Transthyretin (TTR) amyloidosis (ATTR) is a form of amyloidosis caused by the accumulation of misfolded TTR protein.
When TTR becomes unstable due to inherited variants or aging, it can accumulate as amyloid fibrils in various organs in the body, causing ATTR. TTR amyloid deposits predominantly in the heart and/or peripheral nerves, causing cardiomyopathy (CM) and/or polyneuropathy (PN).
As many as 13% to 19% of all patients with heart failure (HF) with preserved ejection fraction (pEF), commonly referred to as HFpEF, may have ATTR-CM, though it is currently significantly underdiagnosed and undertreated.
ATTR often dramatically impacts the quality of life, functional independence and life expectancy of patients, as well as impacting caregivers due to the progressive nature of the disease. If left untreated life expectancy from diagnosis is 2 to 5 years.
WHAT HAPPENS WHEN A HELPFUL PROTEIN BECOMES HARMFUL?
Transformative scientific research
At Eidos Therapeutics, we believe that providing optimal therapies for ATTR requires a clear understanding of its root cause. Thanks to decades of thoughtful experiments by researchers across the globe, we now have a detailed understanding of the mechanism of ATTR disease pathophysiology.
Eidos is dedicated to applying this knowledge to potentially prevent, or even halt, the advancement of ATTR.
Native biology of TTR
TTR is a naturally occurring abundant protein that is named for its known roles in transporting thyroxine (thyroid hormone) and retinol (Vitamin A). TTR is normally produced by the liver, circulates as a tetramer in the blood, and returns to the liver and other tissues to be cleared. Historically, TTR is also commonly referred to as pre-albumin.
TTR is highly evolutionarily conserved circulating in the blood of all vertebrates. Its role as an important transporter protein is critical to the function of multiple organ systems, including kidneys, eyes, bones, heart, and muscles. None of the documented human TTR variants result in a lack of the protein, suggesting that it may be required for healthy development or survival. The long-term consequences of reducing TTR levels in humans are unknown.
At Eidos Therapeutics, we believe that retaining TTR will preserve healthy biology, physiologic homeostasis, and may yield optimal long-term outcomes
ATTR-CM—a path to disease
Due to a genetic variant or unknown factors associated with aging, TTR tetramers can become unstable, leading to dissociation into component monomers that are prone to misfold and aggregate.
Aggregates result in the accumulation of toxic amyloid deposits.
Genetics and pharmacology
More than 140 destabilizing ATTR-causing variants have been described, and the severity of disease is associated with the level of destabilization caused by each variant. There are some variants that can stabilize TTR (e.g., R104H, T119M). Individuals who inherit these stabilizing variants are partially or completely protected against the development of ATTR.
In an analysis of extended long-term follow-up data from an open-label extension study of a TTR-stabilizing medicine in patients with ATTR-CM, a higher dose of the treatment demonstrated a significant benefit relative to a lower dose. These data suggest that a greater level of TTR stabilization may lead to improved clinical benefit in ATTR patients.
We believe that maximizing TTR stabilization will prevent amyloid formation and potentially halt or prevent the development of ATTR
The safety and efficacy of AG10 has not been established. There is no guarantee that AG10 will receive health authority approval or become commercially available in any country for the uses being investigated.
The safety and efficacy of AG10 has not been established. There is no guarantee that AG10 will receive health authority approval or become commercially available in any country for the uses being investigated.
CLINICAL TRIALS CURRENTLY ENROLLING
ATTRibute-CM – Multicenter, double-blind, randomized, placebo-controlled trial of AG10 to evaluate the efficacy and safety in patients with symptomatic transthyretin amyloid cardiomyopathy.
