Cerdelga® (eliglustat) Osteonecrosis Study

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Risk factors for osteonecrosis were evaluated in patients receiving therapy.^1-3

Observational, retrospective, 20‑year study: Evaluation of risk factors for osteonecrosis in patients receiving treatment for Gaucher disease type 1 (GD1)⁴

Understanding the risk of osteonecrosis (also known as avascular necrosis, or AVN) is crucial when managing GD1. Osteonecrosis is one of the most debilitating, severe, and irreversible manifestations of GD1, and any patient with GD1 is at risk, even when receiving treatment.^4,5

This 20-year, observational, retrospective study evaluated certain risk factors contributing to osteonecrosis in patients receiving therapy.⁴

Patients with GD1 may be at increased risk for osteonecrosis if they have⁴:

Heteroallelic p.N409S GBA1 genotype

Increased residual glucosylsphingosine (lyso-GL-1) levels after starting treatment

Treatment history with a specific ERT

History of osteonecrosis prior to initiation of treatment

About osteonecrosis

GD1 causes cellular accumulation of glucosylceramide and lyso-GL-1, leading to complex bone diseases, including osteonecrosis⁴

Osteonecrosis refers to the death of bone tissue, which may be caused by a lack of blood supply⁴

Osteonecrosis from GD1 is devastating and irreversible, causing⁵:

Pain
Chronic disability
Need for orthopedic surgeries
Reduced quality of life

The underlying mechanism(s) of osteonecrosis in Gaucher disease is not fully understood⁴

82% of patients with GD1 have evidence of bone disease, including osteonecrosis, which can manifest at all ages.³

Patients with GD1 are at risk for osteonecrosis, even while on treatment⁴

Observational, retrospective, 20-year study: Study design

Retrospective, observational, single‑center study of 155 patients with GD1 followed longitudinally for 20 years
Patients were followed every 1 to 2 years with standard-of-care evaluations, including magnetic resonance imaging (MRI) to assess organomegaly and bone marrow infiltration, and laboratory testing
Serum samples were collected at each clinic visit to determine biomarker trends for lyso-GL-1 and chitotriosidase (chito), as well as other indicators of disease
During the observational period, patients received a total of 834 treatment years for imiglucerase (ERT), 310 treatment years for velaglucerase alfa (ERT), and 238 treatment years for Cerdelga (SRT)

This is a single-center study. It was also retrospective and observational. This study was not a randomized, controlled study
Tertiary referral center: The incidences of osteonecrosis reported in this study may or may not be reflective of the incidence that would be observed in other clinics, particularly ones that are not tertiary referral centers for Gaucher disease
The treatment and management decisions reported were directed by the clinical judgment of the treatment team at this single center. Treatment decisions for each patient are due to a number of different factors, including but not limited to the patient’s clinical status and availability of each therapy option

No patients taking Cerdelga experienced osteonecrosis in this observational, 20-year study⁴

Incidence of osteonecrosis while on therapy

Osteonecrosis episodes were counted per total number of years on each type of treatment; over this 20-year period, some patients may have switched from one treatment to another
During the 20-year span of this study, there were 16 episodes of osteonecrosis in 14 patients, with 2 episodes each occurring in 2 patients

For Cerdelga and velaglucerase alfa, data are only available starting from 2014 and 2010, respectively, when they were approved by the FDA.^6,7

For more information about this data and the study, see the article in eLife.

How treatment impacted GD-1–associated biomarkers over 20 years⁴

Levels of lyso-GL-1 while on therapy

Normal healthy control levels of lyso-GL-1 were ≤1 ng/mL.⁴

Patients with high levels of residual lyso‑GL-1^a had an increased risk for osteonecrosis in this observational study^4,8

Levels of chitotriosidase while on therapy

CHIT1 genotyping was performed to normalize serum levels.⁴

There was no observed association between levels of residual chito and the risk of osteonecrosis in this group of patients⁴

This study was observational and not designed to compare the outcomes of treatment or draw conclusions on the effect of one treatment over another.⁴

During this 20-year period, some patients may have switched treatments.⁴

^aResidual lyso-GL-1 refers to serum concentration measured in a sample taken at close proximity to the onset of osteonecrosis (but not levels prior to treatment initiation).⁴

Findings: The 4 risk factors for osteonecrosis in patients with GD1⁴

Heteroallelic p.N409S GBA1 genotype

Heteroallelic N409S GD1 patients were 10 times more likely than N409S homozygous GD1 patients to develop osteonecrosis during treatment⁴

Increased residual lyso-GL-1 levels after starting treatment

A higher residual serum lyso‑GL-1^a was correlated with an increased risk of developing osteonecrosis during treatment⁴

Treatment history with a specific ERT

Patients received cumulative 310 treatment years velaglucerase and there were 10 episodes of osteonecrosis, which is 3.2 episodes per 100 treatment years of velaglucerase⁴

History of osteonecrosis prior to initiation of treatment

Patients had a 4.8 times higher risk for osteonecrosis while receiving treatment if they had a history of osteonecrosis prior to treatment initiation⁴

^aResidual lyso-GL-1 refers to serum concentration measured in a sample taken at close proximity to the onset of osteonecrosis (but not prior to treatment initiation).⁴

Curious how Cerdelga impacted other bone health parameters in patients with GD1?

Explore clinical trial results for bone marrow burden, bone mineral density, and bone pain for patients with GD1

Bone data in patients new to treatment

Learn More →

Bone data in switch patients

Learn More →

Indication

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.

Indication

Important Safety Information

References: 1. Data on file. Sanofi. 2. Cox TM, Charrow J, Lukina E, et al. Long-term effects of eliglustat on skeletal manifestations in clinical trials of patients with Gaucher disease type 1. Genet Med. 2023;25(2):100329. 3. Goker-Alpan O. Mol Genet Metab. 2011;104(4):438-447. 4. Basiri M, Ghaffari ME, Ruan J, et al. Osteonecrosis in Gaucher disease in the era of multiple therapies: biomarker set for risk stratification from a tertiary referral center. Elife. 2023;12:e87537. 5. Hughes D, Mikosch P, Belmatoug N, et al. Gaucher disease in bone: from pathophysiology to practice. J Bone Miner Res. 2019;34(6):996-1013. 6. Cerdelga (eliglustat) [prescribing information]. Genzyme Corporation, Cambridge, MA. 7. VPRIV (velaglucerase alfa) [prescribing information]. Takeda Pharmaceuticals, Lexington, MA. 8. Murugesan V, Chuang WL, Liu J, et al. Glucosylsphingosine is a key biomarker of Gaucher disease. Am J Hematol. 2016;91(11):1082‑1089.

Cerdelga® (eliglustat) Osteonecrosis Retrospective Study

Risk factors for osteonecrosis were evaluated in patients receiving therapy.1-3

Observational, retrospective, 20‑year study: Evaluation of risk factors for osteonecrosis in patients receiving treatment for Gaucher disease type 1 (GD1)4

Patients with GD1 may be at increased risk for osteonecrosis if they have4:

About osteonecrosis

82% of patients with GD1 have evidence of bone disease, including osteonecrosis, which can manifest at all ages.3

Patients with GD1 are at risk for osteonecrosis, even while on treatment4

Observational, retrospective, 20-year study: Study design

Study Overview4

Inclusion Criteria4

Study Limitations4

No patients taking Cerdelga experienced osteonecrosis in this observational, 20-year study4

Incidence of osteonecrosis while on therapy

Osteonecrosis and Bone Pain

How treatment impacted GD-1–associated biomarkers over 20 years4

Findings: The 4 risk factors for osteonecrosis in patients with GD14

Heteroallelic p.N409S GBA1 genotype

Increased residual lyso-GL-1 levels after starting treatment

Treatment history with a specific ERT

History of osteonecrosis prior to initiation of treatment

Curious how Cerdelga impacted other bone health parameters in patients with GD1?

Explore clinical trial results for bone marrow burden, bone mineral density, and bone pain for patients with GD1

Bone data in patients new to treatment

Bone data in switch patients

Indication

Limitations of Use:

Important Safety Information

Contraindications

Warnings and Precautions

Adverse Reactions

Drug interactions

Use in specific populations

Indication

Important Safety Information

Cerdelga^® (eliglustat) Osteonecrosis Retrospective Study

Risk factors for osteonecrosis were evaluated in patients receiving therapy.^1-3

Observational, retrospective, 20‑year study: Evaluation of risk factors for osteonecrosis in patients receiving treatment for Gaucher disease type 1 (GD1)⁴

Patients with GD1 may be at increased risk for osteonecrosis if they have⁴:

82% of patients with GD1 have evidence of bone disease, including osteonecrosis, which can manifest at all ages.³

Patients with GD1 are at risk for osteonecrosis, even while on treatment⁴

No patients taking Cerdelga experienced osteonecrosis in this observational, 20-year study⁴

How treatment impacted GD-1–associated biomarkers over 20 years⁴

Findings: The 4 risk factors for osteonecrosis in patients with GD1⁴