World Congress on Treatment and Research in Multiple Sclerosis
Written by Susan Wells Courtney
More than 5,000 medical professionals attended this year's first World Congress on Treatment and Research in Multiple Sclerosis, held in Montreal, Canada this past September. MSAA's Chief Medical Officer Jack Burks, MD, not only attended the meeting, but also reviewed approximately 1,000 poster presentations - specifically about the latest in MS news and research.
From this vast amount of information, cutting-edge studies, and exciting drugs in development, Dr. Burks selected those posters which he found to be of greatest interest, and summarized them in a presentation to MSAA staff. To follow are some highlights from Dr. Burks' presentation.
General MS Information
An estimated two and a half million people worldwide are now thought to have MS. Most individuals with MS are diagnosed between the ages of 15 and 45. Four times as many women are diagnosed than men, and 85 percent of those diagnosed begin with the relapsing-remitting form of MS (RRMS). Without treatment, half of these patients will advance to secondary-progressive MS (SPMS) within 10 years, where symptoms usually do not remit, and patients are more likely to develop greater disability.
Years ago, MS in children was considered to be extremely rare. Presently, up to five percent of the MS population is under the age of 18 (pediatric MS), and pediatric MS centers have been setup to address the special needs of this age group.
While adult MS has a much greater female population, pediatric MS is more evenly divided between the genders. Among common symptoms experienced, approximately 70 percent have mental health issues - such as depression and attention deficit hyperactive disorder (ADHD). Fatigue is another symptom seen frequently in pediatric MS, which can greatly impact daily activities.
Approximately 25 percent of children with MS have cognitive problems. For adults and children, cognitive dysfunction can also impact many aspects of one's life, affecting memory, concentration, and mental quickness. Cognitive rehabilitation and cognitive functioning are getting more attention from researchers. While much is not known about the evaluation and treatment of this symptom, the development of cognitive retraining at some MS centers has had some exciting results.
Although fewer African-Americans develop MS, this subset of the MS community tends to have a more aggressive disease course. The B cells in the immune system may be a factor, versus the immune system's T cells. These T cells have traditionally been believed to be the primary source of inflammation. These findings may lead to new research into different types of treatment for specific groups of individuals.
Neuromyelitis optica (NMO), also known as Devic's disease, is a disorder that can appear to be very similar to MS, affecting the spinal cord and optic nerve. Although this is not a progressive disease, it can be recurrent with severe symptoms. A new test has been developed to help doctors differentiate some NMO patients from MS patients. New treatments for NMO are being studied. Rituxan ® (rituximab) is one example.
Research from Many Directions
Research into the cause of MS is focusing on four areas:
Damage from MS occurs in two different ways: inflammation and degeneration. Early in the disease, inflammation occurs as the body's immune system attacks the brain. Anti-inflammatory drugs, such as the current disease-modifying therapies (DMTs) for MS, minimize the damage from inflammation and reduce the attacks.
Cells can be damaged and then recover, but may be destined to not live as long - because they have been previously damaged. This could be a link to the second component in the disease process: cell degeneration.
The degeneration is more pronounced later in the disease, and is characterized by loss of axons and nerve cells, as well as myelin. This damage occurs without the intense inflammation to the axons (nerve fibers) and the neurons (the grey matter in the brain). This grey matter in the brain can also be damaged, which may affect cognition.
If later degeneration is related to earlier inflammation, early treatment might stop or at least slow this damage. With this in mind, how can MS be diagnosed and treated sooner? MRI findings can lead to treating patients after their first attack.
Researchers are searching for the causes of the degeneration. A number of theories exist; some say that this latter degenerative phase is independent of inflammation, but others believe that the two phases are linked.
Does brain atrophy (shrinkage) occur only late in the disease? Researchers have shown that brain atrophy starts early in the disorder. One study found reductions in brain volume to be similar in early and late stages of the disease.
The good news is that the body's natural process of making new myelin - while not as efficient in the white matter of the brain - is much more efficient in the grey matter of the brain. As mentioned earlier, damage to the grey matter can affect cognition, and this is because it is the "thinking" area of the brain.
One possibility for the lack of new myelin production in the white matter is interference from the inflammatory cells. A study in Tokyo found that a molecule called "TIP30" may inhibit the cells that normally repair nerves.
With MS, a protein called "fetuin-A" has been found to be increased in the spinal fluid and the brain, especially around lesions. These and other new biomarkers for MS could possibly be measured to help researchers discover more about the disease, in terms of diagnosis and disease course.
Gene expression changes dramatically with different disorders. Researchers can now map changes when a patient is sick and prescribe drugs that change specific gene expression. These are referred to as "boutique therapies." Using the Human Genome Map, this type of treatment may one day be developed for individuals with MS.
Risk factors for MS continue to be investigated. These include:
Osteoporosis is another concern for individuals with MS. Patients are at a higher risk, partly from steroid treatment, which reduces calcium in the body. In addition, while pulse steroids may seem like a good idea, they can destroy joints, a process known as "osteonecrosis." One group of MS scientists reported that approximately seven percent of individuals treated with pulse steroids develop this disorder.
A growing number of patients (with no MS-type of symptoms) are being diagnosed with "Radiologic Isolated Syndrome." This is where a patient undergoes an MRI for some unrelated reason, and MS-type lesions are found. Researchers are seeing more of asymptomatic patients. Of those patients followed, 80 percent later developed new lesions, and 21 percent went on to have a neurological attack.
The Success of Disease-Modifying Therapies
The approved disease-modifying therapies (DMTs) for MS can help to reduce the number of relapses, decrease the number of active lesions on MRI, and slow the progression of disability. Several also delay the onset of clinically definite MS (CDMS) following the first neurologic event, which is called a clinically isolated syndrome (CIS). In long-term follow-up studies of 15 years or more, patients taking DMTs frequently report a high quality of life and reduced disability. Many continue to remain ambulatory.
With the interferons, 15 years of data show that patients who stay on Avonex® (interferon beta-1a) continue to do well. Most individuals taking Avonex long-term state that their health is excellent, and a significant percentage of these long-term users are able to walk unassisted.
When treating CIS with Betaseron® (interferon beta-1b), immediate treatment decreased disability by 40 percent at three years and by 24 percent at five years versus those whose treatment was delayed until the second attack or at two years. Betaseron users also report a high quality of life.
Rebif® (interferon beta-1a) has tested a reformulated product, which improved tolerability and reduced neutralizing antibodies. Also, a 16-week study showed fewer MRI lesions in treated patients versus patients on placebo. The new formulation is undergoing Food and Drug Administration (FDA) review for possible approval in the United States.
Also, generic versions of DMTs are becoming available in foreign countries (Mexico, Argentina, Korea, and Iran). The similarity of these to brand-name drugs is being challenged. Some experts believe these biogenerics lack adequate safety and efficacy data.
Looking at Copaxone® (glatiramer acetate), those with a clinically isolated syndrome (CIS) were 45 percent less likely to be diagnosed with clinically definite MS (CDMS) within two years if taking Copaxone versus placebo. This drug may also offer protection of the axons (nerve fibers). A study showed that a higher dose did not offer any benefits over the regular dose, although every-other-day dosing may be of equal benefit - but more studies are needed. Copaxone's long-term follow-up of 15 years shows an improvement in relapses and disability. More than 80 percent of patients were walking unaided.
Novantrone® (mitoxantrone) is used as a rescue therapy. A "rescue therapy" is used for patients with a suboptimal response to a DMT given as a first-line of treatment. Patients need to be monitored carefully as it may cause heart failure, loss of menstruation, and even leukemia. Treatment is limited to a maximum of two to three years and regular heart testing is recommended. A small study in Italy administered gonadotrophin releasing hormone (GnRH)-analogue treatment in conjunction with Novantrone, in an effort to avoid the premature loss of menstruation. At the time of this report, half of the women had completed their treatment with both medications, and these six women now have normal menstrual cycles.
Tysabri® (natalizumab) continues to be an effective DMT, but risks still exist. Two new cases of Progressive Multifocal Leukoencephalopathy (PML) occurred in July 2008, with two men in Europe. At last report, due to early diagnosis, both continue to be stable (PML is an often fatal viral infection of the brain). Other potential adverse events include low platelet count, as well as herpes virus encephalitis and meningitis. Tysabri has also been shown to be very effective in treating pediatric MS patients, whose MS is highly active.
Rescue therapies which are not FDA approved for MS include: pulse steroids; Rituxan; Cellcept ® (mycophenolate mofetil); and high-dose Cytoxan® (cyclophosphamide).
Emerging MS Therapies
Campath® (alemtuzumab) shows much potential in the treatment of MS, with a significant reduction in annual relapse rates, disability, and MRI lesions. Toxicity with this drug is still an issue, with an increased risk of low platelets and Graves' disease. One successful study used Campath as a rescue therapy in RRMS.
Rituxan is a monoclonal antibody that reduces specific antibodies. Positive data in RRMS has been demonstrated. In primary-progressive MS (PPMS), overall results were negative, but patients under 55 with active MRI lesions showed a benefit in an analysis that was completed after the study. For other diseases treated with Rituxan, PML has been reported. As noted earlier, this drug is also showing positive effects in preliminary studies in NMO.
Oral cladbribine will be the first oral therapy to report phase III trial data to the FDA, with results available in 2009. It reduces certain T-lymphocytes, which may help in the treatment of MS.
In a Phase II RRMS trial, oral fingolomod (FTY720) demonstrated reductions in relative relapse rate and the development of new MRI lesions versus placebo. A phase III RRMS study with more than 3,000 participants is underway. Two patients in this study died from viral infections. While fingolomod has not been proven to have caused these deaths, the association cannot be ruled out at this time. A study with PPMS patients is also underway (outside of the United States), with plans to begin United States' enrollment in January 2009.
Parasites are another interesting area of research in the treatment of MS. In general, countries with a high prevalence of parasite infections have low prevalence of MS. Parasites may help to regulate immune activity. One study involving parasites and MS is underway.
MBP8298 has been granted fast-track designation from the United States Food and Drug Administration (FDA) for SPMS. Fast-track designation can help in the development of drugs for serious or life-threatening conditions, as well as speed-up the review process. This treatment is being studied in RRMS and SPMS; it appears to be well tolerated. Other similar drugs are also being tested in MS. Their aim is to "tolerize" the immune system from attacking the myelin.
CDP323, an oral drug with action similar to Tysabri, is being studied. It has a shorter half-life than Tysabri, which means that it does not stay in the body as long. This may have a lower risk of PML, and is currently in phase II studies.
Stem cell studies are ongoing. Stem cells taken from bone marrow have shown some evidence of revitalizing brain tissue in RRMS.
An eight-week study with Low Dose Naltrexone (LDN) was found to increase quality of life. Specifically, mental health was improved, but physical measures were not affected. In animal studies, higher doses caused damaging effects in an MS-like disease.
Flavinoids, green tea, and red wine are showing some positive effects. These may possibly help to protect nerve fibers. Researchers are also looking at the potential value of a diet rich in fish, as well as the benefits of olive oil.
Whether vitamin D supplements can help protect people from developing MS, or help reduce the effects of MS, is not yet known. More research is needed to determine the potential for treating with vitamin D. The appropriate doses also need to be identified.
Other emerging therapies for MS include: Zenapax® (dacilzumab); teriflunomide; BHT-3009; NM-166; intravenous immunoglobulin (IVIg); estriol, menocycline; doxycycline; Prozac (fluoxetine); laquinimod; BG 12 (fumarate); antisense oligonucleotide (ATL1102); bone-marrow transplant (BMT); oral IFN-Tau; Atacicept (ATAMS); PEGylation of IFN-B in EAE; Rilutek ® (riluzole); ATX-MS1467 (4 MBP Peptides); RTL1000 (recombinant T-cell receptor ligand); glucosamine sulfate; semaphorins (guidance molecules for remyelination); Tovaxin ™ (T-cell vaccination); and statins, among many others.
In summary, researchers now have a better understanding of MS, its causes, and its pathology. Researchers are learning more about pediatric MS as well. The presently approved DMTs are working well, and many emerging therapies - including oral medications - are showing much potential. However, toxicity is always a concern, and members of the MS community and medical fields must continue to exercise caution until the potential side effects of a treatment are known.
New symptom management strategies continue to be developed - from exercise rehabilitation (found to improve fatigue) to cooling (to reduce symptoms in heat-sensitive individuals). Other treatments such as Fampridine-SR for walking speed and leg strength, and Duloxetine for depression, pain, bladder problems, fatigue, and quality of life, may prove to be of great benefit to the MS community. Other drugs are being developed such as Zenvia ™, to treat pseudo-bulbar affect (PBA), which is a condition where individuals experience emotional instability.
For a more complete list of treatments - both approved and experimental - please refer to the cover story from the Summer 2008 issue of The Motivator, "MS Research Update 2008." This may be viewed or downloaded from MSAA's website at www.mymsaa.org. Readers may also order a copy by calling MSAA's Helpline at (800) 532-7667. The upcoming Winter 2009 issue of The Motivator will focus on approved and experimental treatments for symptom management.
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|Last Updated on Tuesday, 05 February 2013 11:16|