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

Abstract

Eliglustat is a first‐line oral therapy for adults with Gaucher disease type 1 (GD1) and poor, intermediate or extensive CYP2D6‐metabolizer phenotypes (>90% of patients). We report the final results of a Phase 2 trial and extension (NCT00358150) in previously untreated adult GD1 patients who had splenomegaly with thrombocytopenia and/or anemia and received 50 or 100 mg eliglustat tartrate (equivalent to 42 or 84 mg eliglustat) twice daily for 8 years. In total, 19 of 26 patients completed the trial. After 8 years of eliglustat, mean spleen and liver volumes decreased by 69% and 34%, respectively. Mean hemoglobin concentration and platelet count increased by 2.2 g/dL and 113%, respectively. All patients met at least 3 of 4 therapeutic goals established for patients on long‐term enzyme replacement therapy. Mean final values for patients with severe splenomegaly (n = 6), moderate‐to‐severe anemia (n = 6), or severe thrombocytopenia (n = 8) were similar to patients with milder disease at baseline and within long‐term therapeutic goal thresholds. Biomarker median percent changes from baseline were ‐91% for chitotriosidase, ‐87% for CCL18, ‐92% for glucosylsphingosine, and ‐80% for plasma glucosylceramide. Mean lumbar spine T‐score increased by 0.96, moving from the osteopenic to the normal range. Mean quality‐of‐life scores, mostly below normal at baseline, moved into ranges seen in healthy adults. Eliglustat was well‐tolerated; 98% of adverse events were mild or moderate and 94% were considered unrelated to treatment. Clinically meaningful improvements in all parameters continued or were maintained over 8 years, with the largest margins of improvement seen in the most severely affected patients.

Value of Glucosylsphingosine (Lyso-Gb1) as a Biomarker in Gaucher Disease: A Systematic Literature Review

“…For most patients, a significant reduction in plasma lyso-Gb1 occurred after ERT initiation before levelling off at a lower concentration and increasing when ERT was stopped [ 39 , 50 ]. Similar findings were observed after the initiation of SRT [ 43 ]. A retrospective analysis of 25 non-splenectomized patients with GD homozygous for the non-neuronopathic N370S GBA mutation in the GBA1 gene who received low-dose ERT (15 units/kg/month) revealed an exponential decay (Pearson product moment determination coefficient ( r 2 ), 0.84) in lyso-Gb1 plasma over 72 months [ 37 ].…”

“…Using the NICE STA method, risk of bias in the sole randomized controlled trial was deemed low, although bias regarding the allocation concealment process and between-group baseline similarities was unclear ( Table S1 ) [ 36 ]. Thirty non-randomized clinical trials and observational studies with full-study reporting were assessed using the Newcastle–Ottawa scoring tool [ 3 , 26 , 33 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 ], of which 19 were deemed to have a high risk of bias (score 0–3; Table S2 ). Thirty-two animal studies were assessed using the SYRCLE risk of bias tool [ 45 , 53 , 58 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , …”

“…In 17 studies, cross-sectional and longitudinal data on lyso-Gb1 in treated and untreated patients with GD were compared [ 33 , 36 , 37 , 38 , 39 , 40 , 41 , 43 , 44 , 45 , 47 , 48 , 49 , 50 , 51 , 52 , 53 ]. Results from 16 of the 17 studies showed that treatment with enzyme replacement therapy (ERT) and substrate reduction therapy (SRT) either alone or in combination produced marked reductions in lyso-Gb1 concentrations in plasma, cerebrospinal fluid (CSF), and urine relative to baseline or control ( Table S6 ).…”

“…Ten of the 17 studies provided different evidence levels of information on lyso-Gb1 as a response biomarker in GD ( Table 6 ) [ 36 , 37 , 38 , 39 , 40 , 43 , 44 , 47 , 49 , 51 ]. The results of a prospective, multicenter, cross-sectional, case-control study in treatment-naïve and splenectomized patients with type 1 GD showed that lyso-Gb1 concentrations in plasma (Pearson product moment correlation coefficient ( r ), –0.83) and RBC membranes (−0.65) correlated inversely with hematocrit [ 38 ].…”

Real‐world effectiveness of eliglustat in treatment‐naïve and switch patients enrolled in the International Collaborative Gaucher Group Gaucher Registry

“…While the treatment‐naïve cohort had less severe baseline disease than treatment‐naïve patients in the Phase 2 and Phase 3 ENGAGE clinical trials, it showed comparable improvements with eliglustat treatment, 12,13 achieving responses within therapeutic goal thresholds. Importantly, the largest therapeutic responses were seen in patients with the worst baseline disease status 19 (Figure 2). Similarly, improvements in switch patients paralleled those in the ENCORE switch trial of stable patients (34% of whom had a partial or total splenectomy 3 or more years before enrollment) at predefined therapeutic goals who switched to eliglustat after a mean of 10 years on ERT 20 .…”