Amyvid and Irrelevance

The FDA finally gave marketing approval to Lilly’s (via Avid) Amyvid/florbetapirradio-labeled imaging agent, for use in PET-scan identification of beta-amyloid plaque. Approval had been delayed due to concerns regarding interrater variability/reliability. But reliability is not, in our view, the biggest issue here. The overriding questions are validity and clinical utility.

The validity issue harkens back to the longrunning debate regarding beta-amyloid and Alzheimer’s: Is it a cause, a result, or neither? And if it is a causal factor, in what form does it exert these pathological effects? The sentiment in the field has distinctly shifted to a focus on soluble, non-plaque forms of beta-amyloid as a target for intervention. Which begs the question–what do positive or negative plaque findings from a florbetapir-assisted PET-scan really mean? If a patient has significant cognitive decline, negative findings may reduce the likelihood that the cause is Alzheimer’s per se, since even if it is soluble AB that ‘caused’ the deterioration, one would expect some buildup of insoluble AB as well. Yet the potential for false positives remains troubling, where individuals without cognitive decline have been found to be riddled with plaque post-mortem.

But setting those questions aside for the moment, what about clinical utility? Since one would/should not interpret the presence of plaque as indicating AD in the absence of cognitive decline (and one would hope, a clinician would not order a PET-scan on someone who is asymptomatic), the Amyvid-scan would be ostensibly used in patients wherein cognitive decline has already been identified. In which case, other (and cheaper) evaluative procedures are available to rule out other potential causes of decline (e.g. depressive pseudodementia). And if these other etiologies do not appear relevant, the question is then–How would the results of the PET-scan inform treatment? If plaque turns out salient, one has the option of using typical dementia drugs like Namenda and Aricept. If plaque is not seen, leaving open the possibility that soluble beta-amyloid is having a pathological effect, or that it is a vascular dementia, one again has the option of using typical dementia drugs like Namenda and Aricept.

Amyvid offers an expensive, out-of-pocket avenue to not-informing treatment decisions. The wholesale price of Amyvid will be $1600, which we suspect, will boost the price of Amyvid-potentiated PET-scans towards the upper end of the $3000-5000 range often cited for PET-scans. Medicare will not, at least for now, cover these costs.

Well-off early adopters may embrace these scans as an additional diagnostic tool, which they are. But for most families, it will be less-than-convincing to be told: “We’d like to order a scan for your (mother, father, other elderly family member). It involves injecting a radioactive substance intravenously, and will cost you or them $5000. It will add some tentative clarity to the diagnosis, but it will not affect which of our very limited treatment choices will be used.” ‘It hurts less than a lumbar puncture’ is not a marketing motto with a future.

As has been the case with other AD-relevant imaging agents, Amyvid can confirm target-engagement for amyloid-targeting therapeutics. It is still unclear whether reducing amyloid plaque is good, bad, or irrelevant. We certainly do not concur with Public Citizen’s Sidney Wolfe, whose predictably histrionic comment was that Amyvid is “dangerous” and should not have been approved. That’s silly and hyperbolic. We can only wish that Amyvid had enough clinical meaningfulness to even be ‘dangerous.’ But it’s not, it’s just superfluous.

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2 Responses to Amyvid and Irrelevance

  1. Willy Eidsaunet says:

    Are you serious? Is the ability to potentially measure non-invasivly the build up of a potentially involved protein in the disease progression irrelevant (superfluous)? All the other aspects of AD symptomatology/patophysiology, including several indeces of brain function and morphology, can be assessed, possibly quantified, non-ivasively by means of much more cost effective imaging methods such as SPECT and MRI, with an overall, probably very similar, potential impact on patient management. I am very surprised to see the FDA apparently yield on the requirement that ‘sponsors’ demonstrate clinical utility for new imaging agents!

  2. Yes, I’m serious. The ability to “potentially measure non-invasively the build up of a potentially involved protein” does not sound like a clinically relevant intervention, not at this price. It may be useful for drug developers in assessing target-engagement, but as I noted, it has yet to be established what changes in plaque would be a desirable outcome.

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