Precision Glyco-Modulation of Macrophages with EF-M2 (ImmutalonTM) Improves Function and Lowers Inflammatory Biomarkers in Aging Dogs: A Double-Blind, Placebo-Controlled Trial

We evaluated whether macrophage-targeted glyco-modulation can improve day-to-day function in aging companion animals. In a multicenter, randomized, double-blind, placebo-controlled trial, 60 client-owned geriatric dogs (≥10 years) received subcutaneous EF-M2 (0.1 μg/kg, every 72 h for 4 weeks; protocolized, blinded step-up to every 48 h at day 14 for partial responders) or matched placebo, followed by 4 weeks off-treatment. Two prespecified co-primary endpoints were tested hierarchically: change in accelerometer-measured active minutes/day at week 1 and change in a day-28 vitality composite (z-score of inverted CBPI-PSS, HRQL-vitality, and appetite VAS). EF-M2 was superior to placebo on both: +23.05 min/day at week 1 (95% CI, 18.16-27.94; <i>p</i> < 0.001) and +2.01 z-units at day 28 (95% CI, 1.52-2.50; <i>p</i> < 0.001). Key secondaries favored EF-M2, including greater week-4 activity (+33.00 min/day, 26.83-39.18; <i>p</i> < 0.001), lower BAER auditory threshold (-5.28 dB, -7.53 to -3.04; <i>p</i> < 0.001), and reduced transepidermal water loss (-1.35 g/m²·h, -2.45 to -0.25; <i>p</i> = 0.02); multiplicity was controlled with Holm-Bonferroni procedures. Owner-reported global improvement was more frequent with EF-M2 at day 28 (93.3% vs. 10.0%) and remained higher at day 56 off-treatment (50.0% vs. 16.7%). Prespecified pharmacodynamic markers shifted in directions consistent with M2-skewing (ARG1:iNOS ratio and IL-10 increased; TNF-α decreased) by day 7. Adverse events were infrequent, mild, and similar to placebo; no treatment-related withdrawals or serious events occurred. These findings support macrophage-targeted glyco-modulation as a promising approach to rapidly improve real-world activity and multidomain vitality in older dogs, with short-term signals persisting off-treatment; longer, adequately powered trials are warranted to define durability, structural outcomes, and phenotype-specific benefits.