An empirical drug-disease model to characterize the effect of Ranibizumab on disease progression in wet AMD patients
Cheikh Diack, Dietmar Schwab, Nicolas Frey
F. Hoffmann-La Roche Ltd
Objectives: Ranibizumab, an anti-VEGF is the standard of care for the wet form age-related macular degeneration (AMD). The characterization of the time course of visual acuity with and without anti-VEGF treatment may prove useful for the development of new drugs.
Methods: A drug-disease model for visual acuity was developed on the 24-month patient level data of 2 phase 3 monthly dosing trials of Ranibizumab (~1100 patients including ~230 untreated patients). Adaptations of a model in [1] combined with a K-PD approach to account for the change in dosing frequency over time and an Emax model to represent the drug effect were fitted to the data(cf. (1) and (2)) .
(1) VAt=VA0 -(VA0-VAss).(1-EXP(-kpr.t))+Emax.IR/(E50+IR)
(2) VAt=VA0 -(VA0-VAss).(1-EXP(-kpr(1-IR/(Ed50+IR)).t))+Emax.IR/(E50+IR)
VAt, VA0 and VAss are respectively the visual acuity at time t, at entry in trial and at steady state when the patient is not treated. IR is proportional to the amount of drug a time t; kpr represents the rate of progression of the disease.
Several baseline covariates were tested on model parameters. The final model was further tested against 2 other phase 3 trials of Ranibizumab with different dosing regimen (including monthly, quarterly and PRN dosing, ~ 1200 patients).
Results: Model (2) was preferred over (1) as it was shown using a deconvolution process, that to adequately describes the data, the model parameter kpr is affected by the treatment in a manner which slows down wet AMD progression. It was shown that some baseline covariates have an influence on the model parameters VA0, Kpr and E50. The time course of visual acuity from trials not used during model development were adequately described using only the baseline characteristics of patients.
Conclusions: The dynamic of visual acuity for wet AMD patients with or without treatment was characterized using a disease model. The influences of several baseline covariates were tested on model parameters and relevant covariates were included in the final model. The final model suggests two sites of effect of Ranibizumab: an additive (symptomatic) effect and an effect slowing down the progression of the disease (protective effect). The low E50 compared to Ed50, suggests that Ranibizumab is more potent for restoring the visual acuity than for slowing down wet AMD progression. The model was successfully tested against trial data of different dose and dosing regimen to data used for its development. This suggests that the model can suitably be used for clinical trial simulations.
References:
[1] Satyendra et al. Empirical Disease Progression Model for Ranibizumab in Age Related Macular Degeneration. University of Tennessee Health Science Center, Memphis, TN, ACCP poster 2009
