Lecture 36-39 - Pharmacology of MS Drugs

Question 1

There are three categories of MS treatment:

Answer 1

1. Treatment of acute attacks (relapses, exacerbations)
2. Disease-modifying therapies (DMTs):
3. Symptomatic therapies

Question 2

Treatment of acute attacks (relapses, exacerbations)

Answer 2

methylprednisolone, prednisone,
adrenocorticotropic hormone (ACTH)

Question 3

Disease-modifying therapies (DMTs):

Answer 3

• reduce relapse rates, may slow the progression of disability (*generally used to treat relapsing rather than progressive forms of MS)

Question 4

Disease-modifying therapies (DMTs): First line

Answer 4

interferon β1a (Avonex®, Rebif®)
interferon β1b (Betaseron®, Extavia®)
glatiramer acetate (Copaxone®)
fingolimod (Gilenya®)

Question 5

Disease-modifying therapies (DMTs): Second line

Answer 5

natalizumab (Tysabri®)

mitoxantrone (Novantrone®)

Question 6

Disease-modifying therapies (DMTs): Third line

Answer 6

teriflunomide (Aubagio®)
dimethyl fumarate (Tecfidera®)
cladribine (Mylinax®)

Question 7

Corticosteroids

Answer 7

methylprednisolone
prednisone
- primary corticosteroid treatments for acute attacks:
→ methylprednisolone (IV or oral)
→ prednisone (oral)
→ adrenocorticotropic hormone (ACTH) (*rarely used due to cost)
- corticosteroids likely act by up-regulating anti-inflammatory genes, down-regulating pro-inflammatory genes, and alleviating edema in demyelinated areas.

Question 8

Interferon β1a (Avonex®, Rebif®) and interferon β1b (Betaseron®, Extavia®): MOA

Answer 8

act in the periphery and at the BBB
- inhibition of autoreactive lymphocytes – T cells, dendritic cells (DC)
- inhibition of BBB penetration by ↓ matrix metalloproteinase (MMP)

Question 9

Interferon β1a (Avonex®, Rebif®) and interferon β1b (Betaseron®, Extavia®): Clinical features

Answer 9

efficacy reduced by neutralizing antibodies

Question 10

Glatiramer acetate (Copaxone®): MOA

Answer 10

synthetic polypeptide, mimics antigenic properties of myelin basic protein
- modulation of antigen-presenting cells such as dendritic cells (DC), leading to decreased T cell activation.

Question 11

Fingolimod (Gilenya®): MOA

Answer 11

sphingosine-1-phosphate (S1P) receptor agonist
- stimulation of oligodendrocyte survival, remyelination
- interference with lymphocyte movement out of lymphoid organs

Question 12

Fingolimod (Gilenya®): Clinical features

Answer 12

progressive multifocal leukoencephalopathy
(PML), a potentially lethal brain infection

Question 13

Natalizumab (Tysabri®): MOA

Answer 13

monoclonal antibody specific for α4 integrin
- α4-integrin pairs with β1-integrin to produce ‘very late antigen’ (VLA-4)
- inhibition of VLA-4 binding to its ligand (VCAM-1 on CNS vascular endothelium) and interferes with B and T cell movement into the CNS

Question 14

Natalizumab (Tysabri®): Clinical features

Answer 14

a key side effect is the development of PML
induces the development of neutralizing antibodies → allergic reactions

Question 15

Mitoxantrone (Novantrone®): MOA

Answer 15

anthracenedione with cytotoxic activity
- reduces lymphocyte numbers by (i) causing DNA strand breaks via intercalation, and (ii) delaying DNA repair via inhibition of topoisomerase II
first cytotoxic drug licensed for SPMS

Question 16

Teriflunomide (Aubagio®): MOA

Answer 16

cytotoxic agent that inhibits dihydroorotate dehydrogenase, an enzyme involved in de novo pyrimidine biosynthesis
- inhibits proliferation of peripheral lymphocytes (e.g. activated B and T cells)

Question 17

Dimethyl fumarate (Tecfidera®) Diroximel fumarate (Vumerity®) Monomethyl fumarate (Bafiertam®): MOA

Answer 17

metabolized by esterases in the GI tract, blood, tissues
- activate Nrf2-mediated cellular antioxidant responses and anti-inflammatory pathways (active form of the drug is the monomethyl ester).
- may promote remyelination
- suppress activated T cells, dendritic cells in the periphery

Question 18

Dimethyl fumarate (Tecfidera®) Diroximel fumarate (Vumerity®) Monomethyl fumarate (Bafiertam®): Clinical features

Answer 18

SE: PML

Question 19

Nrf2 antioxidant response pathway (in astrocytes)

Answer 19

• under basal conditions, Nrf2 is continually targeted for destruction as a result of its interaction with Keap1, an antagonist that promotes Nrf2 ubiquitylation.
• when the cell is exposed to electrophilic toxins or subjected to oxidative stress, Keap1 becomes covalently modified on key cysteine residues.
• covalently modified Keap1 can no longer promote Nrf2 ubiquitylation, and thus Nrf2 accumulates and enters the nucleus, where it activates the transcription of genes regulated by the antioxidant response element (ARE).
• genes under the control of the ARE include genes encoding enzymes involved in (i) glutathione biosynthesis, and (ii) detoxification (glutathione-S- transferase or GST). These enzymes are part of the phase II response.

Question 20

Siponimod (BAF312) (Mayzent®),
Ozanimod (Zeposia®),
Ponesimod (Ponvory®): MOA

Answer 20

sphingosine-1-phosphate (S1P) receptor agonists (same mechanism as fingolimod)
- may stimulate oligodendrocyte survival, remyelination
- interference with lymphocyte movement out of lymphoid organs
indicated for RRMS and SPMS

Question 21

Cladribine (Mylinax®): MOA

Answer 21

taken up in cells by purine nucleoside transporters
in cells with a high ratio of deoxycytidine kinase to deoxynucleotidase (e.g.
lymphocytes, monocytes), cladribine is phosphorylated to the triphosphate form, 2-chloro-dATP.
2-chloro-dATP damages DNA and interferes with DNA metabolism, resulting in cell death -> lymphocyte depletion.

Question 22

New antibody therapies

Answer 22

• Rituximab (Rituxan®, MabThera®, Zytux®): targets CD20 (B cell marker)
  → also known as Ocrelizumab
  → approved for non-Hodgkin lymphomas and rheumatoid arthritis
  (repositioned drug – used off label)
  → stops RRMS (based on MRI, relapses), effective for some PPMS patients

Question 23

Ocrelizumab (Ocrevus®), aka Rituximab (Roche): MOA

Answer 23

• humanized monoclonal antibody that targets CD20, a marker of mature B-cells
• doesn’t bind CD20 on stem cells or plasma cells, so that key immune functions
  are unperturbed.
• decreased disease progression in PPMS (first example)
• decreased relapse rate in RRMS

Question 24

Experimental MS drugs

Answer 24

Antisense oligonucleotides: ATL1102, an ASO targeting VLA-4 → predicted to have same outcome as natalizumab

Question 25

Which of the following drugs is active in both the periphery and CNS?

Answer 25

dimethyl fumarate

Question 26

Drugs that only act in the periphery (including the BBB)

Answer 26

interferon-β, glatiramer acetate, natalizumab, mitoxantrone, teriflunomide, cladribine, rituximab (ocrelizumab), ATL1102

Question 27

Drugs that act in the periphery and CNS

Answer 27

fingolimod, siponimod, ozanimod, ponesimod
dimethyl fumarate, monomethyl fumarate, diroximel fumarate

Question 28

Drugs that act at the BBB

Answer 28

interferon-β, natalizumab, ATL1102

Question 29

Drugs that act via a cytotoxic effect

Answer 29

mitoxantrone, teriflunomide, cladribine

Question 30

Drugs that can increase the risk of PML

Answer 30

fingolimod, natalizumab
dimethyl fumarate, monomethyl fumarate, diroximel fumarate

Question 31

Drugs whose effectiveness may be limited by neutralizing antibodies

Answer 31

interferon-β, natalizumab, rituximab (ocrelizumab)

Question 32

Drugs that can be used to treat PPMS

Answer 32

rituximab (ocrelizumab)