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FDA approves afamelanotide for treatment of rare condition with light-induced pain
The Food and Drug Administration has approved , a rare condition that causes extremely painful reactions when skin is exposed to light, according to an FDA announcement.
This is the first treatment approved to help patients with this condition increase their exposure to light, according to the release.
Afamelanotide, administered in a subcutaneous implant, is a melanocortin-1 receptor (MC1-R) agonist, which “increases the production of eumelanin in the skin independent of exposure to sunlight or artificial light sources,” the release says.
Approval is based on a pair of parallel-group clinical trials that compared the number of hours spent in sunlight in the treatment and placebo groups. The first trial enrolled 93 patients; 48 received afamelanotide. The treated patients spent a median of 61 hours in total over 180 days in direct sunlight between 10 a.m. and 6 p.m. on days with no pain, compared with 41 hours for patients taking placebo.
The second trial assessed the total number of hours over 270 days spent outdoors between 10 a.m. and 3 p.m. on days with no pain for which “most of the day” was spent in direct sunlight. In this study, 38 patients treated with afamelanotide spent a median total of 6 hours, compared with 0.75 hours among the remaining 36 who were taking a placebo.
The most common side effects include implant site reaction, nausea, and oropharyngeal pain. The implant should be administered only by trained professionals. Because afamelanotide may cause skin darkening, it’s recommended that patients should undergo twice-yearly skin examinations. Patients are also encouraged to maintain sun protection measures to help prevent phototoxic reactions.
“Today’s approval is one example of the FDA’s ongoing commitment to encourage industry innovation of therapies to treat rare diseases, and work with drug developers to make promising new therapies available to patients as safely and efficiently as possible,” said Julie Beitz, MD, director of FDA’s Center for Drug Evaluation and Research Office of Drug Evaluation III in the FDA release.
The Food and Drug Administration has approved , a rare condition that causes extremely painful reactions when skin is exposed to light, according to an FDA announcement.
This is the first treatment approved to help patients with this condition increase their exposure to light, according to the release.
Afamelanotide, administered in a subcutaneous implant, is a melanocortin-1 receptor (MC1-R) agonist, which “increases the production of eumelanin in the skin independent of exposure to sunlight or artificial light sources,” the release says.
Approval is based on a pair of parallel-group clinical trials that compared the number of hours spent in sunlight in the treatment and placebo groups. The first trial enrolled 93 patients; 48 received afamelanotide. The treated patients spent a median of 61 hours in total over 180 days in direct sunlight between 10 a.m. and 6 p.m. on days with no pain, compared with 41 hours for patients taking placebo.
The second trial assessed the total number of hours over 270 days spent outdoors between 10 a.m. and 3 p.m. on days with no pain for which “most of the day” was spent in direct sunlight. In this study, 38 patients treated with afamelanotide spent a median total of 6 hours, compared with 0.75 hours among the remaining 36 who were taking a placebo.
The most common side effects include implant site reaction, nausea, and oropharyngeal pain. The implant should be administered only by trained professionals. Because afamelanotide may cause skin darkening, it’s recommended that patients should undergo twice-yearly skin examinations. Patients are also encouraged to maintain sun protection measures to help prevent phototoxic reactions.
“Today’s approval is one example of the FDA’s ongoing commitment to encourage industry innovation of therapies to treat rare diseases, and work with drug developers to make promising new therapies available to patients as safely and efficiently as possible,” said Julie Beitz, MD, director of FDA’s Center for Drug Evaluation and Research Office of Drug Evaluation III in the FDA release.
The Food and Drug Administration has approved , a rare condition that causes extremely painful reactions when skin is exposed to light, according to an FDA announcement.
This is the first treatment approved to help patients with this condition increase their exposure to light, according to the release.
Afamelanotide, administered in a subcutaneous implant, is a melanocortin-1 receptor (MC1-R) agonist, which “increases the production of eumelanin in the skin independent of exposure to sunlight or artificial light sources,” the release says.
Approval is based on a pair of parallel-group clinical trials that compared the number of hours spent in sunlight in the treatment and placebo groups. The first trial enrolled 93 patients; 48 received afamelanotide. The treated patients spent a median of 61 hours in total over 180 days in direct sunlight between 10 a.m. and 6 p.m. on days with no pain, compared with 41 hours for patients taking placebo.
The second trial assessed the total number of hours over 270 days spent outdoors between 10 a.m. and 3 p.m. on days with no pain for which “most of the day” was spent in direct sunlight. In this study, 38 patients treated with afamelanotide spent a median total of 6 hours, compared with 0.75 hours among the remaining 36 who were taking a placebo.
The most common side effects include implant site reaction, nausea, and oropharyngeal pain. The implant should be administered only by trained professionals. Because afamelanotide may cause skin darkening, it’s recommended that patients should undergo twice-yearly skin examinations. Patients are also encouraged to maintain sun protection measures to help prevent phototoxic reactions.
“Today’s approval is one example of the FDA’s ongoing commitment to encourage industry innovation of therapies to treat rare diseases, and work with drug developers to make promising new therapies available to patients as safely and efficiently as possible,” said Julie Beitz, MD, director of FDA’s Center for Drug Evaluation and Research Office of Drug Evaluation III in the FDA release.
Hypoxia-related discoveries net Nobel Prize
Three researchers have won the 2019 Nobel Prize in Physiology or Medicine “for their discoveries of how cells sense and adapt to oxygen availability.”
William G. Kaelin Jr., MD; Sir Peter J. Ratcliffe, MB ChB, MD; and Gregg L. Semenza, MD, PhD, described the molecular machinery that regulates gene activity in response to oxygen levels.
Their work “established the basis for our understanding of how oxygen levels affect cellular metabolism and physiological function” and “paved the way for promising new strategies to fight anemia, cancer, and many other diseases,” according to a statement by The Nobel Assembly at Karolinska Institutet.
Dr. Semenza, of Johns Hopkins Medicine in Baltimore, studied how the erythropoietin (EPO) gene is regulated by oxygen levels. Via experiments in mice, he identified DNA segments next to the EPO gene that mediate the response to hypoxia.
Dr. Ratcliffe, of the University of Oxford (England) and the Francis Crick Institute in London, also studied oxygen-dependent regulation of the EPO gene. Both his and Dr. Semenza’s groups found the oxygen-sensing mechanism was present in nearly all tissues.
Dr. Semenza also discovered a protein complex, hypoxia-inducible factor (HIF), that binds to the identified DNA segments in an oxygen-dependent manner. Additional investigation revealed that HIF consists of two transcription factors, HIF-1a and ARNT.
Several research groups found that HIF-1a is protected from degradation in hypoxia. In low-oxygen conditions, the amount of HIF-1a increases so it can bind to and regulate EPO and other genes with HIF-binding DNA segments. However, at normal oxygen levels, ubiquitin is added to HIF-1a, tagging it for degradation in the proteasome. It wasn’t clear how ubiquitin binds to HIF-1a in an oxygen-dependent manner, but Dr. Kaelin’s work provided some insight.
Dr. Kaelin, of the Dana-Farber Cancer Institute and Harvard Medical School, both in Boston, was researching von Hippel-Lindau’s (VHL) syndrome, an inherited disorder in which mutations can lead to tumors in multiple organs. He found the VHL gene encodes a protein that prevents cancer onset, and cancer cells without a functional VHL gene express high levels of hypoxia-regulated genes.
Research by other groups showed that VHL is part of a complex that labels proteins with ubiquitin, tagging them for degradation. Dr. Ratcliffe and his group found that VHL is required for the degradation of HIF-1a at normal oxygen levels.
Dr. Kaelin’s and Dr. Ratcliffe’s groups also showed that, under normal oxygen conditions, hydroxyl groups are added at two locations in HIF-1a. This modification – prolyl hydroxylation – allows VHL to bind to HIF-1a. So the researchers found that normal oxygen levels control HIF-1a degradation with the help of prolyl hydroxylases.
Additional research by Dr. Ratcliffe’s group and others revealed the specific prolyl hydroxylases involved in HIF-1a degradation. The researchers also found that HIF-1a’s gene-activating function was regulated by oxygen-dependent hydroxylation.
This work has improved the understanding of how different oxygen levels regulate physiological processes. In particular, oxygen sensing is essential for erythropoiesis, so these findings have implications for the treatment of anemia.
“There are several drugs that are now in clinical trials that serve to increase HIF activity and, as a result, will increase the production of erythropoietin and stimulate red blood cell production,” Dr. Semenza said in an interview after the announcement of his Nobel win. “These are all small molecules that can be given by mouth, and that may be a great convenience for patients who, at the present time, may require injections of recombinant human erythropoietin.”
Three researchers have won the 2019 Nobel Prize in Physiology or Medicine “for their discoveries of how cells sense and adapt to oxygen availability.”
William G. Kaelin Jr., MD; Sir Peter J. Ratcliffe, MB ChB, MD; and Gregg L. Semenza, MD, PhD, described the molecular machinery that regulates gene activity in response to oxygen levels.
Their work “established the basis for our understanding of how oxygen levels affect cellular metabolism and physiological function” and “paved the way for promising new strategies to fight anemia, cancer, and many other diseases,” according to a statement by The Nobel Assembly at Karolinska Institutet.
Dr. Semenza, of Johns Hopkins Medicine in Baltimore, studied how the erythropoietin (EPO) gene is regulated by oxygen levels. Via experiments in mice, he identified DNA segments next to the EPO gene that mediate the response to hypoxia.
Dr. Ratcliffe, of the University of Oxford (England) and the Francis Crick Institute in London, also studied oxygen-dependent regulation of the EPO gene. Both his and Dr. Semenza’s groups found the oxygen-sensing mechanism was present in nearly all tissues.
Dr. Semenza also discovered a protein complex, hypoxia-inducible factor (HIF), that binds to the identified DNA segments in an oxygen-dependent manner. Additional investigation revealed that HIF consists of two transcription factors, HIF-1a and ARNT.
Several research groups found that HIF-1a is protected from degradation in hypoxia. In low-oxygen conditions, the amount of HIF-1a increases so it can bind to and regulate EPO and other genes with HIF-binding DNA segments. However, at normal oxygen levels, ubiquitin is added to HIF-1a, tagging it for degradation in the proteasome. It wasn’t clear how ubiquitin binds to HIF-1a in an oxygen-dependent manner, but Dr. Kaelin’s work provided some insight.
Dr. Kaelin, of the Dana-Farber Cancer Institute and Harvard Medical School, both in Boston, was researching von Hippel-Lindau’s (VHL) syndrome, an inherited disorder in which mutations can lead to tumors in multiple organs. He found the VHL gene encodes a protein that prevents cancer onset, and cancer cells without a functional VHL gene express high levels of hypoxia-regulated genes.
Research by other groups showed that VHL is part of a complex that labels proteins with ubiquitin, tagging them for degradation. Dr. Ratcliffe and his group found that VHL is required for the degradation of HIF-1a at normal oxygen levels.
Dr. Kaelin’s and Dr. Ratcliffe’s groups also showed that, under normal oxygen conditions, hydroxyl groups are added at two locations in HIF-1a. This modification – prolyl hydroxylation – allows VHL to bind to HIF-1a. So the researchers found that normal oxygen levels control HIF-1a degradation with the help of prolyl hydroxylases.
Additional research by Dr. Ratcliffe’s group and others revealed the specific prolyl hydroxylases involved in HIF-1a degradation. The researchers also found that HIF-1a’s gene-activating function was regulated by oxygen-dependent hydroxylation.
This work has improved the understanding of how different oxygen levels regulate physiological processes. In particular, oxygen sensing is essential for erythropoiesis, so these findings have implications for the treatment of anemia.
“There are several drugs that are now in clinical trials that serve to increase HIF activity and, as a result, will increase the production of erythropoietin and stimulate red blood cell production,” Dr. Semenza said in an interview after the announcement of his Nobel win. “These are all small molecules that can be given by mouth, and that may be a great convenience for patients who, at the present time, may require injections of recombinant human erythropoietin.”
Three researchers have won the 2019 Nobel Prize in Physiology or Medicine “for their discoveries of how cells sense and adapt to oxygen availability.”
William G. Kaelin Jr., MD; Sir Peter J. Ratcliffe, MB ChB, MD; and Gregg L. Semenza, MD, PhD, described the molecular machinery that regulates gene activity in response to oxygen levels.
Their work “established the basis for our understanding of how oxygen levels affect cellular metabolism and physiological function” and “paved the way for promising new strategies to fight anemia, cancer, and many other diseases,” according to a statement by The Nobel Assembly at Karolinska Institutet.
Dr. Semenza, of Johns Hopkins Medicine in Baltimore, studied how the erythropoietin (EPO) gene is regulated by oxygen levels. Via experiments in mice, he identified DNA segments next to the EPO gene that mediate the response to hypoxia.
Dr. Ratcliffe, of the University of Oxford (England) and the Francis Crick Institute in London, also studied oxygen-dependent regulation of the EPO gene. Both his and Dr. Semenza’s groups found the oxygen-sensing mechanism was present in nearly all tissues.
Dr. Semenza also discovered a protein complex, hypoxia-inducible factor (HIF), that binds to the identified DNA segments in an oxygen-dependent manner. Additional investigation revealed that HIF consists of two transcription factors, HIF-1a and ARNT.
Several research groups found that HIF-1a is protected from degradation in hypoxia. In low-oxygen conditions, the amount of HIF-1a increases so it can bind to and regulate EPO and other genes with HIF-binding DNA segments. However, at normal oxygen levels, ubiquitin is added to HIF-1a, tagging it for degradation in the proteasome. It wasn’t clear how ubiquitin binds to HIF-1a in an oxygen-dependent manner, but Dr. Kaelin’s work provided some insight.
Dr. Kaelin, of the Dana-Farber Cancer Institute and Harvard Medical School, both in Boston, was researching von Hippel-Lindau’s (VHL) syndrome, an inherited disorder in which mutations can lead to tumors in multiple organs. He found the VHL gene encodes a protein that prevents cancer onset, and cancer cells without a functional VHL gene express high levels of hypoxia-regulated genes.
Research by other groups showed that VHL is part of a complex that labels proteins with ubiquitin, tagging them for degradation. Dr. Ratcliffe and his group found that VHL is required for the degradation of HIF-1a at normal oxygen levels.
Dr. Kaelin’s and Dr. Ratcliffe’s groups also showed that, under normal oxygen conditions, hydroxyl groups are added at two locations in HIF-1a. This modification – prolyl hydroxylation – allows VHL to bind to HIF-1a. So the researchers found that normal oxygen levels control HIF-1a degradation with the help of prolyl hydroxylases.
Additional research by Dr. Ratcliffe’s group and others revealed the specific prolyl hydroxylases involved in HIF-1a degradation. The researchers also found that HIF-1a’s gene-activating function was regulated by oxygen-dependent hydroxylation.
This work has improved the understanding of how different oxygen levels regulate physiological processes. In particular, oxygen sensing is essential for erythropoiesis, so these findings have implications for the treatment of anemia.
“There are several drugs that are now in clinical trials that serve to increase HIF activity and, as a result, will increase the production of erythropoietin and stimulate red blood cell production,” Dr. Semenza said in an interview after the announcement of his Nobel win. “These are all small molecules that can be given by mouth, and that may be a great convenience for patients who, at the present time, may require injections of recombinant human erythropoietin.”
Novel research aims to improve ED care in sickle cell disease
Several initiatives are in the works to improve the management of patients with sickle cell disease in the ED, experts said at a recent webinar held by the National Heart, Lung, and Blood Institute.
In 2014, the NHLBI released evidence-based guidelines for the management of patients with sickle cell disease. The expert panel provided recommendations on the treatment of acute complications of sickle cell disease, many of which are common reasons for ED visits.
Optimizing the treatment of acute complications, namely vasoocclusive crisis, is essential to ensure improved long-term outcomes, explained Paula Tanabe, PhD, of Duke University, Durham, N.C.
Pain management
While the majority of pain-related ED visits in sickle cell are the result of vasoocclusive crisis, other causes, such as acute chest syndrome, abdominal catastrophes, and splenic sequestration, are also important.
The hallmark of pain management in this population is rapid and aggressive treatment with intravenous opioids. The use of individualized doses is also important, but if not available, an sickle cell disease–specific pain protocol can be used, she explained.
Recent evidence has confirmed the benefit of using an individualized (patient-specific) dosing protocol. Dr. Tanabe reported the results of a randomized pilot study that compared two pain protocols for patients undergoing a vasoocclusive episode in the ED.
“The reason we pursued this project is to generate additional evidence beyond the expert panel,” she said.
The primary outcome of the study was the difference in pain scores from arrival to discharge between patients receiving an individualized or weight-based dosing protocol. Secondary outcomes included safety, pain experience, and side effects, among others.
The researchers found that patients who received an individualized protocol had significantly lower pain scores, compared with a standard weight-based protocol (between-protocol pain score difference, 15.6 plus or minus 5.0; P = .002).
Additionally, patients in the individualized dosing arm were admitted less often than those in the weight-based arm (P = .03), Dr. Tanabe reported.
The findings from the previous study formed the basis for an ongoing study that is further examining the impact of patient-specific dosing in patients who present with a vasoocclusive episode. The COMPARE VOE study is currently enrolling patients and is being funded by NHLBI.
The NHLBI also provides funding to eight Sickle Cell Disease Implementation Consortium sites throughout the United States. The objective of this grant funding is to help implement NHLBI recommendations in the emergency setting.
Quality improvement
“One area [that] we want to improve is how quickly we administer [analgesic therapy] to patients when they are experiencing a vasoocclusive episode,” said Caroline Freiermuth, MD, of the University of Cincinnati.
Some common barriers to delivering rapid analgesia in this setting include difficulties in obtaining intravenous access, high patient volumes, lack of education, and provider biases, she explained.
With respect to high patient volumes, one strategy that may help overcome this barrier is to triage patients as Emergency Severity Index level 2, allowing for accelerated room placement.
Sickle cell patients undergoing vasoocclusive crisis meet the criteria for level 2 based on morbidity, degree of pain, and the level of resources often required.
Another important strategy is improving education related to sickle cell disease, particularly the high morbidity and mortality seen in these patients, Dr. Freiermuth said.
“The median lifespan for patients with HbSS disease is in the 40s, basically half of the lifespan of a typical American,” she said.
At present, acute chest syndrome is the principal cause of death in patients with sickle cell disease, and most frequently occurs during a vasoocclusive episode. As a result, screening for this complication is essential to reduce mortality in the emergency setting.
Dr. Freiermuth explained that one of the best ways to prevent acute chest syndrome is to encourage the use of incentive spirometry in patients undergoing a vasoocclusive episode.
In order to increase the likelihood of obtaining intravenous access, the use of ultrasound may help guide placement. Educating nurses on the proper use of ultrasound-guided placement of intravenous catheters is one practical approach, she said.
Alternatively, opioid analgesia can be administered subcutaneously. Benefits of subcutaneous delivery include comparable pharmacokinetics, less pain, and a reduced likelihood of sterile abscesses that are often seen with intramuscular administration.
Dr. Freiermuth outlined the quality-improvement initiative being tested at her institution, which involves the administration of parenteral opioid therapy during triage for sickle cell patients undergoing a suspected vasoocclusive crisis. The initiative was developed with input from both the emergency and hematology departments at the site.
Early results have shown no significant changes using this approach, but the data is still preliminary. Initial feedback has revealed that time to room placement has been the greatest barrier, she reported.
Dr. Tanabe reported grant/research support from the National Institutes of Health and the Agency for Healthcare Research and Quality. Dr. Freiermuth reported research support from Pfizer.
Several initiatives are in the works to improve the management of patients with sickle cell disease in the ED, experts said at a recent webinar held by the National Heart, Lung, and Blood Institute.
In 2014, the NHLBI released evidence-based guidelines for the management of patients with sickle cell disease. The expert panel provided recommendations on the treatment of acute complications of sickle cell disease, many of which are common reasons for ED visits.
Optimizing the treatment of acute complications, namely vasoocclusive crisis, is essential to ensure improved long-term outcomes, explained Paula Tanabe, PhD, of Duke University, Durham, N.C.
Pain management
While the majority of pain-related ED visits in sickle cell are the result of vasoocclusive crisis, other causes, such as acute chest syndrome, abdominal catastrophes, and splenic sequestration, are also important.
The hallmark of pain management in this population is rapid and aggressive treatment with intravenous opioids. The use of individualized doses is also important, but if not available, an sickle cell disease–specific pain protocol can be used, she explained.
Recent evidence has confirmed the benefit of using an individualized (patient-specific) dosing protocol. Dr. Tanabe reported the results of a randomized pilot study that compared two pain protocols for patients undergoing a vasoocclusive episode in the ED.
“The reason we pursued this project is to generate additional evidence beyond the expert panel,” she said.
The primary outcome of the study was the difference in pain scores from arrival to discharge between patients receiving an individualized or weight-based dosing protocol. Secondary outcomes included safety, pain experience, and side effects, among others.
The researchers found that patients who received an individualized protocol had significantly lower pain scores, compared with a standard weight-based protocol (between-protocol pain score difference, 15.6 plus or minus 5.0; P = .002).
Additionally, patients in the individualized dosing arm were admitted less often than those in the weight-based arm (P = .03), Dr. Tanabe reported.
The findings from the previous study formed the basis for an ongoing study that is further examining the impact of patient-specific dosing in patients who present with a vasoocclusive episode. The COMPARE VOE study is currently enrolling patients and is being funded by NHLBI.
The NHLBI also provides funding to eight Sickle Cell Disease Implementation Consortium sites throughout the United States. The objective of this grant funding is to help implement NHLBI recommendations in the emergency setting.
Quality improvement
“One area [that] we want to improve is how quickly we administer [analgesic therapy] to patients when they are experiencing a vasoocclusive episode,” said Caroline Freiermuth, MD, of the University of Cincinnati.
Some common barriers to delivering rapid analgesia in this setting include difficulties in obtaining intravenous access, high patient volumes, lack of education, and provider biases, she explained.
With respect to high patient volumes, one strategy that may help overcome this barrier is to triage patients as Emergency Severity Index level 2, allowing for accelerated room placement.
Sickle cell patients undergoing vasoocclusive crisis meet the criteria for level 2 based on morbidity, degree of pain, and the level of resources often required.
Another important strategy is improving education related to sickle cell disease, particularly the high morbidity and mortality seen in these patients, Dr. Freiermuth said.
“The median lifespan for patients with HbSS disease is in the 40s, basically half of the lifespan of a typical American,” she said.
At present, acute chest syndrome is the principal cause of death in patients with sickle cell disease, and most frequently occurs during a vasoocclusive episode. As a result, screening for this complication is essential to reduce mortality in the emergency setting.
Dr. Freiermuth explained that one of the best ways to prevent acute chest syndrome is to encourage the use of incentive spirometry in patients undergoing a vasoocclusive episode.
In order to increase the likelihood of obtaining intravenous access, the use of ultrasound may help guide placement. Educating nurses on the proper use of ultrasound-guided placement of intravenous catheters is one practical approach, she said.
Alternatively, opioid analgesia can be administered subcutaneously. Benefits of subcutaneous delivery include comparable pharmacokinetics, less pain, and a reduced likelihood of sterile abscesses that are often seen with intramuscular administration.
Dr. Freiermuth outlined the quality-improvement initiative being tested at her institution, which involves the administration of parenteral opioid therapy during triage for sickle cell patients undergoing a suspected vasoocclusive crisis. The initiative was developed with input from both the emergency and hematology departments at the site.
Early results have shown no significant changes using this approach, but the data is still preliminary. Initial feedback has revealed that time to room placement has been the greatest barrier, she reported.
Dr. Tanabe reported grant/research support from the National Institutes of Health and the Agency for Healthcare Research and Quality. Dr. Freiermuth reported research support from Pfizer.
Several initiatives are in the works to improve the management of patients with sickle cell disease in the ED, experts said at a recent webinar held by the National Heart, Lung, and Blood Institute.
In 2014, the NHLBI released evidence-based guidelines for the management of patients with sickle cell disease. The expert panel provided recommendations on the treatment of acute complications of sickle cell disease, many of which are common reasons for ED visits.
Optimizing the treatment of acute complications, namely vasoocclusive crisis, is essential to ensure improved long-term outcomes, explained Paula Tanabe, PhD, of Duke University, Durham, N.C.
Pain management
While the majority of pain-related ED visits in sickle cell are the result of vasoocclusive crisis, other causes, such as acute chest syndrome, abdominal catastrophes, and splenic sequestration, are also important.
The hallmark of pain management in this population is rapid and aggressive treatment with intravenous opioids. The use of individualized doses is also important, but if not available, an sickle cell disease–specific pain protocol can be used, she explained.
Recent evidence has confirmed the benefit of using an individualized (patient-specific) dosing protocol. Dr. Tanabe reported the results of a randomized pilot study that compared two pain protocols for patients undergoing a vasoocclusive episode in the ED.
“The reason we pursued this project is to generate additional evidence beyond the expert panel,” she said.
The primary outcome of the study was the difference in pain scores from arrival to discharge between patients receiving an individualized or weight-based dosing protocol. Secondary outcomes included safety, pain experience, and side effects, among others.
The researchers found that patients who received an individualized protocol had significantly lower pain scores, compared with a standard weight-based protocol (between-protocol pain score difference, 15.6 plus or minus 5.0; P = .002).
Additionally, patients in the individualized dosing arm were admitted less often than those in the weight-based arm (P = .03), Dr. Tanabe reported.
The findings from the previous study formed the basis for an ongoing study that is further examining the impact of patient-specific dosing in patients who present with a vasoocclusive episode. The COMPARE VOE study is currently enrolling patients and is being funded by NHLBI.
The NHLBI also provides funding to eight Sickle Cell Disease Implementation Consortium sites throughout the United States. The objective of this grant funding is to help implement NHLBI recommendations in the emergency setting.
Quality improvement
“One area [that] we want to improve is how quickly we administer [analgesic therapy] to patients when they are experiencing a vasoocclusive episode,” said Caroline Freiermuth, MD, of the University of Cincinnati.
Some common barriers to delivering rapid analgesia in this setting include difficulties in obtaining intravenous access, high patient volumes, lack of education, and provider biases, she explained.
With respect to high patient volumes, one strategy that may help overcome this barrier is to triage patients as Emergency Severity Index level 2, allowing for accelerated room placement.
Sickle cell patients undergoing vasoocclusive crisis meet the criteria for level 2 based on morbidity, degree of pain, and the level of resources often required.
Another important strategy is improving education related to sickle cell disease, particularly the high morbidity and mortality seen in these patients, Dr. Freiermuth said.
“The median lifespan for patients with HbSS disease is in the 40s, basically half of the lifespan of a typical American,” she said.
At present, acute chest syndrome is the principal cause of death in patients with sickle cell disease, and most frequently occurs during a vasoocclusive episode. As a result, screening for this complication is essential to reduce mortality in the emergency setting.
Dr. Freiermuth explained that one of the best ways to prevent acute chest syndrome is to encourage the use of incentive spirometry in patients undergoing a vasoocclusive episode.
In order to increase the likelihood of obtaining intravenous access, the use of ultrasound may help guide placement. Educating nurses on the proper use of ultrasound-guided placement of intravenous catheters is one practical approach, she said.
Alternatively, opioid analgesia can be administered subcutaneously. Benefits of subcutaneous delivery include comparable pharmacokinetics, less pain, and a reduced likelihood of sterile abscesses that are often seen with intramuscular administration.
Dr. Freiermuth outlined the quality-improvement initiative being tested at her institution, which involves the administration of parenteral opioid therapy during triage for sickle cell patients undergoing a suspected vasoocclusive crisis. The initiative was developed with input from both the emergency and hematology departments at the site.
Early results have shown no significant changes using this approach, but the data is still preliminary. Initial feedback has revealed that time to room placement has been the greatest barrier, she reported.
Dr. Tanabe reported grant/research support from the National Institutes of Health and the Agency for Healthcare Research and Quality. Dr. Freiermuth reported research support from Pfizer.
REPORTING FROM AN NIH WEBINAR
Ongoing research aims to improve transplant outcomes in sickle cell
Researchers are leading several studies designed to improve hematopoietic stem cell transplantation (HSCT) for patients with sickle cell disease (SCD), experts at the National Heart, Lung, and Blood Institute reported during a recent webinar.
“HSCT offers a potential cure [for SCD], which may improve quantity and quality of life [for patients],” said Courtney D. Fitzhugh, MD, a Lasker Clinical Research Scholar in the Laboratory of Early Sickle Mortality Prevention at NHLBI.
Currently, HLA-matched sibling and matched unrelated donor sources provide the best outcomes for sickle cell patients undergoing allogeneic HSCT, she explained. Alternative stem cell sources include umbilical cord blood and haploidentical donors.
Over the past 2 years, the majority of novel transplant techniques have been primarily aimed at improving conditioning regimens and lowering rates of graft-versus-host disease (GVHD).
Recent evidence
A recent international survey found high survival rates in patients with SCD who underwent HLA-matched sibling HSCT during 1986-2013. At 5-years, overall- and event-free survival rates were 92.9% and 91.4%, respectively, with even higher rates (95% and 93%) seen in children aged younger than 16 years.
With respect to safety, the cumulative incidence rates of acute and chronic GVHD were 14.8% and 14.3%, Dr. Fitzhugh reported.
Much of the success seen with HLA-matched sibling donors is attributable to recent data demonstrating that complete transformation of patient’s bone marrow is unnecessary to illicit a curative effect.
With donor myeloid chimerism levels of at least 20%, the sickle disease phenotype can be reversed, and there’s a reduced risk of GVHD, she said.
In mouse models, researchers have found that inclusion of sirolimus in HLA-matched pretransplant conditioning regimens leads to higher levels of donor cell engraftment. As a result, some conditioning regimens now administer sirolimus (target 10-15 ng/dL) one-day prior to transplantation.
In 55 patients transplanted using this technique, overall- and event-free survival rates of 93% and 87% have been reported, with no transplant-related mortality or evidence of GVHD. Other institutions have also begun to adopt this technique, and have reported similar findings, Dr. Fitzhugh reported.
“When you [administer high-dose] chemotherapy, you don’t expect that patients are able to have children, but we are excited to report that 8 of our patients have had 13 healthy babies post transplant,” Dr. Fitzhugh said.
As a whole, several recent studies have emphasized the importance of the conditioning regimen in successful transplantation for patients with SCD.
With HLA-matched sibling donors, myeloablative regimens that include antithymocyte globulin have demonstrated greater efficacy, she said.
In patients receiving a transplant from a matched unrelated donor, early use of alemtuzumab is linked to higher rates of GVHD, while ongoing studies are exploring whether abatacept reduces the risk of GVHD, she further explained.
With respect to haploidentical and unrelated umbilical cord donors, T-cell depletion and higher-intensity conditioning have been shown to reduce graft rejection rates, she said.
Dr. Fitzhugh acknowledged that long-term efficacy and safety of these novel conditioning regimens is largely unknown. Thus, ongoing follow-up is essential to monitor for potential late effects.
NHLBI-funded trials
Nancy L. DiFronzo, PhD, program director at NHLBI, explained that the agency has funded specific clinical studies evaluating allogeneic HSCT in patients with severe SCD.
“[Surprisingly], this treatment modality is [actually] quite rare, with [only] approximately 9,000 allogeneic transplants occurring in the United States each year,” she said.
One of the primary barriers to HSCT for SCD is a lack of compatible donors. Currently, fewer than 20% of sickle cell patients have a matched unrelated donor or HLA-matched sibling donor, she reported.
Another common barrier are the risks associated with the procedure, including treatment-related toxicities and death. Active participation in a clinical trial is one strategy that can mitigate these risks, she said.
The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) is a group of transplant centers that are recognized experts in HSCT. Dr. DiFronzo explained that the consortium is cosponsored by the National Cancer Institute and NHLBI, with the goal of improving outcomes for both pediatric and adult patients with SCD undergoing HSCT.
At present, the BMT CTN has directly funded three multicenter clinical studies for SCD, including the SCURT study, which has now been completed, as well as the STRIDE2 and Haploidentical HCT trials, both of which are currently enrolling patients.
“The goal of these new approaches [being studied in these 3 trials] is cure, where individuals can live longer with a better quality of life,” Dr. DiFronzo said. “We’ve [specifically] adjusted regimens with [this goal] in mind.”
Dr. Fitzhugh and Dr. DiFronzo did not provide information on financial disclosures.
Researchers are leading several studies designed to improve hematopoietic stem cell transplantation (HSCT) for patients with sickle cell disease (SCD), experts at the National Heart, Lung, and Blood Institute reported during a recent webinar.
“HSCT offers a potential cure [for SCD], which may improve quantity and quality of life [for patients],” said Courtney D. Fitzhugh, MD, a Lasker Clinical Research Scholar in the Laboratory of Early Sickle Mortality Prevention at NHLBI.
Currently, HLA-matched sibling and matched unrelated donor sources provide the best outcomes for sickle cell patients undergoing allogeneic HSCT, she explained. Alternative stem cell sources include umbilical cord blood and haploidentical donors.
Over the past 2 years, the majority of novel transplant techniques have been primarily aimed at improving conditioning regimens and lowering rates of graft-versus-host disease (GVHD).
Recent evidence
A recent international survey found high survival rates in patients with SCD who underwent HLA-matched sibling HSCT during 1986-2013. At 5-years, overall- and event-free survival rates were 92.9% and 91.4%, respectively, with even higher rates (95% and 93%) seen in children aged younger than 16 years.
With respect to safety, the cumulative incidence rates of acute and chronic GVHD were 14.8% and 14.3%, Dr. Fitzhugh reported.
Much of the success seen with HLA-matched sibling donors is attributable to recent data demonstrating that complete transformation of patient’s bone marrow is unnecessary to illicit a curative effect.
With donor myeloid chimerism levels of at least 20%, the sickle disease phenotype can be reversed, and there’s a reduced risk of GVHD, she said.
In mouse models, researchers have found that inclusion of sirolimus in HLA-matched pretransplant conditioning regimens leads to higher levels of donor cell engraftment. As a result, some conditioning regimens now administer sirolimus (target 10-15 ng/dL) one-day prior to transplantation.
In 55 patients transplanted using this technique, overall- and event-free survival rates of 93% and 87% have been reported, with no transplant-related mortality or evidence of GVHD. Other institutions have also begun to adopt this technique, and have reported similar findings, Dr. Fitzhugh reported.
“When you [administer high-dose] chemotherapy, you don’t expect that patients are able to have children, but we are excited to report that 8 of our patients have had 13 healthy babies post transplant,” Dr. Fitzhugh said.
As a whole, several recent studies have emphasized the importance of the conditioning regimen in successful transplantation for patients with SCD.
With HLA-matched sibling donors, myeloablative regimens that include antithymocyte globulin have demonstrated greater efficacy, she said.
In patients receiving a transplant from a matched unrelated donor, early use of alemtuzumab is linked to higher rates of GVHD, while ongoing studies are exploring whether abatacept reduces the risk of GVHD, she further explained.
With respect to haploidentical and unrelated umbilical cord donors, T-cell depletion and higher-intensity conditioning have been shown to reduce graft rejection rates, she said.
Dr. Fitzhugh acknowledged that long-term efficacy and safety of these novel conditioning regimens is largely unknown. Thus, ongoing follow-up is essential to monitor for potential late effects.
NHLBI-funded trials
Nancy L. DiFronzo, PhD, program director at NHLBI, explained that the agency has funded specific clinical studies evaluating allogeneic HSCT in patients with severe SCD.
“[Surprisingly], this treatment modality is [actually] quite rare, with [only] approximately 9,000 allogeneic transplants occurring in the United States each year,” she said.
One of the primary barriers to HSCT for SCD is a lack of compatible donors. Currently, fewer than 20% of sickle cell patients have a matched unrelated donor or HLA-matched sibling donor, she reported.
Another common barrier are the risks associated with the procedure, including treatment-related toxicities and death. Active participation in a clinical trial is one strategy that can mitigate these risks, she said.
The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) is a group of transplant centers that are recognized experts in HSCT. Dr. DiFronzo explained that the consortium is cosponsored by the National Cancer Institute and NHLBI, with the goal of improving outcomes for both pediatric and adult patients with SCD undergoing HSCT.
At present, the BMT CTN has directly funded three multicenter clinical studies for SCD, including the SCURT study, which has now been completed, as well as the STRIDE2 and Haploidentical HCT trials, both of which are currently enrolling patients.
“The goal of these new approaches [being studied in these 3 trials] is cure, where individuals can live longer with a better quality of life,” Dr. DiFronzo said. “We’ve [specifically] adjusted regimens with [this goal] in mind.”
Dr. Fitzhugh and Dr. DiFronzo did not provide information on financial disclosures.
Researchers are leading several studies designed to improve hematopoietic stem cell transplantation (HSCT) for patients with sickle cell disease (SCD), experts at the National Heart, Lung, and Blood Institute reported during a recent webinar.
“HSCT offers a potential cure [for SCD], which may improve quantity and quality of life [for patients],” said Courtney D. Fitzhugh, MD, a Lasker Clinical Research Scholar in the Laboratory of Early Sickle Mortality Prevention at NHLBI.
Currently, HLA-matched sibling and matched unrelated donor sources provide the best outcomes for sickle cell patients undergoing allogeneic HSCT, she explained. Alternative stem cell sources include umbilical cord blood and haploidentical donors.
Over the past 2 years, the majority of novel transplant techniques have been primarily aimed at improving conditioning regimens and lowering rates of graft-versus-host disease (GVHD).
Recent evidence
A recent international survey found high survival rates in patients with SCD who underwent HLA-matched sibling HSCT during 1986-2013. At 5-years, overall- and event-free survival rates were 92.9% and 91.4%, respectively, with even higher rates (95% and 93%) seen in children aged younger than 16 years.
With respect to safety, the cumulative incidence rates of acute and chronic GVHD were 14.8% and 14.3%, Dr. Fitzhugh reported.
Much of the success seen with HLA-matched sibling donors is attributable to recent data demonstrating that complete transformation of patient’s bone marrow is unnecessary to illicit a curative effect.
With donor myeloid chimerism levels of at least 20%, the sickle disease phenotype can be reversed, and there’s a reduced risk of GVHD, she said.
In mouse models, researchers have found that inclusion of sirolimus in HLA-matched pretransplant conditioning regimens leads to higher levels of donor cell engraftment. As a result, some conditioning regimens now administer sirolimus (target 10-15 ng/dL) one-day prior to transplantation.
In 55 patients transplanted using this technique, overall- and event-free survival rates of 93% and 87% have been reported, with no transplant-related mortality or evidence of GVHD. Other institutions have also begun to adopt this technique, and have reported similar findings, Dr. Fitzhugh reported.
“When you [administer high-dose] chemotherapy, you don’t expect that patients are able to have children, but we are excited to report that 8 of our patients have had 13 healthy babies post transplant,” Dr. Fitzhugh said.
As a whole, several recent studies have emphasized the importance of the conditioning regimen in successful transplantation for patients with SCD.
With HLA-matched sibling donors, myeloablative regimens that include antithymocyte globulin have demonstrated greater efficacy, she said.
In patients receiving a transplant from a matched unrelated donor, early use of alemtuzumab is linked to higher rates of GVHD, while ongoing studies are exploring whether abatacept reduces the risk of GVHD, she further explained.
With respect to haploidentical and unrelated umbilical cord donors, T-cell depletion and higher-intensity conditioning have been shown to reduce graft rejection rates, she said.
Dr. Fitzhugh acknowledged that long-term efficacy and safety of these novel conditioning regimens is largely unknown. Thus, ongoing follow-up is essential to monitor for potential late effects.
NHLBI-funded trials
Nancy L. DiFronzo, PhD, program director at NHLBI, explained that the agency has funded specific clinical studies evaluating allogeneic HSCT in patients with severe SCD.
“[Surprisingly], this treatment modality is [actually] quite rare, with [only] approximately 9,000 allogeneic transplants occurring in the United States each year,” she said.
One of the primary barriers to HSCT for SCD is a lack of compatible donors. Currently, fewer than 20% of sickle cell patients have a matched unrelated donor or HLA-matched sibling donor, she reported.
Another common barrier are the risks associated with the procedure, including treatment-related toxicities and death. Active participation in a clinical trial is one strategy that can mitigate these risks, she said.
The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) is a group of transplant centers that are recognized experts in HSCT. Dr. DiFronzo explained that the consortium is cosponsored by the National Cancer Institute and NHLBI, with the goal of improving outcomes for both pediatric and adult patients with SCD undergoing HSCT.
At present, the BMT CTN has directly funded three multicenter clinical studies for SCD, including the SCURT study, which has now been completed, as well as the STRIDE2 and Haploidentical HCT trials, both of which are currently enrolling patients.
“The goal of these new approaches [being studied in these 3 trials] is cure, where individuals can live longer with a better quality of life,” Dr. DiFronzo said. “We’ve [specifically] adjusted regimens with [this goal] in mind.”
Dr. Fitzhugh and Dr. DiFronzo did not provide information on financial disclosures.
CDC awards $1.2 million to learn about people with sickle cell disease
The Centers for Disease Control and Prevention will be awarding $1.2 million in funding to help states collect data on issues faced by people with sickle cell disease.
Currently, only Georgia and California work with the CDC on the Sickle Cell Data Collection program to gather population-based, comprehensive health information about people with sickle cell disease. The new funding will expand that base to nine states. The money will go toward a 1-year project that will build infrastructure for recipient sites to gather unique data and conduct in-depth analyses in people with sickle cell disease, the CDC noted.
The sites that were awarded funding are Duke University, Durham, N.C.; Georgia State University, Atlanta; the Indiana Hemophilia and Thrombosis Center in Indianapolis; the Michigan Department of Health & Human Services; the Minnesota Department of Health; the Public Health Institute in Oakland, Calif.; the University of Alabama at Birmingham; the University of Tennessee Health Science Center in Memphis; and the Virginia Department of Health.
“Data is vital to informing new treatments and clinical care that will improve the lives of people affected by sickle cell disease. This new funding expands CDC’s partner network across the country which will accelerate efforts to ensure sickle cell patients live longer and healthier lives,” said CDC Director Robert R. Redfield, MD.
Find the full press release on the CDC website.
The Centers for Disease Control and Prevention will be awarding $1.2 million in funding to help states collect data on issues faced by people with sickle cell disease.
Currently, only Georgia and California work with the CDC on the Sickle Cell Data Collection program to gather population-based, comprehensive health information about people with sickle cell disease. The new funding will expand that base to nine states. The money will go toward a 1-year project that will build infrastructure for recipient sites to gather unique data and conduct in-depth analyses in people with sickle cell disease, the CDC noted.
The sites that were awarded funding are Duke University, Durham, N.C.; Georgia State University, Atlanta; the Indiana Hemophilia and Thrombosis Center in Indianapolis; the Michigan Department of Health & Human Services; the Minnesota Department of Health; the Public Health Institute in Oakland, Calif.; the University of Alabama at Birmingham; the University of Tennessee Health Science Center in Memphis; and the Virginia Department of Health.
“Data is vital to informing new treatments and clinical care that will improve the lives of people affected by sickle cell disease. This new funding expands CDC’s partner network across the country which will accelerate efforts to ensure sickle cell patients live longer and healthier lives,” said CDC Director Robert R. Redfield, MD.
Find the full press release on the CDC website.
The Centers for Disease Control and Prevention will be awarding $1.2 million in funding to help states collect data on issues faced by people with sickle cell disease.
Currently, only Georgia and California work with the CDC on the Sickle Cell Data Collection program to gather population-based, comprehensive health information about people with sickle cell disease. The new funding will expand that base to nine states. The money will go toward a 1-year project that will build infrastructure for recipient sites to gather unique data and conduct in-depth analyses in people with sickle cell disease, the CDC noted.
The sites that were awarded funding are Duke University, Durham, N.C.; Georgia State University, Atlanta; the Indiana Hemophilia and Thrombosis Center in Indianapolis; the Michigan Department of Health & Human Services; the Minnesota Department of Health; the Public Health Institute in Oakland, Calif.; the University of Alabama at Birmingham; the University of Tennessee Health Science Center in Memphis; and the Virginia Department of Health.
“Data is vital to informing new treatments and clinical care that will improve the lives of people affected by sickle cell disease. This new funding expands CDC’s partner network across the country which will accelerate efforts to ensure sickle cell patients live longer and healthier lives,” said CDC Director Robert R. Redfield, MD.
Find the full press release on the CDC website.
Novel gene therapies show promise for sickle cell cure
Early results indicate experimental gene therapies could illicit a cure for sickle cell disease (SCD), but many barriers to access remain, namely cost, experts reported during a recent webinar sponsored by the National Heart, Lung, and Blood Institute.
At present, allogeneic hematopoietic stem cell transplant remains the only curative therapy available for patients with SCD. Newer transplant techniques include the use of mobilized blood stem cells, where stem cells are collected from the circulation using blood cell growth factors, explained Mark Walters, MD, of UCSF Benioff Children’s Hospital Oakland in California.
The most promising experimental gene therapies currently undergoing clinical development are gene-addition and gene-editing therapies, he said. Another technique, in vivo gene editing to correct the sickle mutation, is also being investigated, but has not yet reached clinical development.
Gene-addition therapy
Gene-addition therapy is a technique where a fetal hemoglobin (HbF) or anti-sickling beta-hemoglobin gene is inserted into a hematopoietic stem cell to illicit a curative effect. In this technique, the corrective gene is harvested from a patient’s own blood stem cells.
In patients with SCD, when HbF levels are elevated, the likelihood of sickling is reduced, resulting in a milder form of disease. As a result, raising HbF levels is a therapeutic target that forms the basis of several ongoing clinical studies.
The technique involves packaging an HbF rescue gene into a viral vector and coincubating the vector with a patient’s own blood stem cells. Subsequently, the corrected stem cells are injected back into the patient to produce higher levels of HbF.
The ongoing phase 1/2 HGB-206 clinical study is evaluating this technique in patients aged 12-50 years with severe SCD in multiple centers throughout Europe and the United States.
In those treated thus far, initial results appear promising, Dr. Walters reported, with one patient experiencing a rise in Hb levels from 10.7 g/dL at 3 months to 15.0 g/dL at 15 months follow-up.
Dr. Walters also reported that some of these patients no longer exhibit any signs or symptoms of SCD, such as anemia or painful adverse events. While these initial findings are compelling, whether these benefits will be maintained is still unknown.
“While it’s too early to call this a cure, if [these results] could be extended for 5, 10, or 15 years, I think everyone would agree that this would be a cure,” he said.
This technique could be universally available, he said, since a patient’s own blood stem cells are used. Other complications, such as graft-versus-host disease (GVHD) or immune-related reactions, are negated with this form of therapy, he said.
Recent evidence has demonstrated that only about 20% of donor stem cells need to be corrected to illicit a very strong effect. This principle is now being applied in gene-editing techniques, as correcting every gene in every stem cell would be very challenging, Dr. Walters explained.
Gene editing
Another technique being investigated in SCD is gene editing, in which the fetal hemoglobin gene is “reawakened,” or other techniques are used to correct the sickle gene directly, such as CRISPR-Cas9 technology, Dr. Walters said.
In this technique, the Cas9 protein makes a cut and repairs an individual’s genomic DNA by inserting a strand of corrected donor DNA. The novel technology would allow for targeted genome editing that is specific to the SCD patient.
Currently, this experimental therapy is being investigated in preclinical studies. Dr. Walters said that he and his colleagues hope to begin enrolling patients in clinical trials within the next 1-2 years.
But while some gene therapies have been approved in other disorders, such as spinal muscle atrophy, a limiting factor to widespread availability is cost. Despite promising initial results in SCD, the affordability of future gene therapies will be a key factor to universal access, Dr. Walters said.
The Cure Sickle Cell Initiative
Traci Mondoro, PhD, chief of the Translational Blood Science and Resources Branch at NHLBI, explained that the NHLBI has funded a large proportion of the research that has formed the basis of several genetically based clinical studies.
One of the primary goals of the Cure Sickle Cell Initiative is to bridge the gap between new research and the SCD community. Their aim is to improve access for patients to participate in genetically based studies to advance cures.
The comprehensive approach is intended to fill in existing gaps by funding breakthrough research in both academic and private settings.
By establishing partnerships with key stakeholders, institutions, and patient groups, Dr. Mondoro said they hope to increase patient participation in clinical trials involving curative therapies. In the future, they also intend to establish a large body of evidence to provide adequate safety data to study these therapies in pediatric populations.
Dr. Walters and Dr. Mondoro did not provide information on financial disclosures.
Early results indicate experimental gene therapies could illicit a cure for sickle cell disease (SCD), but many barriers to access remain, namely cost, experts reported during a recent webinar sponsored by the National Heart, Lung, and Blood Institute.
At present, allogeneic hematopoietic stem cell transplant remains the only curative therapy available for patients with SCD. Newer transplant techniques include the use of mobilized blood stem cells, where stem cells are collected from the circulation using blood cell growth factors, explained Mark Walters, MD, of UCSF Benioff Children’s Hospital Oakland in California.
The most promising experimental gene therapies currently undergoing clinical development are gene-addition and gene-editing therapies, he said. Another technique, in vivo gene editing to correct the sickle mutation, is also being investigated, but has not yet reached clinical development.
Gene-addition therapy
Gene-addition therapy is a technique where a fetal hemoglobin (HbF) or anti-sickling beta-hemoglobin gene is inserted into a hematopoietic stem cell to illicit a curative effect. In this technique, the corrective gene is harvested from a patient’s own blood stem cells.
In patients with SCD, when HbF levels are elevated, the likelihood of sickling is reduced, resulting in a milder form of disease. As a result, raising HbF levels is a therapeutic target that forms the basis of several ongoing clinical studies.
The technique involves packaging an HbF rescue gene into a viral vector and coincubating the vector with a patient’s own blood stem cells. Subsequently, the corrected stem cells are injected back into the patient to produce higher levels of HbF.
The ongoing phase 1/2 HGB-206 clinical study is evaluating this technique in patients aged 12-50 years with severe SCD in multiple centers throughout Europe and the United States.
In those treated thus far, initial results appear promising, Dr. Walters reported, with one patient experiencing a rise in Hb levels from 10.7 g/dL at 3 months to 15.0 g/dL at 15 months follow-up.
Dr. Walters also reported that some of these patients no longer exhibit any signs or symptoms of SCD, such as anemia or painful adverse events. While these initial findings are compelling, whether these benefits will be maintained is still unknown.
“While it’s too early to call this a cure, if [these results] could be extended for 5, 10, or 15 years, I think everyone would agree that this would be a cure,” he said.
This technique could be universally available, he said, since a patient’s own blood stem cells are used. Other complications, such as graft-versus-host disease (GVHD) or immune-related reactions, are negated with this form of therapy, he said.
Recent evidence has demonstrated that only about 20% of donor stem cells need to be corrected to illicit a very strong effect. This principle is now being applied in gene-editing techniques, as correcting every gene in every stem cell would be very challenging, Dr. Walters explained.
Gene editing
Another technique being investigated in SCD is gene editing, in which the fetal hemoglobin gene is “reawakened,” or other techniques are used to correct the sickle gene directly, such as CRISPR-Cas9 technology, Dr. Walters said.
In this technique, the Cas9 protein makes a cut and repairs an individual’s genomic DNA by inserting a strand of corrected donor DNA. The novel technology would allow for targeted genome editing that is specific to the SCD patient.
Currently, this experimental therapy is being investigated in preclinical studies. Dr. Walters said that he and his colleagues hope to begin enrolling patients in clinical trials within the next 1-2 years.
But while some gene therapies have been approved in other disorders, such as spinal muscle atrophy, a limiting factor to widespread availability is cost. Despite promising initial results in SCD, the affordability of future gene therapies will be a key factor to universal access, Dr. Walters said.
The Cure Sickle Cell Initiative
Traci Mondoro, PhD, chief of the Translational Blood Science and Resources Branch at NHLBI, explained that the NHLBI has funded a large proportion of the research that has formed the basis of several genetically based clinical studies.
One of the primary goals of the Cure Sickle Cell Initiative is to bridge the gap between new research and the SCD community. Their aim is to improve access for patients to participate in genetically based studies to advance cures.
The comprehensive approach is intended to fill in existing gaps by funding breakthrough research in both academic and private settings.
By establishing partnerships with key stakeholders, institutions, and patient groups, Dr. Mondoro said they hope to increase patient participation in clinical trials involving curative therapies. In the future, they also intend to establish a large body of evidence to provide adequate safety data to study these therapies in pediatric populations.
Dr. Walters and Dr. Mondoro did not provide information on financial disclosures.
Early results indicate experimental gene therapies could illicit a cure for sickle cell disease (SCD), but many barriers to access remain, namely cost, experts reported during a recent webinar sponsored by the National Heart, Lung, and Blood Institute.
At present, allogeneic hematopoietic stem cell transplant remains the only curative therapy available for patients with SCD. Newer transplant techniques include the use of mobilized blood stem cells, where stem cells are collected from the circulation using blood cell growth factors, explained Mark Walters, MD, of UCSF Benioff Children’s Hospital Oakland in California.
The most promising experimental gene therapies currently undergoing clinical development are gene-addition and gene-editing therapies, he said. Another technique, in vivo gene editing to correct the sickle mutation, is also being investigated, but has not yet reached clinical development.
Gene-addition therapy
Gene-addition therapy is a technique where a fetal hemoglobin (HbF) or anti-sickling beta-hemoglobin gene is inserted into a hematopoietic stem cell to illicit a curative effect. In this technique, the corrective gene is harvested from a patient’s own blood stem cells.
In patients with SCD, when HbF levels are elevated, the likelihood of sickling is reduced, resulting in a milder form of disease. As a result, raising HbF levels is a therapeutic target that forms the basis of several ongoing clinical studies.
The technique involves packaging an HbF rescue gene into a viral vector and coincubating the vector with a patient’s own blood stem cells. Subsequently, the corrected stem cells are injected back into the patient to produce higher levels of HbF.
The ongoing phase 1/2 HGB-206 clinical study is evaluating this technique in patients aged 12-50 years with severe SCD in multiple centers throughout Europe and the United States.
In those treated thus far, initial results appear promising, Dr. Walters reported, with one patient experiencing a rise in Hb levels from 10.7 g/dL at 3 months to 15.0 g/dL at 15 months follow-up.
Dr. Walters also reported that some of these patients no longer exhibit any signs or symptoms of SCD, such as anemia or painful adverse events. While these initial findings are compelling, whether these benefits will be maintained is still unknown.
“While it’s too early to call this a cure, if [these results] could be extended for 5, 10, or 15 years, I think everyone would agree that this would be a cure,” he said.
This technique could be universally available, he said, since a patient’s own blood stem cells are used. Other complications, such as graft-versus-host disease (GVHD) or immune-related reactions, are negated with this form of therapy, he said.
Recent evidence has demonstrated that only about 20% of donor stem cells need to be corrected to illicit a very strong effect. This principle is now being applied in gene-editing techniques, as correcting every gene in every stem cell would be very challenging, Dr. Walters explained.
Gene editing
Another technique being investigated in SCD is gene editing, in which the fetal hemoglobin gene is “reawakened,” or other techniques are used to correct the sickle gene directly, such as CRISPR-Cas9 technology, Dr. Walters said.
In this technique, the Cas9 protein makes a cut and repairs an individual’s genomic DNA by inserting a strand of corrected donor DNA. The novel technology would allow for targeted genome editing that is specific to the SCD patient.
Currently, this experimental therapy is being investigated in preclinical studies. Dr. Walters said that he and his colleagues hope to begin enrolling patients in clinical trials within the next 1-2 years.
But while some gene therapies have been approved in other disorders, such as spinal muscle atrophy, a limiting factor to widespread availability is cost. Despite promising initial results in SCD, the affordability of future gene therapies will be a key factor to universal access, Dr. Walters said.
The Cure Sickle Cell Initiative
Traci Mondoro, PhD, chief of the Translational Blood Science and Resources Branch at NHLBI, explained that the NHLBI has funded a large proportion of the research that has formed the basis of several genetically based clinical studies.
One of the primary goals of the Cure Sickle Cell Initiative is to bridge the gap between new research and the SCD community. Their aim is to improve access for patients to participate in genetically based studies to advance cures.
The comprehensive approach is intended to fill in existing gaps by funding breakthrough research in both academic and private settings.
By establishing partnerships with key stakeholders, institutions, and patient groups, Dr. Mondoro said they hope to increase patient participation in clinical trials involving curative therapies. In the future, they also intend to establish a large body of evidence to provide adequate safety data to study these therapies in pediatric populations.
Dr. Walters and Dr. Mondoro did not provide information on financial disclosures.
Can we eradicate malaria by 2050?
A new report by members of the Lancet Commission on Malaria Eradication has called for ending malaria in Africa within a generation, specifically aiming at the year 2050.
The Lancet Commission on Malaria Eradication is a joint endeavor between The Lancet and the University of California, San Francisco, and was convened in 2017 to consider the feasibility and affordability of malaria eradication, as well as to identify priority actions for the achievement of the goal. Eradication was considered “a necessary one given the never-ending struggle against drug and insecticide resistance and the social and economic costs associated with a failure to eradicate.”
Between 2000 and 2017, the worldwide annual incidence of malaria declined by 36%, and the annual death rate declined by 60%, according to the report. In 2007, Bill and Melinda Gates proposed that controlling malaria was not enough and complete eradication was the only scientifically and ethically defensible objective. This goal was adopted by the World Health Organization and other interested parties, and by 2015, global strategies and a potential timeline for eradication were developed.
“Global progress has stalled since 2015 and the malaria community is now at a critical moment, faced with a decision to either temper its ambitions as it did in 1969 or recommit to an eradication goal,” according to the report.
In the report, the authors used new modeling analysis to estimate plausible scenarios for the distribution and intensity of malaria in 2030 and 2050. Socioeconomic and environmental trends, together with enhanced access to high-quality diagnosis, treatment, and vector control, could lead to a “world largely free of malaria” by 2050, but with pockets of low-level transmission persisting across a belt of Africa.
Current statistics lend weight to the promise of eventual eradication, according to the report.
Between 2000 and 2017, 20 countries – constituting about one-fifth of the 106 malaria-endemic countries in 2000 – eliminated malaria transmission within their borders, reporting zero indigenous malaria cases for at least 1 year. However, this was counterbalanced by the fact that between 2015 and 2017, 55 countries had an increase in cases, and 38 countries had an increase in deaths.
“The good news is that 38 countries had incidences of fewer than ten cases per 1,000 population in 2017, with 25 countries reporting fewer than one case per 1,000 population. The same 38 countries reported just 5% of total malaria deaths. Nearly all of these low-burden countries are actively working towards national and regional elimination goals of 2030 or earlier,” according to the report.
The analysis undertaken for the report consisted of the following four steps:
1. Development of a machine-learning model to capture associations between malaria endemicity data and a wide range of socioeconomic and environmental geospatial covariates.
2. Mapping of covariate estimates to the years 2030 and 2050 on the basis of projected global trends.
3. Application of the associations learned in the first step to projected covariates generated in the second step to estimate the possible future global landscape of malaria endemicity.
4. Use of a mathematical transmission model to explore the potential effect of differing levels of malaria interventions.
The report indicates that an annual spending of $6 billion or more is required, while the current global expenditure is approximately $4.3 billion. An additional investment of $2 billion per year is necessary, with a quarter of the funds coming from increased development assistance from external donors and the rest from government health spending in malaria-endemic countries, according to the report.
However, other areas of concern remain, including the current lack of effective and widely deployable outdoor biting technologies, though these are expected to be available within the next decade, according to the report.
In terms of the modeling used in the report, the authors noted that past performance does not “capture the effect of mass drug administration or mass chemoprevention because these interventions are either relatively new or have yet to be applied widely. These underestimates might be counteracted by the absence of drug or insecticide resistance from our projections,which result in overly optimistic estimates for the continued efficacy of current tools.”
The commission was launched in October 2017 by the Global Health Group at the University of California, San Francisco. The commission built on the 2010 Lancet Malaria Elimination Series, “which evaluated the operational, technical, and financial requirements for malaria elimination and helped shape and build early support for the eradication agenda,” according to the report.
SOURCE: Feachem RGA et al. Lancet. 2019 Sept 8. doi: 10.1016/S0140-6736(19)31139-0.
A new report by members of the Lancet Commission on Malaria Eradication has called for ending malaria in Africa within a generation, specifically aiming at the year 2050.
The Lancet Commission on Malaria Eradication is a joint endeavor between The Lancet and the University of California, San Francisco, and was convened in 2017 to consider the feasibility and affordability of malaria eradication, as well as to identify priority actions for the achievement of the goal. Eradication was considered “a necessary one given the never-ending struggle against drug and insecticide resistance and the social and economic costs associated with a failure to eradicate.”
Between 2000 and 2017, the worldwide annual incidence of malaria declined by 36%, and the annual death rate declined by 60%, according to the report. In 2007, Bill and Melinda Gates proposed that controlling malaria was not enough and complete eradication was the only scientifically and ethically defensible objective. This goal was adopted by the World Health Organization and other interested parties, and by 2015, global strategies and a potential timeline for eradication were developed.
“Global progress has stalled since 2015 and the malaria community is now at a critical moment, faced with a decision to either temper its ambitions as it did in 1969 or recommit to an eradication goal,” according to the report.
In the report, the authors used new modeling analysis to estimate plausible scenarios for the distribution and intensity of malaria in 2030 and 2050. Socioeconomic and environmental trends, together with enhanced access to high-quality diagnosis, treatment, and vector control, could lead to a “world largely free of malaria” by 2050, but with pockets of low-level transmission persisting across a belt of Africa.
Current statistics lend weight to the promise of eventual eradication, according to the report.
Between 2000 and 2017, 20 countries – constituting about one-fifth of the 106 malaria-endemic countries in 2000 – eliminated malaria transmission within their borders, reporting zero indigenous malaria cases for at least 1 year. However, this was counterbalanced by the fact that between 2015 and 2017, 55 countries had an increase in cases, and 38 countries had an increase in deaths.
“The good news is that 38 countries had incidences of fewer than ten cases per 1,000 population in 2017, with 25 countries reporting fewer than one case per 1,000 population. The same 38 countries reported just 5% of total malaria deaths. Nearly all of these low-burden countries are actively working towards national and regional elimination goals of 2030 or earlier,” according to the report.
The analysis undertaken for the report consisted of the following four steps:
1. Development of a machine-learning model to capture associations between malaria endemicity data and a wide range of socioeconomic and environmental geospatial covariates.
2. Mapping of covariate estimates to the years 2030 and 2050 on the basis of projected global trends.
3. Application of the associations learned in the first step to projected covariates generated in the second step to estimate the possible future global landscape of malaria endemicity.
4. Use of a mathematical transmission model to explore the potential effect of differing levels of malaria interventions.
The report indicates that an annual spending of $6 billion or more is required, while the current global expenditure is approximately $4.3 billion. An additional investment of $2 billion per year is necessary, with a quarter of the funds coming from increased development assistance from external donors and the rest from government health spending in malaria-endemic countries, according to the report.
However, other areas of concern remain, including the current lack of effective and widely deployable outdoor biting technologies, though these are expected to be available within the next decade, according to the report.
In terms of the modeling used in the report, the authors noted that past performance does not “capture the effect of mass drug administration or mass chemoprevention because these interventions are either relatively new or have yet to be applied widely. These underestimates might be counteracted by the absence of drug or insecticide resistance from our projections,which result in overly optimistic estimates for the continued efficacy of current tools.”
The commission was launched in October 2017 by the Global Health Group at the University of California, San Francisco. The commission built on the 2010 Lancet Malaria Elimination Series, “which evaluated the operational, technical, and financial requirements for malaria elimination and helped shape and build early support for the eradication agenda,” according to the report.
SOURCE: Feachem RGA et al. Lancet. 2019 Sept 8. doi: 10.1016/S0140-6736(19)31139-0.
A new report by members of the Lancet Commission on Malaria Eradication has called for ending malaria in Africa within a generation, specifically aiming at the year 2050.
The Lancet Commission on Malaria Eradication is a joint endeavor between The Lancet and the University of California, San Francisco, and was convened in 2017 to consider the feasibility and affordability of malaria eradication, as well as to identify priority actions for the achievement of the goal. Eradication was considered “a necessary one given the never-ending struggle against drug and insecticide resistance and the social and economic costs associated with a failure to eradicate.”
Between 2000 and 2017, the worldwide annual incidence of malaria declined by 36%, and the annual death rate declined by 60%, according to the report. In 2007, Bill and Melinda Gates proposed that controlling malaria was not enough and complete eradication was the only scientifically and ethically defensible objective. This goal was adopted by the World Health Organization and other interested parties, and by 2015, global strategies and a potential timeline for eradication were developed.
“Global progress has stalled since 2015 and the malaria community is now at a critical moment, faced with a decision to either temper its ambitions as it did in 1969 or recommit to an eradication goal,” according to the report.
In the report, the authors used new modeling analysis to estimate plausible scenarios for the distribution and intensity of malaria in 2030 and 2050. Socioeconomic and environmental trends, together with enhanced access to high-quality diagnosis, treatment, and vector control, could lead to a “world largely free of malaria” by 2050, but with pockets of low-level transmission persisting across a belt of Africa.
Current statistics lend weight to the promise of eventual eradication, according to the report.
Between 2000 and 2017, 20 countries – constituting about one-fifth of the 106 malaria-endemic countries in 2000 – eliminated malaria transmission within their borders, reporting zero indigenous malaria cases for at least 1 year. However, this was counterbalanced by the fact that between 2015 and 2017, 55 countries had an increase in cases, and 38 countries had an increase in deaths.
“The good news is that 38 countries had incidences of fewer than ten cases per 1,000 population in 2017, with 25 countries reporting fewer than one case per 1,000 population. The same 38 countries reported just 5% of total malaria deaths. Nearly all of these low-burden countries are actively working towards national and regional elimination goals of 2030 or earlier,” according to the report.
The analysis undertaken for the report consisted of the following four steps:
1. Development of a machine-learning model to capture associations between malaria endemicity data and a wide range of socioeconomic and environmental geospatial covariates.
2. Mapping of covariate estimates to the years 2030 and 2050 on the basis of projected global trends.
3. Application of the associations learned in the first step to projected covariates generated in the second step to estimate the possible future global landscape of malaria endemicity.
4. Use of a mathematical transmission model to explore the potential effect of differing levels of malaria interventions.
The report indicates that an annual spending of $6 billion or more is required, while the current global expenditure is approximately $4.3 billion. An additional investment of $2 billion per year is necessary, with a quarter of the funds coming from increased development assistance from external donors and the rest from government health spending in malaria-endemic countries, according to the report.
However, other areas of concern remain, including the current lack of effective and widely deployable outdoor biting technologies, though these are expected to be available within the next decade, according to the report.
In terms of the modeling used in the report, the authors noted that past performance does not “capture the effect of mass drug administration or mass chemoprevention because these interventions are either relatively new or have yet to be applied widely. These underestimates might be counteracted by the absence of drug or insecticide resistance from our projections,which result in overly optimistic estimates for the continued efficacy of current tools.”
The commission was launched in October 2017 by the Global Health Group at the University of California, San Francisco. The commission built on the 2010 Lancet Malaria Elimination Series, “which evaluated the operational, technical, and financial requirements for malaria elimination and helped shape and build early support for the eradication agenda,” according to the report.
SOURCE: Feachem RGA et al. Lancet. 2019 Sept 8. doi: 10.1016/S0140-6736(19)31139-0.
FROM THE LANCET
U.S. and African programs aim to improve understanding, treatment of sickle cell disease
Researchers are leading several programs designed to serve the sickle cell community in the United States and sub-Saharan Africa, officials at the National Heart, Lung, and Blood Institute (NHLBI) said during a recent webinar.
One program based in the United States is focused on building a registry for patients with sickle cell disease (SCD) and conducting studies designed to improve SCD care. Another program involves building “an information-sharing network and patient-powered registry” in the United States.
The programs in sub-Saharan Africa were designed to establish a database of SCD patients, optimize the use of hydroxyurea in children with SCD, and aid genomic studies of SCD.
W. Keith Hoots, MD, director of the Division of Blood Diseases and Resources at NHLBI, began the webinar with an overview of the programs in sub-Saharan Africa. He described four programs with sites in nine countries (Angola, Cameroon, Democratic Republic of Congo, Ghana, Kenya, Nigeria, South Africa, Tanzania, and Uganda).
SPARCO and SADaCC
Dr. Hoots outlined the scope the Sickle Pan-African Research Consortium (SPARCO) and the Sickle Africa Data Coordinating Center (SADaCC), both part of the Sickle In Africa consortium.
A major goal of SPARCO and SADaCC is to create a Research Electronic Data Capture database that encompasses SCD patients in sub-Saharan Africa. As of April 2019, the database included 6,578 patients. The target is 13,000 patients.
Other goals of SPARCO and SADaCC are to “harmonize” SCD phenotype definitions and ontologies, create clinical guidelines for SCD management in sub-Saharan Africa, plan future cohort studies, and develop programs for newborn screening, infection prevention, and increased use of hydroxyurea.
“So far, they’re well along in establishing a registry and a database system,” Dr. Hoots said. “They’ve agreed on the database elements, phenotype definitions, and ontologies, they’ve developed some regionally appropriate clinical management guidelines, and they’ve begun skills development on the ground at all respective sites.”
REACH
Another program Dr. Hoots discussed is Realizing Effectiveness Across Continents With Hydroxyurea (REACH), a phase 1/2 pilot study of hydroxyurea in children (aged 1-10 years) with SCD in sub-Saharan Africa.
The goals of REACH are to determine the optimal dose of hydroxyurea in this population; teach African physicians how to administer hydroxyurea; assess the safety, feasibility, and benefits of hydroxyurea; study variability in response to hydroxyurea; gather data for the Research Electronic Data Capture database; and establish a research infrastructure for future collaborations.
Results from more than 600 children enrolled in REACH were presented at the 2018 annual meeting of the American Society of Hematology and simultaneously published in the New England Journal of Medicine (N Engl J Med. 2019 Jan 10; 380[2]:121-31).
SickleGenAfrica
SickleGenAfrica is part of the H3Africa consortium and aims to “build capacity for genomic research in Africa,” Dr. Hoots said.
Under this program, researchers will conduct three studies to test the hypothesis that genetic variation affects the defense against hemolysis and organ damage in patients with SCD. The researchers will study existing cohorts of SCD patients including children and adults.
Other goals of SickleGenAfrica are to establish a molecular hematology and sickle cell mouse core, an SCD biorepository core, a bioinformatics core, and an administrative core for the coordination of activities. The program will also be used to train “future science leaders” in SCD research, Dr. Hoots said.
SCDIC
Cheryl Anne Boyce, PhD, chief of the Implementation Science Branch at the Center for Translation Research and Implementation Science at NHLBI, discussed the United States–based Sickle Cell Disease Implementation Consortium (SCDIC).
“The goals of the consortium are to develop a registry in collaboration with other centers and the NHLBI, as well as a needs-based community assessment of the barriers to care for subjects with sickle cell disease,” Dr. Boyce said. “We also wanted to design implementation research studies that address the identified barriers to care.”
Dr. Boyce said the SCDIC’s registry is open to patients aged 15-45 years who have a confirmed SCD diagnosis, speak English, and are able to consent to and complete a survey. The registry has enrolled almost 2,400 patients from eight centers over 18 months.
The SCDIC has also performed a needs assessment that prompted the development of three implementation research studies. The first study involves using mobile health interventions to, ideally, increase patient adherence to hydroxyurea and improve provider knowledge of hydroxyurea.
With the second study, researchers aim to improve the care of SCD patients in the emergency department by using an inpatient portal. The goals of the third study are to establish a standard definition for unaffiliated patients, conduct a needs assessment for this group, and develop an intervention that can provide these patients with guideline-based SCD care.
Get Connected
Kim Smith-Whitley, MD, director of the Comprehensive Sickle Cell Center at the Children’s Hospital of Philadelphia and a board member of the Sickle Cell Disease Association of America (SCDAA), described Get Connected, “an information-sharing network and patient-powered registry” created by SCDAA.
Dr. Smith-Whitley said one purpose of Get Connected is to provide a network that facilitates “the distribution of information related to clinical care, research, health services, health policy, and advocacy.”
The network is open to families living with SCD and sickle cell trait, SCDAA member organizations, health care providers, clinical researchers, and community-based organizations.
Get Connected also includes a registry for SCD patients that stores information on their diagnosis and treatment, as well as online communities that can be used to share information and provide psychosocial support.
Thus far, Get Connected has enrolled 6,329 individuals. This includes 5,100 children and adults with SCD, 652 children and adults with sickle cell trait, and 577 nonpatients.
The webinar presenters did not disclose any conflicts of interest.
Researchers are leading several programs designed to serve the sickle cell community in the United States and sub-Saharan Africa, officials at the National Heart, Lung, and Blood Institute (NHLBI) said during a recent webinar.
One program based in the United States is focused on building a registry for patients with sickle cell disease (SCD) and conducting studies designed to improve SCD care. Another program involves building “an information-sharing network and patient-powered registry” in the United States.
The programs in sub-Saharan Africa were designed to establish a database of SCD patients, optimize the use of hydroxyurea in children with SCD, and aid genomic studies of SCD.
W. Keith Hoots, MD, director of the Division of Blood Diseases and Resources at NHLBI, began the webinar with an overview of the programs in sub-Saharan Africa. He described four programs with sites in nine countries (Angola, Cameroon, Democratic Republic of Congo, Ghana, Kenya, Nigeria, South Africa, Tanzania, and Uganda).
SPARCO and SADaCC
Dr. Hoots outlined the scope the Sickle Pan-African Research Consortium (SPARCO) and the Sickle Africa Data Coordinating Center (SADaCC), both part of the Sickle In Africa consortium.
A major goal of SPARCO and SADaCC is to create a Research Electronic Data Capture database that encompasses SCD patients in sub-Saharan Africa. As of April 2019, the database included 6,578 patients. The target is 13,000 patients.
Other goals of SPARCO and SADaCC are to “harmonize” SCD phenotype definitions and ontologies, create clinical guidelines for SCD management in sub-Saharan Africa, plan future cohort studies, and develop programs for newborn screening, infection prevention, and increased use of hydroxyurea.
“So far, they’re well along in establishing a registry and a database system,” Dr. Hoots said. “They’ve agreed on the database elements, phenotype definitions, and ontologies, they’ve developed some regionally appropriate clinical management guidelines, and they’ve begun skills development on the ground at all respective sites.”
REACH
Another program Dr. Hoots discussed is Realizing Effectiveness Across Continents With Hydroxyurea (REACH), a phase 1/2 pilot study of hydroxyurea in children (aged 1-10 years) with SCD in sub-Saharan Africa.
The goals of REACH are to determine the optimal dose of hydroxyurea in this population; teach African physicians how to administer hydroxyurea; assess the safety, feasibility, and benefits of hydroxyurea; study variability in response to hydroxyurea; gather data for the Research Electronic Data Capture database; and establish a research infrastructure for future collaborations.
Results from more than 600 children enrolled in REACH were presented at the 2018 annual meeting of the American Society of Hematology and simultaneously published in the New England Journal of Medicine (N Engl J Med. 2019 Jan 10; 380[2]:121-31).
SickleGenAfrica
SickleGenAfrica is part of the H3Africa consortium and aims to “build capacity for genomic research in Africa,” Dr. Hoots said.
Under this program, researchers will conduct three studies to test the hypothesis that genetic variation affects the defense against hemolysis and organ damage in patients with SCD. The researchers will study existing cohorts of SCD patients including children and adults.
Other goals of SickleGenAfrica are to establish a molecular hematology and sickle cell mouse core, an SCD biorepository core, a bioinformatics core, and an administrative core for the coordination of activities. The program will also be used to train “future science leaders” in SCD research, Dr. Hoots said.
SCDIC
Cheryl Anne Boyce, PhD, chief of the Implementation Science Branch at the Center for Translation Research and Implementation Science at NHLBI, discussed the United States–based Sickle Cell Disease Implementation Consortium (SCDIC).
“The goals of the consortium are to develop a registry in collaboration with other centers and the NHLBI, as well as a needs-based community assessment of the barriers to care for subjects with sickle cell disease,” Dr. Boyce said. “We also wanted to design implementation research studies that address the identified barriers to care.”
Dr. Boyce said the SCDIC’s registry is open to patients aged 15-45 years who have a confirmed SCD diagnosis, speak English, and are able to consent to and complete a survey. The registry has enrolled almost 2,400 patients from eight centers over 18 months.
The SCDIC has also performed a needs assessment that prompted the development of three implementation research studies. The first study involves using mobile health interventions to, ideally, increase patient adherence to hydroxyurea and improve provider knowledge of hydroxyurea.
With the second study, researchers aim to improve the care of SCD patients in the emergency department by using an inpatient portal. The goals of the third study are to establish a standard definition for unaffiliated patients, conduct a needs assessment for this group, and develop an intervention that can provide these patients with guideline-based SCD care.
Get Connected
Kim Smith-Whitley, MD, director of the Comprehensive Sickle Cell Center at the Children’s Hospital of Philadelphia and a board member of the Sickle Cell Disease Association of America (SCDAA), described Get Connected, “an information-sharing network and patient-powered registry” created by SCDAA.
Dr. Smith-Whitley said one purpose of Get Connected is to provide a network that facilitates “the distribution of information related to clinical care, research, health services, health policy, and advocacy.”
The network is open to families living with SCD and sickle cell trait, SCDAA member organizations, health care providers, clinical researchers, and community-based organizations.
Get Connected also includes a registry for SCD patients that stores information on their diagnosis and treatment, as well as online communities that can be used to share information and provide psychosocial support.
Thus far, Get Connected has enrolled 6,329 individuals. This includes 5,100 children and adults with SCD, 652 children and adults with sickle cell trait, and 577 nonpatients.
The webinar presenters did not disclose any conflicts of interest.
Researchers are leading several programs designed to serve the sickle cell community in the United States and sub-Saharan Africa, officials at the National Heart, Lung, and Blood Institute (NHLBI) said during a recent webinar.
One program based in the United States is focused on building a registry for patients with sickle cell disease (SCD) and conducting studies designed to improve SCD care. Another program involves building “an information-sharing network and patient-powered registry” in the United States.
The programs in sub-Saharan Africa were designed to establish a database of SCD patients, optimize the use of hydroxyurea in children with SCD, and aid genomic studies of SCD.
W. Keith Hoots, MD, director of the Division of Blood Diseases and Resources at NHLBI, began the webinar with an overview of the programs in sub-Saharan Africa. He described four programs with sites in nine countries (Angola, Cameroon, Democratic Republic of Congo, Ghana, Kenya, Nigeria, South Africa, Tanzania, and Uganda).
SPARCO and SADaCC
Dr. Hoots outlined the scope the Sickle Pan-African Research Consortium (SPARCO) and the Sickle Africa Data Coordinating Center (SADaCC), both part of the Sickle In Africa consortium.
A major goal of SPARCO and SADaCC is to create a Research Electronic Data Capture database that encompasses SCD patients in sub-Saharan Africa. As of April 2019, the database included 6,578 patients. The target is 13,000 patients.
Other goals of SPARCO and SADaCC are to “harmonize” SCD phenotype definitions and ontologies, create clinical guidelines for SCD management in sub-Saharan Africa, plan future cohort studies, and develop programs for newborn screening, infection prevention, and increased use of hydroxyurea.
“So far, they’re well along in establishing a registry and a database system,” Dr. Hoots said. “They’ve agreed on the database elements, phenotype definitions, and ontologies, they’ve developed some regionally appropriate clinical management guidelines, and they’ve begun skills development on the ground at all respective sites.”
REACH
Another program Dr. Hoots discussed is Realizing Effectiveness Across Continents With Hydroxyurea (REACH), a phase 1/2 pilot study of hydroxyurea in children (aged 1-10 years) with SCD in sub-Saharan Africa.
The goals of REACH are to determine the optimal dose of hydroxyurea in this population; teach African physicians how to administer hydroxyurea; assess the safety, feasibility, and benefits of hydroxyurea; study variability in response to hydroxyurea; gather data for the Research Electronic Data Capture database; and establish a research infrastructure for future collaborations.
Results from more than 600 children enrolled in REACH were presented at the 2018 annual meeting of the American Society of Hematology and simultaneously published in the New England Journal of Medicine (N Engl J Med. 2019 Jan 10; 380[2]:121-31).
SickleGenAfrica
SickleGenAfrica is part of the H3Africa consortium and aims to “build capacity for genomic research in Africa,” Dr. Hoots said.
Under this program, researchers will conduct three studies to test the hypothesis that genetic variation affects the defense against hemolysis and organ damage in patients with SCD. The researchers will study existing cohorts of SCD patients including children and adults.
Other goals of SickleGenAfrica are to establish a molecular hematology and sickle cell mouse core, an SCD biorepository core, a bioinformatics core, and an administrative core for the coordination of activities. The program will also be used to train “future science leaders” in SCD research, Dr. Hoots said.
SCDIC
Cheryl Anne Boyce, PhD, chief of the Implementation Science Branch at the Center for Translation Research and Implementation Science at NHLBI, discussed the United States–based Sickle Cell Disease Implementation Consortium (SCDIC).
“The goals of the consortium are to develop a registry in collaboration with other centers and the NHLBI, as well as a needs-based community assessment of the barriers to care for subjects with sickle cell disease,” Dr. Boyce said. “We also wanted to design implementation research studies that address the identified barriers to care.”
Dr. Boyce said the SCDIC’s registry is open to patients aged 15-45 years who have a confirmed SCD diagnosis, speak English, and are able to consent to and complete a survey. The registry has enrolled almost 2,400 patients from eight centers over 18 months.
The SCDIC has also performed a needs assessment that prompted the development of three implementation research studies. The first study involves using mobile health interventions to, ideally, increase patient adherence to hydroxyurea and improve provider knowledge of hydroxyurea.
With the second study, researchers aim to improve the care of SCD patients in the emergency department by using an inpatient portal. The goals of the third study are to establish a standard definition for unaffiliated patients, conduct a needs assessment for this group, and develop an intervention that can provide these patients with guideline-based SCD care.
Get Connected
Kim Smith-Whitley, MD, director of the Comprehensive Sickle Cell Center at the Children’s Hospital of Philadelphia and a board member of the Sickle Cell Disease Association of America (SCDAA), described Get Connected, “an information-sharing network and patient-powered registry” created by SCDAA.
Dr. Smith-Whitley said one purpose of Get Connected is to provide a network that facilitates “the distribution of information related to clinical care, research, health services, health policy, and advocacy.”
The network is open to families living with SCD and sickle cell trait, SCDAA member organizations, health care providers, clinical researchers, and community-based organizations.
Get Connected also includes a registry for SCD patients that stores information on their diagnosis and treatment, as well as online communities that can be used to share information and provide psychosocial support.
Thus far, Get Connected has enrolled 6,329 individuals. This includes 5,100 children and adults with SCD, 652 children and adults with sickle cell trait, and 577 nonpatients.
The webinar presenters did not disclose any conflicts of interest.
Mitapivat elicits positive response in pyruvate kinase deficiency
Mitapivat showed positive safety and efficacy outcomes in patients with pyruvate kinase deficiency, according to results from a phase 2 trial.
After 24 weeks of treatment, the therapy was associated with a rapid rise in hemoglobin levels in 50% of study participants, while the majority of toxicities reported were transient and low grade.
“The primary objective of this study was to assess the safety and side-effect profile of mitapivat administration in patients with pyruvate kinase deficiency,” wrote Rachael F. Grace, MD, of the Dana-Farber Cancer Institute and Harvard Medical School, Boston, and coinvestigators. The findings were published in the New England Journal of Medicine.
The uncontrolled study included 52 adults with pyruvate kinase deficiency who were not undergoing regular transfusions.
The median age at baseline was 34 years (range, 18-61 years), 62% of patients were male, and the median baseline hemoglobin level was 8.9 g/dL (range, 6.5-12.3 g/dL). In addition, 73% and 83% of patients had previously undergone cholecystectomy and splenectomy, respectively.
Study patients received oral mitapivat at 50 mg or 300 mg twice weekly for a total of 24 weeks. Eligible participants were subsequently enrolled into an extension phase that continued to monitor safety.
At 24 weeks, the team reported that 26 patients – 50% – experienced a greater than 1.0-g/dL rise in hemoglobin levels, with a maximum mean increase of 3.4 g/dL (range, 1.1-5.8 g/dL). The first rise of greater than 1.0 g/dL was observed after a median duration of 10 days (range, 7-187 days).
Of the 26 patients, 20 had an increase from baseline of more than 1.0 g/dL at more than half of the assessment during the core study period. That met the definition for hemoglobin response, according to the researchers.
“The hemoglobin response was maintained in the 19 patients who were continuing to be treated in the extension phase, all of whom had at least 21.6 months of treatment,” they wrote.
With respect to safety, the majority of adverse events were of low severity (grade 1-2) and transient in nature, with most resolving within 7 days. The most frequently reported toxicities in the core period and extension phase were headache (46%), insomnia (42%), and nausea (40%). The most serious reported toxicities were pharyngitis (4%) and hemolytic anemia (4%).
“Patient-reported quality of life was not assessed in this phase 2 safety study, although such outcome measures are being evaluated in the ongoing phase 3 trials,” Dr. Grace and colleagues wrote. “This study establishes proof of concept for a molecular therapy targeting the underlying enzymatic defect of a hereditary enzymopathy,” they concluded.
Agios Pharmaceuticals funded the study. Dr. Grace reported research funding from and consulting for Agios, and several authors reported employment, consulting, or research funding with the company.
SOURCE: Grace RF et al. N Engl J Med. 2019;381:933-44.
Mitapivat showed positive safety and efficacy outcomes in patients with pyruvate kinase deficiency, according to results from a phase 2 trial.
After 24 weeks of treatment, the therapy was associated with a rapid rise in hemoglobin levels in 50% of study participants, while the majority of toxicities reported were transient and low grade.
“The primary objective of this study was to assess the safety and side-effect profile of mitapivat administration in patients with pyruvate kinase deficiency,” wrote Rachael F. Grace, MD, of the Dana-Farber Cancer Institute and Harvard Medical School, Boston, and coinvestigators. The findings were published in the New England Journal of Medicine.
The uncontrolled study included 52 adults with pyruvate kinase deficiency who were not undergoing regular transfusions.
The median age at baseline was 34 years (range, 18-61 years), 62% of patients were male, and the median baseline hemoglobin level was 8.9 g/dL (range, 6.5-12.3 g/dL). In addition, 73% and 83% of patients had previously undergone cholecystectomy and splenectomy, respectively.
Study patients received oral mitapivat at 50 mg or 300 mg twice weekly for a total of 24 weeks. Eligible participants were subsequently enrolled into an extension phase that continued to monitor safety.
At 24 weeks, the team reported that 26 patients – 50% – experienced a greater than 1.0-g/dL rise in hemoglobin levels, with a maximum mean increase of 3.4 g/dL (range, 1.1-5.8 g/dL). The first rise of greater than 1.0 g/dL was observed after a median duration of 10 days (range, 7-187 days).
Of the 26 patients, 20 had an increase from baseline of more than 1.0 g/dL at more than half of the assessment during the core study period. That met the definition for hemoglobin response, according to the researchers.
“The hemoglobin response was maintained in the 19 patients who were continuing to be treated in the extension phase, all of whom had at least 21.6 months of treatment,” they wrote.
With respect to safety, the majority of adverse events were of low severity (grade 1-2) and transient in nature, with most resolving within 7 days. The most frequently reported toxicities in the core period and extension phase were headache (46%), insomnia (42%), and nausea (40%). The most serious reported toxicities were pharyngitis (4%) and hemolytic anemia (4%).
“Patient-reported quality of life was not assessed in this phase 2 safety study, although such outcome measures are being evaluated in the ongoing phase 3 trials,” Dr. Grace and colleagues wrote. “This study establishes proof of concept for a molecular therapy targeting the underlying enzymatic defect of a hereditary enzymopathy,” they concluded.
Agios Pharmaceuticals funded the study. Dr. Grace reported research funding from and consulting for Agios, and several authors reported employment, consulting, or research funding with the company.
SOURCE: Grace RF et al. N Engl J Med. 2019;381:933-44.
Mitapivat showed positive safety and efficacy outcomes in patients with pyruvate kinase deficiency, according to results from a phase 2 trial.
After 24 weeks of treatment, the therapy was associated with a rapid rise in hemoglobin levels in 50% of study participants, while the majority of toxicities reported were transient and low grade.
“The primary objective of this study was to assess the safety and side-effect profile of mitapivat administration in patients with pyruvate kinase deficiency,” wrote Rachael F. Grace, MD, of the Dana-Farber Cancer Institute and Harvard Medical School, Boston, and coinvestigators. The findings were published in the New England Journal of Medicine.
The uncontrolled study included 52 adults with pyruvate kinase deficiency who were not undergoing regular transfusions.
The median age at baseline was 34 years (range, 18-61 years), 62% of patients were male, and the median baseline hemoglobin level was 8.9 g/dL (range, 6.5-12.3 g/dL). In addition, 73% and 83% of patients had previously undergone cholecystectomy and splenectomy, respectively.
Study patients received oral mitapivat at 50 mg or 300 mg twice weekly for a total of 24 weeks. Eligible participants were subsequently enrolled into an extension phase that continued to monitor safety.
At 24 weeks, the team reported that 26 patients – 50% – experienced a greater than 1.0-g/dL rise in hemoglobin levels, with a maximum mean increase of 3.4 g/dL (range, 1.1-5.8 g/dL). The first rise of greater than 1.0 g/dL was observed after a median duration of 10 days (range, 7-187 days).
Of the 26 patients, 20 had an increase from baseline of more than 1.0 g/dL at more than half of the assessment during the core study period. That met the definition for hemoglobin response, according to the researchers.
“The hemoglobin response was maintained in the 19 patients who were continuing to be treated in the extension phase, all of whom had at least 21.6 months of treatment,” they wrote.
With respect to safety, the majority of adverse events were of low severity (grade 1-2) and transient in nature, with most resolving within 7 days. The most frequently reported toxicities in the core period and extension phase were headache (46%), insomnia (42%), and nausea (40%). The most serious reported toxicities were pharyngitis (4%) and hemolytic anemia (4%).
“Patient-reported quality of life was not assessed in this phase 2 safety study, although such outcome measures are being evaluated in the ongoing phase 3 trials,” Dr. Grace and colleagues wrote. “This study establishes proof of concept for a molecular therapy targeting the underlying enzymatic defect of a hereditary enzymopathy,” they concluded.
Agios Pharmaceuticals funded the study. Dr. Grace reported research funding from and consulting for Agios, and several authors reported employment, consulting, or research funding with the company.
SOURCE: Grace RF et al. N Engl J Med. 2019;381:933-44.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: Major finding: At 24 weeks, 50% of patients experienced a greater than 1.0-g/dL rise in hemoglobin levels, with a maximum mean increase of 3.4 g/dL (range, 1.1-5.8 g/dL).
Study details: A phase 2 study of 52 patients with pyruvate kinase deficiency.
Disclosures: Agios Pharmaceuticals funded the study. Dr. Grace reported research funding from and consulting for Agios, and several authors reported employment, consulting, or research funding with the company.
Source: Grace RF et al. N Engl J Med. 2019;381:933-44.
Quercetin may reduce iron overload in beta-thalassemia major
Combination quercetin and desferrioxamine could decrease iron overload in patients with transfusion-dependent beta-thalassemia major, according to a randomized clinical study.
Over the course of treatment, quercetin was well tolerated and no major complications were reported. The findings highlight the potential of quercetin to lower ferritin levels in patients with thalassemia major.
“Quercetin is a member of flavone family that mainly exists in apples, onions, tea, red wines, and berries,” wrote Zohreh Sajadi Hezaveh of Iran University of Medical Sciences in Tehran and colleagues. The findings of the study were published in Complementary Therapies in Medicine.
The researchers conducted a randomized, double-blind trial of 84 patients with thalassemia major. Of those enrolled, 71 patients were included in the final analysis.
Study patients were randomly assigned to receive either oral quercetin 500 mg daily or placebo for a total of 12 weeks. At baseline, all patients received desferrioxamine monotherapy. All participants were enrolled in the single-center study from April 2017 to March 2018. The team measured several inflammatory and iron-related markers during the study.
In comparison with placebo, combined therapy significantly improved high sensitivity C-reactive protein (P = .046), ferritin (P = .043), serum iron (P = .036), transferrin (P = .045), and transferrin saturation (P = .008), but not tumor necrosis factor–alpha (P = .310) or total iron-binding capacity (P = .734).
With respect to ferritin levels, a significant decrease was observed in the quercetin group, while patients in the placebo group had a marginal increase in levels.
“Insignificant results for [tumor necrosis factor–alpha] prevents us from making definitive comments [about inflammation],” the researchers wrote.
One key limitation of the study was the significant loss to follow-up seen in the placebo group. As a result, the generalizability of the findings may be limited.
“These results need to be confirmed by studies with larger sample size, longer follow-up period, and different doses of quercetin,” the researchers concluded.
The study was funded by the Iran University of Medical Sciences. The authors reported having no conflicts of interest.
SOURCE: Sajadi Hezaveh Z et al. Complement Ther Med. 2019;46:24-8.
Combination quercetin and desferrioxamine could decrease iron overload in patients with transfusion-dependent beta-thalassemia major, according to a randomized clinical study.
Over the course of treatment, quercetin was well tolerated and no major complications were reported. The findings highlight the potential of quercetin to lower ferritin levels in patients with thalassemia major.
“Quercetin is a member of flavone family that mainly exists in apples, onions, tea, red wines, and berries,” wrote Zohreh Sajadi Hezaveh of Iran University of Medical Sciences in Tehran and colleagues. The findings of the study were published in Complementary Therapies in Medicine.
The researchers conducted a randomized, double-blind trial of 84 patients with thalassemia major. Of those enrolled, 71 patients were included in the final analysis.
Study patients were randomly assigned to receive either oral quercetin 500 mg daily or placebo for a total of 12 weeks. At baseline, all patients received desferrioxamine monotherapy. All participants were enrolled in the single-center study from April 2017 to March 2018. The team measured several inflammatory and iron-related markers during the study.
In comparison with placebo, combined therapy significantly improved high sensitivity C-reactive protein (P = .046), ferritin (P = .043), serum iron (P = .036), transferrin (P = .045), and transferrin saturation (P = .008), but not tumor necrosis factor–alpha (P = .310) or total iron-binding capacity (P = .734).
With respect to ferritin levels, a significant decrease was observed in the quercetin group, while patients in the placebo group had a marginal increase in levels.
“Insignificant results for [tumor necrosis factor–alpha] prevents us from making definitive comments [about inflammation],” the researchers wrote.
One key limitation of the study was the significant loss to follow-up seen in the placebo group. As a result, the generalizability of the findings may be limited.
“These results need to be confirmed by studies with larger sample size, longer follow-up period, and different doses of quercetin,” the researchers concluded.
The study was funded by the Iran University of Medical Sciences. The authors reported having no conflicts of interest.
SOURCE: Sajadi Hezaveh Z et al. Complement Ther Med. 2019;46:24-8.
Combination quercetin and desferrioxamine could decrease iron overload in patients with transfusion-dependent beta-thalassemia major, according to a randomized clinical study.
Over the course of treatment, quercetin was well tolerated and no major complications were reported. The findings highlight the potential of quercetin to lower ferritin levels in patients with thalassemia major.
“Quercetin is a member of flavone family that mainly exists in apples, onions, tea, red wines, and berries,” wrote Zohreh Sajadi Hezaveh of Iran University of Medical Sciences in Tehran and colleagues. The findings of the study were published in Complementary Therapies in Medicine.
The researchers conducted a randomized, double-blind trial of 84 patients with thalassemia major. Of those enrolled, 71 patients were included in the final analysis.
Study patients were randomly assigned to receive either oral quercetin 500 mg daily or placebo for a total of 12 weeks. At baseline, all patients received desferrioxamine monotherapy. All participants were enrolled in the single-center study from April 2017 to March 2018. The team measured several inflammatory and iron-related markers during the study.
In comparison with placebo, combined therapy significantly improved high sensitivity C-reactive protein (P = .046), ferritin (P = .043), serum iron (P = .036), transferrin (P = .045), and transferrin saturation (P = .008), but not tumor necrosis factor–alpha (P = .310) or total iron-binding capacity (P = .734).
With respect to ferritin levels, a significant decrease was observed in the quercetin group, while patients in the placebo group had a marginal increase in levels.
“Insignificant results for [tumor necrosis factor–alpha] prevents us from making definitive comments [about inflammation],” the researchers wrote.
One key limitation of the study was the significant loss to follow-up seen in the placebo group. As a result, the generalizability of the findings may be limited.
“These results need to be confirmed by studies with larger sample size, longer follow-up period, and different doses of quercetin,” the researchers concluded.
The study was funded by the Iran University of Medical Sciences. The authors reported having no conflicts of interest.
SOURCE: Sajadi Hezaveh Z et al. Complement Ther Med. 2019;46:24-8.
FROM COMPLEMENTARY THERAPIES IN MEDICINE