CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 211172Orig1s000 CLINICAL REVIEW(S) Combined Clinical/Biostatistical Review Clinical Reviewer – Breder; Statistical Reviewer – Massie NDA 211172 Tegsedi (inotersen) CLINICAL REVIEW Application Type Original NDA Application Number(s) 211172 Priority or Standard Priority Submit Date(s) 11/6/17 Received Date(s) 11/6/17 PDUFA Goal Date 10/6/18 (Extension); 7/6/18 (Original) Division/Office DNP/ODEI Reviewer Name(s) Clinical Reviewer – Christopher Breder; Statistical Reviewer – Tristan Massie Review Completion Date October 4, 2018 Established/Proper Name Inotersen (Proposed) Trade Name Tegsedi Applicant Ionis Pharmaceuticals, Inc. Dosage Form(s) 284 mg inotersen (300 mg sodium salt)/ 1.5 mL in a single- dose, prefilled syringe including a safety syringe device. Applicant Proposed (b) (4) Dosing Regimen(s) doses should be administered once every week (b) (4) Applicant Proposed For treatment of adult patients with hereditary TTR amyloidosis Indication(s)/Population(s) with polyneuropathy (hATTR-PN) (b) (4) Recommendation on Substantial evidence of effectiveness has been provided Regulatory Action Recommended For treatment of the polyneuropathy of hereditary transthyretin- Indication(s)/Population(s) mediated amyloidosis (if applicable) 1 Reference ID: 4330479 Combined Clinical/Biostatistical Review Clinical Reviewer – Breder; Statistical Reviewer – Massie NDA 211172 Tegsedi (inotersen) Table of Contents Glossary .......................................................................................................................................... 6 1. Executive Summary ................................................................................................................. 8 1.1. Product Introduction ......................................................................................................... 8 1.2. Conclusions on the Substantial Evidence of Effectiveness .............................................. 8 1.3. Benefit-Risk Assessment.................................................................................................. 9 1.4. Patient Experience Data ................................................................................................. 12 2. Therapeutic Context .............................................................................................................. 13 2.1. Analysis of Condition..................................................................................................... 13 2.2. Analysis of Current Treatment Options ......................................................................... 14 3. Regulatory Background ......................................................................................................... 14 3.1. U.S. Regulatory Actions and Marketing History ........................................................... 14 3.2. Summary of Presubmission/Submission Regulatory Activity ....................................... 15 3.3. Foreign Regulatory Actions and Marketing History ...................................................... 15 4. Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety ............................................................................................................... 15 4.1. Office of Scientific Investigations (OSI) ....................................................................... 15 4.2. Product Quality ............................................................................................................. 16 4.3. Clinical Microbiology .................................................................................................... 16 4.4. Nonclinical Pharmacology/Toxicology.......................................................................... 16 4.5. Clinical Pharmacology ................................................................................................... 17 5. Sources of Clinical Data and Review Strategy ...................................................................... 17 5.1. Table of Clinical Studies ................................................................................................ 17 5.2. Review Strategy ............................................................................................................. 18 6. Review of Relevant Individual Trials Used to Support Efficacy .......................................... 18 6.1. Study 1 (“ISIS 420915-CS2”, “CS2”): A Phase 2/3 Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of ISIS 420915 in Patients with Familial Amyloid Polyneuropathy (NEURO-TTR Study) ....................................................... 18 6.1.1. Study Design ........................................................................................................... 18 6.1.2. Overview and Objective ......................................................................................... 18 6.1.3. Trial Design ............................................................................................................ 18 2 Reference ID: 4330479 Combined Clinical/Biostatistical Review Clinical Reviewer – Breder; Statistical Reviewer – Massie NDA 211172 Tegsedi (inotersen) 6.1.4. Regimen .................................................................................................................. 18 6.1.5. Study Results .......................................................................................................... 36 6.2. ISIS 420915-CS3: An Open-Label Extension Study to Assess the Long-Term Safety and Efficacy of ISIS 420915 in Patients with Familial Amyloid Polyneuropathy (FAP) ........ 64 6.2.1. Study Design ........................................................................................................... 64 6.2.2. Study Results .......................................................................................................... 67 6.3. Abbreviated Description of Clinical Study Report 420915-CS1: A Double Blind, Placebo-Controlled, Dose-Escalation, Phase 1 Study to Assess the Safety, Tolerability and Pharmacokinetics of Single and Multiple Doses of ISIS 420915 Administered Subcutaneously to Healthy Volunteers (ISIS Study Number ............................................................................. 76 6.3.1. Study Design ........................................................................................................... 76 6.3.2. Study Results .......................................................................................................... 77 Disposition ........................................................................................................................ 77 7. Review of Safety ................................................................................................................... 78 8. Advisory Committee Meeting and Other External Consultations ......................................... 78 9. Labeling Recommendations .................................................................................................. 78 9.1. Prescription Drug Labeling ............................................................................................ 79 10. Risk Evaluation and Mitigation Strategies (REMS) .............................................................. 79 11. Postmarketing Requirements and Commitments .................................................................. 79 12. Appendices ............................................................................................................................ 80 12.1. Financial Disclosure ................................................................................................... 80 13. References ............................................................................................................................. 81 3 Reference ID: 4330479 Combined Clinical/Biostatistical Review Clinical Reviewer – Breder; Statistical Reviewer – Massie NDA 211172 Tegsedi (inotersen) Table of Tables Table 1 Listing of Clinical Trials Relevant to this NDA ............................................................. 17 Table 2 Stages of Amyloid Polyneuropathy[3] ............................................................................ 20 Table 3 Scoring for the NIS composite score ............................................................................... 25 Table 4 Scoring for the m+7 Composite Score ............................................................................. 26 Table 5 Amendments by Country Version of the CS2 Protocol ................................................... 34 Table 6 Disposition of Patients ..................................................................................................... 38 Table 7 Number of Patients by Analysis Dataset (% of Total)..................................................... 39 Table 8 Demographic Characteristics ........................................................................................... 40 Table 9 Other Baseline Characteristics (e.g., disease characteristics, concomitant drugs) .......... 41 Table 10 Imbalances in Baseline Demographics Identified by Applicant .................................... 43 Table 11 Exposure to Drug in Study CS2 ..................................................................................... 45 Table 12 Evaluation of mNIS+7 by Subgroup ............................................................................. 48 Table 13 Norfolk QoL-DN by Stratification