HT Staff

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).

Photo from UAB

Children may have an increased risk of premature death decades after allogeneic hematopoietic stem cell transplant (allo-HSCT), according to a study published in JAMA Oncology.

The leading causes of death in the patients studied were infection and chronic graft-vs-host disease (GVHD), patients’ primary disease, and subsequent cancers.

“This study shows that, while we are able to save the life of the child during their cancer treatment, we need to continue to provide proactive follow-up care with these types of patients throughout the rest of their life, as they are still an at-risk population,” said study author Smita Bhatia, MBBS, of the University of Alabama at Birmingham (UAB).

“The high intensity of therapeutic exposures at a young age lends itself to cause morbidities and organ compromise once they reach adulthood.”

Dr Bhatia and her colleagues conducted this retrospective study of children who underwent allo-HSCT between January 1, 1974, and December 31, 2010, and were followed until December 31, 2016.

The study included 1388 patients who lived 2 years or more after transplant. Their median age at transplant was 14.6 years (range, 0-21). The majority of patients were non-Hispanic white (70.7%), and most were male (59.7%).

Patients underwent allo-HSCT to treat acute lymphoblastic leukemia (ALL, 25.1%), acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS, 23.5%), inborn errors of metabolism (13.8%), severe aplastic anemia (SAA, 10.6%), Fanconi anemia (8.3%), chronic myelogenous leukemia (CML, 6.5%), immune disorders (4%), sickle cell disease or thalassemia (1.9%), and other diseases.

Most patients had a related donor (57.9%), and most received a bone marrow transplant (73.4%).

The most common component of conditioning was cyclophosphamide (80.5%), followed by total body irradiation (TBI, 64.3%). About half of patients (49.8%) received both cyclophosphamide and TBI, and nearly a quarter (23.5%) received busulfan and cyclophosphamide.

Outcomes

The researchers found that allo-HSCT recipients had a 14.4-fold greater risk of premature death than the general population.

The team said the absolute excess risk of all-cause mortality was 12.0 per 1000 person-years, and relative mortality remained elevated 25 years or more after transplant (standardized mortality ratio, 2.9).

At a median follow-up of 14.9 years (range, 2.0 to 41.2), 295 patients had died. The 20-year overall survival rate was 79.3%.

The cause of death was available for 82.7% of patients (244/295), and some of these patients had more than 1 cause listed. Causes of death included:

• Infection and/or chronic GVHD—49.6%
• Primary disease—24.6%
• Subsequent malignant neoplasm—18.4%
• Cardiac disease—9.8%
• Pulmonary disease—7.8%
• External causes—2.9%
• Other causes—18.0%.

The hazard of all-cause late mortality was higher among patients who were older at transplant (hazard ratio [HR], 1.03; P=0.004) and those who had a high risk of relapse at transplant (HR, 1.95; P<0.001).

Compared to patients treated for ALL, the hazard of all-cause late mortality was lower among patients with AML/MDS (HR, 0.72; P=0.04), CML (HR, 0.53; P=0.02), Fanconi anemia (HR, 0.49; P=0.03), immune disorders (HR, 0.32; P=0.006), and SAA (HR, 0.33; P<0.001).

The hazard of all-cause late mortality was lower for patients who received conditioning with busulfan and cyclophosphamide (HR, 0.62; P=0.03) than for those who received TBI and cyclophosphamide.

Compared to patients treated for ALL, the hazard of relapse-related mortality was lower among patients with AML/MDS (HR, 0.39; P=0.01) and SAA (HR, 0.09; P=0.03), and the hazard of non-relapse mortality was lower for patients with SAA (HR, 0.36; P=0.004) and immune disorders (HR, 0.14; P=0.009).

The hazard of non-relapse mortality was higher for patients who were older at transplant (HR, 1.03; P=0.03), patients who received peripheral blood stem cells rather than bone marrow (HR, 2.39; P=0.01), and patients who had a high risk of relapse at transplant (HR, 2.05; P<0.001).

Photo from UAB

Children may have an increased risk of premature death decades after allogeneic hematopoietic stem cell transplant (allo-HSCT), according to a study published in JAMA Oncology.

The leading causes of death in the patients studied were infection and chronic graft-vs-host disease (GVHD), patients’ primary disease, and subsequent cancers.

“This study shows that, while we are able to save the life of the child during their cancer treatment, we need to continue to provide proactive follow-up care with these types of patients throughout the rest of their life, as they are still an at-risk population,” said study author Smita Bhatia, MBBS, of the University of Alabama at Birmingham (UAB).

“The high intensity of therapeutic exposures at a young age lends itself to cause morbidities and organ compromise once they reach adulthood.”

Dr Bhatia and her colleagues conducted this retrospective study of children who underwent allo-HSCT between January 1, 1974, and December 31, 2010, and were followed until December 31, 2016.

The study included 1388 patients who lived 2 years or more after transplant. Their median age at transplant was 14.6 years (range, 0-21). The majority of patients were non-Hispanic white (70.7%), and most were male (59.7%).

Patients underwent allo-HSCT to treat acute lymphoblastic leukemia (ALL, 25.1%), acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS, 23.5%), inborn errors of metabolism (13.8%), severe aplastic anemia (SAA, 10.6%), Fanconi anemia (8.3%), chronic myelogenous leukemia (CML, 6.5%), immune disorders (4%), sickle cell disease or thalassemia (1.9%), and other diseases.

Most patients had a related donor (57.9%), and most received a bone marrow transplant (73.4%).

The most common component of conditioning was cyclophosphamide (80.5%), followed by total body irradiation (TBI, 64.3%). About half of patients (49.8%) received both cyclophosphamide and TBI, and nearly a quarter (23.5%) received busulfan and cyclophosphamide.

Outcomes

The researchers found that allo-HSCT recipients had a 14.4-fold greater risk of premature death than the general population.

The team said the absolute excess risk of all-cause mortality was 12.0 per 1000 person-years, and relative mortality remained elevated 25 years or more after transplant (standardized mortality ratio, 2.9).

At a median follow-up of 14.9 years (range, 2.0 to 41.2), 295 patients had died. The 20-year overall survival rate was 79.3%.

The cause of death was available for 82.7% of patients (244/295), and some of these patients had more than 1 cause listed. Causes of death included:

• Infection and/or chronic GVHD—49.6%
• Primary disease—24.6%
• Subsequent malignant neoplasm—18.4%
• Cardiac disease—9.8%
• Pulmonary disease—7.8%
• External causes—2.9%
• Other causes—18.0%.

The hazard of all-cause late mortality was higher among patients who were older at transplant (hazard ratio [HR], 1.03; P=0.004) and those who had a high risk of relapse at transplant (HR, 1.95; P<0.001).

Compared to patients treated for ALL, the hazard of all-cause late mortality was lower among patients with AML/MDS (HR, 0.72; P=0.04), CML (HR, 0.53; P=0.02), Fanconi anemia (HR, 0.49; P=0.03), immune disorders (HR, 0.32; P=0.006), and SAA (HR, 0.33; P<0.001).

The hazard of all-cause late mortality was lower for patients who received conditioning with busulfan and cyclophosphamide (HR, 0.62; P=0.03) than for those who received TBI and cyclophosphamide.

Compared to patients treated for ALL, the hazard of relapse-related mortality was lower among patients with AML/MDS (HR, 0.39; P=0.01) and SAA (HR, 0.09; P=0.03), and the hazard of non-relapse mortality was lower for patients with SAA (HR, 0.36; P=0.004) and immune disorders (HR, 0.14; P=0.009).

The hazard of non-relapse mortality was higher for patients who were older at transplant (HR, 1.03; P=0.03), patients who received peripheral blood stem cells rather than bone marrow (HR, 2.39; P=0.01), and patients who had a high risk of relapse at transplant (HR, 2.05; P<0.001).

Photo from UAB

Children may have an increased risk of premature death decades after allogeneic hematopoietic stem cell transplant (allo-HSCT), according to a study published in JAMA Oncology.

The leading causes of death in the patients studied were infection and chronic graft-vs-host disease (GVHD), patients’ primary disease, and subsequent cancers.

“This study shows that, while we are able to save the life of the child during their cancer treatment, we need to continue to provide proactive follow-up care with these types of patients throughout the rest of their life, as they are still an at-risk population,” said study author Smita Bhatia, MBBS, of the University of Alabama at Birmingham (UAB).

“The high intensity of therapeutic exposures at a young age lends itself to cause morbidities and organ compromise once they reach adulthood.”

Dr Bhatia and her colleagues conducted this retrospective study of children who underwent allo-HSCT between January 1, 1974, and December 31, 2010, and were followed until December 31, 2016.

The study included 1388 patients who lived 2 years or more after transplant. Their median age at transplant was 14.6 years (range, 0-21). The majority of patients were non-Hispanic white (70.7%), and most were male (59.7%).

Patients underwent allo-HSCT to treat acute lymphoblastic leukemia (ALL, 25.1%), acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS, 23.5%), inborn errors of metabolism (13.8%), severe aplastic anemia (SAA, 10.6%), Fanconi anemia (8.3%), chronic myelogenous leukemia (CML, 6.5%), immune disorders (4%), sickle cell disease or thalassemia (1.9%), and other diseases.

Most patients had a related donor (57.9%), and most received a bone marrow transplant (73.4%).

The most common component of conditioning was cyclophosphamide (80.5%), followed by total body irradiation (TBI, 64.3%). About half of patients (49.8%) received both cyclophosphamide and TBI, and nearly a quarter (23.5%) received busulfan and cyclophosphamide.

Outcomes

The researchers found that allo-HSCT recipients had a 14.4-fold greater risk of premature death than the general population.

The team said the absolute excess risk of all-cause mortality was 12.0 per 1000 person-years, and relative mortality remained elevated 25 years or more after transplant (standardized mortality ratio, 2.9).

At a median follow-up of 14.9 years (range, 2.0 to 41.2), 295 patients had died. The 20-year overall survival rate was 79.3%.

The cause of death was available for 82.7% of patients (244/295), and some of these patients had more than 1 cause listed. Causes of death included:

• Infection and/or chronic GVHD—49.6%
• Primary disease—24.6%
• Subsequent malignant neoplasm—18.4%
• Cardiac disease—9.8%
• Pulmonary disease—7.8%
• External causes—2.9%
• Other causes—18.0%.

The hazard of all-cause late mortality was higher among patients who were older at transplant (hazard ratio [HR], 1.03; P=0.004) and those who had a high risk of relapse at transplant (HR, 1.95; P<0.001).

Compared to patients treated for ALL, the hazard of all-cause late mortality was lower among patients with AML/MDS (HR, 0.72; P=0.04), CML (HR, 0.53; P=0.02), Fanconi anemia (HR, 0.49; P=0.03), immune disorders (HR, 0.32; P=0.006), and SAA (HR, 0.33; P<0.001).

The hazard of all-cause late mortality was lower for patients who received conditioning with busulfan and cyclophosphamide (HR, 0.62; P=0.03) than for those who received TBI and cyclophosphamide.

Compared to patients treated for ALL, the hazard of relapse-related mortality was lower among patients with AML/MDS (HR, 0.39; P=0.01) and SAA (HR, 0.09; P=0.03), and the hazard of non-relapse mortality was lower for patients with SAA (HR, 0.36; P=0.004) and immune disorders (HR, 0.14; P=0.009).

The hazard of non-relapse mortality was higher for patients who were older at transplant (HR, 1.03; P=0.03), patients who received peripheral blood stem cells rather than bone marrow (HR, 2.39; P=0.01), and patients who had a high risk of relapse at transplant (HR, 2.05; P<0.001).

Photo by Chad McNeeley

The European Medicines Agency’s (EMA’s) Committee for Orphan Medicinal Products (COMP) has issued a positive opinion recommending orphan drug designation for OMS721 as a treatment for high-risk hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA).

OMS721 is a monoclonal antibody targeting MASP-2, the effector enzyme of the lectin pathway of the complement system.

The COMP’s positive opinion of OMS721 for HSCT-TMA is expected to be adopted by the European Commission in August.

Orphan drug designation in Europe is available to companies developing products intended to treat a life-threatening or chronically debilitating condition that affects fewer than 5 in 10,000 people in the European Union (EU).

This designation allows for financial and regulatory incentives that include 10 years of marketing exclusivity in the EU after product approval, reduced EMA advisory, inspection and filing fees pre- and post-approval, and guaranteed access to centralized marketing authorization valid in all EU member states as well as in European Economic Area countries (ie, Iceland, Liechtenstein, and Norway).

Phase 2 trial

OMS721 is currently under evaluation in a phase 2 trial (NCT02222545). Omeros Corporation, the company developing OMS721, released some results from this study in February.

Results were reported for 18 adults with HSCT-TMA persisting for at least 2 weeks following immunosuppressive regimen modification or more than 30 days post-transplant. The patients received weekly OMS721 treatments for 4 to 8 weeks at the discretion of the investigator.

These patients had a significantly longer median overall survival than historical controls—347 days and 21 days, respectively (P<0.0001).

Omeros also reported that markers of TMA activity significantly improved following OMS721 treatment.

The mean platelet count increased from 18,100 x 10⁶/mL at baseline to 52,300 x 10⁶/mL (P=0.017). The mean LDH decreased from 591 U/L to 250 U/L (P<0.001). And the mean haptoglobin increased from 8 mg/dL to 141 mg/dL (P=0.003).

Mean creatinine remained stable—at approximately 120 μmol/L—but a majority of patients had co-existing conditions for which they were receiving nephrotoxic medications. These conditions included graft-versus-host disease, cytomegalovirus and human herpes virus 6 infections, prior sepsis, diffuse alveolar hemorrhage, and residual underlying malignancies.

The most commonly reported adverse events in this trial were diarrhea and neutropenia.

Four deaths occurred. One of these—due to acute renal and respiratory failure—was considered possibly related to OMS721.

The other deaths were due to progression of acute myeloid leukemia (n=1) and neutropenic sepsis (n=2).

Photo by Chad McNeeley

The European Medicines Agency’s (EMA’s) Committee for Orphan Medicinal Products (COMP) has issued a positive opinion recommending orphan drug designation for OMS721 as a treatment for high-risk hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA).

OMS721 is a monoclonal antibody targeting MASP-2, the effector enzyme of the lectin pathway of the complement system.

The COMP’s positive opinion of OMS721 for HSCT-TMA is expected to be adopted by the European Commission in August.

Orphan drug designation in Europe is available to companies developing products intended to treat a life-threatening or chronically debilitating condition that affects fewer than 5 in 10,000 people in the European Union (EU).

This designation allows for financial and regulatory incentives that include 10 years of marketing exclusivity in the EU after product approval, reduced EMA advisory, inspection and filing fees pre- and post-approval, and guaranteed access to centralized marketing authorization valid in all EU member states as well as in European Economic Area countries (ie, Iceland, Liechtenstein, and Norway).

Phase 2 trial

OMS721 is currently under evaluation in a phase 2 trial (NCT02222545). Omeros Corporation, the company developing OMS721, released some results from this study in February.

Results were reported for 18 adults with HSCT-TMA persisting for at least 2 weeks following immunosuppressive regimen modification or more than 30 days post-transplant. The patients received weekly OMS721 treatments for 4 to 8 weeks at the discretion of the investigator.

These patients had a significantly longer median overall survival than historical controls—347 days and 21 days, respectively (P<0.0001).

Omeros also reported that markers of TMA activity significantly improved following OMS721 treatment.

The mean platelet count increased from 18,100 x 10⁶/mL at baseline to 52,300 x 10⁶/mL (P=0.017). The mean LDH decreased from 591 U/L to 250 U/L (P<0.001). And the mean haptoglobin increased from 8 mg/dL to 141 mg/dL (P=0.003).

Mean creatinine remained stable—at approximately 120 μmol/L—but a majority of patients had co-existing conditions for which they were receiving nephrotoxic medications. These conditions included graft-versus-host disease, cytomegalovirus and human herpes virus 6 infections, prior sepsis, diffuse alveolar hemorrhage, and residual underlying malignancies.

The most commonly reported adverse events in this trial were diarrhea and neutropenia.

Four deaths occurred. One of these—due to acute renal and respiratory failure—was considered possibly related to OMS721.

The other deaths were due to progression of acute myeloid leukemia (n=1) and neutropenic sepsis (n=2).

Photo by Chad McNeeley

The European Medicines Agency’s (EMA’s) Committee for Orphan Medicinal Products (COMP) has issued a positive opinion recommending orphan drug designation for OMS721 as a treatment for high-risk hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA).

OMS721 is a monoclonal antibody targeting MASP-2, the effector enzyme of the lectin pathway of the complement system.

The COMP’s positive opinion of OMS721 for HSCT-TMA is expected to be adopted by the European Commission in August.

Orphan drug designation in Europe is available to companies developing products intended to treat a life-threatening or chronically debilitating condition that affects fewer than 5 in 10,000 people in the European Union (EU).

This designation allows for financial and regulatory incentives that include 10 years of marketing exclusivity in the EU after product approval, reduced EMA advisory, inspection and filing fees pre- and post-approval, and guaranteed access to centralized marketing authorization valid in all EU member states as well as in European Economic Area countries (ie, Iceland, Liechtenstein, and Norway).

Phase 2 trial

OMS721 is currently under evaluation in a phase 2 trial (NCT02222545). Omeros Corporation, the company developing OMS721, released some results from this study in February.

Results were reported for 18 adults with HSCT-TMA persisting for at least 2 weeks following immunosuppressive regimen modification or more than 30 days post-transplant. The patients received weekly OMS721 treatments for 4 to 8 weeks at the discretion of the investigator.

These patients had a significantly longer median overall survival than historical controls—347 days and 21 days, respectively (P<0.0001).

Omeros also reported that markers of TMA activity significantly improved following OMS721 treatment.

The mean platelet count increased from 18,100 x 10⁶/mL at baseline to 52,300 x 10⁶/mL (P=0.017). The mean LDH decreased from 591 U/L to 250 U/L (P<0.001). And the mean haptoglobin increased from 8 mg/dL to 141 mg/dL (P=0.003).

Mean creatinine remained stable—at approximately 120 μmol/L—but a majority of patients had co-existing conditions for which they were receiving nephrotoxic medications. These conditions included graft-versus-host disease, cytomegalovirus and human herpes virus 6 infections, prior sepsis, diffuse alveolar hemorrhage, and residual underlying malignancies.

The most commonly reported adverse events in this trial were diarrhea and neutropenia.

Four deaths occurred. One of these—due to acute renal and respiratory failure—was considered possibly related to OMS721.

The other deaths were due to progression of acute myeloid leukemia (n=1) and neutropenic sepsis (n=2).

Hospital/Justin Veneman

New findings could help improve treatment of an inherited bone marrow disorder known as myelodysplasia and leukemia syndrome with monosomy 7 (MLSM7), according to researchers.

While studying families affected by MLSM7, researchers identified germline mutations in SAMD9L or SAMD9 in patients who had hematologic abnormalities, myelodysplastic syndromes (MDS), or acute myeloid leukemia (AML).

However, these mutations were also present in apparently healthy family members, and the researchers found that bone marrow monosomy 7 sometimes resolved without treatment.

The team recounted these findings in JCI Insight.

The researchers analyzed blood samples from 16 siblings in 5 families affected by MLSM7 and found they all carried germline mutations in SAMD9 or SAMD9L. In 3 of the 5 families, there were apparently healthy parents who also carried the mutations.

“Surprisingly, the health consequences of these mutations varied tremendously for reasons that must still be determined, but the findings are already affecting how we may choose to manage these patients,” said study author Jeffery Klco, MD, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

Three of the 16 siblings developed AML and died of the disease or related complications. Two other siblings were diagnosed with MDS.

The remaining 11 siblings with the mutations were apparently healthy, although several had been treated for anemia and other conditions associated with low blood counts.

Some of these patients had a previous history of bone marrow monosomy 7 that spontaneously corrected over time. These patients, despite no therapy, appeared to have normal bone marrow function.

“This was an even greater surprise,” Dr Klco said. “The spontaneous recovery experienced by some children with the germline mutations suggests some patients with SAMD9 and SAMD9L mutations who were previously considered candidates for bone marrow transplantation may recover hematologic function on their own.”

Dr Klco and his colleagues have a theory that could explain the spontaneous correction. The team noted that SAMD9 and SAMD9L are activated in response to viral infections. While the normal function of both proteins is poorly understood, abnormally activated SAMD9 and SAMD9L are known to inhibit cell growth.

In this study, deep sequencing showed that selective pressure on developing blood cells favors cells without the SAMD9 or SAMD9L mutations. That may increase pressure for cells to selectively jettison chromosome 7 with the gene alteration or take other molecular measures to counteract the mutant protein.

Implications for treatment

This research also showed that, in patients who developed AML, loss of chromosome 7 was associated with the development of mutations in additional genes, including ETV6, KRAS, SETBP1, and RUNX1.

These same mutations are broadly associated with monosomy 7 in AML, which suggests that understanding how SAMD9 and SAMD9L mutations contribute to leukemia has implications beyond familial cases.

The presence of secondary mutations may also help clinicians identify which patients will benefit from immediate treatment, including chemotherapy or transplant to prevent or treat AML or myelodysplasia, Dr Klco said.

For patients without the mutations or significant symptoms due to low blood cell counts, watchful waiting with careful follow-up may sometimes be an option.

“Now that we know this disease can resolve without treatment in some patients, we need to focus on developing screening and treatment guidelines,” Dr Klco said. “We want to reserve hematopoietic bone marrow transplantation for those who truly need the procedure. These findings will help to point the way.”

“So little is known about SAMD9 and SAMD9L that we need to continue working in the lab to better understand how these mutations impact blood cell development and how they are activated in response to infections and other types of stress.”

Hospital/Justin Veneman

New findings could help improve treatment of an inherited bone marrow disorder known as myelodysplasia and leukemia syndrome with monosomy 7 (MLSM7), according to researchers.

While studying families affected by MLSM7, researchers identified germline mutations in SAMD9L or SAMD9 in patients who had hematologic abnormalities, myelodysplastic syndromes (MDS), or acute myeloid leukemia (AML).

However, these mutations were also present in apparently healthy family members, and the researchers found that bone marrow monosomy 7 sometimes resolved without treatment.

The team recounted these findings in JCI Insight.

The researchers analyzed blood samples from 16 siblings in 5 families affected by MLSM7 and found they all carried germline mutations in SAMD9 or SAMD9L. In 3 of the 5 families, there were apparently healthy parents who also carried the mutations.

“Surprisingly, the health consequences of these mutations varied tremendously for reasons that must still be determined, but the findings are already affecting how we may choose to manage these patients,” said study author Jeffery Klco, MD, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

Three of the 16 siblings developed AML and died of the disease or related complications. Two other siblings were diagnosed with MDS.

The remaining 11 siblings with the mutations were apparently healthy, although several had been treated for anemia and other conditions associated with low blood counts.

Some of these patients had a previous history of bone marrow monosomy 7 that spontaneously corrected over time. These patients, despite no therapy, appeared to have normal bone marrow function.

“This was an even greater surprise,” Dr Klco said. “The spontaneous recovery experienced by some children with the germline mutations suggests some patients with SAMD9 and SAMD9L mutations who were previously considered candidates for bone marrow transplantation may recover hematologic function on their own.”

Dr Klco and his colleagues have a theory that could explain the spontaneous correction. The team noted that SAMD9 and SAMD9L are activated in response to viral infections. While the normal function of both proteins is poorly understood, abnormally activated SAMD9 and SAMD9L are known to inhibit cell growth.

In this study, deep sequencing showed that selective pressure on developing blood cells favors cells without the SAMD9 or SAMD9L mutations. That may increase pressure for cells to selectively jettison chromosome 7 with the gene alteration or take other molecular measures to counteract the mutant protein.

Implications for treatment

This research also showed that, in patients who developed AML, loss of chromosome 7 was associated with the development of mutations in additional genes, including ETV6, KRAS, SETBP1, and RUNX1.

These same mutations are broadly associated with monosomy 7 in AML, which suggests that understanding how SAMD9 and SAMD9L mutations contribute to leukemia has implications beyond familial cases.

The presence of secondary mutations may also help clinicians identify which patients will benefit from immediate treatment, including chemotherapy or transplant to prevent or treat AML or myelodysplasia, Dr Klco said.

For patients without the mutations or significant symptoms due to low blood cell counts, watchful waiting with careful follow-up may sometimes be an option.

“Now that we know this disease can resolve without treatment in some patients, we need to focus on developing screening and treatment guidelines,” Dr Klco said. “We want to reserve hematopoietic bone marrow transplantation for those who truly need the procedure. These findings will help to point the way.”

“So little is known about SAMD9 and SAMD9L that we need to continue working in the lab to better understand how these mutations impact blood cell development and how they are activated in response to infections and other types of stress.”

Hospital/Justin Veneman

New findings could help improve treatment of an inherited bone marrow disorder known as myelodysplasia and leukemia syndrome with monosomy 7 (MLSM7), according to researchers.

While studying families affected by MLSM7, researchers identified germline mutations in SAMD9L or SAMD9 in patients who had hematologic abnormalities, myelodysplastic syndromes (MDS), or acute myeloid leukemia (AML).

However, these mutations were also present in apparently healthy family members, and the researchers found that bone marrow monosomy 7 sometimes resolved without treatment.

The team recounted these findings in JCI Insight.

The researchers analyzed blood samples from 16 siblings in 5 families affected by MLSM7 and found they all carried germline mutations in SAMD9 or SAMD9L. In 3 of the 5 families, there were apparently healthy parents who also carried the mutations.

“Surprisingly, the health consequences of these mutations varied tremendously for reasons that must still be determined, but the findings are already affecting how we may choose to manage these patients,” said study author Jeffery Klco, MD, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

Three of the 16 siblings developed AML and died of the disease or related complications. Two other siblings were diagnosed with MDS.

The remaining 11 siblings with the mutations were apparently healthy, although several had been treated for anemia and other conditions associated with low blood counts.

Some of these patients had a previous history of bone marrow monosomy 7 that spontaneously corrected over time. These patients, despite no therapy, appeared to have normal bone marrow function.

“This was an even greater surprise,” Dr Klco said. “The spontaneous recovery experienced by some children with the germline mutations suggests some patients with SAMD9 and SAMD9L mutations who were previously considered candidates for bone marrow transplantation may recover hematologic function on their own.”

Dr Klco and his colleagues have a theory that could explain the spontaneous correction. The team noted that SAMD9 and SAMD9L are activated in response to viral infections. While the normal function of both proteins is poorly understood, abnormally activated SAMD9 and SAMD9L are known to inhibit cell growth.

In this study, deep sequencing showed that selective pressure on developing blood cells favors cells without the SAMD9 or SAMD9L mutations. That may increase pressure for cells to selectively jettison chromosome 7 with the gene alteration or take other molecular measures to counteract the mutant protein.

Implications for treatment

This research also showed that, in patients who developed AML, loss of chromosome 7 was associated with the development of mutations in additional genes, including ETV6, KRAS, SETBP1, and RUNX1.

These same mutations are broadly associated with monosomy 7 in AML, which suggests that understanding how SAMD9 and SAMD9L mutations contribute to leukemia has implications beyond familial cases.

The presence of secondary mutations may also help clinicians identify which patients will benefit from immediate treatment, including chemotherapy or transplant to prevent or treat AML or myelodysplasia, Dr Klco said.

For patients without the mutations or significant symptoms due to low blood cell counts, watchful waiting with careful follow-up may sometimes be an option.

“Now that we know this disease can resolve without treatment in some patients, we need to focus on developing screening and treatment guidelines,” Dr Klco said. “We want to reserve hematopoietic bone marrow transplantation for those who truly need the procedure. These findings will help to point the way.”

“So little is known about SAMD9 and SAMD9L that we need to continue working in the lab to better understand how these mutations impact blood cell development and how they are activated in response to infections and other types of stress.”

Photo courtesy of the CDC

Depression and the use of antidepressants are each associated with an increased risk of venous thromboembolism (VTE), according to a review and meta-analysis published in Annals of Medicine.

The research also showed that each of the various classes of antidepressant medications is associated with an increased risk of VTE.

The researchers noted that this study does not prove cause and effect, and further studies are needed to determine what is driving the observed increase in VTE risk.

Some previous studies have indicated that depression and antidepressant use might be associated with an increased risk of VTE, but other studies have shown no evidence of associations.

Therefore, Setor Kunutsor, MD, PhD, of the University of Bristol in Bristol, UK, and his colleagues conducted a systematic review and meta-analysis of observational studies evaluating the associations of depression and antidepressant use with VTE risk.

The researchers looked at 8 observational studies with data on 960,113 non-overlapping participants. There were 9027 cases of VTE in this population.

To determine the association between depression and VTE, the researchers conducted a pooled analysis of 3 studies comparing patients with depression and without. These studies included 865,878 participants and 4676 cases of VTE.

The relative risk (RR) for VTE was 1.31 (95% CI, 1.13-1.53) among patients with depression.

The researchers also conducted a pooled analysis of 6 studies comparing antidepressant users to non-users. These studies included 828,327 participants and 8273 cases of VTE.

The RR for VTE was 1.27 (95% CI, 1.06-1.51) among patients taking antidepressants.

In addition, individual antidepressants were associated with an increased risk of VTE. This includes:

• Tricyclic antidepressants—RR=1.16 (95% CI, 1.06-1.27)
• Selective serotonin reuptake inhibitors—RR=1.12 (95% CI, 1.02-1.23)
• “Other” antidepressants*—RR=1.59 (95% CI, 1.21-2.09).

The researchers said these data show that antidepressant use and depression are each associated with an increased risk of VTE, and these results add to accumulating evidence that a relationship exists between depression, antidepressant use, and VTE.

“These findings are very useful to me as both a clinician and a researcher,” Dr Kunutsor said. “It gives me the information I need, especially when prescribing antidepressant medications to my patients.”

Still, Dr Kunutsor and his colleagues conceded that more research is needed to determine if the observed associations are causal and if depression, antidepressant use, or both drive the increased risk of VTE.

To so this, studies would need to isolate depression from antidepressant medications. For example, researchers could assess if non-depressed individuals who use antidepressants for other conditions have an increased risk of VTE.

*The “other” antidepressants include monoamine oxidase inhibitors, triazolopyridine, serotonin norepinephrine reuptake inhibitors, and norepinephrine dopamine reuptake inhibitors.

Photo courtesy of the CDC

Depression and the use of antidepressants are each associated with an increased risk of venous thromboembolism (VTE), according to a review and meta-analysis published in Annals of Medicine.

The research also showed that each of the various classes of antidepressant medications is associated with an increased risk of VTE.

The researchers noted that this study does not prove cause and effect, and further studies are needed to determine what is driving the observed increase in VTE risk.

Some previous studies have indicated that depression and antidepressant use might be associated with an increased risk of VTE, but other studies have shown no evidence of associations.

Therefore, Setor Kunutsor, MD, PhD, of the University of Bristol in Bristol, UK, and his colleagues conducted a systematic review and meta-analysis of observational studies evaluating the associations of depression and antidepressant use with VTE risk.

The researchers looked at 8 observational studies with data on 960,113 non-overlapping participants. There were 9027 cases of VTE in this population.

To determine the association between depression and VTE, the researchers conducted a pooled analysis of 3 studies comparing patients with depression and without. These studies included 865,878 participants and 4676 cases of VTE.

The relative risk (RR) for VTE was 1.31 (95% CI, 1.13-1.53) among patients with depression.

The researchers also conducted a pooled analysis of 6 studies comparing antidepressant users to non-users. These studies included 828,327 participants and 8273 cases of VTE.

The RR for VTE was 1.27 (95% CI, 1.06-1.51) among patients taking antidepressants.

In addition, individual antidepressants were associated with an increased risk of VTE. This includes:

• Tricyclic antidepressants—RR=1.16 (95% CI, 1.06-1.27)
• Selective serotonin reuptake inhibitors—RR=1.12 (95% CI, 1.02-1.23)
• “Other” antidepressants*—RR=1.59 (95% CI, 1.21-2.09).

The researchers said these data show that antidepressant use and depression are each associated with an increased risk of VTE, and these results add to accumulating evidence that a relationship exists between depression, antidepressant use, and VTE.

“These findings are very useful to me as both a clinician and a researcher,” Dr Kunutsor said. “It gives me the information I need, especially when prescribing antidepressant medications to my patients.”

Still, Dr Kunutsor and his colleagues conceded that more research is needed to determine if the observed associations are causal and if depression, antidepressant use, or both drive the increased risk of VTE.

To so this, studies would need to isolate depression from antidepressant medications. For example, researchers could assess if non-depressed individuals who use antidepressants for other conditions have an increased risk of VTE.

*The “other” antidepressants include monoamine oxidase inhibitors, triazolopyridine, serotonin norepinephrine reuptake inhibitors, and norepinephrine dopamine reuptake inhibitors.

Photo courtesy of the CDC

Depression and the use of antidepressants are each associated with an increased risk of venous thromboembolism (VTE), according to a review and meta-analysis published in Annals of Medicine.

The research also showed that each of the various classes of antidepressant medications is associated with an increased risk of VTE.

The researchers noted that this study does not prove cause and effect, and further studies are needed to determine what is driving the observed increase in VTE risk.

Some previous studies have indicated that depression and antidepressant use might be associated with an increased risk of VTE, but other studies have shown no evidence of associations.

Therefore, Setor Kunutsor, MD, PhD, of the University of Bristol in Bristol, UK, and his colleagues conducted a systematic review and meta-analysis of observational studies evaluating the associations of depression and antidepressant use with VTE risk.

The researchers looked at 8 observational studies with data on 960,113 non-overlapping participants. There were 9027 cases of VTE in this population.

To determine the association between depression and VTE, the researchers conducted a pooled analysis of 3 studies comparing patients with depression and without. These studies included 865,878 participants and 4676 cases of VTE.

The relative risk (RR) for VTE was 1.31 (95% CI, 1.13-1.53) among patients with depression.

The researchers also conducted a pooled analysis of 6 studies comparing antidepressant users to non-users. These studies included 828,327 participants and 8273 cases of VTE.

The RR for VTE was 1.27 (95% CI, 1.06-1.51) among patients taking antidepressants.

In addition, individual antidepressants were associated with an increased risk of VTE. This includes:

• Tricyclic antidepressants—RR=1.16 (95% CI, 1.06-1.27)
• Selective serotonin reuptake inhibitors—RR=1.12 (95% CI, 1.02-1.23)
• “Other” antidepressants*—RR=1.59 (95% CI, 1.21-2.09).

The researchers said these data show that antidepressant use and depression are each associated with an increased risk of VTE, and these results add to accumulating evidence that a relationship exists between depression, antidepressant use, and VTE.

“These findings are very useful to me as both a clinician and a researcher,” Dr Kunutsor said. “It gives me the information I need, especially when prescribing antidepressant medications to my patients.”

Still, Dr Kunutsor and his colleagues conceded that more research is needed to determine if the observed associations are causal and if depression, antidepressant use, or both drive the increased risk of VTE.

To so this, studies would need to isolate depression from antidepressant medications. For example, researchers could assess if non-depressed individuals who use antidepressants for other conditions have an increased risk of VTE.

*The “other” antidepressants include monoamine oxidase inhibitors, triazolopyridine, serotonin norepinephrine reuptake inhibitors, and norepinephrine dopamine reuptake inhibitors.

Image by Spencer Phillips

The European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use has granted accelerated assessment for the upcoming marketing authorization application (MAA) for LentiGlobin™.

LentiGlobin is a gene therapy intended for the treatment of adolescents and adults with transfusion-dependent β-thalassemia (TDT) and a non-β0/β0 genotype.

bluebird bio intends to file an MAA for LentiGlobin with the EMA this year.

Accelerated assessment can reduce the active review time of an MAA from 210 days to 150 days once it has been validated by the EMA.

An accelerated assessment is granted to products deemed to be of major interest for public health and represent therapeutic innovation.

The accelerated assessment for LentiGlobin is supported by data from clinical studies, including the phase 1/2 Northstar (HGB-204) study, phase 1/2 HGB-205 study, phase 3 Northstar-2 (HGB-207) study, and the long-term follow-up study LTF-303.

The EMA previously granted PRIME (Priority Medicines) eligibility and orphan designation to LentiGlobin for the treatment of TDT.

LentiGlobin is also part of the EMA’s Adaptive Pathways pilot program, which is part of the EMA’s effort to improve timely access to new medicines.

Phase 1/2 trials

Results from the phase 1/2 trials of LentiGlobin—HGB-204 and HGB-205—were published in NEJM in April.

HGB-204 is a completed study that included 18 patients with TDT. Eight patients had a β0/β0 genotype, 6 had a βE/β0 genotype, and 4 had other genotypes.

HGB-205 is an ongoing study, and results were reported for 4 patients with TDT. Three patients had a βE/β0 genotype. The remaining patient was homozygous for the IVS1-110 mutation and had a severe clinical presentation similar to that seen in β0/β0 genotypes.

For both studies, the researchers harvested hematopoietic stem and progenitor cells (mobilized with filgrastim and plerixafor) from the patients. CD34+ cells were transduced ex vivo with LentiGlobin BB305 vector, which encodes adult hemoglobin (HbA) with a T87Q amino acid substitution (HbAT87Q).

The patients underwent myeloablative conditioning with busulfan, and the final LentiGlobin product was infused into patients after a 72-hour washout period.

In HGB-205 only, patients received enhanced red blood cell (RBC) transfusions for at least 3 months before stem cell mobilization and harvest to maintain a hemoglobin level of more than 11.0 g/dL.

Safety

In HGB-204, there were 5 grade 1 adverse events (AEs) considered possibly or probably related to LentiGlobin—abdominal pain (n=2), dyspnea (n=1), hot flush (n=1), and non-cardiac chest pain (n=1).

There were 9 serious AEs. Grade 3 serious AEs included 2 episodes of veno-occlusive liver disease that were attributed to busulfan, Klebsiella infection, cardiac ventricular thrombosis, cellulitis, hyperglycemia, and gastroenteritis. Grade 2 serious AEs included device-related thrombosis and infectious diarrhea.

In HGB-205, there were no AEs considered possibly or probably related to LentiGlobin. The 3 serious AEs were tooth infection (grade 3),  major depression (grade 3), and pneumonia (grade 2).

Efficacy

The median time to neutrophil engraftment was 18.5 days (range, 14.0 to 30.0) in HGB-204 and 16.5 days (range, 14.0 to 29.0) in HGB-205.

The median time to platelet engraftment was 39.5 days (range, 19.0 to 191.0) and 23.0 days (range, 20.0 to 26.0), respectively.

In both studies, the median follow-up was 26 months (range, 15 to 42) after LentiGlobin infusion.

At last follow-up, all but 1 of the 13 patients with a non-β0/β0 genotype had stopped receiving RBC transfusions.

In the 8 patients with a β0/β0 genotype and the 1 patient with 2 copies of the IVS1-110 mutation, the median annualized transfusion volume decreased by 73% after LentiGlobin administration.

Two patients with a β0/β0 genotype were able to stop receiving RBC transfusions, as was the patient with 2 copies of the IVS1-110 mutation.

Image by Spencer Phillips

The European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use has granted accelerated assessment for the upcoming marketing authorization application (MAA) for LentiGlobin™.

LentiGlobin is a gene therapy intended for the treatment of adolescents and adults with transfusion-dependent β-thalassemia (TDT) and a non-β0/β0 genotype.

bluebird bio intends to file an MAA for LentiGlobin with the EMA this year.

Accelerated assessment can reduce the active review time of an MAA from 210 days to 150 days once it has been validated by the EMA.

An accelerated assessment is granted to products deemed to be of major interest for public health and represent therapeutic innovation.

The accelerated assessment for LentiGlobin is supported by data from clinical studies, including the phase 1/2 Northstar (HGB-204) study, phase 1/2 HGB-205 study, phase 3 Northstar-2 (HGB-207) study, and the long-term follow-up study LTF-303.

The EMA previously granted PRIME (Priority Medicines) eligibility and orphan designation to LentiGlobin for the treatment of TDT.

LentiGlobin is also part of the EMA’s Adaptive Pathways pilot program, which is part of the EMA’s effort to improve timely access to new medicines.

Phase 1/2 trials

Results from the phase 1/2 trials of LentiGlobin—HGB-204 and HGB-205—were published in NEJM in April.

HGB-204 is a completed study that included 18 patients with TDT. Eight patients had a β0/β0 genotype, 6 had a βE/β0 genotype, and 4 had other genotypes.

HGB-205 is an ongoing study, and results were reported for 4 patients with TDT. Three patients had a βE/β0 genotype. The remaining patient was homozygous for the IVS1-110 mutation and had a severe clinical presentation similar to that seen in β0/β0 genotypes.

For both studies, the researchers harvested hematopoietic stem and progenitor cells (mobilized with filgrastim and plerixafor) from the patients. CD34+ cells were transduced ex vivo with LentiGlobin BB305 vector, which encodes adult hemoglobin (HbA) with a T87Q amino acid substitution (HbAT87Q).

The patients underwent myeloablative conditioning with busulfan, and the final LentiGlobin product was infused into patients after a 72-hour washout period.

In HGB-205 only, patients received enhanced red blood cell (RBC) transfusions for at least 3 months before stem cell mobilization and harvest to maintain a hemoglobin level of more than 11.0 g/dL.

Safety

In HGB-204, there were 5 grade 1 adverse events (AEs) considered possibly or probably related to LentiGlobin—abdominal pain (n=2), dyspnea (n=1), hot flush (n=1), and non-cardiac chest pain (n=1).

There were 9 serious AEs. Grade 3 serious AEs included 2 episodes of veno-occlusive liver disease that were attributed to busulfan, Klebsiella infection, cardiac ventricular thrombosis, cellulitis, hyperglycemia, and gastroenteritis. Grade 2 serious AEs included device-related thrombosis and infectious diarrhea.

In HGB-205, there were no AEs considered possibly or probably related to LentiGlobin. The 3 serious AEs were tooth infection (grade 3),  major depression (grade 3), and pneumonia (grade 2).

Efficacy

The median time to neutrophil engraftment was 18.5 days (range, 14.0 to 30.0) in HGB-204 and 16.5 days (range, 14.0 to 29.0) in HGB-205.

The median time to platelet engraftment was 39.5 days (range, 19.0 to 191.0) and 23.0 days (range, 20.0 to 26.0), respectively.

In both studies, the median follow-up was 26 months (range, 15 to 42) after LentiGlobin infusion.

At last follow-up, all but 1 of the 13 patients with a non-β0/β0 genotype had stopped receiving RBC transfusions.

In the 8 patients with a β0/β0 genotype and the 1 patient with 2 copies of the IVS1-110 mutation, the median annualized transfusion volume decreased by 73% after LentiGlobin administration.

Two patients with a β0/β0 genotype were able to stop receiving RBC transfusions, as was the patient with 2 copies of the IVS1-110 mutation.

Image by Spencer Phillips

The European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use has granted accelerated assessment for the upcoming marketing authorization application (MAA) for LentiGlobin™.

LentiGlobin is a gene therapy intended for the treatment of adolescents and adults with transfusion-dependent β-thalassemia (TDT) and a non-β0/β0 genotype.

bluebird bio intends to file an MAA for LentiGlobin with the EMA this year.

Accelerated assessment can reduce the active review time of an MAA from 210 days to 150 days once it has been validated by the EMA.

An accelerated assessment is granted to products deemed to be of major interest for public health and represent therapeutic innovation.

The accelerated assessment for LentiGlobin is supported by data from clinical studies, including the phase 1/2 Northstar (HGB-204) study, phase 1/2 HGB-205 study, phase 3 Northstar-2 (HGB-207) study, and the long-term follow-up study LTF-303.

The EMA previously granted PRIME (Priority Medicines) eligibility and orphan designation to LentiGlobin for the treatment of TDT.

LentiGlobin is also part of the EMA’s Adaptive Pathways pilot program, which is part of the EMA’s effort to improve timely access to new medicines.

Phase 1/2 trials

Results from the phase 1/2 trials of LentiGlobin—HGB-204 and HGB-205—were published in NEJM in April.

HGB-204 is a completed study that included 18 patients with TDT. Eight patients had a β0/β0 genotype, 6 had a βE/β0 genotype, and 4 had other genotypes.

HGB-205 is an ongoing study, and results were reported for 4 patients with TDT. Three patients had a βE/β0 genotype. The remaining patient was homozygous for the IVS1-110 mutation and had a severe clinical presentation similar to that seen in β0/β0 genotypes.

For both studies, the researchers harvested hematopoietic stem and progenitor cells (mobilized with filgrastim and plerixafor) from the patients. CD34+ cells were transduced ex vivo with LentiGlobin BB305 vector, which encodes adult hemoglobin (HbA) with a T87Q amino acid substitution (HbAT87Q).

The patients underwent myeloablative conditioning with busulfan, and the final LentiGlobin product was infused into patients after a 72-hour washout period.

In HGB-205 only, patients received enhanced red blood cell (RBC) transfusions for at least 3 months before stem cell mobilization and harvest to maintain a hemoglobin level of more than 11.0 g/dL.

Safety

In HGB-204, there were 5 grade 1 adverse events (AEs) considered possibly or probably related to LentiGlobin—abdominal pain (n=2), dyspnea (n=1), hot flush (n=1), and non-cardiac chest pain (n=1).

There were 9 serious AEs. Grade 3 serious AEs included 2 episodes of veno-occlusive liver disease that were attributed to busulfan, Klebsiella infection, cardiac ventricular thrombosis, cellulitis, hyperglycemia, and gastroenteritis. Grade 2 serious AEs included device-related thrombosis and infectious diarrhea.

In HGB-205, there were no AEs considered possibly or probably related to LentiGlobin. The 3 serious AEs were tooth infection (grade 3),  major depression (grade 3), and pneumonia (grade 2).

Efficacy

The median time to neutrophil engraftment was 18.5 days (range, 14.0 to 30.0) in HGB-204 and 16.5 days (range, 14.0 to 29.0) in HGB-205.

The median time to platelet engraftment was 39.5 days (range, 19.0 to 191.0) and 23.0 days (range, 20.0 to 26.0), respectively.

In both studies, the median follow-up was 26 months (range, 15 to 42) after LentiGlobin infusion.

At last follow-up, all but 1 of the 13 patients with a non-β0/β0 genotype had stopped receiving RBC transfusions.

In the 8 patients with a β0/β0 genotype and the 1 patient with 2 copies of the IVS1-110 mutation, the median annualized transfusion volume decreased by 73% after LentiGlobin administration.

Two patients with a β0/β0 genotype were able to stop receiving RBC transfusions, as was the patient with 2 copies of the IVS1-110 mutation.