Annovis Bio Releases Promising Phase III ... - Cure Parkinson's
Annovis Bio Releases Promising Phase III Parkinson’s Data
This looks very promising. Some people are concerned that they didn’t meet the primary endpoint, but cognitive improvement is huge!
Annovis missed their endpoints in the intent to treat population. They got good results in a post hoc subgroup of patients more than 3 years past diagnosis. This makes sense as a subgroup because early patients have mild symptoms making it hard to demonstrate much improvement. Also early patients only progress slowly so there will not be much progression in the placebo group either. (For these reasons I believe IKT is making a mistake by only taking unmedicated patients in their trial). I do find this result encouraging.
The results suggest the possibility of efficacy. At least there is no dose inconsistency this time. But it's a contrived post hoc.The normal consensus backed by clinical trial is that PD progresses linearly during the first 5 years. It doesn’t hardly move inperceptably for 3 years and then leap off a Cliffe.
There were 168 patients in the over 3 years group. So about 300 on the excluded under 3 years group.
I think we need to see the unedited full trial top line data before we jump to conclusions. The fact that Annovis have delayed it's release for so long and opted for this post hoc analysis first is a concern
Inhibikase 201 trial is a phase 2,not a phase 3
You are right to want to see the full data. Interestingly, the intent to treat group UPDRS part III response to 20 mg was the same as the subgroup. The difference was the overall group responded to placebo equally, whereas the subgroup did not respond to placebo at all. This strikes me as a better result than a non response to treatment.
There are some troubling inconsistencies based on what little we know (just using Marc Anderson as our "mole"
Recruitment criteria - "off times less than 2 hours" ?
H&Y 1-3 ?
(what does MRi FUS and a host of other interventions do to the mix?)
The overall ITT - with a large enough population for a phase 3 is a total flunk. Placebo outperforms 10 & 20mg. So now we know PD has a huge placebo response in the short term, and this trial was too short for a phase 3
the sub-group post-hoc is a tantallising tease - but the implications need confirmation in a suitable trial
That Maria's presentation is not "precise" -
1 she refers to Alzheimers when discussing PD groups
2 she states specifically that patients with severe PIGD are found in all H&Y groups including zero. Bollocks!
"PIGD patients walked in on walkers and walked out without" - at that stage could be on placebo
"All of this group responded with huge improvement"
Again, Marc was definitely in these groups. He only reported improved constipation , (he might have been in the placebo group)
So hard data doesnt match the spin
Here is my take on the PIGD data.
It looks like patients with PIGD got the lions share of the improvement. Actually they got more than the lion's share. Looking at part III of the UPDRS, we have the 1/3 of the 98 patients, those taking the 20 mg dose, getting an impressive average 25-point improvement. A sum total of about 800 points of improvement in this group of patients. Based on these numbers it seems to me to be convincing evidence that it works for these patients. Presumably Marc was not in that 1/3 of patients getting the 20 mg dose. If he was I agree that would be problematic.
If we go back to the intent to treat slide, we have 1/3 of the 523 patients, all those taking the 20 mg dose, getting an average of 2.5 points of improvement in part III. Multiplying these numbers out we get a sum total of 436 points improvement for all patients taking 20 mg.. For these numbers to add up, on the average those who were not PIGD patients would have to get about one point worse on their part III. A similar analysis holds for part II.
I copied these slides off this afternoon's Zoom presentation. Hopefully the company will post a version of this presentation on their website.
While I'll readily admit I don't understand the problem with analyzing subgroups, (if we are waiting for a drug that will benefit every subgroup of PD (might as well be Waiting for Godot,) I've gone back and listened to her presentation again and feel there is reason to be hopeful.
I understand that it did not benefit everyone equally, but, there are vastly more pwp who are >3 years, PIGD, and cog impaired, than < 3 years.
While I'm not buying their stock, I not giving up on them.
In this case, the effect may be real because it is so large in the designated subgroup. It still needs to be proven in another trial, although the FDA has become so lax they might approve it anyway.
The classical way to cheat with post hoc subgroup analysis goes like this: you have an intervention that does nothing. You keep slicing and dicing the data using different subgroups until you find one that shows improvement. If you keep trying you will eventually find one based on random variation. Then you can parade that around as evidence. The only problem is it's random and the remaining participants do as poorly as the designated subgroup does well. Running a new trial with the subgroup pre-specified avoids this kind of problem.
The Annovis data is troubling in this regard, because according to this kind of analysis, which I did above, there was a negative impact on non-subgroup members. I would have much preferred to have seen at least a small positive impact. At least the improvement in the designated subgroup was greater than the negative impact in the remainder of the participants. Time will tell whether it is real.
Thanks. Got it.
Are you saying what WTP said, that the drug adversely effected the <3 year people?
Yes - "For these numbers to add up, on the average those who were not PIGD patients would have to get about one point worse on their part III. A similar analysis holds for part II."
I'm not saying the drug makes people under 3 years from diagnosis worse. I'm saying that's what the invalid methodology Maria is using "proves". And that's why the FDA wont be taken in by the nonsense spin that is fooling so many
Thanks for clarifying.
They led us to believe there would be an open label extension if the results were good.
We'll see if they honor that.
Also, I suggested they measure results/improvement using digital wearables which have been show to be much more accurate then interviewing subjects.
Maria said there would be an open label extension
From my last comment, here we go bud. 😊 Thank you.
Q1 of 2025 is the open label trial
They have scheduled a webcast on July 2
zoom.us/webinar/register/WN...
I signed up to listen…
we tried to get Buntanetap under right to try from them and I really think it should be made available now, as cog impairment is untouchable otherwise.
A little “Hope” is a beautiful thing!!!
I. for one , am greatly relieved that they are committed to an open label extension. I was impressed by her remarks. Wee-ha. A solid reason for hope - even for us old timers.
You are in your prime. How did this drug make you feel better, Marc?
I thought it relieved me of constipation on the 90th day, but that must have been something else because I was in the placebo arm.🤥
Hi, Marc! When did you find out you were in the placebo group? I have been trying to find out what group I was in, but the folks in Kansas City have not been able to give me an answer.
7:45 AM this morning.
How did you find out?
I got an email from the trial site I participated with.
I just got a call from my neurologist's office in KC. I was in the placebo group. They were sketchy on the open label extension details.
I also received a call from Kansas City and was also given the placebo. I wouldn't take the real thing if it was eventually offered.
Mind if I ask why not?
Because it failed to meet its primary end points and I am already in another trial. I hope I'm proven wrong, but I don't think Buntanetap is the solution to PD. I'm also unimpressed with the company's attempt to claim success in certain subgroups and their apparent shift to Alzheimer's now that they failed in PD.
how come?
See above. Also the cost of getting from Wisconsin to Kansas City on a monthly basis isn't worth what I perceive as a very slim chance of any benefit.
I won't get my expectations up, but we'll see.
I watched the investor presentation just now, and she’s probably going to apply for FDA approval in October, even though she says that’s aggressive. They also will seek approval to open label it, which means trial participants can continue to get the drug.
I thought she said we'd get it until it's approved.
I heard that the open label would be starting Q1 2025, 6 moths prescription or supply with 6 month check ins. Continued until the drug was commercially available
Maria said she welcomed the support of patient advocacy groups in making the application to the FDA. She indicated some had already reached out to ask how they can help. So, if you want access to the drug, ask your organization what they are doing to support to approval.
Annovis Bio’s stock rockets 119% after reporting positive data in Parkinson’s disease trial
marketwatch.com/story/annov...
I've said it before and I will say it again. I think Annovis Bio is much better at attracting investors than it is at treating Parkinson's Disease. I don't own Annovis Bio stock, but if I did, I would sell right now. Unless I am missing something, the rise in stock price and all the post hoc "spin" completely ignores the obvious: It failed to meet its primary end points. Period.
fiercebiotech.com/biotech/a...
The CEO is very effective in attracting the investors due her superb communication skills
Adam Feuerstein on twitter
$ANVS The Parkinson's study failed. Of course, it did. And of course, the company is claiming positive results based a post-hoc subgroup analysis
The primary endpoint was MDS-UPDRS Part II in the ITT population n=523
Maria: "This is the ITT population before subdividing them into the groups. And if you look at MDS-UPDRS Part II, you see that it pretty much doesn't move. The total ITT population does not change at all in MDS-UPDRS Part II."
MDS-UPDRS Part III is the most important secondary endpoint. It also failed.
Maria: "Now, the MDS-UPDRS Part III part in the ITT population looks pretty much identical to the ITT population in our Alzheimer patients, everybody improves because that's what we see. We had high placebo, we had good response. Minus 3 is excellent response, but the placebo also has minus 3."
And below is the Annovis graph showing the failure. Lowered scores in MDS-UPDRS means improvement. Placebo performed better than butanetap.
This is why Annovis is falsely touting a win on a small subgroup of study participants with a Parkinson's diagnosis of greater than 3 years. The analysis is invalid and will be laughed out of the FDA if the company tries to file on it, but that's a story for another time.
I wonder if the point park_bear made, i.e., that many drug trials exclude people well (5 to 10 years) beyond diagnosis explains, in part, why some fail to meet end points because those people <5 years often experience little progression?
That is, they would be more likely to see measurable improvement in people where there is a wider range of possible improvement?
Perhaps they do that thinking that people with less damage will be easier to resuscitate?
youtu.be/nPdtJrR44sI?si=tOe...
what the heck? "We has a few patients that came in on crack"
LoL just kidding! I'll see myself out, now.
Jim & Farooqji are correct. This study failed, and the share price suggests a very naieve investor group. I firmly believe that PD research and trials should recognise the variations in this condition and pursue approval of medications which help a definable sub-group of PD patients.
But that is not what is happening here. From a purely selfish viewpoint I was looking for it to succeed on the basis of slowing progression significantly. This phase 3 trial was far far too short to demonstrate that. If it is approved for PIGD, or approved for dementia, I am in neither group and the drug is irrelevant
And it isn't going to be approved for those groups without further phase 3 trials specifically designed to prove those clinical applications - and they are going to cost a lot of dollars, which Annovis doesn't have. The proposed trial to demonstrate slowed progression in the whole PD population is likely to cost $50 million.
Just to show how frivolous these post-hoc evaluations are, if 450 participants (first slide) showed 100 and 200 mg no different to placebo for UPDRS 2 & 3 (and combined) placebo out performs the drug. If 150 people in the longer than 3 years post diagnosis group did better on the drug than placebo, then the 300 people in the other sub-group experienced severe worsening of their disease compared with placebo (untreated). This demonstrates Buntanetap aggravates disease severity and progression in newly diagnosed Parkinsons patients
Lies, damn lies, and statistics!!
Shouldn't we be hoping for a drug that is successful in the subgroup of those beyond recent diagnosis? Wouldn't it be a good thing for a drug to at least benefit some?
I agree the study failed to meet it primary end points. As commonly done, there was a subgroup analysis.
Maria excluded the those recently diagnosed (< three years) in the subgroup showing efficacy as it was hard to measure an effect. She included those diagnosed more than three years ago with H&Y of 1 or 2. This does not mean others would not benefit, just that it was not easy to discern an effect.
As in other neurodegenerative diseases, therapies are better able to help earlier in the disease progression. Neurons are being killed. The existing therapies hide the symptoms, but the process continues. Some proposed therapies seek to grow new neurons, but I believe these are not near-term solutions. In any event, I expect a longer study of buntanetap would show an effect in the more recently diagnosed and other groups.
Maria suggests she will seek approval of buntanetap as a symptom modifying therapy but intends to pursue subsequent approval as a disease modifying therapy. Emstadler71 below suggests her treatment was not a temporary symptom modification. Rather, the disease progress appears to have been affected - sample size of 1.
GLTA
emstadler is a great example of whats wrong with the data and the idea this post-hoc exercise is valid for anything more than interesting ideas for further research. emstadler was in the 10mg group. Only the 20mg group did better than placebo statistically. emstadlers 10mg group indicated buntanetap did no better than placebo.
it needs proper validation
On part III and total those patients on 10 mg who had been diagnosed for longer than 3 years DID show improvement over the placebo though not as much improvement as the 20 mg (10 mg is the bright green in the chat). And I know my part II improved though the chart for that one shows that overall 10 mg patients did not improve but did not get worse at the same rate as the placebo. My benefits: walking improved, arm swing returned, improved tap test on affected side, left side progression (my good side) almost gone, I can get up out of a low car or chair, I can button my jeans again, I can cut up my food, increased energy, my handwriting improved, my fine motor skills were/are better, no more urge incontinence. And yes, I have retained most of these. The biggest issue I’ve had since going off is increased tremor. I am excited about OLE and hoping it is the 20 mg.
My favorite quote from Shawshank Redemption is “Hope is a good thing, maybe the best of things, and no good thing ever dies.”
Yes. A drug which helps a sub-group is something to hope for. Like any drug seeking approval it needs to design a phase 3 trial with maybe 300 participants to prove that. All this trial proves is that most people improve impressively by taking buntanetap, but they improve even more impressively if they think they are taking buntanetap but aren't really
like moi
Also, its interesting to note that when the investors hi-jacked this site a few months ago, they listed Marc as one of those experiencing a positive improvement on the drug, as an indication the drug was likely to work. Marc was on the placebo.
This was a poorly designed trial, which failed. That doesnt mean the drug is for definite entirely without merit, but if it does have clinical validity it is going to take further, properly designed trials which succeed in the primary endpoints, to prove the point, and enable FDA (or EMA) authorisation
And the potential is luke-warm, and Annovis have no money
I just found out that I was on the 10 mg dose!! I am in the category of being diagnosed for longer than 3 years (will be 7 this fall). I saw significant benefit and can’t wait for the OLE in January.
I have maintained my arm swing and improved right hand tap test (which improved over the course of the trial) even though it’s been a year since I finished the trial. I got married 2 weeks ago and had enough fine motor ability to glue 1400 tiny rhinestones to my dress.
Just wanted to update once I knew for sure I was on the drug since I had posted here earlier about what I was experiencing.
You would make a good advocate.
Seems to me, you have a vested financial interest in ANNOVIS BIO’s success????
I have been following the development of buntanetap (formerly Posiphen) for about a decade and have been invested since 2016.
I appreciate your response, but your bio says nothing about who you are and whether or not you have Parkinson’s.
From an observational standpoint, your posts appear to be guiding the discussion towards ANNOVIS BIO, and you seem to have a direct channel to Maria. Specifically in the manner you state “Marie said…..”.
So the appearance seems to be that you are directly employed by, or are on this forum trying to sway public opinion for your own financial gain.
If ANNOVIS BIO is onto something that will better the lives of those in this community, then hallelujah. But one thing I’m not real fond of, is individuals that are trying to better their lives financially by getting on this forum and swaying the opinion in hopes of getting more investors to jump on board and push a product that it is yet proven 100%.
I have not been diagnosed with Parkinson’s disease. Both my parents died following dementia. My apologies for any false hope I may have caused.
There is a table of therapeutics under development in PD maintained by Kevin McFarthing and others. Notably, it is called the Parkinson’s Hope List. As of March 2024 it lists 162 clinical trials of which 76 are listed as disease modifying. I encourage you to look at it.
There is tremendous investment in unproven therapeutics. I can’t tell you which drug will be successful. Only that there is hope.
Congrats. Proof there is life after diagnosis.
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