VPRIV - Scientific Information
|Form:||Intravenous (IV), Powder|
|Ingredients:||velaglucerase alfa, citric acid monohydrate, polysorbate 20, sodium citrate dihydrate, and sucrose|
|Proper name:||velaglucerase alfa|
|Chemical name:||glucocerebrosidase, β-D-glucosyl-N-acylsphingosine glucohydrolase, acid-β-glucosidase|
|Molecular formula and molecular mass:||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|
|Structural formula:||Velaglucerase alfa is human glucocerebrosidase secreted from a transfected continuous human cell line (HT-1080), generated using gene activation technology. Velaglucerase alfa is manufactured to contain predominantly high mannose-type N-linked glycans. There are 5 potential N-linked glycosylation sites; four of these sites are occupied.|
|Physicochemical properties:||Velaglucerase alfa drug substance is a frozen liquid, formulated in 50 mM sodium citrate at pH 6.0 containing 0.01% (vol/vol) polysorbate 20. The specific activity is 40 U/mg.|
Study Demographics and Trial Design
|Study #||Trial Design||Dosage, Route of Administration, Duration||Study Subjectsa|
|025||Phase I/II, Single center, Open label||15 U/kg to 60 U/kgb velaglucerase alfa EOW, IV infusion|
(18.8 - 69.8)
|Male and Female|
|025EXT||Phase I/II, Multicenter, Open label extension||60 U/kg-30 U/kg velaglucerase alfa EOW, IV infusion|
(19 - 63)
|Male and Female|
|032||Phase III, Multicenter, Randomized, Double-blind, Parallel group, Controlled||45 U/kg or 60 U/kg velaglucerase alfa EOW, IV infusion|
(4.0 - 62)
|Male and Female|
|039||Phase III, Multicenter, Randomized, Double-blind, Active comparator, Controlled||60 U/kg velaglucerase alfa EOW, IV infusion for 60 minutes|
60 U/kg imiglucerase
EOW, IV infusion for 1-2 hours
(3.0 - 73)
|Male and Female|
|034||Phase II/III, Multicenter, Open label||15 U/kg to 60 U/kg velaglucerase alfa EOW, IV infusion|
(9.0 - 71)
|Male and Female|
|044||Phase I/II, Multicenter, Open-label extension||15 U/kg to 60 U/kg velaglucerase alfa EOW, IV infusion||95||30|
|Male and Female|
|058||Phase III Open-label Treatment Protocol||15 U/kg to 60 U/kg velaglucerase alfa EOW, IV infusion||211||50.6 (6-89)||Male and Female|
a Number of patients dosed
b The first patient dosed with VPRIV in the dose-escalation phase received two 15-U/kg doses and then one 30-U/kg escalation dose. Based on acceptable safety evaluations, all 3 patients in the dose-escalation cohort had their doses increased to 60 U/kg. All subsequent patients in this study received 60 U/kg every other week for the entire study
The safety and efficacy of VPRIV (velaglucerase alfa) were assessed in 5 clinical studies in a total of 94 patients with type 1 Gaucher disease who were age 2 years and older. Studies 025, 032, and 039 were conducted in patients naïve to enzyme replacement therapy. Study 025EXT was an extension to Study 025. A treatment-naïve patient was defined differently for each study. Study 034 was conducted in patients who were receiving imiglucerase treatment. Study 044 was an extension study of patients from Studies 032, 039, and 034.
In both treatment-naïve patients and patients switched from imiglucerase to VPRIV, VPRIV was administered every other week at doses ranging from 15 to 60 U/kg. Of the 54 treatment-naïve
patients who received VPRIV, 41 (76%) received a starting dose of 60 U/kg every other week. VPRIV was administered by IV infusion over 60 minutes.
In Studies 025EXT and 034, patients for whom VPRIV was well-tolerated were offered home therapy under the direction of the Investigator. In Study 025EXT, 7 of 10 patients (70%) received home therapy at least once during 60 months of treatment. In Study 034, 25 of 40 patients (63%) received home therapy at least once during the 12-month study.
Studies in Treatment Naïve Patients
Study 025 was a 9-month, open-label study in 12 adult (≥18 years) patients who were naïve to enzyme replacement therapy (defined as having not been treated with enzyme replacement therapy for at least 12 months prior to study entry). VPRIV was initially administered in a dose-escalating fashion in the first 3 patients (15, 30, 60 U/kg) and the 9 remaining patients began treatment with 60 U/kg.
Clinically meaningful and statistically significant improvements from baseline were observed in hemoglobin 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 VPRIV.
Ten (10) of the patients who completed Study 025 enrolled in an open-label extension study (Study 025EXT). After a minimum of 12 months of continuous treatment with VPRIV, all patients qualified to have the dose of VPRIV reduced in a step-wise fashion from 60 to 30 U/kg after achieving at least 2 of the 4 “Year 1” therapeutic goals of ERT for type 1 Gaucher disease. Patients received VPRIV at a median dose of 35 U/kg (34 to 60 U/kg) every other week for up to 84 months (7 years). VPRIV continued to demonstrate sustained clinical activity during treatment observed by improvements in hemoglobin concentrations and platelet counts and reduced liver and spleen volumes (see Table 2).
|Clinical Parameters||Median Observed Values Baseline ⚹ [Range]||Median Observed Values|
7 Years § [Range]
|Mean Change from Baseline (95% CI)|
7 years §
|Hemoglobin concentration (g/dL)||11.10 [9.8, 12.9]||13.40 [11.6, 16]||2.0 (1.4, 2.6)|
|Platelet count (x 109/L)||62.25 [37.0, 98.5]||122.0 [88, 166]||63.9 (45.7, 82.1)|
|Liver volume†||4.40 [2.6, 5.8]||2.30 [1.6, 4.0]||−1.8 (−2.5, −1.2)|
|Spleen volume†||3.80 [2.2, 6.5]||0.50 [0.4, 4.9]||−3.0 (−3.9, −2.2)|
⚹ Baseline is defined as data collected at the basline visit in Study 025
§ The last MRI assessment in the study was at 81 months of observation
† Normalized % of body weight.
For the 10 patients in Study 025EXT, the liver multiple of normal was 1.760 [range: 1.04, 2.32] and 0.920 [range: 0.64, 1.6] at baseline (in Study 025) and 7 years, respectively. The spleen multiple of normal was 19.00 [range: 11.00, 32.50] and 2.5 [range: 2, 24.5] at baseline (in Study 025) and 7 years, respectively.
The effect of VPRIV on bone parameters, including bone marrow burden (BMB) assessed by magnetic resonance imaging and bone mineral density (BMD) assessed by dual x-ray absorptiometry, was examined in this study. The median BMB score at baseline was 6.0. At month 9, the median BMB was 3.5. By month 57, 8 patients remained in 025EXT and had achieved a clinically meaningful reduction from baseline of at least 2 points in the lumbar spine BMB score. The mean change from baseline after 7 years of treatment with VPRIV for the lumbar spine and femoral neck BMDs (Z-score) were 0.7 (95%CI: 0.4, 1.0) and 0.5 (95%CI: 0.2, 0.7), respectively. Z-score changes in the lumbar spine and femoral neck were clinically meaningful and statistically significant by 24 and 33 months, respectively.
Study 032 was a 12-month, randomized, double-blind, parallel-group efficacy study in 25 patients age 2 years and older who were naïve to enzyme replacement therapy (defined as having not been treated with enzyme replacement therapy for at least 30 months prior to study entry). Patients were required to have Gaucher disease-related anemia and either thrombocytopenia or organomegaly. Patients were randomized to receive VPRIV at a dose of either 45 U/kg (N=13) or 60 U/kg (N=12) every other week. A dose-related effect in favor of 60 U/kg was observed in relation to the 45 U/kg dose group after 12 months of treatment (see Table 3). There were no data to suggest that there were any clinically significant differences between the 60 U/kg and 45 U/kg dose groups in terms of safety.
|Clinical Parameters||Mean Change from Baseline ± SE|
60 U/kg EOW
45 U/kg EOW
|Hemoglobin Concentration (g/dL)||2.43 ±0.32|
|Platelet count (x 109/L)||50.9 ±12.2|
1 p-value based on paired t-test
⚹⚹ Statistically significant after adjusting for performing multiple tests [on the following endpoints: mean within patient changes in hemoglobin concentration (45 U/kg arm only), platelet counts, and liver and spleen volumes from baseline to Month 12 separately for each randomized treatment group.]
The reductions in liver and spleen volumes were larger in the 60 U/kg VPRIV dose group. In this group, 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%). In the 45 U/kg group, 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, randomized, double-blind, active-comparator (imiglucerase) controlled, non-inferiority, parallel-group efficacy study in 34 patients age 2 years and older who were naïve to enzyme replacement therapy (defined as having not been treated with enzyme replacement therapy for at least 12 months prior to study entry). Patients were required to have Gaucher disease-related anemia and either thrombocytopenia or organomegaly. Patients received either 60 U/kg of VPRIV (N=17) or 60 U/kg of imiglucerase (N=17) every other week.
The mean absolute increase from baseline in hemoglobin concentrations was 1.624 g/dL (±0.223 SE) following 9 months of treatment with VPRIV. This increase in hemoglobin concentration was demonstrated to be clinically and statistically non-inferior to imiglucerase (mean treatment difference of change from baseline to 9 months [VPRIV – imiglucerase]: 0.135 g/dL). There were no statistically significant differences between VPRIV and imiglucerase in changes in platelet counts and liver and spleen volumes after 9 months of VPRIV treatment, and the time to first hemoglobin response (defined as 1g/dL increase from baseline).
Study in Patients Switching from Imiglucerase Treatment to VPRIV
Study 034 was a 12-month, open-label safety study in 40 patients age 2 years and older who had been receiving treatment with imiglucerase at doses ranging between 15 to 60 U/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 enrollment. Treatment with VPRIV was administered as the same number of units and regimen as their imiglucerase dose. Hemoglobin 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 VPRIV, hemoglobin concentrations and platelet counts were sustained at therapeutic levels through 12 months of treatment. The median value for hemoglobin concentrations at baseline was 13.8 g/dL (range: 10.4, 16.5) and after 12 months of treatment with VPRIV the median value was 13.5 g/dL (range: 10.8, 16.1). The median value for platelet counts at baseline was 162 x 109/L (range: 29.0, 399.0) and after 12 months of treatment with VPRIV the median value was 174 x 109/L (range: 24.0, 408.0).
Extension Study 044 [032, 034 and 039]
A total of 95 adult and pediatric patients, who received VPRIV in Studies 032, 034, and 039 enrolled in this open-label extension study. Fifty-seven (57) patients were treatment-naïve and 22 were 17 years of age or younger. All patients received at least 2 years of enzyme replacement therapy and were followed for a mean of 4.5 years (min 2.3 yrs, max 5.8 yrs). In this study, in treatment-naïve patients after 24 months of VPRIV treatment versus baseline the mean hemoglobin concentration increased by 2.75 g/dL (95% CI: 2.28, 3.22), mean platelet count increased by 87.85 X109/L (95% CI: 72.69, 103.00), normalized liver volume decreased by 1.21 (95% CI: -1.50, -0.91) and normalized spleen volume decreased by 2.66 (95% CI: -3.50, -1.82). In patients who switched from imiglucerase to VPRIV, hemoglobin concentrations and platelet counts were sustained through 24 months of treatment with a mean change from baseline in hemoglobin of -0.05 g/dL (95% CI: -0.34, 0.25) and a mean change from baseline in platelet count of 9.03 X 109/L (95% CI: -2.60, 20.66). Normalized liver and spleen volumes were also sustained, with a mean change from baseline in normalized liver volume of -0.026% body weight (CI: -0.10, 0.047) and a mean change in normalized spleen volume of -0.11% body weight (CI: - 0.191, -0.029). In children, increases in the mean height Z-score were seen through 60 months of treatment in the overall treatment-naïve population. Similar treatment effects were seen through 48 months in children who received 9 months of imiglucerase followed by VPRIV. Treatment effects on hemoglobin, platelet count, organ volumes, bone mineral density and height were maintained through the end of the study. The safety profile observed in the extension study is consistent with that observed in other studies.
In this study, which enrolled both treatment-naïve and patients transitioning from imiglucerase, the safety profile in 205 patients previously treated with imiglucerase was similar to that observed in other clinical trials. Observation regarding treatment goals suggests that an apparent
increase from baseline in hemoglobin concentration and platelet count was observed in the 4 treatment-naïve patients with post-baseline data. Among previously treated patients mean hemoglobin concentration and platelet count were maintained throughout the study and remained within the normal range.
Comparative Bioavailability Studies
No comparative bioavailability studies have been performed with VPRIV.
A series of studies were performed comparing the biological and biochemical effects of velaglucerase alfa and imiglucerase in a mouse model of Gaucher disease (9V/null mouse) following repeat administration of both enzymes (5, 15, or 60 U/kg). Results showed that velaglucerase alfa and imiglucerase similarly restored normal lipid (glucocerebroside) content in the liver, while the lipid content in the spleen was unaffected in comparison to wild-type controls. Neither enzyme affected the lipid content of the lung. Both enzymes comparably reduced the number of Gaucher cells in liver.
A series of nonclinical pharmacokinetic studies in rats, dogs, and rhesus monkeys demonstrated that velaglucerase alfa was distributed into the tissue by 1st order elimination kinetics. The serum elimination half-life of velaglucerase alfa at a low-dose of 0.84 mg/kg was approximately 2, 4, and 5 minutes in rats, dogs, and rhesus monkeys, respectively. In rhesus monkeys, the elimination half-lives increased from 5 minutes at 0.84 mg/kg to 11 minutes at the maximum dose of 17 mg/kg. Cmax was proportional to dose in all 3 species evaluated, whereas AUC was not dose-proportional. Serum clearance mechanisms (presumably via mannose receptors) appear to become saturated at dose levels >3 mg/kg.
A tissue biodistribution study in rats using 125 I-labeled velaglucerase alfa demonstrated that the greatest amount of administered dose was found in the liver 20 minutes after dosing (~70% at a dose of 1.1 mg/kg) with lesser amounts localized in other organs (1.5% in spleen, 3.0% in kidney, and 0.5% in bone/bone marrow). Tissue elimination from the liver and spleen, organs associated with Gaucher disease, was biphasic. Initial half-lives were approximately 1 hour in both organs and elimination half-lives ranged from 13 hours (spleen) to 17 hours (liver), suggesting that velaglucerase alfa would not be expected to accumulate in these organs following repeated, every other week, IV dosing.
Nonclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, single dose toxicity, repeated dose toxicity, and developmental and reproductive toxicology studies. The only treatment-related finding was observed in the rat repeat-dose and reproduction studies, manifesting as swelling and/or redness of the face and/or paws. Swelling was transient, lasting for 1 to 4 hours post-dosing. Histamine monitoring revealed increased values at 15 minutes post-treatment, whereas complement levels were unaffected. However, a similar response was not observed for rabbits, dogs or monkeys. Hence, the post-dosing swelling was considered to be a rat-specific response to velaglucerase alfa. Genotoxic and carcinogenic potential are not expected.
Acute Toxicity Studies
The acute toxicity of velaglucerase alfa was evaluated in rats. Doses of velaglucerase alfa up to 23 mg/kg, 15-fold the recommended dose in humans, have been tested without any adverse toxicity.
Repeat-dose Toxicity Studies
Nonclinical data reveal no special hazard for humans based on 3- and 6-month, repeat-dose toxicology studies in rats and a 6-month, repeat-dose toxicity study in rhesus monkeys. The maximum no observed effect level of at least 17 mg/kg velaglucerase alfa was established, providing safety margins (on a mg/kg basis) of approximately 44-fold for the lowest human dose (0.38 mg/kg, 15 U/kg) and 11-fold for the highest human dose (1.5 mg/kg; 60 U/kg).
Reproduction and Teratology
A series of developmental and reproductive toxicology studies were conducted in rats and rabbits. These studies included a Segment I study in rats (male and female fertility and early embryonic development), Segment II studies in rats and rabbits (embryo-fetal development; dose-range finding and definitive studies), and a Segment III study in rats (pre- and post-natal development and maternal function).
Reproductive toxicity studies performed in male and female rats included doses up to 17 mg/kg, or 11-fold the maximum human dose of 60 U/kg on a mg-per-kg basis, and revealed no evidence of impaired male or female fertility. Developmental toxicity studies performed in female rats and rabbits at maximum doses of 17 and 20 mg/kg, or 11-fold and 13-fold the maximum human dose of 60 U/kg on a mg-per-kg basis, resulted in no maternal or developmental treatment-related effects.
Mutagenicity and Carcinogenicity Studies
No animal studies have been conducted to assess the mutagenic, genotoxic, and carcinogenic potential for velaglucerase alfa. This is consistent with the ICH guidelines S1A “Guidelines on the Need for Carcinogenicity Studies of Pharmaceuticals” and S6 “Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals.” As a purified form of the naturally occurring enzyme glucocerebrosidase, such potential is not expected for velaglucerase alfa.