Pharmacy

Blood samples

Photo by Graham Colm

The US Food and Drug Administration (FDA) has granted orphan designation to an immunotherapy known as CMD-003, which is under development to treat Epstein-Barr-virus (EBV)-positive non-Hodgkin lymphomas.

CMD-003 consists of T cells derived from blood samples that are activated and expanded through a proprietary process developed for commercial-scale use.

Researchers have treated more than 250 patients with prototypes of CMD-003. And the prototypes have produced promising results in a range of malignancies.

CMD-003 is under development by Cell Medica and the Center for Cell and Gene Therapy (CAGT) at Baylor College of Medicine, Texas Children’s Hospital, and Houston Methodist Hospital.

Orphan designation from the FDA will provide CMD-003’s developers with several benefits, including accessibility to grants to support clinical development, 7 years of market exclusivity if the treatment is approved in the US, and tax credits on US clinical trials.

CMD-003 prototype

Researchers have not published any trials of CMD-003, but they have studied other EBV-specific T-cell products related to CMD-003.

In their most recent study, published in the Journal of Clinical Oncology, the researchers administered cytotoxic T lymphocytes (CTLs) in 50 patients with EBV-associated Hodgkin or non-Hodgkin lymphoma.

Twenty-nine of the patients were in remission when they received CTL infusions, but they were at a high risk of relapse. The remaining 21 patients had relapsed or refractory disease at the time of CTL infusion.

Twenty-seven of the patients who received CTLs as an adjuvant treatment remained in remission from their disease at 3.1 years after treatment.

Their 2-year event-free survival rate was 82%. None of them died of lymphoma, but 9 died from complications associated with the chemotherapy and radiation they had received.

Of the 21 patients with relapsed or refractory disease, 13 responded to CTL infusions, and 11 patients achieved a complete response. In this group, the 2-year event-free survival rate was about 50%.

The researchers said there were no toxicities that were definitively related to CTL infusion.

One patient had central nervous system deterioration 2 weeks after infusion. This was attributed to disease progression but could possibly have been treatment-related.

Another patient developed respiratory complications about 4 weeks after a second CTL infusion that may have been treatment-related. However, the researchers attributed it to an intercurrent infection, and the patient made a complete recovery.

Blood samples

Photo by Graham Colm

The US Food and Drug Administration (FDA) has granted orphan designation to an immunotherapy known as CMD-003, which is under development to treat Epstein-Barr-virus (EBV)-positive non-Hodgkin lymphomas.

CMD-003 consists of T cells derived from blood samples that are activated and expanded through a proprietary process developed for commercial-scale use.

Researchers have treated more than 250 patients with prototypes of CMD-003. And the prototypes have produced promising results in a range of malignancies.

CMD-003 is under development by Cell Medica and the Center for Cell and Gene Therapy (CAGT) at Baylor College of Medicine, Texas Children’s Hospital, and Houston Methodist Hospital.

Orphan designation from the FDA will provide CMD-003’s developers with several benefits, including accessibility to grants to support clinical development, 7 years of market exclusivity if the treatment is approved in the US, and tax credits on US clinical trials.

CMD-003 prototype

Researchers have not published any trials of CMD-003, but they have studied other EBV-specific T-cell products related to CMD-003.

In their most recent study, published in the Journal of Clinical Oncology, the researchers administered cytotoxic T lymphocytes (CTLs) in 50 patients with EBV-associated Hodgkin or non-Hodgkin lymphoma.

Twenty-nine of the patients were in remission when they received CTL infusions, but they were at a high risk of relapse. The remaining 21 patients had relapsed or refractory disease at the time of CTL infusion.

Twenty-seven of the patients who received CTLs as an adjuvant treatment remained in remission from their disease at 3.1 years after treatment.

Their 2-year event-free survival rate was 82%. None of them died of lymphoma, but 9 died from complications associated with the chemotherapy and radiation they had received.

Of the 21 patients with relapsed or refractory disease, 13 responded to CTL infusions, and 11 patients achieved a complete response. In this group, the 2-year event-free survival rate was about 50%.

The researchers said there were no toxicities that were definitively related to CTL infusion.

One patient had central nervous system deterioration 2 weeks after infusion. This was attributed to disease progression but could possibly have been treatment-related.

Another patient developed respiratory complications about 4 weeks after a second CTL infusion that may have been treatment-related. However, the researchers attributed it to an intercurrent infection, and the patient made a complete recovery.

Blood samples

Photo by Graham Colm

The US Food and Drug Administration (FDA) has granted orphan designation to an immunotherapy known as CMD-003, which is under development to treat Epstein-Barr-virus (EBV)-positive non-Hodgkin lymphomas.

CMD-003 consists of T cells derived from blood samples that are activated and expanded through a proprietary process developed for commercial-scale use.

Researchers have treated more than 250 patients with prototypes of CMD-003. And the prototypes have produced promising results in a range of malignancies.

CMD-003 is under development by Cell Medica and the Center for Cell and Gene Therapy (CAGT) at Baylor College of Medicine, Texas Children’s Hospital, and Houston Methodist Hospital.

Orphan designation from the FDA will provide CMD-003’s developers with several benefits, including accessibility to grants to support clinical development, 7 years of market exclusivity if the treatment is approved in the US, and tax credits on US clinical trials.

CMD-003 prototype

Researchers have not published any trials of CMD-003, but they have studied other EBV-specific T-cell products related to CMD-003.

In their most recent study, published in the Journal of Clinical Oncology, the researchers administered cytotoxic T lymphocytes (CTLs) in 50 patients with EBV-associated Hodgkin or non-Hodgkin lymphoma.

Twenty-nine of the patients were in remission when they received CTL infusions, but they were at a high risk of relapse. The remaining 21 patients had relapsed or refractory disease at the time of CTL infusion.

Twenty-seven of the patients who received CTLs as an adjuvant treatment remained in remission from their disease at 3.1 years after treatment.

Their 2-year event-free survival rate was 82%. None of them died of lymphoma, but 9 died from complications associated with the chemotherapy and radiation they had received.

Of the 21 patients with relapsed or refractory disease, 13 responded to CTL infusions, and 11 patients achieved a complete response. In this group, the 2-year event-free survival rate was about 50%.

The researchers said there were no toxicities that were definitively related to CTL infusion.

One patient had central nervous system deterioration 2 weeks after infusion. This was attributed to disease progression but could possibly have been treatment-related.

Another patient developed respiratory complications about 4 weeks after a second CTL infusion that may have been treatment-related. However, the researchers attributed it to an intercurrent infection, and the patient made a complete recovery.

Vials of drug

Photo by Bill Branson

The US Food and Drug Administration (FDA) has strengthened an existing warning that serious, potentially fatal, allergic reactions can occur with the anemia drug Feraheme (ferumoxytol).

The FDA changed the drug’s prescribing information and approved a boxed warning detailing this risk.

The agency also added a new contraindication, which advises against the use of Feraheme in patients who have had an allergic reaction to any intravenous (IV) iron replacement product.

The FDA said it is continuing to monitor and evaluate the risk of serious allergic reactions with all IV iron products, and the agency will update the public as new information becomes available.

About Feraheme

Feraheme is an IV iron replacement product used to treat iron-deficiency anemia in patients with chronic kidney disease. Like other IV iron products, Feraheme may only be given where emergency personnel and equipment are immediately available to treat the potentially life-threatening allergic reactions that can occur with treatment.

All IV iron products carry a risk of potentially life-threatening allergic reactions. At the time of Feraheme’s approval in 2009, this risk was described in the “Warnings and Precautions” section of the drug label.

Since then, serious reactions, including deaths, have occurred, despite the proper use of therapies to treat these reactions and emergency resuscitation measures.

Serious reactions reported

In the initial clinical trials of Feraheme, conducted predominantly in patients with chronic kidney disease, serious hypersensitivity reactions were reported in 0.2% (3/1726) of patients receiving Feraheme.

Other adverse reactions potentially associated with hypersensitivity (eg, pruritus, rash, urticaria, or wheezing) were reported in 3.7% (63/1726) of these patients.

In other trials that did not include patients with chronic kidney disease, moderate to severe hypersensitivity reactions, including anaphylaxis, were reported in 2.6% (26/1014) of patients treated with Feraheme.

Since the approval of Feraheme on June 30, 2009, cases of serious hypersensitivity reactions, including death, have occurred.

A search of the FDA Adverse Event Reporting System database revealed 79 cases of anaphylactic reactions associated with Feraheme administration, reported from the time of approval to June 30, 2014. Of the 79 cases, 18 were fatal, despite immediate medical intervention and emergency resuscitation attempts.

The 79 patients ranged in age from 19 to 96 years. In nearly half of all cases, the anaphylactic reactions occurred with the first dose of Feraheme. For approximately 75% (60/79) of the cases, the reaction began during the infusion or within 5 minutes after administration was complete.

Frequently reported symptoms included cardiac arrest, hypotension, dyspnea, nausea, vomiting, and flushing. Of the 79 patients, 43% (34/79) had a medical history of drug allergy, and 24% had a history of multiple drug allergies.

Recommendations for administering Feraheme

Initial symptoms of fatal and serious hypersensitivity reactions associated with Feraheme may include hypotension, syncope, unresponsiveness, and cardiac/cardiorespiratory arrest, with or without signs of rash.

All IV iron products carry a risk of anaphylaxis, so these products should be administered only in patients who require IV iron therapy.

Feraheme is only approved for use in adults with iron-deficiency anemia in the setting of chronic kidney disease. The drug is contraindicated in patients with a history of hypersensitivity to Feraheme or any other IV iron product.

Only administer Feraheme and other IV iron products when personnel and therapies are immediately available for the treatment of anaphylaxis and other hypersensitivity reactions.

Patients with a history of multiple drug allergies may have a greater risk of anaphylaxis with parenteral iron products. Carefully consider the potential risks and benefits before administering Feraheme to these patients.

Feraheme should only be administered as an IV infusion in 50-200 mL of 0.9% sodium chloride or 5% dextrose over a minimum period of 15 minutes following dilution. Do not administer Feraheme by undiluted IV injection.

Closely monitor patients for signs and symptoms of hypersensitivity reactions, including monitoring blood pressure and pulse during administration and for at least 30 minutes following each infusion of Feraheme.

Elderly patients 65 years of age and older with multiple or serious comorbidities who experience hypersensitivity reactions, hypotension, or both following administration of Feraheme may have more severe outcomes.

Advise patients to immediately report any signs and symptoms of hypersensitivity that may develop during and following Feraheme administration, such as respiratory distress, hypotension, dizziness or lightheadedness, edema, rash, or itching. Advise patients to seek immediate medical attention if these signs and symptoms occur.

Allow at least 30 minutes between administration of Feraheme and administration of other medications that could potentially cause serious hypersensitivity reactions, hypotension, or both, such as chemotherapeutic agents or monoclonal antibodies.

Report adverse events involving Feraheme to the FDA’s MedWatch Program.

Vials of drug

Photo by Bill Branson

The US Food and Drug Administration (FDA) has strengthened an existing warning that serious, potentially fatal, allergic reactions can occur with the anemia drug Feraheme (ferumoxytol).

The FDA changed the drug’s prescribing information and approved a boxed warning detailing this risk.

The agency also added a new contraindication, which advises against the use of Feraheme in patients who have had an allergic reaction to any intravenous (IV) iron replacement product.

The FDA said it is continuing to monitor and evaluate the risk of serious allergic reactions with all IV iron products, and the agency will update the public as new information becomes available.

About Feraheme

Feraheme is an IV iron replacement product used to treat iron-deficiency anemia in patients with chronic kidney disease. Like other IV iron products, Feraheme may only be given where emergency personnel and equipment are immediately available to treat the potentially life-threatening allergic reactions that can occur with treatment.

All IV iron products carry a risk of potentially life-threatening allergic reactions. At the time of Feraheme’s approval in 2009, this risk was described in the “Warnings and Precautions” section of the drug label.

Since then, serious reactions, including deaths, have occurred, despite the proper use of therapies to treat these reactions and emergency resuscitation measures.

Serious reactions reported

In the initial clinical trials of Feraheme, conducted predominantly in patients with chronic kidney disease, serious hypersensitivity reactions were reported in 0.2% (3/1726) of patients receiving Feraheme.

Other adverse reactions potentially associated with hypersensitivity (eg, pruritus, rash, urticaria, or wheezing) were reported in 3.7% (63/1726) of these patients.

In other trials that did not include patients with chronic kidney disease, moderate to severe hypersensitivity reactions, including anaphylaxis, were reported in 2.6% (26/1014) of patients treated with Feraheme.

Since the approval of Feraheme on June 30, 2009, cases of serious hypersensitivity reactions, including death, have occurred.

A search of the FDA Adverse Event Reporting System database revealed 79 cases of anaphylactic reactions associated with Feraheme administration, reported from the time of approval to June 30, 2014. Of the 79 cases, 18 were fatal, despite immediate medical intervention and emergency resuscitation attempts.

The 79 patients ranged in age from 19 to 96 years. In nearly half of all cases, the anaphylactic reactions occurred with the first dose of Feraheme. For approximately 75% (60/79) of the cases, the reaction began during the infusion or within 5 minutes after administration was complete.

Frequently reported symptoms included cardiac arrest, hypotension, dyspnea, nausea, vomiting, and flushing. Of the 79 patients, 43% (34/79) had a medical history of drug allergy, and 24% had a history of multiple drug allergies.

Recommendations for administering Feraheme

Initial symptoms of fatal and serious hypersensitivity reactions associated with Feraheme may include hypotension, syncope, unresponsiveness, and cardiac/cardiorespiratory arrest, with or without signs of rash.

All IV iron products carry a risk of anaphylaxis, so these products should be administered only in patients who require IV iron therapy.

Feraheme is only approved for use in adults with iron-deficiency anemia in the setting of chronic kidney disease. The drug is contraindicated in patients with a history of hypersensitivity to Feraheme or any other IV iron product.

Only administer Feraheme and other IV iron products when personnel and therapies are immediately available for the treatment of anaphylaxis and other hypersensitivity reactions.

Patients with a history of multiple drug allergies may have a greater risk of anaphylaxis with parenteral iron products. Carefully consider the potential risks and benefits before administering Feraheme to these patients.

Feraheme should only be administered as an IV infusion in 50-200 mL of 0.9% sodium chloride or 5% dextrose over a minimum period of 15 minutes following dilution. Do not administer Feraheme by undiluted IV injection.

Closely monitor patients for signs and symptoms of hypersensitivity reactions, including monitoring blood pressure and pulse during administration and for at least 30 minutes following each infusion of Feraheme.

Elderly patients 65 years of age and older with multiple or serious comorbidities who experience hypersensitivity reactions, hypotension, or both following administration of Feraheme may have more severe outcomes.

Advise patients to immediately report any signs and symptoms of hypersensitivity that may develop during and following Feraheme administration, such as respiratory distress, hypotension, dizziness or lightheadedness, edema, rash, or itching. Advise patients to seek immediate medical attention if these signs and symptoms occur.

Allow at least 30 minutes between administration of Feraheme and administration of other medications that could potentially cause serious hypersensitivity reactions, hypotension, or both, such as chemotherapeutic agents or monoclonal antibodies.

Report adverse events involving Feraheme to the FDA’s MedWatch Program.

Vials of drug

Photo by Bill Branson

The US Food and Drug Administration (FDA) has strengthened an existing warning that serious, potentially fatal, allergic reactions can occur with the anemia drug Feraheme (ferumoxytol).

The FDA changed the drug’s prescribing information and approved a boxed warning detailing this risk.

The agency also added a new contraindication, which advises against the use of Feraheme in patients who have had an allergic reaction to any intravenous (IV) iron replacement product.

The FDA said it is continuing to monitor and evaluate the risk of serious allergic reactions with all IV iron products, and the agency will update the public as new information becomes available.

About Feraheme

Feraheme is an IV iron replacement product used to treat iron-deficiency anemia in patients with chronic kidney disease. Like other IV iron products, Feraheme may only be given where emergency personnel and equipment are immediately available to treat the potentially life-threatening allergic reactions that can occur with treatment.

All IV iron products carry a risk of potentially life-threatening allergic reactions. At the time of Feraheme’s approval in 2009, this risk was described in the “Warnings and Precautions” section of the drug label.

Since then, serious reactions, including deaths, have occurred, despite the proper use of therapies to treat these reactions and emergency resuscitation measures.

Serious reactions reported

In the initial clinical trials of Feraheme, conducted predominantly in patients with chronic kidney disease, serious hypersensitivity reactions were reported in 0.2% (3/1726) of patients receiving Feraheme.

Other adverse reactions potentially associated with hypersensitivity (eg, pruritus, rash, urticaria, or wheezing) were reported in 3.7% (63/1726) of these patients.

In other trials that did not include patients with chronic kidney disease, moderate to severe hypersensitivity reactions, including anaphylaxis, were reported in 2.6% (26/1014) of patients treated with Feraheme.

Since the approval of Feraheme on June 30, 2009, cases of serious hypersensitivity reactions, including death, have occurred.

A search of the FDA Adverse Event Reporting System database revealed 79 cases of anaphylactic reactions associated with Feraheme administration, reported from the time of approval to June 30, 2014. Of the 79 cases, 18 were fatal, despite immediate medical intervention and emergency resuscitation attempts.

The 79 patients ranged in age from 19 to 96 years. In nearly half of all cases, the anaphylactic reactions occurred with the first dose of Feraheme. For approximately 75% (60/79) of the cases, the reaction began during the infusion or within 5 minutes after administration was complete.

Frequently reported symptoms included cardiac arrest, hypotension, dyspnea, nausea, vomiting, and flushing. Of the 79 patients, 43% (34/79) had a medical history of drug allergy, and 24% had a history of multiple drug allergies.

Recommendations for administering Feraheme

Initial symptoms of fatal and serious hypersensitivity reactions associated with Feraheme may include hypotension, syncope, unresponsiveness, and cardiac/cardiorespiratory arrest, with or without signs of rash.

All IV iron products carry a risk of anaphylaxis, so these products should be administered only in patients who require IV iron therapy.

Feraheme is only approved for use in adults with iron-deficiency anemia in the setting of chronic kidney disease. The drug is contraindicated in patients with a history of hypersensitivity to Feraheme or any other IV iron product.

Only administer Feraheme and other IV iron products when personnel and therapies are immediately available for the treatment of anaphylaxis and other hypersensitivity reactions.

Patients with a history of multiple drug allergies may have a greater risk of anaphylaxis with parenteral iron products. Carefully consider the potential risks and benefits before administering Feraheme to these patients.

Feraheme should only be administered as an IV infusion in 50-200 mL of 0.9% sodium chloride or 5% dextrose over a minimum period of 15 minutes following dilution. Do not administer Feraheme by undiluted IV injection.

Closely monitor patients for signs and symptoms of hypersensitivity reactions, including monitoring blood pressure and pulse during administration and for at least 30 minutes following each infusion of Feraheme.

Elderly patients 65 years of age and older with multiple or serious comorbidities who experience hypersensitivity reactions, hypotension, or both following administration of Feraheme may have more severe outcomes.

Advise patients to immediately report any signs and symptoms of hypersensitivity that may develop during and following Feraheme administration, such as respiratory distress, hypotension, dizziness or lightheadedness, edema, rash, or itching. Advise patients to seek immediate medical attention if these signs and symptoms occur.

Allow at least 30 minutes between administration of Feraheme and administration of other medications that could potentially cause serious hypersensitivity reactions, hypotension, or both, such as chemotherapeutic agents or monoclonal antibodies.

Report adverse events involving Feraheme to the FDA’s MedWatch Program.

Red blood cells

Image courtesy of NHLBI

The US Food and Drug Administration (FDA) has granted orphan drug designation to AG-348 for the treatment of pyruvate kinase deficiency (PKD), a rare form of hemolytic anemia.

AG-348 is a small molecule allosteric activator of pyruvate kinase-R enzymes that directly targets the underlying metabolic defect in PKD.

The orphan designation will provide Agios Pharmaceuticals, the company developing AG-348, with certain benefits. These include market exclusivity upon regulatory approval and exemption from FDA application fees and tax credits for qualified clinical trials.

According to Agios, AG-348 exhibited favorable safety and pharmacokinetic profiles in a pair of phase 1 studies conducted in healthy volunteers.

Study investigators also observed dose-dependent changes in adenosine triphosphate (ATP) and 2,3-DPG blood levels, which are consistent with increased activity of the glycolytic pathway, the expected pharmacodynamic effect of AG-348.

Results from both studies were presented in a poster at the 2014 ASH Annual Meeting (abstract 4007*). One of the studies was a single ascending dose (SAD) study, and the other was a multiple ascending dose (MAD) study.

SAD study

In this study, healthy volunteers were randomized to receive AG-348 (n=36) or placebo (n=12). Patients were divided into 6 dosing cohorts: 30 mg, 120 mg, 360 mg, 700 mg, 1400 mg, and 2500 mg.

The maximum-tolerated dose of AG-348 was not reached, and there were no serious adverse events (AEs) or early withdrawals among AG-348-treated subjects. Overall, the rate of AEs was 33.3% in the placebo arm and 44.4% in the AG-348 arm.

The rate of AEs that were considered possibly treatment-related was 16.7% in the placebo arm and 30.6% in the AG-348 arm. The most common treatment-related AEs were headache (occurring in 16.7% and 11.1% of patients, respectively), nausea (0% and 13.9%, respectively), and vomiting (0% and 5.6%, respectively).

Exposure to AG-348, as measured by area under the concentration × time curve (AUC), increased in a dose-proportional manner after a single dose. And absorption was rapid (median T_max ranged from 0.77 to 4.07 hours), although T_max increased and there was a less-than-proportional increase in C_max at higher doses.

When AG-348 was administered from 30 mg to 360 mg, there was a dose-dependent decrease in blood 2,3-DPG levels over 24 hours—up to a 49% mean decrease. Increasing the dose beyond 360 mg did not result in additional decreases in 2,3-DPG levels. And levels returned to placebo levels after about 72 hours.

There were minimal increases in blood ATP levels after AG-348 treatment at any dose.

MAD study

At the time of the presentation, 2 cohorts of 8 subjects each (6 receiving AG-348 and 2 receiving placebo) had completed treatment in the MAD study. One cohort received drug or placebo at 120 mg BID, and the other received 360 mg BID.

The pharmacokinetic results for day 1 of this study were consistent with those of the SAD study. However, the C_max and AUC_0-Ʈ were lower on day 14 than day 1. Investigators said this suggests that multiple doses of AG-348 increase the rate of its own metabolism.

They also said the decrease in exposure observed on day 14 is consistent with preclinical data that suggest AG-348 is a moderate inducer of CYP3A4, which is the major route of the oxidative metabolism of AG-348.

As in the SAD study, the investigators observed decreases in 2,3-DPG blood levels after the first dose in cohorts 1 and 2—up to a 48% mean decrease from baseline for both doses. Concentrations returned to placebo levels between 48 and 72 hours after the last dose.

Unlike in the SAD study, patients in this study had increases in ATP—up to a 52% mean increase from baseline in both dosing cohorts. ATP levels remained elevated through 72 hours after the last dose.

The investigators said the results of these 2 studies have informed dose selection for the planned phase 2 study of AG-348 in PKD patients, which is expected to begin soon.

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

Red blood cells

Image courtesy of NHLBI

The US Food and Drug Administration (FDA) has granted orphan drug designation to AG-348 for the treatment of pyruvate kinase deficiency (PKD), a rare form of hemolytic anemia.

AG-348 is a small molecule allosteric activator of pyruvate kinase-R enzymes that directly targets the underlying metabolic defect in PKD.

The orphan designation will provide Agios Pharmaceuticals, the company developing AG-348, with certain benefits. These include market exclusivity upon regulatory approval and exemption from FDA application fees and tax credits for qualified clinical trials.

According to Agios, AG-348 exhibited favorable safety and pharmacokinetic profiles in a pair of phase 1 studies conducted in healthy volunteers.

Study investigators also observed dose-dependent changes in adenosine triphosphate (ATP) and 2,3-DPG blood levels, which are consistent with increased activity of the glycolytic pathway, the expected pharmacodynamic effect of AG-348.

Results from both studies were presented in a poster at the 2014 ASH Annual Meeting (abstract 4007*). One of the studies was a single ascending dose (SAD) study, and the other was a multiple ascending dose (MAD) study.

SAD study

In this study, healthy volunteers were randomized to receive AG-348 (n=36) or placebo (n=12). Patients were divided into 6 dosing cohorts: 30 mg, 120 mg, 360 mg, 700 mg, 1400 mg, and 2500 mg.

The maximum-tolerated dose of AG-348 was not reached, and there were no serious adverse events (AEs) or early withdrawals among AG-348-treated subjects. Overall, the rate of AEs was 33.3% in the placebo arm and 44.4% in the AG-348 arm.

The rate of AEs that were considered possibly treatment-related was 16.7% in the placebo arm and 30.6% in the AG-348 arm. The most common treatment-related AEs were headache (occurring in 16.7% and 11.1% of patients, respectively), nausea (0% and 13.9%, respectively), and vomiting (0% and 5.6%, respectively).

Exposure to AG-348, as measured by area under the concentration × time curve (AUC), increased in a dose-proportional manner after a single dose. And absorption was rapid (median T_max ranged from 0.77 to 4.07 hours), although T_max increased and there was a less-than-proportional increase in C_max at higher doses.

When AG-348 was administered from 30 mg to 360 mg, there was a dose-dependent decrease in blood 2,3-DPG levels over 24 hours—up to a 49% mean decrease. Increasing the dose beyond 360 mg did not result in additional decreases in 2,3-DPG levels. And levels returned to placebo levels after about 72 hours.

There were minimal increases in blood ATP levels after AG-348 treatment at any dose.

MAD study

At the time of the presentation, 2 cohorts of 8 subjects each (6 receiving AG-348 and 2 receiving placebo) had completed treatment in the MAD study. One cohort received drug or placebo at 120 mg BID, and the other received 360 mg BID.

The pharmacokinetic results for day 1 of this study were consistent with those of the SAD study. However, the C_max and AUC_0-Ʈ were lower on day 14 than day 1. Investigators said this suggests that multiple doses of AG-348 increase the rate of its own metabolism.

They also said the decrease in exposure observed on day 14 is consistent with preclinical data that suggest AG-348 is a moderate inducer of CYP3A4, which is the major route of the oxidative metabolism of AG-348.

As in the SAD study, the investigators observed decreases in 2,3-DPG blood levels after the first dose in cohorts 1 and 2—up to a 48% mean decrease from baseline for both doses. Concentrations returned to placebo levels between 48 and 72 hours after the last dose.

Unlike in the SAD study, patients in this study had increases in ATP—up to a 52% mean increase from baseline in both dosing cohorts. ATP levels remained elevated through 72 hours after the last dose.

The investigators said the results of these 2 studies have informed dose selection for the planned phase 2 study of AG-348 in PKD patients, which is expected to begin soon.

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

Red blood cells

Image courtesy of NHLBI

The US Food and Drug Administration (FDA) has granted orphan drug designation to AG-348 for the treatment of pyruvate kinase deficiency (PKD), a rare form of hemolytic anemia.

AG-348 is a small molecule allosteric activator of pyruvate kinase-R enzymes that directly targets the underlying metabolic defect in PKD.

The orphan designation will provide Agios Pharmaceuticals, the company developing AG-348, with certain benefits. These include market exclusivity upon regulatory approval and exemption from FDA application fees and tax credits for qualified clinical trials.

According to Agios, AG-348 exhibited favorable safety and pharmacokinetic profiles in a pair of phase 1 studies conducted in healthy volunteers.

Study investigators also observed dose-dependent changes in adenosine triphosphate (ATP) and 2,3-DPG blood levels, which are consistent with increased activity of the glycolytic pathway, the expected pharmacodynamic effect of AG-348.

Results from both studies were presented in a poster at the 2014 ASH Annual Meeting (abstract 4007*). One of the studies was a single ascending dose (SAD) study, and the other was a multiple ascending dose (MAD) study.

SAD study

In this study, healthy volunteers were randomized to receive AG-348 (n=36) or placebo (n=12). Patients were divided into 6 dosing cohorts: 30 mg, 120 mg, 360 mg, 700 mg, 1400 mg, and 2500 mg.

The maximum-tolerated dose of AG-348 was not reached, and there were no serious adverse events (AEs) or early withdrawals among AG-348-treated subjects. Overall, the rate of AEs was 33.3% in the placebo arm and 44.4% in the AG-348 arm.

The rate of AEs that were considered possibly treatment-related was 16.7% in the placebo arm and 30.6% in the AG-348 arm. The most common treatment-related AEs were headache (occurring in 16.7% and 11.1% of patients, respectively), nausea (0% and 13.9%, respectively), and vomiting (0% and 5.6%, respectively).

Exposure to AG-348, as measured by area under the concentration × time curve (AUC), increased in a dose-proportional manner after a single dose. And absorption was rapid (median T_max ranged from 0.77 to 4.07 hours), although T_max increased and there was a less-than-proportional increase in C_max at higher doses.

When AG-348 was administered from 30 mg to 360 mg, there was a dose-dependent decrease in blood 2,3-DPG levels over 24 hours—up to a 49% mean decrease. Increasing the dose beyond 360 mg did not result in additional decreases in 2,3-DPG levels. And levels returned to placebo levels after about 72 hours.

There were minimal increases in blood ATP levels after AG-348 treatment at any dose.

MAD study

At the time of the presentation, 2 cohorts of 8 subjects each (6 receiving AG-348 and 2 receiving placebo) had completed treatment in the MAD study. One cohort received drug or placebo at 120 mg BID, and the other received 360 mg BID.

The pharmacokinetic results for day 1 of this study were consistent with those of the SAD study. However, the C_max and AUC_0-Ʈ were lower on day 14 than day 1. Investigators said this suggests that multiple doses of AG-348 increase the rate of its own metabolism.

They also said the decrease in exposure observed on day 14 is consistent with preclinical data that suggest AG-348 is a moderate inducer of CYP3A4, which is the major route of the oxidative metabolism of AG-348.

As in the SAD study, the investigators observed decreases in 2,3-DPG blood levels after the first dose in cohorts 1 and 2—up to a 48% mean decrease from baseline for both doses. Concentrations returned to placebo levels between 48 and 72 hours after the last dose.

Unlike in the SAD study, patients in this study had increases in ATP—up to a 52% mean increase from baseline in both dosing cohorts. ATP levels remained elevated through 72 hours after the last dose.

The investigators said the results of these 2 studies have informed dose selection for the planned phase 2 study of AG-348 in PKD patients, which is expected to begin soon.

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

Drug production

Photo courtesy of the US FDA

The Israeli Ministry of Health has granted regulatory approval for the kinase inhibitor ponatinib (Iclusig) to treat certain adults with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph⁺ ALL).

The drug can now be used to treat adults with any phase of CML who have the T315I mutation or are resistant to/cannot tolerate dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate.

Ponatinib is also approved to treat patients with Ph⁺ ALL who have the T315I mutation or are resistant to/cannot tolerate dasatinib and for whom subsequent treatment with imatinib is not clinically appropriate.

Ariad Pharmaceuticals, Inc., the company developing ponatinib, said the drug should be available in Israel in the second quarter of 2015.

Trial results

The Ministry of Health’s decision to approve ponatinib was based on results from the phase 2 PACE trial, which included patients with CML or Ph⁺ ALL who were resistant to or intolerant of prior tyrosine kinase inhibitor therapy, or who had the T315I mutation.

The median follow-up times were 15.3 months in chronic-phase CML patients, 15.8 months in accelerated-phase CML patients, and 6.2 months in patients with blast-phase CML or Ph⁺ ALL.

In chronic-phase CML, the primary endpoint was major cytogenetic response, and it occurred in 56% of patients. Among chronic-phase patients with the T315I mutation, 70% achieved a major cytogenetic response. Among patients who had failed treatment with dasatinib or nilotinib, 51% achieved a major cytogenetic response.

In accelerated-phase CML, the primary endpoint was major hematologic response. This occurred in 57% of all patients in this group, 50% of patients with the T315I mutation, and 58% of patients who had failed treatment with dasatinib or nilotinib.

The primary endpoint was major hematologic response in blast-phase CML/Ph⁺ ALL as well. Thirty-four percent of all patients in this group met this endpoint, as did 33% of patients with the T315I mutation and 35% of patients who had failed treatment with dasatinib or nilotinib.

Common non-hematologic adverse events included rash (38%), abdominal pain (38%), headache (35%), dry skin (35%), constipation (34%), fatigue (27%), pyrexia (27%), nausea (26%), arthralgia (25%), hypertension (21%), increased lipase (19%), and increased amylase (7%).

Hematologic events of any grade included thrombocytopenia (42%), neutropenia (24%), and anemia (20%). Serious adverse events of arterial thromboembolism, including arterial stenosis, occurred in patients with cardiovascular risk factors.

Safety issues

Extended follow-up data from the PACE trial, collected in 2013, suggested ponatinib can increase the risk of thrombotic events. When these data came to light, officials in the European Union and the US, where ponatinib had already been approved, began to investigate the drug.

Ponatinib was pulled from the US market for a little over 2 months, and trials of the drug were placed on partial hold while the Food and Drug Administration evaluated the drug’s safety. Ponatinib went back on the market in January 2014, with new safety measures in place.

The drug was not pulled from the market in the European Union, but the European Medicine’s Agency released recommendations for safer use of ponatinib. The Committee for Medicinal Products for Human Use reviewed data on ponatinib and decided the drug’s benefits outweigh its risks.

Drug production

Photo courtesy of the US FDA

The Israeli Ministry of Health has granted regulatory approval for the kinase inhibitor ponatinib (Iclusig) to treat certain adults with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph⁺ ALL).

The drug can now be used to treat adults with any phase of CML who have the T315I mutation or are resistant to/cannot tolerate dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate.

Ponatinib is also approved to treat patients with Ph⁺ ALL who have the T315I mutation or are resistant to/cannot tolerate dasatinib and for whom subsequent treatment with imatinib is not clinically appropriate.

Ariad Pharmaceuticals, Inc., the company developing ponatinib, said the drug should be available in Israel in the second quarter of 2015.

Trial results

The Ministry of Health’s decision to approve ponatinib was based on results from the phase 2 PACE trial, which included patients with CML or Ph⁺ ALL who were resistant to or intolerant of prior tyrosine kinase inhibitor therapy, or who had the T315I mutation.

The median follow-up times were 15.3 months in chronic-phase CML patients, 15.8 months in accelerated-phase CML patients, and 6.2 months in patients with blast-phase CML or Ph⁺ ALL.

In chronic-phase CML, the primary endpoint was major cytogenetic response, and it occurred in 56% of patients. Among chronic-phase patients with the T315I mutation, 70% achieved a major cytogenetic response. Among patients who had failed treatment with dasatinib or nilotinib, 51% achieved a major cytogenetic response.

In accelerated-phase CML, the primary endpoint was major hematologic response. This occurred in 57% of all patients in this group, 50% of patients with the T315I mutation, and 58% of patients who had failed treatment with dasatinib or nilotinib.

The primary endpoint was major hematologic response in blast-phase CML/Ph⁺ ALL as well. Thirty-four percent of all patients in this group met this endpoint, as did 33% of patients with the T315I mutation and 35% of patients who had failed treatment with dasatinib or nilotinib.

Common non-hematologic adverse events included rash (38%), abdominal pain (38%), headache (35%), dry skin (35%), constipation (34%), fatigue (27%), pyrexia (27%), nausea (26%), arthralgia (25%), hypertension (21%), increased lipase (19%), and increased amylase (7%).

Hematologic events of any grade included thrombocytopenia (42%), neutropenia (24%), and anemia (20%). Serious adverse events of arterial thromboembolism, including arterial stenosis, occurred in patients with cardiovascular risk factors.

Safety issues

Extended follow-up data from the PACE trial, collected in 2013, suggested ponatinib can increase the risk of thrombotic events. When these data came to light, officials in the European Union and the US, where ponatinib had already been approved, began to investigate the drug.

Ponatinib was pulled from the US market for a little over 2 months, and trials of the drug were placed on partial hold while the Food and Drug Administration evaluated the drug’s safety. Ponatinib went back on the market in January 2014, with new safety measures in place.

The drug was not pulled from the market in the European Union, but the European Medicine’s Agency released recommendations for safer use of ponatinib. The Committee for Medicinal Products for Human Use reviewed data on ponatinib and decided the drug’s benefits outweigh its risks.

Drug production

Photo courtesy of the US FDA

The Israeli Ministry of Health has granted regulatory approval for the kinase inhibitor ponatinib (Iclusig) to treat certain adults with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph⁺ ALL).

The drug can now be used to treat adults with any phase of CML who have the T315I mutation or are resistant to/cannot tolerate dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate.

Ponatinib is also approved to treat patients with Ph⁺ ALL who have the T315I mutation or are resistant to/cannot tolerate dasatinib and for whom subsequent treatment with imatinib is not clinically appropriate.

Ariad Pharmaceuticals, Inc., the company developing ponatinib, said the drug should be available in Israel in the second quarter of 2015.

Trial results

The Ministry of Health’s decision to approve ponatinib was based on results from the phase 2 PACE trial, which included patients with CML or Ph⁺ ALL who were resistant to or intolerant of prior tyrosine kinase inhibitor therapy, or who had the T315I mutation.

The median follow-up times were 15.3 months in chronic-phase CML patients, 15.8 months in accelerated-phase CML patients, and 6.2 months in patients with blast-phase CML or Ph⁺ ALL.

In chronic-phase CML, the primary endpoint was major cytogenetic response, and it occurred in 56% of patients. Among chronic-phase patients with the T315I mutation, 70% achieved a major cytogenetic response. Among patients who had failed treatment with dasatinib or nilotinib, 51% achieved a major cytogenetic response.

In accelerated-phase CML, the primary endpoint was major hematologic response. This occurred in 57% of all patients in this group, 50% of patients with the T315I mutation, and 58% of patients who had failed treatment with dasatinib or nilotinib.

The primary endpoint was major hematologic response in blast-phase CML/Ph⁺ ALL as well. Thirty-four percent of all patients in this group met this endpoint, as did 33% of patients with the T315I mutation and 35% of patients who had failed treatment with dasatinib or nilotinib.

Common non-hematologic adverse events included rash (38%), abdominal pain (38%), headache (35%), dry skin (35%), constipation (34%), fatigue (27%), pyrexia (27%), nausea (26%), arthralgia (25%), hypertension (21%), increased lipase (19%), and increased amylase (7%).

Hematologic events of any grade included thrombocytopenia (42%), neutropenia (24%), and anemia (20%). Serious adverse events of arterial thromboembolism, including arterial stenosis, occurred in patients with cardiovascular risk factors.

Safety issues

Extended follow-up data from the PACE trial, collected in 2013, suggested ponatinib can increase the risk of thrombotic events. When these data came to light, officials in the European Union and the US, where ponatinib had already been approved, began to investigate the drug.

Ponatinib was pulled from the US market for a little over 2 months, and trials of the drug were placed on partial hold while the Food and Drug Administration evaluated the drug’s safety. Ponatinib went back on the market in January 2014, with new safety measures in place.

The drug was not pulled from the market in the European Union, but the European Medicine’s Agency released recommendations for safer use of ponatinib. The Committee for Medicinal Products for Human Use reviewed data on ponatinib and decided the drug’s benefits outweigh its risks.

Prescription drugs

Photo courtesy of CDC

The UK’s National Institute for Health and Care Excellence (NICE) has issued final guidance documents for rivaroxaban (Xarelto) and pomalidomide (Imnovid).

The agency is recommending rivaroxaban (in combination) as an option for preventing atherothrombotic events in patients with acute coronary syndrome (ACS).

But NICE said it cannot recommend pomalidomide (in combination) for the treatment of relapsed/refractory multiple myeloma (MM).

Rivaroxaban

Rivaroxaban is licensed in the European Union to prevent atherothrombotic events in adults who have an ACS severe enough to result in the release of cardiac biomarkers into the blood. The drug is given with aspirin and clopidogrel or aspirin alone.

Based on results of the ATLAS-ACS 2-TIMI 51 trial, an appraisal committee advising NICE concluded that rivaroxaban given at 2.5 mg twice daily in combination with aspirin plus clopidogrel or with aspirin alone was more effective than aspirin plus clopidogrel or aspirin alone for preventing further cardiovascular deaths and myocardial infarction in patients with ACS and raised cardiac biomarkers.

The committee also found rivaroxaban to be a cost-effective use of National Health Service (NHS) resources. They noted, however, that the drug can increase the risk of bleeding.

“Because rivaroxaban is associated with a higher risk of causing bleeding than clopidogrel in combination with aspirin or aspirin alone, the guidance recommends that, before starting treatment, doctors should carry out a careful assessment of a person’s bleeding risk,” said Carole Longson, NICE Health Technology Evaluation Centre Director.

“The decision to start treatment should be made after an informed discussion between the doctor and patient about the benefits and risks of rivaroxaban. Also, because there is limited experience of treatment with rivaroxaban up to 24 months, the guidance recommends careful consideration should be given to whether treatment is continued beyond 12 months.”

Pomalidomide

NICE’s final guidance on pomalidomide said the agency cannot recommend the drug as a treatment option for MM.

Pomalidomide is approved in the European Union for use in combination with dexamethasone to treat adults with relapsed and refractory MM who have had at least 2 prior treatments, including lenalidomide and bortezomib, and whose disease has progressed on the last therapy.

“Unfortunately, we cannot recommend pomalidomide, as the analyses from Celgene, the company that markets the drug, showed that it does not offer enough benefit to justify its high price,” said Sir Andrew Dillon, NICE chief executive.

NICE said the appraisal committee could not judge with any confidence how effective pomalidomide is compared to current treatment options based on the available evidence provided before and after consultation.

Bearing in mind the magnitude of the differences in the overall survival estimates between pomalidomide and high-dose dexamethasone in the phase 3 MM-003 trial and all data presented to the committee for comparators, the committee was persuaded that pomalidomide extends life for at least 3 months on average when compared with standard NHS care.

However, considering the incremental cost-effectiveness ratios, the committee concluded that, even with the end-of-life criteria met, the weighting that would have to be placed on the quality-adjusted life-years gained would be too high to consider pomalidomide a cost-effective use of NHS resources.

The committee also said the uncertainty in the relative effectiveness of pomalidomide compared with established NHS practice would affect any weighting that could be placed on quality-adjusted life-years gained.

Prescription drugs

Photo courtesy of CDC

The UK’s National Institute for Health and Care Excellence (NICE) has issued final guidance documents for rivaroxaban (Xarelto) and pomalidomide (Imnovid).

The agency is recommending rivaroxaban (in combination) as an option for preventing atherothrombotic events in patients with acute coronary syndrome (ACS).

But NICE said it cannot recommend pomalidomide (in combination) for the treatment of relapsed/refractory multiple myeloma (MM).

Rivaroxaban

Rivaroxaban is licensed in the European Union to prevent atherothrombotic events in adults who have an ACS severe enough to result in the release of cardiac biomarkers into the blood. The drug is given with aspirin and clopidogrel or aspirin alone.

Based on results of the ATLAS-ACS 2-TIMI 51 trial, an appraisal committee advising NICE concluded that rivaroxaban given at 2.5 mg twice daily in combination with aspirin plus clopidogrel or with aspirin alone was more effective than aspirin plus clopidogrel or aspirin alone for preventing further cardiovascular deaths and myocardial infarction in patients with ACS and raised cardiac biomarkers.

The committee also found rivaroxaban to be a cost-effective use of National Health Service (NHS) resources. They noted, however, that the drug can increase the risk of bleeding.

“Because rivaroxaban is associated with a higher risk of causing bleeding than clopidogrel in combination with aspirin or aspirin alone, the guidance recommends that, before starting treatment, doctors should carry out a careful assessment of a person’s bleeding risk,” said Carole Longson, NICE Health Technology Evaluation Centre Director.

“The decision to start treatment should be made after an informed discussion between the doctor and patient about the benefits and risks of rivaroxaban. Also, because there is limited experience of treatment with rivaroxaban up to 24 months, the guidance recommends careful consideration should be given to whether treatment is continued beyond 12 months.”

Pomalidomide

NICE’s final guidance on pomalidomide said the agency cannot recommend the drug as a treatment option for MM.

Pomalidomide is approved in the European Union for use in combination with dexamethasone to treat adults with relapsed and refractory MM who have had at least 2 prior treatments, including lenalidomide and bortezomib, and whose disease has progressed on the last therapy.

“Unfortunately, we cannot recommend pomalidomide, as the analyses from Celgene, the company that markets the drug, showed that it does not offer enough benefit to justify its high price,” said Sir Andrew Dillon, NICE chief executive.

NICE said the appraisal committee could not judge with any confidence how effective pomalidomide is compared to current treatment options based on the available evidence provided before and after consultation.

Bearing in mind the magnitude of the differences in the overall survival estimates between pomalidomide and high-dose dexamethasone in the phase 3 MM-003 trial and all data presented to the committee for comparators, the committee was persuaded that pomalidomide extends life for at least 3 months on average when compared with standard NHS care.

However, considering the incremental cost-effectiveness ratios, the committee concluded that, even with the end-of-life criteria met, the weighting that would have to be placed on the quality-adjusted life-years gained would be too high to consider pomalidomide a cost-effective use of NHS resources.

The committee also said the uncertainty in the relative effectiveness of pomalidomide compared with established NHS practice would affect any weighting that could be placed on quality-adjusted life-years gained.

Prescription drugs

Photo courtesy of CDC

The UK’s National Institute for Health and Care Excellence (NICE) has issued final guidance documents for rivaroxaban (Xarelto) and pomalidomide (Imnovid).

The agency is recommending rivaroxaban (in combination) as an option for preventing atherothrombotic events in patients with acute coronary syndrome (ACS).

But NICE said it cannot recommend pomalidomide (in combination) for the treatment of relapsed/refractory multiple myeloma (MM).

Rivaroxaban

Rivaroxaban is licensed in the European Union to prevent atherothrombotic events in adults who have an ACS severe enough to result in the release of cardiac biomarkers into the blood. The drug is given with aspirin and clopidogrel or aspirin alone.

Based on results of the ATLAS-ACS 2-TIMI 51 trial, an appraisal committee advising NICE concluded that rivaroxaban given at 2.5 mg twice daily in combination with aspirin plus clopidogrel or with aspirin alone was more effective than aspirin plus clopidogrel or aspirin alone for preventing further cardiovascular deaths and myocardial infarction in patients with ACS and raised cardiac biomarkers.

The committee also found rivaroxaban to be a cost-effective use of National Health Service (NHS) resources. They noted, however, that the drug can increase the risk of bleeding.

“Because rivaroxaban is associated with a higher risk of causing bleeding than clopidogrel in combination with aspirin or aspirin alone, the guidance recommends that, before starting treatment, doctors should carry out a careful assessment of a person’s bleeding risk,” said Carole Longson, NICE Health Technology Evaluation Centre Director.

“The decision to start treatment should be made after an informed discussion between the doctor and patient about the benefits and risks of rivaroxaban. Also, because there is limited experience of treatment with rivaroxaban up to 24 months, the guidance recommends careful consideration should be given to whether treatment is continued beyond 12 months.”

Pomalidomide

NICE’s final guidance on pomalidomide said the agency cannot recommend the drug as a treatment option for MM.

Pomalidomide is approved in the European Union for use in combination with dexamethasone to treat adults with relapsed and refractory MM who have had at least 2 prior treatments, including lenalidomide and bortezomib, and whose disease has progressed on the last therapy.

“Unfortunately, we cannot recommend pomalidomide, as the analyses from Celgene, the company that markets the drug, showed that it does not offer enough benefit to justify its high price,” said Sir Andrew Dillon, NICE chief executive.

NICE said the appraisal committee could not judge with any confidence how effective pomalidomide is compared to current treatment options based on the available evidence provided before and after consultation.

Bearing in mind the magnitude of the differences in the overall survival estimates between pomalidomide and high-dose dexamethasone in the phase 3 MM-003 trial and all data presented to the committee for comparators, the committee was persuaded that pomalidomide extends life for at least 3 months on average when compared with standard NHS care.

However, considering the incremental cost-effectiveness ratios, the committee concluded that, even with the end-of-life criteria met, the weighting that would have to be placed on the quality-adjusted life-years gained would be too high to consider pomalidomide a cost-effective use of NHS resources.

The committee also said the uncertainty in the relative effectiveness of pomalidomide compared with established NHS practice would affect any weighting that could be placed on quality-adjusted life-years gained.

Vials of drug and a syringe

The European Commission has granted orphan drug designation for intravenous (IV) alpha-1 antitrypsin (AAT) to treat graft-versus-host disease (GVHD).

AAT is a protein derived from human plasma that has demonstrated immunomodulatory, anti-inflammatory, tissue-protective, antimicrobial, and anti-apoptotic properties.

AAT may attenuate inflammation by lowering levels of pro-inflammatory mediators such as cytokines, chemokines, and proteases associated with GVHD.

The European Commission granted IV AAT orphan designation based on preliminary clinical and preclinical research.

Orphan designation is granted to a medicine intended to treat a rare condition occurring in not more than 5 in 10,000 people in the European Union. The designation allows the drug’s maker to benefit from incentives such as a 10-year period of market exclusivity, reduced regulatory fees, and protocol assistance from the European Medicines Agency.

IV AAT also has orphan designation to treat GVHD in the US.

Studies of AAT

AAT is being investigated in a phase 1/2 study involving 24 patients with GVHD who had an inadequate response to steroid treatment. The patients are enrolled in 4 dose cohorts, in which they receive up to 8 doses of AAT.

Interim results from this study were presented at the 2014 ASH Annual Meeting (abstract 3927). Preliminary results indicated that continuous administration of AAT as therapy for steroid-resistant gut GVHD is feasible in the subject population.

Following AAT administration, the researchers observed a decrease in diarrhea, a decrease in intestinal AAT loss, and improvement in endoscopic evaluation. In addition, AAT administration suppressed serum levels of pro-inflammatory cytokines and interfered with GVHD biomarkers.

Investigators have also published research on AAT in Blood. This study suggested that AAT has a protective effect against GVHD and enhances graft-vs-leukemia effects.

Kamada Ltd., the company developing IV AAT, plans to begin a phase 3 trial of the treatment in 2016 and get the product to market in 2019 or later.

Vials of drug and a syringe

The European Commission has granted orphan drug designation for intravenous (IV) alpha-1 antitrypsin (AAT) to treat graft-versus-host disease (GVHD).

AAT is a protein derived from human plasma that has demonstrated immunomodulatory, anti-inflammatory, tissue-protective, antimicrobial, and anti-apoptotic properties.

AAT may attenuate inflammation by lowering levels of pro-inflammatory mediators such as cytokines, chemokines, and proteases associated with GVHD.

The European Commission granted IV AAT orphan designation based on preliminary clinical and preclinical research.

Orphan designation is granted to a medicine intended to treat a rare condition occurring in not more than 5 in 10,000 people in the European Union. The designation allows the drug’s maker to benefit from incentives such as a 10-year period of market exclusivity, reduced regulatory fees, and protocol assistance from the European Medicines Agency.

IV AAT also has orphan designation to treat GVHD in the US.

Studies of AAT

AAT is being investigated in a phase 1/2 study involving 24 patients with GVHD who had an inadequate response to steroid treatment. The patients are enrolled in 4 dose cohorts, in which they receive up to 8 doses of AAT.

Interim results from this study were presented at the 2014 ASH Annual Meeting (abstract 3927). Preliminary results indicated that continuous administration of AAT as therapy for steroid-resistant gut GVHD is feasible in the subject population.

Following AAT administration, the researchers observed a decrease in diarrhea, a decrease in intestinal AAT loss, and improvement in endoscopic evaluation. In addition, AAT administration suppressed serum levels of pro-inflammatory cytokines and interfered with GVHD biomarkers.

Investigators have also published research on AAT in Blood. This study suggested that AAT has a protective effect against GVHD and enhances graft-vs-leukemia effects.

Kamada Ltd., the company developing IV AAT, plans to begin a phase 3 trial of the treatment in 2016 and get the product to market in 2019 or later.

Vials of drug and a syringe

The European Commission has granted orphan drug designation for intravenous (IV) alpha-1 antitrypsin (AAT) to treat graft-versus-host disease (GVHD).

AAT is a protein derived from human plasma that has demonstrated immunomodulatory, anti-inflammatory, tissue-protective, antimicrobial, and anti-apoptotic properties.

AAT may attenuate inflammation by lowering levels of pro-inflammatory mediators such as cytokines, chemokines, and proteases associated with GVHD.

The European Commission granted IV AAT orphan designation based on preliminary clinical and preclinical research.

Orphan designation is granted to a medicine intended to treat a rare condition occurring in not more than 5 in 10,000 people in the European Union. The designation allows the drug’s maker to benefit from incentives such as a 10-year period of market exclusivity, reduced regulatory fees, and protocol assistance from the European Medicines Agency.

IV AAT also has orphan designation to treat GVHD in the US.

Studies of AAT

AAT is being investigated in a phase 1/2 study involving 24 patients with GVHD who had an inadequate response to steroid treatment. The patients are enrolled in 4 dose cohorts, in which they receive up to 8 doses of AAT.

Interim results from this study were presented at the 2014 ASH Annual Meeting (abstract 3927). Preliminary results indicated that continuous administration of AAT as therapy for steroid-resistant gut GVHD is feasible in the subject population.

Following AAT administration, the researchers observed a decrease in diarrhea, a decrease in intestinal AAT loss, and improvement in endoscopic evaluation. In addition, AAT administration suppressed serum levels of pro-inflammatory cytokines and interfered with GVHD biomarkers.

Investigators have also published research on AAT in Blood. This study suggested that AAT has a protective effect against GVHD and enhances graft-vs-leukemia effects.

Kamada Ltd., the company developing IV AAT, plans to begin a phase 3 trial of the treatment in 2016 and get the product to market in 2019 or later.

Blood smear showing PV

Image courtesy of AFIP

The European Commission (EC) has approved ruxolitinib (Jakavi) to treat adults with polycythemia vera (PV) who are resistant to or cannot tolerate hydroxyurea.

This is the first targeted treatment the EC has approved for these patients.

The approval applies to all 28 member states of the European Union (EU), plus Iceland, Norway, and Liechtenstein.

Ruxolitinib is already approved to treat PV in the US, and additional regulatory applications for ruxolitinib in PV are ongoing worldwide.

The drug is also approved to treat adults with primary myelofibrosis (MF), post-PV MF, or post-essential thrombocythemia MF in more than 70 countries, including EU member states and the US.

“The European Commission’s approval of Jakavi [for PV] is encouraging news for patients,” said Claire Harrison, MD, a consultant hematologist at Guy’s and St Thomas’ NHS Foundation Trust in London, England.

“Jakavi will fill an unmet need as the first treatment shown to significantly improve hematocrit, as well as symptom control and reduce spleen size in patients with polycythemia vera resistant to or intolerant of hydroxyurea.”

RESPONSE trial

The EC’s approval is based on data from the phase 3 RESPONSE trial. The study included 222 patients who had PV for at least 24 weeks. All patients had an inadequate response to or could not tolerate hydroxyurea, had undergone a phlebotomy, and had splenomegaly.

Patients were randomized to receive ruxolitinib starting at 10 mg twice daily or best available therapy (BAT) as determined by the investigator. The ruxolitinib dose was adjusted as needed.

The study’s primary endpoint was a composite of hematocrit control and spleen reduction. To meet the endpoint, patients had to experience a 35% or greater reduction in spleen volume from baseline, as assessed by imaging at week 32.

And a patient’s hematocrit was considered under control if he was not eligible for phlebotomy from week 8 through 32 (and had no more than one instance of phlebotomy eligibility between randomization and week 8). Patients who were deemed eligible for phlebotomy had hematocrit that was greater than 45% or had increased 3 or more percentage points from the time they entered the study.

Twenty-one percent of ruxolitinib-treated patients met this endpoint (achieving hematocrit control and spleen reduction), compared to 1% of patients who received BAT (P<0.001).

And the researchers said ruxolitinib was well-tolerated. Common adverse events included headache, diarrhea, and fatigue.

Grade 3/4 anemia, grade 3/4 thrombocytopenia, and herpes zoster infections of all grades were more common in the ruxolitinib arm than the BAT arm. But thromboembolic events were more common with BAT than ruxolitinib.

This trial was funded by the Incyte Corporation, which markets ruxolitinib in the US. Novartis licensed ruxolitinib from Incyte for development and commercialization outside the US.

For more details on ruxolitinib, see the full prescribing information, available at www.jakavi.com.

Blood smear showing PV

Image courtesy of AFIP

The European Commission (EC) has approved ruxolitinib (Jakavi) to treat adults with polycythemia vera (PV) who are resistant to or cannot tolerate hydroxyurea.

This is the first targeted treatment the EC has approved for these patients.

The approval applies to all 28 member states of the European Union (EU), plus Iceland, Norway, and Liechtenstein.

Ruxolitinib is already approved to treat PV in the US, and additional regulatory applications for ruxolitinib in PV are ongoing worldwide.

The drug is also approved to treat adults with primary myelofibrosis (MF), post-PV MF, or post-essential thrombocythemia MF in more than 70 countries, including EU member states and the US.

“The European Commission’s approval of Jakavi [for PV] is encouraging news for patients,” said Claire Harrison, MD, a consultant hematologist at Guy’s and St Thomas’ NHS Foundation Trust in London, England.

“Jakavi will fill an unmet need as the first treatment shown to significantly improve hematocrit, as well as symptom control and reduce spleen size in patients with polycythemia vera resistant to or intolerant of hydroxyurea.”

RESPONSE trial

The EC’s approval is based on data from the phase 3 RESPONSE trial. The study included 222 patients who had PV for at least 24 weeks. All patients had an inadequate response to or could not tolerate hydroxyurea, had undergone a phlebotomy, and had splenomegaly.

Patients were randomized to receive ruxolitinib starting at 10 mg twice daily or best available therapy (BAT) as determined by the investigator. The ruxolitinib dose was adjusted as needed.

The study’s primary endpoint was a composite of hematocrit control and spleen reduction. To meet the endpoint, patients had to experience a 35% or greater reduction in spleen volume from baseline, as assessed by imaging at week 32.

And a patient’s hematocrit was considered under control if he was not eligible for phlebotomy from week 8 through 32 (and had no more than one instance of phlebotomy eligibility between randomization and week 8). Patients who were deemed eligible for phlebotomy had hematocrit that was greater than 45% or had increased 3 or more percentage points from the time they entered the study.

Twenty-one percent of ruxolitinib-treated patients met this endpoint (achieving hematocrit control and spleen reduction), compared to 1% of patients who received BAT (P<0.001).

And the researchers said ruxolitinib was well-tolerated. Common adverse events included headache, diarrhea, and fatigue.

Grade 3/4 anemia, grade 3/4 thrombocytopenia, and herpes zoster infections of all grades were more common in the ruxolitinib arm than the BAT arm. But thromboembolic events were more common with BAT than ruxolitinib.

This trial was funded by the Incyte Corporation, which markets ruxolitinib in the US. Novartis licensed ruxolitinib from Incyte for development and commercialization outside the US.

For more details on ruxolitinib, see the full prescribing information, available at www.jakavi.com.

Blood smear showing PV

Image courtesy of AFIP

The European Commission (EC) has approved ruxolitinib (Jakavi) to treat adults with polycythemia vera (PV) who are resistant to or cannot tolerate hydroxyurea.

This is the first targeted treatment the EC has approved for these patients.

The approval applies to all 28 member states of the European Union (EU), plus Iceland, Norway, and Liechtenstein.

Ruxolitinib is already approved to treat PV in the US, and additional regulatory applications for ruxolitinib in PV are ongoing worldwide.

The drug is also approved to treat adults with primary myelofibrosis (MF), post-PV MF, or post-essential thrombocythemia MF in more than 70 countries, including EU member states and the US.

“The European Commission’s approval of Jakavi [for PV] is encouraging news for patients,” said Claire Harrison, MD, a consultant hematologist at Guy’s and St Thomas’ NHS Foundation Trust in London, England.

“Jakavi will fill an unmet need as the first treatment shown to significantly improve hematocrit, as well as symptom control and reduce spleen size in patients with polycythemia vera resistant to or intolerant of hydroxyurea.”

RESPONSE trial

The EC’s approval is based on data from the phase 3 RESPONSE trial. The study included 222 patients who had PV for at least 24 weeks. All patients had an inadequate response to or could not tolerate hydroxyurea, had undergone a phlebotomy, and had splenomegaly.

Patients were randomized to receive ruxolitinib starting at 10 mg twice daily or best available therapy (BAT) as determined by the investigator. The ruxolitinib dose was adjusted as needed.

The study’s primary endpoint was a composite of hematocrit control and spleen reduction. To meet the endpoint, patients had to experience a 35% or greater reduction in spleen volume from baseline, as assessed by imaging at week 32.

And a patient’s hematocrit was considered under control if he was not eligible for phlebotomy from week 8 through 32 (and had no more than one instance of phlebotomy eligibility between randomization and week 8). Patients who were deemed eligible for phlebotomy had hematocrit that was greater than 45% or had increased 3 or more percentage points from the time they entered the study.

Twenty-one percent of ruxolitinib-treated patients met this endpoint (achieving hematocrit control and spleen reduction), compared to 1% of patients who received BAT (P<0.001).

And the researchers said ruxolitinib was well-tolerated. Common adverse events included headache, diarrhea, and fatigue.

Grade 3/4 anemia, grade 3/4 thrombocytopenia, and herpes zoster infections of all grades were more common in the ruxolitinib arm than the BAT arm. But thromboembolic events were more common with BAT than ruxolitinib.

This trial was funded by the Incyte Corporation, which markets ruxolitinib in the US. Novartis licensed ruxolitinib from Incyte for development and commercialization outside the US.

For more details on ruxolitinib, see the full prescribing information, available at www.jakavi.com.

US dollars

Photo by Petr Kratochvil

Increasingly high prices for cancer drugs are affecting patient care and the overall healthcare system in the US, according to authors of an article in Mayo Clinic Proceedings.

The authors noted that the average price of cancer drugs for about a year of therapy increased from $5000 to $10,000 before 2000, and to more than $100,000 by 2012.

Over nearly the same period, the average household income in the US decreased by about 8%.

“Americans with cancer pay 50% to 100% more for the same patented drug than patients in other countries,” said author S. Vincent Rajkumar, MD, of the Mayo Clinic in Rochester, Minnesota.

“As oncologists, we have a moral obligation to advocate for affordable cancer drugs for our patients.”

Dr Rajkumar and co-author Hagop Kantarjian, MD, of MD Anderson Cancer Center in Houston, Texas, rebutted the major arguments the pharmaceutical industry uses to justify the high price of cancer drugs; namely, the expense of conducting research and drug development, the comparative benefits to patients, that market forces will settle prices to reasonable levels, and that price controls on cancer drugs will stifle innovation.

“One of the facts that people do not realize is that cancer drugs, for the most part, are not operating under a free market economy,” Dr Rajkumar said. “The fact that there are 5 approved drugs to treat an incurable cancer does not mean there is competition.”

“Typically, the standard of care is that each drug is used sequentially or in combination, so that each new drug represents a monopoly with exclusivity granted by patent protection for many years.”

Drs Rajkumar and Kantarjian said other reasons for the high cost of cancer drugs include legislation that prevents Medicare from being able to negotiate drug prices and a lack of value-based pricing, which ties the cost of a drug to its relative effectiveness compared to other drugs.

The authors recommended a set of potential solutions to help control and reduce the high cost of cancer drugs in the US. Some of their recommendations are already in practice in other developed countries. Their recommendations include:

• Allow Medicare to negotiate drug prices
• Develop cancer treatment pathways/guidelines that incorporate the cost and benefit of cancer drugs
• Allow the Food and Drug Administration or physician panels to recommend target prices based on a drug’s magnitude of benefit (value-based pricing)
• Eliminate “pay-for-delay” strategies in which a pharmaceutical company with a brand name drug shares profits on that drug with a generic drug manufacturer for the remainder of a patent period, effectively eliminating a patent challenge and competition
• Allow the importation of drugs from abroad for personal use
• Allow the Patient-Centered Outcomes Research Institute and other cancer advocacy groups to consider cost in their recommendations
• Create patient-driven grassroots movements and organizations to advocate effectively for the interests of patients with cancer to balance advocacy efforts of pharmaceutical companies, insurance companies, pharmacy outlets, and hospitals.

Dr Kantarjian has organized a petition, which is available on change.org, asking the federal government to implement these changes.

US dollars

Photo by Petr Kratochvil

Increasingly high prices for cancer drugs are affecting patient care and the overall healthcare system in the US, according to authors of an article in Mayo Clinic Proceedings.

The authors noted that the average price of cancer drugs for about a year of therapy increased from $5000 to $10,000 before 2000, and to more than $100,000 by 2012.

Over nearly the same period, the average household income in the US decreased by about 8%.

“Americans with cancer pay 50% to 100% more for the same patented drug than patients in other countries,” said author S. Vincent Rajkumar, MD, of the Mayo Clinic in Rochester, Minnesota.

“As oncologists, we have a moral obligation to advocate for affordable cancer drugs for our patients.”

Dr Rajkumar and co-author Hagop Kantarjian, MD, of MD Anderson Cancer Center in Houston, Texas, rebutted the major arguments the pharmaceutical industry uses to justify the high price of cancer drugs; namely, the expense of conducting research and drug development, the comparative benefits to patients, that market forces will settle prices to reasonable levels, and that price controls on cancer drugs will stifle innovation.

“One of the facts that people do not realize is that cancer drugs, for the most part, are not operating under a free market economy,” Dr Rajkumar said. “The fact that there are 5 approved drugs to treat an incurable cancer does not mean there is competition.”

“Typically, the standard of care is that each drug is used sequentially or in combination, so that each new drug represents a monopoly with exclusivity granted by patent protection for many years.”

Drs Rajkumar and Kantarjian said other reasons for the high cost of cancer drugs include legislation that prevents Medicare from being able to negotiate drug prices and a lack of value-based pricing, which ties the cost of a drug to its relative effectiveness compared to other drugs.

The authors recommended a set of potential solutions to help control and reduce the high cost of cancer drugs in the US. Some of their recommendations are already in practice in other developed countries. Their recommendations include:

• Allow Medicare to negotiate drug prices
• Develop cancer treatment pathways/guidelines that incorporate the cost and benefit of cancer drugs
• Allow the Food and Drug Administration or physician panels to recommend target prices based on a drug’s magnitude of benefit (value-based pricing)
• Eliminate “pay-for-delay” strategies in which a pharmaceutical company with a brand name drug shares profits on that drug with a generic drug manufacturer for the remainder of a patent period, effectively eliminating a patent challenge and competition
• Allow the importation of drugs from abroad for personal use
• Allow the Patient-Centered Outcomes Research Institute and other cancer advocacy groups to consider cost in their recommendations
• Create patient-driven grassroots movements and organizations to advocate effectively for the interests of patients with cancer to balance advocacy efforts of pharmaceutical companies, insurance companies, pharmacy outlets, and hospitals.

Dr Kantarjian has organized a petition, which is available on change.org, asking the federal government to implement these changes.

US dollars

Photo by Petr Kratochvil

Increasingly high prices for cancer drugs are affecting patient care and the overall healthcare system in the US, according to authors of an article in Mayo Clinic Proceedings.

The authors noted that the average price of cancer drugs for about a year of therapy increased from $5000 to $10,000 before 2000, and to more than $100,000 by 2012.

Over nearly the same period, the average household income in the US decreased by about 8%.

“Americans with cancer pay 50% to 100% more for the same patented drug than patients in other countries,” said author S. Vincent Rajkumar, MD, of the Mayo Clinic in Rochester, Minnesota.

“As oncologists, we have a moral obligation to advocate for affordable cancer drugs for our patients.”

Dr Rajkumar and co-author Hagop Kantarjian, MD, of MD Anderson Cancer Center in Houston, Texas, rebutted the major arguments the pharmaceutical industry uses to justify the high price of cancer drugs; namely, the expense of conducting research and drug development, the comparative benefits to patients, that market forces will settle prices to reasonable levels, and that price controls on cancer drugs will stifle innovation.

“One of the facts that people do not realize is that cancer drugs, for the most part, are not operating under a free market economy,” Dr Rajkumar said. “The fact that there are 5 approved drugs to treat an incurable cancer does not mean there is competition.”

“Typically, the standard of care is that each drug is used sequentially or in combination, so that each new drug represents a monopoly with exclusivity granted by patent protection for many years.”

Drs Rajkumar and Kantarjian said other reasons for the high cost of cancer drugs include legislation that prevents Medicare from being able to negotiate drug prices and a lack of value-based pricing, which ties the cost of a drug to its relative effectiveness compared to other drugs.

The authors recommended a set of potential solutions to help control and reduce the high cost of cancer drugs in the US. Some of their recommendations are already in practice in other developed countries. Their recommendations include:

• Allow Medicare to negotiate drug prices
• Develop cancer treatment pathways/guidelines that incorporate the cost and benefit of cancer drugs
• Allow the Food and Drug Administration or physician panels to recommend target prices based on a drug’s magnitude of benefit (value-based pricing)
• Eliminate “pay-for-delay” strategies in which a pharmaceutical company with a brand name drug shares profits on that drug with a generic drug manufacturer for the remainder of a patent period, effectively eliminating a patent challenge and competition
• Allow the importation of drugs from abroad for personal use
• Allow the Patient-Centered Outcomes Research Institute and other cancer advocacy groups to consider cost in their recommendations
• Create patient-driven grassroots movements and organizations to advocate effectively for the interests of patients with cancer to balance advocacy efforts of pharmaceutical companies, insurance companies, pharmacy outlets, and hospitals.

Dr Kantarjian has organized a petition, which is available on change.org, asking the federal government to implement these changes.

Bone marrow aspirate

showing MM

The European Medicines Agency (EMA) has given a novel vaccine orphan designation as a treatment for multiple myeloma (MM).

The vaccine, known as ImMucin, targets the signal peptide domain of the MUC1 tumor antigen.

ImMucin works by “teaching” the immune system to identify and destroy cells that display a short, specific, 21-mer portion from MUC1, which appears on 90% of all cancer cells but not in patients’ blood.

Results of a phase 1/2 trial suggested that ImMucin was safe and active in MM patients. The trial included 15 MUC1-positive patients who had residual or biochemically progressive disease after autologous stem cell transplant.

The patients received 6 or 12 bi-weekly intradermal doses of ImMucin co-administered with human granulocyte-macrophage colony-stimulating factor.

The researchers said the vaccine was well-tolerated, as all adverse events were temporary, grade 1-2 in nature, and resolved spontaneously.

There was a significant decrease in soluble MUC1 levels in 9 patients, and 11 patients had stable disease or clinical improvement that persisted for 17.5 months to more than 41.3 months.

A follow-on study (which is ongoing) in patients who responded to ImMucin has shown that some patients can go more than 4 years without requiring any further treatment for their disease.

ImMucin is also being evaluated in a phase 1/2 study to treat patients with metastatic breast cancer who are receiving first-line hormone therapy.

ImMucin is under development by Vaxil Biotherapeutics Ltd.

About orphan designation

The EMA grants orphan designation to promote the clinical development of drugs that treat rare, life-threatening, or debilitating conditions and are expected to provide significant therapeutic advantage over existing treatments.

Orphan designation provides the company developing a drug with significant benefits, including 10 years of market exclusivity following approval, reductions in the fees and costs of the regulatory process, and scientific assistance from the EMA in clinical development.

Bone marrow aspirate

showing MM

The European Medicines Agency (EMA) has given a novel vaccine orphan designation as a treatment for multiple myeloma (MM).

The vaccine, known as ImMucin, targets the signal peptide domain of the MUC1 tumor antigen.

ImMucin works by “teaching” the immune system to identify and destroy cells that display a short, specific, 21-mer portion from MUC1, which appears on 90% of all cancer cells but not in patients’ blood.

Results of a phase 1/2 trial suggested that ImMucin was safe and active in MM patients. The trial included 15 MUC1-positive patients who had residual or biochemically progressive disease after autologous stem cell transplant.

The patients received 6 or 12 bi-weekly intradermal doses of ImMucin co-administered with human granulocyte-macrophage colony-stimulating factor.

The researchers said the vaccine was well-tolerated, as all adverse events were temporary, grade 1-2 in nature, and resolved spontaneously.

There was a significant decrease in soluble MUC1 levels in 9 patients, and 11 patients had stable disease or clinical improvement that persisted for 17.5 months to more than 41.3 months.

A follow-on study (which is ongoing) in patients who responded to ImMucin has shown that some patients can go more than 4 years without requiring any further treatment for their disease.

ImMucin is also being evaluated in a phase 1/2 study to treat patients with metastatic breast cancer who are receiving first-line hormone therapy.

ImMucin is under development by Vaxil Biotherapeutics Ltd.

About orphan designation

The EMA grants orphan designation to promote the clinical development of drugs that treat rare, life-threatening, or debilitating conditions and are expected to provide significant therapeutic advantage over existing treatments.

Orphan designation provides the company developing a drug with significant benefits, including 10 years of market exclusivity following approval, reductions in the fees and costs of the regulatory process, and scientific assistance from the EMA in clinical development.

Bone marrow aspirate

showing MM

The European Medicines Agency (EMA) has given a novel vaccine orphan designation as a treatment for multiple myeloma (MM).

The vaccine, known as ImMucin, targets the signal peptide domain of the MUC1 tumor antigen.

ImMucin works by “teaching” the immune system to identify and destroy cells that display a short, specific, 21-mer portion from MUC1, which appears on 90% of all cancer cells but not in patients’ blood.

Results of a phase 1/2 trial suggested that ImMucin was safe and active in MM patients. The trial included 15 MUC1-positive patients who had residual or biochemically progressive disease after autologous stem cell transplant.

The patients received 6 or 12 bi-weekly intradermal doses of ImMucin co-administered with human granulocyte-macrophage colony-stimulating factor.

The researchers said the vaccine was well-tolerated, as all adverse events were temporary, grade 1-2 in nature, and resolved spontaneously.

There was a significant decrease in soluble MUC1 levels in 9 patients, and 11 patients had stable disease or clinical improvement that persisted for 17.5 months to more than 41.3 months.

A follow-on study (which is ongoing) in patients who responded to ImMucin has shown that some patients can go more than 4 years without requiring any further treatment for their disease.

ImMucin is also being evaluated in a phase 1/2 study to treat patients with metastatic breast cancer who are receiving first-line hormone therapy.

ImMucin is under development by Vaxil Biotherapeutics Ltd.

About orphan designation

The EMA grants orphan designation to promote the clinical development of drugs that treat rare, life-threatening, or debilitating conditions and are expected to provide significant therapeutic advantage over existing treatments.

Orphan designation provides the company developing a drug with significant benefits, including 10 years of market exclusivity following approval, reductions in the fees and costs of the regulatory process, and scientific assistance from the EMA in clinical development.

Syringe

The US Food and Drug Administration (FDA) is warning healthcare professionals not to use Treanda (bendamustine hydrochloride) solution with closed-system transfer devices (CSTD), adapters, and syringes containing polycarbonate or acrylonitrile-butadiene-styrene (ABS).

Most marketed CSTDs contain either polycarbonate or ABS. And these materials dissolve when they come into contact with N, N-dimethylacetamide (DMA), an ingredient in Treanda solution.

This can lead to device failure, possible product contamination, and potential serious adverse health consequences, including skin reactions in healthcare professionals preparing and administering this product and the risk of small blood vessel blockage in patients.

Discovering the incompatibility

Treanda, which is manufactured by Teva, is used to treat patients with chronic lymphocytic leukemia and indolent B-cell non-Hodgkin lymphoma that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen.

Treanda is available as a solution—Treanda Injection (45 mg/0.5 mL or 180 mg/2 mL solution)—and a lyophilized powder—Treanda for Injection (25mg/vial or 100 mg/vial lyophilized powder).

The incompatibility of DMA with polycarbonate and ABS is only an issue with Treanda solution—not the lyophilized powder.

Since December 2014, Teva has received 40 complaints of the incompatibility issue, which was recently brought to the FDA’s attention. The agency also received a notification of device incompatibility with Treanda solution from a pharmacist.

These incompatibility issues included leaking of the CSTD, breaking or operational failure of the CSTD components, and a cloudy appearance or presence of particulate matter in the intravenous bag after dilution. To date, no adverse events have been reported related to the incompatibility.

FDA recommendations

The FDA has required label changes for both the solution and the powder formulations of Treanda to reflect the following safe preparation information.

The agency is recommending that healthcare professionals use Treanda solution only with polypropylene syringes containing a metal needle and a polypropylene hub. Polypropylene syringes are translucent in appearance.

Treanda solution should be inspected visually for particulate matter and discoloration prior to administration whenever the solution and container permit. The solution must be withdrawn and transferred for dilution in a biosafety cabinet or containment isolator.

If they aim to use a CSTD with Treanda solution, healthcare professionals should verify with the CSTD manufacturer or Teva US Medical Information (1-800-896-5855) that the CSTD is compatible with Treanda solution before preparing the drug.

Alternatively, healthcare professionals can use Treanda lyophilized powder with a CSTD. The solution and lyophilized powder formulations of Treanda should not be mixed.

For additional details on safe preparation of Treanda solution and lyophilized powder, see Teva’s Dear Health Care Provider letter.

Adverse events or quality problems associated with the use of Treanda products can be reported to the FDA’s MedWatch Adverse Event Reporting Program.

Syringe

The US Food and Drug Administration (FDA) is warning healthcare professionals not to use Treanda (bendamustine hydrochloride) solution with closed-system transfer devices (CSTD), adapters, and syringes containing polycarbonate or acrylonitrile-butadiene-styrene (ABS).

Most marketed CSTDs contain either polycarbonate or ABS. And these materials dissolve when they come into contact with N, N-dimethylacetamide (DMA), an ingredient in Treanda solution.

This can lead to device failure, possible product contamination, and potential serious adverse health consequences, including skin reactions in healthcare professionals preparing and administering this product and the risk of small blood vessel blockage in patients.

Discovering the incompatibility

Treanda, which is manufactured by Teva, is used to treat patients with chronic lymphocytic leukemia and indolent B-cell non-Hodgkin lymphoma that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen.

Treanda is available as a solution—Treanda Injection (45 mg/0.5 mL or 180 mg/2 mL solution)—and a lyophilized powder—Treanda for Injection (25mg/vial or 100 mg/vial lyophilized powder).

The incompatibility of DMA with polycarbonate and ABS is only an issue with Treanda solution—not the lyophilized powder.

Since December 2014, Teva has received 40 complaints of the incompatibility issue, which was recently brought to the FDA’s attention. The agency also received a notification of device incompatibility with Treanda solution from a pharmacist.

These incompatibility issues included leaking of the CSTD, breaking or operational failure of the CSTD components, and a cloudy appearance or presence of particulate matter in the intravenous bag after dilution. To date, no adverse events have been reported related to the incompatibility.

FDA recommendations

The FDA has required label changes for both the solution and the powder formulations of Treanda to reflect the following safe preparation information.

The agency is recommending that healthcare professionals use Treanda solution only with polypropylene syringes containing a metal needle and a polypropylene hub. Polypropylene syringes are translucent in appearance.

Treanda solution should be inspected visually for particulate matter and discoloration prior to administration whenever the solution and container permit. The solution must be withdrawn and transferred for dilution in a biosafety cabinet or containment isolator.

If they aim to use a CSTD with Treanda solution, healthcare professionals should verify with the CSTD manufacturer or Teva US Medical Information (1-800-896-5855) that the CSTD is compatible with Treanda solution before preparing the drug.

Alternatively, healthcare professionals can use Treanda lyophilized powder with a CSTD. The solution and lyophilized powder formulations of Treanda should not be mixed.

For additional details on safe preparation of Treanda solution and lyophilized powder, see Teva’s Dear Health Care Provider letter.

Adverse events or quality problems associated with the use of Treanda products can be reported to the FDA’s MedWatch Adverse Event Reporting Program.

Syringe

The US Food and Drug Administration (FDA) is warning healthcare professionals not to use Treanda (bendamustine hydrochloride) solution with closed-system transfer devices (CSTD), adapters, and syringes containing polycarbonate or acrylonitrile-butadiene-styrene (ABS).

Most marketed CSTDs contain either polycarbonate or ABS. And these materials dissolve when they come into contact with N, N-dimethylacetamide (DMA), an ingredient in Treanda solution.

This can lead to device failure, possible product contamination, and potential serious adverse health consequences, including skin reactions in healthcare professionals preparing and administering this product and the risk of small blood vessel blockage in patients.

Discovering the incompatibility

Treanda, which is manufactured by Teva, is used to treat patients with chronic lymphocytic leukemia and indolent B-cell non-Hodgkin lymphoma that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen.

Treanda is available as a solution—Treanda Injection (45 mg/0.5 mL or 180 mg/2 mL solution)—and a lyophilized powder—Treanda for Injection (25mg/vial or 100 mg/vial lyophilized powder).

The incompatibility of DMA with polycarbonate and ABS is only an issue with Treanda solution—not the lyophilized powder.

Since December 2014, Teva has received 40 complaints of the incompatibility issue, which was recently brought to the FDA’s attention. The agency also received a notification of device incompatibility with Treanda solution from a pharmacist.

These incompatibility issues included leaking of the CSTD, breaking or operational failure of the CSTD components, and a cloudy appearance or presence of particulate matter in the intravenous bag after dilution. To date, no adverse events have been reported related to the incompatibility.

FDA recommendations

The FDA has required label changes for both the solution and the powder formulations of Treanda to reflect the following safe preparation information.

The agency is recommending that healthcare professionals use Treanda solution only with polypropylene syringes containing a metal needle and a polypropylene hub. Polypropylene syringes are translucent in appearance.

Treanda solution should be inspected visually for particulate matter and discoloration prior to administration whenever the solution and container permit. The solution must be withdrawn and transferred for dilution in a biosafety cabinet or containment isolator.

If they aim to use a CSTD with Treanda solution, healthcare professionals should verify with the CSTD manufacturer or Teva US Medical Information (1-800-896-5855) that the CSTD is compatible with Treanda solution before preparing the drug.

Alternatively, healthcare professionals can use Treanda lyophilized powder with a CSTD. The solution and lyophilized powder formulations of Treanda should not be mixed.

For additional details on safe preparation of Treanda solution and lyophilized powder, see Teva’s Dear Health Care Provider letter.

Adverse events or quality problems associated with the use of Treanda products can be reported to the FDA’s MedWatch Adverse Event Reporting Program.