AG10 More Completely Stabilizes TTR Variants That Range in Intrinsic Instability Than Tafamidis

Caused by destabilizing transthyretin (TTR) mutations and age-related factors, TTR amyloidosis (ATTR) is a progressive, fatal disease. Protein misfolding is initiated by the dissociation of tetrameric TTR. The process is accelerated through destabilizing TTR mutations; increased severity of mutation destabilization correlates with a more severe clinical phenotype. TTR stabilizers such as diflunisal and tafamidis, which stabilize tetrameric TTR and thereby slow disease progression, have shown proven clinical benefit. A novel stabilizer, AG10, is currently under development for the treatment of ATTR.

Investigators hypothesized that pathogenic TTR variants with varying degrees of intrinsic instability display differential stabilization when treated with AG10 or tafamidis. Following accelerated dissociation at pH 3.8 for 72 hours, the researchers used immune blot quantitation of tetrameric TTR to assess TTR stabilization. They also used fluorescent probe exclusion (FPE) to measure binding site occupancy in patient serum.

Following the addition of AG10, or commercially available tafamidis at their respective therapeutic plasma concentrations, a spectrum of intrinsic instability and clinical phenotypes (V122I, T60A, A97S) were assayed among individual patient samples.

AG10 bound serum TTR to a greater extent than either peak or trough levels of tafamidis at therapeutic target trough concentrations. Adding AG10 resulted in greater and more durable TTR tetramer stabilization than adding tafamidis in all patient plasma samples tested, as shown in immune blot assays.

AG10 more completely stabilized variant TTR samples representative of a range of destabilizing mutations and clinical phenotypes than did tafamidis, at therapeutic concentrations. AG10 has the potential to be clinically efficacious in patients with a variety of genotypes associated with both TTR cardiomyopathy and polyneuropathy.

Source: Wong P, Ji A, Fox J, et al. Differential ex vivo stabilization of transthyretin by AG10 and tafamidis in samples from patients with moderate or severely destabilizing mutations. Presented at: XVII International Symposium on Amyloidosis 2020; September 14-18, 2020. Abstract PW025.

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