MedChem of MS

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The Immune System

por Virginia Tang

NUR 9211 Hematology 2018

por Jennifer Maurer

16- viral hep.

por Ameena Khaled Yusuf Khalifa Isa Budalama

Biomolecules concept map by Jax Julkowski

por Jax Julkowski

MedChem of MS

Pathology of MS

• Demyelinated areas (plaques/lesions) in the CNS:
• Loss of myelin + oligodendrocytes
• White/grey matter (lesions)
• Brain and spinal cord
• Early MS: axons/neurons preserved
• Ongoing MS: axons/neurons lost
• Brain atrophy + ventricular enlargement

Treatment :D

Symptomatic therapies

-maintain QOL; manage sxs (muscle spasticity, bladder sxs, sensory sxs, fatigue)

Disease modification treatment

Slow disease course, reduce progression

Rituximab was once considered for MS but was suspended.

Daclizumab was approved 2016, removed in 2018. Urgent review after 7 cases of serious inflammatory brain disorders and encephalitis meningoencephalitis.

Other classes:

Fumarates:

Monomethyl fumarate: Relapsing MS, SPMS

Unknown MOA, may decrease blood vessel permeability. Eliminated mainly as CO2.

Diroximel fumarate: Relapsing MS, SPMS

Less likely to cause GI ADEs due to substitution of methanol with inert 2-hydroxyethyl succinamide

Dimethyl fumarate: Relapsing MS, SPMS

Metabolized by esterase in liver and GI tract to active MMF

Cladribine

ADEs: -Cytotoxic -Malignancies -Lymphopenia/hematologic toxicity -Infections -Liver injury -Cardiac failure -Risk of teratogenicity

MOA: -Adenosine analog --> inhibits nucleoside metabolism --> toxic to B/T cells --> red lympho counts

Indication: MS, SPMS (used when other txt unacceptable)

Mitoxantrone

ADEs: -Bone marrow suppression -Neutropenia -Menstrual disorder

MOA: Binds to+ breaks DNA --> reduce lympho proliferation

Indication: SPMS, PRMS, or worsening RRMS (LAST RESORT)

Teriflunomide

ADEs: -Liver toxicity (CI in hepatic imp) -Teratogenicity

MOA: -Reduce inflammation -Reduce pyrimidine synthesis --> reduce T/B cell proliferation --> reduce lymphocytes in CNS

Glatiramer Acetate (Copaxone)

MOA: -Mimics myelin basic protein of the myelin sheath --> decoy to T-cell attack -Mixture of polypeptides containing L-Glu, L-Lys, L-Ala, L-Tyr

S1P Receptor modulators

Ozanimod: MS/SPMS

ADEs: -somnolence, fatigue, headache, dizziness, bradycardia, HTN, liver injury, N

Siponimod: MS/SPMS ** similar to Fingolimod

Fingolimod: Relapsing MS

ADEs: -Heart toxicity: -Bradycardia (1st dose monitor) -QTc prolongation, other arrhythmias, need heart monitor for 6h after 1st dose -CI: I/III anti arrhythmic drugs, 2/3 AV block, prolonged QTc, recent cardiac diseases

MOA: -Sphingosine 1-phosphate receptor modulators -Bind to S1P1R/S1P5R --> sequesters lymphocytes in lymph nodes/thymus/GI tract --> reduces circ. T cells/macrophages --> reduce CNS infiltration of immune cells

Antibodies

Ofatumumab

ADEs: -Hepatitis B reactivation -Progressive PML

MOA: -IgG, CD20 -Bind to CD20 --> Ab-depnd cytolysis

Indication: Relapsing MS or SPMS

Ocrelizumab

ADEs: -Infused-related reaction -Infections

is there a difference b/w infusion related rxn and infusion associated rxn???

MOA: -IgG monoclonal antibody -Target CD20 on surface of B cells -Induce B cell self-destruction

Indication: MS or PPMS

Natalizumab

ADEs: -IAR -Risk of PML (progressive multifocal leukoencephalopathy) due to human polyomavirus (check pts) -risk of immune reconstitution inflammation syndrome (IRIS) when D/C due to PML -depression, infection, fatigue

Human Polyomavirus (John Cunningham (JC) Virus):

• infected by inhalation
• resides in bone marrow/kidneys
• reactivated by immunosuppression
• Enters CNS --> attacks oligodendrocytes --> causes PML

MOA: -Humanized IgG monoclonal antibody -binds to interns, reduces lymphocyte entry through BBB

Indication: Relapsing MS

Alemtuzumab

ADEs: -Infusion Associated Rxn (IAR) in 90% of pts -Mild-mod: headache, rash, pyrexia, N, resp/urinary tract infections -Increased herpes infection risk (prophylactic acyclovir txt) -secondary autoimmune disease mainly changing thyroid func (30-40% of pts)

MOA: -CD52 monoclonal antibody -depletes T+B cells

Indication: High efficacy for relapsing MS -Use after inadeq response to 2 other drugs

Interferon-B1a/B1b

ADEs: -Flu-like sxs -depression -Caution: dev. of neutralizing antibodies (NABs) --> dec efficacy overtime

Agents: B1a (glycosylated): -Avonex, Rebif B1b (non-glycol): -Betaseron, Extavia Pegylated-IFNB1a: -Plegridy

Glycosylation improves activity and has a stabilizing influence

MOA: -Immunomodulation -reduces inflammatory response

Indication: Relapsing MS -Reduce MRI lesion activity -reduce brain atrophy -inc time to reach clinic def MS -decrease relapse rate -reduce risk of sustained disability progression

Treatment of exacerbations (early RRMS):

-shorten duration/reduce severity

-IV high dose corticosteroid

MS Categorization

Inflammation is present at ALL stages

Late

-Fewer immune cell infiltration (adaptive immune cell exhaustion) -Chronic CNS inflammation+ neurodegeneration -Mutual stim b/w astrocytes/microglia may produce a vicious cycle

Early

-Immune cell infiltration from periphery via: -BBB, subarachnoid space, choroid plexus -Peri immune cells + activated CNS resident microglia + astrocytes promote: -Demyelination, oligo injury, axonal injury

Clinical Course Categories of MS

Disease Course of MS

Primary/Secondary Porgressive

-Mainly due to continuous axonal loss -Above clinical threshold

Relapsing-remitting

Same as pre + -sometimes above clinical threshold -axonal loss continues

Pre-symptomatic

Episode immune attack/inflammation of myelin -Below clinical threshold -Initial axonal loss

Progressive Relapsing MS (PRMS)

Rare form of MS, steadily worsening disease state from the onset

Primary progressive MS (PPMS)

Uncommon, slowly worsening sxs from the onset w NO relapses or remissions

Secondary Progressive MS (SPMS)

Sxs worsen more steadily over time w/wo the occurrence of relapses and remissions -most ppl who are diagnosed w/ RRMS will --> SPMS

Relapsing-Remitting MS (RRMS)

The most common form, characterized by temporary periods of relapses and remissions