Anemia

Red blood cells

Image courtesy of NHLBI

The US Food and Drug Administration (FDA) has approved the use of a powder formulation of ferric pyrophosphate citrate (Triferic powder packet) to maintain hemoglobin in adult patients with hemodialysis-dependent chronic kidney disease.

The FDA previously approved ferric pyrophosphate citrate solution (Triferic) in ampule form. It is an iron-replacement drug intended to treat anemia in chronic kidney disease patients receiving hemodialysis.

Triferic is delivered to hemodialysis patients via dialysate, replacing the ongoing iron loss that occurs during their dialysis treatment. The drug is added to the bicarbonate concentrate on-site at the dialysis clinic.

Once in dialysate, Triferic crosses the dialyzer membrane and enters the blood, where it immediately binds to transferrin and is transported to the erythroid precursor cells to be incorporated into hemoglobin.

Triferic is designed to deliver sufficient iron to the bone marrow and maintain hemoglobin without increasing iron stores.

“We are pleased to obtain this FDA approval for the Triferic powder packet,” said Robert L. Chioini, founder, chairman, and chief executive officer of Rockwell Medical, Inc., makers of Triferic.

“The Triferic powder packet is similar to the size of a packet of sugar. It is much smaller and lighter than the current Triferic liquid ampule, and it enables us to place 3-times greater the number of units in an even smaller carton.”

“This presentation is much more convenient for customers, as it reduces storage space and requires fewer reorders to maintain inventory. We expect it to be commercially available shortly.”

Red blood cells

Image courtesy of NHLBI

The US Food and Drug Administration (FDA) has approved the use of a powder formulation of ferric pyrophosphate citrate (Triferic powder packet) to maintain hemoglobin in adult patients with hemodialysis-dependent chronic kidney disease.

The FDA previously approved ferric pyrophosphate citrate solution (Triferic) in ampule form. It is an iron-replacement drug intended to treat anemia in chronic kidney disease patients receiving hemodialysis.

Triferic is delivered to hemodialysis patients via dialysate, replacing the ongoing iron loss that occurs during their dialysis treatment. The drug is added to the bicarbonate concentrate on-site at the dialysis clinic.

Once in dialysate, Triferic crosses the dialyzer membrane and enters the blood, where it immediately binds to transferrin and is transported to the erythroid precursor cells to be incorporated into hemoglobin.

Triferic is designed to deliver sufficient iron to the bone marrow and maintain hemoglobin without increasing iron stores.

“We are pleased to obtain this FDA approval for the Triferic powder packet,” said Robert L. Chioini, founder, chairman, and chief executive officer of Rockwell Medical, Inc., makers of Triferic.

“The Triferic powder packet is similar to the size of a packet of sugar. It is much smaller and lighter than the current Triferic liquid ampule, and it enables us to place 3-times greater the number of units in an even smaller carton.”

“This presentation is much more convenient for customers, as it reduces storage space and requires fewer reorders to maintain inventory. We expect it to be commercially available shortly.”

Red blood cells

Image courtesy of NHLBI

The US Food and Drug Administration (FDA) has approved the use of a powder formulation of ferric pyrophosphate citrate (Triferic powder packet) to maintain hemoglobin in adult patients with hemodialysis-dependent chronic kidney disease.

The FDA previously approved ferric pyrophosphate citrate solution (Triferic) in ampule form. It is an iron-replacement drug intended to treat anemia in chronic kidney disease patients receiving hemodialysis.

Triferic is delivered to hemodialysis patients via dialysate, replacing the ongoing iron loss that occurs during their dialysis treatment. The drug is added to the bicarbonate concentrate on-site at the dialysis clinic.

Once in dialysate, Triferic crosses the dialyzer membrane and enters the blood, where it immediately binds to transferrin and is transported to the erythroid precursor cells to be incorporated into hemoglobin.

Triferic is designed to deliver sufficient iron to the bone marrow and maintain hemoglobin without increasing iron stores.

“We are pleased to obtain this FDA approval for the Triferic powder packet,” said Robert L. Chioini, founder, chairman, and chief executive officer of Rockwell Medical, Inc., makers of Triferic.

“The Triferic powder packet is similar to the size of a packet of sugar. It is much smaller and lighter than the current Triferic liquid ampule, and it enables us to place 3-times greater the number of units in an even smaller carton.”

“This presentation is much more convenient for customers, as it reduces storage space and requires fewer reorders to maintain inventory. We expect it to be commercially available shortly.”

Red blood cells

Researchers say they have used a rational design approach to create a safer variant of the drug erythropoietin (EPO).

This “targeted EPO” effectively stimulated red blood cell production in mice and had a minimal impact on platelets.

The team believes this approach could allow for the use of higher restorative doses of EPO without platelet-mediated side effects, and it might improve drug pharmacokinetics.

Devin Burrill, PhD, of the Wyss Institute for Biologically Inspired Engineering at Harvard University in Boston, Massachusetts, and his colleagues described the approach in PNAS.

The researchers noted that EPO has been widely used to treat anemia, but the drug also poses a risk of thrombotic complications. To combat this problem, the team set out to design a more effective, multi-part drug molecule.

“Compared to currently available EPO drugs, our molecule is engineered to prevent EPO from binding to and activating cells that promote side effects such as blood clotting or tumor growth,” said Jeffrey Way, PhD, also of the Wyss Institute.

“This cell-targeted EPO approach demonstrates a new theoretical basis for the rational design of engineered protein fusion drugs.”

To create their drug, the researchers first mutated EPO to reduce its ability to bind to EPO receptors.

Then, using a chain of amino acids as a flexible linker, they attached mutated EPO to an antibody fragment that specifically binds the human red blood cell marker glycophorin A (huGYPA). This antibody fragment binds to red blood cell precursors while avoiding other types of blood cells.

When the team’s fusion protein molecules were delivered to huGYPA transgenic mice, the antibody fragments piloted toward and bound to the membranes of red blood cell precursors, towing along EPO molecules on the other end of their linkers.

In such close proximity to the surface of the cells, a high concentration of tethered EPO bounced around until it ultimately toggled into place on the cells’ receptors. In this way, red blood cell production was increased with only minimal effects on platelets.

“Our rational design strategy is unique compared to current industry approaches,” Dr Burrill said. “Our goal is to use our method to advance predictive drug design and minimize the time between drug concept and commercialization.”

“The principles of synthetic biology influenced our efforts,” added James Collins, PhD, of the Wyss Institute.

“In drug development, the focus is typically on increasing the strength of interaction with a drug target, but, here, we found that weakening an interaction was useful. This illustrates how we need to adopt alternative, non-traditional approaches if we want to build complex, multi-part therapeutics.”

The researchers said this specific, cell-targeted approach could be applied quite broadly. In addition to “targeted EPO,” the team has developed “targeted interferon-alfa.”

Red blood cells

Researchers say they have used a rational design approach to create a safer variant of the drug erythropoietin (EPO).

This “targeted EPO” effectively stimulated red blood cell production in mice and had a minimal impact on platelets.

The team believes this approach could allow for the use of higher restorative doses of EPO without platelet-mediated side effects, and it might improve drug pharmacokinetics.

Devin Burrill, PhD, of the Wyss Institute for Biologically Inspired Engineering at Harvard University in Boston, Massachusetts, and his colleagues described the approach in PNAS.

The researchers noted that EPO has been widely used to treat anemia, but the drug also poses a risk of thrombotic complications. To combat this problem, the team set out to design a more effective, multi-part drug molecule.

“Compared to currently available EPO drugs, our molecule is engineered to prevent EPO from binding to and activating cells that promote side effects such as blood clotting or tumor growth,” said Jeffrey Way, PhD, also of the Wyss Institute.

“This cell-targeted EPO approach demonstrates a new theoretical basis for the rational design of engineered protein fusion drugs.”

To create their drug, the researchers first mutated EPO to reduce its ability to bind to EPO receptors.

Then, using a chain of amino acids as a flexible linker, they attached mutated EPO to an antibody fragment that specifically binds the human red blood cell marker glycophorin A (huGYPA). This antibody fragment binds to red blood cell precursors while avoiding other types of blood cells.

When the team’s fusion protein molecules were delivered to huGYPA transgenic mice, the antibody fragments piloted toward and bound to the membranes of red blood cell precursors, towing along EPO molecules on the other end of their linkers.

In such close proximity to the surface of the cells, a high concentration of tethered EPO bounced around until it ultimately toggled into place on the cells’ receptors. In this way, red blood cell production was increased with only minimal effects on platelets.

“Our rational design strategy is unique compared to current industry approaches,” Dr Burrill said. “Our goal is to use our method to advance predictive drug design and minimize the time between drug concept and commercialization.”

“The principles of synthetic biology influenced our efforts,” added James Collins, PhD, of the Wyss Institute.

“In drug development, the focus is typically on increasing the strength of interaction with a drug target, but, here, we found that weakening an interaction was useful. This illustrates how we need to adopt alternative, non-traditional approaches if we want to build complex, multi-part therapeutics.”

The researchers said this specific, cell-targeted approach could be applied quite broadly. In addition to “targeted EPO,” the team has developed “targeted interferon-alfa.”

Red blood cells

Researchers say they have used a rational design approach to create a safer variant of the drug erythropoietin (EPO).

This “targeted EPO” effectively stimulated red blood cell production in mice and had a minimal impact on platelets.

The team believes this approach could allow for the use of higher restorative doses of EPO without platelet-mediated side effects, and it might improve drug pharmacokinetics.

Devin Burrill, PhD, of the Wyss Institute for Biologically Inspired Engineering at Harvard University in Boston, Massachusetts, and his colleagues described the approach in PNAS.

The researchers noted that EPO has been widely used to treat anemia, but the drug also poses a risk of thrombotic complications. To combat this problem, the team set out to design a more effective, multi-part drug molecule.

“Compared to currently available EPO drugs, our molecule is engineered to prevent EPO from binding to and activating cells that promote side effects such as blood clotting or tumor growth,” said Jeffrey Way, PhD, also of the Wyss Institute.

“This cell-targeted EPO approach demonstrates a new theoretical basis for the rational design of engineered protein fusion drugs.”

To create their drug, the researchers first mutated EPO to reduce its ability to bind to EPO receptors.

Then, using a chain of amino acids as a flexible linker, they attached mutated EPO to an antibody fragment that specifically binds the human red blood cell marker glycophorin A (huGYPA). This antibody fragment binds to red blood cell precursors while avoiding other types of blood cells.

When the team’s fusion protein molecules were delivered to huGYPA transgenic mice, the antibody fragments piloted toward and bound to the membranes of red blood cell precursors, towing along EPO molecules on the other end of their linkers.

In such close proximity to the surface of the cells, a high concentration of tethered EPO bounced around until it ultimately toggled into place on the cells’ receptors. In this way, red blood cell production was increased with only minimal effects on platelets.

“Our rational design strategy is unique compared to current industry approaches,” Dr Burrill said. “Our goal is to use our method to advance predictive drug design and minimize the time between drug concept and commercialization.”

“The principles of synthetic biology influenced our efforts,” added James Collins, PhD, of the Wyss Institute.

“In drug development, the focus is typically on increasing the strength of interaction with a drug target, but, here, we found that weakening an interaction was useful. This illustrates how we need to adopt alternative, non-traditional approaches if we want to build complex, multi-part therapeutics.”

The researchers said this specific, cell-targeted approach could be applied quite broadly. In addition to “targeted EPO,” the team has developed “targeted interferon-alfa.”

Red blood cells

The investigational therapy roxadustat can effectively treat anemia in patients with chronic kidney disease (CKD) who are not on dialysis, according to a phase 2 study.

Roxadustat increased and maintained hemoglobin levels and decreased hepcidin levels in these patients, who had not received previous treatment with

erythropoiesis-stimulating agents and were treated with roxadustat regardless of their baseline iron repletion status.

In addition, researchers said there were no serious adverse events related to roxadustat.

Robert Provenzano, MD, of St. John Hospital and Medical Center in Detroit, Michigan, and his colleagues reported these results in the Clinical Journal of the American Society of Nephrology.

The study was sponsored by FibroGen, Inc., the company developing roxadustat in collaboration with AstraZeneca.

Roxadustat (FG-4592) is an oral, small-molecule inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase activity. HIF is a transcription factor that induces the natural physiological response to conditions of low oxygen, “turning on” erythropoiesis and other protective pathways.

In this randomized, phase 2 study of roxadustat, 145 patients with anemia (hemoglobin < 10.5 g/dL at baseline) and non-dialysis CKD were randomized into 1 of 6 cohorts of approximately 24 patients.

The cohorts had varying roxadustat starting doses (tiered weight and fixed amounts) and frequencies (2 and 3 times weekly), followed by hemoglobin maintenance with roxadustat 1 to 3 times weekly. The treatment duration was 16 or 24 weeks.

Results

Of the 143 patients evaluable for efficacy, 92% achieved a hemoglobin response—defined as a hemoglobin increase of > 1.0 g/dL from baseline and a hemoglobin of > 11.0 g/dL by the end of treatment (up to 16 weeks of treatment in 47 patients, and up to 24 weeks of treatment in 96 patients).

Generally, patients in all cohorts who received higher starting doses of roxadustat demonstrated earlier achievement of the hemoglobin response.

Roxadustat increased hemoglobin independently of the patients’ baseline iron repletion and inflammatory status, as measured by baseline C–reactive protein levels. Intravenous iron was not permitted throughout the study period, and 52.4% of patients were iron-replete at baseline.

Over 16 weeks of treatment, roxadustat decreased hepcidin levels by 16.9% (P=0.004), maintained reticulocyte hemoglobin content, and increased hemoglobin by a mean (±SD) of 1.83 (±0.09) g/dL (P<0.001).

After 8 weeks of roxadustat, total cholesterol levels decreased by a mean (±SD) of 26 (±30) mg/dL (P<0.001).

“In this study, anemia correction was achieved under a range of treatment options, including tiered-weight as well as fixed-starting-dose strategies,” Dr Provenzano said. “Correction of anemia and maintenance of hemoglobin response were seen at different dose frequencies—2 or 3 times weekly for achievement of hemoglobin response; 1, 2, or 3 times weekly for maintenance.”

“Secondary analyses showing decreases in hepcidin and increased iron utilization, as well as reductions in total cholesterol levels, suggest roxadustat consistently affects these parameters.”

Treatment-emergent adverse events were reported in 80% of all patients.

The most common events that occurred in more than 5% of patients were nausea (9.7%), diarrhea (8.3%), constipation (6.2%), vomiting (5.5%), peripheral edema (12.4%), urinary tract infection (9.7%), nasopharyngitis (9.0%), sinusitis (5.5%), dizziness (6.2%), headache (5.5%), and hypertension (7.6%).

Red blood cells

The investigational therapy roxadustat can effectively treat anemia in patients with chronic kidney disease (CKD) who are not on dialysis, according to a phase 2 study.

Roxadustat increased and maintained hemoglobin levels and decreased hepcidin levels in these patients, who had not received previous treatment with

erythropoiesis-stimulating agents and were treated with roxadustat regardless of their baseline iron repletion status.

In addition, researchers said there were no serious adverse events related to roxadustat.

Robert Provenzano, MD, of St. John Hospital and Medical Center in Detroit, Michigan, and his colleagues reported these results in the Clinical Journal of the American Society of Nephrology.

The study was sponsored by FibroGen, Inc., the company developing roxadustat in collaboration with AstraZeneca.

Roxadustat (FG-4592) is an oral, small-molecule inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase activity. HIF is a transcription factor that induces the natural physiological response to conditions of low oxygen, “turning on” erythropoiesis and other protective pathways.

In this randomized, phase 2 study of roxadustat, 145 patients with anemia (hemoglobin < 10.5 g/dL at baseline) and non-dialysis CKD were randomized into 1 of 6 cohorts of approximately 24 patients.

The cohorts had varying roxadustat starting doses (tiered weight and fixed amounts) and frequencies (2 and 3 times weekly), followed by hemoglobin maintenance with roxadustat 1 to 3 times weekly. The treatment duration was 16 or 24 weeks.

Results

Of the 143 patients evaluable for efficacy, 92% achieved a hemoglobin response—defined as a hemoglobin increase of > 1.0 g/dL from baseline and a hemoglobin of > 11.0 g/dL by the end of treatment (up to 16 weeks of treatment in 47 patients, and up to 24 weeks of treatment in 96 patients).

Generally, patients in all cohorts who received higher starting doses of roxadustat demonstrated earlier achievement of the hemoglobin response.

Roxadustat increased hemoglobin independently of the patients’ baseline iron repletion and inflammatory status, as measured by baseline C–reactive protein levels. Intravenous iron was not permitted throughout the study period, and 52.4% of patients were iron-replete at baseline.

Over 16 weeks of treatment, roxadustat decreased hepcidin levels by 16.9% (P=0.004), maintained reticulocyte hemoglobin content, and increased hemoglobin by a mean (±SD) of 1.83 (±0.09) g/dL (P<0.001).

After 8 weeks of roxadustat, total cholesterol levels decreased by a mean (±SD) of 26 (±30) mg/dL (P<0.001).

“In this study, anemia correction was achieved under a range of treatment options, including tiered-weight as well as fixed-starting-dose strategies,” Dr Provenzano said. “Correction of anemia and maintenance of hemoglobin response were seen at different dose frequencies—2 or 3 times weekly for achievement of hemoglobin response; 1, 2, or 3 times weekly for maintenance.”

“Secondary analyses showing decreases in hepcidin and increased iron utilization, as well as reductions in total cholesterol levels, suggest roxadustat consistently affects these parameters.”

Treatment-emergent adverse events were reported in 80% of all patients.

The most common events that occurred in more than 5% of patients were nausea (9.7%), diarrhea (8.3%), constipation (6.2%), vomiting (5.5%), peripheral edema (12.4%), urinary tract infection (9.7%), nasopharyngitis (9.0%), sinusitis (5.5%), dizziness (6.2%), headache (5.5%), and hypertension (7.6%).

Red blood cells

The investigational therapy roxadustat can effectively treat anemia in patients with chronic kidney disease (CKD) who are not on dialysis, according to a phase 2 study.

Roxadustat increased and maintained hemoglobin levels and decreased hepcidin levels in these patients, who had not received previous treatment with

erythropoiesis-stimulating agents and were treated with roxadustat regardless of their baseline iron repletion status.

In addition, researchers said there were no serious adverse events related to roxadustat.

Robert Provenzano, MD, of St. John Hospital and Medical Center in Detroit, Michigan, and his colleagues reported these results in the Clinical Journal of the American Society of Nephrology.

The study was sponsored by FibroGen, Inc., the company developing roxadustat in collaboration with AstraZeneca.

Roxadustat (FG-4592) is an oral, small-molecule inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase activity. HIF is a transcription factor that induces the natural physiological response to conditions of low oxygen, “turning on” erythropoiesis and other protective pathways.

In this randomized, phase 2 study of roxadustat, 145 patients with anemia (hemoglobin < 10.5 g/dL at baseline) and non-dialysis CKD were randomized into 1 of 6 cohorts of approximately 24 patients.

The cohorts had varying roxadustat starting doses (tiered weight and fixed amounts) and frequencies (2 and 3 times weekly), followed by hemoglobin maintenance with roxadustat 1 to 3 times weekly. The treatment duration was 16 or 24 weeks.

Results

Of the 143 patients evaluable for efficacy, 92% achieved a hemoglobin response—defined as a hemoglobin increase of > 1.0 g/dL from baseline and a hemoglobin of > 11.0 g/dL by the end of treatment (up to 16 weeks of treatment in 47 patients, and up to 24 weeks of treatment in 96 patients).

Generally, patients in all cohorts who received higher starting doses of roxadustat demonstrated earlier achievement of the hemoglobin response.

Roxadustat increased hemoglobin independently of the patients’ baseline iron repletion and inflammatory status, as measured by baseline C–reactive protein levels. Intravenous iron was not permitted throughout the study period, and 52.4% of patients were iron-replete at baseline.

Over 16 weeks of treatment, roxadustat decreased hepcidin levels by 16.9% (P=0.004), maintained reticulocyte hemoglobin content, and increased hemoglobin by a mean (±SD) of 1.83 (±0.09) g/dL (P<0.001).

After 8 weeks of roxadustat, total cholesterol levels decreased by a mean (±SD) of 26 (±30) mg/dL (P<0.001).

“In this study, anemia correction was achieved under a range of treatment options, including tiered-weight as well as fixed-starting-dose strategies,” Dr Provenzano said. “Correction of anemia and maintenance of hemoglobin response were seen at different dose frequencies—2 or 3 times weekly for achievement of hemoglobin response; 1, 2, or 3 times weekly for maintenance.”

“Secondary analyses showing decreases in hepcidin and increased iron utilization, as well as reductions in total cholesterol levels, suggest roxadustat consistently affects these parameters.”

Treatment-emergent adverse events were reported in 80% of all patients.

The most common events that occurred in more than 5% of patients were nausea (9.7%), diarrhea (8.3%), constipation (6.2%), vomiting (5.5%), peripheral edema (12.4%), urinary tract infection (9.7%), nasopharyngitis (9.0%), sinusitis (5.5%), dizziness (6.2%), headache (5.5%), and hypertension (7.6%).

Vials of drug

Photo by Bill Branson

The thrombopoietin receptor agonist romiplostim can produce durable platelet responses in children with symptomatic chronic immune thrombocytopenia (ITP), according to a phase 3 study.

Fifty-two percent of patients who received romiplostim achieved a durable platelet response, compared to 10% of placebo-treated patients.

Investigators said these results suggest romiplostim may be a treatment option for this patient population.

“The results of this study suggest that romiplostim could reduce the frequency and severity of bleeding events for children suffering from symptomatic ITP, thus providing them with another potential treatment option,” said Michael D. Tarantino, MD, of the University of Illinois College of Medicine-Peoria.

Dr Tarantino and his colleagues reported the results in The Lancet. The study was supported by Amgen, which markets romiplostim (Nplate) as a treatment for adults with chronic ITP.

This double-blind study included 62 children (ages 6 to 14) who had ITP for more than 6 months and were randomized to weekly romiplostim (n=42) or placebo (n=20) for 24 weeks. Baseline characteristics were well-balanced between the treatment arms.

The median time since ITP diagnosis was about 2 years for both arms, and the median age at diagnosis was about 7. The median baseline platelet counts were 17.8 x 10⁹/L in the romiplostim arm and 17.7 x 10⁹/L in the placebo arm.

Durable platelet response, the primary endpoint of the study, was defined as achieving weekly platelet responses without rescue medication in at least 6 of the final 8 weeks of the study.

The rates of durable platelet response were 52% (22/42) in the romiplostim arm and 10% (2/20) in the placebo arm (P=0.002, odds ratio 9.1, 95% CI: 1.9, 43.2).

The rates of overall platelet response were 71% (30/42) in the romiplostim arm and 20% in the placebo arm (P=0.0002, odds ratio 9.0, 95% CI: 2.5, 32.3), and the rates of any platelet response were 81% (34/42) and 55% (11/20), respectively (P=0.0313).

The most frequently reported adverse events (AEs) observed in patients receiving romiplostim were contusion (50%), epistaxis (48%), headache (43%), and upper respiratory tract infection (38%).

Oropharyngeal pain occurred more frequently with romiplostim than placebo—26.2% (11/42) and 5.3% (1/19), respectively.

In the 11 romiplostim-treated patients with oropharyngeal pain, streptococcal pharyngitis (n=2), allergic rhinitis (n=2), gastroesophageal reflux (n=1), and serum sickness from IVIg (n=1) were also reported. No oropharyngeal pain AEs were serious or considered treatment-related.

Serious AEs occurred in 23.8% of romiplostim-treated patients and 5.3% of placebo-treated patients.

Serious AEs in the romiplostim arm included epistaxis (n=2), contusion (n=2), headache (n=2), bronchiolitis (n=1), nausea (n=1), petechiae (n=1), epilepsy (n=1), fever (n=1), thrombocytosis (n=1), urinary tract infection (n=1), and vomiting (n=1).

One subject with treatment-related serious AEs experienced headache and thrombocytosis, which did not recur when romiplostim was restarted.

There were no thrombotic events, none of the patients withdrew due to AEs, and none died.

“These data are important in understanding how Nplate may play a role in helping children manage this disease,” said Sean E. Harper, MD, executive vice president of research and development at Amgen.

“We will work with regulatory authorities towards an approval for Nplate for pediatric patients.”

Vials of drug

Photo by Bill Branson

The thrombopoietin receptor agonist romiplostim can produce durable platelet responses in children with symptomatic chronic immune thrombocytopenia (ITP), according to a phase 3 study.

Fifty-two percent of patients who received romiplostim achieved a durable platelet response, compared to 10% of placebo-treated patients.

Investigators said these results suggest romiplostim may be a treatment option for this patient population.

“The results of this study suggest that romiplostim could reduce the frequency and severity of bleeding events for children suffering from symptomatic ITP, thus providing them with another potential treatment option,” said Michael D. Tarantino, MD, of the University of Illinois College of Medicine-Peoria.

Dr Tarantino and his colleagues reported the results in The Lancet. The study was supported by Amgen, which markets romiplostim (Nplate) as a treatment for adults with chronic ITP.

This double-blind study included 62 children (ages 6 to 14) who had ITP for more than 6 months and were randomized to weekly romiplostim (n=42) or placebo (n=20) for 24 weeks. Baseline characteristics were well-balanced between the treatment arms.

The median time since ITP diagnosis was about 2 years for both arms, and the median age at diagnosis was about 7. The median baseline platelet counts were 17.8 x 10⁹/L in the romiplostim arm and 17.7 x 10⁹/L in the placebo arm.

Durable platelet response, the primary endpoint of the study, was defined as achieving weekly platelet responses without rescue medication in at least 6 of the final 8 weeks of the study.

The rates of durable platelet response were 52% (22/42) in the romiplostim arm and 10% (2/20) in the placebo arm (P=0.002, odds ratio 9.1, 95% CI: 1.9, 43.2).

The rates of overall platelet response were 71% (30/42) in the romiplostim arm and 20% in the placebo arm (P=0.0002, odds ratio 9.0, 95% CI: 2.5, 32.3), and the rates of any platelet response were 81% (34/42) and 55% (11/20), respectively (P=0.0313).

The most frequently reported adverse events (AEs) observed in patients receiving romiplostim were contusion (50%), epistaxis (48%), headache (43%), and upper respiratory tract infection (38%).

Oropharyngeal pain occurred more frequently with romiplostim than placebo—26.2% (11/42) and 5.3% (1/19), respectively.

In the 11 romiplostim-treated patients with oropharyngeal pain, streptococcal pharyngitis (n=2), allergic rhinitis (n=2), gastroesophageal reflux (n=1), and serum sickness from IVIg (n=1) were also reported. No oropharyngeal pain AEs were serious or considered treatment-related.

Serious AEs occurred in 23.8% of romiplostim-treated patients and 5.3% of placebo-treated patients.

Serious AEs in the romiplostim arm included epistaxis (n=2), contusion (n=2), headache (n=2), bronchiolitis (n=1), nausea (n=1), petechiae (n=1), epilepsy (n=1), fever (n=1), thrombocytosis (n=1), urinary tract infection (n=1), and vomiting (n=1).

One subject with treatment-related serious AEs experienced headache and thrombocytosis, which did not recur when romiplostim was restarted.

There were no thrombotic events, none of the patients withdrew due to AEs, and none died.

“These data are important in understanding how Nplate may play a role in helping children manage this disease,” said Sean E. Harper, MD, executive vice president of research and development at Amgen.

“We will work with regulatory authorities towards an approval for Nplate for pediatric patients.”

Vials of drug

Photo by Bill Branson

The thrombopoietin receptor agonist romiplostim can produce durable platelet responses in children with symptomatic chronic immune thrombocytopenia (ITP), according to a phase 3 study.

Fifty-two percent of patients who received romiplostim achieved a durable platelet response, compared to 10% of placebo-treated patients.

Investigators said these results suggest romiplostim may be a treatment option for this patient population.

“The results of this study suggest that romiplostim could reduce the frequency and severity of bleeding events for children suffering from symptomatic ITP, thus providing them with another potential treatment option,” said Michael D. Tarantino, MD, of the University of Illinois College of Medicine-Peoria.

Dr Tarantino and his colleagues reported the results in The Lancet. The study was supported by Amgen, which markets romiplostim (Nplate) as a treatment for adults with chronic ITP.

This double-blind study included 62 children (ages 6 to 14) who had ITP for more than 6 months and were randomized to weekly romiplostim (n=42) or placebo (n=20) for 24 weeks. Baseline characteristics were well-balanced between the treatment arms.

The median time since ITP diagnosis was about 2 years for both arms, and the median age at diagnosis was about 7. The median baseline platelet counts were 17.8 x 10⁹/L in the romiplostim arm and 17.7 x 10⁹/L in the placebo arm.

Durable platelet response, the primary endpoint of the study, was defined as achieving weekly platelet responses without rescue medication in at least 6 of the final 8 weeks of the study.

The rates of durable platelet response were 52% (22/42) in the romiplostim arm and 10% (2/20) in the placebo arm (P=0.002, odds ratio 9.1, 95% CI: 1.9, 43.2).

The rates of overall platelet response were 71% (30/42) in the romiplostim arm and 20% in the placebo arm (P=0.0002, odds ratio 9.0, 95% CI: 2.5, 32.3), and the rates of any platelet response were 81% (34/42) and 55% (11/20), respectively (P=0.0313).

The most frequently reported adverse events (AEs) observed in patients receiving romiplostim were contusion (50%), epistaxis (48%), headache (43%), and upper respiratory tract infection (38%).

Oropharyngeal pain occurred more frequently with romiplostim than placebo—26.2% (11/42) and 5.3% (1/19), respectively.

In the 11 romiplostim-treated patients with oropharyngeal pain, streptococcal pharyngitis (n=2), allergic rhinitis (n=2), gastroesophageal reflux (n=1), and serum sickness from IVIg (n=1) were also reported. No oropharyngeal pain AEs were serious or considered treatment-related.

Serious AEs occurred in 23.8% of romiplostim-treated patients and 5.3% of placebo-treated patients.

Serious AEs in the romiplostim arm included epistaxis (n=2), contusion (n=2), headache (n=2), bronchiolitis (n=1), nausea (n=1), petechiae (n=1), epilepsy (n=1), fever (n=1), thrombocytosis (n=1), urinary tract infection (n=1), and vomiting (n=1).

One subject with treatment-related serious AEs experienced headache and thrombocytosis, which did not recur when romiplostim was restarted.

There were no thrombotic events, none of the patients withdrew due to AEs, and none died.

“These data are important in understanding how Nplate may play a role in helping children manage this disease,” said Sean E. Harper, MD, executive vice president of research and development at Amgen.

“We will work with regulatory authorities towards an approval for Nplate for pediatric patients.”

Doctor examines patient

with sickle cell anemia

Photo courtesy of St. Jude

Results of a large, retrospective study suggest the use of transcranial Doppler (TCD) screening is on the rise in US children and adolescents with sickle cell anemia.

However, the rate of TCD screening in these patients falls well below national recommendations.

In addition, TCD screening rates vary greatly by state, and the use of screening tends to decrease as patients grow older.

Sarah L. Reeves, PhD, of University of Michigan, Ann Arbor, and her colleagues reported these findings in JAMA Pediatrics.

The researchers noted that guidelines from the National Heart, Lung, and Blood Institute recommend that patients with sickle cell anemia receive annual TCD screenings from age 2 to 16 to identify those patients at the highest risk of stroke.

Dr Reeves and her colleagues wanted to determine if this recommendation is being followed. So they analyzed Medicaid claims data from 2005 through 2010 for Florida, Illinois, Louisiana, Michigan, South Carolina, and Texas.

The data included 4775 patients, ages 2 to 16, with sickle cell anemia. For these patients, TCD screening rates increased from 22% in 2005 to 44% in 2010 (P<0.001).

The researchers found that TCD screening rates varied significantly by state (P=0.004), and Texas had the lowest screening rate at any time point (7% in 2005).

The team also analyzed a subset of 2388 patients who were enrolled for 2 or more consecutive years to examine potential predictors of TCD screening.

This analysis revealed that, with each year of increasing age, a patient’s odds of receiving TCD screening decreased (odds ratio=0.97, P=0.002).

On the other hand, an increasing number of well-child visits was associated with higher odds of receiving TCD screening (odds ratio=1.10, P=0.007).

And the odds of receiving TCD screening were higher for patients who previously underwent TCD screening (odds ratio=2.44, P<0.001).

The researchers said these results suggest that, despite national recommendations, TCD screening rates remain low in young patients with sickle cell anemia in the US.

Doctor examines patient

with sickle cell anemia

Photo courtesy of St. Jude

Results of a large, retrospective study suggest the use of transcranial Doppler (TCD) screening is on the rise in US children and adolescents with sickle cell anemia.

However, the rate of TCD screening in these patients falls well below national recommendations.

In addition, TCD screening rates vary greatly by state, and the use of screening tends to decrease as patients grow older.

Sarah L. Reeves, PhD, of University of Michigan, Ann Arbor, and her colleagues reported these findings in JAMA Pediatrics.

The researchers noted that guidelines from the National Heart, Lung, and Blood Institute recommend that patients with sickle cell anemia receive annual TCD screenings from age 2 to 16 to identify those patients at the highest risk of stroke.

Dr Reeves and her colleagues wanted to determine if this recommendation is being followed. So they analyzed Medicaid claims data from 2005 through 2010 for Florida, Illinois, Louisiana, Michigan, South Carolina, and Texas.

The data included 4775 patients, ages 2 to 16, with sickle cell anemia. For these patients, TCD screening rates increased from 22% in 2005 to 44% in 2010 (P<0.001).

The researchers found that TCD screening rates varied significantly by state (P=0.004), and Texas had the lowest screening rate at any time point (7% in 2005).

The team also analyzed a subset of 2388 patients who were enrolled for 2 or more consecutive years to examine potential predictors of TCD screening.

This analysis revealed that, with each year of increasing age, a patient’s odds of receiving TCD screening decreased (odds ratio=0.97, P=0.002).

On the other hand, an increasing number of well-child visits was associated with higher odds of receiving TCD screening (odds ratio=1.10, P=0.007).

And the odds of receiving TCD screening were higher for patients who previously underwent TCD screening (odds ratio=2.44, P<0.001).

The researchers said these results suggest that, despite national recommendations, TCD screening rates remain low in young patients with sickle cell anemia in the US.

Doctor examines patient

with sickle cell anemia

Photo courtesy of St. Jude

Results of a large, retrospective study suggest the use of transcranial Doppler (TCD) screening is on the rise in US children and adolescents with sickle cell anemia.

However, the rate of TCD screening in these patients falls well below national recommendations.

In addition, TCD screening rates vary greatly by state, and the use of screening tends to decrease as patients grow older.

Sarah L. Reeves, PhD, of University of Michigan, Ann Arbor, and her colleagues reported these findings in JAMA Pediatrics.

The researchers noted that guidelines from the National Heart, Lung, and Blood Institute recommend that patients with sickle cell anemia receive annual TCD screenings from age 2 to 16 to identify those patients at the highest risk of stroke.

Dr Reeves and her colleagues wanted to determine if this recommendation is being followed. So they analyzed Medicaid claims data from 2005 through 2010 for Florida, Illinois, Louisiana, Michigan, South Carolina, and Texas.

The data included 4775 patients, ages 2 to 16, with sickle cell anemia. For these patients, TCD screening rates increased from 22% in 2005 to 44% in 2010 (P<0.001).

The researchers found that TCD screening rates varied significantly by state (P=0.004), and Texas had the lowest screening rate at any time point (7% in 2005).

The team also analyzed a subset of 2388 patients who were enrolled for 2 or more consecutive years to examine potential predictors of TCD screening.

This analysis revealed that, with each year of increasing age, a patient’s odds of receiving TCD screening decreased (odds ratio=0.97, P=0.002).

On the other hand, an increasing number of well-child visits was associated with higher odds of receiving TCD screening (odds ratio=1.10, P=0.007).

And the odds of receiving TCD screening were higher for patients who previously underwent TCD screening (odds ratio=2.44, P<0.001).

The researchers said these results suggest that, despite national recommendations, TCD screening rates remain low in young patients with sickle cell anemia in the US.

Children and adolescents with sickle cell anemia still are not being screened for stroke risk using transcranial Doppler, despite clinical guidelines that strongly recommend annual screening and despite these patients’ frequent health care encounters, according to a report published online April 11 in JAMA Pediatrics.

Approximately 10% of children and adolescents with sickle cell anemia experience stroke before the age of 20 years, unless those at high risk are identified and treated preemptively with blood transfusions, which reduces stroke risk by 92%. The National Heart, Lung, and Blood Institute clinical practice guideline on treating sickle cell disease calls for patients aged 2-16 years to undergo transcranial Doppler every year to detect any elevated velocity of cerebral blood flow, which indicates high stroke risk, said Sarah L. Reeves, Ph.D., of the Child Health Evaluation and Research Unit, University of Michigan, Ann Arbor, and her associates.

CDC/Janice Haney Carr

To assess screening rates, the investigators performed a retrospective cross-sectional analysis of administrative claims data for 4,775 affected children and adolescents treated during a 5-year period in Florida, Illinois, Louisiana, Michigan, South Carolina, and Texas. This yielded 10,787 person-years of data.

Overall, screening rates increased somewhat across all six states during the study period – from 22% to 44% – but “even the highest rates we report are suboptimal,” Dr. Reeves and her associates noted (JAMA Ped. 2016 Apr 11. doi: 10.1001/jamapediatrics.2015.4859).

This is especially true given that the average patient had 20.0 disease-related outpatient visits, 2.1 disease-related hospitalizations, 3.7 emergency department visits, and 1 well-child visit each year – numerous missed opportunities when they could have been referred for screening.

One way to improve screening rates would be to integrate transcranial Doppler exams into comprehensive sickle-cell healthcare, rather than requiring separate scheduled appointments at imaging facilities, they added.

This study was funded by the Agency for Healthcare Research and Quality and the Centers for Medicare & Medicaid Services. Dr. Reeves and her associates reported having no relevant financial disclosures.

Children and adolescents with sickle cell anemia still are not being screened for stroke risk using transcranial Doppler, despite clinical guidelines that strongly recommend annual screening and despite these patients’ frequent health care encounters, according to a report published online April 11 in JAMA Pediatrics.

Approximately 10% of children and adolescents with sickle cell anemia experience stroke before the age of 20 years, unless those at high risk are identified and treated preemptively with blood transfusions, which reduces stroke risk by 92%. The National Heart, Lung, and Blood Institute clinical practice guideline on treating sickle cell disease calls for patients aged 2-16 years to undergo transcranial Doppler every year to detect any elevated velocity of cerebral blood flow, which indicates high stroke risk, said Sarah L. Reeves, Ph.D., of the Child Health Evaluation and Research Unit, University of Michigan, Ann Arbor, and her associates.

CDC/Janice Haney Carr

To assess screening rates, the investigators performed a retrospective cross-sectional analysis of administrative claims data for 4,775 affected children and adolescents treated during a 5-year period in Florida, Illinois, Louisiana, Michigan, South Carolina, and Texas. This yielded 10,787 person-years of data.

Overall, screening rates increased somewhat across all six states during the study period – from 22% to 44% – but “even the highest rates we report are suboptimal,” Dr. Reeves and her associates noted (JAMA Ped. 2016 Apr 11. doi: 10.1001/jamapediatrics.2015.4859).

This is especially true given that the average patient had 20.0 disease-related outpatient visits, 2.1 disease-related hospitalizations, 3.7 emergency department visits, and 1 well-child visit each year – numerous missed opportunities when they could have been referred for screening.

One way to improve screening rates would be to integrate transcranial Doppler exams into comprehensive sickle-cell healthcare, rather than requiring separate scheduled appointments at imaging facilities, they added.

This study was funded by the Agency for Healthcare Research and Quality and the Centers for Medicare & Medicaid Services. Dr. Reeves and her associates reported having no relevant financial disclosures.

Children and adolescents with sickle cell anemia still are not being screened for stroke risk using transcranial Doppler, despite clinical guidelines that strongly recommend annual screening and despite these patients’ frequent health care encounters, according to a report published online April 11 in JAMA Pediatrics.

Approximately 10% of children and adolescents with sickle cell anemia experience stroke before the age of 20 years, unless those at high risk are identified and treated preemptively with blood transfusions, which reduces stroke risk by 92%. The National Heart, Lung, and Blood Institute clinical practice guideline on treating sickle cell disease calls for patients aged 2-16 years to undergo transcranial Doppler every year to detect any elevated velocity of cerebral blood flow, which indicates high stroke risk, said Sarah L. Reeves, Ph.D., of the Child Health Evaluation and Research Unit, University of Michigan, Ann Arbor, and her associates.

CDC/Janice Haney Carr

To assess screening rates, the investigators performed a retrospective cross-sectional analysis of administrative claims data for 4,775 affected children and adolescents treated during a 5-year period in Florida, Illinois, Louisiana, Michigan, South Carolina, and Texas. This yielded 10,787 person-years of data.

Overall, screening rates increased somewhat across all six states during the study period – from 22% to 44% – but “even the highest rates we report are suboptimal,” Dr. Reeves and her associates noted (JAMA Ped. 2016 Apr 11. doi: 10.1001/jamapediatrics.2015.4859).

This is especially true given that the average patient had 20.0 disease-related outpatient visits, 2.1 disease-related hospitalizations, 3.7 emergency department visits, and 1 well-child visit each year – numerous missed opportunities when they could have been referred for screening.

One way to improve screening rates would be to integrate transcranial Doppler exams into comprehensive sickle-cell healthcare, rather than requiring separate scheduled appointments at imaging facilities, they added.

This study was funded by the Agency for Healthcare Research and Quality and the Centers for Medicare & Medicaid Services. Dr. Reeves and her associates reported having no relevant financial disclosures.

AMSTERDAM – Five people with confirmed Zika virus infections have died in Colombia, and all had medical comorbidities, including leukemia, diabetes, sickle cell anemia, and hypertension.

All of the deaths occurred last October in northern and central Colombia, Dr. Alfonso Rodriguez-Morales said at the European Society of Clinical Microbiology and Infectious Diseases annual congress.

Four of the cases were simultaneously published April 7 in the Lancet Infectious Diseases (2016 Apr 7. doi: 10.1016/S1473-3099[16]30006-8). The fifth case occurred in northern Colombia, and was reported in Emerging Infectious Diseases (2016 May. doi: 10.3201/eid2205.151934).

Reports of confirmed Zika-related deaths are rare. Brazil, the only other country to disclose them, has now reported three, said Dr. Rodriguez-Morales of the Universidad Tecnológica de Pereira, Colombia.

©bakhtiar_zein/Thinkstock

“Before the current outbreak in Latin America, Zika virus was not linked to deaths,” he noted. But the eight confirmed Zika-related deaths in South America “call attention to the need for evidence-based guidelines for clinical management of Zika, as well as the possible occurrence of atypical and severe cases, including possibly congenitally related microcephaly.”

Because they all occurred in medically compromised patients, Dr. Rodriguez-Morales also urged clinicians to cast a wary eye on such patients who present with arbovirus-type symptoms, including fever and rash.

From September 2015 to March 2016, Colombia had 58,838 reported cases of Zika. Of those, only 2,361 were lab confirmed. The rest were either diagnosed clinically or were suspected cases, Dr. Rodriguez-Morales said. Although Colombia has a much smaller population than Brazil (49 million vs. 210 million), its Zika case rate is much higher, 120 cases per 100,000 people vs. 34 cases per 100,000 people.

The group of four deaths occurred in central Colombia, and included a 2-year-old girl, a 30-year-old woman, a 61-year-old man, and a 72-year-old woman. All presented with 2-6 days of fever. All were initially suspected to have dengue fever or chikungunya. None tested positive for dengue, but the man was coinfected with chikungunya.

All patients presented with anemia. All but the older man also had severe thrombocytopenia.

The toddler presented with hepatomegaly, mucosal hemorrhage, progressive respiratory collapse, progressive thrombocytopenia, and intravascular coagulation. She died 5 days after symptom onset and was found to have had unrecognized lymphoblastic leukemia.

The 30-year-old woman presented with a severe rash on both arms. She also exhibited coagulation dysfunction, including severe thrombocytopenia and leukopenia that progressed to intracerebral and subarachnoid hemorrhage. She died 12 days after symptom onset. She was determined to have had unrecognized acute myeloid leukemia.

The elderly man had a history of medically controlled hypertension. He experienced mucosal hemorrhage and respiratory distress. He died 7 days after symptom onset. On autopsy, his liver showed necrotic areas, and his spleen indicated a systemic inflammatory response.

The elderly woman had a history of insulin-controlled type 2 diabetes. Her symptoms included gastrointestinal distress, thrombocytopenia, and acute respiratory failure. She died 48 hours after symptom onset; her brain showed edema and ischemic lesions.

The 15-year-old girl in northern Colombia had a 5-year history of sickle cell disease, which, Dr. Rodriguez-Morales pointed out, is a risk factor for arbovirus diseases. However, the patient had never been hospitalized for a vasoocclusive crisis. She presented with a high fever; joint, muscle, and abdominal pain; and jaundice. She was assumed to have dengue virus. Within another day, she had progressed into respiratory failure and was on a ventilator. She died less than 2 days later.

Her autopsy showed hepatic necrosis and severe decrease of splenic lymphoid tissue with splenic sequestration. Systemic inflammation probably triggered a fatal vasoocclusive crisis and splenic sequestration.

Dr. Rodriguez-Morales had no financial disclosures.

[email protected]

AMSTERDAM – Five people with confirmed Zika virus infections have died in Colombia, and all had medical comorbidities, including leukemia, diabetes, sickle cell anemia, and hypertension.

All of the deaths occurred last October in northern and central Colombia, Dr. Alfonso Rodriguez-Morales said at the European Society of Clinical Microbiology and Infectious Diseases annual congress.

Four of the cases were simultaneously published April 7 in the Lancet Infectious Diseases (2016 Apr 7. doi: 10.1016/S1473-3099[16]30006-8). The fifth case occurred in northern Colombia, and was reported in Emerging Infectious Diseases (2016 May. doi: 10.3201/eid2205.151934).

Reports of confirmed Zika-related deaths are rare. Brazil, the only other country to disclose them, has now reported three, said Dr. Rodriguez-Morales of the Universidad Tecnológica de Pereira, Colombia.

©bakhtiar_zein/Thinkstock

“Before the current outbreak in Latin America, Zika virus was not linked to deaths,” he noted. But the eight confirmed Zika-related deaths in South America “call attention to the need for evidence-based guidelines for clinical management of Zika, as well as the possible occurrence of atypical and severe cases, including possibly congenitally related microcephaly.”

Because they all occurred in medically compromised patients, Dr. Rodriguez-Morales also urged clinicians to cast a wary eye on such patients who present with arbovirus-type symptoms, including fever and rash.

From September 2015 to March 2016, Colombia had 58,838 reported cases of Zika. Of those, only 2,361 were lab confirmed. The rest were either diagnosed clinically or were suspected cases, Dr. Rodriguez-Morales said. Although Colombia has a much smaller population than Brazil (49 million vs. 210 million), its Zika case rate is much higher, 120 cases per 100,000 people vs. 34 cases per 100,000 people.

The group of four deaths occurred in central Colombia, and included a 2-year-old girl, a 30-year-old woman, a 61-year-old man, and a 72-year-old woman. All presented with 2-6 days of fever. All were initially suspected to have dengue fever or chikungunya. None tested positive for dengue, but the man was coinfected with chikungunya.

All patients presented with anemia. All but the older man also had severe thrombocytopenia.

The toddler presented with hepatomegaly, mucosal hemorrhage, progressive respiratory collapse, progressive thrombocytopenia, and intravascular coagulation. She died 5 days after symptom onset and was found to have had unrecognized lymphoblastic leukemia.

The 30-year-old woman presented with a severe rash on both arms. She also exhibited coagulation dysfunction, including severe thrombocytopenia and leukopenia that progressed to intracerebral and subarachnoid hemorrhage. She died 12 days after symptom onset. She was determined to have had unrecognized acute myeloid leukemia.

The elderly man had a history of medically controlled hypertension. He experienced mucosal hemorrhage and respiratory distress. He died 7 days after symptom onset. On autopsy, his liver showed necrotic areas, and his spleen indicated a systemic inflammatory response.

The elderly woman had a history of insulin-controlled type 2 diabetes. Her symptoms included gastrointestinal distress, thrombocytopenia, and acute respiratory failure. She died 48 hours after symptom onset; her brain showed edema and ischemic lesions.

The 15-year-old girl in northern Colombia had a 5-year history of sickle cell disease, which, Dr. Rodriguez-Morales pointed out, is a risk factor for arbovirus diseases. However, the patient had never been hospitalized for a vasoocclusive crisis. She presented with a high fever; joint, muscle, and abdominal pain; and jaundice. She was assumed to have dengue virus. Within another day, she had progressed into respiratory failure and was on a ventilator. She died less than 2 days later.

Her autopsy showed hepatic necrosis and severe decrease of splenic lymphoid tissue with splenic sequestration. Systemic inflammation probably triggered a fatal vasoocclusive crisis and splenic sequestration.

Dr. Rodriguez-Morales had no financial disclosures.

[email protected]

AMSTERDAM – Five people with confirmed Zika virus infections have died in Colombia, and all had medical comorbidities, including leukemia, diabetes, sickle cell anemia, and hypertension.

All of the deaths occurred last October in northern and central Colombia, Dr. Alfonso Rodriguez-Morales said at the European Society of Clinical Microbiology and Infectious Diseases annual congress.

Four of the cases were simultaneously published April 7 in the Lancet Infectious Diseases (2016 Apr 7. doi: 10.1016/S1473-3099[16]30006-8). The fifth case occurred in northern Colombia, and was reported in Emerging Infectious Diseases (2016 May. doi: 10.3201/eid2205.151934).

Reports of confirmed Zika-related deaths are rare. Brazil, the only other country to disclose them, has now reported three, said Dr. Rodriguez-Morales of the Universidad Tecnológica de Pereira, Colombia.

©bakhtiar_zein/Thinkstock

“Before the current outbreak in Latin America, Zika virus was not linked to deaths,” he noted. But the eight confirmed Zika-related deaths in South America “call attention to the need for evidence-based guidelines for clinical management of Zika, as well as the possible occurrence of atypical and severe cases, including possibly congenitally related microcephaly.”

Because they all occurred in medically compromised patients, Dr. Rodriguez-Morales also urged clinicians to cast a wary eye on such patients who present with arbovirus-type symptoms, including fever and rash.

From September 2015 to March 2016, Colombia had 58,838 reported cases of Zika. Of those, only 2,361 were lab confirmed. The rest were either diagnosed clinically or were suspected cases, Dr. Rodriguez-Morales said. Although Colombia has a much smaller population than Brazil (49 million vs. 210 million), its Zika case rate is much higher, 120 cases per 100,000 people vs. 34 cases per 100,000 people.

The group of four deaths occurred in central Colombia, and included a 2-year-old girl, a 30-year-old woman, a 61-year-old man, and a 72-year-old woman. All presented with 2-6 days of fever. All were initially suspected to have dengue fever or chikungunya. None tested positive for dengue, but the man was coinfected with chikungunya.

All patients presented with anemia. All but the older man also had severe thrombocytopenia.

The toddler presented with hepatomegaly, mucosal hemorrhage, progressive respiratory collapse, progressive thrombocytopenia, and intravascular coagulation. She died 5 days after symptom onset and was found to have had unrecognized lymphoblastic leukemia.

The 30-year-old woman presented with a severe rash on both arms. She also exhibited coagulation dysfunction, including severe thrombocytopenia and leukopenia that progressed to intracerebral and subarachnoid hemorrhage. She died 12 days after symptom onset. She was determined to have had unrecognized acute myeloid leukemia.

The elderly man had a history of medically controlled hypertension. He experienced mucosal hemorrhage and respiratory distress. He died 7 days after symptom onset. On autopsy, his liver showed necrotic areas, and his spleen indicated a systemic inflammatory response.

The elderly woman had a history of insulin-controlled type 2 diabetes. Her symptoms included gastrointestinal distress, thrombocytopenia, and acute respiratory failure. She died 48 hours after symptom onset; her brain showed edema and ischemic lesions.

The 15-year-old girl in northern Colombia had a 5-year history of sickle cell disease, which, Dr. Rodriguez-Morales pointed out, is a risk factor for arbovirus diseases. However, the patient had never been hospitalized for a vasoocclusive crisis. She presented with a high fever; joint, muscle, and abdominal pain; and jaundice. She was assumed to have dengue virus. Within another day, she had progressed into respiratory failure and was on a ventilator. She died less than 2 days later.

Her autopsy showed hepatic necrosis and severe decrease of splenic lymphoid tissue with splenic sequestration. Systemic inflammation probably triggered a fatal vasoocclusive crisis and splenic sequestration.

Dr. Rodriguez-Morales had no financial disclosures.

[email protected]

Cells from a mouse with SCD

Image courtesy of the

University of Michigan

Activating the antioxidant regulator Nrf2 may slow the progression of sickle cell disease (SCD), according to preclinical research published in JCI Insight.

Investigators found the severity of hemolytic anemia, vascular inflammation, and lung injury increased with age in mice with SCD.

However, activating Nrf2 in young animals had a prophylactic effect, reducing the severity of these adverse effects and improving survival.

To uncover these findings, Solomon Ofori-Acquah, PhD, of the University of Pittsburgh in Pennsylvania, and his colleagues conducted a 10-month longitudinal observational study of mice with SCD.

The team found that, in mice with homozygous SCD (SS), there was a link between intravascular hemolysis, vascular inflammation, lung injury, and early death.

Mice as young as 2 months showed exacerbation of intravascular hemolysis. And additional investigation linked worsening intravascular hemolysis and oxidative stress to the release of VE-cadherin and progressive lung damage in aging SS mice.

The investigators knew that Nrf2 regulates the expression of genes that protect against the effects of intravascular hemolysis. So they decided to see if activating Nrf2 in young mice with SCD would slow the disease progression that occurs with age.

The team took SS mice that were about a month old and randomized them to receive 3H-1, 2-dithiole-3-thione (D3T) or a DMSO vehicle for 3 months or longer.

Treatment with D3T stabilized the concentration of hemoglobin, increased white blood cell counts, increased reticulocyte counts (though not significantly), kept HO-1 levels stable, increased levels of NQO1 and ferritin, and impeded the progression of endothelial dysfunction.

The investigators also looked at the role of Nrf2 in nonhematopoietic tissues and were surprised to find that Nrf2 deficiency in nonhematopoietic tissues exacerbated anemia and caused premature pulmonary edema in mice with SCD.

The team said this suggests a dominant protective role for nonhematopoietic Nrf2 against tissue damage in both erythroid and nonerythroid tissues in SCD.

And, when taken together, the results of this research indicate that activating Nrf2 can impede the onset of the severe adult phenotype of SCD in mice.

Cells from a mouse with SCD

Image courtesy of the

University of Michigan

Activating the antioxidant regulator Nrf2 may slow the progression of sickle cell disease (SCD), according to preclinical research published in JCI Insight.

Investigators found the severity of hemolytic anemia, vascular inflammation, and lung injury increased with age in mice with SCD.

However, activating Nrf2 in young animals had a prophylactic effect, reducing the severity of these adverse effects and improving survival.

To uncover these findings, Solomon Ofori-Acquah, PhD, of the University of Pittsburgh in Pennsylvania, and his colleagues conducted a 10-month longitudinal observational study of mice with SCD.

The team found that, in mice with homozygous SCD (SS), there was a link between intravascular hemolysis, vascular inflammation, lung injury, and early death.

Mice as young as 2 months showed exacerbation of intravascular hemolysis. And additional investigation linked worsening intravascular hemolysis and oxidative stress to the release of VE-cadherin and progressive lung damage in aging SS mice.

The investigators knew that Nrf2 regulates the expression of genes that protect against the effects of intravascular hemolysis. So they decided to see if activating Nrf2 in young mice with SCD would slow the disease progression that occurs with age.

The team took SS mice that were about a month old and randomized them to receive 3H-1, 2-dithiole-3-thione (D3T) or a DMSO vehicle for 3 months or longer.

Treatment with D3T stabilized the concentration of hemoglobin, increased white blood cell counts, increased reticulocyte counts (though not significantly), kept HO-1 levels stable, increased levels of NQO1 and ferritin, and impeded the progression of endothelial dysfunction.

The investigators also looked at the role of Nrf2 in nonhematopoietic tissues and were surprised to find that Nrf2 deficiency in nonhematopoietic tissues exacerbated anemia and caused premature pulmonary edema in mice with SCD.

The team said this suggests a dominant protective role for nonhematopoietic Nrf2 against tissue damage in both erythroid and nonerythroid tissues in SCD.

And, when taken together, the results of this research indicate that activating Nrf2 can impede the onset of the severe adult phenotype of SCD in mice.

Cells from a mouse with SCD

Image courtesy of the

University of Michigan

Activating the antioxidant regulator Nrf2 may slow the progression of sickle cell disease (SCD), according to preclinical research published in JCI Insight.

Investigators found the severity of hemolytic anemia, vascular inflammation, and lung injury increased with age in mice with SCD.

However, activating Nrf2 in young animals had a prophylactic effect, reducing the severity of these adverse effects and improving survival.

To uncover these findings, Solomon Ofori-Acquah, PhD, of the University of Pittsburgh in Pennsylvania, and his colleagues conducted a 10-month longitudinal observational study of mice with SCD.

The team found that, in mice with homozygous SCD (SS), there was a link between intravascular hemolysis, vascular inflammation, lung injury, and early death.

Mice as young as 2 months showed exacerbation of intravascular hemolysis. And additional investigation linked worsening intravascular hemolysis and oxidative stress to the release of VE-cadherin and progressive lung damage in aging SS mice.

The investigators knew that Nrf2 regulates the expression of genes that protect against the effects of intravascular hemolysis. So they decided to see if activating Nrf2 in young mice with SCD would slow the disease progression that occurs with age.

The team took SS mice that were about a month old and randomized them to receive 3H-1, 2-dithiole-3-thione (D3T) or a DMSO vehicle for 3 months or longer.

Treatment with D3T stabilized the concentration of hemoglobin, increased white blood cell counts, increased reticulocyte counts (though not significantly), kept HO-1 levels stable, increased levels of NQO1 and ferritin, and impeded the progression of endothelial dysfunction.

The investigators also looked at the role of Nrf2 in nonhematopoietic tissues and were surprised to find that Nrf2 deficiency in nonhematopoietic tissues exacerbated anemia and caused premature pulmonary edema in mice with SCD.

The team said this suggests a dominant protective role for nonhematopoietic Nrf2 against tissue damage in both erythroid and nonerythroid tissues in SCD.

And, when taken together, the results of this research indicate that activating Nrf2 can impede the onset of the severe adult phenotype of SCD in mice.

Doctor examines child

Photo by Logan Tuttle

The European Commission (EC) has approved eltrombopag (Revolade), a once-daily oral thrombopoietin receptor agonist, to treat pediatric patients (age 1 and older) with chronic immune thrombocytopenia (ITP) that is refractory to other therapies.

This approval includes the use of tablets and a new oral suspension formulation of eltrombopag, which is designed for younger children who may not be able to swallow tablets.

The approval applies to all 28 member states of the European Union plus Iceland, Norway, and Liechtenstein.

Eltrombopag was previously approved by the EC for use in adults with refractory chronic ITP. The drug is also approved in the EC to treat adults with severe aplastic anemia and adults with chronic hepatitis C virus infection who have thrombocytopenia.

Eltrombopag is made by Novartis. For more details on the drug, see the full Summary of Product Characteristics, available on the European Medicines Agency’s website.

The EC’s latest approval of eltrombopag was based on data from 2 double-blind, placebo-controlled trials—the phase 2 PETIT trial and the phase 3 PETIT2 trial.

PETIT trials: Efficacy

The PETIT trial included 67 ITP patients stratified by age cohort (12-17 years, 6-11 years, and 1-5 years). They were randomized (2:1) to receive eltrombopag or placebo for 7 weeks. The eltrombopag dose was titrated to a target platelet count of 50-200 x 10⁹/L.

The primary efficacy endpoint was the proportion of subjects achieving platelet counts of 50 x 10⁹/L or higher at least once between days 8 and 43 of the randomized period of the study.

Significantly more patients in the eltrombopag arm met this endpoint—62.2%—compared to 31.8% in the placebo arm (P=0.011).

The PETIT2 trial enrolled 92 patients with chronic ITP who were randomized (2:1) to receive eltrombopag or placebo for 13 weeks. The eltrombopag dose was titrated to a target platelet count of 50-200 x 10⁹/L.

The primary efficacy endpoint was the proportion of subjects who achieved platelet counts of 50 x 10⁹/L or higher for at least 6 out of 8 weeks, between weeks 5 and 12 of the randomized period.

Significantly more patients in the eltrombopag arm met this endpoint—41.3%—compared to 3.4% of patients in the placebo arm (P<0.001).

PETIT trials: Safety

For both trials, there were 107 eltrombopag-treated patients evaluable for safety.

The most common adverse events that occurred more frequently in the eltrombopag arms than the placebo arms were upper respiratory tract infection, nasopharyngitis, cough, diarrhea, pyrexia, rhinitis, abdominal pain, oropharyngeal pain, toothache, increased ALT/AST, rash, and rhinorrhea.

Serious adverse events were reported in 8% of patients during the randomized part of both trials, although no serious adverse event occurred in more than 1 patient.

An ALT elevation of at least 3 times the upper limit of normal occurred in 5% of eltrombopag-treated patients. Of those patients, 2% had ALT increases of at least 5 times the upper limit of normal.

There were no deaths or thromboembolic events during either study.

Doctor examines child

Photo by Logan Tuttle

The European Commission (EC) has approved eltrombopag (Revolade), a once-daily oral thrombopoietin receptor agonist, to treat pediatric patients (age 1 and older) with chronic immune thrombocytopenia (ITP) that is refractory to other therapies.

This approval includes the use of tablets and a new oral suspension formulation of eltrombopag, which is designed for younger children who may not be able to swallow tablets.

The approval applies to all 28 member states of the European Union plus Iceland, Norway, and Liechtenstein.

Eltrombopag was previously approved by the EC for use in adults with refractory chronic ITP. The drug is also approved in the EC to treat adults with severe aplastic anemia and adults with chronic hepatitis C virus infection who have thrombocytopenia.

Eltrombopag is made by Novartis. For more details on the drug, see the full Summary of Product Characteristics, available on the European Medicines Agency’s website.

The EC’s latest approval of eltrombopag was based on data from 2 double-blind, placebo-controlled trials—the phase 2 PETIT trial and the phase 3 PETIT2 trial.

PETIT trials: Efficacy

The PETIT trial included 67 ITP patients stratified by age cohort (12-17 years, 6-11 years, and 1-5 years). They were randomized (2:1) to receive eltrombopag or placebo for 7 weeks. The eltrombopag dose was titrated to a target platelet count of 50-200 x 10⁹/L.

The primary efficacy endpoint was the proportion of subjects achieving platelet counts of 50 x 10⁹/L or higher at least once between days 8 and 43 of the randomized period of the study.

Significantly more patients in the eltrombopag arm met this endpoint—62.2%—compared to 31.8% in the placebo arm (P=0.011).

The PETIT2 trial enrolled 92 patients with chronic ITP who were randomized (2:1) to receive eltrombopag or placebo for 13 weeks. The eltrombopag dose was titrated to a target platelet count of 50-200 x 10⁹/L.

The primary efficacy endpoint was the proportion of subjects who achieved platelet counts of 50 x 10⁹/L or higher for at least 6 out of 8 weeks, between weeks 5 and 12 of the randomized period.

Significantly more patients in the eltrombopag arm met this endpoint—41.3%—compared to 3.4% of patients in the placebo arm (P<0.001).

PETIT trials: Safety

For both trials, there were 107 eltrombopag-treated patients evaluable for safety.

The most common adverse events that occurred more frequently in the eltrombopag arms than the placebo arms were upper respiratory tract infection, nasopharyngitis, cough, diarrhea, pyrexia, rhinitis, abdominal pain, oropharyngeal pain, toothache, increased ALT/AST, rash, and rhinorrhea.

Serious adverse events were reported in 8% of patients during the randomized part of both trials, although no serious adverse event occurred in more than 1 patient.

An ALT elevation of at least 3 times the upper limit of normal occurred in 5% of eltrombopag-treated patients. Of those patients, 2% had ALT increases of at least 5 times the upper limit of normal.

There were no deaths or thromboembolic events during either study.

Doctor examines child

Photo by Logan Tuttle

The European Commission (EC) has approved eltrombopag (Revolade), a once-daily oral thrombopoietin receptor agonist, to treat pediatric patients (age 1 and older) with chronic immune thrombocytopenia (ITP) that is refractory to other therapies.

This approval includes the use of tablets and a new oral suspension formulation of eltrombopag, which is designed for younger children who may not be able to swallow tablets.

The approval applies to all 28 member states of the European Union plus Iceland, Norway, and Liechtenstein.

Eltrombopag was previously approved by the EC for use in adults with refractory chronic ITP. The drug is also approved in the EC to treat adults with severe aplastic anemia and adults with chronic hepatitis C virus infection who have thrombocytopenia.

Eltrombopag is made by Novartis. For more details on the drug, see the full Summary of Product Characteristics, available on the European Medicines Agency’s website.

The EC’s latest approval of eltrombopag was based on data from 2 double-blind, placebo-controlled trials—the phase 2 PETIT trial and the phase 3 PETIT2 trial.

PETIT trials: Efficacy

The PETIT trial included 67 ITP patients stratified by age cohort (12-17 years, 6-11 years, and 1-5 years). They were randomized (2:1) to receive eltrombopag or placebo for 7 weeks. The eltrombopag dose was titrated to a target platelet count of 50-200 x 10⁹/L.

The primary efficacy endpoint was the proportion of subjects achieving platelet counts of 50 x 10⁹/L or higher at least once between days 8 and 43 of the randomized period of the study.

Significantly more patients in the eltrombopag arm met this endpoint—62.2%—compared to 31.8% in the placebo arm (P=0.011).

The PETIT2 trial enrolled 92 patients with chronic ITP who were randomized (2:1) to receive eltrombopag or placebo for 13 weeks. The eltrombopag dose was titrated to a target platelet count of 50-200 x 10⁹/L.

The primary efficacy endpoint was the proportion of subjects who achieved platelet counts of 50 x 10⁹/L or higher for at least 6 out of 8 weeks, between weeks 5 and 12 of the randomized period.

Significantly more patients in the eltrombopag arm met this endpoint—41.3%—compared to 3.4% of patients in the placebo arm (P<0.001).

PETIT trials: Safety

For both trials, there were 107 eltrombopag-treated patients evaluable for safety.

The most common adverse events that occurred more frequently in the eltrombopag arms than the placebo arms were upper respiratory tract infection, nasopharyngitis, cough, diarrhea, pyrexia, rhinitis, abdominal pain, oropharyngeal pain, toothache, increased ALT/AST, rash, and rhinorrhea.

Serious adverse events were reported in 8% of patients during the randomized part of both trials, although no serious adverse event occurred in more than 1 patient.

An ALT elevation of at least 3 times the upper limit of normal occurred in 5% of eltrombopag-treated patients. Of those patients, 2% had ALT increases of at least 5 times the upper limit of normal.

There were no deaths or thromboembolic events during either study.

Red blood cells

Top-line results from a phase 3 trial suggest the oral, iron-based drug ferric citrate is more effective than placebo for treating iron deficiency anemia in adults with stage 3-5, non-dialysis-dependent chronic kidney disease.

Fifty-two percent of patients who received ferric citrate achieved at least a 1 g/dL increase in hemoglobin over a 16-week period, compared to 19% of patients who received placebo.

Researchers said the safety profile of ferric citrate in this trial was consistent with that in previous studies.

Keryx Biopharmaceuticals, Inc., the company developing ferric citrate, recently announced these results.

Patients and treatment

In this phase 3 study, researchers compared treatment with ferric citrate to placebo in 234 patients who previously had not adequately responded to or tolerated current oral iron therapies. The patients were not allowed to receive any iron (intravenous or oral) or erythropoiesis-stimulating agents during this study.

The patients were randomized 1:1 to receive ferric citrate (n=117) or placebo (n=115). Two patients in the placebo arm discontinued the study and were not included in the efficacy analysis. One discontinued after randomization prior to receiving placebo, and the other discontinued after taking a dose of placebo but before having laboratory values drawn.

The study had a 16-week, randomized, double-blind, placebo-controlled efficacy period, followed by an 8-week, open-label safety extension period. During the extension period, all patients remaining in the study, including the placebo arm, received ferric citrate.

During the efficacy period, ferric citrate was administered at a starting dose of 3 tablets per day, with food, and could be titrated every 4 weeks by an additional 3 tablets, for up to 12 tablets per day. The mean dose of ferric citrate was 5 tablets per day.

Baseline laboratory values were similar between the treatment arms. The mean hemoglobin was 10.4 g/dL in both arms.

The mean transferrin saturation was 20.2% in the ferric citrate arm and 19.6% in the placebo arm. The mean ferritin was 85.9 ng/mL and 81.7 ng/mL, respectively. And the mean serum phosphate was 4.2 mg/dL and 4.1 mg/dL, respectively.

Efficacy results

The study achieved its primary endpoint, with 52.1% (61/117) of patients who received ferric citrate achieving a 1g/dL or greater rise in hemoglobin at any time point during the 16-week efficacy period, compared to 19.1% (22/115) of patients in the placebo arm (P<0.001).

The researchers also observed significant differences in all pre-specified secondary efficacy endpoints.

The mean change in hemoglobin was 0.75 g/dL in the ferric citrate arm and -0.08 g/dL in the placebo arm (P<0.001). The mean change in transferrin saturation was 17.8% and -0.6%, respectively (P<0.001).

The mean change in ferritin was 162.5 ng/mL and -7.7 ng/mL, respectively (P<0.001). And the mean change in serum phosphate was -0.43 mg/dL and -0.22 mg/dL, respectively (P=0.02).

The proportion of patients with a durable response during the efficacy period was 48.7% in the ferric citrate arm and 14.8% in the placebo arm (P<0.001).

A durable response was defined as a mean change in hemoglobin from baseline of at least 0.75 g/dL over any 4-week time period during the efficacy period, provided that an increase of at least 1.0 g/dL had occurred during that 4-week period.

Safety results

During the efficacy period, the majority of adverse events (AEs) were mild to moderate. The most common AEs—in the ferric citrate and placebo arms, respectively—were diarrhea (20.5% vs 16.4%), constipation (18.8% vs 12.9%), discolored feces (14.5% vs 0%), and nausea (11.1% vs 2.6%).

Hypophosphatemia was reported in 4 patients—1 in the ferric citrate arm and 3 in the placebo arm.

Twenty-six percent (31/117) of ferric citrate-treated patients and 30% (35/116) of patients receiving placebo discontinued treatment during the efficacy period. Twelve patients treated with ferric citrate discontinued due to an AE, as did 10 patients who received placebo.

During the efficacy period, the rate of serious AEs was balanced between the ferric citrate and placebo arms, at 12% and 10%, respectively. None of the serious AEs were deemed drug-related.

Over the course of the study, there were 2 deaths reported. Both occurred in patients receiving ferric citrate, but neither were considered drug-related.

Red blood cells

Top-line results from a phase 3 trial suggest the oral, iron-based drug ferric citrate is more effective than placebo for treating iron deficiency anemia in adults with stage 3-5, non-dialysis-dependent chronic kidney disease.

Fifty-two percent of patients who received ferric citrate achieved at least a 1 g/dL increase in hemoglobin over a 16-week period, compared to 19% of patients who received placebo.

Researchers said the safety profile of ferric citrate in this trial was consistent with that in previous studies.

Keryx Biopharmaceuticals, Inc., the company developing ferric citrate, recently announced these results.

Patients and treatment

In this phase 3 study, researchers compared treatment with ferric citrate to placebo in 234 patients who previously had not adequately responded to or tolerated current oral iron therapies. The patients were not allowed to receive any iron (intravenous or oral) or erythropoiesis-stimulating agents during this study.

The patients were randomized 1:1 to receive ferric citrate (n=117) or placebo (n=115). Two patients in the placebo arm discontinued the study and were not included in the efficacy analysis. One discontinued after randomization prior to receiving placebo, and the other discontinued after taking a dose of placebo but before having laboratory values drawn.

The study had a 16-week, randomized, double-blind, placebo-controlled efficacy period, followed by an 8-week, open-label safety extension period. During the extension period, all patients remaining in the study, including the placebo arm, received ferric citrate.

During the efficacy period, ferric citrate was administered at a starting dose of 3 tablets per day, with food, and could be titrated every 4 weeks by an additional 3 tablets, for up to 12 tablets per day. The mean dose of ferric citrate was 5 tablets per day.

Baseline laboratory values were similar between the treatment arms. The mean hemoglobin was 10.4 g/dL in both arms.

The mean transferrin saturation was 20.2% in the ferric citrate arm and 19.6% in the placebo arm. The mean ferritin was 85.9 ng/mL and 81.7 ng/mL, respectively. And the mean serum phosphate was 4.2 mg/dL and 4.1 mg/dL, respectively.

Efficacy results

The study achieved its primary endpoint, with 52.1% (61/117) of patients who received ferric citrate achieving a 1g/dL or greater rise in hemoglobin at any time point during the 16-week efficacy period, compared to 19.1% (22/115) of patients in the placebo arm (P<0.001).

The researchers also observed significant differences in all pre-specified secondary efficacy endpoints.

The mean change in hemoglobin was 0.75 g/dL in the ferric citrate arm and -0.08 g/dL in the placebo arm (P<0.001). The mean change in transferrin saturation was 17.8% and -0.6%, respectively (P<0.001).

The mean change in ferritin was 162.5 ng/mL and -7.7 ng/mL, respectively (P<0.001). And the mean change in serum phosphate was -0.43 mg/dL and -0.22 mg/dL, respectively (P=0.02).

The proportion of patients with a durable response during the efficacy period was 48.7% in the ferric citrate arm and 14.8% in the placebo arm (P<0.001).

A durable response was defined as a mean change in hemoglobin from baseline of at least 0.75 g/dL over any 4-week time period during the efficacy period, provided that an increase of at least 1.0 g/dL had occurred during that 4-week period.

Safety results

During the efficacy period, the majority of adverse events (AEs) were mild to moderate. The most common AEs—in the ferric citrate and placebo arms, respectively—were diarrhea (20.5% vs 16.4%), constipation (18.8% vs 12.9%), discolored feces (14.5% vs 0%), and nausea (11.1% vs 2.6%).

Hypophosphatemia was reported in 4 patients—1 in the ferric citrate arm and 3 in the placebo arm.

Twenty-six percent (31/117) of ferric citrate-treated patients and 30% (35/116) of patients receiving placebo discontinued treatment during the efficacy period. Twelve patients treated with ferric citrate discontinued due to an AE, as did 10 patients who received placebo.

During the efficacy period, the rate of serious AEs was balanced between the ferric citrate and placebo arms, at 12% and 10%, respectively. None of the serious AEs were deemed drug-related.

Over the course of the study, there were 2 deaths reported. Both occurred in patients receiving ferric citrate, but neither were considered drug-related.

Red blood cells

Top-line results from a phase 3 trial suggest the oral, iron-based drug ferric citrate is more effective than placebo for treating iron deficiency anemia in adults with stage 3-5, non-dialysis-dependent chronic kidney disease.

Fifty-two percent of patients who received ferric citrate achieved at least a 1 g/dL increase in hemoglobin over a 16-week period, compared to 19% of patients who received placebo.

Researchers said the safety profile of ferric citrate in this trial was consistent with that in previous studies.

Keryx Biopharmaceuticals, Inc., the company developing ferric citrate, recently announced these results.

Patients and treatment

In this phase 3 study, researchers compared treatment with ferric citrate to placebo in 234 patients who previously had not adequately responded to or tolerated current oral iron therapies. The patients were not allowed to receive any iron (intravenous or oral) or erythropoiesis-stimulating agents during this study.

The patients were randomized 1:1 to receive ferric citrate (n=117) or placebo (n=115). Two patients in the placebo arm discontinued the study and were not included in the efficacy analysis. One discontinued after randomization prior to receiving placebo, and the other discontinued after taking a dose of placebo but before having laboratory values drawn.

The study had a 16-week, randomized, double-blind, placebo-controlled efficacy period, followed by an 8-week, open-label safety extension period. During the extension period, all patients remaining in the study, including the placebo arm, received ferric citrate.

During the efficacy period, ferric citrate was administered at a starting dose of 3 tablets per day, with food, and could be titrated every 4 weeks by an additional 3 tablets, for up to 12 tablets per day. The mean dose of ferric citrate was 5 tablets per day.

Baseline laboratory values were similar between the treatment arms. The mean hemoglobin was 10.4 g/dL in both arms.

The mean transferrin saturation was 20.2% in the ferric citrate arm and 19.6% in the placebo arm. The mean ferritin was 85.9 ng/mL and 81.7 ng/mL, respectively. And the mean serum phosphate was 4.2 mg/dL and 4.1 mg/dL, respectively.

Efficacy results

The study achieved its primary endpoint, with 52.1% (61/117) of patients who received ferric citrate achieving a 1g/dL or greater rise in hemoglobin at any time point during the 16-week efficacy period, compared to 19.1% (22/115) of patients in the placebo arm (P<0.001).

The researchers also observed significant differences in all pre-specified secondary efficacy endpoints.

The mean change in hemoglobin was 0.75 g/dL in the ferric citrate arm and -0.08 g/dL in the placebo arm (P<0.001). The mean change in transferrin saturation was 17.8% and -0.6%, respectively (P<0.001).

The mean change in ferritin was 162.5 ng/mL and -7.7 ng/mL, respectively (P<0.001). And the mean change in serum phosphate was -0.43 mg/dL and -0.22 mg/dL, respectively (P=0.02).

The proportion of patients with a durable response during the efficacy period was 48.7% in the ferric citrate arm and 14.8% in the placebo arm (P<0.001).

A durable response was defined as a mean change in hemoglobin from baseline of at least 0.75 g/dL over any 4-week time period during the efficacy period, provided that an increase of at least 1.0 g/dL had occurred during that 4-week period.

Safety results

During the efficacy period, the majority of adverse events (AEs) were mild to moderate. The most common AEs—in the ferric citrate and placebo arms, respectively—were diarrhea (20.5% vs 16.4%), constipation (18.8% vs 12.9%), discolored feces (14.5% vs 0%), and nausea (11.1% vs 2.6%).

Hypophosphatemia was reported in 4 patients—1 in the ferric citrate arm and 3 in the placebo arm.

Twenty-six percent (31/117) of ferric citrate-treated patients and 30% (35/116) of patients receiving placebo discontinued treatment during the efficacy period. Twelve patients treated with ferric citrate discontinued due to an AE, as did 10 patients who received placebo.

During the efficacy period, the rate of serious AEs was balanced between the ferric citrate and placebo arms, at 12% and 10%, respectively. None of the serious AEs were deemed drug-related.

Over the course of the study, there were 2 deaths reported. Both occurred in patients receiving ferric citrate, but neither were considered drug-related.