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Treatments appear comparable for VTE in cancer
Results of the phase 3 CATCH trial suggest that 6 months of treatment with the low-molecular weight heparin tinzaparin produces similar results as conventional venous thromboembolism (VTE) prophylaxis in patients with active cancer and acute, symptomatic VTE.
The rates of VTE recurrence, overall death, and major bleeding were not significantly different in patients who received only tinzaparin and those who received tinzaparin followed by warfarin.
However, patients who received tinzaparin alone had a significantly lower rate of clinically relevant, nonmajor bleeding.
Agnes Y. Y. Lee, MD, of the University of British Columbia in Vancouver, Canada, and her colleagues reported these results in JAMA. The study was previously presented at ASH 2014.
The researchers enrolled 900 adult patients with active cancer and documented deep vein thrombosis or pulmonary embolism. The patients were enrolled at 164 centers in Asia, Africa, Europe, and
North, Central, and South America between August 2010 and November 2013.
The patients were randomized to receive tinzaparin (at 175 IU/kg) once daily for 6 months (n=449) or conventional therapy with tinzaparin (at 175 IU/kg) once daily for 5 to 10 days followed by dose-adjusted warfarin for the rest of the 6-month period (n=451).
The researchers saw no significant difference in the 6-month cumulative incidence of recurrent VTE between the tinzaparin and warfarin arms—7.2% (n=31) and 10.5% (n=45), respectively (hazard ratio [HR]=0.65, P=0.07).
Likewise, there was no significant difference in major bleeding (HR=0.89, P=0.77) or overall mortality (HR=1.08, P=0.54). Major bleeding occurred in 12 patients in the tinzaparin arm and 11 patients in the warfarin arm. And there were 150 deaths in the tinzaparin arm and 138 deaths in the warfarin arm.
There was a significant reduction in clinically relevant, nonmajor bleeding in the tinzaparin arm (HR=0.58, P=0.004). There were 49 such bleeds in the tinzaparin arm and 69 in the warfarin arm.
The researchers said these results suggest a full therapeutic dose of tinzaparin is safe in cancer patients for up to 6 months, and additional studies are needed to assess whether the efficacy outcomes would be different in patients at a higher risk of recurrent VTE.
This study was sponsored and funded by LEO Pharma (the company developing tinzaparin as Innohep) and had research support from the Sondra and Stephen Hardis Endowed Chair in Oncology Research and the Scott Hamilton CARES Initiative. 
Results of the phase 3 CATCH trial suggest that 6 months of treatment with the low-molecular weight heparin tinzaparin produces similar results as conventional venous thromboembolism (VTE) prophylaxis in patients with active cancer and acute, symptomatic VTE.
The rates of VTE recurrence, overall death, and major bleeding were not significantly different in patients who received only tinzaparin and those who received tinzaparin followed by warfarin.
However, patients who received tinzaparin alone had a significantly lower rate of clinically relevant, nonmajor bleeding.
Agnes Y. Y. Lee, MD, of the University of British Columbia in Vancouver, Canada, and her colleagues reported these results in JAMA. The study was previously presented at ASH 2014.
The researchers enrolled 900 adult patients with active cancer and documented deep vein thrombosis or pulmonary embolism. The patients were enrolled at 164 centers in Asia, Africa, Europe, and
North, Central, and South America between August 2010 and November 2013.
The patients were randomized to receive tinzaparin (at 175 IU/kg) once daily for 6 months (n=449) or conventional therapy with tinzaparin (at 175 IU/kg) once daily for 5 to 10 days followed by dose-adjusted warfarin for the rest of the 6-month period (n=451).
The researchers saw no significant difference in the 6-month cumulative incidence of recurrent VTE between the tinzaparin and warfarin arms—7.2% (n=31) and 10.5% (n=45), respectively (hazard ratio [HR]=0.65, P=0.07).
Likewise, there was no significant difference in major bleeding (HR=0.89, P=0.77) or overall mortality (HR=1.08, P=0.54). Major bleeding occurred in 12 patients in the tinzaparin arm and 11 patients in the warfarin arm. And there were 150 deaths in the tinzaparin arm and 138 deaths in the warfarin arm.
There was a significant reduction in clinically relevant, nonmajor bleeding in the tinzaparin arm (HR=0.58, P=0.004). There were 49 such bleeds in the tinzaparin arm and 69 in the warfarin arm.
The researchers said these results suggest a full therapeutic dose of tinzaparin is safe in cancer patients for up to 6 months, and additional studies are needed to assess whether the efficacy outcomes would be different in patients at a higher risk of recurrent VTE.
This study was sponsored and funded by LEO Pharma (the company developing tinzaparin as Innohep) and had research support from the Sondra and Stephen Hardis Endowed Chair in Oncology Research and the Scott Hamilton CARES Initiative.
Results of the phase 3 CATCH trial suggest that 6 months of treatment with the low-molecular weight heparin tinzaparin produces similar results as conventional venous thromboembolism (VTE) prophylaxis in patients with active cancer and acute, symptomatic VTE.
The rates of VTE recurrence, overall death, and major bleeding were not significantly different in patients who received only tinzaparin and those who received tinzaparin followed by warfarin.
However, patients who received tinzaparin alone had a significantly lower rate of clinically relevant, nonmajor bleeding.
Agnes Y. Y. Lee, MD, of the University of British Columbia in Vancouver, Canada, and her colleagues reported these results in JAMA. The study was previously presented at ASH 2014.
The researchers enrolled 900 adult patients with active cancer and documented deep vein thrombosis or pulmonary embolism. The patients were enrolled at 164 centers in Asia, Africa, Europe, and
North, Central, and South America between August 2010 and November 2013.
The patients were randomized to receive tinzaparin (at 175 IU/kg) once daily for 6 months (n=449) or conventional therapy with tinzaparin (at 175 IU/kg) once daily for 5 to 10 days followed by dose-adjusted warfarin for the rest of the 6-month period (n=451).
The researchers saw no significant difference in the 6-month cumulative incidence of recurrent VTE between the tinzaparin and warfarin arms—7.2% (n=31) and 10.5% (n=45), respectively (hazard ratio [HR]=0.65, P=0.07).
Likewise, there was no significant difference in major bleeding (HR=0.89, P=0.77) or overall mortality (HR=1.08, P=0.54). Major bleeding occurred in 12 patients in the tinzaparin arm and 11 patients in the warfarin arm. And there were 150 deaths in the tinzaparin arm and 138 deaths in the warfarin arm.
There was a significant reduction in clinically relevant, nonmajor bleeding in the tinzaparin arm (HR=0.58, P=0.004). There were 49 such bleeds in the tinzaparin arm and 69 in the warfarin arm.
The researchers said these results suggest a full therapeutic dose of tinzaparin is safe in cancer patients for up to 6 months, and additional studies are needed to assess whether the efficacy outcomes would be different in patients at a higher risk of recurrent VTE.
This study was sponsored and funded by LEO Pharma (the company developing tinzaparin as Innohep) and had research support from the Sondra and Stephen Hardis Endowed Chair in Oncology Research and the Scott Hamilton CARES Initiative.
Return on investment slipping in biomedical research
Photo by Rhoda Baer
As more and more money has been spent on biomedical research in the US over the past 50 years, there has been diminished return on investment in terms of life expectancy gains and new drug approvals, according to a report published in PNAS.
Investigators found that the number of scientists in the US has increased about 9-fold since 1965, and the National Institutes of Health (NIH) budget has increased about 4-fold.
But the number of new drugs approved by the Food and Drug Administration has only increased about 2-fold, and life expectancy gains have remained constant, at roughly 2 months per year.
“The idea of public support for biomedical research is to make lives better, but there is increasing friction in the system,” said study author Arturo Casadevall, MD, PhD, of the Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland.
“We are spending more money now just to get the same results we always have, and this is going to keep happening if we don’t fix things.”
“There is something wrong in the process, but there are no simple answers,” said study author Anthony Bowen, an MD/PhD student at Albert Einstein College of Medicine in the Bronx, New York.
“It may be a confluence of factors that are causing us not to be getting more bang for our buck.”
Bowen and Dr Casadevall said one such factor may be that increased regulations have added to the non-scientific burdens on scientists who could otherwise spend more time at the bench.
Another potential explanation is that the “easy” cures for various conditions have been found, but to tackle cancers, Alzheimer’s disease, and autoimmune diseases, for example, is inherently more complex.
Dr Casadevall and Bowen also cited “perverse” incentives for researchers to cut corners or oversimplify their studies to gain acceptance into top-tier medical journals. The pair said this has led to an “epidemic” of retractions and findings that cannot be reproduced and are therefore worthless.
“The medical literature isn’t as good as it used to be,” Dr Casadevall said. “The culture of science appears to be changing. Less important work is being hyped, when the quality of work may not be clear until decades later when someone builds on your success to find a cure.”
In one recent study, researchers estimated that more than $28 billion, from both public and private sources, is spent each year in the US on preclinical research that can’t be reproduced, and the prevalence of these studies in the literature is 50%.
“We have more journals and more papers than ever,” Bowen said. “But the number of biomedical publications has dramatically outpaced the production of new drugs, which are key to improving people’s lives, especially in areas for which we have no good treatments.”
Dr Casadevall said he doesn’t doubt that more cures for diseases are out there to be found, and a more efficient system of biomedical research could help push along scientific discovery.
“Scientists, regulators, and citizens need to take a hard look at the scientific enterprise and see which [problems] can be resolved,” he said. “We need a system with rigor, reproducibility, and integrity, and we need to find a way to get there as soon as we can.”
Photo by Rhoda Baer
As more and more money has been spent on biomedical research in the US over the past 50 years, there has been diminished return on investment in terms of life expectancy gains and new drug approvals, according to a report published in PNAS.
Investigators found that the number of scientists in the US has increased about 9-fold since 1965, and the National Institutes of Health (NIH) budget has increased about 4-fold.
But the number of new drugs approved by the Food and Drug Administration has only increased about 2-fold, and life expectancy gains have remained constant, at roughly 2 months per year.
“The idea of public support for biomedical research is to make lives better, but there is increasing friction in the system,” said study author Arturo Casadevall, MD, PhD, of the Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland.
“We are spending more money now just to get the same results we always have, and this is going to keep happening if we don’t fix things.”
“There is something wrong in the process, but there are no simple answers,” said study author Anthony Bowen, an MD/PhD student at Albert Einstein College of Medicine in the Bronx, New York.
“It may be a confluence of factors that are causing us not to be getting more bang for our buck.”
Bowen and Dr Casadevall said one such factor may be that increased regulations have added to the non-scientific burdens on scientists who could otherwise spend more time at the bench.
Another potential explanation is that the “easy” cures for various conditions have been found, but to tackle cancers, Alzheimer’s disease, and autoimmune diseases, for example, is inherently more complex.
Dr Casadevall and Bowen also cited “perverse” incentives for researchers to cut corners or oversimplify their studies to gain acceptance into top-tier medical journals. The pair said this has led to an “epidemic” of retractions and findings that cannot be reproduced and are therefore worthless.
“The medical literature isn’t as good as it used to be,” Dr Casadevall said. “The culture of science appears to be changing. Less important work is being hyped, when the quality of work may not be clear until decades later when someone builds on your success to find a cure.”
In one recent study, researchers estimated that more than $28 billion, from both public and private sources, is spent each year in the US on preclinical research that can’t be reproduced, and the prevalence of these studies in the literature is 50%.
“We have more journals and more papers than ever,” Bowen said. “But the number of biomedical publications has dramatically outpaced the production of new drugs, which are key to improving people’s lives, especially in areas for which we have no good treatments.”
Dr Casadevall said he doesn’t doubt that more cures for diseases are out there to be found, and a more efficient system of biomedical research could help push along scientific discovery.
“Scientists, regulators, and citizens need to take a hard look at the scientific enterprise and see which [problems] can be resolved,” he said. “We need a system with rigor, reproducibility, and integrity, and we need to find a way to get there as soon as we can.”
Photo by Rhoda Baer
As more and more money has been spent on biomedical research in the US over the past 50 years, there has been diminished return on investment in terms of life expectancy gains and new drug approvals, according to a report published in PNAS.
Investigators found that the number of scientists in the US has increased about 9-fold since 1965, and the National Institutes of Health (NIH) budget has increased about 4-fold.
But the number of new drugs approved by the Food and Drug Administration has only increased about 2-fold, and life expectancy gains have remained constant, at roughly 2 months per year.
“The idea of public support for biomedical research is to make lives better, but there is increasing friction in the system,” said study author Arturo Casadevall, MD, PhD, of the Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland.
“We are spending more money now just to get the same results we always have, and this is going to keep happening if we don’t fix things.”
“There is something wrong in the process, but there are no simple answers,” said study author Anthony Bowen, an MD/PhD student at Albert Einstein College of Medicine in the Bronx, New York.
“It may be a confluence of factors that are causing us not to be getting more bang for our buck.”
Bowen and Dr Casadevall said one such factor may be that increased regulations have added to the non-scientific burdens on scientists who could otherwise spend more time at the bench.
Another potential explanation is that the “easy” cures for various conditions have been found, but to tackle cancers, Alzheimer’s disease, and autoimmune diseases, for example, is inherently more complex.
Dr Casadevall and Bowen also cited “perverse” incentives for researchers to cut corners or oversimplify their studies to gain acceptance into top-tier medical journals. The pair said this has led to an “epidemic” of retractions and findings that cannot be reproduced and are therefore worthless.
“The medical literature isn’t as good as it used to be,” Dr Casadevall said. “The culture of science appears to be changing. Less important work is being hyped, when the quality of work may not be clear until decades later when someone builds on your success to find a cure.”
In one recent study, researchers estimated that more than $28 billion, from both public and private sources, is spent each year in the US on preclinical research that can’t be reproduced, and the prevalence of these studies in the literature is 50%.
“We have more journals and more papers than ever,” Bowen said. “But the number of biomedical publications has dramatically outpaced the production of new drugs, which are key to improving people’s lives, especially in areas for which we have no good treatments.”
Dr Casadevall said he doesn’t doubt that more cures for diseases are out there to be found, and a more efficient system of biomedical research could help push along scientific discovery.
“Scientists, regulators, and citizens need to take a hard look at the scientific enterprise and see which [problems] can be resolved,” he said. “We need a system with rigor, reproducibility, and integrity, and we need to find a way to get there as soon as we can.”
Method can predict prognosis in MM, group says
Photo courtesy of NIH
Assessing certain genetic abnormalities and a patient’s International Staging System (ISS) stage can reveal patients with high-risk multiple myeloma (MM), according to research published in the Journal of Clinical Oncology.
Investigators said this method can identify a majority of newly diagnosed MM patients who will relapse or die prematurely.
The team began this work by performing whole-exome sequencing on the 463 patients enrolled in the Myeloma XI trial.
This revealed 15 genes that were significantly mutated—IRF4, KRAS, NRAS, MAX, HIST1H1E, RB1, EGR1, TP53, TRAF3, FAM46C, DIS3, BRAF, LTB, CYLD, and FGFR3.
The investigators noted that mutations in the RAS (43%) and NF-κB (17%) pathways were common but proved prognostically neutral.
On the other hand, mutations in CCND1 and DNA repair pathway alterations—TP53, ATM, ATR, and ZNFHX4 mutations—were associated with poor survival.
For example, 2-year overall survival (OS) was 38.1% in patients with CCND1 mutations and 80% in those without them (P=0.005). Likewise, 2-year OS was 50% in patients with ATM mutations and 80.3% in those without them (P=0.01).
Conversely, mutations in IRF4 and EGR1 were associated with superior survival. Two-year OS was 100% in patients with IRF4 mutations and 79% in those without them (P=0.05). And 2-year OS was 100% in patients with EGR1 mutations and 78% in those without them (P=0.04).
In a multivariable analysis, an ISS stage of III, TP53 variants, CCND1 mutations, ATM and ATR mutations, amp(1q), and MYC translocations were independently associated with OS.
An ISS stage of III, age older than 70 years, t(4;14), MYC translocations, TP53 variants, ATM and ATR mutations, and ZFHX4 mutations were independently associated with progression-free survival (PFS).
In an attempt to predict PFS and OS accurately in newly diagnosed MM patients, the investigators combined the genetic risk factors they identified—mutations and copy number and structural abnormalities (CNSAs)—with clinical information captured by the ISS.
This led to 3 prognostic groups. Patients in group 1 (low-risk) had ISS I/II and no mutations/CNSAs. Patients in group 2 (moderate-risk) had ISS III with no mutations/CNSAs or ISS I/II/III with 1 mutation/CNSA. And patients in group 3 (high-risk) had 2 mutations/CNSAs regardless of their ISS.
The investigators said classifying patients in this way can identify 83% of patients who will relapse prematurely and 92% of patients who will die prematurely.
“Our study has identified genetic features which can identify those patients whose myeloma is likely to prove aggressive and to progress quickly,” said study author Gareth Morgan, MD, PhD, of The Institute of Cancer Research, London in the UK.
“We hope our study ultimately paves the way for genetic testing to pick out the minority of patients with myeloma with a poor prognosis, who might benefit from the most intensive possible treatment.”
Photo courtesy of NIH
Assessing certain genetic abnormalities and a patient’s International Staging System (ISS) stage can reveal patients with high-risk multiple myeloma (MM), according to research published in the Journal of Clinical Oncology.
Investigators said this method can identify a majority of newly diagnosed MM patients who will relapse or die prematurely.
The team began this work by performing whole-exome sequencing on the 463 patients enrolled in the Myeloma XI trial.
This revealed 15 genes that were significantly mutated—IRF4, KRAS, NRAS, MAX, HIST1H1E, RB1, EGR1, TP53, TRAF3, FAM46C, DIS3, BRAF, LTB, CYLD, and FGFR3.
The investigators noted that mutations in the RAS (43%) and NF-κB (17%) pathways were common but proved prognostically neutral.
On the other hand, mutations in CCND1 and DNA repair pathway alterations—TP53, ATM, ATR, and ZNFHX4 mutations—were associated with poor survival.
For example, 2-year overall survival (OS) was 38.1% in patients with CCND1 mutations and 80% in those without them (P=0.005). Likewise, 2-year OS was 50% in patients with ATM mutations and 80.3% in those without them (P=0.01).
Conversely, mutations in IRF4 and EGR1 were associated with superior survival. Two-year OS was 100% in patients with IRF4 mutations and 79% in those without them (P=0.05). And 2-year OS was 100% in patients with EGR1 mutations and 78% in those without them (P=0.04).
In a multivariable analysis, an ISS stage of III, TP53 variants, CCND1 mutations, ATM and ATR mutations, amp(1q), and MYC translocations were independently associated with OS.
An ISS stage of III, age older than 70 years, t(4;14), MYC translocations, TP53 variants, ATM and ATR mutations, and ZFHX4 mutations were independently associated with progression-free survival (PFS).
In an attempt to predict PFS and OS accurately in newly diagnosed MM patients, the investigators combined the genetic risk factors they identified—mutations and copy number and structural abnormalities (CNSAs)—with clinical information captured by the ISS.
This led to 3 prognostic groups. Patients in group 1 (low-risk) had ISS I/II and no mutations/CNSAs. Patients in group 2 (moderate-risk) had ISS III with no mutations/CNSAs or ISS I/II/III with 1 mutation/CNSA. And patients in group 3 (high-risk) had 2 mutations/CNSAs regardless of their ISS.
The investigators said classifying patients in this way can identify 83% of patients who will relapse prematurely and 92% of patients who will die prematurely.
“Our study has identified genetic features which can identify those patients whose myeloma is likely to prove aggressive and to progress quickly,” said study author Gareth Morgan, MD, PhD, of The Institute of Cancer Research, London in the UK.
“We hope our study ultimately paves the way for genetic testing to pick out the minority of patients with myeloma with a poor prognosis, who might benefit from the most intensive possible treatment.”
Photo courtesy of NIH
Assessing certain genetic abnormalities and a patient’s International Staging System (ISS) stage can reveal patients with high-risk multiple myeloma (MM), according to research published in the Journal of Clinical Oncology.
Investigators said this method can identify a majority of newly diagnosed MM patients who will relapse or die prematurely.
The team began this work by performing whole-exome sequencing on the 463 patients enrolled in the Myeloma XI trial.
This revealed 15 genes that were significantly mutated—IRF4, KRAS, NRAS, MAX, HIST1H1E, RB1, EGR1, TP53, TRAF3, FAM46C, DIS3, BRAF, LTB, CYLD, and FGFR3.
The investigators noted that mutations in the RAS (43%) and NF-κB (17%) pathways were common but proved prognostically neutral.
On the other hand, mutations in CCND1 and DNA repair pathway alterations—TP53, ATM, ATR, and ZNFHX4 mutations—were associated with poor survival.
For example, 2-year overall survival (OS) was 38.1% in patients with CCND1 mutations and 80% in those without them (P=0.005). Likewise, 2-year OS was 50% in patients with ATM mutations and 80.3% in those without them (P=0.01).
Conversely, mutations in IRF4 and EGR1 were associated with superior survival. Two-year OS was 100% in patients with IRF4 mutations and 79% in those without them (P=0.05). And 2-year OS was 100% in patients with EGR1 mutations and 78% in those without them (P=0.04).
In a multivariable analysis, an ISS stage of III, TP53 variants, CCND1 mutations, ATM and ATR mutations, amp(1q), and MYC translocations were independently associated with OS.
An ISS stage of III, age older than 70 years, t(4;14), MYC translocations, TP53 variants, ATM and ATR mutations, and ZFHX4 mutations were independently associated with progression-free survival (PFS).
In an attempt to predict PFS and OS accurately in newly diagnosed MM patients, the investigators combined the genetic risk factors they identified—mutations and copy number and structural abnormalities (CNSAs)—with clinical information captured by the ISS.
This led to 3 prognostic groups. Patients in group 1 (low-risk) had ISS I/II and no mutations/CNSAs. Patients in group 2 (moderate-risk) had ISS III with no mutations/CNSAs or ISS I/II/III with 1 mutation/CNSA. And patients in group 3 (high-risk) had 2 mutations/CNSAs regardless of their ISS.
The investigators said classifying patients in this way can identify 83% of patients who will relapse prematurely and 92% of patients who will die prematurely.
“Our study has identified genetic features which can identify those patients whose myeloma is likely to prove aggressive and to progress quickly,” said study author Gareth Morgan, MD, PhD, of The Institute of Cancer Research, London in the UK.
“We hope our study ultimately paves the way for genetic testing to pick out the minority of patients with myeloma with a poor prognosis, who might benefit from the most intensive possible treatment.”
Study shows rivaroxaban can cross placenta
Photo by Nina Matthews
New research suggests the anticoagulant rivaroxaban can cross the placenta in pregnant women, raising concerns that the drug might
cause side effects in unborn children.
The ex vivo study, published in the American Journal of Obstetrics & Gynecology, showed that rivaroxaban can rapidly cross the human placenta in both directions.
The researchers did not draw any conclusions about the potential link between rivaroxaban and birth defects, but they said additional research is needed to explore this possibility.
Gideon Koren, MD, of the Hospital for Sick Children in Toronto, Ontario, Canada, and his colleagues conducted this study using an ex vivo placenta perfusion model.
They added rivaroxaban (250 ng/mL) to the maternal circulation, the fetal circulation, or both and observed the effects over 3 hours. They measured rivaroxaban concentrations via liquid chromatography-tandem mass spectrometry.
The researchers said they saw “rapid transfer” of rivaroxaban across the placenta, both in the maternal-to-fetal and fetal-to-maternal directions.
Three hours after they added rivaroxaban to the maternal reservoir, the median fetal concentration of the drug was 69.5 ng/mL, and the median fetal-to-maternal ratio was 0.69.
Three hours after they added rivaroxaban to the fetal reservoir, the maternal concentration of rivaroxaban was 58.2 ng/mL, and the maternal-to-fetal ratio was 0.69.
When the researchers added equal concentrations of rivaroxaban to both reservoirs, the fetal-to-maternal ratio remained relatively constant over the 3-hour period. And the rate of rivaroxaban disappearance was similar in both reservoirs—1.51 ng/mL/min in the maternal reservoir and 1.86 ng/mL/min in the fetal reservoir.
The researchers said this is the first direct evidence of rivaroxaban transfer across the placenta from both directions.
However, they also noted that, because rivaroxaban is highly bound to plasma proteins, the amount of unbound drug that may reach the fetus is likely much lower than observed in these experiments.
Nevertheless, additional studies should be conducted before rivaroxaban can be safely administered to pregnant women.
Photo by Nina Matthews
New research suggests the anticoagulant rivaroxaban can cross the placenta in pregnant women, raising concerns that the drug might
cause side effects in unborn children.
The ex vivo study, published in the American Journal of Obstetrics & Gynecology, showed that rivaroxaban can rapidly cross the human placenta in both directions.
The researchers did not draw any conclusions about the potential link between rivaroxaban and birth defects, but they said additional research is needed to explore this possibility.
Gideon Koren, MD, of the Hospital for Sick Children in Toronto, Ontario, Canada, and his colleagues conducted this study using an ex vivo placenta perfusion model.
They added rivaroxaban (250 ng/mL) to the maternal circulation, the fetal circulation, or both and observed the effects over 3 hours. They measured rivaroxaban concentrations via liquid chromatography-tandem mass spectrometry.
The researchers said they saw “rapid transfer” of rivaroxaban across the placenta, both in the maternal-to-fetal and fetal-to-maternal directions.
Three hours after they added rivaroxaban to the maternal reservoir, the median fetal concentration of the drug was 69.5 ng/mL, and the median fetal-to-maternal ratio was 0.69.
Three hours after they added rivaroxaban to the fetal reservoir, the maternal concentration of rivaroxaban was 58.2 ng/mL, and the maternal-to-fetal ratio was 0.69.
When the researchers added equal concentrations of rivaroxaban to both reservoirs, the fetal-to-maternal ratio remained relatively constant over the 3-hour period. And the rate of rivaroxaban disappearance was similar in both reservoirs—1.51 ng/mL/min in the maternal reservoir and 1.86 ng/mL/min in the fetal reservoir.
The researchers said this is the first direct evidence of rivaroxaban transfer across the placenta from both directions.
However, they also noted that, because rivaroxaban is highly bound to plasma proteins, the amount of unbound drug that may reach the fetus is likely much lower than observed in these experiments.
Nevertheless, additional studies should be conducted before rivaroxaban can be safely administered to pregnant women.
Photo by Nina Matthews
New research suggests the anticoagulant rivaroxaban can cross the placenta in pregnant women, raising concerns that the drug might
cause side effects in unborn children.
The ex vivo study, published in the American Journal of Obstetrics & Gynecology, showed that rivaroxaban can rapidly cross the human placenta in both directions.
The researchers did not draw any conclusions about the potential link between rivaroxaban and birth defects, but they said additional research is needed to explore this possibility.
Gideon Koren, MD, of the Hospital for Sick Children in Toronto, Ontario, Canada, and his colleagues conducted this study using an ex vivo placenta perfusion model.
They added rivaroxaban (250 ng/mL) to the maternal circulation, the fetal circulation, or both and observed the effects over 3 hours. They measured rivaroxaban concentrations via liquid chromatography-tandem mass spectrometry.
The researchers said they saw “rapid transfer” of rivaroxaban across the placenta, both in the maternal-to-fetal and fetal-to-maternal directions.
Three hours after they added rivaroxaban to the maternal reservoir, the median fetal concentration of the drug was 69.5 ng/mL, and the median fetal-to-maternal ratio was 0.69.
Three hours after they added rivaroxaban to the fetal reservoir, the maternal concentration of rivaroxaban was 58.2 ng/mL, and the maternal-to-fetal ratio was 0.69.
When the researchers added equal concentrations of rivaroxaban to both reservoirs, the fetal-to-maternal ratio remained relatively constant over the 3-hour period. And the rate of rivaroxaban disappearance was similar in both reservoirs—1.51 ng/mL/min in the maternal reservoir and 1.86 ng/mL/min in the fetal reservoir.
The researchers said this is the first direct evidence of rivaroxaban transfer across the placenta from both directions.
However, they also noted that, because rivaroxaban is highly bound to plasma proteins, the amount of unbound drug that may reach the fetus is likely much lower than observed in these experiments.
Nevertheless, additional studies should be conducted before rivaroxaban can be safely administered to pregnant women.
PICCs linked to lower- and upper-extremity DVT
A study of more than 70,000 patients suggests the use of peripherally inserted central catheters (PICCs) is not only associated with upper-extremity deep vein thrombosis (DVT).
It’s linked to lower-extremity DVT as well. However, PICC use was not associated with pulmonary embolism (PE).
Vineet Chopra, MD, of the University of Michigan in Ann Arbor, and his colleagues reported these findings in The American Journal of Medicine.
“Our study confirmed that PICCs are strongly associated with DVT in upper limbs,” Dr Chopra said. “However, what is novel and noteworthy in this study is that the presence of a PICC was also associated with an increased risk of lower-extremity DVT. Prior studies had not assessed whether PICCs are independently associated with an increase in the risk of subsequent lower-extremity DVT.”
Dr Chopra and his colleagues analyzed data from 76,242 patients hospitalized at 48 Michigan hospitals.
The team reviewed PICC placement, existing medical conditions, risk factors for venous thromboembolism (VTE), and thrombotic events occurring within 90 days of hospital admission.
A total of 3790 patients received a PICC during hospitalization. And there were 876 VTEs, including 208 upper-extremity DVTs, 372 lower-extremity DVTs, and 296 PEs.
After adjusting for risk factors other than PICC use, the researchers found that PICCs were independently associated with all-cause VTE, upper-extremity DVT, and lower-extremity DVT, but not PE. The hazard ratios were 3.16, 10.49, 1.48, and 1.34, respectively.
The team also found that VTE prophylaxis did not reduce the risk of DVT.
“Taken together, these findings suggest that the thrombotic burden associated with peripherally inserted central catheters may not be restricted to the extremity where the device resides or easily attenuated after insertion,” Dr Chopra said.
He and his colleagues therefore concluded that clinicians should weigh the risks and benefits of PICC use and consider using alternative devices in patients at high risk of DVT. And clinicians should not focus only on the extremity where a PICC resides but the composite risk of VTE among patients who receive a PICC.
A study of more than 70,000 patients suggests the use of peripherally inserted central catheters (PICCs) is not only associated with upper-extremity deep vein thrombosis (DVT).
It’s linked to lower-extremity DVT as well. However, PICC use was not associated with pulmonary embolism (PE).
Vineet Chopra, MD, of the University of Michigan in Ann Arbor, and his colleagues reported these findings in The American Journal of Medicine.
“Our study confirmed that PICCs are strongly associated with DVT in upper limbs,” Dr Chopra said. “However, what is novel and noteworthy in this study is that the presence of a PICC was also associated with an increased risk of lower-extremity DVT. Prior studies had not assessed whether PICCs are independently associated with an increase in the risk of subsequent lower-extremity DVT.”
Dr Chopra and his colleagues analyzed data from 76,242 patients hospitalized at 48 Michigan hospitals.
The team reviewed PICC placement, existing medical conditions, risk factors for venous thromboembolism (VTE), and thrombotic events occurring within 90 days of hospital admission.
A total of 3790 patients received a PICC during hospitalization. And there were 876 VTEs, including 208 upper-extremity DVTs, 372 lower-extremity DVTs, and 296 PEs.
After adjusting for risk factors other than PICC use, the researchers found that PICCs were independently associated with all-cause VTE, upper-extremity DVT, and lower-extremity DVT, but not PE. The hazard ratios were 3.16, 10.49, 1.48, and 1.34, respectively.
The team also found that VTE prophylaxis did not reduce the risk of DVT.
“Taken together, these findings suggest that the thrombotic burden associated with peripherally inserted central catheters may not be restricted to the extremity where the device resides or easily attenuated after insertion,” Dr Chopra said.
He and his colleagues therefore concluded that clinicians should weigh the risks and benefits of PICC use and consider using alternative devices in patients at high risk of DVT. And clinicians should not focus only on the extremity where a PICC resides but the composite risk of VTE among patients who receive a PICC.
A study of more than 70,000 patients suggests the use of peripherally inserted central catheters (PICCs) is not only associated with upper-extremity deep vein thrombosis (DVT).
It’s linked to lower-extremity DVT as well. However, PICC use was not associated with pulmonary embolism (PE).
Vineet Chopra, MD, of the University of Michigan in Ann Arbor, and his colleagues reported these findings in The American Journal of Medicine.
“Our study confirmed that PICCs are strongly associated with DVT in upper limbs,” Dr Chopra said. “However, what is novel and noteworthy in this study is that the presence of a PICC was also associated with an increased risk of lower-extremity DVT. Prior studies had not assessed whether PICCs are independently associated with an increase in the risk of subsequent lower-extremity DVT.”
Dr Chopra and his colleagues analyzed data from 76,242 patients hospitalized at 48 Michigan hospitals.
The team reviewed PICC placement, existing medical conditions, risk factors for venous thromboembolism (VTE), and thrombotic events occurring within 90 days of hospital admission.
A total of 3790 patients received a PICC during hospitalization. And there were 876 VTEs, including 208 upper-extremity DVTs, 372 lower-extremity DVTs, and 296 PEs.
After adjusting for risk factors other than PICC use, the researchers found that PICCs were independently associated with all-cause VTE, upper-extremity DVT, and lower-extremity DVT, but not PE. The hazard ratios were 3.16, 10.49, 1.48, and 1.34, respectively.
The team also found that VTE prophylaxis did not reduce the risk of DVT.
“Taken together, these findings suggest that the thrombotic burden associated with peripherally inserted central catheters may not be restricted to the extremity where the device resides or easily attenuated after insertion,” Dr Chopra said.
He and his colleagues therefore concluded that clinicians should weigh the risks and benefits of PICC use and consider using alternative devices in patients at high risk of DVT. And clinicians should not focus only on the extremity where a PICC resides but the composite risk of VTE among patients who receive a PICC.
FDA approves new formulation of pain patch for cancer patients
receiving treatment
Photo by Rhoda Baer
The US Food and Drug Administration (FDA) has approved a new formulation of fentanyl buccal soluble film CII (Onsolis), a patch used to manage breakthrough pain in adult cancer patients who are opioid-tolerant.
This decision allows BioDelivery Sciences International, Inc. (BDSI), the company developing Onsolis, to bring the product back to the US marketplace.
However, the company said this will not happen before 2016.
Onsolis is an opioid agonist indicated for the management of breakthrough pain in cancer patients 18 years of age and older who are already receiving and are tolerant to opioid therapy for their underlying persistent cancer pain.
Onsolis utilizes BioErodible MucoAdhesive drug delivery technology, which consists of a small, bioerodible polymer film that is applied to the inner lining of the cheek. Onsolis is the only differentiated fentanyl-containing product for this indication that provides buccal administration.
Onsolis off the US market
Onsolis was originally approved by the FDA in July 2009, but BDSI stopped manufacturing the product in March 2012, after the FDA uncovered 2 issues with Onsolis.
The FDA found that, during Onsolis’s 24-month shelf-life, microscopic crystals formed on the product, and the color faded slightly. BDSI said these changes did not affect the product’s underlying integrity or safety, but the FDA thought the fading color in particular might cause patients to question the product’s efficacy.
So the FDA required that Onsolis be modified before additional product could be manufactured and distributed. Supplies of Onsolis that were already on the market remained on the market.
An analysis by BDSI showed that the changes in Onsolis were related to an excipient used in the manufacturing process that could be removed to resolve the problem.
The excipient was specific to the manufacture of Onsolis in the US. Therefore, it did not impact the launch of Breakyl, which is the brand name for Onsolis in the European Union.
Return to market
After BDSI reformulated Onsolis to prevent the aforementioned changes in the product’s appearance, the FDA approved the product’s return to market.
“We are pleased to have obtained FDA approval of our [supplemental new drug application] and to now be in a position to move toward returning Onsolis to the US marketplace,” said Mark A. Sirgo, PharmD, President and Chief Executive Officer of BDSI.
“Although we have options for Onsolis, including commercializing it on our own, our current plan is to determine the value we can secure in a partnership with a company that has access to the target physician audience. We have been engaged with a number of potential partners, and, with this approval, we can now proceed forward with those discussions in earnest. We will provide more definitive timing in the near future about the reintroduction, but this would not be prior to 2016.”
Once Onsolis does return to the market, it will only be available via the Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS) program. This is an FDA-required program designed to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors with the use of TIRF medicines.
Outpatients, healthcare professionals who prescribe to outpatients, pharmacies, and distributors must enroll in the program to receive Onsolis. Further information is available at www.TIRFREMSAccess.com.
receiving treatment
Photo by Rhoda Baer
The US Food and Drug Administration (FDA) has approved a new formulation of fentanyl buccal soluble film CII (Onsolis), a patch used to manage breakthrough pain in adult cancer patients who are opioid-tolerant.
This decision allows BioDelivery Sciences International, Inc. (BDSI), the company developing Onsolis, to bring the product back to the US marketplace.
However, the company said this will not happen before 2016.
Onsolis is an opioid agonist indicated for the management of breakthrough pain in cancer patients 18 years of age and older who are already receiving and are tolerant to opioid therapy for their underlying persistent cancer pain.
Onsolis utilizes BioErodible MucoAdhesive drug delivery technology, which consists of a small, bioerodible polymer film that is applied to the inner lining of the cheek. Onsolis is the only differentiated fentanyl-containing product for this indication that provides buccal administration.
Onsolis off the US market
Onsolis was originally approved by the FDA in July 2009, but BDSI stopped manufacturing the product in March 2012, after the FDA uncovered 2 issues with Onsolis.
The FDA found that, during Onsolis’s 24-month shelf-life, microscopic crystals formed on the product, and the color faded slightly. BDSI said these changes did not affect the product’s underlying integrity or safety, but the FDA thought the fading color in particular might cause patients to question the product’s efficacy.
So the FDA required that Onsolis be modified before additional product could be manufactured and distributed. Supplies of Onsolis that were already on the market remained on the market.
An analysis by BDSI showed that the changes in Onsolis were related to an excipient used in the manufacturing process that could be removed to resolve the problem.
The excipient was specific to the manufacture of Onsolis in the US. Therefore, it did not impact the launch of Breakyl, which is the brand name for Onsolis in the European Union.
Return to market
After BDSI reformulated Onsolis to prevent the aforementioned changes in the product’s appearance, the FDA approved the product’s return to market.
“We are pleased to have obtained FDA approval of our [supplemental new drug application] and to now be in a position to move toward returning Onsolis to the US marketplace,” said Mark A. Sirgo, PharmD, President and Chief Executive Officer of BDSI.
“Although we have options for Onsolis, including commercializing it on our own, our current plan is to determine the value we can secure in a partnership with a company that has access to the target physician audience. We have been engaged with a number of potential partners, and, with this approval, we can now proceed forward with those discussions in earnest. We will provide more definitive timing in the near future about the reintroduction, but this would not be prior to 2016.”
Once Onsolis does return to the market, it will only be available via the Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS) program. This is an FDA-required program designed to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors with the use of TIRF medicines.
Outpatients, healthcare professionals who prescribe to outpatients, pharmacies, and distributors must enroll in the program to receive Onsolis. Further information is available at www.TIRFREMSAccess.com.
receiving treatment
Photo by Rhoda Baer
The US Food and Drug Administration (FDA) has approved a new formulation of fentanyl buccal soluble film CII (Onsolis), a patch used to manage breakthrough pain in adult cancer patients who are opioid-tolerant.
This decision allows BioDelivery Sciences International, Inc. (BDSI), the company developing Onsolis, to bring the product back to the US marketplace.
However, the company said this will not happen before 2016.
Onsolis is an opioid agonist indicated for the management of breakthrough pain in cancer patients 18 years of age and older who are already receiving and are tolerant to opioid therapy for their underlying persistent cancer pain.
Onsolis utilizes BioErodible MucoAdhesive drug delivery technology, which consists of a small, bioerodible polymer film that is applied to the inner lining of the cheek. Onsolis is the only differentiated fentanyl-containing product for this indication that provides buccal administration.
Onsolis off the US market
Onsolis was originally approved by the FDA in July 2009, but BDSI stopped manufacturing the product in March 2012, after the FDA uncovered 2 issues with Onsolis.
The FDA found that, during Onsolis’s 24-month shelf-life, microscopic crystals formed on the product, and the color faded slightly. BDSI said these changes did not affect the product’s underlying integrity or safety, but the FDA thought the fading color in particular might cause patients to question the product’s efficacy.
So the FDA required that Onsolis be modified before additional product could be manufactured and distributed. Supplies of Onsolis that were already on the market remained on the market.
An analysis by BDSI showed that the changes in Onsolis were related to an excipient used in the manufacturing process that could be removed to resolve the problem.
The excipient was specific to the manufacture of Onsolis in the US. Therefore, it did not impact the launch of Breakyl, which is the brand name for Onsolis in the European Union.
Return to market
After BDSI reformulated Onsolis to prevent the aforementioned changes in the product’s appearance, the FDA approved the product’s return to market.
“We are pleased to have obtained FDA approval of our [supplemental new drug application] and to now be in a position to move toward returning Onsolis to the US marketplace,” said Mark A. Sirgo, PharmD, President and Chief Executive Officer of BDSI.
“Although we have options for Onsolis, including commercializing it on our own, our current plan is to determine the value we can secure in a partnership with a company that has access to the target physician audience. We have been engaged with a number of potential partners, and, with this approval, we can now proceed forward with those discussions in earnest. We will provide more definitive timing in the near future about the reintroduction, but this would not be prior to 2016.”
Once Onsolis does return to the market, it will only be available via the Transmucosal Immediate Release Fentanyl (TIRF) Risk Evaluation and Mitigation Strategy (REMS) program. This is an FDA-required program designed to mitigate the risk of misuse, abuse, addiction, overdose, and serious complications due to medication errors with the use of TIRF medicines.
Outpatients, healthcare professionals who prescribe to outpatients, pharmacies, and distributors must enroll in the program to receive Onsolis. Further information is available at www.TIRFREMSAccess.com.
Hemophilia A product performs well in 3 trials
DALLAS—Results of 3 studies suggest the full-length recombinant factor VIII product BAY 81-8973 can be safe and effective in children, adolescents, and adults with severe hemophilia A.
Patients who received BAY 81-8973 as routine prophylaxis had low annualized bleeding rates (ABRs)—significantly lower than patients who received on-demand treatment.
None of the patients developed inhibitors, and no adverse event occurred in more than 10% of patients.
These results were presented in posters at the National Hemophilia Foundation’s 67th Annual Meeting. All 3 trials were sponsored by Bayer Healthcare AG, the company developing BAY 81-8973.
LEOPOLD trials
The 3 trials are part of the LEOPOLD Clinical Development Program, which was designed to evaluate BAY 81-8973 in patients with severe hemophilia A.
The first trial, LEOPOLD I, included male patients ages 12 to 65 who had at least 150 previous exposure days with a factor VIII product. For this study, they received BAY 81-8973 at 20-50 IU/kg 2 or 3 times a week (according to investigator decision) for 12 months.
The second trial, LEOPOLD II, also enrolled previously treated (≥ 150 previous exposure days) male subjects ages 12 to 65. The subjects were randomized to receive BAY 81-8973 as a low-dose prophylaxis regimen (20-30 IU/kg) twice a week, high-dose prophylaxis (30-40 IU/kg) 3 times a week, or on-demand.
In the third trial, LEOPOLD Kids, researchers evaluated BAY 81-8973 in previously treated children ages 12 and younger. Patients received BAY 81-8973 at 20-50 IU/kg twice a week, 3 times a week, or every other day (according to investigator decision) for at least 50 exposure days.
Another part of LEOPOLD KIDS, in which researchers are evaluating BAY 81-8973 in previously untreated children, is ongoing.
Efficacy results
The ABR was the primary efficacy endpoint in LEOPOLD I and II. In LEOPOLD KIDS, the primary efficacy endpoint was the ABR for total bleeds occurring within 48 hours of previous prophylaxis treatment, but the researchers also analyzed the ABR independent of the time of injection.
For all 3 trials, 193 patients were evaluable for efficacy. One hundred and forty patients received BAY 81-8973 for 12 months or more. The median exposure days were 155 for LEOPOLD I and 153 for LEOPOLD II.
In LEOPOLD I (n=62), the median ABR was 1.0 for all patients who received prophylaxis, 1.0 for patients who received twice-weekly prophylaxis, and 2.0 for patients who received thrice-weekly prophylaxis.
Sixteen patients did not experience any bleeds while on study—6 patients on the twice-weekly prophylaxis regimen and 10 on the thrice-weekly prophylaxis regimen.
LEOPOLD II included 28 patients who received twice-weekly prophylaxis, 31 who received thrice-weekly prophylaxis, and 21 who received on-demand treatment.
The median ABR was significantly lower in patients who received either prophylactic regimen than those who received on-demand treatment—2.0 and 60.0, respectively (P<0.0001). The median ABR was 4.0 for patients who received twice-weekly prophylaxis and 2.0 for patients who received thrice-weekly prophylaxis.
Again, 16 patients who received prophylaxis did not have any bleeds during the study period. This included 8 patients on the twice-weekly prophylaxis regimen and 8 on the thrice-weekly prophylaxis regimen.
In LEOPOLD KIDS (n=51), the median ABR within 48 hours of prophylactic injection was 0, and the median ABR independent of the time of injection was 1.9.
Twenty-three patients did not have any bleeds during the 6-month treatment period—10 children younger than 6 and 13 children ages 6 to 12.
Safety results
For all 3 trials, 193 patients were evaluable for safety. Adverse reactions were defined as treatment-emergent adverse events with
at least a reasonable suspected causal relationship to BAY 81-8973.
The researchers said the frequency, type, and severity of adverse reactions in children were similar to those observed in adults and adolescents.
The adverse reactions included headache (7.3%), pyrexia (4.1%), pruritus (3.1%), injection site reactions (2.6%), insomnia (2.6%), rash (2.6%), abdominal pain (2.1%), dyspepsia (2.1%), abdominal discomfort (1.6%), lymphadenopathy (1%), dizziness (1%), allergic dermatitis (1%), heart palpitations (1%), sinus tachycardia (1%), chest discomfort (1%), hypersensitivity (0.5%), dysgeusia (0.5%), urticaria (0.5%), and flushing (0.5%).
None of the patients developed factor VIII inhibitors.
DALLAS—Results of 3 studies suggest the full-length recombinant factor VIII product BAY 81-8973 can be safe and effective in children, adolescents, and adults with severe hemophilia A.
Patients who received BAY 81-8973 as routine prophylaxis had low annualized bleeding rates (ABRs)—significantly lower than patients who received on-demand treatment.
None of the patients developed inhibitors, and no adverse event occurred in more than 10% of patients.
These results were presented in posters at the National Hemophilia Foundation’s 67th Annual Meeting. All 3 trials were sponsored by Bayer Healthcare AG, the company developing BAY 81-8973.
LEOPOLD trials
The 3 trials are part of the LEOPOLD Clinical Development Program, which was designed to evaluate BAY 81-8973 in patients with severe hemophilia A.
The first trial, LEOPOLD I, included male patients ages 12 to 65 who had at least 150 previous exposure days with a factor VIII product. For this study, they received BAY 81-8973 at 20-50 IU/kg 2 or 3 times a week (according to investigator decision) for 12 months.
The second trial, LEOPOLD II, also enrolled previously treated (≥ 150 previous exposure days) male subjects ages 12 to 65. The subjects were randomized to receive BAY 81-8973 as a low-dose prophylaxis regimen (20-30 IU/kg) twice a week, high-dose prophylaxis (30-40 IU/kg) 3 times a week, or on-demand.
In the third trial, LEOPOLD Kids, researchers evaluated BAY 81-8973 in previously treated children ages 12 and younger. Patients received BAY 81-8973 at 20-50 IU/kg twice a week, 3 times a week, or every other day (according to investigator decision) for at least 50 exposure days.
Another part of LEOPOLD KIDS, in which researchers are evaluating BAY 81-8973 in previously untreated children, is ongoing.
Efficacy results
The ABR was the primary efficacy endpoint in LEOPOLD I and II. In LEOPOLD KIDS, the primary efficacy endpoint was the ABR for total bleeds occurring within 48 hours of previous prophylaxis treatment, but the researchers also analyzed the ABR independent of the time of injection.
For all 3 trials, 193 patients were evaluable for efficacy. One hundred and forty patients received BAY 81-8973 for 12 months or more. The median exposure days were 155 for LEOPOLD I and 153 for LEOPOLD II.
In LEOPOLD I (n=62), the median ABR was 1.0 for all patients who received prophylaxis, 1.0 for patients who received twice-weekly prophylaxis, and 2.0 for patients who received thrice-weekly prophylaxis.
Sixteen patients did not experience any bleeds while on study—6 patients on the twice-weekly prophylaxis regimen and 10 on the thrice-weekly prophylaxis regimen.
LEOPOLD II included 28 patients who received twice-weekly prophylaxis, 31 who received thrice-weekly prophylaxis, and 21 who received on-demand treatment.
The median ABR was significantly lower in patients who received either prophylactic regimen than those who received on-demand treatment—2.0 and 60.0, respectively (P<0.0001). The median ABR was 4.0 for patients who received twice-weekly prophylaxis and 2.0 for patients who received thrice-weekly prophylaxis.
Again, 16 patients who received prophylaxis did not have any bleeds during the study period. This included 8 patients on the twice-weekly prophylaxis regimen and 8 on the thrice-weekly prophylaxis regimen.
In LEOPOLD KIDS (n=51), the median ABR within 48 hours of prophylactic injection was 0, and the median ABR independent of the time of injection was 1.9.
Twenty-three patients did not have any bleeds during the 6-month treatment period—10 children younger than 6 and 13 children ages 6 to 12.
Safety results
For all 3 trials, 193 patients were evaluable for safety. Adverse reactions were defined as treatment-emergent adverse events with
at least a reasonable suspected causal relationship to BAY 81-8973.
The researchers said the frequency, type, and severity of adverse reactions in children were similar to those observed in adults and adolescents.
The adverse reactions included headache (7.3%), pyrexia (4.1%), pruritus (3.1%), injection site reactions (2.6%), insomnia (2.6%), rash (2.6%), abdominal pain (2.1%), dyspepsia (2.1%), abdominal discomfort (1.6%), lymphadenopathy (1%), dizziness (1%), allergic dermatitis (1%), heart palpitations (1%), sinus tachycardia (1%), chest discomfort (1%), hypersensitivity (0.5%), dysgeusia (0.5%), urticaria (0.5%), and flushing (0.5%).
None of the patients developed factor VIII inhibitors.
DALLAS—Results of 3 studies suggest the full-length recombinant factor VIII product BAY 81-8973 can be safe and effective in children, adolescents, and adults with severe hemophilia A.
Patients who received BAY 81-8973 as routine prophylaxis had low annualized bleeding rates (ABRs)—significantly lower than patients who received on-demand treatment.
None of the patients developed inhibitors, and no adverse event occurred in more than 10% of patients.
These results were presented in posters at the National Hemophilia Foundation’s 67th Annual Meeting. All 3 trials were sponsored by Bayer Healthcare AG, the company developing BAY 81-8973.
LEOPOLD trials
The 3 trials are part of the LEOPOLD Clinical Development Program, which was designed to evaluate BAY 81-8973 in patients with severe hemophilia A.
The first trial, LEOPOLD I, included male patients ages 12 to 65 who had at least 150 previous exposure days with a factor VIII product. For this study, they received BAY 81-8973 at 20-50 IU/kg 2 or 3 times a week (according to investigator decision) for 12 months.
The second trial, LEOPOLD II, also enrolled previously treated (≥ 150 previous exposure days) male subjects ages 12 to 65. The subjects were randomized to receive BAY 81-8973 as a low-dose prophylaxis regimen (20-30 IU/kg) twice a week, high-dose prophylaxis (30-40 IU/kg) 3 times a week, or on-demand.
In the third trial, LEOPOLD Kids, researchers evaluated BAY 81-8973 in previously treated children ages 12 and younger. Patients received BAY 81-8973 at 20-50 IU/kg twice a week, 3 times a week, or every other day (according to investigator decision) for at least 50 exposure days.
Another part of LEOPOLD KIDS, in which researchers are evaluating BAY 81-8973 in previously untreated children, is ongoing.
Efficacy results
The ABR was the primary efficacy endpoint in LEOPOLD I and II. In LEOPOLD KIDS, the primary efficacy endpoint was the ABR for total bleeds occurring within 48 hours of previous prophylaxis treatment, but the researchers also analyzed the ABR independent of the time of injection.
For all 3 trials, 193 patients were evaluable for efficacy. One hundred and forty patients received BAY 81-8973 for 12 months or more. The median exposure days were 155 for LEOPOLD I and 153 for LEOPOLD II.
In LEOPOLD I (n=62), the median ABR was 1.0 for all patients who received prophylaxis, 1.0 for patients who received twice-weekly prophylaxis, and 2.0 for patients who received thrice-weekly prophylaxis.
Sixteen patients did not experience any bleeds while on study—6 patients on the twice-weekly prophylaxis regimen and 10 on the thrice-weekly prophylaxis regimen.
LEOPOLD II included 28 patients who received twice-weekly prophylaxis, 31 who received thrice-weekly prophylaxis, and 21 who received on-demand treatment.
The median ABR was significantly lower in patients who received either prophylactic regimen than those who received on-demand treatment—2.0 and 60.0, respectively (P<0.0001). The median ABR was 4.0 for patients who received twice-weekly prophylaxis and 2.0 for patients who received thrice-weekly prophylaxis.
Again, 16 patients who received prophylaxis did not have any bleeds during the study period. This included 8 patients on the twice-weekly prophylaxis regimen and 8 on the thrice-weekly prophylaxis regimen.
In LEOPOLD KIDS (n=51), the median ABR within 48 hours of prophylactic injection was 0, and the median ABR independent of the time of injection was 1.9.
Twenty-three patients did not have any bleeds during the 6-month treatment period—10 children younger than 6 and 13 children ages 6 to 12.
Safety results
For all 3 trials, 193 patients were evaluable for safety. Adverse reactions were defined as treatment-emergent adverse events with
at least a reasonable suspected causal relationship to BAY 81-8973.
The researchers said the frequency, type, and severity of adverse reactions in children were similar to those observed in adults and adolescents.
The adverse reactions included headache (7.3%), pyrexia (4.1%), pruritus (3.1%), injection site reactions (2.6%), insomnia (2.6%), rash (2.6%), abdominal pain (2.1%), dyspepsia (2.1%), abdominal discomfort (1.6%), lymphadenopathy (1%), dizziness (1%), allergic dermatitis (1%), heart palpitations (1%), sinus tachycardia (1%), chest discomfort (1%), hypersensitivity (0.5%), dysgeusia (0.5%), urticaria (0.5%), and flushing (0.5%).
None of the patients developed factor VIII inhibitors.
FDA expands indication for VWD drug
Photo by Piotr Bodzek
The US Food and Drug Administration (FDA) has expanded the approved indication for a human von Willebrand factor/coagulation factor VIII complex (Wilate) to include prevention of excessive bleeding during and after minor and major surgery in adult and pediatric patients with von Willebrand disease (VWD).
The product was previously approved for the treatment of spontaneous and trauma-induced bleeding episodes in patients with severe VWD, as well as patients with mild or moderate VWD in whom the use of desmopressin is known or suspected to be ineffective or contraindicated.
About Wilate
Wilate is a plasma-derived, highly purified concentrate of freeze-dried human von Willebrand factor and coagulation factor VIII. Two virus-inactivation steps are incorporated into the manufacturing process of the product: a solvent/detergent and terminal dry-heat treatment.
Investigators evaluated Wilate’s safety and efficacy in surgical procedures in a single-arm, phase 3 study known as WONDERS. The investigators enrolled 41 patients, 30 of whom completed the trial.
The patients had type 1, type 2 or type 3 VWD. They had a median age of 39.7, and most were female. All patients underwent surgery—21 major and 9 minor surgeries.
The hemostatic efficacy of Wilate was assessed intra-operatively by the surgeon and post-operatively by investigators. The overall hemostatic efficacy—success or failure—of Wilate was based on both assessments, using a 4-point ordinal efficacy scale.
In the 29 evaluable surgeries, the success rate was 96.7%. Wilate was successful in 100% of minor surgeries (n=9) and 95.2% of major surgeries (n=20).
There were 2 serious adverse events—erosive gastritis and vaginal hemorrhage. Nonserious events included nausea (7 cases in 6 patients), vomiting (n=6), pain (n=4), pyrexia (n=4), procedural pain (10 cases in 8 patients), decrease in hemoglobin (6 cases in 4 patients), and hypertension (n=4).
Wilate is under development by Octapharma. For more information on the product, visit www.WILATEusa.com.
Photo by Piotr Bodzek
The US Food and Drug Administration (FDA) has expanded the approved indication for a human von Willebrand factor/coagulation factor VIII complex (Wilate) to include prevention of excessive bleeding during and after minor and major surgery in adult and pediatric patients with von Willebrand disease (VWD).
The product was previously approved for the treatment of spontaneous and trauma-induced bleeding episodes in patients with severe VWD, as well as patients with mild or moderate VWD in whom the use of desmopressin is known or suspected to be ineffective or contraindicated.
About Wilate
Wilate is a plasma-derived, highly purified concentrate of freeze-dried human von Willebrand factor and coagulation factor VIII. Two virus-inactivation steps are incorporated into the manufacturing process of the product: a solvent/detergent and terminal dry-heat treatment.
Investigators evaluated Wilate’s safety and efficacy in surgical procedures in a single-arm, phase 3 study known as WONDERS. The investigators enrolled 41 patients, 30 of whom completed the trial.
The patients had type 1, type 2 or type 3 VWD. They had a median age of 39.7, and most were female. All patients underwent surgery—21 major and 9 minor surgeries.
The hemostatic efficacy of Wilate was assessed intra-operatively by the surgeon and post-operatively by investigators. The overall hemostatic efficacy—success or failure—of Wilate was based on both assessments, using a 4-point ordinal efficacy scale.
In the 29 evaluable surgeries, the success rate was 96.7%. Wilate was successful in 100% of minor surgeries (n=9) and 95.2% of major surgeries (n=20).
There were 2 serious adverse events—erosive gastritis and vaginal hemorrhage. Nonserious events included nausea (7 cases in 6 patients), vomiting (n=6), pain (n=4), pyrexia (n=4), procedural pain (10 cases in 8 patients), decrease in hemoglobin (6 cases in 4 patients), and hypertension (n=4).
Wilate is under development by Octapharma. For more information on the product, visit www.WILATEusa.com.
Photo by Piotr Bodzek
The US Food and Drug Administration (FDA) has expanded the approved indication for a human von Willebrand factor/coagulation factor VIII complex (Wilate) to include prevention of excessive bleeding during and after minor and major surgery in adult and pediatric patients with von Willebrand disease (VWD).
The product was previously approved for the treatment of spontaneous and trauma-induced bleeding episodes in patients with severe VWD, as well as patients with mild or moderate VWD in whom the use of desmopressin is known or suspected to be ineffective or contraindicated.
About Wilate
Wilate is a plasma-derived, highly purified concentrate of freeze-dried human von Willebrand factor and coagulation factor VIII. Two virus-inactivation steps are incorporated into the manufacturing process of the product: a solvent/detergent and terminal dry-heat treatment.
Investigators evaluated Wilate’s safety and efficacy in surgical procedures in a single-arm, phase 3 study known as WONDERS. The investigators enrolled 41 patients, 30 of whom completed the trial.
The patients had type 1, type 2 or type 3 VWD. They had a median age of 39.7, and most were female. All patients underwent surgery—21 major and 9 minor surgeries.
The hemostatic efficacy of Wilate was assessed intra-operatively by the surgeon and post-operatively by investigators. The overall hemostatic efficacy—success or failure—of Wilate was based on both assessments, using a 4-point ordinal efficacy scale.
In the 29 evaluable surgeries, the success rate was 96.7%. Wilate was successful in 100% of minor surgeries (n=9) and 95.2% of major surgeries (n=20).
There were 2 serious adverse events—erosive gastritis and vaginal hemorrhage. Nonserious events included nausea (7 cases in 6 patients), vomiting (n=6), pain (n=4), pyrexia (n=4), procedural pain (10 cases in 8 patients), decrease in hemoglobin (6 cases in 4 patients), and hypertension (n=4).
Wilate is under development by Octapharma. For more information on the product, visit www.WILATEusa.com.
Warfarin associated with real-world benefits in AF
Routine use of warfarin is associated with clinical benefits in ischemic stroke patients with atrial fibrillation (AF), according to research published in BMJ.
When compared to patients who did not receive anticoagulant therapy, patients who received warfarin at hospital discharge had a lower incidence of major adverse cardiovascular events (MACE), less time spent in an institutional care facility, and a lower risk of all-cause mortality.
Warfarin seemed particularly beneficial for patients older than 80 years of age, women, and patients with more severe strokes.
Ying Xian, MD, PhD, of the Duke Clinical Research Institute in Durham, North Carolina, and his colleagues conducted this research, analyzing the association between warfarin treatment and longitudinal outcomes after ischemic stroke among AF patients.
The researchers evaluated 12,552 warfarin-naive AF patients who were admitted to 1487 hospitals across the US and were discharged between 2009 and 2011. Each patient had at least 1 year of follow-up after discharge.
In all, 11,039 (87.9%) were treated with warfarin at discharge. These patients were slightly younger and less likely to have a history of previous stroke or coronary artery disease than patients who did not receive warfarin.
Unadjusted results
At 2 years of follow-up, the incidence of MACE was significantly lower in patients treated with warfarin than in untreated patients—54.7% and 66.8%, respectively (P<0.001).
In addition, on average, patients who received warfarin had 86 more days alive and out of institutional care in the 2-year follow-up period than patients who did not receive warfarin (P<0.001).
The incidence of readmission due to ischemic stroke was significantly lower among warfarin-treated patients than untreated patients—7.9% and 11.8%, respectively (P<0.001)—but there was no significant difference in readmission due to hemorrhagic stroke—1.4% and 1.1%, respectively (P=0.50).
The incidence of all-cause mortality was significantly lower among warfarin-treated patients—32.4% and 50%, respectively (P<0.001).
Adjusted results
In adjusted analysis (weighting by the inverse probability of treatment and control for other discharge drugs), patients treated with warfarin at discharge had a significantly lower risk of MACE over 2 years. The adjusted hazard ratio (aHR) was 0.87.
Warfarin-treated patients were also more likely to spend more days alive and out of institutional care. The adjusted home-time difference was 47.6 days.
Patients on warfarin had a lower risk of all-cause mortality (aHR=0.72) and ischemic stroke readmission (aHR=0.63), but there was no significant difference between treated and untreated patients with regard to hemorrhagic stroke readmission (aHR=1.37).
The researchers said the benefits associated with warfarin were consistent across clinically relevant groups by age, sex, stroke severity, and history of stroke and coronary artery disease.
Patients aged 80 and older, women, and those with more severe stroke seemed to enjoy greater benefits from warfarin treatment, even though these groups were less likely to receive warfarin.
The researchers speculated that this might result from clinicians’ misperception of warfarin’s risks and benefits for these patient groups.
Routine use of warfarin is associated with clinical benefits in ischemic stroke patients with atrial fibrillation (AF), according to research published in BMJ.
When compared to patients who did not receive anticoagulant therapy, patients who received warfarin at hospital discharge had a lower incidence of major adverse cardiovascular events (MACE), less time spent in an institutional care facility, and a lower risk of all-cause mortality.
Warfarin seemed particularly beneficial for patients older than 80 years of age, women, and patients with more severe strokes.
Ying Xian, MD, PhD, of the Duke Clinical Research Institute in Durham, North Carolina, and his colleagues conducted this research, analyzing the association between warfarin treatment and longitudinal outcomes after ischemic stroke among AF patients.
The researchers evaluated 12,552 warfarin-naive AF patients who were admitted to 1487 hospitals across the US and were discharged between 2009 and 2011. Each patient had at least 1 year of follow-up after discharge.
In all, 11,039 (87.9%) were treated with warfarin at discharge. These patients were slightly younger and less likely to have a history of previous stroke or coronary artery disease than patients who did not receive warfarin.
Unadjusted results
At 2 years of follow-up, the incidence of MACE was significantly lower in patients treated with warfarin than in untreated patients—54.7% and 66.8%, respectively (P<0.001).
In addition, on average, patients who received warfarin had 86 more days alive and out of institutional care in the 2-year follow-up period than patients who did not receive warfarin (P<0.001).
The incidence of readmission due to ischemic stroke was significantly lower among warfarin-treated patients than untreated patients—7.9% and 11.8%, respectively (P<0.001)—but there was no significant difference in readmission due to hemorrhagic stroke—1.4% and 1.1%, respectively (P=0.50).
The incidence of all-cause mortality was significantly lower among warfarin-treated patients—32.4% and 50%, respectively (P<0.001).
Adjusted results
In adjusted analysis (weighting by the inverse probability of treatment and control for other discharge drugs), patients treated with warfarin at discharge had a significantly lower risk of MACE over 2 years. The adjusted hazard ratio (aHR) was 0.87.
Warfarin-treated patients were also more likely to spend more days alive and out of institutional care. The adjusted home-time difference was 47.6 days.
Patients on warfarin had a lower risk of all-cause mortality (aHR=0.72) and ischemic stroke readmission (aHR=0.63), but there was no significant difference between treated and untreated patients with regard to hemorrhagic stroke readmission (aHR=1.37).
The researchers said the benefits associated with warfarin were consistent across clinically relevant groups by age, sex, stroke severity, and history of stroke and coronary artery disease.
Patients aged 80 and older, women, and those with more severe stroke seemed to enjoy greater benefits from warfarin treatment, even though these groups were less likely to receive warfarin.
The researchers speculated that this might result from clinicians’ misperception of warfarin’s risks and benefits for these patient groups.
Routine use of warfarin is associated with clinical benefits in ischemic stroke patients with atrial fibrillation (AF), according to research published in BMJ.
When compared to patients who did not receive anticoagulant therapy, patients who received warfarin at hospital discharge had a lower incidence of major adverse cardiovascular events (MACE), less time spent in an institutional care facility, and a lower risk of all-cause mortality.
Warfarin seemed particularly beneficial for patients older than 80 years of age, women, and patients with more severe strokes.
Ying Xian, MD, PhD, of the Duke Clinical Research Institute in Durham, North Carolina, and his colleagues conducted this research, analyzing the association between warfarin treatment and longitudinal outcomes after ischemic stroke among AF patients.
The researchers evaluated 12,552 warfarin-naive AF patients who were admitted to 1487 hospitals across the US and were discharged between 2009 and 2011. Each patient had at least 1 year of follow-up after discharge.
In all, 11,039 (87.9%) were treated with warfarin at discharge. These patients were slightly younger and less likely to have a history of previous stroke or coronary artery disease than patients who did not receive warfarin.
Unadjusted results
At 2 years of follow-up, the incidence of MACE was significantly lower in patients treated with warfarin than in untreated patients—54.7% and 66.8%, respectively (P<0.001).
In addition, on average, patients who received warfarin had 86 more days alive and out of institutional care in the 2-year follow-up period than patients who did not receive warfarin (P<0.001).
The incidence of readmission due to ischemic stroke was significantly lower among warfarin-treated patients than untreated patients—7.9% and 11.8%, respectively (P<0.001)—but there was no significant difference in readmission due to hemorrhagic stroke—1.4% and 1.1%, respectively (P=0.50).
The incidence of all-cause mortality was significantly lower among warfarin-treated patients—32.4% and 50%, respectively (P<0.001).
Adjusted results
In adjusted analysis (weighting by the inverse probability of treatment and control for other discharge drugs), patients treated with warfarin at discharge had a significantly lower risk of MACE over 2 years. The adjusted hazard ratio (aHR) was 0.87.
Warfarin-treated patients were also more likely to spend more days alive and out of institutional care. The adjusted home-time difference was 47.6 days.
Patients on warfarin had a lower risk of all-cause mortality (aHR=0.72) and ischemic stroke readmission (aHR=0.63), but there was no significant difference between treated and untreated patients with regard to hemorrhagic stroke readmission (aHR=1.37).
The researchers said the benefits associated with warfarin were consistent across clinically relevant groups by age, sex, stroke severity, and history of stroke and coronary artery disease.
Patients aged 80 and older, women, and those with more severe stroke seemed to enjoy greater benefits from warfarin treatment, even though these groups were less likely to receive warfarin.
The researchers speculated that this might result from clinicians’ misperception of warfarin’s risks and benefits for these patient groups.
Team reports phase 3 results with abandoned MPN drug
Researchers have reported results of the phase 3 JAKARTA trial, in which they evaluated the selective JAK2 inhibitor fedratinib in patients with myelofibrosis (MF).
Fedratinib was being developed as a treatment for myeloproliferative neoplasms (MPNs), but Sanofi Oncology stopped clinical development of the drug in 2013, after it was linked to a neurological condition known as Wernicke encephalopathy.
There were 4 confirmed cases of Wernicke encephalopathy in the JAKARTA trial, in addition to other adverse events (AEs). However, fedratinib also lessened the severity of MF symptoms in about 35% to 40% of patients.
These results have been published in JAMA Oncology alongside an invited commentary. The study was sponsored by Sanofi.
Treatment and response
The study enrolled 289 adult patients with intermediate-2 or high-risk primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF. Patients were randomized to receive fedratinib at 400 mg once a day, fedratinib at 500 mg once a day, or placebo for at least 6 consecutive, 4-week cycles.
The study’s primary endpoint was spleen response, or a 35% or greater reduction in spleen volume from baseline (determined by MRI or CT) at week 24 and confirmed 4 weeks later.
Thirty-six percent (35/96) of patients in the 400 mg arm and 40% (39/97) in the 500 mg arm achieved the primary endpoint, compared to 1% (1/96) of patients in the placebo arm (P<0.001).
The main secondary endpoint was symptom response, or a 50% or greater reduction in total symptom score (assessed using the modified Myelofibrosis Symptom Assessment Form).
At week 24, symptom response rates were 36% (33/91) in the 400 mg arm, 34% (31/91) in the 500 mg arm, and 7% (6/85) in the placebo arm (P<0.001).
Safety data
Treatment-emergent AEs occurred in 100% of patients in the 400 mg arm, 98% in the 500 mg arm, and 94% in the placebo arm. Serious AEs occurred in 27%, 31%, and 23%, respectively. AEs leading to discontinuation occurred in 14%, 25%, and 8%, respectively.
Infections occurred in 42% of patients in the 400 mg arm, 39% of patients in the 500 mg arm, and 27% of patients of patients in the placebo arm.
Nonhematologic AEs occurring in at least 10% of patients in any group were diarrhea (66%, 56%, and 16%, respectively), vomiting (42%, 55%, and 5%, respectively), nausea (64%, 51%, and 15%, respectively), constipation (10%, 18%, and 7%, respectively), asthenia (9%, 16%, and 6%, respectively), abdominal pain (15%, 12%, and 16%, respectively), fatigue (16%, 10%, and 10%, respectively), dyspnea (8%, 10%, and 6%, respectively), and weight loss (4%, 10%, and 5%, respectively).
Hematologic AEs occurring in at least 10% of patients in any group were anemia (99%, 98%, and 91%, respectively), thrombocytopenia (63%, 57%, and 51%, respectively), lymphopenia (57%, 66%, and 54%, respectively), leukopenia (47%, 53%, and 19%, respectively), and neutropenia (28%, 44%, and 15%, respectively).
One patient in each fedratinib arm and 2 in the placebo arm transformed to acute myeloid leukemia.
There were 24 deaths during the first 24 weeks of the study—4 in the 400 mg arm, 10 in the 500 mg arm, and 10 in the placebo arm. Nine of the deaths were attributed to AEs—1, 4, and 4, respectively.
Wernicke encephalopathy
There were 4 cases of Wernicke encephalopathy, all in women who received fedratinib at 500 mg. All of these cases were confirmed by an independent expert safety panel, 3 on the basis of clinical features and MRI results, and 1 on the basis of clinical symptoms alone.
The patients developed symptoms 6 weeks to 44 weeks after beginning fedratinib treatment, and all discontinued treatment permanently.
Cognitive symptoms manifested in the context of persistent vomiting, malnutrition, and cachexia in 1 patient, vomiting and hyponatremia in 1 patient, and renal failure with mild hyponatremia in 1 patient.
All of the patients received intravenous thiamine and showed responses to the treatment, but all had persistent cognitive defects at last follow-up.
Researchers have reported results of the phase 3 JAKARTA trial, in which they evaluated the selective JAK2 inhibitor fedratinib in patients with myelofibrosis (MF).
Fedratinib was being developed as a treatment for myeloproliferative neoplasms (MPNs), but Sanofi Oncology stopped clinical development of the drug in 2013, after it was linked to a neurological condition known as Wernicke encephalopathy.
There were 4 confirmed cases of Wernicke encephalopathy in the JAKARTA trial, in addition to other adverse events (AEs). However, fedratinib also lessened the severity of MF symptoms in about 35% to 40% of patients.
These results have been published in JAMA Oncology alongside an invited commentary. The study was sponsored by Sanofi.
Treatment and response
The study enrolled 289 adult patients with intermediate-2 or high-risk primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF. Patients were randomized to receive fedratinib at 400 mg once a day, fedratinib at 500 mg once a day, or placebo for at least 6 consecutive, 4-week cycles.
The study’s primary endpoint was spleen response, or a 35% or greater reduction in spleen volume from baseline (determined by MRI or CT) at week 24 and confirmed 4 weeks later.
Thirty-six percent (35/96) of patients in the 400 mg arm and 40% (39/97) in the 500 mg arm achieved the primary endpoint, compared to 1% (1/96) of patients in the placebo arm (P<0.001).
The main secondary endpoint was symptom response, or a 50% or greater reduction in total symptom score (assessed using the modified Myelofibrosis Symptom Assessment Form).
At week 24, symptom response rates were 36% (33/91) in the 400 mg arm, 34% (31/91) in the 500 mg arm, and 7% (6/85) in the placebo arm (P<0.001).
Safety data
Treatment-emergent AEs occurred in 100% of patients in the 400 mg arm, 98% in the 500 mg arm, and 94% in the placebo arm. Serious AEs occurred in 27%, 31%, and 23%, respectively. AEs leading to discontinuation occurred in 14%, 25%, and 8%, respectively.
Infections occurred in 42% of patients in the 400 mg arm, 39% of patients in the 500 mg arm, and 27% of patients of patients in the placebo arm.
Nonhematologic AEs occurring in at least 10% of patients in any group were diarrhea (66%, 56%, and 16%, respectively), vomiting (42%, 55%, and 5%, respectively), nausea (64%, 51%, and 15%, respectively), constipation (10%, 18%, and 7%, respectively), asthenia (9%, 16%, and 6%, respectively), abdominal pain (15%, 12%, and 16%, respectively), fatigue (16%, 10%, and 10%, respectively), dyspnea (8%, 10%, and 6%, respectively), and weight loss (4%, 10%, and 5%, respectively).
Hematologic AEs occurring in at least 10% of patients in any group were anemia (99%, 98%, and 91%, respectively), thrombocytopenia (63%, 57%, and 51%, respectively), lymphopenia (57%, 66%, and 54%, respectively), leukopenia (47%, 53%, and 19%, respectively), and neutropenia (28%, 44%, and 15%, respectively).
One patient in each fedratinib arm and 2 in the placebo arm transformed to acute myeloid leukemia.
There were 24 deaths during the first 24 weeks of the study—4 in the 400 mg arm, 10 in the 500 mg arm, and 10 in the placebo arm. Nine of the deaths were attributed to AEs—1, 4, and 4, respectively.
Wernicke encephalopathy
There were 4 cases of Wernicke encephalopathy, all in women who received fedratinib at 500 mg. All of these cases were confirmed by an independent expert safety panel, 3 on the basis of clinical features and MRI results, and 1 on the basis of clinical symptoms alone.
The patients developed symptoms 6 weeks to 44 weeks after beginning fedratinib treatment, and all discontinued treatment permanently.
Cognitive symptoms manifested in the context of persistent vomiting, malnutrition, and cachexia in 1 patient, vomiting and hyponatremia in 1 patient, and renal failure with mild hyponatremia in 1 patient.
All of the patients received intravenous thiamine and showed responses to the treatment, but all had persistent cognitive defects at last follow-up.
Researchers have reported results of the phase 3 JAKARTA trial, in which they evaluated the selective JAK2 inhibitor fedratinib in patients with myelofibrosis (MF).
Fedratinib was being developed as a treatment for myeloproliferative neoplasms (MPNs), but Sanofi Oncology stopped clinical development of the drug in 2013, after it was linked to a neurological condition known as Wernicke encephalopathy.
There were 4 confirmed cases of Wernicke encephalopathy in the JAKARTA trial, in addition to other adverse events (AEs). However, fedratinib also lessened the severity of MF symptoms in about 35% to 40% of patients.
These results have been published in JAMA Oncology alongside an invited commentary. The study was sponsored by Sanofi.
Treatment and response
The study enrolled 289 adult patients with intermediate-2 or high-risk primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF. Patients were randomized to receive fedratinib at 400 mg once a day, fedratinib at 500 mg once a day, or placebo for at least 6 consecutive, 4-week cycles.
The study’s primary endpoint was spleen response, or a 35% or greater reduction in spleen volume from baseline (determined by MRI or CT) at week 24 and confirmed 4 weeks later.
Thirty-six percent (35/96) of patients in the 400 mg arm and 40% (39/97) in the 500 mg arm achieved the primary endpoint, compared to 1% (1/96) of patients in the placebo arm (P<0.001).
The main secondary endpoint was symptom response, or a 50% or greater reduction in total symptom score (assessed using the modified Myelofibrosis Symptom Assessment Form).
At week 24, symptom response rates were 36% (33/91) in the 400 mg arm, 34% (31/91) in the 500 mg arm, and 7% (6/85) in the placebo arm (P<0.001).
Safety data
Treatment-emergent AEs occurred in 100% of patients in the 400 mg arm, 98% in the 500 mg arm, and 94% in the placebo arm. Serious AEs occurred in 27%, 31%, and 23%, respectively. AEs leading to discontinuation occurred in 14%, 25%, and 8%, respectively.
Infections occurred in 42% of patients in the 400 mg arm, 39% of patients in the 500 mg arm, and 27% of patients of patients in the placebo arm.
Nonhematologic AEs occurring in at least 10% of patients in any group were diarrhea (66%, 56%, and 16%, respectively), vomiting (42%, 55%, and 5%, respectively), nausea (64%, 51%, and 15%, respectively), constipation (10%, 18%, and 7%, respectively), asthenia (9%, 16%, and 6%, respectively), abdominal pain (15%, 12%, and 16%, respectively), fatigue (16%, 10%, and 10%, respectively), dyspnea (8%, 10%, and 6%, respectively), and weight loss (4%, 10%, and 5%, respectively).
Hematologic AEs occurring in at least 10% of patients in any group were anemia (99%, 98%, and 91%, respectively), thrombocytopenia (63%, 57%, and 51%, respectively), lymphopenia (57%, 66%, and 54%, respectively), leukopenia (47%, 53%, and 19%, respectively), and neutropenia (28%, 44%, and 15%, respectively).
One patient in each fedratinib arm and 2 in the placebo arm transformed to acute myeloid leukemia.
There were 24 deaths during the first 24 weeks of the study—4 in the 400 mg arm, 10 in the 500 mg arm, and 10 in the placebo arm. Nine of the deaths were attributed to AEs—1, 4, and 4, respectively.
Wernicke encephalopathy
There were 4 cases of Wernicke encephalopathy, all in women who received fedratinib at 500 mg. All of these cases were confirmed by an independent expert safety panel, 3 on the basis of clinical features and MRI results, and 1 on the basis of clinical symptoms alone.
The patients developed symptoms 6 weeks to 44 weeks after beginning fedratinib treatment, and all discontinued treatment permanently.
Cognitive symptoms manifested in the context of persistent vomiting, malnutrition, and cachexia in 1 patient, vomiting and hyponatremia in 1 patient, and renal failure with mild hyponatremia in 1 patient.
All of the patients received intravenous thiamine and showed responses to the treatment, but all had persistent cognitive defects at last follow-up.