How well do we understand progressive MS today? was the closing keynote address for the Consortium of MS Centers annual meeting, given by Alan Thompson, MD. He is a leading authority on progressive multiple sclerosis and Dr. Thompson is on the faculty of Brain Sciences, University College London, and serves in high level positions of the boards of MS international Federation, the International Progressive MS Alliances, and the National Multiple Sclerosis Association. He serves as the editor-in –chief for Multiple Sclerosis Journal.
I had the opportunity to ask Dr. Thompson at an advance press briefing if he could identify what was the driving force behind the recent initiatives to find answers about progressive MS. For quite some time the majority of the research and attention has been focused on Relapsing Remitting MS (RRMS), according to Dr. Thompson, and he strongly expressed the research community should be ashamed of themselves for waiting so long to take a harder look at progressive forms. He said part of the push for progressive MS research is because the MS patient community has been vocal about the need. Dr. Thompson said this momentum grew because each time a new therapy for RRMS was approved, the people with progressive forms of MS felt overlooked, again removed from research focus and further alienated. There are now 13 FDA approved disease modifying therapies for RRMS (this includes the newly approved generic form of Copaxone), and one rarely used approved treatment (mitoxantrone) for progressive forms.
Dr. Thompson notes that treating progressive forms of MS is now considered a top priority and is why the International Progressive Multiple Sclerosis Alliance was founded in 2012 by the MS societies of Canada, Italy, Netherlands, United Kingdom and the United States. An additional 6 countries have since joined, bringing the number of sponsoring MS Societies to eleven.
For his talk, progressive includes both secondary and primary progressive MS, and he addressed the point that the majority of people (65%) with relapsing remitting MS (RRMS) will eventually change to Secondary Progressive MS (SPMS). There is also the group of an estimated 15% of people with MS who have the Primary Progressive MS (PPMS) form, meaning they experience no relapses and have continuous progression of their disease. Doctors know that the onset of progression is the main determinant of disability and there needs to be therapies to stop progression.
Dr. Thompson clearly shared the challenges of research for progressive MS, including understanding the phenotype, understanding the pathological mechanisms of progression, and much more. He pointed out that some of the POSSIBLE pathological signs of progression could include slowly expanding pre-existing lesions, B cell/antibody inflammation, failure to remyelinate, loss of axons/neurons, and cortical involvement of the gray matter. Also confusing the picture is how early stages of MS involve inflammation while late it almost always changes to degeneration.
Designing clinical trials for progressive MS poses another challenge – because progression may take place over a very long period of time, a trial to prove efficacy of a treatment could take 10-15 years or longer for a new drug. The length of studies could be shortened if the research was repurposing existing drugs, but the observation time would still be lengthy.
Dr. Thompson shared the list of 9 trials for progressive MS treatments that have failed, but those date from 1990-2011. There are two current trials in the UK for SPMS that may show some positive response but they have not yet been concluded. The first is CUPID, in Phase III, which is using the active treatment Tetra-hydrocanabinol, which has a primary outcome measure of the time for confirmed worsening of disability. The second active trial is MS-STAT, which is in Phase IIb, and is using the cholesterol drug, simvastatin, and monitoring its success through MRI imaging of brain atrophy. Dr. Thompson said the statins have shown positive value after the first year.
There are several additional ongoing studies for progressive MS, and Dr. Thompson identified the following as key trials and notes not all have had a positive outcome:
- Mastinib, Phase 2/3 PPMS and SPMS, a report on the trial data is expected in late 2015
- The INFORMS trial, which looked at Fingolimod (Gilenya) as the active agent to slow SPMS and was clearly a failure.
- The ORATORIO trial is in Phase 3 and is looking at Ocrelizumab; the trial data is expected Q4 201
- Laquinimod is the active agent for the ARPEGGIO Trial, and that data is not expected until 2018
One common drug, Biotin, a vitamin, has shown some success in an earlier trial, and will be looked at further for use in both SPMS and PPMS. According to “Effect of MD1003 (High Doses of Biotin) in Progressive Multiple Sclerosis” presented at the American Academy of Neurology earlier this year “Biotin is a water-soluble vitamin acting as a coenzyme for carboxylases involved in key steps of energy metabolism and fatty acids synthesis. Among others, biotin activates acetylCoA carboxylase, a potentially key-enzyme in myelin synthesis. In one previous open-label pilot study involving 23 patients, it was found that high doses of biotin (100 to 600 mg/day) resulted in progressive and sustained improvement of disability in primary and secondary PMS patients.”
Dr. Thompson elicited a slight chuckle from the crowd when he suggested with all the studies being done to repurpose drugs, one should be concerned if the number of authors outweighs the number of study patients.
Dr. Thompson concluded his talk with a section looking at future opportunities in progressive MS studies and the funded work of the Progressive MS Alliance (which I will cover in a separate article). His short list of research targets includes neuroprotection, repair/remyelination, lifestyle, rehabilitation and enhancing plasticity. In particular, he is an advocate of the approach that at time of diagnosis everyone should be treated aggressively and not allowed to become in the progressive state. He is realistic that the researchers will also have to design new ways to prove their early treatment approach is effective.
Wishing you well,