ZANVASTRO - Ionis Pharmaceuticals Inc.

Administer ZANVASTRO intrathecally after dilution using a lumbar puncture by, or under the direction of, healthcare professionals experienced in performing lumbar punctures.

The recommended dosage of ZANVASTRO is 50 mg intrathecally every 3 months.

The final dose volume of the intrathecal injection is determined by the patient’s age [see Dilution and Preparation Instructions ( 2.2)] .

Missed Dose(s)

If a dose of ZANVASTRO is missed, administer ZANVASTRO as soon as possible. Resume treatment at the recommended dosing frequency from the date of the most recently administered dose.

Read the entire Instructions for Use provided in the carton before diluting and preparing ZANVASTRO for intrathecal administration.

Each carton contains 1 vial of ZANVASTRO and 1 vial of diluent to be used together to prepare a single dose. The diluent vial contains more volume than needed. Discard excess diluent prior to dilution as instructed below.

Prepare ZANVASTRO according to the instructions below and in Table 1.

Use aseptic technique when preparing and administering ZANVASTRO intrathecally.

1. Use a 3 mL and/or 10 mL syringe with an 18G to 22G needle to withdraw excess aCSF diluent from the diluent vial as determined by Table 1 based on the patient’s age. Keep the diluent vial containing the remaining diluent for Step 3. Discard the syringe(s) containing the excess diluent.
2. Use a 3 mL syringe with an 18G to 22G needle to withdraw 2.8 mL of ZANVASTRO from the ZANVASTRO vial.
3. Add the withdrawn volume of ZANVASTRO to the diluent vial.
4. Gently invert the diluent vial (which now also contains ZANVASTRO) several times to mix the solution.
5. Attach an 18G or 19G filter needle (5 micron) to a 20 mL syringe. Withdraw the recommended dose volume of diluted ZANVASTRO from the diluent vial as determined by Table 1 based on the patient’s age.
6. Remove the filter needle. Attach a syringe tip cap to the prepared dosing syringe.
7. Label the prepared dosing syringe per institution procedures prior to use or transport.
8. Discard any unused portion of the diluted solution and any unused contents of the ZANVASTRO vial.

Storage of Prepared Dosing Syringe

ZANVASTRO contains no preservatives. Once drawn into the dosing syringe, the solution must be administered within:

• 4 hours of preparation if kept at room temperature up to 30°C (86°F).
• 24 hours of preparation if refrigerated at 2°C to 8°C (36°F to 46°F).

Do not freeze. Do not expose to heat. Protect the prepared dosing syringe from light as a precaution.

Procedural Preparation Instructions

• If indicated by the clinical condition of the patient, consider sedation or local anesthesia.
• If indicated by the clinical condition of the patient, consider imaging to guide intrathecal administration of ZANVASTRO.
• Evaluate patients prior to intrathecal injection for factors that increase risks associated with lumbar puncture.

Administration
If the prepared dosing syringe is refrigerated prior to administration, allow the dosing syringe to warm to room temperature for at least 30 minutes prior to use for patient comfort. Do not use external heat sources to warm the dosing syringe [see Storage and Handling (16.2)] .

Prior to administration, remove a volume of the patient’s CSF approximately equal to the intended dose volume as appropriate for age, based on Table 2, using a lumbar puncture needle.

 Administer ZANVASTRO as an intrathecal bolus injection over 1 to 3 minutes using the lumbar puncture needle. Do not flush the needle or any attached extension catheter, if used, after administration.

Discard the dosing syringe.

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)] .

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.

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)] .

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)].

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.

ZANVASTRO is an antisense oligonucleotide that causes degradation of glial fibrillary acidic protein (GFAP) pre-mRNA through binding to GFAP pre-mRNA, which results in a reduction of GFAP protein synthesis.

Effect of Zilganersen on Plasma GFAP

Plasma GFAP, an indirect measure of target engagement, was evaluated longitudinally in patients with Alexander disease  [see Clinical Studies ( 14)] . At week 61 (after 5 doses), the geometric mean ratio to baseline in plasma GFAP was 33.6% lower in patients on ZANVASTRO compared to controls (see Figure 2).

Figure 2. Mean Change from Baseline in Plasma GFAP (Geometric Mean Ratio ± SE) in Patients Treated with ZANVASTRO 50 mg or Control (Study 1; Main Study)

Mean Change from Baseline in Plasma GFAP (Geometric Mean Ratio ± SE) in Patients Treated with Zilganersen 50 mg or Control

Cardiac Electrophysiology

Based on the chemical properties of zilganersen and the absence of cardiac electrophysiology findings in nonclinical studies, zilganersen is not expected to affect the QTc interval.

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 _maxand AUC _0-24hvalues 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.

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.

ZANVASTRO is supplied as a carton (NDC 71860-304-01) that contains the following:

• One single-dose vial of ZANVASTRO: 56 mg/2.8 mL (20 mg/mL) of a sterile, preservative free, clear, colorless to slightly yellow solution.
• One single-dose vial of artificial cerebrospinal fluid (aCSF) diluent: 21 mL of sterile, preservative free, clear and colorless solution for dilution of ZANVASTRO.

Not made with natural rubber latex.

Store the ZANVASTRO vial and diluent vial in the refrigerator between 2°C and 8°C (36°F and 46°F) in the original carton to protect from light.

Once taken out of the refrigerator, the ZANVASTRO vial and diluent vial can be stored at room temperature up to 30°C (86°F) in the original carton for up to 14 days. If not used within the 14 days stored at room temperature, discard ZANVASTRO.

Do not freeze. Do not expose to heat. Protect from light as a precaution.

See Dosage and Administration ( 2.2) for instructions on how to store ZANVASTRO diluted solution.