PMID- 36478476
OWN - NLM
STAT- MEDLINE
DCOM- 20230320
LR  - 20230320
IS  - 1468-3083 (Electronic)
IS  - 0926-9959 (Linking)
VI  - 37
IP  - 4
DP  - 2023 Apr
TI  - Oral orismilast: Efficacy and safety in moderate-to-severe psoriasis and 
      development of modified release tablets.
PG  - 711-720
LID - 10.1111/jdv.18812 [doi]
AB  - BACKGROUND: Orismilast is a high-potency phosphodiesterase 4 (PDE4) inhibitor 
      with enhanced selectivity for the PDE4B and PDE4D subtypes. OBJECTIVES: The 
      objective of this phase 2a trial was to examine the efficacy and safety of 
      orismilast for psoriasis using a first-generation immediate-release (IR) 
      formulation. The objective of the subsequent phase 1 trial was to test new 
      formulations designed to minimize the gastrointestinal (GI)-related adverse 
      events (AEs) observed with the first-generation IR formulation. We examined the 
      following: (1) pharmacokinetic (PK) properties of orismilast modified release 
      (MR) and IR, (2) food effects on PK properties of orismilast MR or IR, (3) safety 
      of orismilast MR compared to placebo. METHODS: In a phase 2a prospective, 
      randomized, double-blind, placebo-controlled trial, patients with 
      moderate-to-severe psoriasis were randomized to receive 30 mg oral orismilast IR 
      or placebo over 16 weeks. The single-site phase 1 trial consisted of three parts: 
      (1) participants received a single 30 mg dose of orismilast MR and IR 
      (open-label), (2) participants received 30 mg orismilast MR or IR under either 
      fasting condition, following a high-fat meal or low-fat meal (open-label) and (3) 
      participants received up to 60 mg orismilast MR twice-daily or a placebo for 
      17 days (double-blind). RESULTS: In the phase 2a trial, treatment with orismilast 
      IR significantly improved the mean Psoriasis Area Severity Index score at week 16 
      compared to placebo. The phase 1 trial revealed comparable PK properties of the 
      orismilast MR and IR formulations, with participants in the orismilast MR group 
      experiencing fewer GI-related AEs than those receiving orismilast IR (16.7% vs. 
      33.3%). CONCLUSION: Orismilast IR displayed higher efficacy compared to placebo 
      in patients with moderate-to-severe psoriasis at week 16. Orismilast MR had 
      similar PK properties and fewer GI disorders compared to the IR formulation in 
      healthy participants. Future development of orismilast will be based on the MR 
      formulation.
CI  - (c) 2022 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 - Warren, Richard B
AU  - Warren RB
AD  - Dermatology Centre, Salford Royal NHS Foundation Trust, Manchester NIHR 
      Biomedical Research Centre, The University of Manchester, Manchester, UK.
FAU - Strober, Bruce
AU  - Strober B
AUID- ORCID: 0000-0002-8394-2057
AD  - Yale University and Central Connecticut Dermatology, Connecticut, New Haven, USA.
FAU - Silverberg, Jonathan I
AU  - Silverberg JI
AUID- ORCID: 0000-0003-3686-7805
AD  - George Washington University School of Medicine and Health Sciences, Washington, 
      District of Columbia, USA.
FAU - Guttman, Emma
AU  - Guttman E
AUID- ORCID: 0000-0002-9363-324X
AD  - Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New 
      York, USA.
FAU - Andres, Philippe
AU  - Andres P
AD  - UNION therapeutics A/S, Hellerup, Denmark.
FAU - Felding, Jakob
AU  - Felding J
AD  - UNION therapeutics A/S, Hellerup, Denmark.
FAU - Tutkunkardas, Deniz
AU  - Tutkunkardas D
AUID- ORCID: 0000-0002-9390-6105
AD  - UNION therapeutics A/S, Hellerup, Denmark.
FAU - Kjoller, Kim
AU  - Kjoller K
AD  - UNION therapeutics A/S, Hellerup, Denmark.
FAU - Sommer, Morten O A
AU  - Sommer MOA
AD  - UNION therapeutics A/S, Hellerup, Denmark.
AD  - Novo Nordisk Foundation Center for Biosustainability, Technical University of 
      Denmark, Kongens Lyngby, Denmark.
FAU - French, Lars E
AU  - French LE
AUID- ORCID: 0000-0002-4629-1486
AD  - Department of Dermatology and Allergy, University Hospital, Ludwig Maximilian 
      University (LMU) Munich, Munich, Germany.
AD  - Dr. Philip Frost, Department of Dermatology and Cutaneous Surgery, University of 
      Miami Miller School of Medicine, Miami, Florida, USA.
LA  - eng
GR  - LEO Pharma A/S/
GR  - UNION therapeutics A/S/
GR  - Manchester National Institute for Health and Care Research (NIHR) Biomedical 
      Research Centre/
GR  - NNF20CC0035580/The Novo Nordisk Foundation/
PT  - Journal Article
PT  - Randomized Controlled Trial
DEP - 20230118
PL  - England
TA  - J Eur Acad Dermatol Venereol
JT  - Journal of the European Academy of Dermatology and Venereology : JEADV
JID - 9216037
RN  - 0 (Phosphodiesterase 4 Inhibitors)
RN  - 0 (Tablets)
SB  - IM
MH  - Humans
MH  - Prospective Studies
MH  - *Psoriasis/drug therapy
MH  - *Phosphodiesterase 4 Inhibitors/adverse effects
MH  - Tablets/therapeutic use
MH  - Fasting
MH  - Double-Blind Method
MH  - Treatment Outcome
EDAT- 2022/12/09 06:00
MHDA- 2023/03/21 06:00
CRDT- 2022/12/08 13:03
PHST- 2022/08/18 00:00 [received]
PHST- 2022/11/21 00:00 [accepted]
PHST- 2022/12/09 06:00 [pubmed]
PHST- 2023/03/21 06:00 [medline]
PHST- 2022/12/08 13:03 [entrez]
AID - 10.1111/jdv.18812 [doi]
PST - ppublish
SO  - J Eur Acad Dermatol Venereol. 2023 Apr;37(4):711-720. doi: 10.1111/jdv.18812. 
      Epub 2023 Jan 18.