Model-based development of the secukinumab dosing regimen for the treatment of moderate-to-severe chronic plaque psoriasis
Oliver Sander, Achim Guettner, Charis Papavassilis, Michael Looby
Novartis Pharmaceuticals, Basel Switzerland
Objectives: In order to identify optimized dosing regimens for phase 3, this model-based analysis integrated data from several phase 2 studies that were collected under different conditions (i.e., different routes of administration, doses and dosing regimens, and study duration). The analysis was subsequently used to justify the selected regimens in the phase 3 study protocols, and at health authority meetings (end-of-phase-2 and advisory committee meeting after phase 3).
Methods: Accompanying the phase 2 program, a PKPD model was built in serveral iterations. When a new study read out, prior predictions of the read-out were checked against the new results and the model was subsequently refined and updated. A two-compartment PK model with zero-order (to account for IV adminstration) and first-order absorption (to account for SC administration) was fit to concentration data. Turnover models were fit to the continuous efficacy data (PASI score). Model assessment was performed using standard goodness of fit diagnostics, visual predictive checks, and external validation by prosectively predicting outcomes of the next read-outs.
Results: PK was described by a two compartment disposition model. PD was described by a turnover model with stimulatory effect on the decrease of disease activity (Kout), driven by a sigmoidal Emax model as a function of drug concentration. This model was considered predictive, as it captured the main trends across doses, dosing regimens and routes well. Based on this model, regimens were evaluated and two SC regimens were selected to move into phase 3: 150mg and 300mg given at weeks 0, 1, 2, 3, and 4 followed by dosing every 4 weeks. These two regimens were predicted to improve response over the subcutaneous regimens used in phase 2 and other available treatments.
Conclusions: Through sequential integration of phase 2 data in model-based analyses, it was possible to recommend dosing regimens for phase 3 which had not been previously tested.The phase 3 studies confirmed the efficacy and safety of these new regimens, leading to regulatory approval of a product with optimized efficacy. With complex development programs, aimed at answering a set of complex questions – e.g. different routes of administration, a large space of possible regimens, comparison to competitors, short- and long-term effects – model-based integration of “the puzzle pieces” offers a rational and quantitative approach to support decision making.
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[2] Langley RG, Elewski BE, Lebwohl M, Reich K, Griffiths CE, Papp K, Puig L, Nakagawa H, Spelman L, Sigurgeirsson B, Rivas E, Tsai TF, Wasel N, Tyring S, Salko T, Hampele I, Notter M, Karpov A, Helou S, Papavassilis C; ERASURE Study Group; FIXTURE Study Group. Secukinumab in plaque psoriasis--results of two phase 3 trials. N Engl J Med. (2014) 371(4):326-38.
