This article was originally posted on the Motor Neurone Disease Association research blog on January 15, 2019. Thank you to the author Dr. Nicholas Cole, Head of Research, as well as the Motor Neuron Disease Association for giving ALS Canada permission to re-post this content.


There has recently been a flood of news stories on the outcomes of the Australian Phase 1 clinical trial investigating Copper ATSM (CuATSM) which is a small man-made compound that can selectively deliver copper to cells. The results were first presented at our International Symposium in Glasgow back in December.

MND is a terrible disease and anyone affected by it is looking for good news. We really hope that CuATSM will provide a new treatment for MND that is going to have a positive effect on people’s disease progression.

However, CuATSM is not yet at a stage where a clinician can prescribe it as a treatment. Drug development is a long journey, where any drug has to pass important rigorous checks before approval as a medicine. This trial is an important ‘first’ in the drug development process.

The reported Phase 1 trial was only designed to test the safety and dosage of the compound CuATSM and the researchers have demonstrated that this drug is safe to consume. Historically, many promising drugs have failed at this stage, and so to get to this stage and pass is vital for its success and further development. The next and important stage is to perform the trial on a larger number of people and really see if it can alter the disease progression.

We have a duty to people with MND, their families and carers to be as accurate and factual on these stories as possible. We must be realistic and not over-interpret promising early data.

Although the data showed the average rate of decline of the ALSFRS-R (ALS Functional Rating Scale – revised) score is lower than observational control cohorts, is it right to claim a 70% slowing of disease from a small open label Phase 1 study, and can this be substantiated? To find this out we must take a deep dive into the details of the actual study and its data.

The Study

Firstly, the trial was a Phase 1 trial (see our clinical trials info sheet) which is primarily designed and performed to find a safe dose of medicine (monitoring side effects) and is not designed to determine efficacy (effectiveness against the disease). These trials normally only use a small number of participants.

The primary objective was to define a recommended dose for Phase 2, the dose that can be taken with minimum side effects. This is then the dosage, that can then be tested in a larger clinical trial, which will also look at effects on disease symptoms.

The study was an ‘open-label’ trial. Open-label means that everyone involved, including the participants, know that they were receiving the drug rather than being given a placebo. Whether a trial is open-label or ‘blind’ is a crucial consideration, the consensus being a double blind trial is more reliable when determining drug effectiveness. Double blind means that neither the participant nor clinician know whether the patient is receiving the trial drug or a placebo.

In the study, 32 participants (29 finished the trial) were split into five ‘dosage’ groups (with no more than seven participants in any one group) where each dosage group was given a different amount of CuATSM (either 3, 12, 36, 72 or 144mg/day) to determine the highest safe amount of the drug. Based on safety and pharmacokinetic (PK) data (to determine how the body handles the substance) the recommended dose was determined as 72 mg/day.

During the trial, each person was given an assessment of disease severity by ALSFRS-R score, breathing function by forced vital capacity (FVC), and cognitive function by Edinburgh Cognitive and Behavioural (ECAS) score. These were measured at the start (baseline) and after the first and sixth month of daily CuATSM treatment. Sniff nasal pressure (SNP) and the urinary p75 biomarker of disease progression was also measured but this data is not reported.

The reported data (ALSFRS-R and FVC) comes from the 72mg/day group.  Their averaged data was compared to a historical control group of 8,600 people with MND in the PRO-ACT database.

When compared to the historical cohort over a six-month period the results from the 72mg/day group showed:

  • improved lung function (+1.1 % predicted/month vs -2.24 % predicted/month for FVC)
  • improved cognitive ability (+10 points vs no changes* for ECAS score)
  • slowed rate of averaged disease progression (-0.29 points/month vs the expected -1.02 points/month on ALSFRS-R)

* Some improvements in cognitive function have been reported in control subjects in other studies. This may be related to participants becoming more familiar with the tests.

Taken at face value it is clear to see why the data looks and sounds promising. However, this was over a relatively short time period (most large-scale trials last for at least 12 months) with an open label study with very small number of participants. When a test is performed only in a small number of people you can sometimes get a result that is a little misleading.  Therefore, we must exercise optimistic caution in reading too much into the data at this point.

Reasons for caution in interpreting the results.

  • This was a trial with only a small number of participants. MND is a heterogeneous disease, meaning every person’s disease is different. Disease progression is non-linear and can slow, pause or even reverse for short periods in people with MND. The trial was performed for 24 weeks. It has been shown that, in control datasets from people with MND, over a six-month period, one quarter of all participants enrolled in a trial will show periods of slow or stopped decline in ALSFRS score even though they are not being given any active compound. If a few of these events occur in a trial with very small numbers of participants involved, the data can be severely affected in either direction. For example, if there is just one person whose progression has a natural (unrelated to the treatment) periods of slowing of progression, (e.g. they ‘appear’ stable on the drug) then in a small study there will not be enough other participants to smooth out this single datapoint.
  • The trial was ‘open label’, meaning the participants know they were taking the drug, opening the data to the very real but not really understood ‘placebo’ effect. The open label means that both the participant and the clinician, nurse, (person recording the ALSFRS or ECAS score) knows that the participant is taking the real drug, all of which changes their outlook and approach (consciously or otherwise).
  • Historical controls were used. This gives only an average, effectively ‘virtual’ person with MND to compare the experimental data with. We know from other clinical studies in the past, such as diaphragm pacing, that the use of historical control data can be highly misleading.
  • The attention-grabbing headline ‘the copper-delivery drug CuATSM slowed the progression of the disease in patients by 70 per cent’ is really overinterpretation and overstatement given the potential for progression variation with only a small number of participants in the group. Also, the points scale of the ALSFRS does not directly correspond to life expectancy. The figure comes from the difference in final ALSFRS-R score in the 72mg/day group compared to the historical controls used (-0.29 points/month vs the expected -1.02 points/month taken from the historical controls).

What next?

What is needed now is to test CuATSM in a follow up trial with a large number of people. The great news is that this is going to happen. Further work is needed and is planned in a randomized, placebo-controlled Phase 2 clinical trial of CuATSM. The Phase 2 trial begins later this year in Sydney and Melbourne.

We really hope that these results from this small dose-determining trial can be confirmed and that CuATSM will provide an effective treatment for MND.

It is positive to see such a clear example of how the money raised by charity supporters can effectively drive research to the point of a Phase 1 clinical trial for this compound which has been in development for some time. Everyone involved, (from the school child selling cupcakes, the walkers, swimmers, to the marathon runner, patients, families, supporters, nurses, clinicians and volunteers) should be congratulated on this achievement.

Please note: CuATSM is a specialised compound and is not the same as taking copper supplements, which can be poisonous in high doses.

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