HT Staff

Researchers in the lab

Photo by Rhoda Baer

In an attempt to crowd-source cancer research, a pair of Canadian organizations made a small molecule they developed freely available to researchers.

The goal was to fast-track the testing of new treatment strategies and facilitate sharing of the results.

Researchers have already completed preclinical studies of this molecule, a WDR5 inhibitor called OICR-9429, showing that it is active against breast cancer and acute myeloid leukemia (AML).

The organizations that developed OICR-9429 are the Ontario Institute for Cancer Research (OICR) and the Structural Genomics Consortium (SGC).

“In the time that it would normally take to negotiate a legal agreement to provide OICR-9429 to other research teams, we have received results back from our collaborators showing that it can kill 2 different types of cancer cells,” said Cheryl Arrowsmith, PhD, of SGC Toronto in Ontario, Canada.

“Opening our chemistry capabilities to the world’s scientists allowed us to crowd-source and accelerate the research.”

A study published in Nature Chemical Biology suggested that WDR5 is a therapeutic target for a subtype of AML, and OICR-9429 could therefore be used to treat the disease.

The researchers noted that mutations in C/EBPα occur in about 9% of AML cases and lead to the expression of a 30-kDa dominant negative isoform (C/EBPα-p30).

Their experiments revealed that C/EBPα p30 preferentially interacts with WDR5. So it was no surprise that OICR-9429 inhibited proliferation and induced differentiation in p30-expressing AML cells.

In a study published in Nature, OICR-9429 inhibited cancer cell growth in a panel of breast cancer cell lines driven by mutated forms of p53.

Researchers said this work has implications beyond breast cancer because p53 is mutated in at least half of all cancers and is dysregulated in others.

“It is remarkable how quickly our research results were translated into discoveries by the groups around the world,” said Rima Al-awar, PhD, of OICR in Toronto.

“We are looking forward to seeing more research conducted with OICR-9429 and showing that this new approach to early stage drug discovery has significant advantages.”

The SGC and OICR teams said they are continuing their collaboration to identify additional molecules to advance cancer drug discovery.

Researchers in the lab

Photo by Rhoda Baer

In an attempt to crowd-source cancer research, a pair of Canadian organizations made a small molecule they developed freely available to researchers.

The goal was to fast-track the testing of new treatment strategies and facilitate sharing of the results.

Researchers have already completed preclinical studies of this molecule, a WDR5 inhibitor called OICR-9429, showing that it is active against breast cancer and acute myeloid leukemia (AML).

The organizations that developed OICR-9429 are the Ontario Institute for Cancer Research (OICR) and the Structural Genomics Consortium (SGC).

“In the time that it would normally take to negotiate a legal agreement to provide OICR-9429 to other research teams, we have received results back from our collaborators showing that it can kill 2 different types of cancer cells,” said Cheryl Arrowsmith, PhD, of SGC Toronto in Ontario, Canada.

“Opening our chemistry capabilities to the world’s scientists allowed us to crowd-source and accelerate the research.”

A study published in Nature Chemical Biology suggested that WDR5 is a therapeutic target for a subtype of AML, and OICR-9429 could therefore be used to treat the disease.

The researchers noted that mutations in C/EBPα occur in about 9% of AML cases and lead to the expression of a 30-kDa dominant negative isoform (C/EBPα-p30).

Their experiments revealed that C/EBPα p30 preferentially interacts with WDR5. So it was no surprise that OICR-9429 inhibited proliferation and induced differentiation in p30-expressing AML cells.

In a study published in Nature, OICR-9429 inhibited cancer cell growth in a panel of breast cancer cell lines driven by mutated forms of p53.

Researchers said this work has implications beyond breast cancer because p53 is mutated in at least half of all cancers and is dysregulated in others.

“It is remarkable how quickly our research results were translated into discoveries by the groups around the world,” said Rima Al-awar, PhD, of OICR in Toronto.

“We are looking forward to seeing more research conducted with OICR-9429 and showing that this new approach to early stage drug discovery has significant advantages.”

The SGC and OICR teams said they are continuing their collaboration to identify additional molecules to advance cancer drug discovery.

Researchers in the lab

Photo by Rhoda Baer

In an attempt to crowd-source cancer research, a pair of Canadian organizations made a small molecule they developed freely available to researchers.

The goal was to fast-track the testing of new treatment strategies and facilitate sharing of the results.

Researchers have already completed preclinical studies of this molecule, a WDR5 inhibitor called OICR-9429, showing that it is active against breast cancer and acute myeloid leukemia (AML).

The organizations that developed OICR-9429 are the Ontario Institute for Cancer Research (OICR) and the Structural Genomics Consortium (SGC).

“In the time that it would normally take to negotiate a legal agreement to provide OICR-9429 to other research teams, we have received results back from our collaborators showing that it can kill 2 different types of cancer cells,” said Cheryl Arrowsmith, PhD, of SGC Toronto in Ontario, Canada.

“Opening our chemistry capabilities to the world’s scientists allowed us to crowd-source and accelerate the research.”

A study published in Nature Chemical Biology suggested that WDR5 is a therapeutic target for a subtype of AML, and OICR-9429 could therefore be used to treat the disease.

The researchers noted that mutations in C/EBPα occur in about 9% of AML cases and lead to the expression of a 30-kDa dominant negative isoform (C/EBPα-p30).

Their experiments revealed that C/EBPα p30 preferentially interacts with WDR5. So it was no surprise that OICR-9429 inhibited proliferation and induced differentiation in p30-expressing AML cells.

In a study published in Nature, OICR-9429 inhibited cancer cell growth in a panel of breast cancer cell lines driven by mutated forms of p53.

Researchers said this work has implications beyond breast cancer because p53 is mutated in at least half of all cancers and is dysregulated in others.

“It is remarkable how quickly our research results were translated into discoveries by the groups around the world,” said Rima Al-awar, PhD, of OICR in Toronto.

“We are looking forward to seeing more research conducted with OICR-9429 and showing that this new approach to early stage drug discovery has significant advantages.”

The SGC and OICR teams said they are continuing their collaboration to identify additional molecules to advance cancer drug discovery.

Platelets in a blood smear

The US Food and Drug Administration (FDA) has granted orphan drug designation to the SYK inhibitor fostamatinib as a treatment for patients

with chronic immune thrombocytopenia (ITP).

Fostamatinib (also known as R935788 or R788) has been shown to increase platelet counts in patients with chronic ITP.

The drug, which comes in tablet form, is thought to prevent macrophages from destroying platelets by inhibiting SYK activation.

Fostamatinib previously produced promising results in a phase 2 trial of ITP patients and is now under investigation in a pair of phase 3 trials (NCT02076412 and NCT02076399).

Results from these trials are expected in mid-2016, according to Rigel Pharmaceuticals, Inc., the company developing fostamatinib.

Phase 2 trial

The trial included 16 adults with chronic ITP. Fostamatinib doses began at 75 mg and were increased until a patient experienced a persistent response, toxicity occurred, or the patient reached the maximum dose—175 mg twice daily.

Eight patients achieved persistent responses. They maintained platelet counts above 50,000/mm³ on a median of 95% of study visits and were able to avoid receiving other treatments.

Four other patients experienced transient responses. They had an increase in platelet count from a median minimum of 17,000/mm³ at baseline to a median maximum of 177,000/mm³.

In all 12 responders, the median platelet count increased from 16,000/mm³ at baseline to a median peak of 105,000/mm³ while on fostamatinib.

Adverse events considered probably related to fostamatinib were diarrhea (n=6), an increase in systolic blood pressure of more than 10 mm Hg (n=5), nausea (n=4), headache (n=4), weight gain of more than 5 kg (n=3), vomiting (n=3), abdominal pain (n=3), constipation (n=2), and alanine aminotransferase levels greater than 2 times the upper limit of normal (n=2).

Three patients stopped treatment due to adverse events. One patient developed a urinary tract infection and deep vein thrombosis (both considered unrelated to treatment).

The second patient withdrew consent due to gastrointestinal toxicity. And the last patient withdrew consent due to preexisting elevated transaminase levels that worsened on fostamatinib and prevented increases in the dose.

About orphan designation

The FDA grants orphan designation to drugs that are intended to treat diseases or conditions affecting fewer than 200,000 patients in the US.

Orphan designation provides the sponsor of a drug with various development incentives, including opportunities to apply for research-related tax credits and

grant funding, assistance in designing clinical trials, and 7 years of US marketing exclusivity if the drug is approved.

Platelets in a blood smear

The US Food and Drug Administration (FDA) has granted orphan drug designation to the SYK inhibitor fostamatinib as a treatment for patients

with chronic immune thrombocytopenia (ITP).

Fostamatinib (also known as R935788 or R788) has been shown to increase platelet counts in patients with chronic ITP.

The drug, which comes in tablet form, is thought to prevent macrophages from destroying platelets by inhibiting SYK activation.

Fostamatinib previously produced promising results in a phase 2 trial of ITP patients and is now under investigation in a pair of phase 3 trials (NCT02076412 and NCT02076399).

Results from these trials are expected in mid-2016, according to Rigel Pharmaceuticals, Inc., the company developing fostamatinib.

Phase 2 trial

The trial included 16 adults with chronic ITP. Fostamatinib doses began at 75 mg and were increased until a patient experienced a persistent response, toxicity occurred, or the patient reached the maximum dose—175 mg twice daily.

Eight patients achieved persistent responses. They maintained platelet counts above 50,000/mm³ on a median of 95% of study visits and were able to avoid receiving other treatments.

Four other patients experienced transient responses. They had an increase in platelet count from a median minimum of 17,000/mm³ at baseline to a median maximum of 177,000/mm³.

In all 12 responders, the median platelet count increased from 16,000/mm³ at baseline to a median peak of 105,000/mm³ while on fostamatinib.

Adverse events considered probably related to fostamatinib were diarrhea (n=6), an increase in systolic blood pressure of more than 10 mm Hg (n=5), nausea (n=4), headache (n=4), weight gain of more than 5 kg (n=3), vomiting (n=3), abdominal pain (n=3), constipation (n=2), and alanine aminotransferase levels greater than 2 times the upper limit of normal (n=2).

Three patients stopped treatment due to adverse events. One patient developed a urinary tract infection and deep vein thrombosis (both considered unrelated to treatment).

The second patient withdrew consent due to gastrointestinal toxicity. And the last patient withdrew consent due to preexisting elevated transaminase levels that worsened on fostamatinib and prevented increases in the dose.

About orphan designation

The FDA grants orphan designation to drugs that are intended to treat diseases or conditions affecting fewer than 200,000 patients in the US.

Orphan designation provides the sponsor of a drug with various development incentives, including opportunities to apply for research-related tax credits and

grant funding, assistance in designing clinical trials, and 7 years of US marketing exclusivity if the drug is approved.

Platelets in a blood smear

The US Food and Drug Administration (FDA) has granted orphan drug designation to the SYK inhibitor fostamatinib as a treatment for patients

with chronic immune thrombocytopenia (ITP).

Fostamatinib (also known as R935788 or R788) has been shown to increase platelet counts in patients with chronic ITP.

The drug, which comes in tablet form, is thought to prevent macrophages from destroying platelets by inhibiting SYK activation.

Fostamatinib previously produced promising results in a phase 2 trial of ITP patients and is now under investigation in a pair of phase 3 trials (NCT02076412 and NCT02076399).

Results from these trials are expected in mid-2016, according to Rigel Pharmaceuticals, Inc., the company developing fostamatinib.

Phase 2 trial

The trial included 16 adults with chronic ITP. Fostamatinib doses began at 75 mg and were increased until a patient experienced a persistent response, toxicity occurred, or the patient reached the maximum dose—175 mg twice daily.

Eight patients achieved persistent responses. They maintained platelet counts above 50,000/mm³ on a median of 95% of study visits and were able to avoid receiving other treatments.

Four other patients experienced transient responses. They had an increase in platelet count from a median minimum of 17,000/mm³ at baseline to a median maximum of 177,000/mm³.

In all 12 responders, the median platelet count increased from 16,000/mm³ at baseline to a median peak of 105,000/mm³ while on fostamatinib.

Adverse events considered probably related to fostamatinib were diarrhea (n=6), an increase in systolic blood pressure of more than 10 mm Hg (n=5), nausea (n=4), headache (n=4), weight gain of more than 5 kg (n=3), vomiting (n=3), abdominal pain (n=3), constipation (n=2), and alanine aminotransferase levels greater than 2 times the upper limit of normal (n=2).

Three patients stopped treatment due to adverse events. One patient developed a urinary tract infection and deep vein thrombosis (both considered unrelated to treatment).

The second patient withdrew consent due to gastrointestinal toxicity. And the last patient withdrew consent due to preexisting elevated transaminase levels that worsened on fostamatinib and prevented increases in the dose.

About orphan designation

The FDA grants orphan designation to drugs that are intended to treat diseases or conditions affecting fewer than 200,000 patients in the US.

Orphan designation provides the sponsor of a drug with various development incentives, including opportunities to apply for research-related tax credits and

grant funding, assistance in designing clinical trials, and 7 years of US marketing exclusivity if the drug is approved.

Researcher in the lab

Photo by Darren Baker

Researchers say they have created a model that can show how nearly any drug behaves in P-glycoprotein (P-gp), a protein associated with chemotherapy failure.

The team developed this computer-generated model to overcome the problem of relying on static images for the structure of P-gp.

When the researchers introduced drugs into the model, the drugs responded the way they do in real life and behaved according to predictions.

John G. Wise, PhD, of Southern Methodist University in Dallas, Texas, and his colleagues described the model in Biochemistry.

“The value of this fundamental research is that it generates dynamic mechanisms that let us understand something in biochemistry, in biology,” Dr Wise said. “And by understanding P-gp in such detail, we can now think of ways to better and more specifically inhibit it.”

Dr Wise and his colleagues noted that P-gp protects cells by pumping out toxins, but that can include chemotherapy drugs. So inhibiting P-gp’s pumping action might circumvent chemotherapy failure.

With than in mind, the team tested tariquidar, a P-gp inhibitor in clinical trials, in their model.

It hasn’t been clear exactly where tariquidar binds in P-gp. But the model showed the drug prefers to bind high in the protein. Tariquidar also behaved as expected. It wasn’t effectively pumped from the cell.

“Now we have more details on how tariquidar inhibits P-gp, where it inhibits, and what it’s actually binding to,” Dr Wise said.

He and his colleagues also used their model to uncover additional details about the behavior of other drugs in P-gp.

“For a long time, it’s been thought that there are at least a couple of distinct binding sites for drugs,” Dr Wise said.

“Sure enough, with our models, we found that [the chemotherapeutic agent] daunorubicin, at least, prefers to bind on one side of the P-gp model, while verapamil—a commonly prescribed blood pressure medicine—prefers the other side.”

Not only did the researchers show computationally that there are 2 different starting points for drugs, they also showed that there are 2 different pathways to get the drugs through.

“The 2 different drugs start at different sites, and they’re funneled to the outside by being pushed by the protein,” Dr Wise said. “But the actual parts of the protein that are pushing the drugs out are different.”

Drug discovery

Being able to watch molecular machinery up close, while it is doing its job the way it does in real life, may spark new drug discoveries to fight cancer, Dr Wise said.

“Having an accurate model that actually moves—that shows the dynamics of the thing—is incredibly helpful in developing therapies against a molecular target to inhibit it,” Dr Wise said. “The only other ways to do it are blind, and the chances of success using blind methods are very low.”

“Scientists have tried for 30 years to find inhibitors of this pump and have done it without knowing the structure and with only little knowledge about the mechanism, screening more or less blindly for compounds that inhibit the thing.”

“They found drugs that worked in the test tube and that worked in cultured cells but that didn’t work in the patient. With our model, because we can see the pump moving, we can probably predict better what’s going to make an inhibitor actually work well.”

Dr Wise and his colleagues used the P-gp model to virtually screen millions of publicly available compounds. They discovered 3 new drug leads that could ultimately inhibit P-gp and offer better odds of survival to prostate cancer patients.

The researchers reported these findings in Pharmacology Research & Perspectives.

Creating the model

To build the P-gp model, Dr Wise and his colleagues used static structures from the US Protein Data Bank repository. They used structures showing various stages of transport to simulate 4 points of reference.

From there, the team fed a supercomputer parameters and characteristics of the protein, as well as how it should behave physically, including when kinetic energy was added to bring the protein and its surrounding membrane and water up to body temperature.

The animated model resulted from calculating differences between 2 structures and using targeted molecular dynamics programs to slightly nudge the model to the next step.

“You do that several million times and make several trillion calculations, and you arrive at the next structure,” Dr Wise said. “In this way, we can nudge P-gp through a full catalytic transport cycle.”

Finally, using a docking program, the researchers individually introduced daunorubicin and other drugs into the protein and watched the drugs move through P-gp’s catalytic cycle.

“What happened was: the drugs moved,” Dr Wise said. “And they moved the way they should move, clinically, biochemically, physiologically, to pump the compounds out of the cell.”

Challenging the model

The researchers ran a critical control to further test if the model worked.

“We thought maybe anything you put in the protein, relevant or not, would get pumped through,” Dr Wise said. “So we put in something that is not a transport substrate of P-gp, something that, biochemically, would never be transported by P-gp.”

“We put it in, starting where daunorubicin is effectively pumped out, and, very quickly, the compound left the protein. But it left the opposite way, back into the cell. This experiment gave us more confidence that what we are seeing in these models is reflecting what happens in the cell.”

Dr Wise admitted that, until he saw it for himself, he had doubts the virtual P-gp model would behave like real-life P-gp.

“It’s a crude approximation of a complex, sophisticated human protein, but it’s so much better than the static images available now,” Dr Wise said.

“I’ve got to emphasize for all the disbelievers, for the ‘culture of doubters’ out there, that this model works. It moves the drugs through the membrane. That speaks for itself. What P-gp does in the cell, cancerous or normal, it does in our simulations.”

Researcher in the lab

Photo by Darren Baker

Researchers say they have created a model that can show how nearly any drug behaves in P-glycoprotein (P-gp), a protein associated with chemotherapy failure.

The team developed this computer-generated model to overcome the problem of relying on static images for the structure of P-gp.

When the researchers introduced drugs into the model, the drugs responded the way they do in real life and behaved according to predictions.

John G. Wise, PhD, of Southern Methodist University in Dallas, Texas, and his colleagues described the model in Biochemistry.

“The value of this fundamental research is that it generates dynamic mechanisms that let us understand something in biochemistry, in biology,” Dr Wise said. “And by understanding P-gp in such detail, we can now think of ways to better and more specifically inhibit it.”

Dr Wise and his colleagues noted that P-gp protects cells by pumping out toxins, but that can include chemotherapy drugs. So inhibiting P-gp’s pumping action might circumvent chemotherapy failure.

With than in mind, the team tested tariquidar, a P-gp inhibitor in clinical trials, in their model.

It hasn’t been clear exactly where tariquidar binds in P-gp. But the model showed the drug prefers to bind high in the protein. Tariquidar also behaved as expected. It wasn’t effectively pumped from the cell.

“Now we have more details on how tariquidar inhibits P-gp, where it inhibits, and what it’s actually binding to,” Dr Wise said.

He and his colleagues also used their model to uncover additional details about the behavior of other drugs in P-gp.

“For a long time, it’s been thought that there are at least a couple of distinct binding sites for drugs,” Dr Wise said.

“Sure enough, with our models, we found that [the chemotherapeutic agent] daunorubicin, at least, prefers to bind on one side of the P-gp model, while verapamil—a commonly prescribed blood pressure medicine—prefers the other side.”

Not only did the researchers show computationally that there are 2 different starting points for drugs, they also showed that there are 2 different pathways to get the drugs through.

“The 2 different drugs start at different sites, and they’re funneled to the outside by being pushed by the protein,” Dr Wise said. “But the actual parts of the protein that are pushing the drugs out are different.”

Drug discovery

Being able to watch molecular machinery up close, while it is doing its job the way it does in real life, may spark new drug discoveries to fight cancer, Dr Wise said.

“Having an accurate model that actually moves—that shows the dynamics of the thing—is incredibly helpful in developing therapies against a molecular target to inhibit it,” Dr Wise said. “The only other ways to do it are blind, and the chances of success using blind methods are very low.”

“Scientists have tried for 30 years to find inhibitors of this pump and have done it without knowing the structure and with only little knowledge about the mechanism, screening more or less blindly for compounds that inhibit the thing.”

“They found drugs that worked in the test tube and that worked in cultured cells but that didn’t work in the patient. With our model, because we can see the pump moving, we can probably predict better what’s going to make an inhibitor actually work well.”

Dr Wise and his colleagues used the P-gp model to virtually screen millions of publicly available compounds. They discovered 3 new drug leads that could ultimately inhibit P-gp and offer better odds of survival to prostate cancer patients.

The researchers reported these findings in Pharmacology Research & Perspectives.

Creating the model

To build the P-gp model, Dr Wise and his colleagues used static structures from the US Protein Data Bank repository. They used structures showing various stages of transport to simulate 4 points of reference.

From there, the team fed a supercomputer parameters and characteristics of the protein, as well as how it should behave physically, including when kinetic energy was added to bring the protein and its surrounding membrane and water up to body temperature.

The animated model resulted from calculating differences between 2 structures and using targeted molecular dynamics programs to slightly nudge the model to the next step.

“You do that several million times and make several trillion calculations, and you arrive at the next structure,” Dr Wise said. “In this way, we can nudge P-gp through a full catalytic transport cycle.”

Finally, using a docking program, the researchers individually introduced daunorubicin and other drugs into the protein and watched the drugs move through P-gp’s catalytic cycle.

“What happened was: the drugs moved,” Dr Wise said. “And they moved the way they should move, clinically, biochemically, physiologically, to pump the compounds out of the cell.”

Challenging the model

The researchers ran a critical control to further test if the model worked.

“We thought maybe anything you put in the protein, relevant or not, would get pumped through,” Dr Wise said. “So we put in something that is not a transport substrate of P-gp, something that, biochemically, would never be transported by P-gp.”

“We put it in, starting where daunorubicin is effectively pumped out, and, very quickly, the compound left the protein. But it left the opposite way, back into the cell. This experiment gave us more confidence that what we are seeing in these models is reflecting what happens in the cell.”

Dr Wise admitted that, until he saw it for himself, he had doubts the virtual P-gp model would behave like real-life P-gp.

“It’s a crude approximation of a complex, sophisticated human protein, but it’s so much better than the static images available now,” Dr Wise said.

“I’ve got to emphasize for all the disbelievers, for the ‘culture of doubters’ out there, that this model works. It moves the drugs through the membrane. That speaks for itself. What P-gp does in the cell, cancerous or normal, it does in our simulations.”

Researcher in the lab

Photo by Darren Baker

Researchers say they have created a model that can show how nearly any drug behaves in P-glycoprotein (P-gp), a protein associated with chemotherapy failure.

The team developed this computer-generated model to overcome the problem of relying on static images for the structure of P-gp.

When the researchers introduced drugs into the model, the drugs responded the way they do in real life and behaved according to predictions.

John G. Wise, PhD, of Southern Methodist University in Dallas, Texas, and his colleagues described the model in Biochemistry.

“The value of this fundamental research is that it generates dynamic mechanisms that let us understand something in biochemistry, in biology,” Dr Wise said. “And by understanding P-gp in such detail, we can now think of ways to better and more specifically inhibit it.”

Dr Wise and his colleagues noted that P-gp protects cells by pumping out toxins, but that can include chemotherapy drugs. So inhibiting P-gp’s pumping action might circumvent chemotherapy failure.

With than in mind, the team tested tariquidar, a P-gp inhibitor in clinical trials, in their model.

It hasn’t been clear exactly where tariquidar binds in P-gp. But the model showed the drug prefers to bind high in the protein. Tariquidar also behaved as expected. It wasn’t effectively pumped from the cell.

“Now we have more details on how tariquidar inhibits P-gp, where it inhibits, and what it’s actually binding to,” Dr Wise said.

He and his colleagues also used their model to uncover additional details about the behavior of other drugs in P-gp.

“For a long time, it’s been thought that there are at least a couple of distinct binding sites for drugs,” Dr Wise said.

“Sure enough, with our models, we found that [the chemotherapeutic agent] daunorubicin, at least, prefers to bind on one side of the P-gp model, while verapamil—a commonly prescribed blood pressure medicine—prefers the other side.”

Not only did the researchers show computationally that there are 2 different starting points for drugs, they also showed that there are 2 different pathways to get the drugs through.

“The 2 different drugs start at different sites, and they’re funneled to the outside by being pushed by the protein,” Dr Wise said. “But the actual parts of the protein that are pushing the drugs out are different.”

Drug discovery

Being able to watch molecular machinery up close, while it is doing its job the way it does in real life, may spark new drug discoveries to fight cancer, Dr Wise said.

“Having an accurate model that actually moves—that shows the dynamics of the thing—is incredibly helpful in developing therapies against a molecular target to inhibit it,” Dr Wise said. “The only other ways to do it are blind, and the chances of success using blind methods are very low.”

“Scientists have tried for 30 years to find inhibitors of this pump and have done it without knowing the structure and with only little knowledge about the mechanism, screening more or less blindly for compounds that inhibit the thing.”

“They found drugs that worked in the test tube and that worked in cultured cells but that didn’t work in the patient. With our model, because we can see the pump moving, we can probably predict better what’s going to make an inhibitor actually work well.”

Dr Wise and his colleagues used the P-gp model to virtually screen millions of publicly available compounds. They discovered 3 new drug leads that could ultimately inhibit P-gp and offer better odds of survival to prostate cancer patients.

The researchers reported these findings in Pharmacology Research & Perspectives.

Creating the model

To build the P-gp model, Dr Wise and his colleagues used static structures from the US Protein Data Bank repository. They used structures showing various stages of transport to simulate 4 points of reference.

From there, the team fed a supercomputer parameters and characteristics of the protein, as well as how it should behave physically, including when kinetic energy was added to bring the protein and its surrounding membrane and water up to body temperature.

The animated model resulted from calculating differences between 2 structures and using targeted molecular dynamics programs to slightly nudge the model to the next step.

“You do that several million times and make several trillion calculations, and you arrive at the next structure,” Dr Wise said. “In this way, we can nudge P-gp through a full catalytic transport cycle.”

Finally, using a docking program, the researchers individually introduced daunorubicin and other drugs into the protein and watched the drugs move through P-gp’s catalytic cycle.

“What happened was: the drugs moved,” Dr Wise said. “And they moved the way they should move, clinically, biochemically, physiologically, to pump the compounds out of the cell.”

Challenging the model

The researchers ran a critical control to further test if the model worked.

“We thought maybe anything you put in the protein, relevant or not, would get pumped through,” Dr Wise said. “So we put in something that is not a transport substrate of P-gp, something that, biochemically, would never be transported by P-gp.”

“We put it in, starting where daunorubicin is effectively pumped out, and, very quickly, the compound left the protein. But it left the opposite way, back into the cell. This experiment gave us more confidence that what we are seeing in these models is reflecting what happens in the cell.”

Dr Wise admitted that, until he saw it for himself, he had doubts the virtual P-gp model would behave like real-life P-gp.

“It’s a crude approximation of a complex, sophisticated human protein, but it’s so much better than the static images available now,” Dr Wise said.

“I’ve got to emphasize for all the disbelievers, for the ‘culture of doubters’ out there, that this model works. It moves the drugs through the membrane. That speaks for itself. What P-gp does in the cell, cancerous or normal, it does in our simulations.”

Blood for transfusion

Photo by Elise Amendola

Results of a single-center study seem to support the use of tranexamic acid (TXA) in all eligible patients undergoing hip or knee replacement.

By giving TXA to every eligible patient undergoing hip or knee arthroplasty, a Canadian hospital significantly reduced its use of red blood cell transfusions during these surgeries without increasing the incidence of adverse events or the patients’ length of hospital stay.

The results were published in the Canadian Journal of Anesthesia.

TXA is known to prevent excessive blood loss during surgeries and has proven effective in orthopedic, trauma, and cardiac patients.

However, a few years ago, less than half of eligible patients at St. Michael’s Hospital in Toronto, Ontario, were receiving TXA because of a province-wide shortage. The drug was given only to patients at high risk of requiring a blood transfusion.

The TXA shortage ended in early 2013 and, in October 2013, St. Michael’s implemented a protocol to facilitate universal administration of TXA in patients undergoing total hip or knee arthroplasty.

“We wanted to optimize TXA’s use in patients undergoing hip or knee replacements because these procedures often result in high blood loss and frequently require transfusions,” said study author Greg Hare, MD, PhD, an anesthesiologist at St. Michael’s.

“The drug costs about $10 per patient, while the average cost of transfusing one unit of blood is $1200.”

So every eligible patient undergoing hip or knee replacement received TXA at 20 mg/kg⁻¹. The drug was not used in patients considered at risk of thromboembolic events, stroke, or any other cardiovascular issues.

A total of 402 patients received the drug from October 21, 2013, to April 30, 2014. The researchers compared this group of patients to a group of 422 hip/knee replacement patients treated before the universal administration protocol was implemented (when TXA was given to high-risk patients only).

As expected, there was a significant increase in TXA use post-protocol, from 45.8% to 95.3% (P<0.001). And the rate of red blood cell transfusions decreased from 8.8% to 5.2% (P=0.043).

There was no significant difference in mean preoperative hemoglobin (Hb) levels between the pre- and post-protocol groups—133 g/L^-1 and 135 g/L^-1, respectively (P=0.073).

But there was a significant increase in Hb in the post-protocol group on days 1 and 3 after surgery. On day 1, the mean Hb was 108 g/L^-1 in the pre-protocol group and 112 g/L^-1 in the post-protocol group (P<0.001). On day 3, the mean Hb was 97 g/L^-1 and 101 g/L^-1, respectively (P<0.001).

There was no significant difference between the groups with regard to length of hospital stay. The mean length of stay was 3.93 days pre-protocol and 3.87 days post-protocol (P=0.652).

The adverse events assessed were death, myocardial infarction (MI), stroke, seizure, pulmonary embolism (PE), deep vein thrombosis (DVT), and acute kidney injury (AKI).

There were 13 such events in the pre-protocol group, including 1 MI, 3 PEs, and 9 AKIs. And there were 19 such events in the post-protocol group, including 1 MI, 1 DVT, 1 PE, and 16 AKIs (P=0.368 for all events and P=0.223 for AKIs).

Because TXA decreased the use of transfusions without increasing the rate of adverse events, Dr Hare and his colleagues consider their universal administration protocol a success.

“Making TXA mandatory for eligible patients has made care more efficient, ensuring the best possible care for our patients,” Dr Hare said.

“Other hospitals and surgical centers should consider making TXA mandatory for similar surgeries because it can improve quality of care, decrease the need for blood transfusions, and even save money.”

Blood for transfusion

Photo by Elise Amendola

Results of a single-center study seem to support the use of tranexamic acid (TXA) in all eligible patients undergoing hip or knee replacement.

By giving TXA to every eligible patient undergoing hip or knee arthroplasty, a Canadian hospital significantly reduced its use of red blood cell transfusions during these surgeries without increasing the incidence of adverse events or the patients’ length of hospital stay.

The results were published in the Canadian Journal of Anesthesia.

TXA is known to prevent excessive blood loss during surgeries and has proven effective in orthopedic, trauma, and cardiac patients.

However, a few years ago, less than half of eligible patients at St. Michael’s Hospital in Toronto, Ontario, were receiving TXA because of a province-wide shortage. The drug was given only to patients at high risk of requiring a blood transfusion.

The TXA shortage ended in early 2013 and, in October 2013, St. Michael’s implemented a protocol to facilitate universal administration of TXA in patients undergoing total hip or knee arthroplasty.

“We wanted to optimize TXA’s use in patients undergoing hip or knee replacements because these procedures often result in high blood loss and frequently require transfusions,” said study author Greg Hare, MD, PhD, an anesthesiologist at St. Michael’s.

“The drug costs about $10 per patient, while the average cost of transfusing one unit of blood is $1200.”

So every eligible patient undergoing hip or knee replacement received TXA at 20 mg/kg⁻¹. The drug was not used in patients considered at risk of thromboembolic events, stroke, or any other cardiovascular issues.

A total of 402 patients received the drug from October 21, 2013, to April 30, 2014. The researchers compared this group of patients to a group of 422 hip/knee replacement patients treated before the universal administration protocol was implemented (when TXA was given to high-risk patients only).

As expected, there was a significant increase in TXA use post-protocol, from 45.8% to 95.3% (P<0.001). And the rate of red blood cell transfusions decreased from 8.8% to 5.2% (P=0.043).

There was no significant difference in mean preoperative hemoglobin (Hb) levels between the pre- and post-protocol groups—133 g/L^-1 and 135 g/L^-1, respectively (P=0.073).

But there was a significant increase in Hb in the post-protocol group on days 1 and 3 after surgery. On day 1, the mean Hb was 108 g/L^-1 in the pre-protocol group and 112 g/L^-1 in the post-protocol group (P<0.001). On day 3, the mean Hb was 97 g/L^-1 and 101 g/L^-1, respectively (P<0.001).

There was no significant difference between the groups with regard to length of hospital stay. The mean length of stay was 3.93 days pre-protocol and 3.87 days post-protocol (P=0.652).

The adverse events assessed were death, myocardial infarction (MI), stroke, seizure, pulmonary embolism (PE), deep vein thrombosis (DVT), and acute kidney injury (AKI).

There were 13 such events in the pre-protocol group, including 1 MI, 3 PEs, and 9 AKIs. And there were 19 such events in the post-protocol group, including 1 MI, 1 DVT, 1 PE, and 16 AKIs (P=0.368 for all events and P=0.223 for AKIs).

Because TXA decreased the use of transfusions without increasing the rate of adverse events, Dr Hare and his colleagues consider their universal administration protocol a success.

“Making TXA mandatory for eligible patients has made care more efficient, ensuring the best possible care for our patients,” Dr Hare said.

“Other hospitals and surgical centers should consider making TXA mandatory for similar surgeries because it can improve quality of care, decrease the need for blood transfusions, and even save money.”

Blood for transfusion

Photo by Elise Amendola

Results of a single-center study seem to support the use of tranexamic acid (TXA) in all eligible patients undergoing hip or knee replacement.

By giving TXA to every eligible patient undergoing hip or knee arthroplasty, a Canadian hospital significantly reduced its use of red blood cell transfusions during these surgeries without increasing the incidence of adverse events or the patients’ length of hospital stay.

The results were published in the Canadian Journal of Anesthesia.

TXA is known to prevent excessive blood loss during surgeries and has proven effective in orthopedic, trauma, and cardiac patients.

However, a few years ago, less than half of eligible patients at St. Michael’s Hospital in Toronto, Ontario, were receiving TXA because of a province-wide shortage. The drug was given only to patients at high risk of requiring a blood transfusion.

The TXA shortage ended in early 2013 and, in October 2013, St. Michael’s implemented a protocol to facilitate universal administration of TXA in patients undergoing total hip or knee arthroplasty.

“We wanted to optimize TXA’s use in patients undergoing hip or knee replacements because these procedures often result in high blood loss and frequently require transfusions,” said study author Greg Hare, MD, PhD, an anesthesiologist at St. Michael’s.

“The drug costs about $10 per patient, while the average cost of transfusing one unit of blood is $1200.”

So every eligible patient undergoing hip or knee replacement received TXA at 20 mg/kg⁻¹. The drug was not used in patients considered at risk of thromboembolic events, stroke, or any other cardiovascular issues.

A total of 402 patients received the drug from October 21, 2013, to April 30, 2014. The researchers compared this group of patients to a group of 422 hip/knee replacement patients treated before the universal administration protocol was implemented (when TXA was given to high-risk patients only).

As expected, there was a significant increase in TXA use post-protocol, from 45.8% to 95.3% (P<0.001). And the rate of red blood cell transfusions decreased from 8.8% to 5.2% (P=0.043).

There was no significant difference in mean preoperative hemoglobin (Hb) levels between the pre- and post-protocol groups—133 g/L^-1 and 135 g/L^-1, respectively (P=0.073).

But there was a significant increase in Hb in the post-protocol group on days 1 and 3 after surgery. On day 1, the mean Hb was 108 g/L^-1 in the pre-protocol group and 112 g/L^-1 in the post-protocol group (P<0.001). On day 3, the mean Hb was 97 g/L^-1 and 101 g/L^-1, respectively (P<0.001).

There was no significant difference between the groups with regard to length of hospital stay. The mean length of stay was 3.93 days pre-protocol and 3.87 days post-protocol (P=0.652).

The adverse events assessed were death, myocardial infarction (MI), stroke, seizure, pulmonary embolism (PE), deep vein thrombosis (DVT), and acute kidney injury (AKI).

There were 13 such events in the pre-protocol group, including 1 MI, 3 PEs, and 9 AKIs. And there were 19 such events in the post-protocol group, including 1 MI, 1 DVT, 1 PE, and 16 AKIs (P=0.368 for all events and P=0.223 for AKIs).

Because TXA decreased the use of transfusions without increasing the rate of adverse events, Dr Hare and his colleagues consider their universal administration protocol a success.

“Making TXA mandatory for eligible patients has made care more efficient, ensuring the best possible care for our patients,” Dr Hare said.

“Other hospitals and surgical centers should consider making TXA mandatory for similar surgeries because it can improve quality of care, decrease the need for blood transfusions, and even save money.”

Pregnant woman

Photo by Nina Matthews

Taking iron supplements during pregnancy does not increase a woman’s risk of contracting malaria,  according to research published in JAMA.

Investigators studied nearly 500 pregnant women in a malaria-endemic region, comparing those who received daily iron supplements to those who received placebo.

Roughly half of the women in each group developed malaria, and iron supplementation was associated with benefits for mothers and children.

Martin N. Mwangi, PhD, of Wageningen University in The Netherlands, and his colleagues conducted this research.

The team said current estimates suggest that anemia affects 57% of pregnant women in Africa. And although iron deficiency is the most common cause, iron supplementation during pregnancy has uncertain health benefits.

There is some evidence to suggest that iron supplementation may increase the risk of infectious diseases, including malaria.

To investigate this association, Dr Mwangi and his colleagues studied 470 pregnant women living in a malaria-endemic area in Kenya. The subjects were randomized to daily supplementation with 60 mg of iron (n=237) or placebo (n=233) until 1 month postpartum.

All women received 5.7 mg iron per day through flour fortification during the intervention, as well as the usual intermittent preventive treatment against malaria.

Among the 470 participating women, 40 women (22 in the iron group and 18 in the placebo group) were lost to follow-up or excluded at birth. Twelve mothers were lost to follow-up postpartum (5 iron, 7 placebo). At study entry, 190 of 318 women (60%) were iron-deficient.

After childbirth, there was no significant difference in Plasmodium infection between the treatment groups. Infection occurred in 50.9% of women in the iron group and 52.1% in the placebo group (P=0.83).

There was a significant increase in hemoglobin concentration and a significant decrease in anemia among mothers who received iron (P<0.001 for both). Mothers in the iron group also had a significantly lower mean zinc protoporphyrin (ZPP)-heme ratio in whole blood (P<0.001) and erythrocytes (P<0.001).

Children born to mothers in the iron group had a significantly higher mean birth weight (P=0.002), lower risk of low birth weight (<2500 g, P=0.02), older gestational age at delivery (P=0.009), and lower risk of premature birth (P=0.02).

However, there was no significant difference between the treatment groups with regard to birth-weight-for-gestational-age z score (P=0.20), neonatal length (P=0.07), head circumference (P=0.28), hemoglobin concentration in cord blood (P=0.14), cord blood ZPP-heme ratio (P=0.82), or cord erythrocyte ZPP-heme ratio (P=0.88).

Based on these results, the investigators said the benefits of universal iron supplementation during pregnancy (in countries where it is impractical to screen for iron status) outweigh the possible risks.

Pregnant woman

Photo by Nina Matthews

Taking iron supplements during pregnancy does not increase a woman’s risk of contracting malaria,  according to research published in JAMA.

Investigators studied nearly 500 pregnant women in a malaria-endemic region, comparing those who received daily iron supplements to those who received placebo.

Roughly half of the women in each group developed malaria, and iron supplementation was associated with benefits for mothers and children.

Martin N. Mwangi, PhD, of Wageningen University in The Netherlands, and his colleagues conducted this research.

The team said current estimates suggest that anemia affects 57% of pregnant women in Africa. And although iron deficiency is the most common cause, iron supplementation during pregnancy has uncertain health benefits.

There is some evidence to suggest that iron supplementation may increase the risk of infectious diseases, including malaria.

To investigate this association, Dr Mwangi and his colleagues studied 470 pregnant women living in a malaria-endemic area in Kenya. The subjects were randomized to daily supplementation with 60 mg of iron (n=237) or placebo (n=233) until 1 month postpartum.

All women received 5.7 mg iron per day through flour fortification during the intervention, as well as the usual intermittent preventive treatment against malaria.

Among the 470 participating women, 40 women (22 in the iron group and 18 in the placebo group) were lost to follow-up or excluded at birth. Twelve mothers were lost to follow-up postpartum (5 iron, 7 placebo). At study entry, 190 of 318 women (60%) were iron-deficient.

After childbirth, there was no significant difference in Plasmodium infection between the treatment groups. Infection occurred in 50.9% of women in the iron group and 52.1% in the placebo group (P=0.83).

There was a significant increase in hemoglobin concentration and a significant decrease in anemia among mothers who received iron (P<0.001 for both). Mothers in the iron group also had a significantly lower mean zinc protoporphyrin (ZPP)-heme ratio in whole blood (P<0.001) and erythrocytes (P<0.001).

Children born to mothers in the iron group had a significantly higher mean birth weight (P=0.002), lower risk of low birth weight (<2500 g, P=0.02), older gestational age at delivery (P=0.009), and lower risk of premature birth (P=0.02).

However, there was no significant difference between the treatment groups with regard to birth-weight-for-gestational-age z score (P=0.20), neonatal length (P=0.07), head circumference (P=0.28), hemoglobin concentration in cord blood (P=0.14), cord blood ZPP-heme ratio (P=0.82), or cord erythrocyte ZPP-heme ratio (P=0.88).

Based on these results, the investigators said the benefits of universal iron supplementation during pregnancy (in countries where it is impractical to screen for iron status) outweigh the possible risks.

Pregnant woman

Photo by Nina Matthews

Taking iron supplements during pregnancy does not increase a woman’s risk of contracting malaria,  according to research published in JAMA.

Investigators studied nearly 500 pregnant women in a malaria-endemic region, comparing those who received daily iron supplements to those who received placebo.

Roughly half of the women in each group developed malaria, and iron supplementation was associated with benefits for mothers and children.

Martin N. Mwangi, PhD, of Wageningen University in The Netherlands, and his colleagues conducted this research.

The team said current estimates suggest that anemia affects 57% of pregnant women in Africa. And although iron deficiency is the most common cause, iron supplementation during pregnancy has uncertain health benefits.

There is some evidence to suggest that iron supplementation may increase the risk of infectious diseases, including malaria.

To investigate this association, Dr Mwangi and his colleagues studied 470 pregnant women living in a malaria-endemic area in Kenya. The subjects were randomized to daily supplementation with 60 mg of iron (n=237) or placebo (n=233) until 1 month postpartum.

All women received 5.7 mg iron per day through flour fortification during the intervention, as well as the usual intermittent preventive treatment against malaria.

Among the 470 participating women, 40 women (22 in the iron group and 18 in the placebo group) were lost to follow-up or excluded at birth. Twelve mothers were lost to follow-up postpartum (5 iron, 7 placebo). At study entry, 190 of 318 women (60%) were iron-deficient.

After childbirth, there was no significant difference in Plasmodium infection between the treatment groups. Infection occurred in 50.9% of women in the iron group and 52.1% in the placebo group (P=0.83).

There was a significant increase in hemoglobin concentration and a significant decrease in anemia among mothers who received iron (P<0.001 for both). Mothers in the iron group also had a significantly lower mean zinc protoporphyrin (ZPP)-heme ratio in whole blood (P<0.001) and erythrocytes (P<0.001).

Children born to mothers in the iron group had a significantly higher mean birth weight (P=0.002), lower risk of low birth weight (<2500 g, P=0.02), older gestational age at delivery (P=0.009), and lower risk of premature birth (P=0.02).

However, there was no significant difference between the treatment groups with regard to birth-weight-for-gestational-age z score (P=0.20), neonatal length (P=0.07), head circumference (P=0.28), hemoglobin concentration in cord blood (P=0.14), cord blood ZPP-heme ratio (P=0.82), or cord erythrocyte ZPP-heme ratio (P=0.88).

Based on these results, the investigators said the benefits of universal iron supplementation during pregnancy (in countries where it is impractical to screen for iron status) outweigh the possible risks.

Prescription drugs

Photo courtesy of CDC

England’s National Health Service (NHS) plans to remove several drugs used to treat hematologic malignancies from the Cancer Drugs Fund (CDF).

The plan is that, as of November 4, 2015, pomalidomide, lenalidomide, ibrutinib, dasatinib, brentuximab, bosutinib, and bendamustine will no longer be funded via the CDF for certain indications.

Ofatumumab was removed from the CDF list yesterday but is now available through the NHS.

Drugs used to treat solid tumor malignancies are set to be de-funded through CDF in November as well.

However, the NHS said the proposal to remove a drug from the CDF is not necessarily a final decision.

In cases where a drug offers enough clinical benefit, the pharmaceutical company developing that drug has the opportunity to reduce the price they are asking the NHS to pay to ensure that it achieves a satisfactory level of value for money. The NHS said a number of such negotiations are underway.

In addition, patients who are currently receiving the drugs set to be removed from the CDF will continue to have access to those drugs.

About the CDF and the NHS

The CDF—set up in 2010 and currently due to run until March 2016—is money the government has set aside to pay for cancer drugs that haven’t been approved by the National Institute for Health and Care Excellence (NICE) and aren’t available within the NHS in England. Most cancer drugs are routinely funded outside of the CDF.

NHS England and NICE are planning to consult on a proposed new system for commissioning cancer drugs. The NHS said the new system will be designed to provide the agency with a more systematic approach to getting the best price for cancer drugs.

Reason for drug removals

The NHS previously increased the budget for the CDF from £200 million in 2013/14, to £280 million in 2014/15, and £340 million from April 2015. This represents a total increase of 70% since August 2014.

However, current projections suggest that spending would rise to around £410 million for this year, an over-spend of £70 million, in the absence of further prioritization. The NHS said this money could be used for other aspects of cancer treatment or NHS services for other patient groups.

Therefore, some drugs are set to be removed from the CDF. The NHS said all decisions on drugs to be maintained in the CDF were based on the advice of clinicians, the best available evidence, and the cost of the treatment.

“There is no escaping the fact that we face a difficult set of choices, but it is our duty to ensure we get maximum value from every penny available on behalf of patients,” said Peter Clark, chair of the CDF.

“We must ensure we invest in those treatments that offer the most benefit, based on rigorous evidence-based clinical analysis and an assessment of the cost of those treatments.”

While de-funding certain drugs will reduce costs, the CDF is not expected to be back on budget this financial year. The NHS does expect the CDF will be operating within its budget during 2016/17.

Blood cancer drugs to be removed

The following drugs are currently on the CDF list for the following indications, but they are set to be de-listed on November 4, 2015.

Bendamustine

For the treatment of chronic lymphocytic leukemia (CLL) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• CLL (not licensed in this indication)
• Second-line indication, third-line indication, or fourth-line indication
• To be used within the treating Trust’s governance framework, as bendamustine is not licensed in this indication

For the treatment of relapsed mantle cell lymphoma (MCL) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• MCL
• Option for second- or subsequent-line chemotherapy
• No previous treatment with bendamustine
• To be used within the treating Trust’s governance framework, as bendamustine is not licensed in this indication

*Bendamustine will remain on the CDF for other indications.

Bosutinib

For the treatment of refractory, chronic phase chronic myeloid leukemia (CML) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Chronic phase CML
• Refractory to nilotinib or dasatinib (if dasatinib accessed via a clinical trial or via its current approved CDF indication)

For the treatment of refractory, accelerated phase CML where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Accelerated phase CML
• Refractory to nilotinib or dasatinib (if dasatinib accessed via a clinical trial or via its current approved CDF indication)
• Significant intolerance to nilotinib (grade 3 or 4 events)

For the treatment of accelerated phase CML where there is intolerance of treatments and where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Accelerated phase CML
• Significant intolerance to dasatinib (grade 3 or 4 adverse events; if dasatinib accessed via its current approved CDF indication)
• Significant intolerance to nilotinib (grade 3 or 4 events)

*Bosutinib will still be available through the CDF for patients with chronic phase CML that is intolerant of other treatments.

Brentuximab

For the treatment of refractory, systemic anaplastic lymphoma where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Relapsed or refractory systemic anaplastic large-cell lymphoma

For the treatment of relapsed or refractory CD30+ Hodgkin lymphoma where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Relapsed or refractory CD30+ Hodgkin lymphoma
• Following autologous stem cell transplant or following at least 2 prior therapies when autologous stem cell transplant or multi-agent chemotherapy is not an option

Dasatinib

For the treatment of Philadelphia-chromosome-positive (Ph+) acute lymphoblastic leukemia where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Refractory or significant intolerance or resistance to prior therapy including imatinib (grade 3 or 4 adverse events)
• Second-line indication or third-line indication

*Dasatinib will still be available for chronic phase and accelerated phase CML.

Ibrutinib

For the treatment of relapsed/refractory CLL where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Confirmed CLL
• Must have received at least 1 prior therapy for CLL
• Considered not appropriate for treatment or retreatment with purine-analogue-based therapy due to:

  • Failure to respond to chemo-immunotherapy or
  • A progression-free interval of less than 3 years or
  • Age of 70 years or more or
  • Age of 65 years or more plus the presence of comorbidities or
  • A 17p or TP53 deletion

• ECOG performance status of 0-2
• A neutrophil count of ≥0.75 x 10⁹/L
• A platelet count of ≥30 x 10⁹/L
• Patient not on warfarin or CYP3A4/5 inhibitors
• No prior treatment with idelalisib

For the treatment of relapsed/refractory MCL where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Confirmed MCL with cyclin D1 overexpression or translocation breakpoints at t(11;14)
• Failure to achieve at least partial response with, or documented disease progression disease after, the most recent treatment regimen
• ECOG performance status of 0-2
• At least 1 but no more than 5 previous lines of treatment

Lenalidomide

For the second-line treatment of multiple myeloma (MM) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• MM
• Second-line indication
• Contraindication to bortezomib or previously received bortezomib in the first-line setting

*Lenalidomide will still be available for patients with myelodysplastic syndromes with 5q deletion.

Pomalidomide

For the treatment of relapsed and refractory MM where the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically
• MM
• Performance status of 0-2
• Previously received treatment with adequate trials of at least all of the following options of therapy: bortezomib, lenalidomide, and alkylating agents
• Failed treatment with bortezomib or lenalidomide, as defined by: progression on or before 60 days of treatment, progressive disease 6 months or less after achieving a partial response, or intolerance to bortezomib
• Refractory disease to previous treatment
• No resistance to high-dose dexamethasone used in the last line of therapy
• No peripheral neuropathy of grade 2 or more

A complete list of proposed changes to the CDF, as well as the drugs that were de-listed on March 12, 2015, is available on the NHS website.

Prescription drugs

Photo courtesy of CDC

England’s National Health Service (NHS) plans to remove several drugs used to treat hematologic malignancies from the Cancer Drugs Fund (CDF).

The plan is that, as of November 4, 2015, pomalidomide, lenalidomide, ibrutinib, dasatinib, brentuximab, bosutinib, and bendamustine will no longer be funded via the CDF for certain indications.

Ofatumumab was removed from the CDF list yesterday but is now available through the NHS.

Drugs used to treat solid tumor malignancies are set to be de-funded through CDF in November as well.

However, the NHS said the proposal to remove a drug from the CDF is not necessarily a final decision.

In cases where a drug offers enough clinical benefit, the pharmaceutical company developing that drug has the opportunity to reduce the price they are asking the NHS to pay to ensure that it achieves a satisfactory level of value for money. The NHS said a number of such negotiations are underway.

In addition, patients who are currently receiving the drugs set to be removed from the CDF will continue to have access to those drugs.

About the CDF and the NHS

The CDF—set up in 2010 and currently due to run until March 2016—is money the government has set aside to pay for cancer drugs that haven’t been approved by the National Institute for Health and Care Excellence (NICE) and aren’t available within the NHS in England. Most cancer drugs are routinely funded outside of the CDF.

NHS England and NICE are planning to consult on a proposed new system for commissioning cancer drugs. The NHS said the new system will be designed to provide the agency with a more systematic approach to getting the best price for cancer drugs.

Reason for drug removals

The NHS previously increased the budget for the CDF from £200 million in 2013/14, to £280 million in 2014/15, and £340 million from April 2015. This represents a total increase of 70% since August 2014.

However, current projections suggest that spending would rise to around £410 million for this year, an over-spend of £70 million, in the absence of further prioritization. The NHS said this money could be used for other aspects of cancer treatment or NHS services for other patient groups.

Therefore, some drugs are set to be removed from the CDF. The NHS said all decisions on drugs to be maintained in the CDF were based on the advice of clinicians, the best available evidence, and the cost of the treatment.

“There is no escaping the fact that we face a difficult set of choices, but it is our duty to ensure we get maximum value from every penny available on behalf of patients,” said Peter Clark, chair of the CDF.

“We must ensure we invest in those treatments that offer the most benefit, based on rigorous evidence-based clinical analysis and an assessment of the cost of those treatments.”

While de-funding certain drugs will reduce costs, the CDF is not expected to be back on budget this financial year. The NHS does expect the CDF will be operating within its budget during 2016/17.

Blood cancer drugs to be removed

The following drugs are currently on the CDF list for the following indications, but they are set to be de-listed on November 4, 2015.

Bendamustine

For the treatment of chronic lymphocytic leukemia (CLL) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• CLL (not licensed in this indication)
• Second-line indication, third-line indication, or fourth-line indication
• To be used within the treating Trust’s governance framework, as bendamustine is not licensed in this indication

For the treatment of relapsed mantle cell lymphoma (MCL) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• MCL
• Option for second- or subsequent-line chemotherapy
• No previous treatment with bendamustine
• To be used within the treating Trust’s governance framework, as bendamustine is not licensed in this indication

*Bendamustine will remain on the CDF for other indications.

Bosutinib

For the treatment of refractory, chronic phase chronic myeloid leukemia (CML) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Chronic phase CML
• Refractory to nilotinib or dasatinib (if dasatinib accessed via a clinical trial or via its current approved CDF indication)

For the treatment of refractory, accelerated phase CML where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Accelerated phase CML
• Refractory to nilotinib or dasatinib (if dasatinib accessed via a clinical trial or via its current approved CDF indication)
• Significant intolerance to nilotinib (grade 3 or 4 events)

For the treatment of accelerated phase CML where there is intolerance of treatments and where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Accelerated phase CML
• Significant intolerance to dasatinib (grade 3 or 4 adverse events; if dasatinib accessed via its current approved CDF indication)
• Significant intolerance to nilotinib (grade 3 or 4 events)

*Bosutinib will still be available through the CDF for patients with chronic phase CML that is intolerant of other treatments.

Brentuximab

For the treatment of refractory, systemic anaplastic lymphoma where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Relapsed or refractory systemic anaplastic large-cell lymphoma

For the treatment of relapsed or refractory CD30+ Hodgkin lymphoma where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Relapsed or refractory CD30+ Hodgkin lymphoma
• Following autologous stem cell transplant or following at least 2 prior therapies when autologous stem cell transplant or multi-agent chemotherapy is not an option

Dasatinib

For the treatment of Philadelphia-chromosome-positive (Ph+) acute lymphoblastic leukemia where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Refractory or significant intolerance or resistance to prior therapy including imatinib (grade 3 or 4 adverse events)
• Second-line indication or third-line indication

*Dasatinib will still be available for chronic phase and accelerated phase CML.

Ibrutinib

For the treatment of relapsed/refractory CLL where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Confirmed CLL
• Must have received at least 1 prior therapy for CLL
• Considered not appropriate for treatment or retreatment with purine-analogue-based therapy due to:

  • Failure to respond to chemo-immunotherapy or
  • A progression-free interval of less than 3 years or
  • Age of 70 years or more or
  • Age of 65 years or more plus the presence of comorbidities or
  • A 17p or TP53 deletion

• ECOG performance status of 0-2
• A neutrophil count of ≥0.75 x 10⁹/L
• A platelet count of ≥30 x 10⁹/L
• Patient not on warfarin or CYP3A4/5 inhibitors
• No prior treatment with idelalisib

For the treatment of relapsed/refractory MCL where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Confirmed MCL with cyclin D1 overexpression or translocation breakpoints at t(11;14)
• Failure to achieve at least partial response with, or documented disease progression disease after, the most recent treatment regimen
• ECOG performance status of 0-2
• At least 1 but no more than 5 previous lines of treatment

Lenalidomide

For the second-line treatment of multiple myeloma (MM) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• MM
• Second-line indication
• Contraindication to bortezomib or previously received bortezomib in the first-line setting

*Lenalidomide will still be available for patients with myelodysplastic syndromes with 5q deletion.

Pomalidomide

For the treatment of relapsed and refractory MM where the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically
• MM
• Performance status of 0-2
• Previously received treatment with adequate trials of at least all of the following options of therapy: bortezomib, lenalidomide, and alkylating agents
• Failed treatment with bortezomib or lenalidomide, as defined by: progression on or before 60 days of treatment, progressive disease 6 months or less after achieving a partial response, or intolerance to bortezomib
• Refractory disease to previous treatment
• No resistance to high-dose dexamethasone used in the last line of therapy
• No peripheral neuropathy of grade 2 or more

A complete list of proposed changes to the CDF, as well as the drugs that were de-listed on March 12, 2015, is available on the NHS website.

Prescription drugs

Photo courtesy of CDC

England’s National Health Service (NHS) plans to remove several drugs used to treat hematologic malignancies from the Cancer Drugs Fund (CDF).

The plan is that, as of November 4, 2015, pomalidomide, lenalidomide, ibrutinib, dasatinib, brentuximab, bosutinib, and bendamustine will no longer be funded via the CDF for certain indications.

Ofatumumab was removed from the CDF list yesterday but is now available through the NHS.

Drugs used to treat solid tumor malignancies are set to be de-funded through CDF in November as well.

However, the NHS said the proposal to remove a drug from the CDF is not necessarily a final decision.

In cases where a drug offers enough clinical benefit, the pharmaceutical company developing that drug has the opportunity to reduce the price they are asking the NHS to pay to ensure that it achieves a satisfactory level of value for money. The NHS said a number of such negotiations are underway.

In addition, patients who are currently receiving the drugs set to be removed from the CDF will continue to have access to those drugs.

About the CDF and the NHS

The CDF—set up in 2010 and currently due to run until March 2016—is money the government has set aside to pay for cancer drugs that haven’t been approved by the National Institute for Health and Care Excellence (NICE) and aren’t available within the NHS in England. Most cancer drugs are routinely funded outside of the CDF.

NHS England and NICE are planning to consult on a proposed new system for commissioning cancer drugs. The NHS said the new system will be designed to provide the agency with a more systematic approach to getting the best price for cancer drugs.

Reason for drug removals

The NHS previously increased the budget for the CDF from £200 million in 2013/14, to £280 million in 2014/15, and £340 million from April 2015. This represents a total increase of 70% since August 2014.

However, current projections suggest that spending would rise to around £410 million for this year, an over-spend of £70 million, in the absence of further prioritization. The NHS said this money could be used for other aspects of cancer treatment or NHS services for other patient groups.

Therefore, some drugs are set to be removed from the CDF. The NHS said all decisions on drugs to be maintained in the CDF were based on the advice of clinicians, the best available evidence, and the cost of the treatment.

“There is no escaping the fact that we face a difficult set of choices, but it is our duty to ensure we get maximum value from every penny available on behalf of patients,” said Peter Clark, chair of the CDF.

“We must ensure we invest in those treatments that offer the most benefit, based on rigorous evidence-based clinical analysis and an assessment of the cost of those treatments.”

While de-funding certain drugs will reduce costs, the CDF is not expected to be back on budget this financial year. The NHS does expect the CDF will be operating within its budget during 2016/17.

Blood cancer drugs to be removed

The following drugs are currently on the CDF list for the following indications, but they are set to be de-listed on November 4, 2015.

Bendamustine

For the treatment of chronic lymphocytic leukemia (CLL) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• CLL (not licensed in this indication)
• Second-line indication, third-line indication, or fourth-line indication
• To be used within the treating Trust’s governance framework, as bendamustine is not licensed in this indication

For the treatment of relapsed mantle cell lymphoma (MCL) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• MCL
• Option for second- or subsequent-line chemotherapy
• No previous treatment with bendamustine
• To be used within the treating Trust’s governance framework, as bendamustine is not licensed in this indication

*Bendamustine will remain on the CDF for other indications.

Bosutinib

For the treatment of refractory, chronic phase chronic myeloid leukemia (CML) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Chronic phase CML
• Refractory to nilotinib or dasatinib (if dasatinib accessed via a clinical trial or via its current approved CDF indication)

For the treatment of refractory, accelerated phase CML where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Accelerated phase CML
• Refractory to nilotinib or dasatinib (if dasatinib accessed via a clinical trial or via its current approved CDF indication)
• Significant intolerance to nilotinib (grade 3 or 4 events)

For the treatment of accelerated phase CML where there is intolerance of treatments and where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Accelerated phase CML
• Significant intolerance to dasatinib (grade 3 or 4 adverse events; if dasatinib accessed via its current approved CDF indication)
• Significant intolerance to nilotinib (grade 3 or 4 events)

*Bosutinib will still be available through the CDF for patients with chronic phase CML that is intolerant of other treatments.

Brentuximab

For the treatment of refractory, systemic anaplastic lymphoma where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Relapsed or refractory systemic anaplastic large-cell lymphoma

For the treatment of relapsed or refractory CD30+ Hodgkin lymphoma where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Relapsed or refractory CD30+ Hodgkin lymphoma
• Following autologous stem cell transplant or following at least 2 prior therapies when autologous stem cell transplant or multi-agent chemotherapy is not an option

Dasatinib

For the treatment of Philadelphia-chromosome-positive (Ph+) acute lymphoblastic leukemia where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Refractory or significant intolerance or resistance to prior therapy including imatinib (grade 3 or 4 adverse events)
• Second-line indication or third-line indication

*Dasatinib will still be available for chronic phase and accelerated phase CML.

Ibrutinib

For the treatment of relapsed/refractory CLL where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Confirmed CLL
• Must have received at least 1 prior therapy for CLL
• Considered not appropriate for treatment or retreatment with purine-analogue-based therapy due to:

  • Failure to respond to chemo-immunotherapy or
  • A progression-free interval of less than 3 years or
  • Age of 70 years or more or
  • Age of 65 years or more plus the presence of comorbidities or
  • A 17p or TP53 deletion

• ECOG performance status of 0-2
• A neutrophil count of ≥0.75 x 10⁹/L
• A platelet count of ≥30 x 10⁹/L
• Patient not on warfarin or CYP3A4/5 inhibitors
• No prior treatment with idelalisib

For the treatment of relapsed/refractory MCL where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• Confirmed MCL with cyclin D1 overexpression or translocation breakpoints at t(11;14)
• Failure to achieve at least partial response with, or documented disease progression disease after, the most recent treatment regimen
• ECOG performance status of 0-2
• At least 1 but no more than 5 previous lines of treatment

Lenalidomide

For the second-line treatment of multiple myeloma (MM) where all the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anticancer therapy
• MM
• Second-line indication
• Contraindication to bortezomib or previously received bortezomib in the first-line setting

*Lenalidomide will still be available for patients with myelodysplastic syndromes with 5q deletion.

Pomalidomide

For the treatment of relapsed and refractory MM where the following criteria are met:

• Application made by and first cycle of systemic anticancer therapy to be prescribed by a consultant specialist specifically
• MM
• Performance status of 0-2
• Previously received treatment with adequate trials of at least all of the following options of therapy: bortezomib, lenalidomide, and alkylating agents
• Failed treatment with bortezomib or lenalidomide, as defined by: progression on or before 60 days of treatment, progressive disease 6 months or less after achieving a partial response, or intolerance to bortezomib
• Refractory disease to previous treatment
• No resistance to high-dose dexamethasone used in the last line of therapy
• No peripheral neuropathy of grade 2 or more

A complete list of proposed changes to the CDF, as well as the drugs that were de-listed on March 12, 2015, is available on the NHS website.

Panobinostat (Farydak)

Photo courtesy of Novartis

The European Commission has approved panobinostat (Farydak) for use in combination with other agents to treat patients with relapsed and/or refractory

multiple myeloma (MM).

The histone deacetylase (HDAC) inhibitor is now approved, in combination with bortezomib and dexamethasone, to treat adults with MM who have received at least 2 prior treatment regimens, including bortezomib and an immunomodulatory agent (IMiD).

The approval marks the first time an HDAC inhibitor with epigenetic activity is available in the European Union (EU). The approval applies to all 28 EU member states plus Iceland, Norway, and Liechtenstein.

The European Commission approved panobinostat based on results of a subgroup analysis of 147 patients in the phase 3 PANORAMA-1 trial.

PANORAMA-1 was a randomized, double-blind, placebo-controlled trial of 768 MM patients. The study showed that, overall, panobinostat plus bortezomib and dexamethasone increased progression-free survival (PFS) by about 4 months when compared to placebo plus bortezomib and dexamethasone.

Full results of the PANORAMA-1 study were published in The Lancet Oncology last year.  Results from the substudy of 147 patients were presented at ASCO 2015.

The 147 patients had relapsed or relapsed and refractory MM and had received 2 or more prior regimens, including bortezomib and an IMiD.

The median PFS benefit in this subgroup increased by 7.8 months in the panobinostat arm compared to the placebo arm. The median PFS was 12.5 months (n=73) and 4.7 months (n=74), respectively (hazard ratio=0.47).

Common grade 3/4 non-hematologic adverse events in the panobinostat arm and placebo arm, respectively, included diarrhea (33.3% vs 15.1%), asthenia/fatigue (26.4% vs 13.7%), and peripheral neuropathy (16.7% vs 6.8%).

The most common grade 3/4 hematologic events in the panobinostat arm and placebo arm, respectively, were thrombocytopenia (68.1% vs 44.4%), lymphopenia (48.6% vs 49.3%), and neutropenia (40.3% vs 16.4%).

Cardiac events (most frequently atrial fibrillation, tachycardia, palpitation, and sinus tachycardia) were reported in 17.6% of panobinostat-treated patients and 9.8% of placebo-treated patients. Syncope was reported in 6.0% and 2.4%, respectively.

The percentage of on-treatment deaths was similar in the panobinostat and placebo arms—6.9% and 6.8%, respectively. But on-treatment deaths not due to the study indication (MM) were reported in 6.8% and 3.2% of patients, respectively.

Panobinostat in combination with bortezomib and dexamethasone is also approved in the US, Chile, and Japan for certain patients with previously treated MM. The exact indication for panobinostat varies by country.

Panobinostat (Farydak)

Photo courtesy of Novartis

The European Commission has approved panobinostat (Farydak) for use in combination with other agents to treat patients with relapsed and/or refractory

multiple myeloma (MM).

The histone deacetylase (HDAC) inhibitor is now approved, in combination with bortezomib and dexamethasone, to treat adults with MM who have received at least 2 prior treatment regimens, including bortezomib and an immunomodulatory agent (IMiD).

The approval marks the first time an HDAC inhibitor with epigenetic activity is available in the European Union (EU). The approval applies to all 28 EU member states plus Iceland, Norway, and Liechtenstein.

The European Commission approved panobinostat based on results of a subgroup analysis of 147 patients in the phase 3 PANORAMA-1 trial.

PANORAMA-1 was a randomized, double-blind, placebo-controlled trial of 768 MM patients. The study showed that, overall, panobinostat plus bortezomib and dexamethasone increased progression-free survival (PFS) by about 4 months when compared to placebo plus bortezomib and dexamethasone.

Full results of the PANORAMA-1 study were published in The Lancet Oncology last year.  Results from the substudy of 147 patients were presented at ASCO 2015.

The 147 patients had relapsed or relapsed and refractory MM and had received 2 or more prior regimens, including bortezomib and an IMiD.

The median PFS benefit in this subgroup increased by 7.8 months in the panobinostat arm compared to the placebo arm. The median PFS was 12.5 months (n=73) and 4.7 months (n=74), respectively (hazard ratio=0.47).

Common grade 3/4 non-hematologic adverse events in the panobinostat arm and placebo arm, respectively, included diarrhea (33.3% vs 15.1%), asthenia/fatigue (26.4% vs 13.7%), and peripheral neuropathy (16.7% vs 6.8%).

The most common grade 3/4 hematologic events in the panobinostat arm and placebo arm, respectively, were thrombocytopenia (68.1% vs 44.4%), lymphopenia (48.6% vs 49.3%), and neutropenia (40.3% vs 16.4%).

Cardiac events (most frequently atrial fibrillation, tachycardia, palpitation, and sinus tachycardia) were reported in 17.6% of panobinostat-treated patients and 9.8% of placebo-treated patients. Syncope was reported in 6.0% and 2.4%, respectively.

The percentage of on-treatment deaths was similar in the panobinostat and placebo arms—6.9% and 6.8%, respectively. But on-treatment deaths not due to the study indication (MM) were reported in 6.8% and 3.2% of patients, respectively.

Panobinostat in combination with bortezomib and dexamethasone is also approved in the US, Chile, and Japan for certain patients with previously treated MM. The exact indication for panobinostat varies by country.

Panobinostat (Farydak)

Photo courtesy of Novartis

The European Commission has approved panobinostat (Farydak) for use in combination with other agents to treat patients with relapsed and/or refractory

multiple myeloma (MM).

The histone deacetylase (HDAC) inhibitor is now approved, in combination with bortezomib and dexamethasone, to treat adults with MM who have received at least 2 prior treatment regimens, including bortezomib and an immunomodulatory agent (IMiD).

The approval marks the first time an HDAC inhibitor with epigenetic activity is available in the European Union (EU). The approval applies to all 28 EU member states plus Iceland, Norway, and Liechtenstein.

The European Commission approved panobinostat based on results of a subgroup analysis of 147 patients in the phase 3 PANORAMA-1 trial.

PANORAMA-1 was a randomized, double-blind, placebo-controlled trial of 768 MM patients. The study showed that, overall, panobinostat plus bortezomib and dexamethasone increased progression-free survival (PFS) by about 4 months when compared to placebo plus bortezomib and dexamethasone.

Full results of the PANORAMA-1 study were published in The Lancet Oncology last year.  Results from the substudy of 147 patients were presented at ASCO 2015.

The 147 patients had relapsed or relapsed and refractory MM and had received 2 or more prior regimens, including bortezomib and an IMiD.

The median PFS benefit in this subgroup increased by 7.8 months in the panobinostat arm compared to the placebo arm. The median PFS was 12.5 months (n=73) and 4.7 months (n=74), respectively (hazard ratio=0.47).

Common grade 3/4 non-hematologic adverse events in the panobinostat arm and placebo arm, respectively, included diarrhea (33.3% vs 15.1%), asthenia/fatigue (26.4% vs 13.7%), and peripheral neuropathy (16.7% vs 6.8%).

The most common grade 3/4 hematologic events in the panobinostat arm and placebo arm, respectively, were thrombocytopenia (68.1% vs 44.4%), lymphopenia (48.6% vs 49.3%), and neutropenia (40.3% vs 16.4%).

Cardiac events (most frequently atrial fibrillation, tachycardia, palpitation, and sinus tachycardia) were reported in 17.6% of panobinostat-treated patients and 9.8% of placebo-treated patients. Syncope was reported in 6.0% and 2.4%, respectively.

The percentage of on-treatment deaths was similar in the panobinostat and placebo arms—6.9% and 6.8%, respectively. But on-treatment deaths not due to the study indication (MM) were reported in 6.8% and 3.2% of patients, respectively.

Panobinostat in combination with bortezomib and dexamethasone is also approved in the US, Chile, and Japan for certain patients with previously treated MM. The exact indication for panobinostat varies by country.

Thrombus

Image by Andre E.X. Brown

The US Food and Drug Administration (FDA) has expanded the approved use of the antiplatelet agent ticagrelor (Brilinta).

The FDA first approved ticagrelor in 2011 to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS).

Now, the agency has approved a 60 mg dose that can be used long-term. The 60 mg tablet is expected to be available in pharmacies by the end of this month.

The recommended dosing for ticagrelor is a loading dose of 180 mg, followed by 90 mg twice daily during the first year after the ACS event. The drug is combined with aspirin, typically at a loading dose of 325 mg, followed by a daily maintenance dose of 75-100 mg.

After 1 year, patients can now receive ticagrelor at 60 mg twice daily.

The expanded indication for ticagrelor has been approved under FDA Priority Review, a designation granted to medicines with the potential to provide significant improvements in the treatment, prevention, or diagnosis of a disease.

Ticagrelor has been approved in more than 100 countries and is included in 12 major ACS treatment guidelines globally. The drug is under development by AstraZeneca.

Trial results

The FDA’s expanded approval of ticagrelor is based on results of the PEGASUS TIMI-54 trial, a large-scale study involving more than 21,000 patients.

Investigators compared ticagrelor (at 60 mg or 90 mg) plus low-dose aspirin to placebo plus low-dose aspirin in patients who had experienced a heart attack 1 to 3 years prior to study enrollment.

The primary efficacy endpoint was a composite of cardiovascular death, myocardial infarction, or stroke. And the investigators found that patients in either ticagrelor arm were significantly less likely to achieve this endpoint.

At 3 years, the proportion of patients meeting the endpoint was 7.85% in the 90 mg group, 7.77% in the 60 mg group, and 9.04% in the placebo group (P=0.008 for 90 mg vs placebo and P=0.004 for 60 mg vs placebo).

Patients receiving ticagrelor also had a significantly higher incidence of major bleeding and dyspnea. The rate of TIMI major bleeding was 2.60% in the 90 mg group, 2.30% in the 60 mg group, and 1.06% in the placebo group (P<0.001 for each ticagrelor dose vs placebo).

The rate of dyspnea was 18.93% in the 90 mg group, 15.84% in 60 mg group, and 6.38% in the placebo group (P<0.001 for both comparisons). The rate of dyspnea leading to treatment discontinuation was 6.5% in the 90 mg group, 4.55% in the 60 mg group, and 0.79% in the placebo group (P<0.001 for both).

Thrombus

Image by Andre E.X. Brown

The US Food and Drug Administration (FDA) has expanded the approved use of the antiplatelet agent ticagrelor (Brilinta).

The FDA first approved ticagrelor in 2011 to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS).

Now, the agency has approved a 60 mg dose that can be used long-term. The 60 mg tablet is expected to be available in pharmacies by the end of this month.

The recommended dosing for ticagrelor is a loading dose of 180 mg, followed by 90 mg twice daily during the first year after the ACS event. The drug is combined with aspirin, typically at a loading dose of 325 mg, followed by a daily maintenance dose of 75-100 mg.

After 1 year, patients can now receive ticagrelor at 60 mg twice daily.

The expanded indication for ticagrelor has been approved under FDA Priority Review, a designation granted to medicines with the potential to provide significant improvements in the treatment, prevention, or diagnosis of a disease.

Ticagrelor has been approved in more than 100 countries and is included in 12 major ACS treatment guidelines globally. The drug is under development by AstraZeneca.

Trial results

The FDA’s expanded approval of ticagrelor is based on results of the PEGASUS TIMI-54 trial, a large-scale study involving more than 21,000 patients.

Investigators compared ticagrelor (at 60 mg or 90 mg) plus low-dose aspirin to placebo plus low-dose aspirin in patients who had experienced a heart attack 1 to 3 years prior to study enrollment.

The primary efficacy endpoint was a composite of cardiovascular death, myocardial infarction, or stroke. And the investigators found that patients in either ticagrelor arm were significantly less likely to achieve this endpoint.

At 3 years, the proportion of patients meeting the endpoint was 7.85% in the 90 mg group, 7.77% in the 60 mg group, and 9.04% in the placebo group (P=0.008 for 90 mg vs placebo and P=0.004 for 60 mg vs placebo).

Patients receiving ticagrelor also had a significantly higher incidence of major bleeding and dyspnea. The rate of TIMI major bleeding was 2.60% in the 90 mg group, 2.30% in the 60 mg group, and 1.06% in the placebo group (P<0.001 for each ticagrelor dose vs placebo).

The rate of dyspnea was 18.93% in the 90 mg group, 15.84% in 60 mg group, and 6.38% in the placebo group (P<0.001 for both comparisons). The rate of dyspnea leading to treatment discontinuation was 6.5% in the 90 mg group, 4.55% in the 60 mg group, and 0.79% in the placebo group (P<0.001 for both).

Thrombus

Image by Andre E.X. Brown

The US Food and Drug Administration (FDA) has expanded the approved use of the antiplatelet agent ticagrelor (Brilinta).

The FDA first approved ticagrelor in 2011 to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS).

Now, the agency has approved a 60 mg dose that can be used long-term. The 60 mg tablet is expected to be available in pharmacies by the end of this month.

The recommended dosing for ticagrelor is a loading dose of 180 mg, followed by 90 mg twice daily during the first year after the ACS event. The drug is combined with aspirin, typically at a loading dose of 325 mg, followed by a daily maintenance dose of 75-100 mg.

After 1 year, patients can now receive ticagrelor at 60 mg twice daily.

The expanded indication for ticagrelor has been approved under FDA Priority Review, a designation granted to medicines with the potential to provide significant improvements in the treatment, prevention, or diagnosis of a disease.

Ticagrelor has been approved in more than 100 countries and is included in 12 major ACS treatment guidelines globally. The drug is under development by AstraZeneca.

Trial results

The FDA’s expanded approval of ticagrelor is based on results of the PEGASUS TIMI-54 trial, a large-scale study involving more than 21,000 patients.

Investigators compared ticagrelor (at 60 mg or 90 mg) plus low-dose aspirin to placebo plus low-dose aspirin in patients who had experienced a heart attack 1 to 3 years prior to study enrollment.

The primary efficacy endpoint was a composite of cardiovascular death, myocardial infarction, or stroke. And the investigators found that patients in either ticagrelor arm were significantly less likely to achieve this endpoint.

At 3 years, the proportion of patients meeting the endpoint was 7.85% in the 90 mg group, 7.77% in the 60 mg group, and 9.04% in the placebo group (P=0.008 for 90 mg vs placebo and P=0.004 for 60 mg vs placebo).

Patients receiving ticagrelor also had a significantly higher incidence of major bleeding and dyspnea. The rate of TIMI major bleeding was 2.60% in the 90 mg group, 2.30% in the 60 mg group, and 1.06% in the placebo group (P<0.001 for each ticagrelor dose vs placebo).

The rate of dyspnea was 18.93% in the 90 mg group, 15.84% in 60 mg group, and 6.38% in the placebo group (P<0.001 for both comparisons). The rate of dyspnea leading to treatment discontinuation was 6.5% in the 90 mg group, 4.55% in the 60 mg group, and 0.79% in the placebo group (P<0.001 for both).

Patient receiving chemotherapy

Photo by Rhoda Baer

Last March, the US Food and Drug Administration (FDA) issued a statement warning healthcare professionals not to use the chemotherapy drug Treanda Injection (bendamustine hydrochloride) with closed system transfer devices (CSTDs), adapters, and syringes containing polycarbonate or acrylonitrile-butadiene-styrene (ABS).

Now, the FDA is providing a list of devices that were tested and deemed compatible with the drug (see the tables below).

The devices were tested by Treanda’s manufacturer, Teva Pharmaceuticals.

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

Treanda is available in 2 formulations: a solution, Treanda Injection (45 mg/0.5 mL or 180 mg/2 mL solution), and a lyophilized powder, Treanda for Injection (25 mg/vial or 100 mg/vial lyophilized powder).  The information discussed here is referring to compatibility with the solution, Treanda Injection.

Treanda Injection contains N, N-dimethylacetamide (DMA), which is incompatible with devices that contain polycarbonate or ABS. Devices including CSTDs, adapters, and syringes that contain polycarbonate or ABS have been shown to dissolve when they come in contact with DMA in the drug.

This incompatibility leads to device failure, such as leaking, breaking, or operational failure of CSTD components; possible product contamination; and potential serious adverse health consequences to practitioners, such as skin reactions, or to patients, including the risk of small blood vessel blockage if the product is contaminated with dissolved ABS or polycarbonate.

Users should contact device manufacturers prior to using the specific devices listed below to ensure there have been no changes made to the material composition of the devices and that the devices are compatible with Treanda use.

Table 1. The compatibility of Treanda Injection with specific CSTDs, syringes, vial adapters, and gloves (based on testing conducted by Teva from February 2015 through June 2015).

*Part numbers reflect a specific size glove used in the compatibility tests.

Table 2. The IV administration set found to be compatible with Treanda Injection after dilution in a 500 mL 0.9% sodium chloride IV infusion bags (based on testing conducted by Teva from February 2015 through June 2015*).

*Compatibility studies did not include testing with 2.5% dextrose/0.45% sodium chloride injection. However, the results of these studies are not expected to change. So either diluent, 0.9% sodium chloride or 2.5% dextrose/0.45% sodium chloride injection, can be used with Treanda injection.

The FDA required label changes for both the solution and the powder formulations of Treanda to include information for safe preparation and handling for IV administration. See the full prescribing information for details.

For more details on the compatibility of Treanda Injection with specific CSTDs, syringes, vial adapters, gloves, and IV administration sets, see Teva’s Dear Health Care Provider letter.

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

Patient receiving chemotherapy

Photo by Rhoda Baer

Last March, the US Food and Drug Administration (FDA) issued a statement warning healthcare professionals not to use the chemotherapy drug Treanda Injection (bendamustine hydrochloride) with closed system transfer devices (CSTDs), adapters, and syringes containing polycarbonate or acrylonitrile-butadiene-styrene (ABS).

Now, the FDA is providing a list of devices that were tested and deemed compatible with the drug (see the tables below).

The devices were tested by Treanda’s manufacturer, Teva Pharmaceuticals.

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

Treanda is available in 2 formulations: a solution, Treanda Injection (45 mg/0.5 mL or 180 mg/2 mL solution), and a lyophilized powder, Treanda for Injection (25 mg/vial or 100 mg/vial lyophilized powder).  The information discussed here is referring to compatibility with the solution, Treanda Injection.

Treanda Injection contains N, N-dimethylacetamide (DMA), which is incompatible with devices that contain polycarbonate or ABS. Devices including CSTDs, adapters, and syringes that contain polycarbonate or ABS have been shown to dissolve when they come in contact with DMA in the drug.

This incompatibility leads to device failure, such as leaking, breaking, or operational failure of CSTD components; possible product contamination; and potential serious adverse health consequences to practitioners, such as skin reactions, or to patients, including the risk of small blood vessel blockage if the product is contaminated with dissolved ABS or polycarbonate.

Users should contact device manufacturers prior to using the specific devices listed below to ensure there have been no changes made to the material composition of the devices and that the devices are compatible with Treanda use.

Table 1. The compatibility of Treanda Injection with specific CSTDs, syringes, vial adapters, and gloves (based on testing conducted by Teva from February 2015 through June 2015).

*Part numbers reflect a specific size glove used in the compatibility tests.

Table 2. The IV administration set found to be compatible with Treanda Injection after dilution in a 500 mL 0.9% sodium chloride IV infusion bags (based on testing conducted by Teva from February 2015 through June 2015*).

*Compatibility studies did not include testing with 2.5% dextrose/0.45% sodium chloride injection. However, the results of these studies are not expected to change. So either diluent, 0.9% sodium chloride or 2.5% dextrose/0.45% sodium chloride injection, can be used with Treanda injection.

The FDA required label changes for both the solution and the powder formulations of Treanda to include information for safe preparation and handling for IV administration. See the full prescribing information for details.

For more details on the compatibility of Treanda Injection with specific CSTDs, syringes, vial adapters, gloves, and IV administration sets, see Teva’s Dear Health Care Provider letter.

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

Patient receiving chemotherapy

Photo by Rhoda Baer

Last March, the US Food and Drug Administration (FDA) issued a statement warning healthcare professionals not to use the chemotherapy drug Treanda Injection (bendamustine hydrochloride) with closed system transfer devices (CSTDs), adapters, and syringes containing polycarbonate or acrylonitrile-butadiene-styrene (ABS).

Now, the FDA is providing a list of devices that were tested and deemed compatible with the drug (see the tables below).

The devices were tested by Treanda’s manufacturer, Teva Pharmaceuticals.

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

Treanda is available in 2 formulations: a solution, Treanda Injection (45 mg/0.5 mL or 180 mg/2 mL solution), and a lyophilized powder, Treanda for Injection (25 mg/vial or 100 mg/vial lyophilized powder).  The information discussed here is referring to compatibility with the solution, Treanda Injection.

Treanda Injection contains N, N-dimethylacetamide (DMA), which is incompatible with devices that contain polycarbonate or ABS. Devices including CSTDs, adapters, and syringes that contain polycarbonate or ABS have been shown to dissolve when they come in contact with DMA in the drug.

This incompatibility leads to device failure, such as leaking, breaking, or operational failure of CSTD components; possible product contamination; and potential serious adverse health consequences to practitioners, such as skin reactions, or to patients, including the risk of small blood vessel blockage if the product is contaminated with dissolved ABS or polycarbonate.

Users should contact device manufacturers prior to using the specific devices listed below to ensure there have been no changes made to the material composition of the devices and that the devices are compatible with Treanda use.

Table 1. The compatibility of Treanda Injection with specific CSTDs, syringes, vial adapters, and gloves (based on testing conducted by Teva from February 2015 through June 2015).

*Part numbers reflect a specific size glove used in the compatibility tests.

Table 2. The IV administration set found to be compatible with Treanda Injection after dilution in a 500 mL 0.9% sodium chloride IV infusion bags (based on testing conducted by Teva from February 2015 through June 2015*).

*Compatibility studies did not include testing with 2.5% dextrose/0.45% sodium chloride injection. However, the results of these studies are not expected to change. So either diluent, 0.9% sodium chloride or 2.5% dextrose/0.45% sodium chloride injection, can be used with Treanda injection.

The FDA required label changes for both the solution and the powder formulations of Treanda to include information for safe preparation and handling for IV administration. See the full prescribing information for details.

For more details on the compatibility of Treanda Injection with specific CSTDs, syringes, vial adapters, gloves, and IV administration sets, see Teva’s Dear Health Care Provider letter.

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

Monoclonal antibodies

Photo by Linda Bartlett

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for ACE910 to prevent bleeding in hemophilia A patients age 12 and older who have factor VIII inhibitors.

ACE910 is the first factor VIIIa-mimetic bispecific antibody to be investigated for the prophylactic treatment of hemophilia A.

Breakthrough therapy designation is designed to accelerate the development and review of medicines that demonstrate early clinical evidence of a substantial improvement over current treatment options for serious diseases.

The breakthrough therapy designation for ACE910 was granted based on results of a phase 1 study of ACE910 in patients with severe hemophilia A.

About ACE910

ACE910 is an investigational, humanized, bispecific monoclonal antibody engineered to simultaneously bind factors IXa and X. ACE910 thereby mimics the cofactor function of factor VIII and is designed to promote blood coagulation in hemophilia A patients, regardless of whether they have developed inhibitors to factor VIII.

ACE910 is administered subcutaneously once weekly. As it is distinct in structure from factor VIII, it is not expected to lead to the formation of factor VIII inhibitors.

ACE910 was created by Chugai Pharmaceutical Co., Ltd. and is being co-developed by Genentech.

ACE910 research

Results of the phase 1 trial suggested that once-weekly, subcutaneous administration of ACE910 can reduce annualized bleeding rates (ABRs) in adults and adolescents with severe hemophilia A, with or without factor VIII inhibitors.

At ISTH 2015 (abstract AS017), researchers presented data on 18 Japanese patients with severe hemophilia A (factor VIII: C<1%, ages 12 to 58 years).

Patients received once-weekly subcutaneous ACE910 at one of the following dose levels: 0.3 mg/kg (cohort 1), 1 mg/kg (cohort 2), or 3 mg/kg (cohort 3). There were 6 patients in each cohort.

The patients were followed for 5.6 months to 18.5 months.

Efficacy

Whether or not they had inhibitors, patients experienced a decrease in ABR with ACE910. The changes in ABR per treatment cohort and according to inhibitor status are as follows:

*One patient did not report bleeding episodes at baseline or during the study.

Safety

There were 93 adverse events. The researchers said all events were of mild or moderate intensity. One patient discontinued ACE910 due to mild injection-site redness.

There were no thromboembolic events, even when ACE910 was given concomitantly with factor VIII products or bypassing agents as episodic treatment for breakthrough bleeds.

Three patients developed anti-ACE910 antibodies, but they did not affect ACE910 pharmacokinetics or pharmacodynamics.

Genentech is planning to initiate a phase 3 trial of ACE910 in patients with hemophilia A and factor VIII inhibitors by the end of 2015, a phase 3 trial in patients without inhibitors in 2016, and a trial in pediatric patients with hemophilia A in 2016.

Monoclonal antibodies

Photo by Linda Bartlett

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for ACE910 to prevent bleeding in hemophilia A patients age 12 and older who have factor VIII inhibitors.

ACE910 is the first factor VIIIa-mimetic bispecific antibody to be investigated for the prophylactic treatment of hemophilia A.

Breakthrough therapy designation is designed to accelerate the development and review of medicines that demonstrate early clinical evidence of a substantial improvement over current treatment options for serious diseases.

The breakthrough therapy designation for ACE910 was granted based on results of a phase 1 study of ACE910 in patients with severe hemophilia A.

About ACE910

ACE910 is an investigational, humanized, bispecific monoclonal antibody engineered to simultaneously bind factors IXa and X. ACE910 thereby mimics the cofactor function of factor VIII and is designed to promote blood coagulation in hemophilia A patients, regardless of whether they have developed inhibitors to factor VIII.

ACE910 is administered subcutaneously once weekly. As it is distinct in structure from factor VIII, it is not expected to lead to the formation of factor VIII inhibitors.

ACE910 was created by Chugai Pharmaceutical Co., Ltd. and is being co-developed by Genentech.

ACE910 research

Results of the phase 1 trial suggested that once-weekly, subcutaneous administration of ACE910 can reduce annualized bleeding rates (ABRs) in adults and adolescents with severe hemophilia A, with or without factor VIII inhibitors.

At ISTH 2015 (abstract AS017), researchers presented data on 18 Japanese patients with severe hemophilia A (factor VIII: C<1%, ages 12 to 58 years).

Patients received once-weekly subcutaneous ACE910 at one of the following dose levels: 0.3 mg/kg (cohort 1), 1 mg/kg (cohort 2), or 3 mg/kg (cohort 3). There were 6 patients in each cohort.

The patients were followed for 5.6 months to 18.5 months.

Efficacy

Whether or not they had inhibitors, patients experienced a decrease in ABR with ACE910. The changes in ABR per treatment cohort and according to inhibitor status are as follows:

*One patient did not report bleeding episodes at baseline or during the study.

Safety

There were 93 adverse events. The researchers said all events were of mild or moderate intensity. One patient discontinued ACE910 due to mild injection-site redness.

There were no thromboembolic events, even when ACE910 was given concomitantly with factor VIII products or bypassing agents as episodic treatment for breakthrough bleeds.

Three patients developed anti-ACE910 antibodies, but they did not affect ACE910 pharmacokinetics or pharmacodynamics.

Genentech is planning to initiate a phase 3 trial of ACE910 in patients with hemophilia A and factor VIII inhibitors by the end of 2015, a phase 3 trial in patients without inhibitors in 2016, and a trial in pediatric patients with hemophilia A in 2016.

Monoclonal antibodies

Photo by Linda Bartlett

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for ACE910 to prevent bleeding in hemophilia A patients age 12 and older who have factor VIII inhibitors.

ACE910 is the first factor VIIIa-mimetic bispecific antibody to be investigated for the prophylactic treatment of hemophilia A.

Breakthrough therapy designation is designed to accelerate the development and review of medicines that demonstrate early clinical evidence of a substantial improvement over current treatment options for serious diseases.

The breakthrough therapy designation for ACE910 was granted based on results of a phase 1 study of ACE910 in patients with severe hemophilia A.

About ACE910

ACE910 is an investigational, humanized, bispecific monoclonal antibody engineered to simultaneously bind factors IXa and X. ACE910 thereby mimics the cofactor function of factor VIII and is designed to promote blood coagulation in hemophilia A patients, regardless of whether they have developed inhibitors to factor VIII.

ACE910 is administered subcutaneously once weekly. As it is distinct in structure from factor VIII, it is not expected to lead to the formation of factor VIII inhibitors.

ACE910 was created by Chugai Pharmaceutical Co., Ltd. and is being co-developed by Genentech.

ACE910 research

Results of the phase 1 trial suggested that once-weekly, subcutaneous administration of ACE910 can reduce annualized bleeding rates (ABRs) in adults and adolescents with severe hemophilia A, with or without factor VIII inhibitors.

At ISTH 2015 (abstract AS017), researchers presented data on 18 Japanese patients with severe hemophilia A (factor VIII: C<1%, ages 12 to 58 years).

Patients received once-weekly subcutaneous ACE910 at one of the following dose levels: 0.3 mg/kg (cohort 1), 1 mg/kg (cohort 2), or 3 mg/kg (cohort 3). There were 6 patients in each cohort.

The patients were followed for 5.6 months to 18.5 months.

Efficacy

Whether or not they had inhibitors, patients experienced a decrease in ABR with ACE910. The changes in ABR per treatment cohort and according to inhibitor status are as follows:

*One patient did not report bleeding episodes at baseline or during the study.

Safety

There were 93 adverse events. The researchers said all events were of mild or moderate intensity. One patient discontinued ACE910 due to mild injection-site redness.

There were no thromboembolic events, even when ACE910 was given concomitantly with factor VIII products or bypassing agents as episodic treatment for breakthrough bleeds.

Three patients developed anti-ACE910 antibodies, but they did not affect ACE910 pharmacokinetics or pharmacodynamics.

Genentech is planning to initiate a phase 3 trial of ACE910 in patients with hemophilia A and factor VIII inhibitors by the end of 2015, a phase 3 trial in patients without inhibitors in 2016, and a trial in pediatric patients with hemophilia A in 2016.