HE3286: A Novel Synthetic Steroid as an Oral Treatment for Autoimmune Disease

Abstract

HE3286 (17alpha-ethynyl-5-androstene-3beta, 7beta, 17beta-triol) is a synthetic derivative of a natural anti-inflammatory steroid, beta-AET (5-androstene-3beta, 7beta, 17beta-triol). HE3286 is orally bioavailable and treats established disease in models of ulcerative colitis, collagen-induced arthritis, and collagen antibody-induced arthritis, reducing clinical signs of disease and proinflammatory signals, including IL-6 and matrix metallopeptidase 3. HE3286 modulates nuclear factor kappaB through an unknown mechanism but does not interact with any of the steroid-binding nuclear hormone receptors and is not immune suppressive. HE3286 was safe and well tolerated in phase I studies and is under evaluation in multicenter phase I/II clinical trials for ulcerative colitis and arthritis. HE3286 may provide a new treatment option for patients with inflammatory and autoimmune diseases.

Oral treatment with HE3286 ameliorates disease in rodent models of rheumatoid arthritis

“…In addition, we show herein that HE3286 was not immune suppressive in MLR studies and that extended pre-treatments were safe and may even have provided benefit in the murine model of myocarditis induced by CB3V infection. The present studies confirm the anti-inflammatory activity reported for HE3286 in our previous publications (23,24,26).…”

“…Our previous studies with AET showed benefit in rodent models of ulcerative colitis and multiple sclerosis (23,24). Thus, a broad based anti-inflammatory activity is perhaps central to the activities of HE3286 in auto-immune disease.…”

“…23). Previously we showed that subcutaneous (s.c) injection of androstene-3ß, 7ß, 17ß-triol (AET) provided benefit in rodent models of ulcerative colitis (24) and experimental autoimmune encephalitis (25). By virtue of its anti-inflammatory activity, AET improved survival in a rodent model of traumatic shock (26).…”

Pharmacology and immune modulating properties of 5-androstene-3β,7β,17β-triol, a DHEA metabolite in the human metabolome

“…In contrast, the immunological effects of ␤AET in the PLN assay suggested Th2 promotion of antigen specific responses. These later observations are consistent with our previous reports that ␤AET treatment reduced disease in rodent models of experimental autoimmune encephalomyelitis [53] and TNBS-induced colitis [49]. In these models, reduced disease is often associated with an immune shift from a Th1/Th17 status to a Th2/regulatory T cell profile [54,55].…”

“…Qualitatively, the activity we observed was similar to DHEA [4], 5-androstenediol [27], and 17␣-alkynyl-␤AET [30,49] in chronic inflammation models. ␤AET's activity in RAW264.7 cells was similar to DHEA [50,51], although both DHEA and ␤AET were active only at 10 M, a concentration not readily achieved or sustained in vivo.…”