30 May 2017

Improving osteoarthritis trials: "We have to start by identifying biological markers for disease progression"

Interview with Professor John Loughlin, Newcastle University

An estimated 9.6% of men and 18% of women over the age of 60 experience the debilitating symptoms of osteoarthritis, a condition that also affects some younger people and athletes. John Loughlin, Professor of Musculoskeletal Research at Newcastle University, has the ambition to improve treatments for the condition. “We have to start by identifying biological markers for disease progression,” Loughlin explained. 

No cure

Professor John Loughlin

Aging and trauma can contribute to the development of osteoarthritis, but the underlying biological mechanisms are still unknown. As well as its human cost, the direct and indirect financial costs of osteoarthritis are high: in the UK, they have been estimated at 1% of gross national product. There are many devices and palliative medicines to relieve pain and improve quality of life, but as yet no pharmaceutical products to halt or reverse the condition.

John Loughlin said that trials of new osteoarthritis treatment candidates are especially challenging: “Most trials to date have been unsuccessful, and the pan-European APPROACH project is an IMI*-funded consortium that is working to address this. It has created a unified database of more than 10,000 patients, and aims to improve future trials by identifying biological markers for disease progression.”

Costly measurements

Loughlin explained that two potential reasons for a lack of successful trials are poor compound specificity and high trial costs: “A drug for treating osteoarthritis needs to halt or reverse cartilage loss, but may also have unwanted effects on surrounding tissues. This can be a problem even when treatments are given intra-articularly (directly into the joint gap). For big pharma companies, trial timescales are another major issue. Any improvements in patients with osteoarthritis will typically be seen over years rather than weeks or months, so trials are lengthy and labour-intensive.” 

Measurement of existing trial results is costly, relying on x-rays, MRI scans and reporting of pain perception by patients. The recent OARSI 2017† conference, with its parallel sessions on research and clinical work, highlighted the scale of the challenge that still lies ahead, with many small-scale trials but no standout results. Some companies are claiming positive results, but large trial results are awaited.

Biological markers of disease progression

Loughlin said that the APPROACH project aims to identify which patients can expect to see their condition progress (if untreated) over the timescale of a clinical trial: “APPROACH seeks biological markers of disease progression in order to allow shorter, lower cost and more effective trials – one example might be chemical indicators of cartilage breakdown in the bloodstream.”

The APPROACH consortium is a public-private partnership (PPP) involving a multidisciplinary group of 25 European clinical centres, basic research institutes, small and medium-sized businesses and pharmaceutical companies. Past biomedical data from more than 10,000 patients has been included in a unified APPROACH database, which includes biomarkers of disease progression, imaging analysis and chemical markers. Machine learning has now been completed, and the mathematical analysis is underway.

Patient subtypes

Osteoarthritis has many different manifestations, and treatment targeted more specifically at different disease phenotypes might lead to improved outcomes. “The APPROACH project team will identify groups or subtypes of patients who have similar profiles,” said Loughlin. “Defining such subtypes should help bring about improved drug development and diagnostic tools, as well as more personalised treatments. A clinical trial will be used to validate the subtypes found, involving a longitudinal cohort based on innovative stratification methods.”

300 patients in France, The Netherlands, Norway and Spain will be taking part in the two-year APPROACH clinical study ending in 2020. The focus will be on knee osteoarthritis, which is ideal because it has been extensively examined in large groups of patients and offers large amounts of standardised data such as x-ray and MRI measurements. Refinements will be made as the trial progresses, with continuous mathematical modelling.

Advice from Patients

Loughlin said that a Patient Council of 6–8 patients from Europe is also taking part: “The Patient Council is supported by representatives from the Dutch Arthritis Foundation (Reumafonds) and Arthritis Research UK. It has made useful contributions to the design of the clinical study, and will stay in close contact with the researchers throughout the project.”

* Innovative Medicines Initiative: Europe's largest public-private initiative aiming to speed up the development of better and safer medicines for patients.

Osteoarthritis Research Society International