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

Role of Myostatin in Muscle Growth: Key Learnings From PK/PD Modeling Analysis 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 www.rosaandco.com/webinar http://www.rosaandco.com/webinar . 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 www.rosaandco.com/webinar http://www.rosaandco.com/webinar . 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 408-480-7314 <mailto:tgordi http://www.rosaandco.com/ www.rosaandco.com The information contained in this e-mail message, e-mail message sequence, and/or any enclosures is confidential, and it may be privileged and protected from unauthorized use and/or disclosure. If you are not the intended recipient, any use, dissemination, distribution, or copying is strictly prohibited. If you received this e-mail in error, PLEASE NOTIFY THE SENDER immediately and destroy this message, any enclosures, and any copies of the message and/or the enclosures. Thank you.

Role of Myostatin in Muscle Growth: Key Learnings From PK/PD Modeling Analysis 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 www.rosaandco.com/webinar http://www.rosaandco.com/webinar . 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 www.rosaandco.com/webinar http://www.rosaandco.com/webinar . 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 408-480-7314 <mailto:[email protected]> [email protected] http://www.rosaandco.com/ www.rosaandco.com The information contained in this e-mail message, e-mail message sequence, and/or any enclosures is confidential, and it may be privileged and protected from unauthorized use and/or disclosure. If you are not the intended recipient, any use, dissemination, distribution, or copying is strictly prohibited. If you received this e-mail in error, PLEASE NOTIFY THE SENDER immediately and destroy this message, any enclosures, and any copies of the message and/or the enclosures. Thank you.