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 Sinha1, Satish I. Rao1, Jonathan Fox1, Robert Zamboni1, Neil Kumar1, Isabella Graef2 and Mamoun Alhamadsheh3

1Eidos Therapeutics, 2Stanford University, 3University of the Pacific

High unmet medical need

2

Source: Grogan, M et al. JACC 2016, 68:1014-20; Planté-Bordeneuve, V. and Said, G. Lancet Neurol 2011, 10:1086-97

ATTR cardiomyopathy (ATTR-CM)

▪ Deposition of mutant (e.g., V122I) or wild-type TTR amyloid in the heart – Leads to predominantly diastolic heart failure – Afib/stroke and heart block frequently seen ▪ Affects 200K+ worldwide, likely underdiagnosed ▪ Late onset (50-60+), death within 4-6 years ▪ No FDA-approved treatments

Multisystem Disease, High Disease Burden

CNS Ocular GI Manifestations Nephropathy Carpal Tunnel Polyneuropathy

ATTR polyneuropathy (ATTR-PN)

▪ Affects ~10K worldwide, primarily in EU and JP ▪ Exclusively caused by mutant TTR (e.g., V30M) ▪ No FDA-approved treatments

Disease mechanism and therapeutic approach

3 Native TTR tetramer Dissociation into monomers initiates pathogenesis Monomers aggregate, deposited as amyloid

Stable tetramer Reduced amyloid formation and deposition

Disease mechanism Therapeutic hypothesis

TTRwt

5.3Å 6.0Å 6.0Å 5.3Å S117 S117’ S117 S117’

AG10 stabilizes TTR by mimicking the disease suppressing T119M variant

4

AG10 stabilizes TTR by mimicking the disease suppressing T119M variant

S117 S117’ S117 S117’ 4.6Å 5.0Å 2.8Å 2.8Å

T119M-TTR

5

AG10 stabilizes TTR by mimicking the disease suppressing T119M variant

6

AG10:TTRwt

S117 S117 S117’ S117’ 4.8Å 4.9Å 4.9Å 4.5Å 2.8Å 2.8Å 2.8Å 2.9Å

AG10 Dose Responsively stabilizes TTR in Human Serum

7

• AG10 binds to TTR at native ligand binding sites
• Fluorescence probe binding assay correlates to other measures of

stabilization

Time (hours) % Fluorescence 1 2 3 4 5 6 20 40 60 80 100

1.25 2.5 5 7.5 10 20 40 AG10 (µM)

Pharmacokinetics of Orally Dosed AG10

8

• Low systemic clearance and volume of distribution in all species tested
• Absolute oral bioavailability = 31% – 60 %

24 48 72 96 10 100 1000 10000

PO at 5 mg/kg Time (hr) AG10 Conc. (ng/mL)

Rat Dog Monkey

Orally administered AG10 effectively stabilizes TTR in Dogs

9 Dashed line = Background RFU Line = Median, ♦ = Mean

AG10 effectively stabilizes TTR in Monkeys

10 Dashed line = Background RFU Line = Median, ♦ = Mean

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