Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Genzyme Europe B.V., Paasheuvelweg 25, 1105 BP Amsterdam, The Netherlands
Pharmacotherapeutic group: Other alimentary tract and metabolism products, various alimentary tract and metabolism products
ATC code: A16AX10
Eliglustat is a potent and specific inhibitor of glucosylceramide synthase, and acts as a substrate reduction therapy (SRT) for GD1. SRT aims to reduce the rate of synthesis of the major substrate glucosylceramide (GL-1) to match its impaired rate of catabolism in patients with GD1, thereby preventing glucosylceramide accumulation and alleviating clinical manifestations.
In clinical trials in treatment-naïve GD1 patients, plasma GL-1 levels were elevated in the majority of these patients and decreased upon Cerdelga treatment. Additionally, in a clinical trial in GD1 patients stabilised on enzyme replacement therapy (ERT) (i.e. having already achieved therapeutic goals on ERT prior to initiating Cerdelga treatment), plasma GL-1 levels were normal in most patients and decreased upon Cerdelga treatment.
The recommended dosing regimens (see section 4.2) are based on modelling, either of PK/PD data from the dose-titration regimens applied in the clinical studies for IMs and EMs, or physiologically- based PK data for PMs.
Study 02507 was a randomized, double-blind, placebo-controlled, multicenter clinical study in 40 patients with GD1. In the Cerdelga group 3 (15%) patients received a starting dose of 42 mg eliglustat twice daily during the 9-month primary analysis period and 17 (85%) patients received a dose escalation to 84 mg twice daily based on plasma trough concentration.
Table 2. Change from baseline to Month 9 (primary analysis period) in treatment-naïve patients with GD1 receiving treatment with Cerdelga in study 02507:
| Placebo* (n=20)α | Cerdelga (n=20)α | Difference (Cerdelga – Placebo) [95% CI] | p valueβ | |
|---|---|---|---|---|
| Percentage Change in Spleen Volume MN (%) (primary endpoint) | 2,26 | -27,77 | -30,0 [-36,8, -23,2] | <0,0001 |
| Absolute Change in Haemoglobin Level (g/dL) (secondary endpoint) | -0,54 | 0,69 | 1,22 [0,57, 1,88] | 0,0006 |
| Percentage Change in Liver Volume MN (%) (secondary endpoint) | 1,44 | -5,20 | -6,64 [-11,37, -1,91] | 0,0072 |
| Percentage Change in Platelet Count (%) (secondary endpoint) | -9,06 | 32,00 | 41,06 [23,95, 58,17] | <0,0001 |
MN = Multiples of Normal, CI = confidence interval
a At baseline, mean spleen volumes were 12.5 and 13.9 MN in the placebo and Cerdelga groups, respectively, and mean liver volumes were 1.4 MN for both groups. Mean haemoglobin levels were 12.8 and 12.1 g/dL, and platelet counts were 78.5 and 75.1 × 10 9 /L, respectively.
b Estimates and p-values are based on an ANCOVA model
* All patients transitioned to Cerdelga treatment after Month 9.
During the open-label long term treatment period with Cerdelga (extension phase), all patients with complete data who continued to receive Cerdelga showed further improvements throughout the extension phase. Results (change from baseline) after 18 months, 30 months and 4.5 years of exposure to Cerdelga on the following endpoints were: absolute change in haemoglobin level (g/dL) 1.1 (1.03) [n=39], 1.4 (0.93) [n=35], and 1.4 (1.31) [n=12]; mean increase in platelet count (mm³) 58.5% (40.57%) [n=39], 74.6% (49.57%) [n=35], and 86.8% (54.20%) [n=12]; mean reduction in spleen volume (MN) 46.5% (9.75%) [n=38], 54.2% (9.51%) [n=32], and 65.6% (7.43%) [n=13]; and mean reduction in liver volume (MN) 13.7% (10.65%) [n=38], 18.5% (11.22%) [n=32], and 23.4% (10.59%) [n=13].
Study 304 was a single-arm, open-label, multicenter study of Cerdelga in 26 patients. Nineteen patients completed 4 years of treatment. Fifteen (79%) of these patients received a dose escalation to 84 mg eliglustat twice daily; 4 (21%) patients continued to receive 42 mg twice daily.
Eighteen patients completed 8 years of treatment. One patient (6%) received a further dose escalation to 127 mg twice daily. Fourteen (78%) continued on 84 mg Cerdelga twice daily. Three (17%) patients continued to receive 42 mg twice daily. Sixteen patients had an efficacy endpoint assessment at year 8.
Cerdelga showed sustained improvements in organ volume and haematological parameters over the 8 year treatment period (see Table 3).
Table 3. Change from baseline to year 8 in study 304:
| N | Baseline Value (Mean) | Change from Baseline (Mean) | Standard Deviation | |
|---|---|---|---|---|
| Spleen Volume (MN) | 15 | 17,34 | -67,9% | 17,11 |
| Haemoglobin Level (g/dL) | 16 | 11,33 | 2,08 | 1,75 |
| Liver Volume (MN) | 15 | 1,60 | -31,0% | 13,51 |
| Platelet Count (x109/l) | 16 | 67,53 | 109,8% | 114,73 |
MN = Multiples of Normal
Study 02607 was a randomized, open-label, active-controlled, non-inferiority, multicenter clinical study in 159 patients previously stabilised with ERT. In the Cerdelga group 34 (32%) patients received a dose escalation to 84 mg eliglustat twice daily and 51 (48%) to 127 mg twice daily during the 12- month primary analysis period , and 21 (20%) patients continued to receive 42 mg twice daily.
Based on the aggregate data from all doses tested in this study, Cerdelga met the criteria set in this study to be declared non-inferior to Cerezyme (imiglucerase) in maintaining patient stability. After 12 months of treatment, the percentage of patients meeting the primary composite endpoint (composed of all four components mentioned in Table 4) was 84.8% [95% confidence interval 76.2% - 91.3%] for the Cerdelga group compared to 93.6% [95% confidence interval 82.5% - 98.7 %] for the Cerezyme group. Of the patients who did not meet stability criteria for the individual components, 12 of 15 Cerdelga patients and 3 of 3 Cerezyme patients remained within therapeutic goals for GD1.
There were no clinically meaningful differences between groups for any of the four individual disease parameters (see Table 4).
Table 4. Changes from baseline to Month 12 (primary analysis period) in patients with GD1 switching to Cerdelga in study 02607:
| Cerezyme (N=47)** Mean [95% CI] | Cerdelga (N=99) Mean [95% CI] | |
|---|---|---|
| Spleen Volume | ||
| Percentage of Patients with stable spleen volume*a | 100% | 95,8% |
| Percentage Change in Spleen Volume MN (%)* | -3,01 [-6,41, 0,40] | -6,17 [-9,54, -2,79] |
| Haemoglobin Leve | ||
| Percentage of Patients with stable haemoglobin levela | 100% | 94,9% |
| Absolute Change in Haemoglobin Level (g/dl) | 0,038 [-0,16, 0,23] | -0,21 [-0,35, -0,07] |
| Liver Volume | ||
| Percentage of Patients with stable liver volumea | 93,6% | 96,0% |
| Percentage Change in Liver Volume MN (%) | 3,57 [0,57, 6,58] | ,78 [-0,15, 3,71] |
| Platelet Count | ||
| Percentage of Patients with stable platelet counta | 100% | 92,9% |
| Percentage Change in Platelet Count (%) | 2,93 [-0,56, 6,42] | 3,79 [0,01, 7,57] |
MN = Multiples of Normal, CI = confidence interval
* Excludes patients with a total splenectomy.
** All patients transitioned to Cerdelga treatment after 52 weeks
a The stability criteria based on changes between baseline and 12 months: haemoglobin level ≤1.5 g/dL decrease, platelet count ≤25% decrease, liver volume ≤20% increase, and spleen volume ≤25% increase.
All patient number (N)= Per Protocol Population
During the open-label long term treatment period with Cerdelga (extension phase) the percentage of patients with complete data meeting the composite stability endpoint was maintained at 84.6% (n=136) after 2 years, 84.4% (n=109) after 3 years and 91.1% (n=45) after 4 years. The majority of extension phase discontinuations were due to transition to commercial product from year 3 onwards. Individual disease parameters of spleen volume, liver volume, haemoglobin levels and platelet count remained stable through 4 years (see Table 5).
Table 5. Changes from Month 12 (primary analysis period) to Month 48 in patients with GD1 in the Long Term Treatment Period on Cerdelga in study 02607:
| Year 2 | Year 3 | Year 4 | ||||
|---|---|---|---|---|---|---|
| Cerezyme/Cerdelgaa Mean [95% CI] | Cerdelgab Mean [95% CI] | Cerezyme/Cerdelgaa Mean [95% CI] | Cerdelgab Mean [95% CI] | Cerezyme/Cerdelgaa Mean [95% CI] | Cerdelgab Mean [95% CI] | |
| Patients at start of year (N) | 51 | 101 | 46 | 98 | 42 | 96 |
| Patients at start of year (N) | 46 | 98 | 42 | 96 | 21 | 44 |
| Patients with available data (N) | 39 | 97 | 16 | 93 | 3 | 42 |
| Spleen Volume | ||||||
| Patients with stable spleen volume (%)* | 31/33 (93,9) [0,798, 0,993] | 69/72 (95,8) [0,883, 0,991] | 12/12 (100,0) [0,735, 1,000] | 65/68 (95.6) [0,876, 0,991] | 2/2 (100,0) [0,158, 1,000] | 28/30 (93,3) [0,779, 0,992] |
| Change in Spleen Volume MN (%)* | -3,946 [-8,80, 0,91] | -6,814 [-10,61, -3,02] | -10,267 [-20,12, -0,42] | -7,126 [-11,70, -2,55] | -27,530 [-89,28, 34,22] | -13,945 [-20,61, -7,28] |
| Haemoglobin Level | ||||||
| Patients with stable haemoglobin level (%) | 38/39 (97,4) [0,865, 0,999] | 95/97 (97,9) [0,927, 0,997] | 16/16 (100,0) [0,794, 1,000] | 90/93 (96,8) [0,909, 0,993] | 3/3 (100,0) (0,292, 1,000] | 42/42 (100,0) [0,916, 1,000] |
| Change from baseline in Haemoglobin Level (g/dL) | 0,034 [-0,31, 0,38] | -0,112 [-0,26, 0,04] | 0,363 [-0,01, 0,74] | 0,383 [-1,62, 2,39] | 0,290 [0,06, 0,53] | |
| Liver Volume | ||||||
| Patients with stable liver volume (%)* | 38/39 (97,4) [0,865, 0,999] | 94/97 (96,9) [0,912, 0,994] | 15/16 (93,8) [0,698, 0,998] | 87/93 (93,5) (0,865,0,976) | 3/3 (100,0) [0,292, 1,000] | 40/42 (95,2) [0,838, 0,994] |
| Change from baseline in Liver Volume MN (%) | 0,080 [-3,02, 3,18] | 2,486 [0,50, 4,47] | -4,908 [-11,53, 1,71] | 3,018 [0,52, 5,52] | -14,410 [-61,25, 32,43] | -1,503 [-5,27, 2,26] |
| Platelet Count | ||||||
| Patients with stable platelet count (%) | 33/39 (84,6) [0,695, 0,941] | 92/97 (94,8) [0,884, 0,983] | 13/16 (81,3) [0,544, 0,960] | 87/93 (93,5) [0,865, 0,976] | 3/3 (100,0) [0,292, 1,000] | 40/42 (95,2) [0,838, 0,994] |
| Change in Platelet Count (%) | -0,363 [-6,60, 5,88] | 2,216 [-1,31, 5,74] | 0,719 [-8,20, 9,63] | 5,403 [1,28, 9,52] | -0,163 [-35,97, 35,64] | 7,501 [1,01, 13,99] |
| Composite Stability Endpoint | ||||||
| Patients who are Stable on Cerdelga (%) | 30/39 (76,9) [0,607, 0,889] | 85/97 (87,6) [0,794, 0,934] | 12/16 (75,0) [0,476, 0,927] | 80/93 (86,0) [0,773, 0,923] | 3/3 (100,0) [0,292, 1,000] | 38/42 (90,5) [0,774, 0,973] |
MN = Multiples of Normal, CI = confidence interval
* Excludes patients with a total splenectomy.
a Cerezyme/Cerdelga – Originally Randomized to Cerezyme
b Cerdelga – Originally Randomized to Cerdelga
There is limited experience with Cerdelga treatment of patients who are PMs or URMs. In the primary analysis periods of the three clinical studies, a total of 5 PMs and 5 URMs were treated with Cerdelga. All PMs received 42 mg eliglustat twice daily, and four of these (80%) had an adequate clinical response. The majority of URMs (80%) received a dose escalation to 127 mg eliglustat twice daily, all of which had adequate clinical responses. The one URM who received 84 mg twice daily did not have an adequate response.
The predicted exposures with 84 mg eliglustat once daily in patients who are PMs are expected to be similar to exposures observed with 84 mg eliglustat twice daily in CYP2D6 intermediate metabolisers (IMs). Patients who are URMs may not achieve adequate concentrations to achieve a therapeutic effect. No dosing recommendation for URMs can be given.
After 9 months of treatment, in Study 02507, bone marrow infiltration by Gaucher cells, as determined by the total Bone Marrow Burden (BMB) score (assessed by MRI in lumbar spine and femur) decreased by a mean of 1.1 points in Cerdelga treated patients (n=19) compared to no change in patients receiving placebo (n=20). Five Cerdelga-treated patients (26%) achieved a reduction of at least 2 points in the BMB score.
After 18 and 30 months of treatment, BMB score had decreased by a mean 2.2 points (n=18) and 2.7 (n=15), respectively for the patients originally randomised to Cerdelga, compared to a mean decrease of 1 point (n=20) and 0.8 (n=16) in those originally randomised to placebo.
After 18 months of Cerdelga treatment in the open-label extension phase, the mean (SD) lumbar spine Bone Mineral Density T-score increased from -1.14 (1.0118) at Baseline (n=34) to -0.918 (1.1601) (n=33) in the normal range. After 30 months and 4.5 years of treatment, the T-score further increased to -0.722 (1.1250) (n=27) and -0.533 (0.8031) (n=9), respectively.
Results of study 304 indicate that skeletal improvements are maintained or continue to improve during at least 8 years of treatment with Cerdelga.
In study 02607, lumbar spine and femur BMD T- and Z-scores were maintained within the normal range in patients treated with Cerdelga for up to 4 years.
No clinically significant QTc prolonging effect of eliglustat was observed for single doses up to 675 mg.
Heart-rate corrected QT interval using Fridericia’s correction (QTcF) was evaluated in a randomized, placebo and active (moxifloxacin 400 mg) controlled cross-over, single-dose study in 47 healthy subjects. In this trial with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo-adjusted, baseline-corrected QTcF was below 10 msec, the threshold for regulatory concern. While there was no apparent effect on heart rate, concentration-related increases were observed for the placebo corrected change from baseline in the PR, QRS, and QTc intervals. Based on PK/PD modelling, eliglustat plasma concentrations 11-fold the predicted human Cmax are expected to cause mean (upper bound of the 95% confidence interval) increases in the PR, QRS, and QTcF intervals of 18.8 (20.4), 6.2 (7.1), and 12.3 (14.2) msec, respectively.
A limited number of patients aged 65 years (n=10) and over were enrolled in clinical trials. No significant differences were found in the efficacy and safety profiles of elderly patients and younger patients.
The European Medicines Agency has waived the obligation to submit the results of studies with Cerdelga in all subsets of the paediatric population in Gaucher disease Type 2 (see section 4.2 for information on paediatric use).
The European Medicines Agency has deferred the obligation to submit the results of studies with Cerdelga in the subsets of the paediatric population from 24 months to less than 18 years in Gaucher disease Type 1 and Type 3 (see section 4.2 for information on paediatric use).
Median time to reach maximum plasma concentrations occurs between 1.5 to 6 hours after dosing, with low oral bioavailability (<5%) due to significant first-pass metabolism. Eliglustat is a substrate of the efflux transporter P-gp. Food does not have a clinically relevant effect on eliglustat pharmacokinetics. Following repeated dosing of eliglustat 84 mg twice daily in non-PMs and once daily in PMs, steady state was reached by 4 days, with an accumulation ratio of 3-fold or less.
Eliglustat is moderately bound to human plasma proteins (76 to 83%) and is mainly distributed in plasma. After intravenous administration, the volume of distribution was 816 L, suggesting wide distribution to tissues in humans. Nonclinical studies demonstrated a wide distribution of eliglustat to tissues, including bone marrow.
Eliglustat is extensively metabolized with high clearance, mainly by CYP2D6 and to a lesser extent CYP3A4. Primary metabolic pathways of eliglustat involve sequential oxidation of the octanoyl moiety followed by oxidation of the 2,3-dihydro-1,4-benzodioxane moiety, or a combination of the two pathways, resulting in multiple oxidative metabolites.
After oral administration, the majority of the administered dose is excreted in urine (41.8%) and faeces (51.4%), mainly as metabolites. After intravenous administration, eliglustat total body clearance was 86 L/h. After repeated oral doses of 84 mg eliglustat twice daily, eliglustat elimination half-life is approximately 4-7 hours in non-PMs and 9 hours in PMs.
Population pharmacokinetic analysis shows that the CYP2D6 predicted phenotype based on genotype is the most important factor affecting pharmacokinetic variability. Individuals with a CYP2D6 poor metaboliser predicted phenotype (approximately 5 to 10% of the population) exhibit higher eliglustat concentrations than intermediate or extensive CYP2D6 metabolisers.
Based on the population pharmacokinetic analysis, gender, body weight, age, and race had limited or no impact on the pharmacokinetics of eliglustat.
Effects of mild and moderate hepatic impairment were evaluated in a single dose phase 1 study. After a single 84 mg dose, eliglustat Cmax and AUC were 1.2- and 1.2-fold higher in CYP2D6 extensive metabolisers (EMs) with mild hepatic impairment, and 2.8- and 5.2-fold higher in CYP2D6 extensive metabolisers (EMs) with moderate hepatic impairment compared to healthy CYP2D6 extensive metabolisers (EMs).
After repeated 84 mg twice daily doses of Cerdelga, Cmax and AUC0-12 are predicted to be 2.4- and 2.9-fold higher in CYP2D6 extensive metabolisers (EMs) with mild hepatic impairment and 6.4- and 8.9-fold higher in CYP2D6 extensive metabolisers (EMs) with moderate hepatic impairment compared to healthy CYP2D6 extensive metabolisers (EMs).
After repeated 84 mg once daily doses of Cerdelga, Cmax and AUC0-24 are predicted to be 3.1- and 3.2-fold higher in CYP2D6 extensive metabolisers (EMs) with moderate hepatic impairment compared to healthy CYP2D6 extensive metabolisers (EMs) receiving Cerdelga 84 mg twice daily (see sections 4.2 and 4.4). Steady state PK exposure could not be predicted in CYP2D6 intermediate metabolisers (IMs) and poor metabolisers (PMs) with mild and moderate hepatic impairment due to limited or no single-dose data. The effect of severe hepatic impairment was not studied in subjects with any CYP2D6 phenotype (see sections 4.2, 4.3 and 4.4).
Effect of severe renal impairment was evaluated in a single dose phase 1 study. After a single 84 mg dose, eliglustat Cmax and AUC were similar in CYP2D6 extensive metabolisers (EMs) with severe renal impairment and healthy CYP2D6 extensive metabolisers (EMs).
Limited or no data were available in patients with ESRD and in CYP2D6 intermediate metabolisers (IMs) or poor metabolisers(PMs) with severe renal impairment (see sections 4.2 and 4.4).
The principal target organs for eliglustat in toxicology studies are the GI tract, lymphoid organs, the liver in rat only and, in the male rat only, the reproductive system. Effects of eliglustat in toxicology studies were reversible and exhibited no evidence of delayed or recurring toxicity. Safety margins for the chronic rat and dog studies ranged between 8-fold and 15-fold using total plasma exposure and 1- to 2-fold using unbound (free fraction) plasma exposures.
Eliglustat did not have effects on CNS or respiratory functions. Concentration-dependent cardiac effects were observed in nonclinical studies: inhibition of human cardiac ion channels, including potassium, sodium, and calcium, at concentrations ≥7-fold of predicted human Cmax; sodium ion channel-mediated effects in an ex-vivo electrophysiology study in dog Purkinje fibres (2-fold of predicted human unbound plasma Cmax); and increases in QRS and PR intervals in dog telemetry and cardiac conduction studies in anaesthesised dogs, with effects seen at concentrations 14-fold of predicted human total plasma Cmax, or 2-fold of predicted human unbound plasma Cmax.
Eliglustat was not mutagenic in a standard battery of genotoxicity tests and did not show any carcinogenic potential in standard lifetime bioassays in mice and rats. Exposures in the carcinogenicity studies were approximately 4-fold and 3-fold greater in mice and rats, respectively, than the mean predicted human eliglustat total plasma exposure, or less than 1-fold using unbound plasma exposure.
In mature male rats, no effects on sperm parameters were observed at systemically non-toxic doses. Reversible inhibition of spermatogenesis was observed in the rat at 10-fold of predicted human exposure based on AUC, a systemically toxic dose. In rat repeated dose toxicity studies, seminiferous epithelial degeneration and segmental hypoplasia of the testes was seen at 10-fold of predicted human exposure based on AUC.
Placental transfer of eliglustat and its metabolites was shown in the rat. At 2 and 24 hours post-dose, 0.034% and 0.013% of labelled dose was detected in foetal tissue, respectively.
At maternal toxic doses in rats, foetuses showed a higher incidence of dilated cerebral ventricles, abnormal number of ribs or lumbar vertebrae, and many bones showed poor ossification.
Embryofoetal development in rats and rabbits was not affected up to clinically relevant exposure (based on AUC).
A lactation study in the rat showed that 0.23% of labelled dose was transferred to pups during 24 hours post-dose, indicating milk excretion of eliglustat and/or its related materials.
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