Screening Experience of Phase 2 Autonomy Study Provides Insights for Anti-Tau Trials in Alzheimer Disease

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Key Takeaways

The Autonomy trial used plasma biomarkers for prescreening, linking tau PET SUVr to clinical outcomes in Alzheimer's disease.
Posdinemab, a monoclonal antibody, demonstrated safety, tolerability, and dose-dependent reductions in p-tau217 in phase 1 studies.
Screening showed a high failure rate, mainly due to unmet plasma p-tau217 criteria, emphasizing the challenge of patient selection.
The study underscored the potential of plasma biomarkers in Alzheimer's disease management, particularly in early symptomatic stages.

In total, more than half of the screened population failed by not meeting plasma p-tau217 criteria and of the remaining, most participants were not in the intermediate tau PET range.

In the phase 2 Autonomy trial (NCT04619420), a study assessing an anti-phosphorylated tau (ptau) agent posdinemab (Janssen) in early Alzheimer disease (AD), investigators reported several lessons learned from the screening experience of the study, which is the first to employ a plasma biomarker as a prescreening tool. All told, baseline tau PET standardized uptake value ratio (SUVr) was linked to clinical outcomes across multiple brain areas, especially immediate and delayed memory which moderately correlated with brain regions that included the hippocampus.¹

These findings were reported in an oral presentation presented at the 2024 Clinical Trials on Alzheimer’s Disease (CTAD) conference, held October 29-November 1 in Madrid, Spain. Autonomy, an ongoing, double-blind, placebo-controlled, randomized, parallel-group, common-close study, assesses the effect of 2 doses of posninemab (low or high dose) or placebo, every 4 weeks, for a 104-week period. Patients were eligible to enter the study if they had early symptomatic AD and met clinical and plasma p-tau217 criteria followed by intermediate levels of tau burden on tau PET.

Led by study investigator David Henley, MD, executive medical director, Alzheimer's Disease Area Strategy Lead at Johnson & Johnson, the study screened 2670 participants across 115 sites, with 523 of these selected. · Using a plasma p217 tau assay prior to tau PET reduced the required tau PET scans by 48.9%. Of the 809 tau PET scans performed, 15.2% were ineligible due to having too low tau, 16.2% were ineligible due to having too widespread tau and 68.6% met the intermediate tau criteria. The overall screen failure rate was 80.4% as predicted by the study team.

Within the intermediate tau PET range, 44.7% were in the low and 55.3% were in the high tau strata. In addition, baseline tau PET SUVr correlated with baseline Alzheimer’s Disease Assessment Cognitive subscale 13 (ADAS-Cog13) score in various regions of interest (rs = 0.35-0.38; P <.01), and the strongest correlation between tau PET and baseline Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) immediate memory domain score was in the total cortex region of interest (rs= 0.42 p<0.01). Coming into the study, all 522 participants who received at least 1 dose of blinded treatment had screening Clinical Dementia Rating (CDR) global score of 0.5.

Previously known as JNJ-63733657, posdinemab is a humanized IgG1 monoclonal antibody that binds with high affinity to PHF tau and very weakly to non-ptau. The parent molecule of the agent, PT3, was raised against AD brain purified PHF, and preclinical studies with the humanized version, posdinemab, having demonstrated reductions in tau seeding. The mid-domain region where posdinemab binds differs from that of other anti-tau monoclonal antibodies that target the N-terminus.

The mean population age of Autonomy was 71.4 years, with most patients reporting as White (78.4%) and some (11.1%) as Hispanic. The screening analysis showed that prodromal AD accounts for 56.4% of the clinical diagnoses and 58% of the population was taking acetylcholinesterase inhibitors/memantine at baseline.

At baseline, patients had a mean Modified integrated Alzheimer’s Disease Rating Scale (iADRS) mild cognitive impairment (MCI) version total score, the primary end point, of 101.8 (SD, 11.8). Regarding secondary end points, the mean baseline scores on ADAS Cog13 were 25.18 (SD, 7.98), 41.91 (SD, 6.27) for Alzheimer’s Disease Cooperative Study–Activities of Daily Living for Mild Cognitive Impairment (ADCS-ADL-MCI), 71.56 (SD, 13.26) for RBANS, 57.36 (SD, 16.60) for RBANS DMI, and 2.89 (SD, 1.15) for CDR-sum of boxes.

Recently, in early September, a published analysis examined the tolerability, safety, pharmacokinetics, immunogenicity of posdinemab in phase 1 studies that featured healthy participants and participants with prodromal or mild AD. Assessing both single and multiple doses of posdinemab, results showed that the therapy was safe and well-tolerated in both patient populations. In healthy participants and those with AD, posdinemab demonstrated linear pharmacokinetics, and serum Cmax and area under the operating curve were approximately dose proportional following single and multiple doses. Notably, dose-dependent reductions in free and total p-tau217 in cerebrospinal fluid were observed.²

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REFERENCES
1. Henley D, Bogert J, Saad ZS, et al. Study design and screening experience from the phase 2 Autonomy trial of anti-p-tau monoclonal antibody posdinemab for early Alzheimer’s disease. Presented at: Clinical Trials on Alzheimer’s Disease conference; October 29-November 1, 2024; Madrid, Spain. ABSTRACT OC12.
2. Galpern WR, Triana-Baltzer G, Li L, et al. Phase 1 studies of the anti-tau monoclonal antibody JNJ-63733657 in healthy participants and participants with Alzheimer’s disease. Journal of Preven of Alzheims. Published online September 10, 2024. doi:10.14283/jpad.2024.163