Pharmacy

Photo courtesy of Amgen

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has released 2 new opinions regarding blinatumomab (Blincyto).

The CHMP recommended expanding the approved use of blinatumomab to include pediatric patients, but the committee also recommended against approving blinatumomab to treat patients with minimal residual disease (MRD).

Blinatumomab is already approved by the European Commission (EC) as monotherapy for adults with Philadelphia chromosome-negative (Ph-), CD19-positive, relapsed or refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL).

Now, the CHMP has recommended expanding this use to include blinatumomab as monotherapy for patients age 1 and older with Ph-, CD19-positive, relapsed/refractory BCP-ALL. These patients must have at least 2 prior therapies or have relapsed after allogeneic hematopoietic stem cell transplant.

This recommendation was supported by data from Study ‘205. Results from this phase 1/2 study were published in the Journal of Clinical Oncology in 2016.

The CHMP has also recommended against approving blinatumomab to treat BCP-ALL patients with MRD.

This decision was influenced by data from the BLAST study. Results from this phase 2 study were published in Blood earlier this year.

The CHMP noted that, although blinatumomab helped clear away residual cells in many patients in the BLAST trial, there is no strong evidence that this leads to improved survival.

Given the uncertainty, the CHMP was of the opinion that the benefits of blinatumomab do not outweigh its risks in MRD-positive BCP-ALL patients.

Amgen, the company developing and marketing blinatumomab, can request a re-examination of the CHMP’s opinion within 15 days of receiving it.

The CHMP’s recommendations are reviewed by the EC, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.

The EC usually makes a decision within 67 days of CHMP recommendations.

Photo courtesy of Amgen

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has released 2 new opinions regarding blinatumomab (Blincyto).

The CHMP recommended expanding the approved use of blinatumomab to include pediatric patients, but the committee also recommended against approving blinatumomab to treat patients with minimal residual disease (MRD).

Blinatumomab is already approved by the European Commission (EC) as monotherapy for adults with Philadelphia chromosome-negative (Ph-), CD19-positive, relapsed or refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL).

Now, the CHMP has recommended expanding this use to include blinatumomab as monotherapy for patients age 1 and older with Ph-, CD19-positive, relapsed/refractory BCP-ALL. These patients must have at least 2 prior therapies or have relapsed after allogeneic hematopoietic stem cell transplant.

This recommendation was supported by data from Study ‘205. Results from this phase 1/2 study were published in the Journal of Clinical Oncology in 2016.

The CHMP has also recommended against approving blinatumomab to treat BCP-ALL patients with MRD.

This decision was influenced by data from the BLAST study. Results from this phase 2 study were published in Blood earlier this year.

The CHMP noted that, although blinatumomab helped clear away residual cells in many patients in the BLAST trial, there is no strong evidence that this leads to improved survival.

Given the uncertainty, the CHMP was of the opinion that the benefits of blinatumomab do not outweigh its risks in MRD-positive BCP-ALL patients.

Amgen, the company developing and marketing blinatumomab, can request a re-examination of the CHMP’s opinion within 15 days of receiving it.

The CHMP’s recommendations are reviewed by the EC, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.

The EC usually makes a decision within 67 days of CHMP recommendations.

Photo courtesy of Amgen

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has released 2 new opinions regarding blinatumomab (Blincyto).

The CHMP recommended expanding the approved use of blinatumomab to include pediatric patients, but the committee also recommended against approving blinatumomab to treat patients with minimal residual disease (MRD).

Blinatumomab is already approved by the European Commission (EC) as monotherapy for adults with Philadelphia chromosome-negative (Ph-), CD19-positive, relapsed or refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL).

Now, the CHMP has recommended expanding this use to include blinatumomab as monotherapy for patients age 1 and older with Ph-, CD19-positive, relapsed/refractory BCP-ALL. These patients must have at least 2 prior therapies or have relapsed after allogeneic hematopoietic stem cell transplant.

This recommendation was supported by data from Study ‘205. Results from this phase 1/2 study were published in the Journal of Clinical Oncology in 2016.

The CHMP has also recommended against approving blinatumomab to treat BCP-ALL patients with MRD.

This decision was influenced by data from the BLAST study. Results from this phase 2 study were published in Blood earlier this year.

The CHMP noted that, although blinatumomab helped clear away residual cells in many patients in the BLAST trial, there is no strong evidence that this leads to improved survival.

Given the uncertainty, the CHMP was of the opinion that the benefits of blinatumomab do not outweigh its risks in MRD-positive BCP-ALL patients.

Amgen, the company developing and marketing blinatumomab, can request a re-examination of the CHMP’s opinion within 15 days of receiving it.

The CHMP’s recommendations are reviewed by the EC, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.

The EC usually makes a decision within 67 days of CHMP recommendations.

Red blood cells

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended a change to the terms of marketing authorization for 3 versions of epoetin alfa—Abseamed, Binocrit, and Epoetin alfa Hexal.

The CHMP is recommending that all 3 products be approved to treat symptomatic anemia (hemoglobin concentration of ≤ 10 g/dL) in adults with low- or intermediate-1-risk primary myelodysplastic syndromes who have low serum erythropoietin (< 200 mU/mL).

The CHMP’s recommendation will be reviewed by the European Commission (EC), which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.

The EC usually makes a decision within 67 days of the CHMP’s recommendation.

Abseamed, Binocrit, and Epoetin alfa Hexal are already EC-approved for the following indications:

• To treat symptomatic anemia associated with chronic renal failure in adults and children ages 1 to 18 on hemodialysis and adults on peritoneal dialysis
• To treat symptomatic anemia associated with chronic renal failure in adults with renal insufficiency not yet undergoing dialysis for the treatment of severe anemia of renal origin accompanied by clinical symptoms in patients
• For adults receiving chemotherapy for solid tumors, malignant lymphoma, or multiple myeloma who are at risk of transfusion as assessed by the patient’s general status (eg, cardiovascular status, pre-existing anemia at the start of chemotherapy) for the treatment of anemia and reduction of transfusion requirements
• For adults in a predonation program to increase the yield of autologous blood; treatment should only be given to patients with moderate anemia (hemoglobin concentration range between 10 to 13 g/dL [6.2 to 8.1 mmol/L], no iron deficiency) if blood-saving procedures are not available or insufficient when the scheduled major elective surgery requires a large volume of blood (4 or more units for females or 5 or more units for males)
• For non-iron-deficient adults set to undergo major elective orthopedic surgery who have a high perceived risk for transfusion complications to reduce exposure to allogeneic blood transfusions; use should be restricted to patients with moderate anemia (eg, hemoglobin concentration range between 10 to 13 g/dL or 6.2 to 8.1 mmol/L) who do not have an autologous predonation program available and with expected moderate blood loss (900 to 1800 mL).

The marketing authorization holders are Medice Arzneimittel Pütter GmbH & Co. KG for Abseamed, Sandoz GmbH for Binocrit, and Hexal AG for Epoetin alfa Hexal.

Red blood cells

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended a change to the terms of marketing authorization for 3 versions of epoetin alfa—Abseamed, Binocrit, and Epoetin alfa Hexal.

The CHMP is recommending that all 3 products be approved to treat symptomatic anemia (hemoglobin concentration of ≤ 10 g/dL) in adults with low- or intermediate-1-risk primary myelodysplastic syndromes who have low serum erythropoietin (< 200 mU/mL).

The CHMP’s recommendation will be reviewed by the European Commission (EC), which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.

The EC usually makes a decision within 67 days of the CHMP’s recommendation.

Abseamed, Binocrit, and Epoetin alfa Hexal are already EC-approved for the following indications:

• To treat symptomatic anemia associated with chronic renal failure in adults and children ages 1 to 18 on hemodialysis and adults on peritoneal dialysis
• To treat symptomatic anemia associated with chronic renal failure in adults with renal insufficiency not yet undergoing dialysis for the treatment of severe anemia of renal origin accompanied by clinical symptoms in patients
• For adults receiving chemotherapy for solid tumors, malignant lymphoma, or multiple myeloma who are at risk of transfusion as assessed by the patient’s general status (eg, cardiovascular status, pre-existing anemia at the start of chemotherapy) for the treatment of anemia and reduction of transfusion requirements
• For adults in a predonation program to increase the yield of autologous blood; treatment should only be given to patients with moderate anemia (hemoglobin concentration range between 10 to 13 g/dL [6.2 to 8.1 mmol/L], no iron deficiency) if blood-saving procedures are not available or insufficient when the scheduled major elective surgery requires a large volume of blood (4 or more units for females or 5 or more units for males)
• For non-iron-deficient adults set to undergo major elective orthopedic surgery who have a high perceived risk for transfusion complications to reduce exposure to allogeneic blood transfusions; use should be restricted to patients with moderate anemia (eg, hemoglobin concentration range between 10 to 13 g/dL or 6.2 to 8.1 mmol/L) who do not have an autologous predonation program available and with expected moderate blood loss (900 to 1800 mL).

The marketing authorization holders are Medice Arzneimittel Pütter GmbH & Co. KG for Abseamed, Sandoz GmbH for Binocrit, and Hexal AG for Epoetin alfa Hexal.

Red blood cells

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended a change to the terms of marketing authorization for 3 versions of epoetin alfa—Abseamed, Binocrit, and Epoetin alfa Hexal.

The CHMP is recommending that all 3 products be approved to treat symptomatic anemia (hemoglobin concentration of ≤ 10 g/dL) in adults with low- or intermediate-1-risk primary myelodysplastic syndromes who have low serum erythropoietin (< 200 mU/mL).

The CHMP’s recommendation will be reviewed by the European Commission (EC), which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.

The EC usually makes a decision within 67 days of the CHMP’s recommendation.

Abseamed, Binocrit, and Epoetin alfa Hexal are already EC-approved for the following indications:

• To treat symptomatic anemia associated with chronic renal failure in adults and children ages 1 to 18 on hemodialysis and adults on peritoneal dialysis
• To treat symptomatic anemia associated with chronic renal failure in adults with renal insufficiency not yet undergoing dialysis for the treatment of severe anemia of renal origin accompanied by clinical symptoms in patients
• For adults receiving chemotherapy for solid tumors, malignant lymphoma, or multiple myeloma who are at risk of transfusion as assessed by the patient’s general status (eg, cardiovascular status, pre-existing anemia at the start of chemotherapy) for the treatment of anemia and reduction of transfusion requirements
• For adults in a predonation program to increase the yield of autologous blood; treatment should only be given to patients with moderate anemia (hemoglobin concentration range between 10 to 13 g/dL [6.2 to 8.1 mmol/L], no iron deficiency) if blood-saving procedures are not available or insufficient when the scheduled major elective surgery requires a large volume of blood (4 or more units for females or 5 or more units for males)
• For non-iron-deficient adults set to undergo major elective orthopedic surgery who have a high perceived risk for transfusion complications to reduce exposure to allogeneic blood transfusions; use should be restricted to patients with moderate anemia (eg, hemoglobin concentration range between 10 to 13 g/dL or 6.2 to 8.1 mmol/L) who do not have an autologous predonation program available and with expected moderate blood loss (900 to 1800 mL).

The marketing authorization holders are Medice Arzneimittel Pütter GmbH & Co. KG for Abseamed, Sandoz GmbH for Binocrit, and Hexal AG for Epoetin alfa Hexal.

Photo from Amgen

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for 2 pegfilgrastim biosimilar candidates—Udenyca and Pelgraz.

Both products have been deemed highly similar to the reference product, Neulasta, a growth-colony-stimulating factor intended to reduce the duration of neutropenia and the incidence of febrile neutropenia due to chemotherapy.

The CHMP’s recommendations for Pelgraz and Udenyca will be reviewed by the European Commission, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.

The European Commission usually makes a decision within 67 days of the CHMP’s recommendation.

If approved, Udenyca and Pelgraz will be available as 6 mg solutions for injection.

The full indication for both products will be to reduce the duration of neutropenia and the incidence of febrile neutropenia in adults receiving cytotoxic chemotherapy for malignancies, except chronic myeloid leukemia and myelodysplastic syndromes.

The CHMP said data have shown that Pelgraz and Udenyca both have comparable quality, safety, and efficacy to Neulasta.

Pelgraz’s marketing authorization application is supported by data from a phase 1 pharmacokinetic (PK) and pharmacodynamic (PD) study in healthy volunteers and a phase 3 study of breast cancer patients receiving docetaxel, doxorubicin, and cyclophosphamide.

Results from the phase 1 study were published in Clinical Pharmacology in Drug Development in 2016.

Udenyca’s marketing authorization application is supported by data from an immunogenicity study as well as a PK/PD study comparing Udenyca (formerly CHS-1701) and Neulasta in healthy subjects.

Results from the PK/PD trial were presented at the 2017 ASCO Annual Meeting.

The applicant for Udenyca is ERA Consulting GmbH. The applicant for Pelgraz is Accord Healthcare Limited (the international arm of Intas Pharmaceuticals Ltd).

Photo from Amgen

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for 2 pegfilgrastim biosimilar candidates—Udenyca and Pelgraz.

Both products have been deemed highly similar to the reference product, Neulasta, a growth-colony-stimulating factor intended to reduce the duration of neutropenia and the incidence of febrile neutropenia due to chemotherapy.

The CHMP’s recommendations for Pelgraz and Udenyca will be reviewed by the European Commission, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.

The European Commission usually makes a decision within 67 days of the CHMP’s recommendation.

If approved, Udenyca and Pelgraz will be available as 6 mg solutions for injection.

The full indication for both products will be to reduce the duration of neutropenia and the incidence of febrile neutropenia in adults receiving cytotoxic chemotherapy for malignancies, except chronic myeloid leukemia and myelodysplastic syndromes.

The CHMP said data have shown that Pelgraz and Udenyca both have comparable quality, safety, and efficacy to Neulasta.

Pelgraz’s marketing authorization application is supported by data from a phase 1 pharmacokinetic (PK) and pharmacodynamic (PD) study in healthy volunteers and a phase 3 study of breast cancer patients receiving docetaxel, doxorubicin, and cyclophosphamide.

Results from the phase 1 study were published in Clinical Pharmacology in Drug Development in 2016.

Udenyca’s marketing authorization application is supported by data from an immunogenicity study as well as a PK/PD study comparing Udenyca (formerly CHS-1701) and Neulasta in healthy subjects.

Results from the PK/PD trial were presented at the 2017 ASCO Annual Meeting.

The applicant for Udenyca is ERA Consulting GmbH. The applicant for Pelgraz is Accord Healthcare Limited (the international arm of Intas Pharmaceuticals Ltd).

Photo from Amgen

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for 2 pegfilgrastim biosimilar candidates—Udenyca and Pelgraz.

Both products have been deemed highly similar to the reference product, Neulasta, a growth-colony-stimulating factor intended to reduce the duration of neutropenia and the incidence of febrile neutropenia due to chemotherapy.

The CHMP’s recommendations for Pelgraz and Udenyca will be reviewed by the European Commission, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.

The European Commission usually makes a decision within 67 days of the CHMP’s recommendation.

If approved, Udenyca and Pelgraz will be available as 6 mg solutions for injection.

The full indication for both products will be to reduce the duration of neutropenia and the incidence of febrile neutropenia in adults receiving cytotoxic chemotherapy for malignancies, except chronic myeloid leukemia and myelodysplastic syndromes.

The CHMP said data have shown that Pelgraz and Udenyca both have comparable quality, safety, and efficacy to Neulasta.

Pelgraz’s marketing authorization application is supported by data from a phase 1 pharmacokinetic (PK) and pharmacodynamic (PD) study in healthy volunteers and a phase 3 study of breast cancer patients receiving docetaxel, doxorubicin, and cyclophosphamide.

Results from the phase 1 study were published in Clinical Pharmacology in Drug Development in 2016.

Udenyca’s marketing authorization application is supported by data from an immunogenicity study as well as a PK/PD study comparing Udenyca (formerly CHS-1701) and Neulasta in healthy subjects.

Results from the PK/PD trial were presented at the 2017 ASCO Annual Meeting.

The applicant for Udenyca is ERA Consulting GmbH. The applicant for Pelgraz is Accord Healthcare Limited (the international arm of Intas Pharmaceuticals Ltd).

Image by Andre E.X. Brown

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has reiterated its negative opinion of betrixaban.

Once again, the CHMP has concluded that it cannot recommend approval of betrixaban for the prevention of venous thromboembolism (VTE) in adults hospitalized for an acute medical illness with risk factors for VTE, including VTE-related death.

The CHMP previously issued a negative opinion of betrixaban in March, but Portola Pharmaceuticals, Inc., requested a re-examination of that opinion.

The CHMP agreed to re-examine the opinion and confirmed the refusal of the marketing authorization on July 26.

The marketing authorization application for betrixaban was supported by data from the phase 3 APEX study. In this trial, researchers compared oral betrixaban to injectable enoxaparin for the prevention of VTE in patients with acute medical illnesses.

The CHMP said APEX did not satisfactorily show betrixaban’s effectiveness when used for preventing VTE in patients admitted to the hospital for recent medical illness.

In addition, patients treated with betrixaban had more episodes of bleeding than patients who received enoxaparin.

The CHMP said the excess bleeding was an important concern because betrixaban was expected to be used in patients with serious underlying conditions for whom any episode of bleeding could have serious consequences, and betrixaban’s long persistence in the body could complicate management of bleeding.

Overall, the CHMP said the benefits of betrixaban did not outweigh its risks.

Portola said this decision will not affect patients currently enrolled in clinical trials of betrixaban.

The company also said it will continue working with regulatory authorities in countries outside the European Union to potentially bring betrixaban to patients as quickly as possible.

“We are disappointed by the committee’s assessment given both the unmet need and the clinically meaningful outcomes of the APEX trial in reducing VTE and VTE-related deaths in a vulnerable patient population,” said John T. Curnutte, MD, PhD, interim co-president and head of research and development for Portola.

“We remain confident in the potential public health impact of betrixaban and will maintain focus on the US commercial launch as we continue to work toward our goal of expanding patient access to betrixaban around the world.”

Betrixaban was approved in the US in June 2017 under the trade name Bevyxxa.

Image by Andre E.X. Brown

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has reiterated its negative opinion of betrixaban.

Once again, the CHMP has concluded that it cannot recommend approval of betrixaban for the prevention of venous thromboembolism (VTE) in adults hospitalized for an acute medical illness with risk factors for VTE, including VTE-related death.

The CHMP previously issued a negative opinion of betrixaban in March, but Portola Pharmaceuticals, Inc., requested a re-examination of that opinion.

The CHMP agreed to re-examine the opinion and confirmed the refusal of the marketing authorization on July 26.

The marketing authorization application for betrixaban was supported by data from the phase 3 APEX study. In this trial, researchers compared oral betrixaban to injectable enoxaparin for the prevention of VTE in patients with acute medical illnesses.

The CHMP said APEX did not satisfactorily show betrixaban’s effectiveness when used for preventing VTE in patients admitted to the hospital for recent medical illness.

In addition, patients treated with betrixaban had more episodes of bleeding than patients who received enoxaparin.

The CHMP said the excess bleeding was an important concern because betrixaban was expected to be used in patients with serious underlying conditions for whom any episode of bleeding could have serious consequences, and betrixaban’s long persistence in the body could complicate management of bleeding.

Overall, the CHMP said the benefits of betrixaban did not outweigh its risks.

Portola said this decision will not affect patients currently enrolled in clinical trials of betrixaban.

The company also said it will continue working with regulatory authorities in countries outside the European Union to potentially bring betrixaban to patients as quickly as possible.

“We are disappointed by the committee’s assessment given both the unmet need and the clinically meaningful outcomes of the APEX trial in reducing VTE and VTE-related deaths in a vulnerable patient population,” said John T. Curnutte, MD, PhD, interim co-president and head of research and development for Portola.

“We remain confident in the potential public health impact of betrixaban and will maintain focus on the US commercial launch as we continue to work toward our goal of expanding patient access to betrixaban around the world.”

Betrixaban was approved in the US in June 2017 under the trade name Bevyxxa.

Image by Andre E.X. Brown

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has reiterated its negative opinion of betrixaban.

Once again, the CHMP has concluded that it cannot recommend approval of betrixaban for the prevention of venous thromboembolism (VTE) in adults hospitalized for an acute medical illness with risk factors for VTE, including VTE-related death.

The CHMP previously issued a negative opinion of betrixaban in March, but Portola Pharmaceuticals, Inc., requested a re-examination of that opinion.

The CHMP agreed to re-examine the opinion and confirmed the refusal of the marketing authorization on July 26.

The marketing authorization application for betrixaban was supported by data from the phase 3 APEX study. In this trial, researchers compared oral betrixaban to injectable enoxaparin for the prevention of VTE in patients with acute medical illnesses.

The CHMP said APEX did not satisfactorily show betrixaban’s effectiveness when used for preventing VTE in patients admitted to the hospital for recent medical illness.

In addition, patients treated with betrixaban had more episodes of bleeding than patients who received enoxaparin.

The CHMP said the excess bleeding was an important concern because betrixaban was expected to be used in patients with serious underlying conditions for whom any episode of bleeding could have serious consequences, and betrixaban’s long persistence in the body could complicate management of bleeding.

Overall, the CHMP said the benefits of betrixaban did not outweigh its risks.

Portola said this decision will not affect patients currently enrolled in clinical trials of betrixaban.

The company also said it will continue working with regulatory authorities in countries outside the European Union to potentially bring betrixaban to patients as quickly as possible.

“We are disappointed by the committee’s assessment given both the unmet need and the clinically meaningful outcomes of the APEX trial in reducing VTE and VTE-related deaths in a vulnerable patient population,” said John T. Curnutte, MD, PhD, interim co-president and head of research and development for Portola.

“We remain confident in the potential public health impact of betrixaban and will maintain focus on the US commercial launch as we continue to work toward our goal of expanding patient access to betrixaban around the world.”

Betrixaban was approved in the US in June 2017 under the trade name Bevyxxa.

Photo courtesy of the CDC

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended a new indication for rivaroxaban (Xarelto) 2.5 mg tablets.

The recommendation is for rivaroxaban co-administered with acetylsalicylic acid (ASA) for the prevention of atherothrombotic events in adults with coronary artery disease or symptomatic peripheral artery disease at high risk of ischemic events.

The CHMP’s recommendation will be reviewed by the European Commission (EC), which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.

The EC usually makes a decision within 67 days of the CHMP’s recommendation.

Rivaroxaban is already EC-approved for use in combination with ASA alone or ASA plus clopidogrel or ticlopidine for the prevention of atherothrombotic events in adults with acute coronary syndrome and elevated cardiac biomarkers.

The CHMP’s positive opinion for rivaroxaban in coronary artery disease and symptomatic peripheral artery disease is based on data from the COMPASS study. Results from this study were presented at ESC Congress 2017 and published simultaneously in NEJM.

COMPASS enrolled 27,395 patients with stable atherosclerotic vascular disease. They were randomized to receive rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily), rivaroxaban alone (5 mg twice daily), or aspirin alone (100 mg once daily).

The study’s primary outcome was a composite of cardiovascular death, stroke, or myocardial infarction. This outcome occurred in 4.1% of patients in the rivaroxaban-aspirin arm, 4.9% of those in the rivaroxaban-alone arm, and 5.4% of those in the aspirin-alone arm.

There was a significant difference in the primary outcome between the rivaroxaban-aspirin arm and the aspirin-alone arm (P<0.001) but not between the rivaroxaban-alone arm and the aspirin-alone arm (P=0.12).

The incidence of major bleeding was 3.1% in the rivaroxaban-aspirin arm, 2.8% in the rivaroxaban-alone arm, and 1.9% in the aspirin-alone arm.

There was a significant difference in major bleeding between the rivaroxaban-aspirin arm and the aspirin-alone arm (P<0.001) as well as between the rivaroxaban-alone arm and the aspirin-alone arm (P<0.001).

Photo courtesy of the CDC

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended a new indication for rivaroxaban (Xarelto) 2.5 mg tablets.

The recommendation is for rivaroxaban co-administered with acetylsalicylic acid (ASA) for the prevention of atherothrombotic events in adults with coronary artery disease or symptomatic peripheral artery disease at high risk of ischemic events.

The CHMP’s recommendation will be reviewed by the European Commission (EC), which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.

The EC usually makes a decision within 67 days of the CHMP’s recommendation.

Rivaroxaban is already EC-approved for use in combination with ASA alone or ASA plus clopidogrel or ticlopidine for the prevention of atherothrombotic events in adults with acute coronary syndrome and elevated cardiac biomarkers.

The CHMP’s positive opinion for rivaroxaban in coronary artery disease and symptomatic peripheral artery disease is based on data from the COMPASS study. Results from this study were presented at ESC Congress 2017 and published simultaneously in NEJM.

COMPASS enrolled 27,395 patients with stable atherosclerotic vascular disease. They were randomized to receive rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily), rivaroxaban alone (5 mg twice daily), or aspirin alone (100 mg once daily).

The study’s primary outcome was a composite of cardiovascular death, stroke, or myocardial infarction. This outcome occurred in 4.1% of patients in the rivaroxaban-aspirin arm, 4.9% of those in the rivaroxaban-alone arm, and 5.4% of those in the aspirin-alone arm.

There was a significant difference in the primary outcome between the rivaroxaban-aspirin arm and the aspirin-alone arm (P<0.001) but not between the rivaroxaban-alone arm and the aspirin-alone arm (P=0.12).

The incidence of major bleeding was 3.1% in the rivaroxaban-aspirin arm, 2.8% in the rivaroxaban-alone arm, and 1.9% in the aspirin-alone arm.

There was a significant difference in major bleeding between the rivaroxaban-aspirin arm and the aspirin-alone arm (P<0.001) as well as between the rivaroxaban-alone arm and the aspirin-alone arm (P<0.001).

Photo courtesy of the CDC

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended a new indication for rivaroxaban (Xarelto) 2.5 mg tablets.

The recommendation is for rivaroxaban co-administered with acetylsalicylic acid (ASA) for the prevention of atherothrombotic events in adults with coronary artery disease or symptomatic peripheral artery disease at high risk of ischemic events.

The CHMP’s recommendation will be reviewed by the European Commission (EC), which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.

The EC usually makes a decision within 67 days of the CHMP’s recommendation.

Rivaroxaban is already EC-approved for use in combination with ASA alone or ASA plus clopidogrel or ticlopidine for the prevention of atherothrombotic events in adults with acute coronary syndrome and elevated cardiac biomarkers.

The CHMP’s positive opinion for rivaroxaban in coronary artery disease and symptomatic peripheral artery disease is based on data from the COMPASS study. Results from this study were presented at ESC Congress 2017 and published simultaneously in NEJM.

COMPASS enrolled 27,395 patients with stable atherosclerotic vascular disease. They were randomized to receive rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily), rivaroxaban alone (5 mg twice daily), or aspirin alone (100 mg once daily).

The study’s primary outcome was a composite of cardiovascular death, stroke, or myocardial infarction. This outcome occurred in 4.1% of patients in the rivaroxaban-aspirin arm, 4.9% of those in the rivaroxaban-alone arm, and 5.4% of those in the aspirin-alone arm.

There was a significant difference in the primary outcome between the rivaroxaban-aspirin arm and the aspirin-alone arm (P<0.001) but not between the rivaroxaban-alone arm and the aspirin-alone arm (P=0.12).

The incidence of major bleeding was 3.1% in the rivaroxaban-aspirin arm, 2.8% in the rivaroxaban-alone arm, and 1.9% in the aspirin-alone arm.

There was a significant difference in major bleeding between the rivaroxaban-aspirin arm and the aspirin-alone arm (P<0.001) as well as between the rivaroxaban-alone arm and the aspirin-alone arm (P<0.001).

Agios Pharmaceuticals

The US Food and Drug Administration (FDA) has granted full approval for the isocitrate dehydrogenase-1 (IDH1) inhibitor ivosidenib (Tibsovo®).

The drug is approved to treat adults with relapsed or refractory acute myeloid leukemia (AML) who have an IDH1 mutation, as detected by an FDA-approved test.

Ivosidenib was approved concurrently with the RealTime IDH1 Assay, a companion diagnostic that can detect IDH1 mutation.

The FDA granted approval of ivosidenib to Agios Pharmaceuticals, Inc., and approval of the RealTime IDH1 Assay to Abbott Laboratories.

The FDA’s approval of ivosidenib was based on data from a single-arm, phase 1 study. Agios received fast track, priority review, and orphan drug designations for ivosidenib.

Safety risks

Ivosidenib must be dispensed with a patient medication guide that describes important information about the drug’s uses and risks.

The prescribing information for ivosidenib includes a Boxed Warning noting that patients treated with ivosidenib have experienced symptoms of differentiation syndrome, which can be fatal if not treated.

Signs and symptoms of differentiation syndrome may include fever, dyspnea, acute respiratory distress, radiographic pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain, peripheral edema, or hepatic, renal, or multi-organ dysfunction.

At first suspicion of symptoms, doctors should treat patients with corticosteroids and monitor them closely until symptoms subside.

Ivosidenib also poses a risk of life-threatening QT prolongation and Guillain-Barré syndrome, so patients should be monitored for these adverse events (AEs) as well.

Phase 1 trial

Results from the phase 1 trial of ivosidenib were presented at the 2018 ASCO Annual Meeting and published simultaneously in NEJM. The following data were pulled from the drug’s prescribing information.

Efficacy results were available for 174 adults with relapsed/refractory AML and an IDH1 mutation identified or confirmed by the Abbott RealTime™ IDH1 assay. The patients received ivosidenib at a starting dose of 500 mg daily until disease progression, unacceptable toxicity, or hematopoietic stem cell transplant.

The patients had a median age of 67 (range, 18 to 87) and had received a median of 2 prior therapies (range, 1 to 6). Sixty-three percent were refractory to previous therapy, and 33% had secondary AML.

The study’s primary endpoint was the combined rate of complete remission (CR) rate and CR with partial hematologic improvement (CRh).

The CR+CRh rate was 32.8% (57/174), the CR rate was 24.7% (43/174), and the CRh rate was 8% (14/174).

The median duration of CR+CRh was 8.2 months (95% CI 5.6, 12). The median time to best response of CR or CRh was 2.0 months (range, 0.9 to 5.6 months).

Twelve percent of patients (21/174) went on to transplant.

The researchers evaluated the safety of ivosidenib in 179 patients treated with a dose of 500 mg daily. The median duration of exposure to ivosidenib was 3.9 months (range, 0.1 to 39.5 months).

Nineteen percent of patients (34/179) experienced differentiation syndrome. Seventy-nine percent of these patients (27/34) recovered after treatment or ivosidenib dose interruption.

The most frequent serious AEs (>5%) were differentiation syndrome (10%), leukocytosis (10%), and electrocardiogram QT prolongation (7%). There was one case of progressive multifocal leukoencephalopathy.

The most common AEs leading to dose interruption were QT prolongation (7%), differentiation syndrome (3%), leukocytosis (3%), and dyspnea (3%). AEs leading to a dose reduction included QT prolongation (1%), diarrhea (1%), nausea (1%), decreased hemoglobin (1%), and increased transaminases (1%).

AEs leading to permanent discontinuation of ivosidenib included Guillain-Barré syndrome (1%), rash (1%), stomatitis (1%), and creatinine increase (1%).

For additional data and more details on ivosidenib, see the full prescribing information or visit Tibsovo.com.

Agios Pharmaceuticals

The US Food and Drug Administration (FDA) has granted full approval for the isocitrate dehydrogenase-1 (IDH1) inhibitor ivosidenib (Tibsovo®).

The drug is approved to treat adults with relapsed or refractory acute myeloid leukemia (AML) who have an IDH1 mutation, as detected by an FDA-approved test.

Ivosidenib was approved concurrently with the RealTime IDH1 Assay, a companion diagnostic that can detect IDH1 mutation.

The FDA granted approval of ivosidenib to Agios Pharmaceuticals, Inc., and approval of the RealTime IDH1 Assay to Abbott Laboratories.

The FDA’s approval of ivosidenib was based on data from a single-arm, phase 1 study. Agios received fast track, priority review, and orphan drug designations for ivosidenib.

Safety risks

Ivosidenib must be dispensed with a patient medication guide that describes important information about the drug’s uses and risks.

The prescribing information for ivosidenib includes a Boxed Warning noting that patients treated with ivosidenib have experienced symptoms of differentiation syndrome, which can be fatal if not treated.

Signs and symptoms of differentiation syndrome may include fever, dyspnea, acute respiratory distress, radiographic pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain, peripheral edema, or hepatic, renal, or multi-organ dysfunction.

At first suspicion of symptoms, doctors should treat patients with corticosteroids and monitor them closely until symptoms subside.

Ivosidenib also poses a risk of life-threatening QT prolongation and Guillain-Barré syndrome, so patients should be monitored for these adverse events (AEs) as well.

Phase 1 trial

Results from the phase 1 trial of ivosidenib were presented at the 2018 ASCO Annual Meeting and published simultaneously in NEJM. The following data were pulled from the drug’s prescribing information.

Efficacy results were available for 174 adults with relapsed/refractory AML and an IDH1 mutation identified or confirmed by the Abbott RealTime™ IDH1 assay. The patients received ivosidenib at a starting dose of 500 mg daily until disease progression, unacceptable toxicity, or hematopoietic stem cell transplant.

The patients had a median age of 67 (range, 18 to 87) and had received a median of 2 prior therapies (range, 1 to 6). Sixty-three percent were refractory to previous therapy, and 33% had secondary AML.

The study’s primary endpoint was the combined rate of complete remission (CR) rate and CR with partial hematologic improvement (CRh).

The CR+CRh rate was 32.8% (57/174), the CR rate was 24.7% (43/174), and the CRh rate was 8% (14/174).

The median duration of CR+CRh was 8.2 months (95% CI 5.6, 12). The median time to best response of CR or CRh was 2.0 months (range, 0.9 to 5.6 months).

Twelve percent of patients (21/174) went on to transplant.

The researchers evaluated the safety of ivosidenib in 179 patients treated with a dose of 500 mg daily. The median duration of exposure to ivosidenib was 3.9 months (range, 0.1 to 39.5 months).

Nineteen percent of patients (34/179) experienced differentiation syndrome. Seventy-nine percent of these patients (27/34) recovered after treatment or ivosidenib dose interruption.

The most frequent serious AEs (>5%) were differentiation syndrome (10%), leukocytosis (10%), and electrocardiogram QT prolongation (7%). There was one case of progressive multifocal leukoencephalopathy.

The most common AEs leading to dose interruption were QT prolongation (7%), differentiation syndrome (3%), leukocytosis (3%), and dyspnea (3%). AEs leading to a dose reduction included QT prolongation (1%), diarrhea (1%), nausea (1%), decreased hemoglobin (1%), and increased transaminases (1%).

AEs leading to permanent discontinuation of ivosidenib included Guillain-Barré syndrome (1%), rash (1%), stomatitis (1%), and creatinine increase (1%).

For additional data and more details on ivosidenib, see the full prescribing information or visit Tibsovo.com.

Agios Pharmaceuticals

The US Food and Drug Administration (FDA) has granted full approval for the isocitrate dehydrogenase-1 (IDH1) inhibitor ivosidenib (Tibsovo®).

The drug is approved to treat adults with relapsed or refractory acute myeloid leukemia (AML) who have an IDH1 mutation, as detected by an FDA-approved test.

Ivosidenib was approved concurrently with the RealTime IDH1 Assay, a companion diagnostic that can detect IDH1 mutation.

The FDA granted approval of ivosidenib to Agios Pharmaceuticals, Inc., and approval of the RealTime IDH1 Assay to Abbott Laboratories.

The FDA’s approval of ivosidenib was based on data from a single-arm, phase 1 study. Agios received fast track, priority review, and orphan drug designations for ivosidenib.

Safety risks

Ivosidenib must be dispensed with a patient medication guide that describes important information about the drug’s uses and risks.

The prescribing information for ivosidenib includes a Boxed Warning noting that patients treated with ivosidenib have experienced symptoms of differentiation syndrome, which can be fatal if not treated.

Signs and symptoms of differentiation syndrome may include fever, dyspnea, acute respiratory distress, radiographic pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain, peripheral edema, or hepatic, renal, or multi-organ dysfunction.

At first suspicion of symptoms, doctors should treat patients with corticosteroids and monitor them closely until symptoms subside.

Ivosidenib also poses a risk of life-threatening QT prolongation and Guillain-Barré syndrome, so patients should be monitored for these adverse events (AEs) as well.

Phase 1 trial

Results from the phase 1 trial of ivosidenib were presented at the 2018 ASCO Annual Meeting and published simultaneously in NEJM. The following data were pulled from the drug’s prescribing information.

Efficacy results were available for 174 adults with relapsed/refractory AML and an IDH1 mutation identified or confirmed by the Abbott RealTime™ IDH1 assay. The patients received ivosidenib at a starting dose of 500 mg daily until disease progression, unacceptable toxicity, or hematopoietic stem cell transplant.

The patients had a median age of 67 (range, 18 to 87) and had received a median of 2 prior therapies (range, 1 to 6). Sixty-three percent were refractory to previous therapy, and 33% had secondary AML.

The study’s primary endpoint was the combined rate of complete remission (CR) rate and CR with partial hematologic improvement (CRh).

The CR+CRh rate was 32.8% (57/174), the CR rate was 24.7% (43/174), and the CRh rate was 8% (14/174).

The median duration of CR+CRh was 8.2 months (95% CI 5.6, 12). The median time to best response of CR or CRh was 2.0 months (range, 0.9 to 5.6 months).

Twelve percent of patients (21/174) went on to transplant.

The researchers evaluated the safety of ivosidenib in 179 patients treated with a dose of 500 mg daily. The median duration of exposure to ivosidenib was 3.9 months (range, 0.1 to 39.5 months).

Nineteen percent of patients (34/179) experienced differentiation syndrome. Seventy-nine percent of these patients (27/34) recovered after treatment or ivosidenib dose interruption.

The most frequent serious AEs (>5%) were differentiation syndrome (10%), leukocytosis (10%), and electrocardiogram QT prolongation (7%). There was one case of progressive multifocal leukoencephalopathy.

The most common AEs leading to dose interruption were QT prolongation (7%), differentiation syndrome (3%), leukocytosis (3%), and dyspnea (3%). AEs leading to a dose reduction included QT prolongation (1%), diarrhea (1%), nausea (1%), decreased hemoglobin (1%), and increased transaminases (1%).

AEs leading to permanent discontinuation of ivosidenib included Guillain-Barré syndrome (1%), rash (1%), stomatitis (1%), and creatinine increase (1%).

For additional data and more details on ivosidenib, see the full prescribing information or visit Tibsovo.com.

Photo courtesy of the CDC

Clinical trials supporting the approval of drugs with breakthrough therapy designation¹ do not meet the same standards as trials for non-breakthrough drugs, according to researchers.

Between 2012 and 2017, the US Food and Drug Administration (FDA) approved 46 breakthrough therapeutics on the basis of 89 pivotal trials.

Researchers found these trials “commonly lacked randomization, double-blinding, and control groups, used surrogate markers as primary endpoints, and enrolled small numbers of patients.”

Joseph S. Ross, MD, of the Yale School of Medicine in New Haven, Connecticut, and his colleagues detailed these findings in a letter to JAMA.

“To be clear, I think the FDA, as directed by Congress, is doing everything it can to expedite the development and review of drugs that treat serious and life-threatening conditions,” Dr Ross said.

“Our research suggests that FDA approval of these breakthrough therapies is generally based on shorter and smaller clinical trials than those that support FDA approval of non-breakthrough therapy drugs.”

Analyzing the approvals

More than half of the 46 approvals analyzed were for cancer therapeutics (n=25; 54.3%), and an equal number were considered first-in-class.

All 46 products received priority review², 30 (65.2%) received orphan designation³, 24 qualified for fast track⁴ review (52.2%), and 18 received accelerated approval⁵ (39.1%).

The median time from an investigational new drug activation to final FDA approval was 4.9 years. The median time from the submission of the new drug application to FDA approval was 6.9 months.

The median number of pivotal trials per indication was 1, and the median number of patients supporting an indication was 222.

Of all the approvals, 27 (58.7%) were made based on randomized trials, 21 (45.7%) were based on double-blind allocation, and 25 (54.3%) used an active or placebo comparator. Only 10 (21.7%) used a clinical primary endpoint.

The analysis also showed that trials supporting breakthrough drugs with accelerated approval were significantly less likely to be randomized, double-blinded, or have an active/placebo control group.

Of 18 trials that were used to grant drugs accelerated approval, 3 (16.7%) trials were randomized, 1 (5.6%) was double-blinded, and 3 (16.7%) had an active/placebo control group.

Of 28 trials supporting drugs without accelerated approval, 24 (85.7%) trials were randomized, 20 (71.4%) were double-blinded, and 22 (78.6%) had an active/placebo control group.

All 18 accelerated approvals had at least 1 safety analysis or efficacy-focused postmarketing requirement.

Dr Ross pointed out that when approvals are based on shorter and smaller clinical trials, there is greater uncertainty at the time of approval.

For example, will effects observed in a small, single trial be observed in a larger population or in another independent study? Will effects observed over a short period persist over time? Will new risks (or benefits) be observed over a longer period? And will the effect observed on the outcomes used in these shorter trials—usually surrogate endpoints believed to predict a clinical benefit—be confirmed by clinical outcomes?

“If we are going to be making this trade-off to allow novel drugs to come to market on the basis of evidence that is generally accompanied by greater uncertainty, we must be committed as a clinical and scientific community to ensuring that high-quality, rigorous postmarketing trials are conducted within a reasonable period of time,” Dr Ross said.

He noted that postmarketing trials will resolve some of the uncertainty and will ensure that drugs are associated with the benefit/safety profile that is expected based on the initial clinical studies.

“This will allow clinicians and patients to make fully informed decisions about whether to use these novel treatments,” he said.

1. The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions. Breakthrough designation entitles sponsors to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review. To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.

2. The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions. The FDA aims to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.

3. The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US. Orphan designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

4. The FDA’s fast track program is designed to expedite clinical development and submission of applications for drugs with the potential to treat serious or life-threatening conditions and address unmet medical needs. Fast track designation facilitates frequent interactions with the FDA review team, including meetings to discuss the drug’s development plan and written communications about issues such as trial design and use of biomarkers. Drugs that receive fast track designation may be eligible for accelerated approval and priority review if relevant criteria are met. Fast track drugs may also be eligible for rolling review, which allows a developer to submit individual sections of a drug’s application for review as they are ready, rather than waiting until all sections are complete.

5. The FDA’s accelerated approval program allows conditional approval of a drug that fills an unmet medical need for a serious condition. Accelerated approval is based on surrogate or intermediate endpoints that are reasonably likely to predict clinical benefit. Continued approval of drugs granted accelerated approval may be contingent upon verification of clinical benefit in confirmatory trials.

Photo courtesy of the CDC

Clinical trials supporting the approval of drugs with breakthrough therapy designation¹ do not meet the same standards as trials for non-breakthrough drugs, according to researchers.

Between 2012 and 2017, the US Food and Drug Administration (FDA) approved 46 breakthrough therapeutics on the basis of 89 pivotal trials.

Researchers found these trials “commonly lacked randomization, double-blinding, and control groups, used surrogate markers as primary endpoints, and enrolled small numbers of patients.”

Joseph S. Ross, MD, of the Yale School of Medicine in New Haven, Connecticut, and his colleagues detailed these findings in a letter to JAMA.

“To be clear, I think the FDA, as directed by Congress, is doing everything it can to expedite the development and review of drugs that treat serious and life-threatening conditions,” Dr Ross said.

“Our research suggests that FDA approval of these breakthrough therapies is generally based on shorter and smaller clinical trials than those that support FDA approval of non-breakthrough therapy drugs.”

Analyzing the approvals

More than half of the 46 approvals analyzed were for cancer therapeutics (n=25; 54.3%), and an equal number were considered first-in-class.

All 46 products received priority review², 30 (65.2%) received orphan designation³, 24 qualified for fast track⁴ review (52.2%), and 18 received accelerated approval⁵ (39.1%).

The median time from an investigational new drug activation to final FDA approval was 4.9 years. The median time from the submission of the new drug application to FDA approval was 6.9 months.

The median number of pivotal trials per indication was 1, and the median number of patients supporting an indication was 222.

Of all the approvals, 27 (58.7%) were made based on randomized trials, 21 (45.7%) were based on double-blind allocation, and 25 (54.3%) used an active or placebo comparator. Only 10 (21.7%) used a clinical primary endpoint.

The analysis also showed that trials supporting breakthrough drugs with accelerated approval were significantly less likely to be randomized, double-blinded, or have an active/placebo control group.

Of 18 trials that were used to grant drugs accelerated approval, 3 (16.7%) trials were randomized, 1 (5.6%) was double-blinded, and 3 (16.7%) had an active/placebo control group.

Of 28 trials supporting drugs without accelerated approval, 24 (85.7%) trials were randomized, 20 (71.4%) were double-blinded, and 22 (78.6%) had an active/placebo control group.

All 18 accelerated approvals had at least 1 safety analysis or efficacy-focused postmarketing requirement.

Dr Ross pointed out that when approvals are based on shorter and smaller clinical trials, there is greater uncertainty at the time of approval.

For example, will effects observed in a small, single trial be observed in a larger population or in another independent study? Will effects observed over a short period persist over time? Will new risks (or benefits) be observed over a longer period? And will the effect observed on the outcomes used in these shorter trials—usually surrogate endpoints believed to predict a clinical benefit—be confirmed by clinical outcomes?

“If we are going to be making this trade-off to allow novel drugs to come to market on the basis of evidence that is generally accompanied by greater uncertainty, we must be committed as a clinical and scientific community to ensuring that high-quality, rigorous postmarketing trials are conducted within a reasonable period of time,” Dr Ross said.

He noted that postmarketing trials will resolve some of the uncertainty and will ensure that drugs are associated with the benefit/safety profile that is expected based on the initial clinical studies.

“This will allow clinicians and patients to make fully informed decisions about whether to use these novel treatments,” he said.

1. The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions. Breakthrough designation entitles sponsors to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review. To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.

2. The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions. The FDA aims to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.

3. The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US. Orphan designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

4. The FDA’s fast track program is designed to expedite clinical development and submission of applications for drugs with the potential to treat serious or life-threatening conditions and address unmet medical needs. Fast track designation facilitates frequent interactions with the FDA review team, including meetings to discuss the drug’s development plan and written communications about issues such as trial design and use of biomarkers. Drugs that receive fast track designation may be eligible for accelerated approval and priority review if relevant criteria are met. Fast track drugs may also be eligible for rolling review, which allows a developer to submit individual sections of a drug’s application for review as they are ready, rather than waiting until all sections are complete.

5. The FDA’s accelerated approval program allows conditional approval of a drug that fills an unmet medical need for a serious condition. Accelerated approval is based on surrogate or intermediate endpoints that are reasonably likely to predict clinical benefit. Continued approval of drugs granted accelerated approval may be contingent upon verification of clinical benefit in confirmatory trials.

Photo courtesy of the CDC

Clinical trials supporting the approval of drugs with breakthrough therapy designation¹ do not meet the same standards as trials for non-breakthrough drugs, according to researchers.

Between 2012 and 2017, the US Food and Drug Administration (FDA) approved 46 breakthrough therapeutics on the basis of 89 pivotal trials.

Researchers found these trials “commonly lacked randomization, double-blinding, and control groups, used surrogate markers as primary endpoints, and enrolled small numbers of patients.”

Joseph S. Ross, MD, of the Yale School of Medicine in New Haven, Connecticut, and his colleagues detailed these findings in a letter to JAMA.

“To be clear, I think the FDA, as directed by Congress, is doing everything it can to expedite the development and review of drugs that treat serious and life-threatening conditions,” Dr Ross said.

“Our research suggests that FDA approval of these breakthrough therapies is generally based on shorter and smaller clinical trials than those that support FDA approval of non-breakthrough therapy drugs.”

Analyzing the approvals

More than half of the 46 approvals analyzed were for cancer therapeutics (n=25; 54.3%), and an equal number were considered first-in-class.

All 46 products received priority review², 30 (65.2%) received orphan designation³, 24 qualified for fast track⁴ review (52.2%), and 18 received accelerated approval⁵ (39.1%).

The median time from an investigational new drug activation to final FDA approval was 4.9 years. The median time from the submission of the new drug application to FDA approval was 6.9 months.

The median number of pivotal trials per indication was 1, and the median number of patients supporting an indication was 222.

Of all the approvals, 27 (58.7%) were made based on randomized trials, 21 (45.7%) were based on double-blind allocation, and 25 (54.3%) used an active or placebo comparator. Only 10 (21.7%) used a clinical primary endpoint.

The analysis also showed that trials supporting breakthrough drugs with accelerated approval were significantly less likely to be randomized, double-blinded, or have an active/placebo control group.

Of 18 trials that were used to grant drugs accelerated approval, 3 (16.7%) trials were randomized, 1 (5.6%) was double-blinded, and 3 (16.7%) had an active/placebo control group.

Of 28 trials supporting drugs without accelerated approval, 24 (85.7%) trials were randomized, 20 (71.4%) were double-blinded, and 22 (78.6%) had an active/placebo control group.

All 18 accelerated approvals had at least 1 safety analysis or efficacy-focused postmarketing requirement.

Dr Ross pointed out that when approvals are based on shorter and smaller clinical trials, there is greater uncertainty at the time of approval.

For example, will effects observed in a small, single trial be observed in a larger population or in another independent study? Will effects observed over a short period persist over time? Will new risks (or benefits) be observed over a longer period? And will the effect observed on the outcomes used in these shorter trials—usually surrogate endpoints believed to predict a clinical benefit—be confirmed by clinical outcomes?

“If we are going to be making this trade-off to allow novel drugs to come to market on the basis of evidence that is generally accompanied by greater uncertainty, we must be committed as a clinical and scientific community to ensuring that high-quality, rigorous postmarketing trials are conducted within a reasonable period of time,” Dr Ross said.

He noted that postmarketing trials will resolve some of the uncertainty and will ensure that drugs are associated with the benefit/safety profile that is expected based on the initial clinical studies.

“This will allow clinicians and patients to make fully informed decisions about whether to use these novel treatments,” he said.

1. The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions. Breakthrough designation entitles sponsors to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review. To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.

2. The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions. The FDA aims to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.

3. The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US. Orphan designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

4. The FDA’s fast track program is designed to expedite clinical development and submission of applications for drugs with the potential to treat serious or life-threatening conditions and address unmet medical needs. Fast track designation facilitates frequent interactions with the FDA review team, including meetings to discuss the drug’s development plan and written communications about issues such as trial design and use of biomarkers. Drugs that receive fast track designation may be eligible for accelerated approval and priority review if relevant criteria are met. Fast track drugs may also be eligible for rolling review, which allows a developer to submit individual sections of a drug’s application for review as they are ready, rather than waiting until all sections are complete.

5. The FDA’s accelerated approval program allows conditional approval of a drug that fills an unmet medical need for a serious condition. Accelerated approval is based on surrogate or intermediate endpoints that are reasonably likely to predict clinical benefit. Continued approval of drugs granted accelerated approval may be contingent upon verification of clinical benefit in confirmatory trials.

Obinutuzumab (Gazyva)

Health Canada has expanded the approved use of obinutuzumab (Gazyva®).

The anti-CD20 monoclonal antibody is now approved for use in combination with chemotherapy to treat patients with previously untreated follicular lymphoma (FL) that is advanced (stage II bulky, stage III, or stage IV).

In patients who respond to this treatment, obinutuzumab monotherapy can be given as maintenance.

Health Canada previously approved obinutuzumab for the following indications:

• In combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia
• First in combination with bendamustine, then as monotherapy, in FL patients who relapsed after or are refractory to a rituximab-containing regimen.

Phase 3 results

Health Canada’s latest approval of obinutuzumab is based on results from the phase 3 GALLIUM study, which were published in NEJM in October 2017. The following are updated data from the product monograph.

GALLIUM included 1385 patients with previously untreated non-Hodgkin lymphoma, and 1202 of these patients had previously untreated, advanced FL.

Half of the FL patients (n=601) were randomized to receive obinutuzumab plus chemotherapy (followed by obinutuzumab maintenance for up to 2 years), and half were randomized to rituximab plus chemotherapy (followed by rituximab maintenance for up to 2 years).

The different chemotherapies used were CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), CVP (cyclophosphamide, vincristine, and prednisone), and bendamustine.

At a median observation time of 41.1 months, the overall response rate was 91% in the obinutuzumab arm and 88% in the rituximab arm. The complete response rates were 28% and 27%, respectively.

The median progression-free survival was not reached in either arm. The hazard ratio, for obinutuzumab compared to rituximab, was 0.72 (95% CI, 0.56-0.93, P=0.0118).

The estimated 3-year progression-free survival was 78.9% in the rituximab arm and 83.4% in the obinutuzumab arm.

Safety was evaluated based on all 1385 patients in the study, 86% of whom had FL and 14% of whom had marginal zone lymphoma.

Serious adverse events (AEs) occurred in 50% of patients in the obinutuzumab arm and 43% in the rituximab arm. Fatal AEs occurred in 5% and 4%, respectively. Infections and second malignancies were the leading causes of these deaths.

During the monotherapy period, the most common AEs (≥ 5%) in patients treated with obinutuzumab were cough (21%), neutropenia (19%), upper respiratory tract infection (15%), viral upper respiratory tract infection (15%), diarrhea (13%), arthralgia (10%), fatigue (9%), sinusitis (9%), infusion reactions (8%), pneumonia (8%), herpes zoster (8%), lower respiratory tract infection (7%), pyrexia (7%), back pain (6%), headache (6%), urinary tract infection (6%), nausea (6%), bronchitis (5%), and vomiting (5%).

Grade 3-4 AEs (≥1%) in patients treated with obinutuzumab included neutropenia (17%), pneumonia (3%), and febrile neutropenia (2%). There were 2 deaths due to pneumonia in the obinutuzumab arm.

Obinutuzumab (Gazyva)

Health Canada has expanded the approved use of obinutuzumab (Gazyva®).

The anti-CD20 monoclonal antibody is now approved for use in combination with chemotherapy to treat patients with previously untreated follicular lymphoma (FL) that is advanced (stage II bulky, stage III, or stage IV).

In patients who respond to this treatment, obinutuzumab monotherapy can be given as maintenance.

Health Canada previously approved obinutuzumab for the following indications:

• In combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia
• First in combination with bendamustine, then as monotherapy, in FL patients who relapsed after or are refractory to a rituximab-containing regimen.

Phase 3 results

Health Canada’s latest approval of obinutuzumab is based on results from the phase 3 GALLIUM study, which were published in NEJM in October 2017. The following are updated data from the product monograph.

GALLIUM included 1385 patients with previously untreated non-Hodgkin lymphoma, and 1202 of these patients had previously untreated, advanced FL.

Half of the FL patients (n=601) were randomized to receive obinutuzumab plus chemotherapy (followed by obinutuzumab maintenance for up to 2 years), and half were randomized to rituximab plus chemotherapy (followed by rituximab maintenance for up to 2 years).

The different chemotherapies used were CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), CVP (cyclophosphamide, vincristine, and prednisone), and bendamustine.

At a median observation time of 41.1 months, the overall response rate was 91% in the obinutuzumab arm and 88% in the rituximab arm. The complete response rates were 28% and 27%, respectively.

The median progression-free survival was not reached in either arm. The hazard ratio, for obinutuzumab compared to rituximab, was 0.72 (95% CI, 0.56-0.93, P=0.0118).

The estimated 3-year progression-free survival was 78.9% in the rituximab arm and 83.4% in the obinutuzumab arm.

Safety was evaluated based on all 1385 patients in the study, 86% of whom had FL and 14% of whom had marginal zone lymphoma.

Serious adverse events (AEs) occurred in 50% of patients in the obinutuzumab arm and 43% in the rituximab arm. Fatal AEs occurred in 5% and 4%, respectively. Infections and second malignancies were the leading causes of these deaths.

During the monotherapy period, the most common AEs (≥ 5%) in patients treated with obinutuzumab were cough (21%), neutropenia (19%), upper respiratory tract infection (15%), viral upper respiratory tract infection (15%), diarrhea (13%), arthralgia (10%), fatigue (9%), sinusitis (9%), infusion reactions (8%), pneumonia (8%), herpes zoster (8%), lower respiratory tract infection (7%), pyrexia (7%), back pain (6%), headache (6%), urinary tract infection (6%), nausea (6%), bronchitis (5%), and vomiting (5%).

Grade 3-4 AEs (≥1%) in patients treated with obinutuzumab included neutropenia (17%), pneumonia (3%), and febrile neutropenia (2%). There were 2 deaths due to pneumonia in the obinutuzumab arm.

Obinutuzumab (Gazyva)

Health Canada has expanded the approved use of obinutuzumab (Gazyva®).

The anti-CD20 monoclonal antibody is now approved for use in combination with chemotherapy to treat patients with previously untreated follicular lymphoma (FL) that is advanced (stage II bulky, stage III, or stage IV).

In patients who respond to this treatment, obinutuzumab monotherapy can be given as maintenance.

Health Canada previously approved obinutuzumab for the following indications:

• In combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia
• First in combination with bendamustine, then as monotherapy, in FL patients who relapsed after or are refractory to a rituximab-containing regimen.

Phase 3 results

Health Canada’s latest approval of obinutuzumab is based on results from the phase 3 GALLIUM study, which were published in NEJM in October 2017. The following are updated data from the product monograph.

GALLIUM included 1385 patients with previously untreated non-Hodgkin lymphoma, and 1202 of these patients had previously untreated, advanced FL.

Half of the FL patients (n=601) were randomized to receive obinutuzumab plus chemotherapy (followed by obinutuzumab maintenance for up to 2 years), and half were randomized to rituximab plus chemotherapy (followed by rituximab maintenance for up to 2 years).

The different chemotherapies used were CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), CVP (cyclophosphamide, vincristine, and prednisone), and bendamustine.

At a median observation time of 41.1 months, the overall response rate was 91% in the obinutuzumab arm and 88% in the rituximab arm. The complete response rates were 28% and 27%, respectively.

The median progression-free survival was not reached in either arm. The hazard ratio, for obinutuzumab compared to rituximab, was 0.72 (95% CI, 0.56-0.93, P=0.0118).

The estimated 3-year progression-free survival was 78.9% in the rituximab arm and 83.4% in the obinutuzumab arm.

Safety was evaluated based on all 1385 patients in the study, 86% of whom had FL and 14% of whom had marginal zone lymphoma.

Serious adverse events (AEs) occurred in 50% of patients in the obinutuzumab arm and 43% in the rituximab arm. Fatal AEs occurred in 5% and 4%, respectively. Infections and second malignancies were the leading causes of these deaths.

During the monotherapy period, the most common AEs (≥ 5%) in patients treated with obinutuzumab were cough (21%), neutropenia (19%), upper respiratory tract infection (15%), viral upper respiratory tract infection (15%), diarrhea (13%), arthralgia (10%), fatigue (9%), sinusitis (9%), infusion reactions (8%), pneumonia (8%), herpes zoster (8%), lower respiratory tract infection (7%), pyrexia (7%), back pain (6%), headache (6%), urinary tract infection (6%), nausea (6%), bronchitis (5%), and vomiting (5%).

Grade 3-4 AEs (≥1%) in patients treated with obinutuzumab included neutropenia (17%), pneumonia (3%), and febrile neutropenia (2%). There were 2 deaths due to pneumonia in the obinutuzumab arm.

Photo by Steven Harbour

An investigative report has unearthed potential conflicts of interest among physicians who serve on advisory panels for the US Food and Drug Administration (FDA).

The investigation revealed that some FDA advisers are receiving significant post-hoc payments from the makers of drugs they reviewed.

The investigation also uncovered relationships between advisers and drug companies that predate drug reviews.

Journalist Charles Piller and his colleagues conducted this investigation and detailed the results in Science.

The report includes data—from the federal Open Payments website—on 107 physicians who voted on FDA advisory committees between 2013 and 2016.

Forty of these advisers received more than $10,000 in post-hoc earnings or research support from the makers of drugs they reviewed or from competing drug companies.

Twenty-six advisers received more than $100,000, and 7 advisers received more than $1 million.

The 17 top earners received more than $300,000 each. For these advisers, 94% of their earnings came from the makers of drugs they previ­ously reviewed or from those companies’ competitors.

The data also show that some advisers received funds from drug companies concurrent with or in the year before their advisory service.

Of the 17 top-earning advisers, 11 received financial sup­port from competing companies on one or more of the drugs they reviewed. Five advisers also received support from the makers of one or more of the drugs reviewed.

The FDA did not disclose this information to the public or issue waivers for these potential conflicts. The FDA can issue a waiver to allow the participation of an adviser with an active conflict or one that ended in the year before a vote, as long as the adviser in question can provide expertise that cannot be provided by someone else.

It is possible that the FDA dismissed the aforementioned financial ties that predated drug reviews, deciding these relationships were not conflicts and did not require a waiver. However, it is also possible that the FDA did not know about these potential conflicts.

Piller and his colleagues were unable to determine what the FDA knew, as the agency refused to release disclosure documents, discuss individual advisers, or explain what steps, if any, the FDA takes to validate advisers’ disclosures.

Photo by Steven Harbour

An investigative report has unearthed potential conflicts of interest among physicians who serve on advisory panels for the US Food and Drug Administration (FDA).

The investigation revealed that some FDA advisers are receiving significant post-hoc payments from the makers of drugs they reviewed.

The investigation also uncovered relationships between advisers and drug companies that predate drug reviews.

Journalist Charles Piller and his colleagues conducted this investigation and detailed the results in Science.

The report includes data—from the federal Open Payments website—on 107 physicians who voted on FDA advisory committees between 2013 and 2016.

Forty of these advisers received more than $10,000 in post-hoc earnings or research support from the makers of drugs they reviewed or from competing drug companies.

Twenty-six advisers received more than $100,000, and 7 advisers received more than $1 million.

The 17 top earners received more than $300,000 each. For these advisers, 94% of their earnings came from the makers of drugs they previ­ously reviewed or from those companies’ competitors.

The data also show that some advisers received funds from drug companies concurrent with or in the year before their advisory service.

Of the 17 top-earning advisers, 11 received financial sup­port from competing companies on one or more of the drugs they reviewed. Five advisers also received support from the makers of one or more of the drugs reviewed.

The FDA did not disclose this information to the public or issue waivers for these potential conflicts. The FDA can issue a waiver to allow the participation of an adviser with an active conflict or one that ended in the year before a vote, as long as the adviser in question can provide expertise that cannot be provided by someone else.

It is possible that the FDA dismissed the aforementioned financial ties that predated drug reviews, deciding these relationships were not conflicts and did not require a waiver. However, it is also possible that the FDA did not know about these potential conflicts.

Piller and his colleagues were unable to determine what the FDA knew, as the agency refused to release disclosure documents, discuss individual advisers, or explain what steps, if any, the FDA takes to validate advisers’ disclosures.

Photo by Steven Harbour

An investigative report has unearthed potential conflicts of interest among physicians who serve on advisory panels for the US Food and Drug Administration (FDA).

The investigation revealed that some FDA advisers are receiving significant post-hoc payments from the makers of drugs they reviewed.

The investigation also uncovered relationships between advisers and drug companies that predate drug reviews.

Journalist Charles Piller and his colleagues conducted this investigation and detailed the results in Science.

The report includes data—from the federal Open Payments website—on 107 physicians who voted on FDA advisory committees between 2013 and 2016.

Forty of these advisers received more than $10,000 in post-hoc earnings or research support from the makers of drugs they reviewed or from competing drug companies.

Twenty-six advisers received more than $100,000, and 7 advisers received more than $1 million.

The 17 top earners received more than $300,000 each. For these advisers, 94% of their earnings came from the makers of drugs they previ­ously reviewed or from those companies’ competitors.

The data also show that some advisers received funds from drug companies concurrent with or in the year before their advisory service.

Of the 17 top-earning advisers, 11 received financial sup­port from competing companies on one or more of the drugs they reviewed. Five advisers also received support from the makers of one or more of the drugs reviewed.

The FDA did not disclose this information to the public or issue waivers for these potential conflicts. The FDA can issue a waiver to allow the participation of an adviser with an active conflict or one that ended in the year before a vote, as long as the adviser in question can provide expertise that cannot be provided by someone else.

It is possible that the FDA dismissed the aforementioned financial ties that predated drug reviews, deciding these relationships were not conflicts and did not require a waiver. However, it is also possible that the FDA did not know about these potential conflicts.

Piller and his colleagues were unable to determine what the FDA knew, as the agency refused to release disclosure documents, discuss individual advisers, or explain what steps, if any, the FDA takes to validate advisers’ disclosures.

Photo by Rhoda Baer

The European Commission (EC) has expanded the marketing authorization for dasatinib (Sprycel).

The drug is now approved to treat patients ages 1 to 18 with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase (CP).

The EC has also approved a new formulation of dasatinib—a powder for oral suspension (PFOS) intended for patients who cannot swallow tablets whole or who weigh 10 kg or less.

Dasatinib is also EC-approved to treat adults with:

• Newly diagnosed Ph+ CML-CP
• Chronic, accelerated, or blast phase CML with resistance or intolerance to prior therapy, including imatinib
• Ph+ acute lymphoblastic leukemia and lymphoid blast CML with resistance or intolerance to prior therapy.

The EC’s latest approval of dasatinib is supported by results from a phase 2 trial (NCT00777036), which were published in the Journal of Clinical Oncology in March.

The trial included 29 patients with imatinib-resistant/intolerant CML-CP and 84 patients with newly diagnosed CML-CP.

The previously treated patients received dasatinib tablets. Newly diagnosed patients were treated with dasatinib tablets (n=51) or PFOS (n=33).

Patients who started on PFOS could switch to tablets after receiving PFOS for at least 1 year. Sixty-seven percent of patients on PFOS switched to tablets due to patient preference.

The average daily dose of dasatinib was 58.18 mg/m² in the previously treated patients and 59.84 mg/m² in the newly diagnosed patients (for both tablets and PFOS). The median duration of treatment was 49.91 months (range, 1.9 to 90.2) and 42.30 months (range, 0.1 to 75.2), respectively.

Rates of confirmed complete hematologic response (CHR) at any time were 93% in the previously treated patients and 96% in the newly diagnosed patients.

At 12 months, previously treated patients had a major molecular response (MMR) rate of 41% and a complete molecular response (CMR) rate of 7%. In newly diagnosed patients, MMR was 52%, and CMR was 8%.

At 24 months, previously treated patients had an MMR rate of 55% and a CMR rate of 17%. In the newly diagnosed patients, MMR was 70%, and CMR was 21%.

The rate of major cytogenetic response (MCyR) at any time was 89.7% in all previously treated patients and 90% when the researchers excluded patients with MCyR or unknown cytogenetic status at baseline.

The rate of complete cytogenetic response (CCyR) at any time was 94% in all newly diagnosed patients and 93.9% when the researchers excluded patients with CCyR or unknown cytogenetic status at baseline.

The median progression-free survival and overall survival had not been reached at last follow-up.

The estimated 48-month progression-free survival was 78% in the previously treated patients and 93% in the newly diagnosed patients. The estimated 48-month overall survival was 96% and 100%, respectively.

Dasatinib-related adverse events (AEs) occurring in at least 10% of the previously treated patients included nausea/vomiting (31%), myalgia/arthralgia (17%), fatigue (14%), rash (14%), diarrhea (14%), hemorrhage (10%), bone growth and development events (10%), and shortness of breath (10%).

Dasatinib-related AEs occurring in at least 10% of the newly diagnosed patients included nausea/vomiting (20%), myalgia/arthralgia (10%), fatigue (11%), rash (19%), diarrhea (18%), and hemorrhage (10%).

Photo by Rhoda Baer

The European Commission (EC) has expanded the marketing authorization for dasatinib (Sprycel).

The drug is now approved to treat patients ages 1 to 18 with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase (CP).

The EC has also approved a new formulation of dasatinib—a powder for oral suspension (PFOS) intended for patients who cannot swallow tablets whole or who weigh 10 kg or less.

Dasatinib is also EC-approved to treat adults with:

• Newly diagnosed Ph+ CML-CP
• Chronic, accelerated, or blast phase CML with resistance or intolerance to prior therapy, including imatinib
• Ph+ acute lymphoblastic leukemia and lymphoid blast CML with resistance or intolerance to prior therapy.

The EC’s latest approval of dasatinib is supported by results from a phase 2 trial (NCT00777036), which were published in the Journal of Clinical Oncology in March.

The trial included 29 patients with imatinib-resistant/intolerant CML-CP and 84 patients with newly diagnosed CML-CP.

The previously treated patients received dasatinib tablets. Newly diagnosed patients were treated with dasatinib tablets (n=51) or PFOS (n=33).

Patients who started on PFOS could switch to tablets after receiving PFOS for at least 1 year. Sixty-seven percent of patients on PFOS switched to tablets due to patient preference.

The average daily dose of dasatinib was 58.18 mg/m² in the previously treated patients and 59.84 mg/m² in the newly diagnosed patients (for both tablets and PFOS). The median duration of treatment was 49.91 months (range, 1.9 to 90.2) and 42.30 months (range, 0.1 to 75.2), respectively.

Rates of confirmed complete hematologic response (CHR) at any time were 93% in the previously treated patients and 96% in the newly diagnosed patients.

At 12 months, previously treated patients had a major molecular response (MMR) rate of 41% and a complete molecular response (CMR) rate of 7%. In newly diagnosed patients, MMR was 52%, and CMR was 8%.

At 24 months, previously treated patients had an MMR rate of 55% and a CMR rate of 17%. In the newly diagnosed patients, MMR was 70%, and CMR was 21%.

The rate of major cytogenetic response (MCyR) at any time was 89.7% in all previously treated patients and 90% when the researchers excluded patients with MCyR or unknown cytogenetic status at baseline.

The rate of complete cytogenetic response (CCyR) at any time was 94% in all newly diagnosed patients and 93.9% when the researchers excluded patients with CCyR or unknown cytogenetic status at baseline.

The median progression-free survival and overall survival had not been reached at last follow-up.

The estimated 48-month progression-free survival was 78% in the previously treated patients and 93% in the newly diagnosed patients. The estimated 48-month overall survival was 96% and 100%, respectively.

Dasatinib-related adverse events (AEs) occurring in at least 10% of the previously treated patients included nausea/vomiting (31%), myalgia/arthralgia (17%), fatigue (14%), rash (14%), diarrhea (14%), hemorrhage (10%), bone growth and development events (10%), and shortness of breath (10%).

Dasatinib-related AEs occurring in at least 10% of the newly diagnosed patients included nausea/vomiting (20%), myalgia/arthralgia (10%), fatigue (11%), rash (19%), diarrhea (18%), and hemorrhage (10%).

Photo by Rhoda Baer

The European Commission (EC) has expanded the marketing authorization for dasatinib (Sprycel).

The drug is now approved to treat patients ages 1 to 18 with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase (CP).

The EC has also approved a new formulation of dasatinib—a powder for oral suspension (PFOS) intended for patients who cannot swallow tablets whole or who weigh 10 kg or less.

Dasatinib is also EC-approved to treat adults with:

• Newly diagnosed Ph+ CML-CP
• Chronic, accelerated, or blast phase CML with resistance or intolerance to prior therapy, including imatinib
• Ph+ acute lymphoblastic leukemia and lymphoid blast CML with resistance or intolerance to prior therapy.

The EC’s latest approval of dasatinib is supported by results from a phase 2 trial (NCT00777036), which were published in the Journal of Clinical Oncology in March.

The trial included 29 patients with imatinib-resistant/intolerant CML-CP and 84 patients with newly diagnosed CML-CP.

The previously treated patients received dasatinib tablets. Newly diagnosed patients were treated with dasatinib tablets (n=51) or PFOS (n=33).

Patients who started on PFOS could switch to tablets after receiving PFOS for at least 1 year. Sixty-seven percent of patients on PFOS switched to tablets due to patient preference.

The average daily dose of dasatinib was 58.18 mg/m² in the previously treated patients and 59.84 mg/m² in the newly diagnosed patients (for both tablets and PFOS). The median duration of treatment was 49.91 months (range, 1.9 to 90.2) and 42.30 months (range, 0.1 to 75.2), respectively.

Rates of confirmed complete hematologic response (CHR) at any time were 93% in the previously treated patients and 96% in the newly diagnosed patients.

At 12 months, previously treated patients had a major molecular response (MMR) rate of 41% and a complete molecular response (CMR) rate of 7%. In newly diagnosed patients, MMR was 52%, and CMR was 8%.

At 24 months, previously treated patients had an MMR rate of 55% and a CMR rate of 17%. In the newly diagnosed patients, MMR was 70%, and CMR was 21%.

The rate of major cytogenetic response (MCyR) at any time was 89.7% in all previously treated patients and 90% when the researchers excluded patients with MCyR or unknown cytogenetic status at baseline.

The rate of complete cytogenetic response (CCyR) at any time was 94% in all newly diagnosed patients and 93.9% when the researchers excluded patients with CCyR or unknown cytogenetic status at baseline.

The median progression-free survival and overall survival had not been reached at last follow-up.

The estimated 48-month progression-free survival was 78% in the previously treated patients and 93% in the newly diagnosed patients. The estimated 48-month overall survival was 96% and 100%, respectively.

Dasatinib-related adverse events (AEs) occurring in at least 10% of the previously treated patients included nausea/vomiting (31%), myalgia/arthralgia (17%), fatigue (14%), rash (14%), diarrhea (14%), hemorrhage (10%), bone growth and development events (10%), and shortness of breath (10%).

Dasatinib-related AEs occurring in at least 10% of the newly diagnosed patients included nausea/vomiting (20%), myalgia/arthralgia (10%), fatigue (11%), rash (19%), diarrhea (18%), and hemorrhage (10%).