ROCK2, a critical regulator of immune modulation and fibrosis has emerged as a therapeutic target in chronic graft-versus-host disease

Zanin-Zhorov, Alexandra; Blazar, Bruce R.

doi:10.1016/j.clim.2021.108823

Cited by 36 publications

(21 citation statements)

References 68 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[6][7][8][9][10][11] Inhibition of ROCK 2 has emerged as a promising treatment of cGVHD. 12 Belumosudil (REZUROCK) is a selective ROCK2 inhibitor approved for the treatment of adults and pediatric patients (≥12 years of age) with cGVHD after failure of at least 2 prior lines of therapy. 13 Early clinical trials with belumosudil employed a capsule formulation consisting of the active pharmaceutical ingredient belumosudil mesylate, encapsulated without excipients in opaque hard yellow gelatin shells.…”

mentioning

confidence: 99%

“…In cGVHD, ROCK2 drives proinflammatory immune responses and fibrosis that contribute to cGVHD pathogenesis 6–11 . Inhibition of ROCK 2 has emerged as a promising treatment of cGVHD 12 . Belumosudil (REZUROCK) is a selective ROCK2 inhibitor approved for the treatment of adults and pediatric patients (≥12 years of age) with cGVHD after failure of at least 2 prior lines of therapy 13 …”

mentioning

confidence: 99%

See 1 more Smart Citation

Phase 1 Studies to Evaluate the Food Effect and Relative Bioavailability of Tablet and Capsule Formulations of Belumosudil in Healthy Adult Subjects

Schueller¹,

McDermott

Evans

et al. 2022

Clinical Pharm in Drug Dev

View full text Add to dashboard Cite

Belumosudil is a selective Rho‐associated coiled‐coil containing protein kinase 2 inhibitor. A capsule formulation was used during early clinical development of belumosudil; it was later replaced by a tablet formulation, which mimicked the capsule's release properties and facilitated manufacturing scalability. To assess belumosudil's pharmacokinetics, including potential food effects, and evaluate the relative bioavailability of the 2 formulations, 2 phase 1 clinical trials were conducted. Administration of both belumosudil tablets and capsules with food increased exposure ≈2× as compared to the fasted state and delayed time to maximum concentration by 0.5 hour, indicating a decrease in the rate but increase in the extent of absorption with fed administration. Relative bioavailability was slightly higher when belumosudil was administered as tablets vs capsules, although the difference was not clinically meaningful. Safety and tolerability were generally consistent with the known safety profile of belumosudil. The results of these studies support administration of belumosudil with food.

show abstract

mentioning

confidence: 99%

mentioning

confidence: 99%

Phase 1 Studies to Evaluate the Food Effect and Relative Bioavailability of Tablet and Capsule Formulations of Belumosudil in Healthy Adult Subjects

Schueller¹,

McDermott

Evans

et al. 2022

Clinical Pharm in Drug Dev

View full text Add to dashboard Cite

show abstract

“…Inhibition of ROCK2 has been shown to restore immune homeostasis and reduce fibrosis. Therefore, ROCK2 inhibition has emerged as a promising therapeutic for the treatment of cGVHD 7 . Belumosudil (REZUROCK) is an orally available selective ROCK2 inhibitor approved for the treatment of adult and pediatric patients aged ≥12 years with cGVHD after failure of at least 2 prior lines of systemic therapy 8 …”

mentioning

confidence: 99%

“…Therefore, ROCK2 inhibition has emerged as a promising therapeutic for the treatment of cGVHD. 7 Belumosudil (REZUROCK) is an orally available selective ROCK2 inhibitor approved for the treatment of adult and pediatric patients aged ≥12 years with cGVHD after failure of at least 2 prior lines of systemic therapy. 8 Belumosudil undergoes metabolism to form a ROCK2-active metabolite, KD025m1, and a metabolite that is relatively less active against ROCK2, KD025m2.…”

mentioning

confidence: 99%

A Phase 1 Pharmacokinetic Drug Interaction Study of Belumosudil Coadministered With CYP3A4 Inhibitors and Inducers and Proton Pump Inhibitors

Schueller¹,

Willson

Singh

et al. 2022

Clinical Pharm in Drug Dev

View full text Add to dashboard Cite

Belumosudil is a selective Rho-associated protein kinase 2 inhibitor. Inhibition of Rho-associated protein kinase 2 has emerged as a promising treatment for chronic graft-versus-host disease by restoring immune homeostasis and reducing fibrosis. In vitro assessments have suggested that metabolism of belumosudil is primarily dependent on cytochrome P450 (CYP) 3A4 activity and that the solubility of belumosudil is pH dependent. As such, this 2-part clinical drug-drug interaction study was conducted to assess the effect of itraconazole (a strong CYP3A4 inhibitor), rifampicin (a strong CYP3A4 inducer), rabeprazole, and omeprazole (both proton pump inhibitors) on the pharmacokinetics of belumosudil. No clinically relevant change in belumosudil exposure was observed following a 200-mg single oral dose of belumosudil with itraconazole; however, exposure of main metabolite, KD025m2, was decreased. Consistent with the proposed metabolic pathway of belumosudil, the strong CYP3A4 inducer rifampicin significantly decreased exposure of belumosudil and KD025m2 and increased KD025m1 exposure. When a 200-mg single oral dose of belumosudil was coadministered with both rabeprazole and omeprazole, parent and metabolite exposures were largely reduced, suggesting that belumosudil dosage should be increased when given with PPIs. Administration of belumosudil with and without perpetrator drugs was safe, and no notable adverse events were reported.

show abstract

“…Notably, KD025 (also named SLx-2119) was published in 2008, and it is the first highly selective ROCK2-isoform inhibitor achieving a high isoform selectivity of > 200-fold for ROCK2 vs. ROCK1 (Boerma et al 2008). Its therapeutic potential has been explored in fibrotic disease (Boerma et al 2008), focal cerebral ischemia (Akhter et al 2018;Lee et al 2014;Sadeghian et al 2018), and auto-immune disease Weiss et al 2016;Zanin-Zhorov and Blazar 2021;Zanin-Zhorov et al 2014. Interestingly, hypotensive phenotype was not observed when KD025 was tested in systemic application (Lee et al 2014).…”

Section: Development and Therapeutic Effects Of Rock Inhibitorsmentioning

confidence: 99%

Rho Kinases in Embryonic Development and Stem Cell Research

Shi

Wei

2022

Arch. Immunol. Ther. Exp.

View full text Add to dashboard Cite

The Rho-associated coiled-coil containing kinases (ROCKs or Rho kinases) belong to the AGC (PKA/PKG/PKC) family of serine/threonine kinases and are major downstream effectors of small GTPase RhoA, a key regulator of actin-cytoskeleton reorganization. The ROCK family contains two members, ROCK1 and ROCK2, which share 65% overall identity and 92% identity in kinase domain. ROCK1 and ROCK2 were assumed to be functionally redundant, based largely on their major common activators, their high degree kinase domain homology, and study results from overexpression with kinase constructs or chemical inhibitors. ROCK signaling research has expanded to all areas of biology and medicine since its discovery in 1996. The rapid advance is befitting ROCK’s versatile functions in modulating various cell behavior, such as contraction, adhesion, migration, proliferation, polarity, cytokinesis, and differentiation. The rapid advance is noticeably driven by an extensive linking with clinical medicine, including cardiovascular abnormalities, aberrant immune responsive, and cancer development and metastasis. The rapid advance during the past decade is further powered by novel biotechnologies including CRISPR-Cas and single cell omics. Current consensus, derived mainly from gene targeting and RNA interference approaches, is that the two ROCK isoforms have overlapping and distinct cellular, physiological and pathophysiology roles. In this review, we present an overview of the milestone discoveries in ROCK research. We then focus on the current understanding of ROCK signaling in embryonic development, current research status using knockout and knockin mouse models, and stem cell research.

show abstract

ROCK2, a critical regulator of immune modulation and fibrosis has emerged as a therapeutic target in chronic graft-versus-host disease

Cited by 36 publications

References 68 publications

Phase 1 Studies to Evaluate the Food Effect and Relative Bioavailability of Tablet and Capsule Formulations of Belumosudil in Healthy Adult Subjects

Phase 1 Studies to Evaluate the Food Effect and Relative Bioavailability of Tablet and Capsule Formulations of Belumosudil in Healthy Adult Subjects

A Phase 1 Pharmacokinetic Drug Interaction Study of Belumosudil Coadministered With CYP3A4 Inhibitors and Inducers and Proton Pump Inhibitors

Rho Kinases in Embryonic Development and Stem Cell Research

Contact Info

Product

Resources

About