Acoramidis Shows Encouraging Results in ATTR Cardiomyopathy

August 27, 2023

AMSTERDAM — Another drug for the treatment of transthyretin amyloid cardiomyopathy (ATTR-CM) has shown encouraging results in a phase 3 trial.

The drug, acoramidis (BridgeBio Pharma), showed a significant reduction compared with placebo in the primary endpoint, a hierarchical analysis of all-cause mortality, cumulative frequency of cardiovascular hospitalizations, and change from baseline in N-terminal pro–B-type natriuretic peptide (NT-proBNP) and 6-minute walking distance, in the ATTRibute-CM trial.

The combination of all-cause mortality/cardiovascular hospitalization was also significantly reduced.

The trial was presented at the European Society of Cardiology (ESC) 2023 Congress on August 27 by Julian Gillmore, MD, head of the University College London Centre for Amyloidosis, United Kingdom.

"ATTRibute-CM was a robustly positive trial, showing benefits across the board for acoramidis, and suggest the tantalizing possibility of genuine clinical improvements," Gillmore concluded.

ATTR-CM is a debilitating and progressive condition that increases mortality and reduces quality of life. Although this form of cardiomyopathy was considered to be very rare not long ago, improvements in imaging techniques and treatment developments have resulted in an upsurge in diagnosis throughout the world, and the disease is being diagnosed at an earlier stage, Gillmore noted.

ATTR-CM results from aggregation and deposition of transthyretin amyloid fibrils in the heart and various tissues. Acoramidis stabilizes the TTR tetramer and avoids the production of the fibrils.

Another similar drug, tafamidis (Vyndaqel, Vyndamax, Pfizer), was approved by the U.S. Food and Drug Administration (FDA) in 2019 for ATTR-CM and is now available in several counties, including Japan and Europe.

BridgeBio Pharma is planning to file for FDA approval for acoramidis toward the end of 2023 and in other countries in 2024, Gillmore reported.

"It will be a huge benefit to patients to have another effective drug available," he said.

Tafamidis also showed impressive results with its pivotal trial — ATTR-ACT — including a significant reduction in all-cause mortality, which was not seen in the ATTRibute-CM trial with acoramidis.  

Asked about this, Gillmore replied: "It is difficult to comment on comparison with tafamidis as there isn't a head-to-head trial. All I can say is that these results with acoramidis are fantastically encouraging, and I think we are going to have two effective drugs to treat this progressive and fatal condition."

He elaborated that the difference in all-cause mortality results between the trials was "entirely consistent" with differences in the trial populations, with the ATTRibute-CM trial recruiting much lower-risk patients, in line with the earlier diagnosis of the condition that is now occurring.

"The survival in the placebo group in the ATTRibute study was greater than that in the treatment group in the ATTR-ACT study. So, it's not all that surprising, given the reduced number of events, that mortality alone was not statistically significant in ATTRibute. What is important is that the trend in mortality was in the right direction, with an impressive risk reduction," Gillmore noted.

"Incredibly, survival at 30 months and hospitalization rates among patients receiving acoramidis approached that of age-matched individuals who do not have ATTR," he added.

Noting that more patients in the placebo group started taking tafamidis during the trial, Gillmore suggested that this would be expected to dilute the treatment effect of acoramidis.

"To have such a strongly positive study despite the change in the patient population and drop-in use of tafamidis is incredibly powerful," he concluded.

ATTRibute Trial

The randomized double-blind ATTRibute-CM trial included 632 patients with ATTR-CM and New York Heart Association class 1 to 3 heart failure.

They were randomly assigned 2 to 1 to acoramidis (800 mg twice daily) or placebo, with a follow-up of 30 months. After the first 12 months, tafamidis was permitted if available. This was more prevalent in the placebo arm (22% vs 14%).

The trial met the primary endpoint — a hierarchical analysis of all-cause mortality, cumulative frequency of cardiovascular hospitalizations, and change from baseline in NT-proBNP and 6-minute walking distance — with a win ratio of 1.8, which was highly statistically significant (P < .0001).

Results were consistent across all components of the primary endpoint and across all subgroups, Gillmore reported.

"Importantly, 58% of the win ratio ties were broken by the first two components of the hierarchical analysis —  all-cause mortality and cardiovascular hospitalizations — and a separate analysis of these two components alone was also statistically significant," he noted.

A trend was seen toward a treatment effect on all-cause mortality favoring acoramidis, with an 81% survival rate in the treated group, representing an absolute risk reduction of 6.4 percentage points and a relative risk reduction of 25%.

Of the deaths reported in the study, 78% were cardiovascular in nature. Cardiovascular death also showed a trend favoring treatment with the study drug (14.9% in the acoramidis group vs 21.3% in the placebo group), giving an absolute risk reduction of 6.4 percentage points and a relative risk reduction of 30%.

Acoramidis was also associated with 50% reduction in cardiovascular hospitalizations, which was highly significant ( P  < .0001).

A treatment effect was also seen in terms of functional status; at 30 months, the difference in 6-minute walk distance between the groups was 40 meters, a "highly statistically significant improvement and clinically important difference, Gillmore said. Improvement from baseline occurred in 40% of the acoramidis group vs 22% of the placebo group.

Acoramidis recipients showed a blunting of the progressive rise of NT-proBNP, which Gillmore noted has been shown to be strongly associated with outcomes, with 45% of the acoramidis treated patients showing an improvement in NT-proBNP levels compared with 9% of placebo group.

There was also a relative preservation of quality of life in the acoramidis group consistent with the separation of NT-proBNP curves, he added.

"Consistent with the mechanism of action and preclinical data showing near-complete stabilization of TTR at therapeutic drug concentrations, serum TTR (an in vivo reflection of TTR stabilization) was promptly and persistently elevated in patients receiving acoramidis," Gillmore said.

Safety data showed that treatment-related adverse events were equal between the two groups, and there were fewer treatment emergent serious adverse events in the acoramidis group. The drug was said to be "generally well tolerated, with no findings of potential clinical concern."

Second Primary Endpoint Not Significant

Discussant of the study at the ESC Hotline session, Thibaud Damy, MD, Hospital Henri Mondor, Paris East Creteil University, France, pointed out that a second primary endpoint of the study, change from baseline to month 12 in the 6-minute walking test, did not significantly differ between acoramidis and placebo.

Damy also highlighted the significant all-cause mortality reduction seen with tafamidis in ATTR-ACT but not achieved with acoramidis in ATTRibute.

He agreed with Gillmore's interpretation that this was probably due to the ATTRibute trial recruiting lower-risk patients, pointing out that patients in this trial had lower levels of NT-proBNP and less severe heart failure.

"It is clear that there is a place for acoramidis in patients with ATTR-CM," Damy concluded, adding that many other treatments are in development.

The ATTribute trial was supported by BridgeBio Pharma. Gillmore reports advisory/consultant roles with BridgeBio, Alnylam, Ionis, AstraZeneca, Intellia, Pfizer, ATTRalus and Lycia.

European Society of Cardiology (ESC) 2023 Congress. Presented August 27, 2023.

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