Can already registered drugs contribute to better treatment of patients with osteoarthritis? Most probably yes, according to an analysis by RARE-NL in collaboration with ReumaNederland and FAST. Some promising drugs are being investigated further with support from ZonMw and ReumaNederland. Based on analyses of this kind, FAST ultimately wants to work towards a sustainable revenue model that will make existing drugs available to (osteoarthritis) patients at an affordable price.

Osteoarthritis is one of the most common disorders, with over one and a half million patients in the Netherlands. The condition has a major impact on the quality of life of individuals and their loved ones and on society and the economy. ReumaNederland is therefore conducting an ‘arthrosis offensive’, to clear up the many misunderstandings about this condition and stimulate research into better treatments. This also includes the Arthrosis Roadmap, which outlines how research and innovation can contribute to effective, better treatment of osteoarthritis.

Corné Baatenburg de Jong, deputy director of ReumaNederland and responsible, among other things, for the organisation’s research policy: ‘Many people still have the impression that osteoarthritis is a kind of wear and tear that can’t be treated. But if you look at the fascinating research with knee traction, for example, you see that cartilage can indeed repair and osteoarthritis is therefore in principle a treatable disease’. In knee traction, the upper and lower leg are mechanically pulled apart for six weeks, creating space for regeneration. In clinical studies, knee traction has been shown to work in people whose knee cartilage had already almost disappeared. There are also several drugs already in development that aim to regenerate the cartilage of osteoarthritis patients, reduce pain and allow them to move better again.

Developments
In the cooperation between FAST and ReumaNederland for drug repurposing in osteoarthritis, several developments come together, according to Baatenburg de Jong. To start with, there is ReumaNederland’s aforementioned Osteoarthritis Roadmap. Last year, KPMG published the report ‘Qualitative in-depth analysis of gaps in drug development’ commissioned by the Ministry of Health, Welfare and Sport. In it, osteoarthritis was named as one of the conditions where it is expected that a lot of gains can be made through additional research efforts. ‘Yet osteoarthritis was almost excluded from the analysis, because of that prejudice that osteoarthritis would be a kind of irreversible wear and tear after all. Fortunately, I heard about it in time and we contacted the researchers’.

Another development that may contribute to successful drug repurposing for osteoarthritis is an initiative by Maastricht professor of experimental orthopaedics Prof Tim Welting, who, thanks to a  contribution from ReumaNederland, can test a large number of substances for their curative effects in osteoarthritis. Baatenburg de Jong: ‘A lot is already known about the various biological pathways that can lead to osteoarthritis. And there are quite a few existing drugs that act on one or more of these pathways. So it is very plausible that we can already make a lot of progress with existing drugs’.

Report
RARE-NL, the FAST hub for rare diseases and drug repurposing, investigated the state of play of a number of drug repurposing projects in osteoarthritis in the Netherlands. ‘You see that many different research groups in the Netherlands and abroad are experimenting with existing drugs,’ says Saco de Visser, scientific director of FAST. RARE-NL’s analysis contributes to the insight that there are already a number of interesting drugs that require further research. Some of these receive grants from the ZonMw programme Good Use of Medicines, partly supplemented by a grant from ReumaNederland. ‘With RARE-NL, we want to focus on several diseases. The analysis for ReumaNederland is a nice example of the potential that drug repurposing has. It would be nice if that could provide an incentive for further drug development under social conditions’.

Here, according to the RARE-NL report, it is important to think at an early stage about the optimal form in which the drug should reach the patient. The ideal here is a registered drug reimbursed by the basic health insurance at a socially acceptable price, but sometimes other variants such as offlabel use are the highest achievable. In the report, RARE-NL makes recommendations in this area for four molecules and four research projects within drug repurposing for osteoarthritis. It also contains tips for RARE-NL on how to take long-term availability of repurposed drugs into account in grant reviews.

Another key recommendation is to seek collaboration with other researchers in the early exploratory phase. De Visser: ‘We want to promote consistency, for example in the way researchers look at efficacy. If you use a combination of methods to see what are the best candidates for further clinical research, you are likely to achieve more’.
If promising drug candidates emerge from preclinical and early clinical research, the question then arises of how to make them available to patients in a socially responsible way. De Visser: ‘In that phase, researchers often face obstacles and challenges unknown to them. For example, they have to talk to authorities about market authorisation and reimbursement. These are generally issues that transcend the indication, such as osteoarthritis in this case. Then it’s good to know that there are drug repurposing initiatives like RARE-NL that have experience with this, so researchers or organisations like ReumaNederland don’t have to reinvent the wheel’.

Searching for solutions
Ideally, an existing (generic) drug could enter the market at a much lower price than new drugs. ‘But the whole system is not yet set up for that,’ says De Visser. ‘I recently published an international paper on this, with Sibren van den Berg (RARE-NL), Arend Mosterd (Meander Medisch Centrum) and Donald Lo (Eatris/REMEDI4ALL). What we want to work towards, using concrete examples, is a system where manufacturers can also invest in research into new applications of an existing drug and then be allowed to charge a reasonable, substantiated margin on top of the ordinary, often extraordinarily low, generic price for that indication. In short, we want a system where it pays to invest in drug repurposing without leading to sky-high prices’.

To encourage this development, concrete examples are necessary to see which issues still need to be solved in practice. RARE-NL offers help with such cases, substantively but sometimes also by helping mobilise funding from a new company to actually get the medicine to the patient. As long as it wants to work according to the principles of transparent, socially acceptable pricing. Hopefully, in the future RARE-NL can help organise a demonstrator fund for drug repurposing, i.e. a fund through which promising initiatives can show what is possible. FAST believes that pioneering with researchers and organisations is the key to solutions that can accelerate the availability of drugs for patients, which is why FAST facilitates collaboration hubs such as RARE-NL.

ReumaNetherlands, meanwhile, is going firmly into drug repurposing for osteoarthritis. Baatenburg de Jong: ‘We making an employee at our office available for half-time to focus on directing these processes, to ensure that the whole process from pre-clinical to availability for the osteoarthritis patient will be much faster’.