FDA Grants FDA Fast Track Designation to Anti-pTau Agent JNJ-2056 for Alzheimer Disease

According to a recent announcement, the FDA has granted fast track designation to AC Immune SA’s anti-phosphorylated tau (pTau) immunotherapy candidate JNJ-2056, formerly known as ACI-35.030, in development for the treatment of patients with Alzheimer disease (AD). The company also announced that it is recruiting participants for its phase 2b ReTain trial, which is designed to test whether JNJ-2056 has a disease-modifying effect that can delay or prevent the onset of cognitive impairment or other clinical symptoms in patients with preclinical AD.¹

Launched in December 2023, 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 JNJ-2056 or placebo for a maximum of 4 years.² Change in Preclinical AD Cognitive Composite 5 (PACC-5) score, which combines tests of episodic memory, timed executive function, and global cognition, will serve as the primary end point. The key secondary efficacy end point will evaluate the effect of JNJ-2056 on the propagation and/or accumulation of Tau pathology compared with placebo, as measured by Tau PET imaging.

“Fast track designation is an important recognition of the differentiation and potential value for patients of our anti-pTau active immunotherapy, ACI-35.030. The phase 2b ReTain study is the first time any active immunotherapy is being tested in a preclinical AD population. We believe this modality has the potential to offer therapeutic advantages, as well as benefits in terms of convenience and access,” Andrea Pfeifer, PhD, CEO at AC Immune SA, said in a statement.¹ “Fast track designation offers opportunities for more efficient development and regulatory review. More importantly, this underscores and validates the potential therapeutic impact of an active immunotherapy specifically targeting pTau, the key pathologic species of Tau protein.”

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JNJ-2056, 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 JNJ-2056 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 JNJ-2056 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.³

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 JNJ-2056, 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 JNJ-2056, the IgG response was shown to be more homogenous with a stronger disproportional binding to the end terminal antibodies.

“In phase 1b/2a clinical testing, JNJ-2056 was shown to specifically target this toxic form of Tau and spare normal endogenous forms of the protein. We and our partners continue to drive innovation in the treatment and potential prevention of AD, developing new mechanisms of action and first-in-class potential therapeutics that are safe and simple to use for the hundreds of millions of people living with or at risk of the disease,” Pfeifer added in a statement.¹

REFERENCES
1. AC Immune’s ACI-35.030 (now “JNJ-2056”) Granted FDA Fast Track Designation for Alzheimer’s Disease. News Release. AC Immune. Published July 25, 2024. Accessed August 5, 2024. https://www.biospace.com/ac-immunes-aci-35-030-now-jnj-2056-granted-fda-fast-track-designation-for-alzheimers-disease
2. 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
3. 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