halting Phase III trials of aducanumab

[DLP]

I wonder if there is any data comparing the results for the Apoe4 and the non-carriers. I can't find any so far.

[sabaka]

I wonder if there is any data comparing the results for the Apoe4 and the non-carriers. I can't find any so far.

Based on the Biogen website, 2/3 of participants were Apoe4 carriers. Apoe4 carriers were initially titrated to 6mg/kg (low dose of non-carriers) and only later were titrated to 10 mg/kg (high dose for non-carriers). Does it mean that aducanumab resurrection could be attributed to the results of 10mg/kg Apoe4 carriers group becoming available? Not "just" the mistake in statistical model (hard to believe in it )

[Julie G]

Here we go: from the Biogen website: https://investors.biogen.com/static-fil ... ccb1d64b65 Lots of data and explanations of decision-making.

Thank you, NF52, I'm still looking for the actual primary data (as opposed to the analysis) so I can put this into perspective. Your link does show that those on 10mg over 78 weeks demonstrated a reduction in rate of decline as compared to placebo measured by CDR-SB by 0.75 points in EMERGE and 0.50 points in ENGAGE. Both arms still declined, the treated arm just declined more slowly.

For those unfamiliar, the CDR® Dementia Staging Instrument is a 5-point scale used to characterize six domains of cognitive and functional performance applicable to Alzheimer disease and related dementias: Memory, Orientation, Judgment & Problem Solving, Community Affairs, Home & Hobbies, and Personal Care. This score is useful for characterizing and tracking a patient's level of impairment/dementia:

0 = Normal
0.5 = Very Mild Dementia
1 = Mild Dementia
2 = Moderate Dementia
3 = Severe Dementia

The Biogen analysis shows that cognition improves the longer one is on the treatment. I'm wondering if this improvement will be sustained over time? For instance, cholinesterase inhibitors improve symptoms for several months before efficacy falls off with some evidence showing an ultimate hastening of cognitive decline in those that were treated vs. placebo.

A potential downside for our population is the ARIA-E (cerebral edema) side effect at higher doses typically affects E4 carriers more dramatically. All in all, this is a very exciting development that I plan to watch closely.

[broiler_x]

I am very dubious about this, but I am in the minority as Biogen's stock price rocketed up on this news. Large companies don't abandon huge, expensive trials out of "futility" unless there is a substantial reason too. And their stock price took a huge hit when they announced that bad news. Now suddenly, upon looking at the data some more, they believe that this is a useful drug? That tells me that you really have to squint at the data to find any meaningful positive data, because a clear positive signal should have been revealed in the initial data. This sounds like possible statistics trickery or worse. But again I'm in the minority in this opinion. But for me, when the BACE inhibitors failed their trials, that was the end of the amyloid hypothesis. They were able to reduce beta amyloid to essentially zero without any effect on cognition. It just doesn't appear that clearing amyloid alone will do the trick. And as Julie mentioned, at the highest dose there is significant brain swelling (edema). And those are the only doses that they claim may work.

I really wanted this antibody (aducanumab) to work, and I'm very well acquainted with it's history and story. It was originally discovered in a human that spontaneously had a reversal in AD (or at least that was how it was reported). It has a great story and looked very promising early on. But it has failed multiple trials now, and the hypothesis has totally fallen out of favor. This just screams desperation on Biogen's part to me. I hope I'm wrong!

[PBW]

Interesting I just found this thread and recognized that the success and approval of Aducanumab was reported in the Denver Post yesterday.

[Jmac]

So, Biogen is asking the FDA to approve aducanumab, based on a new data analysis.

Susan,
Thanks for posting this highly encouraging news about two related studies, each with two-thirds (2/3) of the participants being APOE4 carriers!

This article from yesterday:
https://seekingalpha.com/article/429872 ... abbit-hole
Biogen, Amyloid, And Alzheimer's Disease: Once More Down The Rabbit Hole
Summary

• Biogen claims that its drug aducanumab reduces the rate of decline in early Alzheimer's disease by 23 percent.
  This percentage is considerably less for non-APOE4 carriers and probably slightly less for APOE4 carriers.
  The imbalance between a substantial number of APOE4 carriers in the placebo group versus a relatively few APOE4 carriers in the drug group may still be skewing the data.
  I would recommend selling shares in Biogen before the data catches up with the claims.

[NF52]

This article from yesterday:
https://seekingalpha.com/article/429872 ... abbit-hole
Biogen, Amyloid, And Alzheimer's Disease: Once More Down The Rabbit Hole

Biogen claims that its drug aducanumab reduces the rate of decline in early Alzheimer's disease by 23 percent.
This percentage is considerably less for non-APOE4 carriers and probably slightly less for APOE4 carriers.
The imbalance between a substantial number of APOE4 carriers in the placebo group versus a relatively few APOE4 carriers in the drug group may still be skewing the data.
I would recommend selling shares in Biogen before the data catches up with the claims.

Hi jmac,

It's helpful to see the counter-views on this news. I hope you don't mind that I put Lane Simonian's views in a quote box, so that they are easily distinguished from your post.

Here's my problem with his analysis: Both the central quote in his article, and the claim he makes that this study is flawed because more ApoE 4s were in the placebo arm (and so would be expected to do worse over time) is based on a completely different Biogen drug BAN2401 in a completely different study. He directly quotes from a conference in October 2018. He acknowledges that this is a different drug if you read carefully, but it's buried near the end of his article.

Biogen is clear that the "arms" between placebo, low and high dose in aducanumab trials were balanced with about 2/3 of those receiving the placebo, the low, medium and high doses having one or two copies of ApoE 4. It is true that Biogen got approval to move all high-dose ApoE 4 carriers to a 10 mg dose. What may have diluted the results earlier is that the low-dose group was divided into a 3mg dose for ApoE 4 carriers and a 6 mg. dose for non-Apoe4 carriers (presumably due to fears of ARIA micro-bleeds with ApoE4). The high dose group was initially 6mg for ApoE4 and 10 mg for everyone else. That means the "low dose" group of ApoE 4 carriers, who may have had a higher risk of progression, actually got half the dose of non-ApoE carriers in the low-dose group. It seems to be that the reason for the delayed results is that they finally had enough data on people taking a 10mg dose to realize how effective and safe it was.

To be balanced, it's not all rosy news: The 329 people who completed the Emerge study on a low dose of aducanumab, showed a 16% reduction in their decline on their CDR-SB baseline score compared to those on placebo. The 340 people who completed the Emerge study on the high dose showed a 23% reduction in their decline from baseline score compared to the placebo group. In the Engage trial, it appears that the high dose group actually showed a 6% increase compared to placebo, while the low dose group showed an 8% decrease, but neither of those met the criteria for statistical significance with the number of trial participants, meaning it's possible the results were due to chance.

However, the caregiver interviews in the AD Cooperative Study-Activities of Daily Living Inventory Mild Cognitive Impairment Version showed a 46% reduction in decline of daily living skills compared to placebo group for the high dose participants, at the 0.0002 level of significance. These are people who do not know whether their loved one was getting a "sham" shot, a small dose or a high dose of aducanumab.

By the way, Biogen plans to ask the FDA for approval to offer aducanumab to all participants who had been in the two trials. That would be consistent with what clinical trials call the Extension arm: completed trial participants are offered the active drug, without being told (I believe) whether they had been on the active drug or a placebo in the completed trial. Doesn't require the enormous approval process of a new trial, and allows for continued monitoring and up to a doubling in size of the treatment group.

Here's the link to the details I cited:
https://investors.biogen.com/static-fil ... ccb1d64b65

[Jmac]

It's helpful to see the counter-views on this news. I hope you don't mind that I put Lane Simonian's views in a quote box, so that they are easily distinguished from your post.

Here's my problem with his analysis: Both the central quote in his article, and the claim he makes that this study is flawed because more ApoE 4s were in the placebo arm (and so would be expected to do worse over time) is based on a completely different Biogen drug BAN2401 in a completely different study. He directly quotes from a conference in October 2018. He acknowledges that this is a different drug if you read carefully, but it's buried near the end of his article.

I don't mind at all! Thanks for posting thoughts, info!