Mechanism of Action

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

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

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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

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

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

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

Indication

REZUROCKTM (belumosudil) is indicated for the treatment of adult and pediatric patients 12 years and older with chronic graft-versus-host disease (chronic GVHD) after failure of at least two prior lines of systemic therapy.

IMPORTANT SAFETY INFORMATION

Warnings and Precautions

Embryo-Fetal Toxicity: Based on findings in animals and its mechanism of action, REZUROCK can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with REZUROCK and for at least one week after the last dose

Adverse Reactions

The most common (≥ 20%) adverse reactions, including laboratory abnormalities, were infections, asthenia, nausea, diarrhea, dyspnea, cough, edema, hemorrhage, abdominal pain, musculoskeletal pain, headache, phosphate decreased, gamma glutamyl transferase increased, lymphocytes decreased, and hypertension

Permanent discontinuation of REZUROCK due to adverse reactions occurred in 18% of patients. The adverse reactions which resulted in permanent discontinuation of REZUROCK in > 3% of patients included nausea (4%). Adverse reactions leading to dose interruption occurred in 29% of patients. The adverse reactions leading to dose interruption in ≥ 2% were infections (11%), diarrhea (4%), and asthenia, dyspnea, hemorrhage, hypotension, liver function test abnormal, nausea, pyrexia, edema, and renal failure with (2% each)

Monitor total bilirubin, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) at least monthly

Drug Interactions

Strong CYP3A Inducers: Coadministration of REZUROCK with strong CYP3A inducers decreases belumosudil exposure, which may reduce the efficacy of REZUROCK. Increase the dosage of REZUROCK to 200 mg twice daily when coadministered with strong CYP3A inducers

Proton Pump Inhibitors: Coadministration of REZUROCK with proton pump inhibitors decreases belumosudil exposure, which may reduce the efficacy of REZUROCK. Increase the dosage of REZUROCK to 200 mg twice daily when coadministered with proton pump inhibitors

Use in Specific Populations

Pregnancy: Based on findings from animal studies and the mechanism of action, REZUROCK can cause fetal harm when administered to pregnant women. There are no available human data on REZUROCK use in pregnant women to evaluate for a drug-associated risk. Advise pregnant women and females of reproductive potential of the potential risk to the fetus

Lactation: There are no data available on the presence of belumosudil or its metabolites in human milk or the effects on the breastfed child, or milk production. Because of the potential for serious adverse reactions from belumosudil in the breastfed child, advise lactating women not to breastfeed during treatment with REZUROCK and for at least one week after the last dose

Pediatric Use: The safety and effectiveness of REZUROCK have been established in pediatric patients 12 years and older. The safety and effectiveness of REZUROCK in pediatric patients less than 12 years old have not been established

Geriatric Use: Of the 186 patients with chronic GVHD in clinical studies of REZUROCK, 26% were 65 years and older. No clinically meaningful differences in safety or effectiveness of REZUROCK were observed in comparison to younger patients

Renal and Hepatic Impairment: Treatment with REZUROCK has not been studied in patients with pre-existing severe renal or hepatic impairment. For patients with pre-existing severe renal or hepatic impairment, consider the risks and potential benefits before initiating treatment with REZUROCK

Please see full Prescribing Information for additional Important Safety Information.

You are encouraged to report side effects of prescription drugs to the FDA. Visit www.FDA.gov/medwatch or call 1-800-FDA-1088. You may also contact Kadmon Pharmaceuticals, LLC, at 1-877-377-7862 to report side effects.

Indication

REZUROCKTM (belumosudil) is indicated for the treatment of adult and pediatric patients 12 years and older with chronic graft-versus-host disease (chronic GVHD) after failure of at least two prior lines of systemic therapy.

Important safety information Warnings and Precautions

Embryo-Fetal Toxicity: Based on findings in animals and its mechanism of action, REZUROCK can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with REZUROCK and for at least one week after the last dose

Indication & Important safety information

REZUROCKTM (belumosudil) is indicated for the treatment of adult and pediatric patients 12 years and older with chronic graft-versus-host disease (chronic GVHD) after failure of at least two prior lines of systemic therapy.