By Dr Graeme Bertuch OAM

TRIALS AND TRIBULATIONS!

Let’s take a look at some PRECLINICAL and CURRENT TRIALS of medication being offered to patients with ALS/MND to understand the thinking of researchers and in which direction they are heading.

ANTIRETROVIRAL

The first we will look at is treatment for ‘fossil’ genes, thought to be part of our genetic makeup for millions of years and introduced by retroviruses. A retrovirus is a single stranded RNA virus that invades the host cell and uses its own enzymes to introduce DNA into the host cell. Because this is the reverse of what usually happens it is prefixed with retro. HIV is a modern example of one of these invading retroviruses. These “fossils” called HERV’s [ Human Endogenous Retroviruses] were thought to be inactive, as it was thought that they had become defective or mutated over millions of years. They comprise up to 8% of the human genome. There is now evidence to suggest they are not inactive. HERV-K has been found in the brains of patients with ALS/MND and has been directly linked to motor neurone damage. This HERV gene can jump from one part of the genome to another and replicate itself. It ultimately causes disease by making abnormal proteins and then possibly triggering ALS/MND.

There is a study being done in Australia called the Lighthouse Project which is trialling an antiretroviral drug, Triumeq, to see if it can change the quality of life of patients affected by ALS/MND, looking at changes to respiratory and muscle function. Biomarkers are also being measured. The markers P75 and NfL [neurofilament- light chain] have been found to be higher in patients with ALS/MND than in normal controls. These will help to establish whether Triumeq has a positive effect.

IMMUNOTHERAPY

A trial of Interleukin-2, which is a form of immunotherapy, has been investigated in France and the UK in a study called MICROCALS. This treatment is usually used to treat cancer [metastatic melanoma and metastatic kidney cancer] by using the immune system. One particular immune cell called a Regulatory T Cell or Treg is thought to play a part in helping to protect nerve cells against damage. The drug Interleukin-2 can increase the levels of T cells in the blood and might be able to protect motor neurones in ALS/MND by reducing inflammation. In this trial lower doses were used, which were expected to alter aspects of the immune system without the side effects experienced by cancer treatment, and then to see if the progression of ALS/MND was altered. Biomarkers will be used to see if the inflammatory response in the nervous system is modified. The project will be completed in 2019.

COPPER THERAPY

Trials are underway in Melbourne and Sydney with the copper containing compound Cu-ATSM. This is a molecule which for many years has been used in imaging tissues, including the brain, which aren’t receiving sufficient oxygen [hypoxic tissues]. Scientists found that it had the ability to deliver copper safely to cells in the body and that copper could prevent the malformation of proteins known to cause neurodegenerative diseases such as ALS/MND. SOD1 protein mis-folding is one of the genetic related causes of ALS/MND. The compound Cu-ATSM was found to extend the life of genetically modified mice to a significant degree. Although mutant SOD1 related disease is only a small fraction of the total causes of ALS/MND in humans, mainly in the inherited disease, the trial will test the reaction in sporadic ALS/MND as there is some evidence to suggest Cu-ATSM will work in all cases.

ANTIOXIDANT

In May, the FDA, the organization that approves drugs for use in America, granted a licence for the drug known as Endaravone [trade name Radicava] for the treatment of ALS/MND. Initially developed as a drug to treat strokes, it has been re-invented for treatment of motor neurone disease. It is an antioxidant drug that works by mopping up “free radicals” in the body, in this instance from the mitochondria [powerhouses of the cell nucleus] in motor neurons. In some clinical trials, Endaravone had been found to slow the progression on ALS/MND, potentially helping people preserve function for longer. The drug is administered intravenously every day for 2 weeks before a two week break. This is repeated indefinitely. Initial studies on the drug did not show any significant benefit, but then a small group was examined within the study who appeared to gain some benefit. These people had ALS/MND for less than 2 years and their disease hadn’t progressed very much. This group represents about 7% of sufferers. The drug has currently not been registered for use in Australia.

ANTIEXCITATORY

Although not subject to any specific trials, Riluzole is included to represent an antiexcitatory/glutamic acid inhibitor. Riluzole is the only drug that can be prescribed in Australia for ALS/MND and has been

so since the1990’s. Riluzole has neuroprotective, anticonvulsant and sedative properties and acts by inhibiting the release of glutamic acid from the motor nerve endings thereby reducing overstimulation which leads eventually to death of the motor neuron. Riluzole [100mg daily] is reasonably safe and probably prolongs median survival by 2-3 months.

OTHER NOVEL DRUGS

Over the last few years other drugs have been trialled such as GM604, a peptide which appears to be a neurotrophic factor. Neurotrophic factors play a crucial role in the development of the nervous system and there have been studies of their potential for treatment of ALS/MND. They have been effective in keeping neurons in a dish alive and also in mouse models of neurodegenerative disease but not been demonstrably effective in clinical trials in humans.

PMX205 is a novel drug which blocks a key component of the nervous system involved in inflammation. The complement C5a is thought to speed up the death of motor neurones. PMX205 is an inhibitor of C5a and dampens down inflammation. Research at the University of Queensland has shown slowing of the disease progression in mice which helps the case to take PMX205 towards further clinical trials which are expected to start in late 2018.

Another Queensland initiative has found that a protein called EphA4 plays a role in delaying the repair of damaged neurones. Researchers are looking to develop an EphA4 inhibitor which could be effective in treating ALS/MND.

Lithium was also trialled in 2008 in Italy. Some studies showed a reduction in disease progression but this was not born out by larger studies in the UK and USA. However, a recent review of the studies has found that lithium can improve survival in a small subgroup of people with a gene that is found to enhance survival [UNC13A]. Having this gene increases the probability of one year survival from 40% to 70%. No influence was found in people with the C9orf72 gene.

Small studies in isolation can throw up misleading results and findings on drugs such as GM604, PMX205 and EphA4 need to be reproduced on a large scale over a significantly long time period to establish whether there are any beneficial effects and no significant side effects.

TRIBULATIONS - ARE MOST PUBLISHED RESEARCH FINDINGS FALSE?

Earlier this year Duncan Bayly [MND Vic Board Member living with MND] sent me an article first published in 2005 by J P A Ioannidis which stated that most published research findings are false. This article had caused Duncan some concern. The paper was based on the premise that most research articles do not reach formal statistical significance. “There is increasing concern that in modern research false findings may be in the majority of published research claims. It can be proven that most claimed research findings are false”. This question has significance for the MND “community” as a lot of research is being done giving much hope to the MND affected that treatment is attainable. Do we ask the research community about this hypothesis? If we do and they agree with the paper, then they would necessarily doubt the veracity of their own research. Apart from the statistical proof to support the leading statement, other reasons or corollaries were also advanced. I won’t mention all of them but some will ring a bell.

1. The smaller the studies conducted in a scientific field, the less likely the research findings are to be true.

2. The smaller the effect size, the less likely the research findings are to be true.

3. The greater the flexibility in the way the research is set up [designs, definitions, outcomes] the less likely the research findings are to be true.

4. The greater the financial and other interests and prejudices in the scientific field, the less likely the research findings are to be true.

5. The “hotter” a scientific field [with more teams involved] the less likely the research findings are to be true. This point may explain why we occasionally see major excitement followed rapidly by severe disappointments in fields that draw wide attention. This has certainly been noted in the MND field of research. With many teams working in the same field and with massive experimental data being produced, timing is the essence in beating competition. It must be said, however, that there seems to be international connectivity and sharing in the MND research community that could mitigate this corollary.

So has Duncan cause to be worried? I suppose only time will tell, but given that after intensive research in the last 30 years we are no closer to having a significant treatment despite great strides in identifying the genetic basis of MND: then it is right to ask the question.

This article was originally published in MND News: November/December 2017