Disease Stability Maintained for the 4 Clinical Parameters Studied in Patients Who Switched From ERT to Cerdelga
The efficacy and safety of Cerdelga in adult patients with Gaucher disease type 1 (GD1) previously treated with enzyme replacement therapy (ERT) were studied in a Phase 3 trial (ENCORE). ENCORE included a primary and open-label extension phase of Cerdelga, in which patients were evaluated at 12 months and 2 years. Some patients were observed for up to 4 years.1,2
KEY STUDY DESIGN PARAMETERS (PRIMARY AND OPEN-LABEL EXTENSION PHASES)1,2
- ENCORE was a randomized, open-label, active-controlled, noninferiority, multicenter clinical study
- 159 adult patients previously treated with ERT were randomized 2:1 to receive Cerdelga or imiglucerase for the duration of the 12-month primary analysis period
- All patients who completed the 12-month primary analysis period were allowed to participate in the open-label extension phase and receive Cerdelga
Phase 3 switch key study design parameters (primary and open-label extension phases)1-4
Patients in Cerdelga capsules
group switched from:
Primary Composite Endpoint
Stability in all 4 component domains (hemoglobin level, platelet count, liver volume, and spleen volume) based on changes between baseline and 12 months.
The percentages of patients meeting the criteria for stability in the individual components of the composite endpoint based on mean changes between baseline and 12 months.
Mean changes in markers of bone disease, including bone marrow burden score, lumbar spine Z-score, and femur Z-score from baseline to 12 months.
Median changes in disease biomarker levels including chitotriosidase, GL-1, and GM3 from baseline to 12 months.
Open-label Extension Phase Composite Stability Endpoint
Stability in clinical parameters (composite of spleen and liver volume, hemoglobin level, and platelet count)
- At 1 and 2 years, clinical parameters were evaluated for patients
- Some patients were observed for up to 4 years
Mean changes in bone marrow burden score, lumbar spine Z-score, and femur Z-score from 12 months to 4 years.
Median changes in disease biomarker levels including chitotriosidase, GL-1, and GM3 from 12 months to 4 years.
- Diagnosis of Gaucher disease type 1
- All patients were previously treated with ERT (≥3 years of ERT) and met prespecified baseline therapeutic goals of stabilized disease in hemoglobin concentrations, platelet count, spleen volume, liver volume, and bone disease
Prespecified thresholds of change: hemoglobin level <1.5 g/dL decrease, platelet count <25% decrease, liver volume <20% increase, and spleen volume <25% increase.
Key Exclusion Criteria
- Current symptomatic bone disease
- Bone crisis within 12 months before randomization
- Neurological complications
ENCORE Switch Patient Trial Primary Analysis Data
After 1 year of treatment, ENCORE study results showed noninferiority to imiglucerase; 85% of patients receiving Cerdelga met the primary composite endpoint compared with 94% in the patients receiving imiglucerase. The lower bound of the 95% CI for the difference in percentage (–17.6%) was within the prespecified noninferiority threshold of –25%. There were no clinically meaningful differences between groups for any of the 4 parameters.1,4
Cerdelga Demonstrated Noninferior Efficacy to imiglucerase (ERT) in Maintaining Disease Stability Across the 4 Clinical Parameters Studied in Switch Patients After 1 Year1,4
Of the patients who did not meet stability criteria for the individual components, 12 of 15 Cerdelga patients and 3 of 3 imiglucerase patients remained within published therapeutic goals for Gaucher disease type 1.1
Per-protocol population. Note: Error bars represent exact 95% CIs around the proportion.
*Spleen percentages are based on the total number of nonsplenectomized patients in each treatment group.4
Adapted from Cox et al. Lancet. 2015.
Maintained stability in spleen and liver volume for up to 12 months1,4,5
Maintained stability in hemoglobin level and platelet count for up to 12 months 1,4,5
Baseline is defined as before the first dose of study medication in the primary analysis phase. MN=multiples of normal.
All patients who completed the 12-month primary analysis period were allowed to participate in the open-label extension (OLE) phase and receive Cerdelga. Of the 159 patients in the primary analysis phase, 152 entered the extension phase (101/102 patients in the Cerdelga arm and 51/52 patients in the imiglucerase arm continued in the OLE phase and switched to Cerdelga).
ENCORE Long-term, Open-label Extension Period
Cerdelga maintained stability in visceral and hematologic disease parameters for up to 4 years in patients previously stabilized on ERT2
- In the open-label extension phase of ENCORE, 141 of 146 patients (42 patients previously treated with enzyme treatment therapy and 99 who continued treatment with Cerdelga) were evaluated for stability, as defined in the initial 12 months of the trial, in clinical parameters (composite of spleen volume, liver volume, hemoglobin level, and platelet count)1
- Stability was shown in 120/141 (85%) patients at 1 year and 111/129 (86%) patients at 2 years of Cerdelga exposure1
- 91% of patients (42/46) treated with Cerdelga for 4 years maintained stability relative to their baseline values for all 4 clinical variables (liver and spleen volumes, hemoglobin level, and platelet count)2
- 96% of patients (44/46) maintained all 4 of these values within prespecified therapeutic goals2
Some patients were followed for up to 4 years of Cerdelga treatment. Due to decreasing sample size, results after the 2-year analysis require cautious interpretation.
Mean changes from baseline in individual components of the primary endpoint composite score2
Adapted from Cox et al. Blood. 2017.
Overall, 157 patients in the ENCORE study were treated with Cerdelga during the primary analysis and/or extension phase; 46 of these patients had data available for a period of 4 years. Due to decreasing sample size, results after the 2-year analysis require cautious interpretation.2
Baseline was defined as the last available assessment before Cerdelga treatment initiation (Day 1 for patients originally randomized to Cerdelga and week 52 + 1 day for patients originally randomized to imiglucerase).2
LS=least-square; CI=confidence interval; MN=multiples of normal.
After 1 year, 98% (138/141) of patients with Gaucher disease type 1 who switched to Cerdelga after long-term ERT preferred an oral treatment over intravenous therapy2
Watch a Video of a Real Patient Who Switched to Cerdelga
Patient stories reflect the real-life experiences of persons diagnosed with Gaucher disease type 1 who have been prescribed Cerdelga. However, individual experiences may vary. Patient stories are not necessarily representative of what another person using Cerdelga may experience. This patient was compensated for their time creating this video.
My name is Shauna Mangum. I was diagnosed with Gaucher disease in July of 1995.
Experiences from as far back as I can remember were nosebleeds—that was the major thing that comes to mind—they indicated there was something not right. I would have nosebleeds that would last several hours; they were frequent, sometimes every day. I also had bone pains, which was dismissed as growing pains. In 1990 I was hospitalized for a severe bleeding episode. They immediately called a hematologist because the lab had notified my doctor. So I was moved over to another hospital and seen by a hematologist right away who immediately admitted me into the hospital. I had a platelet count of 11,000. He said I had an enlarged spleen, and he was concerned that I could have leukemia. That took 5 years for a diagnosis.
Yeah, I feel like I’ve [been] given a second chance at experiencing what life has to offer. I began enzyme replacement therapy in March of 2000. It was exciting at first, but the time—very time consuming spending 3 to 4 hours getting an IV every 2 weeks for a busy mom with young children. It’s hard to find a babysitter, or you take the kids with you and hope that they don’t run all over the infusion site destroying things.
It’s extremely important to have a good relationship with a physician that is knowledgeable about Gaucher disease. Together, we discuss challenges, treatments, complex issues that they may want to address.
Currently I take Cerdelga. Cerdelga is an oral treatment, and I take a capsule in the morning and a capsule at night, every day. I have more time for myself. I don’t have to schedule ERT. I don’t have to know that I’ve got those 3 hours that I have to commit to ERT every 2 weeks. I don’t have to do that anymore. It’s just become part of my routine. I—all I have to do is take a pill and go on my way.
Today I feel really good; I am much more engaged in many more activities in my life than I ever thought I would be. I continue to run. I’ve run 2 full marathons, 2 half marathons. I run because I enjoy running. My kids are busy, and they keep me going. I work full time.
Talk with your doctor to find out if Cerdelga is right for you.
You may also go to www.Cerdelga.com for the Full Prescribing Information including the Patient Medication Guide, or call Genzyme Corporation at 1-800-745-4447.
CERDELGA (eliglustat) is a prescription medicine used for the long-term treatment of Gaucher disease type 1 (GD1) in adults who are CYP2D6 extensive metabolizers (EMs), intermediate metabolizers (IMs), or poor metabolizers (PMs) as detected by an FDA-cleared test. Your doctor will perform a test to make sure that CERDELGA is right for you.
Limitations of Use:
CYP2D6 ultra-rapid metabolizers may not achieve adequate concentrations of CERDELGA to achieve a therapeutic effect.
A specific dose cannot be recommended for CYP2D6 indeterminate metabolizers.
Important Safety Information
Certain patients should not use CERDELGA based on their CYP2D6 metabolizer status due to an increased risk of side effects, including heart problems. Do not use CERDELGA if you are:
An Extensive Metabolizer (EM) taking a medicine that is a strong or moderate CYP2D6 inhibitor along with another medicine that is a strong or moderate CYP3A inhibitor, an EM with moderate or severe liver problems, or an EM with mild liver problems and taking a medicine that is a strong or moderate CYP2D6 inhibitor. An Intermediate Metabolizer (IM) taking a medicine that is a strong or moderate CYP2D6 inhibitor along with another medicine that is a strong or moderate CYP3A inhibitor, an IM taking a medicine that is a strong CYP3A inhibitor, or an IM with any degree of liver problems.
A Poor Metabolizer (PM) taking a medicine that is a strong CYP3A inhibitor, or a PM with any degree of liver problems.
Your doctor will perform a test to help determine if CERDELGA is right for you.
CERDELGA can affect the way other medicines work and other medicines can affect how CERDELGA works. Using CERDELGA with other medicines or herbal supplements may cause an increased risk of side effects, including changes in electrical activity of your heart (ECG changes) and irregular heart beat (arrhythmias). Especially tell your doctor if you take St. John's Wort, or medicines for fungal infections, tuberculosis, seizures, heart conditions, high blood pressure, or depression or other mental health problems. Your doctor may need to prescribe a different medicine, change your dose of other medicines, or change your dose of CERDELGA. Tell your doctor about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements before you start taking them.
Before taking CERDELGA, tell your doctor about all of your medical conditions, including heart problems (including a condition called long QT syndrome), a history of heart attack, kidney or liver problems. If you are pregnant or plan to become pregnant or breastfeed, talk to your doctor. It is not known if CERDELGA will harm your unborn baby. Talk to your doctor if you are breastfeeding or planning to breastfeed. It is not known if CERDELGA passes into your breast milk. You and your doctor will decide if you should take CERDELGA or breastfeed. You should not do both.
CERDELGA, used with certain other medications, may cause changes in the electrical activity of your heart (ECG changes) and irregular heartbeat (arrhythmias). Tell your doctor if you have new symptoms such as palpitations, fainting, or dizziness.
The most common side effects (≥10%) of CERDELGA include: tiredness, headache, nausea diarrhea, back pain, pain in extremities, and upper abdominal pain. Call your doctor for medical advice about adverse effects.
Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of CERDELGA. Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.
It is not known if CERDELGA is safe and effective in children.
Please see the full Prescribing Information, including the Patient Medication Guide, for CERDELGA.
ENCORE Bone Data in Adult Patients Who Switched From ERT to Cerdelga
Changes in exploratory bone data from baseline to 12 months4
The ENCORE 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 score6
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:
Marked to severe: 9-16
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.
Change of mean was calculated by subtracting mean (SD) values at baseline from mean (SD) values at 12 months (as reported in Cox et al, Blood, 2015).
Changes in exploratory bone data from baseline to 4 years2,7
The mean total BMB score remained in the moderate range over 4 years with Cerdelga treatment. Due to decreasing sample size and the exploratory nature of the endpoint, the results of this analysis require cautious interpretation.
SEM=standard error of the mean.
Exploratory disease-related biomarker reductions in ERT switch patients over time2
Biomarker data were exploratory endpoints and the clinical significance of these data is unknown. Patients were followed for up to 4 years of Cerdelga treatment. Due to decreasing sample size and the exploratory nature of the endpoint, results require cautious interpretation.
Adapted from Cox et al. Blood. 2017.
aExcludes patients with absent chitotriosidase activity due to a homozygous null mutation in the CHIT1 gene.2
Adverse reactions occurring in ≥5% of patients switching from ERT to Cerdelga and more frequently than imiglucerase in the primary analysis period1,4*
- Two (2%) patients given Cerdelga discontinued the study due to adverse events in the primary analysis period4
- No new safety signals were observed in the open-label extension period2
*ENCORE was not designed to support comparative claims for Cerdelga for the adverse reactions reported in this table.
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
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.
The most common adverse reactions (≥10%) to CERDELGA include: fatigue, headache, nausea, diarrhea, back pain, pain in extremities, and upper abdominal pain.
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. Cox TM, Drelichman G, Cravo R, et al. Eliglustat maintains long-term clinical stability in patients with Gaucher disease type 1 stabilized on enzyme therapy. Blood. 2017;129(17):2375-2383. 3. Data on file. Sanofi. 4. Cox TM, Drelichman G, Cravo R, et al. Eliglustat compared with imiglucerase in patients with Gaucher’s disease type 1 stabilised on enzyme replacement therapy: a phase 3, randomized, open-label, non-inferiority trial. Lancet. 2015;385(9985):2355-2362 and suppl. 5. Data on file. Sanofi. 6. 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. 7. 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.