Acoramidis Therapy Yields Positive Results in Patients With ATTR-CM by Reducing Hospitalizations

In the second part of a three-part interview, Georgia Vasilakis, MD, of the CardioNerds, speaks with Kevin Alexander, MD, of Stanford Medicine, to discuss the ATTRibute-CM trial in acoramidis, a near-complete TTR stabilizer. Dr. Alexander spoke about the therapy’s mechanism of action and delves into research he presented at AHA 2024, titled the ‘Relationship Between CVH and Survival in the Acoramidis-treated Participants Within ATTRibute-CM.’ Ultimately, the study showed that cardiovascular hospitalization is a robust predictor of mortality in patients with ATTR-CM, and reinforces the importance of having an effective therapy like acoramidis that reduces hospitalizations in this patient population.

Dr. Georgia Vasilakis

Okay. Now let’s dive into the ATTRibute-CM trial specifically, and its recent data. Can you summarize the eligibility criteria for this trial as well as the methods and results?

Dr. Kevin Alexander

Of course. So this was a pivotal Phase III clinical trial studying patients with ATTR-CM, either wild type or hereditary. Over 600 patients were included and they had class one to class three heart failure, and their disease was confirmed either by biopsy or technetium or nuclear scintigraphy scanning. They’re randomized in a two-to-one fashion to acoramidis, which is a twice daily pill versus placebo, and followed out to 30 months with a primary endpoint of a composite mortality, cardiovascular hospitalization, change in six-minute walk and change in NT-proBNP.

And similar to the ATTRACT trial, which studied tafamidis, this composite endpoint was studied in a hierarchical fashion, so it prioritized mortality in cardiovascular hospitalizations. And so this trial reached its primary endpoint in the 30-month analysis, and then more recently published at American Heart Association was the open label extension data, which showed continued benefit for the primary endpoint as well as overall mortality. And so the composite of all these data is what led to culminating its approval in November.

Dr. Georgia Vasilakis

Awesome. Thanks so much for sharing. And since it’s been a little bit of time since the meeting and since the trial has been completed, what does the latest post-hoc analysis tell us about acoramidis-treated participants with cardiovascular-related hospitalizations compared to those without?

Dr. Kevin Alexander

Yeah, I think that this field for ATTR is rapidly evolving and while remains highly fatal condition, we are starting to diagnose people earlier and they’re living longer with earlier diagnosis and earlier treatment initiation. So one thing that we’ve observed in the trials after ATTRACT with tafamidis is that the mortality rates are lower and probably just reflects a contemporary patient population. And so while mortality, looking at mortality in trials is important, I think increasing focus will be on second important additional endpoints, mainly things like cardiovascular hospitalization, functional endpoints, and patient-reported outcomes.

So we know that cardiovascular hospitalizations, particularly heart failure hospitalizations are a big morbidity to patients and a big cost to the healthcare system. And so better understanding the burden of cardiovascular hospitalizations in the ATTRC population, I think is increasingly important. And so some of the post-hoc analyses presented at AHA started to dive into some of that data from the ATTRibute-CM trial.

Dr. Georgia Vasilakis

Awesome. And so if you could summarize this rapidly evolving field into its clinical impact so far regarding cardiovascular-related hospitalizations and overall survival, what would you say based on this analysis?

Dr. Kevin Alexander

I’d say that we saw a clear trend in that analysis that if you’ve had one or more cardiovascular hospitalization, you’re at a markedly increased risk of mortality in subsequent years. And I think that as clinicians, that’s really important because when we see patients in outpatient clinics, some of them may have been hospitalized in the interim and they’re looking fine now. Their heart failure has been addressed or they’re compensated again. But I think we have to reflect and realize that this is someone that’s at higher risk of worse outcomes in the next six months, 12 months, 24 months, and start to think about what additional interventions we can offer.

I think this will become increasingly important as more disease-specific treatments for ATTR develop, but also all the kind of supportive therapies in terms of diuretic titration. Thinking about things like SGLT2 inhibitors, et cetera, will become increasingly important. So I think these data support that cardiovascular hospitalization is an important tool for risk stratification in this population. And as we become more nuanced with our care for ATTR-CM, hopefully can help to guide future treatment decisions as well.