Pharmacy

Doctor and patient

Credit: NIH

The US Food and Drug Administration and the European Commission have granted volasertib orphan designation for the treatment of acute myeloid leukemia (AML).

Volasertib, an investigational inhibitor of polo-like kinase 1 (Plk1), works by arresting the cell cycle and inducing apoptosis.

The drug is under evaluation as a potential treatment for patients aged 65 or older with previously untreated AML who are ineligible for intensive remission induction therapy.

In both the US and the European Union, orphan designation is awarded for drugs intended to treat rare conditions for which no authorized treatment exists. The designation gives the company developing volasertib, Boehringer Ingelheim, regulatory support and incentives to help the development and authorization process.

Volasertib has already been tested in a phase 1/2 trial of patients with newly diagnosed AML who were considered ineligible for intensive remission induction therapy. The results were presented at the 2012 ASH Annual Meeting as abstract 411.

In this study, volasertib in combination with low-dose cytarabine (LDAC) elicited higher rates of objective response and an improvement in event-free survival, when compared to LDAC alone.

Eighty-seven AML patients were assigned to receive volasertib + LDAC (n=42) or LDAC alone (n=45). Patient characteristics were similar between the 2 groups.

The objective response rate was 31% among patients who received volasertib + LDAC and 11.1% in those who received LDAC alone. The complete response rates were 16.7% and 6.7%, respectively.

The median event-free survival was 169 days for patients who received volasertib + LDAC and 69 days for patients who received LDAC alone.

Grade 3 or higher adverse events were more common in the volasertib + LDAC arm than the LDAC-alone arm—95.2% vs 68.9%.

The most frequent adverse events of any grade occurring in the volasertib + LDAC arm were febrile neutropenia (50%), constipation (45.2%), nausea (40.5%), and anemia (40.5%).

In the LDAC-alone arm, the most common adverse events were nausea (33.3%), anemia (28.9%), pyrexia (28.9%), constipation (26.7%), asthenia (26.7%), and diarrhea (26.7%).

Based on these results, researchers initiated a phase 3 study, called POLO-AML-2, comparing volasertib plus LDAC to LDAC plus placebo in older AML patients.

Doctor and patient

Credit: NIH

The US Food and Drug Administration and the European Commission have granted volasertib orphan designation for the treatment of acute myeloid leukemia (AML).

Volasertib, an investigational inhibitor of polo-like kinase 1 (Plk1), works by arresting the cell cycle and inducing apoptosis.

The drug is under evaluation as a potential treatment for patients aged 65 or older with previously untreated AML who are ineligible for intensive remission induction therapy.

In both the US and the European Union, orphan designation is awarded for drugs intended to treat rare conditions for which no authorized treatment exists. The designation gives the company developing volasertib, Boehringer Ingelheim, regulatory support and incentives to help the development and authorization process.

Volasertib has already been tested in a phase 1/2 trial of patients with newly diagnosed AML who were considered ineligible for intensive remission induction therapy. The results were presented at the 2012 ASH Annual Meeting as abstract 411.

In this study, volasertib in combination with low-dose cytarabine (LDAC) elicited higher rates of objective response and an improvement in event-free survival, when compared to LDAC alone.

Eighty-seven AML patients were assigned to receive volasertib + LDAC (n=42) or LDAC alone (n=45). Patient characteristics were similar between the 2 groups.

The objective response rate was 31% among patients who received volasertib + LDAC and 11.1% in those who received LDAC alone. The complete response rates were 16.7% and 6.7%, respectively.

The median event-free survival was 169 days for patients who received volasertib + LDAC and 69 days for patients who received LDAC alone.

Grade 3 or higher adverse events were more common in the volasertib + LDAC arm than the LDAC-alone arm—95.2% vs 68.9%.

The most frequent adverse events of any grade occurring in the volasertib + LDAC arm were febrile neutropenia (50%), constipation (45.2%), nausea (40.5%), and anemia (40.5%).

In the LDAC-alone arm, the most common adverse events were nausea (33.3%), anemia (28.9%), pyrexia (28.9%), constipation (26.7%), asthenia (26.7%), and diarrhea (26.7%).

Based on these results, researchers initiated a phase 3 study, called POLO-AML-2, comparing volasertib plus LDAC to LDAC plus placebo in older AML patients.

Doctor and patient

Credit: NIH

The US Food and Drug Administration and the European Commission have granted volasertib orphan designation for the treatment of acute myeloid leukemia (AML).

Volasertib, an investigational inhibitor of polo-like kinase 1 (Plk1), works by arresting the cell cycle and inducing apoptosis.

The drug is under evaluation as a potential treatment for patients aged 65 or older with previously untreated AML who are ineligible for intensive remission induction therapy.

In both the US and the European Union, orphan designation is awarded for drugs intended to treat rare conditions for which no authorized treatment exists. The designation gives the company developing volasertib, Boehringer Ingelheim, regulatory support and incentives to help the development and authorization process.

Volasertib has already been tested in a phase 1/2 trial of patients with newly diagnosed AML who were considered ineligible for intensive remission induction therapy. The results were presented at the 2012 ASH Annual Meeting as abstract 411.

In this study, volasertib in combination with low-dose cytarabine (LDAC) elicited higher rates of objective response and an improvement in event-free survival, when compared to LDAC alone.

Eighty-seven AML patients were assigned to receive volasertib + LDAC (n=42) or LDAC alone (n=45). Patient characteristics were similar between the 2 groups.

The objective response rate was 31% among patients who received volasertib + LDAC and 11.1% in those who received LDAC alone. The complete response rates were 16.7% and 6.7%, respectively.

The median event-free survival was 169 days for patients who received volasertib + LDAC and 69 days for patients who received LDAC alone.

Grade 3 or higher adverse events were more common in the volasertib + LDAC arm than the LDAC-alone arm—95.2% vs 68.9%.

The most frequent adverse events of any grade occurring in the volasertib + LDAC arm were febrile neutropenia (50%), constipation (45.2%), nausea (40.5%), and anemia (40.5%).

In the LDAC-alone arm, the most common adverse events were nausea (33.3%), anemia (28.9%), pyrexia (28.9%), constipation (26.7%), asthenia (26.7%), and diarrhea (26.7%).

Based on these results, researchers initiated a phase 3 study, called POLO-AML-2, comparing volasertib plus LDAC to LDAC plus placebo in older AML patients.

Monoclonal antibodies

Credit: Linda Bartlett

The US Food and Drug Administration (FDA) has approved ofatumumab (Arzerra) in combination with chlorambucil for previously untreated patients with chronic lymphocytic leukemia (CLL) who should not receive fludarabine-based therapy.

Ofatumumab, a CD20-directed monoclonal antibody, is already FDA-approved as monotherapy for CLL patients who are refractory to fludarabine and alemtuzumab.

The latest approval was based on results of the phase 3 COMPLEMENT 1 trial.

In this randomized trial, researchers compared single-agent chlorambucil to chlorambucil plus ofatumumab. They enrolled 447 patients for whom fludarabine-based therapy was considered inappropriate (due to factors such as advanced age or comorbidities).

In the overall trial population, the median age was 69 years (range, 35 to 92). Seventy-two percent of patients had 2 or more comorbidities, and 48% of patients had a creatinine clearance of less than 70 mL/min.

The researchers randomized 221 patients to receive chlorambucil plus ofatumumab and 226 patients to receive chlorambucil alone.

Patients in the ofatumumab arm received the drug as an intravenous infusion according to the following schedule: 300 mg in cycle 1 on day 1, 1000 mg in cycle 1 on day 8, and 1000 mg administered on day 1 of all subsequent 28-day cycles.

In both arms, patients received chlorambucil at a dose of 10 mg/m² orally on days 1 to 7, every 28 days.

Prior to each infusion of ofatumumab, patients received acetaminophen, an antihistamine, and a glucocorticoid.

The primary endpoint of the trial was progression-free survival, as assessed by a blinded independent review committee using the 2008 International Workshop on Chronic Lymphocytic Leukemia update of the National Cancer Institute Working Group guidelines.

The median progression-free survival was 22.4 months for patients receiving ofatumumab and chlorambucil, compared to 13.1 months for patients receiving chlorambucil alone. The hazard ratio was 0.57 (P<0.001).

The most common adverse reactions observed in patients receiving ofatumumab and chlorambucil (at least 2% more than in the control arm) were infusion reactions, neutropenia, asthenia, headache, leukopenia, herpes simplex, lower respiratory tract infection, arthralgia, and upper abdominal pain.

Overall, 67% of patients who received ofatumumab experienced 1 or more symptoms of infusion reaction. Ten percent of patients experienced a grade 3 or greater infusion reaction.

The drug’s label carries a boxed warning detailing the risk of hepatitis B virus reactivation—which can result in fulminant hepatitis, hepatic failure, and death—as well as the risk of progressive multifocal leukoencephalopathy—which can result in death.

The recommended dose and schedule for ofatumumab in previously untreated CLL is 300 mg on day 1, followed 1 week later by 1000 mg on day 8 (cycle 1), followed by 1000 mg on day 1 of subsequent 28-day cycles, for a minimum of 3 cycles until best response or a maximum of 12 cycles.

Ofatumumab is under development by GlaxoSmithKline and GenMab. For more details on the drug, see the full prescribing information.

Monoclonal antibodies

Credit: Linda Bartlett

The US Food and Drug Administration (FDA) has approved ofatumumab (Arzerra) in combination with chlorambucil for previously untreated patients with chronic lymphocytic leukemia (CLL) who should not receive fludarabine-based therapy.

Ofatumumab, a CD20-directed monoclonal antibody, is already FDA-approved as monotherapy for CLL patients who are refractory to fludarabine and alemtuzumab.

The latest approval was based on results of the phase 3 COMPLEMENT 1 trial.

In this randomized trial, researchers compared single-agent chlorambucil to chlorambucil plus ofatumumab. They enrolled 447 patients for whom fludarabine-based therapy was considered inappropriate (due to factors such as advanced age or comorbidities).

In the overall trial population, the median age was 69 years (range, 35 to 92). Seventy-two percent of patients had 2 or more comorbidities, and 48% of patients had a creatinine clearance of less than 70 mL/min.

The researchers randomized 221 patients to receive chlorambucil plus ofatumumab and 226 patients to receive chlorambucil alone.

Patients in the ofatumumab arm received the drug as an intravenous infusion according to the following schedule: 300 mg in cycle 1 on day 1, 1000 mg in cycle 1 on day 8, and 1000 mg administered on day 1 of all subsequent 28-day cycles.

In both arms, patients received chlorambucil at a dose of 10 mg/m² orally on days 1 to 7, every 28 days.

Prior to each infusion of ofatumumab, patients received acetaminophen, an antihistamine, and a glucocorticoid.

The primary endpoint of the trial was progression-free survival, as assessed by a blinded independent review committee using the 2008 International Workshop on Chronic Lymphocytic Leukemia update of the National Cancer Institute Working Group guidelines.

The median progression-free survival was 22.4 months for patients receiving ofatumumab and chlorambucil, compared to 13.1 months for patients receiving chlorambucil alone. The hazard ratio was 0.57 (P<0.001).

The most common adverse reactions observed in patients receiving ofatumumab and chlorambucil (at least 2% more than in the control arm) were infusion reactions, neutropenia, asthenia, headache, leukopenia, herpes simplex, lower respiratory tract infection, arthralgia, and upper abdominal pain.

Overall, 67% of patients who received ofatumumab experienced 1 or more symptoms of infusion reaction. Ten percent of patients experienced a grade 3 or greater infusion reaction.

The drug’s label carries a boxed warning detailing the risk of hepatitis B virus reactivation—which can result in fulminant hepatitis, hepatic failure, and death—as well as the risk of progressive multifocal leukoencephalopathy—which can result in death.

The recommended dose and schedule for ofatumumab in previously untreated CLL is 300 mg on day 1, followed 1 week later by 1000 mg on day 8 (cycle 1), followed by 1000 mg on day 1 of subsequent 28-day cycles, for a minimum of 3 cycles until best response or a maximum of 12 cycles.

Ofatumumab is under development by GlaxoSmithKline and GenMab. For more details on the drug, see the full prescribing information.

Monoclonal antibodies

Credit: Linda Bartlett

The US Food and Drug Administration (FDA) has approved ofatumumab (Arzerra) in combination with chlorambucil for previously untreated patients with chronic lymphocytic leukemia (CLL) who should not receive fludarabine-based therapy.

Ofatumumab, a CD20-directed monoclonal antibody, is already FDA-approved as monotherapy for CLL patients who are refractory to fludarabine and alemtuzumab.

The latest approval was based on results of the phase 3 COMPLEMENT 1 trial.

In this randomized trial, researchers compared single-agent chlorambucil to chlorambucil plus ofatumumab. They enrolled 447 patients for whom fludarabine-based therapy was considered inappropriate (due to factors such as advanced age or comorbidities).

In the overall trial population, the median age was 69 years (range, 35 to 92). Seventy-two percent of patients had 2 or more comorbidities, and 48% of patients had a creatinine clearance of less than 70 mL/min.

The researchers randomized 221 patients to receive chlorambucil plus ofatumumab and 226 patients to receive chlorambucil alone.

Patients in the ofatumumab arm received the drug as an intravenous infusion according to the following schedule: 300 mg in cycle 1 on day 1, 1000 mg in cycle 1 on day 8, and 1000 mg administered on day 1 of all subsequent 28-day cycles.

In both arms, patients received chlorambucil at a dose of 10 mg/m² orally on days 1 to 7, every 28 days.

Prior to each infusion of ofatumumab, patients received acetaminophen, an antihistamine, and a glucocorticoid.

The primary endpoint of the trial was progression-free survival, as assessed by a blinded independent review committee using the 2008 International Workshop on Chronic Lymphocytic Leukemia update of the National Cancer Institute Working Group guidelines.

The median progression-free survival was 22.4 months for patients receiving ofatumumab and chlorambucil, compared to 13.1 months for patients receiving chlorambucil alone. The hazard ratio was 0.57 (P<0.001).

The most common adverse reactions observed in patients receiving ofatumumab and chlorambucil (at least 2% more than in the control arm) were infusion reactions, neutropenia, asthenia, headache, leukopenia, herpes simplex, lower respiratory tract infection, arthralgia, and upper abdominal pain.

Overall, 67% of patients who received ofatumumab experienced 1 or more symptoms of infusion reaction. Ten percent of patients experienced a grade 3 or greater infusion reaction.

The drug’s label carries a boxed warning detailing the risk of hepatitis B virus reactivation—which can result in fulminant hepatitis, hepatic failure, and death—as well as the risk of progressive multifocal leukoencephalopathy—which can result in death.

The recommended dose and schedule for ofatumumab in previously untreated CLL is 300 mg on day 1, followed 1 week later by 1000 mg on day 8 (cycle 1), followed by 1000 mg on day 1 of subsequent 28-day cycles, for a minimum of 3 cycles until best response or a maximum of 12 cycles.

Ofatumumab is under development by GlaxoSmithKline and GenMab. For more details on the drug, see the full prescribing information.

Thrombus

Credit: Andre E.X. Brown

The US Food and Drug Administration (FDA) has approved dabigatran etexilate (Pradaxa) for the treatment and prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients who have already received anticoagulation therapy.

The drug is now approved to treat DVT and PE in patients who have received parenteral anticoagulant therapy for 5 to 10 days.

And it is approved as prophylaxis to reduce the risk of recurrent DVT and PE in previously treated patients.

The FDA’s approval of dabigatran is based on the results of four phase 3 trials.

The first of these, the RE-COVER trial, was published in NEJM in 2009. The results suggested that a fixed dose of dabigatran was as effective as warfarin for treating acute venous thromboembolism (VTE). And the safety profiles of the 2 drugs were deemed similar.

Data from a second trial, RE-SONATE, indicated that dabigatran was significantly more effective than placebo as long-term VTE prophylaxis. But the anticoagulant posed a higher risk of clinically relevant bleeding.

Results from the third trial, RE-MEDY, suggested dabigatran was non-inferior to warfarin as VTE prophylaxis. And warfarin conferred a higher risk of clinically relevant bleeding.

Both RE-MEDY and RE-SONATE were published in NEJM last year.

Data from the fourth trial, RE-COVER II, indicated that dabigatran had a similar effect on VTE recurrence and a lower risk of bleeding than warfarin when used to treat acute VTE. These results were published in Circulation last year.

Dabigatran is already approved by the FDA as prophylaxis for stroke and systemic embolism in patients with non-valvular atrial fibrillation. The drug is marketed as Pradaxa by Boehringer Ingelheim.

Thrombus

Credit: Andre E.X. Brown

The US Food and Drug Administration (FDA) has approved dabigatran etexilate (Pradaxa) for the treatment and prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients who have already received anticoagulation therapy.

The drug is now approved to treat DVT and PE in patients who have received parenteral anticoagulant therapy for 5 to 10 days.

And it is approved as prophylaxis to reduce the risk of recurrent DVT and PE in previously treated patients.

The FDA’s approval of dabigatran is based on the results of four phase 3 trials.

The first of these, the RE-COVER trial, was published in NEJM in 2009. The results suggested that a fixed dose of dabigatran was as effective as warfarin for treating acute venous thromboembolism (VTE). And the safety profiles of the 2 drugs were deemed similar.

Data from a second trial, RE-SONATE, indicated that dabigatran was significantly more effective than placebo as long-term VTE prophylaxis. But the anticoagulant posed a higher risk of clinically relevant bleeding.

Results from the third trial, RE-MEDY, suggested dabigatran was non-inferior to warfarin as VTE prophylaxis. And warfarin conferred a higher risk of clinically relevant bleeding.

Both RE-MEDY and RE-SONATE were published in NEJM last year.

Data from the fourth trial, RE-COVER II, indicated that dabigatran had a similar effect on VTE recurrence and a lower risk of bleeding than warfarin when used to treat acute VTE. These results were published in Circulation last year.

Dabigatran is already approved by the FDA as prophylaxis for stroke and systemic embolism in patients with non-valvular atrial fibrillation. The drug is marketed as Pradaxa by Boehringer Ingelheim.

Thrombus

Credit: Andre E.X. Brown

The US Food and Drug Administration (FDA) has approved dabigatran etexilate (Pradaxa) for the treatment and prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients who have already received anticoagulation therapy.

The drug is now approved to treat DVT and PE in patients who have received parenteral anticoagulant therapy for 5 to 10 days.

And it is approved as prophylaxis to reduce the risk of recurrent DVT and PE in previously treated patients.

The FDA’s approval of dabigatran is based on the results of four phase 3 trials.

The first of these, the RE-COVER trial, was published in NEJM in 2009. The results suggested that a fixed dose of dabigatran was as effective as warfarin for treating acute venous thromboembolism (VTE). And the safety profiles of the 2 drugs were deemed similar.

Data from a second trial, RE-SONATE, indicated that dabigatran was significantly more effective than placebo as long-term VTE prophylaxis. But the anticoagulant posed a higher risk of clinically relevant bleeding.

Results from the third trial, RE-MEDY, suggested dabigatran was non-inferior to warfarin as VTE prophylaxis. And warfarin conferred a higher risk of clinically relevant bleeding.

Both RE-MEDY and RE-SONATE were published in NEJM last year.

Data from the fourth trial, RE-COVER II, indicated that dabigatran had a similar effect on VTE recurrence and a lower risk of bleeding than warfarin when used to treat acute VTE. These results were published in Circulation last year.

Dabigatran is already approved by the FDA as prophylaxis for stroke and systemic embolism in patients with non-valvular atrial fibrillation. The drug is marketed as Pradaxa by Boehringer Ingelheim.

Update: The hold on this trial has been lifted. Click here for additional details.

Memorial Sloan-Kettering Cancer Center has temporarily suspended enrollment in a study of chimeric antigen receptor (CAR) T-cell therapy, due to 2 patient deaths.

The study is an evaluation of CD19-targeted CAR T cells in patients with B-cell acute lymphoblastic leukemia (ALL).

Of the 22 patients enrolled on the study to date, 10 have died. But only 2 of these deaths gave researchers pause and made them question enrollment criteria.

Six deaths were a result of disease relapse or progression, and 2 patients died of complications from stem cell transplant.

The 2 deaths that prompted the suspension of enrollment occurred within 2 weeks of the patients receiving CAR T cells.

“The first of these patients had a prior history of cardiac disease, while the second patient died due to complications associated with persistent seizure activity,” said Renier Brentjens, MD, PhD, of Memorial Sloan-Kettering in New York.

“As a matter of routine review at Sloan-Kettering for adverse events on-study, our center made the decision to pause enrollment and review these 2 patients in greater detail.”

“And as a consequence of this review, we’ve amended the enrollment criteria in regards to comorbidities, thereby excluding patients with cardiac disease, and adjusted the T-cell dose based on the extent of disease, [in the] hope that this modification will reduce the cytokine release syndrome that these patients with morphological disease have experienced.”

The researchers expect the trial to resume enrollment soon.

Some results from this study were recently published in Science Translational Medicine, and Dr Brentjens presented the latest results at the AACR Annual Meeting 2014 in San Diego (abstract CT102*).

Thus far, the researchers have enrolled 22 adult patients who had relapsed or refractory B-ALL, were minimal residual disease-positive, or were in the first complete remission (CR1) at enrollment. Patients in CR1 were monitored and only received CAR T cells if they relapsed.

The remaining patients received re-induction chemotherapy (physician’s choice), followed by CAR T-cell infusion. After treatment, the options were allogeneic transplant, a different salvage therapy, or monitoring.

In all, 20 patients received a CAR T-cell dose of 3 x 10⁶ T cells/kg. Eighty-two percent of patients initially achieved a CR, and 72% had a morphologic CR. The average time to CR was about 24.5 days.

Twelve of the responders were eligible for transplant. Of the 8 patients who ultimately underwent transplant and survived, 1 relapsed, but the rest remain in remission.

Dr Brentjens noted that some patients developed cytokine release syndrome, and this was related to the amount of disease present at the time of CAR T-cell infusion.

“Those patients that had only minimal residual disease at the time of CAR T-cell infusion . . .  less than 5% blasts, generally had either no fever or very transient, low-grade fever,” he said.

“In contrast, all those patients that had morphologic residual disease at the time of CAR T-cell infusion demonstrated a high, persistent spike in fevers . . . , became hypotensive, and required transfer—for additional, closer monitoring—to our ICU.”

The researchers initially treated these patients with high-dose steroids, which reduced cytokine levels in the serum and ameliorated fevers. But it also rapidly reduced T-cell populations to undetectable levels.

Fortunately, another group of researchers subsequently discovered that the monoclonal antibody tocilizumab can treat cytokine release syndrome without inducing this side effect. So Dr Brentjens and his colleagues began using this drug and found it both safe and effective.

*Information in the abstract differs from that presented at the meeting.

Update: The hold on this trial has been lifted. Click here for additional details.

Memorial Sloan-Kettering Cancer Center has temporarily suspended enrollment in a study of chimeric antigen receptor (CAR) T-cell therapy, due to 2 patient deaths.

The study is an evaluation of CD19-targeted CAR T cells in patients with B-cell acute lymphoblastic leukemia (ALL).

Of the 22 patients enrolled on the study to date, 10 have died. But only 2 of these deaths gave researchers pause and made them question enrollment criteria.

Six deaths were a result of disease relapse or progression, and 2 patients died of complications from stem cell transplant.

The 2 deaths that prompted the suspension of enrollment occurred within 2 weeks of the patients receiving CAR T cells.

“The first of these patients had a prior history of cardiac disease, while the second patient died due to complications associated with persistent seizure activity,” said Renier Brentjens, MD, PhD, of Memorial Sloan-Kettering in New York.

“As a matter of routine review at Sloan-Kettering for adverse events on-study, our center made the decision to pause enrollment and review these 2 patients in greater detail.”

“And as a consequence of this review, we’ve amended the enrollment criteria in regards to comorbidities, thereby excluding patients with cardiac disease, and adjusted the T-cell dose based on the extent of disease, [in the] hope that this modification will reduce the cytokine release syndrome that these patients with morphological disease have experienced.”

The researchers expect the trial to resume enrollment soon.

Some results from this study were recently published in Science Translational Medicine, and Dr Brentjens presented the latest results at the AACR Annual Meeting 2014 in San Diego (abstract CT102*).

Thus far, the researchers have enrolled 22 adult patients who had relapsed or refractory B-ALL, were minimal residual disease-positive, or were in the first complete remission (CR1) at enrollment. Patients in CR1 were monitored and only received CAR T cells if they relapsed.

The remaining patients received re-induction chemotherapy (physician’s choice), followed by CAR T-cell infusion. After treatment, the options were allogeneic transplant, a different salvage therapy, or monitoring.

In all, 20 patients received a CAR T-cell dose of 3 x 10⁶ T cells/kg. Eighty-two percent of patients initially achieved a CR, and 72% had a morphologic CR. The average time to CR was about 24.5 days.

Twelve of the responders were eligible for transplant. Of the 8 patients who ultimately underwent transplant and survived, 1 relapsed, but the rest remain in remission.

Dr Brentjens noted that some patients developed cytokine release syndrome, and this was related to the amount of disease present at the time of CAR T-cell infusion.

“Those patients that had only minimal residual disease at the time of CAR T-cell infusion . . .  less than 5% blasts, generally had either no fever or very transient, low-grade fever,” he said.

“In contrast, all those patients that had morphologic residual disease at the time of CAR T-cell infusion demonstrated a high, persistent spike in fevers . . . , became hypotensive, and required transfer—for additional, closer monitoring—to our ICU.”

The researchers initially treated these patients with high-dose steroids, which reduced cytokine levels in the serum and ameliorated fevers. But it also rapidly reduced T-cell populations to undetectable levels.

Fortunately, another group of researchers subsequently discovered that the monoclonal antibody tocilizumab can treat cytokine release syndrome without inducing this side effect. So Dr Brentjens and his colleagues began using this drug and found it both safe and effective.

*Information in the abstract differs from that presented at the meeting.

Update: The hold on this trial has been lifted. Click here for additional details.

Memorial Sloan-Kettering Cancer Center has temporarily suspended enrollment in a study of chimeric antigen receptor (CAR) T-cell therapy, due to 2 patient deaths.

The study is an evaluation of CD19-targeted CAR T cells in patients with B-cell acute lymphoblastic leukemia (ALL).

Of the 22 patients enrolled on the study to date, 10 have died. But only 2 of these deaths gave researchers pause and made them question enrollment criteria.

Six deaths were a result of disease relapse or progression, and 2 patients died of complications from stem cell transplant.

The 2 deaths that prompted the suspension of enrollment occurred within 2 weeks of the patients receiving CAR T cells.

“The first of these patients had a prior history of cardiac disease, while the second patient died due to complications associated with persistent seizure activity,” said Renier Brentjens, MD, PhD, of Memorial Sloan-Kettering in New York.

“As a matter of routine review at Sloan-Kettering for adverse events on-study, our center made the decision to pause enrollment and review these 2 patients in greater detail.”

“And as a consequence of this review, we’ve amended the enrollment criteria in regards to comorbidities, thereby excluding patients with cardiac disease, and adjusted the T-cell dose based on the extent of disease, [in the] hope that this modification will reduce the cytokine release syndrome that these patients with morphological disease have experienced.”

The researchers expect the trial to resume enrollment soon.

Some results from this study were recently published in Science Translational Medicine, and Dr Brentjens presented the latest results at the AACR Annual Meeting 2014 in San Diego (abstract CT102*).

Thus far, the researchers have enrolled 22 adult patients who had relapsed or refractory B-ALL, were minimal residual disease-positive, or were in the first complete remission (CR1) at enrollment. Patients in CR1 were monitored and only received CAR T cells if they relapsed.

The remaining patients received re-induction chemotherapy (physician’s choice), followed by CAR T-cell infusion. After treatment, the options were allogeneic transplant, a different salvage therapy, or monitoring.

In all, 20 patients received a CAR T-cell dose of 3 x 10⁶ T cells/kg. Eighty-two percent of patients initially achieved a CR, and 72% had a morphologic CR. The average time to CR was about 24.5 days.

Twelve of the responders were eligible for transplant. Of the 8 patients who ultimately underwent transplant and survived, 1 relapsed, but the rest remain in remission.

Dr Brentjens noted that some patients developed cytokine release syndrome, and this was related to the amount of disease present at the time of CAR T-cell infusion.

“Those patients that had only minimal residual disease at the time of CAR T-cell infusion . . .  less than 5% blasts, generally had either no fever or very transient, low-grade fever,” he said.

“In contrast, all those patients that had morphologic residual disease at the time of CAR T-cell infusion demonstrated a high, persistent spike in fevers . . . , became hypotensive, and required transfer—for additional, closer monitoring—to our ICU.”

The researchers initially treated these patients with high-dose steroids, which reduced cytokine levels in the serum and ameliorated fevers. But it also rapidly reduced T-cell populations to undetectable levels.

Fortunately, another group of researchers subsequently discovered that the monoclonal antibody tocilizumab can treat cytokine release syndrome without inducing this side effect. So Dr Brentjens and his colleagues began using this drug and found it both safe and effective.

*Information in the abstract differs from that presented at the meeting.

Genome testing

Credit: NIGMS

Few pharmacogenomic studies focus on orphan or tropical diseases prevalent in developing countries, according to research published in Global Public Health.

Researchers found that, from 1997 to 2010, pharmacogenomics research most commonly focused on cancers, depression or psychological disorders, and cardiovascular disease.

Less than 4% of publications dealt with orphan or infectious diseases.

According to the researchers, this suggests pharmacogenomic research follows the 90/10 rule.

“It is recognized that the distribution of technology and research follows the so-called 90/10 ratio rule; that is, 90% of global funding for health research, including the development drugs, is invested to treat 10% of the world’s population,” said study author Catherine Olivier, a PhD candidate at the University of Montreal’s School of Public Health.

This inequality between rich and poor countries led the United Nations (UN) to make the fight against HIV-AIDS, malaria, and neglected tropical diseases one of its 8 Millennium Development Goals, adopted in September 2000 by the 189 UN member states.

To verify the extent to which pharmacogenomic research has addressed orphan and tropical diseases, Olivier searched for pharmacogenomic studies published from 1997 to 2010. She identified 626 studies in 171 journals.

Each study was analyzed according to the type of disease it concerned, the origin of its authors, and their affiliation with pharmaceutical companies, if any.

“The information collected allowed us to draw a map showing current and historical trends in the development of pharmacogenomic research,” Olivier said.

She found that, from 1997 to 2003, there were 401 publications on pharmacogenomics in the PubMed database. And the majority of them (67%) were published in a single journal, Pharmacogenetics. Then, from 2003 to 2010, the number of studies doubled.

However, the apparent enthusiasm for this type of research seems to have been artificially inflated. Olivier noted that the percentage of nonoriginal publications, including reviews, meta-analyses, and debates, increased from 15% in 1997 to 51% in 2010.

“The number of original articles—that is, studies focusing on a new aspect of pharmacogenomics—began to decline after 2002,” Olivier said.

Moreover, during the period analyzed, nearly 23% of published studies in pharmacogenomics dealt with the area of oncology, followed by depression and psychological disorders (14.7%), and cardiovascular disorders (13.6%).

“Rare diseases, tropical infections, and maternal health, which should have benefited from pharmacogenomic research under the Millennium Development Goals, represented only 3.8% of published studies,” Olivier explained.

She noted that investigators from countries most likely to be interested in these areas of research conducted few studies on rare diseases and tropical infections.

“Of the 65 publications from BRICS countries—Brazil, Russia, India, China, and South Africa—only 2 concerned rare diseases and tropical infections,” Olivier said.

Yet these diseases represented nearly half (45.5%) of the main causes of mortality in underdeveloped countries, and 15% in developing countries, according to 2008 data issued by the UN.

“Unfortunately, our study indicates that we are far from fulfilling the promise to reduce health inequalities in the world,” Olivier said, “a promise which was made before the adoption of the Millennium Declaration.”

Genome testing

Credit: NIGMS

Few pharmacogenomic studies focus on orphan or tropical diseases prevalent in developing countries, according to research published in Global Public Health.

Researchers found that, from 1997 to 2010, pharmacogenomics research most commonly focused on cancers, depression or psychological disorders, and cardiovascular disease.

Less than 4% of publications dealt with orphan or infectious diseases.

According to the researchers, this suggests pharmacogenomic research follows the 90/10 rule.

“It is recognized that the distribution of technology and research follows the so-called 90/10 ratio rule; that is, 90% of global funding for health research, including the development drugs, is invested to treat 10% of the world’s population,” said study author Catherine Olivier, a PhD candidate at the University of Montreal’s School of Public Health.

This inequality between rich and poor countries led the United Nations (UN) to make the fight against HIV-AIDS, malaria, and neglected tropical diseases one of its 8 Millennium Development Goals, adopted in September 2000 by the 189 UN member states.

To verify the extent to which pharmacogenomic research has addressed orphan and tropical diseases, Olivier searched for pharmacogenomic studies published from 1997 to 2010. She identified 626 studies in 171 journals.

Each study was analyzed according to the type of disease it concerned, the origin of its authors, and their affiliation with pharmaceutical companies, if any.

“The information collected allowed us to draw a map showing current and historical trends in the development of pharmacogenomic research,” Olivier said.

She found that, from 1997 to 2003, there were 401 publications on pharmacogenomics in the PubMed database. And the majority of them (67%) were published in a single journal, Pharmacogenetics. Then, from 2003 to 2010, the number of studies doubled.

However, the apparent enthusiasm for this type of research seems to have been artificially inflated. Olivier noted that the percentage of nonoriginal publications, including reviews, meta-analyses, and debates, increased from 15% in 1997 to 51% in 2010.

“The number of original articles—that is, studies focusing on a new aspect of pharmacogenomics—began to decline after 2002,” Olivier said.

Moreover, during the period analyzed, nearly 23% of published studies in pharmacogenomics dealt with the area of oncology, followed by depression and psychological disorders (14.7%), and cardiovascular disorders (13.6%).

“Rare diseases, tropical infections, and maternal health, which should have benefited from pharmacogenomic research under the Millennium Development Goals, represented only 3.8% of published studies,” Olivier explained.

She noted that investigators from countries most likely to be interested in these areas of research conducted few studies on rare diseases and tropical infections.

“Of the 65 publications from BRICS countries—Brazil, Russia, India, China, and South Africa—only 2 concerned rare diseases and tropical infections,” Olivier said.

Yet these diseases represented nearly half (45.5%) of the main causes of mortality in underdeveloped countries, and 15% in developing countries, according to 2008 data issued by the UN.

“Unfortunately, our study indicates that we are far from fulfilling the promise to reduce health inequalities in the world,” Olivier said, “a promise which was made before the adoption of the Millennium Declaration.”

Genome testing

Credit: NIGMS

Few pharmacogenomic studies focus on orphan or tropical diseases prevalent in developing countries, according to research published in Global Public Health.

Researchers found that, from 1997 to 2010, pharmacogenomics research most commonly focused on cancers, depression or psychological disorders, and cardiovascular disease.

Less than 4% of publications dealt with orphan or infectious diseases.

According to the researchers, this suggests pharmacogenomic research follows the 90/10 rule.

“It is recognized that the distribution of technology and research follows the so-called 90/10 ratio rule; that is, 90% of global funding for health research, including the development drugs, is invested to treat 10% of the world’s population,” said study author Catherine Olivier, a PhD candidate at the University of Montreal’s School of Public Health.

This inequality between rich and poor countries led the United Nations (UN) to make the fight against HIV-AIDS, malaria, and neglected tropical diseases one of its 8 Millennium Development Goals, adopted in September 2000 by the 189 UN member states.

To verify the extent to which pharmacogenomic research has addressed orphan and tropical diseases, Olivier searched for pharmacogenomic studies published from 1997 to 2010. She identified 626 studies in 171 journals.

Each study was analyzed according to the type of disease it concerned, the origin of its authors, and their affiliation with pharmaceutical companies, if any.

“The information collected allowed us to draw a map showing current and historical trends in the development of pharmacogenomic research,” Olivier said.

She found that, from 1997 to 2003, there were 401 publications on pharmacogenomics in the PubMed database. And the majority of them (67%) were published in a single journal, Pharmacogenetics. Then, from 2003 to 2010, the number of studies doubled.

However, the apparent enthusiasm for this type of research seems to have been artificially inflated. Olivier noted that the percentage of nonoriginal publications, including reviews, meta-analyses, and debates, increased from 15% in 1997 to 51% in 2010.

“The number of original articles—that is, studies focusing on a new aspect of pharmacogenomics—began to decline after 2002,” Olivier said.

Moreover, during the period analyzed, nearly 23% of published studies in pharmacogenomics dealt with the area of oncology, followed by depression and psychological disorders (14.7%), and cardiovascular disorders (13.6%).

“Rare diseases, tropical infections, and maternal health, which should have benefited from pharmacogenomic research under the Millennium Development Goals, represented only 3.8% of published studies,” Olivier explained.

She noted that investigators from countries most likely to be interested in these areas of research conducted few studies on rare diseases and tropical infections.

“Of the 65 publications from BRICS countries—Brazil, Russia, India, China, and South Africa—only 2 concerned rare diseases and tropical infections,” Olivier said.

Yet these diseases represented nearly half (45.5%) of the main causes of mortality in underdeveloped countries, and 15% in developing countries, according to 2008 data issued by the UN.

“Unfortunately, our study indicates that we are far from fulfilling the promise to reduce health inequalities in the world,” Olivier said, “a promise which was made before the adoption of the Millennium Declaration.”

AML cells

The US Food and Drug Administration (FDA) has granted orphan designation for eryaspase to treat acute myeloid leukemia (AML).

Eryaspase, also known as ERY-ASP or GRASPA, is L-asparaginase encapsulated in red blood cells.

These donor-derived, enzyme-loaded red blood cells function as bioreactors to eliminate circulating asparagine and “starve”

leukemic cells, thereby inducing their death.

Research has suggested this delivery system provides improved pharmacodynamics. It protects L-aspariginase from circulating proteolytic enzymes and prevents early liver or renal clearance.

The system also appears to reduce the risk of adverse events.

Eryaspase is currently under investigation in a phase 3 trial for acute lymphoblastic leukemia (ALL) and a phase 2b trial for AML in Europe. A phase 1 study in adult ALL is being launched in the US.

Eryaspase now has orphan designation for ALL, AML and pancreatic cancer, both in Europe and the US.

In the US, orphan designation is generally granted for drugs or biologics intended to treat disorders of high unmet medical need that affect fewer than 200,000 people.

This designation conveys special incentives to the product’s sponsor, including 7 years of US market exclusivity for the drug or biologic upon FDA approval, a prescription drug user fee waiver, and certain tax credits.

AML cells

The US Food and Drug Administration (FDA) has granted orphan designation for eryaspase to treat acute myeloid leukemia (AML).

Eryaspase, also known as ERY-ASP or GRASPA, is L-asparaginase encapsulated in red blood cells.

These donor-derived, enzyme-loaded red blood cells function as bioreactors to eliminate circulating asparagine and “starve”

leukemic cells, thereby inducing their death.

Research has suggested this delivery system provides improved pharmacodynamics. It protects L-aspariginase from circulating proteolytic enzymes and prevents early liver or renal clearance.

The system also appears to reduce the risk of adverse events.

Eryaspase is currently under investigation in a phase 3 trial for acute lymphoblastic leukemia (ALL) and a phase 2b trial for AML in Europe. A phase 1 study in adult ALL is being launched in the US.

Eryaspase now has orphan designation for ALL, AML and pancreatic cancer, both in Europe and the US.

In the US, orphan designation is generally granted for drugs or biologics intended to treat disorders of high unmet medical need that affect fewer than 200,000 people.

This designation conveys special incentives to the product’s sponsor, including 7 years of US market exclusivity for the drug or biologic upon FDA approval, a prescription drug user fee waiver, and certain tax credits.

AML cells

The US Food and Drug Administration (FDA) has granted orphan designation for eryaspase to treat acute myeloid leukemia (AML).

Eryaspase, also known as ERY-ASP or GRASPA, is L-asparaginase encapsulated in red blood cells.

These donor-derived, enzyme-loaded red blood cells function as bioreactors to eliminate circulating asparagine and “starve”

leukemic cells, thereby inducing their death.

Research has suggested this delivery system provides improved pharmacodynamics. It protects L-aspariginase from circulating proteolytic enzymes and prevents early liver or renal clearance.

The system also appears to reduce the risk of adverse events.

Eryaspase is currently under investigation in a phase 3 trial for acute lymphoblastic leukemia (ALL) and a phase 2b trial for AML in Europe. A phase 1 study in adult ALL is being launched in the US.

Eryaspase now has orphan designation for ALL, AML and pancreatic cancer, both in Europe and the US.

In the US, orphan designation is generally granted for drugs or biologics intended to treat disorders of high unmet medical need that affect fewer than 200,000 people.

This designation conveys special incentives to the product’s sponsor, including 7 years of US market exclusivity for the drug or biologic upon FDA approval, a prescription drug user fee waiver, and certain tax credits.

Saline solution

In an attempt to alleviate the shortage of saline (0.9% sodium chloride injection) in the US, the Food and Drug Administration (FDA) is allowing saline products to be imported from Norway.

The company importing the products is Fresenius Kabi USA. The FDA inspected the company’s Norway manufacturing facility and found the site meets FDA standards.

So Fresenius Kabi has begun importing Sodium Chloride 0.9% Freeflex Injection Solution for Intravenous Infusion.

The European product contains the same active ingredient in the same concentration as the 0.9% sodium chloride injection products approved in the US.

For a complete list of all the Fresenius Kabi saline products, as well as a list of differences between the European and US prescribing information, see the “Dear Healthcare Professional” letter posted on the FDA website.

The FDA is asking that healthcare professionals contact Fresenius Kabi USA directly to obtain saline products. The company’s customer service number is 1-888-386-1300.

The FDA concedes that, while the shipments from Norway will help, they will not resolve the saline shortage. However, the agency says it is working closely with manufacturers to meet the needs for saline across the US.

Saline solution

In an attempt to alleviate the shortage of saline (0.9% sodium chloride injection) in the US, the Food and Drug Administration (FDA) is allowing saline products to be imported from Norway.

The company importing the products is Fresenius Kabi USA. The FDA inspected the company’s Norway manufacturing facility and found the site meets FDA standards.

So Fresenius Kabi has begun importing Sodium Chloride 0.9% Freeflex Injection Solution for Intravenous Infusion.

The European product contains the same active ingredient in the same concentration as the 0.9% sodium chloride injection products approved in the US.

For a complete list of all the Fresenius Kabi saline products, as well as a list of differences between the European and US prescribing information, see the “Dear Healthcare Professional” letter posted on the FDA website.

The FDA is asking that healthcare professionals contact Fresenius Kabi USA directly to obtain saline products. The company’s customer service number is 1-888-386-1300.

The FDA concedes that, while the shipments from Norway will help, they will not resolve the saline shortage. However, the agency says it is working closely with manufacturers to meet the needs for saline across the US.

Saline solution

In an attempt to alleviate the shortage of saline (0.9% sodium chloride injection) in the US, the Food and Drug Administration (FDA) is allowing saline products to be imported from Norway.

The company importing the products is Fresenius Kabi USA. The FDA inspected the company’s Norway manufacturing facility and found the site meets FDA standards.

So Fresenius Kabi has begun importing Sodium Chloride 0.9% Freeflex Injection Solution for Intravenous Infusion.

The European product contains the same active ingredient in the same concentration as the 0.9% sodium chloride injection products approved in the US.

For a complete list of all the Fresenius Kabi saline products, as well as a list of differences between the European and US prescribing information, see the “Dear Healthcare Professional” letter posted on the FDA website.

The FDA is asking that healthcare professionals contact Fresenius Kabi USA directly to obtain saline products. The company’s customer service number is 1-888-386-1300.

The FDA concedes that, while the shipments from Norway will help, they will not resolve the saline shortage. However, the agency says it is working closely with manufacturers to meet the needs for saline across the US.

 

 

Syringe

 

The European Commission (EC) has approved a subcutaneous (SC) formulation of rituximab (MabThera) to treat patients with follicular lymphoma or diffuse large B-cell lymphoma.

This formulation allows for 5-minute administration, a significant decrease over the 2.5-hour infusion time required to administer intravenous (IV) rituximab.

The drug’s maker, Roche, plans to begin launching SC rituximab in a number of European markets this year.

The EC’s approval of this formulation was primarily based on data from the SABRINA trial, which was recently published in The Lancet Oncology and funded by Roche.

In this phase 3 trial, researchers compared 3-week cycles of fixed-dose, SC rituximab to IV rituximab. They enrolled 127 patients with previously untreated, grade 1-3a, CD20-positive follicular lymphoma.

Patients were randomized to receive IV rituximab (375 mg/m²) or SC rituximab (1400 mg). After randomization, they received 1 induction dose of IV rituximab in cycle 1 and then their allocated treatment for cycles 2 through 8. Patients with a complete or partial response continued their treatment as maintenance every 8 weeks.

The study’s primary endpoint was the ratio of observed rituximab serum trough concentrations (C_trough) between the 2 groups at cycle 7.

Pharmacokinetic data were available for 75% of patients (48/64) in the IV arm and 86% of the patients (54/63) in the SC arm.

An analysis of these data suggested SC rituximab was non-inferior to the IV formulation. The geometric mean C_trough was 83.13 μg/mL in the IV arm and 134.58 μg/mL in the SC arm (ratio, 1.62).

The rate of adverse events was similar between the 2 arms, occurring in 88% (57/65) of patients in the IV arm and 92% (57/62) of patients in the SC arm. Grade 3 or higher adverse events occurred in 46% (n=30) and 47% (n=29) of patients, respectively.

The most common grade 3 or higher adverse event in both arms was neutropenia. It occurred in 22% (n=14) of patients in the IV arm and 26% (n=16) in the SC arm.

Adverse events related to administration were mostly grade 1-2. And they occurred more often in the SC arm than in the IV arm, in 50% (n=31) and 32% (n=21) of patients, respectively.

The researchers said these results suggest the SC formulation of rituximab is non-inferior to the IV formulation and poses no new safety concerns.

 

 

Syringe

 

The European Commission (EC) has approved a subcutaneous (SC) formulation of rituximab (MabThera) to treat patients with follicular lymphoma or diffuse large B-cell lymphoma.

This formulation allows for 5-minute administration, a significant decrease over the 2.5-hour infusion time required to administer intravenous (IV) rituximab.

The drug’s maker, Roche, plans to begin launching SC rituximab in a number of European markets this year.

The EC’s approval of this formulation was primarily based on data from the SABRINA trial, which was recently published in The Lancet Oncology and funded by Roche.

In this phase 3 trial, researchers compared 3-week cycles of fixed-dose, SC rituximab to IV rituximab. They enrolled 127 patients with previously untreated, grade 1-3a, CD20-positive follicular lymphoma.

Patients were randomized to receive IV rituximab (375 mg/m²) or SC rituximab (1400 mg). After randomization, they received 1 induction dose of IV rituximab in cycle 1 and then their allocated treatment for cycles 2 through 8. Patients with a complete or partial response continued their treatment as maintenance every 8 weeks.

The study’s primary endpoint was the ratio of observed rituximab serum trough concentrations (C_trough) between the 2 groups at cycle 7.

Pharmacokinetic data were available for 75% of patients (48/64) in the IV arm and 86% of the patients (54/63) in the SC arm.

An analysis of these data suggested SC rituximab was non-inferior to the IV formulation. The geometric mean C_trough was 83.13 μg/mL in the IV arm and 134.58 μg/mL in the SC arm (ratio, 1.62).

The rate of adverse events was similar between the 2 arms, occurring in 88% (57/65) of patients in the IV arm and 92% (57/62) of patients in the SC arm. Grade 3 or higher adverse events occurred in 46% (n=30) and 47% (n=29) of patients, respectively.

The most common grade 3 or higher adverse event in both arms was neutropenia. It occurred in 22% (n=14) of patients in the IV arm and 26% (n=16) in the SC arm.

Adverse events related to administration were mostly grade 1-2. And they occurred more often in the SC arm than in the IV arm, in 50% (n=31) and 32% (n=21) of patients, respectively.

The researchers said these results suggest the SC formulation of rituximab is non-inferior to the IV formulation and poses no new safety concerns.

 

 

Syringe

 

The European Commission (EC) has approved a subcutaneous (SC) formulation of rituximab (MabThera) to treat patients with follicular lymphoma or diffuse large B-cell lymphoma.

This formulation allows for 5-minute administration, a significant decrease over the 2.5-hour infusion time required to administer intravenous (IV) rituximab.

The drug’s maker, Roche, plans to begin launching SC rituximab in a number of European markets this year.

The EC’s approval of this formulation was primarily based on data from the SABRINA trial, which was recently published in The Lancet Oncology and funded by Roche.

In this phase 3 trial, researchers compared 3-week cycles of fixed-dose, SC rituximab to IV rituximab. They enrolled 127 patients with previously untreated, grade 1-3a, CD20-positive follicular lymphoma.

Patients were randomized to receive IV rituximab (375 mg/m²) or SC rituximab (1400 mg). After randomization, they received 1 induction dose of IV rituximab in cycle 1 and then their allocated treatment for cycles 2 through 8. Patients with a complete or partial response continued their treatment as maintenance every 8 weeks.

The study’s primary endpoint was the ratio of observed rituximab serum trough concentrations (C_trough) between the 2 groups at cycle 7.

Pharmacokinetic data were available for 75% of patients (48/64) in the IV arm and 86% of the patients (54/63) in the SC arm.

An analysis of these data suggested SC rituximab was non-inferior to the IV formulation. The geometric mean C_trough was 83.13 μg/mL in the IV arm and 134.58 μg/mL in the SC arm (ratio, 1.62).

The rate of adverse events was similar between the 2 arms, occurring in 88% (57/65) of patients in the IV arm and 92% (57/62) of patients in the SC arm. Grade 3 or higher adverse events occurred in 46% (n=30) and 47% (n=29) of patients, respectively.

The most common grade 3 or higher adverse event in both arms was neutropenia. It occurred in 22% (n=14) of patients in the IV arm and 26% (n=16) in the SC arm.

Adverse events related to administration were mostly grade 1-2. And they occurred more often in the SC arm than in the IV arm, in 50% (n=31) and 32% (n=21) of patients, respectively.

The researchers said these results suggest the SC formulation of rituximab is non-inferior to the IV formulation and poses no new safety concerns.

Vials and a syringe

The US Food and Drug Administration (FDA) has approved a recombinant factor IX Fc fusion protein  (rFIXFc, Alprolix) for use in adults and children with hemophilia B.

The product is intended to help control, prevent, or reduce the frequency of bleeding episodes that can occur day-to-day in patients with hemophilia B, as well as manage bleeding in patients undergoing surgery.

rFIXFc is made by fusing factor IX to the Fc portion of the IgG1 protein. Scientists believe this enables the product to use a naturally occurring pathway to prolong the time the therapy remains in the body.

The FDA’s approval is the second worldwide approval of rFIXFc. The product was recently authorized for use in Canada.

Researchers evaluated the safety, efficacy, and pharmacokinetics of rFIXFc in the phase 3 B-LONG study, which was funded by the product’s developers, Biogen Idec and Sobi.

Investigators tested rFIXFc in 123 males with hemophilia B who were at least 12 years of age. The patients were assigned to 1 of 4 treatment arms: weekly prophylaxis, individualized-interval prophylaxis, on-demand treatment to control bleeding, and perioperative management.

The overall median annualized bleeding rates were 2.95 for the weekly prophylaxis arm, 1.38 for the individualized-interval prophylaxis arm, and 17.69 in the on-demand treatment arm.

The overall median dosing interval with individualized-interval prophylaxis was 12.5 days. During the last 6 months of the study, the median dosing interval was 13.8 days.

Of the patients who received rFIXFc for perioperative management, 85.7% required a single injection of the product to maintain hemostasis during their operation. The median dose was 90.9 IU/kg per injection.

Most patients required 1 to 2 injections of the product the day before and the day of surgery. And most required 2 to 3 injections from days 1 to 3 after surgery.

The most common adverse events associated with rFIXFc (an incidence of ≥ 5% in a pooled analysis of treatment arms 1, 2, and 3) were nasopharyngitis, influenza, arthralgia, upper respiratory tract infection, hypertension, and headache.

The results of this study were released by Biogen Idec and Sobi in September 2012, presented at ISTH 2013, and published in NEJM in December 2013.

Vials and a syringe

The US Food and Drug Administration (FDA) has approved a recombinant factor IX Fc fusion protein  (rFIXFc, Alprolix) for use in adults and children with hemophilia B.

The product is intended to help control, prevent, or reduce the frequency of bleeding episodes that can occur day-to-day in patients with hemophilia B, as well as manage bleeding in patients undergoing surgery.

rFIXFc is made by fusing factor IX to the Fc portion of the IgG1 protein. Scientists believe this enables the product to use a naturally occurring pathway to prolong the time the therapy remains in the body.

The FDA’s approval is the second worldwide approval of rFIXFc. The product was recently authorized for use in Canada.

Researchers evaluated the safety, efficacy, and pharmacokinetics of rFIXFc in the phase 3 B-LONG study, which was funded by the product’s developers, Biogen Idec and Sobi.

Investigators tested rFIXFc in 123 males with hemophilia B who were at least 12 years of age. The patients were assigned to 1 of 4 treatment arms: weekly prophylaxis, individualized-interval prophylaxis, on-demand treatment to control bleeding, and perioperative management.

The overall median annualized bleeding rates were 2.95 for the weekly prophylaxis arm, 1.38 for the individualized-interval prophylaxis arm, and 17.69 in the on-demand treatment arm.

The overall median dosing interval with individualized-interval prophylaxis was 12.5 days. During the last 6 months of the study, the median dosing interval was 13.8 days.

Of the patients who received rFIXFc for perioperative management, 85.7% required a single injection of the product to maintain hemostasis during their operation. The median dose was 90.9 IU/kg per injection.

Most patients required 1 to 2 injections of the product the day before and the day of surgery. And most required 2 to 3 injections from days 1 to 3 after surgery.

The most common adverse events associated with rFIXFc (an incidence of ≥ 5% in a pooled analysis of treatment arms 1, 2, and 3) were nasopharyngitis, influenza, arthralgia, upper respiratory tract infection, hypertension, and headache.

The results of this study were released by Biogen Idec and Sobi in September 2012, presented at ISTH 2013, and published in NEJM in December 2013.

Vials and a syringe

The US Food and Drug Administration (FDA) has approved a recombinant factor IX Fc fusion protein  (rFIXFc, Alprolix) for use in adults and children with hemophilia B.

The product is intended to help control, prevent, or reduce the frequency of bleeding episodes that can occur day-to-day in patients with hemophilia B, as well as manage bleeding in patients undergoing surgery.

rFIXFc is made by fusing factor IX to the Fc portion of the IgG1 protein. Scientists believe this enables the product to use a naturally occurring pathway to prolong the time the therapy remains in the body.

The FDA’s approval is the second worldwide approval of rFIXFc. The product was recently authorized for use in Canada.

Researchers evaluated the safety, efficacy, and pharmacokinetics of rFIXFc in the phase 3 B-LONG study, which was funded by the product’s developers, Biogen Idec and Sobi.

Investigators tested rFIXFc in 123 males with hemophilia B who were at least 12 years of age. The patients were assigned to 1 of 4 treatment arms: weekly prophylaxis, individualized-interval prophylaxis, on-demand treatment to control bleeding, and perioperative management.

The overall median annualized bleeding rates were 2.95 for the weekly prophylaxis arm, 1.38 for the individualized-interval prophylaxis arm, and 17.69 in the on-demand treatment arm.

The overall median dosing interval with individualized-interval prophylaxis was 12.5 days. During the last 6 months of the study, the median dosing interval was 13.8 days.

Of the patients who received rFIXFc for perioperative management, 85.7% required a single injection of the product to maintain hemostasis during their operation. The median dose was 90.9 IU/kg per injection.

Most patients required 1 to 2 injections of the product the day before and the day of surgery. And most required 2 to 3 injections from days 1 to 3 after surgery.

The most common adverse events associated with rFIXFc (an incidence of ≥ 5% in a pooled analysis of treatment arms 1, 2, and 3) were nasopharyngitis, influenza, arthralgia, upper respiratory tract infection, hypertension, and headache.

The results of this study were released by Biogen Idec and Sobi in September 2012, presented at ISTH 2013, and published in NEJM in December 2013.

Red blood cells

Health Canada has approved a recombinant factor IX Fc fusion protein (rFIXFc, Alprolix), for adults and children aged 12 and older with hemophilia B.

The product is intended to prevent or reduce the frequency of bleeding episodes via prophylactic infusions, starting at once weekly or once every 10 to 14 days.

This is the first regulatory approval of rFIXFc, which is under review by regulatory authorities in several other countries.

Health Canada’s approval of the product is based on results from the phase 3 B-LONG study, which was funded by Biogen Idec and Sobi, the companies developing rFIXFc.

Results of the B-LONG study

In this multicenter, open-label trial, researchers evaluated the efficacy, safety, and pharmacokinetics of rFIXFc in 123 males aged 12 years and older with hemophilia B.

Patients were assigned to 1 of 4 treatment arms: weekly prophylaxis, individualized-interval prophylaxis, on-demand treatment to control bleeding, and perioperative management.

The overall median annualized bleeding rates were 2.95 for the weekly prophylaxis arm, 1.38 for the individualized-interval prophylaxis arm, and 17.69 in the on-demand treatment arm.

The overall median dosing interval with individualized-interval prophylaxis was 12.5 days. During the last 6 months of the study, the median dosing interval was 13.8 days.

Of the patients who received rFIXFc for perioperative management, 85.7% required a single injection of the product to maintain hemostasis during their operation. The median dose was 90.9 IU/kg per injection.

Most patients required 1 to 2 injections of the product the day before and the day of surgery. And most required 2 to 3 injections from days 1 to 3 after surgery.

The most common adverse events associated with rFIXFc (incidence of ≥ 5% in a pooled analysis of treatment arms 1, 2, and 3) were nasopharyngitis, influenza, arthralgia, upper respiratory tract infection, hypertension, and headache.

Results of this study were released by Biogen Idec and Sobi in September 2012, presented at ISTH 2013, and published in NEJM in December 2013.

Red blood cells

Health Canada has approved a recombinant factor IX Fc fusion protein (rFIXFc, Alprolix), for adults and children aged 12 and older with hemophilia B.

The product is intended to prevent or reduce the frequency of bleeding episodes via prophylactic infusions, starting at once weekly or once every 10 to 14 days.

This is the first regulatory approval of rFIXFc, which is under review by regulatory authorities in several other countries.

Health Canada’s approval of the product is based on results from the phase 3 B-LONG study, which was funded by Biogen Idec and Sobi, the companies developing rFIXFc.

Results of the B-LONG study

In this multicenter, open-label trial, researchers evaluated the efficacy, safety, and pharmacokinetics of rFIXFc in 123 males aged 12 years and older with hemophilia B.

Patients were assigned to 1 of 4 treatment arms: weekly prophylaxis, individualized-interval prophylaxis, on-demand treatment to control bleeding, and perioperative management.

The overall median annualized bleeding rates were 2.95 for the weekly prophylaxis arm, 1.38 for the individualized-interval prophylaxis arm, and 17.69 in the on-demand treatment arm.

The overall median dosing interval with individualized-interval prophylaxis was 12.5 days. During the last 6 months of the study, the median dosing interval was 13.8 days.

Of the patients who received rFIXFc for perioperative management, 85.7% required a single injection of the product to maintain hemostasis during their operation. The median dose was 90.9 IU/kg per injection.

Most patients required 1 to 2 injections of the product the day before and the day of surgery. And most required 2 to 3 injections from days 1 to 3 after surgery.

The most common adverse events associated with rFIXFc (incidence of ≥ 5% in a pooled analysis of treatment arms 1, 2, and 3) were nasopharyngitis, influenza, arthralgia, upper respiratory tract infection, hypertension, and headache.

Results of this study were released by Biogen Idec and Sobi in September 2012, presented at ISTH 2013, and published in NEJM in December 2013.

Red blood cells

Health Canada has approved a recombinant factor IX Fc fusion protein (rFIXFc, Alprolix), for adults and children aged 12 and older with hemophilia B.

The product is intended to prevent or reduce the frequency of bleeding episodes via prophylactic infusions, starting at once weekly or once every 10 to 14 days.

This is the first regulatory approval of rFIXFc, which is under review by regulatory authorities in several other countries.

Health Canada’s approval of the product is based on results from the phase 3 B-LONG study, which was funded by Biogen Idec and Sobi, the companies developing rFIXFc.

Results of the B-LONG study

In this multicenter, open-label trial, researchers evaluated the efficacy, safety, and pharmacokinetics of rFIXFc in 123 males aged 12 years and older with hemophilia B.

Patients were assigned to 1 of 4 treatment arms: weekly prophylaxis, individualized-interval prophylaxis, on-demand treatment to control bleeding, and perioperative management.

The overall median annualized bleeding rates were 2.95 for the weekly prophylaxis arm, 1.38 for the individualized-interval prophylaxis arm, and 17.69 in the on-demand treatment arm.

The overall median dosing interval with individualized-interval prophylaxis was 12.5 days. During the last 6 months of the study, the median dosing interval was 13.8 days.

Of the patients who received rFIXFc for perioperative management, 85.7% required a single injection of the product to maintain hemostasis during their operation. The median dose was 90.9 IU/kg per injection.

Most patients required 1 to 2 injections of the product the day before and the day of surgery. And most required 2 to 3 injections from days 1 to 3 after surgery.

The most common adverse events associated with rFIXFc (incidence of ≥ 5% in a pooled analysis of treatment arms 1, 2, and 3) were nasopharyngitis, influenza, arthralgia, upper respiratory tract infection, hypertension, and headache.

Results of this study were released by Biogen Idec and Sobi in September 2012, presented at ISTH 2013, and published in NEJM in December 2013.