Daniel M. Keller, PhD

April 22, 2013

Taipei, Taiwan — In an early-phase trial, a candidate vaccine against amyloid-β (Aβ) appears safe and well tolerated in patients with mild to moderate Alzheimer's disease (AD), overcoming serious problems of adverse effects seen with previous vaccines.

In addition, it produced a specific antibody response in all of the patients tested, Shugene Lynn, PhD, from United Biomedical Inc, reported here at the Alzheimer's Disease International (ADI) 28th International Conference.

In this phase 1 study, the vaccine showed improvements in tests of cognitive function, including 1 test where the result correlated with antibody titers. A subset analysis showed it to be most effective in older patients with mild AD, the researchers report.

Dr. Lynn said that an upcoming phase 2 placebo-controlled trial will enroll 45 persons age 60 years or older with amyloid positivity on positron emission tomography. Endpoints will be safety and tolerability, antibody response rates and titers, changes in cognitive and functional scores, and changes in amyloid burden.

Early Trial Shows Vaccine Safe, Efficacious

The vaccine, UB-311, is an equimolar mixture of 2 synthetic peptides coupled through an oligonucleotide spacer to the N-terminal 14-amino acid fragment of Aβ (Aβ1-14). It is designed to elicit specific B cell responses and broad T cell responses.

Previous work in animal models has been promising. In guinea pigs, UB-311 produced better antibody responses than did Aβ1-14 or the N-terminal 28-amino acid fragment (Aβ1-28) alone or Aβ1-14 coupled to keyhole limpet hemocyanin, a very large, immunogenic carrier molecule. In transgenic mice, the vaccine decreased the amount of Aβ deposited in brain cortex or in the hippocampus, and it improved learning and short-term memory in these animals.

In cynomolgus macaque monkeys, vaccine administration elicited specific antibody responses with anamnestic responses to rechallenge at 18 months. When tested against Aβ1-42, the antibodies reacted only with the Aβ1-14 N-terminus site, indicating specificity for the epitope contained in the vaccine. Importantly, there was no evidence of adverse effects, including meningoencephalitis, and repeated dosing appeared safe.

In a core clinical trial and an observational extension phase, 19 Taiwanese patients aged 50 to 80 years with mild to moderate AD were given 300 μg of the vaccine by intramuscular injection at weeks 0, 4, and 12.

All patients responded; peak antibody titers occurred at week 16 (2.70 log10) and dropped off but were still elevated at week 48 (1.74 log10) compared with week 0.

In patients with mild AD 60 years of age and older, preliminary efficacy data showed the patients had improvement measured on the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog), the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC), and the Mini-Mental State Examination (MMSE), Dr. Lynn reported.

Weight Stabilization

In an subset of patients (n = 6) assessed at 48 weeks, there were a 2.3-point improvement on the ADAS-Cog, a 0.7-point improvement on ADCS-CGIC, and a 0.5-point improvement on the MMSE compared with baseline.

For the group of all patients age 60 years or older, including those with moderate disease, performance on ADAS-Cog deteriorated and responses on the other 2 tests improved only slightly. The group of patients of any age with mild disease showed a 1.3-point improvement on ADAS-Cog, a 0.2-point improvement on ADCS-CGIC, and a 0.6-point deterioration on the MMSE.

The improvement in ADAS-Cog at week 24 compared with baseline correlated with the antibody titer at week 24 (correlation coefficient, r = 0.70; P < .01).

AD patients typically lose body weight over the course of their disease. However, in this trial, administration of UB-311 was associated with stabilization of weight (P = .991 at week 24 vs baseline).

Most adverse effects were judged unlikely to be related to the drug except tenderness over the injection site. No one withdrew from the trial, no patients presented with symptoms consistent with meningoencephalitis, and there were no clinically significant changes on electrocardiography or MRI.

Session chair Daisy Acosta, MD, past president of Alzheimer's Disease International and a geriatric psychiatrist in private practice in the Dominican Republic, commented to Medscape Medical News that the vaccine looks safe, "contrary to the other vaccines that we have up to now."

Although these vaccines have been promising, antibodies may develop; this can produce inflammation in the brain, she said. "So apparently UB-311 doesn't have that effect up to now."

Dr. Acosta was intrigued that the vaccine stabilized patients' weight, although she was uncertain by what mechanism this might occur.

Dr. Lynn is an employee of United Biomedical. Dr. Acosta, who was not involved in the study, has disclosed no relevant financial relationships.

Alzheimer's Disease International (ADI) 28th International Conference. Abstract OC025. Presented: April 19, 2013.