Jack Antel Flashcards
what is ms
a cns demyelinating disease associated with inflammation, demyalination, and concurent loss of axoms
what is the ms disease course
-acute
-chronic active
-chronic
relapse contribute to the accumulation of what
-disability, primarily early in ms
what is pira
progression in absence of relapse activity
when does pira start
in relapsing remitting ms
what becomes the dominant driver of disability in ms as the disease evolves
pira
what are the principal risk factors for further disability accumulation
pre existing disability and an older age
true or false: the use of disease modifying therapies delays disability accrual by months
false, by years
-with the potential to gain time being the highest in the earliest stages of ms
what is the prevalence of ms
100/ 100 000 in european descended populations
true or false: asians also can get ms
true, western type ms in asians when they move to the west
what is the age of onset of ms
30-40yrs
what is the ratio of men vs women having ms
either 3 or 2: 1
-increasing
-reduced activity in pregnancy
Familial aggregation is determined by….
genes
-population risk is strongly influenced by environments
Concordance rate in monozygotic female twins
is for ms
35% vs 1-2% in discordant twins
rr ms: common factors among autoimmune diseases
hls-dr region more than 250 weak association
for progressive ms what are the genetic factors
distinct cns related genes
what are the enviromental risk factors for ms
-ebv exposure
-vitamin d
-microbiome
-smoking
-western diet
Clonally expanded B cells in multiple sclerosis bind what
EBV EBNA1 and GlialCAM
Cross-reactive EBNA1 immunity targets what
alpha-crystallin B and is
associated with multiple sclerosis
Ineffective control of Epstein-Barr-virus-induced autoimmunity increases risk for what
ms
Siblings reduce multiple sclerosis risk by preventing
delayed primary ebv infection
The first neuro-immunologic observation made over a century ago was of …
paralytic encephalomyelitis in patients receiving injections of Pasteurs’ new rabies vaccine
Post vaccination encephalomyelitis, what happened
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”
what are the koch postulate
-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
what are some antibody mediated diseases
Prototype: myasthenia gravis
Recent:, MOGAD, NMO
what is the autoimmune revisited: rose/bona 1933
-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
what is the hypothesis of the origin of ms
a disorder initiated by an immune response directed
at oligodendrocytes or their myelin membranes
Dynamic aspects of CNS
allo graft persistance or rejection status of systemic immune system
Basis of Disease Progression in MS
-Continued tissue loss without new systemic inflammatory lesions
- focal inflammation; metabolic failure
-failure of repair – little ongoing remyelination
what does white matter show in ms
expanding lesions
extensive subpial cortical demyalination is specific to what?
MS
when did the research for ms treatment start
1877
tho it took like 100 yrs to have anything
when did we start having good treatments for ms
1990
-from bench to bedside; controlled clinical trials
what was the pre mri era treatment
Use of potent immuno-ablative therapy when disease severity
apparent
Intensive immunosuppression in progressive
multiple sclerosis. A randomized, three-arm
study of high-dose intravenous ……
-cyclophosphamide, plasma exchange, and ACTH
-was positive in 1983
-but in 1991 it was shown to be negative in older/longer disease duration
what was the first good ms treatment in the mri era
Intrathecal natural interferon reduces exacerbations of multiple sclerosis.
-recombinant molecule: large scale trial n=372
what is Glatiramer acetate
-antigen directed therapy in ms
-aka copaxone
-immunomodulator
what does copaxone consists of
-4 mbp amino acid family
-glutamic acid
-alanine
-tyrosine
-lysine
what is an altered peptide ligand
-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
wht dies the altered peptide ligand kinda slays
because the inappropriate recognition could lead to anergy, apoptosis or alterations in the cytokine released
true or false: an APL can also generate what
a regulatory cell that is th2 in nature capable of controlling the pathogenic th1 cells
true or false: if there is a relapse during apl therapy, there are more antigen specific T cells
true you get more mbp and apls
Interferon γ - EAE is more severe in….
infy ko animals
Tumor necrosis factor - EAE is inhibited by removing….
TNF with
soluble TNF receptor or TNF antibody; Soluble TNF receptor or TNF antibody are effective in rheumatoid arthritis
IL-17- IL-17 antibody directed therapy (secukinumab) – effective in….
-eae
-effective in psoriasis and rheumatoid arthritis
what should be investigated as
candidates for experimental therapy
Agents that specifically inhibit gamma interferon production or counteract its effects on immune cells
what is the name of the il 17 therapy for ms
secukinumab
what is the activity of secukinumab
-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 %
FTY720 (fingolimod) – sphingosine-1-phosphate
receptor modulator – blocks what?
cell egress from LNs
Retention of healthy foreign tissue grafts can be facilitated and autoimmune tissue damage minimized by…..
prophylactic manipulation of the S1P–S1P1 GPCR system
Oral fingolimod improved what? and what did it not slow down
-improved: the relapse rate, the
risk of disability progression, and end points on
MRI.
- did not slow disease progression in primary progressive multiple sclerosis
what does natalizumab do
Migration directed therapies - Adhesion molecule (VLA-4
(alpha4/beta1 integrin)) directed therapy
Phase 3 Clinical Trial Results – natalizumab
- 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
Dimethyl fumarate: anti inflammatory
- Inhibits production of
inflammatory mediators
– Effects via NFkB, HO-1,
others? - Inhibits migration of neutrophils
into CNS during EA
-
Dimethyl fumarate: neuroprotection
- Induces anti-oxidant response
element genes
– Binds KEAP-1, activates
Nrf2… others?
Anti-CD20 therapy (Rituximab/Ocrelizumab)
-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
true or false: the cost of ms drugs keep increasing
true
true or false: third line treatments for ms are way more dangerous but work af
true
economic burden of ms
$85.4 billion, with a direct medical cost of $63.3 billion and indirect and nonmedical costs of $22.1 billion.
The average excess per-person annual medical costs for PwMS was…
$65,612; at $35,154 per person, disease-modifying therapies (DMTs) accounted for the largest proportion of this cost
what are the 3 largest components of ms costs
-Retail prescription medication (54%);
-clinic-administered drugs, medication, and administration (12%);
-outpatient care (9%)
true or false: the prevalence of ms is among the highest reported in the world
true
how many canadians have ms
An estimated 93,500 Canadians in private households, and 3,800 in long-term care facilities, have MS
Last year, Novartis’ multiple sclerosis drug Gilenya generated more than
3 billion half comes it from the us
Teva Canada Announces the Launch of a Bioequivalent Generic Version of [Pr]Gilenya®….
[Pr]Teva-Fingolimod
Capsules for the treatment of
Relapsing-Remitting Multiple
Sclerosis (MS)
Coverage of generic drugs (Quebec)
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
what is the coverage of generic drugs in quebec exceptions
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:
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 ….
60% if there is only one generic producer, and 54% if there are two or more generic producers
of the product.
Relative costs - Rituximab is six-fold to three-fold less
expensive than….
ocrelizumab
true or false: rituximab is approved in quebec
Ocrevus approval in Quebec– rituximab not approved by
RAMQ for MS – does cover related disorders eg NMO in which Ocrevus not approved.
Given the lack of bioequivalence, biosimilars
are generally …
not considered to be
interchangeable with the originator*,
what are nbcd
-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.”
NBCDs are complex non-biological drugs composed of…
large high molecular weight molecules
true or false: nbcd include nanoparticular structures
true like liposomes and block copolymer mycelles
a subsequent entry NBCD (Glatopa) was
considered through the generic review stream and was approved
based on bioequivalence data in…
april 2015
the approval of glatiramer acetate was based on what
based on large-scale, multicenter phase III data assessing the equivalence of the product to the branded product.30
e World Health Organization (WHO) added three disease modifying-therapies (DMTs)
for multiple sclerosis (MS) onto its Essential Medicines List for…..
the first time
With this landmark decision, the WHO acknowledges the critical importance of making MS
treatments available in all health systems at all times particulary for….
n low- and middle-income countries or low-resource settings, who face significant barriers to accessing MS treatments.
The three treatments added onto the WHO Essential Medicines List are
rituximab, cladribine
and glatiramer acetate
Cladribine
As a purine analog, it is a synthetic chemotherapy agent that targets lymphocytes
and selectively suppresses the immune system
what does cladribine mimic
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
Cladribine is taken up by
cells via a transporter. Once inside a cell cladribine is activated mostly
-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.
Non-patented agents - Minocycline
Pilot study of minocycline in relapsing-remitting
multiple sclerosis
-currently in phase 3 trial
Neuromyelitis optica (NMO), also known…
-as Devic’s disease
-is an autoimmune disorder that primarily affects the optic nerves and the spinal cord.
how id nmo diagnosed
-mri
-anti-aquaporin 4 antibody in serum
treatment of nmo
*Eculizumab, a complement inhibitor
*Inebilizumab, an anti-CD19 agent
*Satralizumab, an anti-interleukin-6 receptor
Eculizumab must be infused at a…
medical center every
two weeks and costs about $710,000 a year
Satralizumab is injected….
under the skin at home once a month.
It costs $219,000 the first year and $190,000 a year
Inebilizumab must be infused at a medical center every
six months.
It costs $393,000 the first year and $262,000 a year after that
Rituximab, a monoclonal antibody often used to treat…
-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.
Risk of new drug development - Brutton tyrosine kinase inhibitor inhibitors (Btkis)
- Inhibit B cells and myeloid cell (microglia) activity
- Potential to impact relapsing and progressive MS
- Multiple clinical trials for RR, SP, and PP MS
Phase II clinical trial data of evobrutinib demonstrated
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
Late-breaking data showed evobrutinib-treated patients mounted an antibody response to….
mRNA COVID vaccinations similar to that of healthy subjects
Evobrutinib is an investigational highly-selective, oral, CNS-penetrant BTK inhibitor with
the potential to become….
a best-in-class treatment option for people living with RMS
ACTRIMS 2024: Evobrutinib fails to show superiority to …. in Phase 3 trials
Aubagio
…. KGaA drops BTK inhibitor evobrutinib, marking end of road for blockbuster
Merck
