Clinical Research in Neuromuscular Disease

Question 1

Difficulties in Clinical Trials in NM Disease

Answer 1

• Incidence and prevalence is low, making it hard to recruit eligible patients
• Disease progression is often slow, so it takes a long time to see a treatment effect
• There is very little natural history data about how the disease progresses and what outcome measures to use
• Difficult to design and validate endpoints which meet regulatory requirements
• Lack of viable candidates in phase I/II studies to undergo further testing

Question 2

Positives of Clinical Trials in NM Diseases

Answer 2

• Knowledge of genetics is improving, and pathophysiology is better understood
• Increased number of potential disease-mitigating targets
• Improved preclinical discovery/development tools
• Greater diagnostic capacity for identification and stratification of subject
• Better infrastructure to support proof of concept trials

Question 3

Rarity of NM Disorders

Answer 3

It is difficult to design RCT with sufficient power

Orphan drug legislation provides an incentive to research rare diseases -> reduces fees, assists protocol, 10 year market exclusivity (to make profit for longer)
- disease needs to be rare and life-threatening or chronically debilitating

Question 4

Preclinical Studies

Answer 4

There is a failure of animal efficacy translating to humans and an inability to independently replicate the original preclinical data

Preclinical studies must be conducted with same rigour as RCT, there should be early communication between preclinical and clinical and the ultimate use of candidate drug established

Question 5

Clinical Trial Design

Answer 5

Should avoid RCTs in which proof-of-concept is weak or the molecular target is not fully understood

Learn from positive and negative trials

Aim to conduct exploratory trials before large phase III trials

Adaptive designs -> small dose-finding studies, then futility analyses, then efficacy analyses

Use Bayesian approaches to reduce required sample sizes and drug to placebo ratio

Question 6

Outcome Measures and Biomarkers

Answer 6

Strength testing - MMT, dynamometry
QST - sensation, pain, vibration thresholds
Pulmonary function
Physical function - IBMFRS< ALSFRS, HAQ
Mobility - 6MWD
Health related QOL
Muscle mass
Biomarkers which are demonstrated to respond to the intervention in the same way as the relevant clincial outcome

Question 7

MRI as a Biomarker of IBM

Answer 7

Water sensitive and fat sensitive MRI can be used to assess changes in the same patient over time

Can qualitatively and quantitatively assess the fat accumulation seen in muscles

Has validity as the more fat accumulation, the more disabled the patient and the more function the patient will lose over time = quantifies IBM progression

Question 8

Arimoclomol for IBM

Answer 8

Oral drug which upregulates the HSR and aids accumulation of abnormal proteins seen in IBM

Improvement of key pathological features in in vitro and in vivo data (but no true animal model of IBM)

Well tolerated and no toxicity in human trials but no clinical success