Podcast: ATTR-CM: What do we know about blood levels of the TTR protein? A discussion with experts

Abstract

Transthyretin (TTR) amyloid cardiomyopathy occurs when stable TTR, normally a 4-protein tetramer, becomes misfolded and aggregates to form amyloid fibrils that accumulate in the heart. Progressive accumulation causes cardiomyopathy, leading to arrhythmia and heart failure. Acoramidis is a high-affinity TTR stabilizer (⩾90%) evaluated in the ATTRibute-CM clinical trial. In this podcast discussion, Dr Mathew Maurer and Dr Adam Castaño provide insights into their recent analysis of prognostic implications of acoramidis-mediated changes to serum TTR (sTTR) in 557 patients and the associated implications for all-cause mortality. For the patients included in this analysis, acoramidis fully mediated a sharp and significant early rise in sTTR levels (mean 9.1 mg/dL) by day 28, sustained through month 30. Incremental changes (+5 mg/dL) in sTTR were associated with a 31.6% lower odds of mortality through month 30. This evidence strongly supports a direct association between early, sustained sTTR increases with acoramidis treatment and survival.

Plain language summary

Acoramidis rapidly increases serum TTR concentrations, which is associated with improved survival

Proteins are biological machines in living things. A protein called transthyretin, abbreviated as “TTR,” normally flows in blood to move certain chemicals from one place to another. For normal function, 4 copies of TTR need to be folded together in a specific way. If TTR becomes unfolded or folds the wrong way, it will clump with other TTR proteins. These clumps stick to organ tissues and build up over time. As the sticky clumps grow, they prevent the organs from working properly. When this happens in the heart, it can lead to a weakened heart muscle and eventually death. Acoramidis is a drug that keeps the 4 copies of TTR together and folded correctly. In this medical study, doctors looked at the amount of TTR in the blood of 557 people with misfolded TTR. They found treatment with acoramidis quickly increased the amount of TTR in blood, which lowered the risk of death by more than one-fourth.

Infographic

Podcast transcript

Dr Castaño:

I’m Adam Castaño, Vice President of Clinical Development at Bridge Bio Pharma. Joining me today is Dr Mathew Maurer, Professor of Cardiology and Director of the Cardiac Amyloidosis Program at Columbia University. Today we’re speaking about a heart condition called transthyretin amyloid cardiomyopathy, or ATTR-CM, and some of the drugs that are approved to treat it. We will also be discussing results from our new research study published in the Journal of the American College of Cardiology, or JACC, ¹ one of the major cardiology journals.

So, Dr Maurer, tell us, what is ATTR-CM and why is it such a serious condition?

Dr Maurer:

It’s a pleasure to be with you. Transthyretin amyloid cardiomyopathy (ATTR-CM) is a serious heart condition caused by a protein called transthyretin (TTR). It’s also known as prealbumin. It becomes unstable, breaks apart, and misfolds into harmful clumps that form amyloid fibrils. These fibrils build up in the heart, making it stiff and less able to pump blood properly. This condition is called a restrictive or infiltrative cardiomyopathy.

The name ATTR-CM can be broken down, where A is for amyloidosis, described earlier as the clumping of proteins; TTR, we also described earlier as the protein transthyretin that breaks apart and forms amyloid fibrils; and CM refers to the cardiomyopathy. ² ATTR-CM will worsen over time as there is more amyloid in the heart, making it stiff and difficult to pump blood. This eventually causes heart failure and can, unfortunately, be fatal.

Dr Castaño:

Thanks, Dr Maurer. That’s a nice, comprehensive overview. So, tell us, when does ATTR-CM typically occur in the lifespan of an individual, and can you describe the various types of ATTR-CM?

Dr Maurer:

ATTR-CM can occur in the setting of advanced age, known as wild-type ATTR-CM or ATTRwt-CM for short, which is the non-genetic form of the disease. ¹ When a faulty version of the variant of the gene can also be passed on to families, that is known as the ATTR-CM variant or ATTRv-CM for short. ATTR-CM usually starts sooner and gets worse faster in people with the variant form than in people with the age-related or wild-type form of the disease. ³ It has negative effects on the person’s quality of life. ² Common symptoms are prolonged tiredness, fatigue, and weakness, being unable to take breaths when doing small amounts of exercise, abnormal heart rhythms, and, rarely, a stroke when a person’s blood flow to a part of the body, such as the brain, is blocked and that part of the body shuts down. Affected persons may have many hospitalizations and hospital visits in the years before ATTR-CM is diagnosed. ³

Dr Castaño:

Thank you, Dr Maurer. We mentioned transthyretin, or TTR, a couple of times. So tell us, what does TTR do in the body?

Dr Maurer:

Yeah, great question. So TTR was named prealbumin when it was first discovered, ² at Columbia University. It’s a protein, mostly made primarily in the liver, and it plays an important role by helping to transport vitamin A or retinol and thyroid hormone through the body. For a long time, the level of TTR found in the blood was a reliable measure of a person’s nutritional health. However, we now know that low or low-to-normal TTR levels in the blood can also occur in a subset of people with genetic variants that cause ATTR-CM, and that these low levels are associated, unfortunately, with worse survival. ¹

Dr Castaño:

Thanks for describing that. So, now that we know about ATTR-CM and how it’s caused, tell us what medicines are available now to treat this disease?

Dr Maurer:

Yeah, one type of drug to treat ATTR-CM is called a TTR stabilizer because it stabilizes or holds together the unstable TTR protein, like super glue. These drugs raise the level of TTR in the blood that functions normally. The mechanism underlying why TTR stabilizers increase the level of the TTR in the blood is not well understood, but TTR levels may be useful to demonstrate the effectiveness of stabilization.

There are two TTR stabilizers currently available, tafamidis and acoramidis. Acoramidis is an oral medicine that tightly binds and stabilizes the TTR protein, preventing it from breaking apart and depositing harmful fibrils in the heart. Acoramidis was designed to mimic the naturally occurring rare genetic form called T119M or p.T139M that slows or prevents ATTR in a person who has an inherited associated variant. ⁴ This drug works very effectively, keeping more than 90% of the TTR stable. ⁵

Another type of treatment for ATTR-CM works in a different way than the stabilizers. These are called TTR silencers because they knock down TTR production in the liver by about 80% from baseline, reducing the amount of dissociated circulating TTR. ⁶

So, Adam, maybe you could tell us, how does acoramidis help people with ATTR-CM?

Dr Castaño:

Great question. In the clinical study of people with ATTR-CM called ATTRibute-CM,^7,8 patients who were given acoramidis had better disease outcomes than those given an inactive drug or placebo. Patients treated with acoramidis were less likely to die from any cause, they were less likely to be hospitalized for cardiovascular-related symptoms, and they had a slower rise in their blood of a different type of protein called NT-proBNP (N-terminal pro-B-type natriuretic peptide). That protein increases when the disease gets worse, normally. The patients also had better performance in a walking test for exercise endurance.

Now, Dr Maurer, tell us, what was the purpose of this study that we just published in JACC?

Dr Maurer:

Yeah, our study published in JACC provides further evidence and information demonstrating that among patients with ATTR-CM with very low, that is, below the normal range of serum TTR levels, those individuals have lower survival (Infographic). ¹ In patients with ATTR-CM, acoramidis was able to increase TTR quickly by day 28 and maintained the high levels throughout the end of the study. Acoramidis kept TTR levels stable to the end of the study until month 30, and these increases we found were associated with longer survival than in people in the study who received a placebo, which is obviously a sugar pill. The study also showed that even a small increase in TTR in the blood of people with ATTR-CM was associated with longer survival. And in fact, for every 5-mg/dL increase in TTR, for example, the risk of death was lowered by approximately one-third relative to patients who were treated with a placebo.

Dr Castaño:

Thanks for describing that. So finally, what are the implications of the findings that we can take away from the study that was published in JACC?

Dr Maurer:

I think the acoramidis-mediated quick and long-lasting increases in TTR blood levels that we found in our research suggest that TTR blood levels may be a new ATTR-CM-specific marker that can be used to predict the risk of death in patients receiving TTR stabilizers. Additional research is needed to understand the mechanism by which acoramidis increases serum TTR levels in the blood and what may be the potential clinical implications of the observations reported in this article.

Dr Castaño:

Thank you, Dr Maurer, for your time and for discussing these important study results. The ATTRibute-CM study was funded by Bridge Bio Pharma, and other disclosures are noted in the article itself. It’s always a pleasure to talk with you, Mat, about this disease.

Dr Maurer:

My pleasure. Keep up the great work. I’m really thankful for all that you guys have done to advance the care of patients with ATTR-CM.