On January 20, an FDA advisory committee will give its opinion on whether to approve Eli Lilly’s radiological tracer that promises to revolutionise Alzheimer’s disease diagnosis.
True diagnosis of the disease is currently only achievable from a post-mortem biopsy of the brain. The Indianapolis giant thinks florbetapir F18 (18F-AV-45) has the potential to spot specific disease signatures via brain scan, and crucially in early stages. Expert panelists are likely to scrutinise whether results of a patient’s brain scan truly correlate with the incidence of those disease biomarkers observed in an autopsy; data so far, while not perfect, have shown significant promise. Lilly’s recent $800m acquisition of Avid Radiopharmaceuticals was mainly geared at harnessing the value of the diagnostic. If approved, the agent holds significant deal value for Avid’s shareholders, and an important complimentary tool to Lilly’s pivotal Alzheimer’s candidate, solanezumab.
|Product||Florbetapir F18 (18F-AV-45)|
|Event type||FDA advisory committee|
|Date||January 20, 2011|
As biopsy is the only true diagnosis of Alzheimer’s, standard of care for diagnosing the disease involves a relatively primitive process of elimination where a physician will first rule out other neurodegenerative disorders and use basic tools such as memory tests. Misdiagnoses are therefore common.
Florbetapir, radio-tagged with fluoride 18, binds to beta-amyloid plaques in the brain. These deposits are thought to be biological hallmarks of Alzheimer’s disease, as opposed to other forms of dementia or amnesia, and can appear years before symptoms emerge.
Phase III data found tracer-bound plaques lit up under PET imaging. Avid studied severely-ill patients, who had agreed to a brain biopsy after death, to test the agent. Autopsy results found that areas emitting radiation correlated with areas of plaque accumulation.
In separate studies conducted at Johns Hopkins University, researchers could easily distinguish between Alzheimer’s-diagnosed and healthy subjects using florbetapir images very quickly after injection, with no side effects.
Avid’s programme followed pioneering work by the University of Pittsburgh and University of Uppsala in Sweden on Pittsburgh Compound B (PiB), a similar diagnostic labelled with carbon 11. Studies showed that Alzheimer’s patients had high retention of PiB in the cortex, and low volumes in the hippocampus; the opposite was true for normal subjects; those with non-Alzheimer’s amnesia and dementia came somewhere in the middle.
However, PiB remains a research tool as carbon 11 has a half-life of just 20 minutes. This means it must be manufactured in specialist and relatively scarce facilities in some hospitals or medical centres, to be injected into the patient immediately on-site.
Fluoride 18 on the other hand has a two-hour half life, and the opportunity to transport the test to sites away from manufacturing facilities could be looked upon very favourably.
The real deal value
While the $300m upfront payment is fairly small fry for a giant like Lilly trying to expand into the diagnostics business, the extra $500m milestone payments to Avid’s shareholders would be very welcome, contingent in part on florbetapir’s approval and achieving certain sales targets (Eli Lilly snaps up leading Alzheimer's diagnostic, November 8, 2010).
The real value for Lilly therefore lies with florbetapir’s ability to predict efficacy for beta-amyloid-targeted drugs like solanezumab, which has a net present value of $616m – 2% of Lilly’s current market capitalisation and its fifth-most valuable pipeline candidate. Pivotal results are expected later in the year, or 2012.
Pipeline pressure has mounted as Lilly approaches its infamous patent cliff, primarily hitting its neurological disease programmes with schizophrenia treatment Zyprexa losing protection later this year, and antidepressant Cymbalta in 2013. Proving solanezumab’s efficacy could significantly increase the value of that product.
Lilly and Avid estimate the global market for Alzheimer’s diagnosis between $1bn and $5bn. To put the size of this potential market into context, the single biggest selling diagnostic around today is GE Healthcare’s Visipaque, a cardiovascular imaging agent which generates annual revenues of around $500m.
Analysts have yet to assign any tangible value to florbetapir's commercial potential, so a positive advisory committee and FDA approval could add some much needed revenues to weak-looking forecast models.
It is widely thought that beta-amyloid plaques are central to the disease. Most therapies in development target beta-amyloid as a matter of course, although one expert – Dr Karl Herrup of Rutgers University – recently voiced concerns in the Journal of Neuroscience that amyloid plaques might not be disease-causing. He thinks perhaps that Alzheimer’s therapies have hit a glass ceiling with beta-amyloid, and the treatment paradigm may need to shift dramatically.
This of course is one opinion; however, beta-amyloid has been extensively studied with no significant disease-modifying breakthroughs. Any shift away from the beta-amyloid theory could limit florbetapir's potential as well as harm dozens of existing drugs programmes (Therapeutic focus - What are plan B options if A-beta Alzheimer's hypothesis is void?, August 19, 2010).
Competition is also expected as GE Healthcare and Bayer are developing Fluoride18-based diagnostics in pivotal trials, thought to be trailing Avid by 12 months.
Nevertheless, an ability to visualise only beta-amyloid plaques, distinguishing from other possible dementias, along with strong safety profile, seem to address the obvious questions an advisory committee would pose. Florbetapir F18 also benefits from a long half-life, and looks the logical alternative for a disease extremely difficult to diagnose. An approval would indeed be a breakthrough for Alzheimer’s, and potential source of decent revenue for Lilly.