Etalanetug reduces CSF tau biomarkers in dominantly inherited Alzheimer's disease in phase 1b/2 study.

INTRODUCTION: Etalanetug (E2814) is designed to delay the clinical progression of Alzheimer's disease (AD) by binding to the microtubule binding region (MTBR) of tau implicated in seeding and spreading of tau pathology. Dominantly inherited Alzheimer's disease (DIAD) is a rare form of the disease (< 1%), having similar changes in the tau distribution and pathology to sporadic AD. Herein, we report the safety, pharmacology and biomarker results of the etalanetug Study 103 in DIAD patients. METHODS: Study 103 enrolled participants with mild-to-moderate cognitive impairment due to DIAD who received etalanetug intravenously every 4 weeks escalating from 750 mg, 1500 mg, 3000 mg, to 4500 mg. After ascending to 4500 mg, patients received 4500 mg for up to 108 weeks. Tau pathology biomarkers, ptau217 and MTBR-tau243 were measured in CSF. Additional assessments included tau PET ([F]MK-6240) and MRI. Pharmacodynamic effects of etalanetug on biomarkers were evaluated. Untreated participants from the DIAN Observational and DIAN-TU studies trial served as natural history controls. RESULTS: Overall, 8 participants enrolled in Study 103. Etalanetug reduced concentrations of ptau217 30.4% after 12 weeks (n = 7), 48.6% at 36 weeks (n = 5), and 57.9% at 108 weeks (n = 2). Etalanetug treatment reduced concentrations of MTBR-tau243 by 50.6% in DIAD participants (n = 7) after 12 weeks of treatment. Maximal reduction in MTBR-tau243 levels (71.6%) was observed at week 36 (n = 4) and was sustained to 108 weeks (n = 2). In healthy volunteers who lack tau pathology, etalanetug had no effect on MTBR-tau243 or ptau217 after 12 weeks of treatment. Three DIAD patients had tau PET acquired at week 60 and week 108. The data indicate that the tau PET SUVr signal remains stable overall, with a trend towards decrease over time. At 108 weeks, no tau accumulation was observed via tau PET in any of the 3 patients. Three participants experienced treatment-related adverse events (AEs) with the 3000 mg dose; additionally, 5 serious AEs total were reported in 3 participants. DISCUSSION: Etalanetug treatment in these symptomatic participants with DIAD was tolerated across dose levels, and immunogenicity was found to be minimal. Etalanetug demonstrated effects on both hyperphosphorylated tau and tau tangle pathology. Taken together, the data support continued evaluation of etalanetug as an AD disease-modifying therapy. TRIAL REGISTRATION: NCT04971733 (registration date: 2021-07-20).