Introduction
Wainua (eplontersen) is a novel antisense oligonucleotide therapy developed for the treatment of hereditary transthyretin-mediated amyloidosis (hATTR). This rare, progressive, and fatal disease results from mutations in the transthyretin (TTR) gene, leading to the accumulation of amyloid deposits in various tissues and organs. Wainua represents a significant advancement in the management of hATTR amyloidosis, offering a targeted approach to reduce the production of pathogenic TTR protein.
Mechanism of Action
Wainua works through an antisense mechanism targeting TTR messenger RNA (mRNA). The drug is designed to bind specifically to the 3' untranslated region of human TTR mRNA. This binding promotes degradation of TTR mRNA through RNase H1-mediated cleavage, thereby reducing the production of both mutant and wild-type TTR protein. By decreasing circulating TTR levels, Wainua reduces the substrate available for amyloid formation, potentially slowing disease progression in patients with hATTR amyloidosis.
Indications
Wainua is indicated for the treatment of hereditary transthyretin-mediated amyloidosis (hATTR) in adults. This includes patients with:
- Polyneuropathy of hATTR amyloidosis
- Cardiomyopathy of hATTR amyloidosis
- Mixed phenotype hATTR amyloidosis
The approval was based on demonstrated reduction in serum TTR concentration and clinical benefits in neurological and cardiac manifestations.
Dosage and Administration
Recommended dosage: 45 mg administered by subcutaneous injection every 4 weeks Administration:- Administer as a subcutaneous injection in the abdomen, thigh, or upper arm
- Rotate injection sites with each administration
- Allow the prefilled syringe to reach room temperature for approximately 30 minutes before administration
- Do not shake the product
- Visually inspect for particulate matter and discoloration before administration
- Renal impairment: No dosage adjustment recommended for mild to moderate impairment. Use with caution in severe renal impairment.
- Hepatic impairment: No dosage adjustment recommended for mild to moderate impairment. Not studied in severe hepatic impairment.
- Elderly: No dosage adjustment required based on age alone.
Pharmacokinetics
Absorption: Following subcutaneous administration, Wainua is absorbed with a median Tmax of 3-4 hours. Absolute bioavailability is approximately 70-80%. Distribution: Volume of distribution is approximately 300-400 mL/kg. Plasma protein binding is minimal (<10%). Metabolism: Wainua undergoes metabolism by nucleases to shorter oligonucleotides. The drug is not metabolized by cytochrome P450 enzymes. Elimination: Elimination occurs primarily through urinary excretion of metabolites. The terminal elimination half-life is approximately 3-4 weeks.Contraindications
Wainua is contraindicated in patients with:
- Known hypersensitivity to eplontersen or any component of the formulation
- History of anaphylactic reactions to antisense oligonucleotides
Warnings and Precautions
1. Reduced Serum Vitamin A Levels: Wainua reduces serum vitamin A levels. Supplement with the recommended daily allowance of vitamin A. Higher doses may be necessary, but do not exceed maximum recommended daily intake. 2. Injection Site Reactions: May include erythema, pain, swelling, or pruritus. Rotate injection sites and monitor for reactions. 3. Thrombocytopenia: Monitor platelet counts during treatment. Interrupt treatment if platelet counts drop significantly. 4. Renal Toxicity: Monitor renal function during treatment. Increased albuminuria and elevated serum creatinine have been observed. 5. Hepatic Effects: Monitor liver enzymes periodically during treatment. 6. Fetal Toxicity: May cause fetal harm based on mechanism of action. Advise patients of reproductive potential of potential risk.Drug Interactions
Formal drug interaction studies have not been conducted, but consider the following:- Vitamin A supplements: Requires careful management due to Wainua's effect on vitamin A levels
- Other TTR stabilizers: Concurrent use with tafamidis or diflunisal has not been studied
- Anticoagulants/antiplatelets: Theoretical increased bleeding risk due to thrombocytopenia potential
- Nephrotoxic drugs: May enhance renal toxicity
Adverse Effects
Most common adverse reactions (≥10%):- Injection site reactions (erythema, pain, swelling)
- Fatigue
- Arthralgia
- Upper respiratory tract infection
- Headache
- Nausea
- Thrombocytopenia
- Renal toxicity
- Hepatic enzyme elevations
- Reduced vitamin A levels requiring supplementation
Monitoring Parameters
Baseline and periodic monitoring should include:- Serum TTR levels (every 3-6 months)
- Complete blood count with platelets (monthly for first 3 months, then every 3 months)
- Renal function (serum creatinine, urinalysis for albuminuria)
- Liver function tests
- Serum vitamin A levels
- Neurological assessment (mNIS+7, Norfolk QOL-DN)
- Cardiac assessment (echocardiography, NT-proBNP) for patients with cardiac involvement
- Nutritional status assessment
Patient Education
Key points to discuss with patients:- Wainua is not a cure for hATTR amyloidosis but may slow disease progression
- Administration technique for subcutaneous injections
- Importance of vitamin A supplementation as directed
- Recognition and reporting of injection site reactions
- Signs of bleeding or bruising (potential thrombocytopenia)
- Importance of regular monitoring and follow-up appointments
- Pregnancy prevention and counseling for patients of reproductive potential
- Storage requirements for the medication
- Do not discontinue treatment without consulting healthcare provider
References
1. FDA prescribing information for Wainua (eplontersen) 2. Coelho T, et al. Eplontersen for Hereditary Transthyretin Amyloidosis with Polyneuropathy. JACC. 2023 3. Benson MD, et al. NEURO-TTRansform: A phase 3 study of eplontersen in patients with hereditary transthyretin-mediated amyloid polyneuropathy. Neurology. 2022 4. ClinicalTrials.gov: NCT04136184, NCT04136171 5. Adams D, et al. Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis. NEJM. 2018 6. Sekijima Y. Transthyretin (ATTR) amyloidosis: clinical spectrum, molecular pathogenesis and disease-modifying treatments. J Neurol Neurosurg Psychiatry. 2015
Note: This monograph is based on current available evidence and may be updated as new clinical data emerges. Always consult the most current prescribing information and clinical guidelines before making treatment decisions.