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Drug gets orphan status for PNH in US
The US Food and Drug Administration (FDA) has granted the complement inhibitor AMY-101 orphan status as a treatment for paroxysmal nocturnal
hemoglobinuria (PNH).
Roughly 2 months ago, the European Medicines Agency (EMA) did the same.
Orphan designation will allow Amyndas Pharmaceuticals, the company developing AMY-101, to proceed with expedited clinical development. The company is
planning to move the drug into clinical trials in 2015.
If AMY-101 is approved by the FDA, orphan status will allow for a 7-year period of market exclusivity from product launch in the US. It will also allow Amyndas to apply for research funding, tax credits for certain research expenses, and assistance for clinical research study design. It provides a waiver from the FDA’s Prescription Drug User Fee as well.
“Receiving the orphan drug designation from both the FDA and the EMA is an important achievement and a key milestone in the development pathway of AMY-101, and we are optimistic regarding the long-term potential of this potent complement inhibitor,” said John Lambris, PhD, of the University of Pennsylvania.
Dr Lambris developed AMY-101 at the University of Pennsylvania, and the university licensed the drug to Amyndas Pharmaceuticals. Dr Lambris is a founder and equity holder of Amyndas Pharmaceuticals.
About AMY-101 and PNH
PNH is caused by the defective expression of regulatory proteins on the surface of blood cells, which leaves them vulnerable to complement attack. This can lead to hemolysis, which results in severe anemia and contributes to a high risk of thrombosis.
The monoclonal antibody eculizumab is often successful in treating PNH, but roughly a third of patients do not respond well to the drug and still require blood transfusions to manage their anemia.
Research has suggested this lack of response is due to fragments of complement C3 proteins on the surface of the patients’ red blood cells, which are eventually attacked by immune cells.
In an attempt to overcome this problem, Dr Lambris and his colleagues developed AMY-101. The drug is designed to inhibit C3, thereby preventing hemolysis and immune cell recognition.
The researchers have investigated the effects of AMY-101 on self-attack and the resulting hemolysis in human PNH cells and found the drug to be active.
These results have not been published, but the group has published results with a C3 inhibitor known as Cp40, and AMY-101 is based on Cp40.
The researchers reported in Blood that Cp40 and its long-acting form, PEG-Cp40, effectively inhibited hemolysis and efficiently prevented the deposition of C3 fragments on red blood cells from patients with PNH. 
The US Food and Drug Administration (FDA) has granted the complement inhibitor AMY-101 orphan status as a treatment for paroxysmal nocturnal
hemoglobinuria (PNH).
Roughly 2 months ago, the European Medicines Agency (EMA) did the same.
Orphan designation will allow Amyndas Pharmaceuticals, the company developing AMY-101, to proceed with expedited clinical development. The company is
planning to move the drug into clinical trials in 2015.
If AMY-101 is approved by the FDA, orphan status will allow for a 7-year period of market exclusivity from product launch in the US. It will also allow Amyndas to apply for research funding, tax credits for certain research expenses, and assistance for clinical research study design. It provides a waiver from the FDA’s Prescription Drug User Fee as well.
“Receiving the orphan drug designation from both the FDA and the EMA is an important achievement and a key milestone in the development pathway of AMY-101, and we are optimistic regarding the long-term potential of this potent complement inhibitor,” said John Lambris, PhD, of the University of Pennsylvania.
Dr Lambris developed AMY-101 at the University of Pennsylvania, and the university licensed the drug to Amyndas Pharmaceuticals. Dr Lambris is a founder and equity holder of Amyndas Pharmaceuticals.
About AMY-101 and PNH
PNH is caused by the defective expression of regulatory proteins on the surface of blood cells, which leaves them vulnerable to complement attack. This can lead to hemolysis, which results in severe anemia and contributes to a high risk of thrombosis.
The monoclonal antibody eculizumab is often successful in treating PNH, but roughly a third of patients do not respond well to the drug and still require blood transfusions to manage their anemia.
Research has suggested this lack of response is due to fragments of complement C3 proteins on the surface of the patients’ red blood cells, which are eventually attacked by immune cells.
In an attempt to overcome this problem, Dr Lambris and his colleagues developed AMY-101. The drug is designed to inhibit C3, thereby preventing hemolysis and immune cell recognition.
The researchers have investigated the effects of AMY-101 on self-attack and the resulting hemolysis in human PNH cells and found the drug to be active.
These results have not been published, but the group has published results with a C3 inhibitor known as Cp40, and AMY-101 is based on Cp40.
The researchers reported in Blood that Cp40 and its long-acting form, PEG-Cp40, effectively inhibited hemolysis and efficiently prevented the deposition of C3 fragments on red blood cells from patients with PNH.
The US Food and Drug Administration (FDA) has granted the complement inhibitor AMY-101 orphan status as a treatment for paroxysmal nocturnal
hemoglobinuria (PNH).
Roughly 2 months ago, the European Medicines Agency (EMA) did the same.
Orphan designation will allow Amyndas Pharmaceuticals, the company developing AMY-101, to proceed with expedited clinical development. The company is
planning to move the drug into clinical trials in 2015.
If AMY-101 is approved by the FDA, orphan status will allow for a 7-year period of market exclusivity from product launch in the US. It will also allow Amyndas to apply for research funding, tax credits for certain research expenses, and assistance for clinical research study design. It provides a waiver from the FDA’s Prescription Drug User Fee as well.
“Receiving the orphan drug designation from both the FDA and the EMA is an important achievement and a key milestone in the development pathway of AMY-101, and we are optimistic regarding the long-term potential of this potent complement inhibitor,” said John Lambris, PhD, of the University of Pennsylvania.
Dr Lambris developed AMY-101 at the University of Pennsylvania, and the university licensed the drug to Amyndas Pharmaceuticals. Dr Lambris is a founder and equity holder of Amyndas Pharmaceuticals.
About AMY-101 and PNH
PNH is caused by the defective expression of regulatory proteins on the surface of blood cells, which leaves them vulnerable to complement attack. This can lead to hemolysis, which results in severe anemia and contributes to a high risk of thrombosis.
The monoclonal antibody eculizumab is often successful in treating PNH, but roughly a third of patients do not respond well to the drug and still require blood transfusions to manage their anemia.
Research has suggested this lack of response is due to fragments of complement C3 proteins on the surface of the patients’ red blood cells, which are eventually attacked by immune cells.
In an attempt to overcome this problem, Dr Lambris and his colleagues developed AMY-101. The drug is designed to inhibit C3, thereby preventing hemolysis and immune cell recognition.
The researchers have investigated the effects of AMY-101 on self-attack and the resulting hemolysis in human PNH cells and found the drug to be active.
These results have not been published, but the group has published results with a C3 inhibitor known as Cp40, and AMY-101 is based on Cp40.
The researchers reported in Blood that Cp40 and its long-acting form, PEG-Cp40, effectively inhibited hemolysis and efficiently prevented the deposition of C3 fragments on red blood cells from patients with PNH.
Drug granted orphan status for PNH in EU
A novel compound has received orphan status in the Europe Union to treat paroxysmal nocturnal hemoglobinuria (PNH), a life-threatening disease that causes severe anemia and confers a high risk of thrombosis.
The compound, AMY-101, works by inhibiting C3, a central component of the complement immune system.
AMY-101 was developed by John Lambris, PhD, of the University of Pennsylvania, and subsequently licensed to Amyndas Pharmaceuticals.
AMY-101’s orphan status provides Amyndas with benefits such as tax incentives, market exclusivity for 10 years, possibilities for additional research funding, and additional guidance from the European Medicines Agency during clinical development.
How AMY-101 works
PNH is caused by the defective expression of regulatory proteins on the surface of blood cells, which leaves them vulnerable to complement attack. This can lead to hemolysis, which results in severe anemia and contributes to a high risk of thrombosis.
The monoclonal antibody eculizumab is often successful in treating PNH, but roughly a third of patients do not respond well to the drug and still require blood transfusions to manage their anemia.
Research has suggested this lack of response is due to fragments of complement C3 proteins on the surface of the patients’ red blood cells, which are eventually attacked by immune cells.
In an attempt to overcome this problem, Dr Lambris and his colleagues developed AMY-101. The drug is designed to inhibit the complement cascade, thereby preventing hemolysis and immune cell recognition.
The researchers have investigated the effects of AMY-101 on self-attack and the resulting hemolysis in human PNH cells and found the drug to be active.
These results have not been published, but the group has published results with a C3 inhibitor known as Cp40, and AMY-101 is based on Cp40.
The researchers reported in Blood that Cp40 and its long-acting form, PEG-Cp40, effectively inhibited hemolysis and efficiently prevented the deposition of C3 fragments on red blood cells from patients with PNH.
A novel compound has received orphan status in the Europe Union to treat paroxysmal nocturnal hemoglobinuria (PNH), a life-threatening disease that causes severe anemia and confers a high risk of thrombosis.
The compound, AMY-101, works by inhibiting C3, a central component of the complement immune system.
AMY-101 was developed by John Lambris, PhD, of the University of Pennsylvania, and subsequently licensed to Amyndas Pharmaceuticals.
AMY-101’s orphan status provides Amyndas with benefits such as tax incentives, market exclusivity for 10 years, possibilities for additional research funding, and additional guidance from the European Medicines Agency during clinical development.
How AMY-101 works
PNH is caused by the defective expression of regulatory proteins on the surface of blood cells, which leaves them vulnerable to complement attack. This can lead to hemolysis, which results in severe anemia and contributes to a high risk of thrombosis.
The monoclonal antibody eculizumab is often successful in treating PNH, but roughly a third of patients do not respond well to the drug and still require blood transfusions to manage their anemia.
Research has suggested this lack of response is due to fragments of complement C3 proteins on the surface of the patients’ red blood cells, which are eventually attacked by immune cells.
In an attempt to overcome this problem, Dr Lambris and his colleagues developed AMY-101. The drug is designed to inhibit the complement cascade, thereby preventing hemolysis and immune cell recognition.
The researchers have investigated the effects of AMY-101 on self-attack and the resulting hemolysis in human PNH cells and found the drug to be active.
These results have not been published, but the group has published results with a C3 inhibitor known as Cp40, and AMY-101 is based on Cp40.
The researchers reported in Blood that Cp40 and its long-acting form, PEG-Cp40, effectively inhibited hemolysis and efficiently prevented the deposition of C3 fragments on red blood cells from patients with PNH.
A novel compound has received orphan status in the Europe Union to treat paroxysmal nocturnal hemoglobinuria (PNH), a life-threatening disease that causes severe anemia and confers a high risk of thrombosis.
The compound, AMY-101, works by inhibiting C3, a central component of the complement immune system.
AMY-101 was developed by John Lambris, PhD, of the University of Pennsylvania, and subsequently licensed to Amyndas Pharmaceuticals.
AMY-101’s orphan status provides Amyndas with benefits such as tax incentives, market exclusivity for 10 years, possibilities for additional research funding, and additional guidance from the European Medicines Agency during clinical development.
How AMY-101 works
PNH is caused by the defective expression of regulatory proteins on the surface of blood cells, which leaves them vulnerable to complement attack. This can lead to hemolysis, which results in severe anemia and contributes to a high risk of thrombosis.
The monoclonal antibody eculizumab is often successful in treating PNH, but roughly a third of patients do not respond well to the drug and still require blood transfusions to manage their anemia.
Research has suggested this lack of response is due to fragments of complement C3 proteins on the surface of the patients’ red blood cells, which are eventually attacked by immune cells.
In an attempt to overcome this problem, Dr Lambris and his colleagues developed AMY-101. The drug is designed to inhibit the complement cascade, thereby preventing hemolysis and immune cell recognition.
The researchers have investigated the effects of AMY-101 on self-attack and the resulting hemolysis in human PNH cells and found the drug to be active.
These results have not been published, but the group has published results with a C3 inhibitor known as Cp40, and AMY-101 is based on Cp40.
The researchers reported in Blood that Cp40 and its long-acting form, PEG-Cp40, effectively inhibited hemolysis and efficiently prevented the deposition of C3 fragments on red blood cells from patients with PNH.
Thalidomide offers short-term efficacy in HHT
MILAN—Results of a phase 2 trial suggest thalidomide can elicit solid—though not necessarily durable—responses among patients with hereditary hemorrhagic telangiectasia (HHT) suffering from severe, recurrent epistaxis.
All 29 evaluable patients responded to thalidomide, with 4 achieving a complete response.
Unfortunately, 11 patients relapsed at a median of 43 weeks. But re-treatment was possible for a few patients and did prompt additional responses.
“Our results strongly support the hypothesis that low-dose thalidomide is safe and very effective for the treatment of severe epistaxis in HHT patients who did not benefit from other available modalities of treatment,” said Rosangela Invernizzi, MD, of the University of Pavia in Italy.
“However, the effect of thalidomide is not permanent, and maintenance therapy may be required.”
Dr Invernizzi presented these discoveries at the 19th Congress of the European Hematology Association (EHA) as abstract S692.
She and her colleagues enrolled 31 HHT patients on this phase 2 study. The patients had a median age of 64 years (range, 44-84). Nine had grade 2 epistaxis, and 22 had grade 3.
Previous treatments included argon plasma coagulation (n=19), electrocautery (n=12), embolization (n=7), laser coagulation (n=2), septodermoplasty (n=2), and arterial ligation (n=1). Eighteen patients had received less than 10 units of red blood cells, and 13 had received 10 or more units.
For this study, patients received thalidomide at 50 mg a day for 4 weeks. Complete responders received 8 additional weeks of treatment at the same dosage. Partial responders received 16 additional weeks of treatment at the same dosage.
For non-responders, the dose was increased by 50 mg per day every 4 weeks until they attained a complete or partial response (with a maximum dose of 200 mg). If patients did not respond, they received 24 additional weeks of treatment. Thalidomide courses could be repeated 3 times at the most.
Response and relapse
The median follow-up was 67 weeks (range, 3-130 weeks). All of the 29 evaluable patients achieved a response, with 4 complete responses (14%) and 25 partial responses (86%).
Twenty-four patients responded within 4 weeks of treatment initiation, and 5 responded within 8 weeks. The minimum dose of thalidomide was 50 mg, and the maximum was 100 mg.
“A significant decrease of all epistaxis parameters—frequency [P=0.001], intensity [P<0.0001], and duration [P=0.0001]—was recorded,” Dr Invernizzi noted.
“As a consequence, thalidomide treatment significantly increased hemoglobin levels [P=0.02] and abolished or greatly decreased transfusion need [P=0.0003] and improved the quality of life.”
However, 11 patients relapsed at a median of 43 weeks. Patients who relapsed within 52 weeks of ending thalidomide could be treated again for 8 weeks at the same maximum dose employed during induction.
Four patients received re-treatment and achieved partial responses. One of these patients relapsed again at 13 weeks. But, for the other 3 patients, clinical improvement persisted at more than 17 weeks, more than 26 weeks, and more than 27 weeks.
Safety and tolerability
Dr Invernizzi said there were no noticeable side effects associated with re-treatment of relapsed patients.
The most common adverse events among all patients were gastrointestinal symptoms, such as constipation, vomiting, and dry mouth (n=15); drowsiness (n=9); and constitutional symptoms, such as asthenia, malaise, and peripheral edema (n=7).
There were 2 patients with psychiatric symptoms (confusion, depression) and 2 patients with thyroid dysfunction.
There was 1 cardiovascular event, (bradycardia, heart failure), 1 patient with low hematologic counts, 1 patient with neurologic symptoms (peripheral neuropathy, dizziness, tremor), 1 dermatologic event (toxic cutaneous rashes, skin dryness), and 1 infection.
MILAN—Results of a phase 2 trial suggest thalidomide can elicit solid—though not necessarily durable—responses among patients with hereditary hemorrhagic telangiectasia (HHT) suffering from severe, recurrent epistaxis.
All 29 evaluable patients responded to thalidomide, with 4 achieving a complete response.
Unfortunately, 11 patients relapsed at a median of 43 weeks. But re-treatment was possible for a few patients and did prompt additional responses.
“Our results strongly support the hypothesis that low-dose thalidomide is safe and very effective for the treatment of severe epistaxis in HHT patients who did not benefit from other available modalities of treatment,” said Rosangela Invernizzi, MD, of the University of Pavia in Italy.
“However, the effect of thalidomide is not permanent, and maintenance therapy may be required.”
Dr Invernizzi presented these discoveries at the 19th Congress of the European Hematology Association (EHA) as abstract S692.
She and her colleagues enrolled 31 HHT patients on this phase 2 study. The patients had a median age of 64 years (range, 44-84). Nine had grade 2 epistaxis, and 22 had grade 3.
Previous treatments included argon plasma coagulation (n=19), electrocautery (n=12), embolization (n=7), laser coagulation (n=2), septodermoplasty (n=2), and arterial ligation (n=1). Eighteen patients had received less than 10 units of red blood cells, and 13 had received 10 or more units.
For this study, patients received thalidomide at 50 mg a day for 4 weeks. Complete responders received 8 additional weeks of treatment at the same dosage. Partial responders received 16 additional weeks of treatment at the same dosage.
For non-responders, the dose was increased by 50 mg per day every 4 weeks until they attained a complete or partial response (with a maximum dose of 200 mg). If patients did not respond, they received 24 additional weeks of treatment. Thalidomide courses could be repeated 3 times at the most.
Response and relapse
The median follow-up was 67 weeks (range, 3-130 weeks). All of the 29 evaluable patients achieved a response, with 4 complete responses (14%) and 25 partial responses (86%).
Twenty-four patients responded within 4 weeks of treatment initiation, and 5 responded within 8 weeks. The minimum dose of thalidomide was 50 mg, and the maximum was 100 mg.
“A significant decrease of all epistaxis parameters—frequency [P=0.001], intensity [P<0.0001], and duration [P=0.0001]—was recorded,” Dr Invernizzi noted.
“As a consequence, thalidomide treatment significantly increased hemoglobin levels [P=0.02] and abolished or greatly decreased transfusion need [P=0.0003] and improved the quality of life.”
However, 11 patients relapsed at a median of 43 weeks. Patients who relapsed within 52 weeks of ending thalidomide could be treated again for 8 weeks at the same maximum dose employed during induction.
Four patients received re-treatment and achieved partial responses. One of these patients relapsed again at 13 weeks. But, for the other 3 patients, clinical improvement persisted at more than 17 weeks, more than 26 weeks, and more than 27 weeks.
Safety and tolerability
Dr Invernizzi said there were no noticeable side effects associated with re-treatment of relapsed patients.
The most common adverse events among all patients were gastrointestinal symptoms, such as constipation, vomiting, and dry mouth (n=15); drowsiness (n=9); and constitutional symptoms, such as asthenia, malaise, and peripheral edema (n=7).
There were 2 patients with psychiatric symptoms (confusion, depression) and 2 patients with thyroid dysfunction.
There was 1 cardiovascular event, (bradycardia, heart failure), 1 patient with low hematologic counts, 1 patient with neurologic symptoms (peripheral neuropathy, dizziness, tremor), 1 dermatologic event (toxic cutaneous rashes, skin dryness), and 1 infection.
MILAN—Results of a phase 2 trial suggest thalidomide can elicit solid—though not necessarily durable—responses among patients with hereditary hemorrhagic telangiectasia (HHT) suffering from severe, recurrent epistaxis.
All 29 evaluable patients responded to thalidomide, with 4 achieving a complete response.
Unfortunately, 11 patients relapsed at a median of 43 weeks. But re-treatment was possible for a few patients and did prompt additional responses.
“Our results strongly support the hypothesis that low-dose thalidomide is safe and very effective for the treatment of severe epistaxis in HHT patients who did not benefit from other available modalities of treatment,” said Rosangela Invernizzi, MD, of the University of Pavia in Italy.
“However, the effect of thalidomide is not permanent, and maintenance therapy may be required.”
Dr Invernizzi presented these discoveries at the 19th Congress of the European Hematology Association (EHA) as abstract S692.
She and her colleagues enrolled 31 HHT patients on this phase 2 study. The patients had a median age of 64 years (range, 44-84). Nine had grade 2 epistaxis, and 22 had grade 3.
Previous treatments included argon plasma coagulation (n=19), electrocautery (n=12), embolization (n=7), laser coagulation (n=2), septodermoplasty (n=2), and arterial ligation (n=1). Eighteen patients had received less than 10 units of red blood cells, and 13 had received 10 or more units.
For this study, patients received thalidomide at 50 mg a day for 4 weeks. Complete responders received 8 additional weeks of treatment at the same dosage. Partial responders received 16 additional weeks of treatment at the same dosage.
For non-responders, the dose was increased by 50 mg per day every 4 weeks until they attained a complete or partial response (with a maximum dose of 200 mg). If patients did not respond, they received 24 additional weeks of treatment. Thalidomide courses could be repeated 3 times at the most.
Response and relapse
The median follow-up was 67 weeks (range, 3-130 weeks). All of the 29 evaluable patients achieved a response, with 4 complete responses (14%) and 25 partial responses (86%).
Twenty-four patients responded within 4 weeks of treatment initiation, and 5 responded within 8 weeks. The minimum dose of thalidomide was 50 mg, and the maximum was 100 mg.
“A significant decrease of all epistaxis parameters—frequency [P=0.001], intensity [P<0.0001], and duration [P=0.0001]—was recorded,” Dr Invernizzi noted.
“As a consequence, thalidomide treatment significantly increased hemoglobin levels [P=0.02] and abolished or greatly decreased transfusion need [P=0.0003] and improved the quality of life.”
However, 11 patients relapsed at a median of 43 weeks. Patients who relapsed within 52 weeks of ending thalidomide could be treated again for 8 weeks at the same maximum dose employed during induction.
Four patients received re-treatment and achieved partial responses. One of these patients relapsed again at 13 weeks. But, for the other 3 patients, clinical improvement persisted at more than 17 weeks, more than 26 weeks, and more than 27 weeks.
Safety and tolerability
Dr Invernizzi said there were no noticeable side effects associated with re-treatment of relapsed patients.
The most common adverse events among all patients were gastrointestinal symptoms, such as constipation, vomiting, and dry mouth (n=15); drowsiness (n=9); and constitutional symptoms, such as asthenia, malaise, and peripheral edema (n=7).
There were 2 patients with psychiatric symptoms (confusion, depression) and 2 patients with thyroid dysfunction.
There was 1 cardiovascular event, (bradycardia, heart failure), 1 patient with low hematologic counts, 1 patient with neurologic symptoms (peripheral neuropathy, dizziness, tremor), 1 dermatologic event (toxic cutaneous rashes, skin dryness), and 1 infection.
Eltrombopag reduces bleeding in children with chronic immune thrombocytopenia
MILAN – Eltrombopag significantly improved platelet counts and halved bleeding events in children with chronic immune thrombocytopenia in the phase III PETIT2 study.
"It was great to see in this study that not only did we improve platelet counts, but we also significantly reduced bleeding," study author Dr. John Grainger said at the annual congress of the European Hematology Association.
Bleeding events were reduced by 50% at week 12 and by 66% at study’s end.
"Eltrombopag is a potential new treatment for children with immune thrombocytopenia," Dr. Grainger, a consultant pediatric hematologist at the Royal Manchester (England) Children’s Hospital, said during a press briefing at the meeting highlighting the results.
Immune thrombocytopenia (ITP) is a rare autoimmune disorder that affects 5 in 100,000 children and is characterized by a low platelet count, bruising, and petechiae.
Most children with ITP get better without drug intervention, but 30% will have persistent disease. Current treatments such as splenectomy and corticosteroids often fail and carry long-term risks such as infection and bone health effects, Dr. Grainger said.
Eltrombopag (Promacta/Revolade), a thrombopoietin receptor agonist, is approved in about 90 countries, including the United States, as a treatment for adult chronic ITP, and for thrombocytopenia in patients with chronic hepatitis C infection.
Eltrombopag is not approved for use in the pediatric setting, though drug maker GlaxoSmithKline will seek a pediatric chronic ITP indication shortly, according to Dr. Peter Langmuir, vice president of clinical development at GSK Oncology.
The multicenter PETIT2 study, the largest clinical trial in pediatric ITP to date, enrolled 92 children with ITP for at least 12 months who had failed at least one prior treatment and had particularly low platelet counts of less than 30 Gi/L, which increased their risk of bleeding, Dr. Grainger observed. Children were initially randomized to daily eltrombopag or placebo for 13 weeks, with all children receiving eltrombopag for 24 weeks in the second phase of the study. Dosing ranged from 12.5 mg/kg to 75 mg based on age and weight, and was titrated according to platelet response.
In all, 40% of children on eltrombopag achieved a persistent platelet response for 6-8 weeks between weeks 5 and 12, compared with 3.4% on placebo (P less than .001).
"It should be noted that the children all started on a relatively low dose of the drug, and in some children it took a considerable time to build up responses," he said. "But on average, responses were seen between 3 and 4 weeks, so it didn’t really take long to get this durable response."
Treatment with eltrombopag also allowed 61% of children to stop or reduce other ITP treatments such as steroids, Dr. Grainger said.
Four children came off study due to a lack of response, and 5 children had abnormal liver tests, but these returned to normal after treatment discontinuation.
The most common adverse events with eltrombopag were nasopharyngitis, rhinitis, cough, and respiratory tract infections. Grade 3/4 adverse events occurred in 12.7% of children on eltrombopag and 10.3% of children on placebo, and serious events in 8% and 14%.
"This is a safe drug for children to have," Dr. Grainger said.
GlaxoSmithKline sponsored the study. Dr. Grainger has received research nurse support from Baxter and honoraria for participation on advisory boards for Amgen, Baxter, and GlaxoSmithKline.
MILAN – Eltrombopag significantly improved platelet counts and halved bleeding events in children with chronic immune thrombocytopenia in the phase III PETIT2 study.
"It was great to see in this study that not only did we improve platelet counts, but we also significantly reduced bleeding," study author Dr. John Grainger said at the annual congress of the European Hematology Association.
Bleeding events were reduced by 50% at week 12 and by 66% at study’s end.
"Eltrombopag is a potential new treatment for children with immune thrombocytopenia," Dr. Grainger, a consultant pediatric hematologist at the Royal Manchester (England) Children’s Hospital, said during a press briefing at the meeting highlighting the results.
Immune thrombocytopenia (ITP) is a rare autoimmune disorder that affects 5 in 100,000 children and is characterized by a low platelet count, bruising, and petechiae.
Most children with ITP get better without drug intervention, but 30% will have persistent disease. Current treatments such as splenectomy and corticosteroids often fail and carry long-term risks such as infection and bone health effects, Dr. Grainger said.
Eltrombopag (Promacta/Revolade), a thrombopoietin receptor agonist, is approved in about 90 countries, including the United States, as a treatment for adult chronic ITP, and for thrombocytopenia in patients with chronic hepatitis C infection.
Eltrombopag is not approved for use in the pediatric setting, though drug maker GlaxoSmithKline will seek a pediatric chronic ITP indication shortly, according to Dr. Peter Langmuir, vice president of clinical development at GSK Oncology.
The multicenter PETIT2 study, the largest clinical trial in pediatric ITP to date, enrolled 92 children with ITP for at least 12 months who had failed at least one prior treatment and had particularly low platelet counts of less than 30 Gi/L, which increased their risk of bleeding, Dr. Grainger observed. Children were initially randomized to daily eltrombopag or placebo for 13 weeks, with all children receiving eltrombopag for 24 weeks in the second phase of the study. Dosing ranged from 12.5 mg/kg to 75 mg based on age and weight, and was titrated according to platelet response.
In all, 40% of children on eltrombopag achieved a persistent platelet response for 6-8 weeks between weeks 5 and 12, compared with 3.4% on placebo (P less than .001).
"It should be noted that the children all started on a relatively low dose of the drug, and in some children it took a considerable time to build up responses," he said. "But on average, responses were seen between 3 and 4 weeks, so it didn’t really take long to get this durable response."
Treatment with eltrombopag also allowed 61% of children to stop or reduce other ITP treatments such as steroids, Dr. Grainger said.
Four children came off study due to a lack of response, and 5 children had abnormal liver tests, but these returned to normal after treatment discontinuation.
The most common adverse events with eltrombopag were nasopharyngitis, rhinitis, cough, and respiratory tract infections. Grade 3/4 adverse events occurred in 12.7% of children on eltrombopag and 10.3% of children on placebo, and serious events in 8% and 14%.
"This is a safe drug for children to have," Dr. Grainger said.
GlaxoSmithKline sponsored the study. Dr. Grainger has received research nurse support from Baxter and honoraria for participation on advisory boards for Amgen, Baxter, and GlaxoSmithKline.
MILAN – Eltrombopag significantly improved platelet counts and halved bleeding events in children with chronic immune thrombocytopenia in the phase III PETIT2 study.
"It was great to see in this study that not only did we improve platelet counts, but we also significantly reduced bleeding," study author Dr. John Grainger said at the annual congress of the European Hematology Association.
Bleeding events were reduced by 50% at week 12 and by 66% at study’s end.
"Eltrombopag is a potential new treatment for children with immune thrombocytopenia," Dr. Grainger, a consultant pediatric hematologist at the Royal Manchester (England) Children’s Hospital, said during a press briefing at the meeting highlighting the results.
Immune thrombocytopenia (ITP) is a rare autoimmune disorder that affects 5 in 100,000 children and is characterized by a low platelet count, bruising, and petechiae.
Most children with ITP get better without drug intervention, but 30% will have persistent disease. Current treatments such as splenectomy and corticosteroids often fail and carry long-term risks such as infection and bone health effects, Dr. Grainger said.
Eltrombopag (Promacta/Revolade), a thrombopoietin receptor agonist, is approved in about 90 countries, including the United States, as a treatment for adult chronic ITP, and for thrombocytopenia in patients with chronic hepatitis C infection.
Eltrombopag is not approved for use in the pediatric setting, though drug maker GlaxoSmithKline will seek a pediatric chronic ITP indication shortly, according to Dr. Peter Langmuir, vice president of clinical development at GSK Oncology.
The multicenter PETIT2 study, the largest clinical trial in pediatric ITP to date, enrolled 92 children with ITP for at least 12 months who had failed at least one prior treatment and had particularly low platelet counts of less than 30 Gi/L, which increased their risk of bleeding, Dr. Grainger observed. Children were initially randomized to daily eltrombopag or placebo for 13 weeks, with all children receiving eltrombopag for 24 weeks in the second phase of the study. Dosing ranged from 12.5 mg/kg to 75 mg based on age and weight, and was titrated according to platelet response.
In all, 40% of children on eltrombopag achieved a persistent platelet response for 6-8 weeks between weeks 5 and 12, compared with 3.4% on placebo (P less than .001).
"It should be noted that the children all started on a relatively low dose of the drug, and in some children it took a considerable time to build up responses," he said. "But on average, responses were seen between 3 and 4 weeks, so it didn’t really take long to get this durable response."
Treatment with eltrombopag also allowed 61% of children to stop or reduce other ITP treatments such as steroids, Dr. Grainger said.
Four children came off study due to a lack of response, and 5 children had abnormal liver tests, but these returned to normal after treatment discontinuation.
The most common adverse events with eltrombopag were nasopharyngitis, rhinitis, cough, and respiratory tract infections. Grade 3/4 adverse events occurred in 12.7% of children on eltrombopag and 10.3% of children on placebo, and serious events in 8% and 14%.
"This is a safe drug for children to have," Dr. Grainger said.
GlaxoSmithKline sponsored the study. Dr. Grainger has received research nurse support from Baxter and honoraria for participation on advisory boards for Amgen, Baxter, and GlaxoSmithKline.
AT THE EHA CONGRESS
Key clinical point: Eltrombopag may soon be a treatment option for children with chronic immune thrombocytopenia.
Major finding: Platelet response was durable at 6-8 weeks in 40% of children on eltrombopag versus 3.4% of children on placebo (P less than .001).
Data source: A phase III randomized study in 92 children.
Disclosures: GlaxoSmithKline sponsored the study. Dr. Grainger has received research nurse support from Baxter and honoraria for participation on advisory boards for Amgen, Baxter, and GlaxoSmithKline.
New approach for treating PNH
Investigators have identified a novel strategy for treating paroxysmal nocturnal hemoglobinuria (PNH), according to a paper published in Blood.
In patients with PNH, defective expression of regulatory proteins on the surface of red blood cells leaves the cells vulnerable to attack by the complement immune system.
This can lead to hemolysis, which results in severe anemia and contributes to a high risk of thrombosis.
Eculizumab is the only approved therapeutic for PNH. The drug reduces hemolysis and can provide patients with relief from blood transfusions.
However, eculizumab is costly (currently more than $400,000 per year per patient), and one third of PNH patients who receive eculizumab continue to require blood transfusions to manage their anemia.
Investigators previously discovered that this non-response is due to fragments of complement C3 proteins on the surface of red blood cells, which are eventually attacked by immune cells.
Therefore, John Lambris, PhD, of the University of Pennsylvania, and his colleagues hypothesized that using small molecules to inhibit the complement cascade at the level of C3 proteins might be an effective strategy for treating PNH.
The team thought this method would prevent both hemolysis and immune cell recognition, and it might be more cost-effective than the current antibody-based treatment.
So they investigated the effect of a C3 inhibitor called Cp40 and its long-acting form, PEG-Cp40, on self-attack and resulting hemolysis using human PNH cells. Both compounds effectively inhibited hemolysis and efficiently prevented deposition of C3 fragments on PNH red blood cells.
In non-human primates, a single injection of PEG-Cp40 had an elimination half-life of more than 5 days. However, the investigators found evidence to suggest the drug may affect plasma levels of C3.
“We think these 2 compounds are excellent and potentially cost-effective candidates for further clinical investigation,” Dr Lambris said.
He hopes the compounds will be tested in clinical trials by 2015. Dr Lambris and his colleague, Daniel Ricklin, PhD, are the inventors of patents and patent applications owned by the University of Pennsylvania that describe the use of complement inhibitors for therapeutic purposes.
And Dr Lambris is a founder and equity holder of Amyndas Pharmaceuticals, which has exclusively licensed the Cp40 and PEG-Cp40 technologies from the university and is developing complement inhibitors for clinical applications.
Investigators have identified a novel strategy for treating paroxysmal nocturnal hemoglobinuria (PNH), according to a paper published in Blood.
In patients with PNH, defective expression of regulatory proteins on the surface of red blood cells leaves the cells vulnerable to attack by the complement immune system.
This can lead to hemolysis, which results in severe anemia and contributes to a high risk of thrombosis.
Eculizumab is the only approved therapeutic for PNH. The drug reduces hemolysis and can provide patients with relief from blood transfusions.
However, eculizumab is costly (currently more than $400,000 per year per patient), and one third of PNH patients who receive eculizumab continue to require blood transfusions to manage their anemia.
Investigators previously discovered that this non-response is due to fragments of complement C3 proteins on the surface of red blood cells, which are eventually attacked by immune cells.
Therefore, John Lambris, PhD, of the University of Pennsylvania, and his colleagues hypothesized that using small molecules to inhibit the complement cascade at the level of C3 proteins might be an effective strategy for treating PNH.
The team thought this method would prevent both hemolysis and immune cell recognition, and it might be more cost-effective than the current antibody-based treatment.
So they investigated the effect of a C3 inhibitor called Cp40 and its long-acting form, PEG-Cp40, on self-attack and resulting hemolysis using human PNH cells. Both compounds effectively inhibited hemolysis and efficiently prevented deposition of C3 fragments on PNH red blood cells.
In non-human primates, a single injection of PEG-Cp40 had an elimination half-life of more than 5 days. However, the investigators found evidence to suggest the drug may affect plasma levels of C3.
“We think these 2 compounds are excellent and potentially cost-effective candidates for further clinical investigation,” Dr Lambris said.
He hopes the compounds will be tested in clinical trials by 2015. Dr Lambris and his colleague, Daniel Ricklin, PhD, are the inventors of patents and patent applications owned by the University of Pennsylvania that describe the use of complement inhibitors for therapeutic purposes.
And Dr Lambris is a founder and equity holder of Amyndas Pharmaceuticals, which has exclusively licensed the Cp40 and PEG-Cp40 technologies from the university and is developing complement inhibitors for clinical applications.
Investigators have identified a novel strategy for treating paroxysmal nocturnal hemoglobinuria (PNH), according to a paper published in Blood.
In patients with PNH, defective expression of regulatory proteins on the surface of red blood cells leaves the cells vulnerable to attack by the complement immune system.
This can lead to hemolysis, which results in severe anemia and contributes to a high risk of thrombosis.
Eculizumab is the only approved therapeutic for PNH. The drug reduces hemolysis and can provide patients with relief from blood transfusions.
However, eculizumab is costly (currently more than $400,000 per year per patient), and one third of PNH patients who receive eculizumab continue to require blood transfusions to manage their anemia.
Investigators previously discovered that this non-response is due to fragments of complement C3 proteins on the surface of red blood cells, which are eventually attacked by immune cells.
Therefore, John Lambris, PhD, of the University of Pennsylvania, and his colleagues hypothesized that using small molecules to inhibit the complement cascade at the level of C3 proteins might be an effective strategy for treating PNH.
The team thought this method would prevent both hemolysis and immune cell recognition, and it might be more cost-effective than the current antibody-based treatment.
So they investigated the effect of a C3 inhibitor called Cp40 and its long-acting form, PEG-Cp40, on self-attack and resulting hemolysis using human PNH cells. Both compounds effectively inhibited hemolysis and efficiently prevented deposition of C3 fragments on PNH red blood cells.
In non-human primates, a single injection of PEG-Cp40 had an elimination half-life of more than 5 days. However, the investigators found evidence to suggest the drug may affect plasma levels of C3.
“We think these 2 compounds are excellent and potentially cost-effective candidates for further clinical investigation,” Dr Lambris said.
He hopes the compounds will be tested in clinical trials by 2015. Dr Lambris and his colleague, Daniel Ricklin, PhD, are the inventors of patents and patent applications owned by the University of Pennsylvania that describe the use of complement inhibitors for therapeutic purposes.
And Dr Lambris is a founder and equity holder of Amyndas Pharmaceuticals, which has exclusively licensed the Cp40 and PEG-Cp40 technologies from the university and is developing complement inhibitors for clinical applications.
Platelets, iron may affect stroke risk in HHT patients
Credit: Andre E.X. Brown
New research suggests patients with hereditary hemorrhagic telangiectasia (HHT) have an increased risk of ischemic stroke if they are iron deficient, and this may be due to enhanced platelet aggregation.
In the last few years, several studies have shown that iron deficiency may be a risk factor for ischemic stroke, but exactly how this occurs has been unclear.
Previous research also revealed a possible link between iron deficiency and platelet aggregation, but it has been largely overlooked, until now.
Claire Shovlin, PhD, of Imperial College London in the UK, and her colleagues found that HHT patients who are iron deficient have both an increased risk of stroke and enhanced aggregation of circulating platelets.
The researchers reported these findings in PLOS ONE.
The team had studied 497 HHT patients who had enlarged blood vessels in the lungs known as pulmonary arteriovenous malformations.
Normally, the lungs’ blood vessels act as a filter to remove small clots before blood enters arteries. In patients with pulmonary arteriovenous malformations, blood is able to bypass the filter, so small blood clots can travel to the brain.
Dr Shovlin and her colleagues found that patients with iron deficiency had a greater risk of stroke than patients with normal iron levels. Even moderately low iron levels, around 6 μmol/L, approximately doubled the risk of stroke when compared with levels in the middle of the normal range (7 to 27 μmol/L).
The researchers evaluated platelet activity in 15 patients, dividing them into 2 groups according to serum ferritin. Iron-deficient patients (n=7) had ferritin levels ranging from 2 μg/L to 17 μg/L. Control subjects (n=8) had ferritin levels of 24 μg/L to 98 μg/L. (None of the patients had levels between 17μg/L and 24 μg/L.)
The team found that ADP induced similar, dose-dependent platelet aggregation in iron-deficient patients and control subjects. But iron-deficient patients exhibited enhanced total aggregation to 5HT over a 5-minute period. And the iron-deficient group displayed faster rates of aggregation in response to 5HT.
“Since platelets in the blood stick together more if you are short of iron, we think this may explain why being short of iron can lead to strokes, though much more research will be needed to prove this link,” Dr Shovlin said.
“The next step is to test whether we can reduce high-risk patients’ chances of having a stroke by treating their iron deficiency. We will be able to look at whether their platelets become less sticky.”
“There are many additional steps from a clot blocking a blood vessel to the final stroke developing, so it is still unclear just how important sticky platelets are to the overall process. We would certainly encourage more studies to investigate this link.”
Credit: Andre E.X. Brown
New research suggests patients with hereditary hemorrhagic telangiectasia (HHT) have an increased risk of ischemic stroke if they are iron deficient, and this may be due to enhanced platelet aggregation.
In the last few years, several studies have shown that iron deficiency may be a risk factor for ischemic stroke, but exactly how this occurs has been unclear.
Previous research also revealed a possible link between iron deficiency and platelet aggregation, but it has been largely overlooked, until now.
Claire Shovlin, PhD, of Imperial College London in the UK, and her colleagues found that HHT patients who are iron deficient have both an increased risk of stroke and enhanced aggregation of circulating platelets.
The researchers reported these findings in PLOS ONE.
The team had studied 497 HHT patients who had enlarged blood vessels in the lungs known as pulmonary arteriovenous malformations.
Normally, the lungs’ blood vessels act as a filter to remove small clots before blood enters arteries. In patients with pulmonary arteriovenous malformations, blood is able to bypass the filter, so small blood clots can travel to the brain.
Dr Shovlin and her colleagues found that patients with iron deficiency had a greater risk of stroke than patients with normal iron levels. Even moderately low iron levels, around 6 μmol/L, approximately doubled the risk of stroke when compared with levels in the middle of the normal range (7 to 27 μmol/L).
The researchers evaluated platelet activity in 15 patients, dividing them into 2 groups according to serum ferritin. Iron-deficient patients (n=7) had ferritin levels ranging from 2 μg/L to 17 μg/L. Control subjects (n=8) had ferritin levels of 24 μg/L to 98 μg/L. (None of the patients had levels between 17μg/L and 24 μg/L.)
The team found that ADP induced similar, dose-dependent platelet aggregation in iron-deficient patients and control subjects. But iron-deficient patients exhibited enhanced total aggregation to 5HT over a 5-minute period. And the iron-deficient group displayed faster rates of aggregation in response to 5HT.
“Since platelets in the blood stick together more if you are short of iron, we think this may explain why being short of iron can lead to strokes, though much more research will be needed to prove this link,” Dr Shovlin said.
“The next step is to test whether we can reduce high-risk patients’ chances of having a stroke by treating their iron deficiency. We will be able to look at whether their platelets become less sticky.”
“There are many additional steps from a clot blocking a blood vessel to the final stroke developing, so it is still unclear just how important sticky platelets are to the overall process. We would certainly encourage more studies to investigate this link.”
Credit: Andre E.X. Brown
New research suggests patients with hereditary hemorrhagic telangiectasia (HHT) have an increased risk of ischemic stroke if they are iron deficient, and this may be due to enhanced platelet aggregation.
In the last few years, several studies have shown that iron deficiency may be a risk factor for ischemic stroke, but exactly how this occurs has been unclear.
Previous research also revealed a possible link between iron deficiency and platelet aggregation, but it has been largely overlooked, until now.
Claire Shovlin, PhD, of Imperial College London in the UK, and her colleagues found that HHT patients who are iron deficient have both an increased risk of stroke and enhanced aggregation of circulating platelets.
The researchers reported these findings in PLOS ONE.
The team had studied 497 HHT patients who had enlarged blood vessels in the lungs known as pulmonary arteriovenous malformations.
Normally, the lungs’ blood vessels act as a filter to remove small clots before blood enters arteries. In patients with pulmonary arteriovenous malformations, blood is able to bypass the filter, so small blood clots can travel to the brain.
Dr Shovlin and her colleagues found that patients with iron deficiency had a greater risk of stroke than patients with normal iron levels. Even moderately low iron levels, around 6 μmol/L, approximately doubled the risk of stroke when compared with levels in the middle of the normal range (7 to 27 μmol/L).
The researchers evaluated platelet activity in 15 patients, dividing them into 2 groups according to serum ferritin. Iron-deficient patients (n=7) had ferritin levels ranging from 2 μg/L to 17 μg/L. Control subjects (n=8) had ferritin levels of 24 μg/L to 98 μg/L. (None of the patients had levels between 17μg/L and 24 μg/L.)
The team found that ADP induced similar, dose-dependent platelet aggregation in iron-deficient patients and control subjects. But iron-deficient patients exhibited enhanced total aggregation to 5HT over a 5-minute period. And the iron-deficient group displayed faster rates of aggregation in response to 5HT.
“Since platelets in the blood stick together more if you are short of iron, we think this may explain why being short of iron can lead to strokes, though much more research will be needed to prove this link,” Dr Shovlin said.
“The next step is to test whether we can reduce high-risk patients’ chances of having a stroke by treating their iron deficiency. We will be able to look at whether their platelets become less sticky.”
“There are many additional steps from a clot blocking a blood vessel to the final stroke developing, so it is still unclear just how important sticky platelets are to the overall process. We would certainly encourage more studies to investigate this link.”
von Willebrand Disease: Approach to Diagnosis and Management
von Willebrand disease (VWD) is an inherited bleeding disorder caused by deficient or defective plasma von Willebrand factor (VWF). VWF is an adhesive multimeric plasma glycoprotein that performs 2 major functions in hemostasis: it mediates platelet adhesion to injured subendothelium via glycoprotein 1bα (GPIbα), and it binds and stabilizes factor VIII (FVIII) in circulation, protecting it from proteolytic degradation by enzymes. The current VWD classification recognizes 3 types. In order to understand the role of the numerous laboratory investigations as well as the classification of VWD, it is important to review the structure and function of the VWF subunit. Bleeding symptoms reflect the defect in primary hemostasis: mucocutaneous bleeding and excessive bleeding after surgery or trauma. Treatment focuses on increasing VWF levels with desmopressin (1-deamino-8-D-arginine vasopressin, DDAVP) or clotting factor concentrates containing both VWF and FVIII (VWF/FVIII concentrate). Nonspecific treatment options include antifibrinolytic agents (tranexamic acid) and hormone therapy (oral contraceptive pill).
To read the full article in PDF:
von Willebrand disease (VWD) is an inherited bleeding disorder caused by deficient or defective plasma von Willebrand factor (VWF). VWF is an adhesive multimeric plasma glycoprotein that performs 2 major functions in hemostasis: it mediates platelet adhesion to injured subendothelium via glycoprotein 1bα (GPIbα), and it binds and stabilizes factor VIII (FVIII) in circulation, protecting it from proteolytic degradation by enzymes. The current VWD classification recognizes 3 types. In order to understand the role of the numerous laboratory investigations as well as the classification of VWD, it is important to review the structure and function of the VWF subunit. Bleeding symptoms reflect the defect in primary hemostasis: mucocutaneous bleeding and excessive bleeding after surgery or trauma. Treatment focuses on increasing VWF levels with desmopressin (1-deamino-8-D-arginine vasopressin, DDAVP) or clotting factor concentrates containing both VWF and FVIII (VWF/FVIII concentrate). Nonspecific treatment options include antifibrinolytic agents (tranexamic acid) and hormone therapy (oral contraceptive pill).
To read the full article in PDF:
von Willebrand disease (VWD) is an inherited bleeding disorder caused by deficient or defective plasma von Willebrand factor (VWF). VWF is an adhesive multimeric plasma glycoprotein that performs 2 major functions in hemostasis: it mediates platelet adhesion to injured subendothelium via glycoprotein 1bα (GPIbα), and it binds and stabilizes factor VIII (FVIII) in circulation, protecting it from proteolytic degradation by enzymes. The current VWD classification recognizes 3 types. In order to understand the role of the numerous laboratory investigations as well as the classification of VWD, it is important to review the structure and function of the VWF subunit. Bleeding symptoms reflect the defect in primary hemostasis: mucocutaneous bleeding and excessive bleeding after surgery or trauma. Treatment focuses on increasing VWF levels with desmopressin (1-deamino-8-D-arginine vasopressin, DDAVP) or clotting factor concentrates containing both VWF and FVIII (VWF/FVIII concentrate). Nonspecific treatment options include antifibrinolytic agents (tranexamic acid) and hormone therapy (oral contraceptive pill).
To read the full article in PDF:
Inhibitor strengthens RBCs in PNH
Credit: NHLBI
The apoptosis inhibitor aurin tricarboxylic acid (ATA) is active against paroxysmal nocturnal hemoglobinemia (PNH), according to research published in PLOS ONE.
PNH is a rare condition in which red blood cells (RBCs) become vulnerable to attacks by the complement immune system and subsequently rupture.
This can lead to complications such as anemia, kidney disease, and fatal thromboses.
PNH results from a lack of 2 proteins that protect RBCs from destruction: decay-accelerating factor (CD55), an inhibitor of alternative pathway C3 convertase, and protectin (CD59), an inhibitor of membrane attack complex (MAC) formation.
Because previous studies suggested that ATA selectively blocks complement activation at the C3 convertase stage and MAC formation at the C9 insertion stage, researchers thought ATA might prove effective against PNH.
First, they compared RBCs from 5 patients with PNH (who were on long-term treatment with eculizumab) to RBCs from healthy individuals.
Despite the eculizumab, the PNH patients’ RBCs were twice as vulnerable to complement-induced lysis as the healthy subjects’ RBCs. And western blot revealed both C3 and C5 convertases on the membranes of patients’ RBCs.
However, when the researchers added ATA to patients’ blood samples, the RBCs were protected from complement attack. In fact, the drug restored the RBCs’ resistance to the same level as normal RBCs.
“Our study suggests that ATA could offer more complete protection as an oral treatment for PNH, while eliminating the need for infusions,” said study author Patrick McGeer, MD, PhD, of the University of British Columbia in Vancouver, Canada.
“PNH is a disease that may happen to anyone through a chance mutation, and, if nature were to design a perfect fix for this mutation, it would be ATA.”
Dr McGeer added that many diseases are caused or worsened by an overactive complement immune system. So his group’s findings could have implications for conditions such as Alzheimer’s disease, Parkinson’s disease, macular degeneration, amyotrophic lateral sclerosis, multiple sclerosis, and rheumatoid arthritis.
He and his colleagues are now proceeding with further testing, and Dr McGeer expects ATA could be available in clinics within a year.
Credit: NHLBI
The apoptosis inhibitor aurin tricarboxylic acid (ATA) is active against paroxysmal nocturnal hemoglobinemia (PNH), according to research published in PLOS ONE.
PNH is a rare condition in which red blood cells (RBCs) become vulnerable to attacks by the complement immune system and subsequently rupture.
This can lead to complications such as anemia, kidney disease, and fatal thromboses.
PNH results from a lack of 2 proteins that protect RBCs from destruction: decay-accelerating factor (CD55), an inhibitor of alternative pathway C3 convertase, and protectin (CD59), an inhibitor of membrane attack complex (MAC) formation.
Because previous studies suggested that ATA selectively blocks complement activation at the C3 convertase stage and MAC formation at the C9 insertion stage, researchers thought ATA might prove effective against PNH.
First, they compared RBCs from 5 patients with PNH (who were on long-term treatment with eculizumab) to RBCs from healthy individuals.
Despite the eculizumab, the PNH patients’ RBCs were twice as vulnerable to complement-induced lysis as the healthy subjects’ RBCs. And western blot revealed both C3 and C5 convertases on the membranes of patients’ RBCs.
However, when the researchers added ATA to patients’ blood samples, the RBCs were protected from complement attack. In fact, the drug restored the RBCs’ resistance to the same level as normal RBCs.
“Our study suggests that ATA could offer more complete protection as an oral treatment for PNH, while eliminating the need for infusions,” said study author Patrick McGeer, MD, PhD, of the University of British Columbia in Vancouver, Canada.
“PNH is a disease that may happen to anyone through a chance mutation, and, if nature were to design a perfect fix for this mutation, it would be ATA.”
Dr McGeer added that many diseases are caused or worsened by an overactive complement immune system. So his group’s findings could have implications for conditions such as Alzheimer’s disease, Parkinson’s disease, macular degeneration, amyotrophic lateral sclerosis, multiple sclerosis, and rheumatoid arthritis.
He and his colleagues are now proceeding with further testing, and Dr McGeer expects ATA could be available in clinics within a year.
Credit: NHLBI
The apoptosis inhibitor aurin tricarboxylic acid (ATA) is active against paroxysmal nocturnal hemoglobinemia (PNH), according to research published in PLOS ONE.
PNH is a rare condition in which red blood cells (RBCs) become vulnerable to attacks by the complement immune system and subsequently rupture.
This can lead to complications such as anemia, kidney disease, and fatal thromboses.
PNH results from a lack of 2 proteins that protect RBCs from destruction: decay-accelerating factor (CD55), an inhibitor of alternative pathway C3 convertase, and protectin (CD59), an inhibitor of membrane attack complex (MAC) formation.
Because previous studies suggested that ATA selectively blocks complement activation at the C3 convertase stage and MAC formation at the C9 insertion stage, researchers thought ATA might prove effective against PNH.
First, they compared RBCs from 5 patients with PNH (who were on long-term treatment with eculizumab) to RBCs from healthy individuals.
Despite the eculizumab, the PNH patients’ RBCs were twice as vulnerable to complement-induced lysis as the healthy subjects’ RBCs. And western blot revealed both C3 and C5 convertases on the membranes of patients’ RBCs.
However, when the researchers added ATA to patients’ blood samples, the RBCs were protected from complement attack. In fact, the drug restored the RBCs’ resistance to the same level as normal RBCs.
“Our study suggests that ATA could offer more complete protection as an oral treatment for PNH, while eliminating the need for infusions,” said study author Patrick McGeer, MD, PhD, of the University of British Columbia in Vancouver, Canada.
“PNH is a disease that may happen to anyone through a chance mutation, and, if nature were to design a perfect fix for this mutation, it would be ATA.”
Dr McGeer added that many diseases are caused or worsened by an overactive complement immune system. So his group’s findings could have implications for conditions such as Alzheimer’s disease, Parkinson’s disease, macular degeneration, amyotrophic lateral sclerosis, multiple sclerosis, and rheumatoid arthritis.
He and his colleagues are now proceeding with further testing, and Dr McGeer expects ATA could be available in clinics within a year.
Eculizumab decreases risk of thrombosis in PNH
VIENNA—Long-term treatment with eculizumab, a recombinant humanized monoclonal antibody, significantly reduces the risk of thrombosis in patients with paroxysmal nocturnal hemoglobinuria (PNH), according to the results of a recent multicenter study.
Peter Hillmen, MD, of the Leeds Teaching Hospitals NHS Trust, reported the results of the study at the 12th Congress of the European Hematology Association in June 2007.
Dr Hillmen and colleagues prospectively examined the aggregate thromboembolism (TE) event rate in eculizumab-treated patients from 3 recent parent studies, as well as a subsequent common extension study. They compared those rates to the TE rate in the same patients’ pre-eculizumab treatment.
Eculizumab, which is designed to inhibit activation of terminal complement components that have been implicated in the development of PNH, reduced the TE rate in each of the three parent studies.
Most importantly, the aggregate TE event rate during eculizumab treatment was significantly reduced by 85% (P=<0.001), when compared with the same patients before eculizumab treatment.
With restriction of the pretreatment observation period to the 12 months immediately preceding eculizumab treatment, the TE event rate during treatment was reduced by 94% (P=0.002). The TE event rate in patients with TE prior to the trials was also reduced by 89% (P=<0.001).
Most TE events prior to eculizumab treatment occurred in patients receiving antithrombotics, either therapeutically or prophylactically. This indicates that the therapy may be insufficient to prevent thrombosis.
Pre-eculizumab treatment, 195 patients experienced 124 TE events. Of the 195 patients, 103 were on antithrombotics.
Of the 103 patients on antithrombotics, there were 54 TE events in 30 patients pre-eculizumab, compared to 1 TE event during eculizumab treatment. This demonstrates that eculizumab significantly reduces the risk of thrombosis in PNH patients, despite treatment with antithrombotics (P=<0.001).
Pre-eculizumab, TE was frequent in patients with lower levels of hemolysis and with mild anemia. Eculizumab significantly reduced TE across these and other subgroups (P=<0.001).
Dr Hillman said these data demonstrate the efficacy of long-term eculizumab treatment in its ability to significantly reduce the occurrence of thrombosis in PNH patients. Because TE accounts for the majority of deaths in PNH, it is reasonable to expect that eculizumab treatment, by decreasing the risk of TE, will increase the life-expectancy in PNH.
PNH is a rare, acquired, and potentially life-threatening disease of the blood characterized by hemolytic anemia, thrombosis, and red-colored urine, resulting from the breakdown of red blood cells.
TE is one of the most feared complications associated with PNH and accounts for approximately 45% of PNH patient deaths. The disease can occur even in individuals who have no previous history of thrombosis.
Patients with PNH are usually treated with anticoagulants on a prophylactic basis. However, these anticoagulants increase the risk of life-threatening hemorrhage without eliminating the potential for thrombosis, which can occur in as many as 30% of the patients who receive anticoagulant treatment. 
VIENNA—Long-term treatment with eculizumab, a recombinant humanized monoclonal antibody, significantly reduces the risk of thrombosis in patients with paroxysmal nocturnal hemoglobinuria (PNH), according to the results of a recent multicenter study.
Peter Hillmen, MD, of the Leeds Teaching Hospitals NHS Trust, reported the results of the study at the 12th Congress of the European Hematology Association in June 2007.
Dr Hillmen and colleagues prospectively examined the aggregate thromboembolism (TE) event rate in eculizumab-treated patients from 3 recent parent studies, as well as a subsequent common extension study. They compared those rates to the TE rate in the same patients’ pre-eculizumab treatment.
Eculizumab, which is designed to inhibit activation of terminal complement components that have been implicated in the development of PNH, reduced the TE rate in each of the three parent studies.
Most importantly, the aggregate TE event rate during eculizumab treatment was significantly reduced by 85% (P=<0.001), when compared with the same patients before eculizumab treatment.
With restriction of the pretreatment observation period to the 12 months immediately preceding eculizumab treatment, the TE event rate during treatment was reduced by 94% (P=0.002). The TE event rate in patients with TE prior to the trials was also reduced by 89% (P=<0.001).
Most TE events prior to eculizumab treatment occurred in patients receiving antithrombotics, either therapeutically or prophylactically. This indicates that the therapy may be insufficient to prevent thrombosis.
Pre-eculizumab treatment, 195 patients experienced 124 TE events. Of the 195 patients, 103 were on antithrombotics.
Of the 103 patients on antithrombotics, there were 54 TE events in 30 patients pre-eculizumab, compared to 1 TE event during eculizumab treatment. This demonstrates that eculizumab significantly reduces the risk of thrombosis in PNH patients, despite treatment with antithrombotics (P=<0.001).
Pre-eculizumab, TE was frequent in patients with lower levels of hemolysis and with mild anemia. Eculizumab significantly reduced TE across these and other subgroups (P=<0.001).
Dr Hillman said these data demonstrate the efficacy of long-term eculizumab treatment in its ability to significantly reduce the occurrence of thrombosis in PNH patients. Because TE accounts for the majority of deaths in PNH, it is reasonable to expect that eculizumab treatment, by decreasing the risk of TE, will increase the life-expectancy in PNH.
PNH is a rare, acquired, and potentially life-threatening disease of the blood characterized by hemolytic anemia, thrombosis, and red-colored urine, resulting from the breakdown of red blood cells.
TE is one of the most feared complications associated with PNH and accounts for approximately 45% of PNH patient deaths. The disease can occur even in individuals who have no previous history of thrombosis.
Patients with PNH are usually treated with anticoagulants on a prophylactic basis. However, these anticoagulants increase the risk of life-threatening hemorrhage without eliminating the potential for thrombosis, which can occur in as many as 30% of the patients who receive anticoagulant treatment.
VIENNA—Long-term treatment with eculizumab, a recombinant humanized monoclonal antibody, significantly reduces the risk of thrombosis in patients with paroxysmal nocturnal hemoglobinuria (PNH), according to the results of a recent multicenter study.
Peter Hillmen, MD, of the Leeds Teaching Hospitals NHS Trust, reported the results of the study at the 12th Congress of the European Hematology Association in June 2007.
Dr Hillmen and colleagues prospectively examined the aggregate thromboembolism (TE) event rate in eculizumab-treated patients from 3 recent parent studies, as well as a subsequent common extension study. They compared those rates to the TE rate in the same patients’ pre-eculizumab treatment.
Eculizumab, which is designed to inhibit activation of terminal complement components that have been implicated in the development of PNH, reduced the TE rate in each of the three parent studies.
Most importantly, the aggregate TE event rate during eculizumab treatment was significantly reduced by 85% (P=<0.001), when compared with the same patients before eculizumab treatment.
With restriction of the pretreatment observation period to the 12 months immediately preceding eculizumab treatment, the TE event rate during treatment was reduced by 94% (P=0.002). The TE event rate in patients with TE prior to the trials was also reduced by 89% (P=<0.001).
Most TE events prior to eculizumab treatment occurred in patients receiving antithrombotics, either therapeutically or prophylactically. This indicates that the therapy may be insufficient to prevent thrombosis.
Pre-eculizumab treatment, 195 patients experienced 124 TE events. Of the 195 patients, 103 were on antithrombotics.
Of the 103 patients on antithrombotics, there were 54 TE events in 30 patients pre-eculizumab, compared to 1 TE event during eculizumab treatment. This demonstrates that eculizumab significantly reduces the risk of thrombosis in PNH patients, despite treatment with antithrombotics (P=<0.001).
Pre-eculizumab, TE was frequent in patients with lower levels of hemolysis and with mild anemia. Eculizumab significantly reduced TE across these and other subgroups (P=<0.001).
Dr Hillman said these data demonstrate the efficacy of long-term eculizumab treatment in its ability to significantly reduce the occurrence of thrombosis in PNH patients. Because TE accounts for the majority of deaths in PNH, it is reasonable to expect that eculizumab treatment, by decreasing the risk of TE, will increase the life-expectancy in PNH.
PNH is a rare, acquired, and potentially life-threatening disease of the blood characterized by hemolytic anemia, thrombosis, and red-colored urine, resulting from the breakdown of red blood cells.
TE is one of the most feared complications associated with PNH and accounts for approximately 45% of PNH patient deaths. The disease can occur even in individuals who have no previous history of thrombosis.
Patients with PNH are usually treated with anticoagulants on a prophylactic basis. However, these anticoagulants increase the risk of life-threatening hemorrhage without eliminating the potential for thrombosis, which can occur in as many as 30% of the patients who receive anticoagulant treatment.