Today The Cure Parkinson's Trust, in partnership with the Van Andel Institute and the John Black Charitable Foundation, announced the publication of the results of a Phase II clinical trial that evaluated the safety and tolerability of a drug called ambroxol to treat Parkinson's.
The results of the AiM-PD study indicate that ambroxol is safe, well tolerated and able to increase GCase levels in the spinal fluid of people with Parkinson’s. This is an important step to now allow us to find out whether this drug can slow the progress of Parkinson’s.
There was a 6.8 reduction (indicating improvement) in the clinician-based rating scale measurement and these effects were seen in those participants with and without GBA mutations
A very tiny study with 17 participants. Once again for the upmpteenth zillionth time, if you don't have the GCase mutation this drug and drug trial is irrelevant. In plain English, nothing exists to indicate this drug has any efficacy in slowing or modifying the progression of PD outside of this specific mutation cohort.
Ambroxol therapy has potential for study as a neuroprotective compound for the treatment of patients with Parkinson disease both with and without glucocerebrosidase gene mutations.
And this from Simon Stott in his most recent Science of Parkinson's post:
The clinical assessments of the participants suggest that that treatment improved motor features associated with Parkinson’s (a 6.8 point reduction (indicating improvement) in the Movement Disorders Society unified Parkinson disease rating scale (MDS-UPDRS) Part III. Interestingly, these effects were observed in participants with and without GBA1 mutations.
"Interpretation of the changes in MDS-UPDRS and MoCA results is difficult (they basically never changed from baseline for MoCA for all participants-Sharon) in the context of a nonplacebo-controlled study. However, the changes support the clinical impression that no substantial deleterious effect of ambroxol was observed among participants taking ambroxol, including any adverse effect on the motor features of their PD."
Translation? it is difficult to draw ANY conclusion from this study about the significance of any of the changes observed.
So many other red flags. 1) a cohort of a tiny, tiny number of 17 participants. Furthermore, it was a trial that was 2) non-randomized, 3) non-controlled, and 4) open label... 5) without a placebo ... can't get any flakier than that.
Beyond those flags, 50% of the participants had the mutation; 50% did not. 6) Were the positive changes "uniform in UPDRS" across both groups? Study report for some reason was silent on this issue. Perhaps it was buried somewhere in the supplements.
7) Escalation of doses over the trial period with the allowance of up to 3 other PD medicines raises another red flag. In other words, this drug was not used in an "isolated" pharmaceutical environment to prevent cross contamination of results from other working PD drugs. Was this drug the independent variable in terms of the positive results? IMPOSSIBLE to state.
If someone reads the trial results carefully, it was all about testing for increases/decreases in the lysosomal enzyme glucocerebrosidase. Pretty esoteric stuff. Of course the hyped headlines didn't see it that way.
I seriously doubt a further trial will prove anything in terms of a practical application unless they dramatically correct some of the design flaws. Way off in the future perhaps because this trial was so tentative and flawed, as they admitted (deep, deep in the text).
The "hype" usually washes out as these projects progress as we have seen over, and over, and over again. The end of the rainbow seldom has a pot of gold.
On balance, I think what you are saying is "do a better trial" rather than "forget about ambroxol for PD".
What Simon is saying is "A larger and longer [placebo-controlled] study is still required to determine if ambroxol can have any actual clinical benefits in slowing the progression of Parkinson’s." Or, in fewer words, "do a better trial".
If sponsors are available (e.g. CPT, APM etc.), the design work for such a trial could start now, rather than "way off in the future".
Thanks for providing an opinion. The Phase III should provide an answer. In the meantime, I'm pleased that the Director of Research for the Cure Parkinson's Trust and the authors of a peer reviewed article from the Journal of the American Medical Association both flatly contradict your premature and condescending conclusion that "Once again for the upmpteenth zillionth time, if you don't have the GCase mutation this drug and drug trial is irrelevant."
You MIGHT be right, Sharon, but guess what? You might be dead wrong.
Unfortunately I have more experience in CTs than they do combined, but I enjoy your unbounded, unfailing optimism about all these theoretical projects.
This drug has been marketed for more than 50 years in probably 9-10 different formulations, so "re-purposing" has become the new game in research town.
We shall see in 5-10 years if the hype was worth it.
Sharon, is there any current clinical trial that you believe has any chance of succeeding or anything in the drug pipeline that you see as having potential?
A dry spell of almost 10 years occurred between the last drug (or a adjuvant therapy) approval for PD by the US FDA and the 3 latest, the latest which was Nourinanz approved in the Fall of 2019.
It is an adenosine A2A antagonist for supposedly minimizing PD OFF times which become progressively longer as time passes. This drug approaches PD from the "signalling" theory perspective. It is NOT a stand alone but is an add-on drug. As we have seen before in these CT results, unwanted side effects are quite common. With this drug, it is increased dyskinesia, which may or may to be attributable to its linkage to sinemet/rytary in the CTs. The design of the trial didn't control for it.
2 years before this drug was granted approval, the FDA approved in 2017 the drug XADAGO, which is a sifinamide MAO-B, which again supposedly reduces "off" time, but the CTs were placebo trials so it is relatively difficult to ascertain whether or not it is any better than the other classic MAO-Bs . It is another add-on drug and should not stand alone (presumably) given the manner it was used in the CTs.
Also in late 2017, the FDA approved GOCOVRI (sometimes better known as amantadine) extended release for the treatment of dyskinesia specifically (a first such approval). Also taken in conjunction with sinemet/rytary. The clinical trials were rather controversial due to the measurement of dyskinesia by using the UDRS, a newly developed scale, the use of "home" diaries for participants to somehow record their results in an objective manner, and the"pooling" of data from 2 previous phase 3s.
Some true believers will claim these 3 drug approvals are true "breakthrough" types. Others who know better will take a wait and see attitude.
The recent push towards "re-purposing" some old drugs for PD tells me the new drug pipeline isn't exactly gushing over with truly new ideas. For those PD types younger than say 65, this news isn't exactly good news.
again of it. A former patient of me (yes, I'm a therapist with PD), who want
to get me, with whole her heart, better, has sent me the link.
I almos bought 3 liters of sirup :-)..........then I was considering me >>> why didn't I heart anything about it on HealthUnlocked >>> searched a little bit, and then find
your posts.......
So, a bit realipointed
(my word for a mix of reality and disappointed) I'm going
to sleep and keep on going with my own trial (following the strategy of Dr.
Joachim Mutter, perhaps already now articles in english of him)....
On Mutter's observation regarding genetic predisposition towards PD:
"Genetic background accounts for only 5 to 10% of the reported cases of Parkinson's disease (PD)." So much for debunking the gene theory of PD.
And his negative observations on mercury fillings: "Mercury is one of the most toxic elements and causes a multitude of health problems. It is ten times more toxic to neurons than lead." Too bad dentists think they continue with mercury because they encapsulate it.
Right on Herr Mutter; right on.
(this drug is a blank bullet, not a silver bullet, but sometimes nothing convinces people with PD)
FYI: I started GOCOVRI four weeks ago. I was having quite a bit of dyskensia and after two weeks, there was a big improvement in dyskensia and now it's 98% - 100% gone. It has also made my transitions from off to on smoother.
GOCOVRI = Amantadine approved in 2017 by the FDA specifically for dyskinesia, which was a first. Unfortunately, this drug can and often does cause hallucinations. Just be careful with it, especially if you use stimulants. Minimize your intake or stop your stimulants and any SSRIs you might be taking if you have problems.
That's exactly what I told the doctor I did not want. I told them I didn't want anything that would give me hallucinations. I'm on 20 mg of Lexapro, Prior to the GOCOVRI, I was on Amantadine 1 mg/twice a day for several years, maybe 8 yrs. Does the GOCOVRI give you more hallucinations than what the regular Amantadine would? Do you think the Lexapro is too much? So far I haven't had any hallucinations.
GOCOVRI is an extend release oral form of Amantadine. So, it is designed to remain in your system longer (and presumably) in doing so spread the positive effect of the drug over a longer period of time in a more controlled manner. It is formulated for night time delivery at 274 mgs. so it can peak during day time.
Adamas Pharma claims GOCOVRI is simply not a duplicate of Armantadine, which is now a generic but distinctly different in its impact. And the FDA agrees with them. I'm not sure I do.
Hallucinations, edema, etc. for both drugs run in excess of 15% in all of the clinical trial results that have taken place. So the risk for either formulation is not insignificant for these conditions (actually at the high end for an approved drug).
I will repeat what I said before (many times on other threads) about SSRIs with other drugs...."Minimize your intake or stop (gradually) your stimulants and any SSRIs you might be taking if you have problems." Lexapro is a SSRI.
Just be careful with an SSRI and ANY type of PD drug. They normally are antagonistic with one another. You might be an exception, but you never know.
Since there is no "big money" to be made from ambroxol, it will be interesting to see whether sponsors can be found (e.g. CPT, APM, etc.) for a next-phase clinical trial.
"A larger and longer study is still required to determine if ambroxol can have any actual clinical benefits in slowing the progression of Parkinson’s."
From that link "....In truth, I am finding this frustrating because, as it happens, my lived experience of the trial was that it definitely reduced my tremor. Two years on, said tremor has only recently returned to its pre-trial level. I’m fully aware that this is entirely subjective and not statistically significant. I know that my sort of Parkinson’s is not the same as your sort of Parkinson’s, so what works for me may not work for you. I do know that the placebo effect can be extremely powerful and, particularly with a brain condition, expectations can influence outcome...."
"One subject was given an ineffective control solution vehicle, another subject received 22.5 mg/day of ambroxol and the third subject received 100 mg/day of ambroxol. They showed that daily administration 100 mg/day of ambroxol results in increased levels of GCase activity in the brain (approximately 20% increase on average across different areas of the brain). Importantly, the 22.5 mg treatment did not result in any increase."
So 100 mg per day. If you were a Babboon wanting to recreate this you could just get some cough syrup.
For humans though it was 1.26g
So on ebay (uk) I find Mucosolvan 200ml
Composition 5 ml: Ambroxol hydrochloride 30 mg
Effectively you would have to drink the whole bottle of syrup a day to get the same effect. Given the other stuff in there its probably not worth it.
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