BiotechTracker: Antisense Drug Shows Promise for Diabetes Treatment

BiotechTracker: Antisense Drug Shows Promise for Diabetes Treatment

September 17, 2003 Isis’s (NASDAQ: ISIS) ISIS 113715 has generated reassuring safety, tolerability, and pharmacologic activity profiles in randomized, double-blind, dose-escalating, phase I investigation. The initial human data add to preclinical rodent model as well as normal and obese primate model data. Isis has initiated a 3-month, open-label, dose-escalation, phase II clinical trial designed to assess the construct’s ability to regulate glucose in patients with type II diabetes.

20 volunteers unaffected with type II diabetes received parenteral ISIS 113715 or placebo for one week. ISIS 113715 5.0 mg/kg and 7.5 mg/kg, the highest dose levels, produced reassuring glucose tolerance improvement profiles following a glucose challenge.

ISIS 113715 is an antisense construct that targets the gene encoding protein tyrosine phosphatase 1B (PTP-1B), an enzyme that dampens intracellular signaling triggered by insulin binding to its receptor. Clinically this manifests as insulin resistance with its attendant elevated blood sugar and, potentially, its chronic metabolic, vascular, and other ill-health consequences. Loss of PTP-1B activity is known to enhance insulin sensitivity as well as resistance to weight gain. Isis hopes that inhibiting PTP-1B facilitates enhanced insulin receptor activity such that sugar uptake, from blood, into cells is improved for insulin-resistant individuals. Moreover, if its glucose modulating properties are unaccompanied by weight gain, it could represent a considerably more attractive option than multiple marketed hypoglycemic agents. The construct has the potential to complement existing treatments for the early phases of type II diabetes and could possibly benefit pre-diabetics with impaired glucose tolerance falling short of definitive diabetes.

A recent acceleration of interest has been seen for PTP-1B as a diabetes drug target. Historically a challenging target, recent data from x-ray crystallographic, in vitro and, especially, in silico work has led to several attractive PTP-1B inhibitors. These compounds include peptides, small molecules, and antisense constructs.

Isis will face competition from several companies developing PTP-1B inhibitors, including Cengent Therapeutics (the merged company formed from Structural Bioinformatics and GeneFormatics, both privately held), Novo Nordisk (NYSE: NVO), Abbott (NYSE: ABT), Wyeth (NYSE: WYE), Glaxo (NYSE: GSK), Merck (NYSE: MRK), Pfizer (NYSE: PFE), Ontogen (privately held), Astex (privately held), and Cetek (privately held). Cengent has a compelling preclinical portfolio in this area, and its small molecule PTP-1B inhibitors are orally available. Abbott investigators published a high-profile manuscript in PNAS a year ago demonstrating preclinical progress with an anti-PTP-1B antisense construct. Wyeth has yet to revive its PTP-1B program after the phase II failure of PTP 112 in June 2002.

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