Research Article | 14 Jul 2025

Adjunct EF-M2 therapy improves clinical activity, steroid-sparing, and macrophage-linked biomarkers in feline chronic enteropathy: A randomized, double-blind, and placebo-controlled trial

Evgeny Pokushalov1,2 , Claire Garcia1 , John Smith1 , Dmitry Kudlay3,4 , Nikolai Revkov5, Anastasya Shcherbakova6, Michael Johnson1 , and Richard Miller1 Show more
VETERINARY WORLD | pg no. 3914-3928 | Vol. 18, Issue 12 | DOI: 10.14202/vetworld.2025.3914-3928
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Abstract

          
Background and Aim: Feline chronic enteropathy (CE), often manifesting along the triaditis-axis with concurrent pancreatitis, remains difficult to manage despite standardized dietary modification and cobalamin supplementation. Dysregulated macrophage activity contributes to persistent mucosal and pancreatic inflammation. EF-M2 (ImmutalonTM, Activator MAF LLC, Russia) is an analytically defined, alpha-N-acetylgalactosamine (α-GalNAc) –bearing Gc protein-derived macrophage-activating factor 2.0 (GcMAF 2.0) ligand designed to engage C-type lectin domain family 10 member A (CLEC10A) and promote M2-leaning macrophage-programming. This study aimed to evaluate whether adjunct EF-M2 improves clinical disease activity compared with placebo and to determine whether clinical responses align with macrophage-linked pharmacodynamic (PD) biomarkers. 
Materials and Methods: A multicenter, randomized, double-blind, placebo-controlled, parallel-group trial was conducted in client-owned cats with CE (modified intention-to-treat = 36). Cats received EF-M2 or volume-matched saline twice weekly for 4 weeks in addition to standardized diet/B12 care, followed by a 4-week off-drug period (day 56). The primary endpoint was the change in the feline CE activity index (FCEAI) at day 28. Secondary outcomes included responder rate (≥50% reduction), steroid-sparing effect, serum specific feline pancreatic lipase (Spec fPL), blinded abdominal ultrasonography, PD markers arginase-1 to inducible nitric oxide synthase (ARG1/iNOS) ratio, interleukin-10 [IL-10], and tumor necrosis factor-alpha [TNF-α]). Safety was assessed using Veterinary Cooperative Oncology Group – Common Terminology Criteria for Adverse Events (VCOG-CTCAE) criteria. 
Results: EF-M2 significantly improved FCEAI scores at day 28 compared with placebo (least-squares mean difference −2.5; 95% confidence interval −3.7 to −1.3; p = 0.0007). Responder rates were higher with EF-M2 (61% vs. 28%), and more cats remained steroid-free through day 28 (72% vs. 39%). Clinical benefits partially persisted to day 56 (between-group difference in FCEAI −2.1; p = 0.004). In the pancreatitis-positive subgroup, EF-M2 produced a greater reduction in Spec fPL (−2.1 vs. −0.3 μg/L; p = 0.009) and improved pancreatic ultrasonography indices. PD markers shifted consistently with the intended mechanism (ARG1/iNOS ↑, IL-10 ↑, TNF-α ↓; all p ≤ 0.01), and ΔARG1/iNOS correlated with ΔFCEAI (r = −0.57; p = 0.001). Adverse events were mild and comparable between groups, with no treatment-related serious events. 
Conclusion: Short-course adjunct EF-M2 achieved clinically meaningful improvement in disease activity, reduced steroid exposure, and improved pancreatitis-associated indicators in cats with CE. The coherent M2-leaning PD signature supports macrophage-programming as a biologically plausible mechanism. EF-M2 demonstrated favorable tolerability and represents a promising adjunctive option for triaditis-axis disease. 
          
Keywords: CLEC10A, EF-M2, feline chronic enteropathy, M2 polarization, macrophage-programming, spec fPL, steroid-sparing, triaditis.