Safety, efficacy, and authorization of eliglustat as a first-line therapy in Gaucher disease type 1

Mistry, Pramod K.; Balwani, Manisha; Baris, Hagit N.; Turkia, Hadhami Ben; Burrow, T.; Charrow, Joel; Cox, Gerald F.; Danda, Sumita; Dragosky, Marta; Drelichman, Guillermo; El‐Beshlawy, Amal; Fraga, Cristina; Freisens, Selena; Gaemers, Sebastiaan J.M.; Hadjiev, Evgueniy; Kishnani, Priya S.; Lukina, Elena; Maison‐Blanche, Pierre; Martins, Ana María; Pastores, Gregory M.; Petakov, Мilan; Peterschmitt, Michel; Rosenbaum, Hanna; Rosenbloom, Barry E.; Underhill, Lisa; Cox, Timothy M.

doi:10.1016/j.bcmd.2018.04.001

Cited by 28 publications

(23 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Supratherapeutic levels of eliglustat in the range predicted to cause clinically meaningful changes in cardiac conduction and repolarization (i.e., greater than 500 ng/mL) were not observed in any patients in the eliglustat clinical trials. The highest plasma concentration observed (261 ng/mL due to an accidental overdose when a patient in the ENCORE trial took a 450 mg dose by mistake) was in an asymptomatic patient without ECG findings [30].…”

Section: Resultsmentioning

confidence: 99%

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

Peterschmitt

Freisens

Underhill

et al. 2019

Orphanet J Rare Dis

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Resultsmentioning

confidence: 99%

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

Peterschmitt

Freisens

Underhill

et al. 2019

Orphanet J Rare Dis

Self Cite

View full text Add to dashboard Cite

show abstract

“…Oral inhibitors of GCS (Miglustat and Eliglustat) are approved drugs. Eliglustat therapy resembles ERT in efficacy [155]. Brain-permeable inhibitors of GCS are presently designed and tested [156].…”

Section: Therapies Of Gaucher Disease: Ert Srt Pct/eetmentioning

confidence: 99%

Glucocerebrosidase: Functions in and Beyond the Lysosome

Boer

Smeden

Bouwstra

et al. 2020

JCM

View full text Add to dashboard Cite

Glucocerebrosidase (GCase) is a retaining β-glucosidase with acid pH optimum metabolizing the glycosphingolipid glucosylceramide (GlcCer) to ceramide and glucose. Inherited deficiency of GCase causes the lysosomal storage disorder named Gaucher disease (GD). In GCase-deficient GD patients the accumulation of GlcCer in lysosomes of tissue macrophages is prominent. Based on the above, the key function of GCase as lysosomal hydrolase is well recognized, however it has become apparent that GCase fulfills in the human body at least one other key function beyond lysosomes. Crucially, GCase generates ceramides from GlcCer molecules in the outer part of the skin, a process essential for optimal skin barrier property and survival. This review covers the functions of GCase in and beyond lysosomes and also pays attention to the increasing insight in hitherto unexpected catalytic versatility of the enzyme.

show abstract

“…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.…”

Section: Perspectivesmentioning

confidence: 99%

“…Two drugs [Miglustat, N -butyl-deoxynojirimycin (NB-DNJ) and Eliglustat ( N -[(1 R ,2 R )-1-(2,3-Dihydro-1,4-benzodioxin-6-yl)-1-hydroxy-3-(1-pyrrolidinyl)-2-propanyl] octanamide)] are presently approved for treatment of type 1 GD patients (Figure 4B). Treatment with the more potent and specific Eliglustat is found to result in visceral improvements in patients on a par with ERT (Mistry et al, 2018). Unfortunately, Eliglustat fails to penetrate the brain effectively and can neither be applied to treat neuropathic GD.…”

Section: Introduction To Glycosphingolipidsmentioning

confidence: 99%

Glycosphingolipids and Infection. Potential New Therapeutic Avenues

Aerts

Artola

Eijk

et al. 2019

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Glycosphingolipids (GSLs), the main topic of this review, are a subclass of sphingolipids. With their glycans exposed to the extracellular space, glycosphingolipids are ubiquitous components of the plasma membrane of cells. GSLs are implicated in a variety of biological processes including specific infections. Several pathogens use GSLs at the surface of host cells as binding receptors. In addition, lipid-rafts in the plasma membrane of host cells may act as platform for signaling the presence of pathogens. Relatively common in man are inherited deficiencies in lysosomal glycosidases involved in the turnover of GSLs. The associated storage disorders (glycosphingolipidoses) show lysosomal accumulation of substrate(s) of the deficient enzyme. In recent years compounds have been identified that allow modulation of GSLs levels in cells. Some of these agents are well tolerated and already used to treat lysosomal glycosphingolipidoses. This review summarizes present knowledge on the role of GSLs in infection and subsequent immune response. It concludes with the thought to apply glycosphingolipid-lowering agents to prevent and/or combat infections.

show abstract

Safety, efficacy, and authorization of eliglustat as a first-line therapy in Gaucher disease type 1

Cited by 28 publications

References 38 publications

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

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

Glucocerebrosidase: Functions in and Beyond the Lysosome

Glycosphingolipids and Infection. Potential New Therapeutic Avenues

Contact Info

Product

Resources

About