In its native tetrameric form, transthyretin (TTR) protein, which is primarily produced in the liver, serves as a carrier for thyroxin and retinol binding protein [Citation1]. TTR tetramers can dissociate into monomers, which have the propensity to misfold and aggregate into amyloid [Citation2]. Amyloid TTR (ATTR) amyloidosis is characterised by deposition of toxic amyloid fibrils formed from misfolded TTR (misTTR) protein in a variety of organs, most often the heart and peripheral nerves, disrupting tissue structure and function [Citation3, Citation4]. Clinical manifestations and severity of the disease depend on the affected organ, the degree of amyloid accumulation and the genotype of the disease (variant [ATTRv] or wild type [ATTRwt]) [Citation1]. Morbidity and mortality among patients with ATTRv and ATTRwt amyloidosis are often driven by the development of cardiomyopathy and congestive heart failure, but sensory-motor neuropathy and autonomic disturbances, including severe gastrointestinal dysfunction, are also common in ATTRv and could be severely incapacitating [Citation1, Citation3–5].
Despite progress in understanding the underlying mechanisms of ATTR amyloidosis pathology, effective treatment options that target TTR amyloid deposits directly are not available [Citation1]. Approved therapeutic approaches focus on either decreasing TTR protein production or stabilising the TTR tetramer; however, these therapies are not designed to directly target and deplete TTR amyloid deposits [Citation6]. Tafamidis, a benzoxazole derivative that binds and stabilises tetrameric TTR, is currently the only approved treatment for ATTR cardiomyopathy in patients with ATTRv and ATTRwt [Citation7]. In a phase 3 randomised controlled trial (NCT01994889), tafamidis reduced all-cause mortality and frequency of cardiovascular-related hospitalisations in patients with ATTR cardiomyopathy, compared with placebo [Citation8]; however, this therapy has shown limited benefit in patients with more advanced cardiac disease [Citation9], possibly due to the extent of amyloid already deposited in their organs. Although tafamidis provides some clinical benefit, it does not reverse the course of the disease [Citation8, Citation10, Citation11]. Therefore, there is an unmet medical need for effective therapies that can directly clear deposited amyloid and prevent re-accumulation.
PRX004 (now continuing development as coramitug [NNC6019-0001]) is an investigational, humanised monoclonal antibody designed to deplete TTR amyloid deposits that cause ATTR amyloidosis and to prevent new amyloid formation [Citation12]. In a preclinical study, PRX004 has been shown to opsonise and promote clearance of TTR amyloid via antibody-dependent phagocytosis [Citation12]. Furthermore, PRX004 binds specifically to soluble misTTR, inhibiting the formation of amyloid fibrils without interfering with the function of the native, tetrameric TTR protein [Citation12]. Owing to its dual mechanism of action, PRX004 represents a new experimental treatment option to clear both soluble misTTR and amyloid deposited in the tissues of patients with ATTR amyloidosis (‘amyloid-depleting mechanism of action’).
Here, we report the results of an open-label, multicentre, phase 1 dose-escalation and long-term extension (LTE) study of PRX004 in patients with ATTRv amyloidosis. The primary objectives of this trial were to determine (1) the maximum tolerated dose and (2) the recommended phase 2 dose(s) of PRX004 by evaluating the safety, tolerability, pharmacokinetics and pharmacodynamics of PRX004. An exploratory objective was to determine preliminary efficacy of PRX004.
Acknowledgments
Medical writing and editorial support was provided by Jenna Bassett PhD and Kristin E. Larsen PhD of Peloton Advantage, LLC (Parsippany, NJ, USA), an OPEN Health company, and funded by Prothena Biosciences Inc, as well as by Johanna Scheinost DPhil of Oxford PharmaGenesis (Oxford, UK) in accordance with Good Publication Practice (GPP 2022) guidelines (www.ismpp.org/gpp-2022), with funding from Novo Nordisk A/S.
Disclosure statement
O.B. Suhr has served as a consultant for Akcea, Alnylam and Prothena; has served on a speakers’ bureau for Akcea and Alnylam; and has received research support from the Swedish Heart and Lung Foundation. M. Grogan has received research funding and consulting fees (funds paid to her institution, no personal compensation) from Akcea, Alnylam, Eidos, Pfizer and Prothena. A. Martins da Silva has served as a consultant for Alnylam and Prothena; and has served on a speakers’ bureau for Akcea, Alnylam and Pfizer. C. Karam has served on advisory boards for Akcea, Alnylam and Ionis; and has given educational talks supported by Akcea and Alnylam. P. Garcia-Pavia reports speaker fees from Alnylam Pharmaceuticals, AstraZeneca, Bridgebio, Intellia, Ionis Pharmaceuticals, Novo Nordisk and Pfizer; consulting fees from Alexion, Alnylam Pharmaceuticals, AstraZeneca, Attralus, Bridgebio, General Electric, Intellia, Neuroimmune, Novo Nordisk and Pfizer; and research/educational support to his institution from Alnylam Pharmaceuticals, AstraZeneca, Bridgebio, Intellia, Novo Nordisk and Pfizer. B. Drachman has served on advisory boards for Akcea, Alnylam and Eidos. W. Zago and G.G. Kinney are employees and shareholders of Prothena. R. Tripuraneni was an employee and shareholder of Prothena at the time the study was conducted.