TY - JOUR

T1 - 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

AU - Pokushalov, Evgeny

AU - Garcia, Claire

AU - Smith, John

AU - Kudlay, Dmitry

AU - Revkov, Nikolai

AU - Shcherbakova, Anastasya

AU - Johnson, Michael

AU - Miller, Richard

N1 - Pokushalov E, Garcia C, Smith J, Kudlay D, Revkov N, Shcherbakova A, Johnson M, Miller R (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, Veterinary World, 18(12): 3914–3928. The authors would like to thank the clinical staff of VEGA and BALTO Veterinary Clinics for their exemplary husbandry and data recording and the cat owners for their trust and partnership. The Center for New Medical Technologies (Novosibirsk) provided technical assistance. Triangel Scientific provided editorialsupport in the form of manuscript proofreading under a service agreement. This research was supported by an unrestricted research grant from Activator MAF, LLC, Novosibirsk, Russian Federation (Grant No. AMAF-FELINE-2025-01), and by internal funds of the Scientific Research Laboratory, Triangel Scientific (San Francisco, USA). The sponsor had no role in the study design, data collection, analysis, or interpretation, manuscript writing, or decision to publish the results.

PY - 2025/12

Y1 - 2025/12

N2 - 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.

AB - 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.

KW - CLEC10A

KW - EF-M2

KW - M2 polarization

KW - feline chronic enteropathy

KW - macrophage-programming

KW - spec fPL

KW - steroid-sparing

KW - triaditis

UR - https://www.scopus.com/pages/publications/105024858128

UR - https://www.mendeley.com/catalogue/d45a4bca-d4c1-3cba-88f7-773bdea6ce67/

U2 - 10.14202/vetworld.2025.3914-3928

DO - 10.14202/vetworld.2025.3914-3928

M3 - Article

VL - 18

SP - 3914

EP - 3928

JO - Veterinary World

JF - Veterinary World

SN - 0972-8988

IS - 12

ER -