PHASE 2A STUDY OF ALXN1007, A NOVEL C5A INHIBITOR, IN SUBJECTS WITH NEWLY DIAGNOSED ACUTE GRAFT-VERSUS-HOST DISEASE (GVHD) INVOLVING THE LOWER GASTROINTESTINAL TRACT
(Abstract release date: 05/19/16)
EHA Library. Alousi A. 06/09/16; 135380; LB2269
Disclosure(s): Dr. Alousi has received research funding from Alexion Pharmaceuticals, Inc.
Dr. Amin Majid Alousi
Contributions
Contributions
Abstract
Abstract: LB2269
Type: Eposter Presentation
Background
Murine models implicate complement in multiple steps of the acute GVHD cascade. Transplantation of donor T cells deficient in C3a and C5a as well as pharmacologic exposure to C5a receptor blockade have all been shown to reduce GVHD lethality in mice. In humans, complement activation has been correlated with gastrointestinal (GI) GVHD.
Aims
For this reason, we performed a multicenter Phase 2a trial (NCT02245412) of ALXN1007, a recombinant humanized monoclonal C5a antibody, in patients with newly diagnosed acute GVHD of the lower GI tract.
Methods
Between 14 Nov 2014 and 13 Nov 2015, a total of 15 patients with biopsy-confirmed acute GVHD of the lower GI tract consented, enrolled, and received weekly intravenous administration of 10 mg/kg ALXN1007, in combination with methylprednisolone at an initial dose of 2 mg/kg, through day 56. The primary objective was to assess the day 28 overall acute GVHD response rate along with safety and pharmacokinetics/pharmacodynamics (PK/PD).
Results
Median age was 60 years (range, 25-69); 60% were male, and acute myeloid leukemia was the most common diagnosis (33%). At enrollment, lower GI stages 1, 2, and 3 were present in 7, 2, and 6 patients, respectively. Day 28 overall acute GVHD response rate was 77% (2 patients were nonevaluable due to leukemia relapse at day 18 or early withdrawal). Complete GI GVHD response rates at days 28 and 56 were 69% and 77%, respectively. Day 56 overall acute GVHD response rate, day 180 nonrelapse mortality, and overall survival were 77%, 12.5%, and 69.2%, respectively. PK/PD analyses suggest that the dose may have been suboptimal with 10/13 patients achieving <90% inhibition of C5a. Day 28 response rate was higher in those achieving 90% inhibition (3/3) versus in those with less C5a inhibition (6/10). The drug was well tolerated with just 1 grade 2 infusion-related reaction and no grade 3 or higher adverse events attributable to the study drug.
Conclusion
The efficacy and safety data suggest that ALXN1007 is a promising therapy for patients with acute GVHD involving the lower GI tract. The level of C5a inhibition might be an important biologic parameter to predict clinical response. PK/PD analyses suggested higher doses and frequency may be needed to optimize C5a inhibition and maximize clinical response. For this reason, the trial has been amended to test 20 mg/kg weekly and twice-weekly dosing.
Session topic: E-poster
Keyword(s): Complement, Gastrointestinal GVHD, Graft-versus-host disease (GVHD), Inhibitor
Type: Eposter Presentation
Background
Murine models implicate complement in multiple steps of the acute GVHD cascade. Transplantation of donor T cells deficient in C3a and C5a as well as pharmacologic exposure to C5a receptor blockade have all been shown to reduce GVHD lethality in mice. In humans, complement activation has been correlated with gastrointestinal (GI) GVHD.
Aims
For this reason, we performed a multicenter Phase 2a trial (NCT02245412) of ALXN1007, a recombinant humanized monoclonal C5a antibody, in patients with newly diagnosed acute GVHD of the lower GI tract.
Methods
Between 14 Nov 2014 and 13 Nov 2015, a total of 15 patients with biopsy-confirmed acute GVHD of the lower GI tract consented, enrolled, and received weekly intravenous administration of 10 mg/kg ALXN1007, in combination with methylprednisolone at an initial dose of 2 mg/kg, through day 56. The primary objective was to assess the day 28 overall acute GVHD response rate along with safety and pharmacokinetics/pharmacodynamics (PK/PD).
Results
Median age was 60 years (range, 25-69); 60% were male, and acute myeloid leukemia was the most common diagnosis (33%). At enrollment, lower GI stages 1, 2, and 3 were present in 7, 2, and 6 patients, respectively. Day 28 overall acute GVHD response rate was 77% (2 patients were nonevaluable due to leukemia relapse at day 18 or early withdrawal). Complete GI GVHD response rates at days 28 and 56 were 69% and 77%, respectively. Day 56 overall acute GVHD response rate, day 180 nonrelapse mortality, and overall survival were 77%, 12.5%, and 69.2%, respectively. PK/PD analyses suggest that the dose may have been suboptimal with 10/13 patients achieving <90% inhibition of C5a. Day 28 response rate was higher in those achieving 90% inhibition (3/3) versus in those with less C5a inhibition (6/10). The drug was well tolerated with just 1 grade 2 infusion-related reaction and no grade 3 or higher adverse events attributable to the study drug.
Conclusion
The efficacy and safety data suggest that ALXN1007 is a promising therapy for patients with acute GVHD involving the lower GI tract. The level of C5a inhibition might be an important biologic parameter to predict clinical response. PK/PD analyses suggested higher doses and frequency may be needed to optimize C5a inhibition and maximize clinical response. For this reason, the trial has been amended to test 20 mg/kg weekly and twice-weekly dosing.
Session topic: E-poster
Keyword(s): Complement, Gastrointestinal GVHD, Graft-versus-host disease (GVHD), Inhibitor
Abstract: LB2269
Type: Eposter Presentation
Background
Murine models implicate complement in multiple steps of the acute GVHD cascade. Transplantation of donor T cells deficient in C3a and C5a as well as pharmacologic exposure to C5a receptor blockade have all been shown to reduce GVHD lethality in mice. In humans, complement activation has been correlated with gastrointestinal (GI) GVHD.
Aims
For this reason, we performed a multicenter Phase 2a trial (NCT02245412) of ALXN1007, a recombinant humanized monoclonal C5a antibody, in patients with newly diagnosed acute GVHD of the lower GI tract.
Methods
Between 14 Nov 2014 and 13 Nov 2015, a total of 15 patients with biopsy-confirmed acute GVHD of the lower GI tract consented, enrolled, and received weekly intravenous administration of 10 mg/kg ALXN1007, in combination with methylprednisolone at an initial dose of 2 mg/kg, through day 56. The primary objective was to assess the day 28 overall acute GVHD response rate along with safety and pharmacokinetics/pharmacodynamics (PK/PD).
Results
Median age was 60 years (range, 25-69); 60% were male, and acute myeloid leukemia was the most common diagnosis (33%). At enrollment, lower GI stages 1, 2, and 3 were present in 7, 2, and 6 patients, respectively. Day 28 overall acute GVHD response rate was 77% (2 patients were nonevaluable due to leukemia relapse at day 18 or early withdrawal). Complete GI GVHD response rates at days 28 and 56 were 69% and 77%, respectively. Day 56 overall acute GVHD response rate, day 180 nonrelapse mortality, and overall survival were 77%, 12.5%, and 69.2%, respectively. PK/PD analyses suggest that the dose may have been suboptimal with 10/13 patients achieving <90% inhibition of C5a. Day 28 response rate was higher in those achieving 90% inhibition (3/3) versus in those with less C5a inhibition (6/10). The drug was well tolerated with just 1 grade 2 infusion-related reaction and no grade 3 or higher adverse events attributable to the study drug.
Conclusion
The efficacy and safety data suggest that ALXN1007 is a promising therapy for patients with acute GVHD involving the lower GI tract. The level of C5a inhibition might be an important biologic parameter to predict clinical response. PK/PD analyses suggested higher doses and frequency may be needed to optimize C5a inhibition and maximize clinical response. For this reason, the trial has been amended to test 20 mg/kg weekly and twice-weekly dosing.
Session topic: E-poster
Keyword(s): Complement, Gastrointestinal GVHD, Graft-versus-host disease (GVHD), Inhibitor
Type: Eposter Presentation
Background
Murine models implicate complement in multiple steps of the acute GVHD cascade. Transplantation of donor T cells deficient in C3a and C5a as well as pharmacologic exposure to C5a receptor blockade have all been shown to reduce GVHD lethality in mice. In humans, complement activation has been correlated with gastrointestinal (GI) GVHD.
Aims
For this reason, we performed a multicenter Phase 2a trial (NCT02245412) of ALXN1007, a recombinant humanized monoclonal C5a antibody, in patients with newly diagnosed acute GVHD of the lower GI tract.
Methods
Between 14 Nov 2014 and 13 Nov 2015, a total of 15 patients with biopsy-confirmed acute GVHD of the lower GI tract consented, enrolled, and received weekly intravenous administration of 10 mg/kg ALXN1007, in combination with methylprednisolone at an initial dose of 2 mg/kg, through day 56. The primary objective was to assess the day 28 overall acute GVHD response rate along with safety and pharmacokinetics/pharmacodynamics (PK/PD).
Results
Median age was 60 years (range, 25-69); 60% were male, and acute myeloid leukemia was the most common diagnosis (33%). At enrollment, lower GI stages 1, 2, and 3 were present in 7, 2, and 6 patients, respectively. Day 28 overall acute GVHD response rate was 77% (2 patients were nonevaluable due to leukemia relapse at day 18 or early withdrawal). Complete GI GVHD response rates at days 28 and 56 were 69% and 77%, respectively. Day 56 overall acute GVHD response rate, day 180 nonrelapse mortality, and overall survival were 77%, 12.5%, and 69.2%, respectively. PK/PD analyses suggest that the dose may have been suboptimal with 10/13 patients achieving <90% inhibition of C5a. Day 28 response rate was higher in those achieving 90% inhibition (3/3) versus in those with less C5a inhibition (6/10). The drug was well tolerated with just 1 grade 2 infusion-related reaction and no grade 3 or higher adverse events attributable to the study drug.
Conclusion
The efficacy and safety data suggest that ALXN1007 is a promising therapy for patients with acute GVHD involving the lower GI tract. The level of C5a inhibition might be an important biologic parameter to predict clinical response. PK/PD analyses suggested higher doses and frequency may be needed to optimize C5a inhibition and maximize clinical response. For this reason, the trial has been amended to test 20 mg/kg weekly and twice-weekly dosing.
Session topic: E-poster
Keyword(s): Complement, Gastrointestinal GVHD, Graft-versus-host disease (GVHD), Inhibitor
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