AAN 2017: Treating Progressive MS
American Academy of Neurology annual meeting, Boston MA, 22-28 April 2017
Over a dozen medications are available to treat relapsing-remitting MS. But few drugs have been shown to be effective in progressive MS – either secondary-progressive MS (SPMS), which often develops in people after the initial relapsing-remitting phase; or primary-progressive MS (PPMS), in which there are few or no relapses, but an accumulation of disability from the outset.
RRMS medications primarily target inflammation, which causes the relapses and MRI lesions that are characteristic of MS. Inflammation is also believed to be the starting point of progressive MS, but nerve damage and faltering repair mechanisms are what drives the accumulation of worsening disability in SPMS and PPMS.
Inflammation may be more evident in the earlier phase of progressive MS, so conventional MS medications can have some impact. This was shown in an early study, called SPECTRIMS, which looked at the use of Rebif in SPMS (Li and colleagues. Neurology 2001;56:1505-1513). Rebif was able to reduce the number of inflammatory lesions on an MRI, but failed to slow disability.
Since that trial, numerous drugs that reduce inflammation have tried and failed to show a benefit in progressive MS, including Copaxone (PROMISE study), Tysabri (ASCEND study), and Gilenya (INFORMS study). An SPMS trial of Tecfidera (INSPIRE) was cancelled before there were any results.
The success or failure of a study can depend on who is being studied. For example, in the OLYMPUS trial of people with PPMS, Rituxan (a drug that targets B cells) failed to slow disability in the group overall (Hawker and colleagues. Ann Neurol 2009;66:460-471). However, there was some benefit in younger people, and those with ongoing inflammatory activity. So when Ocrevus, the sister compound of Rituxan, was being studied in PPMS, the trial (called ORATORIO) enrolled younger people, and about one-quarter had active inflammation. As a result, Ocrevus was shown to have a modest effect in slowing disability progression (Montalban and colleagues. N Engl J Med 2017;376:209-220), and is now available (in some countries) to treat PPMS.
A new analysis of ORATORIO data was presented at AAN 2017 (Wolinsky and colleagues. AAN 2017; abstract P4.384). The measure used was NEPAD, which stands for “no evidence of progression or active disease”. “Progression” (i.e. worsening disability) was assessed using two measures, and “active disease” was defined as relapses and new MRI lesions. Using this yardstick, 29.9% of people taking Ocrevus achieved NEPAD, compared to 9.4% of those on placebo. However, this may overstate the benefits. In the original study, using the more conventional measure of EDSS score, the proportion of people who had worsening disability was 32.9% with Ocrevus compared to 39.3% with placebo.
Three other studies presented at AAN 2017 looked at current therapies to see if there was any benefit in progressive MS. In the unpublished ASCEND trial, Tysabri failed to slow disability progression in people with SPMS. However, there was some gain in terms of upper limb function. During the three-year extension of that study, there appeared to be some benefit on other disability measures (Hartung and colleagues. AAN 2017; abstract P5.330). One interpretation is that in progressive MS there’s a “treatment lag”, i.e. it may take a few years of treatment before a benefit is shown because tissue that’s already damaged by inflammation cannot be salvaged even if inflammation is been shut down. This idea was floated last year using an analysis that showed that Rebif and Copaxone start to show a benefit in progressive MS – but only after 2-3 years of treatment (Sormani et al. ECTRIMS 2016; abstract 215).
In the second analysis, researchers looked at the small number of people with progressive MS who were treated in two trials of Aubagio (TEMSO and TOWER). Over a follow-up period of up to nine years, 80% of these people with progressive MS showed no worsening of their disability (Nelson and colleagues. AAN 2017; abstract S33.008). However, it should be noted that this analysis only looked at a small proportion of people (122 out of more than 2,200) enrolled in those trials.
The third study looked at 15 people with SPMS who hadn’t responded to numerous therapies and were put on Lemtrada (Berkovich and colleagues. AAN 2017; abstract P5.356). Disability scores improved slightly, walking speed improved by about one-third, and there were some gains in cognition as well. These results are encouraging but very preliminary.
New treatments in development
Three novel treatments in development also presented data at AAN 2017 in progressive MS.
Siponimod is a next-generation Gilenya in phase III testing for SPMS (Kappos and colleagues. AAN 2017; CT002). The trial (called EXPAND) reported that siponimod reduced the risk of worsening disability by 26% compared to a placebo. Interestingly, a benefit was seen even in people without inflammatory activity. Side effects were similar to what is seen with Gilenya, such as headache, urinary tract infection and effects on the liver (Fox and colleagues. AAN 2017; abstract S33.007). The dose of siponimod is slowly increased at the start, so, unlike Gilenya, there’s no need for an initial six-hour observation period.
MIS416 is an experimental therapy (called an “immunomodulatory microparticle”) in development for spinal cord injury and SPMS (Girvan and colleagues. AAN 2017; abstract P5.333). Preliminary studies indicate that it may modulate the innate immune response, which then stimulates repair mechanisms in the spinal cord. A phase II trial in humans is now underway.
Mesenchymal stem cell (MSC) transplants use a type of stem cell found in various tissues (e.g. bone marrow, placenta, umbilical cord); like other stem cells, they have the ability to become different types of tissue, replacing damaged tissue. MSC neural progenitors release growth and repair factors that may heal damaged nerve tissue, and phase I testing has begun in progressive MS (Harris and colleagues. AAN 2017; abstract P5.378). Thus far, 20 people have received three infusions over a nine-month period. The study was not designed to assess efficacy, but most people did show improvements in neurological function and muscle strength. The most common side effects are headache and fever. A phase II trial is now underway.
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