Results Published from First Human Clinical Trials of “Anti-LINGO” Myelin Repair Strategy

August 27, 2014

Results from two phase I human safety trials of an exploratory treatment aimed at repairing myelin damaged by multiple sclerosis have now been published. One to two treatments with Biogen Idec’s BIIB033 (anti-LINGO monoclonal antibody) were given by injection under the skin or into the vein of healthy volunteers and people with relapsing-remitting or secondary-progressive MS. No serious adverse safety events were reported, and although these studies were not designed to evaluate effectiveness, the results were considered positive and have led to a phase II trial, now underway in relapsing MS. The results were published on August 27, 2014 in the online journal Neurology® Neuroimmunology & Neuroinflammation.
“It’s encouraging to see an entirely new treatment strategy aimed at repairing MS myelin damage moving forward in clinical trials,” noted Dr. Timothy Coetzee, Chief Advocacy, Services and Research Officer at the National MS Society. “Repairing myelin may be the best way to protect the nervous system from MS damage, and it holds potential for restoring function that has been lost in people living with this disease,” he added.
Background: In MS, immune attacks lead to the loss of myelin that coats and protects nerve fibers in the brain and spinal cord. Repairing the nervous system was just a dream a few years ago. Today it holds significant promise as a strategy to restore the function that MS has taken from people; and reducing or stopping MS progression. This remarkable progress is due in large part to the National MS Society’s comprehensive efforts and multi-million dollar research investments. Today the Society is supporting 87 research projects in nervous system repair, with multi-year commitments totaling over $35 million.
The first human trials of anti-LINGO leverage research aimed at stimulating the body's natural healing abilities. LINGO is a protein seen in neurons and myelin-producing cells (oligodendrocytes), and blockading this protein with a monoclonal antibody called anti-LINGO has been shown to promote remyelination in animal models.
Details: In these first tests of anti-LINGO in humans, 72 healthy people and 47 people with relapsing-remitting MS or secondary-progressive MS were given anti-LINGO or inactive placebo by injection under the skin or into the vein. The participants with MS were given two treatments, two weeks apart.
All participants were monitored extensively for any signs of adverse reactions. There were no serious adverse safety events noted. The most common side effects included headache, upper respiratory tract infection, stuffy nose, GI symptoms and urinary tract infection, and these were experienced by participants who were on placebo as well as those who received doses of anti-LINGO.
Generally phase I studies are not designed to detect benefit, but largely to evaluate the safety and tolerability of exploratory therapies, to refine appropriate dosing, and to determine whether they reach their targets – in this case, the central nervous system. That is true of these trials, and there was no evidence from MRI or other tests that showed clear evidence that existing brain lesions healed from this short exposure to anti-LINGO. However, the safety, dosing and pharmacology results were considered positive and have led to the design and launch of a phase II trial by Biogen Idec, now underway in relapsing MS.

New Study Yields Clues to How Nervous System Damage Occurs in MS

Understanding the damage that occurs to the brain and spinal cord during multiple sclerosis is key to finding ways to stopping MS progression. A new study by researchers in Austria provides new clues to the type and extent of nervous system damage in MS, opening new paths for further exploration that could eventually lead to better treatments to stop MS in its tracks. Lukas Haider, MD, Josa Frischer, MD and colleagues (Medical University of Vienna) report their findings in the Journal of Neurology, Neurosurgery and Psychiatry (Published Online June 4, 2014). The study was supported by the Austrian Science Fund.
Background: MS involves immune system attacks to the brain and spinal cord. The “white matter” in the brain consists of nerve fibers, which transmit messages to, from, and throughout the brain, and myelin. Myelin, the fatty substance that surrounds and protects nerve fibers, is white in color and is a major target of the immune system in MS. The “gray matter” in the brain includes the nerve cells and several associated structures. Recent research suggests that the gray matter is also damaged by MS, may be damaged early in the disease process, and has been linked to cognitive symptoms and disease progression.
The Study: Dr. Haider’s team studied the distribution of lesions – areas of damage – in brain tissue obtained from 75 people with MS via autopsy, as well as 12 controls without MS. Using a series of sophisticated laboratory techniques, they found that damage to gray matter was most prominent in the area of the brain known as the “basal ganglia,” an area associated with motor abilities, learning, cognition, and emotion.
Both white and gray matter damage were found in people with all types of MS. The extent of gray matter damage was similar in people with all types of MS, but white matter damage was more extensive in people with progressive MS. These findings indicate that there are important differences in the mechanisms by which white and gray matter damage develops, and these differences are apparent as well when damage develops in different parts of the brain.
The team also found elevated levels of iron in gray matter lesions, which appears to be liberated from myelin-making cells during injury and which may mean that these levels play a role in nerve cell degeneration in MS. Iron has been implicated in amplifying oxidative injury (a process wherein “free radicals,” normal byproducts of bodily processes, cause tissue injury).
Conclusion: This study provides some new information on nervous system damage caused by MS. More research, which is currently underway by investigators worldwide, is needed to understand the timing of the damage and to determine how this knowledge can be translated to new approaches to stopping MS progression.

Online Radio Station for MS is First of its Kind

MSFocusRadio.org offers 24/7/365 education, empowerment for MS community.

 

The Multiple Sclerosis Foundation (MSF) is proud to announce the launch of a new online radio station, MSFocus Radio. Found on the web at www.MSFocusRadio.org, or on mobile devices via a free app, this service of the MSF is a first of its kind for the MS community.

 

Featuring original content produced by the MSF in conjunction with our panel of healthcare experts, MSFocus Radio provides motivation, education, and empowerment to people affected by multiple sclerosis, 24 hours a day, seven days a week. MSFocus Radio is the MS resource that travels anywhere, thanks to free apps for both iOS and Android devices (available through iTunes and Google Play) provided by the MSF. 

 

Noting the station’s worldwide availability and round-the-clock scheduling, MSF Co-Executive Director Jules Kuperberg commented, “MSFocus Radio has dramatically broadened the scope of MSF's outreach both nationally and worldwide.”

 

To listen to MSFocusRadio or download the apps, visit www.msfocusradio.org now.

Teams Report Success Enhancing Myelin Repair in Mice Using Stem Cells and Other Novel Approaches

Two teams of researchers funded in part by the National MS Society report success in stimulating the repair of nerve-insulating myelin in mouse models of MS. Myelin is a major target of immune attacks in MS, and although these are early results and further work is needed, these findings show some promise for strategies to repair damage and restore function for people with multiple sclerosis.
Background: In MS, myelin, the material that surrounds and protects nerve fibers, is damaged in the brain and spinal cord, and so are the cells that make myelin, called oligodendrocytes. Though the replacement cells that could repair myelin, called oligodendrocyte precursor cells (OPCs), exist in the brain, in MS they cannot adequately repair the damaged myelin.
Stem Cell Study: Lu Chen, PhD, Thomas Lane, PhD (University of California, Irvine) and colleagues report that administering neural precursor cells (nerve stem cells) to mice with MS-like disease reduced inflammation, decreased myelin damage, and increased myelin repair.
The team injected the stem cells into the spinal cord of mice with an MS-like disease induced by a virus. Although the stem cells were rejected by the body, and were not detectable within eight days after transplant, they were effective nevertheless in reducing the disease. Improvements in motor abilities of the treated mice were still apparent after six months.
The team noted that improvements went along with an increase in a type of immune cell called “regulatory T cells,” or “Tregs.” To test whether the Tregs contributed to the improvements, they blocked Tregs activity, which reduced the stem cells treatments’ impact.
The team speculates that the stem cells may be stimulating the immune environment in a way that activates mouse OPCs, even though the stem cells themselves do not turn into myelin-making OPCs. They are now investigating this idea further to discover the factors released by the stem cells. Ultimately, this information could contribute to the development of stem cell therapies and even cell-free therapies that stimulate recovery in people with MS.
Stimulating Resident Cells: Jessica Williams, PhD, Robyn S. Klein, MD, PhD, and colleagues (Washington University School of Medicine) report that targeting a signaling receptor (docking site) called “CXCR7” on immature oligodendrocytes in mice enhances myelin repair.
Dr. Klein’s team focused on a messenger protein (chemokine) that interacts with the immature OPCs. They studied mice that were given a toxin called cuprizone, which mimics myelin damage that occurs in the brain during MS. Once cuprizone is withdrawn, myelin repair occurs. The team found that CXCR7 activity increased during myelin damage, and then reduced with myelin repair. When the team administered an experimental compound that inhibits CXCR7, the numbers of OPCs, as well as mature oligodendrocytes, increased within myelin-damaged areas. Myelin repair was enhanced.
These data suggest that CXCR7 might serve as an important therapeutic target to promote myelin repair. Since these studies were conducted in mice, further research is necessary to ultimately determine whether this approach might be an effective approach for stimulating myelin repair in people with MS.
Conclusion:  Achieving success in the Society’s priority area of nervous system repair would provide life-changing advances for people with MS.  

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.