With the recent approvals of several oral drugs to reduce disease flares in relapsing-remitting multiple sclerosis, the top researchers agree that the next major frontier is the disease's progressive forms.
But, on the basis of presentations and discussions at last week's annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), progressive MS now stands at about the same place that relapsing-remitting MS stood 3 decades ago -- that is, still many years away from an effective therapy or even a solid understanding of its pathophysiology.
At an ECTRIMS session devoted to progressive MS, opening speaker Robert Fox, MD, of the Cleveland Clinic in Ohio, said an international collaboration has been formed to take on the condition's challenges. Initial meetings have produced a list of five major research needs.
That list highlights how far the field needs to advance before it can even test a potential therapy properly. Currently lacking, but necessary for development of treatments, are the following:
- An experimental model for preclinical research
- High-throughput screening tools for drug discovery
- Appropriate outcome measures for phase II trials
- Appropriate outcome measures for phase III trials
- Outcomes to target for symptomatic treatments
Fox was followed to the platform by Finn Sellebjerg, MD, of the University of Copenhagen (the meeting's host city), who delved into the heterogeneity of progressive MS. This goes beyond the familiar distinction between primary and secondary progressive forms, to include what is sometimes called progressive-relapsing MS, in which periodic disease flares are superimposed on a background of steadily worsening symptom severity and disability.
Sellebjerg also argued that progressive MS may, in some cases, be a misnomer -- in many patients, their disease course may better be characterized as "incomplete remission after relapse" rather than true progression.
Other speakers in the session discussed different aspects of progressive versus relapsing-remitting forms, such as measures of axonal damage, cerebrospinal fluid protein levels, and variant genes for NMDA (N-methyl-D-aspartate) neurotransmitter receptors.
But none of these appeared to be foolproof approaches to distinguishing the different forms of MS clinically, let alone offering therapeutic targets for drug development.
On the other hand, Fox and Sellebjerg noted that a host of drugs are now or soon will be in clinical trials for progressive MS, because preclinical tests or findings in other neurodegenerative diseases suggested a potential for benefit.
These include simvastatin (Zocor), natalizumab (Tysabri), and alemtuzumab (Lemtrada), as well as a combination of ibudilast, amiloride, and riluzole. This last drug failed in a monotherapy trial in relapsing MS reported at the meeting. On the other hand, drugs for relapsing MS have mostly failed to show benefit in progressive forms, and it would not be surprising if the reverse were true, since the conditions are believed to be fundamentally different.
Sellebjerg said results from a pilot study of natalizumab, in which he had been an investigator, would be reported soon. The topline finding was that the drug showed positive effects in some measures, but brain atrophy continued. Also, although the drug appeared to improve disability scores, Sellebjerg called the magnitude "clinically questionable."