Impact of weight on the efficacy and safety of ustekinumab in patients with moderate to severe psoriasis: Rationale for dosing recommendations - 24/04/13

Doi : 10.1016/j.jaad.2009.11.012

Mark Lebwohl, MD ^a,^⁎ , Newman Yeilding, MD ^b, Philippe Szapary, MD ^b, Yuhua Wang, PhD ^b, Shu Li, MS ^b, Yaowei Zhu, PhD ^b, Kristian Reich, MD ^c, Richard G. Langley, MD ^d, Kim A. Papp, MD ^e
^a Mount Sinai School of Medicine, New York, New York
^b Centocor Research & Development Inc, Malvern, Pennsylvania
^c Dermatologikum Hamburg, Hamburg, Germany
^d Dalhousie University, Halifax, Nova Scotia, Canada
^e Probity Medical Research, Waterloo and University of Western Ontario, for the PHOENIX 1 and 2 Study Investigators, London, Ontario, Canada

Reprint requests: Mark Lebwohl, MD, Mount Sinai School of Medicine, 5 E 98th St, New York, NY 10029.

Abstract

Background

Patients with psoriasis tend to be overweight, and the efficacy of fixed-dose biologics may be compromised by high body weight.

Objective

We sought to determine whether the optimal dose of ustekinumab is affected by weight in patients with psoriasis.

Methods

Patients were randomized in two phase III trials (PHOENIX 1 and 2) to receive 45 mg or 90 mg of ustekinumab every 12 weeks (n = 1331) or placebo with crossover to ustekinumab at week 12 (n = 665). Efficacy and serum ustekinumab concentrations were to be evaluated by 10-kg increments of body weight at week 28 (steady-state trough level).

Results

Mean baseline weight was 93.9 and 91.0 kg in PHOENIX 1 and 2, respectively. Based on the analyses by 10-kg increments, a cutoff of 100 kg was determined to best differentiate the dose response. The proportion of patients with at least 75% improvement from baseline in Psoriasis Area and Severity Index score was 74.2% for 90 mg and 54.6% for 45 mg in heavier patients (>100 kg), but the proportion with a response of at least 75% improvement from baseline in Psoriasis Area and Severity Index score was similar between doses (80.8% vs 76.9%) in lighter patients (≤100 kg). Serum ustekinumab concentrations were also affected by weight, with lower serum concentrations observed in heavier patients at each dose. Safety was not affected by weight.

Limitations

Low numbers of patients at the extremes of body weight may limit the analyses of these subgroups.

Conclusion

Results of weight-based analyses of clinical and pharmacokinetic data indicate that fixed dosing of ustekinumab based on weight is appropriate for the treatment of patients with psoriasis.

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Key words : psoriasis, Psoriasis Area and Severity Index, serum concentration, ustekinumab, weight-based dose

Abbreviations used : LLOQ, PASI, PASI 75, PGA

Plan

Patient characteristics

Supported by Centocor Research & Development, Inc.

Disclosure: Dr Lebwohl has served as advisor for DermiPsor, Medicis, Nycomed, Pfizer, Abbott Laboratories, Amgen, Astellas, Centocor, Galderma, Genentech, Glaxo SmithKline, Graceway, Magen Biosciences, Neostrata, Novartis, Ranbaxy, Taro, and Warner Chilcott; received other compensation from Incyte; and has received honoraria from all these companies. Dr Reich has served as speaker and investigator for Biogen-Idec; has served as advisor and speaker for Centocor and Janssen-Cilag; has served as advisor, speaker, and investigator for Abbott Laboratories, Schering-Plough, Serono, and Wyeth; and has received grants and honoraria from Abbott Laboratories as well as honoraria from all other companies listed here. Dr Langley has served as an advisor and a speaker for Abbott, Amgen, Biogen, Centocor, Novartis, and Wyeth; has served as investigator for all these companies as well as Celgene and Pfizer; has served as advisor for Leo Pharma; and has received honoraria or grants from all these companies. Dr Papp has served as advisor, speaker, investigator, and consultant and received grants and honoraria from Abbott, Amgen, Centocor, and Schering Plough. Drs Yeilding, Szapary, and Wang, and Ms Li are employees of Johnson & Johnson and receive salaries and own stock and stock options in the company. Dr Zhu receives a salary as an employee of Johnson & Johnson.