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“However, the compound only marginally decreased SDS- and formic acid-soluble Aß1- 42 brain contents, and only in male mice”
https://anavex.com/wp-content/uploads/Chronic-Treatment-with-the-Tetrahydrofuran.pdf
All the ones one I checked on CT.gov were only labeled with low, mid, high etc.
Now why would they do that? Probably to maintain complete blinding.
Which of the following doses would make you refuse to sign up for their trial if they revealed the doses they were using?
Over 54 weeks, 33% of patients on the 6-mg dose developed ARIA (amyloid-related imaging abnormalities that include fluid effusions and microbleeds in the brain, seen with anti-amyloid therapies), which was lower than the 47% seen with the 10-mg dose, they reported.
“Patients were randomized to one of four doses of aducanumab (1, 3, 6, or 10 mg) or to placebo once every 4 weeks for 54 weeks. They were also assessed by ApoE4 status.
They found that the 3, 6, and 10-mg doses significantly lowered amyloid levels in the brain at 54 weeks (P<0.001 for all), but the 1-mg dose group did not.
Patients in all groups had worsening on the MMSE at one year, but those in the 3-mg and 10-mg groups had significantly less worsening (P<0.05):
Placebo: 2.81
1 mg: 2.18
3 mg: 0.70
6 mg: 1.96
10 mg: 0.56
Similarly, all groups had worsening on the CDR-SB, but there was significantly less worsening only for the 10-mg group (P<0.05):
Placebo: 1.87
1 mg: 1.72
3 mg: 1.37
6 mg: 1.11
10 mg: 0.63
Sevigny and colleagues found that the most common adverse events were ARIA:
1 mg: 6%
3 mg: 13%
6 mg: 33%
10 mg: 47%
Placebo: 5%
They also found that ARIA-E was dose and ApoE4 dependent. Rates for gene carriers and non-gene carriers, respectively, were as follows:
1 mg: 5% versus 0%
3 mg: 5% versus 9%
6 mg: 43% versus 22%
10 mg: 55% versus 17%
A total of 20% of the patients on aducanumab reported headache, compared with 5% of the placebo group.
Biogen is bypassing phase II trials for aducanumab and moving directly into phase III.
"After many [amyloid antibody] failures, aducanumab finally shows convincing evidence of a clinical benefit," said Sam Gandy, MD, PhD, of Mount Sinai Hospital in New York City, who was not involved in the study.
No way in hell I would sign up to receive any of those doses, but I would bet they are using somewhere from 3 to 10 mgs. I don’t blame them for not revealing the doses. Do you?
https://www.medpagetoday.com/meetingcoverage/aaic/52705
Didn’t think it would. Do you still see 150 for the blinded trial or do you see “undetermined”?
Could it be that Anavex is trying to use the open label extension as a way to reduce the likelihood of a blinded trial failure by adding patients until they see what they want to see in the OLE?
Weird. Mine doesn’t. (Yes I refreshed)
EXPECTED PARTICIPANTS
Undetermined
A Phase II, Double-Blind, Randomized, Placebo-Controlled Study to Evaluate the Safety, Tolerability, and Efficacy of ANAVEX2-73 for Cognitive Impairment in Parkinson¿s Disease with Dementia Patients.
https://reec.aemps.es/reec/public/detail.html
EXPECTED PARTICIPANTS
150
Open Label Extension Study for Patients with Parkinson¿s Disease with Dementia Previously Enrolled in ANAVEX2-73-PDD-001 Study for Continued Safety Assessment
Thank you very much. I see now that the OLE does say 150 but it looks to me like the blinded trial actually says “Expected participants” “undetermined”
I think both are probably 150 though. If you care enough, I would bet emailing the CRO contact for clarification would be a successful endeavor.
All I’m sayin’ is it would be a good strategic maneuver.
But then there is this part that might not fit.
“The scientific evidence may therefore be less comprehensive than would typically be required, but needs to be adequate and convincing evidence based on clinical trials (usually randomised controlled trials).”
Now see, this kind of makes sense to me.
Why finish a blinded trial that could prove your drug actually does not work when you can get a government run health care system to let you sell your drug with the slimmest of proof that it actually works.
“The determination application is based on preliminary data and a plan for comprehensive data that confirms predicted benefit and safety as early as possible in the provisional registration period.
“Assessment of preliminary data could be based on:
a non-validated surrogate endpoint
a single arm study
a non-randomised comparison
an interim analysis/duration of study
a small database
recruitment from a narrow group of patients”
I don’t believe that private insurance companies would ever volunteer to pay for drugs with qualifications like those.
But, it would make perfect sense that Anavex would slam the brakes on the PDD trial rather than risk it failing if they think a government run healthcare system with let them run without real proof their drug works.
Heck, I wonder if the government will also pay for the drug or if patients will have to pay. Being government run I wouldn’t doubt they would even reimburse the drug costs.
Thanks, if that’s the speculation, it at least seems “possible”, a hell of a stretch, but possible.
I really do hope y’all get luck with this raffle ticket stock.
I wish I could join in the fun, but crap like Dr M’s strangely small “insider purchases” while simultaneously tapping LPC,
only revealing the dosing change for the Alzheimer’s trial in an interview for an article rather than updating the clinical trials sight
Calling the doses “mid” and “high” now instead of stating the mg’s. Sorry, but I just don’t buy the “to maintain complete blinding” statement because I can’t find a single reference for what that actually means. Why was the EU trial able to reveal the dosing then? Did that “break the blind” for that trial?
As long as you don’t invest more than you can afford to lose, perhaps your right about the risk reward profile of Anavex though. Good luck to all longs.
On a positive note.
Did you notice this?
“Karuna Therapeutics News: KRTX Stock Skyrockets 415% on Positive Schizophrenia Trial”
“Muscarinic receptor agonists emerged in the 1990s as a promising innovative approach for treating psychosis and cognitive impairment. Muscarinic receptors are g-protein linked receptors (GPCRs) that bind the neurotransmitter acetylcholine. There are five distinct muscarinic receptors, M1-M5, found in the brain as well as various peripheral tissues.
The link between muscarinic receptor stimulation in the CNS, particularly stimulation of M1 and M4 receptors, and the reduction of psychotic symptoms and cognitive impairment, has been well studied and is supported by data from preclinical studies and randomized, double-blind, placebo-controlled clinical trials with xanomeline published in peer reviewed journals. However, the successful development of a therapeutic agent targeting muscarinic receptors has been limited by undesirable side effects that are believed to arise primarily as a result of stimulation of muscarinic receptors in peripheral tissues. We believe a therapeutic agent that can preferentially target and stimulate muscarinic receptors in the CNS, but not in peripheral tissues, has the potential to treat psychosis in schizophrenia and AD, including the associated agitation in patients with AD. We also believe the preferential stimulation of M1 and M4 muscarinic receptors in the CNS may address the negative symptoms of schizophrenia, such as apathy, reduced social drive and loss of motivation, as well as cognitive deficits in working memory and attention, all of which currently lack any approved treatments. This approach has the potential to produce a differentiated therapy relative to current D2 dopamine receptor-based antipsychotic drugs and to beneficially impact the lives of millions of patients with schizophrenia and other psychotic and cognitive disorders.”
https://karunatx.com/programs/
Could it have implications for this..
“ANAVEX2-73 acts as a muscarinic receptor and a moderate sigma1 receptor agonist. “
And be why Anavex is doing this...
Event-Related Potential (ERP) Biomarkers in Subjects With Schizophrenia and Healthy Volunteer Subjects
https://clinicaltrials.gov/ct2/show/NCT04025502?term=Anavex&draw=2&rank=7
Aug. 07, 2019 8:04 PM ET
“Edward Marks
Moving onto the Parkinson’s dementia study. I was hoping you could provide a little more information on what the enrollment status might be for that trial as well. And then after it’s fully enrolled, when might the top line data become available?
Christopher Missling
The expectation is that we are – that we have the study completed very soon. We are almost there and it’s a great accomplishment by the team. And we know that the study has a 14 week treatment duration. So if we are able to complete the study, that will then needed to be added this 14 week in order then to have the data locked and then subsequently becoming – possibly available in a press release, the top line data.
https://seekingalpha.com/article/4282937-anavex-life-sciences-avxl-ceo-christopher-missling-q3-2019-results-earnings-call-transcript
Primary Completion: November 2019
-Changed to-
July 31, 2020 [Anticipated]
https://clinicaltrials.gov/ct2/history/NCT03774459?A=1&B=3&C=merged#StudyPageTop
Reconcile these statements for me then.
Using these parameters, MTD was determined at 50.58 mg, i.e., when this dose is administered, a DLT event will occur in half of the 5% most frail patients in the population.
These results closely reflect the practical course of the study where 25% of the patients remained on their initially allocated dose level of 50 mg while 75% of the total number of patients remained in the 30 mg dose level after five weeks of treatment
How does the first part “closely reflect” the practical course of the study?
https://anavex.com/wp-content/uploads/New-Alzheimers-Drug-ANAVEX-2-73-Phase-2A-Study.pdf
Is everyone in the study a “most frail patient in the population”?
“Actual Study Completion Date :
?November 2016
A spin would be that 208 week data will not be compiled in time.
An alternative answer would be that it’s an unblinded trial and thus they know what the 208 week data shows, and that’s why they are presenting 104 week data instead.
Actual Study Start Date :
December 2014
Actual Primary Completion Date :
November 2015
Actual Study Completion Date :
November 2016
https://clinicaltrials.gov/ct2/show/NCT02244541?term=Anavex&draw=2&rank=1
I’m addressing this post to you because you appear to have first hand knowledge far beyond most of us here.
“Using these parameters, MTD was determined at 50.58 mg, i.e., when this dose is administered, a DLT event will occur in half of the 5% most frail patients in the population.
These results closely reflect the practical course of the study where 25% of the patients remained on their initially allocated dose level of 50 mg while 75% of the total number of patients remained in the 30 mg dose level after five weeks of treatment.”
1. I assume “DLT” stands for “dose limiting toxicity”?
2. If only half of the 5% of the most frail patients should experience a “dlt” then why did they reduce 75% of the patients who were initially assigned to the 50 mg group?
Assuming that they divided half of the 32 patients to each planned arm ( 30 or 50 mg oral capsule) I believe it would mean that of the 16 assigned to 50 mg, 12 had to have their dosing reduced.
Although they don’t specify say “why” they reduced the dosage , it seems logical to me that they somehow felt that they “had” to reduce the dosage, rather than they just decided to do it.
Why would they have to reduce the dosage if patients were experiencing only mild to moderate AE’s and none were “SAE’s”? Is that common practice?
“Experimental: Anavex2-73 30 mg oral formulation
Participants will receive the 30 mg Anavex2-73 hard gelatin capsule orally once daily for 52 weeks.
Drug: ANAVEX2-73 Oral
30 mg hard gelatin capsule
Experimental: Anavex2-73 50 mg oral formulation
Participants will receive the 50 mg Anavex2-73 hard gelatin capsule orally once daily for 52 weeks.
Drug: ANAVEX2-73 Oral
50 mg hard gelatin capsule
https://clinicaltrials.gov/ct2/show/NCT02244541?term=Anavex&draw=2&rank=1
https://anavex.com/wp-content/uploads/New-Alzheimers-Drug-ANAVEX-2-73-Phase-2A-Study.pdf
You are reading it incorrectly.
“considering United Therapeutics recently agreed to sell its Rare Pediatric Disease Priority Review Voucher to a subsidiary of AbbVie for $350 million.”
It was an example value of what a voucher “if received could” have been worth to CTIX (now IPIX). Never came to fruition!
Sigh. The salable voucher only comes with approval for sale of the drug for the priority review indication.
CTIX never even started a trial for retinoblastoma. If they wanted they could begin the trial and would be given priority review for their trial but if and only if the trial was successful would they get the second prv voucher that they could sell if they could find a buyer.
Their Kevetrin Ovarian cancer trial in adults failed. So they will probably never run the retinoblastoma trial.
My example price was an old one I had handy, prices paid for the voucher have fallen.
“Priority review voucher prices fall again after Spark’s $110m sale”
https://pharmaphorum.com/news/spark-sells-priority-review-voucher-to-jazz/
Still roughly AVXL’s current market cap. .
But again, it only comes when and if the FDA approves Anavex’s drug for sale to treat RETT Syndrome.
As I understand it, the initial designation is used for the trial you are performing. The second one comes as a “reward” that can be used for a drug that would otherwise not qualify for priority review but it only comes when and if the drug is approved for sale by the FDA. A company can use that voucher to speed up one of their own trials or they can sell the voucher.
What is a priority review vouche r and when is it awarded?
Under section 529(a)(2) of the FD&C Act, a priority review voucher is a voucher that FDA
issues to the sponsor of a rare pediatric disease product application at the time of the marketing application approval. This voucher entitles the holder to designate a single human drug
656 application submitted under section 505(b)(1) of the FD&C Act47 or section 351 of the PHS Act
657 as qualifying for a priority review. Such a subsequent application would not have to meet the
658 usual requirements for a priority review, but it would have to be submitted after the approval of
659 the rare pediatric disease product application.
https://www.fda.gov/media/90014/download
Not that I can find. Not surprising though because imho their management team was not as skilled at the financing aspect of biotech as Anavex’s management.
Although today’s news is good, I would hope folks keep it in prospective. It’s not that difficult to get the designation Anavex received. Kevetrin was a flop.
“Anavex Life Sciences Receives Rare Pediatric Disease Designation from FDA for ANAVEX®2-73 (blarcamesine) for the Treatment of Rett Syndrome “
“Cellceutix Corporation (OTC: CTIX) (the "Company"), a clinical stage biopharmaceutical company developing innovative therapies with oncology, dermatology, anti-inflammatory and antibiotic applications, is pleased to announce that on November 30, 2015 the U.S. Food and Drug Administration (FDA) granted Rare Pediatric Disease Designation to Kevetrin for the treatment of retinoblastoma, a rare form of eye cancer that begins in the retina, the light sensitive nerve tissue that lines the back of the eye. Retinoblastoma is most generally found in children, usually before the age of three, and rarely found in adults. It is sight threatening and potentially fatal if not diagnosed early.”
I believe efficacy is the hurdle now. Dosing seems set.
“AbbVie buys special review voucher for $350 million”
https://www.reuters.com/article/us-abbvie-priorityreview-idUSKCN0QO1LQ20150819
Have to actually get the approval to market the drug by successfully completing the trials first but the rpdv is worth a lot of money.
I would classify it as prudent management.
You sure the unblinded, subjective, results from the A2-73 Rett trial were not impacted by things like this?...
“She KNOWS it works and she’s waiting very patiently for it. Sometimes when she’s very upset, I tell her…when Trofinetide comes, this will be alright… and she calms right down.”
https://trailtoatexastrial.wordpress.com/
Why wouldn’t it be a good idea to take a peek at top line data before actually telling investors the trial is finished? That way, if things don’t look promising, management can put more money in the bank before the stock price is impacted negatively.