Long-term adverse event profile from four completed trials of oral eliglustat in adults with Gaucher disease type 1

Abstract

Background Eliglustat is a first-line oral treatment for adults with Gaucher disease type 1 who have an extensive, intermediate or poor CYP2D6 metabolizer phenotype (> 90% of patients). Whereas enzyme replacement therapy for Gaucher disease has been widely used for more than two decades, eliglustat has only been in commercial use since 2014. Clinicians and patients want to better understand which adverse events are most commonly associated with eliglustat, as well as their severity, frequency, and duration. Methods This pooled analysis of treatment-emergent adverse events combines data from four completed eliglustat clinical trials involving 393 Gaucher disease type 1 patients. It represents 1400 patient-years of eliglustat exposure and a mean treatment duration of 3.6 years (maximum: 9.3 years). Results Eighty-one percent of patients remained in their respective trial until commercial availability of eliglustat (US patients only) or until trial completion. Nine patients (2.3%) withdrew from their respective trial due to one or more adverse events reported as eliglustat treatment-related; all but one of these events were mild or moderate. Overall, 97% of adverse events were mild or moderate and 86% were reported by the investigator as unrelated to eliglustat treatment. The overall rate of adverse events decreased over time and did not increase with increasing eliglustat dose. We evaluated frequency, duration, and severity of 14 adverse event terms reported at least once as treatment-related in 2% or more of all patients: dyspepsia (5.9%), headache (5.3%), abdominal pain upper (5.1%), dizziness (5.1%), diarrhea (4.6%), nausea (4.6%), arthralgia (3.6%), constipation (3.3%), abdominal pain (2.8%), gastroesophageal reflux disease (2.8%), fatigue (2.8%), palpitations (2.8%), abdominal distension (2.5%), and gastritis (2.3%). For abdominal pain upper, diarrhea, nausea, abdominal pain, and headache events, median duration was less than 14 days. All 14 adverse event terms, except for arthralgia and headache, were reported only once per patient in more than 70% of patients experiencing the event. Conclusions This final pooled analysis of treatment-emergent adverse events reinforces the favorable safety profile of eliglustat. The majority of the most frequently reported treatment-related adverse events were mild or moderate, transient, and occurred only once per patient. Electronic supplementary material The online version of this article (10.1186/s13023-019-1085-6) contains supplementary material, which is available to authorized users.

Outcomes after 8 years of eliglustat therapy for Gaucher disease type 1: Final results from the Phase 2 trial

“…The long‐term safety data from this trial extend the safety and tolerability profile of eliglustat reported among treatment‐naïve patients during 1.5 years in the Phase 3 ENGAGE trial, ERT switch patients during 4 years in the Phase 3 ENCORE trial, and mostly ERT switch patients in the EDGE trial comparing once‐ vs twice‐daily dosing of eliglustat . These 4 trials represent a total of 393 eliglustat‐treated patients and 1400.3 patient‐years of eliglustat exposure, with a mean duration of 3.6 years on eliglustat . Nineteen of the 20 patients who entered the Phase 2 trial extension after the 1‐year primary analysis completed the trial, with just one withdrawal at 2 years for administrative reasons.…”

Real‐world effectiveness of eliglustat in treatment‐naïve and switch patients enrolled in the International Collaborative Gaucher Group Gaucher Registry

“…Discontinuation could be attributable to adverse events, preference for ERT, limited commercial availability or reimbursement for eliglustat, or, in the seven women of childbearing age who discontinued treatment, because of pregnancy or desire to become pregnant, as eliglustat is not recommended for women during pregnancy. In a pooled analysis of adverse events from all four eliglustat clinical trials representing a mean of 3.6 years on treatment, 83% of patients remained in their trial until they were switched to commercial eliglustat (patients living in the United States) or the trial was completed, with 2.3% of the combined trial population discontinuing treatment due to an adverse event that was considered related to eliglustat 21 …”

Glycosphingolipids and Infection. Potential New Therapeutic Avenues

“…The long-term outcome of treatment of patients suffering from GD with agents that reduce GSLs is, however, remarkably positive. No major side-effects are observed in individuals treated for a number of years (Mistry et al, 2018; Lewis and Gaemers, 2019). So far, the agents used do not achieve significant reduction in GSLs in the brain, however, a new generation of compounds aiming at that is being tested at the moment.…”