Written by Jack Burks, MD
Ampyra™ Approved to Improve Walking for Individuals with MS
On January 22, 2010, the United States' Food and Drug Administration (FDA) approved Ampyra™ (dalfampridine), to improve walking in individuals with MS. Ampyra is an oral, timed-release medication developed to improve the conduction of impulses between damaged nerves of the central nervous system (CNS). Phase III clinical trials showed that a greater number of individuals with MS experienced improvement in walking speed when taking Ampyra, compared to when taking a placebo.
Ampyra (pronounced "am-PEER-ah") was developed by Acorda Therapeutics and is manufactured by Elan Corporation. Formerly known as Fampridine-SR, Ampyra is a sustained-release version of 4-aminopyridine (4AP). In earlier studies, larger doses of the drug were given and the risk of seizures became a concern. Given in timed-release tablets, the risk of seizures did not differ from the placebo group.
MSAA Chief Medical Officer Jack Burks, MD notes, "The majority of my patients experience problems with mobility, so this approval comes as welcomed news to the entire MS community, especially since it has shown positive results with both relapsing and progressive forms of MS.
"Following the instructions for correct dosing is absolutely essential. Taking more than one tablet within 12 hours, or crushing or splitting a tablet, will increase the risk for seizures. Some patients tend to think that taking more of a symptom-management drug will result in greater effectiveness, but this is definitely not the case with this type of medication. I strongly advise patients not to exceed the recommended dosing."
Individuals with a history or evidence of seizures, or with moderate to severe kidney problems, should not be given Ampyra. Kidney function is important, since nearly all of this medication is removed from the body through the kidneys. If the kidneys are not functioning properly, levels of the drug will rise and increase the risk for seizures.
Ampyra is a symptom-management drug to improve walking in MS patients. It may be given in conjunction with any FDA-approved disease-modifying therapy and with other symptom-management drugs, but patients need to check with their doctor before combining Ampyra with other medications.
According to the FDA, the most common side effects reported for Ampyra include urinary tract infection, insomnia, dizziness, headache, nausea, weakness, back pain, balance disorder, swelling in the nose or throat, constipation, diarrhea, indigestion, throat pain, and burning, tingling, or itching of skin.
Anyone interested in this drug for symptom management should consult his or her physician, who can help to determine if this drug is appropriate. It is distributed exclusively through a network of specialty pharmacies, coordinated by Ampyra Patient Support Services. Consumers as well as healthcare professionals may contact Ampyra Patient Support Services at (888) 881-1918 or visit www.ampyra.com for more information.
For a more detailed version of this article, please refer to MSAA's online version, which may be accessed by visiting www.mymsaa.org and then selecting "Recent News." To request a printed copy of the online article, or to speak with one of MSAA's Helpline consultants, please call (800) 532-7667.
FDA Approves Botox® for Upper Extremity Spasticity
On March 9, 2010, the United States' Food and Drug Administration (FDA) approved Botox® (onabotulinumtoxin A) for the treatment of spasticity in the flexor muscles of the elbow, wrist, and fingers in adults. Manufactured by Allergan, Inc., this drug is administered via injection by a medical professional and is available through prescription only. The approval includes its use for individuals with MS.
Spasticity or muscle stiffness and tightness is experienced by many people with multiple sclerosis (MS), stroke, brain injury, or other neurological conditions. Spasticity can severely limit the use of one's arms and hands as well as produce pain.
Botox is given by an injection directly into the affected muscles. It blocks conduction between nerves and muscles which temporarily paralyzes spastic muscles, usually for a few months. This drug was first approved 20 years ago by the FDA for the treatment of certain eye-muscle disorders. Since that time it has also been approved by the FDA to treat three other disorders, which include a condition causing abnormal head position and neck pain; symptoms of severe underarm sweating; and the cosmetic use of temporarily improving the appearance of severe frown lines between the eyebrows.
The risks and benefits associated with Botox should be discussed with one's doctor. The most common side effects include nausea, fatigue, bronchitis, pain, and muscle weakness. Breathing and swallowing difficulties have been reported.
Botox injections add another treatment to the growing list of medications that may help MS symptoms. Botox is a symptomatic treatment only and is not a disease-modifying therapy for MS, so it should not be used as a substitute for these therapies. The FDA points out that Botox "is not intended to substitute for physical therapy or other rehabilitative care." Individuals who may benefit from this treatment for spasticity in the elbow, wrist, and fingers should consult their physician for specific recommendations.
For additional product information, readers may visit www.allergan.com or call Allergan's Customer Service at (800) 433-8871. For a more detailed version of this article, please refer to MSAA's online version, which may be accessed by visiting www.mymsaa.org and then selecting "Recent News." To request a printed copy of the online article, or to speak with one of MSAA's Helpline consultants, please call (800) 532-7667.
Chronic Cerebrospinal Venous Insufficiency (CCSVI) and Multiple Sclerosis (MS)
A great deal of media attention has been given recently to the possible connection between chronic cerebrospinal venous insufficiency (CCSVI) and multiple sclerosis (MS). CCSVI is a complex condition involving changes in blood flow from the brain back to the heart, which some researchers theorize could possibly lead to activation of the immune system, excess iron deposits, loss of myelin, and other nervous system damage.
Please note that all of these findings should still be considered preliminary at this time. Further studies are needed to confirm the theories proposed in this article.
Altered Blood Flow and Its Potential Effects
With CCSVI, the veins located on the outside of the brain (extracranial cerebrospinal veins) - those designed to transport blood from the brain back to the heart - collapse and/or become blocked, a condition known as "stenosis." As a result, blood leaving the brain must be rerouted through smaller vessels around these primary veins, referred to as "substitute circles." These ancillary veins, however, cannot transport the blood as quickly or efficiently as those larger ones designed for this purpose. Not only does the blood flow slow down, but the blood may also flow backwards (referred to as "reflux"), and studies suggest that both the reflux of blood as well as a pulsing (back and forth) flow may be much more common in MS patients versus controls.
Studies have shown that when the normal blood flow is altered, especially when the flow of blood is reversed, the body may react with an inflammatory response. Of particular importance is the activation of surface adhesion molecules, which enable damaging immune-system cells (such as macrophages and T cells) to cross the blood-brain barrier, infiltrate the central nervous system (consisting of the brain and spinal cord), and potentially injure brain tissue, myelin (the protective covering of the nerves), and nerve cells.
The proposed damage from CCSVI also involves an iron overload for individuals with MS. As with certain other neurodegenerative conditions, unusually high levels of iron may be present. Iron levels may be particularly high in the brain and spinal cord of individuals with MS. With CCSVI, where blood flow out of the brain is slowed down and even reversed, extra iron is believed to be deposited and stored in sites near these vessels.
How Iron Affects the Body
Iron is needed by all living things. In addition to maintaining cellular balance and enabling nerve cells to perform routine functions, iron forms tissues and blood vessels; it transports oxygen through the body via blood circulation; it enables nerve impulses to be transmitted; and is essential to the development of myelin and oligodendrocytes (which produce and maintain healthy myelin). Iron is deposited in varying amounts to the different cells within the body, according to their specific need for proper functioning.
While the benefits of iron in normal levels are clear - and critical for bodily function - conversely, too much stored iron can cause problems. For instance, as people age, iron is more likely to accumulate in the brain. Conditions such as Alzheimer's disease and Parkinson's disease can occur in connection with iron stores. The processes associated with excess iron in the body are very complex, but it has been characterized as, "...one of the most dangerous catalytic elements responsible for the neurodegenerative process." (Levenson and Tassabehji, 2004)
Since the first description of MS by Charcot in the mid-1800s, MS lesions have been known to be "venocentric," or occurring around blood vessels. More recent studies have also shown that with MS, iron stores may be found constantly encircling venous walls. Additionally, iron overload is found in MS lesions, although this is a feature also observed with other neurodegenerative diseases. Excessive iron may occur as a result (versus a cause) of MS damage.
Please note that individuals should not reduce their iron intake unless recommended by their physician. Iron deficiencies can cause serious complications.
An Experimental Treatment Trial with Endovascular Widening of Narrowed and Blocked Veins
A leader in the current CCSVI research is Paolo Zamboni, MD, director of the Vascular Diseases Center at the University of Ferrara in Milan, Italy. He and others have been studying blood flow, inflammation, and iron stores in MS for several years. The results of Dr. Zamboni's pilot study in Italy were presented at the 25th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) held in September 2009.
More recently, Zamboni and colleagues have published their treatment data of 65 MS patients who underwent an angioplasty type of experimental procedure to potentially improve blood flow from the brain to the heart.
With CCSVI, reduced blood flow is seen in the internal jugular (IJV) veins and the azygous (AZY) veins. Reduced blood flow is observed in these veins to varying degrees in the head, neck, and spinal cord. This condition requires a combination of veins to be collapsed. According to the study results presented in the December 2009 issue of the Journal of Vascular Surgery, "CCSVI is strongly associated with multiple sclerosis."
An experimental endovascular procedure was used to widen the narrowed or blocked veins in a study of 65 MS patients (endovascular is defined as "within a blood vessel"). Lead investigator Dr. Zamboni refers to this as the "liberation procedure." One of the purposes of this study was to evaluate the safety and clinical outcome of this procedure in the treatment of CCSVI with MS.
The 65 participants included 35 individuals with relapsing-remitting MS (RRMS), 20 with secondary-progressive MS (SPMS), and 10 with primary-progressive MS (PPMS). A number of criteria were used to select the patients, including a confirmed diagnosis of MS as well as CCSVI, and normal kidney function. In addition, RRMS patients must have been taking FDA-approved disease-modifying treatments.
In this study, percutaneous transluminal angioplasty (PTA) was performed on the 65 MS patients by using a tiny balloon inserted into an affected vein. The veins were accessed from a remote location in the groin, and the balloon was threaded through a vein until reaching the affected areas. The balloon was first inflated, held for 30 to 60 seconds, and then deflated. This process was repeated several times in each affected vein before the balloon was removed.
The procedure was done as day surgery using a local anesthetic, and patients were released after four hours of postoperative observation. Other physicians at other institutions have used stents to open collapsed veins. These patients were given a preventative dose of a blood thinner for three weeks following the procedure to reduce the risk of blood clots.
Safety and Vascular Study Results
According to Dr. Zamboni, the procedure was well tolerated, with no serious operative or postoperative complications. Six of the 65 patients reported postoperative headache that was temporary and went away on its own.
A major issue in the months following the procedure was that restenosis (where veins narrowed again) occurred in the IJV vein of 47 percent of the patients treated for IJV stenosis. This disappointing outcome occurred in the IJVs 16-times more frequently than in the AZY, and most often occurred at the eight-to-nine-month point following the procedure. Researchers state that a stent might be a logical solution, although dedicated devices of the correct size for IJVs are not readily available at this time. Technical improvements would be needed in the future.
Four patterns of stenosis were observed, and researchers note that certain patterns appeared to be associated with the different types of MS. According to the published results, in 90 percent of the PPMS patients (9 of the 10), the stenoses were limited to the veins which drain blood from the spinal cord. The reduced blood flow in the spinal cord, which occurred in several locations, may explain why the patients with PPMS experienced less benefit from the procedure than those with RRMS.
Neurologic Study Results
According to the published report, RRMS patients showed a "highly statistical improvement at 18 months" on the Multiple Sclerosis Functional Composite (MSFC), which measures leg and arm function, ambulation, dexterity, and cognitive function. Progressive patients (individuals with SPMS and PPMS), showed a "significant but limited improvement" at six months, but no improvement with respect to baseline at 18 months.
With regards to relapses in RRMS patients, 27 percent of these individuals were relapse-free during the year prior to the endovascular procedure. Postoperatively, 50 percent of the individuals with RRMS were relapse-free as of the 18-month follow-up time, which is a significant increase in the number of patients who did not experience a relapse.
However, the lack of an MS control group limits interpretation, since many MS trials have shown that the placebo-treated group may also improve in certain outcomes. The practice effect of repeated testing may have influenced the positive MSFC outcomes as well.
All of the RRMS patients whose veins remained open were relapse-free following the procedure. However, the numbers are small and the overall annual relapse rate (ARR) for the entire RRMS group was not significantly affected, since this included those RRMS patients who had a restenosis of the IJVs.
In terms of MRI results, the percentage of patients with active gadolinium-enhanced lesions at MRI was significantly reduced from 50 percent to 12 percent. However, the authors note that different MRI equipment was used, and this lack of consistency could have an effect on the actual outcome. Also, without an MS control group, "regression to the mean" may be a partial explanation for improvement. (This means that patients with active lesions on an MRI are more likely to have less MRI lesions on subsequent studies, even without therapy.)
Interpretation of Study Results from MSAA's Chief Medical Officer
MSAA Chief Medical Officer Jack Burks, MD, points out the value of putting forth a new hypothesis such as this, which is both creative and encouraging. He also explains that "thinking out of the box" may be needed to develop future treatments. Dr. Burks adds, "Finding interesting data to support this hypothesis is intriguing. These mixed results in a small pilot study are not surprising and may lead to more precise findings in larger, scientific trials in the future.
"Over the past century, more than 100 proposed treatments for MS have reached this stage of development," Dr. Burks continues. "From here, scientifically valid, multi-center studies are needed to demonstrate efficacy without significant adverse effects. The CCSVI scientists recognize the need for these additional studies and are not recommending this procedure, except as part of future clinical trials. For example, researchers need to agree on the most sensitive and accurate diagnostic test."
Specifically, in an article from Medscape Medical News (dated December 3, 2009 and written by Susan Jeffrey), Dr. Zamboni emphasizes that "...the current report should be viewed as an interesting finding that urgently requires replication by other groups."
Dr. Burks explains, "Dr. Zamboni is not advising patients to rush out and have this procedure. I agree with his perspective. Additionally, in non-experienced hands, surgery may not be as safe as demonstrated by Dr. Zamboni. Changes in the surgical approach may be forthcoming (such as stents versus balloon catheterization). Future trial results may be better, with fewer incidences of restenosis.
"This procedure cannot be considered a proven treatement at this time. Fifty percent of RRMS patients still had relapses after surgery. In addition, all RRMS patients were on DMTs. The specific relationship to relapses and restenosis is important. The researchers are planning the right steps. However, the results from future studies are needed before relevant conclusions and recommendations can be established."
The CTEVD Study by the University at Buffalo
As a follow-up to the small, pilot study conducted in Italy by Dr. Zamboni, a larger study is now underway. Titled, "Combined Transcranial and Extracranial Venous Doppler (CTEVD) Evaluation in MS and related Diseases," this larger study is being conducted at the University at Buffalo in New York.
According to the University, "The main goal of the CTEVD study is to investigate the prevalence (frequency) of CCSVI in patients with multiple sclerosis (MS) when compared to healthy controls (HC) and controls with other neurological disorders (OND). Another important aim of the CTEVD study is to investigate the relationship between CCSVI and clinical, magnetic resonance imaging (MRI), and environmental-genetic outcomes in MS patients, HC, and controls with OND."
In February 2010, researchers from the University at Buffalo reported preliminary results from the initial phase of this study. Based on the first 500 participants, more than 55 percent of the individuals with MS were found to have CCSVI. Less than half as many healthy controls were found to have this blood-flow abnormality.
On March 12, 2010, the University at Buffalo gave an update on the CTEVD study. The program has been modified as advised by the University's Institutional Review Board. According to the update, "The purpose of the program modification was to ensure that individual study results were not proffered by BNAC as a diagnosis for which any treatment is implied or advised." The report also notes that at this time, funds are not available to support the study and participants will need to pay their own fees for tests ($4,500 per person).
For more information, readers may go to www.buffalo.edu/news/10937 to view the February press release from the University of Buffalo. Readers may also go to www.bnac.net/?page_id=517 for specific information on study enrollment at the University at Buffalo. Individuals without internet access may contact MSAA's Helpline consultants for assistance at (800) 532-7667.
Dr. Burks concludes, "To date the data establish an association, but do not yet establish a causal relationship of CCSVI and MS. Fortunately, research funding is rapidly becoming available to answer some of the important questions regarding the potential causal link. Also, researchers are working to better determine the most accurate diagnostic tests as well as the most effective and safest procedural approaches for correcting the situation.
"What is the status of the current treatments for CCSVI? Two approaches have been tried. Venous angioplasty is done by placing a catheter into the 'closed' veins to 'open' them up. However, this current procedure may not keep veins open for long, since almost 50 percent of some veins re-stenosed in less than a year in Dr. Zamboni's paper. Another potential corrective surgical procedure is placing stents in the veins to keep them open. However, these stents may break off, since the walls of veins may be very fragile. On one occasion, an emergency heart surgery was performed.
"Therefore, we still have more to learn before researchers establish the possible causal link as well as establish the best diagnostic tests and treatments. I wish them success in getting us these answers quickly.
"While the researchers work diligently to find answers, I recommend these procedures be focused in the research arena. The next steps are to better understand the causation issues, the proper diagnostic procedures, and the safest/most effective way to treat the abnormality. We are not there yet but the research is already underway. We need to let the science proceed as planned and to wish the researchers much success. MSAA will continue to provide balanced updates as the research work progresses. For now, your doctor is your best guide."
For a more detailed version of this article with resources, please refer to MSAA's online version, which may be accessed by visiting www.mymsaa.org and then selecting "Recent News." To request a printed copy of the online article, or to speak with one of MSAA's Helpline consultants, please call (800) 532-7667.
Positive Study Results with Oral FTY720 Leads to Granting of Priority Review Status by FDA
In January 2010, the results from two large Phase III trials with oral FTY720 (fingolimod) were published in The New England Journal of Medicine. According to a press release from Novartis Pharmaceuticals Corporation (makers of FTY720), the TRANSFORMS and FREEDOMS studies showed positive results in reducing relapses, disability progression, and MRI lesions when MS patients were given FTY720.
TRANSFORMS was a one-year study with 1,292 individuals with MS. Participants were given either FTY720 or interferon beta-1a (Avonex®). FREEDOMS was a two-year study with 1,272 MS patients. This latter study compared FTY720 with a placebo. Two dose levels were used in both studies (0.5 mg and 1.25 mg). Given the best benefit-risk profile, Novartis will be seeking FDA (and European) approval for the smaller dose of 0.5 mg taken once daily.
In the lower-dose group of the one and two-year studies, relapses were reduced by 52 percent and 54 percent, respectively. Also in both studies, the lower dose reduced the risk of disability progression, as well as reduced brain lesion activity and brain volume loss, as measured by magnetic resonance imaging (MRI).
In February 2010, Novartis announced that FTY720, now given the new brand name of Gilenia®, had been granted priority review status by the FDA. This designation reduces the FDA's review process from 10 months down to six months. The drug was submitted for review in December 2009, so a decision on the approval of FTY720 could come as early as June 2010.
Such a decision would make FTY720 the first approved disease-modifying therapy taken orally (by mouth) for the treatment of MS. However, Novartis cautions that this investigational drug contains an ingredient which has not been approved before (a "New Molecular Entity"), and this may require an extension of the review process beyond the anticipated June 2010 deadline.
FTY720 is from a new class of drugs referred to as "sphingosine 1-phosphate (S1P) receptor modulators." It works by preventing the release of certain lymphocytes (immune system cells) from the lymph nodes, so these damaging cells cannot reach the brain. According to Novartis, FTY720 reduces inflammation and may also have a beneficial effect on cells in the central nervous system (CNS).
The most commonly reported side effects from both the treated and control groups were inflammation of the nasal passages and upper part of the throat (nasopharyngitis), headache, and fatigue. Drug-related adverse events included: a reduction in heart rate (dose-related and transient); infrequent transient AV conduction block of the heart; a mild increase in blood pressure; macular edema (an eye condition that can affect vision, more common with the higher dose); and reversible elevation of liver enzymes.
Phase 2 CHOICE Study Reports Positive Effects with Daclizumab
Biogen Idec and Facet Biotech Corporation, developers of daclizumab, report that when added to an interferon regimen, this drug reduces the number of new or enlarged MS lesions in patients with active, relapsing forms of MS. Additionally, daclizumab showed an increase in the number of a certain type of cell that helps to regulate the immune system. These results were published in the online edition of The Lancet Neurology and in the April 2010 issue of The Lancet Neurology .
The Phase 2 CHOICE study enrolled 230 patients with "active" relapsing MS (those having at least one relapse or one MS lesion during the past year while on interferon treatment), and who were currently taking an interferon treatment for at least six months prior to enrollment. Participants continued taking their interferon throughout the 24-week study and were given one of three add-on treatments: high-dose daclizumab every two weeks; low-dose daclizumab every four weeks; or placebo. The daclizumab and placebo add-on treatments were administered via subcutaneous injection.
In the high-dose group receiving both daclizumab and interferon treatment, new or enlarged gadolinium contrast-enhancing lesions (those enhanced on MRI with a dye) were reduced by 72 percent, compared to those taking interferon alone. The low-dose group experienced a 25-percent reduction. Daclizumab also resulted in a significant increase (seven-to-eight times the amount) in one type of "natural killer" (or NK) cells, which help to regulate the immune system and are associated with a decrease in disease activity.
Daclizumab is a humanized monoclonal antibody that binds to CD25. This is a receptor that is expressed at high levels on certain immune system cells (non-resting T cells) which may be activated with MS. This experimental treatment is thought to work by selectively targeting immune-system cells which play an important role in the MS process, without depleting "healthy" immune cells needed to help protect against other infections or illnesses.
Common adverse events (or side effects) were similar for individuals taking daclizumab with interferon and those taking a placebo with interferon. The most frequent, more serious adverse events were infections, occurring in 7 percent of the treated patients and 3 percent of the placebo group. All of these infections were resolved with standard therapies.
The developers of daclizumab are conducting a Phase 2b SELECT trial to evaluate the effectiveness and safety of monthly subcutaneous injections of this drug as a single therapy versus a placebo (no other disease-modifying therapies would be given). A Phase 3 DECIDE trial is planned to begin in mid-2010.
Continued Efficacy and Safety Seen with 15-Year Evaluation of Copaxone
In February 2010, Teva Pharmaceutical Industries Ltd. announced the publication of their data from 15 years of prospective and continuous evaluation of Copaxone®. The 15-year study findings appeared in the February 2010 issue of the journal, Multiple Sclerosis. Given the positive results, this study has been extended to 20 years, and is presently in its 19th year. Copaxone is given via daily subcutaneous injections and is approved for individuals with relapsing-remitting MS (RRMS).
In terms of efficacy, more than 80 percent of individuals with RRMS taking Copaxone for 15 years are still walking without assistance. (This group had a mean average of disease duration of 22 years.) Additionally, two-thirds of these patients have not transitioned to secondary-progressive MS (SPMS), a form of the disease that follows RRMS and is defined by a progressive worsening of symptoms, versus relapses and remissions.
The annual relapse rate was reduced by 78 percent, and more than half of the study participants are reported to have experienced either stable or improved rates of disability. Their rates were measured by the Kurtzke Expanded Disability Status Scale (EDSS). This standardized test gives scores from one to 10 to measure disability, largely in terms of mobility.
In regard to safety, local injection-site reactions and immediate (but transient) post-injection reactions are the most common adverse events with Copaxone. No infections, cancers, or other immune-mediated conditions have been reported.
MSAA Chief Medical Officer Dr. Jack Burks comments, "Once again, long-term Copaxone data has proven it to be very safe, tolerable, and effective in those patients who have remained on therapy for 15 years. The data that 80 percent of Copaxone patients remain able to walk without any aids, after having MS for an average of 22 years, is remarkable. This report should encourage all patients to keep on medications for the long run. This data along with other long-term data, show how much the current medications have helped so many patients."
|Last Updated on Wednesday, 30 January 2013 10:12|