Celebration Thread! Biogen is going to the FDA with Aducan.

[Julie G]

More: Expert panel votes down Biogen’s Alzheimer’s drug, and rebukes the FDA in the process

[NF52]

More: Expert panel votes down Biogen’s Alzheimer’s drug, and rebukes the FDA in the process

Thanks for linking to this Julie; here's one of the quotes from it that I think shows researchers taking great care in drug approval recommendations:

Joel Perlmutter, a neurologist at Washington University School of Medicine in St. Louis, said that the risk of approving aducanumab was actually greater than the risk of rejecting it. “If we approve something where the data is not strong we have a risk of delaying good treatment and effective treatment for more than a couple years,” he said.

Dr.Perlmutter may be referring to the reported rate of ARIA-E (Amyloid Imaging-Related Abnormalities-Edema) of up to 40% of participants at the recommended dose. That compares to a rate of about 9% for BAN-2401, which is beginning to be used in AHEAD 3-45, two trials in preclinical (healthy).

Two others promising drugs (among many in the pipelines) that Dr.Perlmutter may be waiting to see results from are ALZ-801, with an upcoming trial in healthy (preclinical) Apoe 4/4 carriers or CT11812 (Elaytra) which is designed to protect synapses by preventing toxic oligomers from binding to them.

It appears that after everything had been signed off by the FDA that they brought in some high level statisticians that had greater insight into how the trials could have been confounded...

Here's some additional summary on what the panelists saw as positives and negatives from Alz Forum (emphases added on the quotes):

The panelists agreed that the evidence for aducanumab removing amyloid plaques was strong, and commended Biogen for pushing the program forward. At the same time, they questioned whether the data gathered thus far showed that this amyloid removal was meaningful for efficacy, noting a weak correlation between plaque clearance and the slowing of cognitive decline, and a paucity of biomarker and pathophysiology evidence downstream of plaque removal.

Here's an excerpt from an article I posted about in August that explains the important knowledge gained from painstaking clinical trials in just the last few years about the need to target amyloid beta oligomers over removal of plaques: 4 drugs which may get approval in 3-5 years

Engagement of amyloid oligomers drives clinical and biomarker efficacy

A substantial body of evidence supports the role of Aβ oligomers as early triggers of AD pathology. Brain levels of neurotoxic soluble Aβ oligomers, rather than plaques or fibrils, correlate closely with onset and progression of AD symptoms [/b]. Aβ oligomers damage synapses, induce tau hyperphosphorylation and neuroinflammation, and impair memory formation in preclinical models, as well as brains of AD patients...agents that engage amyloid oligomers also reduce downstream tau pathology and cognitive decline .

The four late-stage anti-amyloid agents with clinical efficacy and biomarker effects include three injectable antibodies and the oral small molecule, ALZ-801... Aducanumab and gantenerumab preferentially target insoluble amyloid plaques and fibrils and engage oligomers only partially, while BAN2401 preferentially targets oligomers over plaques , and ALZ-801 selectively blocks the formation of Aβ oligomers without binding amyloid plaque

... ALZ-801 which selectively blocks the formation of Aβ oligomers showed significant, clinically meaningful effects on cognition and function in APOE4/4 homozygotes [31], which were similar in magnitude to BAN2401 benefits in APOE4 carriers. One explanation for the higher efficacy of these agents in APOE4 carriers versus noncarriers is their several-fold higher burden of soluble Aβ oligomers .

In remarkable contrast to the association between the level of engagement of soluble Aβ oligomers and clinical efficacy, no such association has been reported for the clearance of insoluble amyloid plaques and clinical efficacy.

In spite of our best prevention efforts, it appears we ApoE 4 carriers are magnets for amyloid beta oligomers. While I hope the FDA approves a "Phase Four" trial (in effect) to allow further study of aducanumab, I applaud the careful consideration by biostatisticians and continuing trials of other drugs.

[J11]

From what I understand as of now aducanumab was effective.
The confusion about the 301 study disappears when you understand the
problem that occurred with the dosing differences between 301 and 302.
In the below files it is noted that when you select for those 301 patients who
actually received the same dosing as the 302 patients they actually had the same
response.

Would have been good if they included the placebo patients in the figure below.
Also would have liked the actual correlation to be included with the slide.

Dose Response.GIF

https://www.fda.gov/media/143506/download
https://www.fda.gov/media/143508/download
https://www.fda.gov/media/143507/download

[roxanne]

Hi NF52: This is all well for people that are healthy but some people are desperate to try something that might work. I do know that science works slowly but boy, I cannot help but feel very angry at this turn of events. I have a brother that has MCI for the last 2 years and he's been kept stable with the protocol but I was so hoping for the FDA approval.

[J11]

NF52, the comment that there was minimal correlation between amyloid removal and the cognitive readout is strongly rebutted by my previous post. In the figure almost everything falls on the line. The only outlier is the nominal "high dose" 301 which is only a label as it actually was largely not high dose. The urls from my previous post spoke of how when you actually look at the de jure "high dose" 301 it did fall on the line as expected.

I am surprised that they would allow the extreme outliers to have so much potential influence on the outcome. Why didn't they show the waterfall of all the patients. Surprising to me that this would not have been a prespecified part of the analysis. Finding the centroid of the actual response would seem to me to be an important reportable finding of the trials. You want to have a good read out for how median patients did in the different arms and not have the result skewed by extreme outliers. It really would have been for the best if they had sourced the patients from an AD patient registry. You would then KNOW what their decline trajectory was even before entering the trial. You would have all that data on the trial computer to help you understand what was happening. Very disappointing that this knowledge seems to often be ignored.

[J11]

roxanne, is your brother enrolled in the aducan trials? 301 or 302?

[roxanne]

No, he's not, unfortunately, but I was hoping that the drug would have been approved in the next year or so. I have been following your posts and was very optimistic. It is so disappointing!!!

[J11]

I am sorry that my posts have raised your hopes beyond what might have been justified. However, from what I understand now aducanumab is actually an approvable medication. When you read through the FDA's own briefing document (especially the first 246 pages) it is transparently obvious that the FDA also believed that it should be approved. This is just one of the times when an organization has people rowing in different directions and it is not entirely clear which direction the boat will actually move after the net force is determined. The FDA and Biogen have been carefully analyzing the results from the phase 3 trials for a year and a half. Commentators who casually dismiss this effort are clearly not fairly recognizing the deep thought that has been expended.

What is also of interest is that BioArctic has a similar amyloid treatment in BAN2401 and this therapy has results quite similar to those of aducan. What is particularly odd was today BioArctic's stock had a meltdown even though it has already posted strong results. In fact, if aducanumab were to be approved then BioArctic could immediately submit BAN2401 for marketing approval because it has already accumuated clinical evidence on par (if not better than) aducan.

[NF52]

Hi NF52: This is all well for people that are healthy but some people are desperate to try something that might work. I do know that science works slowly but boy, I cannot help but feel very angry at this turn of events. I have a brother that has MCI for the last 2 years and he's been kept stable with the protocol but I was so hoping for the FDA approval.

Roxanne, I am so sorry about your brother's diagnosis of MCI. Please know that I have posted before about the promising results of aducanumab and am VERY GLAD that Biogen in March 2020 started an open-label study for 2,400 previous aducanumab trial participants, who will receive monthly injections of 10/kg for two years. No participants will receive a placebo. I know three people who are thrilled to be in this new trial themselves or with their partner--all of whom have a similar diagnosis to your brother. It is projected to run through September 2023.

What this trial will answer, that seemed to be a real concern of some on the review panel is safety, especially the risk in ApoE 4 carriers of ARIA-E Here's Wikipedia on ARIA-E:

ARIA-E refers to cerebral edema, involving the breakdown of the tight endothelial junctions of the blood-brain barrier and subsequent accumulation of fluid...The effect of ARIA-E depends on the severity and location of the edema. Symptoms may include headache, changes in mental state, confusion, vomiting, nausea, tremor and gait disturbances.

https://en.wikipedia.org/wiki/Amyloid-r ... ormalities

And here's what Clinical Trials.gov website shows for the risks they will be monitoring as Primary Outcome Measures (i.e. the most important results of the study):

Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Up to Week 118 ]
An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. A SAE is any untoward medical occurrence that at any dose results in death, life-threatening event, requires inpatient hospitalization, significant disability/incapacity or congenital anomaly.

Number of Participants with AEs Leading to Treatment Discontinuation or Study Withdrawal [ Time Frame: Up to Week 118 ]
An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.

Number of Participants with Amyloid-related Imaging Abnormality-Edema (ARIA-E) [ Time Frame: Up to Week 102 ]
Magnetic resonance imaging (MRI) readings will be used to assess ARIA-E severity as mild, moderate and severe.

Number of Participants with Amyloid-related Imaging Abnormality- Hemorrhage or Superficial Siderosis (ARIA-H) [ Time Frame: Up to Week 102 ]
MRI readings will be used to assess severity of ARIA-H microhemorrhages and superficial siderosis.

https://clinicaltrials.gov/ct2/show/NCT ... w=2&rank=1

I wish there was a way to determine the safety sooner. As J11 notes, and as I did also, there are several other promising drugs being tested on people with MCI. In addition, just last week I watched a conference talk which showed positive cognitive and behavioral effects from aerobic exercise in people with MCI. If you are interested in knowing about other drugs targeting MCI (one of which is a transdermal nicotine patch!) let me know on a post or PM what your brother's location is and I'd be glad to make a list for him.

[J11]

The next series of figures are the linear regressions for the figure that I posted above.
The first one is my attempt at eyeballing the regression line that I thought would best fit
the data given that there was a placebo point that was omitted from the figure for some reason.

The figure is the regression line drawn by the computer for the instance in which a placebo is present.
The correlation is ~0.945.
Next the figure with no placebo that is as drawn above ~0.93 correlation.

https://apps.automeris.io/wpd/

-0.275612062590394 -1.05477641145789
-0.224730862613954 -0.647830867195016
-0.186691033553006 -0.865159715450613
-0.147008566585735 -0.418594530212103
-0.064558614686884 -0.071441660176829
0.000478066530107 -0.009106496600198
0.0004780665301 -0.00910649660019

(The workaround I used for the regression to have a weighted regression was to add in two (0,0) when needed.
I slightly changed the end values in the last row in order to make sure the computer recognized that there were two separate points very close to (0,0). Probably should have changed these values so that one of them was exactly (0,0) because we know by definition that the point is exactly at the origin. The titration dose point appears to have had less patients and so the dot is smaller in the figure, though I decided to simply to have all the treatment points with the same weight as I was not clear what the baseline treatment group size was.)

Dose Response2.gif

(Below figure has no placebo just as the above figure does not include placebo. I think my by eye regression is quite an admirable effort. It is quite close to that derived from the computer. I could use the dot plotter to find exactly how accurate the above regression was.)

Dose Response 3.GIF

Dose Response 4.GIF