User login
EC approves carfilzomib for relapsed MM
Photo courtesy of Amgen
The European Commission (EC) has granted marketing authorization for carfilzomib (Kyprolis) to be used in combination with lenalidomide and dexamethasone to treat adults with multiple myeloma (MM) who have received at least 1 prior therapy.
Carfilzomib is the first irreversible proteasome inhibitor approved in the European Union (EU) as part of combination treatment for patients with relapsed MM.
Carfilzomib was granted orphan designation in the EU in 2008. The drug also received accelerated assessment, which shortened the review period from 210 days to 150 days.
Carfilzomib is a product of Onyx Pharmaceuticals, Inc., a subsidiary of Amgen that holds development and commercialization rights to the drug globally, excluding Japan.
ASPIRE trial
The EC approved carfilzomib based on data from the phase 3 ASPIRE trial, which were presented at ASH 2014 and published in NEJM.
The trial enrolled 792 patients with relapsed or refractory MM who had received 1 to 3 prior lines of therapy. The patients were randomized (1:1) to receive carfilzomib plus lenalidomide and dexamethasone (KRd) or just lenalidomide and dexamethasone (Rd) for 18 cycles.
Lenalidomide and dexamethasone were continued thereafter until disease progression. There was no planned cross-over from the control arm to treatment with carfilzomib.
The study’s primary endpoint was progression-free survival. The median progression-free survival was significantly longer in the KRd arm than the Rd arm—26.3 months and 17.6 months, respectively (hazard ratio=0.69, P=0.0001).
At the time of analysis, the difference in overall survival did not reach the prespecified boundary for statistical significance.
The overall response rate was 87% in the KRd arm and 67% in the Rd arm. The median duration of response was 28.6 months and 21.2 months, respectively.
The rates of death due to adverse events (AEs) within 30 days of the last dose were similar between the treatment arms.
The most common causes of death not due to progressive disease occurring in patients in the KRd arm and the Rd arm, respectively, were cardiac disorders (3% vs 2%), infection (2% vs 3%), renal events (0% vs less than 1%), and other AEs (2% vs 3%).
Serious AEs were reported in 60% of patients in the KRd arm and 54% in the Rd arm. The most common serious AEs reported in the KRd arm and the Rd arm, respectively, were pneumonia (14% vs 11%), respiratory tract infection (4% vs 2%), pyrexia (4% vs 2%), and pulmonary embolism (3% vs 2%).
Global development
In the US, carfilzomib is approved for use in combination with lenalidomide and dexamethasone to treat MM patients who have received 1 to 3 prior lines of therapy.
Carfilzomib also has accelerated approval in the US as a single agent to treat MM patients who have received at least 2 prior therapies, including bortezomib and an immunomodulatory agent, and have demonstrated disease progression on or within 60 days of the completion of last therapy.
Amgen plans to submit data from the phase 3 ENDEAVOR trial for potential authorization of carfilzomib in combination with dexamethasone in the EU.
This data serves as the basis of the supplemental new drug application of carfilzomib in combination with dexamethasone for patients with relapsed MM, which has been accepted for priority review in the US.
In addition to the US and EU, carfilzomib is approved for use in Argentina, Israel, Kuwait, Mexico, Thailand, and Colombia. Additional regulatory applications for the drug have been submitted to health authorities worldwide. 
Photo courtesy of Amgen
The European Commission (EC) has granted marketing authorization for carfilzomib (Kyprolis) to be used in combination with lenalidomide and dexamethasone to treat adults with multiple myeloma (MM) who have received at least 1 prior therapy.
Carfilzomib is the first irreversible proteasome inhibitor approved in the European Union (EU) as part of combination treatment for patients with relapsed MM.
Carfilzomib was granted orphan designation in the EU in 2008. The drug also received accelerated assessment, which shortened the review period from 210 days to 150 days.
Carfilzomib is a product of Onyx Pharmaceuticals, Inc., a subsidiary of Amgen that holds development and commercialization rights to the drug globally, excluding Japan.
ASPIRE trial
The EC approved carfilzomib based on data from the phase 3 ASPIRE trial, which were presented at ASH 2014 and published in NEJM.
The trial enrolled 792 patients with relapsed or refractory MM who had received 1 to 3 prior lines of therapy. The patients were randomized (1:1) to receive carfilzomib plus lenalidomide and dexamethasone (KRd) or just lenalidomide and dexamethasone (Rd) for 18 cycles.
Lenalidomide and dexamethasone were continued thereafter until disease progression. There was no planned cross-over from the control arm to treatment with carfilzomib.
The study’s primary endpoint was progression-free survival. The median progression-free survival was significantly longer in the KRd arm than the Rd arm—26.3 months and 17.6 months, respectively (hazard ratio=0.69, P=0.0001).
At the time of analysis, the difference in overall survival did not reach the prespecified boundary for statistical significance.
The overall response rate was 87% in the KRd arm and 67% in the Rd arm. The median duration of response was 28.6 months and 21.2 months, respectively.
The rates of death due to adverse events (AEs) within 30 days of the last dose were similar between the treatment arms.
The most common causes of death not due to progressive disease occurring in patients in the KRd arm and the Rd arm, respectively, were cardiac disorders (3% vs 2%), infection (2% vs 3%), renal events (0% vs less than 1%), and other AEs (2% vs 3%).
Serious AEs were reported in 60% of patients in the KRd arm and 54% in the Rd arm. The most common serious AEs reported in the KRd arm and the Rd arm, respectively, were pneumonia (14% vs 11%), respiratory tract infection (4% vs 2%), pyrexia (4% vs 2%), and pulmonary embolism (3% vs 2%).
Global development
In the US, carfilzomib is approved for use in combination with lenalidomide and dexamethasone to treat MM patients who have received 1 to 3 prior lines of therapy.
Carfilzomib also has accelerated approval in the US as a single agent to treat MM patients who have received at least 2 prior therapies, including bortezomib and an immunomodulatory agent, and have demonstrated disease progression on or within 60 days of the completion of last therapy.
Amgen plans to submit data from the phase 3 ENDEAVOR trial for potential authorization of carfilzomib in combination with dexamethasone in the EU.
This data serves as the basis of the supplemental new drug application of carfilzomib in combination with dexamethasone for patients with relapsed MM, which has been accepted for priority review in the US.
In addition to the US and EU, carfilzomib is approved for use in Argentina, Israel, Kuwait, Mexico, Thailand, and Colombia. Additional regulatory applications for the drug have been submitted to health authorities worldwide.
Photo courtesy of Amgen
The European Commission (EC) has granted marketing authorization for carfilzomib (Kyprolis) to be used in combination with lenalidomide and dexamethasone to treat adults with multiple myeloma (MM) who have received at least 1 prior therapy.
Carfilzomib is the first irreversible proteasome inhibitor approved in the European Union (EU) as part of combination treatment for patients with relapsed MM.
Carfilzomib was granted orphan designation in the EU in 2008. The drug also received accelerated assessment, which shortened the review period from 210 days to 150 days.
Carfilzomib is a product of Onyx Pharmaceuticals, Inc., a subsidiary of Amgen that holds development and commercialization rights to the drug globally, excluding Japan.
ASPIRE trial
The EC approved carfilzomib based on data from the phase 3 ASPIRE trial, which were presented at ASH 2014 and published in NEJM.
The trial enrolled 792 patients with relapsed or refractory MM who had received 1 to 3 prior lines of therapy. The patients were randomized (1:1) to receive carfilzomib plus lenalidomide and dexamethasone (KRd) or just lenalidomide and dexamethasone (Rd) for 18 cycles.
Lenalidomide and dexamethasone were continued thereafter until disease progression. There was no planned cross-over from the control arm to treatment with carfilzomib.
The study’s primary endpoint was progression-free survival. The median progression-free survival was significantly longer in the KRd arm than the Rd arm—26.3 months and 17.6 months, respectively (hazard ratio=0.69, P=0.0001).
At the time of analysis, the difference in overall survival did not reach the prespecified boundary for statistical significance.
The overall response rate was 87% in the KRd arm and 67% in the Rd arm. The median duration of response was 28.6 months and 21.2 months, respectively.
The rates of death due to adverse events (AEs) within 30 days of the last dose were similar between the treatment arms.
The most common causes of death not due to progressive disease occurring in patients in the KRd arm and the Rd arm, respectively, were cardiac disorders (3% vs 2%), infection (2% vs 3%), renal events (0% vs less than 1%), and other AEs (2% vs 3%).
Serious AEs were reported in 60% of patients in the KRd arm and 54% in the Rd arm. The most common serious AEs reported in the KRd arm and the Rd arm, respectively, were pneumonia (14% vs 11%), respiratory tract infection (4% vs 2%), pyrexia (4% vs 2%), and pulmonary embolism (3% vs 2%).
Global development
In the US, carfilzomib is approved for use in combination with lenalidomide and dexamethasone to treat MM patients who have received 1 to 3 prior lines of therapy.
Carfilzomib also has accelerated approval in the US as a single agent to treat MM patients who have received at least 2 prior therapies, including bortezomib and an immunomodulatory agent, and have demonstrated disease progression on or within 60 days of the completion of last therapy.
Amgen plans to submit data from the phase 3 ENDEAVOR trial for potential authorization of carfilzomib in combination with dexamethasone in the EU.
This data serves as the basis of the supplemental new drug application of carfilzomib in combination with dexamethasone for patients with relapsed MM, which has been accepted for priority review in the US.
In addition to the US and EU, carfilzomib is approved for use in Argentina, Israel, Kuwait, Mexico, Thailand, and Colombia. Additional regulatory applications for the drug have been submitted to health authorities worldwide.
FDA approves first monoclonal antibody for MM
Photo courtesy of Janssen
The US Food and Drug Administration (FDA) has granted accelerated approval for daratumumab (Darzalex).
The drug is now approved to treat patients with multiple myeloma (MM) who have received at least 3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, or who are double-refractory to a proteasome inhibitor and an immunomodulatory agent.
Daratumumab is the first monoclonal antibody approved to treat MM.
The drug works by binding to CD38 on the surface of MM cells. It triggers the patient’s own immune system to attack MM cells, resulting in cell death through multiple mechanisms of action.
Daratumumab is being developed by Janssen Biotech. The drug was previously granted breakthrough designation, orphan designation, and priority review from the FDA.
Daratumumab was approved under the FDA’s accelerated approval program, which allows the agency to approve a drug to treat a serious or life-threatening disease based on clinical data showing the drug has an effect on a surrogate endpoint reasonably likely to predict clinical benefit to patients.
As a condition of this accelerated approval, Janssen is required to conduct a multicenter, randomized trial establishing the superiority of daratumumab over standard therapy to verify and describe the clinical benefit of daratumumab. Janssen has several ongoing, multicenter, randomized trials with a primary endpoint of progression-free survival.
The recommended dose and schedule for daratumumab is 16 mg/kg once every week for 8 weeks, then once every 2 weeks for 16 weeks, then once every 4 weeks until disease progression.
The FDA said blood banks should be informed that patients are receiving daratumumab because the drug may interfere with tests such as antibody screening.
In addition, women who are pregnant should not use daratumumab, and women planning to become pregnant should use effective contraceptives during and for at least 3 months after stopping daratumumab.
Trial data
The FDA’s approval of daratumumab was based on results of 2 studies—the phase 2 MMY2002 (SIRIUS) study and the phase 1/2 GEN501 study.
The GEN501 study enrolled 102 patients with relapsed MM or relapsed MM that was refractory to 2 or more prior lines of therapy. The patients received daratumumab at a range of doses and on a number of different schedules.
The results suggested that daratumumab is most effective at a dose of 16 mg/kg. At this dose, the overall response rate was 36%.
Most adverse events in this study were grade 1 or 2, although serious events did occur.
The SIRIUS study enrolled 124 MM patients who had received 3 or more prior lines of therapy. They received daratumumab at different doses and on different schedules, but 106 of the patients received the drug at 16 mg/kg.
Twenty-nine percent of the 106 patients responded to treatment, and the median duration of response was 7 months. Thirty percent of patients experienced serious adverse events.
Photo courtesy of Janssen
The US Food and Drug Administration (FDA) has granted accelerated approval for daratumumab (Darzalex).
The drug is now approved to treat patients with multiple myeloma (MM) who have received at least 3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, or who are double-refractory to a proteasome inhibitor and an immunomodulatory agent.
Daratumumab is the first monoclonal antibody approved to treat MM.
The drug works by binding to CD38 on the surface of MM cells. It triggers the patient’s own immune system to attack MM cells, resulting in cell death through multiple mechanisms of action.
Daratumumab is being developed by Janssen Biotech. The drug was previously granted breakthrough designation, orphan designation, and priority review from the FDA.
Daratumumab was approved under the FDA’s accelerated approval program, which allows the agency to approve a drug to treat a serious or life-threatening disease based on clinical data showing the drug has an effect on a surrogate endpoint reasonably likely to predict clinical benefit to patients.
As a condition of this accelerated approval, Janssen is required to conduct a multicenter, randomized trial establishing the superiority of daratumumab over standard therapy to verify and describe the clinical benefit of daratumumab. Janssen has several ongoing, multicenter, randomized trials with a primary endpoint of progression-free survival.
The recommended dose and schedule for daratumumab is 16 mg/kg once every week for 8 weeks, then once every 2 weeks for 16 weeks, then once every 4 weeks until disease progression.
The FDA said blood banks should be informed that patients are receiving daratumumab because the drug may interfere with tests such as antibody screening.
In addition, women who are pregnant should not use daratumumab, and women planning to become pregnant should use effective contraceptives during and for at least 3 months after stopping daratumumab.
Trial data
The FDA’s approval of daratumumab was based on results of 2 studies—the phase 2 MMY2002 (SIRIUS) study and the phase 1/2 GEN501 study.
The GEN501 study enrolled 102 patients with relapsed MM or relapsed MM that was refractory to 2 or more prior lines of therapy. The patients received daratumumab at a range of doses and on a number of different schedules.
The results suggested that daratumumab is most effective at a dose of 16 mg/kg. At this dose, the overall response rate was 36%.
Most adverse events in this study were grade 1 or 2, although serious events did occur.
The SIRIUS study enrolled 124 MM patients who had received 3 or more prior lines of therapy. They received daratumumab at different doses and on different schedules, but 106 of the patients received the drug at 16 mg/kg.
Twenty-nine percent of the 106 patients responded to treatment, and the median duration of response was 7 months. Thirty percent of patients experienced serious adverse events.
Photo courtesy of Janssen
The US Food and Drug Administration (FDA) has granted accelerated approval for daratumumab (Darzalex).
The drug is now approved to treat patients with multiple myeloma (MM) who have received at least 3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, or who are double-refractory to a proteasome inhibitor and an immunomodulatory agent.
Daratumumab is the first monoclonal antibody approved to treat MM.
The drug works by binding to CD38 on the surface of MM cells. It triggers the patient’s own immune system to attack MM cells, resulting in cell death through multiple mechanisms of action.
Daratumumab is being developed by Janssen Biotech. The drug was previously granted breakthrough designation, orphan designation, and priority review from the FDA.
Daratumumab was approved under the FDA’s accelerated approval program, which allows the agency to approve a drug to treat a serious or life-threatening disease based on clinical data showing the drug has an effect on a surrogate endpoint reasonably likely to predict clinical benefit to patients.
As a condition of this accelerated approval, Janssen is required to conduct a multicenter, randomized trial establishing the superiority of daratumumab over standard therapy to verify and describe the clinical benefit of daratumumab. Janssen has several ongoing, multicenter, randomized trials with a primary endpoint of progression-free survival.
The recommended dose and schedule for daratumumab is 16 mg/kg once every week for 8 weeks, then once every 2 weeks for 16 weeks, then once every 4 weeks until disease progression.
The FDA said blood banks should be informed that patients are receiving daratumumab because the drug may interfere with tests such as antibody screening.
In addition, women who are pregnant should not use daratumumab, and women planning to become pregnant should use effective contraceptives during and for at least 3 months after stopping daratumumab.
Trial data
The FDA’s approval of daratumumab was based on results of 2 studies—the phase 2 MMY2002 (SIRIUS) study and the phase 1/2 GEN501 study.
The GEN501 study enrolled 102 patients with relapsed MM or relapsed MM that was refractory to 2 or more prior lines of therapy. The patients received daratumumab at a range of doses and on a number of different schedules.
The results suggested that daratumumab is most effective at a dose of 16 mg/kg. At this dose, the overall response rate was 36%.
Most adverse events in this study were grade 1 or 2, although serious events did occur.
The SIRIUS study enrolled 124 MM patients who had received 3 or more prior lines of therapy. They received daratumumab at different doses and on different schedules, but 106 of the patients received the drug at 16 mg/kg.
Twenty-nine percent of the 106 patients responded to treatment, and the median duration of response was 7 months. Thirty percent of patients experienced serious adverse events.
FDA approves pegylated product for hemophilia A
The US Food and Drug Administration (FDA) has approved Adynovate, a recombinant pegylated factor VIII (FVIII) product, for use in patients age 12 and older with hemophilia A.
The product can be used as routine prophylaxis and for on-demand treatment and control of bleeding episodes.
Adynovate will be available in the US in the coming weeks, according to Baxalta US Inc., the company developing the product.
Adynovate (formerly BAX 855) is built on the full-length Advate, a recombinant antihemophilic factor product that was approved by the FDA in 2003.
Adynovate consists of the full-length FVIII molecule linked to other molecules, known as polyethylene glycol (pegylated). This link extends the circulating half-life of the product and therefore extends the time between treatments.
So patients on Adynovate can receive twice-weekly doses rather than the 3 to 4 weekly doses typically required with other full-length FVIII products.
“The approval of Adynovate provides an important therapeutic option for use in the care of patients with hemophilia A and reduces the frequency of FVIII infusions needed to avoid bleeding,” said Karen Midthun, MD, director of the FDA’s Center for Biologics Evaluation and Research.
The FDA approved Adynovate based on results of a phase 2/3 trial. The study included 137 previously treated hemophilia A patients who were 12 to 65 years of age.
Patients were assigned to either twice-weekly prophylaxis (40-50 IU/kg, n=120) or on-demand treatment (10-60 IU/kg, n=17) with Adynovate.
Patients in the twice-weekly prophylaxis arm had far fewer annual bleeds than patients treated on-demand. The median annual bleed rates were 1.9 and 41.5, respectively.
Nearly all (96%) bleeding episodes (n=591) were controlled with 1 or 2 infusions of Adynovate.
None of the patients developed inhibitors to the treatment. However, there were 171 adverse events in the 73 patients who received Adynovate for about 6 months.
There were 7 events (occurring in 6 patients) that were considered possibly related to Adynovate. These included diarrhea, nausea, headache, and flushing.
Studies of Adynovate are ongoing in previously treated patients with severe hemophilia A undergoing surgery and in previously treated patients with severe hemophilia A who are under the age of 12. Baxalta is also planning to initiate a study in previously untreated patients with severe hemophilia A.
The company has filed for regulatory approval of Adynovate in Japan and expects to file for marketing authorization in Europe once the pediatric study is complete.
The US Food and Drug Administration (FDA) has approved Adynovate, a recombinant pegylated factor VIII (FVIII) product, for use in patients age 12 and older with hemophilia A.
The product can be used as routine prophylaxis and for on-demand treatment and control of bleeding episodes.
Adynovate will be available in the US in the coming weeks, according to Baxalta US Inc., the company developing the product.
Adynovate (formerly BAX 855) is built on the full-length Advate, a recombinant antihemophilic factor product that was approved by the FDA in 2003.
Adynovate consists of the full-length FVIII molecule linked to other molecules, known as polyethylene glycol (pegylated). This link extends the circulating half-life of the product and therefore extends the time between treatments.
So patients on Adynovate can receive twice-weekly doses rather than the 3 to 4 weekly doses typically required with other full-length FVIII products.
“The approval of Adynovate provides an important therapeutic option for use in the care of patients with hemophilia A and reduces the frequency of FVIII infusions needed to avoid bleeding,” said Karen Midthun, MD, director of the FDA’s Center for Biologics Evaluation and Research.
The FDA approved Adynovate based on results of a phase 2/3 trial. The study included 137 previously treated hemophilia A patients who were 12 to 65 years of age.
Patients were assigned to either twice-weekly prophylaxis (40-50 IU/kg, n=120) or on-demand treatment (10-60 IU/kg, n=17) with Adynovate.
Patients in the twice-weekly prophylaxis arm had far fewer annual bleeds than patients treated on-demand. The median annual bleed rates were 1.9 and 41.5, respectively.
Nearly all (96%) bleeding episodes (n=591) were controlled with 1 or 2 infusions of Adynovate.
None of the patients developed inhibitors to the treatment. However, there were 171 adverse events in the 73 patients who received Adynovate for about 6 months.
There were 7 events (occurring in 6 patients) that were considered possibly related to Adynovate. These included diarrhea, nausea, headache, and flushing.
Studies of Adynovate are ongoing in previously treated patients with severe hemophilia A undergoing surgery and in previously treated patients with severe hemophilia A who are under the age of 12. Baxalta is also planning to initiate a study in previously untreated patients with severe hemophilia A.
The company has filed for regulatory approval of Adynovate in Japan and expects to file for marketing authorization in Europe once the pediatric study is complete.
The US Food and Drug Administration (FDA) has approved Adynovate, a recombinant pegylated factor VIII (FVIII) product, for use in patients age 12 and older with hemophilia A.
The product can be used as routine prophylaxis and for on-demand treatment and control of bleeding episodes.
Adynovate will be available in the US in the coming weeks, according to Baxalta US Inc., the company developing the product.
Adynovate (formerly BAX 855) is built on the full-length Advate, a recombinant antihemophilic factor product that was approved by the FDA in 2003.
Adynovate consists of the full-length FVIII molecule linked to other molecules, known as polyethylene glycol (pegylated). This link extends the circulating half-life of the product and therefore extends the time between treatments.
So patients on Adynovate can receive twice-weekly doses rather than the 3 to 4 weekly doses typically required with other full-length FVIII products.
“The approval of Adynovate provides an important therapeutic option for use in the care of patients with hemophilia A and reduces the frequency of FVIII infusions needed to avoid bleeding,” said Karen Midthun, MD, director of the FDA’s Center for Biologics Evaluation and Research.
The FDA approved Adynovate based on results of a phase 2/3 trial. The study included 137 previously treated hemophilia A patients who were 12 to 65 years of age.
Patients were assigned to either twice-weekly prophylaxis (40-50 IU/kg, n=120) or on-demand treatment (10-60 IU/kg, n=17) with Adynovate.
Patients in the twice-weekly prophylaxis arm had far fewer annual bleeds than patients treated on-demand. The median annual bleed rates were 1.9 and 41.5, respectively.
Nearly all (96%) bleeding episodes (n=591) were controlled with 1 or 2 infusions of Adynovate.
None of the patients developed inhibitors to the treatment. However, there were 171 adverse events in the 73 patients who received Adynovate for about 6 months.
There were 7 events (occurring in 6 patients) that were considered possibly related to Adynovate. These included diarrhea, nausea, headache, and flushing.
Studies of Adynovate are ongoing in previously treated patients with severe hemophilia A undergoing surgery and in previously treated patients with severe hemophilia A who are under the age of 12. Baxalta is also planning to initiate a study in previously untreated patients with severe hemophilia A.
The company has filed for regulatory approval of Adynovate in Japan and expects to file for marketing authorization in Europe once the pediatric study is complete.
FDA: Long-term clopidogrel doesn’t affect risk of death
A review conducted by the US Food and Drug Administration (FDA) indicates that long-term use of the antiplatelet drug clopidogrel (Plavix) does not increase or decrease the overall risk of death in patients with, or at risk for, heart disease.
In addition, the FDA said there is no evidence to suggest that clopidogrel increases the risk of cancer or death from cancer.
These findings contradict those of the Dual Antiplatelet Therapy (DAPT) trial, the study that prompted the FDA’s review.
In this trial, researchers compared 12 months of DAPT (either clopidogrel or prasugrel plus aspirin) to 30 months of DAPT in patients who had a drug-eluting coronary stent.
Compared to patients taking clopidogrel for 12 months, patients who received clopidogrel for 30 months had lower rates of heart attacks and stent thrombosis but higher rates of death, primarily from cancer or trauma.
To investigate these findings, the FDA examined data from the DAPT trial and performed trial-level meta-analyses of other large, long-term trials.
The trials had a clopidogrel-plus-aspirin arm (long-term treatment was 12 months or longer) and a comparator arm of either aspirin alone or short-term clopidogrel plus aspirin (6 months or less). They also had a planned follow-up of at least 1 year.
All-cause death
In the DAPT trial, extended use of clopidogrel plus aspirin was associated with a significantly increased risk of death (2.2% for 30 months vs 1.5% for 12 months). But there was no increased risk for prasugrel plus aspirin (1.6% for 30 months vs 1.6% for 12 months).
The FDA’s initial meta-analysis on mortality included 12 trials (56,799 patients). The incidence of all-cause mortality was 6.7% for the long-term clopidogrel-plus-aspirin arm and 6.6% for the comparator arm, resulting in a Mantel Haenszel Risk Difference (MH RD) of 0.04% (95% CI, -0.35%-0.44%).
The FDA also conducted a meta-analysis of 9 of the 12 trials (45,374 patients), which enrolled patients with coronary artery disease or patients at risk of coronary artery disease. This analysis showed no difference in the risk of all-cause mortality—MH RD of -0.07% (95% CI, -0.43%-0.29%).
Cancer and death in DAPT
In the DAPT trial, the risk of cancer reported as an adverse event was not different between the 30-month (2.4% ) and 12-month (2.3%) groups receiving clopidogrel, when considering cancers reported after enrollment (from month 0 to 33 of the study).
The FDA performed several analyses of the cancer adverse event data, and the relative risk of cancer for the 30-month vs 12-month arm in the clopidogrel group ranged from 0.95 to 1.2, depending on the analysis.
Similar analyses for the prasugrel group revealed relative risks of cancer-related adverse events ranging from 1.4 to 1.6.
The FDA noted that, although there was no increase in the risk of cancer-related adverse events for clopidogrel in the 30-month arm, the risk of cancer-related death was higher than in the 12-month arm—0.7% and 0.2%, respectively.
For prasugrel, there was a trend toward a higher risk of cancer adverse events in the 30-month arm than in the 12-month arm, but the risk of cancer death was identical in both arms—0.4% vs 0.4%.
The FDA said these findings are difficult to reconcile.
Meta-analyses of cancer and death
The FDA performed 2 trial-level meta-analyses to investigate the role of clopidogrel in cancer and cancer death.
The first was an analysis of cancer-related adverse events from 4 trials (37,835 patients) that compared long-term clopidogrel and aspirin to either aspirin alone or short-term clopidogrel plus aspirin.
The incidence of cancer adverse events was 4.2% for the long-term clopidogrel-plus-aspirin arm and 4.0% for the comparator arm (MH RD of 0.19%; 95% CI, -0.2%-0.59%).
The FDA conducted the second meta-analysis to assess cancer-related death. The analysis included 5 trials (40,855 patients).
The incidence of cancer death was 0.9% for the long-term clopidogrel-plus-aspirin arm and 1.1% for the comparator arm (MH RD of -0.14%; 95% CI, -0.33%-0.06%).
The FDA said that, taken together, the results of this review do not suggest an increased risk of cancer adverse events, cancer-related death, or all-cause mortality with long-term clopidogrel therapy.
More details can be found in the FDA’s Drug Safety Communication on this topic.
A review conducted by the US Food and Drug Administration (FDA) indicates that long-term use of the antiplatelet drug clopidogrel (Plavix) does not increase or decrease the overall risk of death in patients with, or at risk for, heart disease.
In addition, the FDA said there is no evidence to suggest that clopidogrel increases the risk of cancer or death from cancer.
These findings contradict those of the Dual Antiplatelet Therapy (DAPT) trial, the study that prompted the FDA’s review.
In this trial, researchers compared 12 months of DAPT (either clopidogrel or prasugrel plus aspirin) to 30 months of DAPT in patients who had a drug-eluting coronary stent.
Compared to patients taking clopidogrel for 12 months, patients who received clopidogrel for 30 months had lower rates of heart attacks and stent thrombosis but higher rates of death, primarily from cancer or trauma.
To investigate these findings, the FDA examined data from the DAPT trial and performed trial-level meta-analyses of other large, long-term trials.
The trials had a clopidogrel-plus-aspirin arm (long-term treatment was 12 months or longer) and a comparator arm of either aspirin alone or short-term clopidogrel plus aspirin (6 months or less). They also had a planned follow-up of at least 1 year.
All-cause death
In the DAPT trial, extended use of clopidogrel plus aspirin was associated with a significantly increased risk of death (2.2% for 30 months vs 1.5% for 12 months). But there was no increased risk for prasugrel plus aspirin (1.6% for 30 months vs 1.6% for 12 months).
The FDA’s initial meta-analysis on mortality included 12 trials (56,799 patients). The incidence of all-cause mortality was 6.7% for the long-term clopidogrel-plus-aspirin arm and 6.6% for the comparator arm, resulting in a Mantel Haenszel Risk Difference (MH RD) of 0.04% (95% CI, -0.35%-0.44%).
The FDA also conducted a meta-analysis of 9 of the 12 trials (45,374 patients), which enrolled patients with coronary artery disease or patients at risk of coronary artery disease. This analysis showed no difference in the risk of all-cause mortality—MH RD of -0.07% (95% CI, -0.43%-0.29%).
Cancer and death in DAPT
In the DAPT trial, the risk of cancer reported as an adverse event was not different between the 30-month (2.4% ) and 12-month (2.3%) groups receiving clopidogrel, when considering cancers reported after enrollment (from month 0 to 33 of the study).
The FDA performed several analyses of the cancer adverse event data, and the relative risk of cancer for the 30-month vs 12-month arm in the clopidogrel group ranged from 0.95 to 1.2, depending on the analysis.
Similar analyses for the prasugrel group revealed relative risks of cancer-related adverse events ranging from 1.4 to 1.6.
The FDA noted that, although there was no increase in the risk of cancer-related adverse events for clopidogrel in the 30-month arm, the risk of cancer-related death was higher than in the 12-month arm—0.7% and 0.2%, respectively.
For prasugrel, there was a trend toward a higher risk of cancer adverse events in the 30-month arm than in the 12-month arm, but the risk of cancer death was identical in both arms—0.4% vs 0.4%.
The FDA said these findings are difficult to reconcile.
Meta-analyses of cancer and death
The FDA performed 2 trial-level meta-analyses to investigate the role of clopidogrel in cancer and cancer death.
The first was an analysis of cancer-related adverse events from 4 trials (37,835 patients) that compared long-term clopidogrel and aspirin to either aspirin alone or short-term clopidogrel plus aspirin.
The incidence of cancer adverse events was 4.2% for the long-term clopidogrel-plus-aspirin arm and 4.0% for the comparator arm (MH RD of 0.19%; 95% CI, -0.2%-0.59%).
The FDA conducted the second meta-analysis to assess cancer-related death. The analysis included 5 trials (40,855 patients).
The incidence of cancer death was 0.9% for the long-term clopidogrel-plus-aspirin arm and 1.1% for the comparator arm (MH RD of -0.14%; 95% CI, -0.33%-0.06%).
The FDA said that, taken together, the results of this review do not suggest an increased risk of cancer adverse events, cancer-related death, or all-cause mortality with long-term clopidogrel therapy.
More details can be found in the FDA’s Drug Safety Communication on this topic.
A review conducted by the US Food and Drug Administration (FDA) indicates that long-term use of the antiplatelet drug clopidogrel (Plavix) does not increase or decrease the overall risk of death in patients with, or at risk for, heart disease.
In addition, the FDA said there is no evidence to suggest that clopidogrel increases the risk of cancer or death from cancer.
These findings contradict those of the Dual Antiplatelet Therapy (DAPT) trial, the study that prompted the FDA’s review.
In this trial, researchers compared 12 months of DAPT (either clopidogrel or prasugrel plus aspirin) to 30 months of DAPT in patients who had a drug-eluting coronary stent.
Compared to patients taking clopidogrel for 12 months, patients who received clopidogrel for 30 months had lower rates of heart attacks and stent thrombosis but higher rates of death, primarily from cancer or trauma.
To investigate these findings, the FDA examined data from the DAPT trial and performed trial-level meta-analyses of other large, long-term trials.
The trials had a clopidogrel-plus-aspirin arm (long-term treatment was 12 months or longer) and a comparator arm of either aspirin alone or short-term clopidogrel plus aspirin (6 months or less). They also had a planned follow-up of at least 1 year.
All-cause death
In the DAPT trial, extended use of clopidogrel plus aspirin was associated with a significantly increased risk of death (2.2% for 30 months vs 1.5% for 12 months). But there was no increased risk for prasugrel plus aspirin (1.6% for 30 months vs 1.6% for 12 months).
The FDA’s initial meta-analysis on mortality included 12 trials (56,799 patients). The incidence of all-cause mortality was 6.7% for the long-term clopidogrel-plus-aspirin arm and 6.6% for the comparator arm, resulting in a Mantel Haenszel Risk Difference (MH RD) of 0.04% (95% CI, -0.35%-0.44%).
The FDA also conducted a meta-analysis of 9 of the 12 trials (45,374 patients), which enrolled patients with coronary artery disease or patients at risk of coronary artery disease. This analysis showed no difference in the risk of all-cause mortality—MH RD of -0.07% (95% CI, -0.43%-0.29%).
Cancer and death in DAPT
In the DAPT trial, the risk of cancer reported as an adverse event was not different between the 30-month (2.4% ) and 12-month (2.3%) groups receiving clopidogrel, when considering cancers reported after enrollment (from month 0 to 33 of the study).
The FDA performed several analyses of the cancer adverse event data, and the relative risk of cancer for the 30-month vs 12-month arm in the clopidogrel group ranged from 0.95 to 1.2, depending on the analysis.
Similar analyses for the prasugrel group revealed relative risks of cancer-related adverse events ranging from 1.4 to 1.6.
The FDA noted that, although there was no increase in the risk of cancer-related adverse events for clopidogrel in the 30-month arm, the risk of cancer-related death was higher than in the 12-month arm—0.7% and 0.2%, respectively.
For prasugrel, there was a trend toward a higher risk of cancer adverse events in the 30-month arm than in the 12-month arm, but the risk of cancer death was identical in both arms—0.4% vs 0.4%.
The FDA said these findings are difficult to reconcile.
Meta-analyses of cancer and death
The FDA performed 2 trial-level meta-analyses to investigate the role of clopidogrel in cancer and cancer death.
The first was an analysis of cancer-related adverse events from 4 trials (37,835 patients) that compared long-term clopidogrel and aspirin to either aspirin alone or short-term clopidogrel plus aspirin.
The incidence of cancer adverse events was 4.2% for the long-term clopidogrel-plus-aspirin arm and 4.0% for the comparator arm (MH RD of 0.19%; 95% CI, -0.2%-0.59%).
The FDA conducted the second meta-analysis to assess cancer-related death. The analysis included 5 trials (40,855 patients).
The incidence of cancer death was 0.9% for the long-term clopidogrel-plus-aspirin arm and 1.1% for the comparator arm (MH RD of -0.14%; 95% CI, -0.33%-0.06%).
The FDA said that, taken together, the results of this review do not suggest an increased risk of cancer adverse events, cancer-related death, or all-cause mortality with long-term clopidogrel therapy.
More details can be found in the FDA’s Drug Safety Communication on this topic.
FDA grants drug priority review as FL therapy
The US Food and Drug Administration (FDA) has accepted for priority review a supplemental biologics license application for obinutuzumab (Gazyva) to treat patients with follicular lymphoma (FL) who have relapsed after or are refractory to a rituximab-containing regimen.
Obinutuzumab is a glycoengineered, humanized, monoclonal antibody that selectively binds to the extracellular domain of the CD20 antigen on B cells.
The drug is already FDA-approved for use in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia.
A priority review designation is granted to drugs thought to have the potential to provide significant improvements in the treatment, prevention, or diagnosis of a disease.
The designation means the FDA’s goal is to take action on a drug application within 6 months, compared to 10 months under standard review.
The FDA has accepted the supplemental application for obinutuzumab in FL based on results of the phase 3 GADOLIN study.
Interim results from this trial were presented at the 2015 ASCO Annual Meeting (abstract LBA8502). Additional data are scheduled to be presented at the 2015 ASH Annual Meeting in December (abstracts 1532 and 3978).
GADOLIN study
The trial included 413 patients with rituximab-refractory non-Hodgkin lymphoma, including FL, marginal zone lymphoma, small lymphocytic lymphoma, and Waldenstrom’s macroglobulinemia.
The patients were randomized to receive bendamustine alone (control arm) or a combination of bendamustine and obinutuzumab (OB) followed by obinutuzumab maintenance (every 2 months for 2 years or until progression).
In all, 156 patients completed induction in the OB arm, as did 129 patients in the control arm. Thirty-six patients completed maintenance with obinutuzumab, and 46 were still receiving maintenance at the time of the interim analysis.
According to an independent radiology facility, 69.2% of patients in the OB arm had responded to treatment at the end of induction, as had 63% of the control arm. The best overall response by the 12-month mark was 78.7% and 76.6%, respectively.
According to the radiology facility, the median progression-free survival (PFS) had not been reached in the OB arm at a median follow-up of 21 months. In the control arm, the median PFS was 14.9 months (P<0.0001).
According to investigators, the median PFS was 29.2 months and 14 months, respectively (P<0.0001).
The median overall survival had not been reached in either arm (P=0.4017). Thirty-four patients (18%) in the OB arm died, as did 41 (20%) in the control arm.
About 99% of patients in the OB arm experienced at least 1 adverse event (AE), as did 98% of patients in the control arm. Severe AEs occurred in 38.1% and 32.8% of patients, respectively, and grade 3/4 AEs occurred in 67% and 62.1%, respectively.
AEs leading to treatment withdrawal occurred in 18% and 15.7% of patients, respectively. And AEs leading to death occurred in 6.2% and 6.1%, respectively.
The US Food and Drug Administration (FDA) has accepted for priority review a supplemental biologics license application for obinutuzumab (Gazyva) to treat patients with follicular lymphoma (FL) who have relapsed after or are refractory to a rituximab-containing regimen.
Obinutuzumab is a glycoengineered, humanized, monoclonal antibody that selectively binds to the extracellular domain of the CD20 antigen on B cells.
The drug is already FDA-approved for use in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia.
A priority review designation is granted to drugs thought to have the potential to provide significant improvements in the treatment, prevention, or diagnosis of a disease.
The designation means the FDA’s goal is to take action on a drug application within 6 months, compared to 10 months under standard review.
The FDA has accepted the supplemental application for obinutuzumab in FL based on results of the phase 3 GADOLIN study.
Interim results from this trial were presented at the 2015 ASCO Annual Meeting (abstract LBA8502). Additional data are scheduled to be presented at the 2015 ASH Annual Meeting in December (abstracts 1532 and 3978).
GADOLIN study
The trial included 413 patients with rituximab-refractory non-Hodgkin lymphoma, including FL, marginal zone lymphoma, small lymphocytic lymphoma, and Waldenstrom’s macroglobulinemia.
The patients were randomized to receive bendamustine alone (control arm) or a combination of bendamustine and obinutuzumab (OB) followed by obinutuzumab maintenance (every 2 months for 2 years or until progression).
In all, 156 patients completed induction in the OB arm, as did 129 patients in the control arm. Thirty-six patients completed maintenance with obinutuzumab, and 46 were still receiving maintenance at the time of the interim analysis.
According to an independent radiology facility, 69.2% of patients in the OB arm had responded to treatment at the end of induction, as had 63% of the control arm. The best overall response by the 12-month mark was 78.7% and 76.6%, respectively.
According to the radiology facility, the median progression-free survival (PFS) had not been reached in the OB arm at a median follow-up of 21 months. In the control arm, the median PFS was 14.9 months (P<0.0001).
According to investigators, the median PFS was 29.2 months and 14 months, respectively (P<0.0001).
The median overall survival had not been reached in either arm (P=0.4017). Thirty-four patients (18%) in the OB arm died, as did 41 (20%) in the control arm.
About 99% of patients in the OB arm experienced at least 1 adverse event (AE), as did 98% of patients in the control arm. Severe AEs occurred in 38.1% and 32.8% of patients, respectively, and grade 3/4 AEs occurred in 67% and 62.1%, respectively.
AEs leading to treatment withdrawal occurred in 18% and 15.7% of patients, respectively. And AEs leading to death occurred in 6.2% and 6.1%, respectively.
The US Food and Drug Administration (FDA) has accepted for priority review a supplemental biologics license application for obinutuzumab (Gazyva) to treat patients with follicular lymphoma (FL) who have relapsed after or are refractory to a rituximab-containing regimen.
Obinutuzumab is a glycoengineered, humanized, monoclonal antibody that selectively binds to the extracellular domain of the CD20 antigen on B cells.
The drug is already FDA-approved for use in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia.
A priority review designation is granted to drugs thought to have the potential to provide significant improvements in the treatment, prevention, or diagnosis of a disease.
The designation means the FDA’s goal is to take action on a drug application within 6 months, compared to 10 months under standard review.
The FDA has accepted the supplemental application for obinutuzumab in FL based on results of the phase 3 GADOLIN study.
Interim results from this trial were presented at the 2015 ASCO Annual Meeting (abstract LBA8502). Additional data are scheduled to be presented at the 2015 ASH Annual Meeting in December (abstracts 1532 and 3978).
GADOLIN study
The trial included 413 patients with rituximab-refractory non-Hodgkin lymphoma, including FL, marginal zone lymphoma, small lymphocytic lymphoma, and Waldenstrom’s macroglobulinemia.
The patients were randomized to receive bendamustine alone (control arm) or a combination of bendamustine and obinutuzumab (OB) followed by obinutuzumab maintenance (every 2 months for 2 years or until progression).
In all, 156 patients completed induction in the OB arm, as did 129 patients in the control arm. Thirty-six patients completed maintenance with obinutuzumab, and 46 were still receiving maintenance at the time of the interim analysis.
According to an independent radiology facility, 69.2% of patients in the OB arm had responded to treatment at the end of induction, as had 63% of the control arm. The best overall response by the 12-month mark was 78.7% and 76.6%, respectively.
According to the radiology facility, the median progression-free survival (PFS) had not been reached in the OB arm at a median follow-up of 21 months. In the control arm, the median PFS was 14.9 months (P<0.0001).
According to investigators, the median PFS was 29.2 months and 14 months, respectively (P<0.0001).
The median overall survival had not been reached in either arm (P=0.4017). Thirty-four patients (18%) in the OB arm died, as did 41 (20%) in the control arm.
About 99% of patients in the OB arm experienced at least 1 adverse event (AE), as did 98% of patients in the control arm. Severe AEs occurred in 38.1% and 32.8% of patients, respectively, and grade 3/4 AEs occurred in 67% and 62.1%, respectively.
AEs leading to treatment withdrawal occurred in 18% and 15.7% of patients, respectively. And AEs leading to death occurred in 6.2% and 6.1%, respectively.
EC expands indication for azacitidine in AML
The European Commission (EC) has expanded the approved indication for azacitidine for injection (Vidaza) in acute myeloid leukemia (AML).
Now, the drug is approved to treat AML patients age 65 and older who are ineligible for hematopoietic stem cell transplant (HSCT) and have more than 30% myeloblasts according to the WHO classification.
Previously, HSCT-ineligible elderly AML patients could only receive azacitidine if they had less than 30% blasts.
Because this new indication for azacitidine is thought to bring significant clinical benefit in comparison with existing therapies, the drug will receive extended market protection in all its indications for an additional year throughout the European Economic Area.
In addition to the aforementioned AML indications, azacitidine is approved in the European Economic Area to treat HSCT-ineligible adults with intermediate-2- and high-risk myelodysplastic syndromes and HSCT-ineligible adults who have chronic myelomonocytic leukemia and 10%-29% marrow blasts without myeloproliferative disorder.
Azacitidine is marketed as Vidaza by Celgene.
AML-001 trial
The EC’s recommendation to expand the indication of azacitidine in AML was based on data from the AML-001 trial. This randomized study included patients age 65 and older with newly diagnosed or secondary AML with greater than 30% blasts.
Patients were pre-selected to receive 1 of 3 regimens per investigator’s choice. This included intensive chemotherapy (standard 7+3 regimen), low-dose cytarabine (20 mg subcutaneously twice a day for 10 days of each 28-day cycle), or best supportive care only.
Patients were then randomized to receive either azacitidine (75 mg/m2/day subcutaneously for 7 days of each 28-day cycle, n=241) or their predetermined conventional care regimen (CCR, n=247).
Median overall survival, the study’s primary endpoint, was 10.4 months for patients receiving azacitidine and 6.5 months for patients receiving CCR (hazard ratio=0.85, P=0.1009).
One-year survival rates with azacitidine and CCR were 46.5% and 34.2%, respectively.
Grade 3/4 anemia occurred in 16% of patients who received azacitidine, 5% who received best supportive care, 23% who received low-dose cytarabine, and 14% who received intensive chemotherapy.
Grade 3/4 neutropenia occurred in 26%, 5%, 25%, and 33% of patients, respectively. Grade 3/4 febrile neutropenia occurred in 28%, 28%, 30%, and 31%, respectively. And grade 3/4 thrombocytopenia occurred in 24%, 5%, 28%, and 21%, respectively.
The European Commission (EC) has expanded the approved indication for azacitidine for injection (Vidaza) in acute myeloid leukemia (AML).
Now, the drug is approved to treat AML patients age 65 and older who are ineligible for hematopoietic stem cell transplant (HSCT) and have more than 30% myeloblasts according to the WHO classification.
Previously, HSCT-ineligible elderly AML patients could only receive azacitidine if they had less than 30% blasts.
Because this new indication for azacitidine is thought to bring significant clinical benefit in comparison with existing therapies, the drug will receive extended market protection in all its indications for an additional year throughout the European Economic Area.
In addition to the aforementioned AML indications, azacitidine is approved in the European Economic Area to treat HSCT-ineligible adults with intermediate-2- and high-risk myelodysplastic syndromes and HSCT-ineligible adults who have chronic myelomonocytic leukemia and 10%-29% marrow blasts without myeloproliferative disorder.
Azacitidine is marketed as Vidaza by Celgene.
AML-001 trial
The EC’s recommendation to expand the indication of azacitidine in AML was based on data from the AML-001 trial. This randomized study included patients age 65 and older with newly diagnosed or secondary AML with greater than 30% blasts.
Patients were pre-selected to receive 1 of 3 regimens per investigator’s choice. This included intensive chemotherapy (standard 7+3 regimen), low-dose cytarabine (20 mg subcutaneously twice a day for 10 days of each 28-day cycle), or best supportive care only.
Patients were then randomized to receive either azacitidine (75 mg/m2/day subcutaneously for 7 days of each 28-day cycle, n=241) or their predetermined conventional care regimen (CCR, n=247).
Median overall survival, the study’s primary endpoint, was 10.4 months for patients receiving azacitidine and 6.5 months for patients receiving CCR (hazard ratio=0.85, P=0.1009).
One-year survival rates with azacitidine and CCR were 46.5% and 34.2%, respectively.
Grade 3/4 anemia occurred in 16% of patients who received azacitidine, 5% who received best supportive care, 23% who received low-dose cytarabine, and 14% who received intensive chemotherapy.
Grade 3/4 neutropenia occurred in 26%, 5%, 25%, and 33% of patients, respectively. Grade 3/4 febrile neutropenia occurred in 28%, 28%, 30%, and 31%, respectively. And grade 3/4 thrombocytopenia occurred in 24%, 5%, 28%, and 21%, respectively.
The European Commission (EC) has expanded the approved indication for azacitidine for injection (Vidaza) in acute myeloid leukemia (AML).
Now, the drug is approved to treat AML patients age 65 and older who are ineligible for hematopoietic stem cell transplant (HSCT) and have more than 30% myeloblasts according to the WHO classification.
Previously, HSCT-ineligible elderly AML patients could only receive azacitidine if they had less than 30% blasts.
Because this new indication for azacitidine is thought to bring significant clinical benefit in comparison with existing therapies, the drug will receive extended market protection in all its indications for an additional year throughout the European Economic Area.
In addition to the aforementioned AML indications, azacitidine is approved in the European Economic Area to treat HSCT-ineligible adults with intermediate-2- and high-risk myelodysplastic syndromes and HSCT-ineligible adults who have chronic myelomonocytic leukemia and 10%-29% marrow blasts without myeloproliferative disorder.
Azacitidine is marketed as Vidaza by Celgene.
AML-001 trial
The EC’s recommendation to expand the indication of azacitidine in AML was based on data from the AML-001 trial. This randomized study included patients age 65 and older with newly diagnosed or secondary AML with greater than 30% blasts.
Patients were pre-selected to receive 1 of 3 regimens per investigator’s choice. This included intensive chemotherapy (standard 7+3 regimen), low-dose cytarabine (20 mg subcutaneously twice a day for 10 days of each 28-day cycle), or best supportive care only.
Patients were then randomized to receive either azacitidine (75 mg/m2/day subcutaneously for 7 days of each 28-day cycle, n=241) or their predetermined conventional care regimen (CCR, n=247).
Median overall survival, the study’s primary endpoint, was 10.4 months for patients receiving azacitidine and 6.5 months for patients receiving CCR (hazard ratio=0.85, P=0.1009).
One-year survival rates with azacitidine and CCR were 46.5% and 34.2%, respectively.
Grade 3/4 anemia occurred in 16% of patients who received azacitidine, 5% who received best supportive care, 23% who received low-dose cytarabine, and 14% who received intensive chemotherapy.
Grade 3/4 neutropenia occurred in 26%, 5%, 25%, and 33% of patients, respectively. Grade 3/4 febrile neutropenia occurred in 28%, 28%, 30%, and 31%, respectively. And grade 3/4 thrombocytopenia occurred in 24%, 5%, 28%, and 21%, respectively.
Drug gets orphan designation for BPDCN
The European Medicines Agency (EMA) has granted orphan drug designation to SL-401 for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN).
SL-401 is a targeted therapy directed to the interleukin-3 receptor (IL-3R), which is present on cancer stem cells and tumor bulk in a range of hematologic malignancies.
The drug is composed of human IL-3 coupled to a truncated diphtheria toxin payload that inhibits protein synthesis.
SL-401 already has orphan designation from the EMA to treat acute myeloid leukemia (AML) and from the US Food and Drug Administration (FDA) for the treatment of AML and BPDCN. The drug is under development by Stemline Therapeutics, Inc.
SL-401 research
At ASH 2012 (abstract 3625), researchers reported results with SL-401 in a study of patients with AML, BPDCN, and myelodysplastic syndromes (MDS).
At that time, the study had enrolled 80 patients, including 59 with relapsed or refractory AML, 11 with de novo AML unfit for chemotherapy, 7 with high-risk MDS, and 3 with relapsed/refractory BPDCN.
Patients received a single cycle of SL-401 as a 15-minute intravenous infusion in 1 of 2 dosing regimens to determine the maximum tolerated dose (MTD) and assess antitumor activity.
With regimen A, 45 patients received doses ranging from 4 μg/kg to 12.5 μg/kg every other day for up to 6 doses. With regimen B, 35 patients received doses ranging from 7.1 μg/kg to 22.1 μg/kg daily for up to 5 doses.
Of the 59 patients with relapsed/refractory AML, 2 achieved complete responses (CRs), 5 had partial responses (PRs), and 8 had minor responses (MRs). One CR lasted more than 8 months, and the other lasted more than 25 months.
Of the 11 patients with AML who were not candidates for chemotherapy, 2 had PRs and 1 had an MR. Among the 7 patients with high-risk MDS, there was 1 PR and 1 MR.
And among the 3 patients with BPDCN, there were 2 CRs. One CR lasted more than 2 months, and the other lasted more than 4 months.
The MTD was not achieved with regimen A, but the MTD for regimen B was 16.6 μg/kg/day. The dose-limiting toxicities were a gastrointestinal bleed (n=1), transaminase and creatinine kinase elevations (n=1), and capillary leak syndrome (n=3). There was no evidence of treatment-related bone marrow suppression.
Last year, researchers reported additional results in BPDCN patients (Frankel et al, Blood 2014).
Eleven BPDCN patients received a single course of SL-401 (at 12.5 μg/kg intravenously over 15 minutes) daily for up to 5 doses. Three patients who had initial responses to SL-401 received a second course while in relapse.
Seven of 9 evaluable (78%) patients responded to a single course of SL-401. There were 5 CRs and 2 PRs. The median duration of responses was 5 months (range, 1-20+ months).
The most common adverse events were transient and included fever, chills, hypotension, edema, hypoalbuminemia, thrombocytopenia, and transaminasemia.
Three multicenter clinical trials of SL-401 are currently open in the following indications:
- BPDCN and relapsed/refractory AML
- AML patients in first complete remission with minimal residual disease
- Four types of advanced, high-risk myeloproliferative neoplasms, including systemic mastocytosis, advanced symptomatic hypereosinophilic disorder, myelofibrosis, and chronic myelomonocytic leukemia.
Additional SL-401 studies are planned for patients with myeloma, lymphomas, and other leukemias.
About orphan designation
In the European Union, orphan designation is granted to therapies intended to treat a life-threatening or chronically debilitating condition that affects no more than 5 in 10,000 persons and where no satisfactory treatment is available.
Companies that obtain orphan designation for a drug in the European Union benefit from a number of incentives, including protocol assistance, a type of scientific advice specific for designated orphan medicines, and 10 years of market exclusivity once the medicine is on the market. Fee reductions are also available, depending on the status of the sponsor and the type of service required.
The FDA grants orphan designation to drugs that are intended to treat diseases or conditions affecting fewer than 200,000 patients in the US.
In the US, orphan designation provides the sponsor of a drug with various development incentives, including opportunities to apply for research-related tax credits and grant funding, assistance in designing clinical trials, and 7 years of US market exclusivity if the drug is approved.
The European Medicines Agency (EMA) has granted orphan drug designation to SL-401 for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN).
SL-401 is a targeted therapy directed to the interleukin-3 receptor (IL-3R), which is present on cancer stem cells and tumor bulk in a range of hematologic malignancies.
The drug is composed of human IL-3 coupled to a truncated diphtheria toxin payload that inhibits protein synthesis.
SL-401 already has orphan designation from the EMA to treat acute myeloid leukemia (AML) and from the US Food and Drug Administration (FDA) for the treatment of AML and BPDCN. The drug is under development by Stemline Therapeutics, Inc.
SL-401 research
At ASH 2012 (abstract 3625), researchers reported results with SL-401 in a study of patients with AML, BPDCN, and myelodysplastic syndromes (MDS).
At that time, the study had enrolled 80 patients, including 59 with relapsed or refractory AML, 11 with de novo AML unfit for chemotherapy, 7 with high-risk MDS, and 3 with relapsed/refractory BPDCN.
Patients received a single cycle of SL-401 as a 15-minute intravenous infusion in 1 of 2 dosing regimens to determine the maximum tolerated dose (MTD) and assess antitumor activity.
With regimen A, 45 patients received doses ranging from 4 μg/kg to 12.5 μg/kg every other day for up to 6 doses. With regimen B, 35 patients received doses ranging from 7.1 μg/kg to 22.1 μg/kg daily for up to 5 doses.
Of the 59 patients with relapsed/refractory AML, 2 achieved complete responses (CRs), 5 had partial responses (PRs), and 8 had minor responses (MRs). One CR lasted more than 8 months, and the other lasted more than 25 months.
Of the 11 patients with AML who were not candidates for chemotherapy, 2 had PRs and 1 had an MR. Among the 7 patients with high-risk MDS, there was 1 PR and 1 MR.
And among the 3 patients with BPDCN, there were 2 CRs. One CR lasted more than 2 months, and the other lasted more than 4 months.
The MTD was not achieved with regimen A, but the MTD for regimen B was 16.6 μg/kg/day. The dose-limiting toxicities were a gastrointestinal bleed (n=1), transaminase and creatinine kinase elevations (n=1), and capillary leak syndrome (n=3). There was no evidence of treatment-related bone marrow suppression.
Last year, researchers reported additional results in BPDCN patients (Frankel et al, Blood 2014).
Eleven BPDCN patients received a single course of SL-401 (at 12.5 μg/kg intravenously over 15 minutes) daily for up to 5 doses. Three patients who had initial responses to SL-401 received a second course while in relapse.
Seven of 9 evaluable (78%) patients responded to a single course of SL-401. There were 5 CRs and 2 PRs. The median duration of responses was 5 months (range, 1-20+ months).
The most common adverse events were transient and included fever, chills, hypotension, edema, hypoalbuminemia, thrombocytopenia, and transaminasemia.
Three multicenter clinical trials of SL-401 are currently open in the following indications:
- BPDCN and relapsed/refractory AML
- AML patients in first complete remission with minimal residual disease
- Four types of advanced, high-risk myeloproliferative neoplasms, including systemic mastocytosis, advanced symptomatic hypereosinophilic disorder, myelofibrosis, and chronic myelomonocytic leukemia.
Additional SL-401 studies are planned for patients with myeloma, lymphomas, and other leukemias.
About orphan designation
In the European Union, orphan designation is granted to therapies intended to treat a life-threatening or chronically debilitating condition that affects no more than 5 in 10,000 persons and where no satisfactory treatment is available.
Companies that obtain orphan designation for a drug in the European Union benefit from a number of incentives, including protocol assistance, a type of scientific advice specific for designated orphan medicines, and 10 years of market exclusivity once the medicine is on the market. Fee reductions are also available, depending on the status of the sponsor and the type of service required.
The FDA grants orphan designation to drugs that are intended to treat diseases or conditions affecting fewer than 200,000 patients in the US.
In the US, orphan designation provides the sponsor of a drug with various development incentives, including opportunities to apply for research-related tax credits and grant funding, assistance in designing clinical trials, and 7 years of US market exclusivity if the drug is approved.
The European Medicines Agency (EMA) has granted orphan drug designation to SL-401 for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN).
SL-401 is a targeted therapy directed to the interleukin-3 receptor (IL-3R), which is present on cancer stem cells and tumor bulk in a range of hematologic malignancies.
The drug is composed of human IL-3 coupled to a truncated diphtheria toxin payload that inhibits protein synthesis.
SL-401 already has orphan designation from the EMA to treat acute myeloid leukemia (AML) and from the US Food and Drug Administration (FDA) for the treatment of AML and BPDCN. The drug is under development by Stemline Therapeutics, Inc.
SL-401 research
At ASH 2012 (abstract 3625), researchers reported results with SL-401 in a study of patients with AML, BPDCN, and myelodysplastic syndromes (MDS).
At that time, the study had enrolled 80 patients, including 59 with relapsed or refractory AML, 11 with de novo AML unfit for chemotherapy, 7 with high-risk MDS, and 3 with relapsed/refractory BPDCN.
Patients received a single cycle of SL-401 as a 15-minute intravenous infusion in 1 of 2 dosing regimens to determine the maximum tolerated dose (MTD) and assess antitumor activity.
With regimen A, 45 patients received doses ranging from 4 μg/kg to 12.5 μg/kg every other day for up to 6 doses. With regimen B, 35 patients received doses ranging from 7.1 μg/kg to 22.1 μg/kg daily for up to 5 doses.
Of the 59 patients with relapsed/refractory AML, 2 achieved complete responses (CRs), 5 had partial responses (PRs), and 8 had minor responses (MRs). One CR lasted more than 8 months, and the other lasted more than 25 months.
Of the 11 patients with AML who were not candidates for chemotherapy, 2 had PRs and 1 had an MR. Among the 7 patients with high-risk MDS, there was 1 PR and 1 MR.
And among the 3 patients with BPDCN, there were 2 CRs. One CR lasted more than 2 months, and the other lasted more than 4 months.
The MTD was not achieved with regimen A, but the MTD for regimen B was 16.6 μg/kg/day. The dose-limiting toxicities were a gastrointestinal bleed (n=1), transaminase and creatinine kinase elevations (n=1), and capillary leak syndrome (n=3). There was no evidence of treatment-related bone marrow suppression.
Last year, researchers reported additional results in BPDCN patients (Frankel et al, Blood 2014).
Eleven BPDCN patients received a single course of SL-401 (at 12.5 μg/kg intravenously over 15 minutes) daily for up to 5 doses. Three patients who had initial responses to SL-401 received a second course while in relapse.
Seven of 9 evaluable (78%) patients responded to a single course of SL-401. There were 5 CRs and 2 PRs. The median duration of responses was 5 months (range, 1-20+ months).
The most common adverse events were transient and included fever, chills, hypotension, edema, hypoalbuminemia, thrombocytopenia, and transaminasemia.
Three multicenter clinical trials of SL-401 are currently open in the following indications:
- BPDCN and relapsed/refractory AML
- AML patients in first complete remission with minimal residual disease
- Four types of advanced, high-risk myeloproliferative neoplasms, including systemic mastocytosis, advanced symptomatic hypereosinophilic disorder, myelofibrosis, and chronic myelomonocytic leukemia.
Additional SL-401 studies are planned for patients with myeloma, lymphomas, and other leukemias.
About orphan designation
In the European Union, orphan designation is granted to therapies intended to treat a life-threatening or chronically debilitating condition that affects no more than 5 in 10,000 persons and where no satisfactory treatment is available.
Companies that obtain orphan designation for a drug in the European Union benefit from a number of incentives, including protocol assistance, a type of scientific advice specific for designated orphan medicines, and 10 years of market exclusivity once the medicine is on the market. Fee reductions are also available, depending on the status of the sponsor and the type of service required.
The FDA grants orphan designation to drugs that are intended to treat diseases or conditions affecting fewer than 200,000 patients in the US.
In the US, orphan designation provides the sponsor of a drug with various development incentives, including opportunities to apply for research-related tax credits and grant funding, assistance in designing clinical trials, and 7 years of US market exclusivity if the drug is approved.
Iron chelator tablets may now be crushed
Photo courtesy of the CDC
The US Food and Drug Administration (FDA) has approved a label change for Jadenu, an oral formulation of the iron chelator Exjade (deferasirox).
Jadenu comes in tablet form, and the previous label stated that Jadenu tablets must be swallowed whole.
Now, the medication can also be crushed to help simplify administration for patients who have difficulty swallowing whole tablets.
Jadenu tablets may be crushed and mixed with soft foods, such as yogurt or applesauce, immediately prior to use.
The label notes that commercial crushers with serrated surfaces should be avoided for crushing a single 90 mg tablet. The dose should be consumed immediately and not stored.
Jadenu was granted accelerated approval from the FDA earlier this year.
It is approved to treat patients 2 years of age and older who have chronic iron overload resulting from blood transfusions, as well as to treat chronic iron overload in patients 10 years of age and older who have non-transfusion-dependent thalassemia.
The full prescribing information for Jadenu can be found at http://www.pharma.us.novartis.com/product/pi/pdf/jadenu.pdf.
Photo courtesy of the CDC
The US Food and Drug Administration (FDA) has approved a label change for Jadenu, an oral formulation of the iron chelator Exjade (deferasirox).
Jadenu comes in tablet form, and the previous label stated that Jadenu tablets must be swallowed whole.
Now, the medication can also be crushed to help simplify administration for patients who have difficulty swallowing whole tablets.
Jadenu tablets may be crushed and mixed with soft foods, such as yogurt or applesauce, immediately prior to use.
The label notes that commercial crushers with serrated surfaces should be avoided for crushing a single 90 mg tablet. The dose should be consumed immediately and not stored.
Jadenu was granted accelerated approval from the FDA earlier this year.
It is approved to treat patients 2 years of age and older who have chronic iron overload resulting from blood transfusions, as well as to treat chronic iron overload in patients 10 years of age and older who have non-transfusion-dependent thalassemia.
The full prescribing information for Jadenu can be found at http://www.pharma.us.novartis.com/product/pi/pdf/jadenu.pdf.
Photo courtesy of the CDC
The US Food and Drug Administration (FDA) has approved a label change for Jadenu, an oral formulation of the iron chelator Exjade (deferasirox).
Jadenu comes in tablet form, and the previous label stated that Jadenu tablets must be swallowed whole.
Now, the medication can also be crushed to help simplify administration for patients who have difficulty swallowing whole tablets.
Jadenu tablets may be crushed and mixed with soft foods, such as yogurt or applesauce, immediately prior to use.
The label notes that commercial crushers with serrated surfaces should be avoided for crushing a single 90 mg tablet. The dose should be consumed immediately and not stored.
Jadenu was granted accelerated approval from the FDA earlier this year.
It is approved to treat patients 2 years of age and older who have chronic iron overload resulting from blood transfusions, as well as to treat chronic iron overload in patients 10 years of age and older who have non-transfusion-dependent thalassemia.
The full prescribing information for Jadenu can be found at http://www.pharma.us.novartis.com/product/pi/pdf/jadenu.pdf.
WHO recommends pilot projects for malaria vaccine
a malaria-endemic region
Photo by Sarah Mattison
More testing is needed before the malaria vaccine candidate RTS,S/AS01 (Mosquirix) can be put into widespread use, according to a pair of World Health Organization (WHO) advisory committees.
The WHO’s Strategic Advisory Group of Experts on Immunization (SAGE) and the Malaria Policy Advisory Committee (MPAC) are recommending that RTS,S be introduced in 3 to 5 pilot projects to determine the best way to deliver the vaccine to young children.
The issue, according to the committees, is that the vaccine must be administered in 4 doses and therefore requires repeat contact with the healthcare system.
The first 3 doses are given 1 month apart, and the last dose is given 18 months later. Without the fourth dose, children in a phase 3 study of RTS,S had no overall reduction in severe malaria.
So SAGE and MPAC want to be sure this vaccination schedule is feasible.
“The question about how the malaria vaccine may best be delivered still needs to be answered,” said Jon S. Abramson, chair of SAGE. “After detailed assessment of all the evidence, we recommended that this question is best addressed by having 3 to 5 large pilot implementation projects.”
This could delay widespread implementation of RTS,S for 3 to 5 years. Alternatively, if it is not possible to deliver all 4 doses of RTS,S consistently, Abramson said the vaccine may not be used at all.
RTS,S is being assessed as a complementary malaria control tool that could potentially be added to—but not replace—the core package of proven malaria preventive, diagnostic, and treatment measures.
The vaccine acts against Plasmodium falciparum, the most deadly malaria parasite globally and the most prevalent in Africa.
In a phase 3 trial, young children who received 4 doses of RTS,S had a 36% reduction in the number of clinical episodes of malaria at 4 years. Infants who received 4 doses of RTS,S had a 26% reduction in the number of clinical malaria episodes over 3 years.
Children had a significantly lower incidence of severe malaria only if they received all 4 doses of RTS,S. The vaccine did not confer the same benefit in infants, regardless of the doses given.
Results of a subsequent study suggested that genetic variation influences the vaccine’s ability to ward off malaria in young children but not in infants.
RTS,S was recently granted a positive opinion from the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) via Article 58 of Regulation No 726/2004.
This allows the CHMP, in cooperation with the WHO, to give a scientific opinion on a medicinal product intended for markets outside the European Union. This assessment requires products to meet the same standards as products intended for use in the European Union.
Once the CHMP issued a positive opinion of RTS,S, the WHO began formulating a policy recommendation on use of the vaccine in national immunization programs. RTS,S must pass the WHO pre-qualification process and be approved by national regulatory authorities before it can be used in such programs.
a malaria-endemic region
Photo by Sarah Mattison
More testing is needed before the malaria vaccine candidate RTS,S/AS01 (Mosquirix) can be put into widespread use, according to a pair of World Health Organization (WHO) advisory committees.
The WHO’s Strategic Advisory Group of Experts on Immunization (SAGE) and the Malaria Policy Advisory Committee (MPAC) are recommending that RTS,S be introduced in 3 to 5 pilot projects to determine the best way to deliver the vaccine to young children.
The issue, according to the committees, is that the vaccine must be administered in 4 doses and therefore requires repeat contact with the healthcare system.
The first 3 doses are given 1 month apart, and the last dose is given 18 months later. Without the fourth dose, children in a phase 3 study of RTS,S had no overall reduction in severe malaria.
So SAGE and MPAC want to be sure this vaccination schedule is feasible.
“The question about how the malaria vaccine may best be delivered still needs to be answered,” said Jon S. Abramson, chair of SAGE. “After detailed assessment of all the evidence, we recommended that this question is best addressed by having 3 to 5 large pilot implementation projects.”
This could delay widespread implementation of RTS,S for 3 to 5 years. Alternatively, if it is not possible to deliver all 4 doses of RTS,S consistently, Abramson said the vaccine may not be used at all.
RTS,S is being assessed as a complementary malaria control tool that could potentially be added to—but not replace—the core package of proven malaria preventive, diagnostic, and treatment measures.
The vaccine acts against Plasmodium falciparum, the most deadly malaria parasite globally and the most prevalent in Africa.
In a phase 3 trial, young children who received 4 doses of RTS,S had a 36% reduction in the number of clinical episodes of malaria at 4 years. Infants who received 4 doses of RTS,S had a 26% reduction in the number of clinical malaria episodes over 3 years.
Children had a significantly lower incidence of severe malaria only if they received all 4 doses of RTS,S. The vaccine did not confer the same benefit in infants, regardless of the doses given.
Results of a subsequent study suggested that genetic variation influences the vaccine’s ability to ward off malaria in young children but not in infants.
RTS,S was recently granted a positive opinion from the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) via Article 58 of Regulation No 726/2004.
This allows the CHMP, in cooperation with the WHO, to give a scientific opinion on a medicinal product intended for markets outside the European Union. This assessment requires products to meet the same standards as products intended for use in the European Union.
Once the CHMP issued a positive opinion of RTS,S, the WHO began formulating a policy recommendation on use of the vaccine in national immunization programs. RTS,S must pass the WHO pre-qualification process and be approved by national regulatory authorities before it can be used in such programs.
a malaria-endemic region
Photo by Sarah Mattison
More testing is needed before the malaria vaccine candidate RTS,S/AS01 (Mosquirix) can be put into widespread use, according to a pair of World Health Organization (WHO) advisory committees.
The WHO’s Strategic Advisory Group of Experts on Immunization (SAGE) and the Malaria Policy Advisory Committee (MPAC) are recommending that RTS,S be introduced in 3 to 5 pilot projects to determine the best way to deliver the vaccine to young children.
The issue, according to the committees, is that the vaccine must be administered in 4 doses and therefore requires repeat contact with the healthcare system.
The first 3 doses are given 1 month apart, and the last dose is given 18 months later. Without the fourth dose, children in a phase 3 study of RTS,S had no overall reduction in severe malaria.
So SAGE and MPAC want to be sure this vaccination schedule is feasible.
“The question about how the malaria vaccine may best be delivered still needs to be answered,” said Jon S. Abramson, chair of SAGE. “After detailed assessment of all the evidence, we recommended that this question is best addressed by having 3 to 5 large pilot implementation projects.”
This could delay widespread implementation of RTS,S for 3 to 5 years. Alternatively, if it is not possible to deliver all 4 doses of RTS,S consistently, Abramson said the vaccine may not be used at all.
RTS,S is being assessed as a complementary malaria control tool that could potentially be added to—but not replace—the core package of proven malaria preventive, diagnostic, and treatment measures.
The vaccine acts against Plasmodium falciparum, the most deadly malaria parasite globally and the most prevalent in Africa.
In a phase 3 trial, young children who received 4 doses of RTS,S had a 36% reduction in the number of clinical episodes of malaria at 4 years. Infants who received 4 doses of RTS,S had a 26% reduction in the number of clinical malaria episodes over 3 years.
Children had a significantly lower incidence of severe malaria only if they received all 4 doses of RTS,S. The vaccine did not confer the same benefit in infants, regardless of the doses given.
Results of a subsequent study suggested that genetic variation influences the vaccine’s ability to ward off malaria in young children but not in infants.
RTS,S was recently granted a positive opinion from the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) via Article 58 of Regulation No 726/2004.
This allows the CHMP, in cooperation with the WHO, to give a scientific opinion on a medicinal product intended for markets outside the European Union. This assessment requires products to meet the same standards as products intended for use in the European Union.
Once the CHMP issued a positive opinion of RTS,S, the WHO began formulating a policy recommendation on use of the vaccine in national immunization programs. RTS,S must pass the WHO pre-qualification process and be approved by national regulatory authorities before it can be used in such programs.
New melphalan formulation denied approval
Photo by Chad McNeeley
The US Food and Drug Administration (FDA) has said that, at present, it cannot approve a propylene glycol-free melphalan formulation (Evomela) for use in patients with multiple myeloma (MM).
Spectrum Pharmaceuticals is seeking approval for Evomela as a high-dose conditioning treatment for MM patients undergoing hematopoietic stem cell transplant (HSCT) and for palliative treatment in MM patients for whom oral therapy is not appropriate.
The FDA issued a Complete Response Letter stating that the new drug application (NDA) for Evomela cannot be approved in its present form.
However, the FDA did not identify any clinical deficiency in the NDA package.
“We will work swiftly with the FDA to address the Complete Response Letter,” said Rajesh C. Shrotriya, MD, chairman and chief executive officer of Spectrum Pharmaceuticals. “We remain committed to bringing Evomela to the market for patients and plan to work closely with the FDA.”
About Evomela
Evomela is a Captisol-enabled, propylene glycol-free melphalan formulation. This formulation eliminates the need to use a propylene glycol-containing custom diluent, which is required with other intravenous melphalan formulations and has been reported to cause renal and cardiac side effects.
The use of Captisol technology to reformulate melphalan is reported to improve the drug’s stability, extending its use time to 5 hours. This is anticipated to simplify preparation and administration logistics and allow for slower infusion rates and longer administration durations for pre-transplant chemotherapy.
Captisol is a patent-protected, chemically modified cyclodextrin with a structure designed to optimize the solubility and stability of drugs.
Spectrum Pharmaceuticals gained global development and commercialization rights to Evomela from Ligand Pharmaceuticals Incorporated in March 2013. Spectrum assumed responsibility for completing the pivotal phase 2 clinical trial and was responsible for filing the NDA. Spectrum filed the NDA in December 2014, and the FDA accepted the application the following March.
The FDA has granted Evomela orphan drug designation for use as a high-dose conditioning regimen for MM patients undergoing HSCT.
Phase 2 study
Researchers have evaluated Evomela in a phase 2, multicenter trial. Initial results from this trial (phase 2a) were published in Bone Marrow Transplantation in June 2014. Phase 2b results were published in Biology of Blood and Marrow Transplantation last month.
The latest publication includes data on 61 patients. Fifty-six had newly diagnosed MM, and 5 had relapsed MM following prior HSCT. The patients received Evomela at 200 mg/m2 given as 2 doses on Day -3 and Day -2 prior to HSCT (Day 0).
Efficacy was assessed by clinical response at Day +100. According to investigator assessment, the overall response rate was 95%, and the complete response (CR) rate was 31%.
According to independent pathology review, the overall response rate was 100%, and the CR rate was 21%. The lower rate of confirmed CRs in the independent review was due to missing data.
All 5 patients who had previously relapsed from a prior HSCT responded to Evomela.
All patients in the study achieved myeloablation with a median of 5 days post-HSCT. All patients had successful neutrophil and platelet engraftment at a median of 12 days and 13 days post-HSCT, respectively.
Treatment-related mortality was 0%, and non-hematologic adverse events were mostly grade 1 and 2 in severity. The incidence of grade 3 mucositis and grade 3 stomatitis were 10% and 5%, respectively, with no grade 4 mucositis or stomatitis reported.
Twenty percent of patients experienced treatment-emergent serious adverse events, most of which were grade 3 and consisted of events commonly reported in patients undergoing myeloablative chemotherapy. No new safety signals were identified.
Photo by Chad McNeeley
The US Food and Drug Administration (FDA) has said that, at present, it cannot approve a propylene glycol-free melphalan formulation (Evomela) for use in patients with multiple myeloma (MM).
Spectrum Pharmaceuticals is seeking approval for Evomela as a high-dose conditioning treatment for MM patients undergoing hematopoietic stem cell transplant (HSCT) and for palliative treatment in MM patients for whom oral therapy is not appropriate.
The FDA issued a Complete Response Letter stating that the new drug application (NDA) for Evomela cannot be approved in its present form.
However, the FDA did not identify any clinical deficiency in the NDA package.
“We will work swiftly with the FDA to address the Complete Response Letter,” said Rajesh C. Shrotriya, MD, chairman and chief executive officer of Spectrum Pharmaceuticals. “We remain committed to bringing Evomela to the market for patients and plan to work closely with the FDA.”
About Evomela
Evomela is a Captisol-enabled, propylene glycol-free melphalan formulation. This formulation eliminates the need to use a propylene glycol-containing custom diluent, which is required with other intravenous melphalan formulations and has been reported to cause renal and cardiac side effects.
The use of Captisol technology to reformulate melphalan is reported to improve the drug’s stability, extending its use time to 5 hours. This is anticipated to simplify preparation and administration logistics and allow for slower infusion rates and longer administration durations for pre-transplant chemotherapy.
Captisol is a patent-protected, chemically modified cyclodextrin with a structure designed to optimize the solubility and stability of drugs.
Spectrum Pharmaceuticals gained global development and commercialization rights to Evomela from Ligand Pharmaceuticals Incorporated in March 2013. Spectrum assumed responsibility for completing the pivotal phase 2 clinical trial and was responsible for filing the NDA. Spectrum filed the NDA in December 2014, and the FDA accepted the application the following March.
The FDA has granted Evomela orphan drug designation for use as a high-dose conditioning regimen for MM patients undergoing HSCT.
Phase 2 study
Researchers have evaluated Evomela in a phase 2, multicenter trial. Initial results from this trial (phase 2a) were published in Bone Marrow Transplantation in June 2014. Phase 2b results were published in Biology of Blood and Marrow Transplantation last month.
The latest publication includes data on 61 patients. Fifty-six had newly diagnosed MM, and 5 had relapsed MM following prior HSCT. The patients received Evomela at 200 mg/m2 given as 2 doses on Day -3 and Day -2 prior to HSCT (Day 0).
Efficacy was assessed by clinical response at Day +100. According to investigator assessment, the overall response rate was 95%, and the complete response (CR) rate was 31%.
According to independent pathology review, the overall response rate was 100%, and the CR rate was 21%. The lower rate of confirmed CRs in the independent review was due to missing data.
All 5 patients who had previously relapsed from a prior HSCT responded to Evomela.
All patients in the study achieved myeloablation with a median of 5 days post-HSCT. All patients had successful neutrophil and platelet engraftment at a median of 12 days and 13 days post-HSCT, respectively.
Treatment-related mortality was 0%, and non-hematologic adverse events were mostly grade 1 and 2 in severity. The incidence of grade 3 mucositis and grade 3 stomatitis were 10% and 5%, respectively, with no grade 4 mucositis or stomatitis reported.
Twenty percent of patients experienced treatment-emergent serious adverse events, most of which were grade 3 and consisted of events commonly reported in patients undergoing myeloablative chemotherapy. No new safety signals were identified.
Photo by Chad McNeeley
The US Food and Drug Administration (FDA) has said that, at present, it cannot approve a propylene glycol-free melphalan formulation (Evomela) for use in patients with multiple myeloma (MM).
Spectrum Pharmaceuticals is seeking approval for Evomela as a high-dose conditioning treatment for MM patients undergoing hematopoietic stem cell transplant (HSCT) and for palliative treatment in MM patients for whom oral therapy is not appropriate.
The FDA issued a Complete Response Letter stating that the new drug application (NDA) for Evomela cannot be approved in its present form.
However, the FDA did not identify any clinical deficiency in the NDA package.
“We will work swiftly with the FDA to address the Complete Response Letter,” said Rajesh C. Shrotriya, MD, chairman and chief executive officer of Spectrum Pharmaceuticals. “We remain committed to bringing Evomela to the market for patients and plan to work closely with the FDA.”
About Evomela
Evomela is a Captisol-enabled, propylene glycol-free melphalan formulation. This formulation eliminates the need to use a propylene glycol-containing custom diluent, which is required with other intravenous melphalan formulations and has been reported to cause renal and cardiac side effects.
The use of Captisol technology to reformulate melphalan is reported to improve the drug’s stability, extending its use time to 5 hours. This is anticipated to simplify preparation and administration logistics and allow for slower infusion rates and longer administration durations for pre-transplant chemotherapy.
Captisol is a patent-protected, chemically modified cyclodextrin with a structure designed to optimize the solubility and stability of drugs.
Spectrum Pharmaceuticals gained global development and commercialization rights to Evomela from Ligand Pharmaceuticals Incorporated in March 2013. Spectrum assumed responsibility for completing the pivotal phase 2 clinical trial and was responsible for filing the NDA. Spectrum filed the NDA in December 2014, and the FDA accepted the application the following March.
The FDA has granted Evomela orphan drug designation for use as a high-dose conditioning regimen for MM patients undergoing HSCT.
Phase 2 study
Researchers have evaluated Evomela in a phase 2, multicenter trial. Initial results from this trial (phase 2a) were published in Bone Marrow Transplantation in June 2014. Phase 2b results were published in Biology of Blood and Marrow Transplantation last month.
The latest publication includes data on 61 patients. Fifty-six had newly diagnosed MM, and 5 had relapsed MM following prior HSCT. The patients received Evomela at 200 mg/m2 given as 2 doses on Day -3 and Day -2 prior to HSCT (Day 0).
Efficacy was assessed by clinical response at Day +100. According to investigator assessment, the overall response rate was 95%, and the complete response (CR) rate was 31%.
According to independent pathology review, the overall response rate was 100%, and the CR rate was 21%. The lower rate of confirmed CRs in the independent review was due to missing data.
All 5 patients who had previously relapsed from a prior HSCT responded to Evomela.
All patients in the study achieved myeloablation with a median of 5 days post-HSCT. All patients had successful neutrophil and platelet engraftment at a median of 12 days and 13 days post-HSCT, respectively.
Treatment-related mortality was 0%, and non-hematologic adverse events were mostly grade 1 and 2 in severity. The incidence of grade 3 mucositis and grade 3 stomatitis were 10% and 5%, respectively, with no grade 4 mucositis or stomatitis reported.
Twenty percent of patients experienced treatment-emergent serious adverse events, most of which were grade 3 and consisted of events commonly reported in patients undergoing myeloablative chemotherapy. No new safety signals were identified.