HT Staff

Testosterone cypionate

(Depo-Testosterone)

Starting testosterone treatment is associated with an increased risk of venous thromboembolism (VTE) that peaks within 6 months and declines thereafter, according to research published in The BMJ.

Previous studies have reported contradictory results regarding testosterone use and VTE.

Researchers involved in the current study believe that failure to investigate the timing and duration of testosterone use may explain the conflicting findings.

For this study, David Handelsman, MBBS, PhD, of the University of Sydney in New South Wales, Australia, and his colleagues set out to determine the risk of VTE associated with use of testosterone treatment in men, focusing particularly on the timing of the risk.

The study involved data from 19,215 patients with confirmed VTE and 909,530 age-matched controls registered with the UK Clinical Practice Research Database between January 2001 and May 2013.

The researchers divided subjects into 3 mutually exclusive testosterone exposure groups: current treatment, recent treatment, and no treatment in the previous 2 years. The “current treatment” group was subdivided into durations of more or less than 6 months.

After adjusting for confounding factors, the researchers estimated rates of VTE.

The adjusted rate ratio of VTE was 1.25 for current testosterone treatment as compared to no testosterone treatment.

In the first 6 months of treatment, the rate ratio of VTE was 1.63, which corresponded to 10 additional cases of VTE above the base rate of 15.8 per 10,000 person-years.

The risk of VTE declined after more than 6 months of treatment and after treatment stopped. The rate ratio after more than 6 months of treatment was 1.00. After treatment stopped, the rate ratio was 0.68.

The researchers noted that this is an observational study, so no firm conclusions can be drawn about cause and effect. The team also stressed that the increased risks observed are temporary and still relatively low in absolute terms.

Nevertheless, they said their study suggests “a transient increase in the risk of venous thromboembolism that peaks during the first 3 to 6 months and declines gradually thereafter.”

The team said additional research is needed to confirm the temporal increase in the risk of VTE they observed as well as the absence of risk with long-term testosterone use.

Testosterone cypionate

(Depo-Testosterone)

Starting testosterone treatment is associated with an increased risk of venous thromboembolism (VTE) that peaks within 6 months and declines thereafter, according to research published in The BMJ.

Previous studies have reported contradictory results regarding testosterone use and VTE.

Researchers involved in the current study believe that failure to investigate the timing and duration of testosterone use may explain the conflicting findings.

For this study, David Handelsman, MBBS, PhD, of the University of Sydney in New South Wales, Australia, and his colleagues set out to determine the risk of VTE associated with use of testosterone treatment in men, focusing particularly on the timing of the risk.

The study involved data from 19,215 patients with confirmed VTE and 909,530 age-matched controls registered with the UK Clinical Practice Research Database between January 2001 and May 2013.

The researchers divided subjects into 3 mutually exclusive testosterone exposure groups: current treatment, recent treatment, and no treatment in the previous 2 years. The “current treatment” group was subdivided into durations of more or less than 6 months.

After adjusting for confounding factors, the researchers estimated rates of VTE.

The adjusted rate ratio of VTE was 1.25 for current testosterone treatment as compared to no testosterone treatment.

In the first 6 months of treatment, the rate ratio of VTE was 1.63, which corresponded to 10 additional cases of VTE above the base rate of 15.8 per 10,000 person-years.

The risk of VTE declined after more than 6 months of treatment and after treatment stopped. The rate ratio after more than 6 months of treatment was 1.00. After treatment stopped, the rate ratio was 0.68.

The researchers noted that this is an observational study, so no firm conclusions can be drawn about cause and effect. The team also stressed that the increased risks observed are temporary and still relatively low in absolute terms.

Nevertheless, they said their study suggests “a transient increase in the risk of venous thromboembolism that peaks during the first 3 to 6 months and declines gradually thereafter.”

The team said additional research is needed to confirm the temporal increase in the risk of VTE they observed as well as the absence of risk with long-term testosterone use.

Testosterone cypionate

(Depo-Testosterone)

Starting testosterone treatment is associated with an increased risk of venous thromboembolism (VTE) that peaks within 6 months and declines thereafter, according to research published in The BMJ.

Previous studies have reported contradictory results regarding testosterone use and VTE.

Researchers involved in the current study believe that failure to investigate the timing and duration of testosterone use may explain the conflicting findings.

For this study, David Handelsman, MBBS, PhD, of the University of Sydney in New South Wales, Australia, and his colleagues set out to determine the risk of VTE associated with use of testosterone treatment in men, focusing particularly on the timing of the risk.

The study involved data from 19,215 patients with confirmed VTE and 909,530 age-matched controls registered with the UK Clinical Practice Research Database between January 2001 and May 2013.

The researchers divided subjects into 3 mutually exclusive testosterone exposure groups: current treatment, recent treatment, and no treatment in the previous 2 years. The “current treatment” group was subdivided into durations of more or less than 6 months.

After adjusting for confounding factors, the researchers estimated rates of VTE.

The adjusted rate ratio of VTE was 1.25 for current testosterone treatment as compared to no testosterone treatment.

In the first 6 months of treatment, the rate ratio of VTE was 1.63, which corresponded to 10 additional cases of VTE above the base rate of 15.8 per 10,000 person-years.

The risk of VTE declined after more than 6 months of treatment and after treatment stopped. The rate ratio after more than 6 months of treatment was 1.00. After treatment stopped, the rate ratio was 0.68.

The researchers noted that this is an observational study, so no firm conclusions can be drawn about cause and effect. The team also stressed that the increased risks observed are temporary and still relatively low in absolute terms.

Nevertheless, they said their study suggests “a transient increase in the risk of venous thromboembolism that peaks during the first 3 to 6 months and declines gradually thereafter.”

The team said additional research is needed to confirm the temporal increase in the risk of VTE they observed as well as the absence of risk with long-term testosterone use.

A sickled red blood cell

beside a normal one

Image by Betty Pace

The European Commission (EC) has designated GBT440 as an orphan medicinal product for the treatment of sickle cell disease (SCD).

GBT440 is being developed as a potentially disease-modifying therapy for SCD. The drug works by increasing hemoglobin’s affinity for oxygen.

Since oxygenated sickle hemoglobin does not polymerize, it is believed that GBT440 blocks polymerization and the resultant sickling of red blood cells.

If GBT440 can restore normal hemoglobin function and improve oxygen delivery, the drug may be capable of modifying the progression of SCD.

Preclinical research published in the British Journal of Haematology earlier this year suggests that GBT440 is disease-modifying.

Early results from an ongoing phase 1/2 study of GBT440, which were presented at the 2015 ASH Annual Meeting, appeared promising as well.

Results from that study suggest that GBT440 can increase hemoglobin levels while decreasing reticulocyte counts, erythropoietin levels, and sickle cell counts.

Researchers also found the drug to be well tolerated, with no serious adverse events attributed to GBT440.

“Receiving orphan designation from the EC marks a significant milestone both for the SCD community and for GBT [Global Blood Therapeutics Inc.],” said Ted W. Love, MD, president and chief executive officer of Global Blood Therapeutics Inc., the company developing GBT440.

“SCD is a devastatingly severe disease with limited treatment options, and this designation, together with our fast track and orphan drug designations by the United States Food and Drug Administration, reflect the recognition of the broader regulatory community of this urgent unmet medical need.”

The EC grants orphan designation to therapies intended to treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

Orphan designation provides the company developing a drug with regulatory and financial incentives, including protocol assistance, 10 years of market exclusivity once the drug is approved, and reductions in, or exemptions from, fees.

A sickled red blood cell

beside a normal one

Image by Betty Pace

The European Commission (EC) has designated GBT440 as an orphan medicinal product for the treatment of sickle cell disease (SCD).

GBT440 is being developed as a potentially disease-modifying therapy for SCD. The drug works by increasing hemoglobin’s affinity for oxygen.

Since oxygenated sickle hemoglobin does not polymerize, it is believed that GBT440 blocks polymerization and the resultant sickling of red blood cells.

If GBT440 can restore normal hemoglobin function and improve oxygen delivery, the drug may be capable of modifying the progression of SCD.

Preclinical research published in the British Journal of Haematology earlier this year suggests that GBT440 is disease-modifying.

Early results from an ongoing phase 1/2 study of GBT440, which were presented at the 2015 ASH Annual Meeting, appeared promising as well.

Results from that study suggest that GBT440 can increase hemoglobin levels while decreasing reticulocyte counts, erythropoietin levels, and sickle cell counts.

Researchers also found the drug to be well tolerated, with no serious adverse events attributed to GBT440.

“Receiving orphan designation from the EC marks a significant milestone both for the SCD community and for GBT [Global Blood Therapeutics Inc.],” said Ted W. Love, MD, president and chief executive officer of Global Blood Therapeutics Inc., the company developing GBT440.

“SCD is a devastatingly severe disease with limited treatment options, and this designation, together with our fast track and orphan drug designations by the United States Food and Drug Administration, reflect the recognition of the broader regulatory community of this urgent unmet medical need.”

The EC grants orphan designation to therapies intended to treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

Orphan designation provides the company developing a drug with regulatory and financial incentives, including protocol assistance, 10 years of market exclusivity once the drug is approved, and reductions in, or exemptions from, fees.

A sickled red blood cell

beside a normal one

Image by Betty Pace

The European Commission (EC) has designated GBT440 as an orphan medicinal product for the treatment of sickle cell disease (SCD).

GBT440 is being developed as a potentially disease-modifying therapy for SCD. The drug works by increasing hemoglobin’s affinity for oxygen.

Since oxygenated sickle hemoglobin does not polymerize, it is believed that GBT440 blocks polymerization and the resultant sickling of red blood cells.

If GBT440 can restore normal hemoglobin function and improve oxygen delivery, the drug may be capable of modifying the progression of SCD.

Preclinical research published in the British Journal of Haematology earlier this year suggests that GBT440 is disease-modifying.

Early results from an ongoing phase 1/2 study of GBT440, which were presented at the 2015 ASH Annual Meeting, appeared promising as well.

Results from that study suggest that GBT440 can increase hemoglobin levels while decreasing reticulocyte counts, erythropoietin levels, and sickle cell counts.

Researchers also found the drug to be well tolerated, with no serious adverse events attributed to GBT440.

“Receiving orphan designation from the EC marks a significant milestone both for the SCD community and for GBT [Global Blood Therapeutics Inc.],” said Ted W. Love, MD, president and chief executive officer of Global Blood Therapeutics Inc., the company developing GBT440.

“SCD is a devastatingly severe disease with limited treatment options, and this designation, together with our fast track and orphan drug designations by the United States Food and Drug Administration, reflect the recognition of the broader regulatory community of this urgent unmet medical need.”

The EC grants orphan designation to therapies intended to treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

Orphan designation provides the company developing a drug with regulatory and financial incentives, including protocol assistance, 10 years of market exclusivity once the drug is approved, and reductions in, or exemptions from, fees.

Pomalidomide (Pomalyst)

Photo from Business Wire

The National Institute for Health and Care Excellence (NICE) has issued a final appraisal determination recommending that pomalidomide be made available through the National Health Service (NHS).

NICE is recommending pomalidomide be available for use in combination with low-dose dexamethasone to treat adults with multiple myeloma who have received at least 3 previous treatments, including lenalidomide and bortezomib.

NICE previously evaluated pomalidomide in 2015 and said it could not recommend the drug, as analyses suggested pomalidomide doesn’t provide enough benefit to justify its high price.

Since that time, a committee advising NICE has reviewed additional data on pomalidomide.

And Celgene, the company that makes pomalidomide, has agreed to provide the NHS with a discount.

The cost of pomalidomide is £8884 per 21-tablet pack (excluding tax). The average cost of a course of treatment is £44,420 (excluding tax).

The discount Celgene will provide to the NHS is confidential.

NICE’s final appraisal determination on pomalidomide is now with consultees who have the opportunity to appeal against it. If there is no appeal, or an appeal is not upheld, the final appraisal determination is issued by NICE as a guidance.

The final guidance is expected in January 2017. Once NICE issues a final guidance on pomalidomide, the NHS must make the drug available within 3 months.

Pomalidomide (Pomalyst)

Photo from Business Wire

The National Institute for Health and Care Excellence (NICE) has issued a final appraisal determination recommending that pomalidomide be made available through the National Health Service (NHS).

NICE is recommending pomalidomide be available for use in combination with low-dose dexamethasone to treat adults with multiple myeloma who have received at least 3 previous treatments, including lenalidomide and bortezomib.

NICE previously evaluated pomalidomide in 2015 and said it could not recommend the drug, as analyses suggested pomalidomide doesn’t provide enough benefit to justify its high price.

Since that time, a committee advising NICE has reviewed additional data on pomalidomide.

And Celgene, the company that makes pomalidomide, has agreed to provide the NHS with a discount.

The cost of pomalidomide is £8884 per 21-tablet pack (excluding tax). The average cost of a course of treatment is £44,420 (excluding tax).

The discount Celgene will provide to the NHS is confidential.

NICE’s final appraisal determination on pomalidomide is now with consultees who have the opportunity to appeal against it. If there is no appeal, or an appeal is not upheld, the final appraisal determination is issued by NICE as a guidance.

The final guidance is expected in January 2017. Once NICE issues a final guidance on pomalidomide, the NHS must make the drug available within 3 months.

Pomalidomide (Pomalyst)

Photo from Business Wire

The National Institute for Health and Care Excellence (NICE) has issued a final appraisal determination recommending that pomalidomide be made available through the National Health Service (NHS).

NICE is recommending pomalidomide be available for use in combination with low-dose dexamethasone to treat adults with multiple myeloma who have received at least 3 previous treatments, including lenalidomide and bortezomib.

NICE previously evaluated pomalidomide in 2015 and said it could not recommend the drug, as analyses suggested pomalidomide doesn’t provide enough benefit to justify its high price.

Since that time, a committee advising NICE has reviewed additional data on pomalidomide.

And Celgene, the company that makes pomalidomide, has agreed to provide the NHS with a discount.

The cost of pomalidomide is £8884 per 21-tablet pack (excluding tax). The average cost of a course of treatment is £44,420 (excluding tax).

The discount Celgene will provide to the NHS is confidential.

NICE’s final appraisal determination on pomalidomide is now with consultees who have the opportunity to appeal against it. If there is no appeal, or an appeal is not upheld, the final appraisal determination is issued by NICE as a guidance.

The final guidance is expected in January 2017. Once NICE issues a final guidance on pomalidomide, the NHS must make the drug available within 3 months.

Ibrutinib (Imbruvica)

Photo courtesy of Janssen

The National Institute for Health and Care Excellence (NICE) has issued a final appraisal determination recommending that ibrutinib come off the Cancer Drugs Fund (CDF) and be made available through the National Health Service (NHS).

Ibrutinib is a Bruton’s tyrosine kinase inhibitor approved by the European Commission treat patients with chronic lymphocytic leukemia (CLL).

NICE is recommending that ibrutinib be made available through the NHS for previously treated CLL patients and untreated CLL patients who have 17p deletion or TP53 mutation.

This means patients will no longer have to apply to the CDF to obtain ibrutinib. The CDF is money the English government sets aside to pay for cancer drugs that haven’t been approved by NICE and aren’t available within the NHS.

Though certain NICE products and services are provided to Wales, Scotland, and Northern Ireland, the governments of these countries do not have a CDF

or similar program.

Following the decision to reform the CDF earlier this year, NICE began to reappraise all drugs in the CDF in April.

New recommendation

NICE previously said it could not recommend ibrutinib for routine NHS use. However, Janssen, the company that makes ibrutinib, agreed to reduce the

price of the drug for the NHS. Because of the discount, an independent appraisal committee was able to deem ibrutinib cost-effective.

The list price for a single tablet of ibrutinib (140 mg) is £51.10 (excluding tax). The cost of a year’s course of ibrutinib treatment is £55,954.50 (excluding tax).

The discount the NHS will receive is confidential. The Department of Health said the cost of ibrutinib will not constitute an excessive administrative burden on the NHS.

NICE’s final appraisal determination on ibrutinib is now with consultees who have the opportunity to appeal against it. If there is no appeal, or an appeal is not upheld, the final appraisal determination is issued by NICE as a guidance.

Once NICE issues a final guidance on ibrutinib, the NHS must make the drug available within 3 months.

Ibrutinib (Imbruvica)

Photo courtesy of Janssen

The National Institute for Health and Care Excellence (NICE) has issued a final appraisal determination recommending that ibrutinib come off the Cancer Drugs Fund (CDF) and be made available through the National Health Service (NHS).

Ibrutinib is a Bruton’s tyrosine kinase inhibitor approved by the European Commission treat patients with chronic lymphocytic leukemia (CLL).

NICE is recommending that ibrutinib be made available through the NHS for previously treated CLL patients and untreated CLL patients who have 17p deletion or TP53 mutation.

This means patients will no longer have to apply to the CDF to obtain ibrutinib. The CDF is money the English government sets aside to pay for cancer drugs that haven’t been approved by NICE and aren’t available within the NHS.

Though certain NICE products and services are provided to Wales, Scotland, and Northern Ireland, the governments of these countries do not have a CDF

or similar program.

Following the decision to reform the CDF earlier this year, NICE began to reappraise all drugs in the CDF in April.

New recommendation

NICE previously said it could not recommend ibrutinib for routine NHS use. However, Janssen, the company that makes ibrutinib, agreed to reduce the

price of the drug for the NHS. Because of the discount, an independent appraisal committee was able to deem ibrutinib cost-effective.

The list price for a single tablet of ibrutinib (140 mg) is £51.10 (excluding tax). The cost of a year’s course of ibrutinib treatment is £55,954.50 (excluding tax).

The discount the NHS will receive is confidential. The Department of Health said the cost of ibrutinib will not constitute an excessive administrative burden on the NHS.

NICE’s final appraisal determination on ibrutinib is now with consultees who have the opportunity to appeal against it. If there is no appeal, or an appeal is not upheld, the final appraisal determination is issued by NICE as a guidance.

Once NICE issues a final guidance on ibrutinib, the NHS must make the drug available within 3 months.

Ibrutinib (Imbruvica)

Photo courtesy of Janssen

The National Institute for Health and Care Excellence (NICE) has issued a final appraisal determination recommending that ibrutinib come off the Cancer Drugs Fund (CDF) and be made available through the National Health Service (NHS).

Ibrutinib is a Bruton’s tyrosine kinase inhibitor approved by the European Commission treat patients with chronic lymphocytic leukemia (CLL).

NICE is recommending that ibrutinib be made available through the NHS for previously treated CLL patients and untreated CLL patients who have 17p deletion or TP53 mutation.

This means patients will no longer have to apply to the CDF to obtain ibrutinib. The CDF is money the English government sets aside to pay for cancer drugs that haven’t been approved by NICE and aren’t available within the NHS.

Though certain NICE products and services are provided to Wales, Scotland, and Northern Ireland, the governments of these countries do not have a CDF

or similar program.

Following the decision to reform the CDF earlier this year, NICE began to reappraise all drugs in the CDF in April.

New recommendation

NICE previously said it could not recommend ibrutinib for routine NHS use. However, Janssen, the company that makes ibrutinib, agreed to reduce the

price of the drug for the NHS. Because of the discount, an independent appraisal committee was able to deem ibrutinib cost-effective.

The list price for a single tablet of ibrutinib (140 mg) is £51.10 (excluding tax). The cost of a year’s course of ibrutinib treatment is £55,954.50 (excluding tax).

The discount the NHS will receive is confidential. The Department of Health said the cost of ibrutinib will not constitute an excessive administrative burden on the NHS.

NICE’s final appraisal determination on ibrutinib is now with consultees who have the opportunity to appeal against it. If there is no appeal, or an appeal is not upheld, the final appraisal determination is issued by NICE as a guidance.

Once NICE issues a final guidance on ibrutinib, the NHS must make the drug available within 3 months.

Prescription medications

Photo courtesy of the CDC

Researchers say they have developed biodegradable hydrophilic carriers that could provide oral delivery of factor IX (FIX) to treat hemophilia B.

Preclinical experiments have shown these carriers can be loaded with FIX and release it in response to environmental

stimuli.

Sarena Horava, PhD, of Triton Systems, Inc. in Chelmsford, Massachusetts, and her colleagues described the carriers in the International Journal of Pharmaceutics.

The current work builds on a previous delivery system devised by Dr Horova and Nicholas A. Peppas, ScD, of The University of Texas at Austin.

Although that system was successful in transporting FIX, the researchers found that modifications were needed to improve the oral bioavailability of FIX.

The team noted that FIX is delicate and unstable in the body’s various pH environments. So the new system is designed to capitalize on the body’s pH and changes in enzymes inside the gastrointestinal tract.

Specifically, the researchers developed a biodegradable, pH-responsive hydrogel microcarrier system based on the poly(methacrylic acid)-grafted-poly(ethylene glycol) [P(MAA-g-EG)].

The team said the incorporation of an enzymatically degradable peptide crosslinking agent allows for site-specific degradation by trypsin in the small intestine.

The carrier is designed to remain intact as it moves through the body. Once it reaches the small intestine, the carrier should begin to swell with the increase in pH. The carrier should then be degraded by trypsin and slowly release FIX over time.

The researchers said their experiments confirmed that the peptide crosslinked P(MAA-g-EG) microparticles are capable of loading FIX and releasing it under intestinal conditions.

They said the biodegradable component allowed for increased levels of FIX to be released, when compared to the previous system.

Furthermore, both the microparticles and the degradation products enhanced the in vitro absorption of FIX.

“Based on the current capabilities of this system, approximately 2 capsules would be equivalent to 1 injection [of FIX],” Dr Horava said. “However, we anticipate that we will make further improvements to the delivery capacity of the oral delivery system and therefore decrease the capsule amount.”

The researchers plan to conduct additional preclinical experiments with this system before starting clinical trials.

Prescription medications

Photo courtesy of the CDC

Researchers say they have developed biodegradable hydrophilic carriers that could provide oral delivery of factor IX (FIX) to treat hemophilia B.

Preclinical experiments have shown these carriers can be loaded with FIX and release it in response to environmental

stimuli.

Sarena Horava, PhD, of Triton Systems, Inc. in Chelmsford, Massachusetts, and her colleagues described the carriers in the International Journal of Pharmaceutics.

The current work builds on a previous delivery system devised by Dr Horova and Nicholas A. Peppas, ScD, of The University of Texas at Austin.

Although that system was successful in transporting FIX, the researchers found that modifications were needed to improve the oral bioavailability of FIX.

The team noted that FIX is delicate and unstable in the body’s various pH environments. So the new system is designed to capitalize on the body’s pH and changes in enzymes inside the gastrointestinal tract.

Specifically, the researchers developed a biodegradable, pH-responsive hydrogel microcarrier system based on the poly(methacrylic acid)-grafted-poly(ethylene glycol) [P(MAA-g-EG)].

The team said the incorporation of an enzymatically degradable peptide crosslinking agent allows for site-specific degradation by trypsin in the small intestine.

The carrier is designed to remain intact as it moves through the body. Once it reaches the small intestine, the carrier should begin to swell with the increase in pH. The carrier should then be degraded by trypsin and slowly release FIX over time.

The researchers said their experiments confirmed that the peptide crosslinked P(MAA-g-EG) microparticles are capable of loading FIX and releasing it under intestinal conditions.

They said the biodegradable component allowed for increased levels of FIX to be released, when compared to the previous system.

Furthermore, both the microparticles and the degradation products enhanced the in vitro absorption of FIX.

“Based on the current capabilities of this system, approximately 2 capsules would be equivalent to 1 injection [of FIX],” Dr Horava said. “However, we anticipate that we will make further improvements to the delivery capacity of the oral delivery system and therefore decrease the capsule amount.”

The researchers plan to conduct additional preclinical experiments with this system before starting clinical trials.

Prescription medications

Photo courtesy of the CDC

Researchers say they have developed biodegradable hydrophilic carriers that could provide oral delivery of factor IX (FIX) to treat hemophilia B.

Preclinical experiments have shown these carriers can be loaded with FIX and release it in response to environmental

stimuli.

Sarena Horava, PhD, of Triton Systems, Inc. in Chelmsford, Massachusetts, and her colleagues described the carriers in the International Journal of Pharmaceutics.

The current work builds on a previous delivery system devised by Dr Horova and Nicholas A. Peppas, ScD, of The University of Texas at Austin.

Although that system was successful in transporting FIX, the researchers found that modifications were needed to improve the oral bioavailability of FIX.

The team noted that FIX is delicate and unstable in the body’s various pH environments. So the new system is designed to capitalize on the body’s pH and changes in enzymes inside the gastrointestinal tract.

Specifically, the researchers developed a biodegradable, pH-responsive hydrogel microcarrier system based on the poly(methacrylic acid)-grafted-poly(ethylene glycol) [P(MAA-g-EG)].

The team said the incorporation of an enzymatically degradable peptide crosslinking agent allows for site-specific degradation by trypsin in the small intestine.

The carrier is designed to remain intact as it moves through the body. Once it reaches the small intestine, the carrier should begin to swell with the increase in pH. The carrier should then be degraded by trypsin and slowly release FIX over time.

The researchers said their experiments confirmed that the peptide crosslinked P(MAA-g-EG) microparticles are capable of loading FIX and releasing it under intestinal conditions.

They said the biodegradable component allowed for increased levels of FIX to be released, when compared to the previous system.

Furthermore, both the microparticles and the degradation products enhanced the in vitro absorption of FIX.

“Based on the current capabilities of this system, approximately 2 capsules would be equivalent to 1 injection [of FIX],” Dr Horava said. “However, we anticipate that we will make further improvements to the delivery capacity of the oral delivery system and therefore decrease the capsule amount.”

The researchers plan to conduct additional preclinical experiments with this system before starting clinical trials.

Ponatinib (Iclusig)

Photo from Business Wire

The US Food and Drug Administration (FDA) has granted full approval for the kinase inhibitor ponatinib (Iclusig®) and updated the drug’s label.

Ponatinib now has full approval as a treatment for adults with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) when no other tyrosine kinase inhibitor is indicated.

Ponatinib is also approved to treat adults with T315I-positive CML or T315I-positive Ph+ ALL.

Ponatinib was initially approved in December 2012 under the FDA’s accelerated approval program.

This program allows the FDA to approve a drug to treat a serious or life-threatening disease based on clinical data showing the drug has an effect on a surrogate endpoint reasonably likely to predict clinical benefit to patients.

The company developing the drug must conduct post-approval research to determine if the drug provides a clinical benefit. If so, the drug can be granted full approval.

The full approval and label update for ponatinib is based on 48-month follow-up data (as of August 2015) from the phase 2 PACE trial, which enrolled heavily pretreated patients with resistant or intolerant CML or Ph+ ALL. These data were presented at the 2016 ASCO Annual Meeting.

“The longer follow up of the PACE study confirms the clinical benefit of ponatinib in this setting,” said Jorge Cortes, MD, a professor at The University of Texas MD Anderson Cancer Center in Houston and a leading investigator in the PACE trial.

“We had learned from the initial report of the high response rate with ponatinib among CML patients with resistance or intolerance to prior therapies. The 4-year follow-up and updated safety profile demonstrate durability of responses in this heavily pretreated population. These results solidify ponatinib as an important and valuable treatment option for refractory patients with CML where no other TKI therapy is appropriate, including those who have the T315I mutation.”

Past problems with ponatinib

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

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

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

Ponatinib (Iclusig)

Photo from Business Wire

The US Food and Drug Administration (FDA) has granted full approval for the kinase inhibitor ponatinib (Iclusig®) and updated the drug’s label.

Ponatinib now has full approval as a treatment for adults with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) when no other tyrosine kinase inhibitor is indicated.

Ponatinib is also approved to treat adults with T315I-positive CML or T315I-positive Ph+ ALL.

Ponatinib was initially approved in December 2012 under the FDA’s accelerated approval program.

This program allows the FDA to approve a drug to treat a serious or life-threatening disease based on clinical data showing the drug has an effect on a surrogate endpoint reasonably likely to predict clinical benefit to patients.

The company developing the drug must conduct post-approval research to determine if the drug provides a clinical benefit. If so, the drug can be granted full approval.

The full approval and label update for ponatinib is based on 48-month follow-up data (as of August 2015) from the phase 2 PACE trial, which enrolled heavily pretreated patients with resistant or intolerant CML or Ph+ ALL. These data were presented at the 2016 ASCO Annual Meeting.

“The longer follow up of the PACE study confirms the clinical benefit of ponatinib in this setting,” said Jorge Cortes, MD, a professor at The University of Texas MD Anderson Cancer Center in Houston and a leading investigator in the PACE trial.

“We had learned from the initial report of the high response rate with ponatinib among CML patients with resistance or intolerance to prior therapies. The 4-year follow-up and updated safety profile demonstrate durability of responses in this heavily pretreated population. These results solidify ponatinib as an important and valuable treatment option for refractory patients with CML where no other TKI therapy is appropriate, including those who have the T315I mutation.”

Past problems with ponatinib

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

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

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

Ponatinib (Iclusig)

Photo from Business Wire

The US Food and Drug Administration (FDA) has granted full approval for the kinase inhibitor ponatinib (Iclusig®) and updated the drug’s label.

Ponatinib now has full approval as a treatment for adults with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) when no other tyrosine kinase inhibitor is indicated.

Ponatinib is also approved to treat adults with T315I-positive CML or T315I-positive Ph+ ALL.

Ponatinib was initially approved in December 2012 under the FDA’s accelerated approval program.

This program allows the FDA to approve a drug to treat a serious or life-threatening disease based on clinical data showing the drug has an effect on a surrogate endpoint reasonably likely to predict clinical benefit to patients.

The company developing the drug must conduct post-approval research to determine if the drug provides a clinical benefit. If so, the drug can be granted full approval.

The full approval and label update for ponatinib is based on 48-month follow-up data (as of August 2015) from the phase 2 PACE trial, which enrolled heavily pretreated patients with resistant or intolerant CML or Ph+ ALL. These data were presented at the 2016 ASCO Annual Meeting.

“The longer follow up of the PACE study confirms the clinical benefit of ponatinib in this setting,” said Jorge Cortes, MD, a professor at The University of Texas MD Anderson Cancer Center in Houston and a leading investigator in the PACE trial.

“We had learned from the initial report of the high response rate with ponatinib among CML patients with resistance or intolerance to prior therapies. The 4-year follow-up and updated safety profile demonstrate durability of responses in this heavily pretreated population. These results solidify ponatinib as an important and valuable treatment option for refractory patients with CML where no other TKI therapy is appropriate, including those who have the T315I mutation.”

Past problems with ponatinib

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

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

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

Micrograph showing MM

The European Commission (EC) has granted conditional marketing authorization for ixazomib (Ninlaro^TM) to be used in combination with lenalidomide and dexamethasone to treat adults with multiple myeloma (MM) who have received at least 1 prior therapy.

This decision makes ixazomib the first oral proteasome inhibitor approved to treat MM in the European Economic Area.

“With the approval of Ninlaro by the European Commission, physicians across the region will have the option to prescribe an all-oral triplet regimen to treat patients with multiple myeloma who have received at least 1 prior therapy,” said Philippe Moreau, MD, of the University Hospital of Nantes in France.

Conditional marketing authorization represents an expedited path for approval. The EC grants this type of authorization before pivotal registration studies are completed.

Conditional marketing authorization is granted to products whose benefits are thought to outweigh their risks, products that address unmet needs, and products that are expected to provide a significant public health benefit.

The conditional authorization for ixazomib means the company developing the drug, Takeda Pharmaceutical Company Limited, is required to provide post-approval updates on safety and efficacy analyses from ongoing studies to demonstrate the long-term effects of ixazomib.

Phase 3 trial

The EC’s decision to grant ixazomib conditional marketing authorization is based on results from the phase 3 TOURMALINE-MM1 trial, which were presented at the 2015 ASH Annual Meeting.

The trial included 722 patients with relapsed or refractory MM. The patients were randomized to receive ixazomib, lenalidomide, and dexamethasone (IRd, n=360) or placebo, lenalidomide, and dexamethasone (Rd, n=362).

Baseline patient characteristics were similar between the treatment arms. Fifty-nine percent of patients in both arms had received 1 prior line of therapy, and 41% in both arms had 2 or 3 prior lines of therapy.

Seventy-eight percent of patients responded to IRd, and 72% responded to Rd (P=0.035). The rates of complete response were 12% and 7%, respectively (P=0.019).

At a median follow-up of about 15 months, the median progression-free survival was 20.6 months in the IRd arm and 14.7 months in the Rd arm. The hazard ratio was 0.742 (P=0.012).

At a median follow-up of about 23 months, the median overall survival had not been reached in either treatment arm. Follow-up analyses for overall survival are planned for 2017.

The incidence of adverse events (AEs) was 98% in the IRd arm and 99% in the Rd arm. The incidence of grade 3 or higher AEs was 74% and 69%, respectively. The incidence of serious AEs was 47% and 49%, respectively.

Common AEs in the IRd and Rd arms, respectively, were diarrhea (45% vs 39%), constipation (35% vs 26%), nausea (29% vs 22%), vomiting (23% vs 12%), rash (36% vs 23%), back pain (24% vs 17%), upper respiratory tract infection (23% vs 19%), thrombocytopenia (31% vs 16%), peripheral neuropathy (27% vs 22%), peripheral edema (28% vs 20%), thromboembolism (8% vs 11%), and neutropenia (33% vs 31%).

Micrograph showing MM

The European Commission (EC) has granted conditional marketing authorization for ixazomib (Ninlaro^TM) to be used in combination with lenalidomide and dexamethasone to treat adults with multiple myeloma (MM) who have received at least 1 prior therapy.

This decision makes ixazomib the first oral proteasome inhibitor approved to treat MM in the European Economic Area.

“With the approval of Ninlaro by the European Commission, physicians across the region will have the option to prescribe an all-oral triplet regimen to treat patients with multiple myeloma who have received at least 1 prior therapy,” said Philippe Moreau, MD, of the University Hospital of Nantes in France.

Conditional marketing authorization represents an expedited path for approval. The EC grants this type of authorization before pivotal registration studies are completed.

Conditional marketing authorization is granted to products whose benefits are thought to outweigh their risks, products that address unmet needs, and products that are expected to provide a significant public health benefit.

The conditional authorization for ixazomib means the company developing the drug, Takeda Pharmaceutical Company Limited, is required to provide post-approval updates on safety and efficacy analyses from ongoing studies to demonstrate the long-term effects of ixazomib.

Phase 3 trial

The EC’s decision to grant ixazomib conditional marketing authorization is based on results from the phase 3 TOURMALINE-MM1 trial, which were presented at the 2015 ASH Annual Meeting.

The trial included 722 patients with relapsed or refractory MM. The patients were randomized to receive ixazomib, lenalidomide, and dexamethasone (IRd, n=360) or placebo, lenalidomide, and dexamethasone (Rd, n=362).

Baseline patient characteristics were similar between the treatment arms. Fifty-nine percent of patients in both arms had received 1 prior line of therapy, and 41% in both arms had 2 or 3 prior lines of therapy.

Seventy-eight percent of patients responded to IRd, and 72% responded to Rd (P=0.035). The rates of complete response were 12% and 7%, respectively (P=0.019).

At a median follow-up of about 15 months, the median progression-free survival was 20.6 months in the IRd arm and 14.7 months in the Rd arm. The hazard ratio was 0.742 (P=0.012).

At a median follow-up of about 23 months, the median overall survival had not been reached in either treatment arm. Follow-up analyses for overall survival are planned for 2017.

The incidence of adverse events (AEs) was 98% in the IRd arm and 99% in the Rd arm. The incidence of grade 3 or higher AEs was 74% and 69%, respectively. The incidence of serious AEs was 47% and 49%, respectively.

Common AEs in the IRd and Rd arms, respectively, were diarrhea (45% vs 39%), constipation (35% vs 26%), nausea (29% vs 22%), vomiting (23% vs 12%), rash (36% vs 23%), back pain (24% vs 17%), upper respiratory tract infection (23% vs 19%), thrombocytopenia (31% vs 16%), peripheral neuropathy (27% vs 22%), peripheral edema (28% vs 20%), thromboembolism (8% vs 11%), and neutropenia (33% vs 31%).

Micrograph showing MM

The European Commission (EC) has granted conditional marketing authorization for ixazomib (Ninlaro^TM) to be used in combination with lenalidomide and dexamethasone to treat adults with multiple myeloma (MM) who have received at least 1 prior therapy.

This decision makes ixazomib the first oral proteasome inhibitor approved to treat MM in the European Economic Area.

“With the approval of Ninlaro by the European Commission, physicians across the region will have the option to prescribe an all-oral triplet regimen to treat patients with multiple myeloma who have received at least 1 prior therapy,” said Philippe Moreau, MD, of the University Hospital of Nantes in France.

Conditional marketing authorization represents an expedited path for approval. The EC grants this type of authorization before pivotal registration studies are completed.

Conditional marketing authorization is granted to products whose benefits are thought to outweigh their risks, products that address unmet needs, and products that are expected to provide a significant public health benefit.

The conditional authorization for ixazomib means the company developing the drug, Takeda Pharmaceutical Company Limited, is required to provide post-approval updates on safety and efficacy analyses from ongoing studies to demonstrate the long-term effects of ixazomib.

Phase 3 trial

The EC’s decision to grant ixazomib conditional marketing authorization is based on results from the phase 3 TOURMALINE-MM1 trial, which were presented at the 2015 ASH Annual Meeting.

The trial included 722 patients with relapsed or refractory MM. The patients were randomized to receive ixazomib, lenalidomide, and dexamethasone (IRd, n=360) or placebo, lenalidomide, and dexamethasone (Rd, n=362).

Baseline patient characteristics were similar between the treatment arms. Fifty-nine percent of patients in both arms had received 1 prior line of therapy, and 41% in both arms had 2 or 3 prior lines of therapy.

Seventy-eight percent of patients responded to IRd, and 72% responded to Rd (P=0.035). The rates of complete response were 12% and 7%, respectively (P=0.019).

At a median follow-up of about 15 months, the median progression-free survival was 20.6 months in the IRd arm and 14.7 months in the Rd arm. The hazard ratio was 0.742 (P=0.012).

At a median follow-up of about 23 months, the median overall survival had not been reached in either treatment arm. Follow-up analyses for overall survival are planned for 2017.

The incidence of adverse events (AEs) was 98% in the IRd arm and 99% in the Rd arm. The incidence of grade 3 or higher AEs was 74% and 69%, respectively. The incidence of serious AEs was 47% and 49%, respectively.

Common AEs in the IRd and Rd arms, respectively, were diarrhea (45% vs 39%), constipation (35% vs 26%), nausea (29% vs 22%), vomiting (23% vs 12%), rash (36% vs 23%), back pain (24% vs 17%), upper respiratory tract infection (23% vs 19%), thrombocytopenia (31% vs 16%), peripheral neuropathy (27% vs 22%), peripheral edema (28% vs 20%), thromboembolism (8% vs 11%), and neutropenia (33% vs 31%).

Cancer patient

receiving chemotherapy

Photo by Rhoda Baer

Patients with TP53-mutated myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) may benefit from treatment with decitabine, according to a study published in NEJM.

All patients in this study who had TP53 mutations responded to decitabine.

Although these responses were not durable, the patients’ median overall survival was similar to that of patients with lower-risk disease who received decitabine.

“The findings need to be validated in a larger trial, but they do suggest that TP53 mutations can reliably predict responses to decitabine, potentially prolonging survival in this ultra-high-risk group of patients and providing a bridge to transplantation in some patients who might not otherwise be candidates,” said study author Timothy J. Ley, MD, of Washington University School of Medicine in St. Louis, Missouri.

For this study, Dr Ley and his colleagues analyzed 116 patients—54 with AML, 36 with relapsed AML, and 26 with MDS.

Eighty-four of the patients were enrolled in a prospective trial and received decitabine at a dose of 20 mg/m²/day for 10 consecutive days in monthly cycles. Thirty-two additional patients received decitabine on different protocols.

To determine whether genetic mutations could be used to predict responses to decitabine, the researchers performed enhanced exome or gene-panel sequencing in 67 of the patients. The team also performed sequencing at multiple time points to evaluate patterns of mutation clearance in 54 patients.

Response

Thirteen percent of patients (n=15) achieved a complete response (CR), 21% (n=24) had a CR with incomplete count recovery, 5% (n=6) had a morphologic CR with hematologic improvement, and 7% (n=8) had a morphologic CR without hematologic improvement.

Eight percent of patients (n=9) had a partial response, 20% (n=23) had stable disease, and 16% (n=19) had progressive disease.

There were 21 patients with TP53 mutations, and all of them achieved bone marrow blast clearance with less than 5% blasts.

Nineteen percent (n=4) had a CR, 43% (n=9) had a CR with incomplete count recovery, 24% (n=5) had morphologic CR with hematologic improvement, and 14% (n=3) had morphologic CR without hematologic improvement.

“What’s really unique here is that all the patients in the study with TP53 mutations had a response to decitabine and achieved an initial remission,” Dr Ley said.

“With standard aggressive chemotherapy, we only see about 20% to 30% of these patients achieving remission, which is the critical first step to have a chance to cure patients with additional therapies.”

Dr Ley and his colleagues also found that patients in this study were likely to respond to decitabine if they were considered “unfavorable risk” based on extensive chromosomal rearrangements. (Many of these patients also had TP53 mutations.)

Indeed, 67% (29/43) of patients with an unfavorable risk had less than 5% blasts after treatment with decitabine, compared with 34% (24/71) of patients with intermediate or favorable risk.

“The challenge with using decitabine has been knowing which patients are most likely to respond,” said study author Amanda Cashen, MD, of Washington University School of Medicine.

“The value of this study is the comprehensive mutational analysis that helps us figure out which patients are likely to benefit. This information opens the door to using decitabine in a more targeted fashion to treat not just older patients, but also younger patients who carry TP53 mutations.”

Survival and next steps

The researchers found that responses to decitabine were usually short-lived. The drug did not provide complete mutation clearance, which led to relapse.

“Remissions with decitabine typically don’t last long, and no one was cured with this drug,” Dr Ley noted. “But patients who responded to decitabine live longer than what you would expect with aggressive chemotherapy, and that can mean something. Some people live a year or 2 and with a good quality of life because the chemotherapy is not too toxic.”

The median overall survival was 11.6 months among patients with unfavorable risk and 10 months among patients with favorable or intermediate risk (P=0.29).

The median overall survival was 12.7 months among patients with TP53 mutations and 15.4 months among patients with wild-type TP53 (P=0.79).

“It’s important to note that patients with an extremely poor prognosis in this relatively small study had the same survival outcomes as patients facing a better prognosis, which is encouraging,” said study author John Welch, MD, PhD, of Washington University School of Medicine.

“We don’t yet understand why patients with TP53 mutations consistently respond to decitabine, and more work is needed to understand that phenomenon. We’re now planning a larger trial to evaluate decitabine in AML patients of all ages who carry TP53 mutations. It’s exciting to think we may have a therapy that has the potential to improve response rates in this group of high-risk patients.”

Cancer patient

receiving chemotherapy

Photo by Rhoda Baer

Patients with TP53-mutated myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) may benefit from treatment with decitabine, according to a study published in NEJM.

All patients in this study who had TP53 mutations responded to decitabine.

Although these responses were not durable, the patients’ median overall survival was similar to that of patients with lower-risk disease who received decitabine.

“The findings need to be validated in a larger trial, but they do suggest that TP53 mutations can reliably predict responses to decitabine, potentially prolonging survival in this ultra-high-risk group of patients and providing a bridge to transplantation in some patients who might not otherwise be candidates,” said study author Timothy J. Ley, MD, of Washington University School of Medicine in St. Louis, Missouri.

For this study, Dr Ley and his colleagues analyzed 116 patients—54 with AML, 36 with relapsed AML, and 26 with MDS.

Eighty-four of the patients were enrolled in a prospective trial and received decitabine at a dose of 20 mg/m²/day for 10 consecutive days in monthly cycles. Thirty-two additional patients received decitabine on different protocols.

To determine whether genetic mutations could be used to predict responses to decitabine, the researchers performed enhanced exome or gene-panel sequencing in 67 of the patients. The team also performed sequencing at multiple time points to evaluate patterns of mutation clearance in 54 patients.

Response

Thirteen percent of patients (n=15) achieved a complete response (CR), 21% (n=24) had a CR with incomplete count recovery, 5% (n=6) had a morphologic CR with hematologic improvement, and 7% (n=8) had a morphologic CR without hematologic improvement.

Eight percent of patients (n=9) had a partial response, 20% (n=23) had stable disease, and 16% (n=19) had progressive disease.

There were 21 patients with TP53 mutations, and all of them achieved bone marrow blast clearance with less than 5% blasts.

Nineteen percent (n=4) had a CR, 43% (n=9) had a CR with incomplete count recovery, 24% (n=5) had morphologic CR with hematologic improvement, and 14% (n=3) had morphologic CR without hematologic improvement.

“What’s really unique here is that all the patients in the study with TP53 mutations had a response to decitabine and achieved an initial remission,” Dr Ley said.

“With standard aggressive chemotherapy, we only see about 20% to 30% of these patients achieving remission, which is the critical first step to have a chance to cure patients with additional therapies.”

Dr Ley and his colleagues also found that patients in this study were likely to respond to decitabine if they were considered “unfavorable risk” based on extensive chromosomal rearrangements. (Many of these patients also had TP53 mutations.)

Indeed, 67% (29/43) of patients with an unfavorable risk had less than 5% blasts after treatment with decitabine, compared with 34% (24/71) of patients with intermediate or favorable risk.

“The challenge with using decitabine has been knowing which patients are most likely to respond,” said study author Amanda Cashen, MD, of Washington University School of Medicine.

“The value of this study is the comprehensive mutational analysis that helps us figure out which patients are likely to benefit. This information opens the door to using decitabine in a more targeted fashion to treat not just older patients, but also younger patients who carry TP53 mutations.”

Survival and next steps

The researchers found that responses to decitabine were usually short-lived. The drug did not provide complete mutation clearance, which led to relapse.

“Remissions with decitabine typically don’t last long, and no one was cured with this drug,” Dr Ley noted. “But patients who responded to decitabine live longer than what you would expect with aggressive chemotherapy, and that can mean something. Some people live a year or 2 and with a good quality of life because the chemotherapy is not too toxic.”

The median overall survival was 11.6 months among patients with unfavorable risk and 10 months among patients with favorable or intermediate risk (P=0.29).

The median overall survival was 12.7 months among patients with TP53 mutations and 15.4 months among patients with wild-type TP53 (P=0.79).

“It’s important to note that patients with an extremely poor prognosis in this relatively small study had the same survival outcomes as patients facing a better prognosis, which is encouraging,” said study author John Welch, MD, PhD, of Washington University School of Medicine.

“We don’t yet understand why patients with TP53 mutations consistently respond to decitabine, and more work is needed to understand that phenomenon. We’re now planning a larger trial to evaluate decitabine in AML patients of all ages who carry TP53 mutations. It’s exciting to think we may have a therapy that has the potential to improve response rates in this group of high-risk patients.”

Cancer patient

receiving chemotherapy

Photo by Rhoda Baer

Patients with TP53-mutated myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) may benefit from treatment with decitabine, according to a study published in NEJM.

All patients in this study who had TP53 mutations responded to decitabine.

Although these responses were not durable, the patients’ median overall survival was similar to that of patients with lower-risk disease who received decitabine.

“The findings need to be validated in a larger trial, but they do suggest that TP53 mutations can reliably predict responses to decitabine, potentially prolonging survival in this ultra-high-risk group of patients and providing a bridge to transplantation in some patients who might not otherwise be candidates,” said study author Timothy J. Ley, MD, of Washington University School of Medicine in St. Louis, Missouri.

For this study, Dr Ley and his colleagues analyzed 116 patients—54 with AML, 36 with relapsed AML, and 26 with MDS.

Eighty-four of the patients were enrolled in a prospective trial and received decitabine at a dose of 20 mg/m²/day for 10 consecutive days in monthly cycles. Thirty-two additional patients received decitabine on different protocols.

To determine whether genetic mutations could be used to predict responses to decitabine, the researchers performed enhanced exome or gene-panel sequencing in 67 of the patients. The team also performed sequencing at multiple time points to evaluate patterns of mutation clearance in 54 patients.

Response

Thirteen percent of patients (n=15) achieved a complete response (CR), 21% (n=24) had a CR with incomplete count recovery, 5% (n=6) had a morphologic CR with hematologic improvement, and 7% (n=8) had a morphologic CR without hematologic improvement.

Eight percent of patients (n=9) had a partial response, 20% (n=23) had stable disease, and 16% (n=19) had progressive disease.

There were 21 patients with TP53 mutations, and all of them achieved bone marrow blast clearance with less than 5% blasts.

Nineteen percent (n=4) had a CR, 43% (n=9) had a CR with incomplete count recovery, 24% (n=5) had morphologic CR with hematologic improvement, and 14% (n=3) had morphologic CR without hematologic improvement.

“What’s really unique here is that all the patients in the study with TP53 mutations had a response to decitabine and achieved an initial remission,” Dr Ley said.

“With standard aggressive chemotherapy, we only see about 20% to 30% of these patients achieving remission, which is the critical first step to have a chance to cure patients with additional therapies.”

Dr Ley and his colleagues also found that patients in this study were likely to respond to decitabine if they were considered “unfavorable risk” based on extensive chromosomal rearrangements. (Many of these patients also had TP53 mutations.)

Indeed, 67% (29/43) of patients with an unfavorable risk had less than 5% blasts after treatment with decitabine, compared with 34% (24/71) of patients with intermediate or favorable risk.

“The challenge with using decitabine has been knowing which patients are most likely to respond,” said study author Amanda Cashen, MD, of Washington University School of Medicine.

“The value of this study is the comprehensive mutational analysis that helps us figure out which patients are likely to benefit. This information opens the door to using decitabine in a more targeted fashion to treat not just older patients, but also younger patients who carry TP53 mutations.”

Survival and next steps

The researchers found that responses to decitabine were usually short-lived. The drug did not provide complete mutation clearance, which led to relapse.

“Remissions with decitabine typically don’t last long, and no one was cured with this drug,” Dr Ley noted. “But patients who responded to decitabine live longer than what you would expect with aggressive chemotherapy, and that can mean something. Some people live a year or 2 and with a good quality of life because the chemotherapy is not too toxic.”

The median overall survival was 11.6 months among patients with unfavorable risk and 10 months among patients with favorable or intermediate risk (P=0.29).

The median overall survival was 12.7 months among patients with TP53 mutations and 15.4 months among patients with wild-type TP53 (P=0.79).

“It’s important to note that patients with an extremely poor prognosis in this relatively small study had the same survival outcomes as patients facing a better prognosis, which is encouraging,” said study author John Welch, MD, PhD, of Washington University School of Medicine.

“We don’t yet understand why patients with TP53 mutations consistently respond to decitabine, and more work is needed to understand that phenomenon. We’re now planning a larger trial to evaluate decitabine in AML patients of all ages who carry TP53 mutations. It’s exciting to think we may have a therapy that has the potential to improve response rates in this group of high-risk patients.”

 

 

Micrograph showing DLBCL

 

The US Food and Drug Administration (FDA) has granted fast track designation for tazemetostat as a treatment for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) with EZH2 activating mutations.

Tazemetostat inhibits EZH2, a histone methyltransferase that appears to play a role in the growth and proliferation of a number of cancers, including DLBCL.

Tazemetostat is being developed by Epizyme, Inc.

The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.

Through the FDA’s fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the biologic license application or new drug application on a rolling basis as data become available.

Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.

Tazemetostat trials

Tazemetostat is under investigation as monotherapy and in combination with other agents as a treatment for multiple cancers.

Results from a phase 1 study suggested tazemetostat monotherapy can produce durable responses in patients with advanced non-Hodgkin lymphomas, including DLBCL. The study was presented at the 2015 ASH Annual Meeting.

Now, Epizyme is conducting a phase 2 study of tazemetostat monotherapy in adults with relapsed or refractory DLBCL or follicular lymphoma.

Tazemetostat is also being evaluated in 2 combination studies in patients with DLBCL.

In a phase 1b/2 trial, researchers are investigating tazemetostat in combination with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) as a front-line treatment for patients with DLBCL.

In a phase 1b study, researchers are evaluating tazemetostat in combination with atezolizumab, an anti-PD-L1 immunotherapy, in patients with relapsed and refractory DLBCL.

 

 

Micrograph showing DLBCL

 

The US Food and Drug Administration (FDA) has granted fast track designation for tazemetostat as a treatment for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) with EZH2 activating mutations.

Tazemetostat inhibits EZH2, a histone methyltransferase that appears to play a role in the growth and proliferation of a number of cancers, including DLBCL.

Tazemetostat is being developed by Epizyme, Inc.

The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.

Through the FDA’s fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the biologic license application or new drug application on a rolling basis as data become available.

Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.

Tazemetostat trials

Tazemetostat is under investigation as monotherapy and in combination with other agents as a treatment for multiple cancers.

Results from a phase 1 study suggested tazemetostat monotherapy can produce durable responses in patients with advanced non-Hodgkin lymphomas, including DLBCL. The study was presented at the 2015 ASH Annual Meeting.

Now, Epizyme is conducting a phase 2 study of tazemetostat monotherapy in adults with relapsed or refractory DLBCL or follicular lymphoma.

Tazemetostat is also being evaluated in 2 combination studies in patients with DLBCL.

In a phase 1b/2 trial, researchers are investigating tazemetostat in combination with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) as a front-line treatment for patients with DLBCL.

In a phase 1b study, researchers are evaluating tazemetostat in combination with atezolizumab, an anti-PD-L1 immunotherapy, in patients with relapsed and refractory DLBCL.

 

 

Micrograph showing DLBCL

 

The US Food and Drug Administration (FDA) has granted fast track designation for tazemetostat as a treatment for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) with EZH2 activating mutations.

Tazemetostat inhibits EZH2, a histone methyltransferase that appears to play a role in the growth and proliferation of a number of cancers, including DLBCL.

Tazemetostat is being developed by Epizyme, Inc.

The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.

Through the FDA’s fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the biologic license application or new drug application on a rolling basis as data become available.

Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.

Tazemetostat trials

Tazemetostat is under investigation as monotherapy and in combination with other agents as a treatment for multiple cancers.

Results from a phase 1 study suggested tazemetostat monotherapy can produce durable responses in patients with advanced non-Hodgkin lymphomas, including DLBCL. The study was presented at the 2015 ASH Annual Meeting.

Now, Epizyme is conducting a phase 2 study of tazemetostat monotherapy in adults with relapsed or refractory DLBCL or follicular lymphoma.

Tazemetostat is also being evaluated in 2 combination studies in patients with DLBCL.

In a phase 1b/2 trial, researchers are investigating tazemetostat in combination with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) as a front-line treatment for patients with DLBCL.

In a phase 1b study, researchers are evaluating tazemetostat in combination with atezolizumab, an anti-PD-L1 immunotherapy, in patients with relapsed and refractory DLBCL.

Emergency department team

caring for a patient

Photo by Tom Watanabe

A new study has revealed which drugs most commonly caused adverse events (AEs) leading to emergency department (ED) visits in the US in 2013 and 2014.

The drug class most often implicated in ED visits was anticoagulants.

Other common drug classes were antibiotics, diabetes agents, and opioid analgesics.

Nadine Shehab, PharmD, of the US Centers for Disease Control and Prevention in Atlanta, Georgia, and her colleagues reported these findings in JAMA.

The researchers examined characteristics of ED visits for drug-related AEs in the US in 2013-2014 and changes in ED visits for drug-related AEs since 2005-2006.

The team analyzed nationally representative data from 58 EDs participating in the National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance project.

Based on data from 42,585 cases, the researchers estimated that 4 ED visits for drug-related AEs occurred per 1000 individuals annually in 2013 and 2014. And 27% of ED visits for drug-related AEs resulted in hospitalization.

Results by drug class

The most commonly implicated drug classes were anticoagulants (18%), antibiotics (16%), diabetes agents (13%), opioid analgesics (7%), antiplatelet agents (7%), renin-angiotensin system inhibitors (4%), antineoplastic agents (3%), and sedative or hypnotic agents (3%).

Four anticoagulants (warfarin, rivaroxaban, dabigatran, and enoxaparin) and 5 diabetes agents (insulin and 4 oral agents) were among the 15 most common drugs implicated.

Results by age

Antibiotics were the most common drug class implicated in ED visits for drug-related AEs among children age 5 or younger (56%) and among children and adolescents ages 6 to 19 (32%).

Drugs not belonging to the most common classes (overall) were most commonly implicated in ED visits for adults ages 20 to 34 (26%), 35 to 49 (26%), and 50 to 64 (23%).

Anticoagulants were the most common drug class implicated in ED visits for adults ages 65 to 79 (28%) and adults age 80 or older (39%).

Changes over time

Since 2005-2006, the proportions of ED visits for drug-related AEs from anticoagulants and diabetes agents have increased, whereas the proportion from antibiotics has decreased.

Population rates of ED visits for drug-related AEs increased from 2005-2006 to 2013-2014 among adults age 65 and older—5.2 visits per 1000 individuals to 9.7 visits per 1000 individuals, respectively.

An increase was also observed for adults ages 50 to 64—2.5 visits per 1000 individuals in 2005-2006, compared to 4.3 visits per 1000 individuals in 2013-2014.

However, the population rates for other age groups were similar for both time periods.

Anticoagulants and antiplatelet agents

Overall, anticoagulants were implicated in 18% of ED visits for drug-related AEs, and 49% of anticoagulant-related AEs led to hospitalization.

Anticoagulant-related ED visits were most commonly related to vitamin K antagonists (15%), followed by factor Xa inhibitors, unfractionated and low-molecular-weight heparins, and oral direct thrombin inhibitors (about 1% each).

Antiplatelet agents were implicated in 7% of ED visits for drug-related AEs, and 44% of antiplatelet agent-related AEs led to hospitalization.

Antiplatelet-related ED visits were most commonly related to platelet P2Y12 receptor antagonists (5%) and aspirin with or without dipyridamole (4%).

Warfarin was implicated in 15% of ED visits for drug-related AEs, clopidogrel and aspirin were each implicated in 4%, and rivaroxaban was implicated in 1%.

Emergency department team

caring for a patient

Photo by Tom Watanabe

A new study has revealed which drugs most commonly caused adverse events (AEs) leading to emergency department (ED) visits in the US in 2013 and 2014.

The drug class most often implicated in ED visits was anticoagulants.

Other common drug classes were antibiotics, diabetes agents, and opioid analgesics.

Nadine Shehab, PharmD, of the US Centers for Disease Control and Prevention in Atlanta, Georgia, and her colleagues reported these findings in JAMA.

The researchers examined characteristics of ED visits for drug-related AEs in the US in 2013-2014 and changes in ED visits for drug-related AEs since 2005-2006.

The team analyzed nationally representative data from 58 EDs participating in the National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance project.

Based on data from 42,585 cases, the researchers estimated that 4 ED visits for drug-related AEs occurred per 1000 individuals annually in 2013 and 2014. And 27% of ED visits for drug-related AEs resulted in hospitalization.

Results by drug class

The most commonly implicated drug classes were anticoagulants (18%), antibiotics (16%), diabetes agents (13%), opioid analgesics (7%), antiplatelet agents (7%), renin-angiotensin system inhibitors (4%), antineoplastic agents (3%), and sedative or hypnotic agents (3%).

Four anticoagulants (warfarin, rivaroxaban, dabigatran, and enoxaparin) and 5 diabetes agents (insulin and 4 oral agents) were among the 15 most common drugs implicated.

Results by age

Antibiotics were the most common drug class implicated in ED visits for drug-related AEs among children age 5 or younger (56%) and among children and adolescents ages 6 to 19 (32%).

Drugs not belonging to the most common classes (overall) were most commonly implicated in ED visits for adults ages 20 to 34 (26%), 35 to 49 (26%), and 50 to 64 (23%).

Anticoagulants were the most common drug class implicated in ED visits for adults ages 65 to 79 (28%) and adults age 80 or older (39%).

Changes over time

Since 2005-2006, the proportions of ED visits for drug-related AEs from anticoagulants and diabetes agents have increased, whereas the proportion from antibiotics has decreased.

Population rates of ED visits for drug-related AEs increased from 2005-2006 to 2013-2014 among adults age 65 and older—5.2 visits per 1000 individuals to 9.7 visits per 1000 individuals, respectively.

An increase was also observed for adults ages 50 to 64—2.5 visits per 1000 individuals in 2005-2006, compared to 4.3 visits per 1000 individuals in 2013-2014.

However, the population rates for other age groups were similar for both time periods.

Anticoagulants and antiplatelet agents

Overall, anticoagulants were implicated in 18% of ED visits for drug-related AEs, and 49% of anticoagulant-related AEs led to hospitalization.

Anticoagulant-related ED visits were most commonly related to vitamin K antagonists (15%), followed by factor Xa inhibitors, unfractionated and low-molecular-weight heparins, and oral direct thrombin inhibitors (about 1% each).

Antiplatelet agents were implicated in 7% of ED visits for drug-related AEs, and 44% of antiplatelet agent-related AEs led to hospitalization.

Antiplatelet-related ED visits were most commonly related to platelet P2Y12 receptor antagonists (5%) and aspirin with or without dipyridamole (4%).

Warfarin was implicated in 15% of ED visits for drug-related AEs, clopidogrel and aspirin were each implicated in 4%, and rivaroxaban was implicated in 1%.

Emergency department team

caring for a patient

Photo by Tom Watanabe

A new study has revealed which drugs most commonly caused adverse events (AEs) leading to emergency department (ED) visits in the US in 2013 and 2014.

The drug class most often implicated in ED visits was anticoagulants.

Other common drug classes were antibiotics, diabetes agents, and opioid analgesics.

Nadine Shehab, PharmD, of the US Centers for Disease Control and Prevention in Atlanta, Georgia, and her colleagues reported these findings in JAMA.

The researchers examined characteristics of ED visits for drug-related AEs in the US in 2013-2014 and changes in ED visits for drug-related AEs since 2005-2006.

The team analyzed nationally representative data from 58 EDs participating in the National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance project.

Based on data from 42,585 cases, the researchers estimated that 4 ED visits for drug-related AEs occurred per 1000 individuals annually in 2013 and 2014. And 27% of ED visits for drug-related AEs resulted in hospitalization.

Results by drug class

The most commonly implicated drug classes were anticoagulants (18%), antibiotics (16%), diabetes agents (13%), opioid analgesics (7%), antiplatelet agents (7%), renin-angiotensin system inhibitors (4%), antineoplastic agents (3%), and sedative or hypnotic agents (3%).

Four anticoagulants (warfarin, rivaroxaban, dabigatran, and enoxaparin) and 5 diabetes agents (insulin and 4 oral agents) were among the 15 most common drugs implicated.

Results by age

Antibiotics were the most common drug class implicated in ED visits for drug-related AEs among children age 5 or younger (56%) and among children and adolescents ages 6 to 19 (32%).

Drugs not belonging to the most common classes (overall) were most commonly implicated in ED visits for adults ages 20 to 34 (26%), 35 to 49 (26%), and 50 to 64 (23%).

Anticoagulants were the most common drug class implicated in ED visits for adults ages 65 to 79 (28%) and adults age 80 or older (39%).

Changes over time

Since 2005-2006, the proportions of ED visits for drug-related AEs from anticoagulants and diabetes agents have increased, whereas the proportion from antibiotics has decreased.

Population rates of ED visits for drug-related AEs increased from 2005-2006 to 2013-2014 among adults age 65 and older—5.2 visits per 1000 individuals to 9.7 visits per 1000 individuals, respectively.

An increase was also observed for adults ages 50 to 64—2.5 visits per 1000 individuals in 2005-2006, compared to 4.3 visits per 1000 individuals in 2013-2014.

However, the population rates for other age groups were similar for both time periods.

Anticoagulants and antiplatelet agents

Overall, anticoagulants were implicated in 18% of ED visits for drug-related AEs, and 49% of anticoagulant-related AEs led to hospitalization.

Anticoagulant-related ED visits were most commonly related to vitamin K antagonists (15%), followed by factor Xa inhibitors, unfractionated and low-molecular-weight heparins, and oral direct thrombin inhibitors (about 1% each).

Antiplatelet agents were implicated in 7% of ED visits for drug-related AEs, and 44% of antiplatelet agent-related AEs led to hospitalization.

Antiplatelet-related ED visits were most commonly related to platelet P2Y12 receptor antagonists (5%) and aspirin with or without dipyridamole (4%).

Warfarin was implicated in 15% of ED visits for drug-related AEs, clopidogrel and aspirin were each implicated in 4%, and rivaroxaban was implicated in 1%.