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Advancing Transthyretin Amyloidosis Drug Development in an Evolving Treatment Landscape: Amyloidosis Forum Meeting Proceedings

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Abstract

Introduction

Hereditary transthyretin amyloidosis (ATTRv, also referred to as hATTR; ORPHA 271861) and wild-type ATTR amyloidosis (ATTRwt; ORPHA 330001) are rare, progressive, systemic protein misfolding disorders with heterogeneous clinical presentations. ATTRv and ATTRwt amyloidosis are characterized by the deposition of amyloid fibrils in multiple organs including the heart, nerves, eyes, and soft tissues. The management of ATTR amyloidosis is complex because of its multisystemic nature and progression despite available treatment options. Morbidity is high and there are many unmet medical needs for patients. While contemporary ATTR amyloidosis cohorts are diagnosed earlier, have lower risk disease and lower mortality compared with the previous era, these advances coupled with the emergence of effective disease-modifying therapies have confounded the design of future prospective clinical trials and interpretation of historical control data.

Main Body

The Amyloidosis Forum is a public–private partnership between the US Food and Drug Administration Center for Drug Evaluation and Research and the nonprofit Amyloidosis Research Consortium (www.arci.org). This article summarizes proceedings from the 21 June 2023 Amyloidosis Forum on advancing drug development in ATTR amyloidosis in an evolving treatment landscape. The Forum focused on elements of clinical trial design to address these challenges and discussed their strengths and weaknesses from multiple stakeholder perspectives (i.e., patient, sponsor, statistician, clinician, and regulatory authorities).

Conclusion

Given rapid evolution of natural history in ATTR amyloidosis, the utility of historical control data is limited. Leveraging contemporary real-world data is essential for clinical trial design. Evidence generation from clinical trials should address clinically relevant questions. Key factors in successful trial design must be informed by up-to-date data on natural history, prognostic factors, clinically meaningful thresholds, and sharing available clinical trial data. The Amyloidosis Forum includes the community of patients with ATTR amyloidosis, the physicians who treat them, and the sponsors and regulators who collectively stand ready to support further studies in order to develop novel effective therapies.

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Data Availability

All Amyloidosis Forum meetings are publicly available (https://amyloidosisforum.org/). Recordings from the 21 June 2023 meeting, Advancing Drug Development in ATTR Amyloidosis in an Evolving Treatment Landscape, are available at https://amyloidosisforum.org.

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Acknowledgements

The Amyloidosis Forum Steering Committee acknowledges and extends appreciation to the contributions of all stakeholders and participants, including the members and employees of the Amyloidosis Research Consortium and the FDA who made this meeting possible. The authors would especially like to recognize the patients and caregivers who provided insights and presented powerful patient perspectives as part of the Amyloidosis Forum. Jamie Zigterman provided project management and administrative support as part of the Amyloidosis Research Consortium.

Amyloidosis Forum Meeting Panelists: Ahmad Masri, Oregon Health & Science University; Alanna Morris, Emory University School of Medicine; Angela Dispenzieri, May Clinic College of Medicine; John Berk, Boston University Chobanian & Avedisian School of Medicine: Amyloidosis Center; Keith Ferdinand, Tulane University School of Medicine; Keyur Shah, Virginia Commonwealth University Health Pauley Health Center; Kristen McCausland, QualityMetric; Lynnette Henshaw, Boston Medical Center; Martha Grogan, Mayo Clinic; Megan Azzarone, Shields Health Solutions; Michael Polydefkis, Johns Hopkins University School of Medicine; Mona Fiuzat, Duke University, Heart Failure Collaboratory; Renee P. Bullock-Palmer, Deborah Heart and Lung Center; Benjamin Booth, US Food & Drug Administration; Charu Gandotra, US Food & Drug Administration; Clemens Mittmann, Federal Institute for Drugs and Medical Devices (Germany); Cynthia Welsh, US Food & Drug Administration; Dalia Dawoud, National Institute for Health and Care Excellence (UK); Emmanouil Zouridakis, Medicines and Health Care Products Regulatory Agency (UK); Francesca Cunningham, US Department of Veterans Affairs Pharmacy Benefits Management Services; Jean-Michel Race, National Agency for the Safety of Medicines and Health Products (France); Jie Li, US Food & Drug Administration; Ken Sakushima, Pharmaceuticals and Medical Devices Agency (Japan); Laura Jawidzik, US Food & Drug Administration; Michelle Campbell, US Food & Drug Administration; Motiur Rahman, US Food & Drug Administration; Norman L. Stockbridge, US Food & Drug Administration; Rhea Lloyd, US Food & Drug Administration; Robyn Bent, US Food & Drug Administration; Sylvia Kuehn, Federal Institute for Drugs and Medical Devices (Germany); Wiley Chambers, US Food & Drug Administration; Andrew Slugg, Alnylam Pharmaceuticals; Franca Angeli, Pfizer; Johnathan Fox, BridgeBio Pharma; Martin Cowie, AstraZeneca; Matt Meldorf, ATTRalus; Michael Maitland, Intellia Therapeutics, University of Virginia; Michael Roberts, Corino Therapeutics; Michele Mercuri, Alexion/AstraZeneca Rare Disease; Sam Tsimikas, Ionis Pharmaceuticals; Victoria Sanjurjo, Ionis Pharmaceuticals

Medical Writing/Editorial Assistance

Kimberly Denis-Mize provided professional writing services in the preparation of this manuscript and was funded by the Amyloidosis Research Consortium.

Funding

The Amyloidosis Forum is funded by ARC. ARC is funded through private/philanthropic donations and grants from for-profit pharmaceutical and biotechnology companies. ARC retains all influence, control and autonomy over projects for which it has received external support. ARC received grants from Alexion, Alnylam, AstraZeneca and Ionis, GlaxoSmithKline, Intellia Therapeutics, Janssen, ATTRalus, BridgeBio, Pfizer, and Protego in support of the Amyloidosis Forum Advancing Drug Development in ATTR Amyloidosis meeting. ARC was responsible for designing the meeting, co-develo** the meeting agenda and discussion points, production of meeting materials, hosting the virtual meeting, and publications. ARC funded the journal’s Rapid Service Fee. Research reported in this publication was supported by the National Institute on Aging of the National Institute of Health (NIH; Award Number 1R13AG082492-01). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Author information

Authors and Affiliations

  1. Division of Cardiology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA

    Mathew S. Maurer

  2. University of Pittsburgh Medical Center, UPMC Heart and Vascular Institute, Cardiac Amyloidosis Center, Pittsburg, PA, USA

    Prem Soman

  3. Duke University School of Medicine, Duke Clinical Research Center, Durham, NC, USA

    Adrian Hernandez

  4. Hospital Universitario Puerta de Hierro Majadahonda, IDIPHISA, CIBERCV, Madrid, Spain

    Pablo Garcia-Pavia

  5. Spanish National Cardiovascular Research Institute (CNIC), Madrid, Spain

    Pablo Garcia-Pavia

  6. Analysis Group, Boston, MA, USA

    James Signorovitch

  7. T.H. Chan School of Public Health, Biostatistics, Harvard University, Boston, MA, USA

    L. J. Wei

  8. Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH, USA

    Mazen Hanna

  9. Chobanian and Avedisian School of Medicine, Department of Medicine, Boston University, Boston, MA, USA

    Frederick L. Ruberg

  10. Cedars-Sinai, Smidt Heart Institute, Los Angeles, CA, USA

    Michelle Kittleson

  11. Beth Israel Deaconess Medical Center, Cardiac Critical Care Unit; Richard A. and Susan F. Smith Center for Outcomes Research in Cardiology, Health Economics, Boston, MA, USA

    Dhruv Kazi

  12. Brigham and Women’s Hospital, Cardiovascular Medicine, Nuclear Radiology, Boston, MA, USA

    Sharmila Dorbala

  13. Amyloidosis Research Consortium, 320 Nevada Street, Suite 210, Newton, MA, 02460, USA

    Kristen Hsu & Isabelle Lousada

  14. Center for Drug Evaluation and Research, Division of Cardiology and Nephrology, US Food and Drug Administration, Silver Spring, MD, USA

    Rosalyn Adigun

  15. Janssen Research and Development Data Sciences, Cardiovascular/Metabolic and Pulmonary Hypertension, Raritan, NJ, USA

    Preston Dunnmon

  16. Department of Chemistry, Scripps Research Institute, San Diego, CA, USA

    Jeffery Kelly

  17. UK National Amyloidosis Centre, London, UK

    Julian Gillmore

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  1. Mathew S. Maurer
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  2. Prem Soman
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Consortia

the Amyloidosis Forum Meeting Panelists

  • Ahmad Masri
  • , Alanna Morris
  • , Angela Dispenzieri
  • , John Berk
  • , Keith Ferdinand
  • , Keyur Shah
  • , Kristen McCausland
  • , Lynnette Henshaw
  • , Martha Grogan
  • , Megan Azzarone
  • , Michael Polydefkis
  • , Mona Fiuzat
  • , Renee P. Bullock-Palmer
  • , Benjamin Booth
  • , Charu Gandotra
  • , Clemens Mittmann
  • , Cynthia Welsh
  • , Dalia Dawoud
  • , Emmanouil Zouridakis
  • , Francesca Cunningham
  • , Jean-Michel Race
  • , Jie Li
  • , Ken Sakushima
  • , Laura Jawidzik
  • , Michelle Campbell
  • , Motiur Rahman
  • , Norman L. Stockbridge
  • , Rhea Lloyd
  • , Robyn Bent
  • , Sylvia Kuehn
  • , Wiley Chambers
  • , Andrew Slugg
  • , Franca Angeli
  • , Johnathan Fox
  • , Martin Cowie
  • , Matt Meldorf
  • , Michael Maitland
  • , Michael Roberts
  • , Michele Mercuri
  • , Sam Tsimikas
  •  & Victoria Sanjurjo

Contributions

All authors participated in the 21 June 2023 Amyloidosis Forum meeting, which formed the basis for the final manuscript. Mathew Maurer, Julian Gillmore, Prem Soman, Mazen Hanna, Rosalyn Adigun, Preston Dunnmon, Jeffery Kelly, Adrian Hernandez, James Signorovitch, LJ Wei, Pablo Garcia-Pavia, Sharmila Dorbala, Dhruv Kazi, and Kristen Hsu contributed to the content and conceptual design. Isabelle Lousada contributed to the content, conceptual design, and provided patient perspectives. Frederick Ruberg and Michelle Kittleson provided important clinician perspectives. All authors participated in the Forum as either moderator, speaker, or panelist; all authors participated in manuscript preparation and approved the final manuscript.

Corresponding author

Correspondence to Isabelle Lousada.

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Conflict of Interest

Mathew Maurer: Grant support from NIH R01HL139671 and R01AG081582-01; grants and personal fees from Alnylam, Pfizer, Eidos, Prothena, and Ionis; and personal fees from AstraZeneca, Akcea, Intellia, and Novo-Nordisk. Prem Soman: Grant support Pfizer; Personal fees from Alnylam and BridgeBio. Adrian Hernandez: Consultant/scientific advisor to Amgen, AstraZeneca, Bayer, Bioforumis, Bristol Myer Squibb, Boehringer Engelheim, Boston Scientific, Cytokinetics, Eidos/Bridgebio, GlaxoSmith Kline, Intercept Pharmaceuticals, Intellia Therapeutics, MyoKardia, Novartis, NovoNordisk, Pfizer and TikkunLev. Research support from American Heart Association, Aires Pharmaceuticals, Amgen, American Regent, AstraZeneca, Boehringer Engelheim, Bristol-Myers Squibb, Cytokinetics, Intellia Therapeutics, Genentech, GlaxoSmithKleine, Merck, National Heart, Lung, and Blood Institute (NHLBI), Novartis, Patient-Centered Outcomes Research Institute (PCORI), Pfizer and Verily. Pablo Garcia-Pavia: Speaking fees from Pfizer, BridgeBio, Ionis Pharmaceuticals, AstraZeneca, NovoNordisk, Intellia and Alnylam Pharmaceuticals, consulting fees from Pfizer, BridgeBio, Neuroimmune, Alnylam Pharmaceuticals, AstraZeneca, NovoNordisk, ATTRalus, Intellia, General Electric and Alexion, and research/educational support to his institution from Pfizer, BridgeBio and Alnylam Pharmaceuticals. James Signorovitch: Employee of Analysis Group Inc., which provides research and consulting services to biopharma and has received consulting fees from ARC. Mazen Hanna: Served on advisory boards for Pfizer, BridgeBio, Ionis Pharmaceuticals, and Alexion Pharmaceuticals. Frederick Ruberg: Research support: NIH/NHLBI (R01 HL139671), Pfizer, Akcea/Ionis, Alnylam Consulting: ATTRalus, AstraZeneca. Sharmila Dorbala: Grant support from NIH; grants from Pfizer, ATTRalus, Siemens, Phillips; Consulting fees from Pfizer, Novo-Nordisk, BridgeBio. Jeffery Kelly: Consultant/scientific advisor to ATTRalus, George E. Hewitt Foundation for Medical Research, NeoChromosome, Pfizer, Protego, Curebound, Yumanity. Board of Directors member for George E. Hewitt Foundation for Medical Research, Protego, Yumanity. Stock in NeoChromosome, Pfizer, Protego, Yumanity. Julian Gillmore: Consultancy fees from Alnylam, Pfizer, BridgeBio, Ionis, AstraZeneca, ATTRalus, Intellia, Lycia. L J Wei, Michelle Kittleson, Dhruv Kazi, Kristen Hsu, Isabelle Lousada, Rosalyn Adigun, Preston Dunnmon have nothing to disclose.

Ethical Approval

The information contained in this article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors. Permission was received by the Amyloidosis Forum to publish this review article.

Additional information

Food and Drug Administration (FDA) Disclaimer: This article reflects the views of the authors and should not be construed to represent FDA’s views or policies.

Prior Presentation: The information and data in this publication were presented at the Amyloidosis Forum Meeting, Advancing Drug Development in ATTR Amyloidosis in an Evolving Treatment Landscape, held at the US Food and Drug Administration White Oak Campus on 21 June 2023, Silver Spring, MD, USA. Presentations are available at https://amyloidosisforum.org.

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Maurer, M.S., Soman, P., Hernandez, A. et al. Advancing Transthyretin Amyloidosis Drug Development in an Evolving Treatment Landscape: Amyloidosis Forum Meeting Proceedings. Adv Ther 41, 2723–2742 (2024). https://doi.org/10.1007/s12325-024-02891-0

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