Valérie Cosson (1), Vincent Buchheit (1), Heidemarie Kletzl (1)
(1) Clinical Pharmacology, Pharmaceutical Sciences, Roche Pharma Research & Early Development (pRED), Roche Innovation Center Basel, Switzerland
Objectives: RG6206 (RO7239361) is a fully human anti-myostatin adnectin-IgG1-Fc-fusion protein that binds to and neutralizes the biological activity of myostatin, a protein that prevents muscle cell growth and differentiation. This blockade is expected to lead to larger and stronger muscles in human. The compound is currently in development for the treatment of patients with Duchenne Muscular Dystrophy (DMD). The objectives of the analysis are to describe the PK of RG6206 and the PKPD relationship between total RG6206 and free myostatin serum concentrations in healthy adults (HVs) and DMD patients using the population approach.
Methods: Blood samples for RG6206 and myostatin analysis were collected in two studies after subcutaneous administration: a single and multiple ascending dose study in HVs and a multiple ascending dose study in DMD boys. In total data from 109 HVs and 43 DMD boys were included in this analysis. Both total RG6206 and free myostatin serum concentrations were fitted together using the quasi-steady-state approximation of the full target-mediated drug disposition (TMDD) model [1-3]. HVs and DMD patient data were modelled separately since the bioanalytical methods for measurement of free myostatin were different. All models were developed using non-linear mixed-effects modelling implemented in NONMEM V7.4.0 [4].
Results: Total RG6206 and free myostatin serum concentrations in HVs were well characterized by the TMDD model. The PK was described with a one-compartment model with linear absorption and elimination. A positive feedback control was added on the myostatin endogenous production to describe the rebound of the free myostatin concentrations after the end of the treatment. It is known that increasing levels of active myostatin protein down-regulate its own expression [5,6] and an up-regulation can therefore be expected in case of inhibition of myostatin activity. The BSV on CL/F and V/F were moderate (<29%), and the BSV on Ka was large (83%). The BSV on PKPD parameters were 36% for Ksyn (myostatin production rate), 37% for Kint (RG6206-Myostatin complex degradation rate) and 53% for Kin (moderator production rate). Body weight was found to have a significant effect on CL/F and V/F with exponents fixed to the allometric values, 0.75 for CL/F and 1 for V/F. When the free myostatin is saturated, the half-life of RG6206 is estimated at ~14 days.
In DMD boys, the PK was described by the same model as in HVs but with an additional weight effect on Ka to capture the slower absorption observed with increasing weight. The population CL/F and V/F parameters and their associated weight effect were fixed in DMD boys to those estimated in HVs to ensure PK continuity between the two populations. The limitation of the PD sampling scheme and the absence of sampling after the end of treatment prevented the estimation of all TMDD parameters so Kss and Kint were fixed to those estimated in HVs. Contrary to HVs, the positive feedback control on the myostatin synthesis was not present in DMD boys. The reason is unknown, but does not seem to be due to the sampling scheme since this feedback estimated in HVs should lead to a slow increase of the free myostatin trough levels under treatment and that was not observed in DMD boys. BSV on CL/F and V/F were moderate (<30%) while BSV on Ka and Ksyn were large 60 and 80% respectively. The body weight effect on CL/F and V/F of RG6206 in DMD boys could be well captured by the allometric coefficients used in the HVs model. The simulations show that the PK and PD steady states were reached after ~12 and 6 weeks, respectively, of QW administration of RG6206 to DMD boys weighing 16 to 46 kg. At steady-state, RG6206 maintains a reduction in free myostatin from baseline of ~77, 92 and 97% over the dosing interval with the weekly 4, 12.5 and 35 mg dose, respectively.
Conclusions: The PK of RG6206 and its effect on the free myostatin in HVs were accurately described by a model based on the TMDD concept with a positive feedback on the synthesis of myostatin. In DMD boys, a similar PKPD model structure as in adult HVs could accurately described the data however no positive feedback was needed.
References:
[1] G. Levy. Pharmacologic target-mediated drug disposition. Clin. Pharmacol. Ther. 1994; 56: 248–252
[2] D. E. Mager and W. J. Jusko. General Pharmacokinetic Model for Drugs Exhibiting Target-Mediated Drug Disposition. J. Pharmacokin. Pharmacodyn. 28:507-532 (2001).
[3] L. Gibiansky, E. Gibiansky, T. Kakkar, P Ma. Approximations of the target-mediated drug disposition model and identifiability of model parameters. J Pharmacokinet Pharmacodyn. 2008; 35(5): 573–59
[4] S. L. Beal, L. B. Sheiner, A. J. Boeckmann, and R. J. Bauer (Eds.). NONMEM Users Guides. 1989-2011. Icon Development Solutions, Ellicott City, Maryland, USA.
[5] C. McFarlane, et al. Proteolytic processing of myostatin is auto-regulated during myogenesis. Developmental Biology. 2005;283:58 – 69
[6] D. Forbes, et al. Myostatin auto-regulates its expression by feedback loop through Smad7 dependent mechanism. J Cell Physiol. 2006; 206: 264–272.
Reference: PAGE 28 (2019) Abstr 8821 [www.page-meeting.org/?abstract=8821]
Poster: Drug/Disease Modelling - Endocrine