Elosulfase alfa

Risk Summary

Available data from published case reports and postmarketing experience with elosulfase alfa use in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, no effects on embryo-fetal development were observed in rats given daily administration of elosulfase alfa up to 33 times the human steady-state AUC (area under the concentration-time curve) at the recommended human weekly dose premating and through the period of organogenesis. No effects on embryo-fetal development were observed in rabbits given daily administration of elosulfase alfa at doses up to 8 times the human steady-state AUC at the recommended weekly dose during organogenesis, which produced maternal toxicity. A dose-dependent increase in stillbirths was observed when elosulfase alfa was administered daily in rats during organogenesis through lactation at doses 5 times the human steady-state AUC at the recommended human weekly dose. An increase in pup mortality was observed at doses producing maternal toxicity.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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 embryo/fetal risk

Pregnancy can exacerbate preexisting clinical manifestations of MPS and lead to adverse outcomes for both mother and fetus.

Data

Animal Data

All reproductive studies with rats included pre-treatment with diphenhydramine to prevent or minimize hypersensitivity reactions. The effects of elosulfase alfa were evaluated based on comparison to a control group treated with diphenhydramine alone. Daily intravenous administration of up to 20 mg/kg elosulfase alfa in rats (33 times the human steady-state AUC at the recommended weekly dose of 2 mg/kg) during a 15-day pre-mating period, mating, and the period of organogenesis, produced no maternal toxicity or effects on embryo-fetal development. Daily intravenous administration of up to 10 mg/kg in rabbits (8 times the human steady-state AUC at the recommended weekly dose) during the period of organogenesis had no effects on embryo-fetal development. However, maternal toxicity (gross changes in liver) was observed in rabbits given doses of 1 mg/kg/day and higher (0.1 times the human steady-state AUC at the recommended weekly dose). Elosulfase alfa produced an increase in the percentage of stillbirths when administered daily to rats at intravenous doses of 6 mg/kg and higher (5 times the human steady-state AUC at the recommended weekly dose) during the period of organogenesis through lactation. Daily intravenous administration of 20 mg/kg (33 times the human steady-state AUC at the recommended weekly dose) produced maternal toxicity and an increase in mortality of offspring during the lactation period. This study lacked a full evaluation of neurodevelopmental milestones; however, no effects of elosulfase alfa were noted in tests for learning and memory.

Risk Summary

There are no data on the presence of elosulfase alfa in human milk, the effects on the breastfed infant, or the effects on milk production. Elosulfase alfa is present in milk from treated rats (see Data). When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for elosulfase alfa and any potential adverse effects on the breastfed infant from elosulfase alfa or from the underlying maternal condition.

Data

Animal Data

Elosulfase alfa was detected in 1 of 5 milk samples from rat dams administered 6 mg/kg/day elosulfase alfa and 4 of 5 milk samples from dams administered 20 mg/kg/day elosulfase alfa. The concentration of drug in animal milk does not necessarily predict the concentration of drug in human milk.

Long-term studies in animals to evaluate carcinogenic potential or studies to evaluate mutagenic potential have not been performed with elosulfase alfa. Based on the mechanism of action, elosulfase alfa is not expected to be tumorigenic. Daily intravenous administration of elosulfase alfa in rats at doses up to 20 mg/kg (55 times the human steady-state AUC in male rats and 33 times the human steady-state AUC in female rats at the recommended human weekly dose) had no effects on fertility or reproductive performance.

• Anaphylaxis and hypersensitivity reactions
• Risk of acute respiratory complications
• Spinal or cervical cord compression

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

A 24-week, randomized, double-blind, placebo-controlled clinical trial of elosulfase alfa was conducted in 176 patients with MPS IVA, ages 5 to 57 years old. Approximately half of the patients (49%) were male. Of the 176 patients, 65% were White, 23% Asian, 3% Black, and 10% Other race. The majority of patients (78%) were non-Hispanic. Patients were randomized to three treatment groups: elosulfase alfa 2 mg/kg once per week (n=58), elosulfase alfa 2 mg/kg once every other week (n=59), or placebo (n=59). All patients were treated with antihistamines prior to each infusion.

The following table summarizes the most common adverse reactions that occurred in the placebo-controlled trial with an incidence of ≥10% in patients treated with elosulfase alfa 2 mg/kg once per week and with a higher incidence than in the placebo-treated patients.

Adverse Reactions That Occurred in the Placebo-Controlled Trial in At Least 10% of Patients in the Elosulfase alfa 2 mg/kg Once Per Week Group and with a Higher Incidence than in the Placebo Group:

Extension Trial

An open-label extension trial was conducted in 173 patients who completed the placebo-controlled trial. No new adverse reactions were reported.

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 other studies or to other elosulfase alfa products may be misleading.

All patients treated with elosulfase alfa 2 mg/kg once per week in the placebo-controlled trial developed antidrug antibodies by Week 4. Anti-drug antibody titers were sustained or increased for the duration of elosulfase alfa treatment. Because all patients developed anti-drug antibodies, associations between antibody titers and reductions in treatment effect or the occurrence of anaphylaxis or other hypersensitivity reactions could not be determined.

All patients treated with elosulfase alfa 2 mg/kg once per week tested positive for neutralizing antibodies capable of inhibiting the drug from binding to the mannose-6-phosphate receptor at least once during the trial. Binding to this receptor is required for elosulfase alfa to be taken into cells where it is active. Neutralizing antibody titers were not determined in the patients. Therefore, the possibility of an association between neutralizing antibody titer and treatment effect cannot be assessed.