Case of PML Reported in Person Taking Tecfidera®

In December 2014, important label changes were made to the prescribing information for Tecfidera® (dimethyl fumarate, Biogen Idec) including information regarding an individual who developed PML. Most recently, Biogen has confirmed report of a second case of PML (progressive multifocal leukoencephalopathy, a viral infection of the brain that often leads to death or severe disability) that occurred in a person taking Tecfidera. According to the company, the 64-year-old patient has primary progressive MS and experienced severe and prolonged lymphopenia (decreased white blood cells) during treatment with Tecfidera. Severe and prolonged lymphopenia is a known risk factor for PML and Consideration should be given to interrupting treatment if lymphocyte counts are low for more than six months.  The patient is stable and is not hospitalized. Biogen has reported the case to the U.S. Food and Drug Administration (FDA).

PML is caused by the re-activation of a virus called the JC (John Cunningham) virus, a common virus to which many people have been exposed. PML has emerged in people using other medications, including the MS treatment Tysabri® (natalizumab, Biogen), and the MS treatment Gilenya® (fingolimod, Novartis AG).

It is not possible at this point to determine a person’s risk for developing PML because there have been so few cases in people taking Tecfidera. There have been two reported cases of PML in people with MS among the more than 155,000 individuals who have been treated with Tecfidera to date.

The symptoms of PML are diverse and can be similar to MS symptoms. For this reason, individuals should be alert to any new or worsening symptoms and report them promptly to their MS healthcare provider.  Learn more about the risk factors and symptoms of PML from the web site of The PML Consortium. Individuals who have concerns about this report should discuss it with their MS healthcare providers.

If and when the FDA or Biogen provide additional information or recommendations for people taking Tecfidera or other MS medications, the National MS Society will share it as soon as possible.

New molecule may lead to inflammation inhibitor

Scientists have developed a new drug-like molecule that can inhibit inflammation. The find has shown promise in preventing the progression of multiple sclerosis.

Walter and Eliza Hall Institute scientists have developed a small drug-like molecule called WEHI-345 that binds to and inhibits a key immune signaling protein called RIPK2. This prevents the release of inflammatory cytokines. Examining WEHI-345’s potential to treat immune diseases in experimental models of MS, it was found that WEHI-345 prevented further progression of the disease in 50 percent of cases after symptoms of MS first appeared.

Results of mouse model studies sometimes do not translate to humans and may be years away from being a marketable treatment. Calling the results extremely important, researchers said WEHI-345 had potential as an anti-inflammatory agent.

The study’s lead author, Dr Ueli Nachbur, said institute scientists would use WEHI-345 to further investigate the signaling pathway that produced inflammatory cytokines and to develop a better, stronger inhibitor of RIPK2 for treating inflammatory disease. “This signaling pathway must be finely balanced, because WEHI-345 only delayed signaling rather than blocked it. Nevertheless, this delay is enough to completely shut off cytokine production,” he said.

The research was published in the journal Nature Communications.

FDA Accepts Resubmitted Lemtrada™ Application for Review*

Genzyme, a Sanofi company, announced today that the United States Food and Drug Administration (FDA) has accepted for review the supplemental Biologics License Application (sBLA) for Lemtrada™ (alemtuzumab), a proposed treatment for relapsing forms of multiple sclerosis (MS). This application was recently submitted after the FDA did not approve Lemtrada in late December 2013, when Genzyme stated that they had received a Complete Response Letter from the FDA. This letter informed them that the application for their drug was “not ready for approval.” A new decision is expected in the last quarter of 2014.

The reason that the drug did not receive approval, according to the FDA, lies in the design of the Phase III studies. These compared the effectiveness and adverse effects of Lemtrada against an approved treatment for MS, versus a placebo (with no active ingredients). Because of dramatically different side effects between the two different medications, these studies were “unblinded,” meaning that both the patients and treating doctors were aware of which drug each of the patients was receiving. Whenever possible, clinical trials are double-blinded to prevent any potential bias toward the treatment being evaluated.

In order to resubmit the application, Genzyme and the FDA had “constructive discussions” to determine what would be necessary for the medication to be reconsidered for approval. In the resubmitted application, Genzyme provided additional data to address the specific issues that are of concern to the FDA. These data are from the same studies that were included in the original application.

Lemtrada is a humanized monoclonal antibody given in annual courses by intravenous (IV) infusion. It works by depleting the circulating lymphocytes (B and T cells). Lymphocytes are immune-system cells produced to fight infection and disease, and with MS, these cells are misdirected to cause damage to the nerves of the central nervous system (CNS) and the nerves’ protective covering (myelin). Lemtrada was originally approved by the FDA in 2001 for the treatment of a certain type of leukemia (B-cell chronic lymphocytic leukemia), using “Campath” as the trade name.
Lemtrada is already approved in 33 countries for the treatment of MS, including 28 countries in the European Union. Additional marketing applications for this MS medication are under review by other regulatory agencies around the world.

*Note:________________________________________________
Lemtrada™ (alemtuzumab, formerly Campath) did not receive approval from the United States Food and Drug Administration (FDA) for the treatment of relapsing forms of multiple sclerosis (MS) in December, 2013 because of the design of the Phase III studies.

New Guideline from the American Academy of Neurology

The American Academy of Neurology, an association of neurologists and neuroscientists dedicated to promoting high-quality care for people with nervous system disorders, has released a guideline on the use of complementary and alternative medicine (CAM) in MS. The guideline was created by a panel of medical experts who evaluated all available published research studies. Through a comprehensive process, the panel carefully assessed the outcomes of relevant research studies, and also whether study findings could be generalized to the larger population of people with MS, and whether any safety concerns should be considered by physicians and patients who might use these treatments.
The widespread use of CAM by people with MS highlights the unmet need for more research and better therapies that will help people with MS live their best lives. Summaries of the guideline are available for patients and for clinicians.
Specific Guideline Information
Among studies of several forms of marijuana and its derivatives that were evaluated by the panel, the guideline reports that evidence suggests that:

• Oral cannabis extract and synthetic THC (tetrahydrocannabinol, a major active component of marijuana) are effective for reducing patient-reported spasticity and pain, but not MS-related tremor or spasticity measured by tests administered by the physician;
• Sativex oral spray (GW Pharmaceuticals) is effective for improving patient-reported spasticity, pain, and urinary frequency, but not bladder incontinence, MS-related tremor or spasticity measured by tests administered by the physician;
• Smoked marijuana research studies have not produced enough evidence to assess its safety or effectiveness for treating MS symptoms including spasticity, pain, balance, posture, and cognition.

Oral cannabis extract, THC and Sativex are not currently approved by the FDA for use by people with MS. The guideline notes that, as with any therapy, along with potential benefits come potential side effects, and for these cannabis derivatives the most commonly reported side effects were dizziness, drowsiness, difficulty concentrating and memory disturbance.
The guideline also points out that the long-term safety of marijuana use for MS symptom management is not yet known.
Read about the National MS Society’s position statement and more about the use of marijuana for MS symptoms.
Among other CAM therapy studies in MS evaluated by the panel, the available research evidence suggested that:

• ginkgo biloba is ineffective for improving cognitive function, but might reduce fatigue;
• magnetic therapy might reduce fatigue;
• reflexology might help ease unusual skin sensations such as tingling, but there is insufficient evidence to evaluate its potential for treating pain, fatigue, and other symptoms;
• the use of omega-3 fatty acids with low-fat diet to reduce relapses or disability, or improving quality of life is not supported by current evidence.

The guideline includes a table of all of the CAM therapies that were evaluated. For many of these, the panel concluded that there was not enough evidence from research studies to advise as to their effectiveness in treating MS or its symptoms. The guideline also indicates that there is little known about how CAM therapies interact in the body with each other or with disease-modifying therapies that individuals may be taking. The effects and side effects reported from non-MS studies were not evaluated.
While many people with MS report that they experience benefits from CAM therapies, this guideline confirms the need for more research to demonstrate the effectiveness of these treatment strategies. The National MS Society is committed to ensuring that no opportunity is wasted in our mission to stop MS progression, restore function lost to MS, and end MS forever so that people with MS can live their best lives. We have supported, and will continue to support, CAM research and will continue to advocate for additional government funding for CAM research.

Mom's Story

The Second Edition is now available with new treatments available for MS discussed.

Company Decides Not to Seek Approval of Cladribine for MS

Merck Serono announced that it has decided not to pursue approval of its oral therapy Cladribine for the treatment of relapsing forms of multiple sclerosis. According to a company press release, discussions with the U.S. Food and Drug Administration made it apparent that the ongoing clinical trials of the therapy would not address the FDA’s requirements for approval. Details of these requirements have not been made public.


In March 2011, the company received a letter from the FDA indicating that its application for approval was not ready in its current form and outlining requirements for additional information. The company has stated that it plans to complete the current clinical trials and patient registry that are underway, and that results will be published.

“It’s disappointing that completion of the Cladribine trials will not lead to approval of a new therapy option for people living with MS,” says Dr. Timothy Coetzee, Chief Research Officer at the National MS Society. “However, thanks to the many people who participated in these clinical trials, results from these studies will add to the body of knowledge about MS and should help spur new leads toward stopping MS, reversing its damage and ending MS forever.”

Additional therapies, including oral therapies, are currently making their way through the development pipeline.

New MS Treatments

A number of new multiple-sclerosis medications are beginning to hit the market that promise to make it easier for patients to control flare-ups of the disease and slow its progression.

The drugs, designed to be taken orally, represent a new generation of treatment for MS. Currently, people with the disease can choose from a range of drugs that are administered by injection.

Physicians say many people are reluctant to stick themselves with a needle and would be more comfortable taking a pill once or twice a day. This could encourage a greater number of MS patients to take medication as needed and could spur earlier treatment, which is important since disability from MS is cumulative.

Cost of the new drugs is expected to be high. Novartis AG's Gilenya, so far the only oral MS drug on the market, is priced at about $48,000 a year; the drugs still being developed are expected to cost about the same. That's higher than injectable drugs currently in use, which cost roughly $40,000 a year. Health insurers often pick up most of the expense of MS drugs.

There is a "tremendous desire" among MS patients to begin using oral treatments because of their ease of use, says Joseph Herbert, director of the MS Care Center at NYU Langone Medical Center. Still, he says, many physicians are being cautious about prescribing the oral drugs because their side effects can't be fully assessed until they are used widely for an extended period of time.

Among its side effects, Gilenya can increase a person's risk of infection and potentially lead to toxicity of the liver and an eye disease called macular edema, clinical trials have shown. Some of the oral drugs still in development are expected to have somewhat milder side effects.

The current injectable drugs have generally less severe side effects, including injection-site irritation and flu-like symptoms, although some patients incur more serious problems such as liver damage.

Elizabeth Fuchs, an MS patient on Staten Island, N.Y., began taking Gilenya about two months ago. The 49-year-old was diagnosed with MS about 12 years ago and had tried several injectable medications. Avonex, made by Biogen Idec Inc., required weekly intramuscular injections. She later switched to Copaxone, from Teva Pharmaceutical Industries, which is administered with a daily subcutaneous injection.

"It is just much easier to put a pill in your mouth and take a glass of water," Ms. Fuchs says. Not having to inject herself has made her feel more positive about having MS and even allows her to forget she has the disease, she says.

There is no cure for MS, a chronic, inflammatory condition that occurs when the body's immune system attacks its own central nervous system.

MS, which affects about 400,000 people in the U.S., is marked by symptoms such as vision problems, limb numbness and paralysis. Women are more likely to get the disease than men, and genetic factors may make certain individuals more susceptible, according to the National Multiple Sclerosis Society.

Gilenya, which received Food and Drug Administration approval last fall, is thought to work by reducing the quantity of circulating immune cells that can cause damage in an MS attack. More than 6,500 patients are taking the drug, according to the most recent Novartis data.

Recent data from large clinical trials of other drugs being developed, including Biogen Idec's BG-12, Teva Pharmaceutical's laquinimod, and teriflunomide, from Sanofi-Aventis SA, show they are also effective at controlling MS flare-ups and slowing the progression of disability from the disease. More data on the drugs are expected later this year and, assuming FDA approval, they could all be on the market in late 2012.

The success of any of these drugs isn't guaranteed. Another oral MS drug, Merck KGaA's cladribine, was rejected by U.S. and European regulators earlier this year amid long-term safety-related questions, including an increased cancer rate in patients taking the drug. The company says it remains committed to gaining approval.

Another drug, Biogen's Tysabri, was approved in 2004 but was later temporarily pulled from the market after it was linked to a rare brain infection. Tysabri, administered by intravenous infusion, became available again in 2006 but is limited mainly to patients who don't respond to other treatments.

A recent analysis by Novartis showed that Gilenya reduced relapses among MS patients by 54%. Disability progression was reduced by 30%, using a standard measurement of this process.

Biogen's BG-12 drug reduced MS flare-ups by a similar amount as Gilenya, but with fewer side effects. Smaller reductions in flare-ups were seen in trials with patients using laquinimod (23%) and teriflunomide (31%).

By comparison, Avonex, one of the leading injectable drugs, has been shown to reduce MS flare-ups by 32% and disability progression by 37% over two years.

Physicians say MS cases vary greatly and some drugs won't work for certain patients. Also, it is difficult to directly compare two different clinical trials.

NYU's Dr. Herbert says it is a challenge to get patients to use prescribed injectable therapies. Oral medications' ease of use should increase the number of patients who use the drug as required, he says. This also is expected to encourage some patients, especially those in the initial stages of MS, to begin therapy before the disease advances significantly.

"The data certainly suggest that starting therapy earlier does slow down the progression of the disease," says Timothy Coetzee, chief research officer for the National Multiple Sclerosis Society.

Doctors say they aren't likely to recommend a patient switch to one of the new oral drugs if an injectable drug currently in use is working. Although the ease of taking a pill, rather than an injection, is important, effectiveness of a given drug takes precedence. Patients who switch treatments run the risk of the new drug not being the right fit for them, says Mayo Clinic neurologist Mark Keegan.

Write to Thomas Gryta at thomas.gryta@dowjones.com