Amyloid Vaccine UB-311 Demonstrates Positive Findings With No ARIA-E Cases in Published Phase 2 Study

Jeffrey Cummings, MD, PhD

Vaxxinity announced the publication of its phase 2 study (NCT02551809) assessing its investigational synthetic, peptide-based active immunotherapy, UB-311, in individuals with mild Alzheimer disease (AD). Published in The Lancet’s eBioMedicine, the candidate demonstrated a safe and tolerable profile, with positive trends on several secondary outcomes of cognitive, functional, behavioral, and global assessments.

"The UB-311 Phase 2a program accomplished its goals of establishing safety and tolerability, while generating high levels of anti-amyloid antibodies. The gradual, natural titration of antibody titers through this approach may have contributed to a lack of ARIA-E in this study,” study investigator Jeffrey Cummings, MD, PhD, director of the Chambers-Grundy Center for Transformative Neuroscience, University of Nevada, Las Vegas, said in a statement.¹ "Vaccine approaches such as UB-311 represent important ways forward in advancing treatment and prevention of Alzheimer’s disease and offer the potential to transform the treatment landscape by providing participants with an accessible therapeutic option."

Conducted in Taiwan, the randomized, double-blind, placebo-controlled, parallel-group study randomly assigned 43 individuals with mild AD 1:1:1 to receive either 7 intramuscular injections of UB-311 (Q3M arm, 5 doses of UB-311 with 2 doses of placebo (Q6M arm) or 7 doses of placebo. UB-311, an antiamyloid vaccine, differs from previously approved agents in the class, with less frequent dosing and ease of administration through intramuscular injection as well as lower rates of amyloid-related imaging abnormalities (ARIA).

Trial retention rate was high, with 41 (95%) participants completing all 78 weeks of assessments. None of the treatment discontinuations were because of a drug-related treatment emergent adverse event (TEAE). Across all arms, “general disorders and administration site conditions,” experienced by 12 (28%) participants, was the most common system organ class of TEAE observed. TEAEs with the highest incidence included injection-site pain (14 TEAEs by 7 individuals; Q3M: 0; Q6M: 4; placebo: 10), ARIA-H (12 TEAEs by 6 participants; Q3M: 5; Q6M: 3: placebo: 4), and diarrhea (5 TEAEs by 5 participants; Q3M: 0; Q6M: 1; placebo: 4).

From previous visits, a total of 11 new ARIA-H imaging events were observed, 4 in the Q3M arm, 4 in the Q6M arm, and 3 in the placebo group. One participant in the Q3M dosing arm had a new ARIA-H event consisting of both microhemorrhage and superficial siderosis that was counted as a single new ARIA-H imaging event but was reported as two separate ARIA-H TEAEs. All other new ARIA-H events were microhemorrhages. Of note, 8 of the 11 (73%) new cases of microhemorrhage occurred in apolipoprotein e4 carriers, considered the highest risk for AD.

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Across the cohorts, 6 participants experienced 6 serious AEs, with no apparent differences between the UB-311 and placebo arms. Of note, there were 2 serious AEs assessed as being possibly related to treatment: 1 case of colon cancer maximum severity Grade 4 in the UB-311 Q3M arm, and another participant in the placebo arm who experienced pneumonia of maximum severity grade 2.

Cognitive, functional, and global measures were captured through the Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog), Mini-Mental State Examination, ADCS-ADL, and Clinical Dementia Rating-Sum of Boxes (CDR-SB) score. Over the 78-week treatment period, both groups declined on these assessments; however, point estimates showed slower decline for the Q3M dosing arm (CDR-SB: –0.59; ADAS-Cog: –1.85; ADCS-ADL: 4.65). No statistically significant differences by treatment group were observed in these prespecified secondary end point assessments.

"This publication supports the innovative work that we and our collaborators are conducting to advance UB-311 for the potential treatment, and even prevention, of Alzheimer disease,” Mei Mei Hu, chief executive officer, Vaxxinity, said in a statement.¹ "Imagine expanding the addressable patient population of beta-amyloid immunotherapies by multiple orders of magnitude, potentially over 1,000x, and delivering life-changing medicine at a fraction of the cost. That is our vision for UB-311 and the potential power of active immunotherapies."

Nonsignificant trends in standardized uptake value ratio reduction at week 52 were observed in the UB-311 treatment arms, whereas there was a slight nonsignificant increase in amyloid burden for all brain regions in the placebo group. Trends for decreased amyloid burden at week 78 were observed only in the Q3M treatment group.

REFERENCES
1. Vaxxinity announces publication of UB-311 safety, tolerability, immunogenicity, and clinical efficacy data from phase 2a trial in Alzheimer disease. News release. August 10, 2023. Accessed August 10, 2023. https://www.globenewswire.com/news-release/2023/08/10/2722636/0/en/Vaxxinity-Announces-Publication-of-UB-311-Safety-Tolerability-Immunogenicity-and-Clinical-Efficacy-Data-from-Phase-2a-Trial-in-Alzheimer-s-Disease.html#:~:text=(Nasdaq%3A%20VAXX)%2C%20a,clinical%20data%20demonstrating%20a%20trend
2. Yu HJ, Dickson SP, Wang P, et al. Safety, tolerability, immunogenicity, and efficacy of UB-311 in participants with mild Alzheimer’s disease: a randomized, double-blind, placebo-controlled, phase 2a study. The Lancet. 2023;94:104665. doi:10.1016/j.ebiom.2023.104665