Garito, Tania (2018) PhD Thesis of Tania Garito, MD: THE METABOLIC IMPLICATIONS OF CHANGES IN BODY COMPOSITION. Thesis, University of Milan.

Abstract

Development of a new drug product in pharmacology is a complex, expensive and time-consuming process: only one out of 5.000-10.000 candidates actually reaches the market, at a cost that is on average 1.4 billion dollars [DiMasi 2015].
There are multiple phases of drug development and the first are the discovery, identification and characterization of drug candidates. On average, 250 molecules are then tested in preclinical studies on animals, to elucidate safety, pharmacological effect and pharmacokinetics; up to 5 promising compounds are tested, first in small human studies in Phase 1, followed by larger studies (Phase 2), which assess efficacy, safety and tolerability under longer exposure, and seek to define the optimum dose. Only one of these molecules reaches Phase 3, the large-scale efficacy and safety studies, which provide the basis for market approval. Phase 3 trials are then followed by a period of intense review by Regulatory Authorities that ultimately bring to product labeling and to the final phase, approval and post-marketing surveillance; to reach this phase the lifecycle of the drug takes approximately 12 years [IFPMA 2017].

Bimagrumab is a human monoclonal antibody that blocks type II activin receptors (ActRII A and B), preventing the binding of their natural ligands – myostatin, activins, and growth and differentiation factor 11 (GDF-11). Bimagrumab is being developed to target muscle weakness conditions, namely sarcopenia and hip fracture recovery, and obesity [Rooks 2017, Garito 2017]. A number of preclinical studies have been conducted with bimagrumab: results in animal models, either mice or rats, showed muscle hypertrophy, up to 25%-50%, increased muscle volume, prevention of glucocorticoid induced atrophy, inhibition of cancer cachexia and sarcopenia, and increased brown adipose tissue [Lach-Trifilief 2014, Fournier 2012]. The first-in-human study was initiated in 2010 and showed safety and tolerability of bimagrumab in healthy volunteers; nineteen subsequent studies confirmed safety and tolerability as well as PK and efficacy of bimagrumab in healthy volunteers and many different patient populations. Results from human studies confirmed the increase of muscle mass and showed a significant decrease of fat mass with an overall improvement of body composition [Amato 2014, Rooks 2017, Garito 2017].
The BYM338X2206 trial was designed to verify the possible translation of fat loss into an improvement in insulin sensitivity in a population of insulin resistant adults, while the BYM338X2108 trial was designed to test any possible interference with neurohormonal pathways which could lead to safety issues. The results from these two studies were promising, confirmed the effect on muscle mass, by a mean increase of 2.7%, with a decrease by 7.9% of fat mass over placebo and a significant improvement of glycated hemoglobin (HbA1c) in insulin resistant subjects; no significant changes in circulating androgens emerged in both sexes, but a significant decrease in FSH levels was observed in post-menopausal women.
The BYM338X2211 study is currently ongoing (ClinicalTrials.gov number: NCT03005288), to verify whether the observations on body composition and related metabolic improvement from Phase 1 studies translate into an effect in a population of obese diabetic patients.

Item Type:	Article
Date Deposited:	28 Aug 2018 00:45
Last Modified:	28 Aug 2018 00:45
URI:	https://oak.novartis.com/id/eprint/35979