Detecting drug effects in ALS patients using electrophysiological biomarkers

Amyotrophic Lateral Sclerosis (ALS) is a devasting and fatal motor neuron
disease, affecting the upper and lower motor neurons. This results in
progressive loss of muscle function, which eventually leads to the loss of
respiratory muscle function and death. Approximately 500 people are diagnosed
with ALS each year in the Netherlands alone, and mean survival is three years
after onset of symptoms. The disease can unfold at any age, but most often
reveals itself in patients aged 50 to 75. Currently, patients are treated with
Riluzole, a drug expanding life by an average of three months. Though Riluzole
has been standard clinical practice for over two decades, its exact mechanism
of neuroprotective effects remains unclear.

Current efforts to significantly slow down ALS and prolong patient survival
have proven to be extremely difficult. Whilst only the most promising
preclinical drugs are advanced to clinical trials, only about 1% of these are
actually approved for use in clinical practice. A major challenge is the
translation from preclinical results (e.g., gained from cellular models and/or
animal experiments) to clinical results with patients. A key bottleneck is the
inability to verify target engagement in patients early, meaning that it is
often unclear whether the drug*s mechanism of action is different in patients
from that what was observed in preclinical models. As such, researchers have no
early determinants to assess if the target engagement is similar in patients.
This forces investigators to rely on expensive clinical trials of long
duration. Insensitive clinical endpoints, such as patient survival or
functional loss, further complicates the assessment of a drugs effect and
potential. New to this trial, we aim to investigate the feasibility of nerve
excitability testing as a biomarker to assist in the translation between
preclinical and clinical ALS medication development. Nerve excitability testing
is a technique related to the clinical EMG, that assesses the excitability
properties of axons of peripheral motor neurons. It is non-invasive and can be
performed both in pre-clinical and clinical setting.

A frequently observed preclinical phenomenon of ALS is the altered
excitability properties of central and peripheral motor neurons. Abnormal
peripheral excitability properties have been suggested to be a result of
altered ion channel functioning, including potassium and sodium channels. These
alterations in ion channel functioning have been linked to ALS progression rate
and survival, and can be mapped using nerve excitability testing. Explorative
research illustrates that ALS-medications such as Riluzole can alter the nerve
excitability properties in ALS patients, with significant results four weeks
after initiation of Riluzole. This study was however explorative. In this
study, we will therefore aim to develop a detailed protocol for assessing
ion-channel changes induced by Riluzole in ALS patients, using nerve
excitability testing. We aim to gather enough data to build a translational
tool capable of assisting researchers in search of a cure for ALS. In future
research, we could further obtain the available preclinical data of published
meta-results showing effects of Riluzole on motor neuron excitability,
integrating them into a translational preclinical-to-clinical framework. If
this proves successful, this model could assist in future drug development.

Main objective is to determine whether nerve excitability can detect
drug-induced effects of Riluzole in yet treatment- naïve patients with ALS.
Secondary objectives are to determine the correlation between the Riluzole
plasma concentration levels and motor nerve excitability indices, to assess the
effect of Riluzole use on neurofilament levels, to investigate their
relationships with the disease course in patients with ALS and to determine the
diagnostic value of nerve excitability and CMAP scan assessments.

Observational longitudinal design with 115 study subjects:
- 25 MND-suspected patients, without a definitive ALS diagnosis after their
diagnostic day
- 50 newly diagnosed ALS patients starting on Riluzole


Furthermore, we will examine 40 healthy controls in a mainly cross-sectional
setup, as reference to pathological changes.

The risks associated with study participation are very slim. Nerve excitability
testing and the CMAP scan have been used in previous METC-approved clinical
studies, using a total of hundreds of study subjects without any harmfull
complications. Some study subjects have experienced a slight local reddening of
the skin, which has always been temporary. Nearly all study subjects do not
find the scan painfull, but otherwise we can stop the measurements instantly.
Some patients even fall asleep during the test.

During the collection of blood samples (for patients with ALS in part 2), it is
possible to create a local hematoma. To minimise this chance, only experienced
and qualified hospital staff will collect these samples.

Clinical tests involved in this study, e.g. the assessment of lung capacity,
strength assessment of the hand, neurolocial clinical assessment and the ALS
questionnaire, are without any risks.

Whilst the risks associated with participation in this trial are very slim,
there is some burdens for patients, mostly in the additional visits associated
with participation. After diagnostic day, we aim to assess patients five
additional times. In order to minimise their hospital visits, we attempt to
coïncide as many visits with their regular hospital visits as possible. We
except that this is possible additional visits to the hospital can be reduced
to 2-3 visits.

There are no clear benefits for the individual patients associated with
participating in this study. However, if nerve-excitability proves to be
suitable in detecting drug effects in our patients, it could speed up the
development of future drugs. In such an instance, the ALS community will
benefit directly from the results of this study.