911417-87-3, SLx-2119, KD-025, KD 025, WHO 11343
UPDATE FDA APPROVED 7/16/2021 To treat chronic graft-versus-host disease after failure of at least two prior lines of systemic therapy, Rezurock
New Drug Application (NDA): 214783
Company: KADMON PHARMA LLC
200 MG TABLET
FDA approves belumosudil for chronic graft-versus-host disease
On July 16, 2021, the Food and Drug Administration approved belumosudil (Rezurock, Kadmon Pharmaceuticals, LLC), a kinase inhibitor, for 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.
Efficacy was evaluated in KD025-213 (NCT03640481), a randomized, open-label, multicenter dose-ranging trial that included 65 patients with chronic GVHD who were treated with belumosudil 200 mg taken orally once daily.
The main efficacy outcome measure was overall response rate (ORR) through Cycle 7 Day 1 where overall response included complete response (CR) or partial response (PR) according to the 2014 criteria of the NIH Consensus Development Project on Clinical Trials in Chronic Graft-versus-Host Disease. The ORR was 75% (95% CI: 63, 85); 6% of patients achieved a CR, and 69% achieved a PR. The median time to first response was 1.8 months (95% CI: 1.0, 1.9). The median duration of response, calculated from first response to progression, death, or new systemic therapies for chronic GVHD, was 1.9 months (95% CI: 1.2, 2.9). In patients who achieved response, no death or new systemic therapy initiation occurred in 62% (95% CI: 46, 74) of patients for at least 12 months since response.
The most common adverse reactions (≥ 20%), 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.
The recommended dosage of belumosudil is 200 mg taken orally once daily with food.
This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For this review, FDA collaborated with Australia’s Therapeutic Goods Administration, Health Canada, Switzerland’s Swissmedic, and the United Kingdom’s Medicines and Healthcare products Regulatory Agency.
This review used the Real-Time Oncology Review (RTOR) pilot program, which streamlined data submission prior to the filing of the entire clinical application, and the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment. The FDA approved this application 6 weeks ahead of the FDA goal date.
This application was granted priority review and breakthrough therapy designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.
Belumosudil mesylate is an orally available rho kinase 2 (ROCK 2) inhibitor being developed at Kadmon. In 2020, the drug candidate was submitted for a new drug application (NDA) in the U.S., under a real-time oncology review pilot program, for the treatment of chronic graft-versus-host disease (cGVHD). The compound is also in phase II clinical development for the treatment of idiopathic pulmonary fibrosis and diffuse cutaneous systemic sclerosis. Formerly, the company had also been conducting clinical research for the treatment of psoriasis and non-alcoholic steatohepatitis (NASH); however, no further development has been reported for these indications. Originally developed by Nano Terra, the product was licensed to Kadmon on an exclusive global basis in 2011. In 2019, Kadmon entered into a strategic partnership with BioNova Pharmaceuticals and established a joint venture, BK Pharmaceuticals, to exclusively develop and commercialize KD-025 for the treatment of graft-versus-host disease in China. The compound has been granted breakthrough therapy designation in the U.S. for the treatment of cGVHD and orphan drug designations for cGVHD and systemic sclerosis. In the E.U. belumosudil was also granted orphan drug status in the E.U. for the treatment of cGVHD.
Kadmon , under license from NT Life Sciences , is developing belumosudil as mesylate salt, a ROCK-2 inhibitor, for treating IPF, chronic graft-versus-host disease, hepatic impairment and scleroderma. In July 2021, belumosudil was reported to be in pre-registration phase.
Belumosudil (formerly KD025 and SLx-2119) is an experimental drug being explored for the treatment of chronic graft versus host disease (cGvHD), idiopathic pulmonary fibrosis (IPF), and moderate to severe psoriasis. It is an inhibitor of Rho-associated coiled-coil kinase 2 (ROCK2; ROCK-II). 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. Originally developed by Surface Logix, Inc, Belumosudil was later acquired by Kadmon Corporation. As of July 2020 the drug was in completed or ongoing Phase II clinical studies for cGvHD, IPF and psoriasis.
cGvHD is a complication that can follow 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 cGvHD 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 cGvHD and reversed the symptoms of the disease. In October 2017 KD025 was granted orphan drug status in the United States for treatment of patients with cGvHD.
IPF is a progressive fibrotic disease where the lining of the lungs become thickened and scarred. 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. Belumosudil may have a therapeutic benefit in IPF by targeting the fibrotic processes mediated by the ROCK signaling pathway.
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.
“Substance Name:Substance Name: Belumosudil [USAN]”.
WO 2014055996, WO 2015157556
Novel crystalline polymorphic forms (N1, N2 and N15) of KD-025 (also known as belumosudil ), useful as a Rho A kinase 2 (ROCK-2) inhibitor for treating multiple sclerosis, psoriasis, rheumatoid arthritis, idiopathic pulmonary fibrosis (IPF), atherosclerosis, non-alcoholic fatty liver and systemic sclerosis. Represents the first filing from Sunshine Lake Pharma or its parent HEC Pharm that focuses on belumosudil.KD-025 is a selective ROCK2 (Rho-associated protein kinase 2, Rho-related protein kinase 2) inhibitor. It has multiple clinical indications such as the treatment of multiple sclerosis, psoriasis, rheumatoid arthritis, and Primary pulmonary fibrosis, atherosclerosis, non-alcoholic fatty liver, etc., among which many indications are in clinical phase I, and psoriasis and systemic sclerosis are in clinical phase II.
The structure of KD-025 is shown in the following formula (1).
Example 1 Preparation method of crystal form N1 of KD-025300mg of KD-025 solid was suspended and stirred in 10mL methanol at room temperature. After 22h, it was filtered, suction filtered and placed in a drying oven at 50°C under vacuum overnight to obtain 262mg of powder. The obtained crystal was detected by XPRD and confirmed to be KD-025 crystal form N1; its X-ray powder diffraction pattern was basically the same as that of Fig. 1, its DSC pattern was basically the same as that of Fig. 2, and the TGA pattern was basically the same as that of Fig. 3.
Belumosudil product pat,
protection in the EU states until March 2026, expires in the US in May 2029 with US154 extension.
 A suspension of 2-(3-(4-(lH-indazol-5-ylamino)qumazolin-2-yl)ρhenoxy)acetic acid (70 mg, 0.14 mmol), PyBOP® (40 mg, 0.077 mmol), DlEA (24 μL, 0.14 mmol) in dry CH2Cl2 : DMF (2 : 0.1 mL) was stirred at RT for 15 minutes. To this solution of activated acid was added propan-2-amine (5.4 mg, 0.091 mmol). After 30 minutes, 1.0 equivalent of DIEA and 0.55 equivalents of PyBOP® were added. After stirring the solution for 15 minutes, 0.65 equivalents of propan-2-aminewere added and the mixture was stirred for an additional 30 minutes. The solvent was removed in vacuo and the crude product was purified using prep HPLC (25-50 90 rnins) to afford 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-isopropylacetamide. (40 mg, 0.086 mmol, 61 %).
- ^ Jump up to:a b 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.
- ^ 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.
- ^ “KD025 – Clinical Trials”. ClinicalTrials.gov. Retrieved 25 July 2020.
- ^ 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.
- ^ Shanley M (October 6, 2017). “Therapy to Treat Transplant Complications Gets Orphan Drug Designation”. RareDiseaseReport. Retrieved 25 July 2018.
- ^ “Pulmonary Fibrosis”. The Mayo Clinic. Retrieved July 25, 2018.
- ^ Semedo D (June 5, 2016). “Phase 2 Study of Molecule Inhibitor for Idiopathic Pulmonary Fibrosis Begins”. Lung Disease News. BioNews Services, LLC. Retrieved 25 July 2018.
- ^ 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.
|Oral administration (tablets or capsules)|
|CompTox Dashboard (EPA)||DTXSID80238425|
|Chemical and physical data|
|Molar mass||452.518 g·mol−1|
|3D model (JSmol)||Interactive image|
////////////BELUMOSUDIL, SLx-2119, KD-025, KD 025, WHO 11343, PHASE 2, cGvHD, IPF, psoriasis, Breakthrough Therapy, Orphan Drug Designation
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