Clinical trial NCT05001945
Conditions: Hypertension, Renal
Keywords: Blood pressure Uncontrolled hypertension Phase II
Sponsor: Mineralys Therapeutics Inc.
Start date: 2021-07-01; Completion date: 2022-10-07
Enrollment: 200 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A randomized, double-blind, placebo-controlled, dose-ranging, Phase II study to evaluate the safety, efficacy, and tolerability of MLS-101 in Subjects With Uncontrolled Hypertension

Detailed description:

Arms: arm 1: Placebo tablet(s) by mouth once or twice daily. arm 2: MLS-101 tablet(s) by mouth once or twice daily. arm 3: MLS-101 tablet(s) by mouth once or twice daily. arm 4: MLS-101 tablet(s) by mouth once or twice daily. arm 5: Placebo tablet(s) by mouth once daily. arm 6: MLS-101 tablet(s) by mouth once daily.
Interventions: intervention 1: MLS-101 (Part I) intervention 2: Placebo (Part I) intervention 3: Placebo (Part II) intervention 4: MLS-101 (Part II)
Intervention descriptions: intervention 1: MLS-101 tablet(s) by mouth once or twice daily. intervention 2: Placebo tablet(s) by mouth once or twice daily. intervention 3: Placebo tablet(s) by mouth once daily. intervention 4: MLS-101 tablet(s) by mouth once daily.

Protocol documents:
Prot_000.pdf: 
Mineralys Therapeutics, Inc. 
Protocol MLS-101-201 
Investigational Product: MLS-101 
Version 7.0 
CONFIDENTIAL 
Page 1 of 130 
  CLINICAL PROTOCOL 
Protocol Title: 
A Randomized, Double-blind, Placebo-controlled, Dose-ranging, 
Multicenter Phase 2 Study to Evaluate the Safety, Efficacy, and 
Tolerability of MLS-101 in Subjects With Uncontrolled 
Hypertension 
Protocol Number: 
MLS-101-201 
Investigational Product: 
MLS-101 
Study Phase: 
2 
IND Number: 
151496 
NCT Number: 
NCT05001945 
Study Sponsor: 
Mineralys Therapeutics, Inc. 
150 N. Radnor Chester Rd. – Suite F200 
Radnor, PA 19087 
SAE Reporting: 
Email: Safety-Inbox.biotech@iqvia.com 
Phone: +1 919-313-7111 
Fax: +1 919-313-1412 
Original Protocol Date: 
06 February 2021 
Amendment 1 Date: 
15 April 2021 
Amendment 2 Date: 
01 June 2021 
Amendment 3 Date: 
24 August 2021 
Amendment 4 Date: 
10 January 2022 
Amendment 5 Date: 
17 February 2022 
Amendment 6 Date: 
07 July 2022 
The information contained in this document is proprietary to Mineralys Therapeutics, Inc. and is 
not to be copied, disclosed, or otherwise distributed by an outside authority to any person or 
persons without the prior written permission of Mineralys Therapeutics, Inc. 


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TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................................2 
LIST OF TABLES ...........................................................................................................................5 
LIST OF FIGURES .........................................................................................................................6 
1.
SYNOPSIS ..............................................................................................................................7 
2.
INTRODUCTION ................................................................................................................20 
2.1. 
Study Rationale ................................................................................................................20 
2.2. 
Background ......................................................................................................................20 
2.3. 
Benefit/Risk Assessment ..................................................................................................21 
3.
STUDY OBJECTIVES AND ENDPOINTS ........................................................................23 
3.1. 
Study Objectives ...............................................................................................................23 
3.1.1. 
Primary Objective ..........................................................................................................23 
3.1.2. 
Secondary Objectives ....................................................................................................23 
3.2. 
Study Endpoints ...............................................................................................................23 
3.2.1. 
Primary Efficacy Endpoint ............................................................................................23 
3.2.2. 
Secondary Efficacy Endpoints ......................................................................................23 
3.2.3. 
Safety Endpoints ............................................................................................................23 
3.2.4. 
Pharmacokinetics Endpoints .........................................................................................24 
3.2.5. 
Pharmacodynamics Endpoints ......................................................................................24 
4.
STUDY DESIGN..................................................................................................................25 
4.1. 
Overall Study Design .......................................................................................................25 
4.2. 
Scientific Rationale for Study Design ..............................................................................28 
4.3. 
Number of Subjects/Number of Centers ..........................................................................28 
4.4. 
Study Duration .................................................................................................................29 
4.5. 
Justification for Dose ........................................................................................................29 
4.6. 
End of Study Definition ...................................................................................................30 
4.7. 
Criteria for Study Termination .........................................................................................30 
4.8. 
Study Conduct ..................................................................................................................30 
4.8.1. 
Pre-Screening (Visit 1, Study Days -28 to -14 for Part 1 or -42 to -14 for Part 2) .......30 
4.8.2. 
Screening/Start of Placebo Run-in (Visit 2/Visit 3, Study Day -14 ± 2 Days) .............31 
4.8.3. 
Single-blind Placebo Run-In Week 2 (Visit 4, Study Day -7 ± 2 Days) .......................31 
4.8.4. 
Telephone or Office Visit (Visit 5, Study Day 0) .........................................................32 
4.8.5. 
Randomization/Baseline (Visit 6, Study Day 1) ...........................................................32 
4.8.6. 
Study Week 1 (Visit 7, Study Day 7 ± 2 Days) ............................................................33 
4.8.7. 
Study Week 2 (Visit 8, Study Day 14 ± 2 Days) ..........................................................33 
4.8.8. 
Study Week 3 (Visit 9, Study Day 21 ± 2 Days) ..........................................................34 
4.8.9. 
Study Week 4 (Visit 10, Study Day 28 ± 2 Days) ........................................................34 
4.8.10. 
Study Week 5 (Visit 11, Study Day 35 ± 2 Days) ........................................................34 
4.8.11. 
Study Week 6 (Visit 12, Study Day 42 ± 2 Days) ........................................................35 
4.8.12. 
Study Week 7 (Visit 13, Study Day 49 ± 2 Days) ........................................................35 
4.8.13. 
Study Week 8 (Visit 14, Study Day 56 ± 2 Days) ........................................................35 


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4.8.14. 
Telephone Visit (Visit 15, BP check; Study Day 59 + 2 Days) ....................................36 
4.8.15. 
Study Week 10 (Part 2 Only: Visit 16, End of Study; Study Day 70 ± 3 Days) ...........36 
4.8.16. 
Study Week 12 (Part 1 Only: Visit 16, End of Study; Study Day 84 ± 3 Days) ...........36 
4.9. 
Modifications to Study Conduct Due to the Coronavirus Disease 2019 (COVID-19) 
Pandemic ..........................................................................................................................37 
5.
STUDY POPULATION .......................................................................................................38 
5.1. 
Inclusion Criteria ..............................................................................................................38 
5.2. 
Exclusion Criteria .............................................................................................................39 
5.3. 
Lifestyle Considerations ...................................................................................................41 
5.3.1. 
Meals and Dietary Restrictions .....................................................................................41 
5.3.2. 
Caffeine, Alcohol, and Tobacco ....................................................................................41 
5.3.3. 
Activity/Exercise ...........................................................................................................41 
5.4. 
Screen Failures .................................................................................................................41 
6.
STUDY DRUG ADMINISTRATION AND MANAGEMENT ..........................................42 
6.1. 
Study Drug Administration ..............................................................................................42 
6.1.1. 
Description of Study Drug ............................................................................................42 
6.1.2. 
Dosing and Administration ...........................................................................................42 
6.2. 
Preparation, Handling, Storage, and Accountability ........................................................42 
6.2.1. 
Study Drug Preparation .................................................................................................42 
6.2.2. 
Study Drug Packaging and Labeling .............................................................................43 
6.2.3. 
Study Drug Handling and Disposal ...............................................................................43 
6.2.4. 
Study Drug Storage .......................................................................................................43 
6.2.5. 
Study Drug Accountability ............................................................................................43 
6.3. 
Randomization and Blinding ............................................................................................43 
6.4. 
Study Drug Compliance ...................................................................................................44 
6.5. 
Dose Modification ............................................................................................................44 
6.5.1. 
Hyperkalemia ................................................................................................................45 
6.5.2. 
Hypotension ...................................................................................................................45 
6.5.3. 
Adrenal Insufficiency ....................................................................................................46 
6.6. 
Treatment of Overdose .....................................................................................................46 
6.7. 
Concomitant Therapy .......................................................................................................47 
6.7.1. 
Prohibited Treatments ...................................................................................................47 
6.7.2. 
Permitted Treatments ....................................................................................................48 
7.
DISCONTINUATION/WITHDRAWAL CRITERIA .........................................................49 
7.1. 
Discontinuation of Study Drug .........................................................................................49 
7.2. 
Discontinuation/Withdrawal of Subjects ..........................................................................49 
7.3. 
Lost to Follow Up .............................................................................................................50 
8.
STUDY ASSESSMENTS AND PROCEDURES ................................................................51 
8.1. 
Efficacy Assessments .......................................................................................................51 


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8.1.1. 
Automated Office-Measured Blood Pressure ................................................................51 
8.1.2. 
24-hour Ambulatory Blood Pressure Monitoring .........................................................52 
8.2. 
Safety Assessments ..........................................................................................................52 
8.2.1. 
Medical History .............................................................................................................52 
8.2.2. 
Physical Examination ....................................................................................................52 
8.2.3. 
Vital Signs .....................................................................................................................52 
8.2.4. 
Electrocardiogram .........................................................................................................53 
8.2.5. 
Clinical Safety Laboratory Tests ...................................................................................53 
8.2.6. 
Spot Urine and 24-Hour Urine Collection ....................................................................53 
8.2.7. 
Pregnancy Testing .........................................................................................................53 
8.3. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting ..........................53 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information .........................54 
8.3.2. 
Method of Detecting AEs and SAEs .............................................................................54 
8.3.3. 
Follow-up of AEs and SAEs .........................................................................................55 
8.3.4. 
Regulatory Reporting Requirements for SAEs .............................................................55 
8.3.5. 
Pregnancy ......................................................................................................................55 
8.3.6. 
Death Events ..................................................................................................................56 
8.3.7. 
Adverse Events of Special Interest ................................................................................56 
8.3.8. 
Safety Monitoring Considerations .................................................................................56 
8.4. 
Pharmacokinetics ..............................................................................................................57 
8.5. 
Pharmacodynamics ...........................................................................................................57 
9. 
STATISTICAL CONSIDERATIONS..................................................................................58 
9.1. 
Analysis Sets ....................................................................................................................58 
9.2. 
Sample Size Determination ..............................................................................................58 
9.3. 
Statistical Methods ...........................................................................................................58 
9.3.1. 
Disposition, Demographics and Baseline Characteristics .............................................58 
9.3.2. 
Efficacy Analyses ..........................................................................................................59 
9.3.3. 
Safety Analyses .............................................................................................................59 
9.3.4. 
Pharmacokinetics Analyses ...........................................................................................60 
9.3.5. 
Pharmacodynamics Analyses ........................................................................................60 
9.4. 
Handling of Missing Data ................................................................................................60 
9.5. 
Interim Analysis ...............................................................................................................60 
10. ETHICAL AND ADMINISTRATIVE CONSIDERATIONS .............................................62 
10.1. 
Compliance Statement ......................................................................................................62 
10.2. 
Investigator Responsibilities ............................................................................................62 
10.3. 
Institutional Review Board/Independent Ethics Committee Review ...............................62 
10.4. 
Informed Consent and Human Subject Protection ...........................................................63 
10.5. 
Confidentiality ..................................................................................................................64 
10.6. 
Urgent Safety Measures ...................................................................................................64 
10.7. 
Study Monitoring .............................................................................................................64 
10.8. 
Audits and Inspections .....................................................................................................65 
10.9. 
Data Collection and Handling ..........................................................................................65 


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10.10. Maintenance of Source Documents and Recordkeeping Requirements ..........................66 
10.11. Long-term Retention of Samples for Additional Future Research ...................................66 
10.12. Publication Policy .............................................................................................................67 
11. REFERENCES .....................................................................................................................68 
12. APPENDICES ......................................................................................................................70 
12.1. 
List of Abbreviations and Definition of Terms ................................................................70 
12.2. 
Study Contacts ..................................................................................................................72 
12.3. 
Investigator’s Agreement .................................................................................................73 
12.4. 
Sponsor’s Signature ..........................................................................................................74 
12.5. 
Standing Blood Pressure Measurement ............................................................................75 
12.6. 
Dietary Restrictions ..........................................................................................................76 
12.7. 
ACTH Stimulation Test ....................................................................................................77 
12.8. 
Contraceptive and Barrier Guidance ................................................................................78 
12.8.1. 
Definitions .....................................................................................................................78 
12.8.2. 
Contraception Guidance ................................................................................................78 
12.9. 
Clinical Laboratory Tests .................................................................................................80 
12.10. Definitions and Procedures for Adverse Events ...............................................................81 
12.10.1. Definition of Adverse Event ..........................................................................................81 
12.10.2. Definition of Serious Adverse Event .............................................................................81 
12.10.3. Recording and Follow-Up of AE and/or SAE ...............................................................82 
12.10.4. Reporting of AEs and SAEs ..........................................................................................84 
12.11. Protocol Amendment Summary .......................................................................................85 
12.11.1. Amendment 6 (07 July 2022) ........................................................................................86 
12.11.2. Amendment 5 (17 February 2022) ................................................................................90 
12.11.3. Amendment 4 (10 January 2022) ................................................................................101 
12.11.4. Amendment 3 (24 August 2021) .................................................................................112 
12.11.5. Amendment 2 (01 June 2021) .....................................................................................121 
12.11.6. Amendment 1 (15 April 2021) ....................................................................................125 
 
LIST OF TABLES 
Table 1: 
Schedule of Assessments for Part 1 .......................................................................16 
Table 2: 
Schedule of Assessments for Part 2 .......................................................................18 
Table 3: 
MLS-101 Dose Reduction Schedule ......................................................................45 
Table 4: 
Highly Effective Contraceptive Methods Permitted in Study ...............................79 
Table 5: 
Acceptable Contraceptive Methods Permitted in Study ........................................79 
Table 6: 
Clinical Laboratory Analytes .................................................................................80 
 


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Investigational Product: MLS-101 
 
Version 7.0 
 
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LIST OF FIGURES 
Figure 1: 
MLS-101-201 Study Schema .................................................................................15 


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Version 7.0 
 
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1. SYNOPSIS 
Name of Sponsor/Company: 
Mineralys Therapeutics, Inc. 
Name of Investigational Product: 
MLS-101: 
 
Name of Active Ingredient: 
MLS-101 
Title of Study: A Randomized, Double-blind, Placebo-controlled, Dose-ranging, Multicenter Phase 2 
Study to Evaluate the Safety, Efficacy, and Tolerability of MLS-101 in Subjects With Uncontrolled 
Hypertension 
Number of Study Center(s): Approximately 50 centers in the United States for Part 1 and 
approximately 10 centers in the United States for Part 2 
Study Period: 
Date first subject enrolled: 30 July 2021 
Estimated date last subject last visit: Q3 2022 
Phase of Development:  
Phase 2 
Objectives and Endpoints: 
Objectives: 
Primary: 
• To characterize the effect of MLS-101 on blood pressure (BP) at 5 dosing regimens versus 
placebo when administered orally for the treatment of uncontrolled hypertension as add-on 
therapy to stable background treatment  
Secondary: 
• To investigate the safety and tolerability of MLS-101 at 5 dosing regimens versus placebo when 
administered orally for the treatment of uncontrolled hypertension as add-on therapy to stable 
background treatment 
• To investigate the pharmacokinetic (PK) profile of MLS-101 at 5 dosing regimens when 
administered orally for the treatment of uncontrolled hypertension as add-on therapy to stable 
background treatment  
• To investigate the pharmacodynamic (PD) parameters of MLS-101 at 5 dosing regimens when 
administered orally for the treatment of uncontrolled hypertension as add-on therapy to stable 
background treatment 
Endpoints: 
Efficacy 
Primary: 
• Change in office-measured (average of last 2 of 5 unattended measurements using an automated 
oscillometric sphygmomanometer device after approximately 5 minutes of rest in the seated 
position) systolic blood pressure (SBP) from baseline to the end of Study Week 8 (ie, Study Day 
56 ± 2 or end-of-treatment period) 
Secondary: 
• Change in 24-hour ambulatory blood pressure monitoring (ABPM) parameters (systolic and 
diastolic) from baseline to the end of Study Week 7 (ie, Study Day 49 ± 2) 


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• Change in office-measured (average of last 2 of 5 unattended measurements using an automated 
oscillometric sphygmomanometer device after approximately 5 minutes of rest in the seated 
position) SBP and diastolic blood pressure (DBP) from baseline to the end of Study Weeks 1, 2, 
3, 4, 5, 6 and 7 (± 2 days); change in office-measured DBP from baseline to the end of Study 
Week 8 (ie, Study Day 56 ± 2 or end-of-treatment period) 
• Proportion of subjects who achieve office-measured BP of ≤ 130/80 mmHg by the end of Study 
Week 8 (ie, Study Day 56 ± 2 or end-of-treatment period) 
Safety 
• Incidence and severity of all spontaneously reported adverse events (AEs) 
• Changes in vital signs (SBP, DBP, body temperature, heart rate, and respiratory rate) 
• Changes in electrocardiogram parameters (including cardiac intervals: PR, QRS, QT, and 
corrected QT interval using Fridericia’s formula)  
• Changes in clinical laboratory assessments (hematology, chemistry, coagulation, and urinalysis) 
• Change in office-measured SBP from Study Week 8 (end-of-treatment period) to Study Week 12 
for Part 1 and Study Week 10 for Part 2 (end of follow-up) 
Pharmacokinetics 
• PK parameters, including, if feasible, area under the plasma concentration versus time curve 
(AUC), maximum plasma concentration (Cmax), time to maximum concentration (Tmax), and half-
life (t1/2) will be summarized descriptively for Randomization (baseline) and Study Weeks 1, 4, 
and 8 
Pharmacodynamics 
• Change in plasma 11-deoxycortisol and plasma renin activity (PRA) from baseline to the end of 
Study Weeks 4 and 12 for Part 1 and end of Study Weeks 4 and 10 for Part 2 (end of follow-up) 
• Change in serum aldosterone, cortisol, and 11-deoxycorticosterone concentration from baseline to 
the end of Study Weeks 4 and 12 for Part 1 and end of Study Weeks 4 and 10 for Part 2 (end of 
follow-up) 
Methodology: 
This is a 2-part Phase 2 randomized, double-blind, placebo-controlled, dose-ranging, multicenter 
study designed to evaluate the effect of orally administered MLS-101 on BP for the treatment of 
uncontrolled hypertension (hypertensive despite receiving ≥ 2 antihypertensives) when used as add-
on therapy to stable background treatment in male and female subjects ≥ 18 years of age. Stable 
background treatment must include ≥ 2 antihypertensives (note: a combination pill = 2 
antihypertensives) that have been stable at their prescribed doses and stable for at least 4 weeks prior 
to signing the Screening/main study informed consent form (ICF). Background therapy may be 
adjusted at the investigator’s discretion. 
Subjects with a history consistent with inadequately controlled hypertension, (ie, SBP ≥ 135 mmHg 
on a stable treatment regimen of ≥ 2 antihypertensives), will undergo pre-Screening laboratory tests 
for PRA and aldosterone following their agreement to enter pre-Screening and completion of a pre-
Screening ICF that has been approved by the Institutional Review Board (IRB). In Part 1 of the study, 
the value of PRA must be ≤ 1 ng/mL/h based on morning measurement. If the value of 
PRA > 1 ng/mL/h based on morning measurement, then subjects may be eligible to enter Part 2 of the 
study. The value for aldosterone must be ≥ 1 ng/dL based on morning measurement for both Part 1 
and Part 2. Alternative target PRA and/or aldosterone criteria for the study may be provided by the 
sponsor. These alternative targets may be adjusted during conduct of the trial based on ongoing 
review of PRA and serum aldosterone values. Subjects with PRA and serum aldosterone values 
meeting the stipulated guidance criteria will then enter the study Screening process. If PRA and/or 


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serum aldosterone do not meet the target guidance values during pre-Screening, the PRA and 
aldosterone measurements may be repeated 1 time and the pre-Screening window will reset to 2 
weeks for Part 1 or 4 weeks for Part 2. If guidance criteria are revised, then previously pre-screened 
individuals who meet the revised criteria may be considered for entry into the Screening process with 
consent of the sponsor, and the pre-Screening window will reset to 2 weeks for Part 1 and 4 weeks for 
Part 2. 
The current estimate is that approximately 1100 subjects will undergo up to 2 weeks of pre-Screening 
for Part 1 and 4 weeks of pre-Screening for Part 2. It is estimated that approximately 270 subjects will 
have qualifying PRA and serum aldosterone levels to be eligible to enter Screening/start of Placebo 
Run-in for Part 1 after completing a Screening/main study ICF that has been approved by the IRB. 
Assuming an approximately 40% screen failure rate, a total of approximately 160 subjects will meet 
all eligibility requirements to qualify for enrollment in Part 1 of the study. For Part 2, it is estimated 
that approximately 60 subjects will have qualifying PRA and serum aldosterone levels to be eligible 
to enter Screening/start of Placebo Run-in for Part 2 after completing a Screening/main study ICF that 
has been approved by the IRB. Assuming an approximately 40% screen failure rate, a total of 36 
subjects will meet all eligibility requirements to qualify for enrollment in Part 2 of the study. 
At the Screening/start of Placebo Run-in visit (V2/V3), subjects will complete the Screening 
assessments and begin a single-blind (subjects blinded to treatment allocation) run-in period (up to 
2 weeks) of twice-daily (BID) oral treatment with placebo in Part 1 and once daily (QD) oral 
treatment with placebo in Part 2, while continuing to remain on stable doses of their background 
antihypertensive medications. Using an automated oscillometric sphygmomanometer device, SBP 
and DBP will be measured 5 times after approximately 5 minutes of rest in the seated position 
according to the American Heart Association (AHA) Guidelines (Muntner 2019). The average of the 
last 2 of 5 unattended measurements of SBP and DBP, respectively, will be used for the analysis. 
Subjects may also be provided with an automated digital oscillometric home BP device to measure 
BP at home at the investigator’s discretion. In addition to sitting measurements, standing BP will be 
measured at the Screening/start of Placebo Run-in visit, Randomization, Study Week 1, and Study 
Week 8 with an automated office blood pressure (AOBP) device according to the procedure 
described in Appendix 12.5. Subjects will return to the research facility at the start of Week 2 of the 
run-in period (V4) for protocol-defined assessments including BP measurements. 
At the second clinic visit of the Placebo Run-in period, subjects will be evaluated for eligibility based 
on Screening data, and if eligible, will continue Week 2 of Placebo Run-in. Subjects will be given an 
ABPM device and instructions on how to perform the ABPM procedure at home by the investigator. 
The ABPM procedure will be initiated at home approximately 24 hours before Randomization (Study 
Day 1) and again in the clinic at the end of Study Week 4 (ie, Visit 10, Study Day 28 ± 2) in Part 2 
and Study Week 7 (ie, Visit 13; Study Day 49 ± 2) in Parts 1 and 2. Alternatively, sites may choose to 
schedule an abbreviated office visit on Study Day 0 (Visit 5) to initiate the ABPM procedure. At the 
end of Study Weeks 4 and 7, the ABPM procedure can be initiated at home in extraordinary 
circumstances, such as site closure due to coronavirus disease 2019 (COVID-19), subject exposure to 
COVID-19, or subject testing positive for COVID-19. If, for any reason, the ABPM procedure is 
deemed a failure at the end of Study Week 7, it can be repeated at Study Week 8. In addition, subjects 
will be given either a spot urine collection kit for Part 1 or a 24-hour urine collection kit for Part 2 on 
the second visit of the placebo-run in period (Visit 4) to take home for use on Study Day 1. In Part 1 
of the study, first morning urine will be collected prior to morning dose of study drug on Study Day 1 
and again at the end of Study Week 8 (ie, Study Day 56 ± 2 or end-of-treatment period) for 
determination of potassium, sodium, and creatinine levels. In Part 2 of the study, 24-hour urine 
collection will be performed on Study Day 1 and again at the end of Study Week 4 (ie, Visit 10, 
Study Day 28 ± 2) for determination of potassium, sodium, creatinine, and aldosterone levels. After 
completion of the single-blind, Placebo Run-in period, subjects will participate in a telephone visit on 
Study Day 0 (Visit 5) in which they will be reminded of the instructions by the investigator or study 


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coordinator on how to perform the ABPM procedure and the spot/24-hour urine collection at home. 
Subjects will return to the clinic on Study Day 1, and those who continue to meet all eligibility 
requirements and complete all baseline procedures will be randomized to MLS-101 or placebo and 
undergo up to 8 weeks of treatment and either 4 weeks of follow-up in Part 1 or 2 weeks of follow-up 
in Part 2. 
A planned interim analysis (Section 9.5) was conducted for Part 1 of the study and all available safety 
and tolerability data (vital signs, BP measurements, adverse events, and safety laboratory values) 
were reviewed by a Data and Safety Monitoring Board (DSMB) (Section 8.3.8). A second interim 
analysis at the end of Part 1 to review all available safety and tolerability data (vital signs, BP 
measurements, adverse events, and safety laboratory values) will be conducted. This analysis will 
also include Part 2 subjects that have completed week 4 at the time of data cut off.  An additional 
interim analysis may be performed to support drug development decisions. 
NOTE: In the previous version of the protocol, subjects in Part 1 of the study were randomized into 6 
equal treatment groups (1:1:1:1:1:1) to 12.5 mg BID, 25 mg BID, 12.5 mg QD, 50 mg QD, 100 mg 
QD, or placebo. After a review of the clinical data at the December 2021 interim analysis, it was 
decided that the 2 lowest dose levels (12.5 mg QD and 12.5 mg BID) would be dropped due to lack 
of consistent meaningful reduction of blood pressure. Effective with Amendment 4, subjects will be 
randomized into 4 equal treatment groups (1:1:1:1) to 25 mg BID, 50 mg QD, 100 mg QD, or 
placebo. 
For Part 1, approximately 120 of 160 enrolled subjects ≥ 18 years of age will be randomized into 4 
equal treatment groups (1:1:1:1) to 25 mg BID, 50 mg QD, 100 mg QD, or placebo; each treatment 
group will consist of approximately 30 subjects stratified by BP (seated SBP ≤ 160 mmHg and seated 
SBP > 160 mmHg). Approximately 40 of 160 enrolled subjects were enrolled and completed the 
study in the 2 low dose cohorts that were discontinued with Amendment 4 as described above. 
For Part 2, approximately 36 enrolled subjects ≥ 18 years of age will be randomized (5:1) to either 
100 mg QD MLS-101 or placebo such that the MLS-101 treatment group will consist of 
approximately 30 subjects and the placebo treatment group will consist of approximately 6 subjects. 
Subjects will orally administer the assigned study drug (MLS-101 or placebo) according to the 
assigned dosing regimen for 8 weeks beginning on Study Day 1. All subjects in Part 1 (regardless of 
dosing group) will receive BID dosing to preserve the integrity of the blind; active drug is 
administered as the morning dose for all QD dose groups. All subjects in Part 2 will receive QD 
dosing to be administered in the morning. Subjects will return to the research facility or be seen by 
the clinical investigator or approved home health care professional at the end of Study Weeks 1, 2, 3, 
4, 5, 6, 7, and 8 (± 2 days) for protocol-defined efficacy and safety assessments and procedures, 
assessment of AEs, and confirmation of compliance with study drug usage. Subjects will also 
complete a telephone visit and BP check at home approximately 3 days post last dose of study drug. 
Subjects will attend up to 14 full clinic visits, including a pre-Screening visit, a Screening/start of 
Placebo Run-in visit, a second visit during Placebo Run-in, a clinic visit to initiate the ABPM 
procedure, a Randomization visit, 8 weekly visits during double-blind treatment, and an end-of-study 
visit scheduled 4 weeks after the last study treatment in Part 1 and 2 weeks after the last study 
treatment in Part 2 for final efficacy and safety assessments. Subjects should be in a fasted state for 
all study visits in Part 2 unless there is a medical reason not to fast as determined by the investigator. 
Safety Criteria for Dose Adjustment or Stopping Treatment: 
If, at any time during the study, a subject meets 1 or more of the clinical or laboratory exclusion 
criteria for the study (eg, seated SBP ≥ 175 mmHg or DBP ≥ 100 mmHg, serum potassium 
> 5.2 mEq/L, serum cortisol < 3 mcg/dL), laboratory test values will be confirmed using a local lab 
and BP measurements will be repeated. If laboratory exclusion criteria are met, the subject’s dose of 
study drug may be temporarily withheld, adjusted, or stopped by the investigator in consultation with 
the medical monitor. The subject will receive appropriate antihypertensive treatment if clinically 


Mineralys Therapeutics, Inc. 
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Investigational Product: MLS-101 
 
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CONFIDENTIAL 
Page 11 of 130 
indicated, and will remain in the study for further safety monitoring. Guidelines for dose 
adjustment/stopping in the management of hyperkalemia are included in Section 6.5.1. All subjects 
will be given dietary counseling to avoid foods high in potassium during the study (Appendix 12.6). 
Guidelines for the management of hypotension are included in Section 6.5.2. In addition, serum 
cortisol levels will be monitored throughout the study, and all subjects will be monitored for signs 
and symptoms of adrenal insufficiency (ie, nausea, vomiting, light-headedness, low BP, or electrolyte 
abnormalities) at every study visit. Based on changes in cortisol levels, an adrenocorticotropic 
hormone (ACTH) stimulation test (Appendix 12.7) may be performed and the subject’s dose of study 
drug may be stopped. Guidelines for potential dose discontinuation in the management of adrenal 
insufficiency are included in Section 6.5.3. 
Subjects who wish to stop treatment for any reason may stop at any time during the study. If the study 
treatment is permanently discontinued, the subject will remain in the study to complete all study 
assessments as described in the schedule of assessments (SoA) (Table 1 and Table 2) through Study 
Week 8 (end-of-treatment visit). Subjects should also be encouraged to return for a final follow-up 
visit 4 weeks after the Study Week 8 visit for Part 1 and 2 weeks after the Study Week 8 visit for Part 
2, at which the end-of-study assessments will be performed. 
An overview of the study design is presented in the Study Schema (Figure 1). Safety and efficacy 
assessments and study procedures are outlined in the SoA (Table 1 and Table 2). Detailed 
descriptions of study assessments are provided in Section 4.8 and Section 8. 
Number of Subjects (planned): 
 
 
Eligibility Criteria: 
Inclusion Criteria 
1. 
Male and nonpregnant, nonlactating female subjects ≥ 18 years of age. Fertile male and 
female subjects and their partners must agree to use either highly effective or acceptable 
methods of contraception as defined in Appendix 12.8 from Screening to 90 days post last 
dose of study drug 
2. 
Written informed consent, Health Insurance Portability and Accountability Act authorization, 
and local patient privacy required documentation for this study have been obtained 
3. 
Average of the AOBP measurements taken at Screening/start of the Placebo Run-in Visit and 
Randomization with SBP ≥ 130 mmHg  
4. 
Background antihypertensive treatment of ≥ 2 drugs (note: a combination pill = 2 
antihypertensives) that have been stable at their prescribed doses for at least 4 weeks prior to 
signing the Screening/main study ICF 
5. 
For Part 1, inclusion based on morning pre-Screening visit measurement of PRA, and the 
value for PRA must be ≤ 1 ng/mL/h. For Part 2, inclusion based on morning pre-Screening 
visit measurement of PRA, and the value of PRA must be > 1 ng/mL/h. Alternative target 
PRA criteria for the study may be provided by the sponsor. These alternative targets may be 
adjusted during the conduct of the trial based on ongoing review of PRA values.  
6. 
Inclusion based on morning pre-Screening visit measurement of  serum aldosterone for Part 1 
and pre-Screening visit measurement of aldosterone for Part 2. The value for aldosterone must 
be ≥ 1 ng/dL based on morning measurement. Alternative target aldosterone criteria for the 
study may be provided by the sponsor. These alternative targets may be adjusted during the 
conduct of the trial based on ongoing review of serum aldosterone values.   
7. 
Serum cortisol ≥ 18 mcg/dL (morning measurement) or serum cortisol > 3 and < 18 mcg/dL 
(morning measurement) at Screening/start of Placebo Run-in visit if there is no evidence of 


Mineralys Therapeutics, Inc. 
Protocol MLS-101-201 
Investigational Product: MLS-101 
 
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CONFIDENTIAL 
Page 12 of 130 
adrenal insufficiency based on normal ACTH stimulation test results. In the event that ACTH 
stimulation testing cannot be performed due to logistical challenges, including supply chain 
limitations to availability of synthetic ACTH, then subjects may be entered into the trial if 
morning serum cortisol is > 3 mcg/dL and they fulfill the criteria for no recent use of 
exogenous corticosteroid medications in dosages that could potentially cause adrenal 
suppression (ie, Exclusion Criteria 16a).  
8. 
Women of childbearing potential must have a negative serum pregnancy test prior to 
Randomization 
9. 
Willing and able to comply with the study instructions and attend all scheduled study visits 
Exclusion Criteria 
1. 
Concomitant use of epithelial sodium channel inhibitors or mineralocorticoid receptor 
antagonists, including, but not limited to amiloride, triamterene, spironolactone, eplerenone 
2. 
Use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers 
(ARBs) in combination (ie, concomitant ACE inhibitors plus ARB therapy) as background 
antihypertensive treatment  
3. 
Subjects with hypokalemia, ie, serum potassium < 3.0 mEq/L at Screening 
4. 
Subjects with hyperkalemia, ie, serum potassium > 5.2 mEq/L at Screening for Part 1 and 
> 4.8 mEq/L at Screening for Part 2 
5. 
Subjects with serum cortisol < 3 mcg/dL based on morning measurement at Screening 
6. 
Subjects with serum sodium < 135 mEq/L at Screening 
7. 
Subjects with estimated glomerular filtration rate < 60 mL/min/1.73m2 at Screening  
8. 
Subjects with type 1 or uncontrolled (hemoglobin A1c ≥ 9%) type 2 diabetes mellitus 
9. 
Subjects with body mass index > 40 kg/m2 
10. Subjects with unstable angina who are taking short-acting oral or sublingual nitroglycerin or 
who have history of myocardial infarction or stroke within 6 months of Screening, sustained 
atrial fibrillation, ie, lasting > 12 months, or permanent atrial fibrillation; paroxysmal atrial 
fibrillation that terminates spontaneously or with intervention within 7 days is allowed. 
Chronic long-acting oral nitrates that have been stable at their prescribed doses for at least 
2 weeks prior to signing the Screening/main study ICF are allowed. 
11. Subjects with office SBP ≥ 175 mmHg or DBP ≥ 100 mmHg for Part 1 and SBP ≥ 160 mmHg 
or DBP ≥ 100 mmHg for Part 2 (average of last 2 of 5 unattended measurements using an 
automated oscillometric sphygmomanometer device after approximately 5 minutes of rest in 
the seated position) at Pre-Screening, Screening/Start of Placebo Run-in, or Randomization 
12. Subjects with a decrease in SBP ≥ 20 mmHg or DBP ≥ 10 mmHg from sitting to standing 
position at Screening (may be repeated during Screening at the investigator’s discretion) 
13. Subjects who, in the opinion of the investigator, have suspected nonadherence to 
antihypertensive treatment 
14. Subjects who, in the opinion of the investigator, have any major medical illness or symptoms 
of a clinically significant illness that may limit their ability to complete the study or influence 
subject safety and/or the study outcome (eg, active malignancy, HIV infection) 
15. Subjects who, in the opinion of the investigator, have any acute or chronic medical or 
psychiatric condition or laboratory abnormality that would make them unsuitable for 
participation in this study or that would place the subject at undue risk (eg, history of drug, 
alcohol, or other substance abuse) or who have other factors limiting the ability of the subject 
to cooperate and to comply with this protocol 


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Page 13 of 130 
16. Subjects undergoing treatment with any of the following medications: 
a. Chronically administered oral or topical corticosteroids within 3 months of Screening or 
during study participation. Short-term (ie, ≤ 2 weeks) of topical corticosteroids are 
allowed if taken ≥ 1 month prior to Randomization. 
b. Sympathomimetic decongestants within 1 week of Screening or during study participation 
c. Theophylline unless treatment has been stable at optimum dose for at least 4 weeks prior 
to Screening and remains stable during study participation  
d. Regular use of phosphodiesterase type 5 inhibitors within 3 months of Screening or 
during study participation  
e. Chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs), other than low dose 
aspirin (81-325 mg), where chronic use is defined as > 3 consecutive or nonconsecutive 
days of treatment per week, within 2 weeks of Screening. Note: intermittent use of 
NSAIDs is strongly discouraged; if required, NSAIDs must not be taken more than a total 
of 2 days during the study (defined as the period from Randomization to the end of study 
period). If analgesics are required, acetaminophen is recommended. 
f. Intramuscular steroids within 3 months of Screening or during study participation 
g. Estrogen- or progesterone-containing oral contraceptives or implantable progesterone 
devices 
h. Strong cytochrome P450 3A (CYP3A) and CYP3A4 inhibitors (eg, clarithromycin, 
telithromycin, nefazodone, itraconazole, ketoconazole, atazanavir, darunavir, indinavir, 
lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir) 
i. 
Strong CYP3A and CYP3A4 inducers (eg, apalutamide, carbamazepine, enzalutamide, 
fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, St. 
John’s Wort) 
17. Subjects with known hypersensitivity to MLS-101 or any of the excipients 
18. Subjects who are night-shift workers 
19. Subjects who are unable to comply with protocol requirements, including treatment 
compliance and instructions for ABPM 
20. Subjects who are currently enrolled in an investigational drug or device study or have used an 
investigational drug or an investigational device treatment within 4 weeks of Screening 
(Note: Subjects who are enrolled in a long-term follow-up study and are not actively receiving 
an investigational drug or device treatment may be eligible for participation in this study) 
Investigational Product, Dosage, and Mode of Administration: 
MLS-101 will be administered orally in the dosage 25 mg BID, 50 mg QD, or 100 mg QD in Part 1 
and orally in the dosage 100 mg QD in Part 2. 
Duration of Subject Participation Including Follow-up: 
For Part 1, subjects will participate in up to 2 weeks of pre-Screening, followed by up to 2 weeks of a 
Screening/single-blind Placebo Run-in period, 8 weeks of double-blind treatment with study drug, 
and a 4-week follow-up period, for a total duration of up to 16 weeks. For Part 2, subjects will 
participate in up to 4 weeks of pre-Screening, followed by up to 2 weeks of a Screening/single-blind 
Placebo Run-in period, 8 weeks of double-blind treatment with study drug, and a 2-week follow-up 
period, for a total duration of up to 16 weeks. 


Mineralys Therapeutics, Inc. 
Protocol MLS-101-201 
Investigational Product: MLS-101 
 
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CONFIDENTIAL 
Page 14 of 130 
Reference Therapy, Dosage and Mode of Administration: 
Placebo will be administered orally in the dosage form of a tablet and will mirror the color, shape, 
and packaging of the respective MLS-101 tablet.  
Statistical Methods:  
The primary estimand in the study aims to answer the research question on the treatment effect of 
investigational therapy versus placebo in addition to standard of care on the change in office-
measured blood pressure from baseline to Week 8. Data summaries for this study will be primarily 
descriptive in nature. Both safety and efficacy will focus on subjects receiving at least 1 dose of study 
treatment. Endpoints measured as categorical outcomes (including binary endpoints) will be 
summarized as frequencies and percentages. Continuous endpoints will be summarized using the 
following descriptive statistics: sample size, mean, median, quartiles and standard deviation. For 
efficacy endpoints, confidence intervals and tests of significance will use a 10% (2-sided) 
significance level. Given the exploratory nature of this study, no adjustments for multiplicity will be 
used. 
Sample Size 
This study has been designed to provide preliminary information regarding the appropriate dose and 
frequency of dosing for MLS-101 with respect to changes in SBP after 8 weeks of treatment. The 
sample size has been determined to provide estimates of the placebo-adjusted mean change in SBP 
from baseline for each dose that are of adequate precision assuming a 90% 2-sided confidence 
interval and an effect size of 10.0. With 30 subjects planned per arm in Part 1, the mean placebo 
adjusted change from baseline in SBP for each dose will be estimated with a precision of ± 3.8, 
assuming a standard deviation of 9 in the subject level changes in SBP from baseline. All analyses 
based on Part 2 of the study will be exploratory in nature; no formal sample size considerations will 
be made for Part 2. 
 
The study schema for Study MLS-101-201 is presented in Figure 1. The SoA are presented in 
Table 1 and Table 2 for Part 1 and Part 2 of the study, respectively. Detailed descriptions of 
study assessments are provided in Section 4.8 and Section 8. 


Mineralys Therapeutics, Inc. 
Protocol MLS-101-201 
Investigational Product: MLS-101 
 
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CONFIDENTIAL 
Page 15 of 130 
Figure 1: MLS-101-201 Study Schema 
 
ABPM = ambulatory blood pressure monitoring; BP = blood pressure; BID = twice daily; EOT = end of treatment; 
FU = follow up; PRA = plasma renin activity; QD = once daily 
a If Screening results are available, inclusion/exclusion evaluation will be performed. If subject is not eligible based on 
Screening results, they will not continue to Visit 4. If Screening results are not available, subject proceeds to Visit 4. If 
Screening results are not available at Visit 4, subject should attend Visit 5 to determine final eligibility. If eligible based on 
Screening results, ABPM assessment can begin at Visit 5. 
b The ABPM procedure will be initiated at home approximately 24 hours before Randomization (Study Day 1). Alternatively, 
sites may choose to schedule an office visit on Study Day 0 (Visit 5) to initiate the ABPM procedure. Training for the ABPM 
procedure can be done at an office visit or via phone. 
 


Mineralys Therapeutics, Inc. 
Protocol MLS-101-201 
Investigational Product: MLS-101 
 
Version 7.0 
 
CONFIDENTIAL 
Page 16 of 130 
Table 1: Schedule of Assessments for Part 1 
Study Periods 
Pre-
Screen 
Screening/Start 
of Placebo 
Run-in Week 1 
Single-
blind 
Placebo  
Run-in 
Week 2 
Phone 
or 
Office 
Visit 
Random-
izationa 
Double-blind Treatment 
Phone 
Visit 
Follow 
Up 
Study Visit (V) 
V1 
V2/V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 V11 V12 V13 V14 
V15 
V16 
Study Week 
-4 to -2 
-2 
-1 
0 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
12 
Study Day 
-28 to -14 
-14±2 
-7±2 
0 
1 
7±2 14±2 21±2 28±2 35±2 42±2 49±2 56±2 
59+2 
84±3 
Test/Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consentb 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Assessment 
 
X 
Xc 
Xd 
X 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Vital Signse 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
AOBPf 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Home BP checkg 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Standing BPh 
 
X 
 
 
X 
X 
 
 
 
 
 
 
X 
 
 
24-hour ABPMi 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
12-lead ECGj 
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Pregnancy Testk 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
PD Sample Collectionl 
Xm 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
Safety Labs (hematology, chemistry, 
coags, cortisol, ACTH)n 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Safety Labs (ACTH stimulation test)o 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Safety Labs (urinalysis)p 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Spot Urine Collectionq 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
PK Sample Collectionr 
 
 
 
 
X 
X 
 
 
X 
 
 
 
X 
 
 
Adverse Eventss 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Concomitant Medications 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Study Drug Compliance 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
IP Administrationt 
 
Xu 
Xu 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ABPM = ambulatory blood pressure monitoring; ACTH = adrenocorticotropic hormone; AOBP = automated office blood pressure; BID = twice daily; BP = blood pressure; 
coags = coagulation tests; COVID-19 = coronavirus disease 2019; ECG = electrocardiogram; ICF = informed consent form; IP = investigational product; PD = pharmacodynamic; 
PK = pharmacokinetic; PRA = plasma renin activity 


Mineralys Therapeutics, Inc. 
Protocol MLS-101-201 
Investigational Product: MLS-101 
Version 7.0 
CONFIDENTIAL 
Page 17 of 130 
a Subjects who continue to meet all eligibility requirements will be randomized to receive MLS-101 or placebo. 
b A pre-Screening ICF must be signed before entering pre-Screening period. A Screening/main study ICF must be signed before entering Screening period. 
c If Screening results are available, inclusion/exclusion evaluation will be performed. If subject is not eligible based on Screening results, they will not continue to Visit 4. If 
Screening results are not available, subject proceeds to Visit 4. 
d If Screening results are not available at Visit 4, subject should attend Visit 5 to determine final eligibility. If eligible based on Screening results, ABPM assessment can begin at 
Visit 5. 
e Body temperature, heart rate, and respiratory rate will be measured. 
f AOBP measurement is defined as the average of the last 2 of 5 unattended measurements using an automated oscillometric sphygmomanometer device after approximately 
5 minutes of rest in the seated position. 
g Blood pressure measurement to be performed at home. 
h In addition to sitting measurements, standing BP will be measured at Screening/start of Placebo Run-in, Randomization, Study Week 1, and Study Week 8 with the AOBP 
device according to the procedure described in Appendix 12.5. In addition, standing blood pressure measurements will be measured if a subject reports symptoms of 
hypotension (eg, light-headedness, dizziness, presyncope, or syncope); the standing BP measurement will be assessed weekly for these subjects until symptoms resolve. 
i Subjects will be given the ABPM device on the second visit of the placebo-run in period (Visit 4; Study Day -7 ± 2). The ABPM procedure will be initiated at home 
approximately 24 hours before Randomization (Study Day 1) and again in the clinic at the end of Study Week 7 (ie, Visit 13; Study Day 49 ± 2). Alternatively, sites may 
choose to schedule an abbreviated office visit on Study Day 0 (Visit 5) to initiate the ABPM procedure. At the end of Study Week 7, the ABPM procedure can be initiated at 
home in extraordinary circumstances, such as site closure due to COVID-19, subject exposure to COVID-19, or subject testing positive for COVID-19. Training for the ABPM 
procedure can be done at an office visit or via phone. If, for any reason, the ABPM procedure is deemed a failure at the end of Study Week 7, it can be repeated at the end of 
Study Week 8.  
j ECG changes consistent with hyperkalemia will require confirmation of potassium levels at a local laboratory. 
k Women of childbearing potential only. A sample for serum pregnancy test will be collected at Screening/start of the single-blind, Placebo Run-in, ie, Study Day -14 ± 2, and a 
sample for urine pregnancy test will be collected on Study Day 1, Study Day 28 ± 2 (Study Week 4), and at the end-of-treatment visit, Study Day 56 ± 2. Follicle stimulating 
hormone must be used to confirm postmenopausal status in all postmenopausal women at Screening/start of Placebo Run-in. 
l Blood samples for aldosterone, cortisol, 11-deoxycorticosterone, 11-deoxycortisol, and PRA will be collected. Cortisol assessment should occur before 10 am on the morning
of the study visit.
m Pre-Screening labs include blood samples for aldosterone and PRA only and should be collected in the morning after at least 8 hours of fasting. 
n Blood samples for hematology, chemistry, and coags will be collected, including hemoglobin A1c concentration, cortisol, and ACTH (see Table 6). Cortisol assessment should 
occur before 10 am on the morning of the study visit. 
o ACTH stimulation test should be performed as described in Appendix 12.7 at Screening/start of Placebo Run-in, Study Week 8, and whenever low cortisol levels are noted as
per Section 6.5.3. ACTH stimulation test may be waived with sponsor’s approval.
p Urine will be collected for urinalysis (see Table 6). 
q Subjects will be given a urine collection kit on the second visit of the placebo-run in period (Visit 4; Study Day -7 ± 2). First morning urine will be collected prior to morning 
dose of study drug on Study Day 1 and again at the end of Study Week 8 (ie, Study Day 56 ± 2 or end-of-treatment period) for determination of potassium, sodium, and 
creatinine levels.  
r Single blood samples for determination of MLS-101 will be collected at baseline (predose) and at Study Weeks 1, 4, and 8 (trough levels). Additional blood samples for long-
term storage for metabolites, drug-drug interaction profiles of background therapy, or other exploratory analyses will also be collected at baseline (predose) and at Study 
Weeks 1, 4, and 8. In addition, blood samples for determination of MLS-101 (and metabolites) will be collected predose, and 1, 2, 3, and 4 hours postdose on Study Days 1 
(Randomization) and 28 (Study Week 4). 
s Adverse events and serious adverse events will be collected from the signing of the Screening/main study ICF to 30 days post last dose of study drug. 
t On site visit days, subjects should be instructed to take their morning dose of study drug at the site. 
u Single-blind, 2-week run-in period of BID oral treatment with placebo.


Mineralys Therapeutics, Inc. 
Protocol MLS-101-201 
Investigational Product: MLS-101 
 
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Table 2: Schedule of Assessments for Part 2 
Study Periods 
Pre-
Screen 
Screening/Start 
of Placebo 
Run-in Week 1 
Single-
blind 
Placebo  
Run-in 
Week 2 
Phone 
or 
Office 
Visit 
Random-
izationa 
Double-blind Treatment 
Phone 
Visit 
Follow 
Up 
Study Visit (V) 
V1 
V2/V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 V11 V12 V13 V14 
V15 
V16 
Study Week 
-6 to -2 
-2 
-1 
0 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Study Day 
-42 to -14 
-14±2 
-7±2 
0 
1 
7±2 14±2 21±2 28±2 35±2 42±2 49±2 56±2 
59+2 
70±3 
Test/Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consentb 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Assessment 
 
X 
Xc 
Xd 
X 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Vital Signse 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
AOBPf 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Home BP checkg 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Standing BPh 
 
X 
 
 
X 
X 
 
 
 
 
 
 
X 
 
 
24-hour ABPMi 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
12-lead ECGj 
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Pregnancy Testk 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
PD Sample Collectionl 
Xm 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
Safety Labs (hematology, chemistry, 
coags, cortisol, ACTH)n 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Safety Labs (ACTH stimulation test)o 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Safety Labs (urinalysis)p 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
24-Hour Urine Collectionq 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
PK Sample Collectionr 
 
 
 
 
X 
X 
 
 
X 
 
 
 
X 
 
 
Adverse Eventss 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Concomitant Medications 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Study Drug Compliance 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
IP Administrationt 
 
Xu 
Xu 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ABPM = ambulatory blood pressure monitoring; ACTH = adrenocorticotropic hormone; AOBP = automated office blood pressure; BP = blood pressure; coags = coagulation tests; 
COVID-19 = coronavirus disease 2019; ECG = electrocardiogram; ICF = informed consent form; IP = investigational product; PD = pharmacodynamic; PK = pharmacokinetic; 
PRA = plasma renin activity; QD = once daily 


Mineralys Therapeutics, Inc. 
Protocol MLS-101-201 
Investigational Product: MLS-101 
 
Version 7.0 
 
CONFIDENTIAL 
Page 19 of 130 
a Subjects who continue to meet all eligibility requirements will be randomized to receive MLS-101 or placebo. 
b A pre-Screening ICF must be signed before entering pre-Screening period. A Screening/main study ICF must be signed before entering Screening period. 
c If Screening results are available, inclusion/exclusion evaluation will be performed. If subject is not eligible based on Screening results, they will not continue to Visit 4. If 
Screening results are not available, subject proceeds to Visit 4. 
d If Screening results are not available at Visit 4, subject should attend Visit 5 to determine final eligibility. If eligible based on Screening results, ABPM assessment can begin at 
Visit 5. 
e Body temperature, heart rate, and respiratory rate will be measured. 
f AOBP measurement is defined as the average of the last 2 of 5 unattended measurements using an automated oscillometric sphygmomanometer device after approximately 
5 minutes of rest in the seated position. 
g Blood pressure measurement to be performed at home. 
h In addition to sitting measurements, standing BP will be measured at Screening/start of Placebo Run-in, Randomization, Study Week 1, and Study Week 8 with the AOBP 
device according to the procedure described in Appendix 12.5. In addition, standing blood pressure measurements will be measured if a subject reports symptoms of 
hypotension (eg, light-headedness, dizziness, presyncope, or syncope); the standing BP measurement will be assessed weekly for these subjects until symptoms resolve. 
i Subjects will be given the ABPM device on the second visit of the placebo-run in period (Visit 4; Study Day -7 ± 2). The ABPM procedure will be initiated at home 
approximately 24 hours before Randomization (Study Day 1) and again in the clinic at the end of at the end of Study Week 4 (ie, Study Day 28 ± 2) and Study Week 7 (ie, 
Visit 13; Study Day 49 ± 2). Alternatively, sites may choose to schedule an abbreviated office visit on Study Day 0 (Visit 5) to initiate the ABPM procedure. At the end of 
Study Week 7, the ABPM procedure can be initiated at home in extraordinary circumstances, such as site closure due to COVID-19, subject exposure to COVID-19, or subject 
testing positive for COVID-19. Training for the ABPM procedure can be done at an office visit or via phone. If, for any reason, the ABPM procedure is deemed a failure at the 
end of Study Week 7, it can be repeated at the end of Study Week 8.  
j ECG changes consistent with hyperkalemia will require confirmation of potassium levels at a local laboratory. 
k Women of childbearing potential only. A sample for serum pregnancy test will be collected at Screening/start of the single-blind, Placebo Run-in, ie, Study Day -14 ± 2, and a 
sample for urine pregnancy test will be collected on Study Day 1, Study Day 28 ± 2 (Study Week 4), and at the end-of-treatment visit, Study Day 56 ± 2. Follicle stimulating 
hormone must be used to confirm postmenopausal status in all postmenopausal women at Screening/start of Placebo Run-in. 
l Blood samples for aldosterone, cortisol, 11-deoxycorticosterone, 11-deoxycortisol, and PRA will be collected. Cortisol assessment should occur before 10 am on the morning 
of the study visit. Subjects should be in a fasted state unless there is a medical reason not to fast as determined by the investigator. 
m Pre-Screening labs include blood samples for aldosterone and PRA only and should be collected in the morning after at least 8 hours of fasting. 
n Blood samples for hematology, chemistry, and coags will be collected, including hemoglobin A1c concentration, cortisol, and ACTH (see Table 6). Cortisol assessment should 
occur before 10 am on the morning of the study visit. Subjects should be in a fasted state unless there is a medical reason not to fast as determined by the investigator. 
o ACTH stimulation test should be performed as described in Appendix 12.7 at Screening/start of Placebo Run-in, Study Week 8, and whenever low cortisol levels are noted as 
per Section 6.5.3. ACTH stimulation test may be waived with sponsor’s approval. 
p Urine will be collected for urinalysis (see Table 6). 
q Subjects will be given a 24-hour urine collection kit on the second visit of the placebo-run in period (Visit 4; Study Day -7 ± 2). The first morning urine should be discarded 
before the 24-hour collection is started.  Urine should be collected for 24 hours prior to V6 (Randomization) for determination of potassium, sodium, creatinine, and 
aldosterone levels.  A second 24-hour urine collection will occur 24 hours prior to V10 (Study Week 4, Study Day 28 ± 2).    
r Single blood samples for determination of MLS-101 will be collected at baseline (predose) and at Study Weeks 1, 4, and 8 (trough levels). Additional blood samples for long-
term storage for metabolites, drug-drug interaction profiles of background therapy, or other exploratory analyses will also be collected at baseline (predose) and at Study 
Weeks 1, 4, and 8. In addition, blood samples for determination of MLS-101 (and metabolites) will be collected predose, and 1, 2, 3, and 4 hours postdose on Study Days 1 
(Randomization) and 28 (Study Week 4). Subjects should be in a fasted state unless there is a medical reason not to fast as determined by the investigator. 
s Adverse events and serious adverse events will be collected from the signing of the Screening/main study ICF to 15 days post last dose of study drug. 
t Subjects should administer study drug QD in the morning. On site visit days, subjects should be instructed to take their dose of study drug at the site. 
u Single-blind, 2-week run-in period of QD oral treatment with placebo. 
 
 


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2. INTRODUCTION 
2.1. Study Rationale 
Mineralys is currently developing MLS-101, a selective aldosterone synthase inhibitor, for the 
treatment of uncontrolled hypertension in the presence of autonomous aldosterone production. 
This study will evaluate the safety, efficacy, and tolerability of MLS-101 in subjects with low-
renin hypertension. Phase 1 data support the safety and selectivity profile of the drug with 
pharmacodynamically relevant changes in aldosterone and renin levels consistent with the 
mechanism of action of the drug. The primary objective of this Phase 2 study is to evaluate the 
blood pressure (BP) response in subjects with uncontrolled hypertension (hypertensive despite 
receiving ≥ 2 antihypertensives). Various dose levels and dose regimens will be tested to identify 
a dose response and a therapeutic index to inform subsequent studies to support an indication in 
uncontrolled hypertension, with particular emphasis on defined patient populations such as low-
renin hypertension. Data from this study will be used to inform dose selection for future studies.  
If successful, MLS-101 could provide the first targeted therapeutic option in patients with 
hypertension. By identifying patients who have hypertension associated with autonomous 
aldosterone production, Mineralys hopes to maximize the benefit risk profile of MLS-101 and 
create an avenue for the pursuit of future targeted therapeutic approaches in hypertension. 
2.2. Background 
Hypertension remains an important global health challenge due to its high prevalence and 
contribution to the development and progression of cardiovascular disease and chronic kidney 
disease and associated morbidity and mortality. The diagnosis and management of hypertension 
have not materially changed in the last 20 years, with little to no innovation in the development 
of novel antihypertensive therapeutics with unique mechanisms of action. With clinical practice 
guideline recommendations to manage BP to less than 130/80 (Whelton 2018) and recent data 
from the Systolic Blood Pressure Intervention Trial (SPRINT) (Wright 2015) suggesting the 
benefit of a lower systolic blood pressure (SBP) target in patients with underlying cardiovascular 
disease, additional options for clinicians to manage BP are warranted.  
Hypertension has historically been considered idiopathic, and the approach for antihypertensive 
treatment is rarely directed toward a primary underlying mechanism. Recent evidence suggests 
that up to approximately 30% of patients (Baudrand 2018) who otherwise would have been 
classified as essential or idiopathic hypertension patients may indeed have hypertension that is 
mediated by an underlying mechanism - autonomous aldosterone production. As part of a 
physiologic negative feedback loop, these patients have suppressed systemic renin levels and fall 
within a category previously described as low-renin hypertension (Jose 1970, Channick 1969). 
Low-renin hypertension occurs predominantly in patients with autonomous nonsuppressible 
aldosterone production in which plasma levels of aldosterone are inappropriately high relative to 
the renin level. Previously, patients with low-renin hypertension had pathophysiologic changes 
that were classically defined as overt primary aldosteronism (PA). However, accumulating 
evidence indicates that a much larger and clinically relevant spectrum of renin-independent 
aldosterone production may exist (Vaidya 2018). While assays are readily available to identify 
patients with low-renin hypertension mediated by aldosterone, epidemiologic studies suggest that 
these patients have largely been underdiagnosed. 


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Data from the Prevention and Treatment of Hypertension With Algorithm based Therapy-2 
(PATHWAY-2) study (Williams 2015) in patients with resistant hypertension highlights the 
clinical rationale for identifying patients with low-renin hypertension and the benefit of 
aldosterone blockade. Specifically, this trial demonstrated a greater BP lowering response of 
aldosterone blockade using a mineralocorticoid receptor antagonist (MRA) in patients with low 
renin levels. This finding points to the opportunity to use renin as a diagnostic tool to identify 
patients who might be best suited for aldosterone targeted therapies. 
Despite these data and clinical practice guidelines (Whelton 2018) that recommend the use of 
MRAs in patients with resistant hypertension, the use of MRAs has been strikingly low and 
market data from 2019 demonstrated that fewer than 4% of treated patients were receiving 
MRAs when indicated (Decision Resources Group 2019). Currently, MRAs are the only 
available aldosterone targeted therapies and their limited use may be explained by tolerability 
concerns seen with spironolactone, the short acting nature of newer generation MRAs like 
eplerenone, which have demonstrated more modest effects on BP, and the prevalence of 
hyperkalemia in MRA-treated patients. Thus, novel approaches to targeting aldosterone are 
needed. 
2.3. Benefit/Risk Assessment  
First-line treatment of hypertension includes dietary and lifestyle changes, with drug therapy as 
second-line treatment. The most common drugs used to treat hypertension include angiotensin-
converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), calcium channel 
blockers, thiazide diuretics, and alpha- and beta-blockers. Despite a plethora of available 
treatment options, over 50% of patients currently using prescription medication to lower BP have 
uncontrolled hypertension (Million Hearts 2020) putting them at greater risk for all-cause 
mortality and cardiovascular disease outcomes. Furthermore, it is estimated that 10% to 15% of 
hypertensive patients have resistant hypertension defined as uncontrolled hypertension despite 
taking ≥ 3 antihypertensive drugs (Oparil 2015). In addition, nonadherence or intolerance to 
available antihypertensive agents contributes to the proportion of hypertensive patients with 
uncontrolled BP (Oparil 2015). 
Aldosterone is a mineralocorticoid that regulates electrolyte and volume homeostasis in normal 
subjects, and can contribute to the development of hypertension when elevated. It is synthesized 
in the zona glomerulosa of the adrenal cortex from 11-deoxycorticosterone by aldosterone 
synthase, which is encoded by the cytochrome P450 11B2 (CYP11B2) gene (Oparil 2015). 
Aldosterone regulates BP mainly by acting via mineralocorticoid receptors (MRs) on organs 
such as renal tubules and large intestines to increase the amount of sodium reabsorbed into the 
bloodstream and the amount of potassium removed in the urine. Aldosterone also causes water to 
be reabsorbed along with sodium, which has the effect of increasing fluid volume and indirectly 
contributes to vascular disorders via elevated BP. Furthermore, some nonclinical studies have 
reported a wider distribution of MR not only in the renal tubules but also in the nonepithelial 
cells, including vascular smooth muscle cells (Ishikawa 2005) and mesangial cells 
(Nishiyama 2005), suggesting that overproduction of aldosterone may directly injure the 
cardiovascular system and kidneys. 
Mineralocorticoid receptor antagonists have been used to inhibit the function of aldosterone in 
the treatment of essential and resistant hypertension, heart failure, PA, and edema. However, 
blockade of MR induces a counter-regulatory increase in plasma aldosterone concentration 


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(PAC), potentially limiting the efficacy of the MR blockade and enhancing the MR-independent 
effect of aldosterone, such as vasoconstriction (Romagni 2003). This suggests that decreasing 
PAC may be a preferable therapeutic alternative to MR blockade. 
In addition to the negative effects of increasing PAC, MRAs may put patients at risk of 
hyperkalemia. Cortisol, like aldosterone, binds to the MRs (Arriza 1987), which enhances the 
excretion of potassium in urine (Mills 1960). Thus, if the action of the MR is blocked by an 
MRA, the excretion of potassium in urine will be reduced putting the patient at risk for 
hyperkalemia (Ramsay 1976). For this reason, MRAs are contraindicated in patients with 
hyperkalemia. In addition, MR antagonists require careful monitoring of plasma potassium, 
especially in patients who are at high risk for hyperkalemia such as patients with renal 
impairment. Given these limitations, alternative approaches to antagonizing aldosterone activity 
and its contribution to hypertension and end-organ damage are warranted. Inhibition of 
aldosterone production in the adrenal gland as opposed to blockade of aldosterone activity at the 
receptor represents a promising alternative approach. 
Inhibition of aldosterone synthesis is not free of risks. Aldosterone synthase inhibitors may cause 
hyperkalemia and hyponatremia similar to mineralocorticoid receptor blockade 
(Hargovan 2014). Furthermore, the long-term effect of aldosterone synthase inhibitors on kidney 
function is not known. However, recent evidence suggests less risk for hyperkalemia when 
antagonizing aldosterone using nonsteroidal MRAs (Bakris 2020). 
The investigational product (IP) MLS-101 is an inhibitor of CYP11B2 (aldosterone synthase), 
which is a rate-limiting enzyme for aldosterone production. In nonclinical studies, single oral 
administration of 3172473 (free-base form of MLS-101) significantly decreased PAC in a 
sodium-depleted monkey model. On the other hand, single oral administration of 3172473 did 
not affect plasma cortisol concentrations in adrenocorticotropic hormone (ACTH)-loaded 
monkeys even at a dose 100-fold higher than that required to reduce PAC. These results indicate 
that MLS-101 inhibits CYP11B2 with higher selectivity over CYP11B1, which is an enzyme for 
cortisol production. This high selectivity was also shown in the first-in-human study 
(MT-4129-E01). This study confirmed that MLS-101 decreased PAC and did not decrease serum 
cortisol in healthy subjects, indicating that MLS-101 may have a lower potential risk of 
hyperkalemia than MRAs. 
Emerging evidence suggests that nonsuppressible aldosterone production can be identified in a 
substantial proportion of patients with hypertension who have low renin levels, and these patients 
can be identified using commercially available assays assessing plasma renin activity (PRA) 
(Brown 2020). Further, randomized controlled trials have shown that patients with low renin 
levels experience dramatic BP lowering when treated with aldosterone antagonists 
(Williams 2015). This evidence, in combination with the results from the first-in-human study 
with MLS-101 (Study MT-4129-E01), suggests that the identification of patients with low-renin 
hypertension for a novel targeted therapy using an aldosterone synthase inhibitor such as 
MLS-101 can maximize the benefit/risk ratio of a new therapeutic in this subpopulation of 
patients, directly addressing the underlying pathophysiology of their disease. Further, 
identification of these patients for an aldosterone-targeted therapy may not only improve blood 
pressure responses, but may also result in a more efficient therapeutic option that minimizes the 
use of relatively ineffective additional components. 


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3. STUDY OBJECTIVES AND ENDPOINTS 
3.1. Study Objectives 
3.1.1. Primary Objective 
• To characterize the effect of MLS-101 on BP at 5 dosing regimens versus placebo when 
administered orally for the treatment of uncontrolled hypertension as add-on therapy to stable 
background treatment 
3.1.2. Secondary Objectives 
• To investigate the safety and tolerability of MLS-101 at 5 dosing regimens versus placebo 
when administered orally for the treatment of uncontrolled hypertension as add-on therapy to 
stable background treatment 
• To investigate the pharmacokinetic (PK) profile of MLS-101 at 5 dosing regimens when 
administered orally for the treatment of uncontrolled hypertension as add-on therapy to stable 
background treatment  
• To investigate the pharmacodynamic (PD) parameters of MLS-101 at 5 dosing regimens 
when administered orally for the treatment of uncontrolled hypertension as add-on therapy to 
stable background treatment 
3.2. Study Endpoints 
3.2.1. Primary Efficacy Endpoint 
• Change in office-measured (average of last 2 of 5 unattended measurements using an 
automated oscillometric sphygmomanometer device after approximately 5 minutes of rest in 
the seated position) SBP from baseline to the end of Study Week 8 (ie, Study Day 56 ± 2 or 
end-of-treatment period) 
3.2.2. Secondary Efficacy Endpoints 
• Change in 24-hour ambulatory blood pressure monitoring (ABPM) parameters (systolic and 
diastolic) from baseline to the end of Study Week 7 (ie, Study Day 49 ± 2) 
• Change in office-measured (average of last 2 of 5 unattended measurements using an 
automated oscillometric sphygmomanometer device after approximately 5 minutes of rest in 
the seated position) SBP and diastolic blood pressure (DBP) from baseline to the end of 
Study Weeks 1, 2, 3, 4, 5, 6, and 7 (± 2 days); change in office-measured DBP from baseline 
to the end of Study Week 8 (ie, Study Day 56 ± 2 or end-of-treatment period) 
• Proportion of subjects who achieve in office-measured BP of ≤ 130/80 mmHg by the end of 
Study Week 8 (ie, Study Day 56 ± 2 or end-of-treatment period) 
3.2.3. Safety Endpoints 
• Incidence and severity of all spontaneously reported adverse events (AEs) 
• Changes in vital signs (SBP, DBP, body temperature, heart rate, and respiratory rate) 
• Changes in electrocardiogram parameters (including cardiac intervals: PR, QRS, QT, and 
corrected QT interval using Fridericia’s formula)  


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• Changes in clinical laboratory assessments (hematology, chemistry, coagulation, and 
urinalysis) 
• Change in office-measured SBP from Study Week 8 (end-of-treatment period) to Study 
Week 12 for Part 1 and Study Week 10 for Part 2 (end of follow-up) 
3.2.4. Pharmacokinetics Endpoints 
• PK parameters including, if feasible, area under the plasma concentration versus time curve 
(AUC), maximum plasma concentration (Cmax), time to maximum concentration (Tmax), and 
half-life (t1/2) will be summarized descriptively for Randomization (baseline) and Study 
Weeks 1, 4, and 8 
3.2.5. Pharmacodynamics Endpoints 
• Change in plasma 11-deoxycortisol and PRA from baseline to the end of Study Weeks 4 and 
12 for Part 1 and end of Study Weeks 4 and 10 for Part 2 (end of follow-up) 
• Change in serum aldosterone, cortisol, and 11-deoxycorticosterone concentration from 
baseline to the end of Study Weeks 4 and 12 for Part 1 and end of Study Weeks 4 and 10 for 
Part 2 (end of follow-up) 


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4. STUDY DESIGN 
4.1. Overall Study Design 
This is a 2-part Phase 2 randomized, double-blind, placebo-controlled, dose-ranging, 
multicenter study designed to evaluate the effect of orally administered MLS-101 on BP for the 
treatment of uncontrolled hypertension (hypertensive despite receiving ≥ 2 antihypertensives) 
when used as add-on therapy to stable background treatment in male and female subjects ≥ 18 
years of age. Stable background treatment must include ≥ 2 antihypertensives (note: a 
combination pill = 2 antihypertensives) that have been stable at their prescribed doses and stable 
for at least 4 weeks prior to signing the Screening/main study informed consent form (ICF). 
Background therapy may be adjusted at the investigator’s discretion. 
Subjects with a history consistent with inadequately controlled hypertension, (ie, SBP ≥ 135 
mmHg on a stable treatment regimen of ≥ 2 antihypertensives), will undergo pre-Screening 
laboratory tests for PRA and aldosterone following their agreement to enter pre-Screening and 
completion of a pre-Screening ICF that has been approved by the Institutional Review Board 
(IRB). In Part 1 of the study, the value of PRA must be ≤ 1 ng/mL/h based on morning 
measurement. If the value of PRA > 1 ng/mL/h based on morning measurement, then subjects 
may be eligible to enter Part 2 of the study. The value for aldosterone must be ≥ 1 ng/dL based 
on morning measurement for both Part 1 and Part 2. Alternative target PRA and/or aldosterone 
criteria for the study may be provided by the sponsor. These alternative targets may be adjusted 
during conduct of the trial based on ongoing review of PRA and serum aldosterone values. 
Subjects with PRA and serum aldosterone values meeting the stipulated guidance criteria will 
then enter the study Screening process. If PRA and/or serum aldosterone do not meet the target 
guidance values during pre-Screening, the PRA and aldosterone measurements may be repeated 
1 time and the pre-Screening window will reset to 2 weeks for Part 1 or 4 weeks for Part 2. If 
guidance criteria are revised, then previously pre-screened individuals who meet the revised 
criteria may be considered for entry into the Screening process with consent of the sponsor, and 
the pre-Screening window will reset to 2 weeks for Part 1 and 4 weeks for Part 2. 
The current estimate is that approximately 1100 subjects will undergo up to 2 weeks of pre-
Screening for Part 1 and 4 weeks of pre-Screening for Part 2. It is estimated that approximately 
270 subjects will have qualifying PRA and serum aldosterone levels to be eligible to enter 
Screening/start of Placebo Run-in for Part 1 after completing a Screening/main study ICF that 
has been approved by the IRB. Assuming an approximately 40% screen failure rate, a total of 
approximately 160 subjects will meet all eligibility requirements to qualify for enrollment in 
Part 1 of the study. For Part 2, it is estimated that approximately 60 subjects will have 
qualifying PRA and serum aldosterone levels to be eligible to enter Screening/start of Placebo 
Run-in for Part 2 after completing a Screening/main study ICF that has been approved by the 
IRB. Assuming an approximately 40% screen failure rate, a total of 36 subjects will meet all 
eligibility requirements to qualify for enrollment in Part 2 of the study. 
At the Screening/start of Placebo Run-in visit (V2/V3), subjects will complete the Screening 
assessments and begin a single-blind (subjects blinded to treatment allocation) run-in period (up 
to 2 weeks) of twice-daily (BID) oral treatment with placebo in Part 1 and once daily (QD) oral 
treatment with placebo in Part 2, while continuing to remain on stable doses of their background 
antihypertensive medications. Using an automated oscillometric sphygmomanometer device, 
SBP and DBP will be measured 5 times after approximately 5 minutes of rest in the seated 


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position according to the American Heart Association (AHA) Guidelines (Muntner 2019). The 
averge of the last 2 of 5 unattended measurements of SBP and DBP, respectively, will be used 
for the analysis. Subjects may also be provided with an automated digital oscillometric home 
BP device to measure BP at home at the investigator’s discretion. In addition to sitting 
measurements, standing BP will be measured at the Screening/start of Placebo Run-in visit, 
Randomization, Study Week 1, and Study Week 8 with an automated office blood pressure 
(AOBP) device according to the procedure described in Appendix 12.5. Subjects will return to 
the research facility at the start of Week 2 of the run-in period (V4) for protocol-defined 
assessments including BP measurements. 
At the second clinic visit of the Placebo Run-in period, subjects will be evaluated for eligibility 
based on Screening data, and if eligible, will continue Week 2 of Placebo Run-in. Subjects will 
be given an ABPM device and instructions on how to perform the ABPM procedure at home by 
the investigator. The ABPM procedure will be initiated at home approximately 24 hours before 
Randomization (Study Day 1) and again in the clinic at the end of Study Week 4 (ie, Visit 10, 
Study Day 28 ± 2) in Part 2 and Study Week 7 (ie, Visit 13; Study Day 49 ± 2) in Parts 1 and 2. 
Alternatively, sites may choose to schedule an abbreviated office visit on Study Day 0 (Visit 5) 
to initiate the ABPM procedure. At the end of Study Weeks 4 and 7, the ABPM procedure can 
be initiated at home in extraordinary circumstances, such as site closure due to coronavirus 
disease 2019 (COVID-19), subject exposure to COVID-19, or subject testing positive for 
COVID-19. If, for any reason, the ABPM procedure is deemed a failure at the end of Study 
Week 7, it can be repeated at Study Week 8. In addition, subjects will be given either a spot 
urine collection kit for Part 1 or a 24-hour urine collection kit for Part 2 on the second visit of 
the placebo-run in period (Visit 4) to take home for use on Study Day 1. In Part 1 of the study, 
first morning urine will be collected prior to morning dose of study drug on Study Day 1 and 
again at the end of Study Week 8 (ie, Study Day 56 ± 2 or end-of-treatment period) for 
determination of potassium, sodium, and creatinine levels. In Part 2 of the study, 24-hour urine 
collection will be performed on Study Day 1 and again at the end of Study Week 4 (ie, Visit 10, 
Study Day 28 ± 2) for determination of potassium, sodium, creatinine, and aldosterone levels. 
After completion of the single-blind, Placebo Run-in period, subjects will participate in a 
telephone visit on Study Day 0 (Visit 5) in which they will be reminded of the instructions by 
the investigator or study coordinator on how to perform the ABPM procedure and the spot/24-
hour urine collection at home. Subjects will return to the clinic on Study Day 1, and those who 
continue to meet all eligibility requirements and complete all baseline procedures will be 
randomized to MLS-101 or placebo and undergo up to 8 weeks of treatment and either 4 weeks 
of follow-up in Part 1 or 2 weeks of follow-up in Part 2. 
A planned interim analysis (Section 9.5) was conducted for Part 1 of the study and all available 
safety and tolerability data (vital signs, BP measurements, adverse events, and safety laboratory 
values) were reviewed by a Data and Safety Monitoring Board (DSMB) (Section 8.3.8). A 
second interim analysis at the end of Part 1 to review all available safety and tolerability data 
(vital signs, BP measurements, adverse events, and safety laboratory values) will be conducted.  
This analysis will also include Part 2 subjects that have completed week 4 at the time of data cut 
off.    An additional interim analysis may be performed to support drug development decisions. 
NOTE: In the previous version of the protocol, subjects in Part 1 of the study were randomized 
into 6 equal treatment groups (1:1:1:1:1:1) to 12.5 mg BID, 25 mg BID, 12.5 mg QD, 50 mg 
QD, 100 mg QD, or placebo. After a review of the clinical data at the December 2021 interim 


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analysis, it was decided that the 2 lowest dose levels (12.5 mg QD and 12.5 mg BID) will be 
dropped due to lack of consistent meaningful reduction of blood pressure. Effective with 
Amendment 4, subjects will be randomized into 4 equal treatment groups (1:1:1:1) to 25 mg 
BID, 50 mg QD, 100 mg QD, or placebo. 
For Part 1, approximately 120 of 160 enrolled subjects ≥ 18 years of age will be randomized 
into 4 equal treatment groups (1:1:1:1) to 25 mg BID, 50 mg QD, 100 mg QD, or placebo; each 
treatment group will consist of approximately 30 subjects stratified by BP (seated SBP 
≤ 160 mmHg and seated SBP > 160 mmHg). Approximately 40 of 160 enrolled subjects were 
enrolled and completed the study in the 2 low dose cohorts that were discontinued with 
Amendment 4 as described above. 
For Part 2, approximately 36 enrolled subjects ≥ 18 years of age will be randomized (5:1) to either 100 
mg QD MLS-101 or placebo such that the MLS-101 treatment group will consist of approximately 
30 subjects and the placebo treatment group will consist of approximately 6 subjects. 
Subjects will orally administer the assigned study drug (MLS-101 or placebo) according to the 
assigned dosing regimen for 8 weeks beginning on Study Day 1. All subjects in Part 1 
(regardless of dosing group) will receive BID dosing to preserve the integrity of the blind; 
active drug is administered as the morning dose for all QD dose groups. All subjects in Part 2 
will receive QD dosing to be administered in the morning. Subjects will return to the research 
facility or be seen by the clinical investigator or approved home health care professional at the 
end of Study Weeks 1, 2, 3, 4, 5, 6, 7, and 8 (± 2 days) for protocol-defined efficacy and safety 
assessments and procedures, assessment of AEs, and confirmation of compliance with study 
drug usage. Subjects will also complete a telephone visit and BP check at home approximately 
3 days post last dose of study drug. Subjects will attend up to 14 full clinic visits, including a 
pre-Screening visit, a Screening/start of Placebo Run-in visit, a second visit during Placebo 
Run-in, a clinic visit to initiate the ABPM procedure, a Randomization visit, 8 weekly visits 
during double-blind treatment, and an end-of-study visit scheduled 4 weeks after the last study 
treatment in Part 1 and 2 weeks after the last study treatment in Part 2 for final efficacy and 
safety assessments. Subjects should be in a fasted state for all study visits in Part 2 unless there 
is a medical reason not to fast as determined by the investigator. 
Safety Criteria for Dose Adjustment or Stopping Treatment: 
If, at any time during the study, a subject meets 1 or more of the clinical or laboratory exclusion 
criteria for the study (eg, seated SBP ≥ 175 mmHg or DBP ≥ 100 mmHg, serum potassium 
> 5.2 mEq/L, serum cortisol < 3 mcg/dL), laboratory test values will be confirmed using a local 
lab and BP measurements will be repeated. If laboratory exclusion criteria are met, the subject’s 
dose of study drug may be temporarily withheld, adjusted, or stopped by the investigator in 
consultation with the medical monitor. The subject will receive appropriate antihypertensive 
treatment if clinically indicated, and will remain in the study for further safety monitoring. 
Guidelines for dose adjustment/stopping in the management of hyperkalemia are included in 
Section 6.5.1. All subjects will be given dietary counseling to avoid foods high in potassium 
during the study (Appendix 12.6). Guidelines for the management of hypotension are included in 
Section 0. In addition, serum cortisol levels will be monitored throughout the study, and all 
subjects will be monitored for signs and symptoms of adrenal insufficiency (ie, nausea, vomiting, 
light-headedness, low BP, or electrolyte abnormalities) at every study visit. Based on changes in 
cortisol levels, an adrenocorticotropic hormone (ACTH) stimulation test (Appendix 12.7) may be 


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performed and the subject’s dose of study drug may be stopped. Guidelines for potential dose 
discontinuation in the management of adrenal insufficiency are included in Section 6.5.3. 
Subjects who wish to stop treatment for any reason may stop at any time during the study. If the 
study treatment is permanently discontinued, the subject will remain in the study to complete all 
study assessments as described in the schedule of assessments (SoA) (Table 1 and Table 2) 
through Study Week 8 (end-of-treatment visit). Subjects should also be encouraged to return for 
a final follow-up visit 4 weeks after the Study Week 8 visit for Part 1 and 2 weeks after the Study 
Week 8 visit for Part 2, at which the end-of-study assessments will be performed.  
An overview of the study design is presented in the Study Schema (Figure 1). Safety and 
efficacy assessments and study procedures are outlined in the SoA (Table 1 and Table 2). 
Detailed descriptions of study assessments are provided in Section 4.8 and Section 8. 
4.2. Scientific Rationale for Study Design 
The objective of Part 1 of the Phase 2 study is to evaluate both QD and BID dosing across a total 
daily dose of 12.5 mg to 100 mg for 8 weeks of treatment to determine at which doses substantial 
reductions in blood pressure occur and to determine if there is a dose response on BP with 
increasing doses. The dose range chosen was based on the Phase 1 study findings, and is 
considered to be a wide enough dose range to examine whether a dose-dependent response on 
BP could be observed. Further, we are interested in determining if BID dosing may be a better 
dosing regimen to sustain reductions in aldosterone over a 24-hour period, reduce any 
concomitant rise in trough aldosterone levels, and ultimately lead to a greater reduction in BP in 
patients. The examination of PK, PD (eg, aldosterone concentration), and BP at the doses 
proposed should enable a better understanding of dose requirements to be further examined in 
subsequent trials. 
The key efficacy endpoints, both primary and secondary, were selected to assess the changes in 
BP from baseline with treatment. The treatment period of 8 weeks was considered sufficient to 
assess the maximum effect on BP for a given dose and to assess safety. The assessment of BP, 
assessing changes in both systolic and diastolic BP, has been standard for previous BP trials with 
novel therapeutics. 
Data obtained from the interim analyses performed in Part 1 of the study will be used to inform 
Part 2. 
4.3. Number of Subjects/Number of Centers 
Approximately 1100 subjects will undergo up to 2 weeks of pre-Screening. For Part 1, it is 
estimated that approximately 270 subjects will have qualifying PRA and serum aldosterone 
levels to be eligible to enter Screening/start of Placebo Run-in, and (assuming an approximately 
40% screen failure rate) a total of approximately 160 subjects will meet all eligibility 
requirements to qualify for enrollment in Part 1 of the study. The subjects who qualify for 
enrollment will be randomly divided into 4 equal treatment groups (1:1:1:1 with approximately 
30 subjects per group, stratified by BP, ie, seated SBP ≤ 160 mmHg and seated SBP 
> 160 mmHg) across approximately 50 study centers in the United States. 
For Part 2, it is estimated that approximately 60 subjects will have qualifying PRA and serum 
aldosterone levels to be eligible to enter Screening/start of Placebo Run-in, and (assuming an 
approximately 40% screen failure rate) a total of 36 subjects will meet all eligibility 


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requirements to qualify for enrollment in Part 2 of the study. The subjects who qualify for 
enrollment will be randomized (5:1) to either 100 mg QD MLS-101 or placebo such that the 
MLS-101 treatment group will consist of approximately 30 subjects and the placebo treatment 
group will consist of approximately 6 subjects across approximately 10 study centers in the 
United States. 
4.4. Study Duration 
It is anticipated that each subject’s duration of participation in Part 1 will be approximately 16 
weeks (up to 2 weeks of pre-Screening followed by up to 2 weeks of a Screening/single-blind 
Placebo Run-in period, 8 weeks of double-blind treatment with study drug, and a 4-week follow-
up period). For Part 2, subject’s duration of participation will be approximately 16 weeks (up to 
4 weeks of pre-Screening, followed by up to 2 weeks of a Screening/single-blind Placebo Run-in 
period, 8 weeks of double-blind treatment with study drug, and a 2-week follow-up period). 
Total duration of the study will be approximately 21 months which includes periods for site 
activation, subject recruitment, treatment, and follow-up. 
4.5. Justification for Dose 
This Phase 2 study will evaluate both QD and BID dosing across a total daily dose of 12.5 mg to 
100 mg for 8 weeks of treatment to determine if there is a dose-response on BP with increasing 
doses. The dose range chosen was based on the Phase 1 study findings. It is considered to be a 
wide enough dose range to examine whether a dose-dependent response on BP can be observed, 
and to identify the minimum effective and maximum tolerated doses. Further, the study will 
examine if BID dosing may be a better dosing regimen to sustain reductions in aldosterone over 
a 24-hour period, reduce any concomitant rise in trough aldosterone levels, and ultimately lead to 
a greater reduction in BP in patients, whereas QD dosing may provide for a break in aldosterone 
inhibition within a 24-hour cycle to minimize changes in serum potassium without 
compromising blood pressure efficacy. 
The Phase 1 multiple ascending dose study demonstrated comparable physiological effects on 
mineralocorticoid-mediated renal tubular potassium reabsorption, a surrogate for sodium 
excretion and diuresis, at all dose levels tested from 40 mg QD through 360 mg QD. Based on 
these results, the upper end of the dose range to be tested in this study includes 50 mg QD, which 
is predicted to be efficacious at lowering BP, and 100 mg QD, which should result in a 
somewhat longer period of Cyp11B2 inhibition (10 hours versus 14 hours) while still providing a 
period of time during which the kidney can escape from inhibition and perform the aldosterone-
mediated function of regulating potassium homeostasis. The lower end of the dose range, 
12.5 mg QD, was selected based on in vitro potency and the ability to inhibit Cyp11B2 for at 
least 6 hours per day. This dose is anticipated to be submaximally effective in most 
individuals. The intermediate dosing regimens of 12.5 mg BID and 25 mg BID were selected to 
define the benefit/risk of BID versus QD dosing regimens with 12.5 mg BID and 25 mg BID 
providing temporarily more consistent inhibition of Cyp11B2. A PK/PD model was used to 
simulate steady state profiles and noncompartmental exposure parameters under several potential 
Phase 2 regimens. Details of the PK/PD model are included in the Investigator’s Brochure (IB). 
Based on additional modeling, 100 mg BID and 300 mg QD dosing regimens are not anticipated 
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The doses that are evaluated in this study will inform dose selection for further study in 
a randomized, double-blind, active-controlled Phase 2/3 study. 
4.6. End of Study Definition 
The end of study is defined as the date of the last visit of the last participant in the study. A 
participant is considered to have completed the study if he/she has completed all periods of the 
study including Visit 16 (end-of-study visit) at Study Week 12 and Study Week 10 for Parts 1 
and 2, respectively. 
At the time of study completion or early discontinuation, subjects will be queried regarding any 
AEs, concomitant medications, and concurrent procedures, which will be recorded on the 
appropriate page(s) of the source documents and electronic case report form (eCRF). At the final 
study visit, subjects with ongoing AEs that are considered by the investigator to be serious, study 
drug-related, or associated with the target area will be requested to continue to follow up with the 
investigator until the AE resolves, is stable, or follow-up is no longer possible/necessary. Any 
death that occurs while on study or within 30 days (Part 1) and 15 days (Part 2) after the 
subject’s last dose of study drug must be reported to the sponsor/designee for the study within 24 
hours after the center becomes aware of the event. 
4.7. Criteria for Study Termination 
Both the sponsor and the investigator reserve the right to terminate the study according to the 
study contract. The sponsor may issue a protocol amendment or discontinue the study entirely, 
based on regulatory authority or IRB/Independent Ethics Committee (IEC) recommendations, 
drug safety or availability concerns, discontinuation of the development program for MLS-101, 
or at the sponsor’s discretion with at least 30 days’ notice. The DSMB may also recommend 
study termination based on a review of the safety data. 
4.8. Study Conduct 
A schedule of study assessments is presented in Table 1. Details of study assessments are 
provided in Sections 4.8.1 to 4.8.15 and Section 8. Subjects should be in a fasted state for all 
study visits in Part 2 unless there is a medical reason not to fast as determined by the 
investigator. 
4.8.1. Pre-Screening (Visit 1, Study Days -28 to -14 for Part 1 or -42 to -14 for Part 2) 
Subjects with a history of hypertension, ie, SBP ≥ 135 mmHg, who meet the protocol definition 
for stable background treatment defined as ≥ 2 antihypertensives (note: a combination pill = 2 
antihypertensives) that have been stable at their prescribed doses for at least 4 weeks prior to 
signing the pre-Screening informed consent will enter up to 2 weeks of pre-Screening for Part 1 
and 4 weeks of pre-Screening for Part 2 upon completion of the IRB-approved pre-Screening 
informed consent and the following procedures will be performed:  
• Review medical history 
• Vital signs (body temperature, heart rate, respiratory rate) 
• AOBP (average of the last 2 of 5 unattended measurements using an automated oscillometric 
sphygmomanometer device after approximately 5 minutes of rest in the seated position) 


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• Blood draw – blood samples for aldosterone and PRA to be collected in the morning after at 
least 8 hours of fasting 
4.8.2. Screening/Start of Placebo Run-in (Visit 2/Visit 3, Study Day -14 ± 2 Days) 
All subjects with PRA and serum aldosterone values meeting the pre-Screening criteria (ie, PRA 
≤ 1 ng/mL/h and aldosterone ≥ 1 ng/dL for Part 1; PRA > 1 ng/mL/h and aldosterone ≥ 1 ng/dL 
for Part 2; or alternative target guidance provided by the sponsor) will be eligible to enter 
Screening/Placebo Run-in. The investigator (or appropriate delegate at the investigator site) will 
obtain Screening informed consent from each subject and the following procedures will be 
performed: 
• Inclusion/exclusion assessment 
• Review medical history 
• Physical examination 
• Vital signs (body temperature, heart rate, respiratory rate) 
• AOBP (average of the last 2 of 5 unattended measurements using an automated oscillometric 
sphygmomanometer device after approximately 5 minutes of rest in the seated position) 
• Standing BP assessment (Appendix 12.5) 
• Standard 12-lead electrocardiogram (ECG); ECG changes consistent with hyperkalemia will 
require confirmation of potassium levels at a local laboratory 
• Pregnancy test (serum; women of childbearing potential only; follicle stimulating hormone to 
confirm postmenopausal status in postmenopausal women)  
• Blood draw (Table 6) 
o Blood samples for aldosterone, cortisol, 11-deoxycorticosterone, 11-deoxycortisol, and 
PRA will be collected.  
o Blood samples for hematology, chemistry, and coagulation tests (coags) will be collected, 
including hemoglobin A1c concentration and ACTH 
o Blood samples for ACTH stimulation test (Appendix 12.7) 
• ACTH stimulation test (may be waived with sponsor’s approval) 
• Urine collection for urinalysis (Table 6) 
• Review of concomitant medications 
Once all Screening procedures are complete, subjects immediately enter the single-blind run-in 
period of BID (Part 1) or QD (Part 2) oral treatment with placebo while continuing to remain on 
stable doses of their background antihypertensive medications.  
4.8.3. Single-blind Placebo Run-In Week 2 (Visit 4, Study Day -7 ± 2 Days) 
Subjects will return to the research facility at the beginning of Week 2 of the run-in period for 
the following procedures: 
• Inclusion/exclusion assessment (based on Screening assessment results from V2/V3). If 
Screening results are available, and subject is determined to be ineligible for the study, the 
site will review AEs, concomitant medications, and study drug compliance. Vital signs and 
AOBP will not be performed. 
• Vital signs (body temperature, heart rate, respiratory rate) only if subject is eligible for the 
study or if Screening results are not yet available 


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• AOBP (average of the last 2 of 5 unattended measurements using an automated oscillometric 
sphygmomanometer device after approximately 5 minutes of rest in the seated position) only 
if subject is eligible for the study or if Screening results are not yet available 
• Review of AEs, concomitant medications, and study drug compliance for all subjects 
regardless of eligibility status 
Subjects will be evaluated for eligibility based on Screening results and if eligible, or if 
Screening results are not available, subjects will continue on Week 2 of Placebo Run-in and will 
be given an ABPM device and instructions on how to perform the ABPM procedure by the 
investigator to take home for use on Study Day 0, approximately 24 hours before Randomization 
(Study Day 1). Note: only subjects who have Screening results and are considered eligible 
should be provided with the ABPM for home use. Subjects who do not have Screening results 
available should attend Visit 5. In addition, subjects will be given either a spot urine collection 
kit for Part 1 or a 24-hour urine collection kit for Part 2 to take home for use on Study Day 1. In 
Part 1 of the study, first morning urine will be collected prior to morning dose of study drug on 
Study Day 1 and again at the end of Study Week 8 (ie, Study Day 56 ± 2 or end-of-treatment 
period) for determination of potassium, sodium, and creatinine levels. In Part 2 of the study, 24-
hour urine collection will be performed on Study Day 1 and again at the end of Study Week 4 
(ie, Visit 10, Study Day 28 ± 2) for determination of potassium, sodium, creatinine, and 
aldosterone levels. 
4.8.4. Telephone or Office Visit (Visit 5, Study Day 0) 
After completion of the single-blind, Placebo Run-in period, subjects will participate in a 
telephone or office visit on Study Day 0 in which they will be reminded how to perform the 
ABPM and spot urine collection procedures by the investigator or study coordinator. If 
Screening results were not available at Placebo Run-in Visit 4, subjects should participate in an 
office visit to review eligibility. If eligible, ABPM procedure will be initiated. The following 
procedures will be performed: 
• Inclusion/exclusion assessment (if necessary) 
• 24-hour ABPM 
4.8.5. Randomization/Baseline (Visit 6, Study Day 1) 
After first morning spot (Part 1) or 24-hour (Part 2) urine collection at home, subjects will return 
to the clinic on Study Day 1 (morning visit), and those who continue to meet all eligibility 
requirements will be randomized to MLS-101 or placebo and the following procedures 
performed prior to administration of the initial morning dose of study drug: 
• Inclusion/exclusion assessment 
• Physical examination 
• Vital signs (body temperature, heart rate, respiratory rate) 
• AOBP (average of the last 2 of 5 unattended measurements using an automated oscillometric 
sphygmomanometer device after approximately 5 minutes of rest in the seated position) 
• Standing BP assessment (Appendix 12.5) 
• Spot urine collection (Part 1 only) 
• 24-hour urine collection (Part 2 only) 


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• Standard 12-lead ECG; ECG changes consistent with hyperkalemia will require confirmation 
of potassium levels at a local laboratory 
• Pregnancy test (urine; women of childbearing potential only)  
• Blood draw (Table 6) 
o Blood samples for aldosterone, cortisol, 11-deoxycorticosterone, 11-deoxycortisol, and 
PRA will be collected 
o Blood samples for hematology, chemistry, and coags will be collected, including 
hemoglobin A1c concentration and ACTH  
o Single blood samples for determination of MLS-101 will be collected. Additional blood 
samples for long-term storage for metabolites, drug-drug interaction profiles of 
background therapy, or other exploratory analyses will also be collected.  
o Serial PK sampling – if subject consents to additional blood draws, blood samples for 
determination of MLS-101 (and metabolites) are to be collected predose, and 1, 2, 3, and 
4 hours postdose. 
• Urine collection for urinalysis (Table 6) 
• Review of AEs, concomitant medications, and study drug compliance 
4.8.6. Study Week 1 (Visit 7, Study Day 7 ± 2 Days) 
On Study Day 7 ± 2 days, subjects will return to the site and the following procedures will be 
performed prior to site administration of the morning dose of study drug: 
• Vital signs (body temperature, heart rate, respiratory rate) 
• AOBP (average of the last 2 of 5 unattended measurements using an automated oscillometric 
sphygmomanometer device after approximately 5 minutes of rest in the seated position) 
• Standing BP assessment (Appendix 12.5) 
• Blood draw (Table 6) 
o Blood samples for hematology, chemistry, and coags will be collected, including 
hemoglobin A1c concentration, cortisol, and ACTH  
o Single blood samples for determination of MLS-101 will be collected. Additional blood 
samples for long-term storage for metabolites, drug-drug interaction profiles of 
background therapy, or other exploratory analyses will also be collected. 
• Urine collection for urinalysis (Table 6) 
• Review of AEs, concomitant medications, and study drug compliance 
4.8.7. Study Week 2 (Visit 8, Study Day 14 ± 2 Days) 
On Study Day 14 ± 2 days, subjects will return to the site and the following procedures will be 
performed prior to site administration of the morning dose of study drug: 
• Vital signs (body temperature, heart rate, respiratory rate) 
• AOBP (average of the last 2 of 5 unattended measurements using an automated oscillometric 
sphygmomanometer device after approximately 5 minutes of rest in the seated position) 
• Blood draw - blood samples for hematology, chemistry, and coags will be collected, 
including hemoglobin A1c concentration, cortisol, and ACTH (Table 6) 
• Urine collection for urinalysis (Table 6) 


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• Review of AEs, concomitant medications, and study drug compliance 
4.8.8. Study Week 3 (Visit 9, Study Day 21 ± 2 Days) 
On Study Day 21 ± 2 days, subjects will return to the site and the following procedures will be 
performed prior to site administration of the morning dose of study drug: 
• Vital signs (body temperature, heart rate, respiratory rate) 
• AOBP (average of the last 2 of 5 unattended measurements using an automated oscillometric 
sphygmomanometer device after approximately 5 minutes of rest in the seated position) 
• Blood draw – blood samples for hematology, chemistry, and coags will be collected, 
including hemoglobin A1c concentration, cortisol, and ACTH (Table 6) 
• Urine collection for urinalysis (Table 6) 
• Review of AEs, concomitant medications, and study drug compliance 
4.8.9. Study Week 4 (Visit 10, Study Day 28 ± 2 Days) 
On Study Day 28 ± 2 days, subjects will return to the site and the following procedures will be 
performed prior to site administration of the morning dose of study drug: 
• Vital signs (body temperature, heart rate, respiratory rate) 
• AOBP (average of the last 2 of 5 unattended measurements using an automated oscillometric 
sphygmomanometer device after approximately 5 minutes of rest in the seated position) 
• Initiate 24-hour ABPM (Part 2 only) 
• 24-hour urine collection (Part 2 only) 
• Blood draw (Table 6) 
o Blood samples for aldosterone, cortisol, 11-deoxycorticosterone, 11-deoxycortisol, and 
PRA will be collected 
o Blood samples for hematology, chemistry, and coags will be collected, including 
hemoglobin A1c concentration and ACTH  
o Single blood samples for determination of MLS-101 will be collected. Additional blood 
samples for long-term storage for metabolites, drug-drug interaction profiles of 
background therapy, or other exploratory analyses will also be collected.  
o Serial PK sampling – if subject consents to additional blood draws, blood samples for 
determination of MLS-101 (and metabolites) are to be collected predose, and 1, 2, 3, and 
4 hours postdose. 
• Urine collection for urinalysis (Table 6) 
• Pregnancy test (urine; women of childbearing potential only) 
• Review of AEs, concomitant medications, and study drug compliance 
4.8.10. Study Week 5 (Visit 11, Study Day 35 ± 2 Days) 
On Study Day 35 ± 2 days, subjects will return to the site and the following procedures will be 
performed prior to site administration of the morning dose of study drug: 
• Vital signs (body temperature, heart rate, respiratory rate) 
• AOBP (average of the last 2 of 5 unattended measurements using an automated oscillometric 
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• Blood draw – blood samples for hematology, chemistry, and coags will be collected, 
including hemoglobin A1c concentration, cortisol, and ACTH (Table 6) 
• Urine collection for urinalysis (Table 6) 
• Review of AEs, concomitant medications, and study drug compliance 
4.8.11. Study Week 6 (Visit 12, Study Day 42 ± 2 Days) 
On Study Day 42 ± 2 days, subjects will return to the site and the following procedures will be 
performed prior to site administration of the morning dose of study drug: 
• Vital signs (body temperature, heart rate, respiratory rate) 
• AOBP (average of the last 2 of 5 unattended measurements using an automated oscillometric 
sphygmomanometer device after approximately 5 minutes of rest in the seated position) 
• Blood draw – blood samples for hematology, chemistry, and coags will be collected, 
including hemoglobin A1c concentration, cortisol, and ACTH (Table 6) 
• Urine collection for urinalysis (Table 6) 
• Review of AEs, concomitant medications, and study drug compliance 
4.8.12. Study Week 7 (Visit 13, Study Day 49 ± 2 Days) 
On Study Day 49 ± 2 days, subjects will return to the site and the following procedures will be 
performed prior to site administration of the morning dose of study drug: 
• Vital signs (body temperature, heart rate, respiratory rate) 
• AOBP (average of the last 2 of 5 unattended measurements using an automated oscillometric 
sphygmomanometer device after approximately 5 minutes of rest in the seated position) 
• Initiate 24-hour ABPM 
• Blood draw – blood samples for hematology, chemistry, and coags will be collected, 
including hemoglobin A1c concentration, cortisol, and ACTH (Table 6) 
• Urine will be collected for urinalysis (Table 6) 
• Review of AEs, concomitant medications, and study drug compliance 
4.8.13. Study Week 8 (Visit 14, Study Day 56 ± 2 Days) 
At the Study Week 8 visit (Visit 14), subjects will begin 24-hour ABPM procedure. On Study 
Day 56 ± 2 days, subjects will return to the site and the following procedures will be performed 
prior to site administration of the morning dose of study drug: 
• Physical examination 
• Vital signs (body temperature, heart rate, respiratory rate) 
• AOBP (average of the last 2 of 5 unattended measurements using an automated oscillometric 
sphygmomanometer device after approximately 5 minutes of rest in the seated position) 
• Standing BP assessment (Appendix 12.5) 
• Repeat 24-hour ABPM if procedure at Study Week 7 deemed a failure 
• Spot urine collection (Part 1 only) 
• Standard 12-lead ECG; ECG changes consistent with hyperkalemia will require confirmation 
of potassium levels at a local laboratory 
• Pregnancy test (urine; women of childbearing potential only)  
• Blood draw (Table 6) 


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o Blood samples for hematology, chemistry, and coags will be collected, including 
hemoglobin A1c concentration, cortisol, and ACTH 
o Single blood samples for determination of MLS-101 will be collected. Additional blood 
samples for long-term storage for metabolites, drug-drug interaction profiles of 
background therapy, or other exploratory analyses will also be collected. 
o Blood samples for ACTH stimulation test (Appendix 12.7) 
• ACTH stimulation test (may be waived with sponsor’s approval) 
• Urine collection for urinalysis (Table 6) 
• Review of AEs, concomitant medications, and study drug compliance 
4.8.14. Telephone Visit (Visit 15, BP check; Study Day 59 + 2 Days) 
Subjects will complete a BP check approximately 3 days post last dose of study drug. On Study 
Day 59 ± 2 days, subjects will participate in a telephone visit during which they will perform the 
following procedure at home: 
• BP check  
4.8.15. Study Week 10 (Part 2 Only: Visit 16, End of Study; Study Day 70 ± 3 Days) 
On Study Day 70 ± 3 days, subjects will return to the site for an end-of-study visit scheduled 
2 weeks after the last treatment with study drug and the following procedures will be performed: 
• Vital signs (body temperature, heart rate, respiratory rate) 
• AOBP (average of the last 2 of 5 unattended measurements using an automated oscillometric 
sphygmomanometer device after approximately 5 minutes of rest in the seated position) 
• Blood draw (Table 6) 
o Blood samples for aldosterone, cortisol, 11-deoxycorticosterone, 11-deoxycortisol, and 
PRA will be collected  
o Blood samples for hematology, chemistry, and coags will be collected, including 
hemoglobin A1c concentration and ACTH 
• Urine will be collected for urinalysis (Table 6) 
• Review of AEs and concomitant medications  
4.8.16. Study Week 12 (Part 1 Only: Visit 16, End of Study; Study Day 84 ± 3 Days) 
On Study Day 84 ± 3 days, subjects will return to the site for an end-of-study visit scheduled 
4 weeks after the last treatment with study drug and the following procedures will be performed: 
• Vital signs (body temperature, heart rate, respiratory rate) 
• AOBP (average of the last 2 of 5 unattended measurements using an automated oscillometric 
sphygmomanometer device after approximately 5 minutes of rest in the seated position) 
• Blood draw (Table 6) 
o Blood samples for aldosterone, cortisol, 11-deoxycorticosterone, 11-deoxycortisol, and 
PRA will be collected  
o Blood samples for hematology, chemistry, and coags will be collected, including 
hemoglobin A1c concentration and ACTH 


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• Urine will be collected for urinalysis (Table 6) 
• Review of AEs and concomitant medications  
4.9. Modifications to Study Conduct Due to the Coronavirus Disease 2019 (COVID-19) 
Pandemic 
As a consequence of the COVID-19 pandemic that has had a worldwide impact, control 
measures in place may impact the ability to adhere to some of the study procedures described in 
this protocol. Due to challenges that include, but are not limited to, subject COVID-19 
infections, site closures, travel restrictions, and quarantines, some modifications to study conduct 
during the COVID-19 pandemic may be necessary to ensure study continuity, including 
conducting virtual visits when on-site study visits are considered not feasible. Such 
modifications in study conduct always must be in accordance with local regulations/mandates. 
The following are allowable, as necessary, modifications to study conduct during the COVID-19 
pandemic: 
• Prior to a study visit at the site, the subject may be contacted and screened for potential 
exposure or infection to COVID-19 per site, local, or federal requirements. If the subject is 
suspected to be exposed or infected with COVID-19, the on-site visit should either be re-
scheduled or a virtual visit may be performed instead, as applicable. 
• In the event that a subject cannot attend their regularly scheduled study visits in person due to 
COVID-19 necessitating a limit on in-person contact, the investigator may perform safety 
and efficacy assessments by phone or video. The investigator may use the technology 
platform that is currently available to them. Virtual assessments may include home blood 
pressure evaluation initiated by the subject, adverse events, and concomitant medication 
review. Virtual assessments will be recorded by site staff in the source documents. 
• Clinical laboratory tests (chemistry and hematology) and pregnancy tests may be performed 
by local laboratory, if sample collection cannot be performed at the study site due to COVID-
19 related limitations, including but not limited to site closure. Abnormal laboratory results 
should be promptly communicated to the medical monitor. Subjects’ anonymity must be 
maintained when communicating results to the medical monitor.  
• At home IP administration may continue for up to 2 weeks (at multiple times during the 
study if required due to COVID-19, although not consecutively) if the subject has no relevant 
clinically significant out of range values per previous lab reports. 
• Source documentation should note that the visit was performed virtually (not face-to-face) 
and note the name of the local lab where laboratory tests were done, if applicable. 
• If certain study procedures or assessments cannot be completed per the schedule of events, 
the reason for the missed assessment (ie, laboratory tests, vital signs, physical examinations, 
etc) must be noted in the source documentation (eg, COVID-19), captured in the protocol 
deviations documentation, and reported to the IRB, as applicable. 
A detailed assessment of COVID-19 related risk and mitigation measures will be documented in 
the appropriate study plans. 


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5. STUDY POPULATION 
5.1. Inclusion Criteria 
1. Male and nonpregnant, nonlactating female subjects ≥ 18 years of age. Fertile male 
and female subjects and their partners must agree to use either highly effective or 
acceptable methods of contraception as defined in Appendix 12.8 from Screening to 
90 days post last dose of study drug 
2. Written informed consent Health Insurance Portability and Accountability Act 
authorization, and local patient privacy required documentation for this study have 
been obtained 
3. Average of AOBP measurements taken at Screening/start of the Placebo Run-in Visit 
and Randomization with SBP ≥ 130 mmHg 
4. Background antihypertensive treatment of ≥ 2 drugs (note: a combination pill = 2 
antihypertensives) that have been stable at their prescribed doses for at least 4 weeks 
prior to signing the Screening/main study ICF 
5. For Part 1, inclusion based on morning pre-Screening visit measurement of PRA, and 
the value for PRA must be ≤ 1 ng/mL/h. For Part 2, inclusion based on morning pre-
Screening visit measurement of PRA, and the value of PRA must be > 1 ng/mL/h. 
Alternative target PRA criteria for the study may be provided by the sponsor. These 
alternative targets may be adjusted during the conduct of the trial based on ongoing 
review of PRA values.   
6. Inclusion based on morning pre-Screening visit measurement of serum aldosterone 
for Part 1 and pre-Screening visit measurement of aldosterone for Part 2. The value 
for aldosterone must be ≥ 1 ng/dL based on morning measurement. Alternative target 
aldosterone criteria for the study may be provided by the sponsor. These alternative 
targets may be adjusted during the conduct of the trial based on ongoing review of 
serum aldosterone values.   
7. Serum cortisol ≥ 18 mcg/dL (morning measurement) or serum cortisol > 3 and 
< 18 mcg/dL (morning measurement) at Screening/start of Placebo Run-in visit if 
there is no evidence of adrenal insufficiency based on normal ACTH stimulation test 
results. In the event that ACTH stimulation testing cannot be performed due to 
logistical challenges, including supply chain limitations to availability of synthetic 
ACTH, then subjects may be entered into the trial if morning serum cortisol is > 3 
mcg/dL and they fulfill the criteria for no recent use of exogenous corticosteroid 
medications in dosages that could potentially cause adrenal suppression (ie, Exclusion 
Criteria 16a). 
8. Women of childbearing potential must have a negative serum pregnancy test prior to 
Randomization 
9. Willing and able to comply with the study instructions and attend all scheduled study 
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5.2. Exclusion Criteria 
1. Concomitant use of epithelial sodium channel inhibitors or mineralocorticoid receptor 
antagonists, including, but not limited to amiloride, triamterene, spironolactone, 
eplerenone 
2. Use of ACE inhibitors and ARBs in combination (ie, concomitant ACE inhibitors 
plus ARB therapy) as background antihypertensive treatment 
3. Subjects with hypokalemia, ie, serum potassium < 3.0 mEq/L at Screening  
4. Subjects with hyperkalemia, ie, serum potassium > 5.2 mEq/L at Screening for Part 1 
and > 4.8 mEq/L at Screening for Part 2 
5. Subjects with serum cortisol < 3 mcg/dL based on morning measurement at 
Screening 
6. Subjects with serum sodium < 135 mEq/L at Screening 
7. Subjects with estimated glomerular filtration rate < 60 mL/min/1.73m2 at Screening  
8. Subjects with type 1 or uncontrolled (hemoglobin A1c ≥ 9%) type 2 diabetes mellitus 
9. Subjects with body mass index > 40 kg/m2 
10. Subjects with unstable angina who are taking short-acting oral or sublingual 
nitroglycerin or who have history of myocardial infarction or stroke within 6 months 
of Screening, sustained atrial fibrillation, ie, lasting > 12 months, or permanent atrial 
fibrillation; paroxysmal atrial fibrillation that terminates spontaneously or with 
intervention within 7 days is allowed. Chronic long-acting oral nitrates that have been 
stable at their prescribed doses for at least 2 weeks prior to signing the 
Screening/main study ICF are allowed. 
11. Subjects with office SBP ≥ 175 mmHg or DBP ≥ 100 mmHg for Part 1 and SBP 
≥ 160 mmHg or DBP ≥ 100 mmHg for Part 2 (average of last 2 of 5 unattended 
measurements using an automated oscillometric sphygmomanometer device after 
approximately 5 minutes of rest in the seated position) at Pre-Screening, 
Screening/Start of Placebo Run-in, or Randomization 
12. Subjects with a decrease in SBP ≥ 20 mmHg or DBP ≥ 10 mmHg from sitting to 
standing position at Screening (may be repeated during Screening at the investigator’s 
discretion) 
13. Subjects who, in the opinion of the investigator, have suspected nonadherence to 
antihypertensive treatment 
14. Subjects who, in the opinion of the investigator, have any major medical illness or 
symptoms of a clinically significant illness that may limit their ability to complete the 
study or influence subject safety and/or the study outcome (eg, active malignancy, 
HIV infection) 
15. Subjects who, in the opinion of the investigator, have any acute or chronic medical or 
psychiatric condition or laboratory abnormality that would make them unsuitable for 
participation in this study or that would place the subject at undue risk (eg, history of 


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drug, alcohol, or other substance abuse) or who have other factors limiting the ability 
of the subject to cooperate and to comply with this protocol 
16. Subjects undergoing treatment with any of the following medications: 
a. 
Chronically administered oral or topical corticosteroids within 3 months of 
Screening or during study participation. Short-term (ie, ≤ 2 weeks) of topical 
corticosteroids are allowed if taken ≥ 1 month prior to Randomization. 
b. 
Sympathomimetic decongestants within 1 week of Screening or during study 
participation 
c. 
Theophylline unless treatment has been stable at optimum dose for at least 4 
weeks prior to Screening and remains stable during study participation  
d. 
Regular use of phosphodiesterase type 5 inhibitors within 3 months of Screening 
or during study participation  
e. 
Chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs), other than low 
dose aspirin (81-325 mg), where chronic use is defined as > 3 consecutive or 
nonconsecutive days of treatment per week, within 2 weeks of Screening. Note: 
intermittent use of NSAIDs is strongly discouraged; if required, NSAIDs must 
not be taken more than a total of 2 days during the study (defined as the period 
from Randomization to the end of study period). If analgesics are required, 
acetaminophen is recommended. 
f. 
Intramuscular steroids within 3 months of Screening or during study 
participation 
g. 
Estrogen- or progesterone-containing oral contraceptives or implantable 
progesterone devices 
h. 
Strong CYP3A and CYP3A4 inhibitors (eg, clarithromycin, telithromycin, 
nefazodone, itraconazole, ketoconazole, atazanavir, darunavir, indinavir, 
lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir) 
i. 
Strong CYP3A and CYP3A4 inducers (eg, apalutamide, carbamazepine, 
enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin, 
primidone, rifampin, St. John’s Wort) 
17. Subjects with known hypersensitivity to MLS-101 or any of the excipients 
18. Subjects who are night-shift workers 
19. Subjects who are unable to comply with protocol requirements, including treatment 
compliance and instructions for ABPM 
20. Subjects who are currently enrolled in an investigational drug or device study or have 
used an investigational drug or an investigational device treatment within 4 weeks of 
Screening (Note: Subjects who are enrolled in a long-term follow-up study and are 
not actively receiving an investigational drug or investigational device treatment may 
be eligible for participation in this study) 


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5.3. Lifestyle Considerations 
5.3.1. Meals and Dietary Restrictions 
Dietary counseling reflecting the current standard of care will be provided to all subjects at each 
visit according to the instructions described in Appendix 12.6. 
5.3.2. Caffeine, Alcohol, and Tobacco 
• Subjects will abstain from ingesting caffeine- or xanthine-containing products (eg, coffee, 
tea, cola drinks, and chocolate) for 30 minutes before the start of BP measurement and 
12hours before the start of dosing until after collection of the final PK (on Study Days 1, 7 ± 
2, and 28 ± 2) and/or PD (at Pre-Screening, Screening/start of Placebo Run-in, and on Study 
Days 1, 28 ± 2, and 84 ± 3) sample. 
• Subjects will abstain from alcohol for 30 minutes before the start of BP measurement and 24 
hours before the start of dosing until after collection of the final PK (on Study Days 1, 7 ± 2, 
and 28 ± 2) and/or PD (at Pre-Screening, Screening/start of Placebo Run-in, and on Study 
Days 1, 28 ± 2, and 84 ± 3). 
• Subjects who use tobacco products will be instructed that use of nicotine-containing products 
(including nicotine patches or gums and e-cigarettes) will not be permitted while they are in 
the clinical unit. Subjects will abstain from smoking for 30 minutes before the start of BP 
measurement. 
5.3.3. Activity/Exercise 
Subjects will abstain from strenuous exercise for 30 minutes before the start of BP measurement 
and for 24 hours before each blood collection for clinical laboratory tests. Subjects may 
participate in light recreational activities (eg, watching television, reading). 
5.4. Screen Failures 
Screen failures are defined as study participants who consent to participate in the clinical study, 
but are not subsequently randomly assigned to treatment/entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure 
participants to meet the Consolidated Standards of Reporting Trials publishing requirements and 
to respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any serious adverse event (SAE). Individuals who 
do not meet the Screening criteria for participation in this study (screen failures) may be 
rescreened up to 3 times.  


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6. STUDY DRUG ADMINISTRATION AND MANAGEMENT 
6.1. Study Drug Administration 
6.1.1. Description of Study Drug 
The study drug product is an immediate release formulation containing standard excipients 
generally recognized as safe including bulking agent, disintegrant, glidant, and lubricant that are 
compressed into a tablet. The MLS-101 tablet contains 12.5 to 100 mg of MLS-101 drug 
substance (as a free-base form: 
). The MLS-101 tablet and matching placebo tablet 
are round, white, film-coated tablets with no identifying mark. MLS-101 tablets of 12.5 mg, 
25 mg, and 100 mg and placebo tablets are packaged in either 30 count 60 cc white round high 
density polyethylene bottles with a child-resistant cap or polyvinyl chloride/Aclar blisters with 
foil backing and 7 tablets per blister strip. Packaged tablets will be assigned a unique identifying 
number, used by the interactive web response system (IWRS) to identify the content but 
maintaining the blind of the subject and site. The test materials will be identified by the lot, batch 
numbers, retest date, and certificate of analysis. 
6.1.2. Dosing and Administration 
Placebo Run-In: In Part 1, upon signing the Screening/main study ICF, subjects will begin a 
single-blind (subjects blinded to treatment allocation), up to 2-week run-in period of BID oral 
treatment with placebo, while continuing to remain on stable doses of their background 
antihypertensive medications. Subjects will orally administer placebo morning and evening, 
approximately 12 hours apart. On site visit days, subjects should be instructed to take their 
morning dose of study drug at the site. In Part 2, upon signing the Screening/main study ICF, 
subjects will begin a single-blind (subjects blinded to treatment allocation), up to 2-week run-in 
period of QD oral treatment with placebo, while continuing to remain on stable doses of their 
background antihypertensive medications. 
8-Week Treatment Period: In Part 1, subjects will orally administer the assigned study drug 
(MLS-101 [25 mg BID, 50 mg QD, 100 mg QD] or placebo) according to the assigned dosing 
regimen for 8 weeks beginning on Study Day 1. To maintain the integrity of the blind, all 
subjects (regardless of dosing group) will orally administer study drug morning and evening, 
approximately 12 hours apart; active drug is administered as the morning dose for all QD dose 
groups. Subjects will be monitored by ABPM for 24 hours before the first morning dose on 
Study Day 1 and for 24 hours after the morning dose on Study Day 49 ± 2 days (end of Week 7). 
On site visit days, subjects should be instructed to take their morning dose of study drug at the 
site. In Part 2, subjects will orally administer the assigned study drug (MLS-101 [100 mg QD] or 
placebo) according to the assigned dosing regimen for 8 weeks beginning on Study Day 1. 
Subjects will be monitored by ABPM for 24 hours before the first morning dose on Study Day 1, 
for 24 hours beginning on Study Day 28 ± 2 days (Week 4), and for 24 hours after the morning 
dose on Study Day 49 ± 2 days (end of Week 7). 
6.2. Preparation, Handling, Storage, and Accountability 
6.2.1. Study Drug Preparation 
Not applicable. 


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6.2.2. Study Drug Packaging and Labeling 
PCI Clinical Services will label, pack and release study drug in accordance with the Clinical 
Trials Directive 2001/20/EC and Good Manufacturing Practice Directive 2003/94/EC for 
Investigational Medicinal Products.  
As this is a double-blind study, labeling of the tablet package will not show the treatment 
allocation. All other information required by regulation will appear on the label. 
6.2.3. Study Drug Handling and Disposal 
All study drug supplies are to be used only for this clinical study and not for any other purpose. 
Authorized study personnel must maintain a full record of study drug disposition (ie, a log by 
date received, dispensation date and subject, date of return from the subject, and detailed study 
drug usage by each study subject). 
After reconciliation, used study drug will be returned according to instructions provided by the 
sponsor. At study conclusion, all remaining used supplies will be similarly returned and 
disposed. Authorized study personnel will record any unaccounted supplies in the final 
accountability records.  
6.2.4. Study Drug Storage  
The study drug should be stored at room temperature (59°F to 77°F [15°C to 25°C]) in an 
approved storage area with access limited to authorized study personnel. 
6.2.5. Study Drug Accountability 
Study drug (including placebo) will be maintained under adequate security by appropriate site 
personnel (eg, pharmacist) and in accordance with applicable regulatory requirements. Study 
drug remaining at the end of the study will be returned to the sponsor or their representative, or 
destroyed on behalf of the sponsor.  
The investigator or designee must maintain adequate records of receipt and distribution of all 
study drug, using appropriate accountability records. 
6.3. Randomization and Blinding 
All subjects who qualify for Part 1 based on inclusion/exclusion criteria and complete up to a 2-
week Placebo Run-in period and 24-hour ABPM procedure will be randomized into 4 equal 
treatment groups (1:1:1:1) to 25 mg BID, 50 mg QD, 100 mg QD, or placebo; each treatment 
group will consist of approximately 30 subjects stratified by BP (seated SBP ≤ 160 mmHg and 
seated SBP > 160 mmHg). All subjects who qualify for Part 2 based on inclusion/exclusion 
criteria and complete up to a 2-week Placebo Run-in period and 24-hour ABPM procedure will 
be randomized (5:1) to either 100 mg QD MLS-101 or placebo such that the MLS-101 treatment 
group will consist of approximately 30 subjects and the placebo treatment group will consist of 
approximately 6 subjects.. The sponsor will arrange for Randomization of study subjects by 
study drug dosage group and treatment assignment. Randomization numbers and study drug 
supplies will be assigned using IWRS. Access to the Randomization codes will be controlled and 
documented. 


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The study will be conducted in a double-blind manner so that neither the center personnel nor the 
subject is aware of which treatment is administered. The identity of study drug assignments 
(MLS-101 or placebo) will be concealed from the investigator, the subject, research center staff, 
and all personnel involved in the conduct of the study, with the exception of the unblinded 
sponsor drug management staff who will oversee the study drug allocations and 
IWRS/dispensing compliance at the study centers. 
Except when it is essential for the medical management of the subject, unblinding the treatment 
assignment will be considered a protocol deviation. Emergency treatment allocation information 
will be available by secured access to the IWRS system. If possible, the investigator should 
contact the sponsor before unblinding any subject’s treatment assignment. In the event that this is 
not possible, the sponsor should be notified within 24 hours after the unblinding event. After 
unblinding, the subject will be discontinued from study drug treatment and will undergo Study 
Week 8 (end-of-treatment) assessments. Subjects will be asked to return for final follow-up 
approximately 4 weeks later (ie, Study Week 12/end-of-study visit). The reason for unblinding 
must be documented in the eCRF. 
6.4. Study Drug Compliance 
Compliance with study drug will be assessed at each visit. Compliance will be assessed by direct 
questioning and counting returned tablets during the site visits and documented in the source 
documents and relevant case report form. Deviation(s) from the prescribed dosage regimen 
should be recorded. 
A record of the quantity of study drug dispensed to and administered by each subject must be 
maintained and reconciled with study intervention and compliance records. Study drug start and 
stop dates, including dates for study drug delays and/or dose reductions will also be recorded. 
6.5. Dose Modification 
In general, if, at any time during the study, a subject meets 1 or more of the laboratory exclusion 
criteria for the study (eg, seated SBP ≥ 175 mmHg or DBP ≥ 100 mmHg, serum potassium 
> 5.2 mEq/L, serum cortisol < 3 mcg/dL), laboratory test values will be confirmed using a local 
lab and BP measurements will be repeated at home. If laboratory exclusion criteria are met, the 
subject’s dose of study drug may be temporarily withheld, adjusted, or stopped by the 
investigator in consultation with the medical monitor. The subject will receive appropriate 
antihypertensive treatment if clinically indicated, and will remain in the study for further safety 
monitoring. Guidelines for dose reduction/stopping in the management of hyperkalemia are 
included in Section 6.5.1. All subjects will be given dietary counseling to avoid foods high in 
potassium during the study (Appendix 12.6). Guidelines for the management of hypotension are 
included in Section 0. In addition, serum cortisol levels will be monitored throughout the study, 
and all subjects will be monitored for signs and symptoms of adrenal insufficiency (ie, nausea, 
vomiting, light-headedness, low BP, or electrolyte abnormalities) at every study visit. Based on 
changes in cortisol levels, an ACTH stimulation test (Appendix 12.7) may be performed and the 
subject’s dose of study drug may be stopped. Guidelines for potential dose discontinuation in the 
management of adrenal insufficiency are included in Section 6.5.3.  


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6.5.1. Hyperkalemia 
If serum potassium level is elevated at the central laboratory measurement, the following actions 
are to be taken: 
• Serum potassium > 5.2 and ≤ 5.5 mEq/L: Retest at local lab to confirm. If potassium remains 
elevated, reduce the MLS-101 dose according to Table 3 (first dose-reduced level). Wait 2 to 
7 days, then retest. If potassium remains elevated, reduce the MLS-101 dose again according 
to Table 3 (second dose-reduced level). 
• Serum potassium > 5.5 and ≤ 6 mEq/L: Retest at local lab to confirm. If potassium remains 
elevated, hold dose. Wait 2 to 7 days, then retest. If potassium ≤ 5.2 mEq/L, resume dosing. 
If potassium > 5.2 mEq/, continue to hold dose. Wait 2 to 7 days, then retest. If potassium 
≤ 5.2 mEq/L after second retest, restart at first dose-reduced level according to Table 3. If 
potassium > 5.2 mEq/L after second retest discontinue study drug. 
• Serum potassium > 6 mEq/L: Hold study drug dose and bring subject in for an unscheduled 
study visit for safety ECG and serum potassium retest at local lab; subject attends next 
regularly scheduled visit. If potassium from local lab retest ≤ 5.2 mEq/L, resume dosing. If 
potassium > 5.2 mEq/L, contact the sponsor’s medical monitor for further guidance. 
Note: If a retest of serum potassium level falls into a higher range than the original test, follow 
the instructions for the higher potassium range. 
Table 3: MLS-101 Dose Reduction Schedule 
Assigned Dose Level  
First Dose-reduced Level 
Second Dose-reduced Level 
25 mg BID 
12.5 mg BID 
0 
50 mg QD 
12.5 mg QD 
0 
100 mg QD 
50 mg QD 
25 mg QD 
BID = twice daily; QD = once daily 
 
6.5.2. Hypotension 
6.5.2.1. 
Orthostatic Hypotension 
Standardized assessment of standing BP will be performed at Screening/start of Placebo Run-in, 
Randomization, Study Week 1, and Study Week 8 as described in Appendix 12.5. In addition, 
assessment of standing BP will be performed if a subject reports symptoms of hypotension (eg, 
light-headedness, dizziness, presyncope, or syncope) during the study, and the standing BP 
measurement will be assessed weekly for these subjects until symptoms resolve.  
Orthostatic hypotension is defined as a decrease in SBP ≥ 20 mmHg or DBP ≥ 10 mmHg from 
sitting to standing position within 3 minutes of standing. If subjects experience orthostatic 
hypotension with symptoms (eg, light-headedness, dizziness, presyncope, or syncope) during the 
study, it will be medically managed by the investigator; adjustment to background therapy and/or 
dose reduction of study drug according to Table 3 may be considered.  


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If subjects experience orthostatic hypotension during Screening/start of Placebo Run-in, 
measurement may be repeated during the Screening period to be eligible for study enrollment, 
and background therapy may be adjusted at the investigator’s discretion. 
6.5.2.2. 
Symptomatic Hypotension 
If subjects experience symptoms of hypotension (eg, light-headedness, dizziness, presyncope, or 
syncope) during the study, it will be medically managed by the investigator; adjustment to 
background therapy and/or dose reduction of study drug according to Table 3 may be considered. 
6.5.3. Adrenal Insufficiency 
Serum cortisol levels will be measured at Screening/start of Placebo Run-in, Randomization, 
Study Weeks 1, 2, 3, 4, 5, 6, 7, 8, and at the follow up visit (Study Week 12). Cortisol 
assessment should occur before 10 am on the morning of the study visit. In addition, subjects 
should be monitored for signs and symptoms of adrenal insufficiency (ie, nausea, vomiting, 
light-headedness, low BP, or electrolyte abnormalities) at every study visit. If adrenal 
insufficiency is suspected, glucocorticoid replacement therapy should be initiated until adrenal 
insufficiency can be ruled out. 
Based on morning cortisol level at the central laboratory measurement, the following actions are 
to be taken: 
• Serum cortisol ≥ 18 mcg/dL: No action required. 
• Serum cortisol > 3 and < 18 mcg/dL: If there are no signs or symptoms of adrenal 
insufficiency (see above), then no action is required. If signs or symptoms of adrenal 
insufficiency are observed, then an ACTH stimulation test should be performed as described 
in Appendix 12.7 to rule out adrenal insufficiency. If there is no evidence of adrenal 
insufficiency based on ACTH stimulation test results, then continue at current dose. If ACTH 
stimulation test is abnormal, then study drug should be discontinued. ACTH stimulation test 
may be waived with sponsor’s approval. 
• Serum cortisol < 3 mcg/dL: If at any time during the study serum cortisol < 3 mcg/dL, then 
measurement should be repeated. If confirmed, then an ACTH stimulation test should be 
performed as described in Appendix 12.7 to rule out adrenal insufficiency. If there is no 
evidence of adrenal insufficiency based on ACTH stimulation test results, then continue at 
current dose. If ACTH stimulation test is abnormal, then study drug should be discontinued. 
ACTH stimulation test may be waived with sponsor’s approval. 
Any subject who is withdrawn from the study or has low cortisol levels at the final study visit 
should be evaluated until full normalization of the hypothalamic-pituitary-adrenal axis occurs. In 
addition, all subjects should be instructed to carry a card at all times identifying the potential risk 
for adrenal insufficiency. The card should include the subject’s information, the investigator’s 
contact information, and the potential need for glucocorticoids in the settings of shock, surgery, 
etc. 
6.6. Treatment of Overdose 
For this study, any dose of study drug greater than 300 mg within a 24-hour time period will be 
considered an overdose. 
In the event of an overdose, the investigator should: 


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• Contact the medical monitor immediately 
• Evaluate the subject to determine, in consultation with the medical monitor, whether study 
drug should be interrupted or whether the subsequent study dose should be reduced 
• Closely monitor the participant for any AE/SAE and laboratory abnormalities 
6.7. Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, recreational 
drugs, vitamins, and/or herbal supplements) that the subject is receiving at the time of enrollment 
or receives during the study must be recorded along with: 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 
MLS-101 may alter the clearance of drugs that rely on multidrug and toxin extrusion 1 (MATE1) 
transport for clearance. While the diabetic medication metformin is transported by MATE1, it 
can also be cleared by MATE2 and organic cation transporter; thus, significant changes in 
metformin bioavailability are thought to be unlikely. However, it is prudent to periodically 
monitor blood glucose levels as per protocol in study subjects taking metformin. Clinically 
significant changes in glucose control should be considered possibly related to study drug and 
treated accordingly with laboratory confirmation and appropriate medical interventions deemed 
appropriate by the site investigator and other treating healthcare providers. The medical monitor 
should be consulted if discontinuation of study drug is considered. 
6.7.1. Prohibited Treatments 
The following medications are prohibited: 
• Concomitant use of epithelial sodium channel inhibitors or mineralocorticoid receptor 
antagonists, including, but not limited to amiloride, triamterene, spironolactone, eplerenone 
• ACE inhibitors and ARBs in combination as background antihypertensive treatment 
• Chronically administered oral or topical corticosteroids within 3 months of Screening or 
during study participation. Short-term (ie, ≤ 2 weeks) of topical corticosteroids are allowed if 
taken ≥ 1 month prior to Randomization. 
• Sympathomimetic decongestants within 1 week of Screening or during study participation 
• Theophylline unless treatment has been stable at optimum dose for at least 4 weeks prior to 
Screening and remains stable during study participation  
• Regular use of phosphodiesterase type 5 inhibitors within 3 months of Screening or during 
study participation  
• Chronic use of NSAIDs, other than low dose aspirin (81-325 mg), where chronic use is 
defined as > 3 consecutive or nonconsecutive days of treatment per week. Note: intermittent 
use of NSAIDs is strongly discouraged; if required, NSAIDs must not be taken more than a 
total of 2 days during the study (defined as the period from Randomization to the end of 
study period). If analgesics are required, acetaminophen is recommended. 
• Intramuscular steroids within 3 months of Screening or during study participation 
• Short-acting nitrates taken for angina for underlying cardiac disease. Chronic, long-acting 
doses of nitrates are acceptable. 
• Estrogen- or progesterone-containing oral contraceptives or implantable progesterone devices 


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• Strong CYP3A and CYP3A4 inhibitors (eg, clarithromycin, telithromycin, nefazodone, 
itraconazole, ketoconazole, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, 
saquinavir, tipranavir) 
• Strong CYP3A and CYP3A4 inducers (eg, apalutamide, carbamazepine, enzalutamide, 
fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, St. 
John’s Wort) 
The decision to administer a prohibited medication/treatment during the study period is done 
with the safety of the subject as the primary consideration. When possible, the sponsor is to be 
notified before the prohibited medication/treatment is administered. If the investigator 
determines that any of the prohibited treatments listed above are necessary for proper care of the 
subject during the study, the investigator should recommend a treatment plan in consultation 
with the medical monitor that will allow the subject to remain in the study. 
6.7.2. Permitted Treatments 
Background antihypertensive treatment of ≥ 2 drugs (note: a combination pill = 2 
antihypertensives) that have been stable at their prescribed doses for at least 4 weeks prior to 
signing the Screening/main study ICF are permitted. Any treatment other than those listed in 
Section 6.7.1 is allowed and should be documented in the eCRF. 


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7. DISCONTINUATION/WITHDRAWAL CRITERIA 
7.1. Discontinuation of Study Drug 
Subjects who wish to stop treatment for any reason may stop at any time during the study. If the 
study treatment is permanently discontinued, the subject will remain in the study to complete all 
assessments as described in the SoA (Table 1 and Table 2) through Study Week 8 (end-of-
treatment visit). Subjects should also be encouraged to return for a final follow-up visit 4 weeks 
after the Study Week 8 visit for Part 1 and 2 weeks after the Study Week 8 visit for Part 2, at 
which the end-of-study assessments will be performed. 
Details regarding subjects who discontinue study drug before Study Week 12 in Part 1 or Study 
Week 10 in Part 2 will be recorded on the appropriate page(s) of the eCRF. If a subject 
discontinues study drug because of an AE, the investigator may be requested to schedule follow-
up visits until the event has resolved or stabilized (Section 8.3.3). 
Reasons for discontinuing study drug may include: 
• Use of prohibited/excluded medications (see Section 6.7.1) 
• Administrative decision by the investigator or the sponsor 
• Subject noncompliance with the study drug dosing schedule (Section 6.4)  
• Development of an AE (Section 8.3) 
• Unblinding of subject’s study drug treatment assignment (Section 6.3) 
• Subject becomes pregnant (Section 8.3.5) 
• Other 
7.2. Discontinuation/Withdrawal of Subjects 
Subjects have the right to withdraw participation from the study at any time and for any reason 
and will be removed from the study upon request. However, the investigator will encourage 
subjects to return for subsequent observations in order to minimize the number of missing data 
points. If a subject is unable or unwilling to return, the reason for withdrawal will be recorded. 
Each subject’s right to withdraw will be honored; subjects who desire no further follow-up 
contact will be asked to declare so in writing. Details regarding subjects who choose to 
discontinue study participation before Study Week 12 in Part 1 or Study Week 10 in Part 2 will 
be recorded on the appropriate page(s) of the eCRF. 
Reasons for discontinuing/withdrawing from study may include: 
• Withdrawal from participation due to subject convenience (ie, due to a change in the 
subject’s willingness or ability to attend study visits, eg, resulting from new job, work 
schedule change, or move to another geographical area)  
• Lost to follow-up (ie the investigator has exhausted all reasonable methods of contacting the 
subject, which should be documented by at least 3 unsuccessful attempts to contact the 
subject) (Section 7.3) 
• Death 
• Other 


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7.3. Lost to Follow Up 
A subject will be considered lost to follow-up if he/she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. 
The following actions must be taken if a subject fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible, counsel the subject on the importance of maintaining the assigned visit schedule, 
and ascertain whether the subject wishes to and/or should continue in the study. 
• Before a subject is deemed lost to follow-up, the investigator or designee must make every 
effort to regain contact with the subject (where possible, [3] telephone calls, and if necessary, 
a certified letter to the subject’s last known mailing address or local equivalent methods). 
These contact attempts should be documented in the subject’s medical record. 
• Should the subject continue to be unreachable, he/she will be considered to have withdrawn 
from the study. 


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8. STUDY ASSESSMENTS AND PROCEDURES 
Table 1, Table 2, and Section 4.8 outline the SoA and study conduct details, respectively, for all 
subjects and all study periods (Pre-Screening, Screening, Placebo Run-in, Double-blind 
Treatment, and Follow-up) 
• Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed. 
• Acute safety concerns should be discussed with the sponsor immediately upon occurrence or 
awareness to determine if the subject requires dose modification or discontinuation of study 
drug. 
• Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
• All Screening evaluations must be completed and reviewed to confirm that potential subjects 
meet all eligibility criteria. The investigator will maintain a Screening log to record details of 
all subjects screened and to confirm eligibility or record reasons for Screening failure, as 
applicable. 
• Procedures conducted as part of the subject’s routine clinical management (eg, blood count) 
and obtained before signing of the Screening/main study ICF may be utilized for Screening 
or baseline purposes provided the procedures met the protocol-specified criteria and were 
performed within the timeframe defined in the SoA. 
• Safety results that could unblind the study will not be reported to investigative sites or other 
blinded personnel until the study has been unblinded. 
8.1. Efficacy Assessments 
8.1.1. Automated Office-Measured Blood Pressure  
Accurate measurement of BP is essential to classify individuals and record study treatment 
effect; consequently, BP should be measured by an automatic BP device at the site that is 
identical for all participating sites and managed by qualified personnel. In addition, the same 
person should use the BP device for a given subject at each visit whenever possible, and the 
measurement should be performed using the same arm of the subject and the appropriate cuff 
size, as determined during the pre-Screening visit. 
The BP must be measured at trough (ie, before study drug administration) and at approximately 
the same time of day (preferably between 7:00 and 10:00 am ±1 hour). The subject should be 
relaxed, sitting in a chair (feet on floor, back supported) for > 5 minutes. The subject should 
avoid caffeine, exercise, and smoking for at least 30 min before measurement, and ensure patient 
has emptied his/her bladder. Neither the subject nor the observer should talk during the rest 
period or during the measurement. Remove all clothing covering the location of cuff placement. 
Details on BP procedure (measurement and transfer of data) including subject preparation (eg, 
arm selection, arm position, cuff size) will be provided in the BP manual and will follow the 
AHA guidelines. 
At each timepoint indicated in the SoA, SBP and DBP will be measured 5 times using an 
automated oscillometric sphygmomanometer device provided by the sponsor after approximately 
5 minutes of rest in the seated position according to the AHA Guidelines (Muntner 2019); the 
repeated measurements should be separated by 1 to 2 minutes. The last 2 of 5 unattended 


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measurements of SBP and DBP will be averaged for the analysis. In addition to sitting 
measurements, standing BP will be measured at Screening/start of Placebo Run-in, 
Randomization, Study Week 1, and Study Week 8 with the AOBP device to assess for 
hypotension according to the procedure provided in Appendix 12.5. 
8.1.2. 24-hour Ambulatory Blood Pressure Monitoring 
Subjects will be monitored by ABPM for 24 hours before the first dose on Study Day 1 and 
before the first dose on Study Day 49 ± 2 days (end of Week 7) according to the method 
described in the AHA scientific statement on measuring BP in humans (Muntner 2019). Blood 
pressure will be measured automatically every 15 to 30 minutes for a 24-hour period using an 
ABPM device provided to each site by the central BP laboratory or the sponsor for the duration 
of the study. The ABPM data will be electronically transferred to the central BP laboratory and 
subsequently to the contract research organization. Details on ABPM procedure (installation, 
recording, and transfer of data), including subject preparation, will be provided in the BP 
manual. At the second clinic visit of the Placebo Run-in period (Visit 4), subjects will be given 
an ABPM device and instructions by the investigator on how to perform the ABPM procedure at 
home. Subjects will participate in a telephone visit on Study Day 0 (Visit 5) in which they will 
be reminded of the instructions on how to perform the ABPM procedure at home by the 
investigator or study coordinator. The ABPM procedure will be initiated at home approximately 
24 hours before Randomization (Study Day 1) and again in the clinic at the end of Study Week 4 
(ie, Visit 10, Study Day 28 ± 2) in Part 2 and Study Week 7 (ie, Visit 13; Study Day 49 ± 2) in 
Parts 1 and 2. Alternatively, sites may choose to schedule an office visit on Study Day 0 (Visit 5) 
to initiate the ABPM procedure (the ABPM procedure will be initiated in the clinic at Study 
Weeks 4 and 7 unless a subject is not able to attend the visit due to extraordinary circumstances, 
such as COVID-19 restrictions including site closure, subject exposure to COVID-19, or subject 
testing positive for COVID-19). If, for any reason, the ABPM procedure is deemed a failure at 
the end of Study Week 7, it can be repeated at Study Week 8. Training for the ABPM procedure 
can be done at an office visit or via phone. 
8.2. Safety Assessments  
8.2.1. Medical History 
Medical history data are to be collected at the time of Pre-Screening and updated at the time of 
Screening. 
8.2.2. Physical Examination 
A complete physical examination, including height and weight, will be carried out by trained 
medical personnel at Screening/start of Placebo Run-in, Randomization, and at Study Week 8 
(end of treatment). 
8.2.3. Vital Signs  
Vital signs including body temperature, heart rate, and respiratory rate are to be recorded at each 
study visit throughout the study. All measurements will be assessed with the subject in a seated 
position. Subjects should be seated for at least 5 minutes before taking the measurement. Pulse 
should be measured in the brachial/radial artery for at least 15 seconds. 


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8.2.4. Electrocardiogram 
Single 12-lead ECGs will be recorded at Screening/start of Placebo Run-in, Randomization 
(Baseline), and at the Study Week 8 (end-of-treatment) visit. Parameters to be recorded include 
PR, QRS, and QT intervals, and corrected QT interval using Fridericia’s formula. 
Measurements will be taken after the subject has rested for at least 10 minutes in a supine 
position using a 12-lead (I, II, III, aVR, aVL, aVF, V1-V6) ECG system over a duration of 
10 seconds. The chart speed will be set at 25 mm/sec. ECG changes consistent with 
hyperkalemia will require confirmation of potassium levels at a local laboratory. 
8.2.5. Clinical Safety Laboratory Tests 
Clinical safety laboratory tests will be conducted by a central laboratory according to the time 
points specified in Table 1 and Table 2. Instructions for collection, preparation, handling, and 
shipping clinical laboratory specimens are provided in the Laboratory Manual for the study. 
Analytes for clinical safety labs are listed in Table 6 (Appendix 12.9). 
8.2.6. Spot Urine and 24-Hour Urine Collection 
Subjects will be given either a spot urine collection kit for Part 1 or a 24-hour urine collection kit 
for Part 2 on the second visit of the placebo-run in period (Visit 4) to take home for use on Study 
Day 1. In Part 1 of the study, first morning urine will be collected prior to morning dose of study 
drug on Study Day 1 and again at the end of Study Week 8 (ie, Study Day 56 ± 2 or end-of-
treatment period) for determination of potassium, sodium, and creatinine levels. In Part 2 of the 
study, 24-hour urine will be collected on Study Day 1 and again at the end of Study Week 4 (ie, 
Visit 10, Study Day 28 ± 2) for determination of potassium, sodium, creatinine, and aldosterone 
levels.  
8.2.7. Pregnancy Testing 
Pregnancy tests will be performed as shown in Table 1 and Table 2. A serum pregnancy test will 
be performed at Screening/start of Placebo Run-in, and urine pregnancy tests will be performed 
at Randomization (Study Day 1) and at the Study Week 4 and Study Week 8 (end-of-treatment) 
visits. Pregnancy tests are required for women of childbearing potential only. Note that a woman 
is considered to be of childbearing potential, ie, fertile, following menarche and until becoming 
postmenopausal unless permanently sterile. Permanent sterilization methods include 
hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. A postmenopausal state is 
defined as no menses for 12 months without an alternative medical cause. A high follicle 
stimulating hormone level in the postmenopausal range must be used to confirm postmenopausal 
status in all postmenopausal women at Screening/start of Placebo Run-in. 
8.3. Adverse Events, Serious Adverse Events, and Other Safety Reporting 
The definitions of AEs and SAEs are provided in Appendix 12.10. Adverse events will be 
reported by the subject. The investigator and any qualified designees are responsible for 
detecting, documenting, and recording events that meet the definition of an AE or SAE, and 
remain responsible for following up on all AEs and SAEs. The method of recording, evaluating, 
and assessing causality of AEs and SAEs, as well as the procedures for completing and 
transmitting safety event report forms are provided in Appendix 12.10.  


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8.3.1. Time Period and Frequency for Collecting AE and SAE Information 
All AEs and SAEs will be collected from Screening/start of Placebo Run-in (after signed 
Screening/main study ICF) until 30 days post last dose of study drug in Part 1 (Study Week 12) 
and 15 days post last dose of study drug in Part 2 (Study Week 10) at the timepoints specified in 
the SoA (Table 1 and Table 2). 
Adverse events that begin before the start of study drug, but after obtaining informed consent 
will not be considered treatment-emergent AEs. Adverse events collected during Placebo Run-in 
are considered treatment-emergent events.  
All SAEs occurring from Screening/start of Placebo Run-in (after signed Screening/main study 
ICF) until 30 days post last dose of study drug in Part 1 (Study Week 12) and 15 days post last 
dose of study drug in Part 2 (Study Week 10) will be recorded and reported to the sponsor or 
designee immediately and under no circumstance should this exceed 24 hours. The investigator 
will submit any updated SAE data to the sponsor within 24 hours of it being available. 
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion of 
the study participation. However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the event to be 
reasonably related to the study drug or study participation, the investigator must promptly notify 
the sponsor. 
In the event that study drug is interrupted, AEs and SAEs will be collected throughout the 
interruption. If study drug is discontinued for any reason, the reason will be recorded and the 
subject should be encouraged to remain in the study so that important safety information can be 
obtained. All AEs and SAEs leading to discontinuation of study drug or discontinuation of study 
will be collected. Once a subject withdraws consent to participate in the study, no further 
information can be collected from the subject. 
8.3.2. Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the subject is the preferred method to inquire about AE 
occurrences. 
Investigators will seek information on AEs at each subject contact. All AEs, whether reported by 
the subject or noted by study personnel, will be recorded in the subject’s medical record and on 
the AE eCRF.  
A consistent, nondirective questioning methodology should be adopted for eliciting AE 
information at all subject evaluation timepoints. Examples of nondirective questions include the 
following:  
• “How have you felt since your last clinic visit?”  
• “Have you had any new or changed health problems since you were last here?”  
The method of recording, evaluating, and assessing causality of AEs and SAEs, and the 
procedures for completing and transmitting SAE reports are provided in Appendix 12.10. 


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8.3.3. Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each subject at 
subsequent visits/contacts. All SAEs and AEs of special interest (as defined in Section 8.3.7) will 
be followed until resolution, stabilization, the event is otherwise explained, or the subject is lost 
to follow-up (as defined in Section 7.3).  
8.3.4. Regulatory Reporting Requirements for SAEs 
• Prompt notification (within 24 hours) by the investigator to the sponsor/designee of an SAE 
is essential so that legal obligations and ethical responsibilities towards the safety of subject 
and the safety of a study intervention under clinical investigation are met. 
• The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/IECs, and investigators. 
• An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will review 
and then file it along with the Investigator Brochure and will notify the IRB/IEC, if 
appropriate according to local requirements. 
• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and sponsor policy and forwarded to 
investigators as necessary. 
• Any life-threatening (ie, imminent risk of death) or fatal AE that occurs while on study drug 
should be submitted to the medical monitor/designee with written case details on a safety 
event report form within 24 hours. 
8.3.5. Pregnancy 
• Details of all pregnancies in female subjects and female partners of male subjects will be 
collected after the start of the Placebo Run-in and until 30 days (Part 1) and 15 days (Part 2) 
after the last subject visit. 
• If a pregnancy is reported, the investigator will record pregnancy information on the 
appropriate form and submit it to the sponsor within 24 hours of learning of the female 
subject or female partner of male subject (after obtaining the necessary signed informed 
consent from the female partner) pregnancy. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be reported as an AE or SAE. 
• Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs and will be reported as such. 
• The subject/pregnant female partner will be followed to determine the outcome of the 
pregnancy. The investigator will collect follow-up information on the subject/pregnant 
female partner and the neonate and the information will be forwarded to the 
sponsor/designee. 
• Any poststudy pregnancy-related SAE considered reasonably related to the study drug by the 
investigator will be reported to the sponsor as described in Section 8.3.4. While the 
investigator is not obligated to actively seek this information in former study 


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subject/pregnant female partner, he or she may learn of an SAE through spontaneous 
reporting. 
8.3.6. Death Events 
Any AE resulting in death that occurs during the study or within 30 days (Part 1) and 15 days 
(Part 2) after the subject’s final dose of study drug, regardless of when the final visit occurs, is 
considered a SAE and must be reported to the sponsor (or designee) and/or the study medical 
monitor within 24 hours of awareness of the event. 
All deaths that occur during the protocol-specified AE reporting period (Section 8.3.1), 
regardless of attribution, will be recorded on an eCRF and reported in a safety event report form 
and expeditiously sent to the sponsor/designee. This includes death attributed to progression of 
disease. 
When recording a death on an eCRF or safety event report form, the event or condition that 
caused or contributed to the fatal outcome should be recorded as the single medical concept 
whenever possible. When reporting SAEs, “death” should not be reported as an SAE term, but 
rather as the outcome of a specific SAE unless the event preceding the death in unknown. If an 
autopsy was performed, the autopsy report should be provided. 
8.3.7. Adverse Events of Special Interest 
Adverse events of special interest (AESI) are required to be reported by the investigator to the 
sponsor/designee immediately (ie, no more than 24 hours after learning of the event) regardless 
of their causality to the study drug treatment. The most appropriate diagnosis should be recorded, 
or if a diagnosis cannot be established, the abnormal laboratory values should be recorded on the 
safety event report form and reported to the sponsor/designee immediately, either as an AESI or 
and/or a SAE.  
NOTE: If any of the following events were reported as SAEs then there is no need to complete a 
separate AESI form. 
The AESIs for all study drugs (MLS-101 and placebo) include the following: 
• Hyperkalemia with dose modification (dose reduction, dose hold, or permanent dose 
withdrawal) 
• Hypotension with symptoms (eg, light-headedness, dizziness, presyncope, or syncope) 
• Adrenal Insufficiency 
8.3.8. Safety Monitoring Considerations 
A DSMB will meet periodically to monitor the study. The primary function of this committee is 
safety monitoring, and the committee will not discontinue the study for a finding of positive 
efficacy for any of the doses being considered. As part of these reviews, the DSMB will receive 
summaries of study conduct measures as well as unblinded safety and efficacy data. The DSMB 
may recommend discontinuing enrollment for a dose for safety or lack of efficacy. The 
remaining sample for a discontinued dose may be shifted to 1 or more of the remaining arms 
subject to DSMB recommendation.  


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The full scope and responsibilities of the DSMB will be described in the DMSB Charter per the 
Guidance for Clinical Trial Sponsors: Establishment and Operation of Clinical Trial Data 
Monitoring Committees. 
8.4. Pharmacokinetics 
Single blood samples will be collected and tested for concentration of MLS-101 on Study Day 1 
(predose) and at Study Weeks 1, 4, and 8 (trough levels). Additional blood samples for long-term 
storage for metabolites, drug-drug interaction profiles of background therapy, or other 
exploratory analyses will also be collected at baseline (predose) and at Study Weeks 1, 4, and 8. 
At selected sites, blood samples for determination of MLS-101 (and metabolites) will be 
collected predose, and 1, 2, 3, and 4 hours postdose on Study Days 1 (Randomization) and 28 
(Study Week 4). 
Instructions for collection, preparation, handling, and shipping PK specimens are provided in the 
Laboratory Manual for the study. 
8.5. Pharmacodynamics 
Blood samples for aldosterone and PRA will be collected at Pre-Screening. Blood samples for 
aldosterone, cortisol, 11-deoxycorticosterone, 11-deoxycortisol, and PRA will be collected at 
Screening/start of Placebo Run-in, Study Day 1 (baseline), Study Week 4, and Study Week 10 
for Part 2 or Study Week 12 for Part 1 (end of follow up). 


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9. STATISTICAL CONSIDERATIONS 
The statistical analysis plan (SAP) will be finalized prior to database lock and it will include a 
more technical and detailed description of the statistical analyses described in this section. This 
section is a summary of the planned statistical analyses of the most important endpoints 
including primary and key secondary endpoints. 
9.1. Analysis Sets 
Five analysis sets defined across both parts of the study (ie, Part 1 and Part 2 data combined) are: 
• All randomized set: all randomized subjects. This analysis set will be used for summaries of 
subject study disposition with subjects analyzed according to the randomized treatment 
group.  
• Full analysis set (FAS): all subjects randomized and who received at least 1 dose of study 
treatment. All efficacy analyses will be performed using the full analysis set; subjects will be 
analyzed according to the randomized treatment group. 
• Per protocol set: all subjects in the FAS who have completed the Study Week 8 visit 
without any major protocol deviation that could influence the validity of the data for the 
primary efficacy evaluations; subjects will be analyzed according to the randomized  
treatment group. 
• PK/PD analysis set: subjects in the Safety analysis set who have sufficient data available for 
the analysis of pharmacokinetic and pharmacodynamic measurements; subjects will be 
analyzed according to the actual treatment received.  
• Safety analysis set: all enrolled subjects who received at least 1 dose of study treatment. All 
safety analyses will be performed using the safety analysis set; subjects will be analyzed 
according to the actual treatment received. 
9.2. Sample Size Determination  
 
 
 
 
 
 
 
 
  
9.3. Statistical Methods 
Unless otherwise noted, summaries will be provided on the data combined from Part 1 and Part 
2. 
9.3.1. Disposition, Demographics and Baseline Characteristics 
The number and disposition of screened subjects, randomized subjects and treated subjects will 
be summarized by treatment group. Reasons for incomplete follow-up and treatment will be 
summarized. 


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Demographic and baseline characteristics will be summarized for the all randomized set, using 
descriptive statistics, by treatment. 
9.3.2. Efficacy Analyses 
The FAS will be used for the efficacy analyses. In general, descriptive statistics for continuous 
variables will consist of subject count, mean, standard deviation, median, and range (min, max). 
Descriptive statistics for categorical variables will consist of subject counts and percentages. The 
primary estimand is designed to answer the research question on the treatment effect of 
investigational therapy versus placebo in addition to standard of care on the change in office-
measured blood pressure from baseline to Study Week 8. Details of the estimand components are 
provided in the SAP.  
The primary efficacy endpoint is the Study Week 8 change from baseline in SBP. The primary 
efficacy analysis will be performed using a mixed model repeated measures approach with fixed 
effects of categorical terms for treatment, week, and treatment by week interaction and baseline 
SBP as a fixed continuous covariate. A least square estimate, along with the 90% CI, of the mean 
difference between each dose group and the placebo group will be provided for each time point, 
with the primary analysis inference based on the evaluation of the Week 8 estimates. P-values 
corresponding to the pairwise tests, not adjusted for multiplicity, of the difference between each 
dose group versus placebo will be provided only for the Study Week 8 time point. 
For the office-measured secondary efficacy endpoints, a similar approach will be used as for the 
primary estimand analysis. Both primary and secondary SBP and DBP endpoints will be 
summarized descriptively by study week. The ABPM parameters (SBP and DBP) will also be 
summarized descriptively by study week. 
A response to treatment assessment will be based upon whether or not the office-measured BP 
achieved values of ≤ 130/80 mmHg by the end of Study Week 8. Subjects without an assessment 
at Study Week 8 or who have received rescue medications will be considered as failures. The 
proportion of successes will be calculated for each treatment group. The timing of the first value 
of ≤ 130/80 mmHg will be summarized using a Kaplan-Meier approach within treatment group, 
and the relationship to baseline SBP and DBP will also be explored. 
All secondary efficacy endpoints analyses will be considered supportive and any inferential 
statistics will be considered descriptive in nature. No adjustment for multiplicity will be 
performed. Further details of the estimand definition, analysis model, sensitivity and 
supplementary analyses, including the analyses of the data collected after Study Week 8, are 
given in the SAP. 
Efficacy analyses will be repeated using the FAS subset of 100 mg treatment groups in order to 
evaluate whether there are any differences in the treatment effect depending on the levels of PRA 
at baseline. 
9.3.3. Safety Analyses 
The safety analysis set will be used for the safety analyses. Subjects will be analyzed based upon 
the treatment received. Select safety summaries will be repeated using the FAS subset of 100 mg 
treatment groups where subjects will be tabulated separately by PRA cohort at baseline (Part 1 or 
Part 2). 


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All AEs will be coded using the Medical Dictionary for Regulatory Affairs. The focus of the 
analyses will be on treatment emergent AEs. Results will be presented by system organ class, 
preferred term, and treatment group and summarized for frequency, severity, and relationship to 
study treatment. No formal statistical testing will be performed. 
Concomitant medications will be coded using the most current World Health Organization Drug 
Dictionary and summarized by drug class and medication term with results presented by 
treatment group. 
Quantitative data will be summarized by mean, standard deviation, median, and range. 
Laboratory abnormalities will be analyzed by summarizing frequency, severity, and changes 
from Baseline. Categorical data will be summarized by as counts and percentages. All results 
will be presented by treatment group. 
9.3.4. Pharmacokinetics Analyses 
Descriptive statistics (mean, standard deviation, coefficient of variation, standard error of the 
mean, number, minimum, maximum, and median) will be calculated for all PK parameters for 
MLS-101. 
Pharmacokinetic data will be evaluated by noncompartmental analysis using a prespecified 
analysis plan. If feasible, AUC, Cmax, Tmax, and t1/2 will be estimated. A population PK model 
may be developed to identify and characterize patient factors which may influence MLS-101 
pharmacokinetic disposition. 
9.3.5. Pharmacodynamics Analyses 
The mean change from baseline in plasma 11-deoxycortisol and PRA will be summarized for 
each week recorded. The mean change will be based upon observed data. The mean change from 
baseline in serum aldosterone, cortisol, and 11-deoxycorticosterone concentration will be 
summarized for each week recorded. The mean change will be based upon observed data. A 
population PK-PD model may be developed to evaluate the relationship between systemic 
MLS-101 exposure and plasma aldosterone synthesis and disposition. 
9.4. Handling of Missing Data 
Given the preliminary nature of this study, no formal imputation for missing data is planned. For 
the office-measured efficacy endpoints, values post rescue medications will be set to missing and 
imputed using the last value observed before start of rescue medication. All other missing values 
will not be imputed. 
9.5. Interim Analysis 
An interim analysis of the unblinded safety and efficacy data was performed after the first 5 to 
10 subjects in each dose group (30 to 60 subjects total) completed 4 weeks of treatment in Part 1. 
Safety summaries included tabulation of treatment emergent AEs, SAEs, and AESIs, as well as 
select lab and PD parameters, summarized by study visit. 
At the time of the interim analysis, additional exploratory efficacy analyses using the primary 
efficacy endpoint was conducted within each dose group. The results of these analyses had 
limited, prespecified distribution and were used for internal decision making and development 
planning. The details of these planned analysis are provided in the final SAP.  


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A second interim analysis at the end of Part 1 to review all available safety and tolerability data 
(vital signs, BP measurements, adverse events, and safety laboratory values) will be conducted.  
This analysis will also include Part 2 subjects that have completed week 4 at the time of data cut 
off.  
An additional interim analysis may be performed to support drug development decisions. 


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10. ETHICAL AND ADMINISTRATIVE CONSIDERATIONS 
10.1. Compliance Statement 
This study will be conducted in accordance with the protocol and with US Food and Drug 
Administration (FDA) and the ICH Good Clinical Practice (GCP) guidelines, the Declaration of 
Helsinki, and any applicable local health authority and IRB/ IEC requirements. 
To the extent applicable, all references to the FDA, Federal Food, Drug, and Cosmetic Act, Code 
of Federal Regulations (CFR), ICH, GCP, and the like shall be interpreted as also referring to 
any corresponding requirements of local regulatory agencies, regulations, and laws. If there is 
any discrepancy between FDA, ICH, and local requirements, the most stringent standard shall 
apply. 
10.2. Investigator Responsibilities 
As required by FDA regulation (21 CFR Part 56) and ICH guidelines for GCP, the investigator at 
each study site must obtain IRB/IEC review and approval of the study protocol, ICFs, subject 
recruitment materials, and any other pertinent documents before any study related activities 
involving subjects are performed. 
As required in 21 CFR Part 50 and ICH guidelines for GCP, the investigator or designee must 
comply with the informed consent process, and ensure that each subject enrolled in this clinical 
study understands the information presented in the IRB/IEC approved ICF and agrees voluntarily 
to participate in the clinical study. 
The investigator or designee must submit to the IRB/IEC any written safety report or update (eg, 
amended IB or safety amendments and updates) provided by the sponsor or representative, 
according to the IEC specific reporting requirements. 
The investigator must inform the IRB/IEC of the progress of the clinical study and report any 
non-administrative changes made to the protocol; in any case, the investigator must provide an 
update to the IRB/IEC at least once a year or in accordance with IRB/IEC continuing approval 
requirements. 
The investigator must maintain a list of appropriately qualified persons to whom he/she has 
delegated study duties. All persons authorized to make entries and/or corrections on eCRFs or 
other reporting forms will be included on a Delegation of Authority form. 
The clinical study report will be signed by the investigator or, in the case of multicenter studies, 
the coordinating investigator. The coordinating investigator, identified by the sponsor, will be 
any or all of the following: 
• a recognized expert in the therapeutic area. 
• an investigator who provided significant contributions to either the design or interpretation of 
the study. 
• an investigator contributing a high number of eligible subjects. 
10.3. Institutional Review Board/Independent Ethics Committee Review 
A copy of the protocol, proposed ICF, other written subject information, and any proposed 
advertising material must be submitted to the IRB/IEC for written approval. A copy of the 


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written approval of the protocol and ICF must be received by the sponsor before recruitment of 
subjects into the study and shipment of investigational product. 
The investigator must submit and, where necessary, obtain approval from the IRB/IEC for all 
subsequent protocol amendments and changes to the informed consent document. The 
investigator is to notify the IRB/IEC of deviations from the protocol or SAEs occurring at the 
site and other AE reports received from the sponsor, in accordance with local procedures. 
The investigator is responsible for obtaining annual IRB/IEC approval/renewal as applicable 
throughout the duration of the study. Copies of the investigator’s reports and the IRB/IEC 
continuance of approval must be sent to the sponsor.  
10.4. Informed Consent and Human Subject Protection  
An initial sample pre-Screening ICF and Screening/main study ICF will be provided for the 
investigator to prepare the informed consent documents to be used at his or her site. Updates to 
the template are to be communicated formally in writing from the sponsor’s study monitor to the 
investigator. The written informed consent document is to be prepared in the language(s) of the 
potential subject population. 
Before a subject’s participation in the clinical study, the investigator is responsible for obtaining 
written informed consent (pre-Screening and Screening/main study) from the subject or legally 
acceptable representative after adequate explanation of the aims, methods, anticipated benefits, 
and potential hazards of the study and before any protocol specific Screening procedures or any 
investigational products are administered. A legally acceptable representative is an individual or 
other body authorized under applicable law to consent, on behalf of a prospective subject, to the 
subject’s participation in the clinical study. 
The investigator is also responsible for asking the subject if the subject has a primary care 
physician and if the subject agrees to have his/her primary care physician informed of the 
subject’s participation in the clinical study. If the subject agrees to such notification, the 
investigator is to inform the subject’s primary care physician of the subject’s participation in the 
clinical study. If the subject does not have a primary care physician and the investigator will be 
acting in that capacity, the investigator is to document such in the subject’s medical record. The 
acquisition of informed consent and the subject’s agreement or refusal of his/her notification of 
the primary care physician is to be documented in the subject’s medical records, and the ICF is to 
be signed and personally dated by the subject, or a legally acceptable representative, and by the 
person who conducted the informed consent discussion. The original signed ICF is to be retained 
in accordance with institutional policy, and a copy of the signed consent form is to be provided 
to the subject or legally acceptable representative. 
If a potential subject is illiterate or visually impaired and does not have a legally acceptable 
representative, the investigator must provide an impartial witness to read the ICF to the subject 
and must allow for questions. Thereafter, both the subject and the witness must sign the ICF to 
attest that informed consent was freely given and understood. 


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10.5. Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained for documents 
submitted to the sponsor, including the following: 
• Subjects are to be identified by a unique subject identification number. 
• Where permitted, date of birth is to be documented and formatted in accordance with local 
laws and regulations. 
• On the eCRF demographics page, in addition to the unique subject identification number, the 
subject’s age at time of enrollment is to be included. 
• For SAEs reported to the sponsor, any source documentation provided (eg, medical records, 
laboratory results) must have any subject identifier (eg, subject name, initials, medical 
records number) fully redacted (ie, blacked out) prior to transmission. 
• Documents that are not submitted to the sponsor (eg, signed ICFs) are to be kept in 
confidence by the investigator, except as described below. 
In compliance with the CFR/ ICH GCP Guidelines, it is required that the investigator and 
institution permit authorized representatives of the company, of the regulatory agency(s), and the 
IRB/IEC direct access to review the subject’s original medical records for verification of study 
related procedures and data. Direct access includes examining, analyzing, verifying, and 
reproducing any records and reports that are important to the evaluation of the study. The 
investigator is obligated to inform and obtain the consent of the subject to permit such 
individuals to have access to his/her study related records, including personal information. 
10.6. Urgent Safety Measures 
The sponsor or investigator may take appropriate urgent safety measures to protect trial 
participants from any immediate hazard to their health or safety. Urgent safety measures may be 
taken without prior authorization. The trial may continue with the urgent safety measures in 
place. 
The investigator must inform the sponsor IMMEDIATELY if the study site initiates an urgent 
safety measure. 
The notification must include all of the following: 
• Date of the urgent safety measure 
• Who made the decision 
• Why the action was taken 
The investigator will provide any other information that may be required to enable the sponsor to 
report and manage the urgent safety measure in accordance with the current regulatory and 
ethical requirements for expedited reporting and closeout. 
10.7. Study Monitoring 
The sponsor’s representative(s) are responsible for contacting and visiting the investigator for the 
purpose of inspecting the facilities and, upon request, inspecting the various records of the 
clinical study (eg, eCRFs and other pertinent data) provided that subject confidentiality is 
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The sponsor’s representative(s) are responsible for verifying the eCRFs at regular intervals 
throughout the study to verify adherence to the protocol; completeness, accuracy, and 
consistency of the data; and adherence to local regulations on the conduct of clinical research. 
The sponsor’s representative(s) are to have access to subject medical records and other study 
related records needed to verify the entries on the eCRFs. 
The investigator agrees to cooperate with the sponsor’s representative(s) to ensure that any 
problems detected in the course of these monitoring visits, including delays in completing 
eCRFs, are resolved. 
10.8. Audits and Inspections 
As stipulated by 21 CFR §312.58 and ICH guidelines for GCP, a representative of the sponsor, 
the FDA, or other regulatory agencies may conduct periodic site audits or inspections. The 
investigator or designee will provide these representatives with access to all requested materials, 
including eCRFs and supporting source documents. In addition, the investigator or other 
qualified study site personnel are to be available to answer questions, hold interviews, and 
provide facility tours, if requested. 
10.9. Data Collection and Handling 
The investigator is responsible for complying with the requirements for all assessments and data 
collection (including subjects not receiving protocol required therapies), as stipulated in the 
protocol for each subject in the study. For subjects who withdraw prior to completion of all 
protocol-required visits and procedures, the investigator may search publicly available records 
(where permitted) to ascertain survival status. This ensures that the data sets produced as an 
outcome of the study are as comprehensive as possible. 
The investigator agrees to maintain adequate case histories for the subjects treated as part of the 
research under this protocol. Data collection will involve the use of an electronic data capture 
system, to which only authorized personnel will have access. The investigator agrees to maintain 
accurate eCRFs or paper case report forms and source documentation as part of the case 
histories. The sponsor will supply the eCRF, which is to be completed in English. 
The investigator or designee must enter all results collected during the clinical study into eCRFs. 
Guidelines for completion of eCRFs will be reviewed with study site personnel at the site 
initiation visits. Investigators are responsible for approval of the entered/corrected data. Detailed 
instructions may be found in the other study specific documents. 
All entries made on the eCRF must be verifiable against source documents. In addition to 
periodic monitoring occurring within the system by study monitors, programmatic edit checks 
and data listings will be used to review the data for completeness, logic, and adherence to study 
protocol. As a result of this monitoring and these checks, queries may be electronically issued to 
the clinical study sites and electronically resolved by those sites. 
All data collected in the context of this study will be stored and evaluated according to regulatory 
requirements and applicable guidance for electronic records. Also, data will be stored and 
evaluated in such a way as to assure subject confidentiality in accordance with the legal and 
regulatory requirements applying to protected health information. Study records (eg, copies of 
eCRFs, regulatory documents) will be retained at the study site, along with adequate source 
documentation. The study file and all source data must be retained for the time period required 


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by applicable regulatory requirements and will not be destroyed until written notification is given 
by the sponsor or designee for destruction. 
10.10. Maintenance of Source Documents and Recordkeeping Requirements  
As stipulated by 21 CFR §312.57 and ICH E6 GCP Consolidated Guidance Section 8, the 
investigator or designee will maintain source documentation for this clinical study that 
documents the treatment and study course of subjects as described in the study manual. 
Source documents are original documents, data, and records from which the subject’s eCRF data 
are obtained. These include, but are not limited to hospital records, clinical and office charts, 
laboratory and pharmacy records, diaries, microfiches, radiographs, and correspondence. 
The investigator and study staff are responsible for maintaining a comprehensive and centralized 
filing system of all study related (essential) documentation, suitable for inspection at any time by 
representatives from the sponsor and/or applicable regulatory authorities. 
The investigator must retain all essential documents for this clinical study until 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 until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the study drug. However, the 
investigator may need to retain these documents for a longer period, if required by the applicable 
regulatory requirements or by an agreement with the sponsor. A sponsor representative will be 
responsible for informing the investigator and study site regarding when they no longer need to 
retain these documents. Before destroying any records, the investigator must notify the sponsor 
and reach agreement on record destruction, or the sponsor may request an additional retention 
period. 
10.11. Long-term Retention of Samples for Additional Future Research 
Blood specimens will be collected and stored for additional analyses. These samples will be 
retained for long-term storage by the sponsor and described in the informed consent. 
Any blood sample collected according to the SoA may be analyzed for any of the tests outlined 
in the protocol and for any tests necessary to minimize risks to study subjects. This includes 
testing to ensure that analytical methods produce reliable and valid data throughout the course of 
the study. It may also include, but is not limited to, investigation of unexpected results, incurred 
sample reanalysis, and analyses for method transfer and comparability. 
All samples and associated results will be coded prior to being shipped from the site for analysis 
or storage. Samples will be tracked using a unique identifier that is assigned to the samples for 
the study. Results are stored in a secure database to ensure data integrity and control. 
If permitted by local law and if informed consent is provided by the subject, the sponsor may do 
additional testing on remaining samples (ie, residual and back up) to investigate and better 
understand the disease and the dose response and/or prediction of response to the study drug. 
Results from this analysis are to be documented and maintained, but are not necessarily reported 
as part of this study. Samples may be retained for up to 20 years. 
Since the evaluations are not expected to benefit the subject directly or to alter the subject’s 
treatment course, the results of these exploratory studies are not placed in the subject’s medical 


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record and are not to be made available to the subject, members of the subject’s family, the 
subject’s personal physician, or other third parties, except as specified in the ICF. 
The subject retains the right to request that the sample material be destroyed by contacting the 
investigator. Following the request from the subject, the investigator is to provide the sponsor 
with the required study and subject number so that any remaining blood samples and any other 
components from the cells can be located and destroyed. Samples will be destroyed once all 
protocol-defined procedures have been completed. 
Information collected from samples prior to the request for destruction will be retained by the 
sponsor. The sponsor is the exclusive owner of any data, discoveries, and derivative materials 
from the sample materials and is responsible for the destruction of the sample(s) at the request of 
the subject through the investigator, at the end of the storage period or as appropriate (eg, the 
scientific rationale for experimentation with a certain sample type no longer justifies keeping the 
sample). If a commercial product is developed from this research project, the sponsor owns the 
commercial product. The subject has no commercial rights to such product and has no 
commercial rights to the data, information, discoveries, or derivative materials gained or 
produced from the sample. 
10.12. Publication Policy 
The institution and investigator agree not to publish the results of this study without the prior 
written consent of the sponsor. As used herein, the term ‘publish’ shall include oral 
presentations, written abstracts, written poster presentations, and written manuscripts or reviews, 
etc. 


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11. REFERENCES 
American Heart Association. Managing blood pressure with a heart-healthy diet. Updated 
October 31, 2016. Accessed December 6, 2020. https://www.heart.org/en/health-topics/high-
blood-pressure/changes-you-can-make-to-manage-high-blood-pressure/managing-blood-
pressure-with-a-heart-healthy-diet. 
Arriza JL, Weinberger C, Cerelli G, et al. Cloning of human mineralocorticoid receptor 
complementary DNA: structural and functional kinship with the glucocorticoid receptor. 
Science. 1987;237(4812):268-275. 
Bakris GL, Agarwal R, Anker SD, et al. Effect of finerenone on chronic kidney disease 
outcomes in type 2 diabetes. N Engl J Med. 2020;383(23):2219-2229. 
Baudrand R, Vaidya A. The low-renin hypertension phenotype: genetics and the role of the 
mineralocorticoid receptor. Int J Mol Sci. 2018;19(2):546. 
Brown JM, Siddiqui M, Calhoun DA, et al. The unrecognized prevalence of primary 
aldosteronism: a cross-sectional study. Ann Intern Med. 2020;173(1):10-20. 
Channick BJ, Adlin EV, Marks AD. Suppressed plasma renin activity in hypertension. Arch 
Intern Med. 1969;123(2):131-140. 
Decision Resources Group. Treatment algorithms: claims data analysis in hypertension. 
Published June 2019. 
Hargovan M, Ferro A. Aldosterone synthase inhibitors in hypertension: current status and future 
possibilities. JRSM Cardiovasc Dis. 2014;3:2048004014522440. 
doi:10.1177/2048004014522440 
Ishikawa K, Izawa Y, Ito H, et al. Aldosterone stimulates vascular smooth muscle cell 
proliferation via big mitogen-activated protein kinase 1 activation. Hypertension. 
2005;46(4):1046-1052. 
Jose A, Crout JR, Kaplan NM. Suppressed plasma renin activity in essential hypertension. Roles 
of plasma volume, blood pressure, and sympathetic nervous system. Ann Intern Med. 
1970;72(1):9-16. 
Million Hearts. Estimated hypertension prevalence, treatment, and control among U.S. adults. 
Updated February 5, 2020. Accessed February 5, 2021. https://millionhearts.hhs.gov/data-
reports/hypertension-prevalence.html. 
Mills JN, Thomas S, Williamson KS. The acute effect of hydrocortisone, deoxycorticosterone 
and aldosterone upon the excretion of sodium, potassium and acid by the human kidney. J 
Physiol. 1960;151(2):312-331. 
Muntner P, Shimbo D, Carey RM, Charleston JB, Gaillard T, Misra S, et al. Measurement of 
blood pressure in humans: a scientific statement from the American Heart Association. 
Hypertension. 2019;73(5):e35-e66. 
Nishiyama A, Yao L, Fan Y, et al. Involvement of aldosterone and mineralocorticoid receptors in 
rat mesangial cell proliferation and deformability. Hypertension. 2005;45(4):710-716. 
Oparil S, Schmieder RE. New approaches in the treatment of hypertension. Circ Res. 
2015;116(6):1074-1095. 


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Ramsay LE, Shelton JR, Tidd MJ. The pharmacodynamics of single doses of prorenoate 
potassium and spironolactone in fludrocortisone treated normal subjects. Br J Clin Pharmacol. 
1976;3(3):475-482. 
Romagni P, Rossi F, Guerrini L, Quirini C, Santiemma V. Aldosterone induces contraction of 
the resistance arteries in man. Atherosclerosis. 2003;166(2):345-349. 
Vaidya A, Mulatero P, Baudrand R, Adler GK. The expanding spectrum of primary 
aldosteronism: implications for diagnosis, pathogenesis, and treatment. Endocr Rev. 
2018;39(6):1057-1088. 
Whelton PK, Carey RM, Aronow WS, et al. 2017 
ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the 
prevention, detection, evaluation, and management of high blood pressure in adults: a report of 
the American College of Cardiology/American Heart Association Task Force on Clinical 
Practice Guidelines. Hypertension. 2018;71(6):e13-e115. 
Williams B. MacDonald TM, Morant S, et al. PATHWAY Study Group. Spironolactone versus 
placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant 
hypertension (PATHWAY-2): a randomised, double-blind, crossover trial. Lancet. 
2015;386(10008):2059-2068. 
Wright JT Jr, Williamson JD, Whelton PK, et al. SPRINT Research Group. A randomized trial 
of intensive versus standard blood-pressure control. N Engl J Med. 2015;373(22):2103-2116. 


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12. APPENDICES 
12.1. List of Abbreviations and Definition of Terms 
The following abbreviations and specialist terms are used in this study protocol. 
Abbreviation/Term 
Definition 
ABPM 
ambulatory blood pressure monitoring  
ACE 
angiotensin-converting enzyme 
ACTH 
adrenocorticotropic hormone  
ADL 
activities of daily living 
AE 
adverse event 
AESI 
adverse events of special interest 
AHA 
American Heart Association 
AOBP 
automated office blood pressure  
ARB 
angiotensin receptor blockers 
AUC 
area under the plasma concentration versus time curve 
BID 
twice daily 
BP 
blood pressure 
CFR 
Code of Federal Regulations 
Cmax 
maximum plasma concentration 
coags 
coagulation tests 
COVID-19 
coronavirus disease 2019 
CYP 
cytochrome P450 
DBP 
diastolic blood pressure 
DSMB 
data safety monitoring board 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HIV 
human immunodeficiency virus 
HRT 
hormonal replacement therapy 
IB 
Investigator’s Brochure 
IC50 
half maximal inhibitory concentration 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IP 
investigational product 
IRB 
Institutional Review Board 
IWRS 
interactive web response system 
MATE 
multidrug and toxin extrusion 
MLS-101 
a selective aldosterone synthase inhibitor 
MR 
mineralocorticoid receptor 
MRA 
mineralocorticoid receptor antagonist 
NSAID 
nonsteroidal anti-inflammatory drugs 
PA 
primary aldosteronism 
PAC 
plasma aldosterone concentration 
PD 
pharmacodynamic 


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Abbreviation/Term 
Definition 
PK 
pharmacokinetic 
PR 
time from the onset of the P wave to the start of the QRS complex 
PRA 
plasma renin activity 
QD 
once daily 
QRS 
the series of deflections in an electrocardiogram that represent 
electrical activity generated by ventricular depolarization prior to 
contraction of the ventricles 
QT 
time from the beginning of the QRS complex to the end of the T wave 
QTc 
QT interval corrected by Fridericia’s formula 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SoA 
schedule of assessments 
Tmax 
time to maximum concentration 
t1/2 
half-life 
 


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12.2. Study Contacts 
Role 
Study Participant 
Contact Information 
Medical Monitor 
 
 
IQVIA, Inc. 
Sponsor’s Medical 
Monitor 
 
 
Mineralys Therapeutics, Inc. 
Sponsor’s 
Responsible 
Medical Officer 
 
 
Mineralys Therapeutics, Inc. 
Safety Event 
Reporting 
IQVIA Biotech Safety 
 


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12.3. Investigator’s Agreement 
Study Number: 
MLS-101-201 
Study Title: 
A Randomized, Double-blind, Placebo-controlled, Dose-ranging, 
Multicenter Phase 2 Study to Evaluate the Safety, Efficacy, and 
Tolerability of MLS-101 in Subjects With Uncontrolled Hypertension 
Protocol Version: 
7.0 
Approval Date: 
07 July 2022 
I have read the protocol and agree to conduct the study in accordance with the protocol and all 
applicable laws, regulations and guidelines, including, but not limited to, the International 
Conference on Harmonisation (ICH) Guideline for Good Clinical Practice (GCP), the United 
States Code of Federal Regulations, the Directives of the European Union, the ethical principles 
that have their origins in the Declaration of Helsinki, and applicable privacy laws. 
The study will not be commenced without the prior written approval of a properly constituted 
institutional review board (IRB) or independent ethics committee (IEC). No changes will be 
made to the study protocol without the prior written approval of the sponsor and the IRB or IEC, 
except where necessary to eliminate an immediate hazard to subjects. 
I agree to maintain the confidentiality of all information received or developed in connection 
with this protocol.  
 
 
Signature 
 
 
 
Date 
Printed Name of Investigator 
 
 
 
 
 


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12.4. Sponsor’s Signature 
Study Number: 
MLS-101-201 
Study Title: 
A Randomized, Double-blind, Placebo-controlled, Dose-ranging, 
Multicenter Phase 2 Study to Evaluate the Safety, Efficacy, and 
Tolerability of MLS-101 in Subjects With Uncontrolled Hypertension 
Protocol Version: 
7.0 
Approval Date: 
07 July 2022 
 
The protocol has been reviewed and approved by me and is acceptable in its present form. 
 
 
 
 
 
Date 
 
DocuSign Envelope ID: E343696B-445C-49E0-B13C-64B09619D94D
7/7/2022


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12.5. Standing Blood Pressure Measurement 
Standing SBP and DBP will be measured at Screening/start of Placebo Run-in, Randomization, 
Study Week 1, and Study Week 8 with the AOBP device. In addition, assessment of standing BP 
will be performed if a subject reports symptoms of hypotension (eg, light-headedness, dizziness, 
presyncope, or syncope) during the study, and the standing BP measurement will be assessed 
weekly for these subjects until symptoms resolve. 
After seated determinations, subjects will be asked to stand. Beginning when their feet touch the 
floor, BP will be taken approximately 1 minute later in the same arm used for the seated 
measurements, using the BP device. The mean of the last 2 last sitting SBP and DBP values 
measured by the automated device will be compared to the standing BP (within 3 minutes of 
standing). Subjects with a decrease in SBP ≥ 20 mmHg or DBP ≥ 10 mmHg from sitting to 
standing position will not be eligible for Randomization (measurement may be repeated during 
the Screening period to be eligible for study enrollment). 


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12.6. Dietary Restrictions 
Subjects will be instructed to follow a healthy diet for managing blood pressure as recommended 
by the AHA (AHA 2016). 
Aim to eat a diet that's rich in: 
• Fruits (avoid fruits high in potassium, eg, bananas) 
• Vegetables 
• Whole-grains 
• Low-fat dairy products 
• Skinless poultry and fish 
• Nuts and legumes 
• Nontropical vegetable oils 
Limit: 
• Saturated and trans fats 
• Sodium 
• Red meat (if you do eat red meat, compare labels and select the leanest cuts available) 
• Sweets and sugar-sweetened beverages 
 


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12.7. ACTH Stimulation Test 
The ACTH stimulation test assesses the function of the adrenal glands and their ability to 
respond to ACTH. Adrenocorticotropic hormone is a hormone produced in the pituitary gland 
that stimulates the adrenal glands to release cortisol. Based on changes in cortisol levels, an 
ACTH stimulation test may be performed and the subject’s dose of study drug may be withheld. 
The ACTH stimulation test is recognized as the gold standard assay of adrenal insufficiency. 
ACTH stimulation tests may be performed in select patients based on low morning serum 
cortisol levels (ie, < 3 mcg/dL) and clinical evidence of adrenal insufficiency. Cosyntropin is a 
synthetic form of ACTH. The test consists of the following procedures: 
• Obtain blood sample for pretest serum cortisol measurement (collected prior to administering 
synthetic ACTH) 
• Administer 0.25 mg synthetic ACTH via intravenous push 
• Obtain blood samples for serum cortisol measurements at 30 minutes and 60 minutes after 
dosing of synthetic ACTH 
Post-stimulation serum cortisol levels should be greater than 18 mcg/dL. Samples for cortisol 
measurements will be sent to the central laboratory for analysis. 


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12.8. Contraceptive and Barrier Guidance 
12.8.1. Definitions 
Woman of Childbearing Potential (WOCBP)  
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
Women in the following categories are not considered WOCBP: 
1. Premenarchal  
2. Premenopausal female with 1 of the following: 
• Documented hysterectomy 
• Documented bilateral salpingectomy  
• Documented bilateral oophorectomy  
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
3. Postmenopausal female 
• A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. A high follicle-stimulating hormone (FSH) level in the postmenopausal range may be 
used to confirm a postmenopausal state in women not using hormonal contraception or 
hormonal replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, 
a single FSH measurement is insufficient. 
• Females on HRT and whose menopausal status is in doubt will be required to use one of the 
non-hormonal highly effective contraception methods if they wish to continue their HRT 
during the study. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before study enrollment. 
12.8.2. Contraception Guidance 
Investigators should counsel WOCBP and male subjects who are sexually active with WOCBP 
on the importance of pregnancy prevention and the implications of an unexpected pregnancy. 
Investigators shall advise these subjects on the use of adequate methods of contraception and will 
check for adherence during study visits. Subjects must agree to use adequate contraception 
during the study and for 90 days after the last dose of study drug. 
The following methods of contraception are considered adequate for this study: 
• Highly effective methods of contraception (Table 4): Highly effective methods of 
contraception have a failure rate of < 1% per year when used consistently and correctly.  
• Acceptable methods of contraception (Table 5): Acceptable methods of contraception 
which may not be considered as highly effective have a failure rate of > 1% per year when 
used consistently and correctly. 


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Table 4: Highly Effective Contraceptive Methods Permitted in Study 
Nonhormonal intrauterine device (eg, ParaGard®) 
Bilateral tubal occlusion 
Vasectomized Partner 
A vasectomized partner is a highly effective contraception method provided that the partner is the sole 
male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional 
highly effective method of contraception should be used. 
Sexual Abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study treatment. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant. 
 
Table 5: Acceptable Contraceptive Methods Permitted in Study 
Combination of male condom with either cap, diaphragm, or sponge with spermicide (double-barrier 
method) 
Male or female condom with or without spermicide 
Cap, diaphragm, or sponge with spermicide 
 


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12.9. Clinical Laboratory Tests 
Clinical safety laboratory tests will be conducted by a central laboratory according to the time 
points specified in Table 1 and Table 2. Instructions for collection, preparation, handling, and 
shipping clinical laboratory specimens are provided in the Laboratory Manual for the study. 
Analytes for clinical safety labs are listed in Table 6. The investigator must review the laboratory 
report, document this review, and record any clinically significant changes occurring during the 
study as an AE. The laboratory reports must be filed with the source documents. All laboratory 
tests with values considered clinically significantly abnormal during participation in the study or 
within 30 days (Part 1) and 15 days (Part 2) after the last dose of study drug should be repeated 
until the values return to normal or baseline or are no longer considered clinically significant by 
the investigator or medical monitor. If clinically significant values do not return to 
normal/baseline within a period of time judged reasonable by the investigator, the etiology 
should be identified, and the sponsor notified. 
Table 6: Clinical Laboratory Analytes 
Chemistry 
Hematology & 
Coagulation Tests 
Spot/24-Hour Urine 
Collection & Urinalysis 
Other Laboratory 
Measurements 
Sodium 
Potassium 
Chloride 
Bicarbonate 
Total protein 
Albumin 
Calcium 
Magnesium 
Phosphorus 
Glucose 
BUN or Urea 
Creatinine 
Uric acid 
Phosphorus 
Total bilirubin 
Direct bilirubin 
LDH 
AST 
ALT 
Alkaline 
phosphatase 
RBC 
Hemoglobin 
Hematocrit 
Platelets 
WBC Differential 
Neutrophils 
Eosinophils 
Basophils 
Lymphocytes 
Monocytes 
Reticulocytes 
PT, aPTT, and INR  
 
Hemoglobin A1c 
Serum cortisol 
Plasma ACTH 
Spot/24-Hour Urine 
Collection 
Potassium 
Sodium 
Creatinine 
Aldosterone (Part 2) 
 
Urinalysis 
RBC 
Glucose 
Protein  
Urine pH  
Ketones  
Bilirubin  
Urine specific gravity  
Blood 
Pregnancy Testing: 
Serum or Urine 
Pregnancy FSH 
(postmenopausal 
women only) 
 
Pharmacokinetics: 
Plasma MLS-101 and 
metabolites  
 
Pharmacodynamics: 
Serum aldosterone 
Serum cortisol 
Serum 11-
deoxycorticosterone 
Plasma 11-
deoxycortisol 
PRA 
Note: Refer to the Schedule of Assessments (Table 1 and Table 2) for collection timepoints. 
Abbreviations: ACTH = adrenocorticotropic hormone; ALT = alanine aminotransferase; aPTT = activated partial 
thromboplastin time; AST = aspartate aminotransferase; BUN = blood urea nitrogen; FSH = follicle-stimulating 
hormone; INR = international normalized ratio; LDH = lactate dehydrogenase; PRA = plasma renin activity; PT = 
prothrombin time; RBC = red blood cell; WBC = white blood cells. 
 


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12.10. Definitions and Procedures for Adverse Events 
12.10.1. Definition of Adverse Event  
An AE is any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease (new or exacerbated) temporally associated with the use of a study drug or 
other protocol imposed intervention, whether or not considered related to the study drug. Any 
medical condition or clinically significant laboratory abnormality with an onset before the first 
dose of study drug is considered a pre-existing condition that will be captured as part of the 
subject’s medical history and will not be considered an AE unless the condition worsens in 
intensity or frequency after study enrollment.  
Events meeting the AE definition include the following: 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (eg, ECG, radiological scans, vital signs measurements), including those 
that worsen from baseline, considered clinically significant in the medical and scientific 
judgment of the investigator (ie, not related to progression of underlying disease) 
• Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition 
• New condition detected or diagnosed after study intervention administration even though it 
may have been present before the start of the study 
• Signs, symptoms, or the clinical sequelae of a suspected intervention-intervention interaction 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention 
or a concomitant medication. Overdose per se will not be reported as an AE/SAE unless it is 
an intentional overdose taken with possible suicidal/self-harming intent. Such overdoses 
should be reported regardless of sequelae. 
 
Events not meeting the AE definition include the following: 
• Any clinically significant abnormal laboratory findings or other abnormal safety assessments 
that are associated with the underlying disease, unless judged by the investigator to be more 
severe than expected for the participant’s condition 
• The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition 
• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to the 
procedure is the AE 
• Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital) 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen 
12.10.2. Definition of Serious Adverse Event 
An SAE is any untoward medical occurrence that, at any dose, meets 1 or more of the following 
criteria: 
• Is fatal (ie, the AE actually causes or leads to death) 


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• Is life-threatening (ie, the AE, in the view of the investigator, places the subject at immediate 
risk of death at the time of the event; it does not refer to an event which might hypothetically 
have caused death if more severe)  
• Requires or prolongs inpatient hospitalization 
• Results in persistent or significant disability/incapacity (ie, the AE results in substantial 
disruption of the subject’s ability to conduct normal life functions) 
• Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the 
investigational product(s) 
• Is considered a significant medical event by the investigator (ie, may jeopardize the subject 
or may require medical/surgical intervention to prevent one of the outcomes listed above) 
All AEs that do not meet any of the criteria for serious should be regarded as nonserious AEs. 
Elective hospitalizations for conditions that existed before administration of the study drug are 
not to be considered SAEs. However, prestudy conditions that worsen during the course of the 
study and meet the SAE criteria above would be considered SAEs. 
The terms “severe” and “serious” are not synonymous. Severity refers to the intensity of an AE 
(as in mild, moderate, or severe pain); the event itself may be of relatively minor medical 
significance (such as severe headache). “Serious” is a regulatory definition and is based on 
subject or event outcome or action criteria usually associated with events that pose a threat to a 
subject’s life or vital functions. Seriousness (not severity) serves as the guide for defining 
regulatory reporting obligations. 
Severity and seriousness should be independently assessed when recording AEs and SAEs. 
12.10.3. Recording and Follow-Up of AE and/or SAE 
12.10.3.1. Recording of AEs and SAEs 
• When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
• The investigator will then record all relevant AE/SAE information. 
• It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the sponsor in lieu of completion of the required form. 
• There may be instances when copies of medical records for certain cases are requested by the 
sponsor. In this case, all participant identifiers, with the exception of the participant number, 
will be redacted on the copies of the medical records before submission to the sponsor. 
• The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE. 
12.10.3.2. Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it to one of the following categories:  
• Mild: Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 


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• Moderate: Minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental activities of daily living (ADL). Instrumental ADL refers to preparing meals, 
shopping for groceries or clothes, using the telephone, managing money, etc. 
• Severe: Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling, limiting self care ADL. Self care ADL 
refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, 
and not bedridden. 
12.10.3.3. Assessment of Causality 
The investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE. The investigator will use clinical judgment to determine the 
relationship. The guideline below should be used to consider relatedness: 
“Unlikely” or “Not Related” = there is not a reasonable possibility that the event may have been 
caused by study drug. The AE: 
• May be judged to be due to extraneous causes such as disease or environment or toxic factors 
• May be judged to be due to the subject’s clinical state or other therapy being administered 
• Is not biologically plausible 
• Does not reappear or worsen when the study drug is readministered 
• Does not follow a temporal sequence from administration of study drug 
“Possibly” or “Definitely” = there is a reasonable possibility that the AE may have been caused 
by the study drug. The AE: 
• Follows a temporal sequence from administration of study drug 
• Is a known response to the study drug based on clinical or nonclinical data 
• Could not be explained by the known characteristics of the subject’s clinical state, 
environmental or toxic factors, or other therapy administered 
• Disappears or decreases upon cessation or reduction of the study drug 
• Reappears or worsens when the study drug is readministered 
A reasonable possibility of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as 
well as the temporal relationship of the event to study intervention administration, will be 
considered and investigated. The investigator will also consult the IB and/or product information, 
for marketed products, in his/her assessment.  
For each AE/SAE, the investigator must document in the medical notes that he/she has reviewed 
the AE/SAE and has provided an assessment of causality. There may be situations in which an 
SAE has occurred and the investigator has minimal information to include in the initial report to 
the sponsor. However, it is very important that the investigator always make an assessment of 
causality for every event before the initial transmission of the SAE data to the sponsor. 
The investigator may change his/her opinion of causality in light of follow-up information and 
send an SAE follow-up report with the updated causality assessment. The causality assessment is 
one of the criteria used when determining regulatory reporting requirements. 


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12.10.3.4. Follow-up of AEs and SAEs 
• The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may include 
additional laboratory tests or investigations, histopathological examinations, or consultation 
with other health care professionals. 
• New or updated information will be recorded in the originally submitted documents. 
• The investigator will submit any updated SAE data to the sponsor/designee within 24 hours 
of receipt of the information. 
12.10.4. Reporting of AEs and SAEs 
12.10.4.1. AE and SAE Reporting Period 
All AEs and SAEs will be collected from Screening (after signed Screening/main study ICF) 
until 30 days post last dose of study drug in Part 1 (Study Week 12) and 15 days post last dose of 
study drug in Part 2 (Study Week 10) at the timepoints specified in the SoA (Table 1). Adverse 
events will be reported by the subject. The investigator and any qualified designees are 
responsible for detecting, documenting, and recording events that meet the definition of an AE or 
SAE, and remain responsible for following up on all AEs and SAEs. 
12.10.4.2. SAE Reporting to the Sponsor/Designee via Paper Safety Event Report Form 
• Email transmission of the safety event report form is the preferred method to transmit this 
information to the sponsor/designee with facsimile transmission as the back-up method. 
• Initial notification via telephone does not replace the need for the investigator to complete 
and sign the safety event report form within the designated reporting timeframes. 
• Contacts for safety event reporting can be found in Appendix 12.2. 
 


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12.11. Protocol Amendment Summary 
DOCUMENT HISTORY 
Document 
Date 
Amendment 6 
07 July 2022 
Amendment 5 
17 February 2022 
Amendment 4 
10 January 2022 
Amendment 3 
24 August 2021 
Amendment 2 
01 June 2021 
Amendment 1 
15 April 2021 
Original Protocol  
06 February 2021 


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12.11.1. Amendment 6 (07 July 2022) 
This summary includes changes made to Protocol MLS-101-201 Amendment 5 (17 
February 2022). The overall rationale for the changes implemented in this protocol amendment 
was include the changes made using Protocol Clarification Letters.  Changes to the Protocol 
regarding the primary efficacy endpoint, analysis sets and addition of second interim analysis 
were made based on the Statistical Analysis Plan for this study.     
The following is a summary of content-oriented changes that were made to each section of the 
protocol, and a brief rationale for these changes. Minor editorial and document formatting 
revisions have not been summarized. 
Section/Section Title 
Description of Change 
(strikeout denotes a deletion; bold denotes 
an addition) 
Brief Rationale for Change 
Synopsis/ Methodology and Section 
4.1/Overall Study Design 
For Part 2, approximately 36 enrolled 
subjects ≥ 18 years of age will be 
randomized (6:1)(5:1) to either 100 mg 
QD MLS-101 or placebo stratified by 
PRA levels such that the MLS-101 
treatment group will consist of 
approximately 30 subjects and the 
placebo treatment group will consist of 
approximately 6 subjects. 
Clarified that the 
randomization ratio should 
be 5:1 not 6:1 as indicated in 
the protocol 
Synopsis/ Methodology  
Using an automated oscillometric 
sphygmomanometer device, SBP and 
DBP will be measured 5 times after 
approximately 5 minutes of rest in the 
seated position according to the 
American Heart Association (AHA) 
Guidelines (Muntner 2019). The 
meanaverage of the last 2 of 5 
unattended measurements of SBP and 
DBP, respectively, will be 
averagedused for the analysis. 
Updated to align with the 
Statistical Analysis Plan 
Section 4.1/Overall Study Design 
The last 2 of 5 unattended measurements 
of SBP and DBP will be averaged for 
the analysis. The last 2 of 5 unattended 
measurements of SBP and DBP will be 
averaged for the analysis.The averge of 
the last 2 of 5 unattended 
measurements of SBP and DBP, 
respectively, will be averaged used for 
the analysis. 
Updated to align with the 
Statistical Analysis Plan 
Synopsis/Methodolody and Section 
4.1/Overall Study Design and 
Section 9.5/Interim Analysis 
 
A second interim analysis at the end 
of Part 1 to review all available safety 
and tolerability data (vital signs, BP 
measurements, adverse events, and 
safety laboratory values) will be 
conducted.  This analysis will also 
include Part 2 subjects that have 
completed week 4 at the time of data 
cut off. 
Updated to align with the 
Statistical Analysis Plan  


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Section/Section Title 
Description of Change 
(strikeout denotes a deletion; bold denotes 
an addition) 
Brief Rationale for Change 
Section 4.2/Scientific Rationale for 
Study Design 
Data obtained from the interim analysis 
analyses performed in Part 1 of the 
study will be used to inform Part 2. 
Updated to align with the 
Statistical Analysis Plan 
Section 4.3/Number of 
Subjects/Number of Centers 
The subjects who qualify for enrollment 
will be randomized (6:1)(5:1) to either 
100 mg QD MLS-101 or placebo 
stratified by PRA levels such that the 
MLS-101 treatment group will consist 
of approximately 30 subjects and the 
placebo treatment group will consist of 
approximately 6 subjects across 
approximately 10 study centers in the 
United States. 
Clarified that the 
randomization ratio should 
be 5:1 not 6:1 as indicated in 
the protocol 
Section 6.3/Randomization and 
Blinding 
All subjects who qualify for Part 2 
based on inclusion/exclusion criteria 
and complete up to a 2-week Placebo 
Run-in period and 24-hour ABPM 
procedure will be randomized (6:1)(5:1) 
to either 100 mg QD MLS-101 or 
placebo stratified by PRA levels such 
that the MLS-101 treatment group will 
consist of approximately 30 subjects and 
the placebo treatment group will consist 
of approximately 6 subjects. 
Clarified that the 
randomization ratio should 
be 5:1 not 6:1 as indicated in 
the protocol 
Synopsis/Table 2: Schedule of 
Assessments for Part 2 footnote q 
Subjects will be given a 24-hour urine 
collection kit on the second visit of the 
placebo-run in period (Visit 4; Study 
Day -7 ± 2). First morning urine will be 
collected prior to morning dose of study 
drug on Study Day 1 and urine 
collection continued for 24 hours The 
first morning urine should be 
discarded before the 24-hour 
collection is started.  Urine should be 
collected for 24 hours prior to V6 
(Randomization) for determination of 
potassium, sodium, creatinine, and 
aldosterone levels.  A second 24-hour 
urine collection will occur at the end of 
Study Week 4 (ie, Study Day 28 ± 2). 
24 hours prior to V10 (Study Week 4, 
Study Day 28 ± 2).   
Clarified the timing of the 
24-Hour Urine Collection.  
The 24-Hour Collection 
should start the day prior to 
V6 and V10   
Synopsis/Eligibility Criteria and 
Section 5/Study Population 
 
Inclusion Criteria #5 
For Part 1, inclusion based on morning 
pre-Screening visit measurement of 
PRA, and the value for PRA must be ≤ 
1 ng/mL/h. For Part 2, inclusion based 
on morning pre-Screening visit 
measurement of PRA, and the value of 
PRA must be > 1 ng/mL/h. Alternative 
target PRA criteria for the study may be 
provided by the sponsor. These 
alternative targets may be adjusted 
Clarified the inclusion 
measurement of PRA for 
Part 2.   


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Section/Section Title 
Description of Change 
(strikeout denotes a deletion; bold denotes 
an addition) 
Brief Rationale for Change 
during the conduct of the trial based on 
ongoing review of PRA values. 
Synopsis/Eligibility Criteria and 
Section 5/Study Population 
 
Inclusion Criteria #6 
Inclusion based on morning pre-
Screening visit measurement of serum 
aldosterone for Part 1 and pre-
Screening visit measurement of 
aldosterone for Part 2. The value for 
aldosterone must be ≥ 1 ng/dL based on 
morning measurement. Alternative 
target aldosterone criteria for the study 
may be provided by the sponsor. These 
alternative targets may be adjusted 
during the conduct of the trial based on 
ongoing review of serum aldosterone 
values. 
Clarified the inclusion 
measurement of Aldosterone 
for Part 2.   
Section 9.1/Analysis Sets 
PK/PD analysis set: subjects in the FAS 
Safety analysis set who have sufficient 
data available for the analysis of 
pharmacokinetic and pharmacodynamic 
measurements; subjects will be analyzed 
according to the actual treatment 
received. 
Updated to align with the 
Statistical Analysis Plan 
Section 9.3/Statistical Methods 
 
Unless otherwise noted, summaries will 
be provided on the data combined from 
Part 1 and Part 2., with all placebo 
subjects pooled into 1 group for 
tabulations. 
Updated to align with the 
Statistical Analysis Plan 
Section 9.3.2/Efficacy Analyses 
The primary efficacy endpoint is the 
Study Week 8 change from baseline in 
SBP. where the Study Week 8 value 
will be defined as the average of Study 
Week 7 and Study Week 8 
measurement. The primary efficacy 
analysis will be performed using a 
mixed model repeated measures 
approach with fixed effects of 
categorical terms for treatment, week, 
and treatment by week interaction, 
stratification factor, and baseline SBP as 
a fixed continuous covariate. A least 
square estimate, along with the 90% CI, 
of the mean difference between each 
dose group and the placebo group will 
be provided for each time point, with 
the primary analysis inference based on 
the evaluation of the Week 8 estimates. 
P-values corresponding to the pairwise 
tests, not adjusted for multiplicity, of the 
difference between each dose group 
versus placebo will be provided only for 
the Study Week 8 time point. 
Updated the primary 
efficacy endpoint as outlined 
in Statistical Analysis Plan 
Section 9.3.2/Efficacy Analyses 
Efficacy analyses will be repeated using 
the FAS subset of 100 mg treatment 
Updated to align with the 
Statistical Analysis Plan 


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Section/Section Title 
Description of Change 
(strikeout denotes a deletion; bold denotes 
an addition) 
Brief Rationale for Change 
groups in order to evaluate whether 
there are any differences in the 
treatment effect (versus pooled placebo) 
depending on the levels of PRA at 
baseline. 
General Update thoughout the 
protocol 
mmHg 
Updated to remove space 
between mm and Hg 


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12.11.2. Amendment 5 (17 February 2022) 
This summary includes changes made to Protocol MLS-101-201 Amendment 4 
(10 January 2022). The overall rationale for the changes implemented in this protocol 
amendment was to include a Part 2 in the study design so that subjects with high renin (ie, 
PRA > 1 ng/mL/h) could participate in the study. The addition of “Part 1” or “Part 2” was added 
throughout the document where necessary to clarify what is to be done in each part of the study; 
each and every instance of this addition may not be documented in the summary of changes table 
below. 
The following is a summary of content-oriented changes that were made to each section of the 
protocol, and a brief rationale for these changes. Minor editorial and document formatting 
revisions have not been summarized. 
Section/Section Title 
Description of Change 
(strikeout denotes a deletion; bold denotes 
an addition) 
Brief Rationale for Change 
Synopsis/Number of Study 
Centers 
Approximately 50 centers in the United 
States for Part 1 and approximately 10 
centers in the United States for Part 2 
Added number of study 
centers for Part 2 
Synopsis/Endpoints and Section 
3.2.3 Safety Endpoints and 
Section 3.2.5 Pharmacodynamic 
Endpoints 
Safety 
• Change in office-measured SBP from 
Study Week 8 (end-of-treatment period) 
to Study Week 12 for Part 1 and 
Study Week 10 for Part 2 (end of 
follow-up) 
Pharmacodynamics 
• Change in plasma 11-deoxycortisol and 
plasma renin activity (PRA) from 
baseline to the end of Study Weeks 4 
and 12 for Part 1 and end of Study 
Weeks 4 and 10 for Part 2 (end of 
follow-up) 
• Change in serum aldosterone, cortisol, 
and 11-deoxycorticosterone 
concentration from baseline to the end 
of Study Weeks 4 and 12 for Part 1 
and end of Study Weeks 4 and 10 for 
Part 2 (end of follow-up) 
Added appropriate Study 
Weeks for Part 2 
Synopsis/Methodology and 
Section 4.1/Overall Study Design 
This is a 2-part Phase 2 randomized 
Added a Part 2 of the study 
Synopsis/Methodology and 
Section 4.1/Overall Study Design 
TheIn Part 1 of the study, the value forof 
PRA will not exceed must be ≤ 1 ng/mL/h 
based on morning measurement. If the 
value of PRA > 1 ng/mL/h based on 
morning measurement, then subjects 
may be eligible to enter Part 2 of the 
study. The value for aldosterone will 
notmust be less than ≥ 1 ng/dL based on 
morning measurement for both Part 1 
and Part 2. 
To allow subjects with high 
renin (ie, PRA > 1 ng/mL/h) 
to participate in the study  
Synopsis/Methodology and 
Section 4.1/Overall Study Design 
…the pre-Screening window will reset to 2 
weeks for Part 1 or 4 weeks for Part 2. 
The current estimate is that approximately 
10001100 subjects will undergo up to 
• Added 4 weeks of pre-
Screening for Part 2 
• Adjusted number of 


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Section/Section Title 
Description of Change 
(strikeout denotes a deletion; bold denotes 
an addition) 
Brief Rationale for Change 
2 weeks of pre-Screening for Part 1 and 
4 weeks of pre-Screening for Part 2. 
subjects pre-screened 
Synopsis/Methodology and 
Section 4.1/Overall Study Design 
Assuming an approximately 40% drop 
outscreen failure rate, a total of 
approximately 160 subjects will meet all 
eligibility requirements to qualify for 
enrollment in the studyPart 1 of the 
study. For Part 2, it is estimated that 
approximately 60 subjects will have 
qualifying PRA and serum aldosterone 
levels to be eligible to enter 
Screening/start of Placebo Run-in for 
Part 2 after completing a 
Screening/main study ICF that has been 
approved by the IRB. Assuming an 
approximately 40% screen failure rate, 
a total of 36 subjects will meet all 
eligibility requirements to qualify for 
enrollment in Part 2 of the study. 
To clarify how many subjects 
will enter Part 2 of the study 
Synopsis/Methodology and 
Section 4.1/Overall Study Design 
…run-in period (up to 2 weeks) of twice-
daily (BID) oral treatment with placebo in 
Part 1 and once daily (QD) oral 
treatment with placebo in Part 2,… 
To clarify the study treatment 
during the placebo run-in 
period of Part 2 
Synopsis/Methodology and 
Section 4.1/Overall Study Design 
and Section 8.1.2/24-hour 
Ambulatory Blood Pressure 
Monitoring 
The ABPM procedure will be initiated at 
home approximately 24 hours before 
Randomization (Study Day 1) and again in 
the clinic at the end of Study Week 4 (ie, 
Visit 10, Study Day 28 ± 2) in Part 2 and 
Study Week 7 (ie, Visit 13; Study Day 49 
± 2) in Parts 1 and 2. Alternatively, sites 
may choose to schedule an abbreviated 
office visit on Study Day 0 (Visit 5) to 
initiate the ABPM procedure. At the end 
of Study Week Weeks 4 and 7, the ABPM 
procedure can be initiated at home in 
extraordinary circumstances… 
To clarify when the ABPM 
procedure will be done in 
Parts 1 and 2 
Synopsis/Methodology and 
Section 4.1/Overall Study Design 
and Section 8.2.6/Spot Urine and 
24-Hour Urine Collection 
In addition, subjects will be given a urine 
collection kit for a spot urine collection 
that will be performed on Study Day 
either a spot urine collection kit for Part 
1 or a 24-hour urine collection kit for 
Part 2 on the second visit of the placebo-
run in period (Visit 4) to take home for 
use on Study Day 1. In Part 1 of the 
study, first morning urine will be 
collected prior to morning dose of study 
drug on Study Day 1 and again at the end 
of Study Week 8 (ie, Study Day 56 ± 2 or 
end-of-treatment period) for determination 
of potassium, sodium, and creatinine 
levels. In Part 2 of the study, 24-hour 
urine collection will be performed on 
Study Day 1 and again at the end of 
To clarify that a spot urine 
collection will be performed 
for Part 1 and a 24-hour urine 
collection will be performed 
for Part 2 and to specify the 
weeks these collections will 
take place and what analytes 
will be tested 


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Section/Section Title 
Description of Change 
(strikeout denotes a deletion; bold denotes 
an addition) 
Brief Rationale for Change 
Study Week 4 (ie, Visit 10, Study Day 28 
± 2) for determination of potassium, 
sodium, creatinine, and aldosterone 
levels. 
Synopsis/Methodology and 
Section 4.1/Overall Study Design 
…they will be reminded of the instructions 
by the investigator or study coordinator on 
how to perform the ABPM procedure and 
the spot/24-hour urine collection at home. 
Added 24-hour urine instead 
of spot urine collection for 
Part 2 
Synopsis/Methodology and 
Section 4.1/Overall Study Design 
…undergo up to 8 weeks of treatment and 
either 4 weeks of follow-up in Part 1 or 
2 weeks of follow-up in Part 2 
To clarify that Part 1 has 4 
weeks of follow up and Part 
2 has 2 weeks of follow up 
Synopsis/Methodology and 
Section 4.1/Overall Study Design 
For Part 2, approximately 36 enrolled 
subjects ≥ 18 years of age will be 
randomized (6:1) to either 100 mg QD 
MLS-101 or placebo stratified by PRA 
levels such that the MLS-101 treatment 
group will consist of approximately 
30 subjects and the placebo treatment 
group will consist of approximately 6 
subjects. 
To clarify how subjects 
enrolled in Part 2 will be 
randomized  
Synopsis/Methodology and 
Section 4.1/Overall Study Design 
All subjects in Part 2 will receive QD 
dosing to be administered in the 
morning. 
To clarify that subjects in 
Part 2 will receive QD 
morning dose 
Synopsis/Methodology and 
Section 4.1/Overall Study Design 
…and an end-of-study visit scheduled 
4 weeks after the last study treatment in 
Part 1 and 2 weeks after the last study 
treatment in Part 2 for final efficacy and 
safety assessments 
To clarify that Part 1 has 4 
weeks of follow up and Part 
2 has 2 weeks of follow up 
Synopsis/Methodology and 
Section 4.1/Overall Study Design 
and Section 4.8 Study Conduct 
Subjects should be in a fasted state for 
all study visits in Part 2 unless there is a 
medical reason not to fast as determined 
by the investigator. 
To clarify that subjects 
should be fasted in Part 2 
Synopsis/Methodology and 
Section 4.1/Overall Study Design 
Subjects should also be encouraged to 
return for a final follow-up visit 4 weeks 
after the Study Week 8 visit for Part 1 
and 2 weeks after the Study Week 8 visit 
for Part 2, at which the Study Week 12 
(end-of-study assessments) will be 
performed. 
To clarify the follow-up visit 
for Parts 1 and 2 
Synopsis/Number of Subjects 
Approximately 160 subjects are planned to 
be enrolled in Part 1 and approximately 
36 subjects are planned to be enrolled in 
Part 2. 
Adding number of subjects 
to be enrolled in Part 2 
Synopsis/Eligibility Criteria 
(inclusion #5 and #6) and Section 
5.1/Inclusion Criteria (#5 and #6) 
5. InclusionFor Part 1, inclusion based on 
morning pre-Screening visit measurement 
of PRA, Theand the value for PRA will 
not exceedmust be ≤ 1 ng/mL/h. For Part 
2, inclusion based on morning Screening 
visit measurement of PRA, and the value 
of PRA must be > 1 ng/mL/h…  
6. Inclusion based on morning pre-
Screening visit measurement of serum 
To clarify the inclusion 
criteria for Parts 1 and 2  


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Section/Section Title 
Description of Change 
(strikeout denotes a deletion; bold denotes 
an addition) 
Brief Rationale for Change 
aldosterone for Part 1 and Screening visit 
measurement of aldosterone for Part 2. 
The value for aldosterone will not must be 
less than  ≥ 1 ng/dL based on morning 
measurement… 
Synopsis/Eligibility Criteria 
(exclusion #4 and #11) and 
Section 5.2/Exclusion Criteria (#4 
and #11) 
4. Subjects with hyperkalemia, ie, serum 
potassium > 5.2 mEq/L at Screening for 
Part 1 and > 4.8 mEq/L at Screening for 
Part 2 
11. Subjects with office SBP ≥ 175 
mm Hg or DBP ≥ 100 mm Hg for Part 1 
and SBP ≥ 160 mm Hg or 
DBP ≥ 100 mm Hg for Part 2 
To clarify the exclusion 
criteria for Parts 1 and 2 
Synopsis/Investigational Product, 
Dosage, and Mode of 
Administration 
MLS-101 will be administered orally in 
the dosage 25 mg BID, 50 mg QD, or 
100 mg QD in Part 1 and orally in the 
dosage 100 mg QD in Part 2. 
To clarify that subjects in 
Part 2 will receive QD 
100 mg dose 
Synopsis/Duration of Subject 
Participation Including Follow-up 
Up For Part 1, subjects will participate 
in up to 2 weeks of pre-Screening, 
followed by up to 2 weeks of a 
Screening/single-blind Placebo Run-in 
period, 8 weeks of double-blind treatment 
with study drug, and a 4-week follow-up 
period, for a total duration of up to 16 
weeks. For Part 2, subjects will 
participate in up to 4 weeks of pre-
Screening, followed by up to 2 weeks of 
a Screening/single-blind Placebo Run-in 
period, 8 weeks of double-blind 
treatment with study drug, and a 2-
week follow-up period, for a total 
duration of up to 16 weeks. 
To clarify the duration of 
participation for Part 2 
Synopsis/Statistical Methods 
The primary estimand in the study aims 
to answer the research question on the 
treatment effect of investigational 
therapy versus placebo in addition to 
standard of care on the change in office-
measured blood pressure from baseline 
to Week 8…All analyses based on Part 2 
of the study will be exploratory in 
nature; no formal sample size 
considerations will be made for Part 2. 
• To add text regarding the 
primary endpoint 
• To clarify that analyses 
will be exploratory in Part 
2 
Synopsis/Figure 1: Study Schema 
Modified study schema to add Part 2 of the 
study 
Modified study schema to 
add Part 2 of the study 
Synopsis/Table 2 Schedule of 
Assessments for Part 2 
Added Table 2 Schedule of Assessments 
for Part 2 of the study 
Added Table 2 Schedule of 
Assessments for Part 2 of 
the study 
Section 2.1/Study Rationale 
Various dose levels and dose regimens 
will be tested to identify a dose response 
and a therapeutic index to inform 
subsequent studies to support an indication 
in uncontrolled hypertension, with 
To modify the indication 


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Section/Section Title 
Description of Change 
(strikeout denotes a deletion; bold denotes 
an addition) 
Brief Rationale for Change 
particular emphasis on defined patient 
populations such as low-renin 
hypertension. 
Section 3.1.1/Primary Objective 
To characterize the effect of MLS-101 on 
BP at 5 dosing regimens versus placebo 
when administered orally for the treatment 
of low renin uncontrolled hypertension as 
add-on therapy to stable background 
treatment 
To match primary objective 
in synopsis 
Section 4.2/Scientific Rationale 
for Study Design 
Data obtained from the interim analysis 
performed in Part 1 of the study will be 
used to inform Part 2. 
To clarify purpose of 
interim analysis in Part 1 
Section 4.3/Number of Subjects 
Approximately 10001100 subjects will 
undergo up to 2 weeks of pre-Screening. It 
For Part 1, it is estimated that 
approximately 270 subjects will have 
qualifying PRA and serum aldosterone 
levels during pre-Screening to be eligible 
to enter Screening/start of Placebo Run-
in, and (assuming a an approximately 
40% drop out screen failure rate)… 
For Part 2, it is estimated that 
approximately 60 subjects will have 
qualifying PRA and serum aldosterone 
levels to be eligible to enter 
Screening/start of Placebo Run-in, and 
(assuming an approximately 40% 
screen failure rate) a total of 36 subjects 
will meet all eligibility requirements to 
qualify for enrollment in Part 2 of the 
study. The subjects who qualify for 
enrollment will be randomized (6:1) to 
either 100 mg QD MLS-101 or placebo 
stratified by PRA levels such that the 
MLS-101 treatment group will consist of 
approximately 30 subjects and the 
placebo treatment group will consist of 
approximately 6 subjects across 
approximately 10 study centers in the 
United States. 
• To clarify number of 
subjects that will undergo 
pre-Screening 
• To clarify number of 
subjects that will enter 
Screening and enroll in 
Part 2 of the study  
Section 4.4/Study Duration 
For Part 2, subject’s duration of 
participation will be approximately 16 
weeks (up to 4 weeks of pre-Screening, 
followed by up to 2 weeks of a 
Screening/single-blind Placebo Run-in 
period, 8 weeks of double-blind 
treatment with study drug, and a 2-
week follow-up period). 
Added study duration for Part 
2 
Section 4.6/End of Study 
Definition 
…including Visit 16 (end-of-study visit) at 
Study Week 12 and Study Week 10 for 
Parts 1 and 2, respectively. 
Any death that occurs while on study or 
within 30 days (Part 1) and 15 days (Part 
• Added end-of-study visit 
week for Part 2 
• To clarify end of data 
collection for Part 2 


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Section/Section Title 
Description of Change 
(strikeout denotes a deletion; bold denotes 
an addition) 
Brief Rationale for Change 
2) after the subject’s last dose of study 
drug must be reported to the 
sponsor/designee for the study within 24 
hours after the center becomes aware of 
the event. 
Section 4.8.1/Pre-Screening 
will enter up to 2 weeks of pre-Screening 
for Part 1 and 4 weeks of pre-Screening 
for Part 2 upon completion of the IRB-
approved pre-Screening informed consent 
To clarify 4 weeks of pre-
Screening for Part 2 
Section 4.8.2/Screening/Start of 
Placebo Run-in 
…pre-Screening criteria (ie, PRA ≤ 1 
ng/mL/h hr and aldosterone ≥ 1 ng/dL for 
Part 1; PRA > 1 ng/mL/h and 
aldosterone ≥ 1 ng/dL for Part 2; or 
alternative target guidance provided by the 
sponsor)… 
To clarify pre-Screening 
criteria for Part 2 of the study 
Section 4.8.2/Screening/Start of 
Placebo Run-in 
Once all Screening procedures are 
complete, subjects immediately enter the 
single-blind run-in period of BID (Part 1) 
or QD (Part 2) oral treatment with 
placebo 
To clarify that placebo is 
given QD during run-in 
period in Part 2 of the study 
Section 4.8.3/Single-blind 
Placebo Run-In Week 2 
In addition, subjects will be given either a 
spot urine collection kit for Part 1 or a 
24-hour urine collection kit for Part 2 to 
take home for use on Study Day 1. In 
Part 1 of the study, first morning urine 
will be collected prior to morning dose 
of study drug on Study Day 1 and again 
at the end of Study Week 8 (ie, Study 
Day 56 ± 2 or end-of-treatment period) for 
determination of potassium, sodium, and 
creatinine levels. In Part 2 of the study, 
24-hour urine collection will be 
performed on Study Day 1 and again at 
the end of Study Week 4 (ie, Visit 10, 
Study Day 28 ± 2) for determination of 
potassium, sodium, creatinine, and 
aldosterone levels 
To clarify that a spot urine 
collection will be performed 
for Part 1 and a 24-hour 
urine collection will be 
performed for Part 2 and  to 
specify the weeks these 
collections will take place 
and what analytes will be 
tested 
Section 
4.8.5/Randomization/Baseline 
After first morning spot (Part 1) or 24-
hour (Part 2) urine collection at home… 
• Spot urine collection (Part 1 only) 
• 24-hour urine collection (Part 2 only) 
 
To clarify that spot urine is 
performed in Part 1 and 24-
hour urine is performed in 
Part 2 
Section 4.8.9/Study Week 4 
• Initiate 24-hour ABPM (Part 2 only) 
• 24-hour urine collection (Part 2 only) 
To add 24-hour ABPM and 
24-hour urine at Study 
Week 4 for Part 2 
Section 4.8.13/Study Week 8 
• Spot urine collection (Part 1 only) 
To clarify that spot urine is 
performed at StudyWeek 8 
in Part 1 only 
Section 4.8.15/Study Week 10 
On Study Day 84 70 ± 3 days, subjects 
will return to the site for an end-of-study 
visit scheduled 4 2 weeks after the last 
treatment with study drug 
Modified Section 4.8.15 to 
add the end-of-study visit at 
Study Week 10 for Part 2 to 
occur 2 weeks after last 


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Section/Section Title 
Description of Change 
(strikeout denotes a deletion; bold denotes 
an addition) 
Brief Rationale for Change 
study treatment 
Section 4.8.16/Study Week 12 
Added Section 4.8.16 with procedures for 
the end-of-study visit for Part 1 
To clarify that the end-of-
study visit for Part 1 occurs 
at Study Week 12 
Section 6.1.1/Description of 
Study Drug 
MLS-101 Tablets tablets of 12.5 mg, 
25 mg, and 100 mg and placebo tablets are 
packaged in an opaque wallet card blister 
either 30 count 60 cc white round high 
density polyethylene bottles with 35 film 
coated tablest (MLS-101 a child-resistant 
cap or polyvinyl chloride/Aclar blisters 
with foil backing and/or placebo 7 tablets 
per blister (configuration of 5 x 7). Each 
blister pack containing a 1-week supply 
(35 tablets) of study drug strip. Packaged 
tablets will be assigned a unique 
identifying number… 
To update study drug 
packaging 
Section 6.1.2/Dosing and 
Administration 
Placebo Run-In: 
In Part 2, upon signing the 
Screening/main study ICF, subjects will 
begin a single-blind (subjects blinded to 
treatment allocation), up to 2-week run-
in period of QD oral treatment with 
placebo, while continuing to remain on 
stable doses of their background 
antihypertensive medications. 
8-week Treatment Period: 
Subjects will be monitored by ABPM for 
24 hours before the first morning dose on 
Study Day 1 and for 24 hours after the last 
morning dose on Study Day 5649 ± 2 days 
(end of Week 87)…In Part 2, subjects 
will orally administer the assigned study 
drug (MLS-101 [100 mg QD] or 
placebo) according to the assigned 
dosing regimen for 8 weeks beginning 
on Study Day 1. Subjects will be 
monitored by ABPM for 24 hours 
before the first morning dose on Study 
Day 1, for 24 hours beginning on Study 
Day 28 ± 2 days (Week 4), and for 24 
hours after the last morning dose on 
Study Day 49 ± 2 days (end of Week 7). 
• Added dosing for Part 2 in 
Placebo Run-in and 8-
Week Treatment Period 
• Clarified that ABPM is 
performed at end of Study 
Week 7 for Part 1 
Section 6.2.2/Study Drug 
Packaging and Labeling  
…labeling of the tablet blister packs 
package will not show the treatment 
allocation. All other information required 
by regulation will appear on blister pack 
the label. 
To update the study drug 
packaging 
Section 6.3/Randomization and 
Blinding 
All subjects who qualify for Part 2 
based on inclusion/exclusion criteria 
and complete up to a 2-week Placebo 
Run-in period and 24-hour ABPM 
procedure will be randomized (6:1) to 
Added the randomization 
and blinding instructions for 
Part 2 of the study 


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Section/Section Title 
Description of Change 
(strikeout denotes a deletion; bold denotes 
an addition) 
Brief Rationale for Change 
either 100 mg QD MLS-101 or placebo 
stratified by PRA levels such that the 
MLS-101 treatment group will consist of 
approximately 30 subjects and the 
placebo treatment group will consist of 
approximately 6 subjects. 
Section 6.5.1/Hyperkalemia 
• Serum potassium > 5.5 and ≤ 6 mEq/L: 
Retest at local lab to confirm. If 
potassium remains elevated, hold dose. 
Wait 2 to 7 days, then retest. If potassium 
<≤ 5.2 mEq/L, restart at first dose-
reduced level according to 
Table 3.resume dosing. If potassium 
> 5.2 mEq/L, continue to hold dose. Wait 
2 to 7 days, then retest. If potassium < 
≤ 5.2 mEq/L after second retest, restart at 
first dose-reduced level according to 
Table 3. If potassium > 5.2 mEq/L after 
second retest discontinue study drug. 
• Serum potassium > 6 mEq/L: 
Discontinue study drug. 
• Serum potassium > 6 mEq/L: Hold 
study drug dose and bring subject in 
for an unscheduled study visit for 
safety ECG and serum potassium 
retest at local lab; subject attends next 
regularly scheduled visit. If potassium 
from local lab retest ≤ 5.2 mEq/L, 
resume dosing. If potassium 
> 5.2 mEq/L, contact sponsor’s medical 
monitor for further guidance. 
To modify the actions to be 
taken for elevated serum 
potassium levels 
Section 
6.5.1/Hyperkalemia/Table 3 
Modified the second dose-reduced level 
for the 100-mg dose from 12.5 mg to 
25 mg QD 
Modified the second dose-
reduced level for the 100-
mg dose from 12.5 mg to 
25 mg QD 
Section 7.1/Discontinuation of 
Study Drug 
Subjects should also be encouraged to 
return for a final follow-up visit 4 weeks 
after the Study Week 8 visit for Part 1 
and 2 weeks after the Study Week 12 (8 
visit for Part 2, at which the end-of-
study) assessments will be performed. 
To clarify that the follow-up 
visit is 2 weeks after the 
end-of-study visit for Part 1 
and 4 weeks after the end-
of-study visit for Part 2 
Section 7.1/Discontinuation of 
Study Drug and Section 
7.2/Discontinuation/Withdrawal 
of Subjects  
…before Study Week 12 in Part 1 or 
Study Week 10 in Part 2 
To clarify follow-up visit is 
at Study Week 12 in Part 1 
and is at Study Week 10 in 
Part 2 
Section 8.3.1/Time Period and 
Frequency for Collecting AE and 
SAE Information 
All AEs and SAEs will be collected from 
Screening/start of Placebo Run-in (after 
signed Screening/main study ICF) until 30 
days post last dose of study drug in Part 1 
(Study Week 12) and 15 days post last 
dose of study drug in Part 2 (Study 
Week 10) at the timepoints specified in the 
To clarify that AEs and 
SAEs will be collected 30 
days post last dose for Part 1 
and 15 days post last dose 
for Part 2 


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Section/Section Title 
Description of Change 
(strikeout denotes a deletion; bold denotes 
an addition) 
Brief Rationale for Change 
SoA (Table 1 and Table 2). 
 
All SAEs occurring from Screening/start 
of Placebo Run-in (after signed 
Screening/main study ICF) until 30 days 
post last dose of study drug in Part 1 
(Study Week 12) and 15 days post last 
dose of study drug in Part 2 (Study 
Week 10) will be recorded and reported to 
the sponsor or designee immediately and 
under no circumstance should this exceed 
24 hours. 
Section 8.3.5/Pregnancy 
Details of all pregnancies in female 
subjects and female partners of male 
subjects will be collected after the start of 
the Placebo Run-in and until 30 days (Part 
1) and 15 days (Part 2) after the last 
subject visit 
To clarify end of data 
collection for Parts 1 and 2 
Section 8.3.6/Death Events 
Any AE resulting in death that occurs 
during the study or within 30 days (Part 1) 
and 15 days (Part 2) after the subject’s 
final dose of study drug, regardless of 
when the final visit occurs, is considered a 
SAE and must be reported… 
To clarify end of data 
collection for Parts 1 and 2 
Section 8.5/Pharmacodynamics 
…will be collected at Screening/start of 
Placebo Run-in, Study Day 1 (baseline), 
Study Week 4, and Study Week 12 10 for 
Part 2 or Study Week 12 for Part 1 (end 
of follow up). 
To clarify that Week 10 is 
end of follow up for Part 2 
and Week 12 is end of 
follow up for Part 1 
Section 9.1/Analysis Sets 
ThreeFive analysis sets are defined across 
both parts of the study (ie, Part 1 and 
Part 2 data combined) are: 
• All randomized set: all randomized 
subjects. This analysis set will be used 
for summaries of subject study 
disposition with subjects analyzed 
according to the randomized treatment 
group.  
• Full analysis set (FAS): all subjects 
randomized and who received at least 1 
dose of study treatment. All efficacy 
analyses will be performed using the 
full analysis set; subjects will be 
analyzed according to the randomized 
treatment group. 
• Per protocol set: all subjects in the 
FAS who have completed the Study 
Week 8 visit without any major 
protocol deviation that could influence 
the validity of the data for the primary 
efficacy evaluations; subjects will be 
Added 2 analysis sets to 
match SAP 


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Section/Section Title 
Description of Change 
(strikeout denotes a deletion; bold denotes 
an addition) 
Brief Rationale for Change 
analyzed according to the randomized  
treatment group. 
• PK/PD analysis set: subjects in the 
FAS who have sufficient data available 
for the analysis of pharmacokinetic 
and pharmacodynamic measurements; 
subjects will be analyzed according to 
the actual treatment received.  
• Safety analysis set: all enrolled subjects 
who received at least 1 dose of study 
treatment. All safety analyses will be 
performed using the safety analysis set; 
subjects will be analyzed according to 
the actual treatment received. 
Section 9.2/Sample Size 
Determination 
All analyses based on Part 2 of the study 
will be exploratory in nature; no formal 
sample size considerations will be made 
for Part 2. 
To clarify that all analyses 
for Part 2 will be 
exploratory 
Section 9.3/Statistical Methods 
Unless otherwise noted, summaries will 
be provided on the data combined from 
Part 1 and Part 2, with all placebo 
subjects pooled into 1 group for 
tabulations. 
To clarify that data will be 
combined for Parts 1 and 2 
Section 9.3.2/Efficacy Analyses 
In general, descriptive statistics for 
continuous variables will consist of subject 
count, mean, standard deviation, median, 
and range (min, max)…Details of the 
estimand components are provided in 
the SAP. 
• To define the range as 
min, max 
• To specify that 
additional details will be 
provided in the SAP 
Section 9.3.2/Efficacy Analyses 
The primary efficacy analysis will be 
performed using a mixed model repeated 
measures approach with fixed effects of 
categorical terms for treatment, week, and 
treatment by week interaction, 
stratification factor (Seated SBP ≤ 160 mm 
HG, seated SBP > 160 mm Hg), and 
baseline SBP as a fixed continuous 
covariate. 
Deleted stratification factor 
for Part 1 since Part 2 uses a 
different stratification factor 
Section 9.3.2/Efficacy Analyses 
Efficacy analyses will be repeated using 
the FAS subset of 100 mg treatment 
groups in order to evaluate whether 
there are any differences in the 
treatment effect (versus pooled placebo) 
depending on the levels of PRA at 
baseline. 
To clarify additional 
efficacy analyses to be 
performed 
Section 9.3.3/Safety Analyses 
Select safety summaries will be repeated 
using the FAS subset of 100 mg 
treatment groups where subjects will be 
tabulated separately by PRA cohort at 
baseline (Part 1 or Part 2). 
To clarify additional safety 
analyses to be performed 
Section 9.4/Handling of Missing 
Data 
For the office-measured efficacy 
endpoints, values post rescue medications 
To clarify the handling of 
missing data 


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Section/Section Title 
Description of Change 
(strikeout denotes a deletion; bold denotes 
an addition) 
Brief Rationale for Change 
will be set to missing and imputed using 
the last value observed before start of 
rescue medication. All other missing 
values will not be imputed. 
Section 12.2/Study Contacts 
Added sponsor’s medical monitor and 
made minor corrections to table 
Added sponsor’s medical 
monitor and made minor 
corrections to table 
Section 12.9/Clinical Laboratory 
Tests 
All laboratory tests with values considered 
clinically significantly abnormal during 
participation in the study or within 30 days 
(Part 1) and 15 days (Part 2) after the 
last dose of study drug should be repeated 
To clarify end of data 
collection for Parts 1 and 2 
Section 12.9/Clinical Laboratory 
Tests/Table 6 
Added 24-Hour Urine Collection including 
aldosterone for Part 2 
Added 24-Hour Urine 
Collection including 
aldosterone for Part 2 
Section 12.10.4.1/AE and SAE 
Reporting Period 
All AEs and SAEs will be collected from 
Screening (after signed Screening/main 
study ICF) until 30 days post last dose of 
study drug in Part 1 (Study Week 12) and 
15 days post last dose of study drug in 
Part 2 (Study Week 10) at the timepoints 
specified in the SoA (Table 1). 
To clarify the AE and SAE 
reporting period, 
specifically, they will be 
collected 30 days post last 
dose for Part 1 and 15 days 
post last dose for Part 2 


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12.11.3. Amendment 4 (10 January 2022) 
This summary includes changes made to Protocol MLS-101-201 Amendment 3 
(24 August 2021). The overall rationale for the changes implemented in this protocol amendment 
was to reduce the number of cohorts from 6 to 4 by stopping enrollment into the 2 low dose 
cohorts (12.5 mg QD and 12.5 mg BID). This decision was based on a review of the clinical data 
at the December 2021 interim analysis. In addition, the ABPM procedure is now initiated at the 
end of Study Week 7 instead of Study Week 8 to allow for it to be repeated at Study Week 8 if 
deemed a failure at Study Week 7. 
The following is a summary of content-oriented changes that were made to each section of the 
protocol, and a brief rationale for these changes. Minor editorial and document formatting 
revisions have not been summarized. 
Section/Section Title 
Description of Change 
(strikeout denotes a deletion; bold denotes 
an addition) 
Brief Rationale for Change 
Synopsis/Endpoints and 3.2.2/ 
Secondary Efficacy Endpoints 
Change in 24-hour ambulatory blood 
pressure monitoring (ABPM) 
parameters (systolic and diastolic) from 
baseline to the end of Study Week 87 
(ie, Study Day 5649 ± 2 or end-of-
treatment period) 
To allow for the ABPM 
procedure to be repeated at 
Study Week 8 if deemed a 
failure at Study Week 7 
Synopsis/Methodology and 
Section 4.1/Overall Study Design 
and Synopsis/Eligibility Criteria 
and Section 5.1/Inclusion Criteria 
(#5 and #6) 
The value for PRA will not exceed 0.61 
ng/mL based on morning measurement. 
The value for aldosterone will not be 
less than 61 ng/dL based on morning 
measurement. 
To clarify the qualifying 
PRA and serum aldosterone 
levels required at 
prescreening for eligibility 
Synopsis/Methodology and 
Section 4.1/Overall Study Design 
The initialcurrent estimate is that 
approximately 7501000 subjects will 
undergo up to 2 weeks of pre-Screening. 
It is estimated that approximately 
225270 subjects will have qualifying 
PRA and serum aldosterone levels to be 
eligible to enter Screening/start of 
Placebo Run-in after completing a 
Screening/main study ICF that has been 
approved by the IRB. Assuming a 20an 
approximately 40% drop-out rate, a 
total of 180approximately 160 subjects 
will meet all eligibility requirements to 
qualify for enrollment in the study. 
To update the estimate of 
the number of subjects that 
will undergo pre-Screening, 
screening, and enrollment 
based on stopping 
enrollment into the 2 low 
dose cohorts 


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Section/Section Title 
Description of Change 
(strikeout denotes a deletion; bold denotes 
an addition) 
Brief Rationale for Change 
Synopsis/Methodology and 
Section 4.1/Overall Study Design 
The ABPM procedure will be initiated 
at home approximately 24 hours 
before Randomization (Study Day 1) 
and again in the clinic at the end of 
Study Week 7 (ie, Visit 13; Study 
Day 49 ± 2). Alternatively, sites may 
choose to schedule an abbreviated 
office visit on Study Day 0 (Visit 5) to 
initiate the ABPM procedure. At the 
end of Study Week 7, the ABPM 
procedure can be initiated at home in 
extraordinary circumstances, such as 
site closure due to coronavirus disease 
2019 (COVID-19), subject exposure to 
COVID-19, or subject testing positive 
for COVID-19. If, for any reason, the 
ABPM procedure is deemed a failure 
at the end of Study Week 7, it can be 
repeated at Study Week 8… 
Alternatively, sites may choose to 
schedule an abbreviated office visit on 
Study Day 0 (Visit 5) to initiate the 
ABPM procedure (the ABPM procedure 
will be initiated in the clinic at Study 
Week 8). 
To allow for the ABPM 
procedure to be repeated at 
Study Week 8 if deemed a 
failure at Study Week 7 
Synopsis/Methodology and 
Section 4.1/Overall Study Design 
A planned interim analysis 
(Section 9.5) is plannedwas conducted 
and all available safety and tolerability 
data (vital signs, BP measurements, 
adverse events, and safety laboratory 
values) will bewere reviewed by a Data 
and Safety Monitoring Board (DSMB) 
(Section 8.3.8). An additional interim 
analysis may be performed to support 
drug development decisions. 
To clarify that an interim 
analysis was conducted and 
an additional interim 
analysis may be performed 
Synopsis/Methodology and 
Section 4.1/Overall Study Design 
NOTE: In the previous version of the 
protocol, subjects were randomized 
into 6 equal treatment groups 
(1:1:1:1:1:1) to 12.5 mg BID, 25 mg 
BID, 12.5 mg once daily (QD), 50 mg 
QD, 100 mg QD, or placebo. After a 
review of the clinical data at the 
December 2021 interim analysis, it 
was decided that the 2 lowest dose 
levels (12.5 mg QD and 12.5 mg BID) 
will be dropped due to lack of 
consistent meaningful reduction of 
blood pressure. Effective with 
Amendment 4, subjects will be 
randomized into 4 equal treatment 
groups (1:1:1:1) to 25 mg BID, 50 mg 
QD, 100 mg QD, or placebo. 
To clarify that the 2 low 
dose cohorts will stop 
enrollment based on the 
December 2021 interim 
analysis 


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Section/Section Title 
Description of Change 
(strikeout denotes a deletion; bold denotes 
an addition) 
Brief Rationale for Change 
Synopsis/Methodology and 
Section 4.1/Overall Study Design 
Approximately 180 120 of 160 enrolled 
subjects ≥ 18 years of age will be 
randomized into 64 equal treatment 
groups (1:1:1:1:1:1) to 12.5 mg BID, 
25 mg BID, 12.5 mg once daily (QD), 
50 mg QD, 100 mg QD, or placebo; 
each treatment group will consist of 
approximately 30 subjects stratified by 
BP (seated SBP ≤ 160 mm Hg and 
seated SBP > 160 mm Hg). Based on 
accumulated data, when 5 to 10 subjects 
in all cohorts have reached the 4-week 
treatment visit, 2 of the 5 treatment 
groups may be expanded up to a 
maximum of 60 subjects per cohort (not 
to exceed a total of 210 subjects exposed 
to active study drug) in which the 
additional subjects enrolled will have 
morning PRA values greater than the 
PRA cut-off value in effect at the time 
of the cohort expansion. The purpose of 
this limited cohort expansion is to better 
define the predictive value of baseline 
PRA for treatment effect of MLS-101. A 
contemporaneous data safety monitoring 
board (DSMB) review of accumulated 
safety experience will be completed 
before a decision is made to expand 
cohort size. Approximately 40 of 160 
enrolled subjects were enrolled and 
completed the study in the 2 low dose 
cohorts that were discontinued with 
Amendment 4 as described above. 
• To clarify the number of 
planned enrolled subjects 
based on stopping 
enrollment into the 2 low 
dose cohorts 
• To clarify that subjects 
will no longer be enrolled 
into the 2 low dose 
cohorts 
• To clarify that treatment 
groups will not be 
expanded 
Synopsis/Number of Subjects 
(planned) 
Approximately 180160 subjects are 
planned to be enrolled 
To clarify the number of 
planned enrolled subjects 
based on stopping 
enrollment into the 2 low 
dose cohorts 
Synopsis/Eligibility Criteria and 
Section 5.1/Exclusion Criteria (#11) 
Subjects with office SBP ≥ 175 mm Hg 
or DBP ≥ 100 mm Hg (average of last 2 
of 5 unattended measurements using an 
automated oscillometric 
sphygmomanometer device after 
approximately 5 minutes of rest in the 
seated position) at Pre-Screening, 
Screening/Start of Placebo Run-in, or 
Randomization 
To clarify that subjects are 
ineligible if SBP ≥ 175 mm 
Hg or DBP ≥ 100 mm Hg at 
Pre-screening, Screening, or 
Randomization 
Synopsis/Eligibility Criteria and 
Section 5.1/Exclusion Criteria (#12) 
Subjects with a decrease in SBP 
≥ 20 mm Hg or DBP ≥ 10 mm Hg from 
sitting to standing position at Screening 
(may be repeated during Screening at 
the investigator’s discretion) 
To clarify that standing BP 
will be assessed at screening 


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Section/Section Title 
Description of Change 
(strikeout denotes a deletion; bold denotes 
an addition) 
Brief Rationale for Change 
Synopsis/IP, Dosage, and Mode of 
Administration 
MLS-101 will be administered orally in 
the dosage 12.5 mg BID, 25 mg BID, 
12.5 mg QD, 50 mg QD, or 100 mg QD 
To remove the 2 low dose 
cohorts 
Synopsis/Statistical Methods 
With 30 subjects planned per arm, the 
mean placebo adjusted change… 
To clarify that 30 subjects 
per arm are planned 
Synopsis/Figure 1: Study Schema 
Deleted 2 low dose cohorts 
c Based on accumulated data, when 5 to 
10 subjects in all cohorts have reached 
the 4-week treatment visit, 2 of the 5 
treatment groups may be expanded up to 
a maximum of 60 subjects per cohort 
(not to exceed a total of 210 subjects 
exposed to active study drug) 
To clarify that the 2 low 
dose cohorts will stop 
enrollment based on the 
December 2021 interim 
analysis, and to clarify that 
treatment groups will not be 
expanded. 
Synopsis/SOA 
Moved 24-hour ABPM from Study 
Week 8 to Study Week 7 
To allow for the ABPM 
procedure to be repeated at 
Study Week 8 if deemed a 
failure at Study Week 7 
Synopsis/Table 1: Schedule of 
Assessments (footnote i) 
iSubjects will be given the ABPM 
device on the second visit of the 
placebo-run in period (Visit 4; Study 
Day -17 ± 2). The ABPM procedure will 
be initiated at home approximately 24 
hours before Randomization (Study 
Day 1) and again in the clinic at the end 
of Study Week 78 clinic visit (ie, Visit 
1413; Study Day 5649 ± 2 or end-of-
treatment period). Alternatively, sites 
may choose to schedule an abbreviated 
office visit on Study Day 0 (Visit 5) to 
initiate the ABPM procedure. At the 
end of Study Week 7, the ABPM 
procedure can be initiated at home in 
extraordinary circumstances, such as 
site closure due to COVID-19, subject 
exposure to COVID-19, or subject 
testing positive for COVID-19…If, for 
any reason, the ABPM procedure is 
deemed a failure at the end of Study 
Week 7, it can be repeated at the end 
of Study Week 8. 
• To correct the Study Day 
for Visit 4 
• To clarify that the ABPM 
procedure can be initiated 
at home in extraordinary 
circumstances such as 
relating to COVID 
• To allow for the ABPM 
procedure to be repeated 
at Study Week 8 if 
deemed a failure at Study 
Week 7 
Synopsis/Table 1: Schedule of 
Assessments (footnote r) 
rSingle blood…In addition, at selected 
sites, blood samples for determination of 
MLS-101 (and metabolites) will be 
collected predose, and 1, 2, 3, and 4 
hours postdose on Study Days 1 
(Randomization) and 28 (Study 
Week 4). 
To clarify serial PK 
sampling 


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Section/Section Title 
Description of Change 
(strikeout denotes a deletion; bold denotes 
an addition) 
Brief Rationale for Change 
Section 4.3/Number of 
Subjects/Number of Centers 
Approximately 7501000 subjects will 
undergo up to 2 weeks of pre-Screening. 
It is estimated that approximately 
225270 subjects will have qualifying 
PRA and serum aldosterone levels 
during pre-Screening to be eligible to 
enter Screening/Placebo Run-in, and 
(assuming a 2040% drop-out rate) a total 
of 180approximately 160 subjects will 
meet all eligibility requirements to 
qualify for enrollment in the study. The 
subjects who qualify for enrollment will 
be randomly divided into 64 equal 
treatment groups (1:1:1:1:1:1 with 
approximately 30 subjects per group, 
stratified by BP, ie, seated SBP 
≤ 160 mm Hg and seated SBP > 160 
mm Hg) across approximately 50 study 
centers in the United States. Based on 
accumulated data, when 5 to 10 subjects 
in all cohorts have reached the 4-week 
treatment visit, 2 of the 5 treatment 
groups may be expanded up to a 
maximum of 60 subjects per cohort (not 
to exceed a total of 210 subjects exposed 
to active study drug) in which the 
additional subjects enrolled will have 
morning PRA values greater than the 
PRA cut-off value in effect at the time 
of the cohort expansion. The purpose of 
this limited cohort expansion is to better 
define the predictive value of baseline 
PRA for treatment effect of MLS-101. A 
contemporaneous DSMB review of 
accumulated safety experience will be 
completed before a decision is made to 
expand cohort size. 
• To clarify the number of 
planned enrolled subjects 
based on stopping 
enrollment into the 2 low 
dose cohorts 
• To clarify that subjects 
will no longer be enrolled 
into the 2 low dose 
cohorts 
• To clarify that treatment 
groups will not be 
expanded 
Section 4.8.2/Screening/Start of 
Placebo Run-in 
All subjects with PRA and serum 
aldosterone values meeting the pre-
Screening criteria (ie, PRA ≤ 0.61 
ng/mL/hr and aldosterone ≥ 61 ng/dL or 
alternative target guidance provided by 
the sponsor) will be eligible to enter 
Screening/Placebo Run-in 
To clarify the qualifying 
PRA and serum aldosterone 
levels required at 
prescreening for eligibility 
to enter Screening/Placebo 
Run-in 
Section 4.8.5/ 
Randomization/Baseline and 
Section 4.8.9/Study Week 4 
In addition, at selected sites Serial PK 
sampling – if subject consents to 
additional blood draws, blood samples 
for determination of MLS-101 (and 
metabolites) are to be collected predose, 
and 1, 2, 3, and 4 hours postdose 
To clarify that serial PK 
sampling will be done if 
subjects consent to 
additional blood draws 


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Section/Section Title 
Description of Change 
(strikeout denotes a deletion; bold denotes 
an addition) 
Brief Rationale for Change 
Section 4.8.6/Study Week 1 and 
Section 4.8.7/Study Week 2 and 
Section 4.8.8/Study Week 3 and 
Section 4.8.9/Study Week 4 and 
Section 4.8.10/Study Week 5 and 
Section 4.8.11/Study Week 6 and 
Section 4.8.12/Study Week 7 and 
Section 4.8.13/Study Week 8 
…subjects will return to the site and the 
following procedures will be performed 
afterprior to site administration of the 
morning dose of study drug 
To clarify that study 
procedures will be 
performed prior to 
administration of study drug 
Section 4.8.12/Study Week 7 
• Initiate 24-hour ABPM 
To clarify that ABPM will 
be initiated at the end of 
Study Week 7 instead of 
Study Week 8 
Section 4.8.13/Study Week 8 
• Repeat 24-hour ABPM if procedure 
at Study Week 7 deemed a failure 
To allow for the ABPM 
procedure to be repeated at 
Study Week 8 if deemed a 
failure at Study Week 7 
Section 4.9/Modifications to Study 
Conduct Due to the Coronavirus 
Disease 2019 (COVID-19) 
Pandemic 
As a consequence of the COVID-19 
pandemic that has had a worldwide 
impact, control measures in place may 
impact the ability to adhere to some of 
the study procedures described in this 
protocol. Due to challenges that include, 
but are not limited to, subject COVID-
19 infections, site closures, travel 
restrictions, and quarantines, some 
modifications to study conduct during 
the COVID-19 pandemic may be 
necessary to ensure study 
continuity, including conducting virtual 
visits when on-site study visits are 
considered not feasible. Such 
modifications in study conduct always 
must be in accordance with local 
regulations/mandates. 
The following are allowable, as 
necessary, modifications to study 
conduct during the COVID-19 
pandemic: 
• Prior to a study visit at the site, the 
subject may be contacted and 
screened for potential exposure or 
infection to COVID-19 per site, local, 
or federal requirements. If the 
subject is suspected to be exposed or 
infected with COVID-19, the on-site 
visit should either be re-scheduled or 
a virtual visit may be performed 
instead, as applicable. 
• In the event that a subject cannot 
attend their regularly scheduled 
To add language to account 
for deviations in study 
conduct due to COVID-19 


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Section/Section Title 
Description of Change 
(strikeout denotes a deletion; bold denotes 
an addition) 
Brief Rationale for Change 
study visits in person due to COVID-
19 necessitating a limit on in-person 
contact, the investigator may 
perform safety and efficacy 
assessments by phone or video. The 
investigator may use the technology 
platform that is currently available 
to them. Virtual assessments may 
include home blood pressure 
evaluation initiated by the subject, 
adverse events, and concomitant 
medication review. Virtual 
assessments will be recorded by site 
staff in the source documents. 
• Clinical laboratory tests (chemistry 
and hematology) and pregnancy tests 
may be performed by local 
laboratory, if sample collection 
cannot be performed at the study site 
due to COVID-19 related limitations, 
including but not limited to site 
closure. Abnormal laboratory results 
should be promptly communicated 
to the medical monitor. Subjects’ 
anonymity must be maintained when 
communicating results to the 
medical monitor.  
• At home IP administration may 
continue for up to 2 weeks (at 
multiple times during the study if 
required due to COVID-19, although 
not consecutively) if the subject has 
no relevant clinically significant out 
of range values per previous lab 
reports. 
• Source documentation should note 
that the visit was performed 
virtually (not face-to-face) and note 
the name of the local lab where 
laboratory tests were done, if 
applicable. 
• If certain study procedures or 
assessments cannot be completed per 
the schedule of events, the reason for 
the missed assessment (ie, laboratory 
tests, vital signs, physical 
examinations, etc) must be noted in 
the source documentation (eg, 
COVID-19), captured in the protocol 


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Section/Section Title 
Description of Change 
(strikeout denotes a deletion; bold denotes 
an addition) 
Brief Rationale for Change 
deviations documentation, and 
reported to the IRB, as applicable. 
A detailed assessment of COVID-19 
related risk and mitigation measures 
will be documented in the appropriate 
study plans. 
Section 6.1.2/Dosing and 
Administration 
8-Week Treatment Period: Subjects will 
orally administer the assigned study 
drug (MLS-101 [12.5 mg BID, 25 mg 
BID, 12.5 mg QD, 50 mg QD, 100 mg 
QD] or placebo) 
To remove the 2 low dose 
cohorts 
Section 6.3/Randomization and 
Blinding 
…will be randomized into 64 equal 
treatment groups (1:1:1:1:1:1) to 12.5 
mg BID, 25 mg BID, 12.5 mg once 
daily (QD), 50 mg QD, 100 mg QD, or 
placebo; 
To clarify that subjects will 
no longer be enrolled into 
the 2 low dose cohorts 
Section 6.5.1/Hyperkalemia/Table 2 
Modified table to remove the 2 low dose 
cohorts (12.5 mg BID and 12.5 mg QD) 
To remove the 2 low dose 
cohorts 
Section 8.1.2/24-hour Ambulatory 
Blood Pressure Monitoring 
Subjects will be monitored by ABPM 
for 24 hours before the first dose on 
Study Day 1 and afterbefore the lastfirst 
dose on Study Day 5649 ± 2 days (end 
of Week 87)… The ABPM procedure 
will be initiated at home approximately 
24 hours before Randomization (Study 
Day 1) and again at the Study Week 87 
visit (ie, Visit 1413; Study Day 5649 ± 2 
or end-of-treatment period). 
Alternatively, sites may choose to 
schedule an office visit on Study Day 0 
(Visit 5) to initiate the ABPM procedure 
(the ABPM procedure will be initiated 
in the clinic at Study Week 87 unless a 
subject is not able to attend the visit 
due to extraordinary circumstances, 
such as COVID-19 restrictions 
including site closure, subject 
exposure to COVID-19, or subject 
testing positive for COVID-19). If, for 
any reason, the ABPM procedure is 
deemed a failure at the end of Study 
Week 7, it can be repeated at Study 
Week 8. 
• To clarify that ABPM will 
be initiated at the end of 
Study Week 7 instead of 
Study Week 8 
• To add language to 
account for deviations in 
study conduct due to 
COVID-19 
• To allow for the ABPM 
procedure to be repeated 
at Study Week 8 if 
deemed a failure at Study 
Week 7 
Section 8.3.7/Adverse Events of 
Special Interest 
Hyperkalemia with dose modification 
(dose reduction, dose hold, or 
permanent dose withdrawal) 
To update based on new 
guidance that hyperkalemia 
will be considered an AESI 
if it requires dose 
modification 


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Section/Section Title 
Description of Change 
(strikeout denotes a deletion; bold denotes 
an addition) 
Brief Rationale for Change 
Section 9.3.2/Efficacy Analysis 
The full analysis set will be used for the 
efficacy analyses. Subjects will be 
analyzed based upon the treatment 
received. In general, descriptive statistics 
for continuous variables will consist of 
subject count, mean, standard deviation, 
median, and range. Descriptive statistics 
for categorical variables will consist of 
subject counts and percentages. As the 
primary intent of this studyThe primary 
estimand is designed to provide a 
preliminary assessmentanswer the 
research question on the treatment 
effect of investigational therapy versus 
placebo in addition to standard of care 
on the relative efficacy of the doses 
studied, the use of descriptive summary 
statistics and graphical methods rather 
than formal statistical tests of significance 
will be emphasized. Confidence intervals 
(90% 2-sided) will be used to guide these 
assessments. Given the preliminary nature 
of this study, no adjustment for 
multiplicity is anticipatedchange in office 
blood pressure from baseline to Study 
Week 8. 
The primary endpoint will be summarized 
by treatment group using the mean change 
from baseline in SPB. The mean will be 
based upon the last on treatment value 
recorded for each subject prior to the use 
of any antihypertensive medications 
prescribed as “rescue” medications 
(estimand based upon the hypothetical 
treatment strategy per International 
Council for Harmonisation [ICH]-E9 R1) 
and the 90% (2-sided) confidence interval 
will use the t-distribution. The mean 
change from baseline will also be 
calculated using the last recorded value 
(treatment policy strategy). Analyses 
using an analysis of covariance will also 
be conducted to quantify the relationship 
between the change from baseline and the 
baseline value for each treatment group. 
Similarly, the relationship between change 
from baseline and use of ACE 
inhibitors/ARBs at baseline will be 
quantified for each treatment group. The 
primary efficacy endpoint is the Study 
Week 8 change from baseline in SBP 
where the Study Week 8 value will be 
To update language to 
match statistical analysis 
plan 


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Section/Section Title 
Description of Change 
(strikeout denotes a deletion; bold denotes 
an addition) 
Brief Rationale for Change 
defined as the average of Study Week 7 
and Study Week 8 measurement. The 
primary efficacy analysis will be 
performed using a mixed model 
repeated measures approach with fixed 
effects of categorical terms for 
treatment, week, and treatment by 
week interaction, stratification factor 
(Seated SBP ≤ 160 mm HG, seated SBP 
> 160 mm Hg), and baseline SBP as a 
fixed continuous covariate. A least 
square estimate, along with the 90% CI, 
of the mean difference between each 
dose group and the placebo group will 
be provided for each time point, with 
the primary analysis inference based on 
the evaluation of the Week 8 estimates. 
P-values corresponding to the pairwise 
tests, not adjusted for multiplicity, of 
the difference between each dose group 
versus placebo will be provided only for 
the Study Week 8 time point.  
• 
For the office-measured secondary 
efficacy endpoints, a similar 
approach will be used as for the 
primary estimand analysis. Both 
primary and secondary SBP and 
DBP endpoints will be summarized 
descriptively by study week based 
upon the subjects with data. The 
ABPM parameters (SBP and DBP) 
will also be summarized 
descriptively by study week. 
• 
A response to treatment assessment 
will be based upon whether or not 
the office-measured BP achieved 
values of ≤ 130/80 mm Hg by the 
end of Study Week 8. Each subject 
will be assessed as a success if the 
Week 8 values recorded meet this 
definition and will be assessed as a 
failure otherwise (including 
premature termination for any 
reason).Subjects without an 
assessment at Study Week 8 or 
who have received rescue 
medications will be considered as 
failures. The proportion of 
successes will be calculated for 
each treatment group. The timing 
of the first value of ≤ 130/80 mm 
Hg will be summarized using a 


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Section/Section Title 
Description of Change 
(strikeout denotes a deletion; bold denotes 
an addition) 
Brief Rationale for Change 
Kaplan-Meier approach within 
treatment group. The relationship 
to baseline SBP and DBP will also 
be explored. 
All secondary efficacy endpoints 
analyses will be considered supportive 
and any inferential statistics will be 
considered descriptive in nature. No 
adjustment for multiplicity will be 
performed. Further details of the 
estimand definition, analysis model, 
sensitivity and supplementary 
analyses, including the analyses of the 
data collected after Study Week 8, are 
given in the statistical analysis plan. 
Section 9.5/Interim Analysis 
An interim analysis of the unblinded 
safety and efficacy data will bewas 
performed after the first 5 to 10 subjects 
in each dose group (30 to 60 subjects 
total) completed 4 weeks of treatment. 
As this is an exploratory, dose-finding 
study, no formal statistical testing will be 
performed, and adjustments for 
multiplicity will not be implemented. 
Safety summaries included tabulation 
of treatment emergent AEs, SAEs, and 
AESIs, as well as select lab and PD 
parameters, summarized by study 
visit. 
At the time of the interim analysis, 
additional exploratory efficacy analyses 
using the primary efficacy endpoint was 
conducted within each dose group. The 
results of these analyses had limited, 
prespecified distribution and were used 
for internal decision making and 
development planning. The details of 
these planned analysis are provided in the 
final statistical analysis plan.  
An additional interim analysis may be 
performed to support drug 
development decisions. 
To clarify what was done in 
the interim analysis 
performed in 
December 2021 
 


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12.11.4. Amendment 3 (24 August 2021) 
This summary includes changes made to Protocol MLS-101-201 Amendment 2 (01 June 2021). 
The overall rationale for the changes implemented in this protocol amendment was to allow for 
pre-Screening PRA and aldosterone values to be adjusted during conduct of the trial based on 
operational experience gained through continuous review of PRA and serum aldosterone values, 
to allow for possible cohort expansion, and to combined Visits 2 and 3. 
The following is a summary of content-oriented changes that were made to each section of the 
protocol, and a brief rationale for these changes. Minor editorial and document formatting 
revisions have not been summarized. 
Section/Section Title 
Description of Change 
(strikeout denotes a deletion; bold denotes an 
addition) 
Brief Rationale for Change 
Synopsis/Study Period 
Estimated date Date first subject enrolled: 
Q2 30 July 2021 
Added date first subject 
enrolled 
Synopsis/Objectives and 
Endpoints and Section 
3.2.4/Pharmacokinetic Endpoints 
PK parameters of, including, if feasible, 
area under the plasma concentration versus 
time curve… 
To clarify that PK 
parameters will be 
calculated if feasible 
Synopsis/Methodology and 
Section 4.1/Overall Study Design  
Subjects with a history consistent with 
inadequately controlled hypertension who 
meet the protocol definition for, (ie, SBP 
≥ 135 mm Hg on a stable background 
treatment regimen of 
≥ 2 antihypertensives), will undergo… 
To clarify that subjects must 
meet the definition of 
hypertension at pre-
Screening as measured with 
AOBP 
Synopsis/Methodology and 
Section 4.1/Overall Study Design 
Subjects with PRA ≤ 0.6 ng/mL and serum 
aldosterone ≥ 6 ng/dL will then enter the 
study Screening process. The value for 
PRA will not exceed 0.6 ng/mL/hr based 
on morning measurement. The value for 
aldosterone will not be less than 6 ng/dL 
based on morning measurement. 
Alternative target PRA and /or 
aldosterone criteria for the study may be 
provided by the sponsor. These 
alternative targets may be adjusted 
during conduct of the trial based on 
ongoing review of PRA and serum 
aldosterone values. Subjects with PRA 
and serum aldosterone values meeting 
the stipulated guidance criteria will then 
enter the study Screening process. If 
PRA and/or serum aldosterone do not 
meet the target guidance values during 
pre-Screening, the PRA and aldosterone 
measurements may be repeated 1 time 
and the pre-Screening window will reset 
to 2 weeks. If guidance criteria are 
revised, then previously pre-screened 
individuals who meet the revised criteria 
may be considered for entry into the 
Screening process with consent of the 
sponsor, and the pre-Screening window 
will reset to 2 weeks. 
To allow for pre-Screening 
PRA and aldosterone values 
to be adjusted during 
conduct of the trial based on 
operational experience 
gained through continuous 
review of PRA and serum 
aldosterone values 


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Section/Section Title 
Description of Change 
(strikeout denotes a deletion; bold denotes an 
addition) 
Brief Rationale for Change 
Synopsis/Methodology and 
Section 4.1/Overall Study Design 
The initial estimate is that 
Aapproximately 750 subjects will undergo 
up to 2 weeks of pre-Screening. It is 
estimated that approximately 225 subjects 
will have qualifying PRA and serum 
aldosterone levels to be eligible to enter up 
to 4 weeks Screening/start of Placebo 
Run-in after completing… 
To allow for possible cohort 
expansion and to combine 
the Screening and start of 
Placebo Run-in visits 
(V2 and V3) 
Synopsis/Methodology and 
Section 4.1/Overall Study Design 
and Section 4.8.2/Screening 
If PRA is > 0.6 ng/mL during Screening, 
the measurement should be repeated and 
the medical monitor should be contacted. 
To clarify that PRA and 
aldosterone values must be 
met at Pre-Screening only 
for inclusion in the study 
Synopsis/Methodology and 
Section 4.1/Overall Study Design  
Once enrolled, At the Screening/start of 
Placebo Run-in visit (V2/V3), subjects 
will complete the Screening assessments 
and begin a single-blind (subjects blinded 
to treatment allocation), 2-week run-in 
period (up to 2 weeks)…standing BP will 
be measured at the Screening/start of 
Placebo Run-in visit 
To combine the screening 
and start of Placebo Run-in 
visits (V2 and V3) 
Synopsis/Methodology and 
Section 4.1/Overall Study Design 
Subjects will return to the research facility 
once each week at the start of Week 2 of 
the run-in period (V4) for protocol-defined 
assessments including BP measurements. 
To clarify that subjects 
return at start of Week 2 of 
placebo run-in (Visit 4) 
Synopsis/Methodology and 
Section 4.1/Overall Study Design 
At the second clinic visit of the placebo 
runPlacebo Run-in period, subjects will be 
evaluated for eligibility based on 
Screening data, and if eligible, will 
continue Week 2 of Placebo Run-in. 
Subjects… 
To clarify the subjects will 
be evaluated for eligibility 
based on Screening data 
Synopsis/Methodology and 
Section 4.1/Overall Study Design 
and Section 8.1.2/24-hour 
Ambulatory Blood Pressure 
Monitoring 
Alternatively, sites may choose to schedule 
an abbreviated office visit on Study Day 0 
(Visit 5) to initiate the ABPM procedure 
(the ABPM procedure will be initiated in 
the clinic at Study Week 8). 
To clarify that the Study 
Week 8 ABPM is initiated 
in the clinic at the site visit 


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Section/Section Title 
Description of Change 
(strikeout denotes a deletion; bold denotes an 
addition) 
Brief Rationale for Change 
Synopsis/Methodology and 
Section 4.1/Overall Study Design 
and Section 4.3/Number of 
Subjects/Number of Centers 
Based on accumulated data, when 5 to 
10 subjects in all cohorts have reached 
the 4-week treatment visit, 2 of the 
5 treatment groups may be expanded up 
to a maximum of 60 subjects per cohort 
(not to exceed a total of 210 subjects 
exposed to active study drug) in which 
the additional subjects enrolled will have 
morning PRA values greater than the 
PRA cut-off value in effect at the time of 
the cohort expansion. The purpose of 
this limited cohort expansion is to better 
define the predictive value of baseline 
PRA for treatment effect of MLS-101. A 
contemporaneous data safety monitoring 
board (DSMB) review of accumulated 
safety experience will be completed 
before a decision is made to expand 
cohort size. 
To allow for possible cohort 
expansion 
Synopsis/Methodology and 
Section 4.1/Overall Study Design 
Subjects will attend up to 14 full clinic 
visits, including a pre-Sscreening visit, a 
Sscreening/start of Placebo Run-in visit, 
2 visitsa second visit during Pplacebo 
Rrun-in, a clinic visit to initiate the 
ABPM procedure, a Randomization 
visit… 
To clarify subject clinic 
visits 
Synopsis/Methodology and 
Section 4.1/Overall Study Design 
In general, iIf, at any time during the study, 
a subject meets 1 or more of the clinical or 
laboratory exclusion criteria for the 
study…and BP measurements will be 
repeated at home. 
To clarify that clinical and 
laboratory data are used for 
exclusion criteria, and that 
the BP measurement is done 
in the clinic 
Synopsis/Eligibility Criteria and 
Section 5.1/Inclusion Criteria (#3) 
3. Automated office blood pressure 
(Average of AOBP) with SBP ≥ 135 mm 
Hg (average of last 2 of 5 unattended 
measurements taken using an automated 
oscillometric sphygmomanometer device 
after approximately 5 minutes of rest in the 
seated position) at Screening, the /start of 
the 2-week Placebo Run-in Visit period, 
and on the day of Rrandomization with 
SBP ≥ 130 mm Hg 
To clarify that subjects must 
have average AOBP 
measurements at 
Screening/start of Placebo 
Run-in and Randomization 
of SBP ≥ 130 mm Hg 
Synopsis/Eligibility Criteria and 
Section 5.1/Inclusion Criteria (#5) 
5. PRA ≤ 0.6 ng/mL based on morning 
measurement Inclusion based on morning 
pre-Screening visit measurement of 
PRA. The value for PRA will not exceed 
0.6 ng/mL/hr based on morning 
measurement. Alternative target PRA 
criteria for the study may be provided 
by the sponsor. These alternative targets 
may be adjusted during the conduct of 
the trial based on ongoing review of 
PRA values. 
To allow for pre-Screening 
PRA values to be adjusted 
during conduct of the trial 
based on ongoing review of 
PRA values 


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Section/Section Title 
Description of Change 
(strikeout denotes a deletion; bold denotes an 
addition) 
Brief Rationale for Change 
Synopsis/Eligibility Criteria and 
Section 5.1/Inclusion Criteria (#6) 
6. Serum aldosterone ≥ 6 ng/dL based on 
morning measurement Inclusion based on 
morning pre-Screening visit 
measurement of serum aldosterone. The 
value for aldosterone will not be less 
than 6 ng/dL based on morning 
measurement. Alternative target 
aldosterone criteria for the study may be 
provided by the sponsor. These 
alternative targets may be adjusted 
during the conduct of the trial based on 
ongoing review of serum aldosterone 
values. 
To allow for pre-Screening 
aldosterone values to be 
adjusted during conduct of 
the trial based on ongoing 
review of serum aldosterone 
values 
Synopsis/Eligibility Criteria and 
Section 5.1/Inclusion Criteria (#7) 
7. Serum cortisol ≥ 18 mcg/dL (morning 
measurement) or serum cortisol > 3 and 
< 18 mcg/dL (morning measurement) at 
Screening/start of Placebo Run-in visit if 
there is no evidence of adrenal 
insufficiency based on normal ACTH 
stimulation test results. In the event that 
ACTH stimulation testing cannot be 
performed due to logistical challenges, 
including supply chain limitations to 
availability of synthetic ACTH, then 
subjects may be entered into the trial if 
morning serum cortisol is > 3 mcg/dL 
and they fulfill the criteria for no recent 
use of exogenous corticosteroid 
medications in dosages that could 
potentially cause adrenal suppression 
(ie, Exclusion Criteria 16a). 
To clarify the action to be 
taken if ACTH stimulation 
test cannot be performed 
due to logistical challenges 
Synopsis/Eligibility Criteria and 
Section 5.1/Inclusion Criteria (#8) 
Women of childbearing potential must 
have a negative serum pregnancy test 
within 7 days of the start of the single-
blind, placebo run-in, ie, between Study 
Days -21 and -147 prior to 
Randomization 
To clarify that negative 
serum pregnancy test is 
required before 
Randomization 
Synopsis/Eligibility Criteria and 
Section 5.1/Exclusion Criteria (#2) 
2. Use of angiotensin-converting enzyme 
(ACE) inhibitors and angiotensin receptor 
blockers (ARBs) in combination (ie, 
concomitant ACE inhibitors plus ARB 
therapy) as background antihypertensive 
treatment 
To clarify definition of 
using ACE inhibitors and 
ARBs in combination 
Synopsis/Eligibility Criteria and 
Section 5.1/Exclusion Criteria (#3, 
#4, #5, #6, #7) 
…at Screening 
To clarify that these 
measurements are taken at 
the Screening Visit 
Synopsis/Duration of Subject 
Participation Including Follow-up 
Up to 2 weeks of pre-Sscreening and up to 
4 weeks of , followed by up to 2 weeks of 
a Screening/single-blind Pplacebo Rrun-in 
period, 8 weeks of double-blind treatment 
with study drug and a 4-week follow-up 
period, for a total duration of up to 2016 
weeks. 
To clarify duration of 
subject participation 


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Section/Section Title 
Description of Change 
(strikeout denotes a deletion; bold denotes an 
addition) 
Brief Rationale for Change 
Synopsis/Figure 1: Study Schema 
• Deleted Screening box and combined 
Screening with Placebo Run-in 
• AOPBBP = automated office blood 
pressure 
• Added footnotes: 
a If Screening results are available, 
inclusion/exclusion evaluation will be 
performed. If subject is not eligible based 
on Screening results, they will not 
continue to Visit 4. If Screening results 
are not available, subject proceeds to 
Visit 4. If Screening results are not 
available at Visit 4, subject should attend 
Visit 5 to determine final eligibility. If 
eligible based on Screening results, 
ABPM assessment can begin at Visit 5. 
b The ABPM procedure will be initiated 
at home approximately 24 hours before 
Randomization (Study Day 1). 
Alternatively, sites may choose to 
schedule an office visit on Study Day 0 
(Visit 5) to initiate the ABPM procedure. 
Training for the ABPM procedure can 
be done at an office visit or via phone. 
c Based on accumulated data, when 5 to 
10 subjects in all cohorts have reached 
the 4-week treatment visit, 2 of the 5 
treatment groups may be expanded up 
to a maximum of 60 subjects per cohort 
(not to exceed a total of 210 subjects 
exposed to active study drug) 
• To combine the screening 
and start of Placebo Run-
in visits (V2 and V3) 
• To clarify that the BP 
check at Visit 15 is 
performed at home and 
not in the clinic 
• Added footnotes to clarify 
which visits subjects 
should attend, when 
ABPM procedure should 
be initiated, and to allow 
for possible cohort 
expansion 
Synopsis/Table 1: Schedule of 
Assessments 
• Combined Visit 2 and Visit 3 
• Deleted AOBP at Study Week 9 from 
table and replaced with Home BP 
check. 
• Modified footnote a. All data collected 
at Randomization (predose) are 
considered the baseline values for the 
purposes of data analyses. Subjects 
who continue to meet all eligibility 
requirements will be randomized to 
receive MLS-101 or placebo.  
• Added footnote c. If Screening results 
are available, inclusion/exclusion 
evaluation will be performed. If 
subject is not eligible based on 
Screening results, they will not 
continue to Visit 4. If Screening 
results are not available, subject 
proceeds to Visit 4. 
• To combine the 
screening and start of 
Placebo Run-in visits 
(V2 and V3) 
• To clarify that the BP 
check at Visit 15 is 
performed at home and 
not in clinic  
• To delete definition of 
baseline values 
• To clarify eligibility 
based on availability of 
Screening results at 
Visit 4 
• To clarify eligibility 
based on availability of 
Screening results at 
Visit 5 
• To clarify that the BP 
check at Visit 15 is 
performed at home and 


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Section/Section Title 
Description of Change 
(strikeout denotes a deletion; bold denotes an 
addition) 
Brief Rationale for Change 
• Added footnote d. If Screening results 
are not available at Visit 4, subject 
should attend Visit 5 to determine 
final eligibility. If eligible based on 
Screening results, ABPM assessment 
can begin at Visit 5. 
• Added footnote g. Blood pressure 
measurement to be performed at 
home. 
• Modified footnote i. The ABPM 
procedure will be initiated at home 
approximately 24 hours before 
Randomization (Study Day 1) and again 
in the clinic at the Study Week 8 clinic 
visit 
• Modified footnote k. A sample for 
serum pregnancy test will be collected 
at Screening (within 7 days of the /start 
of the single-blind, Pplacebo Rrun-in, 
ie, between Study Days -21 andDay -14 
± 2 
• Modified footnote l. If PRA > 0.6 
ng/mL, measurement should be repeated 
and medical monitor should be 
contacted. 
• Modified footnote t. On site visit days, 
subjects should be instructed to take 
their morning dose of study drug at 
home prior to arriving at the site 
not in clinic 
• To clarify that the 
Study Week 8 ABPM 
procedure will be 
initiated in the clinic 
• To clarify serum 
pregnancy test 
• To clarify that PRA and 
aldosterone values must 
be met at Pre-Screening 
only for inclusion in the 
study 
• To clarify that subjects 
should take morning 
dose of study drug at 
site on site visit days 
Section 4.3/Number of 
Subjects/Number of Centers 
… to be eligible to enter up to 4 weeks of 
screening Screening/Placebo Run-in… 
To combine the screening 
and start of Placebo Run-in 
visits (V2 and V3) 
Section 4.4/Study Duration 
It is anticipated that each subject’s duration 
of participation will be approximately 2016 
weeks (up to 2 weeks of pre-Sscreening 
and up to 4 weeks of screening, followed 
by up to 2 weeks of Screening/single-
blind Pplacebo Rrun-in period, 8 weeks of 
double-blind treatment with study drug, 
and a 4-week follow-up period). Total 
duration of the study will be approximately 
2221 months 
To clarify duration of 
subject participation and 
total study duration 
Section 4.8.1/Pre-Screening 
Subjects with a history of hypertension, ie, 
SBP ≥ 135 mm Hg, who meet the protocol 
definition… 
To clarify criteria subjects 
must meet to enter pre-
Screening 


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Section/Section Title 
Description of Change 
(strikeout denotes a deletion; bold denotes an 
addition) 
Brief Rationale for Change 
Section 4.8.2/Screening/Start of 
Placebo Run-in (Visit 2/Visit 3, 
Study Day -14 ± 2 Days 
• All subjects with PRA ≤ 0.6 ng/mL and 
serum aldosterone values meeting the 
pre-Screening criteria (ie, PRA ≤ 0.6 
ng/mL/hr and aldosterone ≥ 6 ng/dL 
or alternative target guidance 
provided by the sponsor) will be 
eligible to enter up to 4 weeks of 
Screening/Placebo Run-in. 
• If PRA > 0.6 ng/mL, measurement 
should be repeated and medical monitor 
should be contacted. 
• Once all Screening procedures are 
complete, subjects immediately enter 
the single-blind run-in period of BID 
oral treatment with placebo while 
continuing to remain on stable doses 
of their background antihypertensive 
medications. 
• To clarify criteria 
necessary to enter 
Screening/Placebo 
Run-in 
• To clarify that Pre-
Screening 
measurements of PRA 
and aldosterone 
determine ability to 
enter Screening 
Section 4.8.3/Single-blind Placebo 
Run-in Week 2 (Visit 4, Study 
Day -7 ± 2 Days) 
Subjects will return to the research facility at 
the beginning of Week 2 of the run-in period 
for the following procedures: 
• Inclusion/exclusion assessment (based on 
Screening assessment results from 
V2/V3). If Screening results are available, 
and subject is determined to be ineligible 
for the study, the site will review AEs, 
concomitant medications, and study drug 
compliance. Vital signs and AOBP will 
not be performed. 
• Vital signs (body temperature, heart rate, 
respiratory rate) only if subject is eligible 
for the study or if Screening results are 
not yet available 
• AOBP (average of the last 2 of 5 
unattended measurements using an 
automated oscillometric 
sphygmomanometer device after 
approximately 5 minutes of rest in the 
seated position) only if subject is eligible 
for the study or if Screening results are 
not yet available 
• Review of AEs, concomitant medications, 
and study drug compliance On the second 
visit of the placebo-run in period (Visit 
4), for all subjects regardless of 
eligibility status 
Subjects will be evaluated for eligibility 
based on Screening results and if 
eligible, or if Screening results are not 
available, subjects will continue on 
Week 2 of Placebo Run-in and will be 
To clarify the study 
procedures to be done at 
the beginning of Week 2 
of the run-in period 


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Section/Section Title 
Description of Change 
(strikeout denotes a deletion; bold denotes an 
addition) 
Brief Rationale for Change 
given an ABPM device and instructions on 
how to perform the ABPM procedure by 
the investigator to take home for use on 
Study Day 0, approximately 24 hours 
before Randomization (Study Day 1). 
Note: only subjects who have Screening 
results and are considered eligible 
should be provided with the ABPM for 
home use. Subjects who do not have 
Screening results available should attend 
Visit 5. 
Section 4.8.4/Telephone or Office 
Visit 
After completion of the single-blind, 
Pplacebo Rrun-in period, subjects will 
participate in a telephone or office visit on 
Study Day 0 in which they will be reminded 
how to perform the ABPM and spot urine 
collection procedures by the investigator or 
study coordinator. Alternatively, sites may 
choose to schedule If Screening results 
were not available at Placebo Run-in Visit 
4, subjects should participate in an 
abbreviated office visit on Study Day 0 to 
initiate theto review eligibility. If eligible, 
ABPM procedure will be initiated. The 
following procedures will be performed: 
• Inclusion/exclusion assessment (if 
necessary) 
To clarify the study 
procedures to be done at the 
beginning of Week 2 of the 
run-in period 
Section 4.8.6/Study Week 1 and 
Section 4.8.7/Study Week 2 and 
Section 4.8.8/Study Week 3 and 
Section 4.8.9/Study Week 4 and 
Section 4.8.10/Study Week 5 and 
Section 4.8.11/Study Week 6 and 
Section 4.8.12/Study Week 7 and 
Section 4.8.13/Study Week 8 
…subjects will return to the site and the 
following procedures will be performed 
after home site administration of the 
morning dose of study drug: 
To clarify that subjects 
should take morning dose of 
study drug at site on clinic 
days 
Section 4.8.13/Study Week 8 
Added 24-hour ABPM in list of procedures 
To clarify that the Study 
Week 8 ABPM procedure 
will be initiated in the clinic 
Section 4.8.14/Telephone Visit 
…subjects will participate in a telephone 
visit during which they will perform the 
following procedure at home: 
• 
AOBP (average of the last 2 of 5 
unattended measurements using an 
automated oscillometric 
sphygmomanometer device after 
approximately 5 minutes of rest in 
the seated position) 
• BP check 
To clarify that the BP check 
at Visit 15 is performed at 
home and not in clinic 


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Section/Section Title 
Description of Change 
(strikeout denotes a deletion; bold denotes an 
addition) 
Brief Rationale for Change 
Section 5.3.2/Caffeine Alcohol, 
and Tobacco and throughout the 
protocol for consistency (eg, 
Sections 6.5.2.1, 6.5.3, 8.1.1, 
8.2.2, 8.2.4, 8.2.7, 8.3.1, 8.5) 
Screening/start of Placebo Run-in… 
To clarify Screening and 
start of Placebo Run-in are 
combined in the same visit 
Section 5.4/Screen Failures 
Individuals who do not meet the Screening 
criteria for participation in this study 
(screen failures) may be rescreened up to 3 
times during the 4-week Screening period. 
Details on reScreening are provided in the 
study manual. 
To clarify that subjects may 
be rescreened up to 3 times 
with no further details 
provided 
Section 6.1.2/Dosing and 
Administration 
• Placebo Run-In: Once enrolled Upon 
signing the Screening/main study ICF  
• On site visit days, subjects should be 
instructed to take their morning dose of 
study drug at home prior to arriving at 
the site 
• To clarify that subjects 
begin placebo run-in after 
signing ICF 
• To clarify that subjects 
should take morning dose 
of study drug at site on site 
visit days 
Section 6.3/Randomization and 
Blinding 
All subjects who qualify based on 
inclusion/exclusion criteria and complete 
the up to a 2-week Pplacebo Rrun-in 
period… 
To clarify subject eligibility 
to enter Randomization 
Section 9.3.2/Efficacy Analyses 
The mean will be based upon the last on 
treatment value recorded for each subject 
prior to the use of any antihypertensive 
medications prescribed as “rescue” 
medications… 
To clarify that rescue 
medications are defined as 
prescribed antihypertensive 
medications 
 


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12.11.5. Amendment 2 (01 June 2021) 
This summary includes changes made to Protocol MLS-101-201 Amendment 1 (15 April 2021). 
The overall rationale for the changes implemented in this protocol amendment was to modify the 
dose groups. 
The following is a summary of content-oriented changes that were made to each section of the 
protocol, and a brief rationale for these changes. Minor editorial and document formatting 
revisions have not been summarized. 
Section/Section Title 
Description of Change 
(strikeout denotes a deletion; bold denotes 
an addition) 
Brief Rationale for Change 
Synopsis/Objectives and Endpoints 
and Section 3.1/Study Objectives 
at 65 dosing regimens versus placebo 
Changed from 6 to 5 dosing 
regimens versus placebo 
Synopsis/Methodology and 
Section 4.1/Overall Study Design 
Stable background treatment must 
include ≥ 2 antihypertensives (note: a 
combination pill = 2 antihypertensives) 
that have been stable at their maximum 
tolerated prescribed doses and stable 
for at least 4 weeks prior to signing the 
Screening/main study informed consent 
form (ICF). Background therapy may 
be adjusted at the investigator’s 
discretion. 
Modified language 
describing background 
therapy 
Synopsis/Methodology and 
Section 4.1/Overall Study Design 
and Section 4.3 Number of 
Subjects/Number of Study Centers 
Approximately 875 750 subjects will 
undergo up to 2 weeks of pre-Screening. 
It is estimated that approximately 263 
225 subjects will have qualifying 
PRA…Assuming a 20% drop-out rate, a 
total of 210 180 subjects will meet all 
eligibility requirements… 
Adjusted numbers due to 
dropping a dose group 
Synopsis/Methodology and 
Section 4.1/Overall Study Design 
…SBP and DBP will be measured 5 
times after approximately 5 minutes of 
rest in the seated position…Subjects 
may also be provided with an 
automated digital oscillometric home 
BP device to measure BP at home at 
the investigator’s discretion. 
Added the option of 
allowing subjects to measure 
BP at home 
Synopsis/Methodology and 
Section 4.1/Overall Study Design 
and Section 6.3/Randomization and 
Blinding 
Approximately 210 180 enrolled 
subjects ≥ 18 years of age will be 
randomized into 7 6 equal treatment 
groups (1:1:1:1:1:1:1) to 12.5 mg BID, 
25 mg BID, 100 12.5 mg BID 50 mg 
once daily (QD), 100 50 mg QD, 300 
100 mg QD, or placebo 
Modified dose groups 
Synopsis/Number of Subjects 
(planned) 
Approximately 180 210 subjects are 
planned to be enrolled 
Adjusted numbers due to 
dropping a dose group 
Synopsis/Eligibility Criteria and 
Section 5.1/Inclusion Criteria (#4) 
and Section 6.7.2/Permitted 
Treatments 
Background antihypertensive treatment 
of ≥ 2 drugs…that have been stable at 
their maximum tolerated prescribed 
doses 
Modified language 
describing background 
therapy 


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Synopsis/Eligibility Criteria and 
Section 5.2/Exclusion Criteria (#3) 
Subjects with hypokalemia, ie, serum 
potassium < 3.0 mEq/L despite oral 
administration of potassium chloride 
(6 g/day) 
Modified hypokalemia 
exclusion criteria 
Synopsis/Eligibility Criteria and 
Section 5.2/Exclusion Criteria (#10) 
Chronic long-acting oral nitrates that 
have been stable at their maximum 
tolerated prescribed doses 
Modified language 
describing use of nitrates 
Synopsis/Eligibility Criteria and 
Section 5.2/Exclusion Criteria (#12) 
Subjects with a decrease in SBP 
≥ 20 mm Hg or DBP ≥ 10 mm Hg from 
sitting to standing position (may be 
rescreened up to 3 times repeated 
during Screening at the investigator’s 
discretion) 
Clarified that standing BP 
measurement may be 
repeated during Screening 
Synopsis/Eligibility Criteria and 
Section 5.2/Exclusion Criteria (#16) 
and Section 6.7.1/Prohibited 
Treatments 
a. Chronically administered oral or 
topical corticosteroids… Short-term (ie, 
≤ 2 weeks) of topical corticosteroids are 
allowed if taken ≥ 1 month prior to 
Screening Randomization. 
d. Regular use of pPhosphodiesterase 
type 5 inhibitors within 3 months of 
Screening or during study participation 
Clarified short-term 
corticosteroids allowed 
≥ 1 month prior to 
Randomization and that 
regular use of 
phosphodiesterase type 5 
inhibitors are prohibited 
Synopsis/Investigational Product, 
Dosage, and Mode of 
Administration 
MLS-101 will be administered orally in 
the dosage 12.5 mg BID, 25 mg BID, 
100 12.5 mg BID QD, 50 mg QD, or 
100 mg QD, or 300 mg QD 
Modified dose groups 
Synopsis/Figure 1: Study Schema 
Modified dose groups 
Modified dose groups 
Synopsis/Table 1: Schedule of 
Assessments, footnote f and 
Section 8.1.2/24-hour Ambulatory 
Blood Pressure Monitoring  
The ABPM procedure will be initiated at 
home approximately 24 hours before 
Randomization (Study Day 1) and again 
approximately 24 hours before at the 
Study Week 8 visit  
Clarified timing of second 
ABPM procedure 
Synopsis/Table 1: Schedule of 
Assessments, footnote l and 
Section 6.5.3/Adrenal Insufficiency 
ACTH stimulation test may be waived 
with sponsor’s approval 
Added option to waive 
ACTH test 
Synopsis/Table 1: Schedule of 
Assessments, footnote q and 
Section 6.1.2/Dosing and 
Administration 
On site visit days, subjects should be 
instructed to take their morning dose 
of study drug at home prior to 
arriving at the site. 
Clarified that morning dose 
should occur at home on site 
visit days 
Section 4.2/Scientific Rationale for 
Study Drugs and 
Section 4.5/Justification for Dose 
…evaluate both QD and BID dosing 
across a total daily dose of 25 12.5 mg 
to 300 100 mg for 8 weeks… 
Modified dose range 
Section 4.3/Number of 
Subjects/Number of Centers  
The subjects who qualify for enrollment 
will be randomly divided into 7 6 equal 
treatment groups (1:1:1:1:1:1:1 with 
approximately 30 subjects per group 
Changed from 7 to 6 equal 
treatment groups 
Section 4.5/Justification for Dose 
The proposed doses in this study provide 
2 cohorts (100 mg BID and 300 mg QD) 
projected to provide systemic MLS-101 
exposure above the aldosterone synthase 
inhibition half maximal inhibitory 
concentration (IC50) for an average of 24 
hours and 22 hours, respectively, and 4 
cohorts (12.5 mg BID, 25 mg BID, 50 
mg QD, and 100 mg QD) projected to 
provide exposures above the IC50 for an 
Clarified rationale behind 
new dose selection  


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average of 6, 13, 10, and 14 hours, 
respectively, which allows for testing 
the value of aldosterone break. A 25 mg 
QD dose would be below the minimally 
effective dose given the limited time 
above the current IC50 and was therefore 
not considered. Similarly, doses above 
100 mg BID would provide 24-hour 
coverage beyond the current IC50. The 
Phase 1 multiple ascending dose study 
demonstrated comparable 
physiological effects on 
mineralocorticoid-mediated renal 
tubular potassium reabsorption, a 
surrogate for sodium excretion and 
diuresis, at all dose levels tested from 
40 mg QD through 360 mg QD. Based 
on these results, the upper end of the 
dose range to be tested in this study 
includes 50 mg QD, which is predicted 
to be efficacious at lowering BP, and 
100 mg QD, which should result in a 
somewhat longer period of Cyp11B2 
inhibition (10 hours versus 14 hours) 
while still providing a period of time 
during which the kidney can escape 
from inhibition and perform the 
aldosterone-mediated function of 
regulating potassium 
homeostasis. The lower end of the 
dose range, 12.5 mg QD, was selected 
based on in vitro potency and the 
ability to inhibit Cyp11B2 for at least 
6 hours per day. This dose is 
anticipated to be submaximally 
effective in most individuals. The 
intermediate dosing regimens of 12.5 
mg BID and 25 mg BID were selected 
to define the benefit/risk of BID 
versus QD dosing regimens with 12.5 
mg BID and 25 mg BID providing 
temporarily more consistent 
inhibition of Cyp11B2. A PK/PD 
model was used to simulate steady state 
profiles and noncompartmental exposure 
parameters under several potential Phase 
2 regimens. Details of the PK/PD model 
are included in the Investigator’s 
Brochure (IB). Based on additional 
modeling, 100 mg BID and 300 mg 
QD dosing regimens are not 
anticipated to be necessary to achieve 
the PD targets. 


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Section 4.8.1/Pre-Screening  
…stable background treatment defined 
as ≥ 2 antihypertensives (note: a 
combination pill = 2 antihypertensives) 
that have been stable at their maximum 
tolerated prescribed doses… 
Modified language 
describing background 
therapy 
Section 4.8.2/Screening and 
Section 4.8.13/Study Week 8 
• ACTH stimulation test (may be 
waived with sponsor’s approval) 
Added ACTH stimulation 
test 
Section 4.8.6/Study Week 1 and 
Section 4.8.7/Study Week 2 and 
Section 4.8.8/Study Week 3 and 
Section 4.8.9/Study Week 4 and 
Section 4.8.10/Study Week 5 and 
Section 4.8.11/Study Week 6 and 
Section 4.8.12/Study Week 7 
…the following procedures will be 
performed prior to after home 
administration of the morning dose of 
study drug: 
Clarified that morning dose 
should occur at home on site 
visit days  
Section 4.8.13/Study Week 8 
Approximately 24 hours before At the 
Study Week 8 visit… 
Clarified timing of second 
ABPM procedure 
Section 6.1.2/Dosing and 
Administration 
Subjects will orally administer the 
assigned study drug (MLS-101 [12.5 mg 
BID, 25 mg BID, 100 12.5 mg BID QD, 
50 mg QD, 100 mg QD, 300 mg QD] 
Modified dose groups 
Section 6.1.2/Dosing and 
Administration 
Subjects will be monitored by ABPM 
for 24 hours before the first morning 
dose on Study Day 1 and for 24 hours 
before after the last morning… 
Clarified timing of second 
ABPM procedure 
Section 6.5.1/Hyperkalemia, Table 
2 
Modified table to reflect new dosing 
regimens 
Modified table to reflect 
new dosing regimens 
Section 6.5.2.1/Orthostatic 
Hypotension 
In the case of If subjects experience 
orthostatic hypotension during 
Screening, subjects measurement may 
be rescreened up to 3 times repeated 
during the Screening period to be 
eligible for study enrollment… 
Clarified that orthostatic 
hypotension measurement 
may be repeated during 
Screening 
Section 8.1.2/24-hour Ambulatory 
Blood Pressure Monitoring 
Subjects will be monitored by ABPM 
for 24 hours before the first dose on 
Study Day 1 and before after the last 
dose… 
Clarified timing of second 
ABPM procedure 
Section 9.5/Interim Analysis 
…will be performed after the first 5 to 
10 subjects in each dose group (70 30 to 
60 subjects total) complete 4 weeks of 
treatment 
Modified number of total 
subjects required to 
complete 4 weeks of 
treatment before interim 
analysis 
Section 12.2/Study Contacts 
Corrected Sponsor’s email address 
Corrected Sponsor’s email 
address 
Section 12.5 Standing Blood 
Pressure Measurement 
…(measurement may be rescreened up 
repeated during the Screening period 
to be eligible for study enrollment). 
Clarified that orthostatic 
hypotension measurement 
may be repeated during 
Screening 
 


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12.11.6. Amendment 1 (15 April 2021) 
This summary includes changes made to Protocol MLS-101-201 (06 February 2021). The overall 
rationale for the changes implemented in this protocol amendment was to clarify specific 
procedures. 
The following is a summary of content-oriented changes that were made to each section of the 
protocol, and a brief rationale for these changes. Minor editorial and document formatting 
revisions have not been summarized. 
Section/Section Title 
Description of Change 
(strikeout denotes a deletion; bold denotes 
an addition) 
Brief Rationale for Change 
Title of Study and Appendix 12.3 
and Appendix 12.4 
A Randomized, Double-blind, Placebo-
Controlled, Dose-Ranging, Multicenter 
Phase 2 Study to Evaluate the Safety, 
Efficacy, and Tolerability of MLS-101 
in Subjects With Low Renin 
Uncontrolled Hypertension 
Modified definition of 
hypertension 
Synopsis/Objectives and Endpoints 
and Section 3.1.2/Secondary 
Objectives 
…for the treatment of low renin 
uncontrolled hypertension… 
Modified definition of 
hypertension 
Synopsis/Pharmacokinetics and 
Table 1: SoA and 
Section 3.2.4/Pharmacokinetic 
Endpoints 
Added Study Week 8 pharmacokinetic 
assessment 
Additional pharmacokinetic 
measurement 
Synopsis/Pharmacodynamics and 
Section 3.2.5/Pharmacodynamic 
Endpoints 
Change in plasma aldosterone, 11-
deoxycorticosterone, 11-deoxycortisol 
and plasma renin activity (PRA) from 
baseline to the end of Study Weeks 4 
and 12 (end of follow-up) 
Change in serum aldosterone, cortisol, 
and 11-deoxycorticosterone 
concentration from baseline to the end 
of Study Weeks 4 and 12 (end of 
follow-up) 
Clarified that serum 
aldosterone and 
11-deoxycorticosterone will 
be measured (not plasma) 
Synopsis/Methodology and 
Section 2.1/Study Rationale and 
Section 4.1/Overall Study Design 
… low-renin uncontrolled hypertension 
(PRA ≤ 0.6 ng/mL hypertensive 
despite receiving ≥ 2 
antihypertensives)… 
Modified definition of 
hypertension 
Synopsis/Methodology and 
Section 4.1/Overall Study Design 
and Section 6.1.2/Dosing and 
Administration 
…a single-blind (subjects blinded to 
treatment allocation)… 
Clarified who is blinded in 
Placebo Run-in phase 
Synopsis/Methodology and Table 1: 
SoA and Figure 1 and 
Section 4.1/Overall Study Design 
and Section 4.8.4/Telephone or 
Office Visit and Section 8.1.2/ 
24-Hour ABPM 
Alternatively, sites may choose to 
schedule an abbreviated office visit on 
Study Day 0 (Visit 5) to initiate the 
ABPM procedure. 
Added ability to schedule an 
abbreviated office visit to 
initiate ABPM 


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Section/Section Title 
Description of Change 
(strikeout denotes a deletion; bold denotes 
an addition) 
Brief Rationale for Change 
Synopsis/Safety Criteria for Dose 
Adjustment or Stopping Treatment 
and  
Section 4.1/Safety Criteria for Dose 
Adjustment or Stopping Treatment 
and Section 6.5 Dose Adjustment 
a subject meets 1 or more of the 
laboratory exclusion criteria for the 
study (eg, seated SBP ≥ 175 mm Hg or 
DBP ≥ 100 mm Hg, serum potassium 
> 5.2 mEq/L, serum cortisol 
< 3 mcg/dL) 
Added serum cortisol level 
as exclusion criteria 
Synopsis/ Safety Criteria for Dose 
Adjustment or Stopping Treatment 
and  
Section 4.1/Safety Criteria for Dose 
Adjustment or Stopping Treatment 
and 
Section 6.5/Dose Modification 
… and the subject’s dose of study drug 
may be adjusted or temporarily withheld 
at the discretion of the investigator in 
consultation with the medical monitor. 
all subjects will be monitored for signs 
and symptoms of adrenal insufficiency 
(ie, nausea, vomiting, light-
headedness, low BP, or electrolyte 
abnormalities) at every study visit. 
Based on changes in cortisol levels, an 
adrenocorticotropic hormone (ACTH) 
stimulation test (Appendix 12.7) may 
be performed and the subject’s dose of 
study drug may be stopped. Guidelines 
for dose potential dose discontinuation 
in the management of adrenal 
insufficiency are included in 
Section 6.5.3. 
Added more specific 
guidelines regarding adrenal 
insufficiency 
Synopsis/Eligibility Criteria  
and  
Section 5.1/ Inclusion Criteria 
1…female subjects and their partners 
must agree to use 1 of the following 
either highly effective or acceptable 
methods of contraception as defined in 
Appendix 12.8 from Screening to 
90 days post last dose of study drug: 
a. Double barrier method (eg, condom 
with spermicide in conjunction with the 
use of an intrauterine device or 
diaphragm) 
b. Surgical sterilization, ie, tubal 
ligation or vasectomy 
Added more detailed 
contraceptive language in 
Appendix 12.8 
Synopsis/Eligibility Criteria 
and 
Section 5.1/ Inclusion Criteria 
7. Serum cortisol ≥ 18 mcg/dL 
(morning measurement) or serum 
cortisol > 3 and < 18 mcg/dL (morning 
measurement) if there is no evidence 
of adrenal insufficiency based on 
normal ACTH stimulation test results 
Added inclusion criteria 
regarding cortisol 
Synopsis/Eligibility Criteria 
and 
Section 5.2/ Exclusion Criteria 
5. Subjects with serum cortisol 
< 3 mcg/dL based on morning 
measurement 
6. Subjects with serum sodium 
< 135 mEq/L 
Added exclusion criteria 
regarding cortisol and 
sodium 


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Section/Section Title 
Description of Change 
(strikeout denotes a deletion; bold denotes 
an addition) 
Brief Rationale for Change 
Synopsis/Eligibility Criteria 
and 
Section 5.2/ Exclusion Criteria 
and  
Section 6.7.1/Prohibited Treatments 
16a. Chronically administered oral or 
topical corticosteroids within 3 months of 
Screening or during study participation. 
Short-term (ie, ≤ 2 weeks) of topical 
corticosteroids are allowed if taken 
≥ 1 month prior to Screening. 
16e. Chronic use of nonsteroidal anti-
inflammatory drugs (NSAIDs), other 
than low dose aspirin (81-325 mg),… 
Modified exclusion criteria 
16a and 16e 
Table 1: Schedule of Assessments 
• Added pregnancy test at Week 4 
• Added ACTH stimulation test at 
Screening and Week 8 
• Added PK collection at Week 8 
• Modified footnotes 
Addressed safety concerns 
regarding pregnancy and 
cortisol levels 
Table 1: Schedule of Assessments 
(footnotes i, j) and 
Section 4.8/Study Conduct and 
Section 8.5/Pharmacodynamics 
Blood samples plasma for aldosterone 
and… 
Replaced blood plasma with 
blood samples since both 
serum and plasma collected 
Table 1: Schedule of Assessments 
(footnote p) 
All Aadverse events collected during 
Placebo Run-in are not considered 
treatment-emergent events for the 
purposes of data analyses. Sand serious 
adverse events will be collected from 
the signing… 
Clarified timing of adverse 
event collection  
Section 2.1/Study Rationale 
By using a biomarker to identifying 
patients who have low-renin 
hypertension associated with from 
autonomous aldosterone… 
Modified definition of 
hypertension 
Section 4.8.2/Screening 
and Section 4.8.13/Study Week 8  
• Blood samples for ACTH 
stimulation test (Appendix 12.7) 
Added ACTH stimulation 
test at Screening and 
Week 8 
Section 4.8.9/Study Week 4 and 
Section 8.2.7/Pregnancy Testing 
• Pregnancy test (urine; women of 
childbearing potential only) 
Added pregnancy test at 
Week 4 
Section 4.8.13/Study Week 8 
Single blood samples for 
determination of MLS-101 will be 
collected. Additional blood samples for 
long-term storage for metabolites, 
drug-drug interaction profiles of 
background therapy, or other 
exploratory analyses will also be 
collected 
Added PK sample collection 
at Week 8 
Section 6.5.3/Adrenal Insufficiency 
Serum cortisol levels will be measured 
at Screening, Randomization, Study 
Weeks 1, 2, 3, 4, 5, 6, 7, 8, and at the 
follow up visit (Study Week 12). 
Cortisol assessment should occur before 
10 am on the morning of the study visit. 
In addition, subjects should be 
monitored for signs and symptoms of 
adrenal insufficiency (ie, nausea, 
vomiting, light-headedness, low BP, or 
electrolyte abnormalities) at every 
Added Section 6.5.3 on 
adrenal insufficiency and 
instructions of management 
of adrenal insufficiency 


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Section/Section Title 
Description of Change 
(strikeout denotes a deletion; bold denotes 
an addition) 
Brief Rationale for Change 
study visit. If adrenal insufficiency is 
suspected, glucocorticoid replacement 
therapy should be initiated until 
adrenal insufficiency can be ruled out. 
Based on morning cortisol level at the 
central laboratory measurement, the 
following actions are to be taken: 
• Serum cortisol ≥ 18 mcg/dL: No 
action required. 
• Serum cortisol > 3 and 
< 18 mcg/dL: If there are no signs 
or symptoms of adrenal 
insufficiency (see above), then no 
action is required. If signs or 
symptoms of adrenal insufficiency 
are observed, then an ACTH 
stimulation test should be 
performed as described in 
Appendix 12.7 to rule out adrenal 
insufficiency. If there is no 
evidence of adrenal insufficiency 
based on ACTH stimulation test 
results, then continue at current 
dose. If ACTH stimulation test is 
abnormal, then study drug should 
be discontinued. 
• Serum cortisol < 3 mcg/dL: If at 
any time during the study serum 
cortisol < 3 mcg/dL, then 
measurement should be repeated. 
If confirmed, then an ACTH 
stimulation test should be 
performed as described in 
Appendix 12.7 to rule out adrenal 
insufficiency. If there is no 
evidence of adrenal insufficiency 
based on ACTH stimulation test 
results, then continue at current 
dose. If ACTH stimulation test is 
abnormal, then study drug should 
be discontinued.  
Any subject who is withdrawn from 
the study or has low cortisol levels at 
the final study visit should be 
evaluated until full normalization of 
the hypothalamic-pituitary-adrenal 
axis occurs. In addition, all subjects 
should be instructed to carry a card at 
all times identifying the potential risk 
for adrenal insufficiency. The card 
should include the subject’s 
information, the investigator’s contact 


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Section/Section Title 
Description of Change 
(strikeout denotes a deletion; bold denotes 
an addition) 
Brief Rationale for Change 
information, and the potential need for 
glucocorticoids in the settings of shock, 
surgery, etc. 
Section 6.7.1/Prohibited Treatments 
ACE inhibitors and ARBs in 
combination as background 
antihypertensive treatment 
Added prohibited treatment 
to be consistent with 
Exclusion Criteria 
Section 8.2.4/Electrocardiogram 
These ECG readings will be sent to a 
core ECG laboratory for central review. 
Any abnormalities observed at Screening 
will be reported to the investigator to 
assist in Inclusion/Exclusion evaluations. 
Deleted ECG central lab 
review 
Section 8.3.1/Time Period and 
Frequency for Collecting AE and 
SAE Information 
Medical occurrences Adverse events 
that begin before the start of study drug, 
but after obtaining informed consent 
will not be recorded as medical 
history/current medical conditions, not 
as treatment-emergent AEs. Adverse 
events collected during Placebo Run-in 
are not considered treatment-emergent 
events for the purposes of data analyses. 
Clarified timing of 
collection of adverse events  
Section 8.3.7/Adverse Events of 
Special Interest 
The AESIs for all study drugs (MLS-101 
and placebo) include the following: 
• 
Hyperkalemia 
• 
Hypotension with symptoms (eg, 
light-headedness, dizziness, 
presyncope, or syncope) 
• Adrenal Insufficiency 
Clarified definition of study 
drugs and added adrenal 
insufficiency as an AESI 
Section 8.4/Pharmacokinetics 
…on Study Day 1 (predose), and at 
Study Weeks 1, 4, and 8 (trough levels). 
Additional blood samples for long-term 
storage for metabolites, drug-drug 
interaction profiles of background 
therapy, or other exploratory analyses 
will also be collected at baseline 
(predose) and at Study Weeks 1, 4, 
and 8. 
Added additional PK sample 
collection at Study Week 8 
and clarified that additional 
blood samples will also be 
collected at these time 
points 
Section 8.5/Pharmacodynamics 
Blood plasma samples for aldosterone, 
cortisol, 11-deoxycorticosterone, 
11-deoxycortisol, and PRA will be 
collected at Screening, Study Day 1 
(baseline), Study Week 4, and Study 
Week 12 (end of follow up). 
Added cortisol to 
pharmacodynamic 
measurements 
Section 9.3.3/Safety Analyses 
The safety analysis set will be used for 
the efficacysafety analyses. 
Corrected typo 


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Section/Section Title 
Description of Change 
(strikeout denotes a deletion; bold denotes 
an addition) 
Brief Rationale for Change 
Section 9.3.5/Pharmacodynamic 
Analyses 
The mean change from baseline in 
plasma aldosterone, 11-
deoxycorticosterone, 11-deoxycortisol, 
and PRA will be summarized… 
The mean change from baseline in serum 
aldosterone, cortisol, and 
11-deoxycorticosterone concentration 
will be summarized for each week 
recorded 
Clarified that serum 
aldosterone and 
11-deoxycorticosterone will 
be measured (not plasma) 
Section 12.7/ACTH Stimulation 
Test 
Added Appendix 12.7 
Added instructions on 
performing ACTH 
stimulation test 
Section 12.8/Contraceptive and 
Barrier Guidance 
Added Appendix 12.8 
Added contraceptive and 
barrier guidance 
Section 12.9/Clinical Laboratory 
Tests 
Pharmacodynamics:  
Plasma Serum aldosterone 
Plasma Serum cortisol 
Serum 11-deoxycorticosterone 
Clarified that serum 
aldosterone and 
11-deoxycorticosterone will 
be measured (not plasma) 
and that cortisol will be 
collected as part of 
pharmacodynamics 
 

SAP_001.pdf: