WAINUA - AstraZeneca Pharmaceuticals LP

The recommended dosage of WAINUA is 45 mg administered by subcutaneous injection once monthly [see Dosage and Administration (2.2)].

Missed Dose

Administer WAINUA as soon as possible after a missed dose. Resume dosing at monthly intervals from the date of the most recently administered dose.

Each autoinjector and prefilled syringe contains a single dose of WAINUA.

Prior to administration of the autoinjector or prefilled syringe:

• Do not use if WAINUA has been dropped or damaged, appears to be tampered with, or if the expiration date has passed.
• Remove WAINUA from the refrigerator 30 minutes prior to the injection to reach room temperature. Do not use other warming methods.
• Visually inspect WAINUA before use. The solution should appear colorless to yellow. Do not use if cloudiness, particulate matter, or discoloration is observed.

To deliver a 45 mg dose of WAINUA, administer the entire contents of one autoinjector or prefilled syringe [see Dosage and Administration(2.3), (2.4)], as a subcutaneous injection in the upper thigh or the abdomen. The back of the upper arm can also be used as an injection site if a healthcare provider or caregiver administers the injection. Do not inject WAINUA into the area 2 inches (5 cm) around the navel or into areas where the skin is red, warm, tender, bruised, scaly or hard. Rotate the injection site with each injection.

The autoinjector is intended for self-administration by patients or administration by caregivers.

Prior to initiation, train patients and/or caregivers on proper preparation and administration of WAINUA autoinjector [see Instructions for Use].

The prefilled syringe must be administered by a healthcare provider.

Refer to Figure 1 to identify the prefilled syringe components for use in the administration steps.

Do not remove the needle cover until you are ready to inject WAINUA. Do not touch the needle guard activation clips to prevent premature activation of the needle safety guard.

Figure 1: WAINUA Prefilled Syringe Components

Administration Steps

Step 1 Remove the prefilled syringe from its tray. Hold the syringe body and remove the needle cover by pulling straight off. Do not recap. If small air bubbles are present, do not expel them prior to administration.

Step 2 Choose an injection site (i.e., back of upper arm, upper thigh, or abdomen). Gently pinch the skin and insert the needle subcutaneously at approximately a 45° angle into the chosen injection site.

Step 3 Once the entire dose has been injected, the needle safety device will be triggered. As you let go of the plunger, the needle is automatically pulled from the skin, and into the device; the entire needle will be covered by the needle guard.

WAINUA treatment leads to a decrease in serum vitamin A levels [see Adverse Reactions (6.1), Use in Specific Populations (8.1), and Clinical Pharmacology (12.2)].

Supplementation at the recommended daily allowance of vitamin A is advised for patients taking WAINUA. Higher doses than the recommended daily allowance of vitamin A should not be given to try to achieve normal serum vitamin A levels during treatment with WAINUA, as serum vitamin A levels do not reflect the total vitamin A in the body.

Patients should be referred to an ophthalmologist if they develop ocular symptoms suggestive of vitamin A deficiency (e.g., night blindness, dry eyes).

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

In Study 1 [see Clinical Studies (14)], a total of 144 patients with polyneuropathy caused by hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) were randomized to WAINUA and received at least one dose of WAINUA. Of these, 141 patients received at least 6 months of treatment and 107 patients received at least 12 months of treatment. The mean duration of treatment was 15 months (range: 1.9 to 19.4 months). The median patient age at baseline was 52 years and 69% of the patients were male. Seventy-eight percent of patients treated with WAINUA were White, 15% were Asian, 4% were Black, 2% were reported as other races, and <1% were multiple races. Fifty-nine percent of patients had the Val30Met variant in the transthyretin gene; the remaining patients had one of 19 other variants. At baseline, 80% of patients were in Stage 1 of the disease and 20% were in Stage 2 with a mean duration from polyneuropathy diagnosis of 47 months. The mean duration from onset of polyneuropathy symptoms was 68 months.

Table 1 lists the adverse reactions that occurred in at least 5% of patients treated with WAINUA in Study 1.

Three serious adverse reactions of atrioventricular (AV) heart block (2%) occurred in WAINUA-treated patients, including 1 case of complete AV block.

Laboratory Tests

Vitamin A Decrease

In Study 1, patients were instructed to take the recommended daily allowance of vitamin A [see Warnings and Precautions (5.1)]. All patients treated with WAINUA had normal vitamin A levels at baseline, 95% of patients developed low vitamin A levels during the study. In some cases, the decreased vitamin A level was reported as an adverse reaction.

Safety and effectiveness in pediatric patients have not been established.

No dose adjustment is required in patients ≥65 years of age [see Clinical Pharmacology (12.3)]. In Study 1 [see Clinical Studies (14)], 44 (31%) patients were 65 to 74 years of age, and 8 (5.6%) patients were ≥75 years of age. No overall differences in safety or effectiveness were observed between these patients and younger adult patients, but greater sensitivity of some older individuals cannot be ruled out.

No dose adjustment is necessary in patients with mild to moderate renal impairment (estimated glomerular filtration rate [eGFR] ≥30 to <90 mL/min/1.73 m²) [see Clinical Pharmacology (12.3)].

WAINUA has not been studied in patients with severe renal impairment or end-stage renal disease.

No dose adjustment is necessary in patients with mild hepatic impairment (total bilirubin ≤1 x ULN and AST >1 x ULN, or total bilirubin >1.0 to 1.5 x ULN and any AST) [see Clinical Pharmacology (12.3)].

WAINUA has not been studied in patients with moderate or severe hepatic impairment.

Eplontersen is an antisense oligonucleotide-GalNAc conjugate that causes degradation of mutant and wild-type TTR mRNA through binding to the TTR mRNA, which results in a reduction of serum TTR protein and TTR protein deposits in tissues.

In Study 1 [see Clinical Studies (14)], following administration of the recommended WAINUA dosage every 4 weeks to patients with hATTR amyloidosis, a decrease in serum TTR levels was observed at the first assessment and the (least square) mean serum TTR at Week 35 was reduced by 81% from baseline. Similar TTR reductions were observed across subgroups including Val30Met variant status, body weight, sex, age, or race.

Eplontersen also reduced the mean steady state serum vitamin A by 71% by Week 37 [see Warnings and Precautions (5.1)].

The pharmacokinetic (PK) properties of WAINUA were evaluated following subcutaneous administration of single and multiple doses (once every 4 weeks) in healthy subjects and multiple doses (once every 4 weeks) in patients with hATTR amyloidosis.

Eplontersen C_max and AUC showed a slightly greater than dose-proportional increase following single subcutaneous doses ranging from 45 to 120 mg (i.e., 1- to 2.7-times the recommended dose) in healthy volunteers.

Population estimates (mean ± SD) of steady state maximum concentrations (C_max), and area under the curve (AUC_τ) were 283 ± 152 ng/mL, and 2190 ± 689 ng/mL, respectively, following 45 mg monthly dosing in patients with hATTR amyloidosis. No accumulation of eplontersen C_max and AUC was observed in repeated dosing (once every 4 weeks).

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

In Study 1, with duration of treatment up to 85 weeks (mean treatment duration of 445 days (63.2 weeks), range: 57 to 582 days), 53 out of 144 (37%) patients developed treatment-emergent ADAs during treatment with WAINUA. The presence of ADAs did not affect eplontersen plasma C_max or AUC, but increased C_trough. Although anti-drug antibody development was not found to affect the pharmacokinetics, pharmacodynamics, safety, or efficacy of WAINUA in these patients, the available data are too limited to make definitive conclusions.

Carcinogenesis

In a 26-week carcinogenicity study in male and female Tg.rasH2 mice, subcutaneous administration of eplontersen (0, 250, 500, or 1500 mg/kg) monthly for 26 weeks resulted in no increase in neoplasms.

Mutagenesis

Eplontersen was negative for genotoxicity in in vitro (bacterial reverse mutation, chromosomal aberration in Chinese hamster lung cells) and in vivo (mouse bone marrow micronucleus) assays.

Impairment of Fertility

Subcutaneous administration of eplontersen (0, 5, 25, or 75 mg/kg) or a mouse-specific surrogate (25 mg/kg) to male and female mice weekly prior to and during mating and continuing in females throughout the period of organogenesis resulted in no adverse effects on fertility.

WAINUA (eplontersen) injection is a sterile, preservative-free, clear, colorless to yellow solution.

WAINUA is available as:

• carton containing one 45 mg/0.8 mL single-dose autoinjector (NDC 0310-9400-01)
• carton containing one 45 mg/0.8 mL single dose prefilled syringe (NDC 0310-9420-01)

Store refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton protected from light.

If needed, WAINUA can be kept at room temperature (up to 30°C [86°F]) in the original carton for up to 6 weeks. If not used within the 6 weeks stored at room temperature, discard WAINUA.

Do not freeze. Do not expose to heat.