PMID- 28605468
OWN - NLM
STAT- MEDLINE
DCOM- 20170920
LR  - 20191210
IS  - 1945-7197 (Electronic)
IS  - 0021-972X (Linking)
VI  - 102
IP  - 8
DP  - 2017 Aug 1
TI  - Attenuation of Insulin Action by an Allosteric Insulin Receptor Antibody in 
      Healthy Volunteers.
PG  - 3021-3028
LID - 10.1210/jc.2017-00822 [doi]
AB  - BACKGROUND: XOMA 358 (X358) is a fully human monoclonal antibody to the insulin 
      receptor that acts as a negative allosteric modulator of insulin signaling. It is 
      being developed as a novel treatment of hyperinsulinemic hypoglycemia. This 
      report describes pharmacokinetic (PK) and pharmacodynamic (PD) data from a 
      first-in-human clinical trial. METHODS: A double-blind, placebo-controlled, 
      single-ascending-dose study was performed with 29 healthy adult males randomized 
      to intravenous infusion of placebo or X358 at 0.1-, 0.3-, 1-, 3-, 6-, or 9-mg/kg 
      dose levels. The primary objective was to assess safety and tolerability, and 
      secondary objectives included PK and PD analyses. A short insulin tolerance test 
      (ITT) was implemented in the 3- to 9-mg/kg dose cohorts at baseline and 
      postinfusion. RESULTS: There were no deaths, serious adverse events (AEs), or 
      subject discontinuations due to AEs. There were no clinically meaningful safety 
      findings. X358 exhibited dose-proportional PK with a half-life of 21 days. 
      Dose-dependent elevations of circulating insulin levels, likely related to 
      reduced insulin clearance via monoclonal antibody action at receptors, 
      represented a sensitive biomarker of X358 exposure. X358-dependent increases in 
      postprandial glucose levels and fasting homeostatic model assessment of insulin 
      resistance values were observed and persisted for at least 1 week at the higher 
      dose levels. In all the ITT cohorts, the slope for glucose lowering was 
      substantially attenuated after X358 infusion of a similar magnitude, but with 
      increasing duration with rising dose level. CONCLUSION: Single X358 infusions 
      were well tolerated and resulted in a dose-dependent reduction in insulin 
      sensitivity. Clinical development of X358 in hyperinsulinemic, hypoglycemic 
      conditions is proceeding.
CI  - Copyright (c) 2017 Endocrine Society
FAU - Johnson, Kirk W
AU  - Johnson KW
AD  - Research and Development, XOMA Corporation, Berkeley, California 94710.
FAU - Neale, Ann
AU  - Neale A
AD  - Research and Development, XOMA Corporation, Berkeley, California 94710.
FAU - Gordon, Allan
AU  - Gordon A
AD  - Research and Development, XOMA Corporation, Berkeley, California 94710.
FAU - Roessig, Julie
AU  - Roessig J
AD  - Research and Development, XOMA Corporation, Berkeley, California 94710.
FAU - Bezwada, Padma
AU  - Bezwada P
AD  - Research and Development, XOMA Corporation, Berkeley, California 94710.
FAU - Vukelich, Sabine
AU  - Vukelich S
AD  - Research and Development, XOMA Corporation, Berkeley, California 94710.
FAU - Goldfine, Ira
AU  - Goldfine I
AD  - Research and Development, XOMA Corporation, Berkeley, California 94710.
FAU - Rubin, Paul
AU  - Rubin P
AD  - Research and Development, XOMA Corporation, Berkeley, California 94710.
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Randomized Controlled Trial
PL  - United States
TA  - J Clin Endocrinol Metab
JT  - The Journal of clinical endocrinology and metabolism
JID - 0375362
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 0 (Blood Glucose)
RN  - 0 (XOMA 358)
RN  - EC 2.7.10.1 (Receptor, Insulin)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Allosteric Regulation
MH  - Antibodies, Monoclonal/administration & dosage/*pharmacology
MH  - Antibodies, Monoclonal, Humanized
MH  - Blood Glucose/*drug effects
MH  - Double-Blind Method
MH  - Fasting/metabolism
MH  - Half-Life
MH  - Healthy Volunteers
MH  - Humans
MH  - Hyperinsulinism/complications/*drug therapy
MH  - Hypoglycemia/*drug therapy/etiology
MH  - Insulin Resistance
MH  - Male
MH  - Postprandial Period/*drug effects
MH  - Receptor, Insulin/*drug effects/immunology
MH  - Young Adult
EDAT- 2017/06/13 06:00
MHDA- 2017/09/21 06:00
CRDT- 2017/06/13 06:00
PHST- 2017/04/06 00:00 [received]
PHST- 2017/06/06 00:00 [accepted]
PHST- 2017/06/13 06:00 [pubmed]
PHST- 2017/09/21 06:00 [medline]
PHST- 2017/06/13 06:00 [entrez]
AID - 3865691 [pii]
AID - 10.1210/jc.2017-00822 [doi]
PST - ppublish
SO  - J Clin Endocrinol Metab. 2017 Aug 1;102(8):3021-3028. doi: 10.1210/jc.2017-00822.