ACI-35 is a vaccine candidate directed
against another key component of the pathology of AD: phosphorylated Tau proteins, or p-Tau, found in Tau tangles. ACI-35 was developed
using our SupraAntigen technology and is designed to stimulate a patient’s immune system to produce antibodies against the
misfolded and phosphorylated pathogenic conformers of Tau protein that aggregate to create the neurofibrillary tangles that characterize
AD. In pre-clinical testing, the vaccine candidate induced an antibody response that was highly specific to misfolded and phosphorylated
Tau. This antibody response resulted in a significant reduction of phosphorylated Tau and an improvement in clinical parameters.
ACI-35 is the first vaccine candidate against phosphorylated pathological Tau in a clinical study involving patients with mild
to moderate AD. The first clinical study Phase 1b has been completed. A Phase 1b/2a study is currently in preparation and is planned
to start in 2019. In 2014, we entered into a partnership with Janssen, a subsidiary of Johnson & Johnson, for the research,
clinical development, manufacture and commercialization of ACI-35.
Phase 1b Study
Phase 1b Study Design
Safety, tolerability and immunogenicity
of ACI-35 were tested in a Phase 1b study in mild to moderate AD patients. It was a randomized, placebo controlled double blind
study, where ACI-35 was administered via subcutaneous injection. Different doses and dosing schedules were investigated in an ascending
dose design. Multiple injections of ACI-35 were administered per cohort for active or placebo treatment in a three-to-one ratio.
Phase 1b Study Results
The safety and tolerability in the study
was considered acceptable. As previously reported, five serious adverse events were observed in three patients during the clinical
study of ACI-35. Acute pyelonephritis and dizziness were observed in one patient and sick sinus syndrome was reported for a second
patient, and these were labeled as possibly related to the study drug due to the close timing proximity with the last administration
of ACI-35. In the third patient, urosepsis and pyelonephritis were described and classified as unlikely to be related to the study
drug. No death and no further serious adverse events were reported in this study. The only adverse events consistently reported
were injection site reactions which occurred in a dose-dependent manner and were in all cases mild to moderate in severity, transient
and self-limiting. In conclusion, the vaccine ACI-35 is considered to be safe and well tolerated with no events related to CNS
Analysis of the antibody response of the
Phase 1b study demonstrated that ACI-35 elicited a rapid induction of anti-phosphorylated Tau after the first immunization in all
study cohorts, indicating a T-cell independent antibody response which, however, lacked the boosting response desired for an optimal
long-term and potentially preventive application. Therefore in a collaborative effort both research teams of AC Immune and Janssen
have successfully developed a new generation of the anti-Tau vaccine. In non-human primates, the new formulation of the anti-Tau
vaccine demonstrated a high and boostable antibody response.
Due to the encouraging data, AC Immune
and Janssen jointly decided to advance different formulations of the anti-Tau vaccine program to the next stage of development.
In a scientific advisory meeting, the regulatory authorities were highly supportive of a shortened pre-clinical development of
those new second generation vaccines. These promising second generation vaccines are intended to be tested in the next Phase 1b/2a
Pre-clinical Programs moving to Phase
Anti-Tau Morphomers: Morphomers
are conformation-specific, non peptidic, small molecules designed to specifically recognize pathological misfolded and β-sheet-rich
aggregated protein forms (Figure 23 below). Being small molecules, Morphomers show drug like properties including brain penetration
and can enter cells to access intracellular deposits of aggregated proteins. AC Immune has built a robust proprietary library of
around 4,750 Morphomers.