14 CLINICAL STUDIES

14.1 Overview of Clinical Studies of VPRIV for Gaucher Disease

The efficacy of VPRIV was assessed in three clinical trials 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. The long-term safety of VPRIV was assessed in Study IV, an open-label extension trial in a total of 93 patients with type 1 Gaucher disease ages 3 years and older. Patients who had completed Studies I to III were eligible to participate in Study IV. In Studies I through IV, VPRIV was administered intravenously over 60 minutes at a maximum dose of 60 Units/kg every other week. Doses above 60 Units/kg were not studied in these trials.

14.2 Clinical Trials of VPRIV as Initial Therapy

Study I was a 12-month, randomized, double-blind, parallel-dose-group, multinational trial 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. The recommended starting dose in naïve patients is 60 Units/kg. The 45 Units/kg dosage is not recommended as a starting dose in naïve patients [see Dosage and Administration (2.1)].

At baseline, mean hemoglobin concentration was 10.6 g/dL, mean platelet count was 97 × 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 2. The observed change from baseline in the primary endpoint, hemoglobin concentration, was considered to be clinically meaningful in the 60 Units/kg dose, in light of the natural history of untreated Gaucher disease.

Table 2: Mean Change from Baseline to Month 12 for Clinical Parameters in Patients with Type 1 Gaucher Disease Initiating Therapy with VPRIV Given Every Other Week in Study I
Clinical Parameter	VPRIV 45 Units/kg* N = 13 Mean ± SE	VPRIV 60 Units/kg N = 12 Mean ± SE
SE = standard error of the mean
* The recommended starting dose in naïve patients is 60 Units/kg. The 45 Units/kg dosage is not recommended as a starting dose in naïve patients [see Dosage and Administration (2.1)]. † Statistically significant changes from baseline after adjusting for performing multiple tests ‡ Primary study endpoint was hemoglobin concentration change in the 60 Units/kg group, p<0.001
Hemoglobin concentration change (g/dL)	2.4 ± 0.4†	2.4 ± 0.3‡
Platelet count change (× 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†

Study II was a 9-month, randomized, double-blind, active-controlled (imiglucerase), parallel-group, multinational study in 34 patients age 4 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 × 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 both studies, 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.

In Study IV, treatment naïve patients were administered VPRIV. Treatment-naïve patients continued to show improvements in clinical parameters (hemoglobin concentration, platelet count, liver volume, and spleen volume) compared with baseline for up to 60 months of treatment with ERT.

14.3 Clinical Trial 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 [see Dosage and Administration (2.2)].

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 × 109/L (range: 24, 408) vs. the baseline value of 162 × 109/L (range: 29, 399). No patient required dosage adjustment during the 12-month treatment period.

In Study IV, patients who had previously been receiving imiglucerase treatment were administered VPRIV. Patients previously treated with imiglucerase maintained stability in clinical parameters (hemoglobin concentration, platelet count, liver volume, and spleen volume) compared with baseline for up to 60 months of treatment with ERT.