Bleeding Disorders

Synthetic cannabinoids laced with superwarfarin were behind a recent outbreak of severe coagulopathy in Illinois.

In most cases, vitamin K replacement therapy alleviated symptoms, but four patients died after developing intracranial bleeding, said Amar H. Kelkar, MD, of the University of Illinois at Peoria.

Experts continue to look for how and why superwarfarin ended up in synthetic cannabinoids, whose street names include spice and K2, wrote Dr. Kelkar and his associates. Their report is in the New England Journal of Medicine.

Starting in March 2018, more than 150 patients across Illinois presented to hospitals with bleeding diathesis that involved persistent coagulopathy, the investigators explained. Early inquiries revealed that patients had consumed synthetic cannabinoids. Serum tests identified vitamin K antagonists, including brodifacoum, bromadiolone, and difenacoum. During arrests of suspected distributors, police confiscated synthetic cannabinoids that also tested positive for brodifacoum.

To help characterize the outbreak, the investigators reviewed admissions to Saint Francis Medical Center in Peoria, Ill., between March 28 and April 21, 2018. They identified 34 cases in which patients with vitamin K–dependent factor coagulopathy reported recent exposure to synthetic cannabinoids.

Fifteen of these patients underwent confirmatory anticoagulant testing, which universally confirmed superwarfarin poisoning. Brodifacoum was detected in all patients, difenacoum in five patients, bromadiolone in two patients, and warfarin in one patient.

Common presenting symptoms included gross hematuria (56% of patients) and abdominal pain (47%). Computed tomography identified renal abnormalities in 12 patients.

All patients received oral vitamin K₁ (phytonadione). Red cell transfusions, fresh-frozen plasma infusions, and 4-factor prothrombin complex concentrate, or a combination of these treatments, were also used in some patients.

Among the four confirmed deaths in this outbreak, one occurred in a patient in this case series. The patient, a 37-year-old woman presenting to the emergency department with markedly reduced consciousness, was reported by her friends to have recently used synthetic cannabinoids and methamphetamine. She had no personal or family history of coagulopathy.

Computed tomography of the head without contrast material revealed severe acute intraparenchymal hemorrhage of the right basal nuclei and insula with intraventricular extension, a 10-mm left-sided midline shift, and herniation.

She met criteria for brain death 15 hours after hospital admission despite treatment with 10 mg of intravenous vitamin K₁, four units of fresh frozen plasma, and 2,300 units of Kcentra.

Treating these patients after hospital discharge was difficult because of a lack of consensus guidelines and access to follow-up care, Dr. Kelkar and his associates noted. Some patients were quoted $24,000 to $34,000 per month for oral vitamin K1 therapy, which also made caring for them difficult and highlighted the need for confirmatory laboratory testing of suspected cases of superwarfarin poisoning.

Dr. Kelkar reported having no conflicts of interest. Two coinvestigators reported relationships outside the submitted work with Shire, CSL Behring, HEMA Biologics, and other companies.

SOURCE: Kelkar AH et al. N Engl J Med. 2018;379:1216-23.

Synthetic cannabinoids laced with superwarfarin were behind a recent outbreak of severe coagulopathy in Illinois.

In most cases, vitamin K replacement therapy alleviated symptoms, but four patients died after developing intracranial bleeding, said Amar H. Kelkar, MD, of the University of Illinois at Peoria.

Experts continue to look for how and why superwarfarin ended up in synthetic cannabinoids, whose street names include spice and K2, wrote Dr. Kelkar and his associates. Their report is in the New England Journal of Medicine.

Starting in March 2018, more than 150 patients across Illinois presented to hospitals with bleeding diathesis that involved persistent coagulopathy, the investigators explained. Early inquiries revealed that patients had consumed synthetic cannabinoids. Serum tests identified vitamin K antagonists, including brodifacoum, bromadiolone, and difenacoum. During arrests of suspected distributors, police confiscated synthetic cannabinoids that also tested positive for brodifacoum.

To help characterize the outbreak, the investigators reviewed admissions to Saint Francis Medical Center in Peoria, Ill., between March 28 and April 21, 2018. They identified 34 cases in which patients with vitamin K–dependent factor coagulopathy reported recent exposure to synthetic cannabinoids.

Fifteen of these patients underwent confirmatory anticoagulant testing, which universally confirmed superwarfarin poisoning. Brodifacoum was detected in all patients, difenacoum in five patients, bromadiolone in two patients, and warfarin in one patient.

Common presenting symptoms included gross hematuria (56% of patients) and abdominal pain (47%). Computed tomography identified renal abnormalities in 12 patients.

All patients received oral vitamin K₁ (phytonadione). Red cell transfusions, fresh-frozen plasma infusions, and 4-factor prothrombin complex concentrate, or a combination of these treatments, were also used in some patients.

Among the four confirmed deaths in this outbreak, one occurred in a patient in this case series. The patient, a 37-year-old woman presenting to the emergency department with markedly reduced consciousness, was reported by her friends to have recently used synthetic cannabinoids and methamphetamine. She had no personal or family history of coagulopathy.

Computed tomography of the head without contrast material revealed severe acute intraparenchymal hemorrhage of the right basal nuclei and insula with intraventricular extension, a 10-mm left-sided midline shift, and herniation.

She met criteria for brain death 15 hours after hospital admission despite treatment with 10 mg of intravenous vitamin K₁, four units of fresh frozen plasma, and 2,300 units of Kcentra.

Treating these patients after hospital discharge was difficult because of a lack of consensus guidelines and access to follow-up care, Dr. Kelkar and his associates noted. Some patients were quoted $24,000 to $34,000 per month for oral vitamin K1 therapy, which also made caring for them difficult and highlighted the need for confirmatory laboratory testing of suspected cases of superwarfarin poisoning.

Dr. Kelkar reported having no conflicts of interest. Two coinvestigators reported relationships outside the submitted work with Shire, CSL Behring, HEMA Biologics, and other companies.

SOURCE: Kelkar AH et al. N Engl J Med. 2018;379:1216-23.

Synthetic cannabinoids laced with superwarfarin were behind a recent outbreak of severe coagulopathy in Illinois.

In most cases, vitamin K replacement therapy alleviated symptoms, but four patients died after developing intracranial bleeding, said Amar H. Kelkar, MD, of the University of Illinois at Peoria.

Experts continue to look for how and why superwarfarin ended up in synthetic cannabinoids, whose street names include spice and K2, wrote Dr. Kelkar and his associates. Their report is in the New England Journal of Medicine.

Starting in March 2018, more than 150 patients across Illinois presented to hospitals with bleeding diathesis that involved persistent coagulopathy, the investigators explained. Early inquiries revealed that patients had consumed synthetic cannabinoids. Serum tests identified vitamin K antagonists, including brodifacoum, bromadiolone, and difenacoum. During arrests of suspected distributors, police confiscated synthetic cannabinoids that also tested positive for brodifacoum.

To help characterize the outbreak, the investigators reviewed admissions to Saint Francis Medical Center in Peoria, Ill., between March 28 and April 21, 2018. They identified 34 cases in which patients with vitamin K–dependent factor coagulopathy reported recent exposure to synthetic cannabinoids.

Fifteen of these patients underwent confirmatory anticoagulant testing, which universally confirmed superwarfarin poisoning. Brodifacoum was detected in all patients, difenacoum in five patients, bromadiolone in two patients, and warfarin in one patient.

Common presenting symptoms included gross hematuria (56% of patients) and abdominal pain (47%). Computed tomography identified renal abnormalities in 12 patients.

All patients received oral vitamin K₁ (phytonadione). Red cell transfusions, fresh-frozen plasma infusions, and 4-factor prothrombin complex concentrate, or a combination of these treatments, were also used in some patients.

Among the four confirmed deaths in this outbreak, one occurred in a patient in this case series. The patient, a 37-year-old woman presenting to the emergency department with markedly reduced consciousness, was reported by her friends to have recently used synthetic cannabinoids and methamphetamine. She had no personal or family history of coagulopathy.

Computed tomography of the head without contrast material revealed severe acute intraparenchymal hemorrhage of the right basal nuclei and insula with intraventricular extension, a 10-mm left-sided midline shift, and herniation.

She met criteria for brain death 15 hours after hospital admission despite treatment with 10 mg of intravenous vitamin K₁, four units of fresh frozen plasma, and 2,300 units of Kcentra.

Treating these patients after hospital discharge was difficult because of a lack of consensus guidelines and access to follow-up care, Dr. Kelkar and his associates noted. Some patients were quoted $24,000 to $34,000 per month for oral vitamin K1 therapy, which also made caring for them difficult and highlighted the need for confirmatory laboratory testing of suspected cases of superwarfarin poisoning.

Dr. Kelkar reported having no conflicts of interest. Two coinvestigators reported relationships outside the submitted work with Shire, CSL Behring, HEMA Biologics, and other companies.

SOURCE: Kelkar AH et al. N Engl J Med. 2018;379:1216-23.

Photo from Bayer

The Japanese Ministry of Health, Labour and Welfare has approved Jivi® (also known as damoctocog alfa pegol or antihemophilic factor [recombinant] PEGylated-aucl) for the treatment of hemophilia A.

Jivi (formerly BAY94-9027) is a DNA-derived, factor VIII concentrate approved for use in hemophilia A patients age 12 and older.

Jivi is approved for on-demand treatment and control of bleeding episodes, for perioperative management of bleeding, and as routine prophylaxis to reduce the frequency of bleeding episodes.

As prophylaxis, Jivi is typically given twice weekly, but it can also be given every 5 days or once a week, depending on patient needs.

The approval of Jivi in Japan is supported by data from the phase 2/3 PROTECT VIII trial. Some results from this trial were published in the Journal of Thrombosis and Haemostasis in 2016. Additional results are available in the U.S. prescribing information for Jivi.

PROTECT VIII enrolled previously treated adults and adolescents (ages 12 to 65) with severe hemophilia A.

In part A, researchers evaluated different dosing regimens for Jivi used as prophylaxis and on-demand treatment. An optional extension study was available to patients who completed part A.

In part B, researchers evaluated Jivi for perioperative management.

Efficacy

In part A, there were 132 patients in the intent‐to‐treat population—112 in the prophylaxis group and 20 in the on-demand group.

Patients received Jivi for 36 weeks. For the first 10 weeks, patients in the prophylaxis group received twice-weekly dosing at 25 IU/kg.

Patients with more than one bleed during this time went on to receive 30–40 IU/kg twice weekly. Patients with one or fewer bleeds were eligible for randomization to dosing every 5 days (45–60 IU/kg) or every 7 days (60 IU/kg).

The median annualized bleeding rate (ABR) was 4.1 for the patients who were treated twice weekly and were not eligible for randomization (n=13) and 1.9 for patients who were eligible for randomization but continued on twice-weekly treatment (n=11).

The median ABR was 1.9 for patients who were randomized to treatment every 5 days (n=43) and 0.96 for patients who completed prophylaxis with dosing every 7 days (32/43).

The median ABR for patients treated on demand was 24.1.

There were 388 treated bleeds in the on-demand group and 317 treated bleeds in the prophylaxis group. Overall, 73.3% of responses to treatment were considered “excellent” or “good,” 23.3% were considered “moderate,” and 3.3% were considered “poor.”

There were 17 patients who underwent 20 major surgeries in part B or the extension study and 10 patients who underwent minor surgeries in part A. Jivi provided “good” or “excellent” hemostatic control during all surgeries.

Safety

Safety data are available for 148 patients age 12 and older.

Adverse events in these patients included abdominal pain (3%), nausea (5%), vomiting (3%), injection site reactions (1%), pyrexia (5%), hypersensitivity (2%), dizziness (2%), headache (14%), insomnia (3%), cough (7%), erythema (1%), pruritus (1%), rash (2%), and flushing (1%).

A factor VIII inhibitor was reported in one adult patient, but repeat testing did not confirm the report.

One adult with asthma had a clinical hypersensitivity reaction and a transient increase of IgM anti-PEG antibody titer, which was negative upon retesting.

Photo from Bayer

The Japanese Ministry of Health, Labour and Welfare has approved Jivi® (also known as damoctocog alfa pegol or antihemophilic factor [recombinant] PEGylated-aucl) for the treatment of hemophilia A.

Jivi (formerly BAY94-9027) is a DNA-derived, factor VIII concentrate approved for use in hemophilia A patients age 12 and older.

Jivi is approved for on-demand treatment and control of bleeding episodes, for perioperative management of bleeding, and as routine prophylaxis to reduce the frequency of bleeding episodes.

As prophylaxis, Jivi is typically given twice weekly, but it can also be given every 5 days or once a week, depending on patient needs.

The approval of Jivi in Japan is supported by data from the phase 2/3 PROTECT VIII trial. Some results from this trial were published in the Journal of Thrombosis and Haemostasis in 2016. Additional results are available in the U.S. prescribing information for Jivi.

PROTECT VIII enrolled previously treated adults and adolescents (ages 12 to 65) with severe hemophilia A.

In part A, researchers evaluated different dosing regimens for Jivi used as prophylaxis and on-demand treatment. An optional extension study was available to patients who completed part A.

In part B, researchers evaluated Jivi for perioperative management.

Efficacy

In part A, there were 132 patients in the intent‐to‐treat population—112 in the prophylaxis group and 20 in the on-demand group.

Patients received Jivi for 36 weeks. For the first 10 weeks, patients in the prophylaxis group received twice-weekly dosing at 25 IU/kg.

Patients with more than one bleed during this time went on to receive 30–40 IU/kg twice weekly. Patients with one or fewer bleeds were eligible for randomization to dosing every 5 days (45–60 IU/kg) or every 7 days (60 IU/kg).

The median annualized bleeding rate (ABR) was 4.1 for the patients who were treated twice weekly and were not eligible for randomization (n=13) and 1.9 for patients who were eligible for randomization but continued on twice-weekly treatment (n=11).

The median ABR was 1.9 for patients who were randomized to treatment every 5 days (n=43) and 0.96 for patients who completed prophylaxis with dosing every 7 days (32/43).

The median ABR for patients treated on demand was 24.1.

There were 388 treated bleeds in the on-demand group and 317 treated bleeds in the prophylaxis group. Overall, 73.3% of responses to treatment were considered “excellent” or “good,” 23.3% were considered “moderate,” and 3.3% were considered “poor.”

There were 17 patients who underwent 20 major surgeries in part B or the extension study and 10 patients who underwent minor surgeries in part A. Jivi provided “good” or “excellent” hemostatic control during all surgeries.

Safety

Safety data are available for 148 patients age 12 and older.

Adverse events in these patients included abdominal pain (3%), nausea (5%), vomiting (3%), injection site reactions (1%), pyrexia (5%), hypersensitivity (2%), dizziness (2%), headache (14%), insomnia (3%), cough (7%), erythema (1%), pruritus (1%), rash (2%), and flushing (1%).

A factor VIII inhibitor was reported in one adult patient, but repeat testing did not confirm the report.

One adult with asthma had a clinical hypersensitivity reaction and a transient increase of IgM anti-PEG antibody titer, which was negative upon retesting.

Photo from Bayer

The Japanese Ministry of Health, Labour and Welfare has approved Jivi® (also known as damoctocog alfa pegol or antihemophilic factor [recombinant] PEGylated-aucl) for the treatment of hemophilia A.

Jivi (formerly BAY94-9027) is a DNA-derived, factor VIII concentrate approved for use in hemophilia A patients age 12 and older.

Jivi is approved for on-demand treatment and control of bleeding episodes, for perioperative management of bleeding, and as routine prophylaxis to reduce the frequency of bleeding episodes.

As prophylaxis, Jivi is typically given twice weekly, but it can also be given every 5 days or once a week, depending on patient needs.

The approval of Jivi in Japan is supported by data from the phase 2/3 PROTECT VIII trial. Some results from this trial were published in the Journal of Thrombosis and Haemostasis in 2016. Additional results are available in the U.S. prescribing information for Jivi.

PROTECT VIII enrolled previously treated adults and adolescents (ages 12 to 65) with severe hemophilia A.

In part A, researchers evaluated different dosing regimens for Jivi used as prophylaxis and on-demand treatment. An optional extension study was available to patients who completed part A.

In part B, researchers evaluated Jivi for perioperative management.

Efficacy

In part A, there were 132 patients in the intent‐to‐treat population—112 in the prophylaxis group and 20 in the on-demand group.

Patients received Jivi for 36 weeks. For the first 10 weeks, patients in the prophylaxis group received twice-weekly dosing at 25 IU/kg.

Patients with more than one bleed during this time went on to receive 30–40 IU/kg twice weekly. Patients with one or fewer bleeds were eligible for randomization to dosing every 5 days (45–60 IU/kg) or every 7 days (60 IU/kg).

The median annualized bleeding rate (ABR) was 4.1 for the patients who were treated twice weekly and were not eligible for randomization (n=13) and 1.9 for patients who were eligible for randomization but continued on twice-weekly treatment (n=11).

The median ABR was 1.9 for patients who were randomized to treatment every 5 days (n=43) and 0.96 for patients who completed prophylaxis with dosing every 7 days (32/43).

The median ABR for patients treated on demand was 24.1.

There were 388 treated bleeds in the on-demand group and 317 treated bleeds in the prophylaxis group. Overall, 73.3% of responses to treatment were considered “excellent” or “good,” 23.3% were considered “moderate,” and 3.3% were considered “poor.”

There were 17 patients who underwent 20 major surgeries in part B or the extension study and 10 patients who underwent minor surgeries in part A. Jivi provided “good” or “excellent” hemostatic control during all surgeries.

Safety

Safety data are available for 148 patients age 12 and older.

Adverse events in these patients included abdominal pain (3%), nausea (5%), vomiting (3%), injection site reactions (1%), pyrexia (5%), hypersensitivity (2%), dizziness (2%), headache (14%), insomnia (3%), cough (7%), erythema (1%), pruritus (1%), rash (2%), and flushing (1%).

A factor VIII inhibitor was reported in one adult patient, but repeat testing did not confirm the report.

One adult with asthma had a clinical hypersensitivity reaction and a transient increase of IgM anti-PEG antibody titer, which was negative upon retesting.

The hematopoietic action of the thrombopoietin receptor (TPO-R) agonist eltrombopag (Promacta) occurs at the stem cell level through its effects on iron chelation that in turn leads to hematopoietic stem cell (HSC) stimulation and self-renewal, investigators report.

Studying the effects of eltrombopag treatment in mouse models and in bone marrow cells isolated from patients, Britta Will, PhD, from the Albert Einstein College of Medicine, New York, and her colleagues found that eltrombopag’s stimulatory effects on stem cell self-renewal were independent of the thrombopoietin receptor.

“The iron chelation–dependent mechanism of [eltrombopag] is very likely to confer clinical relevance in the context of enhancing TPO-R–dependent HSC stimulation and reinforcing stem cell identity through wide-ranging iron-dependent metabolic reprogramming, which increases healthy stem cells without causing their exhaustion in bone marrow failure syndromes, as well as aid in preserving functional HSCs under cellular stress (such as transplantation, cytotoxic treatment, or irradiation),” they wrote in Science Translational Medicine.

To gain insight into the effects of eltrombopag on the earliest stages of hematopoiesis, the investigators conducted a series of experiments, starting with an assessment of the effects of the agent on the functional hallmarks of primary human stem cells.

Using assays for differentiation, self-renewal, and cell proliferation in human bone marrow cell lines, they found that eltrombopag acts directly on multilineage hematopoiesis by fostering commitment to differentiation at the multipotent progenitor (MPP) cell level and by enhancing self-renewal of hematopoietic stem cells.

Next, they investigated whether eltrombopag promoted hematopoiesis by activating the TPO-R, or through a different mechanism, and found that its action was independent of the thrombopoietin receptor. Specifically, they found that eltrombopag “elicits gene expression alterations in HSCs consistent with a molecular response to reduced intracellular iron content, consisting of decreased glycolysis and enhanced lipid and protein catabolic pathway activation.”

To show that the effect was independent of TPO-R, they then turned to mouse models (eltrombopag is known to activate TPO-R signaling in primate cells, including in humans, but cannot do so in mice, they explained). They showed that in mice, eltrombopag is capable of stimulating HSCs even in the absence of action on the TPO-R.

They also demonstrated that HSCs from both humans and mice have evidence of changes in metabolism and in gene expression that were consistent with reduction of labile iron pools that stem cells rely on for maintenance. When they preloaded cells with iron, the stimulatory effects of eltrombopag were negated, further supporting the iron-chelating effects of the drug on HSC stimulation.

Finally, they looked at HSC function in bone marrow mononuclear cells from patients with immune thrombocytopenia who were being treated with eltrombopag and found a threefold greater increase in the number of functional HSCs, compared with samples from patients treated with the TPO-R agonist romiplostim (Nplate), which does not have iron-chelating properties.

“Together, our data demonstrate a TPO-R–independent stem cell stimulatory function of EP and suggest that free intracellular iron pools may serve as a rheostat for HSC maintenance,” the investigators wrote.

The study was supported by the New York State Department of Health. Dr. Will and two coauthors reported research support from GlaxoSmithKline and Novartis, and serving as consultants for Novartis. Two of the co-authors are employees of Novartis.

SOURCE: Kao YR et al. Sci Transl Med. 2018 Sep 12;10(458). doi: 10.1126/scitranslmed.aas9563.
 

The hematopoietic action of the thrombopoietin receptor (TPO-R) agonist eltrombopag (Promacta) occurs at the stem cell level through its effects on iron chelation that in turn leads to hematopoietic stem cell (HSC) stimulation and self-renewal, investigators report.

Studying the effects of eltrombopag treatment in mouse models and in bone marrow cells isolated from patients, Britta Will, PhD, from the Albert Einstein College of Medicine, New York, and her colleagues found that eltrombopag’s stimulatory effects on stem cell self-renewal were independent of the thrombopoietin receptor.

“The iron chelation–dependent mechanism of [eltrombopag] is very likely to confer clinical relevance in the context of enhancing TPO-R–dependent HSC stimulation and reinforcing stem cell identity through wide-ranging iron-dependent metabolic reprogramming, which increases healthy stem cells without causing their exhaustion in bone marrow failure syndromes, as well as aid in preserving functional HSCs under cellular stress (such as transplantation, cytotoxic treatment, or irradiation),” they wrote in Science Translational Medicine.

To gain insight into the effects of eltrombopag on the earliest stages of hematopoiesis, the investigators conducted a series of experiments, starting with an assessment of the effects of the agent on the functional hallmarks of primary human stem cells.

Using assays for differentiation, self-renewal, and cell proliferation in human bone marrow cell lines, they found that eltrombopag acts directly on multilineage hematopoiesis by fostering commitment to differentiation at the multipotent progenitor (MPP) cell level and by enhancing self-renewal of hematopoietic stem cells.

Next, they investigated whether eltrombopag promoted hematopoiesis by activating the TPO-R, or through a different mechanism, and found that its action was independent of the thrombopoietin receptor. Specifically, they found that eltrombopag “elicits gene expression alterations in HSCs consistent with a molecular response to reduced intracellular iron content, consisting of decreased glycolysis and enhanced lipid and protein catabolic pathway activation.”

To show that the effect was independent of TPO-R, they then turned to mouse models (eltrombopag is known to activate TPO-R signaling in primate cells, including in humans, but cannot do so in mice, they explained). They showed that in mice, eltrombopag is capable of stimulating HSCs even in the absence of action on the TPO-R.

They also demonstrated that HSCs from both humans and mice have evidence of changes in metabolism and in gene expression that were consistent with reduction of labile iron pools that stem cells rely on for maintenance. When they preloaded cells with iron, the stimulatory effects of eltrombopag were negated, further supporting the iron-chelating effects of the drug on HSC stimulation.

Finally, they looked at HSC function in bone marrow mononuclear cells from patients with immune thrombocytopenia who were being treated with eltrombopag and found a threefold greater increase in the number of functional HSCs, compared with samples from patients treated with the TPO-R agonist romiplostim (Nplate), which does not have iron-chelating properties.

“Together, our data demonstrate a TPO-R–independent stem cell stimulatory function of EP and suggest that free intracellular iron pools may serve as a rheostat for HSC maintenance,” the investigators wrote.

The study was supported by the New York State Department of Health. Dr. Will and two coauthors reported research support from GlaxoSmithKline and Novartis, and serving as consultants for Novartis. Two of the co-authors are employees of Novartis.

SOURCE: Kao YR et al. Sci Transl Med. 2018 Sep 12;10(458). doi: 10.1126/scitranslmed.aas9563.
 

The hematopoietic action of the thrombopoietin receptor (TPO-R) agonist eltrombopag (Promacta) occurs at the stem cell level through its effects on iron chelation that in turn leads to hematopoietic stem cell (HSC) stimulation and self-renewal, investigators report.

Studying the effects of eltrombopag treatment in mouse models and in bone marrow cells isolated from patients, Britta Will, PhD, from the Albert Einstein College of Medicine, New York, and her colleagues found that eltrombopag’s stimulatory effects on stem cell self-renewal were independent of the thrombopoietin receptor.

“The iron chelation–dependent mechanism of [eltrombopag] is very likely to confer clinical relevance in the context of enhancing TPO-R–dependent HSC stimulation and reinforcing stem cell identity through wide-ranging iron-dependent metabolic reprogramming, which increases healthy stem cells without causing their exhaustion in bone marrow failure syndromes, as well as aid in preserving functional HSCs under cellular stress (such as transplantation, cytotoxic treatment, or irradiation),” they wrote in Science Translational Medicine.

To gain insight into the effects of eltrombopag on the earliest stages of hematopoiesis, the investigators conducted a series of experiments, starting with an assessment of the effects of the agent on the functional hallmarks of primary human stem cells.

Using assays for differentiation, self-renewal, and cell proliferation in human bone marrow cell lines, they found that eltrombopag acts directly on multilineage hematopoiesis by fostering commitment to differentiation at the multipotent progenitor (MPP) cell level and by enhancing self-renewal of hematopoietic stem cells.

Next, they investigated whether eltrombopag promoted hematopoiesis by activating the TPO-R, or through a different mechanism, and found that its action was independent of the thrombopoietin receptor. Specifically, they found that eltrombopag “elicits gene expression alterations in HSCs consistent with a molecular response to reduced intracellular iron content, consisting of decreased glycolysis and enhanced lipid and protein catabolic pathway activation.”

To show that the effect was independent of TPO-R, they then turned to mouse models (eltrombopag is known to activate TPO-R signaling in primate cells, including in humans, but cannot do so in mice, they explained). They showed that in mice, eltrombopag is capable of stimulating HSCs even in the absence of action on the TPO-R.

They also demonstrated that HSCs from both humans and mice have evidence of changes in metabolism and in gene expression that were consistent with reduction of labile iron pools that stem cells rely on for maintenance. When they preloaded cells with iron, the stimulatory effects of eltrombopag were negated, further supporting the iron-chelating effects of the drug on HSC stimulation.

Finally, they looked at HSC function in bone marrow mononuclear cells from patients with immune thrombocytopenia who were being treated with eltrombopag and found a threefold greater increase in the number of functional HSCs, compared with samples from patients treated with the TPO-R agonist romiplostim (Nplate), which does not have iron-chelating properties.

“Together, our data demonstrate a TPO-R–independent stem cell stimulatory function of EP and suggest that free intracellular iron pools may serve as a rheostat for HSC maintenance,” the investigators wrote.

The study was supported by the New York State Department of Health. Dr. Will and two coauthors reported research support from GlaxoSmithKline and Novartis, and serving as consultants for Novartis. Two of the co-authors are employees of Novartis.

SOURCE: Kao YR et al. Sci Transl Med. 2018 Sep 12;10(458). doi: 10.1126/scitranslmed.aas9563.
 

Photo from Bayer

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for damoctocog alfa pegol, a recombinant human factor VIII therapy.

Bayer is seeking European marketing authorization for damoctocog alfa pegol (formerly BAY94-9027) for the treatment and prophylaxis of bleeding in previously treated patients age 12 and older with hemophilia A.

The CHMP’s recommendation for damoctocog alfa pegol, which is approved in the U.S. under the name Jivi, will be reviewed by the European Commission (EC).

The EC typically makes a decision about marketing authorization within 67 days of the CHMP’s opinion. The EC’s decision will apply to the European Union, Norway, Iceland, and Liechtenstein.

The CHMP’s recommendation for damoctocog alfa pegol is supported by the phase 2/3 PROTECT VIII trial. Some results from this trial were published in the Journal of Thrombosis and Haemostasis in 2016. Additional results are available in the U.S. prescribing information for Jivi.

PROTECT VIII enrolled previously treated adults and adolescents (ages 12 to 65) with severe hemophilia A.

In part A, researchers evaluated different dosing regimens for damoctocog alfa pegol used as prophylaxis and on-demand treatment. An optional extension study was available to patients who completed part A.

In part B, researchers evaluated damoctocog alfa pegol for perioperative management.

Efficacy

In part A, there were 132 patients in the intent‐to‐treat population—112 in the prophylaxis group and 20 in the on-demand group.

Patients received damoctocog alfa pegol for 36 weeks. For the first 10 weeks, patients in the prophylaxis group received twice-weekly dosing at 25 IU/kg.

Patients with more than one bleed during this time went on to receive 30–40 IU/kg twice weekly. Patients with one or fewer bleeds were eligible for randomization to dosing every 5 days (45–60 IU/kg) or every 7 days (60 IU/kg).

The median annualized bleeding rate (ABR) was 4.1 for the patients who were treated twice weekly and were not eligible for randomization (n=13) and 1.9 for patients who were eligible for randomization but continued on twice-weekly treatment (n=11).

The median ABR was 1.9 for patients who were randomized to treatment every 5 days (n=43) and 0.96 for patients who completed prophylaxis with dosing every 7 days (32/43).

The median ABR for patients treated on demand was 24.1.

There were 388 treated bleeds in the on-demand group and 317 treated bleeds in the prophylaxis group. Overall, 73.3% of responses to treatment were considered “excellent” or “good,” 23.3% were considered “moderate,” and 3.3% were considered “poor.”

There were 17 patients who underwent 20 major surgeries in part B or the extension study and 10 patients who underwent minor surgeries in part A. Damoctocog alfa pegol provided “good” or “excellent” hemostatic control during all surgeries.

Safety

Safety data are available for 148 patients age 12 and older.

Adverse events in these patients included abdominal pain (3%), nausea (5%), vomiting (3%), injection site reactions (1%), pyrexia (5%), hypersensitivity (2%), dizziness (2%), headache (14%), insomnia (3%), cough (7%), erythema (1%), pruritus (1%), rash (2%), and flushing (1%).

A factor VIII inhibitor was reported in one adult patient, but repeat testing did not confirm the report.

One adult with asthma had a clinical hypersensitivity reaction and a transient increase of IgM anti-PEG antibody titer, which was negative upon retesting.

Photo from Bayer

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for damoctocog alfa pegol, a recombinant human factor VIII therapy.

Bayer is seeking European marketing authorization for damoctocog alfa pegol (formerly BAY94-9027) for the treatment and prophylaxis of bleeding in previously treated patients age 12 and older with hemophilia A.

The CHMP’s recommendation for damoctocog alfa pegol, which is approved in the U.S. under the name Jivi, will be reviewed by the European Commission (EC).

The EC typically makes a decision about marketing authorization within 67 days of the CHMP’s opinion. The EC’s decision will apply to the European Union, Norway, Iceland, and Liechtenstein.

The CHMP’s recommendation for damoctocog alfa pegol is supported by the phase 2/3 PROTECT VIII trial. Some results from this trial were published in the Journal of Thrombosis and Haemostasis in 2016. Additional results are available in the U.S. prescribing information for Jivi.

PROTECT VIII enrolled previously treated adults and adolescents (ages 12 to 65) with severe hemophilia A.

In part A, researchers evaluated different dosing regimens for damoctocog alfa pegol used as prophylaxis and on-demand treatment. An optional extension study was available to patients who completed part A.

In part B, researchers evaluated damoctocog alfa pegol for perioperative management.

Efficacy

In part A, there were 132 patients in the intent‐to‐treat population—112 in the prophylaxis group and 20 in the on-demand group.

Patients received damoctocog alfa pegol for 36 weeks. For the first 10 weeks, patients in the prophylaxis group received twice-weekly dosing at 25 IU/kg.

Patients with more than one bleed during this time went on to receive 30–40 IU/kg twice weekly. Patients with one or fewer bleeds were eligible for randomization to dosing every 5 days (45–60 IU/kg) or every 7 days (60 IU/kg).

The median annualized bleeding rate (ABR) was 4.1 for the patients who were treated twice weekly and were not eligible for randomization (n=13) and 1.9 for patients who were eligible for randomization but continued on twice-weekly treatment (n=11).

The median ABR was 1.9 for patients who were randomized to treatment every 5 days (n=43) and 0.96 for patients who completed prophylaxis with dosing every 7 days (32/43).

The median ABR for patients treated on demand was 24.1.

There were 388 treated bleeds in the on-demand group and 317 treated bleeds in the prophylaxis group. Overall, 73.3% of responses to treatment were considered “excellent” or “good,” 23.3% were considered “moderate,” and 3.3% were considered “poor.”

There were 17 patients who underwent 20 major surgeries in part B or the extension study and 10 patients who underwent minor surgeries in part A. Damoctocog alfa pegol provided “good” or “excellent” hemostatic control during all surgeries.

Safety

Safety data are available for 148 patients age 12 and older.

Adverse events in these patients included abdominal pain (3%), nausea (5%), vomiting (3%), injection site reactions (1%), pyrexia (5%), hypersensitivity (2%), dizziness (2%), headache (14%), insomnia (3%), cough (7%), erythema (1%), pruritus (1%), rash (2%), and flushing (1%).

A factor VIII inhibitor was reported in one adult patient, but repeat testing did not confirm the report.

One adult with asthma had a clinical hypersensitivity reaction and a transient increase of IgM anti-PEG antibody titer, which was negative upon retesting.

Photo from Bayer

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for damoctocog alfa pegol, a recombinant human factor VIII therapy.

Bayer is seeking European marketing authorization for damoctocog alfa pegol (formerly BAY94-9027) for the treatment and prophylaxis of bleeding in previously treated patients age 12 and older with hemophilia A.

The CHMP’s recommendation for damoctocog alfa pegol, which is approved in the U.S. under the name Jivi, will be reviewed by the European Commission (EC).

The EC typically makes a decision about marketing authorization within 67 days of the CHMP’s opinion. The EC’s decision will apply to the European Union, Norway, Iceland, and Liechtenstein.

The CHMP’s recommendation for damoctocog alfa pegol is supported by the phase 2/3 PROTECT VIII trial. Some results from this trial were published in the Journal of Thrombosis and Haemostasis in 2016. Additional results are available in the U.S. prescribing information for Jivi.

PROTECT VIII enrolled previously treated adults and adolescents (ages 12 to 65) with severe hemophilia A.

In part A, researchers evaluated different dosing regimens for damoctocog alfa pegol used as prophylaxis and on-demand treatment. An optional extension study was available to patients who completed part A.

In part B, researchers evaluated damoctocog alfa pegol for perioperative management.

Efficacy

In part A, there were 132 patients in the intent‐to‐treat population—112 in the prophylaxis group and 20 in the on-demand group.

Patients received damoctocog alfa pegol for 36 weeks. For the first 10 weeks, patients in the prophylaxis group received twice-weekly dosing at 25 IU/kg.

Patients with more than one bleed during this time went on to receive 30–40 IU/kg twice weekly. Patients with one or fewer bleeds were eligible for randomization to dosing every 5 days (45–60 IU/kg) or every 7 days (60 IU/kg).

The median annualized bleeding rate (ABR) was 4.1 for the patients who were treated twice weekly and were not eligible for randomization (n=13) and 1.9 for patients who were eligible for randomization but continued on twice-weekly treatment (n=11).

The median ABR was 1.9 for patients who were randomized to treatment every 5 days (n=43) and 0.96 for patients who completed prophylaxis with dosing every 7 days (32/43).

The median ABR for patients treated on demand was 24.1.

There were 388 treated bleeds in the on-demand group and 317 treated bleeds in the prophylaxis group. Overall, 73.3% of responses to treatment were considered “excellent” or “good,” 23.3% were considered “moderate,” and 3.3% were considered “poor.”

There were 17 patients who underwent 20 major surgeries in part B or the extension study and 10 patients who underwent minor surgeries in part A. Damoctocog alfa pegol provided “good” or “excellent” hemostatic control during all surgeries.

Safety

Safety data are available for 148 patients age 12 and older.

Adverse events in these patients included abdominal pain (3%), nausea (5%), vomiting (3%), injection site reactions (1%), pyrexia (5%), hypersensitivity (2%), dizziness (2%), headache (14%), insomnia (3%), cough (7%), erythema (1%), pruritus (1%), rash (2%), and flushing (1%).

A factor VIII inhibitor was reported in one adult patient, but repeat testing did not confirm the report.

One adult with asthma had a clinical hypersensitivity reaction and a transient increase of IgM anti-PEG antibody titer, which was negative upon retesting.

SAN DIEGO – Positive results of the LEADERS FREE II trial in patients with high bleeding risk undergoing percutaneous coronary intervention may pave the way for approval of a new drug-coated stent in the United States and possibly spell the end for bare-metal stents.

Susan London/MDedge News

Parsing the findings

When asked whether the Food and Drug Administration should approve this stent and whether he would use it for his patients, Dr. Krucoff gave a “yes, but …” reply. “The but here is, we have a lot to learn in this area. These are patients who by and large have been excluded from every pivotal drug-eluting stent study and every pivotal dual-antiplatelet study,” he elaborated. It is therefore unclear, for example, how the stent will perform as more are treated and what the optimal duration of dual-antiplatelet therapy is. Nonetheless, given that these patients make up a sizable share of the PCI [percutaneous coronary intervention] population and that some centers still commonly use bare-metal stents, “I think bringing this stent forward with a label for 30 days [of dual-antiplatelet therapy] in high bleeding risk patients is a yes.”

“To me, the main driving factor for an expeditious [approval] process is, if you put a conservatively critical eye to this, you could say that LEADERS FREE alerts us to a safety signal [about] our intuitive behavior practice of putting bare-metal stents in patients who we know are at high bleeding risk, so we are only going to treat them with 30 days of dual-antiplatelet therapy. There is actually a safety signal that we are potentially doing harm, based on at least one look at this,” Dr. Krucoff added. “There is no question, I think FDA decisions are primarily driven by safety concerns. The unusual thing here is, it’s not a safety concern as a defect in the device, it’s a safety concern relative to our current practice.”

Susan London/MDedge News

Susan London/MDedge News

Trial details

On average, the patients enrolled in LEADERS FREE II were generally similar to counterparts enrolled in LEADERS FREE and had an average of 1.74 factors putting them at high risk for bleeding, according to Dr. Krucoff. Of note, it was an all-comers trial in that there was no restriction on coronary anatomy, lesion complexity, or clinical presentation.

Results reported at the meeting, which was sponsored by the Cardiovascular Research Foundation, showed that the rate of the primary safety endpoint – the composite of cardiac death and myocardial infarction at 1 year – was 8.6% with the drug-coated stent and 12.3% with the bare-metal stent, for an absolute risk difference of –3.7% (hazard ratio, 0.67; P for noninferiority less than .0001; P for superiority = .0025).

Findings were significant for each component individually and were generally consistent across patient subgroups, Dr. Krucoff said. Secondary safety endpoints showed “no sign of a safety signal or concern with the drug-coated stent platform with 30 days of dual-antiplatelet therapy.”

In an additional analysis, the unadjusted rates of the primary safety endpoint were was 8.6% and 9.0% with the drug-coated stent in the LEADERS FREE II and the LEADERS FREE populations, respectively, compared with 12.4% with the bare-metal stent.

SAN DIEGO – Positive results of the LEADERS FREE II trial in patients with high bleeding risk undergoing percutaneous coronary intervention may pave the way for approval of a new drug-coated stent in the United States and possibly spell the end for bare-metal stents.

Susan London/MDedge News

Parsing the findings

When asked whether the Food and Drug Administration should approve this stent and whether he would use it for his patients, Dr. Krucoff gave a “yes, but …” reply. “The but here is, we have a lot to learn in this area. These are patients who by and large have been excluded from every pivotal drug-eluting stent study and every pivotal dual-antiplatelet study,” he elaborated. It is therefore unclear, for example, how the stent will perform as more are treated and what the optimal duration of dual-antiplatelet therapy is. Nonetheless, given that these patients make up a sizable share of the PCI [percutaneous coronary intervention] population and that some centers still commonly use bare-metal stents, “I think bringing this stent forward with a label for 30 days [of dual-antiplatelet therapy] in high bleeding risk patients is a yes.”

“To me, the main driving factor for an expeditious [approval] process is, if you put a conservatively critical eye to this, you could say that LEADERS FREE alerts us to a safety signal [about] our intuitive behavior practice of putting bare-metal stents in patients who we know are at high bleeding risk, so we are only going to treat them with 30 days of dual-antiplatelet therapy. There is actually a safety signal that we are potentially doing harm, based on at least one look at this,” Dr. Krucoff added. “There is no question, I think FDA decisions are primarily driven by safety concerns. The unusual thing here is, it’s not a safety concern as a defect in the device, it’s a safety concern relative to our current practice.”

Susan London/MDedge News

Susan London/MDedge News

Trial details

On average, the patients enrolled in LEADERS FREE II were generally similar to counterparts enrolled in LEADERS FREE and had an average of 1.74 factors putting them at high risk for bleeding, according to Dr. Krucoff. Of note, it was an all-comers trial in that there was no restriction on coronary anatomy, lesion complexity, or clinical presentation.

Results reported at the meeting, which was sponsored by the Cardiovascular Research Foundation, showed that the rate of the primary safety endpoint – the composite of cardiac death and myocardial infarction at 1 year – was 8.6% with the drug-coated stent and 12.3% with the bare-metal stent, for an absolute risk difference of –3.7% (hazard ratio, 0.67; P for noninferiority less than .0001; P for superiority = .0025).

Findings were significant for each component individually and were generally consistent across patient subgroups, Dr. Krucoff said. Secondary safety endpoints showed “no sign of a safety signal or concern with the drug-coated stent platform with 30 days of dual-antiplatelet therapy.”

In an additional analysis, the unadjusted rates of the primary safety endpoint were was 8.6% and 9.0% with the drug-coated stent in the LEADERS FREE II and the LEADERS FREE populations, respectively, compared with 12.4% with the bare-metal stent.

SAN DIEGO – Positive results of the LEADERS FREE II trial in patients with high bleeding risk undergoing percutaneous coronary intervention may pave the way for approval of a new drug-coated stent in the United States and possibly spell the end for bare-metal stents.

Susan London/MDedge News

Parsing the findings

When asked whether the Food and Drug Administration should approve this stent and whether he would use it for his patients, Dr. Krucoff gave a “yes, but …” reply. “The but here is, we have a lot to learn in this area. These are patients who by and large have been excluded from every pivotal drug-eluting stent study and every pivotal dual-antiplatelet study,” he elaborated. It is therefore unclear, for example, how the stent will perform as more are treated and what the optimal duration of dual-antiplatelet therapy is. Nonetheless, given that these patients make up a sizable share of the PCI [percutaneous coronary intervention] population and that some centers still commonly use bare-metal stents, “I think bringing this stent forward with a label for 30 days [of dual-antiplatelet therapy] in high bleeding risk patients is a yes.”

“To me, the main driving factor for an expeditious [approval] process is, if you put a conservatively critical eye to this, you could say that LEADERS FREE alerts us to a safety signal [about] our intuitive behavior practice of putting bare-metal stents in patients who we know are at high bleeding risk, so we are only going to treat them with 30 days of dual-antiplatelet therapy. There is actually a safety signal that we are potentially doing harm, based on at least one look at this,” Dr. Krucoff added. “There is no question, I think FDA decisions are primarily driven by safety concerns. The unusual thing here is, it’s not a safety concern as a defect in the device, it’s a safety concern relative to our current practice.”

Susan London/MDedge News

Susan London/MDedge News

Trial details

On average, the patients enrolled in LEADERS FREE II were generally similar to counterparts enrolled in LEADERS FREE and had an average of 1.74 factors putting them at high risk for bleeding, according to Dr. Krucoff. Of note, it was an all-comers trial in that there was no restriction on coronary anatomy, lesion complexity, or clinical presentation.

Results reported at the meeting, which was sponsored by the Cardiovascular Research Foundation, showed that the rate of the primary safety endpoint – the composite of cardiac death and myocardial infarction at 1 year – was 8.6% with the drug-coated stent and 12.3% with the bare-metal stent, for an absolute risk difference of –3.7% (hazard ratio, 0.67; P for noninferiority less than .0001; P for superiority = .0025).

Findings were significant for each component individually and were generally consistent across patient subgroups, Dr. Krucoff said. Secondary safety endpoints showed “no sign of a safety signal or concern with the drug-coated stent platform with 30 days of dual-antiplatelet therapy.”

In an additional analysis, the unadjusted rates of the primary safety endpoint were was 8.6% and 9.0% with the drug-coated stent in the LEADERS FREE II and the LEADERS FREE populations, respectively, compared with 12.4% with the bare-metal stent.

The European Commission has granted Shire marketing authorization for vonicog alfa (Veyvondi), a recombinant von Willebrand factor (rVWF) product.

The European Commission (EC) approved vonicog alfa for the treatment of bleeding events and treatment/prevention of surgical bleeding in adults with von Willebrand disease (VWD) when desmopressin treatment alone is ineffective or not indicated.

The product was approved in the United States in 2015 for on-demand treatment and control of bleeding episodes in adults.

The approval means Shire is authorized to market vonicog alfa in the European Union as well as in Iceland, Lichtenstein, and Norway.

The EC’s approval of vonicog alfa was based on outcomes from three clinical trials. This includes a phase 1 study and a pair of phase 3 trials – one in a surgical setting and one in a nonsurgical setting.

Data from these studies are available in the Summary of Product Characteristics for vonicog alfa.The phase 1 trial (NCT00816660) enrolled patients with type 3 or severe type 1 VWD.

The goal was to assess the safety and pharmacokinetics of vonicog alfa combined at a fixed ratio with recombinant factor VIII – referred to as “rVWF-rFVIII.” The researchers compared rVWF-rFVIII with plasma-derived (pd) VWF combined with pdFVIII (pdVWF-pdFVIII).

[email protected]

The European Commission has granted Shire marketing authorization for vonicog alfa (Veyvondi), a recombinant von Willebrand factor (rVWF) product.

The European Commission (EC) approved vonicog alfa for the treatment of bleeding events and treatment/prevention of surgical bleeding in adults with von Willebrand disease (VWD) when desmopressin treatment alone is ineffective or not indicated.

The product was approved in the United States in 2015 for on-demand treatment and control of bleeding episodes in adults.

The approval means Shire is authorized to market vonicog alfa in the European Union as well as in Iceland, Lichtenstein, and Norway.

The EC’s approval of vonicog alfa was based on outcomes from three clinical trials. This includes a phase 1 study and a pair of phase 3 trials – one in a surgical setting and one in a nonsurgical setting.

Data from these studies are available in the Summary of Product Characteristics for vonicog alfa.The phase 1 trial (NCT00816660) enrolled patients with type 3 or severe type 1 VWD.

The goal was to assess the safety and pharmacokinetics of vonicog alfa combined at a fixed ratio with recombinant factor VIII – referred to as “rVWF-rFVIII.” The researchers compared rVWF-rFVIII with plasma-derived (pd) VWF combined with pdFVIII (pdVWF-pdFVIII).

[email protected]

The European Commission has granted Shire marketing authorization for vonicog alfa (Veyvondi), a recombinant von Willebrand factor (rVWF) product.

The European Commission (EC) approved vonicog alfa for the treatment of bleeding events and treatment/prevention of surgical bleeding in adults with von Willebrand disease (VWD) when desmopressin treatment alone is ineffective or not indicated.

The product was approved in the United States in 2015 for on-demand treatment and control of bleeding episodes in adults.

The approval means Shire is authorized to market vonicog alfa in the European Union as well as in Iceland, Lichtenstein, and Norway.

The EC’s approval of vonicog alfa was based on outcomes from three clinical trials. This includes a phase 1 study and a pair of phase 3 trials – one in a surgical setting and one in a nonsurgical setting.

Data from these studies are available in the Summary of Product Characteristics for vonicog alfa.The phase 1 trial (NCT00816660) enrolled patients with type 3 or severe type 1 VWD.

The goal was to assess the safety and pharmacokinetics of vonicog alfa combined at a fixed ratio with recombinant factor VIII – referred to as “rVWF-rFVIII.” The researchers compared rVWF-rFVIII with plasma-derived (pd) VWF combined with pdFVIII (pdVWF-pdFVIII).

[email protected]

Photo from Shire

The European Commission (EC) has granted marketing authorization for vonicog alfa (Veyvondi), a recombinant von Willebrand factor (rVWF) product.

The EC approved vonicog alfa for the treatment of bleeding events and treatment/prevention of surgical bleeding in adults (age 18 and older) with von Willebrand disease (VWD) when desmopressin treatment alone is ineffective or not indicated.

The approval means Shire is authorized to market vonicog alfa in the European Union as well as in Iceland, Lichtenstein, and Norway.

The EC’s approval of vonicog alfa was based on outcomes from three clinical trials. This includes a phase 1 study and a pair of phase 3 trials—one in a surgical setting and one in a non-surgical setting.

Data from these studies are available in the Summary of Product Characteristics for vonicog alfa.

Phase 1 trial

This trial (NCT00816660, 070701) enrolled patients with type 3 or severe type 1 VWD.

The goal was to assess the safety and pharmacokinetics of vonicog alfa (rVWF) combined at a fixed ratio with recombinant factor VIII (rFVIII)—referred to as “rVWF-rFVIII.” The researchers compared rVWF-rFVIII to plasma-derived (pd) VWF combined with pdFVIII (pdVWF-pdFVIII).

The safety analysis included 32 patients who received rVWF-rFVIII. There were no thrombotic events, serious adverse events, or new cases of inhibitors to VWF or FVIII in these patients.

The pharmacokinetic analysis included 19 patients. The researchers said the pharmacokinetics of rVWF ristocetin cofactor activity, VWF antigen, and collagen-binding activity were similar with rVWF-rFVIII and pdVWF-pdFVIII.

FVIII levels were higher after infusion with rVWF-rFVIII than with pdVWF-pdFVIII, even after 72 hours. The researchers said this suggests that rVWF alone “could maintain sufficient FVIII activity to treat a bleeding episode once the initial FVIII level has reached a therapeutic threshold.”

These results were published in Blood in 2013.

Phase 3: Non-surgical

This study (NCT01410227, 071001) included 49 patients with VWD who received vonicog alfa with or without rFVIII.

All participants had successful treatment of bleeding episodes. Most (96.9%) treated bleeds (192 bleeds in 22 patients) were given an “excellent” efficacy rating (as good as or better than expected).

Most bleeds (81.8%) were resolved with a single infusion of vonicog alfa, and the treatment had a mean half-life of 21.9 hours.

There were 8 adverse events considered related to vonicog alfa, and 2 were serious. One patient experienced 2 simultaneous serious events—chest discomfort and increased heart rate—but these were resolved.

There were no thrombotic events in this trial, no treatment-related binding or neutralizing antibodies against VWF, and no neutralizing antibodies against FVIII.

These results were published in Blood in 2015.

Phase 3: Surgical setting

This trial (NCT02283268, 071101) enrolled 15 adults with severe VWD who were undergoing elective surgical procedures (10 of them major procedures).

Patients received vonicog alfa at 40 to 60 IU per kg of body weight 12 to 24 hours before surgery. Within 3 hours of surgery, each patient’s FVIII level (FVIII:C) was assessed, with a target of 30 IU/dL for minor surgeries and 60 IU/dL for major surgeries.

Within an hour of surgery, patients received a dose of vonicog alfa, with or without rFVIII, depending on the target FVIII:C levels at the 3-hour assessment.

Ten patients received rVWF alone, 12 did not receive any preoperative FVIII, and 2 did not receive rVWF postoperatively.

Vonicog alfa demonstrated overall hemostatic efficacy, as assessed 24 hours after the last perioperative infusion or the completion of the study visit, whichever occurred earlier.

Intra- and post-operative hemostasis was rated as “excellent” (as good as or better than expected) in 60% of patients and “good” (probably as good as expected) in 40% of patients.

One patient developed deep vein thrombosis 3 days after undergoing hip replacement surgery.

One patient tested positive for binding antibodies to VWF. None of the patients developed binding antibodies against potential impurities such as rFurin, CHO-protein, or mouse IgG.

These results were presented at the WFH 2018 World Congress.

Photo from Shire

The European Commission (EC) has granted marketing authorization for vonicog alfa (Veyvondi), a recombinant von Willebrand factor (rVWF) product.

The EC approved vonicog alfa for the treatment of bleeding events and treatment/prevention of surgical bleeding in adults (age 18 and older) with von Willebrand disease (VWD) when desmopressin treatment alone is ineffective or not indicated.

The approval means Shire is authorized to market vonicog alfa in the European Union as well as in Iceland, Lichtenstein, and Norway.

The EC’s approval of vonicog alfa was based on outcomes from three clinical trials. This includes a phase 1 study and a pair of phase 3 trials—one in a surgical setting and one in a non-surgical setting.

Data from these studies are available in the Summary of Product Characteristics for vonicog alfa.

Phase 1 trial

This trial (NCT00816660, 070701) enrolled patients with type 3 or severe type 1 VWD.

The goal was to assess the safety and pharmacokinetics of vonicog alfa (rVWF) combined at a fixed ratio with recombinant factor VIII (rFVIII)—referred to as “rVWF-rFVIII.” The researchers compared rVWF-rFVIII to plasma-derived (pd) VWF combined with pdFVIII (pdVWF-pdFVIII).

The safety analysis included 32 patients who received rVWF-rFVIII. There were no thrombotic events, serious adverse events, or new cases of inhibitors to VWF or FVIII in these patients.

The pharmacokinetic analysis included 19 patients. The researchers said the pharmacokinetics of rVWF ristocetin cofactor activity, VWF antigen, and collagen-binding activity were similar with rVWF-rFVIII and pdVWF-pdFVIII.

FVIII levels were higher after infusion with rVWF-rFVIII than with pdVWF-pdFVIII, even after 72 hours. The researchers said this suggests that rVWF alone “could maintain sufficient FVIII activity to treat a bleeding episode once the initial FVIII level has reached a therapeutic threshold.”

These results were published in Blood in 2013.

Phase 3: Non-surgical

This study (NCT01410227, 071001) included 49 patients with VWD who received vonicog alfa with or without rFVIII.

All participants had successful treatment of bleeding episodes. Most (96.9%) treated bleeds (192 bleeds in 22 patients) were given an “excellent” efficacy rating (as good as or better than expected).

Most bleeds (81.8%) were resolved with a single infusion of vonicog alfa, and the treatment had a mean half-life of 21.9 hours.

There were 8 adverse events considered related to vonicog alfa, and 2 were serious. One patient experienced 2 simultaneous serious events—chest discomfort and increased heart rate—but these were resolved.

There were no thrombotic events in this trial, no treatment-related binding or neutralizing antibodies against VWF, and no neutralizing antibodies against FVIII.

These results were published in Blood in 2015.

Phase 3: Surgical setting

This trial (NCT02283268, 071101) enrolled 15 adults with severe VWD who were undergoing elective surgical procedures (10 of them major procedures).

Patients received vonicog alfa at 40 to 60 IU per kg of body weight 12 to 24 hours before surgery. Within 3 hours of surgery, each patient’s FVIII level (FVIII:C) was assessed, with a target of 30 IU/dL for minor surgeries and 60 IU/dL for major surgeries.

Within an hour of surgery, patients received a dose of vonicog alfa, with or without rFVIII, depending on the target FVIII:C levels at the 3-hour assessment.

Ten patients received rVWF alone, 12 did not receive any preoperative FVIII, and 2 did not receive rVWF postoperatively.

Vonicog alfa demonstrated overall hemostatic efficacy, as assessed 24 hours after the last perioperative infusion or the completion of the study visit, whichever occurred earlier.

Intra- and post-operative hemostasis was rated as “excellent” (as good as or better than expected) in 60% of patients and “good” (probably as good as expected) in 40% of patients.

One patient developed deep vein thrombosis 3 days after undergoing hip replacement surgery.

One patient tested positive for binding antibodies to VWF. None of the patients developed binding antibodies against potential impurities such as rFurin, CHO-protein, or mouse IgG.

These results were presented at the WFH 2018 World Congress.

Photo from Shire

The European Commission (EC) has granted marketing authorization for vonicog alfa (Veyvondi), a recombinant von Willebrand factor (rVWF) product.

The EC approved vonicog alfa for the treatment of bleeding events and treatment/prevention of surgical bleeding in adults (age 18 and older) with von Willebrand disease (VWD) when desmopressin treatment alone is ineffective or not indicated.

The approval means Shire is authorized to market vonicog alfa in the European Union as well as in Iceland, Lichtenstein, and Norway.

The EC’s approval of vonicog alfa was based on outcomes from three clinical trials. This includes a phase 1 study and a pair of phase 3 trials—one in a surgical setting and one in a non-surgical setting.

Data from these studies are available in the Summary of Product Characteristics for vonicog alfa.

Phase 1 trial

This trial (NCT00816660, 070701) enrolled patients with type 3 or severe type 1 VWD.

The goal was to assess the safety and pharmacokinetics of vonicog alfa (rVWF) combined at a fixed ratio with recombinant factor VIII (rFVIII)—referred to as “rVWF-rFVIII.” The researchers compared rVWF-rFVIII to plasma-derived (pd) VWF combined with pdFVIII (pdVWF-pdFVIII).

The safety analysis included 32 patients who received rVWF-rFVIII. There were no thrombotic events, serious adverse events, or new cases of inhibitors to VWF or FVIII in these patients.

The pharmacokinetic analysis included 19 patients. The researchers said the pharmacokinetics of rVWF ristocetin cofactor activity, VWF antigen, and collagen-binding activity were similar with rVWF-rFVIII and pdVWF-pdFVIII.

FVIII levels were higher after infusion with rVWF-rFVIII than with pdVWF-pdFVIII, even after 72 hours. The researchers said this suggests that rVWF alone “could maintain sufficient FVIII activity to treat a bleeding episode once the initial FVIII level has reached a therapeutic threshold.”

These results were published in Blood in 2013.

Phase 3: Non-surgical

This study (NCT01410227, 071001) included 49 patients with VWD who received vonicog alfa with or without rFVIII.

All participants had successful treatment of bleeding episodes. Most (96.9%) treated bleeds (192 bleeds in 22 patients) were given an “excellent” efficacy rating (as good as or better than expected).

Most bleeds (81.8%) were resolved with a single infusion of vonicog alfa, and the treatment had a mean half-life of 21.9 hours.

There were 8 adverse events considered related to vonicog alfa, and 2 were serious. One patient experienced 2 simultaneous serious events—chest discomfort and increased heart rate—but these were resolved.

There were no thrombotic events in this trial, no treatment-related binding or neutralizing antibodies against VWF, and no neutralizing antibodies against FVIII.

These results were published in Blood in 2015.

Phase 3: Surgical setting

This trial (NCT02283268, 071101) enrolled 15 adults with severe VWD who were undergoing elective surgical procedures (10 of them major procedures).

Patients received vonicog alfa at 40 to 60 IU per kg of body weight 12 to 24 hours before surgery. Within 3 hours of surgery, each patient’s FVIII level (FVIII:C) was assessed, with a target of 30 IU/dL for minor surgeries and 60 IU/dL for major surgeries.

Within an hour of surgery, patients received a dose of vonicog alfa, with or without rFVIII, depending on the target FVIII:C levels at the 3-hour assessment.

Ten patients received rVWF alone, 12 did not receive any preoperative FVIII, and 2 did not receive rVWF postoperatively.

Vonicog alfa demonstrated overall hemostatic efficacy, as assessed 24 hours after the last perioperative infusion or the completion of the study visit, whichever occurred earlier.

Intra- and post-operative hemostasis was rated as “excellent” (as good as or better than expected) in 60% of patients and “good” (probably as good as expected) in 40% of patients.

One patient developed deep vein thrombosis 3 days after undergoing hip replacement surgery.

One patient tested positive for binding antibodies to VWF. None of the patients developed binding antibodies against potential impurities such as rFurin, CHO-protein, or mouse IgG.

These results were presented at the WFH 2018 World Congress.

Antihemophilic factor

CSL Behring has announced that Idelvion (Coagulation Factor IX [Recombinant], Albumin Fusion Protein) is now available in a 3500 IU vial size.

Idelvion is also available in 250 IU, 500 IU, 1000 IU, and 2000 IU vial sizes.

For some patients requiring high doses of Idelvion, the new 3500 IU vial size will reduce the reconstitution time needed to prepare multiple vials for a similar dose.

Idelvion is a fusion protein linking recombinant coagulation factor IX with recombinant albumin, and it is approved by the U.S. Food and Drug Administration to treat children and adults with hemophilia B.

Idelvion can be used as routine prophylaxis to prevent or reduce the frequency of bleeding episodes, for on-demand control and prevention of bleeding episodes, and for the perioperative management of bleeding.

Idelvion is approved for up to 14-day dosing in appropriate patients.

For more details on Idelvion, see the prescribing information.

Antihemophilic factor

CSL Behring has announced that Idelvion (Coagulation Factor IX [Recombinant], Albumin Fusion Protein) is now available in a 3500 IU vial size.

Idelvion is also available in 250 IU, 500 IU, 1000 IU, and 2000 IU vial sizes.

For some patients requiring high doses of Idelvion, the new 3500 IU vial size will reduce the reconstitution time needed to prepare multiple vials for a similar dose.

Idelvion is a fusion protein linking recombinant coagulation factor IX with recombinant albumin, and it is approved by the U.S. Food and Drug Administration to treat children and adults with hemophilia B.

Idelvion can be used as routine prophylaxis to prevent or reduce the frequency of bleeding episodes, for on-demand control and prevention of bleeding episodes, and for the perioperative management of bleeding.

Idelvion is approved for up to 14-day dosing in appropriate patients.

For more details on Idelvion, see the prescribing information.

Antihemophilic factor

CSL Behring has announced that Idelvion (Coagulation Factor IX [Recombinant], Albumin Fusion Protein) is now available in a 3500 IU vial size.

Idelvion is also available in 250 IU, 500 IU, 1000 IU, and 2000 IU vial sizes.

For some patients requiring high doses of Idelvion, the new 3500 IU vial size will reduce the reconstitution time needed to prepare multiple vials for a similar dose.

Idelvion is a fusion protein linking recombinant coagulation factor IX with recombinant albumin, and it is approved by the U.S. Food and Drug Administration to treat children and adults with hemophilia B.

Idelvion can be used as routine prophylaxis to prevent or reduce the frequency of bleeding episodes, for on-demand control and prevention of bleeding episodes, and for the perioperative management of bleeding.

Idelvion is approved for up to 14-day dosing in appropriate patients.

For more details on Idelvion, see the prescribing information.

The European Commission has granted marketing authorization for caplacizumab (Cablivi), a humanized bivalent nanobody that inhibits the interaction between von Willebrand factor and platelets.

Caplacizumab is now approved to treat adults with acquired thrombotic thrombocytopenic purpura (aTTP) in all member countries of the European Union as well as Norway, Iceland, and Liechtenstein.

The drug has been accepted for priority review in the United States and the Food and Drug Administration is expected to make a decision by Feb. 6, 2019.

The European Commission’s approval of caplacizumab is supported by data from the phase 2 TITAN study and the phase 3 HERCULES study.

The TITAN trial included 75 aTTP patients who were randomized to caplacizumab (n = 36) or placebo (n = 39), with all patients receiving the current standard of care – daily plasma exchange and immunosuppressive therapy (N Engl J Med. 2016;374:511-22).

Patients in the caplacizumab arm had a 39% reduction in the median time to response, compared with patients in the placebo arm (P = .005).

The rate of adverse events (AEs) thought to be related to the study drug was 17% in the caplacizumab arm and 11% in the placebo arm. The rate of AEs that were possibly related was 54% and 8%, respectively. The rate of serious AEs was 37% and 32%, respectively.

There were no deaths in the caplacizumab arm and two in the placebo arm. One death was attributable to severe, refractory TTP, and the other was attributable to cerebral hemorrhage.Results from the HERCULES trial were presented at the 2017 annual meeting of the American Society of Hematology.

The study enrolled patients with an acute episode of aTTP. They were randomized to receive caplacizumab (n = 72) or placebo (n = 73) in addition to standard care – plasma exchange and immunosuppression.

The study’s primary endpoint was the time to platelet count response (normalization). There was a significant reduction in time to platelet count response in the caplacizumab arm, compared with the placebo arm. 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 12.7% (n = 9) in the caplacizumab arm and 49.3% (n = 36) in the placebo arm (P less than .0001).

The incidence of aTTP-related death was 0% (n = 0) in the caplacizumab arm and 4.1% (n = 3) in the placebo arm. The incidence of aTTP recurrence was 4.2% (n = 3) in the caplacizumab arm and 38.4% in the placebo arm (n = 28), and the incidence of at least one major thromboembolic event was 8.5% (n = 6) and 8.2% (n = 6), respectively.

[email protected]

The European Commission has granted marketing authorization for caplacizumab (Cablivi), a humanized bivalent nanobody that inhibits the interaction between von Willebrand factor and platelets.

Caplacizumab is now approved to treat adults with acquired thrombotic thrombocytopenic purpura (aTTP) in all member countries of the European Union as well as Norway, Iceland, and Liechtenstein.

The drug has been accepted for priority review in the United States and the Food and Drug Administration is expected to make a decision by Feb. 6, 2019.

The European Commission’s approval of caplacizumab is supported by data from the phase 2 TITAN study and the phase 3 HERCULES study.

The TITAN trial included 75 aTTP patients who were randomized to caplacizumab (n = 36) or placebo (n = 39), with all patients receiving the current standard of care – daily plasma exchange and immunosuppressive therapy (N Engl J Med. 2016;374:511-22).

Patients in the caplacizumab arm had a 39% reduction in the median time to response, compared with patients in the placebo arm (P = .005).

The rate of adverse events (AEs) thought to be related to the study drug was 17% in the caplacizumab arm and 11% in the placebo arm. The rate of AEs that were possibly related was 54% and 8%, respectively. The rate of serious AEs was 37% and 32%, respectively.

There were no deaths in the caplacizumab arm and two in the placebo arm. One death was attributable to severe, refractory TTP, and the other was attributable to cerebral hemorrhage.Results from the HERCULES trial were presented at the 2017 annual meeting of the American Society of Hematology.

The study enrolled patients with an acute episode of aTTP. They were randomized to receive caplacizumab (n = 72) or placebo (n = 73) in addition to standard care – plasma exchange and immunosuppression.

The study’s primary endpoint was the time to platelet count response (normalization). There was a significant reduction in time to platelet count response in the caplacizumab arm, compared with the placebo arm. 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 12.7% (n = 9) in the caplacizumab arm and 49.3% (n = 36) in the placebo arm (P less than .0001).

The incidence of aTTP-related death was 0% (n = 0) in the caplacizumab arm and 4.1% (n = 3) in the placebo arm. The incidence of aTTP recurrence was 4.2% (n = 3) in the caplacizumab arm and 38.4% in the placebo arm (n = 28), and the incidence of at least one major thromboembolic event was 8.5% (n = 6) and 8.2% (n = 6), respectively.

[email protected]

The European Commission has granted marketing authorization for caplacizumab (Cablivi), a humanized bivalent nanobody that inhibits the interaction between von Willebrand factor and platelets.

Caplacizumab is now approved to treat adults with acquired thrombotic thrombocytopenic purpura (aTTP) in all member countries of the European Union as well as Norway, Iceland, and Liechtenstein.

The drug has been accepted for priority review in the United States and the Food and Drug Administration is expected to make a decision by Feb. 6, 2019.

The European Commission’s approval of caplacizumab is supported by data from the phase 2 TITAN study and the phase 3 HERCULES study.

The TITAN trial included 75 aTTP patients who were randomized to caplacizumab (n = 36) or placebo (n = 39), with all patients receiving the current standard of care – daily plasma exchange and immunosuppressive therapy (N Engl J Med. 2016;374:511-22).

Patients in the caplacizumab arm had a 39% reduction in the median time to response, compared with patients in the placebo arm (P = .005).

The rate of adverse events (AEs) thought to be related to the study drug was 17% in the caplacizumab arm and 11% in the placebo arm. The rate of AEs that were possibly related was 54% and 8%, respectively. The rate of serious AEs was 37% and 32%, respectively.

There were no deaths in the caplacizumab arm and two in the placebo arm. One death was attributable to severe, refractory TTP, and the other was attributable to cerebral hemorrhage.Results from the HERCULES trial were presented at the 2017 annual meeting of the American Society of Hematology.

The study enrolled patients with an acute episode of aTTP. They were randomized to receive caplacizumab (n = 72) or placebo (n = 73) in addition to standard care – plasma exchange and immunosuppression.

The study’s primary endpoint was the time to platelet count response (normalization). There was a significant reduction in time to platelet count response in the caplacizumab arm, compared with the placebo arm. 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 12.7% (n = 9) in the caplacizumab arm and 49.3% (n = 36) in the placebo arm (P less than .0001).

The incidence of aTTP-related death was 0% (n = 0) in the caplacizumab arm and 4.1% (n = 3) in the placebo arm. The incidence of aTTP recurrence was 4.2% (n = 3) in the caplacizumab arm and 38.4% in the placebo arm (n = 28), and the incidence of at least one major thromboembolic event was 8.5% (n = 6) and 8.2% (n = 6), respectively.

[email protected]

Vials and a syringe

The European Commission has granted marketing authorization for caplacizumab (Cablivi™), a humanized bivalent nanobody that inhibits the interaction between von Willebrand factor and platelets.

Caplacizumab is now approved to treat adults with acquired thrombotic thrombocytopenic purpura (aTTP) in all member countries of the European Union as well as Norway, Iceland, and Liechtenstein.

Sanofi Genzyme said it will work with relevant local authorities to make caplacizumab available in countries across Europe.

“The approval of Cablivi provides an important addition to the standard-of-care treatment for patients with aTTP in Europe because it can significantly reduce time to platelet count normalization and induce a clinically meaningful reduction in recurrences,” said Marie Scully, MD, of University College Hospital in London, UK.

The European Commission’s approval of caplacizumab is supported by data from the phase 2 TITAN study and the phase 3 HERCULES study.

TITAN

Results from the TITAN trial were published in The New England Journal of Medicine in 2016.

The study included 75 aTTP patients who were randomized to caplacizumab (n=36) or placebo (n=39), with all patients receiving the current standard of care—daily plasma exchange and immunosuppressive therapy.

The study’s primary endpoint was time to response, which was defined as platelet count normalization (150,000/mm³ or higher).

Patients in the caplacizumab arm had a 39% reduction in the median time to response compared to patients in the placebo arm (P=0.005).

Among the 69 patients who had not undergone a plasma exchange session before enrollment, the median time to response was 3.0 days in the caplacizumab arm and 4.9 days in the placebo arm.

Among the 6 patients who did undergo a plasma exchange session before enrollment, the median time to a response was 2.4 days in the caplacizumab arm and 4.3 days in the placebo arm.

The rate of confirmed response was 86.1% (n=31) in the caplacizumab arm and 71.8% (n=28) in the placebo arm.

There were 541 adverse events (AEs) in 34 of the 35 evaluable patients receiving caplacizumab (97%) and 522 AEs in all 37 evaluable patients receiving placebo (100%). TTP exacerbations and relapses were not included as AEs.

The rate of AEs thought to be related to the study drug was 17% in the caplacizumab arm and 11% in the placebo arm. The rate of AEs that were possibly related was 54% and 8%, respectively. The rate of serious AEs was 37% and 32%, respectively.

There were no deaths in the caplacizumab arm and two in the placebo arm. One death was due to severe, refractory TTP, and the other was due to cerebral hemorrhage.

HERCULES

Results from the HERCULES trial were presented at the 2017 ASH Annual Meeting.

The study enrolled patients with an acute episode of aTTP. They were randomized to receive caplacizumab (n=72) or placebo (n=73) in addition to standard care—plasma exchange and immunosuppression.

The study’s primary endpoint was the time to platelet count response (normalization), which was defined as an initial 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 to the placebo arm. The platelet normalization rate ratio was 1.55 (P<0.01).

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 12.7% (n=9) in the caplacizumab arm and 49.3% (n=36) in the placebo arm (P<0.0001).

The incidence of aTTP-related death was 0% (n=0) in the caplacizumab arm and 4.1% (n=3) in the placebo arm. The incidence of aTTP recurrence was 4.2% (n=3) and 38.4% (n=28), respectively. The incidence of at least one major thromboembolic event was 8.5% (n=6) and 8.2% (n=6), respectively.

The proportion of patients with at least one study-drug-related AE was 57.7% in the caplacizumab arm and 43.8% in the placebo arm. The proportion of patients with at least one study-drug-related serious AE was 14.1% (n=10) and 5.5% (n=4), respectively. The rate of discontinuation due to at least one AE was 7.0% and 12.3%, respectively.

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

Vials and a syringe

The European Commission has granted marketing authorization for caplacizumab (Cablivi™), a humanized bivalent nanobody that inhibits the interaction between von Willebrand factor and platelets.

Caplacizumab is now approved to treat adults with acquired thrombotic thrombocytopenic purpura (aTTP) in all member countries of the European Union as well as Norway, Iceland, and Liechtenstein.

Sanofi Genzyme said it will work with relevant local authorities to make caplacizumab available in countries across Europe.

“The approval of Cablivi provides an important addition to the standard-of-care treatment for patients with aTTP in Europe because it can significantly reduce time to platelet count normalization and induce a clinically meaningful reduction in recurrences,” said Marie Scully, MD, of University College Hospital in London, UK.

The European Commission’s approval of caplacizumab is supported by data from the phase 2 TITAN study and the phase 3 HERCULES study.

TITAN

Results from the TITAN trial were published in The New England Journal of Medicine in 2016.

The study included 75 aTTP patients who were randomized to caplacizumab (n=36) or placebo (n=39), with all patients receiving the current standard of care—daily plasma exchange and immunosuppressive therapy.

The study’s primary endpoint was time to response, which was defined as platelet count normalization (150,000/mm³ or higher).

Patients in the caplacizumab arm had a 39% reduction in the median time to response compared to patients in the placebo arm (P=0.005).

Among the 69 patients who had not undergone a plasma exchange session before enrollment, the median time to response was 3.0 days in the caplacizumab arm and 4.9 days in the placebo arm.

Among the 6 patients who did undergo a plasma exchange session before enrollment, the median time to a response was 2.4 days in the caplacizumab arm and 4.3 days in the placebo arm.

The rate of confirmed response was 86.1% (n=31) in the caplacizumab arm and 71.8% (n=28) in the placebo arm.

There were 541 adverse events (AEs) in 34 of the 35 evaluable patients receiving caplacizumab (97%) and 522 AEs in all 37 evaluable patients receiving placebo (100%). TTP exacerbations and relapses were not included as AEs.

The rate of AEs thought to be related to the study drug was 17% in the caplacizumab arm and 11% in the placebo arm. The rate of AEs that were possibly related was 54% and 8%, respectively. The rate of serious AEs was 37% and 32%, respectively.

There were no deaths in the caplacizumab arm and two in the placebo arm. One death was due to severe, refractory TTP, and the other was due to cerebral hemorrhage.

HERCULES

Results from the HERCULES trial were presented at the 2017 ASH Annual Meeting.

The study enrolled patients with an acute episode of aTTP. They were randomized to receive caplacizumab (n=72) or placebo (n=73) in addition to standard care—plasma exchange and immunosuppression.

The study’s primary endpoint was the time to platelet count response (normalization), which was defined as an initial 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 to the placebo arm. The platelet normalization rate ratio was 1.55 (P<0.01).

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 12.7% (n=9) in the caplacizumab arm and 49.3% (n=36) in the placebo arm (P<0.0001).

The incidence of aTTP-related death was 0% (n=0) in the caplacizumab arm and 4.1% (n=3) in the placebo arm. The incidence of aTTP recurrence was 4.2% (n=3) and 38.4% (n=28), respectively. The incidence of at least one major thromboembolic event was 8.5% (n=6) and 8.2% (n=6), respectively.

The proportion of patients with at least one study-drug-related AE was 57.7% in the caplacizumab arm and 43.8% in the placebo arm. The proportion of patients with at least one study-drug-related serious AE was 14.1% (n=10) and 5.5% (n=4), respectively. The rate of discontinuation due to at least one AE was 7.0% and 12.3%, respectively.

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

Vials and a syringe

The European Commission has granted marketing authorization for caplacizumab (Cablivi™), a humanized bivalent nanobody that inhibits the interaction between von Willebrand factor and platelets.

Caplacizumab is now approved to treat adults with acquired thrombotic thrombocytopenic purpura (aTTP) in all member countries of the European Union as well as Norway, Iceland, and Liechtenstein.

Sanofi Genzyme said it will work with relevant local authorities to make caplacizumab available in countries across Europe.

“The approval of Cablivi provides an important addition to the standard-of-care treatment for patients with aTTP in Europe because it can significantly reduce time to platelet count normalization and induce a clinically meaningful reduction in recurrences,” said Marie Scully, MD, of University College Hospital in London, UK.

The European Commission’s approval of caplacizumab is supported by data from the phase 2 TITAN study and the phase 3 HERCULES study.

TITAN

Results from the TITAN trial were published in The New England Journal of Medicine in 2016.

The study included 75 aTTP patients who were randomized to caplacizumab (n=36) or placebo (n=39), with all patients receiving the current standard of care—daily plasma exchange and immunosuppressive therapy.

The study’s primary endpoint was time to response, which was defined as platelet count normalization (150,000/mm³ or higher).

Patients in the caplacizumab arm had a 39% reduction in the median time to response compared to patients in the placebo arm (P=0.005).

Among the 69 patients who had not undergone a plasma exchange session before enrollment, the median time to response was 3.0 days in the caplacizumab arm and 4.9 days in the placebo arm.

Among the 6 patients who did undergo a plasma exchange session before enrollment, the median time to a response was 2.4 days in the caplacizumab arm and 4.3 days in the placebo arm.

The rate of confirmed response was 86.1% (n=31) in the caplacizumab arm and 71.8% (n=28) in the placebo arm.

There were 541 adverse events (AEs) in 34 of the 35 evaluable patients receiving caplacizumab (97%) and 522 AEs in all 37 evaluable patients receiving placebo (100%). TTP exacerbations and relapses were not included as AEs.

The rate of AEs thought to be related to the study drug was 17% in the caplacizumab arm and 11% in the placebo arm. The rate of AEs that were possibly related was 54% and 8%, respectively. The rate of serious AEs was 37% and 32%, respectively.

There were no deaths in the caplacizumab arm and two in the placebo arm. One death was due to severe, refractory TTP, and the other was due to cerebral hemorrhage.

HERCULES

Results from the HERCULES trial were presented at the 2017 ASH Annual Meeting.

The study enrolled patients with an acute episode of aTTP. They were randomized to receive caplacizumab (n=72) or placebo (n=73) in addition to standard care—plasma exchange and immunosuppression.

The study’s primary endpoint was the time to platelet count response (normalization), which was defined as an initial 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 to the placebo arm. The platelet normalization rate ratio was 1.55 (P<0.01).

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 12.7% (n=9) in the caplacizumab arm and 49.3% (n=36) in the placebo arm (P<0.0001).

The incidence of aTTP-related death was 0% (n=0) in the caplacizumab arm and 4.1% (n=3) in the placebo arm. The incidence of aTTP recurrence was 4.2% (n=3) and 38.4% (n=28), respectively. The incidence of at least one major thromboembolic event was 8.5% (n=6) and 8.2% (n=6), respectively.

The proportion of patients with at least one study-drug-related AE was 57.7% in the caplacizumab arm and 43.8% in the placebo arm. The proportion of patients with at least one study-drug-related serious AE was 14.1% (n=10) and 5.5% (n=4), respectively. The rate of discontinuation due to at least one AE was 7.0% and 12.3%, respectively.

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