User login
Inhibitor gets orphan designation for DLBCL
The US Food and Drug Administration (FDA) has granted orphan drug designation to CUDC-907 for the treatment of diffuse large B-cell lymphoma (DLBCL).
CUDC-907 is an oral, dual inhibitor of histone deacetylase and phosphoinositide 3-kinase enzymes. It is currently under investigation in phase 1 trials in patients with relapsed or refractory lymphomas, multiple myeloma, and advanced/relapsed solid tumors.
The FDA grants orphan status to products intended for treating diseases that affect fewer than 200,000 people in the US. Orphan designation qualifies the drug’s developer—in this case, Curis, Inc.—with incentives such as tax credits for qualified trials, the ability to apply for annual grant funding, and 7 years of market exclusivity once the drug is approved.
Phase 1 data
At the 2013 ASH Annual Meeting, researchers presented interim data from a phase 1, dose-escalation trial of CUDC-907 in patients with advanced lymphoma or multiple myeloma.
Thirteen patients had received CUDC-907 on either once-daily (QD) or twice-weekly (BIW) schedules at doses of 30 mg QD (n=7), 60 mg QD (n=3), or 60 mg BIW (n=3).
Dose-limiting toxicities (DLTs) of grade 3 diarrhea and grade 4 hyperglycemia were reported in 1 patient at the 60 mg QD dose. The most frequent grade 3 or 4 adverse events reported in 2 or more patients included thrombocytopenia, diarrhea, and neutropenia. Tolerability limited the ability to further dose escalate using the QD schedule.
No DLTs or dose interruptions were reported for patients enrolled on the BIW schedule. So dose escalation is ongoing with the BIW schedule as well as a separate, thrice-weekly treatment schedule.
Of the 13 patients treated, 11 were evaluable for response. One patient with mixed follicular lymphoma/DLBCL achieved a partial response, with a 70% reduction in a single target lesion observed at the 30 mg QD dose level.
Seven other patients met criteria for stable disease, including 4 with stable disease lasting at least 4 cycles of treatment.
Following the ASH presentation, Curis reported additional data from a subset of patients that suggest CUDC-907 has antitumor activity in patients with DLBCL.
For the November 10, 2014, data cutoff period, 8 patients with DLBCL were evaluable. One of these patients had a complete response, 2 had a partial response (tumor shrinkage greater than 50%), and 4 had tumor shrinkage ranging from 5% to 46%.
The dose-escalation stage of the trial is nearing completion, and Curis expects to present full data this year. Curis has also initiated an expansion cohort to further evaluate CUDC-907 in patients with DLBCL or multiple myeloma at the recommended phase 2 dose. 
The US Food and Drug Administration (FDA) has granted orphan drug designation to CUDC-907 for the treatment of diffuse large B-cell lymphoma (DLBCL).
CUDC-907 is an oral, dual inhibitor of histone deacetylase and phosphoinositide 3-kinase enzymes. It is currently under investigation in phase 1 trials in patients with relapsed or refractory lymphomas, multiple myeloma, and advanced/relapsed solid tumors.
The FDA grants orphan status to products intended for treating diseases that affect fewer than 200,000 people in the US. Orphan designation qualifies the drug’s developer—in this case, Curis, Inc.—with incentives such as tax credits for qualified trials, the ability to apply for annual grant funding, and 7 years of market exclusivity once the drug is approved.
Phase 1 data
At the 2013 ASH Annual Meeting, researchers presented interim data from a phase 1, dose-escalation trial of CUDC-907 in patients with advanced lymphoma or multiple myeloma.
Thirteen patients had received CUDC-907 on either once-daily (QD) or twice-weekly (BIW) schedules at doses of 30 mg QD (n=7), 60 mg QD (n=3), or 60 mg BIW (n=3).
Dose-limiting toxicities (DLTs) of grade 3 diarrhea and grade 4 hyperglycemia were reported in 1 patient at the 60 mg QD dose. The most frequent grade 3 or 4 adverse events reported in 2 or more patients included thrombocytopenia, diarrhea, and neutropenia. Tolerability limited the ability to further dose escalate using the QD schedule.
No DLTs or dose interruptions were reported for patients enrolled on the BIW schedule. So dose escalation is ongoing with the BIW schedule as well as a separate, thrice-weekly treatment schedule.
Of the 13 patients treated, 11 were evaluable for response. One patient with mixed follicular lymphoma/DLBCL achieved a partial response, with a 70% reduction in a single target lesion observed at the 30 mg QD dose level.
Seven other patients met criteria for stable disease, including 4 with stable disease lasting at least 4 cycles of treatment.
Following the ASH presentation, Curis reported additional data from a subset of patients that suggest CUDC-907 has antitumor activity in patients with DLBCL.
For the November 10, 2014, data cutoff period, 8 patients with DLBCL were evaluable. One of these patients had a complete response, 2 had a partial response (tumor shrinkage greater than 50%), and 4 had tumor shrinkage ranging from 5% to 46%.
The dose-escalation stage of the trial is nearing completion, and Curis expects to present full data this year. Curis has also initiated an expansion cohort to further evaluate CUDC-907 in patients with DLBCL or multiple myeloma at the recommended phase 2 dose.
The US Food and Drug Administration (FDA) has granted orphan drug designation to CUDC-907 for the treatment of diffuse large B-cell lymphoma (DLBCL).
CUDC-907 is an oral, dual inhibitor of histone deacetylase and phosphoinositide 3-kinase enzymes. It is currently under investigation in phase 1 trials in patients with relapsed or refractory lymphomas, multiple myeloma, and advanced/relapsed solid tumors.
The FDA grants orphan status to products intended for treating diseases that affect fewer than 200,000 people in the US. Orphan designation qualifies the drug’s developer—in this case, Curis, Inc.—with incentives such as tax credits for qualified trials, the ability to apply for annual grant funding, and 7 years of market exclusivity once the drug is approved.
Phase 1 data
At the 2013 ASH Annual Meeting, researchers presented interim data from a phase 1, dose-escalation trial of CUDC-907 in patients with advanced lymphoma or multiple myeloma.
Thirteen patients had received CUDC-907 on either once-daily (QD) or twice-weekly (BIW) schedules at doses of 30 mg QD (n=7), 60 mg QD (n=3), or 60 mg BIW (n=3).
Dose-limiting toxicities (DLTs) of grade 3 diarrhea and grade 4 hyperglycemia were reported in 1 patient at the 60 mg QD dose. The most frequent grade 3 or 4 adverse events reported in 2 or more patients included thrombocytopenia, diarrhea, and neutropenia. Tolerability limited the ability to further dose escalate using the QD schedule.
No DLTs or dose interruptions were reported for patients enrolled on the BIW schedule. So dose escalation is ongoing with the BIW schedule as well as a separate, thrice-weekly treatment schedule.
Of the 13 patients treated, 11 were evaluable for response. One patient with mixed follicular lymphoma/DLBCL achieved a partial response, with a 70% reduction in a single target lesion observed at the 30 mg QD dose level.
Seven other patients met criteria for stable disease, including 4 with stable disease lasting at least 4 cycles of treatment.
Following the ASH presentation, Curis reported additional data from a subset of patients that suggest CUDC-907 has antitumor activity in patients with DLBCL.
For the November 10, 2014, data cutoff period, 8 patients with DLBCL were evaluable. One of these patients had a complete response, 2 had a partial response (tumor shrinkage greater than 50%), and 4 had tumor shrinkage ranging from 5% to 46%.
The dose-escalation stage of the trial is nearing completion, and Curis expects to present full data this year. Curis has also initiated an expansion cohort to further evaluate CUDC-907 in patients with DLBCL or multiple myeloma at the recommended phase 2 dose.
Drug approved to treat CML, ALL in Canada
Photo courtesy of the FDA
Health Canada has approved ponatinib hydrochloride (Iclusig) to treat adults with any phase of chronic myeloid leukemia (CML) or Philadelphia
chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) for whom other tyrosine kinase inhibitor (TKI) therapy is not appropriate, including CML or Ph+ ALL patients with the T315I mutation and those who have exhibited prior TKI resistance or intolerance.
Ponatinib is approved under the Notice of Compliance with Conditions policy based on promising evidence of clinical effectiveness.
Products approved under this policy are intended for the treatment, prevention, or diagnosis of a serious, life-threatening, or severely debilitating illness. The products must have demonstrated promising benefit, be of high quality, and possess an acceptable safety profile based on a benefit/risk assessment.
These products either respond to a serious unmet medical need in Canada or have demonstrated a significant improvement in the benefit/risk profile over existing therapies.
Ponatinib will be made available in Canada through a controlled distribution program. Prescribers who have completed the certification procedure will be able to prescribe the drug. Trained pharmacies will verify the prescriber’s certified status prior to dispensing ponatinib to the patient.
Health Canada’s decision to approve ponatinib was based on 2-year data from the phase 2 PACE trial.
A trial set to begin in mid-2015 will serve as the confirmatory trial for the Health Canada approval. Investigators will evaluate 3 starting doses of ponatinib in patients with refractory, chronic-phase CML who are resistant to at least 2 approved TKIs.
PACE trial
Researchers conducted this trial in patients with CML or Ph+ ALL who were resistant or intolerant to prior TKI therapy, or who had the T315I mutation.
Ponatinib demonstrated anti-leukemic activity in these patients, prompting a major cytogenetic response (MCyR) in 56% of chronic-phase CML patients and in 70% of patients with the T315I mutation. MCyR within the first 12 months of treatment was the primary endpoint for chronic-phase patients.
In patients with advanced disease, 57% of accelerated-phase CML patients and 31% of blast-phase CML patients achieved a major hematologic response (MaHR). MaHR within the first 6 months was the primary endpoint for patients with advanced disease. In patients with Ph+ ALL, 41% achieved MaHR.
Common non-hematologic adverse events included rash (38%), abdominal pain (38%), headache (35%), dry skin (35%), constipation (34%), fatigue (27%), pyrexia (27%), nausea (26%), arthralgia (25%), hypertension (21%), increased lipase (19%), and increased amylase (7%).
Hematologic events of any grade included thrombocytopenia (42%), neutropenia (24%), and anemia (20%). Serious adverse events of arterial thromboembolism, including arterial stenosis, occurred in patients with cardiovascular risk factors.
Extended follow-up data from the PACE trial, collected in 2013, suggested ponatinib can increase the risk of thrombotic events. When these data came to light, officials in the European Union and the US, where ponatinib had already been approved, began to investigate the drug.
Ponatinib was pulled from the US market for a little over 2 months, and trials of the drug were placed on partial hold while the Food and Drug Administration evaluated the drug’s safety. Ponatinib went back on the market in January 2014, with new safety measures in place.
The drug was not pulled from the market in the European Union, but the European Medicine’s Agency released recommendations for safer use of ponatinib. The Committee for Medicinal Products for Human Use reviewed data on ponatinib and decided the drug’s benefits outweigh its risks.
Photo courtesy of the FDA
Health Canada has approved ponatinib hydrochloride (Iclusig) to treat adults with any phase of chronic myeloid leukemia (CML) or Philadelphia
chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) for whom other tyrosine kinase inhibitor (TKI) therapy is not appropriate, including CML or Ph+ ALL patients with the T315I mutation and those who have exhibited prior TKI resistance or intolerance.
Ponatinib is approved under the Notice of Compliance with Conditions policy based on promising evidence of clinical effectiveness.
Products approved under this policy are intended for the treatment, prevention, or diagnosis of a serious, life-threatening, or severely debilitating illness. The products must have demonstrated promising benefit, be of high quality, and possess an acceptable safety profile based on a benefit/risk assessment.
These products either respond to a serious unmet medical need in Canada or have demonstrated a significant improvement in the benefit/risk profile over existing therapies.
Ponatinib will be made available in Canada through a controlled distribution program. Prescribers who have completed the certification procedure will be able to prescribe the drug. Trained pharmacies will verify the prescriber’s certified status prior to dispensing ponatinib to the patient.
Health Canada’s decision to approve ponatinib was based on 2-year data from the phase 2 PACE trial.
A trial set to begin in mid-2015 will serve as the confirmatory trial for the Health Canada approval. Investigators will evaluate 3 starting doses of ponatinib in patients with refractory, chronic-phase CML who are resistant to at least 2 approved TKIs.
PACE trial
Researchers conducted this trial in patients with CML or Ph+ ALL who were resistant or intolerant to prior TKI therapy, or who had the T315I mutation.
Ponatinib demonstrated anti-leukemic activity in these patients, prompting a major cytogenetic response (MCyR) in 56% of chronic-phase CML patients and in 70% of patients with the T315I mutation. MCyR within the first 12 months of treatment was the primary endpoint for chronic-phase patients.
In patients with advanced disease, 57% of accelerated-phase CML patients and 31% of blast-phase CML patients achieved a major hematologic response (MaHR). MaHR within the first 6 months was the primary endpoint for patients with advanced disease. In patients with Ph+ ALL, 41% achieved MaHR.
Common non-hematologic adverse events included rash (38%), abdominal pain (38%), headache (35%), dry skin (35%), constipation (34%), fatigue (27%), pyrexia (27%), nausea (26%), arthralgia (25%), hypertension (21%), increased lipase (19%), and increased amylase (7%).
Hematologic events of any grade included thrombocytopenia (42%), neutropenia (24%), and anemia (20%). Serious adverse events of arterial thromboembolism, including arterial stenosis, occurred in patients with cardiovascular risk factors.
Extended follow-up data from the PACE trial, collected in 2013, suggested ponatinib can increase the risk of thrombotic events. When these data came to light, officials in the European Union and the US, where ponatinib had already been approved, began to investigate the drug.
Ponatinib was pulled from the US market for a little over 2 months, and trials of the drug were placed on partial hold while the Food and Drug Administration evaluated the drug’s safety. Ponatinib went back on the market in January 2014, with new safety measures in place.
The drug was not pulled from the market in the European Union, but the European Medicine’s Agency released recommendations for safer use of ponatinib. The Committee for Medicinal Products for Human Use reviewed data on ponatinib and decided the drug’s benefits outweigh its risks.
Photo courtesy of the FDA
Health Canada has approved ponatinib hydrochloride (Iclusig) to treat adults with any phase of chronic myeloid leukemia (CML) or Philadelphia
chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) for whom other tyrosine kinase inhibitor (TKI) therapy is not appropriate, including CML or Ph+ ALL patients with the T315I mutation and those who have exhibited prior TKI resistance or intolerance.
Ponatinib is approved under the Notice of Compliance with Conditions policy based on promising evidence of clinical effectiveness.
Products approved under this policy are intended for the treatment, prevention, or diagnosis of a serious, life-threatening, or severely debilitating illness. The products must have demonstrated promising benefit, be of high quality, and possess an acceptable safety profile based on a benefit/risk assessment.
These products either respond to a serious unmet medical need in Canada or have demonstrated a significant improvement in the benefit/risk profile over existing therapies.
Ponatinib will be made available in Canada through a controlled distribution program. Prescribers who have completed the certification procedure will be able to prescribe the drug. Trained pharmacies will verify the prescriber’s certified status prior to dispensing ponatinib to the patient.
Health Canada’s decision to approve ponatinib was based on 2-year data from the phase 2 PACE trial.
A trial set to begin in mid-2015 will serve as the confirmatory trial for the Health Canada approval. Investigators will evaluate 3 starting doses of ponatinib in patients with refractory, chronic-phase CML who are resistant to at least 2 approved TKIs.
PACE trial
Researchers conducted this trial in patients with CML or Ph+ ALL who were resistant or intolerant to prior TKI therapy, or who had the T315I mutation.
Ponatinib demonstrated anti-leukemic activity in these patients, prompting a major cytogenetic response (MCyR) in 56% of chronic-phase CML patients and in 70% of patients with the T315I mutation. MCyR within the first 12 months of treatment was the primary endpoint for chronic-phase patients.
In patients with advanced disease, 57% of accelerated-phase CML patients and 31% of blast-phase CML patients achieved a major hematologic response (MaHR). MaHR within the first 6 months was the primary endpoint for patients with advanced disease. In patients with Ph+ ALL, 41% achieved MaHR.
Common non-hematologic adverse events included rash (38%), abdominal pain (38%), headache (35%), dry skin (35%), constipation (34%), fatigue (27%), pyrexia (27%), nausea (26%), arthralgia (25%), hypertension (21%), increased lipase (19%), and increased amylase (7%).
Hematologic events of any grade included thrombocytopenia (42%), neutropenia (24%), and anemia (20%). Serious adverse events of arterial thromboembolism, including arterial stenosis, occurred in patients with cardiovascular risk factors.
Extended follow-up data from the PACE trial, collected in 2013, suggested ponatinib can increase the risk of thrombotic events. When these data came to light, officials in the European Union and the US, where ponatinib had already been approved, began to investigate the drug.
Ponatinib was pulled from the US market for a little over 2 months, and trials of the drug were placed on partial hold while the Food and Drug Administration evaluated the drug’s safety. Ponatinib went back on the market in January 2014, with new safety measures in place.
The drug was not pulled from the market in the European Union, but the European Medicine’s Agency released recommendations for safer use of ponatinib. The Committee for Medicinal Products for Human Use reviewed data on ponatinib and decided the drug’s benefits outweigh its risks.
New administration option for antiplatelet drug
Photo courtesy of AstraZeneca
The US Food and Drug Administration (FDA) has approved a new administration option for the antiplatelet agent ticagrelor (Brilinta).
The agency has decided that, for patients with acute coronary syndrome (ACS) who cannot swallow ticagrelor tablets whole, the pills may be crushed and administered in water by swallowing or via nasogastric tube.
Ticagrelor is the only P2Y12 inhibitor that is FDA-approved to be administered in this way.
“We know that some patients who experience a heart attack are unable to swallow medications whole, yet it is important for these patients to receive and continue their oral antiplatelet therapy,” said Steven Zelenkofske, DO, Vice President of US Medical Affairs, Cardiovascular, at AstraZeneca, the company developing ticagrelor.
Survey data have shown that 40% of adults in the general population experience problems swallowing pills, and this difficulty may increase with age. Moreover, some patients who experience a heart attack have difficulty swallowing medications in the emergency setting.
So the new administration option for ticagrelor is intended to give healthcare professionals flexibility in treating their ACS patients.
Ticagrelor is a direct-acting P2Y12 receptor antagonist that works by inhibiting platelet activation. The drug is available in 90 mg tablets, to be administered with a single 180 mg oral loading dose (two 90 mg tablets) followed by a twice daily, 90 mg maintenance dose.
Following an initial loading dose of aspirin, ticagrelor should be used with a maintenance dose of aspirin at 75 mg to 100 mg once daily (an 81 mg dose in the US).
Results of the PLATO trial showed that, in ACS patients, ticagrelor can reduce the rate of a combined endpoint of cardiovascular death, myocardial infarction, and stroke, when compared to clopidogrel. The difference between treatments was driven by cardiovascular death and myocardial infarction, with no difference in the rate of stroke.
For more information on ticagrelor, see the full prescribing information.
Photo courtesy of AstraZeneca
The US Food and Drug Administration (FDA) has approved a new administration option for the antiplatelet agent ticagrelor (Brilinta).
The agency has decided that, for patients with acute coronary syndrome (ACS) who cannot swallow ticagrelor tablets whole, the pills may be crushed and administered in water by swallowing or via nasogastric tube.
Ticagrelor is the only P2Y12 inhibitor that is FDA-approved to be administered in this way.
“We know that some patients who experience a heart attack are unable to swallow medications whole, yet it is important for these patients to receive and continue their oral antiplatelet therapy,” said Steven Zelenkofske, DO, Vice President of US Medical Affairs, Cardiovascular, at AstraZeneca, the company developing ticagrelor.
Survey data have shown that 40% of adults in the general population experience problems swallowing pills, and this difficulty may increase with age. Moreover, some patients who experience a heart attack have difficulty swallowing medications in the emergency setting.
So the new administration option for ticagrelor is intended to give healthcare professionals flexibility in treating their ACS patients.
Ticagrelor is a direct-acting P2Y12 receptor antagonist that works by inhibiting platelet activation. The drug is available in 90 mg tablets, to be administered with a single 180 mg oral loading dose (two 90 mg tablets) followed by a twice daily, 90 mg maintenance dose.
Following an initial loading dose of aspirin, ticagrelor should be used with a maintenance dose of aspirin at 75 mg to 100 mg once daily (an 81 mg dose in the US).
Results of the PLATO trial showed that, in ACS patients, ticagrelor can reduce the rate of a combined endpoint of cardiovascular death, myocardial infarction, and stroke, when compared to clopidogrel. The difference between treatments was driven by cardiovascular death and myocardial infarction, with no difference in the rate of stroke.
For more information on ticagrelor, see the full prescribing information.
Photo courtesy of AstraZeneca
The US Food and Drug Administration (FDA) has approved a new administration option for the antiplatelet agent ticagrelor (Brilinta).
The agency has decided that, for patients with acute coronary syndrome (ACS) who cannot swallow ticagrelor tablets whole, the pills may be crushed and administered in water by swallowing or via nasogastric tube.
Ticagrelor is the only P2Y12 inhibitor that is FDA-approved to be administered in this way.
“We know that some patients who experience a heart attack are unable to swallow medications whole, yet it is important for these patients to receive and continue their oral antiplatelet therapy,” said Steven Zelenkofske, DO, Vice President of US Medical Affairs, Cardiovascular, at AstraZeneca, the company developing ticagrelor.
Survey data have shown that 40% of adults in the general population experience problems swallowing pills, and this difficulty may increase with age. Moreover, some patients who experience a heart attack have difficulty swallowing medications in the emergency setting.
So the new administration option for ticagrelor is intended to give healthcare professionals flexibility in treating their ACS patients.
Ticagrelor is a direct-acting P2Y12 receptor antagonist that works by inhibiting platelet activation. The drug is available in 90 mg tablets, to be administered with a single 180 mg oral loading dose (two 90 mg tablets) followed by a twice daily, 90 mg maintenance dose.
Following an initial loading dose of aspirin, ticagrelor should be used with a maintenance dose of aspirin at 75 mg to 100 mg once daily (an 81 mg dose in the US).
Results of the PLATO trial showed that, in ACS patients, ticagrelor can reduce the rate of a combined endpoint of cardiovascular death, myocardial infarction, and stroke, when compared to clopidogrel. The difference between treatments was driven by cardiovascular death and myocardial infarction, with no difference in the rate of stroke.
For more information on ticagrelor, see the full prescribing information.
Japan approves pomalidomide for MM
Photo by Steven Harbour
Japan’s Ministry of Health, Labour and Welfare (MHLW) has granted full marketing authorization for pomalidomide (Pomalyst) to treat patients with relapsed or refractory multiple myeloma (MM) who have previously received lenalidomide and bortezomib.
Pomalidomide will be available in Japan through RevMate, a restricted distribution program that should ensure the proper use of pomalidomide and prevent fetal exposure to the drug.
The MHLW approved pomalidomide based on results of trials in patients with previously treated MM, including the phase 3 MM-003 trial and the phase 2 MM-011 trial.
Phase 2 trial
In the MM-011 trial, which has not yet been published, researchers evaluated the safety and efficacy of pomalidomide in combination with dexamethasone in 36 patients with relapsed/refractory MM.
The patients had received at least 2 prior therapies, including lenalidomide and bortezomib, and had disease progression within 60 days of completing their last therapy.
Twenty-five percent of patients responded to treatment with pomalidomide and dexamethasone, 1 with a complete response and 8 with a partial response.
About 89% of patients (32/36) experienced adverse events, including lab test abnormalities. The most common events were neutropenia (69.4%), thrombocytopenia (33.3%), rash (22.2%), leukocytopenia (13.9%), pyrexia (13.9%), anemia (11.1%), lymphopenia (11.1%), and constipation (11.1%).
Phase 3 trial
The MM-003 study included 455 patients with relapsed or refractory MM. They were randomized to receive either pomalidomide plus low-dose dexamethasone (POM-LoDEX, n=302) or high-dose dexamethasone (HiDEX, n=153). The median follow-up was 10 months.
The overall response rate was 31% (n=95) in the POM-LoDEX arm and 10% (n=15) in the HiDEX arm. The median duration of response was 7.0 months (range, 6 to 9 months) and 6.1 months (range, 1.4 to 8.5 months), respectively.
The median progression-free survival was 4.0 months in the POM-LoDEX arm and 1.9 months in the HiDEX arm (P<0.001). And the median overall survival was 12.7 months in the POM-LoDEX arm and 8.1 months in the HiDEX arm (P=0.028).
Patients in the POM-LoDEX arm experienced more grade 3/4 neutropenia than patients in the HiDEX arm. But rates of grade 3/4 anemia and thrombocytopenia were similar between the 2 arms.
Rates of grade 3/4 non-hematologic toxicities were also similar between the arms and included infection, pneumonia, hemorrhage, glucose intolerance, and fatigue. Other adverse events of note included venous thromboembolism and peripheral neuropathy, which occurred at similar rates in both arms.
Photo by Steven Harbour
Japan’s Ministry of Health, Labour and Welfare (MHLW) has granted full marketing authorization for pomalidomide (Pomalyst) to treat patients with relapsed or refractory multiple myeloma (MM) who have previously received lenalidomide and bortezomib.
Pomalidomide will be available in Japan through RevMate, a restricted distribution program that should ensure the proper use of pomalidomide and prevent fetal exposure to the drug.
The MHLW approved pomalidomide based on results of trials in patients with previously treated MM, including the phase 3 MM-003 trial and the phase 2 MM-011 trial.
Phase 2 trial
In the MM-011 trial, which has not yet been published, researchers evaluated the safety and efficacy of pomalidomide in combination with dexamethasone in 36 patients with relapsed/refractory MM.
The patients had received at least 2 prior therapies, including lenalidomide and bortezomib, and had disease progression within 60 days of completing their last therapy.
Twenty-five percent of patients responded to treatment with pomalidomide and dexamethasone, 1 with a complete response and 8 with a partial response.
About 89% of patients (32/36) experienced adverse events, including lab test abnormalities. The most common events were neutropenia (69.4%), thrombocytopenia (33.3%), rash (22.2%), leukocytopenia (13.9%), pyrexia (13.9%), anemia (11.1%), lymphopenia (11.1%), and constipation (11.1%).
Phase 3 trial
The MM-003 study included 455 patients with relapsed or refractory MM. They were randomized to receive either pomalidomide plus low-dose dexamethasone (POM-LoDEX, n=302) or high-dose dexamethasone (HiDEX, n=153). The median follow-up was 10 months.
The overall response rate was 31% (n=95) in the POM-LoDEX arm and 10% (n=15) in the HiDEX arm. The median duration of response was 7.0 months (range, 6 to 9 months) and 6.1 months (range, 1.4 to 8.5 months), respectively.
The median progression-free survival was 4.0 months in the POM-LoDEX arm and 1.9 months in the HiDEX arm (P<0.001). And the median overall survival was 12.7 months in the POM-LoDEX arm and 8.1 months in the HiDEX arm (P=0.028).
Patients in the POM-LoDEX arm experienced more grade 3/4 neutropenia than patients in the HiDEX arm. But rates of grade 3/4 anemia and thrombocytopenia were similar between the 2 arms.
Rates of grade 3/4 non-hematologic toxicities were also similar between the arms and included infection, pneumonia, hemorrhage, glucose intolerance, and fatigue. Other adverse events of note included venous thromboembolism and peripheral neuropathy, which occurred at similar rates in both arms.
Photo by Steven Harbour
Japan’s Ministry of Health, Labour and Welfare (MHLW) has granted full marketing authorization for pomalidomide (Pomalyst) to treat patients with relapsed or refractory multiple myeloma (MM) who have previously received lenalidomide and bortezomib.
Pomalidomide will be available in Japan through RevMate, a restricted distribution program that should ensure the proper use of pomalidomide and prevent fetal exposure to the drug.
The MHLW approved pomalidomide based on results of trials in patients with previously treated MM, including the phase 3 MM-003 trial and the phase 2 MM-011 trial.
Phase 2 trial
In the MM-011 trial, which has not yet been published, researchers evaluated the safety and efficacy of pomalidomide in combination with dexamethasone in 36 patients with relapsed/refractory MM.
The patients had received at least 2 prior therapies, including lenalidomide and bortezomib, and had disease progression within 60 days of completing their last therapy.
Twenty-five percent of patients responded to treatment with pomalidomide and dexamethasone, 1 with a complete response and 8 with a partial response.
About 89% of patients (32/36) experienced adverse events, including lab test abnormalities. The most common events were neutropenia (69.4%), thrombocytopenia (33.3%), rash (22.2%), leukocytopenia (13.9%), pyrexia (13.9%), anemia (11.1%), lymphopenia (11.1%), and constipation (11.1%).
Phase 3 trial
The MM-003 study included 455 patients with relapsed or refractory MM. They were randomized to receive either pomalidomide plus low-dose dexamethasone (POM-LoDEX, n=302) or high-dose dexamethasone (HiDEX, n=153). The median follow-up was 10 months.
The overall response rate was 31% (n=95) in the POM-LoDEX arm and 10% (n=15) in the HiDEX arm. The median duration of response was 7.0 months (range, 6 to 9 months) and 6.1 months (range, 1.4 to 8.5 months), respectively.
The median progression-free survival was 4.0 months in the POM-LoDEX arm and 1.9 months in the HiDEX arm (P<0.001). And the median overall survival was 12.7 months in the POM-LoDEX arm and 8.1 months in the HiDEX arm (P=0.028).
Patients in the POM-LoDEX arm experienced more grade 3/4 neutropenia than patients in the HiDEX arm. But rates of grade 3/4 anemia and thrombocytopenia were similar between the 2 arms.
Rates of grade 3/4 non-hematologic toxicities were also similar between the arms and included infection, pneumonia, hemorrhage, glucose intolerance, and fatigue. Other adverse events of note included venous thromboembolism and peripheral neuropathy, which occurred at similar rates in both arms.
FDA grants drug orphan designation for DLBCL
The US Food and Drug Administration (FDA) has granted orphan drug designation for IMO-8400, an antagonist of the endosomal toll-like receptors (TLRs) 7, 8, and 9, for the treatment of diffuse large B-cell lymphoma (DLBCL).
The FDA grants orphan designation to drugs intended to treat conditions that affect fewer than 200,000 people in the US.
The designation will provide Idera Pharmaceuticals, the company developing IMO-8400, with certain incentives. These include eligibility for federal grants, research and development tax credits, and a 7-year period of marketing exclusivity if the product is approved.
Relevant research
Preclinical research published in Leukemia showed that the MYD88 L265P oncogenic mutation is an independent prognostic factor in DLBCL. In DLBCL patients with this mutation, TLR signaling is over-activated, which enables tumor cell survival and proliferation.
Data presented at the 2014 AACR Annual Meeting showed that IMO-8400 inhibited the survival and proliferation of DLBCL cells and Waldenstrom’s macroglobulinemia (WM) cells harboring the MYD88 L265P mutation.
A phase 1 trial of IMO-8400 presented at the 2013 FOCIS Annual Meeting showed the drug was active and well-tolerated in 42 healthy subjects. IMO-8400 was given at single and multiple escalating doses up to 0.6 mg/kg for 4 weeks. The drug inhibited immune responses mediated by TLRs 7, 8, and 9.
Idera Pharmaceuticals is currently conducting a phase 1/2 trial of IMO-8400 in patients with relapsed or refractory DLBCL who harbor the MYD88 L265P mutation. The protocol includes 3 dose-escalation cohorts in which IMO-8400 is administered subcutaneously.
Idera is also pursuing clinical development of IMO-8400 in WM. The FDA recently granted the drug orphan designation to treat WM.
The US Food and Drug Administration (FDA) has granted orphan drug designation for IMO-8400, an antagonist of the endosomal toll-like receptors (TLRs) 7, 8, and 9, for the treatment of diffuse large B-cell lymphoma (DLBCL).
The FDA grants orphan designation to drugs intended to treat conditions that affect fewer than 200,000 people in the US.
The designation will provide Idera Pharmaceuticals, the company developing IMO-8400, with certain incentives. These include eligibility for federal grants, research and development tax credits, and a 7-year period of marketing exclusivity if the product is approved.
Relevant research
Preclinical research published in Leukemia showed that the MYD88 L265P oncogenic mutation is an independent prognostic factor in DLBCL. In DLBCL patients with this mutation, TLR signaling is over-activated, which enables tumor cell survival and proliferation.
Data presented at the 2014 AACR Annual Meeting showed that IMO-8400 inhibited the survival and proliferation of DLBCL cells and Waldenstrom’s macroglobulinemia (WM) cells harboring the MYD88 L265P mutation.
A phase 1 trial of IMO-8400 presented at the 2013 FOCIS Annual Meeting showed the drug was active and well-tolerated in 42 healthy subjects. IMO-8400 was given at single and multiple escalating doses up to 0.6 mg/kg for 4 weeks. The drug inhibited immune responses mediated by TLRs 7, 8, and 9.
Idera Pharmaceuticals is currently conducting a phase 1/2 trial of IMO-8400 in patients with relapsed or refractory DLBCL who harbor the MYD88 L265P mutation. The protocol includes 3 dose-escalation cohorts in which IMO-8400 is administered subcutaneously.
Idera is also pursuing clinical development of IMO-8400 in WM. The FDA recently granted the drug orphan designation to treat WM.
The US Food and Drug Administration (FDA) has granted orphan drug designation for IMO-8400, an antagonist of the endosomal toll-like receptors (TLRs) 7, 8, and 9, for the treatment of diffuse large B-cell lymphoma (DLBCL).
The FDA grants orphan designation to drugs intended to treat conditions that affect fewer than 200,000 people in the US.
The designation will provide Idera Pharmaceuticals, the company developing IMO-8400, with certain incentives. These include eligibility for federal grants, research and development tax credits, and a 7-year period of marketing exclusivity if the product is approved.
Relevant research
Preclinical research published in Leukemia showed that the MYD88 L265P oncogenic mutation is an independent prognostic factor in DLBCL. In DLBCL patients with this mutation, TLR signaling is over-activated, which enables tumor cell survival and proliferation.
Data presented at the 2014 AACR Annual Meeting showed that IMO-8400 inhibited the survival and proliferation of DLBCL cells and Waldenstrom’s macroglobulinemia (WM) cells harboring the MYD88 L265P mutation.
A phase 1 trial of IMO-8400 presented at the 2013 FOCIS Annual Meeting showed the drug was active and well-tolerated in 42 healthy subjects. IMO-8400 was given at single and multiple escalating doses up to 0.6 mg/kg for 4 weeks. The drug inhibited immune responses mediated by TLRs 7, 8, and 9.
Idera Pharmaceuticals is currently conducting a phase 1/2 trial of IMO-8400 in patients with relapsed or refractory DLBCL who harbor the MYD88 L265P mutation. The protocol includes 3 dose-escalation cohorts in which IMO-8400 is administered subcutaneously.
Idera is also pursuing clinical development of IMO-8400 in WM. The FDA recently granted the drug orphan designation to treat WM.
FDA approves new formulation of iron overload drug
The US Food and Drug Administration (FDA) has granted accelerated approval for Jadenu, a new oral formulation of Exjade (deferasirox).
Jadenu is now approved to treat patients 2 years of age and older who have chronic iron overload resulting from blood transfusions. The drug is also approved to treat chronic iron overload in patients 10 years of age and older who have non-transfusion-dependent thalassemia.
Jadenu can be swallowed whole and taken with or without a light meal. Exjade is a dispersible tablet that must be mixed in liquid and taken on an empty stomach.
Jadenu has been approved with a boxed warning, which states that the drug may cause serious and fatal renal toxicity (including failure), hepatic toxicity (including failure), and gastrointestinal hemorrhage. Therefore, treatment with Jadenu requires close patient monitoring, including laboratory tests of renal and hepatic function.
The FDA has granted Jadenu accelerated approval based on the drug showing a reduction of liver iron concentrations and serum ferritin levels. Continued FDA approval for Jadenu may be contingent upon verification and description of clinical benefit in confirmatory trials.
Jadenu has been evaluated in trials of healthy volunteers, but there are no clinical data showing the effects of Jadenu in patients with chronic iron overload.
Exjade, on the other hand, has been evaluated in several trials of patients with chronic iron overload resulting from transfusions and patients with non-transfusion-dependent thalassemia who have chronic iron overload.
Data from these trials can be found in the prescribing information for Jadenu, available at www.jadenu.com.
The US Food and Drug Administration (FDA) has granted accelerated approval for Jadenu, a new oral formulation of Exjade (deferasirox).
Jadenu is now approved to treat patients 2 years of age and older who have chronic iron overload resulting from blood transfusions. The drug is also approved to treat chronic iron overload in patients 10 years of age and older who have non-transfusion-dependent thalassemia.
Jadenu can be swallowed whole and taken with or without a light meal. Exjade is a dispersible tablet that must be mixed in liquid and taken on an empty stomach.
Jadenu has been approved with a boxed warning, which states that the drug may cause serious and fatal renal toxicity (including failure), hepatic toxicity (including failure), and gastrointestinal hemorrhage. Therefore, treatment with Jadenu requires close patient monitoring, including laboratory tests of renal and hepatic function.
The FDA has granted Jadenu accelerated approval based on the drug showing a reduction of liver iron concentrations and serum ferritin levels. Continued FDA approval for Jadenu may be contingent upon verification and description of clinical benefit in confirmatory trials.
Jadenu has been evaluated in trials of healthy volunteers, but there are no clinical data showing the effects of Jadenu in patients with chronic iron overload.
Exjade, on the other hand, has been evaluated in several trials of patients with chronic iron overload resulting from transfusions and patients with non-transfusion-dependent thalassemia who have chronic iron overload.
Data from these trials can be found in the prescribing information for Jadenu, available at www.jadenu.com.
The US Food and Drug Administration (FDA) has granted accelerated approval for Jadenu, a new oral formulation of Exjade (deferasirox).
Jadenu is now approved to treat patients 2 years of age and older who have chronic iron overload resulting from blood transfusions. The drug is also approved to treat chronic iron overload in patients 10 years of age and older who have non-transfusion-dependent thalassemia.
Jadenu can be swallowed whole and taken with or without a light meal. Exjade is a dispersible tablet that must be mixed in liquid and taken on an empty stomach.
Jadenu has been approved with a boxed warning, which states that the drug may cause serious and fatal renal toxicity (including failure), hepatic toxicity (including failure), and gastrointestinal hemorrhage. Therefore, treatment with Jadenu requires close patient monitoring, including laboratory tests of renal and hepatic function.
The FDA has granted Jadenu accelerated approval based on the drug showing a reduction of liver iron concentrations and serum ferritin levels. Continued FDA approval for Jadenu may be contingent upon verification and description of clinical benefit in confirmatory trials.
Jadenu has been evaluated in trials of healthy volunteers, but there are no clinical data showing the effects of Jadenu in patients with chronic iron overload.
Exjade, on the other hand, has been evaluated in several trials of patients with chronic iron overload resulting from transfusions and patients with non-transfusion-dependent thalassemia who have chronic iron overload.
Data from these trials can be found in the prescribing information for Jadenu, available at www.jadenu.com.
Immunotherapy gets orphan designation
Photo by Graham Colm
The US Food and Drug Administration (FDA) has granted orphan designation to an immunotherapy known as CMD-003, which is under development to treat Epstein-Barr-virus (EBV)-positive non-Hodgkin lymphomas.
CMD-003 consists of T cells derived from blood samples that are activated and expanded through a proprietary process developed for commercial-scale use.
Researchers have treated more than 250 patients with prototypes of CMD-003. And the prototypes have produced promising results in a range of malignancies.
CMD-003 is under development by Cell Medica and the Center for Cell and Gene Therapy (CAGT) at Baylor College of Medicine, Texas Children’s Hospital, and Houston Methodist Hospital.
Orphan designation from the FDA will provide CMD-003’s developers with several benefits, including accessibility to grants to support clinical development, 7 years of market exclusivity if the treatment is approved in the US, and tax credits on US clinical trials.
CMD-003 prototype
Researchers have not published any trials of CMD-003, but they have studied other EBV-specific T-cell products related to CMD-003.
In their most recent study, published in the Journal of Clinical Oncology, the researchers administered cytotoxic T lymphocytes (CTLs) in 50 patients with EBV-associated Hodgkin or non-Hodgkin lymphoma.
Twenty-nine of the patients were in remission when they received CTL infusions, but they were at a high risk of relapse. The remaining 21 patients had relapsed or refractory disease at the time of CTL infusion.
Twenty-seven of the patients who received CTLs as an adjuvant treatment remained in remission from their disease at 3.1 years after treatment.
Their 2-year event-free survival rate was 82%. None of them died of lymphoma, but 9 died from complications associated with the chemotherapy and radiation they had received.
Of the 21 patients with relapsed or refractory disease, 13 responded to CTL infusions, and 11 patients achieved a complete response. In this group, the 2-year event-free survival rate was about 50%.
The researchers said there were no toxicities that were definitively related to CTL infusion.
One patient had central nervous system deterioration 2 weeks after infusion. This was attributed to disease progression but could possibly have been treatment-related.
Another patient developed respiratory complications about 4 weeks after a second CTL infusion that may have been treatment-related. However, the researchers attributed it to an intercurrent infection, and the patient made a complete recovery.
Photo by Graham Colm
The US Food and Drug Administration (FDA) has granted orphan designation to an immunotherapy known as CMD-003, which is under development to treat Epstein-Barr-virus (EBV)-positive non-Hodgkin lymphomas.
CMD-003 consists of T cells derived from blood samples that are activated and expanded through a proprietary process developed for commercial-scale use.
Researchers have treated more than 250 patients with prototypes of CMD-003. And the prototypes have produced promising results in a range of malignancies.
CMD-003 is under development by Cell Medica and the Center for Cell and Gene Therapy (CAGT) at Baylor College of Medicine, Texas Children’s Hospital, and Houston Methodist Hospital.
Orphan designation from the FDA will provide CMD-003’s developers with several benefits, including accessibility to grants to support clinical development, 7 years of market exclusivity if the treatment is approved in the US, and tax credits on US clinical trials.
CMD-003 prototype
Researchers have not published any trials of CMD-003, but they have studied other EBV-specific T-cell products related to CMD-003.
In their most recent study, published in the Journal of Clinical Oncology, the researchers administered cytotoxic T lymphocytes (CTLs) in 50 patients with EBV-associated Hodgkin or non-Hodgkin lymphoma.
Twenty-nine of the patients were in remission when they received CTL infusions, but they were at a high risk of relapse. The remaining 21 patients had relapsed or refractory disease at the time of CTL infusion.
Twenty-seven of the patients who received CTLs as an adjuvant treatment remained in remission from their disease at 3.1 years after treatment.
Their 2-year event-free survival rate was 82%. None of them died of lymphoma, but 9 died from complications associated with the chemotherapy and radiation they had received.
Of the 21 patients with relapsed or refractory disease, 13 responded to CTL infusions, and 11 patients achieved a complete response. In this group, the 2-year event-free survival rate was about 50%.
The researchers said there were no toxicities that were definitively related to CTL infusion.
One patient had central nervous system deterioration 2 weeks after infusion. This was attributed to disease progression but could possibly have been treatment-related.
Another patient developed respiratory complications about 4 weeks after a second CTL infusion that may have been treatment-related. However, the researchers attributed it to an intercurrent infection, and the patient made a complete recovery.
Photo by Graham Colm
The US Food and Drug Administration (FDA) has granted orphan designation to an immunotherapy known as CMD-003, which is under development to treat Epstein-Barr-virus (EBV)-positive non-Hodgkin lymphomas.
CMD-003 consists of T cells derived from blood samples that are activated and expanded through a proprietary process developed for commercial-scale use.
Researchers have treated more than 250 patients with prototypes of CMD-003. And the prototypes have produced promising results in a range of malignancies.
CMD-003 is under development by Cell Medica and the Center for Cell and Gene Therapy (CAGT) at Baylor College of Medicine, Texas Children’s Hospital, and Houston Methodist Hospital.
Orphan designation from the FDA will provide CMD-003’s developers with several benefits, including accessibility to grants to support clinical development, 7 years of market exclusivity if the treatment is approved in the US, and tax credits on US clinical trials.
CMD-003 prototype
Researchers have not published any trials of CMD-003, but they have studied other EBV-specific T-cell products related to CMD-003.
In their most recent study, published in the Journal of Clinical Oncology, the researchers administered cytotoxic T lymphocytes (CTLs) in 50 patients with EBV-associated Hodgkin or non-Hodgkin lymphoma.
Twenty-nine of the patients were in remission when they received CTL infusions, but they were at a high risk of relapse. The remaining 21 patients had relapsed or refractory disease at the time of CTL infusion.
Twenty-seven of the patients who received CTLs as an adjuvant treatment remained in remission from their disease at 3.1 years after treatment.
Their 2-year event-free survival rate was 82%. None of them died of lymphoma, but 9 died from complications associated with the chemotherapy and radiation they had received.
Of the 21 patients with relapsed or refractory disease, 13 responded to CTL infusions, and 11 patients achieved a complete response. In this group, the 2-year event-free survival rate was about 50%.
The researchers said there were no toxicities that were definitively related to CTL infusion.
One patient had central nervous system deterioration 2 weeks after infusion. This was attributed to disease progression but could possibly have been treatment-related.
Another patient developed respiratory complications about 4 weeks after a second CTL infusion that may have been treatment-related. However, the researchers attributed it to an intercurrent infection, and the patient made a complete recovery.
FDA strengthens warnings for anemia drug
Photo by Bill Branson
The US Food and Drug Administration (FDA) has strengthened an existing warning that serious, potentially fatal, allergic reactions can occur with the anemia drug Feraheme (ferumoxytol).
The FDA changed the drug’s prescribing information and approved a boxed warning detailing this risk.
The agency also added a new contraindication, which advises against the use of Feraheme in patients who have had an allergic reaction to any intravenous (IV) iron replacement product.
The FDA said it is continuing to monitor and evaluate the risk of serious allergic reactions with all IV iron products, and the agency will update the public as new information becomes available.
About Feraheme
Feraheme is an IV iron replacement product used to treat iron-deficiency anemia in patients with chronic kidney disease. Like other IV iron products, Feraheme may only be given where emergency personnel and equipment are immediately available to treat the potentially life-threatening allergic reactions that can occur with treatment.
All IV iron products carry a risk of potentially life-threatening allergic reactions. At the time of Feraheme’s approval in 2009, this risk was described in the “Warnings and Precautions” section of the drug label.
Since then, serious reactions, including deaths, have occurred, despite the proper use of therapies to treat these reactions and emergency resuscitation measures.
Serious reactions reported
In the initial clinical trials of Feraheme, conducted predominantly in patients with chronic kidney disease, serious hypersensitivity reactions were reported in 0.2% (3/1726) of patients receiving Feraheme.
Other adverse reactions potentially associated with hypersensitivity (eg, pruritus, rash, urticaria, or wheezing) were reported in 3.7% (63/1726) of these patients.
In other trials that did not include patients with chronic kidney disease, moderate to severe hypersensitivity reactions, including anaphylaxis, were reported in 2.6% (26/1014) of patients treated with Feraheme.
Since the approval of Feraheme on June 30, 2009, cases of serious hypersensitivity reactions, including death, have occurred.
A search of the FDA Adverse Event Reporting System database revealed 79 cases of anaphylactic reactions associated with Feraheme administration, reported from the time of approval to June 30, 2014. Of the 79 cases, 18 were fatal, despite immediate medical intervention and emergency resuscitation attempts.
The 79 patients ranged in age from 19 to 96 years. In nearly half of all cases, the anaphylactic reactions occurred with the first dose of Feraheme. For approximately 75% (60/79) of the cases, the reaction began during the infusion or within 5 minutes after administration was complete.
Frequently reported symptoms included cardiac arrest, hypotension, dyspnea, nausea, vomiting, and flushing. Of the 79 patients, 43% (34/79) had a medical history of drug allergy, and 24% had a history of multiple drug allergies.
Recommendations for administering Feraheme
Initial symptoms of fatal and serious hypersensitivity reactions associated with Feraheme may include hypotension, syncope, unresponsiveness, and cardiac/cardiorespiratory arrest, with or without signs of rash.
All IV iron products carry a risk of anaphylaxis, so these products should be administered only in patients who require IV iron therapy.
Feraheme is only approved for use in adults with iron-deficiency anemia in the setting of chronic kidney disease. The drug is contraindicated in patients with a history of hypersensitivity to Feraheme or any other IV iron product.
Only administer Feraheme and other IV iron products when personnel and therapies are immediately available for the treatment of anaphylaxis and other hypersensitivity reactions.
Patients with a history of multiple drug allergies may have a greater risk of anaphylaxis with parenteral iron products. Carefully consider the potential risks and benefits before administering Feraheme to these patients.
Feraheme should only be administered as an IV infusion in 50-200 mL of 0.9% sodium chloride or 5% dextrose over a minimum period of 15 minutes following dilution. Do not administer Feraheme by undiluted IV injection.
Closely monitor patients for signs and symptoms of hypersensitivity reactions, including monitoring blood pressure and pulse during administration and for at least 30 minutes following each infusion of Feraheme.
Elderly patients 65 years of age and older with multiple or serious comorbidities who experience hypersensitivity reactions, hypotension, or both following administration of Feraheme may have more severe outcomes.
Advise patients to immediately report any signs and symptoms of hypersensitivity that may develop during and following Feraheme administration, such as respiratory distress, hypotension, dizziness or lightheadedness, edema, rash, or itching. Advise patients to seek immediate medical attention if these signs and symptoms occur.
Allow at least 30 minutes between administration of Feraheme and administration of other medications that could potentially cause serious hypersensitivity reactions, hypotension, or both, such as chemotherapeutic agents or monoclonal antibodies.
Report adverse events involving Feraheme to the FDA’s MedWatch Program.
Photo by Bill Branson
The US Food and Drug Administration (FDA) has strengthened an existing warning that serious, potentially fatal, allergic reactions can occur with the anemia drug Feraheme (ferumoxytol).
The FDA changed the drug’s prescribing information and approved a boxed warning detailing this risk.
The agency also added a new contraindication, which advises against the use of Feraheme in patients who have had an allergic reaction to any intravenous (IV) iron replacement product.
The FDA said it is continuing to monitor and evaluate the risk of serious allergic reactions with all IV iron products, and the agency will update the public as new information becomes available.
About Feraheme
Feraheme is an IV iron replacement product used to treat iron-deficiency anemia in patients with chronic kidney disease. Like other IV iron products, Feraheme may only be given where emergency personnel and equipment are immediately available to treat the potentially life-threatening allergic reactions that can occur with treatment.
All IV iron products carry a risk of potentially life-threatening allergic reactions. At the time of Feraheme’s approval in 2009, this risk was described in the “Warnings and Precautions” section of the drug label.
Since then, serious reactions, including deaths, have occurred, despite the proper use of therapies to treat these reactions and emergency resuscitation measures.
Serious reactions reported
In the initial clinical trials of Feraheme, conducted predominantly in patients with chronic kidney disease, serious hypersensitivity reactions were reported in 0.2% (3/1726) of patients receiving Feraheme.
Other adverse reactions potentially associated with hypersensitivity (eg, pruritus, rash, urticaria, or wheezing) were reported in 3.7% (63/1726) of these patients.
In other trials that did not include patients with chronic kidney disease, moderate to severe hypersensitivity reactions, including anaphylaxis, were reported in 2.6% (26/1014) of patients treated with Feraheme.
Since the approval of Feraheme on June 30, 2009, cases of serious hypersensitivity reactions, including death, have occurred.
A search of the FDA Adverse Event Reporting System database revealed 79 cases of anaphylactic reactions associated with Feraheme administration, reported from the time of approval to June 30, 2014. Of the 79 cases, 18 were fatal, despite immediate medical intervention and emergency resuscitation attempts.
The 79 patients ranged in age from 19 to 96 years. In nearly half of all cases, the anaphylactic reactions occurred with the first dose of Feraheme. For approximately 75% (60/79) of the cases, the reaction began during the infusion or within 5 minutes after administration was complete.
Frequently reported symptoms included cardiac arrest, hypotension, dyspnea, nausea, vomiting, and flushing. Of the 79 patients, 43% (34/79) had a medical history of drug allergy, and 24% had a history of multiple drug allergies.
Recommendations for administering Feraheme
Initial symptoms of fatal and serious hypersensitivity reactions associated with Feraheme may include hypotension, syncope, unresponsiveness, and cardiac/cardiorespiratory arrest, with or without signs of rash.
All IV iron products carry a risk of anaphylaxis, so these products should be administered only in patients who require IV iron therapy.
Feraheme is only approved for use in adults with iron-deficiency anemia in the setting of chronic kidney disease. The drug is contraindicated in patients with a history of hypersensitivity to Feraheme or any other IV iron product.
Only administer Feraheme and other IV iron products when personnel and therapies are immediately available for the treatment of anaphylaxis and other hypersensitivity reactions.
Patients with a history of multiple drug allergies may have a greater risk of anaphylaxis with parenteral iron products. Carefully consider the potential risks and benefits before administering Feraheme to these patients.
Feraheme should only be administered as an IV infusion in 50-200 mL of 0.9% sodium chloride or 5% dextrose over a minimum period of 15 minutes following dilution. Do not administer Feraheme by undiluted IV injection.
Closely monitor patients for signs and symptoms of hypersensitivity reactions, including monitoring blood pressure and pulse during administration and for at least 30 minutes following each infusion of Feraheme.
Elderly patients 65 years of age and older with multiple or serious comorbidities who experience hypersensitivity reactions, hypotension, or both following administration of Feraheme may have more severe outcomes.
Advise patients to immediately report any signs and symptoms of hypersensitivity that may develop during and following Feraheme administration, such as respiratory distress, hypotension, dizziness or lightheadedness, edema, rash, or itching. Advise patients to seek immediate medical attention if these signs and symptoms occur.
Allow at least 30 minutes between administration of Feraheme and administration of other medications that could potentially cause serious hypersensitivity reactions, hypotension, or both, such as chemotherapeutic agents or monoclonal antibodies.
Report adverse events involving Feraheme to the FDA’s MedWatch Program.
Photo by Bill Branson
The US Food and Drug Administration (FDA) has strengthened an existing warning that serious, potentially fatal, allergic reactions can occur with the anemia drug Feraheme (ferumoxytol).
The FDA changed the drug’s prescribing information and approved a boxed warning detailing this risk.
The agency also added a new contraindication, which advises against the use of Feraheme in patients who have had an allergic reaction to any intravenous (IV) iron replacement product.
The FDA said it is continuing to monitor and evaluate the risk of serious allergic reactions with all IV iron products, and the agency will update the public as new information becomes available.
About Feraheme
Feraheme is an IV iron replacement product used to treat iron-deficiency anemia in patients with chronic kidney disease. Like other IV iron products, Feraheme may only be given where emergency personnel and equipment are immediately available to treat the potentially life-threatening allergic reactions that can occur with treatment.
All IV iron products carry a risk of potentially life-threatening allergic reactions. At the time of Feraheme’s approval in 2009, this risk was described in the “Warnings and Precautions” section of the drug label.
Since then, serious reactions, including deaths, have occurred, despite the proper use of therapies to treat these reactions and emergency resuscitation measures.
Serious reactions reported
In the initial clinical trials of Feraheme, conducted predominantly in patients with chronic kidney disease, serious hypersensitivity reactions were reported in 0.2% (3/1726) of patients receiving Feraheme.
Other adverse reactions potentially associated with hypersensitivity (eg, pruritus, rash, urticaria, or wheezing) were reported in 3.7% (63/1726) of these patients.
In other trials that did not include patients with chronic kidney disease, moderate to severe hypersensitivity reactions, including anaphylaxis, were reported in 2.6% (26/1014) of patients treated with Feraheme.
Since the approval of Feraheme on June 30, 2009, cases of serious hypersensitivity reactions, including death, have occurred.
A search of the FDA Adverse Event Reporting System database revealed 79 cases of anaphylactic reactions associated with Feraheme administration, reported from the time of approval to June 30, 2014. Of the 79 cases, 18 were fatal, despite immediate medical intervention and emergency resuscitation attempts.
The 79 patients ranged in age from 19 to 96 years. In nearly half of all cases, the anaphylactic reactions occurred with the first dose of Feraheme. For approximately 75% (60/79) of the cases, the reaction began during the infusion or within 5 minutes after administration was complete.
Frequently reported symptoms included cardiac arrest, hypotension, dyspnea, nausea, vomiting, and flushing. Of the 79 patients, 43% (34/79) had a medical history of drug allergy, and 24% had a history of multiple drug allergies.
Recommendations for administering Feraheme
Initial symptoms of fatal and serious hypersensitivity reactions associated with Feraheme may include hypotension, syncope, unresponsiveness, and cardiac/cardiorespiratory arrest, with or without signs of rash.
All IV iron products carry a risk of anaphylaxis, so these products should be administered only in patients who require IV iron therapy.
Feraheme is only approved for use in adults with iron-deficiency anemia in the setting of chronic kidney disease. The drug is contraindicated in patients with a history of hypersensitivity to Feraheme or any other IV iron product.
Only administer Feraheme and other IV iron products when personnel and therapies are immediately available for the treatment of anaphylaxis and other hypersensitivity reactions.
Patients with a history of multiple drug allergies may have a greater risk of anaphylaxis with parenteral iron products. Carefully consider the potential risks and benefits before administering Feraheme to these patients.
Feraheme should only be administered as an IV infusion in 50-200 mL of 0.9% sodium chloride or 5% dextrose over a minimum period of 15 minutes following dilution. Do not administer Feraheme by undiluted IV injection.
Closely monitor patients for signs and symptoms of hypersensitivity reactions, including monitoring blood pressure and pulse during administration and for at least 30 minutes following each infusion of Feraheme.
Elderly patients 65 years of age and older with multiple or serious comorbidities who experience hypersensitivity reactions, hypotension, or both following administration of Feraheme may have more severe outcomes.
Advise patients to immediately report any signs and symptoms of hypersensitivity that may develop during and following Feraheme administration, such as respiratory distress, hypotension, dizziness or lightheadedness, edema, rash, or itching. Advise patients to seek immediate medical attention if these signs and symptoms occur.
Allow at least 30 minutes between administration of Feraheme and administration of other medications that could potentially cause serious hypersensitivity reactions, hypotension, or both, such as chemotherapeutic agents or monoclonal antibodies.
Report adverse events involving Feraheme to the FDA’s MedWatch Program.
FDA grants drug orphan status to treat PKD
Image courtesy of NHLBI
The US Food and Drug Administration (FDA) has granted orphan drug designation to AG-348 for the treatment of pyruvate kinase deficiency (PKD), a rare form of hemolytic anemia.
AG-348 is a small molecule allosteric activator of pyruvate kinase-R enzymes that directly targets the underlying metabolic defect in PKD.
The orphan designation will provide Agios Pharmaceuticals, the company developing AG-348, with certain benefits. These include market exclusivity upon regulatory approval and exemption from FDA application fees and tax credits for qualified clinical trials.
According to Agios, AG-348 exhibited favorable safety and pharmacokinetic profiles in a pair of phase 1 studies conducted in healthy volunteers.
Study investigators also observed dose-dependent changes in adenosine triphosphate (ATP) and 2,3-DPG blood levels, which are consistent with increased activity of the glycolytic pathway, the expected pharmacodynamic effect of AG-348.
Results from both studies were presented in a poster at the 2014 ASH Annual Meeting (abstract 4007*). One of the studies was a single ascending dose (SAD) study, and the other was a multiple ascending dose (MAD) study.
SAD study
In this study, healthy volunteers were randomized to receive AG-348 (n=36) or placebo (n=12). Patients were divided into 6 dosing cohorts: 30 mg, 120 mg, 360 mg, 700 mg, 1400 mg, and 2500 mg.
The maximum-tolerated dose of AG-348 was not reached, and there were no serious adverse events (AEs) or early withdrawals among AG-348-treated subjects. Overall, the rate of AEs was 33.3% in the placebo arm and 44.4% in the AG-348 arm.
The rate of AEs that were considered possibly treatment-related was 16.7% in the placebo arm and 30.6% in the AG-348 arm. The most common treatment-related AEs were headache (occurring in 16.7% and 11.1% of patients, respectively), nausea (0% and 13.9%, respectively), and vomiting (0% and 5.6%, respectively).
Exposure to AG-348, as measured by area under the concentration × time curve (AUC), increased in a dose-proportional manner after a single dose. And absorption was rapid (median Tmax ranged from 0.77 to 4.07 hours), although Tmax increased and there was a less-than-proportional increase in Cmax at higher doses.
When AG-348 was administered from 30 mg to 360 mg, there was a dose-dependent decrease in blood 2,3-DPG levels over 24 hours—up to a 49% mean decrease. Increasing the dose beyond 360 mg did not result in additional decreases in 2,3-DPG levels. And levels returned to placebo levels after about 72 hours.
There were minimal increases in blood ATP levels after AG-348 treatment at any dose.
MAD study
At the time of the presentation, 2 cohorts of 8 subjects each (6 receiving AG-348 and 2 receiving placebo) had completed treatment in the MAD study. One cohort received drug or placebo at 120 mg BID, and the other received 360 mg BID.
The pharmacokinetic results for day 1 of this study were consistent with those of the SAD study. However, the Cmax and AUC0-Ʈ were lower on day 14 than day 1. Investigators said this suggests that multiple doses of AG-348 increase the rate of its own metabolism.
They also said the decrease in exposure observed on day 14 is consistent with preclinical data that suggest AG-348 is a moderate inducer of CYP3A4, which is the major route of the oxidative metabolism of AG-348.
As in the SAD study, the investigators observed decreases in 2,3-DPG blood levels after the first dose in cohorts 1 and 2—up to a 48% mean decrease from baseline for both doses. Concentrations returned to placebo levels between 48 and 72 hours after the last dose.
Unlike in the SAD study, patients in this study had increases in ATP—up to a 52% mean increase from baseline in both dosing cohorts. ATP levels remained elevated through 72 hours after the last dose.
The investigators said the results of these 2 studies have informed dose selection for the planned phase 2 study of AG-348 in PKD patients, which is expected to begin soon.
*Information in the abstract differs from that presented at the meeting.
Image courtesy of NHLBI
The US Food and Drug Administration (FDA) has granted orphan drug designation to AG-348 for the treatment of pyruvate kinase deficiency (PKD), a rare form of hemolytic anemia.
AG-348 is a small molecule allosteric activator of pyruvate kinase-R enzymes that directly targets the underlying metabolic defect in PKD.
The orphan designation will provide Agios Pharmaceuticals, the company developing AG-348, with certain benefits. These include market exclusivity upon regulatory approval and exemption from FDA application fees and tax credits for qualified clinical trials.
According to Agios, AG-348 exhibited favorable safety and pharmacokinetic profiles in a pair of phase 1 studies conducted in healthy volunteers.
Study investigators also observed dose-dependent changes in adenosine triphosphate (ATP) and 2,3-DPG blood levels, which are consistent with increased activity of the glycolytic pathway, the expected pharmacodynamic effect of AG-348.
Results from both studies were presented in a poster at the 2014 ASH Annual Meeting (abstract 4007*). One of the studies was a single ascending dose (SAD) study, and the other was a multiple ascending dose (MAD) study.
SAD study
In this study, healthy volunteers were randomized to receive AG-348 (n=36) or placebo (n=12). Patients were divided into 6 dosing cohorts: 30 mg, 120 mg, 360 mg, 700 mg, 1400 mg, and 2500 mg.
The maximum-tolerated dose of AG-348 was not reached, and there were no serious adverse events (AEs) or early withdrawals among AG-348-treated subjects. Overall, the rate of AEs was 33.3% in the placebo arm and 44.4% in the AG-348 arm.
The rate of AEs that were considered possibly treatment-related was 16.7% in the placebo arm and 30.6% in the AG-348 arm. The most common treatment-related AEs were headache (occurring in 16.7% and 11.1% of patients, respectively), nausea (0% and 13.9%, respectively), and vomiting (0% and 5.6%, respectively).
Exposure to AG-348, as measured by area under the concentration × time curve (AUC), increased in a dose-proportional manner after a single dose. And absorption was rapid (median Tmax ranged from 0.77 to 4.07 hours), although Tmax increased and there was a less-than-proportional increase in Cmax at higher doses.
When AG-348 was administered from 30 mg to 360 mg, there was a dose-dependent decrease in blood 2,3-DPG levels over 24 hours—up to a 49% mean decrease. Increasing the dose beyond 360 mg did not result in additional decreases in 2,3-DPG levels. And levels returned to placebo levels after about 72 hours.
There were minimal increases in blood ATP levels after AG-348 treatment at any dose.
MAD study
At the time of the presentation, 2 cohorts of 8 subjects each (6 receiving AG-348 and 2 receiving placebo) had completed treatment in the MAD study. One cohort received drug or placebo at 120 mg BID, and the other received 360 mg BID.
The pharmacokinetic results for day 1 of this study were consistent with those of the SAD study. However, the Cmax and AUC0-Ʈ were lower on day 14 than day 1. Investigators said this suggests that multiple doses of AG-348 increase the rate of its own metabolism.
They also said the decrease in exposure observed on day 14 is consistent with preclinical data that suggest AG-348 is a moderate inducer of CYP3A4, which is the major route of the oxidative metabolism of AG-348.
As in the SAD study, the investigators observed decreases in 2,3-DPG blood levels after the first dose in cohorts 1 and 2—up to a 48% mean decrease from baseline for both doses. Concentrations returned to placebo levels between 48 and 72 hours after the last dose.
Unlike in the SAD study, patients in this study had increases in ATP—up to a 52% mean increase from baseline in both dosing cohorts. ATP levels remained elevated through 72 hours after the last dose.
The investigators said the results of these 2 studies have informed dose selection for the planned phase 2 study of AG-348 in PKD patients, which is expected to begin soon.
*Information in the abstract differs from that presented at the meeting.
Image courtesy of NHLBI
The US Food and Drug Administration (FDA) has granted orphan drug designation to AG-348 for the treatment of pyruvate kinase deficiency (PKD), a rare form of hemolytic anemia.
AG-348 is a small molecule allosteric activator of pyruvate kinase-R enzymes that directly targets the underlying metabolic defect in PKD.
The orphan designation will provide Agios Pharmaceuticals, the company developing AG-348, with certain benefits. These include market exclusivity upon regulatory approval and exemption from FDA application fees and tax credits for qualified clinical trials.
According to Agios, AG-348 exhibited favorable safety and pharmacokinetic profiles in a pair of phase 1 studies conducted in healthy volunteers.
Study investigators also observed dose-dependent changes in adenosine triphosphate (ATP) and 2,3-DPG blood levels, which are consistent with increased activity of the glycolytic pathway, the expected pharmacodynamic effect of AG-348.
Results from both studies were presented in a poster at the 2014 ASH Annual Meeting (abstract 4007*). One of the studies was a single ascending dose (SAD) study, and the other was a multiple ascending dose (MAD) study.
SAD study
In this study, healthy volunteers were randomized to receive AG-348 (n=36) or placebo (n=12). Patients were divided into 6 dosing cohorts: 30 mg, 120 mg, 360 mg, 700 mg, 1400 mg, and 2500 mg.
The maximum-tolerated dose of AG-348 was not reached, and there were no serious adverse events (AEs) or early withdrawals among AG-348-treated subjects. Overall, the rate of AEs was 33.3% in the placebo arm and 44.4% in the AG-348 arm.
The rate of AEs that were considered possibly treatment-related was 16.7% in the placebo arm and 30.6% in the AG-348 arm. The most common treatment-related AEs were headache (occurring in 16.7% and 11.1% of patients, respectively), nausea (0% and 13.9%, respectively), and vomiting (0% and 5.6%, respectively).
Exposure to AG-348, as measured by area under the concentration × time curve (AUC), increased in a dose-proportional manner after a single dose. And absorption was rapid (median Tmax ranged from 0.77 to 4.07 hours), although Tmax increased and there was a less-than-proportional increase in Cmax at higher doses.
When AG-348 was administered from 30 mg to 360 mg, there was a dose-dependent decrease in blood 2,3-DPG levels over 24 hours—up to a 49% mean decrease. Increasing the dose beyond 360 mg did not result in additional decreases in 2,3-DPG levels. And levels returned to placebo levels after about 72 hours.
There were minimal increases in blood ATP levels after AG-348 treatment at any dose.
MAD study
At the time of the presentation, 2 cohorts of 8 subjects each (6 receiving AG-348 and 2 receiving placebo) had completed treatment in the MAD study. One cohort received drug or placebo at 120 mg BID, and the other received 360 mg BID.
The pharmacokinetic results for day 1 of this study were consistent with those of the SAD study. However, the Cmax and AUC0-Ʈ were lower on day 14 than day 1. Investigators said this suggests that multiple doses of AG-348 increase the rate of its own metabolism.
They also said the decrease in exposure observed on day 14 is consistent with preclinical data that suggest AG-348 is a moderate inducer of CYP3A4, which is the major route of the oxidative metabolism of AG-348.
As in the SAD study, the investigators observed decreases in 2,3-DPG blood levels after the first dose in cohorts 1 and 2—up to a 48% mean decrease from baseline for both doses. Concentrations returned to placebo levels between 48 and 72 hours after the last dose.
Unlike in the SAD study, patients in this study had increases in ATP—up to a 52% mean increase from baseline in both dosing cohorts. ATP levels remained elevated through 72 hours after the last dose.
The investigators said the results of these 2 studies have informed dose selection for the planned phase 2 study of AG-348 in PKD patients, which is expected to begin soon.
*Information in the abstract differs from that presented at the meeting.
Israel approves ponatinib for CML, Ph+ ALL
Photo courtesy of the US FDA
The Israeli Ministry of Health has granted regulatory approval for the kinase inhibitor ponatinib (Iclusig) to treat certain adults with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).
The drug can now be used to treat adults with any phase of CML who have the T315I mutation or are resistant to/cannot tolerate dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate.
Ponatinib is also approved to treat patients with Ph+ ALL who have the T315I mutation or are resistant to/cannot tolerate dasatinib and for whom subsequent treatment with imatinib is not clinically appropriate.
Ariad Pharmaceuticals, Inc., the company developing ponatinib, said the drug should be available in Israel in the second quarter of 2015.
Trial results
The Ministry of Health’s decision to approve ponatinib was based on results from the phase 2 PACE trial, which included patients with CML or Ph+ ALL who were resistant to or intolerant of prior tyrosine kinase inhibitor therapy, or who had the T315I mutation.
The median follow-up times were 15.3 months in chronic-phase CML patients, 15.8 months in accelerated-phase CML patients, and 6.2 months in patients with blast-phase CML or Ph+ ALL.
In chronic-phase CML, the primary endpoint was major cytogenetic response, and it occurred in 56% of patients. Among chronic-phase patients with the T315I mutation, 70% achieved a major cytogenetic response. Among patients who had failed treatment with dasatinib or nilotinib, 51% achieved a major cytogenetic response.
In accelerated-phase CML, the primary endpoint was major hematologic response. This occurred in 57% of all patients in this group, 50% of patients with the T315I mutation, and 58% of patients who had failed treatment with dasatinib or nilotinib.
The primary endpoint was major hematologic response in blast-phase CML/Ph+ ALL as well. Thirty-four percent of all patients in this group met this endpoint, as did 33% of patients with the T315I mutation and 35% of patients who had failed treatment with dasatinib or nilotinib.
Common non-hematologic adverse events included rash (38%), abdominal pain (38%), headache (35%), dry skin (35%), constipation (34%), fatigue (27%), pyrexia (27%), nausea (26%), arthralgia (25%), hypertension (21%), increased lipase (19%), and increased amylase (7%).
Hematologic events of any grade included thrombocytopenia (42%), neutropenia (24%), and anemia (20%). Serious adverse events of arterial thromboembolism, including arterial stenosis, occurred in patients with cardiovascular risk factors.
Safety issues
Extended follow-up data from the PACE trial, collected in 2013, suggested ponatinib can increase the risk of thrombotic events. When these data came to light, officials in the European Union and the US, where ponatinib had already been approved, began to investigate the drug.
Ponatinib was pulled from the US market for a little over 2 months, and trials of the drug were placed on partial hold while the Food and Drug Administration evaluated the drug’s safety. Ponatinib went back on the market in January 2014, with new safety measures in place.
The drug was not pulled from the market in the European Union, but the European Medicine’s Agency released recommendations for safer use of ponatinib. The Committee for Medicinal Products for Human Use reviewed data on ponatinib and decided the drug’s benefits outweigh its risks.
Photo courtesy of the US FDA
The Israeli Ministry of Health has granted regulatory approval for the kinase inhibitor ponatinib (Iclusig) to treat certain adults with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).
The drug can now be used to treat adults with any phase of CML who have the T315I mutation or are resistant to/cannot tolerate dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate.
Ponatinib is also approved to treat patients with Ph+ ALL who have the T315I mutation or are resistant to/cannot tolerate dasatinib and for whom subsequent treatment with imatinib is not clinically appropriate.
Ariad Pharmaceuticals, Inc., the company developing ponatinib, said the drug should be available in Israel in the second quarter of 2015.
Trial results
The Ministry of Health’s decision to approve ponatinib was based on results from the phase 2 PACE trial, which included patients with CML or Ph+ ALL who were resistant to or intolerant of prior tyrosine kinase inhibitor therapy, or who had the T315I mutation.
The median follow-up times were 15.3 months in chronic-phase CML patients, 15.8 months in accelerated-phase CML patients, and 6.2 months in patients with blast-phase CML or Ph+ ALL.
In chronic-phase CML, the primary endpoint was major cytogenetic response, and it occurred in 56% of patients. Among chronic-phase patients with the T315I mutation, 70% achieved a major cytogenetic response. Among patients who had failed treatment with dasatinib or nilotinib, 51% achieved a major cytogenetic response.
In accelerated-phase CML, the primary endpoint was major hematologic response. This occurred in 57% of all patients in this group, 50% of patients with the T315I mutation, and 58% of patients who had failed treatment with dasatinib or nilotinib.
The primary endpoint was major hematologic response in blast-phase CML/Ph+ ALL as well. Thirty-four percent of all patients in this group met this endpoint, as did 33% of patients with the T315I mutation and 35% of patients who had failed treatment with dasatinib or nilotinib.
Common non-hematologic adverse events included rash (38%), abdominal pain (38%), headache (35%), dry skin (35%), constipation (34%), fatigue (27%), pyrexia (27%), nausea (26%), arthralgia (25%), hypertension (21%), increased lipase (19%), and increased amylase (7%).
Hematologic events of any grade included thrombocytopenia (42%), neutropenia (24%), and anemia (20%). Serious adverse events of arterial thromboembolism, including arterial stenosis, occurred in patients with cardiovascular risk factors.
Safety issues
Extended follow-up data from the PACE trial, collected in 2013, suggested ponatinib can increase the risk of thrombotic events. When these data came to light, officials in the European Union and the US, where ponatinib had already been approved, began to investigate the drug.
Ponatinib was pulled from the US market for a little over 2 months, and trials of the drug were placed on partial hold while the Food and Drug Administration evaluated the drug’s safety. Ponatinib went back on the market in January 2014, with new safety measures in place.
The drug was not pulled from the market in the European Union, but the European Medicine’s Agency released recommendations for safer use of ponatinib. The Committee for Medicinal Products for Human Use reviewed data on ponatinib and decided the drug’s benefits outweigh its risks.
Photo courtesy of the US FDA
The Israeli Ministry of Health has granted regulatory approval for the kinase inhibitor ponatinib (Iclusig) to treat certain adults with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).
The drug can now be used to treat adults with any phase of CML who have the T315I mutation or are resistant to/cannot tolerate dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate.
Ponatinib is also approved to treat patients with Ph+ ALL who have the T315I mutation or are resistant to/cannot tolerate dasatinib and for whom subsequent treatment with imatinib is not clinically appropriate.
Ariad Pharmaceuticals, Inc., the company developing ponatinib, said the drug should be available in Israel in the second quarter of 2015.
Trial results
The Ministry of Health’s decision to approve ponatinib was based on results from the phase 2 PACE trial, which included patients with CML or Ph+ ALL who were resistant to or intolerant of prior tyrosine kinase inhibitor therapy, or who had the T315I mutation.
The median follow-up times were 15.3 months in chronic-phase CML patients, 15.8 months in accelerated-phase CML patients, and 6.2 months in patients with blast-phase CML or Ph+ ALL.
In chronic-phase CML, the primary endpoint was major cytogenetic response, and it occurred in 56% of patients. Among chronic-phase patients with the T315I mutation, 70% achieved a major cytogenetic response. Among patients who had failed treatment with dasatinib or nilotinib, 51% achieved a major cytogenetic response.
In accelerated-phase CML, the primary endpoint was major hematologic response. This occurred in 57% of all patients in this group, 50% of patients with the T315I mutation, and 58% of patients who had failed treatment with dasatinib or nilotinib.
The primary endpoint was major hematologic response in blast-phase CML/Ph+ ALL as well. Thirty-four percent of all patients in this group met this endpoint, as did 33% of patients with the T315I mutation and 35% of patients who had failed treatment with dasatinib or nilotinib.
Common non-hematologic adverse events included rash (38%), abdominal pain (38%), headache (35%), dry skin (35%), constipation (34%), fatigue (27%), pyrexia (27%), nausea (26%), arthralgia (25%), hypertension (21%), increased lipase (19%), and increased amylase (7%).
Hematologic events of any grade included thrombocytopenia (42%), neutropenia (24%), and anemia (20%). Serious adverse events of arterial thromboembolism, including arterial stenosis, occurred in patients with cardiovascular risk factors.
Safety issues
Extended follow-up data from the PACE trial, collected in 2013, suggested ponatinib can increase the risk of thrombotic events. When these data came to light, officials in the European Union and the US, where ponatinib had already been approved, began to investigate the drug.
Ponatinib was pulled from the US market for a little over 2 months, and trials of the drug were placed on partial hold while the Food and Drug Administration evaluated the drug’s safety. Ponatinib went back on the market in January 2014, with new safety measures in place.
The drug was not pulled from the market in the European Union, but the European Medicine’s Agency released recommendations for safer use of ponatinib. The Committee for Medicinal Products for Human Use reviewed data on ponatinib and decided the drug’s benefits outweigh its risks.