FP17-3 ISIS Ptp-1BRx, a Novel Protein Tyrosine Phosphatase (PTP-1B) Antisense Inhibitor, Improves Both Insulin and Leptin Action and Increases HMW Adiponectin Levels in Obese Subjects

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: FP17-Diabetes: New Diagnostic & Treatment Modalities
Sunday, June 16, 2013: 10:45 AM-11:15 AM
Presentation Start Time: 10:55 AM
Room 307 (Moscone Center)

Poster Board SUN-841
Que Liu*1, Shuting Xia1, Wei Cheng1 and Richard Geary2
1Isis Pharmaceuticals Inc., Carlsbad, CA, 2Isis Pharmaceuticals Inc., Carlsbad
PTP-1B is a negative regulator of both insulin and leptin action. Since reduction of PTP-1B activity enhances insulin and leptin sensitivity in preclinical models, PTP-1B inhibitors could be promising therapeutics for T2DM and obesity. However, very few studies have examined the role of PTP-1B in human insulin and leptin resistance due to lack of specific PTP-1B inhibitors. The present randomized (3:1) double-blind, placebo-controlled, Phase 1 study evaluated safety, tolerability and pharmacokinetics (PK) of single or multiple dose levels of a specific PTP-1B antisense inhibitor, ISIS-PTP-1BRx, (50, 100, 200 and 400 mg) administered subcutaneously to 48 healthy subjects (age=49±11yrs,  BMI=30±2.6) over a 4 week treatment period. Primary pharmacodynamic (PD) parameters were analyzed on Day 29 and Day 36. Treatment with ISIS-PTP-1BRx for 4 weeks resulted in dose-dependent increase in HMW adiponectin, with >4-fold increase in HMW adiponectin in the 400 mg group.  As compared to placebo, statistically significant reduction of leptin levels was also observed in ISIS PTP-1BRx cohorts, with a maximal reduction from baseline of 14% (p=0.0295 vs. placebo).  Furthermore, plasma insulin levels were reduced with no changes in FPG, and HOMA-IR was decreased by (14%).  ISIS PTP-1BRx was well tolerated and no SAEs were observed. No clinically significant effects on vital signs, ECG, hepatic or renal function and no hypoglycemia was observed. These data suggest that PTP-1B may be a novel therapeutic target for T2DM and obese patients and support further development of ISIS-PTP-1BRx in these populations.

Disclosure: QL: Clinician, ISIS Pharmaceuticals. RG: Management Position, Isis Pharmaceuticals. Nothing to Disclose: SX, WC

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm