CTAD 2025: Eisai Highlights Etalanetug Tau Reductions and LEQEMBI Protofibril Data; Merck Shares Early MK-2214, MK-1167 Results | Clinical Trials on Alzheimer's Disease 2025 | iPharmaCenter
- Badari Andukuri
- 2 hours ago
- 4 min read
Eisai and Merck used CTAD 2025 to highlight complementary approaches to targeting tau pathology, amyloid protofibrils and cholinergic modulation across early and symptomatic Alzheimer’s disease.
EiSai
Etalanetug: anti‑tau antibody data
Eisai reported new Phase Ib/II data for etalanetug (E2814), an investigational antibody directed against the microtubule‑binding region of tau, in a small cohort of individuals with dominantly inherited Alzheimer’s disease (DIAD). In the E2814‑103 study (n=7), tau PET data in three participants suggested stabilization or a trend toward reduced tau signal after treatment, consistent with an effect on tau seeding and aggregate accumulation.
The program drew particular attention to eMTBR‑tau243, a novel fluid biomarker that captures tau fragments spanning amino acid 243 within the MTBR, thought to arise during neurofibrillary tangle formation. Strong correlations between eMTBR‑tau243 levels and tau PET have been reported in both plasma and CSF, enabling blood‑based tracking of tau pathology.
In the DIAD cohort, etalanetug lowered CSF eMTBR‑tau243 by 62% at three months and 89% at nine months, while plasma concentrations fell by 78% and more than 90% over the same intervals.
Eisai said these reductions reinforce etalanetug’s proposed mechanism of blocking tau seeding and propagation and support continued development as a potential disease‑modifying therapy.
Etalanetug is already being tested as an add‑on to lecanemab in the DIAN‑TU Tau NexGen Phase II/III trial in DIAD, as well as in a global Phase II Study 202 in early sporadic Alzheimer’s disease. Both trials evaluate whether combining tau‑ and amyloid‑directed antibodies can deepen disease modification compared with anti‑amyloid therapy alone.
LEQEMBI: CSF protofibril engagement
Eisai and Biogen also presented new cerebrospinal fluid analyses from a Clarity AD sub‑study (n=410) designed to quantify lecanemab’s binding to soluble Aβ protofibrils in vivo. Using an ultrasensitive assay, investigators measured total protofibril levels in CSF and compared trajectories between placebo and lecanemab‑treated participants over 12 and 18 months.
In the placebo arm, CSF protofibrils rose by 19% at 12 months and 29% at 18 months, reflecting disease‑related accumulation. In contrast, the lecanemab arm showed larger increases of 59% at 12 months and 45% at 18 months, with the 12‑month difference versus placebo reaching statistical significance (p=0.0126). Eisai interprets this pattern as evidence that lecanemab binds protofibrils near amyloid plaques and mobilizes them into CSF, demonstrating pharmacodynamic target engagement.
In the placebo group, rising CSF protofibril levels correlated with changes in neurodegeneration markers such as total tau and neurogranin, as well as tau pathology markers including p‑tau181 and MTBR‑tau243. That relationship disappeared in patients receiving lecanemab, which the companies say supports a reduction in protofibril‑driven neurotoxicity and aligns with prior data showing slower tau tangle accumulation on PET with treatment.
LEQEMBI remains positioned as the only Alzheimer’s therapy that directly targets both soluble neurotoxic protofibrils and deposited amyloid plaque, with the aim of influencing downstream tau pathology and clinical decline. Eisai leads global development and regulatory activities for lecanemab, while co‑commercializing with Biogen.
Merck’s MK‑2214 and MK‑1167
Merck used CTAD 2025 to showcase early‑phase data from two Alzheimer’s candidates—one aimed at tau pathology and the other at symptomatic cognition—while confirming Fast Track status for its tau antibody. The company said the programs reflect a dual strategy spanning disease modification and neurotransmitter‑based symptom relief.
MK‑2214 is a monoclonal antibody directed against phosphorylated serine 413 tau, designed to recognize aberrant tau species that drive aggregation and spread. CTAD presentations summarized three Phase 1 studies: two single‑ascending‑dose trials in healthy volunteers and a multiple‑ascending‑dose trial in people with mild cognitive impairment or mild‑to‑moderate Alzheimer’s disease, all focused on safety, tolerability and pharmacokinetics. Findings from these studies have informed dosing and design of an ongoing Phase 2 trial in early Alzheimer’s disease that is assessing safety, efficacy and imaging‑based brain changes (NCT07033494).
The U.S. Food and Drug Administration has granted MK‑2214 Fast Track designation for the treatment of Alzheimer’s disease, opening the door to more frequent regulatory interactions and rolling review. Merck highlighted this as recognition of both the seriousness of Alzheimer’s and the unmet need for additional disease‑modifying options.
MK‑1167, by contrast, is an oral positive allosteric modulator of the alpha‑7 nicotinic acetylcholine receptor intended to enhance cholinergic signaling and support cognitive function. At CTAD, Merck presented first‑in‑human Phase 1 data in healthy adult men, where single‑dose MK‑1167 was evaluated using 13C‑magnetic resonance spectroscopy to explore effects on glutamate metabolism in the prefrontal cortex. These data supported dose selection for an ongoing Phase 2 trial in patients with mild‑to‑moderate Alzheimer’s dementia already receiving stable donepezil, with endpoints focused on safety, cognition and daily functioning (NCT06721156).