The fibrils also build up in tissues such as the peripheral nerves, the eyes, kidneys, thyroid, bone marrow, central nervous system and gastrointestinal tract, as well as the heart.
This affects the normal function of the tissue and symptoms progressively worsen as more fibrils accumulate; this adversely affects quality of life and, ultimately, leads to death.
A potential treatment is being developed by BridgeBio and Alexion (now part of AstraZeneca).
Acoramidis is a next-generation orally available small molecule stabiliser of TTR that inhibits the dissociation of tetrameric TTR — an effect that significantly stabilises TTR — preventing the misfolding that leads to fibril formation.
A randomised, double-blind, placebo-controlled first-in-human study was done in healthy adult volunteers to evaluate its safety, tolerability, pharmacokinetics and pharmacodynamics.1
Four single and three multiple ascending dose levels of acoramidis or a matching placebo were given orally to subjects. It was well tolerated with no safety signals giving clinical concern.
The drug was found to completely stabilise TTR throughout the entire dosing interval and achieved steady state at the highest tested dose. Serum TTR levels increased from all baselines after 12 days of dosing.
Results of a double-blind Phase III trial have also been reported.2 A total of 632 patients with ATTR-CM were given twice-daily 800 mg doses of acoramidis or a matching placebo for 30 months.
Efficacy was assessed for those patients who had an estimated glomerular filtration rate of at least 30 mL/min per 1.73 m2 of body surface area, with a four-step primary hierarchical analysis including death from any cause, hospitalisation for cardiovascular (CV) reasons and the change from baseline in both 6-minute walk distance and levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP).
Acoramidis was favoured compared with the placebo in the primary analysis, with a win ratio of 1.8; approximately two-thirds of pairwise comparisons favoured acoramidis with the remainder preferring the placebo.
Death from any cause and CV-related hospitalisations contributed more than half of the wins and losses to the win ratio, whereas pairwise comparisons of NT-proBNP gave the highest ratio of wins to losses.
Adverse event profiles were similar throughout both groups, with 98% experiencing some form of adverse event. In addition, 55% of the treated patients and 65% of those given the placebo experienced serious adverse events.
Positive high-level results from a Phase III trial in Japan have also been reported via press release and these were consistent with the wider Phase III results.
In the group of 22 patients who completed the trial, survival, cardiac-related hospitalisations and other measures of improved functions at 30 months were all positive, as were quality of life assessments. A long-term extension period is ongoing.
References
- J.C. Fox, et al., Clin. Pharmacol. Drug Dev. 9, 115 (2020).
- J.D. Gillmore, et al., N. Engl. J. Med. 390, 132 (2024).