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FDA approves new indication for dabigatran
Photo by ec-jpr
The US Food and Drug Administration (FDA) has approved the direct thrombin inhibitor dabigatran etexilate mesylate (Pradaxa) for the prophylaxis of deep venous thrombosis (DVT) and pulmonary embolism (PE) in patients who have undergone hip replacement surgery.
Dabigatran was initially approved by the FDA in 2010 to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation.
In 2014, dabigatran was approved to treat DVT and PE in patients who have been treated with a parenteral anticoagulant for 5 to 10 days and to reduce the risk of recurrent DVT and PE in patients who have been previously treated.
A reversal agent for dabigatran, known as idarucizumab (Praxbind), was approved by the FDA last month.
Trial data
The latest approval of dabigatran is based on results of 2 randomized, double-blind, phase 3 trials in patients undergoing total hip replacement, RE-NOVATE™ and RE-NOVATE II™.
In the RE-NOVATE trial, 3494 patients were randomized to 3 groups receiving prophylactic treatment with 1 of 2 doses of dabigatran (220 mg or 150 mg) once daily or enoxaparin at 40 mg once daily for 28 to 35 days.
The first dabigatran group was given a dose of 110 mg on the day of surgery and 220 mg daily thereafter. The second dabigatran group received a dose of 75 mg on the day of surgery and 150 mg daily thereafter.
Patients taking dabigatran at 220 mg had a lower composite total of venous thromboembolism (VTE) and all-cause death (6.0%) than patients on enoxaparin (6.7%). However, the rate of major bleeding was higher with dabigatran at 220 mg (2.0%) than with enoxaparin (1.6%).
In the RE-NOVATE II trial, 2055 patients were randomized to prophylactic treatment for 28 to 35 days with dabigatran at 220 mg once daily or enoxaparin at 40 mg once daily. Patients receiving dabigatran were treated with a dose of 110 mg on the day of surgery and 220 mg daily thereafter.
The composite total of VTE and all-cause death occurred in 7.7% of patients in the dabigatran group and 8.8% of patients in the enoxaparin group. Again, the rate of major bleeding was higher with dabigatran at 220 mg (1.4%) than with enoxaparin (0.9%).
In both studies, the rate of major gastrointestinal bleeds in patients receiving dabigatran and enoxaparin was the same (0.1%). The rate of any gastrointestinal bleeds was 1.4% for dabigatran and 0.9% for enoxaparin.
The most common adverse events in both studies were gastrointestinal disorders. The incidence was the same across the dabigatran and enoxaparin treatment groups (39.5%).
Dyspepsia (including abdominal pain upper, abdominal pain, abdominal discomfort, and epigastric discomfort) occurred more frequently in patients receiving dabigatran (4.1%) than enoxaparin (3.8%).
Gastritis-like symptoms (including gastritis, GERD, esophagitis, erosive gastritis, and gastric hemorrhage) were less common in patients receiving dabigatran (0.6%) than enoxaparin (1.0%). Clinical myocardial infarction was reported in 2 (0.1%) dabigatran patients and 6 (0.3%) enoxaparin patients.
Dabigatran is marketed as Pradaxa by Boehringer Ingelheim. For more details on the drug, see the prescribing information. 
Photo by ec-jpr
The US Food and Drug Administration (FDA) has approved the direct thrombin inhibitor dabigatran etexilate mesylate (Pradaxa) for the prophylaxis of deep venous thrombosis (DVT) and pulmonary embolism (PE) in patients who have undergone hip replacement surgery.
Dabigatran was initially approved by the FDA in 2010 to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation.
In 2014, dabigatran was approved to treat DVT and PE in patients who have been treated with a parenteral anticoagulant for 5 to 10 days and to reduce the risk of recurrent DVT and PE in patients who have been previously treated.
A reversal agent for dabigatran, known as idarucizumab (Praxbind), was approved by the FDA last month.
Trial data
The latest approval of dabigatran is based on results of 2 randomized, double-blind, phase 3 trials in patients undergoing total hip replacement, RE-NOVATE™ and RE-NOVATE II™.
In the RE-NOVATE trial, 3494 patients were randomized to 3 groups receiving prophylactic treatment with 1 of 2 doses of dabigatran (220 mg or 150 mg) once daily or enoxaparin at 40 mg once daily for 28 to 35 days.
The first dabigatran group was given a dose of 110 mg on the day of surgery and 220 mg daily thereafter. The second dabigatran group received a dose of 75 mg on the day of surgery and 150 mg daily thereafter.
Patients taking dabigatran at 220 mg had a lower composite total of venous thromboembolism (VTE) and all-cause death (6.0%) than patients on enoxaparin (6.7%). However, the rate of major bleeding was higher with dabigatran at 220 mg (2.0%) than with enoxaparin (1.6%).
In the RE-NOVATE II trial, 2055 patients were randomized to prophylactic treatment for 28 to 35 days with dabigatran at 220 mg once daily or enoxaparin at 40 mg once daily. Patients receiving dabigatran were treated with a dose of 110 mg on the day of surgery and 220 mg daily thereafter.
The composite total of VTE and all-cause death occurred in 7.7% of patients in the dabigatran group and 8.8% of patients in the enoxaparin group. Again, the rate of major bleeding was higher with dabigatran at 220 mg (1.4%) than with enoxaparin (0.9%).
In both studies, the rate of major gastrointestinal bleeds in patients receiving dabigatran and enoxaparin was the same (0.1%). The rate of any gastrointestinal bleeds was 1.4% for dabigatran and 0.9% for enoxaparin.
The most common adverse events in both studies were gastrointestinal disorders. The incidence was the same across the dabigatran and enoxaparin treatment groups (39.5%).
Dyspepsia (including abdominal pain upper, abdominal pain, abdominal discomfort, and epigastric discomfort) occurred more frequently in patients receiving dabigatran (4.1%) than enoxaparin (3.8%).
Gastritis-like symptoms (including gastritis, GERD, esophagitis, erosive gastritis, and gastric hemorrhage) were less common in patients receiving dabigatran (0.6%) than enoxaparin (1.0%). Clinical myocardial infarction was reported in 2 (0.1%) dabigatran patients and 6 (0.3%) enoxaparin patients.
Dabigatran is marketed as Pradaxa by Boehringer Ingelheim. For more details on the drug, see the prescribing information.
Photo by ec-jpr
The US Food and Drug Administration (FDA) has approved the direct thrombin inhibitor dabigatran etexilate mesylate (Pradaxa) for the prophylaxis of deep venous thrombosis (DVT) and pulmonary embolism (PE) in patients who have undergone hip replacement surgery.
Dabigatran was initially approved by the FDA in 2010 to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation.
In 2014, dabigatran was approved to treat DVT and PE in patients who have been treated with a parenteral anticoagulant for 5 to 10 days and to reduce the risk of recurrent DVT and PE in patients who have been previously treated.
A reversal agent for dabigatran, known as idarucizumab (Praxbind), was approved by the FDA last month.
Trial data
The latest approval of dabigatran is based on results of 2 randomized, double-blind, phase 3 trials in patients undergoing total hip replacement, RE-NOVATE™ and RE-NOVATE II™.
In the RE-NOVATE trial, 3494 patients were randomized to 3 groups receiving prophylactic treatment with 1 of 2 doses of dabigatran (220 mg or 150 mg) once daily or enoxaparin at 40 mg once daily for 28 to 35 days.
The first dabigatran group was given a dose of 110 mg on the day of surgery and 220 mg daily thereafter. The second dabigatran group received a dose of 75 mg on the day of surgery and 150 mg daily thereafter.
Patients taking dabigatran at 220 mg had a lower composite total of venous thromboembolism (VTE) and all-cause death (6.0%) than patients on enoxaparin (6.7%). However, the rate of major bleeding was higher with dabigatran at 220 mg (2.0%) than with enoxaparin (1.6%).
In the RE-NOVATE II trial, 2055 patients were randomized to prophylactic treatment for 28 to 35 days with dabigatran at 220 mg once daily or enoxaparin at 40 mg once daily. Patients receiving dabigatran were treated with a dose of 110 mg on the day of surgery and 220 mg daily thereafter.
The composite total of VTE and all-cause death occurred in 7.7% of patients in the dabigatran group and 8.8% of patients in the enoxaparin group. Again, the rate of major bleeding was higher with dabigatran at 220 mg (1.4%) than with enoxaparin (0.9%).
In both studies, the rate of major gastrointestinal bleeds in patients receiving dabigatran and enoxaparin was the same (0.1%). The rate of any gastrointestinal bleeds was 1.4% for dabigatran and 0.9% for enoxaparin.
The most common adverse events in both studies were gastrointestinal disorders. The incidence was the same across the dabigatran and enoxaparin treatment groups (39.5%).
Dyspepsia (including abdominal pain upper, abdominal pain, abdominal discomfort, and epigastric discomfort) occurred more frequently in patients receiving dabigatran (4.1%) than enoxaparin (3.8%).
Gastritis-like symptoms (including gastritis, GERD, esophagitis, erosive gastritis, and gastric hemorrhage) were less common in patients receiving dabigatran (0.6%) than enoxaparin (1.0%). Clinical myocardial infarction was reported in 2 (0.1%) dabigatran patients and 6 (0.3%) enoxaparin patients.
Dabigatran is marketed as Pradaxa by Boehringer Ingelheim. For more details on the drug, see the prescribing information.
Companies abuse orphan drug designation, team says
Photo by Steven Harbour
Health experts are calling on US lawmakers and regulators to “close loopholes” in the Orphan Drug Act.
The experts say the loopholes can provide pharmaceutical companies with millions of dollars in unintended subsidies and tax breaks and fuel skyrocketing medication costs.
They argue that companies are exploiting gaps in the law by claiming orphan status for drugs that end up being marketed for more common conditions.
“The industry has been gaming the system by slicing and dicing indications so that drugs qualify for lucrative orphan status benefits,” says Martin Makary, MD, of Johns Hopkins Hospital in Baltimore, Maryland.
“As a result, funding support intended for rare disease medicine is diverted to fund the development of blockbuster drugs.”
Dr Makary and his colleagues express this viewpoint in a commentary published in the American Journal of Clinical Oncology.
The US Food and Drug Administration (FDA) grants orphan designation to encourage the development of drugs for diseases that affect fewer than 200,000 people in the US. The Orphan Drug Act was enacted in 1983 to provide incentives for drug companies to develop treatments for so-called orphan diseases that would be unprofitable because of the limited market.
Dr Makary and his colleagues say the legislation has accomplished that mission and sparked the development of life-saving therapies for a range of rare disorders. However, the authors say the law has also invited abuse.
Under the terms of the act, companies can receive federal taxpayer subsidies of up to half a million dollars a year for up to 4 years per drug, large tax credits, and waivers of marketing application fees that can cost more than $2 million. In addition, the FDA can grant companies 7 years of marketing exclusivity for an orphan drug to ensure that companies recoup the costs of research and development.
Dr Makary says companies exploit the law by initially listing only a single indication for a drug’s use—one narrow enough to qualify for orphan disease benefits. After FDA approval, however, some such drugs are marketed and used off-label more broadly, thus turning large profits.
“This is a financially toxic practice that is also unethical,” says study author Michael Daniel, also of Johns Hopkins.
“It’s time to ensure that we also render it illegal. The practice inflates drug prices, and the costs are passed on to consumers in the form of higher health insurance premiums.”
For example, the drug rituximab was originally approved to treat follicular B-cell non-Hodgkin lymphoma, a disease that affects about 14,000 patients a year. Now, rituximab is also used to treat several other types of cancer, organ rejection following kidney transplant, and autoimmune diseases, including rheumatoid arthritis, which affects 1.3 million Americans.
Rituximab, marketed under several trade names, is the top-selling medication approved as an orphan drug, the 12th all-time drug best-seller in the US, and it generated $3.7 billion in domestic sales in 2014.
In fact, 7 of the top 10 best-selling drugs in the US for 2014 came on the market with an orphan designation, according to Dr Makary and his colleagues.
Of the 41 drugs approved by the FDA in 2014, 18 had orphan status designations. The authors predict that, in 2015, orphan drugs will generate sales totaling $107 billion. And that number is expected to reach $176 billion by 2020.
Dr Makary says this projection represents a yearly growth rate of nearly 11%, or double the growth rate of the overall prescription drug market. The authors also cite data showing that, by 2020, orphan drugs are expected to account for 19% of global prescription drug sales, up from 6% in the year 2000.
Although the reasons for this boom in orphan drugs are likely multifactorial, the exploitation of the orphan drug act is an important catalyst behind this trend, the authors say.
Because orphan designation guarantees a 7-year exclusivity deal to market the drug and protects it from generic competition, the price tags for such medications often balloon rapidly.
For example, the drug imatinib was initially priced at $30,000 per year in 2001. By 2012, it cost $92,000 a year.
The drug’s original designation was for chronic myelogenous leukemia, and it would therefore treat 9000 patients a year in the US. Subsequently, imatinib was given 6 additional orphan designations for various conditions, including gastric cancers and immune disorders.
Dr Makary says, in essence, the exclusivity clause guarantees a hyperextended government-sponsored monopoly. So it’s not surprising that the median cost for orphan drugs is more than $98,000 per patient per year, compared with a median cost of just over $5000 per patient per year for drugs without orphan status.
Overall, nearly 15% of already approved orphan drugs subsequently add far more common diseases to their treatment repertoires.
Dr Makary and his colleagues recommend that, once a drug exceeds the basic tenets of the act—to treat fewer than 200,000 people—it should no longer receive government support or marketing exclusivity.
This can be achieved, the authors say, through pricing negotiations, clauses that reduce marketing exclusivity, and leveling of taxes once a medication becomes a blockbuster treatment for conditions not listed in the original FDA approval.
They say such measures would ensure the spirit of the original act is followed while continuing to provide critical economic incentives for truly rare diseases.
Photo by Steven Harbour
Health experts are calling on US lawmakers and regulators to “close loopholes” in the Orphan Drug Act.
The experts say the loopholes can provide pharmaceutical companies with millions of dollars in unintended subsidies and tax breaks and fuel skyrocketing medication costs.
They argue that companies are exploiting gaps in the law by claiming orphan status for drugs that end up being marketed for more common conditions.
“The industry has been gaming the system by slicing and dicing indications so that drugs qualify for lucrative orphan status benefits,” says Martin Makary, MD, of Johns Hopkins Hospital in Baltimore, Maryland.
“As a result, funding support intended for rare disease medicine is diverted to fund the development of blockbuster drugs.”
Dr Makary and his colleagues express this viewpoint in a commentary published in the American Journal of Clinical Oncology.
The US Food and Drug Administration (FDA) grants orphan designation to encourage the development of drugs for diseases that affect fewer than 200,000 people in the US. The Orphan Drug Act was enacted in 1983 to provide incentives for drug companies to develop treatments for so-called orphan diseases that would be unprofitable because of the limited market.
Dr Makary and his colleagues say the legislation has accomplished that mission and sparked the development of life-saving therapies for a range of rare disorders. However, the authors say the law has also invited abuse.
Under the terms of the act, companies can receive federal taxpayer subsidies of up to half a million dollars a year for up to 4 years per drug, large tax credits, and waivers of marketing application fees that can cost more than $2 million. In addition, the FDA can grant companies 7 years of marketing exclusivity for an orphan drug to ensure that companies recoup the costs of research and development.
Dr Makary says companies exploit the law by initially listing only a single indication for a drug’s use—one narrow enough to qualify for orphan disease benefits. After FDA approval, however, some such drugs are marketed and used off-label more broadly, thus turning large profits.
“This is a financially toxic practice that is also unethical,” says study author Michael Daniel, also of Johns Hopkins.
“It’s time to ensure that we also render it illegal. The practice inflates drug prices, and the costs are passed on to consumers in the form of higher health insurance premiums.”
For example, the drug rituximab was originally approved to treat follicular B-cell non-Hodgkin lymphoma, a disease that affects about 14,000 patients a year. Now, rituximab is also used to treat several other types of cancer, organ rejection following kidney transplant, and autoimmune diseases, including rheumatoid arthritis, which affects 1.3 million Americans.
Rituximab, marketed under several trade names, is the top-selling medication approved as an orphan drug, the 12th all-time drug best-seller in the US, and it generated $3.7 billion in domestic sales in 2014.
In fact, 7 of the top 10 best-selling drugs in the US for 2014 came on the market with an orphan designation, according to Dr Makary and his colleagues.
Of the 41 drugs approved by the FDA in 2014, 18 had orphan status designations. The authors predict that, in 2015, orphan drugs will generate sales totaling $107 billion. And that number is expected to reach $176 billion by 2020.
Dr Makary says this projection represents a yearly growth rate of nearly 11%, or double the growth rate of the overall prescription drug market. The authors also cite data showing that, by 2020, orphan drugs are expected to account for 19% of global prescription drug sales, up from 6% in the year 2000.
Although the reasons for this boom in orphan drugs are likely multifactorial, the exploitation of the orphan drug act is an important catalyst behind this trend, the authors say.
Because orphan designation guarantees a 7-year exclusivity deal to market the drug and protects it from generic competition, the price tags for such medications often balloon rapidly.
For example, the drug imatinib was initially priced at $30,000 per year in 2001. By 2012, it cost $92,000 a year.
The drug’s original designation was for chronic myelogenous leukemia, and it would therefore treat 9000 patients a year in the US. Subsequently, imatinib was given 6 additional orphan designations for various conditions, including gastric cancers and immune disorders.
Dr Makary says, in essence, the exclusivity clause guarantees a hyperextended government-sponsored monopoly. So it’s not surprising that the median cost for orphan drugs is more than $98,000 per patient per year, compared with a median cost of just over $5000 per patient per year for drugs without orphan status.
Overall, nearly 15% of already approved orphan drugs subsequently add far more common diseases to their treatment repertoires.
Dr Makary and his colleagues recommend that, once a drug exceeds the basic tenets of the act—to treat fewer than 200,000 people—it should no longer receive government support or marketing exclusivity.
This can be achieved, the authors say, through pricing negotiations, clauses that reduce marketing exclusivity, and leveling of taxes once a medication becomes a blockbuster treatment for conditions not listed in the original FDA approval.
They say such measures would ensure the spirit of the original act is followed while continuing to provide critical economic incentives for truly rare diseases.
Photo by Steven Harbour
Health experts are calling on US lawmakers and regulators to “close loopholes” in the Orphan Drug Act.
The experts say the loopholes can provide pharmaceutical companies with millions of dollars in unintended subsidies and tax breaks and fuel skyrocketing medication costs.
They argue that companies are exploiting gaps in the law by claiming orphan status for drugs that end up being marketed for more common conditions.
“The industry has been gaming the system by slicing and dicing indications so that drugs qualify for lucrative orphan status benefits,” says Martin Makary, MD, of Johns Hopkins Hospital in Baltimore, Maryland.
“As a result, funding support intended for rare disease medicine is diverted to fund the development of blockbuster drugs.”
Dr Makary and his colleagues express this viewpoint in a commentary published in the American Journal of Clinical Oncology.
The US Food and Drug Administration (FDA) grants orphan designation to encourage the development of drugs for diseases that affect fewer than 200,000 people in the US. The Orphan Drug Act was enacted in 1983 to provide incentives for drug companies to develop treatments for so-called orphan diseases that would be unprofitable because of the limited market.
Dr Makary and his colleagues say the legislation has accomplished that mission and sparked the development of life-saving therapies for a range of rare disorders. However, the authors say the law has also invited abuse.
Under the terms of the act, companies can receive federal taxpayer subsidies of up to half a million dollars a year for up to 4 years per drug, large tax credits, and waivers of marketing application fees that can cost more than $2 million. In addition, the FDA can grant companies 7 years of marketing exclusivity for an orphan drug to ensure that companies recoup the costs of research and development.
Dr Makary says companies exploit the law by initially listing only a single indication for a drug’s use—one narrow enough to qualify for orphan disease benefits. After FDA approval, however, some such drugs are marketed and used off-label more broadly, thus turning large profits.
“This is a financially toxic practice that is also unethical,” says study author Michael Daniel, also of Johns Hopkins.
“It’s time to ensure that we also render it illegal. The practice inflates drug prices, and the costs are passed on to consumers in the form of higher health insurance premiums.”
For example, the drug rituximab was originally approved to treat follicular B-cell non-Hodgkin lymphoma, a disease that affects about 14,000 patients a year. Now, rituximab is also used to treat several other types of cancer, organ rejection following kidney transplant, and autoimmune diseases, including rheumatoid arthritis, which affects 1.3 million Americans.
Rituximab, marketed under several trade names, is the top-selling medication approved as an orphan drug, the 12th all-time drug best-seller in the US, and it generated $3.7 billion in domestic sales in 2014.
In fact, 7 of the top 10 best-selling drugs in the US for 2014 came on the market with an orphan designation, according to Dr Makary and his colleagues.
Of the 41 drugs approved by the FDA in 2014, 18 had orphan status designations. The authors predict that, in 2015, orphan drugs will generate sales totaling $107 billion. And that number is expected to reach $176 billion by 2020.
Dr Makary says this projection represents a yearly growth rate of nearly 11%, or double the growth rate of the overall prescription drug market. The authors also cite data showing that, by 2020, orphan drugs are expected to account for 19% of global prescription drug sales, up from 6% in the year 2000.
Although the reasons for this boom in orphan drugs are likely multifactorial, the exploitation of the orphan drug act is an important catalyst behind this trend, the authors say.
Because orphan designation guarantees a 7-year exclusivity deal to market the drug and protects it from generic competition, the price tags for such medications often balloon rapidly.
For example, the drug imatinib was initially priced at $30,000 per year in 2001. By 2012, it cost $92,000 a year.
The drug’s original designation was for chronic myelogenous leukemia, and it would therefore treat 9000 patients a year in the US. Subsequently, imatinib was given 6 additional orphan designations for various conditions, including gastric cancers and immune disorders.
Dr Makary says, in essence, the exclusivity clause guarantees a hyperextended government-sponsored monopoly. So it’s not surprising that the median cost for orphan drugs is more than $98,000 per patient per year, compared with a median cost of just over $5000 per patient per year for drugs without orphan status.
Overall, nearly 15% of already approved orphan drugs subsequently add far more common diseases to their treatment repertoires.
Dr Makary and his colleagues recommend that, once a drug exceeds the basic tenets of the act—to treat fewer than 200,000 people—it should no longer receive government support or marketing exclusivity.
This can be achieved, the authors say, through pricing negotiations, clauses that reduce marketing exclusivity, and leveling of taxes once a medication becomes a blockbuster treatment for conditions not listed in the original FDA approval.
They say such measures would ensure the spirit of the original act is followed while continuing to provide critical economic incentives for truly rare diseases.
Group uses lettuce to produce clotting factor on large scale
Photo by Daniel Ventura
Investigators have shown they can use lettuce to produce a factor IX product on a large scale.
The product successfully delivered factor IX to mice with hemophilia B while preventing the formation of inhibitors.
“This is a milestone in our field—to make a fully functional drug in plants, produce it at a large scale and in quantities sufficient for human clinical trials,” said Henry Daniell, PhD, of the University of Pennsylvania School of Dental Medicine in Philadelphia.
Dr Daniell and his colleagues described this work in Biomaterials.
This research builds on Dr Daniell’s previous work using genetically modified plants to introduce a protein into the body that would teach the immune system to tolerate clotting factors given as a treatment for hemophilia.
In that study, Dr Daniell and his colleagues successfully stopped and even reversed the production of inhibitors by feeding the plant-based drug to mice with hemophilia A. At that time, the investigators used a tobacco plant platform to “grow” the drug.
To take this approach to humans, Dr Daniell’s team turned to lettuce. They identified the genetic vector to introduce the therapeutic gene into the plant cells’ DNA and grow the drug within the lettuce leaves, which are then freeze-dried and encapsulated.
Two different growing systems were used. One was in Dr Daniell’s greenhouse, a high-tech facility that grows the plants in soil, using natural light.
The second system was used in the Fraunhofer USA facility, which more closely replicates how a commercial pharmaceutical production facility would run, using a hydroponic system and artificial lighting.
The investigators determined they could produce 36,000 doses in just 1000 square feet and harvest a new batch of pharmaceutical-containing lettuce every 4 to 6 weeks.
“This changes the way we think about delivering protein-based drugs and making them affordable to the global population,” Dr Daniell said.
“Over 90% of the global population can’t afford protein drugs, like insulin, due to the expense of production and the required refrigeration for storage or transportation. I am determined to challenge this scenario.”
Photo by Daniel Ventura
Investigators have shown they can use lettuce to produce a factor IX product on a large scale.
The product successfully delivered factor IX to mice with hemophilia B while preventing the formation of inhibitors.
“This is a milestone in our field—to make a fully functional drug in plants, produce it at a large scale and in quantities sufficient for human clinical trials,” said Henry Daniell, PhD, of the University of Pennsylvania School of Dental Medicine in Philadelphia.
Dr Daniell and his colleagues described this work in Biomaterials.
This research builds on Dr Daniell’s previous work using genetically modified plants to introduce a protein into the body that would teach the immune system to tolerate clotting factors given as a treatment for hemophilia.
In that study, Dr Daniell and his colleagues successfully stopped and even reversed the production of inhibitors by feeding the plant-based drug to mice with hemophilia A. At that time, the investigators used a tobacco plant platform to “grow” the drug.
To take this approach to humans, Dr Daniell’s team turned to lettuce. They identified the genetic vector to introduce the therapeutic gene into the plant cells’ DNA and grow the drug within the lettuce leaves, which are then freeze-dried and encapsulated.
Two different growing systems were used. One was in Dr Daniell’s greenhouse, a high-tech facility that grows the plants in soil, using natural light.
The second system was used in the Fraunhofer USA facility, which more closely replicates how a commercial pharmaceutical production facility would run, using a hydroponic system and artificial lighting.
The investigators determined they could produce 36,000 doses in just 1000 square feet and harvest a new batch of pharmaceutical-containing lettuce every 4 to 6 weeks.
“This changes the way we think about delivering protein-based drugs and making them affordable to the global population,” Dr Daniell said.
“Over 90% of the global population can’t afford protein drugs, like insulin, due to the expense of production and the required refrigeration for storage or transportation. I am determined to challenge this scenario.”
Photo by Daniel Ventura
Investigators have shown they can use lettuce to produce a factor IX product on a large scale.
The product successfully delivered factor IX to mice with hemophilia B while preventing the formation of inhibitors.
“This is a milestone in our field—to make a fully functional drug in plants, produce it at a large scale and in quantities sufficient for human clinical trials,” said Henry Daniell, PhD, of the University of Pennsylvania School of Dental Medicine in Philadelphia.
Dr Daniell and his colleagues described this work in Biomaterials.
This research builds on Dr Daniell’s previous work using genetically modified plants to introduce a protein into the body that would teach the immune system to tolerate clotting factors given as a treatment for hemophilia.
In that study, Dr Daniell and his colleagues successfully stopped and even reversed the production of inhibitors by feeding the plant-based drug to mice with hemophilia A. At that time, the investigators used a tobacco plant platform to “grow” the drug.
To take this approach to humans, Dr Daniell’s team turned to lettuce. They identified the genetic vector to introduce the therapeutic gene into the plant cells’ DNA and grow the drug within the lettuce leaves, which are then freeze-dried and encapsulated.
Two different growing systems were used. One was in Dr Daniell’s greenhouse, a high-tech facility that grows the plants in soil, using natural light.
The second system was used in the Fraunhofer USA facility, which more closely replicates how a commercial pharmaceutical production facility would run, using a hydroponic system and artificial lighting.
The investigators determined they could produce 36,000 doses in just 1000 square feet and harvest a new batch of pharmaceutical-containing lettuce every 4 to 6 weeks.
“This changes the way we think about delivering protein-based drugs and making them affordable to the global population,” Dr Daniell said.
“Over 90% of the global population can’t afford protein drugs, like insulin, due to the expense of production and the required refrigeration for storage or transportation. I am determined to challenge this scenario.”
FDA approves ixazomib for MM
The US Food and Drug Administration (FDA) has approved ixazomib (Ninlaro), the first oral proteasome inhibitor, for use in combination with lenalidomide and dexamethasone to treat multiple myeloma (MM) patients who have received at least 1 prior therapy.
The FDA previously granted ixazomib priority review and orphan designation.
The regulatory submission for ixazomib was primarily based on results from the first interim analysis of the phase 3 TOURMALINE-MM1 trial.
In this trial, patients with relapsed and/or refractory MM who received ixazomib plus lenalidomide and dexamethasone had superior progression-free survival when compared to patients who received placebo plus lenalidomide and dexamethasone.
Results from TOURMALINE-MM1 are scheduled to be presented at the 2015 ASH Annual Meeting (abstract 727) in December.
Ixazomib is currently under investigation in 3 other phase 3 trials of MM patients:
- TOURMALINE-MM2, investigating ixazomib vs placebo, both in combination with lenalidomide and dexamethasone in patients with newly diagnosed MM
- TOURMALINE-MM3, investigating ixazomib vs placebo as maintenance therapy in patients with newly diagnosed MM following induction therapy and autologous stem cell transplant
- TOURMALINE-MM4, investigating ixazomib vs placebo as maintenance therapy in patients with newly diagnosed MM who have not undergone autologous stem cell transplant.
Ixazomib is marketed by Takeda Pharmaceuticals.
The US Food and Drug Administration (FDA) has approved ixazomib (Ninlaro), the first oral proteasome inhibitor, for use in combination with lenalidomide and dexamethasone to treat multiple myeloma (MM) patients who have received at least 1 prior therapy.
The FDA previously granted ixazomib priority review and orphan designation.
The regulatory submission for ixazomib was primarily based on results from the first interim analysis of the phase 3 TOURMALINE-MM1 trial.
In this trial, patients with relapsed and/or refractory MM who received ixazomib plus lenalidomide and dexamethasone had superior progression-free survival when compared to patients who received placebo plus lenalidomide and dexamethasone.
Results from TOURMALINE-MM1 are scheduled to be presented at the 2015 ASH Annual Meeting (abstract 727) in December.
Ixazomib is currently under investigation in 3 other phase 3 trials of MM patients:
- TOURMALINE-MM2, investigating ixazomib vs placebo, both in combination with lenalidomide and dexamethasone in patients with newly diagnosed MM
- TOURMALINE-MM3, investigating ixazomib vs placebo as maintenance therapy in patients with newly diagnosed MM following induction therapy and autologous stem cell transplant
- TOURMALINE-MM4, investigating ixazomib vs placebo as maintenance therapy in patients with newly diagnosed MM who have not undergone autologous stem cell transplant.
Ixazomib is marketed by Takeda Pharmaceuticals.
The US Food and Drug Administration (FDA) has approved ixazomib (Ninlaro), the first oral proteasome inhibitor, for use in combination with lenalidomide and dexamethasone to treat multiple myeloma (MM) patients who have received at least 1 prior therapy.
The FDA previously granted ixazomib priority review and orphan designation.
The regulatory submission for ixazomib was primarily based on results from the first interim analysis of the phase 3 TOURMALINE-MM1 trial.
In this trial, patients with relapsed and/or refractory MM who received ixazomib plus lenalidomide and dexamethasone had superior progression-free survival when compared to patients who received placebo plus lenalidomide and dexamethasone.
Results from TOURMALINE-MM1 are scheduled to be presented at the 2015 ASH Annual Meeting (abstract 727) in December.
Ixazomib is currently under investigation in 3 other phase 3 trials of MM patients:
- TOURMALINE-MM2, investigating ixazomib vs placebo, both in combination with lenalidomide and dexamethasone in patients with newly diagnosed MM
- TOURMALINE-MM3, investigating ixazomib vs placebo as maintenance therapy in patients with newly diagnosed MM following induction therapy and autologous stem cell transplant
- TOURMALINE-MM4, investigating ixazomib vs placebo as maintenance therapy in patients with newly diagnosed MM who have not undergone autologous stem cell transplant.
Ixazomib is marketed by Takeda Pharmaceuticals.
EC approves carfilzomib for relapsed MM
Photo courtesy of Amgen
The European Commission (EC) has granted marketing authorization for carfilzomib (Kyprolis) to be used in combination with lenalidomide and dexamethasone to treat adults with multiple myeloma (MM) who have received at least 1 prior therapy.
Carfilzomib is the first irreversible proteasome inhibitor approved in the European Union (EU) as part of combination treatment for patients with relapsed MM.
Carfilzomib was granted orphan designation in the EU in 2008. The drug also received accelerated assessment, which shortened the review period from 210 days to 150 days.
Carfilzomib is a product of Onyx Pharmaceuticals, Inc., a subsidiary of Amgen that holds development and commercialization rights to the drug globally, excluding Japan.
ASPIRE trial
The EC approved carfilzomib based on data from the phase 3 ASPIRE trial, which were presented at ASH 2014 and published in NEJM.
The trial enrolled 792 patients with relapsed or refractory MM who had received 1 to 3 prior lines of therapy. The patients were randomized (1:1) to receive carfilzomib plus lenalidomide and dexamethasone (KRd) or just lenalidomide and dexamethasone (Rd) for 18 cycles.
Lenalidomide and dexamethasone were continued thereafter until disease progression. There was no planned cross-over from the control arm to treatment with carfilzomib.
The study’s primary endpoint was progression-free survival. The median progression-free survival was significantly longer in the KRd arm than the Rd arm—26.3 months and 17.6 months, respectively (hazard ratio=0.69, P=0.0001).
At the time of analysis, the difference in overall survival did not reach the prespecified boundary for statistical significance.
The overall response rate was 87% in the KRd arm and 67% in the Rd arm. The median duration of response was 28.6 months and 21.2 months, respectively.
The rates of death due to adverse events (AEs) within 30 days of the last dose were similar between the treatment arms.
The most common causes of death not due to progressive disease occurring in patients in the KRd arm and the Rd arm, respectively, were cardiac disorders (3% vs 2%), infection (2% vs 3%), renal events (0% vs less than 1%), and other AEs (2% vs 3%).
Serious AEs were reported in 60% of patients in the KRd arm and 54% in the Rd arm. The most common serious AEs reported in the KRd arm and the Rd arm, respectively, were pneumonia (14% vs 11%), respiratory tract infection (4% vs 2%), pyrexia (4% vs 2%), and pulmonary embolism (3% vs 2%).
Global development
In the US, carfilzomib is approved for use in combination with lenalidomide and dexamethasone to treat MM patients who have received 1 to 3 prior lines of therapy.
Carfilzomib also has accelerated approval in the US as a single agent to treat MM patients who have received at least 2 prior therapies, including bortezomib and an immunomodulatory agent, and have demonstrated disease progression on or within 60 days of the completion of last therapy.
Amgen plans to submit data from the phase 3 ENDEAVOR trial for potential authorization of carfilzomib in combination with dexamethasone in the EU.
This data serves as the basis of the supplemental new drug application of carfilzomib in combination with dexamethasone for patients with relapsed MM, which has been accepted for priority review in the US.
In addition to the US and EU, carfilzomib is approved for use in Argentina, Israel, Kuwait, Mexico, Thailand, and Colombia. Additional regulatory applications for the drug have been submitted to health authorities worldwide.
Photo courtesy of Amgen
The European Commission (EC) has granted marketing authorization for carfilzomib (Kyprolis) to be used in combination with lenalidomide and dexamethasone to treat adults with multiple myeloma (MM) who have received at least 1 prior therapy.
Carfilzomib is the first irreversible proteasome inhibitor approved in the European Union (EU) as part of combination treatment for patients with relapsed MM.
Carfilzomib was granted orphan designation in the EU in 2008. The drug also received accelerated assessment, which shortened the review period from 210 days to 150 days.
Carfilzomib is a product of Onyx Pharmaceuticals, Inc., a subsidiary of Amgen that holds development and commercialization rights to the drug globally, excluding Japan.
ASPIRE trial
The EC approved carfilzomib based on data from the phase 3 ASPIRE trial, which were presented at ASH 2014 and published in NEJM.
The trial enrolled 792 patients with relapsed or refractory MM who had received 1 to 3 prior lines of therapy. The patients were randomized (1:1) to receive carfilzomib plus lenalidomide and dexamethasone (KRd) or just lenalidomide and dexamethasone (Rd) for 18 cycles.
Lenalidomide and dexamethasone were continued thereafter until disease progression. There was no planned cross-over from the control arm to treatment with carfilzomib.
The study’s primary endpoint was progression-free survival. The median progression-free survival was significantly longer in the KRd arm than the Rd arm—26.3 months and 17.6 months, respectively (hazard ratio=0.69, P=0.0001).
At the time of analysis, the difference in overall survival did not reach the prespecified boundary for statistical significance.
The overall response rate was 87% in the KRd arm and 67% in the Rd arm. The median duration of response was 28.6 months and 21.2 months, respectively.
The rates of death due to adverse events (AEs) within 30 days of the last dose were similar between the treatment arms.
The most common causes of death not due to progressive disease occurring in patients in the KRd arm and the Rd arm, respectively, were cardiac disorders (3% vs 2%), infection (2% vs 3%), renal events (0% vs less than 1%), and other AEs (2% vs 3%).
Serious AEs were reported in 60% of patients in the KRd arm and 54% in the Rd arm. The most common serious AEs reported in the KRd arm and the Rd arm, respectively, were pneumonia (14% vs 11%), respiratory tract infection (4% vs 2%), pyrexia (4% vs 2%), and pulmonary embolism (3% vs 2%).
Global development
In the US, carfilzomib is approved for use in combination with lenalidomide and dexamethasone to treat MM patients who have received 1 to 3 prior lines of therapy.
Carfilzomib also has accelerated approval in the US as a single agent to treat MM patients who have received at least 2 prior therapies, including bortezomib and an immunomodulatory agent, and have demonstrated disease progression on or within 60 days of the completion of last therapy.
Amgen plans to submit data from the phase 3 ENDEAVOR trial for potential authorization of carfilzomib in combination with dexamethasone in the EU.
This data serves as the basis of the supplemental new drug application of carfilzomib in combination with dexamethasone for patients with relapsed MM, which has been accepted for priority review in the US.
In addition to the US and EU, carfilzomib is approved for use in Argentina, Israel, Kuwait, Mexico, Thailand, and Colombia. Additional regulatory applications for the drug have been submitted to health authorities worldwide.
Photo courtesy of Amgen
The European Commission (EC) has granted marketing authorization for carfilzomib (Kyprolis) to be used in combination with lenalidomide and dexamethasone to treat adults with multiple myeloma (MM) who have received at least 1 prior therapy.
Carfilzomib is the first irreversible proteasome inhibitor approved in the European Union (EU) as part of combination treatment for patients with relapsed MM.
Carfilzomib was granted orphan designation in the EU in 2008. The drug also received accelerated assessment, which shortened the review period from 210 days to 150 days.
Carfilzomib is a product of Onyx Pharmaceuticals, Inc., a subsidiary of Amgen that holds development and commercialization rights to the drug globally, excluding Japan.
ASPIRE trial
The EC approved carfilzomib based on data from the phase 3 ASPIRE trial, which were presented at ASH 2014 and published in NEJM.
The trial enrolled 792 patients with relapsed or refractory MM who had received 1 to 3 prior lines of therapy. The patients were randomized (1:1) to receive carfilzomib plus lenalidomide and dexamethasone (KRd) or just lenalidomide and dexamethasone (Rd) for 18 cycles.
Lenalidomide and dexamethasone were continued thereafter until disease progression. There was no planned cross-over from the control arm to treatment with carfilzomib.
The study’s primary endpoint was progression-free survival. The median progression-free survival was significantly longer in the KRd arm than the Rd arm—26.3 months and 17.6 months, respectively (hazard ratio=0.69, P=0.0001).
At the time of analysis, the difference in overall survival did not reach the prespecified boundary for statistical significance.
The overall response rate was 87% in the KRd arm and 67% in the Rd arm. The median duration of response was 28.6 months and 21.2 months, respectively.
The rates of death due to adverse events (AEs) within 30 days of the last dose were similar between the treatment arms.
The most common causes of death not due to progressive disease occurring in patients in the KRd arm and the Rd arm, respectively, were cardiac disorders (3% vs 2%), infection (2% vs 3%), renal events (0% vs less than 1%), and other AEs (2% vs 3%).
Serious AEs were reported in 60% of patients in the KRd arm and 54% in the Rd arm. The most common serious AEs reported in the KRd arm and the Rd arm, respectively, were pneumonia (14% vs 11%), respiratory tract infection (4% vs 2%), pyrexia (4% vs 2%), and pulmonary embolism (3% vs 2%).
Global development
In the US, carfilzomib is approved for use in combination with lenalidomide and dexamethasone to treat MM patients who have received 1 to 3 prior lines of therapy.
Carfilzomib also has accelerated approval in the US as a single agent to treat MM patients who have received at least 2 prior therapies, including bortezomib and an immunomodulatory agent, and have demonstrated disease progression on or within 60 days of the completion of last therapy.
Amgen plans to submit data from the phase 3 ENDEAVOR trial for potential authorization of carfilzomib in combination with dexamethasone in the EU.
This data serves as the basis of the supplemental new drug application of carfilzomib in combination with dexamethasone for patients with relapsed MM, which has been accepted for priority review in the US.
In addition to the US and EU, carfilzomib is approved for use in Argentina, Israel, Kuwait, Mexico, Thailand, and Colombia. Additional regulatory applications for the drug have been submitted to health authorities worldwide.
FDA approves first monoclonal antibody for MM
Photo courtesy of Janssen
The US Food and Drug Administration (FDA) has granted accelerated approval for daratumumab (Darzalex).
The drug is now approved to treat patients with multiple myeloma (MM) who have received at least 3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, or who are double-refractory to a proteasome inhibitor and an immunomodulatory agent.
Daratumumab is the first monoclonal antibody approved to treat MM.
The drug works by binding to CD38 on the surface of MM cells. It triggers the patient’s own immune system to attack MM cells, resulting in cell death through multiple mechanisms of action.
Daratumumab is being developed by Janssen Biotech. The drug was previously granted breakthrough designation, orphan designation, and priority review from the FDA.
Daratumumab was approved under the FDA’s accelerated approval program, which allows the agency to approve a drug to treat a serious or life-threatening disease based on clinical data showing the drug has an effect on a surrogate endpoint reasonably likely to predict clinical benefit to patients.
As a condition of this accelerated approval, Janssen is required to conduct a multicenter, randomized trial establishing the superiority of daratumumab over standard therapy to verify and describe the clinical benefit of daratumumab. Janssen has several ongoing, multicenter, randomized trials with a primary endpoint of progression-free survival.
The recommended dose and schedule for daratumumab is 16 mg/kg once every week for 8 weeks, then once every 2 weeks for 16 weeks, then once every 4 weeks until disease progression.
The FDA said blood banks should be informed that patients are receiving daratumumab because the drug may interfere with tests such as antibody screening.
In addition, women who are pregnant should not use daratumumab, and women planning to become pregnant should use effective contraceptives during and for at least 3 months after stopping daratumumab.
Trial data
The FDA’s approval of daratumumab was based on results of 2 studies—the phase 2 MMY2002 (SIRIUS) study and the phase 1/2 GEN501 study.
The GEN501 study enrolled 102 patients with relapsed MM or relapsed MM that was refractory to 2 or more prior lines of therapy. The patients received daratumumab at a range of doses and on a number of different schedules.
The results suggested that daratumumab is most effective at a dose of 16 mg/kg. At this dose, the overall response rate was 36%.
Most adverse events in this study were grade 1 or 2, although serious events did occur.
The SIRIUS study enrolled 124 MM patients who had received 3 or more prior lines of therapy. They received daratumumab at different doses and on different schedules, but 106 of the patients received the drug at 16 mg/kg.
Twenty-nine percent of the 106 patients responded to treatment, and the median duration of response was 7 months. Thirty percent of patients experienced serious adverse events.
Photo courtesy of Janssen
The US Food and Drug Administration (FDA) has granted accelerated approval for daratumumab (Darzalex).
The drug is now approved to treat patients with multiple myeloma (MM) who have received at least 3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, or who are double-refractory to a proteasome inhibitor and an immunomodulatory agent.
Daratumumab is the first monoclonal antibody approved to treat MM.
The drug works by binding to CD38 on the surface of MM cells. It triggers the patient’s own immune system to attack MM cells, resulting in cell death through multiple mechanisms of action.
Daratumumab is being developed by Janssen Biotech. The drug was previously granted breakthrough designation, orphan designation, and priority review from the FDA.
Daratumumab was approved under the FDA’s accelerated approval program, which allows the agency to approve a drug to treat a serious or life-threatening disease based on clinical data showing the drug has an effect on a surrogate endpoint reasonably likely to predict clinical benefit to patients.
As a condition of this accelerated approval, Janssen is required to conduct a multicenter, randomized trial establishing the superiority of daratumumab over standard therapy to verify and describe the clinical benefit of daratumumab. Janssen has several ongoing, multicenter, randomized trials with a primary endpoint of progression-free survival.
The recommended dose and schedule for daratumumab is 16 mg/kg once every week for 8 weeks, then once every 2 weeks for 16 weeks, then once every 4 weeks until disease progression.
The FDA said blood banks should be informed that patients are receiving daratumumab because the drug may interfere with tests such as antibody screening.
In addition, women who are pregnant should not use daratumumab, and women planning to become pregnant should use effective contraceptives during and for at least 3 months after stopping daratumumab.
Trial data
The FDA’s approval of daratumumab was based on results of 2 studies—the phase 2 MMY2002 (SIRIUS) study and the phase 1/2 GEN501 study.
The GEN501 study enrolled 102 patients with relapsed MM or relapsed MM that was refractory to 2 or more prior lines of therapy. The patients received daratumumab at a range of doses and on a number of different schedules.
The results suggested that daratumumab is most effective at a dose of 16 mg/kg. At this dose, the overall response rate was 36%.
Most adverse events in this study were grade 1 or 2, although serious events did occur.
The SIRIUS study enrolled 124 MM patients who had received 3 or more prior lines of therapy. They received daratumumab at different doses and on different schedules, but 106 of the patients received the drug at 16 mg/kg.
Twenty-nine percent of the 106 patients responded to treatment, and the median duration of response was 7 months. Thirty percent of patients experienced serious adverse events.
Photo courtesy of Janssen
The US Food and Drug Administration (FDA) has granted accelerated approval for daratumumab (Darzalex).
The drug is now approved to treat patients with multiple myeloma (MM) who have received at least 3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, or who are double-refractory to a proteasome inhibitor and an immunomodulatory agent.
Daratumumab is the first monoclonal antibody approved to treat MM.
The drug works by binding to CD38 on the surface of MM cells. It triggers the patient’s own immune system to attack MM cells, resulting in cell death through multiple mechanisms of action.
Daratumumab is being developed by Janssen Biotech. The drug was previously granted breakthrough designation, orphan designation, and priority review from the FDA.
Daratumumab was approved under the FDA’s accelerated approval program, which allows the agency to approve a drug to treat a serious or life-threatening disease based on clinical data showing the drug has an effect on a surrogate endpoint reasonably likely to predict clinical benefit to patients.
As a condition of this accelerated approval, Janssen is required to conduct a multicenter, randomized trial establishing the superiority of daratumumab over standard therapy to verify and describe the clinical benefit of daratumumab. Janssen has several ongoing, multicenter, randomized trials with a primary endpoint of progression-free survival.
The recommended dose and schedule for daratumumab is 16 mg/kg once every week for 8 weeks, then once every 2 weeks for 16 weeks, then once every 4 weeks until disease progression.
The FDA said blood banks should be informed that patients are receiving daratumumab because the drug may interfere with tests such as antibody screening.
In addition, women who are pregnant should not use daratumumab, and women planning to become pregnant should use effective contraceptives during and for at least 3 months after stopping daratumumab.
Trial data
The FDA’s approval of daratumumab was based on results of 2 studies—the phase 2 MMY2002 (SIRIUS) study and the phase 1/2 GEN501 study.
The GEN501 study enrolled 102 patients with relapsed MM or relapsed MM that was refractory to 2 or more prior lines of therapy. The patients received daratumumab at a range of doses and on a number of different schedules.
The results suggested that daratumumab is most effective at a dose of 16 mg/kg. At this dose, the overall response rate was 36%.
Most adverse events in this study were grade 1 or 2, although serious events did occur.
The SIRIUS study enrolled 124 MM patients who had received 3 or more prior lines of therapy. They received daratumumab at different doses and on different schedules, but 106 of the patients received the drug at 16 mg/kg.
Twenty-nine percent of the 106 patients responded to treatment, and the median duration of response was 7 months. Thirty percent of patients experienced serious adverse events.
FDA approves pegylated product for hemophilia A
The US Food and Drug Administration (FDA) has approved Adynovate, a recombinant pegylated factor VIII (FVIII) product, for use in patients age 12 and older with hemophilia A.
The product can be used as routine prophylaxis and for on-demand treatment and control of bleeding episodes.
Adynovate will be available in the US in the coming weeks, according to Baxalta US Inc., the company developing the product.
Adynovate (formerly BAX 855) is built on the full-length Advate, a recombinant antihemophilic factor product that was approved by the FDA in 2003.
Adynovate consists of the full-length FVIII molecule linked to other molecules, known as polyethylene glycol (pegylated). This link extends the circulating half-life of the product and therefore extends the time between treatments.
So patients on Adynovate can receive twice-weekly doses rather than the 3 to 4 weekly doses typically required with other full-length FVIII products.
“The approval of Adynovate provides an important therapeutic option for use in the care of patients with hemophilia A and reduces the frequency of FVIII infusions needed to avoid bleeding,” said Karen Midthun, MD, director of the FDA’s Center for Biologics Evaluation and Research.
The FDA approved Adynovate based on results of a phase 2/3 trial. The study included 137 previously treated hemophilia A patients who were 12 to 65 years of age.
Patients were assigned to either twice-weekly prophylaxis (40-50 IU/kg, n=120) or on-demand treatment (10-60 IU/kg, n=17) with Adynovate.
Patients in the twice-weekly prophylaxis arm had far fewer annual bleeds than patients treated on-demand. The median annual bleed rates were 1.9 and 41.5, respectively.
Nearly all (96%) bleeding episodes (n=591) were controlled with 1 or 2 infusions of Adynovate.
None of the patients developed inhibitors to the treatment. However, there were 171 adverse events in the 73 patients who received Adynovate for about 6 months.
There were 7 events (occurring in 6 patients) that were considered possibly related to Adynovate. These included diarrhea, nausea, headache, and flushing.
Studies of Adynovate are ongoing in previously treated patients with severe hemophilia A undergoing surgery and in previously treated patients with severe hemophilia A who are under the age of 12. Baxalta is also planning to initiate a study in previously untreated patients with severe hemophilia A.
The company has filed for regulatory approval of Adynovate in Japan and expects to file for marketing authorization in Europe once the pediatric study is complete.
The US Food and Drug Administration (FDA) has approved Adynovate, a recombinant pegylated factor VIII (FVIII) product, for use in patients age 12 and older with hemophilia A.
The product can be used as routine prophylaxis and for on-demand treatment and control of bleeding episodes.
Adynovate will be available in the US in the coming weeks, according to Baxalta US Inc., the company developing the product.
Adynovate (formerly BAX 855) is built on the full-length Advate, a recombinant antihemophilic factor product that was approved by the FDA in 2003.
Adynovate consists of the full-length FVIII molecule linked to other molecules, known as polyethylene glycol (pegylated). This link extends the circulating half-life of the product and therefore extends the time between treatments.
So patients on Adynovate can receive twice-weekly doses rather than the 3 to 4 weekly doses typically required with other full-length FVIII products.
“The approval of Adynovate provides an important therapeutic option for use in the care of patients with hemophilia A and reduces the frequency of FVIII infusions needed to avoid bleeding,” said Karen Midthun, MD, director of the FDA’s Center for Biologics Evaluation and Research.
The FDA approved Adynovate based on results of a phase 2/3 trial. The study included 137 previously treated hemophilia A patients who were 12 to 65 years of age.
Patients were assigned to either twice-weekly prophylaxis (40-50 IU/kg, n=120) or on-demand treatment (10-60 IU/kg, n=17) with Adynovate.
Patients in the twice-weekly prophylaxis arm had far fewer annual bleeds than patients treated on-demand. The median annual bleed rates were 1.9 and 41.5, respectively.
Nearly all (96%) bleeding episodes (n=591) were controlled with 1 or 2 infusions of Adynovate.
None of the patients developed inhibitors to the treatment. However, there were 171 adverse events in the 73 patients who received Adynovate for about 6 months.
There were 7 events (occurring in 6 patients) that were considered possibly related to Adynovate. These included diarrhea, nausea, headache, and flushing.
Studies of Adynovate are ongoing in previously treated patients with severe hemophilia A undergoing surgery and in previously treated patients with severe hemophilia A who are under the age of 12. Baxalta is also planning to initiate a study in previously untreated patients with severe hemophilia A.
The company has filed for regulatory approval of Adynovate in Japan and expects to file for marketing authorization in Europe once the pediatric study is complete.
The US Food and Drug Administration (FDA) has approved Adynovate, a recombinant pegylated factor VIII (FVIII) product, for use in patients age 12 and older with hemophilia A.
The product can be used as routine prophylaxis and for on-demand treatment and control of bleeding episodes.
Adynovate will be available in the US in the coming weeks, according to Baxalta US Inc., the company developing the product.
Adynovate (formerly BAX 855) is built on the full-length Advate, a recombinant antihemophilic factor product that was approved by the FDA in 2003.
Adynovate consists of the full-length FVIII molecule linked to other molecules, known as polyethylene glycol (pegylated). This link extends the circulating half-life of the product and therefore extends the time between treatments.
So patients on Adynovate can receive twice-weekly doses rather than the 3 to 4 weekly doses typically required with other full-length FVIII products.
“The approval of Adynovate provides an important therapeutic option for use in the care of patients with hemophilia A and reduces the frequency of FVIII infusions needed to avoid bleeding,” said Karen Midthun, MD, director of the FDA’s Center for Biologics Evaluation and Research.
The FDA approved Adynovate based on results of a phase 2/3 trial. The study included 137 previously treated hemophilia A patients who were 12 to 65 years of age.
Patients were assigned to either twice-weekly prophylaxis (40-50 IU/kg, n=120) or on-demand treatment (10-60 IU/kg, n=17) with Adynovate.
Patients in the twice-weekly prophylaxis arm had far fewer annual bleeds than patients treated on-demand. The median annual bleed rates were 1.9 and 41.5, respectively.
Nearly all (96%) bleeding episodes (n=591) were controlled with 1 or 2 infusions of Adynovate.
None of the patients developed inhibitors to the treatment. However, there were 171 adverse events in the 73 patients who received Adynovate for about 6 months.
There were 7 events (occurring in 6 patients) that were considered possibly related to Adynovate. These included diarrhea, nausea, headache, and flushing.
Studies of Adynovate are ongoing in previously treated patients with severe hemophilia A undergoing surgery and in previously treated patients with severe hemophilia A who are under the age of 12. Baxalta is also planning to initiate a study in previously untreated patients with severe hemophilia A.
The company has filed for regulatory approval of Adynovate in Japan and expects to file for marketing authorization in Europe once the pediatric study is complete.
FDA: Long-term clopidogrel doesn’t affect risk of death
A review conducted by the US Food and Drug Administration (FDA) indicates that long-term use of the antiplatelet drug clopidogrel (Plavix) does not increase or decrease the overall risk of death in patients with, or at risk for, heart disease.
In addition, the FDA said there is no evidence to suggest that clopidogrel increases the risk of cancer or death from cancer.
These findings contradict those of the Dual Antiplatelet Therapy (DAPT) trial, the study that prompted the FDA’s review.
In this trial, researchers compared 12 months of DAPT (either clopidogrel or prasugrel plus aspirin) to 30 months of DAPT in patients who had a drug-eluting coronary stent.
Compared to patients taking clopidogrel for 12 months, patients who received clopidogrel for 30 months had lower rates of heart attacks and stent thrombosis but higher rates of death, primarily from cancer or trauma.
To investigate these findings, the FDA examined data from the DAPT trial and performed trial-level meta-analyses of other large, long-term trials.
The trials had a clopidogrel-plus-aspirin arm (long-term treatment was 12 months or longer) and a comparator arm of either aspirin alone or short-term clopidogrel plus aspirin (6 months or less). They also had a planned follow-up of at least 1 year.
All-cause death
In the DAPT trial, extended use of clopidogrel plus aspirin was associated with a significantly increased risk of death (2.2% for 30 months vs 1.5% for 12 months). But there was no increased risk for prasugrel plus aspirin (1.6% for 30 months vs 1.6% for 12 months).
The FDA’s initial meta-analysis on mortality included 12 trials (56,799 patients). The incidence of all-cause mortality was 6.7% for the long-term clopidogrel-plus-aspirin arm and 6.6% for the comparator arm, resulting in a Mantel Haenszel Risk Difference (MH RD) of 0.04% (95% CI, -0.35%-0.44%).
The FDA also conducted a meta-analysis of 9 of the 12 trials (45,374 patients), which enrolled patients with coronary artery disease or patients at risk of coronary artery disease. This analysis showed no difference in the risk of all-cause mortality—MH RD of -0.07% (95% CI, -0.43%-0.29%).
Cancer and death in DAPT
In the DAPT trial, the risk of cancer reported as an adverse event was not different between the 30-month (2.4% ) and 12-month (2.3%) groups receiving clopidogrel, when considering cancers reported after enrollment (from month 0 to 33 of the study).
The FDA performed several analyses of the cancer adverse event data, and the relative risk of cancer for the 30-month vs 12-month arm in the clopidogrel group ranged from 0.95 to 1.2, depending on the analysis.
Similar analyses for the prasugrel group revealed relative risks of cancer-related adverse events ranging from 1.4 to 1.6.
The FDA noted that, although there was no increase in the risk of cancer-related adverse events for clopidogrel in the 30-month arm, the risk of cancer-related death was higher than in the 12-month arm—0.7% and 0.2%, respectively.
For prasugrel, there was a trend toward a higher risk of cancer adverse events in the 30-month arm than in the 12-month arm, but the risk of cancer death was identical in both arms—0.4% vs 0.4%.
The FDA said these findings are difficult to reconcile.
Meta-analyses of cancer and death
The FDA performed 2 trial-level meta-analyses to investigate the role of clopidogrel in cancer and cancer death.
The first was an analysis of cancer-related adverse events from 4 trials (37,835 patients) that compared long-term clopidogrel and aspirin to either aspirin alone or short-term clopidogrel plus aspirin.
The incidence of cancer adverse events was 4.2% for the long-term clopidogrel-plus-aspirin arm and 4.0% for the comparator arm (MH RD of 0.19%; 95% CI, -0.2%-0.59%).
The FDA conducted the second meta-analysis to assess cancer-related death. The analysis included 5 trials (40,855 patients).
The incidence of cancer death was 0.9% for the long-term clopidogrel-plus-aspirin arm and 1.1% for the comparator arm (MH RD of -0.14%; 95% CI, -0.33%-0.06%).
The FDA said that, taken together, the results of this review do not suggest an increased risk of cancer adverse events, cancer-related death, or all-cause mortality with long-term clopidogrel therapy.
More details can be found in the FDA’s Drug Safety Communication on this topic.
A review conducted by the US Food and Drug Administration (FDA) indicates that long-term use of the antiplatelet drug clopidogrel (Plavix) does not increase or decrease the overall risk of death in patients with, or at risk for, heart disease.
In addition, the FDA said there is no evidence to suggest that clopidogrel increases the risk of cancer or death from cancer.
These findings contradict those of the Dual Antiplatelet Therapy (DAPT) trial, the study that prompted the FDA’s review.
In this trial, researchers compared 12 months of DAPT (either clopidogrel or prasugrel plus aspirin) to 30 months of DAPT in patients who had a drug-eluting coronary stent.
Compared to patients taking clopidogrel for 12 months, patients who received clopidogrel for 30 months had lower rates of heart attacks and stent thrombosis but higher rates of death, primarily from cancer or trauma.
To investigate these findings, the FDA examined data from the DAPT trial and performed trial-level meta-analyses of other large, long-term trials.
The trials had a clopidogrel-plus-aspirin arm (long-term treatment was 12 months or longer) and a comparator arm of either aspirin alone or short-term clopidogrel plus aspirin (6 months or less). They also had a planned follow-up of at least 1 year.
All-cause death
In the DAPT trial, extended use of clopidogrel plus aspirin was associated with a significantly increased risk of death (2.2% for 30 months vs 1.5% for 12 months). But there was no increased risk for prasugrel plus aspirin (1.6% for 30 months vs 1.6% for 12 months).
The FDA’s initial meta-analysis on mortality included 12 trials (56,799 patients). The incidence of all-cause mortality was 6.7% for the long-term clopidogrel-plus-aspirin arm and 6.6% for the comparator arm, resulting in a Mantel Haenszel Risk Difference (MH RD) of 0.04% (95% CI, -0.35%-0.44%).
The FDA also conducted a meta-analysis of 9 of the 12 trials (45,374 patients), which enrolled patients with coronary artery disease or patients at risk of coronary artery disease. This analysis showed no difference in the risk of all-cause mortality—MH RD of -0.07% (95% CI, -0.43%-0.29%).
Cancer and death in DAPT
In the DAPT trial, the risk of cancer reported as an adverse event was not different between the 30-month (2.4% ) and 12-month (2.3%) groups receiving clopidogrel, when considering cancers reported after enrollment (from month 0 to 33 of the study).
The FDA performed several analyses of the cancer adverse event data, and the relative risk of cancer for the 30-month vs 12-month arm in the clopidogrel group ranged from 0.95 to 1.2, depending on the analysis.
Similar analyses for the prasugrel group revealed relative risks of cancer-related adverse events ranging from 1.4 to 1.6.
The FDA noted that, although there was no increase in the risk of cancer-related adverse events for clopidogrel in the 30-month arm, the risk of cancer-related death was higher than in the 12-month arm—0.7% and 0.2%, respectively.
For prasugrel, there was a trend toward a higher risk of cancer adverse events in the 30-month arm than in the 12-month arm, but the risk of cancer death was identical in both arms—0.4% vs 0.4%.
The FDA said these findings are difficult to reconcile.
Meta-analyses of cancer and death
The FDA performed 2 trial-level meta-analyses to investigate the role of clopidogrel in cancer and cancer death.
The first was an analysis of cancer-related adverse events from 4 trials (37,835 patients) that compared long-term clopidogrel and aspirin to either aspirin alone or short-term clopidogrel plus aspirin.
The incidence of cancer adverse events was 4.2% for the long-term clopidogrel-plus-aspirin arm and 4.0% for the comparator arm (MH RD of 0.19%; 95% CI, -0.2%-0.59%).
The FDA conducted the second meta-analysis to assess cancer-related death. The analysis included 5 trials (40,855 patients).
The incidence of cancer death was 0.9% for the long-term clopidogrel-plus-aspirin arm and 1.1% for the comparator arm (MH RD of -0.14%; 95% CI, -0.33%-0.06%).
The FDA said that, taken together, the results of this review do not suggest an increased risk of cancer adverse events, cancer-related death, or all-cause mortality with long-term clopidogrel therapy.
More details can be found in the FDA’s Drug Safety Communication on this topic.
A review conducted by the US Food and Drug Administration (FDA) indicates that long-term use of the antiplatelet drug clopidogrel (Plavix) does not increase or decrease the overall risk of death in patients with, or at risk for, heart disease.
In addition, the FDA said there is no evidence to suggest that clopidogrel increases the risk of cancer or death from cancer.
These findings contradict those of the Dual Antiplatelet Therapy (DAPT) trial, the study that prompted the FDA’s review.
In this trial, researchers compared 12 months of DAPT (either clopidogrel or prasugrel plus aspirin) to 30 months of DAPT in patients who had a drug-eluting coronary stent.
Compared to patients taking clopidogrel for 12 months, patients who received clopidogrel for 30 months had lower rates of heart attacks and stent thrombosis but higher rates of death, primarily from cancer or trauma.
To investigate these findings, the FDA examined data from the DAPT trial and performed trial-level meta-analyses of other large, long-term trials.
The trials had a clopidogrel-plus-aspirin arm (long-term treatment was 12 months or longer) and a comparator arm of either aspirin alone or short-term clopidogrel plus aspirin (6 months or less). They also had a planned follow-up of at least 1 year.
All-cause death
In the DAPT trial, extended use of clopidogrel plus aspirin was associated with a significantly increased risk of death (2.2% for 30 months vs 1.5% for 12 months). But there was no increased risk for prasugrel plus aspirin (1.6% for 30 months vs 1.6% for 12 months).
The FDA’s initial meta-analysis on mortality included 12 trials (56,799 patients). The incidence of all-cause mortality was 6.7% for the long-term clopidogrel-plus-aspirin arm and 6.6% for the comparator arm, resulting in a Mantel Haenszel Risk Difference (MH RD) of 0.04% (95% CI, -0.35%-0.44%).
The FDA also conducted a meta-analysis of 9 of the 12 trials (45,374 patients), which enrolled patients with coronary artery disease or patients at risk of coronary artery disease. This analysis showed no difference in the risk of all-cause mortality—MH RD of -0.07% (95% CI, -0.43%-0.29%).
Cancer and death in DAPT
In the DAPT trial, the risk of cancer reported as an adverse event was not different between the 30-month (2.4% ) and 12-month (2.3%) groups receiving clopidogrel, when considering cancers reported after enrollment (from month 0 to 33 of the study).
The FDA performed several analyses of the cancer adverse event data, and the relative risk of cancer for the 30-month vs 12-month arm in the clopidogrel group ranged from 0.95 to 1.2, depending on the analysis.
Similar analyses for the prasugrel group revealed relative risks of cancer-related adverse events ranging from 1.4 to 1.6.
The FDA noted that, although there was no increase in the risk of cancer-related adverse events for clopidogrel in the 30-month arm, the risk of cancer-related death was higher than in the 12-month arm—0.7% and 0.2%, respectively.
For prasugrel, there was a trend toward a higher risk of cancer adverse events in the 30-month arm than in the 12-month arm, but the risk of cancer death was identical in both arms—0.4% vs 0.4%.
The FDA said these findings are difficult to reconcile.
Meta-analyses of cancer and death
The FDA performed 2 trial-level meta-analyses to investigate the role of clopidogrel in cancer and cancer death.
The first was an analysis of cancer-related adverse events from 4 trials (37,835 patients) that compared long-term clopidogrel and aspirin to either aspirin alone or short-term clopidogrel plus aspirin.
The incidence of cancer adverse events was 4.2% for the long-term clopidogrel-plus-aspirin arm and 4.0% for the comparator arm (MH RD of 0.19%; 95% CI, -0.2%-0.59%).
The FDA conducted the second meta-analysis to assess cancer-related death. The analysis included 5 trials (40,855 patients).
The incidence of cancer death was 0.9% for the long-term clopidogrel-plus-aspirin arm and 1.1% for the comparator arm (MH RD of -0.14%; 95% CI, -0.33%-0.06%).
The FDA said that, taken together, the results of this review do not suggest an increased risk of cancer adverse events, cancer-related death, or all-cause mortality with long-term clopidogrel therapy.
More details can be found in the FDA’s Drug Safety Communication on this topic.
FDA grants drug priority review as FL therapy
The US Food and Drug Administration (FDA) has accepted for priority review a supplemental biologics license application for obinutuzumab (Gazyva) to treat patients with follicular lymphoma (FL) who have relapsed after or are refractory to a rituximab-containing regimen.
Obinutuzumab is a glycoengineered, humanized, monoclonal antibody that selectively binds to the extracellular domain of the CD20 antigen on B cells.
The drug is already FDA-approved for use in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia.
A priority review designation is granted to drugs thought to have the potential to provide significant improvements in the treatment, prevention, or diagnosis of a disease.
The designation means the FDA’s goal is to take action on a drug application within 6 months, compared to 10 months under standard review.
The FDA has accepted the supplemental application for obinutuzumab in FL based on results of the phase 3 GADOLIN study.
Interim results from this trial were presented at the 2015 ASCO Annual Meeting (abstract LBA8502). Additional data are scheduled to be presented at the 2015 ASH Annual Meeting in December (abstracts 1532 and 3978).
GADOLIN study
The trial included 413 patients with rituximab-refractory non-Hodgkin lymphoma, including FL, marginal zone lymphoma, small lymphocytic lymphoma, and Waldenstrom’s macroglobulinemia.
The patients were randomized to receive bendamustine alone (control arm) or a combination of bendamustine and obinutuzumab (OB) followed by obinutuzumab maintenance (every 2 months for 2 years or until progression).
In all, 156 patients completed induction in the OB arm, as did 129 patients in the control arm. Thirty-six patients completed maintenance with obinutuzumab, and 46 were still receiving maintenance at the time of the interim analysis.
According to an independent radiology facility, 69.2% of patients in the OB arm had responded to treatment at the end of induction, as had 63% of the control arm. The best overall response by the 12-month mark was 78.7% and 76.6%, respectively.
According to the radiology facility, the median progression-free survival (PFS) had not been reached in the OB arm at a median follow-up of 21 months. In the control arm, the median PFS was 14.9 months (P<0.0001).
According to investigators, the median PFS was 29.2 months and 14 months, respectively (P<0.0001).
The median overall survival had not been reached in either arm (P=0.4017). Thirty-four patients (18%) in the OB arm died, as did 41 (20%) in the control arm.
About 99% of patients in the OB arm experienced at least 1 adverse event (AE), as did 98% of patients in the control arm. Severe AEs occurred in 38.1% and 32.8% of patients, respectively, and grade 3/4 AEs occurred in 67% and 62.1%, respectively.
AEs leading to treatment withdrawal occurred in 18% and 15.7% of patients, respectively. And AEs leading to death occurred in 6.2% and 6.1%, respectively.
The US Food and Drug Administration (FDA) has accepted for priority review a supplemental biologics license application for obinutuzumab (Gazyva) to treat patients with follicular lymphoma (FL) who have relapsed after or are refractory to a rituximab-containing regimen.
Obinutuzumab is a glycoengineered, humanized, monoclonal antibody that selectively binds to the extracellular domain of the CD20 antigen on B cells.
The drug is already FDA-approved for use in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia.
A priority review designation is granted to drugs thought to have the potential to provide significant improvements in the treatment, prevention, or diagnosis of a disease.
The designation means the FDA’s goal is to take action on a drug application within 6 months, compared to 10 months under standard review.
The FDA has accepted the supplemental application for obinutuzumab in FL based on results of the phase 3 GADOLIN study.
Interim results from this trial were presented at the 2015 ASCO Annual Meeting (abstract LBA8502). Additional data are scheduled to be presented at the 2015 ASH Annual Meeting in December (abstracts 1532 and 3978).
GADOLIN study
The trial included 413 patients with rituximab-refractory non-Hodgkin lymphoma, including FL, marginal zone lymphoma, small lymphocytic lymphoma, and Waldenstrom’s macroglobulinemia.
The patients were randomized to receive bendamustine alone (control arm) or a combination of bendamustine and obinutuzumab (OB) followed by obinutuzumab maintenance (every 2 months for 2 years or until progression).
In all, 156 patients completed induction in the OB arm, as did 129 patients in the control arm. Thirty-six patients completed maintenance with obinutuzumab, and 46 were still receiving maintenance at the time of the interim analysis.
According to an independent radiology facility, 69.2% of patients in the OB arm had responded to treatment at the end of induction, as had 63% of the control arm. The best overall response by the 12-month mark was 78.7% and 76.6%, respectively.
According to the radiology facility, the median progression-free survival (PFS) had not been reached in the OB arm at a median follow-up of 21 months. In the control arm, the median PFS was 14.9 months (P<0.0001).
According to investigators, the median PFS was 29.2 months and 14 months, respectively (P<0.0001).
The median overall survival had not been reached in either arm (P=0.4017). Thirty-four patients (18%) in the OB arm died, as did 41 (20%) in the control arm.
About 99% of patients in the OB arm experienced at least 1 adverse event (AE), as did 98% of patients in the control arm. Severe AEs occurred in 38.1% and 32.8% of patients, respectively, and grade 3/4 AEs occurred in 67% and 62.1%, respectively.
AEs leading to treatment withdrawal occurred in 18% and 15.7% of patients, respectively. And AEs leading to death occurred in 6.2% and 6.1%, respectively.
The US Food and Drug Administration (FDA) has accepted for priority review a supplemental biologics license application for obinutuzumab (Gazyva) to treat patients with follicular lymphoma (FL) who have relapsed after or are refractory to a rituximab-containing regimen.
Obinutuzumab is a glycoengineered, humanized, monoclonal antibody that selectively binds to the extracellular domain of the CD20 antigen on B cells.
The drug is already FDA-approved for use in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia.
A priority review designation is granted to drugs thought to have the potential to provide significant improvements in the treatment, prevention, or diagnosis of a disease.
The designation means the FDA’s goal is to take action on a drug application within 6 months, compared to 10 months under standard review.
The FDA has accepted the supplemental application for obinutuzumab in FL based on results of the phase 3 GADOLIN study.
Interim results from this trial were presented at the 2015 ASCO Annual Meeting (abstract LBA8502). Additional data are scheduled to be presented at the 2015 ASH Annual Meeting in December (abstracts 1532 and 3978).
GADOLIN study
The trial included 413 patients with rituximab-refractory non-Hodgkin lymphoma, including FL, marginal zone lymphoma, small lymphocytic lymphoma, and Waldenstrom’s macroglobulinemia.
The patients were randomized to receive bendamustine alone (control arm) or a combination of bendamustine and obinutuzumab (OB) followed by obinutuzumab maintenance (every 2 months for 2 years or until progression).
In all, 156 patients completed induction in the OB arm, as did 129 patients in the control arm. Thirty-six patients completed maintenance with obinutuzumab, and 46 were still receiving maintenance at the time of the interim analysis.
According to an independent radiology facility, 69.2% of patients in the OB arm had responded to treatment at the end of induction, as had 63% of the control arm. The best overall response by the 12-month mark was 78.7% and 76.6%, respectively.
According to the radiology facility, the median progression-free survival (PFS) had not been reached in the OB arm at a median follow-up of 21 months. In the control arm, the median PFS was 14.9 months (P<0.0001).
According to investigators, the median PFS was 29.2 months and 14 months, respectively (P<0.0001).
The median overall survival had not been reached in either arm (P=0.4017). Thirty-four patients (18%) in the OB arm died, as did 41 (20%) in the control arm.
About 99% of patients in the OB arm experienced at least 1 adverse event (AE), as did 98% of patients in the control arm. Severe AEs occurred in 38.1% and 32.8% of patients, respectively, and grade 3/4 AEs occurred in 67% and 62.1%, respectively.
AEs leading to treatment withdrawal occurred in 18% and 15.7% of patients, respectively. And AEs leading to death occurred in 6.2% and 6.1%, respectively.
EC expands indication for azacitidine in AML
The European Commission (EC) has expanded the approved indication for azacitidine for injection (Vidaza) in acute myeloid leukemia (AML).
Now, the drug is approved to treat AML patients age 65 and older who are ineligible for hematopoietic stem cell transplant (HSCT) and have more than 30% myeloblasts according to the WHO classification.
Previously, HSCT-ineligible elderly AML patients could only receive azacitidine if they had less than 30% blasts.
Because this new indication for azacitidine is thought to bring significant clinical benefit in comparison with existing therapies, the drug will receive extended market protection in all its indications for an additional year throughout the European Economic Area.
In addition to the aforementioned AML indications, azacitidine is approved in the European Economic Area to treat HSCT-ineligible adults with intermediate-2- and high-risk myelodysplastic syndromes and HSCT-ineligible adults who have chronic myelomonocytic leukemia and 10%-29% marrow blasts without myeloproliferative disorder.
Azacitidine is marketed as Vidaza by Celgene.
AML-001 trial
The EC’s recommendation to expand the indication of azacitidine in AML was based on data from the AML-001 trial. This randomized study included patients age 65 and older with newly diagnosed or secondary AML with greater than 30% blasts.
Patients were pre-selected to receive 1 of 3 regimens per investigator’s choice. This included intensive chemotherapy (standard 7+3 regimen), low-dose cytarabine (20 mg subcutaneously twice a day for 10 days of each 28-day cycle), or best supportive care only.
Patients were then randomized to receive either azacitidine (75 mg/m2/day subcutaneously for 7 days of each 28-day cycle, n=241) or their predetermined conventional care regimen (CCR, n=247).
Median overall survival, the study’s primary endpoint, was 10.4 months for patients receiving azacitidine and 6.5 months for patients receiving CCR (hazard ratio=0.85, P=0.1009).
One-year survival rates with azacitidine and CCR were 46.5% and 34.2%, respectively.
Grade 3/4 anemia occurred in 16% of patients who received azacitidine, 5% who received best supportive care, 23% who received low-dose cytarabine, and 14% who received intensive chemotherapy.
Grade 3/4 neutropenia occurred in 26%, 5%, 25%, and 33% of patients, respectively. Grade 3/4 febrile neutropenia occurred in 28%, 28%, 30%, and 31%, respectively. And grade 3/4 thrombocytopenia occurred in 24%, 5%, 28%, and 21%, respectively.
The European Commission (EC) has expanded the approved indication for azacitidine for injection (Vidaza) in acute myeloid leukemia (AML).
Now, the drug is approved to treat AML patients age 65 and older who are ineligible for hematopoietic stem cell transplant (HSCT) and have more than 30% myeloblasts according to the WHO classification.
Previously, HSCT-ineligible elderly AML patients could only receive azacitidine if they had less than 30% blasts.
Because this new indication for azacitidine is thought to bring significant clinical benefit in comparison with existing therapies, the drug will receive extended market protection in all its indications for an additional year throughout the European Economic Area.
In addition to the aforementioned AML indications, azacitidine is approved in the European Economic Area to treat HSCT-ineligible adults with intermediate-2- and high-risk myelodysplastic syndromes and HSCT-ineligible adults who have chronic myelomonocytic leukemia and 10%-29% marrow blasts without myeloproliferative disorder.
Azacitidine is marketed as Vidaza by Celgene.
AML-001 trial
The EC’s recommendation to expand the indication of azacitidine in AML was based on data from the AML-001 trial. This randomized study included patients age 65 and older with newly diagnosed or secondary AML with greater than 30% blasts.
Patients were pre-selected to receive 1 of 3 regimens per investigator’s choice. This included intensive chemotherapy (standard 7+3 regimen), low-dose cytarabine (20 mg subcutaneously twice a day for 10 days of each 28-day cycle), or best supportive care only.
Patients were then randomized to receive either azacitidine (75 mg/m2/day subcutaneously for 7 days of each 28-day cycle, n=241) or their predetermined conventional care regimen (CCR, n=247).
Median overall survival, the study’s primary endpoint, was 10.4 months for patients receiving azacitidine and 6.5 months for patients receiving CCR (hazard ratio=0.85, P=0.1009).
One-year survival rates with azacitidine and CCR were 46.5% and 34.2%, respectively.
Grade 3/4 anemia occurred in 16% of patients who received azacitidine, 5% who received best supportive care, 23% who received low-dose cytarabine, and 14% who received intensive chemotherapy.
Grade 3/4 neutropenia occurred in 26%, 5%, 25%, and 33% of patients, respectively. Grade 3/4 febrile neutropenia occurred in 28%, 28%, 30%, and 31%, respectively. And grade 3/4 thrombocytopenia occurred in 24%, 5%, 28%, and 21%, respectively.
The European Commission (EC) has expanded the approved indication for azacitidine for injection (Vidaza) in acute myeloid leukemia (AML).
Now, the drug is approved to treat AML patients age 65 and older who are ineligible for hematopoietic stem cell transplant (HSCT) and have more than 30% myeloblasts according to the WHO classification.
Previously, HSCT-ineligible elderly AML patients could only receive azacitidine if they had less than 30% blasts.
Because this new indication for azacitidine is thought to bring significant clinical benefit in comparison with existing therapies, the drug will receive extended market protection in all its indications for an additional year throughout the European Economic Area.
In addition to the aforementioned AML indications, azacitidine is approved in the European Economic Area to treat HSCT-ineligible adults with intermediate-2- and high-risk myelodysplastic syndromes and HSCT-ineligible adults who have chronic myelomonocytic leukemia and 10%-29% marrow blasts without myeloproliferative disorder.
Azacitidine is marketed as Vidaza by Celgene.
AML-001 trial
The EC’s recommendation to expand the indication of azacitidine in AML was based on data from the AML-001 trial. This randomized study included patients age 65 and older with newly diagnosed or secondary AML with greater than 30% blasts.
Patients were pre-selected to receive 1 of 3 regimens per investigator’s choice. This included intensive chemotherapy (standard 7+3 regimen), low-dose cytarabine (20 mg subcutaneously twice a day for 10 days of each 28-day cycle), or best supportive care only.
Patients were then randomized to receive either azacitidine (75 mg/m2/day subcutaneously for 7 days of each 28-day cycle, n=241) or their predetermined conventional care regimen (CCR, n=247).
Median overall survival, the study’s primary endpoint, was 10.4 months for patients receiving azacitidine and 6.5 months for patients receiving CCR (hazard ratio=0.85, P=0.1009).
One-year survival rates with azacitidine and CCR were 46.5% and 34.2%, respectively.
Grade 3/4 anemia occurred in 16% of patients who received azacitidine, 5% who received best supportive care, 23% who received low-dose cytarabine, and 14% who received intensive chemotherapy.
Grade 3/4 neutropenia occurred in 26%, 5%, 25%, and 33% of patients, respectively. Grade 3/4 febrile neutropenia occurred in 28%, 28%, 30%, and 31%, respectively. And grade 3/4 thrombocytopenia occurred in 24%, 5%, 28%, and 21%, respectively.