Regulatory Decision Summary for Wainua

The purpose of this New Drug Submission was to seek approval for Wainua (eplontersen) for the treatment of adult patients with polyneuropathy associated with hereditary transthyretin-mediated amyloidosis (hATTR).

Eplontersen is a 20-mer antisense oligonucleotide that specifically targets variant and wild-type transthyretin (TTR) messenger RNA (mRNA) and is identical in sequence to inotersen (TEGSEDI), approved for the treatment of hATTR amyloidosis in adults. Eplontersen has a mixed phosphorothiate/phosphodiester backbone and an additional three N-acetylgalactosamine (GalNAc) residue conjugate. Eplontersen is rapidly distributed to the liver (the primary source of TTR), where it binds to and degrades TTR mRNA, inhibiting TTR protein synthesis with the goal of reducing amyloid deposition. The incorporation of a mixed backbone of phosphorothioate and phosphodiester internucleotide linkages reduces nonspecific protein binding, while the addition of a GalNAc3 complex facilitates targeted delivery to hepatocytes. Together, these modifications are designed to improve tolerability and increase potency.

Efficacy was supported by a single, ongoing, Phase 3, multi-centre, open-label clinical trial involving familial amyloid polyneuropathy (FAP) Stage 1 and Stage 2 patients (Study ION-682884-CS3). The study utilized an external placebo group, derived from a previous trial with inotersen (Study ISIS 420915-CS2), as well as a concurrent active reference (inotersen). In total, 144 hATTR patients were treated with eplontersen (45 milligrams [mg], subcutaneous [SC] injection every four weeks [Q4W]0, with efficacy assessments conducted at 35 weeks. At the 35 week time point, eplontersen was shown to reduce serum TTR levels by 82%, effectively demonstrating target engagement and pharmacodynamic effect.

The primary pre-specified efficacy analysis showed a statistically and clinically significant change from baseline favouring Wainua over placebo in the modified Neurologic Impairment Score (mNIS+7) after 35 weeks of treatment, with placebo-treated patients declining by 9 points, while eplontersen-treated patients remained stable (p<0.001). Change from baseline in Norfolk Quality of Life-Diabetic Neuropathy (QoL-DN) total score, the key secondary endpoint, also favoured Wainua over placebo at 35 weeks, with eplontersen-treated patients improving by 3.1 points, compared to a decline of 8.7 points in the external placebo group (p<0.001). The use of a subjective assessment in the context of an open-label trial may increase the risk of introducing bias. As no patients with FAP Stage 3 were included, the proposed indication was revised to specify Stage 1 and Stage 2 polyneuropathy in adult patients with hATTR amyloidosis. Longer-term efficacy data was not available at the time of submission.

At the time of data cut-off, 137 patients had completed greater than or equal to 12 months of treatment, with a mean duration of exposure of 500 days. The overall safety profile of Wainua was considered favourable. Limited data was available to address the longer-term safety of Wainua but will become available upon study completion. Eplontersen was generally safe and well-tolerated in patients. The most commonly reported adverse events (AEs) were vitamin A deficiency, vomiting, injection site reactions, proteinuria, vision blurred, and cataract. Some AEs, reported as less common, occurred more frequently in women. Important identified potential risks of Wainua included vitamin A deficiency, and its associated ocular and reproductive issues. Vitamin A supplementation (RDA) was recommended in the Product Monograph. There were, numerically, more AEs of atrioventricular block in eplontersen-treated patients, including 3 serious AEs. While these events are not inconsistent with the underlying condition, causality remains unclear. Due to the limited number of patients exposed to eplontersen in the clinical trials, the occurrence and frequency of uncommon AEs remains uncertain. The incidence of treatment-emergent anti-drug antibody was 36.8% in the eplontersen group and was associated with elevated C_trough , which measures the lowest concentration of medication in an individual measured immediately before the next dose (up to 10 fold). The long-term effect of elevated C_trough levels remains unclear. The safety of eplontersen in pregnant or breast-feeding women, as well as in patients with moderate to severe hepatic impairment, prior liver transplant, severe renal impairment, or end-stage renal disease was not established. All concerns and uncertainties have been thoroughly addressed, through labelling and ongoing pharmacovigilance activities. A Risk Management Plan for Wainua was reviewed, and was considered to be acceptable.

Wainua is presented as a phosphate buffered solution (56 milligrams per millilitre [mg/mL] eplontersen sodium) in a 1 mL pre-filled autoinjector. The recommended dose of Wainua is 45 mg, administered subcutaneously, once monthly (Q1M), into the abdomen, upper arm, or thigh and may be administered by patients or caregivers, once treatment is initiated by a healthcare provider and proper training has been provided.

Any outstanding concerns/uncertainties have been addressed through product labelling and a Risk Management Plan. Based on the safety and efficacy data currently available to Health Canada, the Benefit-Harm-Uncertainty of Wainua (eplontersen injection) in the treatment of polyneuropathy associated with stage 1 and stage 2 hereditary transthyretin-mediated amyloidosis (hATTR) in adults was considered favourable; a Notice of Compliance was recommended.

For further details about Wainua, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.