Outcomes after 18 months of eliglustat therapy in treatment‐naïve adults with Gaucher disease type 1: The phase 3 ENGAGE trial

Abstract

Eliglustat, an oral substrate reduction therapy, is a first‐line treatment for adults with Gaucher disease type 1 (GD1) who are poor, intermediate, or extensive CYP2D6 metabolizers (>90% of patients). In the primary analysis of the Phase 3 ENGAGE trial (NCT00891202), eliglustat treatment for 9 months resulted in significant reductions in spleen and liver volumes and increases in hemoglobin concentration and platelet count compared with placebo. We report 18‐month outcomes of patients who entered the trial extension period, in which all patients received eliglustat. Of 40 trial patients, 39 entered the extension period, and 38 completed 18 months. Absolute values and percent change over time were determined for spleen and liver volume, hemoglobin concentration, platelet count, bone mineral density, bone marrow burden, and Gaucher disease biomarkers. For patients randomized to eliglustat in the double‐blind period, continuing treatment with eliglustat for 9 more months resulted in incremental improvement of all disease parameters. For patients randomized to placebo in the double‐blind period, eliglustat treatment during the 9‐month, open‐label period resulted in significant decrease of spleen and liver volumes and significant increase of hemoglobin and platelets, with a similar rate of change to patients who had received eliglustat in the double‐blind period. Eliglustat treatment was also associated with improvement in bone marrow burden score, bone mineral density, and established biomarkers of Gaucher disease, including reduction of the bioactive lipid, glucosylsphingosine. These findings underscore the efficacy of eliglustat in treatment‐naïve patients. Eliglustat was well‐tolerated, and there were no new safety concerns with longer‐term exposure.

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

“…Final 8‐year data from this open‐label Phase 2 trial confirm and extend the safety and efficacy of eliglustat reported at the 1‐, 2‐, and 4‐year time points, and are consistent with 9‐month, 18‐month, and 4.5 year data from the Phase 3 ENGAGE placebo‐controlled trial, also in treatment‐naïve patients . The long‐term stability observed in this trial is also consistent with the Phase 3 ENCORE trial, in which the same hematologic and visceral parameters remained stable for up to 4 years among patients who had switched from long‐term ERT to eliglustat .…”

“…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 .…”

“…The safety, efficacy, and tolerability of eliglustat therapy have been demonstrated in Phase 3 trials of previously untreated GD1 patients, as well as patients previously treated with enzyme replacement therapy (ERT) infusions, the historical standard of care. In the ENGAGE randomized, double‐blind, placebo‐controlled trial, eliglustat therapy improved hematologic, visceral, and skeletal disease parameters relative to placebo in treatment‐naïve patients after 9 months, and these improvements continued with up to 4.5 years of eliglustat therapy in the open‐label trial extension . In the ENCORE trial of GD1 patients whose disease had been stable after a mean of 10 years on ERT, eliglustat was noninferior to imiglucerase ERT, and the majority of patients maintained stable hematologic, visceral, and skeletal disease parameters for up to 4 years of eliglustat therapy …”

The art and science of choosing efficacy endpoints for rare disease clinical trials

“…Circulating angiotensin‐converting enzyme (ACE) and tartrate‐resistant acid phosphatase (TRAP) levels reflect monocyte/macrophage proliferation (ACE and TRAP), while chemokine [C‐C motif] ligand 19 (CCL18) and chitotriosidase are specific inflammatory mediators that reflect the terminal differentiation of macrophages into morphologically distinct Gaucher cells. Declines in all these biomarkers occur upon treatment with enzyme or substrate reduction therapies (Lukina et al, ; Mistry et al, ; Murugesan et al, ).…”

“…The GL‐3 biomarker for Fabry disease is the only new biomarker for rare diseases to be accepted by FDA as being likely to predict clinical benefit, and its use led to the accelerated approval of agalsidase beta in the United States in 2003. Other trials of lysosomal storage disorders have used reductions in substrate‐related biomarkers as supportive pharmacodynamic endpoints to provide proof of mechanism of action, for example, urinary glycosaminoglycan levels in MPS I (Wraith et al, ), MPS II (Muenzer et al, ), MPS IV (Hendriksz et al, ), MPS VI (Harmatz et al, ), and MPS VII (Kakkis, ), plasma and urinary glucose tetrasaccharide in infantile Pompe disease (An et al, ), and glucosylceramide and lyso‐glucosylceramide for Gaucher disease (Mistry et al, ; Murugesan et al, ).…”