Selection of Nemolizumab Clinical Dosage for Atopic Dermatitis

October 2023 | Volume 22 | Issue 10 | 1017 | Copyright © October 2023


Published online September 29, 2023

doi:10.36849/JDD.7437R1

Nathalie Wagner MSca, Luca Loprete PhDa, Vincent Duval PharmaDb, Petra Jauslin PhDb, Khaled Benkali PhDb, Jonathan I. Silverberg MD PhD MPHc, Andreas Wollenberg MD PhDd, Tomohisa Saito PhDe, Faiz Ahmad MSa, Michael Graeber MDa, Warren Winkelman MD PhDa, Christophe Piketty MD PhDf

aGalderma R&D, Dallas, TX
bCertara Integrated Drug Development, Basel, Switzerland; Khaled Benkali Certara Integrated Drug Development, Paris, France
cDepartment of Dermatology, The George Washington University School of Medicine and Health Sciences, Washington, DC
dDepartment of Dermatology and Allergology, Ludwig-Maximilians-Universitat, Munich, Germany; Vrije Universiteit Brussel, Universitair Ziekenhuis Brussel, Department of Dermatology, Brussels, Belgium
eChugai Pharmaceutical Co., Ltd., Tokyo, Japan
fGalderma R&D, Zug, Switzerland

Abstract
Nemolizumab is a monoclonal antibody directed against the interleukin-31 receptor A subunit, which is involved in the pathogenesis of pruritus and inflammation in atopic dermatitis (AD). Clinical trial results were combined with population PK (popPK) and pharmacokinetic/ pharmacodynamic (PK/PD) models to optimize nemolizumab dosing. Phase 1 and 2a clinical studies indicated that weight-based nemolizumab dosing reduced pruritus in patients with moderate-to-severe AD with good safety and tolerability even at the highest dose (3 mg/kg single dose and 2 mg/kg multiple doses). Nemolizumab PK profile was characterized by a slow absorption with peak serum concentrations reached 4.5-9.2 days post-dose, and a long terminal half-life ranging from 12.6 to 16.5 days. A change from weight-based dosing to flat dose was supported by an additional phase 2b study sponsored by Galderma. Flat dosing provides several practical advantages, including ease of preparation for self- or auto-injection and reduced chance of dosing errors. Doses of 10, 30, and 90 mg were selected based on popPK and PK/PD simulations to result in nemolizumab serum concentrations sufficient to achieve efficacy. Loading doses were administrated at the 2 lower doses in order to achieve target systemic concentrations from the first injection. The efficacy of Nemolizumab in improving cutaneous signs of inflammation and pruritus in AD and its safety profile, combined with popPK and PK/PD analyses, supported selection of the flat-dose regimen of 30 mg (with a 60 mg loading dose) given every 4 weeks subcutaneously for 16 weeks in the phase 3 ARCADIA studies sponsored by Galderma.

J Drugs Dermatol. 2023;22(10):976-984 doi:10.36849/JDD.7437R1

introduction

Nemolizumab is a humanized monoclonal antibody directed against the interleukin (IL)-31 receptor alpha chain (IL-31RA) that blocks signaling from neuroimmune cytokine IL-31. While IL-31 was first thought to be primarily a pruritic cytokine, IL-31 is now thought of as a central neuroimmune mediator that affects many biologic functions, including several key aspects of AD. Nemolizumab is being studied in clinical trials for the treatment of several indications, including atopic dermatitis (AD).1-7 AD is a complex, heterogeneous condition that can manifest with erythema, excoriations, inflammation, sleep disturbance, and - perhaps most characteristically - intense pruritus and xerosis. Patients with AD often have a high level of physical discomfort, emotional and psychosocial distress, embarrassment, and limitations to their daily activities of living8; and these problems worsen as AD severity increases.9 Furthermore, patients report that management of AD, including trigger avoidance and need for multiple medications, can add additional burden to daily life10,11 quality.

One of the most crucial steps in the development of a new biologic is the determination of the dose and regimen to be assessed in phase 3 pivotal studies and subsequently to inform the drug label. The present article describes the approach used to determine the optimal nemolizumab dose for AD through assessments of exposure-response (E-R) and dose-response (D-R) relationships. E-R relationships assess the effects of drug exposure in the blood on efficacy profile. E-R analysis, in its broad definition, includes pharmacokinetic/pharmacodynamic (PK/PD) modeling as a special case where the exposure variable is drug concentration. D-R relationships, assessed in dose-
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