Disease modifying treatment of hereditary transthyretin amyloidosis with polyneuropathy in Germany - expert consensus of the German society of amyloid diseases (DGAK) and the German neurological society (DGN).

Hereditary transthyretin (ATTRv) amyloidosis is a rare, progressive multisystem disease caused by pathogenic variants in the transthyretin (TTR) gene. ATTRv-associated Polyneuropathy (ATTRv-PN) manifests in a length-dependent sensorimotor and autonomic pattern, commonly accompanied by cardiomyopathy. In recent years, clinical trials have introduced two classes of disease modifying treatments (DMT), TTR stabilizers and gene silencers. Across populations and outcome parameters, all trials share one result disease progression was significantly slowed and patients' span and quality of life substantially improved compared to placebo, even though a function once lost would not be retrieved. This expert consensus paper provides recommendations for the treatment of ATTRv-PN in Germany and was jointly developed by experts from the German Society of Amyloid Diseases (DGAK) and the German Neurological Society (DGN). In addition to evidence from pivotal clinical trials, the recommendations incorporate benefit assessments of the German Federal Joint Committee (G-BA). For first-line treatment, the DGAK/DGN recommends one of the two second-generation TTR gene-silencing agents, vutrisiran or eplontersen, for most patients with symptomatic ATTRv-PN. For patients showing even minor signs of disease progression under a TTR stabilizer, the authors recommend immediate switch to a gene silencer. Evidence is limited for or against switching between silencers or combining different agents. Informed patient participation is crucial upon initiation and adaptation of DMT. For central nervous system (CNS) involvement, none of the approved agents sufficiently crosses the blood-brain barrier. Aligned with that, there are no observed or expected CNS side effects of any of the DMTs. In the future, next-generation RNA-interference therapies, gene-editing approaches, and amyloid-depleting antibodies are expected to further expand therapeutic options.