Amgen, can prevent Alzheimer’s in people ages 60 years to 75 years who are cognitively healthy but have two APOE4 genes. APOE4 is a variant of the APOE gene found in a number of Alzheimer’s patients. People with two copies of the APOE4 gene variant are considered to be at high risk of developing mild cog- nitive impairment (a slight decline in cognitive ability, including thinking and memory skills) and/or dementia due to AD. One part of the study will compare 430 individuals given CAD106 as an injection to 260 individuals who will receive a placebo; another will compare 390 people treated with oral CNP520 against a placebo. The study will follow participants for at least 60 months (five years) and up to 96 months (eight years), and is expected to conclude in May 2024. 9,10 According to Antonio Ligi, director of global external communi- cations at Novartis, “We have recruited a sufficient number of sub- jects (65) for the CAD106 cohort to evaluate the effects on amyloid in the brain. We expect to conduct this assessment after two years of treatment at the latest. This is expected to take place in 2020. In parallel, we are working with Banner Alzheimer’s Institute to evaluate whether there are further development options for CAD106.” DNA AB42 Scientists at the University of Texas Southwestern Peter O’Donnell Jr. Brain Institute led by Roger Rosenberg, MD, and Doris Lambracht-Washington, PhD, have developed a DNA vac- cine called DNA AB42 that is on a short list of promising anti- body treatments aimed at protecting against both types of proteins that kill brain cells as they spread in deadly plaques and tangles on the brains of AD patients. The idea for the vaccine was to start with DNA coding for amyloid and inject it into the skin rather than the muscle to produce a different kind of immune response. The injected skin cells make a three-molecule chain of beta-amyloid (AB42), and the body responds by producing antibodies that inhibit the buildup of amyloid and, indirectly, also of tau. 11 The latest study, which consisted of four cohorts of between 15 and 24 mice each, showed a 40 percent reduction of Aβ 42 peptide and a 25 percent to 50 percent reduction of total tau and different phosphorylated tau molecules in mice compared with nonimmu- nized control animals. Plaque and Aβ peptide reductions in the brain were due to the anti-Aβ antibodies generated following the immunizations. Reductions of tau were likely due to indirect actions such as less Aβ in the brain resulting in less tau kinase acti- vation. The vaccine did not induce inflammatory T-cell responses. 12 One strategy still being tested for clinical benefits involves pro- ducing the antibodies in the lab and injecting them into the body. Allowing the body to produce its own antibodies through active immunization would be the preferable strategy since the vaccine would be more accessible and less expensive. It also produces a wider variety of antibody types than the preformed antibodies containing only one specific antibody. 11 According to Dr. Rosenberg, “The DNA AB42 vaccine differ- entiates itself from other AD vaccines currently being researched in that it targets both amyloid and tau, it elicits a different immune response that might be safe for humans, and it produces its own antibodies through active immunization. I’m hopeful this vaccine can prevent or slow the progression of AD, and plans are now underway to obtain funding to test it in humans.” UB-311 United Neuroscience is developing an anti-amyloid endobody vaccine called UB-311. This synthetic peptide vaccine couples a helper T-cell epitope designed with United Biomedical’s UBITh platform to the amino acids 1-14 in the beta amyloid protein, packaged in a proprietary delivery system. The approach aims to stimulate a T-helper type 2 regulatory immune response over a T- helper type 1 pro-inflammatory response, and to avoid cross- reactivity with similar endogenous antigens. 13 A peer-reviewed paper on preclinical studies in small animals, baboons and macaques reported the vaccine generated N-terminal anti-amyloid antibodies, which neutralized amyloid toxicity and promoted plaque clearance. The paper also claimed the vaccine evoked no anti-amyloid cellular responses in a transgenic mouse model for AD, and both acute and chronic dosing were safe and well-tolerated in cynomolgus macaques. In a Phase I clinical trial, the UB-311 vaccine was tested on patients with mild to moderate AD to determine safety, tolerability and immunogenicity. Results concluded the vaccine was safe, well-tolerated and produced a specific antibody response in all par- B IO S UPPLY T RENDS Q UARTERLY | Fall 2019 25