Bapineuzumab Explained

Bapineuzumab (nicknamed "bapi")[1] is a humanized monoclonal antibody that acts on the nervous system and may have potential therapeutic value for the treatment of Alzheimer's disease and possibly glaucoma.[2] However, in 2012 it failed to produce significant cognitive improvements in patients in two major trials, despite lowering key biomarkers of AD, amyloid brain plaque and hyperphosphorylated tau protein in CSF.[3] [4]

Bapineuzumab has been shown to recognise the extreme N-terminal 5 residues of Aβ peptide in a helical conformation (4HIX.pdb) stabilized by internal hydrogen bonds involving the first three amino acids.[5]

Bapineuzumab is an antibody to the beta-amyloid (Aβ) plaques that are believed to underlie Alzheimer's disease neuropathology. In previous clinical trials for vaccination against human beta amyloid, called AN-1792, patients with Alzheimer's disease using active immunization had positive outcomes with removal of plaques, but 6% of subjects developed aseptic meningitis and the trial was stopped.[6]

Testing

Bapineuzumab was being co-developed by the pharmaceutical companies Élan and Wyeth and entered Phase III trials in December 2007.[7] In 2008 a Johnson & Johnson affiliate acquired a substantial portion of Élan's assets related to the Alzheimer's immunotherapy program, which Elan had shared with Wyeth. The program is continuing with Pfizer, which acquired Wyeth in 2009.

Bapineuzumab was the first antibody to be found to cause amyloid-related imaging abnormalities, including an accumulation of fluid in brain tissue (ARIA-E)[8] in patients receiving the highest dose. No health risks were found in subjects receiving either 0.5 or 1 mg of bapineuzumab. Patients who have been receiving or have been scheduled to receive the highest dose will be either removed from the trials or switched to lower doses.[9]

The efficacy of drugs targeted to brain plaques in Alzheimer's patients has been called into question, although such drugs may still be effective for prophylaxis if given to individuals who have not yet developed clinical symptoms.[10] [11]

On August 6, 2012, Pfizer Inc. and Johnson & Johnson said they are ending development of an intravenous formulation of bapineuzumab. Testing showed the drug did not work better than placebo in two late-stage trials in patients who had mild to moderate Alzheimer's disease.[11]

Élan announced that Johnson & Johnson, on July 16, 2013, had discontinued Phase 2 testing of the subcutaneous formulation of bapineuzumab.[12]

Insider trading

Mathew Martoma, formerly of S.A.C. Capital Advisors, was convicted in February 2014 of insider trading[13] on news passed by neurologist Sid Gilman of the cancellation of bapineuzumab's testing.[14]

Notes and References

  1. Brandt C . Fall–Winter 2012. "Team Babcock's" journey. InSight. The Penn Memory Center (Penn Medicine). 1–3. 1 Feb 2014. 28 February 2014. https://web.archive.org/web/20140228061758/http://pennadc.org/wp-content/uploads/2013/07/insight-fall-2012.original.pdf. dead.
  2. Sample I . 2007-08-07 . New Alzheimer's drugs might help prevent glaucoma . . 2008-06-18 .
  3. Web site: Berkrot B . Pfizer, J&J scrap Alzheimer's research as drug fails . Reuters . 7 August 2012 .
  4. Web site: Alzheimer's disease drug shelved after trial failure . BBC News . 7 August 2012 .
  5. Miles LA, Crespi GA, Doughty L, Parker MW . Bapineuzumab captures the N-terminus of the Alzheimer's disease amyloid-beta peptide in a helical conformation . Scientific Reports . 3 . 3 . 1302 . 2013-02-18 . 23416764 . 3575012 . 10.1038/srep01302 . 2013NatSR...3E1302M .
  6. Woodhouse A, Dickson TC, Vickers JC . 28279428 . Vaccination strategies for Alzheimer's disease: A new hope? . Drugs & Aging . 24 . 2 . 107–19 . 2007 . 17313199 . 10.2165/00002512-200724020-00003 . 2010-07-27 . . dead . The vigour of international research on immunotherapy for AD provides significant hope for a strong therapeutic lead for the escalating number of individuals who will develop this otherwise incurable condition. . https://archive.today/20130116103034/http://adisonline.com/aging/Fulltext/2007/24020/Vaccination_Strategies_for_Alzheimer_s_Disease__A.3.aspx . 2013-01-16 .
  7. Elan and Wyeth Announce Encouraging Top-line Results from Phase 2 Clinical Trial of Bapineuzumab for Alzheimer's Disease . . 2008-06-17 . https://archive.today/20130122034056/http://newsroom.elan.com/phoenix.zhtml?c=88326&p=irol-newsArticle&ID=1166655 . dead . 2013-01-22 . 2008-06-18 . Elan and Wyeth plan to continue all four studies in the previously disclosed bapineuzumab Phase 3 clinical program .
  8. DiFrancesco JC, Longoni M, Piazza F . Anti-Aβ Autoantibodies in Amyloid Related Imaging Abnormalities (ARIA): Candidate Biomarker for Immunotherapy in Alzheimer's Disease and Cerebral Amyloid Angiopathy . Frontiers in Neurology . 6 . 207 . 2015-09-25 . 26441825 . 4585101 . 10.3389/fneur.2015.00207 . free .
  9. Pogatchnik S . 2009-04-02 . Drug Makers Stop Top Dosage in Alzheimer's Trial . Drug Discovery & Development . 2009-04-16 .
  10. News: Steenhuysen J . New theory of Alzheimer's explains drug failures . . Chicago . 2 . Reuters . May 12, 2010 .
  11. News: Berkrot B . Pfizer, J&J scrap Alzheimer's studies as drug fails . Reuters . New York . August 7, 2012 . August 7, 2012 .
  12. http://www.elan.com/company/about_us Phase 2 testing of the subcutaneous formulation of bapineuzumab is to be discontinued.
  13. News: Stevenson A, Goldstein M . Ex-SAC Trader Convicted of Securities Fraud . February 22, 2014 . . February 7, 2014 . A1 .
  14. Web site: The Corruption of Sid Gilman-How a top U-M doc lost his way. Betzold M . 2013-01-26. Ann Arbor Observer. 24 February 2014. 2014-02-28. https://web.archive.org/web/20140228055956/http://annarborobserver.com/articles/the_corruption_of_sid_gilman_full_article.html. dead.

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