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Identifying and Addressing Unmet Therapeutic Needs in MS

Clyde E. Markowitz, MD

Department of Neurology and the Multiple Sclerosis Center, the Hospital of the University of Pennsylvania, Philadelphia

Adequately controlling and preventing disease activity for patients with multiple sclerosis (MS) remains an unmet need. Current disease-modifying treatments are partially effective in reducing relapses, reducing new lesion formation, and slowing disability progression, but they are not restorative nor are they effective for progressive forms of MS.1

About 85% of patients present with relapsing-remitting MS (RRMS), which is characterized by unpredictable attacks of neurologic symptoms that partially or fully resolve between exacerbations.2 Most patients who have RRMS will transition to secondary-progressive MS, with a disease course that steadily progresses with or without relapses. Primary-progressive MS, which affects about 10% of MS patients, steadily worsens neurologic function from onset; patients do not experience distinct relapses or remissions. Progressive-relapsing MS, the most rare form of MS, is progressive from onset and punctuated by relapses with or without some recovery after these attacks.2

During relapses, patients experience inflammation and demyelination, which over time with disease progression results in neurodegeneration.3 Current disease-modifying therapies have anti-inflammatory properties, giving them some effectiveness in RRMS, but unmet needs exist, such as treating progressive forms of MS, improving efficacy and safety profiles, comprehensively managing MS symptoms, and developing new agents that focus on neuroprotection (AV 1) .

AV 1. Unmet Needs in MS Treatment (0:36)

AV 1. Unmet Needs in MS Treatment
Treating Progressive Forms of MS

While the number of approved treatments for RRMS has increased, approved medications for progressive forms of MS are desperately needed. One obstacle to conducting studies in progressive MS is the lack of a primary outcome measure that researchers can track on a short-term basis to quantify the effectiveness of an intervention.4 For example, patients with progressive forms of MS do not experience distinct relapses, which is generally a primary outcome measure for most MS studies. Instead, they require monitoring of disability progression over time regardless of relapse, which can require longer and more costly trials.4 Researchers are continuing to search for better ways to study the pathogenesis of progressive MS to make advancements in treating all forms of MS.5

Improving Efficacy and Tolerability

Current disease-modifying treatments for RRMS have clearly significant benefits in reducing relapses and slowing disease progression, but the results are not robust in all patients, such as those with suboptimal response to treatment.6 Additionally, some of the most effective medications that suppress disease activity also have severe safety and tolerability issues. For example, although natalizumab has been shown to reduce disease activity and improve disease severity, it is associated with an increased risk of PML, which can be fatal.7,8 Progress has been made in determining risk factors for PML,8 but there is a lack of studies on how to manage PML if a patient develops it.

While oral medications for MS have improved ease of use compared with injectable and IV medications, they also have adverse effects related to cardiac risk, hepatoxicity, infections, GI problems, and flushing.9 A possible solution to avoid some adverse events is to develop new medications that are more specific for certain neurologic targets. For instance, fingolimod is a nonselective modulator of sphingosine 1-phosphate receptors, but a more selective drug that would not affect certain subtypes of this receptor could potentially limit cardiovascular problems.10

Another safety concern is the level of immunosuppression with MS treatments. Although immunosuppressants display some anti-inflammatory benefits, they can pose toxicity problems and possible long-term risks as well as potential effects on protective autoimmunity.11 For example, alemtuzumab (an agent currently approved for leukemia) was recently up for FDA approval to treat RRMS and was declined despite demonstrating effectiveness because the FDA felt its benefits did not outweigh its risks, which include autoimmune thyroid problems and idiopathic thrombocytopenic purpura (ITP).12 Thus, an unmet need exists for new medications that provide efficacy while avoiding risk for serious complications.

Managing MS Symptoms

Troublesome symptoms of MS include fatigue, impaired gait, vision problems, spasticity, pain, bladder problems, and emotional changes.13 While a few medications are available to manage some of these symptoms, effective symptom control is another area of unmet need, especially for symptoms that are less amenable to therapy, such as fatigue. Finding medications that manage symptoms without adding adverse effects is a challenge. Medications such as amantadine and modafinil are often used off-label to treat fatigue, but they are commonly associated with insomnia, nausea, and anxiety.14 Other medications can be used to treat bladder dysfunction, pain, and depression, but their adverse effects must be considered carefully. Dalfampridine, a potassium-channel antagonist, is FDA-approved to improve walking in patients with MS.15 The availability of more medications that manage MS symptoms would improve the quality of life and daily functioning of patients with MS. For clinicians, managing patients’ symptoms requires knowledge of available treatments and careful timing of the therapy when patients need it the most.

Developing Neuroprotective Agents

AV 2. The Remyelination Process of Neuroprotective Agents in Development (0:44)

AV 2. The Remyelination Process of Neuroprotective Agents in Development

After experiencing an inflammatory attack of MS, patients may have residual neurologic damage, but treatments are lacking for repairing that damage and restoring function, such as myelin repair. Remyelination often occurs early in the course of relapsing forms of MS, which might explain the remission of symptoms between attacks, but this process fails as the disease progresses.1 To avoid accumulation of damage, treatments are needed to restore myelin and to provide neuroprotection against future demyelination and axonal degeneration (AV 2).3,16 Reliable markers of neuroprotection and remyelination are being explored so that agents targeting these areas can be reliably tested and compared.17

Conclusion

Despite the growing armamentarium of disease-modifying therapies for relapsing forms of MS, unmet needs remain to treat progressive forms of MS and to improve the efficacy and tolerability profiles of MS treatments. Some adverse effects could be reduced if medications are developed with more specific treatment targets. Symptom management that balances efficacy and tolerability would help clinicians address symptoms that hinder patients’ daily functioning. Finally, researchers are exploring remyelination and neuroprotection in MS treatment to reverse damage and prevent disease progression.

Clinical Points
  • Recognize the need for approved treatments for progressive forms of MS
  • Realize that MS treatments with improved efficacy often have decreased tolerability and safety
  • Manage patients’ troublesome symptoms as best as possible
  • Watch for upcoming agents with neuroprotective or remyelinating qualities
Drug Names

alemtuzumab (Campath), dalfampridine (Ampyra), fingolimod (Gilenya), modafinil (Provigil and others), natalizumab (Tysabri)

Abbreviations

FDA = US Food and Drug Administration, GI = gastrointestinal, ITP = idiopathic thrombocytopenic purpura, IV = intravenous, MS = multiple sclerosis, PML = progressive multifocal leukoencephalopathy, RRMS = relapsing-remitting multiple sclerosis

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References
  1. Katz Sand IB, Krieger S. Emerging strategies for the treatment of multiple sclerosis. Future Neurol. 2012;7(2):193–207. Full Text
  2. National Multiple Sclerosis Society. Types of MS. http://www.nationalmssociety.org/What-is-MS/Types-of-MS. Accessed August 13, 2014.
  3. Münzel EJ, Williams A. Promoting remyelination in multiple sclerosis: recent advances. Drugs. 2013;73(18):2017–2029. PubMed
  4. Multiple Sclerosis Research Australia. Clinical trials for progressive MS: what’s on the horizon? http://www.mstrials.org.au/clinical-trials-progressive-ms-what%E2%80%99s-horizon. Published May 30, 2012. Accessed August 13, 2014.
  5. Dutta R, Trapp BD. Relapsing and progressive forms of multiple sclerosis: insights from pathology. Curr Opin Neurol. 2014;27(3):271–278. PubMed
  6. Miller AE, Rhoades RW. Treatment of relapsing-remitting multiple sclerosis: current approaches and unmet needs. Curr Opin Neurol. 2012;25(suppl 1):S4–S10. PubMed
  7. Goodin DS, Cohen BA, O’Connor P, et al. Assessment: the use of natalizumab (Tysabri) for the treatment of multiple sclerosis (an evidence-based review): report of the Therapeutics Assessment Subcommittee of the American Academy of Neurology. Neurology. 2008;71(10):766–773. PubMed
  8. Bloomgren G, Richman S, Hotermans C, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med. 2012;366(20):1870–1880. PubMed
  9. Tanasescu R, Ionete C, Chou IJ, et al. Advances in the treatment of relapsing-remitting multiple sclerosis. Biomed J. 2014;37(2):41–49. PubMed
  10. Du C, Xie X. G protein-coupled receptors as therapeutic targets for multiple sclerosis. Cell Res. 2012;22(7):1108–1128. PubMed
  11. Zaffaroni M, Ghezzi A, Comi G. Intensive immunosuppression in multiple sclerosis. Neurol Sci. 2006;27(suppl 1):S13–S17. PubMed
  12. Jeffrey S. FDA declines approval for alemtuzumab (Lemtrada) in MS. http://www.medscape.com/viewarticle/818420. Published December 30, 2013. Accessed August 13, 2014.
  13. National Multiple Sclerosis Society. MS Symptoms. http://www.nationalmssociety.org/Symptoms-Diagnosis/MS-Symptoms. Accessed August 13, 2014.
  14. Braley TJ, Chervin RD. Fatigue in multiple sclerosis: mechanisms, evaluation, and treatment. Sleep. 2010;33(8):1061–1067. PubMed
  15. Ampyra (dalfampridine)[package insert]. Ardsley, NY: Acorda Therapeutics; 2014. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=550eb76a-e4a6-4fa1-ad65-c0fd8b0ce783. Accessed August 13, 2014.
  16. Franklin RJM. Why does remyelination fail in multiple sclerosis? Nat Rev Neurosci. 2002;3(9):705–714. PubMed
  17. Markowitz CE. The current landscape and unmet needs in multiple sclerosis. Am J Manag Care. 2010;16(suppl 8):S211–S218. PubMed

CME Background Information

Supported by educational grants from Genzyme, a Sanofi Company, and Novartis Pharmaceuticals Corporation.

Participants may receive credit by reading the activity, correctly answering the posttest question, and completing the evaluation.

Objective

After completing this educational activity, you should be able to:

  • Understand the need for new treatments to comprehensively manage all forms of MS and presenting symptoms

Financial Disclosure

The faculty for this CME activity and the CME Institute staff were asked to complete a statement regarding all relevant personal and financial relationships between themselves or their spouse/partner and any commercial interest. The CME Institute has resolved any conflicts of interest that were identified. No member of the CME Institute staff reported any relevant personal financial relationships. Faculty financial disclosures are as follows:

Dr Markowitz is a consultant for Biogen Idec, Teva, Bayer, Novartis, Genzyme, and Roche.

The chair for this activity, Harold Moses, Jr, MD, is a consultant for Bayer, Biogen Idec, Genzyme, Teva, and Questcor; has received grant/research support from Novartis, NIH, Biogen Idec, Sanofi, and Genzyme; and is a member of the speakers/advisory boards for Questcor, Avanir, Teva, Biogen Idec, and Bayer.

Accreditation Statement

The CME Institute of Physicians Postgraduate Press, Inc., is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Credit Designation

The CME Institute of Physicians Postgraduate Press, Inc., designates this enduring material for a maximum of 0.5 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

The American Academy of Physician Assistants (AAPA) accepts certificates of participation for educational activities certified for AMA PRA Category 1 Credit™ from organizations accredited by ACCME or a recognized state medical society. Physician assistants may receive a maximum of 0.5 hours of Category I credit for completing this program.

To obtain credit for this activity, study the material and complete the CME Posttest and Evaluation.

Release, Review, and Expiration Dates

This Neurology Report activity was published in December 2014 and is eligible for AMA PRA Category 1 Credit™ through December 31, 2017. The latest review of this material was August 2014.

Statement of Need and Purpose

Multiple sclerosis (MS) affects over 2 million people worldwide and results in reduced quality of life, cognitive impairment, and physical disabilities. The medications initially approved for MS required patients to either self-administer injections or receive hospital-based intravenous infusions. However, the US Food and Drug Administration (FDA) has recently approved oral medications for MS, which has changed patients’ outlook toward MS therapies, and using oral medications may have a positive impact on their quality of life. Oral agents have several benefits, including convenience, ease of use, and greater comfort with taking a pill versus administering an injection, but carry risks as well, especially for potentially serious side effects. Further, long-term safety and efficacy of these new agents remain unknown. Therefore, switching patients to oral medications on the basis of convenience is not a sufficient reason for the change. Because the landscape of MS treatment is changing rapidly, health care providers need information on all of the available treatments to help their patients receive optimal care. This activity was designed to meet the needs of participants in CME activities provided by the CME Institute of Physicians Postgraduate Press, Inc., who have requested information on MS.

Disclosure of Off-Label Usage

Dr Markowitz has determined that alemtuzumab, modafinil, and amantadine are not approved by the US Food and Drug Administration for the treatment of MS.

Review Process

The entire faculty of the series discussed the content at a peer-reviewed planning session, the Chair reviewed the activity for accuracy and fair balance, and a member of the External Advisory CME Board who is without conflict of interest reviewed the activity to determine whether the material is evidence-based and objective.

Acknowledgment

This Neurology Report is derived from the planning teleconference series “The Impact of Oral Medications on the Treatment of Multiple Sclerosis,” which was held in November 2013 and March 2014 and supported by educational grants from Genzyme, a Sanofi Company, and Novartis Pharmaceuticals Corporation. The opinions expressed herein are those of the faculty and do not necessarily reflect the opinions of the CME provider and publisher or the commercial supporter.