14 CLINICAL STUDIES

The efficacy of ZAVESCA in type 1 Gaucher disease has been investigated in two open-label, uncontrolled trials and one randomized, open-label, active-controlled trial with enzyme replacement given as imiglucerase. Patients who received ZAVESCA were treated with doses ranging from 100 to 600 mg a day, although the majority of patients were maintained on doses between 200 to 300 mg a day. Efficacy parameters included the evaluation of liver and spleen organ volume, hemoglobin concentration, and platelet count. A total of 80 patients were exposed to ZAVESCA during the three trials and their extension period.

Open-Label Uncontrolled Monotherapy Trials

In Study 1, ZAVESCA was administered at a starting dose of 100 mg three times daily for 12 months (dose range of 100 once-daily to 200 mg three times daily) to 28 adult patients with type 1 Gaucher disease, who were unable to receive enzyme replacement therapy and who had not taken enzyme replacement therapy in the preceding 6 months. Twenty-two patients completed the trial. After 12 months of treatment, the results showed significant mean percent reductions from baseline in liver volume of 12% and spleen volume of 19%, a non-significant increase from baseline in mean absolute hemoglobin concentration of 0.26 g/dL and a mean absolute increase from baseline in platelet counts of 8×10 9/L (See Tables 3–6).

In Study 2, ZAVESCA was administered at a dose of 50 mg three times daily for 6 months to 18 adult patients with type 1 Gaucher disease who were unable to receive enzyme replacement therapy and who had not taken enzyme replacement therapy in the preceding 6 months. Seventeen patients completed the trial. After 6 months of treatment, the results showed significant mean percent reductions from baseline in liver volume of 6% and spleen volume of 5%. There was a non-significant mean absolute decrease from baseline in hemoglobin concentration of 0.13 g/dL and a non-significant mean absolute increase from baseline in platelet counts of 5×10 9/L (See Tables 3–6).

Extension Period

Eighteen patients were enrolled in a 12-month extension to Study 1. A subset of patients continuing in the extension had larger mean baseline liver volumes, and lower mean baseline platelet counts and hemoglobin concentrations than the original study population (See Tables 3–6). After a total of 24 months of treatment, there were significant mean decreases from baseline in liver and spleen organ volumes of 15% and 27%, respectively, and significant mean absolute increases from baseline in hemoglobin concentration and platelet count of 0.9 g/dL and 14×10 9/L, respectively (See Tables 3–6).

Sixteen patients were enrolled in a 6-month extension to Study 2. After a total of 12 months of treatment, there was a mean decrease from baseline in spleen organ volume of 10%, whereas the mean percent decrease in liver organ volume remained at 6%. There were no significant changes in hemoglobin concentrations or platelet counts (See Tables 3–6).

Liver volume results from Studies 1 and 2 and their extensions are summarized in Table 3:

Table 3: Liver Volume Changes in Two Open-Label Uncontrolled Monotherapy Trials of ZAVESCA with Extension Period
		Liver Volume
	n	Absolute Mean (L) (2-sided 95% CI)	Percent Mean (%) (2-sided 95% CI)
Study 1 (starting dose ZAVESCA 100 mg three times daily)
Baseline (Month 0)	21	2.39
Month 12 Change from baseline		-0.28 (-0.38, -0.18)	-12.1% (-16.4, 7.9)
Study 1 Extension Phase
Baseline (Month 0)	12	2.54
Month 24 Change from baseline		-0.36 (-0.48, -0.24)	-14.5% (-19.3, 9.7)
Study 2 (ZAVESCA 50 mg three times daily)
Baseline (Month 0)	17	2.45
Month 6 Change from baseline		-0.14 (-0.25, -0.03)	-5.9% (-9.9, -1.9)
Study 2 Extension Phase
Baseline (Month 0)	13	2.35
Month 12 Change from baseline		-0.17 (-0.3, -0.0)	-6.2% (-12.0, -0.5)

Spleen volume results from Studies 1 and 2 and their extensions are summarized in Table 4:

Table 4: Spleen Volume Changes in Two Open-Label Uncontrolled Monotherapy Trials of ZAVESCA with Extension Period
		Spleen Volume
	n	Absolute Mean (L) (2-sided 95% CI)	Percent Mean (%) (2-sided 95% CI)
Study 1 (starting dose ZAVESCA 100 mg three times daily)
Baseline (Month 0)	18	1.64
Month 12 Change from baseline		-0.32 (-0.42, -0.22)	-19.0% (-23.7, -14.3)
Study 1 Extension Phase
Baseline (Month 0)	10	1.56
Month 24 Change from baseline		-0.42 (-0.53, -0.30)	-26.4% (-30.4, -22.4)
Study 2 (ZAVESCA 50 mg three times daily)
Baseline (Month 0)	11	1.98
Month 6 Change from baseline		-0.09 (-0.18, -0.01)	-4.5% (-8.2, -0.7)
Study 2 Extension Phase
Baseline (Month 0)	9	1.98
Month 12 Change from baseline		-0.23 (-0.46, 0.00)	-10.1% (-20.1, -0.1)

Hemoglobin concentration results from Studies 1 and 2 and their extensions are summarized in Table 5:

Table 5: Hemoglobin Concentration Changes in Two Open-Label Uncontrolled Monotherapy Trials of ZAVESCA with Extension Period
		Hemoglobin Concentration
	n	Absolute Mean (g/dL) (2-sided 95% CI)	Percent Mean (%) (2-sided 95% CI)
Study 1 (starting dose ZAVESCA 100 mg three times daily)
Baseline (Month 0)	22	11.94
Month 12 Change from baseline		0.26 (-0.05, 0.57)	2.6% (-0.5, 5.7)
Study 1 Extension Phase
Baseline (Month 0)	13	11.03
Month 24 Change from baseline		0.91 (0.30, 1.53)	9.1% (2.9, 15.2)
Study 2 (ZAVESCA 50 mg three times daily)
Baseline (Month 0)	17	11.60
Month 6 Change from baseline		-0.13 (-0.51, 0.24)	-1.3% (-4.4, 1.8)
Study 2 Extension Phase
Baseline (Month 0)	13	11.94
Month 12 Change from baseline		0.06 (-0.73, 0.85)	1.2% (-5.2, 7.7)

Platelet count results from Studies 1 and 2 and their extensions are summarized in Table 6:

Table 6: Platelet Count Changes in Two Open-Label Uncontrolled Monotherapy Trials of ZAVESCA with Extension Period
		Platelet Count
	n	Absolute Mean (10 9/L) (2-sided 95% CI)	Percent Mean (%) (2-sided 95% CI)
Study 1 (starting dose ZAVESCA 100 mg three times daily)
Baseline (Month 0)	22	76.58
Month 12 Change from baseline		8.28 (1.88, 14.69)	16.0% (-0.8, 32.8)
Study 1 Extension Phase
Baseline (Month 0)	13	72.35
Month 24 Change from baseline		13.58 (7.72, 19.43)	26.1% (14.7, 37.5)
Study 2 (ZAVESCA 50 mg three times daily)
Baseline (Month 0)	17	116.47
Month 6 Change from baseline		5.35 (-6.31, 17.02)	2.0% (-6.9, 10.8)
Study 2 Extension Phase
Baseline (Month 0)	13	122.15
Month 12 Change from baseline		14.0 (-3.4, 31.4)	14.7% (-1.4, 30.7)

Open-Label Active-Controlled Trial

Study 3 was an open-label, randomized, active-controlled study of 36 adult patients with type 1 Gaucher disease, who had been receiving enzyme replacement therapy with imiglucerase for a minimum of 2 years prior to study entry. Patients were randomized 1:1:1 to one of three treatment groups, as follows:

ZAVESCA 100 mg three times daily alone
imiglucerase (patient's usual dose) alone
ZAVESCA 100 mg three times daily and imiglucerase (usual dose)

Patients were treated for 6 months, and 33 patients completed the study. Because ZAVESCA is only indicated as monotherapy, the results for the monotherapy arms are described below. At Month 6, the results showed a decrease in mean percent change in liver volume in the ZAVESCA treatment group compared to the imiglucerase alone group. There were no significant differences between the groups for mean absolute changes in liver and spleen volume and hemoglobin concentration. However, there was a significant difference between the ZAVESCA alone and imiglucerase alone groups in platelet counts at Month 6, with the ZAVESCA alone group having a mean absolute decrease in platelet count of 21.6×10 9/L and the imiglucerase alone group having a mean absolute increase in platelet count of 10.1×10 9/L (See Tables 7–10).

Extension period

Twenty-nine patients were enrolled in a 6-month extension to Study 3. In the extension phase, all 29 patients had withdrawn from imiglucerase and received open-label ZAVESCA 100 mg three times daily monotherapy. At Month 12, the results showed non-significant decreases in platelet counts from baseline in all the treatment groups (by original randomization). There was a significant decrease in platelet counts from Month 6 to Month 12 in the group originally randomized to treatment with imiglucerase, and a continued decrease in platelet counts in the group originally randomized to ZAVESCA alone. There were no significant changes in any treatment group for liver volume, spleen volume, or hemoglobin concentration (See Tables 7–10).

Liver volume results from Study 3 and extension are summarized in Table 7:

Table 7: Liver Volume Changes from Study 3 and Extension Phase
	Imiglucerase alone	ZAVESCA alone
* All patients received ZAVESCA 100 mg three times daily monotherapy from Month 6 to Month 12.
Study 3	n=11	n=10
Month 0	1.81	1.58
Month 6 Change (L)	0.04	-0.05
Month 6 % Change	3.6%	-2.9%
Adjusted mean Difference from Imiglucerase (95% CI)		-4.5% (-13.2, 4.2)
Extension Phase *	n=10	n=8
Month 0	1.94	1.60
Month 12 Change (L)	-0.05	-0.01
Month 12 % Change	-0.7%	-0.8%

Spleen volume results from Study 3 and extension are summarized in Table 8:

Table 8: Spleen Volume Changes from Study 3 and Extension Phase
	Imiglucerase alone	ZAVESCA alone
* All patients received ZAVESCA 100 mg three times daily monotherapy from Month 6 to Month 12.
Study 3	n=8	n=7
Month 0	0.61	0.69
Month 6 Change (L)	-0.02	-0.03
Month 6 % Change	-2.1%	-4.8%
Adjusted % Difference from Imiglucerase (95% CI)		-5.8% (-22.1, 10.5)
Extension Phase *	n=7	n=6
Month 0	0.83	0.57
Month 12 Change (L)	0.04	-0.05
Month 12 % Change	1.5%	-6.1%

Hemoglobin concentration results from Study 3 and extension are summarized in Table 9:

Table 9: Hemoglobin Concentration Changes from Study 3 and Extension Phase
	Imiglucerase alone	ZAVESCA alone
* All patients received ZAVESCA 100 mg three times daily monotherapy from Month 6 to Month 12 .
Study 3	n=12	n=10
Month 0	13.18	12.44
Month 6 Change (g/dL)	-0.15	-0.31
Month 6 % Change	-1.2%	-2.4%
Adjusted % Difference from Imiglucerase (95% CI)		-1.9% (-6.4, 2.6)
Extension Phase *	n=10	n=9
Month 0	13.39	12.46
Month 12 Change (g/dL)	-0.48	-0.13
Month 12 % Change	-3.1%	-1.1%

Platelet count results from Study 3 and extension are summarized in Table 10:

Table 10: Platelet Count Changes from Study 3 and Extension Phase
	Imiglucerase alone	ZAVESCA alone
* All patients received ZAVESCA 100 mg three times daily monotherapy from Month 6 to Month 12.
Study 3	n=12	n=10
Month 0	165.75	170.55
Month 6 Change (10 9/L)	15.29	-21.60
Month 6 % Change	10.1%	-9.6%
Adjusted % Difference from Imiglucerase (95% CI)		-17.1% (-32.9, -1.3)
Extension Phase *	n=10	n=9
Month 0	170.05	184.83
Month 12 Change (10 9/L)	-3.75	-27.39
Month 12 % Change	-3.2%	-10.4%

Patients with platelet counts above 150 × 10 9/L at baseline who were randomized to ZAVESCA treatment had significant decreases in platelet counts at Month 12.