HT Staff

After follow-up data from the phase 2 PACE trial revealed that ponatinib-treated patients experienced an increase in arterial and venous thrombotic events, the FDA decided to investigate the drug’s safety.

The agency placed current ponatinib trials on partial clinical hold and asked the drug’s makers, Ariad Pharmaceuticals, to end the phase 3 EPIC trial.

Now, the FDA has asked Ariad to temporarily suspend marketing and sales of ponatinib while the agency further evaluates the drug.

Ponatinib is approved in the US and the European Union to treat adults with chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia that is resistant to or intolerant of other tyrosine kinase inhibitors.

Recommendations for ponatinib use

Until its safety evaluation is complete, the FDA is recommending that healthcare professionals reconsider the use of ponatinib.

For patients who are taking ponatinib but not responding, immediately discontinue their treatment and discuss alternative treatment options.

For patients who are currently taking ponatinib and responding, determine whether the potential benefits of the therapy outweigh the risks. If they do, these patients should be treated under a single-patient investigational new drug (IND) application or expanded access registry program while the FDA’s safety investigation continues.

Do not start treating new patients with ponatinib unless no other treatment options are available and all other available therapies have failed. Patients who meet these criteria can be considered for treatment under an IND or expanded access registry program.

For more information on obtaining access to treatment for your patient under an IND, please refer to the following website: Physician Request for an Individual Patient IND under Expanded Access for Non-emergency or Emergency Use.

Ponatinib safety data

Thus far, the FDA’s investigation of ponatinib has revealed an increased frequency of arterial and venous thrombotic events since the drug was approved in December 2012.

In clinical trials conducted before the drug’s approval, serious arterial thrombosis occurred in 8% of ponatinib-treated patients, and venous thromboembolism occurred in 3%. In the most recent clinical trial data, at least 20% of all participants treated with ponatinib have developed thrombosis or arteriosclerosis.

Serious adverse vascular events have occurred in about 24% of patients in the phase 2 trial of ponatinib (median treatment duration of 1.3 years) and about 48% of patients in the phase 1 trial (median treatment duration of 2.7 years).

These included fatal and life-threatening heart attack, stroke, loss of blood flow to the extremities resulting in tissue death, and severe narrowing of blood vessels in the extremities, heart, and brain requiring urgent surgical procedures to restore blood flow.

In the phase 2 trial, adverse events affecting the blood vessels that supply the heart, brain, and extremities were observed in 12%, 6%, and 8% of patients, respectively. Patients with and without cardiovascular risk factors, including patients in their 20s, have experienced these events.

Serious adverse reactions involving the eyes, which led to blindness or blurred vision, occurred in ponatinib-treated patients. High blood pressure occurred in 67% of patients treated with ponatinib in the trials. Heart failure, including fatalities, occurred in 8% of patients who received the drug.

In some patients, fatal and serious adverse events have occurred as early as 2 weeks after starting ponatinib therapy.

The phase 1 and 2 trials did not include a control group, so it is not possible to determine the relationship of these adverse events to ponatinib. However, the increasing rate and pattern of the events strongly suggests that many are drug-related, according to the FDA.

The agency said it cannot currently identify a dose level or exposure duration of ponatinib that is safe. Prior to the issues with adverse events, the recommended dose of ponatinib was a 45 mg tablet taken once daily.

The FDA said it plans to continue its investigation and will notify healthcare professionals and patients as more information becomes available.

After follow-up data from the phase 2 PACE trial revealed that ponatinib-treated patients experienced an increase in arterial and venous thrombotic events, the FDA decided to investigate the drug’s safety.

The agency placed current ponatinib trials on partial clinical hold and asked the drug’s makers, Ariad Pharmaceuticals, to end the phase 3 EPIC trial.

Now, the FDA has asked Ariad to temporarily suspend marketing and sales of ponatinib while the agency further evaluates the drug.

Ponatinib is approved in the US and the European Union to treat adults with chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia that is resistant to or intolerant of other tyrosine kinase inhibitors.

Recommendations for ponatinib use

Until its safety evaluation is complete, the FDA is recommending that healthcare professionals reconsider the use of ponatinib.

For patients who are taking ponatinib but not responding, immediately discontinue their treatment and discuss alternative treatment options.

For patients who are currently taking ponatinib and responding, determine whether the potential benefits of the therapy outweigh the risks. If they do, these patients should be treated under a single-patient investigational new drug (IND) application or expanded access registry program while the FDA’s safety investigation continues.

Do not start treating new patients with ponatinib unless no other treatment options are available and all other available therapies have failed. Patients who meet these criteria can be considered for treatment under an IND or expanded access registry program.

For more information on obtaining access to treatment for your patient under an IND, please refer to the following website: Physician Request for an Individual Patient IND under Expanded Access for Non-emergency or Emergency Use.

Ponatinib safety data

Thus far, the FDA’s investigation of ponatinib has revealed an increased frequency of arterial and venous thrombotic events since the drug was approved in December 2012.

In clinical trials conducted before the drug’s approval, serious arterial thrombosis occurred in 8% of ponatinib-treated patients, and venous thromboembolism occurred in 3%. In the most recent clinical trial data, at least 20% of all participants treated with ponatinib have developed thrombosis or arteriosclerosis.

Serious adverse vascular events have occurred in about 24% of patients in the phase 2 trial of ponatinib (median treatment duration of 1.3 years) and about 48% of patients in the phase 1 trial (median treatment duration of 2.7 years).

These included fatal and life-threatening heart attack, stroke, loss of blood flow to the extremities resulting in tissue death, and severe narrowing of blood vessels in the extremities, heart, and brain requiring urgent surgical procedures to restore blood flow.

In the phase 2 trial, adverse events affecting the blood vessels that supply the heart, brain, and extremities were observed in 12%, 6%, and 8% of patients, respectively. Patients with and without cardiovascular risk factors, including patients in their 20s, have experienced these events.

Serious adverse reactions involving the eyes, which led to blindness or blurred vision, occurred in ponatinib-treated patients. High blood pressure occurred in 67% of patients treated with ponatinib in the trials. Heart failure, including fatalities, occurred in 8% of patients who received the drug.

In some patients, fatal and serious adverse events have occurred as early as 2 weeks after starting ponatinib therapy.

The phase 1 and 2 trials did not include a control group, so it is not possible to determine the relationship of these adverse events to ponatinib. However, the increasing rate and pattern of the events strongly suggests that many are drug-related, according to the FDA.

The agency said it cannot currently identify a dose level or exposure duration of ponatinib that is safe. Prior to the issues with adverse events, the recommended dose of ponatinib was a 45 mg tablet taken once daily.

The FDA said it plans to continue its investigation and will notify healthcare professionals and patients as more information becomes available.

After follow-up data from the phase 2 PACE trial revealed that ponatinib-treated patients experienced an increase in arterial and venous thrombotic events, the FDA decided to investigate the drug’s safety.

The agency placed current ponatinib trials on partial clinical hold and asked the drug’s makers, Ariad Pharmaceuticals, to end the phase 3 EPIC trial.

Now, the FDA has asked Ariad to temporarily suspend marketing and sales of ponatinib while the agency further evaluates the drug.

Ponatinib is approved in the US and the European Union to treat adults with chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia that is resistant to or intolerant of other tyrosine kinase inhibitors.

Recommendations for ponatinib use

Until its safety evaluation is complete, the FDA is recommending that healthcare professionals reconsider the use of ponatinib.

For patients who are taking ponatinib but not responding, immediately discontinue their treatment and discuss alternative treatment options.

For patients who are currently taking ponatinib and responding, determine whether the potential benefits of the therapy outweigh the risks. If they do, these patients should be treated under a single-patient investigational new drug (IND) application or expanded access registry program while the FDA’s safety investigation continues.

Do not start treating new patients with ponatinib unless no other treatment options are available and all other available therapies have failed. Patients who meet these criteria can be considered for treatment under an IND or expanded access registry program.

For more information on obtaining access to treatment for your patient under an IND, please refer to the following website: Physician Request for an Individual Patient IND under Expanded Access for Non-emergency or Emergency Use.

Ponatinib safety data

Thus far, the FDA’s investigation of ponatinib has revealed an increased frequency of arterial and venous thrombotic events since the drug was approved in December 2012.

In clinical trials conducted before the drug’s approval, serious arterial thrombosis occurred in 8% of ponatinib-treated patients, and venous thromboembolism occurred in 3%. In the most recent clinical trial data, at least 20% of all participants treated with ponatinib have developed thrombosis or arteriosclerosis.

Serious adverse vascular events have occurred in about 24% of patients in the phase 2 trial of ponatinib (median treatment duration of 1.3 years) and about 48% of patients in the phase 1 trial (median treatment duration of 2.7 years).

These included fatal and life-threatening heart attack, stroke, loss of blood flow to the extremities resulting in tissue death, and severe narrowing of blood vessels in the extremities, heart, and brain requiring urgent surgical procedures to restore blood flow.

In the phase 2 trial, adverse events affecting the blood vessels that supply the heart, brain, and extremities were observed in 12%, 6%, and 8% of patients, respectively. Patients with and without cardiovascular risk factors, including patients in their 20s, have experienced these events.

Serious adverse reactions involving the eyes, which led to blindness or blurred vision, occurred in ponatinib-treated patients. High blood pressure occurred in 67% of patients treated with ponatinib in the trials. Heart failure, including fatalities, occurred in 8% of patients who received the drug.

In some patients, fatal and serious adverse events have occurred as early as 2 weeks after starting ponatinib therapy.

The phase 1 and 2 trials did not include a control group, so it is not possible to determine the relationship of these adverse events to ponatinib. However, the increasing rate and pattern of the events strongly suggests that many are drug-related, according to the FDA.

The agency said it cannot currently identify a dose level or exposure duration of ponatinib that is safe. Prior to the issues with adverse events, the recommended dose of ponatinib was a 45 mg tablet taken once daily.

The FDA said it plans to continue its investigation and will notify healthcare professionals and patients as more information becomes available.

The phase 3 EPIC trial, an evaluation of ponatinib (Iclusig) in patients with newly diagnosed chronic myeloid leukemia (CML), is being discontinued due to adverse events.

All trials of ponatinib were placed on partial clinical hold on October 9, after follow-up data from the phase 2 PACE trial revealed an increased incidence of arterial and venous thrombotic events.

That trial involved patients with CML or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) who were resistant to or could not tolerate dasatinib or nilotinib.

The partial clinical hold meant that ponatinib’s makers, Ariad Pharmaceuticals, must pause new enrollment in all ponatinib trials, reduce the doses given to existing patients, and reconsider trial eligibility criteria.

Now, Ariad and the US Food and Drug Administration have agreed that the EPIC trial must be terminated.

“Our decision to stop the EPIC trial at this time is based on our current evaluation of the safety data in the trial since it was placed on partial clinical hold last week,” said Timothy P. Clackson, PhD, president of research and development and chief scientific officer at Ariad.

Patients in the EPIC trial are being removed from treatment and will be transferred to the care of their physicians. A total of 307 patients were enrolled.

The EPIC trial was a randomized, 2-arm, multicenter study comparing the efficacy of ponatinib with that of imatinib in adult patients with newly diagnosed CML in the chronic phase. The trial was being conducted at approximately 150 investigational sites in more than 20 countries.

Patients had to be at least 18 years of age and diagnosed with CML within 6 months prior to enrollment. Approximately 500 patients were to be randomized 1:1 to the standard dose of ponatinib (45 mg once daily) or imatinib (400 mg once daily).

Increasing the imatinib dose to 600 mg or 800 mg per day was permitted. The primary endpoint of the trial was major molecular response at 12 months of treatment.

Ponatinib is still commercially available in the US and European Union for patients with resistant or intolerant CML and Ph+ ALL. Ariad said it is working with health authorities to make appropriate changes to the product labeling to reflect the safety findings from the PACE trial.

For more information about the changes in ponatinib trials, visit www.clinicaltrials.gov, email inquiries to medinfo@ariad.com, or call the Ariad US toll-free number (855) 552-7423, the European Union toll-free number 800 00027423, or the international number +1 (617)-503-7423.

The phase 3 EPIC trial, an evaluation of ponatinib (Iclusig) in patients with newly diagnosed chronic myeloid leukemia (CML), is being discontinued due to adverse events.

All trials of ponatinib were placed on partial clinical hold on October 9, after follow-up data from the phase 2 PACE trial revealed an increased incidence of arterial and venous thrombotic events.

That trial involved patients with CML or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) who were resistant to or could not tolerate dasatinib or nilotinib.

The partial clinical hold meant that ponatinib’s makers, Ariad Pharmaceuticals, must pause new enrollment in all ponatinib trials, reduce the doses given to existing patients, and reconsider trial eligibility criteria.

Now, Ariad and the US Food and Drug Administration have agreed that the EPIC trial must be terminated.

“Our decision to stop the EPIC trial at this time is based on our current evaluation of the safety data in the trial since it was placed on partial clinical hold last week,” said Timothy P. Clackson, PhD, president of research and development and chief scientific officer at Ariad.

Patients in the EPIC trial are being removed from treatment and will be transferred to the care of their physicians. A total of 307 patients were enrolled.

The EPIC trial was a randomized, 2-arm, multicenter study comparing the efficacy of ponatinib with that of imatinib in adult patients with newly diagnosed CML in the chronic phase. The trial was being conducted at approximately 150 investigational sites in more than 20 countries.

Patients had to be at least 18 years of age and diagnosed with CML within 6 months prior to enrollment. Approximately 500 patients were to be randomized 1:1 to the standard dose of ponatinib (45 mg once daily) or imatinib (400 mg once daily).

Increasing the imatinib dose to 600 mg or 800 mg per day was permitted. The primary endpoint of the trial was major molecular response at 12 months of treatment.

Ponatinib is still commercially available in the US and European Union for patients with resistant or intolerant CML and Ph+ ALL. Ariad said it is working with health authorities to make appropriate changes to the product labeling to reflect the safety findings from the PACE trial.

For more information about the changes in ponatinib trials, visit www.clinicaltrials.gov, email inquiries to medinfo@ariad.com, or call the Ariad US toll-free number (855) 552-7423, the European Union toll-free number 800 00027423, or the international number +1 (617)-503-7423.

The phase 3 EPIC trial, an evaluation of ponatinib (Iclusig) in patients with newly diagnosed chronic myeloid leukemia (CML), is being discontinued due to adverse events.

All trials of ponatinib were placed on partial clinical hold on October 9, after follow-up data from the phase 2 PACE trial revealed an increased incidence of arterial and venous thrombotic events.

That trial involved patients with CML or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) who were resistant to or could not tolerate dasatinib or nilotinib.

The partial clinical hold meant that ponatinib’s makers, Ariad Pharmaceuticals, must pause new enrollment in all ponatinib trials, reduce the doses given to existing patients, and reconsider trial eligibility criteria.

Now, Ariad and the US Food and Drug Administration have agreed that the EPIC trial must be terminated.

“Our decision to stop the EPIC trial at this time is based on our current evaluation of the safety data in the trial since it was placed on partial clinical hold last week,” said Timothy P. Clackson, PhD, president of research and development and chief scientific officer at Ariad.

Patients in the EPIC trial are being removed from treatment and will be transferred to the care of their physicians. A total of 307 patients were enrolled.

The EPIC trial was a randomized, 2-arm, multicenter study comparing the efficacy of ponatinib with that of imatinib in adult patients with newly diagnosed CML in the chronic phase. The trial was being conducted at approximately 150 investigational sites in more than 20 countries.

Patients had to be at least 18 years of age and diagnosed with CML within 6 months prior to enrollment. Approximately 500 patients were to be randomized 1:1 to the standard dose of ponatinib (45 mg once daily) or imatinib (400 mg once daily).

Increasing the imatinib dose to 600 mg or 800 mg per day was permitted. The primary endpoint of the trial was major molecular response at 12 months of treatment.

Ponatinib is still commercially available in the US and European Union for patients with resistant or intolerant CML and Ph+ ALL. Ariad said it is working with health authorities to make appropriate changes to the product labeling to reflect the safety findings from the PACE trial.

For more information about the changes in ponatinib trials, visit www.clinicaltrials.gov, email inquiries to medinfo@ariad.com, or call the Ariad US toll-free number (855) 552-7423, the European Union toll-free number 800 00027423, or the international number +1 (617)-503-7423.

B-cell lymphoma

The UK’s National Institute for Health and Care Excellence (NICE) has re-examined its draft guidance for pixantrone (Pixuvri) but come to the same conclusion as before.

The organization is still not recommending pixantrone monotherapy to treat multiply relapsed or refractory B-cell non-Hodgkin lymphoma (NHL).

Of course, this recommendation may change, as this is not NICE’s final guidance on pixantrone.

For this second consultation on the draft guidance, an independent appraisal committee re-examined the clinical and cost-effectiveness of pixantrone.

This time, the committee took into consideration a patient access scheme submitted by pixantrone’s manufacturer, Cell Therapeutics. The scheme was designed to make the drug more cost-effective for the National Health Service (NHS).

“Unfortunately, the committee concluded that this scheme . . . does not overcome the uncertainties in the evidence for the drug’s clinical effectiveness over and above current treatments for this disease,” said NICE Chief Executive Sir Andrew Dillon.

In fact, the committee found the scheme did not make pixantrone cost-effective according to the accepted definition—costing £20,000 to £30,000 per quality-adjusted life year (QALY) gained.

Evaluating trial data

When considering the clinical effectiveness of pixantrone, the appraisal committee analyzed data from the EXTEND PIX301 trial, which was submitted by the manufacturer.

The trial enrolled adults with aggressive, de novo, or transformed NHL that had relapsed after 2 or more chemotherapy regimens, including at least 1 standard anthracycline-containing regimen with a response that lasted at least 24 weeks. Seventy patients were randomized to pixantrone, and 70 were randomized to a physician’s choice of single-agent comparators.

The committee pointed out a number of uncertainties associated with the trial. One was that it did not include the planned number of patients (which was 320), so it may not have been sufficiently powered to detect differences between the treatment arms.

Another concern was that the trial’s primary endpoint was complete or unconfirmed complete response, rather than overall survival or progression-free survival. In fact, there was a lack of statistically significant difference in overall survival between treatment arms. And other differences between the treatment arms were not always statistically significant.

These factors led the committee to conclude that there is insufficient evidence to suggest pixantrone is more clinically effective than treatments currently used in clinical practice.

Suitability for the UK

The appraisal committee also heard evidence from clinical experts and patient representatives. This information revealed differences in previous treatment between the PIX301 trial population and UK clinical practice.

Therefore, the committee said it could not determine the clinical effectiveness of pixantrone for a UK population.

In addition, there is doubt regarding the clinical benefit of pixantrone in patients who previously received rituximab. And this applies to virtually all patients with relapsed or refractory aggressive B-cell lymphoma in England and Wales, the committee noted.

(The European Medicines Agency’s conditional approval of pixantrone stipulated that an additional trial must confirm the clinical benefit of the drug in patients who have previously received rituximab.)

Calculating costs

The committee estimated the patient access scheme for pixantrone would most likely result in an incremental cost-effectiveness ratio of £30,700 per QALY gained. This is above the range normally considered to be cost-effective—usually £20,000 to £30,000 per QALY gained.

This factor, along with the lack of clinical effectiveness, prompted the committee to conclude that pixantrone would not be a cost-effective use of NHS resources.

According to Cell Therapeutics, pixantrone costs £553.50 per 20 mL vial. The recommended dosage of pixantrone is 50 mg/m² on days 1, 8, and 15 of each 28-day cycle, for up to 6 cycles.

The estimated cost of a course of treatment is £19,926. This is based on the median length of treatment in the PIX301 trial—4 cycles, using an average of 3 vials per dose.

About the guidance

Individuals can comment on the pixantrone draft guidance via the NICE website. It is open until November 4, 2013. 

This is the third version of the draft guidance published and the second consultation launched. The draft guidance was initially published for consultation in April 2013, followed by a final draft guidance in June 2013. But this document was withdrawn during the appeal stage because the manufacturer submitted the patient access scheme.

Until the final guidance is issued to the NHS, organizations should make decisions locally on the funding of specific treatments. Once NICE issues its final guidance on a technology, it replaces local recommendations.

B-cell lymphoma

The UK’s National Institute for Health and Care Excellence (NICE) has re-examined its draft guidance for pixantrone (Pixuvri) but come to the same conclusion as before.

The organization is still not recommending pixantrone monotherapy to treat multiply relapsed or refractory B-cell non-Hodgkin lymphoma (NHL).

Of course, this recommendation may change, as this is not NICE’s final guidance on pixantrone.

For this second consultation on the draft guidance, an independent appraisal committee re-examined the clinical and cost-effectiveness of pixantrone.

This time, the committee took into consideration a patient access scheme submitted by pixantrone’s manufacturer, Cell Therapeutics. The scheme was designed to make the drug more cost-effective for the National Health Service (NHS).

“Unfortunately, the committee concluded that this scheme . . . does not overcome the uncertainties in the evidence for the drug’s clinical effectiveness over and above current treatments for this disease,” said NICE Chief Executive Sir Andrew Dillon.

In fact, the committee found the scheme did not make pixantrone cost-effective according to the accepted definition—costing £20,000 to £30,000 per quality-adjusted life year (QALY) gained.

Evaluating trial data

When considering the clinical effectiveness of pixantrone, the appraisal committee analyzed data from the EXTEND PIX301 trial, which was submitted by the manufacturer.

The trial enrolled adults with aggressive, de novo, or transformed NHL that had relapsed after 2 or more chemotherapy regimens, including at least 1 standard anthracycline-containing regimen with a response that lasted at least 24 weeks. Seventy patients were randomized to pixantrone, and 70 were randomized to a physician’s choice of single-agent comparators.

The committee pointed out a number of uncertainties associated with the trial. One was that it did not include the planned number of patients (which was 320), so it may not have been sufficiently powered to detect differences between the treatment arms.

Another concern was that the trial’s primary endpoint was complete or unconfirmed complete response, rather than overall survival or progression-free survival. In fact, there was a lack of statistically significant difference in overall survival between treatment arms. And other differences between the treatment arms were not always statistically significant.

These factors led the committee to conclude that there is insufficient evidence to suggest pixantrone is more clinically effective than treatments currently used in clinical practice.

Suitability for the UK

The appraisal committee also heard evidence from clinical experts and patient representatives. This information revealed differences in previous treatment between the PIX301 trial population and UK clinical practice.

Therefore, the committee said it could not determine the clinical effectiveness of pixantrone for a UK population.

In addition, there is doubt regarding the clinical benefit of pixantrone in patients who previously received rituximab. And this applies to virtually all patients with relapsed or refractory aggressive B-cell lymphoma in England and Wales, the committee noted.

(The European Medicines Agency’s conditional approval of pixantrone stipulated that an additional trial must confirm the clinical benefit of the drug in patients who have previously received rituximab.)

Calculating costs

The committee estimated the patient access scheme for pixantrone would most likely result in an incremental cost-effectiveness ratio of £30,700 per QALY gained. This is above the range normally considered to be cost-effective—usually £20,000 to £30,000 per QALY gained.

This factor, along with the lack of clinical effectiveness, prompted the committee to conclude that pixantrone would not be a cost-effective use of NHS resources.

According to Cell Therapeutics, pixantrone costs £553.50 per 20 mL vial. The recommended dosage of pixantrone is 50 mg/m² on days 1, 8, and 15 of each 28-day cycle, for up to 6 cycles.

The estimated cost of a course of treatment is £19,926. This is based on the median length of treatment in the PIX301 trial—4 cycles, using an average of 3 vials per dose.

About the guidance

Individuals can comment on the pixantrone draft guidance via the NICE website. It is open until November 4, 2013. 

This is the third version of the draft guidance published and the second consultation launched. The draft guidance was initially published for consultation in April 2013, followed by a final draft guidance in June 2013. But this document was withdrawn during the appeal stage because the manufacturer submitted the patient access scheme.

Until the final guidance is issued to the NHS, organizations should make decisions locally on the funding of specific treatments. Once NICE issues its final guidance on a technology, it replaces local recommendations.

B-cell lymphoma

The UK’s National Institute for Health and Care Excellence (NICE) has re-examined its draft guidance for pixantrone (Pixuvri) but come to the same conclusion as before.

The organization is still not recommending pixantrone monotherapy to treat multiply relapsed or refractory B-cell non-Hodgkin lymphoma (NHL).

Of course, this recommendation may change, as this is not NICE’s final guidance on pixantrone.

For this second consultation on the draft guidance, an independent appraisal committee re-examined the clinical and cost-effectiveness of pixantrone.

This time, the committee took into consideration a patient access scheme submitted by pixantrone’s manufacturer, Cell Therapeutics. The scheme was designed to make the drug more cost-effective for the National Health Service (NHS).

“Unfortunately, the committee concluded that this scheme . . . does not overcome the uncertainties in the evidence for the drug’s clinical effectiveness over and above current treatments for this disease,” said NICE Chief Executive Sir Andrew Dillon.

In fact, the committee found the scheme did not make pixantrone cost-effective according to the accepted definition—costing £20,000 to £30,000 per quality-adjusted life year (QALY) gained.

Evaluating trial data

When considering the clinical effectiveness of pixantrone, the appraisal committee analyzed data from the EXTEND PIX301 trial, which was submitted by the manufacturer.

The trial enrolled adults with aggressive, de novo, or transformed NHL that had relapsed after 2 or more chemotherapy regimens, including at least 1 standard anthracycline-containing regimen with a response that lasted at least 24 weeks. Seventy patients were randomized to pixantrone, and 70 were randomized to a physician’s choice of single-agent comparators.

The committee pointed out a number of uncertainties associated with the trial. One was that it did not include the planned number of patients (which was 320), so it may not have been sufficiently powered to detect differences between the treatment arms.

Another concern was that the trial’s primary endpoint was complete or unconfirmed complete response, rather than overall survival or progression-free survival. In fact, there was a lack of statistically significant difference in overall survival between treatment arms. And other differences between the treatment arms were not always statistically significant.

These factors led the committee to conclude that there is insufficient evidence to suggest pixantrone is more clinically effective than treatments currently used in clinical practice.

Suitability for the UK

The appraisal committee also heard evidence from clinical experts and patient representatives. This information revealed differences in previous treatment between the PIX301 trial population and UK clinical practice.

Therefore, the committee said it could not determine the clinical effectiveness of pixantrone for a UK population.

In addition, there is doubt regarding the clinical benefit of pixantrone in patients who previously received rituximab. And this applies to virtually all patients with relapsed or refractory aggressive B-cell lymphoma in England and Wales, the committee noted.

(The European Medicines Agency’s conditional approval of pixantrone stipulated that an additional trial must confirm the clinical benefit of the drug in patients who have previously received rituximab.)

Calculating costs

The committee estimated the patient access scheme for pixantrone would most likely result in an incremental cost-effectiveness ratio of £30,700 per QALY gained. This is above the range normally considered to be cost-effective—usually £20,000 to £30,000 per QALY gained.

This factor, along with the lack of clinical effectiveness, prompted the committee to conclude that pixantrone would not be a cost-effective use of NHS resources.

According to Cell Therapeutics, pixantrone costs £553.50 per 20 mL vial. The recommended dosage of pixantrone is 50 mg/m² on days 1, 8, and 15 of each 28-day cycle, for up to 6 cycles.

The estimated cost of a course of treatment is £19,926. This is based on the median length of treatment in the PIX301 trial—4 cycles, using an average of 3 vials per dose.

About the guidance

Individuals can comment on the pixantrone draft guidance via the NICE website. It is open until November 4, 2013. 

This is the third version of the draft guidance published and the second consultation launched. The draft guidance was initially published for consultation in April 2013, followed by a final draft guidance in June 2013. But this document was withdrawn during the appeal stage because the manufacturer submitted the patient access scheme.

Until the final guidance is issued to the NHS, organizations should make decisions locally on the funding of specific treatments. Once NICE issues its final guidance on a technology, it replaces local recommendations.

As a result of adverse events, all trials of the tyrosine kinase inhibitor ponatinib (Iclusig) have been placed on partial clinical hold.

The US Food and Drug Administration (FDA) has paused new enrollment in the trials.

Patients already enrolled will continue to receive ponatinib, but at reduced doses. If trial enrollment resumes, eligibility criteria will change.

These actions come after ponatinib’s makers, Ariad Pharmaceuticals, reviewed extended follow-up data from the PACE trial and observed an increase in thrombotic events.

This phase 2 trial is testing ponatinib in patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) who have resisted or cannot tolerate therapy with dasatinib or nilotinib.

At a median follow-up of 24 months, 11.8% of PACE patients developed serious arterial thrombosis, including 6.2% with cardiovascular events, 4% with cerebrovascular events, and 3.6% with peripheral vascular events. (Some patients had more than one type of event.) In comparison, 8% of patients had serious arterial thrombosis at 11 months of follow-up.

The rate of serious venous occlusion also increased with extended follow-up. At 24 months, the event had occurred in 2.9% of patients, compared to 2.2% at 11 months of follow-up.

Ariad noted, however, that the incidence rate of arterial thrombotic events has not increased when it is normalized to the duration of treatment exposure. There were 10 events per 100 patient-years in the original analysis and 9.6 events per 100 patient-years in the current analysis.

Nevertheless, Ariad has announced the following changes to the clinical development program for ponatinib.

First, the FDA has paused patient enrollment in all clinical studies of ponatinib. Subject to agreement with the FDA, enrollment will resume with dose changes and other modifications.

Patients who are currently receiving ponatinib will continue on therapy. However, doses will be reduced, on a trial-by-trial basis, from the current 45-mg-daily dose.

The dose in patients enrolled in the EPIC trial will be reduced to 30 mg daily, unless they have achieved a major molecular response. In these patients, the dose will be reduced to 15 mg daily. EPIC is a phase 3 trial testing ponatinib in patients with newly diagnosed CML.

Once enrollment resumes for ponatinib trials, the eligibility criteria will be modified to exclude patients who have experienced prior arterial thrombosis resulting in heart attack or stroke.

The US prescribing information for ponatinib has not yet changed. The drug is still available in the US to patients with resistant or intolerant CML or Ph+ ALL at the approved, once-daily dose of 45 mg. Ponatinib was approved for this indication in the US in December and in the European Union in July.

Ariad is consulting with the FDA and other health authorities about changes in ponatinib’s product labeling to reflect the updated information.

The company is sending a written communication to healthcare providers outlining this information. Ariad is also informing the European Medicines Agency and other regulatory agencies of the changes.

For more information about the changes in ponatinib trials, visit www.clinicaltrials.gov, email inquiries to medinfo@ariad.com, or call the Ariad US toll-free number: (855) 552-7423, the European Union toll-free number: 800 00027423, or the international number: +1 (617)-503-7423.

As a result of adverse events, all trials of the tyrosine kinase inhibitor ponatinib (Iclusig) have been placed on partial clinical hold.

The US Food and Drug Administration (FDA) has paused new enrollment in the trials.

Patients already enrolled will continue to receive ponatinib, but at reduced doses. If trial enrollment resumes, eligibility criteria will change.

These actions come after ponatinib’s makers, Ariad Pharmaceuticals, reviewed extended follow-up data from the PACE trial and observed an increase in thrombotic events.

This phase 2 trial is testing ponatinib in patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) who have resisted or cannot tolerate therapy with dasatinib or nilotinib.

At a median follow-up of 24 months, 11.8% of PACE patients developed serious arterial thrombosis, including 6.2% with cardiovascular events, 4% with cerebrovascular events, and 3.6% with peripheral vascular events. (Some patients had more than one type of event.) In comparison, 8% of patients had serious arterial thrombosis at 11 months of follow-up.

The rate of serious venous occlusion also increased with extended follow-up. At 24 months, the event had occurred in 2.9% of patients, compared to 2.2% at 11 months of follow-up.

Ariad noted, however, that the incidence rate of arterial thrombotic events has not increased when it is normalized to the duration of treatment exposure. There were 10 events per 100 patient-years in the original analysis and 9.6 events per 100 patient-years in the current analysis.

Nevertheless, Ariad has announced the following changes to the clinical development program for ponatinib.

First, the FDA has paused patient enrollment in all clinical studies of ponatinib. Subject to agreement with the FDA, enrollment will resume with dose changes and other modifications.

Patients who are currently receiving ponatinib will continue on therapy. However, doses will be reduced, on a trial-by-trial basis, from the current 45-mg-daily dose.

The dose in patients enrolled in the EPIC trial will be reduced to 30 mg daily, unless they have achieved a major molecular response. In these patients, the dose will be reduced to 15 mg daily. EPIC is a phase 3 trial testing ponatinib in patients with newly diagnosed CML.

Once enrollment resumes for ponatinib trials, the eligibility criteria will be modified to exclude patients who have experienced prior arterial thrombosis resulting in heart attack or stroke.

The US prescribing information for ponatinib has not yet changed. The drug is still available in the US to patients with resistant or intolerant CML or Ph+ ALL at the approved, once-daily dose of 45 mg. Ponatinib was approved for this indication in the US in December and in the European Union in July.

Ariad is consulting with the FDA and other health authorities about changes in ponatinib’s product labeling to reflect the updated information.

The company is sending a written communication to healthcare providers outlining this information. Ariad is also informing the European Medicines Agency and other regulatory agencies of the changes.

For more information about the changes in ponatinib trials, visit www.clinicaltrials.gov, email inquiries to medinfo@ariad.com, or call the Ariad US toll-free number: (855) 552-7423, the European Union toll-free number: 800 00027423, or the international number: +1 (617)-503-7423.

As a result of adverse events, all trials of the tyrosine kinase inhibitor ponatinib (Iclusig) have been placed on partial clinical hold.

The US Food and Drug Administration (FDA) has paused new enrollment in the trials.

Patients already enrolled will continue to receive ponatinib, but at reduced doses. If trial enrollment resumes, eligibility criteria will change.

These actions come after ponatinib’s makers, Ariad Pharmaceuticals, reviewed extended follow-up data from the PACE trial and observed an increase in thrombotic events.

This phase 2 trial is testing ponatinib in patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) who have resisted or cannot tolerate therapy with dasatinib or nilotinib.

At a median follow-up of 24 months, 11.8% of PACE patients developed serious arterial thrombosis, including 6.2% with cardiovascular events, 4% with cerebrovascular events, and 3.6% with peripheral vascular events. (Some patients had more than one type of event.) In comparison, 8% of patients had serious arterial thrombosis at 11 months of follow-up.

The rate of serious venous occlusion also increased with extended follow-up. At 24 months, the event had occurred in 2.9% of patients, compared to 2.2% at 11 months of follow-up.

Ariad noted, however, that the incidence rate of arterial thrombotic events has not increased when it is normalized to the duration of treatment exposure. There were 10 events per 100 patient-years in the original analysis and 9.6 events per 100 patient-years in the current analysis.

Nevertheless, Ariad has announced the following changes to the clinical development program for ponatinib.

First, the FDA has paused patient enrollment in all clinical studies of ponatinib. Subject to agreement with the FDA, enrollment will resume with dose changes and other modifications.

Patients who are currently receiving ponatinib will continue on therapy. However, doses will be reduced, on a trial-by-trial basis, from the current 45-mg-daily dose.

The dose in patients enrolled in the EPIC trial will be reduced to 30 mg daily, unless they have achieved a major molecular response. In these patients, the dose will be reduced to 15 mg daily. EPIC is a phase 3 trial testing ponatinib in patients with newly diagnosed CML.

Once enrollment resumes for ponatinib trials, the eligibility criteria will be modified to exclude patients who have experienced prior arterial thrombosis resulting in heart attack or stroke.

The US prescribing information for ponatinib has not yet changed. The drug is still available in the US to patients with resistant or intolerant CML or Ph+ ALL at the approved, once-daily dose of 45 mg. Ponatinib was approved for this indication in the US in December and in the European Union in July.

Ariad is consulting with the FDA and other health authorities about changes in ponatinib’s product labeling to reflect the updated information.

The company is sending a written communication to healthcare providers outlining this information. Ariad is also informing the European Medicines Agency and other regulatory agencies of the changes.

For more information about the changes in ponatinib trials, visit www.clinicaltrials.gov, email inquiries to medinfo@ariad.com, or call the Ariad US toll-free number: (855) 552-7423, the European Union toll-free number: 800 00027423, or the international number: +1 (617)-503-7423.

The US Food and Drug Administration (FDA) has granted orphan designation to an investigational drug for the treatment of myelodysplastic syndromes (MDS).

The drug, CPI-613, targets metabolic changes that are thought to occur in many cancer cells.

It has demonstrated activity and tolerability in a phase 1 trial of patients with advanced, relapsed/refractory hematologic malignancies.

CPI-613 previously received orphan designation for acute myeloid leukemia (AML) and pancreatic carcinoma.

Orphan designation is granted for drugs intended to treat diseases that affect fewer than 200,000 individuals in the US. This designation gives the makers of CPI-613, Cornerstone Pharmaceuticals, 7 years of US marketing exclusivity once the drug is approved.

The designation also allows the company to apply for government funding to defray trial costs, tax credits for clinical research expenses, and a potential waiver of the FDA’s application user fee.

CPI-613: Mechanism and phase 1 results

CPI-613 induces cancer-specific inhibition of the mitochondrial enzymes pyruvate dehydrogenase (PDH) and alpha ketoglutarate dehydrogenase (KGDH).

Disrupting the function of PDH and KGDH disrupts tumor mitochondrial metabolism. As a result, tumor cells are starved of energy and biosynthetic intermediates, which leads to cell death.

Researchers evaluated CPI-613 in a phase 1 study of patients with advanced, relapsed/refractory hematologic malignancies.

The team, led by Timothy S. Pardee, MD, of Wake Forest Baptist Medical Center in Winston-Salem, North Carolina, presented the results at the 2013 ASCO Annual Meeting as abstract 2516. (Information in the abstract differs slightly from that presented at the meeting.)

The trial was designed to determine the maximum tolerated dose, safety, and anticancer activity of CPI-613 as a single agent.

Twenty-one evaluable patients received CPI-613 on days 1 and 4 for 3 weeks every 28 days. Ten patients received more than 1 cycle of therapy.

The starting dose was 420 mg/m². Treatment could be continued if the patient experienced clinical benefit. Doses were escalated to a final dose of 3780 mg/m².

CPI-613 was generally well-tolerated when infused over 2 hours. Patients did not experience worsening cytopenias at any dose level. However, 1-hour infusions led to grade 3 renal failure in 2 patients.

At a dose of 3780 mg/m², 1 patient had prolonged grade 3 nausea, and 1 patient had grade 3 renal failure. Six patients received a 2-hour infusion of 2940 mg/m² without dose-limiting toxicities, so the researchers considered this the maximum tolerated dose.

Of the 21 patients, 9 achieved a response of stable disease or better. One MDS patient achieved a complete remission and maintained it over 23 cycles. One AML patient achieved a morphologic leukemia-free state.

A Burkitt lymphoma patient and a cutaneous T-cell lymphoma patient maintained partial responses over 16 and 15 cycles, respectively. Two multiple myeloma patients, 2 MDS patients, and 1 AML patient had stable disease.

“We are very encouraged by the tolerability and signals of activity seen in several patients in this phase 1 study for whom there is no available therapy shown to provide clinical benefit,” Dr Pardee said.

“We look forward to further evaluating CPI-613 in the early relapsed/refractory AML patient setting when administered in combination with a standard chemotherapeutic regimen, as well as in early relapsed or refractory MDS patients, with the hope of improving the outcomes and the quality of life for these patients through the combined use of this mechanistically novel agent.”

The AML study is a phase 1 trial investigating CPI-613 in combination with high-dose cytarabine and mitoxantrone, and the MDS study is a phase 2 trial investigating single-agent CPI-613.

The US Food and Drug Administration (FDA) has granted orphan designation to an investigational drug for the treatment of myelodysplastic syndromes (MDS).

The drug, CPI-613, targets metabolic changes that are thought to occur in many cancer cells.

It has demonstrated activity and tolerability in a phase 1 trial of patients with advanced, relapsed/refractory hematologic malignancies.

CPI-613 previously received orphan designation for acute myeloid leukemia (AML) and pancreatic carcinoma.

Orphan designation is granted for drugs intended to treat diseases that affect fewer than 200,000 individuals in the US. This designation gives the makers of CPI-613, Cornerstone Pharmaceuticals, 7 years of US marketing exclusivity once the drug is approved.

The designation also allows the company to apply for government funding to defray trial costs, tax credits for clinical research expenses, and a potential waiver of the FDA’s application user fee.

CPI-613: Mechanism and phase 1 results

CPI-613 induces cancer-specific inhibition of the mitochondrial enzymes pyruvate dehydrogenase (PDH) and alpha ketoglutarate dehydrogenase (KGDH).

Disrupting the function of PDH and KGDH disrupts tumor mitochondrial metabolism. As a result, tumor cells are starved of energy and biosynthetic intermediates, which leads to cell death.

Researchers evaluated CPI-613 in a phase 1 study of patients with advanced, relapsed/refractory hematologic malignancies.

The team, led by Timothy S. Pardee, MD, of Wake Forest Baptist Medical Center in Winston-Salem, North Carolina, presented the results at the 2013 ASCO Annual Meeting as abstract 2516. (Information in the abstract differs slightly from that presented at the meeting.)

The trial was designed to determine the maximum tolerated dose, safety, and anticancer activity of CPI-613 as a single agent.

Twenty-one evaluable patients received CPI-613 on days 1 and 4 for 3 weeks every 28 days. Ten patients received more than 1 cycle of therapy.

The starting dose was 420 mg/m². Treatment could be continued if the patient experienced clinical benefit. Doses were escalated to a final dose of 3780 mg/m².

CPI-613 was generally well-tolerated when infused over 2 hours. Patients did not experience worsening cytopenias at any dose level. However, 1-hour infusions led to grade 3 renal failure in 2 patients.

At a dose of 3780 mg/m², 1 patient had prolonged grade 3 nausea, and 1 patient had grade 3 renal failure. Six patients received a 2-hour infusion of 2940 mg/m² without dose-limiting toxicities, so the researchers considered this the maximum tolerated dose.

Of the 21 patients, 9 achieved a response of stable disease or better. One MDS patient achieved a complete remission and maintained it over 23 cycles. One AML patient achieved a morphologic leukemia-free state.

A Burkitt lymphoma patient and a cutaneous T-cell lymphoma patient maintained partial responses over 16 and 15 cycles, respectively. Two multiple myeloma patients, 2 MDS patients, and 1 AML patient had stable disease.

“We are very encouraged by the tolerability and signals of activity seen in several patients in this phase 1 study for whom there is no available therapy shown to provide clinical benefit,” Dr Pardee said.

“We look forward to further evaluating CPI-613 in the early relapsed/refractory AML patient setting when administered in combination with a standard chemotherapeutic regimen, as well as in early relapsed or refractory MDS patients, with the hope of improving the outcomes and the quality of life for these patients through the combined use of this mechanistically novel agent.”

The AML study is a phase 1 trial investigating CPI-613 in combination with high-dose cytarabine and mitoxantrone, and the MDS study is a phase 2 trial investigating single-agent CPI-613.

The US Food and Drug Administration (FDA) has granted orphan designation to an investigational drug for the treatment of myelodysplastic syndromes (MDS).

The drug, CPI-613, targets metabolic changes that are thought to occur in many cancer cells.

It has demonstrated activity and tolerability in a phase 1 trial of patients with advanced, relapsed/refractory hematologic malignancies.

CPI-613 previously received orphan designation for acute myeloid leukemia (AML) and pancreatic carcinoma.

Orphan designation is granted for drugs intended to treat diseases that affect fewer than 200,000 individuals in the US. This designation gives the makers of CPI-613, Cornerstone Pharmaceuticals, 7 years of US marketing exclusivity once the drug is approved.

The designation also allows the company to apply for government funding to defray trial costs, tax credits for clinical research expenses, and a potential waiver of the FDA’s application user fee.

CPI-613: Mechanism and phase 1 results

CPI-613 induces cancer-specific inhibition of the mitochondrial enzymes pyruvate dehydrogenase (PDH) and alpha ketoglutarate dehydrogenase (KGDH).

Disrupting the function of PDH and KGDH disrupts tumor mitochondrial metabolism. As a result, tumor cells are starved of energy and biosynthetic intermediates, which leads to cell death.

Researchers evaluated CPI-613 in a phase 1 study of patients with advanced, relapsed/refractory hematologic malignancies.

The team, led by Timothy S. Pardee, MD, of Wake Forest Baptist Medical Center in Winston-Salem, North Carolina, presented the results at the 2013 ASCO Annual Meeting as abstract 2516. (Information in the abstract differs slightly from that presented at the meeting.)

The trial was designed to determine the maximum tolerated dose, safety, and anticancer activity of CPI-613 as a single agent.

Twenty-one evaluable patients received CPI-613 on days 1 and 4 for 3 weeks every 28 days. Ten patients received more than 1 cycle of therapy.

The starting dose was 420 mg/m². Treatment could be continued if the patient experienced clinical benefit. Doses were escalated to a final dose of 3780 mg/m².

CPI-613 was generally well-tolerated when infused over 2 hours. Patients did not experience worsening cytopenias at any dose level. However, 1-hour infusions led to grade 3 renal failure in 2 patients.

At a dose of 3780 mg/m², 1 patient had prolonged grade 3 nausea, and 1 patient had grade 3 renal failure. Six patients received a 2-hour infusion of 2940 mg/m² without dose-limiting toxicities, so the researchers considered this the maximum tolerated dose.

Of the 21 patients, 9 achieved a response of stable disease or better. One MDS patient achieved a complete remission and maintained it over 23 cycles. One AML patient achieved a morphologic leukemia-free state.

A Burkitt lymphoma patient and a cutaneous T-cell lymphoma patient maintained partial responses over 16 and 15 cycles, respectively. Two multiple myeloma patients, 2 MDS patients, and 1 AML patient had stable disease.

“We are very encouraged by the tolerability and signals of activity seen in several patients in this phase 1 study for whom there is no available therapy shown to provide clinical benefit,” Dr Pardee said.

“We look forward to further evaluating CPI-613 in the early relapsed/refractory AML patient setting when administered in combination with a standard chemotherapeutic regimen, as well as in early relapsed or refractory MDS patients, with the hope of improving the outcomes and the quality of life for these patients through the combined use of this mechanistically novel agent.”

The AML study is a phase 1 trial investigating CPI-613 in combination with high-dose cytarabine and mitoxantrone, and the MDS study is a phase 2 trial investigating single-agent CPI-613.

A new drug can prevent cytomegalovirus (CMV) in patients undergoing hematopoietic stem cell transplant (HSCT), according to a study published in The New England Journal of Medicine.

The drug, called CMX001, is an oral nucleotide analog lipid-conjugate that blocks replication of double-stranded DNA viruses.

HSCT recipients who took CMX001 after engraftment were less likely to develop CMV than HSCT patients who received placebo, researchers found.

“With current agents, between 3% and 5% of allogeneic transplant patients develop CMV disease within 6 months of transplantation, and a small number of them may die of it,” said investigator Francisco Marty, MD, of the Dana-Farber Cancer Institute in Boston.

“There clearly is a need for better treatments with fewer adverse effects. This clinical trial examined whether the disease can be prevented, rather than waiting for blood tests to show that treatment is needed.”

The phase 2 trial involved 230 HSCT recipients treated at 27 centers across the US. The patients were randomized to receive placebo or CMX001 at doses ranging from 40 mg a week to 200 mg twice a week.

Treatment began after engraftment, at about 2 to 3 weeks post-transplant, and continued for 9 to 11 weeks.

The study’s primary efficacy outcome was a “CMV event,” which was defined as CMV that affects the lung, digestive tract, or other organs, or a detectable amount of CMV in the blood at the end of treatment.

CMV events occurred in 25% (43/171) of patients who received CMX001 and 37% (22/59) of patients who received placebo. However, when CMX001 was given at the optimal dose—100 mg twice a week—only 10% of patients had a CMV event.

“The results show the effectiveness of CMX001 in preventing CMV infections in this group of patients,” Dr Marty said. “Because CMX001 is known to be active against other herpes viruses and against adenoviruses that sometimes affect transplant patients, it may be useful as a preventive or treatment agent for those infections as well.”

Most of the side effects associated with CMX001 were gastrointestinal in nature. Diarrhea was common and often serious in patients who received the drug at 200 mg twice a week.

Patients in this dose group were more likely to experience elevated alanine aminotransferase levels as well. But this was not associated with increases in levels of bilirubin or aspartate aminotransferase.

This research was funded by Chimerix, the company developing CMX001.

A new drug can prevent cytomegalovirus (CMV) in patients undergoing hematopoietic stem cell transplant (HSCT), according to a study published in The New England Journal of Medicine.

The drug, called CMX001, is an oral nucleotide analog lipid-conjugate that blocks replication of double-stranded DNA viruses.

HSCT recipients who took CMX001 after engraftment were less likely to develop CMV than HSCT patients who received placebo, researchers found.

“With current agents, between 3% and 5% of allogeneic transplant patients develop CMV disease within 6 months of transplantation, and a small number of them may die of it,” said investigator Francisco Marty, MD, of the Dana-Farber Cancer Institute in Boston.

“There clearly is a need for better treatments with fewer adverse effects. This clinical trial examined whether the disease can be prevented, rather than waiting for blood tests to show that treatment is needed.”

The phase 2 trial involved 230 HSCT recipients treated at 27 centers across the US. The patients were randomized to receive placebo or CMX001 at doses ranging from 40 mg a week to 200 mg twice a week.

Treatment began after engraftment, at about 2 to 3 weeks post-transplant, and continued for 9 to 11 weeks.

The study’s primary efficacy outcome was a “CMV event,” which was defined as CMV that affects the lung, digestive tract, or other organs, or a detectable amount of CMV in the blood at the end of treatment.

CMV events occurred in 25% (43/171) of patients who received CMX001 and 37% (22/59) of patients who received placebo. However, when CMX001 was given at the optimal dose—100 mg twice a week—only 10% of patients had a CMV event.

“The results show the effectiveness of CMX001 in preventing CMV infections in this group of patients,” Dr Marty said. “Because CMX001 is known to be active against other herpes viruses and against adenoviruses that sometimes affect transplant patients, it may be useful as a preventive or treatment agent for those infections as well.”

Most of the side effects associated with CMX001 were gastrointestinal in nature. Diarrhea was common and often serious in patients who received the drug at 200 mg twice a week.

Patients in this dose group were more likely to experience elevated alanine aminotransferase levels as well. But this was not associated with increases in levels of bilirubin or aspartate aminotransferase.

This research was funded by Chimerix, the company developing CMX001.

A new drug can prevent cytomegalovirus (CMV) in patients undergoing hematopoietic stem cell transplant (HSCT), according to a study published in The New England Journal of Medicine.

The drug, called CMX001, is an oral nucleotide analog lipid-conjugate that blocks replication of double-stranded DNA viruses.

HSCT recipients who took CMX001 after engraftment were less likely to develop CMV than HSCT patients who received placebo, researchers found.

“With current agents, between 3% and 5% of allogeneic transplant patients develop CMV disease within 6 months of transplantation, and a small number of them may die of it,” said investigator Francisco Marty, MD, of the Dana-Farber Cancer Institute in Boston.

“There clearly is a need for better treatments with fewer adverse effects. This clinical trial examined whether the disease can be prevented, rather than waiting for blood tests to show that treatment is needed.”

The phase 2 trial involved 230 HSCT recipients treated at 27 centers across the US. The patients were randomized to receive placebo or CMX001 at doses ranging from 40 mg a week to 200 mg twice a week.

Treatment began after engraftment, at about 2 to 3 weeks post-transplant, and continued for 9 to 11 weeks.

The study’s primary efficacy outcome was a “CMV event,” which was defined as CMV that affects the lung, digestive tract, or other organs, or a detectable amount of CMV in the blood at the end of treatment.

CMV events occurred in 25% (43/171) of patients who received CMX001 and 37% (22/59) of patients who received placebo. However, when CMX001 was given at the optimal dose—100 mg twice a week—only 10% of patients had a CMV event.

“The results show the effectiveness of CMX001 in preventing CMV infections in this group of patients,” Dr Marty said. “Because CMX001 is known to be active against other herpes viruses and against adenoviruses that sometimes affect transplant patients, it may be useful as a preventive or treatment agent for those infections as well.”

Most of the side effects associated with CMX001 were gastrointestinal in nature. Diarrhea was common and often serious in patients who received the drug at 200 mg twice a week.

Patients in this dose group were more likely to experience elevated alanine aminotransferase levels as well. But this was not associated with increases in levels of bilirubin or aspartate aminotransferase.

This research was funded by Chimerix, the company developing CMX001.

Bags of plasma for transfusion
Credit: Cristina Granados

A pooled plasma product that was approved by the Food and Drug Administration in January is now available for use in the US.

The product, called Octaplas, is a sterile, frozen solution of human plasma from several donors that has been treated with a solvent detergent process to minimize the risk of serious virus transmission.

The plasma is collected from US donors who have been screened and tested for diseases transmitted by blood.

Octaplas is indicated for the replacement of multiple coagulation

factors in patients with acquired deficiencies due to liver disease or

undergoing cardiac surgery or liver transplant. Octaplas can also be

used for plasma exchange in patients with thrombotic thrombocytopenic purpura.

Octaplas is contraindicated in patients with IgA deficiency, severe deficiency of protein S, a history of hypersensitivity to fresh-frozen plasma or plasma-derived products including any plasma protein, or a history of hypersensitivity reaction to Octaplas.

Transfusion reactions can occur with ABO blood group mismatches. High infusion rates can induce hypervolemia with consequent pulmonary edema or cardiac failure.

Excessive bleeding due to hyperfibrinolysis can occur due to low levels of alpha2-antiplasmin. Thrombosis can occur due to low levels of protein S, and citrate toxicity can occur with volumes exceeding 1 mL of Octaplas per kg per minute.

Because Octaplas is made from human plasma, it may carry the risk of transmitting infectious agents; for instance, the variant Creutzfeldt-Jakob disease agent.

Administering Octaplas

Octaplas should be matched to the recipient’s blood group to help avoid transfusion reactions. Each lot of the product is tested for composition of key clotting factors and is only released if the levels are within acceptable ranges.

The product is administered by intravenous infusion after thawing, using an infusion set with a filter. An aseptic technique must be used throughout the infusion.

The dosage depends upon the clinical situation and the underlying disorder. But 12 to 15 mL/kg of body weight is a generally accepted starting dose, and it should increase the patient’s plasma coagulation factor levels by about 25%.

It is important to monitor patient response, both clinically and with measurement of prothrombin time, partial thromboplastin time, and/or specific coagulation factor assays.

To order Octaplas, call your local Blood Center or National Hospital Specialties at 800-344-6087. To request product information, call 201-604-1130.

For prescribing information, visit www.octaplasus.com. Octaplas is manufactured by Octapharma USA.

Bags of plasma for transfusion
Credit: Cristina Granados

A pooled plasma product that was approved by the Food and Drug Administration in January is now available for use in the US.

The product, called Octaplas, is a sterile, frozen solution of human plasma from several donors that has been treated with a solvent detergent process to minimize the risk of serious virus transmission.

The plasma is collected from US donors who have been screened and tested for diseases transmitted by blood.

Octaplas is indicated for the replacement of multiple coagulation

factors in patients with acquired deficiencies due to liver disease or

undergoing cardiac surgery or liver transplant. Octaplas can also be

used for plasma exchange in patients with thrombotic thrombocytopenic purpura.

Octaplas is contraindicated in patients with IgA deficiency, severe deficiency of protein S, a history of hypersensitivity to fresh-frozen plasma or plasma-derived products including any plasma protein, or a history of hypersensitivity reaction to Octaplas.

Transfusion reactions can occur with ABO blood group mismatches. High infusion rates can induce hypervolemia with consequent pulmonary edema or cardiac failure.

Excessive bleeding due to hyperfibrinolysis can occur due to low levels of alpha2-antiplasmin. Thrombosis can occur due to low levels of protein S, and citrate toxicity can occur with volumes exceeding 1 mL of Octaplas per kg per minute.

Because Octaplas is made from human plasma, it may carry the risk of transmitting infectious agents; for instance, the variant Creutzfeldt-Jakob disease agent.

Administering Octaplas

Octaplas should be matched to the recipient’s blood group to help avoid transfusion reactions. Each lot of the product is tested for composition of key clotting factors and is only released if the levels are within acceptable ranges.

The product is administered by intravenous infusion after thawing, using an infusion set with a filter. An aseptic technique must be used throughout the infusion.

The dosage depends upon the clinical situation and the underlying disorder. But 12 to 15 mL/kg of body weight is a generally accepted starting dose, and it should increase the patient’s plasma coagulation factor levels by about 25%.

It is important to monitor patient response, both clinically and with measurement of prothrombin time, partial thromboplastin time, and/or specific coagulation factor assays.

To order Octaplas, call your local Blood Center or National Hospital Specialties at 800-344-6087. To request product information, call 201-604-1130.

For prescribing information, visit www.octaplasus.com. Octaplas is manufactured by Octapharma USA.

Bags of plasma for transfusion
Credit: Cristina Granados

A pooled plasma product that was approved by the Food and Drug Administration in January is now available for use in the US.

The product, called Octaplas, is a sterile, frozen solution of human plasma from several donors that has been treated with a solvent detergent process to minimize the risk of serious virus transmission.

The plasma is collected from US donors who have been screened and tested for diseases transmitted by blood.

Octaplas is indicated for the replacement of multiple coagulation

factors in patients with acquired deficiencies due to liver disease or

undergoing cardiac surgery or liver transplant. Octaplas can also be

used for plasma exchange in patients with thrombotic thrombocytopenic purpura.

Octaplas is contraindicated in patients with IgA deficiency, severe deficiency of protein S, a history of hypersensitivity to fresh-frozen plasma or plasma-derived products including any plasma protein, or a history of hypersensitivity reaction to Octaplas.

Transfusion reactions can occur with ABO blood group mismatches. High infusion rates can induce hypervolemia with consequent pulmonary edema or cardiac failure.

Excessive bleeding due to hyperfibrinolysis can occur due to low levels of alpha2-antiplasmin. Thrombosis can occur due to low levels of protein S, and citrate toxicity can occur with volumes exceeding 1 mL of Octaplas per kg per minute.

Because Octaplas is made from human plasma, it may carry the risk of transmitting infectious agents; for instance, the variant Creutzfeldt-Jakob disease agent.

Administering Octaplas

Octaplas should be matched to the recipient’s blood group to help avoid transfusion reactions. Each lot of the product is tested for composition of key clotting factors and is only released if the levels are within acceptable ranges.

The product is administered by intravenous infusion after thawing, using an infusion set with a filter. An aseptic technique must be used throughout the infusion.

The dosage depends upon the clinical situation and the underlying disorder. But 12 to 15 mL/kg of body weight is a generally accepted starting dose, and it should increase the patient’s plasma coagulation factor levels by about 25%.

It is important to monitor patient response, both clinically and with measurement of prothrombin time, partial thromboplastin time, and/or specific coagulation factor assays.

To order Octaplas, call your local Blood Center or National Hospital Specialties at 800-344-6087. To request product information, call 201-604-1130.

For prescribing information, visit www.octaplasus.com. Octaplas is manufactured by Octapharma USA.

Thrombus
Image by Kevin MacKenzie

AMSTERDAM—The oral anticoagulant edoxaban compares favorably with warfarin as treatment for recurrent venous thromboembolism (VTE), according to results of the Hokusai-VTE trial.

Edoxaban given after initial low molecular weight heparin (LMWH) proved equally as effective as warfarin given after LMWH.

And patients treated with edoxaban were less likely to experience clinically relevant bleeding than patients who received warfarin.

Results of the trial also offer new insight into a previously under-represented subgroup of patients with pulmonary embolism (PE), suggesting that treatment for this group might need to be different than for other VTE patients, said lead investigator Harry R. Büller, MD, of the Academic Medical Center in Amsterdam.

Dr Büller presented these findings at the 2013 European Society of Cardiology Congress, which is taking place August 31 through September 4. The study was also published in NEJM on September 1.

“What makes this study unique is new insight that there are subgroups in which we might need to revisit what we currently think about the treatment of VTE,” Dr Büller said.

The Hokusai-VTE trial included a broad spectrum of VTE patients, including a large subgroup (30%) of patients with PE and right ventricular dysfunction, and another subgroup (20%) at high risk for bleeding due to renal impairment and low body weight.

In total, 4921 patients with deep vein thrombosis and 3319 with PE received initial subcutaneous LMWH therapy and were then randomized to receive edoxaban or warfarin daily for 3 to 12 months.

Patients at a higher risk for bleeding—ie, those with creatinine clearance of 30 to 50 mL/min or body weight below 60 kg—received 30 mg of edoxaban. The rest of the patients in the edoxaban arm received 60 mg. Warfarin patients were dosed according to standard of care.

Overall, edoxaban proved as effective as warfarin. Recurrent symptomatic VTE occurred in 3.2% and 3.5% of patients, respectively (P<0.001 for noninferiority).

However, in the subgroup of patients with PE and evidence of right ventricular dysfunction, efficacy was superior with edoxaban—3.3% and 6.2%, respectively.

Edoxaban proved superior when it came to the primary safety outcome as well. Clinically relevant bleeding occurred in 8.5% of edoxaban-treated patients and 10.3% of warfarin-treated patients (P=0.004 for superiority).

In the edoxaban arm, there were 2 fatal bleeds and 13 non-fatal bleeds in a critical site. With warfarin, there were 10 fatal bleeds and 25 non-fatal bleeds in a critical site.

“By halving the daily dose of edoxaban to 30 mg [among patients at high risk of bleeding], efficacy was maintained, with significantly less bleeding than observed in the warfarin group,” Dr Büller said.

In this high-risk subgroup, clinically relevant bleeding occurred in 7.9% of those treated with edoxaban, compared to 12.8% of those treated with warfarin. And recurrent symptomatic VTE occurred in 3.0% and 4.2%, respectively.

Previous trials of oral anticoagulants have not identified these specific subgroups, Dr Büller said.

“Our findings are likely to be generalizable in a global setting,” he added. “We included patients with both provoked and unprovoked venous thromboembolism, and treatment durations varied from 3 to 12 months at the discretion of the treating physician.”

This study was supported by Daiichi Sankyo, the company developing edoxaban.

Thrombus
Image by Kevin MacKenzie

AMSTERDAM—The oral anticoagulant edoxaban compares favorably with warfarin as treatment for recurrent venous thromboembolism (VTE), according to results of the Hokusai-VTE trial.

Edoxaban given after initial low molecular weight heparin (LMWH) proved equally as effective as warfarin given after LMWH.

And patients treated with edoxaban were less likely to experience clinically relevant bleeding than patients who received warfarin.

Results of the trial also offer new insight into a previously under-represented subgroup of patients with pulmonary embolism (PE), suggesting that treatment for this group might need to be different than for other VTE patients, said lead investigator Harry R. Büller, MD, of the Academic Medical Center in Amsterdam.

Dr Büller presented these findings at the 2013 European Society of Cardiology Congress, which is taking place August 31 through September 4. The study was also published in NEJM on September 1.

“What makes this study unique is new insight that there are subgroups in which we might need to revisit what we currently think about the treatment of VTE,” Dr Büller said.

The Hokusai-VTE trial included a broad spectrum of VTE patients, including a large subgroup (30%) of patients with PE and right ventricular dysfunction, and another subgroup (20%) at high risk for bleeding due to renal impairment and low body weight.

In total, 4921 patients with deep vein thrombosis and 3319 with PE received initial subcutaneous LMWH therapy and were then randomized to receive edoxaban or warfarin daily for 3 to 12 months.

Patients at a higher risk for bleeding—ie, those with creatinine clearance of 30 to 50 mL/min or body weight below 60 kg—received 30 mg of edoxaban. The rest of the patients in the edoxaban arm received 60 mg. Warfarin patients were dosed according to standard of care.

Overall, edoxaban proved as effective as warfarin. Recurrent symptomatic VTE occurred in 3.2% and 3.5% of patients, respectively (P<0.001 for noninferiority).

However, in the subgroup of patients with PE and evidence of right ventricular dysfunction, efficacy was superior with edoxaban—3.3% and 6.2%, respectively.

Edoxaban proved superior when it came to the primary safety outcome as well. Clinically relevant bleeding occurred in 8.5% of edoxaban-treated patients and 10.3% of warfarin-treated patients (P=0.004 for superiority).

In the edoxaban arm, there were 2 fatal bleeds and 13 non-fatal bleeds in a critical site. With warfarin, there were 10 fatal bleeds and 25 non-fatal bleeds in a critical site.

“By halving the daily dose of edoxaban to 30 mg [among patients at high risk of bleeding], efficacy was maintained, with significantly less bleeding than observed in the warfarin group,” Dr Büller said.

In this high-risk subgroup, clinically relevant bleeding occurred in 7.9% of those treated with edoxaban, compared to 12.8% of those treated with warfarin. And recurrent symptomatic VTE occurred in 3.0% and 4.2%, respectively.

Previous trials of oral anticoagulants have not identified these specific subgroups, Dr Büller said.

“Our findings are likely to be generalizable in a global setting,” he added. “We included patients with both provoked and unprovoked venous thromboembolism, and treatment durations varied from 3 to 12 months at the discretion of the treating physician.”

This study was supported by Daiichi Sankyo, the company developing edoxaban.

Thrombus
Image by Kevin MacKenzie

AMSTERDAM—The oral anticoagulant edoxaban compares favorably with warfarin as treatment for recurrent venous thromboembolism (VTE), according to results of the Hokusai-VTE trial.

Edoxaban given after initial low molecular weight heparin (LMWH) proved equally as effective as warfarin given after LMWH.

And patients treated with edoxaban were less likely to experience clinically relevant bleeding than patients who received warfarin.

Results of the trial also offer new insight into a previously under-represented subgroup of patients with pulmonary embolism (PE), suggesting that treatment for this group might need to be different than for other VTE patients, said lead investigator Harry R. Büller, MD, of the Academic Medical Center in Amsterdam.

Dr Büller presented these findings at the 2013 European Society of Cardiology Congress, which is taking place August 31 through September 4. The study was also published in NEJM on September 1.

“What makes this study unique is new insight that there are subgroups in which we might need to revisit what we currently think about the treatment of VTE,” Dr Büller said.

The Hokusai-VTE trial included a broad spectrum of VTE patients, including a large subgroup (30%) of patients with PE and right ventricular dysfunction, and another subgroup (20%) at high risk for bleeding due to renal impairment and low body weight.

In total, 4921 patients with deep vein thrombosis and 3319 with PE received initial subcutaneous LMWH therapy and were then randomized to receive edoxaban or warfarin daily for 3 to 12 months.

Patients at a higher risk for bleeding—ie, those with creatinine clearance of 30 to 50 mL/min or body weight below 60 kg—received 30 mg of edoxaban. The rest of the patients in the edoxaban arm received 60 mg. Warfarin patients were dosed according to standard of care.

Overall, edoxaban proved as effective as warfarin. Recurrent symptomatic VTE occurred in 3.2% and 3.5% of patients, respectively (P<0.001 for noninferiority).

However, in the subgroup of patients with PE and evidence of right ventricular dysfunction, efficacy was superior with edoxaban—3.3% and 6.2%, respectively.

Edoxaban proved superior when it came to the primary safety outcome as well. Clinically relevant bleeding occurred in 8.5% of edoxaban-treated patients and 10.3% of warfarin-treated patients (P=0.004 for superiority).

In the edoxaban arm, there were 2 fatal bleeds and 13 non-fatal bleeds in a critical site. With warfarin, there were 10 fatal bleeds and 25 non-fatal bleeds in a critical site.

“By halving the daily dose of edoxaban to 30 mg [among patients at high risk of bleeding], efficacy was maintained, with significantly less bleeding than observed in the warfarin group,” Dr Büller said.

In this high-risk subgroup, clinically relevant bleeding occurred in 7.9% of those treated with edoxaban, compared to 12.8% of those treated with warfarin. And recurrent symptomatic VTE occurred in 3.0% and 4.2%, respectively.

Previous trials of oral anticoagulants have not identified these specific subgroups, Dr Büller said.

“Our findings are likely to be generalizable in a global setting,” he added. “We included patients with both provoked and unprovoked venous thromboembolism, and treatment durations varied from 3 to 12 months at the discretion of the treating physician.”

This study was supported by Daiichi Sankyo, the company developing edoxaban.

Red blood cell culture showing
Staphylococcus infection
Credit: Bill Branson

The US Food and Drug Administration (FDA) has approved the first mass spectrometer system for automated identification of bacteria and yeasts that are known to cause serious illnesses in humans.

The system, called VITEK MS, can identify 193 different microorganisms and perform up to 192 different tests, each of which takes about 1 minute.

The VITEK MS can identify yeasts and bacteria associated with skin infections, pneumonia, meningitis, and bloodstream infections.

Patients whose immune systems are compromised or weakened by HIV/AIDS, cancer treatment, or antirejection therapy following transplants are particularly vulnerable to these infections.

“The ability for laboratories to use 1 device to identify almost 200 different microorganisms is a significant advance in the timely identification of pathogenic microorganisms,” said Alberto Gutierrez, PhD, director of the Office of In Vitro Diagnostics and Radiological Health at FDA’s Center for Devices and Radiological Health.

The VITEK MS incorporates a technology called matrix-assisted laser desorption/ionization–time of flight mass spectrometry. The technology uses a laser to break yeast and bacteria specimens into small particles that form a pattern unique to the microorganism.

The VITEK MS automatically compares the microorganism pattern to 193 known yeasts and bacteria in the system’s database to identify the microorganism.

Compared to other identification methods that require abundant organism growth for testing, mass spectrometry requires only a small amount of yeast or bacterial growth.

So testing can start as soon as growth is visible, generally within 18 to 24 hours. Traditional methods can take up to 5 days to produce the same identification results.

The FDA reviewed the VITEK MS through its de novo classification process, a regulatory pathway for some novel, low-to-moderate-risk medical devices that are not substantially equivalent to an already legally marketed device.

The FDA based its decision on the results of a study of 7068 microorganisms. When compared to sequencing and biochemical testing, the VITEK MS correctly identified the scientific group or family 93.6% of the time (with 87.5% of microorganisms identified to species level).

The system provided a “no identification” result for 3.2% of the microorganisms in the study, 0.8% of the test results were incorrect, and 2.4% were low discrimination with no correct result.

The VITEK MS is manufactured by bioMerieux, Inc., located in Durham, North Carolina.

Red blood cell culture showing
Staphylococcus infection
Credit: Bill Branson

The US Food and Drug Administration (FDA) has approved the first mass spectrometer system for automated identification of bacteria and yeasts that are known to cause serious illnesses in humans.

The system, called VITEK MS, can identify 193 different microorganisms and perform up to 192 different tests, each of which takes about 1 minute.

The VITEK MS can identify yeasts and bacteria associated with skin infections, pneumonia, meningitis, and bloodstream infections.

Patients whose immune systems are compromised or weakened by HIV/AIDS, cancer treatment, or antirejection therapy following transplants are particularly vulnerable to these infections.

“The ability for laboratories to use 1 device to identify almost 200 different microorganisms is a significant advance in the timely identification of pathogenic microorganisms,” said Alberto Gutierrez, PhD, director of the Office of In Vitro Diagnostics and Radiological Health at FDA’s Center for Devices and Radiological Health.

The VITEK MS incorporates a technology called matrix-assisted laser desorption/ionization–time of flight mass spectrometry. The technology uses a laser to break yeast and bacteria specimens into small particles that form a pattern unique to the microorganism.

The VITEK MS automatically compares the microorganism pattern to 193 known yeasts and bacteria in the system’s database to identify the microorganism.

Compared to other identification methods that require abundant organism growth for testing, mass spectrometry requires only a small amount of yeast or bacterial growth.

So testing can start as soon as growth is visible, generally within 18 to 24 hours. Traditional methods can take up to 5 days to produce the same identification results.

The FDA reviewed the VITEK MS through its de novo classification process, a regulatory pathway for some novel, low-to-moderate-risk medical devices that are not substantially equivalent to an already legally marketed device.

The FDA based its decision on the results of a study of 7068 microorganisms. When compared to sequencing and biochemical testing, the VITEK MS correctly identified the scientific group or family 93.6% of the time (with 87.5% of microorganisms identified to species level).

The system provided a “no identification” result for 3.2% of the microorganisms in the study, 0.8% of the test results were incorrect, and 2.4% were low discrimination with no correct result.

The VITEK MS is manufactured by bioMerieux, Inc., located in Durham, North Carolina.

Red blood cell culture showing
Staphylococcus infection
Credit: Bill Branson

The US Food and Drug Administration (FDA) has approved the first mass spectrometer system for automated identification of bacteria and yeasts that are known to cause serious illnesses in humans.

The system, called VITEK MS, can identify 193 different microorganisms and perform up to 192 different tests, each of which takes about 1 minute.

The VITEK MS can identify yeasts and bacteria associated with skin infections, pneumonia, meningitis, and bloodstream infections.

Patients whose immune systems are compromised or weakened by HIV/AIDS, cancer treatment, or antirejection therapy following transplants are particularly vulnerable to these infections.

“The ability for laboratories to use 1 device to identify almost 200 different microorganisms is a significant advance in the timely identification of pathogenic microorganisms,” said Alberto Gutierrez, PhD, director of the Office of In Vitro Diagnostics and Radiological Health at FDA’s Center for Devices and Radiological Health.

The VITEK MS incorporates a technology called matrix-assisted laser desorption/ionization–time of flight mass spectrometry. The technology uses a laser to break yeast and bacteria specimens into small particles that form a pattern unique to the microorganism.

The VITEK MS automatically compares the microorganism pattern to 193 known yeasts and bacteria in the system’s database to identify the microorganism.

Compared to other identification methods that require abundant organism growth for testing, mass spectrometry requires only a small amount of yeast or bacterial growth.

So testing can start as soon as growth is visible, generally within 18 to 24 hours. Traditional methods can take up to 5 days to produce the same identification results.

The FDA reviewed the VITEK MS through its de novo classification process, a regulatory pathway for some novel, low-to-moderate-risk medical devices that are not substantially equivalent to an already legally marketed device.

The FDA based its decision on the results of a study of 7068 microorganisms. When compared to sequencing and biochemical testing, the VITEK MS correctly identified the scientific group or family 93.6% of the time (with 87.5% of microorganisms identified to species level).

The system provided a “no identification” result for 3.2% of the microorganisms in the study, 0.8% of the test results were incorrect, and 2.4% were low discrimination with no correct result.

The VITEK MS is manufactured by bioMerieux, Inc., located in Durham, North Carolina.

Drugs in vials
Credit: Bill Branson

The French National Health Authority’s Transparency Commission has granted market access for the antineoplastic drug pixantrone (Pixuvri).

The drug is intended for use as monotherapy to treat adult patients with aggressive B-cell non-Hodgkin lymphoma who have failed 2 or 3 prior lines of therapy.

Pixantrone has already gained conditional marketing authorization for this indication within the European Union.

In the fourth quarter of 2012, the drug was made available to patients in 8 countries—Sweden, Denmark, Finland, Austria, Norway, Germany, the UK, and the Netherlands.

And last month, pixantrone was granted market access in Italy.

Now, the drug’s developers, Cell Therapeutics Inc., announced that pixantrone has been granted market access in France.
 
The next steps in France’s pharmaceutical reimbursement process are inclusion on the list of medicines approved for hospital use and subsequent publication in the Journal Officiel. And Cell Therapeutics intends to pursue these final goals.

All registered pharmaceuticals in France are subjected to a process known as Evaluation of Therapeutic Benefit, with the resulting evaluation expressed as a classification between 1 and 6. 

The Transparency Commission rated pixantrone at level 5, which allows the drug to be included in the reimbursed drugs list for hospital use. The commission will reassess the rating for the drug within 2 years.

France’s authorization and the European Commission’s conditional marketing authorization are based on data from the phase 3 EXTEND PIX301 trial. Although pixantrone prompted positive results in this trial, the US Food and Drug Administration (FDA) has expressed concerns about the number of patients included.

In fact, the FDA rejected a new drug application for pixantrone in 2010. Cell Therapeutics later resubmitted an application for the drug but withdrew it in January of last year. The company has not confirmed plans to refile with the FDA.

As for the European Commission’s conditional approval of pixantrone, it will be renewed on a yearly basis until Cell Therapeutics fullfills its committment to

provide additional data on patients

treated with pixantrone who previously received rituximab. The company said it expects to

have the results of this research by mid-2015.

Pixantrone is a novel aza-anthracenedione that forms stable DNA adducts. The drug was designed so that it cannot bind iron and perpetuate oxygen radical production or form a long-lived hydroxyl metabolite—both of which are the putative mechanisms for anthracycline-induced acute and chronic cardiotoxicity.

For full prescribing information for pixantrone, including the safety and efficacy profile in the approved indication, visit www.pixuvri.eu.

Drugs in vials
Credit: Bill Branson

The French National Health Authority’s Transparency Commission has granted market access for the antineoplastic drug pixantrone (Pixuvri).

The drug is intended for use as monotherapy to treat adult patients with aggressive B-cell non-Hodgkin lymphoma who have failed 2 or 3 prior lines of therapy.

Pixantrone has already gained conditional marketing authorization for this indication within the European Union.

In the fourth quarter of 2012, the drug was made available to patients in 8 countries—Sweden, Denmark, Finland, Austria, Norway, Germany, the UK, and the Netherlands.

And last month, pixantrone was granted market access in Italy.

Now, the drug’s developers, Cell Therapeutics Inc., announced that pixantrone has been granted market access in France.
 
The next steps in France’s pharmaceutical reimbursement process are inclusion on the list of medicines approved for hospital use and subsequent publication in the Journal Officiel. And Cell Therapeutics intends to pursue these final goals.

All registered pharmaceuticals in France are subjected to a process known as Evaluation of Therapeutic Benefit, with the resulting evaluation expressed as a classification between 1 and 6. 

The Transparency Commission rated pixantrone at level 5, which allows the drug to be included in the reimbursed drugs list for hospital use. The commission will reassess the rating for the drug within 2 years.

France’s authorization and the European Commission’s conditional marketing authorization are based on data from the phase 3 EXTEND PIX301 trial. Although pixantrone prompted positive results in this trial, the US Food and Drug Administration (FDA) has expressed concerns about the number of patients included.

In fact, the FDA rejected a new drug application for pixantrone in 2010. Cell Therapeutics later resubmitted an application for the drug but withdrew it in January of last year. The company has not confirmed plans to refile with the FDA.

As for the European Commission’s conditional approval of pixantrone, it will be renewed on a yearly basis until Cell Therapeutics fullfills its committment to

provide additional data on patients

treated with pixantrone who previously received rituximab. The company said it expects to

have the results of this research by mid-2015.

Pixantrone is a novel aza-anthracenedione that forms stable DNA adducts. The drug was designed so that it cannot bind iron and perpetuate oxygen radical production or form a long-lived hydroxyl metabolite—both of which are the putative mechanisms for anthracycline-induced acute and chronic cardiotoxicity.

For full prescribing information for pixantrone, including the safety and efficacy profile in the approved indication, visit www.pixuvri.eu.

Drugs in vials
Credit: Bill Branson

The French National Health Authority’s Transparency Commission has granted market access for the antineoplastic drug pixantrone (Pixuvri).

The drug is intended for use as monotherapy to treat adult patients with aggressive B-cell non-Hodgkin lymphoma who have failed 2 or 3 prior lines of therapy.

Pixantrone has already gained conditional marketing authorization for this indication within the European Union.

In the fourth quarter of 2012, the drug was made available to patients in 8 countries—Sweden, Denmark, Finland, Austria, Norway, Germany, the UK, and the Netherlands.

And last month, pixantrone was granted market access in Italy.

Now, the drug’s developers, Cell Therapeutics Inc., announced that pixantrone has been granted market access in France.
 
The next steps in France’s pharmaceutical reimbursement process are inclusion on the list of medicines approved for hospital use and subsequent publication in the Journal Officiel. And Cell Therapeutics intends to pursue these final goals.

All registered pharmaceuticals in France are subjected to a process known as Evaluation of Therapeutic Benefit, with the resulting evaluation expressed as a classification between 1 and 6. 

The Transparency Commission rated pixantrone at level 5, which allows the drug to be included in the reimbursed drugs list for hospital use. The commission will reassess the rating for the drug within 2 years.

France’s authorization and the European Commission’s conditional marketing authorization are based on data from the phase 3 EXTEND PIX301 trial. Although pixantrone prompted positive results in this trial, the US Food and Drug Administration (FDA) has expressed concerns about the number of patients included.

In fact, the FDA rejected a new drug application for pixantrone in 2010. Cell Therapeutics later resubmitted an application for the drug but withdrew it in January of last year. The company has not confirmed plans to refile with the FDA.

As for the European Commission’s conditional approval of pixantrone, it will be renewed on a yearly basis until Cell Therapeutics fullfills its committment to

provide additional data on patients

treated with pixantrone who previously received rituximab. The company said it expects to

have the results of this research by mid-2015.

Pixantrone is a novel aza-anthracenedione that forms stable DNA adducts. The drug was designed so that it cannot bind iron and perpetuate oxygen radical production or form a long-lived hydroxyl metabolite—both of which are the putative mechanisms for anthracycline-induced acute and chronic cardiotoxicity.

For full prescribing information for pixantrone, including the safety and efficacy profile in the approved indication, visit www.pixuvri.eu.