Safety, tolerability and immunogenicity of vaccine ALZ-101 in patients with early Alzheimer's disease: randomised, controlled trial.

backgroundALZ-101 is a therapeutic vaccine comprised of a stabilised oligomeric derivative of amyloid-β42 (Aβ42), denoted Aβ42CC, that elicits antibodies targeting a low-abundance, neurotoxic Aβ oligomer species. This first-in-human, single-center Phase 1b trial evaluated the safety, tolerability, and immunogenicity of ALZ-101, with exploratory biomarker and clinical outcomes, in participants with early Alzheimer's disease (AD).

methodsThirty‑two participants with biomarker‑confirmed early AD (mean age ∼69 years, ∼30% female, Mini‑Mental State Examination ∼24, Alzheimer's Disease Composite Score [ADCOMS] ∼0.55, Clinical Dementia Rating-Sum of Boxes ∼3.0, ∼70% APOE ε4 carriers) were enrolled in a randomised, double‑blind, placebo‑controlled main study (Part A1) and a semi‑blinded extension (Part B). In Part A1, participants received intramuscular ALZ‑101 125 µg (n = 10) or 250 µg (n = 10) or placebo (n = 6) at Weeks 0, 4, 8, and 16. After ≥ 14 weeks of follow‑up, eligible participants (n = 23) entered Part B and received two or four additional 250 µg doses of ALZ‑101 with partial blinding of original allocation. An open‑label arm (Part A2) explored ALZ‑101 400 µg (n = 6) on the same schedule as Part A1. Primary endpoints were safety and tolerability. Secondary and exploratory endpoints included Aβ‑specific antibody responses, cerebrospinal fluid (CSF) and plasma biomarkers, and cognitive/functional scales.

resultsALZ-101 was not associated with any clear safety signals, and no serious adverse drug reactions were observed. Sixteen asymptomatic ARIA‑H events, including two superficial siderosis events, occurred in nine participants (two initially on placebo, six on 125 µg, one on 250 µg), and one asymptomatic ARIA‑E occurred in the extension phase in a participant originally randomised to placebo; no ARIA was observed in the 400 µg arm. ALZ‑101 induced robust Aβ‑specific IgG responses in nearly all vaccinated participants, with classical primary/booster kinetics and high responder rates at all dose levels. No statistically significant between‑group differences were detected for pre‑specified CSF biomarkers or cognitive and functional outcomes versus placebo in the randomised phase. Over longer follow‑up in Part B, participants initially randomised to ALZ‑101 showed numerically smaller increases in CSF neurofilament light chain (NfL) and tau and a flatter ADCOMS trajectory than those initially on placebo, but these differences were not statistically significant. For CSF tau, attenuation of the increase seemed to be present already in Part A1, whereas for the more slowly changing NfL, potential attenuation emerged only over the longer Part B.

conclusionIn this small Phase 1 study in early AD, ALZ‑101 was not associated with clear safety signals and elicited strong, durable Aβ‑specific antibody responses. Exploratory biomarker and ADCOMS findings are compatible with a possible disease‑modifying effect, but formal evidence of clinical efficacy is lacking, and all non‑primary analyses should be interpreted with caution. These results support further evaluation of ALZ‑101 in larger, adequately powered trials. Registered at clinicaltrials.gov: NCT05328115, 14 April 2022.