Belumosudil

Belumosudil, sold under the brand name Rezurock among others, is a medication used for the treatment of chronic graft versus host disease (cGvHD).[1][5][6] It is in the class of drugs known as serine/threonine kinase inhibitors.[6] Specifically, it is an inhibitor of Rho-associated coiled-coil kinase 2 (ROCK2; ROCK-II).[7] Belumosudil binds to and inhibits the serine/threonine kinase activity of ROCK2. This inhibits ROCK2-mediated signaling pathways which play major roles in pro- and anti-inflammatory immune cell responses. A genomic study in human primary cells demonstrated that the drug also has effects on oxidative phosphorylation, WNT signaling, angiogenesis, and KRAS signaling.[8]

Belumosudil
Clinical data
Trade namesRezurock, Rholistiq
Other namesKD025, SLx-2119
License data
Pregnancy
category
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Identifiers
  • 2-[3-[4-(1H-Indazol-5-ylamino)quinazolin-2-yl]phenoxy]-N-propan-2-ylacetamide
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC26H24N6O2
Molar mass452.518 g·mol−1
3D model (JSmol)
  • CC(C)NC(=O)COC1=CC=CC(=C1)C2=NC3=CC=CC=C3C(=N2)NC4=CC5=C(C=C4)NN=C5
  • InChI=InChI=1S/C26H24N6O2/c1-16(2)28-24(33)15-34-20-7-5-6-17(13-20)25-30-23-9-4-3-8-21(23)26(31-25)29-19-10-11-22-18(12-19)14-27-32-22/h3-14,16H,15H2,1-2H3,(H,27,32)(H,28,33)(H,29,30,31) checkY
  • Key:GKHIVNAUVKXIIY-UHFFFAOYSA-N checkY

The most common side effects include infection, tiredness or weakness, nausea, diarrhea, shortness of breath, cough, swelling, bleeding, stomach (abdominal) pain, muscle or bone pain, headache, and high blood pressure.[9]

Belumosudil was approved for medical use in the United States in July 2021.[5][6] The US Food and Drug Administration considers it to be a first-in-class medication.[10]

Medical uses

Belumosudil is indicated for the treatment of people aged twelve years and older with chronic graft-versus-host disease (chronic GVHD) after failure of at least two prior lines of systemic therapy.[5][6]

Chronic graft-versus-host disease is a complication that can occur after stem cell or bone marrow transplantation in which the transplanted donor cells attack the transplant recipient’s body.[9]

History

Originally developed by Surface Logix, Inc,[7] belumosudil was later acquired by Kadmon Corporation. By July 2020, the drug completed Phase II clinical studies for cGvHD, IPF, and psoriasis.[11]

Chronic graft-versus-host disease is a complication that can follow allogeneic stem cell or hematopoietic stem cell transplantation where the transplanted cells (graft) attack healthy cells (host). This causes inflammation and fibrosis in multiple tissues. Two cytokines controlled by the ROCK2 signaling pathway, IL-17 and IL-21, have a major role in the chronic graft-versus-host disease response. In a 2016 report using both mouse models and a limited human clinical trial ROCK2 inhibition with belumosudil targeted both the immunologic and fibrotic components of chronic graft-versus-host disease and reversed the symptoms of the disease.[12]

In October 2017, belumosudil was granted orphan drug status in the United States for treatment of people with chronic graft-versus-host disease.[13]

Efficacy of belumosudil was evaluated in clinical trial NCT03640481,[14] a randomized, open-label, multicenter dose-ranging trial that included 65 patients with chronic graft-versus-host disease who were treated with belumosudil 200 mg taken orally once daily.[6][9] A total of eighty-three (83) participants were evaluated for safety; therefore, the number of participants representing efficacy findings may differ from the number of participants representing safety findings due to different pools of study participants analyzed for efficacy and safety.[9] The trial was conducted at 28 sites in the United States.[9]

On 16 July 2021, the US Food and Drug Administration (FDA) approved belumosudil for people aged twelve years and older with chronic graft-versus-host disease after failure of at least two prior lines of systemic therapy.[6][10]

Research

IPF is a progressive fibrotic disease where the lining of the lungs become thickened and scarred.[15] Increased ROCK activity has been found in the lungs of humans and animals with IPF. Treatment with belumosudil reduced lung fibrosis in a bleomycin mouse model study.[16]

Psoriasis is an inflammatory skin condition where patients experiences eruptions and remissions of thickened, erythematous, and scaly patches of skin. Down-regulation of pro-inflammatory responses was observed with KD025 treatment in Phase 2 clinical studies in patients with moderate to severe psoriasis.[17]

References
  1. "Rholistiq". Therapeutic Goods Administration (TGA). 26 November 2021. Archived from the original on 28 December 2021. Retrieved 28 December 2021.
  2. "AusPAR: Belumosudil". Therapeutic Goods Administration (TGA). 10 May 2022. Archived from the original on 10 May 2022. Retrieved 10 May 2022.
  3. "Archived copy" (PDF). Archived (PDF) from the original on 29 June 2022. Retrieved 29 June 2022.{{cite web}}: CS1 maint: archived copy as title (link)
  4. "Summary Basis of Decision - Rholistiq". Health Canada. 23 October 2014. Retrieved 6 August 2022.
  5. "Rezurock- belumosudil tablet". DailyMed. Archived from the original on 21 August 2021. Retrieved 20 August 2021.
  6. "FDA approves belumosudil for chronic graft-versus-host disease". U.S. Food and Drug Administration (FDA). 16 July 2021. Archived from the original on 16 July 2021. Retrieved 16 July 2021. Public Domain This article incorporates text from this source, which is in the public domain.
  7. Boerma M, Fu Q, Wang J, Loose DS, Bartolozzi A, Ellis JL, et al. (October 2008). "Comparative gene expression profiling in three primary human cell lines after treatment with a novel inhibitor of Rho kinase or atorvastatin". Blood Coagulation & Fibrinolysis. 19 (7): 709–18. doi:10.1097/MBC.0b013e32830b2891. PMC 2713681. PMID 18832915.
  8. Park J, Chun KH (5 May 2020). "Identification of novel functions of the ROCK2-specific inhibitor KD025 by bioinformatics analysis". Gene. 737: 144474. doi:10.1016/j.gene.2020.144474. PMID 32057928. S2CID 211111888.
  9. "Drug Trials Snapshots: Rezurock". U.S. Food and Drug Administration. 16 July 2021. Retrieved 25 June 2023. Public Domain This article incorporates text from this source, which is in the public domain.
  10. Advancing Health Through Innovation: New Drug Therapy Approvals 2021 (PDF). U.S. Food and Drug Administration (FDA) (Report). 13 May 2022. Archived from the original on 6 December 2022. Retrieved 22 January 2023. Public Domain This article incorporates text from this source, which is in the public domain.
  11. "KD025 - Clinical Trials". ClinicalTrials.gov. Archived from the original on 25 July 2020. Retrieved 25 July 2020.
  12. Flynn R, Paz K, Du J, Reichenbach DK, Taylor PA, Panoskaltsis-Mortari A, et al. (April 2016). "Targeted Rho-associated kinase 2 inhibition suppresses murine and human chronic GVHD through a Stat3-dependent mechanism". Blood. 127 (17): 2144–54. doi:10.1182/blood-2015-10-678706. PMC 4850869. PMID 26983850.
  13. Shanley M (6 October 2017). "Therapy to Treat Transplant Complications Gets Orphan Drug Designation". RareDiseaseReport. Archived from the original on 14 February 2019. Retrieved 25 July 2018.
  14. Clinical trial number NCT03640481 for "Efficacy and Safety of KD025 in Subjects With cGVHD After At Least 2 Prior Lines of Systemic Therapy" at ClinicalTrials.gov
  15. "Pulmonary Fibrosis". The Mayo Clinic. Archived from the original on 15 July 2014. Retrieved 25 July 2018.
  16. Semedo D (5 June 2016). "Phase 2 Study of Molecule Inhibitor for Idiopathic Pulmonary Fibrosis Begins". Lung Disease News. BioNews Services, LLC. Archived from the original on 8 July 2016. Retrieved 25 July 2018.
  17. Zanin-Zhorov A, Weiss JM, Trzeciak A, Chen W, Zhang J, Nyuydzefe MS, et al. (May 2017). "Cutting Edge: Selective Oral ROCK2 Inhibitor Reduces Clinical Scores in Patients with Psoriasis Vulgaris and Normalizes Skin Pathology via Concurrent Regulation of IL-17 and IL-10". Journal of Immunology. 198 (10): 3809–3814. doi:10.4049/jimmunol.1602142. PMC 5421306. PMID 28389592.
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