Eliglustat effective for maintaining stable Gaucher's disease type 1

Last Updated: 2015-04-07

By Will Boggs MD

NEW YORK (Reuters Health) - Eliglustat, an oral inhibitor of glucosylceramide synthase, is effective for maintaining patients with Gaucher's disease type 1 that has been stabilized by enzyme replacement therapy (ERT), according to results from a phase 3 noninferiority trial.

"The drug is undoubtedly a major clinical advance and offers potential that is very attractive for many (not all) patients," Dr. Timothy M. Cox, from the University of Cambridge, Addenbrooke's Hospital, Cambridge, UK, told Reuters Health by email. "It may reach parts of the disease that other agents will never reach."

ERT is the standard treatment for Gaucher's disease type 1. Substrate reduction therapy with eliglustat aims to enhance the treatment by balancing glucosylceramide production with its impaired rate of degradation, thereby reducing plasma glucosylceramide concentrations and improving the visceral, hematological, and skeletal manifestations of the disease.

Dr. Cox and colleagues in the ENCORE study sought to establish whether patients who had achieved therapeutic goals while receiving alternate-week infusions of ERT would remain stable after switching to oral eliglustat.

The study included 160 patients randomly allocated to oral eliglustat (106, 66%) or continued infusions of imiglucerase ERT (54, 34%).

The percentage of patients whose hematological variables and organ volumes remained stable after 12 months, the composite primary efficacy endpoint, was similar for the eliglustat group (85%) and the imiglucerase group (94%), with the 8.8% difference falling within the prespecified noninferiority margin of 25%.

The individual components of the efficacy endpoint were also similar between the treatment groups, according to the March 26 online report in The Lancet.

By three months into treatment, plasma concentrations of glucosylceramide and the ganglioside GM3 had decreased by more than 50% in the eliglustat group and were maintained within the healthy reference range.

At 12 months, all 93 patients given eliglustat who completed a survey confirmed their preference for oral treatment (on average, they had been on ERT for about 10 years).

Adverse events attributed to eliglustat included diarrhea (5% of patients), arthralgia (4%), fatigue (4%), and headache (4%).

"These findings extend the efficacy profile of eliglustat beyond treatment-naïve adult patients with Gaucher's disease type 1 to include maintenance treatment in adults who have been stabilized on enzyme therapy," the researchers conclude.

"If, as we expect, the drug has the safe long-term benefits we expect, then it will serve as a robust platform for numerous other agents and also a therapeutic army to tackle B-cell cancers and Parkinson disease in Gaucher as well as in the general population," Dr. Cox said.

"If successful, use of eliglustat in children would be an important benefit, avoiding the trauma and inconvenience of infusions and indwelling cannulae," write Dr. Derralyn A. Hughes from Royal Free London NHS Foundation Trust, London, UK and Dr. Gregory M. Pastores from National Centre for Inherited Metabolic Diseases, Dublin, Ireland in a related commentary.

" vailability of a convenient oral treatment creates a new opportunity to explore a role for early treatment in preventing the late and unusual manifestations of Gaucher's disease," the editorial concludes.

"This drug is better tolerated than the other substrate reduction therapy (miglustat)," Dr. Lunawati L. Bennett, from Union University School of Pharmacy, Jackson, Tennessee, told Reuters Health by email. "[It's] also better in causing improvement in hemoglobin level and platelets, decrease in spleen and liver volume, and improvement in spine bone mineral density. But precaution [is needed] for patients who are slow in metabolizing CYP2D6."

Eliglustat is approved by the U.S. Food and Drug Administration (FDA) as a first-line oral drug for treatment of adults with Gaucher's disease type 1 and has been granted marketing authorization by the European Commission.

Genzyme, a Sanofi company, funded the study, employed three of the authors, and had various relationships with the other eight authors.

SOURCE: http://bit.ly/18ZLaC2 and http://bit.ly/1O4KafA

Lancet 2015.