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There are not many treatment options for chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT), and new treatments for cGVHD are urgently needed in the clinic.
Belumosudil (KD025) is a novel oral selective Rho-related coiled-coil protein kinase 2 (ROCK2) inhibitor, specifically for the treatment of cGVHD.
The investigators conducted a phase IIa study to evaluate the effectiveness and safety of Belumosudil in patients with cGVHD.
Yimaitong organizes the main content as follows for the reference of readers.
Research Method The study is a dose exploration, open-label, phase IIa study conducted at seven centers in the United States.
CGVHD occurred after previous 1-3 line systemic treatment (including allogeneic bone marrow transplantation or allogeneic hematopoietic stem cell transplantation [allo-HSCT]) and received glucocorticoid therapy (with or without calcineurin inhibitor) And/or at the same time in vitro optical separation and replacement) patients aged ≥18 years old are eligible for enrollment.
The patients were divided into three cohorts: cohort 1 received 200 mg Belumosudil once a day; cohort 2 received 200 mg Belumosudil twice a day; cohort 3 received 200 mg Belumosudil once a day.
Belumosudil is administered orally in a cycle of 28 days until the disease progresses or intolerable toxicity occurs.
The primary research endpoint is the overall response rate (ORR), and the secondary research endpoints include duration of response (DOR), Lee Symptom Scale (LSS) score, reduction of glucocorticoids, time to next treatment (TTNT), and no failure Lifetime (FFS) and overall survival (OS), etc.
Study Results 01 Patient Characteristics During the period from September 2016 to March 2018, a total of 54 patients were included in the study: cohort 1 had 17 patients, cohort 2 had 16 patients, and cohort 3 had 21 patients.
The data analysis ended on February 19, 2020.
The median follow-up time of cohort 1, cohort 2, and cohort 3 were 36 months, 32 months, and 24 months, respectively.
The overall median follow-up time was 29 months (range: 1-39 months).
The median age of patients at baseline was 52 years (range 20-75 years).
According to the investigator's assessment, 78% of patients have severe cGVHD, and 50% of patients involve ≥4 organs.
The median baseline glucocorticoid doses (mg/kg/d prednisone equivalent) for cohort 1, cohort 2, and cohort 3 were 0.
22, 0.
19, and 0.
17, respectively.
Before enrollment, 73% of patients had no effect on the last systemic treatment.
The median treatment time of cohort 1, cohort 2 and cohort 3 were 8.
5 months (2-39 months), 7.
5 months (1-35 months), and 9 months (1-29 months), respectively.
8% of patients received belumosudil for >18 months.
02 ORR for efficacy: Among the 54 patients studied, the ORR (95% CI) was 65% (51%-77%).
The ORR (95% CI) of each group was similar: cohort 1 was 65% (38%-86%), cohort 2 was 69% (41%-89%), and cohort 3 was 62% (38%-82%).
Patients in the key subgroups achieved remission.
The ORR of patients with severe cGVHD was 60% (25/42), and the ORR of patients who had received ≥2 line system therapy was 66% (23/35).
The ORR of invalid patients was 63% (22/35), and the ORR of patients involving more than 4 organs was 70% (19/27).
TTNT: The median TTNT is 14 months.
Subsequent systemic cGVHD treatments include tacrolimus, sirolimus, ibrutinib, rucotinib, in vitro optical separation and replacement, and mycophenolate mofetil.
FFS and OS: At 6, 12 and 24 months, the FFS rate (95% CI) was 76% (62%-85%), 47% (33%-60%) and 33% (21%-46 %).
FFS is defined as the time from the first dose of belumosudil to the failure event.
Reasons for failure included the initiation of new systemic therapy (n=27), recurrence of underlying disease (n=7), and death (n=2).
At 12 months and 24 months, the OS rate (95% CI) was 91% (79%-96%) and 82% (69%-90%), respectively.
Quality of life assessment: A clinically significant improvement in the LSS score is defined as a decrease of ≥7 points in the total LSS score of 50% of patients during treatment with belumosudil.
In continuous evaluation, 35% of patients (37% of responders and 32% of non-responders) reported a clinically significant improvement in LSS scores.
Glucocorticoid dose: During the treatment with belumosudil, 67% of patients reduced the glucocorticoid dose, and 19% of the patients completely stopped the glucocorticoid.
The average glucocorticoid dose was reduced by 45%.
The median time to stop glucocorticoids was 29 weeks (range: 8-77 weeks).
03 Adverse events (AE) with a safety rate of ≥20% are upper respiratory tract infection (46%), diarrhea (33%), fatigue (33%), nausea (33%), abnormal liver function (33%), breathing Difficulty (30%), headache (24%), peripheral edema (24%), cough (22%) and hypertension (20%).
Serious AEs occurred in 43% of patients, and the serious AEs reported in >1 patients were dyspnea (7%), lung infection (6%), hypoxia (4%) and flu-like illness (4%) .
61% of patients had grade ≥3 AEs, the most common being dyspnea (13%), abnormal liver function (7%), hyperglycemia (7%), and hypoxia (7%).
Two patients (4%) had a cytopenia of grade ≥3.
No cases of cytomegalovirus (CMV) infection or reactivation have been reported.
Belumosudil was discontinued in 3 patients due to potential drug-related adverse events (cohort 1: diarrhea and headache; cohort 3: fatigue).
Four patients in cohort 3 died in the study due to recurrence of leukemia, pneumonia, cardiac arrest, and cGVHD progression, and no deaths were due to Belumosudil.
Research conclusions Belumosudil has a higher ORR and OS rate in the treatment of cGVHD patients, can improve the quality of life, reduce the dose of glucocorticoid, and has good safety.
The data of the study suggests that Belumosudil may be an effective therapy for patients with refractory cGVHD.
Reference source: Madan Jagasia, Aleksandr Lazaryan, Carlos R.
Bachier, et al.
ROCK2 Inhibition With Belumosudil (KD025) for the Treatment of Chronic Graft-Versus-Host Disease.
Published online April 20, 2021.
Journal of Clinical Oncology DOI: 10.
1200 /JCO.
20.
02754.
Stamp "read the original text", we make progress together
Belumosudil (KD025) is a novel oral selective Rho-related coiled-coil protein kinase 2 (ROCK2) inhibitor, specifically for the treatment of cGVHD.
The investigators conducted a phase IIa study to evaluate the effectiveness and safety of Belumosudil in patients with cGVHD.
Yimaitong organizes the main content as follows for the reference of readers.
Research Method The study is a dose exploration, open-label, phase IIa study conducted at seven centers in the United States.
CGVHD occurred after previous 1-3 line systemic treatment (including allogeneic bone marrow transplantation or allogeneic hematopoietic stem cell transplantation [allo-HSCT]) and received glucocorticoid therapy (with or without calcineurin inhibitor) And/or at the same time in vitro optical separation and replacement) patients aged ≥18 years old are eligible for enrollment.
The patients were divided into three cohorts: cohort 1 received 200 mg Belumosudil once a day; cohort 2 received 200 mg Belumosudil twice a day; cohort 3 received 200 mg Belumosudil once a day.
Belumosudil is administered orally in a cycle of 28 days until the disease progresses or intolerable toxicity occurs.
The primary research endpoint is the overall response rate (ORR), and the secondary research endpoints include duration of response (DOR), Lee Symptom Scale (LSS) score, reduction of glucocorticoids, time to next treatment (TTNT), and no failure Lifetime (FFS) and overall survival (OS), etc.
Study Results 01 Patient Characteristics During the period from September 2016 to March 2018, a total of 54 patients were included in the study: cohort 1 had 17 patients, cohort 2 had 16 patients, and cohort 3 had 21 patients.
The data analysis ended on February 19, 2020.
The median follow-up time of cohort 1, cohort 2, and cohort 3 were 36 months, 32 months, and 24 months, respectively.
The overall median follow-up time was 29 months (range: 1-39 months).
The median age of patients at baseline was 52 years (range 20-75 years).
According to the investigator's assessment, 78% of patients have severe cGVHD, and 50% of patients involve ≥4 organs.
The median baseline glucocorticoid doses (mg/kg/d prednisone equivalent) for cohort 1, cohort 2, and cohort 3 were 0.
22, 0.
19, and 0.
17, respectively.
Before enrollment, 73% of patients had no effect on the last systemic treatment.
The median treatment time of cohort 1, cohort 2 and cohort 3 were 8.
5 months (2-39 months), 7.
5 months (1-35 months), and 9 months (1-29 months), respectively.
8% of patients received belumosudil for >18 months.
02 ORR for efficacy: Among the 54 patients studied, the ORR (95% CI) was 65% (51%-77%).
The ORR (95% CI) of each group was similar: cohort 1 was 65% (38%-86%), cohort 2 was 69% (41%-89%), and cohort 3 was 62% (38%-82%).
Patients in the key subgroups achieved remission.
The ORR of patients with severe cGVHD was 60% (25/42), and the ORR of patients who had received ≥2 line system therapy was 66% (23/35).
The ORR of invalid patients was 63% (22/35), and the ORR of patients involving more than 4 organs was 70% (19/27).
TTNT: The median TTNT is 14 months.
Subsequent systemic cGVHD treatments include tacrolimus, sirolimus, ibrutinib, rucotinib, in vitro optical separation and replacement, and mycophenolate mofetil.
FFS and OS: At 6, 12 and 24 months, the FFS rate (95% CI) was 76% (62%-85%), 47% (33%-60%) and 33% (21%-46 %).
FFS is defined as the time from the first dose of belumosudil to the failure event.
Reasons for failure included the initiation of new systemic therapy (n=27), recurrence of underlying disease (n=7), and death (n=2).
At 12 months and 24 months, the OS rate (95% CI) was 91% (79%-96%) and 82% (69%-90%), respectively.
Quality of life assessment: A clinically significant improvement in the LSS score is defined as a decrease of ≥7 points in the total LSS score of 50% of patients during treatment with belumosudil.
In continuous evaluation, 35% of patients (37% of responders and 32% of non-responders) reported a clinically significant improvement in LSS scores.
Glucocorticoid dose: During the treatment with belumosudil, 67% of patients reduced the glucocorticoid dose, and 19% of the patients completely stopped the glucocorticoid.
The average glucocorticoid dose was reduced by 45%.
The median time to stop glucocorticoids was 29 weeks (range: 8-77 weeks).
03 Adverse events (AE) with a safety rate of ≥20% are upper respiratory tract infection (46%), diarrhea (33%), fatigue (33%), nausea (33%), abnormal liver function (33%), breathing Difficulty (30%), headache (24%), peripheral edema (24%), cough (22%) and hypertension (20%).
Serious AEs occurred in 43% of patients, and the serious AEs reported in >1 patients were dyspnea (7%), lung infection (6%), hypoxia (4%) and flu-like illness (4%) .
61% of patients had grade ≥3 AEs, the most common being dyspnea (13%), abnormal liver function (7%), hyperglycemia (7%), and hypoxia (7%).
Two patients (4%) had a cytopenia of grade ≥3.
No cases of cytomegalovirus (CMV) infection or reactivation have been reported.
Belumosudil was discontinued in 3 patients due to potential drug-related adverse events (cohort 1: diarrhea and headache; cohort 3: fatigue).
Four patients in cohort 3 died in the study due to recurrence of leukemia, pneumonia, cardiac arrest, and cGVHD progression, and no deaths were due to Belumosudil.
Research conclusions Belumosudil has a higher ORR and OS rate in the treatment of cGVHD patients, can improve the quality of life, reduce the dose of glucocorticoid, and has good safety.
The data of the study suggests that Belumosudil may be an effective therapy for patients with refractory cGVHD.
Reference source: Madan Jagasia, Aleksandr Lazaryan, Carlos R.
Bachier, et al.
ROCK2 Inhibition With Belumosudil (KD025) for the Treatment of Chronic Graft-Versus-Host Disease.
Published online April 20, 2021.
Journal of Clinical Oncology DOI: 10.
1200 /JCO.
20.
02754.
Stamp "read the original text", we make progress together
