HT Staff

Blood for transfusion

Photo courtesy of UAB Hospital

The US Food and Drug Administration (FDA) has issued a new guidance recommending the deferral of blood donors who have been to areas with active Zika virus transmission, may have been exposed to the virus, or have had a confirmed Zika virus infection.

In areas of the US without active Zika virus transmission, the FDA recommends that donors at risk for Zika virus infection be deferred for 4 weeks.

Individuals considered to be at risk include those who have had symptoms suggestive of Zika virus infection during the past 4 weeks, those who have had sexual contact with a person who has traveled to or resided in an area with active Zika virus transmission during the prior 3 months, and those who have traveled to areas with active transmission of Zika virus during the past 4 weeks.

In areas of the US with active Zika virus transmission (at present, the Commonwealth of Puerto Rico, the US Virgin Islands, and American Samoa), the FDA recommends that whole blood and blood components for transfusion be obtained from areas of the US without active transmission.

Blood establishments may continue collecting and preparing platelets and plasma if an FDA-approved pathogen-reduction device is used.

The FDA’s guidance also recommends that blood establishments update donor education materials with information about the signs and symptoms of Zika virus and ask potentially affected donors to refrain from giving blood.

“Based on the best available evidence, we believe the new recommendations will help reduce the risk of collecting blood and blood components from donors who may be infected with the Zika virus,” said Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research.

There have been no reports to date of Zika virus entering the US blood supply. However, the risk of blood transmission is considered likely based on the most current scientific evidence of how Zika virus and similar viruses (flaviviruses) are spread and recent reports of transfusion-associated infection outside the US.

Furthermore, about 4 out of 5 people infected with Zika virus do not become symptomatic. For these reasons, the FDA is recommending that blood establishments defer blood donations in accordance with the new guidance.

The FDA also intends to issue a guidance that will address appropriate donor deferral measures for human cells, tissues, and cellular and tissue-based products, given recent reports of sexual transmission of the Zika virus.

In addition, the FDA is prioritizing the development of blood screening and diagnostic tests that may be useful for identifying the Zika virus, preparing to evaluate the safety and efficacy of investigational vaccines and therapeutics that might be developed, and reviewing technology that may help suppress populations of mosquitoes that can spread the virus.

Blood for transfusion

Photo courtesy of UAB Hospital

The US Food and Drug Administration (FDA) has issued a new guidance recommending the deferral of blood donors who have been to areas with active Zika virus transmission, may have been exposed to the virus, or have had a confirmed Zika virus infection.

In areas of the US without active Zika virus transmission, the FDA recommends that donors at risk for Zika virus infection be deferred for 4 weeks.

Individuals considered to be at risk include those who have had symptoms suggestive of Zika virus infection during the past 4 weeks, those who have had sexual contact with a person who has traveled to or resided in an area with active Zika virus transmission during the prior 3 months, and those who have traveled to areas with active transmission of Zika virus during the past 4 weeks.

In areas of the US with active Zika virus transmission (at present, the Commonwealth of Puerto Rico, the US Virgin Islands, and American Samoa), the FDA recommends that whole blood and blood components for transfusion be obtained from areas of the US without active transmission.

Blood establishments may continue collecting and preparing platelets and plasma if an FDA-approved pathogen-reduction device is used.

The FDA’s guidance also recommends that blood establishments update donor education materials with information about the signs and symptoms of Zika virus and ask potentially affected donors to refrain from giving blood.

“Based on the best available evidence, we believe the new recommendations will help reduce the risk of collecting blood and blood components from donors who may be infected with the Zika virus,” said Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research.

There have been no reports to date of Zika virus entering the US blood supply. However, the risk of blood transmission is considered likely based on the most current scientific evidence of how Zika virus and similar viruses (flaviviruses) are spread and recent reports of transfusion-associated infection outside the US.

Furthermore, about 4 out of 5 people infected with Zika virus do not become symptomatic. For these reasons, the FDA is recommending that blood establishments defer blood donations in accordance with the new guidance.

The FDA also intends to issue a guidance that will address appropriate donor deferral measures for human cells, tissues, and cellular and tissue-based products, given recent reports of sexual transmission of the Zika virus.

In addition, the FDA is prioritizing the development of blood screening and diagnostic tests that may be useful for identifying the Zika virus, preparing to evaluate the safety and efficacy of investigational vaccines and therapeutics that might be developed, and reviewing technology that may help suppress populations of mosquitoes that can spread the virus.

Blood for transfusion

Photo courtesy of UAB Hospital

The US Food and Drug Administration (FDA) has issued a new guidance recommending the deferral of blood donors who have been to areas with active Zika virus transmission, may have been exposed to the virus, or have had a confirmed Zika virus infection.

In areas of the US without active Zika virus transmission, the FDA recommends that donors at risk for Zika virus infection be deferred for 4 weeks.

Individuals considered to be at risk include those who have had symptoms suggestive of Zika virus infection during the past 4 weeks, those who have had sexual contact with a person who has traveled to or resided in an area with active Zika virus transmission during the prior 3 months, and those who have traveled to areas with active transmission of Zika virus during the past 4 weeks.

In areas of the US with active Zika virus transmission (at present, the Commonwealth of Puerto Rico, the US Virgin Islands, and American Samoa), the FDA recommends that whole blood and blood components for transfusion be obtained from areas of the US without active transmission.

Blood establishments may continue collecting and preparing platelets and plasma if an FDA-approved pathogen-reduction device is used.

The FDA’s guidance also recommends that blood establishments update donor education materials with information about the signs and symptoms of Zika virus and ask potentially affected donors to refrain from giving blood.

“Based on the best available evidence, we believe the new recommendations will help reduce the risk of collecting blood and blood components from donors who may be infected with the Zika virus,” said Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research.

There have been no reports to date of Zika virus entering the US blood supply. However, the risk of blood transmission is considered likely based on the most current scientific evidence of how Zika virus and similar viruses (flaviviruses) are spread and recent reports of transfusion-associated infection outside the US.

Furthermore, about 4 out of 5 people infected with Zika virus do not become symptomatic. For these reasons, the FDA is recommending that blood establishments defer blood donations in accordance with the new guidance.

The FDA also intends to issue a guidance that will address appropriate donor deferral measures for human cells, tissues, and cellular and tissue-based products, given recent reports of sexual transmission of the Zika virus.

In addition, the FDA is prioritizing the development of blood screening and diagnostic tests that may be useful for identifying the Zika virus, preparing to evaluate the safety and efficacy of investigational vaccines and therapeutics that might be developed, and reviewing technology that may help suppress populations of mosquitoes that can spread the virus.

Drug release in a cancer cell

Image courtesy of PNAS

Researchers say they have determined how the investigational drug ONC201 is active against a range of malignancies.

The team found that ONC201 induced apoptosis and cell cycle arrest in multiple myeloma (MM) and solid tumor cell lines.

The drug triggered an increase in the anticancer protein TRAIL and induced cell death through an integrated stress response (ISR) involving the transcription factor ATF4, the transactivator CHOP, and the TRAIL receptor DR5.

The researchers reported these findings in Science Signaling. Some researchers involved in this study are affiliated with Oncoceutics Inc., the company developing ONC201.

“We have revealed, in unprecedented detail, exactly how ONC201 works across a broad range of tumor types, and this has important clinical implications,” said study author Wafik El-Deiry, MD, PhD, of Fox Chase Cancer Center in Philadelphia, Pennsylvania.

“For example, our findings suggest that patients with various solid tumors, as well as multiple myeloma, may be particularly sensitive to the effects of ONC201. We have identified a potential biomarker that could be used to select which patients are most likely to benefit therapeutically from this drug.”

Dr El-Deiry noted that TRAIL has been shown to induce cell death in a range of cancers while sparing normal cells. However, the therapeutic benefit of stimulating TRAIL is limited because of undesirable drug properties, such as a short half-life, difficult and expensive production, the need to give treatment as an intravenous infusion, and poor penetration into certain tissues like the brain.

“This prompted us to look for better options for therapeutics that can kill tumor cells,” Dr El-Deiry said.

He and his colleagues turned to ONC201, which has been shown to stimulate TRAIL. They tested the drug in 23 cancer cell lines representing 9 tumor types—MM, lymphoma, and glioma, as well as lung, colorectal, thyroid, liver, prostate, and breast cancer.

The team found that ONC201 triggers an increase in TRAIL and TRAIL receptor abundance, leading to tumor cell death through the ISR that tumor cells normally use to survive. ONC201 pushes the ISR too far, causing tumor cells to stop dividing and/or die.

ONC201 boosted expression of the gene encoding ATF4, a central component of the ISR, through a translation initiation factor called eIF2α. This process rapidly arrested the cancer’s cell cycle and resulted in cell death.

In essence, ONC201 delivers a double-whammy to tumor cells, Dr El-Deiry said, which may explain why it has such broad-spectrum anticancer activity.

The researchers believe this study has several clinical implications. For one, it suggests that solid tumors or MM cells that normally create large amounts of protein during growth may be particularly sensitive to ONC201. The ISR is often activated in these cells, and ONC201 may push them over the edge.

“Knowing how ONC201 works helps us look for its effects in patient’s tumor cells that have been treated,” Dr El-Deiry said. “Looking in a tumor or liquid biopsy before and after treatment may help predict who is most likely to benefit.”

“We are optimistic that, through basic and clinical research with ONC201, our findings will lead to improved TRAIL-based therapies for individual cancer patients in the future.”

Another study of ONC201, this one focusing only on hematologic malignancies, has been published in Science Signaling.

Early stage clinical trials for ONC201 are currently underway in patients with brain, colorectal, breast, and lung tumors, as well as leukemia and lymphoma.

Drug release in a cancer cell

Image courtesy of PNAS

Researchers say they have determined how the investigational drug ONC201 is active against a range of malignancies.

The team found that ONC201 induced apoptosis and cell cycle arrest in multiple myeloma (MM) and solid tumor cell lines.

The drug triggered an increase in the anticancer protein TRAIL and induced cell death through an integrated stress response (ISR) involving the transcription factor ATF4, the transactivator CHOP, and the TRAIL receptor DR5.

The researchers reported these findings in Science Signaling. Some researchers involved in this study are affiliated with Oncoceutics Inc., the company developing ONC201.

“We have revealed, in unprecedented detail, exactly how ONC201 works across a broad range of tumor types, and this has important clinical implications,” said study author Wafik El-Deiry, MD, PhD, of Fox Chase Cancer Center in Philadelphia, Pennsylvania.

“For example, our findings suggest that patients with various solid tumors, as well as multiple myeloma, may be particularly sensitive to the effects of ONC201. We have identified a potential biomarker that could be used to select which patients are most likely to benefit therapeutically from this drug.”

Dr El-Deiry noted that TRAIL has been shown to induce cell death in a range of cancers while sparing normal cells. However, the therapeutic benefit of stimulating TRAIL is limited because of undesirable drug properties, such as a short half-life, difficult and expensive production, the need to give treatment as an intravenous infusion, and poor penetration into certain tissues like the brain.

“This prompted us to look for better options for therapeutics that can kill tumor cells,” Dr El-Deiry said.

He and his colleagues turned to ONC201, which has been shown to stimulate TRAIL. They tested the drug in 23 cancer cell lines representing 9 tumor types—MM, lymphoma, and glioma, as well as lung, colorectal, thyroid, liver, prostate, and breast cancer.

The team found that ONC201 triggers an increase in TRAIL and TRAIL receptor abundance, leading to tumor cell death through the ISR that tumor cells normally use to survive. ONC201 pushes the ISR too far, causing tumor cells to stop dividing and/or die.

ONC201 boosted expression of the gene encoding ATF4, a central component of the ISR, through a translation initiation factor called eIF2α. This process rapidly arrested the cancer’s cell cycle and resulted in cell death.

In essence, ONC201 delivers a double-whammy to tumor cells, Dr El-Deiry said, which may explain why it has such broad-spectrum anticancer activity.

The researchers believe this study has several clinical implications. For one, it suggests that solid tumors or MM cells that normally create large amounts of protein during growth may be particularly sensitive to ONC201. The ISR is often activated in these cells, and ONC201 may push them over the edge.

“Knowing how ONC201 works helps us look for its effects in patient’s tumor cells that have been treated,” Dr El-Deiry said. “Looking in a tumor or liquid biopsy before and after treatment may help predict who is most likely to benefit.”

“We are optimistic that, through basic and clinical research with ONC201, our findings will lead to improved TRAIL-based therapies for individual cancer patients in the future.”

Another study of ONC201, this one focusing only on hematologic malignancies, has been published in Science Signaling.

Early stage clinical trials for ONC201 are currently underway in patients with brain, colorectal, breast, and lung tumors, as well as leukemia and lymphoma.

Drug release in a cancer cell

Image courtesy of PNAS

Researchers say they have determined how the investigational drug ONC201 is active against a range of malignancies.

The team found that ONC201 induced apoptosis and cell cycle arrest in multiple myeloma (MM) and solid tumor cell lines.

The drug triggered an increase in the anticancer protein TRAIL and induced cell death through an integrated stress response (ISR) involving the transcription factor ATF4, the transactivator CHOP, and the TRAIL receptor DR5.

The researchers reported these findings in Science Signaling. Some researchers involved in this study are affiliated with Oncoceutics Inc., the company developing ONC201.

“We have revealed, in unprecedented detail, exactly how ONC201 works across a broad range of tumor types, and this has important clinical implications,” said study author Wafik El-Deiry, MD, PhD, of Fox Chase Cancer Center in Philadelphia, Pennsylvania.

“For example, our findings suggest that patients with various solid tumors, as well as multiple myeloma, may be particularly sensitive to the effects of ONC201. We have identified a potential biomarker that could be used to select which patients are most likely to benefit therapeutically from this drug.”

Dr El-Deiry noted that TRAIL has been shown to induce cell death in a range of cancers while sparing normal cells. However, the therapeutic benefit of stimulating TRAIL is limited because of undesirable drug properties, such as a short half-life, difficult and expensive production, the need to give treatment as an intravenous infusion, and poor penetration into certain tissues like the brain.

“This prompted us to look for better options for therapeutics that can kill tumor cells,” Dr El-Deiry said.

He and his colleagues turned to ONC201, which has been shown to stimulate TRAIL. They tested the drug in 23 cancer cell lines representing 9 tumor types—MM, lymphoma, and glioma, as well as lung, colorectal, thyroid, liver, prostate, and breast cancer.

The team found that ONC201 triggers an increase in TRAIL and TRAIL receptor abundance, leading to tumor cell death through the ISR that tumor cells normally use to survive. ONC201 pushes the ISR too far, causing tumor cells to stop dividing and/or die.

ONC201 boosted expression of the gene encoding ATF4, a central component of the ISR, through a translation initiation factor called eIF2α. This process rapidly arrested the cancer’s cell cycle and resulted in cell death.

In essence, ONC201 delivers a double-whammy to tumor cells, Dr El-Deiry said, which may explain why it has such broad-spectrum anticancer activity.

The researchers believe this study has several clinical implications. For one, it suggests that solid tumors or MM cells that normally create large amounts of protein during growth may be particularly sensitive to ONC201. The ISR is often activated in these cells, and ONC201 may push them over the edge.

“Knowing how ONC201 works helps us look for its effects in patient’s tumor cells that have been treated,” Dr El-Deiry said. “Looking in a tumor or liquid biopsy before and after treatment may help predict who is most likely to benefit.”

“We are optimistic that, through basic and clinical research with ONC201, our findings will lead to improved TRAIL-based therapies for individual cancer patients in the future.”

Another study of ONC201, this one focusing only on hematologic malignancies, has been published in Science Signaling.

Early stage clinical trials for ONC201 are currently underway in patients with brain, colorectal, breast, and lung tumors, as well as leukemia and lymphoma.

Michael Andreeff, MD, PhD

Preclinical research suggests the investigational anticancer drug ONC201 can be effective against mantle cell lymphoma (MCL) and acute myeloid leukemia (AML).

ONC201 induced p53-independent apoptosis in AML and MCL cell lines and in samples from patients with either disease.

Investigators noted that p53 dysfunction occurs in more than half of malignancies and can promote resistance to standard chemotherapy.

“The clinical challenge posed by p53 abnormalities in blood malignancies is that therapeutic strategies other than standard chemotherapies are required,” said Michael Andreeff, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston.

“We found that ONC201 caused p53-independent cell death and cell cycle arrest in cell lines and in lymphoma and acute leukemia patient samples.”

Dr Andreeff and his colleagues reported these findings in Science Signaling. Some of the investigators involved in this research are affiliated with Oncoceutics Inc., the company developing ONC201.

Dr Andreeff and his colleagues assessed the effects of ONC201 against AML and MCL, in both cultured cell lines and primary cells bearing either wild-type or mutant p53.

The patient samples included those that demonstrated genetic abnormalities linked to poor prognosis (FLT3 mutations, TP53 mutations) or resistance to ibrutinib. The team also tested ONC201 in a bortezomib-resistant myeloma cell line.

The experiments showed that ONC201 exerted anticancer activity regardless of p53 status, FLT3 mutations, or drug resistance. ONC201 proved active in the bortezomib-resistant myeloma cell line and in ibrutinib-resistant samples from MCL patients.

Experiments in mice showed that ONC201 caused cell death in AML and leukemia stem cells while sparing normal bone marrow cells.

And the investigators found that combining ONC201 with the BCL-2 antagonist venetoclax (ABT-199) synergistically increased apoptosis.

Further investigation revealed that ONC201 increased translation of the stress-induced protein ATF4 through stress signals similar to those caused by unfolded protein response (UPR) and integrated stress response (ISR).

“This increase in ATF4 in ONC201-treated hematopoietic cells promoted cell death,” Dr Andreeff explained. “However, unlike with UPR and ISR, the increase in ATF4 in ONC201-treated cells was not regulated by standard molecular signaling, indicating a novel mechanism of stressing cancer cells to death regardless of p53 status.”

The investigators noted that the mechanisms of ONC201 identified in solid tumors—namely, induction of TRAIL and DR5—were not operational in leukemia and lymphoma.

A study of ONC201 in solid tumors and multiple myeloma was published alongside this study in Science Signaling.

“There is clear evidence that ONC201 has clinical potential in hematological malignancies,” Dr Andreeff noted. “Clinical trials in leukemia and lymphoma patients have recently been initiated at MD Anderson.”

Michael Andreeff, MD, PhD

Preclinical research suggests the investigational anticancer drug ONC201 can be effective against mantle cell lymphoma (MCL) and acute myeloid leukemia (AML).

ONC201 induced p53-independent apoptosis in AML and MCL cell lines and in samples from patients with either disease.

Investigators noted that p53 dysfunction occurs in more than half of malignancies and can promote resistance to standard chemotherapy.

“The clinical challenge posed by p53 abnormalities in blood malignancies is that therapeutic strategies other than standard chemotherapies are required,” said Michael Andreeff, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston.

“We found that ONC201 caused p53-independent cell death and cell cycle arrest in cell lines and in lymphoma and acute leukemia patient samples.”

Dr Andreeff and his colleagues reported these findings in Science Signaling. Some of the investigators involved in this research are affiliated with Oncoceutics Inc., the company developing ONC201.

Dr Andreeff and his colleagues assessed the effects of ONC201 against AML and MCL, in both cultured cell lines and primary cells bearing either wild-type or mutant p53.

The patient samples included those that demonstrated genetic abnormalities linked to poor prognosis (FLT3 mutations, TP53 mutations) or resistance to ibrutinib. The team also tested ONC201 in a bortezomib-resistant myeloma cell line.

The experiments showed that ONC201 exerted anticancer activity regardless of p53 status, FLT3 mutations, or drug resistance. ONC201 proved active in the bortezomib-resistant myeloma cell line and in ibrutinib-resistant samples from MCL patients.

Experiments in mice showed that ONC201 caused cell death in AML and leukemia stem cells while sparing normal bone marrow cells.

And the investigators found that combining ONC201 with the BCL-2 antagonist venetoclax (ABT-199) synergistically increased apoptosis.

Further investigation revealed that ONC201 increased translation of the stress-induced protein ATF4 through stress signals similar to those caused by unfolded protein response (UPR) and integrated stress response (ISR).

“This increase in ATF4 in ONC201-treated hematopoietic cells promoted cell death,” Dr Andreeff explained. “However, unlike with UPR and ISR, the increase in ATF4 in ONC201-treated cells was not regulated by standard molecular signaling, indicating a novel mechanism of stressing cancer cells to death regardless of p53 status.”

The investigators noted that the mechanisms of ONC201 identified in solid tumors—namely, induction of TRAIL and DR5—were not operational in leukemia and lymphoma.

A study of ONC201 in solid tumors and multiple myeloma was published alongside this study in Science Signaling.

“There is clear evidence that ONC201 has clinical potential in hematological malignancies,” Dr Andreeff noted. “Clinical trials in leukemia and lymphoma patients have recently been initiated at MD Anderson.”

Michael Andreeff, MD, PhD

Preclinical research suggests the investigational anticancer drug ONC201 can be effective against mantle cell lymphoma (MCL) and acute myeloid leukemia (AML).

ONC201 induced p53-independent apoptosis in AML and MCL cell lines and in samples from patients with either disease.

Investigators noted that p53 dysfunction occurs in more than half of malignancies and can promote resistance to standard chemotherapy.

“The clinical challenge posed by p53 abnormalities in blood malignancies is that therapeutic strategies other than standard chemotherapies are required,” said Michael Andreeff, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston.

“We found that ONC201 caused p53-independent cell death and cell cycle arrest in cell lines and in lymphoma and acute leukemia patient samples.”

Dr Andreeff and his colleagues reported these findings in Science Signaling. Some of the investigators involved in this research are affiliated with Oncoceutics Inc., the company developing ONC201.

Dr Andreeff and his colleagues assessed the effects of ONC201 against AML and MCL, in both cultured cell lines and primary cells bearing either wild-type or mutant p53.

The patient samples included those that demonstrated genetic abnormalities linked to poor prognosis (FLT3 mutations, TP53 mutations) or resistance to ibrutinib. The team also tested ONC201 in a bortezomib-resistant myeloma cell line.

The experiments showed that ONC201 exerted anticancer activity regardless of p53 status, FLT3 mutations, or drug resistance. ONC201 proved active in the bortezomib-resistant myeloma cell line and in ibrutinib-resistant samples from MCL patients.

Experiments in mice showed that ONC201 caused cell death in AML and leukemia stem cells while sparing normal bone marrow cells.

And the investigators found that combining ONC201 with the BCL-2 antagonist venetoclax (ABT-199) synergistically increased apoptosis.

Further investigation revealed that ONC201 increased translation of the stress-induced protein ATF4 through stress signals similar to those caused by unfolded protein response (UPR) and integrated stress response (ISR).

“This increase in ATF4 in ONC201-treated hematopoietic cells promoted cell death,” Dr Andreeff explained. “However, unlike with UPR and ISR, the increase in ATF4 in ONC201-treated cells was not regulated by standard molecular signaling, indicating a novel mechanism of stressing cancer cells to death regardless of p53 status.”

The investigators noted that the mechanisms of ONC201 identified in solid tumors—namely, induction of TRAIL and DR5—were not operational in leukemia and lymphoma.

A study of ONC201 in solid tumors and multiple myeloma was published alongside this study in Science Signaling.

“There is clear evidence that ONC201 has clinical potential in hematological malignancies,” Dr Andreeff noted. “Clinical trials in leukemia and lymphoma patients have recently been initiated at MD Anderson.”

Researchers in the lab

Photo by Rhoda Baer

The peer-review process the National Institutes of Health (NIH) use to allocate government research funds to US scientists may work no better than distributing those dollars at random, according to a group of researchers.

The group said their findings, published in eLife, suggest that peer review is not necessarily funding the best science, and awarding grants by lottery might actually produce equally good, if not better, results.

“The NIH claims that they are funding the best grants by the best scientists,” said study author Arturo Casadevall, MD, PhD, of the Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland.

“While [our] data would argue that the NIH is funding a lot of very good science, they are also leaving a lot of very good science on the table. The government can’t afford to fund every good grant proposal, but the problems with the current system make it worse than awarding grants through a lottery.”

The researchers noted that the NIH rejects the majority of research grant proposals it receives. To decide which proposals to fund, the organization relies on expert panels whose members score each application. Funding decisions are made on the basis of these scores and the amount of available funds.

In recent years, the NIH has only funded those proposals ranked around the top 10%. The 2015 annual research budget for the NIH was $30.1 billion.

For their study, Dr Casadevall and his colleagues reanalyzed data on the 102,740 research project grants funded by the NIH from 1980 through 2008.

Another group of researchers previously collected the data. Their research, published in Science in 2015, suggested that peer review works, as the highest ranked research projects funded by the NIH earned the most citations.

For the current study, Dr Casadevall and his colleagues decided to look only at the top 20% of grants awarded. They found very little difference between the top-ranked projects and those projects ranked in the 20th percentile when it came to citations.

What the peer-review process can do, they determined, is discriminate between very good science and very bad science—that is, those in the top 20% versus those below the 50th percentile.

“We are not criticizing the peer reviewers,” said study author Ferric Fang, MD, of the University of Washington in Seattle.

“We are simply showing that there are limits to the ability of peer review to predict future productivity based on grant applications. This suggests that some of the resources and effort spent on ranking applications might be better spent elsewhere. While the average productivity of grants with better scores was somewhat higher, the differences were extremely small, raising questions as to whether the effort is worthwhile.”

The researchers noted that peer review isn’t cheap. The annual budget of the NIH Center for Scientific Review is $110 million. Individual NIH institutes and centers also spend money on peer review. The team said that money could be used toward more grants.

They also noted that peer review allows for substantial subjectivity. The objection of a single member of the committee can effectively kill a grant proposal, whether that objection is legitimate or not.

“When people’s opinions count a lot, we may be doing worse than choosing at random,” Dr Casadevall said. “A negative word at the table can often swing the debate. And this is how we allocate research funding in this country.”

However, Dr Casadevall and his colleagues do not recommend abandoning the peer-review process completely. They believe a way to improve the system might be to continue using peer review to identify the top proposals but then place those proposals into a lottery, with grants awarded at random.

Researchers in the lab

Photo by Rhoda Baer

The peer-review process the National Institutes of Health (NIH) use to allocate government research funds to US scientists may work no better than distributing those dollars at random, according to a group of researchers.

The group said their findings, published in eLife, suggest that peer review is not necessarily funding the best science, and awarding grants by lottery might actually produce equally good, if not better, results.

“The NIH claims that they are funding the best grants by the best scientists,” said study author Arturo Casadevall, MD, PhD, of the Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland.

“While [our] data would argue that the NIH is funding a lot of very good science, they are also leaving a lot of very good science on the table. The government can’t afford to fund every good grant proposal, but the problems with the current system make it worse than awarding grants through a lottery.”

The researchers noted that the NIH rejects the majority of research grant proposals it receives. To decide which proposals to fund, the organization relies on expert panels whose members score each application. Funding decisions are made on the basis of these scores and the amount of available funds.

In recent years, the NIH has only funded those proposals ranked around the top 10%. The 2015 annual research budget for the NIH was $30.1 billion.

For their study, Dr Casadevall and his colleagues reanalyzed data on the 102,740 research project grants funded by the NIH from 1980 through 2008.

Another group of researchers previously collected the data. Their research, published in Science in 2015, suggested that peer review works, as the highest ranked research projects funded by the NIH earned the most citations.

For the current study, Dr Casadevall and his colleagues decided to look only at the top 20% of grants awarded. They found very little difference between the top-ranked projects and those projects ranked in the 20th percentile when it came to citations.

What the peer-review process can do, they determined, is discriminate between very good science and very bad science—that is, those in the top 20% versus those below the 50th percentile.

“We are not criticizing the peer reviewers,” said study author Ferric Fang, MD, of the University of Washington in Seattle.

“We are simply showing that there are limits to the ability of peer review to predict future productivity based on grant applications. This suggests that some of the resources and effort spent on ranking applications might be better spent elsewhere. While the average productivity of grants with better scores was somewhat higher, the differences were extremely small, raising questions as to whether the effort is worthwhile.”

The researchers noted that peer review isn’t cheap. The annual budget of the NIH Center for Scientific Review is $110 million. Individual NIH institutes and centers also spend money on peer review. The team said that money could be used toward more grants.

They also noted that peer review allows for substantial subjectivity. The objection of a single member of the committee can effectively kill a grant proposal, whether that objection is legitimate or not.

“When people’s opinions count a lot, we may be doing worse than choosing at random,” Dr Casadevall said. “A negative word at the table can often swing the debate. And this is how we allocate research funding in this country.”

However, Dr Casadevall and his colleagues do not recommend abandoning the peer-review process completely. They believe a way to improve the system might be to continue using peer review to identify the top proposals but then place those proposals into a lottery, with grants awarded at random.

Researchers in the lab

Photo by Rhoda Baer

The peer-review process the National Institutes of Health (NIH) use to allocate government research funds to US scientists may work no better than distributing those dollars at random, according to a group of researchers.

The group said their findings, published in eLife, suggest that peer review is not necessarily funding the best science, and awarding grants by lottery might actually produce equally good, if not better, results.

“The NIH claims that they are funding the best grants by the best scientists,” said study author Arturo Casadevall, MD, PhD, of the Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland.

“While [our] data would argue that the NIH is funding a lot of very good science, they are also leaving a lot of very good science on the table. The government can’t afford to fund every good grant proposal, but the problems with the current system make it worse than awarding grants through a lottery.”

The researchers noted that the NIH rejects the majority of research grant proposals it receives. To decide which proposals to fund, the organization relies on expert panels whose members score each application. Funding decisions are made on the basis of these scores and the amount of available funds.

In recent years, the NIH has only funded those proposals ranked around the top 10%. The 2015 annual research budget for the NIH was $30.1 billion.

For their study, Dr Casadevall and his colleagues reanalyzed data on the 102,740 research project grants funded by the NIH from 1980 through 2008.

Another group of researchers previously collected the data. Their research, published in Science in 2015, suggested that peer review works, as the highest ranked research projects funded by the NIH earned the most citations.

For the current study, Dr Casadevall and his colleagues decided to look only at the top 20% of grants awarded. They found very little difference between the top-ranked projects and those projects ranked in the 20th percentile when it came to citations.

What the peer-review process can do, they determined, is discriminate between very good science and very bad science—that is, those in the top 20% versus those below the 50th percentile.

“We are not criticizing the peer reviewers,” said study author Ferric Fang, MD, of the University of Washington in Seattle.

“We are simply showing that there are limits to the ability of peer review to predict future productivity based on grant applications. This suggests that some of the resources and effort spent on ranking applications might be better spent elsewhere. While the average productivity of grants with better scores was somewhat higher, the differences were extremely small, raising questions as to whether the effort is worthwhile.”

The researchers noted that peer review isn’t cheap. The annual budget of the NIH Center for Scientific Review is $110 million. Individual NIH institutes and centers also spend money on peer review. The team said that money could be used toward more grants.

They also noted that peer review allows for substantial subjectivity. The objection of a single member of the committee can effectively kill a grant proposal, whether that objection is legitimate or not.

“When people’s opinions count a lot, we may be doing worse than choosing at random,” Dr Casadevall said. “A negative word at the table can often swing the debate. And this is how we allocate research funding in this country.”

However, Dr Casadevall and his colleagues do not recommend abandoning the peer-review process completely. They believe a way to improve the system might be to continue using peer review to identify the top proposals but then place those proposals into a lottery, with grants awarded at random.

Lab mice

Photo by Aaron Logan

A new screening method has revealed genes that regulate how hematopoietic stem and progenitor cells (HSPCs) grow and thrive in mice.

Researchers used this method to uncover 17 genes that are regulators of hematopoietic stem cell transplant (HSCT).

Thirteen of these genes had never before been linked to HSPC engraftment.

The researchers reported their findings in the Journal of Experimental Medicine.

“We recognized that one barrier to improving [HSCT] is a lack of understanding of how [HSPCs] successfully grow in the challenged environment of transplant, so we set out to identify the genes that control this process,” said Shannon McKinney-Freeman, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

Dr McKinney-Freeman and her colleagues transplanted more than 1300 mice with shRNA-transduced HSPCs and searched for genes that regulate HSPC repopulation.

The team identified 17 such genes—Arhgef5, Armcx1, Cadps2, Crispld1, Emcn, Foxa3, Fstl1, Glis2, Gprasp2, Gpr56, Myct1, Nbea, P2ry14, Smarca2, Sox4, Stat4, and Zfp251.

For most of these genes, knockdown yielded a loss of function. The exceptions were Armcx1 and Gprasp2, whose loss enhanced HSPC repopulation.

“Our functional screen in mice is a first step to enhancing [HSCT],” Dr McKinney-Freeman said. “If we are to improve transplant outcomes in patients, we next need to study these identified genes and the molecules they specify in much more detail.”

“The more we understand the full scope of the molecular mechanisms that regulate stable engraftment of [HSPCs], the better equipped we will be to develop and clinically test novel therapies to improve health outcomes.”

Lab mice

Photo by Aaron Logan

A new screening method has revealed genes that regulate how hematopoietic stem and progenitor cells (HSPCs) grow and thrive in mice.

Researchers used this method to uncover 17 genes that are regulators of hematopoietic stem cell transplant (HSCT).

Thirteen of these genes had never before been linked to HSPC engraftment.

The researchers reported their findings in the Journal of Experimental Medicine.

“We recognized that one barrier to improving [HSCT] is a lack of understanding of how [HSPCs] successfully grow in the challenged environment of transplant, so we set out to identify the genes that control this process,” said Shannon McKinney-Freeman, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

Dr McKinney-Freeman and her colleagues transplanted more than 1300 mice with shRNA-transduced HSPCs and searched for genes that regulate HSPC repopulation.

The team identified 17 such genes—Arhgef5, Armcx1, Cadps2, Crispld1, Emcn, Foxa3, Fstl1, Glis2, Gprasp2, Gpr56, Myct1, Nbea, P2ry14, Smarca2, Sox4, Stat4, and Zfp251.

For most of these genes, knockdown yielded a loss of function. The exceptions were Armcx1 and Gprasp2, whose loss enhanced HSPC repopulation.

“Our functional screen in mice is a first step to enhancing [HSCT],” Dr McKinney-Freeman said. “If we are to improve transplant outcomes in patients, we next need to study these identified genes and the molecules they specify in much more detail.”

“The more we understand the full scope of the molecular mechanisms that regulate stable engraftment of [HSPCs], the better equipped we will be to develop and clinically test novel therapies to improve health outcomes.”

Lab mice

Photo by Aaron Logan

A new screening method has revealed genes that regulate how hematopoietic stem and progenitor cells (HSPCs) grow and thrive in mice.

Researchers used this method to uncover 17 genes that are regulators of hematopoietic stem cell transplant (HSCT).

Thirteen of these genes had never before been linked to HSPC engraftment.

The researchers reported their findings in the Journal of Experimental Medicine.

“We recognized that one barrier to improving [HSCT] is a lack of understanding of how [HSPCs] successfully grow in the challenged environment of transplant, so we set out to identify the genes that control this process,” said Shannon McKinney-Freeman, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

Dr McKinney-Freeman and her colleagues transplanted more than 1300 mice with shRNA-transduced HSPCs and searched for genes that regulate HSPC repopulation.

The team identified 17 such genes—Arhgef5, Armcx1, Cadps2, Crispld1, Emcn, Foxa3, Fstl1, Glis2, Gprasp2, Gpr56, Myct1, Nbea, P2ry14, Smarca2, Sox4, Stat4, and Zfp251.

For most of these genes, knockdown yielded a loss of function. The exceptions were Armcx1 and Gprasp2, whose loss enhanced HSPC repopulation.

“Our functional screen in mice is a first step to enhancing [HSCT],” Dr McKinney-Freeman said. “If we are to improve transplant outcomes in patients, we next need to study these identified genes and the molecules they specify in much more detail.”

“The more we understand the full scope of the molecular mechanisms that regulate stable engraftment of [HSPCs], the better equipped we will be to develop and clinically test novel therapies to improve health outcomes.”

Prescription medications

Photo courtesy of the CDC

New research has revealed inherited genetic variations that may predispose patients to severe toxicity from thiopurines, a class of medications used as anticancer and immunosuppressive drugs.

Investigators identified 4 variations in the NUDT15 gene that alter thiopurine metabolism, leaving patients particularly sensitive to the drugs and at risk for toxicity.

One in 3 Japanese patients in this study carried the variations.

And evidence suggests the variations are common in other populations across Asia and in individuals of Hispanic ethnicity.

Jun J. Yang, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues reported these findings in Nature Genetics.

In 2015, Dr Yang and his colleagues published evidence linking a NUDT15 variant to reduced tolerance of mercaptopurine and reported the variant was more common in patients of East Asian ancestry.

With the current study, the investigators identified 3 additional NUDT15 variants and found that all 4 variants—p.Arg139Cys, p.Arg139His, p.Val18Ile, and p.Val18_Val19insGlyVal—were associated with lower levels of enzymatic activity and imbalance of thiopurine metabolism.

In a group of 270 children with acute lymphoblastic leukemia (ALL), the variants caused a 74.4% to 100% loss of NUDT15 function. They also predicted enzyme activity and mercaptopurine tolerance. In Singapore and Japan, for example, patients with the 2 highest risk variants had the lowest level of enzyme activity.

“These patients had excessive levels of the active drug metabolites per mercaptopurine dose, which suggests we may reduce the drug dose to achieve the level necessary to kill leukemia cells without causing toxicity,” Dr Yang said, adding that the NUDT15 variants have no other known health consequences.

The investigators also checked leukemic cells from 285 children newly diagnosed with ALL and found that patients with NUDT15 variants were more sensitive to thiopurines.

“That suggests we can screen for NUDT15 variants and potentially plan mercaptopurine doses according to each patient’s genotype before the therapy starts,” Dr Yang said. “This way, we hope to avoid toxicity without compromising treatment effectiveness.”

The investigators noted that future studies are needed to determine optimal thiopurine doses for patients with different NUDT15 variants.

Meanwhile, the search continues for variants in NUDT15 or other genes that influence chemotherapy effectiveness and safety. The NUDT15 variants and previously identified TPMT variants could not fully explain why Guatemalan patients in this study tolerated the lowest doses of mercaptopurine.

Prescription medications

Photo courtesy of the CDC

New research has revealed inherited genetic variations that may predispose patients to severe toxicity from thiopurines, a class of medications used as anticancer and immunosuppressive drugs.

Investigators identified 4 variations in the NUDT15 gene that alter thiopurine metabolism, leaving patients particularly sensitive to the drugs and at risk for toxicity.

One in 3 Japanese patients in this study carried the variations.

And evidence suggests the variations are common in other populations across Asia and in individuals of Hispanic ethnicity.

Jun J. Yang, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues reported these findings in Nature Genetics.

In 2015, Dr Yang and his colleagues published evidence linking a NUDT15 variant to reduced tolerance of mercaptopurine and reported the variant was more common in patients of East Asian ancestry.

With the current study, the investigators identified 3 additional NUDT15 variants and found that all 4 variants—p.Arg139Cys, p.Arg139His, p.Val18Ile, and p.Val18_Val19insGlyVal—were associated with lower levels of enzymatic activity and imbalance of thiopurine metabolism.

In a group of 270 children with acute lymphoblastic leukemia (ALL), the variants caused a 74.4% to 100% loss of NUDT15 function. They also predicted enzyme activity and mercaptopurine tolerance. In Singapore and Japan, for example, patients with the 2 highest risk variants had the lowest level of enzyme activity.

“These patients had excessive levels of the active drug metabolites per mercaptopurine dose, which suggests we may reduce the drug dose to achieve the level necessary to kill leukemia cells without causing toxicity,” Dr Yang said, adding that the NUDT15 variants have no other known health consequences.

The investigators also checked leukemic cells from 285 children newly diagnosed with ALL and found that patients with NUDT15 variants were more sensitive to thiopurines.

“That suggests we can screen for NUDT15 variants and potentially plan mercaptopurine doses according to each patient’s genotype before the therapy starts,” Dr Yang said. “This way, we hope to avoid toxicity without compromising treatment effectiveness.”

The investigators noted that future studies are needed to determine optimal thiopurine doses for patients with different NUDT15 variants.

Meanwhile, the search continues for variants in NUDT15 or other genes that influence chemotherapy effectiveness and safety. The NUDT15 variants and previously identified TPMT variants could not fully explain why Guatemalan patients in this study tolerated the lowest doses of mercaptopurine.

Prescription medications

Photo courtesy of the CDC

New research has revealed inherited genetic variations that may predispose patients to severe toxicity from thiopurines, a class of medications used as anticancer and immunosuppressive drugs.

Investigators identified 4 variations in the NUDT15 gene that alter thiopurine metabolism, leaving patients particularly sensitive to the drugs and at risk for toxicity.

One in 3 Japanese patients in this study carried the variations.

And evidence suggests the variations are common in other populations across Asia and in individuals of Hispanic ethnicity.

Jun J. Yang, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues reported these findings in Nature Genetics.

In 2015, Dr Yang and his colleagues published evidence linking a NUDT15 variant to reduced tolerance of mercaptopurine and reported the variant was more common in patients of East Asian ancestry.

With the current study, the investigators identified 3 additional NUDT15 variants and found that all 4 variants—p.Arg139Cys, p.Arg139His, p.Val18Ile, and p.Val18_Val19insGlyVal—were associated with lower levels of enzymatic activity and imbalance of thiopurine metabolism.

In a group of 270 children with acute lymphoblastic leukemia (ALL), the variants caused a 74.4% to 100% loss of NUDT15 function. They also predicted enzyme activity and mercaptopurine tolerance. In Singapore and Japan, for example, patients with the 2 highest risk variants had the lowest level of enzyme activity.

“These patients had excessive levels of the active drug metabolites per mercaptopurine dose, which suggests we may reduce the drug dose to achieve the level necessary to kill leukemia cells without causing toxicity,” Dr Yang said, adding that the NUDT15 variants have no other known health consequences.

The investigators also checked leukemic cells from 285 children newly diagnosed with ALL and found that patients with NUDT15 variants were more sensitive to thiopurines.

“That suggests we can screen for NUDT15 variants and potentially plan mercaptopurine doses according to each patient’s genotype before the therapy starts,” Dr Yang said. “This way, we hope to avoid toxicity without compromising treatment effectiveness.”

The investigators noted that future studies are needed to determine optimal thiopurine doses for patients with different NUDT15 variants.

Meanwhile, the search continues for variants in NUDT15 or other genes that influence chemotherapy effectiveness and safety. The NUDT15 variants and previously identified TPMT variants could not fully explain why Guatemalan patients in this study tolerated the lowest doses of mercaptopurine.

Blood sample collection

Photo by Juan D. Alfonso

The National Institute for Health and Care Excellence (NICE) has said there is not enough evidence to recommend the routine use of 3 new tests to help identify the cause of sepsis.

The agency issued a final diagnostics guidance recommending further research on the tests—the LightCycler SeptiFast Test MGRADE (Roche Diagnostics), SepsiTest (Molzym Molecular Diagnostics), and IRIDICA BAC BSI assay (Abbott Laboratories).

All 3 tests analyze whole blood samples to identify bacterial and fungal DNA. The tests aim to identify the causes of infection much quicker than traditional microbiology techniques, which require blood samples to be incubated and cultured before pathogens can be identified.

“Rapid molecular tests that can identify the cause of an infection in hours rather than the days typically needed for traditional microbiology tests could ensure the most appropriate antibiotics are used much earlier,” said Carole Longson, NICE Health Technology Evaluation Centre Director.

“This, in turn, could improve outcomes for patients with suspected bloodstream infections, as well as help to reduce the spread of resistant microbes. The independent diagnostics advisory committee [advising NICE on the tests] concluded that, although the tests show promise, there is currently not enough evidence to recommend their routine adoption in the NHS [National Health Service].”

“They felt the tests may offer clinical benefit by providing results more quickly, but there was currently too much uncertainty in their accuracy for clinicians to be able to use them as the basis for clinical decision-making in people with suspected bloodstream infections, who can be acutely unwell.”

“The committee therefore decided that further research should be encouraged to provide robust evidence, particularly around demonstrating the value of using the test results in clinical decision-making.”

The diagnostics guidance on the tests is available on the NICE website.

Blood sample collection

Photo by Juan D. Alfonso

The National Institute for Health and Care Excellence (NICE) has said there is not enough evidence to recommend the routine use of 3 new tests to help identify the cause of sepsis.

The agency issued a final diagnostics guidance recommending further research on the tests—the LightCycler SeptiFast Test MGRADE (Roche Diagnostics), SepsiTest (Molzym Molecular Diagnostics), and IRIDICA BAC BSI assay (Abbott Laboratories).

All 3 tests analyze whole blood samples to identify bacterial and fungal DNA. The tests aim to identify the causes of infection much quicker than traditional microbiology techniques, which require blood samples to be incubated and cultured before pathogens can be identified.

“Rapid molecular tests that can identify the cause of an infection in hours rather than the days typically needed for traditional microbiology tests could ensure the most appropriate antibiotics are used much earlier,” said Carole Longson, NICE Health Technology Evaluation Centre Director.

“This, in turn, could improve outcomes for patients with suspected bloodstream infections, as well as help to reduce the spread of resistant microbes. The independent diagnostics advisory committee [advising NICE on the tests] concluded that, although the tests show promise, there is currently not enough evidence to recommend their routine adoption in the NHS [National Health Service].”

“They felt the tests may offer clinical benefit by providing results more quickly, but there was currently too much uncertainty in their accuracy for clinicians to be able to use them as the basis for clinical decision-making in people with suspected bloodstream infections, who can be acutely unwell.”

“The committee therefore decided that further research should be encouraged to provide robust evidence, particularly around demonstrating the value of using the test results in clinical decision-making.”

The diagnostics guidance on the tests is available on the NICE website.

Blood sample collection

Photo by Juan D. Alfonso

The National Institute for Health and Care Excellence (NICE) has said there is not enough evidence to recommend the routine use of 3 new tests to help identify the cause of sepsis.

The agency issued a final diagnostics guidance recommending further research on the tests—the LightCycler SeptiFast Test MGRADE (Roche Diagnostics), SepsiTest (Molzym Molecular Diagnostics), and IRIDICA BAC BSI assay (Abbott Laboratories).

All 3 tests analyze whole blood samples to identify bacterial and fungal DNA. The tests aim to identify the causes of infection much quicker than traditional microbiology techniques, which require blood samples to be incubated and cultured before pathogens can be identified.

“Rapid molecular tests that can identify the cause of an infection in hours rather than the days typically needed for traditional microbiology tests could ensure the most appropriate antibiotics are used much earlier,” said Carole Longson, NICE Health Technology Evaluation Centre Director.

“This, in turn, could improve outcomes for patients with suspected bloodstream infections, as well as help to reduce the spread of resistant microbes. The independent diagnostics advisory committee [advising NICE on the tests] concluded that, although the tests show promise, there is currently not enough evidence to recommend their routine adoption in the NHS [National Health Service].”

“They felt the tests may offer clinical benefit by providing results more quickly, but there was currently too much uncertainty in their accuracy for clinicians to be able to use them as the basis for clinical decision-making in people with suspected bloodstream infections, who can be acutely unwell.”

“The committee therefore decided that further research should be encouraged to provide robust evidence, particularly around demonstrating the value of using the test results in clinical decision-making.”

The diagnostics guidance on the tests is available on the NICE website.

Hematopoietic stem cells

in the bone marrow

Nearly 30 years after the discovery of the hematopoietic stem cell (HSC), researchers believe they have found a marker specific to long-term HSCs—the gene Hoxb5.

If confirmed, this finding would help settle long-standing debates about the identity of long-term HSCs and their support cells.

It may also pave the way for understanding how long-term HSCs maintain themselves and provide scientists with the necessary information to grow HSCs in the lab.

Irving Weissman, MD, of Stanford University School of Medicine in California, and his colleagues described this work in a letter to Nature.

In 1988, Dr Weissman and his colleagues isolated the HSC. Since that time, researchers have had mixed success in their attempts to get a detailed picture of how HSCs maintain themselves and grow in the body.

Over the years, it became clear why. HSCs come in 2 forms—short-term HSCs that lose their powers of replication over time and long-term HSCs that can replicate indefinitely.

With the new study, Dr Weissman and his colleagues believe they have found a reliable way to tell the difference between long-term and short-term HSCs. Namely, the presence of Hoxb5.

“In this paper, we have found a single marker that, in the entire bone marrow, is only found in these long-term stem cells,” Dr Weissman said.

The researchers hope this finding will enable them to look at how nearby cells create a niche where the long-term HSCs are supported and maintained.

“For nearly 30 years, people have been trying to grow HSCs outside the body and have not been able to do it; it’s arguably the ‘holy grail’ in this field,” said James Y. Chen, an MD/PhD candidate at Stanford University School of Medicine.

“Now that we have an anchor, a way to look at long-term HSCs, we can look at the cells around them to understand and, ideally, recreate the niche.”

An extensive search

Over the years, scientists have proposed various markers that they felt were unique to long-term HSCs, but the reliability of each proposed marker has been heatedly debated by other research groups, said Masanori Miyanishi, MD, PhD, also of Stanford University School of Medicine.

In an attempt to settle the issue, Chen and Dr Miyanishi examined a list of more than 100 genes that are expressed in the bone marrow and seemed like good candidates to be unique markers of long-term HSCs.

The researchers eliminated genes that are turned on in areas of the bone that don’t involve the creation of new blood and immune cells. That narrowed the field to 45 genes.

The team then performed an analysis to determine how much protein these genes were making in various cells. They found that only 3 proteins were produced at a high enough level to mark HSCs.

Finally, the researchers needed to find if 1 of these 3 was turned on in long-term HSCs and turned off in short-term HSCs.

Although they couldn’t yet identify which cells were long-term HSCs, the team knew that any collection of HSCs should have both long-term and short-term HSCs, so they expected to find the candidate gene turned off in some cells and on in others. Only 1 gene fit that bill—Hoxb5.

The researchers pointed out that there may be other unique markers of long-term HSCs, such as genes that weren’t among the initial group of genes screened. But among the screened genes, only Hoxb5 was a unique identifier of the long-term HSC.

Finding the niche

The researchers were also able to solve another mystery by showing where in the bone marrow long-term HSCs reside.

Satoshi Yamazaki, PhD, and Hiromitsu Nakauchi, MD, PhD, both from the University of Tokyo in Japan, used new technology to prepare bone marrow tissue and do computational analyses that validated the location and architecture of the HSC niche.

“More than 90% of these cells reside on a particular type of blood vessel called venous sinusoids,” Dr Nakauchi said.

The researchers believe the ability to identify long-term HSCs will give scientists a powerful tool for further study.

“This opens the way to observe long-term HSCs and other cells in the niche as they exist in the body, without transplanting them,” Dr Weissman said. “This is how science works, by getting down to the purest irreducible element—in this case, blood stem cells—in order to develop new tools and understandings.”

Hematopoietic stem cells

in the bone marrow

Nearly 30 years after the discovery of the hematopoietic stem cell (HSC), researchers believe they have found a marker specific to long-term HSCs—the gene Hoxb5.

If confirmed, this finding would help settle long-standing debates about the identity of long-term HSCs and their support cells.

It may also pave the way for understanding how long-term HSCs maintain themselves and provide scientists with the necessary information to grow HSCs in the lab.

Irving Weissman, MD, of Stanford University School of Medicine in California, and his colleagues described this work in a letter to Nature.

In 1988, Dr Weissman and his colleagues isolated the HSC. Since that time, researchers have had mixed success in their attempts to get a detailed picture of how HSCs maintain themselves and grow in the body.

Over the years, it became clear why. HSCs come in 2 forms—short-term HSCs that lose their powers of replication over time and long-term HSCs that can replicate indefinitely.

With the new study, Dr Weissman and his colleagues believe they have found a reliable way to tell the difference between long-term and short-term HSCs. Namely, the presence of Hoxb5.

“In this paper, we have found a single marker that, in the entire bone marrow, is only found in these long-term stem cells,” Dr Weissman said.

The researchers hope this finding will enable them to look at how nearby cells create a niche where the long-term HSCs are supported and maintained.

“For nearly 30 years, people have been trying to grow HSCs outside the body and have not been able to do it; it’s arguably the ‘holy grail’ in this field,” said James Y. Chen, an MD/PhD candidate at Stanford University School of Medicine.

“Now that we have an anchor, a way to look at long-term HSCs, we can look at the cells around them to understand and, ideally, recreate the niche.”

An extensive search

Over the years, scientists have proposed various markers that they felt were unique to long-term HSCs, but the reliability of each proposed marker has been heatedly debated by other research groups, said Masanori Miyanishi, MD, PhD, also of Stanford University School of Medicine.

In an attempt to settle the issue, Chen and Dr Miyanishi examined a list of more than 100 genes that are expressed in the bone marrow and seemed like good candidates to be unique markers of long-term HSCs.

The researchers eliminated genes that are turned on in areas of the bone that don’t involve the creation of new blood and immune cells. That narrowed the field to 45 genes.

The team then performed an analysis to determine how much protein these genes were making in various cells. They found that only 3 proteins were produced at a high enough level to mark HSCs.

Finally, the researchers needed to find if 1 of these 3 was turned on in long-term HSCs and turned off in short-term HSCs.

Although they couldn’t yet identify which cells were long-term HSCs, the team knew that any collection of HSCs should have both long-term and short-term HSCs, so they expected to find the candidate gene turned off in some cells and on in others. Only 1 gene fit that bill—Hoxb5.

The researchers pointed out that there may be other unique markers of long-term HSCs, such as genes that weren’t among the initial group of genes screened. But among the screened genes, only Hoxb5 was a unique identifier of the long-term HSC.

Finding the niche

The researchers were also able to solve another mystery by showing where in the bone marrow long-term HSCs reside.

Satoshi Yamazaki, PhD, and Hiromitsu Nakauchi, MD, PhD, both from the University of Tokyo in Japan, used new technology to prepare bone marrow tissue and do computational analyses that validated the location and architecture of the HSC niche.

“More than 90% of these cells reside on a particular type of blood vessel called venous sinusoids,” Dr Nakauchi said.

The researchers believe the ability to identify long-term HSCs will give scientists a powerful tool for further study.

“This opens the way to observe long-term HSCs and other cells in the niche as they exist in the body, without transplanting them,” Dr Weissman said. “This is how science works, by getting down to the purest irreducible element—in this case, blood stem cells—in order to develop new tools and understandings.”

Hematopoietic stem cells

in the bone marrow

Nearly 30 years after the discovery of the hematopoietic stem cell (HSC), researchers believe they have found a marker specific to long-term HSCs—the gene Hoxb5.

If confirmed, this finding would help settle long-standing debates about the identity of long-term HSCs and their support cells.

It may also pave the way for understanding how long-term HSCs maintain themselves and provide scientists with the necessary information to grow HSCs in the lab.

Irving Weissman, MD, of Stanford University School of Medicine in California, and his colleagues described this work in a letter to Nature.

In 1988, Dr Weissman and his colleagues isolated the HSC. Since that time, researchers have had mixed success in their attempts to get a detailed picture of how HSCs maintain themselves and grow in the body.

Over the years, it became clear why. HSCs come in 2 forms—short-term HSCs that lose their powers of replication over time and long-term HSCs that can replicate indefinitely.

With the new study, Dr Weissman and his colleagues believe they have found a reliable way to tell the difference between long-term and short-term HSCs. Namely, the presence of Hoxb5.

“In this paper, we have found a single marker that, in the entire bone marrow, is only found in these long-term stem cells,” Dr Weissman said.

The researchers hope this finding will enable them to look at how nearby cells create a niche where the long-term HSCs are supported and maintained.

“For nearly 30 years, people have been trying to grow HSCs outside the body and have not been able to do it; it’s arguably the ‘holy grail’ in this field,” said James Y. Chen, an MD/PhD candidate at Stanford University School of Medicine.

“Now that we have an anchor, a way to look at long-term HSCs, we can look at the cells around them to understand and, ideally, recreate the niche.”

An extensive search

Over the years, scientists have proposed various markers that they felt were unique to long-term HSCs, but the reliability of each proposed marker has been heatedly debated by other research groups, said Masanori Miyanishi, MD, PhD, also of Stanford University School of Medicine.

In an attempt to settle the issue, Chen and Dr Miyanishi examined a list of more than 100 genes that are expressed in the bone marrow and seemed like good candidates to be unique markers of long-term HSCs.

The researchers eliminated genes that are turned on in areas of the bone that don’t involve the creation of new blood and immune cells. That narrowed the field to 45 genes.

The team then performed an analysis to determine how much protein these genes were making in various cells. They found that only 3 proteins were produced at a high enough level to mark HSCs.

Finally, the researchers needed to find if 1 of these 3 was turned on in long-term HSCs and turned off in short-term HSCs.

Although they couldn’t yet identify which cells were long-term HSCs, the team knew that any collection of HSCs should have both long-term and short-term HSCs, so they expected to find the candidate gene turned off in some cells and on in others. Only 1 gene fit that bill—Hoxb5.

The researchers pointed out that there may be other unique markers of long-term HSCs, such as genes that weren’t among the initial group of genes screened. But among the screened genes, only Hoxb5 was a unique identifier of the long-term HSC.

Finding the niche

The researchers were also able to solve another mystery by showing where in the bone marrow long-term HSCs reside.

Satoshi Yamazaki, PhD, and Hiromitsu Nakauchi, MD, PhD, both from the University of Tokyo in Japan, used new technology to prepare bone marrow tissue and do computational analyses that validated the location and architecture of the HSC niche.

“More than 90% of these cells reside on a particular type of blood vessel called venous sinusoids,” Dr Nakauchi said.

The researchers believe the ability to identify long-term HSCs will give scientists a powerful tool for further study.

“This opens the way to observe long-term HSCs and other cells in the niche as they exist in the body, without transplanting them,” Dr Weissman said. “This is how science works, by getting down to the purest irreducible element—in this case, blood stem cells—in order to develop new tools and understandings.”

Plasmodium sporozoite

Image by Ute Frevert

and Margaret Shear

Researchers say they have designed a compound that kills malaria parasites—even those resistant to current antimalarial therapy—but

avoids harming human cells.

The compound exploits tiny structural differences between the parasitic and human versions of the proteasome.

In preclinical experiments, this proteasome inhibitor was able to kill artemisinin-resistant malaria parasites and further sensitize parasites to artemisinin.

Matthew Bogyo, PhD, of Stanford University School of Medicine in California, and his colleagues conducted this research and recounted the results in a letter to Nature.

Previous research has shown that proteasome inhibitors can be toxic to the malaria parasite Plasmodium falciparum. But the drugs have tended to inhibit the human version of the proteasome too, resulting in toxicity that would be unacceptable in a malaria drug.

Dr Bogyo and his colleagues wanted to overcome this problem, so they produced highly purified preparations of both human and P falciparum proteasomes. The team then “fed” those 2 preparations a set of protein fragments containing a variety of amino-acid linkages to see which amino-acid linkages the proteasomes would cleave.

The researchers identified 113 amino-acid linkages that are readily cleaved by P falciparum proteasomes but not so well by human proteasomes, and 153 amino-acid linkages where the reverse is the case.

The team used this information to design tiny protein snippets that failed to interact with human proteasomes but inhibited parts of the P falciparum proteasomes responsible for cleaving certain amino-acid links.

The researchers investigated the basis for this selectivity by using high-resolution electron microscopy to map the detailed structure of the parasite and human proteasomes. This allowed them to optimize the protein snippets they were using as parasite-selective proteasome inhibitors.

The 3-amino-acid snippet they ultimately focused on, called WLL, was able to inhibit 2 different catalytic regions in P falciparum proteasomes without having any effect on those of cultured human cells. There was a 600-fold difference in WLL’s potency at killing the parasitic cells over the human cells.

In experiments with mice, the researchers saw a nearly complete reduction of malaria parasites with both single and multiple doses of WLL.

Other tests, performed on artemisinin-resistant parasites infecting human red blood cells, suggested the WLL compound was equally effective at killing artemisinin-resistant parasites and artemisinin-sensitive parasites.

Dr Bogyo pointed out that the artemisinin family of drugs work by modifying proteins in the parasite. Resistance occurs when the parasites’ proteasomes are able to recycle those modified proteins. But this means that artemisinin-treated parasites are particularly sensitive to disruption of normal protein function.

“The compounds we’ve derived can kill artemisinin-resistant parasites because those parasites have an increased need for highly efficient proteasomes,” he said.

“So combining the proteasome inhibitor with artemisinin should make it possible to block the onset of resistance. That will, in turn, allow the continued use of that front-line malaria treatment, which has been so effective up until now.”

Clinical trials of compounds derived from this research remain several years away, Dr Bogyo added.

Study author Leann Tilley, PhD, of the University of Melbourne in Victoria, Australia, and her team are working with experts from Takeda Pharmaceutical Company Limited and Medicines for Malaria Venture to identify additional classes of parasite-specific proteasome inhibitors that could be advanced to clinical trials.

“The next step is screening the Takeda libraries to find a similar drug that doesn’t affect the human proteasome,” Dr Tilley said. “The current drug is a good start, but it’s not yet suitable for humans. It needs to be able to be administered orally and needs to last a long time in the blood stream.”

Dr Tilley said if they can find an existing drug in Takeda’s libraries that matches the structure of the new malaria drug, they could move it toward human trials very quickly.

Plasmodium sporozoite

Image by Ute Frevert

and Margaret Shear

Researchers say they have designed a compound that kills malaria parasites—even those resistant to current antimalarial therapy—but

avoids harming human cells.

The compound exploits tiny structural differences between the parasitic and human versions of the proteasome.

In preclinical experiments, this proteasome inhibitor was able to kill artemisinin-resistant malaria parasites and further sensitize parasites to artemisinin.

Matthew Bogyo, PhD, of Stanford University School of Medicine in California, and his colleagues conducted this research and recounted the results in a letter to Nature.

Previous research has shown that proteasome inhibitors can be toxic to the malaria parasite Plasmodium falciparum. But the drugs have tended to inhibit the human version of the proteasome too, resulting in toxicity that would be unacceptable in a malaria drug.

Dr Bogyo and his colleagues wanted to overcome this problem, so they produced highly purified preparations of both human and P falciparum proteasomes. The team then “fed” those 2 preparations a set of protein fragments containing a variety of amino-acid linkages to see which amino-acid linkages the proteasomes would cleave.

The researchers identified 113 amino-acid linkages that are readily cleaved by P falciparum proteasomes but not so well by human proteasomes, and 153 amino-acid linkages where the reverse is the case.

The team used this information to design tiny protein snippets that failed to interact with human proteasomes but inhibited parts of the P falciparum proteasomes responsible for cleaving certain amino-acid links.

The researchers investigated the basis for this selectivity by using high-resolution electron microscopy to map the detailed structure of the parasite and human proteasomes. This allowed them to optimize the protein snippets they were using as parasite-selective proteasome inhibitors.

The 3-amino-acid snippet they ultimately focused on, called WLL, was able to inhibit 2 different catalytic regions in P falciparum proteasomes without having any effect on those of cultured human cells. There was a 600-fold difference in WLL’s potency at killing the parasitic cells over the human cells.

In experiments with mice, the researchers saw a nearly complete reduction of malaria parasites with both single and multiple doses of WLL.

Other tests, performed on artemisinin-resistant parasites infecting human red blood cells, suggested the WLL compound was equally effective at killing artemisinin-resistant parasites and artemisinin-sensitive parasites.

Dr Bogyo pointed out that the artemisinin family of drugs work by modifying proteins in the parasite. Resistance occurs when the parasites’ proteasomes are able to recycle those modified proteins. But this means that artemisinin-treated parasites are particularly sensitive to disruption of normal protein function.

“The compounds we’ve derived can kill artemisinin-resistant parasites because those parasites have an increased need for highly efficient proteasomes,” he said.

“So combining the proteasome inhibitor with artemisinin should make it possible to block the onset of resistance. That will, in turn, allow the continued use of that front-line malaria treatment, which has been so effective up until now.”

Clinical trials of compounds derived from this research remain several years away, Dr Bogyo added.

Study author Leann Tilley, PhD, of the University of Melbourne in Victoria, Australia, and her team are working with experts from Takeda Pharmaceutical Company Limited and Medicines for Malaria Venture to identify additional classes of parasite-specific proteasome inhibitors that could be advanced to clinical trials.

“The next step is screening the Takeda libraries to find a similar drug that doesn’t affect the human proteasome,” Dr Tilley said. “The current drug is a good start, but it’s not yet suitable for humans. It needs to be able to be administered orally and needs to last a long time in the blood stream.”

Dr Tilley said if they can find an existing drug in Takeda’s libraries that matches the structure of the new malaria drug, they could move it toward human trials very quickly.

Plasmodium sporozoite

Image by Ute Frevert

and Margaret Shear

Researchers say they have designed a compound that kills malaria parasites—even those resistant to current antimalarial therapy—but

avoids harming human cells.

The compound exploits tiny structural differences between the parasitic and human versions of the proteasome.

In preclinical experiments, this proteasome inhibitor was able to kill artemisinin-resistant malaria parasites and further sensitize parasites to artemisinin.

Matthew Bogyo, PhD, of Stanford University School of Medicine in California, and his colleagues conducted this research and recounted the results in a letter to Nature.

Previous research has shown that proteasome inhibitors can be toxic to the malaria parasite Plasmodium falciparum. But the drugs have tended to inhibit the human version of the proteasome too, resulting in toxicity that would be unacceptable in a malaria drug.

Dr Bogyo and his colleagues wanted to overcome this problem, so they produced highly purified preparations of both human and P falciparum proteasomes. The team then “fed” those 2 preparations a set of protein fragments containing a variety of amino-acid linkages to see which amino-acid linkages the proteasomes would cleave.

The researchers identified 113 amino-acid linkages that are readily cleaved by P falciparum proteasomes but not so well by human proteasomes, and 153 amino-acid linkages where the reverse is the case.

The team used this information to design tiny protein snippets that failed to interact with human proteasomes but inhibited parts of the P falciparum proteasomes responsible for cleaving certain amino-acid links.

The researchers investigated the basis for this selectivity by using high-resolution electron microscopy to map the detailed structure of the parasite and human proteasomes. This allowed them to optimize the protein snippets they were using as parasite-selective proteasome inhibitors.

The 3-amino-acid snippet they ultimately focused on, called WLL, was able to inhibit 2 different catalytic regions in P falciparum proteasomes without having any effect on those of cultured human cells. There was a 600-fold difference in WLL’s potency at killing the parasitic cells over the human cells.

In experiments with mice, the researchers saw a nearly complete reduction of malaria parasites with both single and multiple doses of WLL.

Other tests, performed on artemisinin-resistant parasites infecting human red blood cells, suggested the WLL compound was equally effective at killing artemisinin-resistant parasites and artemisinin-sensitive parasites.

Dr Bogyo pointed out that the artemisinin family of drugs work by modifying proteins in the parasite. Resistance occurs when the parasites’ proteasomes are able to recycle those modified proteins. But this means that artemisinin-treated parasites are particularly sensitive to disruption of normal protein function.

“The compounds we’ve derived can kill artemisinin-resistant parasites because those parasites have an increased need for highly efficient proteasomes,” he said.

“So combining the proteasome inhibitor with artemisinin should make it possible to block the onset of resistance. That will, in turn, allow the continued use of that front-line malaria treatment, which has been so effective up until now.”

Clinical trials of compounds derived from this research remain several years away, Dr Bogyo added.

Study author Leann Tilley, PhD, of the University of Melbourne in Victoria, Australia, and her team are working with experts from Takeda Pharmaceutical Company Limited and Medicines for Malaria Venture to identify additional classes of parasite-specific proteasome inhibitors that could be advanced to clinical trials.

“The next step is screening the Takeda libraries to find a similar drug that doesn’t affect the human proteasome,” Dr Tilley said. “The current drug is a good start, but it’s not yet suitable for humans. It needs to be able to be administered orally and needs to last a long time in the blood stream.”

Dr Tilley said if they can find an existing drug in Takeda’s libraries that matches the structure of the new malaria drug, they could move it toward human trials very quickly.

Results of a phase 2 trial suggest an investigational agent may improve upon standard care for acquired thrombotic thrombocytopenic purpura (aTTP).

The agent, caplacizumab, is an anti-von Willebrand factor, humanized, single-variable-domain immunoglobulin that works by inhibiting the interaction between ultralarge von Willebrand factor multimers and platelets.

In the phase 2 TITAN trial, caplacizumab plus standard care induced a faster resolution of aTTP episodes when compared to placebo plus standard care. However, caplacizumab was also associated with a higher risk of bleeding.

Flora Peyvandi, MD, PhD, of the University of Milan in Italy, and her colleagues reported these results in The New England Journal of Medicine. The study was supported by Ablynx, the company developing caplacizumab.

“Caplacizumab has the potential to become an important new component in the standard of care for patients with acquired TTP,” Dr Peyvandi said. “The results from the phase 2 TITAN study showed that caplacizumab acts quickly to control the critical acute phase of the disease and protects patients until immunosuppressive treatments take effect.”

TITAN was a single-blinded, randomized, placebo-controlled study conducted at 56 centers around the world. The trial included 75 aTTP patients who were randomized to caplacizumab (n=36) or placebo (n=39), with all patients receiving the current standard of care (daily plasma exchange and immunosuppressive therapy).

Patients in the caplacizumab arm immediately received an intravenous bolus dose of caplacizumab at 10 mg and then a 10 mg subcutaneous dose of the drug daily until 30 days had elapsed after the final plasma exchange. Patients in the control arm received placebo at the same time points.

Response, recurrence, and relapse

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).

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

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

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

One of the study’s secondary endpoints was exacerbation, which was defined as recurrent thrombocytopenia within 30 days of the end of daily plasma exchange that required reinitiation of daily exchange.

There were fewer exacerbations in the caplacizumab arm than the placebo arm—3 (8.3%) and 11 (28.2%), respectively.

Another secondary endpoint was relapse, which was defined as a TTP event occurring more than 30 days after the end of daily plasma exchange.

There were more relapses in the caplacizumab arm than the placebo arm—8 (22.2%) and 0, respectively. The investigators noted that 7 of the 8 patients had ADAMTS13 activity that remained below 10%, which suggests unresolved autoimmune activity.

Adverse events

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

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

The rate of bleeding-related AEs was 54% in the caplacizumab arm and 38% in the placebo arm. Of the 101 bleeding-related AEs, 84 (83%) were reported as mild, 14 (14%) as moderate, and 3 (3%) as severe.

There were no deaths in the caplacizumab arm and 2 in the placebo arm. One death was due to severe, refractory TTP, and the other was due to cerebral hemorrhage.

Caplacizumab development

The results of this trial will serve as the basis for filing for conditional approval of caplacizumab in Europe in the first half of 2017, according to Ablynx. The company is planning to file in the US in 2018.

Ablynx has started a phase 3 trial of caplacizumab known as the HERCULES study. In this double-blind, placebo-controlled study, investigators are evaluating the safety and efficacy of caplacizumab, in conjunction with the standard of care, in patients with aTTP.

The study is expected to enroll 92 patients at clinical sites across 17 countries. Recruitment is expected to be complete by the end of 2017.

Results of a phase 2 trial suggest an investigational agent may improve upon standard care for acquired thrombotic thrombocytopenic purpura (aTTP).

The agent, caplacizumab, is an anti-von Willebrand factor, humanized, single-variable-domain immunoglobulin that works by inhibiting the interaction between ultralarge von Willebrand factor multimers and platelets.

In the phase 2 TITAN trial, caplacizumab plus standard care induced a faster resolution of aTTP episodes when compared to placebo plus standard care. However, caplacizumab was also associated with a higher risk of bleeding.

Flora Peyvandi, MD, PhD, of the University of Milan in Italy, and her colleagues reported these results in The New England Journal of Medicine. The study was supported by Ablynx, the company developing caplacizumab.

“Caplacizumab has the potential to become an important new component in the standard of care for patients with acquired TTP,” Dr Peyvandi said. “The results from the phase 2 TITAN study showed that caplacizumab acts quickly to control the critical acute phase of the disease and protects patients until immunosuppressive treatments take effect.”

TITAN was a single-blinded, randomized, placebo-controlled study conducted at 56 centers around the world. The trial included 75 aTTP patients who were randomized to caplacizumab (n=36) or placebo (n=39), with all patients receiving the current standard of care (daily plasma exchange and immunosuppressive therapy).

Patients in the caplacizumab arm immediately received an intravenous bolus dose of caplacizumab at 10 mg and then a 10 mg subcutaneous dose of the drug daily until 30 days had elapsed after the final plasma exchange. Patients in the control arm received placebo at the same time points.

Response, recurrence, and relapse

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).

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

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

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

One of the study’s secondary endpoints was exacerbation, which was defined as recurrent thrombocytopenia within 30 days of the end of daily plasma exchange that required reinitiation of daily exchange.

There were fewer exacerbations in the caplacizumab arm than the placebo arm—3 (8.3%) and 11 (28.2%), respectively.

Another secondary endpoint was relapse, which was defined as a TTP event occurring more than 30 days after the end of daily plasma exchange.

There were more relapses in the caplacizumab arm than the placebo arm—8 (22.2%) and 0, respectively. The investigators noted that 7 of the 8 patients had ADAMTS13 activity that remained below 10%, which suggests unresolved autoimmune activity.

Adverse events

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

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

The rate of bleeding-related AEs was 54% in the caplacizumab arm and 38% in the placebo arm. Of the 101 bleeding-related AEs, 84 (83%) were reported as mild, 14 (14%) as moderate, and 3 (3%) as severe.

There were no deaths in the caplacizumab arm and 2 in the placebo arm. One death was due to severe, refractory TTP, and the other was due to cerebral hemorrhage.

Caplacizumab development

The results of this trial will serve as the basis for filing for conditional approval of caplacizumab in Europe in the first half of 2017, according to Ablynx. The company is planning to file in the US in 2018.

Ablynx has started a phase 3 trial of caplacizumab known as the HERCULES study. In this double-blind, placebo-controlled study, investigators are evaluating the safety and efficacy of caplacizumab, in conjunction with the standard of care, in patients with aTTP.

The study is expected to enroll 92 patients at clinical sites across 17 countries. Recruitment is expected to be complete by the end of 2017.

Results of a phase 2 trial suggest an investigational agent may improve upon standard care for acquired thrombotic thrombocytopenic purpura (aTTP).

The agent, caplacizumab, is an anti-von Willebrand factor, humanized, single-variable-domain immunoglobulin that works by inhibiting the interaction between ultralarge von Willebrand factor multimers and platelets.

In the phase 2 TITAN trial, caplacizumab plus standard care induced a faster resolution of aTTP episodes when compared to placebo plus standard care. However, caplacizumab was also associated with a higher risk of bleeding.

Flora Peyvandi, MD, PhD, of the University of Milan in Italy, and her colleagues reported these results in The New England Journal of Medicine. The study was supported by Ablynx, the company developing caplacizumab.

“Caplacizumab has the potential to become an important new component in the standard of care for patients with acquired TTP,” Dr Peyvandi said. “The results from the phase 2 TITAN study showed that caplacizumab acts quickly to control the critical acute phase of the disease and protects patients until immunosuppressive treatments take effect.”

TITAN was a single-blinded, randomized, placebo-controlled study conducted at 56 centers around the world. The trial included 75 aTTP patients who were randomized to caplacizumab (n=36) or placebo (n=39), with all patients receiving the current standard of care (daily plasma exchange and immunosuppressive therapy).

Patients in the caplacizumab arm immediately received an intravenous bolus dose of caplacizumab at 10 mg and then a 10 mg subcutaneous dose of the drug daily until 30 days had elapsed after the final plasma exchange. Patients in the control arm received placebo at the same time points.

Response, recurrence, and relapse

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).

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

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

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

One of the study’s secondary endpoints was exacerbation, which was defined as recurrent thrombocytopenia within 30 days of the end of daily plasma exchange that required reinitiation of daily exchange.

There were fewer exacerbations in the caplacizumab arm than the placebo arm—3 (8.3%) and 11 (28.2%), respectively.

Another secondary endpoint was relapse, which was defined as a TTP event occurring more than 30 days after the end of daily plasma exchange.

There were more relapses in the caplacizumab arm than the placebo arm—8 (22.2%) and 0, respectively. The investigators noted that 7 of the 8 patients had ADAMTS13 activity that remained below 10%, which suggests unresolved autoimmune activity.

Adverse events

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

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

The rate of bleeding-related AEs was 54% in the caplacizumab arm and 38% in the placebo arm. Of the 101 bleeding-related AEs, 84 (83%) were reported as mild, 14 (14%) as moderate, and 3 (3%) as severe.

There were no deaths in the caplacizumab arm and 2 in the placebo arm. One death was due to severe, refractory TTP, and the other was due to cerebral hemorrhage.

Caplacizumab development

The results of this trial will serve as the basis for filing for conditional approval of caplacizumab in Europe in the first half of 2017, according to Ablynx. The company is planning to file in the US in 2018.

Ablynx has started a phase 3 trial of caplacizumab known as the HERCULES study. In this double-blind, placebo-controlled study, investigators are evaluating the safety and efficacy of caplacizumab, in conjunction with the standard of care, in patients with aTTP.

The study is expected to enroll 92 patients at clinical sites across 17 countries. Recruitment is expected to be complete by the end of 2017.