The figures above are from aducan's 2016 Nature article.
These initial results appear to have been largely replicated in the phase 3s.
It was especially impressive to see the amyloid imaging from the earlier study predicting near exactly what was released on Tuesday.
The top figure is of particular importance.
Those patients who had >=1 SD amyloid removal relative to placebo (It is not entirely clear to me what this means)
saw their MMSE score stabilize after 1 year. Those with <1 SD saw a decline of 3 MMSE points. I am also unclear why they do
not include a star or two in these 2 subfigures as it would seem as though they had hit significance. I had not fully expected that there could be this much clinical benefit; I had thought that perhaps everyone would be mostly average. Stabilizing MMSE for at least a year is not average. Clarifying how long the benefit would last and how many would benefit from such stabilizations will be eagerly awaited.
It would be important to report a similar figure for the current results. Often in clinical patients will be grouped merely by treatment arms without considering what change had occurred in the independent variable (here amyloid). When everyone is binned together merely by treatment the actual benefit can become obscure. So instead of binning by treatment one could bin by amyloid change; opening up the theoretical possibility that some of those on placebo could be binned in the large amyloid reducers group.
The top line number of 23% reduction in decline in the high dose group would take on an entirely different meaning if some fraction did not, in fact, have any decline in MMSE etc.. Given that there were over 3200 patients in the phase 3s, there should now be very good information about the amyloid cognition relationship. Perhaps even some patients would be +2 SD and have actually improved on MMSE?
The second figure gives us the actual scores for MMSE in the earlier trial. Placebo decline by ~3 points over a year which is what is expected, the 10 mg/kg declined by .5 (p<0.05). I am not sure how to reconcile this large reduction in decline and the much smaller reported decline in the phase 3s (~ 23% reduction for high dose OTC on MMSE).
[Edit: Notice that these Middle figures are probably what lead to the dosing confusion. They show that the 6 mg dose was not that effective, but that the 3 mg and 10 mg doses were. That result was not very plausible (especially in hindsight). Both the 6 mg and the 3 mg were likely misleading. The 3 mg dose was overstating the benefit and the 6 mg dose was understating it. The phase 3 trials dosed epsilon 4s with 3 mg in the low dose; over an 18 month trial that would not be enough and that is the result reported. It is not easy to see how you could go from a minimal effect in the 1 mg dosage to a big effect with the 3 mg dose. It would have probably been a much easier choice to ignore the 3 mg dose and go right for the 10 mg, though there was likely concern that ARIA might interfere with trial completion.
Nonetheless, it is best to get over all this back talking because the confusion largely resulted from deciding to take a miss on the phase 2s. The phase 2s would have taken years and years more time. So while everything would have been neat and tidy and lined up in triplicate it would have meant that desperate families would be a great while aways from receiving an effective treatment.]
Last figures show the brain amyloid. Increasing doses clears out more and more amyloid.
Celebration Thread! Biogen is going to the FDA with Aducan.
Re: Celebration Thread! Biogen is going to the FDA with Aducan.
Last edited by J11 on Mon Oct 28, 2019 5:05 pm, edited 1 time in total.
Re: Celebration Thread! Biogen is going to the FDA with Aducan.
Is there a blood test out there yet to detect amyloid?
It would be such a great relief to actually proactively manage my disease risk now that there is something to lower amyloid and risk.
I never want to take a look of a PET scan of my brain and see it all filled up with amyloid.
Much better to think of this as a lifestyle illness.
How much for an injection of say 50 mg aducan?
Will it be available off-label once it is approved?
There are probably a whole bunch of people interested in this for pre-dementia use.
What is the typical lifetime amyloid accumulation curve for epsilon 34s?
It would be such a great relief to actually proactively manage my disease risk now that there is something to lower amyloid and risk.
I never want to take a look of a PET scan of my brain and see it all filled up with amyloid.
Much better to think of this as a lifestyle illness.
How much for an injection of say 50 mg aducan?
Will it be available off-label once it is approved?
There are probably a whole bunch of people interested in this for pre-dementia use.
What is the typical lifetime amyloid accumulation curve for epsilon 34s?
Re: Celebration Thread! Biogen is going to the FDA with Aducan.
These are very interesting!
Extended dosing of aducan was given to patients in the early trial.
[Edit: I did not look at the above graph carefully enough. The placebo was not a true placebo.
After 52 weeks it was actually a treatment arm at 3 mg/kg (or 6 mg/kg this is somewhat confusing).
So the actual benefit for aducan is being understated for the last 2 years of the LTE.
The placebo is a treatment arm! Somewhat sneaky. On the graph the deflection from treatment is not completely obvious, though the reported 8 point MMSE decline on placebo did seem on the light side. This could be looked up as this is known to high precision.]
The bottom figure shows that at a dose of 10 mg/kg, a minimum amyloid level is reached after about 110 weeks.
Seems somewhat odd to me that they would set up a dosing plan for 78 weeks in the phase 3s, when they knew
before shutting it down with the futility analysis that maximal amyloid reduction had not yet been achieved.
Looks like they might be able to move down another 7 centiloids of amyloid possibly this will mean that there is
more cognitive benefit that can be offered to those who were on the 10 mg/kg dose. Hopefully, the plan when they
resume is to dose for at least those additional 32 weeks.
The MMSE figure on top gives the longer term view of the effect of aducan. Over the 3 years placebo fell by about 8 points which is quite a lot, though as expected. It does remind us what the cognitive trajectory is like once the neurodegenerative process becomes active. Hopefully this will be enough to scare people into thinking prevention and not trying to avoid self-care.
High dose aducan kept the loss to ~2 point for the first 2 1/2 years, though the final data point fell off a fair amount to ~4 point MMSE decline. At week 132 the cognitive gap between placebo and 10 mg/kg is nearly twice as large as it was at week 76. Here again the phase 3 trials as reported as of now are probably understating a substantial amount of the positive news that would occur with a trial continuation as demonstrated in the earlier extension trials.
It remains confusing for me what they were referring to in the Biogen presentation with the 23% reduction etc. . In the top MMSE figure from the earlier trial , we have 10 mg/kg with a decline of ~1 MMSE point and the placebo at ~4 points 76 (~78 weeks). I would call that 1 in 4 = 25% of the decline (i.e., a 75% reduction in the decline). Though in the presentation the phrasing seems to be saying that there was a 23% reduction in decline which is different and much smaller. With 4 points for the placebo a 23% reduction in the decline would be ~1 point making a 3 point decline for the 10 mg/kg group. Yet, it was measured in the earlier trial as 1 not 3.
Extended dosing of aducan was given to patients in the early trial.
[Edit: I did not look at the above graph carefully enough. The placebo was not a true placebo.
After 52 weeks it was actually a treatment arm at 3 mg/kg (or 6 mg/kg this is somewhat confusing).
So the actual benefit for aducan is being understated for the last 2 years of the LTE.
The placebo is a treatment arm! Somewhat sneaky. On the graph the deflection from treatment is not completely obvious, though the reported 8 point MMSE decline on placebo did seem on the light side. This could be looked up as this is known to high precision.]
The bottom figure shows that at a dose of 10 mg/kg, a minimum amyloid level is reached after about 110 weeks.
Seems somewhat odd to me that they would set up a dosing plan for 78 weeks in the phase 3s, when they knew
before shutting it down with the futility analysis that maximal amyloid reduction had not yet been achieved.
Looks like they might be able to move down another 7 centiloids of amyloid possibly this will mean that there is
more cognitive benefit that can be offered to those who were on the 10 mg/kg dose. Hopefully, the plan when they
resume is to dose for at least those additional 32 weeks.
The MMSE figure on top gives the longer term view of the effect of aducan. Over the 3 years placebo fell by about 8 points which is quite a lot, though as expected. It does remind us what the cognitive trajectory is like once the neurodegenerative process becomes active. Hopefully this will be enough to scare people into thinking prevention and not trying to avoid self-care.
High dose aducan kept the loss to ~2 point for the first 2 1/2 years, though the final data point fell off a fair amount to ~4 point MMSE decline. At week 132 the cognitive gap between placebo and 10 mg/kg is nearly twice as large as it was at week 76. Here again the phase 3 trials as reported as of now are probably understating a substantial amount of the positive news that would occur with a trial continuation as demonstrated in the earlier extension trials.
It remains confusing for me what they were referring to in the Biogen presentation with the 23% reduction etc. . In the top MMSE figure from the earlier trial , we have 10 mg/kg with a decline of ~1 MMSE point and the placebo at ~4 points 76 (~78 weeks). I would call that 1 in 4 = 25% of the decline (i.e., a 75% reduction in the decline). Though in the presentation the phrasing seems to be saying that there was a 23% reduction in decline which is different and much smaller. With 4 points for the placebo a 23% reduction in the decline would be ~1 point making a 3 point decline for the 10 mg/kg group. Yet, it was measured in the earlier trial as 1 not 3.
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Last edited by J11 on Tue Oct 29, 2019 4:37 pm, edited 3 times in total.
Re: Celebration Thread! Biogen is going to the FDA with Aducan.
There's something else that I just thought of.
The placebo group when they get back on site are expected to be dosed with aducan.
Yet, these patients are no longer mild patients, after around 2-4 years they would likely be described as moderate.
However, the pharmas have went to great lengths to only enroll patients who are mild (~25-30 MMSE)
because past trials have found that amyloid medications did not seem effective with more advanced patients.
Of course, as soon as there is FDA approval a fair number of moderate and perhaps severe AD patients will demand to go off-label on the hope that it would help them. Ordinarily, a company might not be willing to invest in a moderate trial (due to the previous lack of efficacy) and just leave it somewhat vague as to whether it is or is not actually effective for this population. In this instance, though, Biogen is largely compelled to do this trial due to the pre-existing arrangements with patients to do an extension and the unavoidable fact that the patients are already set to be dosed.
This is great! It is a billion dollar shakedown of Biogen and is exactly what has given me optimism: There is a massive amount of wealth lying around and some of it can be redirected in unexpected ways to advance the cause. Biogen can always hedge and prespecify that the patients are now moderate in order that their existing dataset is not impaired with the new results.
Strangely, there is another interesting observation: aducan might even be effective in the moderate patients. The Grifolis amyloid treatment reduced progression in moderates by over 60%. Being able to provide evidence of efficacy in more advanced patients would enlarge the market for aducan. While it would not be placebo controlled, 1,000 of the placebo patients would offer a large amount of information, especially as their cognitive trajectories are already well-documented. Families could then make an evidence based (though not randomized) decision that likely would be highly informed. Having such a large amount of clinical research on these moderates will be of great benefit to Alzheimer families trying to provide the best care for their loved ones.
The placebo group when they get back on site are expected to be dosed with aducan.
Yet, these patients are no longer mild patients, after around 2-4 years they would likely be described as moderate.
However, the pharmas have went to great lengths to only enroll patients who are mild (~25-30 MMSE)
because past trials have found that amyloid medications did not seem effective with more advanced patients.
Of course, as soon as there is FDA approval a fair number of moderate and perhaps severe AD patients will demand to go off-label on the hope that it would help them. Ordinarily, a company might not be willing to invest in a moderate trial (due to the previous lack of efficacy) and just leave it somewhat vague as to whether it is or is not actually effective for this population. In this instance, though, Biogen is largely compelled to do this trial due to the pre-existing arrangements with patients to do an extension and the unavoidable fact that the patients are already set to be dosed.
This is great! It is a billion dollar shakedown of Biogen and is exactly what has given me optimism: There is a massive amount of wealth lying around and some of it can be redirected in unexpected ways to advance the cause. Biogen can always hedge and prespecify that the patients are now moderate in order that their existing dataset is not impaired with the new results.
Strangely, there is another interesting observation: aducan might even be effective in the moderate patients. The Grifolis amyloid treatment reduced progression in moderates by over 60%. Being able to provide evidence of efficacy in more advanced patients would enlarge the market for aducan. While it would not be placebo controlled, 1,000 of the placebo patients would offer a large amount of information, especially as their cognitive trajectories are already well-documented. Families could then make an evidence based (though not randomized) decision that likely would be highly informed. Having such a large amount of clinical research on these moderates will be of great benefit to Alzheimer families trying to provide the best care for their loved ones.
Last edited by J11 on Wed Oct 30, 2019 7:22 pm, edited 2 times in total.
Re: Celebration Thread! Biogen is going to the FDA with Aducan.
Thank you for your wonderful comments!
For those who cannot get Aducan... what about Biogen Ban2401?
Is it in the same family of drugs and have results at 30% reduction in cognitive decline been sufficient to suggest similar clinical ffficacy?
John P
For those who cannot get Aducan... what about Biogen Ban2401?
Is it in the same family of drugs and have results at 30% reduction in cognitive decline been sufficient to suggest similar clinical ffficacy?
John P
Re: Celebration Thread! Biogen is going to the FDA with Aducan.
Hi John P,JohnP wrote:Thank you for your wonderful comments!
For those who cannot get Aducan... what about Biogen Ban2401?
Is it in the same family of drugs and have results at 30% reduction in cognitive decline been sufficient to suggest similar clinical ffficacy?
John P
Right now no one can get aducanumab, although Biogen has said that will ask to re-start administration for those participants who were previously enrolled in the two cancelled trials. The study was ended based on a futility analysis in December 2018 which predicted that if trends stayed the same, the drug would not meet its predetermined primary outcome measure. Biogen appears to be planning to argue in early 2020 that the primary outcome WAS achieved in one trial by March 2019 and may still be achieved in the second trial before its planned completion date.
That would still make it likely that we are more than a year at the outside from approval of this drug. Even after that, I expect the FDA could require very specific diagnosis and monitoring for a few years at least.
BAN2401 is also an immunotherapy amti-amyloid drug. That doesn't mean it has the same mechanism of action or the same results as aducanumab. It has been considered to meet criteria for safety and efficacy in Phase 1 and Phase 2 trials.
A Phase 3 trial began in March 2019 and is planned to continue to March 2024, with an estimated 1566 participants in 154 locations in the US and abroad when all sites are up and running. (Each study site has to gain approval from its own Institutional Review Board before they can host the study.) The initial treatment period is 18 months, with a voluntary extension arm of 27 months, for a total of 45 months. Please note that the inclusion and exclusion criteria are very specific. In this case, it starts with a diagnosis of MCI or Mild AD, an age between 50 and 90, a positive amyloid PET scan and extensive screening. ApoE4 is NOT a criteria for participation.
Here is the link for the current study by Esai (a Japanese company) and Biogen, with a link in to Contacts and Locations:
BAN2401 Clinical Trial
Having been through the screening for the Generations twice (I ran out of time on the 90 day window due to an acute eye condition), I can assure anyone interested that you have lots of time to carefully consider the pros and cons of participation, to discuss with a nurse practitioner and/or M.D. any concerns, and for them to be sure that it is safe for you to undertake participation in the study.
4/4 and still an optimist!
Re: Celebration Thread! Biogen is going to the FDA with Aducan.
Thank you!
I believe I read that there was a 30% reduction in cognitive decline compared to placebo?
John P
I believe I read that there was a 30% reduction in cognitive decline compared to placebo?
John P
Re: Celebration Thread! Biogen is going to the FDA with Aducan.
RELATED: Biogen, Eisai's anti-amyloid drug slows Alzheimer's decline, but debate rages on
At CTAD, Biogen and Eisai tried to answer those suggestions with a series of analyses that they claimed show the APO4 carrier imbalance didn’t amplify BAN2401’s effects, and according to Eisai scientist Chad Swanson, Ph.D., senior director of clinical research for neurology, may in fact have underestimated its benefit as patients with the mutation actually did better on the drug than those without.
He said at the time that there was a “statistically meaningful effect of 30% less decline in disease progression seen for 10 mg/kg bi-weekly dose versus placebo at 18 months on ADCOMS [that] was driven by BAN2401 treatment effect and not an imbalance in subject allocation by APOE4 status.”
But the continuing skepticism about BAN2401 seems to stem from the small number of APOE4 carriers in the high-dose group relative to placebo and a pooled analysis of 10 mg/kg bi-weekly and monthly groups. The latter showed 21% less decline overall versus placebo on the ADCOMS score at 18 months, but that was skewed to the carrier group who had a 25% benefit compared to 6% for noncarriers.
Analysts at Jefferies said the data has some good elements but "seems a bit all over the place." In particular, they said it was encouraging that disease progression of carriers and noncarriers is generally consistent "and suggests that the placebo arm and carrier imbalance did not help drive the drug."
Eisai, and partner for this test BioArctic, still hope this confirmatory trial will prove to be a winner and help set up regulatory filings. But the history of AD drug development casts a long shadow, as we saw just yesterday.
Gunilla Osswald, Ph.D., CEO at BioArctic, remained upbeat, saying: “We are very pleased to see that the confirmatory phase 3 study with BAN2401 in early Alzheimer's disease is now initiated. There is a plan for fast recruitment and Eisai is targeting a final readout already in 2022.
“The phase 3 study is designed to confirm the previously observed positive phase 2b results in early Alzheimer's disease patients. The intention with BAN2401 is to slow down the progression of the disease and improve the quality of life for Alzheimer's patients.”
John P
At CTAD, Biogen and Eisai tried to answer those suggestions with a series of analyses that they claimed show the APO4 carrier imbalance didn’t amplify BAN2401’s effects, and according to Eisai scientist Chad Swanson, Ph.D., senior director of clinical research for neurology, may in fact have underestimated its benefit as patients with the mutation actually did better on the drug than those without.
He said at the time that there was a “statistically meaningful effect of 30% less decline in disease progression seen for 10 mg/kg bi-weekly dose versus placebo at 18 months on ADCOMS [that] was driven by BAN2401 treatment effect and not an imbalance in subject allocation by APOE4 status.”
But the continuing skepticism about BAN2401 seems to stem from the small number of APOE4 carriers in the high-dose group relative to placebo and a pooled analysis of 10 mg/kg bi-weekly and monthly groups. The latter showed 21% less decline overall versus placebo on the ADCOMS score at 18 months, but that was skewed to the carrier group who had a 25% benefit compared to 6% for noncarriers.
Analysts at Jefferies said the data has some good elements but "seems a bit all over the place." In particular, they said it was encouraging that disease progression of carriers and noncarriers is generally consistent "and suggests that the placebo arm and carrier imbalance did not help drive the drug."
Eisai, and partner for this test BioArctic, still hope this confirmatory trial will prove to be a winner and help set up regulatory filings. But the history of AD drug development casts a long shadow, as we saw just yesterday.
Gunilla Osswald, Ph.D., CEO at BioArctic, remained upbeat, saying: “We are very pleased to see that the confirmatory phase 3 study with BAN2401 in early Alzheimer's disease is now initiated. There is a plan for fast recruitment and Eisai is targeting a final readout already in 2022.
“The phase 3 study is designed to confirm the previously observed positive phase 2b results in early Alzheimer's disease patients. The intention with BAN2401 is to slow down the progression of the disease and improve the quality of life for Alzheimer's patients.”
John P
Re: Celebration Thread! Biogen is going to the FDA with Aducan.
The results for the highest dose group (injections every other week) showed reductions in decline ranging from 26% to 47%, with a 30% reduction on one measure. Here's a link to one synopsis, with a fair amount of detail. https://www.alzforum.org/news/conferenc ... ve-declineJohnP wrote:Thank you!
I believe I read that there was a 30% reduction in cognitive decline compared to placebo?
John P
And here's an excerpt from that article, with emphasis added by me.
So what were the results? Across the board, the antibody reduced amyloid in the brain. A time- and dose-dependent reduction saw PET SUVRs fall by up to 0.3 units in those on the highest dose, a 93 percent drop. Kramer said that on manual reads of the scans, 81 percent of treated patients went from amyloid-positive to amyloid-negative.
For the cognitive analysis...The 10 mg/kg biweekly group had a 47 percent reduction in cognitive decline as judged by the ADAS-Cog, and a 30 percent reduction on the ADCOMS. A 26 percent slowing on the CDR-SB was not significant. The 10 mg/kg monthly dose group—the one containing mostly APOE4 carriers—performed about midway in between placebo and the highest dose, showing a trend toward slower cognitive decline on the ADAS-Cog, ADCOMS, and CDR-SB but no statistical significance. The placebo group declined at a similar rate to placebo groups in recent large AD studies....
And how about ARIA-E? As with other antibodies, it occurred in a dose- and APOE-dependent way, 48 times total across all groups, including two in placebo. Just shy of 10 percent of participants in the highest dose had an episode of ARIA-E, as did seven of that group’s 48 APOE carriers. Most ARIA-E was detected only on MRI, though five instances caused headache, visual disturbances, or confusion; two of those were in the highest dose, Kramer reported. In toto, this amounts to less ARIA-E than seen with gantenerumab or aducanumab.
4/4 and still an optimist!
Re: Celebration Thread! Biogen is going to the FDA with Aducan.
Is this a good choice for a person with one copy of APOE4? Versus Cortexyme (gingivitis antibiotic?)
Trying to decide between 2 clinical trials?
Thanks
John P
Trying to decide between 2 clinical trials?
Thanks
John P
