Integrating disease progression models, non-clinical pharmacokinetic data and treatment response endpoints to optimize intravitreal dosing regimens

Objective: To rapidly identify patients who will ultimately respond to 1 year of therapy, and optimize their inter-dose interval. Materials and methods: An intravitreal (IVT) ophthalmic dosing paradigm was designed based on clinical efficacy, non-clinical pharmacokinetics (PK), and disease progression modeling. Relevant non-clinical PK models were used to extrapolate IVT drug concentrations to patients. Results: Modeling predicted that > 80% of patients who would respond to 1 year of IVT treatment with an improvement in best-corrected visual acuity (BCVA) could be identified after the first 2 doses of treatment. These 2 initial doses produced similar to 75% of the maximum improvement in BCVA attainable. Moreover, the models also predicted those patients who responded after 1 year of treatment may tolerate an extension of the interdose interval to 12 weeks without significant deterioration of BCVA. In contrast, > 70% of responsive patients who did not respond to 1 year of treatment showed inadequate responses after 2 doses. Conclusions: These models use data from 2 doses to identify those patients likely to benefit after 1 year of treatment, and thereafter can lengthen their interdose interval without deleterious effects. This method identifies potential treatment responders early, and lengthens the interdose interval during long-term administration while allowing non-responders to pursue alternative therapies earlier, thereby minimizing risk to the patient.