AC Immune Advances Anti-Tau Vaccine ACI-35.030 to Phase 2 Trial

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The newly announced trial, dubbed ReTain, will featured 500 individuals with preclinical Alzheimer disease who will be randomized to ACI-35.030 or placebo for a maximum of 4 years.

Andrea Pfeifer, chief executive officer, AC Immune

Andrea Pfeifer

AC Immune SA recently announced the launch of its phase 2b trial, dubbed ReTain, to assess the efficacy and safety of ACI-35.030, an investigational anti-phosphorylated tau (pTau) immunotherapy in development for patients with Alzheimer disease (AD). The registration-enabling trial is designed to test the hypothesis that ACI-35.030 has a disease-modifying effect that can delay or prevent the onset of cognitive impairment or other clinical symptoms in individuals with preclinical AD.1

The phase 2b ReTain trial, a multicenter, double-blind, placebo-controlled study, is expected to include 500 patients with preclinical AD who are randomly assigned 1:1 to a single dose of ACI-35.030 or placebo for a maximum of 4 years. Change in Preclinical AD Cognitive Composite 5 (PACC-5) score, which combines tests of episodic memory, timed executive function, and global cognition, as the primary end point.

"In the recently completed Phase 1b/2a trial, data showed that ACI-35.030 was able to activate patients’ immune systems with a robust polyclonal antibody response against phosphorylated Tau and its neurotoxic aggregated form, which is believed to contribute to the pathology and progression of Alzheimer’s disease," Andrea Pfeifer, chief executive officer, AC Immune, said in a statement.1 "Our partner’s decision to move forward with this robust clinical trial shows that treatment with this active immunotherapy so early in the disease process that individuals are not yet showing symptoms, holds tremendous promise to slow or possibly even prevent progression to symptomatic AD."

According to the announcement, as part of the licensing agreement with Janssen, AC Immune will not receive a milestone payment of CHF 15 million and will receive another milestone payment of CHF 25 million related to achieving a non-disclosed enrollment target. The study will also assess the effect of ACI-35.030 on the propagation and/or accumulation of tau pathology as a secondary end point. Measured by tau PET imaging in the Tau Naïve composite region of interest, this end point may be sufficient for a future biologics license application submission for an accelerated approval of the therapy.

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ACI-35.030, an active immunotherapy, contains a liposomal formulation that incorporates a conformationally-constrained, membrane bound target peptide antigen, pTau, in addition adjuvants and non-Tau T-helper peptides. In a recent phase 1b/2a trial (NCT04445831), both vaccinations of ACI-35.030 and JACI-35.054, AC Immune’s other anti-tau vaccine, were considered safe for the treatment of early diagnosed AD, with no safety concerns observed. Patients on ACI-35.030 showed a high, specific, and sustained anti-pTau and anti-monophosphorylated tau (ePHG) IgG response, with an apparent dose-response between the low- and mid-dose with evidence of immunoglobulin class switch from IgM to IgG.2

Presented at the 2022 Clinical Trials on Alzheimer Disease conference, the study included 8 participants for each dose-level subcohort, which were randomized in a 3:1 active/placebo ratio. The chosen population for the study included 50- to 75-year-old men and women diagnosed with mild AD or mild cognitive impairment because of AD based on criteria from the National Institute on Aging. In the trial, patients were given injections of either ACI-35.030, JACI-35.054, or placebo, during weeks 0, 8, 24, and 48.

All told, results showed that the IgG response displayed a mature and stronger preference for binding ePHF. Notably, the participants given JACI-35.054 showed a high anti-ePHF and anti-pTau IgG response where between the low- and mid-dose, and there was no apparent dose-effect observed. The response of the IgG in patients that received JACI-35.054 reveals the binding capacity to both pTau and the nonpathological, nonphosphorylated Tau. After 3 vaccinations were performed, epitope mapping was conducted for further investigation on the antibody response, specifically on the breadth and selectivity towards pathological pTau. As for the participants that were given ACI-35.030, the IgG response was shown to be more homogenous with a stronger disproportional binding to the end terminal antibodies.

REFERENCES
1. AC Immune’s targeted anti-pTau active immunotherapy for Alzheimer’s disease advances into phase 2b trial. News release. AC Immune SA. December 15, 2023. Accessed December 20, 2023. https://finance.yahoo.com/news/ac-immune-targeted-anti-ptau-122200253.html
2. Streffer J, Mermoud J, Sol O et al. ACI-35.030 and JACI-35.064, two novel anti-phospho-tau vaccines for the treatment of Alzheimer’s disease: interim phase 1B/2A data on safety, tolerability and immunogenicity. Presented at: 2022 CTAD Conference; November 29-Dec 2; San Franciso, California. Oral Communication Abstract 1
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