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SALT LAKE CITY – KD025, an orally available Rho-associated coiled-coil kinase 2–selective inhibitor, is demonstrating encouraging activity and safety in patients with steroid-dependent or refractory chronic graft-versus-host disease (cGVHD) in a phase 2a clinical trial.
Initial results from the ongoing open-label trial known as KD025-208 showed that 11 of 17 patients (65%) and 11 of 16 patients (69%) enrolled in 200-mg daily and 200-mg twice-daily dose cohorts, respectively, had a clinical response with no reported treatment-related serious adverse events at any evaluation time point, Aleksandr Lazaryan, MD, PhD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
The median duration of treatment in the 200-mg daily group (cohort 1) was 37 weeks, and in the 200-mg twice-daily group (cohort 2) was 28 weeks. At last follow-up, eight patients remained active in each cohort, and these patients had a median treatment duration of 53 and 38 weeks, respectively, he said.
In cohort 1, four patients went off the study because of cGVHD progression, and five withdrew, including two who experienced recurrence of their underlying hematologic malignancy. In cohort 2, 7 of the 16 patients experienced progression of cGVHD, he noted.
Patients in cohorts 1 and 2 had a median age of 52 years and had received at least 2 months of steroid treatment and no more than 3 prior lines of therapy. They were comparable with respect to baseline characteristics, including median time to and duration of GVHD, time from diagnosis to enrollment, median prednisone dose, and median number of prior therapies. They had involvement of various – and often multiple – organ systems: 58% had four or more systems affected at the time of enrollment, and 21% had five or more systems affected.
“This, in a way, reflects a real-life mix of the cGVHD population of patients, with some of those patients having advanced cGVHD,” said Dr. Lazaryan.
Responses were observed across all affected organ systems, with complete responses documented in the upper and lower gastrointestinal tracts. About 75% of patients in cohort 1 who had multiple organ systems involved at enrollment demonstrated responses in at least four organ systems.
Furthermore, the responses were rapid: 68% of responses occurred in the first 8 weeks of treatment and appeared durable, Dr. Lazaryan said, noting that 7 of the 17 patients in cohort 1 had sustained responses for more than 20 weeks, and 3 patients had sustained responses for more than 32 weeks.
“The durability data continue to mature in this trial,” he added.
The adverse events that occurred were consistent with what would be expected for the cGVHD patient population treated with steroids, he said, reporting that no patients discontinued treatment because of infection, no opportunistic or fungal infections have been reported to date, and no treatment-related serious adverse events were reported.
Steroid dose reductions were experienced by 40% and 26% of patients in cohorts 1 and 2, respectively. The dose reductions were achieved in both KD025 responders and nonresponders, he noted.
Overall, four patients (12%) were able to discontinue steroids, and 80% in both cohorts experienced reductions in background tacrolimus.
In addition, up to 65% of patients in cohort 1 achieved a greater than seven point reduction on the Lee cGVHD Symptom Scale, with both responders and nonresponders experiencing improvement on this endpoint.
Chronic GVHD remains a leading cause of post-transplant morbidity and mortality. KD025, which is currently in phase 2 development for inflammatory fibrotic disease, has been shown in preclinical models to down-regulate T helper 17 cells and T follicular helper cells while up-regulating anti-inflammatory regulatory T cells, thereby potentially correcting the immunological imbalance seen in cGVHD, Dr. Lazaryan said.
Analysis is ongoing in this study, including in a third cohort of patients treated with 200 mg of KD025 four times daily, which recently completed accrual. An expansion cohort, at a dose yet to be determined, will include approximately 40 patients, he noted.
The trial is sponsored by Kadmon. Dr. Lazaryan reported advisory board membership and consultancy for GLyPharma Therapeutic.
sworcester@frontlinemedcom.com
SOURCE: Lazaryan A et al. 2018 BMT Tandem Meetings, Abstract 38.
SALT LAKE CITY – KD025, an orally available Rho-associated coiled-coil kinase 2–selective inhibitor, is demonstrating encouraging activity and safety in patients with steroid-dependent or refractory chronic graft-versus-host disease (cGVHD) in a phase 2a clinical trial.
Initial results from the ongoing open-label trial known as KD025-208 showed that 11 of 17 patients (65%) and 11 of 16 patients (69%) enrolled in 200-mg daily and 200-mg twice-daily dose cohorts, respectively, had a clinical response with no reported treatment-related serious adverse events at any evaluation time point, Aleksandr Lazaryan, MD, PhD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
The median duration of treatment in the 200-mg daily group (cohort 1) was 37 weeks, and in the 200-mg twice-daily group (cohort 2) was 28 weeks. At last follow-up, eight patients remained active in each cohort, and these patients had a median treatment duration of 53 and 38 weeks, respectively, he said.
In cohort 1, four patients went off the study because of cGVHD progression, and five withdrew, including two who experienced recurrence of their underlying hematologic malignancy. In cohort 2, 7 of the 16 patients experienced progression of cGVHD, he noted.
Patients in cohorts 1 and 2 had a median age of 52 years and had received at least 2 months of steroid treatment and no more than 3 prior lines of therapy. They were comparable with respect to baseline characteristics, including median time to and duration of GVHD, time from diagnosis to enrollment, median prednisone dose, and median number of prior therapies. They had involvement of various – and often multiple – organ systems: 58% had four or more systems affected at the time of enrollment, and 21% had five or more systems affected.
“This, in a way, reflects a real-life mix of the cGVHD population of patients, with some of those patients having advanced cGVHD,” said Dr. Lazaryan.
Responses were observed across all affected organ systems, with complete responses documented in the upper and lower gastrointestinal tracts. About 75% of patients in cohort 1 who had multiple organ systems involved at enrollment demonstrated responses in at least four organ systems.
Furthermore, the responses were rapid: 68% of responses occurred in the first 8 weeks of treatment and appeared durable, Dr. Lazaryan said, noting that 7 of the 17 patients in cohort 1 had sustained responses for more than 20 weeks, and 3 patients had sustained responses for more than 32 weeks.
“The durability data continue to mature in this trial,” he added.
The adverse events that occurred were consistent with what would be expected for the cGVHD patient population treated with steroids, he said, reporting that no patients discontinued treatment because of infection, no opportunistic or fungal infections have been reported to date, and no treatment-related serious adverse events were reported.
Steroid dose reductions were experienced by 40% and 26% of patients in cohorts 1 and 2, respectively. The dose reductions were achieved in both KD025 responders and nonresponders, he noted.
Overall, four patients (12%) were able to discontinue steroids, and 80% in both cohorts experienced reductions in background tacrolimus.
In addition, up to 65% of patients in cohort 1 achieved a greater than seven point reduction on the Lee cGVHD Symptom Scale, with both responders and nonresponders experiencing improvement on this endpoint.
Chronic GVHD remains a leading cause of post-transplant morbidity and mortality. KD025, which is currently in phase 2 development for inflammatory fibrotic disease, has been shown in preclinical models to down-regulate T helper 17 cells and T follicular helper cells while up-regulating anti-inflammatory regulatory T cells, thereby potentially correcting the immunological imbalance seen in cGVHD, Dr. Lazaryan said.
Analysis is ongoing in this study, including in a third cohort of patients treated with 200 mg of KD025 four times daily, which recently completed accrual. An expansion cohort, at a dose yet to be determined, will include approximately 40 patients, he noted.
The trial is sponsored by Kadmon. Dr. Lazaryan reported advisory board membership and consultancy for GLyPharma Therapeutic.
sworcester@frontlinemedcom.com
SOURCE: Lazaryan A et al. 2018 BMT Tandem Meetings, Abstract 38.
SALT LAKE CITY – KD025, an orally available Rho-associated coiled-coil kinase 2–selective inhibitor, is demonstrating encouraging activity and safety in patients with steroid-dependent or refractory chronic graft-versus-host disease (cGVHD) in a phase 2a clinical trial.
Initial results from the ongoing open-label trial known as KD025-208 showed that 11 of 17 patients (65%) and 11 of 16 patients (69%) enrolled in 200-mg daily and 200-mg twice-daily dose cohorts, respectively, had a clinical response with no reported treatment-related serious adverse events at any evaluation time point, Aleksandr Lazaryan, MD, PhD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
The median duration of treatment in the 200-mg daily group (cohort 1) was 37 weeks, and in the 200-mg twice-daily group (cohort 2) was 28 weeks. At last follow-up, eight patients remained active in each cohort, and these patients had a median treatment duration of 53 and 38 weeks, respectively, he said.
In cohort 1, four patients went off the study because of cGVHD progression, and five withdrew, including two who experienced recurrence of their underlying hematologic malignancy. In cohort 2, 7 of the 16 patients experienced progression of cGVHD, he noted.
Patients in cohorts 1 and 2 had a median age of 52 years and had received at least 2 months of steroid treatment and no more than 3 prior lines of therapy. They were comparable with respect to baseline characteristics, including median time to and duration of GVHD, time from diagnosis to enrollment, median prednisone dose, and median number of prior therapies. They had involvement of various – and often multiple – organ systems: 58% had four or more systems affected at the time of enrollment, and 21% had five or more systems affected.
“This, in a way, reflects a real-life mix of the cGVHD population of patients, with some of those patients having advanced cGVHD,” said Dr. Lazaryan.
Responses were observed across all affected organ systems, with complete responses documented in the upper and lower gastrointestinal tracts. About 75% of patients in cohort 1 who had multiple organ systems involved at enrollment demonstrated responses in at least four organ systems.
Furthermore, the responses were rapid: 68% of responses occurred in the first 8 weeks of treatment and appeared durable, Dr. Lazaryan said, noting that 7 of the 17 patients in cohort 1 had sustained responses for more than 20 weeks, and 3 patients had sustained responses for more than 32 weeks.
“The durability data continue to mature in this trial,” he added.
The adverse events that occurred were consistent with what would be expected for the cGVHD patient population treated with steroids, he said, reporting that no patients discontinued treatment because of infection, no opportunistic or fungal infections have been reported to date, and no treatment-related serious adverse events were reported.
Steroid dose reductions were experienced by 40% and 26% of patients in cohorts 1 and 2, respectively. The dose reductions were achieved in both KD025 responders and nonresponders, he noted.
Overall, four patients (12%) were able to discontinue steroids, and 80% in both cohorts experienced reductions in background tacrolimus.
In addition, up to 65% of patients in cohort 1 achieved a greater than seven point reduction on the Lee cGVHD Symptom Scale, with both responders and nonresponders experiencing improvement on this endpoint.
Chronic GVHD remains a leading cause of post-transplant morbidity and mortality. KD025, which is currently in phase 2 development for inflammatory fibrotic disease, has been shown in preclinical models to down-regulate T helper 17 cells and T follicular helper cells while up-regulating anti-inflammatory regulatory T cells, thereby potentially correcting the immunological imbalance seen in cGVHD, Dr. Lazaryan said.
Analysis is ongoing in this study, including in a third cohort of patients treated with 200 mg of KD025 four times daily, which recently completed accrual. An expansion cohort, at a dose yet to be determined, will include approximately 40 patients, he noted.
The trial is sponsored by Kadmon. Dr. Lazaryan reported advisory board membership and consultancy for GLyPharma Therapeutic.
sworcester@frontlinemedcom.com
SOURCE: Lazaryan A et al. 2018 BMT Tandem Meetings, Abstract 38.
REPORTING FROM THE 2018 BMT TANDEM MEETINGS
Key clinical point:
Major finding: Clinical response rates in cohorts 1 and 2 were 65% and 69%, respectively.
Study details: Preliminary findings in 33 patients from a phase 2a trial.
Disclosures: The trial is sponsored by Kadmon. Dr. Lazaryan reported advisory board membership and consultancy for GLyPharma Therapeutic.
Source: Lazaryan A et al. 2018 BMT Tandem Meetings, Abstract 38.