ELELYSO (Page 3 of 4)

12.6 Immunogenicity

The observed incidence of ADA (including neutralizing antibodies [Nab]) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADA in the studies described below with the incidence of ADA in other studies, including those of ELELYSO or of other taliglucerase alfa products.

Anti-Drug Antibodies

In Trials 1, 2, and 3, a greater portion of ELELYSO-treated patients who developed ADA had hypersensitivity reactions compared to those who did not develop ADA [see Adverse Reactions (6.1) and Warnings and Precautions (5.1)].

In Trial 1 (treatment-naïve adults with Gaucher disease) [see Clinical Studies (14.1)] , 17 (53%) of 32 ELELYSO-treated patients developed ADA. Additionally 2 (6%) patients tested positive for ADA at baseline prior to ELELYSO treatment.

In Trial 2 (treatment-naïve pediatric patients with Gaucher disease) [see Clinical Studies (14.1)] , 2 (22%) of 9 Type 1 Gaucher disease ELELYSO-treated patients developed ADA. Additionally, 1 patient was ADA-positive prior to initiation of ELELYSO.

In Trial 3 (switched from imiglucerase to ELELYSO), of 31 ELELYSO-treated patients (26 adult and 5 pediatric patients) [see Clinical Studies (14.2)] , 6 adults (23% of adult patients) developed ADA and no pediatric patient developed ADA. Additionally, 3 (10%) patients were ADA positive prior to initiation of ELELYSO.

There is insufficient information to characterize the ADA response to ELELYSO and the effects of ADA on pharmacokinetics, pharmacodynamics, or effectiveness of taliglucerase alfa products.

Neutralizing Antibodies

In Trials 1, 2 and 3 with a total number of 72 patients, 30 of the 31 ELELYSO-treated adult and pediatric patients who developed ADA or tested positive for ADA at baseline were evaluated for neutralizing activity of the ADA in the mannose receptor binding and enzyme activity assays.

o
Nineteen (63%) of the 30 patients had neutralizing antibodies (Nab) capable of inhibiting in vitro mannose receptor binding of ELELYSO.
o
Eight (42%) of these 19 patients had Nab capable of inhibiting the in vitro enzymatic activity of ELELYSO.

Although the effectiveness was numerically lower (less spleen and liver volume reduction) in ELELYSO-treated patients who developed Nab compared to those that did not develop Nab, the data were not sufficient to fully assess whether the observed Nab reduces effectiveness.

Other Antibodies

Nine (29%) of the 31 ELELYSO-treated adult and pediatric patients who developed ADA during treatment or tested positive for ADA at baseline also developed antibodies against plant-specific glycans in ELELYSO.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals to evaluate carcinogenic potential or studies to evaluate mutagenic potential have not been performed with taliglucerase alfa. In a male and female fertility study in rats, taliglucerase alfa did not cause any significant adverse effect on male or female fertility parameters up to a maximum dose of 55 mg/kg/day (about 5 times the recommended human dose of 60 units/kg based on the body surface area).

14 CLINICAL STUDIES

14.1 Clinical Trials of ELELYSO as Initial Therapy

Clinical Trial in Adult Patients

The safety and efficacy of ELELYSO in the treatment of adult patients with Type 1 Gaucher disease was assessed in a 9-month, multi-center, double-blind, randomized trial (Trial 1) in 31 adult patients with Gaucher disease-related enlarged spleens (>8 times normal) and thrombocytopenia (<120,000 /mm3). Sixteen patients had enlarged livers and ten patients had anemia at baseline. All patients were naïve to enzyme replacement therapy (ERT). Patients with severe neurological symptoms were excluded from the trial.

Patients were randomized to receive ELELYSO at an intravenous dosage of either 30 units/kg (n=15) (50% of the recommended dosage) or 60 units/kg (the recommended dosage) [see Dosage and Administration (2.1)] (n=16) every other week. After 9 months, 26 of the 31 patients continued in the blinded portion of the long-term extension trial for a total treatment duration of 24 months at the same intravenous dosage every other week. Twenty three of those 26 patients continued open-label ELELYSO treatment (30 or 60 units/kg given intravenously every other week) for an additional 12 months (total duration of ELELYSO treatment was 36 months).

Baseline Demographics

In Trial 1, patients were 19 to 74 years of age (mean age 36 years), 48% were male, 97% were White and 29% and 71% were Hispanic/Latino and non Hispanic/Latino, respectively.

Efficacy Results

Table 4 shows the baseline values and mean (SD) changes in clinical parameters (spleen volume, liver volume, platelet count, and hemoglobin) after 9 months of ELELYSO treatment in Trial 1. Liver and spleen volumes were measured by MRI and are reported as percentage of body weight (%BW) and multiples of normal (MN). The observed reduction from baseline in spleen volume (the primary endpoint), was considered to be clinically meaningful in light of the natural history of untreated Gaucher disease.

Table 4: Mean (SD *) Changes in Clinical Parameters from Baseline to 9 Months in Treatment-Naïve Adults with Type 1 Gaucher Disease Treated with ELELYSO (N=31) (Trial 1)
Clinical Parameter ELELYSO 30 units/kg (n=15) Mean (SD) ELELYSO 60 units/kg (n=16) Mean (SD)
*
SD = standard deviation
The recommended ELELYSO dosage in treatment-naïve adult patients is 60 units/kg every other week. ELELYSO 30 units/kg every other week is not a recommended dosage. [see Dosage and Administration (2.1)]
%BW = percentage of body weight
§
MN = multiples of normal

Spleen Volume (%BW )

Baseline

3.1 (1.5)

3.3 (2.7)

Month 9

2.2 (1.3)

2.1 (1.9)

Change

-0.9 (0.4)

-1.3 (1.1)

Spleen Volume (MN §)

Baseline

15.4 (7.7)

16.7 (13.4)

Month 9

11.1 (6.3)

10.4 (9.4)

Change

-4.5 (2.1)

-6.6 (5.4)

Liver Volume (%BW)

Baseline

4.2 (0.9)

3.8 (1.0)

Month 9

3.6 (0.7)

3.1 (0.7)

Change

-0.6 (0.5)

-0.6 (0.4)

Liver Volume (MN)

Baseline

1.7 (0.4)

1.5 (0.4)

Month 9

1.4 (0.3)

1.2 (0.3)

Change

-0.2 (0.2)

-0.3 (0.2)

Platelet Count (mm3)

Baseline

75,320 (40,861)

65,038 (28,668)

Month 9

86,747 (50,989)

106,531 (53,212)

Change

11,427 (20,214)

41,494 (47,063)

Hemoglobin (g/dl)

Baseline

12.2 (1.7)

11.4 (2.6)

Month 9

14.0 (1.4)

13.6 (2.0)

Change

1.6 (1.4)

2.2 (1.4)

The following data are the changes in clinical parameters from baseline to Month 24 (including the 9-month initial period and the 15-month first long-term extension) for the 30 units/kg (n=12) (50% of the recommended dosage) and 60 units/kg (the recommended dosage) [see Dosage and Administration (2.1)] (n=14) treatment groups, respectively: mean (SD) spleen volume (%BW) decreased by 1.4 (0.6) and 2.0 (2.0), in MN by 6.8 (3.0) and 10.2 (9.8); hemoglobin increased by 1.3 (1.7) g/dL and 2.4 (2.3) g/dL; liver volume (%BW) decreased by 1.1 (0.5) and 1.0 (0.7), in MN by 0.4 (0.2) and 0.4 (0.3 and platelet count increased 28,433 (31,996)/mm3 and 72,029 (68,157)/mm3. The 23 patients who continued open-label ELELYSO treatment for additional 12 months demonstrated stability in these clinical parameters.

Clinical Trial in Pediatric Patients 16 Years of Age and Younger

The safety and efficacy of ELELYSO in the treatment of pediatric patients with Type 1 Gaucher disease was assessed in a 12-month, multi-center, double-blind, randomized trial (Trial 2) in 9 treatment-naïve patients. Patients were randomized to receive ELELYSO at an intravenous dosage of either 30 units/kg (n=4) (50% of the recommended dosage) or 60 units/kg (the recommended dosage) [see Dosage and Administration (2.1)] (n=5) every other week. After 12 months, all 9 patients entered a blinded portion of the long-term extension trial (24-months of total treatment) where they continued treatment with ELELYSO at the same dosage every other week.

Baseline Demographics

In Trial 2, patients were 2 to 13 years of age (mean age 8.1 years), 67% were male, 89% were White and 44% and 56% were Hispanic/Latino and non Hispanic/Latino, respectively.

Efficacy Results

The following data in Trial 2 are the changes [median (Q1, Q3)] in clinical parameters from baseline to Month 12 for the 60 units/kg dose group (n=5): spleen volume decreased from 18.4 (14.2, 35.1) MN to 11.0 (8.3, 14.5) MN; hemoglobin increased from 11.1 (9.2, 11.3) g/dL to 11.7 (11.5, 12.9) g/dL; liver volume decreased from 2.1 (2.0, 2.3) MN to 1.6 (1.5, 1.9) MN; platelet count increased from 80,000 (79,000, 87,000)/mm3 to 131,000 (119,000, 215,000)/mm3.

The following data are the changes [median (Q1, Q3)] in clinical parameters from baseline to Month 24 (including the initial 12-month period and the 12-month long-term extension) for the 60 units/kg dose group (n=5): spleen volume decreased by 19.0 (8.3, 41.2) MN; hemoglobin increased by 2.5 (1.9, 3.0) g/dL; liver volume decreased by 0.8 (0.6, 1.1) MN; and platelet count increased by 76,000 (67,000, 100,000)/mm3.

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