Anemia

A novel agent holds promise as a treatment option for anemia in patients with lower-risk myelodysplastic syndromes who are not helped by erythropoiesis-stimulating agents (ESAs), according to results from a phase 2 trial.

Sotatercept (ACE-011) is a first-in-class novel recombinant fusion protein, and was found to be effective and well tolerated, increasing hemoglobin concentrations and decreasing the transfusion burden in this patient population.

Nearly half (29, 47%) of 62 patients with a high transfusion burden achieved hematologic improvement–erythroid (HI-E), which for them was a reduction in red blood cell transfusion from baseline of 4 U or more for at least 56 days. Additionally, 7 of 12 patients (58%) with a low transfusion burden also achieved HI-E, defined as an increase in hemoglobin of 1.5 g/dL or more that was sustained for at least 56 days without a transfusion.

“Taken together, these findings provide proof of principle that the recombinant protein sotatercept can restore ineffective erythropoiesis in patients with lower-risk myelodysplastic syndromes, with an acceptable safety profile,” Rami Komrokji, MD, of Moffitt Cancer Center and Research Institute, Tampa, and his colleagues, wrote in the Lancet Haematology.

There are few effective treatment options available for patients with lower-risk myelodysplastic syndromes who have anemia, especially after they fail primary or secondary treatment with ESAs, or for those who are not likely to benefit from ESA therapy.

In this phase 2 trial, the researchers sought to establish a safe and effective dose of sotatercept in a cohort of 74 patients. Of this group, 7 received 0.1 mg/kg sotatercept, 6 got 0.3 mg/kg, 21 received 0.5 mg/kg, 35 got 1.0 mg/kg, and 5 patients received doses up to 2.0 mg/kg. The primary efficacy endpoint of the study was the proportion of patients who achieved HI-E.

All of the patients were pretreated, having received prior therapy for myelodysplastic syndromes, including ESAs, hypomethylating agents (azacitidine or decitabine), lenalidomide, and other agents including corticosteroids and immunomodulators.

Within this cohort, 36 patients (49%; 95% confidence intervaI, 38-60) achieved HI-E while 20 patients (27%; 95% CI, 18-38) achieved independence from transfusion for at least 56 days.

Fatigue (26%) and peripheral edema (24%) were the most common adverse events reported, while grade 3-4 treatment-emergent adverse events (TEAEs) were reported in 34% of patients. Of these, 4 patients had grade 3-4 TEAEs that were probably related to the treatment. The most common grade 3-4 TEAEs were lipase increase and anemia, and each was reported in three patients. Additionally, 17 patients (23%) experienced at least one serious TEAE, including a death from a treatment-emergent subdural hematoma (which caused the patient to fall).

The study was funded by the Celgene. Dr. Komrokji reported financial relationships with Celgene and Novartis. Other study authors reported relationships with various pharmaceutical companies.

SOURCE: Komrokji R et al. Lancet Haematol. 2018 Jan 10. doi: 10.1016/S2352-3026(18)30002-4.

A novel agent holds promise as a treatment option for anemia in patients with lower-risk myelodysplastic syndromes who are not helped by erythropoiesis-stimulating agents (ESAs), according to results from a phase 2 trial.

Sotatercept (ACE-011) is a first-in-class novel recombinant fusion protein, and was found to be effective and well tolerated, increasing hemoglobin concentrations and decreasing the transfusion burden in this patient population.

Nearly half (29, 47%) of 62 patients with a high transfusion burden achieved hematologic improvement–erythroid (HI-E), which for them was a reduction in red blood cell transfusion from baseline of 4 U or more for at least 56 days. Additionally, 7 of 12 patients (58%) with a low transfusion burden also achieved HI-E, defined as an increase in hemoglobin of 1.5 g/dL or more that was sustained for at least 56 days without a transfusion.

“Taken together, these findings provide proof of principle that the recombinant protein sotatercept can restore ineffective erythropoiesis in patients with lower-risk myelodysplastic syndromes, with an acceptable safety profile,” Rami Komrokji, MD, of Moffitt Cancer Center and Research Institute, Tampa, and his colleagues, wrote in the Lancet Haematology.

There are few effective treatment options available for patients with lower-risk myelodysplastic syndromes who have anemia, especially after they fail primary or secondary treatment with ESAs, or for those who are not likely to benefit from ESA therapy.

In this phase 2 trial, the researchers sought to establish a safe and effective dose of sotatercept in a cohort of 74 patients. Of this group, 7 received 0.1 mg/kg sotatercept, 6 got 0.3 mg/kg, 21 received 0.5 mg/kg, 35 got 1.0 mg/kg, and 5 patients received doses up to 2.0 mg/kg. The primary efficacy endpoint of the study was the proportion of patients who achieved HI-E.

All of the patients were pretreated, having received prior therapy for myelodysplastic syndromes, including ESAs, hypomethylating agents (azacitidine or decitabine), lenalidomide, and other agents including corticosteroids and immunomodulators.

Within this cohort, 36 patients (49%; 95% confidence intervaI, 38-60) achieved HI-E while 20 patients (27%; 95% CI, 18-38) achieved independence from transfusion for at least 56 days.

Fatigue (26%) and peripheral edema (24%) were the most common adverse events reported, while grade 3-4 treatment-emergent adverse events (TEAEs) were reported in 34% of patients. Of these, 4 patients had grade 3-4 TEAEs that were probably related to the treatment. The most common grade 3-4 TEAEs were lipase increase and anemia, and each was reported in three patients. Additionally, 17 patients (23%) experienced at least one serious TEAE, including a death from a treatment-emergent subdural hematoma (which caused the patient to fall).

The study was funded by the Celgene. Dr. Komrokji reported financial relationships with Celgene and Novartis. Other study authors reported relationships with various pharmaceutical companies.

SOURCE: Komrokji R et al. Lancet Haematol. 2018 Jan 10. doi: 10.1016/S2352-3026(18)30002-4.

A novel agent holds promise as a treatment option for anemia in patients with lower-risk myelodysplastic syndromes who are not helped by erythropoiesis-stimulating agents (ESAs), according to results from a phase 2 trial.

Sotatercept (ACE-011) is a first-in-class novel recombinant fusion protein, and was found to be effective and well tolerated, increasing hemoglobin concentrations and decreasing the transfusion burden in this patient population.

Nearly half (29, 47%) of 62 patients with a high transfusion burden achieved hematologic improvement–erythroid (HI-E), which for them was a reduction in red blood cell transfusion from baseline of 4 U or more for at least 56 days. Additionally, 7 of 12 patients (58%) with a low transfusion burden also achieved HI-E, defined as an increase in hemoglobin of 1.5 g/dL or more that was sustained for at least 56 days without a transfusion.

“Taken together, these findings provide proof of principle that the recombinant protein sotatercept can restore ineffective erythropoiesis in patients with lower-risk myelodysplastic syndromes, with an acceptable safety profile,” Rami Komrokji, MD, of Moffitt Cancer Center and Research Institute, Tampa, and his colleagues, wrote in the Lancet Haematology.

There are few effective treatment options available for patients with lower-risk myelodysplastic syndromes who have anemia, especially after they fail primary or secondary treatment with ESAs, or for those who are not likely to benefit from ESA therapy.

In this phase 2 trial, the researchers sought to establish a safe and effective dose of sotatercept in a cohort of 74 patients. Of this group, 7 received 0.1 mg/kg sotatercept, 6 got 0.3 mg/kg, 21 received 0.5 mg/kg, 35 got 1.0 mg/kg, and 5 patients received doses up to 2.0 mg/kg. The primary efficacy endpoint of the study was the proportion of patients who achieved HI-E.

All of the patients were pretreated, having received prior therapy for myelodysplastic syndromes, including ESAs, hypomethylating agents (azacitidine or decitabine), lenalidomide, and other agents including corticosteroids and immunomodulators.

Within this cohort, 36 patients (49%; 95% confidence intervaI, 38-60) achieved HI-E while 20 patients (27%; 95% CI, 18-38) achieved independence from transfusion for at least 56 days.

Fatigue (26%) and peripheral edema (24%) were the most common adverse events reported, while grade 3-4 treatment-emergent adverse events (TEAEs) were reported in 34% of patients. Of these, 4 patients had grade 3-4 TEAEs that were probably related to the treatment. The most common grade 3-4 TEAEs were lipase increase and anemia, and each was reported in three patients. Additionally, 17 patients (23%) experienced at least one serious TEAE, including a death from a treatment-emergent subdural hematoma (which caused the patient to fall).

The study was funded by the Celgene. Dr. Komrokji reported financial relationships with Celgene and Novartis. Other study authors reported relationships with various pharmaceutical companies.

SOURCE: Komrokji R et al. Lancet Haematol. 2018 Jan 10. doi: 10.1016/S2352-3026(18)30002-4.

Micrograph showing MDS

Researchers have developed a technique that may help predict whether patients with myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) will respond to treatment with azacytidine (AZA).

“The new method, called AZA-MS, utilizes a cutting-edge technique known as mass spectrometry to measure the different forms of AZA inside blood cells of patients—such as the AZA molecules that are incorporated into the DNA or RNA,” said Ashwin Unnikrishnan, PhD, of the University of New South Wales in Sydney, Australia.

With this method, Dr Unnikrishnan and his colleagues found that patients who do not respond to AZA may incorporate fewer AZA molecules in their DNA and have lower DNA demethylation than responders. However, this is not always the case.

The researchers reported these findings in Leukemia.

The team initially tested AZA-MS in AZA-treated RKO cells and found that AZA-MS could quantify the ribonucleoside (5-AZA-cR) and deoxyribonucleoside (5-AZA-CdR) forms of AZA in RNA, DNA, and the cytoplasm—all in the same sample.

The researchers also found that AZA induced dose-dependent DNA demethylation but did not have an effect on RNA methylation.

The team then used AZA-MS to analyze bone marrow samples from patients with MDS (n=4) or CMML (n=4) who were undergoing treatment with AZA. All of the patients had received at least 6 cycles of the drug.

Each patient had 3 bone marrow samples collected—one immediately before starting treatment; one on day 8 of cycle 1 (C1d8); and one on day 28 of cycle 1 (C1d28), when they had spent 20 days off the drug.

Four of the patients were complete responders, and 4 were nonresponders. In each group, 2 patients had MDS, and 2 had CMML.

At C1d8, DNA-5-AZA-CdR was significantly greater in responders than nonresponders. And, overall, responders had increased DNA demethylation compared to nonresponders.

However, the researchers also observed differences among the nonresponders. Two nonresponders had very low levels of DNA-5-AZA-CdR at C1d8 and no demethylation. The other 2 nonresponders had much higher DNA-5-AZA-CdR and DNA demethylation levels, which were comparable to levels in responders.

The researchers said they could detect AZA and DNA-5-AZA-CdR intracellularly, as well as RNA-AZA, in the nonresponders with minimal DNA-5-AZA-CdR and DNA demethylation.

The team said this suggests that neither cellular uptake nor intracellular metabolism explain the low DNA-5-AZA-CdR in these patients. Instead, the researchers believe these patients may have a greater proportion of bone marrow cells that are quiescent and not undergoing DNA replication.

The researchers also believe the nonresponders with higher DNA-5-AZA-CdR may be explained by a failure to induce an interferon response, which is necessary for a clinical response.

On the other hand, these nonresponders could have defective immune cell-mediated clearance of dysplastic cells or increased tolerance to this clearance, the researchers said.

The team also noted that, at C1d28, DNA-5-AZA-CdR levels dropped (but were still detectable) in all 8 patients, and DNA methylation had nearly returned to pretreatment levels in all patients.

Micrograph showing MDS

Researchers have developed a technique that may help predict whether patients with myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) will respond to treatment with azacytidine (AZA).

“The new method, called AZA-MS, utilizes a cutting-edge technique known as mass spectrometry to measure the different forms of AZA inside blood cells of patients—such as the AZA molecules that are incorporated into the DNA or RNA,” said Ashwin Unnikrishnan, PhD, of the University of New South Wales in Sydney, Australia.

With this method, Dr Unnikrishnan and his colleagues found that patients who do not respond to AZA may incorporate fewer AZA molecules in their DNA and have lower DNA demethylation than responders. However, this is not always the case.

The researchers reported these findings in Leukemia.

The team initially tested AZA-MS in AZA-treated RKO cells and found that AZA-MS could quantify the ribonucleoside (5-AZA-cR) and deoxyribonucleoside (5-AZA-CdR) forms of AZA in RNA, DNA, and the cytoplasm—all in the same sample.

The researchers also found that AZA induced dose-dependent DNA demethylation but did not have an effect on RNA methylation.

The team then used AZA-MS to analyze bone marrow samples from patients with MDS (n=4) or CMML (n=4) who were undergoing treatment with AZA. All of the patients had received at least 6 cycles of the drug.

Each patient had 3 bone marrow samples collected—one immediately before starting treatment; one on day 8 of cycle 1 (C1d8); and one on day 28 of cycle 1 (C1d28), when they had spent 20 days off the drug.

Four of the patients were complete responders, and 4 were nonresponders. In each group, 2 patients had MDS, and 2 had CMML.

At C1d8, DNA-5-AZA-CdR was significantly greater in responders than nonresponders. And, overall, responders had increased DNA demethylation compared to nonresponders.

However, the researchers also observed differences among the nonresponders. Two nonresponders had very low levels of DNA-5-AZA-CdR at C1d8 and no demethylation. The other 2 nonresponders had much higher DNA-5-AZA-CdR and DNA demethylation levels, which were comparable to levels in responders.

The researchers said they could detect AZA and DNA-5-AZA-CdR intracellularly, as well as RNA-AZA, in the nonresponders with minimal DNA-5-AZA-CdR and DNA demethylation.

The team said this suggests that neither cellular uptake nor intracellular metabolism explain the low DNA-5-AZA-CdR in these patients. Instead, the researchers believe these patients may have a greater proportion of bone marrow cells that are quiescent and not undergoing DNA replication.

The researchers also believe the nonresponders with higher DNA-5-AZA-CdR may be explained by a failure to induce an interferon response, which is necessary for a clinical response.

On the other hand, these nonresponders could have defective immune cell-mediated clearance of dysplastic cells or increased tolerance to this clearance, the researchers said.

The team also noted that, at C1d28, DNA-5-AZA-CdR levels dropped (but were still detectable) in all 8 patients, and DNA methylation had nearly returned to pretreatment levels in all patients.

Micrograph showing MDS

Researchers have developed a technique that may help predict whether patients with myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) will respond to treatment with azacytidine (AZA).

“The new method, called AZA-MS, utilizes a cutting-edge technique known as mass spectrometry to measure the different forms of AZA inside blood cells of patients—such as the AZA molecules that are incorporated into the DNA or RNA,” said Ashwin Unnikrishnan, PhD, of the University of New South Wales in Sydney, Australia.

With this method, Dr Unnikrishnan and his colleagues found that patients who do not respond to AZA may incorporate fewer AZA molecules in their DNA and have lower DNA demethylation than responders. However, this is not always the case.

The researchers reported these findings in Leukemia.

The team initially tested AZA-MS in AZA-treated RKO cells and found that AZA-MS could quantify the ribonucleoside (5-AZA-cR) and deoxyribonucleoside (5-AZA-CdR) forms of AZA in RNA, DNA, and the cytoplasm—all in the same sample.

The researchers also found that AZA induced dose-dependent DNA demethylation but did not have an effect on RNA methylation.

The team then used AZA-MS to analyze bone marrow samples from patients with MDS (n=4) or CMML (n=4) who were undergoing treatment with AZA. All of the patients had received at least 6 cycles of the drug.

Each patient had 3 bone marrow samples collected—one immediately before starting treatment; one on day 8 of cycle 1 (C1d8); and one on day 28 of cycle 1 (C1d28), when they had spent 20 days off the drug.

Four of the patients were complete responders, and 4 were nonresponders. In each group, 2 patients had MDS, and 2 had CMML.

At C1d8, DNA-5-AZA-CdR was significantly greater in responders than nonresponders. And, overall, responders had increased DNA demethylation compared to nonresponders.

However, the researchers also observed differences among the nonresponders. Two nonresponders had very low levels of DNA-5-AZA-CdR at C1d8 and no demethylation. The other 2 nonresponders had much higher DNA-5-AZA-CdR and DNA demethylation levels, which were comparable to levels in responders.

The researchers said they could detect AZA and DNA-5-AZA-CdR intracellularly, as well as RNA-AZA, in the nonresponders with minimal DNA-5-AZA-CdR and DNA demethylation.

The team said this suggests that neither cellular uptake nor intracellular metabolism explain the low DNA-5-AZA-CdR in these patients. Instead, the researchers believe these patients may have a greater proportion of bone marrow cells that are quiescent and not undergoing DNA replication.

The researchers also believe the nonresponders with higher DNA-5-AZA-CdR may be explained by a failure to induce an interferon response, which is necessary for a clinical response.

On the other hand, these nonresponders could have defective immune cell-mediated clearance of dysplastic cells or increased tolerance to this clearance, the researchers said.

The team also noted that, at C1d28, DNA-5-AZA-CdR levels dropped (but were still detectable) in all 8 patients, and DNA methylation had nearly returned to pretreatment levels in all patients.

Image by Betty Pace

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to voxelotor (previously GBT440) for the treatment of sickle cell disease (SCD).

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

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

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

The FDA previously granted voxelotor fast track designation, orphan drug designation, and rare pediatric disease designation.

The FDA’s decision to grant breakthrough therapy designation to voxelotor was based on clinical data submitted from the following studies:

• Part A of the phase 3 HOPE study (GBT440-031)
• A phase 1/2 study and open-label extension in adults (GBT440-001/GBT440-024), which was presented at the 2016 ASH Annual Meeting
• The ongoing phase 2 HOPE-KIDS 1 study in children age 6 to 17 (GBT440-007), which was presented at the 2017 ASH Annual Meeting (abstract 689)
• The compassionate access experience in adults with severe SCD who were not eligible for the HOPE study, which was presented at the 2017 ASH Annual Meeting (abstract 3545).

About breakthrough designation

The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.

The designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review.

To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.

Image by Betty Pace

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to voxelotor (previously GBT440) for the treatment of sickle cell disease (SCD).

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

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

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

The FDA previously granted voxelotor fast track designation, orphan drug designation, and rare pediatric disease designation.

The FDA’s decision to grant breakthrough therapy designation to voxelotor was based on clinical data submitted from the following studies:

• Part A of the phase 3 HOPE study (GBT440-031)
• A phase 1/2 study and open-label extension in adults (GBT440-001/GBT440-024), which was presented at the 2016 ASH Annual Meeting
• The ongoing phase 2 HOPE-KIDS 1 study in children age 6 to 17 (GBT440-007), which was presented at the 2017 ASH Annual Meeting (abstract 689)
• The compassionate access experience in adults with severe SCD who were not eligible for the HOPE study, which was presented at the 2017 ASH Annual Meeting (abstract 3545).

About breakthrough designation

The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.

The designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review.

To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.

Image by Betty Pace

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to voxelotor (previously GBT440) for the treatment of sickle cell disease (SCD).

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

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

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

The FDA previously granted voxelotor fast track designation, orphan drug designation, and rare pediatric disease designation.

The FDA’s decision to grant breakthrough therapy designation to voxelotor was based on clinical data submitted from the following studies:

• Part A of the phase 3 HOPE study (GBT440-031)
• A phase 1/2 study and open-label extension in adults (GBT440-001/GBT440-024), which was presented at the 2016 ASH Annual Meeting
• The ongoing phase 2 HOPE-KIDS 1 study in children age 6 to 17 (GBT440-007), which was presented at the 2017 ASH Annual Meeting (abstract 689)
• The compassionate access experience in adults with severe SCD who were not eligible for the HOPE study, which was presented at the 2017 ASH Annual Meeting (abstract 3545).

About breakthrough designation

The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.

The designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review.

To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.

Marie Scully, MD

ATLANTA—Caplacizumab can improve outcomes in patients with acquired thrombotic thrombocytopenic purpura (aTTP), according to research presented at the 2017 ASH Annual Meeting.

In the phase 3 HERCULES trial, researchers compared caplacizumab, an anti-von Willebrand factor nanobody, plus standard care (plasma exchange and immunosuppression) to placebo plus standard care in patients with aTTP.

Patients who received caplacizumab were significantly more likely to achieve platelet normalization and significantly less likely to experience aTTP-related death, aTTP recurrence, and major thromboembolic events.

Patients in the caplacizumab arm also required plasma exchange less frequently and spent less time in the hospital and intensive care unit (ICU).

Bleeding-related adverse events (AEs) were more common among patients who received caplacizumab than those who received placebo.

Marie Scully, MD, of the University College London Hospitals in London, UK, presented these results from HERCULES as a late-breaking abstract at the ASH Annual Meeting (abstract LBA-1). HERCULES was supported by Ablynx.

Patients and treatment

The study enrolled patients with an acute episode of aTTP. They were randomized to receive either caplacizumab (n=72) or placebo (n=73) in addition to standard care, which consisted of plasma exchange and immunosuppression.

Patients received a single intravenous bolus of 10 mg of caplacizumab or placebo followed by a daily subcutaneous dose of 10 mg of caplacizumab or placebo until 30 days after the last daily plasma exchange. If patients had a recurrence during the 30-day treatment period, they could go on to receive open-label caplacizumab.

If, at the end of the 30-day treatment period, there was evidence of persistent underlying disease activity indicative of an imminent risk for recurrence, caplacizumab or placebo could be extended for additional 7-day periods up to a maximum of 28 days. Patients were followed for a further 28 days after discontinuation of treatment.

In all, 71 patients received caplacizumab, and 58 (80.6%) of them completed the treatment. Seventy-three patients received placebo, and 50 of these patients (68.5%) completed treatment. Twenty-six patients in the placebo arm and 2 patients in the caplacizumab arm received open-label caplacizumab.

“If we look at the demographics, they’re relatively comparable to any data we normally see in patients with immune-mediated TTP,” Dr Scully said.

At baseline, the mean age was 44.9 in the caplacizumab arm and 47.3 in the placebo arm. Most patients in both arms were female—68.1% and 69.9%, respectively.

The proportion of patients with an initial aTTP episode was 66.7% in the caplacizumab arm and 46.6% in the placebo arm. The proportion with a recurrent episode was 33.3% and 53.4%, respectively.

Most patients in both arms had ADAMTS13 activity below 10% at baseline—81.7% in the caplacizumab arm and 90.3% in the placebo arm.

The mean platelet count at baseline was 32.0 x 10⁹/L in the caplacizumab arm and 39.1 x 10⁹/L in the placebo arm.

Efficacy

The study’s primary endpoint was the time to normalization of platelet count response, which was defined as initial platelet count of at least 150 x 10⁹/L with subsequent stop of daily plasma exchange within 5 days.

There was a significant reduction in time to platelet count response in the caplacizumab arm compared to the placebo arm. The platelet normalization rate ratio was 1.55 (P<0.01).

“Patients were 55% more likely to achieve normalization of their platelet count at any time in the caplacizumab group, and this was highly significant,” Dr Scully said.

A secondary endpoint was the combination of aTTP-related death, aTTP recurrence, and at least 1 major thromboembolic event during study treatment. The incidence of this combined endpoint was 12.7% (n=9) in the caplacizumab arm and 49.3% (n=36) in the placebo arm (P<0.0001).

The incidence of aTTP-related death was 0% (n=0) in the caplacizumab arm and 4.1% (n=3) in the placebo arm. The incidence of aTTP recurrence was 4.2% (n=3) and 38.4% (n=28), respectively. And the incidence of at least 1 major thromboembolic event was 8.5% (n=6) and 8.2% (n=6), respectively.

The researchers also assessed aTTP recurrence during the overall study period, which occurred in 12.7% (n=9) of patients in the caplacizumab arm and 38.4% (n=28) in the placebo arm (P<0.001).

During the follow-up period, there were 6 relapses (9.1%) in the caplacizumab arm but none in the placebo arm.

“This tells us something about the pathophysiology of TTP and the role of caplacizumab,” Dr Scully said. “All of these patients, on stopping caplacizumab, had ADAMTS13 levels less than 5%. Therefore, it was important that their treatment was continued to ensure removal of antibody.”

According to the International TTP Working Group consensus definition, none of the patients in the caplacizumab arm and 7.0% (n=5) of patients in the placebo arm had refractory aTTP (P=0.018).

The mean number of days of plasma exchange during the overall treatment period was 5.8 days in the caplacizumab arm and 9.4 days in the placebo arm (a 38% relative reduction). The mean volume of plasma used was 21.3L and 35.9L, respectively (a 41% relative reduction).

The mean duration of hospital stay was 9.9 days in the caplacizumab arm and 14.4 days in the placebo arm (a 31% relative reduction).

For patients admitted to the ICU (28 in the caplacizumab arm and 27 in the placebo arm), the mean number of days in the ICU was 3.4 days in the caplacizumab arm and 9.7 days in the placebo arm (a 65% relative reduction).

Safety

“The safety profile [of caplacizumab] was comparable to previous results and in keeping with the mechanism of action,” Dr Scully said.

The proportion of patients with at least 1 treatment-emergent AE was 97.2% in the caplacizumab arm and 97.3% in the placebo arm.

The proportion of patients with at least 1 study-drug-related AE was 57.7% in the caplacizumab arm and 43.8% in the placebo arm. The rate of discontinuation due to at least 1 AE was 7.0% and 12.3%, respectively.

The incidence of bleeding-related AEs was higher in the caplacizumab arm (45.6%) than the placebo arm (23.3%).

Bleeding-related AEs (in the caplacizumab and placebo arms, respectively) included epistaxis (23.9% and 1.4%), gingival bleeding (11.3% and 0%), bruising (7.0% and 4.1%), hematuria (5.6% and 1.4%), vaginal hemorrhage (4.2% and 1.4%), menorrhagia (2.8% and 1.4%), catheter site hemorrhage (2.8% and 4.1%), injection site bruising (2.8% and 2.7%), hematochezia (2.8% and 0%), and hematoma (2.8% and 0%).

The proportion of patients with at least 1 serious AE was 39.4% (n=28) in the caplacizumab arm and 53.4% (n=39) in the placebo arm. The proportion of patients with at least 1 study-drug-related serious AE was 14.1% (n=10) and 5.5% (n=4), respectively.

During the treatment period, there were no deaths in the caplacizumab arm and 3 deaths in the placebo arm. There was 1 death in the caplacizumab arm during the follow-up period, but it was considered unrelated to caplacizumab.

Marie Scully, MD

ATLANTA—Caplacizumab can improve outcomes in patients with acquired thrombotic thrombocytopenic purpura (aTTP), according to research presented at the 2017 ASH Annual Meeting.

In the phase 3 HERCULES trial, researchers compared caplacizumab, an anti-von Willebrand factor nanobody, plus standard care (plasma exchange and immunosuppression) to placebo plus standard care in patients with aTTP.

Patients who received caplacizumab were significantly more likely to achieve platelet normalization and significantly less likely to experience aTTP-related death, aTTP recurrence, and major thromboembolic events.

Patients in the caplacizumab arm also required plasma exchange less frequently and spent less time in the hospital and intensive care unit (ICU).

Bleeding-related adverse events (AEs) were more common among patients who received caplacizumab than those who received placebo.

Marie Scully, MD, of the University College London Hospitals in London, UK, presented these results from HERCULES as a late-breaking abstract at the ASH Annual Meeting (abstract LBA-1). HERCULES was supported by Ablynx.

Patients and treatment

The study enrolled patients with an acute episode of aTTP. They were randomized to receive either caplacizumab (n=72) or placebo (n=73) in addition to standard care, which consisted of plasma exchange and immunosuppression.

Patients received a single intravenous bolus of 10 mg of caplacizumab or placebo followed by a daily subcutaneous dose of 10 mg of caplacizumab or placebo until 30 days after the last daily plasma exchange. If patients had a recurrence during the 30-day treatment period, they could go on to receive open-label caplacizumab.

If, at the end of the 30-day treatment period, there was evidence of persistent underlying disease activity indicative of an imminent risk for recurrence, caplacizumab or placebo could be extended for additional 7-day periods up to a maximum of 28 days. Patients were followed for a further 28 days after discontinuation of treatment.

In all, 71 patients received caplacizumab, and 58 (80.6%) of them completed the treatment. Seventy-three patients received placebo, and 50 of these patients (68.5%) completed treatment. Twenty-six patients in the placebo arm and 2 patients in the caplacizumab arm received open-label caplacizumab.

“If we look at the demographics, they’re relatively comparable to any data we normally see in patients with immune-mediated TTP,” Dr Scully said.

At baseline, the mean age was 44.9 in the caplacizumab arm and 47.3 in the placebo arm. Most patients in both arms were female—68.1% and 69.9%, respectively.

The proportion of patients with an initial aTTP episode was 66.7% in the caplacizumab arm and 46.6% in the placebo arm. The proportion with a recurrent episode was 33.3% and 53.4%, respectively.

Most patients in both arms had ADAMTS13 activity below 10% at baseline—81.7% in the caplacizumab arm and 90.3% in the placebo arm.

The mean platelet count at baseline was 32.0 x 10⁹/L in the caplacizumab arm and 39.1 x 10⁹/L in the placebo arm.

Efficacy

The study’s primary endpoint was the time to normalization of platelet count response, which was defined as initial platelet count of at least 150 x 10⁹/L with subsequent stop of daily plasma exchange within 5 days.

There was a significant reduction in time to platelet count response in the caplacizumab arm compared to the placebo arm. The platelet normalization rate ratio was 1.55 (P<0.01).

“Patients were 55% more likely to achieve normalization of their platelet count at any time in the caplacizumab group, and this was highly significant,” Dr Scully said.

A secondary endpoint was the combination of aTTP-related death, aTTP recurrence, and at least 1 major thromboembolic event during study treatment. The incidence of this combined endpoint was 12.7% (n=9) in the caplacizumab arm and 49.3% (n=36) in the placebo arm (P<0.0001).

The incidence of aTTP-related death was 0% (n=0) in the caplacizumab arm and 4.1% (n=3) in the placebo arm. The incidence of aTTP recurrence was 4.2% (n=3) and 38.4% (n=28), respectively. And the incidence of at least 1 major thromboembolic event was 8.5% (n=6) and 8.2% (n=6), respectively.

The researchers also assessed aTTP recurrence during the overall study period, which occurred in 12.7% (n=9) of patients in the caplacizumab arm and 38.4% (n=28) in the placebo arm (P<0.001).

During the follow-up period, there were 6 relapses (9.1%) in the caplacizumab arm but none in the placebo arm.

“This tells us something about the pathophysiology of TTP and the role of caplacizumab,” Dr Scully said. “All of these patients, on stopping caplacizumab, had ADAMTS13 levels less than 5%. Therefore, it was important that their treatment was continued to ensure removal of antibody.”

According to the International TTP Working Group consensus definition, none of the patients in the caplacizumab arm and 7.0% (n=5) of patients in the placebo arm had refractory aTTP (P=0.018).

The mean number of days of plasma exchange during the overall treatment period was 5.8 days in the caplacizumab arm and 9.4 days in the placebo arm (a 38% relative reduction). The mean volume of plasma used was 21.3L and 35.9L, respectively (a 41% relative reduction).

The mean duration of hospital stay was 9.9 days in the caplacizumab arm and 14.4 days in the placebo arm (a 31% relative reduction).

For patients admitted to the ICU (28 in the caplacizumab arm and 27 in the placebo arm), the mean number of days in the ICU was 3.4 days in the caplacizumab arm and 9.7 days in the placebo arm (a 65% relative reduction).

Safety

“The safety profile [of caplacizumab] was comparable to previous results and in keeping with the mechanism of action,” Dr Scully said.

The proportion of patients with at least 1 treatment-emergent AE was 97.2% in the caplacizumab arm and 97.3% in the placebo arm.

The proportion of patients with at least 1 study-drug-related AE was 57.7% in the caplacizumab arm and 43.8% in the placebo arm. The rate of discontinuation due to at least 1 AE was 7.0% and 12.3%, respectively.

The incidence of bleeding-related AEs was higher in the caplacizumab arm (45.6%) than the placebo arm (23.3%).

Bleeding-related AEs (in the caplacizumab and placebo arms, respectively) included epistaxis (23.9% and 1.4%), gingival bleeding (11.3% and 0%), bruising (7.0% and 4.1%), hematuria (5.6% and 1.4%), vaginal hemorrhage (4.2% and 1.4%), menorrhagia (2.8% and 1.4%), catheter site hemorrhage (2.8% and 4.1%), injection site bruising (2.8% and 2.7%), hematochezia (2.8% and 0%), and hematoma (2.8% and 0%).

The proportion of patients with at least 1 serious AE was 39.4% (n=28) in the caplacizumab arm and 53.4% (n=39) in the placebo arm. The proportion of patients with at least 1 study-drug-related serious AE was 14.1% (n=10) and 5.5% (n=4), respectively.

During the treatment period, there were no deaths in the caplacizumab arm and 3 deaths in the placebo arm. There was 1 death in the caplacizumab arm during the follow-up period, but it was considered unrelated to caplacizumab.

Marie Scully, MD

ATLANTA—Caplacizumab can improve outcomes in patients with acquired thrombotic thrombocytopenic purpura (aTTP), according to research presented at the 2017 ASH Annual Meeting.

In the phase 3 HERCULES trial, researchers compared caplacizumab, an anti-von Willebrand factor nanobody, plus standard care (plasma exchange and immunosuppression) to placebo plus standard care in patients with aTTP.

Patients who received caplacizumab were significantly more likely to achieve platelet normalization and significantly less likely to experience aTTP-related death, aTTP recurrence, and major thromboembolic events.

Patients in the caplacizumab arm also required plasma exchange less frequently and spent less time in the hospital and intensive care unit (ICU).

Bleeding-related adverse events (AEs) were more common among patients who received caplacizumab than those who received placebo.

Marie Scully, MD, of the University College London Hospitals in London, UK, presented these results from HERCULES as a late-breaking abstract at the ASH Annual Meeting (abstract LBA-1). HERCULES was supported by Ablynx.

Patients and treatment

The study enrolled patients with an acute episode of aTTP. They were randomized to receive either caplacizumab (n=72) or placebo (n=73) in addition to standard care, which consisted of plasma exchange and immunosuppression.

Patients received a single intravenous bolus of 10 mg of caplacizumab or placebo followed by a daily subcutaneous dose of 10 mg of caplacizumab or placebo until 30 days after the last daily plasma exchange. If patients had a recurrence during the 30-day treatment period, they could go on to receive open-label caplacizumab.

If, at the end of the 30-day treatment period, there was evidence of persistent underlying disease activity indicative of an imminent risk for recurrence, caplacizumab or placebo could be extended for additional 7-day periods up to a maximum of 28 days. Patients were followed for a further 28 days after discontinuation of treatment.

In all, 71 patients received caplacizumab, and 58 (80.6%) of them completed the treatment. Seventy-three patients received placebo, and 50 of these patients (68.5%) completed treatment. Twenty-six patients in the placebo arm and 2 patients in the caplacizumab arm received open-label caplacizumab.

“If we look at the demographics, they’re relatively comparable to any data we normally see in patients with immune-mediated TTP,” Dr Scully said.

At baseline, the mean age was 44.9 in the caplacizumab arm and 47.3 in the placebo arm. Most patients in both arms were female—68.1% and 69.9%, respectively.

The proportion of patients with an initial aTTP episode was 66.7% in the caplacizumab arm and 46.6% in the placebo arm. The proportion with a recurrent episode was 33.3% and 53.4%, respectively.

Most patients in both arms had ADAMTS13 activity below 10% at baseline—81.7% in the caplacizumab arm and 90.3% in the placebo arm.

The mean platelet count at baseline was 32.0 x 10⁹/L in the caplacizumab arm and 39.1 x 10⁹/L in the placebo arm.

Efficacy

The study’s primary endpoint was the time to normalization of platelet count response, which was defined as initial platelet count of at least 150 x 10⁹/L with subsequent stop of daily plasma exchange within 5 days.

There was a significant reduction in time to platelet count response in the caplacizumab arm compared to the placebo arm. The platelet normalization rate ratio was 1.55 (P<0.01).

“Patients were 55% more likely to achieve normalization of their platelet count at any time in the caplacizumab group, and this was highly significant,” Dr Scully said.

A secondary endpoint was the combination of aTTP-related death, aTTP recurrence, and at least 1 major thromboembolic event during study treatment. The incidence of this combined endpoint was 12.7% (n=9) in the caplacizumab arm and 49.3% (n=36) in the placebo arm (P<0.0001).

The incidence of aTTP-related death was 0% (n=0) in the caplacizumab arm and 4.1% (n=3) in the placebo arm. The incidence of aTTP recurrence was 4.2% (n=3) and 38.4% (n=28), respectively. And the incidence of at least 1 major thromboembolic event was 8.5% (n=6) and 8.2% (n=6), respectively.

The researchers also assessed aTTP recurrence during the overall study period, which occurred in 12.7% (n=9) of patients in the caplacizumab arm and 38.4% (n=28) in the placebo arm (P<0.001).

During the follow-up period, there were 6 relapses (9.1%) in the caplacizumab arm but none in the placebo arm.

“This tells us something about the pathophysiology of TTP and the role of caplacizumab,” Dr Scully said. “All of these patients, on stopping caplacizumab, had ADAMTS13 levels less than 5%. Therefore, it was important that their treatment was continued to ensure removal of antibody.”

According to the International TTP Working Group consensus definition, none of the patients in the caplacizumab arm and 7.0% (n=5) of patients in the placebo arm had refractory aTTP (P=0.018).

The mean number of days of plasma exchange during the overall treatment period was 5.8 days in the caplacizumab arm and 9.4 days in the placebo arm (a 38% relative reduction). The mean volume of plasma used was 21.3L and 35.9L, respectively (a 41% relative reduction).

The mean duration of hospital stay was 9.9 days in the caplacizumab arm and 14.4 days in the placebo arm (a 31% relative reduction).

For patients admitted to the ICU (28 in the caplacizumab arm and 27 in the placebo arm), the mean number of days in the ICU was 3.4 days in the caplacizumab arm and 9.7 days in the placebo arm (a 65% relative reduction).

Safety

“The safety profile [of caplacizumab] was comparable to previous results and in keeping with the mechanism of action,” Dr Scully said.

The proportion of patients with at least 1 treatment-emergent AE was 97.2% in the caplacizumab arm and 97.3% in the placebo arm.

The proportion of patients with at least 1 study-drug-related AE was 57.7% in the caplacizumab arm and 43.8% in the placebo arm. The rate of discontinuation due to at least 1 AE was 7.0% and 12.3%, respectively.

The incidence of bleeding-related AEs was higher in the caplacizumab arm (45.6%) than the placebo arm (23.3%).

Bleeding-related AEs (in the caplacizumab and placebo arms, respectively) included epistaxis (23.9% and 1.4%), gingival bleeding (11.3% and 0%), bruising (7.0% and 4.1%), hematuria (5.6% and 1.4%), vaginal hemorrhage (4.2% and 1.4%), menorrhagia (2.8% and 1.4%), catheter site hemorrhage (2.8% and 4.1%), injection site bruising (2.8% and 2.7%), hematochezia (2.8% and 0%), and hematoma (2.8% and 0%).

The proportion of patients with at least 1 serious AE was 39.4% (n=28) in the caplacizumab arm and 53.4% (n=39) in the placebo arm. The proportion of patients with at least 1 study-drug-related serious AE was 14.1% (n=10) and 5.5% (n=4), respectively.

During the treatment period, there were no deaths in the caplacizumab arm and 3 deaths in the placebo arm. There was 1 death in the caplacizumab arm during the follow-up period, but it was considered unrelated to caplacizumab.

Photo courtesy of GSK

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to eltrombopag (Promacta®) for use in combination with standard immunosuppressive therapy as first-line treatment for patients with severe aplastic anemia (SAA).

Novartis plans to submit an application to the FDA for this indication later this year.

Eltrombopag is already FDA-approved to treat SAA patients who have had an insufficient response to immunosuppressive therapy.

The drug is also approved to treat patients with chronic immune thrombocytopenia who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

And eltrombopag is approved to treat thrombocytopenia in patients with chronic hepatitis C to allow for the initiation and maintenance of interferon-based therapy.

Trial data

The breakthrough designation for eltrombopag as first-line treatment in SAA is supported by data from a phase 1/2 trial, which were published in NEJM in April 2017.

The trial included 92 patients with previously untreated SAA. They received immunosuppressive therapy and eltrombopag in 3 different cohorts.

Patients in cohort 1 received eltrombopag from day 14 to 6 months. Patients in cohort 2 received the drug from day 14 to 3 months. And patients in cohort 3 received eltrombopag from day 1 to 6 months.

At 6 months, the overall response rate was 80% in cohort 1, 87% in cohort 2, and 94% in cohort 3. The rate of complete response at 6 months was 33%, 26%, and 58%, respectively.

At a median follow-up of 2 years, the overall survival rate was 97%.

Seven patients briefly stopped taking eltrombopag during the first 2 weeks due to transient elevations in liver-enzyme levels.

There were 2 severe adverse events that were related to eltrombopag and resulted in patients stopping the drug. These were a grade 2 and grade 3 cutaneous eruption.

About breakthrough designation

The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.

The designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review.

To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.

Photo courtesy of GSK

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to eltrombopag (Promacta®) for use in combination with standard immunosuppressive therapy as first-line treatment for patients with severe aplastic anemia (SAA).

Novartis plans to submit an application to the FDA for this indication later this year.

Eltrombopag is already FDA-approved to treat SAA patients who have had an insufficient response to immunosuppressive therapy.

The drug is also approved to treat patients with chronic immune thrombocytopenia who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

And eltrombopag is approved to treat thrombocytopenia in patients with chronic hepatitis C to allow for the initiation and maintenance of interferon-based therapy.

Trial data

The breakthrough designation for eltrombopag as first-line treatment in SAA is supported by data from a phase 1/2 trial, which were published in NEJM in April 2017.

The trial included 92 patients with previously untreated SAA. They received immunosuppressive therapy and eltrombopag in 3 different cohorts.

Patients in cohort 1 received eltrombopag from day 14 to 6 months. Patients in cohort 2 received the drug from day 14 to 3 months. And patients in cohort 3 received eltrombopag from day 1 to 6 months.

At 6 months, the overall response rate was 80% in cohort 1, 87% in cohort 2, and 94% in cohort 3. The rate of complete response at 6 months was 33%, 26%, and 58%, respectively.

At a median follow-up of 2 years, the overall survival rate was 97%.

Seven patients briefly stopped taking eltrombopag during the first 2 weeks due to transient elevations in liver-enzyme levels.

There were 2 severe adverse events that were related to eltrombopag and resulted in patients stopping the drug. These were a grade 2 and grade 3 cutaneous eruption.

About breakthrough designation

The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.

The designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review.

To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.

Photo courtesy of GSK

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to eltrombopag (Promacta®) for use in combination with standard immunosuppressive therapy as first-line treatment for patients with severe aplastic anemia (SAA).

Novartis plans to submit an application to the FDA for this indication later this year.

Eltrombopag is already FDA-approved to treat SAA patients who have had an insufficient response to immunosuppressive therapy.

The drug is also approved to treat patients with chronic immune thrombocytopenia who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

And eltrombopag is approved to treat thrombocytopenia in patients with chronic hepatitis C to allow for the initiation and maintenance of interferon-based therapy.

Trial data

The breakthrough designation for eltrombopag as first-line treatment in SAA is supported by data from a phase 1/2 trial, which were published in NEJM in April 2017.

The trial included 92 patients with previously untreated SAA. They received immunosuppressive therapy and eltrombopag in 3 different cohorts.

Patients in cohort 1 received eltrombopag from day 14 to 6 months. Patients in cohort 2 received the drug from day 14 to 3 months. And patients in cohort 3 received eltrombopag from day 1 to 6 months.

At 6 months, the overall response rate was 80% in cohort 1, 87% in cohort 2, and 94% in cohort 3. The rate of complete response at 6 months was 33%, 26%, and 58%, respectively.

At a median follow-up of 2 years, the overall survival rate was 97%.

Seven patients briefly stopped taking eltrombopag during the first 2 weeks due to transient elevations in liver-enzyme levels.

There were 2 severe adverse events that were related to eltrombopag and resulted in patients stopping the drug. These were a grade 2 and grade 3 cutaneous eruption.

About breakthrough designation

The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.

The designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review.

To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.

The Food and Drug Administration has granted breakthrough therapy designation to eltrombopag (Promacta) for use in combination with standard immunosuppressive therapy as a first-line treatment for patients with severe aplastic anemia (SAA).

[email protected]

The Food and Drug Administration has granted breakthrough therapy designation to eltrombopag (Promacta) for use in combination with standard immunosuppressive therapy as a first-line treatment for patients with severe aplastic anemia (SAA).

[email protected]

The Food and Drug Administration has granted breakthrough therapy designation to eltrombopag (Promacta) for use in combination with standard immunosuppressive therapy as a first-line treatment for patients with severe aplastic anemia (SAA).

[email protected]

Hydroxyurea has been approved for use in pediatric sickle cell patients aged 2 years and older to reduce the frequency of painful crises and the need for blood transfusions, the Food and Drug Administration announced on Dec. 21.

This is the first FDA approval of hydroxyurea for use in pediatric sickle cell patients. The recommended initial dose is 20 mg/kg once daily but can be changed based on blood count levels, the agency said in a press release.

The approval of hydroxyurea was based on results from the European Sickle Cell Disease Cohort–Hydroxyurea study (ESCORT UH), an open-label, single-arm trial of 405 pediatric sickle cell patients between the ages of 2 and 18 years. Prior to enrolling in the study, 141 of the patients had not previously used hydroxyurea. Further study of the 141 patients found that hydroxyurea use led to an increase in hemoglobin F. After 12 months of hydroxyurea treatment, the percentage of patients who experienced vaso-occlusive episodes, acute chest syndrome, hospitalization due to sickle cell disease, or blood transfusions decreased.

The most common adverse reactions to hydroxyurea, infections and neutropenia, occurred in less than 10% of patients. Hydroxyurea causes severe myelosuppression and should not be administered to patients with depressed bone marrow function.

Hydroxyurea is manufactured as Siklos by Addmedica. More information concerning hydroxyurea indications, dosing, and precautions can be found here.

[email protected]

SOURCE: FDA press release.

Hydroxyurea has been approved for use in pediatric sickle cell patients aged 2 years and older to reduce the frequency of painful crises and the need for blood transfusions, the Food and Drug Administration announced on Dec. 21.

This is the first FDA approval of hydroxyurea for use in pediatric sickle cell patients. The recommended initial dose is 20 mg/kg once daily but can be changed based on blood count levels, the agency said in a press release.

The approval of hydroxyurea was based on results from the European Sickle Cell Disease Cohort–Hydroxyurea study (ESCORT UH), an open-label, single-arm trial of 405 pediatric sickle cell patients between the ages of 2 and 18 years. Prior to enrolling in the study, 141 of the patients had not previously used hydroxyurea. Further study of the 141 patients found that hydroxyurea use led to an increase in hemoglobin F. After 12 months of hydroxyurea treatment, the percentage of patients who experienced vaso-occlusive episodes, acute chest syndrome, hospitalization due to sickle cell disease, or blood transfusions decreased.

The most common adverse reactions to hydroxyurea, infections and neutropenia, occurred in less than 10% of patients. Hydroxyurea causes severe myelosuppression and should not be administered to patients with depressed bone marrow function.

Hydroxyurea is manufactured as Siklos by Addmedica. More information concerning hydroxyurea indications, dosing, and precautions can be found here.

[email protected]

SOURCE: FDA press release.

Hydroxyurea has been approved for use in pediatric sickle cell patients aged 2 years and older to reduce the frequency of painful crises and the need for blood transfusions, the Food and Drug Administration announced on Dec. 21.

This is the first FDA approval of hydroxyurea for use in pediatric sickle cell patients. The recommended initial dose is 20 mg/kg once daily but can be changed based on blood count levels, the agency said in a press release.

The approval of hydroxyurea was based on results from the European Sickle Cell Disease Cohort–Hydroxyurea study (ESCORT UH), an open-label, single-arm trial of 405 pediatric sickle cell patients between the ages of 2 and 18 years. Prior to enrolling in the study, 141 of the patients had not previously used hydroxyurea. Further study of the 141 patients found that hydroxyurea use led to an increase in hemoglobin F. After 12 months of hydroxyurea treatment, the percentage of patients who experienced vaso-occlusive episodes, acute chest syndrome, hospitalization due to sickle cell disease, or blood transfusions decreased.

The most common adverse reactions to hydroxyurea, infections and neutropenia, occurred in less than 10% of patients. Hydroxyurea causes severe myelosuppression and should not be administered to patients with depressed bone marrow function.

Hydroxyurea is manufactured as Siklos by Addmedica. More information concerning hydroxyurea indications, dosing, and precautions can be found here.

[email protected]

SOURCE: FDA press release.

Children’s Research Hospital

The US Food and Drug Administration (FDA) has approved a hydroxyurea product (Addmedica’s Siklos) for use in pediatric patients with sickle cell anemia.

Siklos is intended to reduce the frequency of painful crises and the need for blood transfusions in pediatric patients age 2 and older who have sickle cell anemia and recurrent moderate to severe painful crises.

The recommended dose of Siklos is 20 mg/kg once daily.

The FDA granted priority review and orphan drug designation to the application for Siklos.

The agency’s approval of Siklos was based on data from the ESCORT HU study (NCT02516579). The trial was an evaluation of Siklos in 405 patients, ages 2 to 18, with sickle cell disease (SCD).

Thirty-five percent of these patients (n=141) had not received hydroxyurea prior to study enrollment and were therefore evaluable for efficacy. The median follow-up was 23 months (range, 12 to 80 months).

The researchers found that Siklos prompted an increase in fetal hemoglobin. Median fetal hemoglobin percentages were 5.6% (range, 1.3 to 15.0) at baseline and 12.8% (range, 2.1 to 37.2) at around 6 months after Siklos initiation (the value closest to 6 months collected between 5 and 14 months).

In addition, the percentage of patients with at least 1 vaso-occlusive episode, 1 episode of acute chest syndrome, 1 hospitalization due to SCD, or 1 blood transfusion decreased after 12 months of Siklos treatment.

The proportion of patients with at least 1 vaso-occlusive episode was 69.2% at baseline and 42.5% at 12 months. The proportion with at least 1 episode of acute chest syndrome was 23.6% and 5.7%, respectively.

The proportion with at least 1 hospitalization due to SCD was 75.5% and 41.8%, respectively. And the proportion with at least 1 blood transfusion was 45.9% and 23.0%, respectively.

The most common adverse events (occurring in at least 10% of patients) were infections (39.8%), gastrointestinal disorders (13.1%), neutropenia (12.6%), nervous system disorders (11.1%), and metabolic and nutrition disorders (10.9%).

Full prescribing information for Siklos is available on the FDA website.

Children’s Research Hospital

The US Food and Drug Administration (FDA) has approved a hydroxyurea product (Addmedica’s Siklos) for use in pediatric patients with sickle cell anemia.

Siklos is intended to reduce the frequency of painful crises and the need for blood transfusions in pediatric patients age 2 and older who have sickle cell anemia and recurrent moderate to severe painful crises.

The recommended dose of Siklos is 20 mg/kg once daily.

The FDA granted priority review and orphan drug designation to the application for Siklos.

The agency’s approval of Siklos was based on data from the ESCORT HU study (NCT02516579). The trial was an evaluation of Siklos in 405 patients, ages 2 to 18, with sickle cell disease (SCD).

Thirty-five percent of these patients (n=141) had not received hydroxyurea prior to study enrollment and were therefore evaluable for efficacy. The median follow-up was 23 months (range, 12 to 80 months).

The researchers found that Siklos prompted an increase in fetal hemoglobin. Median fetal hemoglobin percentages were 5.6% (range, 1.3 to 15.0) at baseline and 12.8% (range, 2.1 to 37.2) at around 6 months after Siklos initiation (the value closest to 6 months collected between 5 and 14 months).

In addition, the percentage of patients with at least 1 vaso-occlusive episode, 1 episode of acute chest syndrome, 1 hospitalization due to SCD, or 1 blood transfusion decreased after 12 months of Siklos treatment.

The proportion of patients with at least 1 vaso-occlusive episode was 69.2% at baseline and 42.5% at 12 months. The proportion with at least 1 episode of acute chest syndrome was 23.6% and 5.7%, respectively.

The proportion with at least 1 hospitalization due to SCD was 75.5% and 41.8%, respectively. And the proportion with at least 1 blood transfusion was 45.9% and 23.0%, respectively.

The most common adverse events (occurring in at least 10% of patients) were infections (39.8%), gastrointestinal disorders (13.1%), neutropenia (12.6%), nervous system disorders (11.1%), and metabolic and nutrition disorders (10.9%).

Full prescribing information for Siklos is available on the FDA website.

Children’s Research Hospital

The US Food and Drug Administration (FDA) has approved a hydroxyurea product (Addmedica’s Siklos) for use in pediatric patients with sickle cell anemia.

Siklos is intended to reduce the frequency of painful crises and the need for blood transfusions in pediatric patients age 2 and older who have sickle cell anemia and recurrent moderate to severe painful crises.

The recommended dose of Siklos is 20 mg/kg once daily.

The FDA granted priority review and orphan drug designation to the application for Siklos.

The agency’s approval of Siklos was based on data from the ESCORT HU study (NCT02516579). The trial was an evaluation of Siklos in 405 patients, ages 2 to 18, with sickle cell disease (SCD).

Thirty-five percent of these patients (n=141) had not received hydroxyurea prior to study enrollment and were therefore evaluable for efficacy. The median follow-up was 23 months (range, 12 to 80 months).

The researchers found that Siklos prompted an increase in fetal hemoglobin. Median fetal hemoglobin percentages were 5.6% (range, 1.3 to 15.0) at baseline and 12.8% (range, 2.1 to 37.2) at around 6 months after Siklos initiation (the value closest to 6 months collected between 5 and 14 months).

In addition, the percentage of patients with at least 1 vaso-occlusive episode, 1 episode of acute chest syndrome, 1 hospitalization due to SCD, or 1 blood transfusion decreased after 12 months of Siklos treatment.

The proportion of patients with at least 1 vaso-occlusive episode was 69.2% at baseline and 42.5% at 12 months. The proportion with at least 1 episode of acute chest syndrome was 23.6% and 5.7%, respectively.

The proportion with at least 1 hospitalization due to SCD was 75.5% and 41.8%, respectively. And the proportion with at least 1 blood transfusion was 45.9% and 23.0%, respectively.

The most common adverse events (occurring in at least 10% of patients) were infections (39.8%), gastrointestinal disorders (13.1%), neutropenia (12.6%), nervous system disorders (11.1%), and metabolic and nutrition disorders (10.9%).

Full prescribing information for Siklos is available on the FDA website.

Waldenstrom disease, also known as Waldenstrom macroglobulinemia, has been linked to a rare bilateral facial nerve palsy in a second case report.

Bilateral facial nerve palsy has been associated with underlying Waldenstrom disease in only one other known published case report, which was published in 2014. In a more recent case report published in the Journal of Clinical Neuroscience, Gabriel Torrealba-Acosta, MD, and colleagues in the department of neurology at Massachusetts General Hospital, Boston, described a second case involving a 67-year-old Hispanic man with a history of Waldenstrom disease who presented with subacute onset of bilateral facial weakness.

Michail Charakidis, David Joseph Russell/Wikimedia Commons/CC BY 2.0

SOURCE: Torrealba-Acosta G et al. J Clin Neurosci. 2017. doi: 10.1016/j.jocn.2017.10.081.

Waldenstrom disease, also known as Waldenstrom macroglobulinemia, has been linked to a rare bilateral facial nerve palsy in a second case report.

Bilateral facial nerve palsy has been associated with underlying Waldenstrom disease in only one other known published case report, which was published in 2014. In a more recent case report published in the Journal of Clinical Neuroscience, Gabriel Torrealba-Acosta, MD, and colleagues in the department of neurology at Massachusetts General Hospital, Boston, described a second case involving a 67-year-old Hispanic man with a history of Waldenstrom disease who presented with subacute onset of bilateral facial weakness.

Michail Charakidis, David Joseph Russell/Wikimedia Commons/CC BY 2.0

SOURCE: Torrealba-Acosta G et al. J Clin Neurosci. 2017. doi: 10.1016/j.jocn.2017.10.081.

Waldenstrom disease, also known as Waldenstrom macroglobulinemia, has been linked to a rare bilateral facial nerve palsy in a second case report.

Bilateral facial nerve palsy has been associated with underlying Waldenstrom disease in only one other known published case report, which was published in 2014. In a more recent case report published in the Journal of Clinical Neuroscience, Gabriel Torrealba-Acosta, MD, and colleagues in the department of neurology at Massachusetts General Hospital, Boston, described a second case involving a 67-year-old Hispanic man with a history of Waldenstrom disease who presented with subacute onset of bilateral facial weakness.

Michail Charakidis, David Joseph Russell/Wikimedia Commons/CC BY 2.0

SOURCE: Torrealba-Acosta G et al. J Clin Neurosci. 2017. doi: 10.1016/j.jocn.2017.10.081.

CONCORD, N.C. – Teenage sickle cell disease patients transitioning to adulthood can often find the move to adult providers challenging, causing some patients to lose interest in self-care at a critical point in life, but a transitional program can help them develop the skills they need to manage their disease and avoid risky behaviors, according to psychologist Anya Griffin, PhD.

Managing pain in teenagers and young adults with sickle cell disease (SCD) is fraught with challenges, said Dr. Griffin, who led the SCD transition program at Children’s Healthcare of Atlanta and is now the clinical director of the Stanford (Calif.) Children’s Health Pediatric Rehabilitation Program, an intensive pain management program for pediatric chronic pain.

“Think about who you are when you’re a teenager, when you’re a young adult, what’s going on: dating, sex, parties, college, all-night study sessions,” she said at a Sickle Cell Disease Symposium held by Carolinas Health Care System. “But in the world of sickle cell, these are critical choices that have dire consequences.” Those consequences include dehydration from drinking, fatigue from lack of sleep, and pain crises.

Compounding these challenges is the prevalence of depression and other psychological complications in this age group. And among SCD patients, there can be a sense of grief, Dr. Griffin said.

“Grief is something we tend not to talk too much about,” she said. That grief can manifest in excessive absences from school or work. “Sudden academic declines are something we really have to pay attention to,” Dr. Griffin said.

Silent strokes are also of concern in this age group. “I don’t know if we fully understand the impact on each individual unless we do neuropsychological testing,” she said. The intervals for neuropsychological testing should be in childhood to determine a baseline, then again in adolescence and adulthood. For college-bound students, testing may be a requirement for them to receive medical and physical accommodations, Dr. Griffin said.

While in their late teens and early twenties, SCD patients often rely on pediatric care and can get caught between pediatric and adult providers, she said. That prompted Children’s Healthcare of Atlanta to start a program that essentially hands off those patients from pediatric to adult providers and works with patients to reduce their risks.

As teens approach age 18, they come to the clinic to meet with adult providers and tour the facility. The program involves social workers, vocational and school counselors, and mentors and peer support. “It takes an entire village to address the concerns of transition,” Dr. Griffin said.

Support groups and home visits by providers can also play a key role in the transition protocol, as can telemedicine. “The technology is now there; now we have to figure out how we’re going to start using it,” she said.

This full transitional process can involve multiple appointments with a variety of providers. It’s also important that patients – not parents – interact with providers, Dr. Griffin said.

From January 2007 to September 2012, 74 patients participated in the SCD transition at Children’s Healthcare of Atlanta. Participants who attended more than one transition clinic visit in Atlanta (n = 9) had an average baseline score of 60% on an SCD knowledge questionnaire. But 6 months later, those scores improved to 80%, on average. “We found that teenagers who came to that type of clinic more than once improved pretty well,” Dr. Griffin said.

Dr. Griffin reported having no relevant financial disclosures.

[email protected]

CONCORD, N.C. – Teenage sickle cell disease patients transitioning to adulthood can often find the move to adult providers challenging, causing some patients to lose interest in self-care at a critical point in life, but a transitional program can help them develop the skills they need to manage their disease and avoid risky behaviors, according to psychologist Anya Griffin, PhD.

Managing pain in teenagers and young adults with sickle cell disease (SCD) is fraught with challenges, said Dr. Griffin, who led the SCD transition program at Children’s Healthcare of Atlanta and is now the clinical director of the Stanford (Calif.) Children’s Health Pediatric Rehabilitation Program, an intensive pain management program for pediatric chronic pain.

“Think about who you are when you’re a teenager, when you’re a young adult, what’s going on: dating, sex, parties, college, all-night study sessions,” she said at a Sickle Cell Disease Symposium held by Carolinas Health Care System. “But in the world of sickle cell, these are critical choices that have dire consequences.” Those consequences include dehydration from drinking, fatigue from lack of sleep, and pain crises.

Compounding these challenges is the prevalence of depression and other psychological complications in this age group. And among SCD patients, there can be a sense of grief, Dr. Griffin said.

“Grief is something we tend not to talk too much about,” she said. That grief can manifest in excessive absences from school or work. “Sudden academic declines are something we really have to pay attention to,” Dr. Griffin said.

Silent strokes are also of concern in this age group. “I don’t know if we fully understand the impact on each individual unless we do neuropsychological testing,” she said. The intervals for neuropsychological testing should be in childhood to determine a baseline, then again in adolescence and adulthood. For college-bound students, testing may be a requirement for them to receive medical and physical accommodations, Dr. Griffin said.

While in their late teens and early twenties, SCD patients often rely on pediatric care and can get caught between pediatric and adult providers, she said. That prompted Children’s Healthcare of Atlanta to start a program that essentially hands off those patients from pediatric to adult providers and works with patients to reduce their risks.

As teens approach age 18, they come to the clinic to meet with adult providers and tour the facility. The program involves social workers, vocational and school counselors, and mentors and peer support. “It takes an entire village to address the concerns of transition,” Dr. Griffin said.

Support groups and home visits by providers can also play a key role in the transition protocol, as can telemedicine. “The technology is now there; now we have to figure out how we’re going to start using it,” she said.

This full transitional process can involve multiple appointments with a variety of providers. It’s also important that patients – not parents – interact with providers, Dr. Griffin said.

From January 2007 to September 2012, 74 patients participated in the SCD transition at Children’s Healthcare of Atlanta. Participants who attended more than one transition clinic visit in Atlanta (n = 9) had an average baseline score of 60% on an SCD knowledge questionnaire. But 6 months later, those scores improved to 80%, on average. “We found that teenagers who came to that type of clinic more than once improved pretty well,” Dr. Griffin said.

Dr. Griffin reported having no relevant financial disclosures.

[email protected]

CONCORD, N.C. – Teenage sickle cell disease patients transitioning to adulthood can often find the move to adult providers challenging, causing some patients to lose interest in self-care at a critical point in life, but a transitional program can help them develop the skills they need to manage their disease and avoid risky behaviors, according to psychologist Anya Griffin, PhD.

Managing pain in teenagers and young adults with sickle cell disease (SCD) is fraught with challenges, said Dr. Griffin, who led the SCD transition program at Children’s Healthcare of Atlanta and is now the clinical director of the Stanford (Calif.) Children’s Health Pediatric Rehabilitation Program, an intensive pain management program for pediatric chronic pain.

“Think about who you are when you’re a teenager, when you’re a young adult, what’s going on: dating, sex, parties, college, all-night study sessions,” she said at a Sickle Cell Disease Symposium held by Carolinas Health Care System. “But in the world of sickle cell, these are critical choices that have dire consequences.” Those consequences include dehydration from drinking, fatigue from lack of sleep, and pain crises.

Compounding these challenges is the prevalence of depression and other psychological complications in this age group. And among SCD patients, there can be a sense of grief, Dr. Griffin said.

“Grief is something we tend not to talk too much about,” she said. That grief can manifest in excessive absences from school or work. “Sudden academic declines are something we really have to pay attention to,” Dr. Griffin said.

Silent strokes are also of concern in this age group. “I don’t know if we fully understand the impact on each individual unless we do neuropsychological testing,” she said. The intervals for neuropsychological testing should be in childhood to determine a baseline, then again in adolescence and adulthood. For college-bound students, testing may be a requirement for them to receive medical and physical accommodations, Dr. Griffin said.

While in their late teens and early twenties, SCD patients often rely on pediatric care and can get caught between pediatric and adult providers, she said. That prompted Children’s Healthcare of Atlanta to start a program that essentially hands off those patients from pediatric to adult providers and works with patients to reduce their risks.

As teens approach age 18, they come to the clinic to meet with adult providers and tour the facility. The program involves social workers, vocational and school counselors, and mentors and peer support. “It takes an entire village to address the concerns of transition,” Dr. Griffin said.

Support groups and home visits by providers can also play a key role in the transition protocol, as can telemedicine. “The technology is now there; now we have to figure out how we’re going to start using it,” she said.

This full transitional process can involve multiple appointments with a variety of providers. It’s also important that patients – not parents – interact with providers, Dr. Griffin said.

From January 2007 to September 2012, 74 patients participated in the SCD transition at Children’s Healthcare of Atlanta. Participants who attended more than one transition clinic visit in Atlanta (n = 9) had an average baseline score of 60% on an SCD knowledge questionnaire. But 6 months later, those scores improved to 80%, on average. “We found that teenagers who came to that type of clinic more than once improved pretty well,” Dr. Griffin said.

Dr. Griffin reported having no relevant financial disclosures.

[email protected]