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Pertuzumab approved as first neoadjuvant treatment for breast cancer
Pertuzumab is now approved by the Food and Drug Administration for the neoadjuvant treatment of breast cancer in the preoperative setting. This is the first time the agency has approved an agent to be used in this manner.
Pertuzumab, a HER2-targeted monoclonal antibody, has been approved for use in combination with trastuzumab and docetaxel for patients with HER2-positive, locally advanced, inflammatory or early-stage breast cancer (tumor greater than 2 cm in diameter or with positive lymph nodes) who are at high risk of recurrence, metastasis, or death.
It is to be used in combination with trastuzumab and docetaxel, and "depending upon the treatment regimen used, may be followed by chemotherapy after surgery. Following surgery, patients should continue to receive trastuzumab to complete one year of treatment," the FDA announced on Sept. 30.
"We are seeing a significant shift in the treatment paradigm for early-stage breast cancer," Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA Center for Drug Evaluation and Research, said in the FDA statement. "By making effective therapies available to high-risk patients in the earliest disease setting, we may delay or prevent cancer recurrences."
The label includes the statement that the neoadjuvant indication is based on a demonstration of an improvement in pathological complete response (pCR) rate, and that "no data are available demonstrating improvement in event-free survival or overall survival."
Because this was an accelerated approval, full approval depends on the results of a confirmatory phase III study that has already enrolled about 4,800 women with HER2-positive breast cancer, a history of prior breast cancer surgery, and a high risk of recurrence, according to the FDA. This study, called APHINITY, is following patients for 10 years, with the first results expected in 2016.
Pertuzumab, marketed as Perjeta by Genentech, was initially approved in 2012 for advanced or late-stage HER2-positive breast cancer.
The accelerated approval is based on the pCR, defined as the absence of invasive cancer in the breast and lymph nodes, in a phase II study of 417 women with early HER2-positive breast cancer, randomized to one of four neoadjuvant treatment regimens. About 39% of those treated with pertuzumab, trastuzumab, and docetaxel achieved a pCR, vs. about 21% of those on trastuzumab and docetaxel. This study was the NEOSPHERE (Neoadjuvant Study of Pertuzumab and Herceptin in an Early Regimen Evaluation) study.
The most common adverse events associated with the treatment were alopecia, diarrhea, nausea, and neutropenia.
The approval was announced less than 3 weeks after the FDA Oncologic Drugs Advisory Committee voted 13 to 0 with one abstention to support approval. At the Sept. 12 meeting, several panelists remarked on the historical significance of the approval of the first drug for breast cancer in the neoadjuvant setting, but also emphasized the importance of the confirmatory trial, to confirm the effectiveness and to provide more data on the safety of the treatment, including effects on cardiac function.
The new approval pathway, using the pCR results, "has made Perjeta available to people with HER2-positive early breast cancer several years earlier than previously possible," Dr. Hal Barron, chief medical officer and head of global product development at Genentech, said in a statement. The company is investigating the option of submitting approval of pertuzumab in the neoadjuvant setting in other countries.
Pertuzumab is now approved by the Food and Drug Administration for the neoadjuvant treatment of breast cancer in the preoperative setting. This is the first time the agency has approved an agent to be used in this manner.
Pertuzumab, a HER2-targeted monoclonal antibody, has been approved for use in combination with trastuzumab and docetaxel for patients with HER2-positive, locally advanced, inflammatory or early-stage breast cancer (tumor greater than 2 cm in diameter or with positive lymph nodes) who are at high risk of recurrence, metastasis, or death.
It is to be used in combination with trastuzumab and docetaxel, and "depending upon the treatment regimen used, may be followed by chemotherapy after surgery. Following surgery, patients should continue to receive trastuzumab to complete one year of treatment," the FDA announced on Sept. 30.
"We are seeing a significant shift in the treatment paradigm for early-stage breast cancer," Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA Center for Drug Evaluation and Research, said in the FDA statement. "By making effective therapies available to high-risk patients in the earliest disease setting, we may delay or prevent cancer recurrences."
The label includes the statement that the neoadjuvant indication is based on a demonstration of an improvement in pathological complete response (pCR) rate, and that "no data are available demonstrating improvement in event-free survival or overall survival."
Because this was an accelerated approval, full approval depends on the results of a confirmatory phase III study that has already enrolled about 4,800 women with HER2-positive breast cancer, a history of prior breast cancer surgery, and a high risk of recurrence, according to the FDA. This study, called APHINITY, is following patients for 10 years, with the first results expected in 2016.
Pertuzumab, marketed as Perjeta by Genentech, was initially approved in 2012 for advanced or late-stage HER2-positive breast cancer.
The accelerated approval is based on the pCR, defined as the absence of invasive cancer in the breast and lymph nodes, in a phase II study of 417 women with early HER2-positive breast cancer, randomized to one of four neoadjuvant treatment regimens. About 39% of those treated with pertuzumab, trastuzumab, and docetaxel achieved a pCR, vs. about 21% of those on trastuzumab and docetaxel. This study was the NEOSPHERE (Neoadjuvant Study of Pertuzumab and Herceptin in an Early Regimen Evaluation) study.
The most common adverse events associated with the treatment were alopecia, diarrhea, nausea, and neutropenia.
The approval was announced less than 3 weeks after the FDA Oncologic Drugs Advisory Committee voted 13 to 0 with one abstention to support approval. At the Sept. 12 meeting, several panelists remarked on the historical significance of the approval of the first drug for breast cancer in the neoadjuvant setting, but also emphasized the importance of the confirmatory trial, to confirm the effectiveness and to provide more data on the safety of the treatment, including effects on cardiac function.
The new approval pathway, using the pCR results, "has made Perjeta available to people with HER2-positive early breast cancer several years earlier than previously possible," Dr. Hal Barron, chief medical officer and head of global product development at Genentech, said in a statement. The company is investigating the option of submitting approval of pertuzumab in the neoadjuvant setting in other countries.
Pertuzumab is now approved by the Food and Drug Administration for the neoadjuvant treatment of breast cancer in the preoperative setting. This is the first time the agency has approved an agent to be used in this manner.
Pertuzumab, a HER2-targeted monoclonal antibody, has been approved for use in combination with trastuzumab and docetaxel for patients with HER2-positive, locally advanced, inflammatory or early-stage breast cancer (tumor greater than 2 cm in diameter or with positive lymph nodes) who are at high risk of recurrence, metastasis, or death.
It is to be used in combination with trastuzumab and docetaxel, and "depending upon the treatment regimen used, may be followed by chemotherapy after surgery. Following surgery, patients should continue to receive trastuzumab to complete one year of treatment," the FDA announced on Sept. 30.
"We are seeing a significant shift in the treatment paradigm for early-stage breast cancer," Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA Center for Drug Evaluation and Research, said in the FDA statement. "By making effective therapies available to high-risk patients in the earliest disease setting, we may delay or prevent cancer recurrences."
The label includes the statement that the neoadjuvant indication is based on a demonstration of an improvement in pathological complete response (pCR) rate, and that "no data are available demonstrating improvement in event-free survival or overall survival."
Because this was an accelerated approval, full approval depends on the results of a confirmatory phase III study that has already enrolled about 4,800 women with HER2-positive breast cancer, a history of prior breast cancer surgery, and a high risk of recurrence, according to the FDA. This study, called APHINITY, is following patients for 10 years, with the first results expected in 2016.
Pertuzumab, marketed as Perjeta by Genentech, was initially approved in 2012 for advanced or late-stage HER2-positive breast cancer.
The accelerated approval is based on the pCR, defined as the absence of invasive cancer in the breast and lymph nodes, in a phase II study of 417 women with early HER2-positive breast cancer, randomized to one of four neoadjuvant treatment regimens. About 39% of those treated with pertuzumab, trastuzumab, and docetaxel achieved a pCR, vs. about 21% of those on trastuzumab and docetaxel. This study was the NEOSPHERE (Neoadjuvant Study of Pertuzumab and Herceptin in an Early Regimen Evaluation) study.
The most common adverse events associated with the treatment were alopecia, diarrhea, nausea, and neutropenia.
The approval was announced less than 3 weeks after the FDA Oncologic Drugs Advisory Committee voted 13 to 0 with one abstention to support approval. At the Sept. 12 meeting, several panelists remarked on the historical significance of the approval of the first drug for breast cancer in the neoadjuvant setting, but also emphasized the importance of the confirmatory trial, to confirm the effectiveness and to provide more data on the safety of the treatment, including effects on cardiac function.
The new approval pathway, using the pCR results, "has made Perjeta available to people with HER2-positive early breast cancer several years earlier than previously possible," Dr. Hal Barron, chief medical officer and head of global product development at Genentech, said in a statement. The company is investigating the option of submitting approval of pertuzumab in the neoadjuvant setting in other countries.
Mortality data prompt boxed warning for tigecycline
The Food and Drug Administration is adding a boxed warning about the increased mortality associated with the use of intravenous tigecycline for both approved and unapproved indications, the agency announced on Sept. 27.
The addition of the warning is based on the FDA’s analysis of data from 10 clinical studies of tigecycline for approved uses – complicated skin and skin structure infections (cSSSIs), complicated intra-abdominal infections (cIAIs), and community-acquired bacterial pneumonia – that showed an increased risk of death among those treated with tigecycline, compared with other antibacterial drugs. The analysis was performed after the FDA issued a drug safety communication about the warning in September 2010.
Tigecycline, a tetracycline-class antibacterial drug marketed as Tygacil by Pfizer, was approved in 2005.
In the statement, the FDA advised health care professionals to "reserve Tygacil for use in situations when alternative treatments are not suitable." The boxed warning says that the cause of the increased morality risk "has not been established."
In the 10 studies of tigecycline for the approved indications, which included studies conducted since it was approved, the mortality rate was 2.5% among those treated with tigecycline vs. 1.8% among those treated with other antimicrobial drugs. The adjusted difference in the mortality risk was 0.6%.
"In general, the deaths resulted from worsening infections, complications of infection, or other underlying medical conditions," the FDA statement said.
The 2010 safety announcement was based on a meta-analysis of 13 phase III and IV studies that found a 4% mortality rate among patients treated with tigecycline vs. 3% among those treated with other antibacterial drugs, for an adjusted risk difference of 0.6%. In that analysis, the greatest increase in mortality risk occurred in patients with ventilator-associated pneumonia, but the risk also increased in patients with cSSSIs, cIAIs, and diabetic foot infections. The drug is not approved for hospital-acquired pneumonia, including ventilator-associated pneumonia, or for diabetic foot infections.
To view the revised label, click here. Serious adverse events associated with tigecycline should be reported to the FDA at 800-332-1088 or via MedWatch.
The Food and Drug Administration is adding a boxed warning about the increased mortality associated with the use of intravenous tigecycline for both approved and unapproved indications, the agency announced on Sept. 27.
The addition of the warning is based on the FDA’s analysis of data from 10 clinical studies of tigecycline for approved uses – complicated skin and skin structure infections (cSSSIs), complicated intra-abdominal infections (cIAIs), and community-acquired bacterial pneumonia – that showed an increased risk of death among those treated with tigecycline, compared with other antibacterial drugs. The analysis was performed after the FDA issued a drug safety communication about the warning in September 2010.
Tigecycline, a tetracycline-class antibacterial drug marketed as Tygacil by Pfizer, was approved in 2005.
In the statement, the FDA advised health care professionals to "reserve Tygacil for use in situations when alternative treatments are not suitable." The boxed warning says that the cause of the increased morality risk "has not been established."
In the 10 studies of tigecycline for the approved indications, which included studies conducted since it was approved, the mortality rate was 2.5% among those treated with tigecycline vs. 1.8% among those treated with other antimicrobial drugs. The adjusted difference in the mortality risk was 0.6%.
"In general, the deaths resulted from worsening infections, complications of infection, or other underlying medical conditions," the FDA statement said.
The 2010 safety announcement was based on a meta-analysis of 13 phase III and IV studies that found a 4% mortality rate among patients treated with tigecycline vs. 3% among those treated with other antibacterial drugs, for an adjusted risk difference of 0.6%. In that analysis, the greatest increase in mortality risk occurred in patients with ventilator-associated pneumonia, but the risk also increased in patients with cSSSIs, cIAIs, and diabetic foot infections. The drug is not approved for hospital-acquired pneumonia, including ventilator-associated pneumonia, or for diabetic foot infections.
To view the revised label, click here. Serious adverse events associated with tigecycline should be reported to the FDA at 800-332-1088 or via MedWatch.
The Food and Drug Administration is adding a boxed warning about the increased mortality associated with the use of intravenous tigecycline for both approved and unapproved indications, the agency announced on Sept. 27.
The addition of the warning is based on the FDA’s analysis of data from 10 clinical studies of tigecycline for approved uses – complicated skin and skin structure infections (cSSSIs), complicated intra-abdominal infections (cIAIs), and community-acquired bacterial pneumonia – that showed an increased risk of death among those treated with tigecycline, compared with other antibacterial drugs. The analysis was performed after the FDA issued a drug safety communication about the warning in September 2010.
Tigecycline, a tetracycline-class antibacterial drug marketed as Tygacil by Pfizer, was approved in 2005.
In the statement, the FDA advised health care professionals to "reserve Tygacil for use in situations when alternative treatments are not suitable." The boxed warning says that the cause of the increased morality risk "has not been established."
In the 10 studies of tigecycline for the approved indications, which included studies conducted since it was approved, the mortality rate was 2.5% among those treated with tigecycline vs. 1.8% among those treated with other antimicrobial drugs. The adjusted difference in the mortality risk was 0.6%.
"In general, the deaths resulted from worsening infections, complications of infection, or other underlying medical conditions," the FDA statement said.
The 2010 safety announcement was based on a meta-analysis of 13 phase III and IV studies that found a 4% mortality rate among patients treated with tigecycline vs. 3% among those treated with other antibacterial drugs, for an adjusted risk difference of 0.6%. In that analysis, the greatest increase in mortality risk occurred in patients with ventilator-associated pneumonia, but the risk also increased in patients with cSSSIs, cIAIs, and diabetic foot infections. The drug is not approved for hospital-acquired pneumonia, including ventilator-associated pneumonia, or for diabetic foot infections.
To view the revised label, click here. Serious adverse events associated with tigecycline should be reported to the FDA at 800-332-1088 or via MedWatch.
FROM THE FDA
Cranial radiotherapy for acute lymphoblastic leukemia linked to impaired neurocognition
Reduced white matter and impaired neuropsychological function were seen 20-30 years later in childhood acute lymphoblastic leukemia and lymphoma survivors who received cranial radiotherapy.
Survivors treated with chemotherapy alone appeared to have milder impairments, with measures that were within one standard deviation of the measures seen in healthy controls, reported Ilse Schuitema of the University of Leiden and her associates.
They also found that a young age at the time of cranial radiotherapy and the radiation dosage were associated with poorer results on the MRI measure used to evaluate the white matter's microstructure. Decreases in this measure were associated with neuropsychological dysfunction. The study was published in the Sept. 20 issue of the Journal of Clinical Oncology (2013;31:3378-88).
The finding "warrants a recommendation to use CRT [cranial radiotherapy] only as a last resort," since chemotherapy is just as effective, based on survival and recurrence rates in patients with acute lymphoblastic leukemia (ALL). Further, indications of accelerated aging seen in survivors given cranial radiotherapy may support screening for early-onset dementia as well as recommending lifestyle modifications such as not smoking and getting regular physical exercise to slow the progress of dementia.
Ms. Schuitema of the department of clinical child and adolescent studies, faculty of social sciences at Leiden (the Netherlands) University, and her co-investigators, followed up with 93 survivors of ALL or lymphoma who had been treated between 1978 and 1990 with cranial radiotherapy or CNS-directed chemotherapy, and compared them with 49 healthy controls. The mean age of patients given chemotherapy only was 27 years and the mean age of those treated with radiotherapy was 31 years.
Testing included magnetic resonance diffusion tensor imaging and neuropsychological tests. Differences in fractional anisotropy on the MRI test were used to analyze white matter microstructure, and whole-brain, voxel-based analysis was performed.
Survivors treated with chemotherapy only had reductions in the MRI measure and neuropsychological performance, but the measures were no more than one standard deviation below the mean values of controls.
When compared with controls, survivors who had cranial radiotherapy had significant reductions in white matter integrity and lower neurocognitive function, with effects that included lower IQ, poorer visuomotor accuracy, and poorer work flow during sustained attention.
Further, there was a "steep decline," in the MRI measure within the frontal and parietal white matter, which "is a strong indication of accelerated aging" the researchers wrote. Some of the anatomical findings among those treated with CRT were similar to those found in people with Alzheimer's disease, suggesting that "the irradiated survivors could be at increased risk of developing early-onset dementia."
The study results highlight the importance of long-term follow-up of children who receive neurotoxic treatments and increase support "for the concept of accelerated aging after CRT implicates screening for early-onset dementia,"the researchers said.
The tests used in the study included the computerized Amsterdam Neuropsychological Tasks (ANT) program, used to assess executive functions, and the four subtest short-form of the Wechsler Adult Intelligence Scale Revised (WAIS-R III).
Ms. Schuitema's coauthors are from the University of Leiden; University Hospitals Leuven, Belgium; and Academic Medical Center, Amsterdam. The authors had no disclosures. The study was funded by grants, including one from the Dutch Cancer Society.
This is one of the first studies to look at the long-term effects of treatment in childhood ALL survivors. These findings raise a significant concern about the long-term CNS and neurocognitive integrity of children who have been treated and are currently being treated with cranial radiotherapy. A significant number of children continue to receive radiation doses that are similar to or higher than the doses that were used to treat the patients in this study. Additional confirmatory studies are needed as is research that may bring about changes in treatment and long-term outcomes for the children we are treating today.
F. Daniel Armstrong, Ph.D., is director of the Mailman Center for Child Development, and professor of pediatrics & psychology at the University of Miami. He made his remarks in an editorial that accompanied the study (J. Clin. Oncol 2013;31:3309-11). He had no relevant disclosures.
This is one of the first studies to look at the long-term effects of treatment in childhood ALL survivors. These findings raise a significant concern about the long-term CNS and neurocognitive integrity of children who have been treated and are currently being treated with cranial radiotherapy. A significant number of children continue to receive radiation doses that are similar to or higher than the doses that were used to treat the patients in this study. Additional confirmatory studies are needed as is research that may bring about changes in treatment and long-term outcomes for the children we are treating today.
F. Daniel Armstrong, Ph.D., is director of the Mailman Center for Child Development, and professor of pediatrics & psychology at the University of Miami. He made his remarks in an editorial that accompanied the study (J. Clin. Oncol 2013;31:3309-11). He had no relevant disclosures.
This is one of the first studies to look at the long-term effects of treatment in childhood ALL survivors. These findings raise a significant concern about the long-term CNS and neurocognitive integrity of children who have been treated and are currently being treated with cranial radiotherapy. A significant number of children continue to receive radiation doses that are similar to or higher than the doses that were used to treat the patients in this study. Additional confirmatory studies are needed as is research that may bring about changes in treatment and long-term outcomes for the children we are treating today.
F. Daniel Armstrong, Ph.D., is director of the Mailman Center for Child Development, and professor of pediatrics & psychology at the University of Miami. He made his remarks in an editorial that accompanied the study (J. Clin. Oncol 2013;31:3309-11). He had no relevant disclosures.
Reduced white matter and impaired neuropsychological function were seen 20-30 years later in childhood acute lymphoblastic leukemia and lymphoma survivors who received cranial radiotherapy.
Survivors treated with chemotherapy alone appeared to have milder impairments, with measures that were within one standard deviation of the measures seen in healthy controls, reported Ilse Schuitema of the University of Leiden and her associates.
They also found that a young age at the time of cranial radiotherapy and the radiation dosage were associated with poorer results on the MRI measure used to evaluate the white matter's microstructure. Decreases in this measure were associated with neuropsychological dysfunction. The study was published in the Sept. 20 issue of the Journal of Clinical Oncology (2013;31:3378-88).
The finding "warrants a recommendation to use CRT [cranial radiotherapy] only as a last resort," since chemotherapy is just as effective, based on survival and recurrence rates in patients with acute lymphoblastic leukemia (ALL). Further, indications of accelerated aging seen in survivors given cranial radiotherapy may support screening for early-onset dementia as well as recommending lifestyle modifications such as not smoking and getting regular physical exercise to slow the progress of dementia.
Ms. Schuitema of the department of clinical child and adolescent studies, faculty of social sciences at Leiden (the Netherlands) University, and her co-investigators, followed up with 93 survivors of ALL or lymphoma who had been treated between 1978 and 1990 with cranial radiotherapy or CNS-directed chemotherapy, and compared them with 49 healthy controls. The mean age of patients given chemotherapy only was 27 years and the mean age of those treated with radiotherapy was 31 years.
Testing included magnetic resonance diffusion tensor imaging and neuropsychological tests. Differences in fractional anisotropy on the MRI test were used to analyze white matter microstructure, and whole-brain, voxel-based analysis was performed.
Survivors treated with chemotherapy only had reductions in the MRI measure and neuropsychological performance, but the measures were no more than one standard deviation below the mean values of controls.
When compared with controls, survivors who had cranial radiotherapy had significant reductions in white matter integrity and lower neurocognitive function, with effects that included lower IQ, poorer visuomotor accuracy, and poorer work flow during sustained attention.
Further, there was a "steep decline," in the MRI measure within the frontal and parietal white matter, which "is a strong indication of accelerated aging" the researchers wrote. Some of the anatomical findings among those treated with CRT were similar to those found in people with Alzheimer's disease, suggesting that "the irradiated survivors could be at increased risk of developing early-onset dementia."
The study results highlight the importance of long-term follow-up of children who receive neurotoxic treatments and increase support "for the concept of accelerated aging after CRT implicates screening for early-onset dementia,"the researchers said.
The tests used in the study included the computerized Amsterdam Neuropsychological Tasks (ANT) program, used to assess executive functions, and the four subtest short-form of the Wechsler Adult Intelligence Scale Revised (WAIS-R III).
Ms. Schuitema's coauthors are from the University of Leiden; University Hospitals Leuven, Belgium; and Academic Medical Center, Amsterdam. The authors had no disclosures. The study was funded by grants, including one from the Dutch Cancer Society.
Reduced white matter and impaired neuropsychological function were seen 20-30 years later in childhood acute lymphoblastic leukemia and lymphoma survivors who received cranial radiotherapy.
Survivors treated with chemotherapy alone appeared to have milder impairments, with measures that were within one standard deviation of the measures seen in healthy controls, reported Ilse Schuitema of the University of Leiden and her associates.
They also found that a young age at the time of cranial radiotherapy and the radiation dosage were associated with poorer results on the MRI measure used to evaluate the white matter's microstructure. Decreases in this measure were associated with neuropsychological dysfunction. The study was published in the Sept. 20 issue of the Journal of Clinical Oncology (2013;31:3378-88).
The finding "warrants a recommendation to use CRT [cranial radiotherapy] only as a last resort," since chemotherapy is just as effective, based on survival and recurrence rates in patients with acute lymphoblastic leukemia (ALL). Further, indications of accelerated aging seen in survivors given cranial radiotherapy may support screening for early-onset dementia as well as recommending lifestyle modifications such as not smoking and getting regular physical exercise to slow the progress of dementia.
Ms. Schuitema of the department of clinical child and adolescent studies, faculty of social sciences at Leiden (the Netherlands) University, and her co-investigators, followed up with 93 survivors of ALL or lymphoma who had been treated between 1978 and 1990 with cranial radiotherapy or CNS-directed chemotherapy, and compared them with 49 healthy controls. The mean age of patients given chemotherapy only was 27 years and the mean age of those treated with radiotherapy was 31 years.
Testing included magnetic resonance diffusion tensor imaging and neuropsychological tests. Differences in fractional anisotropy on the MRI test were used to analyze white matter microstructure, and whole-brain, voxel-based analysis was performed.
Survivors treated with chemotherapy only had reductions in the MRI measure and neuropsychological performance, but the measures were no more than one standard deviation below the mean values of controls.
When compared with controls, survivors who had cranial radiotherapy had significant reductions in white matter integrity and lower neurocognitive function, with effects that included lower IQ, poorer visuomotor accuracy, and poorer work flow during sustained attention.
Further, there was a "steep decline," in the MRI measure within the frontal and parietal white matter, which "is a strong indication of accelerated aging" the researchers wrote. Some of the anatomical findings among those treated with CRT were similar to those found in people with Alzheimer's disease, suggesting that "the irradiated survivors could be at increased risk of developing early-onset dementia."
The study results highlight the importance of long-term follow-up of children who receive neurotoxic treatments and increase support "for the concept of accelerated aging after CRT implicates screening for early-onset dementia,"the researchers said.
The tests used in the study included the computerized Amsterdam Neuropsychological Tasks (ANT) program, used to assess executive functions, and the four subtest short-form of the Wechsler Adult Intelligence Scale Revised (WAIS-R III).
Ms. Schuitema's coauthors are from the University of Leiden; University Hospitals Leuven, Belgium; and Academic Medical Center, Amsterdam. The authors had no disclosures. The study was funded by grants, including one from the Dutch Cancer Society.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Major finding: Compared with controls, survivors who had cranial radiotherapy had significant reductions in white matter integrity and lower neurocognitive function, with effects that included lower IQ, poorer visuomotor accuracy, and poorer work flow during sustained attention.
Data source: Magnetic resonance imaging and neuropsychological test results in 93 survivors of childhood ALL or lymphoma and 49 healthy controls.
Disclosures: The study was supported with grants, including one from the Dutch Cancer Society. The authors had no disclosures.
FDA drops access points from Sapien transcatheter valve label
The labeling for the Sapien transcatheter heart valve no longer includes references to specific access points, which will expand the group of patients who can be treated with the device, the Food and Drug Administration announced.
Approval has been for use via a transfemoral or transapical approach. But revised labeling for the device has been approved, which removes references to specific access points, according to the FDA statement issued on Sept. 23. Spokespersons for the FDA and for Edwards Lifesciences, the manufacturer of the valve, confirmed that the references to specific access points have been dropped for both inoperable and high-risk patients.
The approval for this change was based on data from patient registries in the United States and Europe and other sources, according to the announcement.
The percutaneous valve was approved in 2011 for treating patients with severe aortic stenosis who are considered inoperable, making it the first artificial heart valve that could be used to replace a damaged valve without open heart surgery. That approval was expanded in October 2012 to include patients who are operable but at high risk.
Edwards submitted data to the FDA for the labeling change from the Transcatheter Valve Therapy Registry (TVTR) in the United States, transcatheter heart valve (THV) device registries in Europe, as well as FDA-approved clinical studies and peer-reviewed medical journals. Data from the TVTR, which is managed by the American College of Cardiology (ACC) and the Society of Thoracic Surgeons, came from "several thousand procedures performed on patients using an alternative access point, and showed no evidence that the device performs differently or has a different benefit-risk profile based on the access point," the statement said.
"Just 2 years after the THV entered the market for a specific patient population, data from the TVTR was used to support FDA approval that expands patient access to a lifesaving therapy," Dr. Jeffrey Shuren, director of the FDA’s Center for Devices and Radiological Health, said in the statement. "Medical device registries like the TVTR not only play an important role in the FDA’s postmarket surveillance system, they also collect robust and timely data that can be used to identify additional patient populations that benefit from the therapy," he added.
"Leveraging clinical research inside the framework of a device registry to expand access to therapy for more patients is a new paradigm for the FDA, researchers, registry sponsors, and the medical device industry," Dr. Shuren noted.
Since 2012, the TVTR has collected data on all transcatheter aortic valve replacements performed in the United States. The manufacturer will use these data to evaluate short- and long-term outcomes in patients who receive the Sapien valve through an alternative access site, the FDA statement said.
ACC President John G. Harold, M.D., said in a statement that "the FDA’s decision is a true testament to the efficiency of rigorous clinical registries, which allowed FDA to make a prompt decision that will impact thousands of patients who previously would have not had access to this procedure."
The labeling for the Sapien transcatheter heart valve no longer includes references to specific access points, which will expand the group of patients who can be treated with the device, the Food and Drug Administration announced.
Approval has been for use via a transfemoral or transapical approach. But revised labeling for the device has been approved, which removes references to specific access points, according to the FDA statement issued on Sept. 23. Spokespersons for the FDA and for Edwards Lifesciences, the manufacturer of the valve, confirmed that the references to specific access points have been dropped for both inoperable and high-risk patients.
The approval for this change was based on data from patient registries in the United States and Europe and other sources, according to the announcement.
The percutaneous valve was approved in 2011 for treating patients with severe aortic stenosis who are considered inoperable, making it the first artificial heart valve that could be used to replace a damaged valve without open heart surgery. That approval was expanded in October 2012 to include patients who are operable but at high risk.
Edwards submitted data to the FDA for the labeling change from the Transcatheter Valve Therapy Registry (TVTR) in the United States, transcatheter heart valve (THV) device registries in Europe, as well as FDA-approved clinical studies and peer-reviewed medical journals. Data from the TVTR, which is managed by the American College of Cardiology (ACC) and the Society of Thoracic Surgeons, came from "several thousand procedures performed on patients using an alternative access point, and showed no evidence that the device performs differently or has a different benefit-risk profile based on the access point," the statement said.
"Just 2 years after the THV entered the market for a specific patient population, data from the TVTR was used to support FDA approval that expands patient access to a lifesaving therapy," Dr. Jeffrey Shuren, director of the FDA’s Center for Devices and Radiological Health, said in the statement. "Medical device registries like the TVTR not only play an important role in the FDA’s postmarket surveillance system, they also collect robust and timely data that can be used to identify additional patient populations that benefit from the therapy," he added.
"Leveraging clinical research inside the framework of a device registry to expand access to therapy for more patients is a new paradigm for the FDA, researchers, registry sponsors, and the medical device industry," Dr. Shuren noted.
Since 2012, the TVTR has collected data on all transcatheter aortic valve replacements performed in the United States. The manufacturer will use these data to evaluate short- and long-term outcomes in patients who receive the Sapien valve through an alternative access site, the FDA statement said.
ACC President John G. Harold, M.D., said in a statement that "the FDA’s decision is a true testament to the efficiency of rigorous clinical registries, which allowed FDA to make a prompt decision that will impact thousands of patients who previously would have not had access to this procedure."
The labeling for the Sapien transcatheter heart valve no longer includes references to specific access points, which will expand the group of patients who can be treated with the device, the Food and Drug Administration announced.
Approval has been for use via a transfemoral or transapical approach. But revised labeling for the device has been approved, which removes references to specific access points, according to the FDA statement issued on Sept. 23. Spokespersons for the FDA and for Edwards Lifesciences, the manufacturer of the valve, confirmed that the references to specific access points have been dropped for both inoperable and high-risk patients.
The approval for this change was based on data from patient registries in the United States and Europe and other sources, according to the announcement.
The percutaneous valve was approved in 2011 for treating patients with severe aortic stenosis who are considered inoperable, making it the first artificial heart valve that could be used to replace a damaged valve without open heart surgery. That approval was expanded in October 2012 to include patients who are operable but at high risk.
Edwards submitted data to the FDA for the labeling change from the Transcatheter Valve Therapy Registry (TVTR) in the United States, transcatheter heart valve (THV) device registries in Europe, as well as FDA-approved clinical studies and peer-reviewed medical journals. Data from the TVTR, which is managed by the American College of Cardiology (ACC) and the Society of Thoracic Surgeons, came from "several thousand procedures performed on patients using an alternative access point, and showed no evidence that the device performs differently or has a different benefit-risk profile based on the access point," the statement said.
"Just 2 years after the THV entered the market for a specific patient population, data from the TVTR was used to support FDA approval that expands patient access to a lifesaving therapy," Dr. Jeffrey Shuren, director of the FDA’s Center for Devices and Radiological Health, said in the statement. "Medical device registries like the TVTR not only play an important role in the FDA’s postmarket surveillance system, they also collect robust and timely data that can be used to identify additional patient populations that benefit from the therapy," he added.
"Leveraging clinical research inside the framework of a device registry to expand access to therapy for more patients is a new paradigm for the FDA, researchers, registry sponsors, and the medical device industry," Dr. Shuren noted.
Since 2012, the TVTR has collected data on all transcatheter aortic valve replacements performed in the United States. The manufacturer will use these data to evaluate short- and long-term outcomes in patients who receive the Sapien valve through an alternative access site, the FDA statement said.
ACC President John G. Harold, M.D., said in a statement that "the FDA’s decision is a true testament to the efficiency of rigorous clinical registries, which allowed FDA to make a prompt decision that will impact thousands of patients who previously would have not had access to this procedure."
Study sheds light on exacerbation risks with RA lung disease
An older age at the time of diagnosis and treatment with methotrexate were significantly associated with an increased risk of developing "acute exacerbation" of rheumatoid arthritis–associated interstitial lung disease in a retrospective cohort study of 51 patients.
The other risk factor associated with the development of acute exacerbation (AE) was a specific pattern on high-resolution CT scan, which was also associated with poorer survival, reported Dr. Hironao Hozumi, of Hamamatsu (Japan) University, and associates.
Overall, survival was also significantly lower among those who developed AE, according to the study. As far as the authors know, this is the first study to investigate the risk factors and prognosis associated with AE in patients who have been diagnosed with rheumatoid arthritis–associated interstitial lung disease (RA-ILD). Until this study, risk factors and prognosis for AEs in patients with RA-ILD have been unclear, they said.
AE is "a recently established and an increasingly recognized occurrence" in people with idiopathic pulmonary fibrosis, and it also affects people with other types of interstitial lung diseases, including those associated with collagen vascular disease, the authors noted. It was defined in the study as "acute deterioration in respiratory status, with newly developed bilateral ground-glass opacities and/or consolidations" visible on chest x-ray or CT scans.
The retrospective case-control study evaluated medical records and images of 51 patients consecutively diagnosed with RA-ILD at Hamamatsu University Hospital between 1995 and 2012. The median ages at the time of the RA and ILD diagnoses were 61 and 62 years, respectively. A majority (57%) of the patients were men. The patients had been followed for a median of 8.5 years (range, 1-17 years) before being diagnosed with AE (BMJ Open 2013;3:e003132).
During the observation period of 1-11 years, 11 of the 51 patients (22%) developed AE at a median age of 72 years (range, 60-86 years). In a univariate Cox hazard analysis, an older age at ILD diagnosis was associated with an 11% increased risk for AE occurrence.
Of the 11 patients who developed AE, 7 (64%) died of respiratory failure during the initial episode of AE, compared with 2 (5%) of the 40 patients who did not develop AE.
There was a usual interstitial pneumonia (UIP) pattern on high-resolution CT in 14 (27%) of the 51 patients. This pattern was found in 6 (55%) of the patients who had AE, compared with 8 (20%) of the 40 patients with no AE, a significant difference. This comparison gave a hazard ratio of 1.95 in a univariate Cox hazard analysis. For AE occurrence, a UIP pattern on high-resolution CT had a positive predictive value of 43% and a negative predictive value of 87%. The 1-year incidence of AE was 6.5% among those with a UIP pattern on high-resolution CT, compared with an overall rate of 2.8% in the study.
The overall 5-year survival was 90% for all the patients, but there was a significant difference among those with or without the UIP pattern (70% vs. 97%). Patients’ risk of death more than doubled with an AE occurrence (hazard ratio, 2.47).
The use of methotrexate was associated with a threefold increased risk of developing AE (HR, 3.04) in a univariate Cox hazard analysis. Of 10 patients treated with methotrexate, 6 (55%) in the AE group used the drug (including 5 who had been treated for at least 3 years and 1 treated for 1 year), compared with 4 (10%) in the non-AE group, a significant difference. Although methotrexate was discontinued, the respiratory condition of all six patients in the AE group continued to deteriorate and they had poor responses to corticosteroid therapy.
The authors found no associations with disease activity and the development of AE, so RA activity may not be related to the development of AE, the authors wrote. However, they noted that methotrexate "possibly accelerates the fibroproliferative process of RA-ILD."
There also were no significant differences in factors that included sex, age at the time of diagnosis of RA or RA-ILD, smoking habits, and other factors between those who did and did not develop an AE.
The investigators said that the limitations of the study included the retrospective design and the small sample size, and that "larger prospective studies investigating AEs in RA-ILD are indicated."
The authors had no disclosures to report. The study was partly funded by a grant from Japan’s Ministry of Health, Labor, and Welfare to the Diffuse Lung Diseases Research Group.
An older age at the time of diagnosis and treatment with methotrexate were significantly associated with an increased risk of developing "acute exacerbation" of rheumatoid arthritis–associated interstitial lung disease in a retrospective cohort study of 51 patients.
The other risk factor associated with the development of acute exacerbation (AE) was a specific pattern on high-resolution CT scan, which was also associated with poorer survival, reported Dr. Hironao Hozumi, of Hamamatsu (Japan) University, and associates.
Overall, survival was also significantly lower among those who developed AE, according to the study. As far as the authors know, this is the first study to investigate the risk factors and prognosis associated with AE in patients who have been diagnosed with rheumatoid arthritis–associated interstitial lung disease (RA-ILD). Until this study, risk factors and prognosis for AEs in patients with RA-ILD have been unclear, they said.
AE is "a recently established and an increasingly recognized occurrence" in people with idiopathic pulmonary fibrosis, and it also affects people with other types of interstitial lung diseases, including those associated with collagen vascular disease, the authors noted. It was defined in the study as "acute deterioration in respiratory status, with newly developed bilateral ground-glass opacities and/or consolidations" visible on chest x-ray or CT scans.
The retrospective case-control study evaluated medical records and images of 51 patients consecutively diagnosed with RA-ILD at Hamamatsu University Hospital between 1995 and 2012. The median ages at the time of the RA and ILD diagnoses were 61 and 62 years, respectively. A majority (57%) of the patients were men. The patients had been followed for a median of 8.5 years (range, 1-17 years) before being diagnosed with AE (BMJ Open 2013;3:e003132).
During the observation period of 1-11 years, 11 of the 51 patients (22%) developed AE at a median age of 72 years (range, 60-86 years). In a univariate Cox hazard analysis, an older age at ILD diagnosis was associated with an 11% increased risk for AE occurrence.
Of the 11 patients who developed AE, 7 (64%) died of respiratory failure during the initial episode of AE, compared with 2 (5%) of the 40 patients who did not develop AE.
There was a usual interstitial pneumonia (UIP) pattern on high-resolution CT in 14 (27%) of the 51 patients. This pattern was found in 6 (55%) of the patients who had AE, compared with 8 (20%) of the 40 patients with no AE, a significant difference. This comparison gave a hazard ratio of 1.95 in a univariate Cox hazard analysis. For AE occurrence, a UIP pattern on high-resolution CT had a positive predictive value of 43% and a negative predictive value of 87%. The 1-year incidence of AE was 6.5% among those with a UIP pattern on high-resolution CT, compared with an overall rate of 2.8% in the study.
The overall 5-year survival was 90% for all the patients, but there was a significant difference among those with or without the UIP pattern (70% vs. 97%). Patients’ risk of death more than doubled with an AE occurrence (hazard ratio, 2.47).
The use of methotrexate was associated with a threefold increased risk of developing AE (HR, 3.04) in a univariate Cox hazard analysis. Of 10 patients treated with methotrexate, 6 (55%) in the AE group used the drug (including 5 who had been treated for at least 3 years and 1 treated for 1 year), compared with 4 (10%) in the non-AE group, a significant difference. Although methotrexate was discontinued, the respiratory condition of all six patients in the AE group continued to deteriorate and they had poor responses to corticosteroid therapy.
The authors found no associations with disease activity and the development of AE, so RA activity may not be related to the development of AE, the authors wrote. However, they noted that methotrexate "possibly accelerates the fibroproliferative process of RA-ILD."
There also were no significant differences in factors that included sex, age at the time of diagnosis of RA or RA-ILD, smoking habits, and other factors between those who did and did not develop an AE.
The investigators said that the limitations of the study included the retrospective design and the small sample size, and that "larger prospective studies investigating AEs in RA-ILD are indicated."
The authors had no disclosures to report. The study was partly funded by a grant from Japan’s Ministry of Health, Labor, and Welfare to the Diffuse Lung Diseases Research Group.
An older age at the time of diagnosis and treatment with methotrexate were significantly associated with an increased risk of developing "acute exacerbation" of rheumatoid arthritis–associated interstitial lung disease in a retrospective cohort study of 51 patients.
The other risk factor associated with the development of acute exacerbation (AE) was a specific pattern on high-resolution CT scan, which was also associated with poorer survival, reported Dr. Hironao Hozumi, of Hamamatsu (Japan) University, and associates.
Overall, survival was also significantly lower among those who developed AE, according to the study. As far as the authors know, this is the first study to investigate the risk factors and prognosis associated with AE in patients who have been diagnosed with rheumatoid arthritis–associated interstitial lung disease (RA-ILD). Until this study, risk factors and prognosis for AEs in patients with RA-ILD have been unclear, they said.
AE is "a recently established and an increasingly recognized occurrence" in people with idiopathic pulmonary fibrosis, and it also affects people with other types of interstitial lung diseases, including those associated with collagen vascular disease, the authors noted. It was defined in the study as "acute deterioration in respiratory status, with newly developed bilateral ground-glass opacities and/or consolidations" visible on chest x-ray or CT scans.
The retrospective case-control study evaluated medical records and images of 51 patients consecutively diagnosed with RA-ILD at Hamamatsu University Hospital between 1995 and 2012. The median ages at the time of the RA and ILD diagnoses were 61 and 62 years, respectively. A majority (57%) of the patients were men. The patients had been followed for a median of 8.5 years (range, 1-17 years) before being diagnosed with AE (BMJ Open 2013;3:e003132).
During the observation period of 1-11 years, 11 of the 51 patients (22%) developed AE at a median age of 72 years (range, 60-86 years). In a univariate Cox hazard analysis, an older age at ILD diagnosis was associated with an 11% increased risk for AE occurrence.
Of the 11 patients who developed AE, 7 (64%) died of respiratory failure during the initial episode of AE, compared with 2 (5%) of the 40 patients who did not develop AE.
There was a usual interstitial pneumonia (UIP) pattern on high-resolution CT in 14 (27%) of the 51 patients. This pattern was found in 6 (55%) of the patients who had AE, compared with 8 (20%) of the 40 patients with no AE, a significant difference. This comparison gave a hazard ratio of 1.95 in a univariate Cox hazard analysis. For AE occurrence, a UIP pattern on high-resolution CT had a positive predictive value of 43% and a negative predictive value of 87%. The 1-year incidence of AE was 6.5% among those with a UIP pattern on high-resolution CT, compared with an overall rate of 2.8% in the study.
The overall 5-year survival was 90% for all the patients, but there was a significant difference among those with or without the UIP pattern (70% vs. 97%). Patients’ risk of death more than doubled with an AE occurrence (hazard ratio, 2.47).
The use of methotrexate was associated with a threefold increased risk of developing AE (HR, 3.04) in a univariate Cox hazard analysis. Of 10 patients treated with methotrexate, 6 (55%) in the AE group used the drug (including 5 who had been treated for at least 3 years and 1 treated for 1 year), compared with 4 (10%) in the non-AE group, a significant difference. Although methotrexate was discontinued, the respiratory condition of all six patients in the AE group continued to deteriorate and they had poor responses to corticosteroid therapy.
The authors found no associations with disease activity and the development of AE, so RA activity may not be related to the development of AE, the authors wrote. However, they noted that methotrexate "possibly accelerates the fibroproliferative process of RA-ILD."
There also were no significant differences in factors that included sex, age at the time of diagnosis of RA or RA-ILD, smoking habits, and other factors between those who did and did not develop an AE.
The investigators said that the limitations of the study included the retrospective design and the small sample size, and that "larger prospective studies investigating AEs in RA-ILD are indicated."
The authors had no disclosures to report. The study was partly funded by a grant from Japan’s Ministry of Health, Labor, and Welfare to the Diffuse Lung Diseases Research Group.
FROM BMJ OPEN
Major finding: The use of methotrexate was associated with a threefold increased risk of developing acute exacerbation of RA-ILD (HR, 3.04) in a univariate Cox hazard analysis.
Data source: A retrospective case-control study that looked at the medical records and images of 51 patients diagnosed with RA-ILD at an academic hospital in Japan between 1995 and 2012.
Disclosures: The authors had no disclosures to report. The study was partly funded by a grant from Japan’s Ministry of Health, Labor, and Welfare to the Diffuse Lung Diseases Research Group.
Ustekinumab approved for psoriatic arthritis
Ustekinumab, a human interleukin-12 and -23 antagonist, has been approved for the treatment of adults with active psoriatic arthritis, the manufacturer has announced.
The approved indication is for use alone or in combination with methotrexate, in the form of a 45-mg subcutaneous injection at weeks 0 and 4, and then every 12 weeks. For patients with coexistent moderate-to-severe plaque psoriasis who weigh more than 220 pounds, the recommended dose is a 90-mg subcutaneous injection at weeks 0 and 4, and then every 12 weeks.
Ustekinumab, approved for treating psoriasis in 2009, is marketed as Stelara by Janssen Biotech, which announced the approval in a press release on Sept. 23. Ustekinumab is the first treatment targeting the cytokines interleukin-12 and interleukin-23, according to the statement.
Approval was based on the results of two phase III multicenter, randomized double-blind studies comparing ustekinumab to placebo in 927 patients with active psoriatic arthritis, with at least five tender and five swollen joints and a C-reactive protein (CRP) level of at least 0.3 mg/dL, despite previous treatment with conventional therapy. The primary endpoint was the ACR 20 response at 24 weeks.
In the first trial, PSUMMIT 1, 42% of those on the 45-mg dose and 50% of those on the 90-mg dose achieved an ACR 20 at 24 weeks, vs. 23% of those on placebo. In addition, 57% of those on the 45-mg dose and 62% of those on the 90-mg dose achieved a PASI (Psoriasis Area and Severity Index) 75 response, vs. 11% of those on placebo.
In the second study, PSUMMIT II, 44% of those on a 45-mg dose and 44% of those on a 90-mg dose met the primary endpoint, vs 20% of those on placebo. Also, 51% of those on the 45-mg dose and 56% of those on the 90-mg dose achieved a PASI 75 response, vs. 5% of those on placebo.
The results of the PSUMMIT 1 study were published online in the Lancet on June 13 (doi:10.1016/S0140-6736[13]60594-2).
The warnings and precautions section of the ustekinumab label includes information about the risk of serious infections and other risks associated with treatment.
The updated label is available here.
Ustekinumab, a human interleukin-12 and -23 antagonist, has been approved for the treatment of adults with active psoriatic arthritis, the manufacturer has announced.
The approved indication is for use alone or in combination with methotrexate, in the form of a 45-mg subcutaneous injection at weeks 0 and 4, and then every 12 weeks. For patients with coexistent moderate-to-severe plaque psoriasis who weigh more than 220 pounds, the recommended dose is a 90-mg subcutaneous injection at weeks 0 and 4, and then every 12 weeks.
Ustekinumab, approved for treating psoriasis in 2009, is marketed as Stelara by Janssen Biotech, which announced the approval in a press release on Sept. 23. Ustekinumab is the first treatment targeting the cytokines interleukin-12 and interleukin-23, according to the statement.
Approval was based on the results of two phase III multicenter, randomized double-blind studies comparing ustekinumab to placebo in 927 patients with active psoriatic arthritis, with at least five tender and five swollen joints and a C-reactive protein (CRP) level of at least 0.3 mg/dL, despite previous treatment with conventional therapy. The primary endpoint was the ACR 20 response at 24 weeks.
In the first trial, PSUMMIT 1, 42% of those on the 45-mg dose and 50% of those on the 90-mg dose achieved an ACR 20 at 24 weeks, vs. 23% of those on placebo. In addition, 57% of those on the 45-mg dose and 62% of those on the 90-mg dose achieved a PASI (Psoriasis Area and Severity Index) 75 response, vs. 11% of those on placebo.
In the second study, PSUMMIT II, 44% of those on a 45-mg dose and 44% of those on a 90-mg dose met the primary endpoint, vs 20% of those on placebo. Also, 51% of those on the 45-mg dose and 56% of those on the 90-mg dose achieved a PASI 75 response, vs. 5% of those on placebo.
The results of the PSUMMIT 1 study were published online in the Lancet on June 13 (doi:10.1016/S0140-6736[13]60594-2).
The warnings and precautions section of the ustekinumab label includes information about the risk of serious infections and other risks associated with treatment.
The updated label is available here.
Ustekinumab, a human interleukin-12 and -23 antagonist, has been approved for the treatment of adults with active psoriatic arthritis, the manufacturer has announced.
The approved indication is for use alone or in combination with methotrexate, in the form of a 45-mg subcutaneous injection at weeks 0 and 4, and then every 12 weeks. For patients with coexistent moderate-to-severe plaque psoriasis who weigh more than 220 pounds, the recommended dose is a 90-mg subcutaneous injection at weeks 0 and 4, and then every 12 weeks.
Ustekinumab, approved for treating psoriasis in 2009, is marketed as Stelara by Janssen Biotech, which announced the approval in a press release on Sept. 23. Ustekinumab is the first treatment targeting the cytokines interleukin-12 and interleukin-23, according to the statement.
Approval was based on the results of two phase III multicenter, randomized double-blind studies comparing ustekinumab to placebo in 927 patients with active psoriatic arthritis, with at least five tender and five swollen joints and a C-reactive protein (CRP) level of at least 0.3 mg/dL, despite previous treatment with conventional therapy. The primary endpoint was the ACR 20 response at 24 weeks.
In the first trial, PSUMMIT 1, 42% of those on the 45-mg dose and 50% of those on the 90-mg dose achieved an ACR 20 at 24 weeks, vs. 23% of those on placebo. In addition, 57% of those on the 45-mg dose and 62% of those on the 90-mg dose achieved a PASI (Psoriasis Area and Severity Index) 75 response, vs. 11% of those on placebo.
In the second study, PSUMMIT II, 44% of those on a 45-mg dose and 44% of those on a 90-mg dose met the primary endpoint, vs 20% of those on placebo. Also, 51% of those on the 45-mg dose and 56% of those on the 90-mg dose achieved a PASI 75 response, vs. 5% of those on placebo.
The results of the PSUMMIT 1 study were published online in the Lancet on June 13 (doi:10.1016/S0140-6736[13]60594-2).
The warnings and precautions section of the ustekinumab label includes information about the risk of serious infections and other risks associated with treatment.
The updated label is available here.
FDA approves first generic capecitabine
Capecitabine, first approved for treating metastatic breast cancer in 1998, now will be available in a generic formulation, the Food and Drug Administration announced Sept. 16.
The FDA has approved generic capecitabine (150 mg and 500 mg), manufactured by Teva Pharmaceuticals USA, the first generic formulation of this drug to be approved, the agency said in a written statement.
Capecitabine also has been approved for treating metastatic colorectal cancer (2001) and Dukes’ C colon cancer (2005). It is a nucleoside metabolic inhibitor with antineoplastic activity, and the trade formulation is marketed by Genentech as Xeloda.
Teva is not disclosing launch plans for the product at this time, a Teva spokesperson said.
To view the label for the trade formulation, click here.
*This story was updated 9/17/2013
Capecitabine, first approved for treating metastatic breast cancer in 1998, now will be available in a generic formulation, the Food and Drug Administration announced Sept. 16.
The FDA has approved generic capecitabine (150 mg and 500 mg), manufactured by Teva Pharmaceuticals USA, the first generic formulation of this drug to be approved, the agency said in a written statement.
Capecitabine also has been approved for treating metastatic colorectal cancer (2001) and Dukes’ C colon cancer (2005). It is a nucleoside metabolic inhibitor with antineoplastic activity, and the trade formulation is marketed by Genentech as Xeloda.
Teva is not disclosing launch plans for the product at this time, a Teva spokesperson said.
To view the label for the trade formulation, click here.
*This story was updated 9/17/2013
Capecitabine, first approved for treating metastatic breast cancer in 1998, now will be available in a generic formulation, the Food and Drug Administration announced Sept. 16.
The FDA has approved generic capecitabine (150 mg and 500 mg), manufactured by Teva Pharmaceuticals USA, the first generic formulation of this drug to be approved, the agency said in a written statement.
Capecitabine also has been approved for treating metastatic colorectal cancer (2001) and Dukes’ C colon cancer (2005). It is a nucleoside metabolic inhibitor with antineoplastic activity, and the trade formulation is marketed by Genentech as Xeloda.
Teva is not disclosing launch plans for the product at this time, a Teva spokesperson said.
To view the label for the trade formulation, click here.
*This story was updated 9/17/2013
FDA advisory panel backs approval of neoadjuvant pertuzumab for breast cancer
SILVER SPRING, MD. – Pertuzumab is likely to be approved for the neoadjuvant treatment of breast cancer in the preoperative setting, based on the recommendation of a Food and Drug Administration advisory panel.
At a meeting on Sept. 12, the FDA’s Oncologic Drugs Advisory Committee panel voted 13-0, with 1 abstention, that treatment with pertuzumab, a human epidermal growth factor receptor 2 (HER2)-targeted monoclonal antibody, had a favorable benefit-to-risk profile as a neoadjuvant treatment in combination with trastuzumab and docetaxel before surgery in patients with locally-advanced, inflammatory, or early-stage breast cancers greater than 2 cm in diameter. The neoadjuvant approach would be part of a complete early breast cancer treatment regimen containing fluorouracil, epirubicin, and cyclophosphamide or carboplatin.
The drug is being reviewed under the accelerated approval process, a mechanism that makes drugs available to fill an unmet medical need in patients with serious diseases. Historically, the usual sequence of the FDA approvals for breast cancer agents starts with approval for metastatic disease, followed by approval for early-stage disease years later after the results of large studies with long follow-up periods are available. Pertuzumab, marketed as Perjeta by Genentech, was just approved in 2012 as a first-line treatment for metastatic HER2-positive breast cancer in women who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.
Accelerated approvals are based on a surrogate endpoint that is considered “reasonably likely” to predict clinical benefit. In this instance, pathologic complete response rate (pCR) was used in the phase II NeoSphere study. For this trial, pertuzumab was added to trastuzumab (Herceptin) – another HER2 receptor antagonist – and docetaxel, and was given before surgery to women with HER-2-positive, locally advanced, inflammatory or early-stage breast cancer. The comparator group was patients treated preoperatively with trastuzumab and docetaxel.
The women who received the three-drug neoadjuvant regimen had an 18% improvement in pCR as compared to women given trastuzumab and docetaxel only.
In addition to the NeoSphere study, the panel also considered the body of data on pertuzumab in metastatic breast cancer, the known biology of the pertuzumab, and the activity of HER-2 targeted therapies in breast cancer.
Should pertuzumab receive the accelerated approval, its full approval will be contingent on the final results of APHINITY, a confirmatory study. If the APHINITY results do not confirm the NeoSphere results, the FDA can withdraw the approval for this indication.
The vote to support the first approval of a drug for the neoadjuvant treatment of breast cancer is “a historic moment,” said the panel chair, Dr. Mikkael A. Sekeres of the Cleveland Clinic. “In so doing, we are supporting the rapid movement of a highly active drug for metastatic breast cancer to the first-line setting with the hope that women with earlier stages of breast cancer will live longer and better.”
However, he added, “all eyes will be on the confirmatory APHINITY trial” and on Genentech, to “verify this initial signal of efficacy and to confirm the bandwidth of safety we have seen so far.” If the results are negative, he and other panelists urged the company to voluntarily remove the drug for this indication, and avoid what happened with another Genentech drug, bevacizumab (Avastin), which was granted an accelerated approval as a first-line treatment in combination with paclitaxel for metastatic breast cancer in 2008. The FDA decided to withdraw approval of this indication after studies failed to confirm the benefit. The company appealed the decision, however, delaying the FDA’s withdrawal of the approval until 2011.
NeoSphere, a randomized study conducted outside of the United States, compared four treatment regimens in 417 women newly diagnosed with locally advanced, inflammatory or operable HER2-positive early breast cancer, with tumors greater than 2 cm, treated for four cycles before surgery. The median tumor size was about 5 cm, and two-thirds were node positive.
Based on the pCR definition used by Genentech (the absence of invasive cancer in the breast), almost 46% of those on the combination of pertuzumab, trastuzumab, and docetaxel reached the primary endpoint, compared with 29% of those on trastuzumab and docetaxel – a statistically significant difference of nearly 17%. Based on the FDA-preferred definition of pCR definition (the absence of invasive cancer in the breast and lymph nodes), the pCR rate was almost 18% higher with the three-drug regimen (39.3% vs. 21.5%).
The FDA considers pCR as “reasonably likely” to predict outcomes in HER2-positive breast cancer.
The treatment has the potential to cure more patients in this high risk population, said Dr. Suparna Wedam, a medical officer in FDA’s Office of Hematology and Oncology Products. Yet, still to be determined are whether the regimen has long-term safety and results in improvements in overall survival, progression-free survival, and other improvements in long-term outcomes.
Genentech also provided results from the TRYPHAENA phase II study that compared three neoadjuvant treatment regimens before surgery; as well as the CLEOPATRA phase III study, the basis of the 2012 approval of trastuzumab. In TRYPHAENA, 225 women with HER2-positive, locally advanced, operable or inflammatory breast cancer, received one of three neoadjuvant treatment regimens. The pCR rates, a secondary endpoint, ranged from about 55% to 64% when pertuzumab was added to trastuzumab and chemotherapy. CLEOPATRA enrolled 808 women with HER2-positive, locally recurrent, unresectable or metastatic breast cancer previously untreated with a biologic or chemotherapy for metastatic disease. In that trial, pertuzumab in combination with trastuzumab and docetaxel resulted in significant improvements in progression-free survival and overall survival.
The most common adverse events with the three-drug regimen in the NeoSphere study were neutropenia, diarrhea, nausea, fatigue, mucosal inflammation, and rash, according to the company. No unexpected safety signals were observed with the addition of pertuzumab. The addition of pertuzumab did not appear to increase symptomatic cardiac toxicity when added to trastuzumab-based neoadjuvant or metastatic treatment regimens.
The FDA reviewers noted, however, that the rate of left ventricular dysfunction (mostly asymptomatic) was higher with neoadjuvant pertuzumab treatment. Cardiac toxicity appeared to be reversible, however.
Panel member Deborah Armstrong of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, said that there were “some hints of increased cardiac toxicity.” She encouraged the company to closely evaluate patients on longer-term pertuzumab in trials for cardiac toxicity. Dr. Armstrong voted in favor of the benefit risk profile, but like other panelists, was concerned about the potential for approval “opening the floodgates” to the use of this drug in treating patients for whom it may not yet be appropriate.
Citing the clear potential benefit in the intended population, Dr. Michael Menefee of the division of hematology and oncology at the Mayo Clinic, Jacksonville, Fla., also shared his concerns about the potential for toxicity and overuse of the drug. “My hope is that the FDA is very clear in the ultimate labeling so practitioners have clear guidance as to how to use this drug best and most safely.”
Genentech has completed enrollment in the confirmatory, phase III APHINITY study, which will compare chemotherapy plus trastuzumab with or without pertuzumab before surgery in about 4,800 patients with HER-2 positive early breast cancer. The patients will be followed for 10 years, and the study will evaluate invasive disease-free survival. Results are expected to be first available in 2016.
Panel members have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.
Genentech also markets trastuzumab.
SILVER SPRING, MD. – Pertuzumab is likely to be approved for the neoadjuvant treatment of breast cancer in the preoperative setting, based on the recommendation of a Food and Drug Administration advisory panel.
At a meeting on Sept. 12, the FDA’s Oncologic Drugs Advisory Committee panel voted 13-0, with 1 abstention, that treatment with pertuzumab, a human epidermal growth factor receptor 2 (HER2)-targeted monoclonal antibody, had a favorable benefit-to-risk profile as a neoadjuvant treatment in combination with trastuzumab and docetaxel before surgery in patients with locally-advanced, inflammatory, or early-stage breast cancers greater than 2 cm in diameter. The neoadjuvant approach would be part of a complete early breast cancer treatment regimen containing fluorouracil, epirubicin, and cyclophosphamide or carboplatin.
The drug is being reviewed under the accelerated approval process, a mechanism that makes drugs available to fill an unmet medical need in patients with serious diseases. Historically, the usual sequence of the FDA approvals for breast cancer agents starts with approval for metastatic disease, followed by approval for early-stage disease years later after the results of large studies with long follow-up periods are available. Pertuzumab, marketed as Perjeta by Genentech, was just approved in 2012 as a first-line treatment for metastatic HER2-positive breast cancer in women who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.
Accelerated approvals are based on a surrogate endpoint that is considered “reasonably likely” to predict clinical benefit. In this instance, pathologic complete response rate (pCR) was used in the phase II NeoSphere study. For this trial, pertuzumab was added to trastuzumab (Herceptin) – another HER2 receptor antagonist – and docetaxel, and was given before surgery to women with HER-2-positive, locally advanced, inflammatory or early-stage breast cancer. The comparator group was patients treated preoperatively with trastuzumab and docetaxel.
The women who received the three-drug neoadjuvant regimen had an 18% improvement in pCR as compared to women given trastuzumab and docetaxel only.
In addition to the NeoSphere study, the panel also considered the body of data on pertuzumab in metastatic breast cancer, the known biology of the pertuzumab, and the activity of HER-2 targeted therapies in breast cancer.
Should pertuzumab receive the accelerated approval, its full approval will be contingent on the final results of APHINITY, a confirmatory study. If the APHINITY results do not confirm the NeoSphere results, the FDA can withdraw the approval for this indication.
The vote to support the first approval of a drug for the neoadjuvant treatment of breast cancer is “a historic moment,” said the panel chair, Dr. Mikkael A. Sekeres of the Cleveland Clinic. “In so doing, we are supporting the rapid movement of a highly active drug for metastatic breast cancer to the first-line setting with the hope that women with earlier stages of breast cancer will live longer and better.”
However, he added, “all eyes will be on the confirmatory APHINITY trial” and on Genentech, to “verify this initial signal of efficacy and to confirm the bandwidth of safety we have seen so far.” If the results are negative, he and other panelists urged the company to voluntarily remove the drug for this indication, and avoid what happened with another Genentech drug, bevacizumab (Avastin), which was granted an accelerated approval as a first-line treatment in combination with paclitaxel for metastatic breast cancer in 2008. The FDA decided to withdraw approval of this indication after studies failed to confirm the benefit. The company appealed the decision, however, delaying the FDA’s withdrawal of the approval until 2011.
NeoSphere, a randomized study conducted outside of the United States, compared four treatment regimens in 417 women newly diagnosed with locally advanced, inflammatory or operable HER2-positive early breast cancer, with tumors greater than 2 cm, treated for four cycles before surgery. The median tumor size was about 5 cm, and two-thirds were node positive.
Based on the pCR definition used by Genentech (the absence of invasive cancer in the breast), almost 46% of those on the combination of pertuzumab, trastuzumab, and docetaxel reached the primary endpoint, compared with 29% of those on trastuzumab and docetaxel – a statistically significant difference of nearly 17%. Based on the FDA-preferred definition of pCR definition (the absence of invasive cancer in the breast and lymph nodes), the pCR rate was almost 18% higher with the three-drug regimen (39.3% vs. 21.5%).
The FDA considers pCR as “reasonably likely” to predict outcomes in HER2-positive breast cancer.
The treatment has the potential to cure more patients in this high risk population, said Dr. Suparna Wedam, a medical officer in FDA’s Office of Hematology and Oncology Products. Yet, still to be determined are whether the regimen has long-term safety and results in improvements in overall survival, progression-free survival, and other improvements in long-term outcomes.
Genentech also provided results from the TRYPHAENA phase II study that compared three neoadjuvant treatment regimens before surgery; as well as the CLEOPATRA phase III study, the basis of the 2012 approval of trastuzumab. In TRYPHAENA, 225 women with HER2-positive, locally advanced, operable or inflammatory breast cancer, received one of three neoadjuvant treatment regimens. The pCR rates, a secondary endpoint, ranged from about 55% to 64% when pertuzumab was added to trastuzumab and chemotherapy. CLEOPATRA enrolled 808 women with HER2-positive, locally recurrent, unresectable or metastatic breast cancer previously untreated with a biologic or chemotherapy for metastatic disease. In that trial, pertuzumab in combination with trastuzumab and docetaxel resulted in significant improvements in progression-free survival and overall survival.
The most common adverse events with the three-drug regimen in the NeoSphere study were neutropenia, diarrhea, nausea, fatigue, mucosal inflammation, and rash, according to the company. No unexpected safety signals were observed with the addition of pertuzumab. The addition of pertuzumab did not appear to increase symptomatic cardiac toxicity when added to trastuzumab-based neoadjuvant or metastatic treatment regimens.
The FDA reviewers noted, however, that the rate of left ventricular dysfunction (mostly asymptomatic) was higher with neoadjuvant pertuzumab treatment. Cardiac toxicity appeared to be reversible, however.
Panel member Deborah Armstrong of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, said that there were “some hints of increased cardiac toxicity.” She encouraged the company to closely evaluate patients on longer-term pertuzumab in trials for cardiac toxicity. Dr. Armstrong voted in favor of the benefit risk profile, but like other panelists, was concerned about the potential for approval “opening the floodgates” to the use of this drug in treating patients for whom it may not yet be appropriate.
Citing the clear potential benefit in the intended population, Dr. Michael Menefee of the division of hematology and oncology at the Mayo Clinic, Jacksonville, Fla., also shared his concerns about the potential for toxicity and overuse of the drug. “My hope is that the FDA is very clear in the ultimate labeling so practitioners have clear guidance as to how to use this drug best and most safely.”
Genentech has completed enrollment in the confirmatory, phase III APHINITY study, which will compare chemotherapy plus trastuzumab with or without pertuzumab before surgery in about 4,800 patients with HER-2 positive early breast cancer. The patients will be followed for 10 years, and the study will evaluate invasive disease-free survival. Results are expected to be first available in 2016.
Panel members have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.
Genentech also markets trastuzumab.
SILVER SPRING, MD. – Pertuzumab is likely to be approved for the neoadjuvant treatment of breast cancer in the preoperative setting, based on the recommendation of a Food and Drug Administration advisory panel.
At a meeting on Sept. 12, the FDA’s Oncologic Drugs Advisory Committee panel voted 13-0, with 1 abstention, that treatment with pertuzumab, a human epidermal growth factor receptor 2 (HER2)-targeted monoclonal antibody, had a favorable benefit-to-risk profile as a neoadjuvant treatment in combination with trastuzumab and docetaxel before surgery in patients with locally-advanced, inflammatory, or early-stage breast cancers greater than 2 cm in diameter. The neoadjuvant approach would be part of a complete early breast cancer treatment regimen containing fluorouracil, epirubicin, and cyclophosphamide or carboplatin.
The drug is being reviewed under the accelerated approval process, a mechanism that makes drugs available to fill an unmet medical need in patients with serious diseases. Historically, the usual sequence of the FDA approvals for breast cancer agents starts with approval for metastatic disease, followed by approval for early-stage disease years later after the results of large studies with long follow-up periods are available. Pertuzumab, marketed as Perjeta by Genentech, was just approved in 2012 as a first-line treatment for metastatic HER2-positive breast cancer in women who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.
Accelerated approvals are based on a surrogate endpoint that is considered “reasonably likely” to predict clinical benefit. In this instance, pathologic complete response rate (pCR) was used in the phase II NeoSphere study. For this trial, pertuzumab was added to trastuzumab (Herceptin) – another HER2 receptor antagonist – and docetaxel, and was given before surgery to women with HER-2-positive, locally advanced, inflammatory or early-stage breast cancer. The comparator group was patients treated preoperatively with trastuzumab and docetaxel.
The women who received the three-drug neoadjuvant regimen had an 18% improvement in pCR as compared to women given trastuzumab and docetaxel only.
In addition to the NeoSphere study, the panel also considered the body of data on pertuzumab in metastatic breast cancer, the known biology of the pertuzumab, and the activity of HER-2 targeted therapies in breast cancer.
Should pertuzumab receive the accelerated approval, its full approval will be contingent on the final results of APHINITY, a confirmatory study. If the APHINITY results do not confirm the NeoSphere results, the FDA can withdraw the approval for this indication.
The vote to support the first approval of a drug for the neoadjuvant treatment of breast cancer is “a historic moment,” said the panel chair, Dr. Mikkael A. Sekeres of the Cleveland Clinic. “In so doing, we are supporting the rapid movement of a highly active drug for metastatic breast cancer to the first-line setting with the hope that women with earlier stages of breast cancer will live longer and better.”
However, he added, “all eyes will be on the confirmatory APHINITY trial” and on Genentech, to “verify this initial signal of efficacy and to confirm the bandwidth of safety we have seen so far.” If the results are negative, he and other panelists urged the company to voluntarily remove the drug for this indication, and avoid what happened with another Genentech drug, bevacizumab (Avastin), which was granted an accelerated approval as a first-line treatment in combination with paclitaxel for metastatic breast cancer in 2008. The FDA decided to withdraw approval of this indication after studies failed to confirm the benefit. The company appealed the decision, however, delaying the FDA’s withdrawal of the approval until 2011.
NeoSphere, a randomized study conducted outside of the United States, compared four treatment regimens in 417 women newly diagnosed with locally advanced, inflammatory or operable HER2-positive early breast cancer, with tumors greater than 2 cm, treated for four cycles before surgery. The median tumor size was about 5 cm, and two-thirds were node positive.
Based on the pCR definition used by Genentech (the absence of invasive cancer in the breast), almost 46% of those on the combination of pertuzumab, trastuzumab, and docetaxel reached the primary endpoint, compared with 29% of those on trastuzumab and docetaxel – a statistically significant difference of nearly 17%. Based on the FDA-preferred definition of pCR definition (the absence of invasive cancer in the breast and lymph nodes), the pCR rate was almost 18% higher with the three-drug regimen (39.3% vs. 21.5%).
The FDA considers pCR as “reasonably likely” to predict outcomes in HER2-positive breast cancer.
The treatment has the potential to cure more patients in this high risk population, said Dr. Suparna Wedam, a medical officer in FDA’s Office of Hematology and Oncology Products. Yet, still to be determined are whether the regimen has long-term safety and results in improvements in overall survival, progression-free survival, and other improvements in long-term outcomes.
Genentech also provided results from the TRYPHAENA phase II study that compared three neoadjuvant treatment regimens before surgery; as well as the CLEOPATRA phase III study, the basis of the 2012 approval of trastuzumab. In TRYPHAENA, 225 women with HER2-positive, locally advanced, operable or inflammatory breast cancer, received one of three neoadjuvant treatment regimens. The pCR rates, a secondary endpoint, ranged from about 55% to 64% when pertuzumab was added to trastuzumab and chemotherapy. CLEOPATRA enrolled 808 women with HER2-positive, locally recurrent, unresectable or metastatic breast cancer previously untreated with a biologic or chemotherapy for metastatic disease. In that trial, pertuzumab in combination with trastuzumab and docetaxel resulted in significant improvements in progression-free survival and overall survival.
The most common adverse events with the three-drug regimen in the NeoSphere study were neutropenia, diarrhea, nausea, fatigue, mucosal inflammation, and rash, according to the company. No unexpected safety signals were observed with the addition of pertuzumab. The addition of pertuzumab did not appear to increase symptomatic cardiac toxicity when added to trastuzumab-based neoadjuvant or metastatic treatment regimens.
The FDA reviewers noted, however, that the rate of left ventricular dysfunction (mostly asymptomatic) was higher with neoadjuvant pertuzumab treatment. Cardiac toxicity appeared to be reversible, however.
Panel member Deborah Armstrong of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, said that there were “some hints of increased cardiac toxicity.” She encouraged the company to closely evaluate patients on longer-term pertuzumab in trials for cardiac toxicity. Dr. Armstrong voted in favor of the benefit risk profile, but like other panelists, was concerned about the potential for approval “opening the floodgates” to the use of this drug in treating patients for whom it may not yet be appropriate.
Citing the clear potential benefit in the intended population, Dr. Michael Menefee of the division of hematology and oncology at the Mayo Clinic, Jacksonville, Fla., also shared his concerns about the potential for toxicity and overuse of the drug. “My hope is that the FDA is very clear in the ultimate labeling so practitioners have clear guidance as to how to use this drug best and most safely.”
Genentech has completed enrollment in the confirmatory, phase III APHINITY study, which will compare chemotherapy plus trastuzumab with or without pertuzumab before surgery in about 4,800 patients with HER-2 positive early breast cancer. The patients will be followed for 10 years, and the study will evaluate invasive disease-free survival. Results are expected to be first available in 2016.
Panel members have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.
Genentech also markets trastuzumab.
FDA expands Botox approval to treat crow’s feet
The approval of onabotulinumtoxinA has been expanded to include the cosmetic treatment of the lateral canthal lines known as crow’s feet, the Food and Drug Administration announced on Sept. 11.
The product has been approved for "the temporary improvement in the appearance of moderate to severe lateral canthal lines" in adults, the FDA said in a statement. The product, marketed as Botox Cosmetic, is an acetylcholine release inhibitor and a neuromuscular blocking agent, and it was approved in 2002 for the temporary improvement of glabellar lines.
The new indication "will provide people with a new FDA-approved treatment option for those seeking a smoother appearance by temporarily minimizing the appearance of crow’s feet at the sides of the eyes," Dr. Susan Walker, director of the Division of Dermatology and Dental Products in the FDA’s Center for Drug Evaluation and Research, said in the statement. Treatment for the glabellar lines (between the eyebrows) and the canthal lines can be administered at the same time, she said.
Approval was based on two studies of 833 adults with moderate to severe lateral canthal lines, randomized to treatment or placebo. Those treated with onabotulinumtoxinA had "greater improvement compared to placebo in the appearance of lateral canthal lines," the FDA statement said. Eyelid edema was the most common adverse reaction associated with the treatment.
The product has been used off label for canthal lines.
OnabotulinumtoxinA is also marketed as Botox, and is approved for the treatment of chronic migraine, severe axillary hyperhidrosis, blepharospasm associated with dystonia, strabismus, and several other indications. The label includes a boxed warning about the possibility that all botulinum toxin products may spread from the site of injection to other parts of the body, causing botulism-like symptoms. The warning states that such symptoms have been reported hours to week after the injection, and have included life-threatening cases of swallowing and breathing difficulties, and reports of deaths. The warning also states that the risk is "probably greatest in children treated for spasticity, but symptoms can also occur in adults, particularly in those patients who have an underlying condition that would predispose them to these symptoms."
However, "there has not been a confirmed serious case of toxin spread when Botox or Botox Cosmetic has been used at the recommended dose for the approved indications," according to the FDA’s statement announcing the approval.
Botox and Botox Cosmetic are marketed by Allergan Inc.
Adverse events associated with onabotulinumtoxinA should be reported to the FDA at 800-332-1088 or at MedWatch.
The approval of onabotulinumtoxinA has been expanded to include the cosmetic treatment of the lateral canthal lines known as crow’s feet, the Food and Drug Administration announced on Sept. 11.
The product has been approved for "the temporary improvement in the appearance of moderate to severe lateral canthal lines" in adults, the FDA said in a statement. The product, marketed as Botox Cosmetic, is an acetylcholine release inhibitor and a neuromuscular blocking agent, and it was approved in 2002 for the temporary improvement of glabellar lines.
The new indication "will provide people with a new FDA-approved treatment option for those seeking a smoother appearance by temporarily minimizing the appearance of crow’s feet at the sides of the eyes," Dr. Susan Walker, director of the Division of Dermatology and Dental Products in the FDA’s Center for Drug Evaluation and Research, said in the statement. Treatment for the glabellar lines (between the eyebrows) and the canthal lines can be administered at the same time, she said.
Approval was based on two studies of 833 adults with moderate to severe lateral canthal lines, randomized to treatment or placebo. Those treated with onabotulinumtoxinA had "greater improvement compared to placebo in the appearance of lateral canthal lines," the FDA statement said. Eyelid edema was the most common adverse reaction associated with the treatment.
The product has been used off label for canthal lines.
OnabotulinumtoxinA is also marketed as Botox, and is approved for the treatment of chronic migraine, severe axillary hyperhidrosis, blepharospasm associated with dystonia, strabismus, and several other indications. The label includes a boxed warning about the possibility that all botulinum toxin products may spread from the site of injection to other parts of the body, causing botulism-like symptoms. The warning states that such symptoms have been reported hours to week after the injection, and have included life-threatening cases of swallowing and breathing difficulties, and reports of deaths. The warning also states that the risk is "probably greatest in children treated for spasticity, but symptoms can also occur in adults, particularly in those patients who have an underlying condition that would predispose them to these symptoms."
However, "there has not been a confirmed serious case of toxin spread when Botox or Botox Cosmetic has been used at the recommended dose for the approved indications," according to the FDA’s statement announcing the approval.
Botox and Botox Cosmetic are marketed by Allergan Inc.
Adverse events associated with onabotulinumtoxinA should be reported to the FDA at 800-332-1088 or at MedWatch.
The approval of onabotulinumtoxinA has been expanded to include the cosmetic treatment of the lateral canthal lines known as crow’s feet, the Food and Drug Administration announced on Sept. 11.
The product has been approved for "the temporary improvement in the appearance of moderate to severe lateral canthal lines" in adults, the FDA said in a statement. The product, marketed as Botox Cosmetic, is an acetylcholine release inhibitor and a neuromuscular blocking agent, and it was approved in 2002 for the temporary improvement of glabellar lines.
The new indication "will provide people with a new FDA-approved treatment option for those seeking a smoother appearance by temporarily minimizing the appearance of crow’s feet at the sides of the eyes," Dr. Susan Walker, director of the Division of Dermatology and Dental Products in the FDA’s Center for Drug Evaluation and Research, said in the statement. Treatment for the glabellar lines (between the eyebrows) and the canthal lines can be administered at the same time, she said.
Approval was based on two studies of 833 adults with moderate to severe lateral canthal lines, randomized to treatment or placebo. Those treated with onabotulinumtoxinA had "greater improvement compared to placebo in the appearance of lateral canthal lines," the FDA statement said. Eyelid edema was the most common adverse reaction associated with the treatment.
The product has been used off label for canthal lines.
OnabotulinumtoxinA is also marketed as Botox, and is approved for the treatment of chronic migraine, severe axillary hyperhidrosis, blepharospasm associated with dystonia, strabismus, and several other indications. The label includes a boxed warning about the possibility that all botulinum toxin products may spread from the site of injection to other parts of the body, causing botulism-like symptoms. The warning states that such symptoms have been reported hours to week after the injection, and have included life-threatening cases of swallowing and breathing difficulties, and reports of deaths. The warning also states that the risk is "probably greatest in children treated for spasticity, but symptoms can also occur in adults, particularly in those patients who have an underlying condition that would predispose them to these symptoms."
However, "there has not been a confirmed serious case of toxin spread when Botox or Botox Cosmetic has been used at the recommended dose for the approved indications," according to the FDA’s statement announcing the approval.
Botox and Botox Cosmetic are marketed by Allergan Inc.
Adverse events associated with onabotulinumtoxinA should be reported to the FDA at 800-332-1088 or at MedWatch.
FDA panel backs bronchodilator combo for COPD, with precautions
SILVER SPRING, MD. – A fixed-dose combination of umeclidinium bromide, a new long-acting antimuscarinic agent (LAMA), and vilanterol, a relatively new long-acting beta agonist (LABA), in an inhaled powder formulation, should be approved for treatment of chronic obstructive pulmonary disease, with a recommendation for a postmarketing safety study, according to the majority of a Food and Drug Administration advisory panel.
At a meeting on Sept. 10, the FDA’s Pulmonary-Allergy Drugs Advisory Committee voted 11-2 that the safety and efficacy data on the combined treatment, administered once a day, supported approval for the proposed indication: the long-term once-daily maintenance bronchodilator treatment of airflow obstruction in patients with COPD, including chronic bronchitis and/or emphysema. The daily dose is 62.5 mcg of umeclidinium and 25 mcg of vilanterol (UMEC/VI 62.5/25), provided in one inhalation.
In another vote, the panel unanimously agreed that treatment with UMEC/VI 62.5/25 provided clinically meaningful benefits for this indication, based on the clinical trial results provided by GlaxoSmithKline. However, all the panelists were concerned about potential safety issues in patients with severe heart disease. There was also concern over the generalizability of the use of the combination because of a cardiovascular safety signal in the studies and the types of patients excluded in the research.
Those voting in favor of approval recommended a postmarketing study to evaluate the safety signal further, and a statement in the precautions and warnings section of the label about possible risks. The two panelists voting against approval said that the study should be done before approval.
If approved, this would be the first LAMA/LABA combination product to become available in the United States. Umeclidinium is not yet available in any product, although the FDA is currently reviewing the 62.5-mcg dose as monotherapy. Vilanterol is available only as the LABA component in Breo Ellipta, the combination of vilanterol with the inhaled corticosteroid fluticasone, which was approved in May 2013 for COPD. The same device is used to deliver UMEC/VI 62.5/25, which, if approved, will be marketed as Anoro Ellipta, by GSK and Theravance.
Research details
The four main safety and efficacy studies compared two doses of umeclidinium (125 mcg and 62.5 mcg) combined with 25 mcg of vilanterol to the separate components alone and to placebo (in two studies) or to the approved long-acting antimuscarinic agent tiotropium (two studies) in about 4,700 patients – most of whom were male and white – with moderate to severe COPD. Their mean age was 63 years, almost half were still smoking, and almost 30% had had at least one exacerbation during the previous year that required treatment with corticosteroids and/or antibiotics; about 10% said they had been hospitalized for an exacerbation during the previous year (25% were enrolled in the United States).
In the two placebo-controlled studies, the combination and the two separate components (UMEC and vilanterol) were associated with statistically significant improvements in mean trough forced expiratory volume in 1 second (FEV1) from baseline at 24 weeks (the primary endpoint), compared with placebo. Improvements were also statistically significant for the two combinations over the individual components. In the active controlled study, the two combinations showed improvements in trough FEV1 that were superior to vilanterol alone and to tiotropium alone. The results with the higher dose of umeclidinium and vilanterol were similar to the 62.5-mcg dose, the proposed dose for approval.
The mortality rate and nonfatal serious adverse events were even in the treatment arms, in the four primary efficacy studies, and in long-term safety studies, and adverse events were consistent with those associated with the LAMAs and LABAs, according to GSK. The total number of cardiovascular-related events was fairly low in the safety database that included the four main studies and a long-term safety study. But there were numerical imbalances in ischemia-related events in the primary efficacy studies that were not seen in the long-term safety study, an issue raised by the FDA, although the overall number of events was low, according to the agency.
Panelists raised several safety issues, including the generalizability of the cardiac safety data to patients with more severe cardiac disease, because of exclusion criteria that may have eliminated these patients.
The panel chair, Dr. David Jacoby, professor of medicine in the division of pulmonary and critical care medicine at Oregon Health and Science University, Portland, supported approval but recommended that safety should be studied further in patients with COPD who have more severe cardiac disease.
Also voting for approval, Dr. Nizar Jarjour, professor and head of the section of allergy, pulmonary, and critical care at the University of Wisconsin, Madison, said the data indicated that the product was reasonably safe. But if it were to be used outside the parameters studied in the trials, such as for patients with recent exacerbations of COPD, or severe heart disease, he said he have would "no real confidence" that it would have the same safety profile as seen in the trials.
The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but that was unnecessary at this meeting.
SILVER SPRING, MD. – A fixed-dose combination of umeclidinium bromide, a new long-acting antimuscarinic agent (LAMA), and vilanterol, a relatively new long-acting beta agonist (LABA), in an inhaled powder formulation, should be approved for treatment of chronic obstructive pulmonary disease, with a recommendation for a postmarketing safety study, according to the majority of a Food and Drug Administration advisory panel.
At a meeting on Sept. 10, the FDA’s Pulmonary-Allergy Drugs Advisory Committee voted 11-2 that the safety and efficacy data on the combined treatment, administered once a day, supported approval for the proposed indication: the long-term once-daily maintenance bronchodilator treatment of airflow obstruction in patients with COPD, including chronic bronchitis and/or emphysema. The daily dose is 62.5 mcg of umeclidinium and 25 mcg of vilanterol (UMEC/VI 62.5/25), provided in one inhalation.
In another vote, the panel unanimously agreed that treatment with UMEC/VI 62.5/25 provided clinically meaningful benefits for this indication, based on the clinical trial results provided by GlaxoSmithKline. However, all the panelists were concerned about potential safety issues in patients with severe heart disease. There was also concern over the generalizability of the use of the combination because of a cardiovascular safety signal in the studies and the types of patients excluded in the research.
Those voting in favor of approval recommended a postmarketing study to evaluate the safety signal further, and a statement in the precautions and warnings section of the label about possible risks. The two panelists voting against approval said that the study should be done before approval.
If approved, this would be the first LAMA/LABA combination product to become available in the United States. Umeclidinium is not yet available in any product, although the FDA is currently reviewing the 62.5-mcg dose as monotherapy. Vilanterol is available only as the LABA component in Breo Ellipta, the combination of vilanterol with the inhaled corticosteroid fluticasone, which was approved in May 2013 for COPD. The same device is used to deliver UMEC/VI 62.5/25, which, if approved, will be marketed as Anoro Ellipta, by GSK and Theravance.
Research details
The four main safety and efficacy studies compared two doses of umeclidinium (125 mcg and 62.5 mcg) combined with 25 mcg of vilanterol to the separate components alone and to placebo (in two studies) or to the approved long-acting antimuscarinic agent tiotropium (two studies) in about 4,700 patients – most of whom were male and white – with moderate to severe COPD. Their mean age was 63 years, almost half were still smoking, and almost 30% had had at least one exacerbation during the previous year that required treatment with corticosteroids and/or antibiotics; about 10% said they had been hospitalized for an exacerbation during the previous year (25% were enrolled in the United States).
In the two placebo-controlled studies, the combination and the two separate components (UMEC and vilanterol) were associated with statistically significant improvements in mean trough forced expiratory volume in 1 second (FEV1) from baseline at 24 weeks (the primary endpoint), compared with placebo. Improvements were also statistically significant for the two combinations over the individual components. In the active controlled study, the two combinations showed improvements in trough FEV1 that were superior to vilanterol alone and to tiotropium alone. The results with the higher dose of umeclidinium and vilanterol were similar to the 62.5-mcg dose, the proposed dose for approval.
The mortality rate and nonfatal serious adverse events were even in the treatment arms, in the four primary efficacy studies, and in long-term safety studies, and adverse events were consistent with those associated with the LAMAs and LABAs, according to GSK. The total number of cardiovascular-related events was fairly low in the safety database that included the four main studies and a long-term safety study. But there were numerical imbalances in ischemia-related events in the primary efficacy studies that were not seen in the long-term safety study, an issue raised by the FDA, although the overall number of events was low, according to the agency.
Panelists raised several safety issues, including the generalizability of the cardiac safety data to patients with more severe cardiac disease, because of exclusion criteria that may have eliminated these patients.
The panel chair, Dr. David Jacoby, professor of medicine in the division of pulmonary and critical care medicine at Oregon Health and Science University, Portland, supported approval but recommended that safety should be studied further in patients with COPD who have more severe cardiac disease.
Also voting for approval, Dr. Nizar Jarjour, professor and head of the section of allergy, pulmonary, and critical care at the University of Wisconsin, Madison, said the data indicated that the product was reasonably safe. But if it were to be used outside the parameters studied in the trials, such as for patients with recent exacerbations of COPD, or severe heart disease, he said he have would "no real confidence" that it would have the same safety profile as seen in the trials.
The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but that was unnecessary at this meeting.
SILVER SPRING, MD. – A fixed-dose combination of umeclidinium bromide, a new long-acting antimuscarinic agent (LAMA), and vilanterol, a relatively new long-acting beta agonist (LABA), in an inhaled powder formulation, should be approved for treatment of chronic obstructive pulmonary disease, with a recommendation for a postmarketing safety study, according to the majority of a Food and Drug Administration advisory panel.
At a meeting on Sept. 10, the FDA’s Pulmonary-Allergy Drugs Advisory Committee voted 11-2 that the safety and efficacy data on the combined treatment, administered once a day, supported approval for the proposed indication: the long-term once-daily maintenance bronchodilator treatment of airflow obstruction in patients with COPD, including chronic bronchitis and/or emphysema. The daily dose is 62.5 mcg of umeclidinium and 25 mcg of vilanterol (UMEC/VI 62.5/25), provided in one inhalation.
In another vote, the panel unanimously agreed that treatment with UMEC/VI 62.5/25 provided clinically meaningful benefits for this indication, based on the clinical trial results provided by GlaxoSmithKline. However, all the panelists were concerned about potential safety issues in patients with severe heart disease. There was also concern over the generalizability of the use of the combination because of a cardiovascular safety signal in the studies and the types of patients excluded in the research.
Those voting in favor of approval recommended a postmarketing study to evaluate the safety signal further, and a statement in the precautions and warnings section of the label about possible risks. The two panelists voting against approval said that the study should be done before approval.
If approved, this would be the first LAMA/LABA combination product to become available in the United States. Umeclidinium is not yet available in any product, although the FDA is currently reviewing the 62.5-mcg dose as monotherapy. Vilanterol is available only as the LABA component in Breo Ellipta, the combination of vilanterol with the inhaled corticosteroid fluticasone, which was approved in May 2013 for COPD. The same device is used to deliver UMEC/VI 62.5/25, which, if approved, will be marketed as Anoro Ellipta, by GSK and Theravance.
Research details
The four main safety and efficacy studies compared two doses of umeclidinium (125 mcg and 62.5 mcg) combined with 25 mcg of vilanterol to the separate components alone and to placebo (in two studies) or to the approved long-acting antimuscarinic agent tiotropium (two studies) in about 4,700 patients – most of whom were male and white – with moderate to severe COPD. Their mean age was 63 years, almost half were still smoking, and almost 30% had had at least one exacerbation during the previous year that required treatment with corticosteroids and/or antibiotics; about 10% said they had been hospitalized for an exacerbation during the previous year (25% were enrolled in the United States).
In the two placebo-controlled studies, the combination and the two separate components (UMEC and vilanterol) were associated with statistically significant improvements in mean trough forced expiratory volume in 1 second (FEV1) from baseline at 24 weeks (the primary endpoint), compared with placebo. Improvements were also statistically significant for the two combinations over the individual components. In the active controlled study, the two combinations showed improvements in trough FEV1 that were superior to vilanterol alone and to tiotropium alone. The results with the higher dose of umeclidinium and vilanterol were similar to the 62.5-mcg dose, the proposed dose for approval.
The mortality rate and nonfatal serious adverse events were even in the treatment arms, in the four primary efficacy studies, and in long-term safety studies, and adverse events were consistent with those associated with the LAMAs and LABAs, according to GSK. The total number of cardiovascular-related events was fairly low in the safety database that included the four main studies and a long-term safety study. But there were numerical imbalances in ischemia-related events in the primary efficacy studies that were not seen in the long-term safety study, an issue raised by the FDA, although the overall number of events was low, according to the agency.
Panelists raised several safety issues, including the generalizability of the cardiac safety data to patients with more severe cardiac disease, because of exclusion criteria that may have eliminated these patients.
The panel chair, Dr. David Jacoby, professor of medicine in the division of pulmonary and critical care medicine at Oregon Health and Science University, Portland, supported approval but recommended that safety should be studied further in patients with COPD who have more severe cardiac disease.
Also voting for approval, Dr. Nizar Jarjour, professor and head of the section of allergy, pulmonary, and critical care at the University of Wisconsin, Madison, said the data indicated that the product was reasonably safe. But if it were to be used outside the parameters studied in the trials, such as for patients with recent exacerbations of COPD, or severe heart disease, he said he have would "no real confidence" that it would have the same safety profile as seen in the trials.
The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but that was unnecessary at this meeting.
AT A FOOD AND DRUG ADMINISTRATION ADVISORY PANEL MEETING
