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protein pump inhibitors for prophylaxis. Fluid retention leading to heart failure exacerbation and clinically
significant bleeding were also uncommon. These findings may have been related to the use of lower
diflunisal dosage (250 mg BID) for the treatment of transthyretin amyloidosis than that routinely used for
the treatment of inflammatory conditions. Despite a lack of robust clinical data to guide its use, diflunisal
remains an important pharmacotherapeutic tool in the management of TTR amyloid cardiomyopathy
because of its favorable safety profile and low costs. However, this agent is not FDA approved for use in
patients with TTR amyloidosis.

Investigational compounds
AG-10 (Acoramidis, BridgeBio LLC, formerly Eidos Therapeutics) is an investigational compound that has
the potential to stabilize TTR tetramers and prevent their degradation into amyloidogenic monomer fibrils.
The compound was developed based on the discovery of the T119M is a stabilizing mutation of TTR. This
reduces TTR degradation by 33-fold compared to the wild-type protein. AG-10, like the T119M TTR
variant protein, promotes the formation of hydrogen bonds with serine residues at position 117 and
promotes TTR stabilization. A recent phase II clinical trial of AG-10 with 49 patients showed that it was
effective and generally well-tolerated in patients with ATTR-CM and NYHA functional class II or III
symptoms and baseline high circulating NT-pro-BNP levels . AG-10 led to an average increase in
[24]
circulating TTR levels of 36% with 400 mg dosing and 50% with 800 mg dosing. Patients with variant or
hereditary TTR (ATTRv-CM) had a more robust response than those with wild-type ATTR
cardiomyopathy. Compared to placebo, AG-10 had a slightly higher occurrence of atrial fibrillation,
constipation, diarrhea, and muscle spasms. Serious adverse effects with AG-10 included atrial fibrillation,
congestive heart failure, cellulitis, and dyspnea requiring hospitalization. A phase III randomized clinical
trial of AG-10, ATTRIBUTE-CM, is currently ongoing.

Finally, tolcapone (TASMAR®, Valeant Pharmaceuticals) is an orally active catechol-O-methyltransferase
(COMT) inhibitor that binds to the TTR thyroxine-binding pocket with high affinity. The drug is already
available for the treatment of Parkinson’s disease as an adjunct to carbidopa/levodopa. Tolcapone increases
the concentration of dopamine in the central nervous system by further reducing its degradation. It carries
an FDA black box warning for hepatotoxicity, and was previously removed from the market for safety
concerns before being re-instated. It is now being studied in ATTR. In vitro, it has a higher affinity for the
binding pocket than even tafamidis and was able to reduce degradation of highly unstable TTR variant
tetramers by 40%-50% and degradation of wild-type TTR tetramers by nearly 80%. A prospective clinical
[25]
trial is currently underway .

TTR RESORPTION
Antibody-mediated removal
Serum amyloid protein (SAP) is a non-fibrillar normal plasma-circulating protein that is also bound with
pathogenic TTR amyloid fibrils. Targeted removal of plasma SAP with the ligand miridesap (GSK2315698,
GlaxoSmithKline, and Pentraxin Therapeutics), previously known as CPHPC, leaves behind fibrillin-bound
SAP. This can then be targeted and bound by a therapeutic IgG1 anti-SAP antibody, dezamizumab
(GSK2398852, GlaxoSmithKline and Pentraxin Therapeutics), which activates a complement-based cascade
that could mark TTR amyloid fibrils for destruction by macrophage-derived multinucleated giant cells. A
phase I clinical trial of this antibody-mediated approach to TTR degradation and resorption initially showed
[26]
promise; however, further study was later paused due to futility and toxicity . Some data suggest that
repeat doses of dezamizumab may show clinical benefit , though more investigation is needed.
[27]