Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1      Pharmacodynamic properties

Pharmacotherapeutic group: Other alimentary tract and metabolism products, various alimentary tract and metabolism products, ATC code: A16AX10.

Mechanism of action
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.


Pharmacodynamic effects
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.


Clinical efficacy and safety
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.

Pivotal study of Cerdelga in treatment-naïve GD1 patients – study 02507(ENGAGE) 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
Difference
Placebo*   Cerdelga
(Cerdelga – Placebo)      p valueb
(n=20) a   (n=20) a
[95% CI]
Percentage Change in Spleen Volume MN (%)                                     -30.0 2.26       -27.77                      <0.0001
(primary endpoint)                                                            [-36.8, -23.2] Absolute Change in Haemoglobin Level (g/dL)                                  1.22 -0.54         0.69                       0.0006
(secondary endpoint)                                                          [0.57, 1.88] Percentage Change in Liver Volume MN (%)                                    -6.64 1.44        -5.20                       0.0072
(secondary endpoint)                                                          [-11.37, -1.91] Percentage Change in Platelet Count (%)                                       41.06 -9.06        32.00                      <0.0001
(secondary endpoint)                                                          [23.95, 58.17] 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 x 109/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].


Long-term clinical outcomes in treatment-naïve GD1 patients – study 304 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          Change from             Standard
(Mean)                  Baseline (Mean)         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 9
Platelet Count (x10 /L)     16                 67.53                   109.8%                  114.73 MN = Multiples of Normal

Pivotal study of Cerdelga in GD1 patients switching from ERT– Study 02607 (ENCORE) 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                  Cerdelga
(N=47)**                  (N=99)
Mean [95% CI]             Mean [95% CI]
Spleen Volume
Percentage of Patients with stable spleen
100%                       95.8% volume*a
-6.17 [-9.54, -
Percentage Change in Spleen Volume MN (%)*                       -3.01 [-6.41, 0.40] 2.79]
Haemoglobin Level
Percentage of Patients with stable haemoglobin
100%                      94.9% levela
-0.21 [-0.35, -
Absolute Change in Haemoglobin Level (g/dL)                      0.038 [-0.16, 0.23] 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]         1.78 [-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           Cerdelgab         Cerezyme           Cerdelgab         Cerezyme           Cerdelgab /Cerdelgaa                           /Cerdelgaa                           /Cerdelgaa Mean [95%         Mean [95%          Mean [95%         Mean [95%          Mean [95%         Mean [95% CI]              CI])                CI]               CI]                CI]               CI] 
Patients at start of year (N)        51                101                46                98                 42                96 
Patients at end of year (N)          46                98                 42                96                 21                44 
Patients with available              39                97                 16                93                 3                 42 data (N)

Spleen Volume

Patients with stable spleen     31/33 (93.9)      69/72 (95.8)       12/12 (100.0)     65/68 (95.6)        2/2 (100.0)      28/30 (93.3) volume (%)*                     [0.798, 0.993]   [0.883, 0.991]     [0.735, 1.000]    [0.876, 0.991]     [0.158, 1.000]    [0.779, 0.992] 
Change in Spleen Volume         -3.946[-8.80,    -6.814[-10.61, -   -10.267[-20.12,   -7.126[-11.70, -   -27.530[-89.28,   -13.945[-20.61, MN (%)*                             0.91]             3.02]              -0.42]            2.55]             34.22]            -7.28] 
Haemoglobin Level

Patients with stable            38/39 (97.4)      95/97 (97.9)       16/16 (100.0)     90/93 (96.8)        3/3 (100.0)     42/42 (100.0) haemoglobin level (%)           [0.865, 0.999]   [0.927, 0.997]     [0.794, 1.000]    [0.909, 0.993]     (0.292, 1.000]    [0.916, 1.000] 
Change from baseline in         0.034[-0.31,      -0.112[-0.26,      0.363[-0.01,      -0.103[-0.27,      0.383[-1.62,      0.290[0.06, Haemoglobin Level (g/dL)            0.38]             0.04]              0.74]             0.07]             2.39]             0.53] 
Liver Volume

Patients with stable liver      38/39 (97.4)      94/97 (96.9)       15/16 (93.8)      87/93 (93.5)        3/3 (100.0)      40/42 (95.2) volume (%)                      (0.865, 0.999)   (0.912, 0.994)     [0.698, 0.998]    (0.865, 0.976)     [0.292, 1.000]    [0.838, 0.994] 
Change from baseline in         0.080[-3.02,       2.486[0.50,      -4.908[-11.53,      3.018[0.52,      -14.410[-61.25,    -1.503[-5.27, Liver Volume MN (%)                 3.18]             4.47]              1.71]             5.52]             32.43]            2.26] 
Platelet Count

Patients with stable            33/39 (84.6)      92/97 (94.8)       13/16 (81.3)      87/93 (93.5)        3/3 (100.0)      40/42 (95.2) platelet count (%)              [0.695, 0.941]   [0.884, 0.983]     [0.544, 0.960]    [0.865, 0.976]     [0.292, 1.000]    [0.838, 0.994] 
Change in Platelet Count        -0.363[-6.60,     2.216[-1.31,       0.719[-8.20,       5.403[1.28,      -0.163[-35.97,     7.501[1.01, (%)                                 5.88]             5.74]              9.63]             9.52]             35.64]            13.99] 
Composite Stability Endpoint

Patients who are Stable on 30/39 (76.9)    85/97 (87.6)   12/16 (75.0)   80/93 (86.0)    3/3 (100.0)   38/42 (90.5) Cerdelga (%)               [0.607, 0.889] [0.794, 0.934] [0.476, 0.927] [0.773, 0.923] [0.292, 1.000] [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
Clinical experience in CYP2D6 poor metabolisers (PMs) and ultra-rapid metabolisers (URMs) 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.

Effects on skeletal pathology
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.

Electrocardiographic evaluation
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.

Elderly
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.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption
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.

Distribution

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.

Biotransformation
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.

Elimination
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.

Characteristics in specific groups
CYP2D6 phenotype
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.

Gender, body weight, age, and race
Based on the population pharmacokinetic analysis, gender, body weight, age, and race had limited or no impact on the pharmacokinetics of eliglustat.

Hepatic impairment:
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).

Renal impairment:
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).