PMID- 28556418
OWN - NLM
STAT- MEDLINE
DCOM- 20180705
LR  - 20191210
IS  - 1468-3083 (Electronic)
IS  - 0926-9959 (Print)
IS  - 0926-9959 (Linking)
VI  - 31
IP  - 8
DP  - 2017 Aug
TI  - Phase I randomized study of KHK4083, an anti-OX40 monoclonal antibody, in 
      patients with mild to moderate plaque psoriasis.
PG  - 1324-1332
LID - 10.1111/jdv.14313 [doi]
AB  - BACKGROUND: OX40 (CD134) is expressed in lesional but not healthy skin of 
      patients with psoriasis. KHK4083 is a fully human monoclonal antibody against 
      OX40. OBJECTIVE: The primary aim of this first-in-human phase 1 study was to 
      determine the safety and tolerability of ascending single doses of KHK4083 in 
      patients with mild to moderate plaque psoriasis. Secondary aims were to determine 
      the pharmacokinetics and immunogenicity of KHK4083, and an exploratory objective 
      was to assess clinical activity. METHODS: In phase 1a, single doses of KHK4083 
      0.003 and 0.001 mg/kg IV were administered open label in two cohorts (each n = 
      6). Phase 1b had a multicentre, randomized, double-blind, placebo-controlled, 
      ascending single-dose design in seven cohorts. Randomization was performed 3 : 1 
      to KHK4083 (n = 6) or placebo (n = 2) within each cohort. Ascending doses of 
      KHK4083 were 0.03, 0.1, 0.3, 1.0, 3.0 and 10 mg/kg IV, and 1.0 mg/kg SC. RESULTS: 
      There were no severe or serious adverse events (AEs), or discontinuations because 
      of AEs. The most frequent treatment-related AEs in the 55 patients who received 
      KHK4083 were mild or moderate chills (9.1%), and infusion/injection site 
      reactions (7.3%). No clinically meaningful or dose-related changes from baseline 
      in laboratory values, vital signs, ECG recordings or physical examinations were 
      observed. Some KHK4083 recipients (10/54) developed anti-KHK4083 antibodies 
      following treatment. Mean elimination half-life (t(1/2) ) increased with dose, 
      maximum serum concentration increased in a dose-proportional manner, and area 
      under the serum concentration-time curve increased in a more than 
      dose-proportional manner with increasing IV dose. Absolute bioavailability 
      following SC administration was 73%. There was some indication of improvement in 
      Psoriasis Area Severity Index (PASI) and sPGA scores at the highest IV doses (1.0 
      and 10 mg/kg) and the SC dose (1.0 mg/kg). The largest PASI 50 response and 
      improvement in sPGA score >/=2 occurred with KHK4083 1.0 mg/kg SC. CONCLUSION: 
      KHK4083 administration as a single dose up to 10 mg/kg IV or 1.0 mg/kg SC was 
      generally safe and well tolerated in patients with mild to moderate plaque 
      psoriasis with no dose-limiting AEs.
CI  - (c) 2017 The Authors. Journal of the European Academy of Dermatology and 
      Venereology published by John Wiley & Sons Ltd on behalf of European Academy of 
      Dermatology and Venereology.
FAU - Papp, K A
AU  - Papp KA
AD  - Probity Medical Research Inc., Waterloo, ON, Canada.
FAU - Gooderham, M J
AU  - Gooderham MJ
AD  - Skin Center for Dermatology, Probity Medical Research Inc., Queen's University, 
      Peterborough, ON, Canada.
FAU - Girard, G
AU  - Girard G
AD  - DIEX Recherche Sherbrooke, Sherbrooke, QC, Canada.
FAU - Raman, M
AU  - Raman M
AD  - The Center for Dermatology and Probity Medical Research Inc., Richmond Hill, ON, 
      Canada.
FAU - Strout, V
AU  - Strout V
AD  - Kyowa Kirin Pharmaceutical Development, Inc., Princeton, NJ, USA.
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Multicenter Study
PT  - Randomized Controlled Trial
DEP - 20170614
PL  - England
TA  - J Eur Acad Dermatol Venereol
JT  - Journal of the European Academy of Dermatology and Venereology : JEADV
JID - 9216037
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 0 (KHK4083)
RN  - 0 (Placebos)
RN  - 0 (Receptors, OX40)
RN  - 0 (TNFRSF4 protein, human)
SB  - IM
MH  - Adult
MH  - Antibodies, Monoclonal/administration & dosage/adverse 
      effects/pharmacokinetics/*therapeutic use
MH  - Antibodies, Monoclonal, Humanized
MH  - Cohort Studies
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Humans
MH  - Injection Site Reaction
MH  - Injections, Subcutaneous
MH  - Male
MH  - Middle Aged
MH  - Placebos
MH  - Psoriasis/*drug therapy
MH  - Receptors, OX40/*antagonists & inhibitors/*immunology
MH  - Severity of Illness Index
MH  - Treatment Outcome
PMC - PMC5575535
EDAT- 2017/05/31 06:00
MHDA- 2018/07/06 06:00
PMCR- 2017/08/30
CRDT- 2017/05/31 06:00
PHST- 2017/02/13 00:00 [received]
PHST- 2017/03/31 00:00 [accepted]
PHST- 2017/05/31 06:00 [pubmed]
PHST- 2018/07/06 06:00 [medline]
PHST- 2017/05/31 06:00 [entrez]
PHST- 2017/08/30 00:00 [pmc-release]
AID - JDV14313 [pii]
AID - 10.1111/jdv.14313 [doi]
PST - ppublish
SO  - J Eur Acad Dermatol Venereol. 2017 Aug;31(8):1324-1332. doi: 10.1111/jdv.14313. 
      Epub 2017 Jun 14.