United Neuroscience Ltd. posted top-line results from a phase IIa study of UB-311, its synthetic peptide vaccine candidate targeting beta-amyloid (A-beta) for the treatment of Alzheimer's disease (AD), showing the effort met the primary aims of safety and immunogenicity with a 96 percent response rate. Secondary endpoints, which included amyloid PET burden as well as scores from Clinical Dementia Rating Scale Sum of Boxes, Alzheimer's Disease Cooperative Study-Activities of Daily Living, Alzheimer's Disease Assessment Scale-Cognitive Subscale and Mini-Mental State Exam, pointed directionally in favor of UB-311 but were not statistically significant, which the company attributed to the study sample size.

UB-311 targets the N-terminus of A-beta peptides with the goal of inducing high B-cell specific responses while avoiding T-cell inflammation.

Overall, co-founder and CEO Mei Mei Hu was "cautiously optimistic" about the findings and implications for additional study. She said United Neuro has built its platform by considering previous areas of AD study and leveraging that knowledge to position the company's programs holistically – a philosophy dubbed "democratizing brain health" – rather than seeking to develop a "one-shot wonder."

Acknowledging that the Dublin-based company remains in the early stages of developing an AD agent, "we want an approach that's accessible, ultimately, to the massive population that develops Alzheimer's," Hu told BioWorld. "And that's something that an active immunotherapy can deliver."

A graduate of Harvard Law School and former consultant at McKinsey and Co., Hu knows a little something about vaccines. Her family started parent company United Biomedical Inc. (UBI), of Hauppauge, N.Y., which develops immunotherapeutic and immunodiagnostic products for human and veterinary use. UBI, where Hu sits on the board and formerly served as co-CEO, is one of the world's biggest players in veterinary vaccines, manufacturing a widely used product for swine growth promotion and boar taint. UBI also generates revenue from pharmaceutical contract manufacturing by subsidiary UBI-Asia.

United Neuro's platform technology was developed by UBI, which also pursues synthetic peptide-based biologicals to treat and prevent indications outside neurology. Its pipeline is based on designer peptides, vaccine formulation systems and methods to manufacture therapeutic monoclonal antibodies.

Key to that methodology is what's called the UBITh immunogen. Unlike traditional vaccines that use keyhole limpet hemocyanin or a toxoid carrier so the response is largely directed at the toxoid, UBITh immunogens comprise a custom-designed UBITh antigen and a UBITh peptide carrier. Combined with other proprietary UBITh vaccine components, the result is a vaccine based on a stealthy endobody – an antibody produced by the body against an endogenous protein – designed to elicit a broad response across populations, generate highly specific endobodies against the desired target epitope and do so safely with virtually no off-target response.

'We do recognize there's more work to be done'

In a phase I study of UB-311, United Neuro showed that its so-called endobody approach generated antibodies to specific a-beta oligomers and fibrils with no decrease in antibody levels in patients of advanced age. That basic finding gave the company sufficient confidence to take the next step into a field littered with failure. (See BioWorld, Nov. 3, 2017.)

The phase IIa study was intended to provide directional information on the safety, tolerability and therapeutic potential of UB-311 in AD. The double-blind, placebo-controlled, three-arm, parallel-group study enrolled 43 participants with mild AD across four sites in China, according to Cortellis Clinical Trials Intelligence. One group of patients received three priming doses followed by four booster doses of UB-311, a second received three priming doses followed by two booster doses of UB-311 and two doses of placebo and the third received placebo only.

In October, United Neuro reported at the International Conference on Clinical Trials for Alzheimer's Disease in Barcelona no incidences of treatment induced meningoencephalitis or amyloid-related imaging abnormalities-E (ARIA-E). At that time, all but two patients had completed the week 60 treatment period. The most common reported adverse events were injection site-related reactions and asymptomatic ARIA-H. Overall, two participants terminated early from the study, including one who discontinued after week four and another who withdrew after week 52.

The high response rate from the phase IIa combined with demonstrated antibody target specificity and lack of immunogenic adverse events showed the phase I findings were reproducible and suggested the company is on the right track, Hu said.

"It's always great to get positive data from one trial but it's even better when you can reproduce the data, so that was highly encouraging," she said.

"These are just top-line data," Hu emphasized. "We're conducting more analyses and we're going to present full data later this year and hope to publish it, also."

United Neuro is targeting the 14th International Conference on Alzheimer's and Parkinson's Diseases, scheduled for March in Lisbon, Portugal.

Participants from the phase IIa study will roll over into a long-term extension study of UB-311 while the company seeks to move forward "expeditiously, but in the proper way," Hu said. "In terms of the next stage, we're considering several options. We do recognize there's more work to be done."

From a scientific perspective, the UB-311 findings in AD strengthen the company's conviction in its platform, which also has spawned UB-312, a synthetic peptide endobody vaccine against alpha-synuclein protein aggregates that is expected to move this year into an initial study in Parkinson's disease. In 2020, the company plans to initiate a program in migraine, Hu said. Efforts in other neuroinflammation and neurodegenerative targets could follow.

United Neuro is ramping up to scale its clinical efforts. Last month, the company hired Peter Powchik to the newly created position of executive vice president of R&D. Powchik previously served as senior vice president of clinical development at Regeneron Pharmaceuticals Inc., where he oversaw the company's first five drug approvals, including the blockbuster Eylea (aflibercept) as well as atopic dermatitis treatment Dupixent (dupilumab) and anti-cholesterol therapy Praluent (alirocumab).

Ajay Verma, former chief medical officer, remains a senior advisor to the company.

In terms of a business strategy, United Neuro will seek to advance its vaccine candidate to patients "in the quickest possible manner," Hu said, "and that means securing sufficient resources," whether through partnerships, additional private raises or a run at the public markets.

"At the end of the day, Alzheimer's is a really important, major disease," Hu said. "We want to make sure that we're well positioned to move to the next stage."

The litany of disasters in AD notwithstanding, United Neuro is "extremely hopeful" about its endobody platform and "committed to tackling" the disease, which Hu suggested ultimately will require "threading the needle" scientifically.

"Our approach is highly complementary with other therapeutic initiatives in Alzheimer's," Hu pointed out. "If you look at how we've tackled any other major disease, it's been a combo approach."