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Novel drug shows early efficacy for steroid-dependent chronic GVHD

Aleksandr Lazaryan

SALT LAKE CITY — Treatment with the novel drug KD025 appeared well tolerated and showed encouraging clinical responses for patients with steroid-dependent chronic graft-versus-host disease, according to results of a phase 2a open-label trial presented at the BMT Tandem Meetings.

Chronic GVHD remains a major complication of allogeneic hematopoietic stem cell transplantation, with a substantial unmet medical need for patients who are refractory to the first-line therapy of chronic GVHD with corticosteroids,” Aleksandr Lazaryan, MD, MPH, PhD, assistant professor of medicine in the division of hematology, oncology and transplantation at University of Minnesota, told HemOnc Today. “Patients with chronic GVHD receive prolonged immunosuppression for an average of 2 to 3 years from the initial diagnosis, and approximately 10% of patients who survive beyond 7 years after transplant still require continued immunosuppressive therapy.”

B- and T-cells contribute to pathogenesis of chronic GVHD, which is recognized as a TH17/Tc17- and T-follicular helper cell-mediated disease, Lazaryan added. Concurrent deficiency of T-regulatory cells also contributes to profound immune dysregulation observed in chronic GVHD.

“Overproduction of proinflammatory cytokines, such as IL-17 by the Th17/Tc17 lineage and IL-21 by T-follicular helper cells, has been linked to aberrant activation of STAT3 pathway,” he added. “Rho-associated coiled-coil kinase 2 (ROCK2) is a protein kinase that is dysregulated in many chronic diseases, including chronic GVHD. In preclinical studies, ROCK2 activation was found to be associated with upregulation of STAT3 phosphorylation and downstream overproduction of IL-17 and IL-21, and downregulation of a tolerogenic STAT5 pathway involving T-regulatory cells.”

KD025 (Kadmon Holdings) — an orally available ROCK2-selective inhibitor — downregulates TH17 and T-follicular helper cells while upregulating anti-inflammatory T-regulatory cells, which could correct the immunologic imbalance in chronic GVHD.

In preclinical models, KD025 reduced skin pathology scores, epidermal hyperplasia and keratosis. Also, it reduced pathology scores in the lung, liver and spleen.

Based on these promising preclinical data, Lazaryan and colleagues evaluated data from 17 patients with steroid-dependent or -refractory chronic GVHD who received 200 mg KD025 daily in cohort 1, and 16 patients who received 200 mg KD025 twice daily in cohort 2. Enrollment in a 400-mg dose daily cohort has finished accrual, and enrollment in an expansion cohort is planned.

Patients in cohorts 1 and 2 appeared comparable in terms of age (median, 52 years), time of transplant to chronic GVHD diagnosis (median, 7.9 months), prior lines of chronic GVHD therapy (median, 3) and pre-enrollment prednisone dose (median, 0.2 mg/kg daily). Patients had chronic GVHD for a median of 18.8 months prior to KD025 treatment.

Fifty-eight percent of patients had four or more organ systems affected, and 21% had five or more affected organ systems. Chronic GVHD manifestations appeared across multiple organ systems, including skin (76%), eyes (76%), mouth (73%), joint and facia (70%), lungs (30%), gastrointestinal tract (36%) and liver (3%).

The percentage of patients who achieved an overall response served as the primary activity endpoint. Secondary endpoints included changes in corticosteroids and calcineurin inhibitor dose, as well as changes in chronic GVHD severity using the Physician-Reported Global cGVHD Activity Assessment.

Median treatment duration for patients in cohort 1 was 37 weeks, and eight patients remained active at the time of last follow-up for a median treatment duration of 53 weeks. Four patients discontinued treatment due to chronic GVHD progression, and five patients withdrew from the trial, two of whom had recurrence of their underlying hematologic malignancy.

Median treatment duration in cohort 2 was 28 weeks. Eight patients remained active in this cohort, for a median treatment duration of 38 weeks. Seven of 16 patients experienced progression of chronic GVHD.

Researchers reported an ORR of 65% in cohort 1 and 69% in cohort 2. Sixty-eight percent of responses occurred at the first assessment at 8 weeks.

Responses also appeared durable. Among 17 patients in cohort 1, seven (41%) achieved a sustained response for at least 20 weeks and three (18%) had a response for at least 32 weeks.

Responses occurred across all affected organ systems, with complete responses observed in the upper and lower GI tract, esophagus, mouth, joints/fascia, skin, eyes and liver.

Seventy-five percent of patients with four or more organs involved in cohort 1 and 33% in cohort 2 showed responses in four or more organs.

“So, if these patients did respond, their patients occurred in parallel in multiple organ systems,” Lazaryan said during his presentation.

Median corticosteroid dose reduced 40% in cohort 1 and 26% in cohort 2 while on the study. Further, 18% in cohort 1 and 6% in cohort 2 completely discontinued steroids.

Five of six patients receiving tacrolimus had a dose reduction in cohort 1, and six of 16 did so in cohort 2.

Researchers observed a reduction in symptoms — measured by the Lee cGVHD Symptom Scale — among 65% of patients in cohort 1 and 28% from cohort 2. Improvement in symptoms occurred among both responders (64%) and nonresponders (27%).

Researchers reported no treatment-related serious adverse events, and all adverse events were consistent with those expected for patients receiving corticosteroids for chronic GVHD.

Grade 3 or worse adverse events occurred among 12% of cohort 1 and 25% of cohort 2. Commonly reported adverse events included liver function test abnormalities, anemia, upper respiratory tract infections, diarrhea and nausea. One patient withdrew from the trial due to persistent headache. However, researchers reported no infection and no opportunistic or invasive fungal infections.

“Approximately two-thirds of patients with steroid-refractory chronic GVHD achieved a clinical response with KD025, which was overall well tolerated based on the data from the first two cohorts,” Lazaryan told HemOnc Today. “The third cohort of patients (n = 16) with KD025 dosed at 400 mg daily has recently completed accrual with results currently awaited. The optimal dose of KD025 for future expansion cohort (n = 40) will be determined based on completed analysis of all three cohorts.” – by Alexandra Todak

 

Reference:

Lazaryan A, et al. Abstract 38. Presented at: BMT Tandem Meetings; Feb. 21-25, 2018; Salt Lake City.

 

Disclosures: HemOnc Today could not confirm the researchers’ relevant financial disclosures at the time of reporting.

 

Aleksandr Lazaryan

SALT LAKE CITY — Treatment with the novel drug KD025 appeared well tolerated and showed encouraging clinical responses for patients with steroid-dependent chronic graft-versus-host disease, according to results of a phase 2a open-label trial presented at the BMT Tandem Meetings.

Chronic GVHD remains a major complication of allogeneic hematopoietic stem cell transplantation, with a substantial unmet medical need for patients who are refractory to the first-line therapy of chronic GVHD with corticosteroids,” Aleksandr Lazaryan, MD, MPH, PhD, assistant professor of medicine in the division of hematology, oncology and transplantation at University of Minnesota, told HemOnc Today. “Patients with chronic GVHD receive prolonged immunosuppression for an average of 2 to 3 years from the initial diagnosis, and approximately 10% of patients who survive beyond 7 years after transplant still require continued immunosuppressive therapy.”

B- and T-cells contribute to pathogenesis of chronic GVHD, which is recognized as a TH17/Tc17- and T-follicular helper cell-mediated disease, Lazaryan added. Concurrent deficiency of T-regulatory cells also contributes to profound immune dysregulation observed in chronic GVHD.

“Overproduction of proinflammatory cytokines, such as IL-17 by the Th17/Tc17 lineage and IL-21 by T-follicular helper cells, has been linked to aberrant activation of STAT3 pathway,” he added. “Rho-associated coiled-coil kinase 2 (ROCK2) is a protein kinase that is dysregulated in many chronic diseases, including chronic GVHD. In preclinical studies, ROCK2 activation was found to be associated with upregulation of STAT3 phosphorylation and downstream overproduction of IL-17 and IL-21, and downregulation of a tolerogenic STAT5 pathway involving T-regulatory cells.”

KD025 (Kadmon Holdings) — an orally available ROCK2-selective inhibitor — downregulates TH17 and T-follicular helper cells while upregulating anti-inflammatory T-regulatory cells, which could correct the immunologic imbalance in chronic GVHD.

In preclinical models, KD025 reduced skin pathology scores, epidermal hyperplasia and keratosis. Also, it reduced pathology scores in the lung, liver and spleen.

Based on these promising preclinical data, Lazaryan and colleagues evaluated data from 17 patients with steroid-dependent or -refractory chronic GVHD who received 200 mg KD025 daily in cohort 1, and 16 patients who received 200 mg KD025 twice daily in cohort 2. Enrollment in a 400-mg dose daily cohort has finished accrual, and enrollment in an expansion cohort is planned.

Patients in cohorts 1 and 2 appeared comparable in terms of age (median, 52 years), time of transplant to chronic GVHD diagnosis (median, 7.9 months), prior lines of chronic GVHD therapy (median, 3) and pre-enrollment prednisone dose (median, 0.2 mg/kg daily). Patients had chronic GVHD for a median of 18.8 months prior to KD025 treatment.

Fifty-eight percent of patients had four or more organ systems affected, and 21% had five or more affected organ systems. Chronic GVHD manifestations appeared across multiple organ systems, including skin (76%), eyes (76%), mouth (73%), joint and facia (70%), lungs (30%), gastrointestinal tract (36%) and liver (3%).

The percentage of patients who achieved an overall response served as the primary activity endpoint. Secondary endpoints included changes in corticosteroids and calcineurin inhibitor dose, as well as changes in chronic GVHD severity using the Physician-Reported Global cGVHD Activity Assessment.

Median treatment duration for patients in cohort 1 was 37 weeks, and eight patients remained active at the time of last follow-up for a median treatment duration of 53 weeks. Four patients discontinued treatment due to chronic GVHD progression, and five patients withdrew from the trial, two of whom had recurrence of their underlying hematologic malignancy.

Median treatment duration in cohort 2 was 28 weeks. Eight patients remained active in this cohort, for a median treatment duration of 38 weeks. Seven of 16 patients experienced progression of chronic GVHD.

Researchers reported an ORR of 65% in cohort 1 and 69% in cohort 2. Sixty-eight percent of responses occurred at the first assessment at 8 weeks.

Responses also appeared durable. Among 17 patients in cohort 1, seven (41%) achieved a sustained response for at least 20 weeks and three (18%) had a response for at least 32 weeks.

Responses occurred across all affected organ systems, with complete responses observed in the upper and lower GI tract, esophagus, mouth, joints/fascia, skin, eyes and liver.

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Seventy-five percent of patients with four or more organs involved in cohort 1 and 33% in cohort 2 showed responses in four or more organs.

“So, if these patients did respond, their patients occurred in parallel in multiple organ systems,” Lazaryan said during his presentation.

Median corticosteroid dose reduced 40% in cohort 1 and 26% in cohort 2 while on the study. Further, 18% in cohort 1 and 6% in cohort 2 completely discontinued steroids.

Five of six patients receiving tacrolimus had a dose reduction in cohort 1, and six of 16 did so in cohort 2.

Researchers observed a reduction in symptoms — measured by the Lee cGVHD Symptom Scale — among 65% of patients in cohort 1 and 28% from cohort 2. Improvement in symptoms occurred among both responders (64%) and nonresponders (27%).

Researchers reported no treatment-related serious adverse events, and all adverse events were consistent with those expected for patients receiving corticosteroids for chronic GVHD.

Grade 3 or worse adverse events occurred among 12% of cohort 1 and 25% of cohort 2. Commonly reported adverse events included liver function test abnormalities, anemia, upper respiratory tract infections, diarrhea and nausea. One patient withdrew from the trial due to persistent headache. However, researchers reported no infection and no opportunistic or invasive fungal infections.

“Approximately two-thirds of patients with steroid-refractory chronic GVHD achieved a clinical response with KD025, which was overall well tolerated based on the data from the first two cohorts,” Lazaryan told HemOnc Today. “The third cohort of patients (n = 16) with KD025 dosed at 400 mg daily has recently completed accrual with results currently awaited. The optimal dose of KD025 for future expansion cohort (n = 40) will be determined based on completed analysis of all three cohorts.” – by Alexandra Todak

 

Reference:

Lazaryan A, et al. Abstract 38. Presented at: BMT Tandem Meetings; Feb. 21-25, 2018; Salt Lake City.

 

Disclosures: HemOnc Today could not confirm the researchers’ relevant financial disclosures at the time of reporting.

 

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