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Sickle cell disease phenotype reversed by gene therapy
SAN DIEGO – An adult with sickle cell disease has had significant remissions in symptoms and a near elimination of transfusion requirements after receiving an infusion of autologous stem cells genetically modified to simultaneously induce the fetal form of hemoglobin and decrease sickle hemoglobin.
In a first-in-human, proof-of-concept study, transduction of hematopoietic stem cells with a lentiviral vector targeted against the gamma globin repressor BCL11A in erythroid cells led to rapid induction of fetal hemoglobin and a reversal of the sickle cell disease (SCD) phenotype in the early phase of stem cell reconstitution, reported Erica B. Esrick, MD, from the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center in Boston.
“The potential advantage of this approach over the gene-addition strategy of gene therapy is that we can harness the physiologic switch machinery that exists in the cell to simultaneously increase fetal hemoglobin and decrease sickle hemoglobin,” she said at a briefing prior to her presentation at the annual meeting of the American Society of Hematology.
Several research groups are developing autologous gene therapy for beta-hemoglobinopathies, including the use of CRISPR-Cas9 technology to mimic a rare, naturally occurring mutation that causes the fetal type of hemoglobin to persist into adulthood in some patients with SCD and beta-thalassemia.
Dr. Esrick and her colleagues are trying a different approach: Using gene therapy to knock down BCL11A expression to induce gamma globin expression.
For the treatment, autologous hematopoietic stem cells are collected from patients following mobilization with plerixafor. The cells are then transduced with a lentiviral vector consisting of a novel short hairpin RNA embedded in an endogenous micro-RNA. The investigators refer to the construct as a shmiR (“schmeer”). The construct is designed to be erythroid specific, with BCL11A knocked down only in the red cell lineage, to avoid potential off-target effects of the therapy.
Following stem cell collection and transduction, patients undergo conditioning with busulfan prior to infusion of the modified stem cells.
In three patients treated thus far, the process has been shown to be highly efficient, with approximately 96% of treated cells transduced.
In the patient mentioned before, neutrophil engraftment was confirmed on day 22 after transfusion of the modified cells. He experienced adverse events that were consistent with myeloablative conditioning, but no adverse events associated with the modified cells.
During 6 months of follow-up the patient did not experience SCD-related pain, respiratory events, or neurologic events, and did not have anemia, with a total hemoglobin of 11 g/dL at 6 months. He has not required any transfusions since engraftment.
Patients in the trial will be followed for 2 years, and then will be enrolled in a 15-year follow-up study designed to evaluate the safety and the durability of therapy.
Dr. Esrick reported receiving honoraria from Bluebird Bio, maker of the short hairpin RNA construct used in the trial.
SOURCE: Esrick EB et al. ASH 2018, Abstract 1023.
SAN DIEGO – An adult with sickle cell disease has had significant remissions in symptoms and a near elimination of transfusion requirements after receiving an infusion of autologous stem cells genetically modified to simultaneously induce the fetal form of hemoglobin and decrease sickle hemoglobin.
In a first-in-human, proof-of-concept study, transduction of hematopoietic stem cells with a lentiviral vector targeted against the gamma globin repressor BCL11A in erythroid cells led to rapid induction of fetal hemoglobin and a reversal of the sickle cell disease (SCD) phenotype in the early phase of stem cell reconstitution, reported Erica B. Esrick, MD, from the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center in Boston.
“The potential advantage of this approach over the gene-addition strategy of gene therapy is that we can harness the physiologic switch machinery that exists in the cell to simultaneously increase fetal hemoglobin and decrease sickle hemoglobin,” she said at a briefing prior to her presentation at the annual meeting of the American Society of Hematology.
Several research groups are developing autologous gene therapy for beta-hemoglobinopathies, including the use of CRISPR-Cas9 technology to mimic a rare, naturally occurring mutation that causes the fetal type of hemoglobin to persist into adulthood in some patients with SCD and beta-thalassemia.
Dr. Esrick and her colleagues are trying a different approach: Using gene therapy to knock down BCL11A expression to induce gamma globin expression.
For the treatment, autologous hematopoietic stem cells are collected from patients following mobilization with plerixafor. The cells are then transduced with a lentiviral vector consisting of a novel short hairpin RNA embedded in an endogenous micro-RNA. The investigators refer to the construct as a shmiR (“schmeer”). The construct is designed to be erythroid specific, with BCL11A knocked down only in the red cell lineage, to avoid potential off-target effects of the therapy.
Following stem cell collection and transduction, patients undergo conditioning with busulfan prior to infusion of the modified stem cells.
In three patients treated thus far, the process has been shown to be highly efficient, with approximately 96% of treated cells transduced.
In the patient mentioned before, neutrophil engraftment was confirmed on day 22 after transfusion of the modified cells. He experienced adverse events that were consistent with myeloablative conditioning, but no adverse events associated with the modified cells.
During 6 months of follow-up the patient did not experience SCD-related pain, respiratory events, or neurologic events, and did not have anemia, with a total hemoglobin of 11 g/dL at 6 months. He has not required any transfusions since engraftment.
Patients in the trial will be followed for 2 years, and then will be enrolled in a 15-year follow-up study designed to evaluate the safety and the durability of therapy.
Dr. Esrick reported receiving honoraria from Bluebird Bio, maker of the short hairpin RNA construct used in the trial.
SOURCE: Esrick EB et al. ASH 2018, Abstract 1023.
SAN DIEGO – An adult with sickle cell disease has had significant remissions in symptoms and a near elimination of transfusion requirements after receiving an infusion of autologous stem cells genetically modified to simultaneously induce the fetal form of hemoglobin and decrease sickle hemoglobin.
In a first-in-human, proof-of-concept study, transduction of hematopoietic stem cells with a lentiviral vector targeted against the gamma globin repressor BCL11A in erythroid cells led to rapid induction of fetal hemoglobin and a reversal of the sickle cell disease (SCD) phenotype in the early phase of stem cell reconstitution, reported Erica B. Esrick, MD, from the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center in Boston.
“The potential advantage of this approach over the gene-addition strategy of gene therapy is that we can harness the physiologic switch machinery that exists in the cell to simultaneously increase fetal hemoglobin and decrease sickle hemoglobin,” she said at a briefing prior to her presentation at the annual meeting of the American Society of Hematology.
Several research groups are developing autologous gene therapy for beta-hemoglobinopathies, including the use of CRISPR-Cas9 technology to mimic a rare, naturally occurring mutation that causes the fetal type of hemoglobin to persist into adulthood in some patients with SCD and beta-thalassemia.
Dr. Esrick and her colleagues are trying a different approach: Using gene therapy to knock down BCL11A expression to induce gamma globin expression.
For the treatment, autologous hematopoietic stem cells are collected from patients following mobilization with plerixafor. The cells are then transduced with a lentiviral vector consisting of a novel short hairpin RNA embedded in an endogenous micro-RNA. The investigators refer to the construct as a shmiR (“schmeer”). The construct is designed to be erythroid specific, with BCL11A knocked down only in the red cell lineage, to avoid potential off-target effects of the therapy.
Following stem cell collection and transduction, patients undergo conditioning with busulfan prior to infusion of the modified stem cells.
In three patients treated thus far, the process has been shown to be highly efficient, with approximately 96% of treated cells transduced.
In the patient mentioned before, neutrophil engraftment was confirmed on day 22 after transfusion of the modified cells. He experienced adverse events that were consistent with myeloablative conditioning, but no adverse events associated with the modified cells.
During 6 months of follow-up the patient did not experience SCD-related pain, respiratory events, or neurologic events, and did not have anemia, with a total hemoglobin of 11 g/dL at 6 months. He has not required any transfusions since engraftment.
Patients in the trial will be followed for 2 years, and then will be enrolled in a 15-year follow-up study designed to evaluate the safety and the durability of therapy.
Dr. Esrick reported receiving honoraria from Bluebird Bio, maker of the short hairpin RNA construct used in the trial.
SOURCE: Esrick EB et al. ASH 2018, Abstract 1023.
REPORTING FROM ASH 2018
Key clinical point: Gene therapy to induce the fetal form of hemoglobin reversed the symptoms of sickle cell disease in an adult patient.
Major finding: During 6 months of follow-up the patient did not experience sickle cell disease–related pain, respiratory events, or neurologic events, and did not have anemia.
Study details: A first-in-human study in seven adults with sickle cell disease.
Disclosures: Dr. Esrick reported receiving honoraria from Bluebird Bio, maker of the short hairpin RNA construct used in the trial.
Source: Esrick EB et al. ASH 2018, Abstract 1023.
New brain circuitry found with Parkinson’s disease gene therapy
A gene therapy for Parkinson’s disease, focusing on the subthalamic nucleus, appears to lead to the formation of unique brain circuitry that correlates with clinical improvement.
In a paper published online Nov. 28 in Science Translational Medicine, researchers describe the findings of a metabolic imaging study to explore the mechanism underlying benefits seen in a phase 2, blinded, sham-controlled clinical trial of the gene therapy.
The therapy in question used an adeno-associated viral vector to deliver the gene for glutamic acid decarboxylase into the subthalamic nucleus – a region of the brain known to be overactivated in Parkinson’s disease – which was intended to have an inhibitory effect on the neurons in that region.
Martin Niethammer, MD, PhD, of the Center for Neurosciences at The Feinstein Institute for Medical Research in New York, and his coauthors used 18F-fluorodeoxyglucose positron emission tomography at baseline, 6, and 12 months in 15 gene-therapy patients and 21 sham-treated patients, which revealed the development of new brain circuits in patients treated with the gene therapy.
The circuits, which researchers called the glutamic acid decarboxylase-related pattern, or GADRP, presented with increased metabolism in the premotor region – which also extended into the adjacent motor cortex – and in the supramarginal gyrus. There was also decreased metabolic activity in the caudate, anterior putamen, and adjacent globus pallidus; the ventral anterior and medial dorsal thalamic nuclei; and in the inferior frontal gyrus.
All 15 patients who received the gene therapy showed significant trends in GADRP expression after the treatment, compared with patients who underwent the sham procedure. Furthermore, these correlated significantly with improved clinical outcomes.
The imaging also revealed increased connectivity between regions in the GADRP space among patients who received the gene therapy, with researchers noting five new intrahemispheric node-to-node connections in these patients that were not seen in the sham procedure group.
These included connection linking the left caudate nucleus to the left superior frontal node, the right superior frontal node to the right supramarginal gyrus, and linking the left anterior putamen and globus pallidus with the ipsilateral thalamic node.
The authors also found that overall connectivity in the network rose to “abnormal” levels in the 12 months after gene therapy, while no similar increases were seen in the sham group.
Given that deep brain stimulation for Parkinson’s disease also targets the subthalamic nucleus, researchers looked at changes to the GADRP network in these patients, compared with those who received sham therapy and those who received gene therapy.
They saw that changes in GADRP expression were significantly different between the gene therapy-treated patients and those treated with deep brain stimulation and sham surgery. However, the differences between deep brain stimulation and sham surgery were not significant.
“The current study indicates that customized networks can be characterized using functional imaging data acquired in randomized, controlled phase 2 clinical trials and, if validated, could be used as quantitative outcome measures in more definitive, later-stage clinical trials,” the authors wrote.
The study was supported by Neurologix. Two authors were consultants and stockholders of MeiraGTx.
SOURCE: Niethammer N et al. Sci Transl Med. 2018 Nov 28. doi: 10.1126/scitranslmed.aau0713.
A gene therapy for Parkinson’s disease, focusing on the subthalamic nucleus, appears to lead to the formation of unique brain circuitry that correlates with clinical improvement.
In a paper published online Nov. 28 in Science Translational Medicine, researchers describe the findings of a metabolic imaging study to explore the mechanism underlying benefits seen in a phase 2, blinded, sham-controlled clinical trial of the gene therapy.
The therapy in question used an adeno-associated viral vector to deliver the gene for glutamic acid decarboxylase into the subthalamic nucleus – a region of the brain known to be overactivated in Parkinson’s disease – which was intended to have an inhibitory effect on the neurons in that region.
Martin Niethammer, MD, PhD, of the Center for Neurosciences at The Feinstein Institute for Medical Research in New York, and his coauthors used 18F-fluorodeoxyglucose positron emission tomography at baseline, 6, and 12 months in 15 gene-therapy patients and 21 sham-treated patients, which revealed the development of new brain circuits in patients treated with the gene therapy.
The circuits, which researchers called the glutamic acid decarboxylase-related pattern, or GADRP, presented with increased metabolism in the premotor region – which also extended into the adjacent motor cortex – and in the supramarginal gyrus. There was also decreased metabolic activity in the caudate, anterior putamen, and adjacent globus pallidus; the ventral anterior and medial dorsal thalamic nuclei; and in the inferior frontal gyrus.
All 15 patients who received the gene therapy showed significant trends in GADRP expression after the treatment, compared with patients who underwent the sham procedure. Furthermore, these correlated significantly with improved clinical outcomes.
The imaging also revealed increased connectivity between regions in the GADRP space among patients who received the gene therapy, with researchers noting five new intrahemispheric node-to-node connections in these patients that were not seen in the sham procedure group.
These included connection linking the left caudate nucleus to the left superior frontal node, the right superior frontal node to the right supramarginal gyrus, and linking the left anterior putamen and globus pallidus with the ipsilateral thalamic node.
The authors also found that overall connectivity in the network rose to “abnormal” levels in the 12 months after gene therapy, while no similar increases were seen in the sham group.
Given that deep brain stimulation for Parkinson’s disease also targets the subthalamic nucleus, researchers looked at changes to the GADRP network in these patients, compared with those who received sham therapy and those who received gene therapy.
They saw that changes in GADRP expression were significantly different between the gene therapy-treated patients and those treated with deep brain stimulation and sham surgery. However, the differences between deep brain stimulation and sham surgery were not significant.
“The current study indicates that customized networks can be characterized using functional imaging data acquired in randomized, controlled phase 2 clinical trials and, if validated, could be used as quantitative outcome measures in more definitive, later-stage clinical trials,” the authors wrote.
The study was supported by Neurologix. Two authors were consultants and stockholders of MeiraGTx.
SOURCE: Niethammer N et al. Sci Transl Med. 2018 Nov 28. doi: 10.1126/scitranslmed.aau0713.
A gene therapy for Parkinson’s disease, focusing on the subthalamic nucleus, appears to lead to the formation of unique brain circuitry that correlates with clinical improvement.
In a paper published online Nov. 28 in Science Translational Medicine, researchers describe the findings of a metabolic imaging study to explore the mechanism underlying benefits seen in a phase 2, blinded, sham-controlled clinical trial of the gene therapy.
The therapy in question used an adeno-associated viral vector to deliver the gene for glutamic acid decarboxylase into the subthalamic nucleus – a region of the brain known to be overactivated in Parkinson’s disease – which was intended to have an inhibitory effect on the neurons in that region.
Martin Niethammer, MD, PhD, of the Center for Neurosciences at The Feinstein Institute for Medical Research in New York, and his coauthors used 18F-fluorodeoxyglucose positron emission tomography at baseline, 6, and 12 months in 15 gene-therapy patients and 21 sham-treated patients, which revealed the development of new brain circuits in patients treated with the gene therapy.
The circuits, which researchers called the glutamic acid decarboxylase-related pattern, or GADRP, presented with increased metabolism in the premotor region – which also extended into the adjacent motor cortex – and in the supramarginal gyrus. There was also decreased metabolic activity in the caudate, anterior putamen, and adjacent globus pallidus; the ventral anterior and medial dorsal thalamic nuclei; and in the inferior frontal gyrus.
All 15 patients who received the gene therapy showed significant trends in GADRP expression after the treatment, compared with patients who underwent the sham procedure. Furthermore, these correlated significantly with improved clinical outcomes.
The imaging also revealed increased connectivity between regions in the GADRP space among patients who received the gene therapy, with researchers noting five new intrahemispheric node-to-node connections in these patients that were not seen in the sham procedure group.
These included connection linking the left caudate nucleus to the left superior frontal node, the right superior frontal node to the right supramarginal gyrus, and linking the left anterior putamen and globus pallidus with the ipsilateral thalamic node.
The authors also found that overall connectivity in the network rose to “abnormal” levels in the 12 months after gene therapy, while no similar increases were seen in the sham group.
Given that deep brain stimulation for Parkinson’s disease also targets the subthalamic nucleus, researchers looked at changes to the GADRP network in these patients, compared with those who received sham therapy and those who received gene therapy.
They saw that changes in GADRP expression were significantly different between the gene therapy-treated patients and those treated with deep brain stimulation and sham surgery. However, the differences between deep brain stimulation and sham surgery were not significant.
“The current study indicates that customized networks can be characterized using functional imaging data acquired in randomized, controlled phase 2 clinical trials and, if validated, could be used as quantitative outcome measures in more definitive, later-stage clinical trials,” the authors wrote.
The study was supported by Neurologix. Two authors were consultants and stockholders of MeiraGTx.
SOURCE: Niethammer N et al. Sci Transl Med. 2018 Nov 28. doi: 10.1126/scitranslmed.aau0713.
FROM SCIENCE TRANSLATIONAL MEDICINE
Key clinical point:
Major finding: Gene therapy for Parkinson’s disease was associated with increased brain connectivity.
Study details: A phase 2, blinded, sham-controlled study of 36 patients with Parkinson’s disease.
Disclosures: The study was supported by Neurologix. Two authors were consultants and stockholders of MeiraGTx.
Source: Niethammer N et al. Sci Transl Med. 2018 Nov 28. doi: 10.1126/scitranslmed.aau0713.
Ins and outs of SCD treatment to be covered at ASH
Sickle cell disease (SCD) will take center stage at the 2018 ASH Annual Meeting, according to a recent press briefing.
During the briefing, ASH President Alexis A. Thompson, MD, highlighted four “abstracts to watch” that focus on SCD.
These abstracts cover a pilot study of gene therapy, long-term outcomes of haploidentical hematopoietic stem cell transplant (haplo-HSCT), mortality rates in SCD patients prescribed opioids, and outcomes with hydroxyurea (HU) among patients in sub-Saharan Africa.
“These are all quite different aspects of work being done,” said Dr. Thompson, of Ann and Robert H. Lurie Children’s Hospital of Chicago in Illinois.
Gene therapy
In the pilot study of gene therapy (abstract 1023), investigators used a microRNA-adapted short hairpin RNA lentiviral vector targeting BCL11A for autologous gene therapy in SCD patients.
Preclinical research had shown that this approach could induce fetal hemoglobin in human erythroid cells and “largely” attenuate the hematologic effects of SCD in a murine model, according to investigators.
Initial results from the pilot study suggest this approach is feasible in humans as well. In the first patient infused, investigators observed “rapid” induction of fetal hemoglobin and “marked attenuation of hemolysis in the early phase of autologous reconstitution.”
“We’re looking forward to seeing this initial presentation on their findings with this first administration to humans,” Dr. Thompson said.
Haplo-HSCT
In another study (abstract 162), investigators assessed long-term health-related quality of life in high-risk SCD patients who underwent familial haplo-HSCT.
The patients received myeloablative conditioning and familial haplo-HSCT using CD34 enrichment and mononuclear cell (CD3) addback.
Two years from haplo-HSCT, patients had significant improvements in emotional and physical health-related quality of life, among other outcomes of interest, including neurocognitive outcomes.
Opioid use
A third study (abstract 315) indicates that opioid use is not associated with in-hospital mortality in SCD patients.
This is interesting in the context of the national opioid epidemic, Dr. Thompson said.
Investigators looked at data from the National Inpatient Sample and found no significant increase in in-hospital mortality in SCD patients from 1998 through 2013. This can be compared to the 350% increase in non-SCD opioid prescription-related deaths from 1999 through 2013.
“It should alleviate many concerns about patients with sickle cell who, for legitimate reasons, may require high doses of opioids,” Dr. Thompson said. “While I think we’re being very mindful about opioid use in this patient population, they certainly do need these high doses, but there does not seem to be an extraordinary risk of death associated with their use.”
HU in sub-Saharan Africa
Dr. Thompson said a fourth study worth watching is REACH (abstract 3), a trial of HU in 635 children in sub-Saharan Africa.
The study provides the first prospective data showing the feasibility, safety, and benefits of HU use in this population, according to investigators.
The findings are “quite encouraging,” Dr. Thompson said.
She added that the results looked “very similar” to the United States experience and demonstrated effective clinical trial design and execution in a lower-resource country.
Sickle cell disease (SCD) will take center stage at the 2018 ASH Annual Meeting, according to a recent press briefing.
During the briefing, ASH President Alexis A. Thompson, MD, highlighted four “abstracts to watch” that focus on SCD.
These abstracts cover a pilot study of gene therapy, long-term outcomes of haploidentical hematopoietic stem cell transplant (haplo-HSCT), mortality rates in SCD patients prescribed opioids, and outcomes with hydroxyurea (HU) among patients in sub-Saharan Africa.
“These are all quite different aspects of work being done,” said Dr. Thompson, of Ann and Robert H. Lurie Children’s Hospital of Chicago in Illinois.
Gene therapy
In the pilot study of gene therapy (abstract 1023), investigators used a microRNA-adapted short hairpin RNA lentiviral vector targeting BCL11A for autologous gene therapy in SCD patients.
Preclinical research had shown that this approach could induce fetal hemoglobin in human erythroid cells and “largely” attenuate the hematologic effects of SCD in a murine model, according to investigators.
Initial results from the pilot study suggest this approach is feasible in humans as well. In the first patient infused, investigators observed “rapid” induction of fetal hemoglobin and “marked attenuation of hemolysis in the early phase of autologous reconstitution.”
“We’re looking forward to seeing this initial presentation on their findings with this first administration to humans,” Dr. Thompson said.
Haplo-HSCT
In another study (abstract 162), investigators assessed long-term health-related quality of life in high-risk SCD patients who underwent familial haplo-HSCT.
The patients received myeloablative conditioning and familial haplo-HSCT using CD34 enrichment and mononuclear cell (CD3) addback.
Two years from haplo-HSCT, patients had significant improvements in emotional and physical health-related quality of life, among other outcomes of interest, including neurocognitive outcomes.
Opioid use
A third study (abstract 315) indicates that opioid use is not associated with in-hospital mortality in SCD patients.
This is interesting in the context of the national opioid epidemic, Dr. Thompson said.
Investigators looked at data from the National Inpatient Sample and found no significant increase in in-hospital mortality in SCD patients from 1998 through 2013. This can be compared to the 350% increase in non-SCD opioid prescription-related deaths from 1999 through 2013.
“It should alleviate many concerns about patients with sickle cell who, for legitimate reasons, may require high doses of opioids,” Dr. Thompson said. “While I think we’re being very mindful about opioid use in this patient population, they certainly do need these high doses, but there does not seem to be an extraordinary risk of death associated with their use.”
HU in sub-Saharan Africa
Dr. Thompson said a fourth study worth watching is REACH (abstract 3), a trial of HU in 635 children in sub-Saharan Africa.
The study provides the first prospective data showing the feasibility, safety, and benefits of HU use in this population, according to investigators.
The findings are “quite encouraging,” Dr. Thompson said.
She added that the results looked “very similar” to the United States experience and demonstrated effective clinical trial design and execution in a lower-resource country.
Sickle cell disease (SCD) will take center stage at the 2018 ASH Annual Meeting, according to a recent press briefing.
During the briefing, ASH President Alexis A. Thompson, MD, highlighted four “abstracts to watch” that focus on SCD.
These abstracts cover a pilot study of gene therapy, long-term outcomes of haploidentical hematopoietic stem cell transplant (haplo-HSCT), mortality rates in SCD patients prescribed opioids, and outcomes with hydroxyurea (HU) among patients in sub-Saharan Africa.
“These are all quite different aspects of work being done,” said Dr. Thompson, of Ann and Robert H. Lurie Children’s Hospital of Chicago in Illinois.
Gene therapy
In the pilot study of gene therapy (abstract 1023), investigators used a microRNA-adapted short hairpin RNA lentiviral vector targeting BCL11A for autologous gene therapy in SCD patients.
Preclinical research had shown that this approach could induce fetal hemoglobin in human erythroid cells and “largely” attenuate the hematologic effects of SCD in a murine model, according to investigators.
Initial results from the pilot study suggest this approach is feasible in humans as well. In the first patient infused, investigators observed “rapid” induction of fetal hemoglobin and “marked attenuation of hemolysis in the early phase of autologous reconstitution.”
“We’re looking forward to seeing this initial presentation on their findings with this first administration to humans,” Dr. Thompson said.
Haplo-HSCT
In another study (abstract 162), investigators assessed long-term health-related quality of life in high-risk SCD patients who underwent familial haplo-HSCT.
The patients received myeloablative conditioning and familial haplo-HSCT using CD34 enrichment and mononuclear cell (CD3) addback.
Two years from haplo-HSCT, patients had significant improvements in emotional and physical health-related quality of life, among other outcomes of interest, including neurocognitive outcomes.
Opioid use
A third study (abstract 315) indicates that opioid use is not associated with in-hospital mortality in SCD patients.
This is interesting in the context of the national opioid epidemic, Dr. Thompson said.
Investigators looked at data from the National Inpatient Sample and found no significant increase in in-hospital mortality in SCD patients from 1998 through 2013. This can be compared to the 350% increase in non-SCD opioid prescription-related deaths from 1999 through 2013.
“It should alleviate many concerns about patients with sickle cell who, for legitimate reasons, may require high doses of opioids,” Dr. Thompson said. “While I think we’re being very mindful about opioid use in this patient population, they certainly do need these high doses, but there does not seem to be an extraordinary risk of death associated with their use.”
HU in sub-Saharan Africa
Dr. Thompson said a fourth study worth watching is REACH (abstract 3), a trial of HU in 635 children in sub-Saharan Africa.
The study provides the first prospective data showing the feasibility, safety, and benefits of HU use in this population, according to investigators.
The findings are “quite encouraging,” Dr. Thompson said.
She added that the results looked “very similar” to the United States experience and demonstrated effective clinical trial design and execution in a lower-resource country.
Sickle cell disease: What to watch at ASH
Sickle cell disease will take center stage at the annual meeting of the American Society of Hematology.
, long-term outcomes of haploidentical transplants, mortality rates in patients prescribed opioids, and aspects of care in lower-resource countries, according to Alexis A. Thompson, MD, the current ASH president.
“These are all quite different aspects of work being done,” said Dr. Thompson, associate director of equity and minority health at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University in Chicago.
In the gene therapy study (abstract 1023), investigators will report initial results of genetic targeting of the fetal-to-adult globin switch in sickle cell patients. The clinical pilot study involves autologous gene therapy utilizing microRNA-adapted shRNAs (shRNAmiR) lentiviral vector targeting BCL11A, a repressor of gamma globin expression, according to the investigators.
“We’re looking forward to seeing this initial presentation on their findings with this first administration to humans,” Dr. Thompson said in a media briefing.
In another study (abstract 162), investigators will report long-term results of familial haploidentical stem cell transplantation (HISCT) showing that high-risk sickle cell patients had significantly improved health-related quality of life in long-term follow-up.
Two years after myeloablative conditioning and familial HISCT using CD34 enrichment and mononuclear cell (CD3) addback, recipients had significant improvements in emotional and physical health-related quality of life, among other outcomes of interest, including neurocognitive outcomes.
Another study, which is interesting in the context of the national opioid epidemic, Dr. Thompson said, will show that opioid use was not associated with in-hospital mortality in patients with sickle cell disease (abstract 315).
Looking at data from the National Inpatient Sample, there was no increase in in-hospital mortality in sickle cell patients versus the general population since the onset of the epidemic, which has been documented since 2000, according to the investigators.
“It should alleviate many concerns about patients with sickle cell who, for legitimate reasons, may require high doses of opioids,” Dr. Thompson said. “While I think we’re being very mindful about opioid use in this patient population, they certainly do need these high doses, but there does not seem to be an extraordinary risk of death associated with their use.”
One final study worth watching, according to Dr. Thompson, is REACH, a prospective, multinational trial of hydroxyurea for sickle cell anemia in sub-Saharan Africa (abstract 3).
The study, which included 635 children, provides the first prospective data showing the feasibility, safety, and benefits of hydroxyurea treatment for children with sickle cell anemia in sub-Saharan Africa, according to the investigators.
The findings are “quite encouraging,” said Dr. Thompson, adding that the results looked “very similar” to the United States experience and demonstrated effective clinical trial design and execution in a lower-resource country.
Sickle cell disease will take center stage at the annual meeting of the American Society of Hematology.
, long-term outcomes of haploidentical transplants, mortality rates in patients prescribed opioids, and aspects of care in lower-resource countries, according to Alexis A. Thompson, MD, the current ASH president.
“These are all quite different aspects of work being done,” said Dr. Thompson, associate director of equity and minority health at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University in Chicago.
In the gene therapy study (abstract 1023), investigators will report initial results of genetic targeting of the fetal-to-adult globin switch in sickle cell patients. The clinical pilot study involves autologous gene therapy utilizing microRNA-adapted shRNAs (shRNAmiR) lentiviral vector targeting BCL11A, a repressor of gamma globin expression, according to the investigators.
“We’re looking forward to seeing this initial presentation on their findings with this first administration to humans,” Dr. Thompson said in a media briefing.
In another study (abstract 162), investigators will report long-term results of familial haploidentical stem cell transplantation (HISCT) showing that high-risk sickle cell patients had significantly improved health-related quality of life in long-term follow-up.
Two years after myeloablative conditioning and familial HISCT using CD34 enrichment and mononuclear cell (CD3) addback, recipients had significant improvements in emotional and physical health-related quality of life, among other outcomes of interest, including neurocognitive outcomes.
Another study, which is interesting in the context of the national opioid epidemic, Dr. Thompson said, will show that opioid use was not associated with in-hospital mortality in patients with sickle cell disease (abstract 315).
Looking at data from the National Inpatient Sample, there was no increase in in-hospital mortality in sickle cell patients versus the general population since the onset of the epidemic, which has been documented since 2000, according to the investigators.
“It should alleviate many concerns about patients with sickle cell who, for legitimate reasons, may require high doses of opioids,” Dr. Thompson said. “While I think we’re being very mindful about opioid use in this patient population, they certainly do need these high doses, but there does not seem to be an extraordinary risk of death associated with their use.”
One final study worth watching, according to Dr. Thompson, is REACH, a prospective, multinational trial of hydroxyurea for sickle cell anemia in sub-Saharan Africa (abstract 3).
The study, which included 635 children, provides the first prospective data showing the feasibility, safety, and benefits of hydroxyurea treatment for children with sickle cell anemia in sub-Saharan Africa, according to the investigators.
The findings are “quite encouraging,” said Dr. Thompson, adding that the results looked “very similar” to the United States experience and demonstrated effective clinical trial design and execution in a lower-resource country.
Sickle cell disease will take center stage at the annual meeting of the American Society of Hematology.
, long-term outcomes of haploidentical transplants, mortality rates in patients prescribed opioids, and aspects of care in lower-resource countries, according to Alexis A. Thompson, MD, the current ASH president.
“These are all quite different aspects of work being done,” said Dr. Thompson, associate director of equity and minority health at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University in Chicago.
In the gene therapy study (abstract 1023), investigators will report initial results of genetic targeting of the fetal-to-adult globin switch in sickle cell patients. The clinical pilot study involves autologous gene therapy utilizing microRNA-adapted shRNAs (shRNAmiR) lentiviral vector targeting BCL11A, a repressor of gamma globin expression, according to the investigators.
“We’re looking forward to seeing this initial presentation on their findings with this first administration to humans,” Dr. Thompson said in a media briefing.
In another study (abstract 162), investigators will report long-term results of familial haploidentical stem cell transplantation (HISCT) showing that high-risk sickle cell patients had significantly improved health-related quality of life in long-term follow-up.
Two years after myeloablative conditioning and familial HISCT using CD34 enrichment and mononuclear cell (CD3) addback, recipients had significant improvements in emotional and physical health-related quality of life, among other outcomes of interest, including neurocognitive outcomes.
Another study, which is interesting in the context of the national opioid epidemic, Dr. Thompson said, will show that opioid use was not associated with in-hospital mortality in patients with sickle cell disease (abstract 315).
Looking at data from the National Inpatient Sample, there was no increase in in-hospital mortality in sickle cell patients versus the general population since the onset of the epidemic, which has been documented since 2000, according to the investigators.
“It should alleviate many concerns about patients with sickle cell who, for legitimate reasons, may require high doses of opioids,” Dr. Thompson said. “While I think we’re being very mindful about opioid use in this patient population, they certainly do need these high doses, but there does not seem to be an extraordinary risk of death associated with their use.”
One final study worth watching, according to Dr. Thompson, is REACH, a prospective, multinational trial of hydroxyurea for sickle cell anemia in sub-Saharan Africa (abstract 3).
The study, which included 635 children, provides the first prospective data showing the feasibility, safety, and benefits of hydroxyurea treatment for children with sickle cell anemia in sub-Saharan Africa, according to the investigators.
The findings are “quite encouraging,” said Dr. Thompson, adding that the results looked “very similar” to the United States experience and demonstrated effective clinical trial design and execution in a lower-resource country.
Researchers seek more sickle cell drug research
BETHESDA, MD – While there are experimental treatments such as sevuparin and gene therapy in testing for sickle cell disease (SCD), researchers said this field is lagging because of a lack of funding.
Yogen Saunthararajah, MD, of the Cleveland Clinic, described what he called a “paltry” landscape of new drugs for SCD at Sickle Cell in Focus, a conference held by the National Institutes of Health.
There are only four main approaches taken by drugs now in clinical testing for addressing the root causes of SCD, despite decades’ worth of research of the genetic and mechanistic underpinnings of this disease, he said.
“It’s pretty sad,” Dr. Saunthararajah said, referring to the quantity of efforts, not their quality.
Within days of his presentation at the conference, one of the drugs he highlighted had officially fallen out of contention. An Oct. 26 post on NIH’s Clinicaltrials.gov site said Incyte had terminated its phase 1 study of INCB059872 in SCD “due to a business decision” not to pursue this indication. Incyte confirmed that it dropped development of INCB059872 for SCD but will continue testing it for other indications, including acute myeloid leukemia (AML).
Dr. Saunthararajah said that work on another approach, using decitabine (Dacogen), for which he has done a phase 1 study, is “struggling,” because of the search for funding.
Two other approaches that Dr. Saunthararajah cited in his presentation appear to remain on track. These are gene therapy and the once-daily voxelotor treatment from Global Blood Therapeutics.
In the field of gene therapy, Sangamo Therapeutics and Sanofi’s Bioverativ in May said the Food and Drug Administration had cleared the way for them to start a phase 1/2 clinical trial for the BIVV003 product that they are developing together. This uses zinc finger nuclease (ZFN) gene-editing technology to modifying a short sequence of the BCL11A gene, with the aim of reactivating fetal hemoglobin.
Bluebird Bio’s LentiGlobin gene therapy has advanced as far as phase 3 for transfusion-dependent beta-thalassemia and phase 1/2 for SCD. In October, the European Medicines Agency accepted the company’s application for approval of LentiGlobin gene therapy for the treatment of adolescents and adults with transfusion-dependent beta-thalassemia (TDT) and a non-beta0/beta0 genotype. The company has not said when it expects to file with the FDA for approval of this treatment.
In the field of oral therapies, Global Blood Therapeutics has said it’s in discussions with the FDA about a potential accelerated approval of voxelotor. The tablet is meant to inhibit the underlying mechanism that causes sickling of red blood cells. In June, the company completed a planned review of early data from its phase 3 trial, known as the HOPE study.
“On the primary endpoint (the proportion of patients with greater than 1 g/dL increase in hemoglobin versus baseline), a statistically significant increase was demonstrated with voxelotor at both the 1,500-mg and 900-mg doses after 12 weeks of treatment versus placebo,” Global Blood Therapeutics said in an August regulatory filing with the Securities and Exchange Commission.
The company has said that voxelotor may meet the FDA’s standard for accelerated approval under Subpart H program.
In his presentation at the NIH conference, Tom Williams, MD, PhD, of KEMRI/Wellcome Trust Research Programme highlighted a recent review of experimental SCD treatments by Marilyn Jo Telen, MD, of Duke University, Durham, N.C. (Blood. 2016;127[7]:810-9).
Also among the drugs being tested for SCD is Modus Therapeutics’ sevuparin, which Dr. Williams described as being “a heparin-like molecule without the anticoagulant complications.”
The compound originated as a “passion project” of Mats Wahlgren, MD, PhD, of the Karolinska Institute, Stockholm, who developed it for the treatment of malaria, Dr. Williams said. The company that’s developing sevuparin, Modus Therapeutics, is moving it forward first as a treatment for SCD for commercial reasons, Dr. Williams said.
“They think it’s a better first target,” he said.
An ongoing study of sevuparin for painful crisis is expected to be completed in December, with data then expected to be released in the middle of 2019, Ellen K. Donnelly, PhD, chief executive officer of Modus Therapeutics, said in an interview. She cited a mix of scientific, medical and commercial reasons for her company’s decision to advance sevuparin in SCD.
“First, and most importantly, there is proof of clinical benefit of a similar molecule (the low-molecular-weight heparin called tinzaparin) in patients with sickle cell disease,” Dr. Donnelly said. “Unfortunately, there is a bleeding risk with tinzaparin that limits use of the agent for the treatment of sickle cell disease. Sevuparin does not have the bleeding risk and thus is a strong candidate for SCD.”
Dr. Donnelly also noted the emphasis that the FDA’s Division of Hematology Products has put on development of therapeutics for SCD as a reason for proceeding first with this indication. The agency and the American Society of Hematology in early October held a workshop of experts, physicians, patients, and industry collaborators focused on identifying new endpoints for clinical studies.
Still, she noted that commercial reasons did factor into this decision.
“[I]t is possible for a small company like Modus to take an asset all the way to market when developing a therapeutic for a rare disease given the need for fewer patients and smaller trials,” Dr. Donnelly wrote. “As you can see from www.clinicaltrials.gov, we were able to run our phase 2 study with a small number of sites. In addition, in SCD it is possible to get approval with only one or two confirmatory studies.”
Financial interests
Other drugs in testing for SCD include rivipansel from GlycoMimetics, for which Pfizer is leading development. The sponsors expect to complete the so-called RESET trial by 2019, according to the clinicaltrials.gov. In this study, which is intended to enroll 350 participants, patients who have vaso-occlusive crises are randomly selected for treatment with either rivipansel or placebo.
Speaking during a question-and-answer session at the NIH conference, Robert Swift, PhD, said there’s a need for inexpensive oral drugs to treat SCD. Many other options will remain beyond the finances of people living in poor countries, he said.
“We need to focus not only on the root cause, but on something that is oral and inexpensive to solve the greater sickle cell problem,” Dr. Swift said.
Large drugmakers already have hospital-based sales forces, making SCD drugs administered in this setting attractive to them, he said.
“This is partly about where money is. The drug companies are going where the money is. It’s not oral drugs to treat everybody, it’s something else,” Dr. Swift said. “So someone else is going to have to fund the basic research” into treatments that could be more broadly used.
Dr. Swift said in an interview that he has received NIH funding for developing SCD-101, an oral drug, for which a placebo-controlled crossover study is underway.
Presenters at the NIH conference, including Dr. Saunthararajah, expressed frustration about what they see as relatively little work being done on SCD despite decades of knowledge about the root causes. Like Dr. Swift, he criticized the approach taken in selecting which treatments advance in this field.
“It’s not being driven by what is the most cost effective, what the patients need the most,” Dr. Saunthararajah said. “It’s driven by what will make the most money, not just for [the] drug company, but also for the hospital and also for the physicians.”
Dr. Saunthararajah reported having patents and patent applications around decitabine/tetrahydrouridine, 5-azacytidine/tetrahydrouridine, and differentiation therapy for oncology. He has also been a consultant for EpiDestiny, Novo Nordisk, and Takeda Oncology. Dr. Williams reported having no relevant financial disclosures. Dr. Swift is a managing member of Invenux and reported equity in Mast Therapeutics and SCD Development.
This article was updated on 11/9/2018.
BETHESDA, MD – While there are experimental treatments such as sevuparin and gene therapy in testing for sickle cell disease (SCD), researchers said this field is lagging because of a lack of funding.
Yogen Saunthararajah, MD, of the Cleveland Clinic, described what he called a “paltry” landscape of new drugs for SCD at Sickle Cell in Focus, a conference held by the National Institutes of Health.
There are only four main approaches taken by drugs now in clinical testing for addressing the root causes of SCD, despite decades’ worth of research of the genetic and mechanistic underpinnings of this disease, he said.
“It’s pretty sad,” Dr. Saunthararajah said, referring to the quantity of efforts, not their quality.
Within days of his presentation at the conference, one of the drugs he highlighted had officially fallen out of contention. An Oct. 26 post on NIH’s Clinicaltrials.gov site said Incyte had terminated its phase 1 study of INCB059872 in SCD “due to a business decision” not to pursue this indication. Incyte confirmed that it dropped development of INCB059872 for SCD but will continue testing it for other indications, including acute myeloid leukemia (AML).
Dr. Saunthararajah said that work on another approach, using decitabine (Dacogen), for which he has done a phase 1 study, is “struggling,” because of the search for funding.
Two other approaches that Dr. Saunthararajah cited in his presentation appear to remain on track. These are gene therapy and the once-daily voxelotor treatment from Global Blood Therapeutics.
In the field of gene therapy, Sangamo Therapeutics and Sanofi’s Bioverativ in May said the Food and Drug Administration had cleared the way for them to start a phase 1/2 clinical trial for the BIVV003 product that they are developing together. This uses zinc finger nuclease (ZFN) gene-editing technology to modifying a short sequence of the BCL11A gene, with the aim of reactivating fetal hemoglobin.
Bluebird Bio’s LentiGlobin gene therapy has advanced as far as phase 3 for transfusion-dependent beta-thalassemia and phase 1/2 for SCD. In October, the European Medicines Agency accepted the company’s application for approval of LentiGlobin gene therapy for the treatment of adolescents and adults with transfusion-dependent beta-thalassemia (TDT) and a non-beta0/beta0 genotype. The company has not said when it expects to file with the FDA for approval of this treatment.
In the field of oral therapies, Global Blood Therapeutics has said it’s in discussions with the FDA about a potential accelerated approval of voxelotor. The tablet is meant to inhibit the underlying mechanism that causes sickling of red blood cells. In June, the company completed a planned review of early data from its phase 3 trial, known as the HOPE study.
“On the primary endpoint (the proportion of patients with greater than 1 g/dL increase in hemoglobin versus baseline), a statistically significant increase was demonstrated with voxelotor at both the 1,500-mg and 900-mg doses after 12 weeks of treatment versus placebo,” Global Blood Therapeutics said in an August regulatory filing with the Securities and Exchange Commission.
The company has said that voxelotor may meet the FDA’s standard for accelerated approval under Subpart H program.
In his presentation at the NIH conference, Tom Williams, MD, PhD, of KEMRI/Wellcome Trust Research Programme highlighted a recent review of experimental SCD treatments by Marilyn Jo Telen, MD, of Duke University, Durham, N.C. (Blood. 2016;127[7]:810-9).
Also among the drugs being tested for SCD is Modus Therapeutics’ sevuparin, which Dr. Williams described as being “a heparin-like molecule without the anticoagulant complications.”
The compound originated as a “passion project” of Mats Wahlgren, MD, PhD, of the Karolinska Institute, Stockholm, who developed it for the treatment of malaria, Dr. Williams said. The company that’s developing sevuparin, Modus Therapeutics, is moving it forward first as a treatment for SCD for commercial reasons, Dr. Williams said.
“They think it’s a better first target,” he said.
An ongoing study of sevuparin for painful crisis is expected to be completed in December, with data then expected to be released in the middle of 2019, Ellen K. Donnelly, PhD, chief executive officer of Modus Therapeutics, said in an interview. She cited a mix of scientific, medical and commercial reasons for her company’s decision to advance sevuparin in SCD.
“First, and most importantly, there is proof of clinical benefit of a similar molecule (the low-molecular-weight heparin called tinzaparin) in patients with sickle cell disease,” Dr. Donnelly said. “Unfortunately, there is a bleeding risk with tinzaparin that limits use of the agent for the treatment of sickle cell disease. Sevuparin does not have the bleeding risk and thus is a strong candidate for SCD.”
Dr. Donnelly also noted the emphasis that the FDA’s Division of Hematology Products has put on development of therapeutics for SCD as a reason for proceeding first with this indication. The agency and the American Society of Hematology in early October held a workshop of experts, physicians, patients, and industry collaborators focused on identifying new endpoints for clinical studies.
Still, she noted that commercial reasons did factor into this decision.
“[I]t is possible for a small company like Modus to take an asset all the way to market when developing a therapeutic for a rare disease given the need for fewer patients and smaller trials,” Dr. Donnelly wrote. “As you can see from www.clinicaltrials.gov, we were able to run our phase 2 study with a small number of sites. In addition, in SCD it is possible to get approval with only one or two confirmatory studies.”
Financial interests
Other drugs in testing for SCD include rivipansel from GlycoMimetics, for which Pfizer is leading development. The sponsors expect to complete the so-called RESET trial by 2019, according to the clinicaltrials.gov. In this study, which is intended to enroll 350 participants, patients who have vaso-occlusive crises are randomly selected for treatment with either rivipansel or placebo.
Speaking during a question-and-answer session at the NIH conference, Robert Swift, PhD, said there’s a need for inexpensive oral drugs to treat SCD. Many other options will remain beyond the finances of people living in poor countries, he said.
“We need to focus not only on the root cause, but on something that is oral and inexpensive to solve the greater sickle cell problem,” Dr. Swift said.
Large drugmakers already have hospital-based sales forces, making SCD drugs administered in this setting attractive to them, he said.
“This is partly about where money is. The drug companies are going where the money is. It’s not oral drugs to treat everybody, it’s something else,” Dr. Swift said. “So someone else is going to have to fund the basic research” into treatments that could be more broadly used.
Dr. Swift said in an interview that he has received NIH funding for developing SCD-101, an oral drug, for which a placebo-controlled crossover study is underway.
Presenters at the NIH conference, including Dr. Saunthararajah, expressed frustration about what they see as relatively little work being done on SCD despite decades of knowledge about the root causes. Like Dr. Swift, he criticized the approach taken in selecting which treatments advance in this field.
“It’s not being driven by what is the most cost effective, what the patients need the most,” Dr. Saunthararajah said. “It’s driven by what will make the most money, not just for [the] drug company, but also for the hospital and also for the physicians.”
Dr. Saunthararajah reported having patents and patent applications around decitabine/tetrahydrouridine, 5-azacytidine/tetrahydrouridine, and differentiation therapy for oncology. He has also been a consultant for EpiDestiny, Novo Nordisk, and Takeda Oncology. Dr. Williams reported having no relevant financial disclosures. Dr. Swift is a managing member of Invenux and reported equity in Mast Therapeutics and SCD Development.
This article was updated on 11/9/2018.
BETHESDA, MD – While there are experimental treatments such as sevuparin and gene therapy in testing for sickle cell disease (SCD), researchers said this field is lagging because of a lack of funding.
Yogen Saunthararajah, MD, of the Cleveland Clinic, described what he called a “paltry” landscape of new drugs for SCD at Sickle Cell in Focus, a conference held by the National Institutes of Health.
There are only four main approaches taken by drugs now in clinical testing for addressing the root causes of SCD, despite decades’ worth of research of the genetic and mechanistic underpinnings of this disease, he said.
“It’s pretty sad,” Dr. Saunthararajah said, referring to the quantity of efforts, not their quality.
Within days of his presentation at the conference, one of the drugs he highlighted had officially fallen out of contention. An Oct. 26 post on NIH’s Clinicaltrials.gov site said Incyte had terminated its phase 1 study of INCB059872 in SCD “due to a business decision” not to pursue this indication. Incyte confirmed that it dropped development of INCB059872 for SCD but will continue testing it for other indications, including acute myeloid leukemia (AML).
Dr. Saunthararajah said that work on another approach, using decitabine (Dacogen), for which he has done a phase 1 study, is “struggling,” because of the search for funding.
Two other approaches that Dr. Saunthararajah cited in his presentation appear to remain on track. These are gene therapy and the once-daily voxelotor treatment from Global Blood Therapeutics.
In the field of gene therapy, Sangamo Therapeutics and Sanofi’s Bioverativ in May said the Food and Drug Administration had cleared the way for them to start a phase 1/2 clinical trial for the BIVV003 product that they are developing together. This uses zinc finger nuclease (ZFN) gene-editing technology to modifying a short sequence of the BCL11A gene, with the aim of reactivating fetal hemoglobin.
Bluebird Bio’s LentiGlobin gene therapy has advanced as far as phase 3 for transfusion-dependent beta-thalassemia and phase 1/2 for SCD. In October, the European Medicines Agency accepted the company’s application for approval of LentiGlobin gene therapy for the treatment of adolescents and adults with transfusion-dependent beta-thalassemia (TDT) and a non-beta0/beta0 genotype. The company has not said when it expects to file with the FDA for approval of this treatment.
In the field of oral therapies, Global Blood Therapeutics has said it’s in discussions with the FDA about a potential accelerated approval of voxelotor. The tablet is meant to inhibit the underlying mechanism that causes sickling of red blood cells. In June, the company completed a planned review of early data from its phase 3 trial, known as the HOPE study.
“On the primary endpoint (the proportion of patients with greater than 1 g/dL increase in hemoglobin versus baseline), a statistically significant increase was demonstrated with voxelotor at both the 1,500-mg and 900-mg doses after 12 weeks of treatment versus placebo,” Global Blood Therapeutics said in an August regulatory filing with the Securities and Exchange Commission.
The company has said that voxelotor may meet the FDA’s standard for accelerated approval under Subpart H program.
In his presentation at the NIH conference, Tom Williams, MD, PhD, of KEMRI/Wellcome Trust Research Programme highlighted a recent review of experimental SCD treatments by Marilyn Jo Telen, MD, of Duke University, Durham, N.C. (Blood. 2016;127[7]:810-9).
Also among the drugs being tested for SCD is Modus Therapeutics’ sevuparin, which Dr. Williams described as being “a heparin-like molecule without the anticoagulant complications.”
The compound originated as a “passion project” of Mats Wahlgren, MD, PhD, of the Karolinska Institute, Stockholm, who developed it for the treatment of malaria, Dr. Williams said. The company that’s developing sevuparin, Modus Therapeutics, is moving it forward first as a treatment for SCD for commercial reasons, Dr. Williams said.
“They think it’s a better first target,” he said.
An ongoing study of sevuparin for painful crisis is expected to be completed in December, with data then expected to be released in the middle of 2019, Ellen K. Donnelly, PhD, chief executive officer of Modus Therapeutics, said in an interview. She cited a mix of scientific, medical and commercial reasons for her company’s decision to advance sevuparin in SCD.
“First, and most importantly, there is proof of clinical benefit of a similar molecule (the low-molecular-weight heparin called tinzaparin) in patients with sickle cell disease,” Dr. Donnelly said. “Unfortunately, there is a bleeding risk with tinzaparin that limits use of the agent for the treatment of sickle cell disease. Sevuparin does not have the bleeding risk and thus is a strong candidate for SCD.”
Dr. Donnelly also noted the emphasis that the FDA’s Division of Hematology Products has put on development of therapeutics for SCD as a reason for proceeding first with this indication. The agency and the American Society of Hematology in early October held a workshop of experts, physicians, patients, and industry collaborators focused on identifying new endpoints for clinical studies.
Still, she noted that commercial reasons did factor into this decision.
“[I]t is possible for a small company like Modus to take an asset all the way to market when developing a therapeutic for a rare disease given the need for fewer patients and smaller trials,” Dr. Donnelly wrote. “As you can see from www.clinicaltrials.gov, we were able to run our phase 2 study with a small number of sites. In addition, in SCD it is possible to get approval with only one or two confirmatory studies.”
Financial interests
Other drugs in testing for SCD include rivipansel from GlycoMimetics, for which Pfizer is leading development. The sponsors expect to complete the so-called RESET trial by 2019, according to the clinicaltrials.gov. In this study, which is intended to enroll 350 participants, patients who have vaso-occlusive crises are randomly selected for treatment with either rivipansel or placebo.
Speaking during a question-and-answer session at the NIH conference, Robert Swift, PhD, said there’s a need for inexpensive oral drugs to treat SCD. Many other options will remain beyond the finances of people living in poor countries, he said.
“We need to focus not only on the root cause, but on something that is oral and inexpensive to solve the greater sickle cell problem,” Dr. Swift said.
Large drugmakers already have hospital-based sales forces, making SCD drugs administered in this setting attractive to them, he said.
“This is partly about where money is. The drug companies are going where the money is. It’s not oral drugs to treat everybody, it’s something else,” Dr. Swift said. “So someone else is going to have to fund the basic research” into treatments that could be more broadly used.
Dr. Swift said in an interview that he has received NIH funding for developing SCD-101, an oral drug, for which a placebo-controlled crossover study is underway.
Presenters at the NIH conference, including Dr. Saunthararajah, expressed frustration about what they see as relatively little work being done on SCD despite decades of knowledge about the root causes. Like Dr. Swift, he criticized the approach taken in selecting which treatments advance in this field.
“It’s not being driven by what is the most cost effective, what the patients need the most,” Dr. Saunthararajah said. “It’s driven by what will make the most money, not just for [the] drug company, but also for the hospital and also for the physicians.”
Dr. Saunthararajah reported having patents and patent applications around decitabine/tetrahydrouridine, 5-azacytidine/tetrahydrouridine, and differentiation therapy for oncology. He has also been a consultant for EpiDestiny, Novo Nordisk, and Takeda Oncology. Dr. Williams reported having no relevant financial disclosures. Dr. Swift is a managing member of Invenux and reported equity in Mast Therapeutics and SCD Development.
This article was updated on 11/9/2018.
REPORTING FROM SICKLE CELL IN FOCUS
Sickle cell disease gene therapy seen advancing
BETHESDA, MD. – Experimental gene therapies for sickle cell disease and thalassemia appear to be advancing, with BCL11A among the most promising targets in this field, researchers said at Sickle Cell in Focus, a conference held by the National Institutes of Health. 
Several highly anticipated presentations on the topic are expected for December meeting of the American Society of Hematology.
Alexis A. Thompson, MD, of Northwestern University, Chicago, reviewed highlights from a study in which the majority of patients given a gene therapy for transfusion dependent beta-thalassemia didn’t need subsequent blood transfusions. The New England Journal of Medicine in April published the results of this work done with Bluebird Bio’s LentiGlobin gene therapy (N Engl J Med. 2018; 378:1479-93).
Of the 22 patients in this trial, 15 have become transfusion independent, Dr. Thompson said in her presentation. Those patients that did not have this positive outcome still appear to have been helped by the gene therapy, she said. They had a median of 60% reduction in their transfusion volumes and nearly 60% in their number of transfusions.
“Whether it was transfusion independence or reduction in their transfusion volume or number, the vast majority of individuals in this first large-scale study had clinical benefit” from the therapy, said Dr. Thompson, who was the lead author of the study.
Dr. Thompson, the current president of the American Society of Hematology (ASH), said she’s looking forward to presentations on some of the most advanced gene therapies for sickle cell disease and thalassemia at the group’s annual meeting in December. The ASH presentations include those of John F. Tisdale, MD, who will report the latest data on LentiGlobin gene therapy in sickle cell disease, and Punam Malik, MD, of Cincinnati Children’s Hospital, who has developed a gamma globin lentivirus vector. There also will be a first readout on a particularly novel approach taken by researchers at Boston Children’s Hospital, led by David Williams, MD.
The development of CRISPR-Cas9 “has really opened up the field” of gene therapy, aiding researchers at Boston Children’s in their efforts to develop a treatment to maintain fetal hemoglobin production, Daniel E. Bauer, MD, PhD, of Boston Children’s Hospital, said during his presentation at the NIH conference.
Dr. Bauer provided an update on the BCL11A research that seeks to block what amounts to a genetic “off switch” for production of fetal hemoglobin. It’s long been known that erythrocytes of newborns with sickle cell disease are protected from sickling by high levels of fetal hemoglobin. Clinical manifestations of sickle cell disease then emerge in the first year of life as fetal hemoglobin levels decline.
“A main goal in hematology has been to understand how is it that these alternative fetal hemoglobin genes get silenced and how can we turn them back on,” said Dr. Bauer, a staff physician in pediatric hematology/oncology.
The gene BCL11A also plays key roles in the development of the central nervous system, B lymphatic lymphocyte maturation, and hematopoietic stem cell self-renewal. That led the researchers to hone in on targeting sequences around the BCL11A gene that act as erythroid enhancers, intending to limit potential complications by creating a very specific therapy for sickle cell disease.
In a related clinical trial, using lentiviral gene therapy rather than gene editing, researchers at Boston Children’s began an open-label, nonrandomized, single-center pilot study that involves a single infusion of autologous bone marrow derived CD34+ HSC cells transduced by a vector containing a short-hairpin segment of RNA targeting the gene BCL11A.
The study has a maximum accrual of seven evaluable patients, according to the NIH’s clinical trials website. The protocol is similar to bone marrow transplant, in that native blood stem cells are eliminated by myeloablative conditioning therapy. In this gene therapy, the patient’s own blood stem cells are then infused after the new genetic material has been added to counter the normal BCL11A off switch.
Swee Lay Thein, MBBS, an organizer of the NIH’s sickle cell conference, said in an interview that the “gene therapy side is really looking very optimistic.”
Dr. Thein, a senior investigator for sickle-cell genetics at the National Heart, Lung, and Blood Institute, earlier in her career discovered segments of DNA, including the BCL11A gene. She said that gaining greater understanding about genomic variation might someday aid in determining which people need more intense intervention for their sickle cell disease.
“You would be able to predict who will have more severe disease; we could monitor them more closely and perhaps even advocate for gene therapy or bone marrow transplant before complications have occurred rather than waiting for them to occur,” Dr. Thein said.
She referred to this as her “dream” for care of people with sickle cell disease. “This is still far off in the horizon.”
The NHLBI in September 2018 launched its Cure Sickle Cell Initiative. The agency estimates that it spends about $100 million on sickle cell disease research each year. The inherited blood disorder affects about 100,000 people in the United States and 20 million individuals worldwide. In sickle cell disease, a single genetic mutation causes red blood cells to form abnormal, sickle shapes that can clog the blood vessels and deprive cells of oxygen.
Dr. Thompson reported research funding and consulting agreements with Biomarin, Bluebird Bio, Celgene, Novartis, and Shire. Dr. Bauer reported patents related to BCL11A enhancer editing, consulting agreements with Merck and Pfizer, and research support from Bioverativ.
BETHESDA, MD. – Experimental gene therapies for sickle cell disease and thalassemia appear to be advancing, with BCL11A among the most promising targets in this field, researchers said at Sickle Cell in Focus, a conference held by the National Institutes of Health.
Several highly anticipated presentations on the topic are expected for December meeting of the American Society of Hematology.
Alexis A. Thompson, MD, of Northwestern University, Chicago, reviewed highlights from a study in which the majority of patients given a gene therapy for transfusion dependent beta-thalassemia didn’t need subsequent blood transfusions. The New England Journal of Medicine in April published the results of this work done with Bluebird Bio’s LentiGlobin gene therapy (N Engl J Med. 2018; 378:1479-93).
Of the 22 patients in this trial, 15 have become transfusion independent, Dr. Thompson said in her presentation. Those patients that did not have this positive outcome still appear to have been helped by the gene therapy, she said. They had a median of 60% reduction in their transfusion volumes and nearly 60% in their number of transfusions.
“Whether it was transfusion independence or reduction in their transfusion volume or number, the vast majority of individuals in this first large-scale study had clinical benefit” from the therapy, said Dr. Thompson, who was the lead author of the study.
Dr. Thompson, the current president of the American Society of Hematology (ASH), said she’s looking forward to presentations on some of the most advanced gene therapies for sickle cell disease and thalassemia at the group’s annual meeting in December. The ASH presentations include those of John F. Tisdale, MD, who will report the latest data on LentiGlobin gene therapy in sickle cell disease, and Punam Malik, MD, of Cincinnati Children’s Hospital, who has developed a gamma globin lentivirus vector. There also will be a first readout on a particularly novel approach taken by researchers at Boston Children’s Hospital, led by David Williams, MD.
The development of CRISPR-Cas9 “has really opened up the field” of gene therapy, aiding researchers at Boston Children’s in their efforts to develop a treatment to maintain fetal hemoglobin production, Daniel E. Bauer, MD, PhD, of Boston Children’s Hospital, said during his presentation at the NIH conference.
Dr. Bauer provided an update on the BCL11A research that seeks to block what amounts to a genetic “off switch” for production of fetal hemoglobin. It’s long been known that erythrocytes of newborns with sickle cell disease are protected from sickling by high levels of fetal hemoglobin. Clinical manifestations of sickle cell disease then emerge in the first year of life as fetal hemoglobin levels decline.
“A main goal in hematology has been to understand how is it that these alternative fetal hemoglobin genes get silenced and how can we turn them back on,” said Dr. Bauer, a staff physician in pediatric hematology/oncology.
The gene BCL11A also plays key roles in the development of the central nervous system, B lymphatic lymphocyte maturation, and hematopoietic stem cell self-renewal. That led the researchers to hone in on targeting sequences around the BCL11A gene that act as erythroid enhancers, intending to limit potential complications by creating a very specific therapy for sickle cell disease.
In a related clinical trial, using lentiviral gene therapy rather than gene editing, researchers at Boston Children’s began an open-label, nonrandomized, single-center pilot study that involves a single infusion of autologous bone marrow derived CD34+ HSC cells transduced by a vector containing a short-hairpin segment of RNA targeting the gene BCL11A.
The study has a maximum accrual of seven evaluable patients, according to the NIH’s clinical trials website. The protocol is similar to bone marrow transplant, in that native blood stem cells are eliminated by myeloablative conditioning therapy. In this gene therapy, the patient’s own blood stem cells are then infused after the new genetic material has been added to counter the normal BCL11A off switch.
Swee Lay Thein, MBBS, an organizer of the NIH’s sickle cell conference, said in an interview that the “gene therapy side is really looking very optimistic.”
Dr. Thein, a senior investigator for sickle-cell genetics at the National Heart, Lung, and Blood Institute, earlier in her career discovered segments of DNA, including the BCL11A gene. She said that gaining greater understanding about genomic variation might someday aid in determining which people need more intense intervention for their sickle cell disease.
“You would be able to predict who will have more severe disease; we could monitor them more closely and perhaps even advocate for gene therapy or bone marrow transplant before complications have occurred rather than waiting for them to occur,” Dr. Thein said.
She referred to this as her “dream” for care of people with sickle cell disease. “This is still far off in the horizon.”
The NHLBI in September 2018 launched its Cure Sickle Cell Initiative. The agency estimates that it spends about $100 million on sickle cell disease research each year. The inherited blood disorder affects about 100,000 people in the United States and 20 million individuals worldwide. In sickle cell disease, a single genetic mutation causes red blood cells to form abnormal, sickle shapes that can clog the blood vessels and deprive cells of oxygen.
Dr. Thompson reported research funding and consulting agreements with Biomarin, Bluebird Bio, Celgene, Novartis, and Shire. Dr. Bauer reported patents related to BCL11A enhancer editing, consulting agreements with Merck and Pfizer, and research support from Bioverativ.
BETHESDA, MD. – Experimental gene therapies for sickle cell disease and thalassemia appear to be advancing, with BCL11A among the most promising targets in this field, researchers said at Sickle Cell in Focus, a conference held by the National Institutes of Health.
Several highly anticipated presentations on the topic are expected for December meeting of the American Society of Hematology.
Alexis A. Thompson, MD, of Northwestern University, Chicago, reviewed highlights from a study in which the majority of patients given a gene therapy for transfusion dependent beta-thalassemia didn’t need subsequent blood transfusions. The New England Journal of Medicine in April published the results of this work done with Bluebird Bio’s LentiGlobin gene therapy (N Engl J Med. 2018; 378:1479-93).
Of the 22 patients in this trial, 15 have become transfusion independent, Dr. Thompson said in her presentation. Those patients that did not have this positive outcome still appear to have been helped by the gene therapy, she said. They had a median of 60% reduction in their transfusion volumes and nearly 60% in their number of transfusions.
“Whether it was transfusion independence or reduction in their transfusion volume or number, the vast majority of individuals in this first large-scale study had clinical benefit” from the therapy, said Dr. Thompson, who was the lead author of the study.
Dr. Thompson, the current president of the American Society of Hematology (ASH), said she’s looking forward to presentations on some of the most advanced gene therapies for sickle cell disease and thalassemia at the group’s annual meeting in December. The ASH presentations include those of John F. Tisdale, MD, who will report the latest data on LentiGlobin gene therapy in sickle cell disease, and Punam Malik, MD, of Cincinnati Children’s Hospital, who has developed a gamma globin lentivirus vector. There also will be a first readout on a particularly novel approach taken by researchers at Boston Children’s Hospital, led by David Williams, MD.
The development of CRISPR-Cas9 “has really opened up the field” of gene therapy, aiding researchers at Boston Children’s in their efforts to develop a treatment to maintain fetal hemoglobin production, Daniel E. Bauer, MD, PhD, of Boston Children’s Hospital, said during his presentation at the NIH conference.
Dr. Bauer provided an update on the BCL11A research that seeks to block what amounts to a genetic “off switch” for production of fetal hemoglobin. It’s long been known that erythrocytes of newborns with sickle cell disease are protected from sickling by high levels of fetal hemoglobin. Clinical manifestations of sickle cell disease then emerge in the first year of life as fetal hemoglobin levels decline.
“A main goal in hematology has been to understand how is it that these alternative fetal hemoglobin genes get silenced and how can we turn them back on,” said Dr. Bauer, a staff physician in pediatric hematology/oncology.
The gene BCL11A also plays key roles in the development of the central nervous system, B lymphatic lymphocyte maturation, and hematopoietic stem cell self-renewal. That led the researchers to hone in on targeting sequences around the BCL11A gene that act as erythroid enhancers, intending to limit potential complications by creating a very specific therapy for sickle cell disease.
In a related clinical trial, using lentiviral gene therapy rather than gene editing, researchers at Boston Children’s began an open-label, nonrandomized, single-center pilot study that involves a single infusion of autologous bone marrow derived CD34+ HSC cells transduced by a vector containing a short-hairpin segment of RNA targeting the gene BCL11A.
The study has a maximum accrual of seven evaluable patients, according to the NIH’s clinical trials website. The protocol is similar to bone marrow transplant, in that native blood stem cells are eliminated by myeloablative conditioning therapy. In this gene therapy, the patient’s own blood stem cells are then infused after the new genetic material has been added to counter the normal BCL11A off switch.
Swee Lay Thein, MBBS, an organizer of the NIH’s sickle cell conference, said in an interview that the “gene therapy side is really looking very optimistic.”
Dr. Thein, a senior investigator for sickle-cell genetics at the National Heart, Lung, and Blood Institute, earlier in her career discovered segments of DNA, including the BCL11A gene. She said that gaining greater understanding about genomic variation might someday aid in determining which people need more intense intervention for their sickle cell disease.
“You would be able to predict who will have more severe disease; we could monitor them more closely and perhaps even advocate for gene therapy or bone marrow transplant before complications have occurred rather than waiting for them to occur,” Dr. Thein said.
She referred to this as her “dream” for care of people with sickle cell disease. “This is still far off in the horizon.”
The NHLBI in September 2018 launched its Cure Sickle Cell Initiative. The agency estimates that it spends about $100 million on sickle cell disease research each year. The inherited blood disorder affects about 100,000 people in the United States and 20 million individuals worldwide. In sickle cell disease, a single genetic mutation causes red blood cells to form abnormal, sickle shapes that can clog the blood vessels and deprive cells of oxygen.
Dr. Thompson reported research funding and consulting agreements with Biomarin, Bluebird Bio, Celgene, Novartis, and Shire. Dr. Bauer reported patents related to BCL11A enhancer editing, consulting agreements with Merck and Pfizer, and research support from Bioverativ.
REPORTING FROM SICKLE CELL IN FOCUS
Investigational gene therapy for medically refractory Parkinson’s shows promise
ATLANTA – VY-AADC01, an investigational gene therapy for individuals with medically refractory Parkinson’s disease being developed by Voyager Therapeutics, was well tolerated and decreased the need for antiparkinsonian medications, results from an ongoing phase 1b study showed.
“Prior phase 1 trials also introduced the aromatic l-amino acid decarboxylase (AADC) gene using an adeno-associated virus serotype-2 (AAV2) vector into the putamen of people with Parkinson’s disease (PD),” lead study author Chad Christine, MD, said in an interview in advance of the annual meeting of the American Neurological Association. “Unlike the previous trials, here we increased both vector genome concentration and volume of the AAV2-AADC vector (VY-AADC01) across cohorts and used intraoperative MRI guidance to administer the gene product.”
According to Dr. Christine, a neurologist at the University of California, San Francisco, Parkinson’s Disease Clinic and Research Center, prior trials showed that AAV2-AADC was safe, but there was limited clinical efficacy. This may have been because of the limited volume of putamen treated with the gene therapy. “In our current trial, we admixed VY-AADC01 with gadoteridol (ProHance), an MR imaging agent, which allowed both near real-time MRI monitoring of the location and volume of product infused and postsurgical assessment of the area of the putamen covered by VY-AADC01,” he said. “In addition, we used 18F-Dopa PET, which allowed us to assess the activity of the AADC enzyme in the putamen.”
The researchers enrolled three cohorts of patients who received bilateral infusions of VY-AADC01, admixed with gadoteridol to facilitate intraoperative MRI monitoring of the infusions. In cohort 1, five patients received up to 450 μL/putamen at a concentration of 8.3 × 1011 vg (viral genomes)/mL and were followed for 36 months. In cohort 2, five patients received up to 900 μL/putamen at 8.3 × 1011 vg/mL and were followed for 18 months. In cohort 3, five patients received up to 900 μL/putamen at 2.6 × 1012 vg/mL and were followed for 12 months.
At 12 months, Dr. Christine and his associates observed mean levodopa-equivalent dose (LED) reductions of –10.2%, –32.8%, and –39.3% in cohort 1, cohort 2, and cohort 3, respectively; LED reductions were sustained to 18 months in cohorts 1 and 2. “We were impressed by how well the decrease in need for antiparkinsonian medications paralleled the AADC activity we measured in the putamen of our subjects, which is consistent with the proposed mechanism of action of VY-AADC01,” he said.
In addition, subjects in cohort 1 showed a mean 2.3-hour improvement in Parkinson’s diary-“on” time without troublesome dyskinesia at 24 months, which was maintained at 36 months, while subjects in cohort 2 showed a clinically meaningful 3.5-hour improvement at 18 months. Subjects in cohort 3 showed somewhat less improvement than the other cohorts (1.5 hours at 12 months), but they also had more severe baseline dyskinesia on the Unified Dyskinesia Rating Scale (a mean of 30.2 vs. 19.2 and 17.4 in cohorts 1 and 2, respectively). One patient in the trial experienced two surgery-related serious adverse events (pulmonary embolism and related heart arrhythmia) which resolved completely.
“I think we were somewhat surprised by some of the challenges of the surgical administration,” Dr. Christine said. “Our surgeons improved the administration technique throughout the trial and made a major transition from administering VY-AADC01 using a frontal approach to the putamen to using a posterior approach in our second phase 1 trial.”
He concluded that findings of the current trial suggest that AAV2-AADC gene therapy, administered using intraoperative MRI guidance, appears to be safe and well tolerated. “A number of outcomes suggest that it may offer clinical benefit to patients with advancing Parkinson’s disease, but this will have to be tested in a randomized trial which has recently started,” he said.
Dr. Christine acknowledged that the small sample size and the open-label design of the study limits the generalizability of the findings. The trial received support from Voyager Therapeutics and the Michael J. Fox Foundation. Dr. Christine reported having no disclosures.
Source: Christine et al. ANA 2018, Abstract M300.
ATLANTA – VY-AADC01, an investigational gene therapy for individuals with medically refractory Parkinson’s disease being developed by Voyager Therapeutics, was well tolerated and decreased the need for antiparkinsonian medications, results from an ongoing phase 1b study showed.
“Prior phase 1 trials also introduced the aromatic l-amino acid decarboxylase (AADC) gene using an adeno-associated virus serotype-2 (AAV2) vector into the putamen of people with Parkinson’s disease (PD),” lead study author Chad Christine, MD, said in an interview in advance of the annual meeting of the American Neurological Association. “Unlike the previous trials, here we increased both vector genome concentration and volume of the AAV2-AADC vector (VY-AADC01) across cohorts and used intraoperative MRI guidance to administer the gene product.”
According to Dr. Christine, a neurologist at the University of California, San Francisco, Parkinson’s Disease Clinic and Research Center, prior trials showed that AAV2-AADC was safe, but there was limited clinical efficacy. This may have been because of the limited volume of putamen treated with the gene therapy. “In our current trial, we admixed VY-AADC01 with gadoteridol (ProHance), an MR imaging agent, which allowed both near real-time MRI monitoring of the location and volume of product infused and postsurgical assessment of the area of the putamen covered by VY-AADC01,” he said. “In addition, we used 18F-Dopa PET, which allowed us to assess the activity of the AADC enzyme in the putamen.”
The researchers enrolled three cohorts of patients who received bilateral infusions of VY-AADC01, admixed with gadoteridol to facilitate intraoperative MRI monitoring of the infusions. In cohort 1, five patients received up to 450 μL/putamen at a concentration of 8.3 × 1011 vg (viral genomes)/mL and were followed for 36 months. In cohort 2, five patients received up to 900 μL/putamen at 8.3 × 1011 vg/mL and were followed for 18 months. In cohort 3, five patients received up to 900 μL/putamen at 2.6 × 1012 vg/mL and were followed for 12 months.
At 12 months, Dr. Christine and his associates observed mean levodopa-equivalent dose (LED) reductions of –10.2%, –32.8%, and –39.3% in cohort 1, cohort 2, and cohort 3, respectively; LED reductions were sustained to 18 months in cohorts 1 and 2. “We were impressed by how well the decrease in need for antiparkinsonian medications paralleled the AADC activity we measured in the putamen of our subjects, which is consistent with the proposed mechanism of action of VY-AADC01,” he said.
In addition, subjects in cohort 1 showed a mean 2.3-hour improvement in Parkinson’s diary-“on” time without troublesome dyskinesia at 24 months, which was maintained at 36 months, while subjects in cohort 2 showed a clinically meaningful 3.5-hour improvement at 18 months. Subjects in cohort 3 showed somewhat less improvement than the other cohorts (1.5 hours at 12 months), but they also had more severe baseline dyskinesia on the Unified Dyskinesia Rating Scale (a mean of 30.2 vs. 19.2 and 17.4 in cohorts 1 and 2, respectively). One patient in the trial experienced two surgery-related serious adverse events (pulmonary embolism and related heart arrhythmia) which resolved completely.
“I think we were somewhat surprised by some of the challenges of the surgical administration,” Dr. Christine said. “Our surgeons improved the administration technique throughout the trial and made a major transition from administering VY-AADC01 using a frontal approach to the putamen to using a posterior approach in our second phase 1 trial.”
He concluded that findings of the current trial suggest that AAV2-AADC gene therapy, administered using intraoperative MRI guidance, appears to be safe and well tolerated. “A number of outcomes suggest that it may offer clinical benefit to patients with advancing Parkinson’s disease, but this will have to be tested in a randomized trial which has recently started,” he said.
Dr. Christine acknowledged that the small sample size and the open-label design of the study limits the generalizability of the findings. The trial received support from Voyager Therapeutics and the Michael J. Fox Foundation. Dr. Christine reported having no disclosures.
Source: Christine et al. ANA 2018, Abstract M300.
ATLANTA – VY-AADC01, an investigational gene therapy for individuals with medically refractory Parkinson’s disease being developed by Voyager Therapeutics, was well tolerated and decreased the need for antiparkinsonian medications, results from an ongoing phase 1b study showed.
“Prior phase 1 trials also introduced the aromatic l-amino acid decarboxylase (AADC) gene using an adeno-associated virus serotype-2 (AAV2) vector into the putamen of people with Parkinson’s disease (PD),” lead study author Chad Christine, MD, said in an interview in advance of the annual meeting of the American Neurological Association. “Unlike the previous trials, here we increased both vector genome concentration and volume of the AAV2-AADC vector (VY-AADC01) across cohorts and used intraoperative MRI guidance to administer the gene product.”
According to Dr. Christine, a neurologist at the University of California, San Francisco, Parkinson’s Disease Clinic and Research Center, prior trials showed that AAV2-AADC was safe, but there was limited clinical efficacy. This may have been because of the limited volume of putamen treated with the gene therapy. “In our current trial, we admixed VY-AADC01 with gadoteridol (ProHance), an MR imaging agent, which allowed both near real-time MRI monitoring of the location and volume of product infused and postsurgical assessment of the area of the putamen covered by VY-AADC01,” he said. “In addition, we used 18F-Dopa PET, which allowed us to assess the activity of the AADC enzyme in the putamen.”
The researchers enrolled three cohorts of patients who received bilateral infusions of VY-AADC01, admixed with gadoteridol to facilitate intraoperative MRI monitoring of the infusions. In cohort 1, five patients received up to 450 μL/putamen at a concentration of 8.3 × 1011 vg (viral genomes)/mL and were followed for 36 months. In cohort 2, five patients received up to 900 μL/putamen at 8.3 × 1011 vg/mL and were followed for 18 months. In cohort 3, five patients received up to 900 μL/putamen at 2.6 × 1012 vg/mL and were followed for 12 months.
At 12 months, Dr. Christine and his associates observed mean levodopa-equivalent dose (LED) reductions of –10.2%, –32.8%, and –39.3% in cohort 1, cohort 2, and cohort 3, respectively; LED reductions were sustained to 18 months in cohorts 1 and 2. “We were impressed by how well the decrease in need for antiparkinsonian medications paralleled the AADC activity we measured in the putamen of our subjects, which is consistent with the proposed mechanism of action of VY-AADC01,” he said.
In addition, subjects in cohort 1 showed a mean 2.3-hour improvement in Parkinson’s diary-“on” time without troublesome dyskinesia at 24 months, which was maintained at 36 months, while subjects in cohort 2 showed a clinically meaningful 3.5-hour improvement at 18 months. Subjects in cohort 3 showed somewhat less improvement than the other cohorts (1.5 hours at 12 months), but they also had more severe baseline dyskinesia on the Unified Dyskinesia Rating Scale (a mean of 30.2 vs. 19.2 and 17.4 in cohorts 1 and 2, respectively). One patient in the trial experienced two surgery-related serious adverse events (pulmonary embolism and related heart arrhythmia) which resolved completely.
“I think we were somewhat surprised by some of the challenges of the surgical administration,” Dr. Christine said. “Our surgeons improved the administration technique throughout the trial and made a major transition from administering VY-AADC01 using a frontal approach to the putamen to using a posterior approach in our second phase 1 trial.”
He concluded that findings of the current trial suggest that AAV2-AADC gene therapy, administered using intraoperative MRI guidance, appears to be safe and well tolerated. “A number of outcomes suggest that it may offer clinical benefit to patients with advancing Parkinson’s disease, but this will have to be tested in a randomized trial which has recently started,” he said.
Dr. Christine acknowledged that the small sample size and the open-label design of the study limits the generalizability of the findings. The trial received support from Voyager Therapeutics and the Michael J. Fox Foundation. Dr. Christine reported having no disclosures.
Source: Christine et al. ANA 2018, Abstract M300.
REPORTING FROM ANA 2018
Key clinical point: AAV2-AADC gene therapy, administered using intraoperative MRI guidance, appears to be safe and well tolerated.
Major finding: At 12 months, the researchers observed mean levodopa-equivalent dose (LED) reductions of –10.2%, –32.8%, and –39.3% in cohort 1, cohort 2, and cohort 3, respectively.
Study details: A study of 15 patients in three cohorts who received bilateral infusions of VY-AADC01, admixed with gadoteridol to facilitate intraoperative MRI monitoring of the infusions.
Disclosures: The trial received support from Voyager Therapeutics and the Michael J. Fox Foundation. Dr. Christine reported having no disclosures.
Source: Christine et al. ANA 2018, Abstract M300.
Gene-Replacement Therapy for SMA1 May Necessitate New Rating Measures to Capture Patients’ Motor Function Gains
CHOP-INTEND scores plateaued in a phase I trial of AVXS-101 even as patients reached new motor milestones.
CHICAGO—The Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) was designed to track motor function in patients with spinal muscular atrophy type 1 (SMA1), but the test may not be sensitive to advances in motor function made by patients who receive an investigational gene-replacement therapy, researchers said at the 47th Annual Meeting of the Child Neurology Society.
AVXS-101 is an adeno-associated virus serotype 9 (AAV9)-based gene-replacement therapy that contains a copy of the SMN1 gene. AVXS-101 crosses the blood–brain barrier and is meant to treat the deletion or loss of function of the SMN1 gene in patients with SMA. The treatment may result in sustained SMN protein expression with a one-time dose.
Researchers conducted a phase I, open-label, dose-escalation study to study the treatment. Fifteen patients received AVXS-101 intravenously, and 12 participants received the proposed therapeutic dose.
“Patients treated with AVXS-101 achieved and maintained motor milestones unprecedented in the natural history of SMA1,” said Linda P. Lowes, PT, PhD, Principal Investigator for the Center for Gene Therapy at Nationwide Children’s Hospital in Columbus, Ohio, and Associate Professor of Pediatrics at Ohio State University, and colleagues. “CHOP-INTEND is a reliable tool for detecting early treatment impact, but appears insensitive to further motor function gains among AVXS-101–treated children as they age and develop.”
For example, the scale did not capture skills such as independent rolling and sitting that had not been seen in patients with SMA1, the researchers said.
CHOP-INTEND uses a 0–64-point scale where higher scores indicate better motor function. By six months, essentially no untreated patients with SMA1 achieve a score of 40 or greater points on the CHOP-INTEND, and scores may decrease between age 6 and 12 months. In the phase I trial of AVXS-101, CHOP-INTEND score increased from baseline by a mean of 9.8 points at one month postdose, 15.4 points at three months postdose, and 25.4 points at 24 months (n = 12 at all time points). Eleven of the 12 patients maintained a CHOP-INTEND score greater than 40 points for a mean of 19.5 months. Two children were able to crawl, pull to a stand, and stand and walk independently.
In the study, patients who achieved additional sitting milestones did not have accompanying increases on their CHOP-INTEND scores. For example, the 11 patients who sat for at least 5 seconds had a mean CHOP-INTEND plateau score of 56.9, while the 10 patients who sat for at least 10 seconds had a mean CHOP-INTEND plateau score of 57.0 and the nine patients who sat for at least 30 seconds had a mean CHOP-INTEND plateau score of 57.7.
The investigators suggested that the addition of scoring items such as supported sitting, head lifting, and walking could “mitigate the artificial ceiling effect” with the current scoring system. Other modifications to CHOP-INTEND, such as assessing one side of a patient instead of both sides, could reduce test administration time without affecting scores.
Furthermore, several CHOP-INTEND items may not perform well in assessing patients treated with AVXS-101 because they test primitive reflexes that fade as children live longer (eg, spinal incurvation) or children may become too heavy for the tests (eg, ventral suspension).
The study was sponsored by AveXis.
CHOP-INTEND scores plateaued in a phase I trial of AVXS-101 even as patients reached new motor milestones.
CHOP-INTEND scores plateaued in a phase I trial of AVXS-101 even as patients reached new motor milestones.
CHICAGO—The Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) was designed to track motor function in patients with spinal muscular atrophy type 1 (SMA1), but the test may not be sensitive to advances in motor function made by patients who receive an investigational gene-replacement therapy, researchers said at the 47th Annual Meeting of the Child Neurology Society.
AVXS-101 is an adeno-associated virus serotype 9 (AAV9)-based gene-replacement therapy that contains a copy of the SMN1 gene. AVXS-101 crosses the blood–brain barrier and is meant to treat the deletion or loss of function of the SMN1 gene in patients with SMA. The treatment may result in sustained SMN protein expression with a one-time dose.
Researchers conducted a phase I, open-label, dose-escalation study to study the treatment. Fifteen patients received AVXS-101 intravenously, and 12 participants received the proposed therapeutic dose.
“Patients treated with AVXS-101 achieved and maintained motor milestones unprecedented in the natural history of SMA1,” said Linda P. Lowes, PT, PhD, Principal Investigator for the Center for Gene Therapy at Nationwide Children’s Hospital in Columbus, Ohio, and Associate Professor of Pediatrics at Ohio State University, and colleagues. “CHOP-INTEND is a reliable tool for detecting early treatment impact, but appears insensitive to further motor function gains among AVXS-101–treated children as they age and develop.”
For example, the scale did not capture skills such as independent rolling and sitting that had not been seen in patients with SMA1, the researchers said.
CHOP-INTEND uses a 0–64-point scale where higher scores indicate better motor function. By six months, essentially no untreated patients with SMA1 achieve a score of 40 or greater points on the CHOP-INTEND, and scores may decrease between age 6 and 12 months. In the phase I trial of AVXS-101, CHOP-INTEND score increased from baseline by a mean of 9.8 points at one month postdose, 15.4 points at three months postdose, and 25.4 points at 24 months (n = 12 at all time points). Eleven of the 12 patients maintained a CHOP-INTEND score greater than 40 points for a mean of 19.5 months. Two children were able to crawl, pull to a stand, and stand and walk independently.
In the study, patients who achieved additional sitting milestones did not have accompanying increases on their CHOP-INTEND scores. For example, the 11 patients who sat for at least 5 seconds had a mean CHOP-INTEND plateau score of 56.9, while the 10 patients who sat for at least 10 seconds had a mean CHOP-INTEND plateau score of 57.0 and the nine patients who sat for at least 30 seconds had a mean CHOP-INTEND plateau score of 57.7.
The investigators suggested that the addition of scoring items such as supported sitting, head lifting, and walking could “mitigate the artificial ceiling effect” with the current scoring system. Other modifications to CHOP-INTEND, such as assessing one side of a patient instead of both sides, could reduce test administration time without affecting scores.
Furthermore, several CHOP-INTEND items may not perform well in assessing patients treated with AVXS-101 because they test primitive reflexes that fade as children live longer (eg, spinal incurvation) or children may become too heavy for the tests (eg, ventral suspension).
The study was sponsored by AveXis.
CHICAGO—The Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) was designed to track motor function in patients with spinal muscular atrophy type 1 (SMA1), but the test may not be sensitive to advances in motor function made by patients who receive an investigational gene-replacement therapy, researchers said at the 47th Annual Meeting of the Child Neurology Society.
AVXS-101 is an adeno-associated virus serotype 9 (AAV9)-based gene-replacement therapy that contains a copy of the SMN1 gene. AVXS-101 crosses the blood–brain barrier and is meant to treat the deletion or loss of function of the SMN1 gene in patients with SMA. The treatment may result in sustained SMN protein expression with a one-time dose.
Researchers conducted a phase I, open-label, dose-escalation study to study the treatment. Fifteen patients received AVXS-101 intravenously, and 12 participants received the proposed therapeutic dose.
“Patients treated with AVXS-101 achieved and maintained motor milestones unprecedented in the natural history of SMA1,” said Linda P. Lowes, PT, PhD, Principal Investigator for the Center for Gene Therapy at Nationwide Children’s Hospital in Columbus, Ohio, and Associate Professor of Pediatrics at Ohio State University, and colleagues. “CHOP-INTEND is a reliable tool for detecting early treatment impact, but appears insensitive to further motor function gains among AVXS-101–treated children as they age and develop.”
For example, the scale did not capture skills such as independent rolling and sitting that had not been seen in patients with SMA1, the researchers said.
CHOP-INTEND uses a 0–64-point scale where higher scores indicate better motor function. By six months, essentially no untreated patients with SMA1 achieve a score of 40 or greater points on the CHOP-INTEND, and scores may decrease between age 6 and 12 months. In the phase I trial of AVXS-101, CHOP-INTEND score increased from baseline by a mean of 9.8 points at one month postdose, 15.4 points at three months postdose, and 25.4 points at 24 months (n = 12 at all time points). Eleven of the 12 patients maintained a CHOP-INTEND score greater than 40 points for a mean of 19.5 months. Two children were able to crawl, pull to a stand, and stand and walk independently.
In the study, patients who achieved additional sitting milestones did not have accompanying increases on their CHOP-INTEND scores. For example, the 11 patients who sat for at least 5 seconds had a mean CHOP-INTEND plateau score of 56.9, while the 10 patients who sat for at least 10 seconds had a mean CHOP-INTEND plateau score of 57.0 and the nine patients who sat for at least 30 seconds had a mean CHOP-INTEND plateau score of 57.7.
The investigators suggested that the addition of scoring items such as supported sitting, head lifting, and walking could “mitigate the artificial ceiling effect” with the current scoring system. Other modifications to CHOP-INTEND, such as assessing one side of a patient instead of both sides, could reduce test administration time without affecting scores.
Furthermore, several CHOP-INTEND items may not perform well in assessing patients treated with AVXS-101 because they test primitive reflexes that fade as children live longer (eg, spinal incurvation) or children may become too heavy for the tests (eg, ventral suspension).
The study was sponsored by AveXis.
NHLBI commits to a sickle cell cure
“We have new exigency and intensity of effort to enable curative strategies for sickle cell disease to move forward,” said W. Keith Hoots, MD, the director of the division of blood diseases at NHLBI.
The key word in the cure effort is partnership – whether it’s among federal agencies, with public and private organizations, or with patients and families.
“Developmental strategies are built on partnerships to enhance care and accelerate cure for sickle cell disease in the U.S. and worldwide,” Dr. Hoots said at the 12th annual symposium of the Foundation for Sickle Cell Disease Research in Washington.
The reach also extends internationally. Supporting research in sub-Saharan Africa has promised to accelerate the clinical trial process by bringing advanced research capabilities to a region with a very high per capita rate of SCD. While in the United States, infrastructure is being built for a future research network, with the goal of developing a secure database of shared elements that harmonize and unite existing data.
Future cohort studies, enhanced newborn screening, and higher uptake of hydroxyurea will all be supported as part of this effort, Dr. Hoots said.
In the United States, patients can participate in a meaningful way as citizen-scientists, as new technology makes it possible to crowdsource high-quality data collection securely.
And including both community organizations and primary care providers in the “circle of partners” means not only that advances are brought out to patients expeditiously but also that the voices of patients and families have a clear channel back to researchers and policy makers through formal patient engagement and lay participation at all levels, Dr. Hoots said.
“The number of presently interested partners may surprise you,” Dr. Hoots said.
This multifaceted approach allows for “multiple shots on goal, with the acceptance that there could potentially be some failures,” Dr. Hoots said. Keeping all players better connected, though, should allow efforts to be redirected when needed, with a particular focus on accelerating work toward genetic therapies for SCD.
Perhaps the flagship effort is the Cure Sickle Cell Disease Initiative, a new partnership focused on accelerating cure-focused SCD research by filling in gaps left in the network of other funding strategies.
NHLBI named Edward J. Benz Jr., MD, the president and CEO emeritus of Boston’s Dana-Farber Cancer Institute, as the executive director and the Emmes Corporation, a contract research organization with expertise in clinical trials, as the coordinating center.
Traveling the last mile
New strategies also need to focus on how to boost uptake of such currently available best practices in SCD treatment as hydroxyurea use. To that end, Dr. Hoots said, NHLBI is drawing on implementation science, a discipline that, in a medical setting, can help solve such “last-mile” problems as bringing best practices in SCD treatment to patients.
In clinical practice, this might look like solving transportation issues for family members so that appointments aren’t missed and hydroxyurea prescriptions are filled. For researchers, implementation science can help with thorny details of participant recruitment and retention.
Established in 2016, the Sickle Cell Disease Implementation Consortium comprises nine U.S. research centers and NHLBI, which are each seeking to recruit at least 300 participants with SCD, aged 15-45 years, to study effective identification of barriers to care, and the best means to overcome them.
However, Dr. Hoots said, NHLBI also will continue funding SCD research through the traditional investigator-initiated application process, in conjunction with “a suite of specialized programs that can support translational and clinical research in SCD.”
Some of the features rolling out within the Cure SCD Initiative are included in direct response to stakeholder feedback about pressing needs and top priorities. For example, an economic case needed to be made in order for insurance companies, public and private alike, to reimburse for genetic SCD treatments. This requires an understanding of the lifetime cost burden of SCD, as well as determining what the long-term follow-up of costs of gene therapy will be.
Patients, family members and those providing primary care for SCD patients all agreed that clinical trials should have endpoints that reflect meaningful outcomes for patients and should be designed with the input of both patients and providers.
When queried, sickle cell disease researchers expressed a need to identify common data elements in SCD research, and wished for a secure yet accessible national data warehouse for data from gene and cell therapy trials.
At present, there are three clinical trials of curative stem cell approaches for SCD registered with the Blood and Marrow Transplant Clinical Trials Network and several more early phase clinical trials underway, Dr. Hoots said. A primary focus is the use of autologous cells for genomic editing, gene therapy, and erythroid-specific vectors.
Genetic research
As an example of the new collaboration, research centers and biotechnology companies sent their cell and genetic therapy experts to an NIH-sponsored gathering in March 2017. By pooling expertise in this way, the group was able to “identify some unprecedented opportunities, as well as some necessary barriers to overcome,” he said. These players continue to collaborate in the ongoing clinical trials of novel – and potentially curative – SCD therapies.
The TOPMed (Trans-Omics for Precision Medicine) program is a key mechanism to support SCD-related genetic research. For example, Dr. Hoots said, TOPMed is being used in support of whole-genome sequencing in a longitudinal cohort of patients with SCD who receive transfusion care at four large centers in Brazil.
These renewed efforts, set against the backdrop of paradigm-shifting genetic therapies, represent new promise for a generation of individuals with SCD, Dr. Hoots said. “It takes all of us to address the SCD challenge.”
ASH initiatives
NHLBI isn’t alone in making SCD a priority. The American Society of Hematology also is putting a spotlight on the condition.
The ASH multifaceted sickle cell disease (SCD) initiative addresses the disease burden both within the United States and globally, said LaTasha Lee, PhD, senior manager of sickle cell disease policy and programs for ASH.
Speaking at the 12th annual symposium of the Foundation for Sickle Cell Disease Research, Dr. Lee said that four prongs make up the initiative: disease research, attention to global issues, a renewed focus on access to care in the United States, and work to develop ASH’s new SCD guidelines.
New guidelines on the management of acute and chronic complications of SCD are in the works, with an anticipated 2019 date for publication of five separate guidelines. Topics covered in the guidelines will include pain, cerebrovascular disease, cardiopulmonary and kidney disease, transfusion support, and stem cell transplantation.
“We have new exigency and intensity of effort to enable curative strategies for sickle cell disease to move forward,” said W. Keith Hoots, MD, the director of the division of blood diseases at NHLBI.
The key word in the cure effort is partnership – whether it’s among federal agencies, with public and private organizations, or with patients and families.
“Developmental strategies are built on partnerships to enhance care and accelerate cure for sickle cell disease in the U.S. and worldwide,” Dr. Hoots said at the 12th annual symposium of the Foundation for Sickle Cell Disease Research in Washington.
The reach also extends internationally. Supporting research in sub-Saharan Africa has promised to accelerate the clinical trial process by bringing advanced research capabilities to a region with a very high per capita rate of SCD. While in the United States, infrastructure is being built for a future research network, with the goal of developing a secure database of shared elements that harmonize and unite existing data.
Future cohort studies, enhanced newborn screening, and higher uptake of hydroxyurea will all be supported as part of this effort, Dr. Hoots said.
In the United States, patients can participate in a meaningful way as citizen-scientists, as new technology makes it possible to crowdsource high-quality data collection securely.
And including both community organizations and primary care providers in the “circle of partners” means not only that advances are brought out to patients expeditiously but also that the voices of patients and families have a clear channel back to researchers and policy makers through formal patient engagement and lay participation at all levels, Dr. Hoots said.
“The number of presently interested partners may surprise you,” Dr. Hoots said.
This multifaceted approach allows for “multiple shots on goal, with the acceptance that there could potentially be some failures,” Dr. Hoots said. Keeping all players better connected, though, should allow efforts to be redirected when needed, with a particular focus on accelerating work toward genetic therapies for SCD.
Perhaps the flagship effort is the Cure Sickle Cell Disease Initiative, a new partnership focused on accelerating cure-focused SCD research by filling in gaps left in the network of other funding strategies.
NHLBI named Edward J. Benz Jr., MD, the president and CEO emeritus of Boston’s Dana-Farber Cancer Institute, as the executive director and the Emmes Corporation, a contract research organization with expertise in clinical trials, as the coordinating center.
Traveling the last mile
New strategies also need to focus on how to boost uptake of such currently available best practices in SCD treatment as hydroxyurea use. To that end, Dr. Hoots said, NHLBI is drawing on implementation science, a discipline that, in a medical setting, can help solve such “last-mile” problems as bringing best practices in SCD treatment to patients.
In clinical practice, this might look like solving transportation issues for family members so that appointments aren’t missed and hydroxyurea prescriptions are filled. For researchers, implementation science can help with thorny details of participant recruitment and retention.
Established in 2016, the Sickle Cell Disease Implementation Consortium comprises nine U.S. research centers and NHLBI, which are each seeking to recruit at least 300 participants with SCD, aged 15-45 years, to study effective identification of barriers to care, and the best means to overcome them.
However, Dr. Hoots said, NHLBI also will continue funding SCD research through the traditional investigator-initiated application process, in conjunction with “a suite of specialized programs that can support translational and clinical research in SCD.”
Some of the features rolling out within the Cure SCD Initiative are included in direct response to stakeholder feedback about pressing needs and top priorities. For example, an economic case needed to be made in order for insurance companies, public and private alike, to reimburse for genetic SCD treatments. This requires an understanding of the lifetime cost burden of SCD, as well as determining what the long-term follow-up of costs of gene therapy will be.
Patients, family members and those providing primary care for SCD patients all agreed that clinical trials should have endpoints that reflect meaningful outcomes for patients and should be designed with the input of both patients and providers.
When queried, sickle cell disease researchers expressed a need to identify common data elements in SCD research, and wished for a secure yet accessible national data warehouse for data from gene and cell therapy trials.
At present, there are three clinical trials of curative stem cell approaches for SCD registered with the Blood and Marrow Transplant Clinical Trials Network and several more early phase clinical trials underway, Dr. Hoots said. A primary focus is the use of autologous cells for genomic editing, gene therapy, and erythroid-specific vectors.
Genetic research
As an example of the new collaboration, research centers and biotechnology companies sent their cell and genetic therapy experts to an NIH-sponsored gathering in March 2017. By pooling expertise in this way, the group was able to “identify some unprecedented opportunities, as well as some necessary barriers to overcome,” he said. These players continue to collaborate in the ongoing clinical trials of novel – and potentially curative – SCD therapies.
The TOPMed (Trans-Omics for Precision Medicine) program is a key mechanism to support SCD-related genetic research. For example, Dr. Hoots said, TOPMed is being used in support of whole-genome sequencing in a longitudinal cohort of patients with SCD who receive transfusion care at four large centers in Brazil.
These renewed efforts, set against the backdrop of paradigm-shifting genetic therapies, represent new promise for a generation of individuals with SCD, Dr. Hoots said. “It takes all of us to address the SCD challenge.”
ASH initiatives
NHLBI isn’t alone in making SCD a priority. The American Society of Hematology also is putting a spotlight on the condition.
The ASH multifaceted sickle cell disease (SCD) initiative addresses the disease burden both within the United States and globally, said LaTasha Lee, PhD, senior manager of sickle cell disease policy and programs for ASH.
Speaking at the 12th annual symposium of the Foundation for Sickle Cell Disease Research, Dr. Lee said that four prongs make up the initiative: disease research, attention to global issues, a renewed focus on access to care in the United States, and work to develop ASH’s new SCD guidelines.
New guidelines on the management of acute and chronic complications of SCD are in the works, with an anticipated 2019 date for publication of five separate guidelines. Topics covered in the guidelines will include pain, cerebrovascular disease, cardiopulmonary and kidney disease, transfusion support, and stem cell transplantation.
“We have new exigency and intensity of effort to enable curative strategies for sickle cell disease to move forward,” said W. Keith Hoots, MD, the director of the division of blood diseases at NHLBI.
The key word in the cure effort is partnership – whether it’s among federal agencies, with public and private organizations, or with patients and families.
“Developmental strategies are built on partnerships to enhance care and accelerate cure for sickle cell disease in the U.S. and worldwide,” Dr. Hoots said at the 12th annual symposium of the Foundation for Sickle Cell Disease Research in Washington.
The reach also extends internationally. Supporting research in sub-Saharan Africa has promised to accelerate the clinical trial process by bringing advanced research capabilities to a region with a very high per capita rate of SCD. While in the United States, infrastructure is being built for a future research network, with the goal of developing a secure database of shared elements that harmonize and unite existing data.
Future cohort studies, enhanced newborn screening, and higher uptake of hydroxyurea will all be supported as part of this effort, Dr. Hoots said.
In the United States, patients can participate in a meaningful way as citizen-scientists, as new technology makes it possible to crowdsource high-quality data collection securely.
And including both community organizations and primary care providers in the “circle of partners” means not only that advances are brought out to patients expeditiously but also that the voices of patients and families have a clear channel back to researchers and policy makers through formal patient engagement and lay participation at all levels, Dr. Hoots said.
“The number of presently interested partners may surprise you,” Dr. Hoots said.
This multifaceted approach allows for “multiple shots on goal, with the acceptance that there could potentially be some failures,” Dr. Hoots said. Keeping all players better connected, though, should allow efforts to be redirected when needed, with a particular focus on accelerating work toward genetic therapies for SCD.
Perhaps the flagship effort is the Cure Sickle Cell Disease Initiative, a new partnership focused on accelerating cure-focused SCD research by filling in gaps left in the network of other funding strategies.
NHLBI named Edward J. Benz Jr., MD, the president and CEO emeritus of Boston’s Dana-Farber Cancer Institute, as the executive director and the Emmes Corporation, a contract research organization with expertise in clinical trials, as the coordinating center.
Traveling the last mile
New strategies also need to focus on how to boost uptake of such currently available best practices in SCD treatment as hydroxyurea use. To that end, Dr. Hoots said, NHLBI is drawing on implementation science, a discipline that, in a medical setting, can help solve such “last-mile” problems as bringing best practices in SCD treatment to patients.
In clinical practice, this might look like solving transportation issues for family members so that appointments aren’t missed and hydroxyurea prescriptions are filled. For researchers, implementation science can help with thorny details of participant recruitment and retention.
Established in 2016, the Sickle Cell Disease Implementation Consortium comprises nine U.S. research centers and NHLBI, which are each seeking to recruit at least 300 participants with SCD, aged 15-45 years, to study effective identification of barriers to care, and the best means to overcome them.
However, Dr. Hoots said, NHLBI also will continue funding SCD research through the traditional investigator-initiated application process, in conjunction with “a suite of specialized programs that can support translational and clinical research in SCD.”
Some of the features rolling out within the Cure SCD Initiative are included in direct response to stakeholder feedback about pressing needs and top priorities. For example, an economic case needed to be made in order for insurance companies, public and private alike, to reimburse for genetic SCD treatments. This requires an understanding of the lifetime cost burden of SCD, as well as determining what the long-term follow-up of costs of gene therapy will be.
Patients, family members and those providing primary care for SCD patients all agreed that clinical trials should have endpoints that reflect meaningful outcomes for patients and should be designed with the input of both patients and providers.
When queried, sickle cell disease researchers expressed a need to identify common data elements in SCD research, and wished for a secure yet accessible national data warehouse for data from gene and cell therapy trials.
At present, there are three clinical trials of curative stem cell approaches for SCD registered with the Blood and Marrow Transplant Clinical Trials Network and several more early phase clinical trials underway, Dr. Hoots said. A primary focus is the use of autologous cells for genomic editing, gene therapy, and erythroid-specific vectors.
Genetic research
As an example of the new collaboration, research centers and biotechnology companies sent their cell and genetic therapy experts to an NIH-sponsored gathering in March 2017. By pooling expertise in this way, the group was able to “identify some unprecedented opportunities, as well as some necessary barriers to overcome,” he said. These players continue to collaborate in the ongoing clinical trials of novel – and potentially curative – SCD therapies.
The TOPMed (Trans-Omics for Precision Medicine) program is a key mechanism to support SCD-related genetic research. For example, Dr. Hoots said, TOPMed is being used in support of whole-genome sequencing in a longitudinal cohort of patients with SCD who receive transfusion care at four large centers in Brazil.
These renewed efforts, set against the backdrop of paradigm-shifting genetic therapies, represent new promise for a generation of individuals with SCD, Dr. Hoots said. “It takes all of us to address the SCD challenge.”
ASH initiatives
NHLBI isn’t alone in making SCD a priority. The American Society of Hematology also is putting a spotlight on the condition.
The ASH multifaceted sickle cell disease (SCD) initiative addresses the disease burden both within the United States and globally, said LaTasha Lee, PhD, senior manager of sickle cell disease policy and programs for ASH.
Speaking at the 12th annual symposium of the Foundation for Sickle Cell Disease Research, Dr. Lee said that four prongs make up the initiative: disease research, attention to global issues, a renewed focus on access to care in the United States, and work to develop ASH’s new SCD guidelines.
New guidelines on the management of acute and chronic complications of SCD are in the works, with an anticipated 2019 date for publication of five separate guidelines. Topics covered in the guidelines will include pain, cerebrovascular disease, cardiopulmonary and kidney disease, transfusion support, and stem cell transplantation.
Spinal Muscular Atrophy Added to Recommended Uniform Screening Panel
Screening will enable early detection, but the treatment’s exceptional cost could present a barrier to patients.
Spinal muscular atrophy (SMA) is now among the disorders officially included in the Recommended Uniform Screening Panel (RUSP), which state public health departments use to screen newborns for genetic disorders.
Secretary of the Department of Health and Human Services (HHS) Alex M. Azar II formally added SMA to the panel on July 2 on the recommendation of the Advisory Committee on Heritable Disorders in Newborns and Children.
“Adding SMA to the list will help ensure that babies born with SMA are identified, so that they have the opportunity to benefit from early treatment and intervention,” according to a statement from the Muscular Dystrophy Association about the decision. “This testing can also provide families with a genetic diagnosis—information that often is required to determine whether their child is eligible to participate in clinical trials.”
Adding SMA to the RUSP does not mean that states must screen newborns for the disorder. Each state’s public health apparatus decides independently whether to accept the recommendation and which disorders on the RUSP to screen for. Most states screen for most disorders on the RUSP. Evidence compiled by the advisory committee suggested a wide variation in resources, infrastructure, funding, and time to implementation among states.
Drug Approval Raised Ethical Questions
An estimated one in 11,000 newborns has SMA, a disorder caused by mutations in the survival motor neuron 1 (SMN1) gene. SMA affects motor neurons in the brainstem and spinal cord, thus leading to motor weakness and atrophy. The only treatment for SMA had been palliative care until the FDA approved nusinersen for the disorder in December 2016. The drug’s approval has raised ethical questions.1–3
After reviewing the evidence at its February 8 meeting, the advisory committee recommended adding SMA screening to the RUSP in a March 8 letter from committee chair Joseph A. Bocchini Jr, MD, Professor and Chair of Pediatrics at Louisiana State University Health in Shreveport.
Secretary Azar accepted the recommendation based on the evidence the committee provided; he also requested a follow-up report within two years “describing the status of implementing newborn screening for SMA and clinical outcomes of early treatment, including any potential harms, for infants diagnosed with SMA.”
The advisory committee makes its recommendations to HHS about which heritable disorders to include in the RUSP after it has assessed a systematic, evidence-based review conducted by an external, independent group. Alex R. Kemper, MD, MPH, Professor of Pediatrics at the Ohio State University and Division Chief of Ambulatory Pediatrics at Nationwide Children’s Hospital, both in Columbus, led the review group for SMA. Dr. Kemper is also deputy editor of Pediatrics and a member of the US Preventive Services Task Force.
According to Secretary Azar’s summary in his July 2 letter of acceptance, the evidence review suggested that “early screening and treatment can lead to decreased mortality for individuals with SMA and improved motor milestones.”
“SMA can be detected through newborn screening, and treatment is now available that can not only reduce the risk of death, but decrease the development of neurologic impairment,” he said in an interview. “As with adding any condition to newborn screening, public health laboratories will need to develop strategies to incorporate the screening test. The current FDA-approved treatment, nusinersen, is delivered by lumbar puncture into the spinal fluid. In addition, there are exciting advances in gene therapy leading to new treatment approaches.”
Symptom Onset Distinguishes the Types of SMA
Approximately 95% of SMA cases result from the deletion of exon 7 from both alleles of SMN1. Other, rarer cases are caused by mutations in different genes. Without the SMN protein produced by SMN1, a person gradually loses muscle function.
A similar gene, SMN2, also can produce the SMN protein, but in much lower amounts—typically less than 10% of what a person needs. People can, however, have multiple copies of SMN2, which can produce slightly more SMN protein and slow the disease process.
The five types of SMA are determined according to symptom onset, which directly correlates with disorder severity and prognosis. Approximately 54% of SMA cases are Type I, in which progressive weakness occurs over the first six months of life and results in early death. Only 18% of children with Type I live past age 4, and 68% die by age 2. Type 0 is rarer, but more severe, usually causing fetal loss or early infant death.
Type II represents 18% of SMA cases and causes progressive weakness by age 15 months. Most people with Type II survive to their 30s but later experience respiratory failure and rarely reach their 40s. Individuals with Types III and IV typically have a normal lifespan and only begin to see progressive muscle weakness after age 1 or in adulthood.
Dr. Kemper’s group focused on the three types diagnosed in infancy: Types I, II, and III. “It will be critical to make sure that infants diagnosed with SMA through newborn screening receive follow-up shortly afterward to determine whether they would benefit from nusinersen,” said Dr. Kemper. “More information is needed about the long-term outcomes of those infants who begin treatment following newborn screening, so we not only know about outcomes in later childhood and adolescence, but treatment approaches can be further refined and personalized.”
Long-Term Data on Nusinersen Are Lacking
Nusinersen alters the splicing of precursor messenger RNA in SMN2 so that the mRNA strands are longer, which increases the amount of SMN protein produced. Concerns about the medication, however, have included its cost—$750,000 in the first year and $375,000 every following year for life—and potential adverse events from repeated administration. Nusinersen is injected into the spinal canal four times in the first year and once annually thereafter, and the painful injections require patient immobilization. Potential adverse events include thrombocytopenia and nephrotoxicity, along with potential complications from repeated lumbar punctures over time.2
Other concerns about the drug include its limited evidence base, lack of long-term data, associated costs with administration (eg, travel costs), the potential for patients taking nusinersen to be excluded from future clinical trials on other treatments, and ensuring parents have enough information on the drug’s limitations and potential risks to provide adequate informed consent.2
Yet evidence to date is favorable in children with early onset SMA. Dr. Bocchini wrote in the letter to Secretary Azar that “limited data suggest that treatment effect is greater when the treatment is initiated before symptoms develop and when the individual has more copies of SMN2.”
Dr. Kemper’s group concluded that screening can detect SMA in newborns and that treatment can modify the disease course. “Grey literature suggests those with total disease duration less than or equal to 12 weeks before nusinersen treatment were more likely to have better outcomes than those with longer periods of disease duration.
“Presymptomatic treatment alters the natural history” of the disorder, the group found, although outcome data past age 1 are not yet available. Based on findings from a New York pilot program, they predicted that nationwide newborn screening would avert 33 deaths and 48 cases of children who were dependent on a ventilator among an annual cohort of four million births.
At the time of the evidence review, Massachusetts, Minnesota, Missouri, North Carolina, New York, Utah, and Wisconsin initiated pilot programs or whole-population mandated screening for SMA. Of the three states that reported costs, all reported costs of $1 or less per screen.
The research for the evidence review was funded by a Health Resources and Services Administration grant to Duke University in Durham, North Carolina. No disclosures were provided for evidence review group members.
—Tara Haelle
References
1. King NMP, Bishop CE. New treatments for serious conditions: ethical implications. Gene Ther. 2017;24(9):534-538.
2. Gerrity MS, Prasad V, Obley AJ. Concerns about the approval of nusinersen sodium by the US Food and Drug Administration. JAMA Intern Med. 2018;178(6):743-744.
3. Burgart AM, Magnus D, Tabor HK, et al. Ethical challenges confronted when providing nusinersen treatment for spinal muscular atrophy. JAMA Pediatr. 2018;172(2):188-192.
Screening will enable early detection, but the treatment’s exceptional cost could present a barrier to patients.
Screening will enable early detection, but the treatment’s exceptional cost could present a barrier to patients.
Spinal muscular atrophy (SMA) is now among the disorders officially included in the Recommended Uniform Screening Panel (RUSP), which state public health departments use to screen newborns for genetic disorders.
Secretary of the Department of Health and Human Services (HHS) Alex M. Azar II formally added SMA to the panel on July 2 on the recommendation of the Advisory Committee on Heritable Disorders in Newborns and Children.
“Adding SMA to the list will help ensure that babies born with SMA are identified, so that they have the opportunity to benefit from early treatment and intervention,” according to a statement from the Muscular Dystrophy Association about the decision. “This testing can also provide families with a genetic diagnosis—information that often is required to determine whether their child is eligible to participate in clinical trials.”
Adding SMA to the RUSP does not mean that states must screen newborns for the disorder. Each state’s public health apparatus decides independently whether to accept the recommendation and which disorders on the RUSP to screen for. Most states screen for most disorders on the RUSP. Evidence compiled by the advisory committee suggested a wide variation in resources, infrastructure, funding, and time to implementation among states.
Drug Approval Raised Ethical Questions
An estimated one in 11,000 newborns has SMA, a disorder caused by mutations in the survival motor neuron 1 (SMN1) gene. SMA affects motor neurons in the brainstem and spinal cord, thus leading to motor weakness and atrophy. The only treatment for SMA had been palliative care until the FDA approved nusinersen for the disorder in December 2016. The drug’s approval has raised ethical questions.1–3
After reviewing the evidence at its February 8 meeting, the advisory committee recommended adding SMA screening to the RUSP in a March 8 letter from committee chair Joseph A. Bocchini Jr, MD, Professor and Chair of Pediatrics at Louisiana State University Health in Shreveport.
Secretary Azar accepted the recommendation based on the evidence the committee provided; he also requested a follow-up report within two years “describing the status of implementing newborn screening for SMA and clinical outcomes of early treatment, including any potential harms, for infants diagnosed with SMA.”
The advisory committee makes its recommendations to HHS about which heritable disorders to include in the RUSP after it has assessed a systematic, evidence-based review conducted by an external, independent group. Alex R. Kemper, MD, MPH, Professor of Pediatrics at the Ohio State University and Division Chief of Ambulatory Pediatrics at Nationwide Children’s Hospital, both in Columbus, led the review group for SMA. Dr. Kemper is also deputy editor of Pediatrics and a member of the US Preventive Services Task Force.
According to Secretary Azar’s summary in his July 2 letter of acceptance, the evidence review suggested that “early screening and treatment can lead to decreased mortality for individuals with SMA and improved motor milestones.”
“SMA can be detected through newborn screening, and treatment is now available that can not only reduce the risk of death, but decrease the development of neurologic impairment,” he said in an interview. “As with adding any condition to newborn screening, public health laboratories will need to develop strategies to incorporate the screening test. The current FDA-approved treatment, nusinersen, is delivered by lumbar puncture into the spinal fluid. In addition, there are exciting advances in gene therapy leading to new treatment approaches.”
Symptom Onset Distinguishes the Types of SMA
Approximately 95% of SMA cases result from the deletion of exon 7 from both alleles of SMN1. Other, rarer cases are caused by mutations in different genes. Without the SMN protein produced by SMN1, a person gradually loses muscle function.
A similar gene, SMN2, also can produce the SMN protein, but in much lower amounts—typically less than 10% of what a person needs. People can, however, have multiple copies of SMN2, which can produce slightly more SMN protein and slow the disease process.
The five types of SMA are determined according to symptom onset, which directly correlates with disorder severity and prognosis. Approximately 54% of SMA cases are Type I, in which progressive weakness occurs over the first six months of life and results in early death. Only 18% of children with Type I live past age 4, and 68% die by age 2. Type 0 is rarer, but more severe, usually causing fetal loss or early infant death.
Type II represents 18% of SMA cases and causes progressive weakness by age 15 months. Most people with Type II survive to their 30s but later experience respiratory failure and rarely reach their 40s. Individuals with Types III and IV typically have a normal lifespan and only begin to see progressive muscle weakness after age 1 or in adulthood.
Dr. Kemper’s group focused on the three types diagnosed in infancy: Types I, II, and III. “It will be critical to make sure that infants diagnosed with SMA through newborn screening receive follow-up shortly afterward to determine whether they would benefit from nusinersen,” said Dr. Kemper. “More information is needed about the long-term outcomes of those infants who begin treatment following newborn screening, so we not only know about outcomes in later childhood and adolescence, but treatment approaches can be further refined and personalized.”
Long-Term Data on Nusinersen Are Lacking
Nusinersen alters the splicing of precursor messenger RNA in SMN2 so that the mRNA strands are longer, which increases the amount of SMN protein produced. Concerns about the medication, however, have included its cost—$750,000 in the first year and $375,000 every following year for life—and potential adverse events from repeated administration. Nusinersen is injected into the spinal canal four times in the first year and once annually thereafter, and the painful injections require patient immobilization. Potential adverse events include thrombocytopenia and nephrotoxicity, along with potential complications from repeated lumbar punctures over time.2
Other concerns about the drug include its limited evidence base, lack of long-term data, associated costs with administration (eg, travel costs), the potential for patients taking nusinersen to be excluded from future clinical trials on other treatments, and ensuring parents have enough information on the drug’s limitations and potential risks to provide adequate informed consent.2
Yet evidence to date is favorable in children with early onset SMA. Dr. Bocchini wrote in the letter to Secretary Azar that “limited data suggest that treatment effect is greater when the treatment is initiated before symptoms develop and when the individual has more copies of SMN2.”
Dr. Kemper’s group concluded that screening can detect SMA in newborns and that treatment can modify the disease course. “Grey literature suggests those with total disease duration less than or equal to 12 weeks before nusinersen treatment were more likely to have better outcomes than those with longer periods of disease duration.
“Presymptomatic treatment alters the natural history” of the disorder, the group found, although outcome data past age 1 are not yet available. Based on findings from a New York pilot program, they predicted that nationwide newborn screening would avert 33 deaths and 48 cases of children who were dependent on a ventilator among an annual cohort of four million births.
At the time of the evidence review, Massachusetts, Minnesota, Missouri, North Carolina, New York, Utah, and Wisconsin initiated pilot programs or whole-population mandated screening for SMA. Of the three states that reported costs, all reported costs of $1 or less per screen.
The research for the evidence review was funded by a Health Resources and Services Administration grant to Duke University in Durham, North Carolina. No disclosures were provided for evidence review group members.
—Tara Haelle
References
1. King NMP, Bishop CE. New treatments for serious conditions: ethical implications. Gene Ther. 2017;24(9):534-538.
2. Gerrity MS, Prasad V, Obley AJ. Concerns about the approval of nusinersen sodium by the US Food and Drug Administration. JAMA Intern Med. 2018;178(6):743-744.
3. Burgart AM, Magnus D, Tabor HK, et al. Ethical challenges confronted when providing nusinersen treatment for spinal muscular atrophy. JAMA Pediatr. 2018;172(2):188-192.
Spinal muscular atrophy (SMA) is now among the disorders officially included in the Recommended Uniform Screening Panel (RUSP), which state public health departments use to screen newborns for genetic disorders.
Secretary of the Department of Health and Human Services (HHS) Alex M. Azar II formally added SMA to the panel on July 2 on the recommendation of the Advisory Committee on Heritable Disorders in Newborns and Children.
“Adding SMA to the list will help ensure that babies born with SMA are identified, so that they have the opportunity to benefit from early treatment and intervention,” according to a statement from the Muscular Dystrophy Association about the decision. “This testing can also provide families with a genetic diagnosis—information that often is required to determine whether their child is eligible to participate in clinical trials.”
Adding SMA to the RUSP does not mean that states must screen newborns for the disorder. Each state’s public health apparatus decides independently whether to accept the recommendation and which disorders on the RUSP to screen for. Most states screen for most disorders on the RUSP. Evidence compiled by the advisory committee suggested a wide variation in resources, infrastructure, funding, and time to implementation among states.
Drug Approval Raised Ethical Questions
An estimated one in 11,000 newborns has SMA, a disorder caused by mutations in the survival motor neuron 1 (SMN1) gene. SMA affects motor neurons in the brainstem and spinal cord, thus leading to motor weakness and atrophy. The only treatment for SMA had been palliative care until the FDA approved nusinersen for the disorder in December 2016. The drug’s approval has raised ethical questions.1–3
After reviewing the evidence at its February 8 meeting, the advisory committee recommended adding SMA screening to the RUSP in a March 8 letter from committee chair Joseph A. Bocchini Jr, MD, Professor and Chair of Pediatrics at Louisiana State University Health in Shreveport.
Secretary Azar accepted the recommendation based on the evidence the committee provided; he also requested a follow-up report within two years “describing the status of implementing newborn screening for SMA and clinical outcomes of early treatment, including any potential harms, for infants diagnosed with SMA.”
The advisory committee makes its recommendations to HHS about which heritable disorders to include in the RUSP after it has assessed a systematic, evidence-based review conducted by an external, independent group. Alex R. Kemper, MD, MPH, Professor of Pediatrics at the Ohio State University and Division Chief of Ambulatory Pediatrics at Nationwide Children’s Hospital, both in Columbus, led the review group for SMA. Dr. Kemper is also deputy editor of Pediatrics and a member of the US Preventive Services Task Force.
According to Secretary Azar’s summary in his July 2 letter of acceptance, the evidence review suggested that “early screening and treatment can lead to decreased mortality for individuals with SMA and improved motor milestones.”
“SMA can be detected through newborn screening, and treatment is now available that can not only reduce the risk of death, but decrease the development of neurologic impairment,” he said in an interview. “As with adding any condition to newborn screening, public health laboratories will need to develop strategies to incorporate the screening test. The current FDA-approved treatment, nusinersen, is delivered by lumbar puncture into the spinal fluid. In addition, there are exciting advances in gene therapy leading to new treatment approaches.”
Symptom Onset Distinguishes the Types of SMA
Approximately 95% of SMA cases result from the deletion of exon 7 from both alleles of SMN1. Other, rarer cases are caused by mutations in different genes. Without the SMN protein produced by SMN1, a person gradually loses muscle function.
A similar gene, SMN2, also can produce the SMN protein, but in much lower amounts—typically less than 10% of what a person needs. People can, however, have multiple copies of SMN2, which can produce slightly more SMN protein and slow the disease process.
The five types of SMA are determined according to symptom onset, which directly correlates with disorder severity and prognosis. Approximately 54% of SMA cases are Type I, in which progressive weakness occurs over the first six months of life and results in early death. Only 18% of children with Type I live past age 4, and 68% die by age 2. Type 0 is rarer, but more severe, usually causing fetal loss or early infant death.
Type II represents 18% of SMA cases and causes progressive weakness by age 15 months. Most people with Type II survive to their 30s but later experience respiratory failure and rarely reach their 40s. Individuals with Types III and IV typically have a normal lifespan and only begin to see progressive muscle weakness after age 1 or in adulthood.
Dr. Kemper’s group focused on the three types diagnosed in infancy: Types I, II, and III. “It will be critical to make sure that infants diagnosed with SMA through newborn screening receive follow-up shortly afterward to determine whether they would benefit from nusinersen,” said Dr. Kemper. “More information is needed about the long-term outcomes of those infants who begin treatment following newborn screening, so we not only know about outcomes in later childhood and adolescence, but treatment approaches can be further refined and personalized.”
Long-Term Data on Nusinersen Are Lacking
Nusinersen alters the splicing of precursor messenger RNA in SMN2 so that the mRNA strands are longer, which increases the amount of SMN protein produced. Concerns about the medication, however, have included its cost—$750,000 in the first year and $375,000 every following year for life—and potential adverse events from repeated administration. Nusinersen is injected into the spinal canal four times in the first year and once annually thereafter, and the painful injections require patient immobilization. Potential adverse events include thrombocytopenia and nephrotoxicity, along with potential complications from repeated lumbar punctures over time.2
Other concerns about the drug include its limited evidence base, lack of long-term data, associated costs with administration (eg, travel costs), the potential for patients taking nusinersen to be excluded from future clinical trials on other treatments, and ensuring parents have enough information on the drug’s limitations and potential risks to provide adequate informed consent.2
Yet evidence to date is favorable in children with early onset SMA. Dr. Bocchini wrote in the letter to Secretary Azar that “limited data suggest that treatment effect is greater when the treatment is initiated before symptoms develop and when the individual has more copies of SMN2.”
Dr. Kemper’s group concluded that screening can detect SMA in newborns and that treatment can modify the disease course. “Grey literature suggests those with total disease duration less than or equal to 12 weeks before nusinersen treatment were more likely to have better outcomes than those with longer periods of disease duration.
“Presymptomatic treatment alters the natural history” of the disorder, the group found, although outcome data past age 1 are not yet available. Based on findings from a New York pilot program, they predicted that nationwide newborn screening would avert 33 deaths and 48 cases of children who were dependent on a ventilator among an annual cohort of four million births.
At the time of the evidence review, Massachusetts, Minnesota, Missouri, North Carolina, New York, Utah, and Wisconsin initiated pilot programs or whole-population mandated screening for SMA. Of the three states that reported costs, all reported costs of $1 or less per screen.
The research for the evidence review was funded by a Health Resources and Services Administration grant to Duke University in Durham, North Carolina. No disclosures were provided for evidence review group members.
—Tara Haelle
References
1. King NMP, Bishop CE. New treatments for serious conditions: ethical implications. Gene Ther. 2017;24(9):534-538.
2. Gerrity MS, Prasad V, Obley AJ. Concerns about the approval of nusinersen sodium by the US Food and Drug Administration. JAMA Intern Med. 2018;178(6):743-744.
3. Burgart AM, Magnus D, Tabor HK, et al. Ethical challenges confronted when providing nusinersen treatment for spinal muscular atrophy. JAMA Pediatr. 2018;172(2):188-192.