Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Other alimentary tract and metabolism products, enzymes, ATC code: A16AB10.

Gaucher disease is an autosomal recessive disorder caused by mutations in the GBA gene which results in a deficiency of the lysosomal enzyme beta-glucocerebrosidase. This enzymatic deficiency causes an accumulation of glucocerebroside primarily in macrophages, giving rise to foam cells or "Gaucher cells". In this lysosomal storage disorder (LSD), clinical features are reflective of the distribution of Gaucher cells in the liver, spleen, bone marrow, skeleton, and lungs. The accumulation of glucocerebroside in the liver and spleen leads to organomegaly. Bone involvement results in skeletal abnormalities and deformities as well as bone pain crises. Deposits in the bone marrow and splenic sequestration lead to clinically significant anaemia and thrombocytopenia.

The active substance of VPRIV is velaglucerase alfa, which is produced by gene activation technology in a human cell line. Velaglucerase alfa is a glycoprotein. The monomer is approximately 63 kDa, has 497 amino acids, and the same amino acid sequence as the naturally occurring human enzyme,
glucocerebrosidase. There are 5 potential N-linked glycosylation sites, four of which are occupied.
Velaglucerase alfa is manufactured to contain predominantly high-mannose-type glycans to facilitate internalisation of the enzyme by the phagocytic target cells via the mannose receptor.

Velaglucerase alfa supplements or replaces beta-glucocerebrosidase, the enzyme that catalyses the hydrolysis of glucocerebroside to glucose and ceramide in the lysosome, reducing the amount of accumulated glucocerebroside and correcting the pathophysiology of Gaucher disease. Velaglucerase alfa increases haemoglobin concentration and platelet counts and reduces liver and spleen volumes in patients with type 1 Gaucher disease.

In studies 025EXT and 034, patients were offered home therapy. In study 025EXT, 7 of 10 patients received home therapy at least once during 60 months of treatment. In study 034, 25 of 40 patients received home therapy at least once during the 12-month study.

Clinical efficacy and safety

Studies in treatment naïve patients
Study 025 was a 9 month, open-label study in 12 adult (≥18 years) patients who were naïve to ERT (defined as having not been treated with ERT for at least 12 months prior to study entry).
Velaglucerase alfa was initially administered in a dose-escalating fashion in the first 3 patients (15, 30, 60 Units/kg) and the 9 remaining patients began treatment with 60 Units/kg.

Clinically meaningful improvements from baseline were observed in haemoglobin concentration and platelet counts as early as 3 months and in liver and spleen volumes at both 6 months and 9 months following the initiation of treatment with velaglucerase alfa.

Ten patients who completed Study 025 enrolled in an open-label extension study (025EXT), 8 of whom completed the study. After a minimum of 12 months of continuous treatment with velaglucerase alfa, all patients qualified to have the dose of velaglucerase alfa reduced in a step-wise fashion from 60 to 30 Units/kg after achieving at least 2 of the 4 “Year 1” therapeutic goals of ERT for type 1 Gaucher disease. Patients received doses ranging from 30 to 60 Units/kg (median dose 35 Units/kg) every other week for up to 84 months (7 years). Sustained clinical activity continued to be demonstrated during treatment as observed by improvements in haemoglobin concentrations and platelet counts and reduced liver and spleen volumes.

By month 57, 8 out of the 8 patients had achieved a reduction of at least 2 points in the lumbar spine Bone Marrow Burden (BMB) score as assessed by MRI scan. Improvement from baseline in mean lumbar spine and femoral neck bone mineral density (BMD) Z-scores were observed at month 24 (0.4; 95% CI 0.1, 0.7) and month 33 (0.4; 95% CI 0.2, 0.6), respectively. After seven years of treatment, the mean increase from baseline in Z-scores were 0.7 (95% CI 0.4, 1.0) for the lumbar spine and 0.5 (95% CI 0.2, 0.7) for the femoral neck. No patients were classified at a more severe WHO classification of bone density compared to baseline.

Study 032 was a 12-month, randomised, double-blind, parallel-group efficacy study that enrolled 25 patients aged 4 years and older who were naïve to ERT (defined as having not been treated with
ERT for at least 30 months prior to study entry). Patients were required to have Gaucher disease- related anaemia and either thrombocytopenia or organomegaly. Patients were randomised to receive velaglucerase alfa at a dose of either 45 Units/kg (N=13) or 60 Units/kg (N=12) every other week.

Velaglucerase alfa 60 Units/kg given intravenously every other week demonstrated clinically meaningful increases from baseline in mean haemoglobin concentration (+2.4 g/dl) and platelet count (+50.9 x 109/l), liver volume was reduced from 1.46 to 1.22 times normal (mean reduction of 17%) and spleen volume was reduced from 14.0 to 5.75 times normal (mean reduction of 50%). Meaningful increases from baseline were observed in the 45 Units/kg dose group in haemoglobin concentration (+2.4 g/dl) and platelet count (+40.9 x 109/l), liver volume was reduced from 1.40 to 1.24 times normal (mean reduction of 6%) and spleen volume was reduced from 14.5 to 9.50 times normal (mean reduction of 40%).

Study 039 was a 9-month, randomised, double-blind, non-inferiority, active-comparator (imiglucerase) controlled, parallel-group efficacy study that enrolled 34 patients aged 4 years and older who were naïve to ERT (defined as having not been treated with ERT for at least 12 months prior to study entry).
Patients were required to have Gaucher disease-related anaemia and either thrombocytopenia or organomegaly. Patients received either 60 Units/kg of velaglucerase alfa (N=17) or 60 Units/kg of imiglucerase (N=17) every other week.

The mean absolute increase from baseline in haemoglobin concentrations was 1.624 g/dl (±0.223 SE) following 9 months of treatment with velaglucerase alfa. This increase in haemoglobin concentration was demonstrated to be clinically and statistically non-inferior to imiglucerase (mean treatment difference of change from baseline to 9 months [velaglucerase alfa – imiglucerase]: 0.135 g/dl). There were no statistically significant differences between velaglucerase alfa and imiglucerase in changes in platelet counts and liver and spleen volumes after 9 months of velaglucerase alfa treatment, and in the time to first haemoglobin response (defined as 1 g/dl increase from baseline).

Study in patients switching from imiglucerase treatment to VPRIV

Study 034 was a 12-month, open-label safety study that enrolled 40 patients aged 4 years and older who had been receiving treatment with imiglucerase at doses ranging from 15 to 60 Units/kg for a minimum of 30 consecutive months. Patients were required to have a stable dose of imiglucerase for at least 6 months prior to study enrolment. Treatment with velaglucerase alfa was administered as the same number of units and regimen as their imiglucerase dose. Haemoglobin concentration and platelet counts were evaluated as changes from baseline, which was defined as the end of the patient’s treatment with imiglucerase.

In patients who switched from imiglucerase to velaglucerase alfa, haemoglobin concentrations and platelet counts were sustained at therapeutic levels through 12 months of treatment.
Study 058 was an open-label clinical safety study in 211 patients including 205 patients previously treated with imiglucerase 6 treatment-naïve patients and 57 patients aged 65 years or older (56/57 had switched from imiglucerase to velaglucerase alfa). Patients transferring from imiglucerase were administered velaglucerase alfa infusions every other week at the same number of units as imiglucerase within the range of 15 to 60 Units/kg. Patients transferring from a dose of <15 Units/kg imiglucerase were administered 15 Units/kg of velaglucerase alfa.

Patients previously treated with imiglucerase received a median of 8 velaglucerase alfa infusions with median duration of treatment of 15.1 weeks. The safety profile in these patients was similar to that observed in other clinical studies. Only 1 out of 163 patients assessed developed anti-velaglucerase alfa antibodies during the study.

The mean haemoglobin concentration and platelet count of patients previously treated with imiglucerase were maintained throughout the study and remained within the reference intervals.

Extension study 044

A total of 95 patients (73 adult and 22 paediatric) who participated in studies 032, 034, and 039 enrolled in the open label extension study and were treated with velaglucerase alfa. 57 patients were treatment-naïve. All patients received at least 2 years of ERT and were followed for a mean of 4.5 years (min. 2.3 years, max 5.8 years).

In this study, haemoglobin concentration, platelet count, liver volume and spleen volume were assessed in treatment-naïve patients after 24 months of treatment. The results are presented in Table 2.

Table 2: Results at 24 months - change from baseline – study 044 ITT population 
Clinical parameters                         Overall              Patients treated         Patients who switched velaglucerase alfa         with imiglucerase            from long-term group (N=39)            for 9 months and         imiglucerase treatment then                         to velaglucerase            velaglucerase alfa alfa for 15                  (N=38)
-                   months (N=16)                     -
Mean change from                      -               Mean change from baseline (95% CI)             Mean change             baseline (95% CI) from baseline
(95% CI)
Haemoglobin concentration                    2.75                       2.00                       -0.05 (g/dL)                           (2.28, 3.22)               (1.25, 2.75)               (-0.34, 0.25) Platelet count (x109/L)                    87.85                     160.94                       9.03 (72.69, 103.00)           (117.22, 204.66)             (-2.60, 20.66) Normalised liver volume*                    -1.21                      -1.69                      -0.03 (%BW)                          (-1.50, -0.91 )            (-2.16, -1.21)              (-0.10, 0.05) Normalised spleen volume*                    -2.66                      -3.63                      -0.11 (%BW)§                         (-3.50, -1.82)            (-7.25, - 0.02)             (-0.19, -0.03) § Excludespatients with splenectomy. N=30, 6 and 34 for the 3 above groups.
*Liver and spleen volume are normalised as a percentage of body weight. Normal spleen is defined as 0.2% of body weight; normal liver as 2.5% of body weight.
Note: Imputation was applied to intermittent missing data.

In this study, BMD was assessed using dual x-ray absorptiometry of the lumbar spine and femoral neck. Among 31 treatment-naïve adult patients treated with velaglucerase alfa, the mean lumbar spine BMD Z-score at baseline was -1.820 (95% CI: -2.21, -1.43) and increased by 0.62 (95% CI: 0.39, 0.84) from baseline following 24 months of treatment with velaglucerase alfa. Similar results were seen in treatment-naïve patients who received 9 months of imiglucerase followed by velaglucerase alfa for 15 months. In patients who switched from long-term imiglucerase to velaglucerase alfa, lumbar spine BMD was maintained at 24 months. In contrast, no significant change in femoral neck BMD was observed.

In the paediatric population (ages 4 to 17 years studied), increases in the mean height Z-score were seen through 60 months of treatment in the overall treatment-naïve population, suggesting a beneficial treatment effect with velaglucerase alfa on linear growth. Similar treatment effects were seen through 48 months in the paediatric population who received 9 months of imiglucerase followed by velaglucerase alfa. Paediatric subjects who switched from long-term imiglucerase to velaglucerase alfa in study 034 had greater mean height Z-scores at baseline and their mean height Z-scores remained stable over time.

These treatment effects on haemoglobin, platelet count, organ volumes, bone mineral density and height were maintained through the end of the study.

Study 402

Study 402 was a Phase IV, open-label, single-arm study that evaluated the effect of VPRIV on bone- related pathology in 21 treatment naïve adult subjects with type 1 Gaucher disease. The primary efficacy analysis was conducted in 16 subjects that completed 24 months of VPRIV treatment with a median age of 46 years at baseline and baseline mean (SD) BMD Z-score of -1.93 (0.876).

In this study, the primary efficacy endpoint was the change from baseline to 24 months in LS BMD Z-score as measured by the DXA method. A positive trend for the primary efficacy endpoint was seen [change in LS BMD Z-score baseline to 24 months mean (SD) 0.17 (0.394), 95% CI -0.04, 0.38; but the effect was not statistically significant (p-value 0.1077). No relevant effect of VPRIV on LS BMD Z-score was seen after 1 year of treatment.

The secondary endpoints [ITT population: OC (observed cases)] as seen in Table 3 below were in line with the previous studies.

Table 3: Secondary endpoints in SHP-GCB-402 study – Baseline mean (SD), mean change from baseline to month 24, 95 % CI

Clinical parameters                  Baseline mean (SD)          Mean change from baseline to month 24 [95% CI]
Bone Marrow Burden (BMB)                  7.8 (2.61)                         -3.0 score (n=13)                                                   [-4.4; -1.6] Haemoglobin concentration               13.1 (1.30)                         0.90 (g/dL) (n=18)                                                  [0.29; 1.51] Platelet count (x 109/L) (n=16)         135.3 (47.94)                       69.16 [40.67; 97.64]
Normalised liver volume               2.8 (0.59)                         -0.45 (%BW) (n=15)                                                    [-0.67; -0.22] Normalised spleen volume               1.0 (0.86)                         -0.56 (%BW) (n=15)                                                    [-0.97; -0.15] CI = confidence interval; SD = standard deviation

The safety profile was consistent with data from previous studies as well; no new safety signals were observed.


Paediatric population
Use in the age group 4 to 17 is supported by evidence from controlled studies in adults and paediatric [20 of 94 (21%)] patients. The safety and efficacy profiles were similar between paediatric and adult patients. The studies allowed the inclusion of patients 2 years and older and the safety and efficacy profiles are expected to be similar down to the age of 2 years. However, no data are available for children under the age of 4 years. The effect on height was assessed in the study 044 (see section 5.1, extension study 044).

Phase I/II study HGT-GCB-068 was conducted to explore the efficacy and safety of velaglucerase alfa ERT in treatment naïve children and adolescents with type 3 Gaucher disease. This was a multicentre, open-label study in which 60 U/kg of velaglucerase alfa was administered by intravenous infusion every other week (EOW) over 12 months in 6 patients (2 to 17 years of age at enrolment) with a confirmed diagnosis of type 3 Gaucher disease.

In this small, exploratory study, the non-neurological efficacy findings and the safety profile of intravenous velaglucerase alfa in type 3 Gaucher patients were consistent with those observed in patients with type 1 Gaucher disease. There was no indication of significant improvements of the neurological manifestations of type 3 Gaucher disease except for one patient in this study.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

There were no apparent pharmacokinetic differences between male and female patients with type 1 Gaucher disease. None of the subjects in the pharmacokinetic studies were positive for anti-velaglucerase alfa antibodies on the days of pharmacokinetic evaluation. Therefore, it was not possible to evaluate the effect of antibody response on the pharmacokinetic profile of velaglucerase alfa.

Absorption

Velaglucerase alfa serum concentrations rose rapidly for the first 20 minutes of the 60-minute infusion before levelling off, and Cmax was typically attained between 40 and 60 minutes after the start of the infusion. After the end of the infusion, velaglucerase alfa serum concentrations fell rapidly in a monophasic or biphasic fashion with a mean t1/2 ranging from 5 to 12 minutes at doses of 15, 30, 45, and 60 Units/kg.

Distribution

Velaglucerase alfa exhibited an approximately linear (i.e. first-order) pharmacokinetic profile, and Cmax and AUC increased approximately proportional to the dose over the dose range 15 to 60 Units/kg.
The steady state volume of distribution was approximately 10% of the body weight. The high clearance of velaglucerase alfa from serum (mean 6.7 to 7.6 ml/min/kg) is consistent with the rapid uptake of velaglucerase alfa into macrophages via mannose receptors.

Elimination

The range of velaglucerase alfa clearance in paediatric patients (N=7, age range 4 to 17 years) was contained within the range of clearance values in adult patients (N=15, age range 19 to 62 years).