Promising Therapies On The Horizon For Treatment Of ATTR AmyloidosisNowell Fine, MD, SM, FRCPCLibinCardiovascular Institute of Alberta, Cumming School of Medicine, University of Calgary

Promising Therapies On The Horizon For Treatment Of ATTR AmyloidosisNowell Fine, MD, SM, FRCPCLibinCardiovascular Institute of Alberta, Cumming School of Medicine, University of Calgary Relevant Disclosures•Consulting / honoraria –Pfizer, Akcea, Alnylam, Amgen•Research support –Pfizer, Akcea, Alnylam, Takeda•Off-label use –Diflunisal, Doxycycline, TUDCA/Ursodiol Objectives•Discuss the use of TTR ‘Silencers’ for the treatment of ATTR amyloidosis•Discuss the use of TTR ‘Stabilizers’ for the treatment of ATTR amyloidosis •Discuss the use of ATTR ‘Degraders’for the treatment of ATTR amyloidosis•Will not be discussing issues related to conventional cardiovascular management of ATTR amyloidosis patients Therapeutic Targets of the Amyloidogenic TTR Cascade Silencers: Suppress hepatic TTR productionStabilizers:Stabilize circulating TTR from dissociationDegraders:Breakdown amyloid fibril tissue deposits Castanoet al. Heart Fail Rev 2015;20:163 Myocardial deposition causing ‘cardiac amyloidosis’ clinical syndrome TTR Silencers•Suppress hepatic production of transthyretin•Two agents have recently shown benefit in phase III clinical trials, both for mutant ATTR polyneuropathy•Inotersen-antisense oligonucleotide•Patisiran-small interfering RNA ATTR Pharmacologic Therapies Vranianet al. CurrCardiolRep 2015;17:100 Liver CirculationEnd-organs SilencersPATISIRAN INOTERSEN Inotersen•Weekly subcutaneous dosing•NEURO-TTR RCT (N=172) enrolled ambulatory patients with mATTRpolyneuropathy, Inotersenvs placebo, 17 month FU•Significantly ↓ neuropathy progression, 36% improved•Safety•3 pts had plts↓ <25, 1 ICH death•3 pts had glomerulonephritis•Plt, renal monitoring improved safety•Approved by Heath Canada Oct 2018•Plts>100, eGFR>45, vitamin A supplBenson et al. NEJM 2018;379(1):22 Inotersen-Improved Cardiac Endpoints Interventricular Septum Thickness (IVS) -0.2 -0.1 0.0 0.1 0.2Interventricular Wall Thickness (cm)Change from Baseline (LSM±SE) Left Ventricle MassLV Mass (g)Change from Baseline (LSM±SE) -30 -20 -10 0 10 20 Posterior Wall Thickness -0.2 -0.1 0.0 0.1 0.2 Inotersen (n=35)Placebo (n=16)Inotersen (n=35)Placebo (n=16)Inotersen (n=35)Placebo (n=16) Posterior Wall Thickness (cm)Change from Baseline (LSM±SE) Global Longitudinal Strain Inotersen (n=35)Placebo (n=16) Global Longitudinal Strain (%)Change from Baseline (LSM±SE)p=0.0288p=0.0150p=0.0425p=0.5753 0 1 2 3 4 Benson et al. NEJM 2018;379(1):22Dasguptaet al. ACC 2019 •Single-center open-label investigator-sponsored trial of ATTR CA patients receiving Inotersen•6MWD improved by 13.7 m after 3 years (N=13) •Neuro-TTR study sub-analysis of pts with cardiac involvement Patisiran•Intravenous dosing every 3 weeks•APOLLO RCT (N=225) enrolled ambulatory patients with mATTRpolyneuropathy, Patisiranvs placebo, 18 months FU•Significantly ↓ neuropathy progression, 56% improved•Safety•Similar adverse event rates between groups•19% infusion rxn(9% placebo), none serious•Vitamin A supplementation•Under Health Canada reviewAdams et al. NEJM 2018;379(1):11 Patisiran–Improved Cardiac Endpoints Solomon et al. Circ2019;139:431 •APOLLO study sub-analysis of 126 pts with cardiac involvement •Similar results for LV mass and wall thickness, longitudinal systolic strain, 6MWD Cardiac hospitalizations and all-cause mortalityNTproBNP TTR Stabilizers•Bind to the TTR tetramer and prevent its dissociation into monomers•Tafamidis•Diflunisal•AG10 ATTR Pharmacologic Therapies Vranianet al. CurrCardiolRep 2015;17:100 Liver CirculationEnd-organsStabilizers Tafamidis•Once daily oral dosing•ATTR-ACT RCT (N=441) enrolled patients with mutant (25%) or wtATTR(75%) cardiac amyloidosis, Tafamidisvs placebo, 30 months FU•Significant ↓ all-cause mortality•Reduced decline in 6WMD, QoL•Similar adverse events b/w groups•Under Health Canada review•FDA approval MondayMaurer et al. NEJM 2018;379(11):1007 TTR Stabilizers•Diflunisal•NSAID, twice daily oral dosing, limited cardiac data, no clear evidence of efficacy•Caution in patients with impaired renal function•Off-label use•AG10•Twice daily oral dosing•Mimics stabilizing TTR mutation (T119M) –forms hydrogen bonds between serine residues on neighboring monomer•Well tolerated in phase II trial ATTR CA (N=49), 28 day FU•Normalized serum TTR levels•Phase III RCT startingCastanoet al. Congest Heart Fail 2012;310:2658Judge et al. JACC 2019. In print. ATTR Degraders•Enhance resorption of amyloid tissue deposits•DoxyclinePlus TUDCA/Ursodiol•May attenuate disease progression •10-15% intolerance, GI and derm•Off-label use •Epigallocatechin 3-gallate (EGCG, green tea extract)•May attenuate disease progression•Well tolerated, rare GI side-effectsVranianet al. CurrCardiolRep 2015;17:100Obiciet al. Amyloid 2012;19 (supple I):34Karlstedtet al. J Card Fail 2019;25:147Kristen et al. ClinRes Cardiol2012;101:805Cappelliet al. Intern EmergMed 2018;12:873 Phase III RCTs for ATTR CA•Inotersen•Patisiran•Vutrisiran•TTR silencer, siRNA, SC q 3 months•AG10•Doxy/TUDCA•PRX004•Amyloid degrader, monoclonal Ab that binds to dissociated monomers, aggregates and amyloid deposits •Phase I trial Higakiet al. Amyloid 2016;23:86 Summary•Today there is no approved therapy for ATTR cardiac amyloidosis in Canada•But not for long, the horizon is here!•Emerging therapeutic options act at different points in the TTR amyloidogeniccascade•Silencers–suppress TTR production•Inotersen, Patisiran–slow polyneuropathy progression, RCTs coming for CA•Stabilizers–stabilize TTR from dissociation•Tafamidis–survival benefit in ATTR CA•Degraders–reduce amyloid tissue deposit•Doxy/TUDCA, EGCG –role uncertain•More therapies in development •Combination therapy?? Promising Therapies On The Horizon For Treatment Of ATTR Amyloidosis•Thank you•Questions or comments?•nmfine@ucalgary.ca