Treatment of Cardiac Transthyretin Amyloidosis: An Update

Michele Emdin; Alberto Aimo; Claudio Rapezzi; Marianna Fontana; Federico Perfetto; Petar M. Seferović; Andrea Barison; Vincenzo Castiglione; Giuseppe Vergaro; Alberto Giannoni; Claudio Passino; Giampaolo Merlini


Eur Heart J. 2019;40(45):3699-3706. 

In This Article

Tetramer Stabilization

Selective Stabilizers: Tafamidis, AG10

The benzoxazole tafamidis is a small molecule that inhibits the dissociation of TTR tetramers by binding the T4-binding sites.[25] Tafamidis has become the first disease-modifying drug to be approved for use in adult patients with early-stage ATTRv-related polyneuropathy, while it does not stop disease progression in patients with Stage 2–3 polyneuropathy.[26,27] It is currently available in Europe and Japan for the treatment of ATTRv-related polyneuropathy, while it has not received FDA approval.

In a small open-label, single arm trial on patients with mutations other than the V30M and TTR amyloidosis (i.e. not limited to ATTRv-related polyneuropathy), tafamidis treatment (20 mg daily) achieved TTR tetramer stabilization over 6 weeks. At 12-month follow-up, no deterioration in quality of life and cardiac function, assessed through echocardiographic parameters and plasma NT-proBNP was reported, with some worsening of neurological function.[28] More recently, the positive results of the ATTR-ACT trial have raised great interest. In this phase 3 study, 441 patients with TTR cardiomyopathy (defined as medical history of HF, LV hypertrophy at echocardiography or demonstration of TTR amyloid deposition) were randomized in a 2:1:2 ratio to receive tafamidis 80 mg, tafamidis 20 mg, or placebo for 30 months.[12] When comparing the pooled tafamidis arms (80 mg and 20 mg) with the placebo arm, tafamidis treatment was associated with lower all-cause mortality than placebo [78 of 264 (29.5%) vs. 76 of 177 (42.9%); hazard ratio 0.70, 95% confidence interval (CI) 0.51–0.96], and a lower rate of cardiovascular-related hospitalizations with a relative risk ratio of 0.68 (0.48 per year vs. 0.70 per year; 95% CI 0.56–0.81).[12] The Kaplan–Meier survival curves showed that tafamidis resulted in a reduction in all-cause mortality, with the curves diverging after approximately 18 months of treatment, in agreement with the concept of tafamidis as a disease-modifying drug.[12] Additionally, tafamidis was able to relieve symptoms, as demonstrated by the lower rate of decline in 6-min walking distance and quality of life (measured through the Kansas City Cardiomyopathy Questionnaire-Overall Summary) at 30 months (both P < 0.001).[12] The drug was also well tolerated, with a similar incidence and type of adverse events between the tafamidis and the placebo group; furthermore, diarrhoea and urinary tract infections, i.e. common adverse events in patients with ATTR, were less common among patients receiving tafamidis than placebo.[12] A detailed assessment of the effects of tafamidis on NT-proBNP, troponins and echocardiographic measurements is ongoing.

Across patient subgroups, including ATTRwt vs. ATTRv, New York Heart Association (NYHA) Class I–II vs. III, and tafamidis dose (80 mg vs. 20 mg), the difference in all-cause mortality and frequency of cardiovascular-related hospitalizations favoured tafamidis over placebo.[12] In contrast, among patients in NYHA Class III at baseline, those receiving tafamidis had higher hospitalization rates, possibly because of a longer survival during a more severe phase of the disease.[12] An adequately powered survival analysis in NYHA Class III patients would be worthwhile.

Following these results, tafamidis has received the Breakthrough Therapy designation from the FDA for the treatment of patients with ATTR cardiomyopathy, which may prelude to an accelerated evaluation of tafamidis as a therapy for this condition.

The selective TTR stabilizer AG10 has been evaluated in a phase 2, randomized, double-blind, placebo-controlled, multicentre study enrolling 49 patients with symptomatic ATTR cardiomyopathy, both variant and wt. In November 2018, the positive results of this trial have been announced. AG10 (400 mg or 800 mg per os twice daily for 28 days) was well tolerated, increased circulating TTR levels (considered as a positive effect, possibly linked to lower tissue deposition), and induced near-complete stabilization of TTR. A phase 3 trial is planned to be initiated in the first half of 2019.[29]

Non-selective Agents: Diflunisal

In 2006, a phase 1 study showed that non-steroidal anti-inflammatory drug (NSAID) diflunisal (250 mg per os b.i.d.), complexes to the T4 binding site and stabilizes TTR tetramers, thus preventing amyloid fibril formation in vitro.[30] In a small single-arm, open-label study, diflunisal was not effective in relieving cardiac dysfunction (evaluated as LV mass, ejection fraction or biomarkers), possibly because of the limited follow-up duration (0.9 ± 0.3 years).[30] Diflunisal appeared to be safe in the same patients,[31] although the adverse effects from a chronic NSAID treatment are a source of concern.