Title: Treatment of Pustular Psoriasis with IL-1 receptor antagonist anakinra: a randomised, placebo-controlled trial and associated mechanistic studies.
Funder: Department of Health and Social Care

Abstract: Pustular psoriasis constitutes a group of severe, disabling and occasionally fatal neutrophilic dermatoses with major physical, psychological and social impact. Treatment options are few (http://www.nice.org.uk/Cg153, 2012) with no licensed therapies. Contemporary (2011) genetic studies by our group and others, indicate that pustular psoriasis is associated with deficiency in interleukin-36 receptor antagonist (IL-36RA) consequent on IL36RN gene mutations in up to 40% of patients. This results in unrestrained IL-36 signalling and increased IL-1 production leading to pustulation and inflammation. These abnormalities are not found in patients with plaque psoriasis. We therefore hypothesise that abnormal signalling in the IL-1 pathway is the major driver of pustular psoriasis, and that IL-1 blockade will deliver therapeutic benefit. Reports of patients with pustular psoriasis (n=7) showing rapid, and complete resolution of pustules with human recombinant IL-1RA (anakinra), provide compelling proof of concept data. We propose to test our hypothesis in a two staged, adaptive, randomised, double blind, placebo-controlled, trial (RCT). Our study population will be people with acral pustular psoriasis (APP), i.e.: disease of the hands and/or feet, as the clinical paradigm for all forms of pustular psoriasis. The intervention will be 8 weeks of subcutaneously administered standard dose anakinra 100mg daily or placebo randomized 1:1. The default primary outcome will be number of fresh pustules; secondary endpoints relate to efficacy (e.g.: composite measures of APP, clearance, photography), impact (e.g.: function and pain), adverse events and acceptability of treatment. Patients will be assessed at weeks 0,1,2,4,6,8 (treatment endpoint) and 12 (study endpoint). To mitigate risk of a full scale RCT in the context of futility, and to confirm choice of primary outcome, stage 1 comprises 20 patients (4 centres, m 0-18) with the decision to proceed to stage 2 (44 patients, 15 centres, m 22-38) based on pre-specified efficacy criteria. The calculated total sample size of 64 will give 90% power to detect 1SD mean reduction in fresh pustule count at 5% significance (an effect size comparable to retinoids, a common, first line treatment). Parallel mechanistic studies, in an established centre of psoriasis genomics expertise (King's College London), will investigate the molecular basis of abnormal IL-1 signalling and screen for gene mutations that may predict treatment response. Partnership with the SME company Swedish Orphan Biovitrum AB provides free drug. Specified timelines for delivery of this project (42 months) are realistic and achievable given the experience and track record of the research team, involvement of 4 major UK dermatology tertiary psoriasis centres (Glasgow, London, Manchester and Newcastle), ready access to additional centres via established networks of research active clinicians and requisite infrastructure and operational support provided by the CRC-approved CTU at Kings, UK CRN and UK Dermatology Clinical Trials network. Strong support from the Psoriasis Association and input from PPI groups will ensure findings have relevance to patients. If anakinra is proven to show efficacy, this will deliver a new treatment option for a high need group, and provide strong evidence to industry to invest in further development of IL-1 blockers for this indication.

Lay abstract: Pustular psoriasis is a term used to describe a particular form of psoriasis that is characterised by sore, red skin covered in pustules. Sometimes it can be generalised meaning that it covers most or all of the skin surface. In this instance it can be life threatening. Most forms of pustular psoriasis just affect the hands and feet when it is called Acral Pustular Psoriasis (APP). Although this condition affects the hands and feet exclusively, it makes the skin sore and painful and so walking and manual work are difficult. Treatment options are limited and unsatisfactory; even the recent, 'biologic' treatments that have been developed for the common form of psoriasis (plaque psoriasis) are usually ineffective. Very recently, our research group and others have shown that the biological processes underlying APP are very different from plaque psoriasis. This may explain the lack of response of APP to standard treatments. These studies indicate that a group of proteins involved in inflammation called the interleukin (IL)-1 family are central to the disease process. These laboratory studies are supported clinically by anecdotal reports in the medical literature of a drug called anakinra, an IL1 inhibitor developed for other diseases such as arthritis, being effective for the treatment of APP. We have designed a study to accurately determine how well anakinra works in APP using the gold standard of clinical trial design, namely randomised control trial (RCT). This RCT will be supported by laboratory based investigations designed to understand the role of IL1 in APP and explain exactly how anakinra works. Performing an RCT in APP presents a number of issues. First, it is a relatively uncommon disease. Thus we have engaged with the top 4 psoriasis treatment centres in the UK to ensure that our objectives can be achieved. These centres each have dedicated clinical research centres, expertise in RCT and an ability to handle blood samples from patients. All four centres have many years of collaborative working on psoriasis studies. Secondly, with significant input from experts in clinical trial design, the RCT has been designed to minimise the number of patients needed to test how effective the therapy is. Importantly, we have discussed and planned the objectives and trial design with patients. We believe our group is the best placed worldwide to complete this project successfully, and in a cost-effective manner. Collectively we have a substantial patient base, expertise in RCT and a track record of working together, including through national research networks. Our laboratory at Kings, London, has already established most of the investigational techniques required and has published accordingly. We have established a full collaboration with the company that manufactures and markets anakinra, which includes provision of free drug for the study, so keeping costs to a minimum. Results from this trial, if successful, will provide evidence to support use of anakinra to treat people with both APP, and also, other forms of pustular psoriasis. We anticipate that our data will encourage the Pharmaceutical Industry to invest in developing other IL-1 blockers for use in pustular psoriasis.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: SKIN