MS researchers with major ambitions

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"We have a major need for studies that are based on the interests of the patients and of society," says Fredrik Piehl. Now he and other researchers are carrying out a major pharmaceutical trial based on the needs and priorities of MS patients.

The study has received funding of SEK 73 million, spread across five years. This grant is equivalent to the Swedish Research Council's annual investment in clinical treatment research for the whole of Sweden.

The first drug to treat multiple sclerosis (MS) was licensed 20 years ago. The first high-efficacy drug was developed 10 years ago and several more new drugs have been launched in recent years. Despite this, the most rapidly growing treatment in Sweden today is an older drug that is not only licensed for MS. The drug is called MabThera (rituximab) and is used to treat lymphoma, rheumatoid arthritis (RA) and systemic vasculitis.

"It has become a paradoxical situation. There are many signs that MabThera may have significantly better long-term effects than drugs developed specifically for MS, but there is still a lack of good-quality studies," says Fredrik Piehl, Professor of Clinical Neuroscience at Karolinska Institutet, consultant and, since 2008, Head of the MS clinic at Karolinska University Hospital.

Follows patients in the study

To set about changing this, he and his colleagues at other MS clinics around the country have designed a study that will follow 3,700 relatively recently diagnosed patients over an extended period. The research group is the first outside the USA to receive a grant from the Patient-Centered Outcomes Research Institute, PCORI. This tax-funded institute is part of Obama's "Affordable Care Act" and was established to enable studies to be carried out that are important from a patient and healthcare perspective. The grant of SEK 73 million over five years is almost as much as the Swedish Research Council's entire annual investment in clinical treatment research in Sweden.

"There is a major shift taking place in the treatment of MS and we can contribute important knowledge to this. What we have already seen is that MabThera has similar efficacy to the most effective MS drugs, but with better safety and better tolerability," says Piehl.

One of the reasons why patients prefer MabThera could be that it is administered through IV twice a year, compared with tablets every day or several injections a week, or much more frequent IV.

"If you ask the patients what is important in the drug they have to take for their MS, they say that they want a better quality of life, and this is a complex concept. One aspect that is often overlooked is that patients want to avoid the harmless yet annoying side effects of many MS drugs."

Most of the clinical studies being carried out within MS today have been initiated by the pharmaceutical industry. Thanks to the large research grant from an independent institute, Piehl and his colleagues can now carry out clinical research with a focus on the needs and issues of patients.

"Now we have the opportunity to show that many MS patients receive substandard treatment in the early stage of their illness and are perhaps also overtreated in the later stages." 

There is also a financial argument for treating more patients with MabThera. High-efficacy treatment costs SEK 200,000 per patient per year, while MabThera costs SEK 25,000. The total difference for the entire patient group currently treated with MabThera in Stockholm is SEK 40–130 million per year, depending on whether it is compared with the cheapest or the most expensive MS drug.

"This is not the most important factor for us as researchers and clinics, but it is very important for society as a whole. In a country like Sweden, the cost of drugs has had a relatively low priority, but in a situation where new and often much more expensive drugs are introduced, it becomes increasingly important to use resources wisely. From a global perspective, where many MS patients experience great difficulty obtaining subsidised drugs, it is, of course, interesting if there is an effective preparation that is much less expensive than the traditional drug," says Piehl.

Fredrik Piehl is convinced that the clinical treatment research will make a big difference. “Data from these two studies will have a major influence on the future treatment of MS, not just in Sweden but all over the world”.

The large research grant comes at a time when MabThera is the subject of much discussion, with four government authorities unable to agree on it. The Swedish Medical Products Agency is against large-scale use, the National Board of Health and Welfare is ambivalent, the IVO (Health and Social Care Inspectorate) says it is not wrong to treat MS patients with MabThera, while the TLV (Dental and Pharmaceutical Benefits Agency) is generally positive towards the increased use of generic preparations, provided they have proven efficacy.

The 2017 edition of the Wise Drug Formulary issued by the Pharmaceuticals Committee in Stockholm County has included MabThera as a recommended treatment for MS for the first time.

"From our perspective here at Karolinska, MabThera is effective, safe and popular with patients," says Piehl.

The drug treatment received by MS patients depends on where in Sweden they live. To be certain of being treated with MabThera, you need to be a patient at the University Hospital of Umeå.

"In Umeå almost all patients are given MabThera, in Stockholm County just over 40%, in Västra Götaland 15% and in Skåne 10%. Knowing this enables us to carry out a more reliable study.

The variation in the drug treatment of MS is mainly the result of different interpretations of imperfect data, which is something this study aims to rectify," says Piehl. As the MS register contains around 15,000 patients who have been exposed to drugs, the researchers can carry out linked studies to examine the risks of side effects, such as lung inflammation and cancer.

Thanks to patients self-reporting in the MS register, researchers can also draw up evaluation scales for factors such as quality of life and satisfaction with treatment.

"I believe we have the best conditions in the world for taking an overall approach to determining the efficacy, safety and patient satisfaction for different MS drugs over a longer observation period," says Piehl.

Quality register for MS

All of Sweden's university clinics are taking part in the project. They are using some data that has already been collected and combining it with data collected from this point onwards to improve and quality-assure follow-ups on 100% of the patients. This enables them to state with greater certainty which patients it works best for.

"The reason why we were allocated the grant is the well-developed network we have in Sweden, with prominent researchers in fields such as clinical pharmaceutical epidemiology and molecular biology – and, of course, all our colleagues at the university clinics who readily came on board the project. We have a really good MS community in Sweden, we use the quality register for MS and we have a consensus on everything other than the drugs used," he says with a smile.

The outline application for the MabThera study was submitted one year ago and the agreement has now been signed by both parties. Ahead of the final application, they worked with a group in California and carried out surveys of patients and doctors in both Sweden and the USA – as the grant provider is interested in the situation in America.

"We simply asked what is the most important thing for you as a patient or treating physician. The patient's response was 'quality of life', the neurologists stated 'protection against permanent disability'. This is not something that has been answered by treatment data from randomised controlled studies running over shorter periods," says Piehl.

This study is something of a hybrid, being a prospective cohort study but with some retrospective data. In choosing this design, Piehl wants the best of both worlds.

"The close prospective follow-up of a large group of patients and quality assurance cost money and that is what the grant will be used for," he says.

Alongside this research project, a national academic phase 3 study, led by Anders Svenningsson at KI/Danderyd Hospital, has begun, which compares MabThera with one of the approved MS drugs.

Piehl is convinced that the independent clinical treatment research will make a big difference.

"Data from these two studies will have a major influence on the future treatment of MS, not just in Sweden but all over the world," says Piehl.

Text: Gunilla Eldh, photo: Ingela Wåhlstrand

Fredrik Piehl´s research

Fredrik Piehl's research team is studying inflammation and degeneration in diseases of the central nervous system, with a focus on multiple sclerosis (MS).

The team is now beginning a large national follow-up project for people recently diagnosed with MS that involves all Sweden's university hospitals.

The project is fully funded by the American PCORI foundation. The aim of the project is to show which MS treatments are the safest and most effective over periods longer than those usually studied within the framework of randomised trials.

The research group is the first outside the USA to receive a grant from the Patient-Centered Outcomes Research Institute, PCORI. This tax-funded institute is part of Obama's "Affordable Care Act" and was established to enable studies to be carried out that are important from a patient and healthcare perspective.

The grant of SEK 73 million over five years is almost as much as the Swedish Research Council's entire annual investment in clinical treatment research in Sweden.

"Gold standard" not always best

One downside to RCT, the "gold standard" within medical research, is that it only extends over a shorter period, which becomes a problem when studying an illness such as MS, which only exhibits symptoms occasionally.

"RCT does not always reflect the 'real' patients. In MS studies, for example, there is a concentration of milder forms, as most of them, for ethical reasons, must avoid recruiting patients with aggressive illness to a study in which they risk being allocated a placebo or a less effective treatment. Another weakness is that the primary focus is on relapses and measurements based on magnetic resonance imaging, instead of what our patients and neurologists think is most important," says Piehl.

Observational studies, on the other hand, enable patients to be monitored for an extended period, under real conditions, and show what is happening at both a group and individual level. This means, for example, that the researchers in this study can easily take into account the major differences in treatment that depend on where the patient lives.