Development of An Oral,Brain/Eye penetrating, Second Generation TTR Stabilizer for The Treatment of Transthyretin Amyloidoses

The TTR Amyloidoses (ATTR) are rare, progressive, ultimately fatal diseases that compromise the function of multiple organs, causing a wide range of debilitating clinical symptoms. ATTR is caused by the dissociation of the tetrameric transthyretin (TTR) protein, leading to misfolding and aggregation of the released monomers with toxic oligomer formation and subsequent tissue deposition as physiologically insoluble amyloid fibrils (amyloidogenesis). While circulating TTR is synthesized predominantly in the liver, TTR in the eye and the brain is made locally by retinal pigment and choroid plexus epithelial cells, respectively. Autosomal dominant disease is caused by one of 123 germ-line destabilizing TTR mutations that exhibit a spectrum of disease phenotypes including polyneuropathy, cardiomyopathy, ocular pathology, focal central neurologic episodes and dementia. Sporadic aging-associated Senile Systemic Amyloidosis (SSA), in which wild type TTR is the amyloid precursor, displays a primarily cardiac and carpal tunnel syndrome phenotype.Current treatment options for ATTR are based on 1) eliminating production of the disease-accelerating TTR mutants through TTR gene therapy mediated by liver transplantation (LT) or mRNA lowering agents, such as patisiran and inotersen; and 2) preventing circulating TTR dissociation, which is rate-limiting for aggregation with the small molecule TTR kinetic stabilizer, tafamidis, which selectively binds and stabilizes native tetrameric TTR, thereby effectively halting disease progression. Tafamidis has received regulatory agency approval in ~40 countries for the treatment of Familial Amyloidotic Polyneuropathy caused by TTR mutations; in a recent phase III study, tafamidis also significantly reduced all-cause mortality and cardiac hospitalizations in patients with SSA. Despite achieving significant increases in lifespan and health span, LT, gene knockdown, and tafamidis do not prevent the well documented onset or progression of ocular and central nervous system (CNS) symptoms related to locally synthesized TTR (systemically administered tafamidis does not attain therapeutic concentrations in these tissues). Since kinetic stabilizers such as tafamidis dramatically slows peripheral degenerative disease progression, it is likely that developing a kinetic stabilizer with effective levels in the brain and eyes of ATTR patients will meet an urgent medical need.To achieve that goal, we will conduct a full-fledged drug discovery program including lead identification, SAR guided optimization, in vitro and in vivo pharmacokinetic studies (see preliminary data) to generate a TTR kinetic stabilizer achieving sufficient levels in the eye and/or CNS to slow disease progression. Tafamidis was invented and developed by members of our team (Kelly and Labaudinière), de-risking the 2nd generation kinetic stabilizer strategy. The effort proposed here will be combined with our proprietary early diagnostic and response-to-therapy biomarker strategies, facilitating the generation of a drug candidate ready for pre-clinical, IND-enabling studies.Public Health Relevance Statement: The TTR Amyloidoses (ATTR) are relentlessly progressive, ultimately fatal diseases that compromise the function of multiple organ systems, leading to degenerative phenotypes affecting the heart, peripheral, autonomic and central nervous systems, the eye, and the kidneys. Current and developing treatment options for ATTR, although effective at treating the peripheral degenerative phenotypes, are not likely to be adequate for alleviating the severe CNS and ocular disease phenotypes. Thus, we propose to develop a CNS and eye-penetrating prodrug to address this significant unmet medical need, i.e. ATTR progression in the brain and in the eye even with the available tafamidis and other ATTR treatments.