Protocol No. HML-PHX-005 Version 11.0 02 DEC 2016 A Phase 2, Multi-Center, Open-Label, Ascending Dose Study on the Efficacy, Safety and Tolerability of Perhexiline in Patients with Title Hypertrophic Cardiomyopathy and Moderate-to Severe Heart Failure with Preserved Left Ventricular Function Study Number HML-PHX-005 Treatment of Moderate-to-Severe Symptomatic Hypertrophic Indication Cardiomyopathy Study Phase Phase 2 Sponsor Heart Metabolics, Ltd. US IND 118,826 Study Sites Multicenter Protocol Physician Mark Midei, M.D. Anticipated Initiation: Q3 2016 Study Dates Anticipated Completion: Q1 2017 Version and Date: Version 11.0, 02 December 2016 This document contains information that is confidential and proprietary to the Sponsor, Heart Metabolics, Ltd. This information is being provided to you solely for the purpose of evaluating and/or conducting a clinical trial for the Sponsor. You may disclose the contents of this document only to study personnel under your supervision, the Institutional Review Board, the United States Food and Drug Administration, or duly authorized representatives of regulatory agencies for this purpose under the condition that they maintain confidentiality. The contents of this document may not be used in any other clinical trial, disclosed to any other person or entity, and/or published without the prior written permission of the Sponsor. The foregoing shall not apply to disclosure required by any regulations; however, you will give prompt notice to the Sponsor of any such disclosure. Heart Metabolics — Company Confidential Page 1 of 58 Protocol No. HML-PHX-005 Version 11.0 02 DEC 2016 Table of Contents 1 CLINICAL PROTOCOL SYNOPSIS .................................................................... 7 2 INTRODUCTION .............................................................................................. 14 2.1 Hypertrophic Cardiomyopathy ........................................................................... 14 2.2 Unmet Clinical Need in Symptomatic Hypertrophic Cardiomyopathy ................ 14 2.3 Perhexiline ........................................................................................................ 14 2.4 Mixed Ion Channel Effects of Perhexiline .......................................................... 15 2.5 Perhexiline Thorough QT Study ........................................................................ 15 2.6 Perhexiline Summary ........................................................................................ 15 2.7 PEX-CIS Assay ................................................................................................. 16 2.7.1 Description of PEX-CIS Assay .......................................................................... 16 2.7.2 Use of the PEX-CIS Assay in This Study .......................................................... 16 2.8 Study Rationale ................................................................................................ 16 2.8.1 Therapeutic Window Rationale ......................................................................... 17 2.8.2 Primary Endpoint Rationale .............................................................................. 17 2.8.3 Mitigation of Potential QT Prolongation ............................................................. 17 2.8.4 Monitoring of Systemic Levels and Dose Adjustment of Perhexiline ................. 19 3 OBJECTIVES ................................................................................................... 19 3.1 Primary Objective ............................................................................................. 19 3.2 Secondary Objectives ....................................................................................... 19 4 INVESTIGATIONAL PLAN ................................................................................ 20 4.1 Overall Study Design ........................................................................................ 20 4.2 Inclusion Criteria ............................................................................................... 20 4.2.1 General Inclusion Criteria.................................................................................. 20 4.2.2 Cardiomyopathy-Related Inclusion Criteria ....................................................... 20 4.3 Exclusion Criteria .............................................................................................. 21 4.3.1 General Exclusion Criteria: ............................................................................... 21 4.3.2 QT Interval-Related Exclusion Criteria .............................................................. 22 4.3.3 Other Exclusion Criteria .................................................................................... 22 4.3.4 Cardiomyopathy-related Exclusion Criteria ....................................................... 22 4.4 Study-Drug Dosing and Systemic Drug-Level Monitoring .................................. 22 4.4.1 Study-Drug Dosing............................................................................................ 22 4.4.2 Monitoring of Systemic Perhexiline and cis- and trans-Hydroxy Perhexiline ...... 23 4.4.3 Dose-Adjustment of Study Drug ........................................................................ 23 4.4.4 Dose-Adjustment for QTcF/JTcF Prolongation .................................................. 24 4.5 Management of Possible PEX Overdosage ...................................................... 25 4.6 Patient Withdrawal and Discontinuation ............................................................ 25 4.7 Concomitant Medication ................................................................................... 26 Heart Metabolics — Company Confidential Page 3 of 58 Protocol No. HML-PHX-005 Version 11.0 02 DEC 2016 4.8 Study Monitoring Team ..................................................................................... 26 5 STUDY DRUG SUPPLIES ................................................................................ 27 5.1 Perhexiline ........................................................................................................ 27 5.2 Study Drug Formulation .................................................................................... 27 5.3 Drug Storage .................................................................................................... 27 5.4 Study-Drug Dispensing and Dosing Instructions ............................................... 27 5.5 Withdrawal of Perhexiline at Study Termination ................................................ 28 5.6 Treatment Compliance ...................................................................................... 28 5.7 Drug Accountability ........................................................................................... 28 6 STUDY SCHEDULE AND ACTIVITIES ............................................................. 28 6.1 Scheduling Windows for Study Procedures and Evaluations ............................ 28 6.2 Schedule of Assessments ................................................................................. 29 6.3 Screening ......................................................................................................... 33 6.4 Period 1: Baseline Visit and Commencement of Study-Drug Dosing ................. 33 6.5 Period 1; Day 8 (± 1 Day), After Completion of Week 1 .................................... 35 6.6 Periods 1 and 2 ................................................................................................. 35 6.7 Period 1; Additional Procedures At Completion of Week 8 ................................ 36 6.8 Period 2: End of Treatment and After Completion of Week 16 .......................... 36 6.9 Follow-up Visit (Four Weeks following the conclusion of dosing)....................... 36 6.10 Patient Contact for Dose-Adjustment Instructions ............................................. 37 6.11 Subjects Who Withdraw From the Study ........................................................... 37 7 SAFETY MONITORING .................................................................................... 37 7.1 Adverse Events ................................................................................................. 37 7.2 Life-threatening adverse event or life-threatening suspected adverse reaction . 37 7.3 Serious Adverse Event or Serious Suspected Adverse Reaction ...................... 38 7.4 Suspected Adverse Reaction ............................................................................ 39 7.5 Unexpected Adverse Event or Unexpected Suspected Adverse Reaction. ....... 39 7.6 Assignment of Adverse Event Intensity and Relationship to Perhexiline ........... 39 7.7 Collection and Reporting of Adverse Events ..................................................... 39 7.7.1 Reporting Serious Adverse Events or Serious Suspected Adverse Reaction .... 40 7.7.2 Handling of Expedited Safety Reports .............................................................. 40 7.7.3 Non-serious Adverse Events ............................................................................. 41 7.8 Laboratory Test Abnormalities .......................................................................... 41 7.9 Adverse Device Effects ..................................................................................... 41 7.9.1 Definitions ......................................................................................................... 41 7.9.2 Reporting of ADEs ...........................................................................................