Treatment-naïve Patient Trials

ENGAGE: Proven Efficacy and Safety in Treatment-naïve Patient Trials

The efficacy and safety of Cerdelga were studied in a Phase 3 trial (ENGAGE) of treatment-naïve patients with Gaucher disease type 1 (GD1). ENGAGE included a primary and open-label extension phase of Cerdelga, in which patients were evaluated at 9 months and 2 years and were observed for up to 4.5 years.^1-3

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-naïve 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 naïve 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 Z-score, and femur 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.

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 Z-score, and femur 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.

Key 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-naïve Patients, Cerdelga Showed Statistically Significant Improvements vs Placebo in Visceral and Hematologic Parameters at 9 Months¹

Reduction in spleen and liver volume from baseline^1,2

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 baseline^1,2

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 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 Years^1,5

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 years^1-4

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 years^1-4

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-naïve 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: 0-4
Moderate: 5-8
Marked to severe: 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.

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.

Change in exploratory bone data from baseline to 4.5 years^5,6

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-naïve patients):
The mean total BMB score shifted from the marked-to-severe range at baseline to the moderate range over 4.5 years with Cerdelga treatment. 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.

Exploratory disease-related biomarker reductions in treatment-naïve 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.

Normalized chitotriosidase activity was elevated in all patients at baseline, with a median value 96-fold above the upper limit of normal; the median percent decrease was 48% after 9 months (n=38) and 82% after 4.5 years (n=11)⁵

Adapted from Mistry et al. Am J Hematol. 2021.

Adverse Reactions Occurring in ≥10% of Treatment-naïve Patients and More Frequently Than Placebo in the Primary Analysis Period¹

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)^7-9

PMs=poor metabolizers.

EMs=extensive metabolizers.

PAP=primary analysis period.

NSVT=nonsustained ventricular tachycardia.

Primary Efficacy Endpoint

A composite endpoint requiring improvement from baseline to week 52 in at least 2 of the 3 main efficacy parameters (spleen volume,* 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.

Additional 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 ≥10 x normal)
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 through levels

*Spleen volume was determined from MRI or spiral computed tomography images.

Cerdelga Continued Improvements in Visceral and Hematologic Parameters Through 4 Years^1,7

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 Severity^7,9

Due to small sample size, these analyses require cautious interpretation and clinical significance of these data is unknown

*None: ≥12 g/dL (M), ≥11 g/dL (F), Mild: ≥11 to <12 g/dL (M), ≥10 to <11 g/dL (F), Moderate: ≥9 to <11 g/dL (M), ≥9 to <10 g/dL (F), Severe: <9 g/dL (M and F).
F=female; M=male; MN=multiples of normal.

Exploratory Gaucher disease biomarker reductions over time⁷

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

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.

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Indication and Usage

CERDELGA is indicated for the long-term treatment of adult patients with Gaucher disease type 1 (GD1) who are CYP2D6 extensive metabolizers (EMs), intermediate metabolizers (IMs), or poor metabolizers (PMs) as detected by an FDA-cleared test.

Limitations of Use:

Patients who are CYP2D6 ultra-rapid metabolizers (URMs) may not achieve adequate concentrations of CERDELGA to achieve a therapeutic effect.
A specific dosage cannot be recommended for those patients whose CYP2D6 genotype cannot be determined (indeterminate metabolizers).

Important Safety Information

CONTRAINDICATIONS

CERDELGA is contraindicated in the following patients based on CYP2D6 metabolizer status due to the risk of cardiac arrhythmias from prolongation of the PR, QTc, and/or QRS cardiac intervals:

Extensive Metabolizers (EMs) taking a strong or moderate CYP2D6 inhibitor concomitantly with a strong or moderate CYP3A inhibitor, EMs with moderate or severe hepatic impairment, or EMs with mild hepatic impairment and taking a strong or moderate CYP2D6 inhibitor.
Intermediate Metabolizers (IMs) taking a strong or moderate CYP2D6 inhibitor concomitantly with a strong or moderate CYP3A inhibitor, IMs taking a strong CYP3A inhibitor, or IMs with any degree of hepatic impairment.
Poor Metabolizers (PMs) taking a strong CYP3A inhibitor, or PMs with any degree of hepatic impairment.

WARNINGS AND PRECAUTIONS

CERDELGA is predicted to cause increases in ECG intervals (PR, QTc, and QRS) at substantially elevated plasma concentrations and may increase risk of cardiac arrhythmias. Use of CERDELGA is contraindicated, to be avoided, or requires dosage adjustment in patients taking CYP2D6 or CYP3A inhibitors, depending on CYP2D6 metabolizer status, type of inhibitor, or degree of hepatic impairment. Avoid use of CERDELGA in patients with pre-existing cardiac disease, long QT syndrome, or in combination with Class IA or Class III antiarrhythmic medications.

ADVERSE REACTIONS

The most common adverse reactions (≥10%) to CERDELGA include: fatigue, headache, nausea, diarrhea, back pain, pain in extremities, and upper abdominal pain.

DRUG INTERACTIONS

Coadministration of CERDELGA with CYP2D6 or CYP3A inhibitors may increase eliglustat concentrations, which may increase the risk of cardiac arrhythmias from prolongations of the PR, QTc, and/or QRS cardiac interval. Use of CERDELGA is contraindicated, to be avoided, or may require dosage adjustment depending on the concomitant drug and CYP2D6 metabolizer status. See section 7 of the full Prescribing Information for more details and other potentially significant drug interactions.

USE IN SPECIFIC POPULATIONS

Available data on the use of CERDELGA in pregnant women is not sufficient to assess drug-associated risks of major birth defects, miscarriage, or adverse maternal or fetal outcomes. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CERDELGA and any potential adverse effects on the breastfed child from CERDELGA or from the underlying maternal condition.

Use of CERDELGA in patients with renal impairment is based on the patient’s CYP2D6 metabolizer status. Avoid use of CERDELGA in EMs with end-stage renal disease (ESRD), and IMs and PMs with any degree of renal impairment.

Use of CERDELGA is contraindicated or may require dosage adjustment in patients with hepatic impairment based on CYP2D6 metabolizer status, concomitant use of CYP2D6 or CYP3A inhibitors, and degree of hepatic impairment.

Please see accompanying full Prescribing Information.

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. Lau 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. 10. Scott LJ. Eliglustat: a review in Gaucher disease type 1. Drugs. 2015;75(14):1669-1678.

See Safety

Indication and Usage

Limitations of Use:

Patients who are CYP2D6 ultra-rapid metabolizers (URMs) may not achieve adequate concentrations of CERDELGA to achieve a therapeutic effect.
A specific dosage cannot be recommended for those patients whose CYP2D6 genotype cannot be determined (indeterminate metabolizers).

Important Safety Information

CONTRAINDICATIONS

CERDELGA is contraindicated in the following patients based on CYP2D6 metabolizer status due to the risk of cardiac arrhythmias from prolongation of the PR, QTc, and/or QRS cardiac intervals:

Extensive Metabolizers (EMs) taking a strong or moderate CYP2D6 inhibitor concomitantly with a strong or moderate CYP3A inhibitor, EMs with moderate or severe hepatic impairment, or EMs with mild hepatic impairment and taking a strong or moderate CYP2D6 inhibitor.
Intermediate Metabolizers (IMs) taking a strong or moderate CYP2D6 inhibitor concomitantly with a strong or moderate CYP3A inhibitor, IMs taking a strong CYP3A inhibitor, or IMs with any degree of hepatic impairment.
Poor Metabolizers (PMs) taking a strong CYP3A inhibitor, or PMs with any degree of hepatic impairment.

WARNINGS AND PRECAUTIONS

ADVERSE REACTIONS

The most common adverse reactions (≥10%) to CERDELGA include: fatigue, headache, nausea, diarrhea, back pain, pain in extremities, and upper abdominal pain.

DRUG INTERACTIONS

USE IN SPECIFIC POPULATIONS

Please see accompanying full Prescribing Information.

ENGAGE: Proven Efficacy and Safety in Treatment-naïve Patient Trials

Phase 3 naïve key study design parameters (primary and open-label extension phases)1-5

Primary Endpoint

Secondary Endpoints

Exploratory Endpoints

Open-label Extension Phase

Exploratory Endpoints

Inclusion Criteria

Key Exclusion Criteria

In Treatment-naïve 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

Improvement in hemoglobin level and platelet count from baseline1,2

ENGAGE Long-term, Open-label Extension Period

Improvements in Visceral and Hematologic Parameters Observed Through 4.5 Years1,5

Long-term, open-label extension data

Changes in spleen and liver volume from baseline for up to 2 years1-4

Changes in hemoglobin level and platelet count from baseline for up to 2 years1-4

ENGAGE Bone Data Studied in Treatment-naïve Patients

Changes in exploratory bone data from baseline to 9 months2

Bone marrow burden score2

Z-score

Change in exploratory bone data from baseline to 4.5 years5,6

Exploratory disease-related biomarker reductions in treatment-naïve patients over time5

Adverse Reactions Occurring in ≥10% of Treatment-naïve Patients and More Frequently Than Placebo in the Primary Analysis Period1

Phase 2 open-label key study design parameters (primary and extension phases)7-9

Primary Efficacy Endpoint

Additional Endpoints

Exploratory Endpoints

Key Inclusion Criteria

Key Exclusion Criteria

Dosing

Cerdelga Continued Improvements in Visceral and Hematologic Parameters Through 4 Years1,7

Phase 2 Trial Also Analyzed Subgroups According to Baseline Disease Severity7,9

Due to small sample size, these analyses require cautious interpretation and clinical significance of these data is unknown

Exploratory Gaucher disease biomarker reductions over time7

Have a question about Gaucher disease type 1 or Cerdelga?

Curious about the mechanism of action of Cerdelga?

In Treatment-naïve Patients, Cerdelga Showed Statistically Significant Improvements vs Placebo in Visceral and Hematologic Parameters at 9 Months¹

Reduction in spleen and liver volume from baseline^1,2

Improvement in hemoglobin level and platelet count from baseline^1,2

Improvements in Visceral and Hematologic Parameters Observed Through 4.5 Years^1,5

Changes in spleen and liver volume from baseline for up to 2 years^1-4

Changes in hemoglobin level and platelet count from baseline for up to 2 years^1-4

Changes in exploratory bone data from baseline to 9 months²

Bone marrow burden score²

Change in exploratory bone data from baseline to 4.5 years^5,6

Exploratory disease-related biomarker reductions in treatment-naïve patients over time⁵

Adverse Reactions Occurring in ≥10% of Treatment-naïve Patients and More Frequently Than Placebo in the Primary Analysis Period¹

Phase 2 open-label key study design parameters (primary and extension phases)^7-9

Cerdelga Continued Improvements in Visceral and Hematologic Parameters Through 4 Years^1,7

Phase 2 Trial Also Analyzed Subgroups According to Baseline Disease Severity^7,9

Exploratory Gaucher disease biomarker reductions over time⁷