Dimitris Papanicolaou

A phase IIA randomized, placebo-controlled clinical trial to study the efficacy and safety of the selective androgen receptor modulator (SARM), MK-0773 in female participants with sarcopenia

BackgroundSarcopenia, the age-related loss of muscle mass [defined as appendicular LBM/Height2 (aLBM/ht2) below peak value by>1SD], strength and function, is a major contributing factor to frailty in the elderly. MK-0773 is a selective androgen receptor modulator designed to improve muscle function while minimizing effects on other tissues.ObjectivesThe primary objective of this study was to demonstrate an improvement in muscle strength and lean body mass (LBM) in sarcopenic frail elderly women treated with MK-0773 relative to placebo.DesignThis was a randomized, double-blind, parallel-arm, placebo-controlled, multicenter, 6-month study. Participants were randomized in a 1:1 ratio to receive either MK-0773 50mg b.i.d. or placebo; all participants received Vitamin D and protein supplementation.SettingGeneral community.Participants170 Women aged ≥65 with sarcopenia and moderate physical dysfunction.MeasurementsDual energy X-ray absorptiometry, muscle strength and power, physical performance measures.ResultsParticipants receiving MK-0773 showed a statistically significant increase in LBM from baseline at Month 6 vs. placebo (p<0.001). Participants receiving both MK-0773 and placebo showed a statistically significant increase in strength from baseline to Month 6, but the mean difference between the two groups was not significant (p=0.269). Both groups showed significant improvement from baseline at Month 6 in physical performance measures, but there were no statistically significant differences between participants receiving MK-0773 and placebo. A greater number of participants experienced elevated transaminases in the MK-0773 group vs. placebo, which resolved after discontinuation of study therapy. MK-0773 was generally well-tolerated with no evidence of androgenization.ConclusionsThe MK-0773-induced increase in LBM did not translate to improvement in strength or function vs. placebo. The improvement of strength and physical function in the placebo group could be at least partly attributed to protein and vitamin D supplementation.

Effects of bimagrumab, an activin receptor type II inhibitor, on pituitary neurohormonal axes

Bimagrumab is a human monoclonal antibody inhibitor of activin type II receptors (ActRII), with anabolic action on skeletal muscle mass by blocking binding of myostatin and other negative regulators of muscle growth. Bimagrumab is under evaluation for muscle wasting and associated functional loss in hip fracture and sarcopenia, and in obesity. Bimagrumab also blocks other endogenous ActRII ligands, such as activins, which act on the neurohormonal axes, pituitary, gonads and adrenal glands.

AB0687 Non-Invasive Assessment of Muscle Quality by MRI as a Potential Marker of Disease Modification in Bimagrumab-Treated SIBM Patients

Background Bimagrumab is a monoclonal antibody that inhibits ligand binding to the activin receptor IIA/B thereby stimulating muscle growth. In a proof of concept study, bimagrumab increased thigh muscle volume (TMV) by 6.5% (p=0.024) and decreased intramuscular adipose tissue (IMAT) by 3% (p=n.s.) after 8 weeks of treatment. Objectives Using qualitative muscle MRI to characterize disease severity and modification in sporadic inclusion body myositis (sIBM) patients treated with bimagrumab. Methods 14 patients were randomized to single IV dose (30 mg/kg) of bimagrumab (n=11) or placebo (n=3). Disease severity was assessed by visual scoring of PD images. TMV, IMAT, subcutaneous (SC) adipose tissue volume, and individual muscle volume (IMV) were determined from proton-density (PD) MR images using semi-automated segmentation approaches. In addition, the relative fat fraction (%FF) and apparent coefficient of diffusion (ADC) were measured from three-point Dixon and diffusion-weighted images, respectively. Results After 8 weeks of treatment, mean score for disease activity (21.5±0.6) remained unchanged. Although insignificant, decrease in %FF (−7% vs baseline) was seen at Week-8 in 4 patients while SC and IMAT volumes were slightly reduced. At baseline, fat-infiltrated muscles had lower ADC values than previously reported (1.46±0.11 vs 1.62±0.14 x10-3 mm2/sec) and a trend towards normal values was observed after treatment. At baseline, IMAT content was greater in anterior than in posterior thigh muscles (49% vs 23%, p<0.01). Individual muscle volumes (IMV) increased more in the posterior (+8%) than in anterior thigh compartment (+4%, p<0.01). At Week-16, further decrease in IMAT in all muscles (-7% vs baseline, p<0.05) correlated well with the change from baseline in IMV at Week-8 (r=0.57, p<0.05). Conclusions MRI may be used in a comprehensive non-invasive way to demonstrate potential of bimagrumab as a disease-modifying therapy which may potentially lead to restoration of normal muscle quality and composition. References Amato AA et al. Neurology. 2014;83(24):2239-46. Qi J et al. J Magn Reson Imaging. 2008;27(1):212-7. Acknowledgements Study Supported By: Novartis Pharma AG Disclosure of Interest D. Laurent Shareholder of: Novartis, Employee of: Novartis Institutes for Biomedical Research, Basel, Switzerland, B. Tseng Employee of: Novartis Institutes for Biomedical Research, Cambridge, USA, S. Greenberg Grant/research support from: Novartis Pharma AG, P. Houston Employee of: Novartis Pharma AG, Basel, Switzerland, D. Papanicolaou Employee of: Novartis Pharmaceuticals Corporation, East Hanover, USA, R. Roubenoff Employee of: Novartis Institutes for Biomedical Research, Basel, Switzerland.