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
Bibliographic record
Abstract
Abstract Introduction: Eliglustat, a ceramide analogue, is a novel, oral substrate-reduction therapy in development for Gaucher disease type 1 (GD1). We present 18-month results from ENGAGE (NCT00891202), a randomized, double-blind, placebo-controlled, Phase-3 trial (sponsored by Genzyme, a Sanofi company, Cambridge, MA) investigating the efficacy and safety of eliglustat in untreated adults with GD1. Methods: During the primary analysis period (PAP), 40 patients (mean age: 31.8 years; 20 males) with splenomegaly and thrombocytopenia and/or anemia were randomized 1:1 to receive eliglustat (50 or 100 mg BID depending on plasma levels) or placebo for 9 months and then entered a 9-month, open-label extension phase in which all patients received eliglustat. The primary efficacy endpoint was percent change in spleen volume (multiples of normal). Secondary endpoints included changes in hemoglobin levels, liver volume, and platelet counts. Bone efficacy endpoints included changes in bone marrow burden (BMB) scores, total bone mineral density (BMD), and T- and Z-scores. Results: In the 9-month PAP, eliglustat was superior to placebo in all primary and secondary endpoints; no patients discontinued due to an adverse event. For 18 of 20 patients who received 18 months of eliglustat, mean improvements from baseline continued (spleen: -45%, hemoglobin: +1.02 g/dL; liver: -11%; platelets: +58%). For 20 of 20 patients previously receiving placebo for 9 months who then crossed-over to eliglustat during the extension phase, mean improvements after 9 months of eliglustat were consistent with what was seen in the PAP in the eliglustat-treated patients: spleen: -31%; hemoglobin: +0.79 g/dL; liver: -7.3%; and platelets: +40%. During the PAP, BMB scores, indicating bone marrow infiltration, decreased in eliglustat patients and were unchanged in placebo patients; changes in total BMD and in T- and Z-scores showed a positive trend with eliglustat compared with placebo, although changes were not statistically significant. Eliglustat-treated patients showed continued improvements in bone parameters during the 9-month extension period. No new safety concerns were identified. Conclusion: ENGAGE met its primary and secondary efficacy endpoints in the PAP. Placebo cross-over patients showed improvements during the extension period similar to the eliglustat-treated patients during the PAP. Patients in the eliglustat-treatment group showed continued improvements in the first 9 months of the extension phase. Disclosures Amato: Protalix-Pfizer: Consultancy, travel reimbursement, advisory board fees, travel reimbursement, advisory board fees Other; Actelion: Consultancy, Honoraria, travel reimbursement, advisory board fees, travel reimbursement, advisory board fees Other; Shire: Consultancy, Honoraria, travel reimbursement, advisory board fees, travel reimbursement, advisory board fees Other; Genzyme, a Sanofi Company: Consultancy, Honoraria, Travel reimbursement Other. Off Label Use: Eliglustat is an investigational drug for the treatment of Gaucher disease type 1. Dasouki:Genzyme, a Sanofi Company: Consultancy, Travel reimbursement Other. Packman:Genzyme, a Sanofi Company: Consultancy, Research Funding, Travel reimbursement Other. Pastores:Genzyme, a Sanofi Company: Consultancy, Honoraria, Travel reimbursement Other. Balwani:Genzyme, a Sanofi Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Travel reimbursement Other. Mistry:Genzyme, a Sanofi Company: Consultancy, Honoraria, Research Funding, Travel reimbursement, Research grants Other. Shankar:Biomarin: Consultancy, received funds for fellowship training, for educational and patient meetings , received funds for fellowship training, for educational and patient meetings Other; Protalix-Pfizer: Consultancy, Honoraria, Travel reimbursement, received funds for fellowship training, for educational and patient meetings, Travel reimbursement, received funds for fellowship training, for educational and patient meetings Other; Shire: Consultancy, Honoraria, Travel reimbursement, received funds for fellowship training, for educational and patient meetings, Travel reimbursement, received funds for fellowship training, for educational and patient meetings Other; Genzyme, a Sanofi Company: Consultancy, Honoraria, Travel reimbursement, received funds for fellowship training, for educational and patient meetings Other; Actelion: Consultancy, received funds for fellowship training, for educational and patient meetings Other. Solano:Genzyme, a Sanofi Company: Consultancy, Honoraria, Travel reimbursement Other. Ross:Genzyme, a Sanofi Company: Employment. Angell:Genzyme, a Sanofi Company: Employment. Peterschmitt:Genzyme, a Sanofi Company: Employment.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.001 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.002 | 0.003 |
| Insufficient payload (model declined to judge) | 0.005 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".