New Treatments, New Choices
2010 has been a productive year for MS treatments. New studies on existing disease modifying therapies are providing data that show the continued effectiveness of these medications over 10 years and more. Two symptomatic treatments have received FDA approval, and oral disease modifying treatments are finally here.
Gilenya—the first oral MS disease-modifying medication to treat relapsing multiple sclerosis—was approved in September. Other oral medications, cladribine and laquinimod, have been accepted to the FDA’s Fast Track approval process. It is expected that Cladribine will be approved as soon as December.
Patients and doctors alike have long awaited oral disease modifying treatments. The possibility of no needles, injections, and infusions is attractive to everyone. Published studies of oral fingolimod (Gilenya) show that the drug reduces relapse rates and new or enlarging lesions on MRI, and after 24 months, there was less risk of progression of disability. Cladribine studies also show a significant reduction in relapse rate, risk of disability progression, and MRI measures of disease activity at 96 weeks. While it is clear that these and probably other emerging oral therapies show a true benefit for those with relapsing forms of MS, physicians and their patients need to evaluate the potential benefits and risks. As with injections and infusions, the new oral drugs need to be taken long term.
The possibility of serious side effects from Gilenya means individual patients need pre-testing and on-going monitoring to reduce risk. Common side effects include headache, flu, diarrhea, back pain, liver enzyme elevations, and cough. However, the label carries warnings about decreased heart rate and/or other heart effects after the first dose; increased risk of infections; risk of macular edema (swelling of the center of the retina inside the eye); decrease in lung function; slight increase in blood pressure; increases of liver enzymes; and risk of harm to a fetus (based on animal studies). And obviously, the long-term safety of Gilenya is not yet known.
While it is exciting to have new medications on the market, experience with them is limited to the clinical trial history. That means understanding of the potential risks is limited, as is knowledge of the long term rewards.
If you’ve been on one of the injectables for a short period, there may not have been enough time for it to work. However, the data shows that with long term use effectiveness of these medications actually improves.
There’s about 17 years of history with Betaseron, the first FDA approved MS disease modifying drug. The other treatments followed quickly. All have strong safety profiles, which cannot be overstated. Side effects are the greatest risk for any drug, and the true profile of a medicine is never fully understood until it’s been used widely for a long time. Also, there are promising trials currently underway using different medications in combination, which could out-perform results shown with new meds.
Make no mistake; it is a great option to have Gilenya and the other oral disease modifying therapies that will follow. The decision to take one of the new treatments warrants a discussion with your MS physician, and should include how well you might tolerate side effects, the risk of adverse long term effects, and how well you are already doing on a disease modifying therapy.
As the children of modern medicine, we’ve grown up to expect that the medicine we take will make us better. Medication, however, is not always that simple, as anyone with MS will agree. Oral disease-modifying therapies are only one of many exciting treatments moving through the MS pipeline. For more information on other promising research that address ways to stop MS progression, restore function, and end MS forever go to
Fifteen years ago, MS was a very different disease. Some symptoms could be treated, but there were no drugs available to treat the disease itself. That isn’t so today, thanks to MS research breakthroughs. Still, the need for better treatments remains pressing and MS research continues toward this goal.
There’s no doubt that such research comes at a cost. Bringing an MS drug from idea to reality can cost over a billion dollars.
What exactly makes MS research so expensive?
We asked Timothy Coetzee, PhD, president of Fast Forward, a research subsidiary of the Society established to fast-track research into MS and help bridge the gap between research findings and the companies that will manufacture and market the therapy.
“You pay scientists to design and execute research plans, you pay technicians to analyze results,” Dr. Coetzee told us. This work requires highly specialized equipment in physical plants that the FDA has to approve. “You’re not doing MS research in your garage,” he pointed out.
After all the lab and animal studies, many promising therapies will fail to prove out. For those that do, more time-consuming and expensive tests must be performed to ensure that a new drug is both safe and effective for people.
Testing MS drugs is particularly complex, Dr. Coetzee noted. A blood pressure pill either lowers blood pressure or doesn’t. But with MS, he continued, “We’re trying to measure what happens to a person’s disease course, which you can usually see only over time. Changes in MS are slow and subtle. All that time adds to the cost.”
The Society invests in university-based research across the world. But that research can only become reality — a medication available for physicians to prescribe — with the involvement of the private sector.
“In today’s environment,” Dr. Coetzee said, “there’s no guarantee that even good discoveries will actually make a difference in people’s lives because of the expense involved in doing needed trials. Fast Forward wants to move the ball down the field a little faster. We don’t want to leave it to chance.”
For example, Amplimmune, a startup pharmaceutical company in Rockville, Md., is currently testing a drug called Amplimmune-110 for MS and other autoimmune diseases, with support from Fast Forward.
“We matched Amplimmune up with MS researcher Stephen D. Miller, PhD, of Northwestern University,” Dr. Coetzee said. “Dr. Miller discovered new ways the drug works that Amplimmune’s scientists weren’t aware of. We now hope clinical trials can begin within the next couple of years.”
More than 5,500 neurologists and other investigators from around the world convened in Gothenburg, Sweden on October 13-16 to present findings at the annual ECTRIMS (European Committee for Treatment and Research in Multiple Sclerosis) conference. More than 900 scientific presentations and display posters covered virtually every aspect of research to stop MS, restore function, and end MS forever. Among these were the latest results from pivotal clinical trials of emerging MS therapies, possible risk factors, underlying disease mechanisms, rehabilitation approaches, CCSVI, and much more. For free access to the conference abstracts, go to http://www.congrex.ch/ectrims2010/. The following highlights reflect the rapid pace of MS research today
Research Toward Stopping MS
Experimental Treatments in the Pipeline
- Teriflunomide (sanofi-aventis) is a novel oral compound that inhibits the function of specific immune cells. In a two-year, phase III trial, 1,088 people with relapsing MS, compared two doses of teriflunomide against inactive placebo. Both doses significantly reduced the rate of MS relapses by up to 31.5% relative to placebo, and the higher dose was found to reduce the risk of disability progression by 29.8% compared to placebo. The therapy also reduced the risk of new MS lesions seen on MRI, and reduced disease activity in a range of other MRI measures. The risk of adverse events was the same across all groups, and the most common side effects for active treatment were nausea, diarrhea, mildly elevated liver enzymes and thinning of the hair. Additional clinical trials of teriflunomide are underway.
- There are new attempts to stop MS progression using infusions of an individual's own bone marrow or blood stem cells, called mesenchymal cells, which has been used safely in people with some blood disorders and to a limited extent in people with MS. In 2009 international consensus was developed on using these cells in clinical trials. In collaboration with Dr. Mark Freedman (Ottawa Hospital) and with an open invitation to other investigators willing to follow a strict protocol, a plan is in place to launch a phase I/II study in people with inflammatory MS, including relapsing-remitting MS, secondary-progressive MS and primary-progressive MS. By "inflammatory" they mean that there are signs of active inflammation on brain MRI scans, even in the absence of clinical relapses. Disease activity seen on MRI scans will be the primary outcome measured. Dr. Uccelli explained that the team hopes that the mesenchymal cells will lead to repair of the nervous system, but that so far there is no evidence that they do so.
Research Toward Restoring Function
Several teams reported progress in improving quality of life and specific MS symptoms through exercise and rehabilitation.
- Growing research suggests that exercise may alter the disease process.
- Group physical therapy exercises and supervised aerobics, yoga and resistance training classes were all found to have positive impacts on fatigue, mobility, and health-related quality of life in people with MS with varying degrees of disability. In one of the larger studies, 242 participants were randomly assigned to one of three one-hour exercise classes for ten weeks, or were put into a control group and asked not to change their exercise habits for the duration of the study.. All three classes produced significant reductions of the physical impact of MS (measured by the MS Impact Scale-29, version 2, physical component) compared to before beginning the classes.
CCSVI and MS
Several presentations focused on issues surrounding CCSVI (chronic cerebrospinal venous insufficiency) and MS, presenting mixed or conflicting results.
Among the issues raised were conflicting results from different groups, the lack of "gold standards" for methodology or validated guidelines for what constitutes vein abnormalities, disagreement about which imaging technologies are optimum for evaluating variations in vein flow and structure, and inconclusive results in terms of how or whether vein abnormalities contribute to MS pathology. There was general agreement that invasive procedures to correct narrowing of the veins should only be done in the context of controlled clinical trials.
Exploring nervous system repair
- There are a series of studies that uncovered a group of molecules that reside in structural tissues (extracellular matrix) that may be among several that block the ability of the myelin-making oligodendrocytes to repair damage caused by MS. The molecules, CSPGs (chondroitin sulfate proteoglycans) contribute to scarring, and in lab dishes they reduced the number of oligodendrocyte progenitor cells that matured into myelinating cells. By selectively turning off CSPGs in lab mice with myelin damage, they were able to increase myelin repair. More research should determine whether this approach could be useful for encouraging myelin repair in people with MS.
Research Toward Ending MS Forever
- A growing list of factors that may contribute to an individual's susceptibility to developing MS was reviewed, but none of which are sufficient alone to cause the disease. These include a group of genes that control certain immune activity (called HLA), and environmental/lifestyle factors such as smoking, low vitamin D status, and exposure to the Epstein-Barr virus. He described a promising approach of looking at how modest risk factors interact to produce higher risks. For example, he cited a recent study from Harvard that found the risk of MS was multiplied in people who smoked and who had also been exposed to Epstein-Barr virus.
- For this study they enrolled 135 children under 16 years of age who initially came to them having experienced a single neurological episode and were at risk for developing MS. Their levels of circulating vitamin D were measured, and it was determined whether they carried a specific gene (HLA-DRB1*15) that had previously been shown to increase risk of developing MS. The children were monitored prospectively, and 24% were eventually diagnosed with MS. The team found that those carrying the HLA gene were more likely to develop MS, as were those with the lowest blood levels of vitamin D, but that both risk factors operated independently of one another.