Session: SAT 358-380-Steroid Hormone Biosynthesis & Metabolism
Poster Board SAT-358
Earn H Gan, Katie DR MacArthur, Anna L Mitchell, Beverly A Hughes, Petros Perros, Steve Ball, Andy James, Richard Quinton, Shu Chen, Jadwiga Furmaniak, Wiebke Arlt, Simon HS Pearce
Despite lifelong steroid replacement, there is excess morbidity and mortality associated with autoimmune Addison’s disease (AAD). Adrenal cortical cells undergo continuous self-renewal from a population of subcapsular progenitor cells, under the influence of ACTH. We aimed to determine if synthetic ACTH analogue could revive adrenal steroidogenic function and ameliorate AAD.
We performed an open-label trial of synthetic ACTH1-24 analogue (synacthen) in adults with established AAD for more than 1 year [NCT 01371526]. In phase 1, depot synacthen 1mg was administered subcutaneously alternate days for 10 weeks. In phase 2, participants were then randomised to a further 10 weeks of either a continuous 24h or overnight 12h infusion of synacthen (both administered at 10µg/hr). Dynamic testing of adrenal function was performed at baseline and then every 5 weeks. Thirteen subjects (aged 16-65; 11 female), were treated for either 5 (n=1), 10 (n=2), 20 (n=8) or more (n=2) weeks. Twelve of 13 patients had positive serum 21-hydroxylase antibodies, and these remained stable during the study. All had elevated ACTH levels, 174ng/l or more (normal <55) at baseline.
Serum cortisol levels remained under 100nmol/l (3.6µg/dl) in 11 of 13 participants throughout the study. However, 2 women both with detectable baseline serum cortisol (219 and 179 nmol/l; 7.9 and 6.5 µg/dl) achieved peak serum cortisol concentrations >400nmol/l (14.5µg/dl), after 10 and 29 weeks of synacthen therapy, respectively; allowing withdrawal of replacement medication. Glucocorticoid and mineralocorticoid metabolite excretion increased in these 2 patients from subnormal to above the median of healthy controls. Serum androstenedione and urinary androgen precursors also increased in tandem with glucocorticoid. These 2 responders had established AAD for 8 and 4 years, respectively. One of them remains well with improving serum cortisol (last measurement 672nmol/l; 24.3µg/dl) 24 months after stopping all treatments. The other participant had a gradual reduction in both serum cortisol and aldosterone concentration, hence steroid therapy was recommenced at week-64.
This is the first study to demonstrate that established AAD may be amenable to a regenerative medicine therapy. We have also shown that AAD is heterogeneous in terms of residual adrenal function, and that identification of patients with low-level residual steroidogenesis is an important priority for future therapies.
Disclosure: SC: Employee, RSR ltd.. JF: Employee, RSR ltd. SHP: Speaker, Viropharma, Speaker, Merck & Co.. Nothing to Disclose: EHG, ALM, KM, BAH, PP, SGB, AJ, RQ, WA
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