New Exenatide trial

[Parkinsonjisung]

I'm sure most are aware of the phase 3 exenatide trial ongoing in the UK. A Korean company have a new formulation which they claim has better bbb penetration. Theyve started a trial in Korea with results reporting late next year. Be interested to see if the results match or are better than the previous studies. They could be worse too. Its pharmaceutical money backed too so they usually go faster.

clinicaltrials.gov/ct2/show...

[sharoncrayn]

Another "re-purposed" drug dating back to 2005 FDA approval.

This time a diabetic injection drug to increase insulin secretion and alters 1st phase insulin response in a supposedly positive way.. Since the correlation between type 2 diabetes and PD is relatively high, I guess it is worth looking at, but who really thinks this is going to be a break through? We have had Metformin for type 2 for more than 50 years. It isn't an injection formulation. The two drugs have different mechanisms of action, but Metformin is probably the most studied drug out there.

I believe no published data exists regarding this drug and its efficacy relevant to PD (specifically "early" PD). Might see something of relevance by late 2022 or 2023, but I doubt it.

Sharon

[Hidden in reply to sharoncrayn]

I think you can take it as read that you feel profoundly pessimistic about every possible treatment.

[FMundo in reply to Hidden]

I believe you are correct in your asessment

[sharoncrayn in reply to Hidden]

Horace,

Yes, I am not a big fan of "re-purposed" drugs and their flimsy attempts to reinvent themselves. I am truly sorry to be so pessimistic, but reality is reality.

Sharon

[Hidden in reply to sharoncrayn]

I am truly sorry to inform you that your subjective assessment of possible future events does not constitute "reality", at least so far as the use of a cliche truism like "reality is reality" is concerned.

[sharoncrayn in reply to Hidden]

Horace:

I have No problem with your comment. But instead of criticizing a cliche, why don't you give us your list of Top 10 re-purposed drugs that have provided a substantial benefit to PD patients? NO hurry. I'll wait.

Take your time.

Sharon

[Hidden in reply to sharoncrayn]

I've never claimed that there are any re-purposed drugs that currently provide benefit.

But the that that there are none yet does not mean that dismissing those under consideration (especially when you start by saying there is no evidence, then when evidence is put to you, declaring yourself as underwhelmed) is consistent with "reality", any more than saying no drugs that are blue, or no drugs in liquid form, or no drugs that derive from a plant grown at altitude provide any benefit and therefore the "reality" is that no future successful drugs will have those attributes either.

There are NO drugs that provide proven disease modification and on that basis you could easily say none will ever exist.

You seem either willfully blind to or recklessly indifferent to the fact that PWP are mostly aware that their outlook is not good from a "cure" perspective. I wouldn't worry to much about the average PWP "getting their hopes up" if that is what drives your apparent need to drive home the "realities".

[Cagey84 in reply to sharoncrayn]

Hi Sharon - 2 phase 2 studies have been done, one open label - ncbi.nlm.nih.gov/pubmed/237... - and one double-blind - ncbi.nlm.nih.gov/pubmed/287...

[sharoncrayn in reply to Cagey84]

Cag:

Thanks. Missed these studies for some reason.

However, I am not impressed with this marginal improvement.

From the Open:"Exenatide-treated patients had a mean improvement at 12 months on the MDS-UPDRS of 2.7 points, compared with mean decline of 2.2 points in control patients (P = 0.037). "

from the blind:

"At 60 weeks, off-medication scores on part 3 of the MDS-UPDRS had improved by 1·0 points (95% CI -2·6 to 0·7) in the exenatide group and worsened by 2·1 points (-0·6 to 4·8) in the placebo group, an adjusted mean difference of -3·5 points (-6·7 to -0·3; p=0·0318)."

Unimpressive in terms of substantial benefit.

Sharon

[Hidden in reply to sharoncrayn]

This is a phase 3 trial of a newly formulated version of exenatide. There have already been studies on this exenatide! I am not sure why you mentioned Metformin- it is a different class of medication.

[sharoncrayn in reply to Hidden]

Osidge:

So many thanks for pointing out what I wrote about Metformin.

As to 2 previous CTs with this drug, try to understand that these previous studies on PD were almost meaningless in terms of real benefits. From the better "blind" CT:

"At 60 weeks, off-medication scores on part 3 of the MDS-UPDRS had improved by 1·0 points (95% CI -2·6 to 0·7) in the exenatide group and worsened by 2·1 points (-0·6 to 4·8) in the placebo group, an adjusted mean difference of -3·5 points (-6·7 to -0·3; p=0·0318)." Pretty insignificant differences after 48 weeks of use along with their regular PD meds.

More adverse events with the drug group, which was very small (32).

"Cost" wise, it may prove beneficial for those willing to use an injection form. Many patients are not willing.

For all intents and purposes, it is "re-purposed" without any overwhelming benefit.

Sharon

[Hidden in reply to sharoncrayn]

Many people will take some benefit even if it is not overwhelming.

Metformin is being investigated for its beneficial cardiac and anti-cancer properties. My Endocrinologyst increased my dose to the max because of that.

[Parkinsonjisung in reply to sharoncrayn]

Why are the results meaningless? Its commonly said that ppl with Parkinson's progress 3 points on the motor scale per year. After use of exenatide for one year, the people who were taking it were pretty much the same as when they started. This continued during a washout period. The drug is being described as neuro protective so it was never expected for them to improve. Just for them to not get worse. Theres lots of open questions about the results but the only way we can get answers is with another trial. The fact we have 3 trials all using a similar drug can only help confirm or deny the current results. 2 of the trials are from pharmaceutical companies so they clearly believe enough in the current results to risk spending millions on trials.

[Hidden in reply to Parkinsonjisung]

Sharon is not a PWP. I think this offers substantial insight into her failure to appreciate that a) something that even slows progression a tiny bit would be massive and b) her constantly condescending tone ("try to understand" - as if PWP are not already acutely aware that the landscape for disease modifying treatments is a bit on the bleak side).

[sharoncrayn in reply to Hidden]

Horace:

The cohorts were extremely small (the minimal differences in UPDRS scores were therefore questionable in terms of statistical validity) and in addition, the placebo used was an irrelevant comparison, plus one of the CTs was "open label". "Try to understand". These CTs to prove meaningful, need far more rigor in their design.

If you want to extrapolate the results into something beneficial, as in a "tiny bit", by all means you are free to do so. I have no objection, but realize it is all probably very idiosyncratic...in capitals letters, which means it will not and cannot be generalized in any way, shape, or form.

I'm just giving you my frank opinion. I could be wrong, but I doubt it. I have been doing this CT rodeo for a long time.

Sharon

[Rijk99 in reply to Parkinsonjisung]

I actually have the same question for Sharon. But maybe a better way to put it is "what level of change would be significant in her mind". She seems really knowledgeable and I actually value her opinion...

[Hidden in reply to Rijk99]

She wouldn't believe any study that showed significant improvement. She would find some issue with the study design, or the presentation of the results

[sharoncrayn in reply to Parkinsonjisung]

The cohorts were all too small for anyone to establish statistical or programmatic relevance.

Risk a million on a CT to make 10-20 million? Not bad. (small CTs don't cost "millions").

By all means, believe what you want. I am just trying to inform.

Sharon

[Hidden in reply to sharoncrayn]

The cohorts were of sufficient size to establish what needed to be established and now phase 3. That is often the way that research is done. I am on the management board for some Dementia Research. Our first study was on a limited cohort and the following study is of longer duration and with a multi-national, multi-centre cohort.

[sharoncrayn in reply to Hidden]

Os:

Statistically, the cohorts were not of sufficient size in the "blind" trial and neither are the 3 cohorts of the upcoming CT of sufficient size for statistical validity. 99 participants in total for 3 cohorts (30-35 each) is not going to cut it my friend. Not in my group. A passing grade in Statistics 101 should be mandatory for anyone "on the management board for some Dementia Research." Mandatory.

"That is often the way that research is done". You have just nailed why so much drug research is almost totally worthless. My congratulations on being so incisive in your thinking. Brilliant.

What is somewhat understandable with these trials?

Narrow inclusion/exclusion criteria and small cohort size is understandable in certain trials where the drug has a high level of possible adverse events and/or requires difficulty in administration. This drug meets both criteria, but it doesn't negate the validity issue in terms of efficacy for PD treatment. Sorry.

Sharon

[Hidden in reply to sharoncrayn]

Can you please realise that HU is about supporting people and you are so negative. As to clinical research management boards, you actually know very little.

[sharoncrayn in reply to Parkinsonjisung]

"Its commonly said that ppl with Parkinson's progress 3 points on the motor scale per year."

By whom? If you understood the UPDRS you would never make such a statement. The "motor" segment of the 5 part UPDRS is one of 5 segments within a 199 point total scale. The motor segment contains 13 sub-segments for evaluation.

IOW, progression for PD is simply not isolated by the "motor"segment in the UPDRS.

The UPDRS looks and assesses the totality of all segments (as best it can) of PD.

"The fact we have 3 trials all using a similar drug", They aren't really similar. PT320 is not (supposedly) identical to the generic.

"risk spending millions on trials." None of these trials cost millions. Multi-nation, multi-medical center, hundred of participants, years of participation by the participants, certainly costly but not "millions".

Sharon

[Parkinsonjisung in reply to sharoncrayn]

So you dont think it's a positive sign that the people taking exenatide stayed the same but the people not taking it got worse?

[BUSHPILOTS]

when i looked at the existing UK exenatide trial about to go to phase 3 they were using this same specially formulated SR Exenatide made by Peptron. someone please confirm

[BUSHPILOTS in reply to BUSHPILOTS]

i may be wrong, (it would be a first). what i am seeing as being used in the UK is ER Exenatide

[Cagey84 in reply to BUSHPILOTS]

The phase 3 exenatide is using Bydureon, a sustained release, weekly formulation. The Peptron formulation is only just in phase 2, and is aiming for a 2-weekly dosing.

[BUSHPILOTS in reply to Cagey84]

Thank you. Yes it appears the drug used in the uk is extended release exenatide aka bydureon. While as the reformulated SR by Peptron is different and is used in the Korean phase 2 trials mentioned.

[jeffreyn]

See also the following recent thread (NLY01 Phase 2):

healthunlocked.com/parkinso...

[sharoncrayn]

The way I understand it, without much information from Peptron, is that the upcoming Peptron CT for PD will involve 3 cohorts: ... placebo, 2 mgs of PPT320, and 2.5 mgs of PT320 (alternating placebo and PT320) . They don't identify the placebo, naturally.

Further, they state that "Peptron has developed a sustained-release (SR)-Exenatide, (PT320, Q1W and Q2W), which has shown a higher Blood-Brain Barrier (BBB) penetration rate and better patient compliance (than the existing formulation; I will have to check that statement- Sharon). The other question is whether or not Q1W and Q2W are combined to form PT320 or are somehow distinct? I assume combined.

In addition, "the objective of this study is to evaluate the effect of PT320 on symptom improvement and the inhibition of disease progression in the treatment of patients with early Parkinson's disease. Also, pharmacokinetic analysis of PT320 in blood cerebrospinal fluid (CSF) and exosome analysis of biomarkers related to Exenatide will be being tested, as exploratory measurements."

Please note the emphasis on "early" PD patients and the inclusion of "exploratory" measurements (which may or may not relate to improvement). Also, the half life of this drug, supposedly, is only 2.5 hours. So how does the sustained release formula actually function with a one a week dose schedule?

The answer to the above question seems to come from their non-human primate trial, which they believe will be replicated in the human trial:

"An initial peak occurred at 3 hr post-administration, a secondary peak at 5 days, and achievement of Exenatide steady-state plasma levels from day 10–28. Systemic exposure increased across PT320 doses, and Exenatide levels were maintained above the therapeutic threshold prior to achieving a steady-state. In contrast, Exenatide release from Bydureon exhibited a biphasic profile", ....comparable initially, but followed by a much more rapid decline. ..........................So, PT320 will stay in the system for a long, long time, supposedly.

Some earlier trials with Type 2 patients were discontinued --- why? I have no idea.

27 Jun 2019Discontinued - Phase-II for Type 2 diabetes mellitus in South Korea (SC) (Peptron pipeline, June 2019)

27 Jun 2019Discontinued - Preclinical for Type 2 diabetes mellitus in South Korea (SC) (Peptron pipeline, June 2019)

Sharon

[sharoncrayn in reply to sharoncrayn]

Good luck to anyone participating in this Korean trial with PT320. I sincerely hope the benefits prove substantially beneficial to their target population: early PD patients.

Sharon

[Hidden in reply to sharoncrayn]

I was on both Byetta and Bydureon for a while post PD diagnosis. Thus far, 11 years in, my symptoms have not worsened. I am also on Doxazosin.

[sharoncrayn in reply to Hidden]

Os:

Your experience is truly remarkable. Almost astounding. 11 years into PD without any PD medication, the diabetics Byetta and Bydureon for a short time, and Doxazosin and most importantly, no progression. You are truly part of a small minority.

What is very interesting to me is that Doxazosin is used to treat hypertension (high blood pressure) and benign prostatic hyperplasia (enlarged prostate). Never heard of it used for longer term PD patients.

Perhaps it is a drug that needs to be looked at more closely.

Sharon

[Parkinsonjisung in reply to Hidden]

How long were you using the exenatide drug? Why did u stop? And are you saying that you are the same as you were 11 years ago?

[Hidden]

I was only on Byetta and Bydureon for about a year. After that I was only on Metformin as my blood sugars were at the high end of normal. My PD symptoms have not changed since diagnosis.

[Parkinsonjisung in reply to Hidden]

Wow.. have you increased your c\l over time to achieve this?

[Hidden in reply to Parkinsonjisung]

No. I am on the same dose of Stalevo/Sastravi as I started on.

[Parkinsonjisung in reply to Hidden]

I think we should stop these exenatide trials and just study you. 😃 why do you think you're not progressing?

[Hidden in reply to Parkinsonjisung]

I have no idea but I am pleased that is the case😀. My Father’s sister died 7 years after diagnosis and my Father lasted about 28 years and died of an unrelated problem - aortic aneurism.

[Parkinsonjisung in reply to Hidden]

Seems it runs in the family. Do you have a known genetic mutation?

[Hidden]

I have only one uncommon mutation but cannot remember which it is.