Pain vs Structural Change, Chicken & Egg Problem of Osteoarthritis

Pain vs Structural Change, The Chicken & Egg Problem of Osteoarthritis

With OARSI2018 fast approaching, I thought it would be relevant to have your comments on how osteoarthritis (OA) clinical development paradigms might changes considering novel mechanisms of action for potential drug candidates, new biomarkers and new regulatory view of trial designs.

Sometime ago we have shared an article about various OA imaging biomarkers and their role in the assessment of different stages of OA as well as how biotechnology and pharmaceutical players in the industry are using these to show disease modifying qualities of their new drug candidates. You can find it here.


Just as a reminder, an FDA approved measure for OA drug efficacy assessment is a Join Space Narrowing (JSN) which is measured on the X-ray images acquired over time. Many studies show that JSN is not entirely clinically relevant as a primary endpoint for assessment of disease modifying qualities of therapeutic drug candidates for the reasons listed below

  • OA, as the whole joint disease, will affect all joint structures, including cartilage, meniscus, synovitis, etc, but JSN focuses on the measurement of changes in just articular cartilage and meniscus.
  • JSN is insensitive to measure early OA changes in cartilage and meniscus. Thus, knees with moderate to severe OA (Kellgren and Lawrence Grade 3) are selected for clinical trials to ensure disease progression measurement. However, KLG 3 knees may already represent a late stage of the disease with advanced molecular and biomechanical changes and it may be too late for any pharmacological intervention to alter the course of the disease.
  • JSN is not appropriate to measure the efficacy of cartilage repair products. Magnetic resonance imaging (MRI) and arthroscopy should provide better information for such therapies.
  • Finally, one major limitation has been the paucity of reports demonstrating a correlation of JSN with symptoms, when in fact; the majority of OA literature reports a lack of correlation of JSN with severity of symptoms. [-P.Hellio Le Graverand-Gastineau et al, 2009].

These limitations combined with the fact that it is simply too expensive to wait for 1 to 2 years to assess the efficacy on X-ray have stimulated clinical researchers to use MRI based measures to detect more sensitively OA progression and enabling shorter and smaller Proof of Concept trials.

It is also widely recognized now that a particular OA patient type will respond differently to a particular OA treatment. Many studies highlight the importance of focusing on patient phenotyping, recognizing the fact that injury induced OA will differ from inflammatory type OA, for example.

The most interesting in OA clinical development is of course to follow the companies with late stage disease-modifying drugs, which already demonstrated their efficacy in phase II studies. The two companies, in late stages of OA clinical development are Kolon Tissuegene, who are developing advanced cell therapies and Nordic Biosciences / Merck, who are developing sprifermin, a truncated recombinant human FGF-18 protein thought to induce chondrocyte proliferation and increased extra-cellular matrix (ECM) production. Both are aiming to show that their treatments will impact cartilage growth and repair. A lot of the other drug developers are focusing on the reduction of pain in OA.

Currently, the fast pain reduction is considered to be a must for a successful OA treatment. Also, it is considered to be important to see the pain going first prior to embarking on the disease modifying claim. This of course is perfectly acceptable for pain relieve focused treatments, such as steroid or interventional pain reduction therapies.

However, we yet to see a ‘cured’ OA patient, e.g. a patient with a fully or partly restored cartilage.

If we think of OA as a serious disease with symptoms and causes, pain is really a symptom whereas the loss of cartilage is a reason for the pain and discomfort.

It makes you think that perhaps there is an argument that with a treatment, which first restores the cartilage, we should think of a different trial design and success criteria. In such a trial, it would be expected to see the small change in pain and significant structural change; following the regain of cartilage, a patient should feel much less pain. The question is, how long would it take to get to the point of true pain reduction, the reduction due to cure?

Such a trial might take up to 3-4 years, with the first milestone, after 2 years, showing positive changes in cartilage volume or maybe even in JSN, and then some years later in for the true pain reduction. The next question is if there is a way to monitor this reasoning through more objective measures such as the quantitative imaging. 

Such measures of cartilage and bone quality exist but are not widely used in trials.

Here we should look into the use of advanced sequences and computer aided ways to analyse them to get the right information. Just a few techniques ( and there are many more!) will be presented by our group at OARSI:

  • From MRI, we can assess early cartilage changes and cartilage quality by both intravenous (i.v.) and intra-articular (i.a.) delayed Gadolinium enhanced MRI of cartilage (dGEMRIC). Analysis of the relationship between i.a. dGEMRIC and delayed Gadolinium enhanced MRI of menisci (dGEMRIM), which will be presented as a poster at OARSI2018 will investigate if the approach can be used to assess the morphological degeneration of menisci.


  • From X-ray, by combining the fractal – and entropy-based bone texture analysis to assess the texture of bone, which seems to predict the development of OA. This work will be presented as an oral presentation at OARSI2018.

Once we see can assess the cartilage quality while the patient is under the treatment, we should also plan to assess how sustainable the cartilage volume and its quality post-treatment. But this is perhaps for later, once we have the first therapeutic for OA!

Just like when we need an answer to a complex question, we bring several minds together, in OA clinical development we must bring several modalities and associated biomarkers and look at multi-parametric imaging. This is already a norm in oncology and neurosciences, so why not OA?

As with the research in any clinical indication, it is important to bring together different specialities to give a comprehensive answer, OARSI brings together investors, radiologists, rheumatologists and computer scientists.

Look forward to seeing you there!

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