Cerdelga (Page 4 of 5)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Carcinogenic potential of CERDELGA was assessed in 2-year carcinogenicity studies in rats and mice. In Sprague-Dawley rats, eliglustat was administered by oral gavage at doses up to 75 mg/kg/day in males (about 3.6 times the recommended human daily dose of 84 mg twice daily, based on body surface area) and 50 mg/kg/day in females (about 2.4 times the recommended human daily dose based on body surface area). In CD-1 mice, eliglustat was administered to males and females at up to 75 mg/kg/day (about 1.8 times the recommended human daily dose based on body surface area) via dietary admixture. Eliglustat did not produce any treatment-related neoplasms in rats or mice.

Mutagenesis

Eliglustat was negative in the Ames test, chromosome aberration test in human peripheral blood lymphocytes, mouse lymphoma gene mutation assay and in vivo oral mouse micronucleus test.

Impairment of Fertility

In a fertility and early embryonic development study in rats, eliglustat increased pre-implantation loss at 30 (about 1.5 times the recommended human oral dose based on body surface area) and 100 mg/kg/day (about 5 times the recommended human oral dose based on body surface area).

In mature male rats, eliglustat showed reversible adverse effects on sperm morphology, testes (germ cell necrosis), and sloughed cells in the epididymis at 200 mg/kg/day (about 10 times the recommended human oral dose based on body surface area). Similar effects on sperm were not seen in mature cynomolgus monkeys at 72 mg/kg/day (about 7 times the recommended human oral dose based on body surface area).

14 CLINICAL STUDIES

14.1 CERDELGA in Treatment-Naive GD1 Patients – Trial 1

Trial 1 (NCT00891202) was a randomized, double-blind, placebo-controlled, multicenter clinical study evaluating the efficacy and safety of CERDELGA in 40 treatment- naive GD1 patients 16 years of age or older (median age 30.4 years) with pre-existing splenomegaly and hematological abnormalities. Patients were required to have received no treatment with substrate reduction therapy within 6 months or ERT within 9 months prior to randomization; all but 5 patients in the study had no prior therapy. Patients were stratified according to baseline spleen volume (≤20 or >20 multiples of normal [MN]) and randomized in a 1:1 ratio to receive CERDELGA or placebo for the duration of the 9-month blinded primary analysis period. The CERDELGA treatment group was comprised of IM (5%), EM (90%) and URM (5%) patients. Patients randomized to CERDELGA treatment received a starting dose of 42 mg twice daily, with a dose increase to 84 mg twice daily possible at Week 4 based on the plasma trough concentration at Week 2. The majority of patients (17 [85%]) received a dose escalation to 84 mg twice daily at Week 4, and 3 (15%) continued to receive 42 mg twice daily for the duration of the 9-month blinded primary analysis period.

The primary endpoint was the percentage change in spleen volume (in MN) from baseline to 9 months as compared to placebo. Secondary endpoints were absolute change in hemoglobin level, percentage change in liver volume (in MN), and percentage change in platelet count from baseline to 9 months compared to placebo.

At baseline, mean spleen volumes were 12.5 and 13.9 MN in the placebo and CERDELGA groups, respectively, and mean liver volumes were 1.4 MN for both groups. Mean hemoglobin levels were 12.8 and 12.1 g/dL, and platelet counts were 78.5 and 75.1 × 109 /L, respectively.

During the 9-month primary analysis period, CERDELGA demonstrated statistically significant improvements in all primary and secondary endpoints compared to placebo, as shown in Table 10.

Table 10: Change from Baseline to Month 9 in Treatment-Naive Patients with GD1 Receiving Treatment with CERDELGA in Trial 1
Placebo(n=20) CERDELGA (n=20) Difference(CERDELGA – Placebo)[95% CI] p value *
MN = Multiples of Normal, CI = confidence interval, NA = Not applicable
*
Estimates and p-value are based on ANCOVA model that includes treatment group, baseline spleen severity group (≤20 MN, >20 MN) and baseline parameter value.
Percentage Change in Spleen Volume MN (%) 2.3 -27.8 -30.0[-36.8, -23.2] <0.0001
Absolute Change in Spleen Volume (MN) 0.3 -3.7 -4.1[-5.3, -2.9] NA
Absolute Change in Hemoglobin Level (g/dL) -0.5 0.7 1.2[0.6, 1.9] 0.0006
Percentage Change in Liver Volume MN (%) 1.4 -5.2 -6.6[-11.4, -1.9] 0.0072
Absolute Change in Liver Volume (MN) 0.0 -0.1 -0.1[-0.2, 0.0] NA
Percentage Change in Platelet Count (%) -9.1 32.0 41.1[24.0, 58.2] <0.0001
Absolute Change in Platelet Count (× 109 /L) -7.2 24.1 31.3[18.8, 43.8] NA

In the open-label extension phase of Trial 1 in naive GD1 patients, 38 of 40 patients who continued treatment with CERDELGA for 2 years demonstrated the following changes in clinical parameters from baseline to 2 years: mean (SD) percent change in spleen volume (MN) -51.1% (10.7); mean (SD) percent change in liver volume (MN) -16.1% (11.3); mean (SD) absolute change in hemoglobin level (g/dL) 1.3 (1.2), and mean (SD) percent change in platelet count (mm3) 65.3% (40.9).

In a separate uncontrolled study (NCT00358150) of treatment-naive GD1 patients, improvements in spleen and liver volume, hemoglobin level, and platelet count continued through the 4-year treatment period.

14.2 Patients Switching from Enzyme Replacement Therapy to CERDELGA – Trial 2

Trial 2 (NCT00943111) was a randomized, open-label, active-controlled, non- inferiority, multicenter clinical study evaluating the efficacy and safety of CERDELGA compared with imiglucerase in 159 treated GD1 patients (median age 37.4 years) previously treated with enzyme replacement therapy (≥3 years of enzyme replacement therapy, dosed at 30–130 U/kg/month in at least 6 of the prior 9 months) who met pre-specified therapeutic goals at baseline. Pre-specified baseline therapeutic goals included: no bone crisis and free of symptomatic bone disease within the last year; mean hemoglobin level of ≥11 g/dL in females and ≥12 g/dL in males; mean platelet count ≥100,000/mm3 ; spleen volume <10 times normal and liver volume <1.5 times normal.

Patients were randomized 2:1 to receive CERDELGA or imiglucerase for the duration of the 12-month primary analysis period. Seventy-five percent of patients randomized to CERDELGA were previously treated with imiglucerase; 21% with velaglucerase alfa and 4% were unreported. Patients randomized to CERDELGA treatment received a starting dose of 42 mg twice daily, with dose increases to 84 mg twice daily and 127 mg twice daily possible at Weeks 4 and 8 based on plasma trough concentrations of CERDELGA at Weeks 2 and 6, respectively. The percentage of patients receiving the 3 possible CERDELGA doses was: 42 mg twice daily (20%), 84 mg twice daily (32%) and 127 mg twice daily (48%). The CERDELGA treatment group was comprised of PM (4%), IM (10%), EM (80%) and URM (4%) patients.

At baseline, mean spleen volumes were 2.6 and 3.2 MN in the imiglucerase and CERDELGA groups, respectively, and liver volumes were 0.9 MN in both groups. Mean hemoglobin levels were 13.8 and 13.6 g/dL, and platelet counts were 192 and 207 × 109 /L, respectively.

The primary composite endpoint required stability in all four component domains (hemoglobin level, platelet count, liver volume, and spleen volume) based on changes between baseline and 12 months. Stability was defined by the following pre-specified thresholds of change: hemoglobin level <1.5 g/dL decrease, platelet count <25% decrease, liver volume <20% increase and spleen volume <25% increase. The percentages of patients meeting the criteria for stability in the individual components of the composite endpoint were assessed as secondary efficacy endpoints.

CERDELGA met the criteria to be declared non-inferior to imiglucerase in maintaining patient stability. After 12 months of treatment, the percentage of patients meeting the primary composite endpoint was 84.8% for the CERDELGA group compared to 93.6% for the imiglucerase group. The lower bound of the 95% CI of the 8.8% difference, -17.6%, was within the pre-specified non-inferiority margin of -25%. At Month 12, the percentages of CERDELGA and imiglucerase patients respectively, who met stability criteria for the individual components of the composite endpoint were: hemoglobin level, 94.9% and 100%; platelet count, 92.9% and 100%; spleen volume, 95.8% and 100%; and liver volume, 96.0% and 93.6%. Of the patients who did not meet stability criteria for the individual components, 12 of 15 CERDELGA patients and 3 of 3 imiglucerase patients remained within therapeutic goals for GD1.

Mean changes from baseline in the hematological and visceral parameters through 12 months of treatment are shown in Table 11. There were no clinically meaningful differences between groups for any of the four parameters.

Table 11: Mean Changes from Baseline to Month 12 in Patients with GD1 Switching to CERDELGA in Trial 2
Imiglucerase(N=47)Mean[95% CI] CERDELGA(N=99)Mean[95% CI]
MN = Multiples of Normal, CI = confidence interval
*
Excludes patients with a total splenectomy.
Percentage Change in Spleen Volume MN (%)* -3.0[-6.4, 0.4] -6.2[-9.5, -2.8]
Absolute Change in Spleen Volume (MN)* -0.1[-0.2, 0.0] -0.2[-0.3, -0.1]
Absolute Change in Hemoglobin Level (g/dL) 0.0[-0.2, 0.2] -0.2[-0.4, -0.1]
Percentage Change in Liver Volume MN (%) 3.6[0.6, 6.6] 1.8[-0.2, 3.7]
Absolute Change in Liver Volume (MN) 0.0[0.0, 0.1] 0.0[0.0, 0.0]
Percentage Change in Platelet Count (%) 2.9[-0.6, 6.4] 3.8[0.0, 7.6]
Absolute Change in Platelet Count (× 109 /L) 6.0[-0.9, 13.0] 9.5[1.4, 17.6]
Patients Stable for 52 Weeks, n (%)(Composite Primary Endpoint) 44 (93.6) 84 (84.8)

In the open-label extension phase of Trial 2, 141 of 146 patients (42 patients previously treated with enzyme treatment therapy and 99 who continued treatment with CERDELGA) were evaluated for stability, as defined in the initial 12 months of the trial, in clinical parameters (composite of spleen and liver volume, hemoglobin level, and platelet count). Stability was shown in 120/141 (85%) patients at one year and 111/129 (86%) patients at 2 years of CERDELGA exposure.

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