The Long-Term Adverse Event Profile of Oral Eliglustat for the Treatment of Gaucher Disease Type 1: Pooled Analysis of Data from 393 Patients in 4 Completed Trials

Background: Gaucher disease type 1 (GD1) is a multi-systemic disorder resulting from deficient activity of the lysosomal enzyme acid β-glucosidase leading to lysosomal accumulation of glucosylceramide (GL-1), primarily in macrophages (Gaucher cells). Thrombocytopenia, anemia, hepatosplenomegaly, and skeletal disease are common presenting symptoms, and hematologists often identify and manage the disease. Eliglustat, an oral substrate reduction therapy, is a first-line treatment for adults with GD1 who have extensive, intermediate, or poor CYP2D6 metabolizer phenotypes (>90% of patients). The clinical trial program for eliglustat is the largest to date for Gaucher disease, and encompasses 2 trials in treatment-naïve patients, 1 trial in stable patients switching to eliglustat after long-term enzyme replacement therapy (the historic standard of care), and a dose regimen study in mostly switch patients. Methods: We analyzed pooled treatment-emergent adverse event (AE) data from all 393 patients with GD1 from 29 countries who received at least 1 eliglustat dose in 4 completed clinical trials sponsored by Sanofi Genzyme: Phase 2 (NCT00358150, N=26), Phase 3 ENGAGE (NCT00891202, N=40), Phase 3 ENCORE (NCT00943111, N=157), and Phase 3 EDGE (NCT01074944, N=170). Results: Mean overall treatment duration in all 393 patients from the 4 completed trials was 3.6 years (maximum: 9.3 years), representing 1400 patient-years of eliglustat exposure. Overall, 81% (n=319) of patients remained in their trial until the availability of commercial eliglustat or study completion. Twenty-five (6%) patients withdrew due to AEs, including 9 patients (2%) with AEs considered related to eliglustat: mild thrombocytopenia (1 patient); mild ventricular tachycardia (1 patient); mild vertigo (1 patient); mild lethargy and mild exfoliative rash (1 patient); mild nausea, mild headache, and moderate anemia (1 patient); moderate arrhythmia (1 patient); moderate palpitations (1 patient); moderate gastroesophageal reflux disease and moderate dyspepsia (1 patient); severe upper abdominal pain (1 patient). Other reasons for study withdrawals were: patient wished to withdraw (n=25, 6%), pregnancy (n=15, 4%), noncompliance (n=3, 1%), and "other" (n=6, 2%). There were 2 on-treatment deaths, neither of which were considered related to eliglustat (downhill skiing accident and cardiac arrest due to hemorrhage after blunt abdominal trauma). Most AEs were mild or moderate (97%) in severity and considered unrelated to eliglustat (86%). Four AEs considered related to eliglustat were reported in ≥5% of patients: dyspepsia (6%), headache (5%), abdominal pain upper (5%), and dizziness (5%). Most of these common related AEs were mild or moderate, occurred only once per patient, and lasted less than 2 weeks. A total of 77 (20%) patients reported at least 1 serious AE, the majority of which were due to hospitalizations for intercurrent illnesses (e.g., appendicitis) and underlying diseases for which Gaucher patients are at increased risk (e.g., femur fracture, joint dislocation, hepatocellular carcinoma, and cholecystitis). Eight patients (2%) had at least 1 serious AE considered related by the investigator: ventricular tachycardia; atrioventricular block and atrioventricular block second degree; peripheral neuropathy; intestinal obstruction; syncope (2 patients); syncope and muscular weakness; arrhythmia. Most were mild or moderate, recovered/resolved, and did not lead to study withdrawal. Most reported cardiac AEs were findings detected in asymptomatic patients during protocol-defined periodic 24‐hour Holter monitoring, were classified as mild, and did not lead to study withdrawal. No clinically significant prolongations of the QTcF interval were observed during extensive electrocardiographic and Holter monitoring in the clinical studies. No differences were observed for the overall frequency of AEs by age group, CYP2D6 metabolizer phenotype, or upper 10th percentile for plasma eliglustat exposure. The proportion of patients reporting AEs decreased over time on eliglustat. Conclusions: This pooled analysis of AE data from one Phase 2 and three Phase 3 completed eliglustat trials demonstrates long-term safety and tolerability of eliglustat in the treatment of adults with GD1. Disclosures Peterschmitt: Sanofi Genzyme: Employment. Freisens:Sanofi Genzyme: Employment. Hou:Sanofi Genzyme: Employment. Underhill:Sanofi Genzyme: Employment. Foster:Sanofi Genzyme: Employment. Gaemers:Sanofi Genzyme: Employment.