And what about BAN2401? Remebmer that one?

So aducanumab seems to have flamed out (at least for now), but we have prospects in several other pharmacological candidates, including (but not limited to) NLY01 and AMX0035.  But back in 2018 we wrote hopefully about another monoclonal antibody, BAN2401.  What's going on with that?

Well, a lot.  At the recent Clinical Trials in Alzheimer's Disease conference, the Japanese pharmaceutical company, Esai Ltd., presented results of their phase 2 trial showing that amyloid plaques "plummeted" in test subjects receiving the treatment.  Esai has now recruited 1,200 test subjects for a phase 3 trial for people with MCI. 

BAN2401 was originally developed by the Swedish pharmaceutical company BioArctic.  Bioarctic licensed it to Esai, who subsequently partnered with Biogen to pursue development.

In 2018 they had established that BAN2401 could remove plaques, but the question was, does that lead to cognitive improvement?  The early test results indicated that it probably could if you kept people on it long enough -- and well after it seemed the plaques were gone.

But there's more.  The Alzheimer's Clinical Trial Consortium has begun separate phase 2 and phase 3 studies to measure whether BAN2401 can treat early stage and pre-clinical Alzheimer's disease.  Early stage subjects are being chosen based on evidence in cognitive tests, where they show the earliest Alzheimer's symptoms.  Two other studies, called Ahead345, will see if the treatment can prevent the onset of memory loss.  Since March 2019 they have been looking for subjects age 55-80 who are at risk of developing memory loss from Alzheimer's disease.  

It was not clear to me how they are identifying pre-clinical test subjects, but similar research has relied on genetic tests for the genes most responsible for young onset Alzheimer's disease.  This points to our very great need for blood tests and other diagnostic tools for identifying pre-clinical cases.

The bad news is that this stuff takes time, and covid isn't helping.  The test that began recruiting in 2019 is still not full, and these tests take as long as four years to produce data. 

You can read more here.

Feedburner Hiccups...

For this blog, I use Google's Feedburner to develop the subscription mailing list and send out blog updates.  Only problem is that Feedburner periodically refuses to cooperate with me.  I posted on November 17 and on November 21, but Feedburner skipped most of our subscribers.  

So if you missed those posts, and you're interested in two promising drug trials, you can click these links:

• If not aducanumab, how about NLY01?
• If not NLY01, how about AMX0035? 

BTW, when you click on a link in an article, it gives the blog a point or so in Google's system, so the blog becomes a little (perhaps very little) more visible on the Internet.

If not NLY01, how about AMX0035?

Amlyx Pharmaceuticals is a small, young company in Cambridge, MA.  It was started in 2015 by two Brown University graduates to develop drugs to specifically combat neurodegenerative diseases.  Their initial focus has been on ALS -- Lou Gehrig's disease -- but has now expanded into Alzheimer's disease.  When their investigative drug, AMX0035, was shown to be effective in treating ALS, they began an investigation of its use to treat Alzheimer's disease.  

The phase 2 trial, called the Pegasus Trial, has just been completed, and they are now slicing and dicing the data.  The trial involved 100 test subjects over a period of 24 months.  The test subjects were in the late stage of mild cognitive impairment due to Alzheimer's disease or the early stage of Alzheimer's dementia.  They expect to share their results sometime in the first half of 2021.    

The phase 1 trial was focused on ALS patients, so we don't have a preview of what to expect with the new trial for Alzheimer's patients.  It was not a combined phase 2/3 trial, so it appears to me that we will need a phase 3 trial before the FDA will consider approving it.  The results with this 100 (ultimately 96) test subjects will likely influence approval to begin a phase 3 trial.  But I'll note here that they allowed the phase 3 trials of aducanumab to proceed based primarily on promising results in the small phase 1 trial that were not replicated in the phase 2 trial.  (In Beating the Dementia Monster, we discussed my puzzlement in 2016 over why they were proceeding with the phase 3 trial of aducanumab in the absence of positive results from the phase 2 trial.)

If not aducanumab, how about NLY01?

Hope springs eternal (and it should) for a pharmacological silver bullet for Alzheimer's disease.  It may turn out that aducanumab can help some, but it's not a cure.  We wrote previously about BAN2401, and it is still in trials.  So who knows?  

Among other possibilities is a candidate called NLY01.  It's developer and sponsor, Neuraly, is, of course, quite enthusiastic about this drug.  On November 2, they announced that the FDA has cleared the way for them to begin a new phase 2 trial of the drug which, among other things, has been shown to reduce neuroinflammation.  The drug is already in a phase 2 trial for treatment of Parkinson's disease, so the new Alzheimer's trial is referred to as a phase 2B trial.  So far, it seems safe, but will it work for either Parkinson's or Alzheimer's?

In the new edition of Beating the Dementia Monster, we discussed the role of microglia in Alzheimer's disease.  Microglia are cells in the brain that can help clean up the trash from Alzheimer's disease -- beta amyloid and tau tangle residues -- but at the price of increased inflammation.  (The trash promotes the spread of the disease in the brain.)  Neuroinflammation from microglial activity is especially a problem with older brains, because the behavior of microglia changes over time.  We discussed this here about a year ago.  This article in Nature Medicine discusses how NLY01 can suppress neuroinflammation by suppressing microglial activity.

Neuraly expects to enroll about 500 test subjects at about 100 test sites across the US, Canada, and Europe.  They anticipate results in the fourth quarter of 2023.  So it'll be a while.

It ain't over 'till it's over...

It would appear that Biogen (and their Japanese partner, Eisai) have struck out with getting aducanumab approved in the United States.  But they have other options, and they are pursuing at least one.  In this press release, they announced that the European Medicines Agency has agreed to review aducanumab for approved use in Europe.  You can read more here.

But don't hold your breath.  They got a pretty quick answer from the FDA panel's recommendation (or slapdown), but the European process will take 210 days.  We'll see what that yields.  

Aducanumab DOA -- Probably

It's all over the news.  The FDA's Peripheral and Central Nervous System (PCNS) Drugs Advisory Committee voted against recommending that the FDA approve Aducanumab.  The FDA is not bound by the committee's conclusion, but I would be surprised if the FDA disregarded their recommendation and went ahead with approval.

It's not surprising that Biogen's presentation painted the monoclonal antibody in a positive light.  But it surprised me that the PCNS criticized the FDA for speaking positively about aducanumab when they tasked the committee with their evaluation.

There were 10 voting members of the committee, but only one member supported pursuing approval.

The sponsors, led by Biogen, conducted multiple trials of the drug, but only one trial yielded positive results.  That was the one where the full dose was administered throughout the trial, and Biogen's case was efficacy was proven in that trial.  One of the committee members said that was like shooting an arrow at the side of a barn and then painting a target around it with the arrow in the bull's eye.

You will recall from Beating the Dementia Monster that I auditioned for the third phase trial of aducanumab but was rejected.  I wasn't disappointed in this because I doubted that the drug would be successful.  The treatment had shown promising results in the first phase (probably 12 statistically problematic test subjects), but had not shown promise in phase 2 with a larger cohort of test subjects.  I wondered how they justified proceeding with the third phase.  My conclusion was that there were so few other prospects for an effective pharmacological treatment that grasping at aducanumab seemed to be the only promising near-term option.  This explains the great wailing and gnashing of teeth that followed Biogen's initial conclusion that the treatment was ineffective. 

All of this underscores that the multi-domain lifestyle interventions we describe in Beating the Dementia Monster are, for the moment, what we have for holding back the advance of Alzheimer's disease.