Zhicheng Qian (1)*, Yue Gao (1), Christine Xu (1), John D. Davis (2), Vanaja Kanamaluru (1), Qiang Lu (1)
(1) Sanofi, Bridgewater, NJ, USA; (2) Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA
Objectives: Dupilumab, a fully human anti-interleukin (IL)-4Rα monoclonal antibody, inhibits signaling of IL-4/IL-13, key drivers of Type-2 inflammatory diseases. Dupilumab is approved for subcutaneous (SC) treatment of adult patients with chronic rhinosinusitis with nasal polyposis (CRSwNP) as well as patients aged 12 years and older with moderate-to-severe atopic dermatitis and with moderate-to-severe asthma. This analysis aimed to develop a Pop PK/PD model to characterize the relationship of time course NC score with dupilumab PK exposure, and to identify intrinsic and/or extrinsic factors significantly contributing to NC score variability in CRSwNP patients.
Methods: The Pop PK/PD model was developed using data pooled from one phase 2 study (NCT01920893) and two phase 3 studies (NCT02912468 and NCT02898454) in CRSwNP patients who received subcutaneous dupilumab 300 mg (with 600 mg loading dose) every week (qw) for 16 weeks, 300 mg every two weeks (q2w) for 24 or 52 weeks, 300 mg q2w for 24 weeks followed by a switch to every four weeks (q4w) until 52 weeks (q2w-q4w), or placebo. The Pop PK/PD model was developed in a sequential manner, where the estimated individual PK parameters from a previously published Pop PK model [1] were used to derive serum dupilumab concentrations, which then served as exposure input to drive the effect on NC score. Demographic variables, baseline disease characteristics, Type 2 inflammation biomarkers, anti-drug antibodies (ADA), and asthma history were tested as covariates by forward selection and backward elimination. The model was validated with visual predictive check and bootstrap.
Results: The Pop PK/PD dataset included 11342 NC observations from 777 CRSwNP patients (N=312 treated with placebo, N=465 treated with dupilumab). Both placebo and treatment effects were described by Emax type of models with time or serum dupilumab concentration driving the NC inhibition indirectly. Four transit compartments were employed to describe the delayed treatment effect relative to placebo. Two covariates had a statistically significant influence on NC score variability. The maximum treatment effect was related to body weight, with a better effect in patients with lower body weight. Baseline NC value was related to baseline nasal polyp score (NPS), with a higher baseline NC in patients with a higher baseline NPS. These two statistically significant covariates were not deemed to be clinically relevant based on simulations. None of the other tested covariates, including age, gender, race, region, baseline Type 2 inflammation biomarkers and ADA, were statistically significant. Concomitant use of common NP medication (i.e. systemic corticosteroids) and other comorbidities (asthma history, exacerbated respiratory disease history and allergic rhinitis history) showed no effect on NC response based on covariate analysis or post-hoc NC comparison.
Conclusions: The NC scores over time in CRSwNP patients treated with dupilumab were well characterized by an indirect response model with transit compartments relating dupilumab concentration to NC score. Baseline body weight and NPS were identified as statistically significant, but not clinically relevant, covariates on dupilumab treatment effect in CRSwNP patients.
Acknowledgments:
Research sponsored by Sanofi and Regeneron Pharmaceuticals, Inc. ClinicalTrials.gov Identifiers: NCT01920893, NCT02912468 and NCT02898454.
Disclosures:
Zhicheng Qian, Yue Gao, Christine Xu, Vanaja Kanamaluru, Qiang Lu: Sanofi − employees, may hold stock and/or stock options in the company; John D. Davis: Regeneron Pharmaceuticals, Inc. − employee and shareholder.
References:
[1] Yue Gao, Christine Xu, John D. Davis, Vanaja Kanamaluru, Qiang Lu. Population pharmacokinetic analysis of dupilumab in adult patients with chronic rhinosinusitis with nasal polyposis. ACOP 10, Orlando, FL. Oct 20-23, 2019.
Reference: PAGE () Abstr 9409 [www.page-meeting.org/?abstract=9409]
Poster: Drug/Disease Modelling - Other Topics