First-In-Human, Phase 1, Randomized, Dose-Escalation Trial with Recombinant Anti-IL-20 Monoclonal Antibody in Patients with Psoriasis

Abstract

Background: The current trial was a first-in-human clinical trial evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of the recombinant monoclonal anti-interleukin-20 (IL-20) antibody, NNC0109-0012, which targets the inflammatory cytokine IL-20.

Methods: In total, 48 patients aged 18 to 75 years with moderate to severe stable chronic plaque psoriasis with affected body surface area ≥15% and physician global assessment score ≥3 were enrolled in this randomized, double-blind, multicenter, placebo-controlled, phase 1 dose-escalation trial. Patients were randomized within each single dose cohort (0.01, 0.05, 0.2, 0.6, 1.5, or 3.0 mg/kg) or multiple dose cohort (0.05, 0.2, 0.5, 1.0, or 2.0 mg/kg; 1 dose every other week for 7 weeks) of NNC0109-0012 or placebo in a 3:1 ratio. In the expansion phase, 7 patients were randomized to weekly doses of 2.0 mg/kg NNC0109-0012 or placebo for 7 weeks. The primary objective, safety and tolerability, was assessed by evaluating adverse events (AEs). Additional endpoints included pharmacokinetics, pharmacodynamics, and clinical response (assessed using the Psoriasis Area and Severity Index [PASI] score).

Results: AEs were reported in 85% of patients (n = 40) in the initial study phases (NNC0109-0012, 83%; placebo, 92%) and in 4 of 7 patients in the multiple-dose expansion phase. One serious AE was reported but was judged not to be causally related to NNC0109-0012. No dose-limiting toxicities were reported. NNC0109-0012 pharmacokinetics was similar to other monoclonal antibodies, with an average half-life of approximately 3 weeks. There was a dose-proportional increase in area under the curve and maximum concentration after single dosing. No substantial changes in pharmacodynamic parameters were observed. The expansion phase was terminated early due to apparent lack of PASI improvement.

Conclusion: Single and multiple doses of NNC0109-0012, ranging from 0.05 to 3.0 mg/kg, were well tolerated in patients with psoriasis and exhibited pharmacokinetics similar to that of other monoclonal antibodies.

Trial registration: ClinicalTrials.gov NCT01261767.

Conflict of interest statement

Competing Interests: The authors have the following interests: The study was funded by Novo Nordisk A/S, Denmark. Writing support was provided by Heather Heerssen, PhD, Jane Phillips, PhD, and Maryann Travaglini, PharmD, of Complete Healthcare Communications, Inc. (Chadds Ford, PA, USA). This support was funded by Novo Nordisk. A Gottlieb: Consulting/advisory board: Amgen Inc., Astellas, Akros, Centocor (Janssen), Inc., Celgene Corp., Bristol Myers Squibb Co., Beiersdorf, Inc., Abbott Labs. (AbbVie), TEVA, Actelion, UCB, Novo Nordisk, Novartis, Dermipsor Ltd., Incyte, Pfizer, Canfite, Lilly, Coronado, Vertex, Karyopharm, CSL Behring Biotherapies for Life, GlaxoSmithKline, Xenoport, Catabasis, Sanofi Aventis; DUSA; Research/educational grants (paid to Tufts Medical Center): Centocor (Janssen), Amgen, Abbott (AbbVie), Novartis, Celgene, Pfizer, Lilly, Coronado, Levia, Merck, Xenoport. J Krueger: Consulting/advisory board: Abbvie, Akros, Amgen, Biogen-Idec, Bristol Meyers Squibb, Boehringer-Ingelheim, Centocor/Janssen, Celgene, Delenex, Dermira, Leo Pharma, Eli Lilly, GlaxoSmithKline, Glenmark, Merck, Novartis, Novo Nordisk, Pfizer, Xenoport. M Sandberg Lundblad: Employee and stockholder of Novo Nordisk. M Gothberg: Employee and stockholder of Novo Nordisk. B Skolnick: At the time of manuscript preparation, Dr Skolnick was an employee and stockholder of Novo Nordisk. He is now employed with Cushing Neuroscience Institute, Hofstra North Shore-LIJ School of Medicine, Manhasset, NY. NNC0109-0012 has been patented; however, there are no products in development or marketed products to declare. This does not alter our adherence to all the PLoS ONE policies on sharing data and materials.

Figures

Fig 1. Consort flow diagram.

Patient disposition in (A) the single-dose and multiple-dose dose-escalation phases and (B) the multiple-dose expansion phase. Represents the safety analysis set. AE = adverse event.

Fig 2. Study design.

The first dose in the multiple-dose dose-escalation phase was administered after the third dose level of the single-dose dose-escalation phase (0.2 mg/kg) was evaluated by a study safety group; thereafter, the single- and multiple-dose dose-escalation phases were performed in parallel.

Fig 3. Mean anti‒IL-20 serum concentration-time profiles.

Mean serum concentration-time profiles following (A) single dosing or (B) multiple dosing in the dose-escalation phase and individual anti‒IL-20 serum concentration-time profiles following multiple dosing in (C) the expansion phase on a semi-logarithmic scale in patients with psoriasis.

Fig 4. Mean PASI total score by visit.

Mean PASI total score by visit following (A) single dosing or (B) multiple dosing in the dose-escalation phase and (C) multiple dosing in the expansion phase. PASI = Psoriasis Area and Severity Index.

Fig 5. Histology image from a single patient.

Patient from the expansion phase treated with anti‒IL-20. By week 15, this patient experienced marked improvement in epidermal hyperplasia and acanthosis, a large reduction in keratin 16, associated reductions in proliferating keratinocytes (Ki67), and marked reductions in CD11c+ dendritic cells. CD11c = integrin alpha X chain protein; H&E = hematoxylin and eosin stain; K16 = keratin 16; Ki67 = cellular marker for proliferation; NL = nonlesional (skin); LS = longitudinal section.