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Chronic graft-versus-host disease (cGVHD) is an immune-mediated inflammatory and fibrotic disease characterized by tissue damage and multisystem organ involvement.
Main causes affecting quality of life (QOL)
.
cGVHD affects up to 70% of alloHCT recipients, 42% have ≥4 organ involvement at diagnosis, and patients tend to progress to more severe stages
.
Belumosudil is an oral selective Rho-related coiled-coil kinase 2 (ROCK2) inhibitor that is effective in the treatment of patients with cGVHD
.
We conducted a phase II randomized multicenter registry study (ROCKstar; KD025-213) evaluating belumosudil 200 mg once daily (n = 66) and 200 mg twice daily (n = 66) in patients with prior 2- Efficacy and safety of 5 treatments in patients with cGVHD
.
01 Study Methods Inclusion criteria were: alloHCT patients aged ≥12 years with persistent cGVHD manifestations after receiving 2-5 lines of systemic therapy
.
Subjects were required to receive stable corticosteroid (CS) therapy for 2 weeks prior to screening and had a Karnofsky or Lansky Performance Status Scale score ≥60
.
Subjects with cGVHD received oral belumosudil 200 mg once daily or 200 mg twice daily
.
Randomization was stratified (1:1) according to the severity of cGVHD and prior ibrutinib therapy
.
The primary endpoint was the best overall response rate (ORR)
.
Secondary endpoints included duration of response (DOR), time to response, change in LSS total score, failure-free survival (FFS), CS reduction, and overall survival (OS)
.
The safety of belumosudil was assessed by adverse events (AEs) and serious AEs (SAEs)
.
02 Results of the study Patient characteristics A total of 132 subjects were recruited from October 2018 to August 2019, and the statistical cut-off time for the study was August 19, 2020
.
At enrollment, the median age of subjects was 56 years (range, 21-77), and the median time from cGVHD diagnosis to enrollment was 28 months (range, 2-162)
.
According to the 2014 NIH consensus criteria, 31% of subjects had moderate cGVHD at screening and 67% had severe cGVHD; 52% had ≥4 organ involvement
.
Subjects received a median of 3 prior systemic therapy
.
72% of patients with cGVHD (n = 79) were refractory to their last systemic therapy, 34% (n = 45) had prior ibrutinib, and 29% (n = 38) had prior On ruxolitinib treatment, 72% of patients (n = 95) had received ≥3 prior lines of therapy
.
The median treatment time was 10 months (range, 0.
4-22.
0), and the median follow-up time was 14 months (range, 1-22)
.
44% of subjects were on treatment for more than 12 months
.
The best ORRs for efficacy of Belumosudil 200 mg once daily and 200 mg twice daily were 74% (95% CI, 62-84) and 77% (95% CI, 65-87), respectively (Table 1)
.
Higher ORRs (61-85%) were observed in all subgroups
.
The efficacy of belumosudil was maintained regardless of prior ibrutinib (n = 46) or ruxolitinib (n = 38) treatment
.
The ORR in the subgroup receiving prior ruxolitinib was 68% (95% CI, 51-83)
.
The ORR for the ibrutinib-treated subgroup was 74% (95% CI, 59-86)
.
Table 1: Median time to response for both groups in the modified intention-to-treat (mITT) population was 5 weeks (range, 4-66)
.
91% of responses occurred within 6 months of treatment, and the remaining 9% of responses occurred after 6-12 months of treatment
.
Fifty-nine percent of patients in remission had remissions lasting more than 20 weeks
.
In the responder population, the median DOR was 54 weeks
.
The overall FFS rates at 6 and 12 months were 75% (95% CI, 66-81) and 56% (95% CI, 47-64), respectively
.
Overall, low NRM (7%) and recurrence rates (3%) were observed
.
The 2-year OS rate was 89% (95% CI, 82-93) (Figure 1)
.
Figure 1: Duration of remission with different doses of belumosudil.
During treatment with belumosudil, 65% of subjects had dose reductions in CS
.
In the mlTT population, the mean CS dose was reduced by 45%, and the mean CS dose was reduced by 54% in remission patients
.
CS treatment was discontinued in 21% of subjects
.
In the mITT population, 59% and 62% of subjects in the once-daily and twice-daily groups, respectively, had a clinically meaningful improvement (≥7 point reduction) from baseline in the 7-day LSS total score
.
This improvement was observed in 69% and 71% of responders in the belumosudil 200 mg once daily and 200 mg twice daily treatment groups, respectively, and 29% and 33%, respectively, of those who did not respond.
This improvement
.
Belumosudil was well tolerated with a median relative dose intensity (RDI) of 99.
7%
.
81% of subjects had an RDI >95%
.
AEs in cGVHD patients receiving CS and other immunosuppressants were as expected
.
≥1 SAE occurred in 38% of subjects; the most common was pneumonia (7%)
.
The most common (≥5%) grade 3 or 4 AEs were pneumonia (8%), hypertension (6%), and hyperglycemia (5%)
.
The most common liver-related AE was increased alanine aminotransferase (12%)
.
Of the 83 subjects who discontinued treatment, 28 (21%) discontinued treatment because of AEs, 16 (12%) because of possible drug-related AEs, and 5 (4%) because of underlying malignant disease progression While treatment was discontinued, 21 patients (16%) discontinued treatment due to progression of cGVHD
.
Fourteen subjects died during the study: 2 from multiple organ failure and infection possibly related to Belumosudil, 2 from cardiac arrest, 2 from respiratory failure, and 1 from haemopneumothorax resulting from lung biopsy , 1 died of acute myeloid leukemia relapse, and 6 died during long-term follow-up (>28 days after last dose)
.
03 Conclusion of the study The ROCKstar study showed that belumosudil has good efficacy and good safety in the treatment of SR cGVHD patients
.
The best ORRs for belumosudil 200 mg once daily and 200 mg twice daily were 74% and 77%, respectively
.
Improvements in CR, PR, and LSS and less drug toxicity suggest that belumosudil treatment may have the potential to improve outcomes in patients with cGVHD
.
Reference source: Corey Cutler, Stephanie J.
Lee, Sally Arai, et al.
Blood (2021) 138 (22): 2278–2289.
https://doi.
org/10.
1182/blood.
2021012021.
Click “Read the original text”, we progress together
Main causes affecting quality of life (QOL)
.
cGVHD affects up to 70% of alloHCT recipients, 42% have ≥4 organ involvement at diagnosis, and patients tend to progress to more severe stages
.
Belumosudil is an oral selective Rho-related coiled-coil kinase 2 (ROCK2) inhibitor that is effective in the treatment of patients with cGVHD
.
We conducted a phase II randomized multicenter registry study (ROCKstar; KD025-213) evaluating belumosudil 200 mg once daily (n = 66) and 200 mg twice daily (n = 66) in patients with prior 2- Efficacy and safety of 5 treatments in patients with cGVHD
.
01 Study Methods Inclusion criteria were: alloHCT patients aged ≥12 years with persistent cGVHD manifestations after receiving 2-5 lines of systemic therapy
.
Subjects were required to receive stable corticosteroid (CS) therapy for 2 weeks prior to screening and had a Karnofsky or Lansky Performance Status Scale score ≥60
.
Subjects with cGVHD received oral belumosudil 200 mg once daily or 200 mg twice daily
.
Randomization was stratified (1:1) according to the severity of cGVHD and prior ibrutinib therapy
.
The primary endpoint was the best overall response rate (ORR)
.
Secondary endpoints included duration of response (DOR), time to response, change in LSS total score, failure-free survival (FFS), CS reduction, and overall survival (OS)
.
The safety of belumosudil was assessed by adverse events (AEs) and serious AEs (SAEs)
.
02 Results of the study Patient characteristics A total of 132 subjects were recruited from October 2018 to August 2019, and the statistical cut-off time for the study was August 19, 2020
.
At enrollment, the median age of subjects was 56 years (range, 21-77), and the median time from cGVHD diagnosis to enrollment was 28 months (range, 2-162)
.
According to the 2014 NIH consensus criteria, 31% of subjects had moderate cGVHD at screening and 67% had severe cGVHD; 52% had ≥4 organ involvement
.
Subjects received a median of 3 prior systemic therapy
.
72% of patients with cGVHD (n = 79) were refractory to their last systemic therapy, 34% (n = 45) had prior ibrutinib, and 29% (n = 38) had prior On ruxolitinib treatment, 72% of patients (n = 95) had received ≥3 prior lines of therapy
.
The median treatment time was 10 months (range, 0.
4-22.
0), and the median follow-up time was 14 months (range, 1-22)
.
44% of subjects were on treatment for more than 12 months
.
The best ORRs for efficacy of Belumosudil 200 mg once daily and 200 mg twice daily were 74% (95% CI, 62-84) and 77% (95% CI, 65-87), respectively (Table 1)
.
Higher ORRs (61-85%) were observed in all subgroups
.
The efficacy of belumosudil was maintained regardless of prior ibrutinib (n = 46) or ruxolitinib (n = 38) treatment
.
The ORR in the subgroup receiving prior ruxolitinib was 68% (95% CI, 51-83)
.
The ORR for the ibrutinib-treated subgroup was 74% (95% CI, 59-86)
.
Table 1: Median time to response for both groups in the modified intention-to-treat (mITT) population was 5 weeks (range, 4-66)
.
91% of responses occurred within 6 months of treatment, and the remaining 9% of responses occurred after 6-12 months of treatment
.
Fifty-nine percent of patients in remission had remissions lasting more than 20 weeks
.
In the responder population, the median DOR was 54 weeks
.
The overall FFS rates at 6 and 12 months were 75% (95% CI, 66-81) and 56% (95% CI, 47-64), respectively
.
Overall, low NRM (7%) and recurrence rates (3%) were observed
.
The 2-year OS rate was 89% (95% CI, 82-93) (Figure 1)
.
Figure 1: Duration of remission with different doses of belumosudil.
During treatment with belumosudil, 65% of subjects had dose reductions in CS
.
In the mlTT population, the mean CS dose was reduced by 45%, and the mean CS dose was reduced by 54% in remission patients
.
CS treatment was discontinued in 21% of subjects
.
In the mITT population, 59% and 62% of subjects in the once-daily and twice-daily groups, respectively, had a clinically meaningful improvement (≥7 point reduction) from baseline in the 7-day LSS total score
.
This improvement was observed in 69% and 71% of responders in the belumosudil 200 mg once daily and 200 mg twice daily treatment groups, respectively, and 29% and 33%, respectively, of those who did not respond.
This improvement
.
Belumosudil was well tolerated with a median relative dose intensity (RDI) of 99.
7%
.
81% of subjects had an RDI >95%
.
AEs in cGVHD patients receiving CS and other immunosuppressants were as expected
.
≥1 SAE occurred in 38% of subjects; the most common was pneumonia (7%)
.
The most common (≥5%) grade 3 or 4 AEs were pneumonia (8%), hypertension (6%), and hyperglycemia (5%)
.
The most common liver-related AE was increased alanine aminotransferase (12%)
.
Of the 83 subjects who discontinued treatment, 28 (21%) discontinued treatment because of AEs, 16 (12%) because of possible drug-related AEs, and 5 (4%) because of underlying malignant disease progression While treatment was discontinued, 21 patients (16%) discontinued treatment due to progression of cGVHD
.
Fourteen subjects died during the study: 2 from multiple organ failure and infection possibly related to Belumosudil, 2 from cardiac arrest, 2 from respiratory failure, and 1 from haemopneumothorax resulting from lung biopsy , 1 died of acute myeloid leukemia relapse, and 6 died during long-term follow-up (>28 days after last dose)
.
03 Conclusion of the study The ROCKstar study showed that belumosudil has good efficacy and good safety in the treatment of SR cGVHD patients
.
The best ORRs for belumosudil 200 mg once daily and 200 mg twice daily were 74% and 77%, respectively
.
Improvements in CR, PR, and LSS and less drug toxicity suggest that belumosudil treatment may have the potential to improve outcomes in patients with cGVHD
.
Reference source: Corey Cutler, Stephanie J.
Lee, Sally Arai, et al.
Blood (2021) 138 (22): 2278–2289.
https://doi.
org/10.
1182/blood.
2021012021.
Click “Read the original text”, we progress together
