Anti-fibrotic Effects of MT-5562, a Novel Potent Selective Autotaxin Inhibitor, in Preclinical Studies: Roles of Lysophosphatidic Acid in Autoimmune Diseases and Clues to Treat Skin and Lung Fibrosis in Systemic Sclerosis

Hiroshi Matsuura¹, Masahiro Kondo¹, Ryoko Ohno¹, Akina Ishii¹, Mariam Piruzyan¹, Kaori Funayama¹, Yuuichi Ono¹, Atsushi Iwamura¹, Tadashi Endo¹, Tomoya Akashi¹, Taizo Tomari², Noriko Uchiyama², Noriyasu Seki¹, Kenji Chiba¹, Gabriela Kania³, Przemyslaw Blyszczuk⁴, Oliver Distler⁵, Tsutomu Takeuchi⁶ and Yuko Kaneko⁷, ¹Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan, ²Mitsubishi Tanabe Pharma Corporation, Fujisawa, Japan, ³University of Zurich, Zurich, Switzerland, ⁴Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland, ⁵Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland, ⁶Keio University School of Medicine and Saitama Medical University, Tokyo, Japan, ⁷Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan

Meeting: ACR Convergence 2023

Keywords: Animal Model, autoimmune diseases, Fibroblasts, Dermal, Fibroblasts, Other, Systemic sclerosis

Session Information

Date: Monday, November 13, 2023

Title: (0934–0964) Systemic Sclerosis & Related Disorders – Basic Science Poster

Session Type: Poster Session B

Session Time: 9:00AM-11:00AM

Background/Purpose: Targeted small-molecule therapies to autotaxin (ATX), the lysophosphatidic acid (LPA)-producing enzyme, have been shown to be potentially effective in systemic sclerosis (SSc), but the clinical benefit and safety of selective inhibition remains unclear. To explore the potential of MT-5562, a novel oral selective inhibitor of ATX, as a therapeutic agent for SSc, its efficacy and toxicity in preclinical models were evaluated. Furthermore, the levels of LPA in plasma derived from patients with autoimmune diseases including SSc were also investigated.

Methods: We examined the inhibitory effects of MT-5562 and its free form (MT-5562F) in comparison to other autotaxin inhibitors such as ziritaxestat and cudetaxestat on ATX activity using the choline assay. We also investigated the effects of MT-5562F on the production of IL-6 and connective tissue growth factor (CTGF) by human dermal and lung fibroblasts stimulated with TGF-β. The effects of MT-5562F on skin and lung fibrosis were evaluated using murine SSc models induced by bleomycin (BLM) and the plasma concentrations of MT-5562F and LPA were also determined. The plasma levels of LPA in SSc patients (n=70) were compared with those of healthy controls (n=45) or patients with other autoimmune diseases including rheumatoid arthritis (n=69), systemic lupus erythematosus (n=37) and Sjögren’s syndrome (n=18).

Results: MT-5562F, ziritaxestat, and cudetaxestat inhibited the enzyme activity of human ATX with IC50s of 0.45, 49.3, and 2.77 nmol/L, respectively. MT-5562F and ziritaxestat inhibited the enzyme activity of mouse ATX with IC50s of 0.15 and 10.9 nmol/L, respectively. MT-5562F concentration-dependently inhibited production of IL-6 and CTGF by human fibroblasts stimulated with TGF-β. MT-5562 showed minimal effects on cell viability measured by live cell counting even at the maximum dissolved concentration (60 μmol/L). On the other hand, ziritaxestat showed more cytotoxic effects than MT-5562 on cell viability in vitro. MT-5562 did not show off-target inhibition in receptor binding and kinase profiling assays. In vivo, MT-5562F and ziritaxestat (10, 30 mg/kg) dose-dependently reduced plasma LPA C18:2concentrations in mice, and MT-5562F showed more sustained effects on LPA reduction compared with ziritaxestat. Therapeutic treatment with MT-5562F (30, 60 mg/kg, b.i.d.) significantly reduced skin thickening and the numbers of myofibroblasts in the subcutaneous BLM-induced therapeutic skin fibrosis model. In addition, MT-5562F (30, 60 mg/kg, q.d.) significantly decreased the average Ashcroft score and collagen severity score in the BLM-induced lung fibrosis model in parallel with the reduction of LPA concentration. A total of 5 different LPA species were detectable in plasma derived from patients with autoimmune diseases. Most of the LPA species had significantly higher levels in the plasma of SSc patients compared to other autoimmune diseases.

Conclusion: Our results suggest that multiple LPA species are elevated in plasma of SSc patients and that MT-5562 is a selective and potent ATX inhibitor with a good preclinical safety and efficacy profile. It may offer a good option to treat lung and skin fibrosis in SSc, which has to be analyzed in clinical trials.

Disclosures: H. Matsuura: Mitsubishi Tanabe Pharma Corporation, 3; M. Kondo: Mitsubishi Tanabe Pharma Corporation, 3; R. Ohno: Mitsubishi Tanabe Pharma Corporation, 3; A. Ishii: Mitsubishi Tanabe Pharma Corporation, 3; M. Piruzyan: Mitsubishi Tanabe Pharma Corporation, 3; K. Funayama: Mitsubishi Tanabe Pharma Corporation, 3; Y. Ono: Mitsubishi Tanabe Pharma Corporation, 3; A. Iwamura: Mitsubishi Tanabe Pharma Corporation, 3; T. Endo: Mitsubishi Tanabe Pharma Corporation, 3; T. Akashi: Mitsubishi Tanabe Pharma Corporation, 3; T. Tomari: Mitsubishi Tanabe Pharma Corporation, 3; N. Uchiyama: Mitsubishi Tanabe Pharma Corporation, 3; N. Seki: Mitsubishi Tanabe Pharama Corporation, 3; K. Chiba: Mitsubishi Tanabe Pharma Corporation, 3; G. Kania: None; P. Blyszczuk: None; O. Distler: 4P-Pharma, 2, 5, 6, AbbVie, 2, 5, 6, Acceleron, 2, 5, 6, Alcimed, 2, 5, 6, Altavant Sciences, 2, 5, 6, Amgen, 2, 5, 6, AnaMar, 2, 5, 6, Arxx, 2, 5, 6, AstraZeneca, 2, 5, 6, Bayer, 2, 5, 6, Blade Therapeutics, 2, 5, 6, Boehringer Ingelheim, 2, 5, 6, Citus AG, 12, Co-Founder, Corbus Pharmaceuticals, 2, 5, 6, CSL Behring, 2, 5, 6, Galapagos, 2, 5, 6, Galderma, 2, 5, 6, Glenmark, 2, 5, 6, Gossamer, 2, 5, 6, Horizon Therapeutics, 2, 5, 6, Janssen, 2, 5, 6, Kymera, 2, 5, 6, Lupin, 2, 5, 6, Medscape, 2, 5, 6, Miltenyi Biotec, 2, 5, 6, Mitsubishi Tanabe, 2, 5, 6, MSD, 2, 5, 6, Novartis, 2, 5, 6, Patent issued “mir-29 for the treatment of systemic sclerosis” (US8247389, EP2331143), 10, Prometheus Biosciences, 2, 5, 6, Redx Pharma, 2, 5, 6, Roivant, 2, 5, 6, Topadur, 2, 5, 6; T. Takeuchi: AbbVie, 2, 5, 6, AYUMI, 5, Bristol-Myers Squibb, 6, Chugai, 2, 5, 6, Daiichi Sankyo, 5, Eisai, 5, 6, Eli Lilly Japan, 2, 6, Gilead, 2, 6, Janssen, 6, Mitsubishi-Tanabe, 2, 5, 6, ONO, 5, Pfizer Japan, 6, Taiho, 2; Y. Kaneko: AbbVie/Abbott, 1, 6, Ashai Kasei Pharma, 1, 6, Astellas Pharma, 1, 6, AstraZeneca, 1, 6, AYUMI Pharmacutia, 1, 6, Bristol-Myers Squibb(BMS), 1, 6, Chugai-Pharm, 1, 6, Eisai, 1, 6, Eli Lilly, 1, 6, Gilead Sciences Inc., 1, 6, GlaxoSmithKlein(GSK), 1, 6, Janssen Pharmaceutical KK, 1, 6, Novartis, 1, 6, Pfizer, 1, 6, Tanabe Mitsubishi Pharma, 1, 6, UCB Japan, 1, 6.

To cite this abstract in AMA style:

Matsuura H, Kondo M, Ohno R, Ishii A, Piruzyan M, Funayama K, Ono Y, Iwamura A, Endo T, Akashi T, Tomari T, Uchiyama N, Seki N, Chiba K, Kania G, Blyszczuk P, Distler O, Takeuchi T, Kaneko Y. Anti-fibrotic Effects of MT-5562, a Novel Potent Selective Autotaxin Inhibitor, in Preclinical Studies: Roles of Lysophosphatidic Acid in Autoimmune Diseases and Clues to Treat Skin and Lung Fibrosis in Systemic Sclerosis [abstract]. Arthritis Rheumatol. 2023; 75 (suppl 9). https://acrabstracts.org/abstract/anti-fibrotic-effects-of-mt-5562-a-novel-potent-selective-autotaxin-inhibitor-in-preclinical-studies-roles-of-lysophosphatidic-acid-in-autoimmune-diseases-and-clues-to-treat-skin-and-lung-fibrosis/. Accessed .

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/anti-fibrotic-effects-of-mt-5562-a-novel-potent-selective-autotaxin-inhibitor-in-preclinical-studies-roles-of-lysophosphatidic-acid-in-autoimmune-diseases-and-clues-to-treat-skin-and-lung-fibrosis/