That science fad that cost Biogen 18 billion dollars

ne year after the FDA approved aducanumab, the monoclonal antibody against β-amyloid for Alzheimer's disease, its price dropped from $56,000/year to about half that. They're giving doctors free samples, as if to say “Please, please, oh please take this horrible antibody off our hands!” Even so, no gerontologists or neurologists that I know are willing to prescribe it.

Biogen fell into a common trap: they put a massive spin on what was essentially a failed clinical trial in the hope that investors will think it was a success, only to find that even investors, famous for making bad decisions, rejected it. And so their stock value lost $18 billion, or 30% of its value, not to mention the billions they spent developing and testing it.

There's no convincing evidence that the drug has any benefit for patients. Then crenezumab, another anti-βamyloid antibody which failed to protect patients with familial Alzheimers, killed off the theory behind it for good. Biogen's candidate, like many of the others, causes ARIA, or amyloid-related imaging abnormalities, which are are signs of microhemorrhages in the brain and fluid retention. Between 35.2% and 41.3% of patients given the drug get ARIA. Patients with ApoE4 have even higher rates.

There are rumors that a Japanese company is having success with a different antibody, leading some to hope that getting rid of β-amyloid very early, when cognitive impairment is still mild, might have some benefit. Whether that's really true remains to be seen.

What is ARIA, and why are people ignoring such a big clue?

ARIA is identified by MRI. There are two types. One is ARIA-E (ARIA-edema), identified by FLAIR as vasogenic edema and sulcal effusion. It indicates inflammation of the blood vessels. The other is ARIA-H (ARIA-hemosiderin), which shows up on T2*-weighted gradient echo MRI or susceptibility-weighted imaging as a signal for hemosiderin, an iron storage protein, and indicates microhemorrhage and superficial siderosis.

What this means is that when β-amyloid is removed, the walls of blood vessels throughout the brain are broken down and become leaky, causing blood and fluid to leak out, almost as if some protective molecule is being stripped away. If hemoglobin leaks out as well, we get highly toxic iron on the brain, which is called siderosis. Siderosis is also a big problem in traumatic brain injury.

Some researchers think ARIA may be a sign of autoantibodies against β-amyloid.^[1] This would mean that Alzheimer's is, at least in part, an autoimmune disorder. The radiological signs in MRI scans are not caused by insoluble clumps of antibody-antigen precipitates as you might think, but are evidence of drug-induced removal of existing vascular aggregates, which causes leakage.

ARIA-H also seems to be a symptom of CAA or cerebral amyloid angiopathy, a common phenomenon in Alzheimer's. In CAA, amyloid clumps are found in the small blood vessels throughout the brain, causing hypoperfusion. Hence the term CAA-ri or CAA-related inflammation.

These are all bad things to have, and ARIA causes headache, confusion, dizziness, and nausea. ARIA-E gradually resolves within a few months, while ARIA-H appears to be permanent. But to scientists they are what we call a Big Clue—or they would be if we were interested in what β-amyloid's normal function might be. The problem with fads is that we're not even thinking in those terms.

Fads blind us to what is really going on

It seems to be too much to ask that someone would figure out that if getting rid of something causes a problem, then maybe that thing's function is to prevent that problem. So far everyone thinks of it as an annoyance. The company hopes that by tweaking the dose and more closely monitoring the patients it will go away. But it's happened with almost every antibody that's been tried. Now people are making excuses for why they adhered to the theory for so long, blaming the discoverers of Aβ*56.

Even if someday an antibody works, it won't be a cure. We would need to understand why β-amyloid is being produced. But just try to publish your results on the biochemical signals that induce it. You can't: the reviewers just don't care. The dogma that β-amyloid accumulates because clearance is impaired, which was solidified by a handful of bad papers, is just too strong.

It's a perfect example of how following a fad causes you to ignore something important that's right in front of you. But the larger question is: why do companies, as well as researchers, repeatedly fall for unscientific fads? Last year many big corporations went out of their way to antagonize social conservatives by hopping on the woke bandwagon. Some energy companies claim to believe that we're in a “climate crisis,” which they clearly don't really believe.

The reason seems to be that they're terrified of the wave of scientific illiteracy that's sweeping the country. The public is highly susceptible to hysterical news reports on any number of topics and clamor for greater safety and more regulation. Result: people on all sides of the political spectrum now hate these big companies. When the companies go down in flames, they will all cheer.

Scientists should take note: pandering to fads just makes your remaining allies lose respect for you.

What can scientists do

There's not much that scientists can do when some government bureaucrat puts on a white coat and pretends to be the voice of science. There's also little we can do when a big public health center, whose job used to be to control diseases, puts on its rainbow-hued fluffy bunny slippers and tells us that systemic racism is the world's biggest disease and promises to fight it. Following a fad is safer and easier than striking a new innovative path.

It's harder than ever to get interesting new ideas funded. Example: There are small bodies in the cell called micronuclei, which are caused by radiation therapy and other medical treatments that fragment your DNA. They cause chronic inflammation and there are suggestions that they may be responsible for autoimmune disorders and chronic degenerative diseases. One paper says eliminating them could also treat the adverse effects of radiation therapy. This is an exciting idea.

Is the NIH looking to fund this research? Evidently not: most of these papers are from China, Japan, and other countries. If we want NIH ‘fnudding,’ as I call it, we have to write proposals to match the Program Announce­ments (PAs). To have a decent chance, you narrow it down by selecting a NOSI, or Notice of Special Interest. For example, “Research on the Health of Bisexual and Bisexual+ People” (NOD-OD-22-203), “Climate Change and Health” (NOT-ES-22-006), and topics like that.

What on earth is “bisexual-plus”? According to the all-knowing, all-seeing, and occasionally correct Internet, it means people who experience any kind of attraction to more than one gender. There's one site that will give you an ID card that identifies you as one. They say anyone who chooses to can be one, which I guess means the old theory that they are born that way and you are a bigot if you don't believe it has gone out the window. But NIH still wants to give out money to do research on you.

Fads are a way of avoiding the need to think for oneself. If people are afraid, they look to the group to tell them what to do and what to think. Therefore, fads occur in times when the humans lack the courage to face their fears. Funny how that always seems to make things worse.

sep 26 2022, 6:34 pm updated sept 28 2022 4:56 am