Hollis-Eden Pharmaceuticals, Inc (SAN DIEGO, California), a leader in the development of a new class of small molecule compounds based on endogenous steroid hormones, announced that it has begun a phase I/II clinical trial with Triolexâ„¢ (HE3286). The insulin sensitizer is a novel orally bioavailable adrenal steroid hormone analogue, in ulcerative colitis (UC). The 28-day dose ranging study will evaluate the safety, tolerance, pharmacokinetics and activity of oral Triolex in patients with active, mild-to-moderate UC.

In previously reported data, the agent showed significant (P <.05) benefit in the Wistar rat model of dinitrobenzene sulfonic acid (DNBS)-induced colitis, a preclinical model widely used to test agents as potential treatments for UC. DNBS-challenged rats with induced colitis were treated orally for 7 days with either Triolex or placebo (N = 10 per group). At the end of the treatment period, Triolex-treated animals had significantly reduced disease, as judged by reduced colon weight and reduced area of necrosis, compared with the placebo-treated animals. The agent performed at least as well as sulfazalazine, the standard of care used as a positive control in this model.

Triolex possesses anti-inflammatory and insulin-sensitizing properties and is currently in clinical trials under an open Investigational New Drug (IND) application for the treatment of metabolic disorders. Hollis-Eden has also been cleared under a separate IND to begin clinical trials with the agent for the treatment of rheumatoid arthritis (RA). A safety and pharmacokinetic phase I/II clinical trial in stable RA patients on methotrexate will begin in the second quarter of 2008.

Hollis-Eden believes the broad-based anti-inflammatory activity of Triolex may relate to a partial inhibition of the NF-kappaB pathway. NF-kappaB is a transcription factor that controls genes whose products are involved in the inflammatory signaling pathway, including TNF-α and IL-6. These cytokines are thought to be involved in the pathogenesis of certain autoimmune diseases such as UC and RA. Unlike currently prescribed corticosteroids that act through the glucocorticoid receptor to completely block NF-kappaB activation and cause immune suppression and bone loss, preclinical models to date show that Triolex does not interact with the glucocorticoid receptor, and only results in a partial inhibition of the NF-kappaB pathway without immune suppression or bone loss. The agent has a half-life in humans of 5 to 8 hours.