A Multicenter Dose-Titration Open-Label Study of Nevanimibe Hydrochloride for the Treatment of Classic Congenital Adrenal Hyperplasia
Phase: PHASE2
Conditions: Congenital Adrenal Hyperplasia
Sponsor: Millendo Therapeutics US, Inc.

 
 
 
 
CLINICAL STUDY PROTOCOL 
PRODUCT NAME: NEVANIMIBE HYDROCHLORIDE 
STUDY NUMBER: ATR-101-202 
A Multicenter Dose-Titration Open-Label Study of Nevanimibe 
Hydrochloride for the Treatment of Classic Congenital Adrenal Hyperplasia 
 
 
Study Phase: 2b 
IND Number: 122745 
EudraCT Number: 2017-004878-34 
NCT Number: NCT03669549 
Indication: Classic Congenital Adrenal Hyperplasia 
Sponsor: Millendo Therapeutics US, Inc. 
 
Sponsor Medical Contact: Vivian H. Lin, M.D. 
 
Original Protocol: 22 February 2018 
Global Protocol Amendment 1: 13 March 2018 
Czech Republic Country-Specific Amendment 1: 11 June 2018 
France Country-Specific Amendment 1: 25 June 2018 
Global Protocol Amendment 2: 31 May 2019 
 
Confidentiality Statement 
This confidential document is the property of Millendo Therapeutics, Inc. and its affiliates 
and it is provided for the use of the Investigator and other designated personnel solely in 
connection with the conduct of the study described herein. No information contained herein 
may be disclosed, except as necessary to obtain consent from persons who are considering 
participation in the study, without prior written approval of Millendo Therapeutics, Inc. 

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INVESTIGATOR’S AGREEMENT 
 
Study Title: A Multicenter Dose-Titration Open-Label Study of Nevanimibe Hydrochloride for 
the Treatment of Classic Congenital Adrenal Hyperplasia 
This protocol is provided for use by you, your staff and the Institutional Review Board or Ethics 
Committee. The information contained in this document is confidential and belongs to Millendo 
Therapeutics US, Inc. Except as may be otherwise agreed to in writing, by accepting or 
reviewing these materials, you agree to hold such information in confidence and not to disclose it 
to others (except where required by applicable law) nor use it for unauthorized purposes. In the 
event of actual or suspected breach of this obligation, Millendo Therapeutics US, Inc. must be 
promptly notified. 
STUDY INVESTIGATOR SIGNATURE 
By my signature below, I agree to conduct this clinical study in accordance with applicable 
government regulations or laws, and institutional/ethical review and informed consent practices. 
I have read the Investigator’s Brochure and protocol. I agree to ensure the confidentiality of my 
subjects; however, I agree to make available to Millendo Therapeutics US, Inc. or designee the 
subject’s medical chart specifically for the purposes of this clinical study. I am fully conversant 
with Good Clinical Practices (GCP) and agree to conduct the clinical study in accordance with 
these principles and the procedures described in this protocol. I am aware of my responsibilities 
as an investigator. 
 
Name: 
_________________________________ 
Please print 
 
Title: 
 
 
_________________________________ 
Signature: 
 
_________________________________ 
Date: 
 
_________________________________ 
Address: 
_________________________________ 
 
 
_________________________________ 
 
 
_________________________________ 
 

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SPONSOR SIGNATURE 
 
Study Title: A Multicenter Dose-Titration Open-Label Study of Nevanimibe Hydrochloride for 
the Treatment of Classic Congenital Adrenal Hyperplasia 
SPONSOR SIGNATURE 
I have read and approve the protocol and appendices. My signature, in conjunction with the 
signature of the Investigator, confirms the agreement of both parties that the clinical trial will be 
conducted in accordance with the protocol and all applicable laws and regulations, including, but 
not limited to, the International Council on Harmonisation (ICH) Guidelines for GCP, the US 
Code of Federal Regulations (CFR) and the ethical principles that have their origins in the 
Declaration of Helsinki, as well as all applicable privacy laws.  
 
Name: 
Pharis Mohideen, MD 
Please print 
 
Title: 
 
 
Chief Medical Officer 
Signature: 
 
_________________________________ 
Date: 
 
_________________________________ 
 
Address: 
110 Miller Avenue  
 
 
Suite 100 
 
 
Ann Arbor, MI 48104 
 
 

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SYNOPSIS 
Name of Sponsor/Company: Millendo Therapeutics US, Inc. 
Name of Investigational Product: Nevanimibe hydrochloride (formerly known as ATR-101) 
Study Number: ATR-101-202 
Title of Study: A Multicenter Dose-Titration Open-Label Study of Nevanimibe Hydrochloride for 
the Treatment of Classic Congenital Adrenal Hyperplasia 
Phase of Development: 2b 
Objectives:  
Primary: To evaluate the efficacy and safety of orally administered nevanimibe hydrochloride for the 
treatment of classic congenital adrenal hyperplasia  
Secondary:  
• 
To assess the changes in adrenal cortical steroids and steroid intermediates  
• 
To determine the pharmacokinetic (PK) parameters of nevanimibe and its major metabolite(s) 
• 
To assess the PK/pharmacodynamic (PD) relationships of nevanimibe and its major metabolite(s) 
Study Design:  
This is a multicenter, intra-subject dose-titration open-label study of nevanimibe hydrochloride (HCl) 
for the treatment of classic congenital adrenal hyperplasia (CAH). Following a Screening Period of 
approximately 2-14 weeks, eligible subjects will enter a Baseline Period of approximately 2-8 weeks 
and then a 16-week Treatment Period. During the Treatment Period, subjects will receive nevanimibe 
HCl twice daily (BID) for 16 weeks. All subjects will begin dosing with nevanimibe HCl 500 mg 
BID. Titration of nevanimibe HCl will depend upon the 17-OHP response, which will be assessed 
every 4 weeks during the Treatment Period. The dosing regimens are intended to achieve and 
maintain 17-OHP ≤ 2x the upper limit of normal (ULN) (the primary endpoint) on the lowest possible 
dose of nevanimibe HCl while actively up-titrating if 17-OHP is > 2x ULN. Thus, subjects who are 
found to have met the primary endpoint (i.e., on the previous lower dose of nevanimibe HCl) based 
on their most recent serum 17-OHP value will have their nevanimibe HCl dose down-titrated to the 
dose on which they met the endpoint. Four doses of nevanimibe HCl (500 mg BID, 1000 mg BID, 
1500 mg BID, and 2000 mg BID) are available for use in the study. A study schematic is shown in 
Figure 1. 
After signing informed consent, subjects with classic CAH will enter the Screening Period to assess 
preliminary eligibility for the study based on the inclusion and exclusion criteria. In addition, 
pertinent information will be collected such as past medical history, demographic data, and prior and 
current medications. Laboratory tests will be done as part of study eligibility. 
Subjects with a serum 17-OHP ≥ 4x ULN (Cohort 1) at the initial screening visit (Visit S1) will 
proceed to the Baseline Visit (Visit B1). Cohort 1 subjects will not make any changes in their daily 
maintenance glucocorticoid dose throughout the study (except, for example, for emergency, stress 
dose requirements). Subjects with a serum 17-OHP < 4x ULN (Cohort 2) AND a daily maintenance 
glucocorticoid dose in the suppressive range (≥ the equivalent of approximately 12 mg 
hydrocortisone/m2 body surface area—see Appendix 3) at the initial screening visit (Visit S1) will 
have their glucocorticoid dose decreased by the equivalent of approximately 5 mg hydrocortisone or 1 
mg prednisone or prednisolone (see Appendix 2). They will then return for Visit S2 to have their 17-
OHP level rechecked approximately 2 to 4 weeks after their glucocorticoid dose was changed. If their 
serum 17-OHP level from Visit S2 is ≥ 4x ULN, they will proceed to the Baseline Visit (Visit B1). If 
not, the case should be discussed with the Medical Monitor; if appropriate, the subject may undergo 

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further glucocorticoid dose adjustment and subsequent assessment of serum 17-OHP levels during the 
Screening Period. The Screening Period may last from approximately 2-14 weeks.  
Figure 1: Study Schematic 
 
At the Baseline Visit (Visit B1), additional laboratory tests will be done as part of study eligibility. In 
addition, subjects will be instructed on the use of an electronic diary (eDiary) for recording their 
glucocorticoid, mineralocorticoid (if applicable), and study drug doses (and, for premenopausal 
women, start dates of menstrual periods) during the study. The most recent serum 17-OHP level 
should be ≥ 4x ULN for all subjects prior to Visit B1. Any subject whose Visit B1 serum 17-OHP is < 
4x ULN should be discussed with the Medical Monitor prior to enrolling in the study. Cohort 2 
subjects may require further decreases in glucocorticoid dose and subsequent assessment of serum 17-
OHP during the Baseline Period (see Appendix 2). No study drug will be given during the Baseline 
Period. The Baseline Period may last from approximately 2-8 weeks. 
Subjects who meet all of the inclusion criteria and none of the exclusion criteria may be enrolled into 
the 16-week Treatment Period. Enrollment in either Cohort 1 or Cohort 2 may be capped at the 
Sponsor’s discretion to ensure that a sufficient number of subjects are enrolled into both cohorts. 
All enrolled subjects will receive open-label active treatment with nevanimibe HCl orally starting at a 
dose of 500 mg BID. The first dose of nevanimibe HCl will be given at the study site at Visit T1 (Day 
1; Enrollment). All subjects will receive nevanimibe HCl 500 mg BID for Treatment Period Weeks 1-
4 (Day 1 to Day 28).  
At Visit T2 (Day 29), all subjects will have their nevanimibe HCl dose automatically up-titrated to 
1000 mg BID. At Visits T3 (Day 57) and T4 (Day 85), subjects whose most recent predose serum 17-
OHP met the primary endpoint will remain on the nevanimibe HCl dose on which they met the 
endpoint; and subjects whose most recent predose serum 17-OHP did not meet the primary endpoint 
will have their nevanimibe HCl dose increased to the next higher dose level. 
The serum 17-OHP samples require ~10 days to process. When the predose serum 17-OHP results are 
available following Visits T2, T3, and T4, they will be used to titrate the nevanimibe HCl dose as 
follows: 

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• 
Subjects whose predose serum 17-OHP is ≤ 2x ULN (primary endpoint is met) will have their 
nevanimibe HCl dose decreased to the dose on which they most recently met the endpoint if they 
underwent a dose increase at their most recent treatment period site visit. 
• 
Subjects whose predose serum 17-OHP is > 2x ULN (primary endpoint is not met) will have their 
nevanimibe HCl dose increased to the next higher dose level if they did not already undergo a 
dose increase at their most recent treatment period site visit. 
• 
All other subjects will remain on their current nevanimibe HCl dose. 
During the Treatment Period, nevanimibe HCl doses may also be down-titrated by the Investigator if 
needed based on safety and tolerability with approval of the Medical Monitor.  
The 4-week Follow-up Period will commence immediately after the subject completes the Treatment 
Period. No study drug will be given during the Follow-up Period. The last study visit will take place 
at the completion of the Follow-up Period. 
A detailed schedule of study assessments is provided in Appendix 1. An algorithm for maintenance 
glucocorticoid dose down-titration and subsequent monitoring of serum 17-OHP levels for eligibility 
during the Screening and Baseline periods is provided in Appendix 2. 
Duration of Study:  
Approximately 24-42 weeks (Screening Period of 2-14 weeks, Baseline Period of 2-8 weeks, 
Treatment Period of 16 weeks, and Follow-up Period of 4 weeks) 
Number of Sites: Approximately 10-12 in Israel, Europe, and South America 
Number/Type of Subjects (planned):  
Approximately 20-24 evaluable adults with a documented history of classic CAH will be enrolled 
Diagnosis and Main Criteria for Inclusion:  
Inclusion Criteria:  
1. Provision of signed and dated informed consent prior to any study-specific procedures 
2. Men and women 18 to 80 (70 in the Czech Republic) years of age (inclusive) at the time of 
informed consent 
3. Documented historical diagnosis of classic CAH due to 21-hydroxylase deficiency based on 
either or both of the following criteria: 
• 
Documented genetic mutation in the CYP21A2 enzyme consistent with a diagnosis of classic 
CAH 
• 
Historical documentation of elevated 17-OHP (e.g., in infancy or following a 
cosyntropin/ACTH stimulation test) 
4. Serum 17-OHP ≥ 4x ULN during the Baseline Period 
• 
Premenopausal women in the follicular phase of the menstrual cycle must have serum 
17-OHP ≥ 4x follicular phase ULN 
• 
Premenopausal women in the luteal phase of the menstrual cycle must have serum 17-OHP ≥ 
(4x follicular phase ULN + (luteal phase ULN – follicular phase ULN)) 
5. Chronic glucocorticoid replacement therapy for at least 6 consecutive months prior to Screening 
6. Stable glucocorticoid and mineralocorticoid regimen for at least 4 weeks prior to the Screening 
(S1), Baseline (B1), and Enrollment (T1) Visits 
7. For subjects who undergo maintenance glucocorticoid dose adjustment between Screening and 
Enrollment, stable serum 17-OHP levels (adjusted as needed for menstrual cycle phase) prior to 
Enrollment, defined as the most recent 2 values being within 30% of each other (calculated as 100 
× (1 – (smaller value/larger value))) 

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8. Female subjects of childbearing potential must consent to use two medically acceptable methods 
of contraception, excluding depot progesterone, throughout the study period and for 30 days after 
the last dose of study treatment during any sexual intercourse with a fertile male partner (in 
France: Fertile subjects (male and female) must consent to use two medically acceptable methods 
of contraception, excluding depot progesterone, throughout the study period and for 30 days after 
the last dose of study treatment during any sexual intercourse with a fertile partner of the opposite 
sex) 
Exclusion Criteria: 
1. Nonclassic CAH 
2. Other causes of adrenal insufficiency such as Addison’s disease or adrenalectomy; or classic 
CAH with serum 17-OHP < 4x ULN and daily maintenance glucocorticoid dose in the adrenal 
insufficiency range (e.g., ≤ 8-10 mg hydrocortisone/m2 body surface area per day) 
3. Surgery within the previous three months prior to screening or planned surgery during study 
participation. Minor procedures are permitted (e.g., removal of skin tags or other minor 
dermatological procedures) 
4. History of active cancer requiring medical or surgical therapy within the past 6 months (with the 
exception of successfully treated non-metastatic basal cell or squamous cell carcinoma of the skin 
or carcinoma in situ of the cervix) 
5. Female subjects must not be currently pregnant or breastfeeding or have conceived or given birth 
within 3 months of Screening 
6. Abnormal laboratory tests at Screening: 
• 
ALT or AST > 2x ULN 
• 
Bilirubin > 1.5x ULN  
• 
Serum creatinine > 1.5x ULN 
7. Positive screen for HIV, hepatitis B surface antigen or hepatitis C antibody at Screening 
8. An average QTcF value of > 470 (450 in France) msec at Screening 
9. Current or ongoing use of any prohibited concomitant medications (Section 5.8) 
10. History of substance abuse within the past 1 year prior to informed consent 
11. Positive toxicology screening test for substances of abuse, other than marijuana 
12. Known allergy to nevanimibe HCl (formerly known as ATR-101) 
13. Participation in any study of an investigational drug within 30 days (or 5 half-lives of the 
investigational drug, whichever is longer) prior to Screening 
14. Any other medical or psychiatric condition that, in the opinion of the Investigator, is likely to 
confound the interpretation of the study results or prevent the subject from understanding the 
requirements of or successfully completing the study (e.g., myocardial infarction (MI) or 
cerebrovascular accident/transient ischemic attack (CVA/TIA) within the past 6 months) 
Investigational Product, Dosage and Mode of Administration:  
Clinical supplies of nevanimibe HCl will be provided as 500-mg tablets for oral administration. 
Reference Therapy, Dosage and Mode of Administration: None 
Study Endpoints: 
Primary Efficacy Endpoint: The primary efficacy endpoint is the overall response rate within each 
cohort, defined as the percentage of subjects achieving serum 17-OHP targets as follows: 
• 
Men and postmenopausal women: 17-OHP ≤ 2x ULN 
• 
Premenopausal women: 
- Follicular phase: 17-OHP ≤ 2x follicular phase ULN 

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- Luteal phase: 17-OHP ≤ (2x follicular phase ULN + (luteal phase ULN – follicular phase 
ULN)) 
Safety Endpoints: Safety endpoints include the incidence of treatment-emergent adverse events (AEs) 
and serious adverse events (SAEs), as well as values and changes from baseline in clinical laboratory 
tests, vital signs, physical examinations, and electrocardiogram (ECG) parameters. 
Pharmacokinetic Endpoints: 
The PK and PD endpoints include the following; additional PK and PD endpoints may be described 
in the SAP. 
• 
The Cmax, Tmax, AUC0-4, and other PK parameters of nevanimibe and its major metabolite(s) (as 
appropriate and as the data allow) 
• 
The relationship between the Cmax and AUC0-4 of nevanimibe and its major metabolite(s) in 
relation to the change in 17-OHP levels (as appropriate and as the data allow) 
Statistical Methods: 
Sample Size: 
Based on results of the previous Phase 2 study of nevanimibe HCl in classic CAH (ATR-101-201), 
the sample size of approximately 20-24 evaluable subjects is considered to be sufficient for assessing 
whether nevanimibe HCl at doses of 500-2000 mg BID has clinically meaningful efficacy in the 
treatment of classic CAH. An evaluable subject is defined as a subject who has efficacy data 
following at least 8 weeks of continuous dosing with nevanimibe HCl. 
Efficacy Analyses: 
Only observed case data will be used for the efficacy summaries. The levels of adrenal steroids, 
steroid intermediates, and other measured hormones will be summarized using descriptive statistics, 
including number of non-missing observations (n), mean and/or median, standard deviation (SD) 
and/or percentiles, minimum (min), maximum (max) and 90% confidence intervals, if applicable. The 
analysis will be performed by value and by change from baseline in the value, where appropriate, for 
each time point, overall, by nevanimibe HCl dose, and by cohort. The percentage of subjects 
achieving serum 17-OHP targets, the primary endpoint, will be summarized overall and by cohort. 
The study will be considered positive if 40% or more of enrolled subjects in either cohort achieve the 
primary endpoint. 
Safety Analyses: 
Only observed case data will be used for safety summaries. The summarization of AEs will include 
treatment-emergent AEs (TEAEs; defined as AEs that begin or worsen after the first dose of study 
drug). TEAEs and treatment-emergent SAEs will be summarized by MedDRA system organ class and 
preferred term, severity, and relationship to study drug, overall, by nevanimibe HCl dose, and by 
cohort. Deaths and discontinuations due to AEs will each be summarized, overall, by nevanimibe HCl 
dose, and by cohort. Clinical safety laboratory results, PE findings, vital signs, and ECG readings will 
be summarized by value and by change from baseline in the value, where appropriate, for each time 
point, overall, by nevanimibe HCl dose, and by cohort using summary statistics for continuous 
parameters, including number of non-missing observations (n), mean and/or median, standard 
deviation (SD) and/or percentiles, minimum (min), and maximum (max). Frequencies and 
percentages as well as shift tables will be prepared for categorical parameters. 
Pharmacokinetic Analyses: 
Individual subject PK data will be analyzed along with pooling of subjects’ data at each dose level. 
Individual PK parameters will be computed to the extent allowed by the PK data collection times. 
Tabular summaries will be provided using descriptive summary statistics. PK/PD analyses will be 
detailed in the Statistical Analysis Plan. 
 
 

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TABLE OF CONTENTS 
SYNOPSIS ......................................................................................................................................4 
TABLE OF CONTENTS .................................................................................................................9 
LIST OF TABLES .........................................................................................................................14 
LIST OF FIGURES .......................................................................................................................14 
LIST OF ABBREVIATIONS ........................................................................................................15 
1. 
INTRODUCTION ......................................................................................................18 
1.1. 
Background .................................................................................................................18 
1.2. 
Rationale for the Use of Nevanimibe Hydrochloride in Congenital Adrenal 
Hyperplasia .................................................................................................................19 
2. 
STUDY OBJECTIVES ..............................................................................................20 
2.1. 
Primary Objective .......................................................................................................20 
2.2. 
Secondary Objectives .................................................................................................20 
3. 
INVESTIGATIONAL PLAN .....................................................................................21 
3.1. 
Overall Study Design ..................................................................................................21 
3.1.1. 
Screening Period .........................................................................................................21 
3.1.2. 
Baseline Period ...........................................................................................................22 
3.1.3. 
Treatment Period ........................................................................................................22 
3.1.4. 
Follow-up Period ........................................................................................................23 
3.2. 
Rationale for Study Design .........................................................................................23 
3.3. 
Efficacy Assessment ...................................................................................................25 
3.4. 
Safety Assessment ......................................................................................................26 
3.5. 
Criteria for Study Termination ...................................................................................26 
4. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................27 
4.1. 
Study Population .........................................................................................................27 
4.2. 
Inclusion Criteria ........................................................................................................27 
4.3. 
Exclusion Criteria .......................................................................................................27 
4.4. 
Subject Withdrawal Criteria .......................................................................................28 
5. 
TREATMENT OF SUBJECTS ..................................................................................30 
5.1. 
Assignment of Subject Identification Numbers ..........................................................30 
5.2. 
Description of Study Drug ..........................................................................................30 
5.3. 
Study Drug Administration.........................................................................................30 
5.3.1. 
Timing and Administrative Dosing Conditions ..........................................................31 

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5.3.2. 
Titration of Nevanimibe HCl Dose .............................................................................31 
5.3.3. 
Drug Holidays and Down-Titration ............................................................................32 
5.3.4. 
Missed Doses ..............................................................................................................32 
5.3.5. 
Compliance .................................................................................................................32 
5.3.6. 
Blinding ......................................................................................................................32 
5.4. 
Study Drug Packaging and Labeling ..........................................................................32 
5.5. 
Study Drug Storage and Accountability .....................................................................33 
5.6. 
Investigational Product Retention at the Study Site ...................................................33 
5.7. 
Concomitant Medications ...........................................................................................33 
5.8. 
Prohibited and Restricted Medications .......................................................................34 
5.9. 
Precautions and Warnings ..........................................................................................35 
6. 
STUDY ASSESSMENTS ..........................................................................................36 
6.1. 
Allowable Variation in Time of Procedures ...............................................................36 
6.2. 
Informed Consent .......................................................................................................36 
6.3. 
Eligibility ....................................................................................................................36 
6.4. 
Medical History ..........................................................................................................36 
6.5. 
Prior and/or Concomitant Medication Assessments ...................................................36 
6.6. 
Electronic Diary ..........................................................................................................37 
6.7. 
Vital Signs, Height, Weight and Body Mass Index ....................................................37 
6.8. 
Physical Examination .................................................................................................37 
6.9. 
Electrocardiography and Determination of QTc ........................................................37 
6.10. 
Adverse Events, Serious Adverse Events and Reporting ...........................................38 
6.10.1. 
Definition of Adverse Event, Adverse Drug Reaction and Unexpected 
Adverse Drug Reaction ...............................................................................................38 
6.10.2. 
Assessing Severity of Adverse Events .......................................................................39 
6.10.3. 
Assessing Relationship to Study Treatment ...............................................................39 
6.10.4. 
Serious Adverse Events ..............................................................................................40 
6.10.4.1. 
Definition of Serious Adverse Event ..........................................................................40 
6.10.4.2. 
Reporting SAEs – Procedure for Investigators ...........................................................41 
6.10.5. 
Pregnancy Reporting ..................................................................................................42 
6.10.6. 
Regulatory Reporting of Adverse Events ...................................................................42 
6.11. 
Laboratory Tests .........................................................................................................42 
6.11.1. 
Clinical Laboratory Assessments ...............................................................................43 

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6.11.2. 
Pharmacokinetic Assessments ....................................................................................43 
6.11.3. 
Pharmacodynamic Assessments .................................................................................45 
6.11.4. 
Blood Sample Collection, Storage and Shipping .......................................................45 
7. 
STUDY ACTIVITIES ................................................................................................46 
7.1. 
Screening Period .........................................................................................................46 
7.1.1. 
Visit S1 .......................................................................................................................46 
7.1.2. 
After Visit S1 ..............................................................................................................47 
7.1.3. 
Visit S2 (Cohort 2 Subjects Only) ..............................................................................48 
7.1.4. 
After Visit S2 (Cohort 2 Subjects Only).....................................................................49 
7.2. 
Baseline Period ...........................................................................................................49 
7.2.1. 
Visit B1 (Day -14; Week -2) ......................................................................................49 
7.2.2. 
After Visit B1 .............................................................................................................50 
7.3. 
Treatment Period ........................................................................................................51 
7.3.1. 
Visit T1 (Day 1; Week 1; Enrollment) .......................................................................51 
7.3.2. 
Telephone Visit Between Visits T1 and T2 (Day 15; Week 3) ..................................53 
7.3.3. 
Visit T2 (Day 29; Week 5) .........................................................................................53 
7.3.4. 
Telephone Visit Prior to Treatment Day 43 (Week 7) ...............................................54 
7.3.5. 
Visit T3 (Day 57; Week 9) .........................................................................................55 
7.3.6. 
Telephone Visit Prior to Treatment Day 71 (Week 11) .............................................57 
7.3.7. 
Visit T4 (Day 85; Week 13) .......................................................................................58 
7.3.8. 
Telephone Visit Prior to Treatment Day 99 (Week 13) .............................................59 
7.3.9. 
Visit T5 (Day 113; Week 17; End-of-Treatment) ......................................................60 
7.4. 
Follow-up Period ........................................................................................................61 
7.4.1. 
Visit F1 (Day 141; Week 21; Follow-up Visit) ..........................................................61 
7.5. 
Early Termination (ET) ..............................................................................................62 
8. 
QUALITY CONTROL AND ASSURANCE ............................................................63 
9. 
STATISTICS ..............................................................................................................64 
9.1. 
General Considerations ...............................................................................................64 
9.2. 
Sample Size ................................................................................................................64 
9.3. 
Analysis Populations ..................................................................................................64 
9.4. 
Disposition and Baseline Characteristics ....................................................................64 
9.5. 
Efficacy .......................................................................................................................64 
9.5.1. 
Efficacy Endpoints......................................................................................................64 

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9.5.1.1. 
Primary Efficacy Endpoint .........................................................................................64 
9.5.1.2. 
Secondary Efficacy Endpoints ....................................................................................65 
9.5.2. 
Efficacy Analysis Methodology .................................................................................65 
9.5.2.1. 
Analysis of the Efficacy Endpoints ............................................................................65 
9.5.2.2. 
Exploratory Efficacy Endpoints .................................................................................65 
9.6. 
Safety ..........................................................................................................................65 
9.6.1. 
Safety Endpoints .........................................................................................................65 
9.6.2. 
Safety Analyses ..........................................................................................................65 
9.7. 
Pharmacokinetics and Pharmacodynamics .................................................................66 
9.7.1. 
Pharmacokinetic and Pharmacodynamic Endpoints ...................................................66 
9.7.2. 
Pharmacokinetic and Pharmacodynamic Analyses ....................................................66 
9.8. 
Interim Analysis..........................................................................................................66 
10. 
ADMINISTRATIVE CONSIDERATIONS ..............................................................67 
10.1. 
Institutional Review Board (IRB)/Ethics Committee (EC) ........................................67 
10.2. 
Ethical Conduct of the Study ......................................................................................67 
10.3. 
Subject Information and Consent ...............................................................................67 
10.4. 
Subject Confidentiality ...............................................................................................68 
10.5. 
Study Monitoring ........................................................................................................68 
10.6. 
Audits and Inspections ................................................................................................69 
10.7. 
Case Report Forms and Study Records ......................................................................69 
10.8. 
Data Safety Monitoring Board....................................................................................70 
10.9. 
Protocol Deviations ....................................................................................................70 
10.10. 
Access to Source Documentation ...............................................................................70 
10.11. 
Data Generation and Analysis ....................................................................................70 
10.12. 
Retention of Records ..................................................................................................70 
10.13. 
Financial Disclosure ...................................................................................................71 
10.14. 
Premature Termination of the Study ...........................................................................71 
10.15. 
Clinical Study Report .................................................................................................71 
10.16. 
Subject Insurance and Indemnity ................................................................................71 
10.17. 
Amendments to the Protocol ......................................................................................71 
11. 
REFERENCES ...........................................................................................................72 
12. 
APPENDICES ............................................................................................................74 
APPENDIX 1. STUDY SCHEDULE .........................................................................................75 

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APPENDIX 2. GLUCOCORTICOID (GC) DOSE ADJUSTMENT ALGORITHM ................78 
APPENDIX 3. CALCULATION OF GLUCOCORTICOID DOSE AS EQUIVALENT 
MG OF HYDROCORTISONE/M2 BODY SURFACE AREA .................................79 
APPENDIX 4. DRUGS THAT PROLONG THE QT/QTC INTERVAL ...................................80 
APPENDIX 5. DRUGS KNOWN TO INTERACT WITH CYP3A4 ........................................83 
APPENDIX 6. DRUGS THAT MAY INTERACT WITH P-GLYCOPROTEIN .....................85 
APPENDIX 7. DOSE RATIONALE ..........................................................................................86 
 
 
 

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LIST OF TABLES 
Table 1: 
Investigational Product ...............................................................................................30 
Table 2 
Nevanimibe HCl Dose Levels and Tablet Doses .......................................................31 
Table 3: 
List of Clinical Laboratory Tests ................................................................................43 
Table 4: 
Pharmacokinetic Sampling Time Points .....................................................................44 
Table 5: 
Pharmacokinetic Parameters .......................................................................................44 
Table 6: 
Schedule of Assessments ............................................................................................75 
Table 7: 
Conversion of Various Glucocorticoids to Equivalent mg of Hydrocortisone ...........79 
 
LIST OF FIGURES 
Figure 1: 
Study Schematic .........................................................................................................21 
Figure 2: 
Nevanimibe Doses and Exposure Duration by Dose Cohort, Part 1 of 2 ...................88 
Figure 3: 
Previous CAH Phase 2 Study Nevanimibe Exposures ...............................................90 
 
 
 

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LIST OF ABBREVIATIONS 
Abbreviation 
Explanation 
17-OHP 
17-hydroxyprogesterone 
A4 
androstenedione 
ACAT1 
acyl-CoA:cholesterol O-acyltransferase 1 
ACC 
adrenocortical carcinoma 
ACTH 
adrenocorticotropic hormone 
AE 
adverse event 
ALK-P 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
aPTT 
activated partial thromboplastin time 
AUC 
area under the concentration-time curve 
AUC0-4 
area under the concentration-time curve from time zero to 4 h after dosing 
AUC0-4/D 
dose-normalized AUC0-4, calculated as the ratio of AUC0-4 to dose 
AUC0-∞ 
area under the concentration-time curve from time zero to infinity 
AUC0-t 
area under the concentration-time curve from time zero to the time of the last 
quantified concentration 
AUC%extrap 
percentage of AUC0-∞ extrapolated 
BID 
twice daily 
BMI 
body mass index 
BUN 
blood urea nitrogen 
CAH 
congenital adrenal hyperplasia 
CE 
cholesteryl ester 
CFR 
Code of Federal Regulations 
CL 
clearance 
CL/F 
oral clearance calculated as dose/AUC0-∞ 
CI 
confidence interval 
Clast 
last quantifiable drug concentration determined directly from individual 
concentration-time data 
Cmax 
maximum observed drug concentration determined directly from individual 
concentration-time data 
Cmax/D 
dose-normalized Cmax, calculated as the ratio of Cmax to dose 
CFR 
Code of Federal Regulations 

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Abbreviation 
Explanation 
CQA 
clinical quality assurance 
CPMP 
Committee for Proprietary Medicinal Products 
CRA 
clinical research associate 
CS 
Cushing’s syndrome 
CSR 
clinical study report 
CVA 
cerebrovascular accident 
CYP 
cytochrome P450 
DSMB 
Drug Safety Monitoring Board 
EC 
ethics committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eDiary 
electronic diary 
EoS 
End-of-Study 
EoT 
End-of-Treatment 
ET 
early termination 
FC 
free cholesterol 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practices 
HBsAg 
hepatitis B surface antigen 
HCl 
hydrochloride 
Hct 
hematocrit 
HCV 
hepatitis C virus 
HEENT 
head, eyes, ears, nose and throat 
Hgb 
hemoglobin 
HIV 
human immunodeficiency virus 
HPA 
hypothalamic-pituitary-adrenal 
ICF 
informed consent form 
ICH 
International Council on Harmonisation 
ID 
identification 
INR 
international normalized ratio 
IRB 
institutional review board 
λz 
terminal phase rate constant 
MedDRA 
Medical Dictionary for Regulatory Activities 

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Abbreviation 
Explanation 
MI 
myocardial infarction 
mITT 
modified intention-to-treat 
NOAEL 
No Observed Adverse Effect Level 
NYHA 
New York Heart Association 
P 
progesterone 
PCOS 
polycystic ovary syndrome 
PD 
pharmacodynamic 
PE 
physical examination 
PK 
pharmacokinetic(s) 
PP 
per protocol 
PT 
prothrombin time or preferred term 
QT interval 
the time from the start of the Q wave and the end of the T wave 
QTc 
corrected QT interval 
QTcF 
QT interval corrected using the Fridericia method 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvate transaminase 
SOC 
system organ class 
SP 
Safety Population 
T 
testosterone 
t1/2 
terminal phase half-life 
TBili 
total bilirubin 
TEAE 
treatment-emergent AE 
TESAE 
treatment-emergent SAE 
TIA 
transient ischemic attack 
Tmax 
observed time to reach maximum drug concentration 
TMF 
trial master file 
ULN 
upper limit of normal 
US 
United States 
WBC 
white blood cell 
 

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1. 
INTRODUCTION 
1.1. 
Background 
Congenital adrenal hyperplasia (CAH) consists of genetic disorders affecting the synthesis of 
cortisol from the adrenal glands. CAH is categorized as being “classic” (associated with cortisol 
insufficiency) or “nonclassic” (associated with mild subclinical impairment of cortisol 
synthesis). The hallmark of classic CAH is the inability to produce cortisol. More than 90% of all 
classic CAH cases are due to defects in the cytochrome P450 enzyme steroid 21-hydroxylase, 
also known as 21-hydroxylase or CYP21A2. This enzyme facilitates the conversion of 17-
hydroxyprogesterone (17-OHP) to 11-deoxycortisol, the immediate precursor of cortisol. 
Additionally, 21-hydroxylase is responsible for the conversion of progesterone to 
11-deoxycorticosterone, the precursor of aldosterone (Dauber, 2010). The remaining cases 
(< 10%) of classic CAH are mainly due to four other enzyme deficiencies (i.e., P450scc, 
P450c17, 11β-hydroxylase, 3β-hydroxysteroid dehydrogenase), a defect in the cholesterol 
transfer protein StAR, and a defect in an electron-transfer protein (Sahakitrungruang, 2015).  
In addition to the inability to produce cortisol, approximately 75% or more of classic CAH 
patients do not have the ability to produce mineralocorticoids (e.g., aldosterone) (Arlt, 2010; 
Auchus, 2010). Thus, adrenal steroid precursors (e.g., 17-OHP) accumulate proximal to these 
enzyme blocks and are shunted to the androgen pathway (e.g., androstenedione and testosterone), 
resulting in excess androgens.  
Classic CAH is the most frequent of the congenital endocrine diseases (Arlt, 2010). The 
incidence has been consistently reported to be approximately 1 in 10,000 to 1 in 16,000 live 
births in most Caucasian populations (Krone, 2009; Merke, 2005). Incidence rates vary by 
ethnicity and geographic isolation of affected populations (Merke, 2005). Until the middle of the 
20th century, individuals born with classic CAH died in childhood from glucocorticoid and 
mineralocorticoid deficiency. Today, universal newborn screening and methodologies to identify 
underlying genetic mutations along with sensitive methodologies to determine levels of steroids 
and steroid precursors have enabled accurate diagnosis and early treatment of classic CAH.  
Treatment of classic CAH involves replacement of missing or deficient levels of naturally 
occurring glucocorticoids and/or mineralocorticoids with exogenous products. This has enabled 
individuals to live into adulthood and have a nearly normal life expectancy. However, 
management of classic CAH can be challenging since it is difficult to mimic the normal 
circadian fluctuations of glucocorticoids using exogenous glucocorticoid replacement therapy 
(Arlt, 2010). Additionally, classic CAH patients are often unable to adequately balance the high 
doses of exogenous glucocorticoids required to suppress excess androgen production while 
avoiding the iatrogenic side effects of high dose glucocorticoids (i.e., Cushing’s syndrome). 
Thus, patients are caught between having excess androgens and the associated virilization and 
infertility issues (Auchus, 2010; Auchus, 2013; Auchus, 2015) and suffering from iatrogenic 
Cushing’s syndrome. Women may also develop a secondary polycystic ovary syndrome (PCOS) 
that persists even after adrenal suppression (Barnes, 1994). Men may have complications of 
androgen excess manifesting as suppression of gonadotropins leading to testicular atrophy and 
infertility (Tiitinen, 2002). Additionally, up to 50% of men may have testicular adrenal rest 
tumors, which can become quite large and painful along with causing testicular dysfunction 
(Cabrera, 2001). In children, glucocorticoid management entails unique additional issues of 
achieving and maintaining a normal growth velocity and rate of skeletal maturation. Thus, there 

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are three major concerns for the management of adults with classic CAH: (1) prevention of 
adrenal and gonadal hyperplasia and neoplasia, (2) prevention of long-term consequences of 
adrenal replacement therapies, and (3) restoration of fertility in those who desire to have children 
(Auchus, 2010).  
1.2. 
Rationale for the Use of Nevanimibe Hydrochloride in Congenital 
Adrenal Hyperplasia 
Nevanimibe hydrochloride (HCl), formerly known as ATR-101, is a selective acyl-
CoA:cholesterol O-acyltransferase 1 (ACAT1) inhibitor in development for the treatment of 
diseases that result from dysfunctional adrenal steroidogenesis. ACAT1 is a key enzyme 
functioning proximally in the adrenocortical steroidogenesis cascade. The unique effects of 
proximally inhibiting adrenocortical steroidogenesis suggest a novel approach to targeting the 
adrenal cortex with applications in rare (orphan) endocrine diseases caused by hormone 
dysregulation, such as classic CAH and Cushing’s syndrome (CS), and in the oncology 
indication, adrenocortical carcinoma (ACC).  
One of the first obligatory steps in adrenocortical steroidogenesis is the conversion of free 
cholesterol (FC) to cholesteryl ester (CE). Nevanimibe HCl prevents the esterification of FC to 
CE, thus inhibiting/preventing the accumulation of the CE reservoir required for normal 
adrenocortical steroidogenesis. At higher doses, the same mechanism of action results in 
additional activity that ultimately results in apoptotic effects on adrenocortical cells, including 
malignant cells. Therefore, nevanimibe HCl can be used in different indications based on the 
dose, where the lower dose range inhibits adrenocortical steroidogenesis while the higher dose 
range provides oncologic apoptotic effects (LaPensee, 2016).  
Nevanimibe HCl inhibition of adrenal steroid and steroid intermediate synthesis may provide an 
extremely valuable tool for clinicians managing classic CAH. Inhibition of adrenal 
steroidogenesis across the androgen pathway would negate the need to suppress 
adrenocorticotropic hormone (ACTH) with supra-physiologic doses of glucocorticoid and would 
consequently prevent the risk of iatrogenic Cushing’s syndrome. Classic CAH patients may then 
require only physiologic doses of glucocorticoid replacement. Use of nevanimibe HCl in the 
treatment of classic CAH is supported by extensive mechanism-of-action studies, robust non-
clinical proof-of-concept data, exposure of approximately 60 patients with ACC in a Phase 1 
study (ATR-101-001), and exposure of 10 patients with classic CAH in a previous Phase 2 study 
(ATR-101-201). Additional information may be found in the ATR-101 (nevanimibe HCl) 
Investigator’s Brochure. 
In summary, nevanimibe HCl presents an intriguing spectrum of dose-dependent therapeutic 
options ranging from inhibition of adrenal steroidogenesis at lower doses to apoptotic effects at 
higher doses. The use of nevanimibe HCl for the treatment of classic CAH presents a novel 
therapeutic approach. 
 

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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
• To evaluate the efficacy and safety of orally administered nevanimibe HCl for the treatment 
of classic CAH 
2.2. 
Secondary Objectives 
• To assess the changes in adrenal cortical steroids and steroid intermediates  
• To determine the pharmacokinetic (PK) parameters of nevanimibe and its major 
metabolite(s) 
• To assess the PK/pharmacodynamic (PD) relationships of nevanimibe and its major 
metabolite(s) 

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3. 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design 
This is a multicenter, intra-subject dose-titration open-label study of nevanimibe HCl for the 
treatment of classic CAH. Following a Screening Period of approximately 2-14 weeks, eligible 
subjects will enter a Baseline Period of approximately 2-8 weeks and then a 16-week Treatment 
Period. During the Treatment Period, subjects will receive nevanimibe HCl twice daily (BID) for 
16 weeks. All subjects will begin dosing with nevanimibe HCl 500 mg BID. After the 4-week 
500 mg BID dosing period, serum samples for 17-OHP will be obtained at Visit T2 and the 
nevanimibe HCl dose will be automatically up-titrated to 1000 mg BID for all subjects. Although 
all subjects will receive nevanimibe HCl 1000 mg BID for Weeks 5 and 6, once the 17-OHP 
results from Visit T2 become available, the nevanimibe HCl dose for Weeks 7 and 8 will either 
remain at 1000 mg BID (if the Visit T2 predose serum 17-OHP is > 2x ULN) or be decreased to 
500 mg BID (if the Visit T2 predose serum 17-OHP is ≤ 2x ULN). The dosing regimens are 
intended to achieve and maintain 17-OHP ≤ 2x the upper limit of normal (ULN) (the primary 
endpoint) on the lowest possible dose of nevanimibe HCl while actively up-titrating if 17-OHP is 
> 2x ULN. Thus, subjects who are found to have met the primary endpoint (i.e., on the previous 
lower dose of nevanimibe HCl) based on their most recent serum 17-OHP value will have their 
nevanimibe HCl dose down-titrated to the dose on which they met the endpoint. Subsequent dose 
adjustments will follow the same procedures. Four doses of nevanimibe HCl (500 mg BID, 1000 
mg BID, 1500 mg BID, and 2000 mg BID) are available for use in the study. The study 
schematic is shown in Figure 1. 
Figure 1: 
Study Schematic 
 
3.1.1. 
Screening Period 
After signing informed consent, subjects with classic CAH will enter the Screening Period to 
assess preliminary eligibility for the study based on the inclusion and exclusion criteria. In 

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addition, pertinent information will be collected such as past medical history, demographic data, 
and prior and current medications. Laboratory tests will be done as part of study eligibility.  
Subjects with a serum 17-OHP ≥ 4x ULN (Cohort 1) at the initial screening visit (Visit S1) will 
proceed to the Baseline Visit (Visit B1). Cohort 1 subjects will not make any changes in their 
daily maintenance glucocorticoid dose throughout the study (except, for example, for emergency, 
stress dose requirements). Subjects with a serum 17-OHP < 4x ULN (Cohort 2) AND a daily 
maintenance glucocorticoid dose in the suppressive range (≥ the equivalent of approximately 12 
mg hydrocortisone/m2 body surface area—see Appendix 3) at the initial screening visit (Visit 
S1) will have their glucocorticoid dose decreased by the equivalent of approximately 5 mg 
hydrocortisone or 1 mg prednisone or prednisolone (see Appendix 2). They will then return for 
Visit S2 to have their 17-OHP level rechecked approximately 2 to 4 weeks after their 
glucocorticoid dose was changed. If their serum 17-OHP level from Visit S2 is ≥ 4x ULN, they 
will proceed to the Baseline Visit (Visit B1). If not, the case should be discussed with the 
Medical Monitor; if appropriate, the subject may undergo further glucocorticoid dose adjustment 
and subsequent assessment of serum 17-OHP levels during the Screening Period. The Screening 
Period may last from approximately 2-14 weeks. 
3.1.2. 
Baseline Period 
At the Baseline Visit (Visit B1), additional laboratory tests will be done as part of study 
eligibility. In addition, subjects will be instructed on the use of an electronic diary (eDiary) for 
recording their glucocorticoid, mineralocorticoid (if applicable), and study drug doses (and, for 
premenopausal women, start dates of menstrual periods) during the study. The most recent serum 
17-OHP level should be ≥ 4x ULN for all subjects prior to Visit B1. Any subject whose Visit B1 
serum 17-OHP is < 4x ULN should be discussed with the Medical Monitor prior to enrolling in 
the study. Cohort 2 subjects may require further decreases in glucocorticoid dose and subsequent 
assessment of serum 17-OHP during the Baseline Period (see Appendix 2). No study drug will 
be given during the Baseline Period. The Baseline Period may last from approximately 2-8 
weeks.  
3.1.3. 
Treatment Period 
Subjects who meet all of the inclusion criteria and none of the exclusion criteria may be enrolled 
into the 16-week Treatment Period. Enrollment in either Cohort 1 or Cohort 2 may be capped at 
the Sponsor’s discretion to ensure that a sufficient number of subjects are enrolled into both 
cohorts. 
All enrolled subjects will receive open-label active treatment with nevanimibe HCl orally 
starting at a dose of 500 mg BID. The first dose of nevanimibe HCl will be given at the study site 
at Visit T1 (Day 1; Enrollment). All subjects will receive nevanimibe HCl 500 mg BID for 
Treatment Period Weeks 1-4 (Day 1 to Day 28). At Visit T2 (Day 29), blood for assessment of 
serum 17-OHP will be collected; all subjects will have their nevanimibe HCl dose automatically 
up-titrated to 1000 mg BID and will remain on this dose for Weeks 5-6 (Day 29 to Day 42). The 
Visit T2 (Day 29) serum 17-OHP samples require ~10 days to process and results should be 
available before the beginning of Week 7 (Day 43).  
If the Visit T2 predose 17-OHP is < 2x ULN (primary endpoint is met), subjects will have their 
nevanimibe HCl dose down-titrated from 1000 mg BID to 500 mg BID starting at Week 7 (Day 
43) and remain on this dose until the end of Week 10 (Day 70). If the serum 17-OHP value 

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obtained at Visit T2 is > 2x ULN (primary endpoint is not met), the subject will continue on their 
current 1000 mg BID dose for Weeks 7-8 (Day 43 to Day 56) and will automatically up-titrate to 
1500 mg BID for Weeks 9-10 (Day 57 to Day 70). At Visits T3 (Day 57) and T4 (Day 85), 
subjects whose most recent predose serum 17-OHP met the primary endpoint will remain on the 
nevanimibe HCl dose on which they met the endpoint. Subjects whose most recent predose 
serum 17-OHP did not meet the primary endpoint will have their nevanimibe HCl dose increased 
to the next higher dose level. 
Following Visits T3 and T4, nevanimibe HCl dose adjustment will proceed in a similar manner 
as Visit T2. The serum 17-OHP samples require ~10 days to process. When the predose serum 
17-OHP results are available, they will be used to titrate the nevanimibe HCl dose as follows: 
• Subjects whose predose serum 17-OHP is ≤ 2x ULN (primary endpoint is met) will have 
their nevanimibe HCl dose decreased to the dose on which they most recently met the 
endpoint if they underwent a dose increase at their most recent treatment period site visit. 
• Subjects whose predose serum 17-OHP is > 2x ULN (primary endpoint is not met) will have 
their nevanimibe HCl dose increased if they did not already undergo a dose increase at their 
most recent treatment period site visit. 
• All other subjects will remain on their current nevanimibe HCl dose. 
During the Treatment Period, nevanimibe HCl doses may also be down-titrated by the 
Investigator if needed based on safety and tolerability with approval of the Medical Monitor.  
3.1.4. 
Follow-up Period 
The 4-week Follow-up Period will commence immediately after the subject completes the 
Treatment Period. No study drug will be given during the Follow-up Period. The last study visit 
will take place at the completion of the Follow-up Period.  
Throughout the course of the study, safety evaluations will include assessment of AEs, 
concomitant medications, clinical laboratory tests, vital signs, physical examinations (PEs) and 
12-lead electrocardiograms (ECGs). 
A detailed schedule of study assessments is provided in Appendix 1. An algorithm for 
maintenance glucocorticoid dose down-titration and subsequent monitoring of serum 17-OHP 
levels for eligibility during the Screening and Baseline periods is provided in Appendix 2. 
3.2. 
Rationale for Study Design  
The previous Phase 2 CAH study (ATR-101-201) explored nevanimibe HCl doses ranging from 
125 mg to 1000 mg BID, with each dose lasting 2 weeks followed by a 2-week placebo washout. 
Each subject had the opportunity to dose-escalate based on 17-OHP values assessed after each 
dose level. Eligible subjects had 17-OHP ≥ 4x ULN at screening (i.e., similar to Cohort 1). At 
baseline, the mean 17-OHP was 53x ULN (ranging from 7 to 187x ULN) for the 10 subjects who 
received nevanimibe HCl. In that study, although robust decreases in 17-OHP with nevanimibe 
HCl were observed, only two (20%) subjects were able to achieve 17-OHP levels ≤ 2x ULN. 
However, some of the largest percentage decreases in 17-OHP were observed in subjects with 
the highest baseline 17-OHP values. This finding was entirely consistent with the known 
mechanism of action for ATR-101, where depletion of the cholesteryl ester pool may require 
more than 2 weeks in subjects with markedly elevated 17-OHP (a correlation between larger 

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adrenal size and higher 17-OHP level has been reported in classic CAH subjects). Also, the 
cholesteryl ester stores may have been partially replenished during the 2-week placebo washout 
period that followed each ATR-101 dose period. Thus, hypotheses to be tested for this protocol 
include whether sustained, continuous dosing of nevanimibe HCl will result in greater efficacy 
and whether higher doses are needed to demonstrate this effect. Consequently, this protocol will 
evaluate longer periods of dosing at each dose level with an overall duration of 16 weeks, and 
explore higher doses of nevanimibe HCl (up to 2000 mg BID). Dosing will commence with 
nevanimibe HCl at 500 mg BID for 4 weeks prior to up-titrating to the 1000 mg BID dose, as the 
nevanimibe HCl 500 mg BID dose was well-tolerated in both the previous Phase 2 CAH study 
and in a previous drug-drug interaction study, and experience from previous studies suggests that 
study drug tolerability is improved by longer dosing.  
The intra-subject dose escalation design is appropriate for the current stage of nevanimibe HCl 
development in an orphan indication such as classic CAH. A “traditional” randomized, parallel-
arm, placebo-controlled trial would have severe limitations and would have the potential to 
generate indeterminate study results. In a traditional design, since only ~20 subjects in total are 
being recruited for this study and there are 4 nevanimibe HCl doses being tested, no more than 
~5 subjects per arm would be feasible. If a placebo arm were to be included, then the number of 
subjects per arm could be no more than ~3. Additionally, there would need to be equal 
distribution between subjects in Cohort 1 and Cohort 2 within a given dose. Thus, each dose 
could have no more than ~2 subjects per cohort. With such small numbers, a single outlier (e.g., 
baseline 17-OHP, treatment effect, etc.) in a given cohort (within a dose arm) could completely 
skew the entire arm or render that cohort uninterpretable. In contrast, the design presented in this 
protocol avoids such challenges. 
Use of nevanimibe HCl for subjects in Cohort 1 will attempt to demonstrate sustained decreases 
in 17-OHP with a target value of ≤ 2x ULN while continuing on their generally supra-
physiologic (unchanged) glucocorticoid doses. For this cohort, demonstration of maintenance of 
17-OHP with decreased glucocorticoid doses is not the goal of the present study, as it is not 
reasonable to decrease the glucocorticoid dose in subjects with 17-OHP values already elevated 
beyond 4x ULN; however, in a future study this would be attempted once 17-OHP levels are 
controlled. Conversely, increasing the glucocorticoid dose to suppress 17-OHP has presumably 
already been attempted, would result in further risk of iatrogenic Cushing’s syndrome, and 
would also confound the simultaneous use of nevanimibe HCl.  
Use of nevanimibe HCl in Cohort 2 is designed to demonstrate sustained decreases 17-OHP to a 
target value of ≤ 2x ULN while the subject receives glucocorticoid doses that are lower than their 
doses at screening. Although subjects in Cohort 2 have 17-OHP values at or very close to goal at 
screening (i.e., < 4x ULN), this comes at the “cost” of suppressive glucocorticoid doses and 
associated side effects. In this cohort, the temporary, purposeful rise in 17-OHP associated with a 
decrease in glucocorticoid dose toward non-suppressive levels (see Appendix 2) creates the 
potential for nevanimibe HCl to demonstrate a truly novel clinical therapy. Nevanimibe HCl 
could potentially create the optimal/ideal clinical situation that does not currently exist for classic 
CAH patients, i.e., control of 17-OHP with non-suppressive glucocorticoid doses.  Ultimately, in 
a future study, a similar outcome to that of Cohort 1 could be demonstrated in Cohort 2 with a 
longer duration of treatment (i.e., the glucocorticoid dose could be decreased once the 17-OHP 
has reached the target level).  

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The dose range for this study is supported by the previous CAH Phase 2 study, extensive ACC 
Phase 1 data, and comprehensive non-clinical and in vitro studies conducted with nevanimibe 
HCl (additional information regarding the dose rationale may be found in Appendix 7 and in the 
ATR-101 (nevanimibe HCl) Investigator’s Brochure).  
The ACC Phase 1 study provides tremendous reassurance for the safety of the doses proposed, 
since both the dose levels and the duration of treatment have already far surpassed those being 
proposed in this protocol. The highest dose evaluated in the ACC study was 158.5 mg/kg/day, 
which is approximately 3x the highest dose proposed for this protocol for a 75-kg subject. In 
addition, the average duration of exposure was 58 days across the 14 nevanimibe HCl dose 
cohorts, with several subjects having received nevanimibe HCl for as long as 5 to 12 months at 
doses > 2000 mg BID. Nevanimibe HCl was extremely well tolerated in the ACC study 
population, which is markedly less robust (all had advanced stage cancer and most had 
undergone multiple prior treatment regimens) relative to the classic CAH patient population. 
The dose rationale is further supported by the 13-week dog toxicity study with AUC0-24 hr 
margins relative to the dog No Observed Adverse Effect Level (NOAEL) of 2.0 to 8.0 for the 
highest (2000 mg BID) and lowest (500 mg BID) nevanimibe HCl doses planned, respectively. 
Acceptably managed classic CAH patients generally have mildly elevated, rather than 
completely normal, 17-OHP levels (Speiser, 2010). Thus, the overall goal of the study is to show 
clinically meaningful decreases in 17-OHP that are aligned with clinical practice goals. Two 
classic CAH patient populations have been identified: those with serum 17-OHP ≥ 4x ULN 
(Cohort 1) and those with serum 17-OHP < 4x ULN (Cohort 2) at screening. The vast majority 
of subjects are expected to be on suppressive (supra-physiologic) glucocorticoid doses at 
screening, but it is possible that potential subjects may have an elevated 17-OHP while on less 
than supra-physiologic glucocorticoid doses.  
The study design and dose levels are appropriately supported by existing clinical and nonclinical 
data. 
3.3. 
Efficacy Assessment 
Efficacy will be assessed by changes in adrenal steroids and steroid intermediates. The 
percentage of subjects achieving serum 17-OHP targets will serve as the primary endpoint, as 
this adrenal steroid intermediate is used diagnostically and to aid in the management of 
exogenous glucocorticoid replacement therapy in clinical practice. However, absolute target 
values for 17-OHP or androgens do not currently exist in treatment guidelines put forth by any of 
the medical societies. The entry criterion for 17-OHP is set at ≥ 4 x ULN (for menstruating 
women, this criterion is adjusted for the menstrual cycle phase), which is intended to enroll 
subjects who are not optimally controlled while on exogenous glucocorticoid replacement 
therapy. The primary endpoint is aligned with the clinical goal of achieving a mildly elevated 17-
OHP level, which for this study is defined as serum 17-OHP ≤ 2 x ULN. However, salivary 17-
OHP and other key efficacy parameters in the androgen pathway (i.e., androstenedione, 
testosterone, and 11-ketotestosterone) will also serve to define efficacy. 
ACTH levels will be assessed to determine potential effects on the hypothalamic-pituitary-
adrenal (HPA) axis. Glucocorticoid replacement doses must be stable for at least 4 weeks prior to 
starting study drug, and are expected to remain unchanged during the treatment period (except, 
for example, for emergency, stress dose requirements), so no significant changes in ACTH are 

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anticipated. Confirmation of stable ACTH levels associated with decreases in 17-OHP and 
androgens will help to establish the pharmacodynamic effects of nevanimibe. 
3.4. 
Safety Assessment 
Safety will be assessed by monitoring adverse events, changes in PEs (including vital signs), 
changes in ECGs, and changes in laboratory parameters. Safety assessments will take place 
every 4 weeks during study participation. 
Classic CAH subjects will have been enrolled into the study on stable glucocorticoid and 
mineralocorticoid regimens. Monitoring and management of replacement steroids should 
continue per usual clinical practice. 
3.5. 
Criteria for Study Termination 
The study is open-label and all laboratory results will be able to be viewed by the Investigator 
and Sponsor. The Sponsor will review pooled and individual subject data at regular intervals 
during the course of the study. In addition, a single occurrence of any the following safety events 
will trigger an expedited, ad hoc safety meeting of at least the Sponsor and the Medical Monitor:  
• Marked elevations in transaminases or simultaneous elevations in hepatic transaminases and 
bilirubin (i.e., Hy’s Law)  
• Severe renal impairment  
• Severe cardiovascular dysfunction such as arrhythmia or valvular dysfunction, or New York 
Heart Association (NYHA) Class III or IV heart failure.  
If the Sponsor and the Medical Monitor determine that the event is drug-related and a clear 
safety signal has been identified, the Sponsor and the Medical Monitor will determine whether 
early termination of the study is warranted. 
 

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4. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
4.1. 
Study Population 
The study population will consist of adult men and women with a documented history of classic 
CAH. 
4.2. 
Inclusion Criteria 
Each subject must meet all the following criteria to be enrolled in this study:  
1. Provision of signed and dated informed consent prior to any study-specific procedures 
2. Men and women 18 to 80 (70 in the Czech Republic) years of age (inclusive) at the time of 
informed consent 
3. Documented historical diagnosis of classic CAH due to 21-hydroxylase deficiency based on 
either or both of the following criteria: 
• Documented genetic mutation in the CYP21A2 enzyme consistent with a diagnosis of 
classic CAH 
• Historical documentation of elevated 17-OHP (e.g., in infancy or following a 
cosyntropin/ACTH stimulation test) 
4. Serum 17-OHP ≥ 4x ULN during the Baseline Period 
• Premenopausal women in the follicular phase of the menstrual cycle must have serum 
17-OHP ≥ 4x follicular phase ULN 
• Premenopausal women in the luteal phase of the menstrual cycle must have serum 
17-OHP ≥ (4x follicular phase ULN + (luteal phase ULN – follicular phase ULN)) 
5. Chronic glucocorticoid replacement therapy for at least 6 consecutive months prior to 
Screening 
6. Stable glucocorticoid and mineralocorticoid regimen for at least 4 weeks prior to the 
Screening (S1), Baseline (B1), and Enrollment (T1) Visits 
7. For subjects who undergo maintenance glucocorticoid dose adjustment between Screening 
and Enrollment, stable serum 17-OHP levels (adjusted as needed for menstrual cycle phase) 
prior to Enrollment, defined as the most recent 2 values being within 30% of each other 
(calculated as 100 × (1 – (smaller value/larger value))) 
8. Female subjects of childbearing potential must consent to use two medically acceptable 
methods of contraception, excluding depot progesterone, throughout the study period and for 
30 days after the last dose of study treatment during any sexual intercourse with a fertile male 
partner (in France: Fertile subjects (male and female) must consent to use two medically 
acceptable methods of contraception, excluding depot progesterone, throughout the study 
period and for 30 days after the last dose of study treatment during any sexual intercourse 
with a fertile partner of the opposite sex) 
4.3. 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from participation in the study: 
1. Nonclassic CAH 
2. Other causes of adrenal insufficiency such as Addison’s disease or adrenalectomy; or classic 
CAH with serum 17-OHP < 4x ULN and daily maintenance glucocorticoid dose in the 
adrenal insufficiency range (e.g., ≤ 8-10 mg hydrocortisone/m2 body surface area per day) 

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3. Surgery within the previous three months prior to screening or planned surgery during study 
participation. Minor procedures are permitted (e.g., removal of skin tags or other minor 
dermatological procedures) 
4. History of active cancer requiring medical or surgical therapy within the past 6 months (with 
the exception of successfully treated non-metastatic basal cell or squamous cell carcinoma of 
the skin or carcinoma in situ of the cervix) 
5. Female subjects must not be currently pregnant or breastfeeding or have conceived or given 
birth within 3 months of Screening 
6. Abnormal laboratory tests at Screening: 
• ALT or AST > 2x ULN 
• Bilirubin > 1.5x ULN  
• Serum creatinine > 1.5x ULN 
7. Positive screen for HIV, hepatitis B surface antigen or hepatitis C antibody at Screening 
8. An average QTcF value of > 470 (450 in France) msec at Screening 
9. Current or ongoing use of any prohibited concomitant medications (Section 5.8) 
10. History of substance abuse within the past 1 year prior to informed consent 
11. Positive toxicology screening test for substances of abuse, other than marijuana 
12. Known allergy to nevanimibe HCl (formerly known as ATR-101) 
13. Participation in any study of an investigational drug within 30 days (or 5 half-lives of the 
investigational drug, whichever is longer) prior to Screening 
14. Any other medical or psychiatric condition that, in the opinion of the Investigator, is likely to 
confound the interpretation of the study results or prevent the subject from understanding the 
requirements of or successfully completing the study (e.g., myocardial infarction (MI) or 
cerebrovascular accident/transient ischemic attack (CVA/TIA) within the past 6 months) 
4.4. 
Subject Withdrawal Criteria 
In accordance with the Declaration of Helsinki and subsequent conferences, subjects have the 
right to withdraw from the study at any time for any reason. The Investigator and the Sponsor 
also have the right to withdraw subjects from the study. Subjects may be removed from the study 
for the following reasons: 
1. In the Investigator’s judgment, it is in the best interest of the subject to discontinue study 
participation. 
2. The subject experiences an AE that would preclude further treatment with the study drug.  
3. The subject withdraws consent for continued participation or refuses further treatment with 
the investigational product. 
4. The subject is noncompliant with the protocol. 
Enrolled subjects who withdraw from the study prior to the T5/End-of-Treatment (EoT) visit 
should return to the study site for an Early Termination (ET) visit, which consists of the same 
procedures as at T5/EoT. The reason for and date of withdrawal/removal from the study must be 
documented in the subject’s medical records. Investigational site personnel must attempt to 
determine whether the reason for withdrawal was an AE and if so, this must be reported in 
accordance with the procedures provided in Section 6.10. For all subjects who do not complete 
the study, regardless of the duration of treatment, all relevant information related to the 
withdrawal/removal will be entered into the electronic case report form (eCRF). 

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Subjects who withdraw or are removed from the clinical study after enrollment will not be 
replaced. All enrolled subjects will be fully accounted for and documented in the final clinical 
study report (CSR). 

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5. 
TREATMENT OF SUBJECTS 
5.1. 
Assignment of Subject Identification Numbers 
Once the subject has signed the informed consent form (ICF) at Screening, site personnel will 
assign a subject identification number (ID). This number will be utilized to identify the subject 
throughout the study. Each subject ID will only be assigned to one subject (e.g., if a subject is 
withdrawn from the study early, their subject ID will not be used for a new subject). 
5.2. 
Description of Study Drug 
Nevanimibe HCl Drug Product is supplied as a 500-mg strength tablet for oral administration. 
Each subject will receive sufficient nevanimibe HCl Drug Product Tablets to provide dosing for 
a 4-week period with extra tablets to account for scheduling visit windows and unforeseen 
events. The tablet formulation is described in Table 1. 
Table 1: 
Investigational Product 
 
Investigational Product 
Product Name 
Nevanimibe hydrochloride 
Dosage Form 
tablet 
Unit Dose 
500 mg 
Route of Administration 
Oral 
Physical Description 
White or orange, film-coated oval biconvex tablets with no 
markings 1 
Inactive Ingredients 
Mannitol, microcrystalline cellulose, croscarmellose sodium, 
pregelatinized starch, hypromellose, magnesium stearate, and 
Opadry II white or Opadry II orange 1 
Manufacturer 
Corealis Pharma, Inc. (white tablets) or Patheon, part of Thermo 
Fisher Scientific (orange tablets) 1 
1 The white tablets and the orange tablets are identical in strength, specification, composition, and components, 
except for the coating films. The white tablets are currently in use, and the orange tablets are expected to be 
available after 1 January 2020. 
For more information regarding the nevanimibe HCl tablet, refer to the most recent version of 
the ATR-101 (nevanimibe HCl) Investigator’s Brochure.  
5.3. 
Study Drug Administration 
All enrolled subjects who enter the Treatment Period will begin dosing with nevanimibe HCl 500 
mg BID. During the Treatment Period, a sufficient number of bottles of nevanimibe HCl 500-mg 
tablets will be supplied to last until at least the subject’s next scheduled study visit (see 
Pharmacy Manual). Table 2 presents the tablets and dosing regimen by dose level. An additional 
bottle or bottles may be dispensed to provide sufficient nevanimibe HCl in case of potential up-
titration or for unanticipated scheduling issues. 
 
 

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Table 2 
Nevanimibe HCl Dose Levels and Tablet Doses 
Dose Level 
Nevanimibe HCl Dose 
Nevanimibe HCl  
Tablet Strength Dispensed 
Nevanimibe HCl Dosing 
1 
500 mg BID 
500 mg 
1 tablet BID 
2 
1000 mg BID 
500 mg 
2 tablets BID 
3 
1500 mg BID 
500 mg  
3 tablets BID 
4 
2000 mg BID 
500 mg 
4 tablets BID 
BID: twice daily; HCl: hydrochloride 
5.3.1. 
Timing and Administrative Dosing Conditions 
Study drug should be taken approximately 12 hours apart (twice per day dosing). The time of 
day that the dose is taken should be as consistent as possible (e.g., every morning at 8 AM 
(08:00) and every evening at 8 PM (20:00)). Using the eDiary, subjects should record the actual 
time of their doses of study drug (if applicable), glucocorticoid, and mineralocorticoid (if 
applicable), particularly those taken on the day prior to and the day of study visits. On the 
morning of study visits, including at Visit T5/EoT, subjects should wait to take their morning 
doses of study drug (if applicable), glucocorticoid, and mineralocorticoid (if applicable) until 
directed by personnel at the study site.  
Study drug should be taken with a non-alcoholic beverage (except grapefruit juice) immediately 
after consumption of food. No specific food contents are required and subjects should maintain 
usual eating practices. If a full meal is not possible or not aligned with a subject’s usual eating 
practices, a light snack should be consumed prior to taking study drug.  
The first dose of each dose level will be administered at the site with food. See the Pharmacy 
Manual for more details. 
5.3.2. 
Titration of Nevanimibe HCl Dose 
At Visit T2 (Day 29), all subjects will have their nevanimibe HCl dose up-titrated from 500 mg 
BID to 1000 mg BID and will also have serum 17-OHP levels obtained. Based on the results of 
the Visit T2 serum 17-OHP level (expected to be available prior to Day 43, the start of Week 7), 
if the primary endpoint was not achieved on the nevanimibe HCl 500 mg BID dose, the subject 
will continue on 1000 mg BID (for Weeks 7-8; Days 43-56) and automatically up-titrate to 1500 
mg BID for Weeks 9-10, Days 57-70. If the primary endpoint was achieved, appropriate study 
site personnel will contact the subject via telephone prior to Day 43 to instruct them on down-
titrating their nevanimibe HCl dose from 1000 mg BID to 500 mg BID (for Weeks 7-10; Days 
43-70). Note: subjects should change to their updated dose the day they are contacted by the site 
to do so; they do not need to wait until Day 43 to start the updated dose. The primary endpoint is 
defined as follows: 
• Men and postmenopausal women: 17-OHP ≤ 2x ULN 
• Premenopausal women: 
- Follicular phase: 17-OHP ≤ 2x follicular phase ULN 
- Luteal phase: 17-OHP ≤ (2x follicular phase ULN + (luteal phase ULN – follicular phase 
ULN)) 

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At Visits T3 (Day 57) and T4 (Day 85), all subjects will again have their serum 17-OHP levels 
obtained. The serum 17-OHP samples require ~10 days to process. When the predose serum 17-
OHP results are available following Visits T3 and T4, appropriate study site personnel will 
contact the subjects via telephone to instruct them on any potential dose adjustments:  
• Subjects whose predose serum 17-OHP is ≤ 2x ULN (primary endpoint is met) will have 
their nevanimibe HCl dose decreased to the dose on which they most recently met the 
endpoint if they underwent a dose increase at their most recent treatment period site visit. 
• Subjects whose predose serum 17-OHP is > 2x ULN (primary endpoint is not met) will have 
their nevanimibe HCl dose increased to the next higher dose level if they did not already 
undergo a dose increase at their most recent treatment period site visit. 
• All other subjects will remain on their current nevanimibe HCl dose. 
Note: subjects should change to their updated dose the day they are contacted by the site to do 
so; they do not need to wait until 14 days after their scheduled treatment period site visit to start 
the updated dose. 
5.3.3. 
Drug Holidays and Down-Titration 
During the Treatment Period, the nevanimibe HCl dose may be down-titrated and/or a “drug 
holiday” taken at any time (independent of study visit schedule) for safety-related reasons. 
However, such events should be discussed with the Medical Monitor ahead of time, whenever 
feasible, or after the fact to align on the treatment regimen/plan moving forward.  
5.3.4. 
Missed Doses 
If a subject forgets to take a nevanimibe HCl dose on a given day (e.g., the AM dose was not 
taken), a “make up” dose should not be taken. In general, if more than 4 hours have passed 
beyond the usual time of day when the dose is taken, that particular dose should not be taken.  
5.3.5. 
Compliance 
The study drug is to be dispensed by qualified personnel at the study site and only to subjects 
enrolled in the study. Subject compliance to therapy will be assessed at scheduled study visits by 
counting the number of tablets returned. Treatment compliance is defined as the subject taking 
80% to 120% of the study tablets to be taken during the dosing period for a given dose level. 
Subjects found to be outside of the definition of compliance may be discontinued from the study 
at the discretion of the Investigator.  
5.3.6. 
Blinding 
This is an open-label study. Neither Investigators nor subjects will be blinded to treatment. 
5.4. 
Study Drug Packaging and Labeling 
The formulation and bulk packaging of nevanimibe HCl will be conducted according to standard 
procedures. The drug product will be packaged and labeled by Millendo Therapeutics US, Inc.’s 
designated contract packager and labeler according to regulatory requirements. 

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5.5. 
Study Drug Storage and Accountability 
Study drug must be kept in a secure location and stored at controlled room temperature at the 
study site within its original container. A daily temperature log for monitoring of proper storage 
conditions must be maintained by the site. 
Access to drug must be restricted to designated study personnel only. Under no circumstances 
should the Investigator or site personnel supply study product to other Investigators or clinics, or 
allow the supplies to be used other than as directed by this protocol, without written 
authorization from the Sponsor. The Investigator (or designee) must maintain records of the 
delivery of the study drug to the study site, the inventory at the site, use for each subject, and 
return of the study drug to the Sponsor (or designee) or destruction. Total study site 
accountability will be conducted at the end of the study and the Investigator (or designee) must 
explain all discrepancies. A Site Drug Accountability Log will be supplied by the Sponsor. This 
log must be kept current and should contain the following information: 
• Identification (subject ID) of the subject to whom the study drug was dispensed 
• The dates the study drug was dispensed 
• Initial inventory on receipt of drug at the site 
• Final inventory on completion of the study 
All records and inventory must be available for inspection by the clinical study monitor. 
Additional details on the storage and handling of nevanimibe HCl will be provided in the 
Pharmacy Manual. 
5.6. 
Investigational Product Retention at the Study Site 
At the time of study close-out, the Sponsor will direct the site regarding the disposition of any 
unused study drug, whether it is to be destroyed or be returned to the Sponsor’s designated 
location. The Sponsor will assure that a final report of drug accountability is prepared and 
maintained by the investigative site. Additional details on the inventory of study drug will be 
provided in the Pharmacy Manual. 
5.7. 
Concomitant Medications 
Use of concomitant medications should be kept to a minimum during the study. However, if 
concomitant medications are considered necessary for subject welfare, they may be given at the 
discretion of the Investigator. During the study, any medication given other than the study drug 
(including blood transfusions, parenteral fluids, over-the-counter medications, and herbal 
preparations) is to be considered a concomitant medication and must be documented on the 
eCRF. See Section 6.5 for additional details regarding documentation of prior and concomitant 
medications.  
Glucocorticoid and mineralocorticoid replacement are critical concomitant medications used in 
classic CAH. Subjects must continue to receive glucocorticoid and mineralocorticoid (if 
applicable) according to their individual regimens established prior to enrolling in the study. 
Other than as specified in Appendix 2, the regimen should remain as stable and unchanged as 
possible to minimize potential confounding effects on efficacy outcome measures. However, 
changes are permitted to ensure subject safety. It is not expected that nevanimibe HCl will result 

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in a need for increased doses of glucocorticoid replacement, as the glucocorticoid synthetic 
pathway is already compromised in classic CAH. Therefore, decreasing cortisol precursors (i.e., 
17-OHP) should not result in increased glucocorticoid requirements over the treatment period. 
The timing of glucocorticoid replacement therapy may have an impact on the measurement of 
17-OHP. Consequently, on clinic days when blood and/or saliva samples for adrenal 
steroids/steroid intermediates are to be collected, the morning dose of replacement steroids 
(glucocorticoid and mineralocorticoid) must not be taken until after the sample collection as this 
could confound efficacy endpoint measures. Glucocorticoid and mineralocorticoid replacement 
doses should be taken after samples are obtained for laboratory assessments. Similarly, when 
subjects collect salivary 17-OHP profiles at home, the first (~8 AM/08:00) sample should be 
obtained prior to the morning dose of replacement steroids. See Section 6.11 for additional 
details on the timing of blood and saliva samples. 
Approximately 75% of classic CAH subjects have deficiency in the mineralocorticoid pathway 
in addition to the glucocorticoid pathway (Auchus, 2010). Thus, the majority of subjects in this 
study are anticipated to be on mineralocorticoid replacement. Nevanimibe HCl inhibition of the 
mineralocorticoid pathway for these subjects should not have an effect on mineralocorticoid 
replacement therapy. Subjects who enter the study with sufficiently intact endogenous 
mineralocorticoid production may be impacted by suppression of this pathway by nevanimibe 
HCl. Pharmacological doses of glucocorticoids, especially shorter acting ones such as 
hydrocortisone, also confer mineralocorticoid activity and the need for additional replacement 
mineralocorticoid is not always required (Speiser, 2010). However, mineralocorticoid 
replacement should be initiated as soon as possible if there is suspicion of insufficiency. 
5.8. 
Prohibited and Restricted Medications 
Nevanimibe HCl is most soluble in acidic conditions. Proton pump inhibitors are prohibited and 
calcium preparations and antacids should not be used 2 hours before to 2 hours after nevanimibe 
HCl administration. 
Concurrent use of medications that are known to prolong the QT/QTc interval at therapeutic 
exposures and those that only cause prolonged QT intervals in unusual circumstances (e.g., 
overdosage) may be used with caution (Appendix 4, Lists A, B and C). 
Nevanimibe is metabolized by CYP3A4 and is a moderate inhibitor of CYP3A4. As a 
consequence, nevanimibe may interfere with the metabolism of other medicines that are 
metabolized by CYP3A4. In addition, the metabolism of nevanimibe may be affected by other 
medicines or foods such as grapefruit products that inhibit CYP3A4; thus, grapefruit products 
should be avoided. Drugs known to be metabolized by CYP3A4 are shown in Appendix 5 and 
should be used with caution if they are known to interact with weak or moderate CYP3A4 
inhibitors. 
Nevanimibe may be an inhibitor of P-glycoprotein and OATP1B1. In vitro data indicate that 
nevanimibe may compete with certain drugs for P-glycoprotein in the intestinal lumen. 
Consequently, the drugs listed in Appendix 6 should be used with caution, as they may impact 
nevanimibe exposure or vice versa. Note that some of these drugs may also appear in 
Appendices 3 or 4. 

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5.9. 
Precautions and Warnings 
Preclinical studies have identified adrenal suppression with apoptotic histologic changes with 
nevanimibe HCl dosing. Such changes were associated with exposure levels higher than those 
anticipated for this study. However, occurrence of such changes is a possibility. The 
investigative staff should be familiar with the warnings and precautions for nevanimibe HCl as 
presented in the ATR-101 (nevanimibe HCl) Investigator’s Brochure. 

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6. 
STUDY ASSESSMENTS 
6.1. 
Allowable Variation in Time of Procedures 
The indicated study days for assessments are intended as targets and variations may be made to 
allow for logistical considerations and to accommodate scheduling conflicts. Unless otherwise 
specified in this protocol, study procedures and visits during the Treatment Period have a 
window of ±2 days. Study procedures and visits during the Screening, Baseline, and Follow-up 
Periods have a window of ±7 days, although up to ~14 weeks may be allowed for Screening and 
up to ~8 weeks may be allowed for Baseline (e.g., for additional glucocorticoid dose adjustment 
or stabilization of Cohort 2 subjects—see Appendix 2) with approval of the Medical Monitor. If 
a study visit occurs early or late, the timing of subsequent visits may be re-anchored. 
6.2. 
Informed Consent 
Prior to any study specific screening evaluations and clinical trial participation, written informed 
consent will be obtained from each subject to be involved in the clinical trial by using the 
Institutional Review Board (IRB)/Ethics Committee (EC)-approved ICF. Potential subjects will 
be informed in detail about the study drug and the nature of the clinical investigation with the 
risks and discomforts to be expected. The subjects will also be instructed that they are free to 
withdraw their consent and discontinue their participation in the clinical study at any time. The 
Investigator or qualified designee will verify that the subject has granted consent. Each subject 
will be given a copy of the signed ICF. Certified translated ICFs will be provided by the Sponsor 
in those languages required or requested by investigational sites.  
6.3. 
Eligibility 
Review of all assessable study inclusion/exclusion criteria will be done at/after the Screening 
visit (Visit S1) and before enrolling the subject at Visit T1. 
6.4. 
Medical History  
A complete medical history will be obtained at the Screening visit (Visit S1). The following 
systems will be reviewed: head, eyes, ears, nose and throat (HEENT), respiratory, 
cardiovascular, gastrointestinal/hepatobiliary (specifically, a history of liver dysfunction or the 
presence of hepatomegaly or splenomegaly), genitourinary/ reproductive, musculoskeletal, 
neurological, psychiatric, endocrine/metabolic, blood/lymphatic, dermatologic and immunologic. 
Past surgeries will also be recorded. 
6.5. 
Prior and/or Concomitant Medication Assessments 
Prior and concomitant medications that should be recorded include any treatments taken from 
Screening (Visit S1) until the end of the study (F1/End-of-Study (EoS) visit), as well as any 
replacement glucocorticoids and mineralocorticoids taken during the 4 weeks prior to Screening. 
Glucocorticoid and mineralocorticoid replacement are critical concomitant medications used in 
classic CAH and will be captured on a separate eCRF from other concomitant therapies. Any 
other treatments given during the study other than nevanimibe HCl, including blood transfusions, 
parenteral fluids, over-the-counter medications, and herbal preparations, are also considered to 
be concomitant therapies and must be recorded on the concomitant medications eCRF. 

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6.6. 
Electronic Diary 
At Visit B1, subjects will be instructed in the use of the eDiary for recording glucocorticoid, 
mineralocorticoid, and/or study drug doses. Premenopausal women will also be instructed in the 
use of the eDiary for recording the start dates of their menstrual periods. The eDiary entries will 
be used to help assess compliance with glucocorticoid and study drug dosing and, in 
premenopausal women, they will be used to help assess menstrual cycle phase. The eDiary may 
also be used to provide reminders to subjects.  
6.7. 
Vital Signs, Height, Weight and Body Mass Index 
Vital signs (temperature, systolic and diastolic blood pressure, pulse and respiratory rate) and 
weight will be measured throughout the study.  
Systolic and diastolic blood pressure should be taken in the same arm per subject after the 
subject has been sitting for at least 5 minutes. Any clinically necessary deviations to this will be 
documented but do not need to be confirmed with the Medical Monitor prior to occurrence and 
do not need to be documented as protocol deviations. 
Body weight will be obtained at each study visit. Height will be assessed only at Screening. 
Body mass index will be calculated based on body weight and height. 
6.8. 
Physical Examination 
A complete PE will be obtained at Visits S1, T1, and T5/EoT. A brief PE will be performed at 
Visits T2, T3, T4, and F1/EoS, with particular attention to assessing the subjects for adrenal 
insufficiency. At any time, targeted PEs may be performed if needed based on adverse events 
and positives from review of systems. 
The following systems will be examined for a complete physical examination: HEENT, 
respiratory, cardiovascular, gastrointestinal/hepatobiliary (specifically the presence of 
hepatomegaly or splenomegaly will be assessed), musculoskeletal, neurological, dermatologic, 
and any areas pertinent to any adverse events (AEs) and positives from review of systems. On a 
brief PE, the following systems will be examined: respiratory, cardiovascular, 
gastrointestinal/hepatobiliary and any areas pertinent to any adverse events and positives from 
review of systems. 
6.9. 
Electrocardiography and Determination of QTc 
All subjects will have 12-lead ECGs performed at Visits S1 and T5/EoT. The ECG test tracings 
will be interpreted by usual clinic procedures, and ECG findings will be recorded on the eCRF. 
ECGs will be stored for later analysis if needed. 
If the QTc interval is greater than 470 (450 in France) msec on the Screening (Visit S1) ECG, 
three consecutive ECGs will be obtained and the QTc values corrected by the Fridericia method 
will be averaged. If the average is greater than 470 (450 in France) msec, the subject will be 
ineligible for the study. 
For all ECGs, the QT interval will be corrected using the Fridericia method (QTcF = QT/RR0.33). 
During the study, if the QTcF is greater than 470 (450 in France) msec, a repeat 12-lead ECG 
will be obtained as soon as practicable. 

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In the event of an abnormal ECG (especially in the setting of an intraventricular conduction 
delay) that makes QTc interval determination unreliable by standard means, the QT interval will 
be corrected by the method of Rautaharju et al. (Zhou, 1992; Rautaharju, 2004). 
6.10. 
Adverse Events, Serious Adverse Events and Reporting 
6.10.1. 
Definition of Adverse Event, Adverse Drug Reaction and Unexpected Adverse 
Drug Reaction 
Adverse Event (AE): Any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug-related.  
• All AEs, regardless of relationship to study drug, should be collected beginning from the 
time the subject signs the informed consent form until the last study visit or 30 days after the 
last dose of study drug, whichever is later. (Any serious adverse event (SAE) judged by the 
Investigator to be related to the study treatment should be reported to the Sponsor regardless 
of the length of time that has passed since study completion.) AEs in study subjects include 
any change in the subject’s condition. This includes symptoms, physical findings, or clinical 
syndromes. 
• Wherever possible, a specific disease or syndrome, rather than individual associated signs 
and symptoms, should be identified by the Investigator and recorded. However, if an 
observed or reported sign or symptom is not considered a component of a specific disease or 
syndrome by the Investigator, it should be recorded as a separate AE. Additionally, the 
condition that led to a medical or surgical procedure (e.g., surgery, endoscopy, tooth 
extraction, or transfusion) should be recorded as an AE, not the procedure. Any medical 
condition already present at screening should not be reported as an AE unless the medical 
condition or signs or symptoms present at baseline worsens in severity or seriousness at any 
time during the study. Clinically significant examination (e.g., electrocardiogram) findings 
that are detected during the study or are present at screening and worsen during the study 
should be reported as an AE. 
− An abnormal laboratory value may be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, whether prescribed in the protocol or not. It 
is up to the Investigator to determine whether an abnormal laboratory value constitutes an 
AE. If an abnormal laboratory value is caused by a disease process, the disease process 
and not the laboratory abnormality should be listed as the AE (e.g., if new onset viral 
hepatitis is causing elevated ALT, the specific hepatitis and not the elevated ALT should 
be listed as the AE). 
− Examples of laboratory abnormalities that should be considered AEs include those that 
result in withdrawal of the study treatment or additional concomitant treatment. All 
laboratory abnormalities considered to constitute an AE should be recorded on the 
appropriate AE page of the eCRF. Laboratory abnormalities do not need to be listed as 
separate AEs if they are considered to be part of a clinical syndrome that is being 
reported as an AE. It is the responsibility of the Investigator to review all safety 
laboratory findings in all subjects. Abnormal values should be commented upon as to 
clinical relevance or importance on the eCRF or the laboratory report as appropriate. 

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Medical and scientific judgment should be exercised in deciding whether an isolated 
laboratory abnormality should be classified as an AE. 
• Every effort must be made by the Investigator to categorize each AE according to its severity 
and its relationship to study drug. 
• Subjects who develop toxicity on study will be followed until the event resolves, stabilizes or 
returns to baseline. 
Adverse Reaction: All noxious and unintended responses to study drug at any dose should be 
considered to be adverse reactions. “Responses to study drug” means that there is a causal 
relationship between the study drug and the responses. “Suspected adverse reaction” implies a 
lesser degree of certainty about causality than “adverse reaction.” 
Unexpected Adverse Reaction: An unexpected adverse reaction is defined as an adverse 
reaction, the nature or severity of which is not consistent with the applicable product 
information. For the study drug, the reference safety information is included in the version of the 
ATR-101 (nevanimibe HCl) Investigator's Brochure currently in force.  
6.10.2. 
Assessing Severity of Adverse Events 
The assessment of severity must be provided by the Investigator and based on the Investigator’s 
clinical judgment. Maximum severity should be assigned to one of the following categories: 
• Mild: An AE that is easily tolerated by the subject, causing minimal discomfort and not 
interfering with everyday activities. 
• Moderate: An AE that is sufficiently discomforting to interfere with normal everyday 
activities. 
• Severe: An AE that prevents normal everyday activities. 
An AE that is assessed as severe should not be confused with an SAE. Refer to Section 6.10.4.1 
for the definition of an SAE. 
6.10.3. 
Assessing Relationship to Study Treatment 
The Investigator will categorize each AE as to its potential relationship to study drug: unrelated, 
unlikely related, possibly related, probably related and definitely related. Items to be 
considered when assessing the relationship of an AE to the study treatment are as follows:  
• Temporal relationship of the onset of the event to the initiation of the study treatment 
• The course of the event, considering especially the effect of discontinuation of study 
treatment or reintroduction of study treatment, as applicable 
• Whether the event is known to be associated with the study treatment or with other similar 
treatments 
• The presence of risk factors in the study subject known to increase the occurrence of the 
event 
• The presence of non-study treatment-related factors that are known to be associated with the 
occurrence of the event 

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The relationship categories of unrelated and unlikely related will be summarized for reporting 
purposes as Not Related. For Not Related events, the time course between the administration of 
study drug and the occurrence or worsening of the AE rules out a causal relationship with study 
drug, and another cause of the AE (concomitant drugs, therapies, complications, etc.) is 
suspected. 
The relationship categories of possibly, probably and definitely related will be summarized for 
reporting purposes as Related. Only AEs thought to be caused by the study drug should be 
classified as “related to study drug.” For Related events, the time course between the 
administration of study drug and the occurrence or worsening of the AE is consistent with a 
causal relationship, and no other cause (concomitant drugs, therapies, complications, etc.) can be 
identified. The definition implies a reasonable possibility of a causal relationship between the 
event and the study drug. This means that there are facts (evidence) or arguments to suggest a 
causal relationship. 
6.10.4. 
Serious Adverse Events 
6.10.4.1. Definition of Serious Adverse Event 
A serious adverse event (SAE) is any untoward medical occurrence that: 
• Results in death 
• Is life-threatening (Note: The term “life-threatening” in the definition of “serious” refers to 
an event in which, in view of either the Investigator or Sponsor, the subject was at immediate 
risk of death at the time of the event; it does not refer to an event that hypothetically might 
have caused death if it were more severe.) 
• Requires inpatient hospitalization or prolongation of an existing hospitalization 
Notes:  
Any hospital admission with at least one overnight stay will be considered an inpatient 
hospitalization. An emergency room visit without hospital admission will not be recorded as 
an SAE under this criterion, nor will hospitalization for a procedure scheduled or planned 
before signing of informed consent. However, unexpected complications and/or prolongation 
of hospitalizations that occur during elective surgery should be recorded as AEs and assessed 
for seriousness. 
The following hospitalizations are not considered to be SAEs because there is no AE (i.e., no 
untoward medical occurrence) associated with the hospitalization: 
− Hospitalizations for respite/hospice care  
− Hospitalization planned prior to informed consent (where the condition requiring the 
hospitalization has not changed post study drug administration) 
• Results in persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• Is a congenital anomaly/birth defect, or 
• Is determined to be an important medical event (at the discretion of the Investigator) 

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Note: Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical intervention to prevent 
one of the other outcomes listed in the SAE definition. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 
6.10.4.2. Reporting SAEs – Procedure for Investigators 
Initial Reports 
Adverse events and all information regarding SAEs, whether reported by the subject or observed 
by the investigator/study personnel, must be documented in the subject’s medical record and 
reported by recording all pertinent information on the eCRF AE/SAE Forms in the electronic 
data capture (EDC) system. 
SAEs, regardless of causality assessment, must be collected beginning from the time the subject 
signs the informed consent form until the last study visit or 30 days after the last dose of study 
drug, whichever is longer. All SAEs must be reported within the EDC system by the study site. 
Study site personnel should complete the eCRF AE/SAE Form in the EDC system and the 
investigator should assess the causality within 24 hours of knowledge of the event (this refers to 
any AE that meets any of the aforementioned seriousness criteria). Via the EDC system, Clinical 
Safety will receive the report in parallel via email at clinicalsafety@biomapas.eu. Any SAE 
judged by the Investigator to be related to the study treatment should be reported to the Sponsor 
regardless of the length of time that has passed since study completion.  
The minimum information required for the initial SAE report is covered by the eCRF AE/SAE 
Form. If requested by Clinical Safety,  SAE reports should be followed as soon as possible by 
detailed descriptions including copies of hospital case reports, autopsy reports and other 
documents (see Follow-up Reports, below).  
Clinical Safety contact information for this study is as follows: 
• If the EDC system is unavailable, the SAE will be reported via telephone at +370 37 383 227    
• For urgent safety issues, call the Medical Monitor at +370 37 383 238   
Follow-up Reports 
All AEs and SAEs must be followed to resolution or, if resolution is unlikely, to stabilization.  
Within 24 hours of receipt of follow-up information, the Investigator must update the eCRF 
AE/SAE Form within the EDC system. Any requested supporting documentation (e.g., subject 
discharge summary or autopsy reports) should be submitted to Clinical Safety via e-mail at 
clinicalsafety@biomapas.eu or fax at +370 37 352 321. All personal data must be redacted prior 
to submission; instead, please provide the study number (Millendo ATR-101-202) and the 
subject ID on each document. If the follow-up information changes the Investigator’s assessment 
of causality, this should also be noted in the follow-up section within the eCRF AE/SAE form. 
The Investigator should notify the IRB/EC of the occurrence of the SAE, in writing, in 
accordance with local requirements. A copy of this communication must be filed in the 
Investigator’s files for this study. 

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6.10.5. 
Pregnancy Reporting 
Any pregnancy that occurs following study drug dosing where the estimated date of conception 
occurred either prior to the study termination visit or within 30 days of last study treatment must 
be reported. The Investigator should report the pregnancy using the Pregnancy Form within the 
EDC system within 24 hours of being notified. Via the EDC system, Clinical Safety will receive 
the report in parallel via email at clinicalsafety@biomapas.eu. The contact information for 
reporting pregnancies is the same as for reporting SAEs (Section 6.10.4.2). 
A subject becoming pregnant while on study drug will immediately be withdrawn from the study 
and early termination (ET) study procedures will be performed. 
The subject should be followed by the Investigator until completion of the pregnancy. If the 
pregnancy ends for any reason before the anticipated date, the Investigator should notify Clinical 
Safety as specified in the Safety Manual. At the completion of the pregnancy, the Investigator 
will document the outcome of the pregnancy. If the fetus has a congenital anomaly, the 
Investigator should follow the procedures for reporting an SAE.  
6.10.6. 
Regulatory Reporting of Adverse Events 
AEs will be reported to the regulatory authorities in compliance with local and regional law and 
established guidance by the Sponsor or by a third party acting on behalf of the Sponsor. The 
format of these reports will be dictated by the local and regional requirements. 
6.11. 
Laboratory Tests 
Blood, saliva, and urine samples for assessments of clinical laboratory parameters and/or PK will 
be obtained as shown in the study schedule in Appendix 1. For each study visit, the first hormone 
sample collection that is obtained at the study site should be done between 6-10 AM (06:00-
10:00), as close to 8 AM (08:00) as practicable. Additionally, at study visits, blood and 
corresponding saliva samples will be obtained at approximately the same time (±15 minutes) to 
facilitate correlation of results.  
On days that saliva samples are collected, the timing of glucocorticoid doses, mineralocorticoid 
doses (if applicable), nevanimibe HCl doses (if applicable), and saliva sample collections should 
be kept consistent as much as possible per subject. For salivary profiles collected on  
Days -8, 22, 50, 78, and 106, samples should be obtained at approximately 8 AM (08:00), noon 
(12:00), 4 PM (16:00), 8 PM (20:00), and 10-11 PM (22:00-23:00). At Visits T1, T2, T3, and T4, 
samples will be collected at the study site at approximately 8 AM (08:00), 10 AM (10:00), and 
noon (12:00).  
The 8 AM (8:00) sample should be collected prior to the subjects’ morning dose of 
glucocorticoid and mineralocorticoid (if applicable) and will also be assessed for P (in 
premenopausal women only) and cortisol. The timing of the 8 AM (08:00), 10 AM (10:00), noon 
(12:00) samples should be adjusted to correspond to just before (within 30 minutes before), 2 
hours after, and 4 hours after (respectively) administration of the morning glucocorticoid, 
mineralocorticoid (if applicable) and/or study drug (if applicable) doses. In general, the samples 
should be collected prior to relevant glucocorticoid and mineralocorticoid (if applicable) doses if 
possible. 

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6.11.1. 
Clinical Laboratory Assessments 
Testing of clinical laboratory samples will be carried out by the central clinical laboratory using 
validated methods and will include the tests listed in Table 3. In addition, stored serum and 
plasma samples may be assayed for parameters relevant to hormone metabolism (no DNA 
samples will be stored). Total blood volumes to be collected will be provided in the Laboratory 
Manual. Abnormal, clinically significant results may be verified to rule out laboratory error. 
Persistent relevant abnormal values must be followed up until the cause is determined or until 
they return to the baseline value. Abnormal laboratory findings that are considered clinically 
significant by the Investigator should be recorded as AEs as appropriate (Section 6.10).  
Table 3: 
List of Clinical Laboratory Tests 
Hematology 
hematocrit (Hct), hemoglobin (Hgb), platelet count, red blood cell (RBC) 
count, white blood cell (WBC) count with differential 
Chemistry 
albumin, alkaline phosphatase, alanine aminotransferase (ALT; SGPT), 
aspartate aminotransferase (AST; SGOT), blood urea nitrogen (BUN), 
calcium, creatinine, glucose, total bilirubin, total protein, electrolytes 
(magnesium, sodium, potassium, chloride, bicarbonate) 
Coagulation 
PT, aPTT, INR 
Plasma or Serum 
Hormones 
17-hydroxyprogesterone, androstenedione, adrenocorticotropic hormone, 
cortisol, progesterone, total testosterone, and 11-ketotestosterone  
Salivary 
Hormones 
17-hydroxyprogesterone, progesterone (premenopausal women “08:00” 
sample only), and cortisol (“08:00” sample only) 
Urinalysis 
appearance, bilirubin, color, glucose, ketones, leukocyte esterase, nitrite, 
occult blood, pH, protein, specific gravity, urobilinogen; microscopic 
examination will be performed if leukocyte esterase, nitrite, and/or occult 
blood are positive 
Other 
HBsAg, HCV, HIV, urine drug screen 
aPTT, activated partial thromboplastic time; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; 
HIV, human immunodeficiency virus; INR, international normalized ratio; PT, prothrombin time 
6.11.2. 
Pharmacokinetic Assessments 
Testing of PK samples will be carried out by the central PK laboratory using validated methods. 
Logistic considerations may dictate a deviation from the specified time point; therefore, a 
window is permitted around each sampling time point, as shown in Table 4: sampling times up to 
and including 1 hour postdose have a window of ±5 min and subsequent time points have a 
window of ±10 min. At Treatment Period visits, study drug and replacement glucocorticoid and 
mineralocorticoid (if applicable) doses are expected to be administered at approximately the 
same time. At Treatment Period visits, actual dosing times of nevanimibe HCl, glucocorticoids, 
and mineralocorticoids (if applicable) must be recorded using the eDiary; and actual times of PK 
sampling must be recorded on the eCRF. 

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Table 4: 
Pharmacokinetic Sampling Time Points 
Visit 
Sampling Time Points (Morning Dose Only) 
T1, T2, T3, T4, T5/EoT 
0 hours (trough, within 30 min predose); and 
1 hour (±5 min), 2 hours (±10 min), 3 hours (±10 min) and 
4 hours (±10 min) postdose 
Specific collection and shipment procedures for PK samples are provided in the Laboratory 
Manual. 
PK parameters will be computed using non-compartmental methods. The PK parameters outlined 
in Table 5 will be estimated for nevanimibe and its major metabolite(s) as data permit and as 
appropriate. PK parameters may also be estimated for replacement glucocorticoids and/or 
mineralocorticoids as appropriate. 
Table 5: 
Pharmacokinetic Parameters 
Clast 
last quantifiable drug concentration determined directly from individual 
concentration-time data 
Cmax 
maximum observed drug concentration determined directly from individual 
concentration-time data 
Cmax/D 
dose-normalized Cmax, calculated as the ratio of Cmax to dose 
Tmax 
observed time to reach maximum drug concentration 
AUC0-4 
area under the concentration-time curve from time zero to 4 h after dosing, 
calculated using the linear-up/log-down trapezoidal rule 
AUC0-4/D 
dose-normalized AUC0-4, calculated as the ratio of AUC0-4 to dose 
AUC0-t 
area under the concentration-time curve from time zero to the time of the 
last quantified concentration, calculated using the linear-up/log-down 
trapezoidal rule 
λz 
terminal phase rate constant, estimated by linear regression through the 
terminal phase of the log concentration-time profile 
t½ 
terminal phase half-life, calculated as: 
z
λ
)
2
ln(
t½ =
 
AUC0-∞ 
area under the concentration-time curve from time zero to infinity (first dose 
only), calculated as AUC0-4 + Clast/λz 
AUC%extrap 
percentage of AUC0-∞ extrapolated, represented as  
(1 - AUC0-t/AUC0-∞) x 100 
CL/F 
oral clearance calculated as: 
dose/AUC0-∞ (Day 1 only) 

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6.11.3. 
Pharmacodynamic Assessments 
The relationship between Cmax, Tmax, AUC0-4 and other PK parameters with efficacy assessments 
will be explored as appropriate and as data allow. 
6.11.4. 
Blood Sample Collection, Storage and Shipping  
Sample collection, storage and shipment procedures for clinical laboratory samples are provided 
in the Laboratory Manual. 

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7. 
STUDY ACTIVITIES 
Subjects do not need to be fasting prior to any of the study visits. For each study visit, the first 
hormone sample collection that is obtained at the study site should be done between 6-10 AM 
(06:00-10:00), as close to 8 AM (08:00) as practicable. 
The day before each study visit, subjects should pay particular attention to noting the actual time 
of their last doses of glucocorticoid and study drug (if applicable). On the morning of study 
visits, including Visit T5/EoT, subjects should wait to take their morning doses of study drug (if 
applicable), glucocorticoid, and mineralocorticoid (if applicable) until directed by personnel at 
the study site.  
Study visit designations (S1, B1, T1, F1, etc.) are shown in the detailed schedule of study 
assessments provided in Appendix 1. Please note that below and in Appendix 1, the assigned 
Study Day is the first day of the corresponding Study Week. For example, the Day 85 visit 
occurs following 12 full weeks of dosing with study drug, at the beginning of Week 13.  
7.1. 
Screening Period  
During the Screening Period, the eligibility of the subjects is assessed. The Screening Period may 
last from approximately 2-14 weeks, depending on whether the subject is in Cohort 1 or Cohort 
2, and on the number of maintenance glucocorticoid dose adjustments required for Cohort 2 
subjects. The Screening Period concludes with the start of the Baseline Period.  
Prior to the Screening visit, appropriate study site personnel should: 
• Remind the subjects that on the morning of the Screening visit, they should wait to take their 
morning doses of glucocorticoid and mineralocorticoid (if applicable) until directed by site 
personnel at the study site. 
• Remind the subjects to bring their glucocorticoid and mineralocorticoid (if applicable) 
containers to each study visit. 
7.1.1. 
Visit S1 
The Screening visit can be conducted approximately 2-14 weeks prior to the Baseline visit. The 
date of screening is considered to be the date that the first study-related screening assessment is 
performed. At screening, appropriate study site personnel should: 
• Obtain and document informed consent from the subject prior to any study procedures being 
performed. 
• Assign a study-specific subject number. 
• Obtain and record medical history, demographic data and prior and current medications. If 
the subject is a premenopausal woman, obtain the start date of her last menstrual period. 
• Record any AEs that occurred after informed consent was signed. 
• Record the date and time of the subject’s last dose of glucocorticoid prior to the visit. 
• Record vital signs, height and weight. 
• Perform a complete PE. 

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• Obtain a 12-lead ECG.  
• Review all assessable inclusion and exclusion criteria. 
• Within 30 minutes prior to administration of morning replacement glucocorticoid and 
mineralocorticoid (if applicable) doses, collect blood samples for hematology, chemistry, PT, 
aPTT, INR, HBsAg, HCV, HIV, 17-OHP, P, cortisol, and (for female subjects of 
childbearing potential only) a serum pregnancy test. 
− For each study visit, the first hormone sample collection that is obtained at the study site 
should be done between 6-10 AM (06:00-10:00), as close to 8 AM (08:00) as practicable.  
− Hormones should not be collected if the subject already took their replacement 
glucocorticoid and/or mineralocorticoid dose that morning; instead, the sample collection 
should be rescheduled for the next day or as soon as is feasible. 
− Note: The serum 17-OHP may be repeated one time at the Investigator’s discretion if 
there is reason to suspect the results are inaccurate. 
• Collect a urine sample for urinalysis and urine drug screen. 
• Ask the subject to self-administer their morning replacement glucocorticoid and 
mineralocorticoid (if applicable) doses. Record the time of glucocorticoid and 
mineralocorticoid (if applicable) administration. 
• If the subject is a premenopausal woman, instruct the subject to make note of the first day of 
each of her menstrual periods during the study. 
• Remind the subjects that on the morning of their next study visit, they should wait to take 
their morning dose of glucocorticoid and mineralocorticoid (if applicable) until directed by 
site personnel at the study site. 
• Remind the subjects to bring their glucocorticoid and mineralocorticoid (if applicable) 
containers to their next study visit. 
7.1.2. 
After Visit S1 
Within approximately 2 weeks after Visit S1, appropriate study site personnel should: 
• Review all assessable inclusion and exclusion criteria. 
• Review serum 17-OHP results (see Appendix 2). 
• Contact the subject via telephone to: 
− Record AEs and update medications. If the subject is a premenopausal woman, obtain the 
start date of her last menstrual period. 
− If serum 17-OHP is ≥ 4x ULN (Cohort 1), schedule the subject for the Baseline visit, 
Visit B1. 
− If serum 17-OHP is < 4x ULN (Cohort 2), assess the subject’s maintenance 
glucocorticoid replacement dose in equivalent mg of hydrocortisone/m2 body surface area 
(see Appendix 3).  

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 If ≥ 12 mg/m2, reduce the dose by the equivalent of approximately 5 mg 
hydrocortisone or 1 mg prednisone or prednisolone, and schedule the subject to return 
for Visit S2 approximately 2-4 weeks after the dose change. 
 If < 12 mg/m2, discuss the case with the Medical Monitor; screen-fail the subject if no 
further glucocorticoid dose reduction is possible. 
− Remind the subjects that on the morning of their next study visit, they should wait to take 
their morning dose of glucocorticoid and mineralocorticoid (if applicable) replacement 
until directed by site personnel at the study site. 
− Remind the subjects to bring their glucocorticoid and mineralocorticoid (if applicable) 
containers to their next study visit. 
7.1.3. 
Visit S2 (Cohort 2 Subjects Only) 
Subjects in Cohort 1 should skip Visit S2 and proceed to the Baseline Visit (Visit B1). 
Subjects in Cohort 2 should undergo Visit S2 at least 2 weeks after the last decrease in their 
maintenance glucocorticoid dose.  
At the S2 visit, appropriate study site personnel should: 
• Record AEs and update medications. If the subject is a premenopausal woman, obtain the 
start date of her last menstrual period. 
• Record the date and time of the subject’s last dose of glucocorticoid prior to the visit. 
• Record vital signs and weight. 
• Within 30 minutes prior to administration of morning replacement glucocorticoid and 
mineralocorticoid (if applicable) doses, collect blood samples for 17-OHP, P, and cortisol. 
− For each study visit, the first hormone sample collection that is obtained at the study site 
should be done between 6-10 AM (06:00-10:00), as close to 8 AM (08:00) as practicable. 
− Hormones should not be collected if the subject already took their replacement 
glucocorticoid and/or mineralocorticoid dose that morning; instead, the sample collection 
should be rescheduled for the next day or as soon as is feasible. 
• For female subjects of childbearing potential only, collect a urine sample and perform a urine 
pregnancy test. 
• Ask the subject to self-administer their morning replacement glucocorticoid and 
mineralocorticoid (if applicable) doses. Record the time of glucocorticoid and 
mineralocorticoid (if applicable) administration. 
• Schedule the next study visit (Visit B1) to occur at least 4 weeks after the subject’s last 
maintenance glucocorticoid dose change. 
• Remind the subjects that on the morning of their next visit, they should wait to take their 
morning dose of glucocorticoid and mineralocorticoid (if applicable) until directed by site 
personnel at the study site. 
• Remind the subjects to bring their glucocorticoid and mineralocorticoid (if applicable) 
containers to their next study visit. 

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7.1.4. 
After Visit S2 (Cohort 2 Subjects Only) 
Within approximately 2 weeks after Visit S2, prior to Visit B1, appropriate study site personnel 
should review serum 17-OHP results for Cohort 2 subjects (see Appendix 2): 
• If serum 17-OHP is ≥ 4x ULN, the subject should return for the Baseline visit, Visit B1, as 
scheduled. 
• If serum 17-OHP is < 4x ULN, assess the subject’s maintenance glucocorticoid replacement 
dose in equivalent mg of hydrocortisone/m2 body surface area (see Appendix 3) and discuss 
the case with the Medical Monitor.  
- If ≥ 12 mg/m2, with agreement of the Medical Monitor, it may be possible to further 
reduce the dose by the equivalent of approximately 5 mg hydrocortisone or 1 mg 
prednisone or prednisolone. The subject should then return for an Unscheduled visit 
approximately 2-4 weeks after the dose change (i.e., when the Investigator assesses that 
the subject’s hormone levels have stabilized) to assess 17-OHP levels. Further 
management should be discussed and agreed with the Medical Monitor. 
- If < 12 mg/m2, discuss the case with the Medical Monitor; screen-fail the subject if no 
further glucocorticoid dose reduction is possible. 
7.2. 
Baseline Period 
Subjects who meet all assessable inclusion and exclusion criteria, whose last 17-OHP obtained 
during the Screening Period was ≥ 4x ULN and last maintenance glucocorticoid dose change 
occurred at least 4 weeks prior, may enter the Baseline Period. 
7.2.1. 
Visit B1 (Day -14; Week -2) 
Prior to Visit B1, the Investigator should review whether the subject continues to be eligible for 
the study. If not, the subject should be screen-failed from the study. Please note that the 
Screening serum cortisol level result does not need to be available for the subject to proceed with 
Visit B1. 
At Visit B1, appropriate study site personnel should: 
• Record AEs and update medications. 
• Record the date and time of the subject’s last dose of glucocorticoid prior to the visit. 
• Record vital signs and weight. 
• Within 30 minutes prior to administration of morning replacement glucocorticoid and 
mineralocorticoid (if applicable) doses, collect blood samples for hormones (17-OHP, P, 
cortisol, A4, ACTH, total testosterone, and 11-ketotestosterone), and collect saliva samples 
for 17-OHP, P, and cortisol. 
− For each study visit, the first hormone sample collection that is obtained at the study site 
should be done between 6-10 AM (06:00-10:00), as close to 8 AM (08:00) as practicable. 
− Hormones should not be collected if the subject already took their replacement 
glucocorticoid and/or mineralocorticoid dose that morning; instead, the sample collection 
should be rescheduled for the next day or as soon as is feasible. 

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• For female subjects of childbearing potential only, collect a urine sample and perform a urine 
pregnancy test. 
• Instruct the subject on the use of the eDiary for recording glucocorticoid, mineralocorticoid, 
and/or study drug doses. If needed, provision a device for accessing the eDiary. 
• If the subject is a premenopausal woman, instruct her on the use of the eDiary for recording 
the start date of her last menstrual period, and ask her to record the start date of her last 
menstrual period using the eDiary.  
• Ask the subject to self-administer their morning replacement glucocorticoid and 
mineralocorticoid (if applicable) doses.  
• Ask the subject to record the time of glucocorticoid and mineralocorticoid (if applicable) 
administration using the eDiary. 
• Remind the subjects to collect a salivary 17-OHP profile within approximately one week 
prior to the next study visit (Visit T1). 
• Schedule the next study visit (Visit T1).  
• Remind the subjects to record the actual time of their doses of glucocorticoid and 
mineralocorticoid (if applicable), particularly those taken on the day prior to their next visit, 
using the eDiary. If the subject is a premenopausal woman, also remind her to record the start 
date of her menstrual periods. 
• Remind the subjects that on the morning of their next visit, they should wait to take their 
morning doses of glucocorticoid and mineralocorticoid (if applicable) until directed by site 
personnel at the study site. 
7.2.2. 
After Visit B1 
Within 2 weeks after Visit B1, prior to Visit T1, review serum 17-OHP results (see Appendix 2): 
• If 17-OHP is ≥ 4x ULN: 
− If the subject met criteria for Cohort 1 based on the S1 serum 17-OHP, the subject should 
return for the Enrollment visit, Visit T1, as scheduled. 
− If the subject met criteria for Cohort 2 based on the S1 serum 17-OHP, assess stability of 
17-OHP.  
 For the purposes of this study, “stable” serum 17-OHP levels following a 
glucocorticoid dose reduction are defined as the most recent two 17-OHP levels prior 
to enrollment being with 30% of each other (calculated as 100 × (1 – (smaller 
value/larger value))). 
 If 17-OHP levels are stable, the subject should return for the Enrollment visit, Visit 
T1, as scheduled. 
 If 17-OHP levels are not stable, discuss the case with the Medical Monitor, and 
consider obtaining a repeat serum 17-OHP level(s). Once the repeat 17-OHP levels 
are ≥ 4x ULN and meet stability criteria, the subject may proceed to the Enrollment 
visit, Visit T1. 

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• If 17-OHP is < 4x ULN: 
− If the subject met criteria for Cohort 2 based on the S1 serum 17-OHP, assess the 
subject’s maintenance glucocorticoid replacement dose in equivalent mg of 
hydrocortisone/m2 body surface area (see Appendix 3) and discuss the case with the 
Medical Monitor.  
 If ≥ 12 mg/m2, with agreement of the Medical Monitor, it may be possible to reduce 
the dose by the equivalent of approximately 5 mg hydrocortisone or 1 mg prednisone 
or prednisolone. The subject should then return for an Unscheduled visit at least 2 
weeks after the dose change to assess 17-OHP levels. Further management should be 
discussed and agreed with the Medical Monitor. 
 If < 12 mg/m2, discuss the case with the Medical Monitor. 
− In the unlikely event that a subject in Cohort 1 (based on the S1 serum 17-OHP), has 17-
OHP < 4x ULN, discuss the case with the Medical Monitor.  
7.3. 
Treatment Period 
Subjects who meet all the inclusion criteria and none of the exclusion criteria for the study may 
enter the Treatment Period. 
7.3.1. 
Visit T1 (Day 1; Week 1; Enrollment) 
Prior to Visit T1, the Investigator should review whether the subject continues to be eligible for 
the study. If not, the subject should be failed from the study. Please note that the Visit B1 serum 
cortisol, A4, ACTH, total T, and 11-ketoT results, as well as the salivary hormone results, do not 
need to be available for the subject to proceed with Visit T1. 
At Visit T1, appropriate study site personnel should: 
• Record AEs and update medications. 
• Review the subject’s eDiary entries and reinforce instruction on the use of the eDiary as 
needed.  
• Confirm that the subject has recorded the date and time of their last doses of glucocorticoid 
and mineralocorticoid (if applicable) prior to the visit using the eDiary. If not, ask the subject 
to record the information. 
• If the subject is a premenopausal woman, confirm that she has recorded the start date of her 
last menstrual period using the eDiary. If not, ask her to record the information. 
• Record vital signs and weight. 
• Perform a complete PE. 
• Within 30 minutes prior to administration of study drug and morning replacement 
glucocorticoid and mineralocorticoid (if applicable) doses, collect blood samples for 
hematology, chemistry, hormones (17-OHP, P, cortisol, A4, ACTH, total testosterone, and 
11-ketotestosterone), PK, and a serum storage sample; and collect a saliva sample for 17-
OHP, P, and cortisol. 

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− For each study visit, the first hormone sample collection that is obtained at the study site 
should be done between 6-10 AM (06:00-10:00), as close to 8 AM (08:00) as practicable. 
− Hormones should not be collected if the subject already took their replacement 
glucocorticoid and/or mineralocorticoid dose that morning; instead, the sample collection 
and enrollment should be rescheduled for the next day or as soon as is feasible. 
− Note: On days when both a salivary 17-OHP profile and saliva for 17-OHP, P, and 
cortisol are being collected, only single “8 AM” (“08:00”), “10 AM” (“10:00”), and 
“noon” (“12:00”) saliva samples should be collected.  
• Collect a urine sample for urinalysis. 
• For female subjects of childbearing potential only, collect a urine sample and perform a urine 
pregnancy test. 
• Confirm that the subject meets all of the inclusion criteria and none of the exclusion criteria. 
• Enroll the subject. 
• Dispense study drug and instruct the subject on self-administration of study drug orally twice 
per day. 
− All subjects will start nevanimibe HCl 500 mg BID. 
• Ask the subject to self-administer study drug with food and a nonalcoholic beverage 
(excluding grapefruit juice) while at the study site.  
• Ask the subject to self-administer their morning replacement glucocorticoid and 
mineralocorticoid (if applicable) doses.  
• Ask the subject to record the time of study drug, glucocorticoid, and mineralocorticoid (if 
applicable) administration using the eDiary. 
• Collect plasma PK samples and serum 17-OHP samples at 1, 2, 3 and 4 hours after 
administration of study drug. Collect saliva samples for 17-OHP at 2 and 4 hours after 
administration of study drug. Record the time of each sample collection. 
• Schedule the next study visit (Visit T2).  
• Remind the subjects to record the actual time of their doses of glucocorticoid, 
mineralocorticoid (if applicable), and study drug, particularly those taken on the day prior to 
their next visit, using the eDiary. If the subject is a premenopausal woman, also remind her to 
record the start date of her menstrual periods. 
• Remind the subjects that on the morning of their next visit, they should wait to take their 
morning doses of study drug, glucocorticoid, and mineralocorticoid (if applicable) until 
directed by site personnel at the study site. 
• Remind the subjects to bring all their study drug containers, including the used ones, to their 
next study visit. 
• Remind the subjects to bring their glucocorticoid and mineralocorticoid (if applicable) 
containers to their next study visit. 

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7.3.2. 
Telephone Visit Between Visits T1 and T2 (Day 15; Week 3) 
On approximately Day 15, between Visits T1 and T2, appropriate study site personnel should 
contact the subject via telephone to: 
• Record AEs and update medications. If the subject is a premenopausal woman, obtain the 
start date of her last menstrual period. 
• Remind the subject to collect saliva samples for assessing their salivary 17-OHP profile 
approximately one week prior to their next visit. 
• Remind the subjects that they will need to record the actual time of their doses of 
glucocorticoid, mineralocorticoid (if applicable), and study drug, particularly those taken on 
the day prior to their next visit, using the eDiary. If the subject is a premenopausal woman, 
also remind her to record the start date of her menstrual periods. 
• Remind the subjects that on the morning of their next visit, they should wait to take their 
morning doses of study drug, glucocorticoid, and mineralocorticoid (if applicable) until 
directed by site personnel at the study site. 
• Remind the subjects to bring all their study drug containers, including the used ones, to their 
next study visit. 
• Remind the subjects to bring their glucocorticoid and mineralocorticoid (if applicable) 
containers to their next study visit. 
7.3.3. 
Visit T2 (Day 29; Week 5) 
At Visit T2, appropriate study site personnel should: 
• Record AEs and update medications. 
• Review the subject’s eDiary entries and reinforce instruction on the use of the eDiary as 
needed.  
• Confirm that the subject has recorded the date and time of their last doses of glucocorticoid, 
mineralocorticoid (if applicable), and study drug prior to the visit using the eDiary. If not, ask 
the subject to record the information. 
• If the subject is a premenopausal woman, confirm that she has recorded the start date of her 
last menstrual period using the eDiary. If not, ask her to record the information. 
• Record vital signs and weight. 
• Perform a brief PE, with particular attention to assessing the subject for adrenal 
insufficiency. 
• Within 30 minutes prior to administration of study drug and morning replacement 
glucocorticoid and mineralocorticoid (if applicable) doses, collect blood samples for 
hematology, chemistry, hormones (17-OHP, P, cortisol, A4, ACTH, total testosterone, and 
11-ketotestosterone), PK, and a serum storage sample; and collect a saliva sample for 17-
OHP, P, and cortisol. 
− For each study visit, the first hormone sample collection that is obtained at the study site 
should be done between 6-10 AM (06:00-10:00), as close to 8 AM (08:00) as practicable.  

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− Hormones should not be collected if the subject already took their replacement 
glucocorticoid and/or mineralocorticoid dose that morning; instead, the sample collection 
should be rescheduled for the next day or as soon as is feasible. 
• For female subjects of childbearing potential only, collect a urine sample and perform a urine 
pregnancy test. 
• Collect study drug and assess compliance. 
• Dispense study drug and reinforce self-administration of study drug orally twice per day. 
− All subjects will start nevanimibe HCl 1000 mg BID. 
• Ask the subject to self-administer study drug with food and a nonalcoholic beverage 
(excluding grapefruit juice) while at the study site.  
• Ask the subject to self-administer their morning replacement glucocorticoid and 
mineralocorticoid (if applicable) doses.  
• Ask the subject to record the time of study drug, glucocorticoid, and mineralocorticoid (if 
applicable) administration using the eDiary. 
• Collect plasma PK samples and serum 17-OHP samples at 1, 2, 3 and 4 hours after 
administration of study drug. Collect saliva samples for 17-OHP at 2 and 4 hours after 
administration of study drug. Record the time of each sample collection. 
• Schedule the next study visit (Visit T3).  
• Remind the subjects that they will need to record the actual time of their doses of 
glucocorticoid, mineralocorticoid (if applicable), and study drug, particularly those taken on 
the day prior to their next visit, using the eDiary. If the subject is a premenopausal woman, 
also remind her to record the start date of her menstrual periods. 
• Remind the subjects that on the morning of their next visit, they should wait to take their 
morning doses of study drug, glucocorticoid, and mineralocorticoid (if applicable) until 
directed by site personnel at the study site. 
• Remind the subjects to bring all their study drug containers, including the used ones, to their 
next study visit. 
• Remind the subjects to bring their glucocorticoid and mineralocorticoid (if applicable) 
containers to their next study visit. 
7.3.4. 
Telephone Visit Prior to Treatment Day 43 (Week 7) 
Prior to Day 43, between Visits T2 and T3, appropriate study site personnel should contact the 
subject via telephone to: 
• Record AEs and update medications. If the subject is a premenopausal woman, obtain the 
start date of her last menstrual period. 
• Review serum 17-OHP results from Visit T2 to determine whether the subject met the 
primary endpoint on their previous nevanimibe HCl dose. The primary endpoint is defined as 
having been met as follows: 

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− Men and postmenopausal women: 17-OHP ≤ 2x ULN 
− Premenopausal women: 
 Follicular phase: 17-OHP ≤ 2x follicular phase ULN 
 Luteal phase: 17-OHP ≤ (2x follicular phase ULN + (luteal phase ULN – follicular 
phase ULN)) 
• Adjust the nevanimibe HCl dose if needed as follows: 
− If the subject met the primary endpoint, ask the subject to decrease their nevanimibe HCl 
dose from 1000 mg BID to 500 mg BID (i.e., their previous dose immediately prior to 
Visit T2). 
− If the subject did not meet the primary endpoint, ask the subject to remain on their current 
nevanimibe HCl dose of 1000 mg BID. 
• Remind the subject to collect saliva samples for assessing their salivary 17-OHP profile 
approximately one week prior to their next visit. 
• Remind the subjects that they will need to record the actual time of their doses of 
glucocorticoid, mineralocorticoid (if applicable), and study drug, particularly those taken on 
the day prior to their next visit, using the eDiary. If the subject is a premenopausal woman, 
also remind her to record the start date of her menstrual periods. 
• Remind the subjects that on the morning of their next visit, they should wait to take their 
morning doses of study drug, glucocorticoid, and mineralocorticoid (if applicable) until 
directed by site personnel at the study site. 
• Remind the subjects to bring all their study drug containers, including the used ones, to their 
next study visit. 
• Remind the subjects to bring their glucocorticoid and mineralocorticoid (if applicable) 
containers to their next study visit. 
7.3.5. 
Visit T3 (Day 57; Week 9) 
At Visit T3, appropriate study site personnel should: 
• Record AEs and update medications. 
• Review the subject’s eDiary entries and reinforce instruction on the use of the eDiary as 
needed. 
• Confirm that the subject has recorded the date and time of their last doses of glucocorticoid, 
mineralocorticoid (if applicable), and study drug prior to the visit using the eDiary. If not, ask 
the subject to record the information. 
• If the subject is a premenopausal woman, confirm that she has recorded the start date of her 
last menstrual period using the eDiary. If not, ask her to record the information. 
• Record vital signs and weight. 
• Perform a brief PE, with particular attention to assessing the subject for adrenal 
insufficiency. 

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• Within 30 minutes prior to administration of study drug and morning replacement 
glucocorticoid and mineralocorticoid (if applicable) doses, collect blood samples for 
hematology, chemistry, hormones (17-OHP, P, cortisol, A4, ACTH, total testosterone, and 
11-ketotestosterone), PK, and a serum storage sample; and collect a saliva sample for 17-
OHP, P, and cortisol. 
− For each study visit, the first hormone sample collection that is obtained at the study site 
should be done between 6-10 AM (06:00-10:00), as close to 8 AM (08:00) as practicable.  
− Hormones should not be collected if the subject already took their replacement 
glucocorticoid and/or mineralocorticoid dose that morning; instead, the sample collection 
should be rescheduled for the next day or as soon as is feasible. 
• For female subjects of childbearing potential only, collect a urine sample and perform a urine 
pregnancy test. 
• Collect study drug and assess compliance. 
• Dispense study drug and reinforce self-administration of study drug orally twice per day. 
− Subjects on nevanimibe HCl 1000 mg BID will start nevanimibe HCl 1500 mg BID. 
− Subjects on nevanimibe HCl 500 mg BID will continue nevanimibe HCl 500 mg BID. 
• Ask the subject to self-administer study drug with food and a nonalcoholic beverage 
(excluding grapefruit juice) while at the study site.  
• Ask the subject to self-administer their morning replacement glucocorticoid and 
mineralocorticoid (if applicable) doses.  
• Ask the subject to record the time of study drug, glucocorticoid, and mineralocorticoid (if 
applicable) administration using the eDiary. 
• Collect plasma PK samples and serum 17-OHP samples at 1, 2, 3 and 4 hours after 
administration of study drug. Collect saliva samples for 17-OHP at 2 and 4 hours after 
administration of study drug. Record the time of each sample collection. 
• Schedule the next study visit (Visit T4).  
• Remind the subjects that they will need to record the actual time of their doses of 
glucocorticoid, mineralocorticoid (if applicable), and study drug, particularly those taken on 
the day prior to their next visit, using the eDiary. If the subject is a premenopausal woman, 
also remind her to record the start date of her menstrual periods. 
• Remind the subjects that on the morning of their next visit, they should wait to take their 
morning doses of study drug, glucocorticoid, and mineralocorticoid (if applicable) until 
directed by site personnel at the study site. 
• Remind the subjects to bring all their study drug containers, including the used ones, to their 
next study visit. 
• Remind the subjects to bring their glucocorticoid and mineralocorticoid (if applicable) 
containers to their next study visit. 

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7.3.6. 
Telephone Visit Prior to Treatment Day 71 (Week 11) 
Prior to Day 71, between Visits T3 and T4, appropriate study site personnel should contact the 
subject via telephone to: 
• Record AEs and update medications. If the subject is a premenopausal woman, obtain the 
start date of her last menstrual period. 
• Review serum 17-OHP results from Visit T3 to determine whether the subject met the 
primary endpoint on the nevanimibe HCl dose that they were taking just prior to Visit T3. 
The primary endpoint is defined as having been met as follows: 
− Men and postmenopausal women: 17-OHP ≤ 2x ULN 
− Premenopausal women: 
 Follicular phase: 17-OHP ≤ 2x follicular phase ULN 
 Luteal phase: 17-OHP ≤ (2x follicular phase ULN + (luteal phase ULN – follicular 
phase ULN)) 
• Adjust the nevanimibe HCl dose if needed as follows: 
− If the subject met the primary endpoint, and their nevanimibe HCl dose had been up-
titrated at Visit T3, ask the subject to decrease their nevanimibe HCl dose to their 
previous dose (i.e., their dose immediately prior to Visit T3). 
− If the subject did not meet the primary endpoint, and their nevanimibe HCl dose had not 
been up-titrated at Visit T3, ask the subject to increase their nevanimibe HCl dose to the 
next higher dose level. 
− All other subjects should remain on their current dose of nevanimibe HCl (the dose 
assigned at Visit T3). 
• Remind the subject to collect saliva samples for assessing their salivary 17-OHP profile 
approximately one week prior to their next visit. 
• Remind the subjects that they will need to record the actual time of their doses of 
glucocorticoid, mineralocorticoid (if applicable), and study drug, particularly those taken on 
the day prior to their next visit, using the eDiary. If the subject is a premenopausal woman, 
also remind her to record the start date of her menstrual periods. 
• Remind the subjects that on the morning of their next visit, they should wait to take their 
morning doses of study drug, glucocorticoid, and mineralocorticoid (if applicable) until 
directed by site personnel at the study site. 
• Remind the subjects to bring all their study drug containers, including the used ones, to their 
next study visit. 
• Remind the subjects to bring their glucocorticoid and mineralocorticoid (if applicable) 
containers to their next study visit. 
 

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7.3.7. 
Visit T4 (Day 85; Week 13) 
At Visit T4, appropriate study site personnel should: 
• Record AEs and update medications. 
• Review the subject’s eDiary entries and reinforce instruction on the use of the eDiary as 
needed. 
• Confirm that the subject has recorded the date and time of their last doses of glucocorticoid, 
mineralocorticoid (if applicable), and study drug prior to the visit using the eDiary. If not, ask 
the subject to record the information. 
• If the subject is a premenopausal woman, confirm that she has recorded the start date of her 
last menstrual period using the eDiary. If not, ask her to record the information. 
• Record vital signs and weight. 
• Perform a brief PE, with particular attention to assessing the subject for adrenal 
insufficiency. 
• Within 30 minutes prior to administration of study drug and morning replacement 
glucocorticoid and mineralocorticoid (if applicable) doses, collect blood samples for 
hematology, chemistry, hormones (17-OHP, P, cortisol, A4, ACTH, total testosterone, and 
11-ketotestosterone), PK, and a serum storage sample; and collect a saliva sample for 17-
OHP, P, and cortisol. 
− For each study visit, the first hormone sample collection that is obtained at the study site 
should be done between 6-10 AM (06:00-10:00), as close to 8 AM (08:00) as practicable.  
− Hormones should not be collected if the subject already took their replacement 
glucocorticoid and/or mineralocorticoid dose that morning; instead, the sample collection 
should be rescheduled for the next day or as soon as is feasible. 
• For female subjects of childbearing potential only, collect a urine sample and perform a urine 
pregnancy test. 
• Collect study drug and assess compliance. 
• Dispense study drug and reinforce self-administration of study drug orally twice per day. 
− Subjects whose Visit T3 predose serum 17-OHP met the primary endpoint should 
continue on the nevanimibe HCl dose on which they met the endpoint. 
− Subjects whose Visit T3 predose serum 17-OHP did not meet the primary endpoint 
should have their current nevanimibe HCl dose up-titrated to the next higher dose. 
• Ask the subject to self-administer study drug with food and a nonalcoholic beverage 
(excluding grapefruit juice) while at the study site.  
• Ask the subject to self-administer their morning replacement glucocorticoid and 
mineralocorticoid (if applicable) doses.  
• Ask the subject to record the time of study drug, glucocorticoid, and mineralocorticoid (if 
applicable) administration using the eDiary. 

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• Collect plasma PK samples and serum 17-OHP samples at 1, 2, 3 and 4 hours after 
administration of study drug. Collect saliva samples for 17-OHP at 2 and 4 hours after 
administration of study drug. Record the time of each sample collection. 
• Schedule the next study visit (Visit T4).  
• Remind the subjects that they will need to record the actual time of their doses of 
glucocorticoid, mineralocorticoid (if applicable), and study drug, particularly those taken on 
the day prior to their next visit, using the eDiary. If the subject is a premenopausal woman, 
also remind her to record the start date of her menstrual periods. 
• Remind the subjects that on the morning of their next visit, they should wait to take their 
morning doses of study drug, glucocorticoid, and mineralocorticoid (if applicable) until 
directed by site personnel at the study site. 
• Remind the subjects to bring all their study drug containers, including the used ones, to their 
next study visit. 
• Remind the subjects to bring their glucocorticoid and mineralocorticoid (if applicable) 
containers to their next study visit. 
7.3.8. 
Telephone Visit Prior to Treatment Day 99 (Week 13) 
Prior to Day 99, between Visits T4 and T5, appropriate study site personnel should contact the 
subject via telephone to: 
• Record AEs and update medications. If the subject is a premenopausal woman, obtain the 
start date of her last menstrual period. 
• Review serum 17-OHP results from Visit T4 to determine whether the subject met the 
primary endpoint on the nevanimibe HCl dose that they were taking just prior to Visit T4. 
The primary endpoint is defined as having been met as follows: 
− Men and postmenopausal women: 17-OHP ≤ 2x ULN 
− Premenopausal women: 
 Follicular phase: 17-OHP ≤ 2x follicular phase ULN 
 Luteal phase: 17-OHP ≤ (2x follicular phase ULN + (luteal phase ULN – follicular 
phase ULN)) 
• Adjust the nevanimibe HCl dose if needed as follows: 
− If the subject met the primary endpoint, and their nevanimibe HCl dose had been up-
titrated at Visit T4, ask the subject to decrease their nevanimibe HCl dose to their 
previous dose (i.e., their dose immediately prior to Visit T4). 
− If the subject did not meet the primary endpoint, and their nevanimibe HCl dose had not 
been up-titrated at Visit T4, ask the subject to increase their nevanimibe HCl dose to the 
next higher dose level. 
− All other subjects should remain on their current dose of nevanimibe HCl (the dose 
assigned at Visit T4). 

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• Remind the subject to collect saliva samples for assessing their salivary 17-OHP profile 
approximately one week prior to their next visit. 
• Remind the subjects that they will need to record the actual time of their doses of 
glucocorticoid, mineralocorticoid (if applicable), and study drug, particularly those taken on 
the day prior to their next visit, using the eDiary. If the subject is a premenopausal woman, 
also remind her to record the start date of her menstrual periods. 
• Remind the subjects that on the morning of their next visit, they should wait to take their 
morning doses of study drug, glucocorticoid, and mineralocorticoid (if applicable) until 
directed by site personnel at the study site. 
• Remind the subjects to bring all their study drug containers, including the used ones, to their 
next study visit. 
• Remind the subjects to bring their glucocorticoid and mineralocorticoid (if applicable) 
containers to their next study visit. 
7.3.9. 
Visit T5 (Day 113; Week 17; End-of-Treatment) 
At Visit T5, appropriate study site personnel should: 
• Record AEs and update medications.  
• Review the subject’s eDiary entries and reinforce instruction on the use of the eDiary as 
needed. 
• Confirm that the subject has recorded the date and time of their last doses of glucocorticoid, 
mineralocorticoid (if applicable), and study drug prior to the visit using the eDiary. If not, ask 
the subject to record the information. 
• If the subject is a premenopausal woman, confirm that she has recorded the start date of her 
last menstrual period using the eDiary. If not, ask her to record the information. 
• Record vital signs and weight. 
• Perform a complete PE. 
• Obtain a 12-lead ECG.  
• Within 30 minutes prior to administration of study drug and morning replacement 
glucocorticoid and mineralocorticoid (if applicable) doses, collect blood samples for 
hematology, chemistry, PT, aPTT, INR, hormones (17-OHP, P, cortisol, A4, ACTH, total 
testosterone, and 11-ketotestosterone), PK, and a serum storage sample; and collect a saliva 
sample for 17-OHP, P, and cortisol. 
− For each study visit, the first hormone sample collection that is obtained at the study site 
should be done between 6-10 AM (06:00-10:00), as close to 8 AM (08:00) as practicable. 
− Hormones should not be collected if the subject already took their replacement 
glucocorticoid and/or mineralocorticoid dose that morning; instead, the sample collection 
should be rescheduled for the next day or as soon as is feasible (the subject should also 
continue taking study drug BID until the Visit T5 hormone samples are collected). 
• Collect a urine sample for urinalysis. 

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• For female subjects of childbearing potential only, collect a urine sample and perform a urine 
pregnancy test. 
• If the subject does not have sufficient remaining study drug to administer a single dose, or 
did not bring their study drug to the study visit, dispense study drug. 
• Ask the subject to self-administer study drug with food and a nonalcoholic beverage 
(excluding grapefruit juice) while at the study site.  
• Ask the subject to self-administer their morning replacement glucocorticoid and 
mineralocorticoid (if applicable) doses.  
• As the subject to record the time of study drug, glucocorticoid, and mineralocorticoid (if 
applicable) administration using the eDiary.   
• Collect study drug and assess compliance. 
• Collect plasma PK samples and serum 17-OHP samples at 1, 2, 3 and 4 hours after 
administration of study drug. Collect saliva samples for 17-OHP at 2 and 4 hours after 
administration of study drug. Record the time of each sample collection.  
• Schedule the next study visit (Visit F1).  
• Remind the subjects that they will need to record the actual time of their doses of 
glucocorticoid and mineralocorticoid (if applicable), particularly those taken on the day prior 
to their next visit, using the eDiary. If the subject is a premenopausal woman, also remind her 
to record the start date of her menstrual periods.  
• Remind the subjects that on the morning of their next visit, they should wait to take their 
morning doses of glucocorticoid and mineralocorticoid (if applicable) until directed by site 
personnel at the study site. 
• Remind the subjects to bring their glucocorticoid and mineralocorticoid (if applicable) 
containers to their next study visit. 
7.4. 
Follow-up Period 
During the 4-week follow-up period, the continued safety of the subjects after discontinuation of 
study drug will be assessed. 
7.4.1. 
Visit F1 (Day 141; Week 21; Follow-up Visit)  
The Follow-up Visit should occur approximately 4 weeks after completion of the EoT visit. 
At Visit F1/EoS, appropriate study site personnel should: 
• Record AEs and update medications. 
• Review the subject’s eDiary entries. 
• Confirm that the subject has recorded the date and time of their last doses of glucocorticoid 
and mineralocorticoid (if applicable) prior to the visit using the eDiary. If not, ask the subject 
to record the information. 
• If the subject is a premenopausal woman, confirm that she has recorded the start date of her 
last menstrual period using the eDiary. If not, ask the subject to record the information. 

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• Record vital signs and weight. 
• Perform a brief PE, with particular attention to assessing the subject for adrenal 
insufficiency. 
• Within 30 minutes prior to administration of morning replacement glucocorticoid and 
mineralocorticoid (if applicable) doses, collect blood samples for hematology, chemistry, and 
hormones (17-OHP, P, cortisol, A4, ACTH, total testosterone, and 11-ketotestosterone). 
− For each study visit, the first hormone sample collection that is obtained at the study site 
should be done between 6-10 AM (06:00-10:00), as close to 8 AM (08:00) as practicable. 
− Hormones should not be collected if the subject already took their replacement 
glucocorticoid and/or mineralocorticoid dose that morning; instead, the sample collection 
should be rescheduled for the next day or as soon as is feasible. 
• For female subjects of childbearing potential only, collect a urine sample and perform a urine 
pregnancy test. 
• Ask the subject to self-administer their morning replacement glucocorticoid and 
mineralocorticoid (if applicable) doses. 
• Ask the subject to record the time of glucocorticoid and mineralocorticoid (if applicable) 
administration using the eDiary.  
• Collect any provisioned devices. 
• Once all Visit F1 procedures have been completed, discharge the subject from the study. 
7.5. 
Early Termination (ET) 
Enrolled subjects who withdraw from the study prior to the EoT visit should return to the study 
site for an ET visit, which consists of the same procedures as at EoT. Any provisioned devices 
should also be collected. 

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8. 
QUALITY CONTROL AND ASSURANCE  
Before any subjects can be consented at an investigational site and prior to the conduct of any 
protocol-specific procedures, formal training of investigational site personnel will be conducted. 
The Investigator and all relevant investigational site staff are to be trained on all aspects of the 
study for which they are responsible. Site personnel may be trained at a formal initiation visit, at 
an Investigator’s Meeting, or by another means as necessary. Monitoring and auditing 
procedures will be conducted in compliance with the International Council on Harmonisation 
(ICH) Guidelines for Good Clinical Practice (GCP). Onsite verification of the eCRFs for 
completeness and clarity, crosschecking with source documents and clarification of 
administrative matters will be performed on a regular basis. Monitoring visits will occur at 
regular intervals as noted in the monitoring plan. Through frequent communications with the 
investigational site, the clinical research associate (CRA) will ensure that the investigation is 
conducted according to protocol design and all applicable regulatory requirements. Additional 
details on the monitoring of this study are provided in Section 10.5. During the course of the 
study, investigational sites, the study database and all associated study documentation may be 
subject to quality assurance audits by the Sponsor, or their appointed representatives, on a 
planned or as-needed basis. In addition, representatives of associated regulatory bodies may 
conduct inspections at their discretion. The Investigator is responsible for ensuring direct access 
to all protocol-specific materials for the purpose of these activities. 
 

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9. 
STATISTICS 
9.1. 
General Considerations  
A separate Statistical Analysis Plan that includes a more technical and detailed description of the 
planned statistical analyses will be prepared prior to final database lock. 
9.2. 
Sample Size 
Based on results of the previous Phase 2 study of nevanimibe HCl in classic CAH (ATR-101-
201), the sample size of approximately 20-24 evaluable subjects is considered to be sufficient for 
assessing whether nevanimibe HCl at doses of 500-2000 mg BID has clinically meaningful 
efficacy in the treatment of classic CAH. No formal sample size calculation was done. An 
evaluable subject is defined as a subject who has efficacy data following at least 8 weeks of 
continuous dosing with nevanimibe HCl. 
9.3. 
Analysis Populations  
Efficacy – The modified Intent-to-Treat (mITT) Population, used for all the efficacy summaries, 
is defined as all enrolled subjects who received at least one dose of study drug and had at least 
one post-baseline serum 17-OHP value. 
Per Protocol – The Per Protocol (PP) Population, used for all the efficacy summaries, is defined 
as all enrolled subjects who received at least one dose of study drug, had at least one post-
baseline serum 17-OHP value, and did not have any major protocol deviations that would 
compromise assessment of efficacy. 
Safety – The Safety Population, used for all the safety summaries, is defined as all enrolled 
subjects who received at least one dose of study drug. 
Pharmacokinetic – The Pharmacokinetic (PK) Population will include all subjects with 
measurable study drug concentrations. PK analyses will be based on the PK Population. 
9.4. 
Disposition and Baseline Characteristics 
Disposition, including reason for discontinuation from the study, will be summarized. 
Demographic information and subject characteristics including, but not limited to, race, age, 
baseline vital signs, and baseline glucocorticoid and mineralocorticoid replacement will also be 
summarized for each analysis population. For categorical variables, frequencies (n) and 
percentages (%) will be provided. Continuous variables will be summarized by number of non-
missing observations (n), mean and/or median, standard deviation (SD) and/or percentiles, 
minimum (min), and maximum (max). If applicable, 90% confidence intervals will be calculated. 
9.5. 
Efficacy 
9.5.1. 
Efficacy Endpoints 
9.5.1.1. 
Primary Efficacy Endpoint  
The primary efficacy endpoint is the overall response rate within each cohort, defined as the 
percentage of subjects achieving serum 17-OHP targets as follows: 
• Men and postmenopausal women: 17-OHP ≤ 2x ULN 
• Premenopausal women: 

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- Follicular phase: 17-OHP ≤ 2x follicular phase ULN 
- Luteal phase: 17-OHP ≤ (2x follicular phase ULN + (luteal phase ULN – follicular phase 
ULN)) 
9.5.1.2. 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints will be defined in the SAP. There are no prespecified efficacy 
targets for the secondary efficacy endpoints. 
9.5.2. 
Efficacy Analysis Methodology 
9.5.2.1. 
Analysis of the Efficacy Endpoints  
Only observed case data will be used for the efficacy summaries. The levels of adrenal steroids, 
steroid intermediates, and other measured hormones will be summarized for the mITT and PP 
populations using descriptive statistics, including number of non-missing observations (n), mean 
and/or median, standard deviation (SD) and/or percentiles, minimum (min), maximum (max) and 
90% confidence intervals, if applicable. The analysis will be performed by value and by change 
from baseline in the value, where appropriate, for each time point, overall, by nevanimibe HCl 
dose, and by cohort. The percentage of subjects achieving serum 17-OHP targets, the primary 
endpoint, will be summarized overall and by cohort. The study will be considered positive if 
40% or more of enrolled subjects in either cohort achieve the primary endpoint. 
9.5.2.2. 
Exploratory Efficacy Endpoints 
Additional efficacy endpoints may be prespecified in the SAP, including sensitivity analyses 
associated with drug compliance and missing data issues. 
9.6. 
Safety 
9.6.1. 
Safety Endpoints  
Safety endpoints include the incidence of treatment-emergent AEs and SAEs, as well as the 
values and changes from baseline in clinical laboratory tests, vital signs, PEs and ECG 
parameters. There are no prespecified targets for the safety endpoints. 
9.6.2. 
Safety Analyses  
No inferential statistical analyses will be performed on the safety data from this study. The 
Safety Population will be used for all summaries of safety data. Only observed case data will be 
used. The summarization of AEs will include treatment-emergent AEs (TEAEs; defined as AEs 
that begin or worsen after the first dose of study drug). TEAEs and treatment-emergent SAEs 
(TESAEs) will be summarized by MedDRA system organ class (SOC) and preferred term (PT), 
severity, and relationship to study drug, overall, by nevanimibe HCl dose, and by cohort. Deaths 
and discontinuations due to AEs will each be summarized, overall, by nevanimibe HCl dose, and 
by cohort. Clinical safety laboratory results, PE findings, vital signs, and ECG readings will be 
summarized by value and by change from baseline in the value, where appropriate, for each time 
point, overall, by nevanimibe HCl dose, and by cohort using summary statistics for continuous 
parameters, including number of non-missing observations (n), mean and/or median, standard 
deviation (SD) and/or percentiles, minimum (min), and maximum (max). Frequencies and 
percentages as well as shift tables will be prepared for categorical parameters. 

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9.7. 
Pharmacokinetics and Pharmacodynamics 
9.7.1. 
Pharmacokinetic and Pharmacodynamic Endpoints 
The PK and PD endpoints include the following: 
• The Cmax, Tmax, AUC0-4 and other PK parameters of nevanimibe and its major metabolite(s) 
(as appropriate and as the data allow) 
• The relationship between the Cmax and AUC0-4 of nevanimibe and its major metabolite(s) in 
relation to the change in 17-OHP levels (as appropriate and as the data allow) 
Additional PK and PD endpoints may be described in the SAP.  
9.7.2. 
Pharmacokinetic and Pharmacodynamic Analyses 
The analysis of the PK and PD parameters will be performed on the PK Population. PK 
assessments will be performed at each dose level to determine exposures to nevanimibe and its 
major metabolite(s) and to profile PK/PD relationships. PK assessments will include Cmax, Tmax, 
AUC0-4 and trough levels. 
Individual subject PK data will be analyzed along with pooling of subjects’ data at each dose 
level. Individual PK parameters will be computed to the extent allowed by the PK data collection 
times. Tabular summaries will be provided using descriptive summary statistics, including 
number of non-missing observations (n), arithmetic mean and/or geometric mean and/or median, 
standard deviation (SD) and/or standard error (SE), minimum (min), and maximum (max). 
PK/PD analyses will be detailed in the Statistical Analysis Plan.  
9.8. 
Interim Analysis 
No interim analysis is planned for this study. 

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10. 
ADMINISTRATIVE CONSIDERATIONS 
10.1. 
Institutional Review Board (IRB)/Ethics Committee (EC)  
Prior to initiation of the study at each investigational site, the protocol, the informed consent 
form(s), the subject information sheet(s), details of the subject recruitment procedures and any 
other relevant study documentation will be submitted to the responsible local and/or central 
IRB/EC. A letter from the IRB/EC indicating approval of the Investigator and study site must be 
submitted to the study Sponsor. All reviews and approval by the IRB/EC will be in accordance 
with Title 21 of the Code of Federal Regulations (CFR), Part 56. Initial IRB/EC approval and all 
materials approved by the IRB/EC for this study including the subject consent form and 
recruitment materials must be maintained by the Investigator and made available for inspection. 
The Investigator will promptly report any new information that may adversely affect the safety 
of subjects or the conduct of the study to the IRB/EC. Similarly, the Investigator will submit 
written summaries of the study status to the IRB/EC annually, or more frequently if requested. 
Upon completion of the study, the Investigator will provide the IRB/EC with a brief report of the 
outcome of the study, if required. 
10.2. 
Ethical Conduct of the Study 
The guidelines of the World Medical Association Declaration of Helsinki in its revised edition 
(48th General Assembly, Somerset West, Republic of South Africa, October 1996), the 
guidelines of ICH GCP (Committee for Proprietary Medicinal Products/ICH/135/95), as well as 
the demands of national drug and data protection laws and other applicable regulatory 
requirements, will be strictly followed.  
10.3. 
Subject Information and Consent 
The Investigator is responsible for ensuring that subjects do not undergo any study-related 
examination or activity before giving informed consent. The subject must give written consent 
after the receipt of detailed information regarding the study. The verbal explanation will cover all 
the elements specified in the written information provided to the subject. If the written informed 
consent is provided by the legal guardian because the subject is unable to do so, a written or 
verbal assent from the subject must also be obtained. 
The Investigator will inform the subject of the aims, methods, anticipated benefits and potential 
hazards of the study, including any discomfort it may entail. The subject must be given every 
opportunity to clarify any points he/she does not understand and must be provided with more 
information if requested. At the end of the interview, the subject may be given time to reflect and 
can request more time if needed. The subject and/or legal guardian will be required to sign and 
date the informed consent form. After completion, informed consent forms will be kept and 
archived by the Investigator in the Investigator study file. 
It should be emphasized to the subject that he or she is at liberty to either discontinue study drug 
and/or withdraw consent to participate at any time, without penalty or loss of benefits to which 
he or she is otherwise entitled. Subjects who refuse to give or withdraw written informed consent 
may not be included or continued in this study, but this will not affect their subsequent care. 
Please refer to Title 21 of the CFR, Part 50 – Protection of Human Subjects for specific details 
on this regulation. 

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10.4. 
Subject Confidentiality 
Personal and sensitive data will be treated as confidential. The results of the study will be made 
available for review by authorized representatives of the Sponsor and/or submitted to the 
IRB/EC and regulatory authorities.  
Prior to any screening procedures being performed, the subject’s consent is required for the data 
to be used for these purposes and to gain direct access to their medical records for data 
verification purposes. The subject must be assured that their identity will be protected. To 
facilitate this, a unique identification number will be assigned and it will be used when reporting 
study-related data. 
10.5. 
Study Monitoring 
It is understood that the Sponsor or its designee (e.g., the CRA) will contact and visit the 
Investigator regularly for monitoring purposes. The CRA will be allowed, on request, to inspect 
the various records of the study (i.e., eCRFs, source documents and any other pertinent data), 
provided that subject confidentiality is maintained in accordance with local requirements. It will 
be the CRA’s responsibility to inspect the eCRFs at regular intervals throughout the study, to 
verify adherence to the protocol and to ensure the completeness, consistency and accuracy of the 
data entered. The CRA must have access to all subject records needed to verify the entries on the 
eCRF. The Investigator agrees to cooperate with the CRA to ensure that problems detected 
during these monitoring visits are resolved. 
Before an investigational site can consent a subject into the study, a representative of Millendo 
Therapeutics US, Inc. will evaluate the investigational study site to assess the site including but 
not limited to: 
• Determine the adequacy of the facilities including the site’s ability to carry out the protocol 
• Discuss with the Investigator(s) and other personnel their responsibilities with regard to 
protocol adherence and the responsibilities of Millendo Therapeutics US, Inc. or its 
representatives. This will also be documented in a Clinical Study Agreement between 
Millendo Therapeutics US, Inc. and the Investigator. 
During the study, a monitor from Millendo Therapeutics US, Inc. or representative will have 
regular contacts with the investigational site, for the following but not limited to: 
• Provide information and support to the Investigator(s) 
• Confirm that facilities remain acceptable 
• Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the case report forms and that investigational product accountability 
checks are being performed 
• Perform source data verification. This includes a comparison of the data in the case report 
forms with the subject’s medical records at the hospital or practice and other records relevant 
to the study. This will require direct access to all original records for each subject (e.g., clinic 
charts). 
• Record and report any protocol deviations not previously sent to Millendo Therapeutics US, 
Inc. 

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• Confirm AEs and SAEs have been properly documented on CRFs and confirm any SAEs 
have been forwarded to Millendo Therapeutics US, Inc. and those SAEs that met criteria for 
reporting have been forwarded to the IRB/EC. 
The monitor will be available between visits if the Investigator(s) or other staff needs 
information or advice. 
10.6. 
Audits and Inspections 
Authorized representatives of Millendo Therapeutics US, Inc., a regulatory authority, an EC, or 
an IRB may visit the site to perform audits or inspections, including source data verification. 
Millendo Therapeutics US, Inc. may perform Clinical Quality Assurance (CQA) audits from 
time to time at a random sample of clinical sites, or for cause as warranted. The purpose of a 
Millendo Therapeutics US, Inc. CQA audit or inspection is to systematically and independently 
examine all study-related activities and documents to determine whether these activities were 
conducted and data were recorded, analyzed and accurately reported according to the protocol, 
Good Clinical Practice guidelines of the International Council on Harmonization and any 
applicable regulatory requirements. These audits will be independent of routine monitoring by 
the CRA and initiated with prior written notification provided to the site. 
The Investigator must contact Millendo Therapeutics US, Inc. immediately if contacted by a 
regulatory agency about an inspection. 
10.7. 
Case Report Forms and Study Records 
This study will utilize an EDC system for the management of clinical data. The data will be 
collected in electronic form (i.e., via an eCRF) to allow for data entry at the site from source 
documentation directly into the electronic database. Access to the EDC system will be restricted 
and users will only be able to access the system via authorized individual accounts. All changes 
to data in the database will be tracked and time stamped automatically, including updates to data 
entries and resolution of data queries generated by the CRA or data reviewer.  
Training will be provided to all system users based on their individual access and use 
requirements initially and ongoing throughout the course of the study as needed. Documentation 
of training will be kept in the site regulatory file and in Sponsor’s TMF. 
A comprehensive Data Management Plan will be written outlining the standard operating 
procedures, internal/external security safeguards, system and change controls and training 
procedures and will be filed in the Sponsor’s TMF. A cumulative record will also be kept of the 
user and access privileges for all authorized users across the study.  
The system and procedures for electronic database set-up, entry, review, access, security and 
auditing are designed in specific compliance with 21 CFR 11 and the Food and Drug 
Administration's (FDA’s) Part 11 Guidance for Industry supplement “Computerized Systems 
Used in Clinical Investigations” dated May 2007. Any additional electronic systems that may be 
used by vendors (e.g., the provider of PK analyses) or clinical sites (e.g., electronic medical 
records used as source documents) should comply with these same regulatory standards.  
As a final step in the data management process, a 100% quality control review will be performed 
on the key efficacy and safety parameters. In addition, a random subject sample (approximately 
10%) will be selected to perform a database audit. The purpose of this audit is to detect 
systematic and random errors. 

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All unused study materials are to be returned or destroyed as instructed by Millendo 
Therapeutics US, Inc. after the study has been completed. 
10.8. 
Data Safety Monitoring Board 
The study is open-label and all laboratory results will be able to be viewed by the Investigator 
and Sponsor. Consequently, a Data Safety Monitoring Board (DSMB) is not planned for this 
study. 
10.9. 
Protocol Deviations 
Protocol deviations from inclusion/exclusion criteria, concomitant medication restrictions and 
from any other protocol requirements that could, at least hypothetically, result in significant risk 
to the subject and/or affect the outcome of the study will be collected. Additionally, 
nonadherence to the study procedures or schedule as defined by the protocol such as a missed 
procedure or an out-of-window study visit will be documented as protocol deviations.  
10.10. 
Access to Source Documentation 
The Investigator must permit the authorized Sponsor, agents of the Sponsor and regulatory 
agency employees to enter and inspect any site where the drug or records pertaining to the drug 
are held and to inspect and copy all records relating to an investigation including subject records. 
To ensure the accuracy of data submitted, it is mandatory that representatives of Millendo 
Therapeutics US, Inc. and of the regulatory agencies have direct access to source documents 
(e.g., subject medical records, charts, laboratory reports) for the purpose of quality assurance 
audits either by Millendo Therapeutics US, Inc. or their appointed representatives. Subject 
confidentiality will be protected at all times. 
10.11. 
Data Generation and Analysis 
Data processing and management will be performed by Millendo Therapeutics US, Inc. or its 
designee. Data will be promptly entered into the study database by the site and reviewed and 
issues resolved prior to database closure. 
Personal and sensitive personal data will be treated as confidential. The results of the study will 
be made available for review by authorized representatives of the Millendo Therapeutics US, 
Inc. and/or submitted to the IRB/EC and regulatory authorities. 
10.12. 
Retention of Records 
Copies of all study documents should be retained by the Investigator for at least 2 years after the 
last approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least two years have elapsed since 
the formal discontinuation of clinical development of the investigational product, in accordance 
with 21 CFR 312.62. These documents should be retained for a longer period, however, if 
required by regulatory requirements or by agreement with the Sponsor. The Investigator must 
inform the Sponsor and obtain agreement prior to study documents being moved or destroyed. It 
is the responsibility of Millendo Therapeutics US, Inc. to inform the Investigator/institution as to 
when these documents no longer need to be retained. The final database will be archived by the 
Millendo Therapeutics US, Inc. according to regulatory requirements. 

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10.13. 
Financial Disclosure 
Investigators and Subinvestigators are required to provide full disclosure of any financial 
relationship to the Sponsor or its designee(s) prior to participation in any study-related activities. 
Additionally, Investigators and Subinvestigators are required to promptly provide updated 
information to the Sponsor or its designee(s) regarding any relevant changes in financial interests 
that occur during the course of the study and for 1 year after completion of the study. For 
additional guidance, refer to 21 CFR 312.53(c) (4), 312.64(d), 812.43(c) (5), 812.110(d). 
10.14. 
Premature Termination of the Study 
If the study is prematurely terminated or suspended, the Sponsor will promptly inform the 
Investigators/institutions and the regulatory authority(s) of the termination or suspension and the 
reason(s) for the termination or suspension. The IRB/EC will also be promptly informed and 
provided with the reason(s) for the termination or suspension by Millendo Therapeutics US, Inc. 
or by the Investigator/institution, as specified by the applicable regulatory requirement(s).  
10.15. 
Clinical Study Report 
A CSR will be written for this study with a structure and content that will conform to the ICH 
guidance, “Structure and Content of Clinical Study Reports, ICH Topic E3, July 1996.” 
10.16. 
Subject Insurance and Indemnity 
The Sponsor will provide insurance in accordance with local guidelines and requirements as a 
minimum for the subjects participating in this study. The terms of insurance will be kept in the 
Sponsor’s regulatory files. 
10.17. 
Amendments to the Protocol 
Modifications of the signed protocol are only possible by approved protocol amendments and 
with the agreement of all responsible persons. The procedure for approval of a protocol 
amendment is identical to that for approval of the protocol. The IRB/EC must be informed of all 
protocol amendments and should be asked for its opinion as to whether a full re-evaluation of the 
ethical aspects of the study is necessary by the committee. This should be fully documented. 
The Investigator must not implement any deviation from or change to the protocol without 
discussion and agreement by the Sponsor in writing and prior review and documented 
approval/favorable opinion of the amendment from the relevant IRB/EC, except where it is 
necessary to eliminate an immediate hazard to study subjects or where the change(s) involves 
only logistical or administrative aspects of the study (e.g., change in monitor or change of 
telephone number). 
Protocol amendments will be submitted to the appropriate authority(s) as required by the applicable 
regulatory requirement(s). 

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11. 
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H. F. L., Miller W. L., Montori V. M., Oberfield S. E., Ritzen M., White P. C. (2010). 
Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An 
Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab, 95(9), 4133-
4160. 
Tiitinen, A., & Valimaki, M. (2002). Primary infertility in 45-year-old man with untreated 21-
hydroxylase deficiency: successful outcome with glucocorticoid therapy. Journal of 
Clinical Endocrinology & Metabolism, 87(6), 2442-2445. 
doi:https://dx.doi.org/10.1210/jcem.87.6.8616 
Zhou, S. H., Wong, S., Rautaharju P. M., Kamik N., Calhoun H. P. (1992). Should the JT rather 
than the QT interval be used to detect prolongation of ventricular repolarization?: An 
assessment in normal conduction and in ventricular conduction defects. Journal of 
Electrocardiology, 25, Supplement, 131-136.  
 

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12. 
APPENDICES 
 

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APPENDIX 1. STUDY SCHEDULE 
 
Table 6: 
Schedule of Assessments 
Study Period: 
Screening 
2-14 Weeks 
Baseline 
2-8 Weeks 
Treatment 
16 Weeks 
Follow-up 
4 Weeks 
Target Study Day:a 
-56 
-42 
-28 
-14 
-8 
1 
15 
22 
29 
<43 
50 
57 
<71 
78 
85 
<99 
106 
113 
141 
Study Week:a 
-8 
-6 
-4 
-2 
-1 
1 
3 
4 
5 
7 
8 
9 
11 
12 
13 
15 
16 
17 
21 
Visit:a,b 
S1 
tel 
S2a 
B1 
 
T1 
tel 
 
T2 
tel 
 
T3 
tel 
 
T4 
tel 
 
T5/EoT 
F1/EoS 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ Exclusion Criteria 
X 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History & Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs, Height and Weightc 
X 
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Physical Examinationd 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Hematology & Chemistry 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
PT, aPTT, INR 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Viral Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum 17-OHP, P, and Cortisole 
X 
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Other Blood Hormones (A4, ACTH,  
total T, and 11-ketoT)e 
 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Salivary 17-OHP, P, and Cortisole,f 
 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Salivary 17-OHP Profilef 
 
 
 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
Urinalysis 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Urine Drug Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testg 
X 
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Start Date of Last Menstrual 
Periodg,h 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
GC Dose Adjustment (if needed)i 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
eDiary Instruction/Reviewh 
 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Enrollment 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense and Dose Study Drugb 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Xb 
 
Dose Titration Assessmentj 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Study Drug Compliance 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Dose GC and MC at Siteb 
X 
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Plasma PK and Serum Storagek 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Xb 
 
Medications and Adverse Eventsl 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 

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a  Study procedures and visits during the Treatment Period have a window of ±2 days. Study procedures and visits during the Screening, Baseline, and Follow-up 
Periods have a window of ±7 days. Only Cohort 2 subjects should undergo Visit S2; Cohort 1 subjects should skip Visit S2 and proceed to the Baseline Visit 
(Visit B1). Subjects who discontinue the study during the Treatment Period prior to Visit T5/EoT should undergo an ET visit, which consists of the same 
procedures as Visit T5/EoT. Please note that the assigned Study Day is the first day of the corresponding Study Week. Additionally, target study days shown 
for Screening and Baseline are for a hypothetical Cohort 2 subject who requires 1 GC dose down-titration during Screening and none during Baseline, and has 
17-OHP checked 2 weeks after GC dose down-titration; however, regardless of the assigned Study Day/Week, with agreement of the Medical Monitor, the 
duration of the Screening and Baseline Periods may be adjusted based on the needs of the individual subject. 
b Subjects should note the actual time of their doses of study drug (if applicable), GC, and MC (if applicable), particularly those taken on the day prior to and the 
day of study visits. On the morning of study visits, subjects should wait to take their morning doses of study drug (if applicable) and GC and MC (if 
applicable) replacement until directed by personnel at the study site. On the morning of Visit T5, subjects who do not have sufficient remaining study drug to 
administer a single dose may be dispensed study drug if needed. 
c  Height will be assessed at Visit S1 only. 
d  A complete PE will be performed at Visits S1, T1, and T5/EoT. A brief PE will be performed at Visits T2, T3, T4 and F1/EoS. 
e  For each study visit, the first blood and saliva hormone sample should be collected in the morning prior to the subjects’ morning dose of GC and MC (if 
applicable) replacement, as close to 8 AM (08:00) as practicable and between the hours of 6-10 AM (06:00-10:00). For Cohort 2 subjects who undergo GC 
dose adjustment, results from the serum 17-OHP samples obtained during Screening and Baseline will be used to assess stability of 17-OHP. Cohort 2 subjects 
who undergo GC dose adjustment, whose subsequent serum 17-OHP results during Screening and Baseline do not indicate stable levels, should be discussed 
with the Medical Monitor (see Appendix 2). At Visits T1, T2, T3, T4, and T5/EoT, blood sample collections for 17-OHP will also occur approximately 1, 2, 3, 
and 4 hours after administration of the morning replacement glucocorticoid, mineralocorticoid (if applicable) and/or study drug (if applicable) doses. 
f  A salivary 17-OHP profile should be collected by the subjects on Days -8, 22, 50, 78, and 106. These samples should be obtained at approximately 8 AM 
(08:00), noon (12:00), 4 PM (16:00), 8 PM (20:00), and 10-11 PM (22:00-23:00). At Visits T1, T2, T3, T4, and T5, saliva samples for 17-OHP will be 
collected at the study site at approximately 8 AM (08:00), 10 AM (10:00), and noon (12:00). The 8 AM (8:00) sample should be collected prior to the subjects’ 
morning dose of GC and MC (if applicable) and will also be assessed for P (in premenopausal women only) and cortisol. The timing of the 8 AM (08:00), 10 
AM (10:00) (if applicable), and noon (12:00) samples should be adjusted to correspond to just before, 2 hours after, and 4 hours after (respectively) 
administration of the morning replacement glucocorticoid, mineralocorticoid (if applicable) and/or study drug (if applicable) doses. 
g  On the days marked, a pregnancy test will be done on female subjects of childbearing potential only. A serum pregnancy test will be done at Screening; a urine 
pregnancy test will be done at Visit S2 (if applicable), B1, T1, T2, T3, T4, T5/EoT, and F1/EoS. The start date of the subject’s last menstrual period will be 
obtained for premenopausal women only. 
h  Subjects will use the eDiary to record their glucocorticoid and mineralocorticoid (if applicable) doses (and, for premenopausal women, start dates of menstrual 
periods) from B1 to F1, and will also record their study drug doses from T1 to T5. The eDiary may also be used to provide reminders to subjects. 
i  Subjects with a 17-OHP level from Visit S1 < 4x ULN (Cohort 2) and a daily maintenance GC dose ≥ the equivalent of approximately 12 mg 
hydrocortisone/m2 body surface area (see Appendices 2 and 3) will be contacted approximately 2 weeks after Visit S1 to have their GC dose decreased by the 
equivalent of approximately 5 mg hydrocortisone or 1 mg prednisone or prednisolone. They will then return for Visit S2 at least 2 weeks later. If their 17-OHP 
level from Visit S2 is ≥ 4x ULN, they will enter the Baseline period; if not, the case should be discussed with the Medical Monitor. 
j  All subjects will undergo an up-titration of study drug dose at Visit T2, and subjects whose predose serum 17-OHP levels obtained at the most recent 
scheduled treatment period visit did not meet the primary endpoint will also undergo an up-titration of study drug dose at Visits T3 and T4. Approximately 2 
weeks after each of these visits, the Investigator will review the laboratory results from the visits and determine whether the subject should continue their 
existing dose of nevanimibe HCl or have their dose titrated. 
k  At Visits T1, T2, T3, T4, and T5/EoT, a trough (“0-hour”) PK level and a serum storage sample will be collected within 30 minutes prior to dosing, and plasma 
for PK assessments will also be collected 1, 2, 3, and 4 hours postdose. 
l  AEs will be collected from the time the subject signs the informed consent form until the last study visit or 30 days after the last dose of study drug, whichever 
is later. 

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17-OHP: 17-hydroxyprogesterone; A4: androstenedione; ACTH: adrenocorticotropic hormone; AE: adverse event; aPTT: activated partial thromboplastin time; 
ECG: electrocardiogram; EoS: End-of-Study; EoT: End-of-Treatment; ET: early termination; GC: glucocorticoid; INR: international normalized ratio; MC: 
mineralocorticoid; P: progesterone; PE: physical examination; PK: pharmacokinetic(s) (samples); PT: prothrombin time; T: testosterone; tel: telephone visit 
 

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APPENDIX 2. GLUCOCORTICOID (GC) DOSE ADJUSTMENT ALGORITHM 
 
 
 

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APPENDIX 3. CALCULATION OF GLUCOCORTICOID DOSE AS 
EQUIVALENT MG OF HYDROCORTISONE/M2 BODY 
SURFACE AREA 
 
I. Steps for Calculating Glucocorticoid Dose as Equivalent mg of Hydrocortisone/m2 Body 
Surface Area 
 
1. Calculate the daily glucocorticoid dose in equivalent mg of hydrocortisone (see Table 7 
below). 
2. Calculate the body surface area using the DuBois equation (see below). 
3. Divide the daily glucocorticoid dose in equivalent mg of hydrocortisone by the body surface 
area in m2. 
 
II. Conversion of Glucocorticoid Doses 
 
Table 7: 
Conversion of Various Glucocorticoids to Equivalent mg of Hydrocortisone 
Glucocorticoid: 
Equivalent 
Doses (mg) 
Conversion Factor 
Equivalent mg 
Hydrocortisone 
Hydrocortisone 
20 
1 
20 
Prednisone 
4 
5 1 
20 
Prednisolone 
4 
5 2 
20 
Dexamethasone 
0.25 
80 3 
20 
1 Hindmarsh PC. 2009. Management of the child with congenital adrenal hyperplasia. Best Pract Res Clin 
Endocrinol Metab 23(2):193-208 
2 Finkielstain GP, Kim MS, Sinaii N, Nishitani M, Van Rysin C, Hill SC, Reynolds JC, Hanna RM, Merke DP. 
2012. J Clin Endocrinol Metab 97(12):4429-38 
3 Rivkees SA, Crawford JD. 2000. Dexamethasone treatment of virilizing congenital adrenal hyperplasia: The 
ability to achieve normal growth. Pediatrics 106:767–773 
 
III. Calculation of Body Surface Area 
 
Where weight is in kilograms and height is in centimeters: 
 
Body Surface Area = W0.425 × H0.725 × 0.007184 
 
Du Bois D, Du Bois EF. 1916. A formula to estimate the approximate surface area if height and 
weight be known. Archives of Internal Medicine 17(6): 863-71  
 
The body surface area can also be obtained by entering the weight and height at the following 
website: http://www-users.med.cornell.edu/~spon/picu/calc/bsacalc.htm 
 

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APPENDIX 4. DRUGS THAT PROLONG THE QT/QTC INTERVAL 
 
Appendix 4, List A. Drugs that prolong the QT interval, to be used with caution 
 
 
Generic Name 
Brand Name 
Class/Clinical Use 
Comments 
Amiodarone 
Pacerone® 
Anti-arrhythmic/abnormal heart rhythm 
Females > Males,TdP risk 
regarded as low 
Arsenic trioxide 
Trisenox® 
Anti-cancer/Leukemia 
 
Astemizole 
Hismanal® 
Antihistamine/Allergic rhinitis 
No Longer available in U.S. 
Azithromycin 
Zithromax® 
Antibiotic/bacterial infection 
 
Bepridil 
Vascor® 
Anti-anginal/heart pain 
Females > Males 
Chloroquine 
Aralen® 
Anti-malarial/malaria infection 
 
Chlorpromazine 
Thorazine® 
Anti-psychotic/Anti-emetic/schizophrenia/nausea 
 
Cisapride 
Propulsid® 
GI stimulant/heartburn 
No longer available in U.S.  
Citalopram 
Celexa® 
Anti-depressant/depression 
 
Clarithromycin 
Biaxin® 
Antibiotic/bacterial infection 
 
Disopyramide 
Norpace® 
Anti-arrhythmic/abnormal heart rhythm 
Females > Males 
Dofetilide 
Tikosyn® 
Anti-arrhythmic/abnormal heart rhythm 
Females > Males 
Domperidone 
Motilium® 
Anti-nausea/nausea 
Not available in U.S.  
Droperidol 
Inapsine® 
Sedative; Anti-nausea/anesthesia adjunct, nausea 
 
Erythromycin 
E.E.S.®  
Antibiotic; GI stimulant/bacterial infection; increase GI 
motility 
Females > Males 
Erythromycin 
Erythrocin® 
Antibiotic; GI stimulant/bacterial infection; increase GI 
motility 
Females > Males 
Escitalopram 
Cipralex® 
Anti-depressant/Major depression/Anxiety disorders 
 
Escitalopram 
Lexapro® 
Anti-depressant/Major depression/Anxiety disorders 
 
Flecainide 
Tambocor® 
Anti-arrhythmic/abnormal heart rhythm 
 
Halofantrine 
Halfan® 
Anti-malarial/malaria infection 
Females > Males 
Haloperidol 
Haldol® 
Anti-psychotic/schizophrenia, agitation 
TdP risk with I.V. or excess 
dosage 
Ibutilide 
Corvert® 
Anti-arrhythmic/abnormal heart rhythm 
Females > Males 
Levomethadyl 
Orlaam® 
Opiate agonist/pain control, narcotic dependence 
Not available in U.S.  
Mesoridazine 
Serentil® 
Anti-psychotic/schizophrenia 
 
Methadone 
Dolophine® 
Opiate agonist/pain control, narcotic dependence 
Females > Males 
Methadone 
Methadose® 
Opiate agonist/pain control, narcotic dependence 
Females > Males 
Moxifloxacin 
Avelox® 
Antibiotic/bacterial infection 
 
Pentamidine 
NebuPent® 
Anti-infective/pneumocystis pneumonia 
 Females > Males 
Pentamidine 
Pentam® 
Anti-infective/pneumocystis pneumonia 
 Females > Males 
Pimozide 
Orap® 
Anti-psychotic/Tourette's tics 
 Females > Males 
Probucol 
Lorelco® 
Antilipemic/Hypercholesterolemia 
No longer available in U.S.  
Procainamide 
Pronestyl® 
Anti-arrhythmic/abnormal heart rhythm 
 
Procainamide 
Procan® 
Anti-arrhythmic/abnormal heart rhythm 
 
Quinidine 
Quinaglute® 
Anti-arrhythmic/abnormal heart rhythm 
Females > Males 
Quinidine 
Cardioquin® 
Anti-arrhythmic/abnormal heart rhythm 
Females > Males 
Sevoflurane 
Ulane® 
Anesthetic, general/anesthesia 
Label warning for patients with 
congenital long QT or patients 
taking QT prolonging drugs 
Sevoflurane 
Sojourn® 
Anesthetic, general/anesthesia 
Label warning for patients with 
congenital long QT or patients 
taking QT prolonging drugs 
Sotalol 
Betapace® 
Anti-arrhythmic/abnormal heart rhythm 
Females > Males 
Sparfloxacin 
Zagam® 
Antibiotic/bacterial infection 
No longer available in U.S.  
Terfenadine 
Seldane® 
Antihistamine/Allergic rhinitis 
No longer available in U.S.  
Thioridazine 
Mellaril® 
Anti-psychotic/schizophrenia 
 
Vandetanib 
Caprelsa® 
Anti-cancer/Thyroid cancer 
 

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Appendix 4, LIST B. Drugs with conditional risk of QT prolongation, to be used with caution 
 
Generic Name 
Brand Name 
Class/Clinical Use 
Comments 
Amisulpride 
Solian® and others 
Antipsychotic, atypical 
Risk of TdP with overdose - not available in 
US 
Amitriptyline 
Elavil® 
Tricyclic Antidepressant /depression 
Risk of TdP with overdosage 
Ciprofloxacin 
Cipro® 
Antibiotic/bacterial infection 
Drug interaction risk - metabolic inhibitor 
Clomipramine 
Anafranil® 
Tricyclic Antidepressant /depression 
 
Desipramine 
Pertofrane® 
Tricyclic Antidepressant /depression 
Risk of TdP with overdosage 
Diphenhydramine 
Benadryl® 
Antihistamine/Allergic rhinitis, insomnia 
Risk of QT increase/TdP in overdosages 
Diphenhydramine 
Nytol® 
Antihistamine/Allergic rhinitis, insomnia 
Risk of QT increase/TdP in overdosages 
Doxepin 
Sinequan® 
Tricyclic Antidepressant /depression 
 
Fluconazole 
Diflucan® 
Anti-fungal/fungal infection 
Drug interaction risk metabolic inhibitor. Can 
also increase QT at high doses - 800 mg/day 
Fluoxetine 
Sarafem® 
Anti-depressant/ depression 
 
Fluoxetine 
Prozac® 
Anti-depressant/ depression 
 
Galantamine 
Reminyl® 
Cholinesterase inhibitor /Dementia, 
Alzheimer's 
 
Imipramine 
Norfranil® 
Tricyclic Antidepressant /depression 
TdP risk with excess dosage 
Itraconazole 
Sporanox® 
Anti-fungal/fungal infection 
Drug interaction risk - metabolic inhibitor 
Ketoconazole 
Nizoral® 
Anti-fungal/fungal infection 
Prolongs QT & drug interaction risk – 
metabolic inhibitor. 
Nortriptyline 
 Pamelor® 
Tricyclic Antidepressant /depression 
 
Paroxetine 
Paxil® 
Anti-depressant/ depression 
 
Protriptyline 
Vivactil® 
Tricyclic Antidepressant /depression 
 
Ritonavir 
Norvir® 
Protease inhibitor/HIV 
 
Sertraline 
Zoloft® 
Anti-depressant/ depression 
 
Solifenacin 
VESIcare® 
muscarinic receptor anatagonist/treatment 
of overactive bladder 
 
Trazodone 
Desyrel® 
Anti-depressant/ Depression, insomnia 
 
Trimethoprim-
Sulfa 
Septra® or 
Bactrim® 
Antibiotic/bacterial infection 
Also available in DS (double strength) 
Trimipramine 
Surmontil® 
Tricyclic Antidepressant /depression 
 
 
 
 

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Appendix 4, LIST C. Drugs with possible risk of QT prolongation, to be used with caution 
 
Generic Name 
Brand Name 
Class/Clinical Use 
Comments 
Alfuzosin 
Uroxatral® 
Alpha1-blocker/Benign prostatic hyperplasia 
 
Amantadine 
Symmetrel® 
Dopaminergic/Anti-viral/ Anti-infective/ 
Parkinson's Disease 
 
Artenimol+piperaquine 
Eurartesim® 
Anti-malarial 
Not available in U.S. 
Atazanavir 
Reyataz® 
Protease inhibitor/HIV 
 
Bedaquiline 
Sirturo® 
Anti-infective/Drug resistant Tuberculosis 
Black box for QT 
Chloral hydrate 
Noctec® 
Sedative/sedation/insomnia 
 
Clozapine 
Clozaril® 
Anti-psychotic /schizophrenia 
 
Dolasetron 
Anzemet® 
Anti-nausea/nausea, vomiting 
 
Dronedarone 
Multaq® 
Anti-arrhythmic/Atrial Fibrillation 
 
Eribulin 
Halaven® 
Anti-cancer/metastatic breast neoplasias 
 
Famotidine 
Pepcid® 
H2-receptor antagonist/ Peptic ulcer/ GERD 
 
Felbamate 
Felbatrol® 
Anti-convulsant/seizure 
 
Fingolimod 
Gilenya® 
Immunosuppressant/Multiple Sclerosis 
 
Foscarnet 
Foscavir® 
Anti-viral/HIV infection 
 
Fosphenytoin 
Cerebyx® 
Anti-convulsant/seizure 
 
Gatifloxacin 
Tequin® 
Antibiotic/bacterial infection 
Oral/I.V. forms no longer 
available in U.S. and Canada, 
only ophthalmic 
Gemifloxacin 
Factive® 
Antibiotic/bacterial infection 
 
Granisetron 
Kytril® 
Anti-nausea/nausea and vomiting 
 
Iloperidone 
Fanapt® 
Antipsychotic, atypical/ Schizophrenia 
 
Indapamide 
Lozol® 
Diuretic/stimulate urine & salt loss 
 
Isradipine 
Dynacirc® 
Anti-hypertensive/high blood pressure 
 
Lapatinib 
Tykerb® 
Anti-cancer/breast cancer, metastatic 
 
Lapatinib 
Tyverb® 
Anti-cancer/breast cancer, metastatic 
 
Levofloxacin 
Levaquin® 
Antibiotic/bacterial infection  
 
Lithium 
Lithobid® 
Anti-mania/bipolar disorder 
 
Lithium 
Eskalith® 
Anti-mania/bipolar disorder 
 
Mirtazapine 
Remeron 
Anti-depressant  
 
Moexipril/HCTZ 
Uniretic® 
Anti-hypertensive/high blood pressure 
 
Nicardipine 
Cardene® 
Anti-hypertensive/high blood pressure 
 
Nilotinib 
Tasigna® 
Anti-cancer/Leukemia 
 
Octreotide 
Sandostatin® 
Endocrine/acromegaly, carcinoid diarrhea 
 
Ofloxacin 
Floxin® 
Antibiotic/bacterial infection 
 
Olanzapine 
Zyprexa® 
Antipsychotic, atypical/ Schizophrenia, bipolar 
Combo c fluoxetine: Symbyax 
Ondansetron 
Zofran® 
Anti-emetic/nausea and vomiting 
 
Oxytocin 
Pitocin® 
Oxytocic/Labor stimulation 
 
Paliperidone 
Invega® 
Antipsychotic, atypical/ Schizophrenia 
  
Perflutren lipid 
microspheres 
Definity® 
Imaging contrast agent/ Echocardiography 
 
Quetiapine 
Seroquel® 
Anti-psychotic/schizophrenia 
 
Ranolazine 
Ranexa® 
Anti-anginal/chronic angina 
 
Risperidone 
Risperdal® 
Anti-psychotic/schizophrenia 
 
Roxithromycin 
Rulide® 
Antibiotic/bacterial infection 
Not available in U.S. 
Sertindole 
Serdolect® 
Antipsychotic, atypical/ Anxiety, Schizophrenia 
Not available in U.S. 
Sertindole 
Serlect® 
Antipsychotic, atypical/ Anxiety, Schizophrenia 
Not available in U.S. 
Sunitinib 
Sutent® 
Anti-cancer/RCC, GIST 
 
Tacrolimus 
Prograf® 
Immunosuppressant/ Immune suppression 
 
Tamoxifen 
Nolvadex® 
Anti-cancer/breast cancer 
 
Telithromycin 
Ketek® 
Antibiotic/bacterial infection 
 
Tizanidine 
Zanaflex® 
Muscle relaxant  
 
Vardenafil 
Levitra® 
phosphodiesterase inhibitor/ vasodilator 
 
Venlafaxine 
Effexor® 
Anti-depressant/depression 
 
Voriconazole 
VFend® 
Anti-fungal/anti-fungal 
 
Ziprasidone 
Geodon® 
Anti-psychotic/schizophrenia 
 
 
 
 

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APPENDIX 5. DRUGS KNOWN TO INTERACT WITH CYP3A4 
 
SUBSTRATES: 3A4, 5, 7 
Macrolide antibiotics: 
clarithromycin 
erythromycin (not 3A5) 
NOT azithromycin 
telithromycin 
 
Anti-arrhythmics: 
quinidine-OH (not 3A5) 
 
Benzodiazepines: 
alprazolam 
diazepam-3OH 
midazolam 
triazolam 
 
Immune Modulators: 
cyclosporine 
tacrolimus (FK506) 
 
HIV Antivirals: 
indinavir 
nelfinavir 
ritonavir 
saquinavir 
 
Prokinetics: 
cisapride 
 
Antihistamines: 
astemizole 
chlorpheniramine 
terfenadine 
 
Calcium Channel 
Blockers: 
amlodipine 
diltiazem 
felodipine 
lercanidipine 
nifedipine 
nisoldipine 
nitrendipine 
verapamil 
 
HMG CoA Reductase 
Inhibitors: 
atorvastatin 
cerivastatin 
lovastatin 
NOT pravastatin 
NOT rosuvastatin 
simvastatin 
 
6β-OH Steroids: 
estradiol 
hydrocortisone 
progesterone 
testosterone 
 
Miscellaneous: 
alfentanyl 
apixaban 
aprepitant 
aripiprazole 
buspirone 
cafergot 
caffeine 
cilostazol 
cocaine 
codeine 
dapsone 
dexamethasone 
dextromethorphan 
docetaxel 
domperidone 
eplerenone 
fentanyl 
finasteride 
haloperidol 
imatinib 
irinotecan 
LAAM 
lidocaine 
methadone 
nateglinide 
ondansetron 
pimozide 
 
propranolol 
quetiapine 
quinine 
risperidone 
rivaroxaban 
salmeterol 
sildenafil 
sirolimus 
tamoxifen 
taxol 
terfenadine 
trazodone 
vincristine 
zaleplon 
ziprasidone 
zolpidem 
 
 

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Appendix 5. Drugs known to interact with CYP3A4, continued. 
 
INHIBITORS 3A4,5,7 
HIV Antivirals: 
indinavir 
nelfinavir 
ritonavir 
 
Antibiotics 
clarithromycin 
itraconazole 
ketoconazole 
nefazodone 
saquinavir 
telithromycin 
aprepitant 
erythromycin 
fluconazole 
 
Grapefruit juice 
 
Miscellaneous 
verapamil 
diltiazem 
cimetidine 
amiodarone 
NOT azithromycin 
chloramphenicol 
ciprofloxacin 
delaviridine 
diethyldithiocarbamate 
fluvoxamine 
gestodene 
imatinib 
mibefradil 
mifepristone 
norfloxacin 
norfluoxetine 
star fruit 
voriconazole 
INDUCERS 3A4,5,7 
HIV Antivirals: 
efavirenz 
nevirapine 
 
Miscellaneous 
barbiturates 
carbamazepine 
glucocorticoids 
modafinil 
oxcarbazepine 
phenobarbital 
phenytoin 
pioglitazone 
rifabutin 
rifampin 
St. John's wort 
troglitazone 
 
© Cytochrome P450 Drug Interaction Table 
www.drug-interactions.com 
 

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APPENDIX 6. DRUGS THAT MAY INTERACT WITH P-
GLYCOPROTEIN 
 
Transporter  
MDR1/PgP  
 Gene 
ABCB1  
 Amiodarone  
S/Inhib  
 Amitriptyline  
Inhib  
 Amprenavir  
Induc  
 Astemizole  
Inhib  
 Atorvastatin  
S/Inhib  
 Boceprevir  
S/Inhib  
 Bromocriptine  
Inhib  
 Carvedilol  
Inhib  
 Chlorpromazine  
Inhib  
 Clarithromycin  
Inhib  
 Clotrimazole  
Induc  
 Cyclosporine  
S/Inhib  
 Desipramine  
Inhib  
 Dexverapamil  
Inhib  
 Diltiazem  
S/Inhib  
 Dipyridamole  
Inhib  
 Disulfiram  
Inhib  
 Doxepin  
Inhib  
 Erythromycin  
S/Inhib  
 Fluphenazine  
Inhib  
 Glibenclamide  
Inhib  
 Haloperidol  
Inhib  
 Imipramine  
Inhib  
 Indinavir  
S/Induc  
 Itraconazole  
S/Inhib  
 Ketoconazole  
Inhib  
 Lidocaine  
S/Inhib  
 Lovastatin  
S/Inhib  
 Maprotiline  
Inhib  
 Mefloquine  
Inhib  
 Meperidine  
Inhib  
 Methadone  
Inhib  
 Mibefradil  
Inhib  
 Midazolam  
Inhib  
 Mifepristone  
Inhib  
 Nelfinavir  
S/Induc  
Transporter  
MDR1/PgP  
 Gene 
ABCB1  
 Nicardipine  
S/Inhib  
 Nifedipine  
Inhib  
 Ofloxacin  
Inhib  
 Pentazocine  
Inhib  
 Prazosin  
Induc  
 Prochlorperazine  
Inhib  
 Progesterone  
Inhib/Induc  
 Propafenone  
Inhib  
 Propranolol  
S/Inhib  
 Quercetin  
Induc  
 Quinidine  
S/Inhib  
 Quinine  
Inhib  
 Reserpine  
inhib  
 Retinoic acid  
Induc  
 Rifampin  
S/Induc  
 Ritonavir  
S/inhib  
 Saquinavir  
S/Inhib  
 Simvastatin  
 S/Inhib 
 St. John’s Wort  
Induc  
 Tacrolimus  
S/Inhib  
 Tamoxifen  
Inhib  
 Telaprevir  
S/Inhib  
 Temsirolimus  
S/Inhib  
 Testosterone  
Inhib  
 Trimipramine  
Inhib  
 Vaspodar  
Inhib  
 Verapamil  
S/Inhib  
 
Inhib = Inhibition 
Induc = Induction 
S = Substrate 
MDR = multidrug resistance protein 
 
Source: Pharmacology Weekly 
http://www.pharmacologyweekly.com/content/pages/
medications-drugs-substrates-inhibitors-inducers-
efflux-transporters 
 

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APPENDIX 7. DOSE RATIONALE 
 
The dose range for nevanimibe HCl (hereafter, nevanimibe) in this Phase 2b congenital adrenal 
hyperplasia (CAH) study is supported by previously completed clinical studies (i.e., the previous 
CAH Phase 2 study, the Phase 1 maximum tolerated dose (MTD) study in adrenocortical 
carcinoma (ACC), and healthy volunteer Phase 1 drug-drug interaction and food interaction 
studies) as well as comprehensive non-clinical and in vitro programs. Extensive clinical and non-
clinical pharmacokinetic data have also been generated that further support the clinical dose 
rationale across the nevanimibe development program. 
Nevanimibe is a selective acyl-CoA: cholesterol acyltransferase 1 (ACAT1) inhibitor. ACAT1 is 
highly expressed in the adrenal cortex, where it catalyzes the formation of cholesteryl esters (CE) 
from cholesterol and acyl-coenzyme A. In the adrenal glands, CEs serve as a substrate reservoir 
for steroid biosynthesis. Nevanimibe distributes preferentially to the adrenal glands relative to 
other tissues and disrupts adrenal cholesterol homeostasis via inhibition of ACAT1 (LaPensee, 
2016). At low doses/exposures, nevanimibe results in reduction of the CE reservoir and leads to 
reduced synthesis of adrenal steroids. At higher doses and correspondingly higher exposures, 
nevanimibe causes further disruption of the normal cholesterol:CE ratio, leading to endoplasmic 
reticulum stress and, if left unchecked, activation of the unfolded protein response (LaPensee, 
2016). Thus, nevanimibe may be used at the lower dose range for endocrine indications such as 
CAH and Cushing’s syndrome (CS), while the higher dose range may be used for ACC. 
Based on extensive work conducted to elucidate the mechanism of action, the nevanimibe clinical 
development program followed a step-wise, strategic approach to dose selection. The clinical 
program began with the ACC indication, where the benefit:risk allowed for more aggressive dose 
escalation given the severity and aggressiveness of the disease. The endocrine indications CAH 
and CS started after initiation of the ACC Phase 1 MTD study and used a lower dose range 
aligned with the nevanimibe mechanism of action (i.e., inhibition of adrenal steroidogenesis). The 
robust safety dataset generated in the ACC Phase 1 MTD study provided tremendous reassurance 
for the endocrine studies since ACC subjects had already been treated with markedly higher 
nevanimibe doses for much longer periods of time relative to the doses and treatment periods 
currently used in the endocrine studies. Additionally, the ACC patient population in the 
nevanimibe study is considered to be significantly less robust relative to the CAH and CS 
populations, yet nevanimibe was still very well tolerated. A comprehensive overview of the dosing 
rationale for the CAH Phase 2b study is presented below; additional details can be found in the 
Investigators’ Brochure. 
The previous CAH Phase 2 study (N=10) enrolled adults with classic CAH and uncontrolled 17-
hydroxyprogesterone (17-OHP) levels. The study was designed to evaluate whether nevanimibe 
added to the subjects’ usual maintenance glucocorticoid doses would result in improved control of 
17-OHP levels, and used nevanimibe doses of 125 mg BID, 250 mg BID, 500 mg BID, 750 mg 
BID and 1000 mg BID in a single-blind, intra-subject dose escalation design. A 14-day 
nevanimibe treatment period was used for each dose level followed immediately by a 14-day 
placebo washout period. Seven of the 10 subjects demonstrated biological activity (i.e., decrease 
in 17-OHP) at multiple nevanimibe dose levels, with most subjects up-titrating to the 1000 mg 
BID dose. Nevanimibe was very well tolerated in the previous CAH Phase 2 study with no safety 
events of note. It was hypothesized that continuous dosing beyond 2 weeks and/or higher doses 
may result in a more robust treatment effect. This CAH Phase 2b study will build upon the 

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previous Phase 2 data by using doses of 500 mg BID, 1000 mg BID, 1500 mg BID and 2000 mg 
BID. The combination of sustained dosing and higher doses should provide a more definitive 
assessment of the efficacy of nevanimibe in CAH subjects. 
The nevanimibe 1500 mg BID and 2000 mg BID doses in this CAH Phase 2b study are supported 
by the ACC Phase 1 MTD study (N=63) with long-term exposures and extensive PK data. The 
ACC Phase 1 MTD study used a dose range of 1.6 to 158.5 mg/kg/day (equivalent to 
approximately 11,900 mg/day for a 75-kg individual). Multiple conditions for oral administration 
were used in attempts to increase nevanimibe exposure to the greatest extent possible. A once 
daily, powder-in-capsule formation was used for the first 7 dose cohorts; a tablet formulation 
twice per day (BID) with a non-diet cola to maintain acidic stomach conditions was used for 
Cohorts 8 to 11; and Cohorts 12-14 were dosed with food BID. Even at the highest dose (158.5 
mg/kg/day) a MTD could not be defined as dose-limiting toxicities (DLT) did not occur. Only two 
DLTs were reported during the entire study: a grade 3 elevation of liver enzymes in a subject with 
pre-existing liver disease (occurring at 102.4 mg/kg/day) and grade 3 vomiting and diarrhea 
(occurring at 37.3 mg/kg/day). Some “hints” of efficacy were reported with prolonged periods of 
stable disease observed in multiple subjects (Figure 1). Although a MTD could not be defined, the 
Sponsor voluntarily halted the study due to low grade, chronic gastrointestinal side effects (e.g., 
nausea, diarrhea) secondary to the large number of tablets required (i.e., 158.5 mg/kg/day = ~24 
tablets per day, each 500 mg tablet being 19 mm x 8 mm in size). A dose of 128.2 mg/kg/day 
(equivalent to approximately 9600 mg/day for a 75-kg individual) was declared as the “maximum 
feasible dose” that could be taken on a long-term, chronic basis. This dose is approximately 2.5x 
higher than the highest dose being used in the CAH Phase 2b study.  Thus, the ACC data provides 
a wide safety margin. 
Dosing in the CAH Phase 2b study will commence with nevanimibe HCl at a dose of 500 mg BID, 
as this dose was well-tolerated in both the previous Phase 2 CAH study and in a previous drug-
drug interaction study, and experience from previous studies suggests that study drug tolerability 
is improved by longer dosing. A 3- to 6-fold multiple exists between the 1000-2000-mg BID doses 
in this CAH Phase 2b study and the highest dose used in the ACC Phase 1 MTD study. The CAH 
Phase 2b doses of 1000 mg BID, 1500 mg BID and 2000 mg BID are equivalent to approximately 
27, 40 and 53 mg/kg/day, respectively, for a 75-kg individual. In comparison, the relevant doses in 
the ACC Phase 1 MTD study were 23.3 (n=5), 25.6 (n=6), 37.3 (n=6), 51.2 (n=3), 60.6 (n=5), 97.9 
(n=4 with cola; n=6 with food), 102.4 (n=4), 128.2 (n=5) and 158.5 (n=4) mg/kg/day. Thus, a total 
of 48 ACC subjects have been treated at doses close to or greater than those being used in the 
CAH Phase 2b study. Thirty-one of these 47 subjects remained on study drug until the time of the 
first assessment for disease progression at the month 2 visit. Subjects who were found to have 
ACC disease progression at the month 2 visit did not continue in the study. In fact, the majority of 
study dropouts were driven by disease progression at various time points and not adverse events. 
Nine subjects remained on study drug for at least 3 months, with 8 subjects having at least 4 
months of exposure. The longest durations of exposure were 8, 12, and 13 months at dose levels of 
102.4, 60.6, and 97.9 mg/kg/day, respectively. This robust safety dataset in human subjects 
provides strong reassurance of safety for the lower nevanimibe doses and shorter duration of 
treatment in the CAH Phase 2b study.  Figure 2 presents dose and duration of exposure for the 
entire ACC study population.  

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Figure 2: 
Nevanimibe Doses and Exposure Duration by Dose Cohort, Part 1 of 2 
 
 
 

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Figure 2:  
Nevanimibe Doses and Exposure Duration by Dose Cohort, Part 2 of 2 
 
† Each cycle was approximately 28 days in duration. This subject was on nevanimibe 158.5 mg/kg/day for Cycle 1, 128.2 
mg/kg/day for Cycle 2, and 97.9 mg/kg/day for Cycles 3-6. Dose down-titrations at Cycle 2 and Cycle 3 were done to ameliorate 
adverse events of nausea, diarrhea, and anorexia. 
 
 
† 

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An extensive pharmacokinetic dataset also exists from the ACC Phase 1 MTD study and the two 
healthy volunteer Phase 1 studies (drug-drug interaction and food effects) as detailed in the 
Investigator’s Brochure. Additionally, the previous CAH Phase 2 AUC0-4 hr exposures 
demonstrated step-wise, dose-dependent increases across the 5 nevanimibe doses (Figure 3). 
Similar, step-wise, dose-dependent exposures are anticipated to occur in this CAH Phase 2b study.    
Figure 3: 
Previous CAH Phase 2 Study Nevanimibe Exposures 
 
† n = 9; data do not include AUCs from one subject who received only the 125 and 250 mg BID dose levels due to completing 
the study early by meeting target 17-OHP levels at the 250 mg BID dose. 
 
In summary, the safety profile of nevanimibe has been extremely well characterized for a drug in 
the proof-of-concept stage of development. The step-wise systematic approach to dose selection in 
clinical studies was based on alignment of the known mechanism of action and the disease 
indication. Thus, higher doses and longer durations of exposure (i.e., greater risk) were used 
initially only for ACC subjects where the severity of the disease allows for more aggressive dosing 
but still provides a reasonable benefit:risk. Once this safety profile had been established, use in 
less aggressive disease states such as CAH and CS could be justified with a reasonable benefit:risk 
assessment.