Hollis-Eden Pharmaceuticals, Inc (SAN DIEGO, California) is developing a proprietary new class of small molecule compounds that are metabolites or synthetic analogs of endogenous adrenal steroid hormones. The company announced the initiation of a phase I/II open-label, dose-ranging clinical trial with its investigational, nonimmunosuppressive oral drug candidate Triolex™ (HE3286), a stabilized, synthetic analog of a naturally occurring molecule metabolized by the body from dehydroepiandrosterone in patients diagnosed with rheumatoid arthritis (RA) and who are receiving a stable dose of methotrexate (MTX). The pilot, exploratory study will evaluate the safety, tolerance, pharmacokinetics and potential anti-inflammatory activity of Triolex, when administered orally for 29 days at 5 mg BID, 2 x 5 mg BID, or 4 x 5 mg BID. The study will also evaluate the pharmacokinetics, and metabolism profiles of combination MTX and Triolex.

In a preclinical study in models of RA, Triolex has performed as well or better than other biologics and is effective in models where MTX fails. Hollis-Eden previously reported positive results from preclinical studies with the agent in models of collagen induced arthritis (CIA) and collagen antibody induced arthritis (CAIA). These models represent both the cell-mediated and antibody-mediated aspects of human RA.

In a model of CIA, mice were immunized to induce disease and were then treated orally with Triolex or placebo beginning 1 week after disease onset. Although the severity of arthritis worsened steadily in the placebo-treated group, it nearly resolved or remained at a minimum in the Triolex-treated group (P <.001). Treatment resulted in a difference in arthritis severity that was on average 45% lower in the Triolex-treated group than in the placebo-treated group.

In the murine model of CAIA, the therapy significantly reduced disease in a dose-dependent fashion, with the highest dose completely eliminating disease. Disease was induced by injecting animals with atherogenic antibodies, a method that largely bypasses the animals' own cellular immune systems. Severe joint inflammation occurs within hours after the injection of antibodies. Triolex was highly effective in this model whether treatment began 1 day or 5 days after injection with antibodies. Benefit at the peak of disease was associated with a significant reduction of interleukin-6 (IL-6) and matrix metalloproteinase-3 mRNA from the joints of Triolex-treated animals compared with placebo-treated controls. MTX is far less effective in the CAIA model than in the CIA model, where disease is driven by the animal's own cellular immune system.

Hollis-Eden believes that the benefit of the agent in animals was associated with expansion of regulatory T-cells. The company also believes that the agent may induce resolution in pro-inflammatory pathways, such as those governed by NFκB, a transcription factor that controls many of the genes involved in the inflammatory signaling pathway, including TNFα, IL-1β, and IL-6. Unlike currently prescribed corticosteroids that can cause immune suppression and bone loss, animal studies to date show that Triolex does not interact with the glucocorticoid receptor and only partially inhibits the NFκB pathway without causing immune suppression or bone loss. These observations suggest that rather than blocking the inductive phase of the inflammatory response, which historically leads to profound immune suppression, the agent may drive the active resolution of unproductive inflammation.

Triolex is also currently in clinical trials for the treatment of ulcerative colitis.