A SUBCUTANEOUSLY ADMINISTERED INVESTIGATIONAL RNAI THERAPEUTIC (ALN-CC5) TARGETING COMPLEMENT C5 FOR TREATMENT OF PNH AND COMPLEMENT-MEDIATED DISEASES: INTERIM PHASE 1 STUDY RESULTS
(Abstract release date: 05/19/16)
EHA Library. Hill A. 06/11/16; 135230; S474
Dr. Anita Hill
Contributions
Contributions
Abstract
Abstract: S474
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 12:00 - 12:15
Location: Room H5
Background
Uncontrolled complement activation plays a pivotal role in a variety of disorders such as paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic-uremic syndrome (aHUS). Despite the availability of eculizumab, treatment challenges, including heterogeneity in clinical response combined with inter-individual variation in clearance of eculizumab, remain. ALN-CC5 is a subcutaneous (SC) investigational RNA interference (RNAi) therapeutic targeting complement C5 (C5).
Aims
The aim of this abstract is to report safety, pharmacodynamics (PD) and clinical activity of ALN-CC5 in normal healthy volunteers as well as initial results in patients with PNH.
Methods
A phase 1/2 single-ascending dose (Part A) and multiple-ascending dose (Part B) study of ALN-CC5 in healthy adult volunteers and patients with PNH (Part C) is ongoing. Enrollment of several cohorts of healthy volunteers in both Part A and Part B has been completed. Part C is a 39-week multiple dose study in patients with PNH. Primary endpoints are safety and tolerability. Secondary endpoints include: pharmacokinetics (PK), reduction of circulating C5 and complement activity as measured by CAP/CCP Wieslab ELISA assays and sheep erythrocyte hemolysis assay as well as reduction in LDH (in PNH patients). ALN-CC5 is administered SC at a concentration of 200 mg/mL.
Results
Part A enrolled 32 healthy volunteers who were randomized (1:3) to placebo or a single SC dose of 50, 200, 400, 600 or 900 mg of ALN-CC5. Part B enrolled 24 healthy volunteers who were randomized (1:3) to placebo or up to 13 weekly doses of 100, 200, 400 or 600 mg of ALN-CC5.Among the initial healthy volunteers enrolled, (Part A: n=20; Part B: n=12) ALN-CC5 was considered generally well tolerated with no serious adverse events (SAEs), study discontinuations or clinically significant laboratory findings. Preliminary data showed C5 knockdown up to 99% with nadir residual C5 values as low as 0.6 mcg/mL; complement activity inhibition (CAP & CCP) up to 97% with mean max inhibition of 95 ± 1% for CAP and 96 ± 0.9% for CCP and reduction of serum hemolytic activity up to 98% with mean max inhibition of 84 ± 7.6 %, suggesting potentially clinically meaningful complement inhibition following ALN-CC5 administration. Notably, an up to 97.8% knockdown (KD) of serum C5 at day 98 after a single dose in the top dose cohort and up to 98.3% KD at day 112 after five weekly doses in the 200 mg cohort was maintained. Based on these initial findings, Part C was initiated. In Part C, patients with PNH receive 200 mg weekly doses of ALN-CC5. Updated safety, pharmacodynamics (PD) and clinical activity for all study participants, will be presented.
Conclusion
ALN-CC5 was shown to be generally well tolerated, with no clinically significant, drug-related adverse events to date in healthy volunteers. The PD effects of ALN-CC5 were found to be durable, with clamped C5 knockdown and complement activity inhibition supporting a less frequent as well as SC dose regimen. Collectively, these initial results suggest that the use of a novel RNAi therapeutic targeting C5 is a promising approach for inhibiting complement in PNH, aHUS and other complement-mediated diseases.
Session topic: Bone marrow failure syndromes incl. PNH - Biology
Keyword(s): Complement, PNH, RNA interference (RNAi)
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 12:00 - 12:15
Location: Room H5
Background
Uncontrolled complement activation plays a pivotal role in a variety of disorders such as paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic-uremic syndrome (aHUS). Despite the availability of eculizumab, treatment challenges, including heterogeneity in clinical response combined with inter-individual variation in clearance of eculizumab, remain. ALN-CC5 is a subcutaneous (SC) investigational RNA interference (RNAi) therapeutic targeting complement C5 (C5).
Aims
The aim of this abstract is to report safety, pharmacodynamics (PD) and clinical activity of ALN-CC5 in normal healthy volunteers as well as initial results in patients with PNH.
Methods
A phase 1/2 single-ascending dose (Part A) and multiple-ascending dose (Part B) study of ALN-CC5 in healthy adult volunteers and patients with PNH (Part C) is ongoing. Enrollment of several cohorts of healthy volunteers in both Part A and Part B has been completed. Part C is a 39-week multiple dose study in patients with PNH. Primary endpoints are safety and tolerability. Secondary endpoints include: pharmacokinetics (PK), reduction of circulating C5 and complement activity as measured by CAP/CCP Wieslab ELISA assays and sheep erythrocyte hemolysis assay as well as reduction in LDH (in PNH patients). ALN-CC5 is administered SC at a concentration of 200 mg/mL.
Results
Part A enrolled 32 healthy volunteers who were randomized (1:3) to placebo or a single SC dose of 50, 200, 400, 600 or 900 mg of ALN-CC5. Part B enrolled 24 healthy volunteers who were randomized (1:3) to placebo or up to 13 weekly doses of 100, 200, 400 or 600 mg of ALN-CC5.Among the initial healthy volunteers enrolled, (Part A: n=20; Part B: n=12) ALN-CC5 was considered generally well tolerated with no serious adverse events (SAEs), study discontinuations or clinically significant laboratory findings. Preliminary data showed C5 knockdown up to 99% with nadir residual C5 values as low as 0.6 mcg/mL; complement activity inhibition (CAP & CCP) up to 97% with mean max inhibition of 95 ± 1% for CAP and 96 ± 0.9% for CCP and reduction of serum hemolytic activity up to 98% with mean max inhibition of 84 ± 7.6 %, suggesting potentially clinically meaningful complement inhibition following ALN-CC5 administration. Notably, an up to 97.8% knockdown (KD) of serum C5 at day 98 after a single dose in the top dose cohort and up to 98.3% KD at day 112 after five weekly doses in the 200 mg cohort was maintained. Based on these initial findings, Part C was initiated. In Part C, patients with PNH receive 200 mg weekly doses of ALN-CC5. Updated safety, pharmacodynamics (PD) and clinical activity for all study participants, will be presented.
Conclusion
ALN-CC5 was shown to be generally well tolerated, with no clinically significant, drug-related adverse events to date in healthy volunteers. The PD effects of ALN-CC5 were found to be durable, with clamped C5 knockdown and complement activity inhibition supporting a less frequent as well as SC dose regimen. Collectively, these initial results suggest that the use of a novel RNAi therapeutic targeting C5 is a promising approach for inhibiting complement in PNH, aHUS and other complement-mediated diseases.
Session topic: Bone marrow failure syndromes incl. PNH - Biology
Keyword(s): Complement, PNH, RNA interference (RNAi)
Abstract: S474
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 12:00 - 12:15
Location: Room H5
Background
Uncontrolled complement activation plays a pivotal role in a variety of disorders such as paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic-uremic syndrome (aHUS). Despite the availability of eculizumab, treatment challenges, including heterogeneity in clinical response combined with inter-individual variation in clearance of eculizumab, remain. ALN-CC5 is a subcutaneous (SC) investigational RNA interference (RNAi) therapeutic targeting complement C5 (C5).
Aims
The aim of this abstract is to report safety, pharmacodynamics (PD) and clinical activity of ALN-CC5 in normal healthy volunteers as well as initial results in patients with PNH.
Methods
A phase 1/2 single-ascending dose (Part A) and multiple-ascending dose (Part B) study of ALN-CC5 in healthy adult volunteers and patients with PNH (Part C) is ongoing. Enrollment of several cohorts of healthy volunteers in both Part A and Part B has been completed. Part C is a 39-week multiple dose study in patients with PNH. Primary endpoints are safety and tolerability. Secondary endpoints include: pharmacokinetics (PK), reduction of circulating C5 and complement activity as measured by CAP/CCP Wieslab ELISA assays and sheep erythrocyte hemolysis assay as well as reduction in LDH (in PNH patients). ALN-CC5 is administered SC at a concentration of 200 mg/mL.
Results
Part A enrolled 32 healthy volunteers who were randomized (1:3) to placebo or a single SC dose of 50, 200, 400, 600 or 900 mg of ALN-CC5. Part B enrolled 24 healthy volunteers who were randomized (1:3) to placebo or up to 13 weekly doses of 100, 200, 400 or 600 mg of ALN-CC5.Among the initial healthy volunteers enrolled, (Part A: n=20; Part B: n=12) ALN-CC5 was considered generally well tolerated with no serious adverse events (SAEs), study discontinuations or clinically significant laboratory findings. Preliminary data showed C5 knockdown up to 99% with nadir residual C5 values as low as 0.6 mcg/mL; complement activity inhibition (CAP & CCP) up to 97% with mean max inhibition of 95 ± 1% for CAP and 96 ± 0.9% for CCP and reduction of serum hemolytic activity up to 98% with mean max inhibition of 84 ± 7.6 %, suggesting potentially clinically meaningful complement inhibition following ALN-CC5 administration. Notably, an up to 97.8% knockdown (KD) of serum C5 at day 98 after a single dose in the top dose cohort and up to 98.3% KD at day 112 after five weekly doses in the 200 mg cohort was maintained. Based on these initial findings, Part C was initiated. In Part C, patients with PNH receive 200 mg weekly doses of ALN-CC5. Updated safety, pharmacodynamics (PD) and clinical activity for all study participants, will be presented.
Conclusion
ALN-CC5 was shown to be generally well tolerated, with no clinically significant, drug-related adverse events to date in healthy volunteers. The PD effects of ALN-CC5 were found to be durable, with clamped C5 knockdown and complement activity inhibition supporting a less frequent as well as SC dose regimen. Collectively, these initial results suggest that the use of a novel RNAi therapeutic targeting C5 is a promising approach for inhibiting complement in PNH, aHUS and other complement-mediated diseases.
Session topic: Bone marrow failure syndromes incl. PNH - Biology
Keyword(s): Complement, PNH, RNA interference (RNAi)
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 12:00 - 12:15
Location: Room H5
Background
Uncontrolled complement activation plays a pivotal role in a variety of disorders such as paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic-uremic syndrome (aHUS). Despite the availability of eculizumab, treatment challenges, including heterogeneity in clinical response combined with inter-individual variation in clearance of eculizumab, remain. ALN-CC5 is a subcutaneous (SC) investigational RNA interference (RNAi) therapeutic targeting complement C5 (C5).
Aims
The aim of this abstract is to report safety, pharmacodynamics (PD) and clinical activity of ALN-CC5 in normal healthy volunteers as well as initial results in patients with PNH.
Methods
A phase 1/2 single-ascending dose (Part A) and multiple-ascending dose (Part B) study of ALN-CC5 in healthy adult volunteers and patients with PNH (Part C) is ongoing. Enrollment of several cohorts of healthy volunteers in both Part A and Part B has been completed. Part C is a 39-week multiple dose study in patients with PNH. Primary endpoints are safety and tolerability. Secondary endpoints include: pharmacokinetics (PK), reduction of circulating C5 and complement activity as measured by CAP/CCP Wieslab ELISA assays and sheep erythrocyte hemolysis assay as well as reduction in LDH (in PNH patients). ALN-CC5 is administered SC at a concentration of 200 mg/mL.
Results
Part A enrolled 32 healthy volunteers who were randomized (1:3) to placebo or a single SC dose of 50, 200, 400, 600 or 900 mg of ALN-CC5. Part B enrolled 24 healthy volunteers who were randomized (1:3) to placebo or up to 13 weekly doses of 100, 200, 400 or 600 mg of ALN-CC5.Among the initial healthy volunteers enrolled, (Part A: n=20; Part B: n=12) ALN-CC5 was considered generally well tolerated with no serious adverse events (SAEs), study discontinuations or clinically significant laboratory findings. Preliminary data showed C5 knockdown up to 99% with nadir residual C5 values as low as 0.6 mcg/mL; complement activity inhibition (CAP & CCP) up to 97% with mean max inhibition of 95 ± 1% for CAP and 96 ± 0.9% for CCP and reduction of serum hemolytic activity up to 98% with mean max inhibition of 84 ± 7.6 %, suggesting potentially clinically meaningful complement inhibition following ALN-CC5 administration. Notably, an up to 97.8% knockdown (KD) of serum C5 at day 98 after a single dose in the top dose cohort and up to 98.3% KD at day 112 after five weekly doses in the 200 mg cohort was maintained. Based on these initial findings, Part C was initiated. In Part C, patients with PNH receive 200 mg weekly doses of ALN-CC5. Updated safety, pharmacodynamics (PD) and clinical activity for all study participants, will be presented.
Conclusion
ALN-CC5 was shown to be generally well tolerated, with no clinically significant, drug-related adverse events to date in healthy volunteers. The PD effects of ALN-CC5 were found to be durable, with clamped C5 knockdown and complement activity inhibition supporting a less frequent as well as SC dose regimen. Collectively, these initial results suggest that the use of a novel RNAi therapeutic targeting C5 is a promising approach for inhibiting complement in PNH, aHUS and other complement-mediated diseases.
Session topic: Bone marrow failure syndromes incl. PNH - Biology
Keyword(s): Complement, PNH, RNA interference (RNAi)
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