FDA Approves First Oral Treatment for Relapsing Forms of MS

Novartis Pharmaceuticals Corporation announced today that the United States Food and Drug Administration (FDA) has approved Gilenya (fingolimod) as a first-line treatment for relapsing forms of multiple sclerosis (MS). Gilenya is the first oral disease-modifying therapy available for the long-term treatment of MS. The approval of a treatment that may be taken orally (by mouth), versus injection or infusion, is exciting news for members of the MS community.

Seven other disease-modifying therapies (including two identical drugs marketed under different brand names) have been previously approved by the FDA and are presently available by prescription. These are given via self injections at the patient's home or by infusion at a medical facility.

Gilenya (pronounced as "Jil-EN-ee-ah") presents a new option for individuals with MS. While many members of the MS community presently take one of the previously approved disease-modifying therapies and are doing very well on these therapies, not everyone responds to or is able to tolerate these medications. Particularly for these individuals, and for people who are uncomfortable with injections and/or experience injection-site reactions, the prospect of a new oral medication for MS is very encouraging.

MSAA Chief Medical Officer Dr. Jack Burks explains, "Gilenya represents the first FDA-approved oral drug for MS, which will provide additional opportunities to greatly help many people affected by this disease. The effectiveness data for Gilenya is very impressive. The MS world is excited to add this new class of drug in an oral capsule. However, patients and their doctors must realize that new classes of drugs come with new types of side effects that will require attention. Learning about these adverse events and how to minimize them are an important consideration in deciding if this drug is right for each individual patient."

Administration, Therapeutic Action, Efficacy, and Other Oral Drugs in the Pipeline

This new oral drug will be available by prescription in early October. The dose is a single 0.5 mg capsule taken once daily, with or without food. Since it has been approved as a first-line treatment, doctors may prescribe this medication as a first disease-modifying therapy for MS; in other words, a patient does not need to try other treatments prior to starting on Gilenya.

Formerly known as "FTY720," Gilenya is the first in a new class of immunomodulatory drugs called S1P-receptor modulators. It is similar in structure to a naturally occurring component of cell surface receptors on white blood cells. Gilenya blocks potentially damaging T cells from leaving lymph nodes, lowering their number in the blood and tissues. It may also reduce damage to the central nervous system (CNS) and enhance the repair of damaged neurons. Additionally, animal data suggest that this drug may provide neuroprotective effects. If treatment with Gilenya is discontinued, white blood cells are no longer retained in the lymph nodes and they return to circulation in the body.

Gilenya has been shown to reduce relapse rate and delay the progression of disability, as well as reduce brain lesion activity and brain volume loss as seen on magnetic resonance imaging (MRI), when compared to control groups given a placebo. In addition, in a one-year study, Gilenya compared favorably over interferon beta-1a (Avonex®).

Gilenya is one of five oral medications that have been recently under investigation for the treatment of MS. These include oral cladribine, which has been given Fast Track status by the FDA and may be approved later this year or in early 2011, and oral laquinimod, which has been given Fast Track status as well. Additionally, the developers of oral teriflunomide have recently announced positive data from their pivotal trials, while oral BG-12 (dimethyl fumerate) is also in phase III studies with the hopes of filing for FDA approval in the near future.

Clinical Trial Information

The information in this section is an excerpt from the upcoming cover story, "Multiple Sclerosis Research Update." The full cover story will appear in MSAA's Summer/Fall 2010 issue of The Motivator, due out in late October. The "Multiple Sclerosis Research Update" was written by Diana M. Schneider, Ph.D and reviewed by MSAA's Chief Medical Officer Jack Burks, MD. The information to follow is an overview of some of the pivotal trial results for Gilenya.

The FREEDOMS Phase III study of low-dose (0.5 mg) and high-dose (1.25 mg) Gilenya (fingolimod) versus placebo is scheduled to end in March 2011. Outcome measures to date show the drug to be safe and well tolerated. Interim data show a 60-percent reduction in annualized relapse rate, a significant reduction in disability progression, a 74 to 82-percent reduction in the burden of disease as measured by MRI, and a reduction in whole-brain atrophy.

An extension study, FREEDOMS II, evaluated long-term safety, tolerability and efficacy; all 1,080 participants received Gilenya. Two deaths resulted from Herpes virus infection in the FREEDOMS trials; both of these individuals had received a higher dose than that submitted to the FDA. No deaths were reported in lower-dose group, which used the same dose as approved by the FDA.

The TRANSFORMS Phase III trial was a 12-month study of the efficacy of two doses of Gilenya (0.5 mg and 1.25 mg) as compared to weekly intramuscular injections of Avonex in individuals with RRMS. Its primary outcome measure was a reduction of relapse rate. Secondary measures include frequency of relapses, inflammatory disease activity as measured on MRI, and time to progression of disability.

In the TRANSFORMS trial, the annualized relapse rate was lower with Gilenya 0.5 mg (0.16) versus Avonex (0.33) at 12 months. The proportion of relapse-free patients was also higher with Gilenya. In summary, Gilenya was more effective in reducing relapse rate and relapse frequency, resulted in less deterioration in the ability to independently perform daily activities, was associated with a lower rate of brain atrophy, and showed a greater effect on reducing MRI measures of lesion activity.

Another new clinical trial began in April 2010. It has 1,850 participants, all of whom are receiving Gilenya. This trial is scheduled for completion in April 2011. The primary outcome measure is the safety and tolerability profile in patients with relapsing forms of MS. Secondary measures include the incidence of macular edema (swelling behind the eye) and any changes in heart rate or function as seen on an electrocardiogram. Secondary measures also include patient-reported outcomes based on surveys of health status and treatment satisfaction.

The 36-month INFORMS study in 940 individuals is the only trial now ongoing for PPMS. It will evaluate the effect of Gilenya relative to placebo on delaying the time to sustained disability progression, as well as safety, tolerability, and the effects on MRI parameters.

Side Effects, Adverse Events, and Precautionary Steps to Minimize Risks

These oral medications offer the advantage of not requiring injections or infusions, as with drugs approved prior to September 2010. Oral medications do not cause related side effects such as injection-site reactions and flu-like symptoms. However, these new drugs are not without potential side effects and adverse events, which need to be discussed with one's healthcare provider prior to making any treatment decisions.

The most commonly reported side effects with Gilenya include headache, flu, diarrhea, back pain, abnormal liver tests and cough. Women are strongly advised to use contraception to avoid pregnancy while taking Gilenya - and to continue contraception for two months following the discontinuation of Gilenya. Although no studies have been conducted to see the effects of pregnancy with humans while taking Gilenya, animal studies suggest that it could cause fetal harm. Researchers also do not know if the drug is passed through breast milk, so the makers of Gilenya also strongly advise against breast feeding.

Adverse events with Gilenya include: 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 (a condition that can affect vision, caused by swelling behind the eye); reversible elevation of liver enzymes; and a slight increase in lung infections (primarily bronchitis). Infections, including herpes infection, are also of concern.

A number of precautionary steps have been put in place to minimize risks and enable doctors to better evaluate and treat any possible adverse events. Within six months prior to starting Gilenya, patients should be given a baseline evaluation for any issues with the heart, lungs, liver, eyes and vision, as well as white-blood-cell count (which may indicate an existing infection). Present medications also need to be considered. Vitals (blood pressure, pulse, etc.) should be taken at baseline and periodically while on treatment.

Since the drug causes a reduction in circulating white blood cells, individuals considering Gilenya also need to indicate if they have had chicken pox or a chicken pox vaccination recently; if so, they may need to wait before starting the medication. Individuals who test negative for the chicken pox virus may need to be vaccinated and delay starting Gilenya. Patients will also need to avoid vaccinations with live viruses.

When beginning the drug, patients must be observed at a medical facility for the first six hours following the first dose. This is necessary as Gilenya may slow the heart rate, with the most significant drop usually occurring within the first six hours. While taking this drug, patients need to contact their doctor immediately if they experience any symptoms such as dizziness, tiredness, slow or irregular heartbeat, breathing difficulties, visual changes, or signs of an infection or liver problem.

If an adverse event occurs, the treating physician may determine the best follow-up treatment. In the case of an infection, in studies, Gilenya was usually discontinued for two weeks. No withdraw issues occurred, however, when restarting the drug, patients need to be observed again for the first six hours following the first return dose. In studies, macular edema occurred in a small number (0.4 percent) of those treated with the approved dose. In such instances, study protocol required patients to discontinue Gilenya and the condition generally improved or resolved afterward in most but not all cases.

A Risk Evaluation and Mitigation Strategy (REMS) has been approved to provide information to patients as well as healthcare professionals on how to use the drug safely, along with possible risks that may occur. Novartis will conduct a five-year observational safety study to further evaluate any adverse events. They have also organized a voluntary registry for women who become pregnant while taking or within two months after discontinuing this drug to document possible effects.

For More Information

Both patients as well as medical professionals are encouraged to visit Gilenya's website at www.gilenya.com for more detailed information on this new treatment. Individuals may also call Gilenya's Patient Service Center at (877) 408-4974 for more information. The Patient Service Center can also provide advocacy with insurance claims as well as financial assistance to those who qualify.

What causes multiple sclerosis?

The cause of multiple sclerosis is still unknown. In the last 20 years, researchers have focused on disorders of the immune system and genetics for explanations. The immune system is the body's defender and is highly organized and regulated. If triggered by an aggressor or foreign object, the immune system mounts a defensive action which identifies and attacks the invader and then withdraws. This process depends upon rapid communication among the immune cells and the production of cells that can destroy the intruder. In multiple sclerosis, researchers suspect that a foreign agent such as a virus alters the immune system so that the immune system perceives myelin as an intruder and attacks it. The attack by the immune system on the tissues that it is supposed to protect is called autoimmunity, and multiple sclerosis is believed to be a disease of autoimmunity. While some of the myelin may be repaired after the assault, some of the nerves are stripped of their myelin covering (become demyelinated). Scarring also occurs, and material is deposited into the scars and forms plaques.

Update on ECTRIMS: Multiple Sclerosis Medication Advancements

One of the greatest recent accomplishments in neurology has been the explosion of research in Multiple Sclerosis. The biggest annual meeting for MS takes place in Europe and is called ECTRIMS (European Committee for Treatment and Research in Multiple Sclerosis). The research presentations are a mix of lectures and posters. There were the usual symposia by the big pharmaceutical companies presenting data supporting their disease modifying medications one monthly infusion for , there were preliminary presentations on new forms of therapy for relapsing-remitting MS, such as oral medications, monoclonal antibodies, and therapeutic vaccines. This is very exciting, because before 1993 there were no FDA approved medications for MS, now there are four injectable medications approved for relapsing-remitting MSrelapsing MS and one infusion for worsening or secondary-progressive MS (Novantrone or Mitoxantrone).

As you probably know, there are still no medications FDA approved for primary-progressive MS, but hopefully with newer research this will change in the next few years. Next year at the American Academy of Neurology Annual Meeting in Chicago we will hear about the results of Rituximab (Rituxan) in primary-progressive MS. Rituximab is a monoclonal antibody to CD20, which means that giving this IV medication will reduce B cells. When discussing the immunology of MS, we usually talk about T cells a lot, but we are learning more about how B cells (they make antibodies, which bind usually to "foreign invaders") are important in MS as well, and especially in progressive MS. Rituximab is being studied in relapsing-remitting MS and neuromyelitis optica (Devic's disease) as well.

As you probably know, we are finally entering the era of oral medicines for MS, but it will still be a number of years before these medicines are available outside of clinical trials. One of the oral medicines being studied is called FTY720 (Fingolimod), and the exciting news is that hopefully we will start studying it not only in relapsing-remitting MS, but in primary-progressive MS as well. It would be exciting to have one medicine for both relapsing and progressive MS.

While there is so much hope with all these new advances, I think we also have to be careful in ensuring that our new medicines are safe. One of the great things about the injectable medicines is that they are safe over the long-term, with the newer medicines (oral and monoclonal antibodies) we are seeing side effects that raise some concerns, like the development of other autoimmune diseases, infections, and potentially cancers.

So, how are we going to treat MS in the future? MS patients are all unique, and that's what makes it great to be an MS doctor. It's also what makes it tough sometimes. Eventually we hope to have a blood test where we could know what medicine is going to be right for a specific individual. This will probably be a "genomics" blood test - which will tell us doctors the specific gene expression of an individual patient's MS - and also what medicine makes sense to treat that individual with.

TREATMENT TRENDS

TreatmentTrends®, Multiple Sclerosis Study Uncovers Early Impact Of Gilenya On Perceptions And Anticipated Use Of Products Within The MS Market

Main Category: Multiple Sclerosis
Article Date: 02 Dec 2010 - 7:00 PST

email to a friend printer friendly opinions

Ads by Google

Improve Walking Ability - Has your MS made walking difficult? Learn about this oral treatment. - Improve-MS-Walking.com

The DECIDE Study - Evaluating a new investigational therapy for relapsing remitting MS. - DECIDEstudy.com

Breast Cancer Facts - Find Resources & Treatment Info on Postmenopausal Breast Cancer - Breast-Cancer-Treatment-Options.com

Current Article Ratings:

Patient / Public:
Healthcare Prof:
Article Opinions:	0 posts

BioTrends recently published TreatmentTrends®: Multiple Sclerosis, a syndicated biannual report that provides a comprehensive view of the current and expected future management of multiple sclerosis (MS) based on primary research fielded with 103 neurologists in the U.S. A parallel report covering the European market (EU5) will be published later this month. These reports cover the use of disease-modifying agents (DMAs) for the treatment of MS, as well as attitudes and perceptions toward these products, advantages and disadvantages, ideal patient types, barriers to growth, and expected future use. In addition, respondents were queried about their awareness of and interest in MS-related DMA and symptomatic products in development.

The U.S. study, based on feedback gathered in late October/early November 2010, found that the recent commercial availability of Novartis's Gilenya, the first oral DMA, has already had significant impact on neurologists' perceptions of the traditional injectable DMAs. At one month post launch, over two-fifths of neurologists report use of the product in RRMS patients and even more anticipate trial among RRMS patients within the next six months. The uptake of Gilenya will be explored further in LaunchTrends®: Gilenya, a three wave report series which will track the product at one, three and six months post commercial availability. Neurologists' uptake of Extavia, Novartis's other recently launched DMA, continues to be limited with only about four out of 10 survey respondents reporting trial one year after availability. With the recent bout of market activity, neurologists' anticipate significant changes in their use of DMAs in the next six months.

In terms of new DMAs, neurologists report a high unmet need for products with long term safety data. In fact, this attribute has become more important compared to results from the prior wave of research fielded in Q1 2010, while oral formulations and less frequent dosing have decreased in importance in terms of areas of unmet need. Among seven therapies in development that were profiled in the research, interest was highest for Teva's laquinimod and Biogen Idec's BG-12. Recent market news has negatively impacted perceptions of EMD Serono's Movectro (oral cladribine).

Trial of Acorda's Ampyra (dalfampridine), the first symptomatic agent approved for MS patients, continues to be high seven months post-launch. With greater familiarity and usage, a clearer picture is emerging about the average discontinuation rate and anticipated uptake of Ampyra. While awareness of the five surveyed MS-related symptomatic products is low, neurologists report moderate levels of interest in the products and believe products impacting spasticity (i.e. Otsuka's Sativex) or walking impairment (i.e. Sanofi-Aventis' nerispirdine) would provide the greatest clinical value to their practice.

All company, brand, or product names contained in this document may be trademarks of their respective hol

hase III Results of AVP-923 (formerly called Zenvia) Published, Showing It Can Reduce Episodes of Uncontrollable Laughing or Crying in MS and Other Di

Oct 08, 2010

The results of a Phase III trial of an oral drug designed to treat uncontrollable laughing and/or crying (known as pseudobulbar affect), a troubling symptom experienced by some people with MS, ALS, and other neurological disorders, have now been published. AVP-923 (Avanir Pharmaceuticals) significantly reduced the rate of laughing and crying episodes and appeared to be safe and well tolerated. (Annals of Neurology, published online September 13, 2010)

According to an Avanir press release dated August 5, the U.S. Food and Drug Administration set a date to complete its review of this drug by October 30, 2010. The company also has submitted trade names to the FDA for consideration after receiving notice that the agency did not accept the name “Zenvia” for marketing use.

Background: A small percentage (around 10%) of persons with MS experience episodes of uncontrollable laughing and/or crying that are unpredictable and seem to have little or no relationship to actual events or the individual’s actual feelings. This condition is thought to result from lesions – damaged areas – in emotional pathways in the brain. It is important for family members and caregivers to know this, and realize that people who experience these episodes may not always be able to control their expression of emotions. Some medications have shown benefit in small clinical trials, but there is no medication approved specifically to treat this symptom.

Avanir Pharmaceuticals has been conducting trials of AVP-923 in its current and related formulations for several years as a treatment for pseudobulbar affect in a number of disorders, including MS, ALS, Alzheimer’s disease and stroke. AVP-923 is a patented, orally-administered combination of dextromethorphan and an enzyme inhibitor known as quinidine; quinidine is a drug that inhibits the metabolism of dextromethorphan which results in a sustained elevation of dextromethorphan in the brain. In 2006, Avanir received a letter from the FDA indicating that the drug was “approvable” and requesting that additional studies be conducted, leading to the current study.

Study Details: This trial, called the STAR trial, involved 326 individuals (197 with ALS and 129 with MS) across the U.S. and Latin America who were experiencing pseudobulbar affect. Participants either received one of two doses of AVP-923 or inactive placebo twice a day for twelve weeks.

The primary endpoint established for this trial was the rate of self-reported laughing or crying episodes over the course of the trial. Both doses significantly reduced episode rates by about 47-49 percent compared to placebo. Secondary outcomes, including patient diaries and episode-free days, also suggested significant benefit among groups taking AVP-923, and those on the higher dosage also showed improved measures of social functioning and mental health.

The medication was relatively well tolerated. The adverse events more frequently reported by those on therapy (especially the higher dose) versus those on placebo were dizziness, nausea and diarrhea. There were seven deaths in the study, all occurring in participants who had ALS, and all of which were classified by an independent committee as being likely due to progression of respiratory problems related to the disease.

Follow-up: In an extension of this study, 253 people took the higher dose of AVP-923 for 12 more weeks, during which safety and tolerability were assessed. The drug continued to be well tolerated. (Abstract #P06.128, American Academy of Neurology Annual Meeting, 2010)

Comment: “The availability of a therapy that could safely and effectively treat uncontrollable laughing and crying would be a real breakthrough for those with MS and other neurological conditions who experience this troubling symptom,” said Dr. Nicholas LaRocca, a clinical psychologist who directs the National MS Society’s research programs in patient management and health care delivery and policy.

Read more about MS and emotional changes.

A Clinical Bulletin for physicians, providing details about pseudobulbar affect and its treatment in MS is available on the National MS Society’s Professional Resource Center.

Society Of Interventional Radiology Supports Research For New M.S. Treatments

Recognizing that venous interventions may potentially play an important role in treating some patients who suffer from multiple sclerosis -- an incurable, disabling disease -- the Society of Interventional Radiology has issued a position statement indicating its support for high-quality clinical research to determine the safety and effectiveness of interventional M.S. treatments. SIR's position statement is endorsed by the Canadian Interventional Radiology Association and will be published in the September Journal of Vascular and Interventional Radiology.

"The Society of Interventional Radiology would like to be actively involved in developing evidence-based therapies for the potential treatment of patients with multiple sclerosis," said SIR President James F. Benenati, M.D., FSIR. "Completing high-quality studies -- for example, on chronic cerebrospinal venous insufficiency (CCSVI, a reported abnormality in blood drainage from the brain and spinal cord) and interventional M.S. treatments -- should be a research priority for investigators, funding agencies and M.S. community advocates," added Benenati, who represents nearly 4,700 doctors, scientists and allied health professionals dedicated to improving health care through minimally invasive treatments.

About 500,000 people in the United States have M.S., and SIR understands the public's desire to advance treatment for M.S., generally thought of as an autoimmune disease in which a person's body attacks its own cells. Currently, medicines may slow the disease and help control symptoms. The role of CCSVI in M.S. and its endovascular treatment (through a catheter placed in a vein) by an interventional radiologist via balloon angioplasty and/or stents to open up veins "could be transformative for patients and is being actively investigated," said Benenati. "The idea that there may be a venous component to the etiology (or cause) of some symptoms in patients with M.S. is a radical departure from current medical thinking," he noted.

"SIR recognizes the challenge and the potential opportunity presented by promising early studies of an interventional approach to the treatment of M.S.," said Benenati. SIR is moving rapidly to "catalyze" the development of needed studies by bringing together expert researchers in image-guided venous interventions, neurology, central nervous system imaging, M.S. outcomes assessment and clinical trial methodology, he added. While the use of balloon angioplasty and stents cannot be endorsed yet as a routine clinical treatment for M.S., SIR is committed to assuming a national leadership role in launching needed efforts, said Benenati.

SIR's position statement agrees with M.S. advocates, physicians and other caregivers that the use of any treatment (anti-inflammatory, immunomodulatory, interventional or other) in M.S. patients should be based on an individualized assessment of the patient's disease status, his or her tolerance of previous therapies, the particular treatment's scientific plausibility, and the strength and methodological quality of its supporting clinical evidence. "When conclusive evidence is lacking, SIR believes that these often difficult decisions are best made by individual patients, their families and their physicians," notes "Interventional Endovascular Management of Chronic Cerebrospinal Venous Insufficiency in Patients With Multiple Sclerosis: A Position Statement by the Society of Interventional Radiology, Endorsed by the Canadian Interventional Radiology Association."

If interventional therapy proves to be effective, M.S. patients should be treated by doctors who have specialized expertise and training in delivering image-guided venous treatments, said Benenati. Interventional Radiologists pioneered balloon angioplasty and stent placements and use those treatments on a daily basis in thousands of patients with diverse venous conditions. "Interventional radiologists are steeped in a tradition of innovation and invention -- of pioneering modern medicine with the devices, drugs and methods to treat patients minimally invasively," said Benenati.

Source: Society of Interventional Radiology

LIFE WITH MULTIPLE SCLEROSIS

What is a typical case of multiple sclerosis like? The newly diagnosed usually ask what they should expect from a life with MS; but typical, when it comes to MS, is hard to define.

One thing is clear — life with multiple sclerosis is anything but predictable. MS doesn’t come with a road map, a GPS system, or a set of directions. There is no forgone conclusion — and despite the uncertainty, that is good news.

Plenty of people will tell you horror stories of life with MS, or of folks with MS who climb mountains and run marathons. There is truth in all of it, but none of it necessarily will reflect your experiences or point to your own future.

Are you like Lori Schneider of Bayfield, Wisconsin, who earlier this year became the first person with MS to climb Mount Everest?

Are you like Montel Williams, who was devastated by the diagnosis, suffered through depression, and now raises money for MS research, and advocates for people with MS?

Are you like the United Kingdom’s Debbie Purdy, who fought for the right to choose assisted suicide without fear of prosecution, so that she can control her own end-of-life issues?

Are you using a wheelchair… or living in a nursing home… or struggling with day-to-day living… or… or… or…

Trying to pin down the typical person with MS is like trying to pin down, well, the typical person with MS. We are as varied in our physical condition and our outlook on life as the rest of the human population.

I can’t climb Mount Everest or run a marathon, but I was never the outdoor athletic type, so I’m not about to bemoan my fate in that department. If I had been, my perspective would most certainly be different.

Some people with MS have amazingly positive attitudes; many suffer from deep depression. Some have obvious disabilities; others have a multitude of invisible symptoms and, yes, there are people with only minor symptoms that barely register on their radar screen. Many have additional health problems not associated with MS — we are not immune to other illnesses or symptoms of aging. Some have strong family support while others languish.

Most people with MS manage to remain employed; others are disabled and cannot work. Some have the security of good health insurance coverage; others struggle with the financial burdens associated with a chronic illness, suffering the consequences of that added stress.

It is important to meet and communicate with other people who have MS. The mutual support and kinship is priceless. But it is equally important that we not compare ourselves and the course of our condition, that we not harshly judge others for their choices or what we might view as their shortcomings.

Life is more complicated than that. We all received our diagnosis under different circumstances — our general health, age, financial status, family life, and general outlook were all uniquely ours. Add to that the many variations of relapsing/remitting and progressive forms of MS, and it’s easy to see why answering the “what can I expect of a life with MS?” question is so difficult.

A typical life with MS? Definitely challenging, rife with possibilities, and anything but predictable.