AG10 potently and selectively stabilizes transthyretin in vitro and - PowerPoint PPT Presentation

AG10 potently and selectively stabilizes transthyretin in vitro and upon oral dosing in dogs: Potential for treating transthyretin amyloidosis Uma Sinha 1 , Satish I. Rao 1 , Jonathan Fox 1 , Robert Zamboni 1 , Neil Kumar 1 , Isabella Graef 2 and Mamoun Alhamadsheh 3 1 Eidos Therapeutics, 2 Stanford University, 3 University of the Pacific

High unmet medical need CNS Ocular ATTR cardiomyopathy (ATTR-CM) ▪ Deposition of mutant (e.g., V122I) or wild-type TTR amyloid in the heart Multisystem – Leads to predominantly diastolic heart failure Disease, High – Afib/stroke and heart block frequently seen Disease Burden ▪ Affects 200K+ worldwide, likely underdiagnosed Nephropathy GI Manifestations ▪ Late onset (50-60+), death within 4-6 years ▪ No FDA-approved treatments Carpal Tunnel ATTR polyneuropathy (ATTR-PN) ▪ Affects ~10K worldwide, primarily in EU and JP ▪ Exclusively caused by mutant TTR (e.g., V30M) Polyneuropathy ▪ No FDA-approved treatments 2 Source: Grogan, M et al. JACC 2016, 68:1014-20; Planté-Bordeneuve, V. and Said, G. Lancet Neurol 2011, 10:1086-97

Disease mechanism and therapeutic approach Native TTR tetramer Monomers aggregate, Dissociation into monomers deposited as amyloid initiates pathogenesis Disease mechanism Stable tetramer Therapeutic Reduced amyloid hypothesis formation and deposition 3

AG10 stabilizes TTR by mimicking the disease suppressing T119M variant TTRwt S117 S1 17’ 5.3Å 6.0Å 6.0Å 5.3Å S117 S1 17’ 4

AG10 stabilizes TTR by mimicking the disease suppressing T119M variant T119M-TTR S117 S1 17’ 4.6Å 2.8Å 2.8Å 5.0Å S117 S1 17’ 5

AG10 stabilizes TTR by mimicking the disease suppressing T119M variant AG10:TTRwt 2.8Å 2.9Å S117 S1 17’ 4.8Å 4.9Å 4.9Å 4.5Å S117 S1 17’ 2.8Å 2.8Å 6

AG10 Dose Responsively stabilizes TTR in Human Serum AG10 (µM) 100 0 1.25 80 % Fluorescence 2.5 60 5 7.5 40 10 20 20 40 0 0 1 2 3 4 5 6 Time (hours) • AG10 binds to TTR at native ligand binding sites • Fluorescence probe binding assay correlates to other measures of stabilization 7

Pharmacokinetics of Orally Dosed AG10 PO at 5 mg/kg 10000 Rat AG10 Conc. (ng/mL) Dog Monkey 1000 100 10 0 24 48 72 96 Time (hr) • Low systemic clearance and volume of distribution in all species tested • Absolute oral bioavailability = 31% – 60 % 8

Orally administered AG10 effectively stabilizes TTR in Dogs Dashed line = Background RFU Line = Median, ♦ = Mean 9

AG10 effectively stabilizes TTR in Monkeys Dashed line = Background RFU Line = Median, ♦ = Mean 10

Summary ▪ AG10, a small molecule transthyretin stabilizer, targets disease at its source – TTR mutants with decreased stability predisposes patients to disease, whereas T119M TTR is stabilizing and protective – AG10 binding to TTR mimics structure of T119M variant – Animal PK shows consistent exposure across species – Dog and monkey PD measurements show dose-dependent TTR stabilization ▪ Phase 1 trial in healthy volunteers is in progress – Establish tolerability and PK profile – Measure TTR stabilization 11

Acknowledgement ▪ AG10 Project Team at Eidos Therapeutics ▪ Arindom Pal & Mark Miller at University of the Pacific 12