Breakthrough Shift in Multiple Sclerosis Therapy

Introduction

Multiple sclerosis (MS) is an autoimmune neurodegenerative disorder symptomized by CNS inflammation, demyelination and axonal damage. It is usually diagnosed at a young age (mean age of 30 years) with 2–3 time’s higher occurrence observed in women. According to its clinical course, it is divided into relapse remitting MS (RRMS) or progressive MS. Relapses are episodes of deteriorating neurological functions that may last for 24 hours or more. Clinical symptoms of relapse are optic neuritis, sensory loss and cerebellar ataxia, while progressive MS attacks the spine and causes difficulty in walking, imbalance, cognitive impairment, partial paralysis and spasticity.

According to Multiple Sclerosis International Federation (MSIF) statistics, about 2.3 million people in the world suffer from MS. Although, the actual count is considered higher as it is unreported or undiagnosed in certain regions.

Current Therapeutic Pool

In the last 20 years, MS treatment has evolved from symptomatic treatment to Disease-modifying Drugs (DMDs) targeting different pathways of MS pathophysiology.

Interferon beta (IFNβ) has been the first line of treatment for RRMS and secondary progressive MS (SPMS) ever since the approval of its first formulation in 1993. Three different forms of IFNβ are currently in therapeutic use and have proved to reduce annual relapse rate (ARR) by 30%. Glatiramer acetate was approved for RRMS in 1996; it is a synthetic polymer that enhances regulatory T cells and anti-inflammatory M2 macrophages, thus limiting self-immunity. IFNβ and Glatiramer acetate have relatively better safety profiles than other MS therapies.

Immunologic research has proven that B cells play an eminent role in the pathogenesis of auto immune disorders including MS. It is also apparent by the presence of increased antibodies in cerebrospinal fluids (CSF) of MS patients. Monoclonal antibodies (mAbs) have long been the most efficient therapy targeting B cells. Natalizumab was the first mAb approved for MS in 2004 by United States Food and Drug Administration (FDA).However, it was soon withdrawn due to Adverse event reports (AERs) of progressive multifocal leukoencephalopathy (PML), and reintroduced in 2006, post completion of data analysis of AFFIRM phase III trials with a risk mitigation plan. Natalizumab has shown great efficacy in MS treatment, according to the AFFIRM trial, Natalizumab reduced the ARR by 68% in comparison to placebo in a year.

Since 2010 new DMDs have been approved that show higher efficacy then traditional IFNβ and Glatiramer acetate. Fingolimod was the first oral drug introduced as daily administration for RRMS. It is an immunomodulatory drug that monitors the release of lymphocytes from the lymphoid tissue into blood, hence preventing the CNS from myelin-reactive lymphocytes. Other oral drugs approved for MS include Dimethyl fumarate, Teriflunomide and Cladribine.

Alemtuzumab is an anti-CD52 mAb, it determines a sustained depletion of mainly T and B lymphocytes by inducing cytolysis. Alemtuzumab is more effective compared to IFNβ, with a risk reduction of 49.4%, a decrease of disability accumulation by 42% and better MRI outcomes.

Ocrelizumab: Breakthrough anti-CD20 mAb

Ocrelizumab is an anti-CD20 mAb approved for the treatment of RRMS and Primary progressive MS (PPMS) by FDA in March 2017 and European Medicines Agency (EMA) in January 2018. It is the only approved therapy for PPMS, the most appalling form of the disease, and the first investigational drug in MS to receive the title of breakthrough therapy by FDA. It is a recombinant humanized IgG1 antibody that selectively binds CD20 antigen, expressed B-cells, but not plasma cells, thus preserving immunity. It is administered through intravenous infusions twice a year, except for the first dose which is divided into two 300 mg infusions in 14 days interval.

Compared to IFNβ-1a, it induces a reduction in ARR by 46%, in 12-week-disability progression by 40% , proven in pivotal trials- OPERA I and OPERA II . In PPMS patients it has induced a 25% relative risk reduction in 24-week-confirmed disability progression. In clinical trials most common AEs associated with Ocrelizumab were infusion-related reactions (IRRs), urinary tract infections, nasopharyngitis and respiratory infections of the upper tract. No evidence of disease activity (NEDA), measured as no clinical relapse, progression of disability or radiological activity was achieved by 48% of ocrelizumab-treated patients over week 40.

In post-marketing surveillance, seven cases of PML have been reported so far during of Ocrelizumab, however they were later assessed as carry-over PML from previous treatment with Natalizumab or Fingolimod. Recent meta-analysis studies have concluded that Ocrelizumab is superior, if not comparable to all other approved DMDs and has been a highly effective and safe treatment for patients with MS.

Conclusion

In the most recent years, novice and sophisticated agents with more selective immunosuppressive mechanisms of action have been developed and targeted to specific pathways of MS physiopathology. As a result of this newly developed therapeutic landscape the treatment endpoints have also evolved. Few years ago, treatment success was measured by reduction in relapse rate, while it now targets at ‘no evidence of disease activity’ (NEDA). However, real-life use of these newer drugs has raised safety concerns as long-term effects and potential risks are not yet known. Like in the recent addition, Daclizumab, despite a good tolerability profile during clinical trials, it had to be withdrawn from the market by Biogen after reports of encephalitis in Europe. Both desired outcomes and potential risks should be carefully evaluated and discussed with the patient, while deciding MS therapy.

Finally, after decades of pharmacological research, the first drug for the treatment of PPMS has been approved and has proved safe and efficacious in real world use so far. The opportunity to treat progressive forms of the disease represents a successful advancement in MS management, also leading to a change in attitude towards progressive MS.

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