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Link between hemolysis and infection explained
plate showing a positive
streptococcus infection
Photo by Bill Branson
Patients who suffer from hemolysis have an increased risk of developing bacterial infections, and new research provides an explanation for this phenomenon.
The study refutes the idea that excess circulating iron is to blame.
Instead, it suggests that heme prevents macrophages from engulfing bacteria. And targeting this activity might reduce the risk of bacterial infection in patients with hemolytic disorders.
Sylvia Knapp, MD, PhD, of the Medical University of Vienna in Austria, and her colleagues reported these findings in Nature Immunology.
For decades, iron has been considered the prime suspect responsible for the high rate of bacterial infections in patients with hemolysis. Iron has long been established as an essential nutrient for bacteria.
Since hemolysis leads to the release of iron-containing heme, the threat of serious bacterial infections in these patients was attributed to the excess availability of circulating iron (heme).
However, Dr Knapp and her colleagues found that heme does not act as a willing nutrient to bacteria.
“Using in vitro and preclinical models, we could clearly demonstrate that heme-derived iron is not at all vital for bacterial growth,” said Rui Martins, a PhD student at the Medical University of Vienna.
“In contrast, we found that heme acts on macrophages, the most significant immune cells that are required for mounting an antibacterial response, and it furthermore prevented these cells from eliminating bacteria.”
Heme interfered with the cytoskeleton of macrophages, thereby immobilizing them.
“Heme causes cells to form numerous spikes—like hair standing on end—and then ‘stuns’ the cells within minutes,” Martins explained. “It is reminiscent of a cartoon character sticking his finger in an electrical outlet.”
The cytoskeleton is crucial for the basic functions of macrophages. It consists of long, branching filaments that act as the cell’s internal, highly flexible, and mobile framework.
Through targeted build-up and breakdown of these filaments, phagocytes can move in any direction and engulf invading bacteria. However, this requires a finely tuned signaling program in which the protein DOCK8 plays a central role.
“Through chemical proteomics and biochemical experiments, we discovered that heme interacted with DOCK8, which led to the permanent activation of its downstream target, Cdc42, with deleterious effects,” Dr Knapp said.
In the presence of heme, the cytoskeletal resilience was lost, as filaments grew rampant in all directions, resulting in macrophage paralysis. The cells lost their ability to shape-shift and could no longer chase down and engulf the invading bacteria, allowing the bacteria to multiply virtually unrestricted.
However, Dr Knapp and her colleagues found that an antimalarial drug can restore the functionality of these paralyzed macrophages.
“Quinine, which is clinically used to treat malaria and is suspected to bind heme, blocks the interaction of heme with DOCK8 and thereby improves the outcome from sepsis,” Dr Knapp said.
“This is very promising. We conclusively demonstrate that it is indeed feasible to therapeutically ‘protect’ immune cells and to restore the body’s immune defense against bacteria in hemolytic conditions.” 
plate showing a positive
streptococcus infection
Photo by Bill Branson
Patients who suffer from hemolysis have an increased risk of developing bacterial infections, and new research provides an explanation for this phenomenon.
The study refutes the idea that excess circulating iron is to blame.
Instead, it suggests that heme prevents macrophages from engulfing bacteria. And targeting this activity might reduce the risk of bacterial infection in patients with hemolytic disorders.
Sylvia Knapp, MD, PhD, of the Medical University of Vienna in Austria, and her colleagues reported these findings in Nature Immunology.
For decades, iron has been considered the prime suspect responsible for the high rate of bacterial infections in patients with hemolysis. Iron has long been established as an essential nutrient for bacteria.
Since hemolysis leads to the release of iron-containing heme, the threat of serious bacterial infections in these patients was attributed to the excess availability of circulating iron (heme).
However, Dr Knapp and her colleagues found that heme does not act as a willing nutrient to bacteria.
“Using in vitro and preclinical models, we could clearly demonstrate that heme-derived iron is not at all vital for bacterial growth,” said Rui Martins, a PhD student at the Medical University of Vienna.
“In contrast, we found that heme acts on macrophages, the most significant immune cells that are required for mounting an antibacterial response, and it furthermore prevented these cells from eliminating bacteria.”
Heme interfered with the cytoskeleton of macrophages, thereby immobilizing them.
“Heme causes cells to form numerous spikes—like hair standing on end—and then ‘stuns’ the cells within minutes,” Martins explained. “It is reminiscent of a cartoon character sticking his finger in an electrical outlet.”
The cytoskeleton is crucial for the basic functions of macrophages. It consists of long, branching filaments that act as the cell’s internal, highly flexible, and mobile framework.
Through targeted build-up and breakdown of these filaments, phagocytes can move in any direction and engulf invading bacteria. However, this requires a finely tuned signaling program in which the protein DOCK8 plays a central role.
“Through chemical proteomics and biochemical experiments, we discovered that heme interacted with DOCK8, which led to the permanent activation of its downstream target, Cdc42, with deleterious effects,” Dr Knapp said.
In the presence of heme, the cytoskeletal resilience was lost, as filaments grew rampant in all directions, resulting in macrophage paralysis. The cells lost their ability to shape-shift and could no longer chase down and engulf the invading bacteria, allowing the bacteria to multiply virtually unrestricted.
However, Dr Knapp and her colleagues found that an antimalarial drug can restore the functionality of these paralyzed macrophages.
“Quinine, which is clinically used to treat malaria and is suspected to bind heme, blocks the interaction of heme with DOCK8 and thereby improves the outcome from sepsis,” Dr Knapp said.
“This is very promising. We conclusively demonstrate that it is indeed feasible to therapeutically ‘protect’ immune cells and to restore the body’s immune defense against bacteria in hemolytic conditions.”
plate showing a positive
streptococcus infection
Photo by Bill Branson
Patients who suffer from hemolysis have an increased risk of developing bacterial infections, and new research provides an explanation for this phenomenon.
The study refutes the idea that excess circulating iron is to blame.
Instead, it suggests that heme prevents macrophages from engulfing bacteria. And targeting this activity might reduce the risk of bacterial infection in patients with hemolytic disorders.
Sylvia Knapp, MD, PhD, of the Medical University of Vienna in Austria, and her colleagues reported these findings in Nature Immunology.
For decades, iron has been considered the prime suspect responsible for the high rate of bacterial infections in patients with hemolysis. Iron has long been established as an essential nutrient for bacteria.
Since hemolysis leads to the release of iron-containing heme, the threat of serious bacterial infections in these patients was attributed to the excess availability of circulating iron (heme).
However, Dr Knapp and her colleagues found that heme does not act as a willing nutrient to bacteria.
“Using in vitro and preclinical models, we could clearly demonstrate that heme-derived iron is not at all vital for bacterial growth,” said Rui Martins, a PhD student at the Medical University of Vienna.
“In contrast, we found that heme acts on macrophages, the most significant immune cells that are required for mounting an antibacterial response, and it furthermore prevented these cells from eliminating bacteria.”
Heme interfered with the cytoskeleton of macrophages, thereby immobilizing them.
“Heme causes cells to form numerous spikes—like hair standing on end—and then ‘stuns’ the cells within minutes,” Martins explained. “It is reminiscent of a cartoon character sticking his finger in an electrical outlet.”
The cytoskeleton is crucial for the basic functions of macrophages. It consists of long, branching filaments that act as the cell’s internal, highly flexible, and mobile framework.
Through targeted build-up and breakdown of these filaments, phagocytes can move in any direction and engulf invading bacteria. However, this requires a finely tuned signaling program in which the protein DOCK8 plays a central role.
“Through chemical proteomics and biochemical experiments, we discovered that heme interacted with DOCK8, which led to the permanent activation of its downstream target, Cdc42, with deleterious effects,” Dr Knapp said.
In the presence of heme, the cytoskeletal resilience was lost, as filaments grew rampant in all directions, resulting in macrophage paralysis. The cells lost their ability to shape-shift and could no longer chase down and engulf the invading bacteria, allowing the bacteria to multiply virtually unrestricted.
However, Dr Knapp and her colleagues found that an antimalarial drug can restore the functionality of these paralyzed macrophages.
“Quinine, which is clinically used to treat malaria and is suspected to bind heme, blocks the interaction of heme with DOCK8 and thereby improves the outcome from sepsis,” Dr Knapp said.
“This is very promising. We conclusively demonstrate that it is indeed feasible to therapeutically ‘protect’ immune cells and to restore the body’s immune defense against bacteria in hemolytic conditions.”
Generic bivalirudin available in US
Photo from Business Wire
Fresenius Kabi’s Bivalirudin for Injection, a generic alternative to The Medicines Company’s Angiomax, is now available in the US.
Bivalirudin is a direct thrombin inhibitor indicated for use as an anticoagulant.
Fresenius Kabi’s Bivalirudin for Injection was approved by the US Food and Drug Administration in October.
Bivalirudin for Injection is now available in single-dose vials, each containing 250 mg of bivalirudin.
Bivalirudin for Injection was developed and is manufactured in the US.
Bivalirudin for Injection is indicated for use in:
- Patients with unstable angina who are undergoing percutaneous transluminal coronary angioplasty (PTCA)
- Patients undergoing percutaneous coronary intervention (PCI) with provisional use of glycoprotein IIb/IIIa inhibitors, as in the REPLACE-2 study
- Patients with, or at risk of, heparin-induced thrombocytopenia or heparin-induced thrombocytopenia and thrombosis syndrome who are undergoing PCI.
Bivalirudin for Injection is intended for use with aspirin.
The safety and effectiveness of Bivalirudin for Injection has not been established in patients with acute coronary syndromes who are not undergoing PTCA or PCI.
Photo from Business Wire
Fresenius Kabi’s Bivalirudin for Injection, a generic alternative to The Medicines Company’s Angiomax, is now available in the US.
Bivalirudin is a direct thrombin inhibitor indicated for use as an anticoagulant.
Fresenius Kabi’s Bivalirudin for Injection was approved by the US Food and Drug Administration in October.
Bivalirudin for Injection is now available in single-dose vials, each containing 250 mg of bivalirudin.
Bivalirudin for Injection was developed and is manufactured in the US.
Bivalirudin for Injection is indicated for use in:
- Patients with unstable angina who are undergoing percutaneous transluminal coronary angioplasty (PTCA)
- Patients undergoing percutaneous coronary intervention (PCI) with provisional use of glycoprotein IIb/IIIa inhibitors, as in the REPLACE-2 study
- Patients with, or at risk of, heparin-induced thrombocytopenia or heparin-induced thrombocytopenia and thrombosis syndrome who are undergoing PCI.
Bivalirudin for Injection is intended for use with aspirin.
The safety and effectiveness of Bivalirudin for Injection has not been established in patients with acute coronary syndromes who are not undergoing PTCA or PCI.
Photo from Business Wire
Fresenius Kabi’s Bivalirudin for Injection, a generic alternative to The Medicines Company’s Angiomax, is now available in the US.
Bivalirudin is a direct thrombin inhibitor indicated for use as an anticoagulant.
Fresenius Kabi’s Bivalirudin for Injection was approved by the US Food and Drug Administration in October.
Bivalirudin for Injection is now available in single-dose vials, each containing 250 mg of bivalirudin.
Bivalirudin for Injection was developed and is manufactured in the US.
Bivalirudin for Injection is indicated for use in:
- Patients with unstable angina who are undergoing percutaneous transluminal coronary angioplasty (PTCA)
- Patients undergoing percutaneous coronary intervention (PCI) with provisional use of glycoprotein IIb/IIIa inhibitors, as in the REPLACE-2 study
- Patients with, or at risk of, heparin-induced thrombocytopenia or heparin-induced thrombocytopenia and thrombosis syndrome who are undergoing PCI.
Bivalirudin for Injection is intended for use with aspirin.
The safety and effectiveness of Bivalirudin for Injection has not been established in patients with acute coronary syndromes who are not undergoing PTCA or PCI.
Phase 2 trial of MM drug placed on clinical hold
A phase 2 study of the antibody BI-505 in patients with multiple myeloma (MM) has been placed on full clinical hold.
BioInvent International, the company developing BI-505, said it has received verbal notice of the clinical hold from the US Food and Drug Administration (FDA).
The clinical hold means no new subjects can be enrolled on the trial, and there can be no further dosing of subjects who are already enrolled.
BioInvent International said it has yet to receive written notice of the clinical hold from the FDA. However, based on verbal communications, the clinical hold is due to an adverse cardiopulmonary event.
The study (NCT02756728) is being conducted by BioInvent International in collaboration with investigators at the University of Pennsylvania.
The goal of the study is to determine if BI-505 can deepen therapeutic response and thereby prevent or delay relapse in MM patients undergoing autologous stem cell transplant with high-dose melphalan.
BioInvent International said it will analyze the possibility to obtain release of the clinical hold and will provide updates when there is further information to report.
About BI-505
BI-505 is a human antibody targeting ICAM-1, a protein that is elevated in MM cells. BI-505 has been shown to attack MM in 2 ways—by inducing apoptosis in MM cells and by engaging macrophages to attack and kill MM cells.
According to BioInvent International, the development strategy for BI-505 is focused on eliminating residual disease by combining the antibody with modern standard-of-care drugs used to treat MM.
The company said BI-505 proved safe in a phase 1 trial of patients with relapsed/refractory MM, as well as demonstrating “signs of a positive effect against the disease.” This study was published in Clinical Cancer Research in June 2015.
BI-505 has received orphan drug designation as a treatment for MM from both the FDA and the European Medicines Agency.
A phase 2 study of the antibody BI-505 in patients with multiple myeloma (MM) has been placed on full clinical hold.
BioInvent International, the company developing BI-505, said it has received verbal notice of the clinical hold from the US Food and Drug Administration (FDA).
The clinical hold means no new subjects can be enrolled on the trial, and there can be no further dosing of subjects who are already enrolled.
BioInvent International said it has yet to receive written notice of the clinical hold from the FDA. However, based on verbal communications, the clinical hold is due to an adverse cardiopulmonary event.
The study (NCT02756728) is being conducted by BioInvent International in collaboration with investigators at the University of Pennsylvania.
The goal of the study is to determine if BI-505 can deepen therapeutic response and thereby prevent or delay relapse in MM patients undergoing autologous stem cell transplant with high-dose melphalan.
BioInvent International said it will analyze the possibility to obtain release of the clinical hold and will provide updates when there is further information to report.
About BI-505
BI-505 is a human antibody targeting ICAM-1, a protein that is elevated in MM cells. BI-505 has been shown to attack MM in 2 ways—by inducing apoptosis in MM cells and by engaging macrophages to attack and kill MM cells.
According to BioInvent International, the development strategy for BI-505 is focused on eliminating residual disease by combining the antibody with modern standard-of-care drugs used to treat MM.
The company said BI-505 proved safe in a phase 1 trial of patients with relapsed/refractory MM, as well as demonstrating “signs of a positive effect against the disease.” This study was published in Clinical Cancer Research in June 2015.
BI-505 has received orphan drug designation as a treatment for MM from both the FDA and the European Medicines Agency.
A phase 2 study of the antibody BI-505 in patients with multiple myeloma (MM) has been placed on full clinical hold.
BioInvent International, the company developing BI-505, said it has received verbal notice of the clinical hold from the US Food and Drug Administration (FDA).
The clinical hold means no new subjects can be enrolled on the trial, and there can be no further dosing of subjects who are already enrolled.
BioInvent International said it has yet to receive written notice of the clinical hold from the FDA. However, based on verbal communications, the clinical hold is due to an adverse cardiopulmonary event.
The study (NCT02756728) is being conducted by BioInvent International in collaboration with investigators at the University of Pennsylvania.
The goal of the study is to determine if BI-505 can deepen therapeutic response and thereby prevent or delay relapse in MM patients undergoing autologous stem cell transplant with high-dose melphalan.
BioInvent International said it will analyze the possibility to obtain release of the clinical hold and will provide updates when there is further information to report.
About BI-505
BI-505 is a human antibody targeting ICAM-1, a protein that is elevated in MM cells. BI-505 has been shown to attack MM in 2 ways—by inducing apoptosis in MM cells and by engaging macrophages to attack and kill MM cells.
According to BioInvent International, the development strategy for BI-505 is focused on eliminating residual disease by combining the antibody with modern standard-of-care drugs used to treat MM.
The company said BI-505 proved safe in a phase 1 trial of patients with relapsed/refractory MM, as well as demonstrating “signs of a positive effect against the disease.” This study was published in Clinical Cancer Research in June 2015.
BI-505 has received orphan drug designation as a treatment for MM from both the FDA and the European Medicines Agency.
Panobinostat might treat high-risk ALL subtype
Photo courtesy of Novartis
Researchers say they have identified a high-risk subtype of acute lymphoblastic leukemia (ALL) that may respond to treatment with the histone deacetylase (HDAC) inhibitor panobinostat.
The ALL subtype is characterized by chromosomal rearrangements that involve the MEF2D gene and 1 of 6 partner genes, most often BCL9.
The researchers described this subtype, known as MEF2D-rearranged ALL, in Nature Communications.
“MEF2D is a transcription factor that switches on expression of other genes during normal development,” said study author Charles Mullighan, MD, MBBS, of the St. Jude Children’s Research Hospital in Memphis, Tennessee.
“We found that MEF2D chromosomal rearrangements disrupt expression of those genes and create a vulnerability to at least one targeted therapy, the drug panobinostat.”
Dr Mullighan and his colleagues performed genomic analyses on samples from a total of 1724 children, adolescents, and adults with ALL. This revealed 52 patients with MEF2D rearrangements.
MEF2D-rearranged ALL
The researchers calculated that MEF2D-rearranged ALL accounted for 5.3% of the ALL cases whose genetic basis was unknown.
The team also noted that MEF2D-rearranged ALL occurred most frequently in adolescents. Although, overall, ALL occurs most often in children between 3 and 5 years old, the average patient with MEF2D-rearranged ALL was 14.
In addition, MEF2D-rearranged ALL was associated with reduced survival when compared to some other ALL subtypes. The 5-year cancer-free survival for MEF2D-rearranged ALL patients was 71.6%.
The researchers also found that a fusion protein resulting from the MEF2D rearrangement led to sustained growth of mouse cells when compared to wild-type MEF2D or other proteins.
“That indicates the MEF2D fusion is a key step in transforming a normal white blood cell with a finite lifespan into a leukemic cell that is immortal,” Dr Mullighan said.
Role for panobinostat
MEF2D-rearranged leukemic cells produced high levels of HDAC9, which is targeted by panobinostat.
The researchers tested panobinostat in the lab and found the drug stopped proliferation of human MEF2D-rearranged leukemic cells.
Dr Mullighan said MEF2D-rearranged leukemic cells were exquisitely sensitive to panobinostat, which suggested the drug might function in a more targeted manner against cells with the rearrangement.
“If further testing of panobinostat, either alone or in combination therapy, confirms the anti-proliferative activity, that would lay the foundation for a clinical trial in patients, particularly patients with high-risk disease or those who have relapsed,” he said.
Photo courtesy of Novartis
Researchers say they have identified a high-risk subtype of acute lymphoblastic leukemia (ALL) that may respond to treatment with the histone deacetylase (HDAC) inhibitor panobinostat.
The ALL subtype is characterized by chromosomal rearrangements that involve the MEF2D gene and 1 of 6 partner genes, most often BCL9.
The researchers described this subtype, known as MEF2D-rearranged ALL, in Nature Communications.
“MEF2D is a transcription factor that switches on expression of other genes during normal development,” said study author Charles Mullighan, MD, MBBS, of the St. Jude Children’s Research Hospital in Memphis, Tennessee.
“We found that MEF2D chromosomal rearrangements disrupt expression of those genes and create a vulnerability to at least one targeted therapy, the drug panobinostat.”
Dr Mullighan and his colleagues performed genomic analyses on samples from a total of 1724 children, adolescents, and adults with ALL. This revealed 52 patients with MEF2D rearrangements.
MEF2D-rearranged ALL
The researchers calculated that MEF2D-rearranged ALL accounted for 5.3% of the ALL cases whose genetic basis was unknown.
The team also noted that MEF2D-rearranged ALL occurred most frequently in adolescents. Although, overall, ALL occurs most often in children between 3 and 5 years old, the average patient with MEF2D-rearranged ALL was 14.
In addition, MEF2D-rearranged ALL was associated with reduced survival when compared to some other ALL subtypes. The 5-year cancer-free survival for MEF2D-rearranged ALL patients was 71.6%.
The researchers also found that a fusion protein resulting from the MEF2D rearrangement led to sustained growth of mouse cells when compared to wild-type MEF2D or other proteins.
“That indicates the MEF2D fusion is a key step in transforming a normal white blood cell with a finite lifespan into a leukemic cell that is immortal,” Dr Mullighan said.
Role for panobinostat
MEF2D-rearranged leukemic cells produced high levels of HDAC9, which is targeted by panobinostat.
The researchers tested panobinostat in the lab and found the drug stopped proliferation of human MEF2D-rearranged leukemic cells.
Dr Mullighan said MEF2D-rearranged leukemic cells were exquisitely sensitive to panobinostat, which suggested the drug might function in a more targeted manner against cells with the rearrangement.
“If further testing of panobinostat, either alone or in combination therapy, confirms the anti-proliferative activity, that would lay the foundation for a clinical trial in patients, particularly patients with high-risk disease or those who have relapsed,” he said.
Photo courtesy of Novartis
Researchers say they have identified a high-risk subtype of acute lymphoblastic leukemia (ALL) that may respond to treatment with the histone deacetylase (HDAC) inhibitor panobinostat.
The ALL subtype is characterized by chromosomal rearrangements that involve the MEF2D gene and 1 of 6 partner genes, most often BCL9.
The researchers described this subtype, known as MEF2D-rearranged ALL, in Nature Communications.
“MEF2D is a transcription factor that switches on expression of other genes during normal development,” said study author Charles Mullighan, MD, MBBS, of the St. Jude Children’s Research Hospital in Memphis, Tennessee.
“We found that MEF2D chromosomal rearrangements disrupt expression of those genes and create a vulnerability to at least one targeted therapy, the drug panobinostat.”
Dr Mullighan and his colleagues performed genomic analyses on samples from a total of 1724 children, adolescents, and adults with ALL. This revealed 52 patients with MEF2D rearrangements.
MEF2D-rearranged ALL
The researchers calculated that MEF2D-rearranged ALL accounted for 5.3% of the ALL cases whose genetic basis was unknown.
The team also noted that MEF2D-rearranged ALL occurred most frequently in adolescents. Although, overall, ALL occurs most often in children between 3 and 5 years old, the average patient with MEF2D-rearranged ALL was 14.
In addition, MEF2D-rearranged ALL was associated with reduced survival when compared to some other ALL subtypes. The 5-year cancer-free survival for MEF2D-rearranged ALL patients was 71.6%.
The researchers also found that a fusion protein resulting from the MEF2D rearrangement led to sustained growth of mouse cells when compared to wild-type MEF2D or other proteins.
“That indicates the MEF2D fusion is a key step in transforming a normal white blood cell with a finite lifespan into a leukemic cell that is immortal,” Dr Mullighan said.
Role for panobinostat
MEF2D-rearranged leukemic cells produced high levels of HDAC9, which is targeted by panobinostat.
The researchers tested panobinostat in the lab and found the drug stopped proliferation of human MEF2D-rearranged leukemic cells.
Dr Mullighan said MEF2D-rearranged leukemic cells were exquisitely sensitive to panobinostat, which suggested the drug might function in a more targeted manner against cells with the rearrangement.
“If further testing of panobinostat, either alone or in combination therapy, confirms the anti-proliferative activity, that would lay the foundation for a clinical trial in patients, particularly patients with high-risk disease or those who have relapsed,” he said.
Docs may be uninformed about biosimilars
(filgrastim-sndz), the first
biosimilar approved in the US
© Sandoz Inc. 2015
WASHINGTON, DC—A survey of roughly 1200 US physicians has revealed gaps in their knowledge about biosimilars.
The results showed that some physicians had difficulty defining biosimilars, did not fully understand how the US Food and Drug Administration (FDA) approves biosimilars, and may not know how to prescribe biosimilars appropriately.
The results were published in Advances in Therapy and presented at the DIA Biosimilars 2016 conference.
The 19-question survey was created by the Biosimilars Forum and conducted by SERMO, a global social network organization for physicians, from November 20, 2015, to January 4, 2016.
Responses were obtained from 1201 US physicians across specialties that are high prescribers of biologics, including hematologist-oncologists, dermatologists, gastroenterologists, medical oncologists, nephrologists, and rheumatologists.
Knowledge gaps
The survey revealed 5 major knowledge gaps regarding biosimilars:
- Defining biologics, biosimilars, and biosimilarity1
- Understanding the approval process and the FDA’s use of “totality of evidence” to evaluate biosimilars
- Understanding that the safety profile of a biosimilar is expected to be the same as that of the originator biologic
- Understanding how decisions are made by the FDA for extrapolation2 of indications
- Defining interchangeability3 and the related rules regarding pharmacy-level substitution.
“With 4 biosimilars approved by the FDA and more than 60 in development, the survey highlights the need for greater biosimilars education for physicians and healthcare professionals,” said study author Hillel Cohen, PhD, executive director of scientific affairs at Sandoz Inc.
“Education will help physicians and healthcare professionals have a better understanding and knowledge of biosimilars so that they feel comfortable about administering biosimilars to patients when appropriate.”
FDA approval
Most of the physicians surveyed did not clearly understand the concept of extrapolation as applied to biosimilars. Only 12% of survey respondents said they trust extrapolation of the studied biosimilar indication(s) as the basis to obtain approval of other licensed indications of the originator product.
Almost 60% of respondents correctly understood that, to be approved as “interchangeable” with the originator, a biosimilar must be shown to be safe and effective for back-and-forth switching, with no negative impacts to safety or efficacy.
However, almost 80% of respondents did not agree, or potentially did not realize, that an FDA designation of “interchangeable” may enable a pharmacist to switch between the originator biologic and biosimilar and vice versa.
A little more than half of physicians surveyed knew that, for a biosimilar to be approved, the FDA must find the biosimilar to be equally effective (62.3%) and safe (57.2%) when compared to the originator biologic.
Most physicians surveyed (74.5%) said they trust the FDA’s biosimilar approval decisions.
Biosimilar use
Fewer than half of the survey respondents (44.8%) believed that biosimilars will be safe and appropriate for use in existing patients as well as naïve patients.
Overall, respondents expressed a general agreement that switching an existing patient to a biosimilar may be appropriate, with 9 in 10 (91%) saying they would consider switching a patient from an originator biologic to a biosimilar as an effective alternative to the originator if it would help the patient have better access to his/her medications.
In addition, 82.2% of respondents believed biosimilars will expand treatment options and provide savings to patients and the healthcare system.
“The Biosimilars Forum launched the Partnership for Biosimilar Education and Access to provide evidence-based education for healthcare professionals, patients, and the public,” Dr Cohen said. “The forum will use the survey results to provide education on the key concepts of biosimilars as we advance our mission to encourage awareness, access, and adoption of these important medicines.”
The Biosimilars Forum intends to conduct a similar survey in 2 to 3 years with the same design in order to monitor trends in the awareness, knowledge, and perceptions of biosimilars over time.
1. A biosimilar medicine is a biologic that is highly similar to an FDA-approved biological medicine, known as an originator biologic. A biosimilar must (1) be highly similar to the originator biologic, notwithstanding minor differences in clinically inactive components, and (2) have no clinically meaningful differences in safety or effectiveness compared to the originator biologic. Biosimilars Forum. (2016, March 28). Frequently Asked Questions. Retrieved from: http://www.biosimilarsforum.org/sites/default/files/uploads/biosimilars_faqs_032816opt_0.pdf
2. Extrapolation is the process by which a biosimilar may be approved for one or more indications for which its reference biological product is licensed but for which there was no head-to-head clinical comparison. This approval is based on the extrapolation of the totality of data obtained with the biosimilar molecule in direct comparison to the originator biologic. Every indication for which extrapolation is sought must be scientifically justified. Biosimilars Forum. (2016, March 28). Frequently Asked Questions. Retrieved from: http://www.biosimilarsforum.org/sites/default/files/uploads/biosimilars_faqs_032816opt_0.pdf
3. An interchangeable biologic is a biosimilar that has been demonstrated to produce the same clinical result as its originator biologic in any given patient. In addition, for a product that is administered multiple times to an individual, the risk in terms of safety or diminished efficacy of alternating between use of the interchangeable biologic and its originator biologic is not greater than the risk of using the originator biologic alone. Designation of interchangeability requires additional supporting evidence, which will be further defined by the FDA. An interchangeable biologic may be substituted by a pharmacist for the originator biologic or vice-versa without the intervention of the healthcare professional who wrote the prescription. State laws govern the substitution process, and communication to the healthcare provider who wrote the prescription may be required after the product is dispensed. Biosimilars Forum. (2016, March 28). Frequently Asked Questions. Retrieved from: http://www.biosimilarsforum.org/sites/default/files/uploads/biosimilars_faqs_032816opt_0.pdf
(filgrastim-sndz), the first
biosimilar approved in the US
© Sandoz Inc. 2015
WASHINGTON, DC—A survey of roughly 1200 US physicians has revealed gaps in their knowledge about biosimilars.
The results showed that some physicians had difficulty defining biosimilars, did not fully understand how the US Food and Drug Administration (FDA) approves biosimilars, and may not know how to prescribe biosimilars appropriately.
The results were published in Advances in Therapy and presented at the DIA Biosimilars 2016 conference.
The 19-question survey was created by the Biosimilars Forum and conducted by SERMO, a global social network organization for physicians, from November 20, 2015, to January 4, 2016.
Responses were obtained from 1201 US physicians across specialties that are high prescribers of biologics, including hematologist-oncologists, dermatologists, gastroenterologists, medical oncologists, nephrologists, and rheumatologists.
Knowledge gaps
The survey revealed 5 major knowledge gaps regarding biosimilars:
- Defining biologics, biosimilars, and biosimilarity1
- Understanding the approval process and the FDA’s use of “totality of evidence” to evaluate biosimilars
- Understanding that the safety profile of a biosimilar is expected to be the same as that of the originator biologic
- Understanding how decisions are made by the FDA for extrapolation2 of indications
- Defining interchangeability3 and the related rules regarding pharmacy-level substitution.
“With 4 biosimilars approved by the FDA and more than 60 in development, the survey highlights the need for greater biosimilars education for physicians and healthcare professionals,” said study author Hillel Cohen, PhD, executive director of scientific affairs at Sandoz Inc.
“Education will help physicians and healthcare professionals have a better understanding and knowledge of biosimilars so that they feel comfortable about administering biosimilars to patients when appropriate.”
FDA approval
Most of the physicians surveyed did not clearly understand the concept of extrapolation as applied to biosimilars. Only 12% of survey respondents said they trust extrapolation of the studied biosimilar indication(s) as the basis to obtain approval of other licensed indications of the originator product.
Almost 60% of respondents correctly understood that, to be approved as “interchangeable” with the originator, a biosimilar must be shown to be safe and effective for back-and-forth switching, with no negative impacts to safety or efficacy.
However, almost 80% of respondents did not agree, or potentially did not realize, that an FDA designation of “interchangeable” may enable a pharmacist to switch between the originator biologic and biosimilar and vice versa.
A little more than half of physicians surveyed knew that, for a biosimilar to be approved, the FDA must find the biosimilar to be equally effective (62.3%) and safe (57.2%) when compared to the originator biologic.
Most physicians surveyed (74.5%) said they trust the FDA’s biosimilar approval decisions.
Biosimilar use
Fewer than half of the survey respondents (44.8%) believed that biosimilars will be safe and appropriate for use in existing patients as well as naïve patients.
Overall, respondents expressed a general agreement that switching an existing patient to a biosimilar may be appropriate, with 9 in 10 (91%) saying they would consider switching a patient from an originator biologic to a biosimilar as an effective alternative to the originator if it would help the patient have better access to his/her medications.
In addition, 82.2% of respondents believed biosimilars will expand treatment options and provide savings to patients and the healthcare system.
“The Biosimilars Forum launched the Partnership for Biosimilar Education and Access to provide evidence-based education for healthcare professionals, patients, and the public,” Dr Cohen said. “The forum will use the survey results to provide education on the key concepts of biosimilars as we advance our mission to encourage awareness, access, and adoption of these important medicines.”
The Biosimilars Forum intends to conduct a similar survey in 2 to 3 years with the same design in order to monitor trends in the awareness, knowledge, and perceptions of biosimilars over time.
1. A biosimilar medicine is a biologic that is highly similar to an FDA-approved biological medicine, known as an originator biologic. A biosimilar must (1) be highly similar to the originator biologic, notwithstanding minor differences in clinically inactive components, and (2) have no clinically meaningful differences in safety or effectiveness compared to the originator biologic. Biosimilars Forum. (2016, March 28). Frequently Asked Questions. Retrieved from: http://www.biosimilarsforum.org/sites/default/files/uploads/biosimilars_faqs_032816opt_0.pdf
2. Extrapolation is the process by which a biosimilar may be approved for one or more indications for which its reference biological product is licensed but for which there was no head-to-head clinical comparison. This approval is based on the extrapolation of the totality of data obtained with the biosimilar molecule in direct comparison to the originator biologic. Every indication for which extrapolation is sought must be scientifically justified. Biosimilars Forum. (2016, March 28). Frequently Asked Questions. Retrieved from: http://www.biosimilarsforum.org/sites/default/files/uploads/biosimilars_faqs_032816opt_0.pdf
3. An interchangeable biologic is a biosimilar that has been demonstrated to produce the same clinical result as its originator biologic in any given patient. In addition, for a product that is administered multiple times to an individual, the risk in terms of safety or diminished efficacy of alternating between use of the interchangeable biologic and its originator biologic is not greater than the risk of using the originator biologic alone. Designation of interchangeability requires additional supporting evidence, which will be further defined by the FDA. An interchangeable biologic may be substituted by a pharmacist for the originator biologic or vice-versa without the intervention of the healthcare professional who wrote the prescription. State laws govern the substitution process, and communication to the healthcare provider who wrote the prescription may be required after the product is dispensed. Biosimilars Forum. (2016, March 28). Frequently Asked Questions. Retrieved from: http://www.biosimilarsforum.org/sites/default/files/uploads/biosimilars_faqs_032816opt_0.pdf
(filgrastim-sndz), the first
biosimilar approved in the US
© Sandoz Inc. 2015
WASHINGTON, DC—A survey of roughly 1200 US physicians has revealed gaps in their knowledge about biosimilars.
The results showed that some physicians had difficulty defining biosimilars, did not fully understand how the US Food and Drug Administration (FDA) approves biosimilars, and may not know how to prescribe biosimilars appropriately.
The results were published in Advances in Therapy and presented at the DIA Biosimilars 2016 conference.
The 19-question survey was created by the Biosimilars Forum and conducted by SERMO, a global social network organization for physicians, from November 20, 2015, to January 4, 2016.
Responses were obtained from 1201 US physicians across specialties that are high prescribers of biologics, including hematologist-oncologists, dermatologists, gastroenterologists, medical oncologists, nephrologists, and rheumatologists.
Knowledge gaps
The survey revealed 5 major knowledge gaps regarding biosimilars:
- Defining biologics, biosimilars, and biosimilarity1
- Understanding the approval process and the FDA’s use of “totality of evidence” to evaluate biosimilars
- Understanding that the safety profile of a biosimilar is expected to be the same as that of the originator biologic
- Understanding how decisions are made by the FDA for extrapolation2 of indications
- Defining interchangeability3 and the related rules regarding pharmacy-level substitution.
“With 4 biosimilars approved by the FDA and more than 60 in development, the survey highlights the need for greater biosimilars education for physicians and healthcare professionals,” said study author Hillel Cohen, PhD, executive director of scientific affairs at Sandoz Inc.
“Education will help physicians and healthcare professionals have a better understanding and knowledge of biosimilars so that they feel comfortable about administering biosimilars to patients when appropriate.”
FDA approval
Most of the physicians surveyed did not clearly understand the concept of extrapolation as applied to biosimilars. Only 12% of survey respondents said they trust extrapolation of the studied biosimilar indication(s) as the basis to obtain approval of other licensed indications of the originator product.
Almost 60% of respondents correctly understood that, to be approved as “interchangeable” with the originator, a biosimilar must be shown to be safe and effective for back-and-forth switching, with no negative impacts to safety or efficacy.
However, almost 80% of respondents did not agree, or potentially did not realize, that an FDA designation of “interchangeable” may enable a pharmacist to switch between the originator biologic and biosimilar and vice versa.
A little more than half of physicians surveyed knew that, for a biosimilar to be approved, the FDA must find the biosimilar to be equally effective (62.3%) and safe (57.2%) when compared to the originator biologic.
Most physicians surveyed (74.5%) said they trust the FDA’s biosimilar approval decisions.
Biosimilar use
Fewer than half of the survey respondents (44.8%) believed that biosimilars will be safe and appropriate for use in existing patients as well as naïve patients.
Overall, respondents expressed a general agreement that switching an existing patient to a biosimilar may be appropriate, with 9 in 10 (91%) saying they would consider switching a patient from an originator biologic to a biosimilar as an effective alternative to the originator if it would help the patient have better access to his/her medications.
In addition, 82.2% of respondents believed biosimilars will expand treatment options and provide savings to patients and the healthcare system.
“The Biosimilars Forum launched the Partnership for Biosimilar Education and Access to provide evidence-based education for healthcare professionals, patients, and the public,” Dr Cohen said. “The forum will use the survey results to provide education on the key concepts of biosimilars as we advance our mission to encourage awareness, access, and adoption of these important medicines.”
The Biosimilars Forum intends to conduct a similar survey in 2 to 3 years with the same design in order to monitor trends in the awareness, knowledge, and perceptions of biosimilars over time.
1. A biosimilar medicine is a biologic that is highly similar to an FDA-approved biological medicine, known as an originator biologic. A biosimilar must (1) be highly similar to the originator biologic, notwithstanding minor differences in clinically inactive components, and (2) have no clinically meaningful differences in safety or effectiveness compared to the originator biologic. Biosimilars Forum. (2016, March 28). Frequently Asked Questions. Retrieved from: http://www.biosimilarsforum.org/sites/default/files/uploads/biosimilars_faqs_032816opt_0.pdf
2. Extrapolation is the process by which a biosimilar may be approved for one or more indications for which its reference biological product is licensed but for which there was no head-to-head clinical comparison. This approval is based on the extrapolation of the totality of data obtained with the biosimilar molecule in direct comparison to the originator biologic. Every indication for which extrapolation is sought must be scientifically justified. Biosimilars Forum. (2016, March 28). Frequently Asked Questions. Retrieved from: http://www.biosimilarsforum.org/sites/default/files/uploads/biosimilars_faqs_032816opt_0.pdf
3. An interchangeable biologic is a biosimilar that has been demonstrated to produce the same clinical result as its originator biologic in any given patient. In addition, for a product that is administered multiple times to an individual, the risk in terms of safety or diminished efficacy of alternating between use of the interchangeable biologic and its originator biologic is not greater than the risk of using the originator biologic alone. Designation of interchangeability requires additional supporting evidence, which will be further defined by the FDA. An interchangeable biologic may be substituted by a pharmacist for the originator biologic or vice-versa without the intervention of the healthcare professional who wrote the prescription. State laws govern the substitution process, and communication to the healthcare provider who wrote the prescription may be required after the product is dispensed. Biosimilars Forum. (2016, March 28). Frequently Asked Questions. Retrieved from: http://www.biosimilarsforum.org/sites/default/files/uploads/biosimilars_faqs_032816opt_0.pdf
Study provides new insight into RBC production
Andes who suffers from
chronic mountain sickness
Photo courtesy of
UC San Diego Health
Findings from a study of people living at high altitude have implications for the treatment of red blood cell (RBC) disorders such as anemia and polycythemia, according to researchers.
To better understand why some people adapt well to life at high altitude while others don’t, the researchers studied RBCs derived from representatives of both groups who were living in the Andes Mountains.
The study revealed that high-altitude dwellers prone to chronic mountain sickness produce massive amounts of RBCs thanks to overproduction of the enzyme SENP1.
The researchers reported these findings in the Journal of Experimental Medicine.
“In addition to improving the health of millions of people around the world who live above 8000 feet, information on how Andeans have adapted—or not adapted—to high-altitude life might teach us how to speed up red blood cell production at lower altitudes, such as in anemia or when blood transfusions are needed rapidly,” said study author Gabriel Haddad, MD, of the University of California San Diego School of Medicine.
Dr Haddad and his colleagues noted that chronic mountain sickness affects approximately 20% of people who live at high altitudes, and a critical aspect of the condition is polycythemia.
Some extra RBCs can be beneficial in high-altitude, low-oxygen environments by helping to keep blood oxygenated. However, too many RBCs can increase the risk of heart attack and stroke, even in young adults.
For this study, the researchers collected skin cells from people living in the Andes Mountains—4 who were healthy and 5 who suffer from chronic mountain sickness—plus an additional 3 healthy people who live at sea level and served as controls.
To produce enough RBCs from each participant to study them in the lab, the researchers converted the skin cells into induced pluripotent stem cells (iPSCs).
Then, adding a cocktail of growth factors and other molecules, the team coaxed the iPSCs to differentiate into RBCs. Multiple samples were tested for each person, for a total of at least 24 iPSC lines.
The researchers exposed the RBCs to low-oxygen conditions that mimic high altitude—5% oxygen—for 3 weeks.
RBCs from healthy sea-level or high-altitude-dwelling donors increased a little or not at all. In contrast, RBC counts from high-altitude dwellers with chronic mountain sickness increased 60-fold.
This result led the researchers to question why people with chronic mountain sickness produce so many extra RBCs in response to low oxygen.
In a previous study, the team had compared the genomes of high-altitude dwellers with and without chronic mountain sickness. This revealed a gene that varied between the 2 groups—SENP1, which is increased in low-oxygen situations in people with chronic mountain sickness but not in healthy individuals.
In the current study, the researchers set out to determine if SENP1 plays a role in high-altitude adaptation.
The team inhibited the SENP1 gene in iPSCs from patients with chronic mountain sickness. As a result, excessive RBC production was reduced by more than 90%.
When the researchers added extra SENP1 to healthy, adapted highlander iPSCs, RBC production increased 30-fold, nearly recapitulating that seen in patients with chronic mountains sickness.
Further experiments revealed how SENP1 affects RBC production. Elevated levels of the enzyme in chronic mountain sickness boost levels of several other proteins that promote cell division and survival, including VEGF, GATA1, and Bcl-xL.
“We’re interested in determining the early steps in this process—how low oxygen triggers SENP1 in the first place,” said study author Priti Azad, PhD, of the University of California San Diego School of Medicine.
“We are also investigating how existing altitude sickness medications, such as Diamox, work and whether or not it’s through this same mechanism.”
Andes who suffers from
chronic mountain sickness
Photo courtesy of
UC San Diego Health
Findings from a study of people living at high altitude have implications for the treatment of red blood cell (RBC) disorders such as anemia and polycythemia, according to researchers.
To better understand why some people adapt well to life at high altitude while others don’t, the researchers studied RBCs derived from representatives of both groups who were living in the Andes Mountains.
The study revealed that high-altitude dwellers prone to chronic mountain sickness produce massive amounts of RBCs thanks to overproduction of the enzyme SENP1.
The researchers reported these findings in the Journal of Experimental Medicine.
“In addition to improving the health of millions of people around the world who live above 8000 feet, information on how Andeans have adapted—or not adapted—to high-altitude life might teach us how to speed up red blood cell production at lower altitudes, such as in anemia or when blood transfusions are needed rapidly,” said study author Gabriel Haddad, MD, of the University of California San Diego School of Medicine.
Dr Haddad and his colleagues noted that chronic mountain sickness affects approximately 20% of people who live at high altitudes, and a critical aspect of the condition is polycythemia.
Some extra RBCs can be beneficial in high-altitude, low-oxygen environments by helping to keep blood oxygenated. However, too many RBCs can increase the risk of heart attack and stroke, even in young adults.
For this study, the researchers collected skin cells from people living in the Andes Mountains—4 who were healthy and 5 who suffer from chronic mountain sickness—plus an additional 3 healthy people who live at sea level and served as controls.
To produce enough RBCs from each participant to study them in the lab, the researchers converted the skin cells into induced pluripotent stem cells (iPSCs).
Then, adding a cocktail of growth factors and other molecules, the team coaxed the iPSCs to differentiate into RBCs. Multiple samples were tested for each person, for a total of at least 24 iPSC lines.
The researchers exposed the RBCs to low-oxygen conditions that mimic high altitude—5% oxygen—for 3 weeks.
RBCs from healthy sea-level or high-altitude-dwelling donors increased a little or not at all. In contrast, RBC counts from high-altitude dwellers with chronic mountain sickness increased 60-fold.
This result led the researchers to question why people with chronic mountain sickness produce so many extra RBCs in response to low oxygen.
In a previous study, the team had compared the genomes of high-altitude dwellers with and without chronic mountain sickness. This revealed a gene that varied between the 2 groups—SENP1, which is increased in low-oxygen situations in people with chronic mountain sickness but not in healthy individuals.
In the current study, the researchers set out to determine if SENP1 plays a role in high-altitude adaptation.
The team inhibited the SENP1 gene in iPSCs from patients with chronic mountain sickness. As a result, excessive RBC production was reduced by more than 90%.
When the researchers added extra SENP1 to healthy, adapted highlander iPSCs, RBC production increased 30-fold, nearly recapitulating that seen in patients with chronic mountains sickness.
Further experiments revealed how SENP1 affects RBC production. Elevated levels of the enzyme in chronic mountain sickness boost levels of several other proteins that promote cell division and survival, including VEGF, GATA1, and Bcl-xL.
“We’re interested in determining the early steps in this process—how low oxygen triggers SENP1 in the first place,” said study author Priti Azad, PhD, of the University of California San Diego School of Medicine.
“We are also investigating how existing altitude sickness medications, such as Diamox, work and whether or not it’s through this same mechanism.”
Andes who suffers from
chronic mountain sickness
Photo courtesy of
UC San Diego Health
Findings from a study of people living at high altitude have implications for the treatment of red blood cell (RBC) disorders such as anemia and polycythemia, according to researchers.
To better understand why some people adapt well to life at high altitude while others don’t, the researchers studied RBCs derived from representatives of both groups who were living in the Andes Mountains.
The study revealed that high-altitude dwellers prone to chronic mountain sickness produce massive amounts of RBCs thanks to overproduction of the enzyme SENP1.
The researchers reported these findings in the Journal of Experimental Medicine.
“In addition to improving the health of millions of people around the world who live above 8000 feet, information on how Andeans have adapted—or not adapted—to high-altitude life might teach us how to speed up red blood cell production at lower altitudes, such as in anemia or when blood transfusions are needed rapidly,” said study author Gabriel Haddad, MD, of the University of California San Diego School of Medicine.
Dr Haddad and his colleagues noted that chronic mountain sickness affects approximately 20% of people who live at high altitudes, and a critical aspect of the condition is polycythemia.
Some extra RBCs can be beneficial in high-altitude, low-oxygen environments by helping to keep blood oxygenated. However, too many RBCs can increase the risk of heart attack and stroke, even in young adults.
For this study, the researchers collected skin cells from people living in the Andes Mountains—4 who were healthy and 5 who suffer from chronic mountain sickness—plus an additional 3 healthy people who live at sea level and served as controls.
To produce enough RBCs from each participant to study them in the lab, the researchers converted the skin cells into induced pluripotent stem cells (iPSCs).
Then, adding a cocktail of growth factors and other molecules, the team coaxed the iPSCs to differentiate into RBCs. Multiple samples were tested for each person, for a total of at least 24 iPSC lines.
The researchers exposed the RBCs to low-oxygen conditions that mimic high altitude—5% oxygen—for 3 weeks.
RBCs from healthy sea-level or high-altitude-dwelling donors increased a little or not at all. In contrast, RBC counts from high-altitude dwellers with chronic mountain sickness increased 60-fold.
This result led the researchers to question why people with chronic mountain sickness produce so many extra RBCs in response to low oxygen.
In a previous study, the team had compared the genomes of high-altitude dwellers with and without chronic mountain sickness. This revealed a gene that varied between the 2 groups—SENP1, which is increased in low-oxygen situations in people with chronic mountain sickness but not in healthy individuals.
In the current study, the researchers set out to determine if SENP1 plays a role in high-altitude adaptation.
The team inhibited the SENP1 gene in iPSCs from patients with chronic mountain sickness. As a result, excessive RBC production was reduced by more than 90%.
When the researchers added extra SENP1 to healthy, adapted highlander iPSCs, RBC production increased 30-fold, nearly recapitulating that seen in patients with chronic mountains sickness.
Further experiments revealed how SENP1 affects RBC production. Elevated levels of the enzyme in chronic mountain sickness boost levels of several other proteins that promote cell division and survival, including VEGF, GATA1, and Bcl-xL.
“We’re interested in determining the early steps in this process—how low oxygen triggers SENP1 in the first place,” said study author Priti Azad, PhD, of the University of California San Diego School of Medicine.
“We are also investigating how existing altitude sickness medications, such as Diamox, work and whether or not it’s through this same mechanism.”
Antiviral appears active against tough-to-treat CMV
NEW ORLEANS—The antiviral agent maribavir has shown activity against cytomegalovirus (CMV) in a phase 2 trial.
The trial included transplant recipients with a CMV infection that was resistant or refractory to prior treatment with (val)ganciclovir or foscarnet.
Sixty-seven percent of patients treated with varying doses of maribavir for up to 24 weeks had no detectable levels of CMV in their plasma within 6 weeks of starting treatment.
However, CMV infection did recur in some of these patients.
Dysgeusia was the most commonly reported treatment-emergent adverse event (AE), and one patient died of an AE that was considered possibly related to maribavir.
These results were presented at IDWeek 2016 (abstract 78). The study was sponsored by Shire.
“Cytomegalovirus infection that is resistant or refractory to standard therapy in transplant patients is associated with significant complications and high mortality,” said study investigator Genovefa Papanicolaou, MD, of Memorial Sloan Kettering Cancer Center in New York, New York.
“The phase 2 findings support further research to confirm these results among patients who have limited options to combat the infection.”
Maribavir is a member of a class of drugs called benzimidazole ribosides. Maribavir is thought to inhibit viral DNA assembly and egress of viral capsids from the nucleus of infected cells. The drug has not been shown to affect the maturation of viral DNA or affect the viral DNA polymerase.
This phase 2 study of maribavir included 120 patients ages 12 and older with CMV infection (≥1000 DNA copies/mL of blood plasma) that was resistant or refractory to (val)ganciclovir or foscarnet.
Forty-seven of the patients had received a hematopoietic stem cell transplant, and 73 had a solid organ transplant. The patients’ median age was 55 (range, 18 to 74).
The patients were randomized to 1 of 3 twice-daily oral doses of maribavir—400 mg, 800 mg, or 1200 mg—for up to 24 weeks of treatment.
Efficacy
The study’s primary efficacy endpoint was the proportion of patients with confirmed undetectable plasma CMV DNA within 6 weeks of treatment.
Overall, 67% (80/120) of patients met the primary efficacy endpoint. This included 70% (n=28) of patients in the 400 mg group, 63% (n=25) in the 800 mg group, and 67% (n=27) in the 1200 mg group.
CMV infection recurred in 30 patients, including 7 in the 400 mg group, 11 in the 800 mg group, and 12 in the 1200 mg group.
Safety
The primary safety analysis was focused on the incidence of treatment-emergent AEs. The incidence was 78% (n=93) overall, including 78% (n=31) in the 400 mg group, 80% (n=32) in the 800 mg group, and 75% (n=30) in the 1200 mg group.
Twenty-seven percent of patients died due to any AE, 1 of which (multi-organ failure) was considered possibly related to maribavir.
Forty-one patients (34%) discontinued treatment with maribavir due to an AE, including 17 patients who discontinued due to CMV infection.
Dysgeusia was the most common treatment-emergent AE and led to treatment discontinuation in 1 patient. Dysgeusia occurred in 65% (n=78) of all patients, including 60% (n=24) in the 400 mg group, 63% (n=25) in the 800 mg group, and 73% (n=29) in the 1200 mg group.
Other treatment-emergent AEs (occurring in at least 20% of patients) for all doses included nausea, vomiting, CMV infection, diarrhea, fatigue, and anemia. Immunosuppressant drug level increases were reported as an AE in 10% of all patients.
NEW ORLEANS—The antiviral agent maribavir has shown activity against cytomegalovirus (CMV) in a phase 2 trial.
The trial included transplant recipients with a CMV infection that was resistant or refractory to prior treatment with (val)ganciclovir or foscarnet.
Sixty-seven percent of patients treated with varying doses of maribavir for up to 24 weeks had no detectable levels of CMV in their plasma within 6 weeks of starting treatment.
However, CMV infection did recur in some of these patients.
Dysgeusia was the most commonly reported treatment-emergent adverse event (AE), and one patient died of an AE that was considered possibly related to maribavir.
These results were presented at IDWeek 2016 (abstract 78). The study was sponsored by Shire.
“Cytomegalovirus infection that is resistant or refractory to standard therapy in transplant patients is associated with significant complications and high mortality,” said study investigator Genovefa Papanicolaou, MD, of Memorial Sloan Kettering Cancer Center in New York, New York.
“The phase 2 findings support further research to confirm these results among patients who have limited options to combat the infection.”
Maribavir is a member of a class of drugs called benzimidazole ribosides. Maribavir is thought to inhibit viral DNA assembly and egress of viral capsids from the nucleus of infected cells. The drug has not been shown to affect the maturation of viral DNA or affect the viral DNA polymerase.
This phase 2 study of maribavir included 120 patients ages 12 and older with CMV infection (≥1000 DNA copies/mL of blood plasma) that was resistant or refractory to (val)ganciclovir or foscarnet.
Forty-seven of the patients had received a hematopoietic stem cell transplant, and 73 had a solid organ transplant. The patients’ median age was 55 (range, 18 to 74).
The patients were randomized to 1 of 3 twice-daily oral doses of maribavir—400 mg, 800 mg, or 1200 mg—for up to 24 weeks of treatment.
Efficacy
The study’s primary efficacy endpoint was the proportion of patients with confirmed undetectable plasma CMV DNA within 6 weeks of treatment.
Overall, 67% (80/120) of patients met the primary efficacy endpoint. This included 70% (n=28) of patients in the 400 mg group, 63% (n=25) in the 800 mg group, and 67% (n=27) in the 1200 mg group.
CMV infection recurred in 30 patients, including 7 in the 400 mg group, 11 in the 800 mg group, and 12 in the 1200 mg group.
Safety
The primary safety analysis was focused on the incidence of treatment-emergent AEs. The incidence was 78% (n=93) overall, including 78% (n=31) in the 400 mg group, 80% (n=32) in the 800 mg group, and 75% (n=30) in the 1200 mg group.
Twenty-seven percent of patients died due to any AE, 1 of which (multi-organ failure) was considered possibly related to maribavir.
Forty-one patients (34%) discontinued treatment with maribavir due to an AE, including 17 patients who discontinued due to CMV infection.
Dysgeusia was the most common treatment-emergent AE and led to treatment discontinuation in 1 patient. Dysgeusia occurred in 65% (n=78) of all patients, including 60% (n=24) in the 400 mg group, 63% (n=25) in the 800 mg group, and 73% (n=29) in the 1200 mg group.
Other treatment-emergent AEs (occurring in at least 20% of patients) for all doses included nausea, vomiting, CMV infection, diarrhea, fatigue, and anemia. Immunosuppressant drug level increases were reported as an AE in 10% of all patients.
NEW ORLEANS—The antiviral agent maribavir has shown activity against cytomegalovirus (CMV) in a phase 2 trial.
The trial included transplant recipients with a CMV infection that was resistant or refractory to prior treatment with (val)ganciclovir or foscarnet.
Sixty-seven percent of patients treated with varying doses of maribavir for up to 24 weeks had no detectable levels of CMV in their plasma within 6 weeks of starting treatment.
However, CMV infection did recur in some of these patients.
Dysgeusia was the most commonly reported treatment-emergent adverse event (AE), and one patient died of an AE that was considered possibly related to maribavir.
These results were presented at IDWeek 2016 (abstract 78). The study was sponsored by Shire.
“Cytomegalovirus infection that is resistant or refractory to standard therapy in transplant patients is associated with significant complications and high mortality,” said study investigator Genovefa Papanicolaou, MD, of Memorial Sloan Kettering Cancer Center in New York, New York.
“The phase 2 findings support further research to confirm these results among patients who have limited options to combat the infection.”
Maribavir is a member of a class of drugs called benzimidazole ribosides. Maribavir is thought to inhibit viral DNA assembly and egress of viral capsids from the nucleus of infected cells. The drug has not been shown to affect the maturation of viral DNA or affect the viral DNA polymerase.
This phase 2 study of maribavir included 120 patients ages 12 and older with CMV infection (≥1000 DNA copies/mL of blood plasma) that was resistant or refractory to (val)ganciclovir or foscarnet.
Forty-seven of the patients had received a hematopoietic stem cell transplant, and 73 had a solid organ transplant. The patients’ median age was 55 (range, 18 to 74).
The patients were randomized to 1 of 3 twice-daily oral doses of maribavir—400 mg, 800 mg, or 1200 mg—for up to 24 weeks of treatment.
Efficacy
The study’s primary efficacy endpoint was the proportion of patients with confirmed undetectable plasma CMV DNA within 6 weeks of treatment.
Overall, 67% (80/120) of patients met the primary efficacy endpoint. This included 70% (n=28) of patients in the 400 mg group, 63% (n=25) in the 800 mg group, and 67% (n=27) in the 1200 mg group.
CMV infection recurred in 30 patients, including 7 in the 400 mg group, 11 in the 800 mg group, and 12 in the 1200 mg group.
Safety
The primary safety analysis was focused on the incidence of treatment-emergent AEs. The incidence was 78% (n=93) overall, including 78% (n=31) in the 400 mg group, 80% (n=32) in the 800 mg group, and 75% (n=30) in the 1200 mg group.
Twenty-seven percent of patients died due to any AE, 1 of which (multi-organ failure) was considered possibly related to maribavir.
Forty-one patients (34%) discontinued treatment with maribavir due to an AE, including 17 patients who discontinued due to CMV infection.
Dysgeusia was the most common treatment-emergent AE and led to treatment discontinuation in 1 patient. Dysgeusia occurred in 65% (n=78) of all patients, including 60% (n=24) in the 400 mg group, 63% (n=25) in the 800 mg group, and 73% (n=29) in the 1200 mg group.
Other treatment-emergent AEs (occurring in at least 20% of patients) for all doses included nausea, vomiting, CMV infection, diarrhea, fatigue, and anemia. Immunosuppressant drug level increases were reported as an AE in 10% of all patients.
Drug elicits responses in heavily pretreated cHL
Photo from Business Wire
COLOGNE—Results from the CheckMate -205 study suggest nivolumab can produce a high objective response rate (ORR) in patients with heavily pretreated classical Hodgkin lymphoma (cHL).
Investigators recently presented results from one of the cohorts in this phase 2 trial—cohort C—which included cHL patients who received nivolumab after undergoing autologous hematopoietic stem cell transplant (auto-HSCT) and receiving treatment with brentuximab vedotin (BV).
At a median follow-up of 8.8 months, the ORR, as assessed by an independent radiologic review committee (IRRC), was 73%.
The median progression-free survival (PFS) was 11.2 months, and the 6-month overall survival (OS) was 94%.
Investigators said the safety profile of nivolumab in this patient population was consistent with previously reported data in patients with cHL, and no new clinically meaningful safety signals were identified.
“These data from cohort C build on existing evidence supporting the benefit of Opdivo [nivolumab] in classical Hodgkin lymphoma patients who have relapsed or progressed after autologous hematopoietic stem cell transplantation and post-transplantation brentuximab vedotin,” said investigator Andreas Engert, MD, of the University Hospital of Cologne in Germany.
“Results from cohort C indicated a benefit with Opdivo regardless of the order of prior treatment with autologous hematopoietic stem cell transplantation and brentuximab vedotin, providing important insights as we continue researching the potential role Opdivo could provide for heavily pretreated classical Hodgkin lymphoma patients.”
The results were presented at the 10th International Symposium on Hodgkin Lymphoma (abstract T022). Abstracts from this meeting have been published in haematologica.
The CheckMate -205 trial is sponsored by Bristol-Myers Squibb.
About the trial
CheckMate -205 is a multi-cohort study in which investigators are evaluating the safety and efficacy of nivolumab in adults with cHL.
Cohort A included cHL patients who had received auto-HSCT and were BV-naïve (n=63). Cohort B included cHL patients who had received auto-HSCT followed by BV (n=80).
Cohort C included cHL patients who had received BV before and/or after auto-HSCT (n=100).
The study also includes a cohort D, which is currently enrolling and evaluating nivolumab in combination with chemotherapy in newly diagnosed, advanced-stage cHL patients who are treatment-naïve (n=50).
Patients enrolled in this trial have received nivolumab at 3 mg/kg intravenously every 2 weeks until disease progression or unacceptable toxicity. In cohort C, patients were also treated until investigator-assessed complete response (CR) lasting 1 year.
The study’s primary endpoint was ORR by IRRC assessment. Secondary and other exploratory endpoints included duration of response by IRRC assessment for CR rate and partial response rate, PFS by IRRC assessment, OS, and safety.
Response
The investigators presented results from cohort C (n=100), which included patients with cHL who had received BV before and/or after auto-HSCT.
At a median follow-up of 8.8 months, ORR per the IRRC was 73% (n=73) overall. The investigators said ORR was consistent across patient subgroups, regardless of the timing of prior BV relative to auto-HSCT.
The ORR was 70% (n=23) in patients who received BV only before auto-HSCT, 72% (n=41) in patients who received BV only after auto-HSCT, and 88% (n=7) in patients who received BV before and after auto-HSCT.
The CR rate was 17% (n=17) overall, 18.2% (n=6) in patients who received BV only before auto-HSCT, 12.3% (n=7) in patients who received BV only after auto-HSCT, and 38% (n=3) in patients who received BV before and after auto-HSCT.
Survival
The median PFS was 11.2 months (range, 8.5 months to not achieved) overall, 11.2 months (range, 8.5 months to not achieved) in patients who received BV only before auto-HSCT, 8.9 months (range, 8.3 months to not achieved) in patients who received BV only after auto-HSCT, and not achieved (range, 5.6 months to not achieved) in patients who received BV before and after auto-HSCT.
The 6-month OS was 93.9% overall, 97% in patients who received BV only before auto-HSCT, 91% in patients who received BV only after auto-HSCT, and 100% in patients who received BV before and after auto-HSCT.
Safety
Treatment-related adverse events (AEs) occurred in 68% of patients between the first dose and 30 days after the last dose of nivolumab. The most common treatment-related AEs were diarrhea, infusion-related reaction, and fatigue (11% each).
Grade 3/4 AEs occurred in 19% of patients. Serious treatment-related AEs were reported in 17% of patients, and treatment-related AEs leading to discontinuation occurred in 6% of patients.
At present, no treatment-related deaths have been reported.
Photo from Business Wire
COLOGNE—Results from the CheckMate -205 study suggest nivolumab can produce a high objective response rate (ORR) in patients with heavily pretreated classical Hodgkin lymphoma (cHL).
Investigators recently presented results from one of the cohorts in this phase 2 trial—cohort C—which included cHL patients who received nivolumab after undergoing autologous hematopoietic stem cell transplant (auto-HSCT) and receiving treatment with brentuximab vedotin (BV).
At a median follow-up of 8.8 months, the ORR, as assessed by an independent radiologic review committee (IRRC), was 73%.
The median progression-free survival (PFS) was 11.2 months, and the 6-month overall survival (OS) was 94%.
Investigators said the safety profile of nivolumab in this patient population was consistent with previously reported data in patients with cHL, and no new clinically meaningful safety signals were identified.
“These data from cohort C build on existing evidence supporting the benefit of Opdivo [nivolumab] in classical Hodgkin lymphoma patients who have relapsed or progressed after autologous hematopoietic stem cell transplantation and post-transplantation brentuximab vedotin,” said investigator Andreas Engert, MD, of the University Hospital of Cologne in Germany.
“Results from cohort C indicated a benefit with Opdivo regardless of the order of prior treatment with autologous hematopoietic stem cell transplantation and brentuximab vedotin, providing important insights as we continue researching the potential role Opdivo could provide for heavily pretreated classical Hodgkin lymphoma patients.”
The results were presented at the 10th International Symposium on Hodgkin Lymphoma (abstract T022). Abstracts from this meeting have been published in haematologica.
The CheckMate -205 trial is sponsored by Bristol-Myers Squibb.
About the trial
CheckMate -205 is a multi-cohort study in which investigators are evaluating the safety and efficacy of nivolumab in adults with cHL.
Cohort A included cHL patients who had received auto-HSCT and were BV-naïve (n=63). Cohort B included cHL patients who had received auto-HSCT followed by BV (n=80).
Cohort C included cHL patients who had received BV before and/or after auto-HSCT (n=100).
The study also includes a cohort D, which is currently enrolling and evaluating nivolumab in combination with chemotherapy in newly diagnosed, advanced-stage cHL patients who are treatment-naïve (n=50).
Patients enrolled in this trial have received nivolumab at 3 mg/kg intravenously every 2 weeks until disease progression or unacceptable toxicity. In cohort C, patients were also treated until investigator-assessed complete response (CR) lasting 1 year.
The study’s primary endpoint was ORR by IRRC assessment. Secondary and other exploratory endpoints included duration of response by IRRC assessment for CR rate and partial response rate, PFS by IRRC assessment, OS, and safety.
Response
The investigators presented results from cohort C (n=100), which included patients with cHL who had received BV before and/or after auto-HSCT.
At a median follow-up of 8.8 months, ORR per the IRRC was 73% (n=73) overall. The investigators said ORR was consistent across patient subgroups, regardless of the timing of prior BV relative to auto-HSCT.
The ORR was 70% (n=23) in patients who received BV only before auto-HSCT, 72% (n=41) in patients who received BV only after auto-HSCT, and 88% (n=7) in patients who received BV before and after auto-HSCT.
The CR rate was 17% (n=17) overall, 18.2% (n=6) in patients who received BV only before auto-HSCT, 12.3% (n=7) in patients who received BV only after auto-HSCT, and 38% (n=3) in patients who received BV before and after auto-HSCT.
Survival
The median PFS was 11.2 months (range, 8.5 months to not achieved) overall, 11.2 months (range, 8.5 months to not achieved) in patients who received BV only before auto-HSCT, 8.9 months (range, 8.3 months to not achieved) in patients who received BV only after auto-HSCT, and not achieved (range, 5.6 months to not achieved) in patients who received BV before and after auto-HSCT.
The 6-month OS was 93.9% overall, 97% in patients who received BV only before auto-HSCT, 91% in patients who received BV only after auto-HSCT, and 100% in patients who received BV before and after auto-HSCT.
Safety
Treatment-related adverse events (AEs) occurred in 68% of patients between the first dose and 30 days after the last dose of nivolumab. The most common treatment-related AEs were diarrhea, infusion-related reaction, and fatigue (11% each).
Grade 3/4 AEs occurred in 19% of patients. Serious treatment-related AEs were reported in 17% of patients, and treatment-related AEs leading to discontinuation occurred in 6% of patients.
At present, no treatment-related deaths have been reported.
Photo from Business Wire
COLOGNE—Results from the CheckMate -205 study suggest nivolumab can produce a high objective response rate (ORR) in patients with heavily pretreated classical Hodgkin lymphoma (cHL).
Investigators recently presented results from one of the cohorts in this phase 2 trial—cohort C—which included cHL patients who received nivolumab after undergoing autologous hematopoietic stem cell transplant (auto-HSCT) and receiving treatment with brentuximab vedotin (BV).
At a median follow-up of 8.8 months, the ORR, as assessed by an independent radiologic review committee (IRRC), was 73%.
The median progression-free survival (PFS) was 11.2 months, and the 6-month overall survival (OS) was 94%.
Investigators said the safety profile of nivolumab in this patient population was consistent with previously reported data in patients with cHL, and no new clinically meaningful safety signals were identified.
“These data from cohort C build on existing evidence supporting the benefit of Opdivo [nivolumab] in classical Hodgkin lymphoma patients who have relapsed or progressed after autologous hematopoietic stem cell transplantation and post-transplantation brentuximab vedotin,” said investigator Andreas Engert, MD, of the University Hospital of Cologne in Germany.
“Results from cohort C indicated a benefit with Opdivo regardless of the order of prior treatment with autologous hematopoietic stem cell transplantation and brentuximab vedotin, providing important insights as we continue researching the potential role Opdivo could provide for heavily pretreated classical Hodgkin lymphoma patients.”
The results were presented at the 10th International Symposium on Hodgkin Lymphoma (abstract T022). Abstracts from this meeting have been published in haematologica.
The CheckMate -205 trial is sponsored by Bristol-Myers Squibb.
About the trial
CheckMate -205 is a multi-cohort study in which investigators are evaluating the safety and efficacy of nivolumab in adults with cHL.
Cohort A included cHL patients who had received auto-HSCT and were BV-naïve (n=63). Cohort B included cHL patients who had received auto-HSCT followed by BV (n=80).
Cohort C included cHL patients who had received BV before and/or after auto-HSCT (n=100).
The study also includes a cohort D, which is currently enrolling and evaluating nivolumab in combination with chemotherapy in newly diagnosed, advanced-stage cHL patients who are treatment-naïve (n=50).
Patients enrolled in this trial have received nivolumab at 3 mg/kg intravenously every 2 weeks until disease progression or unacceptable toxicity. In cohort C, patients were also treated until investigator-assessed complete response (CR) lasting 1 year.
The study’s primary endpoint was ORR by IRRC assessment. Secondary and other exploratory endpoints included duration of response by IRRC assessment for CR rate and partial response rate, PFS by IRRC assessment, OS, and safety.
Response
The investigators presented results from cohort C (n=100), which included patients with cHL who had received BV before and/or after auto-HSCT.
At a median follow-up of 8.8 months, ORR per the IRRC was 73% (n=73) overall. The investigators said ORR was consistent across patient subgroups, regardless of the timing of prior BV relative to auto-HSCT.
The ORR was 70% (n=23) in patients who received BV only before auto-HSCT, 72% (n=41) in patients who received BV only after auto-HSCT, and 88% (n=7) in patients who received BV before and after auto-HSCT.
The CR rate was 17% (n=17) overall, 18.2% (n=6) in patients who received BV only before auto-HSCT, 12.3% (n=7) in patients who received BV only after auto-HSCT, and 38% (n=3) in patients who received BV before and after auto-HSCT.
Survival
The median PFS was 11.2 months (range, 8.5 months to not achieved) overall, 11.2 months (range, 8.5 months to not achieved) in patients who received BV only before auto-HSCT, 8.9 months (range, 8.3 months to not achieved) in patients who received BV only after auto-HSCT, and not achieved (range, 5.6 months to not achieved) in patients who received BV before and after auto-HSCT.
The 6-month OS was 93.9% overall, 97% in patients who received BV only before auto-HSCT, 91% in patients who received BV only after auto-HSCT, and 100% in patients who received BV before and after auto-HSCT.
Safety
Treatment-related adverse events (AEs) occurred in 68% of patients between the first dose and 30 days after the last dose of nivolumab. The most common treatment-related AEs were diarrhea, infusion-related reaction, and fatigue (11% each).
Grade 3/4 AEs occurred in 19% of patients. Serious treatment-related AEs were reported in 17% of patients, and treatment-related AEs leading to discontinuation occurred in 6% of patients.
At present, no treatment-related deaths have been reported.
Vector may make gene therapy safer
Photo courtesy of Washington
State University Spokane
Using modified foamy retroviral vectors to deliver gene therapy may reduce the risk of genotoxicity, according to research published in Scientific Reports.
These vectors have demonstrated promise in vitro, and researchers believe they could be used to treat X-linked severe combined immunodeficiency, thalassemia, and other diseases.
“We’ve started to translate this in collaboration with other scientists and medical doctors into the clinic,” said study author Grant Trobridge, PhD, of Washington State University Spokane.
Dr Trobridge and his colleagues said they decided to pursue foamy retroviral vectors as a delivery system for gene therapy because these vectors are less likely than gammaretroviral vectors or lentiviral vectors to activate nearby genes, including proto-oncogenes.
Still, the researchers altered the foamy retroviral vectors to change how they interact with target stem cells in an attempt to ensure the vectors would insert themselves into safer parts of the genome.
The team said they were able to retarget the foamy retroviral vectors away from genes and into satellite regions enriched for trimethylated histone H3 at lysine 9 by modifying the foamy virus Gag and Pol proteins.
These retargeted foamy retroviral vectors integrated near genes significantly less often than unmodified foamy retroviral vectors (P<0.001).
The researchers also noted that their retargeted foamy retroviral vectors can be produced at clinically relevant titers, and engineered target cells are not needed. Any target cell can be used by using alternate foamy helper plasmids during vector production.
Photo courtesy of Washington
State University Spokane
Using modified foamy retroviral vectors to deliver gene therapy may reduce the risk of genotoxicity, according to research published in Scientific Reports.
These vectors have demonstrated promise in vitro, and researchers believe they could be used to treat X-linked severe combined immunodeficiency, thalassemia, and other diseases.
“We’ve started to translate this in collaboration with other scientists and medical doctors into the clinic,” said study author Grant Trobridge, PhD, of Washington State University Spokane.
Dr Trobridge and his colleagues said they decided to pursue foamy retroviral vectors as a delivery system for gene therapy because these vectors are less likely than gammaretroviral vectors or lentiviral vectors to activate nearby genes, including proto-oncogenes.
Still, the researchers altered the foamy retroviral vectors to change how they interact with target stem cells in an attempt to ensure the vectors would insert themselves into safer parts of the genome.
The team said they were able to retarget the foamy retroviral vectors away from genes and into satellite regions enriched for trimethylated histone H3 at lysine 9 by modifying the foamy virus Gag and Pol proteins.
These retargeted foamy retroviral vectors integrated near genes significantly less often than unmodified foamy retroviral vectors (P<0.001).
The researchers also noted that their retargeted foamy retroviral vectors can be produced at clinically relevant titers, and engineered target cells are not needed. Any target cell can be used by using alternate foamy helper plasmids during vector production.
Photo courtesy of Washington
State University Spokane
Using modified foamy retroviral vectors to deliver gene therapy may reduce the risk of genotoxicity, according to research published in Scientific Reports.
These vectors have demonstrated promise in vitro, and researchers believe they could be used to treat X-linked severe combined immunodeficiency, thalassemia, and other diseases.
“We’ve started to translate this in collaboration with other scientists and medical doctors into the clinic,” said study author Grant Trobridge, PhD, of Washington State University Spokane.
Dr Trobridge and his colleagues said they decided to pursue foamy retroviral vectors as a delivery system for gene therapy because these vectors are less likely than gammaretroviral vectors or lentiviral vectors to activate nearby genes, including proto-oncogenes.
Still, the researchers altered the foamy retroviral vectors to change how they interact with target stem cells in an attempt to ensure the vectors would insert themselves into safer parts of the genome.
The team said they were able to retarget the foamy retroviral vectors away from genes and into satellite regions enriched for trimethylated histone H3 at lysine 9 by modifying the foamy virus Gag and Pol proteins.
These retargeted foamy retroviral vectors integrated near genes significantly less often than unmodified foamy retroviral vectors (P<0.001).
The researchers also noted that their retargeted foamy retroviral vectors can be produced at clinically relevant titers, and engineered target cells are not needed. Any target cell can be used by using alternate foamy helper plasmids during vector production.
Combating drug resistance in FLT3-mutated AML
with autophagosomes (green),
a process that happens during
mitophagy in cancer cells
treated with FLT3 inhibitor
Image from Besim Ogretmen
and Mohammed Dany/MUSC
Research published in Blood has revealed a mechanism that confers treatment resistance in FLT3-mutated acute myeloid leukemia (AML), as well as a drug that might overcome that resistance.
Researchers found that ceramide-dependent mitophagy plays a key role in drug-mediated AML cell death.
“Ceramide, a pro-cell-death lipid, kills cancer cells by causing them to eat their own mitochondria,” explained study author Besim Ogretmen, PhD, of the Medical University of South Carolina (MUSC) Hollings Cancer Center in Charleston, South Carolina.
AML cells with FLT3-ITD inhibit ceramide synthesis and thereby become resistant to cell death. FLT3 inhibitors have been developed to combat this resistance, but they’ve fallen short of expectations.
“Unfortunately, regardless of the inhibitor, the problem of resistance to FLT3-targeted therapy has persisted,” said study author Mohammed Dany, an MD/PhD student at MUSC.
However, Dany, Dr Ogretmen, and their colleagues were able to overcome this resistance with a synthetic ceramide analogue known as LCL-461.
In vitro, the drug reactivated mitophagy and killed AML cells that were resistant to treatment with the FLT3 inhibitor crenolanib.
In mice with crenolanib-resistant human AML xenografts, LCL-461 eliminated AML cells from the bone marrow.
A positively charged molecule, LCL-461 is attracted to the mitochondria of cancer cells, which become negatively charged through the Warburg effect. The researchers said this limits off-target effects that can occur with less specific inhibitors of FLT3 signaling.
Furthermore, Dr Ogretmen’s lab has tested the safety of LCL-461 in previous studies and reported that it had no major side effects at therapeutically active doses.
Dr Ogretmen and his colleagues’ next step is to perform large animal studies with LCL-461.
“We are very excited about this,” Dr Ogretmen said. “Head and neck cancers also respond to this drug very well. What we are trying to do is really cure cancer one disease at a time, and we are digging and digging to understand the mechanisms of how these cancer cells escape therapeutic interventions so that we can find mechanism-based therapeutics to have more tools for treatment.”
LCL-461 was developed at MUSC. The MUSC Foundation for Research Development has patented the drug and licensed it to Charleston-based startup SphingoGene, Inc.
with autophagosomes (green),
a process that happens during
mitophagy in cancer cells
treated with FLT3 inhibitor
Image from Besim Ogretmen
and Mohammed Dany/MUSC
Research published in Blood has revealed a mechanism that confers treatment resistance in FLT3-mutated acute myeloid leukemia (AML), as well as a drug that might overcome that resistance.
Researchers found that ceramide-dependent mitophagy plays a key role in drug-mediated AML cell death.
“Ceramide, a pro-cell-death lipid, kills cancer cells by causing them to eat their own mitochondria,” explained study author Besim Ogretmen, PhD, of the Medical University of South Carolina (MUSC) Hollings Cancer Center in Charleston, South Carolina.
AML cells with FLT3-ITD inhibit ceramide synthesis and thereby become resistant to cell death. FLT3 inhibitors have been developed to combat this resistance, but they’ve fallen short of expectations.
“Unfortunately, regardless of the inhibitor, the problem of resistance to FLT3-targeted therapy has persisted,” said study author Mohammed Dany, an MD/PhD student at MUSC.
However, Dany, Dr Ogretmen, and their colleagues were able to overcome this resistance with a synthetic ceramide analogue known as LCL-461.
In vitro, the drug reactivated mitophagy and killed AML cells that were resistant to treatment with the FLT3 inhibitor crenolanib.
In mice with crenolanib-resistant human AML xenografts, LCL-461 eliminated AML cells from the bone marrow.
A positively charged molecule, LCL-461 is attracted to the mitochondria of cancer cells, which become negatively charged through the Warburg effect. The researchers said this limits off-target effects that can occur with less specific inhibitors of FLT3 signaling.
Furthermore, Dr Ogretmen’s lab has tested the safety of LCL-461 in previous studies and reported that it had no major side effects at therapeutically active doses.
Dr Ogretmen and his colleagues’ next step is to perform large animal studies with LCL-461.
“We are very excited about this,” Dr Ogretmen said. “Head and neck cancers also respond to this drug very well. What we are trying to do is really cure cancer one disease at a time, and we are digging and digging to understand the mechanisms of how these cancer cells escape therapeutic interventions so that we can find mechanism-based therapeutics to have more tools for treatment.”
LCL-461 was developed at MUSC. The MUSC Foundation for Research Development has patented the drug and licensed it to Charleston-based startup SphingoGene, Inc.
with autophagosomes (green),
a process that happens during
mitophagy in cancer cells
treated with FLT3 inhibitor
Image from Besim Ogretmen
and Mohammed Dany/MUSC
Research published in Blood has revealed a mechanism that confers treatment resistance in FLT3-mutated acute myeloid leukemia (AML), as well as a drug that might overcome that resistance.
Researchers found that ceramide-dependent mitophagy plays a key role in drug-mediated AML cell death.
“Ceramide, a pro-cell-death lipid, kills cancer cells by causing them to eat their own mitochondria,” explained study author Besim Ogretmen, PhD, of the Medical University of South Carolina (MUSC) Hollings Cancer Center in Charleston, South Carolina.
AML cells with FLT3-ITD inhibit ceramide synthesis and thereby become resistant to cell death. FLT3 inhibitors have been developed to combat this resistance, but they’ve fallen short of expectations.
“Unfortunately, regardless of the inhibitor, the problem of resistance to FLT3-targeted therapy has persisted,” said study author Mohammed Dany, an MD/PhD student at MUSC.
However, Dany, Dr Ogretmen, and their colleagues were able to overcome this resistance with a synthetic ceramide analogue known as LCL-461.
In vitro, the drug reactivated mitophagy and killed AML cells that were resistant to treatment with the FLT3 inhibitor crenolanib.
In mice with crenolanib-resistant human AML xenografts, LCL-461 eliminated AML cells from the bone marrow.
A positively charged molecule, LCL-461 is attracted to the mitochondria of cancer cells, which become negatively charged through the Warburg effect. The researchers said this limits off-target effects that can occur with less specific inhibitors of FLT3 signaling.
Furthermore, Dr Ogretmen’s lab has tested the safety of LCL-461 in previous studies and reported that it had no major side effects at therapeutically active doses.
Dr Ogretmen and his colleagues’ next step is to perform large animal studies with LCL-461.
“We are very excited about this,” Dr Ogretmen said. “Head and neck cancers also respond to this drug very well. What we are trying to do is really cure cancer one disease at a time, and we are digging and digging to understand the mechanisms of how these cancer cells escape therapeutic interventions so that we can find mechanism-based therapeutics to have more tools for treatment.”
LCL-461 was developed at MUSC. The MUSC Foundation for Research Development has patented the drug and licensed it to Charleston-based startup SphingoGene, Inc.