Photo from Bayer

The US Food and Drug Administration (FDA) has approved Jivi® (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 previously treated adults and adolescents (age 12 and older) with hemophilia A.

The product 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.

The initial recommended prophylactic regimen is dosing twice weekly (30-40 IU/kg) with the ability to dose every 5 days (45-60 IU/kg) and further individually adjust to less or more frequent dosing based on bleeding episodes.

The FDA’s approval of Jivi is based on results 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 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 US Food and Drug Administration (FDA) has approved Jivi® (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 previously treated adults and adolescents (age 12 and older) with hemophilia A.

The product 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.

The initial recommended prophylactic regimen is dosing twice weekly (30-40 IU/kg) with the ability to dose every 5 days (45-60 IU/kg) and further individually adjust to less or more frequent dosing based on bleeding episodes.

The FDA’s approval of Jivi is based on results 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 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 US Food and Drug Administration (FDA) has approved Jivi® (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 previously treated adults and adolescents (age 12 and older) with hemophilia A.

The product 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.

The initial recommended prophylactic regimen is dosing twice weekly (30-40 IU/kg) with the ability to dose every 5 days (45-60 IU/kg) and further individually adjust to less or more frequent dosing based on bleeding episodes.

The FDA’s approval of Jivi is based on results 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 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.

Image by Lance Liotta

The European Commission has granted orphan drug designation to onvansertib for the treatment of acute myeloid leukemia (AML).

Onvansertib (formerly PCM-075) is an oral adenosine triphosphate competitive inhibitor of the serine/threonine Polo-like kinase 1 (PLK1) enzyme, which is overexpressed in hematologic and solid tumor malignancies.

Trovagene, Inc., the company developing onvansertib, said the drug has a 24-hour half-life with reversible, on-target hematologic activity.

These factors, combined with an improved dose/scheduling protocol, could mean onvansertib will improve upon long-term outcomes observed in previous studies with a PLK inhibitor in AML.

This includes a phase 2 study in which AML patients who received a PLK inhibitor plus low-dose cytarabine (LDAC) had a higher response rate than patients who received LDAC alone—31% and 13.3%, respectively.

Trovagene said preclinical studies have shown that onvansertib synergizes with more than 10 drugs used to treat hematologic and solid tumor malignancies. This includes FLT3 and HDAC inhibitors, taxanes, and cytotoxins.

Trovagene is now conducting a phase 1b/2 trial of onvansertib in combination with standard care (LDAC or decitabine) in patients with AML (NCT03303339).

The company has already completed a phase 1 dose-escalation study of onvansertib in patients with advanced metastatic solid tumor malignancies. Results from this study were published in Investigational New Drugs.

About orphan designation

Orphan drug designation in Europe is available to companies developing products intended to treat a life-threatening or chronically debilitating condition that affects fewer than 5 in 10,000 people in the European Union (EU).

The designation allows for financial and regulatory incentives that include 10 years of marketing exclusivity in the EU after product approval, eligibility for conditional marketing authorization, protocol assistance from the European Medicines Agency at reduced fees during the product development phase, and direct access to centralized marketing authorization in the EU.

Image by Lance Liotta

The European Commission has granted orphan drug designation to onvansertib for the treatment of acute myeloid leukemia (AML).

Onvansertib (formerly PCM-075) is an oral adenosine triphosphate competitive inhibitor of the serine/threonine Polo-like kinase 1 (PLK1) enzyme, which is overexpressed in hematologic and solid tumor malignancies.

Trovagene, Inc., the company developing onvansertib, said the drug has a 24-hour half-life with reversible, on-target hematologic activity.

These factors, combined with an improved dose/scheduling protocol, could mean onvansertib will improve upon long-term outcomes observed in previous studies with a PLK inhibitor in AML.

This includes a phase 2 study in which AML patients who received a PLK inhibitor plus low-dose cytarabine (LDAC) had a higher response rate than patients who received LDAC alone—31% and 13.3%, respectively.

Trovagene said preclinical studies have shown that onvansertib synergizes with more than 10 drugs used to treat hematologic and solid tumor malignancies. This includes FLT3 and HDAC inhibitors, taxanes, and cytotoxins.

Trovagene is now conducting a phase 1b/2 trial of onvansertib in combination with standard care (LDAC or decitabine) in patients with AML (NCT03303339).

The company has already completed a phase 1 dose-escalation study of onvansertib in patients with advanced metastatic solid tumor malignancies. Results from this study were published in Investigational New Drugs.

About orphan designation

Orphan drug designation in Europe is available to companies developing products intended to treat a life-threatening or chronically debilitating condition that affects fewer than 5 in 10,000 people in the European Union (EU).

The designation allows for financial and regulatory incentives that include 10 years of marketing exclusivity in the EU after product approval, eligibility for conditional marketing authorization, protocol assistance from the European Medicines Agency at reduced fees during the product development phase, and direct access to centralized marketing authorization in the EU.

Image by Lance Liotta

The European Commission has granted orphan drug designation to onvansertib for the treatment of acute myeloid leukemia (AML).

Onvansertib (formerly PCM-075) is an oral adenosine triphosphate competitive inhibitor of the serine/threonine Polo-like kinase 1 (PLK1) enzyme, which is overexpressed in hematologic and solid tumor malignancies.

Trovagene, Inc., the company developing onvansertib, said the drug has a 24-hour half-life with reversible, on-target hematologic activity.

These factors, combined with an improved dose/scheduling protocol, could mean onvansertib will improve upon long-term outcomes observed in previous studies with a PLK inhibitor in AML.

This includes a phase 2 study in which AML patients who received a PLK inhibitor plus low-dose cytarabine (LDAC) had a higher response rate than patients who received LDAC alone—31% and 13.3%, respectively.

Trovagene said preclinical studies have shown that onvansertib synergizes with more than 10 drugs used to treat hematologic and solid tumor malignancies. This includes FLT3 and HDAC inhibitors, taxanes, and cytotoxins.

Trovagene is now conducting a phase 1b/2 trial of onvansertib in combination with standard care (LDAC or decitabine) in patients with AML (NCT03303339).

The company has already completed a phase 1 dose-escalation study of onvansertib in patients with advanced metastatic solid tumor malignancies. Results from this study were published in Investigational New Drugs.

About orphan designation

Orphan drug designation in Europe is available to companies developing products intended to treat a life-threatening or chronically debilitating condition that affects fewer than 5 in 10,000 people in the European Union (EU).

The designation allows for financial and regulatory incentives that include 10 years of marketing exclusivity in the EU after product approval, eligibility for conditional marketing authorization, protocol assistance from the European Medicines Agency at reduced fees during the product development phase, and direct access to centralized marketing authorization in the EU.

© Nevit Dilmen

Preexisting osteoporosis is an important risk factor for mortality in postmenopausal women who develop multiple myeloma (MM), according to researchers.

They found that high fracture risk was associated with an increased risk of death in postmenopausal females with MM, independent of other clinical risk factors.

Ashley E. Rosko, MD, of Ohio State University in Columbus, and her colleagues reported these findings in Clinical Lymphoma, Myeloma and Leukemia.

The researchers studied 362 subjects in the Women’s Health Initiative data set who developed MM but had no history of any cancer at baseline. The women were between 50 and 79 years of age and postmenopausal when they were originally recruited at 40 US centers between 1993 and 1998.

Dr. Rosko and her colleagues calculated bone health for the women using the Fracture Risk Assessment Tool (FRAX), a web-based tool that calculates 10-year probability of hip and other major osteoporotic fractures.

Ninety-eight of the subjects were classified as having high FRAX scores, defined as a 10-year probability of 3% or greater for hip fracture or 20% or greater for other major osteoporosis-related fractures.

With a median follow-up of 10.5 years, the adjusted risk of death was elevated in women with high FRAX scores, with a covariate-adjusted hazard ratio of 1.51 (95% confidence interval, 1.01-2.25; P=0.044) versus women with low FRAX scores.

Of the 362 patients, 226 died during the follow-up period. That included 72% (n=71) of women with high FRAX scores and 59% (n=155) of women with low FRAX scores.

These findings suggest osteoporosis is an “important comorbidity” in women who develop MM, according to Dr. Rosko and her coauthors.

“Recognizing osteoporosis as a risk factor associated with multiple myeloma mortality is an important prognostic factor in postmenopausal women,” the researchers wrote.

This work was supported, in part, by the National Cancer Institute. The researchers reported no relevant financial disclosures.

© Nevit Dilmen

Preexisting osteoporosis is an important risk factor for mortality in postmenopausal women who develop multiple myeloma (MM), according to researchers.

They found that high fracture risk was associated with an increased risk of death in postmenopausal females with MM, independent of other clinical risk factors.

Ashley E. Rosko, MD, of Ohio State University in Columbus, and her colleagues reported these findings in Clinical Lymphoma, Myeloma and Leukemia.

The researchers studied 362 subjects in the Women’s Health Initiative data set who developed MM but had no history of any cancer at baseline. The women were between 50 and 79 years of age and postmenopausal when they were originally recruited at 40 US centers between 1993 and 1998.

Dr. Rosko and her colleagues calculated bone health for the women using the Fracture Risk Assessment Tool (FRAX), a web-based tool that calculates 10-year probability of hip and other major osteoporotic fractures.

Ninety-eight of the subjects were classified as having high FRAX scores, defined as a 10-year probability of 3% or greater for hip fracture or 20% or greater for other major osteoporosis-related fractures.

With a median follow-up of 10.5 years, the adjusted risk of death was elevated in women with high FRAX scores, with a covariate-adjusted hazard ratio of 1.51 (95% confidence interval, 1.01-2.25; P=0.044) versus women with low FRAX scores.

Of the 362 patients, 226 died during the follow-up period. That included 72% (n=71) of women with high FRAX scores and 59% (n=155) of women with low FRAX scores.

These findings suggest osteoporosis is an “important comorbidity” in women who develop MM, according to Dr. Rosko and her coauthors.

“Recognizing osteoporosis as a risk factor associated with multiple myeloma mortality is an important prognostic factor in postmenopausal women,” the researchers wrote.

This work was supported, in part, by the National Cancer Institute. The researchers reported no relevant financial disclosures.

© Nevit Dilmen

Preexisting osteoporosis is an important risk factor for mortality in postmenopausal women who develop multiple myeloma (MM), according to researchers.

They found that high fracture risk was associated with an increased risk of death in postmenopausal females with MM, independent of other clinical risk factors.

Ashley E. Rosko, MD, of Ohio State University in Columbus, and her colleagues reported these findings in Clinical Lymphoma, Myeloma and Leukemia.

The researchers studied 362 subjects in the Women’s Health Initiative data set who developed MM but had no history of any cancer at baseline. The women were between 50 and 79 years of age and postmenopausal when they were originally recruited at 40 US centers between 1993 and 1998.

Dr. Rosko and her colleagues calculated bone health for the women using the Fracture Risk Assessment Tool (FRAX), a web-based tool that calculates 10-year probability of hip and other major osteoporotic fractures.

Ninety-eight of the subjects were classified as having high FRAX scores, defined as a 10-year probability of 3% or greater for hip fracture or 20% or greater for other major osteoporosis-related fractures.

With a median follow-up of 10.5 years, the adjusted risk of death was elevated in women with high FRAX scores, with a covariate-adjusted hazard ratio of 1.51 (95% confidence interval, 1.01-2.25; P=0.044) versus women with low FRAX scores.

Of the 362 patients, 226 died during the follow-up period. That included 72% (n=71) of women with high FRAX scores and 59% (n=155) of women with low FRAX scores.

These findings suggest osteoporosis is an “important comorbidity” in women who develop MM, according to Dr. Rosko and her coauthors.

“Recognizing osteoporosis as a risk factor associated with multiple myeloma mortality is an important prognostic factor in postmenopausal women,” the researchers wrote.

This work was supported, in part, by the National Cancer Institute. The researchers reported no relevant financial disclosures.

Photo from Business Wire

Results of a phase 3 trial showed that prophylaxis with emicizumab significantly reduced bleeds, compared to no prophylaxis, in patients with hemophilia A without inhibitors.

Emicizumab also reduced bleeds when compared to prior factor VIII prophylaxis.

The most common adverse events (AEs) in this trial were injection site reactions, arthralgia, nasopharyngitis, headache, upper respiratory tract infection, and influenza.

Johnny Mahlangu, MBBCh, of the University of the Witwatersrand and NHLS in Johannesburg, South Africa, and his colleagues reported these results, from the HAVEN 3 trial, in NEJM.

The trial was sponsored by F. Hoffmann–La Roche and Chugai Pharmaceutical.

“In the HAVEN 3 study, [emicizumab] showed a significant and clinically meaningful reduction in bleeds in people with hemophilia A without factor VIII inhibitors, while offering multiple subcutaneous dosing options,” Dr. Mahlangu said.

“The publication of these results . . . represents a major advance for hemophilia research and reinforces the potential of [emicizumab] to change the standard of care for people with hemophilia A.”

HAVEN 3 included 152 patients with hemophilia A (age 12 and older) who were previously treated with factor VIII therapy either on-demand or for prophylaxis.

Patients previously treated with on-demand factor VIII were randomized in a 2:2:1 fashion to receive:

• Emicizumab prophylaxis at 3 mg/kg/wk for 4 weeks, followed by 1.5 mg/kg/wk for at least 24 weeks (arm A)
• Emicizumab prophylaxis at 3 mg/kg/wk for 4 weeks, followed by 3 mg/kg/2wks for at least 24 weeks (arm B)
• No prophylaxis for at least 24 weeks (arm C).

Patients previously treated with factor VIII prophylaxis received emicizumab prophylaxis at 3 mg/kg/wk for 4 weeks, followed by 1.5 mg/kg/wk until the end of study (arm D).

Episodic treatment of breakthrough bleeds with factor VIII therapy was allowed per protocol.

Efficacy

Emicizumab reduced treated bleeds by 96% (rate ratio [RR]=0.04; P<0.0001) when given every week and 97% (RR=0.03; P<0.001) when given every 2 weeks, compared to no prophylaxis. The annualized bleeding rate (ABR) was 1.5, 1.3, and 38.2, respectively.

Emicizumab reduced all bleeds by 95% (RR=0.05; P<0.001) when given every week and 94% (RR=0.06; P<0.001) when given every 2 weeks, compared to no prophylaxis. The ABR was 2.5, 2.6, and 47.6, respectively.

There were zero treated bleeds in 55.6% of patients who received emicizumab every week and 60% of patients who received emicizumab every 2 weeks, compared to 0% of patients who did not receive prophylaxis.

In an intra-patient comparison of people who previously received factor VIII prophylaxis in a prospective non-interventional study and switched to emicizumab prophylaxis, emicizumab reduced treated bleeds by 68% (RR=0.32; P<0.001).

The ABR was 1.5 when patients were on emicizumab and 4.8 when they were on prior prophylaxis.

Safety

The most common AEs were injection site reactions (25%), upper respiratory tract infection (11%), nasopharyngitis (12%), arthralgia (19%), headache (11%), and influenza (6%).

One patient in group B stopped treatment due to multiple low-grade AEs considered related to emicizumab. The AEs were insomnia (grade 2), alopecia (grade 1), nightmare (grade 2), lethargy (grade 2), pruritus (grade 1), headache (grade 1), and depressed mood (grade 1).

Serious AEs included bleeding events (n=4), cardiac disorder (n=1), infection (n=3), musculoskeletal disorders (n=3), loosening of an orthopedic device (n=1), psychiatric disorder (n=1), and trauma (n=1). One patient experienced nephrolithiasis after a dose increase to 3 mg/kg/wk.

None of the serious AEs were considered related to emicizumab.

There were no deaths, cases of thrombotic microangiopathy, thrombotic events, or new cases of factor VIII inhibitors.

Two patients had detectable inhibitors at baseline, but titers declined spontaneously during the trial. Another patient had a detectable inhibitor titer at week 13 that spontaneously declined at week 25.

Photo from Business Wire

Results of a phase 3 trial showed that prophylaxis with emicizumab significantly reduced bleeds, compared to no prophylaxis, in patients with hemophilia A without inhibitors.

Emicizumab also reduced bleeds when compared to prior factor VIII prophylaxis.

The most common adverse events (AEs) in this trial were injection site reactions, arthralgia, nasopharyngitis, headache, upper respiratory tract infection, and influenza.

Johnny Mahlangu, MBBCh, of the University of the Witwatersrand and NHLS in Johannesburg, South Africa, and his colleagues reported these results, from the HAVEN 3 trial, in NEJM.

The trial was sponsored by F. Hoffmann–La Roche and Chugai Pharmaceutical.

“In the HAVEN 3 study, [emicizumab] showed a significant and clinically meaningful reduction in bleeds in people with hemophilia A without factor VIII inhibitors, while offering multiple subcutaneous dosing options,” Dr. Mahlangu said.

“The publication of these results . . . represents a major advance for hemophilia research and reinforces the potential of [emicizumab] to change the standard of care for people with hemophilia A.”

HAVEN 3 included 152 patients with hemophilia A (age 12 and older) who were previously treated with factor VIII therapy either on-demand or for prophylaxis.

Patients previously treated with on-demand factor VIII were randomized in a 2:2:1 fashion to receive:

• Emicizumab prophylaxis at 3 mg/kg/wk for 4 weeks, followed by 1.5 mg/kg/wk for at least 24 weeks (arm A)
• Emicizumab prophylaxis at 3 mg/kg/wk for 4 weeks, followed by 3 mg/kg/2wks for at least 24 weeks (arm B)
• No prophylaxis for at least 24 weeks (arm C).

Patients previously treated with factor VIII prophylaxis received emicizumab prophylaxis at 3 mg/kg/wk for 4 weeks, followed by 1.5 mg/kg/wk until the end of study (arm D).

Episodic treatment of breakthrough bleeds with factor VIII therapy was allowed per protocol.

Efficacy

Emicizumab reduced treated bleeds by 96% (rate ratio [RR]=0.04; P<0.0001) when given every week and 97% (RR=0.03; P<0.001) when given every 2 weeks, compared to no prophylaxis. The annualized bleeding rate (ABR) was 1.5, 1.3, and 38.2, respectively.

Emicizumab reduced all bleeds by 95% (RR=0.05; P<0.001) when given every week and 94% (RR=0.06; P<0.001) when given every 2 weeks, compared to no prophylaxis. The ABR was 2.5, 2.6, and 47.6, respectively.

There were zero treated bleeds in 55.6% of patients who received emicizumab every week and 60% of patients who received emicizumab every 2 weeks, compared to 0% of patients who did not receive prophylaxis.

In an intra-patient comparison of people who previously received factor VIII prophylaxis in a prospective non-interventional study and switched to emicizumab prophylaxis, emicizumab reduced treated bleeds by 68% (RR=0.32; P<0.001).

The ABR was 1.5 when patients were on emicizumab and 4.8 when they were on prior prophylaxis.

Safety

The most common AEs were injection site reactions (25%), upper respiratory tract infection (11%), nasopharyngitis (12%), arthralgia (19%), headache (11%), and influenza (6%).

One patient in group B stopped treatment due to multiple low-grade AEs considered related to emicizumab. The AEs were insomnia (grade 2), alopecia (grade 1), nightmare (grade 2), lethargy (grade 2), pruritus (grade 1), headache (grade 1), and depressed mood (grade 1).

Serious AEs included bleeding events (n=4), cardiac disorder (n=1), infection (n=3), musculoskeletal disorders (n=3), loosening of an orthopedic device (n=1), psychiatric disorder (n=1), and trauma (n=1). One patient experienced nephrolithiasis after a dose increase to 3 mg/kg/wk.

None of the serious AEs were considered related to emicizumab.

There were no deaths, cases of thrombotic microangiopathy, thrombotic events, or new cases of factor VIII inhibitors.

Two patients had detectable inhibitors at baseline, but titers declined spontaneously during the trial. Another patient had a detectable inhibitor titer at week 13 that spontaneously declined at week 25.

Photo from Business Wire

Results of a phase 3 trial showed that prophylaxis with emicizumab significantly reduced bleeds, compared to no prophylaxis, in patients with hemophilia A without inhibitors.

Emicizumab also reduced bleeds when compared to prior factor VIII prophylaxis.

The most common adverse events (AEs) in this trial were injection site reactions, arthralgia, nasopharyngitis, headache, upper respiratory tract infection, and influenza.

Johnny Mahlangu, MBBCh, of the University of the Witwatersrand and NHLS in Johannesburg, South Africa, and his colleagues reported these results, from the HAVEN 3 trial, in NEJM.

The trial was sponsored by F. Hoffmann–La Roche and Chugai Pharmaceutical.

“In the HAVEN 3 study, [emicizumab] showed a significant and clinically meaningful reduction in bleeds in people with hemophilia A without factor VIII inhibitors, while offering multiple subcutaneous dosing options,” Dr. Mahlangu said.

“The publication of these results . . . represents a major advance for hemophilia research and reinforces the potential of [emicizumab] to change the standard of care for people with hemophilia A.”

HAVEN 3 included 152 patients with hemophilia A (age 12 and older) who were previously treated with factor VIII therapy either on-demand or for prophylaxis.

Patients previously treated with on-demand factor VIII were randomized in a 2:2:1 fashion to receive:

• Emicizumab prophylaxis at 3 mg/kg/wk for 4 weeks, followed by 1.5 mg/kg/wk for at least 24 weeks (arm A)
• Emicizumab prophylaxis at 3 mg/kg/wk for 4 weeks, followed by 3 mg/kg/2wks for at least 24 weeks (arm B)
• No prophylaxis for at least 24 weeks (arm C).

Patients previously treated with factor VIII prophylaxis received emicizumab prophylaxis at 3 mg/kg/wk for 4 weeks, followed by 1.5 mg/kg/wk until the end of study (arm D).

Episodic treatment of breakthrough bleeds with factor VIII therapy was allowed per protocol.

Efficacy

Emicizumab reduced treated bleeds by 96% (rate ratio [RR]=0.04; P<0.0001) when given every week and 97% (RR=0.03; P<0.001) when given every 2 weeks, compared to no prophylaxis. The annualized bleeding rate (ABR) was 1.5, 1.3, and 38.2, respectively.

Emicizumab reduced all bleeds by 95% (RR=0.05; P<0.001) when given every week and 94% (RR=0.06; P<0.001) when given every 2 weeks, compared to no prophylaxis. The ABR was 2.5, 2.6, and 47.6, respectively.

There were zero treated bleeds in 55.6% of patients who received emicizumab every week and 60% of patients who received emicizumab every 2 weeks, compared to 0% of patients who did not receive prophylaxis.

In an intra-patient comparison of people who previously received factor VIII prophylaxis in a prospective non-interventional study and switched to emicizumab prophylaxis, emicizumab reduced treated bleeds by 68% (RR=0.32; P<0.001).

The ABR was 1.5 when patients were on emicizumab and 4.8 when they were on prior prophylaxis.

Safety

The most common AEs were injection site reactions (25%), upper respiratory tract infection (11%), nasopharyngitis (12%), arthralgia (19%), headache (11%), and influenza (6%).

One patient in group B stopped treatment due to multiple low-grade AEs considered related to emicizumab. The AEs were insomnia (grade 2), alopecia (grade 1), nightmare (grade 2), lethargy (grade 2), pruritus (grade 1), headache (grade 1), and depressed mood (grade 1).

Serious AEs included bleeding events (n=4), cardiac disorder (n=1), infection (n=3), musculoskeletal disorders (n=3), loosening of an orthopedic device (n=1), psychiatric disorder (n=1), and trauma (n=1). One patient experienced nephrolithiasis after a dose increase to 3 mg/kg/wk.

None of the serious AEs were considered related to emicizumab.

There were no deaths, cases of thrombotic microangiopathy, thrombotic events, or new cases of factor VIII inhibitors.

Two patients had detectable inhibitors at baseline, but titers declined spontaneously during the trial. Another patient had a detectable inhibitor titer at week 13 that spontaneously declined at week 25.

An investigational antibody-drug conjugate labeled SGN-CD70A showed signs of efficacy against relapsed or refractory non-Hodgkin lymphomas in a phase 1 trial, but its future is clouded by a high incidence of treatment-associated thrombocytopenia, investigators reported.

Among 20 patients with diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, and other histologies, SGN-CD70A was associated with one complete remission (CR) and three partial remissions (PR), two of which were ongoing at nearly 43 weeks of follow-up.

However, 15 of the 20 patients (75%) had treatment-related thrombocytopenias, and 13 of these adverse events (AEs) were grade 3 or greater in severity, reported Tycel Phillips, MD, of the University of Michigan, Ann Arbor, and his colleagues.

Notwithstanding the antibody-drug conjugate’s apparent efficacy in this early trial, “the applicability of SGN-CD70A is limited by the frequency and severity of thrombocytopenia, despite the long-term of response with limited drug exposure. Given that we are currently unable to mitigate this AE, the rationale for further investigation of SGN-CD70A remains limited and is, therefore, not planned,” they wrote in the journal Investigational New Drugs.

SGN-CD70A consists of an antibody directed against the plasma membrane protein CD70, a protease-cleavable linker, and a DNA-crosslinking pyrrolobenzodiazepine dimer drug. Its mechanism of action is via double-strand DNA breaks in CD70-positive cells that eventually cause programmed cell death.

Dr. Phillips and his colleagues reported on the high-risk non-Hodgkin lymphoma cohort in the phase 1 trial. The cohort included nine patients with DLBCL, five with mantle cell lymphoma, two with transformed DLBCL, one with T- cell/histocyte–rich large B cell lymphoma, and three with unspecified NHL histologies.

The patients had undergone a median of 3.5 prior lines of systemic therapy, and all had relatively good performance status, with Eastern Cooperative Oncology Group scores of 0 or 1.

Patients were started on intravenous SGN-CD70A at a dose of 8 mcg/kg on day 1 of each 3-week cycle, with a planned dose escalation to 200 mcg/kg, The protocol was amended to dosing every 6 weeks, however, after the investigators observed prolonged thrombocytopenias in some patients. A total of 12 patients were treated every 3 weeks, and 8 were treated every 6 weeks.

The most common treatment-related AEs were thrombocytopenias, which occurred in three-quarters of all patients, and were largely grade 3 or greater in severity. Other treatment-related AEs of grade 3 or greater occurring in more than one patient include neutropenia in six patients; anemia in five patients; and congestive heart failure, Clostridium difficile infections, dyspnea, and decreased forced expiratory volume in two patients each.

Other common AEs were nausea and fatigue.

The investigators noted that the cause of the deep and durable thrombocytopenias could not be determined, despite assessment of known biomarkers for this complication.

The duration of the thrombocytopenia and the fact that some of the few responses that did occur were also durable after the end of treatment suggest that the dimer drug, the cytotoxic “payload” of the antibody-drug conjugate, was responsible for the effects they observed, the authors said.

The study was funded by Seattle Genetics. Dr. Phillips reported advisory board membership with the company, and four of the coauthors are employees of the company with equity interests.

SOURCE: Phillips T et al. Invest New Drugs. 2018 Aug 22. doi: 10.1007/s10637-018-0655-0.

An investigational antibody-drug conjugate labeled SGN-CD70A showed signs of efficacy against relapsed or refractory non-Hodgkin lymphomas in a phase 1 trial, but its future is clouded by a high incidence of treatment-associated thrombocytopenia, investigators reported.

Among 20 patients with diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, and other histologies, SGN-CD70A was associated with one complete remission (CR) and three partial remissions (PR), two of which were ongoing at nearly 43 weeks of follow-up.

However, 15 of the 20 patients (75%) had treatment-related thrombocytopenias, and 13 of these adverse events (AEs) were grade 3 or greater in severity, reported Tycel Phillips, MD, of the University of Michigan, Ann Arbor, and his colleagues.

Notwithstanding the antibody-drug conjugate’s apparent efficacy in this early trial, “the applicability of SGN-CD70A is limited by the frequency and severity of thrombocytopenia, despite the long-term of response with limited drug exposure. Given that we are currently unable to mitigate this AE, the rationale for further investigation of SGN-CD70A remains limited and is, therefore, not planned,” they wrote in the journal Investigational New Drugs.

SGN-CD70A consists of an antibody directed against the plasma membrane protein CD70, a protease-cleavable linker, and a DNA-crosslinking pyrrolobenzodiazepine dimer drug. Its mechanism of action is via double-strand DNA breaks in CD70-positive cells that eventually cause programmed cell death.

Dr. Phillips and his colleagues reported on the high-risk non-Hodgkin lymphoma cohort in the phase 1 trial. The cohort included nine patients with DLBCL, five with mantle cell lymphoma, two with transformed DLBCL, one with T- cell/histocyte–rich large B cell lymphoma, and three with unspecified NHL histologies.

The patients had undergone a median of 3.5 prior lines of systemic therapy, and all had relatively good performance status, with Eastern Cooperative Oncology Group scores of 0 or 1.

Patients were started on intravenous SGN-CD70A at a dose of 8 mcg/kg on day 1 of each 3-week cycle, with a planned dose escalation to 200 mcg/kg, The protocol was amended to dosing every 6 weeks, however, after the investigators observed prolonged thrombocytopenias in some patients. A total of 12 patients were treated every 3 weeks, and 8 were treated every 6 weeks.

The most common treatment-related AEs were thrombocytopenias, which occurred in three-quarters of all patients, and were largely grade 3 or greater in severity. Other treatment-related AEs of grade 3 or greater occurring in more than one patient include neutropenia in six patients; anemia in five patients; and congestive heart failure, Clostridium difficile infections, dyspnea, and decreased forced expiratory volume in two patients each.

Other common AEs were nausea and fatigue.

The investigators noted that the cause of the deep and durable thrombocytopenias could not be determined, despite assessment of known biomarkers for this complication.

The duration of the thrombocytopenia and the fact that some of the few responses that did occur were also durable after the end of treatment suggest that the dimer drug, the cytotoxic “payload” of the antibody-drug conjugate, was responsible for the effects they observed, the authors said.

The study was funded by Seattle Genetics. Dr. Phillips reported advisory board membership with the company, and four of the coauthors are employees of the company with equity interests.

SOURCE: Phillips T et al. Invest New Drugs. 2018 Aug 22. doi: 10.1007/s10637-018-0655-0.

An investigational antibody-drug conjugate labeled SGN-CD70A showed signs of efficacy against relapsed or refractory non-Hodgkin lymphomas in a phase 1 trial, but its future is clouded by a high incidence of treatment-associated thrombocytopenia, investigators reported.

Among 20 patients with diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, and other histologies, SGN-CD70A was associated with one complete remission (CR) and three partial remissions (PR), two of which were ongoing at nearly 43 weeks of follow-up.

However, 15 of the 20 patients (75%) had treatment-related thrombocytopenias, and 13 of these adverse events (AEs) were grade 3 or greater in severity, reported Tycel Phillips, MD, of the University of Michigan, Ann Arbor, and his colleagues.

Notwithstanding the antibody-drug conjugate’s apparent efficacy in this early trial, “the applicability of SGN-CD70A is limited by the frequency and severity of thrombocytopenia, despite the long-term of response with limited drug exposure. Given that we are currently unable to mitigate this AE, the rationale for further investigation of SGN-CD70A remains limited and is, therefore, not planned,” they wrote in the journal Investigational New Drugs.

SGN-CD70A consists of an antibody directed against the plasma membrane protein CD70, a protease-cleavable linker, and a DNA-crosslinking pyrrolobenzodiazepine dimer drug. Its mechanism of action is via double-strand DNA breaks in CD70-positive cells that eventually cause programmed cell death.

Dr. Phillips and his colleagues reported on the high-risk non-Hodgkin lymphoma cohort in the phase 1 trial. The cohort included nine patients with DLBCL, five with mantle cell lymphoma, two with transformed DLBCL, one with T- cell/histocyte–rich large B cell lymphoma, and three with unspecified NHL histologies.

The patients had undergone a median of 3.5 prior lines of systemic therapy, and all had relatively good performance status, with Eastern Cooperative Oncology Group scores of 0 or 1.

Patients were started on intravenous SGN-CD70A at a dose of 8 mcg/kg on day 1 of each 3-week cycle, with a planned dose escalation to 200 mcg/kg, The protocol was amended to dosing every 6 weeks, however, after the investigators observed prolonged thrombocytopenias in some patients. A total of 12 patients were treated every 3 weeks, and 8 were treated every 6 weeks.

The most common treatment-related AEs were thrombocytopenias, which occurred in three-quarters of all patients, and were largely grade 3 or greater in severity. Other treatment-related AEs of grade 3 or greater occurring in more than one patient include neutropenia in six patients; anemia in five patients; and congestive heart failure, Clostridium difficile infections, dyspnea, and decreased forced expiratory volume in two patients each.

Other common AEs were nausea and fatigue.

The investigators noted that the cause of the deep and durable thrombocytopenias could not be determined, despite assessment of known biomarkers for this complication.

The duration of the thrombocytopenia and the fact that some of the few responses that did occur were also durable after the end of treatment suggest that the dimer drug, the cytotoxic “payload” of the antibody-drug conjugate, was responsible for the effects they observed, the authors said.

The study was funded by Seattle Genetics. Dr. Phillips reported advisory board membership with the company, and four of the coauthors are employees of the company with equity interests.

SOURCE: Phillips T et al. Invest New Drugs. 2018 Aug 22. doi: 10.1007/s10637-018-0655-0.

Once-daily treatment with the oral second-generation thrombopoietin agonist avatrombopag (Doptelet) significantly reduced the need for platelet transfusion and rescue therapy for up to 7 days after patients with chronic liver disease and thrombocytopenia underwent scheduled procedures, according to the results of two international, randomized, double-blind, phase III, placebo-controlled trials reported in the September issue of Gastroenterology.

SOURCE: AMERICAN GASTROENTEROLOGICAL ASSOCIATION

In the ADAPT-1 trial, 66% of patients in the 60-mg arm met this primary endpoint, as did 88% of patients who received 40 mg for less severe thrombocytopenia, versus 23% and 38% of the placebo arms, respectively (P less than .001 for each comparison). In the ADAPT-2 trial, 69% of the 60-mg group met the primary endpoint, as did 88% of the 40-mg group, versus 35% and 33% of the respective placebo groups (P less than .001 for each comparison).

These results led the Food and Drug Administration to approve avatrombopag in May 2018 under its priority review process. The novel therapy “may be a safe and effective alternative to platelet transfusions” that could simplify the clinical management of patients with chronic liver disease and thrombocytopenia, Norah Terrault, MD, MPH, and her associates wrote in Gastroenterology.

The ADAPT-1 study included 231 patients, while ADAPT-2 included 204 patients. In each trial, patients were randomized on a 2:1 basis to receive oral avatrombopag or placebo once daily for 5 consecutive days. Patients in the intervention arms received 60 mg avatrombopag if their baseline platelet count was less than 40 x 10⁹ per liter, and 40 mg if their baseline platelet count was 40-50 x 10⁹ per liter. Procedures were scheduled for 10-13 days after treatment initiation.

“Platelet counts increased by [treatment] day 4, peaked at days 10-13, and then returned to baseline levels by day 35,” the researchers reported. Among ADAPT-1 patients with low baseline counts, 69% of avatrombopag recipients reached a prespecified target of at least 50 x 10⁹ platelets per liter on their procedure day, versus 4% of placebo recipients (P less than .0001). Corresponding proportions in ADAPT-2 were 67% and 7%, respectively (P less than .0001). Among patients with higher baseline counts, 88% and 20% achieved the target, respectively, in ADAPT-1 (P less than .0001), as did 93% versus 39%, respectively, in ADAPT-2 (P less than .0001).

Avatrombopag and placebo produced similar rates of treatment-emergent adverse events. These most often consisted of abdominal pain, dyspepsia, nausea, pyrexia, dizziness, and headache. Only three avatrombopag patients developed platelet counts above 200 x 10⁹ per liter, and they all remained asymptomatic, the investigators said.

Dova Pharmaceuticals makes avatrombopag and funded medical writing support. Dr. Terrault and three coinvestigators disclosed ties to AbbVie, Allergan, Bristol-Myers Squibb, Eisai, Gilead, Merck, and other pharmaceutical companies. One coinvestigator is chief medical officer of Dova, helped analyze the data and write the manuscript, and gave final approval of the submitted version.

SOURCE: Terrault N et al. Gastroenterology. 2018 May 17. doi: 10.1053/j.gastro.2018.05.025.

Once-daily treatment with the oral second-generation thrombopoietin agonist avatrombopag (Doptelet) significantly reduced the need for platelet transfusion and rescue therapy for up to 7 days after patients with chronic liver disease and thrombocytopenia underwent scheduled procedures, according to the results of two international, randomized, double-blind, phase III, placebo-controlled trials reported in the September issue of Gastroenterology.

SOURCE: AMERICAN GASTROENTEROLOGICAL ASSOCIATION

In the ADAPT-1 trial, 66% of patients in the 60-mg arm met this primary endpoint, as did 88% of patients who received 40 mg for less severe thrombocytopenia, versus 23% and 38% of the placebo arms, respectively (P less than .001 for each comparison). In the ADAPT-2 trial, 69% of the 60-mg group met the primary endpoint, as did 88% of the 40-mg group, versus 35% and 33% of the respective placebo groups (P less than .001 for each comparison).

These results led the Food and Drug Administration to approve avatrombopag in May 2018 under its priority review process. The novel therapy “may be a safe and effective alternative to platelet transfusions” that could simplify the clinical management of patients with chronic liver disease and thrombocytopenia, Norah Terrault, MD, MPH, and her associates wrote in Gastroenterology.

The ADAPT-1 study included 231 patients, while ADAPT-2 included 204 patients. In each trial, patients were randomized on a 2:1 basis to receive oral avatrombopag or placebo once daily for 5 consecutive days. Patients in the intervention arms received 60 mg avatrombopag if their baseline platelet count was less than 40 x 10⁹ per liter, and 40 mg if their baseline platelet count was 40-50 x 10⁹ per liter. Procedures were scheduled for 10-13 days after treatment initiation.

“Platelet counts increased by [treatment] day 4, peaked at days 10-13, and then returned to baseline levels by day 35,” the researchers reported. Among ADAPT-1 patients with low baseline counts, 69% of avatrombopag recipients reached a prespecified target of at least 50 x 10⁹ platelets per liter on their procedure day, versus 4% of placebo recipients (P less than .0001). Corresponding proportions in ADAPT-2 were 67% and 7%, respectively (P less than .0001). Among patients with higher baseline counts, 88% and 20% achieved the target, respectively, in ADAPT-1 (P less than .0001), as did 93% versus 39%, respectively, in ADAPT-2 (P less than .0001).

Avatrombopag and placebo produced similar rates of treatment-emergent adverse events. These most often consisted of abdominal pain, dyspepsia, nausea, pyrexia, dizziness, and headache. Only three avatrombopag patients developed platelet counts above 200 x 10⁹ per liter, and they all remained asymptomatic, the investigators said.

Dova Pharmaceuticals makes avatrombopag and funded medical writing support. Dr. Terrault and three coinvestigators disclosed ties to AbbVie, Allergan, Bristol-Myers Squibb, Eisai, Gilead, Merck, and other pharmaceutical companies. One coinvestigator is chief medical officer of Dova, helped analyze the data and write the manuscript, and gave final approval of the submitted version.

SOURCE: Terrault N et al. Gastroenterology. 2018 May 17. doi: 10.1053/j.gastro.2018.05.025.

Once-daily treatment with the oral second-generation thrombopoietin agonist avatrombopag (Doptelet) significantly reduced the need for platelet transfusion and rescue therapy for up to 7 days after patients with chronic liver disease and thrombocytopenia underwent scheduled procedures, according to the results of two international, randomized, double-blind, phase III, placebo-controlled trials reported in the September issue of Gastroenterology.

SOURCE: AMERICAN GASTROENTEROLOGICAL ASSOCIATION

In the ADAPT-1 trial, 66% of patients in the 60-mg arm met this primary endpoint, as did 88% of patients who received 40 mg for less severe thrombocytopenia, versus 23% and 38% of the placebo arms, respectively (P less than .001 for each comparison). In the ADAPT-2 trial, 69% of the 60-mg group met the primary endpoint, as did 88% of the 40-mg group, versus 35% and 33% of the respective placebo groups (P less than .001 for each comparison).

These results led the Food and Drug Administration to approve avatrombopag in May 2018 under its priority review process. The novel therapy “may be a safe and effective alternative to platelet transfusions” that could simplify the clinical management of patients with chronic liver disease and thrombocytopenia, Norah Terrault, MD, MPH, and her associates wrote in Gastroenterology.

The ADAPT-1 study included 231 patients, while ADAPT-2 included 204 patients. In each trial, patients were randomized on a 2:1 basis to receive oral avatrombopag or placebo once daily for 5 consecutive days. Patients in the intervention arms received 60 mg avatrombopag if their baseline platelet count was less than 40 x 10⁹ per liter, and 40 mg if their baseline platelet count was 40-50 x 10⁹ per liter. Procedures were scheduled for 10-13 days after treatment initiation.

“Platelet counts increased by [treatment] day 4, peaked at days 10-13, and then returned to baseline levels by day 35,” the researchers reported. Among ADAPT-1 patients with low baseline counts, 69% of avatrombopag recipients reached a prespecified target of at least 50 x 10⁹ platelets per liter on their procedure day, versus 4% of placebo recipients (P less than .0001). Corresponding proportions in ADAPT-2 were 67% and 7%, respectively (P less than .0001). Among patients with higher baseline counts, 88% and 20% achieved the target, respectively, in ADAPT-1 (P less than .0001), as did 93% versus 39%, respectively, in ADAPT-2 (P less than .0001).

Avatrombopag and placebo produced similar rates of treatment-emergent adverse events. These most often consisted of abdominal pain, dyspepsia, nausea, pyrexia, dizziness, and headache. Only three avatrombopag patients developed platelet counts above 200 x 10⁹ per liter, and they all remained asymptomatic, the investigators said.

Dova Pharmaceuticals makes avatrombopag and funded medical writing support. Dr. Terrault and three coinvestigators disclosed ties to AbbVie, Allergan, Bristol-Myers Squibb, Eisai, Gilead, Merck, and other pharmaceutical companies. One coinvestigator is chief medical officer of Dova, helped analyze the data and write the manuscript, and gave final approval of the submitted version.

SOURCE: Terrault N et al. Gastroenterology. 2018 May 17. doi: 10.1053/j.gastro.2018.05.025.

Physicians with difficult patient scenarios regularly bring their questions to the AGA Community forum to seek advice from fellow GIs on therapy and disease management options, best practices and diagnoses.

In case you missed it, here are the most popular clinical cases shared in the forum recently:

1. Ulcerative colitis
A 24-year-old male with severe pancolitis is in remission and currently functioning well, but the attending GI is fearful that a relapse is impending based on a fecal calprotectin of 1258 in a “clinically stable patient on long term maximal therapy.”



2. Esophageal varices on Warfarin
A 64-year-old patient with Child-Turcotte-Pugh (CTP) class A cirrhosis had an upper endoscopy that showed large esophageal varices with no prior history of bleeding. View Dr. Miguel Malespin’s take on this popular case in the August issue of AGA Perspectives.



3. Does he have IBS or what?
A 37-year-old male with psoriatic arthritis and abdominal pain experiences rectal bleeding and abnormal findings during colonoscopy.



4. Chronic pancolitis
Quite a few GI experts commented on next steps for this 77-year-old pancolitis patient who has refused biologics based on cost.



5. Pouchitis
This 40-year-old patient developed diarrhea, fever, abdominal pain and other symptoms, with observed ulceration and inflammation in the pouch and proximally.

More clinical cases and discussions are at https://community.gastro.org/discussions.

Physicians with difficult patient scenarios regularly bring their questions to the AGA Community forum to seek advice from fellow GIs on therapy and disease management options, best practices and diagnoses.

In case you missed it, here are the most popular clinical cases shared in the forum recently:

1. Ulcerative colitis
A 24-year-old male with severe pancolitis is in remission and currently functioning well, but the attending GI is fearful that a relapse is impending based on a fecal calprotectin of 1258 in a “clinically stable patient on long term maximal therapy.”



2. Esophageal varices on Warfarin
A 64-year-old patient with Child-Turcotte-Pugh (CTP) class A cirrhosis had an upper endoscopy that showed large esophageal varices with no prior history of bleeding. View Dr. Miguel Malespin’s take on this popular case in the August issue of AGA Perspectives.



3. Does he have IBS or what?
A 37-year-old male with psoriatic arthritis and abdominal pain experiences rectal bleeding and abnormal findings during colonoscopy.



4. Chronic pancolitis
Quite a few GI experts commented on next steps for this 77-year-old pancolitis patient who has refused biologics based on cost.



5. Pouchitis
This 40-year-old patient developed diarrhea, fever, abdominal pain and other symptoms, with observed ulceration and inflammation in the pouch and proximally.

More clinical cases and discussions are at https://community.gastro.org/discussions.

Physicians with difficult patient scenarios regularly bring their questions to the AGA Community forum to seek advice from fellow GIs on therapy and disease management options, best practices and diagnoses.

In case you missed it, here are the most popular clinical cases shared in the forum recently:

1. Ulcerative colitis
A 24-year-old male with severe pancolitis is in remission and currently functioning well, but the attending GI is fearful that a relapse is impending based on a fecal calprotectin of 1258 in a “clinically stable patient on long term maximal therapy.”



2. Esophageal varices on Warfarin
A 64-year-old patient with Child-Turcotte-Pugh (CTP) class A cirrhosis had an upper endoscopy that showed large esophageal varices with no prior history of bleeding. View Dr. Miguel Malespin’s take on this popular case in the August issue of AGA Perspectives.



3. Does he have IBS or what?
A 37-year-old male with psoriatic arthritis and abdominal pain experiences rectal bleeding and abnormal findings during colonoscopy.



4. Chronic pancolitis
Quite a few GI experts commented on next steps for this 77-year-old pancolitis patient who has refused biologics based on cost.



5. Pouchitis
This 40-year-old patient developed diarrhea, fever, abdominal pain and other symptoms, with observed ulceration and inflammation in the pouch and proximally.

More clinical cases and discussions are at https://community.gastro.org/discussions.

Congrats to AGA Research Foundation grantee Amir Zarrinpar, MD, PhD, from UC San Diego whose new microbiome research has been published in Nature Communications. Dr. Zarrinpar — a former AGA Microbiome Junior Investigator Research Award recipient — used his AGA funding to study cyclical fluctuations in the gut microbiome and its effects on host metabolism. This new study in Nature Communications is an unexpected finding resulting from Dr. Zarrinpar’s AGA research project with his collaborator Satchin Panda, PhD, and their colleagues in the Salk Institute.

The study, Antibiotic-induced microbiome depletion alters metabolic homeostasis by affecting gut signaling and colonic metabolism, finds that mice that have their microbiomes depleted with antibiotics have decreased levels of glucose in their blood and better insulin sensitivity. The research has implications for understanding the role of the microbiome in diabetes. It also could lead to better insight into the side effects seen in people who are being treated with high levels of antibiotics.

The next steps for Dr. Zarrinpar and his team are to better understand what bacterial metabolites can affect insulin sensitivity and to functionally manipulate the microbiome to alter gut signaling to treat diabetes and other metabolic diseases. We look forward to seeing additional research on this topic that can eventually translate into improvements in patient care.
 

[email protected]

Congrats to AGA Research Foundation grantee Amir Zarrinpar, MD, PhD, from UC San Diego whose new microbiome research has been published in Nature Communications. Dr. Zarrinpar — a former AGA Microbiome Junior Investigator Research Award recipient — used his AGA funding to study cyclical fluctuations in the gut microbiome and its effects on host metabolism. This new study in Nature Communications is an unexpected finding resulting from Dr. Zarrinpar’s AGA research project with his collaborator Satchin Panda, PhD, and their colleagues in the Salk Institute.

The study, Antibiotic-induced microbiome depletion alters metabolic homeostasis by affecting gut signaling and colonic metabolism, finds that mice that have their microbiomes depleted with antibiotics have decreased levels of glucose in their blood and better insulin sensitivity. The research has implications for understanding the role of the microbiome in diabetes. It also could lead to better insight into the side effects seen in people who are being treated with high levels of antibiotics.

The next steps for Dr. Zarrinpar and his team are to better understand what bacterial metabolites can affect insulin sensitivity and to functionally manipulate the microbiome to alter gut signaling to treat diabetes and other metabolic diseases. We look forward to seeing additional research on this topic that can eventually translate into improvements in patient care.
 

[email protected]

Congrats to AGA Research Foundation grantee Amir Zarrinpar, MD, PhD, from UC San Diego whose new microbiome research has been published in Nature Communications. Dr. Zarrinpar — a former AGA Microbiome Junior Investigator Research Award recipient — used his AGA funding to study cyclical fluctuations in the gut microbiome and its effects on host metabolism. This new study in Nature Communications is an unexpected finding resulting from Dr. Zarrinpar’s AGA research project with his collaborator Satchin Panda, PhD, and their colleagues in the Salk Institute.

The study, Antibiotic-induced microbiome depletion alters metabolic homeostasis by affecting gut signaling and colonic metabolism, finds that mice that have their microbiomes depleted with antibiotics have decreased levels of glucose in their blood and better insulin sensitivity. The research has implications for understanding the role of the microbiome in diabetes. It also could lead to better insight into the side effects seen in people who are being treated with high levels of antibiotics.

The next steps for Dr. Zarrinpar and his team are to better understand what bacterial metabolites can affect insulin sensitivity and to functionally manipulate the microbiome to alter gut signaling to treat diabetes and other metabolic diseases. We look forward to seeing additional research on this topic that can eventually translate into improvements in patient care.
 

[email protected]

Migraine headaches occurred in 5 (3.1%) of 158 patients who underwent cerebral angiography, according to a recent observational cohort study that ascertained the frequency and type of headaches following catheter‐based cerebral angiography. Consecutive patients who underwent cerebral angiography through the transfemoral (or infrequently, radial) route were included. Each patient underwent a brief neurological assessment after the procedure and more detailed assessment was performed if any patient reported occurrence of a headache. The headaches were classified as migraine if the diagnostic criteria specified by International Headache Society were met. Headache severity was classified using a visual numeric rating scale and time to reach pain free status for 2 consecutive hours was ascertained. Researchers found:

• The median severity of migraine headaches was 10/10 and time to resolution of headaches was 120 minutes (range 60–360 minutes).
• Migraine headaches occurred in 4 (18.1%) of 22 patients with a history of migraine and 4 (23.5%) of 17 patients with regular migraine headaches (≥1 episodes per month).
• Headaches occurred in 6 (3.8%) patients who did not meet the criteria for migraine headaches.

Qureshi AI, Naseem N, Saleem MA, Potluri A, Raja F, Wallery SS. Migraine and non‐migraine headaches following diagnostic catheter‐based cerebral angiography. [Published online ahead of print August 16, 2018]. Headache. doi:10.1111/head.13377.

Migraine headaches occurred in 5 (3.1%) of 158 patients who underwent cerebral angiography, according to a recent observational cohort study that ascertained the frequency and type of headaches following catheter‐based cerebral angiography. Consecutive patients who underwent cerebral angiography through the transfemoral (or infrequently, radial) route were included. Each patient underwent a brief neurological assessment after the procedure and more detailed assessment was performed if any patient reported occurrence of a headache. The headaches were classified as migraine if the diagnostic criteria specified by International Headache Society were met. Headache severity was classified using a visual numeric rating scale and time to reach pain free status for 2 consecutive hours was ascertained. Researchers found:

• The median severity of migraine headaches was 10/10 and time to resolution of headaches was 120 minutes (range 60–360 minutes).
• Migraine headaches occurred in 4 (18.1%) of 22 patients with a history of migraine and 4 (23.5%) of 17 patients with regular migraine headaches (≥1 episodes per month).
• Headaches occurred in 6 (3.8%) patients who did not meet the criteria for migraine headaches.

Qureshi AI, Naseem N, Saleem MA, Potluri A, Raja F, Wallery SS. Migraine and non‐migraine headaches following diagnostic catheter‐based cerebral angiography. [Published online ahead of print August 16, 2018]. Headache. doi:10.1111/head.13377.

Migraine headaches occurred in 5 (3.1%) of 158 patients who underwent cerebral angiography, according to a recent observational cohort study that ascertained the frequency and type of headaches following catheter‐based cerebral angiography. Consecutive patients who underwent cerebral angiography through the transfemoral (or infrequently, radial) route were included. Each patient underwent a brief neurological assessment after the procedure and more detailed assessment was performed if any patient reported occurrence of a headache. The headaches were classified as migraine if the diagnostic criteria specified by International Headache Society were met. Headache severity was classified using a visual numeric rating scale and time to reach pain free status for 2 consecutive hours was ascertained. Researchers found:

• The median severity of migraine headaches was 10/10 and time to resolution of headaches was 120 minutes (range 60–360 minutes).
• Migraine headaches occurred in 4 (18.1%) of 22 patients with a history of migraine and 4 (23.5%) of 17 patients with regular migraine headaches (≥1 episodes per month).
• Headaches occurred in 6 (3.8%) patients who did not meet the criteria for migraine headaches.

Qureshi AI, Naseem N, Saleem MA, Potluri A, Raja F, Wallery SS. Migraine and non‐migraine headaches following diagnostic catheter‐based cerebral angiography. [Published online ahead of print August 16, 2018]. Headache. doi:10.1111/head.13377.

Children with chronic headache and migraine who are severely functionally impaired demonstrated linear improvement in pain‐specific patient‐reported outcomes over time, according to a recent study that aimed to evaluate the trajectory of recovery for children undergoing intensive interdisciplinary pain rehabilitation treatment (IIPT). A retrospective analysis was conducted of patient‐reported outcomes in a clinical database of 135 children (mean age 15.2 [SD=2.2] and 74% female) admitted to an IIPT program between the years 2008 and 2014. Available data across 5 separate time points (up to 1‐year post‐discharge) were reviewed. Researchers found:

• A statistically significant improvement was noted in pain‐specific measures of functioning, including daily functioning, emotional functioning, family functioning, and school absences over a 12‐month period.
• A more general measure of quality of life improved during the program, based upon child and parent reports, although these gains did not continue to improve post‐discharge.
• As expected, although children did not report a reduction in pain during rehabilitation, they did report a significant drop in perceived pain in the 12 months following discharge from the program.

Benore E, Webster EE, Wang L, Banez G. Longitudinal analysis of patient‐reported outcomes from an interdisciplinary pediatric pain rehabilitation program for children with chronic migraine and headache. [Published online ahead of print August 23, 2018]. Headache. doi:10.1111/head.13389.

Children with chronic headache and migraine who are severely functionally impaired demonstrated linear improvement in pain‐specific patient‐reported outcomes over time, according to a recent study that aimed to evaluate the trajectory of recovery for children undergoing intensive interdisciplinary pain rehabilitation treatment (IIPT). A retrospective analysis was conducted of patient‐reported outcomes in a clinical database of 135 children (mean age 15.2 [SD=2.2] and 74% female) admitted to an IIPT program between the years 2008 and 2014. Available data across 5 separate time points (up to 1‐year post‐discharge) were reviewed. Researchers found:

• A statistically significant improvement was noted in pain‐specific measures of functioning, including daily functioning, emotional functioning, family functioning, and school absences over a 12‐month period.
• A more general measure of quality of life improved during the program, based upon child and parent reports, although these gains did not continue to improve post‐discharge.
• As expected, although children did not report a reduction in pain during rehabilitation, they did report a significant drop in perceived pain in the 12 months following discharge from the program.

Benore E, Webster EE, Wang L, Banez G. Longitudinal analysis of patient‐reported outcomes from an interdisciplinary pediatric pain rehabilitation program for children with chronic migraine and headache. [Published online ahead of print August 23, 2018]. Headache. doi:10.1111/head.13389.

Children with chronic headache and migraine who are severely functionally impaired demonstrated linear improvement in pain‐specific patient‐reported outcomes over time, according to a recent study that aimed to evaluate the trajectory of recovery for children undergoing intensive interdisciplinary pain rehabilitation treatment (IIPT). A retrospective analysis was conducted of patient‐reported outcomes in a clinical database of 135 children (mean age 15.2 [SD=2.2] and 74% female) admitted to an IIPT program between the years 2008 and 2014. Available data across 5 separate time points (up to 1‐year post‐discharge) were reviewed. Researchers found:

• A statistically significant improvement was noted in pain‐specific measures of functioning, including daily functioning, emotional functioning, family functioning, and school absences over a 12‐month period.
• A more general measure of quality of life improved during the program, based upon child and parent reports, although these gains did not continue to improve post‐discharge.
• As expected, although children did not report a reduction in pain during rehabilitation, they did report a significant drop in perceived pain in the 12 months following discharge from the program.

Benore E, Webster EE, Wang L, Banez G. Longitudinal analysis of patient‐reported outcomes from an interdisciplinary pediatric pain rehabilitation program for children with chronic migraine and headache. [Published online ahead of print August 23, 2018]. Headache. doi:10.1111/head.13389.