Anemia

AML cells

The experimental agent prexigebersen (formerly BP1001) was considered well-tolerated and demonstrated early evidence of activity against relapsed/refractory hematologic disorders in a phase 1/1b trial.

The drug reduced blasts in the bone marrow and peripheral blood for patients with acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and myelodysplastic syndrome (MDS).

When given in combination with low-dose cytarabine, prexigebersen produced complete responses (CRs) in patients with AML.

Researchers said that, overall, the toxic effects of prexigebersen were manageable.

There was 1 patient who had dose-limiting toxicities, 1 who discontinued treatment due to possible drug-related toxic effects, and 1 treatment-related death.

Still, the maximum tolerated dose of prexigebersen was not established.

These results were published in The Lancet Haematology. The study was sponsored by Bio-Path Holdings, Inc., the company developing prexigebersen.

Prexigebersen is an anti-sense oligodeoxynucleotide developed to block Grb2 expression and function. Researchers tested the drug in a single-center, dose-escalation, phase 1/1b trial that enrolled and treated 39 patients.

In the phase 1 portion of the trial, patients received prexigebersen monotherapy. In the phase 1b portion, they received the drug in combination with low-dose cytarabine.

There were 32 patients in the phase 1 portion of the trial. Most (n=23) had AML, 5 had CML in blast phase, and 4 had MDS. The patients’ median age was 63 (range, 56-73), and they had received a median of 4 prior therapies.

All 7 patients in the phase 1b portion had AML. They had a median age of 72 (range, 70-76) and had all received 1 prior therapy.

For phase 1, prexigebersen was administered intravenously, twice weekly for 28 days at doses of 5 mg/m² in cohort 1 (n=13), 10 mg/m² in cohort 2 (n=6), 20 mg/m² in cohort 3 (n=3), 40 mg/m² in cohort 4 (n=3), 60 mg/m² in cohort 5 (n=3), and 90 mg/m² in cohort 6 (n=4).

In the phase 1b portion, patients received prexigebersen at 60 mg/m² (n=4) or 90 mg/m² (n=3) in combination with 20 mg of cytarabine (twice-daily subcutaneous injections).

Safety

Twenty-seven patients were evaluable for dose-limiting toxicity—21 from phase 1 and 6 from 1b.

One patient in cohort 1 developed mucositis and hand-foot syndrome, which were considered possibly related to prexigebersen and deemed dose-limiting toxicities. The patient was also receiving hydroxyurea (3 g/day) for CML and had a history of hydroxyurea-induced mucositis.

There were no other dose-limiting toxicities, and the researchers did not identify a maximum tolerated dose of prexigebersen.

The most common grade 3-4 adverse events (AEs) were cardiopulmonary disorders and fevers (including neutropenic fevers and infections).

In the monotherapy group, 17% of patients had grade 3-4 cardiopulmonary AEs, and 11% had fevers. In the prexigebersen-cytarabine combination group, 8% had grade 3-4 cardiopulmonary AEs, and 6% had fevers.

There were 5 grade 5 AEs in 4 patients, all of whom received monotherapy. These included cardiopulmonary disorders (n=2), fevers (n=2), and multi-organ failure (n=1). One patient had both fever (sepsis) and multi-organ failure.

Efficacy

According to the researchers’ assessments, 22% of phase 1 patients (7/32) benefited from prexigebersen monotherapy and therefore received more than 1 cycle of treatment. Five of these patients had AML, and 2 had MDS.

Single-agent activity was observed in other patients as well.

Thirty-three percent (9/27) of patients who had peripheral blood blasts at baseline saw their blasts reduced by 50% or more while receiving monotherapy. One of these patients had CML, and the rest had AML.

Ten percent (3/29) of patients with bone marrow blasts at baseline had a reduction in blasts of 50% or more while receiving monotherapy.  Two of these patients had AML, and 1 had MDS.

Of the 7 patients receiving prexigebersen with cytarabine, 2 achieved a CR, and 1 had a CR with incomplete hematological recovery.

Two of the patients had stable disease, and the remaining 2 patients progressed. One of the patients with progressive disease withdrew from the study, and the other died.

Deaths

There were a total of 8 deaths.

One death was considered treatment-related. This patient had progressive CML in blast phase and died of multiple organ failure. This was the first patient treated on the trial, who also had the only dose-limiting toxicities.

Two patients with AML and 1 with MDS died of disease progression. Three AML patients died of sepsis, pneumonia, and cardiac arrest. And a CML patient died of respiratory distress.

AML cells

The experimental agent prexigebersen (formerly BP1001) was considered well-tolerated and demonstrated early evidence of activity against relapsed/refractory hematologic disorders in a phase 1/1b trial.

The drug reduced blasts in the bone marrow and peripheral blood for patients with acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and myelodysplastic syndrome (MDS).

When given in combination with low-dose cytarabine, prexigebersen produced complete responses (CRs) in patients with AML.

Researchers said that, overall, the toxic effects of prexigebersen were manageable.

There was 1 patient who had dose-limiting toxicities, 1 who discontinued treatment due to possible drug-related toxic effects, and 1 treatment-related death.

Still, the maximum tolerated dose of prexigebersen was not established.

These results were published in The Lancet Haematology. The study was sponsored by Bio-Path Holdings, Inc., the company developing prexigebersen.

Prexigebersen is an anti-sense oligodeoxynucleotide developed to block Grb2 expression and function. Researchers tested the drug in a single-center, dose-escalation, phase 1/1b trial that enrolled and treated 39 patients.

In the phase 1 portion of the trial, patients received prexigebersen monotherapy. In the phase 1b portion, they received the drug in combination with low-dose cytarabine.

There were 32 patients in the phase 1 portion of the trial. Most (n=23) had AML, 5 had CML in blast phase, and 4 had MDS. The patients’ median age was 63 (range, 56-73), and they had received a median of 4 prior therapies.

All 7 patients in the phase 1b portion had AML. They had a median age of 72 (range, 70-76) and had all received 1 prior therapy.

For phase 1, prexigebersen was administered intravenously, twice weekly for 28 days at doses of 5 mg/m² in cohort 1 (n=13), 10 mg/m² in cohort 2 (n=6), 20 mg/m² in cohort 3 (n=3), 40 mg/m² in cohort 4 (n=3), 60 mg/m² in cohort 5 (n=3), and 90 mg/m² in cohort 6 (n=4).

In the phase 1b portion, patients received prexigebersen at 60 mg/m² (n=4) or 90 mg/m² (n=3) in combination with 20 mg of cytarabine (twice-daily subcutaneous injections).

Safety

Twenty-seven patients were evaluable for dose-limiting toxicity—21 from phase 1 and 6 from 1b.

One patient in cohort 1 developed mucositis and hand-foot syndrome, which were considered possibly related to prexigebersen and deemed dose-limiting toxicities. The patient was also receiving hydroxyurea (3 g/day) for CML and had a history of hydroxyurea-induced mucositis.

There were no other dose-limiting toxicities, and the researchers did not identify a maximum tolerated dose of prexigebersen.

The most common grade 3-4 adverse events (AEs) were cardiopulmonary disorders and fevers (including neutropenic fevers and infections).

In the monotherapy group, 17% of patients had grade 3-4 cardiopulmonary AEs, and 11% had fevers. In the prexigebersen-cytarabine combination group, 8% had grade 3-4 cardiopulmonary AEs, and 6% had fevers.

There were 5 grade 5 AEs in 4 patients, all of whom received monotherapy. These included cardiopulmonary disorders (n=2), fevers (n=2), and multi-organ failure (n=1). One patient had both fever (sepsis) and multi-organ failure.

Efficacy

According to the researchers’ assessments, 22% of phase 1 patients (7/32) benefited from prexigebersen monotherapy and therefore received more than 1 cycle of treatment. Five of these patients had AML, and 2 had MDS.

Single-agent activity was observed in other patients as well.

Thirty-three percent (9/27) of patients who had peripheral blood blasts at baseline saw their blasts reduced by 50% or more while receiving monotherapy. One of these patients had CML, and the rest had AML.

Ten percent (3/29) of patients with bone marrow blasts at baseline had a reduction in blasts of 50% or more while receiving monotherapy.  Two of these patients had AML, and 1 had MDS.

Of the 7 patients receiving prexigebersen with cytarabine, 2 achieved a CR, and 1 had a CR with incomplete hematological recovery.

Two of the patients had stable disease, and the remaining 2 patients progressed. One of the patients with progressive disease withdrew from the study, and the other died.

Deaths

There were a total of 8 deaths.

One death was considered treatment-related. This patient had progressive CML in blast phase and died of multiple organ failure. This was the first patient treated on the trial, who also had the only dose-limiting toxicities.

Two patients with AML and 1 with MDS died of disease progression. Three AML patients died of sepsis, pneumonia, and cardiac arrest. And a CML patient died of respiratory distress.

AML cells

The experimental agent prexigebersen (formerly BP1001) was considered well-tolerated and demonstrated early evidence of activity against relapsed/refractory hematologic disorders in a phase 1/1b trial.

The drug reduced blasts in the bone marrow and peripheral blood for patients with acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and myelodysplastic syndrome (MDS).

When given in combination with low-dose cytarabine, prexigebersen produced complete responses (CRs) in patients with AML.

Researchers said that, overall, the toxic effects of prexigebersen were manageable.

There was 1 patient who had dose-limiting toxicities, 1 who discontinued treatment due to possible drug-related toxic effects, and 1 treatment-related death.

Still, the maximum tolerated dose of prexigebersen was not established.

These results were published in The Lancet Haematology. The study was sponsored by Bio-Path Holdings, Inc., the company developing prexigebersen.

Prexigebersen is an anti-sense oligodeoxynucleotide developed to block Grb2 expression and function. Researchers tested the drug in a single-center, dose-escalation, phase 1/1b trial that enrolled and treated 39 patients.

In the phase 1 portion of the trial, patients received prexigebersen monotherapy. In the phase 1b portion, they received the drug in combination with low-dose cytarabine.

There were 32 patients in the phase 1 portion of the trial. Most (n=23) had AML, 5 had CML in blast phase, and 4 had MDS. The patients’ median age was 63 (range, 56-73), and they had received a median of 4 prior therapies.

All 7 patients in the phase 1b portion had AML. They had a median age of 72 (range, 70-76) and had all received 1 prior therapy.

For phase 1, prexigebersen was administered intravenously, twice weekly for 28 days at doses of 5 mg/m² in cohort 1 (n=13), 10 mg/m² in cohort 2 (n=6), 20 mg/m² in cohort 3 (n=3), 40 mg/m² in cohort 4 (n=3), 60 mg/m² in cohort 5 (n=3), and 90 mg/m² in cohort 6 (n=4).

In the phase 1b portion, patients received prexigebersen at 60 mg/m² (n=4) or 90 mg/m² (n=3) in combination with 20 mg of cytarabine (twice-daily subcutaneous injections).

Safety

Twenty-seven patients were evaluable for dose-limiting toxicity—21 from phase 1 and 6 from 1b.

One patient in cohort 1 developed mucositis and hand-foot syndrome, which were considered possibly related to prexigebersen and deemed dose-limiting toxicities. The patient was also receiving hydroxyurea (3 g/day) for CML and had a history of hydroxyurea-induced mucositis.

There were no other dose-limiting toxicities, and the researchers did not identify a maximum tolerated dose of prexigebersen.

The most common grade 3-4 adverse events (AEs) were cardiopulmonary disorders and fevers (including neutropenic fevers and infections).

In the monotherapy group, 17% of patients had grade 3-4 cardiopulmonary AEs, and 11% had fevers. In the prexigebersen-cytarabine combination group, 8% had grade 3-4 cardiopulmonary AEs, and 6% had fevers.

There were 5 grade 5 AEs in 4 patients, all of whom received monotherapy. These included cardiopulmonary disorders (n=2), fevers (n=2), and multi-organ failure (n=1). One patient had both fever (sepsis) and multi-organ failure.

Efficacy

According to the researchers’ assessments, 22% of phase 1 patients (7/32) benefited from prexigebersen monotherapy and therefore received more than 1 cycle of treatment. Five of these patients had AML, and 2 had MDS.

Single-agent activity was observed in other patients as well.

Thirty-three percent (9/27) of patients who had peripheral blood blasts at baseline saw their blasts reduced by 50% or more while receiving monotherapy. One of these patients had CML, and the rest had AML.

Ten percent (3/29) of patients with bone marrow blasts at baseline had a reduction in blasts of 50% or more while receiving monotherapy.  Two of these patients had AML, and 1 had MDS.

Of the 7 patients receiving prexigebersen with cytarabine, 2 achieved a CR, and 1 had a CR with incomplete hematological recovery.

Two of the patients had stable disease, and the remaining 2 patients progressed. One of the patients with progressive disease withdrew from the study, and the other died.

Deaths

There were a total of 8 deaths.

One death was considered treatment-related. This patient had progressive CML in blast phase and died of multiple organ failure. This was the first patient treated on the trial, who also had the only dose-limiting toxicities.

Two patients with AML and 1 with MDS died of disease progression. Three AML patients died of sepsis, pneumonia, and cardiac arrest. And a CML patient died of respiratory distress.

Image by Betty Pace

The European Commission (EC) has granted orphan designation to Altemia (formerly SC411) for the treatment of pediatric patients with sickle cell disease (SCD).

Altemia gelatin capsules are designed to replenish the lipids destroyed by sickle hemoglobin.

Altemia is intended to be taken once daily to reduce vaso-occlusive crises, anemia, organ damage, and other complications of SCD.

Altemia consists of a mixture of fatty acids, primarily in the form of Ethyl Cervonate (a proprietary blend of docosahexaenoic acid and other omega-3 fatty acids), and surface active agents formulated using Advanced Lipid Technologies.

Advanced Lipid Technologies are proprietary formulation and manufacturing techniques used by Sancilio Pharmaceuticals Company, Inc. (SPCI) to create lipophilic drug products.

Last November, SPCI reported topline data from its phase 2 study of Altemia, the SCOT trial (NCT02973360). The trial included pediatric patients, ages 5 to 17, with SCD.

The study’s primary endpoint was the change from baseline in blood cell membranes’ fatty acids concentration. SPCI said Altemia showed a significant improvement in this endpoint, compared to placebo, within 4 weeks of treatment initiation.

Patients who received Altemia also had significant improvements in markers of coagulation (D-dimer), inflammation (C-reactive protein), and adhesion (E-selectin) after 8 weeks of treatment.

And patients treated with Altemia had a “clinically meaningful” reduction in vaso-occlusive events, according to SPCI.

There were no treatment-related serious adverse events reported.

Ninety-four percent of patients completed the study, and most have chosen to participate in the open-label extension phase, in which researchers will continue monitoring the safety and effectiveness of Altemia.

SPCI said additional analyses of SCOT data are ongoing, and the company plans to present detailed data from the study in journals and at upcoming scientific conferences.

About orphan designation

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 European Medicines Agency during the product development phase and direct access to the centralized authorization procedure.

Image by Betty Pace

The European Commission (EC) has granted orphan designation to Altemia (formerly SC411) for the treatment of pediatric patients with sickle cell disease (SCD).

Altemia gelatin capsules are designed to replenish the lipids destroyed by sickle hemoglobin.

Altemia is intended to be taken once daily to reduce vaso-occlusive crises, anemia, organ damage, and other complications of SCD.

Altemia consists of a mixture of fatty acids, primarily in the form of Ethyl Cervonate (a proprietary blend of docosahexaenoic acid and other omega-3 fatty acids), and surface active agents formulated using Advanced Lipid Technologies.

Advanced Lipid Technologies are proprietary formulation and manufacturing techniques used by Sancilio Pharmaceuticals Company, Inc. (SPCI) to create lipophilic drug products.

Last November, SPCI reported topline data from its phase 2 study of Altemia, the SCOT trial (NCT02973360). The trial included pediatric patients, ages 5 to 17, with SCD.

The study’s primary endpoint was the change from baseline in blood cell membranes’ fatty acids concentration. SPCI said Altemia showed a significant improvement in this endpoint, compared to placebo, within 4 weeks of treatment initiation.

Patients who received Altemia also had significant improvements in markers of coagulation (D-dimer), inflammation (C-reactive protein), and adhesion (E-selectin) after 8 weeks of treatment.

And patients treated with Altemia had a “clinically meaningful” reduction in vaso-occlusive events, according to SPCI.

There were no treatment-related serious adverse events reported.

Ninety-four percent of patients completed the study, and most have chosen to participate in the open-label extension phase, in which researchers will continue monitoring the safety and effectiveness of Altemia.

SPCI said additional analyses of SCOT data are ongoing, and the company plans to present detailed data from the study in journals and at upcoming scientific conferences.

About orphan designation

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 European Medicines Agency during the product development phase and direct access to the centralized authorization procedure.

Image by Betty Pace

The European Commission (EC) has granted orphan designation to Altemia (formerly SC411) for the treatment of pediatric patients with sickle cell disease (SCD).

Altemia gelatin capsules are designed to replenish the lipids destroyed by sickle hemoglobin.

Altemia is intended to be taken once daily to reduce vaso-occlusive crises, anemia, organ damage, and other complications of SCD.

Altemia consists of a mixture of fatty acids, primarily in the form of Ethyl Cervonate (a proprietary blend of docosahexaenoic acid and other omega-3 fatty acids), and surface active agents formulated using Advanced Lipid Technologies.

Advanced Lipid Technologies are proprietary formulation and manufacturing techniques used by Sancilio Pharmaceuticals Company, Inc. (SPCI) to create lipophilic drug products.

Last November, SPCI reported topline data from its phase 2 study of Altemia, the SCOT trial (NCT02973360). The trial included pediatric patients, ages 5 to 17, with SCD.

The study’s primary endpoint was the change from baseline in blood cell membranes’ fatty acids concentration. SPCI said Altemia showed a significant improvement in this endpoint, compared to placebo, within 4 weeks of treatment initiation.

Patients who received Altemia also had significant improvements in markers of coagulation (D-dimer), inflammation (C-reactive protein), and adhesion (E-selectin) after 8 weeks of treatment.

And patients treated with Altemia had a “clinically meaningful” reduction in vaso-occlusive events, according to SPCI.

There were no treatment-related serious adverse events reported.

Ninety-four percent of patients completed the study, and most have chosen to participate in the open-label extension phase, in which researchers will continue monitoring the safety and effectiveness of Altemia.

SPCI said additional analyses of SCOT data are ongoing, and the company plans to present detailed data from the study in journals and at upcoming scientific conferences.

About orphan designation

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 European Medicines Agency during the product development phase and direct access to the centralized authorization procedure.

Platelet-rich plasma

HIT Confirm, a test used to diagnose heparin-induced thrombocytopenia (HIT), has received the CE mark.

This means the test meets regulatory requirements and health, safety, and environmental protection standards for products sold within the European Economic Area.

HIT Confirm is a flow cytometry-based test developed by Emosis. The test can be performed on any flow cytometer and provides results within 30 minutes.

HIT Confirm requires a low-volume sample (microliters) of platelet-rich plasma to confirm the presence of HIT antibodies that lead to the formation of a heparin-antibody-PF4 complex that will bind to platelets and activate them.

HIT Confirm requires a single incubation with 2 fluorophores against a marker of platelets (CD41) and a marker of activated platelets (CD62).

After 30 minutes of incubation with 2 dose levels of heparin (0.3 U/mL and 100 U/mL), the proportion of activated platelets is obtained via flow cytometry.

Results are interpreted using a platelet activation index called HEPLA, which was developed by Emosis.

Research presented at the 2017 ISTH Congress (abstract OC 34.3*) indicated that HIT Confirm produces results comparable to those provided by the serotonin release assay (SRA).

Researchers tested the sensitivity and specificity of SRA and HIT Confirm when analyzing plasma from 290 patients—131 of whom were deemed HIT-positive by experts.

When compared to expert opinion, HIT Confirm provided 90% sensitivity and 94% specificity. SRA provided 80% sensitivity and 94% specificity compared to expert opinion.

For more information on HIT Confirm, visit the Emosis website.

*Data in the abstract differ from data provided by Emosis. The data used here were provided by Emosis.

Platelet-rich plasma

HIT Confirm, a test used to diagnose heparin-induced thrombocytopenia (HIT), has received the CE mark.

This means the test meets regulatory requirements and health, safety, and environmental protection standards for products sold within the European Economic Area.

HIT Confirm is a flow cytometry-based test developed by Emosis. The test can be performed on any flow cytometer and provides results within 30 minutes.

HIT Confirm requires a low-volume sample (microliters) of platelet-rich plasma to confirm the presence of HIT antibodies that lead to the formation of a heparin-antibody-PF4 complex that will bind to platelets and activate them.

HIT Confirm requires a single incubation with 2 fluorophores against a marker of platelets (CD41) and a marker of activated platelets (CD62).

After 30 minutes of incubation with 2 dose levels of heparin (0.3 U/mL and 100 U/mL), the proportion of activated platelets is obtained via flow cytometry.

Results are interpreted using a platelet activation index called HEPLA, which was developed by Emosis.

Research presented at the 2017 ISTH Congress (abstract OC 34.3*) indicated that HIT Confirm produces results comparable to those provided by the serotonin release assay (SRA).

Researchers tested the sensitivity and specificity of SRA and HIT Confirm when analyzing plasma from 290 patients—131 of whom were deemed HIT-positive by experts.

When compared to expert opinion, HIT Confirm provided 90% sensitivity and 94% specificity. SRA provided 80% sensitivity and 94% specificity compared to expert opinion.

For more information on HIT Confirm, visit the Emosis website.

*Data in the abstract differ from data provided by Emosis. The data used here were provided by Emosis.

Platelet-rich plasma

HIT Confirm, a test used to diagnose heparin-induced thrombocytopenia (HIT), has received the CE mark.

This means the test meets regulatory requirements and health, safety, and environmental protection standards for products sold within the European Economic Area.

HIT Confirm is a flow cytometry-based test developed by Emosis. The test can be performed on any flow cytometer and provides results within 30 minutes.

HIT Confirm requires a low-volume sample (microliters) of platelet-rich plasma to confirm the presence of HIT antibodies that lead to the formation of a heparin-antibody-PF4 complex that will bind to platelets and activate them.

HIT Confirm requires a single incubation with 2 fluorophores against a marker of platelets (CD41) and a marker of activated platelets (CD62).

After 30 minutes of incubation with 2 dose levels of heparin (0.3 U/mL and 100 U/mL), the proportion of activated platelets is obtained via flow cytometry.

Results are interpreted using a platelet activation index called HEPLA, which was developed by Emosis.

Research presented at the 2017 ISTH Congress (abstract OC 34.3*) indicated that HIT Confirm produces results comparable to those provided by the serotonin release assay (SRA).

Researchers tested the sensitivity and specificity of SRA and HIT Confirm when analyzing plasma from 290 patients—131 of whom were deemed HIT-positive by experts.

When compared to expert opinion, HIT Confirm provided 90% sensitivity and 94% specificity. SRA provided 80% sensitivity and 94% specificity compared to expert opinion.

For more information on HIT Confirm, visit the Emosis website.

*Data in the abstract differ from data provided by Emosis. The data used here were provided by Emosis.

Photo from UNSW

Researchers have used CRISPR-Cas9 gene editing to reproduce naturally occurring mutations that boost the production of fetal hemoglobin.

The mutations are associated with hereditary persistence of fetal hemoglobin (HPFH), and the researchers believe that introducing these mutations into erythroid cells could be a safe way to treat β-hemoglobinopathies such as sickle cell disease (SCD) and β-thalassemia.

This research was published in Nature Genetics.

“Our new approach can be seen as a forerunner to ‘organic gene therapy’ for a range of common inherited blood disorders, including β-thalassemia and sickle cell anemia,” said study author Merlin Crossley, DPhil, of the University of New South Wales in Sydney, Australia.

“It is organic because no new DNA is introduced into the cells; rather, we engineer in naturally occurring, benign mutations that are known to be beneficial to people with these conditions. It should prove to be a safe and effective therapy, although more research would be needed to scale the processes up into effective treatments.”

Dr Crossley and his colleagues noted that reactivating fetal hemoglobin production has long been a therapeutic goal for SCD and β-thalassemia.

“The fetal hemoglobin gene is naturally silenced after birth,” Dr Crossley explained. “For 50 years, researchers have been competing furiously to find out how it is switched off, so it can be turned back on. Our study, which is the culmination of many years of work, solves that mystery.”

“We have found that 2 genes, called BCL11A and ZBTB7A, switch off the fetal hemoglobin gene by binding directly to it. And the beneficial mutations work by disrupting the 2 sites where these 2 genes bind.”

The “beneficial mutations,” which cause some forms of HPFH, are point mutations in the γ-globin gene promoter at -115 and -200 bp upstream of the transcription start site.

Dr Crossley and his colleagues found that BCL11A31 and ZBTB7A23—2 well-established fetal globin repressors—bind these regions of the γ-globin gene proximal promoter, and mutations at –115 and –200 bp disrupt the binding.

The researchers used CRISPR-Cas9 to introduce the HPFH-associated mutations into erythroid cells and observed both disruption of repressor binding and increased γ-globin gene expression.

“This landmark finding not only contributes to our appreciation of how these globin genes are regulated,” Dr Crossley said. “It means we can now shift our focus to developing therapies for these genetic diseases using CRISPR to target precise changes in the genome.”

Photo from UNSW

Researchers have used CRISPR-Cas9 gene editing to reproduce naturally occurring mutations that boost the production of fetal hemoglobin.

The mutations are associated with hereditary persistence of fetal hemoglobin (HPFH), and the researchers believe that introducing these mutations into erythroid cells could be a safe way to treat β-hemoglobinopathies such as sickle cell disease (SCD) and β-thalassemia.

This research was published in Nature Genetics.

“Our new approach can be seen as a forerunner to ‘organic gene therapy’ for a range of common inherited blood disorders, including β-thalassemia and sickle cell anemia,” said study author Merlin Crossley, DPhil, of the University of New South Wales in Sydney, Australia.

“It is organic because no new DNA is introduced into the cells; rather, we engineer in naturally occurring, benign mutations that are known to be beneficial to people with these conditions. It should prove to be a safe and effective therapy, although more research would be needed to scale the processes up into effective treatments.”

Dr Crossley and his colleagues noted that reactivating fetal hemoglobin production has long been a therapeutic goal for SCD and β-thalassemia.

“The fetal hemoglobin gene is naturally silenced after birth,” Dr Crossley explained. “For 50 years, researchers have been competing furiously to find out how it is switched off, so it can be turned back on. Our study, which is the culmination of many years of work, solves that mystery.”

“We have found that 2 genes, called BCL11A and ZBTB7A, switch off the fetal hemoglobin gene by binding directly to it. And the beneficial mutations work by disrupting the 2 sites where these 2 genes bind.”

The “beneficial mutations,” which cause some forms of HPFH, are point mutations in the γ-globin gene promoter at -115 and -200 bp upstream of the transcription start site.

Dr Crossley and his colleagues found that BCL11A31 and ZBTB7A23—2 well-established fetal globin repressors—bind these regions of the γ-globin gene proximal promoter, and mutations at –115 and –200 bp disrupt the binding.

The researchers used CRISPR-Cas9 to introduce the HPFH-associated mutations into erythroid cells and observed both disruption of repressor binding and increased γ-globin gene expression.

“This landmark finding not only contributes to our appreciation of how these globin genes are regulated,” Dr Crossley said. “It means we can now shift our focus to developing therapies for these genetic diseases using CRISPR to target precise changes in the genome.”

Photo from UNSW

Researchers have used CRISPR-Cas9 gene editing to reproduce naturally occurring mutations that boost the production of fetal hemoglobin.

The mutations are associated with hereditary persistence of fetal hemoglobin (HPFH), and the researchers believe that introducing these mutations into erythroid cells could be a safe way to treat β-hemoglobinopathies such as sickle cell disease (SCD) and β-thalassemia.

This research was published in Nature Genetics.

“Our new approach can be seen as a forerunner to ‘organic gene therapy’ for a range of common inherited blood disorders, including β-thalassemia and sickle cell anemia,” said study author Merlin Crossley, DPhil, of the University of New South Wales in Sydney, Australia.

“It is organic because no new DNA is introduced into the cells; rather, we engineer in naturally occurring, benign mutations that are known to be beneficial to people with these conditions. It should prove to be a safe and effective therapy, although more research would be needed to scale the processes up into effective treatments.”

Dr Crossley and his colleagues noted that reactivating fetal hemoglobin production has long been a therapeutic goal for SCD and β-thalassemia.

“The fetal hemoglobin gene is naturally silenced after birth,” Dr Crossley explained. “For 50 years, researchers have been competing furiously to find out how it is switched off, so it can be turned back on. Our study, which is the culmination of many years of work, solves that mystery.”

“We have found that 2 genes, called BCL11A and ZBTB7A, switch off the fetal hemoglobin gene by binding directly to it. And the beneficial mutations work by disrupting the 2 sites where these 2 genes bind.”

The “beneficial mutations,” which cause some forms of HPFH, are point mutations in the γ-globin gene promoter at -115 and -200 bp upstream of the transcription start site.

Dr Crossley and his colleagues found that BCL11A31 and ZBTB7A23—2 well-established fetal globin repressors—bind these regions of the γ-globin gene proximal promoter, and mutations at –115 and –200 bp disrupt the binding.

The researchers used CRISPR-Cas9 to introduce the HPFH-associated mutations into erythroid cells and observed both disruption of repressor binding and increased γ-globin gene expression.

“This landmark finding not only contributes to our appreciation of how these globin genes are regulated,” Dr Crossley said. “It means we can now shift our focus to developing therapies for these genetic diseases using CRISPR to target precise changes in the genome.”

SALT LAKE CITY – Lentiviral delivery of BB305 gene therapy via autologous hematopoietic stem cell transplant (HSCT) was safe and effective for individuals with transfusion dependent beta thalassemia, according to results of a phase 1/2 study.

None of the study participants died, and the majority of patients are now transfusion independent.

The Northstar study is an international, multicenter open-label, single-arm study of adolescents and adults with transfusion dependent beta thalassemia (TDT). A total of 18 patients at a median 21 years of age – 15 young adults aged 18-35 years and three adolescents aged 12-17 years – have now been treated, Mark Walters, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

Of these, 11 are now transfusion independent, with most patients stopping transfusions within 6 months of receiving gene therapy, said Dr. Walters, director of the blood and marrow transplantation program at the University of California, San Francisco’s Benioff Children’s Hospital, Oakland.

Eight patients had the beta⁰/beta⁰ genotype, and had essentially been transfusion dependent from infancy. Six other patients were beta^E/beta⁰, and had become transfusion dependent over time. Four patients had other thalassemia genotypes.

Patients who enrolled in the Northstar study first had peripheral stem cell collection via apheresis after mobilization with granulocyte-colony stimulating factor and plerixafor. Then they received myeloablative conditioning with busulfan. At the same time, selected CD34+ cells were tranduced with the BB305 lentiviral vector and cryopreserved. Patients were infused with the transduced cells and managed through the engraftment process.

As a measure of annualized pre-procedure transfusion requirements, patients had received a median 163.6 mL/kg/year of packed red blood cells, Dr. Walters said. Not unexpectedly, liver iron concentration was a median 5.7 mg/g, though with a wide range among participants (0.4-26.4 mg/g). However, participants did not show signs of cardiac tissue iron on T2* magnetic resonance imaging . Six patients had undergone a splenectomy.

The median vector copy number was 0.7 (range, 0.3-1.5), with a median 31.5 CD34+ cells transduced (range, 17.0-58.0). The final cell dose delivered was a median 8.1 x 10⁶ CD34+ cells/kg (range, 5.2-18.1).

“All 18 patients have had at least 18 months of follow-up,” said Dr. Walters, and data from 10 patients has been analyzed out to 2 years. Three patients have a full 3 years of follow-up, he said.

The self-inactivating lentiviral vector has behaved as expected; no replication-competent lentivirus has been found, with investigators conducting assessments at months 3, 6, and 12, and then annually through year 5.

The study protocol also calls for integration site analysis every 6 months for 5 years, and additional analyses at years 7, 10, and 15. Thus far, all samples have shown a polyclonal vector integration profile without clonal dominance, Dr. Walter said.

The median time to neutrophil engraftment was study day 18.5 (range, 14-30), while platelet engraftment was more variable, and overall slower, with engraftment at a median of study day 39.5 (range, 19-191).

Dr. Walters said that he and his colleagues examined characteristics of the four patients who still had platelet counts at or less than 100,000/microliters at 12 months after HSCT. They found that two of these patients had had splenectomies, but saw no clear relationship between speed of platelet engraftment and platelet count at 12 months. Three of the four patients had drug product cell doses less than the median.

However, two patients had no bleeding events after neutrophil engraftment, and bleeding events were all grade 1 or 2 in the other two patients. The slower-than-expected platelet engraftment rate was likely attributable to the ex vivo manipulation of the stem cells, Dr. Walters noted.

Looking at safety data from the point of neutrophil engraftment to the last follow-up, there have been no graft failures; six patients have had serious adverse events. Two events of veno-occlusive disease were assessed as grade 3 and attributed to the transplant. Two of these three patients had an extended hospital stay. Other grade 3 events including intracardiac thrombus, central catheter thrombosis, and cellulitis, as well as hyperglycemia and infectious diseases.

No grade 4 or 5 infections were reported, and the researchers saw no viral reactivations or opportunistic infections.

The safety profile for autologous HSCT with LentiGlobin was overall as expected for a myeloablative regimen that used single-agent busulfan, Dr. Walters said.

Most patients (11/18) with transfusion dependent beta thalassemia were able to stop transfusions, and the remaining patients had reduced transfusion requirements. Participants’ clinical status has stayed consistent through up to 3 years of follow-up, he said.

Of the patients who were able to stop transfusions, just two had the beta⁰/beta⁰ genotype. Among all transfusion independent participants, hemoglobin levels at the last study visit ranged from 8.4-13.7 g/dL. Beta⁰/beta⁰ genotype patients still receiving transfusions have seen a 60% median reduction in transfusion volume and a similar reduction in number of transfusions.

In response to an attendee question, Dr. Walters said that an analysis not included in the presentation has shown a fairly direct relationship between vector copy numbers and transfusion independence.

Currently, he said, vector copy numbers are higher, at around 3. With a higher vector copy number, more CD34+ cells will be transduced and infused, so there may be less concern about the dilutional effect of incomplete myeloablation.

“There may be an opportunity in the future to lessen the intensity of the conditioning regimen,” Dr. Walters said.

The study was funded by bluebird bio. Dr. Walters also reported several consulting relationships with pharmaceutical companies and laboratories.
 

koakes@mdedge.com

SOURCE: Walters, M et al. 2018 BMT Tandem Meetings, Abstract 62.

SALT LAKE CITY – Lentiviral delivery of BB305 gene therapy via autologous hematopoietic stem cell transplant (HSCT) was safe and effective for individuals with transfusion dependent beta thalassemia, according to results of a phase 1/2 study.

None of the study participants died, and the majority of patients are now transfusion independent.

The Northstar study is an international, multicenter open-label, single-arm study of adolescents and adults with transfusion dependent beta thalassemia (TDT). A total of 18 patients at a median 21 years of age – 15 young adults aged 18-35 years and three adolescents aged 12-17 years – have now been treated, Mark Walters, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

Of these, 11 are now transfusion independent, with most patients stopping transfusions within 6 months of receiving gene therapy, said Dr. Walters, director of the blood and marrow transplantation program at the University of California, San Francisco’s Benioff Children’s Hospital, Oakland.

Eight patients had the beta⁰/beta⁰ genotype, and had essentially been transfusion dependent from infancy. Six other patients were beta^E/beta⁰, and had become transfusion dependent over time. Four patients had other thalassemia genotypes.

Patients who enrolled in the Northstar study first had peripheral stem cell collection via apheresis after mobilization with granulocyte-colony stimulating factor and plerixafor. Then they received myeloablative conditioning with busulfan. At the same time, selected CD34+ cells were tranduced with the BB305 lentiviral vector and cryopreserved. Patients were infused with the transduced cells and managed through the engraftment process.

As a measure of annualized pre-procedure transfusion requirements, patients had received a median 163.6 mL/kg/year of packed red blood cells, Dr. Walters said. Not unexpectedly, liver iron concentration was a median 5.7 mg/g, though with a wide range among participants (0.4-26.4 mg/g). However, participants did not show signs of cardiac tissue iron on T2* magnetic resonance imaging . Six patients had undergone a splenectomy.

The median vector copy number was 0.7 (range, 0.3-1.5), with a median 31.5 CD34+ cells transduced (range, 17.0-58.0). The final cell dose delivered was a median 8.1 x 10⁶ CD34+ cells/kg (range, 5.2-18.1).

“All 18 patients have had at least 18 months of follow-up,” said Dr. Walters, and data from 10 patients has been analyzed out to 2 years. Three patients have a full 3 years of follow-up, he said.

The self-inactivating lentiviral vector has behaved as expected; no replication-competent lentivirus has been found, with investigators conducting assessments at months 3, 6, and 12, and then annually through year 5.

The study protocol also calls for integration site analysis every 6 months for 5 years, and additional analyses at years 7, 10, and 15. Thus far, all samples have shown a polyclonal vector integration profile without clonal dominance, Dr. Walter said.

The median time to neutrophil engraftment was study day 18.5 (range, 14-30), while platelet engraftment was more variable, and overall slower, with engraftment at a median of study day 39.5 (range, 19-191).

Dr. Walters said that he and his colleagues examined characteristics of the four patients who still had platelet counts at or less than 100,000/microliters at 12 months after HSCT. They found that two of these patients had had splenectomies, but saw no clear relationship between speed of platelet engraftment and platelet count at 12 months. Three of the four patients had drug product cell doses less than the median.

However, two patients had no bleeding events after neutrophil engraftment, and bleeding events were all grade 1 or 2 in the other two patients. The slower-than-expected platelet engraftment rate was likely attributable to the ex vivo manipulation of the stem cells, Dr. Walters noted.

Looking at safety data from the point of neutrophil engraftment to the last follow-up, there have been no graft failures; six patients have had serious adverse events. Two events of veno-occlusive disease were assessed as grade 3 and attributed to the transplant. Two of these three patients had an extended hospital stay. Other grade 3 events including intracardiac thrombus, central catheter thrombosis, and cellulitis, as well as hyperglycemia and infectious diseases.

No grade 4 or 5 infections were reported, and the researchers saw no viral reactivations or opportunistic infections.

The safety profile for autologous HSCT with LentiGlobin was overall as expected for a myeloablative regimen that used single-agent busulfan, Dr. Walters said.

Most patients (11/18) with transfusion dependent beta thalassemia were able to stop transfusions, and the remaining patients had reduced transfusion requirements. Participants’ clinical status has stayed consistent through up to 3 years of follow-up, he said.

Of the patients who were able to stop transfusions, just two had the beta⁰/beta⁰ genotype. Among all transfusion independent participants, hemoglobin levels at the last study visit ranged from 8.4-13.7 g/dL. Beta⁰/beta⁰ genotype patients still receiving transfusions have seen a 60% median reduction in transfusion volume and a similar reduction in number of transfusions.

In response to an attendee question, Dr. Walters said that an analysis not included in the presentation has shown a fairly direct relationship between vector copy numbers and transfusion independence.

Currently, he said, vector copy numbers are higher, at around 3. With a higher vector copy number, more CD34+ cells will be transduced and infused, so there may be less concern about the dilutional effect of incomplete myeloablation.

“There may be an opportunity in the future to lessen the intensity of the conditioning regimen,” Dr. Walters said.

The study was funded by bluebird bio. Dr. Walters also reported several consulting relationships with pharmaceutical companies and laboratories.
 

koakes@mdedge.com

SOURCE: Walters, M et al. 2018 BMT Tandem Meetings, Abstract 62.

SALT LAKE CITY – Lentiviral delivery of BB305 gene therapy via autologous hematopoietic stem cell transplant (HSCT) was safe and effective for individuals with transfusion dependent beta thalassemia, according to results of a phase 1/2 study.

None of the study participants died, and the majority of patients are now transfusion independent.

The Northstar study is an international, multicenter open-label, single-arm study of adolescents and adults with transfusion dependent beta thalassemia (TDT). A total of 18 patients at a median 21 years of age – 15 young adults aged 18-35 years and three adolescents aged 12-17 years – have now been treated, Mark Walters, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

Of these, 11 are now transfusion independent, with most patients stopping transfusions within 6 months of receiving gene therapy, said Dr. Walters, director of the blood and marrow transplantation program at the University of California, San Francisco’s Benioff Children’s Hospital, Oakland.

Eight patients had the beta⁰/beta⁰ genotype, and had essentially been transfusion dependent from infancy. Six other patients were beta^E/beta⁰, and had become transfusion dependent over time. Four patients had other thalassemia genotypes.

Patients who enrolled in the Northstar study first had peripheral stem cell collection via apheresis after mobilization with granulocyte-colony stimulating factor and plerixafor. Then they received myeloablative conditioning with busulfan. At the same time, selected CD34+ cells were tranduced with the BB305 lentiviral vector and cryopreserved. Patients were infused with the transduced cells and managed through the engraftment process.

As a measure of annualized pre-procedure transfusion requirements, patients had received a median 163.6 mL/kg/year of packed red blood cells, Dr. Walters said. Not unexpectedly, liver iron concentration was a median 5.7 mg/g, though with a wide range among participants (0.4-26.4 mg/g). However, participants did not show signs of cardiac tissue iron on T2* magnetic resonance imaging . Six patients had undergone a splenectomy.

The median vector copy number was 0.7 (range, 0.3-1.5), with a median 31.5 CD34+ cells transduced (range, 17.0-58.0). The final cell dose delivered was a median 8.1 x 10⁶ CD34+ cells/kg (range, 5.2-18.1).

“All 18 patients have had at least 18 months of follow-up,” said Dr. Walters, and data from 10 patients has been analyzed out to 2 years. Three patients have a full 3 years of follow-up, he said.

The self-inactivating lentiviral vector has behaved as expected; no replication-competent lentivirus has been found, with investigators conducting assessments at months 3, 6, and 12, and then annually through year 5.

The study protocol also calls for integration site analysis every 6 months for 5 years, and additional analyses at years 7, 10, and 15. Thus far, all samples have shown a polyclonal vector integration profile without clonal dominance, Dr. Walter said.

The median time to neutrophil engraftment was study day 18.5 (range, 14-30), while platelet engraftment was more variable, and overall slower, with engraftment at a median of study day 39.5 (range, 19-191).

Dr. Walters said that he and his colleagues examined characteristics of the four patients who still had platelet counts at or less than 100,000/microliters at 12 months after HSCT. They found that two of these patients had had splenectomies, but saw no clear relationship between speed of platelet engraftment and platelet count at 12 months. Three of the four patients had drug product cell doses less than the median.

However, two patients had no bleeding events after neutrophil engraftment, and bleeding events were all grade 1 or 2 in the other two patients. The slower-than-expected platelet engraftment rate was likely attributable to the ex vivo manipulation of the stem cells, Dr. Walters noted.

Looking at safety data from the point of neutrophil engraftment to the last follow-up, there have been no graft failures; six patients have had serious adverse events. Two events of veno-occlusive disease were assessed as grade 3 and attributed to the transplant. Two of these three patients had an extended hospital stay. Other grade 3 events including intracardiac thrombus, central catheter thrombosis, and cellulitis, as well as hyperglycemia and infectious diseases.

No grade 4 or 5 infections were reported, and the researchers saw no viral reactivations or opportunistic infections.

The safety profile for autologous HSCT with LentiGlobin was overall as expected for a myeloablative regimen that used single-agent busulfan, Dr. Walters said.

Most patients (11/18) with transfusion dependent beta thalassemia were able to stop transfusions, and the remaining patients had reduced transfusion requirements. Participants’ clinical status has stayed consistent through up to 3 years of follow-up, he said.

Of the patients who were able to stop transfusions, just two had the beta⁰/beta⁰ genotype. Among all transfusion independent participants, hemoglobin levels at the last study visit ranged from 8.4-13.7 g/dL. Beta⁰/beta⁰ genotype patients still receiving transfusions have seen a 60% median reduction in transfusion volume and a similar reduction in number of transfusions.

In response to an attendee question, Dr. Walters said that an analysis not included in the presentation has shown a fairly direct relationship between vector copy numbers and transfusion independence.

Currently, he said, vector copy numbers are higher, at around 3. With a higher vector copy number, more CD34+ cells will be transduced and infused, so there may be less concern about the dilutional effect of incomplete myeloablation.

“There may be an opportunity in the future to lessen the intensity of the conditioning regimen,” Dr. Walters said.

The study was funded by bluebird bio. Dr. Walters also reported several consulting relationships with pharmaceutical companies and laboratories.
 

koakes@mdedge.com

SOURCE: Walters, M et al. 2018 BMT Tandem Meetings, Abstract 62.

Red blood cells

The European Commission (EC) has extended the approved indication of ferric maltol (Feraccru) to include treatment of all adults with iron deficiency, with or without anemia.

The drug was previously only approved in Europe for the treatment of iron deficiency anemia in adults with inflammatory bowel disease.

The EC’s extended approval governs the marketing of ferric maltol in all 28 European Union member countries, as well as Iceland, Norway, and Liechtenstein.

“We are extremely pleased [the EC] has so rapidly ratified the expansion of the indication for Feraccru,” said Carl Sterritt, chief executive officer of Shield Therapeutics, the company developing the product.

“This decision confirms a significantly broader patient population target opportunity for Feraccru in Europe, where 40 million* people are estimated to be iron deficient.”

Ferric maltol is a stable, non-salt, oral formulation of ferric iron, which has a different mechanism of action than salt-based oral iron therapies.

When salt-based oral iron therapies are ingested, the iron must dissociate from the salt in the gastrointestinal tract to allow the iron to be absorbed and treat the iron deficiency or anemia. This free iron readily chelates to form insoluble clumps as well as producing free radicals that, together, can cause a range of mild-to-severe gastrointestinal adverse events, including nausea, bloating, and constipation.

Conversely, iron can be absorbed from the ferric maltol molecule. As a result, the treatment is less likely to cause gastrointestinal issues. Ferric maltol has been shown in clinical trials (AEGIS 1 and 2) to be well-tolerated by patients who previously failed treatment with salt-based oral iron therapies.

Prior to the extended approval of ferric maltol, the only treatment option for patients with iron deficiency, with or without anemia, who could not tolerate salt-based oral iron therapies, was intravenous iron therapy.

Intravenous iron quickly increases iron stores via direct administration of very large doses of iron, causing an increase in hemoglobin levels that is physiologically controlled and occurs over a period of weeks, as is the case with ferric maltol. However, intravenous iron therapies can be complex to administer and may produce spontaneous hypersensitivity reactions.

*Levi, M et al. Epidemiology of iron deficiency anaemia in four European countries: a population-based study in primary care. 2016, Eur J Haematol, 97: 583–593. doi:10.1111/ejh.12776

Red blood cells

The European Commission (EC) has extended the approved indication of ferric maltol (Feraccru) to include treatment of all adults with iron deficiency, with or without anemia.

The drug was previously only approved in Europe for the treatment of iron deficiency anemia in adults with inflammatory bowel disease.

The EC’s extended approval governs the marketing of ferric maltol in all 28 European Union member countries, as well as Iceland, Norway, and Liechtenstein.

“We are extremely pleased [the EC] has so rapidly ratified the expansion of the indication for Feraccru,” said Carl Sterritt, chief executive officer of Shield Therapeutics, the company developing the product.

“This decision confirms a significantly broader patient population target opportunity for Feraccru in Europe, where 40 million* people are estimated to be iron deficient.”

Ferric maltol is a stable, non-salt, oral formulation of ferric iron, which has a different mechanism of action than salt-based oral iron therapies.

When salt-based oral iron therapies are ingested, the iron must dissociate from the salt in the gastrointestinal tract to allow the iron to be absorbed and treat the iron deficiency or anemia. This free iron readily chelates to form insoluble clumps as well as producing free radicals that, together, can cause a range of mild-to-severe gastrointestinal adverse events, including nausea, bloating, and constipation.

Conversely, iron can be absorbed from the ferric maltol molecule. As a result, the treatment is less likely to cause gastrointestinal issues. Ferric maltol has been shown in clinical trials (AEGIS 1 and 2) to be well-tolerated by patients who previously failed treatment with salt-based oral iron therapies.

Prior to the extended approval of ferric maltol, the only treatment option for patients with iron deficiency, with or without anemia, who could not tolerate salt-based oral iron therapies, was intravenous iron therapy.

Intravenous iron quickly increases iron stores via direct administration of very large doses of iron, causing an increase in hemoglobin levels that is physiologically controlled and occurs over a period of weeks, as is the case with ferric maltol. However, intravenous iron therapies can be complex to administer and may produce spontaneous hypersensitivity reactions.

*Levi, M et al. Epidemiology of iron deficiency anaemia in four European countries: a population-based study in primary care. 2016, Eur J Haematol, 97: 583–593. doi:10.1111/ejh.12776

Red blood cells

The European Commission (EC) has extended the approved indication of ferric maltol (Feraccru) to include treatment of all adults with iron deficiency, with or without anemia.

The drug was previously only approved in Europe for the treatment of iron deficiency anemia in adults with inflammatory bowel disease.

The EC’s extended approval governs the marketing of ferric maltol in all 28 European Union member countries, as well as Iceland, Norway, and Liechtenstein.

“We are extremely pleased [the EC] has so rapidly ratified the expansion of the indication for Feraccru,” said Carl Sterritt, chief executive officer of Shield Therapeutics, the company developing the product.

“This decision confirms a significantly broader patient population target opportunity for Feraccru in Europe, where 40 million* people are estimated to be iron deficient.”

Ferric maltol is a stable, non-salt, oral formulation of ferric iron, which has a different mechanism of action than salt-based oral iron therapies.

When salt-based oral iron therapies are ingested, the iron must dissociate from the salt in the gastrointestinal tract to allow the iron to be absorbed and treat the iron deficiency or anemia. This free iron readily chelates to form insoluble clumps as well as producing free radicals that, together, can cause a range of mild-to-severe gastrointestinal adverse events, including nausea, bloating, and constipation.

Conversely, iron can be absorbed from the ferric maltol molecule. As a result, the treatment is less likely to cause gastrointestinal issues. Ferric maltol has been shown in clinical trials (AEGIS 1 and 2) to be well-tolerated by patients who previously failed treatment with salt-based oral iron therapies.

Prior to the extended approval of ferric maltol, the only treatment option for patients with iron deficiency, with or without anemia, who could not tolerate salt-based oral iron therapies, was intravenous iron therapy.

Intravenous iron quickly increases iron stores via direct administration of very large doses of iron, causing an increase in hemoglobin levels that is physiologically controlled and occurs over a period of weeks, as is the case with ferric maltol. However, intravenous iron therapies can be complex to administer and may produce spontaneous hypersensitivity reactions.

*Levi, M et al. Epidemiology of iron deficiency anaemia in four European countries: a population-based study in primary care. 2016, Eur J Haematol, 97: 583–593. doi:10.1111/ejh.12776

Red blood cells

Amgen has withdrawn its application to expand the existing marketing authorization for darbepoetin alfa (Aranesp), according to the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP).

The goal with this application was to extend the authorization for darbepoetin alfa to include the treatment of anemia in adults with low-risk or intermediate-1-risk myelodysplastic syndromes (MDS) who have low transfusion demand.

Darbepoetin alfa is currently approved in the European Union (EU) to treat anemia in adults and children with chronic renal failure and adults who are receiving chemotherapy for non-myeloid malignancies.

Amgen withdrew the application for darbepoetin alfa in MDS patients after the CHMP had evaluated initial documentation provided by the company and formulated a list of questions. Amgen had not yet responded to the questions when it notified the CHMP of the withdrawal.

At the time of the withdrawal, the CHMP was of the provisional opinion that darbepoetin alfa could not have been approved for the treatment of anemia in adults with MDS.

This opinion was based on concerns about the data supporting the application—results from the phase 3 ARCADE trial (NCT01362140) and a phase 2 trial (NCT00095264).

The CHMP said changes to the design of the phase 3 trial and the exclusion of a high number of patients from the analysis of the results raise questions about the validity of the data.

In addition, the phase 2 trial, which was conducted in the US, was not in line with EU recommendations for the treatment of MDS patients.

Therefore, at the time of the withdrawal, the CHMP had decided the marketing authorization could not be expanded based on the data provided.

In a letter to the CHMP, Amgen said its decision to withdraw the application is based on the CHMP’s negative opinion.

Red blood cells

Amgen has withdrawn its application to expand the existing marketing authorization for darbepoetin alfa (Aranesp), according to the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP).

The goal with this application was to extend the authorization for darbepoetin alfa to include the treatment of anemia in adults with low-risk or intermediate-1-risk myelodysplastic syndromes (MDS) who have low transfusion demand.

Darbepoetin alfa is currently approved in the European Union (EU) to treat anemia in adults and children with chronic renal failure and adults who are receiving chemotherapy for non-myeloid malignancies.

Amgen withdrew the application for darbepoetin alfa in MDS patients after the CHMP had evaluated initial documentation provided by the company and formulated a list of questions. Amgen had not yet responded to the questions when it notified the CHMP of the withdrawal.

At the time of the withdrawal, the CHMP was of the provisional opinion that darbepoetin alfa could not have been approved for the treatment of anemia in adults with MDS.

This opinion was based on concerns about the data supporting the application—results from the phase 3 ARCADE trial (NCT01362140) and a phase 2 trial (NCT00095264).

The CHMP said changes to the design of the phase 3 trial and the exclusion of a high number of patients from the analysis of the results raise questions about the validity of the data.

In addition, the phase 2 trial, which was conducted in the US, was not in line with EU recommendations for the treatment of MDS patients.

Therefore, at the time of the withdrawal, the CHMP had decided the marketing authorization could not be expanded based on the data provided.

In a letter to the CHMP, Amgen said its decision to withdraw the application is based on the CHMP’s negative opinion.

Red blood cells

Amgen has withdrawn its application to expand the existing marketing authorization for darbepoetin alfa (Aranesp), according to the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP).

The goal with this application was to extend the authorization for darbepoetin alfa to include the treatment of anemia in adults with low-risk or intermediate-1-risk myelodysplastic syndromes (MDS) who have low transfusion demand.

Darbepoetin alfa is currently approved in the European Union (EU) to treat anemia in adults and children with chronic renal failure and adults who are receiving chemotherapy for non-myeloid malignancies.

Amgen withdrew the application for darbepoetin alfa in MDS patients after the CHMP had evaluated initial documentation provided by the company and formulated a list of questions. Amgen had not yet responded to the questions when it notified the CHMP of the withdrawal.

At the time of the withdrawal, the CHMP was of the provisional opinion that darbepoetin alfa could not have been approved for the treatment of anemia in adults with MDS.

This opinion was based on concerns about the data supporting the application—results from the phase 3 ARCADE trial (NCT01362140) and a phase 2 trial (NCT00095264).

The CHMP said changes to the design of the phase 3 trial and the exclusion of a high number of patients from the analysis of the results raise questions about the validity of the data.

In addition, the phase 2 trial, which was conducted in the US, was not in line with EU recommendations for the treatment of MDS patients.

Therefore, at the time of the withdrawal, the CHMP had decided the marketing authorization could not be expanded based on the data provided.

In a letter to the CHMP, Amgen said its decision to withdraw the application is based on the CHMP’s negative opinion.

stem cell graft

LISBON—Phase 1 results suggest a programmed cellular therapy is safe for use in patients with hematologic malignancies.

The therapy, ProTmune, is being developed as a next-generation allogeneic graft intended to reduce the incidence and severity of acute graft-versus-host disease (GVHD) after hematopoietic stem cell transplant (HSCT).

Three of 7 patients who received ProTmune in this trial did develop acute GVHD, and 2 patients died.

However, the remaining 5 patients were still alive and disease-free at last follow-up.

There were no serious adverse events (AEs) attributed to ProTmune. The most common AEs were nausea, vomiting, and chest pain.

These results were presented at the 44th Annual Meeting of the EBMT (abstract A401*).

The trial, known as PROTECT, is sponsored by Fate Therapeutics, the company developing ProTmune.

The phase 1 portion of PROTECT enrolled 7 adults with hematologic malignancies—1 with myelodysplastic syndrome, 3 with acute lymphoblastic leukemia, and 3 with acute myeloid leukemia.

Patients were set to undergo matched, unrelated donor HSCT and received ProTmune as the graft. ProTmune is manufactured by modulating a mobilized peripheral blood graft with 2 small molecules, FT1050 and FT4145.

The patients ranged in age from 34 to 69, and most (n=5) were female. For conditioning, patients received fludarabine/busulfan (n=1), busulfan/cyclophosphamide (n=1), fludarabine/melphalan (n=3), or cyclophosphamide/total body irradiation (n=2).

Results

The data cut-off was February 26, 2018. The median time on study was 228 days (range, 151 to 353).

None of the patients had graft failure. The median time to neutrophil engraftment was 18 days (range, 14 to 22).

Three patients had acute GVHD at day 100 after HSCT. Two patients had grade 2 skin GVHD, and 1 had grade 3 GVHD in the skin and gut.

All 3 patients responded to steroid treatment. GVHD resolved in 5 days for the patient with grade 3 GVHD. For the grade 2 patients, GVHD resolved in 7 days and 8 days, respectively.

None of the patients relapsed, but 2 died—1 of pulmonary edema and 1 of atrial fibrillation.

AEs related to ProTmune included grade 1 vomiting (n=2), grade 2 nausea (n=2), and grade 2 chest pain (n=1).

Phase 2

The phase 2 portion of PROTECT is ongoing. This is a randomized, controlled, double-blinded trial designed to assess the safety and efficacy of ProTmune in up to 60 adults with hematologic malignancies undergoing matched, unrelated donor HSCT following myeloablative conditioning.

Patients are being randomized, in a 1:1 ratio, to receive either ProTmune or a conventional, mobilized peripheral blood cell graft from a matched, unrelated donor.

The primary efficacy endpoint is the cumulative incidence of grade 2-4 acute GVHD by day 100 post-HSCT. Rates of chronic GVHD, cancer relapse, disease-free survival, and overall survival are also being assessed.

*Some data in the abstract differ from the presentation.

stem cell graft

LISBON—Phase 1 results suggest a programmed cellular therapy is safe for use in patients with hematologic malignancies.

The therapy, ProTmune, is being developed as a next-generation allogeneic graft intended to reduce the incidence and severity of acute graft-versus-host disease (GVHD) after hematopoietic stem cell transplant (HSCT).

Three of 7 patients who received ProTmune in this trial did develop acute GVHD, and 2 patients died.

However, the remaining 5 patients were still alive and disease-free at last follow-up.

There were no serious adverse events (AEs) attributed to ProTmune. The most common AEs were nausea, vomiting, and chest pain.

These results were presented at the 44th Annual Meeting of the EBMT (abstract A401*).

The trial, known as PROTECT, is sponsored by Fate Therapeutics, the company developing ProTmune.

The phase 1 portion of PROTECT enrolled 7 adults with hematologic malignancies—1 with myelodysplastic syndrome, 3 with acute lymphoblastic leukemia, and 3 with acute myeloid leukemia.

Patients were set to undergo matched, unrelated donor HSCT and received ProTmune as the graft. ProTmune is manufactured by modulating a mobilized peripheral blood graft with 2 small molecules, FT1050 and FT4145.

The patients ranged in age from 34 to 69, and most (n=5) were female. For conditioning, patients received fludarabine/busulfan (n=1), busulfan/cyclophosphamide (n=1), fludarabine/melphalan (n=3), or cyclophosphamide/total body irradiation (n=2).

Results

The data cut-off was February 26, 2018. The median time on study was 228 days (range, 151 to 353).

None of the patients had graft failure. The median time to neutrophil engraftment was 18 days (range, 14 to 22).

Three patients had acute GVHD at day 100 after HSCT. Two patients had grade 2 skin GVHD, and 1 had grade 3 GVHD in the skin and gut.

All 3 patients responded to steroid treatment. GVHD resolved in 5 days for the patient with grade 3 GVHD. For the grade 2 patients, GVHD resolved in 7 days and 8 days, respectively.

None of the patients relapsed, but 2 died—1 of pulmonary edema and 1 of atrial fibrillation.

AEs related to ProTmune included grade 1 vomiting (n=2), grade 2 nausea (n=2), and grade 2 chest pain (n=1).

Phase 2

The phase 2 portion of PROTECT is ongoing. This is a randomized, controlled, double-blinded trial designed to assess the safety and efficacy of ProTmune in up to 60 adults with hematologic malignancies undergoing matched, unrelated donor HSCT following myeloablative conditioning.

Patients are being randomized, in a 1:1 ratio, to receive either ProTmune or a conventional, mobilized peripheral blood cell graft from a matched, unrelated donor.

The primary efficacy endpoint is the cumulative incidence of grade 2-4 acute GVHD by day 100 post-HSCT. Rates of chronic GVHD, cancer relapse, disease-free survival, and overall survival are also being assessed.

*Some data in the abstract differ from the presentation.

stem cell graft

LISBON—Phase 1 results suggest a programmed cellular therapy is safe for use in patients with hematologic malignancies.

The therapy, ProTmune, is being developed as a next-generation allogeneic graft intended to reduce the incidence and severity of acute graft-versus-host disease (GVHD) after hematopoietic stem cell transplant (HSCT).

Three of 7 patients who received ProTmune in this trial did develop acute GVHD, and 2 patients died.

However, the remaining 5 patients were still alive and disease-free at last follow-up.

There were no serious adverse events (AEs) attributed to ProTmune. The most common AEs were nausea, vomiting, and chest pain.

These results were presented at the 44th Annual Meeting of the EBMT (abstract A401*).

The trial, known as PROTECT, is sponsored by Fate Therapeutics, the company developing ProTmune.

The phase 1 portion of PROTECT enrolled 7 adults with hematologic malignancies—1 with myelodysplastic syndrome, 3 with acute lymphoblastic leukemia, and 3 with acute myeloid leukemia.

Patients were set to undergo matched, unrelated donor HSCT and received ProTmune as the graft. ProTmune is manufactured by modulating a mobilized peripheral blood graft with 2 small molecules, FT1050 and FT4145.

The patients ranged in age from 34 to 69, and most (n=5) were female. For conditioning, patients received fludarabine/busulfan (n=1), busulfan/cyclophosphamide (n=1), fludarabine/melphalan (n=3), or cyclophosphamide/total body irradiation (n=2).

Results

The data cut-off was February 26, 2018. The median time on study was 228 days (range, 151 to 353).

None of the patients had graft failure. The median time to neutrophil engraftment was 18 days (range, 14 to 22).

Three patients had acute GVHD at day 100 after HSCT. Two patients had grade 2 skin GVHD, and 1 had grade 3 GVHD in the skin and gut.

All 3 patients responded to steroid treatment. GVHD resolved in 5 days for the patient with grade 3 GVHD. For the grade 2 patients, GVHD resolved in 7 days and 8 days, respectively.

None of the patients relapsed, but 2 died—1 of pulmonary edema and 1 of atrial fibrillation.

AEs related to ProTmune included grade 1 vomiting (n=2), grade 2 nausea (n=2), and grade 2 chest pain (n=1).

Phase 2

The phase 2 portion of PROTECT is ongoing. This is a randomized, controlled, double-blinded trial designed to assess the safety and efficacy of ProTmune in up to 60 adults with hematologic malignancies undergoing matched, unrelated donor HSCT following myeloablative conditioning.

Patients are being randomized, in a 1:1 ratio, to receive either ProTmune or a conventional, mobilized peripheral blood cell graft from a matched, unrelated donor.

The primary efficacy endpoint is the cumulative incidence of grade 2-4 acute GVHD by day 100 post-HSCT. Rates of chronic GVHD, cancer relapse, disease-free survival, and overall survival are also being assessed.

*Some data in the abstract differ from the presentation.

Photo by Nina Matthews

Pregnant women with severe anemia are twice as likely as those without it to die during or shortly after pregnancy, according to research published in The Lancet Global Health.

Previous studies suggested anemia was strongly associated with death, but this was due to other clinical reasons.

For the current study, researchers took into account factors that influence the development of anemia in pregnancy (such as blood loss or malaria infection) and still found a significant association between anemia and death.

“Anemia in pregnancy is one of the most common medical problems pregnant women encounter, both in low- and high-income countries,” said study author Jahnavi Daru, MBBS, from Queen Mary University of London in the UK.

“We’ve now shown that, if a woman develops severe anemia at any point in her pregnancy or in the 7 days after delivery, she is at a higher risk of dying, making urgent treatment even more important.”

To make this discovery, Dr Daru and her colleagues analyzed World Health Organization data on 312,281 pregnancies in 29 countries* across Latin America, Africa, the Western Pacific region, the Eastern Mediterranean, and South East Asia.

There were 4687 cases of severe anemia (a blood count of less than 70 g/L) and 341 deaths in this group. Deaths were included if they occurred any time after hospital admission until the seventh day post-partum or post-discharge.

The researchers matched 4189 of the women with severe anemia to 8218 women without severe anemia and found a significantly increased risk of death among the women with anemia, both in a crude analysis and an analysis adjusted for potential confounding variables.

In the crude analysis, the odds ratio (OR) for death was 43.35 for women with severe anemia (P<0.0001). In the adjusted analysis, the OR was 2.36 (P<0.0001).

The researchers also conducted a propensity score analysis, matching women with severe anemia to their non-anemic counterparts 1:2. In this analysis, the OR for death was 1.86 (P<0.0001) for the women with severe anemia.

“Anemia is a readily treatable condition, but the existing approaches so far have not been able to tackle the problem,” Dr Daru pointed out. “Clinicians, policy makers, and healthcare professionals should now focus their attention on preventing anemia using a multifaceted approach, not just hoping that iron tablets will solve the problem.”

* The countries included were Afghanistan, Angola, Argentina, Brazil, Cambodia, China, Democratic Republic of the Congo, Ecuador, India, Japan, Jordan, Kenya, Lebanon, Mexico, Mongolia, Nepal, Nicaragua, Niger, Nigeria, Pakistan, Palestine, Paraguay, Peru, Philippines, Qatar, Sri Lanka, Thailand, Uganda, and Vietnam.

Photo by Nina Matthews

Pregnant women with severe anemia are twice as likely as those without it to die during or shortly after pregnancy, according to research published in The Lancet Global Health.

Previous studies suggested anemia was strongly associated with death, but this was due to other clinical reasons.

For the current study, researchers took into account factors that influence the development of anemia in pregnancy (such as blood loss or malaria infection) and still found a significant association between anemia and death.

“Anemia in pregnancy is one of the most common medical problems pregnant women encounter, both in low- and high-income countries,” said study author Jahnavi Daru, MBBS, from Queen Mary University of London in the UK.

“We’ve now shown that, if a woman develops severe anemia at any point in her pregnancy or in the 7 days after delivery, she is at a higher risk of dying, making urgent treatment even more important.”

To make this discovery, Dr Daru and her colleagues analyzed World Health Organization data on 312,281 pregnancies in 29 countries* across Latin America, Africa, the Western Pacific region, the Eastern Mediterranean, and South East Asia.

There were 4687 cases of severe anemia (a blood count of less than 70 g/L) and 341 deaths in this group. Deaths were included if they occurred any time after hospital admission until the seventh day post-partum or post-discharge.

The researchers matched 4189 of the women with severe anemia to 8218 women without severe anemia and found a significantly increased risk of death among the women with anemia, both in a crude analysis and an analysis adjusted for potential confounding variables.

In the crude analysis, the odds ratio (OR) for death was 43.35 for women with severe anemia (P<0.0001). In the adjusted analysis, the OR was 2.36 (P<0.0001).

The researchers also conducted a propensity score analysis, matching women with severe anemia to their non-anemic counterparts 1:2. In this analysis, the OR for death was 1.86 (P<0.0001) for the women with severe anemia.

“Anemia is a readily treatable condition, but the existing approaches so far have not been able to tackle the problem,” Dr Daru pointed out. “Clinicians, policy makers, and healthcare professionals should now focus their attention on preventing anemia using a multifaceted approach, not just hoping that iron tablets will solve the problem.”

* The countries included were Afghanistan, Angola, Argentina, Brazil, Cambodia, China, Democratic Republic of the Congo, Ecuador, India, Japan, Jordan, Kenya, Lebanon, Mexico, Mongolia, Nepal, Nicaragua, Niger, Nigeria, Pakistan, Palestine, Paraguay, Peru, Philippines, Qatar, Sri Lanka, Thailand, Uganda, and Vietnam.

Photo by Nina Matthews

Pregnant women with severe anemia are twice as likely as those without it to die during or shortly after pregnancy, according to research published in The Lancet Global Health.

Previous studies suggested anemia was strongly associated with death, but this was due to other clinical reasons.

For the current study, researchers took into account factors that influence the development of anemia in pregnancy (such as blood loss or malaria infection) and still found a significant association between anemia and death.

“Anemia in pregnancy is one of the most common medical problems pregnant women encounter, both in low- and high-income countries,” said study author Jahnavi Daru, MBBS, from Queen Mary University of London in the UK.

“We’ve now shown that, if a woman develops severe anemia at any point in her pregnancy or in the 7 days after delivery, she is at a higher risk of dying, making urgent treatment even more important.”

To make this discovery, Dr Daru and her colleagues analyzed World Health Organization data on 312,281 pregnancies in 29 countries* across Latin America, Africa, the Western Pacific region, the Eastern Mediterranean, and South East Asia.

There were 4687 cases of severe anemia (a blood count of less than 70 g/L) and 341 deaths in this group. Deaths were included if they occurred any time after hospital admission until the seventh day post-partum or post-discharge.

The researchers matched 4189 of the women with severe anemia to 8218 women without severe anemia and found a significantly increased risk of death among the women with anemia, both in a crude analysis and an analysis adjusted for potential confounding variables.

In the crude analysis, the odds ratio (OR) for death was 43.35 for women with severe anemia (P<0.0001). In the adjusted analysis, the OR was 2.36 (P<0.0001).

The researchers also conducted a propensity score analysis, matching women with severe anemia to their non-anemic counterparts 1:2. In this analysis, the OR for death was 1.86 (P<0.0001) for the women with severe anemia.

“Anemia is a readily treatable condition, but the existing approaches so far have not been able to tackle the problem,” Dr Daru pointed out. “Clinicians, policy makers, and healthcare professionals should now focus their attention on preventing anemia using a multifaceted approach, not just hoping that iron tablets will solve the problem.”

* The countries included were Afghanistan, Angola, Argentina, Brazil, Cambodia, China, Democratic Republic of the Congo, Ecuador, India, Japan, Jordan, Kenya, Lebanon, Mexico, Mongolia, Nepal, Nicaragua, Niger, Nigeria, Pakistan, Palestine, Paraguay, Peru, Philippines, Qatar, Sri Lanka, Thailand, Uganda, and Vietnam.