HT Staff

Nanoparticle-removal chip

Photo from Jacobs School

of Engineering/UC San Diego

Engineers have developed a chip that uses an oscillating electric field to isolate drug-delivery nanoparticles from blood.

They say the device isolated nanoparticles from plasma quickly and easily, without the need to modify the plasma samples or the nanoparticles.

The group believes this technique could be used to separate and recover nanoparticles from other complex fluids for medical, environmental, and industrial applications.

They described the technique in the journal Small.

Previously, nanoparticles proved difficult to separate from plasma due to their small size and low density.

Traditional methods to remove nanoparticles from plasma samples typically involve diluting the plasma, adding a high-concentration sugar solution to the plasma and spinning it in a centrifuge, or attaching a targeting agent to the surface of the nanoparticles.

These methods either alter the normal behavior of the nanoparticles or cannot be applied to some of the most common nanoparticle types.

“This is the first example of isolating a wide range of nanoparticles out of plasma with a minimum amount of manipulation,” said study author Stuart Ibsen, PhD, of the University of California, San Diego.

“We’ve designed a very versatile technique that can be used to recover nanoparticles in a lot of different processes.”

The device used to isolate the drug-delivery nanoparticles was a dime-sized electric chip manufactured by La Jolla-based Biological Dynamics, which licensed the original technology from the University of California, San Diego.

The chip contains hundreds of tiny electrodes that generate a rapidly oscillating electric field that selectively pulls the nanoparticles out of a plasma sample.

The researchers inserted a drop of plasma spiked with nanoparticles into the electric chip and demonstrated nanoparticle recovery within 7 minutes. The technology worked on different types of drug-delivery nanoparticles that are typically studied in various labs.

The researchers said the breakthrough in the technology relies on designing a chip that can work in the high-salt concentration of plasma. The chip’s ability to pull the nanoparticles out of plasma is based on differences in the material properties between the nanoparticles and plasma components.

When the chip’s electrodes apply an oscillating electric field, the positive and negative charges inside the nanoparticles reorient themselves at a different speed than the charges in the surrounding plasma. This momentary imbalance in the charges creates an attractive force between the nanoparticles and the electrodes.

As the electric field oscillates, the nanoparticles are continually pulled toward the electrodes, leaving the rest of the plasma behind. In addition, the electric field is designed to oscillate at just the right frequency: 15,000 times per second.

“It’s amazing that this method works without any modifications to the plasma samples or to the nanoparticles,” Dr Ibsen said.

He and his colleagues believe this technology will enable researchers to better monitor what happens to nanoparticles circulating in a patient’s bloodstream. Researchers could also use this technology in the clinic to determine if the blood chemistry of a particular patient is compatible with the surfaces of certain drug-delivery nanoparticles.

Nanoparticle-removal chip

Photo from Jacobs School

of Engineering/UC San Diego

Engineers have developed a chip that uses an oscillating electric field to isolate drug-delivery nanoparticles from blood.

They say the device isolated nanoparticles from plasma quickly and easily, without the need to modify the plasma samples or the nanoparticles.

The group believes this technique could be used to separate and recover nanoparticles from other complex fluids for medical, environmental, and industrial applications.

They described the technique in the journal Small.

Previously, nanoparticles proved difficult to separate from plasma due to their small size and low density.

Traditional methods to remove nanoparticles from plasma samples typically involve diluting the plasma, adding a high-concentration sugar solution to the plasma and spinning it in a centrifuge, or attaching a targeting agent to the surface of the nanoparticles.

These methods either alter the normal behavior of the nanoparticles or cannot be applied to some of the most common nanoparticle types.

“This is the first example of isolating a wide range of nanoparticles out of plasma with a minimum amount of manipulation,” said study author Stuart Ibsen, PhD, of the University of California, San Diego.

“We’ve designed a very versatile technique that can be used to recover nanoparticles in a lot of different processes.”

The device used to isolate the drug-delivery nanoparticles was a dime-sized electric chip manufactured by La Jolla-based Biological Dynamics, which licensed the original technology from the University of California, San Diego.

The chip contains hundreds of tiny electrodes that generate a rapidly oscillating electric field that selectively pulls the nanoparticles out of a plasma sample.

The researchers inserted a drop of plasma spiked with nanoparticles into the electric chip and demonstrated nanoparticle recovery within 7 minutes. The technology worked on different types of drug-delivery nanoparticles that are typically studied in various labs.

The researchers said the breakthrough in the technology relies on designing a chip that can work in the high-salt concentration of plasma. The chip’s ability to pull the nanoparticles out of plasma is based on differences in the material properties between the nanoparticles and plasma components.

When the chip’s electrodes apply an oscillating electric field, the positive and negative charges inside the nanoparticles reorient themselves at a different speed than the charges in the surrounding plasma. This momentary imbalance in the charges creates an attractive force between the nanoparticles and the electrodes.

As the electric field oscillates, the nanoparticles are continually pulled toward the electrodes, leaving the rest of the plasma behind. In addition, the electric field is designed to oscillate at just the right frequency: 15,000 times per second.

“It’s amazing that this method works without any modifications to the plasma samples or to the nanoparticles,” Dr Ibsen said.

He and his colleagues believe this technology will enable researchers to better monitor what happens to nanoparticles circulating in a patient’s bloodstream. Researchers could also use this technology in the clinic to determine if the blood chemistry of a particular patient is compatible with the surfaces of certain drug-delivery nanoparticles.

Nanoparticle-removal chip

Photo from Jacobs School

of Engineering/UC San Diego

Engineers have developed a chip that uses an oscillating electric field to isolate drug-delivery nanoparticles from blood.

They say the device isolated nanoparticles from plasma quickly and easily, without the need to modify the plasma samples or the nanoparticles.

The group believes this technique could be used to separate and recover nanoparticles from other complex fluids for medical, environmental, and industrial applications.

They described the technique in the journal Small.

Previously, nanoparticles proved difficult to separate from plasma due to their small size and low density.

Traditional methods to remove nanoparticles from plasma samples typically involve diluting the plasma, adding a high-concentration sugar solution to the plasma and spinning it in a centrifuge, or attaching a targeting agent to the surface of the nanoparticles.

These methods either alter the normal behavior of the nanoparticles or cannot be applied to some of the most common nanoparticle types.

“This is the first example of isolating a wide range of nanoparticles out of plasma with a minimum amount of manipulation,” said study author Stuart Ibsen, PhD, of the University of California, San Diego.

“We’ve designed a very versatile technique that can be used to recover nanoparticles in a lot of different processes.”

The device used to isolate the drug-delivery nanoparticles was a dime-sized electric chip manufactured by La Jolla-based Biological Dynamics, which licensed the original technology from the University of California, San Diego.

The chip contains hundreds of tiny electrodes that generate a rapidly oscillating electric field that selectively pulls the nanoparticles out of a plasma sample.

The researchers inserted a drop of plasma spiked with nanoparticles into the electric chip and demonstrated nanoparticle recovery within 7 minutes. The technology worked on different types of drug-delivery nanoparticles that are typically studied in various labs.

The researchers said the breakthrough in the technology relies on designing a chip that can work in the high-salt concentration of plasma. The chip’s ability to pull the nanoparticles out of plasma is based on differences in the material properties between the nanoparticles and plasma components.

When the chip’s electrodes apply an oscillating electric field, the positive and negative charges inside the nanoparticles reorient themselves at a different speed than the charges in the surrounding plasma. This momentary imbalance in the charges creates an attractive force between the nanoparticles and the electrodes.

As the electric field oscillates, the nanoparticles are continually pulled toward the electrodes, leaving the rest of the plasma behind. In addition, the electric field is designed to oscillate at just the right frequency: 15,000 times per second.

“It’s amazing that this method works without any modifications to the plasma samples or to the nanoparticles,” Dr Ibsen said.

He and his colleagues believe this technology will enable researchers to better monitor what happens to nanoparticles circulating in a patient’s bloodstream. Researchers could also use this technology in the clinic to determine if the blood chemistry of a particular patient is compatible with the surfaces of certain drug-delivery nanoparticles.

Anopheles stephensi mosquito

Photo by James Gathany/CDC

Scientists say they have created mosquitoes that can introduce malaria-blocking genes into a mosquito population through their progeny and, ideally, eliminate the insects’ ability to transmit malaria to humans.

The researchers used the CRISPR gene-editing technique to insert a DNA element into the germ line of Anopheles stephensi mosquitoes.

These mosquitoes then passed on genes that may prevent malaria transmission to 99.5% of their offspring.

The scientists said further testing is needed to confirm the efficacy of this approach in preventing malaria transmission, but this is an important first step toward that goal.

“This opens up the real promise that this technique can be adapted for eliminating malaria,” said Anthony James, PhD, of the University of California, Irvine.

Dr James and his colleagues described the technique in PNAS.

In 2012, Dr James and his colleagues showed that antibodies that impair Plasmodium falciparum’s biology could be adapted from the immune systems of mice and introduced into mosquitoes. However, this trait could only be inherited by about half of the progeny.

Earlier this year, Ethan Bier, PhD, and Valentino Gantz, both of the University of California, San Diego, reported a new method for generating mutations in both copies of a gene in fruit flies. This mutagenic chain reaction involved using the CRISPR-associated protein 9 (Cas9) nuclease enzyme and allowed for transmission of mutations through the germ line with an inheritance rate of 95%.

The groups collaborated to fuse Dr Bier and Gantz’s method with Dr James’s mosquitoes. Gantz packaged antimalaria genes with a Cas9 enzyme and a guide RNA to create a genetic “cassette” that, when injected into a mosquito embryo, targeted a highly specific spot on the germ line DNA to insert the antimalaria antibody genes.

To ensure the element carrying the malaria-blocking antibodies had reached the desired DNA site, the researchers included in the cassette a protein that gave the progeny red fluorescence in the eyes. Nearly all offspring—99.5%—exhibited this trait.

Dr James said further testing will be needed to confirm the efficacy of the antibodies, and this could eventually lead to field studies.

“[The current study] is a significant first step,” he said. “We know the gene works. The mosquitoes we created are not the final brand, but we know this technology allows us to efficiently create large populations.”

Anopheles stephensi mosquito

Photo by James Gathany/CDC

Scientists say they have created mosquitoes that can introduce malaria-blocking genes into a mosquito population through their progeny and, ideally, eliminate the insects’ ability to transmit malaria to humans.

The researchers used the CRISPR gene-editing technique to insert a DNA element into the germ line of Anopheles stephensi mosquitoes.

These mosquitoes then passed on genes that may prevent malaria transmission to 99.5% of their offspring.

The scientists said further testing is needed to confirm the efficacy of this approach in preventing malaria transmission, but this is an important first step toward that goal.

“This opens up the real promise that this technique can be adapted for eliminating malaria,” said Anthony James, PhD, of the University of California, Irvine.

Dr James and his colleagues described the technique in PNAS.

In 2012, Dr James and his colleagues showed that antibodies that impair Plasmodium falciparum’s biology could be adapted from the immune systems of mice and introduced into mosquitoes. However, this trait could only be inherited by about half of the progeny.

Earlier this year, Ethan Bier, PhD, and Valentino Gantz, both of the University of California, San Diego, reported a new method for generating mutations in both copies of a gene in fruit flies. This mutagenic chain reaction involved using the CRISPR-associated protein 9 (Cas9) nuclease enzyme and allowed for transmission of mutations through the germ line with an inheritance rate of 95%.

The groups collaborated to fuse Dr Bier and Gantz’s method with Dr James’s mosquitoes. Gantz packaged antimalaria genes with a Cas9 enzyme and a guide RNA to create a genetic “cassette” that, when injected into a mosquito embryo, targeted a highly specific spot on the germ line DNA to insert the antimalaria antibody genes.

To ensure the element carrying the malaria-blocking antibodies had reached the desired DNA site, the researchers included in the cassette a protein that gave the progeny red fluorescence in the eyes. Nearly all offspring—99.5%—exhibited this trait.

Dr James said further testing will be needed to confirm the efficacy of the antibodies, and this could eventually lead to field studies.

“[The current study] is a significant first step,” he said. “We know the gene works. The mosquitoes we created are not the final brand, but we know this technology allows us to efficiently create large populations.”

Anopheles stephensi mosquito

Photo by James Gathany/CDC

Scientists say they have created mosquitoes that can introduce malaria-blocking genes into a mosquito population through their progeny and, ideally, eliminate the insects’ ability to transmit malaria to humans.

The researchers used the CRISPR gene-editing technique to insert a DNA element into the germ line of Anopheles stephensi mosquitoes.

These mosquitoes then passed on genes that may prevent malaria transmission to 99.5% of their offspring.

The scientists said further testing is needed to confirm the efficacy of this approach in preventing malaria transmission, but this is an important first step toward that goal.

“This opens up the real promise that this technique can be adapted for eliminating malaria,” said Anthony James, PhD, of the University of California, Irvine.

Dr James and his colleagues described the technique in PNAS.

In 2012, Dr James and his colleagues showed that antibodies that impair Plasmodium falciparum’s biology could be adapted from the immune systems of mice and introduced into mosquitoes. However, this trait could only be inherited by about half of the progeny.

Earlier this year, Ethan Bier, PhD, and Valentino Gantz, both of the University of California, San Diego, reported a new method for generating mutations in both copies of a gene in fruit flies. This mutagenic chain reaction involved using the CRISPR-associated protein 9 (Cas9) nuclease enzyme and allowed for transmission of mutations through the germ line with an inheritance rate of 95%.

The groups collaborated to fuse Dr Bier and Gantz’s method with Dr James’s mosquitoes. Gantz packaged antimalaria genes with a Cas9 enzyme and a guide RNA to create a genetic “cassette” that, when injected into a mosquito embryo, targeted a highly specific spot on the germ line DNA to insert the antimalaria antibody genes.

To ensure the element carrying the malaria-blocking antibodies had reached the desired DNA site, the researchers included in the cassette a protein that gave the progeny red fluorescence in the eyes. Nearly all offspring—99.5%—exhibited this trait.

Dr James said further testing will be needed to confirm the efficacy of the antibodies, and this could eventually lead to field studies.

“[The current study] is a significant first step,” he said. “We know the gene works. The mosquitoes we created are not the final brand, but we know this technology allows us to efficiently create large populations.”

Blood smear showing

Plasmodium vivax

Image by Mae Melvin

Mass drug administration (MDA) may have helped prevent a resurgence of malaria in Greece, according to research published in PLOS Neglected Tropical Diseases.

Greece was declared malaria-free in 1974 and remained that way until 2011, when there was an outbreak of Plasmodium vivax malaria in Southern Greece.

The outbreak was linked to the presence of agricultural workers from malaria-endemic regions in malaria-receptive areas.

There were 21 P vivax cases from arriving immigrants reported in the Southern agricultural area of Evrotas, along with 36 local cases.

So Greece implemented an integrated control program, with house visits established to screen immigrants from malaria-endemic countries.

Screening included a rapid diagnostic test for those reporting symptoms associated with malaria, along with blood sampling for smear and molecular testing for malaria. Directly observed treatment was provided for all patients who tested positive.

A vector control program was also implemented, with indoor residual spraying and long-lasting insecticide nets provided in areas close to mosquito breeding sites.

Despite these interventions, 20 more cases of malaria were reported in 2012.

Due to fears that the malaria parasite may be re-establishing itself in the area, Greece implemented an MDA program. It consisted of a single course of chloroquine and primaquine, which are the first-line recommended antimalarials for P vivax.

The program was implemented prior to the onset of peak adult mosquito activity, and field teams remained in situ continuing the active case detection until the end of the mosquito season. They recorded and managed adverse events daily.

The researchers identified an immigrant population of 1270 individuals, mostly from Pakistan and Afghanistan. The MDA covered 87% of this population.

No malaria cases were reported for 2013 and 2014, when the MDA was ongoing.

Of the treated individuals, 13% reported gastrointestinal symptoms from primaquine, while 36% reported non-severe side effects from chloroquine, including headaches, dizziness, and gastrointestinal complaints.

One potentially serious adverse event was recorded. It was a case of primaquine-induced hemolysis due to a false-normal G6PD level obtained prior to enrollment. The patient was hospitalized and recovered fully.

The researchers said that, in this case, the MDA program was a suitable and effective response for a small and geographically confined population over a short seasonal transition period. And the combination of 2 drugs minimized the risk of drug resistance.

The team added that, although an observational study of this nature cannot assess the extent to which the MDA program was responsible for eliminating malaria, it indicates that MDA should be considered and can be effective in local settings alongside other malaria control measures.

Blood smear showing

Plasmodium vivax

Image by Mae Melvin

Mass drug administration (MDA) may have helped prevent a resurgence of malaria in Greece, according to research published in PLOS Neglected Tropical Diseases.

Greece was declared malaria-free in 1974 and remained that way until 2011, when there was an outbreak of Plasmodium vivax malaria in Southern Greece.

The outbreak was linked to the presence of agricultural workers from malaria-endemic regions in malaria-receptive areas.

There were 21 P vivax cases from arriving immigrants reported in the Southern agricultural area of Evrotas, along with 36 local cases.

So Greece implemented an integrated control program, with house visits established to screen immigrants from malaria-endemic countries.

Screening included a rapid diagnostic test for those reporting symptoms associated with malaria, along with blood sampling for smear and molecular testing for malaria. Directly observed treatment was provided for all patients who tested positive.

A vector control program was also implemented, with indoor residual spraying and long-lasting insecticide nets provided in areas close to mosquito breeding sites.

Despite these interventions, 20 more cases of malaria were reported in 2012.

Due to fears that the malaria parasite may be re-establishing itself in the area, Greece implemented an MDA program. It consisted of a single course of chloroquine and primaquine, which are the first-line recommended antimalarials for P vivax.

The program was implemented prior to the onset of peak adult mosquito activity, and field teams remained in situ continuing the active case detection until the end of the mosquito season. They recorded and managed adverse events daily.

The researchers identified an immigrant population of 1270 individuals, mostly from Pakistan and Afghanistan. The MDA covered 87% of this population.

No malaria cases were reported for 2013 and 2014, when the MDA was ongoing.

Of the treated individuals, 13% reported gastrointestinal symptoms from primaquine, while 36% reported non-severe side effects from chloroquine, including headaches, dizziness, and gastrointestinal complaints.

One potentially serious adverse event was recorded. It was a case of primaquine-induced hemolysis due to a false-normal G6PD level obtained prior to enrollment. The patient was hospitalized and recovered fully.

The researchers said that, in this case, the MDA program was a suitable and effective response for a small and geographically confined population over a short seasonal transition period. And the combination of 2 drugs minimized the risk of drug resistance.

The team added that, although an observational study of this nature cannot assess the extent to which the MDA program was responsible for eliminating malaria, it indicates that MDA should be considered and can be effective in local settings alongside other malaria control measures.

Blood smear showing

Plasmodium vivax

Image by Mae Melvin

Mass drug administration (MDA) may have helped prevent a resurgence of malaria in Greece, according to research published in PLOS Neglected Tropical Diseases.

Greece was declared malaria-free in 1974 and remained that way until 2011, when there was an outbreak of Plasmodium vivax malaria in Southern Greece.

The outbreak was linked to the presence of agricultural workers from malaria-endemic regions in malaria-receptive areas.

There were 21 P vivax cases from arriving immigrants reported in the Southern agricultural area of Evrotas, along with 36 local cases.

So Greece implemented an integrated control program, with house visits established to screen immigrants from malaria-endemic countries.

Screening included a rapid diagnostic test for those reporting symptoms associated with malaria, along with blood sampling for smear and molecular testing for malaria. Directly observed treatment was provided for all patients who tested positive.

A vector control program was also implemented, with indoor residual spraying and long-lasting insecticide nets provided in areas close to mosquito breeding sites.

Despite these interventions, 20 more cases of malaria were reported in 2012.

Due to fears that the malaria parasite may be re-establishing itself in the area, Greece implemented an MDA program. It consisted of a single course of chloroquine and primaquine, which are the first-line recommended antimalarials for P vivax.

The program was implemented prior to the onset of peak adult mosquito activity, and field teams remained in situ continuing the active case detection until the end of the mosquito season. They recorded and managed adverse events daily.

The researchers identified an immigrant population of 1270 individuals, mostly from Pakistan and Afghanistan. The MDA covered 87% of this population.

No malaria cases were reported for 2013 and 2014, when the MDA was ongoing.

Of the treated individuals, 13% reported gastrointestinal symptoms from primaquine, while 36% reported non-severe side effects from chloroquine, including headaches, dizziness, and gastrointestinal complaints.

One potentially serious adverse event was recorded. It was a case of primaquine-induced hemolysis due to a false-normal G6PD level obtained prior to enrollment. The patient was hospitalized and recovered fully.

The researchers said that, in this case, the MDA program was a suitable and effective response for a small and geographically confined population over a short seasonal transition period. And the combination of 2 drugs minimized the risk of drug resistance.

The team added that, although an observational study of this nature cannot assess the extent to which the MDA program was responsible for eliminating malaria, it indicates that MDA should be considered and can be effective in local settings alongside other malaria control measures.

Micrograph showing ALL

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended marketing authorization for pegaspargase (Oncaspar) as part of combination antineoplastic therapy for pediatric and adult patients with acute lymphoblastic leukemia (ALL).

The CHMP’s opinion has been referred to the European Commission, which grants marketing authorization for drugs in the European Union.

If approved, pegaspargase will be marketed for the aforementioned indication in the 28 member countries of the European Union, as well as Iceland, Liechtenstein, and Norway.

Baxalta Incorporated, the company developing pegaspargase, expects a decision from the European Commission early next year.

First-line ALL

Researchers have evaluated the safety and effectiveness of pegaspargase in a study of 118 pediatric patients (ages 1 to 9) with newly diagnosed ALL. The patients were randomized 1:1 to pegaspargase or native E coli L-asparaginase, both as part of combination therapy.

Asparagine depletion (magnitude and duration) was similar between the 2 treatment arms. Event-free survival rates were also similar (about 80% in both arms), but the study was not designed to evaluate differences in event-free survival.

Grade 3/4 adverse events occurring in the pegaspargase and native E coli L-asparaginase arms, respectively, were abnormal liver tests (5% and 8%), elevated transaminases (3% and 7%), hyperbilirubinemia (2% and 2%), hyperglycemia (5% and 3%), central nervous system thrombosis (3% and 3%), coagulopathy (2% and 5%), pancreatitis (2% and 2%), and clinical allergic reactions to asparaginase (2% and 0%).

Previously treated ALL

Researchers have evaluated the effectiveness of pegaspargase in 4 open-label studies of patients with a history of prior clinical allergic reaction to asparaginase. The studies enrolled a total of 42 patients with multiply relapsed acute leukemia (39 with ALL).

Patients received pegaspargase as a single agent or in combination with multi-agent chemotherapy. The re-induction response rate was 50%—36% complete responses and 14% partial responses.

These results were similar to the overall response rates reported for patients with ALL receiving second-line, native E coli L-asparaginase-containing re-induction chemotherapy. However, antitumor activity was observed with single-agent pegaspargase as well (3 responses).

Adverse event information on pegaspargase in relapsed ALL has been compiled from 5 clinical trials. The studies enrolled a total of 174 patients with relapsed ALL who received pegaspargase as a single agent or in combination with multi-agent chemotherapy.

Sixty-two of the patients had prior hypersensitivity reactions to asparaginase, and 112 did not. Allergic reactions to pegaspargase occurred in 32% of previously hypersensitive patients and 10% of non-hypersensitive patients.

The most common adverse events observed in patients who received pegaspargase were clinical allergic reactions, elevated transaminases, hyperbilirubinemia, and coagulopathies. The most common serious adverse events due to pegaspargase were thrombosis (4%), hyperglycemia requiring insulin therapy (3%), and pancreatitis (1%).

For more details on these trials and pegaspargase, see the product information.

Micrograph showing ALL

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended marketing authorization for pegaspargase (Oncaspar) as part of combination antineoplastic therapy for pediatric and adult patients with acute lymphoblastic leukemia (ALL).

The CHMP’s opinion has been referred to the European Commission, which grants marketing authorization for drugs in the European Union.

If approved, pegaspargase will be marketed for the aforementioned indication in the 28 member countries of the European Union, as well as Iceland, Liechtenstein, and Norway.

Baxalta Incorporated, the company developing pegaspargase, expects a decision from the European Commission early next year.

First-line ALL

Researchers have evaluated the safety and effectiveness of pegaspargase in a study of 118 pediatric patients (ages 1 to 9) with newly diagnosed ALL. The patients were randomized 1:1 to pegaspargase or native E coli L-asparaginase, both as part of combination therapy.

Asparagine depletion (magnitude and duration) was similar between the 2 treatment arms. Event-free survival rates were also similar (about 80% in both arms), but the study was not designed to evaluate differences in event-free survival.

Grade 3/4 adverse events occurring in the pegaspargase and native E coli L-asparaginase arms, respectively, were abnormal liver tests (5% and 8%), elevated transaminases (3% and 7%), hyperbilirubinemia (2% and 2%), hyperglycemia (5% and 3%), central nervous system thrombosis (3% and 3%), coagulopathy (2% and 5%), pancreatitis (2% and 2%), and clinical allergic reactions to asparaginase (2% and 0%).

Previously treated ALL

Researchers have evaluated the effectiveness of pegaspargase in 4 open-label studies of patients with a history of prior clinical allergic reaction to asparaginase. The studies enrolled a total of 42 patients with multiply relapsed acute leukemia (39 with ALL).

Patients received pegaspargase as a single agent or in combination with multi-agent chemotherapy. The re-induction response rate was 50%—36% complete responses and 14% partial responses.

These results were similar to the overall response rates reported for patients with ALL receiving second-line, native E coli L-asparaginase-containing re-induction chemotherapy. However, antitumor activity was observed with single-agent pegaspargase as well (3 responses).

Adverse event information on pegaspargase in relapsed ALL has been compiled from 5 clinical trials. The studies enrolled a total of 174 patients with relapsed ALL who received pegaspargase as a single agent or in combination with multi-agent chemotherapy.

Sixty-two of the patients had prior hypersensitivity reactions to asparaginase, and 112 did not. Allergic reactions to pegaspargase occurred in 32% of previously hypersensitive patients and 10% of non-hypersensitive patients.

The most common adverse events observed in patients who received pegaspargase were clinical allergic reactions, elevated transaminases, hyperbilirubinemia, and coagulopathies. The most common serious adverse events due to pegaspargase were thrombosis (4%), hyperglycemia requiring insulin therapy (3%), and pancreatitis (1%).

For more details on these trials and pegaspargase, see the product information.

Micrograph showing ALL

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended marketing authorization for pegaspargase (Oncaspar) as part of combination antineoplastic therapy for pediatric and adult patients with acute lymphoblastic leukemia (ALL).

The CHMP’s opinion has been referred to the European Commission, which grants marketing authorization for drugs in the European Union.

If approved, pegaspargase will be marketed for the aforementioned indication in the 28 member countries of the European Union, as well as Iceland, Liechtenstein, and Norway.

Baxalta Incorporated, the company developing pegaspargase, expects a decision from the European Commission early next year.

First-line ALL

Researchers have evaluated the safety and effectiveness of pegaspargase in a study of 118 pediatric patients (ages 1 to 9) with newly diagnosed ALL. The patients were randomized 1:1 to pegaspargase or native E coli L-asparaginase, both as part of combination therapy.

Asparagine depletion (magnitude and duration) was similar between the 2 treatment arms. Event-free survival rates were also similar (about 80% in both arms), but the study was not designed to evaluate differences in event-free survival.

Grade 3/4 adverse events occurring in the pegaspargase and native E coli L-asparaginase arms, respectively, were abnormal liver tests (5% and 8%), elevated transaminases (3% and 7%), hyperbilirubinemia (2% and 2%), hyperglycemia (5% and 3%), central nervous system thrombosis (3% and 3%), coagulopathy (2% and 5%), pancreatitis (2% and 2%), and clinical allergic reactions to asparaginase (2% and 0%).

Previously treated ALL

Researchers have evaluated the effectiveness of pegaspargase in 4 open-label studies of patients with a history of prior clinical allergic reaction to asparaginase. The studies enrolled a total of 42 patients with multiply relapsed acute leukemia (39 with ALL).

Patients received pegaspargase as a single agent or in combination with multi-agent chemotherapy. The re-induction response rate was 50%—36% complete responses and 14% partial responses.

These results were similar to the overall response rates reported for patients with ALL receiving second-line, native E coli L-asparaginase-containing re-induction chemotherapy. However, antitumor activity was observed with single-agent pegaspargase as well (3 responses).

Adverse event information on pegaspargase in relapsed ALL has been compiled from 5 clinical trials. The studies enrolled a total of 174 patients with relapsed ALL who received pegaspargase as a single agent or in combination with multi-agent chemotherapy.

Sixty-two of the patients had prior hypersensitivity reactions to asparaginase, and 112 did not. Allergic reactions to pegaspargase occurred in 32% of previously hypersensitive patients and 10% of non-hypersensitive patients.

The most common adverse events observed in patients who received pegaspargase were clinical allergic reactions, elevated transaminases, hyperbilirubinemia, and coagulopathies. The most common serious adverse events due to pegaspargase were thrombosis (4%), hyperglycemia requiring insulin therapy (3%), and pancreatitis (1%).

For more details on these trials and pegaspargase, see the product information.

Dabigatran (Pradaxa)

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.

Dabigatran (Pradaxa)

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.

Dabigatran (Pradaxa)

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.

Preparing a patient

for radiation therapy

Photo by Rhoda Baer

A new template can help standardize plans for long-term care of cancer survivors who have undergone radiation therapy (RT), according to the American Society for Radiation Oncology (ASTRO).

An ASTRO advisory committee created the template to coordinate post-treatment care for cancer survivors among primary care providers (PCPs) and oncology

specialists (radiation, medical, and surgical), as well as patients themselves.

Details on the template appear in Practical Radiation Oncology.

“Factors such as earlier detection of cancer, increasingly effective treatment options, and an aging population lead to a growing number of cancer survivors and, ultimately, a need to educate and empower these individuals for their ongoing care,” said ASTRO chair Bruce D. Minsky, MD.

“The ASTRO template is designed to foster better coordination of post-treatment care for cancer survivors, including greater clarity in the dialogue between radiation oncologists and PCPs for issues such as less common side effects that may appear well after treatment is complete.”

Many radiation oncologists may already provide their patients with post-treatment materials such as diagnosis and treatment summaries, contacts for ancillary services such as financial or nutritional counselling, and information on potential late treatment effects.

But the ASTRO template coordinates these components in a central, plain-language document.

It also enables practices to meet new accreditation requirements set by the American College of Surgeons Commission on Cancer (CoC).

In response to a 2006 recommendation from the Institutes of Medicine that cancer patients be provided with a survivorship care plan (SCP) following treatment, CoC issued a mandate that cancer programs provide SCPs for all curative cancer patients by 2019 to maintain accreditation.

ASTRO’s template includes both elements required by the CoC in SCPs—namely, a summary of past treatment and directions for future care.

The treatment summary outlines the survivor’s diagnosis and stage information; treatment details such as the site, dosage, and schedule of RT; and contact information for providers who delivered the treatment.

The plan for follow-up care covers anticipated toxicities from RT, expected course of recovery from treatment-related toxicities, possible functional and/or social limitations, recommendations for preventative measures and behaviors, cancer information resources, and referrals to supportive care providers.

“This 2-page template facilitates consistency in SCPs across the discipline and also reduces the time and effort required by providers to complete each individual plan,” said Ronald Chen, MD, of the University of North Carolina at Chapel Hill.

“The field of radiation oncology has a long tradition of creating treatment summaries for each patient, even before the Institute of Medicine recommended survivorship care plans in 2006. This radiation-oncology-specific template will serve a dual purpose as both a traditional radiation oncology treatment summary and a plan for survivorship care that meets CoC requirements, thus reducing the burden on radiation oncologists from having to create 2 documents for each patient.”

Preparing a patient

for radiation therapy

Photo by Rhoda Baer

A new template can help standardize plans for long-term care of cancer survivors who have undergone radiation therapy (RT), according to the American Society for Radiation Oncology (ASTRO).

An ASTRO advisory committee created the template to coordinate post-treatment care for cancer survivors among primary care providers (PCPs) and oncology

specialists (radiation, medical, and surgical), as well as patients themselves.

Details on the template appear in Practical Radiation Oncology.

“Factors such as earlier detection of cancer, increasingly effective treatment options, and an aging population lead to a growing number of cancer survivors and, ultimately, a need to educate and empower these individuals for their ongoing care,” said ASTRO chair Bruce D. Minsky, MD.

“The ASTRO template is designed to foster better coordination of post-treatment care for cancer survivors, including greater clarity in the dialogue between radiation oncologists and PCPs for issues such as less common side effects that may appear well after treatment is complete.”

Many radiation oncologists may already provide their patients with post-treatment materials such as diagnosis and treatment summaries, contacts for ancillary services such as financial or nutritional counselling, and information on potential late treatment effects.

But the ASTRO template coordinates these components in a central, plain-language document.

It also enables practices to meet new accreditation requirements set by the American College of Surgeons Commission on Cancer (CoC).

In response to a 2006 recommendation from the Institutes of Medicine that cancer patients be provided with a survivorship care plan (SCP) following treatment, CoC issued a mandate that cancer programs provide SCPs for all curative cancer patients by 2019 to maintain accreditation.

ASTRO’s template includes both elements required by the CoC in SCPs—namely, a summary of past treatment and directions for future care.

The treatment summary outlines the survivor’s diagnosis and stage information; treatment details such as the site, dosage, and schedule of RT; and contact information for providers who delivered the treatment.

The plan for follow-up care covers anticipated toxicities from RT, expected course of recovery from treatment-related toxicities, possible functional and/or social limitations, recommendations for preventative measures and behaviors, cancer information resources, and referrals to supportive care providers.

“This 2-page template facilitates consistency in SCPs across the discipline and also reduces the time and effort required by providers to complete each individual plan,” said Ronald Chen, MD, of the University of North Carolina at Chapel Hill.

“The field of radiation oncology has a long tradition of creating treatment summaries for each patient, even before the Institute of Medicine recommended survivorship care plans in 2006. This radiation-oncology-specific template will serve a dual purpose as both a traditional radiation oncology treatment summary and a plan for survivorship care that meets CoC requirements, thus reducing the burden on radiation oncologists from having to create 2 documents for each patient.”

Preparing a patient

for radiation therapy

Photo by Rhoda Baer

A new template can help standardize plans for long-term care of cancer survivors who have undergone radiation therapy (RT), according to the American Society for Radiation Oncology (ASTRO).

An ASTRO advisory committee created the template to coordinate post-treatment care for cancer survivors among primary care providers (PCPs) and oncology

specialists (radiation, medical, and surgical), as well as patients themselves.

Details on the template appear in Practical Radiation Oncology.

“Factors such as earlier detection of cancer, increasingly effective treatment options, and an aging population lead to a growing number of cancer survivors and, ultimately, a need to educate and empower these individuals for their ongoing care,” said ASTRO chair Bruce D. Minsky, MD.

“The ASTRO template is designed to foster better coordination of post-treatment care for cancer survivors, including greater clarity in the dialogue between radiation oncologists and PCPs for issues such as less common side effects that may appear well after treatment is complete.”

Many radiation oncologists may already provide their patients with post-treatment materials such as diagnosis and treatment summaries, contacts for ancillary services such as financial or nutritional counselling, and information on potential late treatment effects.

But the ASTRO template coordinates these components in a central, plain-language document.

It also enables practices to meet new accreditation requirements set by the American College of Surgeons Commission on Cancer (CoC).

In response to a 2006 recommendation from the Institutes of Medicine that cancer patients be provided with a survivorship care plan (SCP) following treatment, CoC issued a mandate that cancer programs provide SCPs for all curative cancer patients by 2019 to maintain accreditation.

ASTRO’s template includes both elements required by the CoC in SCPs—namely, a summary of past treatment and directions for future care.

The treatment summary outlines the survivor’s diagnosis and stage information; treatment details such as the site, dosage, and schedule of RT; and contact information for providers who delivered the treatment.

The plan for follow-up care covers anticipated toxicities from RT, expected course of recovery from treatment-related toxicities, possible functional and/or social limitations, recommendations for preventative measures and behaviors, cancer information resources, and referrals to supportive care providers.

“This 2-page template facilitates consistency in SCPs across the discipline and also reduces the time and effort required by providers to complete each individual plan,” said Ronald Chen, MD, of the University of North Carolina at Chapel Hill.

“The field of radiation oncology has a long tradition of creating treatment summaries for each patient, even before the Institute of Medicine recommended survivorship care plans in 2006. This radiation-oncology-specific template will serve a dual purpose as both a traditional radiation oncology treatment summary and a plan for survivorship care that meets CoC requirements, thus reducing the burden on radiation oncologists from having to create 2 documents for each patient.”

 

 

Prescription medications

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.

 

 

Prescription medications

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.

 

 

Prescription medications

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.

Lettuce

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.”

Lettuce

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.”

Lettuce

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.”

Multiple myeloma

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.

Multiple myeloma

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.

Multiple myeloma

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.

Carfilzomib (Kyprolis)

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.

Carfilzomib (Kyprolis)

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.

Carfilzomib (Kyprolis)

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.