Transthyretin Stabilization by AG10 in Symptomatic Transthyretin Amyloid Cardiomyopathy

Clinical practice update on heart failure 2019: pharmacotherapy, procedures, devices and patient management. An expert consensus meeting report of the Heart Failure Association of the European Society of Cardiology

“…Novel selective transthyretin stabilizers (e.g. AG10) and TTR gene silencers are at different stages of development . We fully support efforts to reduce the high cost of this therapy.…”

“…Transthyretin amyloidosis has two forms: ATTRm and ATTRwt, which occurs sporadically. ATTR affects 20-30% of people aged >80 years and is Table 2 Exclusion criteria of the ATTR-ACT trial 58 1 They had, in the opinion of the investigator, heart failure that was not due to transthyretin amyloid cardiomyopathy 2 New York Heart Association class IV heart failure 3 The presence of light-chain amyloidosis 4 A history of liver or heart transplantation 5 An implanted cardiac device 6 Previous treatment with tafamidis 7 An estimated glomerular filtration rate <25 mL/min/1.73 m 2 of body surface area 8 Liver transaminase levels exceeding two times the upper limit of the normal range 9 Severe malnutrition as defined by a modified body mass index of <600 calculated as the serum albumin level in g/L multiplied by the conventional body mass index (the weight in kg/m 2 ) 10 Concurrent treatment with non-steroidal anti-inflammatory drugs, tauroursodeoxycholate, doxycycline, calcium channel blockers, or digitalis more common in patients with HFpEF and/or degenerative aortic stenosis. [51][52][53][54][55] Novel single photon emission computed tomography cardiac imaging with bone-avid tracers (99mTc pyrophosphate, 3,3-diphosphono1,2-propanedicarboxylic acid, and hydroxymethylene diphosphonate (HMDP) help identify cases with high specificity, non-invasively, 56 obviating the need for endomyocardial biopsy.…”

Transthyretin cardiac amyloidosis: an update on diagnosis and treatment

“…86 A randomized, double-blind, placebocontrolled, Phase 2 trial (NCT03458130) confirmed the safety and efficacy of AG10 in ATTR-CA patients (wild type or variant). 87 A Phase 3 trial (NCT03860935) in ATTR-CA has been initiated.…”

First‐in‐Human Study of AG10, a Novel, Oral, Specific, Selective, and Potent Transthyretin Stabilizer for the Treatment of Transthyretin Amyloidosis: A Phase 1 Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic Study in Healthy Adult Volunteers

“…A phase 2 study in patients with symptomatic ATTR cardiomyopathy has recently been completed and reported, with consistent findings of good overall tolerability, similar exposures following sustained oral dosing, stabilization of TTR using the same methods reported here, and encouraging results in the ability of AG10 to restore low baseline serum TTR concentrations to the normal reference range. 30 These studies together provide a foundation to investigate the efficacy and safety of AG10 in ATTR with respect to accepted clinical end points, and a phase 3 trial in ATTR-CM has been initiated (clinicaltrials.gov: NCT03860935). AG10 could prove to be an important option among new, disease-modifying treatments, together transforming ATTR from a progressive, fatal disorder into a treatable chronic disease.…”