Zilganersen

There are no available data on zilganersen use in pregnant women to inform drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

No adverse effects on embryofetal development were observed when zilganersen was administered every 2 weeks prior to mating and every two days during mating and through organogenesis at doses up to 60 mg/kg. The high dose was approximately 6 times the maximum recommended human dose on a per-dose BSA basis.

Zilganersen has not been evaluated for potential effects on embryofetal development in rabbits or in pre- and postnatal development toxicity studies.

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. The background risk of major birth defects and miscarriage for the indicated population is unknown.

There are no data on the presence or absence of zilganersen or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. The presence of zilganersen in breast milk was not studied in animals. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for zilganersen and any potential adverse effects on the breastfed child from zilganersen or from the underlying maternal condition.

Carcinogenesis

Long-term studies to assess the carcinogenic potential of zilganersen have not been conducted.

Mutagenesis

Zilganersen was negative in in vitro (bacterial reverse mutation and mammalian cell chromosomal aberration) and in vivo (mouse micronucleus) assays.

Impairment of Fertility

No adverse effects on male or female fertility were observed when zilganersen (0, 10, 30, or 60 mg/kg) was administered by subcutaneous injection to mice every 2 weeks prior to and during mating and continuing in females every other day throughout organogenesis. The NOAEL (60 mg/kg) provides a safety margin of 6 compared to the maximum recommended human dose (MRHD of 50 mg) when normalized to a per-dose BSA basis.

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.

The safety of zilganersen was evaluated in 53 pediatric and adult patients with Alexander disease in Study 1. Thirty-eight patients received zilganersen for 1 year, and 18 patients received zilganersen for 2 years. The median exposure was 60 weeks in all groups.

The most common adverse reactions during the Double-Blind Treatment Period (incidence >25% of patients treated with zilganersen 50 mg and greater than control) were vomiting, back pain, cough, headache, and post-lumbar puncture syndrome. The following table includes the common adverse reactions that occurred in ≥10% of patients treated with zilganersen and 10% greater than control.

Adverse Reactions in Patients with Alexander Disease that Occurred in ≥10% of Patients Treated with Zilganersen and 10% Greater than Control:

Patients Less Than 2 Years of Age

The adverse reactions of patients less than 2 years of age are expected to be similar to that of pediatric patients 2 years of age and older.

Increased White Blood Cell Count in the CSF

Pleocytosis (or increased white blood cell count in CSF) was observed in 7 (29%) patients treated with zilganersen 50 mg following the administration of the first 2 to 4 doses, compared to 3 (18%) patients in the control group in the double-blind treatment period of the Main Study, and in an additional 6 patients treated with zilganersen in the open-label extension period.