ELELYSO (Page 2 of 4)

6.2 Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other taliglucerase alfa products may be misleading.

Anti-Drug Antibodies (ADA)

In a clinical trial of treatment-naïve adults, 17 (53%) of 32 patients developed ADA during treatment with ELELYSO, and 2 (6%) of 32 patients tested positive for ADA at baseline prior to ELELYSO treatment. Of the 17 patients who developed ADA during ELELYSO treatment, 6 patients (35%) developed hypersensitivity reactions, 2 of whom met criteria for anaphylaxis. Two of the 17 patients who developed ADA during ELELYSO treatment discontinued treatment due to hypersensitivity reactions, one of whom had met criteria for anaphylaxis. Of the 2 patients who tested positive for ADA prior to initiation of ELELYSO treatment, one patient developed a hypersensitivity reaction during the first dose of ELELYSO and withdrew from the study. The second patient did not experience a hypersensitivity reaction.

In a clinical trial of treatment-naïve pediatric patients, 2 (22%) of 9 patients developed ADA during treatment with ELELYSO, and one of 9 patients was ADA-positive prior to initiation of ELELYSO. Two of these 3 patients experienced hypersensitivity reactions (1 who developed ADA during treatment and became negative after Week 12 and 1 who was ADA-positive at baseline and became ADA negative after Week 8) and continued treatment with ELELYSO. The third patient who developed ADA during treatment and continued to be ADA-positive until study completion at Week 52 did not experience a hypersensitivity reaction.

In clinical trials of 31 patients (26 adult and 5 pediatric patients) who switched from imiglucerase to ELELYSO treatment, 5 adults (16% of patients) developed ADA during treatment with ELELYSO. Four additional patients (13%, 2 adults and 2 children) tested positive for ADA at baseline but became ADA-negative after the switch to ELELYSO; one of these adult patients subsequently developed ADA to ELELYSO. Two adult patients (1 patient who developed ADA after the switch and 1 who was ADA positive at baseline) experienced hypersensitivity reactions. Both patients continued treatment with ELELYSO.

The relationship between ADA and hypersensitivity reactions is not fully understood. Monitoring for ADA to ELELYSO may be useful in ADA positive patients or in patients who have experienced hypersensitivity reactions to ELELYSO or other enzyme replacement therapies.

Neutralizing Antibodies

Thirty (30) of the 31 adult and pediatric patients who developed ADA to ELELYSO during treatment or tested positive for ADA at baseline were evaluated for neutralizing activity of the ADA in the mannose receptor binding and enzyme activity assays. Nineteen (63%) of the 30 patients had neutralizing antibodies capable of inhibiting mannose receptor binding of ELELYSO. Eight of these 19 patients had neutralizing antibodies capable of inhibiting the enzymatic activity of ELELYSO. Available data do not indicate a clear relationship between the presence of mannose receptor binding neutralizing antibodies or neutralizing antibodies capable of inhibiting the enzymatic activity of ELELYSO and the therapeutic response to ELELYSO.

Other Antibodies

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

6.3 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of ELELYSO. Because these reactions include those reported voluntarily from a population of uncertain size in addition to those from postmarketing studies, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:

  • Gastrointestinal disorders: Vomiting, diarrhea
  • General disorders and administration site conditions: Fatigue
  • Immune system disorders: Anaphylaxis [see Warnings and Precautions (5.1)] , Type III immune-mediated fixed drug eruption
  • Musculoskeletal and connective tissue disorders: Back pain

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

The limited available data on ELELYSO use in pregnant women are not sufficient to inform a drug-associated risk. However, there are clinical considerations [see Clinical Considerations]. In animal reproduction studies when pregnant rats and rabbits were administered taliglucerase alfa at intravenous doses up to 5 times the recommended human dose (RHD), there was no evidence of embryo-fetal toxicity [see Data]. The estimated background risk of major birth defects and miscarriage for the indicated population(s) are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

Women with Type 1 Gaucher disease have an increased risk of spontaneous abortion if disease symptoms are not treated and controlled pre-conception and during a pregnancy. Pregnancy may exacerbate existing Type 1 Gaucher disease symptoms or result in new disease manifestations. Type 1 Gaucher disease manifestations may lead to adverse pregnancy outcomes, including hepatosplenomegaly which can interfere with the normal growth of a fetus and thrombocytopenia which can lead to increased bleeding and possible postpartum hemorrhage requiring transfusion.

Data

Animal Data

Reproduction studies have been performed with taliglucerase alfa administered during the period of organogenesis in rats and rabbits. In rats, intravenous doses up to 55 mg/kg/day (about 5 times the RHD of 60 units/kg based on the body surface area) did not cause any adverse effects on embryo-fetal development. In rabbits, intravenous doses up to 27.8 mg/kg/day (about 5 times the RHD of 60 units/kg based on the body surface area) did not show any embryo-fetal toxicity.

8.2 Lactation

Risk Summary

There are no data on the presence of taliglucerase alfa in human milk, the effects on the breast fed infant or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ELELYSO and any potential adverse effects on the breastfed child from ELELYSO or from the underlying maternal condition.

8.4 Pediatric Use

The use of ELELYSO for treatment of pediatric patients with Type 1 Gaucher disease is supported by evidence of effectiveness from adequate and well-controlled trials of ELELYSO in adults, with additional pharmacodynamic data from 5 pediatric patients and pharmacokinetic data from 9 pediatric patients who participated in clinical trials [see Clinical Studies (14.1, 14.2), Clinical Pharmacology (12.3)]. Data from 14 pediatric patients were included in the safety evaluation [see Adverse Reactions (6.1)]. There are insufficient data to inform dosing in patients less than 4 years of age.

Pediatric patients experienced a higher frequency of vomiting during ELELYSO treatment (4 of 9 treatment-naïve patients) than adult patients, and this may be a symptom of hypersensitivity reaction. The frequencies of other adverse reactions were similar between pediatric and adult patients [see Adverse Reactions (6.1)].

8.5 Geriatric Use

During clinical trials, 8 patients aged 65 or older were treated with ELELYSO. Clinical trials of ELELYSO did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.

11 DESCRIPTION

Taliglucerase alfa is a hydrolytic lysosomal glucocerebroside-specific enzyme produced by recombinant DNA technology using plant cell culture (carrot). Taliglucerase alfa is a monomeric glycoprotein enzyme containing 4 N-linked glycosylation sites (kDa=60.8). Taliglucerase alfa differs from native human glucocerebrosidase by two amino acids at the N terminal and up to 7 amino acids at the C terminal. Taliglucerase alfa is a glycosylated protein with oligosaccharide chains at the glycosylation sites having terminal mannose sugars. These mannose-terminated oligosaccharide chains of taliglucerase alfa are specifically recognized by endocytic carbohydrate receptors on macrophages, the cells that accumulate lipid in Gaucher disease.

A unit is the amount of enzyme that catalyzes the hydrolysis of 1 micromole of the synthetic substrate para-nitrophenyl-β-D-glucopyranoside (p NP-Glc) per minute at 37°C.

ELELYSO (taliglucerase alfa) for injection is supplied as a sterile, preservative-free, lyophilized powder for reconstitution and dilution prior to intravenous infusion. Each single-dose vial contains 200 units of taliglucerase alfa and D-mannitol (206.7 mg), polysorbate 80 (0.56 mg), and sodium citrate (30.4 mg). Citric acid may be added to adjust the pH at the time of manufacture. After reconstitution with 5.1 mL Sterile Water for Injection, USP, taliglucerase alfa concentration is 40 units/mL [see Dosage and Administration (2)]. Reconstituted solutions have a pH of approximately 6.0.

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