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FDA approves first new drug for sickle cell in nearly 20 years
The approval was based on placebo-controlled phase II and phase III trials suggesting that L-glutamate offered moderate benefit to patients with this rare, serious, and potentially fatal blood disorder.
L-glutamine oral powder will be marketed under the brand name Endari by Emmaus Medical. The FDA granted the approval through its orphan drug pathway, which is reserved for treatments of rare diseases or conditions. The National Institutes of Health estimates that sickle cell disorder affects approximately 100,000 individuals in the United States. Previously, the only drug approved for treating sickle cell disorder was hydroxyurea, which the FDA green-lighted in 1998.
The randomized, placebo-controlled, phase III trial on which the approval of L-glutamine was based (GLUSCC09-01) comprised patients aged 5-58 years with sickle cell disease or beta-0 thalassemia who had at least two episodes of painful crises during the 12 months before screening. A total of 152 patients were randomly assigned to receive oral L-glutamine (0.3 mg/kg per day) for 48 weeks followed by a 3-week tapering period, while 78 patients received placebo. Patients who received L-glutamine averaged three hospital visits for painful crises for which they received parenteral narcotics or ketorolac, while the placebo group averaged four such hospital visits. Additionally, the time to second crisis was delayed by 79 days in the treatment group, compared with the placebo group (hazard ratio, 0.68).
L-glutamine also was associated with fewer hospital days (median 6.5 vs. 11 days) and fewer occurrences of potentially life-threatening acute chest syndrome (8.6% vs. 23.1%), investigators reported to the FDA’s Oncologic Drugs Advisory Committee during a meeting on May 24.
Safety studies of L-glutamine included phase II and phase III data from 187 patients who received L-glutamine and 111 patients who received placebo, the investigators reported. Based on these analyses, rates of sickle cell anemia with crisis were 66% in the treatment population and 72% in placebo recipients. Rates of acute chest syndrome were 7% and 19%, respectively. Treatment-emergent adverse events led patients to drop out of the studies in 2.7% and 0.9% of cases. The most common adverse events of L-glutamine therapy were constipation, nausea, headache, cough, pain in the extremities, back pain, chest pain, and abdominal pain.
The FDA advisory committee voted 10-3 in favor of approving L-glutamate after hearing from industry and FDA representatives, physicians who treat patients with sickle cell disorder, and patients and their family members at the May 24 meeting. “No” voters expressed concerns about differing drop-out rates between the study groups, but other committee members emphasized the severe impact of sickle cell disorder on quality of life and the crucial need for more treatments.
The FDA Orphan Products Grants Program provided some of the funding to develop the drug. The FDA committee members had no relevant conflicts of interests.
The approval was based on placebo-controlled phase II and phase III trials suggesting that L-glutamate offered moderate benefit to patients with this rare, serious, and potentially fatal blood disorder.
L-glutamine oral powder will be marketed under the brand name Endari by Emmaus Medical. The FDA granted the approval through its orphan drug pathway, which is reserved for treatments of rare diseases or conditions. The National Institutes of Health estimates that sickle cell disorder affects approximately 100,000 individuals in the United States. Previously, the only drug approved for treating sickle cell disorder was hydroxyurea, which the FDA green-lighted in 1998.
The randomized, placebo-controlled, phase III trial on which the approval of L-glutamine was based (GLUSCC09-01) comprised patients aged 5-58 years with sickle cell disease or beta-0 thalassemia who had at least two episodes of painful crises during the 12 months before screening. A total of 152 patients were randomly assigned to receive oral L-glutamine (0.3 mg/kg per day) for 48 weeks followed by a 3-week tapering period, while 78 patients received placebo. Patients who received L-glutamine averaged three hospital visits for painful crises for which they received parenteral narcotics or ketorolac, while the placebo group averaged four such hospital visits. Additionally, the time to second crisis was delayed by 79 days in the treatment group, compared with the placebo group (hazard ratio, 0.68).
L-glutamine also was associated with fewer hospital days (median 6.5 vs. 11 days) and fewer occurrences of potentially life-threatening acute chest syndrome (8.6% vs. 23.1%), investigators reported to the FDA’s Oncologic Drugs Advisory Committee during a meeting on May 24.
Safety studies of L-glutamine included phase II and phase III data from 187 patients who received L-glutamine and 111 patients who received placebo, the investigators reported. Based on these analyses, rates of sickle cell anemia with crisis were 66% in the treatment population and 72% in placebo recipients. Rates of acute chest syndrome were 7% and 19%, respectively. Treatment-emergent adverse events led patients to drop out of the studies in 2.7% and 0.9% of cases. The most common adverse events of L-glutamine therapy were constipation, nausea, headache, cough, pain in the extremities, back pain, chest pain, and abdominal pain.
The FDA advisory committee voted 10-3 in favor of approving L-glutamate after hearing from industry and FDA representatives, physicians who treat patients with sickle cell disorder, and patients and their family members at the May 24 meeting. “No” voters expressed concerns about differing drop-out rates between the study groups, but other committee members emphasized the severe impact of sickle cell disorder on quality of life and the crucial need for more treatments.
The FDA Orphan Products Grants Program provided some of the funding to develop the drug. The FDA committee members had no relevant conflicts of interests.
The approval was based on placebo-controlled phase II and phase III trials suggesting that L-glutamate offered moderate benefit to patients with this rare, serious, and potentially fatal blood disorder.
L-glutamine oral powder will be marketed under the brand name Endari by Emmaus Medical. The FDA granted the approval through its orphan drug pathway, which is reserved for treatments of rare diseases or conditions. The National Institutes of Health estimates that sickle cell disorder affects approximately 100,000 individuals in the United States. Previously, the only drug approved for treating sickle cell disorder was hydroxyurea, which the FDA green-lighted in 1998.
The randomized, placebo-controlled, phase III trial on which the approval of L-glutamine was based (GLUSCC09-01) comprised patients aged 5-58 years with sickle cell disease or beta-0 thalassemia who had at least two episodes of painful crises during the 12 months before screening. A total of 152 patients were randomly assigned to receive oral L-glutamine (0.3 mg/kg per day) for 48 weeks followed by a 3-week tapering period, while 78 patients received placebo. Patients who received L-glutamine averaged three hospital visits for painful crises for which they received parenteral narcotics or ketorolac, while the placebo group averaged four such hospital visits. Additionally, the time to second crisis was delayed by 79 days in the treatment group, compared with the placebo group (hazard ratio, 0.68).
L-glutamine also was associated with fewer hospital days (median 6.5 vs. 11 days) and fewer occurrences of potentially life-threatening acute chest syndrome (8.6% vs. 23.1%), investigators reported to the FDA’s Oncologic Drugs Advisory Committee during a meeting on May 24.
Safety studies of L-glutamine included phase II and phase III data from 187 patients who received L-glutamine and 111 patients who received placebo, the investigators reported. Based on these analyses, rates of sickle cell anemia with crisis were 66% in the treatment population and 72% in placebo recipients. Rates of acute chest syndrome were 7% and 19%, respectively. Treatment-emergent adverse events led patients to drop out of the studies in 2.7% and 0.9% of cases. The most common adverse events of L-glutamine therapy were constipation, nausea, headache, cough, pain in the extremities, back pain, chest pain, and abdominal pain.
The FDA advisory committee voted 10-3 in favor of approving L-glutamate after hearing from industry and FDA representatives, physicians who treat patients with sickle cell disorder, and patients and their family members at the May 24 meeting. “No” voters expressed concerns about differing drop-out rates between the study groups, but other committee members emphasized the severe impact of sickle cell disorder on quality of life and the crucial need for more treatments.
The FDA Orphan Products Grants Program provided some of the funding to develop the drug. The FDA committee members had no relevant conflicts of interests.
Luspatercept appears safe, effective in β-thalassemia
MADRID—Results of a phase 2 study have shown that luspatercept can produce sustained increases in hemoglobin and reductions in transfusion burden in adults with β-thalassemia.
Some patients are still receiving the drug and experiencing clinical benefits beyond 24 months.
Luspatercept has been well-tolerated in these patients, producing no serious adverse events (AEs).
“Luspatercept has many characteristics that are promising . . .,” said Antonio G. Piga, MD, of Turin University in Turin, Italy.
He presented results of the phase 2 study at the 22nd Congress of the European Hematology Association (EHA) as abstract S129.
The study was sponsored by Celgene in collaboration with Acceleron Pharma.
Dr Piga presented data on 63 patients—32 of whom were transfusion-dependent (TD) and 31 of whom were non-transfusion-dependent (NTD).
For the entire study cohort, the median age was 38 (range, 20-62), 52% of patients were male, and 67% had undergone a splenectomy.
In the NTD patients, the median hemoglobin at baseline was 8.5 g/dL (range, 6.5-9.8).
The TD patients received a median of 8 (range, 4-18) red blood cell (RBC) units every 12 weeks.
For the 3-month base study, patients received luspatercept at 0.2 mg/kg to 1.25 mg/kg every 3 weeks.
In the ongoing extension study, patients can receive luspatercept at 0.8 mg/kg to 1.25 mg/kg every 3 weeks for up to 5 years.
Efficacy in NTD patients
The median duration of treatment for NTD patients (n=31) was 18.6 months (range, 1.3-29.4 months; ongoing).
Over a 12-week period, 71% (22/31) of NTD patients saw at least a 1.0 g/dL increase in mean hemoglobin from baseline. Fifty-two percent (16/31) saw an increase of 1.5 g/dL or greater.
To assess quality of life in NTD patients, the researchers used FACIT-F, a 13-item questionnaire used to assess anemia-related symptoms such as fatigue and weakness.
Fifty-eight percent (7/12) of patients with a baseline FACIT-F deficit (<44 points) had improved by at least 3 points at 48 weeks.
And 86% (6/7) of patients with at least a 3-point increase in FACIT-F score had at least a 1.0 g/dL improvement in mean hemoglobin over a 12-week period.
Efficacy in TD patients
The median duration of treatment for TD patients was 14.2 months (range, 0.7-27.2 months, ongoing).
Seventy-eight percent (25/32) of these patients had at least a 20% reduction in RBC units transfused from 12 weeks pre-treatment to any 12-week interval on treatment. Sixty-nine percent (22/32) had at least a 33% reduction at any 12-week interval.
Fifty percent of patients (12/24) who received an estimated 6 to 20 RBC units every 24 weeks achieved a reduction in transfusion burden from baseline of at least 33% in the fixed 12-week interval from weeks 13 to 24.
Forty-six percent (11/24) achieved a reduction in transfusion burden from baseline of at least 33% in the interval from weeks 37 to 48.
Safety
The most common AEs possibly or probably related to luspatercept were bone pain (38%), headache (28%), myalgia (22%), arthralgia (19%), musculoskeletal pain (17%), asthenia (14%), injection site pain (13%), and back pain (11%).
Most AEs were grade 1 or 2 in severity. Treatment-related grade 3 AEs included bone pain (n=3), asthenia (n=2), and headache (n=1).
Dr Piga said these results support an ongoing phase 3 study of luspatercept in regularly transfused patients with β-thalassemia (BELIEVE, NCT02604433), which recently completed enrollment. 
MADRID—Results of a phase 2 study have shown that luspatercept can produce sustained increases in hemoglobin and reductions in transfusion burden in adults with β-thalassemia.
Some patients are still receiving the drug and experiencing clinical benefits beyond 24 months.
Luspatercept has been well-tolerated in these patients, producing no serious adverse events (AEs).
“Luspatercept has many characteristics that are promising . . .,” said Antonio G. Piga, MD, of Turin University in Turin, Italy.
He presented results of the phase 2 study at the 22nd Congress of the European Hematology Association (EHA) as abstract S129.
The study was sponsored by Celgene in collaboration with Acceleron Pharma.
Dr Piga presented data on 63 patients—32 of whom were transfusion-dependent (TD) and 31 of whom were non-transfusion-dependent (NTD).
For the entire study cohort, the median age was 38 (range, 20-62), 52% of patients were male, and 67% had undergone a splenectomy.
In the NTD patients, the median hemoglobin at baseline was 8.5 g/dL (range, 6.5-9.8).
The TD patients received a median of 8 (range, 4-18) red blood cell (RBC) units every 12 weeks.
For the 3-month base study, patients received luspatercept at 0.2 mg/kg to 1.25 mg/kg every 3 weeks.
In the ongoing extension study, patients can receive luspatercept at 0.8 mg/kg to 1.25 mg/kg every 3 weeks for up to 5 years.
Efficacy in NTD patients
The median duration of treatment for NTD patients (n=31) was 18.6 months (range, 1.3-29.4 months; ongoing).
Over a 12-week period, 71% (22/31) of NTD patients saw at least a 1.0 g/dL increase in mean hemoglobin from baseline. Fifty-two percent (16/31) saw an increase of 1.5 g/dL or greater.
To assess quality of life in NTD patients, the researchers used FACIT-F, a 13-item questionnaire used to assess anemia-related symptoms such as fatigue and weakness.
Fifty-eight percent (7/12) of patients with a baseline FACIT-F deficit (<44 points) had improved by at least 3 points at 48 weeks.
And 86% (6/7) of patients with at least a 3-point increase in FACIT-F score had at least a 1.0 g/dL improvement in mean hemoglobin over a 12-week period.
Efficacy in TD patients
The median duration of treatment for TD patients was 14.2 months (range, 0.7-27.2 months, ongoing).
Seventy-eight percent (25/32) of these patients had at least a 20% reduction in RBC units transfused from 12 weeks pre-treatment to any 12-week interval on treatment. Sixty-nine percent (22/32) had at least a 33% reduction at any 12-week interval.
Fifty percent of patients (12/24) who received an estimated 6 to 20 RBC units every 24 weeks achieved a reduction in transfusion burden from baseline of at least 33% in the fixed 12-week interval from weeks 13 to 24.
Forty-six percent (11/24) achieved a reduction in transfusion burden from baseline of at least 33% in the interval from weeks 37 to 48.
Safety
The most common AEs possibly or probably related to luspatercept were bone pain (38%), headache (28%), myalgia (22%), arthralgia (19%), musculoskeletal pain (17%), asthenia (14%), injection site pain (13%), and back pain (11%).
Most AEs were grade 1 or 2 in severity. Treatment-related grade 3 AEs included bone pain (n=3), asthenia (n=2), and headache (n=1).
Dr Piga said these results support an ongoing phase 3 study of luspatercept in regularly transfused patients with β-thalassemia (BELIEVE, NCT02604433), which recently completed enrollment.
MADRID—Results of a phase 2 study have shown that luspatercept can produce sustained increases in hemoglobin and reductions in transfusion burden in adults with β-thalassemia.
Some patients are still receiving the drug and experiencing clinical benefits beyond 24 months.
Luspatercept has been well-tolerated in these patients, producing no serious adverse events (AEs).
“Luspatercept has many characteristics that are promising . . .,” said Antonio G. Piga, MD, of Turin University in Turin, Italy.
He presented results of the phase 2 study at the 22nd Congress of the European Hematology Association (EHA) as abstract S129.
The study was sponsored by Celgene in collaboration with Acceleron Pharma.
Dr Piga presented data on 63 patients—32 of whom were transfusion-dependent (TD) and 31 of whom were non-transfusion-dependent (NTD).
For the entire study cohort, the median age was 38 (range, 20-62), 52% of patients were male, and 67% had undergone a splenectomy.
In the NTD patients, the median hemoglobin at baseline was 8.5 g/dL (range, 6.5-9.8).
The TD patients received a median of 8 (range, 4-18) red blood cell (RBC) units every 12 weeks.
For the 3-month base study, patients received luspatercept at 0.2 mg/kg to 1.25 mg/kg every 3 weeks.
In the ongoing extension study, patients can receive luspatercept at 0.8 mg/kg to 1.25 mg/kg every 3 weeks for up to 5 years.
Efficacy in NTD patients
The median duration of treatment for NTD patients (n=31) was 18.6 months (range, 1.3-29.4 months; ongoing).
Over a 12-week period, 71% (22/31) of NTD patients saw at least a 1.0 g/dL increase in mean hemoglobin from baseline. Fifty-two percent (16/31) saw an increase of 1.5 g/dL or greater.
To assess quality of life in NTD patients, the researchers used FACIT-F, a 13-item questionnaire used to assess anemia-related symptoms such as fatigue and weakness.
Fifty-eight percent (7/12) of patients with a baseline FACIT-F deficit (<44 points) had improved by at least 3 points at 48 weeks.
And 86% (6/7) of patients with at least a 3-point increase in FACIT-F score had at least a 1.0 g/dL improvement in mean hemoglobin over a 12-week period.
Efficacy in TD patients
The median duration of treatment for TD patients was 14.2 months (range, 0.7-27.2 months, ongoing).
Seventy-eight percent (25/32) of these patients had at least a 20% reduction in RBC units transfused from 12 weeks pre-treatment to any 12-week interval on treatment. Sixty-nine percent (22/32) had at least a 33% reduction at any 12-week interval.
Fifty percent of patients (12/24) who received an estimated 6 to 20 RBC units every 24 weeks achieved a reduction in transfusion burden from baseline of at least 33% in the fixed 12-week interval from weeks 13 to 24.
Forty-six percent (11/24) achieved a reduction in transfusion burden from baseline of at least 33% in the interval from weeks 37 to 48.
Safety
The most common AEs possibly or probably related to luspatercept were bone pain (38%), headache (28%), myalgia (22%), arthralgia (19%), musculoskeletal pain (17%), asthenia (14%), injection site pain (13%), and back pain (11%).
Most AEs were grade 1 or 2 in severity. Treatment-related grade 3 AEs included bone pain (n=3), asthenia (n=2), and headache (n=1).
Dr Piga said these results support an ongoing phase 3 study of luspatercept in regularly transfused patients with β-thalassemia (BELIEVE, NCT02604433), which recently completed enrollment.
FDA clears use of reagents to detect hematopoietic neoplasia
The US Food and Drug Administration (FDA) has allowed marketing of the ClearLLab Reagent Panel, a combination of conjugated antibody cocktails designed to aid the detection of hematopoietic neoplasia.
This includes chronic and acute leukemias, non-Hodgkin lymphoma, myeloma, myelodysplastic syndromes, and myeloproliferative neoplasms.
The ClearLLab reagents are intended for in vitro diagnostic use to identify various cell populations by immunophenotyping on an FC 500 flow cytometer.
The reagents are directed against B, T, and myeloid lineage antigens and intended to identify relevant leukocyte surface molecules.
ClearLLab provides 2 T-cell tubes, 2 B-cell tubes, and a myeloid tube, each consisting of pre-mixed 4- to 5-color cocktails. Together, this totals 18 markers as directly conjugated antibodies.
The reagents can be used with peripheral whole blood, bone marrow, and lymph node specimens.
The results obtained via testing with the ClearLLab reagents should be interpreted along with additional clinical and laboratory findings, according to Beckman Coulter, Inc., the company that will be marketing the reagents.
The FDA reviewed data for the ClearLLab reagents through the de novo premarket review pathway, a regulatory pathway for novel, low-to-moderate-risk devices that are not substantially equivalent to an already legally marketed device.
The FDA’s clearance of the ClearLLab reagents was supported by a study designed to demonstrate the reagents’ performance, which was conducted on 279 samples at 4 independent clinical sites.
Results with the ClearLLab reagents were compared to results with alternative detection methods used at the sites.
The ClearLLab results aligned with the study sites’ final diagnosis 93.4% of the time and correctly detected abnormalities 84.2% of the time.
Along with its clearance of the ClearLLab reagents, the FDA is establishing criteria, called special controls, which clarify the agency’s expectations in assuring the reagents’ accuracy, reliability, and clinical relevance.
These special controls, when met along with general controls, provide reasonable assurance of safety and effectiveness for the ClearLLab reagents and similar tools.
The special controls also describe the least burdensome regulatory pathway for future developers of similar diagnostic tests.
The US Food and Drug Administration (FDA) has allowed marketing of the ClearLLab Reagent Panel, a combination of conjugated antibody cocktails designed to aid the detection of hematopoietic neoplasia.
This includes chronic and acute leukemias, non-Hodgkin lymphoma, myeloma, myelodysplastic syndromes, and myeloproliferative neoplasms.
The ClearLLab reagents are intended for in vitro diagnostic use to identify various cell populations by immunophenotyping on an FC 500 flow cytometer.
The reagents are directed against B, T, and myeloid lineage antigens and intended to identify relevant leukocyte surface molecules.
ClearLLab provides 2 T-cell tubes, 2 B-cell tubes, and a myeloid tube, each consisting of pre-mixed 4- to 5-color cocktails. Together, this totals 18 markers as directly conjugated antibodies.
The reagents can be used with peripheral whole blood, bone marrow, and lymph node specimens.
The results obtained via testing with the ClearLLab reagents should be interpreted along with additional clinical and laboratory findings, according to Beckman Coulter, Inc., the company that will be marketing the reagents.
The FDA reviewed data for the ClearLLab reagents through the de novo premarket review pathway, a regulatory pathway for novel, low-to-moderate-risk devices that are not substantially equivalent to an already legally marketed device.
The FDA’s clearance of the ClearLLab reagents was supported by a study designed to demonstrate the reagents’ performance, which was conducted on 279 samples at 4 independent clinical sites.
Results with the ClearLLab reagents were compared to results with alternative detection methods used at the sites.
The ClearLLab results aligned with the study sites’ final diagnosis 93.4% of the time and correctly detected abnormalities 84.2% of the time.
Along with its clearance of the ClearLLab reagents, the FDA is establishing criteria, called special controls, which clarify the agency’s expectations in assuring the reagents’ accuracy, reliability, and clinical relevance.
These special controls, when met along with general controls, provide reasonable assurance of safety and effectiveness for the ClearLLab reagents and similar tools.
The special controls also describe the least burdensome regulatory pathway for future developers of similar diagnostic tests.
The US Food and Drug Administration (FDA) has allowed marketing of the ClearLLab Reagent Panel, a combination of conjugated antibody cocktails designed to aid the detection of hematopoietic neoplasia.
This includes chronic and acute leukemias, non-Hodgkin lymphoma, myeloma, myelodysplastic syndromes, and myeloproliferative neoplasms.
The ClearLLab reagents are intended for in vitro diagnostic use to identify various cell populations by immunophenotyping on an FC 500 flow cytometer.
The reagents are directed against B, T, and myeloid lineage antigens and intended to identify relevant leukocyte surface molecules.
ClearLLab provides 2 T-cell tubes, 2 B-cell tubes, and a myeloid tube, each consisting of pre-mixed 4- to 5-color cocktails. Together, this totals 18 markers as directly conjugated antibodies.
The reagents can be used with peripheral whole blood, bone marrow, and lymph node specimens.
The results obtained via testing with the ClearLLab reagents should be interpreted along with additional clinical and laboratory findings, according to Beckman Coulter, Inc., the company that will be marketing the reagents.
The FDA reviewed data for the ClearLLab reagents through the de novo premarket review pathway, a regulatory pathway for novel, low-to-moderate-risk devices that are not substantially equivalent to an already legally marketed device.
The FDA’s clearance of the ClearLLab reagents was supported by a study designed to demonstrate the reagents’ performance, which was conducted on 279 samples at 4 independent clinical sites.
Results with the ClearLLab reagents were compared to results with alternative detection methods used at the sites.
The ClearLLab results aligned with the study sites’ final diagnosis 93.4% of the time and correctly detected abnormalities 84.2% of the time.
Along with its clearance of the ClearLLab reagents, the FDA is establishing criteria, called special controls, which clarify the agency’s expectations in assuring the reagents’ accuracy, reliability, and clinical relevance.
These special controls, when met along with general controls, provide reasonable assurance of safety and effectiveness for the ClearLLab reagents and similar tools.
The special controls also describe the least burdensome regulatory pathway for future developers of similar diagnostic tests.
SCD therapy granted access to PRIME program
The European Medicines Agency (EMA) has granted GBT440 access to the agency’s PRIority MEdicines (PRIME) program.
GBT440 is being developed by Global Blood Therapeutics, Inc. as a potentially disease-modifying therapy for sickle cell disease (SCD).
GBT440 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.
About PRIME
The goal of the EMA’s PRIME program is to accelerate the development of therapies that may offer a major advantage over existing treatments or benefit patients with no treatment options.
Through PRIME, the EMA offers early and enhanced support to developers in order to optimize development plans and speed regulatory evaluations to potentially bring therapies to patients more quickly.
To be accepted for PRIME, a therapy must demonstrate the potential to benefit patients with unmet medical need through early clinical or nonclinical data.
Phase 1/2 trial
The GBT440 acceptance in the PRIME program was supported by data from an ongoing phase 1/2 trial (GBT440-001) in which researchers are evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of GBT440 in 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).
The European Medicines Agency (EMA) has granted GBT440 access to the agency’s PRIority MEdicines (PRIME) program.
GBT440 is being developed by Global Blood Therapeutics, Inc. as a potentially disease-modifying therapy for sickle cell disease (SCD).
GBT440 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.
About PRIME
The goal of the EMA’s PRIME program is to accelerate the development of therapies that may offer a major advantage over existing treatments or benefit patients with no treatment options.
Through PRIME, the EMA offers early and enhanced support to developers in order to optimize development plans and speed regulatory evaluations to potentially bring therapies to patients more quickly.
To be accepted for PRIME, a therapy must demonstrate the potential to benefit patients with unmet medical need through early clinical or nonclinical data.
Phase 1/2 trial
The GBT440 acceptance in the PRIME program was supported by data from an ongoing phase 1/2 trial (GBT440-001) in which researchers are evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of GBT440 in 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).
The European Medicines Agency (EMA) has granted GBT440 access to the agency’s PRIority MEdicines (PRIME) program.
GBT440 is being developed by Global Blood Therapeutics, Inc. as a potentially disease-modifying therapy for sickle cell disease (SCD).
GBT440 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.
About PRIME
The goal of the EMA’s PRIME program is to accelerate the development of therapies that may offer a major advantage over existing treatments or benefit patients with no treatment options.
Through PRIME, the EMA offers early and enhanced support to developers in order to optimize development plans and speed regulatory evaluations to potentially bring therapies to patients more quickly.
To be accepted for PRIME, a therapy must demonstrate the potential to benefit patients with unmet medical need through early clinical or nonclinical data.
Phase 1/2 trial
The GBT440 acceptance in the PRIME program was supported by data from an ongoing phase 1/2 trial (GBT440-001) in which researchers are evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of GBT440 in 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).
Plasma lipoprotein perturbations likely contribute to sickle cell vasculopathy
Patients with sickle cell disease have abnormalities of plasma lipoproteins that likely contribute to the disease’s characteristic vasculopathy and would not be addressed by simple red blood cell transfusion, suggesting that it may be time to rethink treatment strategy, according to a new study.
Previous research has shown that sickle cell disease (SCD) is associated with perturbations of cholesterol metabolism, according to the investigators, who were led by Eric Soupene, PhD, of the Children’s Hospital Oakland (Calif.) Research Institute. In particular, altered interactions of HDL particles appear to play a role.
For the study, the investigators analyzed 31 plasma samples obtained from patients with SCD during routine clinic visits and, in a subset, during vaso-occlusive crises, and 12 plasma samples obtained from healthy individuals serving as controls.
Main results showed that the patients with SCD had reduced levels of HDL3 particles (which play roles in macrophage handling of cholesterol and endothelial protection) and altered functionality of HDL2 particles, possibly as a compensatory mechanism (Exp Biol Med [Maywood]. 2017 Jan 1:1535370217706966. doi: 10.1177/1535370217706966). These changes were more pronounced during vaso-occlusive episodes.
In addition, endothelial cells exposed to lipoproteins from patients exhibited enhanced formation of inflammatory mediators, and this response could be blocked by treatment with hemopexin, a naturally occurring protein that scavenges heme.
“These findings indicate a significant imbalance of lipoprotein function,” the investigators write. “Our study adds to the growing evidence that the dysfunctional red blood cell ... in SCD affects the plasma environment, which contributes significantly in the vasculopathy that defines the disease.”
“The use of [red blood cell] concentrates in transfusion therapy of SCD patients underestimates the importance of the dysfunctional plasma compartment, and transfusion of whole blood or plasma may be warranted,” they propose. Furthermore, “[hemopexin] may provide an additional option to reduce inflammatory pathways by lowering the burden of cell-free heme.”
Study details
In the study, the investigators carried out a series of laboratory experiments comparing the quantity and function of lipoproteins between patients with SCD and healthy individuals. Patients receiving transfusion recently or on a long-term basis were not eligible, but patients receiving hydroxyurea were.
Results of gel electrophoresis showed that, compared with healthy individuals, patients with SCD not having a vaso-occlusive episode had a mean ratio of HDL2 to HDL3 that was 1.4 times higher (P less than .006), according to the published data. Moreover, the ratio for patients rose further on the 1st day of a vaso-occlusive episode (P = .005), so that the difference became even more pronounced.
Incubation of red blood cells with plasma from healthy individuals did not alter the HDL2 to HDL3 ratio, whereas incubation with plasma from patients with SCD increased this ratio.
When a fluorescent assay was used to assess oxidation, HDL2 from patients with SCD had altered function, whereby it had greater antioxidant capacity than HDL2 from healthy individuals. In fact, its antioxidant capacity was now very similar to that of HDL3.
Endothelial cells showed a greater increase in expression of long pentraxin 3, an acute phase protein produced in response to inflammatory stimuli, when exposed to HDL2 from patients with SCD as compared with HDL2 from healthy individuals (P less than .05). Hemopexin, the heme scavenger, nearly abolished this increase for SCD patients (P = .003) but had little effect for healthy individuals.
“This links hemolysis to lipoprotein-mediated inflammation in SCD, and hemopexin treatment could be considered,” the investigators maintain.
Dr. Soupene disclosed that he had no relevant conflicts of interest.
Patients with sickle cell disease have abnormalities of plasma lipoproteins that likely contribute to the disease’s characteristic vasculopathy and would not be addressed by simple red blood cell transfusion, suggesting that it may be time to rethink treatment strategy, according to a new study.
Previous research has shown that sickle cell disease (SCD) is associated with perturbations of cholesterol metabolism, according to the investigators, who were led by Eric Soupene, PhD, of the Children’s Hospital Oakland (Calif.) Research Institute. In particular, altered interactions of HDL particles appear to play a role.
For the study, the investigators analyzed 31 plasma samples obtained from patients with SCD during routine clinic visits and, in a subset, during vaso-occlusive crises, and 12 plasma samples obtained from healthy individuals serving as controls.
Main results showed that the patients with SCD had reduced levels of HDL3 particles (which play roles in macrophage handling of cholesterol and endothelial protection) and altered functionality of HDL2 particles, possibly as a compensatory mechanism (Exp Biol Med [Maywood]. 2017 Jan 1:1535370217706966. doi: 10.1177/1535370217706966). These changes were more pronounced during vaso-occlusive episodes.
In addition, endothelial cells exposed to lipoproteins from patients exhibited enhanced formation of inflammatory mediators, and this response could be blocked by treatment with hemopexin, a naturally occurring protein that scavenges heme.
“These findings indicate a significant imbalance of lipoprotein function,” the investigators write. “Our study adds to the growing evidence that the dysfunctional red blood cell ... in SCD affects the plasma environment, which contributes significantly in the vasculopathy that defines the disease.”
“The use of [red blood cell] concentrates in transfusion therapy of SCD patients underestimates the importance of the dysfunctional plasma compartment, and transfusion of whole blood or plasma may be warranted,” they propose. Furthermore, “[hemopexin] may provide an additional option to reduce inflammatory pathways by lowering the burden of cell-free heme.”
Study details
In the study, the investigators carried out a series of laboratory experiments comparing the quantity and function of lipoproteins between patients with SCD and healthy individuals. Patients receiving transfusion recently or on a long-term basis were not eligible, but patients receiving hydroxyurea were.
Results of gel electrophoresis showed that, compared with healthy individuals, patients with SCD not having a vaso-occlusive episode had a mean ratio of HDL2 to HDL3 that was 1.4 times higher (P less than .006), according to the published data. Moreover, the ratio for patients rose further on the 1st day of a vaso-occlusive episode (P = .005), so that the difference became even more pronounced.
Incubation of red blood cells with plasma from healthy individuals did not alter the HDL2 to HDL3 ratio, whereas incubation with plasma from patients with SCD increased this ratio.
When a fluorescent assay was used to assess oxidation, HDL2 from patients with SCD had altered function, whereby it had greater antioxidant capacity than HDL2 from healthy individuals. In fact, its antioxidant capacity was now very similar to that of HDL3.
Endothelial cells showed a greater increase in expression of long pentraxin 3, an acute phase protein produced in response to inflammatory stimuli, when exposed to HDL2 from patients with SCD as compared with HDL2 from healthy individuals (P less than .05). Hemopexin, the heme scavenger, nearly abolished this increase for SCD patients (P = .003) but had little effect for healthy individuals.
“This links hemolysis to lipoprotein-mediated inflammation in SCD, and hemopexin treatment could be considered,” the investigators maintain.
Dr. Soupene disclosed that he had no relevant conflicts of interest.
Patients with sickle cell disease have abnormalities of plasma lipoproteins that likely contribute to the disease’s characteristic vasculopathy and would not be addressed by simple red blood cell transfusion, suggesting that it may be time to rethink treatment strategy, according to a new study.
Previous research has shown that sickle cell disease (SCD) is associated with perturbations of cholesterol metabolism, according to the investigators, who were led by Eric Soupene, PhD, of the Children’s Hospital Oakland (Calif.) Research Institute. In particular, altered interactions of HDL particles appear to play a role.
For the study, the investigators analyzed 31 plasma samples obtained from patients with SCD during routine clinic visits and, in a subset, during vaso-occlusive crises, and 12 plasma samples obtained from healthy individuals serving as controls.
Main results showed that the patients with SCD had reduced levels of HDL3 particles (which play roles in macrophage handling of cholesterol and endothelial protection) and altered functionality of HDL2 particles, possibly as a compensatory mechanism (Exp Biol Med [Maywood]. 2017 Jan 1:1535370217706966. doi: 10.1177/1535370217706966). These changes were more pronounced during vaso-occlusive episodes.
In addition, endothelial cells exposed to lipoproteins from patients exhibited enhanced formation of inflammatory mediators, and this response could be blocked by treatment with hemopexin, a naturally occurring protein that scavenges heme.
“These findings indicate a significant imbalance of lipoprotein function,” the investigators write. “Our study adds to the growing evidence that the dysfunctional red blood cell ... in SCD affects the plasma environment, which contributes significantly in the vasculopathy that defines the disease.”
“The use of [red blood cell] concentrates in transfusion therapy of SCD patients underestimates the importance of the dysfunctional plasma compartment, and transfusion of whole blood or plasma may be warranted,” they propose. Furthermore, “[hemopexin] may provide an additional option to reduce inflammatory pathways by lowering the burden of cell-free heme.”
Study details
In the study, the investigators carried out a series of laboratory experiments comparing the quantity and function of lipoproteins between patients with SCD and healthy individuals. Patients receiving transfusion recently or on a long-term basis were not eligible, but patients receiving hydroxyurea were.
Results of gel electrophoresis showed that, compared with healthy individuals, patients with SCD not having a vaso-occlusive episode had a mean ratio of HDL2 to HDL3 that was 1.4 times higher (P less than .006), according to the published data. Moreover, the ratio for patients rose further on the 1st day of a vaso-occlusive episode (P = .005), so that the difference became even more pronounced.
Incubation of red blood cells with plasma from healthy individuals did not alter the HDL2 to HDL3 ratio, whereas incubation with plasma from patients with SCD increased this ratio.
When a fluorescent assay was used to assess oxidation, HDL2 from patients with SCD had altered function, whereby it had greater antioxidant capacity than HDL2 from healthy individuals. In fact, its antioxidant capacity was now very similar to that of HDL3.
Endothelial cells showed a greater increase in expression of long pentraxin 3, an acute phase protein produced in response to inflammatory stimuli, when exposed to HDL2 from patients with SCD as compared with HDL2 from healthy individuals (P less than .05). Hemopexin, the heme scavenger, nearly abolished this increase for SCD patients (P = .003) but had little effect for healthy individuals.
“This links hemolysis to lipoprotein-mediated inflammation in SCD, and hemopexin treatment could be considered,” the investigators maintain.
Dr. Soupene disclosed that he had no relevant conflicts of interest.
FROM EXPERIMENTAL BIOLOGY AND MEDICINE
Key clinical point:
Major finding: Patients with SCD had reduced levels of HDL3 and altered functionality of HDL2, which were associated with an increased lipoprotein-mediated inflammatory response of endothelial cells.
Data source: An observational cohort study using 31 plasma samples from patients with sickle cell disease and 12 plasma samples from healthy individuals.
Disclosures: Dr. Soupene disclosed that he had no relevant conflicts of interest.
T-cell product improves outcomes of haplo-HSCT
MADRID—Updated results of a phase 1/2 study suggest the T-cell product BPX-501 lowers the risks associated with haploidentical hematopoietic stem cell transplant (haplo-HSCT).
In this ongoing study, researchers are testing BPX-501 in pediatric patients undergoing haplo-HSCT to treat a range of hematologic disorders.
Patients treated thus far have experienced rapid engraftment and early hospital discharge, a low rate of acute graft-versus-host disease (GHVD), no extensive chronic GVHD, and a low rate of transplant-related mortality at 180 days.
“The combination of haploidentical transplantation and BPX-501 infusion is an effective strategy for children in need of an allograft lacking a compatible donor,” said study investigator Mattia Algeri, MD, of Ospedale Pediatrico Bambino Gesù in Rome, Italy.
Dr Algeri presented these results during the Presidential Symposium at the 22nd Congress of the European Hematology Association (EHA) as abstract S146.
The research was sponsored by Bellicum Pharmaceuticals, Inc., the company developing BPX-501.
About BPX-501
BPX-501 consists of genetically modified donor T cells incorporating the CaspaCIDe safety switch, which is designed to eliminate the T cells in the event of toxicity.
Rimiducid is used to activate the CaspaCIDe safety switch, which consists of the CID-binding domain coupled to the signaling domain of caspase-9, an enzyme that is part of the apoptotic pathway.
The goal of this therapy is to allow physicians to more safely perform haplo-HSCTs.
Patients
Dr Algeri and his colleagues have tested BPX-501 in 98 pediatric patients treated at centers in Europe and the US.
Fifty-nine patients had non-malignant conditions, including primary immune deficiency (n=26), thalassemia major (n=8), sickle cell disease (n=5), Diamond-Blackfan anemia (n=2), Swachman-Diamond syndrome (n=1), Fanconi anemia (n=9), hemophagocytic lymphohistiocytosis (n=6), aplastic anemia (n=1), and osteoporosis (n=1).
Thirty-nine patients had malignant conditions, including acute lymphoblastic leukemia (ALL, n=21), acute myeloid leukemia (AML, n=14), myelodysplastic syndromes (MDS, n=3), and non-Hodgkin lymphoma (NHL, n=1).
The patients received BPX-501 after an alpha/beta T-cell-depleted haplo-HSCT. All patients had at least 6 months of follow-up.
Overall results
Ninety-five percent of the patients engrafted (93/98), and the researchers said they observed rapid recovery of T cells, B cells, and immunoglobulins.
At 180 days, the incidence of transplant-related mortality was 5%, and there were no cases of post-transplant lymphoproliferative disorder.
The cumulative incidence of grade 2-4 acute GVHD was 14%. For patients with at least 1 year of follow-up, the cumulative incidence of chronic GVHD at 1 year was 3%.
Eleven patients received rimiducid—10 who had uncontrollable acute GVHD and 1 who developed late acute GVHD. In all of these patients, GVHD resolved and has not recurred.
There were no adverse events associated with BPX-501 or rimiducid.
European cohort
Dr Algeri presented more detailed data on the 61 patients treated at centers in Europe.
Fifteen of these patients had ALL, 10 had AML, 16 had primary immune deficiency, 7 had thalassemia major, 1 had sickle cell disease, 2 had Diamond-Blackfan anemia, 5 had Fanconi anemia, 4 had hemophagocytic lymphohistiocytosis, and 1 had osteoporosis.
Their median age was 4.8 (range, 0.25-17), and 56% were male. The patients received busulfan-based conditioning (41%), total body irradiation (36%), treosulfan-based conditioning (18%), and other conditioning (5%).
Ninety-five percent of the patients had a parent donor, and the other 5% had a sibling donor. The median donor age was 36 (range, 19-50).
The patients’ median time to neutrophil recovery was 15 days (range, 9-75), and their median time to platelet recovery was 10 days (range, 4-64). Their median time to discharge was 25 days (range, 14-122).
The cumulative incidence of acute grade 2-4 GVHD was 9.9%, and the cumulative incidence of acute grade 3-4 GVHD was 3.3%.
There were no cases of transplant-related mortality at 180 days and no cases of extensive chronic GVHD.
“These preliminary data compare favorably to previously published data on matched, unrelated donor transplantation,” Dr Algeri said. “And for this reason, an observational matched, unrelated donor study is being initiated to enable comparison of the safety and efficacy of haploidentical transplantation and BPX-501 infusion to the standard of care for patients without a matched sibling donor.”
MADRID—Updated results of a phase 1/2 study suggest the T-cell product BPX-501 lowers the risks associated with haploidentical hematopoietic stem cell transplant (haplo-HSCT).
In this ongoing study, researchers are testing BPX-501 in pediatric patients undergoing haplo-HSCT to treat a range of hematologic disorders.
Patients treated thus far have experienced rapid engraftment and early hospital discharge, a low rate of acute graft-versus-host disease (GHVD), no extensive chronic GVHD, and a low rate of transplant-related mortality at 180 days.
“The combination of haploidentical transplantation and BPX-501 infusion is an effective strategy for children in need of an allograft lacking a compatible donor,” said study investigator Mattia Algeri, MD, of Ospedale Pediatrico Bambino Gesù in Rome, Italy.
Dr Algeri presented these results during the Presidential Symposium at the 22nd Congress of the European Hematology Association (EHA) as abstract S146.
The research was sponsored by Bellicum Pharmaceuticals, Inc., the company developing BPX-501.
About BPX-501
BPX-501 consists of genetically modified donor T cells incorporating the CaspaCIDe safety switch, which is designed to eliminate the T cells in the event of toxicity.
Rimiducid is used to activate the CaspaCIDe safety switch, which consists of the CID-binding domain coupled to the signaling domain of caspase-9, an enzyme that is part of the apoptotic pathway.
The goal of this therapy is to allow physicians to more safely perform haplo-HSCTs.
Patients
Dr Algeri and his colleagues have tested BPX-501 in 98 pediatric patients treated at centers in Europe and the US.
Fifty-nine patients had non-malignant conditions, including primary immune deficiency (n=26), thalassemia major (n=8), sickle cell disease (n=5), Diamond-Blackfan anemia (n=2), Swachman-Diamond syndrome (n=1), Fanconi anemia (n=9), hemophagocytic lymphohistiocytosis (n=6), aplastic anemia (n=1), and osteoporosis (n=1).
Thirty-nine patients had malignant conditions, including acute lymphoblastic leukemia (ALL, n=21), acute myeloid leukemia (AML, n=14), myelodysplastic syndromes (MDS, n=3), and non-Hodgkin lymphoma (NHL, n=1).
The patients received BPX-501 after an alpha/beta T-cell-depleted haplo-HSCT. All patients had at least 6 months of follow-up.
Overall results
Ninety-five percent of the patients engrafted (93/98), and the researchers said they observed rapid recovery of T cells, B cells, and immunoglobulins.
At 180 days, the incidence of transplant-related mortality was 5%, and there were no cases of post-transplant lymphoproliferative disorder.
The cumulative incidence of grade 2-4 acute GVHD was 14%. For patients with at least 1 year of follow-up, the cumulative incidence of chronic GVHD at 1 year was 3%.
Eleven patients received rimiducid—10 who had uncontrollable acute GVHD and 1 who developed late acute GVHD. In all of these patients, GVHD resolved and has not recurred.
There were no adverse events associated with BPX-501 or rimiducid.
European cohort
Dr Algeri presented more detailed data on the 61 patients treated at centers in Europe.
Fifteen of these patients had ALL, 10 had AML, 16 had primary immune deficiency, 7 had thalassemia major, 1 had sickle cell disease, 2 had Diamond-Blackfan anemia, 5 had Fanconi anemia, 4 had hemophagocytic lymphohistiocytosis, and 1 had osteoporosis.
Their median age was 4.8 (range, 0.25-17), and 56% were male. The patients received busulfan-based conditioning (41%), total body irradiation (36%), treosulfan-based conditioning (18%), and other conditioning (5%).
Ninety-five percent of the patients had a parent donor, and the other 5% had a sibling donor. The median donor age was 36 (range, 19-50).
The patients’ median time to neutrophil recovery was 15 days (range, 9-75), and their median time to platelet recovery was 10 days (range, 4-64). Their median time to discharge was 25 days (range, 14-122).
The cumulative incidence of acute grade 2-4 GVHD was 9.9%, and the cumulative incidence of acute grade 3-4 GVHD was 3.3%.
There were no cases of transplant-related mortality at 180 days and no cases of extensive chronic GVHD.
“These preliminary data compare favorably to previously published data on matched, unrelated donor transplantation,” Dr Algeri said. “And for this reason, an observational matched, unrelated donor study is being initiated to enable comparison of the safety and efficacy of haploidentical transplantation and BPX-501 infusion to the standard of care for patients without a matched sibling donor.”
MADRID—Updated results of a phase 1/2 study suggest the T-cell product BPX-501 lowers the risks associated with haploidentical hematopoietic stem cell transplant (haplo-HSCT).
In this ongoing study, researchers are testing BPX-501 in pediatric patients undergoing haplo-HSCT to treat a range of hematologic disorders.
Patients treated thus far have experienced rapid engraftment and early hospital discharge, a low rate of acute graft-versus-host disease (GHVD), no extensive chronic GVHD, and a low rate of transplant-related mortality at 180 days.
“The combination of haploidentical transplantation and BPX-501 infusion is an effective strategy for children in need of an allograft lacking a compatible donor,” said study investigator Mattia Algeri, MD, of Ospedale Pediatrico Bambino Gesù in Rome, Italy.
Dr Algeri presented these results during the Presidential Symposium at the 22nd Congress of the European Hematology Association (EHA) as abstract S146.
The research was sponsored by Bellicum Pharmaceuticals, Inc., the company developing BPX-501.
About BPX-501
BPX-501 consists of genetically modified donor T cells incorporating the CaspaCIDe safety switch, which is designed to eliminate the T cells in the event of toxicity.
Rimiducid is used to activate the CaspaCIDe safety switch, which consists of the CID-binding domain coupled to the signaling domain of caspase-9, an enzyme that is part of the apoptotic pathway.
The goal of this therapy is to allow physicians to more safely perform haplo-HSCTs.
Patients
Dr Algeri and his colleagues have tested BPX-501 in 98 pediatric patients treated at centers in Europe and the US.
Fifty-nine patients had non-malignant conditions, including primary immune deficiency (n=26), thalassemia major (n=8), sickle cell disease (n=5), Diamond-Blackfan anemia (n=2), Swachman-Diamond syndrome (n=1), Fanconi anemia (n=9), hemophagocytic lymphohistiocytosis (n=6), aplastic anemia (n=1), and osteoporosis (n=1).
Thirty-nine patients had malignant conditions, including acute lymphoblastic leukemia (ALL, n=21), acute myeloid leukemia (AML, n=14), myelodysplastic syndromes (MDS, n=3), and non-Hodgkin lymphoma (NHL, n=1).
The patients received BPX-501 after an alpha/beta T-cell-depleted haplo-HSCT. All patients had at least 6 months of follow-up.
Overall results
Ninety-five percent of the patients engrafted (93/98), and the researchers said they observed rapid recovery of T cells, B cells, and immunoglobulins.
At 180 days, the incidence of transplant-related mortality was 5%, and there were no cases of post-transplant lymphoproliferative disorder.
The cumulative incidence of grade 2-4 acute GVHD was 14%. For patients with at least 1 year of follow-up, the cumulative incidence of chronic GVHD at 1 year was 3%.
Eleven patients received rimiducid—10 who had uncontrollable acute GVHD and 1 who developed late acute GVHD. In all of these patients, GVHD resolved and has not recurred.
There were no adverse events associated with BPX-501 or rimiducid.
European cohort
Dr Algeri presented more detailed data on the 61 patients treated at centers in Europe.
Fifteen of these patients had ALL, 10 had AML, 16 had primary immune deficiency, 7 had thalassemia major, 1 had sickle cell disease, 2 had Diamond-Blackfan anemia, 5 had Fanconi anemia, 4 had hemophagocytic lymphohistiocytosis, and 1 had osteoporosis.
Their median age was 4.8 (range, 0.25-17), and 56% were male. The patients received busulfan-based conditioning (41%), total body irradiation (36%), treosulfan-based conditioning (18%), and other conditioning (5%).
Ninety-five percent of the patients had a parent donor, and the other 5% had a sibling donor. The median donor age was 36 (range, 19-50).
The patients’ median time to neutrophil recovery was 15 days (range, 9-75), and their median time to platelet recovery was 10 days (range, 4-64). Their median time to discharge was 25 days (range, 14-122).
The cumulative incidence of acute grade 2-4 GVHD was 9.9%, and the cumulative incidence of acute grade 3-4 GVHD was 3.3%.
There were no cases of transplant-related mortality at 180 days and no cases of extensive chronic GVHD.
“These preliminary data compare favorably to previously published data on matched, unrelated donor transplantation,” Dr Algeri said. “And for this reason, an observational matched, unrelated donor study is being initiated to enable comparison of the safety and efficacy of haploidentical transplantation and BPX-501 infusion to the standard of care for patients without a matched sibling donor.”
Gene editing aims to recreate beneficial mutation in SCD, beta-thalassemia
MADRID – With some genetic sleight-of-hand, investigators hope to mimic a rare, naturally occurring mutation that protects some patients with beta-thalassemia or sickle-cell disease (SCD) from becoming symptomatic.
Although human studies have yet to begin, investigators in a biotech company report that they can use CRISPR/Cas9 gene editing to recreate the rare condition known as hereditary persistence of fetal hemoglobin, or HPFH, which causes some patients with SCD or beta-thalassemia to continue to produce the fully functional fetal rather than adult form of hemoglobin into adulthood.
To date, there have been no detectable undesirable off-target genetic modifications seen by targeted deep sequencing for the two leading guide RNAs (gRNA) in development, he said at the annual congress of the European Hematology Association.
“Patients with sickle-cell disease and beta-thalassemia are not sick when they are first born, but symptoms develop shortly after birth as the fetal hemoglobin levels decline, and as adult hemoglobin rises,” Dr. Lundberg said.
Fetal hemoglobin has been shown to reduce the risk of sickle events in SCD, and reduce symptoms and morbidity of beta-thalassemia.
“Modest amounts of fetal hemoglobin are beneficial, and more appears to be better,” he said.
In rare instances, the genetic switch to turn off fetal hemoglobin fails, leading to HPFH. It is this rare circumstance that the investigators hope to copy.
CRISPR/Cas9 technology copies a bacterial defense mechanism using clustered regularly interspaced short palindromic (CRISPR) repeats of DNA as a template for adaptive immunity against viruses and plasmids. The system allows bacteria to prevent the activation of invading nucleic acids by effectively snipping out target sequences of foreign DNA.
The investigators plan to harvest hematopoietic stem cells from patients with SCD and beta-thalassemia and use CRISPR/Cas9 technology to modify the cells to express the fetal form of hemoglobin. The reintroduced stem cells would, ideally, proliferate and help protect patients against painful crises and debilitating symptoms of the hemoglobinopathies.
Dr. Lundberg said that to date they have been able to edit blood stem cells with more than 80% on-target efficiency, and that the editing leads to “clinically meaningful” levels of protective fetal hemoglobin, in the range of 30%.
As noted, the investigators have to date seen no evidence of off-target editing that could lead to undesirable or dangerous complications. When introduced into an immunodeficient mouse model (NOD scid gamma, or NSG mice), the edited human cells persisted for long periods.
Finally, the investigators have been able to demonstrate that the modified stem cells are able to differentiate and reconstitute different types of cells in blood.
The company plans to submit a clinical trial application in 2017, and start clinical trials in 2018, Dr. Lundberg said.
At a media briefing where he discussed his research prior to his presentation of data in a symposium, Dr. Lundberg said that to date they have worked only with mouse models and with cells from healthy donors.
He pointed out, however, that there are many thousands of patients with inherited hemoglobin disorders worldwide and beta-thalassemia, and asked “how do you proceed to implement this very expensive treatment?”
Dr. Lundberg acknowledged that the diseases are common in both the developing world and in wealthy countries. He said that the technique relies as much as possible on existing technologies, and pointed out that if the treatment is successful, it’s costs could be at least partially offset by reducing the costs of other forms of therapy.
The work is supported by CRISPR Therapeutics. Dr. Lundberg is an employee and shareholder in the company. Dr. Hagenbeek reported having no relevant conflicts of interest.
MADRID – With some genetic sleight-of-hand, investigators hope to mimic a rare, naturally occurring mutation that protects some patients with beta-thalassemia or sickle-cell disease (SCD) from becoming symptomatic.
Although human studies have yet to begin, investigators in a biotech company report that they can use CRISPR/Cas9 gene editing to recreate the rare condition known as hereditary persistence of fetal hemoglobin, or HPFH, which causes some patients with SCD or beta-thalassemia to continue to produce the fully functional fetal rather than adult form of hemoglobin into adulthood.
To date, there have been no detectable undesirable off-target genetic modifications seen by targeted deep sequencing for the two leading guide RNAs (gRNA) in development, he said at the annual congress of the European Hematology Association.
“Patients with sickle-cell disease and beta-thalassemia are not sick when they are first born, but symptoms develop shortly after birth as the fetal hemoglobin levels decline, and as adult hemoglobin rises,” Dr. Lundberg said.
Fetal hemoglobin has been shown to reduce the risk of sickle events in SCD, and reduce symptoms and morbidity of beta-thalassemia.
“Modest amounts of fetal hemoglobin are beneficial, and more appears to be better,” he said.
In rare instances, the genetic switch to turn off fetal hemoglobin fails, leading to HPFH. It is this rare circumstance that the investigators hope to copy.
CRISPR/Cas9 technology copies a bacterial defense mechanism using clustered regularly interspaced short palindromic (CRISPR) repeats of DNA as a template for adaptive immunity against viruses and plasmids. The system allows bacteria to prevent the activation of invading nucleic acids by effectively snipping out target sequences of foreign DNA.
The investigators plan to harvest hematopoietic stem cells from patients with SCD and beta-thalassemia and use CRISPR/Cas9 technology to modify the cells to express the fetal form of hemoglobin. The reintroduced stem cells would, ideally, proliferate and help protect patients against painful crises and debilitating symptoms of the hemoglobinopathies.
Dr. Lundberg said that to date they have been able to edit blood stem cells with more than 80% on-target efficiency, and that the editing leads to “clinically meaningful” levels of protective fetal hemoglobin, in the range of 30%.
As noted, the investigators have to date seen no evidence of off-target editing that could lead to undesirable or dangerous complications. When introduced into an immunodeficient mouse model (NOD scid gamma, or NSG mice), the edited human cells persisted for long periods.
Finally, the investigators have been able to demonstrate that the modified stem cells are able to differentiate and reconstitute different types of cells in blood.
The company plans to submit a clinical trial application in 2017, and start clinical trials in 2018, Dr. Lundberg said.
At a media briefing where he discussed his research prior to his presentation of data in a symposium, Dr. Lundberg said that to date they have worked only with mouse models and with cells from healthy donors.
He pointed out, however, that there are many thousands of patients with inherited hemoglobin disorders worldwide and beta-thalassemia, and asked “how do you proceed to implement this very expensive treatment?”
Dr. Lundberg acknowledged that the diseases are common in both the developing world and in wealthy countries. He said that the technique relies as much as possible on existing technologies, and pointed out that if the treatment is successful, it’s costs could be at least partially offset by reducing the costs of other forms of therapy.
The work is supported by CRISPR Therapeutics. Dr. Lundberg is an employee and shareholder in the company. Dr. Hagenbeek reported having no relevant conflicts of interest.
MADRID – With some genetic sleight-of-hand, investigators hope to mimic a rare, naturally occurring mutation that protects some patients with beta-thalassemia or sickle-cell disease (SCD) from becoming symptomatic.
Although human studies have yet to begin, investigators in a biotech company report that they can use CRISPR/Cas9 gene editing to recreate the rare condition known as hereditary persistence of fetal hemoglobin, or HPFH, which causes some patients with SCD or beta-thalassemia to continue to produce the fully functional fetal rather than adult form of hemoglobin into adulthood.
To date, there have been no detectable undesirable off-target genetic modifications seen by targeted deep sequencing for the two leading guide RNAs (gRNA) in development, he said at the annual congress of the European Hematology Association.
“Patients with sickle-cell disease and beta-thalassemia are not sick when they are first born, but symptoms develop shortly after birth as the fetal hemoglobin levels decline, and as adult hemoglobin rises,” Dr. Lundberg said.
Fetal hemoglobin has been shown to reduce the risk of sickle events in SCD, and reduce symptoms and morbidity of beta-thalassemia.
“Modest amounts of fetal hemoglobin are beneficial, and more appears to be better,” he said.
In rare instances, the genetic switch to turn off fetal hemoglobin fails, leading to HPFH. It is this rare circumstance that the investigators hope to copy.
CRISPR/Cas9 technology copies a bacterial defense mechanism using clustered regularly interspaced short palindromic (CRISPR) repeats of DNA as a template for adaptive immunity against viruses and plasmids. The system allows bacteria to prevent the activation of invading nucleic acids by effectively snipping out target sequences of foreign DNA.
The investigators plan to harvest hematopoietic stem cells from patients with SCD and beta-thalassemia and use CRISPR/Cas9 technology to modify the cells to express the fetal form of hemoglobin. The reintroduced stem cells would, ideally, proliferate and help protect patients against painful crises and debilitating symptoms of the hemoglobinopathies.
Dr. Lundberg said that to date they have been able to edit blood stem cells with more than 80% on-target efficiency, and that the editing leads to “clinically meaningful” levels of protective fetal hemoglobin, in the range of 30%.
As noted, the investigators have to date seen no evidence of off-target editing that could lead to undesirable or dangerous complications. When introduced into an immunodeficient mouse model (NOD scid gamma, or NSG mice), the edited human cells persisted for long periods.
Finally, the investigators have been able to demonstrate that the modified stem cells are able to differentiate and reconstitute different types of cells in blood.
The company plans to submit a clinical trial application in 2017, and start clinical trials in 2018, Dr. Lundberg said.
At a media briefing where he discussed his research prior to his presentation of data in a symposium, Dr. Lundberg said that to date they have worked only with mouse models and with cells from healthy donors.
He pointed out, however, that there are many thousands of patients with inherited hemoglobin disorders worldwide and beta-thalassemia, and asked “how do you proceed to implement this very expensive treatment?”
Dr. Lundberg acknowledged that the diseases are common in both the developing world and in wealthy countries. He said that the technique relies as much as possible on existing technologies, and pointed out that if the treatment is successful, it’s costs could be at least partially offset by reducing the costs of other forms of therapy.
The work is supported by CRISPR Therapeutics. Dr. Lundberg is an employee and shareholder in the company. Dr. Hagenbeek reported having no relevant conflicts of interest.
AT EHA 2017
Key clinical point: The fetal form of hemoglobin is protective against symptoms of sickle-cell disease (SCD) and beta-thalassemia.
Major finding: Human blood stem cells modified by CRISPR/Cas9 gene editing produced fetal hemoglobin without observable off-target effects.
Data source: Summary of preclinical studies with blood from healthy human volunteers and mouse models.
Disclosures: The work is supported by CRISPR Therapeutics. Dr. Lundberg is an employee and shareholder in the company. Dr. Hagenbeek reported having no relevant conflicts of interest.
Fostamatinib under review by FDA for chronic ITP
The US Food and Drug Administration (FDA) has accepted a new drug application (NDA) for the use of fostamatinib disodium (Tavalisse™) in the treatment of patients with chronic/persistent immune thrombocytopenia (ITP).
Fostamatinib is an oral spleen tyrosine kinase (SYK) inhibitor that investigators believe may address an underlying autoimmune cause of ITP by impeding platelet destruction.
Rigel Pharmaceuticals, the drug’s developer, anticipates an action date by the FDA of April 17, 2018.
The FDA previously granted fostamatinib orphan drug designation.
Data from 3 clinical studies support the new drug application. Study 047 and 048 were randomized placebo-controlled trials, and study 049 was an open-label extension study.
Together with an initial proof of concept study, the application included data on 163 ITP patients. Fostamatinib has been evaluated in over 4,600 individuals across all indications.
The patients enrolled in studies 047 and 048 had been diagnosed with persistent or chronic ITP, had failed at least 1 prior therapy for ITP, and had platelet counts consistently below 30,000/uL.
In both studies, patients were randomized in a 2:1 ratio to receive either fostamatinib or placebo orally twice a day for up to 24 weeks.
Study 047
In this study, 51 patients were randomized to fostamatinib and 25 to placebo.
The median platelet counts at baseline were 15,000/uL and 16,000/uL in the fostamatinib and placebo arms, respectively.
The median age was 57 in both treatment arms. The duration of ITP was 7.5 years (range, 0.6-53) in the fostamatinib arm and 5.5 years (range, 0.4-45) in the placebo arm.
The primary efficacy endpoint in both study 047 and 048 was a stable platelet response, defined as achieving platelet counts greater than 50,000/uL for at least 4 of the 6 scheduled clinic visits between weeks 14 and 24 of treatment.
In study 047, the rate of stable platelet response was significantly higher in the fostamatinib arm than the placebo arm—18% (n=9) and 0%, respectively (P=0.026).
Study 048
Fifty patients were randomized to fostamatinib and 24 to placebo.
Patients’ median platelet counts at baseline were 16,000/uL and 21,000/uL in the fostamatinib and placebo arms, respectively.
The median age was 50 in both treatment arms. The duration of ITP was 8.8 years (range, 0.3-50) in the fostamatinib arm and 10.8 years (range, 0.9-29) in the placebo arm.
In this study, however, the difference in stable platelet response between the 2 arms was not significant—18% (n=9) and 4% (n=1), respectively (P=0.152).
However, when the data from study 047 and 048 were combined, the response rate was significantly higher in the fostamatinib arm than the placebo arm—18% (18/101) and 2% (1/49), respectively (P=0.007).
"The FDA acceptance for filing of our NDA is an exciting milestone for Rigel," Raul Rodriguez, Rigel's president and chief executive officer, said.
The approval of fostamatinib “will provide a new treatment option for patients with chronic or persistent ITP,” he affirmed. “We look forward to working closely with the FDA as they review our submission."
The US Food and Drug Administration (FDA) has accepted a new drug application (NDA) for the use of fostamatinib disodium (Tavalisse™) in the treatment of patients with chronic/persistent immune thrombocytopenia (ITP).
Fostamatinib is an oral spleen tyrosine kinase (SYK) inhibitor that investigators believe may address an underlying autoimmune cause of ITP by impeding platelet destruction.
Rigel Pharmaceuticals, the drug’s developer, anticipates an action date by the FDA of April 17, 2018.
The FDA previously granted fostamatinib orphan drug designation.
Data from 3 clinical studies support the new drug application. Study 047 and 048 were randomized placebo-controlled trials, and study 049 was an open-label extension study.
Together with an initial proof of concept study, the application included data on 163 ITP patients. Fostamatinib has been evaluated in over 4,600 individuals across all indications.
The patients enrolled in studies 047 and 048 had been diagnosed with persistent or chronic ITP, had failed at least 1 prior therapy for ITP, and had platelet counts consistently below 30,000/uL.
In both studies, patients were randomized in a 2:1 ratio to receive either fostamatinib or placebo orally twice a day for up to 24 weeks.
Study 047
In this study, 51 patients were randomized to fostamatinib and 25 to placebo.
The median platelet counts at baseline were 15,000/uL and 16,000/uL in the fostamatinib and placebo arms, respectively.
The median age was 57 in both treatment arms. The duration of ITP was 7.5 years (range, 0.6-53) in the fostamatinib arm and 5.5 years (range, 0.4-45) in the placebo arm.
The primary efficacy endpoint in both study 047 and 048 was a stable platelet response, defined as achieving platelet counts greater than 50,000/uL for at least 4 of the 6 scheduled clinic visits between weeks 14 and 24 of treatment.
In study 047, the rate of stable platelet response was significantly higher in the fostamatinib arm than the placebo arm—18% (n=9) and 0%, respectively (P=0.026).
Study 048
Fifty patients were randomized to fostamatinib and 24 to placebo.
Patients’ median platelet counts at baseline were 16,000/uL and 21,000/uL in the fostamatinib and placebo arms, respectively.
The median age was 50 in both treatment arms. The duration of ITP was 8.8 years (range, 0.3-50) in the fostamatinib arm and 10.8 years (range, 0.9-29) in the placebo arm.
In this study, however, the difference in stable platelet response between the 2 arms was not significant—18% (n=9) and 4% (n=1), respectively (P=0.152).
However, when the data from study 047 and 048 were combined, the response rate was significantly higher in the fostamatinib arm than the placebo arm—18% (18/101) and 2% (1/49), respectively (P=0.007).
"The FDA acceptance for filing of our NDA is an exciting milestone for Rigel," Raul Rodriguez, Rigel's president and chief executive officer, said.
The approval of fostamatinib “will provide a new treatment option for patients with chronic or persistent ITP,” he affirmed. “We look forward to working closely with the FDA as they review our submission."
The US Food and Drug Administration (FDA) has accepted a new drug application (NDA) for the use of fostamatinib disodium (Tavalisse™) in the treatment of patients with chronic/persistent immune thrombocytopenia (ITP).
Fostamatinib is an oral spleen tyrosine kinase (SYK) inhibitor that investigators believe may address an underlying autoimmune cause of ITP by impeding platelet destruction.
Rigel Pharmaceuticals, the drug’s developer, anticipates an action date by the FDA of April 17, 2018.
The FDA previously granted fostamatinib orphan drug designation.
Data from 3 clinical studies support the new drug application. Study 047 and 048 were randomized placebo-controlled trials, and study 049 was an open-label extension study.
Together with an initial proof of concept study, the application included data on 163 ITP patients. Fostamatinib has been evaluated in over 4,600 individuals across all indications.
The patients enrolled in studies 047 and 048 had been diagnosed with persistent or chronic ITP, had failed at least 1 prior therapy for ITP, and had platelet counts consistently below 30,000/uL.
In both studies, patients were randomized in a 2:1 ratio to receive either fostamatinib or placebo orally twice a day for up to 24 weeks.
Study 047
In this study, 51 patients were randomized to fostamatinib and 25 to placebo.
The median platelet counts at baseline were 15,000/uL and 16,000/uL in the fostamatinib and placebo arms, respectively.
The median age was 57 in both treatment arms. The duration of ITP was 7.5 years (range, 0.6-53) in the fostamatinib arm and 5.5 years (range, 0.4-45) in the placebo arm.
The primary efficacy endpoint in both study 047 and 048 was a stable platelet response, defined as achieving platelet counts greater than 50,000/uL for at least 4 of the 6 scheduled clinic visits between weeks 14 and 24 of treatment.
In study 047, the rate of stable platelet response was significantly higher in the fostamatinib arm than the placebo arm—18% (n=9) and 0%, respectively (P=0.026).
Study 048
Fifty patients were randomized to fostamatinib and 24 to placebo.
Patients’ median platelet counts at baseline were 16,000/uL and 21,000/uL in the fostamatinib and placebo arms, respectively.
The median age was 50 in both treatment arms. The duration of ITP was 8.8 years (range, 0.3-50) in the fostamatinib arm and 10.8 years (range, 0.9-29) in the placebo arm.
In this study, however, the difference in stable platelet response between the 2 arms was not significant—18% (n=9) and 4% (n=1), respectively (P=0.152).
However, when the data from study 047 and 048 were combined, the response rate was significantly higher in the fostamatinib arm than the placebo arm—18% (18/101) and 2% (1/49), respectively (P=0.007).
"The FDA acceptance for filing of our NDA is an exciting milestone for Rigel," Raul Rodriguez, Rigel's president and chief executive officer, said.
The approval of fostamatinib “will provide a new treatment option for patients with chronic or persistent ITP,” he affirmed. “We look forward to working closely with the FDA as they review our submission."
Ferrous sulfate bests iron complex in treating IDA in infants, young kids
A trial comparing ferrous sulfate with iron polysaccharide complex to treat infants and young children with nutritional iron-deficiency anemia (IDA) has shown ferrous sulfate to be more effective at raising hemoglobin levels in this population, according to researchers.
Dozens of oral iron supplements exist for IDA treatment, ferrous sulfate being the most commonly used. Iron polysaccharide complex, however, may be better tolerated.
Investigators undertook the BESTIRON study (NCT01904864) to determine whether the iron complex was more efficacious than ferrous sulfate in increasing hemoglobin concentrations in infants and young children aged 9 to 48 months.
Up to 3% of children aged 1 to 2 years in the United States have IDA, as do millions worldwide. IDA is associated with impaired neurodevelopment in the young.
Inadequate dietary iron intake in this group is the most common cause of IDA. It most often results from excessive cow milk consumption and/or prolonged breastfeeding without appropriate iron supplementation.
For this study, investigators randomized 80 infants and young children with nutritional IDA to receive 3 mg/kg of ferrous sulfate (n=40) or iron complex (n=40) drops once daily for 12 weeks.
Patients had to have hemoglobin concentrations of 10 g/dL or less, mean corpuscular volumes of 70 fL or less, reticulocyte hemoglobin equivalents of 25 pg or less, and either serum ferritin level of 15 ng/mL or less or total iron-binding capacity of 425 μg/dL or greater.
And they could have no clinical or laboratory evidence of other causes of anemia.
All 80 patients were included in the primary analysis evaluating change in hemoglobin concentration during the 12 weeks after starting oral iron therapy.
Patient characteristics
Patient characteristics were similar between the groups. The mean age was 23 months and 55% were male.
Most patients (61%) were Hispanic white, 9% were non-Hispanic white, and 11% were black.
Ten patients in the ferrous sulfate group and 8 in the iron complex group had received a packed red blood cell transfusion prior to study enrollment.
Results
Fifty-nine patients completed all study visits, 28 in the ferrous sulfate group and 31 in the iron complex group.
Patients’ mean hemoglobin level in the ferrous sulfate group increased from 7.9 g/dL to 11.9 g/dL over the 12 weeks. In the iron complex group, the patients’ hemoglobin level increased from 7.7 g/dL to 11.1 g/dL.
Using a linear mixed model, the primary outcome demonstrated a significant difference in the change in hemoglobin concentration of 1.0 g/dL (95% CI, 0.4-1.6; P < .001) between the groups, favoring ferrous sulfate.
IDA completely resolved in 8 of 28 (29%) patients in the ferrous sulfate group and 2 of 31 (6%) in the iron complex group (P=0.04).
However, successful administration of the supplement—meaning he child did not spit out the medication—was higher in the iron complex group (94%) than the iron sulfate group (82%), P=0.009.
The median serum ferritin level increased from 3.0 ng/mL to 15.6 ng/mL in the ferrous sulfate arm, which was significantly better than in the iron complex arm, which increased from 2.0 ng/mL to 7.5 ng/mL, P<0.001.
And the mean total iron binding capacity significantly increased in the ferrous sulfate group compared with the iron oxide group (P<0.001).
Safety
The investigators reported that patients treated with iron complex had significantly more diahrrea, while patients treated with ferrous sulfate had more vomiting, although the latter was not statistically significant.
A gastrointestinal adverse effect profile created at the end of the study showed no significant differences between the groups.
The investigators noted a few limitations of the study.
First, it was conducted in a single tertiary-care children’s hospital, the Children’s Medical Center in Dallas, Texas.
Second, a disproportionate number of patients were from lower income and minority families and frequently had severe anemia, with approximately 23% requiring blood transfusion prior to study start.
And third, the trial had a high lost-to-follow-up rate of 25% at the final visit.
So the results may not be generalizable to the general pediatric population.
Nevertheless, the investigators concluded, “Once daily, low-dose ferrous sulfate should be considered for children with nutritional iron-deficiency anemia.”
The team reported their findings in JAMA.
The study was an investigator-initiated trial with sponsorship from Gensavis Pharmaceuticals LLC, the manufacturer of the iron polysaccharide complex used in the trial. The company provided funding for both trial drugs.
The study received additional grant support from the National Center for Advancing Translational Sciences and the National Heart, Lung, and Blood Institute.
A trial comparing ferrous sulfate with iron polysaccharide complex to treat infants and young children with nutritional iron-deficiency anemia (IDA) has shown ferrous sulfate to be more effective at raising hemoglobin levels in this population, according to researchers.
Dozens of oral iron supplements exist for IDA treatment, ferrous sulfate being the most commonly used. Iron polysaccharide complex, however, may be better tolerated.
Investigators undertook the BESTIRON study (NCT01904864) to determine whether the iron complex was more efficacious than ferrous sulfate in increasing hemoglobin concentrations in infants and young children aged 9 to 48 months.
Up to 3% of children aged 1 to 2 years in the United States have IDA, as do millions worldwide. IDA is associated with impaired neurodevelopment in the young.
Inadequate dietary iron intake in this group is the most common cause of IDA. It most often results from excessive cow milk consumption and/or prolonged breastfeeding without appropriate iron supplementation.
For this study, investigators randomized 80 infants and young children with nutritional IDA to receive 3 mg/kg of ferrous sulfate (n=40) or iron complex (n=40) drops once daily for 12 weeks.
Patients had to have hemoglobin concentrations of 10 g/dL or less, mean corpuscular volumes of 70 fL or less, reticulocyte hemoglobin equivalents of 25 pg or less, and either serum ferritin level of 15 ng/mL or less or total iron-binding capacity of 425 μg/dL or greater.
And they could have no clinical or laboratory evidence of other causes of anemia.
All 80 patients were included in the primary analysis evaluating change in hemoglobin concentration during the 12 weeks after starting oral iron therapy.
Patient characteristics
Patient characteristics were similar between the groups. The mean age was 23 months and 55% were male.
Most patients (61%) were Hispanic white, 9% were non-Hispanic white, and 11% were black.
Ten patients in the ferrous sulfate group and 8 in the iron complex group had received a packed red blood cell transfusion prior to study enrollment.
Results
Fifty-nine patients completed all study visits, 28 in the ferrous sulfate group and 31 in the iron complex group.
Patients’ mean hemoglobin level in the ferrous sulfate group increased from 7.9 g/dL to 11.9 g/dL over the 12 weeks. In the iron complex group, the patients’ hemoglobin level increased from 7.7 g/dL to 11.1 g/dL.
Using a linear mixed model, the primary outcome demonstrated a significant difference in the change in hemoglobin concentration of 1.0 g/dL (95% CI, 0.4-1.6; P < .001) between the groups, favoring ferrous sulfate.
IDA completely resolved in 8 of 28 (29%) patients in the ferrous sulfate group and 2 of 31 (6%) in the iron complex group (P=0.04).
However, successful administration of the supplement—meaning he child did not spit out the medication—was higher in the iron complex group (94%) than the iron sulfate group (82%), P=0.009.
The median serum ferritin level increased from 3.0 ng/mL to 15.6 ng/mL in the ferrous sulfate arm, which was significantly better than in the iron complex arm, which increased from 2.0 ng/mL to 7.5 ng/mL, P<0.001.
And the mean total iron binding capacity significantly increased in the ferrous sulfate group compared with the iron oxide group (P<0.001).
Safety
The investigators reported that patients treated with iron complex had significantly more diahrrea, while patients treated with ferrous sulfate had more vomiting, although the latter was not statistically significant.
A gastrointestinal adverse effect profile created at the end of the study showed no significant differences between the groups.
The investigators noted a few limitations of the study.
First, it was conducted in a single tertiary-care children’s hospital, the Children’s Medical Center in Dallas, Texas.
Second, a disproportionate number of patients were from lower income and minority families and frequently had severe anemia, with approximately 23% requiring blood transfusion prior to study start.
And third, the trial had a high lost-to-follow-up rate of 25% at the final visit.
So the results may not be generalizable to the general pediatric population.
Nevertheless, the investigators concluded, “Once daily, low-dose ferrous sulfate should be considered for children with nutritional iron-deficiency anemia.”
The team reported their findings in JAMA.
The study was an investigator-initiated trial with sponsorship from Gensavis Pharmaceuticals LLC, the manufacturer of the iron polysaccharide complex used in the trial. The company provided funding for both trial drugs.
The study received additional grant support from the National Center for Advancing Translational Sciences and the National Heart, Lung, and Blood Institute.
A trial comparing ferrous sulfate with iron polysaccharide complex to treat infants and young children with nutritional iron-deficiency anemia (IDA) has shown ferrous sulfate to be more effective at raising hemoglobin levels in this population, according to researchers.
Dozens of oral iron supplements exist for IDA treatment, ferrous sulfate being the most commonly used. Iron polysaccharide complex, however, may be better tolerated.
Investigators undertook the BESTIRON study (NCT01904864) to determine whether the iron complex was more efficacious than ferrous sulfate in increasing hemoglobin concentrations in infants and young children aged 9 to 48 months.
Up to 3% of children aged 1 to 2 years in the United States have IDA, as do millions worldwide. IDA is associated with impaired neurodevelopment in the young.
Inadequate dietary iron intake in this group is the most common cause of IDA. It most often results from excessive cow milk consumption and/or prolonged breastfeeding without appropriate iron supplementation.
For this study, investigators randomized 80 infants and young children with nutritional IDA to receive 3 mg/kg of ferrous sulfate (n=40) or iron complex (n=40) drops once daily for 12 weeks.
Patients had to have hemoglobin concentrations of 10 g/dL or less, mean corpuscular volumes of 70 fL or less, reticulocyte hemoglobin equivalents of 25 pg or less, and either serum ferritin level of 15 ng/mL or less or total iron-binding capacity of 425 μg/dL or greater.
And they could have no clinical or laboratory evidence of other causes of anemia.
All 80 patients were included in the primary analysis evaluating change in hemoglobin concentration during the 12 weeks after starting oral iron therapy.
Patient characteristics
Patient characteristics were similar between the groups. The mean age was 23 months and 55% were male.
Most patients (61%) were Hispanic white, 9% were non-Hispanic white, and 11% were black.
Ten patients in the ferrous sulfate group and 8 in the iron complex group had received a packed red blood cell transfusion prior to study enrollment.
Results
Fifty-nine patients completed all study visits, 28 in the ferrous sulfate group and 31 in the iron complex group.
Patients’ mean hemoglobin level in the ferrous sulfate group increased from 7.9 g/dL to 11.9 g/dL over the 12 weeks. In the iron complex group, the patients’ hemoglobin level increased from 7.7 g/dL to 11.1 g/dL.
Using a linear mixed model, the primary outcome demonstrated a significant difference in the change in hemoglobin concentration of 1.0 g/dL (95% CI, 0.4-1.6; P < .001) between the groups, favoring ferrous sulfate.
IDA completely resolved in 8 of 28 (29%) patients in the ferrous sulfate group and 2 of 31 (6%) in the iron complex group (P=0.04).
However, successful administration of the supplement—meaning he child did not spit out the medication—was higher in the iron complex group (94%) than the iron sulfate group (82%), P=0.009.
The median serum ferritin level increased from 3.0 ng/mL to 15.6 ng/mL in the ferrous sulfate arm, which was significantly better than in the iron complex arm, which increased from 2.0 ng/mL to 7.5 ng/mL, P<0.001.
And the mean total iron binding capacity significantly increased in the ferrous sulfate group compared with the iron oxide group (P<0.001).
Safety
The investigators reported that patients treated with iron complex had significantly more diahrrea, while patients treated with ferrous sulfate had more vomiting, although the latter was not statistically significant.
A gastrointestinal adverse effect profile created at the end of the study showed no significant differences between the groups.
The investigators noted a few limitations of the study.
First, it was conducted in a single tertiary-care children’s hospital, the Children’s Medical Center in Dallas, Texas.
Second, a disproportionate number of patients were from lower income and minority families and frequently had severe anemia, with approximately 23% requiring blood transfusion prior to study start.
And third, the trial had a high lost-to-follow-up rate of 25% at the final visit.
So the results may not be generalizable to the general pediatric population.
Nevertheless, the investigators concluded, “Once daily, low-dose ferrous sulfate should be considered for children with nutritional iron-deficiency anemia.”
The team reported their findings in JAMA.
The study was an investigator-initiated trial with sponsorship from Gensavis Pharmaceuticals LLC, the manufacturer of the iron polysaccharide complex used in the trial. The company provided funding for both trial drugs.
The study received additional grant support from the National Center for Advancing Translational Sciences and the National Heart, Lung, and Blood Institute.
BM-MSCs may be an option for AA patients refractory to IST
Researchers report that infusions of bone marrow-derived mesenchymal stromal cells (BM-MSCs) may be a treatment option for patients with aplastic anemia (AA) who are refractory to immunosuppressive therapy (IST).
They conducted a phase 2, non-comparative multicenter study to assess the safety and efficacy of this approach and found that after 12 months, 28.4% of patients responded, with 6.8% achieving a complete response (CR) and 21.6% a partial response (PR).
The trial involved 74 patients at 7 centers in China. The research team reported its findings in Stem Cells Translational Medicine.
About 30% to 40% of patients with severe AA (sAA) don’t respond well to IST and continue to have abnormally low levels of red blood cells, white blood cells, and platelets.
The benefit of treatment with BM-MSCs is they support hematopoiesis, express low levels of major histocompatibility (MHC)-I, and lack expression of MHC-II surface molecules.
And BM-MSCs have been reported to cure diseases, including graft-versus-host disease, arthritis, lupus, and other immune and non-immune disorders.
The current study, led by Yan Pang, MD, and Yang Xiao, MD, PhD, of Guangzhou General Hospital of Guangzhou Military Command in China, is based on their previous data evaluating intravenous administration of MSCs from a related donor in 18 patients with refractory AA.
This earlier data showed that 33% of patients with AA refractory to IST achieved a CR or PR to BM-MSC treatment.
So the team undertook to further investigate the use of BM-MSCs in AA.
Study design
Each of the 74 patients received 4 doses of BM-MSCs over a period of 4 weeks. If patients responded after the first month, they continued to receive 4 doses.
Investigators obtained the BM-MSCs from 74 healthy donors—48 males and 26 females. Forty were related donors, 27 haploidentical donors, and 7 unrelated donors.
Patients with AA by standard criteria had to be 16 years or older, had an incomplete response to antithymocyte globulin (ATG) and cyclosporine for at leas 6 months or cyclosporine alone for at least 12 months, did not have a donor available for bone marrow transplantation, and had at least one of the following: hemoglobin <70 g/L, neutrophilic granulocytes <1 × 109/L, or platelet count <30 × 109/L.
Almost half the patients (47%) were between 20 and 40 years, 54% were male, and 32% had severe aplastic anemia.
Patients’ previous therapy for aplastic anemia included cyclosporine and andriol (65%) cyclosporine and ATG (19%), and cyclosporine (16%).
Patients could continue cyclosporine, but no immunosuppressive agents were permitted.
Fifty-three patients (71.6%) completed 1 course of therapy, and 21 patients (18.4%) completed 2 courses.
Response
At 1 year, the overall response rate was 28.4% (n=21) and the PR rate was 21.6% (n=16).
The median time to a leukocyte response was 19 days (range, 11 – 29), to an erythrocyte response 17 days (range, 12 – 25), and to a megakaryocyte response 31 days (range, 26 – 84).
Ten of the patients with hematologic response had normalization of cellularity for more than 1 year.
The median follow-up among survivors was 17 months (range, 3 – 24). The 2-year overall survival was 87.8%.
Three patients progressed to myelodysplasia, 1 with refractory anemia with excess blasts (RAEB)-I and 2 with RAEB-II.
The median time to progression was 11 months (range, 8 – 12).
Nine patients died, all of whom had severe AA. One patient with RAEB-II died of disease progression, two patients died of intracranial hemorrhage, and six patients died of serious infection.
Safety
Adverse events included grade 1 (n=5) and grade 2 (n=2) fever. Two of these patients also had grade 1 headache.
The investigators observed no other adverse events.
Response predictors
The investigators determined that 2 factors predicted response in patients: prior treatment with antithymocyte globulin (ATG) and absence of infection throughout the treatment.
The odds ratio for patients treated with ATG was 1.41 (95% CI: -0.50, 3.31) and for patients without infection, 2.19 (95% CI: 0.50, 3.87).
“Our study strongly indicates that MSC infusion is a promising therapy for severe AA," Dr Pang said, “but improved MSC cultures in vitro and the MSC doses need further study to maximize their therapeutic potential."
Researchers report that infusions of bone marrow-derived mesenchymal stromal cells (BM-MSCs) may be a treatment option for patients with aplastic anemia (AA) who are refractory to immunosuppressive therapy (IST).
They conducted a phase 2, non-comparative multicenter study to assess the safety and efficacy of this approach and found that after 12 months, 28.4% of patients responded, with 6.8% achieving a complete response (CR) and 21.6% a partial response (PR).
The trial involved 74 patients at 7 centers in China. The research team reported its findings in Stem Cells Translational Medicine.
About 30% to 40% of patients with severe AA (sAA) don’t respond well to IST and continue to have abnormally low levels of red blood cells, white blood cells, and platelets.
The benefit of treatment with BM-MSCs is they support hematopoiesis, express low levels of major histocompatibility (MHC)-I, and lack expression of MHC-II surface molecules.
And BM-MSCs have been reported to cure diseases, including graft-versus-host disease, arthritis, lupus, and other immune and non-immune disorders.
The current study, led by Yan Pang, MD, and Yang Xiao, MD, PhD, of Guangzhou General Hospital of Guangzhou Military Command in China, is based on their previous data evaluating intravenous administration of MSCs from a related donor in 18 patients with refractory AA.
This earlier data showed that 33% of patients with AA refractory to IST achieved a CR or PR to BM-MSC treatment.
So the team undertook to further investigate the use of BM-MSCs in AA.
Study design
Each of the 74 patients received 4 doses of BM-MSCs over a period of 4 weeks. If patients responded after the first month, they continued to receive 4 doses.
Investigators obtained the BM-MSCs from 74 healthy donors—48 males and 26 females. Forty were related donors, 27 haploidentical donors, and 7 unrelated donors.
Patients with AA by standard criteria had to be 16 years or older, had an incomplete response to antithymocyte globulin (ATG) and cyclosporine for at leas 6 months or cyclosporine alone for at least 12 months, did not have a donor available for bone marrow transplantation, and had at least one of the following: hemoglobin <70 g/L, neutrophilic granulocytes <1 × 109/L, or platelet count <30 × 109/L.
Almost half the patients (47%) were between 20 and 40 years, 54% were male, and 32% had severe aplastic anemia.
Patients’ previous therapy for aplastic anemia included cyclosporine and andriol (65%) cyclosporine and ATG (19%), and cyclosporine (16%).
Patients could continue cyclosporine, but no immunosuppressive agents were permitted.
Fifty-three patients (71.6%) completed 1 course of therapy, and 21 patients (18.4%) completed 2 courses.
Response
At 1 year, the overall response rate was 28.4% (n=21) and the PR rate was 21.6% (n=16).
The median time to a leukocyte response was 19 days (range, 11 – 29), to an erythrocyte response 17 days (range, 12 – 25), and to a megakaryocyte response 31 days (range, 26 – 84).
Ten of the patients with hematologic response had normalization of cellularity for more than 1 year.
The median follow-up among survivors was 17 months (range, 3 – 24). The 2-year overall survival was 87.8%.
Three patients progressed to myelodysplasia, 1 with refractory anemia with excess blasts (RAEB)-I and 2 with RAEB-II.
The median time to progression was 11 months (range, 8 – 12).
Nine patients died, all of whom had severe AA. One patient with RAEB-II died of disease progression, two patients died of intracranial hemorrhage, and six patients died of serious infection.
Safety
Adverse events included grade 1 (n=5) and grade 2 (n=2) fever. Two of these patients also had grade 1 headache.
The investigators observed no other adverse events.
Response predictors
The investigators determined that 2 factors predicted response in patients: prior treatment with antithymocyte globulin (ATG) and absence of infection throughout the treatment.
The odds ratio for patients treated with ATG was 1.41 (95% CI: -0.50, 3.31) and for patients without infection, 2.19 (95% CI: 0.50, 3.87).
“Our study strongly indicates that MSC infusion is a promising therapy for severe AA," Dr Pang said, “but improved MSC cultures in vitro and the MSC doses need further study to maximize their therapeutic potential."
Researchers report that infusions of bone marrow-derived mesenchymal stromal cells (BM-MSCs) may be a treatment option for patients with aplastic anemia (AA) who are refractory to immunosuppressive therapy (IST).
They conducted a phase 2, non-comparative multicenter study to assess the safety and efficacy of this approach and found that after 12 months, 28.4% of patients responded, with 6.8% achieving a complete response (CR) and 21.6% a partial response (PR).
The trial involved 74 patients at 7 centers in China. The research team reported its findings in Stem Cells Translational Medicine.
About 30% to 40% of patients with severe AA (sAA) don’t respond well to IST and continue to have abnormally low levels of red blood cells, white blood cells, and platelets.
The benefit of treatment with BM-MSCs is they support hematopoiesis, express low levels of major histocompatibility (MHC)-I, and lack expression of MHC-II surface molecules.
And BM-MSCs have been reported to cure diseases, including graft-versus-host disease, arthritis, lupus, and other immune and non-immune disorders.
The current study, led by Yan Pang, MD, and Yang Xiao, MD, PhD, of Guangzhou General Hospital of Guangzhou Military Command in China, is based on their previous data evaluating intravenous administration of MSCs from a related donor in 18 patients with refractory AA.
This earlier data showed that 33% of patients with AA refractory to IST achieved a CR or PR to BM-MSC treatment.
So the team undertook to further investigate the use of BM-MSCs in AA.
Study design
Each of the 74 patients received 4 doses of BM-MSCs over a period of 4 weeks. If patients responded after the first month, they continued to receive 4 doses.
Investigators obtained the BM-MSCs from 74 healthy donors—48 males and 26 females. Forty were related donors, 27 haploidentical donors, and 7 unrelated donors.
Patients with AA by standard criteria had to be 16 years or older, had an incomplete response to antithymocyte globulin (ATG) and cyclosporine for at leas 6 months or cyclosporine alone for at least 12 months, did not have a donor available for bone marrow transplantation, and had at least one of the following: hemoglobin <70 g/L, neutrophilic granulocytes <1 × 109/L, or platelet count <30 × 109/L.
Almost half the patients (47%) were between 20 and 40 years, 54% were male, and 32% had severe aplastic anemia.
Patients’ previous therapy for aplastic anemia included cyclosporine and andriol (65%) cyclosporine and ATG (19%), and cyclosporine (16%).
Patients could continue cyclosporine, but no immunosuppressive agents were permitted.
Fifty-three patients (71.6%) completed 1 course of therapy, and 21 patients (18.4%) completed 2 courses.
Response
At 1 year, the overall response rate was 28.4% (n=21) and the PR rate was 21.6% (n=16).
The median time to a leukocyte response was 19 days (range, 11 – 29), to an erythrocyte response 17 days (range, 12 – 25), and to a megakaryocyte response 31 days (range, 26 – 84).
Ten of the patients with hematologic response had normalization of cellularity for more than 1 year.
The median follow-up among survivors was 17 months (range, 3 – 24). The 2-year overall survival was 87.8%.
Three patients progressed to myelodysplasia, 1 with refractory anemia with excess blasts (RAEB)-I and 2 with RAEB-II.
The median time to progression was 11 months (range, 8 – 12).
Nine patients died, all of whom had severe AA. One patient with RAEB-II died of disease progression, two patients died of intracranial hemorrhage, and six patients died of serious infection.
Safety
Adverse events included grade 1 (n=5) and grade 2 (n=2) fever. Two of these patients also had grade 1 headache.
The investigators observed no other adverse events.
Response predictors
The investigators determined that 2 factors predicted response in patients: prior treatment with antithymocyte globulin (ATG) and absence of infection throughout the treatment.
The odds ratio for patients treated with ATG was 1.41 (95% CI: -0.50, 3.31) and for patients without infection, 2.19 (95% CI: 0.50, 3.87).
“Our study strongly indicates that MSC infusion is a promising therapy for severe AA," Dr Pang said, “but improved MSC cultures in vitro and the MSC doses need further study to maximize their therapeutic potential."