PMID- 26252485 OWN - NLM STAT- MEDLINE DCOM- 20160509 LR - 20191210 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 10 IP - 8 DP - 2015 TI - First-In-Human, Phase 1, Randomized, Dose-Escalation Trial with Recombinant Anti-IL-20 Monoclonal Antibody in Patients with Psoriasis. PG - e0134703 LID - 10.1371/journal.pone.0134703 [doi] LID - e0134703 AB - 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. FAU - Gottlieb, Alice B AU - Gottlieb AB AD - Department of Dermatology, Tufts Medical Center, Boston, MA, United States of America; Department of Dermatology, Tufts University School of Medicine, Boston, MA, United States of America. FAU - Krueger, James G AU - Krueger JG AD - The Rockefeller University, New York, NY, United States of America. FAU - Sandberg Lundblad, Mia AU - Sandberg Lundblad M AD - Clinical Pharmacology, Novo Nordisk A/S, Soborg, Denmark. FAU - Gothberg, Marie AU - Gothberg M AD - Clinical Pharmacology, Novo Nordisk A/S, Soborg, Denmark. FAU - Skolnick, Brett E AU - Skolnick BE AD - Medical-Science, Inflammation, Novo Nordisk Inc., Princeton, NJ, United States of America. LA - eng SI - ClinicalTrials.gov/NCT01261767 PT - Clinical Trial, Phase I PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20150807 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (Antibodies, Monoclonal) RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Antibodies, Neutralizing) RN - 0 (Broadly Neutralizing Antibodies) RN - 0 (Interleukins) RN - 0 (Recombinant Proteins) RN - 82WG3POL9W (Fletikumab) RN - U91R7IMG8U (interleukin 20) SB - IM MH - Adult MH - Antibodies, Monoclonal/adverse effects/pharmacokinetics/pharmacology/*therapeutic use MH - Antibodies, Monoclonal, Humanized MH - Antibodies, Neutralizing/adverse effects/pharmacology/*therapeutic use MH - Broadly Neutralizing Antibodies MH - Dose-Response Relationship, Drug MH - Female MH - Humans MH - Interleukins/*immunology MH - Male MH - Middle Aged MH - Psoriasis/*drug therapy/pathology MH - Recombinant Proteins/adverse effects/pharmacokinetics/pharmacology/therapeutic use MH - Treatment Outcome MH - Young Adult PMC - PMC4529098 COIS- 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. EDAT- 2015/08/08 06:00 MHDA- 2016/05/10 06:00 PMCR- 2015/08/07 CRDT- 2015/08/08 06:00 PHST- 2015/05/19 00:00 [received] PHST- 2015/07/11 00:00 [accepted] PHST- 2015/08/08 06:00 [entrez] PHST- 2015/08/08 06:00 [pubmed] PHST- 2016/05/10 06:00 [medline] PHST- 2015/08/07 00:00 [pmc-release] AID - PONE-D-15-18435 [pii] AID - 10.1371/journal.pone.0134703 [doi] PST - epublish SO - PLoS One. 2015 Aug 7;10(8):e0134703. doi: 10.1371/journal.pone.0134703. eCollection 2015.