Improved patient targeting for better osteoarthritis drug development

To increase the success rate in the search for effective osteoarthritis treatments, rheumatologists have to better distinguish between the different disease phenotypes. This will contribute to personalized drug development which allows to treat osteoarthritis patients more specifically for their individual underlying cause, concluded Eefje van Helvoort (UMC Utrecht) in her PhD thesis that she defended on March 15, 2022.

The ideal treatment for osteoarthritis (OA) would be a drug that would treat pain, reduce inflammation and regenerate damaged cartilage and bone. However, in the absence of such a drug, management of OA is mainly focused on relief of pain symptoms. However, the underlying mechanisms leading to clinical symptoms differ between patients. In the R&D process of new pharmaceutical treatments, the distinction between these different patient phenotypes (with different characteristics and origin), is not sufficiently acknowledged. This explains the often disappointing results of current treatment because such a ‘one size fits all’ approach is not realistic, taking into account the heterogeneity of patient groups. PhD candidate Eefje van Helvoort MD (Department of Rheumatology & Clinical Immunology, UMC Utrecht) played a pivotal role in the development and execution of a cohort study in OA patients of which she also was the coordinator. The key objective of this study was to identify specific patients that subsequently can be matched with new pharmaceuticals that have been developed to treat the symptom complex of a well-defined OA patient population.

APPROACH cohort study

To increase the success rate in future clinical trials of OA treatments, a different approach is needed. The outcomes of the international 2-year APPROACH (Applied Public-Private Research enabling OsteoArthritis Clinical Headway) cohort study in 297 knee OA patients, which was supported by the EU-sponsored public-private Innovative Medicines Initiative (IMI), are contributing to the development of a new, personalized treatment approach in OA patients in several ways:

1. With help of machine learning, the APPROACH study was able to select patients with a high risk of (fast) disease progression. This is important because to be able to proof that a new treatment stops or slows down OA progression, one has to make sure that patients are included that actually do progress without treatment.
2. The APPROACH study combined multiple conventional and novel, explorative, biochemical, clinical and demographic disease markers to monitor OA, allowing the definition of distinctive phenotypes. In this way, possible new treatments could be evaluated in more relevant subgroups of patients, matching the characteristics of the specific treatment modality.

Different phenotypes

One of the key messages in the PhD thesis by Eefje van Helvoort is that the current ‘one-size-fits-all’ approach to find a drug for OA patients is counterproductive. Eefje concluded: “There are several underlying mechanisms that can contribute to OA and in each patient a different mechanism, or combination of mechanisms may play a role. For example, a treatment that targets an underlying inflammation will most likely have less effect in the OA patient in whom a past trauma is the cause of OA. To increase the probability of success in the search for effective treatments for OA, rheumatologists will have to stratify patients according to their OA phenotype. Only then it will be able to develop drugs that treat OA patients more specifically for the underlying cause, both in trials and in clinical practice.”

Burden of disease

Osteoarthritis is a degenerative joint disease that affects knees, hips, hands and the spine. It is estimated that 10-15 percent of people over the age of 60 live with OA. Although it mostly affects older people, younger individuals and athletes are also at risk. The underlying biological mechanisms that cause OA are still largely unknown. Direct and indirect costs of OA are substantial and total annual costs for adaptive aids and devices, medicines, surgery and sick leave are estimated to average 1 percent of gross domestic product in developed countries. Although there is a wide range of treatments available that can relieve pain and improve quality of life, there are currently no pharmaceuticals that can halt or reverse the onset or progression of OA.

PhD defense

Eefje van Helvoort (1991, Oss) defended her PhD thesis on March 15, 2022 at Utrecht University. The title of her thesis is “Osteoarthritis: Towards a progressive APPROACH”. Supervisor was prof. dr. Floris Lafeber (Department of Rheumatology & Clinical Immunology, UMC Utrecht). Co-supervisors were dr. Simon Mastbergen (Department of Rheumatology & Clinical Immunology, UMC Utrecht) and dr. Niels Eijkelkamp (Center for Translational Immunology, UMC Utrecht). Eefje is looking for a new challenge in the direction of policy, consultancy, advisory, innovation and implementation to improve patient care.