OVERVIEW

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Belumosudil – Rezurock®

DRUG CLASS

Protein Kinase Inhibitors

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NO.	MOLECULAR FORMULA	STRUCTURE
Belumosudil	911417-87-3	C26-H24-N6-O2

ANNOTATED BIBLIOGRAPHY

References updated: 15 July 2024

Abbreviations used: GvHD, graft-vs-host disease; ROCK, rho-associated, coiled-coil containing protein kinase; ULN, upper limit of normal.

• Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999.

  (Review of hepatotoxicity published in 1999 before the availability of protein kinase inhibitors such as belumosudil).
• DeLeve LD. Cancer chemotherapy. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 556.

  (Review of hepatotoxicity of cancer chemotherapeutic agents; discusses several kinase inhibitors including imatinib, gefitinib, erlotinib and crizotinib, but not belumosudil).
• Wellstein A, Giaccone G, Atkins MB, Sausville EA. Pathway-targeted therapies: monoclonal antibodies, protein kinase inhibitors, and various small molecules. In, Brunton LL, Hilal-Dandan R, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 13th ed. New York: McGraw-Hill, 2018, pp. 1203-36.

  (Textbook of pharmacology and therapeutics; belumosudil is not discussed).
• FDA. Multidisciplinary Review. https://www​.accessdata​.fda.gov/drugsatfda_docs​/nda/2021/214783Orig1s000TOC.cfm

  (FDA drug approvals website that has product labels [package inserts], letters of approval and full FDA scientific review of the new drug application for safety and efficacy mentions that ALT or AST elevations arose in 33% of patients in the safety cohort of 186 patients and were above 5 times ULN in 7% with drug withdrawal because of liver enzyme elevations in only 3 subjects [1.6%], and there were no episodes of clinically apparent liver injury or liver related deaths attributed to therapy).
• Blair HA. Belumosudil: first approval. Drugs. 2021;81:1677-1682. [PMC free article: PMC8590654] [PubMed: 34463931]

  (Review of the structure, mechanism of action, history of development, pharmacokinetics, clinical efficacy, and safety of belumosudil shortly after its approval in the US as therapy of chronic GvHD, mentions adverse events of infection, asthenia nausea, dyspnea, cough, edema, bleeding, muscle ache, headache, abdominal pain, and hypertension; no mention of ALT elevations or hepatotoxicity).
• Jagasia M, Lazaryan A, Bachier CR, Salhotra A, Weisdorf DJ, Zoghi B, Essel J, et al. ROCK2 inhibition with belumosudil (KD025) for the treatment of chronic graft-versus-host disease. J Clin Oncol. 2021;39:1888-1898. [PMC free article: PMC8189612] [PubMed: 33877856]

  (Among 54 patients with GvHD treated with belumosudil [200 mg daily, 200 mg twice daily, or 400 mg daily] the overall response rates were similar in all groups [62% to 69%] and associated with improved quality of life and corticosteroid sparing, while adverse events arose in 98% of patients and were severe in 43%, ALT or AST elevations occurred in 33% that were above 5 times ULN in 7%, but none were associated with jaundice or symptoms or required discontinuation).
• Cutler C, Lee SJ, Arai S, Rotta M, Zoghi B, Lazaryan A, Ramakrishnan A, et al. Belumosudil for chronic graft-versus-host disease after 2 or more prior lines of therapy: the ROCKstar Study. Blood. 2021;138:2278-2289. [PMC free article: PMC8641099] [PubMed: 34265047]

  (Among 132 patients with refractory GvHD treated with belumosudil [200 mg once vs twice daily], the best overall response rates were 74% vs 77% with symptom reduction in 59% vs 62%, while treatment emergent adverse events occurred in 99% which were severe in 38%, but there were no severe hepatic adverse events and ALT elevations arose in 8%, AST 10%, and GGT 12%, and bilirubin in 1%, but there were no instances of clinically apparent liver injury with jaundice).
• Przepiorka D, Le RQ, Ionan A, Li RJ, Wang YH, Gudi R, Mitra S, et al. FDA approval summary: belumosudil for adult and pediatric patients 12 years and older with chronic GvHD after two or more prior lines of systemic therapy. Clin Cancer Res. 2022;28:2488-2492. [PMC free article: PMC9197942] [PubMed: 35135839]

  (Summary and discussion of the FDA analysis of the clinical efficacy and safety of belumosudil as therapy of refractory GvHD that led to its approval, lists side effects that were reported in open label trials which included ALT elevations in 7% of patients and were above 5 times ULN in 2%).
• Lee GH, Guzman AK, Divito SJ, Soiffer RJ, Silk AW, Schmults CD. Cutaneous squamous-cell carcinoma after treatment with ruxolitinib or belumosudil. N Engl J Med. 2023;389:188-190. [PubMed: 37437151]

  (Two patients with long term chronic refractory GvHD who were treated with ruxolitinib or belumosudil developed rapidly progressive, invasive squamous cell carcinomas).
• Malard F, Mohty M. Updates in chronic graft-versus-host disease management. Am J Hematol. 2023;98:1637-1644. [PubMed: 37483142]

  (Review of the clinical features, pathogenesis, diagnosis, and therapy of chronic GvHD, first line treatment being corticosteroids which are typically required long term and require second line therapy in approximately half of patients, most agents being used off label [such as calcineurin and mTOR inhibitors], while more recently 3 unique kinase inhibitors with immunomodulatory actions have been approved specifically for refractory GvHD: ibrutinib [2017], ruxolitinib [2021), and belumosudil [2021]; no discussion of hepatotoxicity).
• Inamoto Y, Kato K, Kawakita T, Onishi Y, Matsuoka KI, Shiratori S, Ikegame K, et al. Hiramoto N, et al. An open-label study of belumosudil, a selective ROCK2 inhibitor, as second or subsequent line of therapy for steroid-dependent/steroid-resistant chronic GVHD. Am J Hematol. 2024 Jun 27. Epub ahead of print. [PubMed: 38934629]

  (Among 21 Japanese patients with refractory GvHD treated with belumosudil for an average of 9.2 months, 87% had a treatment emergent adverse event, most frequently diarrhea, but none resulted in drug discontinuation or death, 2 patients developed herpes zoster; no mention of ALT elevations or hepatotoxicity).