visit time. The first dose of study drug will be administered at the clinical site 
on Visit 2 (Day 1) after all baseline study procedures are completed. 
10.4.1. 
Instructions for Missed Dose(s) 
Subjects should be instructed that if they forget to take a dose, they can take the dose within 
8 hours of the normal dosing time; otherwise, they should take their next dose at the regular time 
on the following day. If the subject vomits the capsules, he/she should be instructed not to take 
additional capsules on the same day but to take the next dose at the regular time on the following 
day. Subjects should be instructed to contact the Investigator if they miss 2 or more consecutive 
doses. 
10.5. 
Study Drug Dispensing and Accountability 
Subjects will record self-administration of study drug daily in a dosing diary that will be 
reviewed at each clinical site visit during the Double-Blind Treatment Period by site staff. 
Subjects should be instructed to retain the study drug, including the study drug bottle, even if 
empty, and to return it and any remaining study drug to the clinical site at their next visit. The 
site staff should perform study drug accountability and, if applicable, follow-up with the subject 
to retrieve any remaining study drug that has not been returned. 
10.6. 
Study Drug Handling and Disposal 
Study drug will be sent to the clinical site under appropriate storage conditions. Upon receipt of 
study drug, site staff are to open the shipment, and verify that the amount and identity of the 
contents match that stated in the enclosed shipping form. The Sponsor (or designee) is to be 
notified immediately about any irregularities, discrepancies, or damage. 
Study drug will be provided for use only in this study and is not to be used for any other purpose. 
The site staff will maintain a full record of study drug accountability as described in 
Section 10.5. 
Upon completion of the study, used and unused study drug and study drug bottles are to be 
returned to the Sponsor (or designee) or, if prior Sponsor approval is obtained, disposed of in 
accordance with applicable site procedures. Site staff must maintain documentation of any 
missing or unreturned study drug. The final disposition of all study drug received at the site is to 
be documented. 

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10.7. 
Product Quality Complaints 
A product quality complaint (PQC) is defined as any suspicion of a product defect or deficiency 
related to manufacturing, labeling, or packaging (ie, any dissatisfaction relative to the identity, 
quality, durability, reliability, safety, effectiveness, or performance of a product, including its 
labeling or package integrity). A PQC may have an impact on the safety and efficacy of the 
product. Timely, accurate, and complete reporting and analysis of PQC information from studies 
are crucial for the protection of subjects. 
All initial PQCs must be reported to the Sponsor or CRO by clinical-site personnel within 
24 hours after being made aware of the potential defect. Whenever possible, the associated 
product should be maintained in accordance with the label instructions pending further guidance 
from the Sponsor. 
 
11. 
EFFICACY ASSESSMENTS 
The primary efficacy evaluation is based on the UAS, a patient-reported assessment of disease 
activity. Secondary efficacy evaluations include assessments of itching (ISS) and hives (HSS), 
both of which comprise the UAS. Exploratory efficacy evaluations include 
 
 
 All efficacy assessments will be performed as indicated in the Schedule of 
Assessments (Appendix A). 
Examples of the patient-reported assessments are provided in the appendices but are not to be 
distributed to subjects for completion. Subjects will be trained on completion of all patient- 
reported assessments using the study-issued electronic device or application (app). 
All subjects who were given a study-issued device, including those who fail Screening, will be 
required to return it to the site once their participation in the study is complete. 

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12. 
SAFETY ASSESSMENTS 
Safety evaluations, including AEs, concomitant medications, medical history, vital signs, 
physical examinations, standard 12-lead ECGs, and laboratory evaluations of safety will be 
performed as indicated in the Schedule of Assessments (Appendix A). 
12.1. 
Adverse Events 
12.1.1. 
Definition of an Adverse Event 
An AE is defined as any untoward medical occurrence in a subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable or unintended sign (including a clinically 
significant abnormal laboratory finding), symptom, or disease temporally associated with the use 
of a medicinal (investigational) product. 
Medical conditions present at baseline that worsen in severity or frequency after exposure to 
study drug are considered TEAEs. A TEAE is any condition that was not present prior to 
treatment with the study drug but appeared following treatment, was present at treatment 
initiation but worsened during treatment, or was present at treatment initiation but resolved and 
then reappeared while the individual was on treatment (regardless of the intensity of the AE 
when the treatment was initiated). Planned hospital admissions or surgical procedures for an 
illness or a disease that existed before administration of study drug, and for which the condition 
has not worsened since starting study drug, are not to be considered TEAEs/treatment-emergent 
SAEs. Events with emergency room visits that are less than 24 hours will also not be considered 
SAEs unless they meet one of the criteria listed in Section 12.2.1. 

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Clinically significant abnormal laboratory tests, 12-lead ECG assessments, or vital sign results 
may constitute an AE if they meet one of the criteria listed in Section 12.1.4.1. However, 
whenever possible, the underlying diagnosis should be listed in lieu of associated abnormal 
results. Abnormalities deemed not clinically significant by the Investigator should not be 
reported as AEs. 
12.1.2. 
Determining Severity of Adverse Events 
AEs must be graded for severity (ie, intensity) using CTCAE, version 5.0 (HHS 2017). A 
severity category of mild, moderate, severe, life-threatening, or death, as defined in Appendix B, 
must be entered on the AE eCRF. The criteria below are to be used for determining the severity 
of AEs where there is no actual CTCAE term for the specific reported AE found in the CTCAE, 
version 5.0 guideline (Appendix B). It should be noted that the term “severe” used to grade 
intensity is not synonymous with the term “serious”. The assessment of severity is made 
regardless of the relationship to study drug or of the seriousness of the AE. When reporting AEs, 
reference should be made to the CTCAE manual for guidance on appropriate grading. 
Grade 1: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
Grade 2: 
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental activities of daily living 
(eg, preparing meals, shopping for groceries or clothes, using the 
telephone, managing money). 
Grade 3: 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling, 
limiting selfcare activities of daily life (eg, bathing, dressing and 
undressing, feeding self, using the toilet, taking medications, not 
bedridden). 
Grade 4: 
Life-threatening consequences; urgent intervention indicated. 
Grade 5: 
Death related to AE. 
12.1.3. 
Determining Causality of Adverse Events 
Causality refers to the relationship of the event to the study drug (EP262 or placebo). The 
Investigator will assess the causality of the event according to the following criteria: 
• Not related – A reaction for which sufficient data exist to indicate that the etiology is 
unrelated to the study drug. 
• Related – A reaction that follows a reasonable temporal sequence from 
administration of study drug; that follows a known or expected response pattern to the 
study drug, which may or may not reasonably have been produced by a number of 
other factors including underlying disease, complications, concomitant drugs, or 
concurrent treatments; and/or that could not be reasonably explained by other factors 
such as underlying disease, complications, concomitant drugs, or concurrent 
treatments; and/or disappears or decreases on cessation or reduction in study drug 
dose; and/or reappears or worsens when the study drug is administered. 

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12.1.4. 
Recording Adverse Events 
All AEs must be recorded in the source documents and in the eCRFs provided by the Sponsor 
from the signing of the Informed Consent Form (ICF) until the end of study participation. AEs 
will be assessed for likelihood of causal relationship to the study drug (EP262 or placebo) and 
severity. 
The new onset of signs, symptoms, or other findings that occur before signing of the ICF will be 
captured as medical history (Section 12.3). 
12.1.4.1. Special Instructions for Recording Adverse Events in the eCRF 
Diagnosis versus Signs and Symptoms 
If a diagnosis is known at the time of reporting, this should be recorded in the eCRF rather than 
the individual signs and symptoms (eg, record only hepatitis rather than elevated transaminases, 
bilirubin, and jaundice). However, if a constellation of signs and/or symptoms cannot be 
medically characterized as a single diagnosis or syndrome at the time of reporting, each 
individual event should be recorded as an SAE or AE on the eCRF. If a diagnosis is subsequently 
established, it should be reported as follow-up and should replace the individual signs and/or 
symptoms as the event term on the eCRF, unless the signs/symptoms are clinically significant. 
Adverse Events Occurring Secondary to Other Events 
In general, AEs occurring secondary to other events (eg, clinical sequelae or a cascade of events) 
should be identified by their primary cause. For example, if severe vomiting is known to result in 
dehydration, it is sufficient to record only vomiting as an SAE or AE on the eCRF. However, 
medically significant AEs occurring secondary to an initiating event that are separated in time 
should be recorded as independent events on the eCRF. For example, if severe vomiting leads to 
acute renal failure, both events should be recorded on the eCRF. 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution, between subject evaluation 
timepoints. Such events should only be recorded once on the eCRF. If a persistent AE becomes 
more severe or lessens in severity, it should be recorded as a new AE on the eCRF. 
A recurrent AE is one that occurs and resolves between subject evaluation timepoints, and 
subsequently recurs. Each reoccurrence of an AE should be recorded on the eCRF. 
Abnormal Laboratory Values or Vital Signs 
Protocol defined laboratory values and vital signs will be reported as AEs if the abnormal 
laboratory or vital sign result: 
• Requires an adjustment in the study drug(s) or discontinuation of treatment; 
• Requires additional testing, excluding repeat testing of the lab in question, or surgical 
intervention; 
• Is associated with accompanying signs/symptoms that are not considered part of a 
preexisting diagnosis or syndrome; or 
• Is considered clinically significant by the Investigator 

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If an abnormal laboratory value or vital sign is the result of an evaluation of clinical signs, 
symptoms, or suspected diagnosis during the conduct of the study, the signs/symptoms or 
diagnosis should be reported as an AE (or if appropriate, an SAE) only if clinically significant, 
and the associated laboratory value or vital sign should be considered additional information that 
must be collected on the relevant eCRF. 
12.2. 
Serious Adverse Events 
12.2.1. 
Definition of a Serious Adverse Event 
An SAE is any untoward medical occurrence, that at any dose: 
• Results in death; 
• Is life-threatening, ie, the subject is, in the opinion of the Investigator, at immediate 
risk of death from the event as it occurred, (it does not include an event that, had it 
occurred in a more severe form, might have caused death); 
• Requires hospital admission or prolongs hospitalization. Planned hospital admissions 
or surgical procedures for an illness or a disease that existed before administration of 
study drug, and for which the condition has not worsened since starting study drug, 
are not to be considered SAEs. Emergency room visits that are less than 24 hours will 
also not be considered SAEs unless any of the other serious criteria is fulfilled; 
• Results in persistent or significant disability or incapacity; 
• Is a congenital anomaly/birth defect; or 
• Is a medically significant event that, based on appropriate medical judgment, may 
jeopardize the subject and may require medical or surgical intervention to prevent one 
of the outcomes listed above. 
Note: A distinction should be drawn between SAEs and severe AEs. Severity is a measure of the 
intensity of an AE, while the criteria for seriousness are indications of adverse subject outcomes 
for regulatory reporting purposes. A severe AE is not necessarily considered an SAE. For 
example, a headache that persists for several hours may be considered a severe AE but not an 
SAE. Conversely, a wound infection that may be considered minor could be an SAE if it 
prolonged hospitalization. 
12.2.2. 
Reporting Serious Adverse Events 
The Investigator and the Sponsor will monitor safety for this study. A Serious Adverse Event 
Report (SAER) Form is to be completed for each SAE occurring after signing of the ICF until 
30 days after the last dose of study drug, regardless of causality. 
All SAE reports must be reported within 24 hours of the Investigator’s knowledge of the 
event to 
. If requested by the Sponsor, any supporting 
documentation (eg, medical records) sent to 
with the 
SAER Form must have subject identifying information (eg, subject names, subject addresses, 
medical records number) redacted by the site. Follow-up information to all SAEs should be 
submitted to the Sponsor, or designee, in the same timeframe as initial reports. 

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All SAEs will be followed until resolution or medical stabilization (in cases where resolution 
would not be expected). 
In accordance with applicable regulations and local laws, the Sponsor or designee will report all 
serious and unexpected AEs assessed as related to study drug by the Investigator and/or Sponsor, 
to the regulatory authorities within the required timeframe. The Investigator will be responsible 
for reporting this safety information to his or her IRB/IEC. 
If the Investigator becomes aware of an SAE any time after study completion and determines it is 
related to the study drug, the SAE must be reported to the Sponsor or designee within 24 hours 
of the Investigator’s knowledge of the SAE. 
12.2.3. 
Pregnancy 
Pregnancy in and of itself is not an AE, although pregnancies occurring in subjects or partners of 
male subjects are considered immediately reportable events. If a pregnancy occurs in a subject, 
study drug must be discontinued immediately. The pregnancy must be reported to Innovaderm 
Drug Safety via email at EP-262-201_drugsafety@innovaderm.com within 24 hours of the 
Investigator’s knowledge of the pregnancy using the Pregnancy Reporting Form. 
The Investigator will follow the pregnant woman until completion of the pregnancy, and must 
notify the Sponsor, or designee, of the outcome within 24 hours of the Investigator’s knowledge 
of the pregnancy outcome. The Investigator will provide this information on the Pregnancy 
Reporting Form. This notification includes pregnancies resulting in live, “normal” births. 
If the pregnant subject experiences an SAE during pregnancy, or the outcome of the pregnancy 
meets the criteria for immediate classification as an SAE (ie, spontaneous abortion [any 
congenital anomaly detected in an aborted fetus is to be documented], stillbirth, neonatal death, 
or congenital anomaly), the Investigator should follow the procedures for reporting SAEs 
(ie, report the event to the Sponsor via email at 
 
within 24 hours of the Investigator’s knowledge of the event). 
All neonatal deaths and congenital anomalies that occur within 30 days of birth (regardless of 
causality) should be reported as SAEs to the Sponsor or designee. In addition, any infant death or 
congenital anomaly occurring after study completion that the Investigator suspects is related to 
the in-utero exposure to the study drug should also be reported to the Sponsor or designee. 
12.3. 
Medical History 
The Investigator or designee will collect and review the subject’s medical history, including CSU 
disease history, to evaluate the subject’s eligibility for study participation. The new onset of 
signs, symptoms, or other findings that occur from before signing of the ICF will be captured as 
medical history. 
12.4. 
Vital Signs 
Vital signs, including sitting systolic and diastolic blood pressure, pulse rate, body temperature, 
and respiratory rate, will be measured predose (as applicable) after at least 5 minutes of rest. 
Vital signs are to be performed predose if the dose is administered at the site. 

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12.5. 
Body Weight and Height 
Body weight should be measured with no shoes and heavy clothing (outdoor clothing such as 
coats) on and using a calibrated scale throughout the study. Height should be measured using a 
stadiometer with no shoes. 
12.6. 
Physical Examinations 
Physical examinations will include but are not limited to an assessment of general appearance, 
skin, HEENT (head, eyes, ears, nose, throat), musculoskeletal, thyroid/endocrine, cardiovascular, 
chest/lung, neurologic, abdomen, and extremities/general body systems. 
Symptom directed physical examinations to assess clinically significant changes from Screening 
or any new signs or symptoms may be conducted at other visits as determined by the Investigator 
based on subject complaint. 
Clinically significant abnormalities from before signing of the ICF will be recorded as medical 
history, and clinically significant changes after signing the ICF will be recorded as AEs. 
12.7. 
Standard 12-Lead Electrocardiograms 
Twelve-lead ECGs are to be performed predose (as applicable) with subjects in a supine position 
after at least 5 minutes of rest. An ECG is to be performed predose if the dose is administered at 
the site. 
12.8. 
Laboratory Evaluations of Safety 
Samples for the following laboratory tests should be collected after an overnight fast (at least 
8 hours): 
• Chemistry: sodium, albumin, alkaline phosphatase (ALP), bicarbonate, calcium, 
corrected calcium, chloride, bilirubin (total, indirect, and direct), AST, ALT, blood 
urea nitrogen, urea, creatinine, glucose, magnesium, phosphorus, potassium, creatine 
phosphokinase, total cholesterol, triglycerides, high-density lipoprotein cholesterol, 
low-density lipoprotein cholesterol, lactate dehydrogenase, gamma- 
glutamyltransferase, and total protein 
• Hematology: hemoglobin, hematocrit, mean corpuscular hemoglobin, mean 
corpuscular hemoglobin concentration, mean corpuscular volume, white blood cell 
count (total and differential), red blood cell count, platelet count, and platelet volume 
• Urinalysis: leukocyte esterase, nitrites, pH, protein, specific gravity, glucose, occult 
blood, ketones, bilirubin, and urobilinogen; microscopic analysis is to be performed 
only if protein, leukocyte esterase, blood or nitrite is positive 
• Coagulation: activated partial thromboplastin time, international normalized ratio 
(INR), and prothrombin time 
• Pregnancy testing: required for all females; serum test at Screening (Visit 1) and urine 
test for all other visits where pregnancy testing is required 

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The urine pregnancy test for female subjects will be conducted locally; all other planned 
laboratory evaluations of safety will be conducted at a central laboratory. Details for sample 
collection, processing, storage, and shipment will be provided in the Laboratory Manual. 
12.9. 
Other Laboratory Evaluations 
Samples for the following laboratory tests will be collected: 
• Serology: HIV I/II, HBV (hepatitis B surface antigen), HCV 
These planned laboratory evaluations will be conducted at a central laboratory. See the 
Laboratory Manual for additional details. 
12.10. 
Subject Safety Guidelines 
12.10.1. 
Potential Side Effects 
Refer to Section 5.4.2 and the Investigator’s Brochure for additional EP262 information 
regarding potential side effects. 
12.10.2. 
Overdose 
No specific information is available on the treatment of overdose of EP262. Additionally, there is 
no specific antidote to EP262. In a case of overdose, appropriate supportive measures should be 
employed and the case documented as a protocol deviation (Section 18.1). An overdose does not 
constitute an AE; however, the subject should be closely monitored for any potential AEs. 
The overdose must be reported to Innovaderm Drug Safety via email at 
within 24 hours of the Investigator’s knowledge of 
the overdose using the Overdose Reporting Form. 
12.10.3. 
Management of Liver Test Abnormalities 
Subjects with an increase in ALT or AST to >3× ULN OR total bilirubin >2× ULN should be 
followed by repeat testing within 48 to 72 hours of the initial serum chemistry results, if possible, 
to monitor for suspected drug-induced liver injury. Test results from local laboratories and the 
associated normal ranges are to be captured in the database. In conjunction with this, a physical 
examination should be performed and AE information should be collected. If symptoms persist 
or repeat testing shows ALT or AST >3× ULN or total bilirubin >2× ULN, subjects should be 
closely monitored as defined below to determine whether the abnormalities are improving or 
worsening: 
• Repeating liver enzyme and serum bilirubin tests 2 or 3 times weekly. Frequency 
of retesting can decrease to once a week or less if abnormalities stabilize or study 
drug has been discontinued and the subject is asymptomatic. 
• Obtaining a more detailed history of symptoms and prior or concurrent diseases. 
• Obtaining a history of concomitant drug use (including nonprescription 
medications and herbal and dietary supplement preparations), alcohol use, 
recreational drug use, and special diets. 

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• Ruling out acute viral hepatitis types A, B, C, D, and E; autoimmune or alcoholic 
hepatitis; hypoxic/ischemic hepatopathy; and biliary tract disease. 
• Obtaining a history of exposure to environmental chemical agents. 
• Obtaining additional tests to evaluate liver function, as appropriate (eg, INR, 
direct bilirubin). 
If close observation is not possible, study drug should be interrupted until further investigation 
can be performed. 
Rechallenge may be considered if an alternative cause for the abnormal liver tests (ALT, AST, 
total bilirubin) is identified and the laboratory abnormalities resolve to normal or baseline values. 
The Investigator and Sponsor’s designated Medical Monitor must discuss and agree with any 
decision to rechallenge. Rechallenge should not occur when the etiology of the liver test 
abnormalities is considered possibly drug-induced. 
Discontinuation of treatment should be considered if the following abnormality or group of 
abnormalities occur: 
• ALT or AST >8× ULN 
• ALT or AST >5× ULN for more than 2 weeks 
• ALT or AST >3× ULN AND total bilirubin >2× ULN OR INR >1.5 
• ALT or AST >3× ULN with the appearance of new onset fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
 
13. 
PHARMACOKINETICS ASSESSMENTS 
Blood sampling will be collected predose (as applicable) at Visits 2, 3, 4, and 5 (Day 1, Week 3, 
Week 6, and Safety Follow-Up Visit) to analyze trough EP262 concentrations. The EP262 
metabolite profile may also be analyzed from these trough samples. 
 
14. 
PHARMACODYNAMIC ASSESSMENTS 

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15. 
BASELINE CHARACTERIZATION 
 
16. 
STATISTICS 
Data summaries will use descriptive statistics (n, mean, standard deviation, median, minimum, 
and maximum) for continuous variables and frequency and percentage for categorical and 
ordinal variables. Unless otherwise specified, endpoints will use the last pre-treatment value 
prior to the first dose of study drug as baseline. All data collected will be included in subject data 
listings. 
A formal Statistical Analysis Plan (SAP) will be prepared and finalized before database lock. 
Additional statistical analysis details will be included in the SAP. 
16.1. 
Analysis Sets 
The following analysis sets will be considered: 
• Full Analysis Set: All subjects who are randomized and take at least 1 dose of 
randomized study drug will be included in the Full Analysis Set (FAS). Subjects in 
the FAS will be analyzed according to randomized treatment assignment. All efficacy 
and PD analyses will be based on the FAS. 
• Per Protocol Set: The Per Protocol (PP) Set is a subset of the FAS containing 
subjects who meet study eligibility requirements and had no protocol deviations that 
might impact the assessment of efficacy and/or PD measurements. Subjects will be 
analyzed according to randomized treatment assignment. The PP Set will be used for 
sensitivity analyses relating to efficacy and/or PD. The type of protocol deviations 

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governing exclusion from the PP Set will be determined prior to database lock and 
will be detailed in the SAP. 
• Safety Analysis Set: All subjects who are randomized and take at least 1 dose of 
randomized study drug will be included in the Safety Analysis Set. Safety analyses 
will be based upon treatment actually received. 
• PK Set: All subjects who receive at least 1 dose of EP262 and provide adequate 
blood samples for bioanalysis will be included in the PK Set. 
16.2. 
Estimand 
Consistent with the International Council for Harmonisation (ICH) Guideline E9 (R1) addendum 
on estimands and sensitivity analysis in clinical trials to the guideline on statistical principles for 
clinical trials (FDA 2021), the definition of the attributes of the primary estimand of this study is 
provided in this section. 
The primary estimand of the study is to assess the difference in disease activity in pruritus and 
hives in subjects with CSU treated with EP262 or placebo, as measured by change in weekly 
UAS7 after 6 weeks of randomized treatment, regardless of treatment discontinuation and use of 
prohibited and/or rescue medications. 
The population targeted by the scientific question is defined via the inclusion and exclusion 
criteria as part of the protocol. A key aspect of eligibility is that subjects must have moderate-to- 
severe disease activity in CSU at baseline, defined as a UAS7 of at least 16. 
Premature discontinuation from study drug and use of prohibited and/or rescue medications are 
the primary potential intercurrent events that could occur. The treatment policy strategy is used 
for the primary estimand, consistent with the intent-to-treat principle. 
16.3. 
Endpoints 
16.3.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the change from baseline in UAS7 at Visit 4 (Week 6). 
16.3.2. 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are: 
• Change from baseline in ISS7 at Visit 4 (Week 6) 
• Change from baseline in HSS7 at Visit 4 (Week 6) 
16.3.3. 
Exploratory Endpoints 

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16.4. 
Sample Size Considerations 
The study will enroll approximately 154 subjects. 
In Part 1, approximately 114 subjects will be randomized in a 1:1:1 ratio to receive 50 mg of 
EP262, 150 mg of EP262, or placebo. 
In Part 2, approximately 40 subjects will be randomized in a 3:1 ratio to receive 25 mg of EP262 
or placebo. 
Overall, approximately 30, 38, 38, and 48 subjects will be randomized to receive 25 mg EP262, 
50 mg EP262, 150 mg EP262, and placebo, respectively, across both parts of the study. 
For Part 1, a sample size of 34 subjects per treatment group will provide 80% power to detect an 
8-point difference in the UAS7 change from baseline at Visit 4 (Week 6), assuming a standard 
deviation of 13 points, and a 2-sided alpha of 10%. 
For Part 2, a sample size of 27 subjects receiving 25 mg of EP262 and 43 subjects receiving 
placebo pooled from both parts of the study will provide 80% power to detect an 8-point 
difference in the UAS7 change from baseline at Visit 4 (Week 6) between EP262 25 mg and 
placebo, with the same assumption of 13-point standard deviation and 2-sided alpha of 10%. 

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With an estimated early withdrawal rate of approximately 10%, the planned enrollment of 
38 subjects per treatment group (50 mg EP262, 150 mg EP262, and placebo) in Part 1 and 
40 subjects (30 subjects in 25 mg EP262 and 10 subjects in placebo) in Part 2 will ensure 
adequate sample size to complete the 6-week treatment period. 
16.5. 
Subject Disposition 
Disposition of subjects will be summarized by treatment group and overall. Completion status 
and reasons for discontinuation will also be summarized. 
The number and percentage of subjects in each analysis set will be summarized. 
16.6. 
Demographics and Baseline Characteristics 
Demographic data and baseline characteristics for each analysis set will be summarized by 
treatment group and overall using descriptive statistics. 
16.7. 
Study Drug Usage and Compliance 
Compliance rate will be computed for each subject and will be summarized for the Safety 
Analysis Set using summary statistics by treatment group and overall. 
Duration of treatment will also be summarized. 
16.8. 
Efficacy and Pharmacodynamic Analysis 
Efficacy and PD analyses will be based on the FAS. The primary and secondary endpoint 
analyses will also be repeated in the PP Set as supportive analyses. 
Efficacy analyses will compare placebo and each EP262 dose separately. Subjects who receive 
placebo in Parts 1 and 2 will be pooled for analysis. Additional analysis comparing placebo and 
all EP262 doses combined may be performed as appropriate. Statistical testing will be performed 
as a 2-sided test with a statistical significance level of 0.10. 
For UAS, a weekly score will be computed as the sum of the daily UAS over the 7 days prior to 
the timepoint of interest. If a subject has at least 4 completed daily scores on the UAS (both 
domains) over the 7 days prior to the timepoint of interest, the UAS7 will be defined as the 
average daily scores, multiplied by 7. The daily UAS is considered missing if either the ISS or 
HSS is missing. If a subject has fewer than 4 completed daily scores on the UAS over the 7 days 
prior to the timepoint of interest, then the UAS7 will be considered missing for that timepoint. 
All changes from baseline endpoints are defined as absolute change. For select endpoints, 
percent change from baseline will also be summarized. 
16.8.1. 
Primary Efficacy Analysis 
The UAS7 will be analyzed using a mixed effects model for repeated measures based on the data 
from each week up to Week 6. The model will include treatment, week, and treatment by week 
interaction as fixed effects. Additional model covariates will include baseline UAS7 score and 
randomization strata. The treatment effect will be the contrast between EP262 and placebo 
least-squares (LS) means. 

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16.8.2. 
Additional Efficacy and Pharmacodynamic Analyses 
All efficacy and PD endpoints described in Section 16.3.2 and Section 16.3.3 will be 
summarized. Efficacy endpoints that are defined as continuous variables will be analyzed using a 
similar model as described for the primary efficacy endpoint if they are collected at multiple 
post-baseline visits; otherwise, they will be analyzed using analysis of covariance (ANCOVA) 
adjusted for randomization strata and baseline measurements of the response parameter of 
interest. For continuous endpoints that do not meet the normal distribution assumption, they will 
be analyzed by stratified Hodgens-Lehmann estimates for the median, with the 90% confidence 
intervals derived using stratified Van-Elteren test. Other endpoints defined as response 
proportions will be analyzed using a Cochran-Mantel-Haenszel test stratified by randomization 
strata. Time-to-event data will be analyzed using a Cox regression model, stratified by 
randomization strata. 
16.8.3. 
Primary and Sensitivity Analyses to Address Missing Data in the Primary 
Analysis 
The primary analysis of the primary endpoint of change from baseline in UAS7 will include all 
observed data (weekly UAS7 scores considered non-missing) with no data imputations, under 
the assumption of missing at random. 
As a sensitivity analysis, the primary endpoint will also be analyzed with multiple imputation 
procedures (Rubin 1987). The SAP will provide full detail of the methodologies that will be 
used. 
16.9. 
Safety Analysis 
The Safety Analysis Set will be used for the summaries of the safety data. Safety data will be 
summarized by treatment group and overall. 
The safety and tolerability of EP262 will be assessed by comparing the frequency, causality, and 
severity of AEs as well as treatment discontinuations due to AEs. AEs will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA) by System Organ Class and preferred 
term. AEs that begin after the first administration of study drug, or existing AEs that worsen after 
the first dose of study drug, are considered treatment emergent. All AE summaries will include 
TEAEs, and all AEs will be presented in data listings. 
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Dictionary and summarized descriptively by Anatomic Therapeutic Chemistry (ATC) class using 
counts and percentages. Medications started prior to the first dose of study drug will be indicated 
in the data listings. Use of rescue medications will also be summarized. 
Changes in vital signs, standard 12-lead ECGs, and laboratory evaluations will be summarized 
descriptively. 
16.10. 
Pharmacokinetic Analysis 
The PK Set will be used for the summaries of plasma concentrations of EP262. A descriptive 
summary of the observed plasma concentrations will be displayed by time and by treatment 
group. 

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16.11. 
Subgroup Analyses 
Given the small sample size, no formal subgroup analyses are planned for this study. 
16.12. 
Multiple Comparison/Multiplicity 
No adjustment for multiplicity will be performed to control overall family-wise type I error due 
to the hypothesis generating nature of this study. Each pairwise comparison between EP262 and 
placebo will be conducted at a 10% level. 
16.13. 
Interim Analysis 
Given the hypothesis-generating nature of this study, an optional interim analysis may be 
conducted to support business needs. The interim analysis would evaluate the effects of EP262 
on UAS7, other select efficacy endpoints, and safety. 
The decision to conduct an optional interim analysis and the timing of the analysis will be 
documented in the study files prior to conduct of the interim analysis. Additional details about 
the interim analysis, if applicable, will be provided in the SAP, which is to be finalized before 
the database lock and unblinding of the study data, as applicable. The SAP will be amended if 
emerging data from the completed interim analysis leads to substantial change in the study 
protocol that has significant impact on the statistical analyses. 
 
17. 
QUALITY CONTROL AND DATA MANAGEMENT 
17.1. 
Data Quality Assurance 
The following measures will be implemented to ensure accuracy, consistency, completeness, and 
reliability of data: 
• Investigator discussions 
• Site initiation training 
• Early site visits following enrollment 
• Routine site management 
• Ongoing site communication and training 
• Periodic site monitoring 
• Review of the eCRF against source data for all subjects 
• Data management quality control (QC) checks 
• Statistical QC checks 
17.2. 
Data Management 
A database will be designed and built based on the final eCRFs. A Data Management Plan will 
be written specifying the procedures that will be used for medical coding, SAE reconciliation, 

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QC, laboratory data, and data cleaning that will occur for the study. A Data Validation 
Specifications document will be written and edit checks will be programmed and validated. 
17.3. 
Monitoring 
Monitoring visits will be conducted by representatives of the Sponsor according to the ICH 
Guideline for GCP, and applicable regional regulations and guidelines. 
A monitor (or monitors) will review and verify protocol compliance with a focus on AE/SAE 
reporting, eCRF data, source documentation, ICFs, and any other study-related documentation, 
including review of site pharmacy procedures, drug accountability documentation, and drug 
storage facilities and records. 
Monitoring will be on an ongoing basis. Before database lock, 100% eCRF data verification will 
be performed against the source documents. The Investigator will agree to the monitor(s) making 
periodic site visits during the study. The monitor(s) and the site staff will agree upon the timing 
of these visits. 
Centralized monitoring, which consists of remote review of accumulating data from all sites, will 
be performed as detailed in the Centralized Monitoring Plan. 
17.4. 
Confidentiality and Auditing 
The Investigator, the Sponsor, and the Sponsor’s representatives will preserve the confidentiality 
of all subjects participating in this study, in accordance with ICH GCP, local regulations, and 
institutional requirements. Only year of birth, age at Screening, and study subject number will be 
used to identify subjects on the eCRFs and other study-related documents submitted to the 
Sponsor (or designee). Documents that are not submitted to the Sponsor (eg, ICFs) should be 
kept in strict confidence by the investigative staff. 
In compliance with ICH GCP, it is required that the Investigator and institution permit 
authorized representatives of the Sponsor, the IRB/IEC, the United States (US) Food and Drug 
Administration (FDA), the European Medicines Agency, and other appropriate regulatory 
authority or health authority inspectors direct access to all study-related sites, source data, 
documents, and reports for verification of study records and data. Direct access is the permission 
to examine, analyze, verify, and reproduce any records and reports that are important to the 
evaluation of a clinical study. The Investigator is obligated to inform and obtain consent from the 
subject to permit these representatives to have access to their study-related records for this 
verification. Any party (eg, domestic and foreign regulatory authorities, Sponsors, auditors) with 
direct access should take all reasonable precautions within the constraints of the applicable 
regulatory requirement(s) to maintain the confidentiality of subjects. 
In case of data security breach, measures to mitigate possible adverse effects for subjects will be 
applied as per the CRO’s standard operating procedure (SOP). 
17.5. 
Case Report Forms 
eCRFs will be used for this study. Site personnel will receive training on eCRF completion. Each 
eCRF is to be reviewed and approved by the Investigator. 

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During periodic monitoring visits, the eCRFs will be made available to the study monitor so that 
he or she may verify the data entries with the source documentation. 
17.6. 
Source Documents 
The Investigator will prepare and maintain adequate and accurate source documents (eg, medical 
records, 12-lead ECG results, raw data collection forms) to record all observations and other 
pertinent data for each subject enrolled into the study. The data recorded on the eCRFs will be 
derived from these source documents. The Investigator will ensure that data on the eCRFs and 
completed queries are accurate, consistent with source documentation, and submitted to the 
Sponsor in a timely manner. The Investigator will also ensure that all data on required study logs 
are accurate and kept up to date. 
17.7. 
Records Retention 
The Investigator must maintain essential study documents (protocol and amendments, completed 
eCRFs, source documentation, signed ICFs, relevant correspondence and approvals, and all other 
supporting documentation) until notified by the Sponsor. Subject identification codes (subject 
names and corresponding study numbers) will be retained for this same period and stored 
separately. Custody of the records may be transferred to another responsible party, acceptable to 
the Sponsor, which agrees to abide by the retention policies. Written notice of transfer must be 
submitted to the Sponsor. The Investigator must contact the Sponsor before disposing of any 
study records. 
Records retention will follow the data protection requirements in each country. 
17.8. 
Informed Consent 
Written informed consent will be obtained from each subject before any study-related procedures 
are performed. The Investigator has an ethical and legal responsibility to ensure each subject 
being considered for inclusion in the study is given a full explanation of the study. The 
Investigator, or his/her designee, shall inform each subject, in writing, of all aspects pertaining to 
participation in the study, including (but not limited to) aims, methods, anticipated benefits, and 
potential risks. Subjects will have the opportunity to inquire about details of the study and to 
decide whether to participate. Subjects should understand that they are free to refuse to 
participate in, or to withdraw from, the study at any time without prejudice or loss of medical 
care to which they are otherwise entitled. Each subject must personally sign and date a study- 
specific ICF to be a subject in the study. The ICF must be countersigned by the site Investigator 
(or designee) who conducted the informed consent discussion. This will be documented on a 
written ICF. Each ICF will include the elements required by US 21 Code of Federal Regulations 
(CFR) 50 and ICH E6, Section 4.8, Regulation (European Union [EU]) No 536/2014, Chapter V, 
and General Data Protection Regulation (EU) 2016/679 (GDPR). The Investigator agrees to 
obtain approval from the Sponsor of any written informed consent for use in the study before 
submission to the IRB/IEC. 
Each subject who provides written informed consent for the study (by signing and dating the 
ICF), will be given a copy of the signed ICF. The original will be kept in the subject’s medical 
record or study chart as permitted by the institution. The Investigator will inform subjects of new 

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information that may be relevant to the subjects’ willingness to continue participation in the 
study according to local ethics requirements. 
It is important to obtain complete follow-up for all subjects. Every attempt should be made to 
undertake all protocol-specified assessments and complete the eCRFs except for those subjects 
who specifically withdraw consent for release of such information. 
17.9. 
Ethical Conduct of the Study 
This study shall be conducted in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki and that are consistent with GCP, ICH guidelines, other applicable 
regulatory requirements (eg, local requirements), the study protocol, and where applicable, 
Sponsor and/or CRO SOPs. 
17.10. 
Institutional Review Board/Independent Ethics Committee 
The Investigator will not begin the study until the protocol and ICF have been approved by the 
appropriate independent IRB/IEC. Any amendments to the protocol must also be approved in 
writing by the Sponsor and IRB/IEC, before implementation by the Investigator, except where 
necessary to eliminate an immediate hazard to subjects. 
All IRB/IEC correspondence, including progress reports, will be retained on file at the site. 
 
18. 
STUDY MANAGEMENT 
18.1. 
Protocol Deviations 
The Investigator is not permitted to deviate from the protocol in any major way without proper 
notification to the Sponsor (or designee). Only the Sponsor may revise the protocol. Any change 
in study conduct considered necessary by the Investigator will be made only after consultation 
with the Sponsor, who will then issue a formal protocol revision to implement the change and 
obtain regulatory and ethic approval. The only exception is when the Investigator considers a 
subject’s safety to be compromised if immediate action is not taken. 
In the event of an important deviation from the protocol, the Investigator or designee must 
contact the Sponsor or representative at the earliest possible time. This will allow an early joint 
decision regarding the subject’s continuation in the study. 
Examples of important deviations include: 
• Subject did not give appropriate informed consent 
• Inclusion or exclusion criteria not satisfied 
• Non-permitted concomitant medications that may meaningfully impact efficacy or 
safety outcomes 
• Meaningful dosing error 
• Randomization error 

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The Investigator and Sponsor will both document this decision. The IRB/IEC will be informed of 
all important protocol deviations by the Investigator in accordance with established procedures. 
18.2. 
Publications 
No publication of the results shall take place without the Sponsor’s written consent. All 
publication or presentation rights for the findings of the clinical investigation under this protocol 
shall be governed by the appropriate terms of the clinical research agreement between the 
Investigator, the investigational site, and the Sponsor. 
This study will be registered on https://clinicaltrials.gov and https://euclinicaltrials.eu prior to the 
first subject being dosed. 
A summary of the results of the clinical study, together with a summary that is understandable to 
a layperson, will be made available within 1 year from the end of the clinical study. 
18.3. 
Change in Clinical Site Staff 
In the event that the Principal Investigator at a site is unable to continue the study, another 
suitable person will be designated as the Investigator, and documentation testifying to this will 
be submitted to the Sponsor or its designee within 10 days, who must approve the change along 
with the IRB/IEC before the study can be continued at that investigative site. 

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19. 
LIST OF REFERENCES 
 
Azimi E, Reddy VB, Lerner EA. Brief Communication: MRGPRX2, Atopic Dermatitis and Red 
Man Syndrome. Itch (Phila). 2017;2(1):e5. 
 
Babina M. The Pseudo-Allergic/Neurogenic Route of Mast Cell Activation via MRGPRX2: 
Discovery, Functional Programs, Regulation, Relevance to Disease, and Relation with Allergic 
Stimulation. Itch. 2020;5(2):e32. 
 
Baiardini I, Pasquali M, Braido F, et al. A New Tool to Evaluate the Impact of Chronic Urticaria 
on Quality of Life: Chronic Urticaria Quality of Life Questionnaire (CU-QoL). Allergy. 
2005;60(8):1073-8. 
 
Bernstein JA, Lang DM, Khan DA, et al. The Diagnosis and Management of Acute and Chronic 
Urticaria: 2014 Update. J Allergy Clin Immunol. 2014;133(5):1270-7. 
 
Bossi F, Frossi B, Radillo O, et al. Mast Cells are Critically Involved in Serum-Mediated 
Vascular Leakage in Chronic Urticaria Beyond High-Affinity IgE Receptor Stimulation. Allergy. 
2011;66(12):1538-45. 
 
Corbiere A, Loste A, Gaudenzio N. MRGPRX2 Sensing of Cationic Compounds-A Bridge 
Between Nociception and Skin Diseases? Exp Dermatol. 2021;30(2):193-200. 
 
FDA. Guidance for Industry: E9(R1) Statistical Principles for Clinical Trials: Addendum: 
Estimands and Sensitivity Analysis in Clinical Trials. FDA Maryland; 2021. p. 1-19. 
 
Fok JS, Kolkhir P, Church MK, et al. Predictors of Treatment Response in Chronic Spontaneous 
Urticaria. Allergy. 2021;76(10):2965-81. 
 
Folci M, Heffler E, Canonica GW, et al. Cutting Edge: Biomarkers for Chronic Spontaneous 
Urticaria. J Immunol Res. 2018;2018:5615109. 
 
Fujisawa D, Kashiwakura J, Kita H, et al. Expression of Mas-Related Gene X2 on Mast Cells is 
Upregulated in the Skin of Patients with Severe Chronic Urticaria. J Allergy Clin Immunol. 
2014;134(3):622-33 e9. 
Green DP, Limjunyawong N, Gour N, et al. A Mast-Cell-Specific Receptor Mediates 
Neurogenic Inflammation and Pain. Neuron. 2019;101(3):412-20 e3. 
HHS. Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. 2017. p. 1-146. 
Kapp A, Czech W, Krutmann J, et al. Eosinophil Cationic Protein in Sera of Patients with Atopic 
Dermatitis. J Am Acad Dermatol. 1991;24(4):555-8. 

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Kulthanan K, Chularojanamontri L, Rujitharanawong C, et al. Angioedema Quality of Life 
Questionnaire (AE-QoL) - Interpretability and Sensitivity to Change. Health Qual Life 
Outcomes. 2019;17(1):160. 
 
Mathias SD, Crosby RD, Zazzali JL, et al. Evaluating the Minimally Important Difference of the 
Urticaria Activity Score and Other Measures of Disease Activity in Patients with Chronic 
Idiopathic Urticaria. Ann Allergy Asthma Immunol. 2012;108(1):20-4. 
 
Maurer M, Gimenez-Arnau A, Ensina LF, et al. Chronic Urticaria Treatment Patterns and 
Changes in Quality of Life: AWARE Study 2-Year Results. World Allergy Organ J. 
2020;13(9):100460. 
 
Maurer M, Raap U, Staubach P, et al. Antihistamine-Resistant Chronic Spontaneous Urticaria: 1- 
Year Data From the AWARE Study. Clin Exp Allergy. 2019;49(5):655-62. 
 
Meixiong J, Anderson M, Limjunyawong N, et al. Activation of Mast-Cell-Expressed Mas- 
Related G-Protein-Coupled Receptors Drives Non-histaminergic Itch. Immunity. 
2019;50(5):1163-71 e5. 
Metz M, Krull C, Hawro T, et al. Substance P is Upregulated in the Serum of Patients with 
Chronic Spontaneous Urticaria. J Invest Dermatol. 2014;134(11):2833-6. 
Morita H, Yamamoto K, Kitano Y. Elevation of Serum Major Basic Protein in Patients with 
Atopic Dermatitis. J Dermatol Sci. 1995;9(3):165-8. 
Nakamura Y, Oscherwitz J, Cease KB, et al. Staphylococcus Delta-Toxin Induces Allergic Skin 
Disease by Activating Mast Cells. Nature. 2013;503(7476):397-401. 
 
Nattkemper LA, Tey HL, Valdes-Rodriguez R, et al. The Genetics of Chronic Itch: Gene 
Expression in the Skin of Patients with Atopic Dermatitis and Psoriasis with Severe Itch. J Invest 
Dermatol. 2018;138(6):1311-7. 
 
Ogasawara H, Furuno M, Edamura K, et al. Peptides of Major Basic Protein and Eosinophil 
Cationic Protein Activate Human Mast Cells. Biochem Biophys Rep. 2020;21:100719. 
 
Quan P, Guo Y, Sabate-Bresco M, et al., editors. Silencing MRGPRX2 in LAD2 Mast Cells 
Reduces Degranulation Responses Induced In Vitro by Sera from Patients with Chronic 
Spontaneous Urticaria. European Academy of Allergy and Clinical Immunology Congress; 
2022; Prague, Czech Republic. 
 
Rubin DB. Multiple Imputation for Nonresponse in Surveys. New York Wiley; 1987. 
 
Serhan N, Basso L, Sibilano R, et al. House Dust Mites Activate Nociceptor-Mast Cell Clusters 
to Drive Type 2 Skin Inflammation. Nat Immunol. 2019;20(11):1435-43. 

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Shtessel M, Limjunyawong N, Oliver ET, et al. MRGPRX2 Activation Causes Increased Skin 
Reactivity in Patients with Chronic Spontaneous Urticaria. J Invest Dermatol. 2021;141(3):678- 
81 e2. 
 
Subramanian H, Gupta K, Ali H. Roles of MAS-Related G Protein-Coupled Receptor-X2 
(MRGPRX2) on Mast Cell-Mediated Host Defense, Pseudoallergic Drug Reactions and Chronic 
Inflammatory Diseases. J Allergy Clin Immunol. 2016;138(3):700-10. 
 
Thapaliya M, Chompunud Na Ayudhya C, Amponnawarat A, et al. Mast Cell-Specific 
MRGPRX2: A Key Modulator of Neuro-Immune Interaction in Allergic Diseases. Curr Allergy 
Asthma Rep. 2021;21(1):3. 
 
Wang Z, Babina M. MRGPRX2 Signals its Importance in Cutaneous Mast Cell Biology: Does 
MRGPRX2 Connect Mast Cells and Atopic Dermatitis? Exp Dermatol. 2020;29(11):1104-11. 
 
Weller K, Groffik A, Church MK, et al. Development and Validation of the Urticaria Control 
Test: a Patient-Reported Outcome Instrument for Assessing Urticaria Control. J Allergy Clin 
Immunol. 2014;133(5):1365-72, 72 e1-6. 
 
Weller K, Groffik A, Magerl M, et al. Development, Validation, and Initial Results of the 
Angioedema Activity Score. Allergy. 2013;68(9):1185-92. 
Weller K, Zuberbier T, Maurer M. Chronic Urticaria: Tools to Aid the Diagnosis and 
Assessment of Disease Status in Daily Practice. J Eur Acad Dermatol Venereol. 2015;29 Suppl 
3:38-44. 
 
Youngblood S, Tomasevic K. Atopic Dermatitis Skin Biopsies Have High Numbers of Activated 
Mast Cells that are Inhibited by AK002 after Stimulation Ex Vivo. J Allergy Clin Immunol. 
2020;145(2):AB198. 
 
Zheng W, Wang J, Zhu W, et al. Upregulated Expression of Substance P in Basophils of the 
Patients with Chronic Spontaneous Urticaria: Induction of Histamine Release and Basophil 
Accumulation by Substance P. Cell Biol Toxicol. 2016;32(3):217-28. 
 
Zuberbier T, Abdul Latiff AH, Abuzakouk M, et al. The International 
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Diagnosis, and Management of Urticaria. Allergy. 2022;77(3):734-66. 

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APPENDIX A.  SCHEDULE OF ASSESSMENTS 
 
Assessment 
Screening 
Double-Blind Treatment 
Safety 
Follow-Up 
Early Tx 
Terma 
Notes 
Visit 
Visit 1b 
Visit 2 
Visit 3 
Visit 4 
Visit 5c 
Study Day 
Days -30 to -14 Day 1 
Day 22 Day 43 
Day 71 
≤2 days 
after last 
dose 
Study Week 
Week 0 Week 3 Week 6 
Week 10 
Visit Window 
None 
None 
±3 days ±3 days 
±3 days 
Screening or General Assessments 
Informed consent 
X 
Medical history 
X 
Includes CSU disease history. 
Height 
X 
Should be measured using a stadiometer with no shoes. 
Body weight 
X 
X 
X 
X 
Should be measured with no shoes and heavy clothing (outdoor 
clothing such as coats) on and using a calibrated scale. 
HIV, HBV, HCV 
serology 
X 
Eligibility check 
X 
X 
Randomization 
X 
In Part 1, subjects will be randomized via IWRS in a 1:1:1 ratio to 
50 mg EP262, 150 mg EP262, or placebo. In Part 2, subjects will be 
randomized via IWRS in a 3:1 ratio to 25 mg EP262 or placebo. 
Dispense study drug / 
administer dose at site 
X 
X 
Administer orally QD as intact capsules with approximately 240 mL 
(8 fluid ounces) of water on an empty stomach. 
Collect study drug / assess 
study drug accountability 
and compliance 
X 
X 
X 
Subjects will record self-administration of study drug daily in a 
dosing diary that will be reviewed at each clinic visit during the 
Double-Blind Treatment Period following Visit 2 by clinical site 
staff. 
Provide electronic 
device/app training 
X 

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Assessment 
Screening 
Double-Blind Treatment 
Safety 
Follow-Up 
Early Tx 
Terma 
Notes 
Visit 
Visit 1b 
Visit 2 
Visit 3 
Visit 4 
Visit 5c 
Study Day 
Days -30 to -14 Day 1 
Day 22 Day 43 
Day 71 
≤2 days 
after last 
dose 
Study Week 
Week 0 Week 3 Week 6 
Week 10 
Visit Window 
None 
None 
±3 days ±3 days 
±3 days 
Efficacy/Pharmacodynamic Assessments 
UAS 
X 
X 
X 
X 
X 
X 
To be completed daily, in the morning before dosing (as applicable), 
Safety Assessments 
Serum pregnancy testing 
X 
Required for all females. 
Urine pregnancy testing 
X 
X 
X 
X 
X 
Required for all females. 
Physical examination 
X 
Symptom directed physical examinations to assess clinically 
significant changes from Screening or any new signs or symptoms 
may be conducted at other visits as determined by the Investigator 
based on subject complaint. 

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Assessment 
Screening 
Double-Blind Treatment 
Safety 
Follow-Up 
Early Tx 
Terma 
Notes 
Visit 
Visit 1b 
Visit 2 
Visit 3 
Visit 4 
Visit 5c 
Study Day 
Days -30 to -14 Day 1 
Day 22 Day 43 
Day 71 
≤2 days 
after last 
dose 
Study Week 
Week 0 Week 3 Week 6 
Week 10 
Visit Window 
None 
None 
±3 days ±3 days 
±3 days 
Standard 12-lead ECG 
X 
X 
X 
X 
X 
To be performed predose (as applicable) in a supine position after 
≥5 min of rest. 
Vital signs 
X 
X 
X 
X 
X 
X 
Includes sitting systolic and diastolic blood pressure, pulse rate, 
body temperature, and respiratory rate, measured predose (as 
applicable) after ≥5 min of rest. 
Chemistry, hematology, 
and urinalysis 
X 
X 
X 
X 
X 
X 
Drawn after an overnight fast (≥8 hours) and predose (as 
applicable). 
Coagulation 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
Record any prior use of omalizumab. Record all medications taken 
to treat CSU beginning from the date of diagnosis and all other 
medications taken within 14 days before Screening. Record any use 
of rescue medications. 
AE assessment 
X 
X 
X 
X 
X 
X 
To be documented from the signing of the Informed Consent Form 
until the end of study participation. 
Pharmacokinetic Assessments 
Blood sampling for PK 
X 
X 
X 
X 
X 
Samples will be collected predose as applicable. 
Baseline Characterization 
; AE = adverse event; 
; app = application; CSU = chronic spontaneous urticaria; 
e; ECG = electrocardiogram; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human 
immunodeficiency virus; IWRS = Interactive Web Response System; PK = pharmacokinetic; QD = once daily; Term = termination; Tx = treatment; 
UAS = Urticaria Activity Score; 
 UGT1A1 = uridine 5’-diphospho-glucuronosyltransferase 1A1. 

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Subjects should fast for at least 8 hours before study visits that require a blood sample for assessment of clinical chemistry. Water is acceptable in the morning of 
site visits to ensure the subject is hydrated for laboratory sample collection. Subjects should fast at least 4 hours before administration of each dose of study drug 
and refrain from eating for at least 2 hours postdose. Each dose of study drug is to be taken with approximately 240 mL (8 fluid ounces) of water on an empty 
stomach. 
a Early Treatment Termination Visit: Should be conducted as soon as possible after the last dose of study drug, ideally within 2 days after the last dose of study 
drug. 
b Screening: May be conducted over more than 1 day but must be completed between Day -30 and Day -14 (inclusive). 
c Any subject who completes the Double-Blind Treatment Period or discontinues study drug (EP262 or placebo) early will have a Safety Follow-Up Visit 
approximately 4 weeks (±3 days) after the last dose of study drug. 

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APPENDIX B. COMMON TERMINOLOGY CRITERIA FOR ADVERSE 
EVENTS 
The Common Terminology Criteria for Adverse Events (CTCAE) is widely accepted as the 
standard classification and severity grading scale for adverse events in cancer therapy, clinical 
trials, and other oncology settings. Version 5.0 is the most updated document (November 27, 
2017), and may be accessed using the following link: 
 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_R 
eference_8.5x11.pdf 

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APPENDIX C.  URTICARIA ACTIVITY SCORE – EXAMPLE ONLY 
 
Please select the score that represents the intensity of your itch over the past 24 hours. 
 
Itch Severity Score 
Itch Severity 
0 
None 
1 
Mild 
(present but not annoying or troublesome) 
2 
Moderate 
(troublesome but does not interfere with normal daily activity or sleep) 
3 
Intense 
(interferes with normal daily activity or sleep) 
 
Please select the score that corresponds to the number of wheals you have had over the past 
24 hours. 
 
Hives Severity Score 
Hives Severity 
0 
None 
1 
<20 
2 
20-50 
3 
>50 

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APPENDIX H. SUMMARY OF CHANGES BY AMENDMENT 
Summary of Changes for Amendment 4.0 Dated 26 July 2024 
Protocol EP-262-201 has been amended primarily to further characterize the therapeutic dose range. The study will be conducted in 
2 parts: Part 1 will assess 50 mg and 150 mg doses of EP262 and Part 2 will assess a 25 mg dose of EP262. Part 2 will begin after the 
last subject is randomized in Part 1, with approximately 40 subjects randomized in a 3:1 ratio to receive either 25 mg of EP262 or 
placebo. 
Other changes to the protocol include: 
• Correcting the definition of minimal disease activity for UAS7. 
• Clarifying that any interim analysis will be optional. 
• Updating the name of the Medical Monitor. 
• Reflecting that the Sponsor, Escient Pharmaceuticals, Inc., is now a wholly owned subsidiary of the Incyte Corporation. 
Notable changes are included below in the summary table. Revised text in Amendment 4.0 is bolded, and text deleted from 
Amendment 3.0 is crossed out in the table below. Italicized text is used to describe a change. Minor/editorial changes are not listed 
individually in the summary table. 
 
Section 
Amendment 3.0 
Amendment 4.0 
Reason for Change 
Global 
The Sponsor was referred to as Escient 
Pharmaceuticals, Inc. 
The Sponsor is now referred to as Escient 
Pharmaceuticals, Inc., an Incyte company 
Revised to note that Escient 
Pharmaceuticals, Inc. became a 
wholly owned subsidiary of the 
Incyte Corporation. 
Title Page 
The name of the Medical Monitor 
was changed to reflect an update in 
the assignment of responsibilities 
within the study team. 

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Section 
Amendment 3.0 
Amendment 4.0 
Reason for Change 
Sponsor Statement 
The name of the Medical Monitor 
was changed to reflect an update in 
the assignment of responsibilities 
within the study team. 
Synopsis, Exploratory 
Objectives 
6 Trial Objectives and 
Purpose 
16.3.3 Exploratory 
Endpoints 
Synopsis, Methodology 
7.1 Overall Study Design 
The study includes a Screening Period of 
at least 2 weeks and up to 30 days to assess 
subject eligibility that includes collection 
of the daily UAS score; a 6-week Double- 
Blind Treatment Period; and a 4-week 
Safety Follow-Up Period after 
administration of the last dose of study 
drug (EP262 or placebo) for a total study 
duration of up to approximately 14 weeks 
for each subject. Approximately 
114 subjects will be randomized in a 1:1:1 
ratio to receive either a 150 mg dose of 
EP262, 50 mg dose of EP262, or placebo 
orally (PO), once daily (QD) during the 
6-week Double-Blind Treatment Period. 
Enrollment of subjects with prior 
omalizumab use will be limited to 
15 subjects. 
EP-262-201 Study Design 
Screening 
Double-Blind 
Safety 
Period 
Treatment Period 
Follow-Up Period 
50 mg EP262 PO QD 
150 mg EP262 PO QD 
Placebo PO QD 
Screening  Enroll/Randomize 
Follow-Up 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5a 
Day -30 to Day -14 
 
Day 1 
Week 3 
Week 6 
Week 10 
PO = oral; QD = once daily. 
The study will be conducted in 2 parts: 
Part 1 will assess 50 mg and 150 mg doses 
of EP262 and Part 2 will assess a 25 mg 
dose of EP262 to further characterize the 
therapeutic dose range. Part 2 will begin 
after the last subject is randomized into 
Part 1. Part 1 and Part 2 are identical in 
terms of their visit structure, procedures 
conducted, and the populations being 
studied. The primary difference between 
the 2 parts is the EP262 dose levels being 
assessed. 
Each part includes a Screening Period of at 
least 2 weeks and up to 30 days to assess 
subject eligibility that includes collection of 
the daily UAS score; a 6-week Double- 
Blind Treatment Period; and a 4-week 
Safety Follow-Up Period after 
administration of the last dose of study drug 
(EP262 or placebo) for a total study 
duration of up to approximately 14 weeks 
for each subject. In Part 1, approximately 
114 subjects will be randomized in a 1:1:1 
ratio to receive a 150 mg dose of EP262, 
50 mg dose of EP262, or placebo orally 
(PO), once daily (QD) during the 6-week 
Revised to reflect the addition of 
Part 2. 

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Reason for Change 
a Any subject who completes the Double-Blind 
Treatment Period or discontinues study drug (EP262 
or placebo) early will have a Safety Follow-Up Visit 
approximately 4 weeks (±3 days) after the last dose of 
study drug. 
Double-Blind Treatment Period. In Part 2 
of the study, approximately 40 subjects 
will be randomized in a 3:1 ratio to 
receive either a 25 mg dose of EP262 or 
placebo PO, QD, during the 6-week 
Double-Blind Treatment Period. 
Enrollment of subjects with prior 
omalizumab use will be limited to 
15 subjects in Part 1 and 5 subjects in 
Part 2. 
EP-262-201 Study Design 
Screening 
Double-Blind 
Safety 
Period 
Treatment Period 
Follow-Up Period 
Part 1 
Part 2a 
25 mg EP262 PO QD 
Placebo PO QD 
Screening 
 
Enroll/Randomize 
Follow-Up 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5b 
Day -30 to Day -14 
 
Day 1 
Week 3 
Week 6 
Week 10 
PO = oral; QD = once daily. 
a Part 2 will begin after the last subject is 
randomized into Part 1. 
b Any subject who completes the Double-Blind 
Treatment Period or discontinues study drug (EP262 or 
placebo) early will have a Safety Follow-Up Visit 
approximately 4 weeks (±3 days) after the last dose of 
study drug. 
Synopsis, Double-Blind 
Treatment Period 
7.1.2 Double-Blind 
Treatment Period 
Subjects will be randomized in a 1:1:1 
ratio to receive either a 150 mg dose of 
EP262, 50 mg dose of EP262, or placebo 
PO, QD. 
In Part 1, subjects will be randomized in a 
1:1:1 ratio to receive a 150 mg dose of 
EP262, 50 mg dose of EP262, or placebo 
PO, QD. In Part 2, subjects will be 
randomized in a 3:1 ratio to receive 
either a 25 mg dose of EP262 or placebo 
PO, QD. 
Revised to reflect the addition of 
Part 2. 
50 mg EP262 PO QD 
150 mg EP262 PO QD 
Placebo PO QD 

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Section 
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Amendment 4.0 
Reason for Change 
Synopsis, Number of 
Subjects (Planned) 
7.4 Number of Subjects 
Approximately 114 subjects with CSU will 
be randomized in the study. Enrollment of 
subjects with prior omalizumab use will be 
limited to 15 subjects. 
Approximately 154 subjects with CSU will 
be randomized into this study. 
Approximately 114 subjects will be 
randomized in Part 1 and approximately 
40 subjects will be randomized in Part 2. 
Enrollment of subjects with prior 
omalizumab use will be limited to 
20 subjects (15 subjects in Part 1 and 
5 subjects in Part 2). 
Revised to reflect the addition of 
Part 2. 
Synopsis, Study Drug 
10.1 Study Drug 
Capsules containing 25 mg of EP262, 
75 mg of EP262, or placebo will be 
supplied in bottles in a manner to ensure 
the study blind. Each subject will take 
2 capsules per dose. 
In Part 1, capsules containing 25 mg of 
EP262, 75 mg of EP262, or placebo will be 
supplied in bottles in a manner to ensure the 
study blind. Each subject will take 
2 capsules per dose. 
In Part 2, capsules containing 25 mg of 
EP262 or placebo will be supplied in 
bottles in a manner to ensure the study 
blind. Each subject will take 1 capsule 
per dose. 
Revised to reflect the addition of 
Part 2. 
Synopsis,
 
 
11.1 
 
Well-controlled urticaria is defined as a 
 score <6. 
Well-controlled urticaria is defined as a 
 score ≤6. 
Corrected the definition of minimal 
disease activity for 
 
Synopsis, Statistical 
Methods 
16.8 Efficacy and 
Pharmacodynamic Analysis 
Additional analysis comparing placebo and 
both EP262 doses combined may be 
performed as appropriate. 
Subjects who receive placebo in Parts 1 
and 2 will be pooled for analysis. 
Additional analysis comparing placebo and 
all EP262 doses combined may be 
performed as appropriate. 
Revised to reflect the addition of 
Part 2. 
Synopsis, Sample Size 
Considerations 
16.4 Sample Size 
Considerations 
The study will enroll approximately 
114 subjects, randomized in 1:1:1 ratio to 
receive 50 mg EP262, 150 mg EP262, or 
placebo. A sample size of 34 subjects per 
treatment group will provide 80% power to 
The study will enroll approximately 
154 subjects. 
Revised to reflect the addition of 
Part 2. 

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Reason for Change 
detect an 8-point difference in the UAS7 
change from baseline at Visit 4 (Week 6), 
assuming a standard deviation of 13 points, 
and a 2-sided alpha of 10%. 
With an estimated early withdrawal rate of 
approximately 10%, the planned 
enrollment of 38 subjects per treatment 
group (50 mg EP262, 150 mg EP262, and 
placebo) will ensure that at least 
34 subjects per treatment group complete 
the 6-week treatment period. 
In Part 1, approximately 114 subjects will 
be randomized in a 1:1:1 ratio to receive 
50 mg EP262, 150 mg EP262, or placebo. 
In Part 2, approximately 40 subjects will 
be randomized in a 3:1 ratio to receive 
25 mg of EP262 or placebo. 
Overall, approximately 30, 38, 38, and 
48 subjects will be randomized to receive 
25 mg EP262, 50 mg EP262, 150 mg 
EP262, and placebo, respectively, across 
both parts of the study. 
For Part 1, a sample size of 34 subjects per 
treatment group will provide 80% power to 
detect an 8-point difference in the UAS7 
change from baseline at Visit 4 (Week 6), 
assuming a standard deviation of 13 points, 
and a 2-sided alpha of 10%. 
For Part 2, a sample size of 27 subjects 
receiving 25 mg of EP262 and 43 subjects 
receiving placebo pooled from both parts 
of the study will provide 80% power to 
detect an 8-point difference in the UAS7 
change from baseline at Visit 4 (Week 6) 
between EP262 25 mg and placebo, with 
the same assumption of 13-point 
standard deviation and 2-sided alpha of 
10%. 
With an estimated early withdrawal rate of 
approximately 10%, the planned enrollment 
of 38 subjects per treatment group (50 mg 
EP262, 150 mg EP262, and placebo) in 
Part 1 and 40 subjects (30 subjects in 
25 mg EP262 and 10 subjects in placebo) 
in Part 2 will ensure adequate sample size 
to complete the 6-week treatment period. 

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Section 
Amendment 3.0 
Amendment 4.0 
Reason for Change 
5.3 EP262 Dose Rationale 
The 150 mg and 50 mg EP262 dose levels 
to be evaluated in Study EP-262-201 were 
selected based on a variety of factors to 
explore efficacy without adversely 
impacting safety, including results from 
nonclinical pharmacology studies, 
nonclinical toxicology studies, and 
preliminary results from Study EP-262- 
101, a Phase 1 first in human clinical study 
in healthy subjects. 
The 150 mg and 50 mg EP262 dose levels 
to be evaluated in Part 1 of Study EP-262- 
201 were selected based on a variety of 
factors to explore efficacy without 
adversely impacting safety, including 
results from nonclinical pharmacology 
studies, nonclinical toxicology studies, and 
preliminary results from Study EP-262-101, 
a Phase 1 first-in-human clinical study in 
healthy subjects. 
Revised to reflect the addition of 
Part 2. 
5.3 EP262 Dose Rationale 
Thus, it is assumed that EP262 trough 
concentrations of 2000 nM or higher will 
likely be necessary for maximum clinical 
efficacy. 
Consequently, Study EP-262-201 will 
assess 2 dose levels: 
Thus, it was assumed that EP262 trough 
concentrations of 
 nM or higher will 
likely be necessary for maximum clinical 
efficacy. 
Consequently, Part 1 of Study EP-262-201 
was designed to assess 2 dose levels: 
Revised to reflect the addition of 
Part 2. 
5.3 EP262 Dose Rationale 
New text. 
To further characterize the therapeutic 
dose range, Part 2 was added to the 
protocol to evaluate a lower 25 mg EP262 
dose level. The 25 mg dose level will 
target EP262 trough concentrations 
between 
and 
 nM. 
Pharmacologic activity from this lower 
dose is expected to widen the span for the 
exposure-response relationship when 
analyzed with the responses from the 
higher dose levels, thus enhancing the 
calculation of the therapeutic dose range. 
Revised to reflect the addition of 
Part 2. 
9.1 Treatment Assignment 
Approximately 114 subjects will be 
randomized in a 1:1:1 ratio to receive 
either a 50 mg dose of EP262, 150 mg 
dose of EP262, or placebo PO, QD during 
the 6-week Double-Blind Treatment 
Period. 
In Part 1, approximately 114 subjects will 
be randomized in a 1:1:1 ratio to receive a 
50 mg dose of EP262, 150 mg dose of 
EP262, or placebo PO, QD during the 
6-week Double-Blind Treatment Period. In 
Part 2 of the study, approximately 
40 subjects will be randomized in a 
Revised to reflect the addition of 
Part 2. 

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Reason for Change 
3:1 ratio to receive either a 25 mg dose of 
EP262 or placebo PO, QD, during the 
6-week Double-Blind Treatment Period. 
9.3.1 Randomization 
Subjects will be randomized in a 1:1:1 
ratio to receive either a 50 mg dose of 
EP262, 150 mg dose of EP262, or placebo 
PO, QD for 6 weeks during the Double- 
Blind Treatment Period beginning at Visit 
2 (Day 1). 
Beginning at Visit 2 (Day 1), subjects will 
be randomized in a 1:1:1 ratio to receive a 
50 mg dose of EP262, 150 mg dose of 
EP262, or placebo PO, QD for Part 1 or a 
3:1 ratio to receive either a 25 mg dose of 
EP262 or placebo for Part 2 for 6 weeks 
during the Double-Blind Treatment Period. 
 
 
9.3.1 Randomization 
The master randomization list will be 
kept secured until the study blind is 
broken at the end of study. 
Separate randomization lists will be 
utilized for each part of the study. 
The master randomization lists will be 
kept secured until the study blind is 
broken as specified in the study- 
specific blinding and unblinding plan. 
 
 
9.4.2.1 Visit 2 (Day 1) – 
Enrollment and 
Randomization 
• Randomization to 50 mg EP262, 150 mg 
EP262, or placebo in a 1:1:1 ratio via 
IWRS 
• Randomization to study drug treatment 
assignment via IWRS: 
- 
Part 1: 50 mg EP262, 150 mg EP262, 
or placebo in a 1:1:1 ratio 
 
 
16.13 Interim Analysis 
Given the hypothesis-generating nature of 
this study, an interim analysis may be 
conducted to support business needs. 
Given the hypothesis-generating nature of 
this study, an optional interim analysis may 
be conducted to support business needs. 
Added to clarify the nature of the 
interim analysis. 
Appendix A 
Schedule of Assessments 
(Randomization row) 
Subjects will be randomized via IWRS in a 
1:1:1 ratio to 50 mg EP262, 150 mg 
EP262, or placebo. 
In Part 1, subjects will be randomized via 
IWRS in a 1:1:1 ratio to 50 mg EP262, 
150 mg EP262, or placebo. 
 
 
 
 

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Summary of Changes for Amendment 3.0 Dated 05 April 2024 
Protocol EP-262-201 was amended to extend (from 60 days to 84 days [12 weeks]) the duration after the last dose of study drug 
during which subjects with reproductive capability are restricted from egg/sperm donation and are to use acceptable forms of 
contraception. This modification is based on preliminary trends in emerging EP262 pharmacokinetic data from the ongoing clinical 
studies. The extension will remain in effect as a safety precaution until results from definitive reproductive and development toxicity 
studies of EP262 are available. 
This protocol amendment also includes an update regarding excluded medications and clarifies that only female subjects with a 
negative serum pregnancy test at Screening are eligible for participation in the study. 
Notable changes are included below in the summary table. Revised text in Amendment 3.0 is bolded, and text deleted from 
Amendment 2.0 is crossed out in the table below. Italicized text is used to describe a change. Minor/editorial changes are not listed 
individually in the summary table. 
 
Section 
Amendment 2.0 
Amendment 3.0 
Reason for Change 
Synopsis, Inclusion Criteria 
8.1. Subject Inclusion 
Criteria 
6. If female, have a negative serum 
pregnancy test at Screening4, be willing to 
not donate eggs from Screening until 
60 days after the last dose of study drug, 
and: 
a. Is surgically sterile; or 
b. Has been amenorrhoeic for ≥1 year 
without an alternative medical cause; or 
c. If of childbearing potential5, must agree 
to use 2 forms of contraception, which 
includes at least 1 form of highly effective 
and 1 effective method6 of contraception 
from Screening until 60 days after the last 
dose of study drug. 
4 In instances when a serum pregnancy test 
result is confirmed to be indeterminate, the 
result should be discussed with the Escient 
medical team and interpreted by the 
Investigator using clinical judgment; it 
should not automatically result in screen 
failure. 
6. If female, must have a negative serum 
pregnancy test at Screening, be willing to 
not donate eggs from Screening until 
12 weeks after the last dose of study drug, 
and: 
a. Is surgically sterile; or 
b. Has been amenorrhoeic for ≥1 year 
without an alternative medical cause; or 
c. If of childbearing potential3, must agree 
to use 2 forms of contraception, which 
includes at least 1 form of highly effective 
and 1 effective method4 of contraception 
from Screening until 12 weeks after the last 
dose of study drug. 
Modified the duration after the last 
dose of study drug during which 
subjects with reproductive 
capability are restricted from 
egg/sperm donation and are to use 
acceptable forms of contraception 
based on preliminary trends in 
emerging EP262 pharmacokinetic 
data from the ongoing clinical 
studies. 
To clarify that only female subjects 
with a negative serum pregnancy 
test at Screening are eligible for 
participation in the study. 

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Section 
Amendment 2.0 
Amendment 3.0 
Reason for Change 
Synopsis, Inclusion Criteria 
8.1. Subject Inclusion 
Criteria 
7. If male and is not confirmed surgically 
sterile, must be willing to not donate sperm 
and must agree to use a barrier method of 
contraception (eg, condom with 
spermicide) during intercourse and at least 
1 other acceptable contraceptive measure 
for his female partner(s) (eg, hormonal 
contraceptives, intrauterine device, female 
surgical sterilization, abstinence) from 
Screening through 60 days after the last 
dose of study drug 
7. If male and is not confirmed surgically 
sterile, must be willing to not donate sperm 
and must agree to use a barrier method of 
contraception (eg, condom with spermicide) 
during intercourse and at least 1 other 
acceptable contraceptive measure for his 
female partner(s) (eg, hormonal 
contraceptives, intrauterine device, female 
surgical sterilization, abstinence) from 
Screening through 12 weeks after the last 
dose of study drug 
Modified the duration after the last 
dose of study drug during which 
subjects with reproductive 
capability are restricted from 
egg/sperm donation and are to use 
acceptable forms of contraception 
based on preliminary trends in 
emerging EP262 pharmacokinetic 
data from the ongoing clinical 
studies. 
Synopsis, Exclusion Criteria 
8.2. Subject Exclusion 
Criteria 
4. Use of the following prohibited 
treatments: 
a. Drugs that are agonists at the 
MRGPRX2 receptor, including icatibant, 
opioids (eg, codeine, morphine), 
fluoroquinolones (eg, ciprofloxacin, 
levofloxacin), vancomycin, certain 
antidepressants/antipsychotics/antispasmo 
dics (eg, paroxetine, clozapine, 
benztropine), or nondepolarizing 
neuromuscular blocking agents (eg, 
atracurium, rocuronium, vecuronium, 
cisatracurium, mivacurium) within 14 days 
before Screening 
4. Use of the following prohibited 
treatments: 
a. Drugs that are agonists at the MRGPRX2 
receptor, including icatibant, opioids (eg, 
codeine, morphine), vancomycin, 
clomipramine, or nondepolarizing 
neuromuscular blocking agents (eg, 
atracurium, rocuronium, vecuronium, 
cisatracurium, mivacurium) within 14 days 
before Screening 
Revised the list of excluded 
agonists at the MRGPRX2 
receptor based on emerging data to 
remove those that are weak 
agonists of MRGPRX2. 

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Summary of Changes for Amendment 2.0 Dated 11 March 2024 
Protocol EP-262-201 was amended to address the following changes: 
• Increase the number of subjects participating in the study from 90 to 114 
• Provide guidance regarding confirmed indeterminant pregnancy test results at Screening 
• Update excluded medications 
• Update the time to reach the maximum observed concentration and half-life of EP262 based on results from Study EP-262-101 
• Update text to better reflect how the 
 will be administered for this study 
Notable changes are included below in the summary table. Revised text in Amendment 2.0 is bolded, and text deleted from 
Amendment 1.0 is crossed out in the table below. Italicized text is used to describe a change. Minor/editorial changes are not listed 
individually in the summary table. 
 
Section 
Amendment 1.0 
Amendment 2.0 
Reason for Change 
Synopsis, Methodology 
7.1. Overall Study Design 
Approximately 90 subjects will be 
randomized in a 1:1:1 ratio to receive 
either a 150 mg dose of EP262, 50 mg 
dose of EP262, or placebo PO, once daily 
(QD) during the 6-week Double-Blind 
Treatment Period. Enrollment of subjects 
with prior omalizumab use will be limited 
to 12 subjects. 
Approximately 114 subjects will be 
randomized in a 1:1:1 ratio to receive either 
a 150 mg dose of EP262, 50 mg dose of 
EP262, or placebo PO, once daily (QD) 
during the 6-week Double-Blind Treatment 
Period. Enrollment of subjects with prior 
omalizumab use will be limited to 
15 subjects. 
In recent studies evaluating 
Bruton’s tyrosine kinase inhibitors, 
a key class of competitor 
compounds, placebo-corrected 
UAS7 reductions of <9 was 
observed. Thus, the effect size was 
decreased for the sample size 
calculation and the number of 
subjects allowed to participate in 
the study was increased. 
Synopsis, Number of 
Subjects (Planned) 
7.4. Number of Subjects 
Approximately 90 subjects with CSU will 
be randomized in the study. Enrollment of 
subjects with prior omalizumab use will be 
limited to 12 subjects. 
Approximately 114 subjects with CSU will 
be randomized in the study. Enrollment of 
subjects with prior omalizumab use will be 
limited to 15 subjects. 
In recent studies evaluating 
Bruton’s tyrosine kinase inhibitors, 
a key class of competitor 
compounds, placebo-corrected 
UAS7 reductions of <9 was 
observed. Thus, the effect size was 
decreased for the sample size 
calculation and the number of 
subjects allowed to participate in 
the study was increased. 

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Section 
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Amendment 2.0 
Reason for Change 
Synopsis, Inclusion Criteria 
8.1 Subject Inclusion 
Criteria 
6. 
If female, must have a negative serum 
pregnancy test at Screening and be willing 
to not donate eggs from Screening until 
60 days after the last dose of study drug 
and: 
6. 
If female, have a negative serum 
pregnancy test at Screening4, be willing to 
not donate eggs from Screening until 
60 days after the last dose of study drug, 
and: 
4 In instances when a serum pregnancy 
test result is confirmed to be 
indeterminate, the result should be 
discussed with the Escient medical team 
and interpreted by the Investigator using 
clinical judgment; it should not 
automatically result in screen failure. 
Guidance was provided to 
potentially allow women with a 
confirmed indeterminate result the 
opportunity to participate in the 
study, based on the Investigator’s 
clinical judgement. For instance, 
an indeterminant pregnancy test 
result in a surgically sterile or 
postmenopausal subject would not 
necessarily result in her inability to 
participate in the study. 
Synopsis, Exclusion Criteria 
8.2 Subject Exclusion 
Criteria 
4. Use of the following prohibited 
treatments: 
a. 
Drugs that are agonists at the 
MRGPRX2 receptor, including icatibant, 
opioids (eg, codeine, morphine), 
fluoroquinolones (eg, ciprofloxacin, 
levofloxacin), vancomycin, certain 
antidepressants/antipsychotics/ 
antispasmodics (eg, doxepin, paroxetine, 
clozapine, benztropine), or 
nondepolarizing neuromuscular blocking 
agents (eg, atracurium, rocuronium, 
vecuronium, cisatracurium, 
mivacurium)within 14 days before 
Screening 
4. Use of the following prohibited 
treatments: 
a. 
Drugs that are agonists at the 
MRGPRX2 receptor, including icatibant, 
opioids (eg, codeine, morphine), 
fluoroquinolones (eg, ciprofloxacin, 
levofloxacin), vancomycin, certain 
antidepressants/antipsychotics/ 
antispasmodics (eg, paroxetine, clozapine, 
benztropine), or nondepolarizing 
neuromuscular blocking agents (eg, 
atracurium, rocuronium, vecuronium, 
cisatracurium, mivacurium) within 14 days 
before Screening 
Doxepin was removed from the list 
of example antidepressants/ 
antipsychotics/antispasmodics 
given that it is a very weak agonist 
with a Cmax below the 
concentration needed to activate 
MRGPRX2. 
Synopsis, Urticaria Control 
Test Over a 7-Day Period 
(UCT7) 
11.2. Urticaria Control Test 
Over a 7-Day Period 
(UCT7) 
Appendix A. Schedule of 
Assessments (UCT7 row) 
For entries that coincide with a study visit, 
the questionnaire is to be completed in the 
morning before the visit. 
For entries that coincide with Visit 2 
(Day 1), Visit 4 (Week 6), and Visit 5 
(Week 10), and the Early Treatment 
Termination Visit (if applicable), the 
questionnaire is to be completed in the 
morning at study visits before other 
procedures are performed. 
The text was updated to better 
reflect how the UCT7 will be 
administered for this study. 

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Reason for Change 
Synopsis, Sample Size 
Considerations 
16.4. 
Sample Size 
Considerations 
The study will enroll approximately 90 
subjects, randomized in 1:1:1 ratio to 
receive 50 mg EP262, 150 mg EP262, or 
placebo. A sample size of 27 subjects per 
treatment group will provide 80% power to 
detect a 9-point difference in the UAS7 
change from baseline at Visit 4 (Week 6), 
assuming a standard deviation of 13 points, 
and a 2-sided alpha of 10%. 
With an estimated early withdrawal rate of 
approximately 10%, the planned 
enrollment of 30 subjects per treatment 
group (50 mg EP262, 150 mg EP262, and 
placebo) will ensure that at least 27 
subjects per treatment group complete the 
6-week treatment period. 
The study will enroll approximately 114 
subjects, randomized in 1:1:1 ratio to 
receive 50 mg EP262, 150 mg EP262, or 
placebo. A sample size of 34 subjects per 
treatment group will provide 80% power to 
detect an 8-point difference in the UAS7 
change from baseline at Visit 4 (Week 6), 
assuming a standard deviation of 13 points, 
and a 2-sided alpha of 10%. 
With an estimated early withdrawal rate of 
approximately 10%, the planned enrollment 
of 38 subjects per treatment group (50 mg 
EP262, 150 mg EP262, and placebo) will 
ensure that at least 34 subjects per treatment 
group complete the 6-week treatment 
period. 
In recent studies evaluating 
Bruton’s tyrosine kinase inhibitors, 
a key class of competitor 
compounds, placebo-corrected 
UAS7 reductions of <9 was 
observed. Thus, the effect size was 
decreased for the sample size 
calculation and the number of 
subjects allowed to participate in 
the study was increased. 
5.2. EP262 and Study 
Rationale 
The time to reach the maximum EP262 
observed concentration (Tmax) was 
achieved on average at approximately 
hours postdose with a half-life ( t1/2) of 
approximately 
hours, driven by
 
 
The time to reach the maximum EP262 
observed concentration (Tmax) was achieved 
on average at approximately 
 hours 
postdose with a half-life ( t1/2) of 
approximately 
 hours for the
 mg 
dose, driven by 
 
 
The time to reach the maximum 
observed concentration and half- 
life of EP262 was updated based 
on results from Study EP-262-101. 
9.1. Treatment Assignment 
Approximately 90 subjects will be 
randomized in a 1:1:1 ratio to receive 
either a 50 mg dose of EP262, 150 mg 
dose of EP262, or placebo PO, QD during 
the 6-week Double-Blind Treatment 
Period. 
Approximately 114 subjects will be 
randomized in a 1:1:1 ratio to receive either 
a 50 mg dose of EP262, 150 mg dose of 
EP262, or placebo PO, QD during the 
6-week Double-Blind Treatment Period. 
In recent studies evaluating 
Bruton’s tyrosine kinase inhibitors, 
a key class of competitor 
compounds, placebo-corrected 
UAS7 reductions of <9 was 
observed. Thus, the effect size was 
decreased for the sample size 
calculation and the number of 
subjects allowed to participate in 
the study was increased. 

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Confidential 
Page 93 of 99 
 
 
 
Section 
Amendment 1.0 
Amendment 2.0 
Reason for Change 
9.4.1.1. Visit 1 (Day -30 to 
Day -14 [inclusive]) 
For all other days that coincide with a 
study visit (for Visit 2 and beyond), the 
questionnaires are to be completed in the 
morning before the visit. 
For all other days that coincide with a study 
visit (for Visit 2 and beyond), the 
questionnaires are to be completed in the 
morning before the visit, unless specified 
otherwise. 
The text was updated to better 
reflect how the UCT7 will be 
administered for this study. 
9.4.2.1. Visit 2 (Day 1) – 
Enrollment and 
Randomization 
The following assessments will be 
performed during Visit 2 (Day 1): 
• 
Complete 
 
• 
Confirm that the UAS and 
 were 
completed daily from the last visit through 
the morning of Visit 2 (Day 1) 
• 
Confirm 
that 
the 
 
was 
completed the morning of Visit 2 (Day 1) 
The following assessments will be 
performed during Visit 2 (Day 1): 
• 
Complete 
 
 
• 
Confirm that the UAS and 
 were 
completed daily from the last visit through 
the morning of Visit 2 (Day 1) 
The text was updated to better 
reflect how the 
 will be 
administered for this study. 
9.4.2.2. Visit 3 (Week 3) 
The following assessments will be 
performed during Visit 3 (Week 3): 
• 
Complete 
 
• 
Confirm that the UAS and 
 were 
completed daily from the last visit through 
the morning of Visit 3 (Week 3) 
• 
Confirm that the 
 was 
completed weekly from the last visit 
through the morning of Visit 3 (Week 3) 
The following assessments will be 
performed during Visit 3 (Week 3): 
• 
Complete 
 
• 
Confirm that the UAS and 
 were 
completed daily from the last visit through 
the morning of Visit 3 (Week 3) 
• 
Confirm that the 
 was completed 
weekly from the last visit through Visit 3 
(Week 3) 
The text was updated to better 
reflect how the 
 will be 
administered for this study. 
9.4.2.3. Visit 4 (Week 6) 
The following assessments will be 
performed during Visit 4 (Week 6): 
• 
Complete 
 
• 
Confirm that the UAS and 
 were 
completed daily from the last visit through 
the morning of Visit 4 (Week 6) 
• 
Confirm that the 
was 
completed weekly from the last visit 
through the morning of Visit 4 (Week 6) 
The following assessments will be 
performed during Visit 4 (Week 6): 
• 
Complete 
 
 
• 
Confirm that the UAS and 
were 
completed daily from the last visit through 
the morning of Visit 4 (Week 6) 
• 
Confirm that the 
 was completed 
weekly from the last visit through Week 5 
The text was updated to better 
reflect how the 
will be 
administered for this study. 

EP-262-201 Protocol, Amendment 4.0 (26 July 2024) 
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Confidential 
Page 94 of 99 
 
 
 
Section 
Amendment 1.0 
Amendment 2.0 
Reason for Change 
9.4.3.1. Visit 5 (Week 10) 
The following assessments will be 
performed during the Safety Follow-Up 
Visit, approximately 4 weeks after the last 
dose of study drug: 
• 
Confirm that the UAS and 
 were 
completed daily from the last visit through 
the morning of Visit 5 (Week 10) 
• 
Confirm that the 
 was 
completed weekly from the last visit 
through the morning of Visit 5 (Week 10) 
The following assessments will be 
performed during the Safety Follow-Up 
Visit, approximately 4 weeks after the last 
dose of study drug: 
• 
Confirm that the UAS and 
 were 
completed daily from the last visit through 
the morning of Visit 5 (Week 10) 
• 
Confirm that the 
 was completed 
weekly from the last visit through Week 9 
The text was updated to better 
reflect how the 
will be 
administered for this study. 
9.4.4. Early Treatment 
Termination Visit 
Subjects who discontinue from treatment 
early should have the Early Treatment 
Termination Visit conducted as soon as 
possible after the last dose of study drug, 
ideally within 2 days after the last dose of 
study drug. The following assessments will 
be performed during the Early Treatment 
Termination Visit: 
• 
Complete 
 
• 
Confirm that the UAS and 
 were 
completed daily from the last visit through 
the morning of the Early Treatment 
Termination Visit 
• 
Confirm that the 
 was 
completed weekly from the last visit 
through the morning of the Early 
Treatment Termination Visit 
Subjects who discontinue from treatment 
early should have the Early Treatment 
Termination Visit conducted as soon as 
possible after the last dose of study drug, 
ideally within 2 days after the last dose of 
study drug. The following assessments will 
be performed during the Early Treatment 
Termination Visit: 
• 
Complete 
 
 
• 
Confirm that the UAS and 
were 
completed daily from the last visit through 
the morning of the Early Treatment 
Termination Visit 
• 
Confirm that the 
 was completed 
weekly from the last visit through the Early 
Treatment Termination Visit 
The text was updated to better 
reflect how the 
will be 
administered for this study. 

EP-262-201 Protocol, Amendment 4.0 (26 July 2024) 
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Confidential 
Page 95 of 99 
 
 
Summary of Changes for Amendment 1.0 Dated 29 November 2023 
Protocol EP-262-201 was amended to address the following changes: 
• Clarify the mandatory reasons for study termination, discontinuation of study drug, and discontinuation from the study 
• Exclude the use of nondepolarizing neuromuscular blocking agents that are agonists at the MRGPRX2 receptor 
• Add a list of permitted medications 
• Provide a rationale for conducting an interim analysis 
• Clarify that only the use of antidepressants/antipsychotics/antispasmodics that are agonists at the MRGPRX2 receptor are 
excluded 
• Add glucose to the chemistry panel, remove urine albumin from the urinalysis panel, and clarify that dipsticks will not be used 
for urinalysis 
• Reword the precautions regarding sun exposure 
• Expand the recording of medications to include those taken to treat CSU beginning from the date of diagnosis 
• Revised the study day associated with the Week 10 visit from Day 69 to Day 71 
• Introduce the study acronym CALM-CSU 
Notable changes are included below in the summary table. Revised text in Amendment 1.0 is bolded, and text deleted from the 
original version is crossed out in the table below. Italicized text is used to describe a change. Minor/editorial changes are not listed 
individually in the summary table. 
 
Section 
Original 
Amendment 1.0 
Reason for Change 
Title page 
Sponsor Statement 
New text 
Study Acronym: CALM-CSU 
The study acronym was added to 
further denote the study title. 

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Confidential 
Page 96 of 99 
 
 
 
Section 
Original 
Amendment 1.0 
Reason for Change 
Synopsis, Exclusion Criteria 
8.2 Subject Exclusion 
Criteria 
4. Use of the following prohibited 
treatments: 
a. 
Drugs that are agonists at the 
MRGPRX2 receptor, including icatibant, 
opioids (eg, codeine, morphine), 
fluoroquinolones (eg, ciprofloxacin, 
levofloxacin), vancomycin, or 
antidepressants/antipsychotics/ 
antispasmodics (eg, doxepin, paroxetine, 
clozapine, benztropine) within 14 days 
before Screening 
4. Use of the following prohibited 
treatments: 
a. 
Drugs that are agonists at the 
MRGPRX2 receptor, including icatibant, 
opioids (eg, codeine, morphine), 
fluoroquinolones (eg, ciprofloxacin, 
levofloxacin), vancomycin, certain 
antidepressants/antipsychotics/ 
antispasmodics (eg, doxepin, paroxetine, 
clozapine, benztropine), or 
nondepolarizing neuromuscular blocking 
agents (eg, atracurium, rocuronium, 
vecuronium, cisatracurium, mivacurium) 
within 14 days before Screening 
Revised to clarify that only the use 
of antidepressants/antipsychotics/ 
antispasmodics that are agonists at 
the MRGPRX2 receptor are 
excluded. 
Nondepolarizing neuromuscular 
blocking agents are also agonists 
of the MRGPRX2 receptor and 
were added for completeness. 
5.4.2 Risk Summary 
5.4.3 Mitigation Strategy 

EP-262-201 Protocol, Amendment 4.0 (26 July 2024) 
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Page 97 of 99 
 
 
 
Section 
Original 
Amendment 1.0 
Reason for Change 
7.6 Criteria for Study 
Termination 
The Sponsor may terminate the study at a 
clinical site at any time (eg, Good Clinical 
Practice [GCP] noncompliance or poor 
study data quality). The entire study may 
also be terminated by the Sponsor or at the 
request of a regulatory agency, IRB, or 
IEC. 
The Sponsor reserves the right to 
terminate the study at a clinical site at any 
time for any reason at the sole discretion 
of the Sponsor. Potential reasons for 
closure of a clinical site include but are 
not limited to: 
• 
Good Clinical Practice (GCP) 
noncompliance 
• 
Poor study data quality 
The entire study will be terminated by 
the Sponsor should new information 
become available resulting in a clearly 
negative benefit/risk balance. The entire 
study may also be terminated by the 
Sponsor for other reasons or at the request 
of a regulatory agency, IRB or IEC. 
Revised to include a clearly 
negative benefit/risk balance as a 
reason for study termination. 
8.3 Study Restrictions 
8.4. Concomitant 
Medications 
New text 
In addition, all medications taken to treat 
CSU beginning from the date of diagnosis 
should also be recorded. 
Added to collect more information 
about the study population. 
8.5.3 Permitted Medications 
New text 
8.5.3. 
Permitted Medications 
Allowed second generation H1AH 
include bilastine, cetirizine, 
desloratadine, ebastine, fexofenadine, 
levocetirizine, loratadine, and 
rupatadine. Additional H1A1 not listed 
above may be permitted at the discretion 
of the Medical Monitor. 
A list of permitted medications 
was added for completeness. 

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Page 98 of 99 
 
 
 
Section 
Original 
Amendment 1.0 
Reason for Change 
8.6.1 Discontinuation of 
Study Drug 
Study drug may be discontinued in the 
following instances: 
• 
AE 
• 
Withdrawal of consent 
• 
Lost to follow-up 
• 
Protocol deviation 
• 
Investigator decision 
• 
Sponsor decision 
• 
Pregnancy during the study 
(Section 12.2.3) 
• 
Other 
If a subject experiences an AE that is 
Common Terminology Criteria for 
Adverse Events (CTCAE) Grade 4 or 
higher, the study drug must be 
discontinued. AE grading for severity 
using CTCAE criteria is described in 
Section 12.1.2. 
Discontinuation of study drug for a 
subject occurs when the study drug is 
stopped earlier than the protocol planned 
treatment duration. Discontinuation of 
study drug is mandatory in the following 
instances: 
• 
AEs for which continued exposure to 
study drug would be detrimental, 
including AEs that are Common 
Terminology Criteria for Adverse Events 
(CTCAE) Grade 4 or higher 
(Section 12.1.2) 
• 
Abnormal liver laboratory results 
meeting the threshold for discontinuation 
as listed in Section 12.10.3 
• 
Withdrawal of consent 
• 
Lost to follow-up 
• 
Protocol deviation that results in a 
significant risk to the subject’s safety 
• 
Investigator decision 
• 
Sponsor decision 
• 
Pregnancy during the study 
(Section 12.2.3) 
• 
Any circumstance that results in a 
negative benefit:risk balance 
Clarified the circumstances that 
will require mandatory 
discontinuation of study drug. 
8.6.2 Discontinuation from 
the Study 
Subjects may discontinue from the study at 
any time for any of the following reasons: 
Discontinuation from the study is 
mandatory for the following reasons: 
Clarified the circumstances that 
will require mandatory 
discontinuation from the study. 
9.4.1.1 Visit 1 (Day -30 to 
Day -14 [inclusive]) 
• 
Assessment of baseline concomitant 
medications, including any prior use of 
omalizumab and all medications taken 
within 14 days before Screening 
• 
Assessment of baseline concomitant 
medications, including all medications 
taken to treat CSU beginning from the 
date of diagnosis, any prior use of 
omalizumab, and all medications taken 
within 14 days before Screening 
Added to collect more information 
about the study population. 

EP-262-201 Protocol, Amendment 4.0 (26 July 2024) 
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Page 99 of 99 
 
 
 
Section 
Original 
Amendment 1.0 
Reason for Change 
12.8 Laboratory Evaluations 
of Safety 
• 
Chemistry: sodium, albumin, alkaline 
phosphatase (ALP), bicarbonate, calcium, 
corrected calcium, chloride, bilirubin 
(total, indirect, and direct), AST, ALT, 
blood urea nitrogen, urea, creatinine, 
magnesium, phosphorus, potassium, 
creatine phosphokinase, total cholesterol, 
triglycerides, high-density lipoprotein 
cholesterol, low-density lipoprotein 
cholesterol, lactate dehydrogenase, 
gamma-glutamyltransferase, and total 
protein 
• 
Chemistry: sodium, albumin, alkaline 
phosphatase (ALP), bicarbonate, calcium, 
corrected calcium, chloride, bilirubin (total, 
indirect, and direct), AST, ALT, blood urea 
nitrogen, urea, creatinine, glucose, 
magnesium, phosphorus, potassium, 
creatine phosphokinase, total cholesterol, 
triglycerides, high-density lipoprotein 
cholesterol, low-density lipoprotein 
cholesterol, lactate dehydrogenase, gamma- 
glutamyltransferase, and total protein 
Added glucose to the chemistry 
panel for completeness and to 
increase the robustness of safety 
screening and monitoring. 
12.8 Laboratory Evaluations 
of Safety 
• 
Urinalysis (dipstick): leukocyte 
esterase, nitrites, pH, protein, specific 
gravity, glucose, occult blood, ketones, 
bilirubin, urobilinogen, and albumin; 
microscopic analysis is to be performed 
only if protein, leukocyte esterase, blood 
or nitrite is positive 
• 
Urinalysis: leukocyte esterase, nitrites, 
pH, protein, specific gravity, glucose, occult 
blood, ketones, bilirubin, and urobilinogen; 
microscopic analysis is to be performed 
only if protein, leukocyte esterase, blood or 
nitrite is positive 
Corrected text to accurately reflect 
that dipsticks will not be used for 
urinalysis. 
Albumin is not a standard measure 
in urinalysis and not required for 
the safety evaluations in this study. 
16.13 Interim Analysis 
16.13 Planned Interim Analysis 
Given the hypothesis-generating nature of 
this study, an interim analysis may be 
conducted. 
16.13 Interim Analysis 
Given the hypothesis-generating nature of 
this study, an interim analysis may be 
conducted to support business needs. 
Added a rationale for why an 
interim analysis may be conducted. 
Appendix A. Schedule of 
Assessments (Study Day 
Row) 
Day 69 
Day 71 
Day 71 is a more accurate study 
day than Day 69 for the Week 10 
visit. 
Appendix A Schedule of 
Assessments (Concomitant 
medications row) 
Record any prior use of omalizumab. 
Record all medications taken within 
14 days before Screening. 
Record any prior use of omalizumab. 
Record all medications taken to treat CSU 
beginning from the date of diagnosis and 
all other medications taken within 14 days 
before Screening. 
Added to collect more information 
about the study population.