ISTH 2017

Vials and a syringe

BERLIN—Results of a phase 3 study suggest prophylaxis with plasma-derived factor X (pdFX, Coagadex®) prevents or reduces bleeding episodes in children with moderate to severe hereditary factor X deficiency (FXD).

pdFX was well tolerated in this study as well, with no treatment-related adverse events (AEs) reported.

“For the first time, we have data providing physicians with important evidence of the efficacy and safety of Coagadex as a prophylactic regimen for the reduction and prevention of bleeding episodes, as well as potential guidance on dosing for children with hereditary factor X deficiency,” said Michael Gattens, MBChB, a consultant pediatric hematologist at Cambridge University Hospitals in the UK and an investigator involved in this trial.

Data from the trial, known as TEN02, were presented in a poster (PB 818) at the International Society on Thrombosis and Haemostasis (ISTH) 2017 Congress. The trial was sponsored by Bio Products Laboratory Limited.

TEN02 was a prospective study conducted in children younger than 12 years with moderate or severe congenital FXD (basal plasma factor X activity <5 IU/dL at diagnosis) and either a history of severe bleeding or an F10 gene mutation causing a documented severe bleeding type.

The study enrolled 9 patients. Eight had severe FXD (FX:C <1 IU/dL), and 1 had moderate FXD (FX:C 1–5 IU/dL).

The patients’ mean age was 7.3 (range, 2.6 years to 11.9 years). Four patients were in the 0-5 age group, and 5 were in the 6-11 age group. Fifty-six percent of patients were female, 78% were Asian, and 22% were white.

The patients had a total of 21 prior bleeds, including overt (n=10), covert (n=9), and menorrhagic (n=2). The past bleeds were spontaneous (n=16) or caused by injury (n=2), menorrhagia (n=2), or surgery (n=2).

Treatment

Patients received 50 IU/kg of pdFX at visit 1 (baseline), followed 72 hours later by a second dose (visit 2). At the investigator’s discretion, visit 2 may have been conducted 48 hours after the first dose for subjects ages 0 to 5.

Following visit 2, patients used pdFX at 40-50 IU/kg as routine prophylaxis every 72 ± 2 hours or every 48 ± 2 hours for those age 0 to 5, at the investigator’s discretion. Dose and frequency were adjusted over the initial 6 weeks to maintain FX:C levels ≥5 IU/dL (with peak levels ≤120 IU/dL).

Treatment was continued for at least 26 weeks, with a minimum of 50 treatment days.

Following visit 2, patients returned to the study site for 3 additional visits (after 9-28, 29-42, and 50 treatment days/26 weeks; visits 3-5), during which time blood samples were collected to assess FX:C trough levels and vital signs and AEs were checked.

A final bolus dose of 50 IU/kg was administered during visit 5 to assess post-dose incremental recovery.

A dose of 25 IU/kg was recommended to treat minor bleeds, and 50 IU/kg was recommended for major bleeds. Treatment was to be repeated as often as necessary based on FX:C recovery levels and clinical need.

Nine patients completed 11 treatment cycles, including 2 patients who had 50 exposure days but less than 26 study weeks. These patients were re-screened and completed a second, per-protocol treatment cycle.

Results

A total of 537 prophylactic infusions were administered, with a mean dose of 38.6 IU/kg per patient.

Investigators rated the prophylactic efficacy of pdFX as “excellent.”

There were 10 bleeds in 3 patients. Four bleeds in 2 patients (both in the 6-11 age group) required treatment with a single infusion of pdFX (mean dose, 31.7±10.1 IU/kg).

The overall mean 30-minute incremental recovery was 1.66 IU/dL per IU/kg for patients’ baseline visit, 1.82 IU/dL per IU/kg for the end-of-study visit, and 1.74 IU/dL per IU/kg for both visits combined.

Incremental recovery was significantly lower in the 0-5 age group than the 6-11 age group:

• 1.45 vs 1.83 at baseline (P=0.027)
• 1.62 vs 1.99 at end of study (P=0.025)
• 1.53 vs 1.91 combined (P=0.001).

All patients had FX:C trough levels greater than 5% after visit 4 (days 29-42).

There were 28 AEs reported in 8 patients, but none of these events were considered related to treatment.

One patient did have 2 serious treatment-emergent AEs—lower respiratory tract infection and influenza.

There were no other serious AEs, no evidence of factor X inhibitor development, and no deaths.

Vials and a syringe

BERLIN—Results of a phase 3 study suggest prophylaxis with plasma-derived factor X (pdFX, Coagadex®) prevents or reduces bleeding episodes in children with moderate to severe hereditary factor X deficiency (FXD).

pdFX was well tolerated in this study as well, with no treatment-related adverse events (AEs) reported.

“For the first time, we have data providing physicians with important evidence of the efficacy and safety of Coagadex as a prophylactic regimen for the reduction and prevention of bleeding episodes, as well as potential guidance on dosing for children with hereditary factor X deficiency,” said Michael Gattens, MBChB, a consultant pediatric hematologist at Cambridge University Hospitals in the UK and an investigator involved in this trial.

Data from the trial, known as TEN02, were presented in a poster (PB 818) at the International Society on Thrombosis and Haemostasis (ISTH) 2017 Congress. The trial was sponsored by Bio Products Laboratory Limited.

TEN02 was a prospective study conducted in children younger than 12 years with moderate or severe congenital FXD (basal plasma factor X activity <5 IU/dL at diagnosis) and either a history of severe bleeding or an F10 gene mutation causing a documented severe bleeding type.

The study enrolled 9 patients. Eight had severe FXD (FX:C <1 IU/dL), and 1 had moderate FXD (FX:C 1–5 IU/dL).

The patients’ mean age was 7.3 (range, 2.6 years to 11.9 years). Four patients were in the 0-5 age group, and 5 were in the 6-11 age group. Fifty-six percent of patients were female, 78% were Asian, and 22% were white.

The patients had a total of 21 prior bleeds, including overt (n=10), covert (n=9), and menorrhagic (n=2). The past bleeds were spontaneous (n=16) or caused by injury (n=2), menorrhagia (n=2), or surgery (n=2).

Treatment

Patients received 50 IU/kg of pdFX at visit 1 (baseline), followed 72 hours later by a second dose (visit 2). At the investigator’s discretion, visit 2 may have been conducted 48 hours after the first dose for subjects ages 0 to 5.

Following visit 2, patients used pdFX at 40-50 IU/kg as routine prophylaxis every 72 ± 2 hours or every 48 ± 2 hours for those age 0 to 5, at the investigator’s discretion. Dose and frequency were adjusted over the initial 6 weeks to maintain FX:C levels ≥5 IU/dL (with peak levels ≤120 IU/dL).

Treatment was continued for at least 26 weeks, with a minimum of 50 treatment days.

Following visit 2, patients returned to the study site for 3 additional visits (after 9-28, 29-42, and 50 treatment days/26 weeks; visits 3-5), during which time blood samples were collected to assess FX:C trough levels and vital signs and AEs were checked.

A final bolus dose of 50 IU/kg was administered during visit 5 to assess post-dose incremental recovery.

A dose of 25 IU/kg was recommended to treat minor bleeds, and 50 IU/kg was recommended for major bleeds. Treatment was to be repeated as often as necessary based on FX:C recovery levels and clinical need.

Nine patients completed 11 treatment cycles, including 2 patients who had 50 exposure days but less than 26 study weeks. These patients were re-screened and completed a second, per-protocol treatment cycle.

Results

A total of 537 prophylactic infusions were administered, with a mean dose of 38.6 IU/kg per patient.

Investigators rated the prophylactic efficacy of pdFX as “excellent.”

There were 10 bleeds in 3 patients. Four bleeds in 2 patients (both in the 6-11 age group) required treatment with a single infusion of pdFX (mean dose, 31.7±10.1 IU/kg).

The overall mean 30-minute incremental recovery was 1.66 IU/dL per IU/kg for patients’ baseline visit, 1.82 IU/dL per IU/kg for the end-of-study visit, and 1.74 IU/dL per IU/kg for both visits combined.

Incremental recovery was significantly lower in the 0-5 age group than the 6-11 age group:

• 1.45 vs 1.83 at baseline (P=0.027)
• 1.62 vs 1.99 at end of study (P=0.025)
• 1.53 vs 1.91 combined (P=0.001).

All patients had FX:C trough levels greater than 5% after visit 4 (days 29-42).

There were 28 AEs reported in 8 patients, but none of these events were considered related to treatment.

One patient did have 2 serious treatment-emergent AEs—lower respiratory tract infection and influenza.

There were no other serious AEs, no evidence of factor X inhibitor development, and no deaths.

Vials and a syringe

BERLIN—Results of a phase 3 study suggest prophylaxis with plasma-derived factor X (pdFX, Coagadex®) prevents or reduces bleeding episodes in children with moderate to severe hereditary factor X deficiency (FXD).

pdFX was well tolerated in this study as well, with no treatment-related adverse events (AEs) reported.

“For the first time, we have data providing physicians with important evidence of the efficacy and safety of Coagadex as a prophylactic regimen for the reduction and prevention of bleeding episodes, as well as potential guidance on dosing for children with hereditary factor X deficiency,” said Michael Gattens, MBChB, a consultant pediatric hematologist at Cambridge University Hospitals in the UK and an investigator involved in this trial.

Data from the trial, known as TEN02, were presented in a poster (PB 818) at the International Society on Thrombosis and Haemostasis (ISTH) 2017 Congress. The trial was sponsored by Bio Products Laboratory Limited.

TEN02 was a prospective study conducted in children younger than 12 years with moderate or severe congenital FXD (basal plasma factor X activity <5 IU/dL at diagnosis) and either a history of severe bleeding or an F10 gene mutation causing a documented severe bleeding type.

The study enrolled 9 patients. Eight had severe FXD (FX:C <1 IU/dL), and 1 had moderate FXD (FX:C 1–5 IU/dL).

The patients’ mean age was 7.3 (range, 2.6 years to 11.9 years). Four patients were in the 0-5 age group, and 5 were in the 6-11 age group. Fifty-six percent of patients were female, 78% were Asian, and 22% were white.

The patients had a total of 21 prior bleeds, including overt (n=10), covert (n=9), and menorrhagic (n=2). The past bleeds were spontaneous (n=16) or caused by injury (n=2), menorrhagia (n=2), or surgery (n=2).

Treatment

Patients received 50 IU/kg of pdFX at visit 1 (baseline), followed 72 hours later by a second dose (visit 2). At the investigator’s discretion, visit 2 may have been conducted 48 hours after the first dose for subjects ages 0 to 5.

Following visit 2, patients used pdFX at 40-50 IU/kg as routine prophylaxis every 72 ± 2 hours or every 48 ± 2 hours for those age 0 to 5, at the investigator’s discretion. Dose and frequency were adjusted over the initial 6 weeks to maintain FX:C levels ≥5 IU/dL (with peak levels ≤120 IU/dL).

Treatment was continued for at least 26 weeks, with a minimum of 50 treatment days.

Following visit 2, patients returned to the study site for 3 additional visits (after 9-28, 29-42, and 50 treatment days/26 weeks; visits 3-5), during which time blood samples were collected to assess FX:C trough levels and vital signs and AEs were checked.

A final bolus dose of 50 IU/kg was administered during visit 5 to assess post-dose incremental recovery.

A dose of 25 IU/kg was recommended to treat minor bleeds, and 50 IU/kg was recommended for major bleeds. Treatment was to be repeated as often as necessary based on FX:C recovery levels and clinical need.

Nine patients completed 11 treatment cycles, including 2 patients who had 50 exposure days but less than 26 study weeks. These patients were re-screened and completed a second, per-protocol treatment cycle.

Results

A total of 537 prophylactic infusions were administered, with a mean dose of 38.6 IU/kg per patient.

Investigators rated the prophylactic efficacy of pdFX as “excellent.”

There were 10 bleeds in 3 patients. Four bleeds in 2 patients (both in the 6-11 age group) required treatment with a single infusion of pdFX (mean dose, 31.7±10.1 IU/kg).

The overall mean 30-minute incremental recovery was 1.66 IU/dL per IU/kg for patients’ baseline visit, 1.82 IU/dL per IU/kg for the end-of-study visit, and 1.74 IU/dL per IU/kg for both visits combined.

Incremental recovery was significantly lower in the 0-5 age group than the 6-11 age group:

• 1.45 vs 1.83 at baseline (P=0.027)
• 1.62 vs 1.99 at end of study (P=0.025)
• 1.53 vs 1.91 combined (P=0.001).

All patients had FX:C trough levels greater than 5% after visit 4 (days 29-42).

There were 28 AEs reported in 8 patients, but none of these events were considered related to treatment.

One patient did have 2 serious treatment-emergent AEs—lower respiratory tract infection and influenza.

There were no other serious AEs, no evidence of factor X inhibitor development, and no deaths.

Boehringer Ingelheim

BERLIN—Data from the GARFIELD-VTE registry showed that, in the first 6 months after a patient was diagnosed with venous thromboembolism (VTE), death was the most frequent major adverse outcome.

More than half of the deaths were related to cancer, with small percentages of patients dying from VTE complications and bleeding events.

GARFIELD-VTE is a prospective registry designed to provide insight into the management of VTE in everyday clinical practice.

Six-month results from the registry were presented in a poster at the International Society on Thrombosis and Haemostasis (ISTH) 2017 Congress (PB 1196).

The GARFIELD-VTE registry has enrolled more than 10,000 patients with acute VTE—including deep vein thrombosis (DVT) and pulmonary embolism (PE)—from across 415 sites in 28 countries.

Alexander G. G. Turpie, MD, of McMaster University in Hamilton, Ontario, Canada, and his colleagues presented data on 10,315 patients with at least 6 months of follow-up.

Baseline characteristics

The patients’ median age was 60.2 (range, 46.2-71.7), and 49.9% were female. Most patients were white (69.3%), 19.6% were Asian, 4.4% were black, 0.6% were multiracial, 4.3% were classified as “other,” and 1.9% were of unknown race.

Six percent of patients had a family history of VTE (first-degree relatives), 15.1% had a prior episode of DVT and/or PE themselves, and 37.5% had at least 1 provoking factor for VTE.

Most patients (61.8%) had DVT alone, but 38.3% had PE with or without DVT.

The registry included patients with active cancer (9.1%), a history of cancer (10.7%), thrombophilia (2.9%), chronic immobilization (5.6%), heart failure (3.2%), and renal insufficiency (3.5%).

Outcomes

Over 6 months of follow-up, the following events were reported:

• Any bleeding—622 total bleeds or 13.6 per 100 person-years
• All-cause mortality—460 total deaths or 9.7 per 100 person-years
• Recurrent VTE—169 events or 3.6 per 100 person-years
• Major bleeding—106 events or 2.2 per 100 person-years
• Myocardial infarction—42 events or 0.9 per 100 person-years
• Stroke/transient ischemic attack—38 events or 0.8 per 100 person-years.

Nearly 5% of patients died (4.5%, n=460). More than half (54.3%, n=250) of these deaths were cancer-related.

Other causes of death included:

• Cardiac death—7.0% (n=32)
• PE—3.5% (n=16)
• Bleeding—3.3% (n=15)
• VTE complications—1.3% (n=6)
• Stroke—1.1%  (n=5)
• Other cause—17.8% (n=82)
• Unknown cause—11.7% (n=54).

Additional data from the GARFIELD-VTE registry were presented at ISTH 2017 as posters (PB 460 and PB 1188) and in an oral presentation (ASY 35.4). The next set of data from the registry is slated to be presented at the 2017 ASH Annual Meeting.

GARFIELD-VTE is supported by an unrestricted educational grant from Bayer AG. For further information on the registry, visit http://www.garfieldregistry.org.

Boehringer Ingelheim

BERLIN—Data from the GARFIELD-VTE registry showed that, in the first 6 months after a patient was diagnosed with venous thromboembolism (VTE), death was the most frequent major adverse outcome.

More than half of the deaths were related to cancer, with small percentages of patients dying from VTE complications and bleeding events.

GARFIELD-VTE is a prospective registry designed to provide insight into the management of VTE in everyday clinical practice.

Six-month results from the registry were presented in a poster at the International Society on Thrombosis and Haemostasis (ISTH) 2017 Congress (PB 1196).

The GARFIELD-VTE registry has enrolled more than 10,000 patients with acute VTE—including deep vein thrombosis (DVT) and pulmonary embolism (PE)—from across 415 sites in 28 countries.

Alexander G. G. Turpie, MD, of McMaster University in Hamilton, Ontario, Canada, and his colleagues presented data on 10,315 patients with at least 6 months of follow-up.

Baseline characteristics

The patients’ median age was 60.2 (range, 46.2-71.7), and 49.9% were female. Most patients were white (69.3%), 19.6% were Asian, 4.4% were black, 0.6% were multiracial, 4.3% were classified as “other,” and 1.9% were of unknown race.

Six percent of patients had a family history of VTE (first-degree relatives), 15.1% had a prior episode of DVT and/or PE themselves, and 37.5% had at least 1 provoking factor for VTE.

Most patients (61.8%) had DVT alone, but 38.3% had PE with or without DVT.

The registry included patients with active cancer (9.1%), a history of cancer (10.7%), thrombophilia (2.9%), chronic immobilization (5.6%), heart failure (3.2%), and renal insufficiency (3.5%).

Outcomes

Over 6 months of follow-up, the following events were reported:

• Any bleeding—622 total bleeds or 13.6 per 100 person-years
• All-cause mortality—460 total deaths or 9.7 per 100 person-years
• Recurrent VTE—169 events or 3.6 per 100 person-years
• Major bleeding—106 events or 2.2 per 100 person-years
• Myocardial infarction—42 events or 0.9 per 100 person-years
• Stroke/transient ischemic attack—38 events or 0.8 per 100 person-years.

Nearly 5% of patients died (4.5%, n=460). More than half (54.3%, n=250) of these deaths were cancer-related.

Other causes of death included:

• Cardiac death—7.0% (n=32)
• PE—3.5% (n=16)
• Bleeding—3.3% (n=15)
• VTE complications—1.3% (n=6)
• Stroke—1.1%  (n=5)
• Other cause—17.8% (n=82)
• Unknown cause—11.7% (n=54).

Additional data from the GARFIELD-VTE registry were presented at ISTH 2017 as posters (PB 460 and PB 1188) and in an oral presentation (ASY 35.4). The next set of data from the registry is slated to be presented at the 2017 ASH Annual Meeting.

GARFIELD-VTE is supported by an unrestricted educational grant from Bayer AG. For further information on the registry, visit http://www.garfieldregistry.org.

Boehringer Ingelheim

BERLIN—Data from the GARFIELD-VTE registry showed that, in the first 6 months after a patient was diagnosed with venous thromboembolism (VTE), death was the most frequent major adverse outcome.

More than half of the deaths were related to cancer, with small percentages of patients dying from VTE complications and bleeding events.

GARFIELD-VTE is a prospective registry designed to provide insight into the management of VTE in everyday clinical practice.

Six-month results from the registry were presented in a poster at the International Society on Thrombosis and Haemostasis (ISTH) 2017 Congress (PB 1196).

The GARFIELD-VTE registry has enrolled more than 10,000 patients with acute VTE—including deep vein thrombosis (DVT) and pulmonary embolism (PE)—from across 415 sites in 28 countries.

Alexander G. G. Turpie, MD, of McMaster University in Hamilton, Ontario, Canada, and his colleagues presented data on 10,315 patients with at least 6 months of follow-up.

Baseline characteristics

The patients’ median age was 60.2 (range, 46.2-71.7), and 49.9% were female. Most patients were white (69.3%), 19.6% were Asian, 4.4% were black, 0.6% were multiracial, 4.3% were classified as “other,” and 1.9% were of unknown race.

Six percent of patients had a family history of VTE (first-degree relatives), 15.1% had a prior episode of DVT and/or PE themselves, and 37.5% had at least 1 provoking factor for VTE.

Most patients (61.8%) had DVT alone, but 38.3% had PE with or without DVT.

The registry included patients with active cancer (9.1%), a history of cancer (10.7%), thrombophilia (2.9%), chronic immobilization (5.6%), heart failure (3.2%), and renal insufficiency (3.5%).

Outcomes

Over 6 months of follow-up, the following events were reported:

• Any bleeding—622 total bleeds or 13.6 per 100 person-years
• All-cause mortality—460 total deaths or 9.7 per 100 person-years
• Recurrent VTE—169 events or 3.6 per 100 person-years
• Major bleeding—106 events or 2.2 per 100 person-years
• Myocardial infarction—42 events or 0.9 per 100 person-years
• Stroke/transient ischemic attack—38 events or 0.8 per 100 person-years.

Nearly 5% of patients died (4.5%, n=460). More than half (54.3%, n=250) of these deaths were cancer-related.

Other causes of death included:

• Cardiac death—7.0% (n=32)
• PE—3.5% (n=16)
• Bleeding—3.3% (n=15)
• VTE complications—1.3% (n=6)
• Stroke—1.1%  (n=5)
• Other cause—17.8% (n=82)
• Unknown cause—11.7% (n=54).

Additional data from the GARFIELD-VTE registry were presented at ISTH 2017 as posters (PB 460 and PB 1188) and in an oral presentation (ASY 35.4). The next set of data from the registry is slated to be presented at the 2017 ASH Annual Meeting.

GARFIELD-VTE is supported by an unrestricted educational grant from Bayer AG. For further information on the registry, visit http://www.garfieldregistry.org.

Image by AJ Cann

BERLIN—Researchers have reported positive results from an ongoing phase 2 trial of fitusiran in patients with hemophilia A or B, with or without inhibitors.

Once-monthly treatment with fitusiran reduced the median annualized bleeding rate (ABR) from 20 to 1 in all patients. In patients with inhibitors, the median ABR fell from 38 to 0.

Most adverse events (AEs) were mild or moderate in severity, with the most common AEs being alanine aminotransferase (ALT) increases and injection-site reactions.

These results were presented* at the International Society on Thrombosis and Haemostasis (ISTH) 2017 Congress.

The research was sponsored by Alnylam Pharmaceuticals, Inc., the company developing fitusiran in collaboration with Sanofi Genzyme.

Fitusiran is an RNAi therapeutic targeting antithrombin for the treatment of patients with hemophilia A and B. Fitusiran is designed to lower levels of antithrombin and promote sufficient thrombin generation upon activation of the clotting cascade to restore hemostasis and prevent bleeding.

John Pasi, PhD, of Barts and the London School of Medicine and Dentistry in London, UK, and his colleagues tested fitusiran in 33 patients, ages 19 to 61, with hemophilia A (n=27) or hemophilia B (n=6), with inhibitors (n=14) or without (n=19).

Fitusiran was administered as a monthly, subcutaneous, fixed dose of 50 mg (n=13) or 80 mg (n=20).

Patients were treated for up to 20 months, with a median of 11 months on study. Five patients discontinued treatment—4 due to withdrawn consent and 1 due to an AE.

Safety

The incidence of AEs was 70%. Most were mild or moderate in severity and unrelated to fitusiran.

Non-laboratory AEs included injection site reactions (18%, n=6), abdominal pain (9%, n=3), diarrhea (9%, n=3), and headache (9%, n=3).

Eleven patients had asymptomatic ALT increases greater than 3 times the upper limit of normal, without concurrent elevations in bilirubin greater than 2 times the upper limit of normal. All of these patients were hepatitis C antibody-positive.

At last follow-up, all ALT elevations were resolved (n=10) or resolving (n=1).

There were serious AEs in 6 patients, and 2 of these events were considered possibly related to fitusiran. One event was seizure with confusion in a patient with a prior history of seizure disorder.

The other serious AE was an asymptomatic ALT elevation in a patient with chronic hepatitis C virus infection. This patient discontinued treatment due to the event.

There were no thromboembolic events, no laboratory evidence for pathological clot formation, and no instances of anti-drug antibody formation.

Efficacy

Fitusiran resulted in approximately 80% lowering of antithrombin, with corresponding increases in thrombin generation.

In all patients, fitusiran reduced the median ABR from 20 (interquartile range [IQR]: 4-36) to 1 (IQR: 0-3).

In patients with inhibitors, fitusiran reduced the median ABR from 38 (IQR: 20-48) to 0 (IQR: 0-3).

Forty-eight percent of all patients (n=16) remained bleed-free during the observation period, and 67% (n=22) did not experience any spontaneous bleeds.

All breakthrough bleeds were successfully managed with replacement factor (recombinant factor VIII or recombinant factor IX) or bypassing agents (recombinant factor VIIa or activated prothrombin complex concentrate).

Based on these results, Sanofi and Alnylam initiated the ATLAS phase 3 program for fitusiran in patients with hemophilia A and B, with or without inhibitors.

*Data in the abstract differ from data presented at the meeting.

Image by AJ Cann

BERLIN—Researchers have reported positive results from an ongoing phase 2 trial of fitusiran in patients with hemophilia A or B, with or without inhibitors.

Once-monthly treatment with fitusiran reduced the median annualized bleeding rate (ABR) from 20 to 1 in all patients. In patients with inhibitors, the median ABR fell from 38 to 0.

Most adverse events (AEs) were mild or moderate in severity, with the most common AEs being alanine aminotransferase (ALT) increases and injection-site reactions.

These results were presented* at the International Society on Thrombosis and Haemostasis (ISTH) 2017 Congress.

The research was sponsored by Alnylam Pharmaceuticals, Inc., the company developing fitusiran in collaboration with Sanofi Genzyme.

Fitusiran is an RNAi therapeutic targeting antithrombin for the treatment of patients with hemophilia A and B. Fitusiran is designed to lower levels of antithrombin and promote sufficient thrombin generation upon activation of the clotting cascade to restore hemostasis and prevent bleeding.

John Pasi, PhD, of Barts and the London School of Medicine and Dentistry in London, UK, and his colleagues tested fitusiran in 33 patients, ages 19 to 61, with hemophilia A (n=27) or hemophilia B (n=6), with inhibitors (n=14) or without (n=19).

Fitusiran was administered as a monthly, subcutaneous, fixed dose of 50 mg (n=13) or 80 mg (n=20).

Patients were treated for up to 20 months, with a median of 11 months on study. Five patients discontinued treatment—4 due to withdrawn consent and 1 due to an AE.

Safety

The incidence of AEs was 70%. Most were mild or moderate in severity and unrelated to fitusiran.

Non-laboratory AEs included injection site reactions (18%, n=6), abdominal pain (9%, n=3), diarrhea (9%, n=3), and headache (9%, n=3).

Eleven patients had asymptomatic ALT increases greater than 3 times the upper limit of normal, without concurrent elevations in bilirubin greater than 2 times the upper limit of normal. All of these patients were hepatitis C antibody-positive.

At last follow-up, all ALT elevations were resolved (n=10) or resolving (n=1).

There were serious AEs in 6 patients, and 2 of these events were considered possibly related to fitusiran. One event was seizure with confusion in a patient with a prior history of seizure disorder.

The other serious AE was an asymptomatic ALT elevation in a patient with chronic hepatitis C virus infection. This patient discontinued treatment due to the event.

There were no thromboembolic events, no laboratory evidence for pathological clot formation, and no instances of anti-drug antibody formation.

Efficacy

Fitusiran resulted in approximately 80% lowering of antithrombin, with corresponding increases in thrombin generation.

In all patients, fitusiran reduced the median ABR from 20 (interquartile range [IQR]: 4-36) to 1 (IQR: 0-3).

In patients with inhibitors, fitusiran reduced the median ABR from 38 (IQR: 20-48) to 0 (IQR: 0-3).

Forty-eight percent of all patients (n=16) remained bleed-free during the observation period, and 67% (n=22) did not experience any spontaneous bleeds.

All breakthrough bleeds were successfully managed with replacement factor (recombinant factor VIII or recombinant factor IX) or bypassing agents (recombinant factor VIIa or activated prothrombin complex concentrate).

Based on these results, Sanofi and Alnylam initiated the ATLAS phase 3 program for fitusiran in patients with hemophilia A and B, with or without inhibitors.

*Data in the abstract differ from data presented at the meeting.

Image by AJ Cann

BERLIN—Researchers have reported positive results from an ongoing phase 2 trial of fitusiran in patients with hemophilia A or B, with or without inhibitors.

Once-monthly treatment with fitusiran reduced the median annualized bleeding rate (ABR) from 20 to 1 in all patients. In patients with inhibitors, the median ABR fell from 38 to 0.

Most adverse events (AEs) were mild or moderate in severity, with the most common AEs being alanine aminotransferase (ALT) increases and injection-site reactions.

These results were presented* at the International Society on Thrombosis and Haemostasis (ISTH) 2017 Congress.

The research was sponsored by Alnylam Pharmaceuticals, Inc., the company developing fitusiran in collaboration with Sanofi Genzyme.

Fitusiran is an RNAi therapeutic targeting antithrombin for the treatment of patients with hemophilia A and B. Fitusiran is designed to lower levels of antithrombin and promote sufficient thrombin generation upon activation of the clotting cascade to restore hemostasis and prevent bleeding.

John Pasi, PhD, of Barts and the London School of Medicine and Dentistry in London, UK, and his colleagues tested fitusiran in 33 patients, ages 19 to 61, with hemophilia A (n=27) or hemophilia B (n=6), with inhibitors (n=14) or without (n=19).

Fitusiran was administered as a monthly, subcutaneous, fixed dose of 50 mg (n=13) or 80 mg (n=20).

Patients were treated for up to 20 months, with a median of 11 months on study. Five patients discontinued treatment—4 due to withdrawn consent and 1 due to an AE.

Safety

The incidence of AEs was 70%. Most were mild or moderate in severity and unrelated to fitusiran.

Non-laboratory AEs included injection site reactions (18%, n=6), abdominal pain (9%, n=3), diarrhea (9%, n=3), and headache (9%, n=3).

Eleven patients had asymptomatic ALT increases greater than 3 times the upper limit of normal, without concurrent elevations in bilirubin greater than 2 times the upper limit of normal. All of these patients were hepatitis C antibody-positive.

At last follow-up, all ALT elevations were resolved (n=10) or resolving (n=1).

There were serious AEs in 6 patients, and 2 of these events were considered possibly related to fitusiran. One event was seizure with confusion in a patient with a prior history of seizure disorder.

The other serious AE was an asymptomatic ALT elevation in a patient with chronic hepatitis C virus infection. This patient discontinued treatment due to the event.

There were no thromboembolic events, no laboratory evidence for pathological clot formation, and no instances of anti-drug antibody formation.

Efficacy

Fitusiran resulted in approximately 80% lowering of antithrombin, with corresponding increases in thrombin generation.

In all patients, fitusiran reduced the median ABR from 20 (interquartile range [IQR]: 4-36) to 1 (IQR: 0-3).

In patients with inhibitors, fitusiran reduced the median ABR from 38 (IQR: 20-48) to 0 (IQR: 0-3).

Forty-eight percent of all patients (n=16) remained bleed-free during the observation period, and 67% (n=22) did not experience any spontaneous bleeds.

All breakthrough bleeds were successfully managed with replacement factor (recombinant factor VIII or recombinant factor IX) or bypassing agents (recombinant factor VIIa or activated prothrombin complex concentrate).

Based on these results, Sanofi and Alnylam initiated the ATLAS phase 3 program for fitusiran in patients with hemophilia A and B, with or without inhibitors.

*Data in the abstract differ from data presented at the meeting.

Image by Spencer Phillips

BERLIN—New research suggests the investigational gene therapy BMN 270 can allow patients with severe hemophilia A to maintain normal factor VIII (FVIII) levels for over a year.

In a phase 1/2 study, patients who received the highest dose of BMN 270 had median and mean FVIII levels that were consistently within the normal range from week 20 to week 52 and beyond.

The highest dose of BMN 270 reduced the mean annual FVIII infusions by 94% and the mean annualized bleed rate (ABR) by 97%, when compared to prophylaxis.

BMN 270 was also considered well tolerated, and none of the patients developed FVIII inhibitors.

The most common adverse event (AE) in this study was alanine aminotransferase (ALT) elevations. In fact, the increase in ALT levels exceeded a pre-specified threshold, which resulted in the study being placed on hold last year.

However, the hold was ultimately lifted. All cases of ALT increase were non-serious, and all patients with ALT increases have either stopped receiving corticosteroids or are being tapered off of them.

John Pasi, PhD, of Barts and the London School of Medicine and Dentistry in London, UK, presented these results as a late-breaking abstract at the International Society on Thrombosis and Haemostasis (ISTH) 2017 Congress. The research was sponsored by BioMarin.

In this phase 1/2 study, 15 patients with severe hemophilia A (FVIII activity levels less than 1%) received a single dose of BMN 270.

Seven patients received a dose of 6e13 vg/kg, 6 received 4e13 vg/kg, and 2 were treated at lower doses as part of dose-escalation and did not achieve therapeutic efficacy.

Safety

Overall, BMN 270 was considered well tolerated across all doses. None of the patients developed inhibitors to FVIII, and none of them withdrew from the study.

The most common AEs across all dose cohorts were ALT elevations (n=10, 67%), arthralgia (n=7, 47%), and back pain, fatigue, and headache (n=5, 33% each).

All ALT increases were non-serious, of limited duration (lasting 0.4 to 7 weeks), and grade 1 in severity. All 7 patients at the 6e13 vg/kg dose remain off of corticosteroids, with no lasting significant impact on FVIII expression and normal ALT levels.

Three of the 6 patients in the 4e13 vg/kg dose cohort received corticosteroids for ALT increases. One has successfully tapered off corticosteroids, and 2 are still tapering off of them.

Two patients reported serious AEs during the study.

One patient was hospitalized for observation after developing grade 2 pyrexia with myalgia and headache within 24 hours of receiving BMN 270 (4e13 vg/kg dose). The event resolved within 48 hours following treatment with paracetamol. The event was considered related to BMN 270.

The other serious AE—planned total knee replacement for chronic arthropathy—was not related to BMN 270.

FVIII levels: 6e13 vg/kg

For patients in the 6e13 vg/kg dose cohort, median and mean FVIII levels from week 20 through 52 have been consistently within the normal levels post-treatment. At 1 year after dosing, the median and mean FVIII levels continue to be above 50%.

Table 1:  FVIII levels (%) of 6e13 vg/kg dose patients by visit (n=7)

* Weeks were windowed by +/- 2 weeks

** For week 32, one patient had no FVIII reading

***Bolded numbers are in the normal range of FVIII as defined by the World Federation of Hemophilia

FVIII levels: 4e13 vg/kg

For the 4e13 vg/kg dose cohort, the median and mean FVIII levels from week 8 to 24 are in the mild level. Three of these subjects, who have been observed for 24 weeks, are at the upper end of mild.

Table 2:  FVIII levels (%) of 4e13 vg/kg dose patients* by visit (n=6)

*Weeks were windowed by +/- 2 weeks

** Bolded numbers are in the mild range of FVIII as defined by the World Federation of Hemophilia

ABR and FVIII infusions

Six of the 7 patients in the 6e13 vg/kg cohort were on pre-study prophylaxis.

After these patients received a single dose BMN270 and reached a FVIII level above 5%, the mean ABR was reduced by 97%, from 16.3 to 0.5. The median ABR for these patients was reduced from 16.5 to 0.

The mean annualized FVIII infusions were reduced by 94%, from 136.7 to 8.5. And the median annualized FVIII infusions were reduced from 138.5 to 0.

All 6 patients in the 4e13 vg/kg dose cohort were on pre-study prophylaxis.

The mean ABR was reduced from 12.2 pre-study to 0 after they reached an FVIII level above 5%. The median ABR for these patients was reduced from 8.0 to 0.

The mean annualized FVIII infusions were reduced from 144.2 to 0. The median annualized FVIII infusions were reduced from 155.5 to 0.

“Patients at the 2 highest doses have stopped prophylactic treatment and, to date, bleeds have effectively been eliminated,” Dr Pasi noted.

Based on these results, BioMarin is planning a phase 3 registrational study of BMN 270. The study will likely include fewer than 100 patients and collect data for no longer than a year after a single dose of BMN 270, with subsequent long-term follow-up.

The company is moving the 6e13 vg/kg dose forward but will consider doing an additional study with the 4e13 vg/kg dose at a later date. 

Image by Spencer Phillips

BERLIN—New research suggests the investigational gene therapy BMN 270 can allow patients with severe hemophilia A to maintain normal factor VIII (FVIII) levels for over a year.

In a phase 1/2 study, patients who received the highest dose of BMN 270 had median and mean FVIII levels that were consistently within the normal range from week 20 to week 52 and beyond.

The highest dose of BMN 270 reduced the mean annual FVIII infusions by 94% and the mean annualized bleed rate (ABR) by 97%, when compared to prophylaxis.

BMN 270 was also considered well tolerated, and none of the patients developed FVIII inhibitors.

The most common adverse event (AE) in this study was alanine aminotransferase (ALT) elevations. In fact, the increase in ALT levels exceeded a pre-specified threshold, which resulted in the study being placed on hold last year.

However, the hold was ultimately lifted. All cases of ALT increase were non-serious, and all patients with ALT increases have either stopped receiving corticosteroids or are being tapered off of them.

John Pasi, PhD, of Barts and the London School of Medicine and Dentistry in London, UK, presented these results as a late-breaking abstract at the International Society on Thrombosis and Haemostasis (ISTH) 2017 Congress. The research was sponsored by BioMarin.

In this phase 1/2 study, 15 patients with severe hemophilia A (FVIII activity levels less than 1%) received a single dose of BMN 270.

Seven patients received a dose of 6e13 vg/kg, 6 received 4e13 vg/kg, and 2 were treated at lower doses as part of dose-escalation and did not achieve therapeutic efficacy.

Safety

Overall, BMN 270 was considered well tolerated across all doses. None of the patients developed inhibitors to FVIII, and none of them withdrew from the study.

The most common AEs across all dose cohorts were ALT elevations (n=10, 67%), arthralgia (n=7, 47%), and back pain, fatigue, and headache (n=5, 33% each).

All ALT increases were non-serious, of limited duration (lasting 0.4 to 7 weeks), and grade 1 in severity. All 7 patients at the 6e13 vg/kg dose remain off of corticosteroids, with no lasting significant impact on FVIII expression and normal ALT levels.

Three of the 6 patients in the 4e13 vg/kg dose cohort received corticosteroids for ALT increases. One has successfully tapered off corticosteroids, and 2 are still tapering off of them.

Two patients reported serious AEs during the study.

One patient was hospitalized for observation after developing grade 2 pyrexia with myalgia and headache within 24 hours of receiving BMN 270 (4e13 vg/kg dose). The event resolved within 48 hours following treatment with paracetamol. The event was considered related to BMN 270.

The other serious AE—planned total knee replacement for chronic arthropathy—was not related to BMN 270.

FVIII levels: 6e13 vg/kg

For patients in the 6e13 vg/kg dose cohort, median and mean FVIII levels from week 20 through 52 have been consistently within the normal levels post-treatment. At 1 year after dosing, the median and mean FVIII levels continue to be above 50%.

Table 1:  FVIII levels (%) of 6e13 vg/kg dose patients by visit (n=7)

* Weeks were windowed by +/- 2 weeks

** For week 32, one patient had no FVIII reading

***Bolded numbers are in the normal range of FVIII as defined by the World Federation of Hemophilia

FVIII levels: 4e13 vg/kg

For the 4e13 vg/kg dose cohort, the median and mean FVIII levels from week 8 to 24 are in the mild level. Three of these subjects, who have been observed for 24 weeks, are at the upper end of mild.

Table 2:  FVIII levels (%) of 4e13 vg/kg dose patients* by visit (n=6)

*Weeks were windowed by +/- 2 weeks

** Bolded numbers are in the mild range of FVIII as defined by the World Federation of Hemophilia

ABR and FVIII infusions

Six of the 7 patients in the 6e13 vg/kg cohort were on pre-study prophylaxis.

After these patients received a single dose BMN270 and reached a FVIII level above 5%, the mean ABR was reduced by 97%, from 16.3 to 0.5. The median ABR for these patients was reduced from 16.5 to 0.

The mean annualized FVIII infusions were reduced by 94%, from 136.7 to 8.5. And the median annualized FVIII infusions were reduced from 138.5 to 0.

All 6 patients in the 4e13 vg/kg dose cohort were on pre-study prophylaxis.

The mean ABR was reduced from 12.2 pre-study to 0 after they reached an FVIII level above 5%. The median ABR for these patients was reduced from 8.0 to 0.

The mean annualized FVIII infusions were reduced from 144.2 to 0. The median annualized FVIII infusions were reduced from 155.5 to 0.

“Patients at the 2 highest doses have stopped prophylactic treatment and, to date, bleeds have effectively been eliminated,” Dr Pasi noted.

Based on these results, BioMarin is planning a phase 3 registrational study of BMN 270. The study will likely include fewer than 100 patients and collect data for no longer than a year after a single dose of BMN 270, with subsequent long-term follow-up.

The company is moving the 6e13 vg/kg dose forward but will consider doing an additional study with the 4e13 vg/kg dose at a later date. 

Image by Spencer Phillips

BERLIN—New research suggests the investigational gene therapy BMN 270 can allow patients with severe hemophilia A to maintain normal factor VIII (FVIII) levels for over a year.

In a phase 1/2 study, patients who received the highest dose of BMN 270 had median and mean FVIII levels that were consistently within the normal range from week 20 to week 52 and beyond.

The highest dose of BMN 270 reduced the mean annual FVIII infusions by 94% and the mean annualized bleed rate (ABR) by 97%, when compared to prophylaxis.

BMN 270 was also considered well tolerated, and none of the patients developed FVIII inhibitors.

The most common adverse event (AE) in this study was alanine aminotransferase (ALT) elevations. In fact, the increase in ALT levels exceeded a pre-specified threshold, which resulted in the study being placed on hold last year.

However, the hold was ultimately lifted. All cases of ALT increase were non-serious, and all patients with ALT increases have either stopped receiving corticosteroids or are being tapered off of them.

John Pasi, PhD, of Barts and the London School of Medicine and Dentistry in London, UK, presented these results as a late-breaking abstract at the International Society on Thrombosis and Haemostasis (ISTH) 2017 Congress. The research was sponsored by BioMarin.

In this phase 1/2 study, 15 patients with severe hemophilia A (FVIII activity levels less than 1%) received a single dose of BMN 270.

Seven patients received a dose of 6e13 vg/kg, 6 received 4e13 vg/kg, and 2 were treated at lower doses as part of dose-escalation and did not achieve therapeutic efficacy.

Safety

Overall, BMN 270 was considered well tolerated across all doses. None of the patients developed inhibitors to FVIII, and none of them withdrew from the study.

The most common AEs across all dose cohorts were ALT elevations (n=10, 67%), arthralgia (n=7, 47%), and back pain, fatigue, and headache (n=5, 33% each).

All ALT increases were non-serious, of limited duration (lasting 0.4 to 7 weeks), and grade 1 in severity. All 7 patients at the 6e13 vg/kg dose remain off of corticosteroids, with no lasting significant impact on FVIII expression and normal ALT levels.

Three of the 6 patients in the 4e13 vg/kg dose cohort received corticosteroids for ALT increases. One has successfully tapered off corticosteroids, and 2 are still tapering off of them.

Two patients reported serious AEs during the study.

One patient was hospitalized for observation after developing grade 2 pyrexia with myalgia and headache within 24 hours of receiving BMN 270 (4e13 vg/kg dose). The event resolved within 48 hours following treatment with paracetamol. The event was considered related to BMN 270.

The other serious AE—planned total knee replacement for chronic arthropathy—was not related to BMN 270.

FVIII levels: 6e13 vg/kg

For patients in the 6e13 vg/kg dose cohort, median and mean FVIII levels from week 20 through 52 have been consistently within the normal levels post-treatment. At 1 year after dosing, the median and mean FVIII levels continue to be above 50%.

Table 1:  FVIII levels (%) of 6e13 vg/kg dose patients by visit (n=7)

* Weeks were windowed by +/- 2 weeks

** For week 32, one patient had no FVIII reading

***Bolded numbers are in the normal range of FVIII as defined by the World Federation of Hemophilia

FVIII levels: 4e13 vg/kg

For the 4e13 vg/kg dose cohort, the median and mean FVIII levels from week 8 to 24 are in the mild level. Three of these subjects, who have been observed for 24 weeks, are at the upper end of mild.

Table 2:  FVIII levels (%) of 4e13 vg/kg dose patients* by visit (n=6)

*Weeks were windowed by +/- 2 weeks

** Bolded numbers are in the mild range of FVIII as defined by the World Federation of Hemophilia

ABR and FVIII infusions

Six of the 7 patients in the 6e13 vg/kg cohort were on pre-study prophylaxis.

After these patients received a single dose BMN270 and reached a FVIII level above 5%, the mean ABR was reduced by 97%, from 16.3 to 0.5. The median ABR for these patients was reduced from 16.5 to 0.

The mean annualized FVIII infusions were reduced by 94%, from 136.7 to 8.5. And the median annualized FVIII infusions were reduced from 138.5 to 0.

All 6 patients in the 4e13 vg/kg dose cohort were on pre-study prophylaxis.

The mean ABR was reduced from 12.2 pre-study to 0 after they reached an FVIII level above 5%. The median ABR for these patients was reduced from 8.0 to 0.

The mean annualized FVIII infusions were reduced from 144.2 to 0. The median annualized FVIII infusions were reduced from 155.5 to 0.

“Patients at the 2 highest doses have stopped prophylactic treatment and, to date, bleeds have effectively been eliminated,” Dr Pasi noted.

Based on these results, BioMarin is planning a phase 3 registrational study of BMN 270. The study will likely include fewer than 100 patients and collect data for no longer than a year after a single dose of BMN 270, with subsequent long-term follow-up.

The company is moving the 6e13 vg/kg dose forward but will consider doing an additional study with the 4e13 vg/kg dose at a later date. 

Photo by Piotr Bodzek

BERLIN—Final results from the RE-VERSE AD trial suggest idarucizumab can reverse the anticoagulant effect of dabigatran etexilate mesylate in emergency situations.

Patients who required dabigatran reversal because they needed urgent surgery were able to have their procedure a median of 1.6 hours from idarucizumab administration.

In patients who required dabigatran reversal due to uncontrollable bleeding, the median time to bleeding cessation was 2.5 hours. However, the time to bleeding cessation could not be assessed in all patients.

“RE-VERSE AD has shown that idarucizumab reverses the anticoagulant effect of dabigatran within minutes so that treating physicians can fully focus on dealing with the emergency at hand,” said study investigator Charles Pollack, MD, of Sidney Kimmel Medical College of Thomas Jefferson University in Philadelphia, Pennsylvania.

“Prior to idarucizumab, there was no rapid, reliable, and effective method for reversing dabigatran and other orally administered blood thinners, which otherwise may take at least 12 to 24 hours to clear from the body.”

The rate of thrombotic events in RE-VERSE AD was low (6% to 7%), and researchers said there were no serious adverse safety signals related to idarucizumab.

These results were presented at the International Society on Thrombosis and Haemostasis (ISTH) 2017 Congress and published in NEJM. The research was funded by Boehringer Ingelheim Pharmaceuticals.

The phase 3 trial enrolled 503 patients who required dabigatran reversal. They were divided into 2 groups.

Group A included 301 patients with uncontrolled or life-threatening bleeding complications (eg, intracranial hemorrhage or severe trauma after a car accident).

Group B included 202 patients requiring an invasive procedure or an emergency surgery or intervention (eg, surgery for an open fracture after a fall).

Results

The study’s primary endpoint was the degree of reversal of the anticoagulant effect of dabigatran achieved by idarucizumab within 4 hours. This was measured by diluted thrombin time or ecarin clotting time.

The median maximum percentage of dabigatran reversal was 100%. Dabigatran reversal occurred independently of patients’ age, sex, renal function, and dabigatran concentration at baseline.

Group A

Roughly 68% of evaluable patients in Group A (134/203) had confirmed bleeding cessation within 24 hours of idarucizumab administration.

Bleeding cessation was not confirmed in 67 patients, bleeding stopped before treatment in 2 patients, and the time to bleeding cessation could not be assessed in the 98 patients with intracranial bleeding.

Among the 134 patients in who had confirmed bleeding cessation, the median time to hemostasis after idarucizumab administration was 2.5 hours.

Sixty-seven percent (n=201) of patients in Group A received hemostatic treatment, 62% (n=185) received whole blood/blood components, 7% (n=20) received plasma derivatives, and 23% (n=69) received volume expanders, pro-hemostatic agents, albumin, and other treatments.

At 90 days, thrombotic events had occurred in 6.3% of the patients in Group A, and the mortality rate was 18.8%.

Group B

For patients in Group B, their required procedures began a median of 1.6 hours from idarucizumab administration.

Hemostasis during the procedure was described as normal for 93.4% of the patients, mildly abnormal in 5.1%, and moderately abnormal in 1.5%.

Thirty-nine percent (n=79) of patients in Group B received hemostatic treatment, 26% (n=53) received whole blood/blood components, 4% (n=8) received plasma derivatives, and 21% (n=42) received volume expanders, pro-hemostatic agents, albumin, and other treatments.

At 90 days, thrombotic events had occurred in 7.4% of patients in Group B, and the mortality rate was 18.9%.

Photo by Piotr Bodzek

BERLIN—Final results from the RE-VERSE AD trial suggest idarucizumab can reverse the anticoagulant effect of dabigatran etexilate mesylate in emergency situations.

Patients who required dabigatran reversal because they needed urgent surgery were able to have their procedure a median of 1.6 hours from idarucizumab administration.

In patients who required dabigatran reversal due to uncontrollable bleeding, the median time to bleeding cessation was 2.5 hours. However, the time to bleeding cessation could not be assessed in all patients.

“RE-VERSE AD has shown that idarucizumab reverses the anticoagulant effect of dabigatran within minutes so that treating physicians can fully focus on dealing with the emergency at hand,” said study investigator Charles Pollack, MD, of Sidney Kimmel Medical College of Thomas Jefferson University in Philadelphia, Pennsylvania.

“Prior to idarucizumab, there was no rapid, reliable, and effective method for reversing dabigatran and other orally administered blood thinners, which otherwise may take at least 12 to 24 hours to clear from the body.”

The rate of thrombotic events in RE-VERSE AD was low (6% to 7%), and researchers said there were no serious adverse safety signals related to idarucizumab.

These results were presented at the International Society on Thrombosis and Haemostasis (ISTH) 2017 Congress and published in NEJM. The research was funded by Boehringer Ingelheim Pharmaceuticals.

The phase 3 trial enrolled 503 patients who required dabigatran reversal. They were divided into 2 groups.

Group A included 301 patients with uncontrolled or life-threatening bleeding complications (eg, intracranial hemorrhage or severe trauma after a car accident).

Group B included 202 patients requiring an invasive procedure or an emergency surgery or intervention (eg, surgery for an open fracture after a fall).

Results

The study’s primary endpoint was the degree of reversal of the anticoagulant effect of dabigatran achieved by idarucizumab within 4 hours. This was measured by diluted thrombin time or ecarin clotting time.

The median maximum percentage of dabigatran reversal was 100%. Dabigatran reversal occurred independently of patients’ age, sex, renal function, and dabigatran concentration at baseline.

Group A

Roughly 68% of evaluable patients in Group A (134/203) had confirmed bleeding cessation within 24 hours of idarucizumab administration.

Bleeding cessation was not confirmed in 67 patients, bleeding stopped before treatment in 2 patients, and the time to bleeding cessation could not be assessed in the 98 patients with intracranial bleeding.

Among the 134 patients in who had confirmed bleeding cessation, the median time to hemostasis after idarucizumab administration was 2.5 hours.

Sixty-seven percent (n=201) of patients in Group A received hemostatic treatment, 62% (n=185) received whole blood/blood components, 7% (n=20) received plasma derivatives, and 23% (n=69) received volume expanders, pro-hemostatic agents, albumin, and other treatments.

At 90 days, thrombotic events had occurred in 6.3% of the patients in Group A, and the mortality rate was 18.8%.

Group B

For patients in Group B, their required procedures began a median of 1.6 hours from idarucizumab administration.

Hemostasis during the procedure was described as normal for 93.4% of the patients, mildly abnormal in 5.1%, and moderately abnormal in 1.5%.

Thirty-nine percent (n=79) of patients in Group B received hemostatic treatment, 26% (n=53) received whole blood/blood components, 4% (n=8) received plasma derivatives, and 21% (n=42) received volume expanders, pro-hemostatic agents, albumin, and other treatments.

At 90 days, thrombotic events had occurred in 7.4% of patients in Group B, and the mortality rate was 18.9%.

Photo by Piotr Bodzek

BERLIN—Final results from the RE-VERSE AD trial suggest idarucizumab can reverse the anticoagulant effect of dabigatran etexilate mesylate in emergency situations.

Patients who required dabigatran reversal because they needed urgent surgery were able to have their procedure a median of 1.6 hours from idarucizumab administration.

In patients who required dabigatran reversal due to uncontrollable bleeding, the median time to bleeding cessation was 2.5 hours. However, the time to bleeding cessation could not be assessed in all patients.

“RE-VERSE AD has shown that idarucizumab reverses the anticoagulant effect of dabigatran within minutes so that treating physicians can fully focus on dealing with the emergency at hand,” said study investigator Charles Pollack, MD, of Sidney Kimmel Medical College of Thomas Jefferson University in Philadelphia, Pennsylvania.

“Prior to idarucizumab, there was no rapid, reliable, and effective method for reversing dabigatran and other orally administered blood thinners, which otherwise may take at least 12 to 24 hours to clear from the body.”

The rate of thrombotic events in RE-VERSE AD was low (6% to 7%), and researchers said there were no serious adverse safety signals related to idarucizumab.

These results were presented at the International Society on Thrombosis and Haemostasis (ISTH) 2017 Congress and published in NEJM. The research was funded by Boehringer Ingelheim Pharmaceuticals.

The phase 3 trial enrolled 503 patients who required dabigatran reversal. They were divided into 2 groups.

Group A included 301 patients with uncontrolled or life-threatening bleeding complications (eg, intracranial hemorrhage or severe trauma after a car accident).

Group B included 202 patients requiring an invasive procedure or an emergency surgery or intervention (eg, surgery for an open fracture after a fall).

Results

The study’s primary endpoint was the degree of reversal of the anticoagulant effect of dabigatran achieved by idarucizumab within 4 hours. This was measured by diluted thrombin time or ecarin clotting time.

The median maximum percentage of dabigatran reversal was 100%. Dabigatran reversal occurred independently of patients’ age, sex, renal function, and dabigatran concentration at baseline.

Group A

Roughly 68% of evaluable patients in Group A (134/203) had confirmed bleeding cessation within 24 hours of idarucizumab administration.

Bleeding cessation was not confirmed in 67 patients, bleeding stopped before treatment in 2 patients, and the time to bleeding cessation could not be assessed in the 98 patients with intracranial bleeding.

Among the 134 patients in who had confirmed bleeding cessation, the median time to hemostasis after idarucizumab administration was 2.5 hours.

Sixty-seven percent (n=201) of patients in Group A received hemostatic treatment, 62% (n=185) received whole blood/blood components, 7% (n=20) received plasma derivatives, and 23% (n=69) received volume expanders, pro-hemostatic agents, albumin, and other treatments.

At 90 days, thrombotic events had occurred in 6.3% of the patients in Group A, and the mortality rate was 18.8%.

Group B

For patients in Group B, their required procedures began a median of 1.6 hours from idarucizumab administration.

Hemostasis during the procedure was described as normal for 93.4% of the patients, mildly abnormal in 5.1%, and moderately abnormal in 1.5%.

Thirty-nine percent (n=79) of patients in Group B received hemostatic treatment, 26% (n=53) received whole blood/blood components, 4% (n=8) received plasma derivatives, and 21% (n=42) received volume expanders, pro-hemostatic agents, albumin, and other treatments.

At 90 days, thrombotic events had occurred in 7.4% of patients in Group B, and the mortality rate was 18.9%.

Photo by Linda Bartlett

BERLIN—Emicizumab can reduce bleeding in adults and adolescents with hemophilia A and inhibitors to factor VIII, according to a phase 3 trial.

In the HAVEN 1 trial, prophylaxis with emicizumab reduced the treated bleed rate by 87% when compared to no prophylaxis.

Emicizumab reduced the treated bleed rate by 79% when compared to prior prophylaxis with bypassing agents (BPAs).

The incidence of adverse events (AEs) related to emicizumab was 22%, and the incidence of serious AEs was 9%.

There were 3 cases of thrombotic microangiopathy, 2 serious thromboembolic events, and 1 death (from hemorrhage).

These results were presented at the 26th International Society on Thrombosis and Haemostasis (ISTH) Congress and published in NEJM.

The study was funded by F. Hoffmann–La Roche and Chugai Pharmaceutical.

“The HAVEN 1 study is one of the most robust clinical studies conducted to date in people with hemophilia A with inhibitors to factor VIII, including a first-ever intra-patient comparison to prior prophylaxis with bypassing agents,” said study author Johannes Oldenburg, MD, PhD, of the University of Bonn in Bonn, Germany.

“The reduction in bleeding events across all measures seen with emicizumab compared to either on-demand or prophylactic bypassing agents supports that it may be one of the most significant scientific innovations in the treatment of hemophilia A in over 30 years.”

Emicizumab is a bispecific monoclonal antibody designed to bring together factors IXa and X, proteins required to activate the natural coagulation cascade and restore the blood clotting process.

HAVEN 1 is a randomized, phase 3 study of emicizumab that enrolled 109 patients (12 years of age or older) with hemophilia A and inhibitors to factor VIII. The patients were previously treated with BPAs on-demand or as prophylaxis.

Patients previously treated with on-demand BPAs were randomized in a 2:1 fashion to receive emicizumab prophylaxis (Arm A) or no prophylaxis (Arm B).

Patients previously treated with prophylactic BPAs received emicizumab prophylaxis (Arm C). Additional patients previously on BPAs (on-demand or prophylaxis) were also enrolled in a separate arm (Arm D).

On-demand treatment of breakthrough bleeds with BPAs was allowed per protocol in all arms.

Efficacy

The primary endpoint of this study was the number of treated bleeds over time with emicizumab prophylaxis (Arm A) compared with no prophylaxis (Arm B).

There was a significant reduction in treated bleeds of 87% (risk rate [RR]=0.13, P<0.0001) with emicizumab compared with no prophylaxis.

The researchers also performed an intra-patient comparison of bleed rate with emicizumab prophylaxis to bleed rate with prior prophylaxis (with BPAs) for patients in Arm C. A subset of patients in this arm had previously participated in a non-interventional study (NIS), which allowed for the comparison.

The analysis showed a 79% (RR=0.21, P=0.0003) reduction in treated bleeds in patients receiving emicizumab compared with their prior prophylaxis during the NIS.

Additional data on bleeds in Arms A, B, and C are included in the following table.

*Negative binomial regression model

Safety

Safety results in patients who received emicizumab prophylaxis (n=103) are as follows.

*The third thrombotic microangiopathy event occurred after the primary data cut-off. This patient also experienced fatal rectal hemorrhage.

**Serious thromboembolic events consisted of skin necrosis/superficial thrombophlebitis in 1 patient and cavernous sinus thrombosis in a second patient.

None of the patients tested positive for anti-drug antibodies. 

Photo by Linda Bartlett

BERLIN—Emicizumab can reduce bleeding in adults and adolescents with hemophilia A and inhibitors to factor VIII, according to a phase 3 trial.

In the HAVEN 1 trial, prophylaxis with emicizumab reduced the treated bleed rate by 87% when compared to no prophylaxis.

Emicizumab reduced the treated bleed rate by 79% when compared to prior prophylaxis with bypassing agents (BPAs).

The incidence of adverse events (AEs) related to emicizumab was 22%, and the incidence of serious AEs was 9%.

There were 3 cases of thrombotic microangiopathy, 2 serious thromboembolic events, and 1 death (from hemorrhage).

These results were presented at the 26th International Society on Thrombosis and Haemostasis (ISTH) Congress and published in NEJM.

The study was funded by F. Hoffmann–La Roche and Chugai Pharmaceutical.

“The HAVEN 1 study is one of the most robust clinical studies conducted to date in people with hemophilia A with inhibitors to factor VIII, including a first-ever intra-patient comparison to prior prophylaxis with bypassing agents,” said study author Johannes Oldenburg, MD, PhD, of the University of Bonn in Bonn, Germany.

“The reduction in bleeding events across all measures seen with emicizumab compared to either on-demand or prophylactic bypassing agents supports that it may be one of the most significant scientific innovations in the treatment of hemophilia A in over 30 years.”

Emicizumab is a bispecific monoclonal antibody designed to bring together factors IXa and X, proteins required to activate the natural coagulation cascade and restore the blood clotting process.

HAVEN 1 is a randomized, phase 3 study of emicizumab that enrolled 109 patients (12 years of age or older) with hemophilia A and inhibitors to factor VIII. The patients were previously treated with BPAs on-demand or as prophylaxis.

Patients previously treated with on-demand BPAs were randomized in a 2:1 fashion to receive emicizumab prophylaxis (Arm A) or no prophylaxis (Arm B).

Patients previously treated with prophylactic BPAs received emicizumab prophylaxis (Arm C). Additional patients previously on BPAs (on-demand or prophylaxis) were also enrolled in a separate arm (Arm D).

On-demand treatment of breakthrough bleeds with BPAs was allowed per protocol in all arms.

Efficacy

The primary endpoint of this study was the number of treated bleeds over time with emicizumab prophylaxis (Arm A) compared with no prophylaxis (Arm B).

There was a significant reduction in treated bleeds of 87% (risk rate [RR]=0.13, P<0.0001) with emicizumab compared with no prophylaxis.

The researchers also performed an intra-patient comparison of bleed rate with emicizumab prophylaxis to bleed rate with prior prophylaxis (with BPAs) for patients in Arm C. A subset of patients in this arm had previously participated in a non-interventional study (NIS), which allowed for the comparison.

The analysis showed a 79% (RR=0.21, P=0.0003) reduction in treated bleeds in patients receiving emicizumab compared with their prior prophylaxis during the NIS.

Additional data on bleeds in Arms A, B, and C are included in the following table.

*Negative binomial regression model

Safety

Safety results in patients who received emicizumab prophylaxis (n=103) are as follows.

*The third thrombotic microangiopathy event occurred after the primary data cut-off. This patient also experienced fatal rectal hemorrhage.

**Serious thromboembolic events consisted of skin necrosis/superficial thrombophlebitis in 1 patient and cavernous sinus thrombosis in a second patient.

None of the patients tested positive for anti-drug antibodies. 

Photo by Linda Bartlett

BERLIN—Emicizumab can reduce bleeding in adults and adolescents with hemophilia A and inhibitors to factor VIII, according to a phase 3 trial.

In the HAVEN 1 trial, prophylaxis with emicizumab reduced the treated bleed rate by 87% when compared to no prophylaxis.

Emicizumab reduced the treated bleed rate by 79% when compared to prior prophylaxis with bypassing agents (BPAs).

The incidence of adverse events (AEs) related to emicizumab was 22%, and the incidence of serious AEs was 9%.

There were 3 cases of thrombotic microangiopathy, 2 serious thromboembolic events, and 1 death (from hemorrhage).

These results were presented at the 26th International Society on Thrombosis and Haemostasis (ISTH) Congress and published in NEJM.

The study was funded by F. Hoffmann–La Roche and Chugai Pharmaceutical.

“The HAVEN 1 study is one of the most robust clinical studies conducted to date in people with hemophilia A with inhibitors to factor VIII, including a first-ever intra-patient comparison to prior prophylaxis with bypassing agents,” said study author Johannes Oldenburg, MD, PhD, of the University of Bonn in Bonn, Germany.

“The reduction in bleeding events across all measures seen with emicizumab compared to either on-demand or prophylactic bypassing agents supports that it may be one of the most significant scientific innovations in the treatment of hemophilia A in over 30 years.”

Emicizumab is a bispecific monoclonal antibody designed to bring together factors IXa and X, proteins required to activate the natural coagulation cascade and restore the blood clotting process.

HAVEN 1 is a randomized, phase 3 study of emicizumab that enrolled 109 patients (12 years of age or older) with hemophilia A and inhibitors to factor VIII. The patients were previously treated with BPAs on-demand or as prophylaxis.

Patients previously treated with on-demand BPAs were randomized in a 2:1 fashion to receive emicizumab prophylaxis (Arm A) or no prophylaxis (Arm B).

Patients previously treated with prophylactic BPAs received emicizumab prophylaxis (Arm C). Additional patients previously on BPAs (on-demand or prophylaxis) were also enrolled in a separate arm (Arm D).

On-demand treatment of breakthrough bleeds with BPAs was allowed per protocol in all arms.

Efficacy

The primary endpoint of this study was the number of treated bleeds over time with emicizumab prophylaxis (Arm A) compared with no prophylaxis (Arm B).

There was a significant reduction in treated bleeds of 87% (risk rate [RR]=0.13, P<0.0001) with emicizumab compared with no prophylaxis.

The researchers also performed an intra-patient comparison of bleed rate with emicizumab prophylaxis to bleed rate with prior prophylaxis (with BPAs) for patients in Arm C. A subset of patients in this arm had previously participated in a non-interventional study (NIS), which allowed for the comparison.

The analysis showed a 79% (RR=0.21, P=0.0003) reduction in treated bleeds in patients receiving emicizumab compared with their prior prophylaxis during the NIS.

Additional data on bleeds in Arms A, B, and C are included in the following table.

*Negative binomial regression model

Safety

Safety results in patients who received emicizumab prophylaxis (n=103) are as follows.

*The third thrombotic microangiopathy event occurred after the primary data cut-off. This patient also experienced fatal rectal hemorrhage.

**Serious thromboembolic events consisted of skin necrosis/superficial thrombophlebitis in 1 patient and cavernous sinus thrombosis in a second patient.

None of the patients tested positive for anti-drug antibodies.