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.

MS Trial Alert: Researchers in California, Colorado, New Mexico and Pennsylvania Recruiting Women with Progressive or Relapsing MS for Study of Estriol to Improve Cognition

Summary: Investigators in California, Colorado, New Mexico and Pennsylvania are recruiting 64 women with MS relapsing-remitting, secondary-progressive, or primary-progressive for a 12-month study in which the sex hormone estriol will be compared with inactive placebo for effects on cognitive function. Participants can remain on their prescribed MS medication throughout the study. Rhonda Voskuhl, MD (University of California at Los Angeles) is the principal investigator of the trial. The study is funded by various private donors to the UCLA program.

Rationale: Estriol levels rise to very high levels naturally during late pregnancy, a time when most women’s MS disease activity declines. This led some to suspect that estriol may be responsible for this easing of symptoms during pregnancy. Dr. Rhonda Voskuhl (University of California, Los Angeles) and others showed that in mice estriol treatment was indeed protective. They then explored this lead with Society support, showing that estriol decreased disease activity in a small, early-phase trial of estriol in 12 women with MS. The National MS Society funded a team of investigators at 15 medical centers to conduct a two-year, controlled clinical trial of estriol added to standard therapy to treat MS. This trial recently reported results.

Meanwhile, Dr. Voskuhl’s team also has shown that, in mice, treatment with estrogen (a hormone related to estriol) can improve nerve impulse transmission in an area of the brain related to learning and memory, called the hippocampus. Problems with learning, memory and other cognitive functions are common in MS. (Laboratory Investigation 2012;92:1234) These and other observations led to the launch of this clinical trial to test the ability of estriol to improve cognition in women with MS.

Eligibility and Details: The researchers are seeking volunteers who are women 18 to 50 who have been diagnosed with relapsing-remitting, secondary-progressive, or primary-progressive MS. If participants are on standard MS treatments, they may remain on these medications during the study.  Participants should not have had a relapse within 30 days before the day of trial enrollment. A cognitive test called the Paced Auditory Serial Addition Test (PASAT) will be administered to determine whether the participant qualifies for the study. Participants are excluded if they are on oral contraceptives, hormone replacement therapy, progesterone IUDs or other sex hormones during screening and during the 12-month study period. For more details about enrollment criteria, please contact the site nearest you (listed below).

Participants are being randomly assigned to receive oral estrogen (8mg/day) or inactive placebo for one year. The primary outcome is improvement in cognitive function as measured by PASAT scores. Secondary outcomes under study include measurements from brain MRIs, cognition, quality of life, depression, and fatigue.

Contact: To learn more about the enrollment criteria for this study, and to find out if you are eligible to participate, please contact (for information about all sites nationwide):

University of California, Los Angeles
Contact: Jenny Bardens
Phone: (310) 206-2176
Email: jbardens@mednet.ucla.edu

Investigators Recruiting People with MS and Spasticity for a Study of Extended-Release Baclofen

Summary: Investigators nationwide are recruiting 214 people for a study to determine the effectiveness of extended-release baclofen capsules in relieving spasticity and symptoms related to MS. The study is sponsored by Sun Pharma Advanced Research Company Limited.
Rationale: Spasticity refers to feelings of stiffness and a wide range of involuntary muscle spasms (sustained muscle contractions or sudden movements). It is one of the more common and troublesome symptoms of MS. Baclofen acts on the central nervous system to relieve spasms, cramping, and tightness of muscles caused by spasticity. This study is evaluating an extended-release form of baclofen. Extended release – in which a drug is released over time – may allow for it to be taken less often.
Eligibility and Details: Participants should be at least 18 years old, have any form of MS and a known history of spasticity. Participants should be taking immediate-release baclofen (30 to 60 mg) at the same dose and the same schedule for the last 30 days. Further details on enrollment criteria are available from the contact below.
Participants will receive baclofen immediate release capsules daily for one week, and then extended-release capsules daily for up to 16 weeks (doses will increase from 10 to 60 mg). Then participants will be randomly chosen to receive either the investigational drug or an inactive placebo for up to an additional 4 weeks. The dosage will gradually decrease during these 4 weeks.
The primary outcomes being measured are how many participants are able to complete the study, and safety.
Contact: To learn more about the enrollment criteria for this study, and to find out if you are eligible to participate, please contact the site nearest you. The potential subjects should go to the study investigator list at ClinicalTrials.gov to receive contact information for the nearest study site.

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.

Researchers seeking people with progressive MS for nationwide trial of oral therapy

Summary: Investigators are recruiting for a phase II clinical trial of ibudilast (MN-166, MediciNova, Inc.), an oral agent, in 250 people with progressive forms of MS. The study, called the SPRINT-MS trial, is principally funded by the National Institutes of Neurological Diseases and Stroke (NINDS), with additional support by MediciNova, the company that will supply ibudilast, and the National MS Society. The study will be conducted through the NeuroNEXT Network, a clinical trials initiative of the National Institutes of Health. Robert Fox, MD (Cleveland Clinic Foundation) is the principal investigator.
Rationale: Among other actions, ibudilast inhibits an enzyme called phosphodiesterase, and has been shown to protect brain tissue in animal models. . While considered a “New Chemical Entity” in the United States and Europe, ibudilast is marketed in Japan and Korea to treat asthma and symptoms from cerebrovascular disorders. It is being investigated in the U.S. for its potential to treat drug addiction and now, for treating progressive forms of MS. In a previous study, ibudilast did not reduce relapses or MRI-observed new lesions in a phase II trial involving people with relapsing MS. However, some evidence that this agent could protect the nervous system from damage (neuroprotection) was observed, which is why it’s being tested in people with progressive forms of MS. (Neurology 2010;74:1033).
Eligibility and Details: Participants are people between the ages of 21 and 65 who are diagnosed with secondary-progressive or primary-progressive MS who are currently receiving either glatiramer acetate, interferon beta, or neither treatment. . Further details on inclusion and exclusion criteria are available from the contact below.
Participants will be randomly assigned to receive either oral ibudilast (100 mg/day) or inactive placebo daily for 96 weeks. Treatment will be added to existing glatiramer or interferon treatment in patients currently taking those therapies. The primary outcomes being measured are changes in brain tissue volume loss (determined through MRI scans) and safety/tolerability. Secondary outcomes being measured include further imaging outcomes, progression as measured by the EDSS disability scale, quality of life, cognitive function, and pain.
Contact: To learn more about the enrollment criteria for this study, and to find out if you are eligible to participate, please contact the study site nearest you, as listed on clinicaltrials.gov.

Sites will be enrolling in the following cities:
Atlanta, GA
Birmingham, AL
Boston, MA
Bronx, NY
Buffalo, NY
Charlottesville, VA      
Chicago, IL
Cincinnati, OH
Cleveland, OH
Columbus, OH
Dallas, TX
Denver, CO
Kansas City, KS
Los Angeles, CA
Miami, FL
Nashville, TN
New York, NY
Pittsburgh, PA
Portland, OR
Rochester, NY
Sacramento, CA
Salt Lake City, UT
Seattle, WA
St. Louis, MO
Stony Brook, NY
Syracuse, NY

Study Suggests Adolescent Obesity and Genetic Factors Interact to Increase MS Risk

In a study comprising two large populations of people with MS and controls without MS, adolescent obesity was confirmed to increase a person’s risk for later developing multiple sclerosis, and this risk increased substantially in those with specific risk genes that control the immune system (known as HLA). Anna Karin Hedström, MD (Karolinska Institutet, Stockholm, Sweden) and colleagues in Sweden and California report their findings in Neurology (2014;82:1–8). More research is needed to confirm these results and to determine other risk factors that may help determine who is susceptible to MS and who is not.

Background: While MS is not contagious or directly inherited, epidemiologists—the scientists who study patterns of disease—have identified factors in the distribution of MS around the world that may eventually help determine what causes or triggers the disease. These factors include gender, genetics, age, geography, and ethnic background. The MS susceptibility genes identified to date are generally not clinically useful for providing genetic counseling to individuals regarding who may develop MS.

Because the prevalence of obesity has increased dramatically in the past several decades, and obesity is associated with an increase in immune system activity, researchers are seeking to determine if there was any association between obesity and the risk for developing MS.

Researchers recently reported that being overweight or obese was associated with an increased risk of developing MS or clinically isolated syndrome (CIS, a first clinical episode suggestive of MS, indicating increased MS risk) in girls, in a study that compared 75 children or teens with MS or CIS with the health records of more than 900,000 healthy children or teens (Neurology February 5, 2013 80:548-552).

The Study: Investigators used data from two studies on environmental and genetic risk factors, analyzing two populations: one that had 1,510 cases of MS and 2,017 controls without MS and another that comprised 937 cases and 609 controls. They obtained information on two genes previously associated with MS risk (the presence of “HLADRB1*15,” thought to increase MS risk, and absence of “HLA-A*02,” thought to be protective against MS), body mass index at age 20, and development of MS.

In both study populations, adolescent obesity was associated with increased risk of MS, as was the presence of HLADRB1*15or the absence of HLA-A*02. Participants who showed both adolescent obesity and either of the genetic risk factors had nearly an eight-fold increased risk of developing MS compared to those who were not obese in adolescence and who did not have any of the genetic risk factors.  However those who reported adolescent obesity and both of the genetic risk factors had a 16-fold or 14-fold increase in risk of MS. 

Conclusions: This study adds to the growing body of evidence that adolescent obesity is a risk factor for developing MS. The authors note that “biologic explanations are far from clear,” but they suggest that immune mechanisms associated with obesity may be active in driving the disease in people who are genetically susceptible. Additional research is needed to understand this association. It is important to note that not everyone who is obese during adolescence will develop MS, and also that many people develop MS without having been obese during adolescence.

“We should be concerned about these findings,” cautions Ruth Ann Marrie, MD, PhD (University of Manitoba, Winnipeg, Canada) and Christopher A. Beck, PhD (University of Rochester Medical Center, NY) in an accompanying editorial. “It is time to begin developing a targeted approach to prevent MS by improving common health behaviors, including body weight and smoking.”
 

About Multiple Sclerosis

Multiple sclerosis, an unpredictable, often disabling disease of the central nervous system, interrupts the flow of information within the brain, and between the brain and body. Symptoms range from numbness and tingling to blindness and paralysis. The progress, severity and specific symptoms of MS in any one person cannot yet be predicted, but advances in research and treatment are moving us closer to a world free of MS. Most people with MS are diagnosed between the ages of 20 and 50, with at least two to three times more women than men being diagnosed with the disease. MS affects more than 2.3 million people worldwide.

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