Therapeutic decisions in multiple sclerosis: moving beyond efficacy

Abstract

Several innovative disease-modifying treatments (DMTs) for relapsing-remitting multiple sclerosis have been licensed recently or are in late-stage development. The molecular targets of several of these DMTs are well defined. All affect at least 1 of 4 properties, namely (1) trafficking, (2) survival, (3) function, or (4) proliferation. In contrast to β-interferons and glatiramer acetate, the first-generation DMTs, several newer therapies are imbued with safety issues, which may be attributed to their structure or metabolism. In addition to efficacy, understanding the relationship between the mechanism of action of the DMTs and their safety profile is pertinent for decision making and patient care. In this article, we focus primarily on the safety of DMTs in the context of understanding their pharmacological characteristics, including molecular targets, mechanism of action, chemical structure, and metabolism. While understanding mechanisms underlying DMT toxicities is incomplete, it is important to further develop this knowledge to minimize risk to patients and to ensure future therapies have the most advantageous benefit-risk profiles. Recognizing the individual classes of DMTs described here may be valuable when considering use of such agents sequentially or possibly in combination.

Figure 1

Classes of therapeutic antibodies. Green: protein sequences of murine origin; yellow: protein sequences of human origin. MS: multiple sclerosis

Figure 2

Chemical structure of sphingosine-1-phosphate and fingolimod.

Figure 3

Methylfumarates promote activation of the Nrf2 pathway via regulation of Keap1, the Nrf2 inhibitor. (A) Methylfumarates are electrophiles that covalently bind the nucleophilic thiol group (-S-H) of Keap1 residue Cys₁₅₁. Two products can be generated depending upon which carbon of the π bond is conjugated. (B) In the absence of MMF, Keap1 binds Nrf2, promoting its ubiquitylation and consequent degradation. (C) Upon covalent binding of MMF to Keap1, interaction between Keap1 and Nrf2 is disrupted, stabilizing Nrf2, which permits it to bind the anti-oxidant response element (ARE), and promote gene transcription.

Figure 4

Chemical structure of linomide and laquinimod.

Figure 5

Chemical structure of leflunomide and teriflunomide.