Feeling quite Confused

[Hal]

I’ll be honest… I’m writing this post to reach out for clarity and hope. Having now bee on this journey for @ 4 years I’m at the stage where I’m beginning to wonder about the research process for ALS. The more I learn about the disease and the more I understand the trial protocols, the more I question whether significant changes need to be made. The fact that ALS affects everyone differently makes it hard not to question whether there are multiple reasons and causes for Motor Neurons to no longer function. Be it genectics, exposure to pesticide, brain trauma etc… the majority of trials recruit patients early on in the journey with a fast progression. Those that have had the disease for more than 2 years are somewhat pushed aside and left signing there bodies away for after Life research.

Yes, I realize one can occasionally enlist in an expanded access program but honestly I do not understand why patients with a slower progressing disease are not looked at separately with the understanding that maybe they have a completely different reason for Motor Neuron death. One that may be somewhat treatable. I was in the Courage trial and like other folks I ended connecting with after it was shut down actually felt it was helping…and maybe it was for those with certain causes. Just asking… maybe it’s time this disease is broken down by how it effects one and treated that way?

 

[Nikki J]

They are trying. We are seeing occasional trials targeted to people with certain biomarkers. Often gene mutations or variants but also inflammation. Also post hoc analysis looks for subgroups and sometimes a failed trial gets new life. As I have said many times before we need better biomarkers. Until frs is no longer the primary end point there isn’t a good place for slow progressing PALS. It is my absolute belief that drugs work better in less aggressive ALS. We need to be able to prove it. Qalsody experience supports that. Fast progressing variants either died slower or progressed slower. Less aggressive variant carriers stabilized and anecdotally some have improved ( anecdotally from their neurologist)

I have never qualified for a trial or gotten an EAP. Sometimes I am sad and feel it unfailr ( I have given many hours and much blood and csf to observational studies) but it is the way things are now. The researchers do know and are trying

 

[Hal]

Thanks as always Nikki for your thoughtful and intelligent response. The simple fact that you have not qualified for trials speaks to my concern on why it is either time for a change or time for a parallel approach. Again…many thanks .

 

[Buglaw]

Hal, I think everyone is on board and want to do that. We just don’t know enough about the disease yet to stratify people reliably. It’s not that researchers don’t want to do this, they simply have no way to do it right now.

 

[Hal]

Buglaw, thanks for the reply. Identifying those with a slower progression is pretty straightforward. I’m simply suggesting it might be beneficial to approach trials without blocking those that have had the disease for a bit of time. Perhaps a dual approach… or perhaps having a secondary control group that would provide direction outside of the actual study. Again, I was part of a “failed” study that seemed to be working well for a segment of the group… you would think additional analysis on that group would have been warranted versus simply shutting the trial down.

 

[Nikki J]

Post hoc analysis likely happened. You can’t change the study design half way through especially based on perceived benefits. It is really poor science and would introduce all kinds of error. The point of significance even rises every time you do an interim analysis. It increases your risk of your results being due to chance. It sounds crazy as whatever the results are they are whether you look at them or not but it is so. The statistician for Healey explained it in a webinar once. About a year ago I think if you want to search the Healey webinars
If they saw something in their analysis they would have done another targeted trial. Radicava, methylcobalamin, NP001 and Nurown all did this

 

[Hal]

Thanks Nikki…I’ll look at the Healey webinar. I’m not trying to be difficult…just saying that with all the variables associated with ALS and with the rather limited size of the trials that are conducted one could make a statistical argument that from a data point of view all the trials can be questioned. If even 3% of a trial group appears to be benefiting from a trial … well maybe that trial is actually addressing a limited variant of the disease. Add in the fact that most people 2-3 years into their journey are typically no longer eligible for trials and even more reasons for having the disease may be being ignore. As you said in your first response… more biomarkers are needed!

 

[Nikki J]

I don’t disagree that they may miss benefit to subgroups by the trial selection criteria. They have come a long way both in science and approach but have a distance to go yet. I can see the progress better probably because ALS has been part of my life forever.

Today at the MNDA symposium it was pointed out a couple of times that slow progression showed better response. The first was on a tofersen presentation though the data also indicated the early treatment group got more response. The second time was a presentation on a drug that was trialed in c9 ( not gene specific but c9 has biomarkers to show target engagement that SALS does not). It was a very small trial (15 total). All were felt to be slow progression ( though early) i think by chance the treatment group were somewhat faster ( frs drop by .5 a month) the placebo group was slower ( .3 drop monthly). They all got open label extension. Despite starting later the placebo group once they got treatment showed a bigger response in one of the biomarkers. The treatment phase was quite short though so there wasn’t a big delay.

 

[rao]

hlots of researchers have argued that als are a variety of different illnesses that simply has the same clinical outcome ie motor neurons degeneration , if you look at the end to end biochemical process you can see why this is the case tell as there is so much that could go wrong and depending what is failing the progression speed can differs. Imo is too complex to track down exact point of failure, I just hope they find a way to increase motor neurons regeneration overall so can be applied to everyone

 

[Hal]

Thanks for all the feedback…Nikki, you are a true resource but more importantly a truly good person. i think my overall point of view is simply very little advancement has been made in the world without curiosity and sincere questioning of the status quo. In talking to Drs that are considered experts in the field, I’ve often heard that they are not in control of how the trials are structured and who qualifies. I think it’s time to rock that boat a bit. Thanks again….