OBJECTIVES: Hereditary transthyretin-mediated amyloidosis with polyneuropathy (ATTRv-PN) is a rare, fatal neuropathy characterised by amyloid deposits composed of mutant TTR protein, which accumulate in multiple tissues, including the peripheral nervous system. Targeted gene silencers include eplontersen (in development) and vutrisiran (approved by the FDA and EMA). Eplontersen met all co-primary endpoints and secondary endpoints at week 66 versus an external placebo group in the phase III NEURO-TTRansform trial (NCT04136184). In the absence of head-to-head trials, indirect treatment comparisons (ITCs) can compare efficacy of eplontersen and vutrisiran.

METHODS: Feasibility analysis identified unanchored simulated treatment comparison (STC) and unanchored matching-adjusted indirect comparison (MAIC) as the most appropriate approaches for ITC between eplontersen and vutrisiran, as these do not require a common control arm and can partially account for differences between trials. The modified Neuropathy Impairment +7 (mNIS+7) score and Norfolk QoL-DN score for eplontersen at week 35 were extrapolated to compare to the vutrisiran week 39 scores from the HELIOS-A trial. Different versions of mNIS+7 were used in the eplontersen and vutrisiran trial programmes, therefore rescoring for comparability was performed. Reference models adjusted for all pre-specified treatment effect modifiers and prognostic factors (age, sex, race, prior treatment, V30M mutation, familial amyloid polyneuropathy score, cardiac involvement and baseline mNIS+7 or baseline Norfolk QoL-DN). Alternative models, generated using stepwise selection, were also used. NEURO-TTRansform missing data were imputed using the approach reported for HELIOS-A.

RESULTS: Data for eplontersen from NEURO-TTRansform (N=144) were population-adjusted against data for vutrisiran from HELIOS-A (N=122). Both unanchored STC and unanchored MAIC showed no statistically significant difference in mNIS+7 and Norfolk QoL-DN scores between eplontersen and vutrisiran.

CONCLUSIONS: The results from unanchored STC and unanchored MAIC of eplontersen and vutrisiran did not show a statistically significant difference between their effects on change from baseline in mNIS+7 and Norfolk QoL-DN scores at week 39.