FDA ADVISORY COMMITTEE MEETING BRIEFING DOCUMENT
ENDOCRINE AND METABOLIC DRUGS ADVISORY COMMITTEE
MEETING DATE: 10 MAY 2018
ADVISORY COMMITTEE BRIEFING MATERIALS: AVAILABLE FOR PUBLIC RELEASE Volanesorsen (ISIS 304801) Akcea Therapeutics
Endocrine and Metabolic Drugs Advisory Committee Briefing Document 10 May 2018 Meeting
TABLE OF CONTENTS TABLE OF CONTENTS ...... 2 TABLE OF TABLES ...... 6 TABLE OF FIGURES ...... 9 LIST OF ABBREVIATIONS ...... 10 1. EXECUTIVE SUMMARY ...... 11 1.1 Familial Chylomicronemia Syndrome ...... 12 1.1.1 Overview of the Disease and Impact of Elevated Triglyceride Levels ...... 12 1.1.2 Current Treatment Options ...... 14 1.2 Volanesorsen Clinical Development Program ...... 15 1.3 Efficacy and Safety of Volanesorsen ...... 15 1.3.1 Phase 3 Safety and Efficacy Pivotal Study - Study ISIS 304801-CS6 ...... 16 1.3.2 Phase 3 Open-label Extension Study ISIS 304801-CS7...... 24 1.3.3 Phase 3 Study ISIS 304801-CS16 ...... 27 1.3.4 Safety of Volanesorsen Treatment ...... 28 1.4 Risk Mitigation ...... 30 1.5 Benefit and Risks Conclusions ...... 31 2. BACKGROUND ON FAMILIAL CHYLOMICRONEMIA SYNDROME ...... 33 2.1 Overview of Familial Chylomicronemia Syndrome ...... 33 2.2 Clinical Features of FCS ...... 33 2.2.1 FCS Disease Complications ...... 34 2.2.2 Platelet Variability in FCS ...... 37 2.3 FCS Unmet Medical Need ...... 37 3. PRODUCT DESCRIPTION ...... 39 3.1 Proposed Indication and Dosing Regimen ...... 39 3.2 Mechanism of Action ...... 39 4. REGULATORY AND DEVELOPMENT HISTORY ...... 41 4.1 Regulatory Milestones ...... 41 4.2 Clinical Development Program ...... 41 5. NONCLINICAL SUMMARY ...... 47
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6. CLINICAL PHARMACOLOGY ...... 49 6.1 Pharmacokinetics ...... 49 6.1.1 Absorption, Distribution, Clearance, Metabolism, and Elimination ...... 50 6.1.2 Dose-Proportionality of Pharmacokinetics ...... 50 6.1.3 Effect of Intrinsic Factors on Pharmacokinetics ...... 50 6.1.4 Effect of Extrinsic Factors on Pharmacokinetics ...... 52 6.2 Anti-Drug Antibodies ...... 52 6.3 Pharmacodynamics ...... 52 6.3.1 Concentration-Effect Relationships ...... 52 6.3.2 Pharmacodynamic Drug-Drug Interactions ...... 53 7. OVERVIEW OF THE PIVOTAL AND SUPPORTIVE STUDIES ...... 54 7.1 Key Design Features of the Pivotal Phase 3 Study ISIS 304801-CS6 ...... 54 7.1.1 Overview ...... 54 7.1.2 Key Inclusion/Exclusion Criteria ...... 56 7.1.3 Endpoints, Analysis Sets, and Statistical Methods ...... 57 7.1.4 Discussion of Key Design Features ...... 60 7.2 Key Design Features of Study ISIS 304801-CS7 ...... 60 7.3 Key Design Features of Study ISIS 304801-CS16 ...... 61 8. CLINICAL EFFICACY ...... 62 8.1 Phase 2 Study ISIS 304801-CS2 ...... 63 8.2 Phase 3 Safety and Efficacy Pivotal Study - Study ISIS 304801-CS6 ...... 64 8.2.1 Study Enrollment and Disposition ...... 64 8.2.2 Discontinuations ...... 65 8.2.3 Dose Frequency Changes/Dose Pauses ...... 66 8.2.4 Medication Exposure and Treatment Duration ...... 67 8.2.5 Demographics and Baseline Disease Characteristics ...... 67 8.2.6 Primary Endpoint – Percent Change in Fasting Triglycerides from Baseline to Month 3...... 69 8.2.7 Secondary Endpoints ...... 70 8.2.8 Exploratory Endpoints: Remaining Secondary Endpoints ...... 72 8.2.9 Exploratory Endpoints: Post-hoc Analyses ...... 76
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Endocrine and Metabolic Drugs Advisory Committee Briefing Document 10 May 2018 Meeting
8.2.10 Efficacy Following Dose Adjustments ...... 82 8.2.11 Comparison of Results in Subpopulations ...... 84 8.3 Phase 3 Open-label Extension Study ISIS 304801-CS7...... 85 8.3.1 Study Enrollment and Disposition ...... 85 8.3.2 Dose Adjustments and Dose Pauses ...... 86 8.3.3 Demographics and Baseline Characteristics ...... 86 8.3.4 Efficacy Results ...... 86 8.4 Study ISIS 304801-CS16 ...... 88 8.4.1 Study Enrollment and Disposition ...... 88 8.4.2 Demographics and Baseline Disease Characteristics ...... 88 8.4.3 Efficacy Results ...... 88 8.4.4 Effect on Triglycerides ...... 88 8.4.5 Acute Pancreatitis ...... 90 8.5 Quality of Life – ReFOCUS ...... 90 9. SAFETY ...... 92 9.1 Safety Monitoring in Clinical Studies ...... 92 9.2 Treatment Exposure ...... 93 9.3 Common On-Treatment Adverse Events ...... 93 9.4 Deaths ...... 94 9.5 Serious Adverse Events ...... 94 9.5.1 Serious Adverse Events in Studies CS6 and CS16 ...... 94 9.5.2 Serious Adverse Events in Other Studies ...... 95 9.6 Adverse Events Leading to Discontinuation ...... 95 9.7 Analysis of Selected Adverse Events ...... 96 9.7.1 Adverse Drug Reactions ...... 96 9.7.2 Platelet Count Reductions ...... 97 9.7.3 Adverse Events at the Injection Site ...... 106 9.7.4 Antibody and Proinflammatory Events ...... 107 9.7.5 Anaphylactic Events ...... 108 9.8 Safety in Special Populations ...... 109 9.8.1 Gender, Age, Race, and Ethnicity ...... 109
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9.8.2 Body Weight ...... 109 9.8.3 Patients with FCS ...... 110 9.9 Long-Term Safety, Study CS7 ...... 112 9.9.1 Exposure ...... 112 9.9.2 On-Treatment Adverse Events ...... 113 9.10 Other Safety Assessments ...... 115 10. SUMMARY OF THE RISK MITIGATION PROGRAM ...... 116 11. BENEFIT RISK ANALYSIS ...... 121 12. REFERENCES ...... 123 13. APPENDICES ...... 129 13.1 Nonclinical Summary ...... 129 13.1.1 Nonclinical Pharmacology ...... 129 13.1.2 Nonclinical Pharmacokinetic Studies ...... 130 13.1.3 Toxicology ...... 131 13.1.4 Carcinogenicity ...... 137 13.2 Study CS6 Quality of Life Results ...... 140 13.3 Additional Information on Serious Adverse Events ...... 141
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TABLE OF TABLES Table 1: Summary of CS6 Medication Exposure and Treatment Duration – Safety Set ...... 18 Table 2: Summary of Discontinuation Rate per Patient Year of Exposure in Volanesorsen-treated Patients before and after Platelet Monitoring Enhancement in CS6 (N=33) ...... 18 Table 3: Demographic and Baseline Disease Characteristics for Patients with FCS in Studies CS6, CS7, and CS16 (Safety Set) ...... 20 Table 4: Percent Change from Baseline to Month 3 in Fasting Triglycerides (mg/dL) in CS6: Full Analysis Set ...... 21 Table 5: Summary of Adjudication-Confirmed Acute Pancreatitis in Study CS6 - FAS ...... 23 Table 6: Summary of Change from Baseline to Month 3 in Fasting Triglycerides Using OLE and Index Study Baseline - CS7 FAS (31 August 2017 data cutoff) ...... 26 Table 7: On-Treatment Adverse Events Related to Platelet Reductions in Study CS6: Safety Set ...... 29 Table 8: On-Treatment Adverse Events Experienced by > 10% of Pooled Volanesorsen Patients in CS6 and CS16 (Excluding AEs at the Injection Site) ...... 30 Table 9: Percent of 42 Patient FCS Data Set who Experienced Thrombocytopenia < 100,000/mL over Mean of 11 years (Range: 2-31 years) ...... 37 Table 10: Summary of Volanesorsen Clinical Studies ...... 43 Table 11: Algorithm for Platelet Monitoring/Dosing ...... 56 Table 12: Triglyceride Values for Patients with FCS in Study CS2 ...... 63 Table 13: Patient Disposition and Population in CS6-All Screened Patients ...... 66 Table 14: Summary of CS6 Medication Exposure and Treatment Duration – Safety Set ...... 67 Table 15: Demographic and Baseline Disease Characteristics for Patients with FCS in CS6, CS7, and CS16 (Safety Set) ...... 68 Table 16: Eligibility of Patients in CS6 based on Confirmatory Genetics for FCS or Low Lipoprotein Lipase Activity - Full Analysis Set ...... 69 Table 17: Percent Change from Baseline to Month 3 in Fasting Triglycerides (mg/dL) in CS6: Full Analysis Set ...... 70 Table 18: Percent Change from Baseline to Month 6 and Month 12 in Fasting Triglycerides with Multiple Imputation – CS6 Full Analysis Set ...... 71
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Table 19: Analysis of Absolute Change from Baseline in Fasting Triglycerides – CS6 Full Analysis Set ...... 73 Table 20: Study CS6 Quality of Life Data at Baseline ...... 74 Table 21: Summary of Adjudication-Confirmed Acute Pancreatitis in Study CS6 - FAS ...... 75 Table 22: Change from Baseline in Average of Maximum Intensity of Patient Reported Abdominal Pain in During the On-Treatment Period with Missing Imputed to 0 in Patients with Baseline Abdominal Pain – CS6 FAS; Post- hoc Analysis ...... 76 Table 23: Summary of Fasting Lipid Parameters in Study CS6 – Full Analysis Set ...... 80 Table 24: Analysis of Treatment Response Rate in Volanesorsen-treated Patients by Dose Adjustment – CS6...... 82 Table 25: Relationship of Body Weight, Volanesorsen Exposure, and Triglyceride Reduction in Study CS6...... 84 Table 26: Dose Adjustments in CS6 and CS7 as of 31 August 2017 ...... 86 Table 27: Summary of Change from Baseline to Month 3 in Fasting Triglycerides Using OLE and Index Study Baseline - CS7 FAS (31 August 2017 data cutoff) ...... 87 Table 28: Primary Efficacy Endpoints: Change from Baseline to Month 3 in Fasting Triglycerides in CS16 - Full Analysis Set with Multiple Imputations for Missing Dataa ...... 89 Table 29: ReFOCUS: Mean (SD) Number of Symptoms Experienced Prior to and On Volanesorsen (N=22) ...... 91 Table 30: On-Treatment Adverse Events Occurring in >10% of Pooled Volanesorsen Patients in CS6 and CS16 (Excluding AEs at the Injection Site) - Safety Set ...... 94 Table 31 Serious On-Treatment Adverse Events Reported by More Than 1 Patient Overall in CS6 or CS16 - Safety Set ...... 95 Table 32: On-Treatment Adverse Events Leading to Treatment Discontinuation in More Than 1 Volanesorsen-Treated Patient in CS6 or CS16 – Safety Set ...... 96 Table 33: Summary of Adverse Drug Reactions in Study CS6 Occurring in ≥ 10% Patients – Safety Set ...... 97 Table 34: Summary of Patients with Platelet Reduction to < 50,000/mm3 ...... 98 Table 35: Number of Patients with Nadir Platelet Count Meeting Threshold Value at Any Time Post-Baseline in Studies CS6 and CS16 ...... 98 Table 36: Study CS6 Algorithm and Proposed Algorithm for Platelet Monitoring/Dosing ...... 104
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Table 37: Summary of Average Weekly Reduction at Nadir in Platelet Count in Study CS6 (*k/mm3) - Safety Set ...... 105 Table 38: On-Treatment Bleeding Adverse Events Occurring in More than 1 Patient in CS6 or CS16 ...... 105 Table 39: On-Treatment Adverse Events at the Injection Site Occurring in >10% of Volanesorsen Patients in CS6 or CS16 ...... 107 Table 40: Overall Summary of Adverse Events by FCS Diagnosis in CS6, CS16, CS2, and CS4 ...... 111 Table 41: Study Drug Exposure During Index Study and Ongoing Open-Label Study for Treatment-Naïve and CS6-Volanesorsen Patients – CS7 Safety Set as of 31 August 2017 ...... 112 Table 42: On-Treatment Adverse Events (Excluding Injection Site Events) Occurring in ≥ 10% Patients Overall – Study CS7 Safety Set as of 31 August 2017 ...... 113 Table 43: Treatment-Emergent Bleeding Adverse Events occurring in More than 1 Patient in CS7 – Safety Set as of 31 August 2017 ...... 115 Table 44 Summary of Volanesorsen Noteworthy Nonclinical Study Findings and Relationship to Exposure in Animals and Humans ...... 136 Table 45: Significant Neoplasms in Mouse Carcinogenicity Study by Gender (poly-3 pairwise test) ...... 138 Table 46: Summary of SF-36 Weighted Sum of Scores – CS6 Full Analysis Set ...... 140 Table 47: EQ-5D Questionnaires: Score – CS6 Full Analysis Set ...... 141 Table 48 Serious On-Treatment Adverse Events in Study CS6 - Safety Set ...... 142 Table 49 Serious On-Treatment Adverse Events in Study CS16 - Safety Set ...... 143
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TABLE OF FIGURES Figure 1: Disposition of Patients Through CS6 and CS7 ...... 17 Figure 2: Fasting Triglycerides Mean (+/-SEM) Percent Change Over Time for the Cohort of Volanesorsen-Treated Patients in Studies CS6 Continuing into CS7 - Full Analysis Set – Data Through 31 August 2017 ...... 27 Figure 3: Degree of Triglyceride Elevation Correlates with Severity of Pancreatitis ...... 35 Figure 4: Incidence, Frequency, and Severity of Symptoms – IN-FOCUS ...... 36 Figure 5: ApoC-III, Inhibitor of TG Metabolism by Multiple Mechanisms ...... 40 Figure 6: Study Design and Treatment Schema for Study ISIS 304801-CS6 ...... 55 Figure 7: Disposition of Patients Through CS6 and CS7 with Reasons for Discontinuation ...... 65 Figure 8: Mean (± SEM) of Percent Change in Fasting Triglycerides (mg/dL) Over Time- CS6 Full Analysis Set, Observed Data ...... 72 Figure 9: Frequency of Any Abdominal Pain (A), Frequency of Moderate to Severe Abdominal Pain (B), and Worst Intensity (C) of Patient-Reported Abdominal Pain During the On-Treatment Period in Patients with Baseline Abdominal Pain – CS6 Full Analysis Set ...... 77 Figure 10: Mean (SEM) Percent Change in Triglycerides Over Time Including Dose Adjustments and Non-Completers – CS6 Full Analysis Set – Observed Data ...... 83 Figure 11: Individual Patient Platelet Counts over Time Before and After Platelet Count < 25,000/mm3 for Studies CS6 and CS7 ...... 100 Figure 12: Mean (SEM) Absolute Platelet Count Over Time in CS6 ...... 102 Figure 13: Correlation Between Maximum Percent Reduction in Platelets During the On-Treatment Period Versus Baseline Weight (CS6 and CS16, N = 105) ...... 109 Figure 14: Volanesorsen is an Antisense Oligonucleotide against ApoC-III ...... 129
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LIST OF ABBREVIATIONS Abbreviation Definition AE Adverse event ALT Alanine aminotransferase ANCOVA Analysis of covariance apoB Apolipoprotein-B apoC-III Apolipoprotein C-III ASO Antisense oligonucleotide AST Aspartate aminotransferase AUC Area under the curve BMI Body mass index Cmax Maximum concentration Ctrough Trough concentration ETASU Elements to assure safe use ECG Electrocardiogram FAS Full Analysis Set FCS Familial chylomicronemia syndrome FDA Food and Drug Administration FPL Familial Partial Lipodystrophy HDL-C High-density lipoprotein cholesterol LDL-C Low-density lipoprotein cholesterol LLN Lower limit of normal MACE Major acute cardiovascular event MedDRA Medical Dictionary for Regulatory Activities OLE Open-label extension PD Pharmacodynamic PK Pharmacokinetic PPS Per-protocol set QoL Quality of life REMS Risk Evaluation and Mitigation Strategy SAE Serious adverse event SC Subcutaneous ULN Upper limit of normal VLDL-C Very low-density lipoprotein cholesterol
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1. EXECUTIVE SUMMARY Familial chylomicronemia syndrome (FCS) is a rare metabolic disease caused by the inability to process chylomicron particles formed as a product of eating. These particles, made primarily of triglycerides, accumulate in the blood causing chylomicronemia, which leads to a number of clinical symptoms that negatively affect patients’ activities of daily living, including, but not limited to, neurocognitive impairment and recurrent episodes of abdominal pain. There is limited epidemiologic literature on FCS. The most serious complication of chylomicronemia is pancreatitis, which may be life-threatening. Pancreatitis due to hypertriglyceridemia may be even more severe, often leading to multi-organ failure, extended ICU hospitalization, pancreatic necrosis with attendant insufficiencies, and death. Because triglycerides constitute 90% of chylomicron particles, the goal when treating FCS is the reduction of triglycerides, especially to levels below those associated with chylomicronemia and the associated risk of pancreatitis. Currently, there is no approved therapeutic agent specifically indicated for the treatment of FCS, and the management strategy is an extremely restrictive low-fat diet, which is very difficult to comply with and, even when followed, does not prevent symptoms in most patients. Standard therapeutic triglyceride lowering agents such as fibrates, fish oils, and niacin are largely ineffective in this population, as is the use of statins. Standard lipid-lowering therapies are minimally effective in patients with FCS because their effectiveness depends, at least in part, on a functional lipoprotein lipase enzyme which is deficient in these individuals. Volanesorsen is a novel antisense drug targeted at apolipoprotein C-III (apoC-III), a key regulator of lipoprotein lipase, the essential enzyme involved in chylomicron and triglyceride clearance. Volanesorsen is the first drug to achieve significant and sustained reductions in plasma triglyceride levels in patients with FCS. The important points arising from the development program of volanesorsen for the treatment of FCS are summarized below. • In the Phase 3 pivotal study of 66 patients with FCS (CS6), volanesorsen met its pre-specified primary endpoint of percent reduction in plasma triglyceride level at 3 months, achieving an average reduction of 77% compared to baseline and a relative reduction of 94% when compared to placebo (p < 0.0001). • Significant reductions in triglycerides persisted at Months 6 and 12, with average reductions compared to baseline of -53% and -40%, respectively, and relative reductions compared to placebo of -78% and -49% (p<0.0001). • Exploratory analyses identified some effects on abdominal pain and a numeric reduction in events of pancreatitis in volanesorsen-treated patients. • The primary safety finding from the overall clinical development program for volanesorsen was treatment-related reduction in platelet count, including thrombocytopenia and, less commonly, severe thrombocytopenia.
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• In the Phase 3 pivotal study in patients with FCS, 2 patients experienced serious adverse events (SAEs) of severe thrombocytopenia that resolved without significant sequelae with treatment termination and steroid treatment. Following these events, more frequent platelet monitoring and dose adjustments, through reduction of dosing frequency, were instituted. • Overall in the development program as the 31 August 2018 data cutoff for the 4-month Safety Update, 8 patients experienced platelet reductions of <50,000/mm3 and 3 of these patients to levels below <25,000/mm3. These events were reversible upon study drug cessation with or without steroid treatment and were not associated with any major bleeding events. • In consultation with the FDA Endocrine and Metabolic Diseases Division, the Sponsor has developed a Risk Evaluation and Mitigation program (REMS) with Elements to Assure Safe Use (ETASU) to mitigate the risk of serious bleeding related to severe thrombocytopenia with volanesorsen use in patients with FCS. Core elements of the REMS include the education and registration of physicians, patients and pharmacists involved in use of the drug. Drug access will be restricted to certified physicians and pharmacists, and attestation of compliance with the REMS program will be a requirement for continued use. Drug dispensing will be limited to a 4 week supply and central review/audit of compliance of all parties will be an element of the program. • The Sponsor also recognizes the need to collect information on safe use of volanesorsen in additional populations for which limited information currently exists, such as older patients and women in pregnancy. Enhanced pharmacovigilance involving active follow- up by the company with targeted questionnaires will also be conducted for inflammatory, renal and hepatic events to ensure adequate characterization and evaluation of these events in periodic safety reports to the FDA. • Given the high unmet medical need of patients with FCS and the urgency to provide a specific treatment to mitigate the disease manifestations and complications, the proposed REMS is designed to ensure safe use of volanesorsen and ensure a favorable benefit-risk profile is maintained post-approval. 1.1 Familial Chylomicronemia Syndrome 1.1.1 Overview of the Disease and Impact of Elevated Triglyceride Levels Familial chylomicronemia syndrome is a rare, debilitating, and potentially life-threatening disease with a high unmet medical need. FCS is caused by the inability to break down dietary fat carried primarily in chylomicrons (dietary lipid particles). Chylomicrons are large (~ 1 micron in diameter) lipoprotein particles that, if elevated, can result in clinically significant manifestations, including reduction of blood flow though the pancreatic microcirculation leading to severe abdominal pain and pancreatitis (Valdivielso et al. 2014). The inflammatory changes caused by excessive chylomicronemia induce acute pancreatitis, which can be fatal or lead to pancreatic damage, resulting in permanent exocrine or endocrine insufficiency (Symersky et al. 2006), in addition to other symptoms and complications. Because 90% of chylomicron particles consist of
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triglycerides, FCS is characterized by high plasma triglyceride levels (≥ 750 mg/dL) (Jacobson et al. 2015). FCS affects an estimated 3,000-5,000 patients globally and approximately 1,000 to 1,500 patients in the US, and was granted orphan disease designation by the FDA and European Medicines Agency (EMA). FCS is associated with inherited mutations that limit or impair the activity of lipoprotein lipase, an enzyme responsible for the hydrolysis of triglycerides. lipoprotein lipase is inhibited by apolipoprotein C-III (apoC-III), a protein recognized to regulate plasma triglyceride metabolism through multiple mechanisms (Norata et al. 2015). Apo C-III also impacts triglyceride levels by a novel lipoprotein lipase-independent pathway by inhibiting clearance of triglyceride-rich lipoproteins by the liver (Gordts et al. 2016). A specific diagnosis of FCS can be made based on clinical characteristics (Brunzell 1999-2011). Genetic testing can be used for additional information; however, a negative genetic test does not necessarily exclude a diagnosis of FCS because not all mutations are known. The presence of the following clinical criteria provides a specific diagnosis of FCS: 1. Fasting triglyceride levels in excess of 750 mg/dL or 8.5 mmol/L (chylomicronemia) on repeated testing that are refractory to standard lipid lowering therapy (Jacobson et al. 2015) AND 2. At least one of the following: • History of acute pancreatitis • History of childhood pancreatitis • History of recurrent abdominal pain without other explainable cause • Family history of hypertriglyceridemia AND 3. Persistence of chylomicronemia after the exclusion of contributing factors, e.g., the removal of exacerbating causes through diet modification, discontinuation of drugs known to increase triglyceride levels, and/or provision of insulin therapy for patients with poorly treated diabetes mellitus (Miller et al. 2011). In addition, the contribution of other causes of pancreatitis (e.g., alcoholism, gallstones) should also be ruled out. Patients with FCS have a number of severe, and potentially life-threatening complications associated with the disease. Acute pancreatitis presents the most significant risk in patients with FCS, with potential mortality and other significant complications (Davidson et al. 2017). It has been shown that pancreatitis due to severe hypertriglyceridemia (triglycerides > 1000 mg/dL) is more severe with worse outcomes than pancreatitis of other etiologies. Moreover, pancreatitis risk appears to be higher in patients with severely elevated triglycerides than in patients with moderately elevated triglyceride levels (Nawaz et al. 2015).
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Long term complications as a result of acute pancreatitis may include chronic pancreatitis, pancreatogenic (Type 3c) diabetes, and endocrine and exocrine pancreatic insufficiencies, with their attendant complications (Symersky et al. 2006). Enzyme replacement therapy is ineffective due to the short half-life of lipoprotein lipase. Gene therapy, such as Glybera (gene replacement for lipoprotein lipase), failed to show sustained efficacy and only addressed a fraction of the FCS population; that is, those with lipoprotein lipase deficiency. Consequently, Glybera was never approved in the US and was withdrawn from the European market. There are currently no other therapies in advanced development that may benefit FCS patients with all identified gene mutations (Pouwels et al. 2008, Sacks et al. 2014, Brahm and Hegele 2015). Approximately 20% of pancreatitis cases develop complications, including pancreatic necrosis and multiorgan failure (Banks et al. 2013). One study showed that in patients with pancreatitis, 50% of those with triglycerides > 1000 mg/dL will have pancreatic necrosis and mortality is 8%, compared with a mortality rate of 3% in patients with pancreatitis with normal triglycerides (<150 mg/dL) (Nawaz et al. 2015). Because of their very high triglyceride levels, patients with FCS have high risk for severe pancreatitis. In a survey of 21 lipidologists reporting on 251 patients with FCS, mortality from pancreatitis was 6% (Gaudet et al. 2016). A recent Monte Carlo simulation model estimated that adult patients with FCS will experience a cumulative mortality due to acute pancreatitis of 54% and the authors projected that reducing triglycerides by 50% could decrease the number of pancreatitis episodes and add 3.16 years to life expectancy (Lin et al. 2014). Although acute pancreatitis presents the most significant risk, patients with FCS frequently experience other manifestations that have considerable impact on their daily lives. The IN-FOCUS survey of patients with FCS revealed an inventory of symptomology and comorbidities that impart major burden on patients living with the disease (Davidson 2017). These include a wide range of cognitive, emotional, and physical impairments such as abdominal pain, steatorrhea, bloating, asthenia, fatigue, anxiety and feelings of depression, fear and worry, brain fog, lack of concentration, and impairment of memory, all occurring frequently at moderate to severe magnitude (see Figure 4 in Section 2.2.1.2). Recently available natural history data in 87 patients from 3 Canadian clinics (the SMASH registry) showed that patients with FCS experience wide fluctuations in platelet count over time, ranging from moderate to severe thrombocytopenia to thrombocytosis as part of the natural history of the disease (see Section 2.2.2).
1.1.2 Current Treatment Options There is currently no approved therapeutic agent specifically indicated for the treatment of FCS. The best current management option to attempt reductions of plasma triglyceride levels in patients with FCS is an extremely restrictive diet devoid of nearly all dietary fat, ideally no more than 20 g daily (Brahm and Hegele 2015, Stroes et al. 2017) and strict avoidance of alcohol, simple carbohydrates and classes of drugs that are known to increase triglyceride levels. Short- term ingestion of dietary fat or limited alcohol consumption can result in exaggerated
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triglyceride excursions that place the patients at a high risk for acute pancreatitis. Even in patients with strict dietary adherence, triglyceride levels may remain at levels associated with elevated risk of pancreatitis, demonstrating that diet alone does not sufficiently mitigate the risk of pancreatitis in all patients (Gaudet et al. 2010, Ceska et al. 2016, Stroes et al. 2017). In severely ill patients, most often those with acute pancreatitis and triglycerides > 1000 mg/dL plus lipase > 3 × upper limit of normal (ULN), plasmapheresis may be used to quickly decrease triglyceride levels on a short-term basis, but is not a solution for the long-term management of patients with FCS. The limitations of traditional lipid-lowering therapies as well as diet only management strategy were demonstrated in the pivotal Phase 3 study of volanesorsen, CS6, where eligible patients entered a ≥ 6-week diet stabilization period at Screening with diet controlled at ≤ 20 g fat per day. Irrespective of prior lipid-lowering therapies and after the diet run in, mean Baseline triglyceride values were > 2100 mg/dL (i.e., > 15 × ULN), well above levels where pancreatitis and other disease manifestations occur, confirming the unmet need and the clinical ineffectiveness of currently therapies. 1.2 Volanesorsen Clinical Development Program Volanesorsen is a novel 2' MOE (2' O [2 methoxyethyl]) antisense oligonucleotide (ASO) inhibitor of the molecular target apolipoprotein C—III (apoC-III). This drug is designed to selectively and specifically bind to the human apoC-III messenger ribonucleic acid (mRNA) and prevent production of the apoC-III protein. Volanesorsen was developed as a subcutaneous (SC) injectable medication supplied in single-use, prefilled syringes suitable for self-administration. The proposed indication is as an adjunct to diet for the treatment of FCS. A nonclinical program with volanesorsen was conducted using in vitro and in vivo studies to support chronic SC administration for the treatment of patients with FCS. Volanesorsen for the treatment of FCS has been studied in a comprehensive clinical development program that comprises 9 Phase 1, 2, and 3 studies. These studies were conducted or are ongoing in healthy adults, patients with FCS, patients with severe hypertriglyceridemia from causes other than FCS, patients with diabetes, and patients with familial partial lipodystrophy (FPL). Because FCS is an extremely rare metabolic disorder, some studies supporting the safety and efficacy of volanesorsen for treatment of FCS included patients with severe hypertriglyceridemia to provide additional data. Still, 312 patients/subjects were treated with volanesorsen in clinical studies, including 84 patients with FCS. Further details on the volanesorsen clinical development program are provided in Section 4. The 300 mg weekly starting dose of volanesorsen for the pivotal Phase 3 placebo-controlled study CS6 was based on PK/PD modeling of the Phase 1 and 2 studies (see Section 4.2) and a safety profile consistent with continued advancement to Phase 3. 1.3 Efficacy and Safety of Volanesorsen The primary efficacy and safety data supporting the proposed indication for volanesorsen are derived from the pivotal Phase 3 study CS6, described below. Additional 6-month supportive
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efficacy and safety data are provided by the Phase 3 study CS16, which enrolled 7 patients with FCS as well as other patients with severe hypertriglyceridemia. Given the extreme rarity of FCS, the patients with non-FCS hypertriglyceridemia were included to augment the safety database for volanesorsen. The Phase 3 open-label extension study (OLE) CS7 provided data on durability of effect and long-term safety.
1.3.1 Phase 3 Safety and Efficacy Pivotal Study - Study ISIS 304801-CS6 1.3.1.1 Key Design Features of ISIS 304801-CS6 Study CS6 was a multicenter, double-blind, randomized, placebo-controlled Phase 3 study in adult patients with FCS. All patients who completed at least a 6-week diet, lifestyle, and medication stabilization period were randomized 1:1 to receive volanesorsen 300 mg once per week or matching placebo subcutaneously for 52 weeks. Dietary counseling commenced at the start of the diet stabilization period and was reinforced at regular intervals throughout the treatment period. Following completion of the treatment phase, patients could elect to enroll in the OLE study, CS7. Details of inclusion criteria and study design are provided in Section 7.1. In order to address platelet reductions experienced by some patients, the protocol was amended to allow for changes in dosing schedule (to every 2 weeks) and interruptions or pause if needed (see Table 11). The primary efficacy endpoint, as agreed with the FDA, was the percent change from baseline in fasting triglycerides at Month 3 in the Full Analysis Set (FAS), a modified intention-to-treat (mITT) dataset, defined as all patients who were randomized, received at least 1 dose of Study Drug and who had a baseline fasting plasma triglycerides assessment. The secondary endpoints were selected to assess long-term benefit as well as clinically meaningful patient symptoms and were rank ordered and tested according to position in the hierarchy using a sequential closed testing procedure (see Section 7.1.3).
1.3.1.2 Disposition, Demographics, and Exposure in ISIS 304801-CS6 A total of 67 patients with FCS were randomized and 33 patients were treated in each group (1 patient randomized to placebo discontinued prior to being treated because of stratification errors); the 66 treated patients were included in the FAS. Patients were enrolled over 13 months at 40 study centers worldwide, including 12 study centers in the US. The disposition of patients through CS6 and the OLE, CS7, is displayed in Figure 1.
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Figure 1: Disposition of Patients Through CS6 and CS7
*As of 31 August 2017 After the data cutoff and as of 31 December 2017, 68 patients were enrolled and 53 were ongoing in CS7.
All 66 patients in Study CS6 had triglycerides measurement for the primary endpoint at Month 3. Nineteen (58%) of the 33 patients in the volanesorsen group and 32 (94%) of the 33 patients in the placebo group completed the 52-week treatment period of CS6. Study drug exposure was maintained for placebo and volanesorsen-treated patients during the first 3 months of CS6 with all patients in the placebo group and 94% of patients in the volanesorsen group receiving at least 3 months of treatment (Table 1).
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Table 1: Summary of CS6 Medication Exposure and Treatment Duration – Safety Set
Parameter Volanesorsen 300 mg Placebo All Patients Category/Statistic (N=33) (N=33) (N=66) Number of Injections of Study Medication - n (%) ≥1 dose 33 (100.0) 33 (100.0) 66 (100.0) Treatment Duration (Months) - n (%) ≥3 31 (93.9) 33 (100.0) 64 (97.0) ≥6 24 (72.7) 32 (97.0) 56 (84.8) ≥9 21 (63.6) 32 (97.0) 53 (80.3) ≥12 8 (24.2) 21 (63.6) 29 (43.9)
The most common reason for discontinuation of volanesorsen treatment was AE (9 patients, 27%); 5 of the discontinuations were due to platelet reductions and 4 patients withdrew due to AEs unrelated to platelet counts. In the original protocol, treatment interruption followed by reinstitution of the original dose of study drug (300 mg/week) was the only permitted option for managing a platelet decline, other than discontinuing treatment, and the patient was withdrawn from treatment if a second decline in platelets occurred (see Table 11 in Section 7.1.1). As shown in Table 2, the rate of treatment discontinuations due to platelet reductions, and discontinuations for any reason, were higher before the change in the platelet monitoring and dose adjustment algorithm in May 2016. Also, after more frequent platelet monitoring was implemented, no platelet counts < 50,000/mm3 were observed in CS6.
Table 2: Summary of Discontinuation Rate per Patient Year of Exposure in Volanesorsen-treated Patients before and after Platelet Monitoring Enhancement in CS6 (N=33)
Treatment Treatment Platelet Count Discontinuation due to Discontinuation due to < 50,000/mm3 in Total Any Reason in Platelets in Volanesorsen Group Patient Volanesorsen Group Volanesorsen Group Year of Number Rate (%) Exposure Number Rate (%) per Number Rate (%) per of per Patient (years) of Patient Year of of Patient Year Patients Year of Patients Exposure Patients of Exposure Exposure Before/on 27 May 2016 17.8 12 67.6 3 16.9 3 16.9 After 27 May 2016 18.7 2 10.7 2 10.7 0 0
In the volanesorsen group, 30% of patients had their dosing changed from 300 mg weekly to 300 mg every other week (all between Weeks 26 and 46) and 33% of patients had dose interruptions or pauses because of AEs or lab values, with the majority to manage platelet reductions. By
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comparison, no dose regimen adjustments were made in the placebo group and 18% of placebo patients had dose interruptions or pauses, 1 because of platelet reductions.
Demographics were well balanced between treatment arms and were comparable among the patients with FCS across the Phase 3 studies (Table 3). In CS6, patients had extremely high triglyceride levels at baseline following the diet stabilization period; mean baseline triglyceride levels were 2267 mg/dL in the volanesorsen group and 2152 mg/dL in the placebo group and all but 3 patients in the volanesorsen group and 2 patients in the placebo group continued to have triglycerides ≥ 750 mg/dL at baseline. In both treatment groups, > 70% of patients had a documented history of acute pancreatitis prior to screening.
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Table 3: Demographic and Baseline Disease Characteristics for Patients with FCS in Studies CS6, CS7, and CS16 (Safety Set) CS6 CS7 CS16 Volanesorsen Volanesorsen Demographic and Volanesorsen Placebo Naïve Cs6 Rollovers Volanesorsen Placebo Disease Characteristic: (N = 33) (N = 33) (N = 18) (N = 11) (N = 5) (N = 2) Age at Informed Consent (years) n 33 33 18 11 5 2 Mean (SD, SEM) 47 (13, 2) 46 (14, 2) 49 (15, 4) 47 (15, 5) 47 (9, 4) 51 (11, 8) Minimum, Maximum 22, 75 20, 68 22, 69 23, 73 33, 54 43, 58 Mean 95% CI 42, 52 41, 50 42, 57 37, 57 36, 58 -45, 146 Sex n (%) Female 17 (51.5) 19 (57.6) 12 (66.7%) 5 (45.5%) 3 (60.0%) 2 (100.0%) Race - n (%) White 24 (72.7) 29 (87.9) 16 (88.9%) 8 (72.7%) 4 (80.0%) 1 (50.0%) Black 0 0 0 0 0 0 Asian 7 (21.2) 4 (12.1) 2 (11.1%) 3 (27.3%) 1 (20.0%) 1 (50.0%) Other Race 2 (6.1) 0 (0.0) 0 0 0 0 BMI (kg/m²) n 33 33 16 11 5 2 Mean (SD, SEM) 25.9 (6.5, 1.1) 24.1 (4.7, 0.8) 23.3 (3.8, 1.0) 22.7 (4.5, 1.3) 23.1 (3.8, 1.7) 26.6 (7.4, 5.3) Minimum, Maximum 14.9, 46.6 16.5, 38.6 16.6, 32.8 14.6, 30.0 18.6, 27.0 21.3, 31.8 Mean 95% CI 23.6, 28.2 22.4, 25.7 21.2, 25.3 19.7, 25.7 18.4, 27.8 -40.2, 93.3 Fasting Triglycerides (mg/dL) n 33 33 18 11 5 2 Mean (SD, SEM) 2267 (1259, 219) 2152 (1153, 201) 2288 (1075, 253) 1469 (886, 267)a 2134 (1141, 510) 2644 (314, 222) Minimum, Maximum 347, 5660 631, 5475 349, 4651 73, 3283 1074, 3998 2422, 2867 Mean 95% CI 1821, 2714 1743, 2560 1753, 2823 874, 2064 717, 3551 -180, 5468 Abbreviations: P25=25th percentile; P75=75th percentile; SD = standard deviation; SEM = standard error of the mean a Values from Baseline of CS7 for volanesorsen-treated patients previously enrolled in CS6.
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1.3.1.3 Efficacy Results in ISIS 304801-CS6 Primary Endpoint The study met its primary endpoint demonstrating a statistically significant reduction in fasting triglycerides from Baseline to Month 3 for volanesorsen-treated patients compared with placebo patients in the Full Analysis Set (FAS) (-94%; p<0.0001) (Table 4). Because all patients had triglyceride values for this endpoint, the analysis was conducted using the observed data.
Table 4: Percent Change from Baseline to Month 3 in Fasting Triglycerides (mg/dL) in CS6: Full Analysis Set
Volanesorsen 300 mg Placebo Analysis Endpoint Statistic (N = 33) (N = 33) Baseline (mg/dL) Mean (SD) 2267 (1259) 2152 (1153) Month 3 (mg/dL) Mean (SD) 590 (497) 2367 (1315) % Change from Baseline Least Squares Mean (95% CI) -76.5 (-97.4, -55.5) 17.6 (-4.0, 39.2) Treatment Comparison of % Change vs Placebo Relative Difference in % Change -94.1 95% CI (-121.7, -66.6) p-value <0.0001
Secondary Endpoints The study also met the first 3 secondary endpoints, indicating clinically significant lowering of triglycerides and the significant lowering effects continued over the 12-month treatment period. • Secondary Endpoint #1 - Treatment Response Rate: At the Month 3 primary endpoint, among patients with baseline triglycerides ≥ 750 mg/dL, 77% of volanesorsen-treated patients were responders according to reaching the predefined triglyceride threshold of < 750 mg/dL compared with 10% of placebo patients (p=0.0001). • Secondary Endpoints #2 and #3 - Percent Change in Fasting triglycerides to Months 6 and 12: In the volanesorsen group, mean percent reductions from baseline in fasting triglyceride levels using multiple imputation analysis were -53% at Month 6 and -40% at Month 12. In comparison, placebo patients had mean increases from baseline of 25% and 9% at Months 6 and 12, respectively. The differences between volanesorsen and placebo groups from Baseline to Month 6 (-78%) and Month 12 (-49%) were statistically significant (p<0.0001). The apparent decrease in volanesorsen efficacy from Month 3 is likely driven by several patients undergoing dose adjustments as well as discontinued patients who provided continued triglyceride measurements as required by the study protocol.
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A post-hoc analysis of treatment response in volanesorsen-treated patients showed a continued reduction of triglycerides at the 300 mg weekly dose as well as at the 300 mg every 2 weeks dose in patients with dose adjustment (see Section 8.2.10). In the subset of patients with baseline triglycerides ≥ 750 mg/dL, 60% of patients on once a week dosing and 46% of patients on every 2 week dosing had triglyceride values of < 750 mg/dL at Month 12. In comparison, 6.5% of placebo patients achieved this threshold of triglyceride management with diet alone at Month 12. • Secondary Endpoint #4 - Average Maximum Intensity of Patient Reported Abdominal Pain: Patients completed a weekly questionnaire to report abdominal pain and rated the maximum intensity of the pain on a scale of 0 (no pain) to 10 (unbearable pain). There was no significant difference in the average maximum intensity of reported abdominal pain events between the volanesorsen and placebo groups in the FAS; mean values were 0.38 in the volanesorsen group and 0.36 in the placebo group (p=0.8959). Therefore, all subsequent planned secondary endpoints were performed but should be considered as exploratory. Exploratory Endpoints: Remaining Secondary Endpoints Because the analysis of Secondary Endpoint #4 was not significant, all p-values for these exploratory endpoints are nominal and provided only for context. • Secondary Endpoint #5: The effect of volanesorsen on postprandial lipid assessments was nominally significant compared with placebo for mean percent change in postprandial triglyceride AUC(0-9h) (-91.1%; p = 0.0002). • Secondary Endpoint #6: At Month 3, 88% of patients in the volanesorsen group compared with 9% patients in the placebo group were responders (p < 0.0001), as defined by a ≥ 40% reduction in fasting triglycerides. The 40% relative threshold was selected based upon the upper limit of the response that had been observed with fibrates and fish oils in patients with severely elevated triglycerides, noting that this level of efficacy has not been reported in FCS patients with these agents. • Secondary Endpoint #7: The absolute mean triglyceride levels decreased from 2267 mg/dL at Baseline to 590 mg/dL in the volanesorsen group at the Month 3 endpoint, representing a mean change of -1712 mg/dL as compared with a 92 mg/dL change from Baseline to Month 3 in the placebo group (difference of -1804 mg/dL; p < 0.0001). • Secondary Endpoint #8: For this composite endpoint for pancreatitis and pain, a total of 12 (36%) patients in the volanesorsen group and 13 (39%) patients in the placebo group had adjudicated acute pancreatitis and/or moderate/severe abdominal pain. Review of the per-patient per year incidence of episodes of acute pancreatitis and/or reported moderate/severe abdominal pain did not reveal any significant differences between the volanesorsen and placebo groups (2.73 vs 2.04). • Secondary Endpoint #9: There was no significant difference between the placebo and volanesorsen groups in change from Baseline in hepatic volume by MRI at Week 52.
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Other Pre-Specified Exploratory Analyses Adjudication-Confirmed Acute Pancreatitis • Acute pancreatitis events were adjudicated by a blinded, independent adjudication committee as described in Section 7.1.3. During treatment, adjudication-confirmed acute pancreatitis was reported for 1 patient (1 event) in the volanesoren group compared with 3 patients (4 events) in the placebo group (Table 5). Missing data from 7 volanesorsen- treated patients and 1 placebo patient who terminated early from treatment and were not followed for the full 52-week study period was not imputed in the analyses comparing the treatment arms with respect to frequency of adjudication-confirmed acute pancreatitis events. • A post-hoc analysis of patients with a history of recurrent acute pancreatitis events was performed to focus on higher risk patients. Among patients with at least 2 adjudication- confirmed acute pancreatitis events in the 5 years prior to Study Day 1, there was a reduction in acute pancreatitis events in the volanesorsen group compared with the placebo group (Table 5).
Table 5: Summary of Adjudication-Confirmed Acute Pancreatitis in Study CS6 - FAS
Volanesorsen 300 mg Placebo (N = 33) (N = 33) Adjudication-confirmed pancreatitis n Events n Events All patients with any treatment-emergent 1 1 3 4 adjudication-confirmed event* Odds Ratio (95% CI), p-value 3.20 (0.24, 173.14), p = 0.6132
Patients with at least 2 adjudication-confirmed 7 24 4 17 events within 5 years prior to study treatment Patients with any treatment-emergent 0 0 3 4 adjudication-confirmed event* Odds Ratio (95% CI), p-value N/A (1.50, N/A), p = 0.0242 *Includes adjudication-confirmed pancreatitis events for any patient, regardless of prior history of pancreatitis. *Includes adjudication-confirmed pancreatitis events for those subjects with at least 2 adjudication-confirmed events within 5 years prior to study treatment. Effect on other lipid parameters • Mean reductions in chylomicron-triglycerides, apoC-III, and non-HDL-C were consistent with those reported for triglycerides along with mean increases in HDL-C, with p-values reaching nominal significance at the Month 3, Month 6, and Month 12 endpoints (see Table 23 in Section 8.2.9.4).
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Post-hoc Analyses Patient Reported Abdominal Pain from Weekly Questionnaire • During treatment, the incidence of patient reported severe abdominal pain was 15% in the volanesorsen group compared with 24% in the placebo group. • Among patients who had baseline abdominal pain (7 volanesorsen and 10 placebo patients), there was a statistically significant reduction in the average maximum intensity of abdominal pain during treatment in the volanesorsen group compared with the placebo group (least squares mean change -2.28 vs -1.33; p=0.0227). • In the patients with baseline abdominal pain, there was a numeric reduction in frequency of abdominal pain after 7-12 months of treatment in the volanesorsen group compared with the placebo group (3 vs 11 events per patient per year), frequency of episodes of moderate to severe abdominal pain during 4-12 months (2 vs 5 events per patient per year), and 7-12 months of treatment (2 vs 7 events per patient per year). Similarly, a numeric reduction of the worst abdominal pain intensity in volanesorsen-treated patients as compared with placebo-trated patients was demonstrated during 4-12 months (3.14 vs 5.4) and during 7-12 months of treatment (2.4 vs 5.4) (see Figure 9 in Section 8.2.9.1). Efficacy After Dose Reduction • For the 13 completers that had a reduction in dose frequency to every 2 weeks or a dose pause, largely comprised of patients with lower body weight, fasting triglyceride reduction was maintained at 54% average reduction from their baseline at Month 12 (see Table 25 and Figure 10).
1.3.2 Phase 3 Open-label Extension Study ISIS 304801-CS7 Study CS7 enrolled patients with FCS who had completed CS6 or CS16 and new patients with FCS who had not participated in a previous volanesorsen clinical trial. Study CS7 is ongoing.
1.3.2.1 Disposition and Exposure in ISIS 304801-CS7 At the time of the data cutoff for the NDA (06 January 2017), 29 patients were enrolled and had received at least 1 dose of volanesorsen in CS7. Efficacy data are presented for these 29 patients. Of the 29 patients with FCS, 18 patients were volanesorsen treatment-naïve (including 17 patients who enrolled from the CS6 placebo group and 1 patient who enrolled from the CS16 placebo group) and 11 patients had previously received volanesorsen during CS6 (CS6-volanesorsen group). Three of the 29 patients prematurely discontinued from study treatment in CS7 because of AEs, including 2 (11%) treatment-naïve group patients and 1 (9%) CS6-volanesorsen group patient. The mean duration of treatment in CS7 for these 29 patients was 109 days in the treatment-naïve group and 91 days in the CS6-volanesorsen group. For patients in the CS6-volanesorsen group, the mean treatment duration across both CS6 and CS7 was 473 days. Five (28%) patients in the
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treatment-naïve group and 7 of the 11 (64%) patients in the CS6-volanesorsen group had their dosing changed from weekly to every other week. As of the 31 August 2017 data cutoff for the 4-month Safety Update, which was submitted to FDA on 28 December 2017, a total of 60 patients had been enrolled and treated in CS7, including 43 treatment-naïve patients, as well as 14 patients who received volanesorsen in CS6 and 3 patients who received volanesorsen in CS16. Safety data are presented for these 60 patients. Overall, 12 of these 60 patients (7 treatment naïve and 5 CS6-volanesorsen) discontinued prematurely; 8 patients discontinued due to an AE and 4 discontinued due to voluntary withdrawal. The median treatment duration in Study CS7, at the 31 August cutoff, was 162 days in the treatment-naïve group, 257 days in the CS6-volanesorsen group, and 51 days in the CS16-volanesorsen group. For patients who received volanesorsen in either index study (N = 17), the median total treatment duration was 625 days (646 days in the CS6-volanesorsen group and 483 days in the CS16-volanesorsen group). A total of 34 (57%) patients had study medication dose interruptions and/or dose pauses, including 26 (61%) treatment-naïve patients, 7 (50%) CS6-volanesorsen patients, and 1 (33%) CS16-volanesorsen patient. Most dose interruptions/pauses were due to lab values (37%) or AEs (20%). The modification of the protocol allowing dose frequency adjustments was fully operationalized by the start of the CS7 study and was associated with a lower dropout rate in that study relative to the CS6 study. Specifically, 16% (7 of 43) of patients in the treatment naïve group discontinued from CS7, compared to the 42% (14 of 33) of patients in the volanesorsen group that discontinued prematurely from CS6. Treatment naïve patients who enrolled late in CS7 had a short exposure duration as of 31 August 2017, but total duration of exposure was similar between the treatment naïve patients in CS7 and patients treated with volanesorsen in CS6.
1.3.2.2 Efficacy Results in ISIS 304801-CS7 The reductions in triglyceride values in CS7 were consistent with those reported for volanesorsen-treated patients in CS6. The efficacy of volanesorsen shown in CS6 was sustained in longer-term treatment, and there was an expected response of triglycerides reduction in those patients who transferred from placebo treatment (Table 6). Patients in the CS6-volanesorsen group had a lower mean triglyceride level at the OLE baseline compared with their Index Study baseline but elevated from their end of CS6 levels due in part to varying treatment gaps that occurred between the end of treatment in the Index Study and the start of treatment in the OLE.
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Table 6: Summary of Change from Baseline to Month 3 in Fasting Triglycerides Using OLE and Index Study Baseline - CS7 FAS (31 August 2017 data cutoff) Treatment-naïve CS6-Volanesorsen CS16-Volanesorsen CS7 OLE CS6 Index Study CS7 OLE CS16 Index CS7 OLE Baseline Baseline Baseline Study Baseline Baseline (N=43) (N=14) (N=14) (N=3) (N=3) Mean Mean Mean Mean Mean Analysis Endpoint n (SD, SEM) n (SD, SEM) n (SD, SEM) n (SD, SEM) n (SD, SEM) Baseline Observed 43 2140 14 2641 14 1523a 3 2288 3 2081a Fasting triglycerides (1065, 162) (1228, 328) (946, 253) (1524, 880) (706, 408) (mg/dL) OLE Month 3 Observed 38 778 13 1270 13 1270 2 1202 2 1202 Fasting triglycerides (591, 96) (845, 234) (845, 234) (497, 351 (497, 351) (mg/dL) Change in Fasting 38 -1432 13 -1320 13 -256 2 -1692 2 -1281 triglycerides - Baseline to (1071, 174) (958, 266) (763, 212) (1064, 752) (336, 238) OLE Month 3 Percent Change in 38 -58.7 13 -48.1 13 -7.9 2 -56.8 2 -52.1 Fasting triglycerides to (37.8, 6.1) (36.0, 10.0) (44.0, 12.2) (6.1, 4.3) (16.9, 12.0) OLE Month 3 a Many patients had a drug holiday between studies while awaiting regulatory approval for CS7, thus the OLE baseline triglycerides values were higher than the values at the end of the Index Study.
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Figure 2 illustrates the sustained efficacy for CS6-volanesorsen patients with longer-term treatment in CS7. Note that this figure includes data through the date of the 4-month safety cutoff (31 August 2017) and the small number of patients at the last time point is due to some patients not yet reaching that time point in CS7.
Figure 2: Fasting Triglycerides Mean (+/-SEM) Percent Change Over Time for the Cohort of Volanesorsen-Treated Patients in Studies CS6 Continuing into CS7 - Full Analysis Set – Data Through 31 August 2017
Baseline CS6_Month3 CS6_Month6 CS6_Month12 CS7_Month3 CS7_Month6 CS7_Month12
Time Point Number of Subjects 14 14 14 14 13 9 3 At the 06 January 2017 data cutoff for the NDA, there were 9 treatment-naïve patients with open-label baseline triglyceride levels ≥ 750 mg/dL who had Month 3 triglyceride values available, and 4 (44%) of these patients achieved triglyceride levels < 750 mg/dL at Month 3. Among the 4 CS6-volanesorsen patients with Index Study Baseline triglyceride levels ≥ 750 mg/dL who had Month 3 triglyceride values available at the time of the 06 January 2017 data cutoff, 1 (25%) had triglyceride levels < 500 mg/dL at Month 3.
1.3.3 Phase 3 Study ISIS 304801-CS16 The efficacy results in CS16 were consistent with those reported for CS6, supporting the efficacy results for the FCS population in CS6 (see Section 8.4). In the subset of 7 patients with FCS in CS16, whose mean Baseline fasting triglyceride level was 2280 mg/dL, volanesorsen-treated patients (n=5) achieved a mean absolute reduction of 1511 mg/dL at the Month 3 endpoint. This reduction in fasting triglyceride levels correlates to a change of -73% from Baseline after 13 weeks of treatment, compared with a mean increase of 70% in placebo-treated patients (n=2).
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1.3.4 Safety of Volanesorsen Treatment Across the clinical studies, a total of 312 subjects and patients have been exposed to volanesorsen, including 248 subjects/patients exposed to volanesorsen 300 mg SC. A total of 87 patients with FCS have been evaluated, including 84 patients with FCS who were exposed to volanesorsen. All volanesorsen studies included a thorough evaluation of safety. Standard safety assessments conducted in all studies included physical examinations; vital signs; clinical laboratory evaluations, including hematology and chemistry; and 12-lead electrocardiograms (ECGs); echocardiograms, as well as monitoring for AEs and concomitant medication usage. Results from these studies show no evidence of cardiovascular, hepatic, or renal safety signals associated with volanesorsen treatment. In a thorough QT study, treatment with volanesorsen did not prolong QTc, nor did it affect other ECG parameters including heart rate or PR and QRS intervals. Across all studies, the most frequent AEs observed were events related to local tolerability and platelet count reductions; other events occurring in > 10% of patients were mostly mild and moderate. The majority of AEs at the injection site were transient (less than 2 days in duration), and were mild, requiring no treatment. Adverse events at the injection site persisting for at least 2 days, occurred in: • CS6: following 17% (194) of volanesorsen injections and at least once in 26 (79%) of 33 volanesorsen-treated patients and 0 of 33 placebo patients. • CS16: following 39% (514) of volanesorsen injections and at least once in 65 (87%) of 75 volanesorsen-treated patients and 3 (8%) of 38 placebo patients (total of 8 events). • CS7: following 18% (222) of volanesorsen injections and at least once in 41 (68%) of 60 volanesorsen-treated patients. With the exception of 3 severe events in 1 patient in CS7, all were mild or moderate in severity. In the target population of patients with FCS, there was a single discontinuation for injection site related AEs and, in patients with non-FCS severe hypertriglyceridemia, there were 9 discontinuations for these events. In FCS patients in CS6, there were 16 events related to platelet reduction in the volanesorsen group and 1 event in the placebo group (Table 7). Note that platelet count reductions included the Medical Dictionary for Regulatory Activities (MedDRA) preferred terms of either platelet count decreased or thrombocytopenia. The AEs related to platelet reductions were mild in severity in most patients and well managed with dose pauses and adjustments. For most patients who experienced platelet reductions, the reductions were gradual over time with onset during the first 3 months of treatment with a nadir reached at approximately 3 to 6 months after the start of study drug.
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Table 7: On-Treatment Adverse Events Related to Platelet Reductions in Study CS6: Safety Set
Volanesorsen Placebo (N = 33) (N = 33) Preferred Term n (%) Events n (%) Events Platelet reductions 13 (39.3)a 16 1 (3.0) 1 Platelet count decreased 10 (30.3) 12 1 (3.0) 1 Thrombocytopenia 4 (12.1) 4 0 0 Note: An on-treatment AE was defined as any AE that occurred from the first dose of the Study Drug through 28 days post the last dose of Study Drug. a One patient had reports of both platelet count decreased and thrombocytopenia. As of the 31 August 2017 data cutoff for the 4-month Safety Update 3 patients (2 in CS6 and 1 in CS7) had Grade 4 thrombocytopenia (platelets < 25,000/mm3) reported as SAEs because the Investigator determined the events to be medically significant and in 2 cases led to hospitalization. One additional medically significant thrombocytopenia SAE was reported in a patient in CS7 after the data cutoff. All platelet reductions were responsive to dose adjustment or treatment interruption. The serious platelet reductions reversed within weeks of discontinuation of study drug and treatment with glucocorticoids. Reductions in platelet count to < 50,000/mm3 were reported in 8 patients across the clinical development program as of the data cutoff for the 4-month Safety Update (31 August 2017) (see Table 34 in Section 9.7.2.1). There were no major bleeding events in any patients (as defined in Schulman et al. 2005). To better understand possible associations or predictors of the platelet events, data from all clinical studies were evaluated. A statistically significant but moderate inverse correlation between platelet count percent decrease and body weight was observed (p < 0.0001), suggesting that patients with lower weights may have an increased risk of platelet reductions. A 16% higher drug exposure, as represented by AUC, was associated with the low tertile of body weight compared to the middle tertile of body weight while a 11% lower exposure was associated with the high tertile of body weight, for a fixed dose of 300 mg (Section 6.1.3.2). Thus, the observed higher risk of platelet reduction in lighter patients can be partially explained by higher volanesorsen exposure in lighter patients. No other associations were identified. Excluding the injection site events and laboratory abnormalities, the most commonly reported bleeding events (i.e., MedDRA hemorrhages SMQ) in the volanesorsen group in CS6 and CS16 were epistaxis in 6 (7%) patients and petechiae in 5 (6%) patients; none of the patients in the placebo group experienced these events. All clinical bleeding events were mild in severity.
Other commonly reported AEs experienced by > 10% of patients treated with volanesorsen across CS6 and CS16 are summarized in Table 8.
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Table 8: On-Treatment Adverse Events Experienced by > 10% of Pooled Volanesorsen Patients in CS6 and CS16 (Excluding AEs at the Injection Site)
CS6 CS16 Volanesorsen Placebo Volanesorsen Placebo (N = 33) (N = 33) (N = 75) (N = 38) Preferred Term n (%) n (%) n (%) n (%) Platelet Reduction 13 (39.3)a 1 (3.0) 13 (17.3) 4 (10.5) Platelet count decreased 10 (30.3) 1 (3.0) 3 (4.0) 2 (5.3) Thrombocytopenia 4 (12.1) 0 10 (13.3) 2 (5.3) Abdominal pain 7 (21.2) 7 (21.2) 8 (10.7) 0 Headache 7 (21.2) 5 (15.2) 6 (8.0) 4 (10.5) Fatigue 7 (21.2) 3 (9.1) 9 (12.0) 4 (10.5) Nausea 6 (18.2) 2 (6.1) 7 (9.3) 1 (2.6) Nasopharyngitis 5 (15.2) 7 (21.2) 12 (16.0) 5 (13.2) Diarrhea 5 (15.2) 2 (6.1) 10 (13.3) 4 (10.5) Pain in Extremity 4 (12.1) 1 (3.0) 7 (9.3) 1 (2.6) Note: An on-treatment AE was defined as any AE that occurred from the first dose of the Study Drug through 28 days post the last dose of Study Drug. a One patient had reports of both platelet count decreased and thrombocytopenia. 1.4 Risk Mitigation Treatment with volanesorsen has been associated with reductions in platelet count, which may result in thrombocytopenia. The risk of thrombocytopenia was well-managed in clinical trials once frequent platelet monitoring and pre-specified dose adjustments were introduced and no major or serious bleeding events occurred in any patient. When the platelet monitoring and dose adjustment program was initiated and followed, declines in platelet counts were detected promptly, fewer severe declines occurred, and patient discontinuations due to platelet counts were less frequent. Consequently, a similar program of close platelet monitoring and dose adjustments is part of the risk mitigation for the FCS population in the commercial setting. The sponsor is committed to ensuring that the benefits of volanesorsen outweigh the risks. Because of the potential risk of serious bleeding due to severe thrombocytopenia associated with volanesorsen, a Risk Evaluation and Mitigation Strategy (REMS) with the following Elements to Assure Safe Use (ETASU) will be implemented: 1. Healthcare providers who prescribe volanesorsen must be specially certified. 2. Pharmacies that dispense volanesorsen must be specially certified. 3. Volanesorsen may only be dispensed to patients with evidence or other documentation of safe-use conditions.
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4. Patients receiving volanesorsen are subject to monitoring and must be enrolled in a REMS registry. The goals of the volanesorsen REMS is to mitigate the potential risk of serious bleeding due to severe thrombocytopenia associated with volanesorsen by: • Ensuring that healthcare providers are educated on the following thrombocytopenia associated with volanesorsen that could lead to bleeding; monitoring recommendations and treatment modifications for platelet reductions per the Prescribing Information; and the need to counsel patients about the risks of thrombocytopenia and bleeding, and the need for routine platelet monitoring. • Ensuring that patients are informed about the risks of platelet reduction and thrombocytopenia, and the signs and symptoms of bleeding; and the need to monitor platelets during treatment. • Enrollment of all patients in a mandatory registry to further support long-term safety and safe use of volanesorsen Prescribing information will include a platelet monitoring and dose adjustment algorithm to guide healthcare providers and ensure appropriate treatment of patients with volanesorsen. The prescribing information includes a boxed warning for the risk of severe thrombocytopenia with potential risk for serious bleeding and provides information on the risk of thrombocytopenia as well as guidance on who should not be treated with volanesorsen. In addition to the REMS, there will be a comprehensive patient support program with nurse care managers assigned to every patient and regionally based throughout the US. The nurse case managers will be the conduit to ensure delivery of supplemental patient education, compliance and adherence tools in addition to the labeling and REMS requirements. Details of this program can be found in Section 10. Additional pharmacovigilance activities will also be implemented with active follow-up of reportable events to ensure accurate documentation and efficient communication of new AE information. 1.5 Benefit and Risks Conclusions • FCS is a serious, rare disorder of lipid metabolism. There are currently no effective therapies for patients with FCS. • The profound excess of chylomicrons and their component triglycerides confer a high risk of a severe form of pancreatitis. While pancreatitis comprises the most severe morbidity and contributes to mortality in FCS, other triglyceride-related morbidities also occur. • Volanesorsen reduced triglyceride levels by more than 70% in patients with FCS, with most patients achieving levels below those associated with high risk of pancreatitis. Consistent with this result, the data support (but do not prove) a possible reduction in pancreatitis events vs placebo.
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• The primary safety findings from the clinical development program for volanesorsen were treatment-related reduction in platelet count and local injection site reactions. • The primary benefit of volanesorsen is triglyceride reduction that is sufficient to predict decreases in the most severe morbidity and mortality associated with FCS. • The primary risk associated with volanesorsen is thrombocytopenia. • A platelet monitoring and volanesorsen dose adjustment plan, through dosing frequency adjustment, developed during clinical studies was shown to be effective for mitigating the risk of clinically meaningful thrombocytopenia. • Volanesorsen represents the first, and currently only, opportunity for FCS patients to reduce morbidity and mortality associated with chylomicronemia/hypertriglyceridemia. This potential benefit outweighs the potential risk of thrombocytopenia, which was shown to be manageable with appropriate monitoring. No other options offer clinically meaningful triglyceride reduction to patient with FCS. Hence, the manageable risks associated with volanesorsen treatment are overshadowed by the potential reductions in life-threatening complications of chylomicronemia. A comprehensive and tightly controlled risk mitigation proposal will be implemented to ensure that these potential benefits of profound triglyceride reduction outweigh risks for this rare, underserved population.
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1. Fasting triglyceride levels in excess of 750 mg/dL or 8.5 mmol/L (chylomicronemia) that are refractory to standard lipid lowering therapy (Jacobson et al. 2015) AND 2. At least one of the following:
o History of acute pancreatitis o History of childhood pancreatitis o History of recurrent abdominal pain without other explainable cause o Family history of hypertriglyceridemia AND 3. Persistence of chylomicronemia after the exclusion of contributing factors, e.g., the removal of exacerbating causes through diet modification, discontinuation of drugs known to increase triglyceride levels, and/or provision of insulin therapy for patients with poorly treated diabetes mellitus (Miller et al. 2011). In addition, the contribution of other causes of pancreatitis (e.g., alcoholism, gallstones) should also be ruled out. Additional supportive clinical findings can include eruptive xanthomas, lipemia retinalis, and hepatosplenomegaly. Genetic testing can be used for additional information, but a negative genetic test is not exclusionary of FCS. 2.2.1 FCS Disease Complications 2.2.1.1 Risk of Pancreatitis Approximately 65-80% of patients with FCS have experienced acute pancreatitis (Gaudet et al. 2016), with a rate of 0.2 pancreatitis events per year. Acute pancreatitis presents the most significant risk in patients with FCS, with potential mortality and other significant complications (Davidson 2017). Long term complications as a result of acute pancreatitis may include chronic pancreatitis, pancreatogenic (Type 3c) diabetes, and exocrine pancreatic insufficiency, with their attendant complications (Symersky et al. 2006). In general, the risk of acute pancreatitis increases 4% for every 100 mg/dL increase in triglycerides above normal (Murphy et al. 2013). Moreover, pancreatitis risk appears to be higher in patients with severely elevated triglycerides than in patients with moderately elevated triglyceride levels (Nawaz et al. 2015). Decreasing triglycerides below 1000 mg/dL greatly decreases the risk of pancreatitis (Berglund et al. 2012). Prospective, controlled trials to evaluate the impact of triglyceride lowering on the risk of pancreatitis in FCS have been not possible to date, since no effective triglyceride-lowering intervention was available for these patients. Projections from a Monte Carlo simulation model estimate that adults with FCS will experience approximately 10 episodes of acute pancreatitis during their lifetime. Further, the authors predicted that a 50% reduction in triglycerides would prevent 7.7 episodes of acute pancreatitis in adult FCS patients (Lin et al. 2014).
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Pancreatitis associated with severe hypertriglyceridemia (triglycerides > 1000 mg/dL) may be more severe with worse outcomes than pancreatitis of other etiologies. In one study, compared to acute pancreatitis in patients with normal triglyceride levels (< 150 mg/dL), the acute pancreatitis in the cohort of patients with severe hypertriglyceridemia (triglycerides > 1000 mg/dL) resulted in longer median hospital stays (17 days vs. 7 days), increased need for intensive care (60% vs. 23%), a higher rate of pancreatic necrosis (50% vs. 36%), and more frequent persistent (i.e., > 48 hr) organ failure (48% vs. 17%; Figure 3), and higher mortality (8% vs 3%; Nawaz et al. 2015); 6% of patients with FCS die from pancreatitis (Gaudet et al. 2016), even under the care of leading lipidologists.
Figure 3: Degree of Triglyceride Elevation Correlates with Severity of Pancreatitis
Further, patients with FCS may be at enhanced risk of pancreatitis compared to patients with even moderate hypertriglyceridemia. According to a retrospective analysis of a cohort of patients followed at the Chicoutimi Hospital Lipid Clinic (Quebec, Canada), in comparison with patients with normal triglyceride levels, patients with triglycerides > 800 mg/dL (which these authors define as severe hypertriglyceridemia) with FCS had 360-fold greater risk of acute pancreatitis, and a 23-fold greater risk compared to patients with triglycerides values of ~440 – 800 mg/dL, underscoring the need to reduce triglycerides in this population (Gaudet et al. 2010, Tremblay et al. 2011). Both mortality and morbidity associated with very high triglycerides in FCS patients are increased compared to the general high triglyceride patient population; therefore, the primary treatment goal for FCS patients is to reduce their triglyceride levels as substantially as possible to reduce the risk of pancreatitis.
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2.2.1.2 Impact of FCS on Patients’ Quality of Life Patients with FCS frequently experience manifestations of their disease that have considerable impact on their daily lives. A recent survey of patients with FCS not participating in the Sponsor’s development program for volanesorsen, the IN-FOCUS survey, designed with the input of patients and their physicians, collected information on nearly 170 patients with FCS regarding their symptoms experienced over the past 12 months. The results of the first 60 patients were analyzed and indicated a wide range of physical, cognitive, and emotional/psychosocial impairments (Davidson et al. 2017). The incidence, frequency, and severity of physical symptoms reported are displayed in Figure 4. Patients also reported lack of concentration, impairment of memory, brain fog, anxiety and feeling depressed, fear and worry about living with the disease, fear of eating food prepared by others, fear of gastrointestinal pain or pancreatitis. All of these symptoms were reported to occur frequently and at moderate to severe magnitude. Collectively, these have considerable impact on quality of life and activities of daily living, impact on employment choices, ability to secure and maintain employment, and days lost from work. Notably, 78% of patients were unemployed or under-employed. For those employed, patients reported an average of 30 working days lost to illness each year, (range 0-61+) compared with the general US population average of 4-5 sick days taken per year, according the US Bureau of Labor and Statistics.
Figure 4: Incidence, Frequency, and Severity of Symptoms – IN-FOCUS
Severity Key: 1 = very mild; 7 = very severe
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2.2.2 Platelet Variability in FCS Recently available natural history data in 87 patients from 3 Canadian clinics (the SMASH registry) showed that patients with FCS experience wide fluctuations in platelet count over time, ranging from moderate to severe thrombocytopenia to thrombocytosis as part of the natural history of the disease. Across the mean of 11 years (range: 2-31 years) of hematological evaluations, 55% of patients had at least one excursion in platelet values below the lower limit of normal (LLN), and 20% had values < 100,000/mm3 (Gaudet et al. 2016, Gaudet et al. 2017). Based on these observational data, patients with FCS may have natural platelet variability and experience thrombocytopenia, and to a lesser degree of thrombocytosis as part of the natural course of their disease. In a natural history study of 42 FCS patients, platelet counts were below 100,000/mm3 at least once for a third of the patients and more than 10 times for almost 10% of the patients (Table 9). Similar natural platelet variability was noticed in the placebo cohorts in Studies CS6 and CS16.
Table 9: Percent of 42 Patient FCS Data Set who Experienced Thrombocytopenia < 100,000/mL over Mean of 11 years (Range: 2-31 years)
Historical platelet count values under 100,000/mm3 Patients N = 42 % At least once 14 33.3 At least twice 11 26.2 At least 3 times 9 21.4 At least 5 times 6 14.3 More than 10 (up to 55) 4 9.5 Source: Gaudet et al. 2016 2.3 FCS Unmet Medical Need Currently, there is no approved therapeutic agent specifically indicated for the treatment of FCS. The Endocrine Society and American Heart Association clinical guidelines recommend treating triglycerides ≥ 500 mg/dL with medications to reduce the risk of pancreatitis. Traditional lipid- lowering medications used to treat hypertriglyceridemia, such as fibrates, niacin, and fish oils, are minimally effective in lowering triglycerides in patients with FCS because their effectiveness depends, at least in part, on a functional lipoprotein lipase enzyme, notably deficient in these individuals (Brahm and Hegele 2015, Stroes et al. 2017). The treatment goals in FCS are to reduce the risk of pancreatitis and other symptoms associated with disease burden by reducing chylomicrons as measured by plasma triglycerides. The current management option to attempt reductions plasma triglyceride levels in patients with FCS is an extremely restrictive diet devoid of nearly all dietary fat, ideally no more than 20 g daily (Brunzell 1999-2011, Valdivielso et al. 2014) and strict avoidance of alcohol and classes of drugs that are known to increase triglyceride levels. Even short-term ingestion of dietary fat or limited alcohol consumption can result in highly exaggerated triglycerides excursions that place
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the patients at a high risk for acute pancreatitis, despite compliance to their restricted dietary and life-style prescriptions. Even in patients with strict dietary adherence, triglyceride levels may remain at levels associated with an elevated risk of pancreatitis, and symptoms are not alleviated, demonstrating that diet alone does not sufficiently mitigate the risk of pancreatitis in all patients (Gaudet et al. 2010, Ceska et al. 2016, Stroes et al. 2017). In severely ill patients, most often those with acute pancreatitis and triglycerides > 1000 mg/dL plus lipase > 3 × ULN, plasmapheresis may be used to quickly decrease triglyceride levels on a short term basis, but is not a solution for the long term management of patients with FCS. With the high burden and potentially fatal nature of the associated risk of pancreatitis in patients with FCS, coupled with the ineffectiveness of currently available therapies or failed management strategies such as diet alone, a high unmet need exists to bring a drug to this patient population.
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lipoproteins (VLDL-C). Prior to recent work in FCS, apoC-III was believed to regulate plasma triglyceride levels principally through inhibition of lipoprotein lipase activity (Norata et al. 2015). However, because volanesorsen therapy dramatically reduced triglycerides in patients who genetically lacked any functional lipoprotein lipase activity, it demonstrated that apoC-III is also a major regulator of the non-lipoprotein lipase mediated pathway of triglyceride-rich lipoproteins clearance (Figure 5), where its suppression leads to significant reductions in plasma triglycerides in patients with FCS (Gaudet et al. 2014). Thus, in addition to its role in inhibiting lipoprotein lipase, apoC-III inhibits triglyceride-rich lipoproteins uptake by hepatic lipoprotein receptors (Gordts et al. 2016).
Figure 5: ApoC-III, Inhibitor of TG Metabolism by Multiple Mechanisms
ApoC-III=apolipoprotein C-III; HL=hepatic lipase; IDL=intermediate-density lipoprotein; LDL=low-density lipoprotein; lipoprotein lipase=lipoprotein lipase; VLDL=very low-density lipoprotein. Source: (Gordts et al. 2016) Taken together, the available genetic data and a large body of experimental evidence strongly support the centrality of apoC-III in regulation of plasma triglyceride levels (Khetarpal et al. 2016). These data, combined with the efficacy of volanesorsen in lipoprotein lipase-null patients with FCS supported the development of antisense therapy to reduce plasma apoC-III levels in order to reduce the very high circulating triglycerides and chylomicron levels observed in patients with FCS (Gaudet et al. 2010, Gaudet et al. 2014).
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has patients with extended exposure to beyond 12 months and, for some patients, approaching and beyond 36 months.
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Table 10: Summary of Volanesorsen Clinical Studies
Study ID/ Dosage Primary Population Study Title Control Regimen/Duration Objective Number of Patients Treated Phase 3 Studies and Open-label Extension in FCS and Hypertriglyceridemia ISIS 304801-CS6 A Randomized, Double-Blind, Placebo- Placebo Volanesorsen (SC): 300 mg Efficacy Volanesorsen: 33 FCS Controlled, Phase 3 Study of ISIS 304801 Once weekly for 52 weeks Safety Placebo: 33 Administered Subcutaneously to Patients with Familial Chylomicronemia Syndrome ISIS 304801-CS7a An Open-Label Study of Volanesorsen N/A Volanesorsen (SC): 300 mg Safety Volanesorsen: 60 at cutoff FCS Administered Subcutaneously to Patients with Once weekly for 52 weeks (43 volanesorsen naïve) Familial Chylomicronemia Syndrome ISIS 304801-CS16 A Randomized, Double-Blind, Placebo- Placebo Volanesorsen (SC): 300 mg Efficacy Volanesorsen: 75 (5 FCS) Hypertriglyceridemiab Controlled Phase 3 Study of ISIS 304801 Once weekly for 26 weeksc Safety Placebo: 38 (2 FCS) Administered Subcutaneously to Patients with Hypertriglyceridemia Phase 2 Studies in Hypertriglyceridemia ISIS 304801-CS2 A Randomized, Double-Blind, Placebo- Placebo Volanesorsen (SC): 100, Dose Volanesorsen: 64 (3 FCS) Severe or Controlled, Dose Response, Phase 2 Study of 200, 300 mg response 100 mg: 13; 200 mg: 23; Uncontrolled ISIS 304801 Administered Subcutaneously to Once weekly for 13 weeks PD 300 mg: 28 (3 FCS) b Patients with Severe or Uncontrolled Hypertriglyceridemia Safety Placebo: 24 Hypertriglyceridemia ISIS 304801-CS4 A Randomized, Double Blind, Placebo- Placebo Volanesorsen (SC): 300 mg PD Volanesorsen: 10 Hypertriglyceridemia Controlled, Phase 2 Study to Investigate the 13 weeks: every other day Safety Placebo: 5 with Type 2 Diabetes Effects of ISIS 304801 Lowering of ApoC-III for 1 week then once Mellitus on Triglyceride Levels and Insulin Sensitivity weekly for 12 weeks in Subjects with Type 2 Diabetes Mellitus
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Study ID/ Dosage Primary Population Study Title Control Regimen/Duration Objective Number of Patients Treated Phase 1 Studies ISIS 304801-CS1 A Randomized, Double-Blind, Placebo- Placebo Volanesorsen (SC): Safety Volanesorsen: 25 Healthy Volunteers Controlled, Dose-Escalation, Phase 1 Study SAD: 50, 100, 200, and Placebo: 8 to Assess the Safety, Tolerability, and 400 mg Pharmacokinetics of Single and Multiple MAD: 50, 100, 200, and Doses of ISIS 304801 Administered 400 mg for 4 weeks: every Subcutaneously to Healthy Subjects other day for 1 week then once weekly for 3 weeks ISIS 304801-CS13 A Randomized, Placebo-Controlled, Four- Placebo Volanesorsen 300 mg SC, Safety Total: 52 d Healthy Volunteers Period Crossover, Study to Evaluate the volanesorsen 300 mg IV , 49 dosed with volanesorsen, Effect of Volanesorsen (ISIS 304801) on the placebo, and moxifloxacin 46 dosed with volanesorsen QTc Interval Using a Therapeutic and Supra- Crossover study: Single 300 mg SC Therapeutic Dose Compared with Placebo in doses, 1 in each of 4 Healthy Volunteers: a Thorough QT Study treatment periods Phase 2/3 Studies in Familial Partial Lipodystrophy ISIS 304801-CS17 A Randomized, Double-Blind, Placebo- Placebo Volanesorsen (SC): 300 mg Efficacy Ongoing and blinded FPL Controlled, with an Open Label Extension, Once weekly for 52 weeks 22 patients at cutoff, Phase 2/3 Study of ISIS 304801 Administered recruiting up to 60 Subcutaneously to Patients with Familial 1:1 randomization Partial Lipodystrophy volanesorsen:placebo ISIS 304801-CS19e A Randomized, Double Blind, Placebo- Placebo Volanesorsen (SC): 300 mg Efficacy Ongoing and blinded FPL Controlled Study to Assess Efficacy, Safety Once weekly for 68 weeks: 3 patients at cutoff, recruiting and Tolerability of ISIS 304801 in Patients 16 weeks placebo up to 20 with Familial Partial Lipodystrophy with an controlled, 52 weeks OLE 1:1 randomization Open-Label Extension volanesorsen:placebo
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Study ID/ Dosage Primary Population Study Title Control Regimen/Duration Objective Number of Patients Treated All Studies 403 Total 312f Volanesorsen 248f Volanesorsen 300 mg 123f Placebo 87 FCS 84 Volanesorsen FCS Abbreviations: AE = adverse event; FCS = familial chylomicronemia syndrome; FPL = familial partial lipodystrophy; IV = intravenously MAD = multiple ascending dose; NIH = National Institutes of Health; OLE = open label extension; PD = pharmacodynamics; SAD = single ascending dose; SC = subcutaneous Data cutoff was 31 August 2017. a This is an open-label extension (OLE) study in patients with FCS from CS6, CS16, or newly identified patients meeting inclusion criteria. Eleven patients with FCS not enrolled in CS6 or CS16 were enrolled as of the data cut off. b Included patients with FCS. c For CS16, the protocol was amended so that patients that had not already completed ≥ 5 months of dosing as of 27 May 2016 had dose frequency reduced to 300 mg every 2 weeks or dose reduced to 150 mg per week after 13 weeks of treatment. A total of 39 patients had their dose or frequency of dosing changed as a consequence of this amendment. d 2-hour IV infusion acts as supratherapeutic dose. e CS19 is an investigator-initiated, NIH-sponsored study. f For ongoing blinded studies CS17 and CS19 with 1:1 randomization, assume one half of the patients are treated with volanesorsen.
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Clinical trials of volanesorsen began in 2010 with a healthy volunteer study (ISIS 304801-CS1 [hereafter, CS1]), evaluating doses at 50, 100, 200, and 400 mg, to provide initial safety and tolerability data in human subjects. In the multiple ascending dose (MAD) phase of CS1, the time to steady state study was accelerated by administering study drug on alternate days during Week 1 (Days 1, 3, and 5) and then once a week for the next 3 weeks (Days 8, 15, and 22). Data from CS1 demonstrated dose-dependent sustained reductions in total apoC-III and in triglyceride levels, demonstrating dose-dependent pharmacology with respect to the target, apoC-III, and also with respect to the desired therapeutic benefit on triglyceride levels. No maximum tolerated dose was reached and based on the clinically significant dose-dependent sustained reductions in total apoC-III and corresponding reductions in triglyceride levels, 2 placebo-controlled Phase 2 studies (ISIS 304801-CS2 [hereafter, CS2] in patients with hypertriglyceridemia and patients with FCS and ISIS 304801-CS4 [hereafter, CS4] in patients with type 2 diabetes mellitus [T2DM] and hypertriglyceridemia) were initiated. The placebo-controlled studies CS2 and CS4 were designed to evaluate the dose response and PD effect on fasting total apoC-III and triglyceride levels. In CS2, doses of 100, 200, and 300 mg were studied in patients with moderate elevations in triglycerides. To test the hypothesis that apoC-III could be an effective approach to treating FCS, 3 patients with FCS were enrolled in an open-label fashion. Similar dose-dependent responses to CS1 were found in CS2, with time- and dose-dependent reductions in apoC-III and fasting triglycerides, which were also demonstrated in the small cohort of patients with FCS in the study. In CS4, there were also significant reductions in apoC-III and triglycerides, accompanied by increases in HDL-C, improvements in insulin sensitivity, and improved glycemic control. In CS2, the 3 FCS patients presented with platelet levels around the lower limit of normal and decreased further during treatment. This was in contrast to the non-FCS patients in the study where platelet levels did decrease in a dose-dependent manner, however never reaching the lower limit of normal. The starting dose of 300 mg per week for the Phase 3 study in patients with FCS, CS6, was based on PK/PD modeling of CS1 and CS2 and a safety profile consistent with continued advancement to Phase 3. The same starting dose was employed in the Phase 3 study of patients with severe hypertriglyceridemia, CS16, and for the studies of patients with FPL.
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Effects of intrinsic and extrinsic factors on the PK of volanesorsen were assessed via population PK modeling in which no covariate effects were found to be clinically relevant for variations in the starting dose. Based on the population PK analysis, steady-state will be reached approximately 3 months after starting volanesorsen in patients with FCS and the estimated accumulation at steady-state after 300 mg weekly based on Ctrough is 7-fold. The estimated mean steady-state Ctrough values for 300 mg weekly and 300 mg every 2 weeks in patients with FCS are 127 ng/mL and 58.0 ng/mL, respectively. The mean terminal elimination half-life in patients with FCS is estimated to be 31.6 days.
6.1.1 Absorption, Distribution, Clearance, Metabolism, and Elimination
Following SC injection, Cmax was reached within 2 to 4 hours. The geometric mean absolute bioavailability of 300 mg volanesorsen SC relative to IV was 78.7% (CV% 21.3%). Volanesorsen is highly bound to human plasma proteins (> 98%), with a consistently high fraction of the drug bound to plasma proteins independent of drug concentration. The steady- state volume of distribution and apparent volume of distribution in patients with FCS are 303 L and 436 L, respectively, based on a population PK analysis. Intact volanesorsen was the most abundant oligonucleotide detected in human plasma and accounted for > 99% of total detected oligonucleotides. The urinary excretion of intact volanesorsen within the first 24 hours following the last dose on Day 22 (i.e., near steady-state) was low with a mean percent dose excreted intact of 3.23% of the administered dose, which is consistent with most of an administered SC dose of volanesorsen being rapidly and extensively distributed intact into tissues, where the drug is metabolized to chain-shortened metabolites prior to excretion in urine.
6.1.2 Dose-Proportionality of Pharmacokinetics
In CS1, the Cmax increased approximately proportionally with dose at doses from 50 to 400 mg following single and multiple doses. The AUC values increased slightly greater than proportionally over the same dose range but nearly dose proportionally in the dose range of 100 to 400 mg on Day 22. The half-life of volanesorsen estimated in healthy volunteers of 2 to 4 weeks in CS1 remained constant within the evaluated dose range and did not change with repeated dose administration. As expected based on the linear PK, the plasma trough concentration of volanesorsen following every 2-week SC administration was approximately 50% of that seen after weekly SC administration.
6.1.3 Effect of Intrinsic Factors on Pharmacokinetics 6.1.3.1 Age, Sex, and Race A population PK analysis showed that age, sex, and race have no statistically significant effect on the clearance of volanesorsen, and hence on the exposure of the drug.
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6.1.3.2 Body Weight The effect of body size on the PK of volanesorsen was assessed via a population PK analysis. All 4 body size metrics evaluated (body weight, lean body mass, BMI, and body surface area) were shown to have statistically significant but moderate effect on the clearance of volanesorsen, hence its exposure in plasma. The steady-state AUC in subjects with body weight in the lower range (< 75.8 kg) of the pool of subjects included in the population PK analysis composed of healthy volunteers, patients with high triglycerides, and patients with FCS is estimated to be 16% higher than that of reference subjects in the middle weight range (75.8 to 94.0 kg). Potential effects of weight on the safety of volanesorsen are described in Section 9.8.2.
6.1.3.3 Renal and Hepatic Function The population PK analysis showed that renal function, as represented by baseline estimated glomerular filtration rate (eGFR), is not a statistically significant covariate for volanesorsen clearance, in the range of 49.5 to 227 mL/min/1.73 m2. Thus, no dose adjustment is necessary in patients with mild to moderate renal impairment. Given the lack of experience in patients with low, moderate, and severe renal impairment for volanesorsen, no conclusions on the safety in such population can be drawn even though the PK of volanesorsen is expected to be similar across renal function based on almost exclusive clearance of volanesorsen via ubiquitous tissue nucleases. The population PK analysis did not find significant effects of baseline alanine aminotransferase (ALT), total bilirubin, or albumin on the clearance of volanesorsen. Subjects with hepatic impairment were not evaluated.
6.1.3.4 Patient Population The clearance of volanesorsen was not affected by baseline triglyceride level or patient population when a total of 4 populations (healthy volunteers, patients with FCS, patients with high triglycerides with diabetes, and patients with high triglycerides without diabetes) were evaluated. As baseline triglyceride level does not affect drug clearance, the steady-state exposure should be consistent among patients with various baseline triglyceride levels. Hence, no dose adjustments based on incoming triglyceride level is warranted.
6.1.3.5 Subcutaneous Injection Site The population PK analysis identified SC injection site of arm as a statistically significant covariate negatively influencing the bioavailability of volanesorsen compared to SC injection in the abdomen or thigh. As no clinically significant differences between injection sites are expected, the same dose of volanesorsen is recommended across various injection sites and rotation of injections is recommended for all patients.
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6.1.4 Effect of Extrinsic Factors on Pharmacokinetics 6.1.4.1 Drug-Drug Interactions In vitro studies were conducted to evaluate the potential for volanesorsen to interact with concomitantly used medications via inhibition or induction of cytochrome P450 (CYP) or inhibition of transporters. These studies indicated lack of interaction potential, and therefore clinical drug interaction studies were not conducted. The effect of commonly used concomitant medications was evaluated by population PK analysis. While drug-drug interactions, other than for fibrates which are commonly used to reduce triglyceride levels, were not studied, other ASOs have shown no drug-drug interaction effects. Mipomersen, a 2′-MOE ASO, was evaluated for its interaction potential with warfarin, simvastatin, and ezetimibe in dedicated clinical drug interaction studies (Yu et al. 2009, Yu et al. 2013, Li et al. 2014). The effects of administration of a second generation antisense inhibitor of Factor XI (ISIS-FXIRx) on enoxaparin PK and PD have also been studied (Yu et al. 2013). The results from these clinical studies confirmed the lack of PK or PD interaction as anticipated based on in vitro studies performed in advance of the clinical studies. Volanesorsen was further evaluated for drug interaction potential by in vitro studies and population PK analysis. Concomitant use of other lipid modifying agents, hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitors, or platelet aggregation inhibitors (excluding heparin) was not associated with statistically significant changes in the clearance of volanesorsen. Use of fibrates was identified as a significant covariate that reduced volanesorsen clearance but showed no clinically relevant difference in the steady-state AUC0-168h or Cmax. Dose adjustment for volanesorsen when used concomitantly with these agents is not necessary.
6.2 Anti-Drug Antibodies Immunogenicity of volanesorsen was evaluated in all Phase 2 and 3 studies by a series of validated screening, confirmation, and titration assays. Antibodies to volanesorsen were formed in 30% of the patients with FCS treated with volanesorsen in CS6 and the immunogenicity was characterized by a late onset (median onset 6 months) and low antibody titers (median peak titer 400). No consistent relationship between the duration of volanesorsen exposure or dose level and immunogenicity incidence was identified from the available data to date. Anti-drug antibodies were detected approximately 6 months post initiation of treatment and were generally sustained once formed. Even though the presence of anti-drug antibodies increases the Ctrough of volanesorsen in plasma, anti-drug antibodies were not associated with loss of efficacy or increases in safety findings. 6.3 Pharmacodynamics 6.3.1 Concentration-Effect Relationships
In Phase 1 and 2 studies, steady-state Ctrough positively correlated with percent decrease from Baseline in serum apoC-III and triglyceride levels in healthy volunteers and patients with hypertriglyceridemia. A similar relationship between Ctrough and apoC-III and triglyceride
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response was observed in Phase 3 studies CS6 and CS16. These trends became increasingly pronounced through Month 12 as the range of Ctrough values broadened to include lower Ctrough values from subjects that experienced dose adjustments and/or early discontinuation. The observed positive relationship between Ctrough and triglyceride response supports that the starting dose of 300 mg weekly will result in the greatest triglyceride reductions in patients with FCS.
A positive relationship between exposure (AUC, Cmax, and Ctrough) and nadir platelet counts and maximum percent decrease in platelet counts from Baseline was observed in the pooled analysis of studies CS6 and CS16, suggesting that platelet reductions can be managed with dose adjustments. Patients who experience a reduction in platelet counts and undergo a dose adjustment to 300 mg every 2 weeks are predicted to have a 54% mean decrease in volanesorsen Ctrough compared to the 300 mg weekly dosing regimen, which would reduce risk of further platelet reduction. The Emax model for the Ctrough-triglyceride response relationship in FCS patients indicates that a reduction of dose frequency to every 2 weeks still provides Ctrough greater than the IC50 value for triglyceride lowering. Therefore, maintenance of clinically meaningful level of triglyceride reduction and hence reduction of abdominal pain and events of acute pancreatitis are expected with 300 mg every 2 weeks.
6.3.2 Pharmacodynamic Drug-Drug Interactions In CS6, the proportion of volanesorsen-treated patients reporting use of concomitant antiplatelet or anticoagulant agents experiencing a bleeding event (including actual bleeding and lab values per the hemorrhages SMQ analysis) was 60% (6 of 10) compared to 43% (10 of 23) volanesorsen-treated patients not reporting concomitant use of antiplatelet or anticoagulant agents; 50% (5 of 10) of volanesorsen-treated patients had a bleeding event while contemporaneously taking the antiplatelet agents or anticoagulant drugs. In the placebo group, 33% (3 of 9) of patients reporting use of concomitant antiplatelet or anticoagulant agents reported bleeding compared with 4% (1 of 24) not reporting concomitant antiplatelet or anticoagulant agents; 22% (2 of 9) of placebo patients reported bleeding during contemporaneous use of the antiplatelet agents or anticoagulant drugs. Caution is therefore recommended with antithrombotic agents and antiplatelet medications and agents that may lower platelet count. There were no major bleeding events in any patients in the clinical studies (see Section 9.7.2.6).
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Figure 6: Study Design and Treatment Schema for Study ISIS 304801-CS6
Data collection included clinical laboratory parameters (including hematology, serum chemistry, and urinalysis), AEs, concomitant medication/procedure information, lipid panel, volanesorsen plasma trough concentrations, immunogenicity testing, lipoprotein lipase mass/activity, postprandial assessments, liver/spleen MRI, electrocardiogram (ECGs), and echocardiograms. In addition, quality of life (QoL) assessments including self-report of weekly pain, as well as standard QoL tools (SF-36 and EQ-5D) were collected. Dietary counseling commenced at the start of the diet stabilization period and was reinforced at intervals throughout the trial. The starting dose of volanesorsen was 300 mg once weekly. The protocol allowed for changes in dosing schedule and interruptions or pause for reductions in platelets. Dose frequency could be adjusted to every other week if needed because of platelet count reductions. The original design of CS6 employed a platelet monitoring schedule that was subsequently adjusted to more frequent monitoring in order to identifying progressive declines in platelet counts (Table 11). It is important to note that in the original design, there was no option for dose frequency reduction. Treatment interruption followed by reinstitution of the original dose of study drug (300 mg/week) was the only permitted option for managing a platelet decline, other than discontinuing treatment. A population PK/PD model for triglyceride levels was developed with a stimulatory effect on triglyceride elimination rate to reflect the mechanism of action. Model-based simulations for adult FCS patients predicted doses of 300 mg once-weekly and adjusted doses of 300 mg every 2 weeks or 150 mg once-weekly, all assuming 100% dose compliance, to achieve clinically important levels of triglyceride lowering (75% reduction for 300 mg once weekly and 67% reduction for 300 mg every 2 weeks). The dose of 150 mg once weekly under complete compliance is predicted to produce a 70% reduction from baseline in triglycerides. Therefore, 300 mg every 2 weeks or 150 mg once weekly doses can maintain clinically important magnitudes of triglyceride reduction.
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Table 11: Algorithm for Platelet Monitoring/Dosing
Start of CS6 CS6 Enhanced Program December 2014 May 2016 (Original Monitoring Plan) (Enhancement 1) Frequency of Monitoring Every approximately 6 weeks Every 2 weeks Dose Frequency Reduction None < 100,000/mm3 Threshold Dose Pause Threshold < 50,000/mm3 < 75,000/mm3 Permanently Discontinue Study < 50,000/mm3 with major bleeding < 25,000/mm3 Drug < 50,000/mm3 if on 300 mg every 2 weeks
7.1.2 Key Inclusion/Exclusion Criteria Key inclusion criteria for CS6 were as follows: • Men and women 18 years of age or older • Diagnosis of FCS by documentation of at least one of the following: (a) Confirmed homozygote, compound heterozygote or double heterozygote for known loss-of-function mutations in Type 1-causing genes (such as lipoprotein lipase, APOC2, APOA5, GPIHBP1, or LMF1), (b) Post heparin plasma lipoprotein lipase activity of ≤ 20% of normal • Fasting triglycerides ≥ 750 mg/dL (8.4 mmol/L) at Screening • Agreed to follow diet comprising ≤ 20 g fat per day • Documented history of pancreatitis (in at least 70% of patients enrolled) and chylomicronemia Key exclusion criteria were: • Uncontrolled diabetes with glycated hemoglobin ≥ 9% • Severe hypertriglyceridemia other than due to FCS • Active pancreatitis • History within 6 months of screening of acute or unstable cardiac ischemia, stroke, transient ischemic attack or unstable congestive cardiac failure requiring a change in medication or major surgery within 3 months of screening • Uncontrolled hypertension • New York Heart Association Class II • Liver or kidney disease • History of or positive test for HIV, hepatitis C or chronic hepatitis B
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• Use of Glybera gene therapy within 3 years prior to screening
7.1.3 Endpoints, Analysis Sets, and Statistical Methods 7.1.3.1 Study Endpoints The primary efficacy endpoint in this study was the percent change in triglycerides at Month 3, defined as average of Week 12 and Week 13 assessments. Of note, patients and investigators were blinded to triglyceride values determined during the study. The endpoint of triglycerides was chosen as the major metabolic abnormality associated with FCS is hypertriglyceridemia. Secondary endpoints were rank ordered as follows: 1. Treatment response rate, where a patient with fasting plasma triglycerides < 750 mg/dL at the primary analysis time point (3 months) was defined as a responder. Only the subset of patients with baseline fasting plasma triglycerides ≥ 750 mg/dL was included in this population 2. Percent change from baseline to the 6-month time point in fasting triglycerides 3. Percent change from baseline to the 12-month time point in fasting triglycerides 4. Average of maximum intensity of patient reported abdominal pain during the treatment period
5. Postprandial triglycerides area under the curve (AUC)(0-9h) change from Baseline to on treatment measures (between Week 13 and Week 19) 6. Treatment response rate, where a patient who achieves fasting triglycerides ≥ 40% reduction from Baseline at the primary analysis time point is defined as a responder 7. Absolute change from Baseline to the primary analysis time point in fasting triglycerides 8. Frequency of composite of episodes of acute pancreatitis and patient reported abdominal pain during the treatment period 9. Change from Baseline in hepatic volume as assessed by MRI at Week 52 For the analysis of acute pancreatitis, all SAEs reported by the Investigators during the study that were consistent with acute pancreatitis, as identified by the independent adjudication vendor (SOCOR Research SA), were adjudicated by a blinded, independent pancreatitis adjudication committee according to the revised Atlanta classification of acute pancreatitis (Banks et al. 2013). Key data provided by the Investigator included the event description, symptom onset date, hospitalization admission dates and symptoms present, event trigger, clinical care interventions, imaging reports if available, supporting documentation from the hospital stay (lab tests), discharge diagnosis, and relevant medical history. Data provided to the adjudicators did not contain any patient treatment code or information about study treatment allocation.
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In addition, data for episodes of acute pancreatitis or suspected pancreatitis in the medical history 5 years prior to informed consent date, were collected by review of each patient’s medical chart and these events were also adjudicated. The adjudicators classified events by assigning each event to 1 of 4 groups as follows. The first 3 groups were counted as adjudication-confirmed cases of acute pancreatitis: 1. Documented Pancreatitis: Pancreatitis that conforms to the revised Atlanta diagnostic criteria for acute pancreatitis required 2 of the following: • Abdominal pain strongly consistent with acute pancreatitis (acute onset of a persistent, severe, epigastric pain often radiating to the back), • Serum lipase activity (or amylase activity) at least 3 × ULN; • Characteristic findings of acute pancreatitis on contrast-enhanced computed tomography (CECT), magnetic resonance imaging (MRI) or transabdominal ultrasonography 2. Probable Pancreatitis: Clinically Pancreatitis with documentation of typical clinical features plus abnormal amylase/lipase (< 3 × ULN). Requires all of the following: • Abdominal pain strongly consistent with acute pancreatitis (acute onset of a persistent, severe, epigastric pain often radiating to the back). • Typical supportive treatment for pancreatitis is instigated (e.g. nil per mouth, intravenous fluids, prescription of analgesics [stronger than acetaminophen only]). • Amylase and lipase levels are elevated but not above 3 × ULN. • Radiology investigations are either not performed or not diagnostic. • Discharge diagnosis of acute pancreatitis according to the attending physician with no alternative diagnosis proposed. 3. Possible Pancreatitis: Documentation of typical clinical features of pancreatitis in subject with known history of pancreatitis. Requires all of the following: • Previous medical diagnosis of acute pancreatitis has been made. • Abdominal pain strongly consistent with acute pancreatitis (acute onset of a persistent, severe, epigastric pain often radiating to the back). • Typical supportive treatment for pancreatitis is instigated (e.g. nil per mouth, intravenous fluids, prescription of analgesics [stronger than acetaminophen only]). • Serum amylase and lipase levels are either normal, not determined, or missing. • Radiology investigations not performed or not diagnostic. • Discharge diagnosis of acute pancreatitis according to physician, no alternative diagnosis made.
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4. “Other”: • Events that could not be placed in any of the preceding categories based on the available information
7.1.3.2 Analysis Sets The primary efficacy analysis was conducted on the Full Analysis Set (FAS), a modified intention-to-treat (mITT) dataset, defined as all patients who were randomized, received at least 1 dose of Study Drug, and who had a baseline fasting plasma triglycerides assessment. The FAS represents the practically-feasible ITT population as delineated in ICH Guideline E9. Secondary populations for evaluation of efficacy included the per-protocol set (PPS), which included a subset of patients in the FAS who received at least 9 doses of Study Drug and had no significant protocol deviations that were expected to affect efficacy or PD assessments, and a completer analysis set, defined as patients who competed study treatment.
7.1.3.3 Statistical Methods Sample size was based on approximately 80% power to detect a 50% difference in triglyceride levels between treatment groups at an alpha level of 0.01, assuming 60% reduction in the volanesorsen group and 10% reduction in the placebo group. Triglyceride data were analyzed using an analysis of covariance (ANCOVA) model with the 2 randomization stratification factors (presence or absence of history of pancreatitis; presence or absence of concurrent omega-3 fatty acids and/or fibrates) and treatment group as factors and log-transformed baseline triglycerides as a covariate. Missing triglyceride data were imputed using 3 different imputation approaches for Month 6 and Month 12: • The prespecified approach was a multiple imputation model that contained the following variables: Baseline fasting triglycerides and fasting triglyceride values at post-baseline visits and the 2 randomization stratification factors, and the multiple imputation was to be stratified by treatment. The estimates from the 100 fitted models for each of the 100 imputed datasets were combined to provide an overall estimate with corresponding confidence intervals and p-value. • Post-hoc analyses were also done at the Month 6 and 12 endpoints with missing data imputed using bootstrap method. For volanesorsen patients who terminated before Month 6/12, missing triglyceride results were imputed from volanesorsen patients who terminated before Month 6/12 but with Month 6/12 triglycerides measured using bootstrap imputation method. Missing data for placebo patients at Month 6 or Month 12 was imputed using bootstrap method from placebo patients with triglyceride results at Month 6 or Month 12. The bootstrap imputation was repeated 5000 times. The estimates from 5000 fitted models for each of the 5000 imputed datasets were combined to provide an overall estimate with corresponding confidence intervals and p-value.
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• A third imputation approach was used where missing not at random (MNAR) was assumed and the mean function for the missing data from patients treated with volanesorsen who discontinued the treatment were imputed based on baseline value and the imputation model for the placebo. Missing data for placebo patients were imputed under missing at random (MAR) assumption. For the secondary endpoints, in order to control the Type I error, the secondary endpoints were tested according to position in the hierarchy using a sequential closed testing procedure. If the main (FAS) analysis of the first secondary endpoint was statistically significant (p < 0.05) then the second secondary endpoint was to be tested. Otherwise, all endpoints of lower rank were to be considered exploratory. This process was repeated with each secondary endpoint.
7.1.4 Discussion of Key Design Features At the time of initiation of CS6, there were no approved agents in USA for the treatment of patients with FCS. Utilizing the randomized, double-blind, placebo-controlled study design provides the most objective, robust and conclusive evidence for drug efficacy as specified in guidance for clinical trials to prevent bias. Because FCS is a rare condition, it was not considered feasible to adequately power a study to measure a reduction in the frequency of pancreatitis events. Therefore, the percent change from Baseline in fasting triglyceride levels, which are established as being associated with the risk of pancreatitis, was chosen as the primary endpoint for the study. Fasting plasma triglyceride levels > 750 mg/dL are widely thought to represent a threshold above which there is chylomicron accumulation which increases pancreatitis risk (Kjems et al. 2014). The percentage of patients achieving fasting plasma triglyceride levels < 750 mg/dL was used as a key secondary endpoint, followed by percent change from Baseline to Months 6 and 12 in fasting triglycerides and frequency and intensity of abdominal pain. The primary analysis time point was the end of Month 3, as this provided sufficient time on Study Drug to reach steady state PD effect. The study was continued to 12 months to fully characterize the long-term safety profile and evaluate persistence of benefit. Furthermore, acknowledging the inherent variability in triglycerides measurements, triglyceride levels were measured at 2 separate time points prior to the start of study drug and then averaged to obtain the Baseline value, which was used for comparison to on-treatment measurements. 7.2 Key Design Features of Study ISIS 304801-CS7 CS7 is an ongoing OLE study of volanesorsen designed to evaluate the safety and efficacy of extended treatment with volanesorsen in patients with FCS who previously completed CS6 or CS16; in addition, patients not participating in either study with similar eligibility criteria to CS6 are also eligible to participate. The open-label study design increased the exposure to a greater number of patients with FCS and allowed the treating Investigator to manage the patient without the restrictions imposed by blinding the therapeutic response (i.e., triglyceride levels). Approximately 70 patients are planned to be enrolled and to receive 300 mg volanesorsen SC once weekly under the study monitoring and dosing algorithm for 52 weeks. Patients who
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complete the 52-week treatment period will be allowed to continue treatment for up to an additional 52 weeks or until product is available through an alternative mechanism. Patients opting to discontinue treatment with volanesorsen at any time in the study enter a 13-week post- treatment evaluation period. Efficacy endpoints for CS7 include: percent change and absolute change from baseline in fasting triglycerides; frequency and severity of patient reported abdominal pain; percent change and change from baseline in other key fasting lipid measurements; percent change from Baseline in fasting total apoC-III; change from Baseline in QoL; adjudicated acute pancreatitis events rate; and frequency of other symptoms (eruptive xanthoma, lipemia retinalis). For those patients who received volanesorsen in the index study, changes from baseline were assessed relative to the open-label baseline as well as the index study baseline. 7.3 Key Design Features of Study ISIS 304801-CS16 CS16 was a Phase 3, double-blind, randomized, placebo-controlled study of volanesorsen conducted to provide additional safety and efficacy data in a relevant population with severe hypertriglyceridemia and risk of pancreatitis. All patients who completed at least a 6-week diet stabilization period were randomized in a 2:1 ratio to receive SC injections of 300 mg volanesorsen or placebo once weekly for 26 weeks. Randomization was stratified by T2DM status and concurrent lipid-lowering therapy with a statin and/or fibrate. Patients with severe hypertriglyceridemia face many of the same problems as those with FCS, including increased risk pancreatitis, as well as diet and lifestyle restrictions. Therefore, the inclusion and exclusion criteria were aligned with those used for the pivotal trial CS6. To lessen the chance of platelet reductions, the study protocol was amended so that patients were to have the dose frequency reduced to 300 mg every 2 weeks after 13 weeks of treatment (except for patients who had completed ≥5 months of dosing as of 27 May 2016). The CS16 protocol was also amended to include enrollment of patients who screen failed CS6 but qualified for CS16 and patients with FCS who would have qualified for CS6 after enrollment had closed in that study. The latter group of patients, patients with FCS identified after enrollment in CS6 had closed, provided this study with a subset of 7 patients with documented FCS. As in CS6, the primary endpoint for CS16 was the percent change from Baseline in fasting triglycerides at Month 3. Following the Week 26 visit, patients either entered a 13-week post- treatment evaluation period or, if eligible, had the option of entering the OLE CS7.
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the importance of apoC-III in inhibiting non-lipoprotein lipase mediated clearance pathways of triglyceride-rich lipoproteins. These data, when combined with the reductions in triglycerides observed in the other arms, further supported investigation of volanesorsen in patients with FCS. 8.2 Phase 3 Safety and Efficacy Pivotal Study - Study ISIS 304801-CS6 8.2.1 Study Enrollment and Disposition A total of 130 patients were screened at 40 study centers for CS6. There were 63 patients who failed screening due to inclusion/exclusion criteria (46 patients, 73%); Sponsor decision (9 patients, 14.3%); withdrawal of consent (6 patients, 9.5%); Investigator decision (1 patient, 1.6%); and other (1 patient 1.6%). A total of 67 patients were randomized to receive volanesorsen (33 patients) or placebo (34 patients). All 33 (100%) patients in the volanesorsen group received treatment; 33 of the 34 (97%) patients in the placebo group received treatment. One patient randomized to receive placebo was not treated because his stratification information was incorrectly entered into the interactive voice/web-response system. The disposition of patients through CS6 and the OLE, CS7, is displayed in Figure 7.
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Figure 7: Disposition of Patients Through CS6 and CS7 with Reasons for Discontinuation
*As of 31 August 2017 After the data cutoff and as of 31 December 2017, 68 patients were enrolled and 53 were ongoing in CS7. Nineteen (58%) of the 33 patients in the volanesorsen group and 32 (94%) of the 34 randomized patients in the placebo group completed the 52-week study treatment (Table 13). At the Month 12 endpoint, 27 (81%) patients in the volanesorsen group provided triglyceride data despite 14 patients having discontinued study drug early; 32 (97%) patients in the placebo group provided triglyceride data at Month 12.
8.2.2 Discontinuations The most common reason for discontinuation of volanesorsen treatment was AE: 5 were related to platelet reduction and 4 were due to AEs unrelated to platelet counts. As noted earlier, in the original protocol, treatment interruption followed by reinstitution of the original dose of study
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drug was the only permitted option for managing a platelet decline, other than discontinuing treatment, and the patient was withdrawn from treatment if a second decline in platelets occurred. The rate of treatment discontinuations due to platelet reductions, and discontinuations for any reason, were higher before the change in the platelet monitoring and dose adjustment algorithm in May 2016 (Table 2).
Table 13: Patient Disposition and Population in CS6-All Screened Patients
Volanesorsen 300 mg Placebo All Patients Disposition n (%) n (%) n (%) Patients Screened 130 Patients Randomized 33 34 67 Patients Dosed 33 (100.0) 33 (97.1) 66 (98.5) Patients With Triglyceride Values for 33 (100.0) 33 (97.1) 66 (98.5) Primary Endpoint (Month 3) Patients Who Completed the 52-week 19 (57.6) 32 (94.1) 51 (76.1) Study Treatment Patients Who Terminated from the Study 14 (42.4) 2 (5.9) 16 (23.9) Treatment Before Week 13 2 (6.1) 1 (2.9) 3 (4.5) After/On Week 13 and Prior to Week 26 7 (21.2) 1 (2.9) 8 (11.9) After Week 26 5 (15.2) 0 (0.0) 5 (7.5) Main Reason for Termination Investigator judgment 1 (3.0) 0 (0.0) 1 (1.5) Voluntary withdrawal 4 (12.1) 1 (2.9) 5 (7.5) Adverse event or SAE 9 (27.3) 0 (0.0) 9 (13.4) Other 0 (0.0) 1 (2.9) 1 (1.5)
8.2.3 Dose Frequency Changes/Dose Pauses
In CS6, 10 (30%) patients in the volanesorsen group had their dosing changed from weekly to every other week dosing, 8 of which were due to decreased platelets with 2 patients meeting the stopping rules due to platelet count results; all dose adjustments occurred between Weeks 26 and 46. No patient in the placebo group had a dose adjustment. Dose interruptions/pauses were reported for 11 (33%) patients in the volanesorsen group and 6 (18%) patients in the placebo group, with mean number of doses missed of 7 and 2, respectively. Dose adjustments and interruptions/pauses were to manage reductions in platelets in the majority of cases in the volanesorsen group; 1 patient in the placebo group had dose interruption because of platelet reductions (see Section 9.7.2 for a discussion of platelet reductions).
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8.2.4 Medication Exposure and Treatment Duration A summary of study drug exposure and treatment duration for CS6 is provided in Table 14. A higher number of early terminations and dose pauses in the volanesorsen group explains the lower treatment duration compared to the placebo group and a reduction in the frequency of dosing and a higher number of dose interruptions/ pauses and dropouts explain the lower number of drug injections in the volanesorsen group compared to the placebo group.
Table 14: Summary of CS6 Medication Exposure and Treatment Duration – Safety Set
Parameter Volanesorsen 300 mg Placebo All Patients Category/Statistic (N=33) (N=33) (N=66) Mean (SD, SEM) Treatment Duration (days)a 267 (113, 20) 352 (35, 6) 310 (93, 11) Mean (SD, SEM) Number of Study Drug Injections 35 (15, 3) 49 (6, 1) 42 (13, 2) Treatment Durationa (Months) - n (%) ≥3 31 (93.9) 33 (100.0) 64 (97.0) ≥6 24 (72.7) 32 (97.0) 56 (84.8) ≥9 21 (63.6) 32 (97.0) 53 (80.3) ≥12 8 (24.2) 21 (63.6) 29 (43.9)
8.2.5 Demographics and Baseline Disease Characteristics Demographic and baseline disease characteristics for patients in CS6, as well as patients with FCS in CS16 and CS7, are summarized in Table 15. In CS6, the demographics were well balanced between treatment arms. All patients had extremely high triglyceride levels at Baseline following the diet stabilization period and all but 3 patients in the volanesorsen group and 2 patients in the placebo group continued to have triglycerides ≥ 750 mg/dL at baseline. Almost half of patients in CS6 were not on any lipid- lowering agents.
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Table 15: Demographic and Baseline Disease Characteristics for Patients with FCS in CS6, CS7, and CS16 (Safety Set) CS6 CS7 CS16 Volanesorsen Volanesorsen Volanesorsen Placebo Volanesorsen Placebo Demographic and Treatment Naïve CS6 Rollovers (N = 33) (N = 33) (N = 5) (N = 2) Disease Characteristic: (N = 18) (N = 11) Age at Informed Consent (years) Mean (SD, SEM) 47 (13, 2) 46 (14, 2) 49 (15, 4) 47 (15, 5) 47 (9, 4) 51 (11, 8) Minimum, Maximum 22, 75 20, 68 22, 69 23, 73 33, 54 43, 58 Mean 95% CI 42, 52 41, 50 42, 57 37, 57 36, 58 -45, 146 Age Group (years), n (%) Age <65 years old 30 (90.9) 31 (93.9) 15 (83.3) 9 (81.8) 5 (100.0) 2 (100.0) Sex n (%) Female 17 (51.5) 19 (57.6) 12 (66.7) 5 (45.5) 3 (60.0) 2 (100.0) Ethnicity - n (%) Not Hispanic or Latino 26 (78.8) 26 (78.8) 16 (88.9) 11 (100.0) 5 (100.0) 2 (100.0) Race - n (%) White 24 (72.7) 29 (87.9) 16 (88.9) 8 (72.7) 4 (80.0) 1 (50.0) Black 0 0 0 0 0 0 Asian 7 (21.2) 4 (12.1) 2 (11.1) 3 (27.3) 1 (20.0) 1 (50.0) Other Race 2 (6.1) 0 (0.0) 0 0 0 0 Body Weight (kg) Mean (SD, SEM) 72.91 (21.46, 3.74) 67.42 (20.16, 3.51) 63.9 (17.4, 4.1) 63.8 (14.9, 4.5) 61.66 (12.16, 5.44) 63.95 (16.05, 11.35) Minimum, Maximum 37.20, 127.00 43.70, 121.90 42.2, 117.8 36.5, 86.7 45.20, 76.50 52.60, 75.30 Mean 95% CI 65.30, 80.52 60.27, 74.57 55.3, 72.6 53.8, 73.8 46.56, 76.76 -80.27, 208.17 BMI (kg/m²) Mean (SD, SEM) 25.9 (6.5, 1.1) 24.1 (4.7, 0.8) 23.3 (3.8, 1.0)b 22.7 (4.5, 1.3) 23.1 (3.8, 1.7) 26.6 (7.4, 5.3) Minimum, Maximum 14.9, 46.6 16.5, 38.6 16.6, 32.8 14.6, 30.0 18.6, 27.0 21.3, 31.8 Mean 95% CI 23.6, 28.2 22.4, 25.7 21.2, 25.3 19.7, 25.7 18.4, 27.8 -40.2, 93.3 Fasting Triglycerides (mg/dL) Mean (SD, SEM) 2267 (1259, 219) 2152 (1153, 201) 2288 (1075, 253) 1469 (886, 267)a 2134 (1141, 510) 2644 (314, 222) Minimum, Maximum 347, 5660 631, 5475 349, 4651 73, 3283 1074, 3998 2422, 2867 Mean 95% CI 1821, 2714 1743, 2560 1753, 2823 874, 2064 717, 3551 -180, 5468 a Values from Baseline of CS7 for volanesorsen-treated patients previously enrolled in CS6. b n=16
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The majority of patients (65/66) enrolled in Study CS6 qualified for the study based on medical history of documented genetics disease-associated markers or documented low lipoprotein lipase activity and/or on the basis of testing on-study for genetics or low lipoprotein lipase activity (Table 16). One patient initially qualified for the study based on low on-study lipoprotein lipase activity, but the assay was later invalidated because the sample was taken before heparin was administered. This patient was not included in the per protocol set. Table 16: Eligibility of Patients in CS6 based on Confirmatory Genetics for FCS or Low Lipoprotein Lipase Activity - Full Analysis Set
Medical History of or On-Study Confirmatory Genetics for FCS Yes No
Medical History of or On-Study Low Yes 44 8 Lipoprotein Lipase Activity No 13 1
8.2.6 Primary Endpoint – Percent Change in Fasting Triglycerides from Baseline to Month 3 Treatment with volanesorsen led to a significant reduction in triglyceride levels in patients with FCS. The study met its primary endpoint of demonstrating a percentage decrease in fasting triglycerides from Baseline to the primary analysis time point at the end of Month 3 (average of Week 12 and Week 13 values) for volanesorsen compared with placebo in the FAS (Table 17). There were no missing triglycerides values at Month 3 and analyses were conducted using the observed data. Volanesorsen-treated patients in the FAS achieved a mean reduction in triglycerides of 77% from Baseline after 3 months of treatment corresponding to a mean triglyceride decrease from 2267 mg/dL at Baseline to 590 mg/dL at Month 3; this is compared to a mean increase of 18% in placebo-treated patients. The difference in percent reduction in triglycerides of 94% between the volanesorsen and placebo groups was statistically significant (p < 0.0001).
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Table 17: Percent Change from Baseline to Month 3 in Fasting Triglycerides (mg/dL) in CS6: Full Analysis Set
Volanesorsen 300 mg Placebo Analysis Endpoint Statistic (N = 33) (N = 33) Baseline (mg/dL) Mean (SD) 2267 (1259) 2152 (1153) Month 3 (mg/dL) Mean (SD) 590 (497) 2367 (1315) % Change from Baseline Least Squares Mean (95% CI) -76.5 (-97.4, -55.5) 17.6 (-4.0, 39.2) Treatment Comparison of % Change vs Placebo Relative Difference in % Change -94.1 95% CI (-121.7, -66.6) p-value <0.0001
8.2.6.1 Sensitivity Analyses As there were no missing triglycerides values at the primary endpoint, the planned sensitivity analyses using a subset of patients with non-missing data and using controlled imputations were not conducted. Results of sensitivity analyses that were conducted on the primary efficacy analysis were consistent with the primary efficacy results presented in the FAS. In each analysis, treatment with volanesorsen significantly decreased triglyceride levels relative to placebo (p<0.0001). The sensitivity analyses included using average of triglycerides measurements at Weeks 8, 12, and 13 as the primary analysis endpoint (FAS), as well as non-parametric analyses with Wilcoxon rank- sum test and rank ANCOVA (FAS and PPS), and with Wei-Johnson method (FAS and PPS).
8.2.7 Secondary Endpoints The study also met the first 3 secondary endpoints, indicating clinically significant lowering of triglycerides and the significant lowering effects continued over the 12 month treatment period.
8.2.7.1 Secondary Endpoint #1: Treatment Response Rate at Month 3 Among patients with baseline triglycerides ≥ 750 mg/dL, 23 (77%) volanesorsen-treated patients were responders according to reaching the predefined triglyceride threshold of < 750 mg/dL at Month 3, compared with 3 (10%) placebo-treated patients who achieved triglycerides < 750 mg/dL (p=0.0001).
8.2.7.2 Secondary Endpoints #2 and #3: Percent Change in Fasting Triglycerides from Baseline to Month 6 and Month 12 There was a significant reduction in fasting triglycerides from Baseline to both Month 6 and Month 12 in the FAS based on multiple imputations analysis (Table 18). There were statistically significant differences in mean percent change in fasting triglycerides between volanesorsen and
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placebo groups from Baseline to Month 6 (-78%; p<0.0001) and Month 12 (-49%; p = 0.0347). The apparent decrease in volanesorsen efficacy from Month 3 to Month 6 is likely driven by several patients undergoing dose adjustments during that period, discontinued patients who provided triglycerides measurements, and an outlier patient. One patient in the volanesorsen group had Baseline, Month 3, Month 6, and Month 12 triglyceride levels of 1367, 1320, 2362, and 1856 mg/dL corresponding to % triglycerides change from baseline at Month 3, Month 6, and Month 12 of -3%, +73%, +36%, respectively, despite continued dose administration.
Table 18: Percent Change from Baseline to Month 6 and Month 12 in Fasting Triglycerides with Multiple Imputation – CS6 Full Analysis Set
Volanesorsen 300 mg Placebo Analysis Endpoint Statistic (N = 33) (N = 33) Baseline (mg/dL)a Mean (SD) 2267 (1259) 2152 (1153) Month 6 (mg/dL)a Mean (SD) 815 (600) 2423 (1007) % Change from Baseline to Month 6b Least Squares -52.5 (-82.0, -22.9) 25.3 (4.1, 46.5) Mean (95% CI) Relative Difference in % Change; p-value -77.8 (14.6); p < 0.0001* Month 12 (mg/dL)b Mean (SD) 1178 (948) 2307 (1290) % Change from Baselinec Least Squares -40.2 (-86.1, 5.7) 8.9 (-19.7, 37.5) Mean (95% CI) Relative Difference in % Change; p-value -49.1 (23.2); p = 0.0347* *Based on ANCOVA model with percent change from Baseline as the dependent variable, treatment, presence of pancreatitis and presence of concurrent omega-3 fatty acids and/or fibrates as factors, and baseline in logarithm scale as a covariate. Least squared means, standard errors, median confidence intervals, and p-values were combined from 100 fitted ANCOVA model or nonparametric analysis of 100 imputed dataset.
As shown in Figure 8, the decreased triglyceride levels persisted over the course of the study in the volanesorsen group despite the dose adjustments for some patients and inclusion of non-completers who contributed triglyceride data after stopping study drug.
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Figure 8: Mean (± SEM) of Percent Change in Fasting Triglycerides (mg/dL) Over Time- CS6 Full Analysis Set, Observed Data
In a post-hoc analysis using a bootstrap imputation approach, results were consistent with those described above. Among the patients with baseline TG levels ≥ 750 mg/dL, 14 (47%) volanesorsen-treated patients achieved triglyceride levels < 750 mg/dL as compared with no patient in the placebo group at Month 6 (p = 0.0035) and 11 (37%) volanesorsen-treated patients had triglyceride levels < 750 mg/dL as compared with 2 (7%) patients in the placebo group at Month 12 (p = 0.0067). Using the MNAR imputation method, the difference in least squares mean percent change from baseline in triglycerides between the volanesorsen and placebo groups was -74.3% at Month 6 (p < 0.0001) and -40.6% at Month 12 (p=0.0087).
8.2.7.3 Secondary Endpoint #4: Average Maximum Intensity of Patient Reported Abdominal Pain Patients completed a weekly questionnaire to report abdominal pain and rated the maximum intensity of the pain on a scale of 0 (no pain) to 10 (unbearable pain). There was no significant difference in the average maximum intensity of patient reported abdominal pain events between the volanesorsen and placebo groups in the FAS (mean 0.38 vs 0.36; p=0.8959). As the treatment comparison for Secondary Endpoint #4 was not statistically significant, all subsequent planned secondary endpoints were considered exploratory.
8.2.8 Exploratory Endpoints: Remaining Secondary Endpoints All p-values for the exploratory endpoints are nominal, provided only for context.
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8.2.8.1 Effect of Volanesorsen on Postprandial Lipid Assessments (Secondary Endpoint #5)
There was a 91% difference in mean reduction in postprandial triglyceride AUC(0-9h) for patients treated with volanesorsen compared to placebo patients (p = 0.0002) and a 75% difference in mean reduction in postprandial triglyceride AUC(0-4h) (p < 0.0001).
8.2.8.2 Responder Analysis: Patients Achieving 40% Reduction in Fasting Triglycerides at Month 3 (Secondary Endpoint #6) At Month 3, 88% of patients in the volanesorsen group achieved a ≥ 40% reduction in fasting triglyceride levels compared with 9% patients in the placebo group (p < 0.0001).
8.2.8.3 Absolute Change from Baseline to Month 3 in Fasting Triglycerides (Secondary Endpoint #7) There was a significant reduction in absolute mean triglyceride level in the volanesorsen group relative to the placebo group at Month 3 (difference of -1804 mg/dL; p < 0.0001) (Table 19).
Table 19: Analysis of Absolute Change from Baseline in Fasting Triglycerides – CS6 Full Analysis Set
Volanesorsen 300 mg Placebo Analysis Endpoint Statistic (N = 33) (N = 33) Month 3 Endpoint Analysis: n 33 33 Baseline (mg/dL) Mean (SD) 2267 (1259) 2152 (1153) Month 3 Endpoint (mg/dL) Mean (SD) 590 (497) 2367 (1315) Change from Baseline Least Squares Mean (95% -1712 (-2094, -1330) 92 (-301, 486) CI) Least Squares Mean (SE) -1804 (251) Treatment Comparison of Change from 95% CI (-2306, -1302) ANCOVA Model vs Placebo* p-value < 0.0001 *From fitted ANCOVA model with change from Baseline as the dependent variable, treatment, presence of pancreatitis, and presence of concurrent omega-3 fatty acids and/or fibrates as factors, and baseline in logarithm scale as a covariate.
8.2.8.4 Frequency or Composite Episodes of Acute Pancreatitis and Patient Reported Abdominal Pain (Secondary Endpoint #8) Overall in the FAS, 12 (36%) patients in the volanesorsen group and 13 (39%) patients in the placebo group had adjudicated acute pancreatitis and/or moderate/severe abdominal pain on treatment. Review of the per-patient per year incidence of episodes of acute pancreatitis and/or reported moderate/severe abdominal pain did not reveal any significant differences between the volanesorsen and placebo groups (2.73 vs 2.04).
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8.2.8.5 Effect of Volanesorsen on Hepatic Volume (Secondary Endpoint #9) Consistent with the findings of hepatosplenomegaly observed on physical examination in patients with FCS (Brunzell 1993), higher than normal hepatic and spleen volumes were seen at Baseline in the volanesorsen and placebo groups in this study. There was no significant difference between the placebo and volanesorsen groups in change from Baseline in hepatic volume assessed by MRI at Week 52. 8.2.8.6 Quality of Life Study CS6 included the EuroQoL 5 Dimensions 5 Level (EQ-5D-5L) and the Short Form 36 version 2 (SF-36 v2) to assess quality of life in FCS patients in this trial. All patients completed these QoL questionnaires at Baseline (any time prior to first dose), Week 13, Week 26, and Week 52. Both SF-36 and EQ-5D scores were comparable across the volanesorsen and placebo groups and there were no significant differences in changes from Baseline to these time points between the 2 treatment groups. Further details are provided in Section 13.2. The EQ-5D-5L and SF-36 are broad general QoL measures often used in clinical trials to assess the impact of new treatments from the perspective of the patient. At baseline, QoL scores for patients in CS6 indicated a better QoL than published values for the general population or norm samples. For example, at baseline the average EQ-5D-5L visual analog scale (VAS) score for patients in the volanesorsen group (87.75, SD=10.45) was higher than the published US general population value (80) (Janssen and Szende 2014). It is unclear what would cause these FCS patients to report such a good quality of life, but the high baseline values make it difficult to improve during the trial. These measures are not specific to FCS and many aspects of the disease are not well captured by these general QoL measures. No FCS specific QoL measure is available, but the Sponsor is in the process of developing such a scale to better evaluate the effect of treatment in patients with FCS. Table 20: Study CS6 Quality of Life Data at Baseline
CS6 Measure Volanesorsen Placebo General Population
EQ-5D-5L (mean, SD) Index 0.971 (0.048) 0.982 (0.040) 0.856a Visual Analog Scale 88 (10.45) 88 (8.40) 80a SF-36 v2 (mean, SD) Physical Functioning 56(3.61) 56(3.90) Pain 55 (12.42) 55 (6.88) Based on a normed score where 50 is General Health 51 (11.23) 49 (9.72) averageb Mental Health 52 (9.97) 53 (7.70) a Janssen and Szende 2014 b Maruish 2011
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8.2.8.7 Effect of Volanesorsen on Acute Pancreatitis Events Acute pancreatitis represents the most significant risk in patients with FCS. Table 21 summarizes all patients with treatment-emergent adjudication-confirmed acute pancreatitis events, regardless of prior history of pancreatitis; the number of patients with at least 2 adjudication-confirmed acute pancreatitis events within 5 years prior to study treatment; and treatment-emergent adjudication-confirmed acute pancreatitis events for the subset of patients with at least 2 adjudication-confirmed acute pancreatitis events within the 5 years prior to study treatment. One volanesorsen-treated patient experienced 1 treatment-emergent adjudication-confirmed acute pancreatitis event, compared with 3 placebo-treated patients who experienced 4 adjudication-confirmed acute pancreatitis events. The post-hoc analysis of patients with a history of recurrent adjudication-confirmed acute pancreatitis events (more than 1 event in the 5 years prior to Study Day 1) was performed to focus on higher risk patients. In this group of patients, there was a lower number of treatment- emergent adjudication-confirmed acute pancreatitis events in volanesorsen-treated patients compared with placebo patients.
Table 21: Summary of Adjudication-Confirmed Acute Pancreatitis in Study CS6 - FAS
Volanesorsen 300 mg Placebo (N = 33) (N = 33) Adjudication-confirmed pancreatitis n Events n Events All patients with any treatment-emergent adjudication- 1 1 3 4 confirmed eventa Odds Ratio (95% CI), p-valueb 3.20 (0.24, 173.14), p = 0.6132
Patients with at least 2 adjudication-confirmed events 7 24 4 17 within 5 years prior to study treatment Patients with any treatment-emergent adjudication- 0 0 3 4 confirmed eventc Odds Ratio (95% CI), p-valueb N/A (1.50, N/A), p = 0.0242 a Includes treatment-emergent adjudication-confirmed pancreatitis events for any patient, regardless of prior history of pancreatitis. b Odds ratio, its 95% CI and p-value are calculated with Fisher’s exact test. c Includes treatment-emergent adjudication-confirmed pancreatitis events for those subjects with at least 2 adjudication-confirmed events within 5 years prior to treatment. Patients who discontinued treatment early in CS6 were to complete landmark visits up to Week 52 per protocol, during which time any pancreatitis events would have been recorded and included. For patients who discontinued treatment and were withdrawn completely from the CS6 study, any events of pancreatitis occurring after withdrawal from the study could not be recorded as these patients were no longer on study and therefore not included. Missing data from 7 volanesorsen-treated patients and 1 placebo patient who terminated early from treatment and
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were not followed for the full 52-week study period was not imputed in the analyses comparing the treatment arms with respect to frequency of adjudication-confirmed pancreatitis events.
8.2.9 Exploratory Endpoints: Post-hoc Analyses 8.2.9.1 Maximum Intensity of Abdominal Pain Patient reported abdominal pain was rated on a scale of 0 to 10, with 10 being most severe. Overall, fewer patients in the volanesorsen group (15%) reported severe abdominal pain events in comparison with the placebo group (24%). In a post-hoc analysis of the subset of patients who had baseline abdominal pain (i.e. any abdominal pain >0 during screening and Week 1), in which missing data were imputed as 0, there was a nominally significant reduction in the average of maximum intensity of patient reported abdominal pain on treatment in the volanesorsen group compared with the placebo group (p=0.0227; Table 22).
Table 22: Change from Baseline in Average of Maximum Intensity of Patient Reported Abdominal Pain in During the On-Treatment Period with Missing Imputed to 0 in Patients with Baseline Abdominal Pain – CS6 FAS; Post-hoc Analysis
Volanesorsen 300 mg Placebo (N = 33) (N = 33) Baseline, n 7 10 Mean (SD, SEM) 2.25 (2.23, 0.84) 1.45 (1.30, 0.41) Mean 95% CI 0.18, 4.31 0.53, 2.38 On-Treatment Period, n 7 10 Mean (SD, SEM) 0.62 (0.80, 0.30) 0.95 (1.09, 0.34) Mean 95% CI -0.12, 1.36 0.17, 1.72 Change from Baseline Least Squares Mean (95% CI) -2.28 (-3.33, -1.23) -1.33 (-2.10, -0.56) Relative Difference in Change vs Placebo (95% CI) -0.95 (-1.75, -0.16); p=0.0227
In the subset of patients with abdominal pain at baseline, treatment with volanesorsen showed a numeric reduction in frequency of abdominal pain after 7-12 months of treatment (Figure 9A, 3 events per patient per year in volanesorsen group vs 11 in placebo group), frequency of episodes of moderate to severe abdominal pain during 4-12 months (Figure 9B, 2 events per patient per year in the volanesorsen group vs 5 in the placebo group) and 7-12 months of treatment (Figure 9B, 2 events per patient per year in the volanesorsen group vs 7 in the placebo group). Similarly, there was a numeric reduction of the worst abdominal pain intensity in volanesorsen- treated patients as compared with placebo-treated patients during 4-12 months (Figure 9C, 3.14 in volanesorsen group vs 5.4 in the placebo group) and during 7-12 months of treatment
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(Figure 9C, 2.4 in volanesorsen group vs 5.4 in the placebo group). The analyses for 7-12 months were done in the patients who completed study treatment.
Figure 9: Frequency of Any Abdominal Pain (A), Frequency of Moderate to Severe Abdominal Pain (B), and Worst Intensity (C) of Patient-Reported Abdominal Pain During the On-Treatment Period in Patients with Baseline Abdominal Pain – CS6 Full Analysis Set A.
B.
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C.
8.2.9.2 Treatment Response Rates Using the response threshold from Secondary Endpoint #1 of fasting triglycerides < 750 mg/dL, a greater proportion of patients in the volanesorsen group compared with the placebo group met this triglyceride thresholds not only at Month 3 (77% vs 10%), but also at Month 6 (47% vs 0), and Month 12 (37% vs 7%). A greater proportion of patients in the volanesorsen group compared with the placebo group also achieved a therapeutic target triglyceride level of < 1000 mg/dL at Month 3 (80% vs 13%), Month 6 (57% vs 3%), and Month 12 (40% vs 13%). The analysis in the FAS included triglyceride values from those patients who terminated early when available, likely contributing to the lower mean reductions in triglycerides at the Month 6 and Month 12 timepoints. Responder analysis of patients who achieved target triglyceride levels in the FAS using the bootstrap imputation approach was similar to that using multiple imputation, with more patients in the volanesorsen group achieving triglyceride levels < 750 mg/dL and < 1000 mg/dL at Month 6 and Month 12. There were also more responders based on ≥ 40% reduction in triglycerides in the volanesorsen group compared with the placebo group not only at Month 3 (88% vs 9%; Secondary Endpoint #6), but also at Month 6 (73% vs 3%), and Month 12 (64% vs 9%).
8.2.9.3 Absolute Change from Baseline to Months 6 and 12 in Fasting Triglycerides At the Month 6 endpoint (with multiple imputation analysis and including available data from patients off treatment at the Month 6 timepoint), mean triglyceride levels decreased from a baseline value of 2267 mg/dL to 815 mg/dL in the volanesorsen group, representing a change of -1380 mg/dL as compared with a change of 224 mg/dL for placebo (difference of -1604 mg/dL; p < 0.0001). Similarly, the difference in mean changes in triglyceride levels between the volanesorsen and placebo groups at Month 12 was 1025 mg/dL (p = 0.0268). Bootstrap analyses were consistent with the multiple imputation analyses.
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8.2.9.4 Effect of Volanesorsen on Other Lipid Parameters Table 23 presents a summary of changes in other fasting lipid parameters. Mean reductions in chylomicron-triglycerides, apoC-III, and non-HDL-C were consistent with those reported for total triglycerides along with mean increases in HDL-C, reaching nominal significance at the Month 3, Month 6, and Month 12 endpoints. Chylomicrons contribute the bulk of triglycerides when triglyceride levels exceed approximately 750 mg/dL. Therefore, as expected, changes in chylomicron-triglycerides paralleled those seen for total triglyceride levels. The decrease in apoB-48 was consistent with the decrease in chylomicron-triglycerides and this is expected since apoB-48 is an index of chylomicron particles. Although the individual components of the lipoprotein lipase independent pathway have not been identified, the reductions in apoB-48 support the hypothesis that apoC-III inhibits the removal of triglyceride-rich lipoproteins remnants by the liver. The mean percent changes in fasting apoC-III decreased over time in the volanesorsen group as compared with the placebo group, confirming the mechanism of action of volanesorsen. As previously shown in a Phase 2 study, volanesorsen led to significant VLDL-C reductions probably through accelerated conversion to LDL-C (Chan et al. 2008). There were increases in LDL-C from Baseline in the volanesorsen group as compared with the placebo group but the mean values remained below the ULN. Mean fasting non-HDL-C decreased over time in the volanesorsen group as compared with the placebo group. In general, patients experienced a decrease in non-HDL-C and increases in LDL- C and apoB, accompanied by a decrease in VLDL-C.
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Table 23: Summary of Fasting Lipid Parameters in Study CS6 – Full Analysis Set
Volanesorsen 300 mg (N = 33) Placebo (N = 33) Change from % change from Change from % change from Observed Value Baseline Baseline Observed Value Baseline Baseline Time Point n Mean (SD, SEM) Mean (SD, SEM) Mean (SD, SEM) n Mean (SD, SEM) Mean (SD, SEM) Mean (SD, SEM) Fasting Chylomicron-triglycerides (mg/dL) Baselinea 33 1913 (1216, 212) NA NA 33 1785 (1149, 200) NA NA Month 3 Endpointa 33 436 (480, 83) -1477 (1141, 199) -76.6∗ (22.1, 3.8) 33 1991 (1279, 223) 206 (1189, 207) 37.7 (112.4, 19.6) Month 6 Endpointa 29 638 (574, 107) -1452 (1166, 216) -65.3∗ (39.1, 7.3) 31 2026 (1014, 182) 252 (780, 140) 37.7 (75.3, 13.5) Month 12 Endpointa 27 983 (954, 184) -1094 (1182, 227) -52.3∗ (44.9, 8.6) 31 1892 (1258, 226) 130 (1045, 188) 21.9 (79.4, 14.3) ApoB-48 (mg/dL) Baselinea 33 11.18 (7.14, 1.24) NA NA 33 9.25 (5.96, 1.04) NA NA Month 3 Endpointa 33 2.59 (2.38, 0.41) -8.59 (6.44, 1.12) -75.3∗ (22.3, 3.9) 33 9.92 (6.90, 1.20) 0.67 (3.95, 0.69) 16.4 (60.1, 10.5) Month 6 Endpointa 29 4.13 (4.34, 0.81) -7.54 (7.75, 1.44) -58.6∗ (53.9, 10.0) 31 9.51 (6.43, 1.16) 0.48 (3.54, 0.64) 10.0 (47.0, 8.4) Month 12 Endpointa 27 7.17 (7.05, 1.36) -4.70 (8.21, 1.58) -34.0 (70.7, 13.6) 32 9.98 (7.26, 1.28) 1.11 (4.67, 0.83) 15.2 (56.2, 9.9) Fasting ApoC-III (mg/dL) Baselinea 33 31.42 (15.29, 2.66) NA NA 33 28.94 (13.08, 2.28) NA NA Month 3 Endpointa 33 4.58 (2.79, 0.49) -26.84 (14.87, 2.59 -83.8∗ (9.5, 1.7) 33 30.70 (16.11, 2.80) 1.76 (9.87, 1.72) 6.3 (28.0, 4.9) Month 6 Endpointa 29 5.07 (2.97, 0.55) -26.98 (15.62, 2.90) -82.2∗ (12.2, 2.3) 31 27.85 (14.93, 2.68) -0.92 (7.29, 1.31) -3.4 (23.5, 4.2) Month 12 Endpointa 27 11.67 (8.33, 1.60) -21.19 (17.36, 3.34) -60.0∗ (30.9, 5.9) 32 28.24 (13.91, 2.46) -0.98 (8.81, 1.56) -1.2 (24.9, 4.4) Fasting HDL-C (mg/dL) Baselinea 33 17 (4, 1) NA NA 33 17 (4, 1) NA NA Month 3 Endpointa 33 25 (11, 2) 8 (8, 1) 44.8∗ (41.8, 7.3) 33 17 (5, 1) 1 (3, 1) 4.9 (22.0, 3.8) Month 6 Endpointa 29 22 (9, 2) 6 (7, 1) 35.3 (35.4, 6.6) 31 17 (4, 1) 1 (3, 1) 5.3 (18.9, 3.4) Month 12 Endpointa 27 20 (8, 1) 4 (5, 1) 20.3 (27.3, 5.3) 32 18 (6, 1) 1 (4, 1) 5.7 (21.9, 3.9) Fasting LDL-C (mg/dL) Baselinea 33 28 (19, 3) NA NA 33 28 (13, 2) NA NA Month 3 Endpointa 33 61 (39, 7) 33 (30, 5) 139.4∗ (124.8, 21.7) 33 29 (18, 3) 1 (14, 2) 7.4 (42.7, 7.4) Month 6 Endpointa 29 56 (40, 7) 32 (36, 7) 139.7∗ (143.1, 26.6) 31 27 (14, 3) -1 (8, 2) -2.1 (30.6, 5.5) Month 12 Endpointa 27 45 (31, 6) 19 (25, 5) 68.9 (81.7, 15.7) 31 27 (17, 3) -1 (11, 2) -2.4 (34.1, 6.1)
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Volanesorsen 300 mg (N = 33) Placebo (N = 33) Change from % change from Change from % change from Observed Value Baseline Baseline Observed Value Baseline Baseline Time Point n Mean (SD, SEM) Mean (SD, SEM) Mean (SD, SEM) n Mean (SD, SEM) Mean (SD, SEM) Mean (SD, SEM) Fasting ApoB (mg/dL) Baselinea 33 64.69 (19.45, 3.39) NA NA 33 69.38 (19.78, 3.44) NA NA Month 3 Endpointa 33 75.85 (27.13, 4.72) 11.16 (22.03, 3.84) 19.8 (34.8, 6.1) 33 70.41 (22.74, 3.96) 1.03 (12.09, 2.10) 2.2 (18.4, 3.2) Month 6 Endpointa 29 72.17 (29.93, 5.56) 10.57 (22.45, 4.17) 16.2 (31.9, 5.9) 31 66.28 (19.92, 3.58) -3.34 (11.14, 2.00) -3.6 (18.1, 3.2) Month 12 Endpointa 27 69.27 (27.10, 5.22) 4.97 (19.18, 3.69) 6.6 (28.0, 5.4) 32 64.75 (18.37, 3.25) -4.96 (10.76, 1.90) -5.8 (16.6, 2.9) Fasting VLDL-C (mg/dL) Baselinea 33 40 (34, 6) NA NA 33 41 (29, 5) NA NA Month 3 Endpointa 23 13 (10, 2) -27 (27, 5) -65.0∗ (25.4, 5.2) 33 42 (36, 6) 1 (17, 3) 9.0 (79.6, 13.9) Month 6 Endpointa 26 14 (9, 2) -23 (27, 5) -54.5∗ (31.6, 5.9) 31 43(31, 6) 2 (13, 2) 11.9 (54.2, 9.7) Month 12 Endpointa 25 26 (17, 3) -15 (23, 5) -24.2 (39.7, 7.9) 31 38 (27, 5) -2 (11, 2) 5.5 (40.7, 7.3) Fasting non-HDL-C (mg/dL) Baselinea 33 276 (135, 23) NA NA 33 267 (125, 22) NA NA Month 3 Endpointa 33 131 (51, 9) -144 (127, 22) -44.6∗ (28.6, 5.0) 33 287 (134, 23) 20 (113, 20) 14.1 (48.7, 8.5) Month 6 Endpoint 29 148 (53, 10) -135 (125, 23) -39.3∗ (30.7, 5.7) 31 278 (107, 19) 11 (61, 11) 9.7 (28.1, 5.1) Month 12 Endpoint 27 191 (90, 17) -102 (132, 25) -27.9 (34.2, 6.6) 32 270 (136, 24) 7 (90, 16) 5.9 (31.7, 5.6) ∗ = p<0.0001
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8.2.9.5 Effect of Volanesorsen on Spleen Volume and Hepatic Fat Percent An increase in splenic volume was observed at Week 52 in both groups with a mean change from Baseline of 32 cm3 and 107 cm3 in the placebo and volanesorsen treatment groups, respectively. Mean hepatic fat percent in volanesorsen-treated patients decreased from a Baseline value of 8.6% to 5.9% at Week 52, representing a least squares mean change of -1.7%, compared with a least squares mean change of 0.1% in placebo patients. This suggests that the liver is able to metabolically accommodate the increase uptake of triglyceride-rich lipoproteins as a result of apoC-III inhibition.
8.2.10 Efficacy Following Dose Adjustments Treatment with volanesorsen, at either the 300 mg weekly dose or following dose adjustment and continuation at the 300 mg every 2 weeks dose, was associated with continued reduction of triglycerides. As mentioned earlier (Section 7.1.1), the protocol allowed for dose adjustments by reducing the frequency of dose administration. Of the 19 patients who completed the 12-month volanesorsen treatment period, 13 patients had dose adjustments or pause and 6 patients did not. As would be anticipated, fewer patients on adjusted dose of volanesorsen achieved triglyceride values of < 750 mg/dL after 12 months of treatment compared with patients with no dose adjustment or pause (Table 24). However, these levels were still clinically meaningful and 6.5% of placebo patients achieved this threshold of triglyceride management with diet alone.
Table 24: Analysis of Treatment Response Rate in Volanesorsen-treated Patients by Dose Adjustment – CS6
Without Dose Adjustments/Pause With Dose Adjustments (N=6) (N=13) n (%) n (%) Number of Evaluable Patientsa 5 13 Endpoint triglycerides < 750 mg/dL Month 3 4 (80.0) 11 (84.6) Month 6 4 (80.0) 6 (46.2) Month 12 3 (60.0) 6 (46.2) a Evaluable patients are patients with specified post-baseline assessment and Baseline triglycerdes ≥ 750 mg/dL. One patient without dose adjustments/pause had baseline triglycerides < 750 mg/dL
Figure 10 displays triglyceride values over time using observed data for completers, with and without dose adjustments, and non-completers.
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Figure 10: Mean (SEM) Percent Change in Triglycerides Over Time Including Dose Adjustments and Non-Completers – CS6 Full Analysis Set – Observed Data
Volanesorsen treatment with or without dose adjustment was associated with fewer events of pancreatitis, either when assessed as on-study events compared to placebo patients (1 event in patient on weekly volanesorsen vs. 4 events in placebo patient), or as events on study compared to medical history data. This included 5-year records of adjudication-confirmed events in the study population, in particular in those patients judged to be most at risk, those patients with more than 1 event in the past 5 years (24 events in 7 volanesorsen patients in the 5 years pre- study vs. 0 events during the study period). Significant long-term benefit in triglyceride reduction and numerically fewer events of pancreatitis was reported for all patients completing the study. This was true for triglycerides, even including all imputed data from patients discontinuing prior to completing 12 months of treatment, as presented in the FAS analysis (Section 8.2.7.2). Post-hoc Analysis of Predictors of Dose Reduction Body weight was statistically the strongest predictor of platelet decrease in the 19 completing patients, consistent with the correlation observed in the pooled CS6 and CS16 data as shown in Figure 13. Body weight also predicted dose adjustment: 10 of 11 patients who were < 70 kg had a dose adjustment while 3 of 8 patients who were ≥ 70 kg had a dose adjustment. To further evaluate the relationship of drug exposure to body weight and the potential implications of dose reduction on the long-term benefit of treatment with volanesorsen in patients with FCS (effects on triglyceride reduction vs. discontinuation for platelet reductions), the effects of weight- associated changes in dose on long-term triglyceride reduction among the 19 patients continuing through at least 12 months of study drug treatment were evaluated (Table 25). As shown, there
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was a relationship between mean weekly exposure and body weight, while triglyceride reduction remained clinically meaningful in all groups. These data indicate that dose reduction in the lower weight patients, while associated with some reduction of triglyceride-lowering efficacy, maintained triglyceride lowering of at least 60% from baseline, or about 80% of the benefit achieved by patients continuing on full dose on a long-term basis.
Table 25: Relationship of Body Weight, Volanesorsen Exposure, and Triglyceride Reduction in Study CS6
Dose group Average Weekly Dose Average Baseline Average % Triglyceride Reduction in the Last 6 Months Weight at Month 12 from Baseline (mg) (kg) (%) CS6-low dose (N=6) 180.8 55.7 -59.5 CS6-mid dose (N=5) 253.8 73.8 -66.1 CS6-high dose (N=7) 290.1 82.6 -68.7 *Excluding outlier patient CS6-high dose (N=8) 288.5 81.0 -55.7 *Including outlier patient *One patient had Baseline, Month 3, Month 6, and Month 12 triglyceride levels of 1367, 1320, 2362, and 1856 mg/dL corresponding to % triglyceride change from baseline at Month 3, Month 6, and Month 12 of -3%, +73%, +36%, respectively, despite continued dose administration.
8.2.11 Comparison of Results in Subpopulations Overall, there were no clinically meaningful differences in mean percent change in fasting triglycerides from Baseline to the Month 3, Month 6, and Month 12 endpoints when evaluated by age, gender, race, ethnicity, or geographic location. Subgroup analyses of secondary endpoints also showed a similar treatment effect for volanesorsen across each of these subgroups. There was also no clinically meaningful difference in the primary endpoint when evaluated by presence or absence of concurrent omega-3 fatty acids and/or fibrates. At Month 3, least squares mean percent change in triglycerides was -76% in the volanesorsen group compared with 26.6% in the placebo group for patients using concurrent omega-3 fatty acids and/or fibrates (p=0.0002) and -73% vs 11% (p<0.0001) for those not using concurrent omega-3 fatty acids and/or fibrates. A post-hoc subgroup analysis for reduction in triglyceride levels at Months 3, 6, and 12 according to confirmed genetic mutation showed no major differences in efficacy across subgroups, with all showing a robust triglyceride response to volanesorsen treatment. A greater magnitude of reduction in triglycerides and maintenance of effect over time was observed in volanesorsen-treated patients with mutations in non-lipoprotein lipase genes compared to patients with mutations in the lipoprotein lipase gene. In volanesorsen-treated patients, the mean percent change from baseline in triglycerides was 89.8% in the non-lipoprotein lipase mutation subgroup compared with -66.6% in the lipoprotein lipase mutation subgroup at Month 3. In the non-lipoprotein lipase and lipoprotein lipase subgroups, respectively, mean changes were -57.5%
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vs -47.2% at Month 6 and -40.9% vs -18.0% at Month 12. Patients who retain some lipoprotein lipase activity may have a better response to treatment with volanesorsen. This may be explained by increasing residual lipoprotein lipase activity as an additional mechanism for triglyceride reduction as compared to patients with no lipoprotein lipase activity. An exploratory analysis showed a lack of correlation between weight and percent reduction in triglyceride levels despite a moderate inverse correlation between weight and apoC-III response consistent with patients with lower weight having higher exposure, as described in Section 6.1.3.2. Patients in the volanesorsen group of the FAS who tested positive for anti-drug antibodies (n=10) had similar triglyceride reduction (-75.6% at Month 3, -69.1% at Month 6, and -39.2% at Month 12) as those who remained negative for anti-drug antibodies (-70.2% at Month 3, -58.6% at Month 6, and -50.3% at Month 12). Similar results were obtained when the immunogenicity status was assigned based on the first 3 months of volanesorsen treatment. Therefore, the presence of anti-drug antibodies is not associated with loss of efficacy. 8.3 Phase 3 Open-label Extension Study ISIS 304801-CS7 8.3.1 Study Enrollment and Disposition At the time of the data cutoff for the NDA (06 January 2017), enrollment for this study remained ongoing. At that time, a total of 29 patients were enrolled and had received at least 1 dose of volanesorsen in CS7. Of the 29 patients, 18 patients were treatment-naïve (including 17 patients who were enrolled in from the CS6 placebo group and 1 patient from the CS16 placebo group) and 11 patients had previously received volanesorsen in CS6 (CS6-volanesorsen group). Four of these patients prematurely discontinued from study treatment, including 3 (17%) patients in the treatment-naïve group and 1 (9%) patient in the CS6-volanesorsen group patient. Adverse events led to early discontinuation for all 4 patients, 3 of whom discontinued due to thrombocytopenia. The mean duration of treatment for these 29 patients was 109 days in the treatment-naïve group compared with 91 days in the CS6-volanesorsen group. For patients in the CS6-volanesorsen group, the mean treatment duration across both the Index Study and the OLE was 473 days. Five (28%) patients in the treatment-naïve group had their dosing changed from weekly to every 2 weeks; these dose adjustments occurred between Weeks 8 and 17. All of these 5 patients weighed < 70 kg. Seven of the 11 (64%) patients in the CS6-volanesorsen group had their dosing changed from weekly to every 2 weeks (6 patients during CS6, 1 patient during CS7); the remaining 4 patients remained on weekly dosing at the time of data cutoff. At the time of the data cutoff for the 4-month Safety Update (31 August 2017), a total of 60 patients were enrolled and treated in CS7, including 43 treatment-naïve patients, 14 patients who received volanesorsen in CS6, and 3 patients who received volanesorsen in CS16 (Figure 7). Safety data for these 60 patients are included in the summary of safety (Section 9). Overall, 12 patients (7 treatment naïve and 5 CS6-volanesorsen) have discontinued prematurely; 8 discontinued due to AE and 4 discontinued due to voluntary withdrawal.
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The median treatment duration in Study CS7, at the 31 August cutoff, was 162 days in the treatment-naïve group, 257 days in the CS6-volanesorsen group, and 51 days in the CS16-volanesorsen group. For patients who received volanesorsen in either index study (N = 17), the median total treatment duration was 625 days (646 days in the CS6-volanesorsen group and 483 days in the CS16-volanesorsen group).
8.3.2 Dose Adjustments and Dose Pauses Dose adjustments from weekly to every 2 weeks and dose pauses are summarized for the 60 patients in CS7 as of the 31 August 2017 data cutoff and for the 33 patients in the volanesorsen group in CS6 are summarized in Table 26. After additional experience was gained in clinical studies, the monitoring and dosing algorithm was updated as shown in Table 11. As a result, more treated patients had dose adjustments or pauses in CS7 compared with CS6 to address platelet reductions before these led to discontinuation. Overall, in Study CS7 approximately 40% of patients have had dose adjustments and interruptions in order to address platelet reductions and maintain treatment. Table 26: Dose Adjustments in CS6 and CS7 as of 31 August 2017 Study Dose Adjustment Only Dose Pause Only Both Dose Adjustment Group n (%) n (%) and Dose Pause n (%) CS6 Volanesorsen (N = 33) 5 (6.6) 7 (4.71) 5 (6.6) CS7 Treatment naive (N = 43) 4 (9.3) 8 (18.6) 18 (41.8) CS6 Volanesorsena (N = 14) 5 (35.7) 0 6 (42.9) CS16 Volanesorsen (N = 3) 1 (33.3) 0 0 a Includes dose adjustments or combination (dose adjustment and pauses) from index study 8.3.3 Demographics and Baseline Characteristics Demographic and baseline characteristics for the 29 patients in CS7 included in the presentation of efficacy were similar to those for patients in CS6 (Table 15) and there are no notable differences in demographic and baseline characteristics for the 29 CS7 patients as of the 06 January 2017 cutoff and the 60 CS7 patients as of the 31 August 2017 cutoff. 8.3.4 Efficacy Results The reductions in triglyceride values in CS7 were consistent with those reported for volanesorsen-treated patients in CS6. As of the 31 August 2017 data cutoff, treatment-naïve patients in the FAS achieved a mean percent reduction in fasting triglycerides of -60% from OLE Baseline at Month 3 Table 27. Patients who received volanesorsen in CS6 and CS16, including patients who were dose adjusted and started CS7 on every 2 week dosing, maintained a reduction in fasting triglycerides from Index Study Baseline at OLE Month 3, demonstrating that the efficacy of volanesorsen shown in CS6 was sustained in longer-term treatment, Patients treated
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with volanesorsen in the Index Study had a lower mean triglyceride level at the OLE baseline compared with their Index Study baseline but elevated from their end of Index Study levels due in part to varying treatment gaps that occurred between the end of treatment in the Index Study and the start of treatment in the OLE. Table 27: Summary of Change from Baseline to Month 3 in Fasting Triglycerides Using OLE and Index Study Baseline - CS7 FAS (31 August 2017 data cutoff) Treatment-naïve CS6-Volanesorsen CS16-Volanesorsen CS7 OLE CS6 Index Study CS7 OLE CS16 Index CS7 OLE Baseline Baseline Baseline Study Baseline Baseline (N=43) (N=14) (N=14) (N=3) (N=3) Mean Mean Mean Mean Mean Analysis Endpoint n (SD, SEM) n (SD, SEM) n (SD, SEM) n (SD, SEM) n (SD, SEM) Baseline Observed 43 2140 14 2641 14 1523a 3 2288 3 2081a Fasting triglycerides (1065, 162) (1228, 328) (946, 253) (1524, 880) (706, 408) (mg/dL) OLE Month 3 Observed 38 778 13 1270 13 1270 2 1202 2 1202 Fasting triglycerides (591, 96) (845, 234) (845, 234) (497, 351 (497, 351) (mg/dL) Change in Fasting 38 -1432 13 -1320 13 -256 2 -1692 2 -1281 triglycerides - Baseline to (1071, 174) (958, 266) (763, 212) (1064, 752) (336, 238) OLE Month 3 Percent Change in 38 -58.7 13 -48.1 13 -7.9 2 -56.8 2 -52.1 Fasting triglycerides to (37.8, 6.1) (36.0, 10.0) (44.0, 12.2) (6.1, 4.3) (16.9, 12.0) OLE Month 3 a Many patients had a drug holiday between studies while awaiting regulatory approval for CS7, thus the OLE baseline triglycerides values were higher than the values at the end of the Index Study. As shown in Figure 2 in Section 1.3.2.2, the efficacy of volanesorsen treatment was sustained over longer-term treatment in CS7 for patients who received volanesorsen in CS6. For patients as of the 06 January 2017 cutoff for the NDA, there were 9 treatment-naïve patients with OLE baseline triglyceride levels ≥ 750 mg/dL who had Month 3 triglyceride values available at the time of cutoff. Four (44%) of these patients achieved triglyceride levels < 750 mg/dL and 8 (88%) achieved a ≥ 40% reduction of triglyceride levels at Month 3. Among the 4 CS6-volanesorsen patients with Index Study Baseline triglyceride levels ≥ 750 mg/dL who had Month 3 triglyceride values available at the time of 06 January 2017 data cutoff, 1 (25%) patient achieved triglyceride levels < 750 mg/dL and all 4 (100%) achieved a ≥ 40% reduction of triglyceride levels at Month 3. Treatment with volanesorsen also led to positive changes in the treatment-naïve group and sustained changes in the CS6-volanesorsen group in other key fasting lipid parameters at Month 3, with reductions in apoC-III and non-HDL-C, and VLDL-C. Fasting HDL-C, LDL-C, and apoB levels increased at Month 3 but remained below the ULN.
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8.4 Study ISIS 304801-CS16 8.4.1 Study Enrollment and Disposition A second study was conducted primarily in patients without FCS but with severe hypertriglyceridemia to evaluate efficacy and safety of volanesorsen in a similar, but less severely affected, patient group. A total of 114 patients were randomized 2:1 active:placebo and 113 patients received Study Drug in CS16: 75 patients received volanesorsen and 38 patients received placebo. Eighty-five patients, 51 volanesorsen and 34 placebo, completed study treatment. In the volanesorsen group, 39% of patients dose reduced to 300 mg every 2 weeks. Seven patients with FCS enrolled in CS16, 5 were randomized to the volanesorsen group and 2 to placebo. All 7 patients with FCS completed study treatment. Four (80%) patients with FCS in the volanesorsen group had their dosing changed from weekly to every other week dosing. In total, patients with FCS in CS16 received between 16 and 26 doses with the treatment duration lasting between 141 and 177 days.
8.4.2 Demographics and Baseline Disease Characteristics Demographic and baseline disease characteristics for the patients with FCS in CS16 are summarized in Table 15. Demographic and baseline disease characteristics were similar in the FCS patient subgroup to the overall CS16 study population, with the exception of lower body weight and BMI in the FCS subgroup. The demographic parameters were consistent across the Phase 3 studies. In the patients with FCS, mean fasting plasma triglyceride levels at Baseline were 2644 mg/dL and 2134 mg/dL in the placebo and volanesorsen groups, respectively, which were approximately twice the levels of patients without FCS in the study and 14 to 17 times higher than the ULN. Mean fasting plasma triglyceride levels at Baseline in non-FCS patients were 1346 mg/dL and 1115 mg/dL in the placebo and volanesorsen groups, respectively.
8.4.3 Efficacy Results The efficacy results in CS16 were consistent with those reported for CS6, supporting the efficacy results for the FCS population in CS6. In both patients with severe hypertriglyceridemia and in the FCS subgroup, treatment with volanesorsen demonstrated robust reductions in triglyceride levels after 3 months of treatment, with persistent reductions through the 6 months of study treatment.
8.4.4 Effect on Triglycerides The primary study endpoint was met. Using a multiple imputations method, weekly treatment with volanesorsen was associated with a significantly greater mean percent change in triglycerides compared with placebo at Month 3 (Table 28) and the significant and clinically important reduction in triglycerides was sustained through the end of the 26-week treatment period in patients who reduced dosing to every 2 weeks (-62%) and those who remained on weekly treatment (-78%).
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In the subset of 7 patients with FCS, whose mean baseline fasting triglyceride level was 2280 mg/dL, volanesorsen-treated patients (n=5) achieved a mean reduction of -73% from baseline at Month 3, compared with a mean increase of 70% in placebo-treated patients (n=2).
Table 28: Primary Efficacy Endpoints: Change from Baseline to Month 3 in Fasting Triglycerides in CS16 - Full Analysis Set with Multiple Imputations for Missing Dataa
Volanesorsen Placebo Fasting triglycerides FCS Subgroup Total FCS Subgroup Total (mg/dL) (N=5) (N=75) (N=2) (N=38) Baseline Value Mean (SD) 2134 (1141) 1183 (759) 2644 (314) 1414 (1253) Median (P25, P75) 1791 (1464) 878 (679) 2644 (2422) 919 (650) Min, Max 1074, 3998 439, 3998 2422, 2867 482, 6686 Month 3 Endpoint Value Mean (SD) 623 (606) 294 (245) 4317 (2519) 1406 (1409) Median (P25, P75) 424 (219) 228 (168) 4317 (2536) 779 (539) Min, Max 212, 1671 75, 1671 2536, 6098 233, 6098 % Change from Baseline Mean -73.0 (13.9) -71.2 70.1 (115.5) -0.9 95% CI -90.3, -55.8 -79.3, -63.2b -967.4, 1107.6 -13.9, 12.2b p-value NC <0.0001 NA NA a Multiple imputation analysis was for the Total group; there were no missing data at Month 3 in the FCS group. b Least squares mean.
In the FCS volanesorsen group at the Month 6 endpoint, fasting plasma triglyceride levels decreased from Baseline by -78% in the patients receiving 300 mg weekly whereas fasting triglyceride levels in the patients receiving 300 mg biweekly post Week 13 decreased from Baseline by -69%. As was seen in CS6, anti-drug antibodies positive patients in the volanesorsen group in CS16 had similar triglyceride reduction (-73.0% at Month 3, -57.7% at Month 6) as those who remained negative for anti-drug antibodies (-72.7% at Month 3, -68.6% at Month 6). A ≥ 40% reduction in fasting triglyceride levels at the Month 3 primary endpoint achieved in 87% of the volanesorsen-treated patients compared with 13% of placebo-treated patients (p < 0.0001). Results were consistent at the Month 6 endpoint, where 79% of volanesorsen patients achieved a ≥ 40% reduction in fasting triglyceride levels. The treatment response rate at Month 6 was similar to the Month 6 treatment response rate see in the FCS population in CS6 where 24 (73%) patients in the volanesorsen group achieved ≥ 40% reduction of triglyceride levels from Baseline as compared with 1 (3%) patient in the placebo group (p < 0.0001) further supporting the use of patients with severe hypertriglyceridemia for additional efficacy
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information on volanesorsen for treatment of FCS. Results for the responder analysis with missing data imputed by bootstrap imputation were consistent with those described above. Among the volanesorsen treatment group at the Month 6 endpoint, 96% of patients receiving 300 mg weekly achieved a ≥ 40% reduction in fasting triglyceride levels whereas 70% patients that reduced to 300-mg every 2 weeks post Week 13 achieved a ≥ 40% reduction. When compared to placebo, the response rates for both dose regimens were statistically significant (p<0.0001).
8.4.5 Acute Pancreatitis There was a significant decrease in the frequency of adjudication-confirmed acute pancreatitis events in CS16, with 3 (8%) placebo patients having 5 events during the on-treatment period compared to no events in the volanesorsen-treated patients (p=0.0360). Among the 7 FCS patients in CS16, 1 patient in the placebo group had adjudication-confirmed acute pancreatitis during the treatment period. The significant reduction in the incidence of pancreatitis with volanesorsen treatment in this study was unexpected considering the lower incidence of pancreatitis at Baseline compared to CS6 (29% vs 76%, respectively) and the shorter duration of the study (6 vs 12 months). The findings highlight the important role of hypertriglyceridemia as a marker of pancreatitis risk and are likely explained by the very large reductions in plasma triglycerides with volanesorsen treatment as compared to placebo and the documented background events of pancreatitis in the enrolled population. 8.5 Quality of Life – ReFOCUS In addition to the QoL measurements in CS6 (Section 8.2.8.6), a retrospective evaluation of quality of life was performed in patients from CS7. Findings from the IN-FOCUS survey revealed an inventory of symptomology and comorbidities that impart major burden on patients living with FCS, which have considerable impact on quality of life and activities of daily living (Davidson et al. 2017). ReFOCUS was designed to retrospectively capture the daily burden of living with FCS across 2 different time-periods, the 3 months prior to and the most recent 3 months since on volanesorsen. The sole inclusion criterion was that patients must currently be, or have previously been, enrolled in the CS7, and must have received one or more injections of volanesorsen as part of the OLE. Patients who had discontinued their enrollment in the OLE, or who had been on volanesorsen for less than 3 months at the time of study participation were only asked about their experiences before they started taking volanesorsen. Overall, treatment with volanesorsen demonstrated a positive impact on patients’ quality of life and improvement in patients’ activities of daily living across all domains assessed. Patients treated with volanesorsen reported a decrease in the total number of FCS-related symptoms experienced. ReFOCUS results suggest that treatment with volanesorsen improved the physical, emotional and neurocognitive domains associated with FCS (Table 29). These improvements lead to an improved overall ability to perform professional, academic, and social obligations.
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Table 29: ReFOCUS: Mean (SD) Number of Symptoms Experienced Prior to and On Volanesorsen (N=22)
Decrease (% Decrease) Symptom Pre-Volanesorsen On Volanesorsen from Baseline Physical 3.5 (3.6) 2.0 (2.2) 1.5 (43%) Emotional 3.5 (3.7) 1.9 (2.7) 1.6 (47%) Neurocognitive 1.5 (1.6) 0.7 (1.2) 0.9 (56%) Cognitive 0.6 (0.9) 0.3 (0.8) 0.3 (46%) Neuro 1.0 (1.1) 0.4 (0.7) 0.6 (62%) The study has several limitations including selection bias, sample size and potential influence of recall bias, which should be considered when assessing the study findings. However, given that FCS is a rare, chronic disease that all patients in CS6 had lived with for many years, these results suggest a potential quality of life benefit with volanesorsen treatment and are part of the ongoing learning from patients living with FCS.
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Collectively, CS6, CS16, CS2 (300 mg cohort only), and CS4 included safety data from 246 patients, including 146 patients with FCS and/or hypertriglyceridemia who have been treated with a least 1 dose of 300 mg volanesorsen during a placebo-controlled period. Patients were treated for up to 52 weeks (average of approximately 22 weeks). Long-term safety of volanesorsen was derived from CS7, the OLE study in patients with FCS. All volanesorsen clinical studies included a thorough evaluation of the safety. Standard safety assessments conducted in all studies included physical examinations; vital signs; clinical laboratory evaluations, including hematology and chemistry; and 12-lead ECGs; echocardiograms, as well as monitoring for AEs and concomitant medication usage. 9.2 Treatment Exposure The CS6 pivotal trial enrolled 67 patients with FCS (66 treated with Study Drug) and treatment was continued long-term in the OLE CS7, in which all patients received volanesorsen treatment, including those originally on placebo in CS6. CS7 provides additional exposure to volanesorsen for assessment of safety and tolerability, approaching 3 years in some patients. 9.3 Common On-Treatment Adverse Events Overall in CS6, the incidence of on-treatment AEs was comparable between the volanesorsen (97%) and placebo (94%) groups. The most common on-treatment AEs for patients receiving volanesorsen were AEs at the injection site (see Section 9.7.3). Excluding AEs at the injection site, the most commonly reported AEs (i.e., occurring in more than 10% of patients in the volanesorsen group) are summarized in Table 30. Injection site AEs and platelet reductions (reported using the MedDRA preferred terms of either platelet count decreased or thrombocytopenia) were the most commonly reported AEs in the volanesorsen group in CS6. [Of note, the AE term platelet count decreased did not necessarily indicate platelet counts below the LLN (< 140,000/mm3); however, a single report of platelet count decreased was not associated with a platelet count < 140,000/mm3. There was no overlap between patients with AE terms of thrombocytopenia and platelet count decreased with the exception of 1 patient in the volanesorsen group who had both terms reported.] A discussion of observed reductions in platelet counts is presented in Section 9.7.2. Other than local tolerability and events of platelet count reductions, the most commonly reported AEs across CS6 and CS16 in volanesorsen-treated patients were abdominal pain, headache, fatigue, nausea, nasopharyngitis, and diarrhea.
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Table 30: On-Treatment Adverse Events Occurring in >10% of Pooled Volanesorsen Patients in CS6 and CS16 (Excluding AEs at the Injection Site) - Safety Set CS6 CS16 Volanesorsen Placebo Volanesorsen Placebo (N = 33) (N = 33) (N = 75) (N = 38) Preferred Term n (%) n (%) n (%) n (%) Platelet Reduction 13 (39.3)a 1 (3.0) 13 (17.3) 4 (10.5) Platelet count decreased 10 (30.3) 1 (3.0) 3 (4.0) 2 (5.3) Thrombocytopenia 4 (12.1) 0 10 (13.3) 2 (5.3) Abdominal pain 7 (21.2) 7 (21.2) 8 (10.7) 0 Headache 7 (21.2) 5 (15.2) 6 (8.0) 4 (10.5) Fatigue 7 (21.2) 3 (9.1) 9 (12.0) 4 (10.5) Nausea 6 (18.2) 2 (6.1) 7 (9.3) 1 (2.6) Nasopharyngitis 5 (15.2) 7 (21.2) 12 (16.0) 5 (13.2) Diarrhea 5 (15.2) 2 (6.1) 10 (13.3) 4 (10.5) Pain in Extremity 4 (12.1) 1 (3.0) 7 (9.3) 1 (2.6) Note: An on-treatment AE was defined as any AE that occurred from the first dose of the Study Drug through 28 days post the last dose of Study Drug. a One patient had reports of both platelet count decreased and thrombocytopenia. 9.4 Deaths No deaths have been associated with volanesorsen treatment. 9.5 Serious Adverse Events 9.5.1 Serious Adverse Events in Studies CS6 and CS16 On-treatment SAEs were reported in 12 patients during CS6: 7 (21%) patients in the volanesorsen group experienced 8 SAEs and 5 (15%) patients in the placebo group experienced 6 SAEs. In the volanesorsen group, the only SAE reported in more than 1 patient was thrombocytopenia. Two (6%) volanesorsen patients had SAEs of thrombocytopenia, with platelet counts < 25,000/mm3 reported as related to study treatment and led to treatment discontinuation. Subsequent to these events, a more intensive platelet monitoring plan was implemented. Further information is provided in Section 9.7.2. One patient in the volanesorsen group had an SAE of abdominal pain, which was adjudicated as pancreatitis (see Section 8.2.8.7). In the placebo group, acute pancreatitis was reported as an SAE in 2 (6%) patients and 1 (3%) patient reported 2 events of abdominal pain, all of which were adjudicated as pancreatitis. In CS16, on-treatment SAEs were reported in 9 (8%) patients: 6 (8%) patients in the volanesorsen group experienced 7 SAEs and 3 (8%) patients in the placebo group experienced 5 SAEs. Acute pancreatitis was reported as an SAE in 2 (5%) patients in the placebo group, 1 event was moderate and 1 was severe, and a severe event of pancreatitis relapsing was reported
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in 1 placebo patient. All events were adjudicated, assessed as not related to study treatment, and resolved. There were no drug-related MACE in CS6 or CS16. On-treatment SAEs reported in more than 1 patient across CS6 and CS16 are summarized in . All on-treatment SAEs reported in these studies are shown in Section 13.3.
Table 31 Serious On-Treatment Adverse Events Reported by More Than 1 Patient Overall in CS6 or CS16 - Safety Set
CS6 CS16 Volanesorsen Placebo Volanesorsen Placebo (N = 33) (N = 33) (N=75) (N=38) Preferred Term n (%) n (%) n (%) n (%) Patients with any SAE 7 (21.2) 5 (15.2) 6 (8.0) 3 (7.9) SAEs in more than 1 patient Thrombocytopenia 2 (6.1) 0 (0.0) 0 (0.0) 0 (0.0) Pancreatitis acute 0 (0.0) 2 (6.1) 0 (0.0) 2 (5.3) Abdominal pain 1 (3.0) 1 (3.0) 0 (0.0) 0 (0.0)
9.5.2 Serious Adverse Events in Other Studies SAEs reported in CS7 are described in Section 9.9.2. In CS2, 3 patients experienced a total of 6 treatment-emergent SAEs. One SAE of secondary serum sickness-like reaction in a non-FCS patient was reported as related to study drug in a patient in the fibrate combination cohort. The event occurred 4 days after the 11th weekly dose of volanesorsen. Extensive tests including skin biopsy, autoantibody and vasculitis panel, high- sensitivity C-reactive protein, and anti-drug antibodies were all unremarkable. Due to a lack of a clear association with study drug and absence of other events similar to drug hypersensitivity, the event is not considered as an identified or potential risk of volanesorsen. As of 31 August 2017, 22 patients were treated with double-blind study drug in the ongoing CS17 in familial partial lipodystrophy. Based on a blinded review of the 22 randomized patients, 9 SAEs were reported in 7 patients. There were no reports of MACE and no SAEs related to platelet count reduction in CS17. One of the SAEs was anaphylactic reaction (see Section 9.7.5). No SAEs were reported in CS19, an investigator initiated study in familial partial lipodystrophy. Serious AEs reported in the ongoing studies after the 31 August 2017 data cutoff for the 4-month Safety Update are described in Section 13.3. 9.6 Adverse Events Leading to Discontinuation Overall, the majority of AEs that led to discontinuation were related to platelet reduction in CS6 (see Section 9.7.2) and local tolerability in CS16 (see Section 9.7.3). On-treatment AEs leading
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to permanent discontinuation of Study Drug in more than 1 volanesorsen-treated patient in CS6 or CS16 are summarized in Table 32. In CS6, platelet reductions were the most common AEs leading to treatment discontinuation. In addition to the 2 patients described in Section 9.5 who discontinued study treatment because of SAEs of thrombocytopenia, 3 patients discontinued study treatment because of non-serious AEs of mild or moderate decreased platelet counts; all were assessed as treatment-related. In CS16, all AEs leading to treatment discontinuation in more than 1 patient were injection site events.
Table 32: On-Treatment Adverse Events Leading to Treatment Discontinuation in More Than 1 Volanesorsen-Treated Patient in CS6 or CS16 – Safety Set
CS6 CS16 Volanesorsen Placebo Volanesorsen Placebo (N = 33) (N = 33) (N = 75) (N = 38) Preferred Term n (%) n (%) n (%) n (%) Any AE leading to Treatment Discontinuation 9 (27.3) 0 15 (20.0) 2 (5.3) Platelet reduction 5 (15.1) 0 1 (1.3) 0 Platelet count decreased 3 (9.1) 0 0 0 Thrombocytopenia 2 (6.1) 0 1 (1.3) 0 Injection site event 1 (3.0) 0 9 (12.0) 0 Injection site erythema 1 (3.0) 0 6 (8.0) 0 Injection site pain 1 (3.0) 0 6 (8.0) 0 Injection site swelling 0 0 3 (4.0) 0 Fatigue 2 (6.1) 0 0 0 Most events leading to treatment discontinuation occurred early (within the first 13 weeks on study). 9.7 Analysis of Selected Adverse Events 9.7.1 Adverse Drug Reactions Adverse drug reactions, or AEs related or possibly related to Study Drug, in patients with FCS in CS6 were determined by evaluating AEs that occurred with a ≥ 1% overall incidence rate and that 1) occurred with a ≥ 1% difference between the volanesorsen-treated group and the placebo group, and/or 2) had an apparent dose response. Medical judgment was further applied, taking into consideration the extent to which the AE was consistent with the pharmacology of the drug and the consistency of the pattern of symptoms across studies. Additionally, any noteworthy AEs not meeting the ≥ 1% difference between the volanesorsen-treated group versus the placebo group, or those occurring at an incidence rate of < 1% were also evaluated.
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Table 33 presents the most common adverse drug reactions that were reported in ≥ 10% of patients and were more common among those who received volanesorsen compared with those who received placebo during CS6. Table 33: Summary of Adverse Drug Reactions in Study CS6 Occurring in ≥ 10% Patients – Safety Set
Volanesorsen Placebo (N = 33) (N = 33) Adverse Reaction n (%) n (%) Platelet count decreased 11 (33.3) 1 (3.0) Thrombocytopenia 4 (12.1) 0 (0)
9.7.2 Platelet Count Reductions 9.7.2.1 Severe Platelet Reductions (< 50,000/mm3) Reductions in platelet count to < 50,000/mm3 were reported in 8 patients across the clinical development program as of the 31 August 2017 data cutoff for the 4-month Safety Update (Table 34). These events were serious in 3 patients and resulted in treatment discontinuation. The other events were managed with dose pauses and/or concomitant medications and the patients remained on study.
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Table 34: Summary of Patients with Platelet Reduction to < 50,000/mm3 Study Platelet Time to Dosing Regimen Patient Nadir Onset at Onset Duration Associated Bleeding Events CS6 40,000/mm3 85 days Weekly 61 days None Patient D CS6 8,000/mm3 257 days Weekly 36 days Epistaxis and petechiae Patient A* CS6 15,000/mm3 134 days Weekly 32 days Epistaxis, spontaneous hematoma, Patient B* conjunctival hemorrhage CS7 37,000/mm3 78 days Weekly 18 days Epistaxis Patient E CS7 28,000/mm3 155 days Every 2 weeks 7 days Hematoma, ecchymosis Patient F CS7 15,000/mm3 80 days Weekly 11 days Hematoma Patient C* CS16 41,000/mm3 51 days Weekly 14 days Injection site hemorrhage Patient G CS2 49,000/mm3 92 days Weekly 11 days None Patient H *Reported as SAEs Note: One additional patient in CS7 that is not included in this table had an SAE of thrombocytopenia (<50,000/mm3) after the 31 August 2017 data cutoff for the 4-month Safety Update.
Patients with nadir platelet counts meeting threshold values at any time in CS6 and CS16 are summarized in Table 35.
Table 35: Number of Patients with Nadir Platelet Count Meeting Threshold Value at Any Time Post-Baseline in Studies CS6 and CS16
CS6 CS16 Volanesorsen Placebo Volanesorsen Placebo Nadir Platelet Count (N=33) (N=33) (N=75) (N=38) < 140,000/mm3 25 9 30 6 < 100,000/mm3 18 0 9 1 100,000 to < 140,000/mm3 7 9 21 5 75,000 to < 100,000/mm3 6 0 6 1 50,000 to < 75,000/mm3 9 0 2 0 25,000 to < 50,000/mm3 1 0 1 0 < 25,000/mm3 2 0 0 0
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9.7.2.2 Thrombocytopenia SAEs Led to Improvements in Monitoring and Dose Adjustment Initially, platelet monitoring in the volanesorsen Study CS6 was done at 4 to 6 week intervals, but based on the first 2 serious events, enhanced frequency of platelet monitoring and associated dose pausing and stopping rules were implemented in all Phase 3 clinical trials. Platelets were monitored every 2 weeks with more frequent (weekly, or more frequently if needed) monitoring for patients with platelet count below the lower limit of normal in the pivotal study. The individual patient platelet counts for the 2 CS6 and 1 CS7 SAEs of thrombocytopenia are shown in Figure 11 (Patients A, B, and C) with dose administrations and a vertical red line indicating the start of every other week enhanced platelet monitoring. For the CS7 patient, platelet monitoring was weekly, but due to the patient missing monitoring over the Christmas holidays, this patient’s platelet level dropped to 15,000/mm3 before detection. Post-approval, REMS and patient support programs will be implemented to mitigate the risk of missed platelet monitoring visits leading to severe thrombocytopenia (Section 10). Recently, there has been a fourth thrombocytopenia SAE, in Study CS7. Thrombocytopenia (platelet count nadir 17,000/mm3 on study day 306) was reported in a 34-year-old female patient (weight 59 kg) who was receiving volanesorsen 300 mg every 2 weeks. The investigator did not pause volanesorsen dosing when the patient’s platelet test result was 69,000/mm3 because he was waiting for a confirmatory test result (protocol recommends dose pause at < 75,000/mm3). The patient did not experience any bleeding and was treated with a course of corticosteroid therapy with recovery of her thrombocytopenia. For all 4 patients, platelet counts rapidly recovered following discontinuation of Study Drug and with the administration of short-course high-dose corticosteroids. No clinically important bleeding events occurred across the volanesorsen clinical development program.
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Figure 11: Individual Patient Platelet Counts over Time Before and After Platelet Count < 25,000/mm3 for Studies CS6 and CS7
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9.7.2.3 Other Platelet Reductions In CS6, platelet count decreased AEs were reported in 11 (33%) of 33 patients in the volanesorsen group, compared with 1 (3%) patient in the placebo group, and thrombocytopenia was reported in 4 (12%) patients in the volanesorsen group compared with none in the placebo group. The AEs related to platelet reductions were mild in severity for most patients and well managed with dose pauses and adjustments. In the volanesorsen group, 24 (75%) patients had confirmed post-baseline platelet count below the LLN (140,000/mm3) and 13 of the 14 patients with AEs of thrombocytopenia or platelet count decreased patients are included in the 75% with a confirmed platelet count below 140,000/mm3. In CS16, platelet count decreased AEs were reported in 3 (4%) patients in the volanesorsen group and 2 (5%) patients in the placebo group and thrombocytopenia was reported in 10 (13%) patients in the volanesorsen group and 2 (5%) patients in the placebo group. There was no overlap between patients with AE terms of thrombocytopenia and platelet count decreased. In the volanesorsen-treated patients, 28 (37%) had a confirmed post-baseline platelet count below the LLN. All of these 13 patients with AEs of thrombocytopenia or platelet count decreased are included in the 37% with a confirmed platelet count below 140,000/mm3. Platelet reductions reported as SAEs and leading to treatment discontinuation are described in Sections 9.5 and 9.6. In CS6, mean decreases in platelets were observed over time for volanesorsen-treated patients compared with those in the placebo group. The lowest value in the volanesorsen group was at Week 25, with mean platelet count of 134,000 mm3 (Figure 12). Aside from reduction in mean platelet counts, there were no signals for a clinically meaningful effects on other lab parameters associated with volanesorsen.
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Figure 12: Mean (SEM) Absolute Platelet Count Over Time in CS6
The association between platelet count and body weight is described in Section 9.8.2.
9.7.2.4 Further Investigation of Mechanism of Platelet Reductions The potential causes of the observed platelet count changes in volanesorsen clinical studies were investigated, focusing on the known potential causes of platelet count reductions and the background of platelet variability in patients with FCS. There were 2 phenotypes of platelet reductions in volanesorsen studies: 1) a reduction of the group mean platelet count by approximately 30% over the first 3-6 months to near the lower limit of normal; and 2) individual severe declines to less than 25,000/mm3, seen in the FCS population who had longer drug exposures. The role of the PD effects of volanesorsen, cytokine levels, immunological factors, and patient attributes and demographics, were evaluated as potential contributors, which led to the following conclusions: • There was no effect on megakaryocytes seen in bone marrow biopsies performed on two patients with severe platelet reductions. • There was no evidence for platelet activation, thrombotic microangiopathy, disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, or a classical heparin- induced thrombocytopenia-like mechanism. • Platelet aggregation studies in monkeys did not show any effect of volanesorsen on platelet aggregation even at human equivalent concentrations of volanesorsen 2.5-fold higher than the 300 mg/week human therapeutic dose.
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• An in vitro study evaluating the effect of volanesorsen on normal human platelets demonstrated no direct effect on platelet activation. • There were no major or severe bleeding events in patients treated with volanesorsen, including the patients with SAEs of thrombocytopenia. Minor bleeding such as bruising or petechiae were observed more frequently in the volanesorsen-treated group and appeared to be unrelated to platelet count. • Platelet immunology testing showed that drug-independent antiplatelet antibodies (IgG and IgM) and anti-PF4 antibodies (IgM only) were present prior to treatment in the serum of 14% of FCS patients (CS6) but were not detected in patients enrolled in CS16. Treatment-emergent antiplatelet antibodies (IgG only) and anti-PF4 antibodies (IgM only) were seen in both volanesorsen (25% of volanesorsen-treated) and placebo-treated (12% of placebo-treated) patients. Most treatment-emergent antibodies were seen in FCS patients (CS6), but the overall incidence of treatment-emergent antibodies (33%) in volanesorsen-treated FCS patients who were tested is low compared with the overall incidence of thrombocytopenia (~75%), in volanesorsen-treated patients in CS6, so the importance of these findings is uncertain. Some patients tested positive to platelet surface glycoproteins in the platelet antibody bead array test (12 patients of which 2 were positive at Baseline) and these were almost all reactive against GPIIb/IIIa. Two of 3 patients who had a platelet nadir < 25,000/mm3 tested positive for drug-independent antiplatelet IgG together with positive GPIIb/IIIa. However, the third patient tested negative for both antiplatelet IgG and GPIIb/IIIa. All 3 of these patients tested positive for IgM anti-PF4 antibody. The significance of these antibody and epitope test results is uncertain, but it is possible that the combination of IgM anti-PF4 antibodies and/or antiplatelet IgG plus positivity for GPIIb/IIIa may be contributory in some of the cases of Grade 4 thrombocytopenia (platelets < 25,000/mm3). Given the limited findings in relation to the number of patients with events of thrombocytopenia of varying degrees, the presence of baseline positivity and of treatment-emergent conversion of placebo patients, it is concluded that antiplatelet antibodies are unlikely to play a significant role in platelet reductions in this patient population. • Testing of baseline cytokines in patients enrolled in CS6 revealed that several cytokines (MIP-1 beta, SDF-1, TWEAK, BAFF and IL23) were found to be mainly outside of the normal reference range and the baseline levels for all except BAFF correlated with change in platelet count. None of the cytokines evaluated had a sufficient positive or negative predictive value to serve as biomarkers for risk stratification purposes. However, there does seem to be a relationship between baseline level of these cytokines and change in platelet count. Further, these results could indicate that an underlying susceptibility to immune dysregulation is part of FCS. • Body weight was assessed for correlation with a number of PK and PD parameters. Correlations between body weight and exposure as indicated by steady-state AUC and Cmax existed, where exposure increased as body weight decreased. Correlations also existed between body weight and percent platelet count decrease, suggesting that patients with lower weights may have an increased overall risk of platelet reductions.
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In summary, although the results of the investigation to evaluate the potential causes of the observed platelet count changes have not revealed a single underlying cause and the etiology of the observed platelet reductions appears to be complex, platelet count can be readily monitored with standard hematological testing. The aggregate observed platelet count reductions are gradual enough to be detected and reversible and can therefore be effectively managed with monitoring and adjustment to the dose regimen and/or dose pause (see Section 10).
9.7.2.5 Platelet Data from Clinical Studies Support Initial Every Other Week Monitoring A quantitative summary of weekly platelet reduction rates comparing placebo and volanesorsen treated patients in CS6 is provided in Table 37. Average weekly reductions were calculated from Baseline to nadir for the first 13 weeks or from Week 13 to nadir for patients whose nadir platelet count occurred after 13 weeks. The patient with the maximum platelet decline dropped 27,600/mm3 per week. Assuming this as a worst case, platelet counts would decline no more than 55,200/mm3 in 2 weeks, so with every other week monitoring, a patient above 140,000/mm3 would be identified prior to requiring a dose adjustment. The final monitoring program implemented in CS6, which tested for platelet counts at an initial minimum of every 2 weeks, and the program proposed for post-approval, are supported by this analysis (Table 36).
Table 36: Study CS6 Algorithm and Proposed Algorithm for Platelet Monitoring/Dosing
Start of CS6 December 2014 CS6 Enhanced Program Proposed USPI Platelet (Original May 2016 Monitoring and Dose Monitoring Plan) (Enhancement 1) Adjustment Algorithm Frequency of Every approximately Every 2 weeks >140,000/mm3 Every 2 weeks > 100,000/mm3 Monitoring 6 weeks Weekly <140,000/mm3 Weekly >75-100,000/mm3 Every 2-3 days < 75,000/mm3 Twice per week 50-75,000/mm3 Daily < 50,000/ mm3 Dose Frequency None < 100,000/mm3 < 70 kg < 140,000/mm3 Reduction Threshold > 70 kg < 100,000/mm3 Dose Pause Threshold < 50,000/mm3 < 75,000/mm3 < 75,000/mm3 Permanently < 50,000/mm3 with < 25,000/mm3 < 25,000/mm3 Discontinue Study major bleeding < 50,000/mm3 if on 300 mg Drug every 2 weeks
After every other week monitoring was implemented for patients with platelet counts above the lower limit of normal, there were no further severe reductions in platelet count in Study CS6. In the OLE, CS7, platelet reductions were detected quickly and dose interruptions or every other week dose administration allowed most patients to remain on treatment. In Study CS7, 5 patients met the platelet stopping rules and treatment was discontinued as of the 31 August 2017 data cutoff for the 4-month safety update.
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Table 37: Summary of Average Weekly Reduction at Nadir in Platelet Count in Study CS6 (*k/mm3) - Safety Set
Baseline to Nadir Prior to Week 13 Week 13 to Nadir After Week 13 (All Patients)* (Patients with nadir occurred after 13 weeks)** Volanesorsen Volanesorsen Placebo Placebo Item 300 mg 300 mg N 33 32 28 27 Mean (SD, SEM) -0.4 (5.4, 0.9) -3.9 (7.0, 1.2) -2.4 (1.5, 0.3) -4.9 (7.0, 1.3) Median (Q1, Q3) -0.4 (-2.1, 2.0) -4.7 (-7.5, -2.3) -2.1 (-3.2, -1.7) -2.7 (-5.7, -1.3) Min - Max -17.2 - 8.2 -16.8 - 23.0 -6.3 - -0.0 -27.6 - -0.0 Data cutoff date 06 January 2017 * Baseline to Nadir Prior to Week 13 (All Patients): Average weekly reduction in platelet count is defined as: 1) change from baseline at nadir for patients with nadir that occurred before or on Week 13 and, 2) change from baseline on Week 13 for patients with nadir that occurred after Week 13. ** Week 13 to Nadir after Week 13 (Patients with nadir occurred after 13 weeks): Average weekly reduction in platelet count from Week 13 to nadir.
9.7.2.6 Bleeding Events There were no major bleeding events observed. No patients had platelet count reductions to < 50,000/mm3 that were associated with major or severe bleeding. • One patient with a platelet count reduction to < 50,000/mm3 had bleeding events of moderate and mild injection site hemorrhages. • Two patients with platelet counts < 25,000/mm3 experienced episodes of epistaxis that met the protocol-specified definition of clinically relevant non-major bleed; both events were assessed as mild and did not require specific treatment or intervention. Treatment-emergent bleeding adverse events occurring in more than 1 patient in CS6 or CS16 are summarized in Table 38. All actual bleeding events were mild in severity; none were reported as SAEs, and none led to treatment discontinuation.
Table 38: On-Treatment Bleeding Adverse Events Occurring in More than 1 Patient in CS6 or CS16
CS6 CS16 Volanesorsen Placebo Volanesorsen Placebo (N = 33) (N = 33) (N = 75) (N = 38) Preferred Term n (%) Events n (%) Events n (%) Events n (%) Events Patients with any Bleeding 16 (48.5) 44 4 (12.1) 5 21 (28.0) 68 6 (15.8) 7 Events Injection site bruising 5 (15.2) 15 0 0 11 (14.7) 37 1 (2.6) 2
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CS6 CS16 Volanesorsen Placebo Volanesorsen Placebo (N = 33) (N = 33) (N = 75) (N = 38) Preferred Term n (%) Events n (%) Events n (%) Events n (%) Events Injection site haemorrhage 1 (3.0) 1 0 0 7 (9.3) 10 0 0 Epistaxis 5 (15.2) 7 0 0 1 (1.3) 1 0 0 Petechiae 4 (12.1) 4 0 0 1 (1.3) 1 0 0 Injection site haematoma 2 (6.1) 4 0 0 2 (2.7) 3 1 (2.6) 1 Contusion 1 (3.0) 1 1 (3.0) 1 3 (4.0) 5 1 (2.6) 1 Haemoglobin decreased 1 (3.0) 1 2 (6.1) 2 1 (1.3) 1 0 0 Haemorrhage 1 (3.0) 1 0 0 2 (2.7) 3 0 0 Vaginal haemorrhage 1 (3.0) 1 0 0 0 0 0 0 Ecchymosis 0 0 0 0 2 (2.7) 3 0 0 Haematuria 0 0 0 0 1 (1.3) 1 0 0
9.7.3 Adverse Events at the Injection Site Adverse events at the injection were the most common AEs reported in patients treated with volanesorsen. An analysis of AEs at the injection site persisting for at least 2 days was done for CS6, CS7, and CS16. With the exception of 3 severe events in 1 patient in CS7, all were mild or moderate in severity. These events occurred in: • CS6: following 17% (194) of volanesorsen injections and at least once in 26 (79%) of 33 volanesorsen-treated patients and 0 of 33 placebo patients. The mean and median duration to resolution for these events were 43 and 8 days, respectively. • CS16: following 39% (514) of volanesorsen injections and at least once in 65 (87%) of 75 volanesorsen-treated patients and 3 (8%) of 38 placebo patients (total of 8 events). The mean and median duration to resolution of these events were 38 and 6 days respectively in the volanesorsen group and 6 days each in the placebo group. • CS7: following 18% (222) of volanesorsen injections and at least once in 41 (68%) of 60 volanesorsen-treated patients and had a mean and median duration to resolution of 59 and 7 days respectively The majority of AEs at the injection site were transient (< 2 days in duration) and were mild. Most AEs at the injection site were reported within the first 13 weeks of volanesorsen administration. In the target population of patients with FCS, there was a single discontinuation for injection site related AEs and, in patients with severe hypertriglyceridemia, there were 9 discontinuations for these events.
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In both CS6 and CS16, injection site erythema, injection site pain, injection site pruritus, and injection site discoloration were the most commonly reported injection site AEs (Table 39). Most of the injection site AEs were considered related to Study Drug. None were SAEs. Of the 7 volanesorsen-treated patients who experienced discoloration AEs in CS6, 5 remained unresolved at the end of the study.
Table 39: On-Treatment Adverse Events at the Injection Site Occurring in >10% of Volanesorsen Patients in CS6 or CS16
CS6 CS16 Volanesorsen Placebo Volanesorsen Placebo (N=33) (N=33) (N=75) (N=38) Preferred Term n (%) Events n (%) Events n (%) Events n (%) Events Injection site 25 (75.8) 235 (23.9) 1 (3.0) 1 (0.4) 61 (81.3) 459 (22.4) 2 (5.3) 2 (1.0) erythema Injection site pain 15 (45.5) 63 (6.4) 3 (9.1) 25 (11.0) 39 (52.0) 297 (14.5) 2 (5.3) 2 (1.0) Injection site 8 (24.2) 69 (7.0) 0 0 26 (34.7) 157 (7.7) 0 0 pruritus Injection site 7 (21.2) 22 (2.2) 0 0 23 (30.7) 84 (4.1) 0 0 discolouration Injection site 7 (21.2) 36 (3.7) 0 0 17 (22.7) 72 (3.5) 2 (5.3) 2 (1.0) induration Injection site 7 (21.2) 24 (2.4) 2 (6.1) 15 (6.6) 36 (48.0) 177 (8.7) 1 (2.6) 1 (0.5) swelling Injection site 5 (15.2) 15 (1.5) 0 0 11 (14.7) 37 (1.8) 1 (2.6) 2 (1.0) bruising Injection site 5 (15.2) 19 (1.9) 0 0 2 (2.7) 4 (0.2) 0 0 oedema Injection site 4 (12.1) 15 0 0 8 (10.7) 27 0 0 reaction Injection site 1 (3.0) 1 (0.1) 0 0 13 (17.3) 50 (2.4) 1 (2.6) 1 (0.5) discomfort Injection site rash 0 0 0 0 9 (12.0) 24 (1.2) 0 0 a Event percentage is calculated based on the total number of TEAEs for each treatment, which are 985, 227, 2045, and 194 for Volanesorsen CS6, Placebo CS6, Volanesorsen CS16, and Placebo CS16 respectively.
9.7.4 Antibody and Proinflammatory Events Immunogenicity of volanesorsen was evaluated in all Phase 2 and 3 studies by a series of validated screening, confirmation, and titration assays. Antibodies to volanesorsen were formed in 30% of the patients with FCS treated with volanesorsen in CS6 and the immunogenicity was characterized by a median onset of 6 months and low antibody titers (median peak titer 400).
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Overall, there have been no consistent trends between duration of volanesorsen exposure or dose level and immunogenicity incidence observed in Phase 2 and 3 studies. In addition, the development of anti-drug antibodies does not appear to be associated with additional safety risks or change in treatment benefits. The median onset of immunogenicity was generally 6 months post initiation of treatment in all populations and the anti-drug antibody response was sustained in the vast majority of patients. As noted in Section 6.2, even though the presence of anti-drug antibodies increased the Ctrough of volanesorsen in plasma, development of anti-drug antibodies was not associated with loss of efficacy or increase in safety findings. The most commonly reported AEs for volanesorsen in both antibody-positive and antibody- negative patients were events related to local tolerability. The incidence of AEs including local tolerability events and drug discontinuations were similar in antibody-positive and antibody- negative patients. There were no notable differences in the levels of platelet count, ALT, aspartate aminotransferase (AST), creatinine clearance, high sensitivity C-reactive protein, complement C5a, and complement Bb between antibody-positive patients and antibody-negative patients. There was no increased incidence of platelet count reductions or ALT or AST elevations above 3 × ULN in the antibody-positive patients. As of the 31 August 2017 data cutoff for the 4 month Safety Update, all 8 thrombocytopenia events of platelet count reductions to < 50,000/mm3, including the 2 patients with platelet counts < 25,000/mm3, had negative anti- drug antibody responses, with the exception of 1 patient with platelet count reduction to < 50,000/mm3 in Study CS6 who became anti-drug antibody-positive with onset ~200 days after the platelet nadir. A case of severe thrombocytopenia received post Safety Update cutoff was also negative for anti-drug antibodies. Notable also is non detection of volanesorsen anti-drug antibodies in the 2 case reports of serum sickness and serum sickness-like reaction which occurred in patients with non-FCS hypertriglyceridemia. The risk-benefit in patients with positive anti-volanesorsen antibodies appears consistent with the risk-benefit in the full patient population.
9.7.5 Anaphylactic Events One patient with FPL in CS17 experienced a SAE of anaphylactic reaction that resulted in permanent discontinuation of study drug. Approximately 4 months into the OLE phase of CS17, this patient began experiencing mild to moderate nausea, vomiting and muscle aches within approximately 12 hours of each injection of study drug. Study drug was paused on 3 occasions due to these symptoms. The patient had received 3 doses within approximately 3 months prior to the dose proceeding the event of the anaphylactic reaction. On Study Day 593 (Day 220 of the OLE), within 5 minutes of study drug administration, the patient began experiencing shortness of breath, diaphoresis, and nausea followed by profound somnolence. The patient’s vital signs were notable for tachycardia, tachypnea, and hypotension, and the patient was assessed as having an anaphylactic reaction. The patient was treated with epinephrine, methylprednisolone, famotidine, diphenhydramine, and IV solution, as well as prochlorperazine and prednisone. The event was considered resolved the day after onset and was assessed as related to volanesorsen. On Study Day 614 the patient was seen by an allergist who noted the patient had never experienced
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anaphylaxis prior to the event. The allergist was not able to discover an IgE mediated mechanism on skin testing. The patient permanently discontinued study drug due to the SAE of anaphylactic reaction with the last dose administered on Study Day 593. The patient received a total of 77 doses of study drug, 51 of which were blinded, prior to discontinuation. 9.8 Safety in Special Populations 9.8.1 Gender, Age, Race, and Ethnicity Analysis of AEs by gender, age, race, and ethnicity did not reveal and safety signals specific to these subpopulations.
9.8.2 Body Weight A statistically significant but moderate inverse correlation between platelet count percent decrease and body weight was observed in CS6 and CS16 (p < 0.0001; Figure 13), suggesting that patients with lower weights may have an increased risk of platelet reductions. Patients with higher body weights (≥ 70 kg) were less likely to experience reductions in platelet count and therefore more likely to continue volanesorsen at 300 mg weekly, while patients with lower body weight ( < 70 kg) were more likely to require dose pause or dose reduction to 300 mg every 2 weeks due to platelet reductions. This suggests that body weight can be considered an important variable for dose adjustment, as further discussed below.
Figure 13: Correlation Between Maximum Percent Reduction in Platelets During the On-Treatment Period Versus Baseline Weight (CS6 and CS16, N = 105)
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9.8.3 Patients with FCS An analysis of AEs by for patients with FCS and patients without FCS in CS6, CS16, CS2, and CS4 combined is summarized in Table 40. In CS6, all 66 patients (33 in each treatment group) had FCS. In CS16, 7 (5 volanesorsen and 2 placebo) patients had FCS and in the CS2 300 mg open label cohort, 3 FCS patients were treated with volanesorsen. Across the 3 studies, 79% of the patients with FCS completed treatment. Treatment duration was 52 weeks in CS6, 26 weeks in CS16, and 13 weeks in CS2. When all patients with FCS were analyzed (N = 76), the safety profile was comparable to that observed in CS6 (N = 66). Overall, patients with FCS who were treated with volanesorsen experienced a higher proportion of platelet count decreases and a higher proportion of SAEs compared to patients without FCS. There were no differences in the proportion of treatment discontinuations or bleeding events between patients with FCS and those without, however, patients without FCS experienced a higher proportion of discontinuations due to AEs at the injection site compared to patients with FCS. The proportion of patients with at least 1 AE was similar between the patients with and without FCS in the volanesorsen group (97% and 99% respectively) and the placebo group (90% and 92%, respectively). The proportion of patients with FCS who experienced bleeding events was higher compared with patients without FCS in the volanesorsen group, but the incidence was similar in patients with and without FCS in the placebo group. In both the volanesorsen and placebo groups, patients with FCS experienced a lower proportion of AEs at the injection site than patients without FCS. There was a higher incidence of SAEs in patients with FCS compared with patients without FCS in both the volanesorsen and placebo groups. The proportion of patients with AEs leading to treatment discontinuation was similar between the groups of patients with and without FCS in both treatment groups. Among patients with FCS treated with volanesorsen in Studies CS2, CS4, CS6, and CS16, 2 SAEs of thrombocytopenia were reported in patients with FCS; there were no corresponding events in placebo-treated patients. In these same studies, on-treatment SAEs of acute pancreatitis were reported in 1 patient with FCS treated with volanesorsen, while 4 events of pancreatitis were reported among FCS patients receiving placebo. For non-FCS patients, the corresponding incidence of events of pancreatitis was 2 on placebo and none among patients receiving volanesorsen.
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Table 40: Overall Summary of Adverse Events by FCS Diagnosis in CS6, CS16, CS2, and CS4 FCS Not FCS Pooled Volanesorsena Pooled Placeboa Pooled Volanesorsena Pooled Placeboa (N = 41) (N = 35) (N = 105) (N = 65) Patients with n (%) Events n (%) Events n (%) Events n (%) Events Number of Patients and Number of On-Study AEs 41 (100) 1210 35 (100) 237 105 (100) 2798 65 (100) 358 Any On-Study AEb 40 (97.2) 1210 32 (90.4) 237 104 (99.1) 2798 60 (92.0) 358 Any On-Study AE by Severity Mild 9 (25.1) 916 15 (41.8) 187 32 (30.6) 2515 23 (36.4) 269 Moderate 24 (56.6) 286 13 (36.3) 42 59 (57.0) 268 33 (49.3) 81 Severe 7 (15.5) 8 4 (12.4) 8 13 (11.6) 15 4 (6.3) 8 Any On-Study AE Related to Study Drugc 38 (92.8) 985 12 (33.5) 51 102 (97.4) 2319 33 (48.5) 100 Any On-Study AE Related to Study Drug by Severityc Mild 17 (46.2) 758 10 (27.9) 48 58 (54.1) 2160 26 (37.9) 92 Moderate 17 (35.5) 223 2 (5.6) 3 42 (41.5) 157 7 (10.6) 8 Severe 4 (11.2) 4 0 0 2 (1.7) 2 0 0 Any On-Study AE Leading to Permanent Treatment 9 (25.1) 18 0 0 17 (15.4) 48 2 (3.4) 3 Discontinuation Any On-Study AE Leading to Permanent Treatment 9 (25.1) 18 0 0 16 (14.6) 47 1 (1.7) 2 Discontinuation Potentially Related to Study Drugc Any On-Study SAE 8 (19.5) 9 6 (17.9) 9 10 (9.0) 15 3 (5.0) 7 Any On-Study SAE Related to Study Drugc 2 (5.6) 2 0 0 1 (0.9) 1 0 0 Any On-Study AE Leading to Death 0 0 0 0 0 0 0 0 Any Life-Threatening AEs 0 0 1 (2.8) 1 0 0 0 0 Any AE at the Injection Site 34 (81.7) 779 5 (13.9) 42 100 (95.7) 2083 22 (32.0) 56 Any Bleeding AEs 19 (46.2) 52 5 (15.1) 6 39 (37.3) 107 11 (17.0) 12 Note: Data are through the 06 January 2017 data cutoff for the NDA. a Pooled proportion was adjusted by study using the Cochran-Mantel-Haenszel approach. b An on-study AE was defined as any AE occurred from the first dose of the Study Drug through the end of study. c Related was defined as 'related', 'possible', or missing relationship to Study Drug.
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9.9 Long-Term Safety, Study CS7 9.9.1 Exposure At the time of the data cutoff for the 4-month Safety Update (31 August 2017), a total of 60 patients had been enrolled and treated in the OLE CS7, including 43 treatment-naïve (those who received placebo in Studies CS6 or CS16 and new patients who were not previously enrolled in a clinical trial of volanesorsen), 14 patients who received volanesorsen in CS6, and 3 patients who received volanesorsen in CS16. Of these patients, 48 (80%) remained on treatment, including 36 (84%) patients in the treatment-naïve group, 9 (64%) in the CS6-volanesorsen group, and 3 (100%) in the CS16-volanesorsen group. Twelve patients have discontinued from study treatment prematurely; 8 discontinued due to AE or SAE and 4 discontinued due to voluntary withdrawal. Seven patients who discontinued early were from the treatment-naïve group and 5 were from the CS6-volanesorsen group. The median treatment duration was 162 days in the treatment-naïve group, 257 days in the CS6 volanesorsen group, and 51 days in the CS16 volanesorsen group. For patients who received volanesorsen in either index study (N = 17), the median total treatment duration was 625 days (646 days in the CS6-volanesorsen group and 483 days in the CS16 volanesorsen group). A total of 34 (57%) patients had study medication dose interruptions and/or dose pauses, including 26 (61%) treatment-naïve patients, 7 (50%) CS6-volanesorsen patients, and 1 (33%) CS16-volanesorsen patient. Most dose interruptions/pauses were due to lab values (37%) or AEs (20%). A summary of exposure during the index study and the ongoing OLE as of the 31 August 2017 4-month safety cutoff is provided in Table 41 for the treatment-naïve and CS6-volanesorsen groups.
Table 41: Study Drug Exposure During Index Study and Ongoing Open-Label Study for Treatment-Naïve and CS6-Volanesorsen Patients – CS7 Safety Set as of 31 August 2017 Treatment-Naïve CS6-Volanesorsen Overall (N=43) (N=14) (N=57) Disposition n (%) n (%) n (%) Number of Injections of Study Medication - n (%) ≥ 1 dose 43 (100) 14 (100) 57 (100) Treatment Duration (Months) - n (%) ≥ 3 Months 35 (81.4) 14 (100) 49 (86.0) ≥ 6 Months 20 (46.5) 14 (100) 34 (59.6) ≥ 9 Months 12 (27.9) 14 (100) 26 (45.6) ≥ 12 Months 6 (14.0) 14 (100) 20 (35.1) ≥ 18 Months 1 (2.3) 10 (71.4) 11 (19.3) ≥ 24 Months 0 5 (35.7) 5 (8.8)
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9.9.2 On-Treatment Adverse Events Overall, 56 (93%) of 60 patients experienced an AE during CS7, including 40 (93%) patients in the treatment-naïve group, 14 (100%) patients in the CS6-volanesorsen group, and 2 (67%) patients in the CS16-volanesorsen group. The majority of AEs were mild in severity. The most common AEs were events related to local tolerability (see Section 9.7.3). Nine (15%) patients experienced at least 1 AE of discoloration at the injection site and in 8 of these patients the events were not resolved. The most common AEs not related to injection site events are summarized in Table 42.
Table 42: On-Treatment Adverse Events (Excluding Injection Site Events) Occurring in ≥ 10% Patients Overall – Study CS7 Safety Set as of 31 August 2017 Treatment-Naïve CS6-Volanesorsen CS16-Volanesorsen Overall (N = 43) (N = 14) (N = 3) (N = 60) Preferred Terma n (%) n (%) n (%) n (%) At least 1 AE 40 (93.0) 14 (100) 2 (66.7) 56 (93.3) AEs in ≥ 10% Patients Platelet reductions Platelet count decreased 7 (16.3) 2 (14.3) 0 9 (15.0) Thrombocytopenia 5 (11.6) 1 (7.1) 0 6 (10.0) Nasopharyngitis 9 (20.9) 2 (14.3) 0 11 (18.3) Abdominal pain 6 (14.0) 4 (28.6) 0 10 (16.7) Nausea 6 (14.0) 4 (28.6) 0 10 (16.7) Arthralgia 6 (14.0) 1 (7.1) 0 7 (11.7) Fatigue 4 (9.3) 3 (21.4) 0 7 (11.7) Headache 4 (9.3) 3 (21.4) 0 7 (11.7) Diarrhoea 4 (9.3) 1 (7.1) 1 (33.3) 6 (10.0) Dizziness 4 (9.3) 2 (14.3) 0 6 (10.0) Pyrexia 4 (9.3) 2 (14.3) 0 6 (10.0) Urinary tract infection 3 (7.0) 3 (21.4) 0 6 (10.0)
A total of 5 SAEs were reported in 4 (7%) patients, including 2 (5%) in the treatment-naïve group, 1 (7%) in the CS6-volanesorsen group, and 1 (33%) in the CS16-volanesorsen group. SAEs included single reports of thrombocytopenia, diverticulitis, urinary tract infection, clavicle fracture, and myalgia. Only the event of thrombocytopenia was considered related to volanesorsen by the Investigator. SAEs reported after the 31 August 2017 data cutoff are summarized in Section 13.3. Eight (13%) patients have discontinued treatment with volanesorsen due to an AE; these included 4 (9%) patients in the treatment-naïve group and 4 (29%) patients in the
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CS6-volanesorsen group. Adverse events leading to discontinuation included thrombocytopenia (5 patients, 8%), myalgia (2 patients, 3%), and chills, fatigue, vision blurred, abdominal pain, diarrhea, nausea, vomiting, contusion, and headache in 1 patient each (2%). There were no treatment-emergent adjudication-confirmed pancreatitis events or MACE during CS7 as of the data cutoff date of the 4-month Safety Update (31 August 2017). However, 2 patients subsequently experienced SAEs that were adjudicated as acute pancreatitis on- treatment and late post-treatment, respectively. A total of 3 patients had a platelet decline to < 50,000/mm3 and 1 of these 3 patients had a decline to < 25,000/mm3. Platelet count decreased AEs were reported in 9 (15%) patients overall and thrombocytopenia was reported in 6 (10%) patients overall. One patient experienced an SAE of thrombocytopenia and 2 patients experienced severe AEs of thrombocytopenia, as assessed by the Investigator. Among the 58 volanesorsen-treated patients with baseline platelet counts ≥ 140,000/mm3: • 45 (78%) patients had shifts to values below 140,000/mm3 at any time during the on- treatment period • 42 (72%) patients had 2 or more consecutive occurrences of platelet count < 140,000/mm3 • 19 (33%) patients had 2 or more consecutive occurrences of platelet count < 100,000/mm3 • 32 (55%) patients had platelet counts < 140,000/mm3 at the final visit • 7 (12%) had values < 100,000/mm3 at the final visit During CS7, 26 (43%) patients experienced treatment-emergent bleeding events, mostly reported as bleeding at the injection site; the incidence of bleeding events was balanced between treatment-naïve patients and CS6-volanesorsen patients (Table 43). All bleeding AEs were mild (21 patients) or moderate (5 patients). A total of 15 patients were taking concomitant anti- coagulant or anti-platelet medications during CS7; the incidence of bleeding events was comparable for patients on anti-coagulant or anti-platelet medications (47%) and those who were not taking these medications (42%).
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Table 43: Treatment-Emergent Bleeding Adverse Events occurring in More than 1 Patient in CS7 – Safety Set as of 31 August 2017
Bleeding Event Treatment-Naïve CS6-Volanesorsen Preferred Term (N=43) (N=14) n (%) Events n (%) Events Patients with any Bleeding TEAE 20 (46.5) 32 (4.4) 6 (42.9) 13 (3.5) Ecchymosis 4 (9.3) 5 (0.7) 1 (7.1) 1 (0.3) Haematoma 3 (7.0) 3 (0.4) 0 0 Injection site haematoma 3 (7.0) 3 (0.4) 1 (7.1) 2 (0.5) Epistaxis 2 (4.7) 2 (0.3) 2 (14.3) 2 (0.5) Injection site bruising 2 (4.7) 2 (0.3) 1 (7.1) 1 (0.3) Injection site haemorrhage 2 (4.7) 2 (0.3) 1 (7.1) 4 (1.1) Haematuria 2 (4.7) 2 (0.3) 0 0 Contusion 2 (4.7) 2 (0.3) 0 0 Haemoglobin decreased 1 (2.3) 2 (0.3) 1 (7.1) 1 (0.3) No new safety concerns with regard to clinical laboratory, vital signs, or ECG parameters have been identified during CS7. 9.10 Other Safety Assessments Overall, other than decreases in platelet counts as described in Section 9.7.2, there were no clinically relevant changes in laboratory parameters (i.e., chemistry, hematology, coagulation, complement, and urinalysis) in volanesorsen-treated patients during the Phase 2 and 3 studies of volanesorsen. There is no evident association between volanesorsen treatment and changes in renal or liver functions. There were also no clinically relevant changes in vital signs or ECG parameters in volanesorsen- treated patients. Additionally, a thorough QTc study (CS13) performed in healthy volunteers showed that treatment with volanesorsen at therapeutic (300 mg SC) and supra-therapeutic (300 mg IV) doses did not prolong QTc to a clinically significant degree nor did it affect other ECG parameters including heart rate, PR, or QRS intervals.
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- The need to counsel patients about the risks of thrombocytopenia and bleeding, and the need for routine platelet monitoring. • Ensuring that patients are informed about: - The risks of platelet reduction and thrombocytopenia, and the signs and symptoms of bleeding
- The need to monitor platelets during treatment. • Enrollment of all patients in a mandatory registry to further support long-term safety and safe use of volanesorsen The volanesorsen REMS includes the following ETASU: 1. Healthcare providers who prescribe volanesorsen must be specially certified. 2. Pharmacies that dispense volanesorsen must be specially certified. 3. Volanesorsen may only be dispensed to patients with evidence or other documentation of safe-use conditions. 4. Patients receiving volanesorsen are subject to monitoring and must be enrolled in a REMS registry. Prescribers: • Healthcare providers who prescribe volanesorsen will be specifically certified and will be trained and ernooed in the REMS program. • Healthcare providers will review the Prescribing Information, REMS Program Prescriber Training module, REMS Program Letter for Healthcare Providers and successfully complete the Knowledge Assessment before certification in the REMS program. • Healthcare providers must assess patients’ platelet counts at baseline and must enroll patients in the REMS before initiating treatment with volanesorsen. Throughout treatment, healthcare providers must assess patients’ platelet counts at least every 2 weeks, and must complete and submit a Patient Status Form to the REMS program every 90 days in order for patients to be able to continue to receive volanesorsen. Pharmacies: • Only certified pharmacies in the REMS program will be able to dispense volanesorsen prescriptions and must verify prescriptions are from certified prescribers for authorized (enrolled) patients prior to each dispense. • Can only dispense a 1 month supply of volanesorsen. • An authorized representative in each pharmacy will undergo the certification process and oversee training of all pharmacy staff involved in dispensing volanesorsen and implementation and compliance with the REMS Program on behalf of the pharmacy.
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Patients: • Patients must be enrolled in the REMS program in order to be able to receive volanesorsen treatment. • All patients will undergo counselling by a certified prescriber on the risks of thrombocytopenia and bleeding, and the need for routine platelet monitoring, using the Medication Guide. Patients will be provided with a Patient Wallet Card and should carry it with them at all times while receiving volanesorsen. Patients will be instructed to seek medical attention immediately if they experience any signs of bleeding, which can include nose bleeds, bleeding gums, petechiae, spontaneous bruising, subconjunctival bleeding, or other unusual bleeding, neck stiffness, atypical severe headache, or any prolonged bleeding. Patients must acknowledge and agree to get blood samples taken at least every 2 weeks to assess their platelet count. The Sponsor will ensure all educational materials are available for prescriber and pharmacy training including the volanesorsen REMS website with links to all REMS materials. The REMS implementation system will be closely monitored (operations oversight) by the Sponsor for compliance with REMS requirements with prompt governance for any incidents requiring corrective or preventive measures. Assessment of the REMS program will be provided annually to the FDA and will address prescriber knowledge/understanding of REMS requirements, effectiveness of the REMS implementation system and incidence of severe thrombocytopenia and serious bleeding events. Although the REMS with ETASU is a comprehensive program with elements to mitigate failure from human and system factors, it is not designed to address issues such as patient access to platelet testing and support to patients in scheduling tests with reminders and alerts. A Patient Support Program has a significant role in helping patients adhere with requirements of their treatment such as platelet monitoring and providing ongoing education on how to detect bleeding events requiring them to seek immediate medical attention. • Patient Support Program (PSP) A comprehensive patient support program will be implemented for prescribing health care providers and patients. The purpose of the patient support program is to ensure patient safety by maximizing compliance with platelet monitoring and dose adjustments as recommended in prescribing information. The cornerstone of this patient support program is dedicated, nurse case managers assigned to every patient and regionally based throughout the US. The nurse case managers will be the conduit to ensure delivery of supplemental patient education, compliance and adherence tools in addition to the labeling and REMS requirements. In addition, the patient support program will prioritize and ensure platelet monitoring and associated blood draws are as convenient as possible to maximize compliance, through the use of mobile phlebotomy services and laboratory partnerships, facilitated scheduling and active reminders. Lastly the patient support program will employ a tiered alert system based on pre-specified platelet thresholds per the product labeling, with the potential to escalate to a peer-to-peer healthcare provider-to-
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healthcare provider contact in the event of significant platelet drops or under-responsiveness by the prescribing clinician. The prescribing information, REMS with ETASU and patient support program represent risk minimization activities. A comprehensive risk management program also includes risk assessment activities to closely and accurately monitor process and/or outcome measures and assess effectiveness of risk minimization activities. Feedback with preventive/corrective action is provided to enhance risk minimization activities in situations of potential or overt failure and thereby continue to mitigate targeted risks with achievement of stated goals (quality system). The comprehensive and integrated risk mitigation program for the risk of serious bleeding due to severe thrombocytopenia associated with volanesorsen, includes an enhanced pharmacovigilance plan and a global product registry as risk assessment activities. • Enhanced Pharmacovigilance Plan: Active follow-up of thrombocytopenia events will be undertaken to ensure accurate documentation and efficient communication of new adverse event information. A targeted thrombocytopenia questionnaire will be implemented for follow-up of all case reports of thrombocytopenia or platelet count declines. Thrombocytopenia events will be reviewed on an ongoing basis for incidence, severity and risk factor patterns as well as on a monthly basis during signal detection meetings (aggregate data review). Comprehensive evaluations will be undertaken and communicated to the FDA in expedited and periodic reports (PADER).
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11. BENEFIT RISK ANALYSIS Familial chylomicronemia syndrome is a rare, serious metabolic disease and there are currently no effective medical therapies for the patients with FCS. Patients with FCS have a complex of daily and recurrent symptoms as a consequence of chylomicronemia/hypertriglyceridemia that result in significant adjustments to their personal and working lives. The most severe complication of FCS is a high risk of a severe form of pancreatitis, which can be life-threatening. Treatment with volanesorsen demonstrated significant efficacy for reduction of plasma triglyceride levels and also provided early indication of possible impact on reduction of events of acute pancreatitis. Through its novel apoC-III lowering mechanism of action, volanesorsen showed consistent reduction in circulating triglycerides. In patients with FCS with baseline triglyceride levels in the thousands, volanesorsen treatment resulted in triglyceride reductions ranging from a mean of 69% to 77% across 3 separate studies – the largest collection of clinical data in FCS. After 3 months of treatment with volanesorsen in the pivotal Phase 3 study in patients with FCS, the average triglyceride level was reduced by 77% from baseline to 590 mg/dL, and 77% of patients achieved triglyceride levels below those associated with a high risk of pancreatitis (< 750 mg/dL). Significant reductions in triglycerides persisted through Month 6 and 12 and continued with long-term treatment in the open-label extension study, CS7. Exploratory analyses suggested a potential beneficial effect of volanesorsen on frequency of events of pancreatitis, with 1 adjudication-confirmed acute pancreatitis event in the volanesorsen group during CS6 compared with 4 events in the placebo group and no events in volanesorsen- treated patients in CS16 compared with 5 in the placebo group. (Among the 7 FCS patients in CS16, 2 adjudication-confirmed acute pancreatitis event were reported in 1 placebo patient.) The primary safety findings from the clinical development program for volanesorsen were treatment-related reduction in platelet count and local injection site reactions. Injection site reactions were generally transient and mild. Thrombocytopenia was identified as an important risk associated with volanesorsen. The risk of thrombocytopenia was well-managed in clinical trials once frequent monitoring and prespecified dose adjustments were introduced. No major or serious bleeding events occurred in any patient. When the platelet monitoring and dose adjustment program was initiated and followed, declines in platelet counts were detected promptly, and fewer severe declines occurred than before monitoring was implemented. A similar program of close platelet monitoring and dosing adjustments will be part of risk mitigation for the FCS patient population in the commercial setting. The primary benefit of volanesorsen treatment is triglyceride reduction that is sufficient to predict decreases in the most severe morbidity and mortality associated with FCS. The primary risk associated with volanesorsen is thrombocytopenia. A platelet monitoring and volanesorsen dose adjustment plan, through dosing frequency adjustment, developed during
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clinical studies was shown to be effective for mitigating the risk of clinically meaningful thrombocytopenia Volanesorsen represents the first, and currently only, opportunity for FCS patients to reduce morbidity and mortality associated with chylomicronemia/hypertriglyceridemia. This potential benefit outweighs the potential risk of thrombocytopenia, which was shown to be manageable with appropriate monitoring. No other options offer clinically meaningful triglyceride reduction to patient with FCS. Hence, the manageable risks associated with volanesorsen treatment are overshadowed by the potential reductions in life-threatening complications of chylomicronemia. A comprehensive and tightly controlled risk mitigation proposal will be implemented to ensure that these potential benefits of profound triglyceride reduction outweigh risks for this rare, underserved population.
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Graham MJ, Crooke ST, Lemonidis KM, et al. Hepatic distribution of a phosphorothioate oligodeoxynucleotide within rodents following intravenous administration. Biochemical Pharmacology 2001; 62: 297-306.
Graham MJ, Crooke ST, Monteith DK, et al. In vivo distribution and metabolism of a phosphorothioate oligonucleotide within rat liver after intravenous administration. Journal of Pharmacology and Experimental Therapeutics 1998; 286(1): 447-458.
Greinacher A. CLINICAL PRACTICE. Heparin-Induced Thrombocytopenia. N Engl J Med 2015; 373(3): 252-261.
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Henry SP, Jagels MA, Hugli TE, et al. Mechanism of alternative complement pathway dysregulation by a phosphorothioate oligonucleotide in monkey and human serum. Nucleic Acid Ther 2014; 24(5): 326-335.
Henry SP, Johnson M, Zanardi TA, et al. Renal uptake and tolerability of a 2'-O-methoxyethyl modified antisense oligonucleotide (ISIS 113715) in monkey. Toxicology 2012; 301(1-3): 13-20.
Henry SP, Kim T-W, Kramer-Stickland K, et al. Toxicologic Properties of 2' - O-Methoxyethyl Chimeric Antisense Inhibitors in Animals and Man. In: Antisense Drug Technology, Principles, strategies and applications. S. T. Crooke. Boca Raton, FL, Taylor & Francis Group. 2007; 2: 327-364.
Henry SP, Monteith D, Kornbrust DJ, et al. Effects of Intravenous infusion of phosphorothioate oligonucleotides on coagulation, complement activation and hemodynamics. Nucleosides & Nucleotides 1997; 16(7-9): 1673-1676.
Henry SP, Narayanan P, Shen L, et al. Assessment of the Effects of 2'-Methoxyethyl Antisense Oligonucleotides on Platelet Count in Cynomolgus Nonhuman Primates. Nucleic Acid Ther 2017.
Henry SP, Stecker K, Brooks D, et al. Chemically modified oligonucleotides exhibit decreased immune stimulation in mice. Journal of Pharmacology and Experimental Therapeutics 2000; 292(2): 468-479.
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Krieg AM. Immune stimulation by oligonucleotides. In: Antisense Research and Applications. S. T. Crooke. Berlin, Springer-Verlag. 1998; 131: 243-262.
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Levin AL and Henry SP. Toxicology of Oligonucleotide Therapeutics and Understanding the Relevance of the Toxicities. In: Preclinical Safety Evaluation of Biopharmaceuticals: A Science- Based Approach to Facilitating Clinical Trials. J. A. Cavagnaro. Hoboken, NJ, John Wiley & Son. 2008.
Li Z, Hard ML, Grundy JS, et al. Lack of clinical pharmacodynamic and pharmacokinetic drug- drug interactions between warfarin and the antisense oligonucleotide mipomersen. J Cardiovasc Pharmacol 2014; 64(2): 164-171.
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13. APPENDICES 13.1 Nonclinical Summary 13.1.1 Nonclinical Pharmacology Volanesorsen was evaluated in vitro in human and monkey primary hepatocytes, human HepG2 hepatoma cells, APOC3 transgenic mouse primary hepatocytes and mice containing the human APOC3 transgene. The pharmacology of inhibiting apoC-III with species-specific ASOs was also examined in mice, rats, hamsters and monkeys.
Figure 14: Volanesorsen is an Antisense Oligonucleotide against ApoC-III
ApoC-III antisense inhibition reduced hepatic apoC-III mRNA and protein and serum apoC-III protein levels with concomitant suppression of fasting triglycerides and VLDL cholesterol (VLDL-C) in a dose-, drug-, concentration- and time-dependent manner in both normal mice and transgenic mice expressing human APOC3. Decreases in plasma apoC-III correlated with decreases in plasma triglycerides. In addition, treatment increased HDL cholesterol (HDL-C) levels and HDL functionality in cholesteryl ester transfer protein (CETP) transgenic Ldlr -/- mice, potentially through enhanced reverse cholesterol transport. This led to reductions in CETP mRNA, protein and enzymatic activity. Paraoxonase I (PON1) activity, a measure of HDL anti- oxidant capacity, also increased. Treatment produced dose and time-dependent reductions of hepatic apoC-III mRNA, plasma apoC-III protein, triglycerides, VLDL and chylomicron triglyceride levels and increased HDL-C levels in hypertriglyceridemic rhesus monkeys. Other studies indicated that, in addition to inhibiting LpL activity, apoC-III inhibited turnover of triglyceride-rich lipoproteins through an hepatic clearance mechanism mediated by the low density lipoprotein receptor related protein 1 (LRP1) axis (Gordts et al. 2016), thereby explaining the activity observed in patients with FCS lacking LpL activity (Gaudet et al. 2015). Importantly, hepatic steatosis was not observed in mice or monkeys after significant reductions in apoC-III mRNA, protein and serum apoC-III protein levels.
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In single-dose safety pharmacology studies designed to evaluate functional effects on cardiovascular, respiratory or central nervous system functions, no adverse effects were seen in any of these organ systems at doses that were > 5- to10-fold the human equivalent dose.
13.1.2 Nonclinical Pharmacokinetic Studies The bioanalytical methods used were of sufficient sensitivity and specificity to complete a thorough assessment of the absorption, distribution, metabolism, and elimination of volanesorsen. In addition to plasma and urine, extensive characterization of tissue exposure and half-life was made to support the pharmacodynamic assessment of reducing apoC-III mRNA in liver and the half-life to support the effective clinical dose and dose frequency. Plasma and tissue PK were assessed in mice, rats and monkeys as part of the nonclinical toxicology studies. Similar to other 2’-MOE ASOs, volanesorsen was rapidly cleared from plasma and extensively distributed to tissues within hours after SC administration. The absorption of a given dose after SC administration in monkeys was nearly complete. Plasma exposure was dose-dependent and accumulation after multiple doses based on area under the curve (AUC) and maximum plasma concentration (Cmax) was minimal. Plasma trough concentrations showed an accumulation consistent with tissue accumulation. Volanesorsen distributed extensively to kidney and liver in mice, rats, and monkeys. In the monkey, the more relevant model for PK prediction to humans, tissue terminal elimination half-lives ranged from approximately 12.5 to 18.9 days in kidney and liver, respectively, consistent with the plasma terminal elimination half-life (12.7 days). Volanesorsen is metabolized initially by endonuclease-mediated hydrolysis at various positions within the central gap of the parent compound, followed by subsequent exonuclease (3′ and 5′)- mediated hydrolysis of the deoxynucleoside-ends of the formed hemimers. There was an immunogenicity response to volanesorsen in monkeys but not in mice. The anti- drug antibodies were observed starting around 3 months of weekly treatment and were generally present at a low titer. Other than an increase in post-distribution plasma concentrations of volanesorsen, there were no associated alterations in plasm AUC, Cmax, tissue concentration, apoC-III reduction or safety parameters. The plasma exposure in the toxicology studies was dose-dependent and exceeded clinically relevant exposure. In vitro studies have shown that volanesorsen at concentrations up to 100 µM does not induce CYP1A2, CYP2B6, and CYP3A4 or inhibit major cytochrome P450 isoforms. Volanesorsen is also not a substrate or inhibitor of major drug transporters at concentrations of 10 µM and 100 µM (approximately 3 to 30-times higher than human Cmax), respectively. Thus, volanesorsen has a very low potential for involvement in CYP- or transporter-mediated drug- drug interactions. As such, dedicated drug interaction studies with substrates, inhibitors, or inducers of these enzymes and transporters are not appropriate. In summary, the PK studies established a consistent pattern of distribution and uptake volanesorsen into the liver needed for pharmacology and established correlations with plasma PK parameters.
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13.1.3 Toxicology An appropriate series of in vitro and in vivo nonclinical studies were conducted with volanesorsen in order to characterize the toxicity profile of the molecule. The doses for each of the toxicology studies ranged from 3 to 100 mg/kg/wk SC in mice and 3 to 40 mg/kg/wk SC in monkeys and were selected to provide substantial challenge to the test animals (1 to >10-times the human equivalent AUC exposure). Low doses produced approximately clinically relevant levels of exposure and provided no-observed-effect and/or no-observed-adverse-effect levels (NOEL, NOAEL). Adequate margins of drug exposure were achieved in each study to facilitate an adequate risk assessment. There were no adverse effects in reproductive and developmental toxicity studies and volanesorsen was not genotoxic. Volanesorsen also did not alter immune function. In mouse and monkey general toxicity studies, >90% reduction of hepatic apoC-III mRNA was achieved. Reduction of apoC-III for up to 39 weeks of treatment was not associated with any findings that could be considered related to the intended pharmacologic activity. The spectrum of changes described below in the repeat-dose toxicology studies were generally of the expected class effects for 2′-MOE ASOs (Henry et al. 2007). Treatment-related effects observed in these studies were most often mild to moderate in severity and observed at the higher dose levels examined (i.e., ≥25 mg/kg/wk in mice and ≥6 mg/kg/wk in monkeys; Table 44).
13.1.3.1 Renal Effects Following SC administration of volanesorsen, the highest concentration of oligonucleotide is present in the kidney in both monkeys and rodents. Distribution within the kidney is primarily to the proximal tubular epithelium. Renal distribution is a common property of 2′-MOE ASOs as the primary excretion pathway is via the kidney so the implications of renal tolerability have been studied closely for volanesorsen and other related 2′-MOE ASOs. The histologic effects related to kidney uptake of volanesorsen were dose-dependent, and kidney was considered a target organ for distribution in all species. In mice and monkeys there appeared to be little functional consequence related to the accumulation of oligonucleotide in the tubular epithelium (Henry et al. 2012). Histologic changes included basophilic granules and cytoplasmic vacuolatation in proximal tubular epithelium, but generally no associated changes in serum or urine measures of renal function. Basophilic granules (hematoxylin stained ASO) reflect the uptake of 2′-MOE ASO into cells and concentrated into lysosomes (Butler et al. 1997, Henry et al. 2007). These histologic changes were typical of other compounds in this class and in the absence of any other morphologic changes the appearance of basophilic granules and associated adaptive changes such as cellular hypertrophy were not considered toxicologically significant (Henry et al. 2007, Henry et al. 2012). In rats, renal accumulation was associated with proteinuria and an increased severity of chronic progressive nephropathy commonly present in aged rats. Because of the known unique sensitivity of rat kidney to chronic progressive nephropathy, this was considered a rat specific finding with little relevance for human safety (Abrass 2000). Thus, there appears to be sufficient
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safety margins to the proposed clinical dose and the risk of renal toxicity to patients is considered to be limited (Table 44).
13.1.3.2 Hepatic Effects Liver is the pharmacodynamically relevant target organ for oligonucleotide distribution in both mice and monkeys. The liver contained the second highest oligonucleotide concentrations in the species studied (Agrawal et al. 1995, Geary et al. 2003). Unlike the kidney, oligonucleotides are distributed to all cell types in the liver, with the highest concentrations in Kupffer cells and sinusoidal endothelial cells, and lower concentrations in hepatocytes (Graham et al. 1998, Graham et al. 2001). The relative cellular distribution and dose-exposure relationships are similar across species. Kupffer cell hypertrophy/hyperplasia is likely an adaptive response in the liver related to uptake and clearance of exogenous materials and is not considered toxicologically significant or adverse (Braendli-Baiocco et al. 2017). Differences in liver concentrations between species suggest that the mouse is more sensitive to hepatotoxicity (i.e., increased ALT) than the primate. This species difference could be related to the inflammatory effects of volanesorsen evident at high doses in the liver of mice (Monteith et al. 1997, Krieg 1998). Mild hepatic toxicity was limited to mice treated with ≥ 25 mg/kg/wk. There was no evidence of hepatotoxicity in mice treated with ≤ 10 mg/kg/wk for up to 6 months of treatment or in monkeys treated with doses up to 40 mg/kg/wk (15-fold equivalent human exposure) volanesorsen for up to 3 months. The hepatic effects of volanesorsen in mice were dose-dependent, but the monkey is considered the more representative species for assessing safety margins based on the greater sensitivity of mice to the inflammatory effects of volanesorsen and other 2′-MOE ASOs. Thus, based on the safety margin in monkey and the lack of ALT increases in patients, there appears to be sufficient safety margins to the proposed clinical dose (Table 44). As such, the risk to patients is considered to be limited.
13.1.3.3 Complement Activation The 2’-MOE ASO-mediated alternative complement pathway activation is a recognized class effect in monkeys, but it is not observed in other species, including humans (Shen et al. 2014). Transient activation of complement by volanesorsen is a monkey-specific hybridization- independent effect that is due to reversible binding of Factor H to high concentrations of oligonucleotide (Henry et al. 1997, Levin and Henry 2008, Henry et al. 2014). Such phosphorothioate 2′-MOE ASO mediated complement activation occurs in monkeys with a similar dose response and activation threshold for a number of different oligonucleotide sequences (Galbraith et al. 1994, Levin et al. 1998). Several effects that can occur in monkeys secondary to complement activation have been considered in the interpretation of toxicology data from high doses in monkeys. The first is the production of C3a and C5a. These peptides can produce transient changes in hematology parameters, hemodynamic parameters, and inflammatory cytokines. The second is a decrease in individual complement protein levels that results from repeated proteolytic activation and degradation of the parent complement proteins. This turnover of protein is evident in the measurement of serum C3 as decreases in C3 become sustained over the weekly dose interval by
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6 months of treatment (Shen et al. 2016). Low C3 levels can decrease the overall functionality of the complement pathway, which can lead to secondary effects on innate immune surveillance and clearance of immune complexes. In the chronic monkey study, C3 was reduced to levels that can cause dysfunction of the complement pathway. Thus, impairment of innate immune surveillance and reduced clearance of immune complexes have potential secondary effects that may contribute to a number of alterations in monkeys with low serum C3, including the vascular pathology, noted in the chronic monkey study at the 12 and 20 mg/kg/wk dose levels (Shen et al. 2016). Because 2’-MOE ASO-mediated complement activation has been shown to be a monkey specific phenomenon, complement activation and its secondary effects on the toxicology profile of volanesorsen are not considered relevant to patients receiving the drug (Shen et al. 2014).
13.1.3.4 Hematology The primary effect of volanesorsen on hematology was a decrease in platelet count in monkeys that did not affect other hematology parameters. The platelet decrease was dose dependent and occurred either as a gradual decline in most monkeys of approximately 25% from baseline in the chronic study, or a platelet count <50,000 cells/µL in a subset of monkeys at ≥6 mg/kg/wk (approximately 2-fold equivalent human exposure; Table 44). These gradual and self-sustaining declines in platelet count have been reported for some 2’-MOE ASO sequences, but have not been a safety concern because they develop a new stable level with platelet counts well within the normal range and no impairment of hemostasis (Crooke et al. 2017, Henry et al. 2017). There was also no effect on platelet aggregation or platelet function in monkeys treated with volanesorsen. However, the severe thrombocytopenia (< 50,000 cells/µL) is of the greatest concern with regard to human relevance and mechanism. Across the development experience with 2’-MOE ASO, there is approximately at 2 to 4% incidence of monkeys that have sporadic declines in platelet count < 50,000 cells/µL similar to that observed with volanesorsen (Henry et al. 2017). However, severe PLT reduction has not been observed in clinical trials other than the Phase 3 studies in FCS and TTR amyloidosis patients (Crooke et al. 2017, Henry et al. 2017, Narayanan et al. In Progress). While the mechanism(s) for induction of platelet counts < 50,000 cells/µL in monkeys treated with volanesorsen is not well established, there are a number of mechanisms that can be excluded. In general, volanesorsen-treated monkeys, including those with reduced platelet counts, had no evidence of bone marrow cytotoxicity or damage to other hematopoietic centers at doses up to 40 mg/kg/wk for 13-weeks or up to 20 mg/kg/wk for 39-weeks of treatment. In fact, monkeys with low platelet count had compensatory increases in mean platelet volume (MPV), indicative of normal reactive thrombopoiesis. No evidence of systemic thrombus formation was present to implicate these as contributing factors. Although there were anti-drug antibodies formed against volanesorsen in monkeys, these did not appear to contribute to the decreased platelet count. There were, however, increases in markers of inflammation in several affected monkeys. Most consistent were corresponding increases in IL-6 and decreased neutrophil counts in some monkeys with low platelet. There were also tendencies for increases in CRP, globulin, and total serum immunoglobulins and decreased albumin relative to the range of
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control. These data are suggestive of an underlying inflammatory process related to the sporadic platelet decrease in affected monkeys. The most likely explanation for the thrombocytopenia is increased platelet clearance. The association with inflammatory markers has focused the investigation on potential inflammation or immune-mediated mechanisms by assessing the presence of either anti-PF4 or anti-platelet antibodies. At this point it is unlikely the decreased platelet count is attributable to an anti-PF4 antibody response as 7 of the 8 monkeys with the lowest platelet count were negative for either anti-PF4 IgG or anti-PF4 IgM. The general absence of an anti-PF4-mediated mechanism for sporadic low platelet count and, therefore, the absence of a heparin-induced thrombocytopenia (HIT)-like mechanism for platelet change, is consistent with the general absence of the prothrombotic and platelet activation phenotype associated with HIT (Greinacher 2015). At present, the working hypothesis is that the volanesorsen-mediated thrombocytopenia observed in monkeys is possibly caused by the proinflammatory effects, which leads to lymphoproliferative changes and increases in total IgG or IgM. A subset of the increased immunoglobulins appears to cross-react with platelet, resulting in increased platelet clearance. The inflammation or immune mediated clearance mechanism of thrombocytopenia is supported by the rescue with corticosteroid treatment. Importantly, these anti-platelet antibody interactions have been independent of the presence of oligonucleotide. Thus, they are considered “drug- independent” anti-platelet antibodies. This property is consistent with the presence of innate antibodies that cross react with platelets, rather than a drug-dependent hapten that is created on platelet surface proteins bound to oligonucleotides, such as the mechanism of the typical drug- induced thrombocytopenia (Aster and Bougie 2007). The relationship between the mechanism for the severe thrombocytopenia in monkeys and the clinical setting is unclear at this time. A gradual and dose-dependent decrease in platelet count from baseline with a subset of individuals with more severe thrombocytopenia was observed in both monkeys and humans. While treatment-related, the process for severe thrombocytopenia in patients appears to involve a disease component that is obviously not present in monkeys. Importantly, platelet reductions in patients with FCS were reversible and not associated with major bleeding events. Furthermore, there is a plan for frequent platelet monitoring and risk mitigation with recommended dose adjustments.
13.1.3.5 Immune System Subcutaneous injection of volanesorsen was associated with dose-dependent inflammatory effects related to interaction with pattern recognition receptors. Single-stranded 2’-MOE phosphorothioate oligonucleotides as a class can produce dose-dependent inflammatory effects, but the magnitude of these effects is highly dependent on both sequence and chemical modifications (Zhao et al. 1996, Levin et al. 2001). The 2′-MOE ASOs, such as volanesorsen, avoid specific sequence motifs associated with receptor interactions (e.g., CpG), use chemical modifications (e.g., 2′-MOE and 5-methyl cytosine), and compound screening to effectively minimize proinflammatory properties (Zhao et al. 1996, Henry et al. 2007). While inflammatory effects of 2′-MOE ASOs are still evident with volanesorsen, the potency is significantly less than for other sequences (Henry et al. 2000, Henry et al. 2001, Younis et al. 2006).
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Toxicology studies for volanesorsen were designed to characterize the potential inflammatory effects in mice, rats, and monkeys, as well as to assess the overall effects of treatment on immune function. This evaluation included an assessment of lymphoid organ weight and histopathology, measurement of general markers of inflammation such as CRP (monkeys) and total serum immunoglobulin, and measurement of a panel of cytokines and chemokines. Immune function was also assessed in monkeys exposed to a T cell dependent antigen following 9 months of treatment to volanesorsen. These studies characterized the inflammatory effects in each species for dose-response, progression, and reversibility. Information on species sensitivity was also obtained, and it was shown that rodents appear to be the more sensitive species for volanesorsen inflammatory effects. The direct inflammatory effects of oligonucleotides observed in rodents or monkeys are largely a consequence of activation of innate immune cells (macrophages, dendritic cells, and B cells) and subsequent cytokine and chemokine release. The most common manifestation of this in the volanesorsen toxicology studies was local injection site inflammation in mice, rats, and monkeys following SC administration. In mice and rats, there was also a dose-dependent increase in lymphoid organ weight, lymphoid hyperplasia, and multiorgan lymphohistiocytic cell infiltrates. A correlation between serum MCP-1 and increased tissue infiltrates has been established and is considered a potential biomarker for systemic inflammatory effects (Takeshita et al. 2000, Kanda et al. 2006, Younis et al. 2006). The incidence and severity of mononuclear cell infiltrates was generally greater than that in control animals at doses ≥ 30 mg/kg/wk in the mouse and ≥ 10 mg/kg/wk in the rat. This was particularly apparent in the heart, where infiltration of hypertrophied histiocytes in the atria and ventricles was evident in the mouse (≥ 50 mg/kg/wk) and rat (≥ 10 mg/kg/wk) associated with increases in other cytokines, including IL-6. The severity of the histiocytic infiltrates in the heart in mice led to secondary degeneration (minimal to mild in severity) of adjacent cardiac myofibers. The mouse heart may be more sensitive to such immune cell infiltration because it has a resident population of histiocytes in the myocardium (identifiable in the myocardial interstitium and along mural and pericardial blood vessels) that is much less apparent in human or nonhuman primate hearts (Treuting and Dintzis 2011). This anatomical difference between the mouse and monkey, coupled with the greater sensitivity of rodents to volanesorsen-mediated proinflammation, likely explains the presence of these findings in the mouse and not in monkey. One of the major differences in sensitivity to the inflammatory effects between species is the absence of multiorgan lymphohistiocytic cell infiltrates in monkeys. This includes no inflammatory cell infiltrates in the heart in monkeys. In monkeys, the only consistent observation of lymphohistiocytic cell infiltrates was in the skin at SC injection sites. This is thought to be a local reaction to injection of a high concentration of oligonucleotide. The reason for sensitivity differences between species is not entirely known, but may relate to the expression pattern of specific pattern recognition receptors on target mononuclear cells (Verthelyi and Klinman 2003, Roberts et al. 2005). In monkeys treated with 20 mg/kg/wk volanesorsen, there was splenomegaly, increases in IgG, and perivascular infiltrates after 9 months of treatment. There was also evidence of repeated complement activation and C3 depletion that may have
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Endocrine and Metabolic Drugs Advisory Committee Briefing Document 10 May 2018 Meeting
c Finding associated with histiocytic cell infiltrates and secondary compression of myofibers d Monkey specific effect not observed in other species, including human e Mouse plasma exposure data extrapolated from a mouse repeat-dose pharmacokinetic study. Rat plasma exposure data extrapolated based on data from other ASOs at doses with similar tissue concentrations f Based on nominal dose at SC injection site g Cmax h Therapeutic margin in rat is estimated on the basis of mg/kg dose and a 2-fold scaling factor for rat PK parameters
13.1.4 Carcinogenicity The carcinogenic potential of volanesorsen was assessed in 2-yr repeated dose studies in mice and rats. In both studies, 70 animals/sex were assigned to each treatment group (control and volanesorsen-treated). The mouse study also included the murine-specific inhibitor of apoC-III, ISIS 440760, to assess potential effects related to the expected pharmacology. Volanesorsen groups were given SC doses of 6, 25, 40 mg/kg/wk once weekly for a maximum of 104 weeks (approximately 2-fold the equivalent human exposure). The mouse-active surrogate was dosed similarly at 25 mg/kg/wk. In the rat, SC doses of 0.2, 1, and 5 mg/kg were also given once weekly (up to the approximate human equivalent exposure). In both studies, exposure to volanesorsen was assessed by measurement of oligonucleotide concentration in liver and kidney following 3 months of treatment. In the mouse, there were statistically significantly increases of liver masses at necropsy and an increased incidence of a limited spectrum of neoplasms, including hepatocellular adenoma, hemangiosarcoma, histiocytic sarcoma, and pituitary gland adenoma. Hepatocellular adenomas, hemangiosarcoma, and histiocytic sarcomas are common spontaneous neoplasms in the aging mouse that can be increased in incidence due to a variety of nonspecific mechanisms, most notable chronic inflammation. For volanesorsen, the increased incidence in treated mice can be attributed directly to the sensitivity of mice to proinflammatory effects that are not present in monkeys or humans, typified by multi-organ lymphohistiocytic cell infiltrates in mice. The increased incidence of pituitary adenomas was observed only in female mice where the historical incidence in females is greater than in male mice (6.8% vs. 1.7%) and the incidence in the concurrent control group was at the high end of the historical control range. Hyperplasia of the pars-distalis is quite common in aged mice, particularly females, and the increased incidence of adenoma in this study likely reflects the overall increased incidence of hyperplasia in all female dose groups, including controls. It is important to note that volanesorsen is not genotoxic when putting these neoplasms in perspective for risk assessment. While the increased incidence of these tumors was likely due to treatment they are considered to have limited clinical relevance as the increased incidence most likely reflects the greater sensitivity of mice to the proinflammatory effects of volanesorsen compared to primates and the variability of spontaneous pituitary hyperplasia in female mice.
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Table 45: Significant Neoplasms in Mouse Carcinogenicity Study by Gender (poly-3 pairwise test)
Male (mg/kg/wk) Female (mg/kg/wk) 0 6 25 40 25 (440670) 0 6 25 40 25 (440670) Number of Animals (Total) 70 70 70 70 70 70 70 70 70 70 Liver adenoma, hepatocellular, benign a 9 15 30 13 17 3 3 5 6 4 Adj. Incidence (%)b 16% 29% 68%** 50%** 34%* 6% 6% 16% 33%** 9% MPI historical data (%) 6.7-24.6% (MPI) 0-3.3% (MPI) Multicentric Neoplasm hemangiosarcoma, malignant a 2 11 12 10 10 4 9 9 3 2 Adj. Incidence (%)b 4% 21%** 34%** 42%** 19%** 8% 18% 27%* 18% 5% MPI historical data (%) 1.7-15.4% (MPI) 1.7-15% (MPI) histiocytic sarcoma, malignant a 2 7 5 1 5 0 8 6 3 8 Adj. Incidence (%)b 4% 13%* 16%* 6% 10% 0 17%** 20%** 18%** 17%** MPI historical data (%) 0-4.6% (MPI) 1.5-8.3% (MPI) Pituitary Gland adenoma, pars distalis, benign a 0 2 0 0 0 3 3 9 3 7 Adj. Incidence (%)b 0% 4% 0% 0% 0% 6% 6% 28%** 19% 15% MPI historical data (%) 0-1.7% (MPI) 0 to 6.8% (MPI) *p-value, p<0.05; **p-value, p<0.01 a Number of tumor-bearing animals b Number of tumor-bearing animals/adjusted time at risk
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In the rat, there was a dose-dependent incidence of SC masses associated with the injection site. These masses corresponded to a statistically significant incidence of malignant fibrous histiocytoma (MFH) in both males and females at ≥1 mg/kg/wk. These mesenchymal neoplasms are attributable to chronic inflammatory reactions secondary to repeated SC injections of a proinflammatory material but are not considered to be a clinical cause for concern due to the mechanism of formation. MFH occur spontaneously in rats, but are known to arise at the implantation site of inert materials or biopolymers (Kirkpatrick et al. 2000, Engelhardt 2008). The rodent is known to be particularly susceptible to development of sarcomas in the subcutaneous tissue in the presence of chronic tissue irritation and inflammation (Stammberger et al. 2002) as occurred at the injection sites in this study. Again, this occurrence is related to the peculiar sensitivity of rodents to the proinflammatory effects of ASOs.
Overall, the carcinogenicity studies identified no occurrence of rare neoplasms in either species and noted only an increased number of neoplasms reflective of the sensitivity of these species to the proinflammatory effects of oligonucleotides and not to any innate carcinogenic properties of volanesorsen. Even with the lack of a clear mechanism for the development of pituitary adenoma in female mice, the relationship to spontaneous hyperplasia in female mice and the incidence of pituitary hyperplasia in the study, indicate that volanesorsen poses little carcinogenic risk for patients.
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13.2 Study CS6 Quality of Life Results As shown in Table 46 and Table 47, both SF-36 and EQ-5D scores were comparable across the volanesorsen and placebo groups and there were no significant differences in changes from Baseline to these time points between the two treatment groups. Similar results were obtained when the scores were analyzed in subset of patients who reported abdominal pain > 0 or in subset of patients who had pre-dose adjudication-confirmed pancreatitis. Table 46: Summary of SF-36 Weighted Sum of Scores – CS6 Full Analysis Set
Weighted Scores Baseline 3 months 6 months 12 months Mean (SD) Volanesorsen Placebo Volanesorsen Placebo Volanesorsen Placebo Volanesorsen Placebo n 24 26 30 32 23 24 17 22 Physical 55.63 53.77 53.55 53.36 55.63 (3.61) 52.50 (8.37) 51.63 (8.03) 51.12 (8.09) functioning (3.90) (8.00) (8.69) (5.98) 52.48 (7.07) 53.88 51.69 (8.56) 52.39 50.03 (8.77) 53.04 48.04 50.22 Role functioning (4.23) (7.48) (7.00) (11.02) (8.57) 55.08 (12.42) 55.53 53.49 (9.56) 55.33 52.18 56.14 53.63 55.18 Pain (6.88) (9.07) (10.33) (6.86) (10.93) (8.80) 51.18 (11.23) 49.46 50.10 (9.94) 51.14 50.09 51.33 49.21 49.29 General health (9.72) (10.49) (10.38) (9.76) (10.26) (9.64) 55.07 (11.44) 57.06 55.27 (9.18) 56.59 54.28 55.57 56.27 (9.37) 55.97 Vitality (7.85) (9.74) (10.32) (8.31) (7.06) 51.70 (8.66) 53.87 51.66 (7.98) 52.80 48.84 53.37 49.67 (9.23) 52.33 Social functioning (5.07) (8.29) (10.84) (7.68) (7.26) Emotional 52.98 (7.11) 53.76 52.11 (7.26) 51.71 49.81 (7.90) 51.96 50.64 51.42 functioning (4.38) (7.77) (8.47) (11.62) (8.08) 52.39 (9.97) 53.18 52.00 (8.43) 53.65 50.64 (9.02) 53.05 51.95 54.08 Mental health (7.70) (9.54) (9.44) (10.30) (8.58)
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Table 47: EQ-5D Questionnaires: Score – CS6 Full Analysis Set
Dimensions Baseline 3 months 6 months 12 months Mean (SD) Volanesorsen Placebo Volanesorsen Placebo Volanesorsen Placebo Volanesorsen Placebo n 24 26 30 32 23 23 16 22 Overall Health 87.75 88.12 78.23 84.81 81.09 82.74 87.88 84.27 Status VAS (10.45) (8.40) (16.34) (15.44) (15.91) (21.58) (11.01) (16.03) Mobility 1.08 (0.28) 1.00 (0.00) 1.40 (0.67) 1.22 (0.66) 1.35 (0.83) 1.30 (0.93) 1.50 (1.10) 1.14 (0.47) Self Care 1.00 (0.00) 1.00 (0.00) 1.20 (0.55) 1.16 (0.63) 1.17 (0.49) 1.26 (0.92) 1.00 (0.00) 1.09 (0.43) Usual Activities 1.04 (0.20) 1.00 (0.00) 1.40 (0.72) 1.22 (0.66) 1.48 (0.73) 1.26 (0.92) 1.44 (0.81) 1.18 (0.50) Pain/Discomfort 1.29 (0.46) 1.15 (0.37) 1.53 (0.82) 1.47 (0.76) 1.57 (0.84) 1.48 (0.95) 1.19 (0.40) 1.41 (0.67) Anxiety/ 1.08 (0.28) 1.12 (0.33) 1.43 (0.68) 1.31 (0.59) 1.48 (0.73) 1.30 (0.56) 1.31 (0.60) 1.36 (0.73) Depression
13.3 Additional Information on Serious Adverse Events All on-treatment SAEs is studies CS6 and CS16 are summarized in Table 48 and Table 49, respectively. In CS6, 2 SAEs of thrombocytopenia were reported as related to study drug. • Thrombocytopenia (platelet count nadir 8,000/mm3 on Study Day 259) was reported in a 43-year-old male patient (weight 111 kg) who was receiving volanesorsen 300 mg every week. The patient experienced minor bleeding with epistaxis and petechiae and was treated with a course of prednisolone therapy with recovery of his thrombocytopenia (173,000/mm3). Anti-drug antibodies were negative on all days evaluated. • Thrombocytopenia (platelet count nadir 15,000/mm3 on Study Day 134) was reported in a 48-year-old female patient (weight 56 kg) who was receiving volanesorsen 300 mg every week. The patient experienced minor bleeding with epistaxis, spontaneous hematoma and conjunctival hemorrhage and was treated with a course of prednisolone therapy with recovery of thrombocytopenia (173,000/mm3). Bone marrow histology on Study Day 138 was reported as normal. Anti-drug antibodieswere negative through Study Day 180 and converted on the next day and the last day evaluated Study Day 341.
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Table 48 Serious On-Treatment Adverse Events in Study CS6 - Safety Set
CS6 Volanesorsen Placebo (N = 33) (N = 33) Preferred Term n (%) n (%) Patients with any SAE 7 (21.2) 5 (15.2) Thrombocytopenia 2 (6.1) 0 Abdominal pain 1 (3.0) 1 (3.0) Ankle fracture 1 (3.0) 0 Cholangitis 1 (3.0) 0 Cyst 1 (3.0) 0 Dehydration 1 (3.0) 0 Drug-induced liver injury* 1 (3.0) 0 Pancreatitis acute 0 2 (6.1) Colitis ischemic 0 1 (3.0) Liver function test abnormal 0 1 (3.0) *The drug-induced liver injury was reported as caused by diclofenac.
In CS16, 1 SAE of serum sickness was considered potentially related to study treatment. The event was moderate in intensity and the patient was discontinued from study drug. • A 47-year-old male with a medical history including hives and previous tobacco use had a negative ANA IgG by ELISA and dsDNA antibody, and negative IgG by ELISA at Baseline (study day 1). On study day 130, the patient first reported flu-like symptoms of mild severity. On study day 153, 19 days after last dose of study drug, the patient reported fever of 104°F and pain. On study day 175, the rheumatologist diagnosed the patient with serum sickness; lab tests showed ANA Direct was positive, anti-DNA (DS) was 209 IU/mL, Complement C3 was 98 mg/dL (range: 82-167 mg/dL), and Complement C4 was < 5 mg/dL (range: 14-44 mg/dL). On study day 183, the patient was evaluated by a gastroenterologist and was diagnosed with drug-induced hepatitis (hepatocellular injury [secondary to serum sickness]), as a secondary diagnosis to serum sickness. The gastroenterologist felt that it was not autoimmune hepatitis and a liver biopsy was not justified. On study day 185, ANA Direct remained positive and anti-DNA (DS) Ab Qn was 92 IU/mL (range - negative<5). The SAE of serum sickness was considered resolved. The patient permanently discontinued study drug due to the event of serum sickness with the last dose administered Study Day 134). He received a total of 20 doses of Study Drug prior to discontinuation.
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Table 49 Serious On-Treatment Adverse Events in Study CS16 - Safety Set CS16 Volanesorsen Placebo (N=75) (N=38) Preferred Term n (%) n (%) Patients with any SAE 6 (8.0) 3 (7.9) Carotid artery stenosis 1 (1.3) 0 Hemiparesis 1 (1.3) 0 Small intestinal obstruction 1 (1.3) 0 Non-cardiac chest pain 1 (1.3) 0 Serum sickness 1 (1.3) 0 Ulna fracture 1 (1.3) 0 Hypertensive crisis 1 (1.3) 0 Pancreatitis acute 0 2 (5.3) Pancreatitis relapsing 0 1 (2.6) Pancreas infection 0 1 (2.6)
In the ongoing studies, including the OLE CS7 and the blinded studies in patients with FPL, CS17 and CS19, the following SAEs were reported between 31 August 2017 and 31 March 2018. No new safety concerns have been identified from the additional SAE reports in the ongoing studies. Study CS7: 6 SAEs were reported in 6 patients • Acute pancreatitis (2 SAEs in 2 patients) • Thrombocytopenia (1 patient; led to discontinuation of study drug) • Intervertebral disc protrusion (1 patient) • Ovarian cyst (1 patient) • Influenza like illness (1 patient) One SAE (thrombocytopenia) was reported as possibly related to study drug and is described below. • Thrombocytopenia (platelet count nadir 17,000/mm3 on Study Day 306) was reported in a 34-year-old female patient (weight 59 kg) who was receiving volanesorsen 300 mg every 2 weeks. The investigator did not pause volanesorsen dosing when the patient’s platelet test result was 69,000/mm3 because he was waiting for a confirmatory test result (protocol recommends dose pause at < 75,000/mm3). The patient did not experience any bleeding and was treated with a course of corticosteroid therapy with recovery of her thrombocytopenia.
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Study CS17: 6 SAEs were reported in 6 patients. • Sarcoidosis • Systemic inflammatory response syndrome • Atrioventricular block complete • Restrictive pulmonary disease • Drug delivery device removal • Blood creatinine increased Sarcoidosis and systemic inflammatory syndrome were reported as possibly related to study drug and are described below. • A case of sarcoidosis reported from a site in Russia was evaluated by 3 independent sarcoidosis experts (2 US and 1 Netherlands) as a case of “sarcoid-like” features with mediastinal lymphadenopathy (granulomatous inflammation on lymph node biopsy) and lung changes. Assessment of causality was indeterminate. The case was incidentally detected on chest x-ray performed for upper respiratory tract symptoms, 120 days after the last dose of study drug and comprehensive investigations to rule out pathogens (tuberculosis, fungal infections) and occupational/environmental exposures were lacking. • A case of systemic inflammatory syndrome was reported in a 63-year-old female patient who developed arthralgia and body aches 575 days after receiving her first dose of blinded study drug 300 mg weekly. The patient developed a rash (annular erythematous) over her thighs and painful/tender knee, wrist and ankle joints without fever. The patient was seen by a rheumatologist and prednisolone was started with resolution of arthralgia and rash 17 days after onset of symptoms. The investigator stated the diagnosis of systemic inflammatory syndrome was due to the presence of inflammation in several joints and a markedly elevated C-reactive protein. Study CS19: 4 SAEs were reported in 3 patients. • Ascites and cardiac failure (1 patient) • Pancreatitis (2 patients) Cardiac failure and ascites events in 1 patient were reported as possibly related to study drug. A 40-year-old female with congenital generalized lipodystrophy, severe insulin resistance, history of atrial fibrillation and AV node ablation developed cardiac failure with ascites. Echocardiographic measures were most consistent with an underlying fibrotic or infiltrative cardiomyopathy.
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