PMID- 37452623
OWN - NLM
STAT- MEDLINE
DCOM- 20231127
LR  - 20240305
IS  - 1365-2125 (Electronic)
IS  - 0306-5251 (Print)
IS  - 0306-5251 (Linking)
VI  - 89
IP  - 12
DP  - 2023 Dec
TI  - Phase 1 safety, tolerability, pharmacokinetics and pharmacodynamic results of 
      KCL-286, a novel retinoic acid receptor-beta agonist for treatment of spinal cord 
      injury, in male healthy participants.
PG  - 3573-3583
LID - 10.1111/bcp.15854 [doi]
AB  - AIMS: KCL-286 is an orally available agonist that activates the retinoic acid 
      receptor (RAR) beta2, a transcription factor which stimulates axonal outgrowth. The 
      investigational medicinal product is being developed for treatment of spinal cord 
      injury (SCI). This adaptive dose escalation study evaluated the tolerability, 
      safety and pharmacokinetics and pharmacodynamic activity of KCL-286 in male 
      healthy volunteers to establish dosing to be used in the SCI patient population. 
      METHODS: The design was a double blind, randomized, placebo-controlled dose 
      escalation study in 2 parts: a single ascending dose adaptive design with a food 
      interaction arm, and a multiple ascending dose design. RARbeta2 mRNA expression was 
      evaluated in white blood cells. RESULTS: At the highest single and multiple 
      ascending doses (100 mg), no trends or clinically important differences were 
      noted in the incidence or intensity of adverse events (AEs), serious AEs or other 
      safety assessments with none leading to withdrawal from the study. The AEs were 
      dry skin, rash, skin exfoliation, raised liver enzymes and eye disorders. There 
      was an increase in mean maximum observed concentration and area under the plasma 
      concentration-time curve up to 24 h showing a trend to subproportionality with 
      dose. RARbeta2 was upregulated by the investigational medicinal product in white 
      blood cells. CONCLUSION: KCL-286 was well tolerated by healthy human participants 
      following doses that exceeded potentially clinically relevant plasma exposures 
      based on preclinical in vivo models. Target engagement shows the drug candidate 
      activates its receptor. These findings support further development of KCL-286 as 
      a novel oral treatment for SCI.
CI  - (c) 2023 The Authors. British Journal of Clinical Pharmacology published by John 
      Wiley & Sons Ltd on behalf of British Pharmacological Society.
FAU - Goncalves, Maria B
AU  - Goncalves MB
AD  - Neuroscience Drug Discovery Unit, The Wolfson Centre for Age-Related Diseases, 
      King's College London, Guy's Campus, London, UK.
FAU - Mant, Tim
AU  - Mant T
AD  - NIHR Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust and 
      King's College London, Guy's and St Thomas' NHS Foundation Trust, London, UK.
FAU - Taubel, Jorg
AU  - Taubel J
AD  - Richmond Pharmacology Limited, London, UK.
FAU - Clarke, Earl
AU  - Clarke E
AD  - Neuroscience Drug Discovery Unit, The Wolfson Centre for Age-Related Diseases, 
      King's College London, Guy's Campus, London, UK.
FAU - Hassanin, Hana
AU  - Hassanin H
AD  - Surrey Clinical Research Centre, University of Surrey, Surrey, UK.
FAU - Bendel, Daryl
AU  - Bendel D
AD  - Surrey Clinical Research Centre, University of Surrey, Surrey, UK.
FAU - Fok, Henry
AU  - Fok H
AD  - NIHR Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust and 
      King's College London, Guy's and St Thomas' NHS Foundation Trust, London, UK.
FAU - Posner, John
AU  - Posner J
AD  - Centre for Pharmaceutical Medicine Research, Institute of Pharmaceutical Science, 
      King's College London, London, UK.
FAU - Holmes, Jane
AU  - Holmes J
AD  - Nuffield Department of Primary Care Health Sciences, University of Oxford, 
      Oxford, UK.
FAU - Mander, Adrian P
AU  - Mander AP
AD  - Centre for Trials Research, Cardiff University, Cardiff, UK.
FAU - Corcoran, Jonathan P T
AU  - Corcoran JPT
AUID- ORCID: 0000-0002-8390-4720
AD  - Neuroscience Drug Discovery Unit, The Wolfson Centre for Age-Related Diseases, 
      King's College London, Guy's Campus, London, UK.
LA  - eng
GR  - MR/R006466/1/MRC_/Medical Research Council/United Kingdom
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20230809
PL  - England
TA  - Br J Clin Pharmacol
JT  - British journal of clinical pharmacology
JID - 7503323
RN  - 0 (retinoic acid receptor beta)
RN  - 0 (Receptors, Retinoic Acid)
RN  - 0 (Drugs, Investigational)
SB  - IM
MH  - Humans
MH  - Male
MH  - Healthy Volunteers
MH  - Dose-Response Relationship, Drug
MH  - *Receptors, Retinoic Acid
MH  - Area Under Curve
MH  - Double-Blind Method
MH  - *Drugs, Investigational
PMC - PMC10835503
OTO - NOTNLM
OT  - KCL-286
OT  - RARbeta agonist
OT  - pharmacokinetics
OT  - safety
OT  - spinal cord injury
OT  - target engagement
COIS- The authors declare no competing financial interests. MBG and J.P.T.C have a 
      matter of composition patent for KCL-286.
EDAT- 2023/07/15 11:42
MHDA- 2023/11/27 12:42
PMCR- 2023/08/09
CRDT- 2023/07/15 04:42
PHST- 2023/06/23 00:00 [revised]
PHST- 2023/04/20 00:00 [received]
PHST- 2023/07/04 00:00 [accepted]
PHST- 2023/11/27 12:42 [medline]
PHST- 2023/07/15 11:42 [pubmed]
PHST- 2023/07/15 04:42 [entrez]
PHST- 2023/08/09 00:00 [pmc-release]
AID - BCP15854 [pii]
AID - 10.1111/bcp.15854 [doi]
PST - ppublish
SO  - Br J Clin Pharmacol. 2023 Dec;89(12):3573-3583. doi: 10.1111/bcp.15854. Epub 2023 
      Aug 9.