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New Hope for Halting the Progression of Amyloidosis

Transthyretin amyloidosis (ATTR) is a progressive and inevitably fatal condition. This disorder can be caused by pathogenic mutations or aging processes that destabilize and dissociate the native TTR tetramer. The resulting monomeric TTR then misfolds, aggregates as an insoluble protein in the blood, and is deposited as amyloid which causes severe organ damage.

Amyloid deposits in the heart cause it to become stiff and initiate TTR amyloid cardiomyopathy (ATTR-CM). In its early stages, this infiltrative, restrictive cardiomyopathy is characterized by preserved left ventricular ejection fraction (EF) despite right and left heart failure. Patients with ATTR-CM are at high risk for both heart block and atrial fibrillation. “About 10-15% of patients with heart failure and normal EF have amyloidosis but it's not well diagnosed or recognized,” says Daniel Judge, MD, Professor of Cardiology at the Medical University of South Carolina (MUSC). While some patients are recognized, the condition remains widely underdiagnosed, overall.1,2,3 “These patients are unusual in that they have typical heart failure symptoms like shortness of breath on exertion and arrhythmias, but they also often have carpal tunnel syndrome, spinal stenosis, and multiple joint replacements. Interestingly, about 15% of people with amyloidosis have a ruptured biceps tendon–the so-called Popeye Sign. People with amyloidosis can also have high blood pressure that gradually stops being high–that is, they don’t need as much medicine to treat their blood pressure over time. What this actually means is that their heart has become less effective and can’t pump hard enough anymore to generate an elevated pressure,” says Judge.

While there are two therapies approved for familial ATTR neuropathy (one administered intra-venously; the other by sub-cutaneous injection), there are currently no approved therapies specifically for ATTR-CM. Judge and a team of MUSC researchers are working to change that.4 They recently published results from a Phase II clinical trial for a novel, oral ATTR-CM therapy called AG10, that was found to be highly effective in halting disease progression.5 AG10 is a selective TTR stabilizer that mimics a protective TTR mutation (T119M)–a super-stabilizing mutation that helps to prevent carriers from developing the disease. Judge explains, “AG10 was specifically designed to fit into a pocket of this TTR protein to stabilize it. Almost 20 years ago, a researcher recognized that some people had a naturally occurring, 'gain of function' mutation. This second mutation negated the effect of the first mutation that causes the damage. So, that's what this drug mimics. It works like the genetic rescue mutation.”

The Phase II double-blind, randomized, placebo-controlled AG10 study enrolled 49 patients with symptomatic ATTR-CM to receive the therapy at 400mg or 800mg, or placebo for 28 days. Results indicated that AG10 was well-tolerated and achieved near-complete stabilization of TTR. Average serum TTR increased by 36% (±21%) and 51% (±38%) at the 400- and 800mg doses, respectively (both p<0.0001 vs. placebo). Importantly, AG10 treatment restored serum TTR to within the normal range in all subjects even though 80% of those with mutant-type disease and 33% of those with wild-type disease had TTR levels below normal at baseline. “We assessed efficacy by the change in TTR level. We expected that when we stabilized TTR that the blood level would go up–higher TTR concentration was one of our pre-validated markers of stabilization and there was a very clear dose/response relationship,” says Judge. In fact, TTR has only recently been recognized as an independent predictor of survival in ATTR-CM. One study recently suggested that a 1mg/dL decrease in serum TTR was associated with a 7-11% decline in survival.6

Furthermore, AG10 was shown to stabilize TTR equally well in patients with both wild- and mutant-type disease, indicating that it may be effective across the spectrum of clinical phenotypes that arise from a range of TTR mutations.7 (29) “We know that the natural history of the genetic disease is worse than the wild type and so we stratified enrollment in the study for the presence of the gene abnormality. I was really pleased to see that the drug was successful in stabilizing both types of TTR. There are obvious reasons why the mutant-type disease deposits in the heart, because the protein is abnormal, but it was very reassuring that the drug also worked on the other, wild-type,” says Judge.

Judge and his MUSC team are now participating in an international Phase III trial of AG10 and recently enrolled the very first patient in this world-wide study. The hope is that this trial will extend and expand their findings from the Phase II trial. If the new data support prior results, AG10 could become an important disease-modifying treatment that is capable of transforming ATTR from an inevitably progressive, fatal disorder into a treatable chronic disease. For Judge, it’s a personal mission. “Yesterday a patient called and left me a voicemail about everyone in her family that had died from this disease and she was so worried. I’m so glad people who are in this situation can now have some hope that we’ll soon be able to treat and–if we start treatment early enough–even prevent this terrible disease because the progression is really awful. In later stages, patients can lose the ability to hold a fork, or eat, or breathe. It can be a really slow death, and it’s difficult for their family members to see this as it happens to a loved one. So, to be able to stop that process is really exciting,” says Judge.

In the meantime, building awareness of how to diagnose and refer patients with amyloidosis is essential so that emerging therapies like AG10 can reach patients quickly. Judge says, “The main barrier is lack of awareness. Physicians have to think about it. They forget about amyloidosis because it’s relatively rare. Also, for a long time, the rationale has been that since there aren't any treatments, there’s no reason to look for it. In the past, if we found amyloidosis we could only tell a patient to get their affairs in order–especially in the very aggressive types. But now that the prognosis is much better, early diagnosis is really going to be important because new medications should stop the disease from getting worse.”

--Kat Hendrix



  1. Quarta CC, et al. Cardiac amyloidosis. Circulation 2012;126(12):178–183.
  2. Geller HI, et al. Association between ruptured distal biceps tendon and wild-type transthyretin cardiac amyloidosis. J Am Med Assoc. 2017;318(10):962–963.
  3. 8. Sperry BW, et al. Tenosynovial and Cardiac Amyloidosis in Patients Undergoing Carpal Tunnel Release. J Am Coll Cardiol. 2018;72(17):2040–2050.
  4. Ruberg FL, Berk JL. Transthyretin (TTR) cardiac amyloidosis. Circulation. 2012;126(10):1286–1300.
  5. Judge DP, et al. Transthyretin Stabilization by AG10 in Symptomatic Transthyretin Amyloid Cardiomyopathy. J Am Coll Cardiol. 2019, Mar 12. S0735-1097(19)33920-8.
  6. Hanson JLS, et al. Use of Serum Transthyretin as a Prognostic Indicator and Predictor of Outcome in Cardiac Amyloid Disease Associated With Wild-Type Transthyretin. Circ Hear Fail. 2018;11:1-9.
  7. Graef I, et al. Abstract 19616: AG10 Stabilizes Pathogenic TTR Variants With High Potency - Potential for an Effective Treatment for TTR Cardiomyopathy. Circulation 2017;136(suppl_1):A19616.

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