PMID- 36732049
OWN - NLM
STAT- MEDLINE
DCOM- 20230710
LR  - 20231116
IS  - 1468-3288 (Electronic)
IS  - 0017-5749 (Print)
IS  - 0017-5749 (Linking)
VI  - 72
IP  - 8
DP  - 2023 Aug
TI  - Dose escalation randomised study of efmarodocokin alfa in healthy volunteers and 
      patients with ulcerative colitis.
PG  - 1451-1461
LID - 10.1136/gutjnl-2022-328387 [doi]
AB  - BACKGROUND: The interleukin-22 cytokine (IL-22) has demonstrated efficacy in 
      preclinical colitis models with non-immunosuppressive mechanism of action. 
      Efmarodocokin alfa (UTTR1147A) is a fusion protein agonist that links IL-22 to 
      the crystallisable fragment (Fc) of human IgG(4) for improved pharmacokinetic 
      characteristics, but with a mutation to minimise Fc effector functions. METHODS: 
      This randomised, phase 1b study evaluated the safety, tolerability, 
      pharmacokinetics and pharmacodynamics of repeat intravenous dosing of 
      efmarodocokin alfa in healthy volunteers (HVs; n=32) and patients with ulcerative 
      colitis (n=24) at 30-90 microg/kg doses given once every 2 weeks or monthly (every 4 
      weeks) for 12 weeks (6:2 active:placebo per cohort). RESULTS: The most common 
      adverse events (AEs) were on-target, reversible, dermatological effects (dry 
      skin, erythema and pruritus). Dose-limiting non-serious dermatological AEs 
      (severe dry skin, erythema, exfoliation and discomfort) were seen at 90 mug/kg 
      once every 2 weeks (HVs, n=2; patients, n=1). Pharmacokinetics were generally 
      dose-proportional across the dose levels, but patients demonstrated lower drug 
      exposures relative to HVs at the same dose. IL-22 serum biomarkers and 
      IL-22-responsive genes in colon biopsies were induced with active treatment, and 
      microbiota composition changed consistent with a reversal in baseline dysbiosis. 
      As a phase 1b study, efficacy endpoints were exploratory only. Clinical response 
      was observed in 7/18 active-treated and 1/6 placebo-treated patients; clinical 
      remission was observed in 5/18 active-treated and 0/6 placebo-treated patients. 
      CONCLUSION: Efmarodocokin alfa had an adequate safety and pharmacokinetic profile 
      in HVs and patients. Biomarker data confirmed IL-22R pathway activation in the 
      colonic epithelium. Results support further investigation of this 
      non-immunosuppressive potential inflammatory bowel disease therapeutic. TRIAL 
      REGISTRATION NUMBER: NCT02749630.
CI  - (c) Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No 
      commercial re-use. See rights and permissions. Published by BMJ.
FAU - Wagner, Frank
AU  - Wagner F
AD  - Charite Research Organization, Berlin, Germany.
FAU - Mansfield, John C
AU  - Mansfield JC
AUID- ORCID: 0000-0003-2490-7750
AD  - Gastroenterology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle 
      upon Tyne, UK.
FAU - Lekkerkerker, Annemarie N
AU  - Lekkerkerker AN
AD  - Genentech Inc, South San Francisco, California, USA.
FAU - Wang, Yehong
AU  - Wang Y
AD  - Genentech Inc, South San Francisco, California, USA.
FAU - Keir, Mary
AU  - Keir M
AD  - Genentech Inc, South San Francisco, California, USA.
FAU - Dash, Ajit
AU  - Dash A
AD  - Genentech Inc, South San Francisco, California, USA.
FAU - Butcher, Brandon
AU  - Butcher B
AD  - Genentech Inc, South San Francisco, California, USA.
FAU - Harder, Brandon
AU  - Harder B
AUID- ORCID: 0000-0002-2555-7038
AD  - Genentech Inc, South San Francisco, California, USA.
FAU - Orozco, Luz D
AU  - Orozco LD
AD  - Genentech Inc, South San Francisco, California, USA.
FAU - Mar, Jordan S
AU  - Mar JS
AUID- ORCID: 0000-0002-0060-802X
AD  - Genentech Inc, South San Francisco, California, USA.
FAU - Chen, Hao
AU  - Chen H
AD  - Genentech Inc, South San Francisco, California, USA.
FAU - Rothenberg, Michael E
AU  - Rothenberg ME
AUID- ORCID: 0000-0002-4603-6653
AD  - Genentech Inc, South San Francisco, California, USA rothenberg.michael@gene.com.
LA  - eng
SI  - ClinicalTrials.gov/NCT02749630
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Randomized Controlled Trial
DEP - 20230202
PL  - England
TA  - Gut
JT  - Gut
JID - 2985108R
RN  - 0 (Biomarkers)
SB  - IM
MH  - Humans
MH  - *Colitis, Ulcerative/drug therapy/pathology
MH  - Healthy Volunteers
MH  - Administration, Intravenous
MH  - Biomarkers
PMC - PMC10359578
OTO - NOTNLM
OT  - gene expression
OT  - interleukins
OT  - intestinal microbiology
OT  - ulcerative colitis
COIS- Competing interests: ANL, YW, MK, AD, BB, BH, LDO, JSM, HC and MER are employees 
      and stockholders of Genentech/Roche.
EDAT- 2023/02/03 06:00
MHDA- 2023/07/10 06:42
PMCR- 2023/07/21
CRDT- 2023/02/02 21:23
PHST- 2022/07/29 00:00 [received]
PHST- 2023/01/24 00:00 [accepted]
PHST- 2023/07/10 06:42 [medline]
PHST- 2023/02/03 06:00 [pubmed]
PHST- 2023/02/02 21:23 [entrez]
PHST- 2023/07/21 00:00 [pmc-release]
AID - gutjnl-2022-328387 [pii]
AID - 10.1136/gutjnl-2022-328387 [doi]
PST - ppublish
SO  - Gut. 2023 Aug;72(8):1451-1461. doi: 10.1136/gutjnl-2022-328387. Epub 2023 Feb 2.