Anemia

Patients with TP53-mutated myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) may benefit from treatment with decitabine, according to a study published in NEJM.

All patients in this study who had TP53 mutations responded to decitabine.

Although these responses were not durable, the patients’ median overall survival was similar to that of patients with lower-risk disease who received decitabine.

“The findings need to be validated in a larger trial, but they do suggest that TP53 mutations can reliably predict responses to decitabine, potentially prolonging survival in this ultra-high-risk group of patients and providing a bridge to transplantation in some patients who might not otherwise be candidates,” said study author Timothy J. Ley, MD, of Washington University School of Medicine in St. Louis, Missouri.

For this study, Dr Ley and his colleagues analyzed 116 patients—54 with AML, 36 with relapsed AML, and 26 with MDS.

Eighty-four of the patients were enrolled in a prospective trial and received decitabine at a dose of 20 mg/m²/day for 10 consecutive days in monthly cycles. Thirty-two additional patients received decitabine on different protocols.

To determine whether genetic mutations could be used to predict responses to decitabine, the researchers performed enhanced exome or gene-panel sequencing in 67 of the patients. The team also performed sequencing at multiple time points to evaluate patterns of mutation clearance in 54 patients.

Response

Thirteen percent of patients (n=15) achieved a complete response (CR), 21% (n=24) had a CR with incomplete count recovery, 5% (n=6) had a morphologic CR with hematologic improvement, and 7% (n=8) had a morphologic CR without hematologic improvement.

Eight percent of patients (n=9) had a partial response, 20% (n=23) had stable disease, and 16% (n=19) had progressive disease.

There were 21 patients with TP53 mutations, and all of them achieved bone marrow blast clearance with less than 5% blasts.

Nineteen percent (n=4) had a CR, 43% (n=9) had a CR with incomplete count recovery, 24% (n=5) had morphologic CR with hematologic improvement, and 14% (n=3) had morphologic CR without hematologic improvement.

“What’s really unique here is that all the patients in the study with TP53 mutations had a response to decitabine and achieved an initial remission,” Dr Ley said.

“With standard aggressive chemotherapy, we only see about 20% to 30% of these patients achieving remission, which is the critical first step to have a chance to cure patients with additional therapies.”

Dr Ley and his colleagues also found that patients in this study were likely to respond to decitabine if they were considered “unfavorable risk” based on extensive chromosomal rearrangements. (Many of these patients also had TP53 mutations.)

Indeed, 67% (29/43) of patients with an unfavorable risk had less than 5% blasts after treatment with decitabine, compared with 34% (24/71) of patients with intermediate or favorable risk.

“The challenge with using decitabine has been knowing which patients are most likely to respond,” said study author Amanda Cashen, MD, of Washington University School of Medicine.

“The value of this study is the comprehensive mutational analysis that helps us figure out which patients are likely to benefit. This information opens the door to using decitabine in a more targeted fashion to treat not just older patients, but also younger patients who carry TP53 mutations.”

Survival and next steps

The researchers found that responses to decitabine were usually short-lived. The drug did not provide complete mutation clearance, which led to relapse.

“Remissions with decitabine typically don’t last long, and no one was cured with this drug,” Dr Ley noted. “But patients who responded to decitabine live longer than what you would expect with aggressive chemotherapy, and that can mean something. Some people live a year or 2 and with a good quality of life because the chemotherapy is not too toxic.”

 

The median overall survival was 11.6 months among patients with unfavorable risk and 10 months among patients with favorable or intermediate risk (P=0.29).

The median overall survival was 12.7 months among patients with TP53 mutations and 15.4 months among patients with wild-type TP53 (P=0.79).

“It’s important to note that patients with an extremely poor prognosis in this relatively small study had the same survival outcomes as patients facing a better prognosis, which is encouraging,” said study author John Welch, MD, PhD, of Washington University School of Medicine.

“We don’t yet understand why patients with TP53 mutations consistently respond to decitabine, and more work is needed to understand that phenomenon. We’re now planning a larger trial to evaluate decitabine in AML patients of all ages who carry TP53 mutations. It’s exciting to think we may have a therapy that has the potential to improve response rates in this group of high-risk patients.”

Patients with TP53-mutated myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) may benefit from treatment with decitabine, according to a study published in NEJM.

All patients in this study who had TP53 mutations responded to decitabine.

Although these responses were not durable, the patients’ median overall survival was similar to that of patients with lower-risk disease who received decitabine.

“The findings need to be validated in a larger trial, but they do suggest that TP53 mutations can reliably predict responses to decitabine, potentially prolonging survival in this ultra-high-risk group of patients and providing a bridge to transplantation in some patients who might not otherwise be candidates,” said study author Timothy J. Ley, MD, of Washington University School of Medicine in St. Louis, Missouri.

For this study, Dr Ley and his colleagues analyzed 116 patients—54 with AML, 36 with relapsed AML, and 26 with MDS.

Eighty-four of the patients were enrolled in a prospective trial and received decitabine at a dose of 20 mg/m²/day for 10 consecutive days in monthly cycles. Thirty-two additional patients received decitabine on different protocols.

To determine whether genetic mutations could be used to predict responses to decitabine, the researchers performed enhanced exome or gene-panel sequencing in 67 of the patients. The team also performed sequencing at multiple time points to evaluate patterns of mutation clearance in 54 patients.

Response

Thirteen percent of patients (n=15) achieved a complete response (CR), 21% (n=24) had a CR with incomplete count recovery, 5% (n=6) had a morphologic CR with hematologic improvement, and 7% (n=8) had a morphologic CR without hematologic improvement.

Eight percent of patients (n=9) had a partial response, 20% (n=23) had stable disease, and 16% (n=19) had progressive disease.

There were 21 patients with TP53 mutations, and all of them achieved bone marrow blast clearance with less than 5% blasts.

Nineteen percent (n=4) had a CR, 43% (n=9) had a CR with incomplete count recovery, 24% (n=5) had morphologic CR with hematologic improvement, and 14% (n=3) had morphologic CR without hematologic improvement.

“What’s really unique here is that all the patients in the study with TP53 mutations had a response to decitabine and achieved an initial remission,” Dr Ley said.

“With standard aggressive chemotherapy, we only see about 20% to 30% of these patients achieving remission, which is the critical first step to have a chance to cure patients with additional therapies.”

Dr Ley and his colleagues also found that patients in this study were likely to respond to decitabine if they were considered “unfavorable risk” based on extensive chromosomal rearrangements. (Many of these patients also had TP53 mutations.)

Indeed, 67% (29/43) of patients with an unfavorable risk had less than 5% blasts after treatment with decitabine, compared with 34% (24/71) of patients with intermediate or favorable risk.

“The challenge with using decitabine has been knowing which patients are most likely to respond,” said study author Amanda Cashen, MD, of Washington University School of Medicine.

“The value of this study is the comprehensive mutational analysis that helps us figure out which patients are likely to benefit. This information opens the door to using decitabine in a more targeted fashion to treat not just older patients, but also younger patients who carry TP53 mutations.”

Survival and next steps

The researchers found that responses to decitabine were usually short-lived. The drug did not provide complete mutation clearance, which led to relapse.

“Remissions with decitabine typically don’t last long, and no one was cured with this drug,” Dr Ley noted. “But patients who responded to decitabine live longer than what you would expect with aggressive chemotherapy, and that can mean something. Some people live a year or 2 and with a good quality of life because the chemotherapy is not too toxic.”

 

The median overall survival was 11.6 months among patients with unfavorable risk and 10 months among patients with favorable or intermediate risk (P=0.29).

The median overall survival was 12.7 months among patients with TP53 mutations and 15.4 months among patients with wild-type TP53 (P=0.79).

“It’s important to note that patients with an extremely poor prognosis in this relatively small study had the same survival outcomes as patients facing a better prognosis, which is encouraging,” said study author John Welch, MD, PhD, of Washington University School of Medicine.

“We don’t yet understand why patients with TP53 mutations consistently respond to decitabine, and more work is needed to understand that phenomenon. We’re now planning a larger trial to evaluate decitabine in AML patients of all ages who carry TP53 mutations. It’s exciting to think we may have a therapy that has the potential to improve response rates in this group of high-risk patients.”

Patients with TP53-mutated myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) may benefit from treatment with decitabine, according to a study published in NEJM.

All patients in this study who had TP53 mutations responded to decitabine.

Although these responses were not durable, the patients’ median overall survival was similar to that of patients with lower-risk disease who received decitabine.

“The findings need to be validated in a larger trial, but they do suggest that TP53 mutations can reliably predict responses to decitabine, potentially prolonging survival in this ultra-high-risk group of patients and providing a bridge to transplantation in some patients who might not otherwise be candidates,” said study author Timothy J. Ley, MD, of Washington University School of Medicine in St. Louis, Missouri.

For this study, Dr Ley and his colleagues analyzed 116 patients—54 with AML, 36 with relapsed AML, and 26 with MDS.

Eighty-four of the patients were enrolled in a prospective trial and received decitabine at a dose of 20 mg/m²/day for 10 consecutive days in monthly cycles. Thirty-two additional patients received decitabine on different protocols.

To determine whether genetic mutations could be used to predict responses to decitabine, the researchers performed enhanced exome or gene-panel sequencing in 67 of the patients. The team also performed sequencing at multiple time points to evaluate patterns of mutation clearance in 54 patients.

Response

Thirteen percent of patients (n=15) achieved a complete response (CR), 21% (n=24) had a CR with incomplete count recovery, 5% (n=6) had a morphologic CR with hematologic improvement, and 7% (n=8) had a morphologic CR without hematologic improvement.

Eight percent of patients (n=9) had a partial response, 20% (n=23) had stable disease, and 16% (n=19) had progressive disease.

There were 21 patients with TP53 mutations, and all of them achieved bone marrow blast clearance with less than 5% blasts.

Nineteen percent (n=4) had a CR, 43% (n=9) had a CR with incomplete count recovery, 24% (n=5) had morphologic CR with hematologic improvement, and 14% (n=3) had morphologic CR without hematologic improvement.

“What’s really unique here is that all the patients in the study with TP53 mutations had a response to decitabine and achieved an initial remission,” Dr Ley said.

“With standard aggressive chemotherapy, we only see about 20% to 30% of these patients achieving remission, which is the critical first step to have a chance to cure patients with additional therapies.”

Dr Ley and his colleagues also found that patients in this study were likely to respond to decitabine if they were considered “unfavorable risk” based on extensive chromosomal rearrangements. (Many of these patients also had TP53 mutations.)

Indeed, 67% (29/43) of patients with an unfavorable risk had less than 5% blasts after treatment with decitabine, compared with 34% (24/71) of patients with intermediate or favorable risk.

“The challenge with using decitabine has been knowing which patients are most likely to respond,” said study author Amanda Cashen, MD, of Washington University School of Medicine.

“The value of this study is the comprehensive mutational analysis that helps us figure out which patients are likely to benefit. This information opens the door to using decitabine in a more targeted fashion to treat not just older patients, but also younger patients who carry TP53 mutations.”

Survival and next steps

The researchers found that responses to decitabine were usually short-lived. The drug did not provide complete mutation clearance, which led to relapse.

“Remissions with decitabine typically don’t last long, and no one was cured with this drug,” Dr Ley noted. “But patients who responded to decitabine live longer than what you would expect with aggressive chemotherapy, and that can mean something. Some people live a year or 2 and with a good quality of life because the chemotherapy is not too toxic.”

 

The median overall survival was 11.6 months among patients with unfavorable risk and 10 months among patients with favorable or intermediate risk (P=0.29).

The median overall survival was 12.7 months among patients with TP53 mutations and 15.4 months among patients with wild-type TP53 (P=0.79).

“It’s important to note that patients with an extremely poor prognosis in this relatively small study had the same survival outcomes as patients facing a better prognosis, which is encouraging,” said study author John Welch, MD, PhD, of Washington University School of Medicine.

“We don’t yet understand why patients with TP53 mutations consistently respond to decitabine, and more work is needed to understand that phenomenon. We’re now planning a larger trial to evaluate decitabine in AML patients of all ages who carry TP53 mutations. It’s exciting to think we may have a therapy that has the potential to improve response rates in this group of high-risk patients.”

The European Commission (EC) has granted orphan drug designation to RA101495 for the treatment of paroxysmal nocturnal hemoglobinuria (PNH).

RA101495 is a synthetic macrocyclic peptide inhibitor of complement component C5.

Ra Pharmaceuticals is developing RA101495 as a self-administered, subcutaneous injection for the treatment of PNH, refractory generalized myasthenia gravis, and lupus nephritis.

RA101495 binds complement C5 with subnanomolar affinity and allosterically inhibits its cleavage into C5a and C5b upon activation of the classical, alternative, or lectin pathways.

RA101495 also directly binds to C5b, disrupting the interaction between C5b and C6 and preventing assembly of the membrane attack complex.

According to Ra Pharmaceuticals, repeat dosing of RA101495 in vivo has demonstrated “sustained and predictable” inhibition of complement activity with an “excellent” safety profile.

The company also said phase 1 data have suggested that RA101495 is potent inhibitor of C5-mediated hemolysis with a favorable safety profile.

Preclinical research involving RA101495 was presented at the 2015 ASH Annual Meeting, and phase 1 data were presented at the 21st Congress of the European Hematology Association earlier this year.

RA101495’s orphan designation

The EC grants orphan designation to therapies intended to treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

In situations where there is already an approved standard of care—such as with PNH, where the monoclonal antibody eculizumab (Soliris) is currently available—the EC requires companies developing a potential orphan drug to provide evidence that the drug is expected to provide significant benefits over the standard of care.

In the case of RA101495, the decision to grant orphan designation was based on the potential for improved patient convenience with subcutaneous self-administration, as well as the potential to treat patients who do not respond to eculizumab.

Orphan designation provides the company developing a drug with regulatory and financial incentives, including protocol assistance, 10 years of market exclusivity once the drug is approved, and, in some cases, reductions in fees.

The European Commission (EC) has granted orphan drug designation to RA101495 for the treatment of paroxysmal nocturnal hemoglobinuria (PNH).

RA101495 is a synthetic macrocyclic peptide inhibitor of complement component C5.

Ra Pharmaceuticals is developing RA101495 as a self-administered, subcutaneous injection for the treatment of PNH, refractory generalized myasthenia gravis, and lupus nephritis.

RA101495 binds complement C5 with subnanomolar affinity and allosterically inhibits its cleavage into C5a and C5b upon activation of the classical, alternative, or lectin pathways.

RA101495 also directly binds to C5b, disrupting the interaction between C5b and C6 and preventing assembly of the membrane attack complex.

According to Ra Pharmaceuticals, repeat dosing of RA101495 in vivo has demonstrated “sustained and predictable” inhibition of complement activity with an “excellent” safety profile.

The company also said phase 1 data have suggested that RA101495 is potent inhibitor of C5-mediated hemolysis with a favorable safety profile.

Preclinical research involving RA101495 was presented at the 2015 ASH Annual Meeting, and phase 1 data were presented at the 21st Congress of the European Hematology Association earlier this year.

RA101495’s orphan designation

The EC grants orphan designation to therapies intended to treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

In situations where there is already an approved standard of care—such as with PNH, where the monoclonal antibody eculizumab (Soliris) is currently available—the EC requires companies developing a potential orphan drug to provide evidence that the drug is expected to provide significant benefits over the standard of care.

In the case of RA101495, the decision to grant orphan designation was based on the potential for improved patient convenience with subcutaneous self-administration, as well as the potential to treat patients who do not respond to eculizumab.

Orphan designation provides the company developing a drug with regulatory and financial incentives, including protocol assistance, 10 years of market exclusivity once the drug is approved, and, in some cases, reductions in fees.

The European Commission (EC) has granted orphan drug designation to RA101495 for the treatment of paroxysmal nocturnal hemoglobinuria (PNH).

RA101495 is a synthetic macrocyclic peptide inhibitor of complement component C5.

Ra Pharmaceuticals is developing RA101495 as a self-administered, subcutaneous injection for the treatment of PNH, refractory generalized myasthenia gravis, and lupus nephritis.

RA101495 binds complement C5 with subnanomolar affinity and allosterically inhibits its cleavage into C5a and C5b upon activation of the classical, alternative, or lectin pathways.

RA101495 also directly binds to C5b, disrupting the interaction between C5b and C6 and preventing assembly of the membrane attack complex.

According to Ra Pharmaceuticals, repeat dosing of RA101495 in vivo has demonstrated “sustained and predictable” inhibition of complement activity with an “excellent” safety profile.

The company also said phase 1 data have suggested that RA101495 is potent inhibitor of C5-mediated hemolysis with a favorable safety profile.

Preclinical research involving RA101495 was presented at the 2015 ASH Annual Meeting, and phase 1 data were presented at the 21st Congress of the European Hematology Association earlier this year.

RA101495’s orphan designation

The EC grants orphan designation to therapies intended to treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

In situations where there is already an approved standard of care—such as with PNH, where the monoclonal antibody eculizumab (Soliris) is currently available—the EC requires companies developing a potential orphan drug to provide evidence that the drug is expected to provide significant benefits over the standard of care.

In the case of RA101495, the decision to grant orphan designation was based on the potential for improved patient convenience with subcutaneous self-administration, as well as the potential to treat patients who do not respond to eculizumab.

Orphan designation provides the company developing a drug with regulatory and financial incentives, including protocol assistance, 10 years of market exclusivity once the drug is approved, and, in some cases, reductions in fees.

The humanized antibody SelG1 decreased the frequency of acute pain episodes in people with sickle cell disease, based on results from the multinational, randomized, double-blind, placebo-controlled SUSTAIN study that will be presented at the annual meeting of the American Society of Hematology in San Diego.

In other sickle cell disease research to be presented at the meeting, researchers will be presenting new findings from two studies conducted in Africa. One study examines a team approach to reduce mortality in pregnant women with sickle cell disease in Ghana. The other study, called SPIN, is a safety and feasibility study conducted in advance of a randomized trial in Nigerian children at risk for stroke.

CDC/Janice Haney Carr

In the study of SelG1, a first-in-class humanized anti–P-selectin antibody, a research team led by Kenneth Ataga, MD, of the University of North Carolina at Chapel Hill, recruited 198 patients aged 16-65 years with sickle cell disease. The patients were randomized to one of three groups: a 3 mg/kg dose of SelG1, a 5 mg/kg dose of SelG1, or placebo.

After 1 year, the annual rate of sickle cell–related pain crises resulting in a visit to a medical facility was 1.6 in the group receiving the 5 mg/kg dose, compared with 3 in the placebo group. The 47% difference was statistically significant (P = .01).

Also, time to first pain crisis was a median of 4 months in those who received the 5 mg/kg dose and 1.4 months for those in the placebo group (P = .001).

Infections were not seen increased in either of the groups randomized to SelG1, and no treatment-related deaths occurred during the course of the study. The first-in-class agent “appears to be safe and well tolerated,” as well as effective in reducing pain episodes, Dr. Ataga and his colleagues wrote in their abstract.

In the Nigerian trial, led by Najibah Aliyu Galadanci, MD, MPH, of Bayero University in Kano, Nigeria, the goal was to determine whether families of children with sickle cell disease and transcranial Doppler measurements indicative of increased risk for stroke could be recruited and retained in a large clinical trial, and whether they could adhere to the medication regimen. The trial also obtained preliminary evidence for hydroxyurea’s safety in this clinical setting, where transfusion therapy is not an option for most children.

Dr. Galadanci and her colleagues approached 375 families for transcranial Doppler screening, and 90% accepted. Among families of children found to have elevated measures of risk on transcranial Doppler, 92% participated in the study and received a moderate dose of hydroxyurea (20 mg/kg) for 2 years. A comparison group included 210 children without elevated measures on transcranial Doppler. These children underwent regular monitoring but were not offered medication unless transcranial Doppler measures were found to be elevated.

Study adherence was exceptionally high: the families missed no monthly research visits, and no participants in the active treatment group dropped out voluntarily.

Also, at 2 years, the children treated with hydroxyurea did not have evidence of excessive toxicity, compared with the children who did not receive the drug. “Our results provide strong preliminary evidence supporting the current multicenter randomized controlled trial comparing hydroxyurea therapy (20 mg/kg per day vs. 10 mg/kg per day) for preventing primary strokes in children with sickle cell anemia living in Nigeria,” Dr. Galadanci and her colleagues wrote in their abstract.

In the third study, a multidisciplinary team decreased mortality in pregnant women who had sickle cell disease and lived in low and middle income settings, according to Eugenia Vicky Naa Kwarley Asare, MD, of the Ghana Institute of Clinical Genetics and the Korle-Bu Teaching Hospital in Accra.

In a prospective trial in Ghana, where maternal mortality among women with sickle cell disease is estimated to be 8,300 per 100,000 live births, compared with 690 for women without sickle cell disease, Dr. Asare and her colleagues’ multidisciplinary team included obstetricians, hematologists, pulmonologists, and nurses, and the planned intervention protocols included a number of changes to make management more consistent and intensive. A total of 154 pregnancies were evaluated before the intervention, and 91 after. Median gestational age was 24 weeks at enrollment, and median maternal age was 29 years for both pre- and post-intervention cohorts.

Maternal mortality before the intervention was 9.7% (15 of 154) and after the intervention was 1.1% (1 of 91) of total deliveries.

Dr. Ataga’s study was sponsored by Selexys Pharmaceuticals, the drug’s manufacturer, and included coinvestigators who are employees of Selexys Pharmaceuticals or who disclosed relationships with other drug manufacturers. Dr. Galadanci’s and Dr. Asare’s groups disclosed no conflicts of interest.

The humanized antibody SelG1 decreased the frequency of acute pain episodes in people with sickle cell disease, based on results from the multinational, randomized, double-blind, placebo-controlled SUSTAIN study that will be presented at the annual meeting of the American Society of Hematology in San Diego.

In other sickle cell disease research to be presented at the meeting, researchers will be presenting new findings from two studies conducted in Africa. One study examines a team approach to reduce mortality in pregnant women with sickle cell disease in Ghana. The other study, called SPIN, is a safety and feasibility study conducted in advance of a randomized trial in Nigerian children at risk for stroke.

CDC/Janice Haney Carr

In the study of SelG1, a first-in-class humanized anti–P-selectin antibody, a research team led by Kenneth Ataga, MD, of the University of North Carolina at Chapel Hill, recruited 198 patients aged 16-65 years with sickle cell disease. The patients were randomized to one of three groups: a 3 mg/kg dose of SelG1, a 5 mg/kg dose of SelG1, or placebo.

After 1 year, the annual rate of sickle cell–related pain crises resulting in a visit to a medical facility was 1.6 in the group receiving the 5 mg/kg dose, compared with 3 in the placebo group. The 47% difference was statistically significant (P = .01).

Also, time to first pain crisis was a median of 4 months in those who received the 5 mg/kg dose and 1.4 months for those in the placebo group (P = .001).

Infections were not seen increased in either of the groups randomized to SelG1, and no treatment-related deaths occurred during the course of the study. The first-in-class agent “appears to be safe and well tolerated,” as well as effective in reducing pain episodes, Dr. Ataga and his colleagues wrote in their abstract.

In the Nigerian trial, led by Najibah Aliyu Galadanci, MD, MPH, of Bayero University in Kano, Nigeria, the goal was to determine whether families of children with sickle cell disease and transcranial Doppler measurements indicative of increased risk for stroke could be recruited and retained in a large clinical trial, and whether they could adhere to the medication regimen. The trial also obtained preliminary evidence for hydroxyurea’s safety in this clinical setting, where transfusion therapy is not an option for most children.

Dr. Galadanci and her colleagues approached 375 families for transcranial Doppler screening, and 90% accepted. Among families of children found to have elevated measures of risk on transcranial Doppler, 92% participated in the study and received a moderate dose of hydroxyurea (20 mg/kg) for 2 years. A comparison group included 210 children without elevated measures on transcranial Doppler. These children underwent regular monitoring but were not offered medication unless transcranial Doppler measures were found to be elevated.

Study adherence was exceptionally high: the families missed no monthly research visits, and no participants in the active treatment group dropped out voluntarily.

Also, at 2 years, the children treated with hydroxyurea did not have evidence of excessive toxicity, compared with the children who did not receive the drug. “Our results provide strong preliminary evidence supporting the current multicenter randomized controlled trial comparing hydroxyurea therapy (20 mg/kg per day vs. 10 mg/kg per day) for preventing primary strokes in children with sickle cell anemia living in Nigeria,” Dr. Galadanci and her colleagues wrote in their abstract.

In the third study, a multidisciplinary team decreased mortality in pregnant women who had sickle cell disease and lived in low and middle income settings, according to Eugenia Vicky Naa Kwarley Asare, MD, of the Ghana Institute of Clinical Genetics and the Korle-Bu Teaching Hospital in Accra.

In a prospective trial in Ghana, where maternal mortality among women with sickle cell disease is estimated to be 8,300 per 100,000 live births, compared with 690 for women without sickle cell disease, Dr. Asare and her colleagues’ multidisciplinary team included obstetricians, hematologists, pulmonologists, and nurses, and the planned intervention protocols included a number of changes to make management more consistent and intensive. A total of 154 pregnancies were evaluated before the intervention, and 91 after. Median gestational age was 24 weeks at enrollment, and median maternal age was 29 years for both pre- and post-intervention cohorts.

Maternal mortality before the intervention was 9.7% (15 of 154) and after the intervention was 1.1% (1 of 91) of total deliveries.

Dr. Ataga’s study was sponsored by Selexys Pharmaceuticals, the drug’s manufacturer, and included coinvestigators who are employees of Selexys Pharmaceuticals or who disclosed relationships with other drug manufacturers. Dr. Galadanci’s and Dr. Asare’s groups disclosed no conflicts of interest.

The humanized antibody SelG1 decreased the frequency of acute pain episodes in people with sickle cell disease, based on results from the multinational, randomized, double-blind, placebo-controlled SUSTAIN study that will be presented at the annual meeting of the American Society of Hematology in San Diego.

In other sickle cell disease research to be presented at the meeting, researchers will be presenting new findings from two studies conducted in Africa. One study examines a team approach to reduce mortality in pregnant women with sickle cell disease in Ghana. The other study, called SPIN, is a safety and feasibility study conducted in advance of a randomized trial in Nigerian children at risk for stroke.

CDC/Janice Haney Carr

In the study of SelG1, a first-in-class humanized anti–P-selectin antibody, a research team led by Kenneth Ataga, MD, of the University of North Carolina at Chapel Hill, recruited 198 patients aged 16-65 years with sickle cell disease. The patients were randomized to one of three groups: a 3 mg/kg dose of SelG1, a 5 mg/kg dose of SelG1, or placebo.

After 1 year, the annual rate of sickle cell–related pain crises resulting in a visit to a medical facility was 1.6 in the group receiving the 5 mg/kg dose, compared with 3 in the placebo group. The 47% difference was statistically significant (P = .01).

Also, time to first pain crisis was a median of 4 months in those who received the 5 mg/kg dose and 1.4 months for those in the placebo group (P = .001).

Infections were not seen increased in either of the groups randomized to SelG1, and no treatment-related deaths occurred during the course of the study. The first-in-class agent “appears to be safe and well tolerated,” as well as effective in reducing pain episodes, Dr. Ataga and his colleagues wrote in their abstract.

In the Nigerian trial, led by Najibah Aliyu Galadanci, MD, MPH, of Bayero University in Kano, Nigeria, the goal was to determine whether families of children with sickle cell disease and transcranial Doppler measurements indicative of increased risk for stroke could be recruited and retained in a large clinical trial, and whether they could adhere to the medication regimen. The trial also obtained preliminary evidence for hydroxyurea’s safety in this clinical setting, where transfusion therapy is not an option for most children.

Dr. Galadanci and her colleagues approached 375 families for transcranial Doppler screening, and 90% accepted. Among families of children found to have elevated measures of risk on transcranial Doppler, 92% participated in the study and received a moderate dose of hydroxyurea (20 mg/kg) for 2 years. A comparison group included 210 children without elevated measures on transcranial Doppler. These children underwent regular monitoring but were not offered medication unless transcranial Doppler measures were found to be elevated.

Study adherence was exceptionally high: the families missed no monthly research visits, and no participants in the active treatment group dropped out voluntarily.

Also, at 2 years, the children treated with hydroxyurea did not have evidence of excessive toxicity, compared with the children who did not receive the drug. “Our results provide strong preliminary evidence supporting the current multicenter randomized controlled trial comparing hydroxyurea therapy (20 mg/kg per day vs. 10 mg/kg per day) for preventing primary strokes in children with sickle cell anemia living in Nigeria,” Dr. Galadanci and her colleagues wrote in their abstract.

In the third study, a multidisciplinary team decreased mortality in pregnant women who had sickle cell disease and lived in low and middle income settings, according to Eugenia Vicky Naa Kwarley Asare, MD, of the Ghana Institute of Clinical Genetics and the Korle-Bu Teaching Hospital in Accra.

In a prospective trial in Ghana, where maternal mortality among women with sickle cell disease is estimated to be 8,300 per 100,000 live births, compared with 690 for women without sickle cell disease, Dr. Asare and her colleagues’ multidisciplinary team included obstetricians, hematologists, pulmonologists, and nurses, and the planned intervention protocols included a number of changes to make management more consistent and intensive. A total of 154 pregnancies were evaluated before the intervention, and 91 after. Median gestational age was 24 weeks at enrollment, and median maternal age was 29 years for both pre- and post-intervention cohorts.

Maternal mortality before the intervention was 9.7% (15 of 154) and after the intervention was 1.1% (1 of 91) of total deliveries.

Dr. Ataga’s study was sponsored by Selexys Pharmaceuticals, the drug’s manufacturer, and included coinvestigators who are employees of Selexys Pharmaceuticals or who disclosed relationships with other drug manufacturers. Dr. Galadanci’s and Dr. Asare’s groups disclosed no conflicts of interest.

Findings from a study of people living at high altitude have implications for the treatment of red blood cell (RBC) disorders such as anemia and polycythemia, according to researchers.

To better understand why some people adapt well to life at high altitude while others don’t, the researchers studied RBCs derived from representatives of both groups who were living in the Andes Mountains.

The study revealed that high-altitude dwellers prone to chronic mountain sickness produce massive amounts of RBCs thanks to overproduction of the enzyme SENP1.

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

“In addition to improving the health of millions of people around the world who live above 8000 feet, information on how Andeans have adapted—or not adapted—to high-altitude life might teach us how to speed up red blood cell production at lower altitudes, such as in anemia or when blood transfusions are needed rapidly,” said study author Gabriel Haddad, MD, of the University of California San Diego School of Medicine.

Dr Haddad and his colleagues noted that chronic mountain sickness affects approximately 20% of people who live at high altitudes, and a critical aspect of the condition is polycythemia.

Some extra RBCs can be beneficial in high-altitude, low-oxygen environments by helping to keep blood oxygenated. However, too many RBCs can increase the risk of heart attack and stroke, even in young adults.

For this study, the researchers collected skin cells from people living in the Andes Mountains—4 who were healthy and 5 who suffer from chronic mountain sickness—plus an additional 3 healthy people who live at sea level and served as controls.

To produce enough RBCs from each participant to study them in the lab, the researchers converted the skin cells into induced pluripotent stem cells (iPSCs).

Then, adding a cocktail of growth factors and other molecules, the team coaxed the iPSCs to differentiate into RBCs. Multiple samples were tested for each person, for a total of at least 24 iPSC lines.

The researchers exposed the RBCs to low-oxygen conditions that mimic high altitude—5% oxygen—for 3 weeks.

RBCs from healthy sea-level or high-altitude-dwelling donors increased a little or not at all. In contrast, RBC counts from high-altitude dwellers with chronic mountain sickness increased 60-fold.

This result led the researchers to question why people with chronic mountain sickness produce so many extra RBCs in response to low oxygen.

In a previous study, the team had compared the genomes of high-altitude dwellers with and without chronic mountain sickness. This revealed a gene that varied between the 2 groups—SENP1, which is increased in low-oxygen situations in people with chronic mountain sickness but not in healthy individuals.

In the current study, the researchers set out to determine if SENP1 plays a role in high-altitude adaptation.

The team inhibited the SENP1 gene in iPSCs from patients with chronic mountain sickness. As a result, excessive RBC production was reduced by more than 90%.

When the researchers added extra SENP1 to healthy, adapted highlander iPSCs, RBC production increased 30-fold, nearly recapitulating that seen in patients with chronic mountains sickness.

Further experiments revealed how SENP1 affects RBC production. Elevated levels of the enzyme in chronic mountain sickness boost levels of several other proteins that promote cell division and survival, including VEGF, GATA1, and Bcl-xL.

“We’re interested in determining the early steps in this process—how low oxygen triggers SENP1 in the first place,” said study author Priti Azad, PhD, of the University of California San Diego School of Medicine.

 

“We are also investigating how existing altitude sickness medications, such as Diamox, work and whether or not it’s through this same mechanism.”

Findings from a study of people living at high altitude have implications for the treatment of red blood cell (RBC) disorders such as anemia and polycythemia, according to researchers.

To better understand why some people adapt well to life at high altitude while others don’t, the researchers studied RBCs derived from representatives of both groups who were living in the Andes Mountains.

The study revealed that high-altitude dwellers prone to chronic mountain sickness produce massive amounts of RBCs thanks to overproduction of the enzyme SENP1.

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

“In addition to improving the health of millions of people around the world who live above 8000 feet, information on how Andeans have adapted—or not adapted—to high-altitude life might teach us how to speed up red blood cell production at lower altitudes, such as in anemia or when blood transfusions are needed rapidly,” said study author Gabriel Haddad, MD, of the University of California San Diego School of Medicine.

Dr Haddad and his colleagues noted that chronic mountain sickness affects approximately 20% of people who live at high altitudes, and a critical aspect of the condition is polycythemia.

Some extra RBCs can be beneficial in high-altitude, low-oxygen environments by helping to keep blood oxygenated. However, too many RBCs can increase the risk of heart attack and stroke, even in young adults.

For this study, the researchers collected skin cells from people living in the Andes Mountains—4 who were healthy and 5 who suffer from chronic mountain sickness—plus an additional 3 healthy people who live at sea level and served as controls.

To produce enough RBCs from each participant to study them in the lab, the researchers converted the skin cells into induced pluripotent stem cells (iPSCs).

Then, adding a cocktail of growth factors and other molecules, the team coaxed the iPSCs to differentiate into RBCs. Multiple samples were tested for each person, for a total of at least 24 iPSC lines.

The researchers exposed the RBCs to low-oxygen conditions that mimic high altitude—5% oxygen—for 3 weeks.

RBCs from healthy sea-level or high-altitude-dwelling donors increased a little or not at all. In contrast, RBC counts from high-altitude dwellers with chronic mountain sickness increased 60-fold.

This result led the researchers to question why people with chronic mountain sickness produce so many extra RBCs in response to low oxygen.

In a previous study, the team had compared the genomes of high-altitude dwellers with and without chronic mountain sickness. This revealed a gene that varied between the 2 groups—SENP1, which is increased in low-oxygen situations in people with chronic mountain sickness but not in healthy individuals.

In the current study, the researchers set out to determine if SENP1 plays a role in high-altitude adaptation.

The team inhibited the SENP1 gene in iPSCs from patients with chronic mountain sickness. As a result, excessive RBC production was reduced by more than 90%.

When the researchers added extra SENP1 to healthy, adapted highlander iPSCs, RBC production increased 30-fold, nearly recapitulating that seen in patients with chronic mountains sickness.

Further experiments revealed how SENP1 affects RBC production. Elevated levels of the enzyme in chronic mountain sickness boost levels of several other proteins that promote cell division and survival, including VEGF, GATA1, and Bcl-xL.

“We’re interested in determining the early steps in this process—how low oxygen triggers SENP1 in the first place,” said study author Priti Azad, PhD, of the University of California San Diego School of Medicine.

 

“We are also investigating how existing altitude sickness medications, such as Diamox, work and whether or not it’s through this same mechanism.”

Findings from a study of people living at high altitude have implications for the treatment of red blood cell (RBC) disorders such as anemia and polycythemia, according to researchers.

To better understand why some people adapt well to life at high altitude while others don’t, the researchers studied RBCs derived from representatives of both groups who were living in the Andes Mountains.

The study revealed that high-altitude dwellers prone to chronic mountain sickness produce massive amounts of RBCs thanks to overproduction of the enzyme SENP1.

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

“In addition to improving the health of millions of people around the world who live above 8000 feet, information on how Andeans have adapted—or not adapted—to high-altitude life might teach us how to speed up red blood cell production at lower altitudes, such as in anemia or when blood transfusions are needed rapidly,” said study author Gabriel Haddad, MD, of the University of California San Diego School of Medicine.

Dr Haddad and his colleagues noted that chronic mountain sickness affects approximately 20% of people who live at high altitudes, and a critical aspect of the condition is polycythemia.

Some extra RBCs can be beneficial in high-altitude, low-oxygen environments by helping to keep blood oxygenated. However, too many RBCs can increase the risk of heart attack and stroke, even in young adults.

For this study, the researchers collected skin cells from people living in the Andes Mountains—4 who were healthy and 5 who suffer from chronic mountain sickness—plus an additional 3 healthy people who live at sea level and served as controls.

To produce enough RBCs from each participant to study them in the lab, the researchers converted the skin cells into induced pluripotent stem cells (iPSCs).

Then, adding a cocktail of growth factors and other molecules, the team coaxed the iPSCs to differentiate into RBCs. Multiple samples were tested for each person, for a total of at least 24 iPSC lines.

The researchers exposed the RBCs to low-oxygen conditions that mimic high altitude—5% oxygen—for 3 weeks.

RBCs from healthy sea-level or high-altitude-dwelling donors increased a little or not at all. In contrast, RBC counts from high-altitude dwellers with chronic mountain sickness increased 60-fold.

This result led the researchers to question why people with chronic mountain sickness produce so many extra RBCs in response to low oxygen.

In a previous study, the team had compared the genomes of high-altitude dwellers with and without chronic mountain sickness. This revealed a gene that varied between the 2 groups—SENP1, which is increased in low-oxygen situations in people with chronic mountain sickness but not in healthy individuals.

In the current study, the researchers set out to determine if SENP1 plays a role in high-altitude adaptation.

The team inhibited the SENP1 gene in iPSCs from patients with chronic mountain sickness. As a result, excessive RBC production was reduced by more than 90%.

When the researchers added extra SENP1 to healthy, adapted highlander iPSCs, RBC production increased 30-fold, nearly recapitulating that seen in patients with chronic mountains sickness.

Further experiments revealed how SENP1 affects RBC production. Elevated levels of the enzyme in chronic mountain sickness boost levels of several other proteins that promote cell division and survival, including VEGF, GATA1, and Bcl-xL.

“We’re interested in determining the early steps in this process—how low oxygen triggers SENP1 in the first place,” said study author Priti Azad, PhD, of the University of California San Diego School of Medicine.

 

“We are also investigating how existing altitude sickness medications, such as Diamox, work and whether or not it’s through this same mechanism.”

Using modified foamy retroviral vectors to deliver gene therapy may reduce the risk of genotoxicity, according to research published in Scientific Reports.

These vectors have demonstrated promise in vitro, and researchers believe they could be used to treat X-linked severe combined immunodeficiency, thalassemia, and other diseases.

“We’ve started to translate this in collaboration with other scientists and medical doctors into the clinic,” said study author Grant Trobridge, PhD, of Washington State University Spokane.

Dr Trobridge and his colleagues said they decided to pursue foamy retroviral vectors as a delivery system for gene therapy because these vectors are less likely than gammaretroviral vectors or lentiviral vectors to activate nearby genes, including proto-oncogenes.

Still, the researchers altered the foamy retroviral vectors to change how they interact with target stem cells in an attempt to ensure the vectors would insert themselves into safer parts of the genome.

The team said they were able to retarget the foamy retroviral vectors away from genes and into satellite regions enriched for trimethylated histone H3 at lysine 9 by modifying the foamy virus Gag and Pol proteins.

These retargeted foamy retroviral vectors integrated near genes significantly less often than unmodified foamy retroviral vectors (P<0.001).

The researchers also noted that their retargeted foamy retroviral vectors can be produced at clinically relevant titers, and engineered target cells are not needed. Any target cell can be used by using alternate foamy helper plasmids during vector production.

Using modified foamy retroviral vectors to deliver gene therapy may reduce the risk of genotoxicity, according to research published in Scientific Reports.

These vectors have demonstrated promise in vitro, and researchers believe they could be used to treat X-linked severe combined immunodeficiency, thalassemia, and other diseases.

“We’ve started to translate this in collaboration with other scientists and medical doctors into the clinic,” said study author Grant Trobridge, PhD, of Washington State University Spokane.

Dr Trobridge and his colleagues said they decided to pursue foamy retroviral vectors as a delivery system for gene therapy because these vectors are less likely than gammaretroviral vectors or lentiviral vectors to activate nearby genes, including proto-oncogenes.

Still, the researchers altered the foamy retroviral vectors to change how they interact with target stem cells in an attempt to ensure the vectors would insert themselves into safer parts of the genome.

The team said they were able to retarget the foamy retroviral vectors away from genes and into satellite regions enriched for trimethylated histone H3 at lysine 9 by modifying the foamy virus Gag and Pol proteins.

These retargeted foamy retroviral vectors integrated near genes significantly less often than unmodified foamy retroviral vectors (P<0.001).

The researchers also noted that their retargeted foamy retroviral vectors can be produced at clinically relevant titers, and engineered target cells are not needed. Any target cell can be used by using alternate foamy helper plasmids during vector production.

Using modified foamy retroviral vectors to deliver gene therapy may reduce the risk of genotoxicity, according to research published in Scientific Reports.

These vectors have demonstrated promise in vitro, and researchers believe they could be used to treat X-linked severe combined immunodeficiency, thalassemia, and other diseases.

“We’ve started to translate this in collaboration with other scientists and medical doctors into the clinic,” said study author Grant Trobridge, PhD, of Washington State University Spokane.

Dr Trobridge and his colleagues said they decided to pursue foamy retroviral vectors as a delivery system for gene therapy because these vectors are less likely than gammaretroviral vectors or lentiviral vectors to activate nearby genes, including proto-oncogenes.

Still, the researchers altered the foamy retroviral vectors to change how they interact with target stem cells in an attempt to ensure the vectors would insert themselves into safer parts of the genome.

The team said they were able to retarget the foamy retroviral vectors away from genes and into satellite regions enriched for trimethylated histone H3 at lysine 9 by modifying the foamy virus Gag and Pol proteins.

These retargeted foamy retroviral vectors integrated near genes significantly less often than unmodified foamy retroviral vectors (P<0.001).

The researchers also noted that their retargeted foamy retroviral vectors can be produced at clinically relevant titers, and engineered target cells are not needed. Any target cell can be used by using alternate foamy helper plasmids during vector production.

A new gene-editing strategy may be able to cure thalassemia, according to preclinical research published in Nature Communications.

The technique—which involves a combination of nanoparticles, synthetic pieces of DNA, and an intravenous injection—was able to alleviate symptoms of thalassemia in mice.

The strategy also decreases the risk of off-target mutations, when compared to other gene-editing techniques, according to researchers.

The new technique involves biocompatible nanoparticles containing peptide nucleic acids (PNAs), which are small, nano-sized, synthetic molecules in which a protein-like backbone is combined with the nucleobases found in DNA and RNA.

PNAs are designed to open up double-stranded DNA and bind near the target site in a highly specific manner. The PNAs fit inside a nanoparticle delivery system that is approved by the US Food and Drug Administration (FDA) and has already been used to treat neurodegenerative diseases in humans.

“We have developed a system that uses FDA-approved nanoparticles to deliver our PNA molecule along with a donor DNA to repair a malfunctioning gene in living mice,” said study author Danith Ly, PhD, of Carnegie Mellon University in Pittsburgh, Pennsylvania. “This has not been achieved with CRISPR.”

Dr Ly and his colleagues designed a PNA to target the malfunctioning gene in beta-thalassemia, the hemoglobin subunit beta (HBB) gene.

The researchers then loaded the nanoparticles with the PNAs, a donor strand of DNA encoding the sequence for a functional HBB gene, and a stem cell factor that enhances gene editing.

When the PNA binds to the target site in the DNA, it forms a PNA-DNA-PNA triplex, leaving a displaced DNA strand. Formation of such a complex enables the donor DNA to bind to the faulty DNA site within the vicinity.

Taken together, this altered helix engages the cell’s own DNA repair pathways to correct the malfunctioning HBB gene.

In addition to testing this system on mouse and human hematopoietic stem cells, the researchers used an intravenous injection to deliver the gene-editing package in mouse models of beta-thalassemia.

The results showed up to 6.9% successful gene-editing in hematopoietic stem cells. The mice showed elevated levels of hemoglobin—into the normal range—for several months after treatment, a reduction in reticulocytosis, and reversal of splenomegaly.

The researchers said this represents a striking increase in efficacy over typical gene-editing methods, which produce a 0.1% success rate.

“The effect may only be 7%, but that’s curative,” Dr Ly said. “In the case of this particular disease model, you don’t need a lot of correction. You don’t need 100% to see the phenotype return to normal.”

In addition, this gene-editing strategy had “extremely low off-target effects,” according to study author Peter Glazer, MD, of Yale University in New Haven, Connecticut.

The overall off-target modification frequency was 0.0032%.

If this strategy proves effective in clinical studies, it could lead to the development of gene therapy for patients with thalassemia, sickle cell disease, and other inherited blood disorders, Dr Glazer said.

“We might get enough cells corrected that individuals are not anemic anymore,” he added. “We could achieve a symptomatic cure.”

A new gene-editing strategy may be able to cure thalassemia, according to preclinical research published in Nature Communications.

The technique—which involves a combination of nanoparticles, synthetic pieces of DNA, and an intravenous injection—was able to alleviate symptoms of thalassemia in mice.

The strategy also decreases the risk of off-target mutations, when compared to other gene-editing techniques, according to researchers.

The new technique involves biocompatible nanoparticles containing peptide nucleic acids (PNAs), which are small, nano-sized, synthetic molecules in which a protein-like backbone is combined with the nucleobases found in DNA and RNA.

PNAs are designed to open up double-stranded DNA and bind near the target site in a highly specific manner. The PNAs fit inside a nanoparticle delivery system that is approved by the US Food and Drug Administration (FDA) and has already been used to treat neurodegenerative diseases in humans.

“We have developed a system that uses FDA-approved nanoparticles to deliver our PNA molecule along with a donor DNA to repair a malfunctioning gene in living mice,” said study author Danith Ly, PhD, of Carnegie Mellon University in Pittsburgh, Pennsylvania. “This has not been achieved with CRISPR.”

Dr Ly and his colleagues designed a PNA to target the malfunctioning gene in beta-thalassemia, the hemoglobin subunit beta (HBB) gene.

The researchers then loaded the nanoparticles with the PNAs, a donor strand of DNA encoding the sequence for a functional HBB gene, and a stem cell factor that enhances gene editing.

When the PNA binds to the target site in the DNA, it forms a PNA-DNA-PNA triplex, leaving a displaced DNA strand. Formation of such a complex enables the donor DNA to bind to the faulty DNA site within the vicinity.

Taken together, this altered helix engages the cell’s own DNA repair pathways to correct the malfunctioning HBB gene.

In addition to testing this system on mouse and human hematopoietic stem cells, the researchers used an intravenous injection to deliver the gene-editing package in mouse models of beta-thalassemia.

The results showed up to 6.9% successful gene-editing in hematopoietic stem cells. The mice showed elevated levels of hemoglobin—into the normal range—for several months after treatment, a reduction in reticulocytosis, and reversal of splenomegaly.

The researchers said this represents a striking increase in efficacy over typical gene-editing methods, which produce a 0.1% success rate.

“The effect may only be 7%, but that’s curative,” Dr Ly said. “In the case of this particular disease model, you don’t need a lot of correction. You don’t need 100% to see the phenotype return to normal.”

In addition, this gene-editing strategy had “extremely low off-target effects,” according to study author Peter Glazer, MD, of Yale University in New Haven, Connecticut.

The overall off-target modification frequency was 0.0032%.

If this strategy proves effective in clinical studies, it could lead to the development of gene therapy for patients with thalassemia, sickle cell disease, and other inherited blood disorders, Dr Glazer said.

“We might get enough cells corrected that individuals are not anemic anymore,” he added. “We could achieve a symptomatic cure.”

A new gene-editing strategy may be able to cure thalassemia, according to preclinical research published in Nature Communications.

The technique—which involves a combination of nanoparticles, synthetic pieces of DNA, and an intravenous injection—was able to alleviate symptoms of thalassemia in mice.

The strategy also decreases the risk of off-target mutations, when compared to other gene-editing techniques, according to researchers.

The new technique involves biocompatible nanoparticles containing peptide nucleic acids (PNAs), which are small, nano-sized, synthetic molecules in which a protein-like backbone is combined with the nucleobases found in DNA and RNA.

PNAs are designed to open up double-stranded DNA and bind near the target site in a highly specific manner. The PNAs fit inside a nanoparticle delivery system that is approved by the US Food and Drug Administration (FDA) and has already been used to treat neurodegenerative diseases in humans.

“We have developed a system that uses FDA-approved nanoparticles to deliver our PNA molecule along with a donor DNA to repair a malfunctioning gene in living mice,” said study author Danith Ly, PhD, of Carnegie Mellon University in Pittsburgh, Pennsylvania. “This has not been achieved with CRISPR.”

Dr Ly and his colleagues designed a PNA to target the malfunctioning gene in beta-thalassemia, the hemoglobin subunit beta (HBB) gene.

The researchers then loaded the nanoparticles with the PNAs, a donor strand of DNA encoding the sequence for a functional HBB gene, and a stem cell factor that enhances gene editing.

When the PNA binds to the target site in the DNA, it forms a PNA-DNA-PNA triplex, leaving a displaced DNA strand. Formation of such a complex enables the donor DNA to bind to the faulty DNA site within the vicinity.

Taken together, this altered helix engages the cell’s own DNA repair pathways to correct the malfunctioning HBB gene.

In addition to testing this system on mouse and human hematopoietic stem cells, the researchers used an intravenous injection to deliver the gene-editing package in mouse models of beta-thalassemia.

The results showed up to 6.9% successful gene-editing in hematopoietic stem cells. The mice showed elevated levels of hemoglobin—into the normal range—for several months after treatment, a reduction in reticulocytosis, and reversal of splenomegaly.

The researchers said this represents a striking increase in efficacy over typical gene-editing methods, which produce a 0.1% success rate.

“The effect may only be 7%, but that’s curative,” Dr Ly said. “In the case of this particular disease model, you don’t need a lot of correction. You don’t need 100% to see the phenotype return to normal.”

In addition, this gene-editing strategy had “extremely low off-target effects,” according to study author Peter Glazer, MD, of Yale University in New Haven, Connecticut.

The overall off-target modification frequency was 0.0032%.

If this strategy proves effective in clinical studies, it could lead to the development of gene therapy for patients with thalassemia, sickle cell disease, and other inherited blood disorders, Dr Glazer said.

“We might get enough cells corrected that individuals are not anemic anymore,” he added. “We could achieve a symptomatic cure.”

The European Medicines Agency’s (EMA) Committee for Orphan Medicinal Products (COMP) has issued a positive opinion recommending that LJPC-401 receive orphan designation as a treatment for patients with sickle cell disease (SCD).

LJPC-401 is a formulation of synthetic human hepcidin.

La Jolla Pharmaceutical Company is developing LJPC-401 for the treatment of iron overload, which can occur in SCD and other diseases.

LJPC-401 already has orphan designation in the European Union as a treatment for patients with beta-thalassemia intermedia and major.

La Jolla recently reported positive results from a phase 1 study of LJPC-401 in patients at risk of iron overload suffering from hereditary hemochromatosis, thalassemia, or SCD. Fifteen patients received LJPC-401 at escalating dose levels ranging from 1 mg to 20 mg.

The researchers observed a dose-dependent, statistically significant reduction in serum iron (P=0.008 for dose response; not adjusted for multiple comparisons).

At the 20 mg dose level, LJPC-401 reduced serum iron by an average of 58.1% from baseline to hour 8 (P=0.001; not adjusted for potential regression to the mean effect), and serum iron had not returned to baseline through day 7 (21.2% reduction from baseline to the end of day 7).

The researchers also said LJPC-401 was well tolerated, with no dose-limiting toxicities. Injection-site reactions were the most commonly reported adverse event. These were all mild or moderate in severity, self-limiting, and fully resolved.

Now, La Jolla is working to initiate a pivotal study of LJPC-401. This will be a randomized, controlled, multicenter study in beta-thalassemia patients suffering from iron overload. La Jolla plans to initiate this study in mid-2017.

About orphan designation

The EMA’s COMP adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision.

Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

Orphan designation provides a 10-year period of marketing exclusivity if the drug receives regulatory approval. The designation also provides incentives for companies seeking protocol assistance from the EMA during the product development phase and direct access to the centralized authorization procedure.

The European Medicines Agency’s (EMA) Committee for Orphan Medicinal Products (COMP) has issued a positive opinion recommending that LJPC-401 receive orphan designation as a treatment for patients with sickle cell disease (SCD).

LJPC-401 is a formulation of synthetic human hepcidin.

La Jolla Pharmaceutical Company is developing LJPC-401 for the treatment of iron overload, which can occur in SCD and other diseases.

LJPC-401 already has orphan designation in the European Union as a treatment for patients with beta-thalassemia intermedia and major.

La Jolla recently reported positive results from a phase 1 study of LJPC-401 in patients at risk of iron overload suffering from hereditary hemochromatosis, thalassemia, or SCD. Fifteen patients received LJPC-401 at escalating dose levels ranging from 1 mg to 20 mg.

The researchers observed a dose-dependent, statistically significant reduction in serum iron (P=0.008 for dose response; not adjusted for multiple comparisons).

At the 20 mg dose level, LJPC-401 reduced serum iron by an average of 58.1% from baseline to hour 8 (P=0.001; not adjusted for potential regression to the mean effect), and serum iron had not returned to baseline through day 7 (21.2% reduction from baseline to the end of day 7).

The researchers also said LJPC-401 was well tolerated, with no dose-limiting toxicities. Injection-site reactions were the most commonly reported adverse event. These were all mild or moderate in severity, self-limiting, and fully resolved.

Now, La Jolla is working to initiate a pivotal study of LJPC-401. This will be a randomized, controlled, multicenter study in beta-thalassemia patients suffering from iron overload. La Jolla plans to initiate this study in mid-2017.

About orphan designation

The EMA’s COMP adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision.

Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

Orphan designation provides a 10-year period of marketing exclusivity if the drug receives regulatory approval. The designation also provides incentives for companies seeking protocol assistance from the EMA during the product development phase and direct access to the centralized authorization procedure.

The European Medicines Agency’s (EMA) Committee for Orphan Medicinal Products (COMP) has issued a positive opinion recommending that LJPC-401 receive orphan designation as a treatment for patients with sickle cell disease (SCD).

LJPC-401 is a formulation of synthetic human hepcidin.

La Jolla Pharmaceutical Company is developing LJPC-401 for the treatment of iron overload, which can occur in SCD and other diseases.

LJPC-401 already has orphan designation in the European Union as a treatment for patients with beta-thalassemia intermedia and major.

La Jolla recently reported positive results from a phase 1 study of LJPC-401 in patients at risk of iron overload suffering from hereditary hemochromatosis, thalassemia, or SCD. Fifteen patients received LJPC-401 at escalating dose levels ranging from 1 mg to 20 mg.

The researchers observed a dose-dependent, statistically significant reduction in serum iron (P=0.008 for dose response; not adjusted for multiple comparisons).

At the 20 mg dose level, LJPC-401 reduced serum iron by an average of 58.1% from baseline to hour 8 (P=0.001; not adjusted for potential regression to the mean effect), and serum iron had not returned to baseline through day 7 (21.2% reduction from baseline to the end of day 7).

The researchers also said LJPC-401 was well tolerated, with no dose-limiting toxicities. Injection-site reactions were the most commonly reported adverse event. These were all mild or moderate in severity, self-limiting, and fully resolved.

Now, La Jolla is working to initiate a pivotal study of LJPC-401. This will be a randomized, controlled, multicenter study in beta-thalassemia patients suffering from iron overload. La Jolla plans to initiate this study in mid-2017.

About orphan designation

The EMA’s COMP adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision.

Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

Orphan designation provides a 10-year period of marketing exclusivity if the drug receives regulatory approval. The designation also provides incentives for companies seeking protocol assistance from the EMA during the product development phase and direct access to the centralized authorization procedure.

The US Food and Drug Administration (FDA) has approved use of the PreciseType HEA test to screen blood donors for sickle cell trait (SCT).

The test was previously FDA approved for use in determining blood compatibility between donors and transfusion recipients.

The added utility of screening donors for SCT addresses the desire to avoid transfusing red blood cells from SCT donors to neonates or patients with sickle cell disease.

Blood from SCT donors can also present a problem when performing the required filtration of white cells from the blood donation.

The PreciseType HEA test will allow these units to be identified prior to filtration and provide blood center staff with the opportunity to decide how best to utilize the various components of a whole blood donation.

The PreciseType HEA test is manufactured by BioArray Solutions, a wholly owned subsidiary of Immucor, Inc.

“We’ve successfully demonstrated the clinical benefits of our PreciseType HEA test, and this is evident in the FDA broadening its approved use,” said Michael Spigarelli, vice president of medical affairs at Immucor.

“The use of PreciseType HEA to screen donor units for patients with sickle cell disease, neonates, or any individual that may require SCT-negative blood provides a great improvement over previously used methods and offers the first FDA-approved molecular method specifically for screening units.”

SCT screening has traditionally been performed by solubility testing of sickle hemoglobin in buffer, but blood centers have been looking for an alternative due to limitations in this method.

According to Immucor, a molecular approach using PreciseType HEA can overcome the throughput limitations and reduce the false-positive rates observed with the traditional SCT screening method.

“We had already validated the PreciseType HEA test for [SCT screening] in our lab,” said Connie Westhoff, PhD, of the New York Blood Center in New York, New York.

“Our previous screening method required manual testing and interpretation of the results and had high false-positive rates. About 1 in 12 minority donors possess the sickle trait, so accurate results are important to us to avoid unnecessary notifications to donors and deferred blood units. We are now able to identify SCT in our donors utilizing the same PreciseType HEA test we are already running on many of our donors without running additional tests.”

The US Food and Drug Administration (FDA) has approved use of the PreciseType HEA test to screen blood donors for sickle cell trait (SCT).

The test was previously FDA approved for use in determining blood compatibility between donors and transfusion recipients.

The added utility of screening donors for SCT addresses the desire to avoid transfusing red blood cells from SCT donors to neonates or patients with sickle cell disease.

Blood from SCT donors can also present a problem when performing the required filtration of white cells from the blood donation.

The PreciseType HEA test will allow these units to be identified prior to filtration and provide blood center staff with the opportunity to decide how best to utilize the various components of a whole blood donation.

The PreciseType HEA test is manufactured by BioArray Solutions, a wholly owned subsidiary of Immucor, Inc.

“We’ve successfully demonstrated the clinical benefits of our PreciseType HEA test, and this is evident in the FDA broadening its approved use,” said Michael Spigarelli, vice president of medical affairs at Immucor.

“The use of PreciseType HEA to screen donor units for patients with sickle cell disease, neonates, or any individual that may require SCT-negative blood provides a great improvement over previously used methods and offers the first FDA-approved molecular method specifically for screening units.”

SCT screening has traditionally been performed by solubility testing of sickle hemoglobin in buffer, but blood centers have been looking for an alternative due to limitations in this method.

According to Immucor, a molecular approach using PreciseType HEA can overcome the throughput limitations and reduce the false-positive rates observed with the traditional SCT screening method.

“We had already validated the PreciseType HEA test for [SCT screening] in our lab,” said Connie Westhoff, PhD, of the New York Blood Center in New York, New York.

“Our previous screening method required manual testing and interpretation of the results and had high false-positive rates. About 1 in 12 minority donors possess the sickle trait, so accurate results are important to us to avoid unnecessary notifications to donors and deferred blood units. We are now able to identify SCT in our donors utilizing the same PreciseType HEA test we are already running on many of our donors without running additional tests.”

The US Food and Drug Administration (FDA) has approved use of the PreciseType HEA test to screen blood donors for sickle cell trait (SCT).

The test was previously FDA approved for use in determining blood compatibility between donors and transfusion recipients.

The added utility of screening donors for SCT addresses the desire to avoid transfusing red blood cells from SCT donors to neonates or patients with sickle cell disease.

Blood from SCT donors can also present a problem when performing the required filtration of white cells from the blood donation.

The PreciseType HEA test will allow these units to be identified prior to filtration and provide blood center staff with the opportunity to decide how best to utilize the various components of a whole blood donation.

The PreciseType HEA test is manufactured by BioArray Solutions, a wholly owned subsidiary of Immucor, Inc.

“We’ve successfully demonstrated the clinical benefits of our PreciseType HEA test, and this is evident in the FDA broadening its approved use,” said Michael Spigarelli, vice president of medical affairs at Immucor.

“The use of PreciseType HEA to screen donor units for patients with sickle cell disease, neonates, or any individual that may require SCT-negative blood provides a great improvement over previously used methods and offers the first FDA-approved molecular method specifically for screening units.”

SCT screening has traditionally been performed by solubility testing of sickle hemoglobin in buffer, but blood centers have been looking for an alternative due to limitations in this method.

According to Immucor, a molecular approach using PreciseType HEA can overcome the throughput limitations and reduce the false-positive rates observed with the traditional SCT screening method.

“We had already validated the PreciseType HEA test for [SCT screening] in our lab,” said Connie Westhoff, PhD, of the New York Blood Center in New York, New York.

“Our previous screening method required manual testing and interpretation of the results and had high false-positive rates. About 1 in 12 minority donors possess the sickle trait, so accurate results are important to us to avoid unnecessary notifications to donors and deferred blood units. We are now able to identify SCT in our donors utilizing the same PreciseType HEA test we are already running on many of our donors without running additional tests.”

The SYK inhibitor fostamatinib did not meet the primary endpoint in a phase 3 study of adults with chronic/persistent immune thrombocytopenia (ITP), according to Rigel Pharmaceuticals, Inc., the company developing the drug.

However, fostamatinib did meet that endpoint—a significantly higher incidence of stable platelet response compared to placebo—in an identical phase 3 study.

The combined data from both studies—known as FIT 1 and FIT 2—suggest fostamatinib confers a benefit over placebo.

Therefore, Rigel Pharmaceuticals is still planning to submit a new drug application for fostamatinib to the US Food and Drug Administration (FDA) next year, pending feedback from the agency.

“We believe that the totality and consistency of data from the FIT phase 3 program . . . strongly supports a clear treatment effect, with a sustained clinical benefit of fostamatinib,” said Raul Rodriguez, president and chief executive officer of Rigel Pharmaceuticals.

“We are encouraged by these results and believe that the risk/benefit ratio for fostamatinib is positive for patients with chronic/persistent ITP . . . . As a result, we will continue to pursue this opportunity. Our next step is to seek feedback from the FDA.”

About the FIT studies

Rigel’s FIT program consists of 2 identical, multicenter, randomized, double-blind studies of approximately 75 adults each—FIT 1 (Study 047) and FIT 2 (Study 048).

The patients enrolled in each study had been diagnosed with persistent or chronic ITP, had failed at least 1 prior therapy for ITP, and had platelet counts consistently below 30,000/uL of blood.

In both studies, patients were randomized in a 2:1 ratio to receive either fostamatinib or placebo orally twice a day for up to 24 weeks.

Patients were subsequently given the opportunity to enroll in an open-label, long-term, phase 3 extension study (Study 049), which is ongoing.

Patient characteristics

In FIT 1, 51 patients were randomized to fostamatinib and 25 to placebo. The median age was 57 in both treatment arms. The duration of ITP was 7.5 years (range, 0.6-53) in the fostamatinib arm and 5.5 years (range, 0.4-45) in the placebo arm.

Prior treatments (in the fostamatinib and placebo arms, respectively) included steroids (90% and 100%), rituximab (51% and 44%), thrombopoietic agents (50% and 60%), and splenectomy (39% and 40%).

The median platelet count at baseline was 15,000/uL in the fostamatinib arm and 16,000/uL in the placebo arm.

In FIT 2, 50 patients were randomized to fostamatinib and 24 to placebo. The median age was 50 in both treatment arms. The duration of ITP was 8.8 years (range, 0.3-50) in the fostamatinib arm and 10.8 years (range, 0.9-29) in the placebo arm.

Prior treatments (in the fostamatinib and placebo arms, respectively) included steroids (90% and 92%), rituximab (16% and 13%), thrombopoietic agents (40% and 42%), and splenectomy (28% and 38%).

The median platelet count at baseline was 16,000/uL in the fostamatinib arm and 21,000/uL in the placebo arm.

Efficacy

The primary efficacy endpoint in both studies is a stable platelet response, which is defined as achieving platelet counts greater than 50,000/uL of blood for at least 4 of the 6 scheduled clinic visits between weeks 14 and 24 of treatment.

In FIT 1, the rate of stable platelet response was significantly higher in the fostamatinib arm than the placebo arm—18% (n=9) and 0%, respectively (P=0.026).

In FIT 2, however, the difference in stable platelet response between the 2 arms was not significant—18% (n=9) and 4% (n=1), respectively (P=0.152).

When the data from FIT 1 and FIT 2 are combined, the response rate is significantly higher in the fostamatinib arm than the placebo arm—18% (18/101) and 2% (1/49), respectively (P=0.007).

 

The response rate is significantly better in the fostamatinib arm across all subgroups, regardless of whether patients had prior splenectomy, prior exposure to thrombopoietic agents, or baseline platelet counts above or below 15,000/uL.

In the combined dataset, patients who met the primary endpoint had their platelet counts increase from a median of 18,500/uL at baseline to more than 100,000/uL at week 24 of treatment.

In addition, patients who met the primary endpoint had a timely platelet response, and that response was enduring, according to James B. Bussel, MD, a professor at Weill Cornell Medicine in New York, New York, principal investigator on the FIT phase 3 program, and a member of Rigel’s advisory/scientific board.

“The FIT phase 3 studies have both demonstrated that fostamatinib provided a robust and enduring benefit for those patients who responded to the drug,” he said.

Safety

In FIT 1, the overall incidence of adverse events (AEs) was 96% in the fostamatinib arm and 76% in the placebo arm. The incidence of serious AEs was 16% and 20%, respectively. And the incidence of treatment-related AEs was 77% and 28%, respectively.

AEs (in the fostamatinib and placebo arms, respectively) included gastrointestinal complaints (nausea, diarrhea, vomiting, abdominal pain; 61% and 20%), nausea (29% and 4%), diarrhea (45% and 16%), infection (33% and 20%), hypertension during visit (35% and 8%), and transaminase elevation (22% and 0%).

In FIT 2, the overall incidence of AEs was 71% in the fostamatinib arm and 78% in the placebo arm. The incidence of serious AEs was 10% and 26%, respectively. And the incidence of treatment-related AEs was 39% and 26%, respectively.

AEs (in the fostamatinib and placebo arms, respectively) included gastrointestinal complaints (22% in both arms), nausea (8% and 13%), diarrhea (18% and 13%), infection (22% in both arms), hypertension during visit (20% and 17%), and transaminase elevation (6% and 0%).

The SYK inhibitor fostamatinib did not meet the primary endpoint in a phase 3 study of adults with chronic/persistent immune thrombocytopenia (ITP), according to Rigel Pharmaceuticals, Inc., the company developing the drug.

However, fostamatinib did meet that endpoint—a significantly higher incidence of stable platelet response compared to placebo—in an identical phase 3 study.

The combined data from both studies—known as FIT 1 and FIT 2—suggest fostamatinib confers a benefit over placebo.

Therefore, Rigel Pharmaceuticals is still planning to submit a new drug application for fostamatinib to the US Food and Drug Administration (FDA) next year, pending feedback from the agency.

“We believe that the totality and consistency of data from the FIT phase 3 program . . . strongly supports a clear treatment effect, with a sustained clinical benefit of fostamatinib,” said Raul Rodriguez, president and chief executive officer of Rigel Pharmaceuticals.

“We are encouraged by these results and believe that the risk/benefit ratio for fostamatinib is positive for patients with chronic/persistent ITP . . . . As a result, we will continue to pursue this opportunity. Our next step is to seek feedback from the FDA.”

About the FIT studies

Rigel’s FIT program consists of 2 identical, multicenter, randomized, double-blind studies of approximately 75 adults each—FIT 1 (Study 047) and FIT 2 (Study 048).

The patients enrolled in each study had been diagnosed with persistent or chronic ITP, had failed at least 1 prior therapy for ITP, and had platelet counts consistently below 30,000/uL of blood.

In both studies, patients were randomized in a 2:1 ratio to receive either fostamatinib or placebo orally twice a day for up to 24 weeks.

Patients were subsequently given the opportunity to enroll in an open-label, long-term, phase 3 extension study (Study 049), which is ongoing.

Patient characteristics

In FIT 1, 51 patients were randomized to fostamatinib and 25 to placebo. The median age was 57 in both treatment arms. The duration of ITP was 7.5 years (range, 0.6-53) in the fostamatinib arm and 5.5 years (range, 0.4-45) in the placebo arm.

Prior treatments (in the fostamatinib and placebo arms, respectively) included steroids (90% and 100%), rituximab (51% and 44%), thrombopoietic agents (50% and 60%), and splenectomy (39% and 40%).

The median platelet count at baseline was 15,000/uL in the fostamatinib arm and 16,000/uL in the placebo arm.

In FIT 2, 50 patients were randomized to fostamatinib and 24 to placebo. The median age was 50 in both treatment arms. The duration of ITP was 8.8 years (range, 0.3-50) in the fostamatinib arm and 10.8 years (range, 0.9-29) in the placebo arm.

Prior treatments (in the fostamatinib and placebo arms, respectively) included steroids (90% and 92%), rituximab (16% and 13%), thrombopoietic agents (40% and 42%), and splenectomy (28% and 38%).

The median platelet count at baseline was 16,000/uL in the fostamatinib arm and 21,000/uL in the placebo arm.

Efficacy

The primary efficacy endpoint in both studies is a stable platelet response, which is defined as achieving platelet counts greater than 50,000/uL of blood for at least 4 of the 6 scheduled clinic visits between weeks 14 and 24 of treatment.

In FIT 1, the rate of stable platelet response was significantly higher in the fostamatinib arm than the placebo arm—18% (n=9) and 0%, respectively (P=0.026).

In FIT 2, however, the difference in stable platelet response between the 2 arms was not significant—18% (n=9) and 4% (n=1), respectively (P=0.152).

When the data from FIT 1 and FIT 2 are combined, the response rate is significantly higher in the fostamatinib arm than the placebo arm—18% (18/101) and 2% (1/49), respectively (P=0.007).

 

The response rate is significantly better in the fostamatinib arm across all subgroups, regardless of whether patients had prior splenectomy, prior exposure to thrombopoietic agents, or baseline platelet counts above or below 15,000/uL.

In the combined dataset, patients who met the primary endpoint had their platelet counts increase from a median of 18,500/uL at baseline to more than 100,000/uL at week 24 of treatment.

In addition, patients who met the primary endpoint had a timely platelet response, and that response was enduring, according to James B. Bussel, MD, a professor at Weill Cornell Medicine in New York, New York, principal investigator on the FIT phase 3 program, and a member of Rigel’s advisory/scientific board.

“The FIT phase 3 studies have both demonstrated that fostamatinib provided a robust and enduring benefit for those patients who responded to the drug,” he said.

Safety

In FIT 1, the overall incidence of adverse events (AEs) was 96% in the fostamatinib arm and 76% in the placebo arm. The incidence of serious AEs was 16% and 20%, respectively. And the incidence of treatment-related AEs was 77% and 28%, respectively.

AEs (in the fostamatinib and placebo arms, respectively) included gastrointestinal complaints (nausea, diarrhea, vomiting, abdominal pain; 61% and 20%), nausea (29% and 4%), diarrhea (45% and 16%), infection (33% and 20%), hypertension during visit (35% and 8%), and transaminase elevation (22% and 0%).

In FIT 2, the overall incidence of AEs was 71% in the fostamatinib arm and 78% in the placebo arm. The incidence of serious AEs was 10% and 26%, respectively. And the incidence of treatment-related AEs was 39% and 26%, respectively.

AEs (in the fostamatinib and placebo arms, respectively) included gastrointestinal complaints (22% in both arms), nausea (8% and 13%), diarrhea (18% and 13%), infection (22% in both arms), hypertension during visit (20% and 17%), and transaminase elevation (6% and 0%).

The SYK inhibitor fostamatinib did not meet the primary endpoint in a phase 3 study of adults with chronic/persistent immune thrombocytopenia (ITP), according to Rigel Pharmaceuticals, Inc., the company developing the drug.

However, fostamatinib did meet that endpoint—a significantly higher incidence of stable platelet response compared to placebo—in an identical phase 3 study.

The combined data from both studies—known as FIT 1 and FIT 2—suggest fostamatinib confers a benefit over placebo.

Therefore, Rigel Pharmaceuticals is still planning to submit a new drug application for fostamatinib to the US Food and Drug Administration (FDA) next year, pending feedback from the agency.

“We believe that the totality and consistency of data from the FIT phase 3 program . . . strongly supports a clear treatment effect, with a sustained clinical benefit of fostamatinib,” said Raul Rodriguez, president and chief executive officer of Rigel Pharmaceuticals.

“We are encouraged by these results and believe that the risk/benefit ratio for fostamatinib is positive for patients with chronic/persistent ITP . . . . As a result, we will continue to pursue this opportunity. Our next step is to seek feedback from the FDA.”

About the FIT studies

Rigel’s FIT program consists of 2 identical, multicenter, randomized, double-blind studies of approximately 75 adults each—FIT 1 (Study 047) and FIT 2 (Study 048).

The patients enrolled in each study had been diagnosed with persistent or chronic ITP, had failed at least 1 prior therapy for ITP, and had platelet counts consistently below 30,000/uL of blood.

In both studies, patients were randomized in a 2:1 ratio to receive either fostamatinib or placebo orally twice a day for up to 24 weeks.

Patients were subsequently given the opportunity to enroll in an open-label, long-term, phase 3 extension study (Study 049), which is ongoing.

Patient characteristics

In FIT 1, 51 patients were randomized to fostamatinib and 25 to placebo. The median age was 57 in both treatment arms. The duration of ITP was 7.5 years (range, 0.6-53) in the fostamatinib arm and 5.5 years (range, 0.4-45) in the placebo arm.

Prior treatments (in the fostamatinib and placebo arms, respectively) included steroids (90% and 100%), rituximab (51% and 44%), thrombopoietic agents (50% and 60%), and splenectomy (39% and 40%).

The median platelet count at baseline was 15,000/uL in the fostamatinib arm and 16,000/uL in the placebo arm.

In FIT 2, 50 patients were randomized to fostamatinib and 24 to placebo. The median age was 50 in both treatment arms. The duration of ITP was 8.8 years (range, 0.3-50) in the fostamatinib arm and 10.8 years (range, 0.9-29) in the placebo arm.

Prior treatments (in the fostamatinib and placebo arms, respectively) included steroids (90% and 92%), rituximab (16% and 13%), thrombopoietic agents (40% and 42%), and splenectomy (28% and 38%).

The median platelet count at baseline was 16,000/uL in the fostamatinib arm and 21,000/uL in the placebo arm.

Efficacy

The primary efficacy endpoint in both studies is a stable platelet response, which is defined as achieving platelet counts greater than 50,000/uL of blood for at least 4 of the 6 scheduled clinic visits between weeks 14 and 24 of treatment.

In FIT 1, the rate of stable platelet response was significantly higher in the fostamatinib arm than the placebo arm—18% (n=9) and 0%, respectively (P=0.026).

In FIT 2, however, the difference in stable platelet response between the 2 arms was not significant—18% (n=9) and 4% (n=1), respectively (P=0.152).

When the data from FIT 1 and FIT 2 are combined, the response rate is significantly higher in the fostamatinib arm than the placebo arm—18% (18/101) and 2% (1/49), respectively (P=0.007).

 

The response rate is significantly better in the fostamatinib arm across all subgroups, regardless of whether patients had prior splenectomy, prior exposure to thrombopoietic agents, or baseline platelet counts above or below 15,000/uL.

In the combined dataset, patients who met the primary endpoint had their platelet counts increase from a median of 18,500/uL at baseline to more than 100,000/uL at week 24 of treatment.

In addition, patients who met the primary endpoint had a timely platelet response, and that response was enduring, according to James B. Bussel, MD, a professor at Weill Cornell Medicine in New York, New York, principal investigator on the FIT phase 3 program, and a member of Rigel’s advisory/scientific board.

“The FIT phase 3 studies have both demonstrated that fostamatinib provided a robust and enduring benefit for those patients who responded to the drug,” he said.

Safety

In FIT 1, the overall incidence of adverse events (AEs) was 96% in the fostamatinib arm and 76% in the placebo arm. The incidence of serious AEs was 16% and 20%, respectively. And the incidence of treatment-related AEs was 77% and 28%, respectively.

AEs (in the fostamatinib and placebo arms, respectively) included gastrointestinal complaints (nausea, diarrhea, vomiting, abdominal pain; 61% and 20%), nausea (29% and 4%), diarrhea (45% and 16%), infection (33% and 20%), hypertension during visit (35% and 8%), and transaminase elevation (22% and 0%).

In FIT 2, the overall incidence of AEs was 71% in the fostamatinib arm and 78% in the placebo arm. The incidence of serious AEs was 10% and 26%, respectively. And the incidence of treatment-related AEs was 39% and 26%, respectively.

AEs (in the fostamatinib and placebo arms, respectively) included gastrointestinal complaints (22% in both arms), nausea (8% and 13%), diarrhea (18% and 13%), infection (22% in both arms), hypertension during visit (20% and 17%), and transaminase elevation (6% and 0%).

Researchers have described a gene-editing technique that can correct the sickle cell mutation in hematopoietic stem and progenitor cells (HSPCs) isolated from patients with sickle cell disease (SCD).

The investigators said these edited HSPCs produced wild-type adult and fetal hemoglobin.

The HSPCs were also able to engraft in mice and maintained their SCD gene edits long-term without showing any signs of side effects.

“This is an important advance because, for the first time, we show a level of correction in stem cells that should be sufficient for a clinical benefit in persons with sickle cell anemia,” said Mark Walters, MD, of UCSF Benioff Children’s Hospital Oakland in California.

Dr Walters and his colleagues described this work in Science Translational Medicine.

The researchers said they used a ribonucleoprotein complex consisting of Cas9 protein and unmodified single guide RNA, together with a single-stranded DNA oligonucleotide donor, to enable efficient replacement of the SCD mutation in human HSPCs.

The team then differentiated pools of these HSPCs into enucleated erythrocytes and late-stage erythroblasts to measure hemoglobin production.

They said the edited HSPCs produced “substantial amounts” of adult wild-type hemoglobin. The cells also showed a decrease in sickle hemoglobin and an increase in fetal hemoglobin.

When implanted in mice, the edited HSPCs repopulated and maintained their SCD gene edits for 16 weeks, with no signs of side effects. (The mice were sacrificed at 16 weeks.)

“We’re very excited about the promise of this technology,” said study author Jacob Corn, PhD, of the University of California, Berkeley.

“There is still a lot of work to be done before this approach might be used in the clinic, but we’re hopeful that it will pave the way for new kinds of treatment for patients with sickle cell disease.”

In fact, Dr Corn and his lab have joined with Dr Walters to initiate an early phase clinical trial to test this gene-editing approach within the next 5 years.

The investigators also noted that the approach might be effective for treating other disorders, such as β-thalassemia, Wiskott-Aldrich syndrome, and Fanconi anemia.

“Sickle cell disease is just one of many blood disorders caused by a single mutation in the genome,” Dr Corn said. “It’s very possible that other researchers and clinicians could use this type of gene editing to explore ways to cure a large number of diseases.”

Researchers have described a gene-editing technique that can correct the sickle cell mutation in hematopoietic stem and progenitor cells (HSPCs) isolated from patients with sickle cell disease (SCD).

The investigators said these edited HSPCs produced wild-type adult and fetal hemoglobin.

The HSPCs were also able to engraft in mice and maintained their SCD gene edits long-term without showing any signs of side effects.

“This is an important advance because, for the first time, we show a level of correction in stem cells that should be sufficient for a clinical benefit in persons with sickle cell anemia,” said Mark Walters, MD, of UCSF Benioff Children’s Hospital Oakland in California.

Dr Walters and his colleagues described this work in Science Translational Medicine.

The researchers said they used a ribonucleoprotein complex consisting of Cas9 protein and unmodified single guide RNA, together with a single-stranded DNA oligonucleotide donor, to enable efficient replacement of the SCD mutation in human HSPCs.

The team then differentiated pools of these HSPCs into enucleated erythrocytes and late-stage erythroblasts to measure hemoglobin production.

They said the edited HSPCs produced “substantial amounts” of adult wild-type hemoglobin. The cells also showed a decrease in sickle hemoglobin and an increase in fetal hemoglobin.

When implanted in mice, the edited HSPCs repopulated and maintained their SCD gene edits for 16 weeks, with no signs of side effects. (The mice were sacrificed at 16 weeks.)

“We’re very excited about the promise of this technology,” said study author Jacob Corn, PhD, of the University of California, Berkeley.

“There is still a lot of work to be done before this approach might be used in the clinic, but we’re hopeful that it will pave the way for new kinds of treatment for patients with sickle cell disease.”

In fact, Dr Corn and his lab have joined with Dr Walters to initiate an early phase clinical trial to test this gene-editing approach within the next 5 years.

The investigators also noted that the approach might be effective for treating other disorders, such as β-thalassemia, Wiskott-Aldrich syndrome, and Fanconi anemia.

“Sickle cell disease is just one of many blood disorders caused by a single mutation in the genome,” Dr Corn said. “It’s very possible that other researchers and clinicians could use this type of gene editing to explore ways to cure a large number of diseases.”

Researchers have described a gene-editing technique that can correct the sickle cell mutation in hematopoietic stem and progenitor cells (HSPCs) isolated from patients with sickle cell disease (SCD).

The investigators said these edited HSPCs produced wild-type adult and fetal hemoglobin.

The HSPCs were also able to engraft in mice and maintained their SCD gene edits long-term without showing any signs of side effects.

“This is an important advance because, for the first time, we show a level of correction in stem cells that should be sufficient for a clinical benefit in persons with sickle cell anemia,” said Mark Walters, MD, of UCSF Benioff Children’s Hospital Oakland in California.

Dr Walters and his colleagues described this work in Science Translational Medicine.

The researchers said they used a ribonucleoprotein complex consisting of Cas9 protein and unmodified single guide RNA, together with a single-stranded DNA oligonucleotide donor, to enable efficient replacement of the SCD mutation in human HSPCs.

The team then differentiated pools of these HSPCs into enucleated erythrocytes and late-stage erythroblasts to measure hemoglobin production.

They said the edited HSPCs produced “substantial amounts” of adult wild-type hemoglobin. The cells also showed a decrease in sickle hemoglobin and an increase in fetal hemoglobin.

When implanted in mice, the edited HSPCs repopulated and maintained their SCD gene edits for 16 weeks, with no signs of side effects. (The mice were sacrificed at 16 weeks.)

“We’re very excited about the promise of this technology,” said study author Jacob Corn, PhD, of the University of California, Berkeley.

“There is still a lot of work to be done before this approach might be used in the clinic, but we’re hopeful that it will pave the way for new kinds of treatment for patients with sickle cell disease.”

In fact, Dr Corn and his lab have joined with Dr Walters to initiate an early phase clinical trial to test this gene-editing approach within the next 5 years.

The investigators also noted that the approach might be effective for treating other disorders, such as β-thalassemia, Wiskott-Aldrich syndrome, and Fanconi anemia.

“Sickle cell disease is just one of many blood disorders caused by a single mutation in the genome,” Dr Corn said. “It’s very possible that other researchers and clinicians could use this type of gene editing to explore ways to cure a large number of diseases.”