Clinical development of an antisense therapy for the treatment of transthyretin-associated polyneuropathy

Transthyretin (TTR)-associated amyloidosis is a late-onset autosomal-dominant genetic disease. Over 100 amyloidogenic mutations have been identified in TTR which destabilize the TTR tetramer thereby inducing the formation of amyloid fibrils in tissues such as the heart and peripheral nerves. This disease mainly affects peripheral nerves, causing familial amyloid polyneuropathy (FAP) or heart, causing familial amyloid cardiomyopathy (FAC). Circulating TTR is predominantly produced by liver, and the only widely available clinical treatment for FAP is orthotopic liver transplantation (OLT), whereas no treatment currently exists for FAC. Using second-generation antisense technology, we identified an antisense oligonucleotide (ASO) targeting TTR, ISIS-TTRRx, for the treatment of TTR-associated amyloidosis. When tested in a human TTR transgenic mouse model (hTTR Ile84Ser), ISIS-TTRRx showed a dose-dependent reduction of human TTR (up to >80%) at both the mRNA and protein levels. In cynomolgus monkeys, ISIS-TTRRx treatment produced a time-dependent reduction in plasma TTR levels. After 12 weeks of treatment in monkey, liver TTR mRNA and plasma TTR protein levels were reduced by similar to 80%. As expected, treatment with ISIS-TTRRx also produced a significant decrease in plasma RBP4 levels that correlated with reductions in TTR levels. ISIS-TTRRx treatment was well tolerated in both rodents and monkeys and produced a PK/PD profile consistent with prior experiences using this chemistry platform. ISIS-TTRRx is currently under evaluation in a Phase 1 clinical trial in normal healthy volunteers, and interim results of this trial will be presented.