Background

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.

Findings

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 U.S. 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 120 people with mild to moderate Alzheimer's tested two doses of vaccine and two doses of adjuvant at 36 study sites. This trial contained pharmacogenomic and amyloid PET substudies. It ended in December 2012. Partial results were reported in 2014 at AAIC as indicating antibody maturation and continued safety after seven injections and follow-up of 2½ years. Full results of this study were published after peer review (Vandenberghe et al., 2017). The higher-dose vaccine (450 μg) produced a strong antibody response in 80 percent of recipients. Serious adverse events occurred in 24.5 percent of the vaccine group versus 6.7 percent of placebo. ARIA occurred in six cases, all strong responders; none were symptomatic. Strong responders had amyloid reductions that correlated with antibody titer, and a decrease in brain volume.

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 was set to run until 2023, with a five-year treatment period. It planned to enroll 1,340 homozygous ApoE4 carriers between the ages of 60 and 75 who were cognitively normal. About half of participants were to be randomized to compare CAD106 to matching placebo injected intramuscularly at weeks 1, 7, 13, 24 and then quarterly. The other half were to be randomized to compare once-daily umibecestat to matching placebo. As primary outcome, the trial planned to 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 included 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 Jul 2014 conference news, Lopez et al., 2019). As part of this trial, an outreach and screening registry was built (Walsh et al., 2023).

The umibecestat part of the trial was terminated in July 2019, due to worsening cognition in that cohort. The CAD106 portion of the trial was terminated in September 2019, reportedly due to negative results from other anti-amyloid therapies. Results are posted on ClinicalTrials.gov, and were published after peer review (Riviere et al., 2023). Of 65 people randomized, 42 received vaccine, 23 placebo. All but one of vaccinated people developed Aβ antibodies. The immunized group showed no increase in amyloid plaque accumulation over the observation period of 18 months or more, while the placebo group increased at a rate of 8.36 centiloids per year. Of three ARIA cases, one was symptomatic ARIA-E that did not recur with additional vaccine doses. Adverse events were mainly mild to moderate injection reactions, with one severe injection reaction reported.

In September 2019, Novartis noted that it had 'retired' the CAD106 program (see financial report, p 18).

To view all clinical trials, see clinicaltrials.gov. 

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