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Gene variants linked to drug intolerance
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. 
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.
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.
NICE says it can’t recommend sepsis tests
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.
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.
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.
Team finds potential marker of long-term HSCs
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.”
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.”
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.”
Advancing the fight against drug-resistant malaria
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.
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.
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.
Combo can produce durable remissions in PTCL
Photo by Larry Young
SAN FRANCISCO—A combination treatment regimen can produce durable remissions in patients newly diagnosed with peripheral T-cell lymphoma (PTCL), results of a phase 1 study suggest.
The patients received brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisolone (BV+CHP). In some cases, this was followed by BV monotherapy.
The estimated 3-year progression-free survival (PFS) for these patients was 52%, and the overall survival (OS) was 80%.
There was a high rate of peripheral neuropathy (73%), but most cases resolved or improved over time.
Steven Horwitz, MD, of Memorial Sloan Kettering Cancer Center in New York, New York, and his colleagues presented these data as a poster at the 8th Annual T-cell Lymphoma Forum. The study was supported by Seattle Genetics and Millennium Pharmaceuticals.
The researchers presented data on 26 patients newly diagnosed with PTCL. Nineteen patients had systemic anaplastic large-cell lymphoma (ALCL; 16 ALK- and 3 ALK+), 2 had PTCL not otherwise specified, 2 had angioimmunoblastic T-cell lymphoma, 2 had adult T-cell leukemia/lymphoma, and 1 had enteropathy-associated T-cell lymphoma.
The patients’ median age was 56 (range, 21-82). Sixty-nine percent of patients had an IPI score of 2 or higher, and 73% had stage III/IV disease.
Treatment
The patients received BV+CHP every 3 weeks for 6 cycles. Those who achieved at least a partial remission could go on to receive up to 10 additional cycles of single-agent BV at 1.8 mg/kg every 3 weeks.
Twenty-three patients (88%) completed all 6 cycles of BV+CHP, and 21 patients (81%) went on to receive BV monotherapy, 11 of whom (42%) received all 10 cycles.
Fifteen patients (58%) discontinued treatment, 3 due to progressive disease, 3 due to investigator decision, 6 due to adverse events, and 3 due to patient decision.
After a median observation period of 38.7 months (range, 4.6 to 44.3), 77% of patients (n=20) remained on study.
Toxicity
The most common adverse events (occurring in at least 30% of patients) were nausea (69%), peripheral sensory neuropathy (69%), diarrhea (62%), fatigue (58%), alopecia (54%), dyspnea (46%), constipation (35%), myalgia (31%), peripheral edema (31%), chills (31%), anemia (31%), insomnia (31%), and febrile neutropenia.
The most common grade 3 or higher adverse events (occurring in at least 10% of patients) were febrile neutropenia (31%), neutropenia (23%), anemia (15%), and pulmonary embolism (12%).
There were 6 adverse events resulting in treatment discontinuation—peripheral sensory neuropathy (n=3), abdominal pain (n=1), asthenia (n=1), and peripheral motor neuropathy (n=1).
Seventy-three percent of patients (19/26) experienced peripheral neuropathy. Thirty-seven percent (n=7) had a complete resolution of neuropathy, and 58% (n=11) had some improvement. The median time to resolution was 1.3 months. Twelve patients (63%) had ongoing neuropathy at last follow-up, but most had grade 1 (n=10).
Response and survival
The objective response rate was 100%, and the complete response rate was 88% (n=23). One patient who had a partial response at the end of combination therapy achieved a complete response after going on to single-agent BV.
Twenty-one of the 26 patients are still alive—15 with ALCL and 6 with other PTCLs. Sixteen patients have not progressed—9 with ALCL and 5 with other PTCLs.
After progression, 5 patients received BV again, and 3 received stem cell transplants (2 allogeneic and 1 autologous).
The estimated 3-year PFS was 52%, and the estimated OS was 80%. The researchers noted that these rates compare favorably with the historical 3-year PFS and OS rates of 30% and 40%, respectively.
Researchers are currently conducting a phase 3 trial comparing BV+CHP with CHOP as frontline treatment of CD30+ mature T-cell lymphomas (ECHELON-2, NCT01777152).
Photo by Larry Young
SAN FRANCISCO—A combination treatment regimen can produce durable remissions in patients newly diagnosed with peripheral T-cell lymphoma (PTCL), results of a phase 1 study suggest.
The patients received brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisolone (BV+CHP). In some cases, this was followed by BV monotherapy.
The estimated 3-year progression-free survival (PFS) for these patients was 52%, and the overall survival (OS) was 80%.
There was a high rate of peripheral neuropathy (73%), but most cases resolved or improved over time.
Steven Horwitz, MD, of Memorial Sloan Kettering Cancer Center in New York, New York, and his colleagues presented these data as a poster at the 8th Annual T-cell Lymphoma Forum. The study was supported by Seattle Genetics and Millennium Pharmaceuticals.
The researchers presented data on 26 patients newly diagnosed with PTCL. Nineteen patients had systemic anaplastic large-cell lymphoma (ALCL; 16 ALK- and 3 ALK+), 2 had PTCL not otherwise specified, 2 had angioimmunoblastic T-cell lymphoma, 2 had adult T-cell leukemia/lymphoma, and 1 had enteropathy-associated T-cell lymphoma.
The patients’ median age was 56 (range, 21-82). Sixty-nine percent of patients had an IPI score of 2 or higher, and 73% had stage III/IV disease.
Treatment
The patients received BV+CHP every 3 weeks for 6 cycles. Those who achieved at least a partial remission could go on to receive up to 10 additional cycles of single-agent BV at 1.8 mg/kg every 3 weeks.
Twenty-three patients (88%) completed all 6 cycles of BV+CHP, and 21 patients (81%) went on to receive BV monotherapy, 11 of whom (42%) received all 10 cycles.
Fifteen patients (58%) discontinued treatment, 3 due to progressive disease, 3 due to investigator decision, 6 due to adverse events, and 3 due to patient decision.
After a median observation period of 38.7 months (range, 4.6 to 44.3), 77% of patients (n=20) remained on study.
Toxicity
The most common adverse events (occurring in at least 30% of patients) were nausea (69%), peripheral sensory neuropathy (69%), diarrhea (62%), fatigue (58%), alopecia (54%), dyspnea (46%), constipation (35%), myalgia (31%), peripheral edema (31%), chills (31%), anemia (31%), insomnia (31%), and febrile neutropenia.
The most common grade 3 or higher adverse events (occurring in at least 10% of patients) were febrile neutropenia (31%), neutropenia (23%), anemia (15%), and pulmonary embolism (12%).
There were 6 adverse events resulting in treatment discontinuation—peripheral sensory neuropathy (n=3), abdominal pain (n=1), asthenia (n=1), and peripheral motor neuropathy (n=1).
Seventy-three percent of patients (19/26) experienced peripheral neuropathy. Thirty-seven percent (n=7) had a complete resolution of neuropathy, and 58% (n=11) had some improvement. The median time to resolution was 1.3 months. Twelve patients (63%) had ongoing neuropathy at last follow-up, but most had grade 1 (n=10).
Response and survival
The objective response rate was 100%, and the complete response rate was 88% (n=23). One patient who had a partial response at the end of combination therapy achieved a complete response after going on to single-agent BV.
Twenty-one of the 26 patients are still alive—15 with ALCL and 6 with other PTCLs. Sixteen patients have not progressed—9 with ALCL and 5 with other PTCLs.
After progression, 5 patients received BV again, and 3 received stem cell transplants (2 allogeneic and 1 autologous).
The estimated 3-year PFS was 52%, and the estimated OS was 80%. The researchers noted that these rates compare favorably with the historical 3-year PFS and OS rates of 30% and 40%, respectively.
Researchers are currently conducting a phase 3 trial comparing BV+CHP with CHOP as frontline treatment of CD30+ mature T-cell lymphomas (ECHELON-2, NCT01777152).
Photo by Larry Young
SAN FRANCISCO—A combination treatment regimen can produce durable remissions in patients newly diagnosed with peripheral T-cell lymphoma (PTCL), results of a phase 1 study suggest.
The patients received brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisolone (BV+CHP). In some cases, this was followed by BV monotherapy.
The estimated 3-year progression-free survival (PFS) for these patients was 52%, and the overall survival (OS) was 80%.
There was a high rate of peripheral neuropathy (73%), but most cases resolved or improved over time.
Steven Horwitz, MD, of Memorial Sloan Kettering Cancer Center in New York, New York, and his colleagues presented these data as a poster at the 8th Annual T-cell Lymphoma Forum. The study was supported by Seattle Genetics and Millennium Pharmaceuticals.
The researchers presented data on 26 patients newly diagnosed with PTCL. Nineteen patients had systemic anaplastic large-cell lymphoma (ALCL; 16 ALK- and 3 ALK+), 2 had PTCL not otherwise specified, 2 had angioimmunoblastic T-cell lymphoma, 2 had adult T-cell leukemia/lymphoma, and 1 had enteropathy-associated T-cell lymphoma.
The patients’ median age was 56 (range, 21-82). Sixty-nine percent of patients had an IPI score of 2 or higher, and 73% had stage III/IV disease.
Treatment
The patients received BV+CHP every 3 weeks for 6 cycles. Those who achieved at least a partial remission could go on to receive up to 10 additional cycles of single-agent BV at 1.8 mg/kg every 3 weeks.
Twenty-three patients (88%) completed all 6 cycles of BV+CHP, and 21 patients (81%) went on to receive BV monotherapy, 11 of whom (42%) received all 10 cycles.
Fifteen patients (58%) discontinued treatment, 3 due to progressive disease, 3 due to investigator decision, 6 due to adverse events, and 3 due to patient decision.
After a median observation period of 38.7 months (range, 4.6 to 44.3), 77% of patients (n=20) remained on study.
Toxicity
The most common adverse events (occurring in at least 30% of patients) were nausea (69%), peripheral sensory neuropathy (69%), diarrhea (62%), fatigue (58%), alopecia (54%), dyspnea (46%), constipation (35%), myalgia (31%), peripheral edema (31%), chills (31%), anemia (31%), insomnia (31%), and febrile neutropenia.
The most common grade 3 or higher adverse events (occurring in at least 10% of patients) were febrile neutropenia (31%), neutropenia (23%), anemia (15%), and pulmonary embolism (12%).
There were 6 adverse events resulting in treatment discontinuation—peripheral sensory neuropathy (n=3), abdominal pain (n=1), asthenia (n=1), and peripheral motor neuropathy (n=1).
Seventy-three percent of patients (19/26) experienced peripheral neuropathy. Thirty-seven percent (n=7) had a complete resolution of neuropathy, and 58% (n=11) had some improvement. The median time to resolution was 1.3 months. Twelve patients (63%) had ongoing neuropathy at last follow-up, but most had grade 1 (n=10).
Response and survival
The objective response rate was 100%, and the complete response rate was 88% (n=23). One patient who had a partial response at the end of combination therapy achieved a complete response after going on to single-agent BV.
Twenty-one of the 26 patients are still alive—15 with ALCL and 6 with other PTCLs. Sixteen patients have not progressed—9 with ALCL and 5 with other PTCLs.
After progression, 5 patients received BV again, and 3 received stem cell transplants (2 allogeneic and 1 autologous).
The estimated 3-year PFS was 52%, and the estimated OS was 80%. The researchers noted that these rates compare favorably with the historical 3-year PFS and OS rates of 30% and 40%, respectively.
Researchers are currently conducting a phase 3 trial comparing BV+CHP with CHOP as frontline treatment of CD30+ mature T-cell lymphomas (ECHELON-2, NCT01777152).
Drug could aid standard care for aTTP
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.
Chemo linked to long-term learning problems in ALL survivors
Pediatric acute lymphoblastic leukemia (ALL) patients treated with chemotherapy alone are at risk for attention and learning problems that persist after treatment ends, according to a study published in the Journal of Clinical Oncology.
Researchers said this study is the largest assessment to date of neurocognitive outcomes in pediatric ALL survivors treated with intensive chemotherapy alone rather than in combination with cranial radiation.
“This is an important contribution to the literature because the smaller size and design of previous studies made examining the impact of treatment difficult,” said study author Lisa Jacola, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
“The findings underscore the need for neurocognitive and academic screening to be included as part of routine survivorship care for all pediatric ALL survivors.”
The study included patients enrolled in the St. Jude Total Therapy Study XV. They underwent neurocognitive assessments at the beginning of induction (n=142), end of maintenance (n=243), and 2 years after completing treatment (n=211).
The subjects completed standardized tests of overall intelligence, attention, learning, and academic performance. In addition, parents and other caregivers rated the subjects’ attention, learning, and behavior.
Two years after treatment completion, subjects performed as expected for their age (compared to national data) on measures of overall intelligence, learning, and memory. However, study subjects had significant attention deficits and a significantly greater frequency of learning problems (all P≤0.005).
The risk of such problems was greatest for survivors who were less than 5 years old when diagnosed with ALL and for those who received more intensive chemotherapy.
Specifically, the younger subjects had a greater risk of difficulties with attention, learning, working memory, and processing speed (all P≤0.05). And subjects who received higher-intensity, CNS-directed chemotherapy had a greater risk of difficulties in attention, processing speed, and academics (all P≤0.01).
Researchers also found that subjects with attention problems at the end of therapy had lower academic scores 2 years later (all P≤0.05).
“These findings provide additional evidence that neurocognitive functioning has improved in survivors of childhood ALL since cranial irradiation was replaced with intensified chemotherapy,” Dr Jacola said.
“But we also show these young people are at an elevated risk for attention problems that have real-world consequences, particularly for learning and school performance. Attention is a building block for learning, and, in this study, attention difficulties predicted academic problems later. If we know attention problems seen at the end of therapy continue and contribute to academic problems, then our goal is to intervene earlier to reduce or prevent such difficulties.”
Pediatric acute lymphoblastic leukemia (ALL) patients treated with chemotherapy alone are at risk for attention and learning problems that persist after treatment ends, according to a study published in the Journal of Clinical Oncology.
Researchers said this study is the largest assessment to date of neurocognitive outcomes in pediatric ALL survivors treated with intensive chemotherapy alone rather than in combination with cranial radiation.
“This is an important contribution to the literature because the smaller size and design of previous studies made examining the impact of treatment difficult,” said study author Lisa Jacola, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
“The findings underscore the need for neurocognitive and academic screening to be included as part of routine survivorship care for all pediatric ALL survivors.”
The study included patients enrolled in the St. Jude Total Therapy Study XV. They underwent neurocognitive assessments at the beginning of induction (n=142), end of maintenance (n=243), and 2 years after completing treatment (n=211).
The subjects completed standardized tests of overall intelligence, attention, learning, and academic performance. In addition, parents and other caregivers rated the subjects’ attention, learning, and behavior.
Two years after treatment completion, subjects performed as expected for their age (compared to national data) on measures of overall intelligence, learning, and memory. However, study subjects had significant attention deficits and a significantly greater frequency of learning problems (all P≤0.005).
The risk of such problems was greatest for survivors who were less than 5 years old when diagnosed with ALL and for those who received more intensive chemotherapy.
Specifically, the younger subjects had a greater risk of difficulties with attention, learning, working memory, and processing speed (all P≤0.05). And subjects who received higher-intensity, CNS-directed chemotherapy had a greater risk of difficulties in attention, processing speed, and academics (all P≤0.01).
Researchers also found that subjects with attention problems at the end of therapy had lower academic scores 2 years later (all P≤0.05).
“These findings provide additional evidence that neurocognitive functioning has improved in survivors of childhood ALL since cranial irradiation was replaced with intensified chemotherapy,” Dr Jacola said.
“But we also show these young people are at an elevated risk for attention problems that have real-world consequences, particularly for learning and school performance. Attention is a building block for learning, and, in this study, attention difficulties predicted academic problems later. If we know attention problems seen at the end of therapy continue and contribute to academic problems, then our goal is to intervene earlier to reduce or prevent such difficulties.”
Pediatric acute lymphoblastic leukemia (ALL) patients treated with chemotherapy alone are at risk for attention and learning problems that persist after treatment ends, according to a study published in the Journal of Clinical Oncology.
Researchers said this study is the largest assessment to date of neurocognitive outcomes in pediatric ALL survivors treated with intensive chemotherapy alone rather than in combination with cranial radiation.
“This is an important contribution to the literature because the smaller size and design of previous studies made examining the impact of treatment difficult,” said study author Lisa Jacola, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
“The findings underscore the need for neurocognitive and academic screening to be included as part of routine survivorship care for all pediatric ALL survivors.”
The study included patients enrolled in the St. Jude Total Therapy Study XV. They underwent neurocognitive assessments at the beginning of induction (n=142), end of maintenance (n=243), and 2 years after completing treatment (n=211).
The subjects completed standardized tests of overall intelligence, attention, learning, and academic performance. In addition, parents and other caregivers rated the subjects’ attention, learning, and behavior.
Two years after treatment completion, subjects performed as expected for their age (compared to national data) on measures of overall intelligence, learning, and memory. However, study subjects had significant attention deficits and a significantly greater frequency of learning problems (all P≤0.005).
The risk of such problems was greatest for survivors who were less than 5 years old when diagnosed with ALL and for those who received more intensive chemotherapy.
Specifically, the younger subjects had a greater risk of difficulties with attention, learning, working memory, and processing speed (all P≤0.05). And subjects who received higher-intensity, CNS-directed chemotherapy had a greater risk of difficulties in attention, processing speed, and academics (all P≤0.01).
Researchers also found that subjects with attention problems at the end of therapy had lower academic scores 2 years later (all P≤0.05).
“These findings provide additional evidence that neurocognitive functioning has improved in survivors of childhood ALL since cranial irradiation was replaced with intensified chemotherapy,” Dr Jacola said.
“But we also show these young people are at an elevated risk for attention problems that have real-world consequences, particularly for learning and school performance. Attention is a building block for learning, and, in this study, attention difficulties predicted academic problems later. If we know attention problems seen at the end of therapy continue and contribute to academic problems, then our goal is to intervene earlier to reduce or prevent such difficulties.”
Low doses of iron may cause cell damage
Image courtesy of NIH
Low doses of iron can modify the vascular endothelium and induce a DNA-damage response, researchers have reported in PLOS ONE.
The team observed these phenomena in vitro and said the results must be confirmed via additional research.
However, the findings suggest a need to assess the amount of iron given in standard treatments and the effects this may have on the body, according to Claire Shovlin, PhD, of Imperial College London in the UK.
Dr Shovlin and her colleagues studied human endothelial cells, adding either placebo or an iron solution of 10 micromolar, which is a similar concentration to that seen in the blood after taking an iron tablet.
Within 10 minutes, cells treated with the iron solution had activated DNA repair systems, and these were still activated 6 hours later.
“We already knew that iron could be damaging to cells in very high doses,” Dr Shovlin said. “However, in this study, we found that when we applied the kinds of levels of iron you would find in the bloodstream after taking an iron tablet, this also seemed to be able to trigger cell damage—at least in the laboratory. In other words, cells seem more sensitive to iron than we previously thought.”
“This is very early stage research, and we need more work to confirm these findings and investigate what effects this may have on the body. We are still not sure how these laboratory findings translate to blood vessels in the body.”
“However, this study helps to open the conversation about how much iron people take. At the moment, each standard iron tablet contains almost 10 times the amount of iron men are recommended to eat each day, and these dosages haven’t changed for more than 50 years. This research suggests we may need to think more carefully about how much iron we give to people, and try and tailor the dose to the patient.”
Dr Shovlin and her colleagues initially started researching this area after finding that a small proportion of people using iron tablets for hereditary hemorrhagic telangiectasia, which causes abnormalities in the blood vessels, reported their nose bleeds worsened after iron treatment.
Image courtesy of NIH
Low doses of iron can modify the vascular endothelium and induce a DNA-damage response, researchers have reported in PLOS ONE.
The team observed these phenomena in vitro and said the results must be confirmed via additional research.
However, the findings suggest a need to assess the amount of iron given in standard treatments and the effects this may have on the body, according to Claire Shovlin, PhD, of Imperial College London in the UK.
Dr Shovlin and her colleagues studied human endothelial cells, adding either placebo or an iron solution of 10 micromolar, which is a similar concentration to that seen in the blood after taking an iron tablet.
Within 10 minutes, cells treated with the iron solution had activated DNA repair systems, and these were still activated 6 hours later.
“We already knew that iron could be damaging to cells in very high doses,” Dr Shovlin said. “However, in this study, we found that when we applied the kinds of levels of iron you would find in the bloodstream after taking an iron tablet, this also seemed to be able to trigger cell damage—at least in the laboratory. In other words, cells seem more sensitive to iron than we previously thought.”
“This is very early stage research, and we need more work to confirm these findings and investigate what effects this may have on the body. We are still not sure how these laboratory findings translate to blood vessels in the body.”
“However, this study helps to open the conversation about how much iron people take. At the moment, each standard iron tablet contains almost 10 times the amount of iron men are recommended to eat each day, and these dosages haven’t changed for more than 50 years. This research suggests we may need to think more carefully about how much iron we give to people, and try and tailor the dose to the patient.”
Dr Shovlin and her colleagues initially started researching this area after finding that a small proportion of people using iron tablets for hereditary hemorrhagic telangiectasia, which causes abnormalities in the blood vessels, reported their nose bleeds worsened after iron treatment.
Image courtesy of NIH
Low doses of iron can modify the vascular endothelium and induce a DNA-damage response, researchers have reported in PLOS ONE.
The team observed these phenomena in vitro and said the results must be confirmed via additional research.
However, the findings suggest a need to assess the amount of iron given in standard treatments and the effects this may have on the body, according to Claire Shovlin, PhD, of Imperial College London in the UK.
Dr Shovlin and her colleagues studied human endothelial cells, adding either placebo or an iron solution of 10 micromolar, which is a similar concentration to that seen in the blood after taking an iron tablet.
Within 10 minutes, cells treated with the iron solution had activated DNA repair systems, and these were still activated 6 hours later.
“We already knew that iron could be damaging to cells in very high doses,” Dr Shovlin said. “However, in this study, we found that when we applied the kinds of levels of iron you would find in the bloodstream after taking an iron tablet, this also seemed to be able to trigger cell damage—at least in the laboratory. In other words, cells seem more sensitive to iron than we previously thought.”
“This is very early stage research, and we need more work to confirm these findings and investigate what effects this may have on the body. We are still not sure how these laboratory findings translate to blood vessels in the body.”
“However, this study helps to open the conversation about how much iron people take. At the moment, each standard iron tablet contains almost 10 times the amount of iron men are recommended to eat each day, and these dosages haven’t changed for more than 50 years. This research suggests we may need to think more carefully about how much iron we give to people, and try and tailor the dose to the patient.”
Dr Shovlin and her colleagues initially started researching this area after finding that a small proportion of people using iron tablets for hereditary hemorrhagic telangiectasia, which causes abnormalities in the blood vessels, reported their nose bleeds worsened after iron treatment.
NICE publishes guideline for multiple myeloma
Photo courtesy of NIH
The National Institute for Health and Care Excellence (NICE) has published a guideline containing recommendations for diagnosing, treating, and monitoring patients with multiple myeloma (MM).
The aim of the guideline is to help the National Health Service provide optimal care for MM patients over the age of 16 in England.
The guideline complements existing NICE guidance on the treatment of MM.
“Although there is no cure for myeloma, several novel drug treatments have been licensed in the past 10 years that have led to substantial improvements in the quality and length of time it is possible to live with the disease,” said Mark Baker, clinical practice director for NICE.
“However, there is still variation across the country in terms of providing a coherent and consistent approach to the management of myeloma. Myeloma is also a difficult condition to diagnose because many of the symptoms are non-specific. Our guideline sets out best-practice care to ensure people live as normal a life as possible for as long as possible.”
Some of the recommendations in the guideline include:
Communication and support: Offer prompt psychological assessment and support to MM patients at diagnosis and, as appropriate, at the beginning and end of each treatment, whenever the disease progresses, and when patients require end-of-life care.
Laboratory investigations to provide prognostic information: Use the same sample for all diagnostic and prognostic tests on bone marrow so patients only have to have one bone marrow aspirate and trephine biopsy.
Imaging for people with suspected MM: Offer imaging to all people with a plasma cell disorder suspected to be myeloma. Doctors should consider whole-body MRI as the first imaging procedure.
Service organizations: Each hospital treating MM patients should provide regional access through its network to facilities for intensive inpatient chemotherapy or transplantation, renal support, spinal disease management, specialized pain management, therapeutic apheresis, radiotherapy, restorative dentistry and oral surgery, and clinical trials, in particular early phase trials.
Managing relapsed MM: Offer a second autologous stem cell transplant to people with relapsed MM who are suitable and who have completed re-induction therapy without disease progression and had a response duration of more than 24 months after their first transplant. A second autologous stem cell transplant should be considered in people who have had a response duration of between 12 and 24 months after their first transplant.
Photo courtesy of NIH
The National Institute for Health and Care Excellence (NICE) has published a guideline containing recommendations for diagnosing, treating, and monitoring patients with multiple myeloma (MM).
The aim of the guideline is to help the National Health Service provide optimal care for MM patients over the age of 16 in England.
The guideline complements existing NICE guidance on the treatment of MM.
“Although there is no cure for myeloma, several novel drug treatments have been licensed in the past 10 years that have led to substantial improvements in the quality and length of time it is possible to live with the disease,” said Mark Baker, clinical practice director for NICE.
“However, there is still variation across the country in terms of providing a coherent and consistent approach to the management of myeloma. Myeloma is also a difficult condition to diagnose because many of the symptoms are non-specific. Our guideline sets out best-practice care to ensure people live as normal a life as possible for as long as possible.”
Some of the recommendations in the guideline include:
Communication and support: Offer prompt psychological assessment and support to MM patients at diagnosis and, as appropriate, at the beginning and end of each treatment, whenever the disease progresses, and when patients require end-of-life care.
Laboratory investigations to provide prognostic information: Use the same sample for all diagnostic and prognostic tests on bone marrow so patients only have to have one bone marrow aspirate and trephine biopsy.
Imaging for people with suspected MM: Offer imaging to all people with a plasma cell disorder suspected to be myeloma. Doctors should consider whole-body MRI as the first imaging procedure.
Service organizations: Each hospital treating MM patients should provide regional access through its network to facilities for intensive inpatient chemotherapy or transplantation, renal support, spinal disease management, specialized pain management, therapeutic apheresis, radiotherapy, restorative dentistry and oral surgery, and clinical trials, in particular early phase trials.
Managing relapsed MM: Offer a second autologous stem cell transplant to people with relapsed MM who are suitable and who have completed re-induction therapy without disease progression and had a response duration of more than 24 months after their first transplant. A second autologous stem cell transplant should be considered in people who have had a response duration of between 12 and 24 months after their first transplant.
Photo courtesy of NIH
The National Institute for Health and Care Excellence (NICE) has published a guideline containing recommendations for diagnosing, treating, and monitoring patients with multiple myeloma (MM).
The aim of the guideline is to help the National Health Service provide optimal care for MM patients over the age of 16 in England.
The guideline complements existing NICE guidance on the treatment of MM.
“Although there is no cure for myeloma, several novel drug treatments have been licensed in the past 10 years that have led to substantial improvements in the quality and length of time it is possible to live with the disease,” said Mark Baker, clinical practice director for NICE.
“However, there is still variation across the country in terms of providing a coherent and consistent approach to the management of myeloma. Myeloma is also a difficult condition to diagnose because many of the symptoms are non-specific. Our guideline sets out best-practice care to ensure people live as normal a life as possible for as long as possible.”
Some of the recommendations in the guideline include:
Communication and support: Offer prompt psychological assessment and support to MM patients at diagnosis and, as appropriate, at the beginning and end of each treatment, whenever the disease progresses, and when patients require end-of-life care.
Laboratory investigations to provide prognostic information: Use the same sample for all diagnostic and prognostic tests on bone marrow so patients only have to have one bone marrow aspirate and trephine biopsy.
Imaging for people with suspected MM: Offer imaging to all people with a plasma cell disorder suspected to be myeloma. Doctors should consider whole-body MRI as the first imaging procedure.
Service organizations: Each hospital treating MM patients should provide regional access through its network to facilities for intensive inpatient chemotherapy or transplantation, renal support, spinal disease management, specialized pain management, therapeutic apheresis, radiotherapy, restorative dentistry and oral surgery, and clinical trials, in particular early phase trials.
Managing relapsed MM: Offer a second autologous stem cell transplant to people with relapsed MM who are suitable and who have completed re-induction therapy without disease progression and had a response duration of more than 24 months after their first transplant. A second autologous stem cell transplant should be considered in people who have had a response duration of between 12 and 24 months after their first transplant.
Method may reduce toxicity of anticancer agents
Researchers believe they have found a way to make certain anticancer agents safer without compromising their efficacy.
The team noted that Aurora B kinase inhibitors and other agents targeting the cell cycle have proven effective but highly toxic in clinical trials.
In an attempt to solve this problem, the researchers turned to nanotechnology. They encapsulated the Aurora B kinase inhibitor AZD2811 in polymeric nanoparticles called Accurins.
Susan Ashton, of AstraZeneca in Macclesfield, Cheshire, UK, and her colleagues developed the Accurins and described the work in Science Translational Medicine. The work was funded by AstraZeneca.
The Accurins consist of block copolymers of poly-D,L-lactide and poly(ethylene glycol). The researchers used an ion pairing approach to efficiently encapsulate AZD2811 and control release of the drug.
They found the Accurins could release AZD2811 continuously for more than 1 week in vitro. The nanoparticles also reduced tumor phosphorylated histone H3 levels in vivo for up to 96 hours after a single administration.
The researchers tested the AZD2811 Accurins in mice with diffuse large B-cell lymphoma and rats with colorectal tumors. The nanoparticles accumulated specifically in tumors, where they slowly released AZD2811 to cancer cells.
Compared to AZD1152 (a water-soluble prodrug of AZD2811), the AZD2811 Accurins blocked tumor growth more effectively at one-half the drug dose and caused fewer side effects in the rodents.
Based on these results, the researchers said Accurins could provide efficacy and tolerability using a more convenient dosing regimen, which may extend the utility of Aurora B kinase inhibition to a broader range of hematologic and solid tumor malignancies.
A phase 1 study (NCT02579226) testing AZD2811 Accurins in advanced solid tumors is currently recruiting patients.
A related Focus article published in Science Translational Medicine offers more insights on how Accurin nanoparticles may help enhance the safety and antitumor activity of Aurora kinase inhibitors and other molecularly targeted drugs.
Researchers believe they have found a way to make certain anticancer agents safer without compromising their efficacy.
The team noted that Aurora B kinase inhibitors and other agents targeting the cell cycle have proven effective but highly toxic in clinical trials.
In an attempt to solve this problem, the researchers turned to nanotechnology. They encapsulated the Aurora B kinase inhibitor AZD2811 in polymeric nanoparticles called Accurins.
Susan Ashton, of AstraZeneca in Macclesfield, Cheshire, UK, and her colleagues developed the Accurins and described the work in Science Translational Medicine. The work was funded by AstraZeneca.
The Accurins consist of block copolymers of poly-D,L-lactide and poly(ethylene glycol). The researchers used an ion pairing approach to efficiently encapsulate AZD2811 and control release of the drug.
They found the Accurins could release AZD2811 continuously for more than 1 week in vitro. The nanoparticles also reduced tumor phosphorylated histone H3 levels in vivo for up to 96 hours after a single administration.
The researchers tested the AZD2811 Accurins in mice with diffuse large B-cell lymphoma and rats with colorectal tumors. The nanoparticles accumulated specifically in tumors, where they slowly released AZD2811 to cancer cells.
Compared to AZD1152 (a water-soluble prodrug of AZD2811), the AZD2811 Accurins blocked tumor growth more effectively at one-half the drug dose and caused fewer side effects in the rodents.
Based on these results, the researchers said Accurins could provide efficacy and tolerability using a more convenient dosing regimen, which may extend the utility of Aurora B kinase inhibition to a broader range of hematologic and solid tumor malignancies.
A phase 1 study (NCT02579226) testing AZD2811 Accurins in advanced solid tumors is currently recruiting patients.
A related Focus article published in Science Translational Medicine offers more insights on how Accurin nanoparticles may help enhance the safety and antitumor activity of Aurora kinase inhibitors and other molecularly targeted drugs.
Researchers believe they have found a way to make certain anticancer agents safer without compromising their efficacy.
The team noted that Aurora B kinase inhibitors and other agents targeting the cell cycle have proven effective but highly toxic in clinical trials.
In an attempt to solve this problem, the researchers turned to nanotechnology. They encapsulated the Aurora B kinase inhibitor AZD2811 in polymeric nanoparticles called Accurins.
Susan Ashton, of AstraZeneca in Macclesfield, Cheshire, UK, and her colleagues developed the Accurins and described the work in Science Translational Medicine. The work was funded by AstraZeneca.
The Accurins consist of block copolymers of poly-D,L-lactide and poly(ethylene glycol). The researchers used an ion pairing approach to efficiently encapsulate AZD2811 and control release of the drug.
They found the Accurins could release AZD2811 continuously for more than 1 week in vitro. The nanoparticles also reduced tumor phosphorylated histone H3 levels in vivo for up to 96 hours after a single administration.
The researchers tested the AZD2811 Accurins in mice with diffuse large B-cell lymphoma and rats with colorectal tumors. The nanoparticles accumulated specifically in tumors, where they slowly released AZD2811 to cancer cells.
Compared to AZD1152 (a water-soluble prodrug of AZD2811), the AZD2811 Accurins blocked tumor growth more effectively at one-half the drug dose and caused fewer side effects in the rodents.
Based on these results, the researchers said Accurins could provide efficacy and tolerability using a more convenient dosing regimen, which may extend the utility of Aurora B kinase inhibition to a broader range of hematologic and solid tumor malignancies.
A phase 1 study (NCT02579226) testing AZD2811 Accurins in advanced solid tumors is currently recruiting patients.
A related Focus article published in Science Translational Medicine offers more insights on how Accurin nanoparticles may help enhance the safety and antitumor activity of Aurora kinase inhibitors and other molecularly targeted drugs.