FDA says no to marketing FDDNP for CTE

The U.S. Food and Drug Administration recently admonished TauMark™, a brain diagnostics company, for advertising brain scans that can diagnose chronic traumatic encephalopathy (CTE), Alzheimer's disease, and other types of dementia. The Los Angeles Times reported that the FDA ordered UCLA researcher Dr. Gary Small and his colleague/business partner Dr. Jorge Barrio to remove misleading information from their company website (example shown below).

CTE has been in the news because the neurodegenerative condition has been linked to a rash of suicides in retired NFL players, based on post-mortem observations. And the TauMark™ group made headlines two years ago with a preliminary study claiming that CTE pathology is detectable in living players (Small et al., 2013).

The FDA letter stated:

The website suggests in a promotional context that FDDNP, an investigational new drug, is safe and effective for the purpose for which it is being investigated or otherwise promotes the drug. As a result, FDDNP is misbranded under section 502(f)(1) of the FD&C Act...

[¹⁸F]-FDDNP¹ is a molecular imaging probe that crosses the blood brain barrier and binds to several kinds of abnormal proteins in the brain. When tagged with a radioactive tracer, FDDNP can be visualized using PET (positron emission tomography).

Despite what the name of the company implies, FDDNP is not an exclusive tau marker. FDDNP may bind to tau protein [although this is disputed],² but it also binds to beta-amyloid, found in the clumpy plaques that form in the brains of those with Alzheimer's disease. Tau is found in neurofibrillary tangles, also characteristic of Alzheimer's pathology, and seen in other neurodegenerative tauopathies such as CTE.

The big deal with this and other radiotracers is that the pathological proteins can now be visualized in living human beings. Previously, an Alzheimer's diagnosis could only be given at autopsy, when the post-mortem brain tissue was processed to reveal plaques and tangles. So PET imaging is a BIG improvement. But still, a scan alone is not completely diagnostic, as noted by the Alzheimer's Association:

Even though amyloid plaques in the brain are a characteristic feature of Alzheimer's disease, their presence cannot be used to diagnose the disease. Many people have amyloid plaques in the brain but have no symptoms of cognitive decline or Alzheimer's disease. Because amyloid plaques cannot be used to diagnose Alzheimer's disease, amyloid imaging is not recommended for routine use in patients suspected of having Alzheimer's disease.

from TauMark's old website

There are currently three FDA-approved molecular tracers that bind to beta-amyloid: florbetapir, flutemetamol, and florbetaben (note that none of these is FDDNP). But the big selling point of TauMark™ is (of course) the tau marker part, which would also label tau in the brains of individuals with CTE and frontotemporal dementia, diseases not characterized by amyloid plaques. But how can you tell the difference, when FDDNP targets plaques and tangles (and prion proteins, for that matter)?

A new study by the UCLA team demonstrated that the distribution of FDDNP labeling in the brains of Alzheimer's patients differs from that seen in a selected group of former NFL players with cognitive complaints (Barrio et al., 2015). These retired athletes (and others with a history of multiple concussions) are at risk of developing the brain pathology known as chronic traumatic encephalopathy.

from Fig. 1 (Barrio et al., 2015).  mTBI = mild traumatic brain injury, or concussion. T1 to T4 = progressive FDDNP PET signal patterns.


It's a well-established fact that brains with Alzheimer's disease, frontotemporal lobar degeneration, or Lou Gehrig's disease (for example) all show different patterns of neurodegeneration, so why not extend this to CTE? This may seem like a reasonable approach, but there are problems with some of the assumptions.

Perhaps the most deceptive claim is that “TauMark owns the exclusive license of the first and only brain measure of tau protein...” Au contraire! A review of recent developments in tau PET imaging (Zimmer et al., 2014) said that...

...six novel tau imaging agents—[¹⁸F]THK523, [¹⁸F]THK5105, [¹⁸F]THK5117, [¹⁸F]T807, [¹⁸F]T808, and [¹¹C]PBB3—have been described and are considered promising as potential tau radioligands.

Note that [¹⁸F]FDDNP is not among the six.^2,3  In fact, Zimmer et al. (2014) mentioned that in brain slices, “[3H]FDDNP failed to demonstrate overt labeling of tau pathology.” ²

No matter. Former NFL players are clamoring to participate in the TauMark studies.


So to recap, the FDA considered TauMark marketing to be “concerning from a public health perspective.” Their letter warned:

Your website describes FDDNP for use in brain PET scans to diagnose traumatic brain injuries, Alzheimer’s disease, and other neurological conditions. These uses are ones for which a prescription would be needed because they require the supervision of a physician and adequate directions for lay use cannot be written.

(see also Regulatory Focus News and the FDA's own PDF archive of the TauMark site).


At this point, astute followers of The Neurocritic and Neurobollocks might ask, “Hey, how does Dr. Daniel Amen get away with claiming that his SPECT scans can accurately diagnose different types of dementia, each with different ‘treatment plans’?”

Hey FDA, what gives?? Dr. Small and Dr. Barrio have at least 37 peer-reviewed publications on their FDDNP methods and imaging results. Meanwhile, Dr. Amen has two non-peer reviewed poster abstracts on his SPECT results in dementia. With ads like these and appearances on Celebrity Rehab, aren't the Amen Clinics's claims “misbranded” too?

LA Times link via @MichelleNMeyer

Further Reading

Is CTE Detectable in Living NFL Players?

The Ethics of Public Diagnosis Using an Unvalidated Method

Uncertain Diagnoses, Research Data Privacy, & Preference Heterogeneity

Blast Wave Injury and Chronic Traumatic Encephalopathy: What's the Connection?

Little Evidence for a Direct Link between PTSD and Chronic Traumatic Encephalopathy


Footnotes

¹ FDDNP is 2-(1-(6-[(2-[(18)F]fluoroethyl)(methyl)amino]-2-naphthyl)ethylidene)malononitrile.

² Or what is presumed to be tau. FDDNP is supposedly a tracer for both tau and amyloid, but some experts think it's neither. Zimmer et al. (2014) stated:

Though ... [18F]FDDNP appeared to bind both amyloid plaques and tau tangles, a subsequent study using [3H]FDDNP autoradiography in sections containing neurofibrillary tangles (NFTs) failed to demonstrate overt labeling of tau pathology because of a low affinity for NFTs.

Other studies have shown that it binds to a variety of misfolded proteins.

³ James et al. (2015) were more generous in their review of tau PET imaging, mentioning the existence of seven tau tracers (including FDDNP). But again they noted the lack of specificity.  (Parenthetically speaking, [¹⁸F]T807 imaging has been done in a single NFL player, which may be of interest in a future post.)


References

Barrio, J., Small, G., Wong, K., Huang, S., Liu, J., Merrill, D., Giza, C., Fitzsimmons, R., Omalu, B., Bailes, J., & Kepe, V. (2015). In vivo characterization of chronic traumatic encephalopathy using [F-18]FDDNP PET brain imaging. Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.1409952112

Zimmer, E., Leuzy, A., Gauthier, S., & Rosa-Neto, P. (2014). Developments in Tau PET Imaging. The Canadian Journal of Neurological Sciences, 41 (05), 547-553 DOI: 10.1017/cjn.2014.15