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Next Rosa Webinar: Role of Myostatin in Muscle Growth: Key Learnings From PK/PD Modeling Analysis

From: Toufigh Gordi <tgordi>
Date: Thu, 27 Sep 2012 19:35:19 -0700

Role of Myostatin in Muscle Growth: Key Learnings From PK/PD Modeling =

By Pratrap Singh, PhD

Senior Principal Scientist, Pfizer

October 17, 2012, 1:00 PM - 2:00 PM EDT

 Suppression of the myostatin (GDF-8) pathway is considered an important =
therapeutic strategy for the treatment of muscle-wasting disorders, =
including muscular dystrophy, cachexia and sarcopenia. Myostatin is a =
member of TGF-β superfamily and negatively regulates skeletal =
muscle mass, muscle fiber size, and fiber count. Clinical trials =
targeting the myostatin pathways have produced mixed results. ACE-031, a =
Fc fusion of ActRIIB, is a decoy receptor for GDF-8. ACE-O31 was =
reported to increase muscle mass in Phase I/II trials with healthy =
post-menopausal women and in patients with Duchenne muscular dystrophy =
(DMD). In contrast, an antibody against myostatin, MYO-029, failed to =
achieve clinical efficacy in DMD patients. Given these contrasting =
results, it is critical to understand whether the clinical and =
preclinical data support GDF-8 as a novel paradigm for the treatment of =
muscular dystrophy disease. We performed a detailed =
pharmacokinetic-pharmacodynamic (PK/PD) analysis of preclinical and =
clinical data on MYO-029 to address animal model translation and predict =
the level of target inhibition at the clinical doses. A combination of =
mouse, non-human primates, and clinical data were analyzed, and =
exposure-response relationships were established for various =
pharmacodynamic endpoints. These included muscle weight increase in SCID =
mice efficacy studies, muscle circumference changes in a 39-week =
toxicology study in monkeys, and total myostatin levels observed in =
multiple-ascending dose (MAD) studies in Phase I/II trials. Our modeling =
analysis revealed a significant, in-vivo potency shift between mice and =
monkeys species. Further, our results showed that the exposures of =
Myo-029 in humans had low probability of success in modulating the =
target or in providing robust efficacy. The PK/PD analysis presented in =
this report supported the rationale for therapeutic strategies targeting =
the myostatin pathway.

The purpose of the "Impact" series is to foster the use of M&S =
activities in all phases of drug development by illustrating the =
advantages and enhancing the applicability of M&S in product discovery, =
development, and marketing programs. The series is intended for drug =
development project team members from discovery to phase 4 clinical =
trials. This includes pharmacologists, ADME scientists, PK/PD modelers, =
clinical pharmacologists, clinical development team members, regulatory =
affairs specialists, and other interested professionals.
Register for this free webinar at =
<> . After registering you will receive =
a confirmation email containing information about joining the webinar. =
More information about the webinar series, an archive of past webinars, =
and a list of future webinar speakers may be found at = <> .
Please allow 5-10 minutes for a Java applet to be installed on your =
computer prior to joining our webinar series for the first time.

Toufigh Gordi, PhD

President PK/PD and Clinical Pharmacology Services

Rosa & Co. LLC

751 Laurel St., Ste. 127,

San Carlos, CA 94070





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Received on Thu Sep 27 2012 - 22:35:19 EDT

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