Tackling progressive MS: An array of research is putting new treatments on the horizon

By Ted Brown, MD

Illustration by Bruce Blaus copyright via Wikipedia 
Creative Commons

In our last E-zine, we discussed changes in the way that we categorize different types of MS.  We still use the classifications of progressive disease, including Primary Progressive MS (PPMS, progressive disability from onset) and Secondary Progressive MS (SPMS, progressive disability after initial relapsing course).  With this issue, we are going to review some of the exciting work being done in developing treatments for progressive MS, including PPMS and SPMS.

Ted R. Brown, MD, MPH, Medical 

Director - MS Neuro-Rehabilitation

With 13 MS drugs available for relapsing forms of MS, there remains a great need of therapies that target progressive disease.  After all, about 2/3 of people who start with relapsing remitting MS (RRMS) will make a transition to progressive disease (SPMS) within 15 years of diagnosis and 10% of people with MS are diagnosed with progressive disease from onset (PPMS).  The path of drug development in treating progressive MS is littered with disappointments, including some drugs that are highly effective in treating RRMS.  Trials of fingolimod (Gilenya), rituximab (Rituxan), natalizumab (Tysabri) and glatiramer acetate (Copaxone) are among the drugs that have been tested in randomized controlled progressive MS trials and found to be lacking in benefit.  Some unconventional studies including medical marijuana have also been found ineffective.  

Why has it been so difficult to come up with treatments for progressive MS?   First, recently diagnosed patients tend to be the best research candidates.  Since progressive patients are a small minority of such patients, there simply are not as many eligible progressive patients to recruit for studies.  Second, because the disease is slowly progressive, as measured by clinical measures (the Expanded Disability Status Scale, EDSS), it takes a long time to study a progressive population, at least three years to detect progression even in an untreated cohort.  Third, relapses are either absent or much less common than with RRMS, so counting the “relapse rate” is a poor outcome measure.  Fourth, even though the disease is progressing in progressive MS, brain MRI measures of disease activity tend to be stationary.  So, counting the number of new lesions is not very fruitful.  New measures of brain atrophy are being utilized that offer improved MRI monitoring of disease progression to overcome this limitation.  Finally, and most importantly, the basic mechanism of progression in MS is complex.  This includes inflammatory activity at the immune system level, neurodegeneration (deterioration of neural structures) in the brain and spinal cord, effects of aging on the nervous system, dysfunction in energy metabolism at the level of the mitochondria, and perhaps other factors.  So, a treatment that targets one factor may not work on the other mechanisms driving the progression.   

Now, it’s time for the good news.  Over the past five years, there has been an accelerated pace of research in treating progressive disease and this is starting to pay dividends.  Here is a quick list of ongoing or recently completed drug trials in progressive MS that look promising:

• rHIgM22 is a remyelinating antibody being studied for the treatment of multiple sclerosis (MS). In 2015, the first Phase 1 clinical trial showed it was well-tolerated in each of the five tested doses, and the antibody was detected in the cerebrospinal fluid, indicated that it was able to reach the central nervous system (CNS).  A second Phase 1 trial is currently studying the effects on recovery from an acute relapse.  It is hoped that this drug could promote neuronal repair and thereby benefit people with progressive MS.

• Anti-Lingo-1 (BIIB033) is a human monoclonal antibody directed against a factor that suppresses CNS remyelination.  This drug has been studied in acute optic neuritis, generating some evidence that it may promote repair of the optical transmission pathways.   SYNERGY is an ongoing, separate 84-week Phase 2 study of anti-LINGO-1 in people with relapsing multiple sclerosis. The primary outcome measure is the percentage of participants who display improved neurophysical or cognitive function.  Results are expected later in 2016.

• Biotin is a vitamin acting as a coenzyme involved in key steps of energy metabolism and fatty acids synthesis. A year-long placebo-controlled phase III study conducted in France, involved 154 patients diagnosed with secondary or primary progressive MS taking a very high 300-milligram daily dose of biotin.  Researchers wanted to see how many patients showed improvement in either their EDSS score, or in the measure of their timed 25-foot walk (TW25). noted that physicians mostly scored patients receiving biotin (300 mg/day) between no change and much improved, whereas they scored those in the placebo group between no change and much or very much worse. The results were favorable.  Physicians mostly scored patients receiving biotin between no change and much improved, whereas they scored those in the placebo group between no change and much or very much worse.noted that physicians mostly scored patients receiving biotin (300 mg/day) between no change and much improved, whereas they scored those in the placebo group between no change and much or very much worse.noted that physicians mostly scored patients receiving biotin (300 mg/day) between no change and much improved, whereas they scored those in the placebo group between no change and much or very much worse. noted that physicians mostly scored patients receiving biotin (300 mg/day) between no change and much improved, whereas they scored those in the placebo group between no change and much or very much worse.  There is an ongoing trial of high-dose biotin in optic neuritis.  

• Ibudilast is an oral drug in the family of drugs that includes sildenafil (Viagra).  Ibudilast reduced brain atrophy in a phase 2 trial in MS.  It is now being studied in the USA in patients with progressive MS in a 96 week, placebo-controlled trial, titled SPRINT-MS. The effect on brain atrophy, as well as safety, cognitive impairment, neuropathic pain and quality-of-life are being assessed. The study is fully enrolled, but will take two years to complete.

• The MS SMART study being conducted in the U.K. is an ongoing trial of three drugs: fluoxetine (Prozac), riluzole (drug approved for ALS) and amiloride (antihypertensive/diuretic), all of which have shown some promise in MS. The trial is a 96-week, randomized and blinded trial which also looks at effect on brain atrophy as the primary outcome in SPMS. This study is still recruiting, so results will take at least 2 more years.  

• Ocrelizumab is another new monoclonal antibody.  This drug targets B cells, which are an important part of our immune system that produces antibodies, and has other functions.  As reported last year, ORATORIO was a randomized, double-blind, multicenter study evaluating the efficacy and safety of ocrelizumab (administered by intravenous infusion every 6 months) compared with placebo in 732 patients with PPMS. These patients were treated and tested over 120 weeks of the trial.  Results suggested that ocrelizumab significantly reduced the risk of progression of clinical disability by 24%, based on serial EDSS measurements, compared with placebo. It also appeared to improve the outcome in measuring worsening of walking speed over time and reduced the rate of whole brain volume loss (brain atrophy) over the course of the study.  The drug is also being developed for RRMS.  It is expected that ORATORIO results will be submitted to the FDA for further review of efficacy and safety data that may lead to ocrelizumab becoming available for progressive disease. 

• Other promising drugs include phenytoin (Dilantin), an anti-seizure medication which has shown a positive effect on recovery from optic neuritis, but is not currently under study, simvastatin (Zocor), a cholesterol lowering drug showing an impressive effect on brain atrophy in SPMS, but not currently under study, and idebenone, a high-dose anti-oxidant that is in a 3-year trial by the N.I.H. for effect on brain atrophy and disability outcomes in PPMS.  There are also current research studies involving neural repair with stem cell therapies

So, we’re seeing some emerging new drug treatment strategies to address progressive forms of MS.  Let’s not forget the importance of non-drug treatments for progressive MS.  There is a wealth of research indicating that regular exercise can favorably impact strength, fitness, mood and well-being in MS.  Everyone with progressive MS needs to have a regular exercise program.  Talk to your MS care providers about exercise and consider getting involved in an exercise group or consulting a physical therapist.  Don’t forget that your brain needs regular exercise, too.  Do something every day that makes you concentrate, problem-solve or try to remember things.  Read a book or a magazine or a newspaper regularly.  Keep stress under control by exercise, music, hobbies, meditation, keeping up with friends and other relaxing activities.  Make good food choices, don’t overeat and keep well hydrated.

The team at the Evergreen MS Center are available to discuss the latest in MS research, and whatever aspects of your personal wellness program we can help you with.   

We’ll end this with two quotes from the Nobel prize-winning physicist, Niels Bohr:

“Prediction is very difficult, especially if it's about the future.”

“Every great and deep difficulty bears in itself its own solution. It forces us to change our thinking in order to find it.”