Anemia

Photo from Business Wire

Researchers say they have identified genetic mutations that can significantly affect treatment outcomes in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).

The findings come from a clinical trial in which the team examined whether combining vorinostat with azacitidine could improve survival in patients with AML and MDS.

The results showed no additional benefit with the combination, when compared to azacitidine alone.

However, researchers did find that patients had significantly shorter survival times if they had mutations in CDKN2A, IDH1, or TP53.

“This important trial . . . has rapidly answered the important question of whether combining azacitidine with vorinostat improves outcomes for people with AML and MDS and emphasizes the need for further studies with new drug partners for azacitidine,” said Charles Craddock, DPhil, of the Queen Elizabeth Hospital in Birmingham, UK.

“Importantly, the linked molecular studies have shed new light on which people will benefit most from azacitidine. Furthermore, discovering that the CDKN2A gene mutation affects treatment response may be hugely valuable in helping doctors to design new treatment combinations in the future.”

Dr Craddock and his colleagues reported their discoveries in Clinical Cancer Research.

Previous, smaller trials had suggested that adding vorinostat to treatment with azacitidine could improve outcomes for patients with AML and MDS.

To test this idea, Dr Craddock and his colleagues enrolled 259 patients in the current trial. Most of these patients (n=217) had AML—111 were newly diagnosed, 73 had relapsed AML, and 33 had refractory disease.

The remaining 42 patients had MDS—36 were newly diagnosed, 5 had relapsed MDS, and 1 had refractory disease.

Half of patients (n=130) received azacitidine and vorinostat, and the other half received azacitidine alone (n=129).

In both arms, azacitidine was given at 75 mg/m² on a 5-2-2 schedule, beginning on day 1 of a 28-day cycle for up to 6 cycles. In the combination arm, patients also received vorinostat at 300 mg twice daily for 7 consecutive days, beginning on day 3 of each cycle.

Results

The combination did not significantly improve response rates or survival times.

The overall response rate was 41% in the azacitidine arm and 42% in the combination arm (odds ratio [OR]=1.05, P=0.84).

The rate of compete response (CR)/CR with incomplete count recovery/marrow CR was 22% in the azacitidine arm and 26% in the combination arm (OR=0.82, P=0.49).

The median overall survival (OS) was 9.6 months in the azacitidine arm and 11.0 months in the combination arm (hazard ratio[HR]=1.15, P=0.32).

Impact of mutations

In a multivariable analysis adjusted for all clinical variables, mutations in NPM1 were associated with reduced overall response (OR=8.6, P=0.012).

In another multivariate analysis, mutations in CDKN2A, IDH1, and TP53 were associated with decreased OS. The HRs were 10.0 (P<0.001), 3.6 (P=0.001), and 4.7 (P<0.001), respectively.

The median OS was 4.5 months in patients with CDKN2A mutations and 11.0 months in patients without them.

The median OS was 7.6 months in patients with TP53 mutations and 11.3 months in patients without them.

And the median OS was 5.6 months in patients with IDH1 mutations and 11.1 months in patients without them.

The researchers believe that testing patients newly diagnosed with AML and MDS for CDKN2A, IDH1, and TP53 mutations could help doctors tailor treatment for patients who are less likely to do well.

The team also said the information gleaned from this trial will guide the choice of new drug partners with the potential to increase azacitidine’s clinical activity.

Photo from Business Wire

Researchers say they have identified genetic mutations that can significantly affect treatment outcomes in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).

The findings come from a clinical trial in which the team examined whether combining vorinostat with azacitidine could improve survival in patients with AML and MDS.

The results showed no additional benefit with the combination, when compared to azacitidine alone.

However, researchers did find that patients had significantly shorter survival times if they had mutations in CDKN2A, IDH1, or TP53.

“This important trial . . . has rapidly answered the important question of whether combining azacitidine with vorinostat improves outcomes for people with AML and MDS and emphasizes the need for further studies with new drug partners for azacitidine,” said Charles Craddock, DPhil, of the Queen Elizabeth Hospital in Birmingham, UK.

“Importantly, the linked molecular studies have shed new light on which people will benefit most from azacitidine. Furthermore, discovering that the CDKN2A gene mutation affects treatment response may be hugely valuable in helping doctors to design new treatment combinations in the future.”

Dr Craddock and his colleagues reported their discoveries in Clinical Cancer Research.

Previous, smaller trials had suggested that adding vorinostat to treatment with azacitidine could improve outcomes for patients with AML and MDS.

To test this idea, Dr Craddock and his colleagues enrolled 259 patients in the current trial. Most of these patients (n=217) had AML—111 were newly diagnosed, 73 had relapsed AML, and 33 had refractory disease.

The remaining 42 patients had MDS—36 were newly diagnosed, 5 had relapsed MDS, and 1 had refractory disease.

Half of patients (n=130) received azacitidine and vorinostat, and the other half received azacitidine alone (n=129).

In both arms, azacitidine was given at 75 mg/m² on a 5-2-2 schedule, beginning on day 1 of a 28-day cycle for up to 6 cycles. In the combination arm, patients also received vorinostat at 300 mg twice daily for 7 consecutive days, beginning on day 3 of each cycle.

Results

The combination did not significantly improve response rates or survival times.

The overall response rate was 41% in the azacitidine arm and 42% in the combination arm (odds ratio [OR]=1.05, P=0.84).

The rate of compete response (CR)/CR with incomplete count recovery/marrow CR was 22% in the azacitidine arm and 26% in the combination arm (OR=0.82, P=0.49).

The median overall survival (OS) was 9.6 months in the azacitidine arm and 11.0 months in the combination arm (hazard ratio[HR]=1.15, P=0.32).

Impact of mutations

In a multivariable analysis adjusted for all clinical variables, mutations in NPM1 were associated with reduced overall response (OR=8.6, P=0.012).

In another multivariate analysis, mutations in CDKN2A, IDH1, and TP53 were associated with decreased OS. The HRs were 10.0 (P<0.001), 3.6 (P=0.001), and 4.7 (P<0.001), respectively.

The median OS was 4.5 months in patients with CDKN2A mutations and 11.0 months in patients without them.

The median OS was 7.6 months in patients with TP53 mutations and 11.3 months in patients without them.

And the median OS was 5.6 months in patients with IDH1 mutations and 11.1 months in patients without them.

The researchers believe that testing patients newly diagnosed with AML and MDS for CDKN2A, IDH1, and TP53 mutations could help doctors tailor treatment for patients who are less likely to do well.

The team also said the information gleaned from this trial will guide the choice of new drug partners with the potential to increase azacitidine’s clinical activity.

Photo from Business Wire

Researchers say they have identified genetic mutations that can significantly affect treatment outcomes in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).

The findings come from a clinical trial in which the team examined whether combining vorinostat with azacitidine could improve survival in patients with AML and MDS.

The results showed no additional benefit with the combination, when compared to azacitidine alone.

However, researchers did find that patients had significantly shorter survival times if they had mutations in CDKN2A, IDH1, or TP53.

“This important trial . . . has rapidly answered the important question of whether combining azacitidine with vorinostat improves outcomes for people with AML and MDS and emphasizes the need for further studies with new drug partners for azacitidine,” said Charles Craddock, DPhil, of the Queen Elizabeth Hospital in Birmingham, UK.

“Importantly, the linked molecular studies have shed new light on which people will benefit most from azacitidine. Furthermore, discovering that the CDKN2A gene mutation affects treatment response may be hugely valuable in helping doctors to design new treatment combinations in the future.”

Dr Craddock and his colleagues reported their discoveries in Clinical Cancer Research.

Previous, smaller trials had suggested that adding vorinostat to treatment with azacitidine could improve outcomes for patients with AML and MDS.

To test this idea, Dr Craddock and his colleagues enrolled 259 patients in the current trial. Most of these patients (n=217) had AML—111 were newly diagnosed, 73 had relapsed AML, and 33 had refractory disease.

The remaining 42 patients had MDS—36 were newly diagnosed, 5 had relapsed MDS, and 1 had refractory disease.

Half of patients (n=130) received azacitidine and vorinostat, and the other half received azacitidine alone (n=129).

In both arms, azacitidine was given at 75 mg/m² on a 5-2-2 schedule, beginning on day 1 of a 28-day cycle for up to 6 cycles. In the combination arm, patients also received vorinostat at 300 mg twice daily for 7 consecutive days, beginning on day 3 of each cycle.

Results

The combination did not significantly improve response rates or survival times.

The overall response rate was 41% in the azacitidine arm and 42% in the combination arm (odds ratio [OR]=1.05, P=0.84).

The rate of compete response (CR)/CR with incomplete count recovery/marrow CR was 22% in the azacitidine arm and 26% in the combination arm (OR=0.82, P=0.49).

The median overall survival (OS) was 9.6 months in the azacitidine arm and 11.0 months in the combination arm (hazard ratio[HR]=1.15, P=0.32).

Impact of mutations

In a multivariable analysis adjusted for all clinical variables, mutations in NPM1 were associated with reduced overall response (OR=8.6, P=0.012).

In another multivariate analysis, mutations in CDKN2A, IDH1, and TP53 were associated with decreased OS. The HRs were 10.0 (P<0.001), 3.6 (P=0.001), and 4.7 (P<0.001), respectively.

The median OS was 4.5 months in patients with CDKN2A mutations and 11.0 months in patients without them.

The median OS was 7.6 months in patients with TP53 mutations and 11.3 months in patients without them.

And the median OS was 5.6 months in patients with IDH1 mutations and 11.1 months in patients without them.

The researchers believe that testing patients newly diagnosed with AML and MDS for CDKN2A, IDH1, and TP53 mutations could help doctors tailor treatment for patients who are less likely to do well.

The team also said the information gleaned from this trial will guide the choice of new drug partners with the potential to increase azacitidine’s clinical activity.

Image by Betty Pace

The US Food and Drug Administration (FDA) has granted rare pediatric disease designation to Altemia™ soft gelatin capsules for the treatment of children with sickle cell disease (SCD).

Altemia (formerly SC411) is being developed by Sancilio Pharmaceuticals Company, Inc. (SPCI) to treat SCD patients between the ages of 5 and 17 years.

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®.

According to SPCI, Advanced Lipid Technologies are proprietary formulation and manufacturing techniques used to create lipophilic drug products capable of increased bioavailability, avoidance of the first pass effect, and elimination of the food effects commonly associated with oral administration.

Altemia is designed to replenish the lipids destroyed by sickle hemoglobin. The product is intended to be taken once daily to reduce vaso-occlusive crises, anemia, organ damage, and other complications of SCD.

Altemia also has orphan drug designation from the FDA.

SPCI is currently conducting a phase 2 trial of Altemia. In this randomized, double-blind, placebo-controlled trial, researchers are evaluating the efficacy and safety of Altemia in pediatric patients with SCD.

The company plans to report top-line results from the study, known as the SCOT trial, early in the fourth quarter of this year.

About rare pediatric disease designation

Rare pediatric disease designation is granted to drugs that show promise to treat diseases affecting fewer than 200,000 patients in the US, primarily patients age 18 or younger.

The designation provides incentives to advance the development of drugs for rare disease, including access to the FDA’s expedited review and approval programs.

Under the FDA’s Rare Pediatric Disease Priority Review Voucher Program, if a drug with rare pediatric disease designation is approved, the drug’s developer may qualify for a voucher that can be redeemed to obtain priority review for any subsequent marketing application.

Image by Betty Pace

The US Food and Drug Administration (FDA) has granted rare pediatric disease designation to Altemia™ soft gelatin capsules for the treatment of children with sickle cell disease (SCD).

Altemia (formerly SC411) is being developed by Sancilio Pharmaceuticals Company, Inc. (SPCI) to treat SCD patients between the ages of 5 and 17 years.

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®.

According to SPCI, Advanced Lipid Technologies are proprietary formulation and manufacturing techniques used to create lipophilic drug products capable of increased bioavailability, avoidance of the first pass effect, and elimination of the food effects commonly associated with oral administration.

Altemia is designed to replenish the lipids destroyed by sickle hemoglobin. The product is intended to be taken once daily to reduce vaso-occlusive crises, anemia, organ damage, and other complications of SCD.

Altemia also has orphan drug designation from the FDA.

SPCI is currently conducting a phase 2 trial of Altemia. In this randomized, double-blind, placebo-controlled trial, researchers are evaluating the efficacy and safety of Altemia in pediatric patients with SCD.

The company plans to report top-line results from the study, known as the SCOT trial, early in the fourth quarter of this year.

About rare pediatric disease designation

Rare pediatric disease designation is granted to drugs that show promise to treat diseases affecting fewer than 200,000 patients in the US, primarily patients age 18 or younger.

The designation provides incentives to advance the development of drugs for rare disease, including access to the FDA’s expedited review and approval programs.

Under the FDA’s Rare Pediatric Disease Priority Review Voucher Program, if a drug with rare pediatric disease designation is approved, the drug’s developer may qualify for a voucher that can be redeemed to obtain priority review for any subsequent marketing application.

Image by Betty Pace

The US Food and Drug Administration (FDA) has granted rare pediatric disease designation to Altemia™ soft gelatin capsules for the treatment of children with sickle cell disease (SCD).

Altemia (formerly SC411) is being developed by Sancilio Pharmaceuticals Company, Inc. (SPCI) to treat SCD patients between the ages of 5 and 17 years.

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®.

According to SPCI, Advanced Lipid Technologies are proprietary formulation and manufacturing techniques used to create lipophilic drug products capable of increased bioavailability, avoidance of the first pass effect, and elimination of the food effects commonly associated with oral administration.

Altemia is designed to replenish the lipids destroyed by sickle hemoglobin. The product is intended to be taken once daily to reduce vaso-occlusive crises, anemia, organ damage, and other complications of SCD.

Altemia also has orphan drug designation from the FDA.

SPCI is currently conducting a phase 2 trial of Altemia. In this randomized, double-blind, placebo-controlled trial, researchers are evaluating the efficacy and safety of Altemia in pediatric patients with SCD.

The company plans to report top-line results from the study, known as the SCOT trial, early in the fourth quarter of this year.

About rare pediatric disease designation

Rare pediatric disease designation is granted to drugs that show promise to treat diseases affecting fewer than 200,000 patients in the US, primarily patients age 18 or younger.

The designation provides incentives to advance the development of drugs for rare disease, including access to the FDA’s expedited review and approval programs.

Under the FDA’s Rare Pediatric Disease Priority Review Voucher Program, if a drug with rare pediatric disease designation is approved, the drug’s developer may qualify for a voucher that can be redeemed to obtain priority review for any subsequent marketing application.

Image from NIAID

The US Food and Drug Administration (FDA) has granted Regenerative Medicine Advanced Therapy (RMAT) designation to ATIR101™, which is intended to be used as an adjunct to haploidentical hematopoietic stem cell transplant (HSCT).

ATIR101 is a personalized T-cell immunotherapy—a donor lymphocyte preparation selectively depleted of host-alloreactive T cells through the use of photo-dynamic therapy.

Recipient-reactive T cells from the donor are activated in a unidirectional mixed-lymphocyte reaction. The cells are then treated with TH9402 (a rhodamide-like dye), which is selectively retained in activated T cells.

Subsequent light exposure eliminates the activated recipient-reactive T cells but preserves the other T cells.

The final product is infused after CD34-selected haploidentical HSCT with the goal of preventing infectious complications, graft-versus-host disease (GVHD), and relapse.

About RMAT designation

The RMAT pathway is analogous to the breakthrough therapy designation designed for traditional drug candidates and medical devices. RMAT designation was specifically created by the US Congress in 2016 in the hopes of getting new cell therapies and advanced medicinal products to patients earlier.

Just like breakthrough designation, RMAT designation allows companies developing regenerative medicine therapies to interact with the FDA more frequently in the clinical testing process. In addition, RMAT-designated products may be eligible for priority review and accelerated approval.

A regenerative medicine is eligible for RMAT designation if it is intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition, and if preliminary clinical evidence indicates the treatment has the potential to address unmet medical needs for such a disease or condition.

“To receive the RMAT designation from the FDA is an important milestone for Kiadis Pharma and a recognition by the FDA of the significant potential for ATIR101 to help patients receive safer and more effective bone marrow transplantations,” said Arthur Lahr, CEO of Kiadis Pharma, the company developing ATIR101.

“We are now going to work even closer with the FDA to agree a path to make this cell therapy treatment available for patients in the US as soon as possible. In Europe, ATIR101 was filed for registration in April 2017, and we continue to prepare the company for the potential European launch in 2019.”

ATIR101 trials

Results of a phase 2 trial of ATIR101 were presented at the 42nd Annual Meeting of the European Society of Blood and Marrow Transplantation in 2016.

Patients who received ATIR101 after haploidentical HSCT had significant improvements in transplant-related mortality and overall survival when compared to historical controls who received a T-cell-depleted haploidentical HSCT without ATIR101.

None of the patients who received ATIR101 developed grade 3-4 GVHD, but a few patients did develop grade 2 GVHD.

A phase 3 trial of ATIR101 is now underway. The trial is expected to enroll 200 patients with acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome.

The patients will receive a haploidentical HSCT with either a T-cell-depleted graft and adjunctive treatment with ATIR101 or a T-cell-replete graft and post-transplant cyclophosphamide.

Image from NIAID

The US Food and Drug Administration (FDA) has granted Regenerative Medicine Advanced Therapy (RMAT) designation to ATIR101™, which is intended to be used as an adjunct to haploidentical hematopoietic stem cell transplant (HSCT).

ATIR101 is a personalized T-cell immunotherapy—a donor lymphocyte preparation selectively depleted of host-alloreactive T cells through the use of photo-dynamic therapy.

Recipient-reactive T cells from the donor are activated in a unidirectional mixed-lymphocyte reaction. The cells are then treated with TH9402 (a rhodamide-like dye), which is selectively retained in activated T cells.

Subsequent light exposure eliminates the activated recipient-reactive T cells but preserves the other T cells.

The final product is infused after CD34-selected haploidentical HSCT with the goal of preventing infectious complications, graft-versus-host disease (GVHD), and relapse.

About RMAT designation

The RMAT pathway is analogous to the breakthrough therapy designation designed for traditional drug candidates and medical devices. RMAT designation was specifically created by the US Congress in 2016 in the hopes of getting new cell therapies and advanced medicinal products to patients earlier.

Just like breakthrough designation, RMAT designation allows companies developing regenerative medicine therapies to interact with the FDA more frequently in the clinical testing process. In addition, RMAT-designated products may be eligible for priority review and accelerated approval.

A regenerative medicine is eligible for RMAT designation if it is intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition, and if preliminary clinical evidence indicates the treatment has the potential to address unmet medical needs for such a disease or condition.

“To receive the RMAT designation from the FDA is an important milestone for Kiadis Pharma and a recognition by the FDA of the significant potential for ATIR101 to help patients receive safer and more effective bone marrow transplantations,” said Arthur Lahr, CEO of Kiadis Pharma, the company developing ATIR101.

“We are now going to work even closer with the FDA to agree a path to make this cell therapy treatment available for patients in the US as soon as possible. In Europe, ATIR101 was filed for registration in April 2017, and we continue to prepare the company for the potential European launch in 2019.”

ATIR101 trials

Results of a phase 2 trial of ATIR101 were presented at the 42nd Annual Meeting of the European Society of Blood and Marrow Transplantation in 2016.

Patients who received ATIR101 after haploidentical HSCT had significant improvements in transplant-related mortality and overall survival when compared to historical controls who received a T-cell-depleted haploidentical HSCT without ATIR101.

None of the patients who received ATIR101 developed grade 3-4 GVHD, but a few patients did develop grade 2 GVHD.

A phase 3 trial of ATIR101 is now underway. The trial is expected to enroll 200 patients with acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome.

The patients will receive a haploidentical HSCT with either a T-cell-depleted graft and adjunctive treatment with ATIR101 or a T-cell-replete graft and post-transplant cyclophosphamide.

Image from NIAID

The US Food and Drug Administration (FDA) has granted Regenerative Medicine Advanced Therapy (RMAT) designation to ATIR101™, which is intended to be used as an adjunct to haploidentical hematopoietic stem cell transplant (HSCT).

ATIR101 is a personalized T-cell immunotherapy—a donor lymphocyte preparation selectively depleted of host-alloreactive T cells through the use of photo-dynamic therapy.

Recipient-reactive T cells from the donor are activated in a unidirectional mixed-lymphocyte reaction. The cells are then treated with TH9402 (a rhodamide-like dye), which is selectively retained in activated T cells.

Subsequent light exposure eliminates the activated recipient-reactive T cells but preserves the other T cells.

The final product is infused after CD34-selected haploidentical HSCT with the goal of preventing infectious complications, graft-versus-host disease (GVHD), and relapse.

About RMAT designation

The RMAT pathway is analogous to the breakthrough therapy designation designed for traditional drug candidates and medical devices. RMAT designation was specifically created by the US Congress in 2016 in the hopes of getting new cell therapies and advanced medicinal products to patients earlier.

Just like breakthrough designation, RMAT designation allows companies developing regenerative medicine therapies to interact with the FDA more frequently in the clinical testing process. In addition, RMAT-designated products may be eligible for priority review and accelerated approval.

A regenerative medicine is eligible for RMAT designation if it is intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition, and if preliminary clinical evidence indicates the treatment has the potential to address unmet medical needs for such a disease or condition.

“To receive the RMAT designation from the FDA is an important milestone for Kiadis Pharma and a recognition by the FDA of the significant potential for ATIR101 to help patients receive safer and more effective bone marrow transplantations,” said Arthur Lahr, CEO of Kiadis Pharma, the company developing ATIR101.

“We are now going to work even closer with the FDA to agree a path to make this cell therapy treatment available for patients in the US as soon as possible. In Europe, ATIR101 was filed for registration in April 2017, and we continue to prepare the company for the potential European launch in 2019.”

ATIR101 trials

Results of a phase 2 trial of ATIR101 were presented at the 42nd Annual Meeting of the European Society of Blood and Marrow Transplantation in 2016.

Patients who received ATIR101 after haploidentical HSCT had significant improvements in transplant-related mortality and overall survival when compared to historical controls who received a T-cell-depleted haploidentical HSCT without ATIR101.

None of the patients who received ATIR101 developed grade 3-4 GVHD, but a few patients did develop grade 2 GVHD.

A phase 3 trial of ATIR101 is now underway. The trial is expected to enroll 200 patients with acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome.

The patients will receive a haploidentical HSCT with either a T-cell-depleted graft and adjunctive treatment with ATIR101 or a T-cell-replete graft and post-transplant cyclophosphamide.

Micrograph showing MDS

MADRID—Interim results of a phase 1 study suggest flotetuzumab, a CD123 and CD3 bispecific antibody, may be a feasible treatment option for relapsed or refractory acute myeloid leukemia (AML) or intermediate/high-risk myelodysplastic syndromes (MDS).

Researchers said flotetuzumab demonstrated acceptable tolerability in the dose-escalation portion of the study, with infusion-related reactions (IRRs) and cytokine release syndrome (CRS) being the most common adverse events (AEs).

In addition, flotetuzumab exhibited anti-leukemic activity in 8 of 14 response-evaluable patients, with 6 patients achieving a response.

Norbert Vey, MD, of Institut Paoli-Calmettes in Marseille, France, presented these results at the ESMO 2017 Congress (abstract 995O*). The study is sponsored by MacroGenics, Inc., the company developing flotetuzumab.

Flotetuzumab (MGD006) recognizes CD123 and CD3. The primary mechanism of flotetuzumab is thought to be its ability to redirect T cells to kill CD123-expressing cells. To achieve this, the molecule combines a portion of an antibody recognizing CD3 (an activating molecule expressed by T cells) with an arm that recognizes CD123 on the target cancer cells.

In this ongoing phase 1 study of flotetuzumab, researchers have enrolled 47 patients with a median age of 64 (range, 29-84). About 89% of these patients had AML (n=42), and the rest (n=5) had MDS.

Twenty-four percent had relapsed AML (n=10), 55% had refractory AML (n=23), and 21% had failed treatment with hypomethylating agents (n=9). One patient had intermediate-1-risk MDS, 2 had intermediate-2-risk, and 2 had high-risk MDS.

Treatment

The study began with single patients receiving flotetuzumab at escalating doses—3 ng/kg/day, 10 ng/kg/day, 30 ng/kg/day, and 100 ng/kg/day.

Then, patients received a range of doses on 2 different schedules for cycle 1. One group received treatment 7 days a week. The other had a 4-days-on/3-days-off schedule.

All patients received a lead-in dose during the first week of cycle 1. They received 30 ng/kg/day for 3 days, then 100 ng/kg/day for 4 days.

For the rest of cycle 1, patients in the 4 days/3 days group received doses of 500 ng/kg, 700 ng/kg, 900 ng/kg, or 1000 ng/kg. Patients in the daily dosing group received doses of 300 ng/kg, 500 ng/kg, 700 ng/kg, 900 ng/kg, or 1000 ng/kg.

For cycle 2 and beyond, all patients were on the 4-days-on/3-days-off schedule.

Safety

The maximum tolerated dose and schedule was 500 ng/kg/day for 7 days.

Dose-limiting toxicities occurring at the 700 ng/kg/day dose included grade 2 IRRs/CRS in 2 patients and grade 3 myalgia in 1 patient. There was 1 drug-related central nervous system AE that led to treatment discontinuation.

IRRs/CRS occurred in 77% of patients, with 13% of patients having grade 3 events and 8.5% of patients discontinuing treatment due to IRRs/CRS.

The researchers said they found ways to decrease the incidence and severity of CRS. One is early intervention with tocilizumab. The other is a 2-step lead-in dose during week 1. So patients first receive 30 ng/kg, then 100 ng/kg, and then their target dose.

Other grade 3 AEs occurring in this trial include febrile neutropenia (11%), anemia (11%), and decreases in platelets (13%), white blood cells (11%), and lymphocytes (13%).

Efficacy

The researchers said they observed encouraging anti-leukemic activity in patients treated at 500 ng/kg/day or greater.

As of the data cut-off, 14 patients treated at this dose were evaluable for response. Eight (57%) patients had anti-leukemic activity, with 6 (43%) of these patients experiencing an objective response.

One patient achieved a complete response (CR), 2 had a CR with incomplete count recovery, and 1 had a molecular CR.

In most responders, anti-leukemic activity was observed after a single cycle of therapy.

MacroGenics is currently enrolling patients in dose-expansion cohorts. The company plans to present updated results from this trial at another scientific conference later this year.

*Slides from this presentation are available on the MacroGenics website at http://ir.macrogenics.com/events.cfm.

Micrograph showing MDS

MADRID—Interim results of a phase 1 study suggest flotetuzumab, a CD123 and CD3 bispecific antibody, may be a feasible treatment option for relapsed or refractory acute myeloid leukemia (AML) or intermediate/high-risk myelodysplastic syndromes (MDS).

Researchers said flotetuzumab demonstrated acceptable tolerability in the dose-escalation portion of the study, with infusion-related reactions (IRRs) and cytokine release syndrome (CRS) being the most common adverse events (AEs).

In addition, flotetuzumab exhibited anti-leukemic activity in 8 of 14 response-evaluable patients, with 6 patients achieving a response.

Norbert Vey, MD, of Institut Paoli-Calmettes in Marseille, France, presented these results at the ESMO 2017 Congress (abstract 995O*). The study is sponsored by MacroGenics, Inc., the company developing flotetuzumab.

Flotetuzumab (MGD006) recognizes CD123 and CD3. The primary mechanism of flotetuzumab is thought to be its ability to redirect T cells to kill CD123-expressing cells. To achieve this, the molecule combines a portion of an antibody recognizing CD3 (an activating molecule expressed by T cells) with an arm that recognizes CD123 on the target cancer cells.

In this ongoing phase 1 study of flotetuzumab, researchers have enrolled 47 patients with a median age of 64 (range, 29-84). About 89% of these patients had AML (n=42), and the rest (n=5) had MDS.

Twenty-four percent had relapsed AML (n=10), 55% had refractory AML (n=23), and 21% had failed treatment with hypomethylating agents (n=9). One patient had intermediate-1-risk MDS, 2 had intermediate-2-risk, and 2 had high-risk MDS.

Treatment

The study began with single patients receiving flotetuzumab at escalating doses—3 ng/kg/day, 10 ng/kg/day, 30 ng/kg/day, and 100 ng/kg/day.

Then, patients received a range of doses on 2 different schedules for cycle 1. One group received treatment 7 days a week. The other had a 4-days-on/3-days-off schedule.

All patients received a lead-in dose during the first week of cycle 1. They received 30 ng/kg/day for 3 days, then 100 ng/kg/day for 4 days.

For the rest of cycle 1, patients in the 4 days/3 days group received doses of 500 ng/kg, 700 ng/kg, 900 ng/kg, or 1000 ng/kg. Patients in the daily dosing group received doses of 300 ng/kg, 500 ng/kg, 700 ng/kg, 900 ng/kg, or 1000 ng/kg.

For cycle 2 and beyond, all patients were on the 4-days-on/3-days-off schedule.

Safety

The maximum tolerated dose and schedule was 500 ng/kg/day for 7 days.

Dose-limiting toxicities occurring at the 700 ng/kg/day dose included grade 2 IRRs/CRS in 2 patients and grade 3 myalgia in 1 patient. There was 1 drug-related central nervous system AE that led to treatment discontinuation.

IRRs/CRS occurred in 77% of patients, with 13% of patients having grade 3 events and 8.5% of patients discontinuing treatment due to IRRs/CRS.

The researchers said they found ways to decrease the incidence and severity of CRS. One is early intervention with tocilizumab. The other is a 2-step lead-in dose during week 1. So patients first receive 30 ng/kg, then 100 ng/kg, and then their target dose.

Other grade 3 AEs occurring in this trial include febrile neutropenia (11%), anemia (11%), and decreases in platelets (13%), white blood cells (11%), and lymphocytes (13%).

Efficacy

The researchers said they observed encouraging anti-leukemic activity in patients treated at 500 ng/kg/day or greater.

As of the data cut-off, 14 patients treated at this dose were evaluable for response. Eight (57%) patients had anti-leukemic activity, with 6 (43%) of these patients experiencing an objective response.

One patient achieved a complete response (CR), 2 had a CR with incomplete count recovery, and 1 had a molecular CR.

In most responders, anti-leukemic activity was observed after a single cycle of therapy.

MacroGenics is currently enrolling patients in dose-expansion cohorts. The company plans to present updated results from this trial at another scientific conference later this year.

*Slides from this presentation are available on the MacroGenics website at http://ir.macrogenics.com/events.cfm.

Micrograph showing MDS

MADRID—Interim results of a phase 1 study suggest flotetuzumab, a CD123 and CD3 bispecific antibody, may be a feasible treatment option for relapsed or refractory acute myeloid leukemia (AML) or intermediate/high-risk myelodysplastic syndromes (MDS).

Researchers said flotetuzumab demonstrated acceptable tolerability in the dose-escalation portion of the study, with infusion-related reactions (IRRs) and cytokine release syndrome (CRS) being the most common adverse events (AEs).

In addition, flotetuzumab exhibited anti-leukemic activity in 8 of 14 response-evaluable patients, with 6 patients achieving a response.

Norbert Vey, MD, of Institut Paoli-Calmettes in Marseille, France, presented these results at the ESMO 2017 Congress (abstract 995O*). The study is sponsored by MacroGenics, Inc., the company developing flotetuzumab.

Flotetuzumab (MGD006) recognizes CD123 and CD3. The primary mechanism of flotetuzumab is thought to be its ability to redirect T cells to kill CD123-expressing cells. To achieve this, the molecule combines a portion of an antibody recognizing CD3 (an activating molecule expressed by T cells) with an arm that recognizes CD123 on the target cancer cells.

In this ongoing phase 1 study of flotetuzumab, researchers have enrolled 47 patients with a median age of 64 (range, 29-84). About 89% of these patients had AML (n=42), and the rest (n=5) had MDS.

Twenty-four percent had relapsed AML (n=10), 55% had refractory AML (n=23), and 21% had failed treatment with hypomethylating agents (n=9). One patient had intermediate-1-risk MDS, 2 had intermediate-2-risk, and 2 had high-risk MDS.

Treatment

The study began with single patients receiving flotetuzumab at escalating doses—3 ng/kg/day, 10 ng/kg/day, 30 ng/kg/day, and 100 ng/kg/day.

Then, patients received a range of doses on 2 different schedules for cycle 1. One group received treatment 7 days a week. The other had a 4-days-on/3-days-off schedule.

All patients received a lead-in dose during the first week of cycle 1. They received 30 ng/kg/day for 3 days, then 100 ng/kg/day for 4 days.

For the rest of cycle 1, patients in the 4 days/3 days group received doses of 500 ng/kg, 700 ng/kg, 900 ng/kg, or 1000 ng/kg. Patients in the daily dosing group received doses of 300 ng/kg, 500 ng/kg, 700 ng/kg, 900 ng/kg, or 1000 ng/kg.

For cycle 2 and beyond, all patients were on the 4-days-on/3-days-off schedule.

Safety

The maximum tolerated dose and schedule was 500 ng/kg/day for 7 days.

Dose-limiting toxicities occurring at the 700 ng/kg/day dose included grade 2 IRRs/CRS in 2 patients and grade 3 myalgia in 1 patient. There was 1 drug-related central nervous system AE that led to treatment discontinuation.

IRRs/CRS occurred in 77% of patients, with 13% of patients having grade 3 events and 8.5% of patients discontinuing treatment due to IRRs/CRS.

The researchers said they found ways to decrease the incidence and severity of CRS. One is early intervention with tocilizumab. The other is a 2-step lead-in dose during week 1. So patients first receive 30 ng/kg, then 100 ng/kg, and then their target dose.

Other grade 3 AEs occurring in this trial include febrile neutropenia (11%), anemia (11%), and decreases in platelets (13%), white blood cells (11%), and lymphocytes (13%).

Efficacy

The researchers said they observed encouraging anti-leukemic activity in patients treated at 500 ng/kg/day or greater.

As of the data cut-off, 14 patients treated at this dose were evaluable for response. Eight (57%) patients had anti-leukemic activity, with 6 (43%) of these patients experiencing an objective response.

One patient achieved a complete response (CR), 2 had a CR with incomplete count recovery, and 1 had a molecular CR.

In most responders, anti-leukemic activity was observed after a single cycle of therapy.

MacroGenics is currently enrolling patients in dose-expansion cohorts. The company plans to present updated results from this trial at another scientific conference later this year.

*Slides from this presentation are available on the MacroGenics website at http://ir.macrogenics.com/events.cfm.

Photo by Patrick Pelletier

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended granting marketing authorization for Imatinib Teva B.V., a generic of Glivec.

The recommendation is that Imatinib Teva B.V. be approved to treat chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), hypereosinophilic syndrome (HES), chronic eosinophilic leukemia (CEL), myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPNs), gastrointestinal stromal tumors (GIST), and dermatofibrosarcoma protuberans (DFSP).

The European Commission typically adheres to the CHMP’s recommendations and delivers its final decision within 67 days of the CHMP’s recommendation.

The European Commission’s decision will be applicable to the entire European Economic Area—all member states of the European Union plus Iceland, Liechtenstein, and Norway.

If approved, Imatinib Teva B.V. will be available as capsules and film-coated tablets (100 mg and 400 mg). And it will be authorized:

• As monotherapy for pediatric patients with newly diagnosed, Philadelphia-chromosome-positive (Ph+) CML for whom bone marrow transplant is not considered the first line of treatment.
• As monotherapy for pediatric patients with Ph+ CML in chronic phase after failure of interferon-alpha therapy or in accelerated phase or blast crisis.
• As monotherapy for adults with Ph+ CML in blast crisis.
• Integrated with chemotherapy to treat adult and pediatric patients with newly diagnosed, Ph+ ALL.
• As monotherapy for adults with relapsed or refractory Ph+ ALL.
• As monotherapy for adults with MDS/MPNs associated with platelet-derived growth factor receptor gene re-arrangements.
• As monotherapy for adults with advanced HES and/or CEL with FIP1L1-PDGFRα rearrangement.
• As monotherapy for adults with Kit- (CD117-) positive, unresectable and/or metastatic malignant GISTs.
• For the adjuvant treatment of adults who are at significant risk of relapse following resection of Kit-positive GIST. Patients who have a low or very low risk of recurrence should not receive adjuvant treatment.
• As monotherapy for adults with unresectable DFSP and adults with recurrent and/or metastatic DFSP who are not eligible for surgery.

The CHMP said studies have demonstrated the satisfactory quality of Imatinib Teva B.V. and its bioequivalence to the reference product, Glivec.

In adult and pediatric patients, the effectiveness of imatinib is based on:

• Overall hematologic and cytogenetic response rates and progression-free survival in CML
• Hematologic and cytogenetic response rates in Ph+ ALL and MDS/MPNs
• Hematologic response rates in HES/CEL
• Objective response rates in adults with unresectable and/or metastatic GIST and DFSP
• Recurrence-free survival in adjuvant GIST.

The experience with imatinib in patients with MDS/MPNs associated with PDGFR gene re-arrangements is very limited. There are no controlled trials demonstrating a clinical benefit or increased survival for these diseases.

Photo by Patrick Pelletier

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended granting marketing authorization for Imatinib Teva B.V., a generic of Glivec.

The recommendation is that Imatinib Teva B.V. be approved to treat chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), hypereosinophilic syndrome (HES), chronic eosinophilic leukemia (CEL), myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPNs), gastrointestinal stromal tumors (GIST), and dermatofibrosarcoma protuberans (DFSP).

The European Commission typically adheres to the CHMP’s recommendations and delivers its final decision within 67 days of the CHMP’s recommendation.

The European Commission’s decision will be applicable to the entire European Economic Area—all member states of the European Union plus Iceland, Liechtenstein, and Norway.

If approved, Imatinib Teva B.V. will be available as capsules and film-coated tablets (100 mg and 400 mg). And it will be authorized:

• As monotherapy for pediatric patients with newly diagnosed, Philadelphia-chromosome-positive (Ph+) CML for whom bone marrow transplant is not considered the first line of treatment.
• As monotherapy for pediatric patients with Ph+ CML in chronic phase after failure of interferon-alpha therapy or in accelerated phase or blast crisis.
• As monotherapy for adults with Ph+ CML in blast crisis.
• Integrated with chemotherapy to treat adult and pediatric patients with newly diagnosed, Ph+ ALL.
• As monotherapy for adults with relapsed or refractory Ph+ ALL.
• As monotherapy for adults with MDS/MPNs associated with platelet-derived growth factor receptor gene re-arrangements.
• As monotherapy for adults with advanced HES and/or CEL with FIP1L1-PDGFRα rearrangement.
• As monotherapy for adults with Kit- (CD117-) positive, unresectable and/or metastatic malignant GISTs.
• For the adjuvant treatment of adults who are at significant risk of relapse following resection of Kit-positive GIST. Patients who have a low or very low risk of recurrence should not receive adjuvant treatment.
• As monotherapy for adults with unresectable DFSP and adults with recurrent and/or metastatic DFSP who are not eligible for surgery.

The CHMP said studies have demonstrated the satisfactory quality of Imatinib Teva B.V. and its bioequivalence to the reference product, Glivec.

In adult and pediatric patients, the effectiveness of imatinib is based on:

• Overall hematologic and cytogenetic response rates and progression-free survival in CML
• Hematologic and cytogenetic response rates in Ph+ ALL and MDS/MPNs
• Hematologic response rates in HES/CEL
• Objective response rates in adults with unresectable and/or metastatic GIST and DFSP
• Recurrence-free survival in adjuvant GIST.

The experience with imatinib in patients with MDS/MPNs associated with PDGFR gene re-arrangements is very limited. There are no controlled trials demonstrating a clinical benefit or increased survival for these diseases.

Photo by Patrick Pelletier

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended granting marketing authorization for Imatinib Teva B.V., a generic of Glivec.

The recommendation is that Imatinib Teva B.V. be approved to treat chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), hypereosinophilic syndrome (HES), chronic eosinophilic leukemia (CEL), myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPNs), gastrointestinal stromal tumors (GIST), and dermatofibrosarcoma protuberans (DFSP).

The European Commission typically adheres to the CHMP’s recommendations and delivers its final decision within 67 days of the CHMP’s recommendation.

The European Commission’s decision will be applicable to the entire European Economic Area—all member states of the European Union plus Iceland, Liechtenstein, and Norway.

If approved, Imatinib Teva B.V. will be available as capsules and film-coated tablets (100 mg and 400 mg). And it will be authorized:

• As monotherapy for pediatric patients with newly diagnosed, Philadelphia-chromosome-positive (Ph+) CML for whom bone marrow transplant is not considered the first line of treatment.
• As monotherapy for pediatric patients with Ph+ CML in chronic phase after failure of interferon-alpha therapy or in accelerated phase or blast crisis.
• As monotherapy for adults with Ph+ CML in blast crisis.
• Integrated with chemotherapy to treat adult and pediatric patients with newly diagnosed, Ph+ ALL.
• As monotherapy for adults with relapsed or refractory Ph+ ALL.
• As monotherapy for adults with MDS/MPNs associated with platelet-derived growth factor receptor gene re-arrangements.
• As monotherapy for adults with advanced HES and/or CEL with FIP1L1-PDGFRα rearrangement.
• As monotherapy for adults with Kit- (CD117-) positive, unresectable and/or metastatic malignant GISTs.
• For the adjuvant treatment of adults who are at significant risk of relapse following resection of Kit-positive GIST. Patients who have a low or very low risk of recurrence should not receive adjuvant treatment.
• As monotherapy for adults with unresectable DFSP and adults with recurrent and/or metastatic DFSP who are not eligible for surgery.

The CHMP said studies have demonstrated the satisfactory quality of Imatinib Teva B.V. and its bioequivalence to the reference product, Glivec.

In adult and pediatric patients, the effectiveness of imatinib is based on:

• Overall hematologic and cytogenetic response rates and progression-free survival in CML
• Hematologic and cytogenetic response rates in Ph+ ALL and MDS/MPNs
• Hematologic response rates in HES/CEL
• Objective response rates in adults with unresectable and/or metastatic GIST and DFSP
• Recurrence-free survival in adjuvant GIST.

The experience with imatinib in patients with MDS/MPNs associated with PDGFR gene re-arrangements is very limited. There are no controlled trials demonstrating a clinical benefit or increased survival for these diseases.

Photo by Graham Colm

Previous research has suggested that astronauts develop anemia during space flight, but a new study indicates this is not the case for astronauts on long space missions.

“There is an idea of ‘space anemia’ that is associated with space flight,” said Richard Simpson, PhD, of the University of Houston in Texas.

“However, this is based on blood samples from astronauts collected after flight, which may be influenced by various factors—for example, the stress of landing and re-adaptation to conditions on Earth.”

“For this study . . ., living, whole blood samples were collected during space flight and returned to Earth for analysis. This unique sample allowed us to track hematological parameters—such as concentrations of red blood cells, hemoglobin, or hematocrit—in astronauts on board the International Space Station during flight.”

Dr Simpson and his colleagues reported their findings in BMC Hematology.

The researchers found that, during space flight, concentrations of red blood cells (RBCs), platelets, and hemoglobin were higher compared to pre-flight levels. Hematocrit also increased significantly during space flight.

While previous studies had shown this to be the case during the first few days of flight, this is the first study to show that RBC concentrations and hematocrit remain at higher levels even after astronauts’ bodies have adapted to microgravity.

To find out how the blood of astronauts may change if they spend a long time in space, the researchers collected blood samples from 31 astronauts who spent up to 6 months on the International Space Station (ISS). There were 6 female and 25 male subjects, and their mean age was 52 (range, 38–61).

Samples were collected at 180 days and 45 days before the astronauts flew to the ISS. Blood was also collected while they were in space—during the first 2 weeks (early time point), between 2 and 4 months (mid time point), and about 6 months into the mission (late time point).

Samples were returned to Earth for analysis either in Houston or at Star City, Russia, within 48 hours of collection. Post-flight samples were collected 3 to 8 hours after landing and 30 days after the mission had ended.

Results

The researchers said some of the changes observed in the in-flight blood samples were to be expected due to the 48-hour processing delay between sample collection and analysis.

However, the team found that RBC concentration was significantly elevated at all 3 in-flight time points, when compared to the 180-day pre-mission time point (baseline). And RBC counts returned to baseline levels upon Earth landing.

The mean RBC concentrations (x 10⁶ cells/μL) were:

• 4.4 ± 0.4 (range, 3.5–5.1) at baseline
• 4.8 ± 0.5 (range, 3.9–5.7) at the early time point (P<0.05)
• 4.7 ± 0.4 (range, 3.9–5.4) at the mid time point (P<0.05)
• 4.7 ± 0.4 (range, 4.1–5.6) at the late time point (P<0.05).

Hemoglobin was elevated early in flight but returned to pre-flight levels during the mission and fell below baseline levels on landing day. The mean hemoglobin (g/dL) levels were:

• 14.1 ± 1.4 (range, 11.0–17.8) at baseline
• 15.0 ± 1.9 (range, 10.7–17.5) at the early time point (P<0.05)
• 13.5 ± 1.4 (range, 10.1–15.9) on landing day (P<0.05).

Mean corpuscular hemoglobin (MCH) decreased during the mission and was significantly lower than baseline at the late time point. However, MCH returned to pre-flight values upon landing. The mean MCH (pg) was:

• 31.7 ± 1.6 (range, 28.8–36.4) at baseline
• 31.3 ± 1.9 (range 26.3–34.0) at the late time point (P<0.05).

The researchers said they observed significant increases in mean corpuscular volume (MCV) during space flight. However, these reflect the changes observed following the 48-hour processing delay. So there were no variations in MCV attributable to space flight.

The changes observed in hematocrit during space flight were “striking,” according to the researchers. The mean hematocrit levels were:

• 40.9 ± 3.9 (range, 33.1–48.0) at baseline
• 45.9 ± 4.7 (range 38.2–52.1) at the early time point (P<0.05)
• 45.9 ± 5.5 (range 38.9–58.3) at the mid time point (P<0.05)
• 45.0 ± 2.5 (range 38.9–49.9) at the late time point (P<0.05).

Compared to pre-flight levels, hematocrit increased by 12.2% at early, 12.2% at mid, and 10.0% at late time points. In comparison, there was a 4.7% increase in hematocrit in reference samples from non-astronauts after the 48-hour processing delay.

Finally, the researchers found that platelet concentrations were elevated in flight, at the early and mid time points. However, platelets were not significantly elevated at the late time point, and they were stable upon landing.

For all of the astronauts, all blood parameters returned to pre-flight levels within 30 days of landing on Earth.

The researchers said these results are susceptible to the possible influence of dehydration or plasma volume alterations. However, the findings do suggest the increases observed in the ISS samples are partly due to a true in-flight increase in RBC count.

“Although the data does not indicate that significant anemia is present, it must be interpreted in the context of crew plasma volume during flight,” Dr Simpson said. “Overall plasma volume has been shown to be reduced during space flight, but this has not been assessed during long-duration missions.”

“In order to fully interpret the changes to RBC, hematocrit, and other parameters observed in this study, further research into plasma volume during long space missions is needed. This will be addressed in a separate, ongoing NASA investigation.”

Photo by Graham Colm

Previous research has suggested that astronauts develop anemia during space flight, but a new study indicates this is not the case for astronauts on long space missions.

“There is an idea of ‘space anemia’ that is associated with space flight,” said Richard Simpson, PhD, of the University of Houston in Texas.

“However, this is based on blood samples from astronauts collected after flight, which may be influenced by various factors—for example, the stress of landing and re-adaptation to conditions on Earth.”

“For this study . . ., living, whole blood samples were collected during space flight and returned to Earth for analysis. This unique sample allowed us to track hematological parameters—such as concentrations of red blood cells, hemoglobin, or hematocrit—in astronauts on board the International Space Station during flight.”

Dr Simpson and his colleagues reported their findings in BMC Hematology.

The researchers found that, during space flight, concentrations of red blood cells (RBCs), platelets, and hemoglobin were higher compared to pre-flight levels. Hematocrit also increased significantly during space flight.

While previous studies had shown this to be the case during the first few days of flight, this is the first study to show that RBC concentrations and hematocrit remain at higher levels even after astronauts’ bodies have adapted to microgravity.

To find out how the blood of astronauts may change if they spend a long time in space, the researchers collected blood samples from 31 astronauts who spent up to 6 months on the International Space Station (ISS). There were 6 female and 25 male subjects, and their mean age was 52 (range, 38–61).

Samples were collected at 180 days and 45 days before the astronauts flew to the ISS. Blood was also collected while they were in space—during the first 2 weeks (early time point), between 2 and 4 months (mid time point), and about 6 months into the mission (late time point).

Samples were returned to Earth for analysis either in Houston or at Star City, Russia, within 48 hours of collection. Post-flight samples were collected 3 to 8 hours after landing and 30 days after the mission had ended.

Results

The researchers said some of the changes observed in the in-flight blood samples were to be expected due to the 48-hour processing delay between sample collection and analysis.

However, the team found that RBC concentration was significantly elevated at all 3 in-flight time points, when compared to the 180-day pre-mission time point (baseline). And RBC counts returned to baseline levels upon Earth landing.

The mean RBC concentrations (x 10⁶ cells/μL) were:

• 4.4 ± 0.4 (range, 3.5–5.1) at baseline
• 4.8 ± 0.5 (range, 3.9–5.7) at the early time point (P<0.05)
• 4.7 ± 0.4 (range, 3.9–5.4) at the mid time point (P<0.05)
• 4.7 ± 0.4 (range, 4.1–5.6) at the late time point (P<0.05).

Hemoglobin was elevated early in flight but returned to pre-flight levels during the mission and fell below baseline levels on landing day. The mean hemoglobin (g/dL) levels were:

• 14.1 ± 1.4 (range, 11.0–17.8) at baseline
• 15.0 ± 1.9 (range, 10.7–17.5) at the early time point (P<0.05)
• 13.5 ± 1.4 (range, 10.1–15.9) on landing day (P<0.05).

Mean corpuscular hemoglobin (MCH) decreased during the mission and was significantly lower than baseline at the late time point. However, MCH returned to pre-flight values upon landing. The mean MCH (pg) was:

• 31.7 ± 1.6 (range, 28.8–36.4) at baseline
• 31.3 ± 1.9 (range 26.3–34.0) at the late time point (P<0.05).

The researchers said they observed significant increases in mean corpuscular volume (MCV) during space flight. However, these reflect the changes observed following the 48-hour processing delay. So there were no variations in MCV attributable to space flight.

The changes observed in hematocrit during space flight were “striking,” according to the researchers. The mean hematocrit levels were:

• 40.9 ± 3.9 (range, 33.1–48.0) at baseline
• 45.9 ± 4.7 (range 38.2–52.1) at the early time point (P<0.05)
• 45.9 ± 5.5 (range 38.9–58.3) at the mid time point (P<0.05)
• 45.0 ± 2.5 (range 38.9–49.9) at the late time point (P<0.05).

Compared to pre-flight levels, hematocrit increased by 12.2% at early, 12.2% at mid, and 10.0% at late time points. In comparison, there was a 4.7% increase in hematocrit in reference samples from non-astronauts after the 48-hour processing delay.

Finally, the researchers found that platelet concentrations were elevated in flight, at the early and mid time points. However, platelets were not significantly elevated at the late time point, and they were stable upon landing.

For all of the astronauts, all blood parameters returned to pre-flight levels within 30 days of landing on Earth.

The researchers said these results are susceptible to the possible influence of dehydration or plasma volume alterations. However, the findings do suggest the increases observed in the ISS samples are partly due to a true in-flight increase in RBC count.

“Although the data does not indicate that significant anemia is present, it must be interpreted in the context of crew plasma volume during flight,” Dr Simpson said. “Overall plasma volume has been shown to be reduced during space flight, but this has not been assessed during long-duration missions.”

“In order to fully interpret the changes to RBC, hematocrit, and other parameters observed in this study, further research into plasma volume during long space missions is needed. This will be addressed in a separate, ongoing NASA investigation.”

Photo by Graham Colm

Previous research has suggested that astronauts develop anemia during space flight, but a new study indicates this is not the case for astronauts on long space missions.

“There is an idea of ‘space anemia’ that is associated with space flight,” said Richard Simpson, PhD, of the University of Houston in Texas.

“However, this is based on blood samples from astronauts collected after flight, which may be influenced by various factors—for example, the stress of landing and re-adaptation to conditions on Earth.”

“For this study . . ., living, whole blood samples were collected during space flight and returned to Earth for analysis. This unique sample allowed us to track hematological parameters—such as concentrations of red blood cells, hemoglobin, or hematocrit—in astronauts on board the International Space Station during flight.”

Dr Simpson and his colleagues reported their findings in BMC Hematology.

The researchers found that, during space flight, concentrations of red blood cells (RBCs), platelets, and hemoglobin were higher compared to pre-flight levels. Hematocrit also increased significantly during space flight.

While previous studies had shown this to be the case during the first few days of flight, this is the first study to show that RBC concentrations and hematocrit remain at higher levels even after astronauts’ bodies have adapted to microgravity.

To find out how the blood of astronauts may change if they spend a long time in space, the researchers collected blood samples from 31 astronauts who spent up to 6 months on the International Space Station (ISS). There were 6 female and 25 male subjects, and their mean age was 52 (range, 38–61).

Samples were collected at 180 days and 45 days before the astronauts flew to the ISS. Blood was also collected while they were in space—during the first 2 weeks (early time point), between 2 and 4 months (mid time point), and about 6 months into the mission (late time point).

Samples were returned to Earth for analysis either in Houston or at Star City, Russia, within 48 hours of collection. Post-flight samples were collected 3 to 8 hours after landing and 30 days after the mission had ended.

Results

The researchers said some of the changes observed in the in-flight blood samples were to be expected due to the 48-hour processing delay between sample collection and analysis.

However, the team found that RBC concentration was significantly elevated at all 3 in-flight time points, when compared to the 180-day pre-mission time point (baseline). And RBC counts returned to baseline levels upon Earth landing.

The mean RBC concentrations (x 10⁶ cells/μL) were:

• 4.4 ± 0.4 (range, 3.5–5.1) at baseline
• 4.8 ± 0.5 (range, 3.9–5.7) at the early time point (P<0.05)
• 4.7 ± 0.4 (range, 3.9–5.4) at the mid time point (P<0.05)
• 4.7 ± 0.4 (range, 4.1–5.6) at the late time point (P<0.05).

Hemoglobin was elevated early in flight but returned to pre-flight levels during the mission and fell below baseline levels on landing day. The mean hemoglobin (g/dL) levels were:

• 14.1 ± 1.4 (range, 11.0–17.8) at baseline
• 15.0 ± 1.9 (range, 10.7–17.5) at the early time point (P<0.05)
• 13.5 ± 1.4 (range, 10.1–15.9) on landing day (P<0.05).

Mean corpuscular hemoglobin (MCH) decreased during the mission and was significantly lower than baseline at the late time point. However, MCH returned to pre-flight values upon landing. The mean MCH (pg) was:

• 31.7 ± 1.6 (range, 28.8–36.4) at baseline
• 31.3 ± 1.9 (range 26.3–34.0) at the late time point (P<0.05).

The researchers said they observed significant increases in mean corpuscular volume (MCV) during space flight. However, these reflect the changes observed following the 48-hour processing delay. So there were no variations in MCV attributable to space flight.

The changes observed in hematocrit during space flight were “striking,” according to the researchers. The mean hematocrit levels were:

• 40.9 ± 3.9 (range, 33.1–48.0) at baseline
• 45.9 ± 4.7 (range 38.2–52.1) at the early time point (P<0.05)
• 45.9 ± 5.5 (range 38.9–58.3) at the mid time point (P<0.05)
• 45.0 ± 2.5 (range 38.9–49.9) at the late time point (P<0.05).

Compared to pre-flight levels, hematocrit increased by 12.2% at early, 12.2% at mid, and 10.0% at late time points. In comparison, there was a 4.7% increase in hematocrit in reference samples from non-astronauts after the 48-hour processing delay.

Finally, the researchers found that platelet concentrations were elevated in flight, at the early and mid time points. However, platelets were not significantly elevated at the late time point, and they were stable upon landing.

For all of the astronauts, all blood parameters returned to pre-flight levels within 30 days of landing on Earth.

The researchers said these results are susceptible to the possible influence of dehydration or plasma volume alterations. However, the findings do suggest the increases observed in the ISS samples are partly due to a true in-flight increase in RBC count.

“Although the data does not indicate that significant anemia is present, it must be interpreted in the context of crew plasma volume during flight,” Dr Simpson said. “Overall plasma volume has been shown to be reduced during space flight, but this has not been assessed during long-duration missions.”

“In order to fully interpret the changes to RBC, hematocrit, and other parameters observed in this study, further research into plasma volume during long space missions is needed. This will be addressed in a separate, ongoing NASA investigation.”

Lab mouse

Researchers say they have synthesized low molecular weight heparin (LMWH) that may someday replace animal-sourced heparin.

The team created heparin dodecasaccharides (12-mers) using a manufacturing method that yielded gram quantities—roughly 1000-fold more than previous approaches used to synthesize LMWHs.

One of these dodecasaccharides, called 12-mer-1, demonstrated safety and efficacy in animals models.

Robert Linhardt, PhD, of Rensselaer Polytechnic Institute in Troy, New York, and his colleagues detailed this research in Science Translational Medicine.

The researchers tested 12-mer-1 in a mouse model of venous thrombosis induced by stenosis of the inferior vena cava. Twenty-four hours after stenosis, 12-mer-1 had reduced clot weight by about 60% (P<0.05), when compared to phosphate-buffered saline.

The effects of 12-mer-1 were comparable to those achieved with enoxaparin. However, the dose of 12-mer-1 (1.5 mg/kg) was one-fifth the dose of enoxaparin (7.5 mg/kg). This suggests 12-mer-1 has “considerably higher antithrombotic potency” than enoxaparin, according to the researchers.

Dr Linhardt and his colleagues also tested 12-mer-1 in a mouse model of sickle cell disease. The team said the anticoagulant (given at 2.0 mg/kg every 8 hours for 7 days) “significantly attenuated the activation of coagulation” when compared to saline (P<0.05).

The researchers then tested the clearance of 12-mer-1 in mice with severe kidney failure.

The team observed significant impairment of clearance for both high-dose (1.5 mg/kg) and low-dose (0.3 mg/kg) 12-mer-1 (P<0.05). However, the impairment of 12-mer-1 clearance was dependent upon the severity of the kidney injury.

The researchers also performed toxicology studies of 12-mer-1 in rats. The animals received a single dose of 12-mer-1 at 3600 mg/kg per day for 7 consecutive days.

The rats experienced a decrease in white blood cell counts, but this was within the historical control data range. Two additional doses of 12-mer-1 (400 and 1200 mg/kg per day) produced similar results.

Therefore, Dr Linhardt and his colleagues concluded that 12-mer-1 was well-tolerated.

The researchers also noted that anticoagulation with 12-mer-1 was completely reversible via treatment with protamine, which could potentially reduce bleeding risk.

The team believes that, with substantial optimization, 12-mer-1 could be suitable for industrial-scale synthesis.

“This is at the cusp of clinical trials and commercial use,” Dr Linhardt said. “There is no question about the science. We have proven that this is a safer, more effective alternative to its natural counterpart, and what now determines its success or failure is the marketplace.”

Lab mouse

Researchers say they have synthesized low molecular weight heparin (LMWH) that may someday replace animal-sourced heparin.

The team created heparin dodecasaccharides (12-mers) using a manufacturing method that yielded gram quantities—roughly 1000-fold more than previous approaches used to synthesize LMWHs.

One of these dodecasaccharides, called 12-mer-1, demonstrated safety and efficacy in animals models.

Robert Linhardt, PhD, of Rensselaer Polytechnic Institute in Troy, New York, and his colleagues detailed this research in Science Translational Medicine.

The researchers tested 12-mer-1 in a mouse model of venous thrombosis induced by stenosis of the inferior vena cava. Twenty-four hours after stenosis, 12-mer-1 had reduced clot weight by about 60% (P<0.05), when compared to phosphate-buffered saline.

The effects of 12-mer-1 were comparable to those achieved with enoxaparin. However, the dose of 12-mer-1 (1.5 mg/kg) was one-fifth the dose of enoxaparin (7.5 mg/kg). This suggests 12-mer-1 has “considerably higher antithrombotic potency” than enoxaparin, according to the researchers.

Dr Linhardt and his colleagues also tested 12-mer-1 in a mouse model of sickle cell disease. The team said the anticoagulant (given at 2.0 mg/kg every 8 hours for 7 days) “significantly attenuated the activation of coagulation” when compared to saline (P<0.05).

The researchers then tested the clearance of 12-mer-1 in mice with severe kidney failure.

The team observed significant impairment of clearance for both high-dose (1.5 mg/kg) and low-dose (0.3 mg/kg) 12-mer-1 (P<0.05). However, the impairment of 12-mer-1 clearance was dependent upon the severity of the kidney injury.

The researchers also performed toxicology studies of 12-mer-1 in rats. The animals received a single dose of 12-mer-1 at 3600 mg/kg per day for 7 consecutive days.

The rats experienced a decrease in white blood cell counts, but this was within the historical control data range. Two additional doses of 12-mer-1 (400 and 1200 mg/kg per day) produced similar results.

Therefore, Dr Linhardt and his colleagues concluded that 12-mer-1 was well-tolerated.

The researchers also noted that anticoagulation with 12-mer-1 was completely reversible via treatment with protamine, which could potentially reduce bleeding risk.

The team believes that, with substantial optimization, 12-mer-1 could be suitable for industrial-scale synthesis.

“This is at the cusp of clinical trials and commercial use,” Dr Linhardt said. “There is no question about the science. We have proven that this is a safer, more effective alternative to its natural counterpart, and what now determines its success or failure is the marketplace.”

Lab mouse

Researchers say they have synthesized low molecular weight heparin (LMWH) that may someday replace animal-sourced heparin.

The team created heparin dodecasaccharides (12-mers) using a manufacturing method that yielded gram quantities—roughly 1000-fold more than previous approaches used to synthesize LMWHs.

One of these dodecasaccharides, called 12-mer-1, demonstrated safety and efficacy in animals models.

Robert Linhardt, PhD, of Rensselaer Polytechnic Institute in Troy, New York, and his colleagues detailed this research in Science Translational Medicine.

The researchers tested 12-mer-1 in a mouse model of venous thrombosis induced by stenosis of the inferior vena cava. Twenty-four hours after stenosis, 12-mer-1 had reduced clot weight by about 60% (P<0.05), when compared to phosphate-buffered saline.

The effects of 12-mer-1 were comparable to those achieved with enoxaparin. However, the dose of 12-mer-1 (1.5 mg/kg) was one-fifth the dose of enoxaparin (7.5 mg/kg). This suggests 12-mer-1 has “considerably higher antithrombotic potency” than enoxaparin, according to the researchers.

Dr Linhardt and his colleagues also tested 12-mer-1 in a mouse model of sickle cell disease. The team said the anticoagulant (given at 2.0 mg/kg every 8 hours for 7 days) “significantly attenuated the activation of coagulation” when compared to saline (P<0.05).

The researchers then tested the clearance of 12-mer-1 in mice with severe kidney failure.

The team observed significant impairment of clearance for both high-dose (1.5 mg/kg) and low-dose (0.3 mg/kg) 12-mer-1 (P<0.05). However, the impairment of 12-mer-1 clearance was dependent upon the severity of the kidney injury.

The researchers also performed toxicology studies of 12-mer-1 in rats. The animals received a single dose of 12-mer-1 at 3600 mg/kg per day for 7 consecutive days.

The rats experienced a decrease in white blood cell counts, but this was within the historical control data range. Two additional doses of 12-mer-1 (400 and 1200 mg/kg per day) produced similar results.

Therefore, Dr Linhardt and his colleagues concluded that 12-mer-1 was well-tolerated.

The researchers also noted that anticoagulation with 12-mer-1 was completely reversible via treatment with protamine, which could potentially reduce bleeding risk.

The team believes that, with substantial optimization, 12-mer-1 could be suitable for industrial-scale synthesis.

“This is at the cusp of clinical trials and commercial use,” Dr Linhardt said. “There is no question about the science. We have proven that this is a safer, more effective alternative to its natural counterpart, and what now determines its success or failure is the marketplace.”

Red blood cells

Researchers say they have discovered a genetic mutation that triggers erythropoietic protoporphyria (EPP).

The team performed genetic sequencing on members of a family from Northern France who had EPP of a previously unknown genetic signature.

The sequencing revealed a mutation in the gene CLPX that promotes EPP.

Barry Paw MD, PhD, of the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center in Massachusetts, and his colleagues reported this discovery in PNAS.

About EPP

To produce heme, the body goes through porphyrin synthesis, which mainly occurs in the liver and bone marrow. Genetic defects can hinder the body’s ability to produce heme, and a decrease in heme production leads to a buildup of protoporphyrin components.

In the case of EPP, protoporphyrin IX accumulates in the red blood cells, plasma, and sometimes the liver.

When protoporphyrin IX is exposed to light, it produces chemicals that damage surrounding cells. As a result, people with EPP experience swelling, burning, and redness of the skin after exposure to sunlight.

“People with EPP are chronically anemic, which makes them feel very tired and look very pale, with increased photosensitivity because they can’t come out in the daylight,” Dr Paw said. “Even on a cloudy day, there’s enough ultraviolet light to cause blistering and disfigurement of the exposed body parts, ears, and nose.”

Although some genetic pathways leading to the build-up of protoporphyrin IX have already been described, many cases of EPP remain unexplained.

New discovery

Dr Paw and his colleagues noted that heme synthesis is controlled by the mitochondrial AAA+ unfoldase ClpX, which participates in the degradation and activation of δ-aminolevulinate synthase (ALAS).

In their analysis of the French family with EPP, the researchers discovered a dominant mutation in the ATPase active site of CLPX. This mutation—p.Gly298Asp—prompts the accumulation of protoporphyrin IX.

The researchers said the mutation partially inactivates CLPX, which increases the post-translational stability of ALAS. This increases ALAS protein and ALA levels and leads to the accumulation of protoporphyrin IX.

“This newly discovered mutation really highlights the complex genetic network that underpins heme metabolism,” Dr Paw said. “Loss-of-function mutations in any number of genes that are part of this network can result in devastating, disfiguring disorders.”

Dr Paw also noted that identifying the mutations that contribute to EPP and other porphyrias could pave the way for new methods of treating these disorders.

Red blood cells

Researchers say they have discovered a genetic mutation that triggers erythropoietic protoporphyria (EPP).

The team performed genetic sequencing on members of a family from Northern France who had EPP of a previously unknown genetic signature.

The sequencing revealed a mutation in the gene CLPX that promotes EPP.

Barry Paw MD, PhD, of the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center in Massachusetts, and his colleagues reported this discovery in PNAS.

About EPP

To produce heme, the body goes through porphyrin synthesis, which mainly occurs in the liver and bone marrow. Genetic defects can hinder the body’s ability to produce heme, and a decrease in heme production leads to a buildup of protoporphyrin components.

In the case of EPP, protoporphyrin IX accumulates in the red blood cells, plasma, and sometimes the liver.

When protoporphyrin IX is exposed to light, it produces chemicals that damage surrounding cells. As a result, people with EPP experience swelling, burning, and redness of the skin after exposure to sunlight.

“People with EPP are chronically anemic, which makes them feel very tired and look very pale, with increased photosensitivity because they can’t come out in the daylight,” Dr Paw said. “Even on a cloudy day, there’s enough ultraviolet light to cause blistering and disfigurement of the exposed body parts, ears, and nose.”

Although some genetic pathways leading to the build-up of protoporphyrin IX have already been described, many cases of EPP remain unexplained.

New discovery

Dr Paw and his colleagues noted that heme synthesis is controlled by the mitochondrial AAA+ unfoldase ClpX, which participates in the degradation and activation of δ-aminolevulinate synthase (ALAS).

In their analysis of the French family with EPP, the researchers discovered a dominant mutation in the ATPase active site of CLPX. This mutation—p.Gly298Asp—prompts the accumulation of protoporphyrin IX.

The researchers said the mutation partially inactivates CLPX, which increases the post-translational stability of ALAS. This increases ALAS protein and ALA levels and leads to the accumulation of protoporphyrin IX.

“This newly discovered mutation really highlights the complex genetic network that underpins heme metabolism,” Dr Paw said. “Loss-of-function mutations in any number of genes that are part of this network can result in devastating, disfiguring disorders.”

Dr Paw also noted that identifying the mutations that contribute to EPP and other porphyrias could pave the way for new methods of treating these disorders.

Red blood cells

Researchers say they have discovered a genetic mutation that triggers erythropoietic protoporphyria (EPP).

The team performed genetic sequencing on members of a family from Northern France who had EPP of a previously unknown genetic signature.

The sequencing revealed a mutation in the gene CLPX that promotes EPP.

Barry Paw MD, PhD, of the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center in Massachusetts, and his colleagues reported this discovery in PNAS.

About EPP

To produce heme, the body goes through porphyrin synthesis, which mainly occurs in the liver and bone marrow. Genetic defects can hinder the body’s ability to produce heme, and a decrease in heme production leads to a buildup of protoporphyrin components.

In the case of EPP, protoporphyrin IX accumulates in the red blood cells, plasma, and sometimes the liver.

When protoporphyrin IX is exposed to light, it produces chemicals that damage surrounding cells. As a result, people with EPP experience swelling, burning, and redness of the skin after exposure to sunlight.

“People with EPP are chronically anemic, which makes them feel very tired and look very pale, with increased photosensitivity because they can’t come out in the daylight,” Dr Paw said. “Even on a cloudy day, there’s enough ultraviolet light to cause blistering and disfigurement of the exposed body parts, ears, and nose.”

Although some genetic pathways leading to the build-up of protoporphyrin IX have already been described, many cases of EPP remain unexplained.

New discovery

Dr Paw and his colleagues noted that heme synthesis is controlled by the mitochondrial AAA+ unfoldase ClpX, which participates in the degradation and activation of δ-aminolevulinate synthase (ALAS).

In their analysis of the French family with EPP, the researchers discovered a dominant mutation in the ATPase active site of CLPX. This mutation—p.Gly298Asp—prompts the accumulation of protoporphyrin IX.

The researchers said the mutation partially inactivates CLPX, which increases the post-translational stability of ALAS. This increases ALAS protein and ALA levels and leads to the accumulation of protoporphyrin IX.

“This newly discovered mutation really highlights the complex genetic network that underpins heme metabolism,” Dr Paw said. “Loss-of-function mutations in any number of genes that are part of this network can result in devastating, disfiguring disorders.”

Dr Paw also noted that identifying the mutations that contribute to EPP and other porphyrias could pave the way for new methods of treating these disorders.

Red blood cells

Physicians have long known that patients with an underactive thyroid tend to have anemia because thyroid hormone stimulates red blood cell (RBC) production.

Now, researchers say they have determined how this occurs.

Xiaofei Gao, PhD, of Westlake Institute for Advanced Study in Hangzhou, Zhejiang Province, China, and his colleagues conducted this research and reported the results in PNAS.

The team began by studying the formation of human RBCs in culture. They wondered if something in the culture serum was essential for RBC maturation. So they ran the serum through a charcoal filter, which attracts and retains hydrophobic molecules.

Once filtered, the serum no longer supported RBC production. This validated the researchers’ theory that one of the hydrophobic molecules was key to RBC maturation.

In fact, the team found thyroid hormone was essential for the final step of RBC maturation.

When the researchers added thyroid hormone back to the serum, RBC progenitors once again started down the path to maturation.

If thyroid hormone was added at an earlier stage of development, the RBCs short-circuited their usual developmental processes and began turning into mature RBCs.

With further investigation, the researchers pinpointed the receptor inside maturing RBCs to which thyroid hormone binds—thyroid hormone receptor beta (TRβ).

From there, the team found that nuclear receptor coactivator 4 (NCOA4), a protein necessary for thyroid hormone stimulation, works with TRβ to regulate RBC development.

Finally, experiments showed that TRβ agonists could stimulate RBC development and alleviate anemic symptoms in a mouse model of chronic anemia.

The researchers therefore believe this work could lead to new therapies for anemic patients, including those with an underactive thyroid.

Red blood cells

Physicians have long known that patients with an underactive thyroid tend to have anemia because thyroid hormone stimulates red blood cell (RBC) production.

Now, researchers say they have determined how this occurs.

Xiaofei Gao, PhD, of Westlake Institute for Advanced Study in Hangzhou, Zhejiang Province, China, and his colleagues conducted this research and reported the results in PNAS.

The team began by studying the formation of human RBCs in culture. They wondered if something in the culture serum was essential for RBC maturation. So they ran the serum through a charcoal filter, which attracts and retains hydrophobic molecules.

Once filtered, the serum no longer supported RBC production. This validated the researchers’ theory that one of the hydrophobic molecules was key to RBC maturation.

In fact, the team found thyroid hormone was essential for the final step of RBC maturation.

When the researchers added thyroid hormone back to the serum, RBC progenitors once again started down the path to maturation.

If thyroid hormone was added at an earlier stage of development, the RBCs short-circuited their usual developmental processes and began turning into mature RBCs.

With further investigation, the researchers pinpointed the receptor inside maturing RBCs to which thyroid hormone binds—thyroid hormone receptor beta (TRβ).

From there, the team found that nuclear receptor coactivator 4 (NCOA4), a protein necessary for thyroid hormone stimulation, works with TRβ to regulate RBC development.

Finally, experiments showed that TRβ agonists could stimulate RBC development and alleviate anemic symptoms in a mouse model of chronic anemia.

The researchers therefore believe this work could lead to new therapies for anemic patients, including those with an underactive thyroid.

Red blood cells

Physicians have long known that patients with an underactive thyroid tend to have anemia because thyroid hormone stimulates red blood cell (RBC) production.

Now, researchers say they have determined how this occurs.

Xiaofei Gao, PhD, of Westlake Institute for Advanced Study in Hangzhou, Zhejiang Province, China, and his colleagues conducted this research and reported the results in PNAS.

The team began by studying the formation of human RBCs in culture. They wondered if something in the culture serum was essential for RBC maturation. So they ran the serum through a charcoal filter, which attracts and retains hydrophobic molecules.

Once filtered, the serum no longer supported RBC production. This validated the researchers’ theory that one of the hydrophobic molecules was key to RBC maturation.

In fact, the team found thyroid hormone was essential for the final step of RBC maturation.

When the researchers added thyroid hormone back to the serum, RBC progenitors once again started down the path to maturation.

If thyroid hormone was added at an earlier stage of development, the RBCs short-circuited their usual developmental processes and began turning into mature RBCs.

With further investigation, the researchers pinpointed the receptor inside maturing RBCs to which thyroid hormone binds—thyroid hormone receptor beta (TRβ).

From there, the team found that nuclear receptor coactivator 4 (NCOA4), a protein necessary for thyroid hormone stimulation, works with TRβ to regulate RBC development.

Finally, experiments showed that TRβ agonists could stimulate RBC development and alleviate anemic symptoms in a mouse model of chronic anemia.

The researchers therefore believe this work could lead to new therapies for anemic patients, including those with an underactive thyroid.

Image by Betty Pace

The US Food and Drug Administration (FDA) has granted rare pediatric disease designation to GBT440 for the treatment of sickle cell disease (SCD).

GBT440 is being developed by Global Blood Therapeutics, Inc. as a potentially disease-modifying therapy for SCD.

The drug works by increasing hemoglobin’s affinity for oxygen. Since oxygenated sickle hemoglobin does not polymerize, it is believed that GBT440 blocks polymerization and the resultant sickling of red blood cells.

If GBT440 can restore normal hemoglobin function and improve oxygen delivery, the therapy may be capable of modifying the progression of SCD.

The FDA previously granted GBT440 fast track and orphan drug designations.

About rare pediatric disease designation

Rare pediatric disease designation is granted to drugs that show promise to treat diseases affecting fewer than 200,000 patients in the US, primarily patients age 18 or younger.

The designation provides incentives to advance the development of drugs for rare disease, including access to the FDA’s expedited review and approval programs.

Under the FDA’s Rare Pediatric Disease Priority Review Voucher Program, if a drug with rare pediatric disease designation is approved, the drug’s developer may qualify for a voucher that can be redeemed to obtain priority review for any subsequent marketing application.

GBT440 trials

GBT440 is currently under investigation in a phase 1/2 trial (GBT440-001) of healthy subjects and adults with SCD. Data from this trial were presented at the 2016 ASH Annual Meeting.

At that time, there were 41 SCD patients who had been receiving GBT440 for up to 6 months.

All of these patients experienced a “profound and durable” reduction in hemolysis, as assessed by hemoglobin, reticulocytes, and/or bilirubin, according to Global Blood Therapeutics.

Patients treated with GBT440 for at least 90 days demonstrated a “clinically significant” increase in hemoglobin (greater than 1 g/dL increase) when compared with placebo-treated patients (46% vs 0%; P=0.006).

Patients treated with GBT440 also had a sustained reduction in irreversibly sickled cells when compared with placebo-treated patients (-76.6% vs +9.7%; P<0.001).

The most common treatment-related adverse events were grade 1/2 headache and gastrointestinal disorders. These events occurred in similar rates in the placebo and GBT440 arms. There were no drug-related serious or severe adverse events.

No sickle cell crises events occurred while participants were on GBT440. Exercise testing data showed normal tissue oxygen delivery (no change in oxygen consumption compared to placebo).

GBT440 is also under investigation in the phase 3 HOPE study, which includes SCD patients age 12 and older. And the drug is being tested in the phase 2 HOPE-KIDS 1 study, which includes pediatric patients (ages 6 to 17) with SCD.

Image by Betty Pace

The US Food and Drug Administration (FDA) has granted rare pediatric disease designation to GBT440 for the treatment of sickle cell disease (SCD).

GBT440 is being developed by Global Blood Therapeutics, Inc. as a potentially disease-modifying therapy for SCD.

The drug works by increasing hemoglobin’s affinity for oxygen. Since oxygenated sickle hemoglobin does not polymerize, it is believed that GBT440 blocks polymerization and the resultant sickling of red blood cells.

If GBT440 can restore normal hemoglobin function and improve oxygen delivery, the therapy may be capable of modifying the progression of SCD.

The FDA previously granted GBT440 fast track and orphan drug designations.

About rare pediatric disease designation

Rare pediatric disease designation is granted to drugs that show promise to treat diseases affecting fewer than 200,000 patients in the US, primarily patients age 18 or younger.

The designation provides incentives to advance the development of drugs for rare disease, including access to the FDA’s expedited review and approval programs.

Under the FDA’s Rare Pediatric Disease Priority Review Voucher Program, if a drug with rare pediatric disease designation is approved, the drug’s developer may qualify for a voucher that can be redeemed to obtain priority review for any subsequent marketing application.

GBT440 trials

GBT440 is currently under investigation in a phase 1/2 trial (GBT440-001) of healthy subjects and adults with SCD. Data from this trial were presented at the 2016 ASH Annual Meeting.

At that time, there were 41 SCD patients who had been receiving GBT440 for up to 6 months.

All of these patients experienced a “profound and durable” reduction in hemolysis, as assessed by hemoglobin, reticulocytes, and/or bilirubin, according to Global Blood Therapeutics.

Patients treated with GBT440 for at least 90 days demonstrated a “clinically significant” increase in hemoglobin (greater than 1 g/dL increase) when compared with placebo-treated patients (46% vs 0%; P=0.006).

Patients treated with GBT440 also had a sustained reduction in irreversibly sickled cells when compared with placebo-treated patients (-76.6% vs +9.7%; P<0.001).

The most common treatment-related adverse events were grade 1/2 headache and gastrointestinal disorders. These events occurred in similar rates in the placebo and GBT440 arms. There were no drug-related serious or severe adverse events.

No sickle cell crises events occurred while participants were on GBT440. Exercise testing data showed normal tissue oxygen delivery (no change in oxygen consumption compared to placebo).

GBT440 is also under investigation in the phase 3 HOPE study, which includes SCD patients age 12 and older. And the drug is being tested in the phase 2 HOPE-KIDS 1 study, which includes pediatric patients (ages 6 to 17) with SCD.

Image by Betty Pace

The US Food and Drug Administration (FDA) has granted rare pediatric disease designation to GBT440 for the treatment of sickle cell disease (SCD).

GBT440 is being developed by Global Blood Therapeutics, Inc. as a potentially disease-modifying therapy for SCD.

The drug works by increasing hemoglobin’s affinity for oxygen. Since oxygenated sickle hemoglobin does not polymerize, it is believed that GBT440 blocks polymerization and the resultant sickling of red blood cells.

If GBT440 can restore normal hemoglobin function and improve oxygen delivery, the therapy may be capable of modifying the progression of SCD.

The FDA previously granted GBT440 fast track and orphan drug designations.

About rare pediatric disease designation

Rare pediatric disease designation is granted to drugs that show promise to treat diseases affecting fewer than 200,000 patients in the US, primarily patients age 18 or younger.

The designation provides incentives to advance the development of drugs for rare disease, including access to the FDA’s expedited review and approval programs.

Under the FDA’s Rare Pediatric Disease Priority Review Voucher Program, if a drug with rare pediatric disease designation is approved, the drug’s developer may qualify for a voucher that can be redeemed to obtain priority review for any subsequent marketing application.

GBT440 trials

GBT440 is currently under investigation in a phase 1/2 trial (GBT440-001) of healthy subjects and adults with SCD. Data from this trial were presented at the 2016 ASH Annual Meeting.

At that time, there were 41 SCD patients who had been receiving GBT440 for up to 6 months.

All of these patients experienced a “profound and durable” reduction in hemolysis, as assessed by hemoglobin, reticulocytes, and/or bilirubin, according to Global Blood Therapeutics.

Patients treated with GBT440 for at least 90 days demonstrated a “clinically significant” increase in hemoglobin (greater than 1 g/dL increase) when compared with placebo-treated patients (46% vs 0%; P=0.006).

Patients treated with GBT440 also had a sustained reduction in irreversibly sickled cells when compared with placebo-treated patients (-76.6% vs +9.7%; P<0.001).

The most common treatment-related adverse events were grade 1/2 headache and gastrointestinal disorders. These events occurred in similar rates in the placebo and GBT440 arms. There were no drug-related serious or severe adverse events.

No sickle cell crises events occurred while participants were on GBT440. Exercise testing data showed normal tissue oxygen delivery (no change in oxygen consumption compared to placebo).

GBT440 is also under investigation in the phase 3 HOPE study, which includes SCD patients age 12 and older. And the drug is being tested in the phase 2 HOPE-KIDS 1 study, which includes pediatric patients (ages 6 to 17) with SCD.