User login
Inflammation may predict transformation to AML
Inflammatory signaling in mesenchymal niche cells can be used to predict the transformation from pre-leukemic syndrome to acute myeloid leukemia (AML), according to preclinical research published in Cell Stem Cell.
“This discovery sheds new light on the long-standing association between inflammation and cancer,” said study author Marc Raaijmakers, MD, PhD, of the Erasmus MC Cancer Institute in Rotterdam, Netherlands.
“The elucidation of the molecular mechanism underlying this concept opens the prospect of improved diagnosis of patients at increased risk for the development of leukemia and the potential of future, niche-targeted therapy to delay or prevent the development of leukemia.”
In a previous study, Dr Raaijmakers and his colleagues discovered that mutations in mesenchymal progenitor cells can induce myelodysplasia in mice and promote the development of AML.
With the current study, the researchers wanted to build upon those findings by identifying the underlying mechanisms and determining their relevance to human disease.
So the team performed massive parallel RNA sequencing of mesenchymal cells in mice with Shwachman-Diamond syndrome and bone marrow samples from patients with Shwachman-Diamond syndrome, Diamond-Blackfan anemia, and myelodysplastic syndromes (MDS).
The researchers found that mesenchymal cells in these pre-leukemic disorders are under stress. The stress leads to the release of inflammatory molecules called S100A8 and S100A9, which cause mitochondrial and DNA damage in hematopoietic stem and progenitor cells.
The team also found that activation of this inflammatory pathway in mesenchymal cells predicted the development of AML and clinical outcomes in patients with MDS.
Leukemic evolution occurred in 29.4% (5/17) of MDS patients whose mesenchymal cells overexpressed S100A8/9 and 14.2% (4/28) of MDS patients without S100A8/9 overexpression.
The time to leukemic evolution and the length of progression-free survival were both significantly shorter in niche S100A8/9+ patients than niche S100A8/9- patients.
The average time to leukemic evolution was 3.4 months and 18.5 months, respectively (P=0.03). And the median progression-free survival was 11.5 months and 53 months, respectively (P=0.03)
The researchers believe these findings, if confirmed in subsequent studies, could lead to the development of tests to identify patients with pre-leukemic syndromes who have a high risk of developing AML.
“These high-risk patients could be treated more aggressively at an earlier stage, thereby preventing or slowing down disease progression,” Dr Raaijmakers said. “Moreover, the findings suggest that new drugs targeting the inflammatory pathway should be tested in future preclinical studies.” 
Inflammatory signaling in mesenchymal niche cells can be used to predict the transformation from pre-leukemic syndrome to acute myeloid leukemia (AML), according to preclinical research published in Cell Stem Cell.
“This discovery sheds new light on the long-standing association between inflammation and cancer,” said study author Marc Raaijmakers, MD, PhD, of the Erasmus MC Cancer Institute in Rotterdam, Netherlands.
“The elucidation of the molecular mechanism underlying this concept opens the prospect of improved diagnosis of patients at increased risk for the development of leukemia and the potential of future, niche-targeted therapy to delay or prevent the development of leukemia.”
In a previous study, Dr Raaijmakers and his colleagues discovered that mutations in mesenchymal progenitor cells can induce myelodysplasia in mice and promote the development of AML.
With the current study, the researchers wanted to build upon those findings by identifying the underlying mechanisms and determining their relevance to human disease.
So the team performed massive parallel RNA sequencing of mesenchymal cells in mice with Shwachman-Diamond syndrome and bone marrow samples from patients with Shwachman-Diamond syndrome, Diamond-Blackfan anemia, and myelodysplastic syndromes (MDS).
The researchers found that mesenchymal cells in these pre-leukemic disorders are under stress. The stress leads to the release of inflammatory molecules called S100A8 and S100A9, which cause mitochondrial and DNA damage in hematopoietic stem and progenitor cells.
The team also found that activation of this inflammatory pathway in mesenchymal cells predicted the development of AML and clinical outcomes in patients with MDS.
Leukemic evolution occurred in 29.4% (5/17) of MDS patients whose mesenchymal cells overexpressed S100A8/9 and 14.2% (4/28) of MDS patients without S100A8/9 overexpression.
The time to leukemic evolution and the length of progression-free survival were both significantly shorter in niche S100A8/9+ patients than niche S100A8/9- patients.
The average time to leukemic evolution was 3.4 months and 18.5 months, respectively (P=0.03). And the median progression-free survival was 11.5 months and 53 months, respectively (P=0.03)
The researchers believe these findings, if confirmed in subsequent studies, could lead to the development of tests to identify patients with pre-leukemic syndromes who have a high risk of developing AML.
“These high-risk patients could be treated more aggressively at an earlier stage, thereby preventing or slowing down disease progression,” Dr Raaijmakers said. “Moreover, the findings suggest that new drugs targeting the inflammatory pathway should be tested in future preclinical studies.”
Inflammatory signaling in mesenchymal niche cells can be used to predict the transformation from pre-leukemic syndrome to acute myeloid leukemia (AML), according to preclinical research published in Cell Stem Cell.
“This discovery sheds new light on the long-standing association between inflammation and cancer,” said study author Marc Raaijmakers, MD, PhD, of the Erasmus MC Cancer Institute in Rotterdam, Netherlands.
“The elucidation of the molecular mechanism underlying this concept opens the prospect of improved diagnosis of patients at increased risk for the development of leukemia and the potential of future, niche-targeted therapy to delay or prevent the development of leukemia.”
In a previous study, Dr Raaijmakers and his colleagues discovered that mutations in mesenchymal progenitor cells can induce myelodysplasia in mice and promote the development of AML.
With the current study, the researchers wanted to build upon those findings by identifying the underlying mechanisms and determining their relevance to human disease.
So the team performed massive parallel RNA sequencing of mesenchymal cells in mice with Shwachman-Diamond syndrome and bone marrow samples from patients with Shwachman-Diamond syndrome, Diamond-Blackfan anemia, and myelodysplastic syndromes (MDS).
The researchers found that mesenchymal cells in these pre-leukemic disorders are under stress. The stress leads to the release of inflammatory molecules called S100A8 and S100A9, which cause mitochondrial and DNA damage in hematopoietic stem and progenitor cells.
The team also found that activation of this inflammatory pathway in mesenchymal cells predicted the development of AML and clinical outcomes in patients with MDS.
Leukemic evolution occurred in 29.4% (5/17) of MDS patients whose mesenchymal cells overexpressed S100A8/9 and 14.2% (4/28) of MDS patients without S100A8/9 overexpression.
The time to leukemic evolution and the length of progression-free survival were both significantly shorter in niche S100A8/9+ patients than niche S100A8/9- patients.
The average time to leukemic evolution was 3.4 months and 18.5 months, respectively (P=0.03). And the median progression-free survival was 11.5 months and 53 months, respectively (P=0.03)
The researchers believe these findings, if confirmed in subsequent studies, could lead to the development of tests to identify patients with pre-leukemic syndromes who have a high risk of developing AML.
“These high-risk patients could be treated more aggressively at an earlier stage, thereby preventing or slowing down disease progression,” Dr Raaijmakers said. “Moreover, the findings suggest that new drugs targeting the inflammatory pathway should be tested in future preclinical studies.”
Medicare doesn’t lower TKI costs enough, study suggests
cut in half with a pill splitter
Photo by Patrick Pelletier
Significant out-of-pocket costs may delay treatment for Medicare beneficiaries with chronic myeloid leukemia (CML), according to a study published in the Journal of Clinical Oncology.
Researchers studied 393 patients with CML who had federally funded health insurance—specifically, a Medicare Part D plan.
Nearly a third of these patients did not start tyrosine kinase inhibitor (TKI) treatment within 6 months of their diagnosis.
However, patients who had access to subsidies that help cover treatment costs had a shorter median time to the start of therapy.
“There are 2 troubling findings here,” said study author Aaron Winn, a doctoral student at the University of North Carolina at Chapel Hill.
“First, we are seeing that more than 30% of people aren’t starting therapy within 6 months. Second, we are seeing long delays in starting drugs for people without subsidies. This is very concerning as these delays may be an indicator that the patient is trying to find funds to pay for their first treatment.”
Medicare Part D and TKIs
Previous studies have shown that patients insured through Medicare Part D have out of-pocket costs of nearly $3000 for the first month’s supply of a TKI.
According to researchers, the high upfront costs are due to the Medicare Part D benefit design, which requires patients to pay a larger share of medication costs until they have paid at least $4850 out-of-pocket in a year (cost in 2016). After that, patients pay 5% of the monthly drug costs.
In order to qualify for Medicare Part D’s low-income subsidy, an individual must have an annual income of less than $17,820 and assets of less than $13,640 (figures for 2016).
“Once you’re on Medicare Part D, there really aren’t ways to minimize these out-of-pocket costs, other than subsidies,” said Stacie Dusetzina, PhD, of the University of North Carolina at Chapel Hill.
“One of the challenges is that when the Medicare benefit was designed, I don’t think they were really considering these very expensive therapies. The benefit design makes a lot more sense when you’re looking at drugs that cost several hundred dollars versus several thousand dollars or more. We really need to think carefully about how much these high out-of-pocket costs are impacting patients’ access to life-saving drugs.”
Study results
For this study, Dr Dusetzina and her colleagues evaluated data on 393 patients who were diagnosed with CML between 2007 and 2011. The patients’ median age was 77, 47% were married, 48% were male, and 85% were white.
All of the patients were enrolled in Medicare Part D, and 40% qualified for subsidies to lower drug costs.
Of all the patients, there were 32% who had not started treatment with a first-line TKI (imatinib, nilotinib, or dasatinib) within 6 months of diagnosis.
However, having access to subsidies was associated with a shorter time to the start of treatment. The median time to the start of treatment was 58 days for patients with subsidies and 108 days for patients without them.
While the gap between the 2 groups widened after diagnosis, eventually, patients without subsidies did catch up, Dr Dusetzina said.
Ninety days from diagnosis, 48% of patients without subsidies had started treatment, compared to 63% of patients with subsidies. At 6 months from diagnosis, 64% of patients without subsidies had started treatment, compared to 65% of patients with subsidies.
Dr Dusetzina said patients without subsidies could be catching up as they find the financial resources to help cover those initial costs. But overall, patients with subsidies were 35% more likely to start TKI treatment faster.
“We recognize that people have a high cost to even start therapy, and this study really demonstrates the difference between people with and without a subsidy in initiating therapy,” Dr Dusetzina said. “The out-of-pocket costs may be delaying people starting these life-saving drugs.”
cut in half with a pill splitter
Photo by Patrick Pelletier
Significant out-of-pocket costs may delay treatment for Medicare beneficiaries with chronic myeloid leukemia (CML), according to a study published in the Journal of Clinical Oncology.
Researchers studied 393 patients with CML who had federally funded health insurance—specifically, a Medicare Part D plan.
Nearly a third of these patients did not start tyrosine kinase inhibitor (TKI) treatment within 6 months of their diagnosis.
However, patients who had access to subsidies that help cover treatment costs had a shorter median time to the start of therapy.
“There are 2 troubling findings here,” said study author Aaron Winn, a doctoral student at the University of North Carolina at Chapel Hill.
“First, we are seeing that more than 30% of people aren’t starting therapy within 6 months. Second, we are seeing long delays in starting drugs for people without subsidies. This is very concerning as these delays may be an indicator that the patient is trying to find funds to pay for their first treatment.”
Medicare Part D and TKIs
Previous studies have shown that patients insured through Medicare Part D have out of-pocket costs of nearly $3000 for the first month’s supply of a TKI.
According to researchers, the high upfront costs are due to the Medicare Part D benefit design, which requires patients to pay a larger share of medication costs until they have paid at least $4850 out-of-pocket in a year (cost in 2016). After that, patients pay 5% of the monthly drug costs.
In order to qualify for Medicare Part D’s low-income subsidy, an individual must have an annual income of less than $17,820 and assets of less than $13,640 (figures for 2016).
“Once you’re on Medicare Part D, there really aren’t ways to minimize these out-of-pocket costs, other than subsidies,” said Stacie Dusetzina, PhD, of the University of North Carolina at Chapel Hill.
“One of the challenges is that when the Medicare benefit was designed, I don’t think they were really considering these very expensive therapies. The benefit design makes a lot more sense when you’re looking at drugs that cost several hundred dollars versus several thousand dollars or more. We really need to think carefully about how much these high out-of-pocket costs are impacting patients’ access to life-saving drugs.”
Study results
For this study, Dr Dusetzina and her colleagues evaluated data on 393 patients who were diagnosed with CML between 2007 and 2011. The patients’ median age was 77, 47% were married, 48% were male, and 85% were white.
All of the patients were enrolled in Medicare Part D, and 40% qualified for subsidies to lower drug costs.
Of all the patients, there were 32% who had not started treatment with a first-line TKI (imatinib, nilotinib, or dasatinib) within 6 months of diagnosis.
However, having access to subsidies was associated with a shorter time to the start of treatment. The median time to the start of treatment was 58 days for patients with subsidies and 108 days for patients without them.
While the gap between the 2 groups widened after diagnosis, eventually, patients without subsidies did catch up, Dr Dusetzina said.
Ninety days from diagnosis, 48% of patients without subsidies had started treatment, compared to 63% of patients with subsidies. At 6 months from diagnosis, 64% of patients without subsidies had started treatment, compared to 65% of patients with subsidies.
Dr Dusetzina said patients without subsidies could be catching up as they find the financial resources to help cover those initial costs. But overall, patients with subsidies were 35% more likely to start TKI treatment faster.
“We recognize that people have a high cost to even start therapy, and this study really demonstrates the difference between people with and without a subsidy in initiating therapy,” Dr Dusetzina said. “The out-of-pocket costs may be delaying people starting these life-saving drugs.”
cut in half with a pill splitter
Photo by Patrick Pelletier
Significant out-of-pocket costs may delay treatment for Medicare beneficiaries with chronic myeloid leukemia (CML), according to a study published in the Journal of Clinical Oncology.
Researchers studied 393 patients with CML who had federally funded health insurance—specifically, a Medicare Part D plan.
Nearly a third of these patients did not start tyrosine kinase inhibitor (TKI) treatment within 6 months of their diagnosis.
However, patients who had access to subsidies that help cover treatment costs had a shorter median time to the start of therapy.
“There are 2 troubling findings here,” said study author Aaron Winn, a doctoral student at the University of North Carolina at Chapel Hill.
“First, we are seeing that more than 30% of people aren’t starting therapy within 6 months. Second, we are seeing long delays in starting drugs for people without subsidies. This is very concerning as these delays may be an indicator that the patient is trying to find funds to pay for their first treatment.”
Medicare Part D and TKIs
Previous studies have shown that patients insured through Medicare Part D have out of-pocket costs of nearly $3000 for the first month’s supply of a TKI.
According to researchers, the high upfront costs are due to the Medicare Part D benefit design, which requires patients to pay a larger share of medication costs until they have paid at least $4850 out-of-pocket in a year (cost in 2016). After that, patients pay 5% of the monthly drug costs.
In order to qualify for Medicare Part D’s low-income subsidy, an individual must have an annual income of less than $17,820 and assets of less than $13,640 (figures for 2016).
“Once you’re on Medicare Part D, there really aren’t ways to minimize these out-of-pocket costs, other than subsidies,” said Stacie Dusetzina, PhD, of the University of North Carolina at Chapel Hill.
“One of the challenges is that when the Medicare benefit was designed, I don’t think they were really considering these very expensive therapies. The benefit design makes a lot more sense when you’re looking at drugs that cost several hundred dollars versus several thousand dollars or more. We really need to think carefully about how much these high out-of-pocket costs are impacting patients’ access to life-saving drugs.”
Study results
For this study, Dr Dusetzina and her colleagues evaluated data on 393 patients who were diagnosed with CML between 2007 and 2011. The patients’ median age was 77, 47% were married, 48% were male, and 85% were white.
All of the patients were enrolled in Medicare Part D, and 40% qualified for subsidies to lower drug costs.
Of all the patients, there were 32% who had not started treatment with a first-line TKI (imatinib, nilotinib, or dasatinib) within 6 months of diagnosis.
However, having access to subsidies was associated with a shorter time to the start of treatment. The median time to the start of treatment was 58 days for patients with subsidies and 108 days for patients without them.
While the gap between the 2 groups widened after diagnosis, eventually, patients without subsidies did catch up, Dr Dusetzina said.
Ninety days from diagnosis, 48% of patients without subsidies had started treatment, compared to 63% of patients with subsidies. At 6 months from diagnosis, 64% of patients without subsidies had started treatment, compared to 65% of patients with subsidies.
Dr Dusetzina said patients without subsidies could be catching up as they find the financial resources to help cover those initial costs. But overall, patients with subsidies were 35% more likely to start TKI treatment faster.
“We recognize that people have a high cost to even start therapy, and this study really demonstrates the difference between people with and without a subsidy in initiating therapy,” Dr Dusetzina said. “The out-of-pocket costs may be delaying people starting these life-saving drugs.”
Enzyme may be therapeutic target for NHL
telomeres in green
Image by Claus Azzalin
New research indicates that an enzyme called uracil-DNA glycosylase (UNG) protects the ends of B-cell chromosomes to facilitate B-cell proliferation in response to infection.
The study also suggests that targeting UNG may help treat certain types of non-Hodgkin lymphoma (NHL).
Ramiro Verdun, PhD, of Sylvester Comprehensive Cancer Center at the University of Miami in Florida, and his colleagues described the study in The Journal of Experimental Medicine.
The researchers knew that when a B cell first encounters a foreign antigen, it starts to proliferate and produce a DNA-modifying enzyme called activation-induced deaminase (AID).
AID creates mutations in the cell’s immunoglobulin genes so the cell’s progeny produce a diverse array of antibodies that can bind the antigen with high affinity and mediate various immune responses.
But AID can create mutations elsewhere in the B cell’s genome, and, if these mutations are not mended by UNG or other DNA repair proteins, this can lead to NHL and other cancers.
Dr Verdun and his colleagues decided to investigate whether AID targets the telomeres of mouse B cells. They chose this path of investigation because telomeres contain similar DNA sequences to immunoglobulin genes.
The researchers found that, in the absence of UNG, AID created mutations in B-cell telomeres that caused them to rapidly shorten, limiting the proliferation of activated B cells.
UNG helped to repair these mutations, preventing telomere loss and facilitating B-cell expansion. UNG enabled the B cells to continue proliferating while they mutated their immunoglobulin genes, allowing them to mount an effective immune response.
Finally, the researchers found that UNG’s activity may also help NHL cells, which often overexpress AID, to continue proliferating.
The team tested human diffuse large B-cell lymphoma (DLBCL) cells with high or low expression of AID. And they found that inhibiting UNG impaired the growth of DLBCL cells with high AID expression but had no effect on DLBCL cells with low AID expression.
“We show that cancerous human B cells expressing AID require UNG for proliferation, suggesting that targeting UNG may be a means to delay the growth of AID-positive cancers,” Dr Verdun said.
telomeres in green
Image by Claus Azzalin
New research indicates that an enzyme called uracil-DNA glycosylase (UNG) protects the ends of B-cell chromosomes to facilitate B-cell proliferation in response to infection.
The study also suggests that targeting UNG may help treat certain types of non-Hodgkin lymphoma (NHL).
Ramiro Verdun, PhD, of Sylvester Comprehensive Cancer Center at the University of Miami in Florida, and his colleagues described the study in The Journal of Experimental Medicine.
The researchers knew that when a B cell first encounters a foreign antigen, it starts to proliferate and produce a DNA-modifying enzyme called activation-induced deaminase (AID).
AID creates mutations in the cell’s immunoglobulin genes so the cell’s progeny produce a diverse array of antibodies that can bind the antigen with high affinity and mediate various immune responses.
But AID can create mutations elsewhere in the B cell’s genome, and, if these mutations are not mended by UNG or other DNA repair proteins, this can lead to NHL and other cancers.
Dr Verdun and his colleagues decided to investigate whether AID targets the telomeres of mouse B cells. They chose this path of investigation because telomeres contain similar DNA sequences to immunoglobulin genes.
The researchers found that, in the absence of UNG, AID created mutations in B-cell telomeres that caused them to rapidly shorten, limiting the proliferation of activated B cells.
UNG helped to repair these mutations, preventing telomere loss and facilitating B-cell expansion. UNG enabled the B cells to continue proliferating while they mutated their immunoglobulin genes, allowing them to mount an effective immune response.
Finally, the researchers found that UNG’s activity may also help NHL cells, which often overexpress AID, to continue proliferating.
The team tested human diffuse large B-cell lymphoma (DLBCL) cells with high or low expression of AID. And they found that inhibiting UNG impaired the growth of DLBCL cells with high AID expression but had no effect on DLBCL cells with low AID expression.
“We show that cancerous human B cells expressing AID require UNG for proliferation, suggesting that targeting UNG may be a means to delay the growth of AID-positive cancers,” Dr Verdun said.
telomeres in green
Image by Claus Azzalin
New research indicates that an enzyme called uracil-DNA glycosylase (UNG) protects the ends of B-cell chromosomes to facilitate B-cell proliferation in response to infection.
The study also suggests that targeting UNG may help treat certain types of non-Hodgkin lymphoma (NHL).
Ramiro Verdun, PhD, of Sylvester Comprehensive Cancer Center at the University of Miami in Florida, and his colleagues described the study in The Journal of Experimental Medicine.
The researchers knew that when a B cell first encounters a foreign antigen, it starts to proliferate and produce a DNA-modifying enzyme called activation-induced deaminase (AID).
AID creates mutations in the cell’s immunoglobulin genes so the cell’s progeny produce a diverse array of antibodies that can bind the antigen with high affinity and mediate various immune responses.
But AID can create mutations elsewhere in the B cell’s genome, and, if these mutations are not mended by UNG or other DNA repair proteins, this can lead to NHL and other cancers.
Dr Verdun and his colleagues decided to investigate whether AID targets the telomeres of mouse B cells. They chose this path of investigation because telomeres contain similar DNA sequences to immunoglobulin genes.
The researchers found that, in the absence of UNG, AID created mutations in B-cell telomeres that caused them to rapidly shorten, limiting the proliferation of activated B cells.
UNG helped to repair these mutations, preventing telomere loss and facilitating B-cell expansion. UNG enabled the B cells to continue proliferating while they mutated their immunoglobulin genes, allowing them to mount an effective immune response.
Finally, the researchers found that UNG’s activity may also help NHL cells, which often overexpress AID, to continue proliferating.
The team tested human diffuse large B-cell lymphoma (DLBCL) cells with high or low expression of AID. And they found that inhibiting UNG impaired the growth of DLBCL cells with high AID expression but had no effect on DLBCL cells with low AID expression.
“We show that cancerous human B cells expressing AID require UNG for proliferation, suggesting that targeting UNG may be a means to delay the growth of AID-positive cancers,” Dr Verdun said.
Drug could reduce morbidity, mortality in aTTP, doc says
Photo courtesy of ASH
THE HAGUE—Caplacizumab has the potential to reduce morbidity and mortality associated with acquired thrombotic thrombocytopenic purpura (aTTP), according to the principal investigator of the phase 2 TITAN study.
Post-hoc analyses of data from this study suggested that adding caplacizumab to standard therapy can reduce major thromboembolic complications and aTTP-related death, as well as refractoriness to standard treatment.
These findings were recently presented at the European Congress on Thrombosis and Haemostasis (ECTH). The study was sponsored by Ablynx, the company developing caplacizumab.
Caplacizumab is an anti-von Willebrand factor nanobody that works by blocking the interaction of ultra-large von Willebrand factor multimers with platelets.
According to Ablynx, the nanobody has an immediate effect on platelet aggregation and the ensuing formation and accumulation of the micro-clots that cause severe thrombocytopenia and organ and tissue damage in patients with aTTP. This immediate effect protects the patient from the manifestations of the disease while the underlying disease process resolves.
Previous results from TITAN
TITAN was a single-blinded study that enrolled 75 aTTP patients. They all received the current standard of care for aTTP—daily plasma exchange and immunosuppressive therapy. Thirty-six patients were randomized to receive caplacizumab as well, and 39 were randomized to placebo.
The study’s primary endpoint was time to response (platelet count normalization). Patients in the caplacizumab arm had a 39% reduction in the median time to response compared to patients in the placebo arm (P=0.005).
The rate of confirmed response was 86.1% (n=31) in the caplacizumab arm and 71.8% (n=28) in the placebo arm.
There were more relapses in the caplacizumab arm than the placebo arm—8 (22.2%) and 0, respectively. Relapse was defined as a TTP event occurring more than 30 days after the end of daily plasma exchange.
There were fewer exacerbations in the caplacizumab arm than the placebo arm—3 (8.3%) and 11 (28.2%), respectively. Exacerbation was defined as recurrent thrombocytopenia within 30 days of the end of daily plasma exchange that required reinitiation of daily exchange.
The rate of adverse events thought to be related to the study drug was 17% in the caplacizumab arm and 11% in the placebo arm. The rate of events that were possibly related was 54% and 8%, respectively.
These and other results from TITAN were published in NEJM earlier this year.
Post-hoc analyses
Investigators performed post-hoc analyses of TITAN data to assess the impact of caplacizumab on a composite endpoint of major thromboembolic complications and aTTP-related mortality, as well as on refractoriness to standard treatment.
The proportion of patients who died or had at least 1 major thromboembolic event was lower in the caplacizumab arm than the placebo arm—11.4% and 43.2%, respectively.
There were 4 major thromboembolic events in the caplacizumab arm—3 recurrences of TTP during the treatment period and 1 pulmonary embolism.
There were 20 major thromboembolic events in the placebo arm—13 recurrences of TTP during the treatment period (in 11 patients), 2 acute myocardial infarctions, 1 deep vein thrombosis, 1 venous thrombosis, 1 pulmonary embolism, 1 ischemic stroke, and 1 hemorrhagic stroke.
There were no deaths in the caplacizumab arm, but there were 2 deaths in the placebo arm. Both of those patients were refractory to treatment.
Fewer patients in the caplacizumab arm than the placebo arm were refractory to treatment.
When refractoriness was defined as “failure of platelet response after 7 days despite daily plasma exchange treatment,” the rates of refractoriness were 5.7% in the caplacizumab arm and 21.6% in the placebo arm.
When refractoriness was defined as “absence of platelet count doubling after 4 days of standard treatment and lactate dehydrogenase greater than the upper limit of normal,” the rates of refractoriness were 0% in the caplacizumab arm and 10.8% in the placebo arm.
“Acquired TTP is a very severe disease with high unmet medical need,” said TITAN’s principal investigator Flora Peyvandi, MD, PhD, of the University of Milan in Italy.
“Any new treatment option would need to act fast to immediately inhibit the formation of micro-clots in order to protect the patient during the acute phase of the disease and so have the potential to avoid the resulting complications.”
“The top-line results and the subsequent post-hoc analyses of the phase 2 TITAN data demonstrate that caplacizumab has the potential to reduce the major morbidity and mortality associated with acquired TTP, and confirm our conviction that it should become an important pillar in the management of acquired TTP.”
Photo courtesy of ASH
THE HAGUE—Caplacizumab has the potential to reduce morbidity and mortality associated with acquired thrombotic thrombocytopenic purpura (aTTP), according to the principal investigator of the phase 2 TITAN study.
Post-hoc analyses of data from this study suggested that adding caplacizumab to standard therapy can reduce major thromboembolic complications and aTTP-related death, as well as refractoriness to standard treatment.
These findings were recently presented at the European Congress on Thrombosis and Haemostasis (ECTH). The study was sponsored by Ablynx, the company developing caplacizumab.
Caplacizumab is an anti-von Willebrand factor nanobody that works by blocking the interaction of ultra-large von Willebrand factor multimers with platelets.
According to Ablynx, the nanobody has an immediate effect on platelet aggregation and the ensuing formation and accumulation of the micro-clots that cause severe thrombocytopenia and organ and tissue damage in patients with aTTP. This immediate effect protects the patient from the manifestations of the disease while the underlying disease process resolves.
Previous results from TITAN
TITAN was a single-blinded study that enrolled 75 aTTP patients. They all received the current standard of care for aTTP—daily plasma exchange and immunosuppressive therapy. Thirty-six patients were randomized to receive caplacizumab as well, and 39 were randomized to placebo.
The study’s primary endpoint was time to response (platelet count normalization). Patients in the caplacizumab arm had a 39% reduction in the median time to response compared to patients in the placebo arm (P=0.005).
The rate of confirmed response was 86.1% (n=31) in the caplacizumab arm and 71.8% (n=28) in the placebo arm.
There were more relapses in the caplacizumab arm than the placebo arm—8 (22.2%) and 0, respectively. Relapse was defined as a TTP event occurring more than 30 days after the end of daily plasma exchange.
There were fewer exacerbations in the caplacizumab arm than the placebo arm—3 (8.3%) and 11 (28.2%), respectively. Exacerbation was defined as recurrent thrombocytopenia within 30 days of the end of daily plasma exchange that required reinitiation of daily exchange.
The rate of adverse events thought to be related to the study drug was 17% in the caplacizumab arm and 11% in the placebo arm. The rate of events that were possibly related was 54% and 8%, respectively.
These and other results from TITAN were published in NEJM earlier this year.
Post-hoc analyses
Investigators performed post-hoc analyses of TITAN data to assess the impact of caplacizumab on a composite endpoint of major thromboembolic complications and aTTP-related mortality, as well as on refractoriness to standard treatment.
The proportion of patients who died or had at least 1 major thromboembolic event was lower in the caplacizumab arm than the placebo arm—11.4% and 43.2%, respectively.
There were 4 major thromboembolic events in the caplacizumab arm—3 recurrences of TTP during the treatment period and 1 pulmonary embolism.
There were 20 major thromboembolic events in the placebo arm—13 recurrences of TTP during the treatment period (in 11 patients), 2 acute myocardial infarctions, 1 deep vein thrombosis, 1 venous thrombosis, 1 pulmonary embolism, 1 ischemic stroke, and 1 hemorrhagic stroke.
There were no deaths in the caplacizumab arm, but there were 2 deaths in the placebo arm. Both of those patients were refractory to treatment.
Fewer patients in the caplacizumab arm than the placebo arm were refractory to treatment.
When refractoriness was defined as “failure of platelet response after 7 days despite daily plasma exchange treatment,” the rates of refractoriness were 5.7% in the caplacizumab arm and 21.6% in the placebo arm.
When refractoriness was defined as “absence of platelet count doubling after 4 days of standard treatment and lactate dehydrogenase greater than the upper limit of normal,” the rates of refractoriness were 0% in the caplacizumab arm and 10.8% in the placebo arm.
“Acquired TTP is a very severe disease with high unmet medical need,” said TITAN’s principal investigator Flora Peyvandi, MD, PhD, of the University of Milan in Italy.
“Any new treatment option would need to act fast to immediately inhibit the formation of micro-clots in order to protect the patient during the acute phase of the disease and so have the potential to avoid the resulting complications.”
“The top-line results and the subsequent post-hoc analyses of the phase 2 TITAN data demonstrate that caplacizumab has the potential to reduce the major morbidity and mortality associated with acquired TTP, and confirm our conviction that it should become an important pillar in the management of acquired TTP.”
Photo courtesy of ASH
THE HAGUE—Caplacizumab has the potential to reduce morbidity and mortality associated with acquired thrombotic thrombocytopenic purpura (aTTP), according to the principal investigator of the phase 2 TITAN study.
Post-hoc analyses of data from this study suggested that adding caplacizumab to standard therapy can reduce major thromboembolic complications and aTTP-related death, as well as refractoriness to standard treatment.
These findings were recently presented at the European Congress on Thrombosis and Haemostasis (ECTH). The study was sponsored by Ablynx, the company developing caplacizumab.
Caplacizumab is an anti-von Willebrand factor nanobody that works by blocking the interaction of ultra-large von Willebrand factor multimers with platelets.
According to Ablynx, the nanobody has an immediate effect on platelet aggregation and the ensuing formation and accumulation of the micro-clots that cause severe thrombocytopenia and organ and tissue damage in patients with aTTP. This immediate effect protects the patient from the manifestations of the disease while the underlying disease process resolves.
Previous results from TITAN
TITAN was a single-blinded study that enrolled 75 aTTP patients. They all received the current standard of care for aTTP—daily plasma exchange and immunosuppressive therapy. Thirty-six patients were randomized to receive caplacizumab as well, and 39 were randomized to placebo.
The study’s primary endpoint was time to response (platelet count normalization). Patients in the caplacizumab arm had a 39% reduction in the median time to response compared to patients in the placebo arm (P=0.005).
The rate of confirmed response was 86.1% (n=31) in the caplacizumab arm and 71.8% (n=28) in the placebo arm.
There were more relapses in the caplacizumab arm than the placebo arm—8 (22.2%) and 0, respectively. Relapse was defined as a TTP event occurring more than 30 days after the end of daily plasma exchange.
There were fewer exacerbations in the caplacizumab arm than the placebo arm—3 (8.3%) and 11 (28.2%), respectively. Exacerbation was defined as recurrent thrombocytopenia within 30 days of the end of daily plasma exchange that required reinitiation of daily exchange.
The rate of adverse events thought to be related to the study drug was 17% in the caplacizumab arm and 11% in the placebo arm. The rate of events that were possibly related was 54% and 8%, respectively.
These and other results from TITAN were published in NEJM earlier this year.
Post-hoc analyses
Investigators performed post-hoc analyses of TITAN data to assess the impact of caplacizumab on a composite endpoint of major thromboembolic complications and aTTP-related mortality, as well as on refractoriness to standard treatment.
The proportion of patients who died or had at least 1 major thromboembolic event was lower in the caplacizumab arm than the placebo arm—11.4% and 43.2%, respectively.
There were 4 major thromboembolic events in the caplacizumab arm—3 recurrences of TTP during the treatment period and 1 pulmonary embolism.
There were 20 major thromboembolic events in the placebo arm—13 recurrences of TTP during the treatment period (in 11 patients), 2 acute myocardial infarctions, 1 deep vein thrombosis, 1 venous thrombosis, 1 pulmonary embolism, 1 ischemic stroke, and 1 hemorrhagic stroke.
There were no deaths in the caplacizumab arm, but there were 2 deaths in the placebo arm. Both of those patients were refractory to treatment.
Fewer patients in the caplacizumab arm than the placebo arm were refractory to treatment.
When refractoriness was defined as “failure of platelet response after 7 days despite daily plasma exchange treatment,” the rates of refractoriness were 5.7% in the caplacizumab arm and 21.6% in the placebo arm.
When refractoriness was defined as “absence of platelet count doubling after 4 days of standard treatment and lactate dehydrogenase greater than the upper limit of normal,” the rates of refractoriness were 0% in the caplacizumab arm and 10.8% in the placebo arm.
“Acquired TTP is a very severe disease with high unmet medical need,” said TITAN’s principal investigator Flora Peyvandi, MD, PhD, of the University of Milan in Italy.
“Any new treatment option would need to act fast to immediately inhibit the formation of micro-clots in order to protect the patient during the acute phase of the disease and so have the potential to avoid the resulting complications.”
“The top-line results and the subsequent post-hoc analyses of the phase 2 TITAN data demonstrate that caplacizumab has the potential to reduce the major morbidity and mortality associated with acquired TTP, and confirm our conviction that it should become an important pillar in the management of acquired TTP.”
Scientist awarded Nobel Prize for autophagy research
Photo by Mari Honda
The 2016 Nobel Prize in Physiology or Medicine has been awarded to Yoshinori Ohsumi, PhD, for his discoveries related to autophagy.
The concept of autophagy emerged during the 1960s, but little was known about the process until the early 1990s.
That’s when Dr Ohsumi used yeast cells to identify genes essential for autophagy. He cloned several of these genes in yeast and mammalian cells and described the function of the encoded proteins.
According to The Nobel Assembly at Karolinska Institutet, Dr Ohsumi’s discoveries opened the path to understanding the fundamental importance of autophagy in many physiological processes.
The man
Dr Ohsumi was born in 1945 in Fukuoka, Japan. He received a PhD from University of Tokyo in 1974.
After spending 3 years at Rockefeller University in New York, he returned to the University of Tokyo, where he established his research group in 1988. Since 2009, he has been a professor at the Tokyo Institute of Technology.
The research
The Belgian scientist Christian de Duve coined the term autophagy in 1963. However, the process was still not well understood when Dr Ohsumi began his research on autophagy.
In the early 1990s, Dr Ohsumi decided to study autophagy using the budding yeast Saccharomyces cerevisae as a model system.
He was not sure whether autophagy existed in this organism. However, he reasoned that, if it did, and he could disrupt the degradation process in the vacuole while autophagy was active, autophagosomes should accumulate within the vacuole.
Dr Ohsumi cultured mutated yeast lacking vacuolar degradation enzymes and simultaneously stimulated autophagy by starving the cells.
Within hours, the vacuoles were filled with small vesicles that had not been degraded. The vesicles were autophagosomes, and the experiment proved that autophagy exists in yeast cells.
The experiment also provided a method to identify and characterize genes involved in autophagy.
Dr Ohsumi noted that the accumulation of autophagosomes should not occur if genes important for autophagy were inactivated.
So he exposed the yeast cells to a chemical that randomly introduced mutations in many genes, and then he induced autophagy. In this way, he identified 15 genes essential for autophagy in budding yeast.
In his subsequent studies, Dr Ohsumi cloned several of these genes in yeast and mammalian cells and characterized the function of the proteins encoded by these genes.
He found that autophagy is controlled by a cascade of proteins and protein complexes, each regulating a distinct stage of autophagosome initiation and formation.
Insights provided by Dr Ohsumi’s work enabled subsequent research that has revealed the role of autophagy in human physiology and disease.
For more information on Dr Ohsumi and his work, visit the Nobel Prize website.
Photo by Mari Honda
The 2016 Nobel Prize in Physiology or Medicine has been awarded to Yoshinori Ohsumi, PhD, for his discoveries related to autophagy.
The concept of autophagy emerged during the 1960s, but little was known about the process until the early 1990s.
That’s when Dr Ohsumi used yeast cells to identify genes essential for autophagy. He cloned several of these genes in yeast and mammalian cells and described the function of the encoded proteins.
According to The Nobel Assembly at Karolinska Institutet, Dr Ohsumi’s discoveries opened the path to understanding the fundamental importance of autophagy in many physiological processes.
The man
Dr Ohsumi was born in 1945 in Fukuoka, Japan. He received a PhD from University of Tokyo in 1974.
After spending 3 years at Rockefeller University in New York, he returned to the University of Tokyo, where he established his research group in 1988. Since 2009, he has been a professor at the Tokyo Institute of Technology.
The research
The Belgian scientist Christian de Duve coined the term autophagy in 1963. However, the process was still not well understood when Dr Ohsumi began his research on autophagy.
In the early 1990s, Dr Ohsumi decided to study autophagy using the budding yeast Saccharomyces cerevisae as a model system.
He was not sure whether autophagy existed in this organism. However, he reasoned that, if it did, and he could disrupt the degradation process in the vacuole while autophagy was active, autophagosomes should accumulate within the vacuole.
Dr Ohsumi cultured mutated yeast lacking vacuolar degradation enzymes and simultaneously stimulated autophagy by starving the cells.
Within hours, the vacuoles were filled with small vesicles that had not been degraded. The vesicles were autophagosomes, and the experiment proved that autophagy exists in yeast cells.
The experiment also provided a method to identify and characterize genes involved in autophagy.
Dr Ohsumi noted that the accumulation of autophagosomes should not occur if genes important for autophagy were inactivated.
So he exposed the yeast cells to a chemical that randomly introduced mutations in many genes, and then he induced autophagy. In this way, he identified 15 genes essential for autophagy in budding yeast.
In his subsequent studies, Dr Ohsumi cloned several of these genes in yeast and mammalian cells and characterized the function of the proteins encoded by these genes.
He found that autophagy is controlled by a cascade of proteins and protein complexes, each regulating a distinct stage of autophagosome initiation and formation.
Insights provided by Dr Ohsumi’s work enabled subsequent research that has revealed the role of autophagy in human physiology and disease.
For more information on Dr Ohsumi and his work, visit the Nobel Prize website.
Photo by Mari Honda
The 2016 Nobel Prize in Physiology or Medicine has been awarded to Yoshinori Ohsumi, PhD, for his discoveries related to autophagy.
The concept of autophagy emerged during the 1960s, but little was known about the process until the early 1990s.
That’s when Dr Ohsumi used yeast cells to identify genes essential for autophagy. He cloned several of these genes in yeast and mammalian cells and described the function of the encoded proteins.
According to The Nobel Assembly at Karolinska Institutet, Dr Ohsumi’s discoveries opened the path to understanding the fundamental importance of autophagy in many physiological processes.
The man
Dr Ohsumi was born in 1945 in Fukuoka, Japan. He received a PhD from University of Tokyo in 1974.
After spending 3 years at Rockefeller University in New York, he returned to the University of Tokyo, where he established his research group in 1988. Since 2009, he has been a professor at the Tokyo Institute of Technology.
The research
The Belgian scientist Christian de Duve coined the term autophagy in 1963. However, the process was still not well understood when Dr Ohsumi began his research on autophagy.
In the early 1990s, Dr Ohsumi decided to study autophagy using the budding yeast Saccharomyces cerevisae as a model system.
He was not sure whether autophagy existed in this organism. However, he reasoned that, if it did, and he could disrupt the degradation process in the vacuole while autophagy was active, autophagosomes should accumulate within the vacuole.
Dr Ohsumi cultured mutated yeast lacking vacuolar degradation enzymes and simultaneously stimulated autophagy by starving the cells.
Within hours, the vacuoles were filled with small vesicles that had not been degraded. The vesicles were autophagosomes, and the experiment proved that autophagy exists in yeast cells.
The experiment also provided a method to identify and characterize genes involved in autophagy.
Dr Ohsumi noted that the accumulation of autophagosomes should not occur if genes important for autophagy were inactivated.
So he exposed the yeast cells to a chemical that randomly introduced mutations in many genes, and then he induced autophagy. In this way, he identified 15 genes essential for autophagy in budding yeast.
In his subsequent studies, Dr Ohsumi cloned several of these genes in yeast and mammalian cells and characterized the function of the proteins encoded by these genes.
He found that autophagy is controlled by a cascade of proteins and protein complexes, each regulating a distinct stage of autophagosome initiation and formation.
Insights provided by Dr Ohsumi’s work enabled subsequent research that has revealed the role of autophagy in human physiology and disease.
For more information on Dr Ohsumi and his work, visit the Nobel Prize website.
Analysis raises concerns about FDA reviewers
Photo by Steven Harbour
Results of an analysis published in The BMJ have raised concerns about how often drug regulators go on to work in the biopharmaceutical industry.
A pair of researchers evaluated 55 medical reviewers who worked at the US Food and Drug Administration (FDA) between 2001 and 2010.
Forty-seven percent of the reviewers left the FDA, and 58% of those who left were subsequently employed by or consulting for the biopharmaceutical industry.
Vinay Prasad, MD, and Jeffrey Bien, MD, both of Oregon Health and Science University in Portland, conducted this research.
The pair began by identifying hematology-oncology drugs approved by the FDA from 2006 to 2010. They then used the FDA database ([email protected]) to compile a list of all medical reviewers for these drugs.
The researchers then searched publicly available information from the Department of Health and Human Services, LinkedIn, and PubMed to determine the reviewers’ subsequent jobs.
The pair identified 55 unique hematology-oncology medical reviewers who reviewed drug applications between 2001 and 2010.
Forty-nine percent (n=27) of these reviewers continue to work exclusively at the FDA. Four percent (n=2) still work at the FDA but hold secondary appointments (1 with a non-FDA-related consulting position and 1 with another government position).
Forty-seven percent (n=26) of the reviewers left the FDA. The researchers were unable to determine subsequent jobs for 14% (n=8) of the reviewers.
However, 27% (n=15) went on to biopharmaceutical industry employment or consulting. Four percent (n=2) went on to other government positions, and 2% (n=1) went on to work in academia.
Drs Prasad and Bien said this analysis is the first to document the rate of the “revolving door” between the FDA and the biopharmaceutical industry, and the results suggest a sizable percentage of FDA medical reviewers who leave the agency subsequently work in the industry.
The researchers said they are concerned by these findings, and they noted that this analysis may have underestimated the extent of the “revolving door” because they could not identify subsequent jobs for all of the reviewers studied.
Photo by Steven Harbour
Results of an analysis published in The BMJ have raised concerns about how often drug regulators go on to work in the biopharmaceutical industry.
A pair of researchers evaluated 55 medical reviewers who worked at the US Food and Drug Administration (FDA) between 2001 and 2010.
Forty-seven percent of the reviewers left the FDA, and 58% of those who left were subsequently employed by or consulting for the biopharmaceutical industry.
Vinay Prasad, MD, and Jeffrey Bien, MD, both of Oregon Health and Science University in Portland, conducted this research.
The pair began by identifying hematology-oncology drugs approved by the FDA from 2006 to 2010. They then used the FDA database ([email protected]) to compile a list of all medical reviewers for these drugs.
The researchers then searched publicly available information from the Department of Health and Human Services, LinkedIn, and PubMed to determine the reviewers’ subsequent jobs.
The pair identified 55 unique hematology-oncology medical reviewers who reviewed drug applications between 2001 and 2010.
Forty-nine percent (n=27) of these reviewers continue to work exclusively at the FDA. Four percent (n=2) still work at the FDA but hold secondary appointments (1 with a non-FDA-related consulting position and 1 with another government position).
Forty-seven percent (n=26) of the reviewers left the FDA. The researchers were unable to determine subsequent jobs for 14% (n=8) of the reviewers.
However, 27% (n=15) went on to biopharmaceutical industry employment or consulting. Four percent (n=2) went on to other government positions, and 2% (n=1) went on to work in academia.
Drs Prasad and Bien said this analysis is the first to document the rate of the “revolving door” between the FDA and the biopharmaceutical industry, and the results suggest a sizable percentage of FDA medical reviewers who leave the agency subsequently work in the industry.
The researchers said they are concerned by these findings, and they noted that this analysis may have underestimated the extent of the “revolving door” because they could not identify subsequent jobs for all of the reviewers studied.
Photo by Steven Harbour
Results of an analysis published in The BMJ have raised concerns about how often drug regulators go on to work in the biopharmaceutical industry.
A pair of researchers evaluated 55 medical reviewers who worked at the US Food and Drug Administration (FDA) between 2001 and 2010.
Forty-seven percent of the reviewers left the FDA, and 58% of those who left were subsequently employed by or consulting for the biopharmaceutical industry.
Vinay Prasad, MD, and Jeffrey Bien, MD, both of Oregon Health and Science University in Portland, conducted this research.
The pair began by identifying hematology-oncology drugs approved by the FDA from 2006 to 2010. They then used the FDA database ([email protected]) to compile a list of all medical reviewers for these drugs.
The researchers then searched publicly available information from the Department of Health and Human Services, LinkedIn, and PubMed to determine the reviewers’ subsequent jobs.
The pair identified 55 unique hematology-oncology medical reviewers who reviewed drug applications between 2001 and 2010.
Forty-nine percent (n=27) of these reviewers continue to work exclusively at the FDA. Four percent (n=2) still work at the FDA but hold secondary appointments (1 with a non-FDA-related consulting position and 1 with another government position).
Forty-seven percent (n=26) of the reviewers left the FDA. The researchers were unable to determine subsequent jobs for 14% (n=8) of the reviewers.
However, 27% (n=15) went on to biopharmaceutical industry employment or consulting. Four percent (n=2) went on to other government positions, and 2% (n=1) went on to work in academia.
Drs Prasad and Bien said this analysis is the first to document the rate of the “revolving door” between the FDA and the biopharmaceutical industry, and the results suggest a sizable percentage of FDA medical reviewers who leave the agency subsequently work in the industry.
The researchers said they are concerned by these findings, and they noted that this analysis may have underestimated the extent of the “revolving door” because they could not identify subsequent jobs for all of the reviewers studied.
Factor IX therapy approved in Japan
Japan’s Ministry of Health, Labour and Welfare (MHLW) has approved albutrepenonacog alfa (Idelvion) to treat and prevent bleeding in children and adults with hemophilia B.
Albutrepenonacog alfa is a fusion protein linking recombinant coagulation factor IX with recombinant albumin.
The product is now approved for use as routine prophylaxis, for on-demand control of bleeding, and for perioperative management of bleeding.
Albutrepenonacog alfa is being developed by CSL Behring.
The company says the product is the first and only hemophilia B therapy with up to 14-day dosing intervals.
According to CSL Behring, albutrepenonacog alfa can deliver high-level protection from bleeds by maintaining factor IX activity levels at an average of 20% in patients treated prophylactically every 7 days and an average of 12% in patients treated prophylactically every 14 days.
Albutrepenonacog alfa has also been approved in Canada, the European Union, Switzerland, and the US.
Phase 3 trial
The MHLW approved albutrepenonacog alfa based on results of the PROLONG-9FP clinical development program. PROLONG-9FP includes phase 1, 2, and 3 studies evaluating the safety and efficacy of albutrepenonacog alfa in adults and children (ages 1 to 61) with hemophilia B.
Data from the phase 3 study were published in Blood. The study included 63 previously treated male patients with severe hemophilia B. They had a mean age of 33 (range, 12 to 61).
The patients were divided into 2 groups. Group 1 (n=40) received routine prophylaxis with albutrepenonacog alfa once every 7 days for 26 weeks, followed by a 7-, 10-, or 14-day prophylaxis regimen for a mean of 50, 38, or 51 weeks, respectively.
Group 2 received on-demand treatment with albutrepenonacog alfa for bleeding episodes for 26 weeks (n=23) and then switched to a 7-day prophylaxis regimen for a mean of 45 weeks (n=19).
The median annualized bleeding rate (ABR) was 2.0 in the prophylaxis arm (group 1) and 23.5 in the on-demand treatment arm (group 2). The median spontaneous ABRs were 0.0 and 17.0, respectively.
For patients in group 2, there was a significant reduction in median ABRs when patients switched from on-demand treatment to prophylaxis—19.22 and 1.58, respectively (P<0.0001). And there was a significant reduction in median spontaneous ABRs—15.43 and 0.00, respectively (P<0.0001).
Overall, 98.6% of bleeding episodes were treated successfully, including 93.6% that were treated with a single injection of albutrepenonacog alfa.
None of the patients developed inhibitors or experienced thromboembolic events, anaphylaxis, or life-threatening adverse events (AEs).
There were 347 treatment-emergent AEs reported in 54 (85.7%) patients. The most common were nasopharyngitis (25.4%), headache (23.8%), arthralgia (4.3%), and influenza (11.1%).
Eleven mild/moderate AEs in 5 patients (7.9%) were considered possibly related to albutrepenonacog alfa. Two patients discontinued treatment due to AEs—1 with hypersensitivity and 1 with headache.
Japan’s Ministry of Health, Labour and Welfare (MHLW) has approved albutrepenonacog alfa (Idelvion) to treat and prevent bleeding in children and adults with hemophilia B.
Albutrepenonacog alfa is a fusion protein linking recombinant coagulation factor IX with recombinant albumin.
The product is now approved for use as routine prophylaxis, for on-demand control of bleeding, and for perioperative management of bleeding.
Albutrepenonacog alfa is being developed by CSL Behring.
The company says the product is the first and only hemophilia B therapy with up to 14-day dosing intervals.
According to CSL Behring, albutrepenonacog alfa can deliver high-level protection from bleeds by maintaining factor IX activity levels at an average of 20% in patients treated prophylactically every 7 days and an average of 12% in patients treated prophylactically every 14 days.
Albutrepenonacog alfa has also been approved in Canada, the European Union, Switzerland, and the US.
Phase 3 trial
The MHLW approved albutrepenonacog alfa based on results of the PROLONG-9FP clinical development program. PROLONG-9FP includes phase 1, 2, and 3 studies evaluating the safety and efficacy of albutrepenonacog alfa in adults and children (ages 1 to 61) with hemophilia B.
Data from the phase 3 study were published in Blood. The study included 63 previously treated male patients with severe hemophilia B. They had a mean age of 33 (range, 12 to 61).
The patients were divided into 2 groups. Group 1 (n=40) received routine prophylaxis with albutrepenonacog alfa once every 7 days for 26 weeks, followed by a 7-, 10-, or 14-day prophylaxis regimen for a mean of 50, 38, or 51 weeks, respectively.
Group 2 received on-demand treatment with albutrepenonacog alfa for bleeding episodes for 26 weeks (n=23) and then switched to a 7-day prophylaxis regimen for a mean of 45 weeks (n=19).
The median annualized bleeding rate (ABR) was 2.0 in the prophylaxis arm (group 1) and 23.5 in the on-demand treatment arm (group 2). The median spontaneous ABRs were 0.0 and 17.0, respectively.
For patients in group 2, there was a significant reduction in median ABRs when patients switched from on-demand treatment to prophylaxis—19.22 and 1.58, respectively (P<0.0001). And there was a significant reduction in median spontaneous ABRs—15.43 and 0.00, respectively (P<0.0001).
Overall, 98.6% of bleeding episodes were treated successfully, including 93.6% that were treated with a single injection of albutrepenonacog alfa.
None of the patients developed inhibitors or experienced thromboembolic events, anaphylaxis, or life-threatening adverse events (AEs).
There were 347 treatment-emergent AEs reported in 54 (85.7%) patients. The most common were nasopharyngitis (25.4%), headache (23.8%), arthralgia (4.3%), and influenza (11.1%).
Eleven mild/moderate AEs in 5 patients (7.9%) were considered possibly related to albutrepenonacog alfa. Two patients discontinued treatment due to AEs—1 with hypersensitivity and 1 with headache.
Japan’s Ministry of Health, Labour and Welfare (MHLW) has approved albutrepenonacog alfa (Idelvion) to treat and prevent bleeding in children and adults with hemophilia B.
Albutrepenonacog alfa is a fusion protein linking recombinant coagulation factor IX with recombinant albumin.
The product is now approved for use as routine prophylaxis, for on-demand control of bleeding, and for perioperative management of bleeding.
Albutrepenonacog alfa is being developed by CSL Behring.
The company says the product is the first and only hemophilia B therapy with up to 14-day dosing intervals.
According to CSL Behring, albutrepenonacog alfa can deliver high-level protection from bleeds by maintaining factor IX activity levels at an average of 20% in patients treated prophylactically every 7 days and an average of 12% in patients treated prophylactically every 14 days.
Albutrepenonacog alfa has also been approved in Canada, the European Union, Switzerland, and the US.
Phase 3 trial
The MHLW approved albutrepenonacog alfa based on results of the PROLONG-9FP clinical development program. PROLONG-9FP includes phase 1, 2, and 3 studies evaluating the safety and efficacy of albutrepenonacog alfa in adults and children (ages 1 to 61) with hemophilia B.
Data from the phase 3 study were published in Blood. The study included 63 previously treated male patients with severe hemophilia B. They had a mean age of 33 (range, 12 to 61).
The patients were divided into 2 groups. Group 1 (n=40) received routine prophylaxis with albutrepenonacog alfa once every 7 days for 26 weeks, followed by a 7-, 10-, or 14-day prophylaxis regimen for a mean of 50, 38, or 51 weeks, respectively.
Group 2 received on-demand treatment with albutrepenonacog alfa for bleeding episodes for 26 weeks (n=23) and then switched to a 7-day prophylaxis regimen for a mean of 45 weeks (n=19).
The median annualized bleeding rate (ABR) was 2.0 in the prophylaxis arm (group 1) and 23.5 in the on-demand treatment arm (group 2). The median spontaneous ABRs were 0.0 and 17.0, respectively.
For patients in group 2, there was a significant reduction in median ABRs when patients switched from on-demand treatment to prophylaxis—19.22 and 1.58, respectively (P<0.0001). And there was a significant reduction in median spontaneous ABRs—15.43 and 0.00, respectively (P<0.0001).
Overall, 98.6% of bleeding episodes were treated successfully, including 93.6% that were treated with a single injection of albutrepenonacog alfa.
None of the patients developed inhibitors or experienced thromboembolic events, anaphylaxis, or life-threatening adverse events (AEs).
There were 347 treatment-emergent AEs reported in 54 (85.7%) patients. The most common were nasopharyngitis (25.4%), headache (23.8%), arthralgia (4.3%), and influenza (11.1%).
Eleven mild/moderate AEs in 5 patients (7.9%) were considered possibly related to albutrepenonacog alfa. Two patients discontinued treatment due to AEs—1 with hypersensitivity and 1 with headache.
Companies withheld info related to rivaroxaban trial, BMJ says
The pharmaceutical companies developing the anticoagulant rivaroxaban (Xarelto) withheld information about the system used to measure international normalized ratios (INRs) in the ROCKET AF trial, according to an investigation published in The BMJ.
ROCKET AF was used to support the approval of rivaroxaban in the US and European Union, and the Alere INRatio Monitor System was used to measure INRs in the warfarin arm of the trial.
The system was later recalled because it was shown to provide falsely low test results.
The BMJ said Janssen and Bayer, the companies developing rivaroxaban, knew about concerns regarding the accuracy of the INRatio system while ROCKET AF was underway but allowed the system to be used in the trial anyway.
The companies also neglected to mention these concerns to regulatory authorities prior to rivaroxaban’s approval and later failed to notify regulators about the recall of the INRatio system and its potential impact on ROCKET AF.
In addition, Janssen, which was responsible for conducting ROCKET AF, did not tell regulators about a safety program the company launched during the trial to address concerns about the INRatio system.
In fact, The BMJ’s investigation suggests Janssen kept this program a secret from ROCKET AF investigators, the trial’s data and safety monitoring board, and Bayer.
How the events unfolded
ROCKET AF, which was launched in February 2007, was a comparison of rivaroxaban and warfarin in patients with nonvalvular atrial fibrillation.
Results from the trial, published in NEJM in August 2011, suggested rivaroxaban was noninferior to warfarin for preventing stroke or systemic embolism. And there was no significant difference between the treatment arms with regard to major or nonmajor clinically relevant bleeding.
These results were used to support the approval of rivaroxaban in the European Union in September 2011 and in the US in November 2011.
A number of critics, including The BMJ, have questioned the results of ROCKET AF because the INRatio system (INRatio Monitor or INRatio2 Monitor and INRatio Test Strips) has been shown to give falsely low test results.
The system was recalled for certain patients in December 2014 and was withdrawn from the market in July 2016.
The BMJ said Janssen and Bayer did not inform regulatory authorities about the December 2014 recall—and how issues with the INRatio system may have affected ROCKET AF—until The BMJ probed them in September 2015.
Once the authorities knew, they launched investigations. In February 2016, the European Medicine’s Agency (EMA) released a statement saying the defect with the INRatio system does not change the overall conclusions of ROCKET AF.
The US Food and Drug Administration (FDA) is still conducting its investigation but has not changed its recommendations regarding rivaroxaban.
The BMJ also reported that ROCKET AF’s executive committee and trial investigators raised concerns about the INRatio system shortly after the trial began.
Both Janssen and Bayer were aware of these concerns but did not disclose them to the FDA or EMA before rivaroxaban was approved.
Instead, Janssen launched the Covance recheck program in early 2008. This safety program involved an unblinded monitor checking INRatio readings against lab results if an investigator had concerns about the INRatio system.
Janssen did not inform ROCKET AF investigators or the trial’s data and safety monitoring board of the program. Bayer said it did not know about the program until this year, and the FDA and EMA have said the same.
The pharmaceutical companies developing the anticoagulant rivaroxaban (Xarelto) withheld information about the system used to measure international normalized ratios (INRs) in the ROCKET AF trial, according to an investigation published in The BMJ.
ROCKET AF was used to support the approval of rivaroxaban in the US and European Union, and the Alere INRatio Monitor System was used to measure INRs in the warfarin arm of the trial.
The system was later recalled because it was shown to provide falsely low test results.
The BMJ said Janssen and Bayer, the companies developing rivaroxaban, knew about concerns regarding the accuracy of the INRatio system while ROCKET AF was underway but allowed the system to be used in the trial anyway.
The companies also neglected to mention these concerns to regulatory authorities prior to rivaroxaban’s approval and later failed to notify regulators about the recall of the INRatio system and its potential impact on ROCKET AF.
In addition, Janssen, which was responsible for conducting ROCKET AF, did not tell regulators about a safety program the company launched during the trial to address concerns about the INRatio system.
In fact, The BMJ’s investigation suggests Janssen kept this program a secret from ROCKET AF investigators, the trial’s data and safety monitoring board, and Bayer.
How the events unfolded
ROCKET AF, which was launched in February 2007, was a comparison of rivaroxaban and warfarin in patients with nonvalvular atrial fibrillation.
Results from the trial, published in NEJM in August 2011, suggested rivaroxaban was noninferior to warfarin for preventing stroke or systemic embolism. And there was no significant difference between the treatment arms with regard to major or nonmajor clinically relevant bleeding.
These results were used to support the approval of rivaroxaban in the European Union in September 2011 and in the US in November 2011.
A number of critics, including The BMJ, have questioned the results of ROCKET AF because the INRatio system (INRatio Monitor or INRatio2 Monitor and INRatio Test Strips) has been shown to give falsely low test results.
The system was recalled for certain patients in December 2014 and was withdrawn from the market in July 2016.
The BMJ said Janssen and Bayer did not inform regulatory authorities about the December 2014 recall—and how issues with the INRatio system may have affected ROCKET AF—until The BMJ probed them in September 2015.
Once the authorities knew, they launched investigations. In February 2016, the European Medicine’s Agency (EMA) released a statement saying the defect with the INRatio system does not change the overall conclusions of ROCKET AF.
The US Food and Drug Administration (FDA) is still conducting its investigation but has not changed its recommendations regarding rivaroxaban.
The BMJ also reported that ROCKET AF’s executive committee and trial investigators raised concerns about the INRatio system shortly after the trial began.
Both Janssen and Bayer were aware of these concerns but did not disclose them to the FDA or EMA before rivaroxaban was approved.
Instead, Janssen launched the Covance recheck program in early 2008. This safety program involved an unblinded monitor checking INRatio readings against lab results if an investigator had concerns about the INRatio system.
Janssen did not inform ROCKET AF investigators or the trial’s data and safety monitoring board of the program. Bayer said it did not know about the program until this year, and the FDA and EMA have said the same.
The pharmaceutical companies developing the anticoagulant rivaroxaban (Xarelto) withheld information about the system used to measure international normalized ratios (INRs) in the ROCKET AF trial, according to an investigation published in The BMJ.
ROCKET AF was used to support the approval of rivaroxaban in the US and European Union, and the Alere INRatio Monitor System was used to measure INRs in the warfarin arm of the trial.
The system was later recalled because it was shown to provide falsely low test results.
The BMJ said Janssen and Bayer, the companies developing rivaroxaban, knew about concerns regarding the accuracy of the INRatio system while ROCKET AF was underway but allowed the system to be used in the trial anyway.
The companies also neglected to mention these concerns to regulatory authorities prior to rivaroxaban’s approval and later failed to notify regulators about the recall of the INRatio system and its potential impact on ROCKET AF.
In addition, Janssen, which was responsible for conducting ROCKET AF, did not tell regulators about a safety program the company launched during the trial to address concerns about the INRatio system.
In fact, The BMJ’s investigation suggests Janssen kept this program a secret from ROCKET AF investigators, the trial’s data and safety monitoring board, and Bayer.
How the events unfolded
ROCKET AF, which was launched in February 2007, was a comparison of rivaroxaban and warfarin in patients with nonvalvular atrial fibrillation.
Results from the trial, published in NEJM in August 2011, suggested rivaroxaban was noninferior to warfarin for preventing stroke or systemic embolism. And there was no significant difference between the treatment arms with regard to major or nonmajor clinically relevant bleeding.
These results were used to support the approval of rivaroxaban in the European Union in September 2011 and in the US in November 2011.
A number of critics, including The BMJ, have questioned the results of ROCKET AF because the INRatio system (INRatio Monitor or INRatio2 Monitor and INRatio Test Strips) has been shown to give falsely low test results.
The system was recalled for certain patients in December 2014 and was withdrawn from the market in July 2016.
The BMJ said Janssen and Bayer did not inform regulatory authorities about the December 2014 recall—and how issues with the INRatio system may have affected ROCKET AF—until The BMJ probed them in September 2015.
Once the authorities knew, they launched investigations. In February 2016, the European Medicine’s Agency (EMA) released a statement saying the defect with the INRatio system does not change the overall conclusions of ROCKET AF.
The US Food and Drug Administration (FDA) is still conducting its investigation but has not changed its recommendations regarding rivaroxaban.
The BMJ also reported that ROCKET AF’s executive committee and trial investigators raised concerns about the INRatio system shortly after the trial began.
Both Janssen and Bayer were aware of these concerns but did not disclose them to the FDA or EMA before rivaroxaban was approved.
Instead, Janssen launched the Covance recheck program in early 2008. This safety program involved an unblinded monitor checking INRatio readings against lab results if an investigator had concerns about the INRatio system.
Janssen did not inform ROCKET AF investigators or the trial’s data and safety monitoring board of the program. Bayer said it did not know about the program until this year, and the FDA and EMA have said the same.
Ponatinib approved to treat CML, ALL in Japan
Image from UCSD
The Japanese Pharmaceuticals and Medical Devices Agency (PMDA) has approved 2 uses of the tyrosine kinase inhibitor (TKI) ponatinib (Iclusig®).
The drug is now approved to treat recurrent or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) and chronic myeloid leukemia (CML) that was resistant to or intolerant of prior treatment.
Ponatinib will be manufactured and sold by Otsuka Pharmaceutical Co., Ltd.
Due to the limited existing treatment options for patients in Japan, Otsuka said it will provide access to ponatinib free of charge as soon as procedures are in place from an ethical standpoint.
This program will be offered at medical institutions where clinical trials of ponatinib were performed and which are amenable to accepting the drug access program until the product is listed on the Japan National Health Insurance price list.
About ponatinib
Ponatinib is a TKI discovered by ARIAD Pharmaceuticals, Inc. The drug has demonstrated activity against native and mutated BCR-ABL and other kinases.
The PMDA’s approval of ponatinib for CML and Ph+ ALL is based on data from a phase 1/2 trial of Japanese patients, a phase 1 trial, and the phase 2 PACE trial.
Extended follow-up data from the PACE trial, collected in 2013, suggested ponatinib can increase the risk of thrombotic events. When these data came to light, officials in the European Union and the US, where ponatinib had already been approved, began to investigate the drug.
Ponatinib was pulled from the US market for a little over 2 months, and trials of the TKI were placed on partial hold while the US Food and Drug Administration evaluated the drug’s safety. Ponatinib went back on the market in January 2014, with new safety measures in place.
Ponatinib was not pulled from the market in the European Union, but the European Medicine’s Agency released recommendations for safer use of the TKI. The Committee for Medicinal Products for Human Use reviewed data on ponatinib and decided its benefits outweigh its risks.
In addition to the European Union and the US, ponatinib has been approved in Australia, Canada, Israel, and Switzerland.
Image from UCSD
The Japanese Pharmaceuticals and Medical Devices Agency (PMDA) has approved 2 uses of the tyrosine kinase inhibitor (TKI) ponatinib (Iclusig®).
The drug is now approved to treat recurrent or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) and chronic myeloid leukemia (CML) that was resistant to or intolerant of prior treatment.
Ponatinib will be manufactured and sold by Otsuka Pharmaceutical Co., Ltd.
Due to the limited existing treatment options for patients in Japan, Otsuka said it will provide access to ponatinib free of charge as soon as procedures are in place from an ethical standpoint.
This program will be offered at medical institutions where clinical trials of ponatinib were performed and which are amenable to accepting the drug access program until the product is listed on the Japan National Health Insurance price list.
About ponatinib
Ponatinib is a TKI discovered by ARIAD Pharmaceuticals, Inc. The drug has demonstrated activity against native and mutated BCR-ABL and other kinases.
The PMDA’s approval of ponatinib for CML and Ph+ ALL is based on data from a phase 1/2 trial of Japanese patients, a phase 1 trial, and the phase 2 PACE trial.
Extended follow-up data from the PACE trial, collected in 2013, suggested ponatinib can increase the risk of thrombotic events. When these data came to light, officials in the European Union and the US, where ponatinib had already been approved, began to investigate the drug.
Ponatinib was pulled from the US market for a little over 2 months, and trials of the TKI were placed on partial hold while the US Food and Drug Administration evaluated the drug’s safety. Ponatinib went back on the market in January 2014, with new safety measures in place.
Ponatinib was not pulled from the market in the European Union, but the European Medicine’s Agency released recommendations for safer use of the TKI. The Committee for Medicinal Products for Human Use reviewed data on ponatinib and decided its benefits outweigh its risks.
In addition to the European Union and the US, ponatinib has been approved in Australia, Canada, Israel, and Switzerland.
Image from UCSD
The Japanese Pharmaceuticals and Medical Devices Agency (PMDA) has approved 2 uses of the tyrosine kinase inhibitor (TKI) ponatinib (Iclusig®).
The drug is now approved to treat recurrent or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) and chronic myeloid leukemia (CML) that was resistant to or intolerant of prior treatment.
Ponatinib will be manufactured and sold by Otsuka Pharmaceutical Co., Ltd.
Due to the limited existing treatment options for patients in Japan, Otsuka said it will provide access to ponatinib free of charge as soon as procedures are in place from an ethical standpoint.
This program will be offered at medical institutions where clinical trials of ponatinib were performed and which are amenable to accepting the drug access program until the product is listed on the Japan National Health Insurance price list.
About ponatinib
Ponatinib is a TKI discovered by ARIAD Pharmaceuticals, Inc. The drug has demonstrated activity against native and mutated BCR-ABL and other kinases.
The PMDA’s approval of ponatinib for CML and Ph+ ALL is based on data from a phase 1/2 trial of Japanese patients, a phase 1 trial, and the phase 2 PACE trial.
Extended follow-up data from the PACE trial, collected in 2013, suggested ponatinib can increase the risk of thrombotic events. When these data came to light, officials in the European Union and the US, where ponatinib had already been approved, began to investigate the drug.
Ponatinib was pulled from the US market for a little over 2 months, and trials of the TKI were placed on partial hold while the US Food and Drug Administration evaluated the drug’s safety. Ponatinib went back on the market in January 2014, with new safety measures in place.
Ponatinib was not pulled from the market in the European Union, but the European Medicine’s Agency released recommendations for safer use of the TKI. The Committee for Medicinal Products for Human Use reviewed data on ponatinib and decided its benefits outweigh its risks.
In addition to the European Union and the US, ponatinib has been approved in Australia, Canada, Israel, and Switzerland.
Study sheds light on platelet disorders
Image by Andre E.X. Brown
Preclinical research has unearthed additional information about how platelets respond to shear stress, answering a 20-year-old question.
Investigators said this research provides new insights regarding platelet activation and clearance as well as insights into the pathophysiology of von Willebrand disease and related thrombocytopenic disorders.
The team described this work in Nature Communications.
Past research suggested that platelets respond to shear stress through a protein complex called GPIb-IX located on the platelet surface, but how this complex senses and responds to shear stress has remained a mystery for the past 20 years.
With the current study, investigators found that, contrary to popular belief, a certain region within GPIb-IX is structured.
This so-called mechanosensory domain (MSD) becomes unfolded on the platelet surface when von Willebrand factor binds to the GPIbα subunit of GPIb–IX under shear stress and imposes a pulling force on it.
The unfolding of MSD sets off a complex chain of events and sends an intracellular signal into the platelet that results in rapid platelet clearance.
“Every day, your bone marrow generates more than a billion platelets, and, every day, you clear the same number,” said study author Renhao Li, PhD, of Emory University School of Medicine in Atlanta, Georgia.
“It’s critical that your platelet count stays constant. Too few platelets can lead to . . . thrombocytopenia and may cause spontaneous bleeding or stroke. Thus, identifying the molecular ‘switch’ that triggers platelet clearance is important for designing new therapies to treat thrombocytopenia.”
The mechanism behind MSD-unfolding-induced platelet clearance is still unclear, but Dr Li said this research provides a good starting point for further inquiry into the phenomenon.
Image by Andre E.X. Brown
Preclinical research has unearthed additional information about how platelets respond to shear stress, answering a 20-year-old question.
Investigators said this research provides new insights regarding platelet activation and clearance as well as insights into the pathophysiology of von Willebrand disease and related thrombocytopenic disorders.
The team described this work in Nature Communications.
Past research suggested that platelets respond to shear stress through a protein complex called GPIb-IX located on the platelet surface, but how this complex senses and responds to shear stress has remained a mystery for the past 20 years.
With the current study, investigators found that, contrary to popular belief, a certain region within GPIb-IX is structured.
This so-called mechanosensory domain (MSD) becomes unfolded on the platelet surface when von Willebrand factor binds to the GPIbα subunit of GPIb–IX under shear stress and imposes a pulling force on it.
The unfolding of MSD sets off a complex chain of events and sends an intracellular signal into the platelet that results in rapid platelet clearance.
“Every day, your bone marrow generates more than a billion platelets, and, every day, you clear the same number,” said study author Renhao Li, PhD, of Emory University School of Medicine in Atlanta, Georgia.
“It’s critical that your platelet count stays constant. Too few platelets can lead to . . . thrombocytopenia and may cause spontaneous bleeding or stroke. Thus, identifying the molecular ‘switch’ that triggers platelet clearance is important for designing new therapies to treat thrombocytopenia.”
The mechanism behind MSD-unfolding-induced platelet clearance is still unclear, but Dr Li said this research provides a good starting point for further inquiry into the phenomenon.
Image by Andre E.X. Brown
Preclinical research has unearthed additional information about how platelets respond to shear stress, answering a 20-year-old question.
Investigators said this research provides new insights regarding platelet activation and clearance as well as insights into the pathophysiology of von Willebrand disease and related thrombocytopenic disorders.
The team described this work in Nature Communications.
Past research suggested that platelets respond to shear stress through a protein complex called GPIb-IX located on the platelet surface, but how this complex senses and responds to shear stress has remained a mystery for the past 20 years.
With the current study, investigators found that, contrary to popular belief, a certain region within GPIb-IX is structured.
This so-called mechanosensory domain (MSD) becomes unfolded on the platelet surface when von Willebrand factor binds to the GPIbα subunit of GPIb–IX under shear stress and imposes a pulling force on it.
The unfolding of MSD sets off a complex chain of events and sends an intracellular signal into the platelet that results in rapid platelet clearance.
“Every day, your bone marrow generates more than a billion platelets, and, every day, you clear the same number,” said study author Renhao Li, PhD, of Emory University School of Medicine in Atlanta, Georgia.
“It’s critical that your platelet count stays constant. Too few platelets can lead to . . . thrombocytopenia and may cause spontaneous bleeding or stroke. Thus, identifying the molecular ‘switch’ that triggers platelet clearance is important for designing new therapies to treat thrombocytopenia.”
The mechanism behind MSD-unfolding-induced platelet clearance is still unclear, but Dr Li said this research provides a good starting point for further inquiry into the phenomenon.