ZANVASTRO Solution for injection Ref.[116918] Active ingredients: Zilganersen

5.1 Aseptic Meningitis

If symptoms consistent with aseptic meningitis develop, diagnostic workup and treatment should be initiated according to the standard of care.

Adverse reactions of aseptic meningitis (also called chemical meningitis or drug-induced aseptic meningitis) were reported in patients treated with ZANVASTRO during the double-blind and open-label periods of Study 1. One patient experienced a serious adverse reaction of aseptic meningitis during the double-blind treatment period of Study 1, which reoccurred in the open-label extension period and required dose interruption and pretreatment with intravenous dexamethasone prior to subsequent administration of ZANVASTRO. Despite corticosteroid premedication, CSF white blood cell (WBC) and protein increased with continued exposure but the patient remained asymptomatic and did not require discontinuation from treatment. In addition, nonserious adverse drug reactions of CSF WBC increased have also been reported with ZANVASTRO [see Adverse Reactions (6.1)].

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Aseptic Meningitis [see Warnings and Precautions (5.1)]

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 ZANVASTRO was evaluated in 53 pediatric and adult patients with Alexander disease in Study 1 [see Clinical Studies (14)]. Thirty-eight patients received ZANVASTRO for 1 year, and 18 patients received ZANVASTRO 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 ZANVASTRO 50 mg and greater than control) were vomiting, back pain, cough, headache, and post-lumbar puncture syndrome. Table 3 includes the common adverse reactions that occurred in ≥10% of patients treated with ZANVASTRO and 10% greater than control.

Table 3. Adverse Reactions in Patients with Alexander Disease that Occurred in ≥10% of Patients Treated with ZANVASTRO 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 ZANVASTRO 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 ZANVASTRO in the open-label extension period [see Warnings and Precautions (5.1)].

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the study described below with the incidence of anti-drug antibodies in other studies, including those of zilganersen or of other zilganersen products.

The immunogenic response to ZANVASTRO was evaluated in 53 patients for anti-drug antibodies (ADA). Overall, 9/32 (28.1%) ZANVASTRO-treated patients developed treatment-emergent ADA, of which 2 were transient and 7 were persistent. The presence of ADA had no apparent effect on the safety or efficacy profile of ZANVASTRO. The incidence and type of adverse drug reactions were similar between patients who tested ADA-positive and those who were ADA-negative. Two patients developed markedly elevated plasma ADA titers. One of these patients presented with elevations of CSF white blood cell count and protein, in the presence of signs and symptoms of potential aseptic meningitis. No similar findings were observed in other ADA- positive patients.

Zilganersen plasma C_max and AUC_0-24h values were similar between ADA-positive and ADA-negative patients. Although ADA development was not found to affect the PK, safety or efficacy of ZANVASTRO in these patients, the available data are limited to make definitive conclusions.

Risk Summary

There are no available data on ZANVASTRO 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.

Data

Animal Data

No adverse effects on embryofetal development were noted in a combined fertility and embryo-fetal development study in CD1 mice, which were subcutaneously administered zilganersen at doses of 10, 30, and 60 mg/kg every two weeks prior to mating and every two days during mating and through organogenesis (the high dose is equivalent to up to 6 times the maximum recommended human dose [MRHD, 50 mg quarterly] on a per-dose body-surface-area [BSA] basis.

Risk Summary

There are no data on the presence or absence of ZANVASTRO or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. The presence of ZANVASTRO 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 ZANVASTRO and any potential adverse effects on the breastfed child from ZANVASTRO or from the underlying maternal condition.

The safety and effectiveness of ZANVASTRO for the treatment of Alexander disease have been established in pediatric patients. Use of ZANVASTRO in pediatric patients aged 2 to less than 18 years is supported by evidence from an adequate and well-controlled study [see Clinical Studies (14)]. Use of ZANVASTRO in pediatric patients less than 2 years of age is supported by evidence from an adequate and well-controlled study of ZANVASTRO in patients 2 years of age and older with Alexander disease, pharmacokinetic analyses and modeling showing CSF drug exposure levels after a 50 mg dose in patients less than 2 years of age are expected to be similar to those observed after a 50 mg dose in patients 2 years of age and older, and safety data in 4 pediatric patients less than 2 years of age treated with ZANVASTRO [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)].

Juvenile Animal Toxicity Data

Neurobehavioral deficits including locomotor hypoactivity with a pharmacologically active mouse-specific surrogate ASO at 0.1 mg [9 times the maximum recommended human dose (MRHD), normalized to CSF volume] were noted in an intracerebroventricular toxicity study in juvenile mice administered the surrogate ASO every six weeks via the intracerebroventricular route for 13 weeks. No adverse effects were observed at doses up to 0.2 mg, at 17 times the MRHD on a per-dose basis, normalized to CSF volume, in the parallel group administered zilganersen (0, 0.05, 0.1, or 0.2 mg) via the same dosing regimen.

Transient patellar reflex losses, occasionally accompanied by foot grip impairment, at 8 mg and 25 mg at 2-5 times the MRHD and neuronal vacuolation in the brain without neuronal degeneration at 25 mg at 5 times the MRHD, on a per-dose basis, normalized to CSF volume, were noted in an intrathecal toxicity study in 9- to 11-month-old monkeys administered zilganersen every four weeks (0, 3, 8, or 25 mg) via the intrathecal route for 9 months. No vacuoles were noted in animals treated with doses up to 8 mg at 2 times the MRHD on a per-dose basis, normalized to CSF volume.

Clinical studies of ZANVASTRO for the treatment of Alexander disease has not been studied in patients aged 65 years and over. No data are available to determine whether they respond differently than younger adult patients.