MICA: Targeting the RA synovial fibroblast via cyclin dependent kinase inhibition - a phase IIa study

Context
Rheumatoid arthritis (RA) is a condition in which the joints become inflamed and painful. It affects about 1 in every 100 adults in the UK. It is thought to be caused by the patient's immune system mistakenly attacking their joints. The resulting inflammation is not only painful but reduces joint movement and eventually causes joint damage and deformity. RA can also affect other organs such as the lungs, and patients with RA also have a higher than average risk of developing heart attacks and strokes. They are also more susceptible to infections. Many patients lose their jobs soon after the diagnosis is made.

Aims and objectives
Most drugs currently used to treat RA neutralise the inflammation (anti-inflammatory drugs, steroids) or the cells of the immune system and their products (biological therapies or 'magic bullets'). Over the past 20 years the outcome for RA patients has improved, partly because of earlier and more 'aggressive' treatment (more drugs, higher doses) and partly because of new therapies that have been developed (particularly the 'magic bullets'). However, many patients don't respond completely to these treatments and some don't respond at all. We believe that there is another type of cell responsible for the symptoms in these patients. The fibroblast is a cell that is present in healthy joints, where it is important for normal joint function. However, fibroblasts divide inappropriately and become more numerous and 'aggressive' in RA joints. They damage the joint by producing chemicals that eat into cartilage and bone, and also produce inflammatory chemicals themselves.

Thus, a useful cell in health becomes one that causes inflammation and joint damage in RA. As far as we know none of the current treatments affect the behaviour of fibroblasts. Our plan is test a drug in RA patients that we think will do so. The drug interferes with the machinery that is necessary for cells to divide. Fibroblasts in the RA joint seem particularly sensitive to this drug, which we therefore believe can correct their abnormal behaviour. The drug has already been tested in patients with certain types of cancer (in which cells also divide inappropriately) and seems safe enough to test in RA. We aim to show that the treatment is safe in RA, and that it could provide a useful treatment for RA patients.

The research is divided into two parts. In the first part we will test the safety of different doses of the drug over 4 weeks of treatment. We will identify a dose that is both safe and appropriate to test in more patients for a longer period of time. In the second part we will give this dose to 12 RA patients for 12 weeks. At the same time 6 patients will receive an identical 'placebo' treatment. This is important to ensure that any effects we see are due to the drug and not other factors (more visits to the hospital, more interaction with doctors and nurses). As well as checking the patients' symptoms, we will also perform scans of their joints at the start and end of the treatment. We will also take small samples of joint tissue (biopsies). These scans and biopsies will help us to decide whether the treatment is working and how it is working. This is important to help us to decide whether the trial has been a 'success' and whether to perform further trials later on.

Potential applications and benefit
In this trial we will treat patients who have had RA for at least a year and who are already taking treatment but not responding well enough. This will test our idea that we can improve their symptoms by altering the behaviour of the fibroblasts. If this research is successful then we will need to test the treatment in RA patients taking different treatments, at different stages of their illness. Because this treatment works in such a different way to existing drugs, we believe it could be useful for many different types of RA patient. Later on, if safe and effective, it may also be useful in other diseases.

This project aims to repurpose a small molecule anti-cancer drug as an anti-fibroblast drug for RA. The past 20 years have seen major advances in RA therapy; more aggressive use of conventional drugs, and biological targeted therapies have each made a significant impact. However, disease remission remains uncommon and around 20% of patients remain refractory to all therapies. This represents a significant unmet need and suggests key aspects of RA pathogenesis remain untargetted.
In health, a delicate nutritive synovial membrane (SM) lines joint cavities. This comprises a few macrophages and fibroblasts in a loose connective tissue stroma. In RA the SM is the focus of autoimmune attack but, in addition to inflammatory cell infiltration, resident synovial fibroblasts (SF) become hyperplastic, forming a vascularised, inflammatory, quasi-malignant pannus which invades articular cartilage and bone. The resultant joint damage underlies the disability and reduced quality of life that characterise RA.
Cell proliferation relies on the coordinated activation of specific regulatory proteins: orderly progression through the cell cycle is tightly controlled by the formation and activation of complexes comprising cyclin proteins and cyclin-dependent kinases (CDK). These complexes are in turn regulated by endogenous CDK inhibitors (CDKI). The concept of inhibiting CDKs to correct uncontrolled cell proliferation has led to the evaluation of small molecule CDKI in cancer.
RA SF have reduced endogenous CDKI levels, and correction of the deficit normalises their dysregulated phenotype. Indeed, small molecule CDKI ameliorate synovitis in pre-clinical arthritis models. In partnership with the SME Cyclacel, we propose a phase IIa repurposing study of a CDKI in patients with refractory RA. Stage 1 will focus on safety and tolerability, to determine an appropriate dose to progress to stage 2, where we will seek evidence of potential therapeutic activity alongside PK and PD biomarkers.

Our research aims to deliver a new drug and a novel therapeutic approach, therefore potential beneficiaries include patients, the NHS, the life sciences industry, UK plc, Arthritis Research UK and other funders, the project team and other academic researchers.
Patients with RA will derive the most immediate impact from our research, which could provide a novel therapy with a unique mechanism of action. This could result in better disease control, improved quality of life and reduced long-term complications, either as a monotherapy or in combination with existing drugs. Success will also stimulate research into related compounds from the same class as well as alternative anti-fibroblast drugs and targets (eg pro-apoptosis, epigenetic modifiers, anti-proliferative). It will also stimulate research into potential applications in other fibrotic diseases - all with potential downstream beneficial impact on patients. Via our Engagement programmes this work will have a wider impact on patients by reinforcing the benefits of participating in early phase experimental medicine research.
For similar reasons success will provide a boost to the UK life sciences industry. Clearly our Partner would benefit greatly but so too will other SMEs, biotechs, and pharma with alternative drugs from the same class, as well as drugs with the potential to target the fibroblast in a distinct manner. Our research would provide a novel target and a novel paradigm for the treatment of RA and would also trigger a re-analysis of exisiting compounds that may have therapeutic potential in RA or, indeed, other fibrotic diseases. RA remains a disease with a high unmet need and provides potentially high investment returns. Some of the other potential disease targets could become 'orphan' indications, with a more commercially favourable path to the clinic.
Downstream success will lead to a workforce with an improved skill set, including UK/EU contract manufacturing capabilities, and specialist PK testing. Ultimately successful development of a novel drug for RA will deliver substantial revenue to the UK and catalyse additional activity in the healthcare sector. It will also impact on HM Government by reinforcing the benefits of their investment in the life sciences industry.
We are using UK based companies for sub-contracted work. This will have a positive impact on income generated and jobs protected within home countries.
Because our research involves an orally available drug, it would likely be cheaper than the biologic drugs. If it substituted for them in the treatment pathway, or improved their efficacy as hypothesised, this would ultimately result in direct or indirect cost-savings to the NHS.
In addition to the MRC, Arthritis Research UK, NIHR, the Wellcome Trust, the partner Universities and NHS Trusts will benefit from our research, because they are providing some of the infrastructure and staff needed to perform this research. They would therefore be in a position to share in the success. The development of a new drug for RA would likely lead to an increase in charitable donations to relevant charities.
Success will impact on the project team both directly, via the experience and educational opportunities of performing a successful phase II experimental medicine study; and also indirectly from the emotional and psychological benefits of involvement with a study that could potentially benefit thousands of patients.
Lastly, other academic researchers will clearly derive impact from this research, which will provide them directly with new ideas and opportunities, and indirectly by increasing collaborative opportunities with one another and with the life sciences sector.