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“Okay and last question on the dose that is currently valued in the Parkinson's dementia, can you remind us how did they compare to the higher concentration or low concentration that you achieved in the Alzheimer's study?”
“Yes, so the dose is actually very similar to the dose in the Alzheimer's Phase 2a study where we have – we are aiming for a high dose and a medium dose and we believe both doses have potential to be efficacious, both the medium dose as well as the high dose.
PDD trial doses:
Concentration unit mg milligram(s)
Concentration number 10
Concentration number 20
https://www.clinicaltrialsregister.eu/ctr-search/trial/2017-004335-36/ES
Looks muddled to me.
Sorry for the last post. That was some horrible advice I offered. Never a good idea to make assumptions based on something posted here.
No one should be basing their buy/sell decisions on any information I offer on this board.
As I recall, there was a question about the age groups that would be allowed in the PDD trial. I emailed the CRO and consequently the age question was resolved and simultaneous the doses were added.
I believe there are multiple steps by different entities that all need to send and receive and input information correctly for the trial registrations to be entered correctly, so there does indeed appear multiple opportunities for factual errors.
Personally I believe the doses Anavex probably provided to the CRO were probably correctly relayed to Spanish site by the CRO , but that’s just my opinion.
Thanks for pointing that out, I missed it. But the following makes it confusing imho.
“The range of doses employed here (1-30 mg/kg PO) have been used in numerous animal disease models with improvements observed in both behavioral and biochemical readouts. Since the mice equivalent human plasma exposures correspond to human doses of 10-50 mg PO, which have been assessed in previous ANAVEX®2-73 clinical studies, these results pose the possibility that S1R receptor occupancy in humans is similar to that found in mice”
I should note that occupancy figure is for “whole brain” but I believe at least one source (if I recall correctly) showed that A2-73 concentrations varied by different brain regions but didn’t show max occupancy of each region on a dose dependent scale so that might play a factor in dosing schemes.
Possibly, but remember with a masked/blinded trial, results are not evident until unblinding, which doesn’t occur until trial completion.
I have a few “if” “then” comments for your perusal.
“If”
management believes 50mg is the “therapeutic dose”
“Then”
one might be well served to ask themselves why the PDD trial was designed using only 10 and 20 mgs
“The therapeutic dose will be a target of 50mg; however, the final dose will be determined based on the your tolerance. “
https://reec.aemps.es/reec/public/detail.html
“If”
The “mid” and “high” dose of the Alzheimer’s trial is indeed the same as the “mid” and “high” dose of the PDD trial
“Then”
Why is the Alzheimer’s 2b/3 trial also being run with doses well below the “target dose”
“If”
The graph on page 22 represents patients on doses of 10,20,30,40 and 50 mgs and dose roughly corresponds to concentration
http://anavex.com/wp-content/uploads/Anavex-Presentation-March-2018.pdf
“Then”
Aren’t most of the patients on the left side of the graph probably on the 10mg dose?
Does management plan on doing the same thing with the possible Alzheimer’s OLE as they are apparently doing with the PDD OLE?
Here is some DD that seems pertinent imho.
————
quote] Well that is another gap to bridge, I mean from 10mg or 20mg to 50mg is hefty titration jump. This again raises the question why such low doses to start with given that the P2a AD trial has already establish that >4ng/mL blood contraction of A2-73 is the therapeutic window and that high concentration is correlated with high dose? Guess there is a tolerability issue to deal with - not sure what else one could conclude? [/quote]
Warning...My unqualified speculation follows:
What is going on with the whole dosing issue?
From the moment the Michelle Sullivan/Missling article was published, I proposed that there just might be something going on with the dosing/tolerability.
“Dizziness was the most common adverse event (20 incidents in 15 patients), followed by headache (16 in 10 patients). Most (94%) occurred in the first week of treatment. All were mild or moderate. Headache and dizziness are considered signs that patients are approaching their maximum tolerated dose, Dr. Missling said.
The company’s task now is to find a standard minimum dose that is strong enough to get patients to at least 4 ng/mL plasma level, without inducing these side effects”
Setting at least one dose in the PDD at 50 mgs daily would have probably put the matter to bed, (for me anyway). Instead, Anavex apparently decided to use 10 and 20 mgs and labeled those PDD doses “high” and “mid” on the U.S. CTtrial registration site. Only by checking the EU registration would an investor be aware that Anavex was only using 10 and 20 mgs daily in the PDD trial. Do those facts mean anything? It could simply mean management believed that animal model preclinical testing indicated that a 10 and 20 mg daily oral dose would be sufficient to produce the desired improvements in humans suffering from PDD (regardless of what dose preclinical testing indicated would be necessary for Alzheimer’s patients.)
The note added to the OLE PDD certainly adds some doubt to that theory.
“You will receive ANAVEX2-73 if they participate in this study. The therapeutic dose will be a target of 50mg; however, the final dose will be determined based on the your tolerance.”
https://reec.aemps.es/reec/public/detail.html
Based on the new revelation from the OLE PDD, my current working theory is that either the regulating authority would not allow Anavex to use higher doses ...or.. management was concerned that a higher fixed dose would result in too many dropouts (which was imho also why Anavex added the lower doses to the 2A Alzheimer’s trial.)
“Three patients withdrew because of an adverse event in the first 57 weeks; no one has withdrawn because of a side effect since then.”
https://www.mdedge.com/clinicalneurologynews/article/152595/alzheimers-cognition/development-sigma-1-receptor-agonist?channel=180
More under qualified speculation...
What might be happening?
The phase 1 dosing trial which guided Anavex to use 50 mgs in the 2A trial used young patients.
“16 subjects divided into 2 cohorts of 8 subjects:
Cohort A (n=8) and Cohort B (n=8), replacement of drop out subjects for following dose steps (total: 22 subjects)
Main criteria for inclusion:
Healthy male Caucasian subjects between 18 and 55 years
https://anavex.com/wp-content/uploads/A-Phase-1-Dose-Escalation-Study-to-Investigate-Safety.pdf
But later Anavex seems to have discovered something...
“Younger subjects (>18to<65yr) clear the drug twice as fast as elderly Alzheimer’s disease subjects (>65 yr)”
https://www.anavex.com/wp-content/uploads/2018/05/Anavex-ANAVEX2-73-CTAD-Phase-2a-November-2017.pdf
I propose that this difference in the clearance rate between young and old people might be affecting the MTD of Alzheimer’s patients. Seem reasonable?
Note the Methodology Maximum Tolerated Dose (MTD) section of the following poster.
https://anavex.com/wp-content/uploads/New-Alzheimers-Drug-ANAVEX-2-73-Phase-2A-Study.pdf
I believe that section might explain why doses are being limited even before SAE’s occur.
“More precisely, the dose limiting toxicity (DLT) was conceived as an overall event, composed of several graded AEs, referred to as joint toxic events (JTEs):
https://anavex.com/wp-content/uploads/New-Alzheimers-Drug-ANAVEX-2-73-Phase-2A-Study.pdf
See if you can reconcile the following statements from the poster. (I cannot)
“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”
“It can be concluded that doses lower than 50.58 mg could be tolerated by 5% of the most frail patients, whereas, doses higher than 70.28 mg could be administered to 5% of the most robust patients in the population.
https://anavex.com/wp-content/uploads/New-Alzheimers-Drug-ANAVEX-2-73-Phase-2A-Study.pdf
A bit more DD in an already excessively long post.
“If”
The Sigma 1 receptor is where A2-73 is performing it’s magic
“Then”
Why would the dose need to be higher than 10 mgs if receptor occupancy maxes out at that dose?
See chart in upper right.
“Figure 3. This graph represents the percent receptor occupancy in whole brain with ANAVEX®2-73 using the binding potentials calculated from a 60-minute dynamic PET scan...”
https://www.anavex.com/wp-content/uploads/2018/07/AAIC_2018-PET_Anavex_Final.pdf
Cheers, F1
“ANAVEX2-73 has been tested in humans in two studies to ensure the safety and tolerability of the study drug. The two studies were in adults and ANAVEX2-73 was given in oral form. We want to get more information about how ANAVEX2-73 might improve cognition in Parkinson’s disease with dementia.
You will receive ANAVEX2-73 if they participate in this study. The therapeutic dose will be a target of 50mg; however, the final dose will be determined based on the your tolerance. “
https://reec.aemps.es/reec/public/detail.html
N. Competent Authority Decision Authorised
N. Date of Competent Authority Decision 2018-07-04
“NEW YORK – October 30, 2018 – Anavex Life Sciences Corp. (“Anavex” or the “Company”) (Nasdaq: AVXL), a clinical-stage biopharmaceutical company developing differentiated therapeutics for the treatment of neurodegenerative and neurodevelopmental diseases including Alzheimer’s disease, Parkinson’s disease, Rett syndrome and other central nervous system (CNS) diseases, today announced that it has enrolled the first patient in its Phase 2 double-blind, randomized, placebo-controlled, 14-week safety and efficacy trial of ANAVEX®2-73 for the treatment of Parkinson’s disease dementia (PDD).
Note the red asterisk.
I’m not seeing the “start date” . Am I missing it or are you referring to the date the competent authority signed off on the trial?
Date of Competent Authority Decision 2019-12-05
N. Ethics Committee Opinion of the trial application Favourable
N. Ethics Committee Opinion: Reason(s) for unfavourable opinion
N. Date of Ethics Committee Opinion 2019-10-01
https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-002678-29/ES
Can we at least agree that the OLE shouldn’t have started before the ethics committee signed off?
Edited: I see it now but notice the red asterisk. I don’t see the explanation of the asterisk though.
LAST UPDATE: 16/01/2020
Authorization
25/11/2019
Start of Trial
16/01/2020
Why would these two dates be different if it’s just a paperwork issue?
https://reec.aemps.es/reec/public/detail.html
I just noticed this:
“Open Label Extension Study for Patients with Parkinson¿s Disease with Dementia Previously Enrolled in ANAVEX2-73-PDD-001 Study for Continued Safety Assessment “
“ The drug being tested in this study is called ANAVEX2-73. Since it is still being studied (investigational), it is not yet approved by the European Medicines Agency (EMA), the Spanish Agency of Medicines and Medical Devices (AEMPS), the U.S. Food and Drug Administration (FDA), or the Australian Therapeutic Goods Administration (TGA), and doctors cannot prescribe it.
Cognitive impaired patients might have brain cellular dysfunction or cellular stress. In neurodegenerative diseases, like Alzheimer’s and Parkinson’s diseases, chronic cellular stress is possibly caused by age-correlated build-up of cellular insult and hence chronic cellular stress. ANAVEX2-73 activates a protein in the brain called sigma-1 receptor, which function is to reduce cellular stress and stimulates recovery of cell function when activated.
ANAVEX2-73 is a drug that may help regulate behavioural, cognitive, and motor symptoms in patients with Parkinson’s disease with dementia.
ANAVEX2-73 has been tested in humans in two studies to ensure the safety and tolerability of the study drug. The two studies were in adults and ANAVEX2-73 was given in oral form. We want to get more information about how ANAVEX2-73 might improve cognition in Parkinson’s disease with dementia.
You will receive ANAVEX2-73 if they participate in this study. The therapeutic dose will be a target of 50mg; however, the final dose will be determined based on the your tolerance.
https://reec.aemps.es/reec/public/detail.html
Makes me think they may be titrating in the OLE?
It might be a good way to get some idea of where to set expectations for the blinded portion of the trial by seeing how the newly baselines ole patients respond to A2-73. I wonder if they plan to move everyone to the “high” dose, or do both high and medium dose? Probably be more informative to use both imho.
P.S.
#6 and #8 support your theory of 2b/3 requiring hidden doses but #12 apparently does not.
https://clinicaltrials.gov/ct2/results?cond=&term=2b%2F3&cntry=&state=&city=&dist=
If by chance “high” and “medium” doses in the Alzheimer’s trial are indeed only 10 and 20 mgs daily, would that affect your calculations of the probability of success vs 30 and 50 mgs daily?
Correction: Concentration not dose.
Page 22
http://anavex.com/wp-content/uploads/Anavex-Presentation-March-2018.pdf
Would the “high” dose be the most effective dose if the graph portrayed the low dose as 0-4 the mid dose as 4-8 and the high as 8-12?
What was the justification for drawing the graph with unequivocally divided dose ranges?
Quote:
"Suppose I told you that on the ADAS-cog you should expect 48.8% of the patients in Anavex’s trial that are taking the highly effective drug Denepezil to remain the same or improve after 1 year, if A2-73 is completely ineffective?"
“Progression of mild Alzheimer’s disease: knowledge and prediction models required for future treatment strategies
https://alzres.biomedcentral.com/articles/10.1186/alzrt210
See Table 2
https://alzres.biomedcentral.com/articles/10.1186/alzrt210/tables/2
ADAS-cog (0 to 70) score, improved/unchanged patients (%)
12 months
48.8
Well played.
”Nevertheless, the trial must be read as another negative one, said David S. Knopman, MD, who moderated a press briefing where the data were presented.
“I must say I am disappointed by the results because in my view of clinical trials forged from 30 years of experience, the only thing that really counts is the prespecified primary outcome,” said Dr. Knopman of the Mayo Clinic, Rochester, Minn. “I think the secondary results are interesting, especially imaging findings. But our experience of secondary analyses in this field is that they are fraught with hidden biases. And because this is a small subset of just 15%, it’s very difficult to interpret.”
So if Anavex management believes A2-73 works better alone, they probably should have included it as a check in their “endpoints” of the 2b/3.
Did they?
Primary Outcome Measures :
ADAS-Cog (Alzheimer Disease Assessment Scale-Cognition) [ Time Frame: 48 weeks ]
Change from baseline to week 48 in cognition according to the Alzheimer Disease Assessment Scale-Cognition (ADAS-Cog) compared to placebo
ADCS-ADL (Activities of Daily Living) [ Time Frame: 48 weeks ]
Changes from baseline to week 48 in ability to perform daily activities according to the Activities of Daily Living Scale (ADCS-ADL) compared to placebo
Secondary Outcome Measures :
Number of participants with treatment-related adverse events as assessed by CTCAE v4.03 [ Time Frame: 48 weeks ]
Assess the safety and tolerability of ANAVEX2-73 compared to placebo
CDR-SB (Clinical Dementia Rating Scale Sum of Boxes) [ Time Frame: 48 weeks ]
Change from baseline to week 48 on Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) compared to placebo
RSCAQ sleep score [ Time Frame: Weeks 0, 4, 12, 24, 36, and 48 ]
To evaluate whether ANAVEX2-73 improves sleep continuity as assessed on a serial basis (weeks 0, 4, 12, 24, 36, and 48) with a questionnaire that assess reported sleep continuity (RSCAQ)
Other Outcome Measures:
Number of participants with change of brain volume assessed by MRI [ Time Frame: 48 weeks ]
Structural (and optional ASL) MRI scan assessments characteristic for AD pathophysiology from baseline and compared to placebo at +48 weeks
Blood assessment [ Time Frame: 48 weeks ]
Blood assessment from baseline and compared to placebo at +48 weeks: Abeta40, Abeta42, T-tau, NFL, YKL-40, BACE1 concentration
CSF assessment [ Time Frame: 48 weeks ]
Changes in CSF parameters (Abeta40, Abeta42, T-tau, P-tau, NFL, YKL-40, neurogranin, BACE1 concentration) characteristic for AD pathophysiology from baseline and compared to placebo at
+48 weekstreatment differences within subgroups will be performed
Number of participants with pre-specified genetic variants [ Time Frame: 48 weeks ]
AD relevant pre-specified genetic variants will be assessed. Statistical testing of treatment differences within subgroups will be performed
https://clinicaltrials.gov/ct2/show/NCT03790709?term=Anavex&draw=2&rank=5
Ok, take a deep breath and read slowly. I’m going to try and put this “placebo” issue to bed for you.
Group one says placebo’s are bad and we don’t need em (I assume because they believe it forces the patients within a current trial to suffer needlessly when a historical control value could be used instead) (or it denies patients access to the “miracle drug” for longer than necessary.)
Group two says, ya gotta have placebos because of, well, because ya gotta know if it’s the drug working or you are simply observing a “placebo effect” and mistaking it for a positive drug effect.
Here is what both groups seem to misunderstand.
Until the current “miracle cure du jure” for Alzheimer’s is approved, what is someone who is diagnosed with Alzheimer’s to do? (Aside from taking a complete approach and improving diet and exercise and doing mental exercises etc.) I mean what would their doctor recommend they do? Take a prescription for the current standard of care for Alzheimer’s, correct?
So if you allow folks within your clinical trial for Alzheimer’s to be on the current standard of care medication, then you have not forced them to “suffer as a placebo participant” now have you? Perhaps you have delayed them getting the “miracle cure du jure” at least until they enroll in the extension, but by doing so, if the drug actually works, you provide much stronger evidence of efficacy that actually should bring your drug to the masses more quickly.
So if Anavex is allowing folks on Donepezil etc. to enter their trial and be randomized to either the placebo group or the active drug group then the “placebo is cruel” argument is moot now isn’t it.
So is Anavex allowing patients on SOC drugs in their trial?
I don’t see anything that indicates someone on an stable dose of Donepezil couldn’t be in either the placebo or active drug arm of their 2b/3 trial. Do you?
“Being treated with psychoactive medications on a stable dose for less than 3 month.”
https://clinicaltrials.gov/ct2/show/NCT03790709?term=Anavex&draw=2&rank=5
Intervention Model Description:
Randomized 1:1:1 to two different ANAVEX2-73 doses or placebo
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Now please read the following link in it’s entirety and see how it relates.
https://www.mdedge.com/clinicalneurologynews/article/110885/alzheimers-cognition/alzheimers-anti-tau-drug-fails-phase-iii
“The 15-month study comprised 891 patients with mild-moderate Alzheimer’s disease. Most of these (85%) were taking standard-of-care symptomatic Alzheimer’s disease medications. Patients were randomized to 75 mg twice daily, 125 mg twice daily, or placebo, which necessarily consisted of a small amount of the medication. LMTX is a derivative of the dye methylene blue and colors urine when excreted. The inactive dose is enough to provide that color so that blinding can be maintained.
Patients were grouped according to whether they took the study drug as add-on therapy (85%) or as monotherapy (15%)”
Oh look, they even had “super responders”.
“At the study’s end, patients in the monotherapy group taking 75 mg twice daily had declined 6.3 points less on the ADAS-cog than did the grouped placebo patients, indicating preserved cognition. Those taking 125 mg twice daily declined 5.8 points less than did the grouped placebo patients. On the ADCS-ADL, patients taking 75 mg twice daily scored 6.5 points higher than did the placebo group, indicating better function, and those taking 125 mg twice daily scored 6.9 points higher than did the placebo group.
Lateral ventricular volume expansion on MRI was significantly less than that seen in placebo-treated patients. For those taking 75 mg twice a day, ventricular expansion was reduced by 38%; for those taking 125 mg twice a day, expansion was reduced by 33%. This was accompanied by significant slowing of whole brain atrophy, Dr. Gauthier said, adding that this finding has never been reported in an Alzheimer’s drug trial.”
And yet.....
“Nevertheless, the trial must be read as another negative one, said David S. Knopman, MD, who moderated a press briefing where the data were presented.
“I must say I am disappointed by the results because in my view of clinical trials forged from 30 years of experience, the only thing that really counts is the prespecified primary outcome,” said Dr. Knopman of the Mayo Clinic, Rochester, Minn. “I think the secondary results are interesting, especially imaging findings. But our experience of secondary analyses in this field is that they are fraught with hidden biases. And because this is a small subset of just 15%, it’s very difficult to interpret.”
Looks cold but crisp and clear out my window.
Discretion is often the better part of valor. Success many years in the future will probably bring much the same reward to a CEO as success next year but with more years salary on top.
How did rushing headlong into blinded trials work out for Alkon?
Very smart imho.
If I was in his position pulling down a cool half million dollar salary a year it would take me many many years to complete a blinded trial. So far so good.
Had the CEO stated that the enrollment wouldn’t be complete until next year, then that might have made the stock a strong candidate for a short attack with no possible catalyst possible until next year.
Also easier to tap LPC when investors are expecting a near term catalyst. You don’t think a CEO who bought 375 shares at a time is not good at influencing retail investors do you?
Expenses are up, income needs to match the increase to keep making payroll.
“Patients in both analyses were grouped by plasma level, not by their dosage level, although Dr. Missling said higher dosage generally correlated with higher plasma levels.
https://www.mdedge.com/clinicalneurologynews/article/152595/alzheimers-cognition/development-sigma-1-receptor-agonist
I thought correlations were a good thing.
Yes, it’s probably the metabolite instead.