Clinical Trials

Dedicated to funding promising new therapies in clinical trials for Australians living with MND

Click on the tabs below to read about current and upcoming FightMND funded clinical trials

Copper ATSMThe first Phase 1 clinical trial of Copper-ATSM as a potential treatment option for Motor Neurone Disease (MND) will start in 2016. Cu-ATSM therapy was developed in Melbourne Australia, and the trial is a true example of Australian scientific ingenuity and innovation, and demonstrates the calibre of MND researchers we have in this Country. To bring this trial to Australia, we are proud to partner with a USA company called Collaborative Medicinal Development (CMD). We are very excited by the basic scientific work and the pre-clinical trials and data that have lead to this first-in-man clinical study in Australia.

An overview of the research that has been performed to date, the rationale for why this compound may be an effective treatment, and the status of the clinical trial is briefly summarized below.

A brief history of the research

The drug is copper-ATSM. Its chemical name is diacetylbis (4-methylthiosemicarbazonato) copper but is often abbreviated to Cu-ATSM or Cu(II)ATSM. In 2005, Anthony White, Kevin Barnham and Paul Donnelly at the University of Melbourne first began discussing the potential to treat neurodegenerative disease by using Cu-ATSM.

Skipping forward to 2008 was the first time Cu-ATSM was given to specifically bred mice that develop symptoms that mimic human MND. About 10% of all MND cases are familial, which means the disease-causing genes can be passed on from parent to child. Mutations in one of these particular genes affects superoxide dismutase-1 (SOD1) which accounts for a large proportion of familial or inherited MND. The mice most commonly used to study MND in the laboratory that develop MND-like symptoms are genetically engineered to carry this mutation, and hence until recently were our best means of testing potential therapeutics.

Although the first study to test Cu-ATSM in mutant SOD1 mice took many months to complete, the outcomes were very clear: treating with Cu-ATSM protected motor neurones in the spinal cord, improved the animal’s MND-like symptoms, and extended lifespan of the mice. These outcomes were published in 2010 and heralded the beginning of an expanded research effort designed to answer one important question: what is the full therapeutic potential for Cu-ATSM as a treatment for MND?

Subsequent research revealed more provocative and exciting observations for the MND scientific community including:

  1. Cu-ATSM is MORE effective in mutant SOD1 mice than riluzole (the only currently approved treatment for MND that is available to MND patients. Riluzole is known to potentially increase survival or time to needing a ventilator by only 3 months))

  2. The benefits of Cu-ATSM in the mutant SOD1 mice are evident even when the treatment starts after the mice have developed overt MND-like symptoms. This means that it can potentially be started at any point in the MND patient’s illness and still have a beneficial effect.

  3. Cu-ATSM is effective when administered orally. This is very important as it means ease of administration and no need for IV infusions or injection of the drug into the spinal fluid.

  4. In a recent follow-up paper in another mouse model, the benefit of Cu-ATSM was especially compelling (http://www.alzforum.org/news/research-news/copper-rescue-als-mice )

Can Cu-ATSM treat the majority of people with MND who don’t have a SOD1 mutation (sporadic MND)?

Unfortunately, there is no perfect animal model for sporadic MND. However, in 2015 Peter Crouch and colleagues at the University of Melbourne and the Florey Institute of Neuroscience presented studies performed on MND-affected tissues obtained from people who died because of sporadic MND. These studies showed important similarities to mice that responded to Cu-ATSM and suggests that Cu-ATSM may have activity in both sporadic and familial MND.

Moving from the laboratory into the clinic

Despite some interesting challenges, the experimental Cu-ATSM molecule has now been developed into a pharmaceutical suitable for human administration. The clinical trial is now recruiting patients and further details can be found by clicking on this link https://clinicaltrials.gov/ct2/show/NCT02870634

Please note: FightMND plays no part in determining eligibility criteria of the trials it funds. Please consult with your MND specialist to assess your suitability for trial inclusion.

Lighthouse TrialThe “Lighthouse Trial” is  Phase 2 pilot clinical trial of combination oral anti-retroviral therapy  as a potential treatment option for Motor Neurone Disease (MND) and will start in 2016. Excitement about the possibility of this targeted therapy has grown in recent times due to sound scientific evidence discovery, and recent pre-clinical animal studies.

An overview of the research that has been performed to date, the rationale for why this compound may be an effective treatment, and the status of the clinical trial is briefly summarized below.

A brief history of the research

Despite decades of research, the cause and treatment of MND remains unknown. One of the most interesting theories is that MND may be caused or triggered by a human endogenous retrovirus (HERVs). These viruses infected animals and humans during millions of years of evolution and over time they became part of our genetic makeup (genes). Approximately 8% of human genes have retroviral origins. These HERVs were only discovered around 20 years ago and it is still unknown exactly how they may be related to causing human diseases. However, there is very good evidence that in animals these viruses are associated with a number of neurological conditions. Some preliminary research suggests that one particular retrovirus called HERV K may be linked to MND.

Reviews by Alfahad and Nath (Alfahad T, Nath A. Retroviruses and amyotrophic lateral sclerosis. Antiviral Res. 2013;99(2):180-187) have documented the extensive research on reverse transcriptase activity in MND.

In 2014, Al-Chalabi and colleagues from King’s College described the epidemiology of ALS in terms of a six step cascade of disease progression. They suggested this may be consistent with a sequential triggering process that could be associated with a (retro)viral pathogen.

In early 2016 scientists at the NIH showed that brain samples from MND patients had higher than normal levels of messenger RNA (mRNA) encoded by genes of the human endogenous retrovirus K (HERV-K). A protein encoded by a critical HERV-K gene, called env, was found in brain samples from MND patients but not from healthy individuals. They also showed that activation of HERV-K genes killed healthy human neurons grown in petri dishes. To test the role of HERVs in MND, the scientists genetically modified mice so that their neurons activated the HERV-K env gene. The mice died earlier than normal and had problems with balance and walking that progressively worsened with age, showing similar symptoms to human MND. When the scientists inspected the brains, spinal cords and muscles of these mice they found that only motor neurons, the cells that control movements and die in MND, were damaged. Cells in other parts of the nervous system remained healthy. (Click here for the full article)

Moving from the laboratory into the clinic

This will be the first clinical trial in the world conducted with modern combination anti-retroviral therapy to ameliorate disease progression in patients with MND/ALS.

The study is currently recruiting patients. Clinical trials sites are in Sydney and Melbourne. Detailed inclusion criteria and further information about this trial is available by clicking on the following link https://clinicaltrials.gov/ct2/show/NCT02868580

Please note: FightMND plays no part in determining eligibility criteria of the trials it funds. Please consult with your MND specialist to assess your suitability for trial inclusion.

Tecfidera in ALS (TEALS) study

The “Tecfidera in ALS” (TEALS) study will be the largest Australian-run clinical trial in MND/ALS.

The study is a Randomized Double-Blind Placebo-Controlled Phase II Trial which will test the safety, tolerability and efficacy of the drug Tecfidera in up to 150 MND patients. The trial is being headed by Professor Steve Vucic and Professor Matthew Kiernan at the University of Sydney.

Why Tecfidera may help MND patients

The term neuroinflammation describes the triggering of the immune system within the central nervous system (brain and spinal cord). Neuroinflammation is considered to play a very important role in how fast a person with MND’s disease progresses. While some immune cells are considered harmful and contribute to the death of the motor neurons, other immune cells, such as the T-regulatory cells (Tregs), are thought to be protective and may help slow the disease down.

The evidence for this includes:

  • In MND patients, lower Treg numbers have been linked to a faster progression of disease.
  • In MND patients, higher Treg numbers have been linked to a slower progression of disease.
  • MND mice that were given drugs to increase Treg numbers had a slower progressing disease and lived longer than MND mice who didn’t receive treatment.

Tecfidera

The drug, Tecfidera, is a clinically approved drug that is used to treat relapsing multiple sclerosis (MS). It works by reducing neuroinflammation and importantly, Tecfidera has been shown to increase the levels of Tregs in humans. Researchers hope that by administering Tecfidera to MND patients, they will be able to increase the levels of the protective Tregs and slow down the progression of disease.

Moving from the laboratory into the clinic

This will be the first clinical trial in the world to test Tecfidera in patients with MND/ALS. The trial is expected to begin in late Feb 2018 will be run at 6 trial sites across Australia:

Tecfidera trial sites

  • Brain and Mind Centre, Sydney
  • Westmead MND Clinic, Sydney
  • Calvary Health Care Bethlehem, Melbourne
  • Royal Brisbane & Women’s Hospital, Brisbane
  • Flinders Medical Centre, Adelaide
  • Fiona Stanley Hospital, Perth.

For full details on the study protocol visit – https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12618000534280

For more information about this trial and to assess your suitability, please consult with your MND specialists. Please note: FightMND plays no part in determining eligibility criteria of the trials it funds.

 Studies on Tregs in MND/ALS

  1. Henkel JS et al., (2013) Regulatory T-lymphocytes mediate amyotrophic lateral sclerosis progression and survival. EMBO Mol Med. 2013 Jan;5(1):64-79
  2. Beers DR et el., (2010) Endogenous regulatory T lymphocytes ameliorate amyotrophic lateral sclerosis in mice and correlate with disease progression in patients with amyotrophic lateral sclerosis. Brain. 2011 May;134(Pt 5):1293-314
  3. Sheean RK et al., (2018) Association of Regulatory T-Cell Expansion With Progression of Amyotrophic Lateral Sclerosis: A Study of Humans and a Transgenic Mouse Model. JAMA Neurol. Published online March 5 doi:10.1001/jamaneurol.2018.0035

Phase 1b Trial of IC14

The Phase 1b clinical trial of IC14 as a potential treatment option for Motor Neurone Disease (MND) began in 2017. The trial is a small study being run at the Royal Brisbane and Women’s Hospital that will assess the safety and tolerability of the drug IC14 in 10 MND patients. The IC14 trial is supported by FightMND in partnership with Implicit Bioscience.

The role of inflammation in MND

Although MND is a disease that specifically effects the motor neurones in the brain and spinal cord, immune cells are thought to play a role in the rate in which the disease progresses. A type of immune cells, called “microglia”, act as a surveillance system in the central nervous system, restoring injured cells in response to stress or short-term injury and clearing away cellular debris. In this regard, microglia are beneficial and protective towards motor neurones. However, in response to ongoing stress, such as the cellular stress in motor neurones in MND, microglia become activated and can become harmful. In MND patients and animal models of MND, large increases in the numbers of activated microglia can be seen, especially around motor neurones in the areas of the brain (motor cortex) and spinal cord that are most affected in the disease, suggesting that these cells are contributing to the disease and the loss of motor neurones. Microglia also interact T cells, the immune cells from the periphery and trigger protective or harmful response from these cells, depending on their activation state. Research in MND cell and animal models has shown that therapies that target microglia to dampen their activation response can slow disease progression. Therefor treatments that target these immune cells may also help slow disease in MND patients.

 

Why IC14 may help people with MND

The breakdown of motor neurones by microglia is controlled by a number of different molecules interacting together. In the centre of these molecules is CD14, a master regulator of immune cell activation that has been implicated in inflammation of brain cells that are important in MND. IC14 is a type of drug called an “immunotherapeutic monoclonal antibody” which acts to blocks a target molecule. IC14 targets and blocks CD14, which may reduce the activation of microglia and keep peripheral immune cells in the protective state.

IC14 has been tested in patients with a number of other diseases and so has a good safety profile and an established manufacturing system. The emphasis of this study is to determine the safety of administering IC14 in MND patients.

Phase 1b trial of IC14

The trial has been successfully conducted in 10 MND with the following demographics.

MND
Gender (male:female) 7:3
Mean age (years) 55.1 ± 10.47

While the trial outcome is still being assessed, IC14 appears to be safe and the information generated from this trial will likely be used to design a follow-on study to measure therapeutic activity.

Further details can be found by clicking on this link https://clinicaltrials.gov/ct2/show/NCT03487263

References

  1. Boillée S et al., (2006) Onset and Progression in Inherited ALS Determined by Motor Neurons and Microglia. Science. Jun 2;312(5778):1389-92.
  2. McCombe PA & Henderson RD (2011) The Role of immune and inflammatory mechanisms in ALS. Curr Mol Med. Apr;11(3):246-54.

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FightMND is the largest independent financial supporter of MND research and clinical trials in Australia

We fund the best and brightest MND researchers across Australia to help develop promising new therapies in the lab to the roll into clinical trials for Australians living with MND.

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