"The U.S. Food and Drug Administration today approved Cerdelga (eliglustat) for the long-term treatment of adult patients with the Type 1 form of Gaucher disease, a rare genetic disorder.
Gaucher disease occurs in people who do not produce e"...
Mechanism of Action
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. Glucocerebrosidase catalyzes the conversion of the sphingolipid glucocerebroside into glucose and ceramide. The enzymatic deficiency causes an accumulation of glucocerebroside primarily in the lysosomal compartment of macrophages, giving rise to foam cells or “Gaucher cells”. In this lysosomal storage disorder (LSD), clinical features are reflective of the accumulation of Gaucher cells in the liver, spleen, bone marrow, and other organs. The accumulation of Gaucher cells in the liver and spleen leads to organomegaly. Presence of Gaucher cells in the bone marrow and spleen lead to clinically significant anemia and thrombocytopenia.
Velaglucerase alfa catalyzes the hydrolysis of glucocerebroside, reducing the amount of accumulated glucocerebroside.
In a multicenter study conducted in pediatric (N=7, 4 to 17 years old) and adult (N=15, 19 to 62 years old) patients with type 1 Gaucher disease, pharmacokinetic evaluations were performed at Weeks 1 and 37 following 60-minute intravenous infusions of VPRIV 60 Units/kg every other week. Serum velaglucerase alfa concentrations declined rapidly with a mean half life of 11 to 12 minutes. The mean velaglucerase alfa clearance ranged from 6.72 to 7.56 mL/min/kg. The mean volume of distribution at steady state ranged from 82 to 108 mL/kg (8.2% to 10.8% of body weight).
No accumulation or change in velaglucerase alfa pharmacokinetics over time from Weeks 1 to 37 was observed upon multiple-dosing 60 Units/kg every other week.
Based on the limited data, there were no notable pharmacokinetic differences between male and female patients in this study. The effect of age on pharmacokinetics of velaglucerase alfa was inconclusive.
The effect of anti-drug antibody formation on the pharmacokinetic parameters of velaglucerase alfa is unknown.
The efficacy of VPRIV was assessed in three clinical studies in a total of 99 patients with type 1 Gaucher disease: 82 patients age 4 years and older received VPRIV and 17 patients age 3 years and older received imiglucerase. Studies I and II were conducted in patients who were not currently receiving Gaucher disease-specific therapy. Study III was conducted in patients who were receiving imiglucerase treatment immediately before starting VPRIV. In these studies, VPRIV was administered intravenously over 60 minutes at doses ranging from 15 Units/kg to 60 Units/kg every other week.
Studies of VPRIV as Initial Therapy
Study I was a 12-month, randomized, double-blind, parallel-dose-group, multinational study in 25 patients age 4 years and older with Gaucher disease-related anemia and either thrombocytopenia or organomegaly. Patients were not allowed to have had disease-specific therapy for at least the previous 30 months; all but one had no prior therapy. The mean age was 26 years and 60% were male. Patients were randomized to receive VPRIV at a dose of either 45 Units/kg (N=13) or 60 Units/kg (N=12) every other week.
At baseline, mean hemoglobin concentration was 10.6 g/dL, mean platelet count was 97 x 109/L, mean liver volume was 3.6 % of body weight (% BW), and mean spleen volume was 2.9 % BW. For all studies, liver and spleen volumes were measured by MRI. The changes in clinical parameters after 12 months of treatment are shown in Table 4. The observed change from baseline in the primary endpoint, hemoglobin concentration, was considered to be clinically meaningful in light of the natural history of untreated Gaucher disease.
Table 4: Mean Change from Baseline to Month 12 for
Clinical Parameters in Patients with Type 1 Gaucher Disease Initiating Therapy
with VPRIV in Study I
|Clinical Parameter||Mean Changes from Baseline ± Std. Err. of the Mean|
|VPRIV Dose (given every other week)|
N = 13
N = 12
|Hemoglobin concentration change (g/dL)||2.4 ± 0.4*||2.4 ± 0.3**|
|Platelet count change (x 109/L)||41 ± 14*||51 ± 12*|
|Liver volume change (% BW)||-0.30 ± 0.29||-0.84 ± 0.33|
|Spleen volume change (% BW)||-1.9 ± 0.6*||-1.9 ± 0.5*|
|** Primary study endpoint was
hemoglobin concentration change in the 60 Unit/kg group, p < 0.001
* Statistically significant changes from baseline after adjusting for performing multiple tests
Study II was a 9-month, randomized, double-blind, active-controlled (imiglucerase), parallel-group, multinational study in 34 patients age 3 years and older. Patients were required to have Gaucher disease-related anemia and either thrombocytopenia or organomegaly. Patients were not allowed to have had disease-specific therapy for at least the previous 12 months. The mean age was 30 years and 53% were female; the youngest patient who received VPRIV was age 4 years. Patients were randomized to receive either 60 Units/kg of VPRIV (N=17) or 60 Units/kg of imiglucerase (N=17) every other week.
At baseline, the mean hemoglobin concentration was 11.0 g/dL, mean platelet count was 171 x 109/L, and mean liver volume was 4.3 % BW. For the patients who had not had splenectomy (7 in each group) the mean spleen volume was 3.4 % BW. After 9 months of treatment, the mean absolute increase from baseline in hemoglobin concentration was 1.6 g/dL ± 0.2 (SE) for patients treated with VPRIV. The mean treatment difference in change from baseline to 9 months [VPRIV – imiglucerase] was 0.1 g/dL ± 0.4 (SE).
In Studies I and II, examination of age and gender subgroups did not identify differences in response to VPRIV among these subgroups. The number of non-Caucasian patients in these studies was too small to adequately assess any difference in effects by race.
Study in Patients Switching from Imiglucerase Treatment to VPRIV
Study III was a 12-month, open-label, single-arm, multinational study in 40 patients age 9 years and older who had been receiving treatment with imiglucerase at doses ranging between 15 Units/kg to 60 Units/kg for a minimum of 30 consecutive months. Patients also were required to have a stable biweekly dose of imiglucerase for at least 6 months prior to enrollment. The mean age was 36 years and 55% were female. Imiglucerase therapy was stopped, and treatment with VPRIV was administered every other week at the same number of units as the patient's previous imiglucerase dose. Adjustment of dosage was allowed by study criteria if needed in order to maintain clinical parameters.
Hemoglobin concentrations and platelet counts remained stable on average through 12 months of VPRIV treatment. After 12 months of treatment with VPRIV the median hemoglobin concentration was 13.5 g/dL (range: 10.8, 16.1) vs. the baseline value of 13.8 g/dL (range: 10.4, 16.5), and the median platelet count after 12 months was 174 x 109/L (range: 24, 408) vs. the baseline value of 162 x 109/L (range: 29, 399). No patient required dosage adjustment during the 12-month treatment period.
1. Pastores GM, Weinreb NJ, Aerts H, et al. Therapeutic Goals in the Treatment of Gaucher Disease. Semin Hematol. 2004; 41(4 Suppl 5):4-14.
Last reviewed on RxList: 10/21/2013
This monograph has been modified to include the generic and brand name in many instances.
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