RSS Feed Print
Biogen
Keep It 100
Posted: Tuesday, October 22, 2019 2:18 PM
Joined: 2/26/2017
Posts: 503


The cynic in me is highly suspicious of the "great news" about Biogen and aducanumab, resulting in a huge jump in Biogen stock price...when it has now been widely accepted that clearing amyloid plaque does not stop the progression of Alz, and also widely known that the higher doses that were most effective in clearing the plaques also raise the risk of brain swelling and stroke. Just as it has seemed the science is moving in greater force away from this amyloid theory, this happens. Why now? They have conveniently erased all of their losses after the failure of the trial. https://www.cnbc.com/2019/10/22/biogen-to-seek-us-approval-for-alzheimers-drug-sending-shares-soaring-34percent.html
Lane Simonian
Posted: Tuesday, October 22, 2019 8:19 PM
Joined: 12/12/2011
Posts: 4632


I agree one hundred percent.  I think Biogen's new CEO wanted to try to resurrect the company and the amyloid hypothesis.

At six months no dose of Aducanumab performed significantly better than placebo.

https://www.thestreet.com/story/13212080/1/previewing-the-next-look-at-biogens-alzheimers-drug.html#2

The apparent slowing down of the disease at one year for the highest dose group was most likely primarily caused by APOE4 dropouts (do to severe side effects) who appear to progress more rapidly at the early stage of the disease.

Biogen attempted to dismiss this analysis for another one of its anti-amyloid drugs: BAN2401:

According to new data presented at CTAD, APOE4 status did not affect the rate of cognitive decline in the placebo group [this contradicts most other studies suggesting that those with the APOE4 gene progress more rapidly during the early stages of the disease]...

Did APOE4 affect response to treatment? The subgroup analysis said yes, Swanson reported. Carriers on the highest dose had less cognitive decline at 18 months than the noncarriers or the group overall. On the ADCOMS, for example, where the highest dose group declined 30 percent less than placebo, APOE4 carriers declined 63 percent less and noncarriers only 7 percent less. This result indicates that the treatment effect on the high dose was likely not due to the lack of APOE4 carriers,..

To boost those numbers, the investigators combined the 10 mg/kg biweekly and 10 mg/kg monthly groups. The merged cohort comprised 273 APOE4 carriers and 141 noncarriers, a similar makeup to the placebo group. This combined group declined 21 percent less than placebo. Once again, the APOE4 carriers had a better response, declining 25 percent less than placebo, whereas noncarriers declined just 6 percent less.

https://www.alzforum.org/news/conference-coverage/second-look-ban2401-data-still-positive-despite-snafu

A six to seven percent slower decline in non-carriers is nothing.  And the APOE4 dropouts made it look overall like BAN2401 was much more effective at slowing down the progression of early Alzheimer's disease than it actually was.  Moroever, there were still several individuals with two copies of the APOE4 gene in the placebo group but probably few if any in the drug (due to severe adverse effects).  So the company is still comparing apples to oranges--APOE4 carriers may have had a slower rate of progression than non-carriers but not nearly as much as the company suggested.

Aducanumab is supposed to be a more effective anti-amyloid antibody than BAN2401, but it is hard to beat a 93 percent removal of brain amyloid.  Neither drug is likely to be an effective treatment for Alzheimer's disease.

To me this looks like stock manipulation and fraud (or at least close to it).



Keep It 100
Posted: Tuesday, October 22, 2019 8:34 PM
Joined: 2/26/2017
Posts: 503


I appreciate your input. I’m really hoping that the buy/sell trades around this announcement are tracked. It smells very fishy.
Llewis
Posted: Wednesday, October 23, 2019 9:40 AM
Joined: 2/9/2019
Posts: 9


I'm really happy to see the posts in this thread. Shows we have some well informed posters on this board. If the FDA approves this drug from a side-show like this there should be an investigation.

BadMoonRising
Posted: Wednesday, October 23, 2019 12:52 PM
Joined: 4/22/2017
Posts: 298


Biogen recently met with the FDA and were advised "...that it was reasonable to submit the data package for possible approval".

https://www.bloomberg.com/news/articles/2019-10-22/how-biogen-salvaged-its-alzheimer-s-drug-after-a-costly-failure

I'm somewhat cynical as well. Unless I change my mind, I'm scheduled to return to the  Hopkins' Memory Clinic in a few months. I'm interested in my doc's opinion regarding this study.



Keep It 100
Posted: Wednesday, October 23, 2019 2:20 PM
Joined: 2/26/2017
Posts: 503


Thanks for that article. From it: **Given the controversy generated by Biogen’s reversal, the FDA is likely to call on a committee of outside advisers to review the data, said Samuel Gandy, the associate director of the Mount Sinai Alzheimer’s Disease Research Center in New York.

“It will be up to the people on the advisory committee, those who make a recommendation on whether to approve it,” Gandy said. “They have to be positive and enthusiastic. If the advisory panel gives a very negative opinion, it would be hard, in the face of all this failure, to approve it. That would carry the day.”**

My cousin is a neuroscientist, currently in Chicago at the annual conference put on by the Society for Neuroscience https://www.sfn.org/meetings/neuroscience-2019 , and he said all the talk yesterday and today has been this. I am scheduled to chat with him this evening to get an update/the scoop. 


Larrytherunner
Posted: Thursday, October 24, 2019 4:01 AM
Joined: 2/26/2016
Posts: 196


I hope the FDA will not do the same for Alzheimer and dementia drugs that they have been doing with cancer drugs, which is to approve drugs with no proven benefit.

https://www.npr.org/sections/health-shots/2019/05/28/727598045/cancer-drugs-approved-quickly-often-fail-to-measure-up-later


PattieR
Posted: Friday, October 25, 2019 5:03 PM
Joined: 8/13/2019
Posts: 12


I for one, (65 YO recently diagnosed) am trying to be reasonably optimistic about the press release. I will hold back any negative comments/vibes until all data is released and reviewed.  Holding on to SOME hope is better than NO hope.
HowDoYouDeal
Posted: Saturday, October 26, 2019 11:52 PM
Joined: 2/17/2019
Posts: 276


I don't quite understand the data about the drop out rate and how its related to levels of progression.  

 Two things I saw:  Earlier in the trial, they only had approval for 6 mg(?), later they got the approval to test at 10. So those who started at 6, didn't do as well and that skewed the data.

I read something about the company having gotten in trouble in the past for misleading statements. I haven't looked into it.


Lane Simonian
Posted: Sunday, October 27, 2019 10:24 AM
Joined: 12/12/2011
Posts: 4632


The thinking in an earlier version of the trial was that the figures were skewed because  quite a few people with the APOE4 gene(s) had to dropout of the trial due to adverse side effects, but this was not the case for people in the placebo group.  Since APOE4 carriers progress at a faster rate than non-carriers early in Alzheimer's disease, this made the drug at its highest dose look more effective than it actually was.

https://n.neurology.org/content/70/19_Part_2/1842.short

https://www.alzforum.org/news/research-news/apoe4-makes-all-things-tau-worse-beginning-end

https://www.ncbi.nlm.nih.gov/pubmed/12928512/

In its trial for BAN2401, Biogen and its partner Eisai tried to allay this fear, by stating that the drug had a more beneficial effect on APOE4 carriers than non-carriers (a 65% versus a 7% slower rate of decline).  

https://www.alzforum.org/news/conference-coverage/second-look-ban2401-data-still-positive-despite-snafu

A study for another anti-amyloid drug tramiprosate seems to bolster this conclusion.

Results: Highest efficacy was observed in APOE4/4 homozygotes receiving 150mg BID of tramiprostate, showing statistically significant effects on ADAS-cog and positive trends on CDR-SB (respectively, 40-66% and 25-45% benefit compared to placebo).  APOE4 heterozygotes showed intermediate efficacy, and non-carriers showed no benefits.

https://www.ncbi.nlm.nih.gov/pubmed/29199323

This may be the case as the APOE4 gene by increasing the size of lipid rafts amplifies various insults on the brain including amyloid oligomers.  So if you remove the oligomers you may have a somewhat slower progression of the disease early on.

http://www.jlr.org/content/46/5/949.full

In the latest trials, Biogen made two protocol amendments, allowing people who had had adverse effects back into the trial at the original dose (almost all of whom were APOE4 carriers) and to titrate up those with the APOE gene or genes from 6mg to 10mg.  After the futility analysis, those at this highest dose for a little bit longer time, showed a 23% less decline on CDR-SB scores and 25% less decline on ADAS-cog scores.

Aducanumab may only help those with the APOE4 gene or genes.  And then the question is does it help them enough to justify the risk for side effects (even with titration).  

This company has changed protocols, has changed the form of statistical analysis, and overstates the magnitude of the results.  It is rather unsettling.  

 


jfkoc
Posted: Sunday, October 27, 2019 1:58 PM
Joined: 12/4/2011
Posts: 17693


sigh.........
Keep It 100
Posted: Wednesday, October 30, 2019 7:25 AM
Joined: 2/26/2017
Posts: 503


And now, this. 

https://endpts.com/amgen-is-joining-the-biopharma-exodus-out-of-neurosciences-rd/  

 

Yeah, Ronny, so this was a very difficult decision. And as you pointed out, there are new therapies becoming available, some of them nucleic acid based. Many of those I think are targeted at orphan or niche diseases and consistent with our desire to generally target diseases with a large public health impact, based on what we felt was the state-of-the-art in terms of understanding the pathogenesis of major diseases, especially neurodegenerative diseases and our overall portfolio, we made that decision to end our early neuroscience research efforts. As I mentioned, we are looking at ways to maintain a hand in neuroscience through alternative models and we’ll discuss some of that in the future. We believe the genetics will ultimately drive progress in this area, and we’ll continue to work with deCODE to generate insights.

CEO Robert Bradway appended this thought:

Half the genes in the body are expressed in the brain and only the brain, and we have some unique resources to try to capitalize on insights around that. And as Dave suggested, we’ll be exploring potentially different models for doing that with venture capital and perhaps academic institutions as well.

Neurosciences as a whole, though, has been a disaster zone, with Alzheimer’s in particular providing a litany of clinical defeats that collapsed the BACE theory and now leaves Biogen as one of the few major believers in the amyloid beta hypothesis. As a result, big players have either bowed out or retreated to much smaller pipeline efforts. And now there’s one less.


Llewis
Posted: Wednesday, October 30, 2019 2:02 PM
Joined: 2/9/2019
Posts: 9


Lane; You're probably one of the most informed people in the world on ALZ. You probably don't remember but I'm one of those that think big pharma has been chasing the wrong rabbit. I much prefer the new Anavex type approach. My question to you is: I have asked on this board 3 times in the last 9-10 months if anyone has had any contact of any kind with Anavex, or the company or the trials they are running. There has been not one response. How can this be in a country with active trials and in which there have been multiple stories on tv and written press?

Worries me a bit.

 Thanks in advance

Larry L.



Lane Simonian
Posted: Thursday, October 31, 2019 9:38 AM
Joined: 12/12/2011
Posts: 4632


Thany you, Larry.  I appreciate your postings about Anavex 2-73.

I only remember a few times here where people have shared their experiences about an Alzheimer's drug clinical trial (and never about Anavex 2-73)  Much of the work done by Anavex has occurred in Australia.  That along with the relatively few number of participants may partially explain a lack of response on these boards.  

The media attention to Anavex 2-73 has been increasing over the past year or so, but it is still limited.  The next trial results are due in March 2021.  They involve a much larger number of participants and are placebo-controlled.  Unfortunately until then, Anavex 2-73 will probably remain on the fringes in terms of discussions of potentially effective drugs for Alzheimer's disease.  This is unfortunate since the drug at its highest dose has appeared to nearly stabilize Alzheimer's disease for almost three years.  It is one of the few Alzheimer's drugs that acts as a direct antioxidant rather than as just an indirect antioxidant.  As such it has the potential to partially reverse the damage done to the brain during the course of Alzheimer's disease.



Llewis
Posted: Thursday, October 31, 2019 5:30 PM
Joined: 2/9/2019
Posts: 9


Lane;

I've followed Anavex for about 5 years now and have become increasingly hopeful about what it might do for several CNS conditions. Their recent presentation about Rett Syndrome looked really encouraging and as you know they've started trials for that condition and PDD as well. As you stated the ALZ study in Australia was encouraging. My concern is no one acknowledges anything about them. Rett. org will not discuss them or their trials even though they send emails to those of us involved about other companies and trials. No matter what forum I've looked for information; nobody will say anything about them or knows anything about them. . Their CEO too me is less than impressive but if their results are what they say they are word should be spreading.

In the corrupt world we live in it makes one wonder it the company is legit.



Lane Simonian
Posted: Friday, November 1, 2019 9:36 AM
Joined: 12/12/2011
Posts: 4632


Many neurological diseases and conditions such as Alzheimer's disease, Rett Syndrome, and dementia with Parkinson's Disease likely have the same root cause, so it is possible that one compound could help with all of them.  Whether that turns out to be the case for Anavex 2-73 remains to be seen.

There are not too many cheerleaders at Anavex.  One of them, Stephen Macfarlane has been touting the regain of function for several people on the drug.  But he did the same thing with Prana and that drug turned out to be ineffective.

There have been several drug trials now where company officials have pointed to significant improvements as a sign the drug was effective, but so far there has been failure in a larger patient group every time.  Maybe some people just responded better to the drug or perhaps it was the drug in combination with something else that was leading to the improvement.

I am not a big placebo believer for Alzheimer's disease.  There is an historical rate of decline for individuals on placebo in Alzheimer's trials.  Small numbers of participants, on the other hand, can lead to misleading results.  For that reason, I am interested to see the results from larger trials for Anavex.

Dr. Missling (Anavex's CEO)  has been praised for being reasonably cautious and criticized for a lack of boldness.  His approach to clinicial trials can fit into both categories as well.  He is different, which can be refreshing and a bit frustrating, at the same time.



PattieR
Posted: Tuesday, November 5, 2019 5:04 PM
Joined: 8/13/2019
Posts: 12


What do you all think about this latest announcement?

https://www.prnewswire.com/news-releases/green-valley-announces-nmpa-approval-of-oligomannate-for-mild-to-moderate-alzheimers-disease-300950349.html

Green Valley Announces NMPA Approval Of Oligomannate For Mild To Moderate Alzheimer's Disease


BadMoonRising
Posted: Tuesday, November 5, 2019 9:51 PM
Joined: 4/22/2017
Posts: 298


I'm in. Just kidding. I have more hope for this drug than the one from the Biogen study. I would strongly consider joining this study if it came to my neighborhood.  

Here's a link to a little more information from our side of the world. https://www.biopharmadive.com/news/china-alzheimers-drug-oligomannate-approval-green-valley/566540/

 


 


PattieR
Posted: Wednesday, November 6, 2019 2:55 PM
Joined: 8/13/2019
Posts: 12


After reading your linked report, I am more disappointed now than I was when I first ready the press release.  Ive only been diagnosed 3 months ago and have read about so many "hopeful" medications that don't really work on anything other than helping "symptoms". We need a CURE.
Lane Simonian
Posted: Friday, November 22, 2019 9:54 AM
Joined: 12/12/2011
Posts: 4632


The chief scientific officer for Biogen Al Sandrock is now trying to pressure/threaten the FDA to approve aducanumab.

“I don’t think the field has ever seen data like this,” said Sandrock, sounding very much like a man who wants to prove Biogen’s critics wrong.

Sandrock didn’t offer a prediction, but if the FDA rejects the drug now or asks Biogen to conduct another large clinical trial to collect additional data, it would mean “lots more people” would get Alzheimer’s without a drug to help them.

https://www.statnews.com/2019/11/21/biogen-al-sandrock-alzheimers/

The drug was marginally statistically effective in one trial group and not in the other.  The difference was largely due to the fact that in one trial the placebo group dropped by 1.8 points whereas in the other trial the placebo group declined by 1.5 points.

https://investors.biogen.com/static-files/5a31a1e3-4fbb-4165-921a-f0ccb1d64b65 (p. 22).

 A 1.5 points decline after 78 weeks (as measured by CDR-SB scores) seems fairly standard, so the "non-significant" trial group may be the better measure of the effectiveness (or lack thereof) of the drug.   If that turns out to be the case, I don't think the FDA will approve aducanumab.

To me, it seems like Biogen is trying to bully its way to approval.  If the results were really as good as Sandrock says they are, they wouldn't have to do this.

 



HowDoYouDeal
Posted: Thursday, December 5, 2019 11:13 AM
Joined: 2/17/2019
Posts: 276


I just listened to Biogen's data presentation and they are saying that the big issue was that mid-trial they learned that they could safely let people who are APOE Carriers take the 10 mg dose.

I thought it was interesting to hear that Tau was affected by the medication.

When you look at the biomarkers and goals for people who were on the high dose, it was a success. Its never good to change a  clinical trial mid-way through, but they had expected that APOE carriers would benefit the most, so .... in my words, it would be rather mean to prevent them from taking the higher dose.

Yes the earlier trial did not achieve results that were statistically significant, the numbers were moving in the right direction! 

The Biogen presenters said that the drop out rate for both the trials was considered low. 12-15 percent, I think it was

One of the panel noted that in order to be in the trial, a patient would need to have pet scans done, so they can select patients for whom this would be appropriate.

They are bringing the trial back, participants who were previously on placebo will be offered the chance to take the drug.

Perhaps more questions will bring out more negative aspects.  Again, Biogen says that almost to a person, all past trial participants they contacted about going back into trial were excited about it.  That's them.

However, I believed all along, so I may be too easy to convince.

If we are talking about slowing the progression of disease by about 40%, even if it just for the APOE carriers, then that's fantastic news.Who wouldn't want another year of independence? 

This drug isn't the be-all, end all, there are better drugs out there.....I'm looking at you T2 Protect AD.


Lane Simonian
Posted: Thursday, December 5, 2019 1:49 PM
Joined: 12/12/2011
Posts: 4632


Thank you for reporting back on Biogen's data presentation.  I have only looked at their powerpoint presentation and it is not the same thing as seeing it presented via video.

Aducanumab may reduce the rate of decline in APOE4 carriers closer to that of the rate of decline in non-carriers.  I suppose that is something, but hopefully some of the other drug results presented at the clinical trial conference will indeed do better.

Biogen seems to suggest that it is planning to run another trial.  I almost think they have to because the results between the Emerge trial and the Engage trial are so muddled.