Slow and Steady—Active Immunization Crawls Toward Promise

An active vaccine against a small piece of the Aβ42 protein is both safe and tolerable in patients with mild to moderate Alzheimer's disease (AD), according to Phase 1 trial results published in the June 1 Lancet Neurology. This vaccine mimics the N-terminal of Aβ and is designed to avoid the T cell response that scuppered development of AN1792, the first active vaccine for AD.

Researchers across biopharma and academia are aggressively pursuing active and passive immunotherapy approaches for AD. "An active approach would reduce costs considerably compared to a passive one," said first author Bengt Winblad, Karolinska Institute, Stockholm, Sweden. "We hope that our approach will provide a good basis for further development."

The effort to bring immunotherapy to patients is often depicted as a race, and some programs do progress faster than others. CAD106 has been in clinical testing since 2005 and, having Phase 1 data published seven years later, could be said to play the part of the fabled tortoise rather than the hare. Six small trials of this treatment have been completed. In part, this slow pace is because active immunization in an elderly population requires a careful series of tests to establish dosing and time for an immunization scheme by which responders develop stable antibody titers, explained Mathias Staufenbiel, formerly of Novartis. Like many pharmaceutical companies, Novartis is also cutting back on discovery research in brain diseases.

Winblad and colleagues conducted the Phase 1 trial for one year in two cohorts recruited from two Swedish hospitals. Safety, tolerability, and demonstration of an antibody response were primary objectives. The researchers recruited 58 men and women aged 50-80 years with probable Alzheimer's and a Mini-Mental State Examination (MMSE) score of 16-26. One cohort received three 50 microgram injections of CAD106 or placebo over 18 weeks. When they showed no adverse reaction, the second cohort got 150 micrograms over six weeks. (For every four patients on vaccine, one received placebo.) The researchers tested serum and cerebrospinal fluid for antibodies or disease-related biomarkers. All patients came back three times during two years for follow-up and assessment of whether the vaccine caused side effects.

The vaccine appeared to stimulate the immune system. In blood, the researchers detected a surge in antibody-bound Aβ and a drop in the free peptide. However, cerebrospinal fluid biomarkers, such as Aβ40, Aβ42, total tau, and phosphorylated tau, did not budge. The authors noted that the trial was not designed to detect differences in disease progression. Five ongoing Phase 2 studies will address that. To characterize induced antibodies, the researchers used Aβ-laden brain sections from APP23 transgenic mice and tissue from one patient with AD. Participants’ Aβ antiserum reacted with plaques with a strength proportional to the measured titer. No cases of meningitis, meningoencephalitis, or vasogenic edema were recorded. Though the sample sizes were small, researchers had a 95 percent probability of detecting brain inflammation if it occurred at the same rate as seen in the AN1792 trial, where 6 percent of patients had this side effect.

Data from "this new, second-generation vaccine comes as a promising addition to available evidence on what will probably be a long road to the ultimate successful immunotherapy," said Thomas Wisniewski, New York University School of Medicine, New York City, in an accompanying editorial. However, treatment against Aβ may need to start early in order to be effective, he wrote, and tau-targeted therapy may be needed instead of, or in addition to, drugs that reduce Aβ plaque. Several tau programs are in preclinical stages (see ARF related news story and ARF news story). Just recently, Roche’s Genentech unit purchased the rights to AC Immune’s anti-tau antibodies (see related Bloomberg news).

Several other active vaccines based on small bits of Aβ had similar results in Phase 1 and are now in Phase 2. These include Pfizer/Janssen Alzheimer Immunotherapy's ACC-001, Merck’s V950, and AFFiRiS' AD02.—Gwyneth Dickey Zakaib

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References

News Citations

  1. Uppsala: Is Tau Immunotherapy Taking Off?
  2. Stockholm: New Strategies for Immunotherapy

Other Citations

  1. APP23

External Citations

  1. Phase 1 trial
  2. Phase 2 studies
  3. related Bloomberg news
  4. ACC-001
  5. V950
  6. AD02

Further Reading

Papers

  1. Lemere CA, Maier M, Peng Y, Jiang L, Seabrook TJ. Novel Abeta immunogens: is shorter better?. Curr Alzheimer Res. 2007 Sep;4(4):427-36. PubMed.
  2. Wiessner C, Wiederhold KH, Tissot AC, Frey P, Danner S, Jacobson LH, Jennings GT, Lüönd R, Ortmann R, Reichwald J, Zurini M, Mir A, Bachmann MF, Staufenbiel M. The second-generation active Aβ immunotherapy CAD106 reduces amyloid accumulation in APP transgenic mice while minimizing potential side effects. J Neurosci. 2011 Jun 22;31(25):9323-31. PubMed.

Primary Papers

  1. Wisniewski T. Active immunotherapy for Alzheimer's disease. Lancet Neurol. 2012 Jul;11(7):571-2. PubMed.
  2. Winblad B, Andreasen N, Minthon L, Floesser A, Imbert G, Dumortier T, Maguire RP, Blennow K, Lundmark J, Staufenbiel M, Orgogozo JM, Graf A. Safety, tolerability, and antibody response of active Aβ immunotherapy with CAD106 in patients with Alzheimer's disease: randomised, double-blind, placebo-controlled, first-in-human study. Lancet Neurol. 2012 Jul;11(7):597-604. Epub 2012 Jun 6 PubMed.

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