Phar 442 - Multiple Sclerosis

Front 1

What are the fundamental problems and pitfalls in MS clinical trials?

Back 1

1) Animal models of MS are inadequate

2) Drug development is difficult because we don’t yet understand the cause/pathogenesis.immunology

3) Manipulation of Immune system can result in unpredictable Adverse events

4) There is no single test to measure severity of MS

5) There is a significant placebo effect in patients with MS

6) Ethical considerations in placebo controlled trials

7) The time frame of most trials is inadequate

8) The MS course can affect drug response

Front 2

Why are Animal models of MS inadequate?

Back 2

MS does not normally occur in the animal kingdom; therefore we need to give them Experimental Autoimmune Encephalomyelitis (EAE) for them to develop MS

Front 3

"We don't yet understand the cause/pathogenesis/immunology of MS" True or False?

Back 3

TRUE

Front 4

What is an example of manipulating the immune system resulting in an unpredictable adverse event?

Back 4

Natalizumab results in Progressive Multifocal Leukoencephalopathy (PML)

Front 5

"There IS a single test to measure the severity of MS" True or False?

Back 5

FALSE

Front 6

How significant is the placebo effect in patients with MS?

Back 6

50% of placebo taking MS patients in fatigue clinical trials will report improvement

Front 7

What are the ethical considerations in placebo controlled trials of MS?

Back 7

Is is even ethically right to hold drugs back for some patients with MS?

Front 8

Why is the time-frame of most trials for MS inadequate?

Back 8

MS is a life long slowly progressive disease with clinical trials usually lasting 2 years

Front 9

Why is it important for the MS course to be defined?

Back 9

The type of MS course can affect the drug response

Front 10

"Most patients only notice ____ points improvement"

Back 10

>0.5

Front 11

What are the advantages of using Disability (Expanded Disability Status Scale) as an outcome for clinical trials of MS?

Back 11

1) It is the Gold Standard for MS

2) Well recognized and Understood

[0=no neurological symptoms, 10=death due to MS]

Front 12

What are the disadvantages of using Disability (Expanded Disability Status Scale) as an outcome for clinical trials of MS?

Back 12

1) Heavily reliant on ability to walk

2) Does not capture fatigue/cognition

3) Inter & Intra rater variability

4) An ordinal scale (progression is not steady along the scale

Front 13

What are the problems with using Relapse rate as an outcome measure for clinical trials of MS?

Back 13

1) Relapses need to be confirmed by a neurologist

2) Unfortunately reliant on memory

3) It was previously assumed that relapses drove progression (NOT TRUE)

4) Relapse rates decrease with time and at different rates according to patient's age and disease duration

Front 14

"Women are more likely to have a higher relapse rate than men" True or False?

Back 14

TRUE

Front 15

"Both gender's releapse rate drops with time" True or False?

Back 15

TRUE

Front 16

What does the term "Regression to mean" refer to?

Back 16

Periods of high relapse rates are often followed by periods of low release rates

(so a low relapse rate does NOT mean they are improving necessarily)

Front 17

What is the issue with using Magnetic Resonance Imaging (MRI) as an outcome measure in clinical trials of MS?

Back 17

1) It remains an un-validated biomarker with relationship in MS is not defined

2) MRI machine variation

Front 18

"MRIs should only be used as a Secondary Outcome Measure in clinical trials of MS" True or False?

Back 18

TRUE

Front 19

When can MRI's be used as a primary outcome in clnical trials of MS?

Back 19

In short term phase II studies

Front 20

Why is it important to make sure to use the SAME MRI machine when using it as an outcome measure?

Back 20

There is MRI machine to machine variation

Front 21

What is the issue with using Corticosteroids while measuring with Gadolinium-enhanced MRIs?

Back 21

Gadolinium bypasses the BBB and illuminates the newer lesions in the CNS.

Corticosteroids close up the BBB and thus prevents the entry of Gadolinium into the CNS and can affect the results

Front 22

What are the non-drug treatments of MS?

Back 22

Physiotherapy , OT, Exericse

Front 23

What are the 1st line drugs used as Disease Modifying agents for MS?

Back 23

β-INF, Glatiramer Acetate

Front 24

What are the 2nd line drugs used as Disease Modifying agents for MS?

Back 24

Natalizumab, Fingolimod, Dimethyl Fumerate, Teriflunomide, Alemtuzemab, Mitoxantrone

Front 25

What drugs are used for Treating an acute relapse of MS?

Back 25

Corticosteriods (Accelerates the recovery from a relapse)

Front 26

What drugs are used for Symptomatic control of MS?

Back 26

Anything that can alleviate the symptoms of MS; 1) Antidepressants,

2) Baclofen (for spasticity),

3) Oxybutinin (for urinary incontience),

4) Carbamazepine for Trigeminal Neuralgia and Paroxysmal Symptoms

Front 27

What are interferons?

Back 27

Naturally occuring cytokines (proteins) which are produced in response to viruses and bacteria

Front 28

What is Glatiramer Acetate?

Back 28

A synthetic polypeptide analogue of Myelin basic proteins (e.g. L-amino acids: Glutamic Acid, Alanine, Lysine and Tyrosine)

Front 29

How was Interferons developed for MS?

Back 29

First they tried IFN- gamma and it WORSENED MS so they decided to try beta instead

Front 30

What are the doses used for IFN-Beta?

Back 30

i) IFN beta-1b: 250mcg SC alternate days

ii) IFN beta-1a(Rebif): 22mcg or 44mcg SC x 3 weekly

iii) IFN beta-1a(Avonex): 30mcg IM weekly

iv) PEG IFN beta 1a: 125mcg SC every 2 weeks

Front 31

How was GA found to be effective for MS?

Back 31

Developed to induce EAE, instead prevented EAE

Front 32

What is the MOA of β-IFN and GA for MS?

Back 32

Not fully understood.

Both cause a shift from TH1 to TH2 cytokine production (from pro to anti-inflammatory)

Front 33

"Neither IFN nor GA are thought to enter the CNS" True or False?

Back 33

TRUE

Front 34

How does β-IFN and GA exhibit anti-inflammatory effect?

Back 34

1) IFNB down regulates TH1, GA promotes TH2

2) IFNB also activates AT BBB to

i) DECREASE production of Matrix Metalloproteinases (MMP) by T-cells and

ii) DECREASE production of Vascular Cell Adhesion Molecule 1 (VCAM-1) by Endothelium cells

Front 35

What are the Very common adverse effects of IFN? (i.e. >5%)

Back 35

1) Injection site reactions

2) Flu Like Symptoms (fever, chills, myalgia)

3) Elevated LFTs

4) Neutralising Antibodies to IFNB

5) Menstrual Disorders

6) Decreased Lymphocytes

7) Leucopenia 8) Increased Spasticity

9) Sweating 10) Hypertension

11) Injection site necrosis

Front 36

What are the Less common adverse effects of IFN? (i.e. <5%)

Back 36

1) LIVER FAILURE

2) DEPRESSION

3) ANAPHYLAXIS

Front 37

How can you minimize Flu-like symptoms from IFN?

Back 37

i) Dose titration (full dose within 3-5 weeks)

ii) Ibuprofen and/or Acetaminophen (before and after injections)

iii) Inject at bedtime

Front 38

How can you minimize Injection site reactions from IFN?

Back 38

i) Rotate injection sites (to avoid necrosis)

ii) Warm injection to room temperature

iii) Ice packs before injection

Front 39

What is the dose of Glatieramer Acetate for MS?

Back 39

1) 20mg SC daily

2) 40mg SC three times a week (not approved yet in Canada)

Front 40

What are the very common adverse effects of GA? (i.e. >5%)

Back 40

1) Chest pains, Dyspnoea (breathing difficulties), Flushing, Palpitations, Anxiety - LASTS 15 MINS

2) Tachycardia, Injection Site reactions (pain & erythema) ) Lypoatrophy, Nausea, Arthralgia, Migraine, Tremor, Nausea, Sweating, Menstrual Disorders

Front 41

What are the less common adverse effects of GA? (i.e <5%)

Back 41

1) Syncope

2) Nystagmus

3) Lymphadenopathy

Front 42

"Routine Laboratory monitoring is required for Glatiramer Acetate for MS" True or False?

Back 42

False; It is NOT required

Front 43

"Tratment with GA does NOT undermine the body's defense against infections and tumor" True or False?

Back 43

FALSE

Front 44

"Lipoatropy due to GA can continue up to 32 months post cessation of the drug" True or False?

Back 44

TRUE

Front 45

What is the evidence of efficacy for IFN and GA in RRMS?

Back 45

Reduce the relapse rate by 18 -30%

i) IFNB vs GA indicated similar efficacy

ii) Shows major beneficial effects on MRI

iii) Longer time benefits unclear

Front 46

What is the evidence of efficacy for IFN and GA in SPMS?

Back 46

Findings are unimpressive; Probably only effective if patient still experiences relapses

Front 47

What is the evidence of efficacy for IFN and GA in PPMS?

Back 47

Few trials and none have been positive

Front 48

"Oral GA/β-INF is considered as effective as IV" True or False?

Back 48

False; They are not considered as effective

Front 49

"There is NO strong association between β-INF exposure and disability progression in RRMS" True or False?

Back 49

TRUE

Front 50

"Neither GA or β-INF are considred effective in the real world" True or False?

Back 50

TRUE

Front 51

What are the monitoring parameters of IFN?

Back 51

Blood Cell Counts and Liver Tests; before and during treatments

[1,3 and 6 months periodically thereafter)

Front 52

How would you explain a 30% reduction in relapse rate for MS to a patient?

Back 52

If a person was going to have 3 relapses over 3 year, by going on the drug, they would have 2 relapses over 3 years instead. With a cost of 20,000 dollars a year.

Front 53

In Canada when do you use Second Line drugs for MS?

Back 53

You have to fail a first line MS drug before you can start 2nd line drug (i.e. but there is no evidence of 'switching' studies)

Front 54

What is the MOA of Natalizumab?

Back 54

A monoclonal antibody:

Specifcally inhibits α4 integrins which prevents adhesion of lymphocytes and monocytes to vascular endothelium and this limits infiltration into the CNS

Front 55

What is the dose of Natalizumab used for MS?

Back 55

Montly infusion of 300mg

Front 56

What are the very common adverse effects of Natalizumab? (>5%)

Back 56

Neutralizing antibodies to Natalizumab --> reduced efficacy and increased infusion reactions (occurs between 2-6 months after initiation)

Front 57

What are the less common adverse effects of Natalizumab? (<5%)

Back 57

1) Infections (URTI, Influenza, UTIs)

2) Hypersensitivity

3) PML (1 in 300?)

4) Anaphylaxis

5) Depression

6) Headache

Front 58

What are the signs of Hypersensitivity to Natalizumab?

Back 58

Urticaria, Dizziness, Fever, Flushing, Hypotension, Dyspnea, Chest Pain [Within 2 hours of the infusion]

Front 59

What are the risk factors of PML (Progressive multifocal leukoencephalopathy)?

Back 59

1) Presence of JC virus

2) Previous exposure to an Immunosuppressant

3) >2 years exposure to Natalizumab

Front 60

What are the symptoms of PML (Progressive multifocal leukoencephalopathy)?

Back 60

1) Progressive weakness on one side of the body

2) Disturbances of vision

3) Changes in thinking, memory and orientation

4) Confusion and personality changes

5) Symptoms can progress over days to weeks

Front 61

What is the risk of death in patients with Early detection PML (before symptoms develop)?

Back 61

1 in 30 risk of death

Front 62

What is the risk of death in patients with Late detection PML (post symptoms develop)?

Back 62

1 in 4 risk of death and high risk of disability in survivors

Front 63

What is the evidence of efficacy for Natalizumab for MS?

Back 63

1) Beneficial MRI

2) Decreased Relapse Rate in RRMS but NOT SPMS

3) Reduced relapse rates by 68%

4) Rate of disability progression reduced, sustained for 3 months by 42% over 2 years

Front 64

How does the evidence of efficacy for Natalizumab compared to the 1st line agents?

Back 64

The addition of Beta IFN is not useful and is also associated with PML increase

Front 65

How does the efficacy of Natalizumab change with the addition of β-INF?

Back 65

There are no head to head comparisons with Beta IFN or GA