Phase II Clinical Trial Results for the Eidos Therapeutics Approach to Transthyretin Amyloidosis

The protein transthyretin can misfold and form solid deposits of amyloid. This occurs to an increasing degree with age, and it is becoming clear that transthyretin amyloid contributes meaningfully to a range of age-related conditions, and is not only a problem in the small minority of individuals who rise to the level of being diagnosed with transthyretin amyloidosis. Many of those have a mutation in the transthyretin gene that predisposes them to the formation of amyloid, but again, the accumulation of this amyloid is one of the contributing causes of aging and age-related disease for all of us: osteoarthritis, heart failure, spinal stenosis, and more. Thus we should all be quite interested in progress towards the development of therapies.

Eidos Therapeutics is working on a fairly traditional approach to the treatment of transthyretin amyloidosis, a small molecule drug AG10 that must be taken continuously, and that alters the behavior of transthyretin to prevent the formation of amyloid. The company recently raised a sizable amount of funding to support their later stage clinical trials. This was accomplished prior to the publication of phase 2 trial results, but at a point in time at which the company had enough data for the principals to feel quite confident in progressing to much larger phase 3 trials. The paper I'll point out here outlines the results of the phase 2 trial, in which both people with age-related and genetic transthyretin amyloidosis were given AG10. It appears to improve short-term measures of the condition, though it remains to be seen as to whether this approach can actually reverse existing amyloid deposition to any degree, or the consequent pathology.

When it comes to the role of transthyretin in aging, I'm much more in favor of approaches that remove transthyretin amyloid, such as the catalytic antibodies under development at Covalent Biosciences, rather than approaches such as that pioneered by Eidos Therapeutics, in which only the progression of the condition is slowed or stopped. Reversal of the damage via a form of repair is a treatment that can be applied every so often, perhaps once every few years at most, rather than having to be continuously applied. Furthermore it can be applied at any stage of the condition to improve matters for the patient, and can be applied repeated for greater effect. A way of halting the creation of new transthyretin amyloid is only marginally helpful for someone who is greatly impacted by large amounts of the stuff clogging up his or her cardiovascular system.

Transthyretin Stabilization by AG10 in Symptomatic Transthyretin Amyloid Cardiomyopathy

This study represents the first clinical experience with AG10 in the target patient population of transthyretin amyloidosis cardiomyopathy (ATTR-CM). Administration of AG10 was well tolerated and was not associated with safety signals of potential clinical concern. In the present study AG10 treatment increased serum TTR levels from baseline and brought those levels to within the normal range in all subjects, both mutant and wild-type. This included subjects whose baseline levels were markedly below the normal range. The 28-day treatment duration of the present study limits any assessment of clinical benefit.

The serum level of transthyretin, long recognized both as a sensitive index of overall nutritional status and as an acute phase reactant, is becoming more widely appreciated as an independent predictor of survival in ATTR-CM. In one recent study of patients with wild-type ATTR-CM, regression analysis suggested that a 1 mg/dL decrement in serum transthyretin level is associated with a 7-11% decrement in survival.

Patients with an established diagnosis of ATTR-CM and NYHA Class II-III symptoms aged 18-90 years were eligible for the study. Subjects were randomized in a 1:1:1 ratio to AG10, 400mg or 800mg, or matching placebo, administered twice daily. The primary objective of the study was to evaluate the safety and tolerability of AG10 compared to placebo. Secondary endpoints included pharmacokinetics (AG10 plasma concentrations), change from baseline in serum transthyretin concentration, and two distinct ex vivo measures of transthyretin stabilization. The study enrolled 49 subjects, of which 14 (29%) had known mutant ATTR-CM. Subjects ranged in age from 60-86 years, with a mean of 74.1 years, and 92% were male. All subjects had symptomatic, chronic heart failure due to ATTR-CM with NYHA Class II or III symptoms. Importantly, on average subjects had relatively low transthyretin at baseline.

AG10 plasma concentrations were determined at peak following the initial dose, and at peak and trough on Days 14 and 28 of the study. Subjects in the placebo group experienced a mean reduction of 7±15% in serum transthyretin concentration by Day 28 relative to baseline. Conversely, subjects administered either 400mg or 800mg AG10 bid showed a dose-dependent, mean increase in circulating transthyretin of 36±21% and 50±38%, respectively. There was a greater treatment effect observed in AG10-treated subjects with mutant ATTR-CM (67±42%) as compared to subjects with wild-type ATTR-CM (33±20%). This might be explained in part by the lower serum transthyretin levels in mutant ATTR-CM subjects measured at baseline.