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The Clinical Development of Taldefgrobep Alfa: An Anti-Myostatin Adnectin for the Treatment of Duchenne Muscular Dystrophy

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2024年1月8日

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  • Francesco Muntoni,
  • Barry J. Byrne,
  • Hugh J. McMillan,
  • Monique M. Ryan,
  • Brenda L. Wong,
  • Juergen Dukart,
  • Amita Bansal,
  • Valerie Cosson,
  • Roxana Dreghici,
  • Maitea Guridi,
  • Michael Rabbia,
  • Hannah Staunton,
  • Giridhar S. Tirucherai,
  • Karl Yen,
  • Xiling Yuan,
  • Kathryn R. Wagner,
  • Irvith Carvajal,
  • Anjaneya Chimalakonda,
  • Jochem Gokemeijer,
  • Michael Gulianello,
  • Nicole Hellbach,
  • Alexander Kozhich,
  • Daniel Kukral,
  • Harold Malone,
  • Jere E. Meredith Jr,
  • Mathew Pletcher,
  • Ginger Rakestraw,
  • Lumelle Schneeweis,
  • Joanna Swain,
  • Frank Zambito,
  • Ming Chang,
  • Lora Hamuro,
  • Feng Luo,
  • Jon E. Peterson,
  • Peter Hocknell,
  • Zhen Lou,
  • Malavi Madireddi,
  • Mathew Pletcher,
  • Clifford M. Bechtold,
  • Michael K. Ahlijanian,
  • Ming Chang,
  • Lora Hamuro,
  • Leslie K. Jacobsen,
  • Alexander Kozhich,
  • Feng Luo,
  • Jon E. Peterson,
  • Frank Zambito,
  • Heidemarie Kletzl,
  • Alberto L. Dubrovsky,
  • Lilia Mesa,
  • Fernando Chloca,
  • Agustin Jauregu,
  • Kristi Jones,
  • Monique Ryan,
  • Craig Campbell,
  • Jean Mah,
  • Alice Ho,
  • Angela Chiu,
  • Vanessa D’Souza,
  • Raymy Sadowski,
  • Julie Dao,
  • Michaela Grice,
  • Tiffany Price,
  • Hugh McMillan,
  • Erick Sell,
  • Anna McCormick,
  • Teresa Gidaro,
  • Andrea Seferian,
  • Yann Péréon,
  • Armelle Magot,
  • Carole Vuillerot,
  • Ulrike Schara-Schmidt,
  • Valerie Sansone,
  • Emilio Albamonte,
  • Alessandra Di Bari,
  • Jasmine Refran,
  • Francesca Salmin,
  • Giuseppe Vita,
  • Gian Luca Vita,
  • Chiara Consulo,
  • Hirofumi Komaki,
  • Akihiko Ishiyama,
  • Tsuyoshi Matsumura,
  • Toshio Saito,
  • Kana Ichihara,
  • Naoki Hayashi,
  • Kouji Terada,
  • Kenji Takehara,
  • Nobuko Hayashi,
  • Yasuhiro Takeshima,
  • Andres Nascimiento,
  • Daniel Natera,
  • Laura Carrera,
  • Jesica Exposito,
  • Carlos Ortez,
  • Julita Medina,
  • Obdulia Moya,
  • Sandra Roca,
  • Alicia Rodriguez,
  • Maria Valle,
  • Imelda J. M. de Groot,
  • Erik H. Niks,
  • Marjolein J. van Heur-Neuman,
  • Menno van der Holst,
  • Mariacristina Scoto,
  • Chiara Brusa,
  • Abidha Afazal,
  • Eveline Miller,
  • Barry J. Byrne,
  • Linda Cripe,
  • Richard S. Finkel,
  • Peter Heydemann,
  • Katherine Matthews,
  • Chandra Miller,
  • Katie Laubsher,
  • Shelley Mockeler,
  • Han Phan,
  • Kumaraswamy Sivakumar,
  • Kristy Osgood,
  • Jeffrey Statland,
  • Cuixia Tian,
  • Kathryn R. Wagner,
  • Doris Leung,
  • Genila Bibat,
  • Nikia Stinson,
  • Laurent Servais,
  • Eugenio Mercuri,
  • Tina Duong,
  • Mariacristina Scoto,
  • Craig Campbell,
  • Paul Strijbos,
  • Klaas Veenstra

摘要

Introduction

Duchenne muscular dystrophy (DMD) is a genetic muscle disorder that manifests during early childhood and is ultimately fatal. Recently approved treatments targeting the genetic cause of DMD are limited to specific subpopulations of patients, highlighting the need for therapies with wider applications. Pharmacologic inhibition of myostatin, an endogenous inhibitor of muscle growth produced almost exclusively in skeletal muscle, has been shown to increase muscle mass in several species, including humans. Taldefgrobep alfa is an anti-myostatin recombinant protein engineered to bind to and block myostatin signaling. Preclinical studies of taldefgrobep alfa demonstrated significant decreases in myostatin and increased lower limb volume in three animal species, including dystrophic mice.

Methods

This manuscript reports the cumulative data from three separate clinical trials of taldefgrobep alfa in DMD: a phase 1 study in healthy adult volunteers (NCT02145234), and two randomized, double-blind, placebo-controlled studies in ambulatory boys with DMD–a phase 1b/2 trial assessing safety (NCT02515669) and a phase 2/3 trial including the North Star Ambulatory Assessment (NSAA) as the primary endpoint (NCT03039686).

Results

In healthy adult volunteers, taldefgrobep alfa was generally well tolerated and resulted in a significant increase in thigh muscle volume. Treatment with taldefgrobep alfa was associated with robust dose-dependent suppression of free myostatin. In the phase 1b/2 trial, myostatin suppression was associated with a positive effect on lean body mass, though effects on muscle mass were modest. The phase 2/3 trial found that the effects of treatment did not meet the primary endpoint pre-specified futility analysis threshold (change from baseline of ≥ 1.5 points on the NSAA total score).

Conclusions

The futility analysis demonstrated that taldefgrobep alfa did not result in functional change for boys with DMD. The program was subsequently terminated in 2019. Overall, there were no safety concerns, and no patients were withdrawn from treatment as a result of treatment-related adverse events or serious adverse events.

Trial Registration

NCT02145234, NCT02515669, NCT03039686.