AC Immune SA has published peer-reviewed results from its Phase 1b/2a trial of ACI-35.030, an active immunotherapy targeting pathological tau protein in early Alzheimer's disease. The study, published in eBioMedicine, demonstrated that ACI-35.030 achieved remarkable immunogenicity with response rates between 94% and 100% in high-dose cohorts maintained through week 74.
Superior Immunogenic Profile
The trial compared two different formulations targeting the same phosphorylated tau (pTau) peptide sequence: ACI-35.030 using AC Immune's proprietary SupraAntigen® technology and JACI-35.054 using a conventional protein conjugate approach. ACI-35.030 demonstrated superior performance across multiple parameters.
All participants across all dose levels were considered anti-pTau IgG responders at 2 weeks post-treatment with ACI-35.030, requiring only one injection to induce antibody titers in all participants. The therapy consistently boosted antibody levels with subsequent immunizations. In contrast, JACI-35.054 raised a more heterogeneous anti-pTau IgG antibody response and required multiple administrations to reach consistent titers.
Selective Targeting of Pathological Tau
A critical finding was ACI-35.030's selectivity for pathological tau species. Antibody titers against unphosphorylated (normal) tau declined and were not boosted with subsequent administrations, demonstrating specific targeting of pathological tau. JACI-35.054 showed the opposite pattern, inducing antibody titers against normal tau after the second treatment that increased with subsequent administrations.
Most participants generated an anti-ePHF (enriched paired helical filament) antibody response after the first ACI-35.030 administration, with antibody levels further increasing with additional immunizations. This response targets brain-derived tau aggregates considered particularly neurotoxic.
Biomarker Evidence of Target Engagement
An exploratory post-hoc analysis revealed significant biological activity. At multiple time points for the two highest ACI-35.030 doses, treatment resulted in significant (p<0.05) changes from baseline in plasma pTau and brain-derived tau plasma levels compared to the pooled placebo group.
Favorable Safety Profile
The trial reported no clinically relevant safety and tolerability observations for either ACI-35.030 or JACI-35.054 across all tested doses. Dr. Andrea Pfeifer, CEO of AC Immune SA, emphasized that "safety and rapid, durable responses are key advantages of active immunotherapies, which make them particularly well suited to the long-term treatment needed to achieve precision prevention."
Advancement to Phase 2b
Based on these results, ACI-35.030 was selected for further clinical testing and is now being investigated in the ongoing Phase 2b ReTain trial (NCT06544616). This potentially registration-enabling study represents the first active immunotherapy targeting tau to be investigated in approximately 500 participants with preclinical Alzheimer's disease.
The ReTain trial is a randomized, multicenter, double-blind, placebo-controlled study in participants with preclinical AD (cognitively normal, tau positive). Participants will be randomized 1:1 to receive JNJ-64042056 or placebo as intramuscular injections for up to 4 years. The study is being conducted at more than 40 clinical trial sites across the U.S., Japan, UK, and Australia.
The primary endpoint measures cognitive decline using the Preclinical AD Cognitive Composite 5 (PACC-5) score, while the key secondary endpoint assesses tau pathology propagation and accumulation via tau PET imaging.
Technology Platform Validation
Dr. Pfeifer noted that the study demonstrated AC Immune's SupraAntigen® platform's ability to generate highly differentiated active immunotherapies even when using identical immunogens. The SupraAntigen® technology anchors the pTau peptide in a liposome while incorporating non-tau T-cell epitopes and adjuvants, creating a conformationally-constrained, membrane-bound target peptide antigen.
The ReTain trial is fully funded and conducted by Janssen Pharmaceuticals, Inc., a Johnson & Johnson company, under a global license, development and commercialization agreement with AC Immune. This partnership represents part of AC Immune's strategy that has generated over $4.5 billion in potential milestone payments plus royalties across its portfolio.
