P3.18 A Phase 1 multiple ascending dose study to assess the pharmacodynamic effects of ACE-031, an inhibitor of negative muscle regulators, in healthy volunteers

Borgstein, Niels; Barger, Rachel; Yang, Yung‐Kuang; Wilson, Dorian; Haltom, Eric; Attie, Kenneth M.; Sherman, Michael

doi:10.1016/j.nmd.2010.07.160

Cited by 3 publications

(1 citation statement)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition to this review, a potential impact of disease on exposure of biologics was also explored. It was found that ACE‐031, a soluble fusion protein comprised of an extracellular domain of a form of activin receptor type IIb linked to Fc region of IgG1, showed similar PK between DMD pediatric patients and postmenopausal women . Albeit only for 1 molecule, the ACE‐031 example suggested that there was no obvious reason to expect an impact of DMD disease on large‐molecule kinetics.…”

Section: Discussionmentioning

confidence: 99%

Application of Quantitative Pharmacology Approaches in Bridging Pharmacokinetics and Pharmacodynamics of Domagrozumab From Adult Healthy Subjects to Pediatric Patients With Duchenne Muscular Disease

Bhattacharya

Manukyan

Chan

et al. 2017

The Journal of Clinical Pharma

View full text Add to dashboard Cite

Domagrozumab, a monoclonal antibody that binds to myostatin, is being developed for Duchenne muscular dystrophy (DMD) boys following a first-in-human study in healthy adults. Literature reporting pharmacokinetic parameters of monoclonal antibodies suggested that body-weight- and body-surface-area-adjusted clearance and volume of distribution estimates between adults and children are similar for subjects older than 6 years. Population modeling identified a Michaelis-Menten binding kinetics model to optimally characterize the target mediated drug disposition profile of domagrozumab and identified body mass index on the volume of distribution as the only significant covariate. Model parameters were predicted with high-precision pharmacokinetics (clearance 1.01 × 10 L/[h·kg]; central volume of distribution 457 × 10 L/kg; maximum elimination rate 17.5 × 10 nmol/[h·kg], Km 10.6 nmol/L) and pharmacodynamics (myostatin turnover rate 457 × 10 h ; complex removal rate 90 × 10 h ; half-saturation constant 4.32 nmol/L) and were used to predict target coverage for dosage selection in the DMD population. Additionally, allometric approaches (estimated scaling exponents (standard error) for clearance and volume were 0.81 [0.01] and 0.98 [0.02], respectively) in conjunction with a separate analysis to obtain the population mean weight and standard deviation suggested that if dosed per body weight, an only 11% difference in clearance is expected between the heaviest and lightest patient, thus preventing the need for dose adjustment. In summary, quantitative approaches were instrumental in bridging and derisking the fast-track development of domagrozumab in DMD.

show abstract

Section: Discussionmentioning

confidence: 99%

Application of Quantitative Pharmacology Approaches in Bridging Pharmacokinetics and Pharmacodynamics of Domagrozumab From Adult Healthy Subjects to Pediatric Patients With Duchenne Muscular Disease

Bhattacharya

Manukyan

Chan

et al. 2017

The Journal of Clinical Pharma

View full text Add to dashboard Cite

show abstract

Myostatin – The Holy Grail for Muscle, Bone, and Fat?

Buehring

Binkley

2013

Curr Osteoporos Rep

View full text Add to dashboard Cite

Myostatin, a member of the transforming growth factor beta (TGF-β) superfamily, was first described in 1997. Since then, myostatin has gained growing attention because of the discovery that myostatin inhibition leads to muscle mass accrual. Myostatin not only plays a key role in muscle homeostasis, but also affects fat and bone. This review will focus on the impact of myostatin and its inhibition on muscle mass/function, adipose tissue and bone density/geometry in humans. Although existing data are sparse, myostatin inhibition leads to increased lean mass and 1 study found a decrease in fat mass and increase in bone formation. In addition, myostatin levels are increased in sarcopenia, cachexia and bed rest whereas they are increased after resistance training, suggesting physiological regulatory of myostatin. Increased myostatin levels have also been found in obesity and levels decrease after weight loss from caloric restriction. Knowledge on the relationship of myostatin with bone is largely based on animal data where elevated myostatin levels lead to decreased BMD and myostatin inhibition improved BMD. In summary, myostatin appears to be a key factor in the integrated physiology of muscle, fat, and bone. It is unclear whether myostatin directly affects fat and bone, or indirectly via muscle. Whether via direct or indirect effects, myostatin inhibition appears to increase muscle and bone mass and decrease fat tissue-a combination that truly appears to be a holy grail. However, at this time, human data for both efficacy and safety are extremely limited. Moreover, whether increased muscle mass also leads to improved function remains to be determined. Ultimately potential beneficial effects of myostatin inhibition will need to be determined based on hard outcomes such as falls and fractures.

show abstract

Gene expression profiling of skeletal muscles treated with a soluble activin type IIB receptor

Rahimov

King

Warsing

et al. 2011

Physiological Genomics

View full text Add to dashboard Cite

Inhibition of the myostatin signaling pathway is emerging as a promising therapeutic means to treat muscle wasting and degenerative disorders. Activin type IIB receptor (ActRIIB) is the putative myostatin receptor, and a soluble activin receptor (ActRIIB-Fc) has been demonstrated to potently inhibit a subset of transforming growth factor (TGF)-β family members including myostatin. To determine reliable and valid biomarkers for ActRIIB-Fc treatment, we assessed gene expression profiles for quadriceps muscles from mice treated with ActRIIB-Fc compared with mice genetically lacking myostatin and control mice. Expression of 134 genes was significantly altered in mice treated with ActRIIB-Fc over a 2-wk period relative to control mice (fold change > 1.5, P < 0.001), whereas the number of significantly altered genes in mice treated for 2 days was 38, demonstrating a time-dependent response to ActRIIB-Fc in overall muscle gene expression. The number of significantly altered genes in Mstn(-/-) mice relative to control mice was substantially higher (360), but for most of these genes the expression levels in the 2-wk treated mice were closer to the levels in the Mstn(-/-) mice than in control mice (P < 10⁻³⁰). Expression levels of 30 selected genes were further validated with quantitative real-time polymerase chain reaction (qPCR), and a correlation of ≥ 0.89 was observed between the fold changes from the microarray analysis and the qPCR analysis. These data suggest that treatment with ActRIIB-Fc results in overlapping but distinct gene expression signatures compared with myostatin genetic mutation. Differentially expressed genes identified in this study can be used as potential biomarkers for ActRIIB-Fc treatment, which is currently in clinical trials as a therapeutic agent for muscle wasting and degenerative disorders.

show abstract

P3.18 A Phase 1 multiple ascending dose study to assess the pharmacodynamic effects of ACE-031, an inhibitor of negative muscle regulators, in healthy volunteers

Cited by 3 publications

References 0 publications

Application of Quantitative Pharmacology Approaches in Bridging Pharmacokinetics and Pharmacodynamics of Domagrozumab From Adult Healthy Subjects to Pediatric Patients With Duchenne Muscular Disease

Application of Quantitative Pharmacology Approaches in Bridging Pharmacokinetics and Pharmacodynamics of Domagrozumab From Adult Healthy Subjects to Pediatric Patients With Duchenne Muscular Disease

Myostatin – The Holy Grail for Muscle, Bone, and Fat?

Gene expression profiling of skeletal muscles treated with a soluble activin type IIB receptor

Contact Info

Product

Resources

About