BridgeBio Pharma : BBIO – Acoramidis AG10 TTR – ISA 2024 – Rationale & design of ACT-EARLY

Rationale and Design of ACT-EARLY, the Acoramidis Transthyretin Amyloidosis Prevention Trial

Pablo Garcia-Pavia1, Julian D. Gillmore2, David Adams3, Isabel Conceicao4, Teresa Coelho5, Daniel P. Judge6, Mathew S. Maurer7, Frederick L. Ruberg8, Scott Solomon9, Ahmad Masri10, Thibaud Damy3, Marianna Fontana2, Mary M. Reilly2, Nitasha Sarswat11, Peter van der Meer12, Mazen Hanna13, Morie Gertz14, Xiaofan (Martha) Cao15, Ted Lystig15, Uma Sinha15, Adam Castaño15, Leonid Katz15, Jonathan C. Fox15

1Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain; 2University College London, London, UK; 3Assistance Publique-Hôpitaux de Paris, Université Paris Sud, Paris, France; 4Centro Hospitalar Universitário Lisboa Norte, EPE - CHULN, EPE, Lisbon, Portugal; 5Porto University Hospital Center, Porto, Portugal; 6Medical University of South Carolina, Charleston, SC, US; 7Columbia University Irving Medical Center, New York, NY, US; 8Boston University Chobanian & Avedisian School of Medicine, Boston, MA, US; 9Harvard University, Cambridge, MA, US; 10Oregon Health & Science University, Portland, OR, US; 11University of Chicago Medicine, Chicago, IL, US; 12University Medical Center, Groningen, The Netherlands; 13Cleveland Clinic, Cleveland, OH, US; 14Mayo Clinic, Rochester, MN, US; 15BridgeBio Pharma, Inc., San Francisco, CA, US

BACKGROUND

• ATTR is a systemic, progressive, fatal disease.

Dissociation of destabilized, tetrameric TTR into its

constituent monomers facilitates misfolding,

aggregation, and deposition as amyloid in the heart,

peripheral nervous system, and other tissues.

CONCLUSION

• AG10-501ACT-EARLY is the first phase 3 trial to evaluate prophylactic therapy for the prevention of ATTR. ACT-EARLY is also the first phase 3 clinical trial to consider ATTR not by traditional dichotomized cardiomyopathic or polyneuropathic manifestations, but as one disease anchored by a single fundamental pathobiology. Enrollment will begin in 2024

Destabilization is associated with aging (ATTRwt) and

is accelerated by one of over 140 known pathogenic,

destabilizing TTR gene variants (ATTRv)1

• ATTR-CM is an infiltrative, restrictive form of heart

failure, typically presenting as HFpEF.2 ATTR-PN is an

ascending, axonal neuropathy of the sensorimotor

and autonomic peripheral nervous system. The most

common cause of death in ATTRv is end-stage heart

failure, which occurs 10-15 years after diagnosis in

ATTRv-PN and 3-5 years in ATTRv-CM3,4

• Several disease-modifying drugs have been approved

for treating either ATTRv-CM or ATTRv-PN, depending

METHODS

• ACT-EARLYis a prospective, multinational, randomized, double-blind,placebo-controlled study evaluating treatment with acoramidis in asymptomatic carriers of a pathogenic TTR variant (Figure 1). Eligible participants are individuals (age 18-75 years) with a known pathogenic TTR variant who are within 10 years of the predicted age of disease onset for their specific variant (Figure 2). Approximately 600 participants will be randomized 1:1 to receive acoramidis or placebo for up to 7 years. The primary efficacy endpoint is time to development of ATTR-CM and/or ATTR-PN. Additional endpoints include safety and tolerability of acoramidis, and its effects on cardiac imaging parameters, plasma TTR concentration, nerve conduction, and neurofilament light chain

FIGURE 1. AG10-501ACT-EARLY and OLE Schematic. ACT-EARLY is a prospective, multinational, randomized, double-blind,placebo-controlled study evaluating treatment with acoramidis in asymptomatic carriers of a pathogenic TTR variant.

FIGURE 2. Current Care Paradigm as Risk of Clinically Evident ATTRv Increases in Carriers of a Pathogenic TTR Variant. The ideal recruitment window for AG10-501 relies on the predicted age of disease onset.

Asymptomatic	Asymptomatic	Diagnosed
TTR Variant Carrier	At-RiskTTR Variant Carrier	ATTRv Disease

Watchful waiting

Surveillance indicated

Treatment indicated

on the predominant phenotype. None of these agents

have been evaluated or approved for the prevention

of ATTRv in asymptomatic carriers of a pathogenic

TTR variant. Few guidelines have been agreed upon

or established for their clinical surveillance5

• Acoramidis, a next-generation,near-complete TTR

stabilizer, has recently completed and communicated

the results of a pivotal phase 3 trial in patients with

established ATTR-CM.6 The study met its primary

endpoint of a hierarchical analysis of all-cause

mortality, cardiovascular hospitalization, NT-proBNP,

and 6MWT (p<0.0001). The safety profile remains

reassuring with no important safety signals of

potential clinical concern identified to date

• The observation that intervention early in the

natural history of ATTR is associated with greater

AG-ACT-EARLY

Screening Period		Treatment Period

Acoramidis 712 mga PO BID

Asymptomatic carriers of
a pathogenic TTR variant	R 1:1
Approximately 600

Placebo

AG- OLE

Open-Label Extension

Acoramidis 712 mga PO BID

for newly diagnosed ATTR-CMb

PADO-10	PADO
PADO - 10 yrs

Population:

• Asymptomatic carrier with pathogenic TTR variant
  AND

• Age ≥18 to ≤75 yrs
  AND

clinical benefit7-10 suggests a potential prophylactic

role for acoramidis in appropriately selected

at-risk individuals. The AG10-501 study is designed

to test this hypothesis and will include patients

with V30M/pV50M, V122I/pV142I, T60A/pT80A,

and other pathogenic variants

Risk of transitioning to clinically evident ATTRv (CM or PN)

aAcoramidis 712 mg is the content of the moiety equivalent to the 800 mg acoramidis HCL dose used in the pivotal phase 3 ATTRibute-CM trial. bParticipants newly diagnosed with ATTR-PN should seek therapy with standard of care outside of this trial.

• Age ≤10 yrs prior to PADO, where PADO is based on pedigree or published literature

FUNDING: This study was sponsored by BridgeBio Pharma, Inc., San Francisco, CA, US.

ABBREVIATIONS: 6MWT, 6-minute walk test; ATTR, transthyretin amyloidosis; ATTR-CM, ATTR cardiomyopathy; ATTR-PN, ATTR polyneuropathy; ATTRv, ATTR variant; ATTRwt, ATTR wild-type; HFpEF, heart failure with preserved ejection fraction; NT-proBNP,N-terminalpro-B-type natriuretic peptide; OLE, open-label extension; PADO, predicted age of disease onset QoL; R, randomization.

ACKNOWLEDGMENTS: Under the direction of the authors, medical writing assistance was provided by Syneos Health Medical Communications, LLC, and supported by BridgeBio Pharma, Inc. Editorial support and critical review provided by Shweta Rane of BridgeBio Pharma, Inc.

REFERENCES: 1. Ruberg FL, Maurer MS. JAMA. 2024;331(9):778-791.2. Obi CA, et al. Methodist Debakey Cardiovasc J. 2022;18(2):17-26.3. Suhr O, et al. J Intern Med. 1994;235(5):479-485.4. Grogan M, et al. J Am Coll Cardiol. 2016;68(10):1014-1020.5. Conceicao I, et al. Amyloid. 2019;26(1):3-9.6. Gillmore JD, et al. N Engl J Med. 2024;390(2):132-142.7. Adams D, et al. N Engl J Med. 2018;379(1):11-21.8.

Adams D, et al. Amyloid. 2023;30(1):1-9.9. Benson MD, et al. N Engl J Med. 2018;379(1):22-31.10. Maurer MS, et al. N Engl J Med. 2018;379(11):1007-1016.

DISCLOSURES: PGP: Has contributed to research for Alnylam, AstraZeneca, Intellia, Novo Nordisk, and Pfizer; has been a consultant, advisor, and/or speaker for Alnylam, AstraZeneca, Intellia, Pfizer, Novo Nordisk, Alexion, Attralus, BridgeBio, and Ionis. JDG: Has been a consultant, advisor, and/or speaker for Alnylam, AstraZeneca, Attralus, BridgeBio, Ionis, Intellia, and Pfizer. DA: Has been a consultant, advisor, and/or speaker for BridgeBio. IC: Has contributed to research for Alnylam, Ionis, and Pfizer; has been a consultant, advisor, and/or speaker for THAOS. TC: No relevant financial relationships to disclose. DPJ: Has contributed to research for Pfizer, Array, and BridgeBio; has been a consultant, advisor, and/or speaker for Alexion, Alleviant, Alnylam, Blade, Cytokinetics, Lexeo, Novo Nordisk, Pfizer, Renovacor, Tenaya, and GSK. MSM: Has contributed to research for NIH (NIH R01HL139671

and R01AG081582-01), Alnylam, Pfizer, BridgeBio, Prothena, and Ionis; has been a consultant, advisor, and/or speaker for AstraZeneca, Akcea, Intellia, Novo Nordisk, Alnylam, Pfizer, BridgeBio, Prothena, and Ionis. FLR: Has contributed to research for Pfizer, Alnylam, and Akcea; has been a consultant, advisor, and/or speaker for Attralus and AstraZeneca. SS: Has contributed to research for Alexion, Alnylam, Applied Therapeutics, AstraZeneca, Bellerophon, Bayer, BMS, Boston Scientific, Cytokinetics, Edgewise, BridgeBio, Gossamer, GSK, Ionis, Lilly, NIH/NHLBI, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Tenaya, Theracos, and US2. AM: Has contributed to research for Pfizer, Ionis, Attralus, and Cytokinetics; has been a consultant, advisor, and/or speaker for Cytokinetics, BMS, BridgeBio, Pfizer, Ionis, Lexicon, Attralus, Alnylam, Haya, Alexion, Akros, Prothena, BioMarin, AstraZeneca, and

Tenaya. TD: Has been a consultant, advisor, and/or speaker for Akcea, Alexion, Alnylam, AstraZeneca, BridgeBio, Neurimmune, Novartis, Pfizer, and Prothena; has received research funding from Akcea, Alexion, Alnylam, Neurimmune, and Pfizer; MF: Has been a consultant, advisor, and/or speaker for Pfizer, Akcea, Ionis, Alnylam, Alexion, AstraZeneca, BridgeBio, Intellia, Janssen, Novo Nordisk; has received research grants from Pfizer and BridgeBio. MMR: Has been a consultant for BridgeBio and Alnylam. NS: Has been a consultant, advisor, and/or speaker for Pfizer, Akcea, Ionis, Alnylam, Alexion, AstraZeneca, BridgeBio, Intellia, Janssen, Novo Nordisk; has received research grants from Pfizer and BridgeBio. PVDM: Has been a consultant, advisor, and/or speaker for Pfizer, Akcea, Ionis, Alnylam, Alexion, AstraZeneca, BridgeBio, Intellia, Janssen, Novo Nordisk; has received research grants from

Pfizer and BridgeBio. MH: Has been a consultant, advisor, and/or speaker for Pfizer, Alnylam, BridgeBio, Ionis, and Alexion. MG: Has been a consultant, advisor, and/or speaker for Ionis/Akcea, Alnylam, Prothena, Sanofi, Janssen, Aptitude, Ashfield, Juno, AbbVie, Johnson & Johnson, and Celgene; contributed to research for Practice, Sorrento, and i3Health. AC, TL, XC, US, LK, and JCF: Employees and shareholders of BridgeBio.

PRESENTED AT THE 2024 INTERNATIONAL SYMPOSIUM ON AMYLOIDOSIS, MAY 26-30; ROCHESTER, MN, US, AND VIRTUAL.