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Mechanism of Action

REZUROCK targets both the inflammatory and the fibrotic processes of cGVHD1-3

SEE HOW REZUROCK WORKS

REZUROCK, a selective ROCK2 inhibitor, is a targeted therapy designed to restore immune homeostasis

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Inflammation

Mechanisms of chronic inflammation in cGVHD2,4-7

3D rendering depicting the interaction between ROCK2 and STAT3 at the cellular level, leading to the upregulation of Th17 and Tfh cells

ROCK2 interacts with and phosphorylates STAT3, leading to the formation of the JAK2-STAT3 complex and the upregulation of
Th17 and Tfh cells.2,4,5

3D rendering depicting the autoreactive and alloreactive T cells contributing to chronic inflammation

Thymic injury induced by high-dose chemotherapy and irradiation during a BMT inhibits the production of Treg cells and allows autoreactive and alloreactive T cells to escape regulation and contribute to chronic inflammation.6,7

Selective inhibition of ROCK2 by REZUROCK2,4,5

3D rendering depicting how REZUROCK decreases activation of STAT3, leading to the downregulation of pro-inflammatory cytokines

Decreases activation of STAT3, triggering the significant downregulation of both Th17 and Tfh cells, leading to the downregulation of pro-inflammatory cytokines.2,5

3D rendering of how REZUROCK increases phosphorylation of STAT5 to reduce inflammation

Increases phosphorylation of STAT5,
causing the upregulation of Treg cells.4 This has an immunomodulatory effect on STAT3 and STAT5 phosphorylation that reduces inflammation.2,5

FIBROSIS

Mechanisms of fibrosis IN cGVHD8,9

3D rendering depicting the transcription of profibrotic genes

Macrophages activate profibrotic mediators, such as LPA and TGF-β, to subsequently activate ROCK2,8,9 which polymerizes G-actin to F-actin.8 This frees the transcription factor MRTF and leads to transcription of profibrotic genes.8

3D rendering of changes in cellular structure and collagen deposits leading to an increase in tissue stiffness

The process results in
changes to the cellular structure, increasing tissue stiffness.8

Selective inhibition of ROCK2 by REZUROCK3,8

3D rendering of how REZUROCK prevents polymerization of G-actin to F-actin and changes to profibrotic gene expression

Prevents the polymerization of G-actin to F-actin, as well as MRTF changes to profibrotic gene expression.8

3D rendering of how REZUROCK downregulates fibrosis in animal cGVHD models

Downregulates fibrosis, as evidenced by decreased collagen deposition around the bronchioles and the delayed progression of scleroderma in animal cGVHD models.3

Expand to learn more

Inflammation

Mechanisms of chronic inflammation in cGVHD2,4-7

3D rendering depicting the interaction between ROCK2 and STAT3 at the cellular level, leading to the upregulation of Th17 and Tfh cells

ROCK2 interacts with and phosphorylates STAT3, leading to the formation of the JAK2-STAT3 complex and the upregulation of Th17 and Tfh cells.2,4,5

Selective inhibition of ROCK2 by REZUROCK2,4,5

3D rendering depicting how REZUROCK decreases activation of STAT3, leading to the downregulation of pro-inflammatory cytokines

Decreases activation of STAT3, triggering the significant downregulation of both Th17 and
Tfh cells.2,5

Mechanisms of chronic inflammation in cGVHD2,4-7

3D rendering depicting the autoreactive and alloreactive T cells contributing to chronic inflammation

Thymic injury induced by high-dose chemotherapy and irradiation during a BMT inhibits the production of Treg cells and allows autoreactive and alloreactive T cells to escape regulation and contribute to chronic inflammation.6,7

Selective inhibition of ROCK2 by REZUROCK2,4,5

3D rendering of how REZUROCK increases phosphorylation of STAT5 to reduce inflammation

Increases phosphorylation of STAT5, causing the upregulation of Treg cells.4 This has an immunomodulatory effect on STAT3 and STAT5 phosphorylation that reduces inflammation.2,5

FIBROSIS

Mechanisms of fibrosis8,9

3D rendering depicting the transcription of profibrotic genes

Macrophages activate profibrotic mediators, such as LPA and thrombin, to subsequently activate ROCK2,8,9 which polymerizes G-actin to F-actin.8 This frees the transcription factor MRTF and leads to transcription of profibrotic genes.8

Selective inhibition of ROCK2 by REZUROCK3,8

3D rendering of how REZUROCK prevents polymerization of G-actin to F-actin and changes to profibrotic gene expression

Prevents the polymerization of G-actin to F-actin, as well as MRTF changes to profibrotic gene expression.8

Mechanisms of fibrosis8,9

3D rendering of changes in cellular structure and collagen deposits leading to an increase in tissue stiffness

The process results in changes to the cellular structure, increasing tissue stiffness.8

Selective inhibition of ROCK2 by REZUROCK3,8

3D rendering of how REZUROCK downregulates fibrosis in animal cGVHD models

Downregulates fibrosis, as evidenced by decreased collagen deposition around the bronchioles and the delayed progression of scleroderma in animal cGVHD models.3

REZUROCK is an effective and innovative treatment designed to restore immune homeostasis and to downregulate the fibrotic processes of cGVHD.1-3

See the results with a

dual inhibitor of
inflammation and fibrosis.1-3

EXPLORE REZUROCK EFFICACY

BMT, bone marrow transplant; cGVHD, chronic graft-versus-host disease; JAK2, Janus-associated kinase 2; LPA, lysophosphatidic acid; MOA, mechanism of action; MRTF, myocardin-related transcription factor; ROCK2, rho-associated coiled-coil–containing protein kinase-2; STAT3, signal transducer and activator of transcription factor 3; STAT5, signal transducer and activator of transcription factor 5; Tfh, follicular helper T [cell]; TGF-B, transforming growth factor-beta; Th17, type 17 helper T [cell], Treg, regulatory T [cell].

References: 1. REZUROCK. Package insert. Kadmon Pharmaceuticals, LLC; 2021. 2. Zanin-Zhorov A, Weiss JM, Nyuydzefe MS, et al. Selective oral ROCK2 inhibitor down-regulates IL-21 and IL-17 secretion in human T cells via STAT3-dependent mechanism. Proc Natl Acad Sci USA. 2014;111(47):16814-16819. doi:10.1073/pnas.1414189111 3. Flynn R, Paz K, Du J, et al. Targeted rho-associated kinase 2 inhibition suppresses murine and human chronic GVHD through a Stat3-dependent mechanism. Blood. 2016;127(17):2144-2154. doi:10.1182/blood-2015-10-678706 4. Chen W, Nyuydzefe MS, Weiss JM, Zhang J, Waksal SD, Zanin-Zhorov A. ROCK2, but not ROCK1 interacts with phosphorylated STAT3 and co-occupies TH17/TFH gene promoters in TH17-activated human T cells. Sci Rep. 2018;8(1):16636. doi:10.1038/s41598-018-35109-9 5. Weiss JM, Chen W, Nyuydzefe MS, et al. ROCK2 signaling is required to induce a subset of T follicular helper cells through opposing effects on STATs in autoimmune settings. Sci Signal. 2016;9(437):ra73. doi:10.1126/scisignal.aad8953 6. Zeiser R, Blazar BR. Pathophysiology of chronic graft-versus-host disease and therapeutic targets. N Engl J Med. 2017;377(26):2565-2579. doi:10.1056/NEJMra1703472 7. Matsuoka K-I, Kim HT, McDonough S, et al. Altered regulatory T cell homeostasis in patients with CD4+ lymphopenia following allogeneic hematopoietic stem cell transplantation. J Clin Invest. 2010;120(5):1479-1493. doi:10.1172/JC141072 8. Riches DWH, Backos DS, Redente EF. ROCK and Rho: promising therapeutic targets to ameliorate pulmonary fibrosis. Am J Pathol. 2015;185(4):909-912. doi:10.1016/j.ajpath.2015.01.005