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PRAGUE – Patients with hemophilia A or B and inhibitors may have reduced bleeding days when given subcutaneous factor VIIa (FVIIa) marzeptacog alfa, according to early results from a phase 2/3 trial.
The ongoing study is evaluating pharmacokinetics, pharmacodynamics, efficacy, and safety of marzeptacog alfa, which has four engineered amino acid substitutions within the FVIIa protein to increase catalytic activity, reported lead author Howard Levy, MBBCh, PhD, chief medical officer of Catalyst Biosciences in San Francisco, and his colleagues.
“[Marzeptacog alfa] is about nine times as potent as NovoSeven [RT],” Dr. Levy said, referring to the FVIIa product from Novo Nordisk. “This allows for subcutaneous dosing. One of the advantages of subcutaneous dosing is that it further prolongs the half-life.”
Dr. Levy presented the findings at the annual congress of the European Association for Haemophilia and Allied Disorders.
The study involved 12 patients with hemophilia A or B and inhibitors, all of whom began with an annualized bleeding rate (ABR) of more than 12 days per year; of these, 7 have completed dosing.
Following pharmacokinetic analysis, subcutaneous dosing began at an initial dose of 30 mcg/kg daily. As-needed dose escalations were allowed at regular intervals. Specifically, if spontaneous bleeding occurred, then at the next 50-day interval, an individual patient’s dose would be increased to the next level. Dose levels were 30 mcg/kg, 60 mcg/kg, 90 mcg/kg, and 120 mcg/kg.
Any patient completing a 50-day interval without bleeding was finished with the study and proceeded to a 30-day follow-up period, during which time resumption of bleeding was monitored. The primary endpoint was a reduction in the ABR at the final dose level. Secondary endpoints were safety, tolerability, and a lack of inhibitor formation.
As Dr. Levy discussed results, he expressed concern that ABR is an inadequate measure of efficacy. “There is a significant amount hidden by the raw statistic of an annualized bleed rate.” He elaborated further by describing two trial participants who each had an ABR of about 23 days per year but had very different proportions of days with bleeding in the 6-month lead-in period (22% vs. 9%), suggesting that this proportion may provide a clearer impression of efficacy.
Prior to treatment, the mean ABR among all patients was 19 days per year and the median proportion of days with bleeding was 11%. This latter value dropped from 11% to 1% with treatment. The former value, ABR, was reduced in a “clinically significant” fashion, although exact values were not provided (P = .009).
Two patients required dose escalation to 60 mcg/kg, and five out of seven patients had no bleeding (traumatic or spontaneous), at their final dose levels.
Subcutaneous half-life was 13.1 hours, compared with intravenous half-life of 3.9 hours. After more than 260 cumulative days of subcutaneous injections, no thromboses or antidrug antibodies were detected. Two subjects had a total of six injection site reactions, with mild to moderate redness and moderate swelling that resolved without sequelae.
One patient died on day 11 of the trial because of fatal hemorrhagic stroke, but this patient had uncontrolled hypertension and the death was not considered drug related.
More clinical data from this trial will be reported in July 2019 at the annual congress of the International Society on Thrombosis and Haemostasis in Melbourne.
The study was funded by Catalyst Biosciences. Dr. Levy and multiple coauthors are employees, shareholders, or consultants for Catalyst Biosciences.
SOURCE: Levy H et al. EAHAD 2019, Abstract OR11.
PRAGUE – Patients with hemophilia A or B and inhibitors may have reduced bleeding days when given subcutaneous factor VIIa (FVIIa) marzeptacog alfa, according to early results from a phase 2/3 trial.
The ongoing study is evaluating pharmacokinetics, pharmacodynamics, efficacy, and safety of marzeptacog alfa, which has four engineered amino acid substitutions within the FVIIa protein to increase catalytic activity, reported lead author Howard Levy, MBBCh, PhD, chief medical officer of Catalyst Biosciences in San Francisco, and his colleagues.
“[Marzeptacog alfa] is about nine times as potent as NovoSeven [RT],” Dr. Levy said, referring to the FVIIa product from Novo Nordisk. “This allows for subcutaneous dosing. One of the advantages of subcutaneous dosing is that it further prolongs the half-life.”
Dr. Levy presented the findings at the annual congress of the European Association for Haemophilia and Allied Disorders.
The study involved 12 patients with hemophilia A or B and inhibitors, all of whom began with an annualized bleeding rate (ABR) of more than 12 days per year; of these, 7 have completed dosing.
Following pharmacokinetic analysis, subcutaneous dosing began at an initial dose of 30 mcg/kg daily. As-needed dose escalations were allowed at regular intervals. Specifically, if spontaneous bleeding occurred, then at the next 50-day interval, an individual patient’s dose would be increased to the next level. Dose levels were 30 mcg/kg, 60 mcg/kg, 90 mcg/kg, and 120 mcg/kg.
Any patient completing a 50-day interval without bleeding was finished with the study and proceeded to a 30-day follow-up period, during which time resumption of bleeding was monitored. The primary endpoint was a reduction in the ABR at the final dose level. Secondary endpoints were safety, tolerability, and a lack of inhibitor formation.
As Dr. Levy discussed results, he expressed concern that ABR is an inadequate measure of efficacy. “There is a significant amount hidden by the raw statistic of an annualized bleed rate.” He elaborated further by describing two trial participants who each had an ABR of about 23 days per year but had very different proportions of days with bleeding in the 6-month lead-in period (22% vs. 9%), suggesting that this proportion may provide a clearer impression of efficacy.
Prior to treatment, the mean ABR among all patients was 19 days per year and the median proportion of days with bleeding was 11%. This latter value dropped from 11% to 1% with treatment. The former value, ABR, was reduced in a “clinically significant” fashion, although exact values were not provided (P = .009).
Two patients required dose escalation to 60 mcg/kg, and five out of seven patients had no bleeding (traumatic or spontaneous), at their final dose levels.
Subcutaneous half-life was 13.1 hours, compared with intravenous half-life of 3.9 hours. After more than 260 cumulative days of subcutaneous injections, no thromboses or antidrug antibodies were detected. Two subjects had a total of six injection site reactions, with mild to moderate redness and moderate swelling that resolved without sequelae.
One patient died on day 11 of the trial because of fatal hemorrhagic stroke, but this patient had uncontrolled hypertension and the death was not considered drug related.
More clinical data from this trial will be reported in July 2019 at the annual congress of the International Society on Thrombosis and Haemostasis in Melbourne.
The study was funded by Catalyst Biosciences. Dr. Levy and multiple coauthors are employees, shareholders, or consultants for Catalyst Biosciences.
SOURCE: Levy H et al. EAHAD 2019, Abstract OR11.
PRAGUE – Patients with hemophilia A or B and inhibitors may have reduced bleeding days when given subcutaneous factor VIIa (FVIIa) marzeptacog alfa, according to early results from a phase 2/3 trial.
The ongoing study is evaluating pharmacokinetics, pharmacodynamics, efficacy, and safety of marzeptacog alfa, which has four engineered amino acid substitutions within the FVIIa protein to increase catalytic activity, reported lead author Howard Levy, MBBCh, PhD, chief medical officer of Catalyst Biosciences in San Francisco, and his colleagues.
“[Marzeptacog alfa] is about nine times as potent as NovoSeven [RT],” Dr. Levy said, referring to the FVIIa product from Novo Nordisk. “This allows for subcutaneous dosing. One of the advantages of subcutaneous dosing is that it further prolongs the half-life.”
Dr. Levy presented the findings at the annual congress of the European Association for Haemophilia and Allied Disorders.
The study involved 12 patients with hemophilia A or B and inhibitors, all of whom began with an annualized bleeding rate (ABR) of more than 12 days per year; of these, 7 have completed dosing.
Following pharmacokinetic analysis, subcutaneous dosing began at an initial dose of 30 mcg/kg daily. As-needed dose escalations were allowed at regular intervals. Specifically, if spontaneous bleeding occurred, then at the next 50-day interval, an individual patient’s dose would be increased to the next level. Dose levels were 30 mcg/kg, 60 mcg/kg, 90 mcg/kg, and 120 mcg/kg.
Any patient completing a 50-day interval without bleeding was finished with the study and proceeded to a 30-day follow-up period, during which time resumption of bleeding was monitored. The primary endpoint was a reduction in the ABR at the final dose level. Secondary endpoints were safety, tolerability, and a lack of inhibitor formation.
As Dr. Levy discussed results, he expressed concern that ABR is an inadequate measure of efficacy. “There is a significant amount hidden by the raw statistic of an annualized bleed rate.” He elaborated further by describing two trial participants who each had an ABR of about 23 days per year but had very different proportions of days with bleeding in the 6-month lead-in period (22% vs. 9%), suggesting that this proportion may provide a clearer impression of efficacy.
Prior to treatment, the mean ABR among all patients was 19 days per year and the median proportion of days with bleeding was 11%. This latter value dropped from 11% to 1% with treatment. The former value, ABR, was reduced in a “clinically significant” fashion, although exact values were not provided (P = .009).
Two patients required dose escalation to 60 mcg/kg, and five out of seven patients had no bleeding (traumatic or spontaneous), at their final dose levels.
Subcutaneous half-life was 13.1 hours, compared with intravenous half-life of 3.9 hours. After more than 260 cumulative days of subcutaneous injections, no thromboses or antidrug antibodies were detected. Two subjects had a total of six injection site reactions, with mild to moderate redness and moderate swelling that resolved without sequelae.
One patient died on day 11 of the trial because of fatal hemorrhagic stroke, but this patient had uncontrolled hypertension and the death was not considered drug related.
More clinical data from this trial will be reported in July 2019 at the annual congress of the International Society on Thrombosis and Haemostasis in Melbourne.
The study was funded by Catalyst Biosciences. Dr. Levy and multiple coauthors are employees, shareholders, or consultants for Catalyst Biosciences.
SOURCE: Levy H et al. EAHAD 2019, Abstract OR11.
REPORTING FROM EAHAD 2019