Prof mouse pint of neuroscience part ii

#ThinkHandWhy the 9 Hole Peg Test?

DRUG DEVELOPMENT

(Bench to Bedside)

WORKS & SAFE IN PEOPLE WITH DISEASE

PHASE III

APPROVALPOST-MARKETING SURVELLIENCE

PHASE IV

REGULATORS

MHRA Medicines & Healthcare ProductsRegulatory Agency (UK)

EMA European Medicines Agency (EU)FDA Food & Drug Administration (USA)

Select Outcomes which will be a affected by the Treatment

EMA

Expanded Disability Status Scale (EDSS)

Main Clinical Outcome in Trials is Multiple Sclerosis used to Assess Efficacyby the Regulators

Mobility Scale Dominated by Lower Limb functionTypical EDSS trials Cut off >6.5 (20m walk)

REGULATORY OUTRCOMES

500m 200m

100m <5m

TREATMENT PYRAMID

Stop Nerve

Damage

Protect Damaged

Nerves

WHAT ARE THE TREATMENTS?

Repair Nerve

Conduction Issues

Repair Lost

Nerves

Block

Attacks

Block

Progression

Many Drugs Approved

1. DamageDue to Attack

2. Secondary Damagefrom Immune Attack

3. Progressive DamageNot responsive to

Current Drugs Affecting Attacks

+ve

+veSYMPTOMS

NERVE DAMAGE

+ve +veSYMPTOM CONTROL

+ve

+ve

-ve

NEUROPROTECTION

HEALTH

CONTROLING SYMPTOMS

CONTROLING PROGRESSIVE MS

CANNABINOIDS

Study Shows No Evidence to Support an Effect of Main Active

Constituent of Cannabis on MS Progression

CUPID Cannabinoid Use in Progressive Inflammatory Brain Disease

Zajicek J et al. 2013

Study Shows Evidence to Support an Effect of Main Active

Constituent of Cannabis on MS Progression

Subgroup Analysis Starting EDSS less than 5.5

P<0.01

Zajicek J et al. 2013

CUPID Cannabinoid Use in Progressive Inflammatory Brain Disease.

Mobility Scale Dominated by Lower Limb functionTypical EDSS trials Cut off >6.5

People in Wheelchairs are Forgotten and excluded from studies

Why Are Lower Limbs Notably Affected in MSCNS fibre length – motor vs. visual

10cm

2 x 80cm =160cm

vs.

Short axon

Long axon

Length-dependent axonopathy hypothesis

vs.

= focal acute inflammatory lesions

vs.

Short axon

Long axon


distal or anterograde axonal degeneration


vs.

Short axon

Long axon

= chronic inactive lesions


proximal or retrograde axonal degeneration

distal or anterograde axonal degeneration


vs.

Short axon

Long axon

= chronic inactive lesions

secondaryneuronal loss


Therapeutic window 5

Asynchronous progressive MS hypothesis

Motor system to legs

Lower limb sensory

BladderTherapeutic window 1



Upper limb sensory

Upper limb motor

Cognition

Vision

Etc.





Therapeutic window 10, etc….

Diagnosis of clinically-apparent progressive MS

Effective DMTs could still target the remaining windows of therapeutic opportunity for individual neurological systems despite some systems have entered the clinically-apparent progressive phase of the disease

Cerebellar or balance systems

Natalizumab (Antibody that blocks white blood cells entering the CNS & Stops Attacks) in Progressive MS (ASCEND TRIAL)

Concentrating on Lower limb Function Led to a Failed Trial

25 foot Timed Walk

Mobility Scale

Hand Function

Goodkin et al. Ann Neurol. 1995;37:30-40.

✓✓

Oral Methotrexate (immunosuppressive Agents) Reduces the Rate of Progression

Assess Arm Function as Primary Outcome and you Could have had treatment years ago

Hand Function

Leg Function

XX

Hand Function

People with MS

Yes always 21%Yes frequently 51%Yes Infrequently 23%No 5%

Yes 2%Yes (active disease) 61%No 37%

Yes 49%Maybe 33%No 19%

UK MS Neurologists

Importance of Upper Limb Function in Advanced MS

NICE GUIDELINES SAY STOP

Why are these Poster Boards Blank?am I here at the Wrong Time?

Can’t Do it!, Can’t Do it, Can’t Do it

Powerful people resist change in the Status Quo

Views of a Prominent American Neurologist

No New Lesions

T1 MRI detects Damage (Black Holes)Gadolinium (white spots) New Lesions

T2 MRI detects lesions (white spots)New

EXAMPLE OF PERSON IN WHEELCHAIRRESPONDING TO A DMT (CLAD)

ASSESSED BY MRI

TRIALS (& FUTURE DRUGS) FOR PEOPLE IN WHEELCHAIRS

PHARMACEUTICAL-LEDSTUDIES

ACADEMIC-LEDSTUDIES

(CHARIOT TRIAL)

YES WE SHOULD

EXAMPLE OF PERSON IN WHEELCHAIR

#ThinkhandAwareness of Hand Function (Neurologists/Regulators)

Awareness People with Multiple SclerosisSelf Monitoring(To be eligible for drugs you need evidence of Deterioration)

9HPT + Gloved Hand = Sensation Issues9HPT + Weighted Hand = Mobility Issues9HPT + Eye Patch = Depth Perception issues 9HPT + 3D Glasses = Colour & Depth Perception

9HPT + alcohol = Motor-cerebellar co-ordination

ECTRIMS 2016(Neurologist Meeting)

MS-LIFE 2016

Meeting for pwMS

9HPT Plastic vs Cardboard

www.ms-res.orgrg

Recording Your Results

#Thinkhand

Awareness of Hand Function (Neurologists/Regulators)

9HPT + Alcohol = Motor-cerebellar co-ordination

Rugby Team

THANKS FOR LISTENING & PARTICIPATING

I suspect you have not had too many. Any Volunteers to test Students after Sports Day

Hockey Team

Spread HopeTo establish length dependency and therapeutic lag (time to effect) as a theoreticalconstruct to explain progressive MS and influence trial design

S is for Scientific:

P is for Political: To create a political lobby with stakeholders to push the #thinkhand agenda

R is for Regulator: To convince regulators that hand function is important to pwMS and that theyaccept it as a major outcome in progressive phase III trials.

A is for Awareness: To increase awareness of the MS community and public on the importance of handand arm function in pwMS.

HOPE

D is for Debunk: To debunk the dogma that once pwMS have lost lower limb function there is nothingthat can be done. Challenge the evidence that treatment should be stopped

E is for Economic: Show that loss of hand function is of greater economic impact to pwMS & Society.

SPREAD

To focus on hand function as a outcome measure in progressive MS trialsDevelop a new or more appropriate patient-related outcome measure (PROM)This should capture elements of hand function that are important to pwMS

H is for Hand:

O is for Optimism: To give Progressive pwMS hope. Because if you have progressive MS shouldnot mean that nothing can be done

P is for Promise: To truly deliver on funding to develop effective treatments for Progressive pwMSThis means designing, getting funded and doing trials in people with advanced MS.Get pharma to take up the challenge and revisit progressive MS

E is for EDSS: To get neurologists to remove their “EDSS blinkers” and to stop looking atdisability defined by EDSS. The EDSS is not fit for purpose.

Thanks for Listening

#ThinkHand

Prof mouse pint of neuroscience part ii

Entertainment & Humor

Transcript of Prof mouse pint of neuroscience part ii