Hollis-Eden Pharmaceuticals, Inc (SAN DIEGO, California), a company focused on the development of a proprietary new class of small molecules that are metabolites or synthetic analogs of endogenous adrenal steroid hormones, announced additional data on drug candidate HE3286 (TriolexTM), an orally active, second generation, synthetic 17-ethynyl derivative of the steroid hormone dehydroepiandrosterone (DHEA), currently in preclinical and clinical study for the treatment of autoimmune diseases and inflammatory disorders. The data showed that HE3286, which has demonstrated benefit in two animal models of rheumatoid arthritis (RA) also demonstrated benefit in an animal model of ulcerative colitis (UC).

Company collaborators reported that HE3286 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 approximately 7 days with either HE3286 or placebo (N = 10 per group). At the end of the treatment period, HE3286-treated animals had significantly reduced disease, as judged by reduced colon weight and reduced area of necrosis compared with the placebo-treated animals. HE3286, even at relatively low doses, performed as well as or better than sulfasalazine, which is the standard of care and the positive control in this model.

In animal studies conducted to date, HE3286 has demonstrated activity in multiple models of inflammatory conditions, including RA, multiple sclerosis, lupus, and cystic fibrosis. HE3286 produced a statistically significant reduction in disease in mouse models of RA, both at onset of the disease as well as after the disease was well established. As previously reported, in the DBA mouse model of collagen-induced arthritis (CIA), animals receiving oral treatment with HE3286 (50 mg/kg), beginning at onset of disease, significantly decreased CIA peak scores and daily severity of arthritis scores. Benefit was associated with decreases in production of TNFα, IL-6, and IL-17, and decreases in joint inflammation, erosion, and synovial proliferation as judged by histological analysis. The compound was also associated with increases in numbers and function of regulatory T-cells (Tregs). Additional new data obtained by company collaborators show that HE3286 provided significant benefit (P <.05) in an animal model of adjuvant arthritis (a model for chronic, erosive polyarthritis), even when treatment was delayed until disease was well established. In that model, rodents treated orally with HE3286, beginning either at disease onset or 1 week after disease onset, showed markedly reduced disease score and paw edema compared with placebo-treated animals.

An Investigational New Drug (IND) application has been filed with the US FDA for the initiation of a phase I/II trial during the fourth quarter of 2007 of HE3286 in RA patients. Earlier this year, the company completed a single-dose phase I clinical study of HE3286 in healthy volunteers. The compound was shown to be orally bioavailable, with significant drug concentrations from the lowest dosage of 10 mg through 100 mg detected in the blood. HE3286 appeared to be safe and well tolerated with no reported drug related adverse side effects.

Hollis-Eden's compounds are based on naturally occurring human steroid hormones derived from DHEA, which in turn is produced by pregnenalone. The company has in vivo and in vitro data linking the anti-inflammatory activity of HE3286 to the regulation of the NF-kappaB pathway and the production of Tregs. HE3286 may act by limiting the activation of NF-kappaB activation, a transcription factor that controls many of the genes involved in the inflammatory signaling pathway, including TNFα, IL-1β, and IL-6. Unlike corticosteroids that act through the glucocorticoid receptor to completely block NF-kappaB activation and cause immune suppression and bone loss, HE3286 does not interact with the glucocorticoid receptor and only partially inhibits NF-kappaB without immune suppression or bone loss.