Simon seems to think there is reason for optimism, but this paragraph stands out to me:
Unfortunately, there was no significant difference between the liraglutide treated group and the placebo group when the investigators looked at motor symptom scores after 1 year of treatment. Both groups appear to have improved slightly. It could be that there was a placebo response at play there (a placebo response being an effect where there is no biological explanation).
It seems to get better further down:
"The presented results (Source) indicated that of the study participants, 37 people were on liraglutide and 18 on the placebo treatment. The 52 weeks of daily liraglutide treatment was found to be safe and well tolerated.
Unfortunately, there was no significant difference between the liraglutide treated group and the placebo group when the investigators looked at motor symptom scores after 1 year of treatment. Both groups appear to have improved slightly. It could be that there was a placebo response at play there (a placebo response being an effect where there is no biological explanation).
But interestingly, the researchers did see a statistically significant response in the non-motor symptoms: The liraglutide treated group experienced improvements in measures of non-motor symptoms, activities of daily living and quality of life, while the placebo group did not.
Curiously, the liraglutide treated group also reported significant mobility improvements in their self assessments questionnaires. Theses are different to the clinician rated motor scores of the primary endpoint."
I read that, too, and maybe I put too much emphasis on motor symptoms...but if this was the real deal, it should show in objective measurements of motor symptoms.
The problem is surely that one year simply isnt long enough. We know this, because even the placebo group improved their scores.
It probably needs 3 or 4 years to cover the impact of inter-day symptom variability and the ability of PWPs to turn themselves 'on' (to varying degrees) when they are being assessed.
Agreed. As much as it sucks, if after 1 year everybody improved, go another year.
I just hope it’s good enough to make it as an approved therapy and we will really know the potential of it when large numbers of PWP have been on it for a minimum of 3 years. I would think 5 is really needed for a good assessment. Given the risk vs possible reward, I’m taking it. Depleting the bank account for most likely a placebo but we shall see.
5 would be really good and maybe the longest you could go before a significant portion of people start dropping out due to death/cancer/moving away/whatever.
The most encouraging thing* about glp1 is that at least it looks like it doesnt accelarate PD. To which people might say "well duh" but the truth is that we cant say that about a large portion of the things that get discussed here.
*Edit: "most encouraging thing" wasnt correct. I would have been better off saying "one really positive thing we have learned"
I think Ambroxol is also one where it’s safe enough to say, it’s not making it worse. Although I do wonder about it’s affect on the gut especially the mucosal lining of the gut. Odd that researchers that know the now obvious pd gut brain connection and are researching Ambroxol have not researched the affect it has on the gut. Since it decreases mucus I wonder how it might affect the gut barrier function. But other than that, I believe it’s been sufficiently established to not mark matters worse.
What dosage are you taking? Any side effects?
“impact of inter-day symptom variability and the ability of PWPs to turn themselves 'on' (to varying degrees) when they are being assessed.” ?On non- motor symptoms?
I've never heard this one. explain to me please.
I believe it was in this video (it’s been a long time) that Dr. Tom elaborated on the method of action and it was my understanding when I listened many months ago, that the benefit was not so related to reducing insulin and therefore those who do not have high insulin could benefit. I do not understand the benefit but I don’t think the doctors fully understand either.
I’ve been taking it since September 2021 and have been tempted many times to quit.
It might very well be coincidence but in the last 1-2 days preceding my next shot my symptoms are often a little worse. My symptoms do not improve immediately after the shot though. But I’m quite consistently a little better about 1 1/2 to 2 days after the shot. I have assumed that coincidence is more than likely the reason for this but it gives me just barely enough reason to not quit.
I think it might be reasonable to hope that it can slow progression at least a little. Even if it just flows it 10%, that’s something.
Who knows.
Would love to hear from anyone else taking it.
🌸 Newbie
(Yes, it’s “you know who.” Changed my name to not include my real life nickname for privacy. The internet is a smaller world than I realized. IRL people do not know I have PD and I need to keep it that way for work and for my kids.)
How are you able to get it? And is any trying it and finding any help or feeling is stops progression?
One of the problems with the phase 2 Exanatide was that it only (then nearly only on a recount) affected motor symptoms. That wasn't what all the previous trials and theoretical explanation of glp-1 receptor agonists predicted. Worse, if you looked at the motor symptoms, the exanatide group (blue)had a one-off immediate improvement of about 3 UPDRS points and then pretty much tracked the placebo group (orange). If you adjust out the immediate 3 point gain, and plot the adjusted exanatide result (grey) - then they follow a broadly similar slope and end up at week 60 in the same place (I couldn't get the scale on the graph right and haven't time to fiddle with it now). That really isn't what you expect from a disease modifier - you want to see 2 lines growing ever further apart over time
Liragutide is thought to be better at crossing the BBB. Improvements in non-motor scores fit better the disease modifying expected results for the glp-1 receptor agonist mechanism of action (it is the "key", which fits into the glp-1 "lock" on the cells surface, and switches on a result which inhibits cell death pathways, reduces inflammation, reduces oxidative stress, and increases neurotransmitter release.)
12 months is too short. Both trials had only a (relative) few participants. The randomisation in the Exanatide trial was unfortunate.
As for trial duration, 2 years is probably adequate to identify an effect on progress. But the other (possible) problem with the Exanatide trial is it suffers (as does most PD research) from the aggregation of the syndrome into one disease - the subject (I believe) of the next "No Silver bullet" talk. So maybe glp-1 receptor agonists work for some symptoms in some PD sufferers but not others. If you try to find a "works for everybody" solution, you maybe chuck out a lot of useful targeted therapies.
5 years is not really feasible (3 years is the longest so far I am aware of - ignoring open label extensions). There is probably at least a year for recruitment and a year to analyse and publish results. 7 years?!?!?
I think Inhibikase have the right idea for their IKT-148009 molecule, which of course, is NOT repurposed. Reasonably quick trials to establish a symptom relief benefit, get licenced and launch, and then carry out a very large sample extended (5 year?) phase 4 follow up in clinical use to establish a disease modifying effect, at which point the existing licence can be extended from a symptomatic use to a disease modifying use.
Whilst it is tempting to grab at every announcement of a possible new treatment - the PD research road is littered with dropouts. There is always the risk of adverse effects with any medication, compounded when taken in combination with others. At least Exanatide, unusually for a repurposed drug, is being trialled at existing diabetes treatment doses, and so its safety profile in humans, at the PD dose, is well known from a substantial user base. I'm not sure the same applies for other "give it a go" drugs, like Ambroxyl
And the forum is littered with people taking dozens of pharmaceutical and non-pharmaceutical alternatives, who may have improved their condition a bit - but not so dramatically that the search for more is over.
Blimey Winnie. How many weetabix (plus croissants of course 😂) did you have this morning?!
One of the appeals (to me, anyway) of a longer trial is that it may allow you to some subtyping/stratification at the end of it.
Example:
Hypothesis: drug [x] stops the progression of PD.
Duration: 5y
Metric: whatever you decide is best in the absence of an accurate biomarker. UDPRS/scans/skin biopsies/whatever
N: 100
Placebo: 30
Treatment: 70
Now lets say at the end of 5y:
- your placebo cohort progressed as expected (on average, and with a relatively low SD)
- 30 of the treatment cohort progressed along at the same rate as the placebo cohort
- 20 of the treatment cohort did significantly worse than the placebo cohort
- 20 of the treatment cohort didnt progress at all.
Now lets assume that the aggregation of all this is that there was no sig diff between the placebo and treatment cohorts. R Barker talked about this issue in the video (he has his own pre trial subtyping plan)- that good results get averaged out by poor results.
You can pack up and go home, concluding that the thing was a bust, but hold on, 20% of the entire sample didnt progress at all. Even if that was only 5%, suddenly you have very interesting data, becuase not progressing at all for 5 years is rare as rocking horse shit in the PD world. So now you can start identifying the traits of those that responded very well and those that responded very poorly, and this paints a picture of who you are going to give it to next (and who should avoid it).
You cant really do this after 2 years* because even really promising outcomes just dont diverge from the expected untreated outcome by that much over that timeframe, which is okay if you can pull together a giant sample (n=500) but that seems to have proven very difficult for a number of trials.
*Edit: you obviously can do it after 2y, as the post hoc exenatide analysis demonstrates. I just think its far less compelling.
I agree about the need to structure trials to identify the positive outcomes for sub-sets of the PD world. As you say, it was Roger Barkers point too
5 years is a long wait, for us to get the bloody stuff if it works, and for the manufacturer watching his patent expire. 2-3 years, for phase 3 is probably the limit we will see. Post authorisation phase 4 extension trials may well be 5 years
So have anyone in this post done any clinical trials? If someone wants to how do you go about getting in one? Also has anyone checked on CuAtsum from Australia? I haven't been able to find anything more on it.
I was in biogen BIIB054 trial for 2 years. MJJF trial finder is a good place to start
Bydureon (a.k.a., Exenatide), a repurposed Type 2 Diabetes drug is now in third-stage trials in UK for stopping Parkinson’s in its tracks — results expected 2024. Testing — mice, open label, double blind — has been going on since 2010 and it has been positive every time.
scienceofparkinsons.com/201...
According to a very sensitive test, Homeostasis Model Assessment for Insulin Resistance (HOMA-IR), 2/3 of Parkinson’s patients are supposed to be insulin resistant. IR may be treated with Bydureon (Exanatide). Just an angle that might get us one step closer to getting Bydureon.
cureparkinsons.org.uk/news/...
South Korean researchers have learned how to dial our cells back to stem cell stage -- and are now administering monkey stem cells to parts of their brains that are short on dopamine producing cells -- with the hope they will fill in and take over the job.
Started this before with stem cells from other monkeys and had some success I think until local immune systems attacked foreign cells.
So there is even realistic hope for a cure.
Have you read this thread? Bydureon is in a phase 3 trial. It didn't stop parkinson's in its tracks in phase 2. Take a look at the graph. There was an immediate symptomatic improvement up to week 12 followed by steady deteriodation (disease progression) at exactly the same rate as the placebo group
cureparkinsons.org.uk/exena...
" ... 45 volunteers – half of whom had twice-daily injections of exenatide on top of their normal medicines. Those who took exenatide did not experience the decline in movement that we normally see due to Parkinson’s. In fact, they even improved a little. Crucially, some of these benefits were still present when measured one year after they’d stopped taking exenatide ... "
cureparkinsons.org.uk/exena...
Unfortunately it wasn't that simple
Can it be due to data pooling and averaging of results, that the benefits may be lost in reporting?
Read the graph. There was an initial improvement to week 12 after which they progressed from minus 2.5 to minus 1 (1.5 points) which was EXACTLY the same as the placebo group, 1.5 points from (0.5 to 2.0)Extrapolate the graph and both groups are getting worse at the same rate but the exanatide group are a constant 3 points better. Hardly stopped in it's tracks
I'm not trying to be a downer here, but the results seem only marginally successful and similar to the 10 mg melatonin study (RCT) in PwP using a slightly larger group of participants for just 12 weeks :
sciencedirect.com/science/a...
Here is a quote from the study :
>>> ' Compared with the placebo, melatonin supplementation resulted in a significant reduction in serum high sensitivity C-reactive protein (hs-CRP) (β −0.94 mg/L; 95% CI, −1.55, −0.32; P = 0.003) and a significant elevation in plasma total antioxidant capacity (TAC) (β 108.09 mmol/L; 95% CI, 78.21, 137.97; P < 0.001) and total glutathione (GSH) levels (β 77.08 μmol/L; 95% CI, 44.29, 109.86; P < 0.001). Additionally, consuming melatonin significantly decreased serum insulin levels (β −1.79 μIU/mL; 95% CI, −3.12, −0.46; P = 0.009), homeostasis model of assessment-insulin resistance (HOMA-IR) (β −0.47; 95% CI, −0.80, −0.13; P = 0.007), total- (β −13.16 mg/dL; 95% CI, −25.14, −1.17; P = 0.03) and LDL- (β −10.44 mg/dL; 95% CI, −20.55, −0.34; P = 0.04) compared with the placebo.
Conclusions
Overall, melatonin supplementation for 12 weeks to patients with PD had favorable effects on the UPDRS part I score, PSQI, BDI, BAI, hs-CRP, TAC, GSH, insulin levels, HOMA-IR, total-, LDL-cholesterol, and gene expression of TNF-α, PPAR-γ and LDLR, but did not affect other metabolic profiles. ' <<<
The 50 mg melatonin study (RCT) did more than the 10 mg study by returning oxidative stress levels similarly to healthy controls and recovered mitochondrial function in the trial participants. This is essentially what Albert sought to do with his use of sulforaphane.
ncbi.nlm.nih.gov/pmc/articl...
Here is a relevant quote from the study:
>>> ' Taken together, our data showed that melatonin supplementation recovers mitochondrial function and diminishes oxidative stress. Thus, this indolamine could play a role as an adjuvant in the treatment of PD. ' <<<
This is important to PwP for at least two reasons, 1) PwP have elevated oxidative stress levels when compared to healthy controls and 2) it is already established that PD includes mitochondrial dysfunction and damage. When you consider that melatonin works against these two unhealthful conditions throughout the body and not just the brain, the value of melatonin takes on a little more clarity.
It seems like melatonin can do at least as much or likely more than the study drug when you consider these two studies as well as other melatonin/PD study results including protecting the heart. Given that PwP are at increased risk for cardiovascular disease (CVD), having the added advantage of acting as a heart protectant would be very important also.
I realize there is a limited number of study dollars available so choosing studies wisely is important and may mean that high dose melatonin studies may never be done in PwP.
Honestly, I would rather see a 250 mg melatonin study in PwP for at least a year to get a better idea of all that melatonin can do for PwP over a longer period of time at a significantly higher dose than 50 mg /day. Melatonin has the excellent safety profile to make such a study doable and it has already been used in a human study at 3000 mg/day for 6 months, but a PD study is lacking at that 250 mg dose. Such a study could be done in about two to 3 years since melatonin is just an over the counter supplement, not a drug.
Art
From S of PD. Could all the benefit of B1 be the placebo affect? I think it's time for me to switch to benfotiamine instead.
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