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Genzyme Announces Positive New Data from Two Phase 3 Studies for Oral Eliglustat Tartrate for Gaucher Disease

CAMBRIDGE, Mass. – Genzyme, a Sanofi company, 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 enzyme’s registration package for eliglustat tartrate.

The company is developing eliglustat tartrate, a capsule taken orally, to provide a convenient treatment alternative for patients with Gaucher disease type 1 and to provide a broader range of treatment options for patients and physicians. Genzyme’s clinical development program for eliglustat tartrate represents the largest clinical program ever focused on Gaucher disease type 1 with approximately 400 patients treated in 30 countries.

“The data presented at this year’s WORLD symposium reinforce our confidence that eliglustat tartrate may become an important oral option for patients with Gaucher disease,” said Genzyme’s Head of Rare Diseases, Rogerio Vivaldi MD. “We are excited about this therapy’s potential and are making excellent progress in our robust development plan for bringing eliglustat tartrate to the market.”

ENGAGE Study Results:

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 at the WORLD Symposium by Pramod Mistry, MD, PhD, FRCP, Professor of Pediatrics & Internal Medicine at Yale University School of Medicine, and an investigator in the

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.

ENCORE is a multi-national, randomized, controlled, open-label, study 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.

About eliglustat tartrate

Eliglustat tartrate, a novel glucosylceramide analog given orally, was designed to partially inhibit the enzyme glucosylceramide synthase, which results in reduced production of glucosylceramide. Glucosylceramide is the substance that builds up in the cells and tissues of people with Gaucher disease. The concept was initially developed by the late Norman Radin, MD, from the University of Michigan. In pre-clinical studies, the molecule, developed
with James A. Shayman, MD, also from the University of Michigan, has shown high potency and specificity. Initiation of the Phase 2 and 3 studies of eliglustat tartrate in Gaucher disease followed an extensive pre-clinical research effort and a Phase 1 program.