Bleeding Disorders

PRAGUE – Emicizumab appears safe and effective for patients with hemophilia A undergoing surgical procedures, based on experience with a subpopulation of HAVEN 3 trial participants.

Out of 28 minor procedures performed without preventive factor VIII (FVIII), only 2 were associated with postoperative bleeds requiring treatment, reported lead author Elena Santagostino, MD, PhD, of Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico in Milan, and her colleagues.

All events requiring bleeding treatment were associated with dental procedures, highlighting an area where clinicians and dentists may need to exercise caution. Still, overall results supported emicizumab in a surgical setting.

“There were no thrombotic complications or other unexpected events, including inhibitor development,” Dr. Santagostino said at the annual congress of the European Association for Haemophilia and Allied Disorders.

The findings were drawn from 30 patients who underwent 50 surgeries (46 minor, 4 major) during HAVEN 3, a previously reported phase 3 trial investigating the use of emicizumab, a humanized bispecific monoclonal antibody for patients with hemophilia A without inhibitors.

The minor surgeries included dental or orthopedic procedures, esophagogastroduodenoscopy, or colonoscopy. The four major procedures were all orthopedic (knee arthroscopic synovectomy, biceps femoris tear repair, total ankle arthroplasty, and total hip replacement). The investigators analyzed surgery-related bleeds and the nature of FVIII usage.

Preventive FVIII was used in 18 procedures; infusion duration was 24 hours or less in 14 procedures, between 25 hours and 48 hours in 2 procedures, and more than 72 hours in 2 procedures. The median cumulative preventive FVIII dose per procedure was 30 IU/kg.

Of the 46 minor procedures, 28 (61%) were performed without preventive FVIII, and 2 (7.1%) were associated with bleeding requiring treatment, both after dental procedures. Two other participants who received preventive FVIII also needed postoperative bleeding treatment. Of note, these events were also after dental procedures, meaning all four instances of bleeding requiring treatment during the trial were associated with dentistry.

“[I]n this experience, dental procedures were somewhat tricky because the bleeding complications were mainly there,” Dr. Santagostino said.

When asked by an audience member if this trend was unique to mucosal bleeding, Dr. Santagostino said it was too early to draw such a conclusion but offered some insight. “To control and prevent bleeding during a dental procedure is not trivial, because … sometimes if you stop factor VIII treatment quite early, you may have late bleeding, mainly due to local reasons, because … dental procedures are very heterogenous.”

Among three other participants who had postoperative bleeding but did not require treatment, two underwent dental procedures, further supporting this association. Although the study numbers are relatively small, the findings may at least support caution, if not preventive FVIII in the dental setting, Dr. Santagostino said.

The four major procedures – all orthopedic – were knee arthroscopic synovectomy, biceps femoris tear repair, total ankle arthroplasty, and total hip replacement. Along with preoperative preventive FVIII, three of four patients undergoing major surgery received preventive FVIII for 14-18 days postoperatively. Doses ranged from 99-522 IU/kg. No postoperative bleeds occurred in this subgroup.

Study funding was provided by F. Hoffmann–La Roche and Chugai Pharmaceutical. The investigators reported financial relationships with Bayer, Shire, Pfizer, Novo Nordisk, and others.

SOURCE: Santagostino E et al. EAHAD 2019, Abstract OR15.

PRAGUE – Emicizumab appears safe and effective for patients with hemophilia A undergoing surgical procedures, based on experience with a subpopulation of HAVEN 3 trial participants.

Out of 28 minor procedures performed without preventive factor VIII (FVIII), only 2 were associated with postoperative bleeds requiring treatment, reported lead author Elena Santagostino, MD, PhD, of Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico in Milan, and her colleagues.

All events requiring bleeding treatment were associated with dental procedures, highlighting an area where clinicians and dentists may need to exercise caution. Still, overall results supported emicizumab in a surgical setting.

“There were no thrombotic complications or other unexpected events, including inhibitor development,” Dr. Santagostino said at the annual congress of the European Association for Haemophilia and Allied Disorders.

The findings were drawn from 30 patients who underwent 50 surgeries (46 minor, 4 major) during HAVEN 3, a previously reported phase 3 trial investigating the use of emicizumab, a humanized bispecific monoclonal antibody for patients with hemophilia A without inhibitors.

The minor surgeries included dental or orthopedic procedures, esophagogastroduodenoscopy, or colonoscopy. The four major procedures were all orthopedic (knee arthroscopic synovectomy, biceps femoris tear repair, total ankle arthroplasty, and total hip replacement). The investigators analyzed surgery-related bleeds and the nature of FVIII usage.

Preventive FVIII was used in 18 procedures; infusion duration was 24 hours or less in 14 procedures, between 25 hours and 48 hours in 2 procedures, and more than 72 hours in 2 procedures. The median cumulative preventive FVIII dose per procedure was 30 IU/kg.

Of the 46 minor procedures, 28 (61%) were performed without preventive FVIII, and 2 (7.1%) were associated with bleeding requiring treatment, both after dental procedures. Two other participants who received preventive FVIII also needed postoperative bleeding treatment. Of note, these events were also after dental procedures, meaning all four instances of bleeding requiring treatment during the trial were associated with dentistry.

“[I]n this experience, dental procedures were somewhat tricky because the bleeding complications were mainly there,” Dr. Santagostino said.

When asked by an audience member if this trend was unique to mucosal bleeding, Dr. Santagostino said it was too early to draw such a conclusion but offered some insight. “To control and prevent bleeding during a dental procedure is not trivial, because … sometimes if you stop factor VIII treatment quite early, you may have late bleeding, mainly due to local reasons, because … dental procedures are very heterogenous.”

Among three other participants who had postoperative bleeding but did not require treatment, two underwent dental procedures, further supporting this association. Although the study numbers are relatively small, the findings may at least support caution, if not preventive FVIII in the dental setting, Dr. Santagostino said.

The four major procedures – all orthopedic – were knee arthroscopic synovectomy, biceps femoris tear repair, total ankle arthroplasty, and total hip replacement. Along with preoperative preventive FVIII, three of four patients undergoing major surgery received preventive FVIII for 14-18 days postoperatively. Doses ranged from 99-522 IU/kg. No postoperative bleeds occurred in this subgroup.

Study funding was provided by F. Hoffmann–La Roche and Chugai Pharmaceutical. The investigators reported financial relationships with Bayer, Shire, Pfizer, Novo Nordisk, and others.

SOURCE: Santagostino E et al. EAHAD 2019, Abstract OR15.

PRAGUE – Emicizumab appears safe and effective for patients with hemophilia A undergoing surgical procedures, based on experience with a subpopulation of HAVEN 3 trial participants.

Out of 28 minor procedures performed without preventive factor VIII (FVIII), only 2 were associated with postoperative bleeds requiring treatment, reported lead author Elena Santagostino, MD, PhD, of Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico in Milan, and her colleagues.

All events requiring bleeding treatment were associated with dental procedures, highlighting an area where clinicians and dentists may need to exercise caution. Still, overall results supported emicizumab in a surgical setting.

“There were no thrombotic complications or other unexpected events, including inhibitor development,” Dr. Santagostino said at the annual congress of the European Association for Haemophilia and Allied Disorders.

The findings were drawn from 30 patients who underwent 50 surgeries (46 minor, 4 major) during HAVEN 3, a previously reported phase 3 trial investigating the use of emicizumab, a humanized bispecific monoclonal antibody for patients with hemophilia A without inhibitors.

The minor surgeries included dental or orthopedic procedures, esophagogastroduodenoscopy, or colonoscopy. The four major procedures were all orthopedic (knee arthroscopic synovectomy, biceps femoris tear repair, total ankle arthroplasty, and total hip replacement). The investigators analyzed surgery-related bleeds and the nature of FVIII usage.

Preventive FVIII was used in 18 procedures; infusion duration was 24 hours or less in 14 procedures, between 25 hours and 48 hours in 2 procedures, and more than 72 hours in 2 procedures. The median cumulative preventive FVIII dose per procedure was 30 IU/kg.

Of the 46 minor procedures, 28 (61%) were performed without preventive FVIII, and 2 (7.1%) were associated with bleeding requiring treatment, both after dental procedures. Two other participants who received preventive FVIII also needed postoperative bleeding treatment. Of note, these events were also after dental procedures, meaning all four instances of bleeding requiring treatment during the trial were associated with dentistry.

“[I]n this experience, dental procedures were somewhat tricky because the bleeding complications were mainly there,” Dr. Santagostino said.

When asked by an audience member if this trend was unique to mucosal bleeding, Dr. Santagostino said it was too early to draw such a conclusion but offered some insight. “To control and prevent bleeding during a dental procedure is not trivial, because … sometimes if you stop factor VIII treatment quite early, you may have late bleeding, mainly due to local reasons, because … dental procedures are very heterogenous.”

Among three other participants who had postoperative bleeding but did not require treatment, two underwent dental procedures, further supporting this association. Although the study numbers are relatively small, the findings may at least support caution, if not preventive FVIII in the dental setting, Dr. Santagostino said.

The four major procedures – all orthopedic – were knee arthroscopic synovectomy, biceps femoris tear repair, total ankle arthroplasty, and total hip replacement. Along with preoperative preventive FVIII, three of four patients undergoing major surgery received preventive FVIII for 14-18 days postoperatively. Doses ranged from 99-522 IU/kg. No postoperative bleeds occurred in this subgroup.

Study funding was provided by F. Hoffmann–La Roche and Chugai Pharmaceutical. The investigators reported financial relationships with Bayer, Shire, Pfizer, Novo Nordisk, and others.

SOURCE: Santagostino E et al. EAHAD 2019, Abstract OR15.

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.

Will Pass/MDedge News

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.

Will Pass/MDedge News

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.

Will Pass/MDedge News

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 – AMT-061, a gene therapy consisting of an adeno-associated virus serotype 5 (AAV5) vector and a Padua variant human factor IX (hFIX) gene, provides clinically meaningful FIX activity, based on early results from an ongoing, phase 2b study.

Will Pass/ MDedge News

The findings provide traction for a phase 3 trial (HOPE-B; NCT03569891) which is currently enrolling, according to lead author Annette Von Drygalski, MD, PharmD, director of the Hemophilia and Thrombosis Treatment Center at the University of California, San Diego.

Dr. Von Drygalski said that the results also demonstrate the positive impact of switching from a wild-type hFIX gene in AMT-060 to a Padua hFIX variant in AMT-061, achieved by replacing arginine with leucine at R338L.

Speaking at the annual congress of the European Association for Haemophilia and Allied Disorders, Dr. Von Drygalski referred to AMT-061 as the “enhanced version” of AMT-060. Prior to human trials, nonhuman primate studies comparing AMT-060 with AMT-061 demonstrated a 550% increase in factor IX activity, similar to previous reports of 600%-800% boosts from the Padua variant.

The current findings revealed early outcomes for three men with severe hemophilia B who were given AMT-061. The patients were between 43 years and 50 years of age and had been taking clotting factors prophylactically. Among them, annualized bleed rates ranged from one to five events per year. Two of the three men were HIV-positive, one had IgM antibodies against AAV5, and all three had neutralizing antibodies against AAV5.

“Of note,” Dr. Von Drygalski said, “two of the participants had previously been excluded from participation in gene therapy due to preexisting antibodies against AAV.”

Each man was given a single dose of 2 x 10¹³ gene copies/kg of AMT-061 intravenously. The primary endpoint was efficacy at 6 weeks after administration. Ongoing secondary endpoints include patient-reported bleeding and FIX concentrate use, joint health, patient-reported quality of life, and laboratory parameters. Patients will be followed for 1 year.

Within 2 weeks, all three men achieved meaningful levels of FIX. Two of three patients demonstrated an upward trend of FIX activity that peaked at about 50% of normal. The third patient’s levels plateaued sooner, with the most recent reading at week 14 showing 25%. Mean factor IX activity level was 38% of normal 12 weeks after gene therapy.

“These clotting factor activity levels translated into complete control [of bleeding] with no requirement for factor IX replacement after infusion,” Dr. Von Drygalski said. For comparison, AMT-060, the wild-type version, only achieved levels of 3%-13%, which are less clinically meaningful.

Along with demonstrating efficacy, AMT-061 was well tolerated. One patient had two adverse events that resolved without treatment: very mild C-reactive protein elevation and transient headache. One patient had a very mild and transient AST elevation (week 2, 43 U/L; week 4, 48 U/L) that resolved without treatment. No patients had ALT elevations and immunosuppression was not needed.

These findings provide a strong foundation for the phase 3 HOPE-B trial, which will include about 50 patients with FIX activity no greater than 2%. Dr. Von Drygalski noted that patients with AAV5-neutralizing antibodies will not be excluded.

The investigators reported financial relationships with Bayer, UniQure, Pfizer, Novo Nordisk, Shire, and others.

SOURCE: Von Drygalski A et al. EAHAD 2019, Abstract OR10.

PRAGUE – AMT-061, a gene therapy consisting of an adeno-associated virus serotype 5 (AAV5) vector and a Padua variant human factor IX (hFIX) gene, provides clinically meaningful FIX activity, based on early results from an ongoing, phase 2b study.

Will Pass/ MDedge News

The findings provide traction for a phase 3 trial (HOPE-B; NCT03569891) which is currently enrolling, according to lead author Annette Von Drygalski, MD, PharmD, director of the Hemophilia and Thrombosis Treatment Center at the University of California, San Diego.

Dr. Von Drygalski said that the results also demonstrate the positive impact of switching from a wild-type hFIX gene in AMT-060 to a Padua hFIX variant in AMT-061, achieved by replacing arginine with leucine at R338L.

Speaking at the annual congress of the European Association for Haemophilia and Allied Disorders, Dr. Von Drygalski referred to AMT-061 as the “enhanced version” of AMT-060. Prior to human trials, nonhuman primate studies comparing AMT-060 with AMT-061 demonstrated a 550% increase in factor IX activity, similar to previous reports of 600%-800% boosts from the Padua variant.

The current findings revealed early outcomes for three men with severe hemophilia B who were given AMT-061. The patients were between 43 years and 50 years of age and had been taking clotting factors prophylactically. Among them, annualized bleed rates ranged from one to five events per year. Two of the three men were HIV-positive, one had IgM antibodies against AAV5, and all three had neutralizing antibodies against AAV5.

“Of note,” Dr. Von Drygalski said, “two of the participants had previously been excluded from participation in gene therapy due to preexisting antibodies against AAV.”

Each man was given a single dose of 2 x 10¹³ gene copies/kg of AMT-061 intravenously. The primary endpoint was efficacy at 6 weeks after administration. Ongoing secondary endpoints include patient-reported bleeding and FIX concentrate use, joint health, patient-reported quality of life, and laboratory parameters. Patients will be followed for 1 year.

Within 2 weeks, all three men achieved meaningful levels of FIX. Two of three patients demonstrated an upward trend of FIX activity that peaked at about 50% of normal. The third patient’s levels plateaued sooner, with the most recent reading at week 14 showing 25%. Mean factor IX activity level was 38% of normal 12 weeks after gene therapy.

“These clotting factor activity levels translated into complete control [of bleeding] with no requirement for factor IX replacement after infusion,” Dr. Von Drygalski said. For comparison, AMT-060, the wild-type version, only achieved levels of 3%-13%, which are less clinically meaningful.

Along with demonstrating efficacy, AMT-061 was well tolerated. One patient had two adverse events that resolved without treatment: very mild C-reactive protein elevation and transient headache. One patient had a very mild and transient AST elevation (week 2, 43 U/L; week 4, 48 U/L) that resolved without treatment. No patients had ALT elevations and immunosuppression was not needed.

These findings provide a strong foundation for the phase 3 HOPE-B trial, which will include about 50 patients with FIX activity no greater than 2%. Dr. Von Drygalski noted that patients with AAV5-neutralizing antibodies will not be excluded.

The investigators reported financial relationships with Bayer, UniQure, Pfizer, Novo Nordisk, Shire, and others.

SOURCE: Von Drygalski A et al. EAHAD 2019, Abstract OR10.

PRAGUE – AMT-061, a gene therapy consisting of an adeno-associated virus serotype 5 (AAV5) vector and a Padua variant human factor IX (hFIX) gene, provides clinically meaningful FIX activity, based on early results from an ongoing, phase 2b study.

Will Pass/ MDedge News

The findings provide traction for a phase 3 trial (HOPE-B; NCT03569891) which is currently enrolling, according to lead author Annette Von Drygalski, MD, PharmD, director of the Hemophilia and Thrombosis Treatment Center at the University of California, San Diego.

Dr. Von Drygalski said that the results also demonstrate the positive impact of switching from a wild-type hFIX gene in AMT-060 to a Padua hFIX variant in AMT-061, achieved by replacing arginine with leucine at R338L.

Speaking at the annual congress of the European Association for Haemophilia and Allied Disorders, Dr. Von Drygalski referred to AMT-061 as the “enhanced version” of AMT-060. Prior to human trials, nonhuman primate studies comparing AMT-060 with AMT-061 demonstrated a 550% increase in factor IX activity, similar to previous reports of 600%-800% boosts from the Padua variant.

The current findings revealed early outcomes for three men with severe hemophilia B who were given AMT-061. The patients were between 43 years and 50 years of age and had been taking clotting factors prophylactically. Among them, annualized bleed rates ranged from one to five events per year. Two of the three men were HIV-positive, one had IgM antibodies against AAV5, and all three had neutralizing antibodies against AAV5.

“Of note,” Dr. Von Drygalski said, “two of the participants had previously been excluded from participation in gene therapy due to preexisting antibodies against AAV.”

Each man was given a single dose of 2 x 10¹³ gene copies/kg of AMT-061 intravenously. The primary endpoint was efficacy at 6 weeks after administration. Ongoing secondary endpoints include patient-reported bleeding and FIX concentrate use, joint health, patient-reported quality of life, and laboratory parameters. Patients will be followed for 1 year.

Within 2 weeks, all three men achieved meaningful levels of FIX. Two of three patients demonstrated an upward trend of FIX activity that peaked at about 50% of normal. The third patient’s levels plateaued sooner, with the most recent reading at week 14 showing 25%. Mean factor IX activity level was 38% of normal 12 weeks after gene therapy.

“These clotting factor activity levels translated into complete control [of bleeding] with no requirement for factor IX replacement after infusion,” Dr. Von Drygalski said. For comparison, AMT-060, the wild-type version, only achieved levels of 3%-13%, which are less clinically meaningful.

Along with demonstrating efficacy, AMT-061 was well tolerated. One patient had two adverse events that resolved without treatment: very mild C-reactive protein elevation and transient headache. One patient had a very mild and transient AST elevation (week 2, 43 U/L; week 4, 48 U/L) that resolved without treatment. No patients had ALT elevations and immunosuppression was not needed.

These findings provide a strong foundation for the phase 3 HOPE-B trial, which will include about 50 patients with FIX activity no greater than 2%. Dr. Von Drygalski noted that patients with AAV5-neutralizing antibodies will not be excluded.

The investigators reported financial relationships with Bayer, UniQure, Pfizer, Novo Nordisk, Shire, and others.

SOURCE: Von Drygalski A et al. EAHAD 2019, Abstract OR10.

The Food and Drug Administration has approved turoctocog alfa pegol (N8-GP, Esperoct), a glycopegylated recombinant factor VIII product, to treat hemophilia A.

The agency approved turoctocog alfa pegol for use as routine prophylaxis to reduce the frequency of bleeding episodes, for on-demand treatment and control of bleeding episodes, and for perioperative management of bleeding in adults and children with hemophilia A.

Turoctocog alfa pegol will not be available in the United States before 2020, according to Novo Nordisk. The company cannot yet launch the product because of third-party intellectual property agreements.

The FDA’s approval of turoctocog alfa pegol was supported by results from the pathfinder 2 (NCT01480180), pathfinder 3 (NCT01489111), and pathfinder 5 (NCT01731600) trials.

The trials included children, adolescents, and adults with previously treated, severe hemophilia A and no history of inhibitors. Turoctocog alfa pegol was considered effective and well tolerated in these trials.

Pooled results from pathfinder 2 and pathfinder 5 were presented at the 2018 annual meeting of the American Society of Hematology (Blood. 2018:132:1177).

Results from pathfinder 3 were previously published in Haemophilia (2017. Sep;23[5]:689-96).

[email protected]

The Food and Drug Administration has approved turoctocog alfa pegol (N8-GP, Esperoct), a glycopegylated recombinant factor VIII product, to treat hemophilia A.

The agency approved turoctocog alfa pegol for use as routine prophylaxis to reduce the frequency of bleeding episodes, for on-demand treatment and control of bleeding episodes, and for perioperative management of bleeding in adults and children with hemophilia A.

Turoctocog alfa pegol will not be available in the United States before 2020, according to Novo Nordisk. The company cannot yet launch the product because of third-party intellectual property agreements.

The FDA’s approval of turoctocog alfa pegol was supported by results from the pathfinder 2 (NCT01480180), pathfinder 3 (NCT01489111), and pathfinder 5 (NCT01731600) trials.

The trials included children, adolescents, and adults with previously treated, severe hemophilia A and no history of inhibitors. Turoctocog alfa pegol was considered effective and well tolerated in these trials.

Pooled results from pathfinder 2 and pathfinder 5 were presented at the 2018 annual meeting of the American Society of Hematology (Blood. 2018:132:1177).

Results from pathfinder 3 were previously published in Haemophilia (2017. Sep;23[5]:689-96).

[email protected]

The Food and Drug Administration has approved turoctocog alfa pegol (N8-GP, Esperoct), a glycopegylated recombinant factor VIII product, to treat hemophilia A.

The agency approved turoctocog alfa pegol for use as routine prophylaxis to reduce the frequency of bleeding episodes, for on-demand treatment and control of bleeding episodes, and for perioperative management of bleeding in adults and children with hemophilia A.

Turoctocog alfa pegol will not be available in the United States before 2020, according to Novo Nordisk. The company cannot yet launch the product because of third-party intellectual property agreements.

The FDA’s approval of turoctocog alfa pegol was supported by results from the pathfinder 2 (NCT01480180), pathfinder 3 (NCT01489111), and pathfinder 5 (NCT01731600) trials.

The trials included children, adolescents, and adults with previously treated, severe hemophilia A and no history of inhibitors. Turoctocog alfa pegol was considered effective and well tolerated in these trials.

Pooled results from pathfinder 2 and pathfinder 5 were presented at the 2018 annual meeting of the American Society of Hematology (Blood. 2018:132:1177).

Results from pathfinder 3 were previously published in Haemophilia (2017. Sep;23[5]:689-96).

[email protected]

PRAGUE – Fitusiran, a novel small interfering RNA therapeutic that decreases antithrombin (AT) synthesis and bleeding in patients with hemophilia A or B, with or without inhibitors, is reversible upon dosing cessation and becomes effective again with resumption of dosing. That finding is based on data obtained before, during, and after a phase 2 study dosing suspension.

Will Pass/MDedge News

In September 2017, the fitusiran open-label extension study was suspended to investigate a fatal thrombotic event. The suspension was lifted 3 months later, and the trial continued with reduced doses of replacement factors or bypassing agents for breakthrough bleeds.

The pause in the study was used to gather data about the effects of dosing cessation and resumption, which were reported by coauthor Craig Benson, MD, of Sanofi Genzyme in Cambridge, Mass. Dr. Benson presented findings at the annual congress of the European Association for Haemophilia and Allied Disorders on behalf of lead author John Pasi, MD, PhD, of the Haemophilia Centre at the Royal London Hospital and colleagues.

Prior to the suspension, 28 patients with hemophilia A or B, with or without inhibitors, were given 50-80 mg of fitusiran for up to 20 months with a median dose duration of 11 months. During dosing suspension, the investigators measured AT levels, thrombin generation, and annualized bleeding rates (ABR).

“We can see that the antithrombin knockdown effect of fitusiran is reversible with dosing hold,” Dr. Benson said, referring to an upward trend of median AT level.

Within 4 months of stopping fitusiran, median AT level was 60% of normal. This level continued to rise to about 90% by month 7, before returning to normal at month 11.

“This is an AT recovery we had previously seen by a few subjects that had discontinued [fitusiran] prior to the clinical hold,” Dr. Benson said, “but here, with a much larger sample size, we see a fairly consistent AT recovery.”

As expected, while AT levels rose, thrombin generation showed an inverse trend. “We see a similar temporal pattern,” Dr. Benson said. “The bulk of thrombin generation decrease is seen by the 4th month off fitusiran.”

When patients restarted fitusiran after the suspension was lifted, AT levels dropped to about 30% of normal by month 1 and about 20% of normal from month 2 onward. Again, in an inverse manner, thrombin generation increased.

Clinically, changes in AT and thrombin generation before, during, and after study suspension were reflected in median ABR, which rose from 1.43 events per year prior to cessation to 6.47 events per year during treatment hold before falling to 1.25 events per year after restarting fitusiran.

Overall, the results support the efficacy and reversibility of fitusiran. The agent is continuing to be studied in the phase 3 ATLAS trials.

The study was funded by Sanofi Genzyme and Alnylam. Dr. Benson is an employee of Sanofi Genzyme. Other investigators reported financial ties to Sanofi Genzyme, Alnylam, Baxalta, Octapharma, Pfizer, Shire, and others.

SOURCE: Pasi J et al. EAHAD 2019, Abstract OR16.

PRAGUE – Fitusiran, a novel small interfering RNA therapeutic that decreases antithrombin (AT) synthesis and bleeding in patients with hemophilia A or B, with or without inhibitors, is reversible upon dosing cessation and becomes effective again with resumption of dosing. That finding is based on data obtained before, during, and after a phase 2 study dosing suspension.

Will Pass/MDedge News

In September 2017, the fitusiran open-label extension study was suspended to investigate a fatal thrombotic event. The suspension was lifted 3 months later, and the trial continued with reduced doses of replacement factors or bypassing agents for breakthrough bleeds.

The pause in the study was used to gather data about the effects of dosing cessation and resumption, which were reported by coauthor Craig Benson, MD, of Sanofi Genzyme in Cambridge, Mass. Dr. Benson presented findings at the annual congress of the European Association for Haemophilia and Allied Disorders on behalf of lead author John Pasi, MD, PhD, of the Haemophilia Centre at the Royal London Hospital and colleagues.

Prior to the suspension, 28 patients with hemophilia A or B, with or without inhibitors, were given 50-80 mg of fitusiran for up to 20 months with a median dose duration of 11 months. During dosing suspension, the investigators measured AT levels, thrombin generation, and annualized bleeding rates (ABR).

“We can see that the antithrombin knockdown effect of fitusiran is reversible with dosing hold,” Dr. Benson said, referring to an upward trend of median AT level.

Within 4 months of stopping fitusiran, median AT level was 60% of normal. This level continued to rise to about 90% by month 7, before returning to normal at month 11.

“This is an AT recovery we had previously seen by a few subjects that had discontinued [fitusiran] prior to the clinical hold,” Dr. Benson said, “but here, with a much larger sample size, we see a fairly consistent AT recovery.”

As expected, while AT levels rose, thrombin generation showed an inverse trend. “We see a similar temporal pattern,” Dr. Benson said. “The bulk of thrombin generation decrease is seen by the 4th month off fitusiran.”

When patients restarted fitusiran after the suspension was lifted, AT levels dropped to about 30% of normal by month 1 and about 20% of normal from month 2 onward. Again, in an inverse manner, thrombin generation increased.

Clinically, changes in AT and thrombin generation before, during, and after study suspension were reflected in median ABR, which rose from 1.43 events per year prior to cessation to 6.47 events per year during treatment hold before falling to 1.25 events per year after restarting fitusiran.

Overall, the results support the efficacy and reversibility of fitusiran. The agent is continuing to be studied in the phase 3 ATLAS trials.

The study was funded by Sanofi Genzyme and Alnylam. Dr. Benson is an employee of Sanofi Genzyme. Other investigators reported financial ties to Sanofi Genzyme, Alnylam, Baxalta, Octapharma, Pfizer, Shire, and others.

SOURCE: Pasi J et al. EAHAD 2019, Abstract OR16.

PRAGUE – Fitusiran, a novel small interfering RNA therapeutic that decreases antithrombin (AT) synthesis and bleeding in patients with hemophilia A or B, with or without inhibitors, is reversible upon dosing cessation and becomes effective again with resumption of dosing. That finding is based on data obtained before, during, and after a phase 2 study dosing suspension.

Will Pass/MDedge News

In September 2017, the fitusiran open-label extension study was suspended to investigate a fatal thrombotic event. The suspension was lifted 3 months later, and the trial continued with reduced doses of replacement factors or bypassing agents for breakthrough bleeds.

The pause in the study was used to gather data about the effects of dosing cessation and resumption, which were reported by coauthor Craig Benson, MD, of Sanofi Genzyme in Cambridge, Mass. Dr. Benson presented findings at the annual congress of the European Association for Haemophilia and Allied Disorders on behalf of lead author John Pasi, MD, PhD, of the Haemophilia Centre at the Royal London Hospital and colleagues.

Prior to the suspension, 28 patients with hemophilia A or B, with or without inhibitors, were given 50-80 mg of fitusiran for up to 20 months with a median dose duration of 11 months. During dosing suspension, the investigators measured AT levels, thrombin generation, and annualized bleeding rates (ABR).

“We can see that the antithrombin knockdown effect of fitusiran is reversible with dosing hold,” Dr. Benson said, referring to an upward trend of median AT level.

Within 4 months of stopping fitusiran, median AT level was 60% of normal. This level continued to rise to about 90% by month 7, before returning to normal at month 11.

“This is an AT recovery we had previously seen by a few subjects that had discontinued [fitusiran] prior to the clinical hold,” Dr. Benson said, “but here, with a much larger sample size, we see a fairly consistent AT recovery.”

As expected, while AT levels rose, thrombin generation showed an inverse trend. “We see a similar temporal pattern,” Dr. Benson said. “The bulk of thrombin generation decrease is seen by the 4th month off fitusiran.”

When patients restarted fitusiran after the suspension was lifted, AT levels dropped to about 30% of normal by month 1 and about 20% of normal from month 2 onward. Again, in an inverse manner, thrombin generation increased.

Clinically, changes in AT and thrombin generation before, during, and after study suspension were reflected in median ABR, which rose from 1.43 events per year prior to cessation to 6.47 events per year during treatment hold before falling to 1.25 events per year after restarting fitusiran.

Overall, the results support the efficacy and reversibility of fitusiran. The agent is continuing to be studied in the phase 3 ATLAS trials.

The study was funded by Sanofi Genzyme and Alnylam. Dr. Benson is an employee of Sanofi Genzyme. Other investigators reported financial ties to Sanofi Genzyme, Alnylam, Baxalta, Octapharma, Pfizer, Shire, and others.

SOURCE: Pasi J et al. EAHAD 2019, Abstract OR16.

Patient-specific half maximal factor VIII effective concentrations measured using thromboelastography may be an accurate biomarker to predict efficacy of prophylaxis in severe hemophilia A.

Ihosvany Fernández-Bello, PhD, of La Paz University Hospital in Spain, along with his colleagues, used thromboelastography to investigate the pharmacodynamics of FVIII in young patients with severe hemophilia A who were under a long-term-prophylactic regimen. The findings of the observational, cross-sectional study were published in the European Journal of Pharmaceutical Sciences.

The researchers followed 19 patients under 18 years of age with severe hemophilia A receiving prophylactic treatment. They analyzed their joint condition, bleeding phenotype, and physical activity, compared with their individual pharmacodynamic/pharmacokinetic parameters of FVIII.

They analyzed whole blood withdrawn before FVIII administration and at five time points after treatment. Treated spontaneous bleeding events in the previous 2 years were retrospectively assessed.

Dr. Fernández-Bello and his colleagues measured half maximal factor VIII effective concentrations using thromboelastography, which was correlated with variables related to individual bleeding phenotype.

After analysis, only half maximal FVIII effective concentration of FVIII for thromboelastography parameters R-time, K-time, and alpha-angle were correlated with the bleeding phenotype. Other parameters, including joint condition, type of prophylaxis regimen, and FVIII trough concentrations were not predictive of bleeding phenotype.

“Our results are encouraging and offer the added value of having been obtained in a particularly fragile population considered particularly difficult to study,” they wrote.

The authors noted two key limitations were the small sample size and retrospective nature of the study. Despite the low number of participants, statistical significance of key bleeding outcomes were still achieved.

“This study reveals [half maximal effective concentration of FVIII] for the first time as a valuable biomarker to anticipate individual efficacy of prophylaxis in [severe hemophilia A],” they concluded.

The study was supported by grant funding from Novo Nordisk, the World Federation of Hemophilia, and the Spanish Society of Thrombosis and Hemostasis. The authors’ financial affiliations were not reported.

SOURCE: Fernández-Bello I et al. Eur J Pharm Sci. 2019 Feb 1;128:215-21.

Patient-specific half maximal factor VIII effective concentrations measured using thromboelastography may be an accurate biomarker to predict efficacy of prophylaxis in severe hemophilia A.

Ihosvany Fernández-Bello, PhD, of La Paz University Hospital in Spain, along with his colleagues, used thromboelastography to investigate the pharmacodynamics of FVIII in young patients with severe hemophilia A who were under a long-term-prophylactic regimen. The findings of the observational, cross-sectional study were published in the European Journal of Pharmaceutical Sciences.

The researchers followed 19 patients under 18 years of age with severe hemophilia A receiving prophylactic treatment. They analyzed their joint condition, bleeding phenotype, and physical activity, compared with their individual pharmacodynamic/pharmacokinetic parameters of FVIII.

They analyzed whole blood withdrawn before FVIII administration and at five time points after treatment. Treated spontaneous bleeding events in the previous 2 years were retrospectively assessed.

Dr. Fernández-Bello and his colleagues measured half maximal factor VIII effective concentrations using thromboelastography, which was correlated with variables related to individual bleeding phenotype.

After analysis, only half maximal FVIII effective concentration of FVIII for thromboelastography parameters R-time, K-time, and alpha-angle were correlated with the bleeding phenotype. Other parameters, including joint condition, type of prophylaxis regimen, and FVIII trough concentrations were not predictive of bleeding phenotype.

“Our results are encouraging and offer the added value of having been obtained in a particularly fragile population considered particularly difficult to study,” they wrote.

The authors noted two key limitations were the small sample size and retrospective nature of the study. Despite the low number of participants, statistical significance of key bleeding outcomes were still achieved.

“This study reveals [half maximal effective concentration of FVIII] for the first time as a valuable biomarker to anticipate individual efficacy of prophylaxis in [severe hemophilia A],” they concluded.

The study was supported by grant funding from Novo Nordisk, the World Federation of Hemophilia, and the Spanish Society of Thrombosis and Hemostasis. The authors’ financial affiliations were not reported.

SOURCE: Fernández-Bello I et al. Eur J Pharm Sci. 2019 Feb 1;128:215-21.

Patient-specific half maximal factor VIII effective concentrations measured using thromboelastography may be an accurate biomarker to predict efficacy of prophylaxis in severe hemophilia A.

Ihosvany Fernández-Bello, PhD, of La Paz University Hospital in Spain, along with his colleagues, used thromboelastography to investigate the pharmacodynamics of FVIII in young patients with severe hemophilia A who were under a long-term-prophylactic regimen. The findings of the observational, cross-sectional study were published in the European Journal of Pharmaceutical Sciences.

The researchers followed 19 patients under 18 years of age with severe hemophilia A receiving prophylactic treatment. They analyzed their joint condition, bleeding phenotype, and physical activity, compared with their individual pharmacodynamic/pharmacokinetic parameters of FVIII.

They analyzed whole blood withdrawn before FVIII administration and at five time points after treatment. Treated spontaneous bleeding events in the previous 2 years were retrospectively assessed.

Dr. Fernández-Bello and his colleagues measured half maximal factor VIII effective concentrations using thromboelastography, which was correlated with variables related to individual bleeding phenotype.

After analysis, only half maximal FVIII effective concentration of FVIII for thromboelastography parameters R-time, K-time, and alpha-angle were correlated with the bleeding phenotype. Other parameters, including joint condition, type of prophylaxis regimen, and FVIII trough concentrations were not predictive of bleeding phenotype.

“Our results are encouraging and offer the added value of having been obtained in a particularly fragile population considered particularly difficult to study,” they wrote.

The authors noted two key limitations were the small sample size and retrospective nature of the study. Despite the low number of participants, statistical significance of key bleeding outcomes were still achieved.

“This study reveals [half maximal effective concentration of FVIII] for the first time as a valuable biomarker to anticipate individual efficacy of prophylaxis in [severe hemophilia A],” they concluded.

The study was supported by grant funding from Novo Nordisk, the World Federation of Hemophilia, and the Spanish Society of Thrombosis and Hemostasis. The authors’ financial affiliations were not reported.

SOURCE: Fernández-Bello I et al. Eur J Pharm Sci. 2019 Feb 1;128:215-21.

PRAGUE—For previously untreated patients (PUPs) with severe hemophilia A, the risk of developing factor VIII (FVIII) alloantibodies (inhibitors) becomes negligible after 75 exposure days, according to a recent study involving more than 1,000 infants.

Will Pass/ MDedge News

This finding answers a long-standing and important question in the management of hemophilia A, reported lead author H. Marijke van den Berg, MD, PhD, of University Medical Centre in Utrecht, The Netherlands.

Inhibitor development is the biggest safety concern facing infants with severe hemophilia A because it affects 25%-35% of the patient population, but no previous studies have adequately described the associated risk profile, she noted.

“Most studies until now collected data until about 50 [exposure days] and not that far beyond,” Dr. van den Berg said at the annual congress of the European Association for Haemophilia and Allied Disorders. “So we were interested to see the serum plateau in our large cohort.”

Such a plateau would represent the time point at which risk of inhibitor development approaches zero.

Dr. van den Berg and her colleagues followed 1,038 PUPs with severe hemophilia A from first exposure to FVIII onward. Data were from drawn from the PedNet Registry. From the initial group, 943 patients (91%) were followed until 50 exposure days, and 899 (87%) were followed until 75 exposure days.

Inhibitor development was defined by a minimum of two positive inhibitor titers. In addition to determining the point in time of inhibitor development, the investigators performed a survival analysis for inhibitor incidence and reported median ages at first exposure and at exposure day 75.

The results showed that 298 out of 300 instances of inhibitor development occurred within 75 exposure days, and no inhibitors developed between exposure day 75 and 150. The final two instances occurred at exposure day 249 and 262, both with a low titer.

Median age at first exposure was 1.1 years, compared with 2.3 years at exposure day 75.

These findings suggest that risk of inhibitors is “near zero” after 75 days and that risk is approaching zero just 1 year after first exposure to FVIII, she said.

The results from this study could affect the design of future clinical trials for PUPs.

“Our recommendation will be to continue frequent [inhibitor] testing until 75 exposure days,” Dr. van den Berg said.

The time frame involved is very short, so close monitoring should be feasible for investigators, she noted.

Dr. van den Berg said that additional data, including Kaplan-Meier curves, would “hopefully” be published in a journal soon.

Dr. van den Berg reported having no relevant financial disclosures.

SOURCE: van den Berg HM et al. EAHAD 2019, Abstract OR05.

PRAGUE—For previously untreated patients (PUPs) with severe hemophilia A, the risk of developing factor VIII (FVIII) alloantibodies (inhibitors) becomes negligible after 75 exposure days, according to a recent study involving more than 1,000 infants.

Will Pass/ MDedge News

This finding answers a long-standing and important question in the management of hemophilia A, reported lead author H. Marijke van den Berg, MD, PhD, of University Medical Centre in Utrecht, The Netherlands.

Inhibitor development is the biggest safety concern facing infants with severe hemophilia A because it affects 25%-35% of the patient population, but no previous studies have adequately described the associated risk profile, she noted.

“Most studies until now collected data until about 50 [exposure days] and not that far beyond,” Dr. van den Berg said at the annual congress of the European Association for Haemophilia and Allied Disorders. “So we were interested to see the serum plateau in our large cohort.”

Such a plateau would represent the time point at which risk of inhibitor development approaches zero.

Dr. van den Berg and her colleagues followed 1,038 PUPs with severe hemophilia A from first exposure to FVIII onward. Data were from drawn from the PedNet Registry. From the initial group, 943 patients (91%) were followed until 50 exposure days, and 899 (87%) were followed until 75 exposure days.

Inhibitor development was defined by a minimum of two positive inhibitor titers. In addition to determining the point in time of inhibitor development, the investigators performed a survival analysis for inhibitor incidence and reported median ages at first exposure and at exposure day 75.

The results showed that 298 out of 300 instances of inhibitor development occurred within 75 exposure days, and no inhibitors developed between exposure day 75 and 150. The final two instances occurred at exposure day 249 and 262, both with a low titer.

Median age at first exposure was 1.1 years, compared with 2.3 years at exposure day 75.

These findings suggest that risk of inhibitors is “near zero” after 75 days and that risk is approaching zero just 1 year after first exposure to FVIII, she said.

The results from this study could affect the design of future clinical trials for PUPs.

“Our recommendation will be to continue frequent [inhibitor] testing until 75 exposure days,” Dr. van den Berg said.

The time frame involved is very short, so close monitoring should be feasible for investigators, she noted.

Dr. van den Berg said that additional data, including Kaplan-Meier curves, would “hopefully” be published in a journal soon.

Dr. van den Berg reported having no relevant financial disclosures.

SOURCE: van den Berg HM et al. EAHAD 2019, Abstract OR05.

PRAGUE—For previously untreated patients (PUPs) with severe hemophilia A, the risk of developing factor VIII (FVIII) alloantibodies (inhibitors) becomes negligible after 75 exposure days, according to a recent study involving more than 1,000 infants.

Will Pass/ MDedge News

This finding answers a long-standing and important question in the management of hemophilia A, reported lead author H. Marijke van den Berg, MD, PhD, of University Medical Centre in Utrecht, The Netherlands.

Inhibitor development is the biggest safety concern facing infants with severe hemophilia A because it affects 25%-35% of the patient population, but no previous studies have adequately described the associated risk profile, she noted.

“Most studies until now collected data until about 50 [exposure days] and not that far beyond,” Dr. van den Berg said at the annual congress of the European Association for Haemophilia and Allied Disorders. “So we were interested to see the serum plateau in our large cohort.”

Such a plateau would represent the time point at which risk of inhibitor development approaches zero.

Dr. van den Berg and her colleagues followed 1,038 PUPs with severe hemophilia A from first exposure to FVIII onward. Data were from drawn from the PedNet Registry. From the initial group, 943 patients (91%) were followed until 50 exposure days, and 899 (87%) were followed until 75 exposure days.

Inhibitor development was defined by a minimum of two positive inhibitor titers. In addition to determining the point in time of inhibitor development, the investigators performed a survival analysis for inhibitor incidence and reported median ages at first exposure and at exposure day 75.

The results showed that 298 out of 300 instances of inhibitor development occurred within 75 exposure days, and no inhibitors developed between exposure day 75 and 150. The final two instances occurred at exposure day 249 and 262, both with a low titer.

Median age at first exposure was 1.1 years, compared with 2.3 years at exposure day 75.

These findings suggest that risk of inhibitors is “near zero” after 75 days and that risk is approaching zero just 1 year after first exposure to FVIII, she said.

The results from this study could affect the design of future clinical trials for PUPs.

“Our recommendation will be to continue frequent [inhibitor] testing until 75 exposure days,” Dr. van den Berg said.

The time frame involved is very short, so close monitoring should be feasible for investigators, she noted.

Dr. van den Berg said that additional data, including Kaplan-Meier curves, would “hopefully” be published in a journal soon.

Dr. van den Berg reported having no relevant financial disclosures.

SOURCE: van den Berg HM et al. EAHAD 2019, Abstract OR05.

PRAGUE – Despite improvements over the past 60 years, intracranial hemorrhage (ICH) remains a significant complication in hemophilia, occurring most frequently among patients with severe forms of the disease, according to a large-scale meta-analysis involving 56 studies and nearly 80,000 patients.

Will Pass/MDedge News

The consequences of a single incident of ICH can be irreparable and life-changing, so clinician knowledge of incidence rates and risk factors is essential, said lead author Anne-Fleur Zwagemaker, a PhD candidate from Amsterdam University Medical Center.

“Intracranial hemorrhage is one of the most severe and fearful complications in hemophilia,” Ms. Zwagemaker said in a presentation at the annual congress of the European Association for Haemophilia and Allied Disorders. “Our aim was to give more precise estimates of ICH numbers and risk factors in hemophilia.”

The review is notable for its scale and quality. After eliminating studies with fewer than 50 patients or other insufficiencies, the investigators were left with 56 studies conducted between 1960 and 2018, involving 79,818 patients with hemophilia. With a mean observation period of 12 years, the data encompassed almost 1 million person-years of data.

Across all studies, 1,508 ICH events were reported. Incidence and mortality rates were 400 and 80 per 100,000 person-years, respectively.

To optimize accuracy, the investigators further restricted studies to those with a sample size of at least 365 patients, leading to a pooled incidence rate of 3.8%. Studies with relevant data showed that about half of the cases of ICH (48%) were spontaneous. Regarding most common bleed locations, about two-thirds were either subdural (30%) or intracerebral (32%).

Pooled incidence rates of ICH have decreased steadily over time, from 7%-8% during the 1960-1979 time period, to 5%-6% from 1980-1999, and most recently to about 3%.

Mortality rates during the same time periods decreased in a similar fashion, from 300, to 100, to 75 deaths per 100,000 person-years.

Additional analysis revealed an expected relationship between disease severity and likelihood of ICH. Mild cases of hemophilia had an ICH incidence rate of 0.9%, moderate cases had a rate of 1.3%, and severe cases topped the scale at 4.5%, entailing an incidence rate ratio of 2.7 between severe and nonsevere patients.

“I think our data show that in hemophilia, ICH is still a very important and frequent complication,” Ms. Zwagemaker said. “Luckily, we also see a decline in numbers, but I think it’s still very important that we identify those at risk in hemophilia and that we acknowledge it’s still a very important problem.”

Dr. Zwagemaker reported having no relevant financial disclosures.

SOURCE: Zwagemaker AF et al. EAHAD 2019, Abstract OR08.

PRAGUE – Despite improvements over the past 60 years, intracranial hemorrhage (ICH) remains a significant complication in hemophilia, occurring most frequently among patients with severe forms of the disease, according to a large-scale meta-analysis involving 56 studies and nearly 80,000 patients.

Will Pass/MDedge News

The consequences of a single incident of ICH can be irreparable and life-changing, so clinician knowledge of incidence rates and risk factors is essential, said lead author Anne-Fleur Zwagemaker, a PhD candidate from Amsterdam University Medical Center.

“Intracranial hemorrhage is one of the most severe and fearful complications in hemophilia,” Ms. Zwagemaker said in a presentation at the annual congress of the European Association for Haemophilia and Allied Disorders. “Our aim was to give more precise estimates of ICH numbers and risk factors in hemophilia.”

The review is notable for its scale and quality. After eliminating studies with fewer than 50 patients or other insufficiencies, the investigators were left with 56 studies conducted between 1960 and 2018, involving 79,818 patients with hemophilia. With a mean observation period of 12 years, the data encompassed almost 1 million person-years of data.

Across all studies, 1,508 ICH events were reported. Incidence and mortality rates were 400 and 80 per 100,000 person-years, respectively.

To optimize accuracy, the investigators further restricted studies to those with a sample size of at least 365 patients, leading to a pooled incidence rate of 3.8%. Studies with relevant data showed that about half of the cases of ICH (48%) were spontaneous. Regarding most common bleed locations, about two-thirds were either subdural (30%) or intracerebral (32%).

Pooled incidence rates of ICH have decreased steadily over time, from 7%-8% during the 1960-1979 time period, to 5%-6% from 1980-1999, and most recently to about 3%.

Mortality rates during the same time periods decreased in a similar fashion, from 300, to 100, to 75 deaths per 100,000 person-years.

Additional analysis revealed an expected relationship between disease severity and likelihood of ICH. Mild cases of hemophilia had an ICH incidence rate of 0.9%, moderate cases had a rate of 1.3%, and severe cases topped the scale at 4.5%, entailing an incidence rate ratio of 2.7 between severe and nonsevere patients.

“I think our data show that in hemophilia, ICH is still a very important and frequent complication,” Ms. Zwagemaker said. “Luckily, we also see a decline in numbers, but I think it’s still very important that we identify those at risk in hemophilia and that we acknowledge it’s still a very important problem.”

Dr. Zwagemaker reported having no relevant financial disclosures.

SOURCE: Zwagemaker AF et al. EAHAD 2019, Abstract OR08.

PRAGUE – Despite improvements over the past 60 years, intracranial hemorrhage (ICH) remains a significant complication in hemophilia, occurring most frequently among patients with severe forms of the disease, according to a large-scale meta-analysis involving 56 studies and nearly 80,000 patients.

Will Pass/MDedge News

The consequences of a single incident of ICH can be irreparable and life-changing, so clinician knowledge of incidence rates and risk factors is essential, said lead author Anne-Fleur Zwagemaker, a PhD candidate from Amsterdam University Medical Center.

“Intracranial hemorrhage is one of the most severe and fearful complications in hemophilia,” Ms. Zwagemaker said in a presentation at the annual congress of the European Association for Haemophilia and Allied Disorders. “Our aim was to give more precise estimates of ICH numbers and risk factors in hemophilia.”

The review is notable for its scale and quality. After eliminating studies with fewer than 50 patients or other insufficiencies, the investigators were left with 56 studies conducted between 1960 and 2018, involving 79,818 patients with hemophilia. With a mean observation period of 12 years, the data encompassed almost 1 million person-years of data.

Across all studies, 1,508 ICH events were reported. Incidence and mortality rates were 400 and 80 per 100,000 person-years, respectively.

To optimize accuracy, the investigators further restricted studies to those with a sample size of at least 365 patients, leading to a pooled incidence rate of 3.8%. Studies with relevant data showed that about half of the cases of ICH (48%) were spontaneous. Regarding most common bleed locations, about two-thirds were either subdural (30%) or intracerebral (32%).

Pooled incidence rates of ICH have decreased steadily over time, from 7%-8% during the 1960-1979 time period, to 5%-6% from 1980-1999, and most recently to about 3%.

Mortality rates during the same time periods decreased in a similar fashion, from 300, to 100, to 75 deaths per 100,000 person-years.

Additional analysis revealed an expected relationship between disease severity and likelihood of ICH. Mild cases of hemophilia had an ICH incidence rate of 0.9%, moderate cases had a rate of 1.3%, and severe cases topped the scale at 4.5%, entailing an incidence rate ratio of 2.7 between severe and nonsevere patients.

“I think our data show that in hemophilia, ICH is still a very important and frequent complication,” Ms. Zwagemaker said. “Luckily, we also see a decline in numbers, but I think it’s still very important that we identify those at risk in hemophilia and that we acknowledge it’s still a very important problem.”

Dr. Zwagemaker reported having no relevant financial disclosures.

SOURCE: Zwagemaker AF et al. EAHAD 2019, Abstract OR08.

The antifibrinolytic drug tranexamic acid appears to significantly improve quality of life for young women who experience heavy menstrual bleeding, new research suggests.

Writing in the Journal of Pediatric & Adolescent Gynecology, Sarah H. O’Brien, MD, from Nationwide Children’s Hospital and the Ohio State University, both in Columbus, and her coauthors presented the results of an open-label efficacy study of the competitive plasminogen inhibitor in 25 adolescent girls aged 10-19 years who attended pediatric hematology clinics for evaluation or management of heavy menstrual bleeding. The study participants were instructed to take 1,300 mg of tranexamic acid (two tablets) three times a day for up to 5 days during their monthly menstruation for three cycles.

The study found a significant improvement in mean menstrual impact questionnaire (MIQ) scores, which improved from a mean of 3 at baseline to 1.91 (P less than .001). Two-thirds of patients reported at least a one-point improvement from baseline, and all reported that this was clinically meaningful. At baseline, 84% of patients reported heavy to very heavy blood loss, but this decreased to 23% after treatment with tranexamic acid (P less than .001).

The study population included ten individuals (40%) with bleeding disorders. However, the researchers did not see a significant difference in response between those with bleeding disorders and those without.

While the treatment did not significantly affect school attendance (only 24% reported that their heavy bleeding limited school attendance), researchers did see a significant improvement in limitations on physical activities and on social and leisure activities. Patients who reported at baseline that their menstrual bleeding significantly affected their social and leisure activities had an average score improvement of 1.74, a greater than or equal to one point improvement. Participants also reported significant improvements in their Pictorial Blood Assessment Chart scores, which dropped from an average of 255 to 155 (P less than .001).

The treatment did not show any significant effects on hemoglobin or ferritin. The most common adverse events were sinonasal symptoms, such as nasal congestion, headache, and sinus pain, but no thrombotic or ocular adverse events were seen.

Dr. O’Brien and her coauthors wrote that one limitation of their study was using the MIQ score as their primary endpoint as opposed to a more objective measure, such as change in measured blood loss.

“However, a major factor that motivates patients with heavy menstrual bleeding to seek medical care is the negative impact of heavy menstrual bleeding on daily life,” they wrote.

The study drug was supplied by Ferring pharmaceuticals, and the study was supported by the Hemostasis and Thrombosis Research Society. One author disclosed receiving the Joan Fellowship in Pediatric Hemostasis and Thrombosis at Nationwide Children’s Hospital; no other authors said they had relevant financial disclosures.

SOURCE: O’Brien SH et al. J Pediatr Adol Gynec. 2019 Feb 4. doi: 10.1016/j.jpag.2019.01.009.

The antifibrinolytic drug tranexamic acid appears to significantly improve quality of life for young women who experience heavy menstrual bleeding, new research suggests.

Writing in the Journal of Pediatric & Adolescent Gynecology, Sarah H. O’Brien, MD, from Nationwide Children’s Hospital and the Ohio State University, both in Columbus, and her coauthors presented the results of an open-label efficacy study of the competitive plasminogen inhibitor in 25 adolescent girls aged 10-19 years who attended pediatric hematology clinics for evaluation or management of heavy menstrual bleeding. The study participants were instructed to take 1,300 mg of tranexamic acid (two tablets) three times a day for up to 5 days during their monthly menstruation for three cycles.

The study found a significant improvement in mean menstrual impact questionnaire (MIQ) scores, which improved from a mean of 3 at baseline to 1.91 (P less than .001). Two-thirds of patients reported at least a one-point improvement from baseline, and all reported that this was clinically meaningful. At baseline, 84% of patients reported heavy to very heavy blood loss, but this decreased to 23% after treatment with tranexamic acid (P less than .001).

The study population included ten individuals (40%) with bleeding disorders. However, the researchers did not see a significant difference in response between those with bleeding disorders and those without.

While the treatment did not significantly affect school attendance (only 24% reported that their heavy bleeding limited school attendance), researchers did see a significant improvement in limitations on physical activities and on social and leisure activities. Patients who reported at baseline that their menstrual bleeding significantly affected their social and leisure activities had an average score improvement of 1.74, a greater than or equal to one point improvement. Participants also reported significant improvements in their Pictorial Blood Assessment Chart scores, which dropped from an average of 255 to 155 (P less than .001).

The treatment did not show any significant effects on hemoglobin or ferritin. The most common adverse events were sinonasal symptoms, such as nasal congestion, headache, and sinus pain, but no thrombotic or ocular adverse events were seen.

Dr. O’Brien and her coauthors wrote that one limitation of their study was using the MIQ score as their primary endpoint as opposed to a more objective measure, such as change in measured blood loss.

“However, a major factor that motivates patients with heavy menstrual bleeding to seek medical care is the negative impact of heavy menstrual bleeding on daily life,” they wrote.

The study drug was supplied by Ferring pharmaceuticals, and the study was supported by the Hemostasis and Thrombosis Research Society. One author disclosed receiving the Joan Fellowship in Pediatric Hemostasis and Thrombosis at Nationwide Children’s Hospital; no other authors said they had relevant financial disclosures.

SOURCE: O’Brien SH et al. J Pediatr Adol Gynec. 2019 Feb 4. doi: 10.1016/j.jpag.2019.01.009.

The antifibrinolytic drug tranexamic acid appears to significantly improve quality of life for young women who experience heavy menstrual bleeding, new research suggests.

Writing in the Journal of Pediatric & Adolescent Gynecology, Sarah H. O’Brien, MD, from Nationwide Children’s Hospital and the Ohio State University, both in Columbus, and her coauthors presented the results of an open-label efficacy study of the competitive plasminogen inhibitor in 25 adolescent girls aged 10-19 years who attended pediatric hematology clinics for evaluation or management of heavy menstrual bleeding. The study participants were instructed to take 1,300 mg of tranexamic acid (two tablets) three times a day for up to 5 days during their monthly menstruation for three cycles.

The study found a significant improvement in mean menstrual impact questionnaire (MIQ) scores, which improved from a mean of 3 at baseline to 1.91 (P less than .001). Two-thirds of patients reported at least a one-point improvement from baseline, and all reported that this was clinically meaningful. At baseline, 84% of patients reported heavy to very heavy blood loss, but this decreased to 23% after treatment with tranexamic acid (P less than .001).

The study population included ten individuals (40%) with bleeding disorders. However, the researchers did not see a significant difference in response between those with bleeding disorders and those without.

While the treatment did not significantly affect school attendance (only 24% reported that their heavy bleeding limited school attendance), researchers did see a significant improvement in limitations on physical activities and on social and leisure activities. Patients who reported at baseline that their menstrual bleeding significantly affected their social and leisure activities had an average score improvement of 1.74, a greater than or equal to one point improvement. Participants also reported significant improvements in their Pictorial Blood Assessment Chart scores, which dropped from an average of 255 to 155 (P less than .001).

The treatment did not show any significant effects on hemoglobin or ferritin. The most common adverse events were sinonasal symptoms, such as nasal congestion, headache, and sinus pain, but no thrombotic or ocular adverse events were seen.

Dr. O’Brien and her coauthors wrote that one limitation of their study was using the MIQ score as their primary endpoint as opposed to a more objective measure, such as change in measured blood loss.

“However, a major factor that motivates patients with heavy menstrual bleeding to seek medical care is the negative impact of heavy menstrual bleeding on daily life,” they wrote.

The study drug was supplied by Ferring pharmaceuticals, and the study was supported by the Hemostasis and Thrombosis Research Society. One author disclosed receiving the Joan Fellowship in Pediatric Hemostasis and Thrombosis at Nationwide Children’s Hospital; no other authors said they had relevant financial disclosures.

SOURCE: O’Brien SH et al. J Pediatr Adol Gynec. 2019 Feb 4. doi: 10.1016/j.jpag.2019.01.009.

The Food and Drug Administration has approved caplacizumab (Cablivi) in combination with plasma exchange and immunosuppressive therapy for the treatment of adults with acquired thrombotic thrombocytopenic purpura (aTTP).

Caplacizumab is an anti–von Willebrand factor nanobody designed to inhibit the interaction between von Willebrand factor and platelets. The injection previously received orphan drug designation from the FDA and was approved under priority review.

The FDA’s approval of caplacizumab was based on results from the phase 3 HERCULES trial (N Engl J Med 2019 Jan 24;380:335-46).

The trial (NCT02553317) included 145 adults with aTTP. They were randomized to receive caplacizumab (n = 72) or placebo (n = 73), in addition to plasma exchange and immunosuppression.

The study’s primary endpoint was the time to platelet count response (normalization), which was defined as a platelet count of at least 150 x 10⁹/L with subsequent stop of daily plasma exchange within 5 days.

There was a significant reduction in time to platelet count response in the caplacizumab arm, compared with the placebo arm – 2.69 days and 2.88 days, respectively. The platelet normalization rate ratio was 1.55 (P less than .01).

A secondary endpoint was the combination of aTTP-related death, aTTP recurrence, and at least one major thromboembolic event during study treatment. The incidence of this combined endpoint was 12% in the caplacizumab arm and 49% in the placebo arm (P less than .001).

The most common treatment-emergent adverse events (occurring in at least 15% of patients in the caplacizumab and placebo arms, respectively) were epistaxis (32% and 3%), headache (23% and 8%), urticaria (17% and 7%), and hypokalemia (9% and 19%).

During the treatment period, there were no deaths in the caplacizumab arm and three deaths in the placebo arm. There was one death (from cerebral ischemia) in the caplacizumab arm during the follow-up period, but it was considered unrelated to caplacizumab.

For more details on caplacizumab, see the full prescribing information.

[email protected]

The Food and Drug Administration has approved caplacizumab (Cablivi) in combination with plasma exchange and immunosuppressive therapy for the treatment of adults with acquired thrombotic thrombocytopenic purpura (aTTP).

Caplacizumab is an anti–von Willebrand factor nanobody designed to inhibit the interaction between von Willebrand factor and platelets. The injection previously received orphan drug designation from the FDA and was approved under priority review.

The FDA’s approval of caplacizumab was based on results from the phase 3 HERCULES trial (N Engl J Med 2019 Jan 24;380:335-46).

The trial (NCT02553317) included 145 adults with aTTP. They were randomized to receive caplacizumab (n = 72) or placebo (n = 73), in addition to plasma exchange and immunosuppression.

The study’s primary endpoint was the time to platelet count response (normalization), which was defined as a platelet count of at least 150 x 10⁹/L with subsequent stop of daily plasma exchange within 5 days.

There was a significant reduction in time to platelet count response in the caplacizumab arm, compared with the placebo arm – 2.69 days and 2.88 days, respectively. The platelet normalization rate ratio was 1.55 (P less than .01).

A secondary endpoint was the combination of aTTP-related death, aTTP recurrence, and at least one major thromboembolic event during study treatment. The incidence of this combined endpoint was 12% in the caplacizumab arm and 49% in the placebo arm (P less than .001).

The most common treatment-emergent adverse events (occurring in at least 15% of patients in the caplacizumab and placebo arms, respectively) were epistaxis (32% and 3%), headache (23% and 8%), urticaria (17% and 7%), and hypokalemia (9% and 19%).

During the treatment period, there were no deaths in the caplacizumab arm and three deaths in the placebo arm. There was one death (from cerebral ischemia) in the caplacizumab arm during the follow-up period, but it was considered unrelated to caplacizumab.

For more details on caplacizumab, see the full prescribing information.

[email protected]

The Food and Drug Administration has approved caplacizumab (Cablivi) in combination with plasma exchange and immunosuppressive therapy for the treatment of adults with acquired thrombotic thrombocytopenic purpura (aTTP).

Caplacizumab is an anti–von Willebrand factor nanobody designed to inhibit the interaction between von Willebrand factor and platelets. The injection previously received orphan drug designation from the FDA and was approved under priority review.

The FDA’s approval of caplacizumab was based on results from the phase 3 HERCULES trial (N Engl J Med 2019 Jan 24;380:335-46).

The trial (NCT02553317) included 145 adults with aTTP. They were randomized to receive caplacizumab (n = 72) or placebo (n = 73), in addition to plasma exchange and immunosuppression.

The study’s primary endpoint was the time to platelet count response (normalization), which was defined as a platelet count of at least 150 x 10⁹/L with subsequent stop of daily plasma exchange within 5 days.

There was a significant reduction in time to platelet count response in the caplacizumab arm, compared with the placebo arm – 2.69 days and 2.88 days, respectively. The platelet normalization rate ratio was 1.55 (P less than .01).

A secondary endpoint was the combination of aTTP-related death, aTTP recurrence, and at least one major thromboembolic event during study treatment. The incidence of this combined endpoint was 12% in the caplacizumab arm and 49% in the placebo arm (P less than .001).

The most common treatment-emergent adverse events (occurring in at least 15% of patients in the caplacizumab and placebo arms, respectively) were epistaxis (32% and 3%), headache (23% and 8%), urticaria (17% and 7%), and hypokalemia (9% and 19%).

During the treatment period, there were no deaths in the caplacizumab arm and three deaths in the placebo arm. There was one death (from cerebral ischemia) in the caplacizumab arm during the follow-up period, but it was considered unrelated to caplacizumab.

For more details on caplacizumab, see the full prescribing information.

[email protected]