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.
Read the original press release here
Click here to see the original abstract from our International Symposium on ALS/MND (CLT – 26)
Find out more on clinical trials and other topics discussed at the Symposium
ALS Untangled report #43: copper
Hi Nick,
Thanks for a really comprehensive and understandable review of where we are in the testing phase of this compound and the analysis of the data so far. Are you able to say anything more about the proposed mechanism of CuATSM in people with MND?
Hi Scott,
A great question. In short- no one really knows exactly, however a few points come to mind.
Firstly, CuATSM selectively delivers copper to hypoxic (under oxidative stress) cells. It is used as a radiopharmaceutical for the PET imaging of hypoxia (a paper from 2007 here).
https://www.ncbi.nlm.nih.gov/pubmed/17992274). Hypoxia and oxidative stress have been associated with in MND (Anand et al., 2013). The selective activity of CuATSM in MND was demonstrated in PET imaging study which compared 12 MND patients with 9 age-matched healthy controls. The data showed more accumulation of CuATSM in the motor cortex and right superior parietal lobule of the MND patients (Ikawa et al., 2015, Crouch, 2015). So even though the exact mechanisms is not known, it may be getting to where it is most required.
It may be that CuATSM is acting as a metal delivery agent, delivering metal (such as copper and zinc) to where it is needed. For example gene mutations in the first MND associated gene SOD1 have been shown to cause SOD1 to lose the metal ions it required for its normal function and to cause its misfolding. It is possible that CuATSM can therefore promote the stabilisation of the structure of important proteins required for normal processes.
Finally, Peter Crouch, (Associate Professor at Melbourne University) who has led most of the development of CuATSM for MND, talks really clearly about how understanding the precise mechanism of action once a medicine is in the brain and spinal cord of a person is so difficult in this radio interview (listen from 4 minutes in here)
https://omny.fm/shows/the-ray-hadley-morning-show/major-mnd-drug-development-associate-professor-pet
Long answer. I hope the above makes sense.
Again its too early to say if CuATSM will be an effective therapy for MND at this point. We hope it will be. CuATSM does the ‘right things’ in the lab dish and animal models, and it has just passed its first important toxicity milestone (Phase 1- to calculate safe dose without toxicity and side effects). We now all want it to show itself to be effective against the disease in the next important step- the Phase 2 trial.
Good write up. However, I do have one issue with your characterization of the need for placebo groups. The use of the PRO-ACT is much more humane and provides many more data points than a placebo group. It doesn’t merely create one “average” person. Instead, it creates an placebo group with more “participants”. This helps trials fill up faster because people don’t have the fear that they’ll be put in a group, told to stop doing whatever they’re trying to slow the disease, and continue to deteriorate. It’s inhumane, and unnecessary.
Hi Matt,
We completely understand the frustration over using placebo groups, however, this is currently the established way clinical trials for MND are ran. Clinicians across the world do recognise the obvious issue with this design and are working on reducing the need for placebo groups in every trial, which can for example be achieved by platform trials – find out more about this recent development in MND here.
Best Wishes,
Research Development Team
MND Association
Great article. Do you know what the results were in the other groups? Did they have improved lung function and decreased disease progression as well? Knowing this gives a much better idea if the results seemed promising.
Thank you for the question Sandra. Very please you appreciate the article- I hope it helps as many people as possible understand the situation. As far as I know from the available data presented in the poster and from what I can find, there was no measurable difference in the other groups.
My father having MND (progressive Bulbar Palsy) he wants to partcipate in Cu-atsm clinical trial. We are from I NDIA. We want to know how to participate, please send me the link.
Hi Ammulu
Thank you for your comment. You can find out more information about the CuATSM clinical trial here, together with contact details: https://clinicaltrials.gov/ct2/show/NCT02870634?term=copper+ATSM&cond=ALS&rank=1
Please be aware that this trial is being carried out in Australia and that your father may not be eligible to take part.
Kind regards
Mandy
Hii Nick,
Nice article,
My sister is also suffering from ALS and she wants to join phase 2 clinical trial so is it possible for her? And if yes than can you please guide us for that?
Hi Zarana,
Thank you for your comment.
The Phase 2/3 trial record on clinicaltrials.gov has recently been updated and so it is likely that they might start recruiting soon. However, we do not have the information as to when this might be or the location of this trial, which in the past was in Australia. You can find more about the trial here.
Best Wishes,
Research Development Team
MND Association
I see many ALS patients in South Africa. Would you consider them for participation in your trial?
Hi Marcelle,
Thank you for you comment.
We appreciate that there are many people with MND worldwide who are waiting for an opportunity to take part in a clinical trial and effective treatment.
As we are not part of this trial, we cannot advise you on whether people from South Africa would be considered for the trial.
You can find out more about the trial and the lead contacts here.
Best Wishes,
Research Development Team
MND Association
Hi Team…
It’s really seems to be the best news for the sufferers…. But still seems to be in probability than reality coz they say it’s treatment and not prescribed medicine.
When do we expect it to be on floor and get the benefits…. Have any Dr started with it or is there any patient improved.
Please provide the realistic data.
Hi Rajeev,
Unfortunately, we could only write about what was available.
At the moment, the researchers are planning to run a Phase 2/3 trial to see whether the treatment is effective in a larger number of patients. Once this trial is completed, we should have a better idea about its potential benefits.
Find out more about the trial here.
Best Wishes,
Research Development Team
MND Association
Hi it did say maybe the trial would take place in other countries and if so are the Australian scientist not in a larger link with other scientists from around the world?
Hi Sue,
Unfortunately, at this point in time, we are not sure where the trial will be conducted. Although we and other institutions around the world are in touch with the Australian scientists running this trial, the difficulties would mainly lie in the administrative set up of the trial. As mentioned in the article, we would of course be open to collaboration with the Australian scientists.
Best Wishes,
Research Development Team
MND Association
Hi, whats the difference between CuATSM and Copper supplements?
Hi Jimi,
The combination of copper with the ATSM chemical scaffold is important in the therapeutic activity of copper-ATSM. Regular copper supplements available from health food stores are not the same as copper-ATSM and they are not expected to have the same therapeutic activity, and may be toxic in high doses.
Best Wishes,
Research Development Team
MND Association