ATTR Amyloidosis

Transthyretin amyloidosis (ATTR amyloidosis) is a rare, progressive and fatal disease characterized by deposition of abnormal, non-native forms of TTR protein (misTTR) in vital organs.

ATTR amyloidosis can be hereditary (hATTR) when caused by a mutation in the TTR gene, or wild-type (wtATTR) when it occurs sporadically.

It is estimated that there are more than 400,000 patients worldwide with wtATTR amyloidosis and 50,000 patients worldwide with hATTR amyloidosis. In both forms of the disease, patients can experience a spectrum of clinical manifestations affecting multiple organs, most commonly the heart and peripheral nerves. TTR protein (healthy form) is produced primarily in the liver and serves as a carrier for thyroxin and retinol binding protein (a transporter for vitamin A).

The investigational humanized monoclonal antibody PRX004 is designed to target and clear the non-native transthyretin aggregates (misTTR) associated with disease pathology that underlies both wtATTR and hATTR, without affecting the native, or normal tetrameric form of the protein (TTR).

It is generally accepted that, at the time of diagnosis, affected peripheral organs in ATTR patients (both wtATTR and hATTR amyloidosis) contain amyloid deposits. These deposits, together with prefibrillar species, are believed to cause organ dysfunction and failure.  Existing therapies do not address amyloid deposition and are ineffective or untested in moderate-to-advanced cardiomyopathy in patients who are at highest risk of mortality due to amyloid deposition in the heart.

PRX004 is a misTTR depleter, with a differentiated mechanism of action designed to clear existing deposits and prevent new formation. In preclinical studies, PRX004 has been shown to inhibit amyloid fibril formation, neutralize soluble aggregate forms of misTTR and promote clearance of insoluble amyloid fibrils through antibody-mediated phagocytosis. This differentiated mechanism of action could be developed as a monotherapy approach to ATTR amyloidosis and may also complement existing therapeutic approaches which either stabilize or reduce production of the native TTR tetramer.

Based on clinical data to date, patients with moderate-to-advanced cardiomyopathy represent approximately 33% of ATTR amyloidosis patients, who face a significant unmet need due to late diagnosis and limited efficacy of existing therapies.

Prothena has completed a Phase 1 study with PRX004 in patients with hereditary forms of ATTR, in which PRX004 was found to be safe and well tolerated. In July 2021, Novo Nordisk acquired our ATTR amyloidosis program and will initially focus on the development of PRX004 in ATTR cardiomyopathy with a Phase 2 study.