Pharmacy

 

 

CLL cells

 

The European Medicines Agency (EMA) has granted orphan drug designation for selinexor (KPT-330) to treat multiple myeloma (MM) and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), including Richter’s transformation.

Selinexor previously received orphan designation from both the EMA and the US Food and Drug Administration to treat patients with acute myeloid leukemia and those with diffuse large B-cell lymphoma.

Orphan designation is granted to promote the development of drugs that target rare, life-threatening or debilitating conditions and are expected to provide a significant therapeutic advantage over existing treatments.

Orphan designation qualifies a company—in this case, Karyopharm Therapeutics Inc.—for benefits that include targeted scientific advice from the EMA regarding drug development and 10 years of market exclusivity following the drug’s approval.

About selinexor

Selinexor (KPT-330) is a first-in-class, oral selective inhibitor of nuclear export (SINE) compound. Selinexor functions by inhibiting the nuclear export protein XPO1 (also called CRM1).

This leads to the accumulation of tumor suppressor proteins in the cell nucleus, which subsequently reinitiates and amplifies their tumor suppressor function. This is thought to prompt apoptosis in cancer cells while largely sparing normal cells.

Selinexor has shown promise in an ongoing phase 1 study of patients with a range of hematologic malignancies. Results of this trial were presented at the 2014 ASCO Annual Meeting.

At that point, the study included 51 patients who had received selinexor across 8 dose levels, ranging from 3 mg/m² to 60 mg/m².

Among the 43 patients evaluable for response, the overall response rate was 28%, and the complete response rate was 5%.

Most adverse events were gastrointestinal in nature, and most of them were grade 1 or 2. The most common adverse events were nausea, anorexia, and fatigue.

There were 3 dose-limiting toxicities, including 1 MM patient with grade 4 thrombocytopenia, 1 follicular lymphoma patient with grade 4 thrombocytopenia, and 1 CLL patient with grade 2 fatigue.

 

 

CLL cells

 

The European Medicines Agency (EMA) has granted orphan drug designation for selinexor (KPT-330) to treat multiple myeloma (MM) and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), including Richter’s transformation.

Selinexor previously received orphan designation from both the EMA and the US Food and Drug Administration to treat patients with acute myeloid leukemia and those with diffuse large B-cell lymphoma.

Orphan designation is granted to promote the development of drugs that target rare, life-threatening or debilitating conditions and are expected to provide a significant therapeutic advantage over existing treatments.

Orphan designation qualifies a company—in this case, Karyopharm Therapeutics Inc.—for benefits that include targeted scientific advice from the EMA regarding drug development and 10 years of market exclusivity following the drug’s approval.

About selinexor

Selinexor (KPT-330) is a first-in-class, oral selective inhibitor of nuclear export (SINE) compound. Selinexor functions by inhibiting the nuclear export protein XPO1 (also called CRM1).

This leads to the accumulation of tumor suppressor proteins in the cell nucleus, which subsequently reinitiates and amplifies their tumor suppressor function. This is thought to prompt apoptosis in cancer cells while largely sparing normal cells.

Selinexor has shown promise in an ongoing phase 1 study of patients with a range of hematologic malignancies. Results of this trial were presented at the 2014 ASCO Annual Meeting.

At that point, the study included 51 patients who had received selinexor across 8 dose levels, ranging from 3 mg/m² to 60 mg/m².

Among the 43 patients evaluable for response, the overall response rate was 28%, and the complete response rate was 5%.

Most adverse events were gastrointestinal in nature, and most of them were grade 1 or 2. The most common adverse events were nausea, anorexia, and fatigue.

There were 3 dose-limiting toxicities, including 1 MM patient with grade 4 thrombocytopenia, 1 follicular lymphoma patient with grade 4 thrombocytopenia, and 1 CLL patient with grade 2 fatigue.

 

 

CLL cells

 

The European Medicines Agency (EMA) has granted orphan drug designation for selinexor (KPT-330) to treat multiple myeloma (MM) and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), including Richter’s transformation.

Selinexor previously received orphan designation from both the EMA and the US Food and Drug Administration to treat patients with acute myeloid leukemia and those with diffuse large B-cell lymphoma.

Orphan designation is granted to promote the development of drugs that target rare, life-threatening or debilitating conditions and are expected to provide a significant therapeutic advantage over existing treatments.

Orphan designation qualifies a company—in this case, Karyopharm Therapeutics Inc.—for benefits that include targeted scientific advice from the EMA regarding drug development and 10 years of market exclusivity following the drug’s approval.

About selinexor

Selinexor (KPT-330) is a first-in-class, oral selective inhibitor of nuclear export (SINE) compound. Selinexor functions by inhibiting the nuclear export protein XPO1 (also called CRM1).

This leads to the accumulation of tumor suppressor proteins in the cell nucleus, which subsequently reinitiates and amplifies their tumor suppressor function. This is thought to prompt apoptosis in cancer cells while largely sparing normal cells.

Selinexor has shown promise in an ongoing phase 1 study of patients with a range of hematologic malignancies. Results of this trial were presented at the 2014 ASCO Annual Meeting.

At that point, the study included 51 patients who had received selinexor across 8 dose levels, ranging from 3 mg/m² to 60 mg/m².

Among the 43 patients evaluable for response, the overall response rate was 28%, and the complete response rate was 5%.

Most adverse events were gastrointestinal in nature, and most of them were grade 1 or 2. The most common adverse events were nausea, anorexia, and fatigue.

There were 3 dose-limiting toxicities, including 1 MM patient with grade 4 thrombocytopenia, 1 follicular lymphoma patient with grade 4 thrombocytopenia, and 1 CLL patient with grade 2 fatigue.

Eculizumab (Solirus)

Credit: Globovision

The UK’s National Institute for Health and Care Excellence (NICE) has issued a final draft guidance recommending eculizumab (Soliris) for funding to treat atypical hemolytic uremic syndrome (aHUS).

However, the agency has a few requirements. Eculizumab use must be coordinated through an expert center.

And monitoring systems must record the number of people with aHUS, the number who receive eculizumab, and the dose and duration of treatment.

NICE is also requiring a national protocol for starting and stopping eculizumab for clinical reasons and a research program with robust methods to evaluate when stopping treatment or dose adjustment might occur.

“[A NICE advisory] committee accepted that eculizumab is a step change in the management of aHUS and can be considered a significant innovation for a disease with a high unmet clinical need,” said NICE Chief Executive Sir Andrew Dillon.

“Eculizumab offers people with aHUS the possibility of avoiding end-stage renal failure, dialysis, and kidney transplantation, as well as other organ damage. The drug is, however, very expensive. The committee felt that the budget impact of eculizumab would be lower if the potential for dose adjustment and stopping treatment was explored.”

“This is reflected in the draft guidance, which recommends eculizumab should be funded only if important conditions are met, including the development of rules for starting and stopping treatment for clinical reasons. In the meantime, NHS England and the company [developing the drug, Alexion Pharmaceuticals] should consider what opportunities might exist to reduce the cost of eculizumab to the NHS.”

Eculizumab: Dosing, cost, and benefit

Eculizumab is given intravenously in adults as initial treatment at a dose of 900 mg for 4 weeks, then as maintenance treatment at a dose of 1200 mg on week 5, and then every 12 to 16 days. The summary of product characteristics for eculizumab states that “treatment is recommended to continue for a patient’s lifetime, unless discontinuation of treatment is clinically indicated.”

Eculizumab costs £3150 per 30 ml vial (excluding value-added tax). The net budget impact of eculizumab based on the company’s predicted rate of uptake over a 5-year period is confidential.

However, to allow consultees and commentators to properly engage in the consultation process, NICE has prepared an illustration of the possible budget impact of eculizumab for aHUS, using information available in the public domain.

NICE’s estimate is based on a treatment cost of £340,200 per adult patient in the first year (based on the acquisition cost of the drug and the recommended dosing for an adult), and assumes a patient cohort of 170, as estimated by NHS England in its interim commissioning policy.

If it is assumed that all of these adult patients with aHUS are treated with eculizumab, the budget impact for the first year would be £57.8 million.

If an additional 20 new patients are treated the following year (based on a worldwide incidence of 0.4 per million), the budget impact will rise to £62.5 million in year 2, assuming all new patients are treated and all existing patients continue to be treated at the maintenance cost of £327,600 per year.

Using the same assumptions, the budget impact will rise to £69 million in year 3 (190 existing and 20 new patients), £75 million in year 4 (210 existing and 20 new patients), and £82 million in year 5 (230 existing and 20 new patients).

NHS England has indicated that the amount of the budget allocated for highly specialized services in 2013/2014 was £544 million, and the spending on high-cost drugs was £156 million.

The advisory committee acknowledged that the company’s estimate of the incremental cost of eculizumab compared with standard care was considerable and that incremental costs estimated by the evidence review group were higher still (results are confidential).

The company estimated that eculizumab produced 25.22 additional quality-adjusted life-years (QALYs) per patient compared with standard care. Although the QALYs estimated in the evidence review group’s analysis were markedly lower than those calculated by the company, both analyses produced substantial QALY gains of a magnitude that is rarely seen for any new drug treatment.

NICE has not yet issued final guidance on eculizumab in aHUS. The draft guidance is now with consultees, including the company, healthcare professionals, and patient/carer organizations, who have the opportunity to appeal against the draft recommendations.

Final guidance on the use of eculizumab to treat aHUS is expected in January 2015.

Eculizumab (Solirus)

Credit: Globovision

The UK’s National Institute for Health and Care Excellence (NICE) has issued a final draft guidance recommending eculizumab (Soliris) for funding to treat atypical hemolytic uremic syndrome (aHUS).

However, the agency has a few requirements. Eculizumab use must be coordinated through an expert center.

And monitoring systems must record the number of people with aHUS, the number who receive eculizumab, and the dose and duration of treatment.

NICE is also requiring a national protocol for starting and stopping eculizumab for clinical reasons and a research program with robust methods to evaluate when stopping treatment or dose adjustment might occur.

“[A NICE advisory] committee accepted that eculizumab is a step change in the management of aHUS and can be considered a significant innovation for a disease with a high unmet clinical need,” said NICE Chief Executive Sir Andrew Dillon.

“Eculizumab offers people with aHUS the possibility of avoiding end-stage renal failure, dialysis, and kidney transplantation, as well as other organ damage. The drug is, however, very expensive. The committee felt that the budget impact of eculizumab would be lower if the potential for dose adjustment and stopping treatment was explored.”

“This is reflected in the draft guidance, which recommends eculizumab should be funded only if important conditions are met, including the development of rules for starting and stopping treatment for clinical reasons. In the meantime, NHS England and the company [developing the drug, Alexion Pharmaceuticals] should consider what opportunities might exist to reduce the cost of eculizumab to the NHS.”

Eculizumab: Dosing, cost, and benefit

Eculizumab is given intravenously in adults as initial treatment at a dose of 900 mg for 4 weeks, then as maintenance treatment at a dose of 1200 mg on week 5, and then every 12 to 16 days. The summary of product characteristics for eculizumab states that “treatment is recommended to continue for a patient’s lifetime, unless discontinuation of treatment is clinically indicated.”

Eculizumab costs £3150 per 30 ml vial (excluding value-added tax). The net budget impact of eculizumab based on the company’s predicted rate of uptake over a 5-year period is confidential.

However, to allow consultees and commentators to properly engage in the consultation process, NICE has prepared an illustration of the possible budget impact of eculizumab for aHUS, using information available in the public domain.

NICE’s estimate is based on a treatment cost of £340,200 per adult patient in the first year (based on the acquisition cost of the drug and the recommended dosing for an adult), and assumes a patient cohort of 170, as estimated by NHS England in its interim commissioning policy.

If it is assumed that all of these adult patients with aHUS are treated with eculizumab, the budget impact for the first year would be £57.8 million.

If an additional 20 new patients are treated the following year (based on a worldwide incidence of 0.4 per million), the budget impact will rise to £62.5 million in year 2, assuming all new patients are treated and all existing patients continue to be treated at the maintenance cost of £327,600 per year.

Using the same assumptions, the budget impact will rise to £69 million in year 3 (190 existing and 20 new patients), £75 million in year 4 (210 existing and 20 new patients), and £82 million in year 5 (230 existing and 20 new patients).

NHS England has indicated that the amount of the budget allocated for highly specialized services in 2013/2014 was £544 million, and the spending on high-cost drugs was £156 million.

The advisory committee acknowledged that the company’s estimate of the incremental cost of eculizumab compared with standard care was considerable and that incremental costs estimated by the evidence review group were higher still (results are confidential).

The company estimated that eculizumab produced 25.22 additional quality-adjusted life-years (QALYs) per patient compared with standard care. Although the QALYs estimated in the evidence review group’s analysis were markedly lower than those calculated by the company, both analyses produced substantial QALY gains of a magnitude that is rarely seen for any new drug treatment.

NICE has not yet issued final guidance on eculizumab in aHUS. The draft guidance is now with consultees, including the company, healthcare professionals, and patient/carer organizations, who have the opportunity to appeal against the draft recommendations.

Final guidance on the use of eculizumab to treat aHUS is expected in January 2015.

Eculizumab (Solirus)

Credit: Globovision

The UK’s National Institute for Health and Care Excellence (NICE) has issued a final draft guidance recommending eculizumab (Soliris) for funding to treat atypical hemolytic uremic syndrome (aHUS).

However, the agency has a few requirements. Eculizumab use must be coordinated through an expert center.

And monitoring systems must record the number of people with aHUS, the number who receive eculizumab, and the dose and duration of treatment.

NICE is also requiring a national protocol for starting and stopping eculizumab for clinical reasons and a research program with robust methods to evaluate when stopping treatment or dose adjustment might occur.

“[A NICE advisory] committee accepted that eculizumab is a step change in the management of aHUS and can be considered a significant innovation for a disease with a high unmet clinical need,” said NICE Chief Executive Sir Andrew Dillon.

“Eculizumab offers people with aHUS the possibility of avoiding end-stage renal failure, dialysis, and kidney transplantation, as well as other organ damage. The drug is, however, very expensive. The committee felt that the budget impact of eculizumab would be lower if the potential for dose adjustment and stopping treatment was explored.”

“This is reflected in the draft guidance, which recommends eculizumab should be funded only if important conditions are met, including the development of rules for starting and stopping treatment for clinical reasons. In the meantime, NHS England and the company [developing the drug, Alexion Pharmaceuticals] should consider what opportunities might exist to reduce the cost of eculizumab to the NHS.”

Eculizumab: Dosing, cost, and benefit

Eculizumab is given intravenously in adults as initial treatment at a dose of 900 mg for 4 weeks, then as maintenance treatment at a dose of 1200 mg on week 5, and then every 12 to 16 days. The summary of product characteristics for eculizumab states that “treatment is recommended to continue for a patient’s lifetime, unless discontinuation of treatment is clinically indicated.”

Eculizumab costs £3150 per 30 ml vial (excluding value-added tax). The net budget impact of eculizumab based on the company’s predicted rate of uptake over a 5-year period is confidential.

However, to allow consultees and commentators to properly engage in the consultation process, NICE has prepared an illustration of the possible budget impact of eculizumab for aHUS, using information available in the public domain.

NICE’s estimate is based on a treatment cost of £340,200 per adult patient in the first year (based on the acquisition cost of the drug and the recommended dosing for an adult), and assumes a patient cohort of 170, as estimated by NHS England in its interim commissioning policy.

If it is assumed that all of these adult patients with aHUS are treated with eculizumab, the budget impact for the first year would be £57.8 million.

If an additional 20 new patients are treated the following year (based on a worldwide incidence of 0.4 per million), the budget impact will rise to £62.5 million in year 2, assuming all new patients are treated and all existing patients continue to be treated at the maintenance cost of £327,600 per year.

Using the same assumptions, the budget impact will rise to £69 million in year 3 (190 existing and 20 new patients), £75 million in year 4 (210 existing and 20 new patients), and £82 million in year 5 (230 existing and 20 new patients).

NHS England has indicated that the amount of the budget allocated for highly specialized services in 2013/2014 was £544 million, and the spending on high-cost drugs was £156 million.

The advisory committee acknowledged that the company’s estimate of the incremental cost of eculizumab compared with standard care was considerable and that incremental costs estimated by the evidence review group were higher still (results are confidential).

The company estimated that eculizumab produced 25.22 additional quality-adjusted life-years (QALYs) per patient compared with standard care. Although the QALYs estimated in the evidence review group’s analysis were markedly lower than those calculated by the company, both analyses produced substantial QALY gains of a magnitude that is rarely seen for any new drug treatment.

NICE has not yet issued final guidance on eculizumab in aHUS. The draft guidance is now with consultees, including the company, healthcare professionals, and patient/carer organizations, who have the opportunity to appeal against the draft recommendations.

Final guidance on the use of eculizumab to treat aHUS is expected in January 2015.

The US Food and Drug Administration (FDA) has granted orphan drug designation for Actimab-A, an alpha radiolabeled antibody, to treat patients over the age of 60 who are newly diagnosed with acute myeloid leukemia (AML).

Actimab-A consists of the CD33 antibody lintuzumab linked to the actinium-225 payload. The product is currently under investigation in a multicenter, phase 1/2 trial of elderly AML patients.

The company developing Actimab-A, Actinium Pharmaceuticals, Inc., recently announced positive interim data from this trial.

Nine patients were evaluable. They had a median age of 76 (range, 73-81) and intermediate- or poor-risk cytogenetics.

The median overall survival was 5.4 months (range, 2.2-24 months), but survival was better for the 7 patients who had secondary AML. These patients had a median overall survival of 9.1 months from study entry (range, 2.3-24 months).

Two secondary AML patients lived longer than 12 months, and the longest surviving patient lived more than 24 months.

Two dosing levels of Actimab-A have been evaluated to date (0.5 or 1.0 μCi/kg/fraction), and the study is ongoing at higher doses until the maximum tolerated dose is reached.

Actinium expects additional data from this trial to be available in 2015.

“The FDA’s decision to grant orphan drug status for Actimab-A is a significant milestone for the company and recognizes the need for innovative new approaches to treat AML,” said Kaushik J. Dave, PhD, President and CEO of Actinium.

“The designation will provide Actinium access to various development benefits and financial incentives from the agency, including an exemption from prescription drug user fees for Actimab-A for this indication and, if the drug receives marketing approval, it will enjoy 7 years of market exclusivity in the United States.”

The US Food and Drug Administration (FDA) has granted orphan drug designation for Actimab-A, an alpha radiolabeled antibody, to treat patients over the age of 60 who are newly diagnosed with acute myeloid leukemia (AML).

Actimab-A consists of the CD33 antibody lintuzumab linked to the actinium-225 payload. The product is currently under investigation in a multicenter, phase 1/2 trial of elderly AML patients.

The company developing Actimab-A, Actinium Pharmaceuticals, Inc., recently announced positive interim data from this trial.

Nine patients were evaluable. They had a median age of 76 (range, 73-81) and intermediate- or poor-risk cytogenetics.

The median overall survival was 5.4 months (range, 2.2-24 months), but survival was better for the 7 patients who had secondary AML. These patients had a median overall survival of 9.1 months from study entry (range, 2.3-24 months).

Two secondary AML patients lived longer than 12 months, and the longest surviving patient lived more than 24 months.

Two dosing levels of Actimab-A have been evaluated to date (0.5 or 1.0 μCi/kg/fraction), and the study is ongoing at higher doses until the maximum tolerated dose is reached.

Actinium expects additional data from this trial to be available in 2015.

“The FDA’s decision to grant orphan drug status for Actimab-A is a significant milestone for the company and recognizes the need for innovative new approaches to treat AML,” said Kaushik J. Dave, PhD, President and CEO of Actinium.

“The designation will provide Actinium access to various development benefits and financial incentives from the agency, including an exemption from prescription drug user fees for Actimab-A for this indication and, if the drug receives marketing approval, it will enjoy 7 years of market exclusivity in the United States.”

The US Food and Drug Administration (FDA) has granted orphan drug designation for Actimab-A, an alpha radiolabeled antibody, to treat patients over the age of 60 who are newly diagnosed with acute myeloid leukemia (AML).

Actimab-A consists of the CD33 antibody lintuzumab linked to the actinium-225 payload. The product is currently under investigation in a multicenter, phase 1/2 trial of elderly AML patients.

The company developing Actimab-A, Actinium Pharmaceuticals, Inc., recently announced positive interim data from this trial.

Nine patients were evaluable. They had a median age of 76 (range, 73-81) and intermediate- or poor-risk cytogenetics.

The median overall survival was 5.4 months (range, 2.2-24 months), but survival was better for the 7 patients who had secondary AML. These patients had a median overall survival of 9.1 months from study entry (range, 2.3-24 months).

Two secondary AML patients lived longer than 12 months, and the longest surviving patient lived more than 24 months.

Two dosing levels of Actimab-A have been evaluated to date (0.5 or 1.0 μCi/kg/fraction), and the study is ongoing at higher doses until the maximum tolerated dose is reached.

Actinium expects additional data from this trial to be available in 2015.

“The FDA’s decision to grant orphan drug status for Actimab-A is a significant milestone for the company and recognizes the need for innovative new approaches to treat AML,” said Kaushik J. Dave, PhD, President and CEO of Actinium.

“The designation will provide Actinium access to various development benefits and financial incentives from the agency, including an exemption from prescription drug user fees for Actimab-A for this indication and, if the drug receives marketing approval, it will enjoy 7 years of market exclusivity in the United States.”

Micrograph showing amyloidosis

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for the oral proteasome inhibitor ixazomib (MLN9708) to treat relapsed or refractory systemic light-chain (AL) amyloidosis.

This is the first proteasome inhibitor and the first investigational therapy for AL amyloidosis to receive breakthrough designation.

Ixazomib already has orphan drug designation in the US and the European Union for this indication and to treat multiple myeloma (MM).

The FDA’s breakthrough therapy designation is intended to expedite the development and review of new medicines to treat serious or life-threatening conditions. Compounds given the designation receive more intensive FDA guidance on an efficient drug development program and an enhanced agency commitment of senior personnel.

Breakthrough therapy designation requires preliminary clinical evidence indicating the drug may demonstrate substantial improvement on a clinically significant endpoint (or endpoints) over available therapies.

The data used to support this designation for ixazomib came from a phase 1 trial that is set to be presented at the 2014 ASH Annual Meeting as abstract 3450.

The development program for ixazomib in AL amyloidosis progressed directly from a phase 1 to a phase 3 clinical trial, TOURMALINE-AL1. Ixazomib is the first oral proteasome inhibitor to enter phase 3 clinical trials, and 4 global phase 3 trials are ongoing:

• TOURMALINE-MM1, an investigation of ixazomib vs placebo in combination with lenalidomide and dexamethasone in relapsed and/or refractory MM
• TOURMALINE-AL1, an investigation of ixazomib plus dexamethasone in patients with relapsed or refractory AL amyloidosis
• TOURMALINE-MM2, an investigation of ixazomib vs placebo in combination with lenalidomide and dexamethasone in patients with newly diagnosed MM
• TOURMALINE-MM3, an investigation of ixazomib vs placebo as maintenance therapy in patients with newly diagnosed MM following induction therapy and autologous stem cell transplant.

For additional information on the ongoing phase 3 studies, visit www.tourmalinetrials.com or www.clinicaltrials.gov. Ixazomib is under development by Millennium: the Takeda Oncology Company.

Micrograph showing amyloidosis

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for the oral proteasome inhibitor ixazomib (MLN9708) to treat relapsed or refractory systemic light-chain (AL) amyloidosis.

This is the first proteasome inhibitor and the first investigational therapy for AL amyloidosis to receive breakthrough designation.

Ixazomib already has orphan drug designation in the US and the European Union for this indication and to treat multiple myeloma (MM).

The FDA’s breakthrough therapy designation is intended to expedite the development and review of new medicines to treat serious or life-threatening conditions. Compounds given the designation receive more intensive FDA guidance on an efficient drug development program and an enhanced agency commitment of senior personnel.

Breakthrough therapy designation requires preliminary clinical evidence indicating the drug may demonstrate substantial improvement on a clinically significant endpoint (or endpoints) over available therapies.

The data used to support this designation for ixazomib came from a phase 1 trial that is set to be presented at the 2014 ASH Annual Meeting as abstract 3450.

The development program for ixazomib in AL amyloidosis progressed directly from a phase 1 to a phase 3 clinical trial, TOURMALINE-AL1. Ixazomib is the first oral proteasome inhibitor to enter phase 3 clinical trials, and 4 global phase 3 trials are ongoing:

• TOURMALINE-MM1, an investigation of ixazomib vs placebo in combination with lenalidomide and dexamethasone in relapsed and/or refractory MM
• TOURMALINE-AL1, an investigation of ixazomib plus dexamethasone in patients with relapsed or refractory AL amyloidosis
• TOURMALINE-MM2, an investigation of ixazomib vs placebo in combination with lenalidomide and dexamethasone in patients with newly diagnosed MM
• TOURMALINE-MM3, an investigation of ixazomib vs placebo as maintenance therapy in patients with newly diagnosed MM following induction therapy and autologous stem cell transplant.

For additional information on the ongoing phase 3 studies, visit www.tourmalinetrials.com or www.clinicaltrials.gov. Ixazomib is under development by Millennium: the Takeda Oncology Company.

Micrograph showing amyloidosis

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for the oral proteasome inhibitor ixazomib (MLN9708) to treat relapsed or refractory systemic light-chain (AL) amyloidosis.

This is the first proteasome inhibitor and the first investigational therapy for AL amyloidosis to receive breakthrough designation.

Ixazomib already has orphan drug designation in the US and the European Union for this indication and to treat multiple myeloma (MM).

The FDA’s breakthrough therapy designation is intended to expedite the development and review of new medicines to treat serious or life-threatening conditions. Compounds given the designation receive more intensive FDA guidance on an efficient drug development program and an enhanced agency commitment of senior personnel.

Breakthrough therapy designation requires preliminary clinical evidence indicating the drug may demonstrate substantial improvement on a clinically significant endpoint (or endpoints) over available therapies.

The data used to support this designation for ixazomib came from a phase 1 trial that is set to be presented at the 2014 ASH Annual Meeting as abstract 3450.

The development program for ixazomib in AL amyloidosis progressed directly from a phase 1 to a phase 3 clinical trial, TOURMALINE-AL1. Ixazomib is the first oral proteasome inhibitor to enter phase 3 clinical trials, and 4 global phase 3 trials are ongoing:

• TOURMALINE-MM1, an investigation of ixazomib vs placebo in combination with lenalidomide and dexamethasone in relapsed and/or refractory MM
• TOURMALINE-AL1, an investigation of ixazomib plus dexamethasone in patients with relapsed or refractory AL amyloidosis
• TOURMALINE-MM2, an investigation of ixazomib vs placebo in combination with lenalidomide and dexamethasone in patients with newly diagnosed MM
• TOURMALINE-MM3, an investigation of ixazomib vs placebo as maintenance therapy in patients with newly diagnosed MM following induction therapy and autologous stem cell transplant.

For additional information on the ongoing phase 3 studies, visit www.tourmalinetrials.com or www.clinicaltrials.gov. Ixazomib is under development by Millennium: the Takeda Oncology Company.

Cancer patient receiving

chemotherapy

Credit: Rhoda Baer

The UK’s National Institute for Health and Care Excellence (NICE) has updated its guidance to expand the use of erythropoiesis-stimulating agents (ESAs) in cancer patients.

In 2008, NICE issued a guidance recommending ESAs as a possible treatment for certain patients with anemia caused by cancer treatment.

Now, NICE has updated the recommendations to expand the use of ESAs—epoetin alfa, beta, theta, and zeta, as well as darbepoetin alfa—to all other indications within their UK marketing authorizations.

“A lot of people with cancer having chemotherapy will become anemic,” noted Carole Longson, director of the Centre for Health Technology Evaluation at NICE.

“Managing anemia often requires extra trips to the hospital and can significantly affect a person’s quality of life. This updated final guidance recommends more options, epoetin and darbepoetin, that are both clinically and cost-effective and which also significantly improve quality of life for people who develop anemia whilst having cancer therapy.”

The 2008 NICE guidance recommended erythropoietin analogues with iron injections as a possible treatment for anemia caused by cancer treatment only in:

• Women receiving platinum-based chemotherapy for cancer of the ovaries who have a blood hemoglobin level of 8 g/100 mL or lower
• Patients who have very severe anemia and cannot receive blood transfusions.

NICE’s updated final guidance recommends using darbepoetin alfa and epoetin alfa, beta, theta, and zeta within their marketing authorizations as an option for treating anemia in cancer patients undergoing chemotherapy.

Epoetin alfa (Eprex, Janssen-Cilag, and Binocrit, Sandoz), and epoetin zeta (Retacrit, Hospira UK) have UK marketing authorization to treat anemia and to reduce transfusion requirements in adult patients receiving chemotherapy for solid tumors, malignant lymphoma, or multiple myeloma, who are at risk of transfusion as assessed by the patients’ general status (eg, cardiovascular status, pre-existing anemia at the start of chemotherapy).

Binocrit and Retacrit are both biosimilar medicines referenced to Eprex. Eprex, Binocrit, and Retacrit are available in pre-filled syringes at net prices of £5.53, £4.33, and £5.66 per 1000 units, respectively.

Epoetin beta (NeoRecormon, Roche Products) and epoetin theta (Eporatio, Teva UK) have UK marketing authorization to treat symptomatic anemia in adult patients with non-myeloid malignancies who are receiving chemotherapy.

NeoRecormon is available in a pre-filled syringe at a net price of £3.51 per 500 units, and Eporatio is available in a pre-filled syringe at a net price of £5.99 per 1000 units.

Darbepoetin alfa (Aranesp, Amgen) has UK marketing authorization to treat symptomatic anemia in adult cancer patients with non-myeloid malignancies who are receiving chemotherapy. Aranesp is available in a pre-filled syringe at a net price of £14.68 per 10 micrograms.

Costs (excluding value-added tax) may vary in different settings because of negotiated procurement discounts.

Cancer patient receiving

chemotherapy

Credit: Rhoda Baer

The UK’s National Institute for Health and Care Excellence (NICE) has updated its guidance to expand the use of erythropoiesis-stimulating agents (ESAs) in cancer patients.

In 2008, NICE issued a guidance recommending ESAs as a possible treatment for certain patients with anemia caused by cancer treatment.

Now, NICE has updated the recommendations to expand the use of ESAs—epoetin alfa, beta, theta, and zeta, as well as darbepoetin alfa—to all other indications within their UK marketing authorizations.

“A lot of people with cancer having chemotherapy will become anemic,” noted Carole Longson, director of the Centre for Health Technology Evaluation at NICE.

“Managing anemia often requires extra trips to the hospital and can significantly affect a person’s quality of life. This updated final guidance recommends more options, epoetin and darbepoetin, that are both clinically and cost-effective and which also significantly improve quality of life for people who develop anemia whilst having cancer therapy.”

The 2008 NICE guidance recommended erythropoietin analogues with iron injections as a possible treatment for anemia caused by cancer treatment only in:

• Women receiving platinum-based chemotherapy for cancer of the ovaries who have a blood hemoglobin level of 8 g/100 mL or lower
• Patients who have very severe anemia and cannot receive blood transfusions.

NICE’s updated final guidance recommends using darbepoetin alfa and epoetin alfa, beta, theta, and zeta within their marketing authorizations as an option for treating anemia in cancer patients undergoing chemotherapy.

Epoetin alfa (Eprex, Janssen-Cilag, and Binocrit, Sandoz), and epoetin zeta (Retacrit, Hospira UK) have UK marketing authorization to treat anemia and to reduce transfusion requirements in adult patients receiving chemotherapy for solid tumors, malignant lymphoma, or multiple myeloma, who are at risk of transfusion as assessed by the patients’ general status (eg, cardiovascular status, pre-existing anemia at the start of chemotherapy).

Binocrit and Retacrit are both biosimilar medicines referenced to Eprex. Eprex, Binocrit, and Retacrit are available in pre-filled syringes at net prices of £5.53, £4.33, and £5.66 per 1000 units, respectively.

Epoetin beta (NeoRecormon, Roche Products) and epoetin theta (Eporatio, Teva UK) have UK marketing authorization to treat symptomatic anemia in adult patients with non-myeloid malignancies who are receiving chemotherapy.

NeoRecormon is available in a pre-filled syringe at a net price of £3.51 per 500 units, and Eporatio is available in a pre-filled syringe at a net price of £5.99 per 1000 units.

Darbepoetin alfa (Aranesp, Amgen) has UK marketing authorization to treat symptomatic anemia in adult cancer patients with non-myeloid malignancies who are receiving chemotherapy. Aranesp is available in a pre-filled syringe at a net price of £14.68 per 10 micrograms.

Costs (excluding value-added tax) may vary in different settings because of negotiated procurement discounts.

Cancer patient receiving

chemotherapy

Credit: Rhoda Baer

The UK’s National Institute for Health and Care Excellence (NICE) has updated its guidance to expand the use of erythropoiesis-stimulating agents (ESAs) in cancer patients.

In 2008, NICE issued a guidance recommending ESAs as a possible treatment for certain patients with anemia caused by cancer treatment.

Now, NICE has updated the recommendations to expand the use of ESAs—epoetin alfa, beta, theta, and zeta, as well as darbepoetin alfa—to all other indications within their UK marketing authorizations.

“A lot of people with cancer having chemotherapy will become anemic,” noted Carole Longson, director of the Centre for Health Technology Evaluation at NICE.

“Managing anemia often requires extra trips to the hospital and can significantly affect a person’s quality of life. This updated final guidance recommends more options, epoetin and darbepoetin, that are both clinically and cost-effective and which also significantly improve quality of life for people who develop anemia whilst having cancer therapy.”

The 2008 NICE guidance recommended erythropoietin analogues with iron injections as a possible treatment for anemia caused by cancer treatment only in:

• Women receiving platinum-based chemotherapy for cancer of the ovaries who have a blood hemoglobin level of 8 g/100 mL or lower
• Patients who have very severe anemia and cannot receive blood transfusions.

NICE’s updated final guidance recommends using darbepoetin alfa and epoetin alfa, beta, theta, and zeta within their marketing authorizations as an option for treating anemia in cancer patients undergoing chemotherapy.

Epoetin alfa (Eprex, Janssen-Cilag, and Binocrit, Sandoz), and epoetin zeta (Retacrit, Hospira UK) have UK marketing authorization to treat anemia and to reduce transfusion requirements in adult patients receiving chemotherapy for solid tumors, malignant lymphoma, or multiple myeloma, who are at risk of transfusion as assessed by the patients’ general status (eg, cardiovascular status, pre-existing anemia at the start of chemotherapy).

Binocrit and Retacrit are both biosimilar medicines referenced to Eprex. Eprex, Binocrit, and Retacrit are available in pre-filled syringes at net prices of £5.53, £4.33, and £5.66 per 1000 units, respectively.

Epoetin beta (NeoRecormon, Roche Products) and epoetin theta (Eporatio, Teva UK) have UK marketing authorization to treat symptomatic anemia in adult patients with non-myeloid malignancies who are receiving chemotherapy.

NeoRecormon is available in a pre-filled syringe at a net price of £3.51 per 500 units, and Eporatio is available in a pre-filled syringe at a net price of £5.99 per 1000 units.

Darbepoetin alfa (Aranesp, Amgen) has UK marketing authorization to treat symptomatic anemia in adult cancer patients with non-myeloid malignancies who are receiving chemotherapy. Aranesp is available in a pre-filled syringe at a net price of £14.68 per 10 micrograms.

Costs (excluding value-added tax) may vary in different settings because of negotiated procurement discounts.

Thrombus

Credit: Andre E.X. Brown

Health Canada has expanded the indication for the oral anticoagulant apixaban (Eliquis).

The direct factor Xa inhibitor can now be used to prevent venous thromboembolism (VTE) in adult patients who have undergone elective total hip surgery or knee replacement surgery.

The drug was already approved in Canada to treat and prevent recurrent VTE and for the prevention of stroke and systemic embolism in patients with atrial fibrillation.

“The development of VTE or pulmonary embolism is an important risk for patients having major orthopedic surgery such as total knee or hip replacement,” said John Eikelboom, MBBS, of McMaster University in Hamilton, Ontario.

“The approval of apixaban gives Canadian surgeons a new option to help prevent VTE in these patients. As an oral option for patients in hospital and once they return home after surgery, where most clotting complications can take place after they are discharged from hospital, apixaban offers patients an alternative to an injected anticoagulant.”

Health Canada’s approval of apixaban is based on results of the ADVANCE clinical trials. In these trials, researchers randomized 11,659 patients and assessed the efficacy and safety of apixaban compared to enoxaparin.

The primary efficacy endpoint of the trials was the composite of asymptomatic and symptomatic deep vein thrombosis (DVT), nonfatal pulmonary embolism (PE), and death from any cause during study treatment. The principal safety measure was the composite of major and clinically relevant nonmajor bleeding.

Results of the first ADVANCE study suggested apixaban was roughly as effective as enoxaparin at preventing DVT and PE in patients who had undergone total knee replacement surgery. But apixaban posed a significantly lower risk of major and nonmajor bleeding.

The ADVANCE-2 study, on the other hand, indicated that apixaban was a more effective means of thromboprophylaxis than enoxaparin in this patient population. And there was no significant difference between the treatment arms in the frequency of major or clinically relevant bleeding.

The ADVANCE-3 study suggested apixaban was more effective than enoxaparin in preventing DVT and PE among patients undergoing hip replacement. And there was no significant difference between the groups with regard to major or clinically relevant bleeding.

Apixaban is under development in Canada by Bristol-Myers Squibb and Pfizer Canada Inc. For more details on the drug, see the product monograph.

Thrombus

Credit: Andre E.X. Brown

Health Canada has expanded the indication for the oral anticoagulant apixaban (Eliquis).

The direct factor Xa inhibitor can now be used to prevent venous thromboembolism (VTE) in adult patients who have undergone elective total hip surgery or knee replacement surgery.

The drug was already approved in Canada to treat and prevent recurrent VTE and for the prevention of stroke and systemic embolism in patients with atrial fibrillation.

“The development of VTE or pulmonary embolism is an important risk for patients having major orthopedic surgery such as total knee or hip replacement,” said John Eikelboom, MBBS, of McMaster University in Hamilton, Ontario.

“The approval of apixaban gives Canadian surgeons a new option to help prevent VTE in these patients. As an oral option for patients in hospital and once they return home after surgery, where most clotting complications can take place after they are discharged from hospital, apixaban offers patients an alternative to an injected anticoagulant.”

Health Canada’s approval of apixaban is based on results of the ADVANCE clinical trials. In these trials, researchers randomized 11,659 patients and assessed the efficacy and safety of apixaban compared to enoxaparin.

The primary efficacy endpoint of the trials was the composite of asymptomatic and symptomatic deep vein thrombosis (DVT), nonfatal pulmonary embolism (PE), and death from any cause during study treatment. The principal safety measure was the composite of major and clinically relevant nonmajor bleeding.

Results of the first ADVANCE study suggested apixaban was roughly as effective as enoxaparin at preventing DVT and PE in patients who had undergone total knee replacement surgery. But apixaban posed a significantly lower risk of major and nonmajor bleeding.

The ADVANCE-2 study, on the other hand, indicated that apixaban was a more effective means of thromboprophylaxis than enoxaparin in this patient population. And there was no significant difference between the treatment arms in the frequency of major or clinically relevant bleeding.

The ADVANCE-3 study suggested apixaban was more effective than enoxaparin in preventing DVT and PE among patients undergoing hip replacement. And there was no significant difference between the groups with regard to major or clinically relevant bleeding.

Apixaban is under development in Canada by Bristol-Myers Squibb and Pfizer Canada Inc. For more details on the drug, see the product monograph.

Thrombus

Credit: Andre E.X. Brown

Health Canada has expanded the indication for the oral anticoagulant apixaban (Eliquis).

The direct factor Xa inhibitor can now be used to prevent venous thromboembolism (VTE) in adult patients who have undergone elective total hip surgery or knee replacement surgery.

The drug was already approved in Canada to treat and prevent recurrent VTE and for the prevention of stroke and systemic embolism in patients with atrial fibrillation.

“The development of VTE or pulmonary embolism is an important risk for patients having major orthopedic surgery such as total knee or hip replacement,” said John Eikelboom, MBBS, of McMaster University in Hamilton, Ontario.

“The approval of apixaban gives Canadian surgeons a new option to help prevent VTE in these patients. As an oral option for patients in hospital and once they return home after surgery, where most clotting complications can take place after they are discharged from hospital, apixaban offers patients an alternative to an injected anticoagulant.”

Health Canada’s approval of apixaban is based on results of the ADVANCE clinical trials. In these trials, researchers randomized 11,659 patients and assessed the efficacy and safety of apixaban compared to enoxaparin.

The primary efficacy endpoint of the trials was the composite of asymptomatic and symptomatic deep vein thrombosis (DVT), nonfatal pulmonary embolism (PE), and death from any cause during study treatment. The principal safety measure was the composite of major and clinically relevant nonmajor bleeding.

Results of the first ADVANCE study suggested apixaban was roughly as effective as enoxaparin at preventing DVT and PE in patients who had undergone total knee replacement surgery. But apixaban posed a significantly lower risk of major and nonmajor bleeding.

The ADVANCE-2 study, on the other hand, indicated that apixaban was a more effective means of thromboprophylaxis than enoxaparin in this patient population. And there was no significant difference between the treatment arms in the frequency of major or clinically relevant bleeding.

The ADVANCE-3 study suggested apixaban was more effective than enoxaparin in preventing DVT and PE among patients undergoing hip replacement. And there was no significant difference between the groups with regard to major or clinically relevant bleeding.

Apixaban is under development in Canada by Bristol-Myers Squibb and Pfizer Canada Inc. For more details on the drug, see the product monograph.

Pill production

Credit: FDA

New research suggests that 20% of recent drug approvals occurred without pharmaceutical companies and the US Food and Drug Administration (FDA) meeting to discuss pivotal studies.

When these meetings did occur, companies did not comply with a quarter of FDA recommendations regarding study design or primary outcome.

Steven Woloshin, MD, of the Dartmouth Institute for Health Policy and Clinical Practice in Lebanon, New Hampshire, and his colleagues reported these findings in JAMA.

The researchers noted that federal regulations encourage but do not require meetings between pharmaceutical companies and the FDA during the design phase of pivotal studies assessing drug efficacy and safety for the proposed indication.

These meetings often generate FDA recommendations for improving research, but companies are not bound to follow them.

To evaluate this process, Dr Woloshin and his colleagues reviewed and analyzed approximately 200 FDA documents (memos, meeting minutes, filing checklists, and medical, statistical, and summary reviews) for 35 new drugs approved between February 1, 2011, and February 29, 2012.

The researchers identified all FDA comments and analyzed recommendations about pivotal study design or primary outcomes and characterized the effect of recommendations on study quality.

Of 35 new drug approvals, companies met with the FDA to discuss pivotal studies for 28 (80%). The FDA made 53 recommendations about design (eg, controls, doses, study length) or primary outcome for 21 approvals.

Fifty-one recommendations were judged as increasing study quality (eg, adding controls, blinding, or specific measures and frequency for toxicity assessments, lengthening studies to assess outcome durability) and 2 as having an uncertain effect.

Companies complied with 40 of the 53 recommendations (75%). An example of non-compliance is the FDA recommending randomized trials of brentuximab and crizotinib, with the companies conducting uncontrolled studies.

Other cases included primary outcome choice (eg, progression-free survival instead of overall survival) and drug (active comparator) doses tested.

Companies can also request FDA review of pivotal trial protocols. If the FDA endorses the protocol, it agrees not to object to any study design issues when reviewing the drug for approval.

Companies requested protocol review for 21 of the 35 new drug approvals, and the FDA endorsed the protocol for 12.

The researchers said instituting mandatory FDA review of pivotal trial protocols with the power to issue binding recommendations could be an effective way to optimize study quality.

An FDA-commissioned report suggested that stronger early FDA involvement could prevent deficiencies that delay the approval of effective drugs and more clearly identify drugs that are ineffective or harmful.

Pill production

Credit: FDA

New research suggests that 20% of recent drug approvals occurred without pharmaceutical companies and the US Food and Drug Administration (FDA) meeting to discuss pivotal studies.

When these meetings did occur, companies did not comply with a quarter of FDA recommendations regarding study design or primary outcome.

Steven Woloshin, MD, of the Dartmouth Institute for Health Policy and Clinical Practice in Lebanon, New Hampshire, and his colleagues reported these findings in JAMA.

The researchers noted that federal regulations encourage but do not require meetings between pharmaceutical companies and the FDA during the design phase of pivotal studies assessing drug efficacy and safety for the proposed indication.

These meetings often generate FDA recommendations for improving research, but companies are not bound to follow them.

To evaluate this process, Dr Woloshin and his colleagues reviewed and analyzed approximately 200 FDA documents (memos, meeting minutes, filing checklists, and medical, statistical, and summary reviews) for 35 new drugs approved between February 1, 2011, and February 29, 2012.

The researchers identified all FDA comments and analyzed recommendations about pivotal study design or primary outcomes and characterized the effect of recommendations on study quality.

Of 35 new drug approvals, companies met with the FDA to discuss pivotal studies for 28 (80%). The FDA made 53 recommendations about design (eg, controls, doses, study length) or primary outcome for 21 approvals.

Fifty-one recommendations were judged as increasing study quality (eg, adding controls, blinding, or specific measures and frequency for toxicity assessments, lengthening studies to assess outcome durability) and 2 as having an uncertain effect.

Companies complied with 40 of the 53 recommendations (75%). An example of non-compliance is the FDA recommending randomized trials of brentuximab and crizotinib, with the companies conducting uncontrolled studies.

Other cases included primary outcome choice (eg, progression-free survival instead of overall survival) and drug (active comparator) doses tested.

Companies can also request FDA review of pivotal trial protocols. If the FDA endorses the protocol, it agrees not to object to any study design issues when reviewing the drug for approval.

Companies requested protocol review for 21 of the 35 new drug approvals, and the FDA endorsed the protocol for 12.

The researchers said instituting mandatory FDA review of pivotal trial protocols with the power to issue binding recommendations could be an effective way to optimize study quality.

An FDA-commissioned report suggested that stronger early FDA involvement could prevent deficiencies that delay the approval of effective drugs and more clearly identify drugs that are ineffective or harmful.

Pill production

Credit: FDA

New research suggests that 20% of recent drug approvals occurred without pharmaceutical companies and the US Food and Drug Administration (FDA) meeting to discuss pivotal studies.

When these meetings did occur, companies did not comply with a quarter of FDA recommendations regarding study design or primary outcome.

Steven Woloshin, MD, of the Dartmouth Institute for Health Policy and Clinical Practice in Lebanon, New Hampshire, and his colleagues reported these findings in JAMA.

The researchers noted that federal regulations encourage but do not require meetings between pharmaceutical companies and the FDA during the design phase of pivotal studies assessing drug efficacy and safety for the proposed indication.

These meetings often generate FDA recommendations for improving research, but companies are not bound to follow them.

To evaluate this process, Dr Woloshin and his colleagues reviewed and analyzed approximately 200 FDA documents (memos, meeting minutes, filing checklists, and medical, statistical, and summary reviews) for 35 new drugs approved between February 1, 2011, and February 29, 2012.

The researchers identified all FDA comments and analyzed recommendations about pivotal study design or primary outcomes and characterized the effect of recommendations on study quality.

Of 35 new drug approvals, companies met with the FDA to discuss pivotal studies for 28 (80%). The FDA made 53 recommendations about design (eg, controls, doses, study length) or primary outcome for 21 approvals.

Fifty-one recommendations were judged as increasing study quality (eg, adding controls, blinding, or specific measures and frequency for toxicity assessments, lengthening studies to assess outcome durability) and 2 as having an uncertain effect.

Companies complied with 40 of the 53 recommendations (75%). An example of non-compliance is the FDA recommending randomized trials of brentuximab and crizotinib, with the companies conducting uncontrolled studies.

Other cases included primary outcome choice (eg, progression-free survival instead of overall survival) and drug (active comparator) doses tested.

Companies can also request FDA review of pivotal trial protocols. If the FDA endorses the protocol, it agrees not to object to any study design issues when reviewing the drug for approval.

Companies requested protocol review for 21 of the 35 new drug approvals, and the FDA endorsed the protocol for 12.

The researchers said instituting mandatory FDA review of pivotal trial protocols with the power to issue binding recommendations could be an effective way to optimize study quality.

An FDA-commissioned report suggested that stronger early FDA involvement could prevent deficiencies that delay the approval of effective drugs and more clearly identify drugs that are ineffective or harmful.

Prescription pills

The Therapeutic Goods Administration (TGA) has approved marketing of ponatinib (Iclusig) in Australia.

The drug is now approved to treat adults with chronic myeloid leukemia (CML) who could not tolerate or were resistant to at least 2 prior tyrosine kinase inhibitors (TKIs), or those patients with a T315I mutation.

Ponatinib is also approved to treat certain adults with Philadelphia-chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).

These patients must be resistant to or intolerant of dasatinib and ineligible for treatment with imatinib, or they must have a T315I mutation.

Ponatinib is the only TKI approved in Australia for an indication that includes CML and Ph+ ALL patients with the T315I mutation.

The drug’s developers, Ariad Pharmaceuticals, Inc., and Specialized Therapeutics Australia Pty. Ltd., expect to launch ponatinib in early 2015.

The PACE trial

The TGA’s decision to approve ponatinib was based on results from the phase 2 PACE trial, which included patients with CML or Ph+ ALL who were resistant to or intolerant of prior TKI therapy, or who had the T315I mutation.

The median follow-up times were 15.3 months in chronic-phase CML patients, 15.8 months in accelerated-phase CML patients, and 6.2 months in patients with blast-phase CML or Ph+ ALL.

In chronic-phase CML, the primary endpoint was major cytogenetic response, and it occurred in 56% of patients. Among chronic-phase patients with the T315I mutation, 70% achieved a major cytogenetic response. Among patients who had failed treatment with dasatinib or nilotinib, 51% achieved a major cytogenetic response.

In accelerated-phase CML, the primary endpoint was major hematologic response. This occurred in 57% of all patients in this group, 50% of patients with the T315I mutation, and 58% of patients who had failed treatment with dasatinib or nilotinib.

The primary endpoint was major hematologic response in blast-phase CML/Ph+ ALL as well. Thirty-four percent of all patients in this group met this endpoint, as did 33% of patients with the T315I mutation and 35% of patients who had failed treatment with dasatinib or nilotinib.

Common non-hematologic adverse events included rash (38%), abdominal pain (38%), headache (35%), dry skin (35%), constipation (34%), fatigue (27%), pyrexia (27%), nausea (26%), arthralgia (25%), hypertension (21%), increased lipase (19%), and increased amylase (7%).

Hematologic events of any grade included thrombocytopenia (42%), neutropenia (24%), and anemia (20%). And serious adverse events of arterial thromboembolism, including arterial stenosis, occurred in patients with cardiovascular risk factors.

Safety concerns

Ponatinib is also approved to treat CML and Ph+ ALL in the European Union and the US. However, the drug was pulled from the US market for a little over 2 months, and ponatinib trials were placed on partial hold, after extended follow-up from the PACE trial showed an increase in thrombotic events.

The drug went back on the market last January, 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 the drug’s benefits outweigh its risks.

Prescription pills

The Therapeutic Goods Administration (TGA) has approved marketing of ponatinib (Iclusig) in Australia.

The drug is now approved to treat adults with chronic myeloid leukemia (CML) who could not tolerate or were resistant to at least 2 prior tyrosine kinase inhibitors (TKIs), or those patients with a T315I mutation.

Ponatinib is also approved to treat certain adults with Philadelphia-chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).

These patients must be resistant to or intolerant of dasatinib and ineligible for treatment with imatinib, or they must have a T315I mutation.

Ponatinib is the only TKI approved in Australia for an indication that includes CML and Ph+ ALL patients with the T315I mutation.

The drug’s developers, Ariad Pharmaceuticals, Inc., and Specialized Therapeutics Australia Pty. Ltd., expect to launch ponatinib in early 2015.

The PACE trial

The TGA’s decision to approve ponatinib was based on results from the phase 2 PACE trial, which included patients with CML or Ph+ ALL who were resistant to or intolerant of prior TKI therapy, or who had the T315I mutation.

The median follow-up times were 15.3 months in chronic-phase CML patients, 15.8 months in accelerated-phase CML patients, and 6.2 months in patients with blast-phase CML or Ph+ ALL.

In chronic-phase CML, the primary endpoint was major cytogenetic response, and it occurred in 56% of patients. Among chronic-phase patients with the T315I mutation, 70% achieved a major cytogenetic response. Among patients who had failed treatment with dasatinib or nilotinib, 51% achieved a major cytogenetic response.

In accelerated-phase CML, the primary endpoint was major hematologic response. This occurred in 57% of all patients in this group, 50% of patients with the T315I mutation, and 58% of patients who had failed treatment with dasatinib or nilotinib.

The primary endpoint was major hematologic response in blast-phase CML/Ph+ ALL as well. Thirty-four percent of all patients in this group met this endpoint, as did 33% of patients with the T315I mutation and 35% of patients who had failed treatment with dasatinib or nilotinib.

Common non-hematologic adverse events included rash (38%), abdominal pain (38%), headache (35%), dry skin (35%), constipation (34%), fatigue (27%), pyrexia (27%), nausea (26%), arthralgia (25%), hypertension (21%), increased lipase (19%), and increased amylase (7%).

Hematologic events of any grade included thrombocytopenia (42%), neutropenia (24%), and anemia (20%). And serious adverse events of arterial thromboembolism, including arterial stenosis, occurred in patients with cardiovascular risk factors.

Safety concerns

Ponatinib is also approved to treat CML and Ph+ ALL in the European Union and the US. However, the drug was pulled from the US market for a little over 2 months, and ponatinib trials were placed on partial hold, after extended follow-up from the PACE trial showed an increase in thrombotic events.

The drug went back on the market last January, 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 the drug’s benefits outweigh its risks.

Prescription pills

The Therapeutic Goods Administration (TGA) has approved marketing of ponatinib (Iclusig) in Australia.

The drug is now approved to treat adults with chronic myeloid leukemia (CML) who could not tolerate or were resistant to at least 2 prior tyrosine kinase inhibitors (TKIs), or those patients with a T315I mutation.

Ponatinib is also approved to treat certain adults with Philadelphia-chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).

These patients must be resistant to or intolerant of dasatinib and ineligible for treatment with imatinib, or they must have a T315I mutation.

Ponatinib is the only TKI approved in Australia for an indication that includes CML and Ph+ ALL patients with the T315I mutation.

The drug’s developers, Ariad Pharmaceuticals, Inc., and Specialized Therapeutics Australia Pty. Ltd., expect to launch ponatinib in early 2015.

The PACE trial

The TGA’s decision to approve ponatinib was based on results from the phase 2 PACE trial, which included patients with CML or Ph+ ALL who were resistant to or intolerant of prior TKI therapy, or who had the T315I mutation.

The median follow-up times were 15.3 months in chronic-phase CML patients, 15.8 months in accelerated-phase CML patients, and 6.2 months in patients with blast-phase CML or Ph+ ALL.

In chronic-phase CML, the primary endpoint was major cytogenetic response, and it occurred in 56% of patients. Among chronic-phase patients with the T315I mutation, 70% achieved a major cytogenetic response. Among patients who had failed treatment with dasatinib or nilotinib, 51% achieved a major cytogenetic response.

In accelerated-phase CML, the primary endpoint was major hematologic response. This occurred in 57% of all patients in this group, 50% of patients with the T315I mutation, and 58% of patients who had failed treatment with dasatinib or nilotinib.

The primary endpoint was major hematologic response in blast-phase CML/Ph+ ALL as well. Thirty-four percent of all patients in this group met this endpoint, as did 33% of patients with the T315I mutation and 35% of patients who had failed treatment with dasatinib or nilotinib.

Common non-hematologic adverse events included rash (38%), abdominal pain (38%), headache (35%), dry skin (35%), constipation (34%), fatigue (27%), pyrexia (27%), nausea (26%), arthralgia (25%), hypertension (21%), increased lipase (19%), and increased amylase (7%).

Hematologic events of any grade included thrombocytopenia (42%), neutropenia (24%), and anemia (20%). And serious adverse events of arterial thromboembolism, including arterial stenosis, occurred in patients with cardiovascular risk factors.

Safety concerns

Ponatinib is also approved to treat CML and Ph+ ALL in the European Union and the US. However, the drug was pulled from the US market for a little over 2 months, and ponatinib trials were placed on partial hold, after extended follow-up from the PACE trial showed an increase in thrombotic events.

The drug went back on the market last January, 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 the drug’s benefits outweigh its risks.

Blood collection

Credit: Charles Haymond

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for JCAR015, a chimeric antigen receptor (CAR) T-cell therapy, to treat patients with  relapsed or refractory B-cell acute lymphoblastic leukemia (ALL).

Breakthrough designation is designed to help accelerate the development and review of new drugs for serious or life-threatening conditions.

The designation comes with potential benefits, including intensive FDA guidance and eligibility for priority review. It is granted to applicants when preliminary clinical evidence indicates the drug may demonstrate substantial improvement over existing therapies on one or more clinical endpoints.

The FDA recently granted JCAR015 orphan designation to treat ALL as well.

JCAR015 consists of autologous T cells expressing a CD19-specific, CD28/CD3z CAR. The treatment has shown promise in an ongoing phase 1 trial of patients with B-cell ALL.

Initial results from this study were published in Science Translational Medicine last year and in February. Updated results were presented at the AACR Annual Meeting in April.

At that point, the researchers had enrolled 22 adult patients with relapsed or refractory B-ALL who were minimal residual disease-positive or were in first complete remission at enrollment. Patients in complete remission were monitored and only received JCAR015 if they relapsed.

The remaining patients received re-induction chemotherapy (physician’s choice), followed by an infusion of JCAR015. After treatment, patients could receive allogeneic transplant, a different salvage therapy, or monitoring.

Eighty-two percent of patients achieved a complete response to JCAR015. The average time to complete response was about 24.5 days.

Twelve of the responders were eligible for transplant. Of the 8 patients who ultimately underwent transplant and survived, 1 relapsed, but the rest remained in remission.

Ten patients had died at the time of the AACR presentation. Six deaths were a result of disease relapse or progression, and 2 patients died of complications from stem cell transplant.

The 2 remaining deaths prompted a temporary suspension of enrollment in this trial. Those deaths were related to complications from cytokine release syndrome. One patient died of cardiovascular disease, and the other died following persistent seizure activity.

So researchers at the Memorial Sloan-Kettering Cancer Center, where the trial is being conducted, reviewed these cases. The results prompted them to amend trial enrollment criteria and dosing recommendations. Now, patients with cardiac disease are ineligible to receive JCAR015.

And the T-cell dose a patient receives will depend on the extent of his or her disease. The hope is that this will reduce the risk of cytokine release syndrome and any resulting seizures. The researchers also noted that the monoclonal antibody tocilizumab has proven effective in treating cytokine release syndrome.

In addition to this trial, JCAR015 is under investigation at Memorial Sloan-Kettering Cancer Center in a phase 1 trial of patients with relapsed and refractory non-Hodgkin lymphoma.

Two other CAR T-cell product candidates under development by the same company, Juno Therapeutics, Inc., are being tested in clinical trials as well. JCAR017 is under investigation at Seattle Children’s Hospital for relapsed/refractory CD19-positive pediatric leukemia.

JCAR014 is being tested for refractory chronic lymphocytic leukemia, non-Hodgkin lymphoma, and ALL at the Fred Hutchinson Cancer Research Center. Data on these programs are set to be presented at the 56th ASH Annual Meeting next week in San Francisco.

Blood collection

Credit: Charles Haymond

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for JCAR015, a chimeric antigen receptor (CAR) T-cell therapy, to treat patients with  relapsed or refractory B-cell acute lymphoblastic leukemia (ALL).

Breakthrough designation is designed to help accelerate the development and review of new drugs for serious or life-threatening conditions.

The designation comes with potential benefits, including intensive FDA guidance and eligibility for priority review. It is granted to applicants when preliminary clinical evidence indicates the drug may demonstrate substantial improvement over existing therapies on one or more clinical endpoints.

The FDA recently granted JCAR015 orphan designation to treat ALL as well.

JCAR015 consists of autologous T cells expressing a CD19-specific, CD28/CD3z CAR. The treatment has shown promise in an ongoing phase 1 trial of patients with B-cell ALL.

Initial results from this study were published in Science Translational Medicine last year and in February. Updated results were presented at the AACR Annual Meeting in April.

At that point, the researchers had enrolled 22 adult patients with relapsed or refractory B-ALL who were minimal residual disease-positive or were in first complete remission at enrollment. Patients in complete remission were monitored and only received JCAR015 if they relapsed.

The remaining patients received re-induction chemotherapy (physician’s choice), followed by an infusion of JCAR015. After treatment, patients could receive allogeneic transplant, a different salvage therapy, or monitoring.

Eighty-two percent of patients achieved a complete response to JCAR015. The average time to complete response was about 24.5 days.

Twelve of the responders were eligible for transplant. Of the 8 patients who ultimately underwent transplant and survived, 1 relapsed, but the rest remained in remission.

Ten patients had died at the time of the AACR presentation. Six deaths were a result of disease relapse or progression, and 2 patients died of complications from stem cell transplant.

The 2 remaining deaths prompted a temporary suspension of enrollment in this trial. Those deaths were related to complications from cytokine release syndrome. One patient died of cardiovascular disease, and the other died following persistent seizure activity.

So researchers at the Memorial Sloan-Kettering Cancer Center, where the trial is being conducted, reviewed these cases. The results prompted them to amend trial enrollment criteria and dosing recommendations. Now, patients with cardiac disease are ineligible to receive JCAR015.

And the T-cell dose a patient receives will depend on the extent of his or her disease. The hope is that this will reduce the risk of cytokine release syndrome and any resulting seizures. The researchers also noted that the monoclonal antibody tocilizumab has proven effective in treating cytokine release syndrome.

In addition to this trial, JCAR015 is under investigation at Memorial Sloan-Kettering Cancer Center in a phase 1 trial of patients with relapsed and refractory non-Hodgkin lymphoma.

Two other CAR T-cell product candidates under development by the same company, Juno Therapeutics, Inc., are being tested in clinical trials as well. JCAR017 is under investigation at Seattle Children’s Hospital for relapsed/refractory CD19-positive pediatric leukemia.

JCAR014 is being tested for refractory chronic lymphocytic leukemia, non-Hodgkin lymphoma, and ALL at the Fred Hutchinson Cancer Research Center. Data on these programs are set to be presented at the 56th ASH Annual Meeting next week in San Francisco.

Blood collection

Credit: Charles Haymond

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for JCAR015, a chimeric antigen receptor (CAR) T-cell therapy, to treat patients with  relapsed or refractory B-cell acute lymphoblastic leukemia (ALL).

Breakthrough designation is designed to help accelerate the development and review of new drugs for serious or life-threatening conditions.

The designation comes with potential benefits, including intensive FDA guidance and eligibility for priority review. It is granted to applicants when preliminary clinical evidence indicates the drug may demonstrate substantial improvement over existing therapies on one or more clinical endpoints.

The FDA recently granted JCAR015 orphan designation to treat ALL as well.

JCAR015 consists of autologous T cells expressing a CD19-specific, CD28/CD3z CAR. The treatment has shown promise in an ongoing phase 1 trial of patients with B-cell ALL.

Initial results from this study were published in Science Translational Medicine last year and in February. Updated results were presented at the AACR Annual Meeting in April.

At that point, the researchers had enrolled 22 adult patients with relapsed or refractory B-ALL who were minimal residual disease-positive or were in first complete remission at enrollment. Patients in complete remission were monitored and only received JCAR015 if they relapsed.

The remaining patients received re-induction chemotherapy (physician’s choice), followed by an infusion of JCAR015. After treatment, patients could receive allogeneic transplant, a different salvage therapy, or monitoring.

Eighty-two percent of patients achieved a complete response to JCAR015. The average time to complete response was about 24.5 days.

Twelve of the responders were eligible for transplant. Of the 8 patients who ultimately underwent transplant and survived, 1 relapsed, but the rest remained in remission.

Ten patients had died at the time of the AACR presentation. Six deaths were a result of disease relapse or progression, and 2 patients died of complications from stem cell transplant.

The 2 remaining deaths prompted a temporary suspension of enrollment in this trial. Those deaths were related to complications from cytokine release syndrome. One patient died of cardiovascular disease, and the other died following persistent seizure activity.

So researchers at the Memorial Sloan-Kettering Cancer Center, where the trial is being conducted, reviewed these cases. The results prompted them to amend trial enrollment criteria and dosing recommendations. Now, patients with cardiac disease are ineligible to receive JCAR015.

And the T-cell dose a patient receives will depend on the extent of his or her disease. The hope is that this will reduce the risk of cytokine release syndrome and any resulting seizures. The researchers also noted that the monoclonal antibody tocilizumab has proven effective in treating cytokine release syndrome.

In addition to this trial, JCAR015 is under investigation at Memorial Sloan-Kettering Cancer Center in a phase 1 trial of patients with relapsed and refractory non-Hodgkin lymphoma.

Two other CAR T-cell product candidates under development by the same company, Juno Therapeutics, Inc., are being tested in clinical trials as well. JCAR017 is under investigation at Seattle Children’s Hospital for relapsed/refractory CD19-positive pediatric leukemia.

JCAR014 is being tested for refractory chronic lymphocytic leukemia, non-Hodgkin lymphoma, and ALL at the Fred Hutchinson Cancer Research Center. Data on these programs are set to be presented at the 56th ASH Annual Meeting next week in San Francisco.

Thrombus

Credit: Kevin MacKenzie

The US Food and Drug Administration (FDA) has granted orphan drug designation for CCX168, an oral inhibitor targeting the receptor for the complement protein C5a, to treat atypical hemolytic uremic syndrome (aHUS).

This rare but life-threatening disease causes inflammation of the blood vessels and thrombus formation throughout the body.

Patients with aHUS are at constant risk of sudden and progressive damage to, and failure of, vital organs. Roughly 10% to 15% of patients die in the initial, acute phase of aHUS.

The majority of patients—up to 70%—develop end-stage kidney failure requiring dialysis. And 1 in 5 patients has aHUS affecting organs other than the kidneys, most commonly the brain or heart.

“Given the life-threatening nature of aHUS, we are very pleased with the granting of orphan drug designation for CCX168 in this disease,” said Thomas J. Schall, PhD, president and chief executive officer of ChemoCentryx, Inc., the company developing CCX168.

ChemoCentryx has generated positive preclinical data that suggest an important role of C5a receptor inhibition in reducing microvasculature thrombosis formation in aHUS.

The company plans to initiate a phase 2 proof-of-concept study in patients with aHUS by the end of 2014.

CCX168 is also in phase 2 development for the treatment of anti-neutrophil cytoplasmic antibody-associated vasculitis.

The orphan designation for CCX168 will provide ChemoCentryx with a 7-year period of US marketing exclusivity if the drug is approved to treat aHUS, tax credits for clinical research costs, the ability to apply for annual grant funding, clinical research trial design assistance, and the waiver of prescription drug user fees.

Thrombus

Credit: Kevin MacKenzie

The US Food and Drug Administration (FDA) has granted orphan drug designation for CCX168, an oral inhibitor targeting the receptor for the complement protein C5a, to treat atypical hemolytic uremic syndrome (aHUS).

This rare but life-threatening disease causes inflammation of the blood vessels and thrombus formation throughout the body.

Patients with aHUS are at constant risk of sudden and progressive damage to, and failure of, vital organs. Roughly 10% to 15% of patients die in the initial, acute phase of aHUS.

The majority of patients—up to 70%—develop end-stage kidney failure requiring dialysis. And 1 in 5 patients has aHUS affecting organs other than the kidneys, most commonly the brain or heart.

“Given the life-threatening nature of aHUS, we are very pleased with the granting of orphan drug designation for CCX168 in this disease,” said Thomas J. Schall, PhD, president and chief executive officer of ChemoCentryx, Inc., the company developing CCX168.

ChemoCentryx has generated positive preclinical data that suggest an important role of C5a receptor inhibition in reducing microvasculature thrombosis formation in aHUS.

The company plans to initiate a phase 2 proof-of-concept study in patients with aHUS by the end of 2014.

CCX168 is also in phase 2 development for the treatment of anti-neutrophil cytoplasmic antibody-associated vasculitis.

The orphan designation for CCX168 will provide ChemoCentryx with a 7-year period of US marketing exclusivity if the drug is approved to treat aHUS, tax credits for clinical research costs, the ability to apply for annual grant funding, clinical research trial design assistance, and the waiver of prescription drug user fees.

Thrombus

Credit: Kevin MacKenzie

The US Food and Drug Administration (FDA) has granted orphan drug designation for CCX168, an oral inhibitor targeting the receptor for the complement protein C5a, to treat atypical hemolytic uremic syndrome (aHUS).

This rare but life-threatening disease causes inflammation of the blood vessels and thrombus formation throughout the body.

Patients with aHUS are at constant risk of sudden and progressive damage to, and failure of, vital organs. Roughly 10% to 15% of patients die in the initial, acute phase of aHUS.

The majority of patients—up to 70%—develop end-stage kidney failure requiring dialysis. And 1 in 5 patients has aHUS affecting organs other than the kidneys, most commonly the brain or heart.

“Given the life-threatening nature of aHUS, we are very pleased with the granting of orphan drug designation for CCX168 in this disease,” said Thomas J. Schall, PhD, president and chief executive officer of ChemoCentryx, Inc., the company developing CCX168.

ChemoCentryx has generated positive preclinical data that suggest an important role of C5a receptor inhibition in reducing microvasculature thrombosis formation in aHUS.

The company plans to initiate a phase 2 proof-of-concept study in patients with aHUS by the end of 2014.

CCX168 is also in phase 2 development for the treatment of anti-neutrophil cytoplasmic antibody-associated vasculitis.

The orphan designation for CCX168 will provide ChemoCentryx with a 7-year period of US marketing exclusivity if the drug is approved to treat aHUS, tax credits for clinical research costs, the ability to apply for annual grant funding, clinical research trial design assistance, and the waiver of prescription drug user fees.