(M-123) Streamlining Dupilumab Nasal Polyposis Clinical Development Strategy: Leveraging Modeling and Biomarker Bridging for the Phase 3 Dose Selection

Zhaoling Meng, Ph.D – Global Head of Clinical Modeling & Evidence Integration, Sanof; Mohamed Kamal, Ph.D – Sr Group Director, Regeneron Pharmaceuticals, Inc.; John Davis, Ph – VP, Regeneron Pharmaceuticals, Inc.

Objectives: Dupilumab is a fully human monoclonal antibody, that binds to the shared receptor component for interleukin (IL)-4 and IL-13, cytokines that are key drivers of type 2 inflammatory diseases. Dupilumab is approved in multiple indications including asthma and chronic rhinosinusitis with nasal polyps (CRSwNP). During clinical development for CRSwNP, a modeling and simulation approach was used to leverage clinical data accumulated across CRSwNP and asthma indications and streamline clinical development to move directly from the proof-of-concept (POC) study to Phase 3 studies.

Methods: In a randomized, double-blind, placebo-controlled, phase 2 POC study (NCT01920893), patients with CRSwNP received SC dupilumab 300 mg every week (qw) over 16 weeks of blinded treatment and 16 weeks of follow-up. In a randomized, double-blind, placebo-controlled, dose range finding phase 2b study (NCT01854047), patients with asthma were randomly assigned (1:1:1:1:1) to receive SC dupilumab 200 mg or 300 mg every 2 weeks (q2w) or every 4 weeks (q4w), or placebo, over a 24-week period. Considering the high comorbidity of the two patient populations, the clinical data from the asthma dose ranging study were used to bridge the dose-response relationships to patients with CRSwNP. Sino-nasal Outcome Test (SNOT-22) and pharmacokinetic (PK) data were pooled from the POC study in patients with CRSwNP and the dose range finding study in patients with asthma and comorbid CRSwNP. Other efficacy endpoints such as nasal polyps score (NPS) were also modelled and extrapolated to the lower doses based on the POC study in patients with CRSwNP.

Results: The PK/PD model of SNOT-22 based on the pooled datasets was developed and used to predict dupilumab effects at the lower doses in patients with CRSwNP. Baseline biomarker and patient characteristics were incorporated to adjust for differences between the two studies. The modeling approach predicted similar effects of 300 mg q2w as 300 mg qw at Week 24. The improvement of efficacy endpoints between Week 24 and later time points was small or minimal. Based on the PK/PD modeling results, the 300 mg q2w dose was recommended in the Phase 3 studies with 24 weeks as the primary treatment period. The results of phase 3 clinical studies in patients with CRSwNP confirmed the efficacy of the selected dose.

Conclusions: Leveraging comorbidity of CRSwNP and asthma populations, PK/PD modeling guided the phase 3 dose selection for CRSwNP based on pooled data for a wide dose range crossing two populations. The approach illustrates a way to leverage data and information across indications to enable more efficient and robust clinical development design and planning.

Acknowledgments:
Research sponsored by Sanofi and Regeneron Pharmaceuticals, Inc. The authors thank Leda Mannent, Nikhil Amin, and Qiang Lu for insights and guidance.

Citations: ClinicalTrials.gov Identifiers: NCT01920893, NCT01854047.