Randomized phase 2 study of<scp>ACE</scp>‐083, a<scp>muscle‐promoting</scp>agent, in facioscapulohumeral muscular dystrophy

Statland, Jeffrey; Campbell, Craig; Desai, Urvi; Karam, Chafic; Díaz-Manera, Jordi; Guptill, Jeffrey T.; Genge, Angela; Tawil, Rabi; Elman, Lauren; Joyce, Nanette C.; Wagner, Kathryn R.; Manousakis, Georgios; Amato, Anthony A.; Butterfield, Russell J.; Shieh, Perry B.; Wicklund, Matthew; Gamez, Josep; Bodkin, Cynthia; Pestronk, Alan; Weihl, Conrad C.; Vílchez-Padilla, J.J.; Johnson, Nicholas E.; Mathews, Katherine D.; Miller, Barry; Leneus, Ashley; Fowler, Marcie; Rijn, Marc van de; Attie, Kenneth M.

doi:10.1002/mus.27558

Cited by 14 publications

(12 citation statements)

References 32 publications

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“…One example is the phase I/IIA clinical trial for the use of a follistatin construct introduced via an adeno-associated virus for the treatment of Becker muscular dystrophy [ 108 ]. Recombinant follistatin has also been developed, such as ACE-083, although results on its efficacy against facioscapulohumeral muscular dystrophy conditions have not been promising [ 107 , 109 ]. Furthermore, because other isoforms of activin and inhibin have not been identified as relevant in PAH conditions, other agents that could restore the balance of activin/inhibin signaling have not been thoroughly investigated in clinical settings.…”

Section: Clinical Landscape Of Activin-targeting Treatments In Pahmentioning

confidence: 99%

Inactivating the Uninhibited: The Tale of Activins and Inhibins in Pulmonary Arterial Hypertension

Ryanto

Musthafa

Hara

et al. 2023

IJMS

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Advances in technology and biomedical knowledge have led to the effective diagnosis and treatment of an increasing number of rare diseases. Pulmonary arterial hypertension (PAH) is a rare disorder of the pulmonary vasculature that is associated with high mortality and morbidity rates. Although significant progress has been made in understanding PAH and its diagnosis and treatment, numerous unanswered questions remain regarding pulmonary vascular remodeling, a major factor contributing to the increase in pulmonary arterial pressure. Here, we discuss the role of activins and inhibins, both of which belong to the TGF-β superfamily, in PAH development. We examine how these relate to signaling pathways implicated in PAH pathogenesis. Furthermore, we discuss how activin/inhibin-targeting drugs, particularly sotatercep, affect pathophysiology, as these target the afore-mentioned specific pathway. We highlight activin/inhibin signaling as a critical mediator of PAH development that is to be targeted for therapeutic gain, potentially improving patient outcomes in the future.

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Section: Clinical Landscape Of Activin-targeting Treatments In Pahmentioning

confidence: 99%

Inactivating the Uninhibited: The Tale of Activins and Inhibins in Pulmonary Arterial Hypertension

Ryanto

Musthafa

Hara

et al. 2023

IJMS

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“…Another follistatin-based fusion protein, ACE-083, also induced localized skeletal muscle hypertrophy and increased focal force generation in a mouse model [149]. However, in a phase II trial of ACE-083, treatment increased muscle mass but did not improve functional outcomes [150]. Associated virus (AAV) serotype 1.…”

Section: Follistatin Fusion Protein and Gene Therapymentioning

confidence: 99%

Sarcopenia in chronic kidney disease: from bench to bedside

Kim¹,

Song²

2023

Korean J Intern Med

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Sarcopenia is a condition characterized by a loss of muscle mass and function. In chronic kidney disease (CKD), where a chronic catabolic state exists, sarcopenia commonly occurs through various mechanisms, resulting in muscle wasting and decreased muscle endurance. Sarcopenic patients with CKD have high morbidity and mortality rates. Indeed, the prevention and treatment of sarcopenia are mandatory. An imbalance between protein synthesis and degradation in muscle and increased oxidative stress and inflammation persist in CKD and induce muscle wasting. In addition, uremic toxins negatively affect muscle maintenance. A variety of potential therapeutic drugs targeting these muscle-wasting mechanisms in CKD have been investigated, but most of the trials focused on aged patients without CKD, and none of these drugs have been approved for the treatment of sarcopenia so far. Further studies on the molecular mechanisms of sarcopenia in CKD and targets for potential therapeutics are needed to improve the outcomes of sarcopenic patients with CKD.

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“…Often, a single trial does not provide a straightforward answer, as myostatin inhibition failed for different reasons in different trials [ 139 ]. Importantly, circulating baseline levels of myostatin are higher in FSHD than in DMD, and the ACE-083 trial demonstrated significant muscle hypertrophy (without an increase in strength) in treated FSHD patients [ 36 ]. Thus, it is conceivable that in combination with a DUX4-targeting therapy, myostatin inhibition might increase muscle function as well as size in FSHD.…”

Section: Dux4-independent Approachesmentioning

confidence: 99%

“…The creation of FSHD-specific therapeutics has been understandably hampered by these challenges, and in the interim, easier avenues have been explored, including compensatory treatments to improve muscle strength or health [ 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ] ( Identifiers: NCT02927080, NCT02603562), immunomodulation ( Identifier: NCT02579239), and most recently, the repurposed FDA-approved drug losmapimod [ 37 ] ( Identifiers: NCT04003974, NCT04264442). Thus far, these treatments have either failed or yielded underwhelming results in clinical trials.…”

Section: Introductionmentioning

confidence: 99%

FSHD Therapeutic Strategies: What Will It Take to Get to Clinic?

Himeda

Jones

2022

JPM

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Facioscapulohumeral muscular dystrophy (FSHD) is arguably one of the most challenging genetic diseases to understand and treat. The disease is caused by epigenetic dysregulation of a macrosatellite repeat, either by contraction of the repeat or by mutations in silencing proteins. Both cases lead to chromatin relaxation and, in the context of a permissive allele, pathogenic misexpression of DUX4 in skeletal muscle. The complex nature of the locus and the fact that FSHD is a toxic, gain-of-function disease present unique challenges for the design of therapeutic strategies. There are three major DUX4-targeting avenues of therapy for FSHD: small molecules, oligonucleotide therapeutics, and CRISPR-based approaches. Here, we evaluate the preclinical progress of each avenue, and discuss efforts being made to overcome major hurdles to translation.

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Randomized phase 2 study ofACE‐083, amuscle‐promotingagent, in facioscapulohumeral muscular dystrophy

Abstract: Introduction/Aims: Facioscapulohumeral muscular dystrophy (FSHD) is a slowly progressive muscular dystrophy without approved therapies. In this study we evaluated whether locally acting ACE-083 could safely increase muscle volume and improve functional outcomes in adults with FSHD.

Cited by 14 publications

References 32 publications

Inactivating the Uninhibited: The Tale of Activins and Inhibins in Pulmonary Arterial Hypertension

Inactivating the Uninhibited: The Tale of Activins and Inhibins in Pulmonary Arterial Hypertension

Sarcopenia in chronic kidney disease: from bench to bedside

FSHD Therapeutic Strategies: What Will It Take to Get to Clinic?

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