Alagebrium (ALT-711)

Alagebrium (ALT-711; 3-phenacyl-4,5-dimethylthiazolium chloride) is the first-in-class advanced glycation end-product (AGE) crosslink breaker to have entered human clinical trials for the reversal of age- and diabetes-associated vascular and myocardial stiffening. Originally developed by Alteon Inc. (Montvale, New Jersey) as a stable, orally bioavailable derivative of the prototype AGE crosslink breaker N-phenacylthiazolium bromide (PTB), alagebrium exerts its principal pharmacological activity through nucleophilic cleavage of carbon-carbon bonds within alpha-diketone crosslinks that accumulate on long-lived extracellular matrix proteins (collagen, elastin) as a consequence of non-enzymatic glycation. The compound additionally demonstrates metal chelation properties, antioxidant activity, and reduction of methylglyoxal synthesis through modulation of triose phosphate metabolism. These combined actions address the structural and functional consequences of protein glycation that contribute to systolic hypertension, diastolic heart failure, arterial stiffening, diabetic nephropathy, and diabetic cardiomyopathy.

Preclinical pharmacology has demonstrated that alagebrium reverses established large-artery stiffness in aged and diabetic animal models across multiple species. Asif et al. (2000) reported that ALT-711 reversed age-related increases in myocardial stiffness in aged dogs. Vaitkevicius et al. (2001) demonstrated reduction of arterial pulse wave velocity and augmentation index with enhanced ventricular stroke volume in aged non-human primates. Wolffenbuttel et al. characterized restoration of large artery compliance in diabetic rats. Additional preclinical demonstrations include prevention and reversal of diabetic nephropathy in db/db mice, attenuation of diabetes-induced myocardial structural changes, and synergistic improvement of systolic and diastolic function when combined with exercise training in aged rat models.

The clinical evidence base derives principally from three Phase 2 studies. The Kass et al. (2001) randomized placebo-controlled trial in 93 elderly subjects with vascular stiffening demonstrated that 210 mg daily of ALT-711 for 56 days improved total arterial compliance by approximately 15 percent (P = 0.015), reduced pulse pressure by 5.3 mm Hg versus 0.6 mm Hg with placebo, and decreased pulse wave velocity by 8 percent. The Little et al. (2005) open-label study in 23 patients with diastolic heart failure showed that 420 mg daily for 16 weeks decreased left ventricular mass, improved diastolic filling parameters, and improved quality of life scores. The Hartog et al. (2011) BENEFICIAL trial, a double-blind placebo-controlled study of 102 patients with systolic heart failure randomized to 200 mg in the published literature or placebo for 36 weeks, did not demonstrate improvement in exercise tolerance or cardiac function, suggesting that AGE crosslink breaking may be more relevant to diastolic than systolic cardiac pathology.

Alagebrium was well tolerated across all clinical studies. In more than 1000 subjects evaluated in clinical trials, no signal of increased myocardial infarction or death was observed. Common adverse events included upper respiratory tract infections, diarrhea, headache, and non-specific pain at rates similar to placebo. A modest increase in serum triglycerides was observed in the Kass et al. study. Clinical development was terminated in January 2009 following the acquisition of Alteon by Synvista Therapeutics in 2007 and subsequent exhaustion of operating capital, rather than due to safety or efficacy concerns at the doses studied. The compound remains available from research chemical suppliers and is a subject of ongoing investigation as a research tool for AGE biology, vascular aging, and diabetic complications. A principal limitation of the alagebrium mechanism is the absence of evidence for activity against glucosepane, the most prevalent AGE crosslink in human tissue.