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Time to market

In July 2021, Besudil mesylate tablets were approved for the first time in the United States for the treatment of adult and pediatric patients with cGVHD aged ≥ 12 years old.

On August 3, 2023, the China National Medical Products Administration approved the marketing of Besudil Mesylate Tablets in China for the treatment of chronic graft-versus-host disease (cGVHD).

Dosage forms and specifications

Each tablet is 200 mg. Besudil mesylate tablets are light yellow oval film-coated tablets, with "KDM" engraved on one side and "200" engraved on the other side.

Indications

Besudil mesylate tablets are suitable for the treatment of patients with chronic graft-versus-host disease (chronic GVHD) in adults and children aged 12 years and above who have failed at least two previous lines of systemic therapy.

Efficacy and effect

It is an inhibitor of rho-related coiled-coil protein kinase (ROCK), inhibiting ROCK2 and ROCK1, with IC50 values ​​of approximately 100 nM and 3µM respectively. Besudil mesylate tablets modulate changes in STAT3/STAT5 phosphorylation and Th17/Treg balance in ex vivo or in vitro human T cell assays.

Besudil mesylate tablets also inhibit abnormal pro-fibrotic signals in vitro. In vivo, beruasidil exhibits activity in animal models of chronic GVHD. Besudil mesylate tablets can reduce the symptoms of cGVHD patients, improve the prognosis of the disease, and improve the patient's quality of life.

Usage and Dosage

The recommended dose is 200mg, administered orally, once a day.

Fifty-four patients with cGVHD who had received 1-3 prior courses of treatment (LOTs) were enrolled in a Phase IIa, open-label, dose-finding study. The median time from diagnosis to enrollment was 20 months. 78% of patients had severe cGVHD, 50% had ≥ 4 organ involvement, 73% were refractory to the last batch of cGVHD, and 50% had received ≥ 3 previous batches of cGVHD.

The overall median follow-up time was 29 months. The ORR (95% CI) of besudil mesylate tablets 200 mg once daily, 200 mg twice daily and 400 mg once daily were 65%, 69% and 62% respectively. Responses were clinically meaningful, with a median duration of response of 35 weeks, and were associated with improved quality of life and corticosteroid (CS) dose reduction. 19% of patients discontinued CS treatment. The 6-month and 12-month failure-free survival rates were 76% and 47% respectively, and the 2-year overall survival rate was 82%.

Besudil mesylate tablets treatment resulted in high ORR and overall survival rate, and demonstrated improved quality of life, reduced CS dose, and limited toxicity.

Side effects

1. Gastrointestinal diseases: nausea, diarrhea, abdominal pain.

2. Respiratory system, chest and mediastinal diseases: dyspnea, cough, nasal congestion.

3. Vascular diseases: bleeding, hypertension.

4. Musculoskeletal and connective tissue diseases: skeletal muscle pain, muscle spasm, joint pain.

5. Nervous system diseases: headache.

6. Metabolic and nutritional diseases: loss of appetite.

7. Skin and subcutaneous tissue diseases: rash, itching.

8. Systemic diseases: fatigue, edema, fever.

Dose adjustment

1. Hepatotoxicity

1. Grade 3 AST or ALT (5x to 20xULN) or grade 2 bilirubin (1.5x to 3xULN): Suspend Besudil Mesylate Tablets treatment until bilirubin, AST and ALT recover to grade 0-1, and then resume Besudil Mesylate Tablets administration at the recommended dose.

2. Grade 4 AST or ALT (more than 20×ULN) or grade ≥3 bilirubin (more reduction >3×ULN): Permanently discontinue Besudil Mesylate Tablets.

2. Other adverse reactions

Level 1 and 3: Suspend the administration of Besudil Mesylate Tablets until it returns to Level 0-1, and then resume the administration of Besudil Mesylate Tablets at the recommended dose level.

Level 4: Permanently discontinue Besudil Mesylate Tablets.

Dose adjustment for drug interactions

1. Strong CYP3A inducers: When administered together with strong CYP3A inducers, increase the dose of besudil mesylate tablets to 200 mg twice daily.

2. Proton pump inhibitors: When besudil mesylate tablets are administered together with proton pump inhibitors, the dose of besudil mesylate tablets should be increased to 200 mg twice a day.

Precautions

1. Based on the results of animal studies and its mechanism of action, Besudil mesylate tablets can cause fetal damage when administered to pregnant women. In animal reproduction studies, besudil mesylate was associated with adverse developmental outcomes, including embryo-fetal death and malformations, in pregnant rats and rabbits administered during organogenesis at maternal exposures (AUC) below those at recommended patient doses.

Pregnant women should be informed of the potential risks to the fetus before taking the drug. It is recommended that women of childbearing potential and men with female partners of childbearing potential take effective contraceptive measures during treatment and 1 week after the last dose.

2. It is recommended that women should not breastfeed during treatment and within 1 week after the last dose.

Price

The price of a box of 200mg*30 tablets is about $216,750, which is expensive, and you need to buy it at your own expense, which puts a lot of financial pressure.

Storage conditions

Store at room temperature of 20°C-25°C (68°F-77°F), and the allowed fluctuation range is 15°C-30°C.

References:

Jagasia M, Lazaryan A, Bachier CR, Salhotra A, Weisdorf DJ, Zoghi B, Essell J, Green L, Schueller O, Patel J, Zanin-Zhorov A, Weiss JM, Yang Z, Eiznhamer D, Aggarwal SK, Blazar BR, Lee SJ. ROCK2 Inhibition With Belumosudil (KD025) for the Treatment of Chronic Graft-Versus-Host Disease. J Clin Oncol. 2021 Jun 10;39(17):1888-1898. doi: 10.1200/JCO.20.02754. Epub 2021 Apr 20. PMID: 33877856; PMCID: PMC8189612.

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