EPLONTERSEN: 250 Adverse Event Reports & Safety Profile

Eplontersen is a transthyretin-directed antisense oligonucleotide (ASO), covalently linked to a ligand containing three N-acetyl galactosamine (GalNAc) residues to enable delivery of the ASO to hepatocytes. WAINUA contains eplontersen sodium as the active ingredient. Eplontersen sodium is a white to yellow solid and it is freely soluble in water and in phosphate buffer. The molecular formula of eplontersen sodium is C 296 H 417 N 77 O 156 P 20 S 13 Na 20 and the molecular weight is 9046.1 daltons. The chemical name of eplontersen sodium is DNA, d([2′-O-(2-methoxyethyl)]m5rU-sp-[2′-O-(2-methoxyethyl)]m5rC-[2′-O-(2-methoxyethyl)]m5rU-[2′-O-(2-methoxyethyl)]m5rU-[2′-O-(2-methoxyethyl)]rG-G-sp-T-sp-T-sp-A-sp-m5C-sp-A-sp-T-sp-G-sp-A-sp-A-sp-[2′-O-(2-methoxyethyl)]rA-[2′-O-(2-methoxyethyl)]m5rU-[2′-O-(2-methoxyethyl)]m5rC-sp-[2′-O-(2-methoxyethyl)]m5rC-sp-[2′-O-(2-methoxyethyl)]m5rC), 5′-[26-[[2-(acetylamino)-2-deoxy-β-D-galactopyranosyl]oxy]-14,14-bis[[3-[[6-[[2-(acetylamino)-2-deoxy-β-D-galactopyranosyl]oxy]hexyl]amino]-3-oxopropoxy]methyl]-8,12,19-trioxo-16-oxa-7,13,20-triazahexacos-1-yl hydrogen phosphate], sodium salt (1:20). The structure of eplontersen sodium is presented below: WAINUA is a sterile, preservative-free, aqueous solution for subcutaneous injection. Each single-dose autoinjector contains 45 mg eplontersen (equivalent to 47 mg eplontersen sodium) in 0.8 mL of solution. The solution also contains 0.868 mg dibasic sodium phosphate, anhydrous (buffering agent); 0.238 mg monobasic sodium phosphate, dihydrate (buffering agent); 4.2 mg sodium chloride (tonicity modifier); water for injection; and may include hydrochloric acid and/or sodium hydroxide for pH adjustment between 6.9 - 7.9. Each dose of WAINUA injection contains less than 5 mg of sodium and less than 5 mg of phosphorus. Chemical_Structure

AND USAGE WAINUA is indicated for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults. WAINUA is a transthyretin-directed antisense oligonucleotide indicated for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults. ( 1 )

AND ADMINISTRATION

• The recommended dosage of WAINUA is 45 mg administered by subcutaneous injection once monthly. ( 2.1 )
• Administer WAINUA into the abdomen or upper thigh region; the back of the upper arm can be used if a healthcare provider or caregiver administers the injection. ( 2.2 )

2.1 Recommended Dosage The recommended dosage of WAINUA is 45 mg administered by subcutaneous injection once monthly <span class="opacity-50 text-xs">[see Dosage and Administration (2.2) ]</span> .

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.

2.2 Administration Instructions Prior to initiation, train patients and/or caregivers on proper preparation and administration of WAINUA <span class="opacity-50 text-xs">[see Instructions for Use ]</span> . Remove the single-dose autoinjector from the refrigerator 30 minutes prior to the injection and allow to warm to room temperature. Do not use other warming methods. Inspect WAINUA visually for particulate matter and discoloration prior to administration. The solution should appear colorless to yellow. Do not use if cloudiness, particulate matter, or discoloration is observed prior to administration. Administer WAINUA as a subcutaneous injection into the abdomen or upper thigh region. The back of the upper arm can also be used as an injection site if a healthcare provider or caregiver administers the injection.

None. None. ( 4 )

REACTIONS The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling:

• Reduced Serum Vitamin A Levels and Recommended Supplementation [see Warnings and Precautions (5.1) ]. Most common adverse reactions (that occurred in at least 9% of patients treated with WAINUA) were vitamin A decreased and vomiting. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience 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.

Table

1: Adverse Reactions Reported in at least 5% of Patients Treated with WAINUA (Study 1)

Adverse

Reaction WAINUA N=144 % Vitamin A decreased Vitamin A decreased includes vitamin A deficiency and vitamin A decrease. 15 Vomiting 9 Proteinuria 8 Injection site reactions Injection site reactions includes erythema, pain, and pruritis. 7 Blurred vision 6 Cataract 6 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.

AND PRECAUTIONS Reduced Serum Vitamin A Levels and Recommended Supplementation : Supplement with the recommended daily allowance of vitamin A. Refer to an ophthalmologist if ocular symptoms suggestive of vitamin A deficiency occur. ( 5.1 )

5.1 Reduced Serum Vitamin A Levels and Recommended Supplementation WAINUA treatment leads to a decrease in serum vitamin A levels <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) , Use in Specific Populations (8.1) , and Clinical Pharmacology (12.2) ]</span> . 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).