MICA: Evaluation of the selective endothelin A-receptor antagonist zibotentan as a treatment for renal disease in systemic sclerosis (scleroderma)

Systemic sclerosis (SSc), also called scleroderma, is a serious rheumatic disease. Although skin thickening, or hardening, occurs in almost all cases, justifying the term "scleroderma", the disease is much more than "skin-deep" since it often causes damage many internal organs including the heart, lungs, kidney, bowel and blood vessels. It is important because, although uncommon, it causes more deaths than any other rheumatic disease, with around half of the patients diagnosed with scleroderma eventually dying as a direct result of the condition. It also causes many severe non-life threatening problems such as pain, loss of hand function and disability.

The kidneys are often affected in scleroderma and this can occur in two main ways. First, around 1 in 8 cases of severe systemic sclerosis develop kidney failure associated with very high blood pressure. This is called a scleroderma renal crisis (SRC). Although previously usually fatal, most patients now survive SRC but up to half can have long term renal failure and require dialysis or transplantation. In addition to SRC, scleroderma also affects kidneys in a second way that is much more frequent. Due to long term blood vessel damage and scarring (or fibrosis) scleroderma causes long term (chronic) renal damage. Although less immediately life-threatening than SRC this chronic renal damage may impact on long term survival and quality of life, and have a major effect on medication or the severity of other scleroderma complications.

The present application will assess the potential benefit of using a novel drug to block a specific protein called endothelin that may be driving the renal abnormalities in systemic sclerosis. Endothelin is produced by blood vessel lining cells and high levels appear to damage tissues including the kidneys. It exerts its effect through two specific cell surface receptors termed ET-A and ET-B. Endothelin levels are increased in SRC and there is evidence for increased endothelin activity in several complications of systemic sclerosis. Zibotentan is a very potent drug that blocks one receptor for endothelin, the ET-A receptor. This is important as other receptors, specifically the ET-B receptor, may be important for normal kidney function. Thus blocking ET-A is expected to improve outcome in SRC and may also reverse or prevent less severe forms of renal disease. We will explore this by first defining the best measures of renal disease in systemic sclerosis and then undertake a clinical trial of zibtentan compared with control in cases of SSc that have moderate kidney disease. In parallel we will assess the benefit of adding zibotentan to standard treatments for SRC that include routine use of other blood pressure lowering drugs such as ACE inhibitors.

Together the results of this work will define the benefit of blocking ET-A, whilst retaining the likely beneficial effects of ET-B signalling, and may have relevance for complications of scleroderma outside the kidney, and to other commoner medical conditions.

Although uncommon, systemic sclerosis (scleroderma: SSc) is important because of its unmet medical need and high burden of complications, with more than half of patients dying as a direct result of SSc. Endothelin (ET-1) is implicated as a pathogenic mediator in SSc; elevated circulating levels of ET-1 occur in SSc-associated pulmonary arterial hypertension (PAH-SSc) and in SSc renal crisis (SRC). ET-1 antagonists are an approved therapy for PAH and for ischaemic digital ulceration in SSc, and may have major benefit in treating important renal complications of SSc; however, this has not been adequately addressed. Renal manifestations of SSc include acute renal failure and hypertension (SRC), but also chronic renal impairment in up to half of SSc cases. Histological similarities of vasculopathy in SRC and PAH-SSc, evidence of upregulation of the ET-1 ligand-receptor axis in SRC, and our open label study confirming the safety of the non-selective ET-1 receptor antagonist (ERA) bosentan in SRC, make ET-1 receptor blockade a valid therapeutic approach. There is evidence of benefit from bosentan in SRC cases compared with a recent comparator cohort, with better renal function 3-12 months after SRC and worsening blood pressure control after stopping bosentan. We believe that a selective ERA that blocks the ETA, but not ETB, receptor subtype might be particularly advantageous in treating renal complications of SSc, because of potential adverse effects of ETB blockade that could worsen intra-renal vasoconstriction and cause renal sodium and water retention. We will test this hypothesis in a parallel group placebo controlled study of the highly selective ETA antagonist zibotentan in SSc with confirmed mild-to-moderate renal impairment, and also assess the safety and potential benefit of adding zibotentan to standard therapy in SRC. This study will address an important clinical question and help to elucidate key pathogenic mechanisms in the renal complications of SSc.

The main beneficiaries from this research will be:

1. Patients with scleroderma and related connective tissue diseases
Scleroderma and related connective tissue diseases are uncommon, affecting approximately 1 in 10,000 individuals in the UK but represent a very important chronic disease population through the high case-specific mortality (more than half cases diagnosed with scleroderma eventually die as a direct result of the disease) and because of a major burden of non-lethal complications including pain, digital ulceration and psychosocial impact.

2. General public stakeholders associated with the themes of Lifelong health and wellbeing and ageing.
Vascular disease and fibrosis or scarring are core processes that lead to renal pathology in scleroderma but these processes and their assessment have much in common with the fundamental biology of ageing and long term health. Fibrosis is a common pathway to damage and dysfunction in almost all body systems and has particular relevance to cardiovascular disease, lung disease and kidney pathology. The application will explore assessment and treatment of renal disease in scleroderma but this is an important model system that has relevance to normal age-related pathology including decline in renal function and also to common medical conditions. Specifically we will define better ways to assess renal function that can be applied in a broader context and also the specific role of endothelin and its receptor subtypes in renal pathology. Other common diseases associated with hypertension such as pre-eclampsia may also be very relevant and these areas are likely to benefit from work outlined in this proposal.

3. Academic/private sector collaboration and future benefits for the economy
The important unmet medical need of scleroderma and related diseases that could benefit from progress in this area and other diseases in which renal impairment, vascular disease or fibrosis are prominent may lead to important economic and commercial benefits. The development of new indications for medications that have been developed for other indications (repurposing) is important and there may also be economic benefits from developing better ways of assessing renal and other pathologies that emerge from this study.

4. International academic colleagues working in scleroderma and fibrosis
The PI is an international leader in the field of scleroderma and fibrosis and has a strong track record of translational research that includes preclinical studies, clinical trials and outcomes research. The academic community will benefit from work outlined in this proposal through interaction at regular international meetings and collaborative endeavours through organisations including the EULAR scleroderma trial and research group (EUSTAR) and scleroderma clinical trials consortium (SCTC).

5. Personnel funded on this grant
The PI has mentored the career development of more than 10 clinical fellows over the past decade, many of whom are now established in NHS consultant or university posts and active in academic medicine. The clinical fellow funded through this award will receive outstanding training and opportunities in clinical and translational research that will provide an outstanding platform to a future academic medical career. This will have broad future value in the disciplines of academic rheumatology and renal medicine.