Hi @Mateo335, you have made a very telling statement that many of our ‘new’ visitors here on HC seemed to have overlooked. You state ... “It would have been a hectic 4-5 days at ATH HQ trying to sort and present all the endpoints”. This is so true, but not appreciated by some here.
I think I have mentioned before that this trial is very ambitious ... not just in the fact that it is tackling such a challenging condition, but in the fact that they ‘bravely’ entertained such a wide range of endpoints. To me it showed a high level of confidence, and fortunately this has been justified by these wonderful results.
I seriously cannot understand some of the ‘knockers’ and ‘nit-pickers’ that have suddenly appeared on these threads. They either can’t recognise a successful trial, or they have other motives altogether. I am starting to suspect the later.
Unfortunately, I am already spending too much time here on HC, so I will be stepping back as soon as I can, but I thought I would share a few thoughts on our recent data release, before I disappear again.
Personally, I am surprised that several ‘punters’ were shocked by the ‘apparent’ differences in the UMSARS-1 baseline points between placebo vs 50mg vs 75mg. Seriously?
434-201 was a randomised, double blind, placebo-controlled trial of seriously ill, mainly elderly patients. The entry inclusion/exclusions certainly had some scope for differences in the entry baseline data, and considering the small data set, we should not be that surprised. I suggest that our ‘visitors’ do some simple research around how a randomised, double blind, placebo-controlled trial is conducted so they may gain a better understanding. I would also suggest that some patients, desperate to gain entry to a trial that offers hope, where there was none before, may ‘fudge’ a little, just to increase their chance of selection. There would have been no two patients anywhere near identical, either in disease severity, number or range of symptoms, iron readouts, time into the disease, etc, etc.
What these punters should be focusing on is the disease trajectory over the 26 and 52 months going forward. The placebo showed steady decline at the rate expected (noted from previous studies) while the low dose (50mg) separated clearly from placebo by 52 weeks. What more do you want? Yes, I agree, it’s a small sample ... but clearly with significant p-values.
As Stamler has stated ... “UMSARS is the most important clinical endpoint that will be used to support approval” ... and as I have mentioned before, this will be what the FDA want to see.
The data that stood out for David Stamler was this, the Clinical Global Impression of Severity (ie. the big picture) 50mg mean change -0.81, therefore p=0.009 !!!!
The wearable sensors data was also impressive and showed increases in step count, bouts of walking, total time walked and standing time. This is not a personal observation, but taken from these innovative monitors. Clear results and very, very positive.
Any neurologist will tell you that this science is at the cutting edge. ATH’s work around ‘proving’ changes in brain volume and brain iron levels needs a very technical analysis. Team ATH (including Vanderbilt), have actually demonstrated target engagement, with either reduction or stablisation of iron content, particularly in the low dose (50mg), in the putamen and pallidum areas of the brain. The putamen sits at the ‘outer reaches’ of the basal ganglia and shares major connections with the globus pallidus and the substantia nigra. This is an area of great interest in Parkinson’s disease(PD). Daugherty & Raz (2015) found ... In middle-aged and older adults, iron accumulation in the putamen precedes shrinkage (so) ... regional brain iron content may be a promising biomarker of impending structural decline in the aging brain. ATH agrees of course, and has shown target engagement.
Obviously, there is still more to unpack in this important study, along with a pharmacokinetics analysis, which we should see in the following months. Daniel Claassen has already flagged an interest in the role of neuromelanin and oxidative stress in the substantia nigra, so we may also hear more about this also.
David Stamler is interested in the unpacking of what he calls the ‘earlier group’ of this already early group study. He may suspect that if we hit this disease even earlier with ATH 434, we will see even more impact, and that suffers will gain greater benefits. Fingers and toes crossed for these people.
I am also very encouraged to see the enthusiasm of Daniel Claassen, a leader in the field and a clinician himself, when he shares the feedback of other clinicians. I believe that this will be a highly sort after treatment and one that will have little trouble attracting a quality partner.
As I have already stated this is an ambitious study that may well be ‘game changing’. In the words of David Stamler ... “a striking result”. I have to agree. Please do your own research, get across this amazing science, and try to avoid the ‘shade throwers’. I believe this is the ‘real deal’. Exciting times.
As always, just the opinion of one poster.
(20min delay)