Biogen stock up 10% for Alzheimer's drug

[Vikingman]

[Vikingman]

https://www.neurologylive.com/clinical- ... er-disease

[J11]

viking, thank you for being on this story!
This is very large news for the AD community.

[NF52]

https://www.neurologylive.com/clinical- ... er-disease

Thanks for posting this, Vikingman. Biogen had already been given permission by the FDA to re-start the previously cancelled trials for 2400 participants with MCI or early-stage AD. Those are the participants whose interim results convinced Biogen to re-apply now for expedited approval to use Aducanumab. Because the drug was especially helpful for people with ApoE 4/4 when given at the highest dose, but does carry a risk of some side effects at that dose, it does seem likely that if (when?) approved, the FDA will require frequent monitoring including MRIs for the first year of treatment.

Aducanumab, like other immunotherapy drugs currently in or near Phase III trials, is based on a very different target than the "amyloid cascade hypothesis", which proved to be ineffective. Researchers found that the culprits are specific types of amyloid beta called amyloid beta oligomers ("ABO") which have been linked to insulin resistance, synapse loss, oxidative stress, neuron death, tau formation, loss of plasticity, etc.

Here's a vivid graphic of what might researchers using drugs which removes ABOs hope to reduce: AB Oligomer Toxicity from The Amyloid-β Oligomer Hypothesis: Beginning of the Third Decade

Aducanumab or similar drugs may well extend the health span of people already diagnosed with MCI and mild AD. They will not take away the importance of prevention of high risk factors on the path the high amyloid,. Nor will they be sufficient to "cure" AD, given the numerous paths to Alzheimer's. Here's a comment from another source, with emphasis added"

Our results show that ... different aggregated forms of Aβ42 [i.e. AB Oligomers] may differ in their contributions to different mechanisms of toxicity that develop during the progression of AD and other misfolding disorders associate with Aβ self-assembly. We therefore anticipate that effective strategies aimed at targeting pathogenic Aβ42 species formed during the progression of disease may involve the use of cocktails of therapeutic agents targeting the diversity of species that are populated during the aggregation process.

https://www.nature.com/articles/s41467-019-09477-3

But I know of trial participants who are eager re-start aducanumab, which resulted in noticeable improvement in their daily lives after diagnosis of biomarkers, clinical and behavioral signs of AD progression.

[Vikingman]

That is wonderful news! My mother is 4/4 and she told me that she had been diagnosed with MCI. Hopefully this will help her at some point soon. Is there anyway to become a trial participant?

[J11]

viking, I hope that your mother will benefit from aducanumab.
I will be interested to hear what strategy you might take with dosing.
In the phase 3 clinical trials, they maximally dosed even epsilon 4s at 10 mg/kg.
The result was ~40% of 4s developed ARIA.
They needed to monitor these patients carefully and for some they did repeat scans at $4,000
a pop to make sure that ARIA resolved.

Yet, as a patient there is no great need to drive past the speed limit on the highway.
You might even choose to dawdle somewhat below the limit and reduce the risk.
It would depend on the exact stage that your mother has reached, though it might
be worthwhile to consider where the point of optimum cost-benefit exists.

Go too fast --> ARIA, must dose down
Go too slow --> illness advances (time is brain)
Go just right --> hit the sweet spot

Of course, you would be in a highly advantage position if FDA approval occurs.
You would not need to drive past the limit, you would not even need to drive close to the
limit; you could walk. If you are decades ahead of your age of onset, there would be no
great reason to hurry unnecessarily.

[NF52]

That is wonderful news! My mother is 4/4 and she told me that she had been diagnosed with MCI. Hopefully this will help her at some point soon. Is there anyway to become a trial participant?

Sorry to be late to trying to answer your great question, Vikingman. Here's what I know:

1. Right now, only people who had previously been on one of the stopped trials of aducanumab will be re-enrolled in a trial.

2. All others, like your mother, will have to wait until probably early 2021, for a decision by the FDA on approval. As someone with ApoE 4/4 and MCI, your mother would likely be in a target population to be eligible for the drug if approved--provided that she meets any criteria set up by the FDA and/or Biogen.

3. It is likely that people will have to be close enough to an established study site (or academic medical center) which has experience in working with patients with MCI and ALSO doing regular blood work, MRIs and cognitive testing, since the FDA may want close monitoring for at least a few years.

4. As j11 points out, a side effect in a small percentage of people is ARIA-E or ARIA-H. This stands for Amyloid-Related Imaging Abnormality-Edema or Hemorrhage. It appears that the clearance of amyloid oligomers from the brain sometimes causes micro-hemorrhages from brain vessels (ARIA-H) or swelling of the brain (ARIA-E), most of which is asymptomatic (not felt by the person). It can be seen on an MRI and probably can be lessened by starting the dosage low and then working up like thyroid and other medications which are started at low doses. It also can be treated with anti-inflammatory medications and temporarily stopping treatment. It seems to be most likely to happen early in the treatment, which is why it's likely that any approval for the drug will require regular MRIs until this is better understood.

5. Although driving at the speed limit, as J11 suggests, it a great idea, it does appear that for people with ApoE 4/4, the highest dose is what is necessary to effectively remove toxic amyloid. It may be in the future that drugs are given early on with much lower dosage at much earlier stages of amyloid oligomer development, but with someone who has MCI, the goal would be to prevent the addition of toxic tau, synapse loss and neuron death and irreversible changes.

There are other clinical trials seeking to enroll people with MCI underway or coming relatively soon. Here's an article about a drug that will be studied in people with MCI and early-stage AD through the Alzheimer's Clinical Trial Consortium through a $75 million grant from the National Institute of Aging. https://cogrx.com/cognition-receives-ni ... ctc-study/ It has an completely different target: the receptor that the oligomer attaches to on a neuron's synapse. This study also will probably be starting in 2021.

If you are interested in current studies that your mother would be eligible for, here's a list from Clinicaltrials.gov. a service of the NIH with trials in the US for people with MCI: Or you could post or Private Message me the city closest to where your mother lives and I'd be glad to link you to studies specific to her region. Most require a "study partner" who is able to come to some visits with her, and can be a reliable informant on changes seen between visits. With COVID-19, many studies have suspended recruitment and visits. IN some areas with low rates of infections, studies are likely to resume, with lots of safety precautions for participants and moves to telephone interviews and doing some online assessments. Clinical Trials.US. MCI, currently recruiting

Hope this info helps. Your mother might also benefit from the dozen fairly easy-to-do strategies recommended in Dr. Stavia's PRIMER.

[J11]

It needs to be remembered that ARIA is actually a fairly common occurrence in those treated with aducan. CTAD 2019 reported that over 40% of epsilon 4 carriers experienced ARIA-E on high dose aducan in EMERGE. ARIA-E is described as imaging abnormalities due to vasogenic edema. ~20% of those on high dose experienced ARIA-H-- microhemorrhages. The epsilon 4 status for ARIA-H was not disclosed, though one would expect that ARIA-H was also higher in the epsilon 4 subgroup. They do not report specifically the epsilon 44 rates for ARIA, though one suspects that they would be higher than that of epsilon single 4 carrier rates. (I believe that previous research has found this.) There is a substantial amount of ARIA that occurs with aducan and other anti-amyloids. Fortunately much of it resolves with dose reduction. Within the context of a clinical trial, there is a fair amount of hurry to reach the desired clinical readout as quickly as possible. Patients, though may or may not, be in a similar hurry when they choose their own dosing.