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Cerdelga provides significant, long-term improvements in visceral and hematologic parameters in treatment-naive patients1
ENGAGE: Proven efficacy and safety in treatment-naive patient trials
The efficacy and safety of Cerdelga were studied in a Phase 3 trial (ENGAGE) of treatment-naive patients with Gaucher disease type 1 (GD1). ENGAGE included primary and open-label extension phases, in which patients were evaluated at 9 months and 2 years and were observed for up to 4.5 years.1-3
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Key study design parameters (primary and open-label extension phases)1,4
- ENGAGE was a randomized, double-blind, placebo-controlled, multicenter clinical study
- 40 treatment-naive patients were stratified according to baseline spleen volume and randomized in a 1:1 ratio to receive Cerdelga or placebo for the duration of the 9-month blinded primary analysis period
- On completing the 9-month primary analysis period, all patients had the opportunity to continue in the open-label ENGAGE trial extension, in which all patients received Cerdelga
Phase 3 naive key study design parameters (primary and open-label extension phases)1-5
IMs=intermediate metabolizers; EMs=extensive metabolizers; URMs=ultra-rapid metabolizers.
Primary Endpoint
% change in spleen volume (in multiples of normal [MN]) from baseline to 9 months as compared with placebo.
Secondary Endpoints
% change in liver volume and platelet count, and absolute change in hemoglobin level from baseline to 9 months as compared with placebo.
Exploratory Endpoints
Change in markers of bone disease, including bone marrow burden score, lumbar spine BMD Z-score, and femur BMD Z-score from baseline to 9 months as compared with placebo.
Median changes in disease biomarker levels including GM3, MIP-1ß, lyso-GL-1, chitotriosidase, and GL-1 from baseline to 9 months.
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Open-label Extension Phase
Mean increase in hemoglobin level and platelet count, and mean reduction in spleen and liver volumes from baseline in MN.
- At 2 years, clinical parameters were evaluated for patients
- Some patients were observed for up to 4.5 years
Exploratory Endpoints
Mean changes in bone marrow burden score, lumbar spine BMD Z-score, and femur BMD Z-score from 9 months to 4.5 years.
Median changes in disease biomarker levels including GM3, MIP-1β, lyso-GL-1, chitotriosidase, and GL-1 from 9 months to 4.5 years.
Inclusion Criteria
- Diagnosis of Gaucher disease type 1
- All patients had preexisting splenomegaly and hematologic abnormalities
- Patients were required to have received no treatment with SRT within 6 months or ERT within 9 months prior to randomization. All but 5 patients in the study had no prior therapy
Exclusion Criteria
- Current symptomatic bone disease
- Bone crises within 12 months before randomization
- History of splenectomy (partial or total), evidence of neurologic or pulmonary involvement
In treatment-naive patients, Cerdelga showed statistically significant improvements vs placebo in visceral and hematologic parameters at 9 months1
Reduction in spleen and liver volume from baseline1,2
Difference between treatment groups was 30% (p<0.0001). At baseline, mean spleen volumes were 12.5 MN (placebo) and 13.9 MN (Cerdelga).
Difference between treatment groups was 6.6% (p=0.0072). At baseline, mean liver volumes were 14 MN (placebo) and 14 MN (Cerdelga).
Improvement in hemoglobin level and platelet count from baseline1,2
Difference between treatment groups was 1.2 g/dL (p=0.0006). At baseline, mean hemoglobin levels were 12.8 g/dL (placebo) and 12.1 g/dL (Cerdelga).
Difference between treatment groups was 41% (p<0.0001). At baseline, mean platelet counts were 78.5 x 109/L (placebo) and 75.1 x 109/L (Cerdelga).
Baseline is defined as before the first dose of study medication or placebo in the primary analysis phase.
MN=multiples of normal.
ENGAGE long-term, open-label extension period
Improvements in visceral and hematologic parameters observed through 4.5 years1,5
Following the 9-month primary analysis period, all patients had the opportunity to continue to participate in the open-label ENGAGE trial extension, in which all patients received Cerdelga.4
Of the 40 patients in the primary analysis phase, 39 entered the extension phase, including the 20 patients in the placebo arm of the primary analysis phase. All patients were treated with Cerdelga, and some patients were followed for up to 4.5 years.3,4
Long-term, open-label extension data
All 20 patients in the placebo arm of the primary analysis phase joined the Cerdelga arm of the open-label extension phase.
Changes in spleen and liver volume from baseline for up to 2 years1-4
At the start of the primary analysis, mean spleen volumes were 12.5 MN (placebo) and 13.9 MN (Cerdelga).
At the start of the primary analysis, mean liver volumes were 1.4 MN (placebo) and 1.4 MN (Cerdelga).
Changes in hemoglobin level and platelet count from baseline for up to 2 years1-4
At the start of the primary analysis, mean hemoglobin levels were 12.8 g/dL (placebo) and 12.1 g/dL (Cerdelga).
At the start of the primary analysis, mean platelet counts were 78.5 x 109/L (placebo) and 75.1 x 109/L (Cerdelga).
Some patients were followed for up to 4.5 years of Cerdelga treatment. Due to decreasing sample size, results after the 2-year analysis require cautious interpretation.3
Baseline is defined as before the first dose of study medication in the primary analysis phase or open-label extension phase.
SEM=standard error of the mean; MN=multiples of normal; SD=standard deviation.
ENGAGE bone data studied in treatment-naive patients
Changes in exploratory bone data from baseline to 9 months2
The ENGAGE study was not powered or designed to detect treatment effect of Cerdelga on bone mineral density (BMD), and no conclusions may be drawn regarding BMD efficacy, reduction in fracture risk, or other bone pathologies in GD1.
Bone marrow burden score2
Bone marrow burden, or BMB score, is an MRI-based scoring that has been validated as a measure of bone marrow infiltration by Gaucher cells and as an indicator of the skeletal response to ERT.
Bone marrow burden score is the sum of lumbar spine and femur bone marrow burden scores, each ranging from 0 to 8.
Characterized BMB scores:
| Mild | Moderate | Marked as severe |
| 0-4 | 5-8 | 9-16 |
Z-score
DXA images of lumbar spine and femur were obtained for measurement of bone density. A Z-score compares a patient's bone density with the average bone density of people with the same gender and age. Z-score bone density scores are normal when >-2 and below normal when ≤-2.
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A majority of patients had moderate-to-severe marrow infiltration indicated by BMB score.
Exclusion criteria: Current symptomatic bone disease, bone crisis within 12 months before randomization.
LS=least squares; SD=standard deviation.
Exclusion criteria: Current symptomatic bone disease, bone crisis within 12 months before randomization.
LS=least squares; SD=standard deviation.
Exclusion criteria: Current symptomatic bone disease, bone crisis within 12 months before randomization.
LS=least squares; SD=standard deviation.
A majority of patients had moderate-to-severe marrow infiltration indicated by BMB score.
Exclusion criteria: Current symptomatic bone disease, bone crisis within 12 months before randomization.
LS=least squares; SD=standard deviation.
Exclusion criteria: Current symptomatic bone disease, bone crisis within 12 months before randomization.
LS=least squares; SD=standard deviation.
Exclusion criteria: Current symptomatic bone disease, bone crisis within 12 months before randomization.
LS=least squares; SD=standard deviation.
Changes in exploratory bone data from baseline to 4.5 years5,6
All 20 patients in the placebo arm of the primary analysis phase joined the Cerdelga arm of the open-label extension phase.4,5
ENGAGE (treatment-naive patients):
Due to decreasing sample size and the exploratory nature of the endpoint, the results of this analysis require cautious interpretation.
BMB=bone marrow burden; SEM=standard error of the mean.
SEM=standard error of the mean.
SEM=standard error of the mean.
BMB=bone marrow burden; SEM=standard error of the mean.
SEM=standard error of the mean.
SEM=standard error of the mean.
Exploratory disease-related biomarker reductions in ERT switch patients over time5
Biomarker data were exploratory endpoints and the clinical significance of these data is unknown. Patients were followed for up to 4.5 years of Cerdelga treatment. Due to decreasing sample size and the exploratory nature of the endpoint, results require cautious interpretation.
Serum lyso-GL-1 values were elevated in all patients at baseline, with a median value 61-fold above the upper limit of normal. Among patients with follow-up data, median decrease in serum lyso-GL-1 levels was 59% after 9 months (n=37) and 84% after 4.5 years (n=10).5
Adapted from Mistry et al. Am J Hematol. 2021.
Adverse reactions occurring in ≥10% of treatment-naive patients and more frequently than placebo in the primary analysis period1
| Adverse Reaction | Cerdelga (n=20) | Placebo (n=20) |
| Number of patients (%) | Number of patients (%) | |
| Arthralgia | 9 (45%) | 2 (10%) |
| Headache | 8 (40%) | 6 (30%) |
| Migraine | 2 (10%) | 0 (%) |
| Flatulence | 2 (10%) | 1 (5%) |
| Nausea | 2 (10%) | 1 (5%) |
| Oropharyngeal Pain | 2 (10%) | 1 (5%) |
- No patients discontinued the ENGAGE study due to adverse events (AEs) in the primary analysis period2
- No new safety signals were observed in the open-label extension period4
Phase 2 open-label key study design parameters (primary and extension phases)7,8
PMs=poor metabolizers; EMs=extensive metabolizers; PAP=primary analysis period; NSVT=nonsustained ventricular tachycardia.
Primary Endpoint
A composite endpoint requiring improvement from baseline to week 52 in at least 2 of the 3 main efficacy parameters (spleen volume,a hemoglobin level, and platelet count) that met the inclusion criteria for abnormal at baseline. Improvements were defined as a reduction of at least 15% in spleen volume and increases of at least 0.5 g/dL in hemoglobin level and 15% in platelet count.
Secondary Endpoints
Changes over time in the main efficacy parameters and liver volume MN (normal=2.5% of body weight).
This study was also designed to assess the safety and pharmacokinetics of Cerdelga.
Exploratory Endpoints
Median changes in disease biomarker levels including chitotriosidase, CCL18, GL-1, and lyso-GL-1 from baseline to week 52.
Key Inclusion Criteria
- Diagnosis of Gaucher disease type 1
- 18 to 65 years of age
- Splenomegaly (volume of at least 10MN)
- Thrombocytopenia and/or anemia
Key Exclusion Criteria
- Splenectomy
- ERT or miglustat in past 12 months
- Bisphosphonates in past 3 months
- Active bone disease in the past 12 months
- Neurological complications
Dosing
- 50 mg or 100 mg eliglustat tartrate (equivalent to 42 or 84 mg Cerdelga) dosed by plasma trough levels
aSpleen volume was determined from MRI or spiral computed tomography images.
MN=multiples of normal.
Cerdelga continued improvements in visceral and hematologic parameters through 4 years1,7
In an uncontrolled study, improvements in spleen volume, liver volume, hemoglobin level, and platelet count continued through the 4-year treatment period. Some patients were then observed up to 8 years.7
Phase 2 trial also analyzed subgroups according to baseline disease severity7
Due to small sample size, these analyses require cautious interpretation and clinical significance of these data is unknown
aAnemia: none/mild (hemoglobin ≥11 to <12 g/dL males; ≥10 to <11 g/dL females) vs moderate/severe (hemoglobin ≥9 to <11 g/dL males; ≥9 to <10 g/dL females)
Exploratory Gaucher disease biomarker reductions over time7
Biomarker data were exploratory endpoints and the clinical significance of these data is unknown.
Due to small sample size and exploratory nature of the endpoint, these analyses require cautious interpretation.
Adapted from Lukina et al. Am J Hematol. 2019.7
aExcludes 2 patients with absent chitotriosidase activity due to a homozygous null mutation in the CHIT1 gene.7
Normal ranges: GL-1, <2.0 to 6.6 μg/mL; CCL18, 17 to 246 ng/mL; chitotriosidase, <15 to 181 nmol/hr/mL; lyso-GL-1, <5 ng/mL.7
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Indication
References: 1. Cerdelga [prescribing information]. Cambridge, MA: Sanofi. 2. Mistry PK, Lukina E, Ben Turkia H, et al. Effect of oral eliglustat on splenomegaly in patients with Gaucher disease type 1. The ENGAGE randomized clinical trial. JAMA. 2015;313(7):695-706. 3. Data on file. Sanofi. 4. Mistry PK, Lukina E, Ben Turkia H, et al. Outcomes after 18 months of eliglustat therapy in treatment-naïve adults with Gaucher disease type 1: the phase 3 ENGAGE trial. Am J Hematol. 2017;92(11):1170-1176. 5. Mistry PK, Lukina E, Ben Turkia H, et al. Clinical outcomes after 4.5 years of eliglustat therapy for Gaucher disease type 1: Phase 3 ENGAGE trial final results. Am J Hematol. 2021;96(9):1156-1165. 6. Cox TM, Charrow J, Lukina E, Mistry PK, Foster MC, Peterschmitt MJ. Long-term effects of eliglustat on skeletal manifestations in clinical trials of patients with Gaucher disease type 1. Genet Med. 2023;25(2):100329. 7. Lukina E, Watman N, Dragosky M, et al. Outcomes after 8 years of eliglustat therapy for Gaucher disease type 1: final results from the phase 2 trial. Am J Hematol. 2019;94(1):29-38. 8. Lukina E, Watman N, Arreguin EA, et al. A phase 2 study of eliglustat tartrate (Genz-112638), an oral substrate reduction therapy for Gaucher disease type 1. Blood. 2010;116(6):893-899. 9. Scott LJ. Eliglustat: a review in Gaucher disease type 1. Drugs. 2015;75(14):1669-1678. 10. H, Lukina E, Watman N, et al. Long-term treatment response based on severity of Gaucher disease type 1 at baseline after 8 years of treatment with oral eliglustat: final efficacy and safety results from a phase 2 clinical trial in treatment-naïve adults. Oral presentation at: WORLDSymposium™; February 5-9, 2018; San Diego.
