Phase 3 Paper on Amyloid Ligand Out Just Before FDA Meeting

A new way to measure fibrillar Aβ deposits in the brains of living people has met success in Phase 3 and is poised to ask for regulatory approval (see ARF spotlight). The data are formally published today in the Journal of the American Medical Association after first author Christopher Clark of Avid Radiopharmaceuticals in Philadelphia, Pennsylvania, presented these data in July 2010 at the International Conference on Alzheimer’s Disease in Honolulu, Hawaii (see ARF related conference story).

Currently, the brain’s amyloid burden can be visualized and quantified using positron emission tomography with the original ligand, Pittsburgh Compound B, plus a handful of newer ones; however, the 20-minute half-life of PIB’s 11C radionucleotide restricts its use to research centers able to synthesize the compound on site. The new ligand uses the longer-lasting F18 as the PET ligand, which would allow this method to be more widely used by physicians and researchers. Variously known as AV-45 or florbetapir, the ligand was newly branded as Amyvid following the recent acquisition of Avid Radiopharmaceuticals by Eli Lilly and Company for an upfront pretty penny of $300 million.

A prior 2008 FDA Advisory Committee meeting had required, to industry’s private chagrin at the time, a formal Phase 3 histopathology confirmation study as part of a new drug application for an amyloid imaging ligand. Hence, Clark and colleagues used Amyvid to visualize amyloid deposits in the brains of 29 volunteers near the end of their lives, and then compared the image results to immunohistochemistry and silver stains performed at autopsy. Of the 15 participants whose brains revealed Alzheimer’s pathology at death, 14 were positive for AD by florbetapir scan. The 14 volunteers without AD were negative for florbetapir, for a specificity of 100 percent in this small sample. The authors also scanned the brains of 74 healthy young people to determine the rate of false positives with florbetapir; all were negative.

The results indicate that florbetapir retention correlates well with actual β amyloid deposits, but more research is needed to discover how useful the technique is in diagnosing AD, the authors conclude.

Hard on the heels of the paper, that is, tomorrow, comes the Food and Drug Administration’s Peripheral and Central Nervous System Drugs Advisory Committee meeting to discuss Avid’s New Drug Application for Amyvid. The meeting is open to the public either in person or by way of a webcast starting at 8 a.m. EST. For more information, click through starting from the FDA Advisory Committee Calendar.

Importantly for anyone trying to place advance bets on what the oracle will say, two sets of briefing information, one by Avid and one by FDA reviewers, are freely available for download. In the latter, one reviewer stated that both primary endpoints in the Phase 3 study accompanying this application were met. At the same time, the reviewer points out limitations having to do with how the scans were read, and states on page 21: “This reviewer supports the opinion of the primary clinical reviewer that the efficacy data in this NDA fails to provide convincing evidence to support the efficacy of Amyvid PET for imaging β amyloid aggregates in the brain.”

FDA reviewers drill down into the raw data of any NDA with greater rigor than many casual readers of the requisite scientific papers, and certainly most journalists chasing their deadlines. Perhaps unsurprisingly, then, the overall impression from the reviewer’s briefing document seems less sanguine than were the news reports at the time (e.g., New York Times story; New York Times story; ARF related conference story; ARF conference story).

Big problem? Small fixable glitch? Issue only for Amyvid, or amyloid imaging at large? Read the briefing docs and then see for yourself how it all plays out tomorrow.—Madolyn Bowman Rogers and Gabrielle Strobel

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References

News Citations

  1. Honolulu: FDA Approval in Sight for 18F Amyloid Tracer Florbetapir?
  2. Toronto: Last Gift to Science—Hospice Patients Validate Amyloid Ligand

External Citations

  1. recent acquisition
  2. webcast starting at 8 a.m. EST
  3. FDA Advisory Committee Calendar
  4. freely available for download
  5. New York Times story
  6. New York Times story

Further Reading

Primary Papers

  1. Clark CM, Schneider JA, Bedell BJ, Beach TG, Bilker WB, Mintun MA, Pontecorvo MJ, Hefti F, Carpenter AP, Flitter ML, Krautkramer MJ, Kung HF, Coleman RE, Doraiswamy PM, Fleisher AS, Sabbagh MN, Sadowsky CH, Reiman EP, Reiman PE, Zehntner SP, Skovronsky DM, . Use of florbetapir-PET for imaging beta-amyloid pathology. JAMA. 2011 Jan 19;305(3):275-83. PubMed.

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