A model-based meta-marker to characterize the response to ranibizumab in wet AMD patients
Cheikh Diack, Dietmar Schwab, Norman Mazer, Vincent Buchheit, Valerie Cosson, Nicolas Frey
) Roche Pharma Research and Early Development, Clinical Pharmacology, Roche Innovation Center Basel, F.Hoffmann-La Roche Ltd, Switzerland
Objectives: To derive a composite parameter (meta-marker) from the baseline characteristics that quantitates the high heterogeneity in response to ranibizumab and in deterioration of vision in wet AMD.
Methods: An empirical drug-disease progression model for visual acuity (VA) was developed on the 24-month patient level data from phase 3 and 4 trials of ranibizumab (MARINA, ANCHOR, PIER and HARBOR). Details of the trial designs and patient characteristics have been reported previously [1,2]. Data from untreated patients (sham) were included. The model (an updated version [3]) describes the change over time in VA of patients receiving ranibizumab or sham injections in three components: baseline of VA, decay of VA over time and drug effect on VA.
The influences of available baseline covariates from fundus fluorescence angiography (FFA) and from optical coherence tomography (OCT) on all model parameters were tested.
Results: Using the final model, a meta-marker that is a function of baseline covariates was derived. The meta-marker is a single value which can be determined at entry into the trial and allows the characterization of individual AMD patients into “poor”, “moderate” and “super” responders to ranibizumab treatment. In addition to this innovative tool for the prediction of response at study entry, we show that “poor” and “super” responders, when assessed by the change from baseline are comparably benefiting from treatment when drug response is assessed as the simulated change from the untreated progressed state.
Conclusions: The proposed model-based meta-marker can prove to be an important factor in explaining the heterogeneity in response to ranibizumab treatment. Based on the model we also suggest that the main difference between “poor” and “super’ responders is that the former would have a much greater deterioration in VA if left untreated than the latter patient population.
References:
[1] Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006; 355(14):1419–1431.
[2] Regillo CD, Brown DM, Abraham P, et al. Randomized, doublemasked,sham-controlled trial of ranibizumab for neovascular age- related macular degeneration: PIER Study year 1. Am.J.Ophthalmol.2008;145(2):239–248.
[3] Diack C., Schwab D., Frey N. An empirical drug-disease model to characterize the effect of Ranibizumab on disease progression in wet AMD patients. PAGE 24 (2015) Abstr 3569 [www.page-meeting.org/?abstract=3569].
