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2018 Research Update: Clinical Trials


25 July 2018


A summary of research from the 2018 Australasian MND Symposium.

This information will be of interest to neurologists and researchers with an interest in MND, and people affected by MND who have a strong interest in scientific research.

This update discusses some key global and Australian clinical trials in 2018, the current issues in clinical trial design, and new biomarkers being developed for better clinical trial results.

1. Global MND Clinical Trials

Overall, there are more new therapeutic approaches to MND than ever before, increasing the likeihood
that new therapies will soon be available that provide a meaningful impact on the lives of MND patients.

Multidisciplinary clinics (MDTs) are the biggest advance – patients in MDTs live on average a year longer.
However: Progress in ALS therapeutic development has been slow. Multiple failed trials between riluzole
and edaravone. People with MND have very few therapeutic disease-modifying options. Why is this?

  • high disease variability – MND is an infinitely complicated disorder
  • lack of relevant sporadic MND models
  • lack of human models
  • incomplete understanding of ALS triggers and cascade
  • experimental designs that are inefficient
  • insensitivity of outcome measures in clinical trials
  • clinical trial process begins well after system begins dysfunctioning

The clinical hetergeneity (variety) of MND means it is very easy to include people in trial control or drug
group that have different disease (genetic factors, environmental factors, progression rate and pattern) to
the others. If we ignore these design points in clinical trials we will come to the wrong conclusions. How can
we improve clinical trials for greater success?

  • better define target populations to get a more homogeneous group
  • find better biomarkers to measure the effectiveness of any treatment
  • improve patient selection
  • use markers of disease progression so trials are more sensitive
  • develop better endpoints (the measurements which indicate whether an intervention has been
    effective in a trial) related to disease progression
  • make clinical trials cheaper by reducing sample sizes by having patients self-measure daily
  • earlier diagnosis = earlier enrollment in clinical trials

Only 375 new patients diagnosed with ALS in Australia each year, but many clinical studies. Should probably
be thinking about sequential studies. And including New Zealanders!

Evidence-based medicine = include people with different genetic, environmental and progression courses
in one trial.

Precision-based medicine = stratification, screening (biomarkers), understanding disease mechanism,
individualised response to treatment – complementary to evidence-based medicine.

We urgently need biomarkers that reflect the underlying biology of MND, to guide more targeted clinical
trials. Biomarkers could stratify people into take the drug. However, in the patients who continued, there was preservation of vital capacity –
dropped about one-third slower on the drug.

Second generation version of tirasemtiv has been developed – CK-107. Increases force in muscles. Currently being testing in phase two study.

Stem cell studies

  • Brainstorm BCT-001-US (NurOwn) clinical trial, stem cell treatment injected into spinal fluid.
  • Had some difficulty with tolerability but no severe adverse events.
  • Data encouraging but tentative. At two weeks and 4 weeks reduction in slope of progression of
    ALSFRS. Neurotrophic factors increased in spinal fluid.
  • Promising; further clinical trial in progress.

Other studies

  • AMX0035 – looks at oxidative cell death of neurons. In a phase two trial.
  • Acetyl-L-Carnitine (ALC) important in mitochondrial function, shown to be protective against variety
    of insults. Met primary outcome in 2013, now others are trying to reproduce results.
  • Actermra
  • retigabine, mexiletine
  • mRNAs
  • tecfidera (immunoregulation)

Clinical Trials Design for ALS trials

Clinical trials should be a worldwide effort.

Progress in ALS therapeutic development has been slow. Multiple failed trials between riluzole and

Main barriers:

  • incomplete understanding of ALS triggers and cascade (insufficient animal models)
  • experimental designs that are inefficient and insensitive

Design issues we can change.

We can better define target populations to get a more homogeneous group.

We can find better biomarkers.

Prof Shefner describes some failed clinical studies (telempanel, cefriaxone, dexpramipexole) and
why they failed. “This is the depressing part of the presentation.”

Why aren’t our phase 2 studies predicting these poor phase 3 results? Prof Shefner thinks they are
predicting this.

“The big challenge is going from Phase 2 to Phase 3 trials” which can be addressed by improving
patient selection & using markers of disease progression so that our trials are more sensitive

To improve: develop better endpoints (the measurements which indicate whether an intervention
has been effective in a trial) related to disease progression for functional analysis in phase 2.

Patients measuring themselves every day give accurate results because of volume of
measurements, offer the chance of being able to significantly reduce sample sizes. Some potentially
useful endpoints are:

  • electrical impedance myography (painless, non-invasive test of tissue resistance in muscle);
  • hand held dynameter (measure force in muscles)

Combination therapy – The effect of edaravone is only known in conjunction with riluzole. If
edaravone was a pill, all new studies will be in combination of riluzole + edaravone. We have to add
an investigatory agent on top of a known therapy.

Staging system – shows how long patients spend in a particular stage and predicts how long until
they enter the next stage. This can also show when a treatment may be useful (eg riluzole). As an
outcome measure in clinical trials – need to move toward a more precise outcome measure. Just
four outcomes (the stages) risks losing outcome sensitivity. Timing to a particular stage could be an
outcome measure.

Cognitive measures – we increasingly recognise that cognitive change in an important and intrinsic
part of the disease in a sub-set of patients. ‘ECAS’ (Edinborough scale) includes behavioural and
cognitive component. Longitudinal studies show cognitive change increases as disease progresses
(up to 50% show some small affects by end of disease).

Why are people with PEGs so often excluded from clinical trial? If medicine if a pill it is for practical
reasons. It also gathers a more homogeneous population, to help demonstrate efficacy.


Modelling early phase pathogensis in MND
Prof Kevin Talbot
Head of Clinical Neurology, University of Oxford, UK

Kevin Talbot studies what's happening in the early stages of using neurons derived from stem cells,
modelling the disease in a dish.

When does ALS begin? Susceptibility based on genetic profile lasts decades. Unknown period of
time where system in a state of dysfunction but patient is compensating. Begin to see patients
when compensation is breaking down and symptoms beginning.

The clinical trial process therefore begins well after system begins dysfunctioning. This suggests
clinical trials are too late.

“MND is a loss of tolerance for cell mutations.”

Talbot’s research focussed on the earliest phases of ALS and FTD. “We know TDP-43 overexpression
is highly toxic.” It is a stress response reaction during times of cellular stress.

Other key molecular discovery is ALS/FTD connection. The most common mutation in ALS, the
repeat expansion in the chromosome C9orf72, explains 40% of ALS/FTD.

Making sense of big data
Prof Naomi Wray
Queensland Brain Institute, University of Queensland, Australia

Big data is important because of precision medicine initiatives – tailoring medicine to the individual.
Big data can help separate patients into groups.

Is big data overhyped? Results from machines are only as good as the data that go in. Need to
maximise the number of people in the data. “Every person counts”

Salsa Systems Genomics Consortium was awarded a grant after the Ice Bucket Challenge in 2015.
Now launched in sites all over Australia. Collects hundreds of biological samples in 3 labs working to
consistent protocols. Soon to start screening for known genetic mutations. About to launch
environmental questionnaire (linked to European studies and census data). This will build up
multiple layers of data for the same people.

It’s only if we have many risk factors to our genomic profile that we are at risk of disease.

When we understand more genes associated with MND, they can be correlated. This lead to last
year’s paper showing a correlation between MND and schizophrenia. You can also start mapping
which specific cells are involved in disease.

2. Australian Clinical Trials


Introducing the Fight MND Drug Screening Program
Associate Professor Brad Turner
Florey Institute of Neuroscience and Mental Health, Melbourne, Australia

Objective: Rapid drug screening for sporadic MND using stem cells from pwMND.
• $5 million programme funded by Victoria State Government, Fight MND and Balcon Group.
• Take skin biopsy from forearm, culture skin cells (fibroblasts), turn into iPS stem cells, reprogram
into motor neurons. End up with ‘MND in a dish’. Takes 3-4 months to create.
• Funded to collect 150 pw sporadic and familial MND and 30 healthy controls.
• Use robots, automation, a live cell microscope to test existing drug libraries and hopefully identify
drug hits.
• Just ordered first drug library: 4,500 prescription meds.
• By July 2018 will be into serious high throughput drug screening.
• Programme originally focused on Victoria, but people have flown interstate to be part of the
programme. Early onset disease is model patient because responds well in the petri dish.
• Patient recruitment is ongoing. Register at Fight MND website, click ‘drug screening platform’.


Phase 1 study of CuATSM in MND
Craig Rosenfeld, CEO, Collaborative Medicinal Development, USA

• The drug CuATSM delivers copper to motor neurons. Anterior horn of brain in pwMND is copper
deficient. CuATSM crosses the BBB in ALS patients.
• It extended lifespan in 4 out of 4 mouse models (SOD1). First time in 15 years that ALS-TDI
confirmed efficacy of an ALS treatment previously published by others.
• Objectives of clinical trial: evaluate safety and tolerability of single and repeated oral dosage.
Secondary objective to assess changes over 6 months. Open-label study (no placebo).
• Safety data collected for four dose levels, efficacy data collected for three dose levels.
• Mean decrease in ALSRFS of 4.7 points over 6 months.
• Disease stabilisation of 4 patients.
• Mean increase in ECAS (cognitive) scores of 8 points over 6 months (14 out of 15 showed
• 144mg cohort clinical trial is ongoing – recommended to be dose for phase 2.
• Phase 1 study should fully complete by end of 2018.


Phase 2 study of antiretroviral therapy, Triumeq, in MND – The Lighthouse Project
Professor Julian Gold, Sydney Medical School, Australia

Objective: Repurpose HIV antiretroviral drug Triumeq to see if useful for MND.
Hypothesis: HERV-K activation is a casual mechanism in ALS, and prevention of HERV-K expression using
antiretroviral drugs could be an effective treatment.
• The Lighthouse Project is a clinical trial to test whether MND is caused or triggered by human
endogenous retroviruses (HERVs). HERVs are mostly inactive in adults, but have affected humans
for all generations. 8% of our genome is composed of viral DNA that has been integrated into
mammal DNA over <40 million years.
• We know of 5 retroviruses that are infecting humans now. HIV is a retrovirus that took 40 million
• HERV-K is a human endogenous retrovirus associated with MND, incorporated into our DNA
100,000+ years ago. This gene virus can be upregulated and turned on. When turned on, it can
infect other cells. People with ALS have very statisitical significant increase in HERV-K.
• In 2016 USA National Institute of Health took proteins from HERV-K, injected it into mice, and the
mice developed ALS.
• Can antiretroviral drugs impact HERV replication? Developed for people with HIV, used for 15
years, turned HIV from a universally fatal disease to a manageable chronic illness. People who take
this medication are expected to live a normal life span. Can we re-purpose these drugs for MND?
Results: 40 patients from Sydney and Melbourne, 6 months of open-label treatment (no control group)
with Triumeq (combination of three antiretroviral drugs in once a day tablet, taken by around 250,000
people with HIV). Primary outcome achieved with Triumeq shown to be safe and well tolerated in patients
with ALS. No interactions with Riluzole. Some people ‘responders', others ‘non-responders'. Statistically
five people should have died over the time, but no one died during the study. The study will continue.
PK enhancement of retroviral therapy in HERV-K in ALS-FTD

Dr Ton Blunt
CEO, Izumi Biosciences, USA
• About half pwMND seem to have reverse transcriptase enzyme (retrovirus) in blood – 5 studies
replicate these findings.
• In 1980s some young HIV patients developed ALS. Partial, transient response to antiretroviral
• The blood-brain barrier (BBB) protects the central nervous system (CNS), only 2% of FDA approved
small molecule drugs cross the BBB. In MND, early stage blood/spinal cord barrier (BSCB)
breakdown/leakage could precede motor neuron death.
• Dose of drug into CNS like hose into swimming pool. Drain/pumps in back could drain pool in
seconds. ‘Pumps’ overexpressed in pwMND. In principal, if we block the ‘pumps’ we can keep drugs
in brain and spinal cord.
• The PK enhancer Elacridar maintains therapeutic drug levels in pump-protected ‘sanctuary’ parts of
brain. If combine PK enhancer with FDA approved drugs, you enhance therapeutic drug levels in
• Compounds that can normally only be given via IV, now become orally available.
• Suggest: Start with patients who have HERV-K in blood. Use PK-enhancer to drive ARVT drugs into
NB: This speaker was heavily criticised: ARVT already cross BBB and are able to suppress HIV in the brain
indefinitely if you continue to take them.


Phase 1b study of anti-CD14 (IC14) in MND
Prof Robert Henderson, Royal Brisbane & Women’s Hospital, University of Queensland
• Whatever causes MND results in misfolded proteins, which triggers an immune response, which
causes inflammation, which causes damage to functional cells. Cell stress leads to motor neuron
death leads to motor function loss.
• Inflammation and microglial activation is common in neurodegenerative diseases. In MND,
destructive microglial activation is accompanied by expression of pathogen-association molecular
patterns and multiple damage-associated molecular patterns.
• The drug IC14 is a master regulator of immune function and inflammatory response. Has an
extensive clinical history and good safety profile.
• Believe that immunotherapy has great promise for MND.
• People in this study were more than happy to have a lumbar puncture, which shows how keen
pwMND are to participate in research.
Results: All patients completed the study, will be complete by April 18. IC14 well tolerated, no adverse
events or withdrawals. Biomarker data may suggest modulated inflammatory response. Planning underway
for phase 3 study in rapidly progressing MND.

Phase 2 study of Tecfidera in ALS (TEALS)
Prof Steve Vucic
Western Clinical School, University of Sydney, Australia
• Reduced regulatory T cells (T-regs) in ALS patients are associated with a rapid disease prognosis.
Those with higher rates have slower rate of progression of MND.
• Tecfidera is safe and effective at increasing a person’s T-reg numbers. Has an antioxidant response
and anti-inflammatory response. Significantly improves responsiveness of T cells for
immunoregulation by T-regs.
• Tecfidera has been shown to reduce cortical hyperexcitability, modulate microglial activity
(inflammation) and has anti-oxidant effects.
Results: Has not yet started. TEALS study: will screen 150 pw sporadic ALS. Recruit 120. Will be largest
phase 2 study in Australia. Hopes to reduce ALSFRS scores by five points over 9 months. Should have
results by early 2019.

Phase 3: Clinical development of oral formulation of edaravone (TW001)
Inez de Greef-van der Sandt, CEO Treeway (Netherlands)

• TW001 is an oral form of Edaravone which aims to delay disease progression by targeting oxidative
• TW001 is designed to be a daily single dose that requires no drug holiday unlike the intravenous
delivery of Radicut and Radicava. An oral version will be more patient-friendly, can give every day in
a home setting. If can give it daily, efficacy may also be higher.
• TW001 has bioavailability of 70-80%. With continuous daily dosing, monthly exposure to drug is
2.8-fold increase over Radicava.
• Have done 4 x Phase 1 studies. Proven safe and tolerable.
Results: Upcoming phase 3 trial designed for Europe and Australia. 5th clinical study, 300 pwMND, 40 week
trial but continue dosing til 72 weeks. Hope to have drug product available by end of 2018.
Audience question: What isn’t Treeway dose-finding in current study? Because want phase 3 with highest
chance of success. Maybe afterward will test other dosing schemes.


Phase 2 study of cannabis based medicine extract (CBME) in ALS – EMERALD trial
Associate Professor Arman Sabat
Gold Coast University Hospital, Australia

Objective: Trial high CBD, low THC cannabidiol (CBD) in pwMND to study the efficacy extending ALS survival
and alleviating symptoms such as spasticity, pain, weight loss and assess quality of life.
• Animal MND models – review of 7 studies demonstrate cannabinoids significantly prolonged
survival time.
• Cannabis has over 400 complex compounds. THC is the most active compound producing
psychoactive effects. Next is CBD which is a protects against inflammation, oxidative stress and the
proposed mechanism of ALS – glutamate excitotoxicity.
• Our body has endocannabinoid system (ECS) found in all vertebrates. Two types of cannabinoid
receptors, CB1 and CB2. CB1 receptors are predominant in the brain, CB2 receptors are found in
the immune system.
Results: About to start at Gold Coast Hospital. 30 pwMND, 6-month trial. Using CannTrust CBD oil (1:17
THC:CBD) in capsule form. Efficacy is the primary objective. Secondary objective is to evaluate safety,
tolerability, effects on pain management.
Aidoence question: What do you tell patients who see clinical drug cannabis being tested, why not access
cannabis through other sources? Decision to be made by the patient. Tell them there’s really no data.
Studies are to start providing information for patients.
Recommended further reading: Current Therapeutic Cannabis Controver

3. Disease Biomarkers

Discovery and Use of Biomarkers for MND/ALS
Prof Robert Bowser
Barrow Neurological Institute, USA

• In 2005 early profile of cerebrospinal fluid looked for biomarkers for ALS – probably the first use of
these types of technologies.
• Oncology is always ahead of MND research, this approach had been used for cancer for a decade
• Now bio samples from well over 3000 subjects in different studies can be used to identify
• Neurofilament proteins are a known biomarker for MND – a prognostic marker too, that may help
predict survival. Levels are higher in people with familial C9orf72 ALS.
• Neurofilament protein-based tests are now being commercialised and used in clinical trials. Testing
will be available in the US this year, and is already available in Europe.
• We also need other types of biomarkers to reflect the different mechanisms of MND eg for neuroinflammation.
• He described biomarkers as a toolkit that will allow us to track biochemical changes in disease
progression, guide patient enrollment in clinical trials & monitor drug efficacy.
• Analysis of cerebrospinal fluid from people with fast and slow progressing MND found that the
groups had different levels of the biomarker chitinase.
• Biomarkers can be used to identify changes to specific cells types in MND, which could be used to
choose the patients who will best fit clinical trials. In future biomarkers will be used to define
patients that will best respond to a particular treatment.
• Artificial intelligence can now be used to find biomarkers, combine datasets and clinical
information to create a precision medicine approach.

The role of biomarkers in therapy development
Prof Michael Benatar
Chief of Neuromuscular Division and Exec Director of ALS Center, University of Miami, USA
• There is a plethora of candidate biomarkers. It’s important to develop only those that are fit for
• It’s important to establish the intended clinical use of any biomarker and conduct large
population studies similar to clinical trials. This is the next step for p75 and Neurofilament protein
biomarker development.
• For future development of biomarkers, need to have a heavy focus on what the potential future
application will be.
• There are four purposes for biomarkers: diagnostic, prognostic, predictive, pharamacodynamic.
1. Diagnostic biomarkers: Tests with high sensitivity are needed. We need to test the
biomarkers in populations where a diagnosis of MND is unknown. We really need to get people to a
neurologist as quickly as possible if MND is suspected.
2. Predictive biomarkers are mostly restricted to genetic markers so far. We urgently need
biomarkers that reflect the underlying biology of MND, to guide more targeted clinical trials.
3. Prognostic biomarkers need to add value to what we can already tell.
4. Pharmacodynamic biomarkers indicate a biological response to drugs or disease
progression. Need to fully understand what things look like without treatment, to truly see the
impact of a treatment.

Validation of urinary biomarker p75
Mary-Louise Rogers
Centre for Neuroscience, Flinders University, Australia
• Major barrier to successful clinical trial is the insensitivity of outcome measures. We need markers
to measure the effectiveness of any treatment.
• p75 is a neurotrophin receptor that is expressed following nerve injury. It has long been known to
be found in MND. Injured nerves shed p75, then it appears in urine.
• Urinary p75 is significantly higher in people with MND. It’s also easy to measure and not invasive
to collect.
• p75 is also raised in cerebrospinal fluid in people with MND and may also be raised in blood serum.
This shows that it must be present in the fluid that bathes the spinal cord as the motor neurons are
• Research then looked at whether levels of urinary p75 changed over time and therefore could mark
disease progression and prognosis.
• Urinary p75 levels did increase in each patient as disease progressed, as motor function declined.
There was a correlation between p75 and the ALSFRS (which is a more subjective measure
currently used to measure progression in clinical trials).
• p75 is also a predictor of survival: high baseline p75 is a predictor of worse survival.
• Now being used in some clinical trials. It’s an opportunity to get further validation of the use of p75
in clinical trials.

Whole blood transcriptome analyses
Wouter van Rheenan
Department of Neurology, University Medical Centre Utrecht, Netherlands
• The search for a diagnostic and predictive biomarker in the Netherlands.
• Blood is drawn at first visit (pre-diagnosis). They looked at the genes that were deferentially
expressed in people with MND compared to healthy controls.
• More work needs to be done to make sure results are more specific for MND. They are uploading
their data to make it available to other researchers around the world.
• (It’s great to see this sharing of data and IP to advance research into MND!)

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