Therapy Type: Immunotherapy (active) (timeline)
Target Type: Amyloid-Related (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2/3)
Company: Novartis Pharmaceuticals Corporation
Approved for: None
This is an active vaccination strategy that aims to elicit a strong antibody response while avoiding inflammatory T cell activation (reviewed in Lemere and Masliah, 2010). CAD106 combines multiple copies of Aβ1-6 peptide derived from the N-terminal B cell epitope of Aβ, coupled to a Qβ virus-like particle. In animals, CAD106 induced Aβ-antibody titers without activating Aβ-reactive T cells. Administration of CAD106 to APP-transgenic mice showed a reduction of amyloid accumulation in the brain (Wiessner et al., 2011).
In March 2015, GlaxoSmithKline bought Novartis' vaccine business, but CAD106 was not part of this transaction.
In 2008, a one-year Phase 1 trial of two doses of CAD106 in 58 people with mild to moderate Alzheimer's disease in Sweden concluded that the vaccine dose-dependently induced Aβ IgG titers that met prespecified "responder" criteria for an immune response while being generally safe and well-tolerated. No meningoencephalitis was reported (Winblad et al., 2012).
CAD106 has since been tested with subcutaneous and intramuscular injections in five multicenter Phase 2 trials in the United States and Europe. Two 66-week extension trials ending in 2010 and 2011 explored antibody response and tolerability of additional doses, i.e., different longer-injection/booster-shot regimens. They found prolonged antibody titers in responders (Farlow et al., 2015). A 90-week trial of 177 people with mild to moderate Alzheimer's tested two doses of vaccine and two doses of adjuvant at 36 study sites. This trial contains pharmacogenomic and amyloid PET substudies. This trial has concluded. Partial results were reported in 2014 at AAIC as indicating antibody maturation and continued safety after seven injections and follow-up of 2½ years.
In July 2014, Novartis partnered with the Banner Alzheimer Research Institute to conduct a secondary prevention trial within the Alzheimer Prevention Initiative (API, see July 2014 conference news). This Phase 2/3 trial began in November 2015 and is set to run until 2023, with a 5-year treatment period. This study aims to enroll 1,340 homozygous ApoE4 carriers between the ages of 60 and 75 who are cognitively normal. About half of participants will be randomized to compare CAD106 to matching placebo injected intramuscularly at weeks 1, 7, 13, 24 and then quarterly. The other half will be randomized to compare once-daily CNP520 to matching placebo. As primary outcome, the trial will measure ability to delay diagnosis to MCI or AD dementia and change on the APICC cognitive composite (Langbaum et al., 2015). An extensive list of secondary outcomes include change on the Clinical Dementia Rating Scale sum of boxes (CDR-SB) along with other cognitive/functional scales, fluid biomarkers including CSF Aβ and tau, brain imaging including volumetric MRI plus amyloid PET and tau PET measurement of brain amyloid and tangle deposition, respectively, as well as safety measures and Aβ titers (see Aug 2014 conference news, clinicaltrials.gov).
To view all clinical trials, see clinicaltrials.gov.
Clinical Trial Timeline
- Phase 2
- Study completed / Planned end date
- Planned end date unavailable
- Study aborted
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- 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.
- Farlow MR, Andreasen N, Riviere ME, Vostiar I, Vitaliti A, Sovago J, Caputo A, Winblad B, Graf A. Long-term treatment with active Aβ immunotherapy with CAD106 in mild Alzheimer's disease. Alzheimers Res Ther. 2015;7(1):23. Epub 2015 Apr 27 PubMed.
- Langbaum JB, Hendrix S, Ayutyanont N, Bennett DA, Shah RC, Barnes LL, Lopera F, Reiman EM, Tariot PN. Establishing Composite Cognitive Endpoints for Use in Preclinical Alzheimer's Disease Trials. J Prev Alzheimers Dis. 2015 Mar;2(1):2-3. PubMed.
- Lemere CA, Masliah E. Can Alzheimer disease be prevented by amyloid-beta immunotherapy?. Nat Rev Neurol. 2010 Feb;6(2):108-19. PubMed.
- 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.
- Kingwell K. Alzheimer disease: Amyloid-β immunotherapy CAD106 passes first safety test in patients with Alzheimer disease. Nat Rev Neurol. 2012 Aug;8(8):414. PubMed.