Clinical Trial Therapies

KevinM

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Hi everyone. I was looking at the ongoing and soon-to-begin clinical trials, and was certainly impressed by the number of proposed treatments being evaluated.

I was wondering if anyone here with a much deeper knowledge of biochemistry and who may have done a much more in-depth evaluation of the various treatments and early test results has an opinion on whether any therapy to treat sporadic ALS stands out to you as holding more promise. There seems to be several very exciting therapies moving forward for familial ALS, but sporadic ALS appears to be a much more challenging nut to crack in many ways.

I am not asking this so that I can rush to enroll, though I understand the argument that participating an any trial helps further research whether or not the treatment proves effective. I’m just looking for any reason to feel mildly optimistic.

We all know about AMX0035, CuATSM, and NurOwn, but there are so many other trials that I get lost trying to evaluate their potential. I’m very aware that early results can be misleading and most will fail on either safety, efficacy, or both, but I’d love to hear anyone’s thoughts. Thanks, Kevin
 

Nikki J

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There are 5 drugs currently in phase 3 I think including one of the platform trial drugs. Anything that made it to phase 3 has some decent amount of hope.

generally I think trials are more promising because we understand the pathophysiology better even in SALS. Not everyone is going to benefit from the same therapy though. Some target inflammation and not all PALS have that as a major factor for example. Biomarkers are going to make for better trials. I think having frs as a primary endpoint is going to be outmoded soon fortunately

genetic research can help SALS too. right now there is an aso designed to work on ATXN2 that is believed to help SALS potentially. There is a c9 trial in the works to target TDP-43 a factor in c9 ALS that is also found in many SALS.

however the way answers get found is if people who are able step up for trials and observational studies. Observational studies are key to biomarkers. I am in one study at mgh where they think they have identified a biomarker that could cut a trial for an inflammation targeting drug from 6 months / 200 participants to 8 weeks/ 30 participants
 

KevinM

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Very helpful. Thanks Nikki.
 

Ed340hp

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If you are contemplating entering a trial, first understand most trials have a 24 month cutoff from diagnosis to qualify. If March 2019 is your diagnosis, you may only have the next few months to enter a trial.

If you have a choice of trials, decide if you want to test biochemistry treatments (drug/supplement compounds) or genetic treatments (CRISPR, for Familar ALS, etc.). Your Neurologist should be able to help decide what may help the most (for you, and for research).

Five years ago treatment research was more focused on a single (patent potential) compound or peptide to improve cell life or mitochondria function. Now it is fairly accepted a cocktail of compounds will be needed to improve function or to suppress what triggers neuron death.

In the long term, as trials come and go, you may want to read up on what supplements are common to slow progression PALS. Only a very few research studues look at slow progressing PALS to identify what may work to slow progression (a big hole missing in ALS research). One 2018 study to download and read is: https://www.tandfonline.com/doi/full/10.1080/21678421.2018.1457059

The odds of taking curcumin, luteolin, cannabidiol, azathioprine, copper, glutathione, vitamin D, and fish oil were higher for cases than for controls. It is possible that a reporting or selection bias existed for cannabidiol in controls, as substance misuse would have excluded participants from at least some of the trials included in PRO-ACT. Associations do not prove causation. However, the eight therapies identified here are particularly interesting because they have plausible mechanisms by which they could influence ALS. For example, luteolin, glutathione, and vitamin D attenuate oxidative stress and fish oil, cannabidiol, and azathioprine reduce inflammation (17–22). Additionally, each therapy identified here was temporally associated with at least two reversals. These therapies should be further evaluated in prospective studies.

More recent anecdotal research adds TUDCA as a potential supplement therapy, because it and curcumin enhance liver and kidney function (that may be needed to allow cell division waste and inflamation that is toxic to neurons to be removed). Copper is included because it is needed for the body to make it's own CuASTM (and depleted copper values in blood work is common in PALS).

Money drives research, both to conduct research and the payback goal of a marketable treatment with a patent. Supplements do not have patent potential, so most past research ignored their use in trials cocktails (and AMX0035 success will hopefully change that mindset).

Trial choices that welcome supplement use with a compound designed to trigger neuron health or suppress neuron death would be high on my list of candidates (IMO, if I were not already disqualified for living well past five years from diagnosis).
 

lgelb

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To clarify for those not aware, TUDCA is one of two ingredients in AMX0035, the other being sodium phenylbutyrate to improve uptake of TUDCA.

As for supplements, new formulae are certainly patentable and this happens often. The supplement market is huge and largely unregulated. In addition, several compounds beyond AMX0035 have been formulated into new prescription-only compounds by large pharmaceutical manufacturers. If anything, it's the dismal record of rx trials, exacerbated by the limitations of the ALSFRS, that has fueled interest in repurposing, mixing and matching supplements in ALS. However, there is a lot of quackery involved, e.g. "ALS" or "neurodegenerative disease" combinations that are helpful only to the manufacturer's bank account.

I would also caution anyone, as always, against taking a handful of everything listed in the linked article. Interactions, the energy it takes to metabolize supplements], and side effects are all real.

In addition, association is not causation, e.g. low copper may be a reflection of low or high something else (it competes with zinc, remember, and iron and magnesium also play roles), or a medical condition that is not ALS. So if you supplement copper individually, you could throw other minerals/conditions out of balance if they were normal to begin with. In addition, some studies associate high copper levels with cardiovascular disease and/or dementia, though again chickens and eggs are hard to come by, and research is ongoing.

Some people say "anything is worth trying in ALS." The harms, including death, that even healthy people have experienced from ill-advised dosing argues against that.

Best,
Laurie
 

Nikki J

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To address the issue of supplement exclusions in trial criteria I believe any reputable trial will exclude a drug / supplement that is being studied in another trial. This currently includes TUDCA and theracurmin and other formulations of it. This is good science as it could skew results if it happened that one of those is truly effective and a disproportionate number in either the drug or placebo group took it. The other reason for exclusion would be if a substance interacted poorly with the study drug and was a safety concern.

Drs Paganoni and Cudkowicz explained this during one of their platform trial webinars
 

Ed340hp

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Always consult your GP and Neurologist Doctors before starting with any treatment or supplement, and any clinical trial.

A trial participant's existing supplement, diet, or exercise protocol should not alter the ability to identify a stattistical or significant change in the slope of progression with an effective treatment compound (no different than existing Riluzole treatment).

ALS Trials will always suffer from a lack of a consistent control group, due to progression differences between individual PALS. One of the ALS trial challenges is that a 24 month window from diagnosis does not always allow enough observation time to generate a pretrial progression rate curve for a prospective participant. Most PALS spend their first year from diagnosis in a haze of stress related shock and hypercritical self-evaluation of progression, conditions that prevent identifying an accurate progression rate baseline (and pretrial progression rate curves are seldom, if ever, generated).

The ALSFRS score is severely lacking resolution during early progression, and clinical trial participants and monitors do not have progression rate baselines to compare against to expose an accurate gauge of effectiveness for a newly introduced treatment compound. Trial success and failure is currently left up to a random chance that the participants pool is populated with slow or fast progression PALS. With so much chance already inherent between PALS' progression rates, poor ALSFRS resolution, and no demand for pretrial PALS' progression rate baselines, the trial protocols will never enjoy effective controls to gauge efficacy. Current trial protocol and controls will continue to promote GIGO, until a consistant PALS biomarker is identified (or if by chance a magic bullet cure is identified and trialed).

Recognizng the current random chance state of trial protocols and controls, discuss prospective trials with attention and consideration of your existing diet, blood indicators, supplements, exercise, and progression rate, to guide what trial is best for you (and best for the desired research endpoint).
 

EricInLA

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Y'all are dishing lots of good information here. I understand most of it. Currently I take Riluzole, and I have held off on commencing TUDCA because of the concern that it could disqualify me from the platform trial. I am waiting for Cedars-Sinai here in LA to start enrolling for the Healey platform trial, but I suspect they are delayed due to COVID. I saw yesterday that Cedars-Sinai was chosen as one of the sites to start administering the COVID vaccine, which bolsters my concern.

I agree that ALS clinical trials suffer from lack of precise, apples-to-apples measuring tools. Also, there just aren't enough of us PALS to constitute a really good denominator. This is a very rare disease, with wide degrees of presentation and progression.
 

Nikki J

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TUDCA would disqualify you from the platform So would theracurmin and all its other formulations ( you can eat curry all you want though). This was specifically stated by the doctors I mentioned who are the chief investigators and they stated this was standard because these therapies are being trialed. One can disagree with the reason but it is what is reality now so if someone wants a trial they need to know the rules. And you can’t go for screening and say you will stop. It has to be 30 days prior to screening without whatever

i would hope Cedars can handle both things. The platform trial is not such a huge drain on resources I think a number of trial sites will be at the same major medical centers that can handle the Pfizer vaccine.

yes we need biomarkers which is why you see me saying PALS who are able need to do observational studies
 

lgelb

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ALS is not that rare. Other far rarer diseases have treatments.

As Nikki notes, biomarkers may enable earlier dx as well as better understanding of how well treatments work. So I join her in encouraging PALS to look at all the studies you are eligible for, whether they entail treatments or not. PALS can have a tremendous influence on how fast the work that's needed, gets done.

It wasn't a huge randomized trial of BiPAP or feeding tubes that led to their wide use. It was observation and an understanding of their mechanisms, and what we know about ALS.

Apart from selected supplement trials, the importance of simple observation and thinking is proving true for mindful nutrition in ALS, like veering away from corn syrup/dairy formulas.
 

KenM

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Thanks to all who have contributed to this discussion, I'm learning a lot. This forum continues to be the site of the most thoughtful and informed exchanges of ideas on ALS, and for that I am grateful.
 
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