Development of oral immunomodulatory agents in the management of multiple sclerosis

Figures & data

Table 1 Pre-MS and MS subtypes as potential targets for oral therapies

RRMS subtype	Definition	Risk of second episode/ARR over 2 years
Pre-MS
RIS^Citation13	Inflammatory lesions on MRI in the absence of clinical symptoms indicative of a related neurological episode RIS could underlie the subsequent development of RRMS or PPMS	31% (52/166)^Citation169
CIS^Citation12	A single inflammatory neurological event. Subdivided based on number of MRI lesions present initially MRI: <three lesions on MRI there is a <10% risk of MS at 15 years. If ≥three lesions the risk of MS is 50% at 15 years	<3 MRI lesions: 10% ≥3 MRI lesions: 45%^Citation170
MS
“McDonald Criteria” MS^Citation8	Single neurological episode with MRI evidence of dissemination in time and space	41%^Citation171
Clinically definite MS	Two relapses disseminated in time and space. Group 1: CDMS from 1996, Group 2: CDMS from 2008	Group 1: 1.2 relapses/year Group 2: 0.5 relapses/year^Citation21
RES RRMS^Citation14	Two clinically significant relapses in one year and one or more gadolinium-enhancing lesions on brain MRI or a significant increase in T2 lesion load	1.46 relapses/2 year^Citation172

Note: Risk of second episode and ARR are based on trial placebo data.

Abbreviations: ARR, annualized relapse rate; CIS, clinically isolated syndrome; RES, rapidly evolving severe; RIS, radiologically isolated syndrome; RRMS, relapsing-remitting multiple sclerosis.

Figure 1 Attempts to identify disease activity earlier than clinically definite relapsing-remitting MS (RRMS) has resulted in the identification of “McDonald Criteria” MS, clinically isolated syndrome (CIS), and radiologically isolated syndrome (RIS) based around MRI.

Abbreviation: SPMS, secondary progressive MS.

Figure 2 Resetting immune tolerance can prevent subsequent disability (A); however evidence is emerging that beyond a certain point during the course of MS, a “relapse-suppressive therapy” is not effective (B).

Figure 3 Annualized relapse rates observed in the 26 trials identified in the systematic review by Nicholas et al²¹ plotted against the year in which the paper was published. The dashed line shows the fitted trend line.

Adapted from Nicholas et al.²¹ Copyright © 2011, SAGE Publications. http://msj.sagepub.com

Table 2 Using data from placebo groups over 2 years based on 100 subjects in each group to predict the number of expected relapses

Efficacy	Relapse reduction	30%	30%	50%	70%
Example therapy		IFN-β, GA	terifluonamide	cladribine/fingolimod	natalizumab/mitoxantrone
Side effects (%)	serious	0	0.1	0.8/0.8	0.1/0.7
	ongoing	80%	minimal	minimal	minimal
		Expected relapses with therapy over 2 years
Demyelination syndrome subtype (expected relapses in 2 year period)	Rapidly evolving severe (300)
	Clinically definite – group 1 (240)
	Clinically definite – group 2 (100)
	McDonald (41)
	CIS ≥ 3 MRI lesions (45)
	<3 MRI lesions (10)
	RIS (31)

Notes: Using trial efficacy data the relapses that will occur as result of therapy can be predicted. Acceptability is highlighted: green, acceptable in most health systems; orange: acceptable in US/parts of Europe; red: not acceptable in health systems due to side effects; grey outline: groups in trials that have been tested.

Abbreviations: CIS, clinically isolated syndrome; RIS, radiologically isolated syndrome; GA, glatiramer acetate.

Figure 4 Simplified overview of postulated mechanism of action of standard injectables and new oral therapies. Fingolimod and cladribine reduce available circulating lymphocytes by blockade of lymphocyte egress from lymph nodes (fingolimod), by cytotoxicity and depletion (cladribine). Natalizumab acts by blockade of adhesion and transmigration across the blood–brain barrier. All three drugs (fingolimod, cladribine, and natalizumab), indirectly (fingolimod and cladribine) or directly (natalizumab), reduce the number of lymphocyte in the central nervous system (CNS). In contrast, IFN-β and glatiramer acetate (GA) shift the balance of lymphocytes and modulate cytokine secretion. The newer oral therapies, terifluonamide, laquinimod, and BG-12, do not reduce lymphocytes in the CNS and appear to act in a similar way to IFN-β and GA by modulating cytokines and lymphocyte activation. None of these injectable (IFN-β and GA) and oral (terifluonamide, laquinimod, and BG-12) drugs appear to significantly reduce the numbers of circulating lymphocytes, suggesting an immunomodulatory rather than an immunosuppressive profile.

Table 3 Effect of therapy on long-term adherence

Type	Injectables			Orals
Therapy	IFN-β	GA	Natalizumab	Fingolimod	Cladribine	Teriflunomide
Administration	++ weekly –3 times per week, sc/im	+++ daily sc	+ every 28 days, iv	–	–	–
Day-to-day	++	+	+	±	–	–
Risk of infections	–	–	+	+	±	–
Life threatening (malignancies/infections)	–	–	±	+	++	±
Pregnancy (FDA category)	C	B	C	?	D	?

Notes: Administration is the problem caused by the method and frequency of drug administration. Day-to-day is the ongoing side effects of therapy. The risk of infections requires increasing levels of surveillance by physicians and patients. Life-threatening side effects include infections, malignancy, and other causes of major clinical events.

Abbreviation: GA, glatiramer acetate.

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