Developmental Clinical Studies- Combined Immunotherapy and Trophic Adrenocortical Stimulation in New Onset Autoimmune Addison's Disease

Autoimmune Addison's disease is caused by the immune system attacking and destroying the cortex of the adrenal glands, which gives people a life-threatening problem owing to lack of the adrenal steroid hormones. Symptoms typically include exhaustion, light-headedness, vomiting, weight loss, poor appetite, muscle weakness and cramps. In addition, Addison's people are prone to unpredictable episodes of severe illness, termed adrenal crisis. This means that people with Addison's disease have a life-long dependency on steroid medications, and may become ill within hours of a missed dose. There have been no significant advances in therapy for Addison's disease for sixty years. However, the adrenal cortex is one of the most plastic tissues in the body and this study aims to exploit this innate regenerative capacity to produce a cure for people who have just been diagnosed with Addison's disease.

The idea of this study is to combine a hormone therapy that is a synthetic version of the body's natural adrenal stimulating hormone, termed ACTH (adrenocorticotropic hormone), with a treatment to dampen down the immune system's attack on the adrenal cortex. In a previous study, we have found that alternate day injections with synthetic ACTH is effective in stimulating adrenal gland regeneration, but we do not know what sort of treatment will be effective in dampening down the immune response. This will be important to make sure any adrenal regeneration isn't just rapidly destroyed again by the immune attack. The study will take place in 3 stages, each involving 4 people with newly-diagnosed Addison's disease. In each stage of the study, the participants will receive the same dose of alternate day ACTH. However, the first part of the study will use a drug called rituximab, that removes the antibody-producing B lymphocytes from the blood and tissues for about 6 months, to see if this stops the immune attack on the adrenals and allows permanent regeneration. If this doesn't work, we will try a different sort of immunotherapy called abatacept, that affects the function of the T lymphocytes, which act both as the immune system's radar and assassination team. Both these treatments are antibody therapies that are administered for a short period of time (either 2 or 5 doses), but produce long lasting effects on immune system function, for several months. If neither of these immune system treatments work, we will then use a combination of 3 high-dose steroid infusions followed by a daily immunosuppressive tablet called mycophenolate which will be taken for 12 weeks. After each of these treatments adrenal function will be retested in participants at regular intervals for a year to see if the hormonal function of the adrenal gland had been improved. We believe that this therapeutic approach, combining both a drug to quash the immune system attack on the adrenal glands with hormonal stimulation to promote adrenal regeneration, holds genuine promise for cure of this chronic condition.

The adrenal cortex is one of the most plastic tissues in the body. However, in autoimmune Addison's disease (AAD) it is destroyed, leading to lifelong dependency on daily steroid medication for survival. Importantly, at presentation most AAD patients have subnormal, but detectable circulating concentrations of the major adrenal steroid, cortisol. This demonstrates that there is residual adrenal function in new onset AAD that could be 'rescued' by appropriate therapy. We have been exploring this potential therapeutic window with two early-phase human studies. In the first study, we have demonstrated that B lymphocyte depletion appears to have disease-modifying properties in AAD. In the second study, we have shown proof of the principle that hormonal stimulation with adrenocorticotrophic hormone (ACTH) can improve steroidogenesis even in patients with primary adrenal failure. This information suggests a new treatment strategy.

In this current study, we will use a novel combination of an immunotherapy, to ameliorate the autoimmune attack, together with specific trophic stimulation of residual adrenocortical cell function using synthetic ACTH1-24. We propose a 3-stage, adaptive, open-label trial design with the choice of immunotherapeutic agent as the adaptive component, along with a constant regimen of adrenal trophic stimulation with regular subcutaneous ACTH1-24. The three different immunotherapy stages will be 1). B lymphocyte depletion (rituximab); 2). T lymphocyte co-stimulatory blockade (abatacept) and 3). Conventional immunosuppression with high dose glucocorticoid and mycophenolate mofetil. We believe that this therapeutic approach, combining both immunomodulation and trophic hormonal stimulation of adrenal cortical regeneration, holds genuine promise for cure of this chronic condition.

Health and Well-being:
Patients with Addison's disease, their families and employers are the main people to benefit if this study is successful in identifying a novel treatment to cure new onset autoimmune Addison's disease. The impact of not being dependent upon steroid medication lifelong are self evident, in terms of day to day health improvement and the complications from chronic use of these medications (eg. type 2 diabetes and osteoporosis risk). In addition, the small number of Addison's people who we have rendered 'steroid free' in previous studies have reported an improved sense of well-being and vitality, with better quality of life on several measures. The actual and perceived risk of the unpredictable 'adrenal crisis', which some patients find very limiting, will also be lifted.

General public and society:
In terms of societal benefits, Addison's is a chronic disease, with significant lifelong consumption of extra healthcare resources. An 'acute' but curative regenerative medicine therapy is likely to reduce healthcare consumption overall. With current drug prices, the combination of steroid prescriptions, blood testing, GP and hospital check ups costs the NHS about £1,000 annually for monitoring and review of a 'well' Addison's patient. Thus, the cost of any curative immunotherapy would be recouped quickly in comparison to a life of 30 or 40 yrs of steroid medication dependency. In addition, individuals with Addison's are more likely to be unemployed than others, and are unsuited to certain jobs, such as frontline soldier, police officer or airline pilot. Society stands to benefit if these people can work as normal following acute treatment.

Academic community:
In terms of benefits to the scientific community, long-term 'therapeutic tolerance' is a holy grail approach for autoimmune conditions, as this would mean a therapy that could effectively abrogate the autoimmune process without causing potentially hazardous immunosuppression. Therapeutic tolerance approaches are being pursued on a research basis in several common conditions, the most notable being rheumatoid arthritis, type 1 diabetes and multiple sclerosis. If Addison's disease is a tractable model in which it is possible to re-establish tolerance and regenerate tissue function, this could inform the approach to several other more common diseases as we would be able to elucidate the important mechanistic details involved.