Clinical Research in PD

Question 1

Issues in Preventing/Curing PD

Answer 1

1. Issues with trial design
   - lack of patient stratification
2. Ignoring heterogeneity of PD
3. Difficulties in measuring PD progression
   - few validated biomarkers
   - patient reported outcome
   - OFF medication measures

Question 2

Current Advanced Treatments for PD

Answer 2

1. Apomorphine pump
2. DBS
3. Duodopa intestinal gel
4. Produodopa
5. Focused ultrasound (tremor)

Question 3

Prodrome Non-Motor Symptoms

Answer 3

Olfactory loss
Constipation
Depression
REM sleep disorder

Question 4

Advanced PD Non-Motor Symptoms

Answer 4

Cognitive impairment
Dementia
Speech/swallowing issues
Hypersalivation
Falls
Dysautonomia

Question 5

Alpha Synuclein Pathology

Answer 5

• Too much ‘normal’ aSyn can cause familial PD
• aSyn pathology transmits from one neuron to the next, spreading throughout brain
• Spread of aSyn differs (brain first or body first)
• Exposure to toxins in gut may trigger enteroendocrine cell changes

Question 6

aSyn Seed Amplification Assay

Answer 6

Take lumbar puncture of CSF fluid
Add aSyn seeds to recombinant aSyn
Allow seeds to fragment and elongate
Pathological forms can then be detected

Sensitive to PD and DLB -> not detection in controls or AD

Positive assay in 87.7% of PD patients (PPMI)
- numbers differ between different forms of AD and different symptoms
- helps to understand relationship between aSyn and disease

Can be used without symptoms - helps to stage disease
Can define between different aSyn-opathies
Currently only used in research settings

Question 7

Use of SAA in Clinical Trials

Answer 7

1. Reduces heterogeneity
   - ensures only appropriate disease is included in trial
2. Increases confidence in prodromal cohorts
   - may allow earlier intervention

BUT binary result -> not useful for monitory disease progression or response to treatment

Question 8

Alpha Synuclein Aggregation

Answer 8

Target with:
- aSyn immunotherapy:
Cinpanemab binds to aSyn during transfer between neurons but no benefit to UDPRS
Current phase III prasinezumab trial
Give abnormal aSyn for body to make Abs against it

• Anle138b
  Disrupts H bonds between aggregates so they dissolve
• C-Abl inhibitors
  Used in chronic myeloid leukaemia
  Trials underway
• Probiotic, prebiotics, FMT
  Benefit in chronic c. diff
  Trials underway

Question 9

Lysosomal Dysfunction

Answer 9

Target with:

Lrrk2 inhibition
- LRRK2 variant shows different pathology (aSyn and tau)
- tau SAA in development

Ambroxol
- GCase chaperone
Boosting GCase may reduce aSyn

LTI-291
- GCase allosteric modulator

AAV-GCase Gene Therapy

Question 10

Mitochondrial Dysfunction

Answer 10

Target with:

UDCA (Terazosin)
- Licensed drug for liver disease
- a1-adrenergic receptor antagonist
- activates PGK1 to produce ATP

Question 11

Neuroinflammation

Answer 11

Target with:

NLRP3 Inflammasome inhibitors
- interfere with inflammatory cascade

Question 12

Measuring Efficacy

Answer 12

1. Target engagement
   - F-dopa PET
   - DAT scan (only sig. at 4 years)
   - Cholinergic/serotonergic/noradrenergic
   - Ideally want aSyn tracer
2. Predictors of clinically relevant endpoints
   - Digital wearables -> measures precise movements, detects small changes over time and dives more real world picture

Question 13

MAMS Trial Design

Answer 13

Multi-arm, multi-stage

• Tests multiple drugs simultaneously with only 1 placebo arm
• Stop drugs with no efficacy and replace with another

More flexible and efficient, fewer placebo, can respond to latest research