Date: 2015-02-12
Type of information: Presentation of results at a congress
phase: 3
Announcement: presentation of results at the 11th Annual Lysosomal Disease Network WORLD Symposium in Orlando
Company: Genzyme (USA - MA), a Sanofi company (France)
Product: Cerdelga® (eliglustat tartrate)
Action
mechanism: enzyme inhibitor. Eliglustat is an analog of D-threo-1-phenyl-2-decanoylamino-3-morpholino-propanol. This is a specific ceramide analogue inhibitor of glucosylceramide synthase (IC50 = 10 ng/mL) with broad tissue distribution. It reduces the production of glucosylceramide, so it slows down the production of the fatty materials by inhibiting the metabolic process that forms them.
Disease: Gaucher's disease
Therapeutic area: Rare diseases - Genetic diseases
Country:
Trial
details: The first phase 3 trial, ENCORE, is a randomized, open-label study for adult patients with Gaucher disease type 1, designed to compare eliglustat tartrate to Cerezyme. Adult patients who previously received enzyme replacement therapy for at least three years and have reached their therapeutic goals are enrolled in this trial. Genzyme’s clinical development program for Cerdelga® includes approximately 400 patients treated in 29 countries.
The second trial, ENGAGE, is a randomized, double-blind, placebo-controlled study for patients with Gaucher disease type 1 who were untreated or had not been on treatment for at least nine months prior to study entry. Data from these pivotal registration studies are expected in the first half of 2013.
A third trial, known as EDGE, compares once-daily dosing of eliglustat tartrate with twice-daily dosing.
Latest
news: * On February 12, 2015, Genzyme, a Sanofi company, reported extension study data from its Phase 3 ENGAGE and ENCORE studies of Cerdelga® (eliglustat), a first-line oral therapy approved by the FDA and the European Commission for the treatment of certain adults with Gaucher disease type 1. The results from the studies were presented at the 11th Annual Lysosomal Disease Network WORLD Symposium in Orlando, Fla. Both extension studies demonstrated continued stability and/or improvements across established end points and published therapeutic treatment goals. The oral presentations on these Phase 3 studies were: ENGAGE — A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study to Investigate the Efficacy and Safety of Eliglustat in Adults with Gaucher Disease Type 1: Results after 18 Months, Pramod Mistry, MBBS, PhD, F.R.C.P, Director of Yale Lysosomal Disease Center and Gaucher Disease Treatment Center Yale School of Medicine: In the primary analysis period, improvements were seen across the following endpoints after 9 months on Cerdelga: spleen size, platelet count, hemoglobin concentration, and liver volume. In the 9 month extension phase, patients who switched from placebo to eliglustat showed improvements similar to the eliglustat-treated patients during the primary analysis while the eliglustat-treated patients continued to show improvements during the 9 month extension period. There were no treatment-related discontinuations. ENCORE— a Phase 3, Randomized, Controlled, Open-Label Non-Inferiority Study Comparing Eliglustat to Imiglucerase in Gaucher Disease Type 1 Patients Stabilized on Enzyme Replacement Therapy: 24-Month Results, Timothy M. Cox, MD, FRCP, Research Director and Professor of Medicine, Addenbrooke’s Hospital, Cambridge, UK. The study, which met the primary analysis criteria for non-inferiority to imiglucerase (Cerezyme®), had a composite endpoint of each of the following parameters: spleen volume, hemoglobin concentration, platelet counts, and liver volume at 12 months. During the 12-month extension period, the patients who crossed over to eliglustat treatment from imiglucerase remained stable. Patients treated with eliglustat for 24 months also maintained stability of clinical parameters during the extension period. The most common adverse reactions (≥10%) in the primary analysis periods of ENGAGE and ENCORE were fatigue, headache, nausea, diarrhea, back pain, pain in extremities, and upper abdominal pain. In both extension studies the majority of adverse reactions with Cerdelga were mild and transient, and consistent with those in the primary analysis periods. Most patients in both of the Phase 3 studies continue to receive Cerdelga® in longer term extension periods. The majority of patients are now in their 4th or 5th year of treatment. * On February 15, 2013, Genzyme, a Sanofi company, has announced positive new data from the Phase 3 ENGAGE and ENCORE studies of eliglustat tartrate, its investigational oral therapy for Gaucher disease type 1. The results from the ENGAGE study were presented at the 9th Annual Lysosomal Disease Network WORLD Symposium in Orlando, Fla. In conjunction with this meeting, Genzyme also released topline data from its second Phase 3 study, ENCORE. Both studies met their primary efficacy endpoints and together will form the basis of Genzyme’s registration package for eliglustat tartrate. ENGAGE Study Results: * On February 8, 2012, Genzyme has announced that it has fully enrolled all three phase 3 trials for the oral therapy eliglustat tartrate. Combined, these trials represent the largest clinical program ever focused on Gaucher disease, with participating sites in over 30 countries. In total, more than 350 patients are enrolled in the phase 3 studies.
In ENGAGE, a Phase 3 trial to evaluate the safety and efficacy of eliglustat tartrate in 40 treatment-naïve patients with Gaucher disease type 1, improvements were observed across all primary and secondary efficacy endpoints over the 9-month study period. Results were reported by Pramod Mistry, MD, PhD, FRCP, Professor of Pediatrics & Internal Medicine at Yale University School of Medicine, and an investigator in the trial.
The randomized, double-blind, placebo-controlled study had a primary efficacy endpoint of improvement in spleen size in patients treated with eliglustat tartrate. Patients were stratified at baseline by spleen volume. In the study, a statistically significant improvement in spleen size was observed at nine months in patients treated with eliglustat tartrate compared with placebo. Spleen volume in patients treated with eliglustat tartrate decreased from baseline by a mean of 28 percent compared with a mean increase of two percent in placebo patients, for an absolute difference of 30 percent (p<0.0001).
Secondary endpoints also improved: • Platelet levels increased from baseline by an absolute difference of 41 percent compared with placebo (P<0.0001)
• Hemoglobin levels increased from baseline by an absolute difference of 1.2 g/dL compared with placebo (P<0.0006)
• Liver volume decreased from baseline by an absolute difference of seven percent compared with placebo (P<0.0072)
Among tertiary endpoints: A statistically significant improvement in total bone marrow burden was observed among patients in the eliglustat tartrate arm compared to placebo, and all other markers of bone disease showed trends towards improvement.
In the study, there were no serious adverse events reported in either treatment group. All adverse events reported were mild or moderate, with the most common being headache, arthralgia and diarrhea. One patient withdrew from the trial, for a reason not treatment-related. At the end of the nine months, patients who were on placebo were transitioned to eliglustat tartrate.
ENCORE Study Results:
ENCORE, the second Phase 3 trial in the eliglustat tartrate development program, also met its primary efficacy endpoint. This multi-national, randomized, controlled, open-label, study has been designed to determine whether eliglustat tartrate is non-inferior to Cerezyme® (imiglucerase for injection). In the trial, 160 patients with Gaucher disease type 1 who had begun enzyme replacement therapy at least three years prior to randomization and who had reached therapeutic goals were randomized (2:1) to receive either eliglustat tartrate or Cerezyme for one year.
The primary efficacy endpoint of stability was a composite endpoint of pre-specified change criteria for each of the following parameters: spleen volume, hemoglobin levels, platelet counts, and liver volume. To meet the endpoint for stability, a patient had to remain stable in all four parameters. Eliglustat tartrate met the pre-specified criteria for non-inferiority to Cerezyme®, with the majority of patients in both groups remaining stable one year after randomization (84 percent of eliglustat tartrate patients and 94 percent of Cerezyme® patients).
In an additional, pre-specified, efficacy analysis of the percent change in spleen volume from baseline, a mean change of minus six percent was observed in the eliglustat tartrate arm compared with minus three percent in the Cerezyme arm. This analysis also met the criteria for non-inferiority.
With regard to secondary endpoints, after one year, nearly all patients receiving eliglustat tartrate met the stability criteria for the individual components of the composite endpoint:
• 94 percent of patients met spleen volume criteria
• 95 percent of patients met hemoglobin levels criteria
• 93 percent of patients met platelet levels criteria
• 96 percent of patients met liver volume criteria
The majority of patients had normal bone mineral density scores at study entry for total femur and lumbar spine. These scores were maintained over the 12-month study period.
In the ENCORE trial, two percent (n=2) of eliglustat tartrate patients and two percent (n=1) of Cerezyme® patients discontinued treatment because of an adverse event. Over the course of one year, four adverse events were observed in the eliglustat tartrate treatment group with ?10 percent incidence compared with Cerezyme®: fatigue (14 percent overall incidence), headache (13 percent overall incidence), nausea (12 percent overall incidence), and upper abdominal pain (10 percent overall incidence). The majority of adverse events (AEs) were mild or moderate in severity for both groups. There were no serious adverse events in the study that were considered to be related to therapy by the treating physician.
The results from the ENCORE study are expected to be presented at a medical meeting in the second half of the year.
