Pharmacy

Drug production

Photo courtesy of the FDA

Two newly published studies have raised concerns about the drug approval process in the US.

One study showed that, over the past two decades, the US Food and Drug Administration (FDA) has significantly increased its use of expedited development or review programs when approving new drugs.

Investigators said this increase cannot be attributed to an increase in the number of innovative new drug classes.

The other study revealed “wide variations” in evidence supporting the approval of supplemental drug applications.

Aaron S. Kesselheim, MD, of Brigham and Women’s Hospital in Boston, Massachusetts, and his colleagues conducted these studies and reported the results in The BMJ.

Authors of a related editorial wrote that these studies “give cause for concern about whether most new drugs are any more effective than existing products or whether their safety has been adequately assessed.”

Expedited approval

For the first study, the investigators looked at the FDA’s use of expedited development and review programs for drugs newly approved between 1987 and 2014. This included the orphan designation, fast track designation, priority review, and accelerated approval programs.

The FDA approved 774 drugs during the study period, and 33% of these were first-in-class agents. Priority review (43%) was the most-used program, followed by orphan designation (25%), fast track designation (19%), and accelerated approval (9%).

The investigators observed an increase of 2.6% per year in the number of expedited review and approval programs granted to each newly approved drug (P<0.001) and a 2.4% increase in the proportion of drugs associated with at least one of the programs (P=0.009).

The team noted that “this trend is being driven by drugs that are not first in class and thus potentially less innovative.”

They also said that, by the end of the study period, most newly approved drugs were associated with at least one of the programs. The peak was in 2005, when 75% (15/20) of newly approved drugs were associated with at least one program.

Supplemental approval

For the second study, Dr Kesselheim and his colleagues evaluated the quality of evidence underpinning FDA approval of supplemental drug applications (uses beyond a drug’s original indication) between 2005 and 2014.

The team assessed 295 supplemental drug approvals. They found a lack of trials using clinical outcome endpoints, a lack of trials including active comparators, and differences in the evidence according to types of approval.

Thirty percent of drug approvals for new indications were supported by trials with active comparators, as were 51% of modified-use approvals and 11% of approvals expanding the patient population (P<0.001).

Thirty-two percent of drug approvals for new indications were supported by trials using clinical outcome endpoints, as were 30% of modified-use approvals and 22% of expanded-population approvals (P=0.29).

The investigators said these findings “underscore the need for a robust system of post-approval drug monitoring for efficacy and safety, timely confirmatory studies, and re-examination of existing legislative incentives to promote the optimal delivery of evidence-based medicine.”

Drug production

Photo courtesy of the FDA

Two newly published studies have raised concerns about the drug approval process in the US.

One study showed that, over the past two decades, the US Food and Drug Administration (FDA) has significantly increased its use of expedited development or review programs when approving new drugs.

Investigators said this increase cannot be attributed to an increase in the number of innovative new drug classes.

The other study revealed “wide variations” in evidence supporting the approval of supplemental drug applications.

Aaron S. Kesselheim, MD, of Brigham and Women’s Hospital in Boston, Massachusetts, and his colleagues conducted these studies and reported the results in The BMJ.

Authors of a related editorial wrote that these studies “give cause for concern about whether most new drugs are any more effective than existing products or whether their safety has been adequately assessed.”

Expedited approval

For the first study, the investigators looked at the FDA’s use of expedited development and review programs for drugs newly approved between 1987 and 2014. This included the orphan designation, fast track designation, priority review, and accelerated approval programs.

The FDA approved 774 drugs during the study period, and 33% of these were first-in-class agents. Priority review (43%) was the most-used program, followed by orphan designation (25%), fast track designation (19%), and accelerated approval (9%).

The investigators observed an increase of 2.6% per year in the number of expedited review and approval programs granted to each newly approved drug (P<0.001) and a 2.4% increase in the proportion of drugs associated with at least one of the programs (P=0.009).

The team noted that “this trend is being driven by drugs that are not first in class and thus potentially less innovative.”

They also said that, by the end of the study period, most newly approved drugs were associated with at least one of the programs. The peak was in 2005, when 75% (15/20) of newly approved drugs were associated with at least one program.

Supplemental approval

For the second study, Dr Kesselheim and his colleagues evaluated the quality of evidence underpinning FDA approval of supplemental drug applications (uses beyond a drug’s original indication) between 2005 and 2014.

The team assessed 295 supplemental drug approvals. They found a lack of trials using clinical outcome endpoints, a lack of trials including active comparators, and differences in the evidence according to types of approval.

Thirty percent of drug approvals for new indications were supported by trials with active comparators, as were 51% of modified-use approvals and 11% of approvals expanding the patient population (P<0.001).

Thirty-two percent of drug approvals for new indications were supported by trials using clinical outcome endpoints, as were 30% of modified-use approvals and 22% of expanded-population approvals (P=0.29).

The investigators said these findings “underscore the need for a robust system of post-approval drug monitoring for efficacy and safety, timely confirmatory studies, and re-examination of existing legislative incentives to promote the optimal delivery of evidence-based medicine.”

Drug production

Photo courtesy of the FDA

Two newly published studies have raised concerns about the drug approval process in the US.

One study showed that, over the past two decades, the US Food and Drug Administration (FDA) has significantly increased its use of expedited development or review programs when approving new drugs.

Investigators said this increase cannot be attributed to an increase in the number of innovative new drug classes.

The other study revealed “wide variations” in evidence supporting the approval of supplemental drug applications.

Aaron S. Kesselheim, MD, of Brigham and Women’s Hospital in Boston, Massachusetts, and his colleagues conducted these studies and reported the results in The BMJ.

Authors of a related editorial wrote that these studies “give cause for concern about whether most new drugs are any more effective than existing products or whether their safety has been adequately assessed.”

Expedited approval

For the first study, the investigators looked at the FDA’s use of expedited development and review programs for drugs newly approved between 1987 and 2014. This included the orphan designation, fast track designation, priority review, and accelerated approval programs.

The FDA approved 774 drugs during the study period, and 33% of these were first-in-class agents. Priority review (43%) was the most-used program, followed by orphan designation (25%), fast track designation (19%), and accelerated approval (9%).

The investigators observed an increase of 2.6% per year in the number of expedited review and approval programs granted to each newly approved drug (P<0.001) and a 2.4% increase in the proportion of drugs associated with at least one of the programs (P=0.009).

The team noted that “this trend is being driven by drugs that are not first in class and thus potentially less innovative.”

They also said that, by the end of the study period, most newly approved drugs were associated with at least one of the programs. The peak was in 2005, when 75% (15/20) of newly approved drugs were associated with at least one program.

Supplemental approval

For the second study, Dr Kesselheim and his colleagues evaluated the quality of evidence underpinning FDA approval of supplemental drug applications (uses beyond a drug’s original indication) between 2005 and 2014.

The team assessed 295 supplemental drug approvals. They found a lack of trials using clinical outcome endpoints, a lack of trials including active comparators, and differences in the evidence according to types of approval.

Thirty percent of drug approvals for new indications were supported by trials with active comparators, as were 51% of modified-use approvals and 11% of approvals expanding the patient population (P<0.001).

Thirty-two percent of drug approvals for new indications were supported by trials using clinical outcome endpoints, as were 30% of modified-use approvals and 22% of expanded-population approvals (P=0.29).

The investigators said these findings “underscore the need for a robust system of post-approval drug monitoring for efficacy and safety, timely confirmatory studies, and re-examination of existing legislative incentives to promote the optimal delivery of evidence-based medicine.”

Prescription medications

Photo courtesy of the CDC

The UK’s National Institute for Health and Care Excellence (NICE) has issued a final guidance recommending the oral anticoagulant edoxaban tosylate (Lixiana) as an option for preventing stroke and systemic embolism in adults with non-valvular atrial fibrillation (NVAF).

The patients must have one or more risk factors for stroke, including congestive heart failure, hypertension, diabetes, prior stroke or transient ischemic attack, and age of 75 years or older.

In the UK, such patients are generally treated with warfarin or the newer oral anticoagulants dabigatran, rivaroxaban, and apixaban.

NICE decided that edoxaban should be added to that list because data suggest the drug is a clinically and cost-effective treatment option for these patients.

Edoxaban should be available on the National Health Service within 3 months of the date NICE’s final guidance was issued, September 23.

NICE’s guidance says the decision about whether to start treatment with edoxaban should be made after an informed discussion between the clinician and the patient about the risks and benefits of edoxaban compared with warfarin, apixaban, dabigatran, and rivaroxaban.

For patients considering switching from warfarin, edoxaban’s potential benefits should be weighed against its potential risks, taking into account the patient’s level of international normalized ratio control.

Clinical effectiveness

NICE’s conclusion that edoxaban is clinically effective was based primarily on results of the ENGAGE AF-TIMI 48 trial. In this trial, researchers compared edoxaban and warfarin as prophylaxis for stroke or systemic embolism in patients with NVAF.

Results suggested edoxaban was at least non-inferior to warfarin with regard to efficacy, and edoxaban was associated with a significantly lower rate of major and fatal bleeding.

A committee advising NICE also reviewed a meta-analysis prepared by Daiichi Sankyo Co., Ltd., the company developing edoxaban.

The goal of the meta-analysis was to compare edoxaban with rivaroxaban, apixaban, and dabigatran. The analysis included 4 trials: ENGAGE AF-TIMI 48, ARISTOTLE (apixaban), RE-LY (dabigatran), and ROCKET-AF (rivaroxaban). All 4 trials had a warfarin comparator arm.

The results of the meta-analysis indicated that, for the composite endpoint of stroke and systemic embolism, efficacy was similar for high-dose edoxaban and the other new oral anticoagulants.

However, edoxaban significantly reduced major bleeding risk by 24% compared to rivaroxaban, 28% compared to dabigatran at 150 mg, and 17% compared to dabigatran at 110 mg. Major bleeding rates were similar for high-dose edoxaban and apixaban.

The committee advising NICE said these results should be interpreted with caution, but edoxaban is unlikely to be different from rivaroxaban, apixaban, and dabigatran in clinical practice.

Cost-effectiveness

Edoxaban costs £58.80 for a 28-tablet pack (60 mg or 30 mg), and the daily cost of treatment is £2.10 (excluding value-added tax). However, costs may vary in different settings because of negotiated procurement discounts.

The committee advising NICE analyzed cost information and concluded that edoxaban is cost-effective compared with warfarin, but there is insufficient evidence to distinguish between the clinical and cost-effectiveness of edoxaban and the other new oral anticoagulants.

Prescription medications

Photo courtesy of the CDC

The UK’s National Institute for Health and Care Excellence (NICE) has issued a final guidance recommending the oral anticoagulant edoxaban tosylate (Lixiana) as an option for preventing stroke and systemic embolism in adults with non-valvular atrial fibrillation (NVAF).

The patients must have one or more risk factors for stroke, including congestive heart failure, hypertension, diabetes, prior stroke or transient ischemic attack, and age of 75 years or older.

In the UK, such patients are generally treated with warfarin or the newer oral anticoagulants dabigatran, rivaroxaban, and apixaban.

NICE decided that edoxaban should be added to that list because data suggest the drug is a clinically and cost-effective treatment option for these patients.

Edoxaban should be available on the National Health Service within 3 months of the date NICE’s final guidance was issued, September 23.

NICE’s guidance says the decision about whether to start treatment with edoxaban should be made after an informed discussion between the clinician and the patient about the risks and benefits of edoxaban compared with warfarin, apixaban, dabigatran, and rivaroxaban.

For patients considering switching from warfarin, edoxaban’s potential benefits should be weighed against its potential risks, taking into account the patient’s level of international normalized ratio control.

Clinical effectiveness

NICE’s conclusion that edoxaban is clinically effective was based primarily on results of the ENGAGE AF-TIMI 48 trial. In this trial, researchers compared edoxaban and warfarin as prophylaxis for stroke or systemic embolism in patients with NVAF.

Results suggested edoxaban was at least non-inferior to warfarin with regard to efficacy, and edoxaban was associated with a significantly lower rate of major and fatal bleeding.

A committee advising NICE also reviewed a meta-analysis prepared by Daiichi Sankyo Co., Ltd., the company developing edoxaban.

The goal of the meta-analysis was to compare edoxaban with rivaroxaban, apixaban, and dabigatran. The analysis included 4 trials: ENGAGE AF-TIMI 48, ARISTOTLE (apixaban), RE-LY (dabigatran), and ROCKET-AF (rivaroxaban). All 4 trials had a warfarin comparator arm.

The results of the meta-analysis indicated that, for the composite endpoint of stroke and systemic embolism, efficacy was similar for high-dose edoxaban and the other new oral anticoagulants.

However, edoxaban significantly reduced major bleeding risk by 24% compared to rivaroxaban, 28% compared to dabigatran at 150 mg, and 17% compared to dabigatran at 110 mg. Major bleeding rates were similar for high-dose edoxaban and apixaban.

The committee advising NICE said these results should be interpreted with caution, but edoxaban is unlikely to be different from rivaroxaban, apixaban, and dabigatran in clinical practice.

Cost-effectiveness

Edoxaban costs £58.80 for a 28-tablet pack (60 mg or 30 mg), and the daily cost of treatment is £2.10 (excluding value-added tax). However, costs may vary in different settings because of negotiated procurement discounts.

The committee advising NICE analyzed cost information and concluded that edoxaban is cost-effective compared with warfarin, but there is insufficient evidence to distinguish between the clinical and cost-effectiveness of edoxaban and the other new oral anticoagulants.

Prescription medications

Photo courtesy of the CDC

The UK’s National Institute for Health and Care Excellence (NICE) has issued a final guidance recommending the oral anticoagulant edoxaban tosylate (Lixiana) as an option for preventing stroke and systemic embolism in adults with non-valvular atrial fibrillation (NVAF).

The patients must have one or more risk factors for stroke, including congestive heart failure, hypertension, diabetes, prior stroke or transient ischemic attack, and age of 75 years or older.

In the UK, such patients are generally treated with warfarin or the newer oral anticoagulants dabigatran, rivaroxaban, and apixaban.

NICE decided that edoxaban should be added to that list because data suggest the drug is a clinically and cost-effective treatment option for these patients.

Edoxaban should be available on the National Health Service within 3 months of the date NICE’s final guidance was issued, September 23.

NICE’s guidance says the decision about whether to start treatment with edoxaban should be made after an informed discussion between the clinician and the patient about the risks and benefits of edoxaban compared with warfarin, apixaban, dabigatran, and rivaroxaban.

For patients considering switching from warfarin, edoxaban’s potential benefits should be weighed against its potential risks, taking into account the patient’s level of international normalized ratio control.

Clinical effectiveness

NICE’s conclusion that edoxaban is clinically effective was based primarily on results of the ENGAGE AF-TIMI 48 trial. In this trial, researchers compared edoxaban and warfarin as prophylaxis for stroke or systemic embolism in patients with NVAF.

Results suggested edoxaban was at least non-inferior to warfarin with regard to efficacy, and edoxaban was associated with a significantly lower rate of major and fatal bleeding.

A committee advising NICE also reviewed a meta-analysis prepared by Daiichi Sankyo Co., Ltd., the company developing edoxaban.

The goal of the meta-analysis was to compare edoxaban with rivaroxaban, apixaban, and dabigatran. The analysis included 4 trials: ENGAGE AF-TIMI 48, ARISTOTLE (apixaban), RE-LY (dabigatran), and ROCKET-AF (rivaroxaban). All 4 trials had a warfarin comparator arm.

The results of the meta-analysis indicated that, for the composite endpoint of stroke and systemic embolism, efficacy was similar for high-dose edoxaban and the other new oral anticoagulants.

However, edoxaban significantly reduced major bleeding risk by 24% compared to rivaroxaban, 28% compared to dabigatran at 150 mg, and 17% compared to dabigatran at 110 mg. Major bleeding rates were similar for high-dose edoxaban and apixaban.

The committee advising NICE said these results should be interpreted with caution, but edoxaban is unlikely to be different from rivaroxaban, apixaban, and dabigatran in clinical practice.

Cost-effectiveness

Edoxaban costs £58.80 for a 28-tablet pack (60 mg or 30 mg), and the daily cost of treatment is £2.10 (excluding value-added tax). However, costs may vary in different settings because of negotiated procurement discounts.

The committee advising NICE analyzed cost information and concluded that edoxaban is cost-effective compared with warfarin, but there is insufficient evidence to distinguish between the clinical and cost-effectiveness of edoxaban and the other new oral anticoagulants.

Monoclonal antibodies

Photo by Linda Bartlett

The US Food and Drug Administration (FDA) has granted priority review for an application for ofatumumab (Arzerra) as maintenance therapy in

patients with relapsed chronic lymphocytic leukemia (CLL).

The FDA grants priority review to investigational therapies that, if approved, may offer significant improvements in the treatment, prevention, or diagnosis of a serious condition.

The designation shortens the review period from 10 months to 6 months.

Ofatumumab is a human monoclonal antibody (mAb) designed to target CD20 on the surface of CLL cells and normal B lymphocytes.

The mAb is already FDA-approved to treat patients with CLL that is refractory to fludarabine and alemtuzumab. Ofatumumab is also approved for use in combination with chlorambucil to treat previously untreated patients with CLL for whom fludarabine-based therapy is considered inappropriate.

The FDA said it aims to complete its review of the application for ofatumumab as maintenance therapy in relapsed CLL by January 21, 2016.

PROLONG trial

The application for ofatumumab as maintenance is based on interim results from the phase 3 PROLONG (OMB112517) trial, which were presented at ASH 2014.

In this trial, researchers compared ofatumumab maintenance to no further treatment in patients with a complete or partial response after second-

or third-line treatment for CLL.

Interim results suggested that ofatumumab significantly improves progression-free survival but not overall survival.

The median progression-free survival was about 29 months in patients who received ofatumumab and about 15 months for patients who did not receive

maintenance (P<0.0001).

There was no significant difference in the median overall survival, which was not reached in either treatment arm.

Ofatumumab development

Ofatumumab is approved in more than 50 countries worldwide as monotherapy for CLL patients who are refractory to fludarabine and alemtuzumab.

In the European Union, ofatumumab is approved for use in combination with chlorambucil or bendamustine to treat CLL patients who have not received prior therapy and who are not eligible for fludarabine-based therapy.

Ofatumumab is not approved anywhere in the world as maintenance therapy for relapsed CLL. The drug is being developed by Genmab and Novartis.

Monoclonal antibodies

Photo by Linda Bartlett

The US Food and Drug Administration (FDA) has granted priority review for an application for ofatumumab (Arzerra) as maintenance therapy in

patients with relapsed chronic lymphocytic leukemia (CLL).

The FDA grants priority review to investigational therapies that, if approved, may offer significant improvements in the treatment, prevention, or diagnosis of a serious condition.

The designation shortens the review period from 10 months to 6 months.

Ofatumumab is a human monoclonal antibody (mAb) designed to target CD20 on the surface of CLL cells and normal B lymphocytes.

The mAb is already FDA-approved to treat patients with CLL that is refractory to fludarabine and alemtuzumab. Ofatumumab is also approved for use in combination with chlorambucil to treat previously untreated patients with CLL for whom fludarabine-based therapy is considered inappropriate.

The FDA said it aims to complete its review of the application for ofatumumab as maintenance therapy in relapsed CLL by January 21, 2016.

PROLONG trial

The application for ofatumumab as maintenance is based on interim results from the phase 3 PROLONG (OMB112517) trial, which were presented at ASH 2014.

In this trial, researchers compared ofatumumab maintenance to no further treatment in patients with a complete or partial response after second-

or third-line treatment for CLL.

Interim results suggested that ofatumumab significantly improves progression-free survival but not overall survival.

The median progression-free survival was about 29 months in patients who received ofatumumab and about 15 months for patients who did not receive

maintenance (P<0.0001).

There was no significant difference in the median overall survival, which was not reached in either treatment arm.

Ofatumumab development

Ofatumumab is approved in more than 50 countries worldwide as monotherapy for CLL patients who are refractory to fludarabine and alemtuzumab.

In the European Union, ofatumumab is approved for use in combination with chlorambucil or bendamustine to treat CLL patients who have not received prior therapy and who are not eligible for fludarabine-based therapy.

Ofatumumab is not approved anywhere in the world as maintenance therapy for relapsed CLL. The drug is being developed by Genmab and Novartis.

Monoclonal antibodies

Photo by Linda Bartlett

The US Food and Drug Administration (FDA) has granted priority review for an application for ofatumumab (Arzerra) as maintenance therapy in

patients with relapsed chronic lymphocytic leukemia (CLL).

The FDA grants priority review to investigational therapies that, if approved, may offer significant improvements in the treatment, prevention, or diagnosis of a serious condition.

The designation shortens the review period from 10 months to 6 months.

Ofatumumab is a human monoclonal antibody (mAb) designed to target CD20 on the surface of CLL cells and normal B lymphocytes.

The mAb is already FDA-approved to treat patients with CLL that is refractory to fludarabine and alemtuzumab. Ofatumumab is also approved for use in combination with chlorambucil to treat previously untreated patients with CLL for whom fludarabine-based therapy is considered inappropriate.

The FDA said it aims to complete its review of the application for ofatumumab as maintenance therapy in relapsed CLL by January 21, 2016.

PROLONG trial

The application for ofatumumab as maintenance is based on interim results from the phase 3 PROLONG (OMB112517) trial, which were presented at ASH 2014.

In this trial, researchers compared ofatumumab maintenance to no further treatment in patients with a complete or partial response after second-

or third-line treatment for CLL.

Interim results suggested that ofatumumab significantly improves progression-free survival but not overall survival.

The median progression-free survival was about 29 months in patients who received ofatumumab and about 15 months for patients who did not receive

maintenance (P<0.0001).

There was no significant difference in the median overall survival, which was not reached in either treatment arm.

Ofatumumab development

Ofatumumab is approved in more than 50 countries worldwide as monotherapy for CLL patients who are refractory to fludarabine and alemtuzumab.

In the European Union, ofatumumab is approved for use in combination with chlorambucil or bendamustine to treat CLL patients who have not received prior therapy and who are not eligible for fludarabine-based therapy.

Ofatumumab is not approved anywhere in the world as maintenance therapy for relapsed CLL. The drug is being developed by Genmab and Novartis.

Red blood cells

The US Food and Drug Administration (FDA) has granted fast track designation to a gene therapy product being developed to treat hemophilia B.

The product, DTX101, is designed to deliver factor IX gene expression in a durable fashion to prevent the long-term complications of hemophilia B.

Preclinical studies have indicated that DTX101 has the potential to be a well-tolerated, effective therapy for hemophilia B, according to Dimension Therapeutics, Inc., the company developing DTX101.

The company said it expects to initiate a multicenter, phase 1/2 study to evaluate DTX101 in adults with moderate/severe to severe hemophilia B by the end of this year.

DTX101 also has orphan designation from the FDA.

About fast track designation

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

Through the fast track program, a product may be eligible for priority review. In addition, the company developing the drug 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 with the FDA to discuss the drug’s development plan and ensure collection of the appropriate data needed to support drug approval. And the designation allows for more frequent written communication from the FDA about things such as the design of proposed clinical trials and the use of biomarkers.

Red blood cells

The US Food and Drug Administration (FDA) has granted fast track designation to a gene therapy product being developed to treat hemophilia B.

The product, DTX101, is designed to deliver factor IX gene expression in a durable fashion to prevent the long-term complications of hemophilia B.

Preclinical studies have indicated that DTX101 has the potential to be a well-tolerated, effective therapy for hemophilia B, according to Dimension Therapeutics, Inc., the company developing DTX101.

The company said it expects to initiate a multicenter, phase 1/2 study to evaluate DTX101 in adults with moderate/severe to severe hemophilia B by the end of this year.

DTX101 also has orphan designation from the FDA.

About fast track designation

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

Through the fast track program, a product may be eligible for priority review. In addition, the company developing the drug 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 with the FDA to discuss the drug’s development plan and ensure collection of the appropriate data needed to support drug approval. And the designation allows for more frequent written communication from the FDA about things such as the design of proposed clinical trials and the use of biomarkers.

Red blood cells

The US Food and Drug Administration (FDA) has granted fast track designation to a gene therapy product being developed to treat hemophilia B.

The product, DTX101, is designed to deliver factor IX gene expression in a durable fashion to prevent the long-term complications of hemophilia B.

Preclinical studies have indicated that DTX101 has the potential to be a well-tolerated, effective therapy for hemophilia B, according to Dimension Therapeutics, Inc., the company developing DTX101.

The company said it expects to initiate a multicenter, phase 1/2 study to evaluate DTX101 in adults with moderate/severe to severe hemophilia B by the end of this year.

DTX101 also has orphan designation from the FDA.

About fast track designation

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

Through the fast track program, a product may be eligible for priority review. In addition, the company developing the drug 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 with the FDA to discuss the drug’s development plan and ensure collection of the appropriate data needed to support drug approval. And the designation allows for more frequent written communication from the FDA about things such as the design of proposed clinical trials and the use of biomarkers.

Micrograph showing

multiple myeloma

The US Food and Drug Administration (FDA) has granted priority review for 4 drugs intended to treat multiple myeloma (MM): elotuzumab (Empliciti), daratumumab, ixazomib (MLN9708), and carfilzomib (Kyprolis).

The FDA grants priority review to investigational therapies that, if approved, may offer significant improvements in the treatment, prevention, or diagnosis of a serious condition.

The designation shortens the review period from 10 months to 6 months.

Carfilzomib

Carfilzomib, an injectable proteasome inhibitor, is currently under review for use in combination with dexamethasone to treat patients with relapsed MM who have received at least 1 prior therapy.

Carfilzomib is already FDA-approved for use in combination with lenalidomide and dexamethasone to treat patients with relapsed MM who have received 1 to 3 prior lines of therapy.

Carfilzomib also has accelerated approval from the FDA as monotherapy for MM patients who have received at least 2 prior therapies, including bortezomib and an immunomodulatory agent (IMiD), and have demonstrated disease progression on or within 60 days of completing their last treatment.

The new regulatory submission for carfilzomib is based on data from the phase 3 ENDEAVOR trial, which were presented at ASCO 2015. In this trial, relapsed MM patients who received carfilzomib and low-dose dexamethasone had significantly longer progression-free survival (PFS) than patients who received bortezomib and low-dose dexamethasone.

Carfilzomib is under development by Onyx Pharmaceuticals, Inc., an Amgen subsidiary.

Ixazomib

Ixazomib, an oral proteasome inhibitor, is under review for the treatment of relapsed and/or refractory MM. Ixazomib has orphan drug designation from the FDA for this patient population.

The regulatory submission for ixazomib is primarily based on results of the first interim analysis of the phase 3 TOURMALINE-MM1 trial.

In this trial, patients with relapsed and/or refractory MM who received ixazomib plus lenalidomide and dexamethasone had superior PFS to patients who received placebo plus lenalidomide and dexamethasone, according to Takeda Pharmaceutical Company Limited, the company developing ixazomib. Detailed data from this study have not yet been released.

Ixazomib is currently under investigation in 3 other phase 3 trials of MM patients:

• TOURMALINE-MM2, investigating ixazomib vs placebo, both in combination with lenalidomide and dexamethasone in patients with newly diagnosed MM
• TOURMALINE-MM3, investigating ixazomib vs placebo as maintenance therapy in patients with newly diagnosed MM following induction therapy and autologous stem cell transplant
• TOURMALINE-MM4, investigating ixazomib vs placebo as maintenance therapy in patients with newly diagnosed MM who have not undergone autologous stem cell transplant.

Daratumumab

Daratumumab, an investigational human anti-CD38 monoclonal antibody, is under review as monotherapy for MM patients who are refractory to both a proteasome inhibitor and an IMiD, or who have received 3 or more prior lines of therapy, including a proteasome inhibitor and an IMiD.

Daratumumab already has fast track, breakthrough therapy, and orphan drug designations from the FDA.

The regulatory submission for daratumumab is primarily supported by data from the phase 2 MMY2002 (SIRIUS) monotherapy study, which were presented at ASCO 2015. Results from this study indicated that daratumumab can produce responses in heavily pretreated MM patients.

Additional data from 4 other studies, including the phase 1/2 GEN501 monotherapy study, which was recently published in NEJM, also support the submission.

Daratumumab is under development by Janssen Research & Development, LLC.

Elotuzumab

Elotuzumab, a signaling lymphocyte activation molecule (SLAMF7)-directed immunostimulatory antibody, is under review for use in combination with lenalidomide and dexamethasone to treat MM patients who have received at least 1 prior treatment.

The FDA has already granted elotuzumab breakthrough therapy and orphan drug designations.

The regulatory submission for elotuzumab is primarily supported by data from the ELOQUENT-2 trial, which were presented at ASCO 2015. In this phase 3 study, researchers evaluated elotuzumab in combination with lenalidomide and dexamethasone, compared to lenalidomide and dexamethasone alone.

The submission is also supported by data from the CA204-009 trial, which were presented at EHA 2015. In this phase 2 study, researchers evaluated elotuzumab in combination with bortezomib and dexamethasone compared to bortezomib and dexamethasone alone.

Results from both trials suggested that adding elotuzumab to combination treatment can prolong PFS in MM patients.

Bristol-Myers Squibb and AbbVie are co-developing elotuzumab, with Bristol-Myers Squibb solely responsible for commercial activities.

Micrograph showing

multiple myeloma

The US Food and Drug Administration (FDA) has granted priority review for 4 drugs intended to treat multiple myeloma (MM): elotuzumab (Empliciti), daratumumab, ixazomib (MLN9708), and carfilzomib (Kyprolis).

The FDA grants priority review to investigational therapies that, if approved, may offer significant improvements in the treatment, prevention, or diagnosis of a serious condition.

The designation shortens the review period from 10 months to 6 months.

Carfilzomib

Carfilzomib, an injectable proteasome inhibitor, is currently under review for use in combination with dexamethasone to treat patients with relapsed MM who have received at least 1 prior therapy.

Carfilzomib is already FDA-approved for use in combination with lenalidomide and dexamethasone to treat patients with relapsed MM who have received 1 to 3 prior lines of therapy.

Carfilzomib also has accelerated approval from the FDA as monotherapy for MM patients who have received at least 2 prior therapies, including bortezomib and an immunomodulatory agent (IMiD), and have demonstrated disease progression on or within 60 days of completing their last treatment.

The new regulatory submission for carfilzomib is based on data from the phase 3 ENDEAVOR trial, which were presented at ASCO 2015. In this trial, relapsed MM patients who received carfilzomib and low-dose dexamethasone had significantly longer progression-free survival (PFS) than patients who received bortezomib and low-dose dexamethasone.

Carfilzomib is under development by Onyx Pharmaceuticals, Inc., an Amgen subsidiary.

Ixazomib

Ixazomib, an oral proteasome inhibitor, is under review for the treatment of relapsed and/or refractory MM. Ixazomib has orphan drug designation from the FDA for this patient population.

The regulatory submission for ixazomib is primarily based on results of the first interim analysis of the phase 3 TOURMALINE-MM1 trial.

In this trial, patients with relapsed and/or refractory MM who received ixazomib plus lenalidomide and dexamethasone had superior PFS to patients who received placebo plus lenalidomide and dexamethasone, according to Takeda Pharmaceutical Company Limited, the company developing ixazomib. Detailed data from this study have not yet been released.

Ixazomib is currently under investigation in 3 other phase 3 trials of MM patients:

• TOURMALINE-MM2, investigating ixazomib vs placebo, both in combination with lenalidomide and dexamethasone in patients with newly diagnosed MM
• TOURMALINE-MM3, investigating ixazomib vs placebo as maintenance therapy in patients with newly diagnosed MM following induction therapy and autologous stem cell transplant
• TOURMALINE-MM4, investigating ixazomib vs placebo as maintenance therapy in patients with newly diagnosed MM who have not undergone autologous stem cell transplant.

Daratumumab

Daratumumab, an investigational human anti-CD38 monoclonal antibody, is under review as monotherapy for MM patients who are refractory to both a proteasome inhibitor and an IMiD, or who have received 3 or more prior lines of therapy, including a proteasome inhibitor and an IMiD.

Daratumumab already has fast track, breakthrough therapy, and orphan drug designations from the FDA.

The regulatory submission for daratumumab is primarily supported by data from the phase 2 MMY2002 (SIRIUS) monotherapy study, which were presented at ASCO 2015. Results from this study indicated that daratumumab can produce responses in heavily pretreated MM patients.

Additional data from 4 other studies, including the phase 1/2 GEN501 monotherapy study, which was recently published in NEJM, also support the submission.

Daratumumab is under development by Janssen Research & Development, LLC.

Elotuzumab

Elotuzumab, a signaling lymphocyte activation molecule (SLAMF7)-directed immunostimulatory antibody, is under review for use in combination with lenalidomide and dexamethasone to treat MM patients who have received at least 1 prior treatment.

The FDA has already granted elotuzumab breakthrough therapy and orphan drug designations.

The regulatory submission for elotuzumab is primarily supported by data from the ELOQUENT-2 trial, which were presented at ASCO 2015. In this phase 3 study, researchers evaluated elotuzumab in combination with lenalidomide and dexamethasone, compared to lenalidomide and dexamethasone alone.

The submission is also supported by data from the CA204-009 trial, which were presented at EHA 2015. In this phase 2 study, researchers evaluated elotuzumab in combination with bortezomib and dexamethasone compared to bortezomib and dexamethasone alone.

Results from both trials suggested that adding elotuzumab to combination treatment can prolong PFS in MM patients.

Bristol-Myers Squibb and AbbVie are co-developing elotuzumab, with Bristol-Myers Squibb solely responsible for commercial activities.

Micrograph showing

multiple myeloma

The US Food and Drug Administration (FDA) has granted priority review for 4 drugs intended to treat multiple myeloma (MM): elotuzumab (Empliciti), daratumumab, ixazomib (MLN9708), and carfilzomib (Kyprolis).

The FDA grants priority review to investigational therapies that, if approved, may offer significant improvements in the treatment, prevention, or diagnosis of a serious condition.

The designation shortens the review period from 10 months to 6 months.

Carfilzomib

Carfilzomib, an injectable proteasome inhibitor, is currently under review for use in combination with dexamethasone to treat patients with relapsed MM who have received at least 1 prior therapy.

Carfilzomib is already FDA-approved for use in combination with lenalidomide and dexamethasone to treat patients with relapsed MM who have received 1 to 3 prior lines of therapy.

Carfilzomib also has accelerated approval from the FDA as monotherapy for MM patients who have received at least 2 prior therapies, including bortezomib and an immunomodulatory agent (IMiD), and have demonstrated disease progression on or within 60 days of completing their last treatment.

The new regulatory submission for carfilzomib is based on data from the phase 3 ENDEAVOR trial, which were presented at ASCO 2015. In this trial, relapsed MM patients who received carfilzomib and low-dose dexamethasone had significantly longer progression-free survival (PFS) than patients who received bortezomib and low-dose dexamethasone.

Carfilzomib is under development by Onyx Pharmaceuticals, Inc., an Amgen subsidiary.

Ixazomib

Ixazomib, an oral proteasome inhibitor, is under review for the treatment of relapsed and/or refractory MM. Ixazomib has orphan drug designation from the FDA for this patient population.

The regulatory submission for ixazomib is primarily based on results of the first interim analysis of the phase 3 TOURMALINE-MM1 trial.

In this trial, patients with relapsed and/or refractory MM who received ixazomib plus lenalidomide and dexamethasone had superior PFS to patients who received placebo plus lenalidomide and dexamethasone, according to Takeda Pharmaceutical Company Limited, the company developing ixazomib. Detailed data from this study have not yet been released.

Ixazomib is currently under investigation in 3 other phase 3 trials of MM patients:

• TOURMALINE-MM2, investigating ixazomib vs placebo, both in combination with lenalidomide and dexamethasone in patients with newly diagnosed MM
• TOURMALINE-MM3, investigating ixazomib vs placebo as maintenance therapy in patients with newly diagnosed MM following induction therapy and autologous stem cell transplant
• TOURMALINE-MM4, investigating ixazomib vs placebo as maintenance therapy in patients with newly diagnosed MM who have not undergone autologous stem cell transplant.

Daratumumab

Daratumumab, an investigational human anti-CD38 monoclonal antibody, is under review as monotherapy for MM patients who are refractory to both a proteasome inhibitor and an IMiD, or who have received 3 or more prior lines of therapy, including a proteasome inhibitor and an IMiD.

Daratumumab already has fast track, breakthrough therapy, and orphan drug designations from the FDA.

The regulatory submission for daratumumab is primarily supported by data from the phase 2 MMY2002 (SIRIUS) monotherapy study, which were presented at ASCO 2015. Results from this study indicated that daratumumab can produce responses in heavily pretreated MM patients.

Additional data from 4 other studies, including the phase 1/2 GEN501 monotherapy study, which was recently published in NEJM, also support the submission.

Daratumumab is under development by Janssen Research & Development, LLC.

Elotuzumab

Elotuzumab, a signaling lymphocyte activation molecule (SLAMF7)-directed immunostimulatory antibody, is under review for use in combination with lenalidomide and dexamethasone to treat MM patients who have received at least 1 prior treatment.

The FDA has already granted elotuzumab breakthrough therapy and orphan drug designations.

The regulatory submission for elotuzumab is primarily supported by data from the ELOQUENT-2 trial, which were presented at ASCO 2015. In this phase 3 study, researchers evaluated elotuzumab in combination with lenalidomide and dexamethasone, compared to lenalidomide and dexamethasone alone.

The submission is also supported by data from the CA204-009 trial, which were presented at EHA 2015. In this phase 2 study, researchers evaluated elotuzumab in combination with bortezomib and dexamethasone compared to bortezomib and dexamethasone alone.

Results from both trials suggested that adding elotuzumab to combination treatment can prolong PFS in MM patients.

Bristol-Myers Squibb and AbbVie are co-developing elotuzumab, with Bristol-Myers Squibb solely responsible for commercial activities.

Photo by Octapharma

The US Food and Drug Administration (FDA) has approved the recombinant factor VIII product simoctocog alfa (Nuwiq) for adults and children with hemophilia A.

The approval includes on-demand treatment and control of bleeding episodes, routine prophylaxis to reduce the frequency of bleeding episodes, and perioperative management of bleeding.

Simoctocog alfa is the first B-domain-deleted recombinant factor VIII product derived from a human cell line—not chemically modified or fused with another protein—designed to treat hemophilia A.

Simoctocog alfa is already approved for use in the European Union, Argentina, Australia, and Canada.

In the US, simoctocog alfa is being developed by Octapharma USA, a subsidiary of Octapharma AG.

According to Octapharma USA, simoctocog alfa should be available in the US by early 2016. The company plans to offer hemophilia A patients educational and support services in connection with the product.

Trials of simoctocog alfa

Simoctocog alfa has been evaluated for safety in 5 prospective trials and for efficacy in 3 prospective studies.

A total of 135 previously treated patients with severe hemophilia A have received simoctocog alfa across all the studies. This includes 74 adults, 3 adolescents between ages 12 and 17, and 58 pediatric patients between ages 2 and 11.

The patients were treated with a total of 16,134 infusions over 15,950 exposure days.

In a study of adults, the overall prophylactic efficacy of simoctocog alfa for spontaneous bleeds was rated “excellent” or “good” in 92% of patients. In a study of children, prophylactic efficacy for spontaneous bleeds was rated “excellent” or “good” in 97% of patients.

The mean annualized bleeding rates for spontaneous bleeds during prophylaxis were approximately 1.5 in children and 1.2 in adults.

For hemophilia A patients receiving simoctocog alfa prophylaxis compared to on-demand treatment, the annualized bleeding rates were reduced 96% for adults and 93% for children.

Treatment of breakthrough bleeds during simoctocog alfa prophylaxis was rated as “excellent” or “good” in 100% of bleeds (30/30) in adults and 82% of bleeds (89/108) in children.

For on-demand treatment with simoctocog alfa in 20 adults and 2 adolescents, efficacy for the treatment of bleeds was considered “excellent” or “good” in 94% of bleeds (931/986).

The overall efficacy in surgical prophylaxis was rated “excellent” or “good” in 97% of procedures using simoctocog alfa (32/33).

For all the trials of simoctocog alfa, there were 7 adverse events reported. Each of these events occurred once, with a rate of 0.7% across all 135 patients. The events were paresthesia, headache, injection site inflammation, injection site pain, back pain, vertigo, and dry mouth.

Non-neutralizing anti-factor VIII antibodies (without inhibitory activity as measured by the modified Bethesda assay) were reported in 4 patients (3%). Three of the 4 patients had pre-existing non-neutralizing antibodies prior to simoctocog alfa exposure.

For more details on simoctocog alfa, see the full prescribing information, available at www.octapharmausa.com.

Photo by Octapharma

The US Food and Drug Administration (FDA) has approved the recombinant factor VIII product simoctocog alfa (Nuwiq) for adults and children with hemophilia A.

The approval includes on-demand treatment and control of bleeding episodes, routine prophylaxis to reduce the frequency of bleeding episodes, and perioperative management of bleeding.

Simoctocog alfa is the first B-domain-deleted recombinant factor VIII product derived from a human cell line—not chemically modified or fused with another protein—designed to treat hemophilia A.

Simoctocog alfa is already approved for use in the European Union, Argentina, Australia, and Canada.

In the US, simoctocog alfa is being developed by Octapharma USA, a subsidiary of Octapharma AG.

According to Octapharma USA, simoctocog alfa should be available in the US by early 2016. The company plans to offer hemophilia A patients educational and support services in connection with the product.

Trials of simoctocog alfa

Simoctocog alfa has been evaluated for safety in 5 prospective trials and for efficacy in 3 prospective studies.

A total of 135 previously treated patients with severe hemophilia A have received simoctocog alfa across all the studies. This includes 74 adults, 3 adolescents between ages 12 and 17, and 58 pediatric patients between ages 2 and 11.

The patients were treated with a total of 16,134 infusions over 15,950 exposure days.

In a study of adults, the overall prophylactic efficacy of simoctocog alfa for spontaneous bleeds was rated “excellent” or “good” in 92% of patients. In a study of children, prophylactic efficacy for spontaneous bleeds was rated “excellent” or “good” in 97% of patients.

The mean annualized bleeding rates for spontaneous bleeds during prophylaxis were approximately 1.5 in children and 1.2 in adults.

For hemophilia A patients receiving simoctocog alfa prophylaxis compared to on-demand treatment, the annualized bleeding rates were reduced 96% for adults and 93% for children.

Treatment of breakthrough bleeds during simoctocog alfa prophylaxis was rated as “excellent” or “good” in 100% of bleeds (30/30) in adults and 82% of bleeds (89/108) in children.

For on-demand treatment with simoctocog alfa in 20 adults and 2 adolescents, efficacy for the treatment of bleeds was considered “excellent” or “good” in 94% of bleeds (931/986).

The overall efficacy in surgical prophylaxis was rated “excellent” or “good” in 97% of procedures using simoctocog alfa (32/33).

For all the trials of simoctocog alfa, there were 7 adverse events reported. Each of these events occurred once, with a rate of 0.7% across all 135 patients. The events were paresthesia, headache, injection site inflammation, injection site pain, back pain, vertigo, and dry mouth.

Non-neutralizing anti-factor VIII antibodies (without inhibitory activity as measured by the modified Bethesda assay) were reported in 4 patients (3%). Three of the 4 patients had pre-existing non-neutralizing antibodies prior to simoctocog alfa exposure.

For more details on simoctocog alfa, see the full prescribing information, available at www.octapharmausa.com.

Photo by Octapharma

The US Food and Drug Administration (FDA) has approved the recombinant factor VIII product simoctocog alfa (Nuwiq) for adults and children with hemophilia A.

The approval includes on-demand treatment and control of bleeding episodes, routine prophylaxis to reduce the frequency of bleeding episodes, and perioperative management of bleeding.

Simoctocog alfa is the first B-domain-deleted recombinant factor VIII product derived from a human cell line—not chemically modified or fused with another protein—designed to treat hemophilia A.

Simoctocog alfa is already approved for use in the European Union, Argentina, Australia, and Canada.

In the US, simoctocog alfa is being developed by Octapharma USA, a subsidiary of Octapharma AG.

According to Octapharma USA, simoctocog alfa should be available in the US by early 2016. The company plans to offer hemophilia A patients educational and support services in connection with the product.

Trials of simoctocog alfa

Simoctocog alfa has been evaluated for safety in 5 prospective trials and for efficacy in 3 prospective studies.

A total of 135 previously treated patients with severe hemophilia A have received simoctocog alfa across all the studies. This includes 74 adults, 3 adolescents between ages 12 and 17, and 58 pediatric patients between ages 2 and 11.

The patients were treated with a total of 16,134 infusions over 15,950 exposure days.

In a study of adults, the overall prophylactic efficacy of simoctocog alfa for spontaneous bleeds was rated “excellent” or “good” in 92% of patients. In a study of children, prophylactic efficacy for spontaneous bleeds was rated “excellent” or “good” in 97% of patients.

The mean annualized bleeding rates for spontaneous bleeds during prophylaxis were approximately 1.5 in children and 1.2 in adults.

For hemophilia A patients receiving simoctocog alfa prophylaxis compared to on-demand treatment, the annualized bleeding rates were reduced 96% for adults and 93% for children.

Treatment of breakthrough bleeds during simoctocog alfa prophylaxis was rated as “excellent” or “good” in 100% of bleeds (30/30) in adults and 82% of bleeds (89/108) in children.

For on-demand treatment with simoctocog alfa in 20 adults and 2 adolescents, efficacy for the treatment of bleeds was considered “excellent” or “good” in 94% of bleeds (931/986).

The overall efficacy in surgical prophylaxis was rated “excellent” or “good” in 97% of procedures using simoctocog alfa (32/33).

For all the trials of simoctocog alfa, there were 7 adverse events reported. Each of these events occurred once, with a rate of 0.7% across all 135 patients. The events were paresthesia, headache, injection site inflammation, injection site pain, back pain, vertigo, and dry mouth.

Non-neutralizing anti-factor VIII antibodies (without inhibitory activity as measured by the modified Bethesda assay) were reported in 4 patients (3%). Three of the 4 patients had pre-existing non-neutralizing antibodies prior to simoctocog alfa exposure.

For more details on simoctocog alfa, see the full prescribing information, available at www.octapharmausa.com.

Sickled and normal

red blood cells

Image by Graham Beards

The European Medicines Agency’s (EMA’s) Committee for Orphan Medicinal Products (COMP) has adopted a positive opinion recommending that LJPC-401, a novel formulation of hepcidin, receive orphan designation to treat chronic iron overload requiring chelation therapy.

Chronic iron overload occurs in patients suffering from beta thalassemia, sickle cell disease, and hereditary hemochromatosis.

The COMP’s opinion, which is subject to review and approval by the European Commission, may include all or a subset of these conditions.

About LJPC-401

LJPC-401 is a novel formulation of hepcidin, an endogenous peptide hormone that is the body’s naturally occurring regulator of iron absorption and distribution. Hepcidin prevents excessive iron accumulation in tissues, such as the liver and heart, where it can cause significant damage and even result in death.

La Jolla Pharmaceutical Company is developing LJPC-401 for the treatment of iron overload occurring as a results of hereditary hemochromatosis, beta thalassemia, and sickle cell disease.

LJPC-401 has been shown to be effective in reducing serum iron in preclinical testing, according to La Jolla. The company said it expects to release preliminary results from a phase 1 trial of LJPC-401 by the end of this year.

About orphan designation

The EMA’s COMP adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for endorsement.

In the European Union, orphan designation is granted to therapies intended to treat a life-threatening or chronically debilitating condition that affects no more than 5 in 10,000 persons and where no satisfactory treatment is available.

Companies that obtain orphan designation for a drug benefit from a number of incentives, including protocol assistance, a type of scientific advice specific for designated orphan medicines, and 10 years of market exclusivity if the medicine is approved. Fee reductions are also available, depending on the status of the sponsor and the type of service required.

Sickled and normal

red blood cells

Image by Graham Beards

The European Medicines Agency’s (EMA’s) Committee for Orphan Medicinal Products (COMP) has adopted a positive opinion recommending that LJPC-401, a novel formulation of hepcidin, receive orphan designation to treat chronic iron overload requiring chelation therapy.

Chronic iron overload occurs in patients suffering from beta thalassemia, sickle cell disease, and hereditary hemochromatosis.

The COMP’s opinion, which is subject to review and approval by the European Commission, may include all or a subset of these conditions.

About LJPC-401

LJPC-401 is a novel formulation of hepcidin, an endogenous peptide hormone that is the body’s naturally occurring regulator of iron absorption and distribution. Hepcidin prevents excessive iron accumulation in tissues, such as the liver and heart, where it can cause significant damage and even result in death.

La Jolla Pharmaceutical Company is developing LJPC-401 for the treatment of iron overload occurring as a results of hereditary hemochromatosis, beta thalassemia, and sickle cell disease.

LJPC-401 has been shown to be effective in reducing serum iron in preclinical testing, according to La Jolla. The company said it expects to release preliminary results from a phase 1 trial of LJPC-401 by the end of this year.

About orphan designation

The EMA’s COMP adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for endorsement.

In the European Union, orphan designation is granted to therapies intended to treat a life-threatening or chronically debilitating condition that affects no more than 5 in 10,000 persons and where no satisfactory treatment is available.

Companies that obtain orphan designation for a drug benefit from a number of incentives, including protocol assistance, a type of scientific advice specific for designated orphan medicines, and 10 years of market exclusivity if the medicine is approved. Fee reductions are also available, depending on the status of the sponsor and the type of service required.

Sickled and normal

red blood cells

Image by Graham Beards

The European Medicines Agency’s (EMA’s) Committee for Orphan Medicinal Products (COMP) has adopted a positive opinion recommending that LJPC-401, a novel formulation of hepcidin, receive orphan designation to treat chronic iron overload requiring chelation therapy.

Chronic iron overload occurs in patients suffering from beta thalassemia, sickle cell disease, and hereditary hemochromatosis.

The COMP’s opinion, which is subject to review and approval by the European Commission, may include all or a subset of these conditions.

About LJPC-401

LJPC-401 is a novel formulation of hepcidin, an endogenous peptide hormone that is the body’s naturally occurring regulator of iron absorption and distribution. Hepcidin prevents excessive iron accumulation in tissues, such as the liver and heart, where it can cause significant damage and even result in death.

La Jolla Pharmaceutical Company is developing LJPC-401 for the treatment of iron overload occurring as a results of hereditary hemochromatosis, beta thalassemia, and sickle cell disease.

LJPC-401 has been shown to be effective in reducing serum iron in preclinical testing, according to La Jolla. The company said it expects to release preliminary results from a phase 1 trial of LJPC-401 by the end of this year.

About orphan designation

The EMA’s COMP adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for endorsement.

In the European Union, orphan designation is granted to therapies intended to treat a life-threatening or chronically debilitating condition that affects no more than 5 in 10,000 persons and where no satisfactory treatment is available.

Companies that obtain orphan designation for a drug benefit from a number of incentives, including protocol assistance, a type of scientific advice specific for designated orphan medicines, and 10 years of market exclusivity if the medicine is approved. Fee reductions are also available, depending on the status of the sponsor and the type of service required.

Mantle cell lymphoma

The European Medicines Agency’s (EMA’s) Committee for Orphan Medicinal Products has adopted a positive opinion recommending that KTE-C19 receive orphan designation to treat primary mediastinal B-cell lymphoma (PMBCL) and mantle cell lymphoma.

KTE-C19 is an investigational chimeric antigen receptor (CAR) T-cell therapy designed to target CD19, a protein expressed on the cell surface of B-cell lymphomas and leukemias.

No other product candidate currently has orphan drug designation for the treatment of PMBCL in the European Union (EU).

KTE-C19 already has orphan drug designation to treat diffuse large B-cell lymphoma (DLBCL) in the US and the EU.

“We are conducting a phase 1/2 clinical trial of KTE-C19 in patients with refractory, aggressive non-Hodgkin lymphoma, including DLBCL and PMBCL, and plan to report initial topline results from the phase 1 portion of the trial later this year [at the ASH Annual Meeting],” said Arie Belldegrun, MD, Chairman, President, and Chief Executive Officer of Kite Pharmaceuticals, the company developing KTE-C19.

Trial results

Last year, researchers reported results with KTE-C19 in the Journal of Clinical Oncology. The study included 15 patients with advanced B-cell malignancies.

The patients received a conditioning regimen of cyclophosphamide and fludarabine, followed 1 day later by a single infusion of KTE-C19. The researchers noted that the conditioning regimen is known to be active against B-cell malignancies and could have made a direct contribution to patient responses.

Thirteen patients were evaluable for response. Eight patients achieved a complete response (CR), and 4 had a partial response (PR).

Of the 7 patients with chemotherapy-refractory DLBCL, 4 achieved a CR, 2 achieved a PR, and 1 had stable disease. Of the 4 patients with chronic lymphocytic leukemia, 3 had a CR, and 1 had a PR. Among the 2 patients with indolent lymphomas, 1 achieved a CR, and 1 had a PR.

KTE-C19 was associated with fever, low blood pressure, focal neurological deficits, and delirium. Toxicities largely occurred in the first 2 weeks after infusion.

All but 2 patients experienced grade 3/4 adverse events. Four patients had grade 3/4 hypotension.

All patients had elevations in serum interferon gamma and/or interleukin 6 around the time of peak toxicity, but most did not develop elevations in serum tumor necrosis factor.

Neurologic toxicities included confusion and obtundation, which have been reported in previous studies. However, 3 patients developed unexpected neurologic abnormalities.

About orphan designation

The EMA’s Committee for Orphan Medicinal Products adopts an opinion on the granting of orphan designation, and that opinion is submitted to the European Commission for endorsement.

In the EU, orphan designation is granted to therapies intended to treat a life-threatening or chronically debilitating condition that affects no more than 5 in 10,000 persons and where no satisfactory treatment is available.

Companies that obtain orphan designation for a drug benefit from a number of incentives, including protocol assistance, a type of scientific advice specific for designated orphan medicines, and 10 years of market exclusivity once the medicine is approved. Fee reductions are also available, depending on the status of the sponsor and the type of service required.

Mantle cell lymphoma

The European Medicines Agency’s (EMA’s) Committee for Orphan Medicinal Products has adopted a positive opinion recommending that KTE-C19 receive orphan designation to treat primary mediastinal B-cell lymphoma (PMBCL) and mantle cell lymphoma.

KTE-C19 is an investigational chimeric antigen receptor (CAR) T-cell therapy designed to target CD19, a protein expressed on the cell surface of B-cell lymphomas and leukemias.

No other product candidate currently has orphan drug designation for the treatment of PMBCL in the European Union (EU).

KTE-C19 already has orphan drug designation to treat diffuse large B-cell lymphoma (DLBCL) in the US and the EU.

“We are conducting a phase 1/2 clinical trial of KTE-C19 in patients with refractory, aggressive non-Hodgkin lymphoma, including DLBCL and PMBCL, and plan to report initial topline results from the phase 1 portion of the trial later this year [at the ASH Annual Meeting],” said Arie Belldegrun, MD, Chairman, President, and Chief Executive Officer of Kite Pharmaceuticals, the company developing KTE-C19.

Trial results

Last year, researchers reported results with KTE-C19 in the Journal of Clinical Oncology. The study included 15 patients with advanced B-cell malignancies.

The patients received a conditioning regimen of cyclophosphamide and fludarabine, followed 1 day later by a single infusion of KTE-C19. The researchers noted that the conditioning regimen is known to be active against B-cell malignancies and could have made a direct contribution to patient responses.

Thirteen patients were evaluable for response. Eight patients achieved a complete response (CR), and 4 had a partial response (PR).

Of the 7 patients with chemotherapy-refractory DLBCL, 4 achieved a CR, 2 achieved a PR, and 1 had stable disease. Of the 4 patients with chronic lymphocytic leukemia, 3 had a CR, and 1 had a PR. Among the 2 patients with indolent lymphomas, 1 achieved a CR, and 1 had a PR.

KTE-C19 was associated with fever, low blood pressure, focal neurological deficits, and delirium. Toxicities largely occurred in the first 2 weeks after infusion.

All but 2 patients experienced grade 3/4 adverse events. Four patients had grade 3/4 hypotension.

All patients had elevations in serum interferon gamma and/or interleukin 6 around the time of peak toxicity, but most did not develop elevations in serum tumor necrosis factor.

Neurologic toxicities included confusion and obtundation, which have been reported in previous studies. However, 3 patients developed unexpected neurologic abnormalities.

About orphan designation

The EMA’s Committee for Orphan Medicinal Products adopts an opinion on the granting of orphan designation, and that opinion is submitted to the European Commission for endorsement.

In the EU, orphan designation is granted to therapies intended to treat a life-threatening or chronically debilitating condition that affects no more than 5 in 10,000 persons and where no satisfactory treatment is available.

Companies that obtain orphan designation for a drug benefit from a number of incentives, including protocol assistance, a type of scientific advice specific for designated orphan medicines, and 10 years of market exclusivity once the medicine is approved. Fee reductions are also available, depending on the status of the sponsor and the type of service required.

Mantle cell lymphoma

The European Medicines Agency’s (EMA’s) Committee for Orphan Medicinal Products has adopted a positive opinion recommending that KTE-C19 receive orphan designation to treat primary mediastinal B-cell lymphoma (PMBCL) and mantle cell lymphoma.

KTE-C19 is an investigational chimeric antigen receptor (CAR) T-cell therapy designed to target CD19, a protein expressed on the cell surface of B-cell lymphomas and leukemias.

No other product candidate currently has orphan drug designation for the treatment of PMBCL in the European Union (EU).

KTE-C19 already has orphan drug designation to treat diffuse large B-cell lymphoma (DLBCL) in the US and the EU.

“We are conducting a phase 1/2 clinical trial of KTE-C19 in patients with refractory, aggressive non-Hodgkin lymphoma, including DLBCL and PMBCL, and plan to report initial topline results from the phase 1 portion of the trial later this year [at the ASH Annual Meeting],” said Arie Belldegrun, MD, Chairman, President, and Chief Executive Officer of Kite Pharmaceuticals, the company developing KTE-C19.

Trial results

Last year, researchers reported results with KTE-C19 in the Journal of Clinical Oncology. The study included 15 patients with advanced B-cell malignancies.

The patients received a conditioning regimen of cyclophosphamide and fludarabine, followed 1 day later by a single infusion of KTE-C19. The researchers noted that the conditioning regimen is known to be active against B-cell malignancies and could have made a direct contribution to patient responses.

Thirteen patients were evaluable for response. Eight patients achieved a complete response (CR), and 4 had a partial response (PR).

Of the 7 patients with chemotherapy-refractory DLBCL, 4 achieved a CR, 2 achieved a PR, and 1 had stable disease. Of the 4 patients with chronic lymphocytic leukemia, 3 had a CR, and 1 had a PR. Among the 2 patients with indolent lymphomas, 1 achieved a CR, and 1 had a PR.

KTE-C19 was associated with fever, low blood pressure, focal neurological deficits, and delirium. Toxicities largely occurred in the first 2 weeks after infusion.

All but 2 patients experienced grade 3/4 adverse events. Four patients had grade 3/4 hypotension.

All patients had elevations in serum interferon gamma and/or interleukin 6 around the time of peak toxicity, but most did not develop elevations in serum tumor necrosis factor.

Neurologic toxicities included confusion and obtundation, which have been reported in previous studies. However, 3 patients developed unexpected neurologic abnormalities.

About orphan designation

The EMA’s Committee for Orphan Medicinal Products adopts an opinion on the granting of orphan designation, and that opinion is submitted to the European Commission for endorsement.

In the EU, orphan designation is granted to therapies intended to treat a life-threatening or chronically debilitating condition that affects no more than 5 in 10,000 persons and where no satisfactory treatment is available.

Companies that obtain orphan designation for a drug benefit from a number of incentives, including protocol assistance, a type of scientific advice specific for designated orphan medicines, and 10 years of market exclusivity once the medicine is approved. Fee reductions are also available, depending on the status of the sponsor and the type of service required.

Red blood cells

The US Food and Drug Administration (FDA) has granted orphan designation for DTX101 as a treatment for hemophilia B.

DTX101 is designed to deliver factor IX gene expression in a durable fashion to prevent the long-term complications of hemophilia B.

Preclinical studies have indicated that DTX101 has the potential to be a well-tolerated, effective therapy for hemophilia B, according to Dimension Therapeutics, Inc., the company developing DTX101.

The company said it expects to initiate a multicenter, phase 1/2 study to evaluate DTX101 in adults with moderate/severe to severe hemophilia B by the end of this year.

About orphan designation

The FDA grants orphan designation to drugs and biologics intended to treat rare diseases or conditions that affect fewer than 200,000 people in the US.

Orphan designation provides the company developing a drug with certain benefits, such as tax credits for qualified clinical trials, exemption from FDA user fees, and 7 years of market exclusivity if the drug is approved.

Red blood cells

The US Food and Drug Administration (FDA) has granted orphan designation for DTX101 as a treatment for hemophilia B.

DTX101 is designed to deliver factor IX gene expression in a durable fashion to prevent the long-term complications of hemophilia B.

Preclinical studies have indicated that DTX101 has the potential to be a well-tolerated, effective therapy for hemophilia B, according to Dimension Therapeutics, Inc., the company developing DTX101.

The company said it expects to initiate a multicenter, phase 1/2 study to evaluate DTX101 in adults with moderate/severe to severe hemophilia B by the end of this year.

About orphan designation

The FDA grants orphan designation to drugs and biologics intended to treat rare diseases or conditions that affect fewer than 200,000 people in the US.

Orphan designation provides the company developing a drug with certain benefits, such as tax credits for qualified clinical trials, exemption from FDA user fees, and 7 years of market exclusivity if the drug is approved.

Red blood cells

The US Food and Drug Administration (FDA) has granted orphan designation for DTX101 as a treatment for hemophilia B.

DTX101 is designed to deliver factor IX gene expression in a durable fashion to prevent the long-term complications of hemophilia B.

Preclinical studies have indicated that DTX101 has the potential to be a well-tolerated, effective therapy for hemophilia B, according to Dimension Therapeutics, Inc., the company developing DTX101.

The company said it expects to initiate a multicenter, phase 1/2 study to evaluate DTX101 in adults with moderate/severe to severe hemophilia B by the end of this year.

About orphan designation

The FDA grants orphan designation to drugs and biologics intended to treat rare diseases or conditions that affect fewer than 200,000 people in the US.

Orphan designation provides the company developing a drug with certain benefits, such as tax credits for qualified clinical trials, exemption from FDA user fees, and 7 years of market exclusivity if the drug is approved.

Nicotiana benthamiana plants

Scientists have reported a new way to produce the chemotherapeutic agent etoposide, and they believe this discovery could lead to a more stable supply of the drug.

Currently, producing etoposide requires isolating one of its precursors, (–)-podophyllotoxin, from the endangered, slow-growing, Himalayan Mayapple plant (Podophyllum hexandrum).

But researchers found they could generate the immediate precursor to etoposide—(–)-4’-desmethyl-epipodophyllotoxin—in a more easily accessible, faster-growing tobacco plant (Nicotiana benthamiana).

Elizabeth Sattely, PhD, of Stanford University in California, and her graduate student, Warren Lau, described this work in Science.

The pair noted that there are 4 known genes behind (–)-podophyllotoxin production, but the full recipe for this compound has eluded researchers, in part because of the Mayapple’s immense genome.

To tap into the Mayapple’s chemotherapeutic potential, Lau and Dr Sattely first focused on the 4 known genes—PLR, SDH, CYP719A23, and DIR. Then, they analyzed RNA sequencing data from the Mayapple to identify similar genes.

Next, the pair manipulated the tobacco plant to express multiple gene candidates at once and identified the resulting compounds in leaf tissue using mass spectrometry.

Dr Sattely and Lau identified 6 new genes—OMT3, CYP71CU1, OMT1, 2-ODD, CYP71BE54, and CYP82D61.

These genes, when expressed with the original 4, produce the immediate etoposide precursor (–)-4′-desmethyl-epipodophyllotoxin, which outperforms (–)-podophyllotoxin as a chemotherapy ingredient.

The researchers said this work has revealed a simpler and more direct route to etoposide that circumvents the semisynthetic epimerization and demethylation required to produce etoposide from (–)-podophyllotoxin.

However, Dr Sattely said the eventual goal is to use yeast instead of plants to produce etoposide. Yeast can be grown in large vats and may therefore provide a more stable source of drugs.

In addition, yeast provides the opportunity to modify genes to produce proteins with slightly different functions. And it may be possible to feed the yeast a slightly different starting product, thereby changing the chemical a molecular assembly line churns out.

These approaches could provide a way of tweaking existing drugs in an effort to improve them.

Nicotiana benthamiana plants

Scientists have reported a new way to produce the chemotherapeutic agent etoposide, and they believe this discovery could lead to a more stable supply of the drug.

Currently, producing etoposide requires isolating one of its precursors, (–)-podophyllotoxin, from the endangered, slow-growing, Himalayan Mayapple plant (Podophyllum hexandrum).

But researchers found they could generate the immediate precursor to etoposide—(–)-4’-desmethyl-epipodophyllotoxin—in a more easily accessible, faster-growing tobacco plant (Nicotiana benthamiana).

Elizabeth Sattely, PhD, of Stanford University in California, and her graduate student, Warren Lau, described this work in Science.

The pair noted that there are 4 known genes behind (–)-podophyllotoxin production, but the full recipe for this compound has eluded researchers, in part because of the Mayapple’s immense genome.

To tap into the Mayapple’s chemotherapeutic potential, Lau and Dr Sattely first focused on the 4 known genes—PLR, SDH, CYP719A23, and DIR. Then, they analyzed RNA sequencing data from the Mayapple to identify similar genes.

Next, the pair manipulated the tobacco plant to express multiple gene candidates at once and identified the resulting compounds in leaf tissue using mass spectrometry.

Dr Sattely and Lau identified 6 new genes—OMT3, CYP71CU1, OMT1, 2-ODD, CYP71BE54, and CYP82D61.

These genes, when expressed with the original 4, produce the immediate etoposide precursor (–)-4′-desmethyl-epipodophyllotoxin, which outperforms (–)-podophyllotoxin as a chemotherapy ingredient.

The researchers said this work has revealed a simpler and more direct route to etoposide that circumvents the semisynthetic epimerization and demethylation required to produce etoposide from (–)-podophyllotoxin.

However, Dr Sattely said the eventual goal is to use yeast instead of plants to produce etoposide. Yeast can be grown in large vats and may therefore provide a more stable source of drugs.

In addition, yeast provides the opportunity to modify genes to produce proteins with slightly different functions. And it may be possible to feed the yeast a slightly different starting product, thereby changing the chemical a molecular assembly line churns out.

These approaches could provide a way of tweaking existing drugs in an effort to improve them.

Nicotiana benthamiana plants

Scientists have reported a new way to produce the chemotherapeutic agent etoposide, and they believe this discovery could lead to a more stable supply of the drug.

Currently, producing etoposide requires isolating one of its precursors, (–)-podophyllotoxin, from the endangered, slow-growing, Himalayan Mayapple plant (Podophyllum hexandrum).

But researchers found they could generate the immediate precursor to etoposide—(–)-4’-desmethyl-epipodophyllotoxin—in a more easily accessible, faster-growing tobacco plant (Nicotiana benthamiana).

Elizabeth Sattely, PhD, of Stanford University in California, and her graduate student, Warren Lau, described this work in Science.

The pair noted that there are 4 known genes behind (–)-podophyllotoxin production, but the full recipe for this compound has eluded researchers, in part because of the Mayapple’s immense genome.

To tap into the Mayapple’s chemotherapeutic potential, Lau and Dr Sattely first focused on the 4 known genes—PLR, SDH, CYP719A23, and DIR. Then, they analyzed RNA sequencing data from the Mayapple to identify similar genes.

Next, the pair manipulated the tobacco plant to express multiple gene candidates at once and identified the resulting compounds in leaf tissue using mass spectrometry.

Dr Sattely and Lau identified 6 new genes—OMT3, CYP71CU1, OMT1, 2-ODD, CYP71BE54, and CYP82D61.

These genes, when expressed with the original 4, produce the immediate etoposide precursor (–)-4′-desmethyl-epipodophyllotoxin, which outperforms (–)-podophyllotoxin as a chemotherapy ingredient.

The researchers said this work has revealed a simpler and more direct route to etoposide that circumvents the semisynthetic epimerization and demethylation required to produce etoposide from (–)-podophyllotoxin.

However, Dr Sattely said the eventual goal is to use yeast instead of plants to produce etoposide. Yeast can be grown in large vats and may therefore provide a more stable source of drugs.

In addition, yeast provides the opportunity to modify genes to produce proteins with slightly different functions. And it may be possible to feed the yeast a slightly different starting product, thereby changing the chemical a molecular assembly line churns out.

These approaches could provide a way of tweaking existing drugs in an effort to improve them.