Development of New Drugs for Multiple Sclerosis Therapy in Patients With Disabilities: A Systematic Literature Review

Introduction

Multiple sclerosis is a life-long disabling autoimmune disease affecting the central nervous system. It is a complex disease, and this has been linked to its patho-and molecular mechanism. The cause is unknown. However, most medical experts agree that the causes encompass genetic susceptibility and environmental exposure. Mitochondria, which is regarded as the powerhouse of cell has been linked to the pathogenesis of MS as well. Today, over 2.5 million people are suffering from this affliction. The prevalence of MS has increased where 30 people in every 100,000 were diagnosed with the condition in 2008, the figure rose to 33 in every 100, 000 in 2014 (Piehl, 2014). There are four categories of MS condition. The disorders are defined based on their clinical course and increasing severity. Relapsing/remitting MS (RRMS) is the first category. It is the most common type of MS affecting over 85% of all MS patients according to Sagawa et al. (2016). The second category is the secondary progressive MS (SPMS). It develops in some patients with RRMS after a short duration of time. The SPMS affects 8 to 10% of MS patients. It is a gradual and continuous neurologic deterioration. Progressive relapsing MS (PRMS) is the fourth category and the least common. It affects less than 5% of all MS patients (Sagawa et al., 2016). The PRMS is similar to PPMS except that it is characterized by overlapping relapses.

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MS leads to demyelination and axonal damage. In the long run, it results in subsequent dysfunction of neurological systems. A bigger proportion of MS patients tend to develop what Piehl (2014) refers to a neurological disability. In fact, MS is one of the most common causes of neurological disability. Until recently, treatment for this complication relied on disease-modifying agents. However, the management of the condition has reached a point where there is an increasing launch of new drugs in the market.

Since there is no known treatment, most intervention measures for MS involve decreasing the frequency of relapses and delaying the progression of the disease. The major objective of such a move is to improve the patient's quality of life, for instance, reducing disabilities. As more information about autoimmune has been acquired, especially with the molecular mechanism involved, several MS treatments have been developed.

According to Lecat, Decavel, Magnin, Lucas, Gremeaux, and Sagawa (2017), Disability is the most debilitating symptom among patients suffering from MS. It accounts for at least 70% of the handled cases.

Disability compromises the daily activities of person and substantially reduces one's quality of life. Functional body and movement is a practice that is utilized in almost all daily activities. As such, it is critical to the social participation and independence of persons. Although there are treatments to minimize the rate of relapse, delay disability progression in RRMS, the long-term impacts of these interventions are scarce. Also, there are limited medical therapies for the treatment of the progressive forms of MS. To this end, there is need to understand the benefit/risk profile of new drugs for MS therapy. Studies suggest that treatment that addresses the disability problems will go a long way in reducing the burden shouldered by individuals with MS.

Aims and Objectives of the Review

The current study reviews literature available on the new drugs launched or have finished Phase III trial within the last 3 years for the therapy of MS patients.

The main objective of this review is to generate evidence-based results aimed at minimizing disabilities among patients with MS. Other main outcomes and adverse events occurred in the studies will be, partly, taken into consideration as well. To conclude, some recommendations will be given for the future researches in this field.

Identification of the Articles for Literature Review

To identify the required articles, the key-words and search terms into various databases. The major archive was PubMed.

Selection of Articles Inclusion and Exclusion criteria

In this phase, the author carefully selected the resources to avoid duplication. Replication was avoided on the basis of the titles of the articles.

Eligibility for InclusionThe researcher selected and included articles on the development of new drugs for MS therapy among patients with walking disability. If the abstracts did not mention at least some of these phrases, the articles were excluded from the review process. Also, publications that did not correspond to drugs developed within the last three years or which are not under research were not selected for the study.

Results and Findings

To this end, three drugs, Ocrelizumab, Daclizumab, and Siponimod have been noted to play an instrumental role in delaying and disrupting debilitation in MS patients. As DMDs, the drugs present different outcomes, especially with EDSS used to measure the disability grade among patients suffering from MS. The findings reveal that these drug therapies can help to delay and disrupt debilitation in MS patients.

Ocrelizumab

Disability improvement confirmed at 12 weeks was 20.7% in the ocrelizumab group, as compared with 15.6% in the interferon beta-1a group (33% higher rate of improvement with ocrelizumab, P = 0.02).

Montalban et al. (2017) observed percentage of patients at 12 and confirmed disability progression at 32.9% with ocrelizumab compared with 39.9% of placebo. The disability progression reduced by 29.6% in 24-week with ocrelizumab compared with 35.7% of placebo. However, disability progression worsened at week 120, for instance, performance on the timed 25-foot walk worsened by 38.9% with ocrelizumab when compared with 55.1% of placebo (P=0.04).

Hauser, Amit, Giancarlo, Giovannoni, Hartung, Hemmer, et al. (2017) observed that disability progression at 9.1% in the ocrelizumab group compared with 13.6% in the interferon beta-1a group. In the 96-week period of trial, the rate of disability progression observed at week 24 recorded 6.9% with the ocrelizumab group compared with 10.5% in the interferon beta-1a group. The results indicate that the effect of ocrelizumab on the risk of confirmed disability progression in each of the two trials was consistent with the pre-specified pooled analysis.

Daclizumab

Gorman, Tillema, Ciliax, Guttmann, and Chitnis (2012) study observed improved and stabilized EDSS sore with a decreased ARR from 2.6 to 0.62. Overall, patients treated with daclizumab with the combination of interferon exhibited reductions in annualized relapse rates (ARRs) with a reduction in EDSS scale score in each patient.

Kappos, Wiendl, Selmaj, Douglas, Arnold, Havrdova, et al. (2015) demonstrated a lower ARR with daclizumab HYP than with interferon beta-1a. Within the 144th week of trial, the estimated incidence of disability progression confirmed at 12 week recorded 16% with daclizumab HYP in comparison with 20% of interferon beta-1a (P=0.16).

Siponimod

Kappos, Bar-Or, Cree, Fox, Giovannoni, Gold et al. (2018) observed that Siponimod reduced the risk of disability progression. Also, Kappos et al. (2018) observed that the Siponimod present a safety profile that is the same as the S1P modulators and, as such, present a potential and useful treatment for SPMS.

Discussion

In the ocrelizumab trial, the results were positive over placebo with regard to the risk of confirmed disability progression during the week 12 period. For example, patients with primary progressive multiple sclerosis demonstrated that the ocrelizumab drug was associated with lower rates of clinical and MRI progression than placebo. Also, the observation was noted in week 24 in disability progression was confirmed in regard to speed ambulation as per the timed 25-foot walk. Therefore, ocrelizumab decreases disability progression in MS. This explains why the ocrelizumab was the first drug to be approved specifically for the primary progression MS in 2017.

From the results, ocrelizumab is superior to interferon beta 1a in relapsing MS. In addition, ocrelizumab demonstrated a higher efficacy in relapsing MS, but the drugs present a high risk of adverse reactions. For instance, Hauser et al. (2017) observed that Infusion related reactions were higher in Ocrelizumab at 34.3%. The same was also observed in Montalban et al. (2017) for example, the infusion-related reactions (39.9 % vs 25.5 %), upper respiratory tract infections (10.9 vs 5.9 %) were higher in Ocrelizumab group. As such, risk and benefit profile must be considered individually.

On its part, daclizumab has proved to be effective in the treatment of pediatric patients with MS. For example, daclizumab is superior to interferon beta 1a in disrupting disability progression in relapsing-remitting MS. During treatment, there has been no difference between low dose and high dose of daclizumab. However, adverse effects reportedly associated with daclizumab therapy resulted in the drug being pulled out of the market in March 2018. The adverse effects such as the elevated liver function, infections, psoriasis, and oral ulcers calls for the need for close monitoring.

On its part, the Siponimod reduce disability progression in secondary progressive MS and relapsing-remitting MS. To this end, Siponimod present a first drug that may potentially be approved for secondary-progressive MS. This is due to the fact that Siponimod was found to not only minimize the risk of disability progression but also present a safety profile is not different from that of other S1P modulators. As such, the drug is likely to be a useful treatment for SPMS.Summary of the three drugs on the disability progression on patients with MS.

DAC OCZ SIP Limitation of the Study

There were several challenges and limitations that affected this study, and which needs to be discussed at this juncture. The first limitation of this study had to do with the drugs. For example, the study is limited to only 3 different drugs. As such, the study could recommend varieties of drugs that can be used in the reducing disability progression among patients with MS.

Another possible source of limitation for this study has to do with the low number of reviewed studies. The study was only limited to only six articles that have explored the three drugs. Therefore, this shortcoming hindered the researcher from having exhaustive review of available drugs that can hinder disability progression. All of these limitations indicate that this study is not conclusive. It makes a significant contribution to this field, but further studies are needed to this end, especially with the short term follow-ups noted in the three drugs.

References

Montalban X, Hauser SL, Kappos L, Arnold DL, Bar-Or A, Comi G, de Seze J, et a...