Satish Rao

Nizam's Institute of Medical Sciences

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Uma Sinha

University College London

Jonathan C. Fox

University College London

Stephen B. Heitner

Cytokinetics (United States)

Daniel P. Judge

Medical University of South Carolina

Ronald Witteles

Cardiovascular Institute of the South

Jesper A. Jernelius

Boston College

Daniel Jacoby

Cytokinetics (United States)

Martha Grogan

Mayo Clinic

Terry O’Reilly

Celerion (United States)

Jennifer Hellawell

Icahn School of Medicine at Mount Sinai

Cooperative Institutions

University College London

Oregon Health & Science University

Nizam's Institute of Medical Sciences

Brigham and Women's Hospital

BridgeBio (United States)

Harvard University

Massachusetts General Hospital

Centro de Investigación Biomédica en Red

Centro de Investigación en Red en Enfermedades Cardiovasculares

British Heart Foundation

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First‐in‐Human Study of AG10, a Novel, Oral, Specific, Selective, and Potent Transthyretin Stabilizer for the Treatment of Transthyretin Amyloidosis: A Phase 1 Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic Study in Healthy Adult Volunteers

Clinical Pharmacology in Drug Development (2019)

Jonathan C. Fox Jennifer Hellawell Satish Rao Terry O’Reilly Rick Lumpkin

Abstract AG10 is a novel, potent, and selective oral transthyretin (TTR) stabilizer being developed to treat TTR amyloidosis (ATTR). This randomized, double‐blind, placebo‐controlled study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics (ex vivo stabilization) of orally administered AG10 in healthy adult volunteers. Both mutant and wild‐type ATTR are underdiagnosed diseases with limited therapeutic options. As TTR amyloidogenesis is initiated by dissociation of TTR tetramers destabilized due to inherited mutations or aging, AG10 is designed to treat the disease at its source. Four single and three multiple ascending dose levels of AG10 or matching placebo were orally administered. Safety and tolerability were assessed by vital signs, electrocardiogram, adverse events, and clinical laboratory tests. Pharmacokinetics were measured using a validated bioanalytical assay. Pharmacodynamics were assessed via three pharmacodynamic assays of TTR stabilization. AG10 was uniformly well tolerated, and no safety signals of clinical concern were observed. Pharmacokinetic observations included time to maximum concentration <1 hour, dose‐dependent maximum concentration and area under the plasma concentration–time curve, low intersubject variability, and half‐life ∼25 hr. Complete (>90%) stabilization of TTR was observed across the entire dosing interval at steady state on the highest dose tested. Serum TTR levels, an in vivo reflection of TTR stabilization by AG10, increased from baseline following 12 days of dosing. AG10 appears to be safe and well tolerated in healthy adult volunteers and can completely stabilize TTR across the dosing interval, establishing clinical proof of concept. Based on these data, AG10 has the potential to be a safe and effective treatment for patients with either mutant or wild‐type ATTR.

Tolerability

Pharmacodynamics

10.1002/cpdd.700

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Citations (50)

Direct and Indirect Exposure-Response Modeling for Transthyretin Amyloid Cardiomyopathy Treated with Acoramidis

Brian Adam Surendhar Chepyala Bill Poland Satish Rao Jean‐François Tamby

Objectives: Acoramidis (AG10) is a novel investigational stabilizer of transthyretin (TTR or prealbumin) that achieves ≥ 90% TTR stabilization, in development for the treatment of TTR amyloid cardiomyopathy (ATTR-CM), a progressive, fatal disease in which the deposition of amyloid resultant of dissociation of either variant or wild-type TTR causes progressive heart failure. The Phase 3, 30-month ATTRibute-CM study showed a 25% risk reduction in all-cause mortality (ACM) with acoramidis relative to placebo. The objective was to evaluate exposure-efficacy relationships based on this study and two Phase 2 studies. Too few serious adverse events (SAE) occurred to establish an exposure-response model between acoramidis exposure and incidence of any particular SAE. Cardiovascular (CV)-related SAEs were excluded from the analysis since ATTR-CM patients are inclined to experience CV-related AEs and acoramidis exposure decreased the expected number of hospitalizations due to CV AEs. Methods: Using individual-subject steady-state exposure measures (plasma AUC, Cmax, and Cmin) estimated with a population pharmacokinetic model based on 8 clinical studies (Phase 1-3), exposure-efficacy relationships were modeled for cumulative CV-related hospitalization (CVH) counts using Poisson regression. Other efficacy measures could not be related directly to exposure but were related to change in serum TTR, an in vivo measure of TTR stabilization that increased with plasma exposure and served as an indirect exposure measure. ACM was modeled with logistic regression, and over time with Cox proportional hazards (CPH), while percent change from baseline (%CfB) in the Six Minute Walk Test (6MWT) at Month 30 was modeled as linear. Results: Change in serum TTR was predictive of ACM risk (p=0.00539) when adjusting for baseline demographic variables, diuretics, New York Heart Association (NYHA) class, baseline serum TTR, TTR variant vs wild-type and National Amyloidosis Centre (NAC) stage. For every 5 mg/dL increase in serum TTR from baseline to Day 28, the models predicted a 26.1% decrease in instantaneous mortality risk (CPH model) and a 30.9% (logistic model) decrease in the odds of mortality by Month 30, and the linear 6MWT model predicted an increase of 8.9 meters in the CfB 6MWT at Month 30. For every 1000 ng/mL increase in acoramidis steady-state Cmax, the Poisson model for CVH predicted a 2.7% decrease in the expected number of cumulative CVH events. Conclusions: Acoramidis exposure was found to directly predict cardiovascular hospitalizations, but change in serum TTR, which increases with acoramidis exposure, was needed to predict improved survival and 6MWT performance in ATTR-CM patients. The need for this indirect exposure measure could be due to limited and sparse concentration data at a single dose.Citations: .

Amyloid (mycology)

10.70534/emru2746

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AG10, A Novel, Potent and Selective Transthyretin Stabilizer, is Well Tolerated at Doses Resulting in Target Therapeutic Blood Levels, and Demonstrates Clinical Proof-of-Concept in Healthy Volunteers

Journal of Cardiac Failure (2018)

Jennifer Hellawell Satish Rao Terry O’Reilly Rick Lumpkin Jesper A. Jernelius

Pharmacodynamics

Therapeutic index

10.1016/j.cardfail.2018.07.091

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Citations (3)

AG10 CONSISTENTLY STABILIZES TRANSTHYRETIN TO A HIGH LEVEL IN BOTH WILD TYPE AND MUTANT AMYLOID CARDIOMYOPATHY: RESPONDER ANALYSES FROM A PHASE 2 CLINICAL TRIAL

Journal of the American College of Cardiology (2019)

Jonathan C. Fox Stephen B. Heitner Rodney H. Falk Martha Grogan Daniel Jacoby

Wild type

10.1016/s0735-1097(19)31268-9

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Transthyretin Stabilization by AG10 in Symptomatic Transthyretin Amyloid Cardiomyopathy

Journal of the American College of Cardiology (2019)

Daniel P. Judge Stephen B. Heitner Rodney H. Falk Matthew J. Maurer Sanjiv J. Shah

Transthyretin (TTR) amyloidosis is an underdiagnosed disease caused by destabilization of TTR due to pathogenic mutations or aging. Both pathogenic and protective mutations illuminate mechanisms of disease and potential interventions. AG10 is a selective, oral TTR stabilizer under development for transthyretin amyloidosis cardiomyopathy (ATTR-CM) that mimics a protective TTR mutation.This randomized, double-blind, placebo-controlled study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of AG10 in ATTR-CM patients with symptomatic, chronic heart failure.ATTR-CM, New York Heart Association functional class II to III subjects (n = 49, mutant or wild-type) were randomized 1:1:1 to AG10 400 mg, AG10 800 mg, or placebo twice daily for 28 days. Safety and tolerability were assessed by clinical and laboratory criteria. AG10 plasma levels were measured. TTR stability was assessed by changes in serum TTR, and 2 established ex vivo assays (fluorescent probe exclusion and Western blot).AG10 treatment was well-tolerated, achieved target plasma concentrations and demonstrated near-complete stabilization of TTR. TTR stabilization was more complete and less variable at the higher dose with stabilization by fluorescent probe exclusion of 92 ± 10% (mean ± SD) at trough and 96 ± 9% at peak (both p < 10-12 vs. placebo). Average serum TTR increased by 36 ± 21% and 51 ± 38% at 400 and 800 mg, respectively (both p < 0.0001 vs. placebo). Baseline serum TTR in treated subjects was below normal in 80% of mutant and 33% of wild-type subjects. AG10 treatment restored serum TTR to the normal range in all subjects.AG10 has the potential to be a safe and effective treatment for patients with ATTR-CM. A phase 3 trial is ongoing. (Study of AG10 in Amyloid Cardiomyopathy; NCT03458130).

Tolerability

10.1016/j.jacc.2019.03.012

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Citations (208)

Cardiac Primitive Neuroectodermal Tumor Presenting As Acute Coronary Syndrome

Journal of Clinical Oncology (2007)

Senthil Rajappa Sadashivudu Gundeti Lalit Varadpande Norman Bethune Satish Rao

Primitive neuroectodermal tumor

10.1200/jco.2006.09.2346

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Citations (9)