db db Mice Induced by AZP3404 a 9Amino Acid of IGFBP2 Michael D Culler 1 Stéphane Milano 1 Michel Ovize 1 Thomas Delale 1 Aart Jan van der Lely 2 David Clemmons 3 ID: 935190
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Slide1
OC12.2
Improved Glucose Metabolism and Decreased Weight Gain in Leptin-Resistant, IGFBP2-Deficient,
db
/db Mice Induced by AZP-3404, a 9-Amino Acid of IGFBP2Michael D. Culler1, Stéphane Milano1, Michel Ovize1, Thomas Delale1, Aart Jan van der Lely2, David Clemmons31Amolyt Pharma, Cambridge, MA, USA and Ecully, France. 2Erasmus University MC, Rotterdam, Netherlands. 3New Paradigm Therapeutics, Chapel Hill, NC, USA
Slide2Disclosures
Nothing to Disclose
Slide3Metabolic effects of leptin mediated by IGFBP-2
Slide4Heparin Binding Domain-1
(HBD-1)13 Amino Acids
AZP-3404
325 Amino Acid Protein- IGF-1 binding not required for metabolic activity9 AA acylated peptideEnzymatically stableEnhanced PKIGFBP-2Independently reproduces metabolic activity of IGFBP-2 on adipose, glucose metabolism and bone
Dose-related increase in glucose
uptake by mouse muscle cells
% Increase Glucose Uptake
HBD-1-derived peptide, AZP-3404, reproduces the metabolic
activity of IGFBP-2
Slide5db/db mouse – Leptin produced, but defective leptin receptor
leptin-resistant = IGFBP-2 deficientIGFBP-2
Wild Type
db/dbHypothesis:obese
Hall et al., 2014
Geng
et al., 2019
IGFBP-2
Slide6Study Plan
Slide7Body weight gain over 8 weeks of treatment
MRI analysis revealed that the decrease in
weight gain was due to decreased fat mass, largely visceral, without impact on lean mass
**** p<0.0001 *** p<0.001 * p<0.05versus Vehicle
Slide84-Week
ipGTT - Highest dose increases glucose disposal
8.3% 9.4% 28.7%
**p<0.006
Slide918.8% 21.4% 23.1%
*
*p<0.05
8-Week ipGTT - All doses increase glucose disposal
Slide108-Week treatment - All doses decrease fasted insulin level
and HOMA-IR
HOMA IR in vehicle-treated animals consistent
with literature values for db/db mice 46% 53% 48%
Slide11Leptin-resistant, IGFBP2-deficient,
db
/
db mice treated with AZP-3404 displayed:A progressive decrease in the rate of body weight gainDue to decreased fat mass, largely visceral, without impact on lean massSignificantly increased glucose disposal following a glucose challengeDecreased fasted insulin levels and improved insulin sensitivity (decrease in the HOMA insulin-resistance score)
The present results demonstrate that AZP-3404 reproduces the weight- and glucose-modulating action of IGFBP-2, and may have potential for therapeutic use in syndromes characterized by insulin resistance and/or obesity
Summary and Conclusions
Slide12Thank you!