PMID- 31758576
OWN - NLM
STAT- MEDLINE
DCOM- 20210728
LR  - 20240328
IS  - 1365-2125 (Electronic)
IS  - 0306-5251 (Print)
IS  - 0306-5251 (Linking)
VI  - 86
IP  - 4
DP  - 2020 Apr
TI  - First-in-human, randomized dose-escalation study of the safety, tolerability, 
      pharmacokinetics, pharmacodynamics and immunogenicity of PF-06480605 in healthy 
      subjects.
PG  - 812-824
LID - 10.1111/bcp.14187 [doi]
AB  - AIMS: Human genetic, tissue expression, proteomics, transcriptomics and 
      nonclinical studies implicate tumour necrosis factor alpha-like ligand 1A (TL1A) as a 
      novel target in inflammatory bowel disease (IBD). PF-06480605, a fully human 
      immunoglobulin G1 monoclonal antibody, targets TL1A. This first-in-human, Phase 
      1, dose-escalation study assessed safety, tolerability, pharmacokinetics, 
      pharmacodynamics and immunogenicity of intravenous (IV) and subcutaneous (SC) 
      PF-06480605 in healthy subjects (NCT01989143). METHODS: Ninety-two subjects were 
      randomized to single ascending doses (SAD), PF-06480605 1 mg, 3 mg, 10 mg, 30 mg, 
      100 mg, 300 mg, 600 mg or 800 mg IV, or multiple ascending doses (MAD), 
      PF-06480605 3 x 500 mg IV, or 3 x 30 mg, 3 x 100 mg, or 3 x 300 mg SC every 2 
      weeks for three doses, or placebo. Safety, tolerability, pharmacokinetics, 
      immunogenicity profiles and total TL1A, anti-drug antibody (ADA) and neutralizing 
      antibody (NAb) levels were assessed at pre-determined times. RESULTS: PF-06480605 
      SAD up to 800 mg IV and MAD up to 300 mg x3 SC and 500 mg x3 IV were well 
      tolerated. Overall, there were 45 and 44 treatment-emergent adverse events in SAD 
      and MAD cohorts, respectively, and no deaths or serious adverse events. 
      PF-06480605 exposure generally increased dose-dependently. ADA and NAb levels did 
      not impact safety, pharmacokinetics, or pharmacodynamics at higher doses. Target 
      engagement was demonstrated through dose-dependent differences in serum total 
      soluble TL1A concentrations for PF-06480605 vs placebo cohorts. CONCLUSIONS: 
      PF-06480605 was generally well tolerated, and binding of soluble TL1A was 
      maintained throughout the dose interval, supporting further study of PF-06480605 
      in patients with IBD and other inflammatory conditions.
CI  - (c) 2019 The British Pharmacological Society.
FAU - Banfield, Christopher
AU  - Banfield C
AD  - Pfizer Inc, Cambridge, Massachusetts.
FAU - Rudin, Dan
AU  - Rudin D
AD  - Pfizer Inc, New Haven, Connecticut.
FAU - Bhattacharya, Indranil
AU  - Bhattacharya I
AD  - Pfizer Inc, Cambridge, Massachusetts.
FAU - Goteti, Kosalaram
AU  - Goteti K
AD  - Pfizer Inc, Cambridge, Massachusetts.
FAU - Li, Gang
AU  - Li G
AD  - Pfizer Inc, Collegeville, Pennsylvania.
FAU - Hassan-Zahraee, Mina
AU  - Hassan-Zahraee M
AD  - Pfizer Inc, Cambridge, Massachusetts.
FAU - Brown, Lisa S
AU  - Brown LS
AD  - Pfizer Inc, Collegeville, Pennsylvania.
FAU - Hung, Kenneth E
AU  - Hung KE
AD  - Pfizer Inc, Cambridge, Massachusetts.
FAU - Pawlak, Sylvester
AU  - Pawlak S
AD  - Pfizer Inc, New Haven, Connecticut.
FAU - Lepsy, Christopher
AU  - Lepsy C
AD  - Pfizer Inc, Andover, Massachusetts.
LA  - eng
SI  - ClinicalTrials.gov/NCT01989143
GR  - Pfizer Inc/International
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20200128
PL  - England
TA  - Br J Clin Pharmacol
JT  - British journal of clinical pharmacology
JID - 7503323
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Antibodies, Neutralizing)
RN  - 0 (Antineoplastic Agents, Immunological)
SB  - IM
MH  - Administration, Intravenous
MH  - Antibodies, Monoclonal
MH  - *Antibodies, Neutralizing
MH  - *Antineoplastic Agents, Immunological
MH  - Dose-Response Relationship, Drug
MH  - Double-Blind Method
MH  - Healthy Volunteers
MH  - Humans
PMC - PMC7098865
OTO - NOTNLM
OT  - Phase 1
OT  - clinical trials
OT  - inflammation
OT  - monoclonal antibodies
OT  - pharmacodynamic
OT  - pharmacokinetic
EDAT- 2019/11/24 06:00
MHDA- 2021/07/29 06:00
PMCR- 2021/04/01
CRDT- 2019/11/24 06:00
PHST- 2019/04/29 00:00 [received]
PHST- 2019/10/25 00:00 [revised]
PHST- 2019/10/29 00:00 [accepted]
PHST- 2019/11/24 06:00 [pubmed]
PHST- 2021/07/29 06:00 [medline]
PHST- 2019/11/24 06:00 [entrez]
PHST- 2021/04/01 00:00 [pmc-release]
AID - BCP14187 [pii]
AID - 10.1111/bcp.14187 [doi]
PST - ppublish
SO  - Br J Clin Pharmacol. 2020 Apr;86(4):812-824. doi: 10.1111/bcp.14187. Epub 2020 
      Jan 28.