Gilenya fails in primary-progressive MS trial
While there are many medications to treat relapsing-remitting multiple sclerosis (RRMS), no drug has been shown to be effective in treating primary-progressive MS (PPMS), the more aggressive, debilitating form that affects about 10-15% of people with MS. Unfortunately, Gilenya (fingolimod) has now joined the long list of failed PPMS medications, according to a press release issued by Novartis, the manufacturer of Gilenya (https://www.novartis.com/news/media-releases/novartis-provides-update-fingolimod-phase-iii-trial-primary-progressive-ms-ppms).
In the phase III INFORMS trial, Gilenya (fingolimod) given for at least three years was no more effective than placebo on a combination of three disability measures. These measures were the EDSS (Expanded Disability Status Scale), which rates disability on a scale of 0 to 10; the 9-Hole Peg Test, which assesses upper limb function; and the Timed 25-Foot Walk, which measures walking speed. Gilenya failed to slow the progression of sustained disability any better than a placebo. No data were provided.
It was hoped that the unique effects of Gilenya on the immune system would prove to be a benefit in PPMS. This doesn’t appear to be the case, and it will likely reawaken old controversies about the nature of PPMS and the best way to treat it.
In RRMS, abnormally activated immune cells (T and B cells) invade the central nervous system (CNS) and cause inflammation and tissue damage. These inflammatory hotspots can be seen as lesions on magnetic resonance imaging (MRI). All of the medications used to treat MS reduce this inflammation to a greater or lesser degree through various mechanisms. In the case of Gilenya, aggressive T cells are locked up in the lymph nodes so they can’t invade the CNS, thereby reducing the amount of damage that occurs. The hope is that during the lifelong course of MS, less tissue damage will mean less disability in the years ahead.
While disability typically takes many years to develop in people with RRMS, the situation is very different in PPMS. PPMS occurs more or less equally in men and women (as opposed to RRMS, which is 3-fold more common in women), people are usually diagnosed in their late 30s or early 40s (so about 10 years later than for RRMS), they may not have any relapses, and disability begins earlier and at a faster rate (Tremlett and colleagues. Neurology 2005;65:1919-1923).
Since inflammatory flare-ups (relapses) affect only a minority of people with PPMS, there has been some debate in the research community about whether RRMS and PPMS reflect different aspects of the same process, or are different diseases that only share some similarities. The general thinking at the moment is that PPMS is the same disease process that’s being seen at a later time point (Confavreux & Vukusic. Rev Prat 2006;56:1313-1320). No genetic differences have been found between RRMS and PPMS (Ratzer and colleagues. Mult Scler 2013;19:1841-1848; Cree BA. Brain 1999;122[Pt 10]:1941-1950). The type of damage that occurs is similar (Antel and colleagues. Acta Neuropathol 2012;123:627-638). And while disability occurs more rapidly in PPMS, because it is diagnosed later, people with PPMS and RRMS reach the same levels of disability at about the same age.
There are many theories about the nature of RRMS and PPMS. In RRMS, disability is initially caused by the damage resulting from inflammatory flare-ups. This may subsequently trigger the neurodegenerative process that predominates in the secondary-progressive phase of MS. However, the neurodegeneration in PPMS may occur largely independently of inflammatory flare-ups, which raises the question of whether there are two separate processes – inflammation and neurodegeneration – going on in MS (Losy J. J Neural Transm 2013;120:1459-1462).
One idea that has emerged in recent years is that focal inflammation (the lesions seen on MRI) trigger a second immune reaction in the brain that manifests as more diffuse inflammation, and it is this widespread, almost undetectable inflammation that drives neurodegeneration (Kutzelnigg and colleagues. Brain 2005;128[Pt 11]:2705-2712).
This is where Gilenya comes in, and why expectations were high that it might be beneficial in PPMS. There is some evidence to suggest that Gilenya, by acting directly on immune processes in the brain, can modulate this diffuse inflammation (Brinkmann V. Br J Pharmacol 2009;158:1173-1182).
So why did Gilenya fail to meet expectations?
One problem may have been the trial itself. The study included a broad range of people (ages 25-69), with various levels of disability (from an EDSS score of 3.5 [moderate disability] to 6.0 [requiring a cane]), who had been living with MS for different amounts of time (from 2 to 10 years). Some would have had relapses, some not. So a treatment effect signal may have been lost in the noise. (Subgroup analyses will undoubtedly sift through the results to try to find if anyone benefited.) In addition, the trial included 970 people, which may have been too small to detect an impact on disability (Harding and colleagues. J Neurol Neurosurg Psychiatry 2014; epublished May 14, 2014).
Identifying disability worsening and whether a treatment is having an impact is also notoriously difficult in PPMS. The EDSS scale is relatively insensitive to short-term changes. A person’s EDSS score can fluctuate before a trial begins, so determining the true baseline can be difficult (Zhang and colleagues. Mult Scler 2013;19:775-781). Adding additional measures of disability (such as the 9-Hole Peg Test and the Timed 25-Foot Walk) improves the detection of disability worsening (Bosma and colleagues. Mult Scler 2012;18:345-350). But these measures are more meaningful over a longer time period. Evaluating sustained disability confirmed after six months or a year may be a better indicator than after three months (Zhang and colleagues. Mult Scler 2014;20:1494-1501), which was the time frame used in the INFORMS study. A longer study duration might have teased out a treatment effect.
All studies have limitations of course, and it may simply be that Gilenya is not effective in PPMS. Unfortunately, it’s not unique in this regard. In recent years, many other MS medications have failed to show a benefit in PPMS, including Avonex (Leary and colleagues. Neurology 2003;60:44-51), Copaxone (Wolinsky and colleagues. Mult Scler 2004;10 Suppl 1:S65-71), cladribine (Rice and colleagues. Neurology 2000;54:1145-1155), and rituximab (Hawker and colleagues. Ann Neurol 2009;66:460-471).
Finding an effective treatment that slows disability in PPMS is the most urgent task for MS research. Pilot studies in PPMS have been completed with a number of other therapies, including Tysabri (Romme Christensen and colleagues. Neurology 2014;82:1499-1507), Tecfidera (Strassburger-Krogias and colleagues. Ther Adv Neurol Disord 2014;7:232-238), and masitinib (Vermersch and colleagues. BMC Neurol 2012;12:36). A phase III study of Tysabri in PPMS is ongoing and results are expected in 2015.
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