In approaching Alzheimer's, the focus has been to go after the rabbits:
downstream biomarkers that are no more than identifiable symptomatic findings.
Rather than trying to understand and cure Alzheimer's, we have settled on targeting
amyloid. In fact, the recent Biogen studies have specifically excluded cognitive
findings as the primary definition, in favor of amyloid as their primary definition of
disease. Rabbits, not dragons.
Telocyte intends to cure Alzheimer's disease by catching dragons, rather than
merely trapping rabbits, the usual approach used by most current pharmaceutical
firms and human trials. Which brings the discussion to aducanumab and the recent
Imagine that we were to define a Covid infection not on the basis of viral
infection, but merely on the basis of fever, then argue that we could cure Covid
because we can lower the fever. Fever is a biomarker, but it's not the disease. If we
prove we can catch rabbits, we not only don't prove we can catch dragons, but we
almost guarantee that we will not catch dragons. Alzheimer's research has for many
years focused on the symptoms associated with Alzheimer's and the dementias;
arguing that these symptoms and biomarkers – these "rabbits" – are causative and
that dementia can be addressed with small molecular chemistry and monoclonal
antibodies. Amyloid theory and Biogen's aducanumab are merely the most recent
example of targeting biomarkers instead of disease.
The FDA now permits aducanumab (Aduhelm) for clinical use. While there was
enormous pressure to allow it, there was unanimous agreement from the advisory
committee that it shouldn't be in clinical use. The need was great, but it has medical
risks, it is financially costly, and it probably doesn't work.
The FDA's action has obvious implications, as well as hidden ones. Many
people have had their faith in the FDA undermined, wondering if the FDA will, in the
future, accept anything as an effective medication, as long as someone wants it
accepted. How are we to know what works and what is merely snake oil? Many
patients and families – and many physicians – are eager to see anything that might
offer hope. Clearly Biogen – the manufacturer – is happy with the outcome, but what
does it mean to the field? Will we be more likely to see truly effective therapies or will
this slow down progress toward an actual cure? What happens to investments and
funding? What happens to startups?
The current cost of aducanumab is pegged at $56k, already a high price, but it
doesn't include the associated costs, such as the mandatory MRI scans (which are
unlikely to be covered by either government or personal health insurance), to say
nothing of infusion, hospital, or physician charges, all of which are estimated to
double the costs. And even the costs that are covered will result in less available
funding for other, more effective medical needs. Do we fund an ineffective
intervention and drop coverage for other patients and other diseases? Releasing
aducanumab results in hard choices, hard questions, and little certainty.
Aducanumab was not released because it improved patients, but because some
of the data in a subset of patients (such as those with APOE4 and only those taking
the highest dose) suggested that it might lower amyloid, yet amyloid has never been
shown to be the cause of Alzheimer's and interventions based on amyloid have
consistently failed to show clinical efficacy. The global consensus is that aducanumab
doesn't work, nor do any approaches based on amyloid as a cause or a biomarker for
Nor is aducanumab safe. ARIA (amyloid-related imaging abnormality) occurs
in 35-40% of patients, risking intracranial bleeding even in previously healthy patients
with early dementia, yet the FDA is releasing it for all patients at all stages (FDA
labelling mentions no contraindications), even those with bleeding risks, such as those
using anticoagulants, etc. While some physicians will try to minimize such risks, many
will find this technically difficult and clinically challenging. What will happen if these
risks prove both intractable and fatal, while the benefits prove to be wishful thinking
as the data suggests? Moreover, aducanumab is merely the foot-in-the-door for similar
ineffective therapies. Roche, whose gantenerumab targets biomarkers only, only in a
specific subset of AD (dominantly inherited AD), and without any evidence for a
cognitive benefit, will likely approach the FDA for acceptance as well.
While the first drug released for a disease may prompt further investment, that
occurs only when that first drug is effective and safe. The current case is different:
aducanumab may well prove to be both ineffective and unsafe. Will future
pharmaceutical firms, biotech companies, researchers, and investors desert
Alzheimer's altogether, afraid of a recurrence of clinical disaster? If that occurs, not
only will Biogen fail, but further investment may flee the field before we can develop
an intervention that truly works: we not only risk current patients, but all future
patients who rely on us to find a cure.
At Telocyte, our aim is to cure dementia, not merely to treat symptoms.
Aducanumab is not a cure and, at best, it is merely a "rabbit". We have a different
idea: we intend to cure Alzheimer's and other age-related neurodegenerative diseases.
We won't stop until we cage the dragon.