Research Advocate
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Two MS Oral Meds in FDA Approval Process
This is an exciting time in the treatment of multiple sclerosis. There are many new options under development by the pharmaceutical industry. Understanding the pros and cons of each drug, how they work and what the risks are is crucial to having a constructive conversation with your doctor about which medication can offer you the best results.
Even with the best scientific data available, there is still no way to truly tell how a patient will respond to a particular treatment until they are actually using it. This reality makes the choice that much more difficult.
Adding to the challenge are news reports about medications in the pipeline. Many of these reports are in the business section, and are intended to inform investors about a company’s future prospects. While the information reported about the medication is generally accurate, the ‘buzz’ they stir up can also influence the doctor-patient discussion, which is not their intent.
Moving forward with that perspective, there is much to be hopeful about. Among the oral medications in development for the treatment of multiple sclerosis, Cladribine and Fingolimod are currently engaged in the FDA’s formal approval process.
Cladribine, which is produced by EMD Serono, received notice from the FDA at the end of July 2010 that its application for “Priority Review” had been accepted. This was particularly good news, because its original application had been refused by the FDA in November of 2009. An FDA refusal notice is often times an administrative response, indicating that the application as presented is incomplete. Priority Review is targeted for six months, which means that the FDA could make a decision on Cladribine as early as December of 2010; however, it could take longer.
Cladribine is designed for people with Relapsing-Remitting MS. Phase II clinical trials have resulted in reduced relapse rates and reduced disease activity. Cladribine can interfere with the activity of lymphocytes, a subset of white blood cells that underlie the immune attacks that cause the unpredictable symptoms of MS. Cladribine also reduces the levels of immune messenger chemicals (cytokines) capable of increasing inflammation.
Fingolimod, which is produced by Novartis International, and is also known as Gilenia, received preliminary approval from an FDA advisory panel in June 2010. This preliminary approval sets the stage for formal approval by the FDA, which could take place in September.
The panel reviewed data about the effectiveness and safety of Fingolimod, plus a proposed plan designed to monitor and mitigate risks – called Risk Evaluation Mitigation Strategies (REMS) that would likely be mandated to monitor safety if the agent is approved. The committee also heard public testimony from individuals and patient advocacy groups, including the National MS Society, which testified to the unmet need for more therapies for people with MS.
The panel also recommended that patients should be monitored during the first dose for possible lowering of heart rate and other potential heart effects, and that some assessments for potential adverse events related to eye (especially macular edema) and lung function be required, to an extent to be determined by the FDA.
Medication is always a balance of risk and reward, and that is a determination to be considered carefully between a patient and a physician. Providing more options is the job of the pharmaceutical industry and the National MS Society. More detailed information about both drugs and about other medications in development can be found at www.nationalMSsociety.org.
Study May Lead to Individualized Treatment
For unclear reasons, a significant number of people with MS do not benefit from interferon therapy, but it can take months or even years to discover this. Since earlier treatment has been linked to better outcomes, being able to predict whether someone will respond to interferon could avert useless treatment and potentially improve results.
A study published in Nature Medicine (March 28, 2010) points the way to an answer why some respond to treatment and others don’t. Dr. Lawrence Steinman of Stanford University and Dr. Chander Raman, of the University of Alabama at Birmingham tested in mice their idea that response to interferon might depend on which types of cytokines (immune messengers) were leading immune attacks. They found that interferon reduced MS-like symptoms in mice whose experimental disease had been produced by T helper 1 cells, but worsened disease when it was caused by T helper 17 cells.
The team then checked blood samples of 26 people with MS and found they could differentiate between those who did and didn’t respond to interferon, based on patterns of cytokines.
Larger studies will be needed to confirm the study’s findings before they will be useful in the clinic. “The data provides a strong foundation for the possibility that we will be able to tell someone before starting treatment if it will work,” said Dr. Steinman.
The study was funded in part by the National MS Society.
Possible Source of Some Depression in MS Identified
A team funded by the National MS Society found evidence that depression is linked to brain volume loss in specific subregions of an area of the brain called the “hippocampus,” which is known to be important in memory. Tissue loss in this area was linked as well with abnormal secretion patterns of the stress-related hormone cortisol. The results also hint that this shrinkage may be reversible with effective treatment of depression in MS.
The authors (Stefan M. Gold, PhD, Nancy Sicotte, MD, University of California, Los Angeles and colleagues) note that further studies are necessary to determine any cause-effect relationship between cortisol levels and brain tissue volume loss, which are commonly found together in people with severe depression who do not have MS. If the UCLA team’s findings are confirmed, it may lead to future therapies that specifically target this cause of depression in people with MS. Several potentially “neuroprotective” therapies are being tested in people with MS which could also be effective in preventing depression in MS, a symptom that can interfere greatly with one’s quality of life
It is also important to note that MS depression may also be “reactive”—the result of difficult life situations or stresses. In addition, people with MS are also subject to the same forms of depression that affect the general population.
FDA Agrees to Fast Track New MS Drug
It was announced by the drug maker Genzyme Corporation (Cambridge, MA) that intravenous alemtuzumab has been designated by the U.S. Food and Drug Administration as a “Fast Track Product.” This designation should expedite its future review by the FDA after the sponsor submits results of current phase 3 trials that are underway (these studies have completed enrollment but are not yet completed).
Multiple sclerosis occurs when the immune system mistakenly attacks the brain and spinal cord. Alemtuzumab is a humanized monoclonal antibody directed at CD52 (a protein on the surface of immune cells) that is currently approved by the FDA as a single agent for treatment of patients with B-cell chronic lymphocytic leukemia. Its ability to target immune cells led to its testing as a possible treatment for relapsing-remitting MS.
Earlier Phase 2 studies showed that treatment with alemtuzumab reduced the accumulation of disability and the frequency of relapses in people with early relapsing-remitting MS, compared to Rebif® (interferon-beta-1a-rebif/index.aspx, interferon beta-1a, EMD Serono, Inc. and Pfizer, Inc.). (New England Journal of Medicine 2008 359;17:30-45)
Rebif is a registered trademark of EMD Serono, Inc. and Pfizer, Inc.
Low-Dose Naltrexone May Improve Quality of Life
Most people with MS experience stress, at least sometimes. A recent pilot clinical trial found that low-dose Naltrexone (LDN) may help. LDN is FDA-approved to treat opioid and alcohol addiction. At significantly lower doses, it has been prescribed as a treatment for certain diseases, including MS.
Up until now, there has been very little clinical study of LDN’s usefulness for people with MS. Dr. Bruce Cree, Dr. Douglas Goodin, and colleagues at the MS Center, University of California at San Francisco, conducted a study of 60 people with MS. Participants received LDN for eight weeks and inactive placebos for eight weeks with one week free of treatment in between.
The investigators found that LDN significantly improved some measures of quality of life—specifically, mental health, pain and self-reported cognitive function. However, they found no impact on symptoms such as fatigue, bowel and bladder control, sexual satisfaction or visual function.
The investigators emphasized that the results did not support the use of LDN instead of proven MS treatments, but they do suggest that it may relieve certain MS symptoms, and that larger studies may be warranted.
What Comes First— Epstein-Barr or MS?
Virtually all people with MS are also infected with Epstein-Barr virus (EBV), but like the chicken and the egg, scientists did not know which came first. Two new studies are adding to an increasing body of evidence that shows a possible role for EBV, a herpes virus that can cause several disorders, in the development of MS.
In the first study to look at whether EBV infection preceded the clinical onset of MS, Dr. Alberto Ascherio, of the Harvard School of Public Health, and colleagues showed that in a sample of 305 people with MS found in U.S. military databases, an EBV-positive blood test came before MS diagnosis. [Annals of Neurology, January 20, 2010] “The results strongly suggest that EBV infection increases MS risk,” said Dr. Ascherio.
At the start of the study, only 5% of the participants, including the control group, tested negative for EBV. None of the people who tested negative for EBV during the follow up developed MS. In contrast, 10 people who initially tested negative for EBV, but who acquired the virus during the follow up, developed MS. Dr. Ascherio and colleagues concluded that MS risk increases significantly following EBV infection.
“From a practical point of view, preventing EBV infection is difficult,” Dr. Ascherio said. “Most people are exposed to it in childhood. We do know that people who have a stronger immune response to EBV are more likely to get MS. There’s also pretty strong evidence that being infected with EBV in the teens or later is a risk factor for MS.”
The Harvard results were supported by a study in Spain, where researchers at the Hospital Universitari Vall d’Hebron, Barcelona, reported that an immune response to a protein associated with EBV was increased in people with MS compared with siblings who did not have MS. [Multiple Sclerosis 2010: 16(3):355-358]
The study found that siblings showed signs of having been infected with a number of viruses. The only marked difference was their immune response to EBNA1, a viral protein associated with EBV. These were significantly higher in people with MS compared to their unaffected siblings.
More research is needed to find the mechanisms underlying the connection between EBV and MS, and a way to put the information to use.