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Business of science > Jack Antel > Flashcards

Jack Antel Flashcards

1
Q

what is ms

A

a cns demyelinating disease associated with inflammation, demyalination, and concurent loss of axoms

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2
Q

what is the ms disease course

A

-acute
-chronic active
-chronic

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3
Q

relapse contribute to the accumulation of what

A

-disability, primarily early in ms

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4
Q

what is pira

A

progression in absence of relapse activity

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5
Q

when does pira start

A

in relapsing remitting ms

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6
Q

what becomes the dominant driver of disability in ms as the disease evolves

A

pira

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7
Q

what are the principal risk factors for further disability accumulation

A

pre existing disability and an older age

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8
Q

true or false: the use of disease modifying therapies delays disability accrual by months

A

false, by years
-with the potential to gain time being the highest in the earliest stages of ms

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9
Q

what is the prevalence of ms

A

100/ 100 000 in european descended populations

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10
Q

true or false: asians also can get ms

A

true, western type ms in asians when they move to the west

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11
Q

what is the age of onset of ms

A

30-40yrs

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12
Q

what is the ratio of men vs women having ms

A

either 3 or 2: 1
-increasing
-reduced activity in pregnancy

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13
Q

Familial aggregation is determined by….

A

genes
-population risk is strongly influenced by environments

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14
Q

Concordance rate in monozygotic female twins
is for ms

A

35% vs 1-2% in discordant twins

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15
Q

rr ms: common factors among autoimmune diseases

A

hls-dr region more than 250 weak association

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16
Q

for progressive ms what are the genetic factors

A

distinct cns related genes

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17
Q

what are the enviromental risk factors for ms

A

-ebv exposure
-vitamin d
-microbiome
-smoking
-western diet

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18
Q

Clonally expanded B cells in multiple sclerosis bind what

A

EBV EBNA1 and GlialCAM

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19
Q

Cross-reactive EBNA1 immunity targets what

A

alpha-crystallin B and is
associated with multiple sclerosis

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20
Q

Ineffective control of Epstein-Barr-virus-induced autoimmunity increases risk for what

A

ms

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21
Q

Siblings reduce multiple sclerosis risk by preventing

A

delayed primary ebv infection

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22
Q

The first neuro-immunologic observation made over a century ago was of …

A

paralytic encephalomyelitis in patients receiving injections of Pasteurs’ new rabies vaccine

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23
Q

Post vaccination encephalomyelitis, what happened

A

that not only has Pasteur’s
method “increased the number
of deaths from hydrophobia”,
but that “there has been added
to these a large number of
deaths due to inoculations of
what ought to be called
Pasteur’s disease”

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24
Q

what are the koch postulate

A

-Presence of agent/immune mediator(s) at site of pathology
-Agent/immune mediator(s) present only in those with the
disease
-Agent/immune mediator(s) can be used to transfer the
disease
-Removal of agent/mediator(s) have therapeutic effects

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25
Q

what are some antibody mediated diseases

A

Prototype: myasthenia gravis
Recent:, MOGAD, NMO

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26
Q

what is the autoimmune revisited: rose/bona 1933

A

-Direct evidence from transfer of pathogenic antibody or pathogenic T cell
-Indirect evidence based on reproduction of the autoimmune disease in
experimental animals
-Circumstantial evidence from clinical clues

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27
Q

what is the hypothesis of the origin of ms

A

a disorder initiated by an immune response directed
at oligodendrocytes or their myelin membranes

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28
Q

Dynamic aspects of CNS

A

allo graft persistance or rejection status of systemic immune system

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29
Q

Basis of Disease Progression in MS

A

-Continued tissue loss without new systemic inflammatory lesions
- focal inflammation; metabolic failure
-failure of repair – little ongoing remyelination

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30
Q

what does white matter show in ms

A

expanding lesions

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31
Q

extensive subpial cortical demyalination is specific to what?

A

MS

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32
Q

when did the research for ms treatment start

A

1877
tho it took like 100 yrs to have anything

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33
Q

when did we start having good treatments for ms

A

1990
-from bench to bedside; controlled clinical trials

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34
Q

what was the pre mri era treatment

A

Use of potent immuno-ablative therapy when disease severity
apparent

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35
Q

Intensive immunosuppression in progressive
multiple sclerosis. A randomized, three-arm
study of high-dose intravenous ……

A

-cyclophosphamide, plasma exchange, and ACTH
-was positive in 1983
-but in 1991 it was shown to be negative in older/longer disease duration

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36
Q

what was the first good ms treatment in the mri era

A

Intrathecal natural interferon reduces exacerbations of multiple sclerosis.
-recombinant molecule: large scale trial n=372

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37
Q

what is Glatiramer acetate

A

-antigen directed therapy in ms
-aka copaxone
-immunomodulator

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38
Q

what does copaxone consists of

A

-4 mbp amino acid family
-glutamic acid
-alanine
-tyrosine
-lysine

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39
Q

what is an altered peptide ligand

A

-is a peptide that binds to the MHC with comparable
affinity as the native peptide but is not recognized “appropriately” by autoreactive
Th-1 cells

40
Q

wht dies the altered peptide ligand kinda slays

A

because the inappropriate recognition could lead to anergy, apoptosis or alterations in the cytokine released

41
Q

true or false: an APL can also generate what

A

a regulatory cell that is th2 in nature capable of controlling the pathogenic th1 cells

42
Q

true or false: if there is a relapse during apl therapy, there are more antigen specific T cells

A

true you get more mbp and apls

43
Q

Interferon γ - EAE is more severe in….

A

infy ko animals

44
Q

Tumor necrosis factor - EAE is inhibited by removing….

A

TNF with
soluble TNF receptor or TNF antibody; Soluble TNF receptor or TNF antibody are effective in rheumatoid arthritis

45
Q

IL-17- IL-17 antibody directed therapy (secukinumab) – effective in….

A

-eae
-effective in psoriasis and rheumatoid arthritis

46
Q

what should be investigated as
candidates for experimental therapy

A

Agents that specifically inhibit gamma interferon production or counteract its effects on immune cells

47
Q

what is the name of the il 17 therapy for ms

A

secukinumab

48
Q

what is the activity of secukinumab

A

-an anti-IL-17A antibody, on brain lesions in RRMS:
-Compared with placebo, secukinumab non-significantly
reduced the number of CUAL observed on 4-weekly MRI
from week 4 to 24 (primary endpoint) by 49 %

49
Q

FTY720 (fingolimod) – sphingosine-1-phosphate
receptor modulator – blocks what?

A

cell egress from LNs

50
Q

Retention of healthy foreign tissue grafts can be facilitated and autoimmune tissue damage minimized by…..

A

prophylactic manipulation of the S1P–S1P1 GPCR system

51
Q

Oral fingolimod improved what? and what did it not slow down

A

-improved: the relapse rate, the
risk of disability progression, and end points on
MRI.
- did not slow disease progression in primary progressive multiple sclerosis

52
Q

what does natalizumab do

A

Migration directed therapies - Adhesion molecule (VLA-4
(alpha4/beta1 integrin)) directed therapy

53
Q

Phase 3 Clinical Trial Results – natalizumab

A
  • 70-80% reduction in clinical relapses and >80% reduction on MRI activity
  • 1-2% of patients will develop progressive multi-focal leukoencephalopathy (PML) if JC virus carrier (50% of population)
  • PML cases will develop immune reconstitution syndrome (IRIS) when stop the
    therapy
54
Q

Dimethyl fumarate: anti inflammatory

A
  • Inhibits production of
    inflammatory mediators
    – Effects via NFkB, HO-1,
    others?
  • Inhibits migration of neutrophils
    into CNS during EA
    -
55
Q

Dimethyl fumarate: neuroprotection

A
  • Induces anti-oxidant response
    element genes
    – Binds KEAP-1, activates
    Nrf2… others?
56
Q

Anti-CD20 therapy (Rituximab/Ocrelizumab)

A

-RR MS – Rituximab and Ocrelizumab - >90% reduction in MRI activity
- effect precedes any reduction in serum or CSF antibody levels
Ocrelizumab -: Results - 96-week confirmed disability progression rates 35.7% placebo, 29.6% ocrelizumab P=0.03 NEJM 2017
-Primary Progressive MS - Rituximab: Results - 96-week confirmed disability progression rates: 38.5% placebo, 30.2% rituximab; p = 0.14)* Ann Neurol 2009

57
Q

true or false: the cost of ms drugs keep increasing

A

true

58
Q

true or false: third line treatments for ms are way more dangerous but work af

A

true

59
Q

economic burden of ms

A

$85.4 billion, with a direct medical cost of $63.3 billion and indirect and nonmedical costs of $22.1 billion.

60
Q

The average excess per-person annual medical costs for PwMS was…

A

$65,612; at $35,154 per person, disease-modifying therapies (DMTs) accounted for the largest proportion of this cost

61
Q

what are the 3 largest components of ms costs

A

-Retail prescription medication (54%);
-clinic-administered drugs, medication, and administration (12%);
-outpatient care (9%)

62
Q

true or false: the prevalence of ms is among the highest reported in the world

A

true

63
Q

how many canadians have ms

A

An estimated 93,500 Canadians in private households, and 3,800 in long-term care facilities, have MS

64
Q

Last year, Novartis’ multiple sclerosis drug Gilenya generated more than

A

3 billion half comes it from the us

65
Q

Teva Canada Announces the Launch of a Bioequivalent Generic Version of [Pr]Gilenya®….

A

[Pr]Teva-Fingolimod
Capsules for the treatment of
Relapsing-Remitting Multiple
Sclerosis (MS)

66
Q

Coverage of generic drugs (Quebec)

A

The public plan covers generics if they are less costly compared to their brand name version.
Please note that you will have to pay the difference between the price of a brand name drug and an equivalent generic if you purchase the brand name drug. Certain exceptions apply

67
Q

what is the coverage of generic drugs in quebec exceptions

A

Brand name drugs with the mention “Ne pas substituer” (do not replace) -The public plan will cover brand name drugs if “Ne pas substituer” (do not replace) is written on them, along with any of the following justifications:

67
Q

The descending price schedule already operates
in Quebec in a limited way, since the maximum
price that may be charged for a generic drug is ….

A

60% if there is only one generic producer, and 54% if there are two or more generic producers
of the product.

68
Q

Relative costs - Rituximab is six-fold to three-fold less
expensive than….

A

ocrelizumab

69
Q

true or false: rituximab is approved in quebec

A

Ocrevus approval in Quebec– rituximab not approved by
RAMQ for MS – does cover related disorders eg NMO in which Ocrevus not approved.

70
Q

Given the lack of bioequivalence, biosimilars
are generally …

A

not considered to be
interchangeable with the originator*,

71
Q

what are nbcd

A

-non biologic complex drugs
-are defined as a “medicinal
product of non-biological origin with an active sub- stance that is not a homo-molecular structure, but consists of different closely related and mostly nanoparticulate structures.”

72
Q

NBCDs are complex non-biological drugs composed of…

A

large high molecular weight molecules

73
Q

true or false: nbcd include nanoparticular structures

A

true like liposomes and block copolymer mycelles

74
Q

a subsequent entry NBCD (Glatopa) was
considered through the generic review stream and was approved
based on bioequivalence data in…

A

april 2015

75
Q

the approval of glatiramer acetate was based on what

A

based on large-scale, multicenter phase III data assessing the equivalence of the product to the branded product.30

76
Q

e World Health Organization (WHO) added three disease modifying-therapies (DMTs)
for multiple sclerosis (MS) onto its Essential Medicines List for…..

A

the first time

77
Q

With this landmark decision, the WHO acknowledges the critical importance of making MS
treatments available in all health systems at all times particulary for….

A

n low- and middle-income countries or low-resource settings, who face significant barriers to accessing MS treatments.

78
Q

The three treatments added onto the WHO Essential Medicines List are

A

rituximab, cladribine
and glatiramer acetate

79
Q

Cladribine

A

As a purine analog, it is a synthetic chemotherapy agent that targets lymphocytes
and selectively suppresses the immune system

80
Q

what does cladribine mimic

A

it mimics the nucleoside adenosine. However, unlike adenosine it is relatively resistant to breakdown by the enzyme adenosine deaminase, which causes it to accumulate in cells and interfere with the cell’s ability to process DNA

81
Q

Cladribine is taken up by
cells via a transporter. Once inside a cell cladribine is activated mostly

A

-lymphocytes, when it is triphosphorylated by the enzyme deoxyadenosine
kinase (dCK). Various phosphatases dephosphorylate cladribine.
-Activated, triphosphorylated, cladribine is incorporated into mitochondrial and nuclear DNA, which triggers apoptosis.

82
Q

Non-patented agents - Minocycline

A

Pilot study of minocycline in relapsing-remitting
multiple sclerosis
-currently in phase 3 trial

83
Q

Neuromyelitis optica (NMO), also known…

A

-as Devic’s disease
-is an autoimmune disorder that primarily affects the optic nerves and the spinal cord.

84
Q

how id nmo diagnosed

A

-mri
-anti-aquaporin 4 antibody in serum

85
Q

treatment of nmo

A

*Eculizumab, a complement inhibitor
*Inebilizumab, an anti-CD19 agent
*Satralizumab, an anti-interleukin-6 receptor

86
Q

Eculizumab must be infused at a…

A

medical center every
two weeks and costs about $710,000 a year

87
Q

Satralizumab is injected….

A

under the skin at home once a month.
It costs $219,000 the first year and $190,000 a year

88
Q

Inebilizumab must be infused at a medical center every

A

six months.
It costs $393,000 the first year and $262,000 a year after that

89
Q

Rituximab, a monoclonal antibody often used to treat…

A

-NMOSD, costs about $18,000 a
year. The cost continues to decline, as the medication is now off patent.
-Regulatory
approval hasn’t been sought for rituximab as an NMOSD treatment.

90
Q

Risk of new drug development - Brutton tyrosine kinase inhibitor inhibitors (Btkis)

A
  • Inhibit B cells and myeloid cell (microglia) activity
  • Potential to impact relapsing and progressive MS
  • Multiple clinical trials for RR, SP, and PP MS
91
Q

Phase II clinical trial data of evobrutinib demonstrated

A

low disease activity and stable
EDSS, with NfL levels, a marker of neuronal injury, remaining low in people with RMS after
three and a half years of therapy

92
Q

Late-breaking data showed evobrutinib-treated patients mounted an antibody response to….

A

mRNA COVID vaccinations similar to that of healthy subjects

93
Q

Evobrutinib is an investigational highly-selective, oral, CNS-penetrant BTK inhibitor with
the potential to become….

A

a best-in-class treatment option for people living with RMS

94
Q

ACTRIMS 2024: Evobrutinib fails to show superiority to …. in Phase 3 trials

A

Aubagio

95
Q

…. KGaA drops BTK inhibitor evobrutinib, marking end of road for blockbuster

A

Merck

96
Q
A

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