A heart-protective mutation in a pill

Transthyretin amyloid cardiomyopathy, or ATTR-CM, is a heart disease most of us have never heard of. ATTR-CM is fatal if untreated and — though still underdiagnosed — it is estimated to affect hundreds of thousands of people worldwide. With symptoms that overlap those of other heart conditions, doctors often fail to recognize ATTR-CM as the source of patients’ heart failure.

For years, that lack of recognition made little difference because doctors had no approved therapies to stop the disease’s progress. Care was limited to lessening symptoms or, in rare cases, a heart transplant.

The outlook for patients, though, has improved tremendously in recent years, due in part to a drug that got its start in a Stanford Medicine laboratory.

That drug, Attruby, was approved by the U.S. Food and Drug Administration in 2024 and is one of three targeted treatments available in the U.S. to treat ATTR-CM. Originally known as AG10, it is the first FDA-approved small-molecule drug patented by Stanford University. As a small-molecule drug, it can be taken as a pill and is able to easily pass through cell membranes to get to where it’s needed. The active ingredient, acoramidis, was identified in 2010 by Isabella Graef, MD, then an assistant professor of pathology at Stanford Medicine, now CEO of Shenandoah Therapeutics Inc., and Mamoun Alhamadsheh, PhD, then a research associate at Stanford Medicine, now a professor at University of the Pacific. To develop the drug, they founded Eidos Therapeutics Inc., which was later acquired by BridgeBio Pharma Inc.

In this Q&A, we hear from Graef about how this advance came about and the emotional impact of the success.

What goes wrong in ATTR-CM and how does acoramidis help?

Transthyretin, or TTR, is a protein secreted by the liver into the bloodstream that’s composed of four identical subunits arranged like a four-leaf clover. In the blood of people with ATTR-CM, the TTR four-leaf clover assembly becomes unstable and falls apart, and the resulting subunits misfold, aggregate and deposit in the heart muscle. These misfolded protein clumps thicken and stiffen the heart walls and lead to heart failure. We designed acoramidis to stabilize TTR.

What led to the insight behind the drug?

The concept was grounded in human biology. An inherited stabilizing TTR variant protects people who carry that gene by stabilizing the four-leaf-clover assembly. We set out to reproduce that protective mutation pharmacologically.

Our key advance came from the realization that to truly stabilize TTR, a molecule couldn’t just “sit” anywhere in the protein’s binding channel. It had to engage the bottom of the binding pocket — the same area where the naturally protective gene variant helps hold TTR together. That idea ran counter to how many of the people in the field were thinking, and it led us to build one of the first screening efforts specifically engineered to find the right kind of TTR binders, not just any binders.

Guided by X-ray images to visualize the interaction of TTR with promising molecules identified by screening, Mamoun designed a compound that fit the TTR pocket extremely well and acted like the protective mutation. That is how AG10 —
Alhamadsheh–Graef molecule 10, later named acoramidis — was born. This precision approach to protein stabilization, anchored in human biology and executed with rigorous chemistry, was what ultimately made meaningful clinical benefit possible.

What has been the impact?

Acoramidis is authorized in the U.S., Europe, the U.K. and Japan, bringing a highly effective disease-modifying option into routine cardiology practice for a condition estimated to affect roughly 300,000 to 500,000 people worldwide, many of whom remain undiagnosed. What makes this feel like a true game changer is that the benefit extends to an especially high-risk hereditary subgroup found in about 3.5% of African Americans that’s associated with rapid progression and poor survival.

What has this meant to you personally?

Protein-misfolding diseases like ATTR-CM are not an abstract interest for us; they are personal. My path toward acoramidis began about 25 years ago, when I diagnosed my mother with a rare and rapidly fatal neurodegenerative protein-folding disease. Even as a physician, nothing in my training prepared me for the devastation of these disorders or the painful reality of how little we could offer. The most honest sentence I could say to my own family and to other families like ours was: “There is nothing we can do.” Mamoun was driven by a similar motivation: He lost his mother in her early 60s to Alzheimer’s disease.

So, the success of acoramidis isn’t only professional satisfaction for us. It feels like a small reversal of that helplessness. It is proof that stubborn, careful science can convert grief into something that helps other families keep the people they love.

What kept you motivated through the inevitable frustrations?

Very early on, around 2010, when Mamoun and I were testing whether AG10/acoramidis could stabilize transthyretin, we worked with our clinical colleagues to collect serum from patients with ATTR-CM. I still remember one patient who was desperately sick, waiting for a heart transplant. He asked to speak with the researcher trying to build a better therapy, and when we met, he thanked me — not for a promise, not for a result, but simply for caring enough to keep trying. It was one of those moments where science and humanity collide.

That encounter became my gyroscope. Especially when it was hard to raise funding to develop AG10 into an FDA-approved drug, I would think of him and patients like him. It reminded me why we had to keep going. Mamoun’s defining patient encounter came later, during the clinical trials: A patient advocate who had lost her mother to hereditary ATTR told him that she was fighting not just for herself, but for her children who might carry the same mutation.

And I am deeply grateful I wasn’t doing it alone. Mamoun was there from the beginning — brilliant and steady — turning our ideas into molecules. Together we carried the emotional weight of a project that was never just academic for either of us.

Who were the essential collaborators?

When Mamoun and I began working side by side almost 20 years ago, something clicked in a way that’s rare in science. We brought two complementary disciplines to the same bench — his precision and inventiveness as a chemist, and my perspective and drive as a physician-scientist grounded in human disease and patient need.

We were also carried forward by people who chose to believe early. The support and mentorship of the team at Stanford Medicine’s translational research program SPARK, especially Daria Mochly-Rosen and Kevin Grimes, was pivotal; they helped us build the foundation when the project was still purely academic. Stanford Medicine clinicians Michaela Liedtke and Ron Witteles anchored the work in the realities of ATTR-CM for patients. Later at Eidos, CEO Neil Kumar, CSO Uma Sinha, and the clinical team provided the expertise to carry AG10/acoramidis through global trials and ultimately to approval.