Treatment Prospects for Multiple Sclerosis. New MS Drugs and Approaches in the 2020s

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Treatment Prospects for Multiple Sclerosis. New MS Drugs and Approaches in the 2020s

12 Jan 2020

Introduction
Mechanisms of Multiple Sclerosis Development and Its Symptoms
Multiple Sclerosis Treatment Strategies
Disease Modifying Medications
Safety Issues
Treatment of Acute Relapses
Symptomatic Treatment
Alternative Approaches for Multiple Sclerosis Management
Prospects of Stem Cell Therapy for Multiple Sclerosis
List of References

Introduction

2-3 million people globally are diagnosed with multiple sclerosis (MS) [1]. Most of them are adult patients in their 20s-40s. Currently, the treatment for multiple sclerosis remains a challenge as there is no medication that can combat the disease completely. Management of multiple sclerosis includes disease-modifying therapy, drugs to treat acute relapses, and symptomatic treatment. There is also a range of complementary and alternative therapies [2]. Researchers are focused on finding new targets for drug therapy and effective therapeutic substances along with innovative approaches such as stem cell treatment.

Mechanisms of Multiple Sclerosis Development and Its Symptoms

Multiple sclerosis is a chronic disease that is characterized by inflammation in the nervous system (the spinal cord and/or the brain). The inflammation is caused by immune system activation. Its specific cells damage the coating of nerve fibers (myelin), leading to impaired conduction of impulses from the brain to other parts of the body and the development of a variety of neurological symptoms. The manifestation of the disease is individual and depends on the location of the neuronal damage. However, the following complaints may be highlighted that are common in most patients:

• pain
• weakness and numbness in limbs
• spasticity and tremors
• coordination problems
• fatigue
• bladder and bowel problems
• visual problems
• cognitive issues

This video demonstrates how nerves work and what happens to them when the disease occurs [3].

Though the exact causes of multiple sclerosis are still unknown, it was shown that the interaction of both hereditary and environmental factors (stress, viruses, vitamin D deficiency, etc.) contributes to the development of the disease [4].

Multiple Sclerosis Treatment Strategies

The cure for multiple sclerosis has not yet been found. Several types of drugs have been shown to combat neuroinflammation and slowdown neuronal damage [5, 6]. Therapy with these medications is called disease-modifying treatment. Usually, additional therapy includes treatment of acute attacks and symptom management. Exercises and physical therapy also play a key role in comprehensive management of the disease.

Disease Modifying Medications

Disease-modifying medications reduce both the frequency and severity of relapses and slow down the development of damage in the brain and/or spinal cord and the accumulation of disability. They are available in several forms depending on the route of administration.

1. Injectable Forms

• Beta interferons have been used for the treatment of relapsing multiple sclerosis since the 90s. They are injected either under the skin or into a muscle by the patient.
• Glatiramer acetate is a moderately effective drug. It is also administered under the skin or into a muscle. This is a synthetic molecule resembling the myelin – the protein that surrounds nerve fibers. It deludes immune cells thus preventing myelin from their attack.

2. Oral Forms

• Teriflunomide suppresses the immune system by inhibiting the division of cells, which are responsible for relapses of multiple sclerosis.

• Fingolimod prevents immune cells (lymphocytes) to enter the central nervous system by attaching to them. Lymphocytes with bonded fingolimod are seized in the lymph glands and cannot cause inflammation and damage to the neurons.

• Dimethyl fumarate is a drug whose mechanism of action is not yet completely clear. It is assumed to modulate the immune system without suppressing it.

• Cladribine was approved in 2019 in the USA and 1-2 years earlier in EU countries for the treatment of multiple sclerosis. This is a chemotherapeutic agent being used for the treatment of certain types of blood cancer. It reduces two types of immune cells involved in the deterioration of the central nervous system.

• Siponimod is the latest medication approved by the FDA. It has not yet been approved in Europe. Like fingolimod, it prevents penetration of immune cells into the central nervous system.

3. Infused Forms

• Alemtuzumab induces the death of immune cells responsible for neurodegeneration in multiple sclerosis.

• Mitoxantrone prevents the division of immune cells.

• Ocrelizumab suppresses the immune system. Its approval may be terminated if the manufacturer does not provide results of additional safety studies on this drug.

• Natalizumab prevents the penetration of immune cells from blood into the central nervous system.

More than a dozen other medications have shown promising preliminary results in their current clinical studies*:

*Several years are required to conduct more extensive research in a larger number of participants. However, some drugs from the list – rituximab, simvastatin, ozanimod, phenytoin, laquinimod, ponesimod – may have more clear results available as soon as 2020-2023.

Safety Issues

Treatment of multiple sclerosis is always an art of balance between efficacy and safety. Disease-modifying drugs provoke serious side effects, and the more effective the drug is, the more severe the reaction it may cause. National regulatory agencies, such as the FDA in the US and EMA in Europe, monitor new data on safety and may deny a drug due to safety reasons (as it was in 2018 when EMA banned daclizumab for risk of serious and potentially fatal immune reactions affecting the brain, liver and other organs) [7]. In April 2019, EMA initiated a review of alemtuzumab due to new reports of immune-mediated conditions and problems with the heart and blood vessels for patients on this medicine, including fatal cases, and more common side effects that significantly impacted the patient’s quality of life. Summary of data on the efficacy of disease modifying treatments’ abilities to postpone relapses and safety of licensed medications for multiple sclerosis is compiled in Table 1 [5, 8].

Treatment of Acute Relapses

Two options are available now to manage sudden attacks of the disease (relapses):

1. Oral corticosteroids (prednisone) to reduce inflammation. Adverse reactions that may be caused by corticosteroids are high blood pressure, weight gain, sleep disorders, mood changes, swelling, osteoporosis, and low infection resistance. High doses of oral or intravenous steroids may be required for severe relapses.
2. Plasma Exchange (Plasmapheresis). The procedure of replacing the patient's liquid part of blood with a donor’s blood that is ‘clean’ of the proteins that caused the attack. This is performed in a hospital or in an outpatient unit and may also pose some risks like decreased blood pressure, bleeding, infection, thrombosis, or allergic reaction.

Symptomatic Treatment

Individual differences in signs and symptoms of multiple sclerosis, as well as different tolerances to disease-modifying medications and symptomatic treatment, require health specialists to find a personalized approach in each case of multiple sclerosis [9]. Current approaches to managing symptoms of multiple sclerosis include both drug therapy and rehabilitation programs. They focus on minimizing disease symptoms and increasing the quality of life. Regular exercise is another key factor in effective management of multiple sclerosis.

Alternative Approaches for Multiple Sclerosis Management

Complementary and alternative therapies are used in addition to conventional treatment recommended by a physician. They aim to improve the overall quality of life by allowing the patient to cope with the symptoms of multiple sclerosis. The following therapies have shown to be effective in the management of symptoms in patients with certain types of Multiple Sclerosis [2]:

• Cannabinoids in various forms. Reduces spasticity and pain and improves urinary frequency. May potentially cause psychopathology and neurocognitive side effects due to their psychoactive properties.
• Ginkgo biloba. Reduces fatigue. May interact with disease-modifying therapies.
• Reflexology. Reduces paresthesia.
• Magnetic therapy. Reduces fatigue.

Other studied complementary and alternative therapies, such as bee venom, low-fat diet with omega-3 fatty acid supplementation, Cari Loder regimen (Lofepramine combined with L-phenylalanine and vitamin B1 plus mind-body practices) either did not show any benefits compared to the control group of patients or had insufficient evidence base [2].

Prospects of Stem Cell Therapy for Multiple Sclerosis

Individual differences in signs and symptoms of multiple sclerosis, as well as differences in tolerance to disease-modifying medications and symptomatic treatment, require health specialists to find a personalized approach in each case of multiple sclerosis [9].

Multiple sclerosis treatment strategies, which include both existing and new drugs to manage disease progression, acute relapses, and symptoms, can be successfully combined with stem cell therapy for long-lasting benefits for patients. Leading scientific and industry societies pay huge attention to the role of regenerative cell biology in the development of care strategies for multiple sclerosis [10]. An increasing number of studies show promising results when using stem cell therapy in addition to other therapies for multiple sclerosis [11], [12]. One of them is to re-set the patient’s immune system through chemotherapy followed by a stem-cell replacement of the immune system using the patient’s own or donor stem cells [13].

Another approach is to use mesenchymal (bone marrow) stem cells sourced from the patient (autologous) and/or obtained from a donor to cure lesions in the central nervous system and to recover functional neurological deficits [14], [15], [16], [17], [18]. Bone marrow-derived mesenchymal stem cells have been shown to reduce inflammatory responses, stimulate neuronal stem cell differentiation, and promote the regeneration of damaged areas in the central nervous system [22]. Both strategies show encouraging results in efficacy as well as safety [11], [12], [19], [20], [21].

Consult our Medical Advisor on stem cell treatment opportunities for multiple sclerosis >>>

– Published on January 12, 2020

by Swiss Medica team

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List of References

1. Multiple Sclerosis International Federation
2. Yadav V et al. Summary of evidence-based guideline: Complementary and alternative medicine in multiple sclerosis. Report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology, 82 (12), 1083-92
3. Multiple Sclerosis Trust, UK
4. International Multiple Sclerosis Genetics Consortium. The Multiple Sclerosis Genomic Map: Role of peripheral immune cells and resident microglia in susceptibility. Science, 365 (6460)
5. Thompson AJ et al. Multiple SclerosisLancet, 391 (10130), 1622-1636.
6. MS Society UK
7. European Medicines Agency
8. www.rxlist.com
9. Gafson A, Craner MJ, Matthews PM. Personalised Medicine for Multiple Sclerosis Care. Mult Scler, 23 (3), 362-369.
10. Salvetti M et al. Progressive MS: From Pathophysiology to Drug DiscoveryMult Scler, 21 (11), 1376-84 Oct 2015.
11. Genc B et al. Stem Cell Therapy for Multiple Sclerosis. Adv Exp Med, 1084, 145-174.
12. Ge F et al. Efficacy and safety of autologous hematopoietic stem-cell transplantation in multiple sclerosis: a systematic review and meta-analysis. Neurol Sci. 2019 Mar; 40(3):479-487.
13. Sormani MP et al. Autologous hematopoietic stem cell transplantation in multiple sclerosis: A meta-analysis. Neurology. 2017 May 30; 88(22):2115-2122.
14. Bai L et al. Hepatocyte growth factor mediates mesenchymal stem cell-induced recovery in multiple sclerosis models. Nature Neuroscience, 15, 862–870.
15. Bell SM, Sharrack B and Snowden, JA. Autologous hematopoietic cell transplantation in multiple sclerosis. Expert Opinion on Biological Therapy, 2017, 17 (1), 77–86.
16. Cohen J A et al. Pilot trial of intravenous autologous culture-expanded mesenchymal stem cell transplantation in multiple sclerosis. Multiple Sclerosis, 2017, 24(4), 501–511.
17. Connick P et al. Autologous mesenchymal stem cells for the treatment of secondary progressive multiple sclerosis: an open-label phase 2a proof-of-concept study. Lancet Neurology. 2012, 11, 150–156.
18. Giacoppo S, Bramanti P and Mazzon, E. The transplantation of mesenchymal stem cells derived from unconventional sources: An innovative approach to multiple sclerosis therapy. Archivum Immunologiae et Therapiae Experimentalis (Warsz). 2017, 65,363.
19. Harris VK, Vyshkina T and Sadiq SA. Clinical safety of intrathecal administration of mesenchymal stromal cell-derived neural progenitors in multiple sclerosis. Cytotherapy. 2016, 18, 1476–1482. https://doi.org/10.1016/j.jcyt.2016.08.007.
20. Harris VK et al. Phase I Trial of Intrathecal Mesenchymal Stem Cell-derived Neural Progenitors in Progressive Multiple Sclerosis. EBioMedicine. 2018 Mar; 29():23-30.
21. Dahbour S et al. Mesenchymal stem cells and conditioned media in the treatment of multiple sclerosis patients: Clinical, ophthalmological and radiological assessments of safety and efficacy. CNS Neurosci Ther. 2017 Nov; 23(11):866-874.
22. Cuascut FX and Hutton GJ. Stem Cell-Based Therapies for Multiple Sclerosis: Current Perspectives Biomedicines. 2019 Jun; 7(2): 26.

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