NDA/BLA Multi-disciplinary Review and Evaluation: NDA 212994 Azstarys (serdexmethylphenidate and dexmethylphenidate) capsules, for oral use NDA/BLA Multi-Disciplinary Review and Evaluation Application Type NME NDA Application Number(s) NDA 212994 Priority or Standard Standard Submit Date(s) 03/02/2020 Received Date(s) 03/02/2020 PDUFA Goal Date 03/02/2021 Division/Office Division of Psychiatry (DP)/Office of Neuroscience Review Completion Date 03/02/2021 Established/Proper Name Serdexmethylphenidate chloride (SDX Cl) & Dexmethylphenidate hydrochloride (d-MPH HCL) (Proposed) Trade Name Azstarys Pharmacologic Class Stimulant (Drugs for Minimal Brain Dysfunction) Code name N/A Applicant Commave Therapeutics SA Dosage form 26.1/5.2 mg, 39.2/7.8 mg, 52.3/10.4 mg (expressed as SDX/d- MPH free base) capsules (for reference, in parts of this review and others, sometimes the doses are also expressed in chloride salt form as 28/6 mg; 42/9 mg; and 56/12 mg respectively) Applicant proposed Dosing 26.1 mg/5.2 mg once daily in the morning. The dose may be Regimen increased weekly in increments of 13.1 mg/2.6 mg per day to a maximum of 52.3 mg/10.4 mg Applicant Proposed Treatment of Attention Deficit-Hyperactivity Disorder (ADHD) Indication(s)/Population(s) in patients ages 6 years and older Applicant Proposed 406506008 SNOMED CT Indication Disease Term for each Proposed Indication Recommendation on Approval Regulatory Action Recommended Treatment of ADHD in patients ages 6 to 12 years Indication(s)/Population(s) (if applicable) Recommended SNOMED 406506008 CT Indication Disease Term for each Indication (if applicable) Recommended Dosing 26.1/5.2 mg once daily in the morning, may be increased Regimen weekly in increments of 13.1/2.6 mg per day with a maximum of 52.3/10.4 mg 1 Version date: July 7, 2019 Reference ID: 4754756 NDA/BLA Multi-disciplinary Review and Evaluation: NDA 212994 Azstarys (serdexmethylphenidate and dexmethylphenidate) capsules, for oral use Table of Contents Table of Tables ................................................................................................................................ 5 Table of Figures ............................................................................................................................... 7 Reviewers of Multi-Disciplinary Review and Evaluation ................................................................ 8 Glossary ......................................................................................................................................... 12 1 Executive Summary ............................................................................................................... 14 Product Introduction ...................................................................................................... 14 Conclusions on the Substantial Evidence of Effectiveness ............................................ 14 Benefit-Risk Assessment ................................................................................................ 15 Patient Experience Data ................................................................................................. 19 2 Therapeutic Context .............................................................................................................. 20 Analysis of Condition ...................................................................................................... 20 Analysis of Current Treatment Options ......................................................................... 20 3 Regulatory Background ......................................................................................................... 21 U.S. Regulatory Actions and Marketing History ............................................................. 21 Summary of Presubmission/Submission Regulatory Activity ........................................ 21 4 Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety ................................................................................................................. 24 Office of Scientific Investigations (OSI) .......................................................................... 24 Product Quality .............................................................................................................. 24 Clinical Microbiology ...................................................................................................... 24 Devices and Companion Diagnostic Issues .................................................................... 24 5 Nonclinical Pharmacology/Toxicology................................................................................... 25 Executive Summary ........................................................................................................ 25 Referenced NDAs, BLAs, DMFs ....................................................................................... 27 Pharmacology ................................................................................................................. 27 ADME/PK ........................................................................................................................ 29 Toxicology ....................................................................................................................... 36 General Toxicology .................................................................................................. 37 Genetic Toxicology .................................................................................................. 41 Carcinogenicity ........................................................................................................ 42 Reproductive and Developmental Toxicology ........................................................ 42 Other Toxicology Studies ........................................................................................ 49 6 Clinical Pharmacology ............................................................................................................ 51 2 Version date: July 7, 2019 Reference ID: 4754756 NDA/BLA Multi-disciplinary Review and Evaluation: NDA 212994 Azstarys (serdexmethylphenidate and dexmethylphenidate) capsules, for oral use Executive Summary ........................................................................................................ 51 6.1.1 Recommendations ................................................................................................. 52 6.2 Summary of Clinical Pharmacology Assessment ............................................................ 53 6.2.1 Pharmacology and Clinical Pharmacokinetics ........................................................ 53 6.2.2 General Dosing and Therapeutic Individualization .................................................. 54 6.3 Comprehensive Clinical Pharmacology Review ............................................................. 55 6.3.1 General Pharmacology and Pharmacokinetic Characteristics ................................ 55 6.3.2 Clinical Pharmacology Questions ............................................................................ 57 7 Sources of Clinical Data and Review Strategy ....................................................................... 67 7.1 Table of Clinical Studies .................................................................................................. 67 Review Strategy ........................................................................................................................ 69 8 Statistical and Clinical Evaluation .......................................................................................... 69 8.1 Review of Relevant Individual Trials Used to Support Efficacy ...................................... 69 8.1.1 Study KP415.E01: A Multicenter, Dose-Optimized, Double-Blind, Randomized, Placebo-Controlled, Parallel Efficacy Laboratory Classroom Study with KP415 in Children with Attention-Deficit/Hyperactivity Disorder ................................................................. 69 8.1.2 Study Results ........................................................................................................... 73 8.1.3 Assessment of Efficacy Across Trials ....................................................................... 88 8.1.4 Integrated Assessment of Effectiveness ................................................................. 89 8.2 Review of Safety ............................................................................................................. 89 8.2.1 Safety Review Approach ......................................................................................... 89 8.2.2 Review of the Safety Database ............................................................................... 89 8.2.3 Adequacy of Applicant’s Clinical Safety Assessments ............................................ 90 8.2.4 Safety Results .......................................................................................................... 93 8.2.5 Analysis of Submission-Specific Safety Issues ....................................................... 108 8.2.6 Clinical Outcome Assessment (COA) Analyses Informing Safety/Tolerability ...... 108 8.2.7 Safety Analyses by Demographic Subgroups ........................................................ 109 8.2.8 Specific Safety Studies/Clinical Trials .................................................................... 110 8.2.9 Additional Safety Explorations .............................................................................