AN ORALLY ADMINISTERED SMALL MOLECULE FACTOR D INHIBITOR (ACH-4471) FOR TREATMENT OF PNH AND COMPLEMENT DISEASES: PRELIMINARY PHASE 1 RESULTS IN HEALTHY VOLUNTEERS
(Abstract release date: 05/19/16)
EHA Library. Ellis-Pegler R. 06/09/16; 135361; LB2250
Mr. Roderick B Ellis-Pegler
Contributions
Contributions
Abstract
Abstract: LB2250
Type: Eposter Presentation
Background
ACH‑4471 is a novel, small molecule complement factor D (fD) inhibitor; to our knowledge, this represents the first clinical data reported for an oral inhibitor of this target. ACH‑4471 prevents cleavage of complement factor B into Ba and Bb in the alternative pathway of the complement cascade, leading to blockade of C3 convertase production. Hence, unlike C5 inhibitors, ACH‑4471 also prevents C3 fragment deposition on PNH cells and may confer a pharmacological advantage by protecting PNH cells from both intravascular and extravascular hemolysis.
Aims
To assess the safety and tolerability of single ascending oral doses of ACH‑4471 in healthy volunteers and to evaluate its pharmacokinetic (PK) and pharmacodynamic (PD) profile and PK/PD relationship as measured by the serum AP activity ex vivo.
Methods
In this Phase 1a study, ACH‑4471 was given as a single oral dose to healthy volunteers. Dose group 1 enrolled 6 active and 6 placebo subjects, while subsequent groups enrolled 6 active and 2 placebo subjects each. Each group was studied for 28 days after dosing. Active treatment subjects in the first 2 groups received 200 and 600 mg ACH‑4471 QD, respectively. Inhibition of serum AP activity was evaluated using the AP Wieslab assay, which tests ACH‑4471 under stringent conditions in the presence of bacterial endotoxin (LPS), a potent AP activator.To date, 20 subjects (Groups 1 and 2) have been dosed and evaluated (19 males, 1 female) with a median age of 23.9 years (range 21.0 - 54.2). For both groups, all subjects were followed for AEs/SAEs through the last scheduled visit at Day 28. Blood samples were collected at predefined time points from Days 1 to 4 to determine plasma concentrations of ACH‑4471.
Results
There have been no drug-related SAEs, TEAEs leading to study discontinuation, or study-drug related Grade 3/4 TEAEs. PK data indicate that peak plasma concentrations (Cmax) are achieved by 1 to 2.5 hours after a single 200- or 600‑mg dose, with the majority of exposure (measured as AUC) occurring over the first 24 hours. The terminal phase begins 16 hours after dosing and the mean terminal half-life is approximately 9 hours.PD data from the ex vivo evaluation of serum AP activity indicate rapid and nearly complete inhibition of AP activity after single 200- or 600‑mg doses. Mean plasma concentrations of ACH‑4471 necessary to achieve >80% or >90% AP inhibition were approximately 180 and 230 ng/mL, respectively. Simulations indicate that these steady-state Ctrough levels could be maintained by twice daily (BID) dosing with the current capsule formulation; ongoing formulation development efforts may allow for once daily dosing. Plasma Bb concentration, an in vivo biomarker for the inhibition of fD activity by ACH‑4471, decreased dose-dependently with a nadir 9 hours after dosing and a gradual recovery to original levels by 48 hours. Taken together, these results indicate that administration of ACH‑4471 results in potent inhibition of AP activity.
Conclusion
ACH‑4471 was well-tolerated at the single dose levels examined to date with no safety trends. PD results indicate that ACH‑4471 potently inhibits AP activity. PK modeling predicts that the current formulation of ACH‑4471 will provide sustained suppression of AP activity with BID dosing, and future formulations may be effective with QD dosing. A 14‑day multiple ascending dose study of ACH‑4471 is planned to start in 2Q2016.
Session topic: E-poster
Keyword(s): Complement, Oral, PNH
Type: Eposter Presentation
Background
ACH‑4471 is a novel, small molecule complement factor D (fD) inhibitor; to our knowledge, this represents the first clinical data reported for an oral inhibitor of this target. ACH‑4471 prevents cleavage of complement factor B into Ba and Bb in the alternative pathway of the complement cascade, leading to blockade of C3 convertase production. Hence, unlike C5 inhibitors, ACH‑4471 also prevents C3 fragment deposition on PNH cells and may confer a pharmacological advantage by protecting PNH cells from both intravascular and extravascular hemolysis.
Aims
To assess the safety and tolerability of single ascending oral doses of ACH‑4471 in healthy volunteers and to evaluate its pharmacokinetic (PK) and pharmacodynamic (PD) profile and PK/PD relationship as measured by the serum AP activity ex vivo.
Methods
In this Phase 1a study, ACH‑4471 was given as a single oral dose to healthy volunteers. Dose group 1 enrolled 6 active and 6 placebo subjects, while subsequent groups enrolled 6 active and 2 placebo subjects each. Each group was studied for 28 days after dosing. Active treatment subjects in the first 2 groups received 200 and 600 mg ACH‑4471 QD, respectively. Inhibition of serum AP activity was evaluated using the AP Wieslab assay, which tests ACH‑4471 under stringent conditions in the presence of bacterial endotoxin (LPS), a potent AP activator.To date, 20 subjects (Groups 1 and 2) have been dosed and evaluated (19 males, 1 female) with a median age of 23.9 years (range 21.0 - 54.2). For both groups, all subjects were followed for AEs/SAEs through the last scheduled visit at Day 28. Blood samples were collected at predefined time points from Days 1 to 4 to determine plasma concentrations of ACH‑4471.
Results
There have been no drug-related SAEs, TEAEs leading to study discontinuation, or study-drug related Grade 3/4 TEAEs. PK data indicate that peak plasma concentrations (Cmax) are achieved by 1 to 2.5 hours after a single 200- or 600‑mg dose, with the majority of exposure (measured as AUC) occurring over the first 24 hours. The terminal phase begins 16 hours after dosing and the mean terminal half-life is approximately 9 hours.PD data from the ex vivo evaluation of serum AP activity indicate rapid and nearly complete inhibition of AP activity after single 200- or 600‑mg doses. Mean plasma concentrations of ACH‑4471 necessary to achieve >80% or >90% AP inhibition were approximately 180 and 230 ng/mL, respectively. Simulations indicate that these steady-state Ctrough levels could be maintained by twice daily (BID) dosing with the current capsule formulation; ongoing formulation development efforts may allow for once daily dosing. Plasma Bb concentration, an in vivo biomarker for the inhibition of fD activity by ACH‑4471, decreased dose-dependently with a nadir 9 hours after dosing and a gradual recovery to original levels by 48 hours. Taken together, these results indicate that administration of ACH‑4471 results in potent inhibition of AP activity.
Conclusion
ACH‑4471 was well-tolerated at the single dose levels examined to date with no safety trends. PD results indicate that ACH‑4471 potently inhibits AP activity. PK modeling predicts that the current formulation of ACH‑4471 will provide sustained suppression of AP activity with BID dosing, and future formulations may be effective with QD dosing. A 14‑day multiple ascending dose study of ACH‑4471 is planned to start in 2Q2016.
Session topic: E-poster
Keyword(s): Complement, Oral, PNH
Abstract: LB2250
Type: Eposter Presentation
Background
ACH‑4471 is a novel, small molecule complement factor D (fD) inhibitor; to our knowledge, this represents the first clinical data reported for an oral inhibitor of this target. ACH‑4471 prevents cleavage of complement factor B into Ba and Bb in the alternative pathway of the complement cascade, leading to blockade of C3 convertase production. Hence, unlike C5 inhibitors, ACH‑4471 also prevents C3 fragment deposition on PNH cells and may confer a pharmacological advantage by protecting PNH cells from both intravascular and extravascular hemolysis.
Aims
To assess the safety and tolerability of single ascending oral doses of ACH‑4471 in healthy volunteers and to evaluate its pharmacokinetic (PK) and pharmacodynamic (PD) profile and PK/PD relationship as measured by the serum AP activity ex vivo.
Methods
In this Phase 1a study, ACH‑4471 was given as a single oral dose to healthy volunteers. Dose group 1 enrolled 6 active and 6 placebo subjects, while subsequent groups enrolled 6 active and 2 placebo subjects each. Each group was studied for 28 days after dosing. Active treatment subjects in the first 2 groups received 200 and 600 mg ACH‑4471 QD, respectively. Inhibition of serum AP activity was evaluated using the AP Wieslab assay, which tests ACH‑4471 under stringent conditions in the presence of bacterial endotoxin (LPS), a potent AP activator.To date, 20 subjects (Groups 1 and 2) have been dosed and evaluated (19 males, 1 female) with a median age of 23.9 years (range 21.0 - 54.2). For both groups, all subjects were followed for AEs/SAEs through the last scheduled visit at Day 28. Blood samples were collected at predefined time points from Days 1 to 4 to determine plasma concentrations of ACH‑4471.
Results
There have been no drug-related SAEs, TEAEs leading to study discontinuation, or study-drug related Grade 3/4 TEAEs. PK data indicate that peak plasma concentrations (Cmax) are achieved by 1 to 2.5 hours after a single 200- or 600‑mg dose, with the majority of exposure (measured as AUC) occurring over the first 24 hours. The terminal phase begins 16 hours after dosing and the mean terminal half-life is approximately 9 hours.PD data from the ex vivo evaluation of serum AP activity indicate rapid and nearly complete inhibition of AP activity after single 200- or 600‑mg doses. Mean plasma concentrations of ACH‑4471 necessary to achieve >80% or >90% AP inhibition were approximately 180 and 230 ng/mL, respectively. Simulations indicate that these steady-state Ctrough levels could be maintained by twice daily (BID) dosing with the current capsule formulation; ongoing formulation development efforts may allow for once daily dosing. Plasma Bb concentration, an in vivo biomarker for the inhibition of fD activity by ACH‑4471, decreased dose-dependently with a nadir 9 hours after dosing and a gradual recovery to original levels by 48 hours. Taken together, these results indicate that administration of ACH‑4471 results in potent inhibition of AP activity.
Conclusion
ACH‑4471 was well-tolerated at the single dose levels examined to date with no safety trends. PD results indicate that ACH‑4471 potently inhibits AP activity. PK modeling predicts that the current formulation of ACH‑4471 will provide sustained suppression of AP activity with BID dosing, and future formulations may be effective with QD dosing. A 14‑day multiple ascending dose study of ACH‑4471 is planned to start in 2Q2016.
Session topic: E-poster
Keyword(s): Complement, Oral, PNH
Type: Eposter Presentation
Background
ACH‑4471 is a novel, small molecule complement factor D (fD) inhibitor; to our knowledge, this represents the first clinical data reported for an oral inhibitor of this target. ACH‑4471 prevents cleavage of complement factor B into Ba and Bb in the alternative pathway of the complement cascade, leading to blockade of C3 convertase production. Hence, unlike C5 inhibitors, ACH‑4471 also prevents C3 fragment deposition on PNH cells and may confer a pharmacological advantage by protecting PNH cells from both intravascular and extravascular hemolysis.
Aims
To assess the safety and tolerability of single ascending oral doses of ACH‑4471 in healthy volunteers and to evaluate its pharmacokinetic (PK) and pharmacodynamic (PD) profile and PK/PD relationship as measured by the serum AP activity ex vivo.
Methods
In this Phase 1a study, ACH‑4471 was given as a single oral dose to healthy volunteers. Dose group 1 enrolled 6 active and 6 placebo subjects, while subsequent groups enrolled 6 active and 2 placebo subjects each. Each group was studied for 28 days after dosing. Active treatment subjects in the first 2 groups received 200 and 600 mg ACH‑4471 QD, respectively. Inhibition of serum AP activity was evaluated using the AP Wieslab assay, which tests ACH‑4471 under stringent conditions in the presence of bacterial endotoxin (LPS), a potent AP activator.To date, 20 subjects (Groups 1 and 2) have been dosed and evaluated (19 males, 1 female) with a median age of 23.9 years (range 21.0 - 54.2). For both groups, all subjects were followed for AEs/SAEs through the last scheduled visit at Day 28. Blood samples were collected at predefined time points from Days 1 to 4 to determine plasma concentrations of ACH‑4471.
Results
There have been no drug-related SAEs, TEAEs leading to study discontinuation, or study-drug related Grade 3/4 TEAEs. PK data indicate that peak plasma concentrations (Cmax) are achieved by 1 to 2.5 hours after a single 200- or 600‑mg dose, with the majority of exposure (measured as AUC) occurring over the first 24 hours. The terminal phase begins 16 hours after dosing and the mean terminal half-life is approximately 9 hours.PD data from the ex vivo evaluation of serum AP activity indicate rapid and nearly complete inhibition of AP activity after single 200- or 600‑mg doses. Mean plasma concentrations of ACH‑4471 necessary to achieve >80% or >90% AP inhibition were approximately 180 and 230 ng/mL, respectively. Simulations indicate that these steady-state Ctrough levels could be maintained by twice daily (BID) dosing with the current capsule formulation; ongoing formulation development efforts may allow for once daily dosing. Plasma Bb concentration, an in vivo biomarker for the inhibition of fD activity by ACH‑4471, decreased dose-dependently with a nadir 9 hours after dosing and a gradual recovery to original levels by 48 hours. Taken together, these results indicate that administration of ACH‑4471 results in potent inhibition of AP activity.
Conclusion
ACH‑4471 was well-tolerated at the single dose levels examined to date with no safety trends. PD results indicate that ACH‑4471 potently inhibits AP activity. PK modeling predicts that the current formulation of ACH‑4471 will provide sustained suppression of AP activity with BID dosing, and future formulations may be effective with QD dosing. A 14‑day multiple ascending dose study of ACH‑4471 is planned to start in 2Q2016.
Session topic: E-poster
Keyword(s): Complement, Oral, PNH
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