Elizabeth Mechcatie

The Food and Drug Administration has approved bevacizumab as a treatment for ovarian cancer, in combination with chemotherapy, based on the results of the AURELIA study, according to a Nov. 14 announcement by Genentech.

The approved indication is bevacizumab – in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan chemotherapy – for the treatment of women with platinum-resistant, recurrent, epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have received no more than two prior chemotherapy regimens.

Bevacizumab, marketed as Avastin, a vascular endothelial growth factor–specific angiogenesis inhibitor, administered intravenously, is also approved for colon, lung, kidney, and cervical cancer indications. For the ovarian cancer indication, it is administered at a dose of 10 mg/kg IV every 2 weeks with paclitaxel, pegylated liposomal doxorubicin, or weekly topotecan; or 15 mg/kg IV every 3 weeks with topotecan given every 3 weeks, according to the updated prescribing information.

In the AURELIA study, a phase III open-label study, 361 women with platinum-resistant recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer and whom had been treated with more than two treatment regimens, were randomized to one of six treatment arms (paclitaxel, topotecan, or pegylated liposomal doxorubicin), with or without bevacizumab. In the intent-to-treat population, the primary endpoint, progression-free survival as assessed by the investigator, was 6.8 months among those on bevacizumab plus chemotherapy, compared with 3.4 months among those on chemotherapy alone, a highly statistically significant difference (hazard ratio, 0.38). Overall survival (a median of 16.6 months vs. 13.3 months) and overall response rates (28% vs. 13%) also favored those in the bevacizumab plus chemotherapy group.

Adverse events were consistent with those seen in studies of bevacizumab for the previously approved indications, “but also included high blood pressure and pain, redness or swelling of the hands or feet,” the company statement said. Grade 3-4 adverse events that affected at least 2% of women on bevacizumab were high blood pressure (6.7% among those on bevacizumab vs. 1.1% of those on chemotherapy alone) and hand-foot syndrome (4.5% vs. 1.7%) .

The bevacizumab label includes a boxed warning about the risk of gastrointestinal perforations, surgery and wound healing complications and hemorrhage associated with treatment.

Genentech, which sponsored the Aurelia study, is a member of the Roche group. The updated Avastin label is available at the FDA.

Serious adverse events associated with bevacizumab should be reported to the FDA’s MedWatch programonline or at 800-332-1088.

[email protected]

The Food and Drug Administration has approved bevacizumab as a treatment for ovarian cancer, in combination with chemotherapy, based on the results of the AURELIA study, according to a Nov. 14 announcement by Genentech.

The approved indication is bevacizumab – in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan chemotherapy – for the treatment of women with platinum-resistant, recurrent, epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have received no more than two prior chemotherapy regimens.

Bevacizumab, marketed as Avastin, a vascular endothelial growth factor–specific angiogenesis inhibitor, administered intravenously, is also approved for colon, lung, kidney, and cervical cancer indications. For the ovarian cancer indication, it is administered at a dose of 10 mg/kg IV every 2 weeks with paclitaxel, pegylated liposomal doxorubicin, or weekly topotecan; or 15 mg/kg IV every 3 weeks with topotecan given every 3 weeks, according to the updated prescribing information.

In the AURELIA study, a phase III open-label study, 361 women with platinum-resistant recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer and whom had been treated with more than two treatment regimens, were randomized to one of six treatment arms (paclitaxel, topotecan, or pegylated liposomal doxorubicin), with or without bevacizumab. In the intent-to-treat population, the primary endpoint, progression-free survival as assessed by the investigator, was 6.8 months among those on bevacizumab plus chemotherapy, compared with 3.4 months among those on chemotherapy alone, a highly statistically significant difference (hazard ratio, 0.38). Overall survival (a median of 16.6 months vs. 13.3 months) and overall response rates (28% vs. 13%) also favored those in the bevacizumab plus chemotherapy group.

Adverse events were consistent with those seen in studies of bevacizumab for the previously approved indications, “but also included high blood pressure and pain, redness or swelling of the hands or feet,” the company statement said. Grade 3-4 adverse events that affected at least 2% of women on bevacizumab were high blood pressure (6.7% among those on bevacizumab vs. 1.1% of those on chemotherapy alone) and hand-foot syndrome (4.5% vs. 1.7%) .

The bevacizumab label includes a boxed warning about the risk of gastrointestinal perforations, surgery and wound healing complications and hemorrhage associated with treatment.

Genentech, which sponsored the Aurelia study, is a member of the Roche group. The updated Avastin label is available at the FDA.

Serious adverse events associated with bevacizumab should be reported to the FDA’s MedWatch programonline or at 800-332-1088.

[email protected]

The Food and Drug Administration has approved bevacizumab as a treatment for ovarian cancer, in combination with chemotherapy, based on the results of the AURELIA study, according to a Nov. 14 announcement by Genentech.

The approved indication is bevacizumab – in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan chemotherapy – for the treatment of women with platinum-resistant, recurrent, epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have received no more than two prior chemotherapy regimens.

Bevacizumab, marketed as Avastin, a vascular endothelial growth factor–specific angiogenesis inhibitor, administered intravenously, is also approved for colon, lung, kidney, and cervical cancer indications. For the ovarian cancer indication, it is administered at a dose of 10 mg/kg IV every 2 weeks with paclitaxel, pegylated liposomal doxorubicin, or weekly topotecan; or 15 mg/kg IV every 3 weeks with topotecan given every 3 weeks, according to the updated prescribing information.

In the AURELIA study, a phase III open-label study, 361 women with platinum-resistant recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer and whom had been treated with more than two treatment regimens, were randomized to one of six treatment arms (paclitaxel, topotecan, or pegylated liposomal doxorubicin), with or without bevacizumab. In the intent-to-treat population, the primary endpoint, progression-free survival as assessed by the investigator, was 6.8 months among those on bevacizumab plus chemotherapy, compared with 3.4 months among those on chemotherapy alone, a highly statistically significant difference (hazard ratio, 0.38). Overall survival (a median of 16.6 months vs. 13.3 months) and overall response rates (28% vs. 13%) also favored those in the bevacizumab plus chemotherapy group.

Adverse events were consistent with those seen in studies of bevacizumab for the previously approved indications, “but also included high blood pressure and pain, redness or swelling of the hands or feet,” the company statement said. Grade 3-4 adverse events that affected at least 2% of women on bevacizumab were high blood pressure (6.7% among those on bevacizumab vs. 1.1% of those on chemotherapy alone) and hand-foot syndrome (4.5% vs. 1.7%) .

The bevacizumab label includes a boxed warning about the risk of gastrointestinal perforations, surgery and wound healing complications and hemorrhage associated with treatment.

Genentech, which sponsored the Aurelia study, is a member of the Roche group. The updated Avastin label is available at the FDA.

Serious adverse events associated with bevacizumab should be reported to the FDA’s MedWatch programonline or at 800-332-1088.

[email protected]

Some of the bigger studies in juvenile idiopathic arthritis at this year’s annual meeting of the American College of Rheumatology deal with choosing treatment, predicting therapeutic response, and birth outcomes.

These topics include evaluations of treatment strategies in patients who have not been treated with disease-modifying antirheumatic drugs, the safety and effectiveness of intra-articular biologic therapy, predictors of response in patients with nonsystemic juvenile idiopathic arthritis (JIA), and birth outcomes among women with a history of JIA.

Those studies, described below, are just a sampling from the numerous sessions on JIA and other pediatric rheumatic diseases that will be offered at the meeting.

Comparing treatment strategies

Investigators from the Netherlands will be presenting 3-month results of the Best for Kids Study (abstract L2), which is comparing three disease-modifying antirheumatic drug (DMARD) strategies in almost 100 DMARD-naive patients with recent-onset JIA, aged 5-7 years at enrollment, over 2 years. The strategies were sequential DMARD monotherapy, starting with sulfasalazine 50 mg/kg/day or methotrexate 10 mg/m²/week, based on physician’s preference; combination therapy with methotrexate 10 mg/m²/week and 4 weeks of prednisolone bridging 0.5 mg/kg/day, tapered to nothing over 2 weeks; and combination therapy with methotrexate 10 mg/m²/week and etanercept 0.8 mg/kg/week. At 3 months, significantly more of the patients initially treated with a combination of methotrexate and etanercept achieved an ACR Pediatric (Pedi) 50 (52%) and an ACR Pedi 70 (34%), compared with those initially treated with methotrexate (39% and 16%, respectively) or DMARD monotherapy (23% and 10%, respectively). Toxicity was similar in the three treatment arms and no serious adverse events were reported.

Intra-articular knee injections with infliximab

Intra-articular injections of infliximab were safe and effective in treating the knee joints in patients with JIA refractory to standard treatment, according to the results of a small study (abstract L14) that will be presented by investigators at Children’s Hospital Srebrnjak, in Zagreb, Croatia. The study evaluated treatment with intra-articular injections of infliximab at a dose of 50 mg or 25 mg, administered to 22 joints (including 20 knee joints) in 14 patients with monoarticular or oligoarticular JIA who were on standard therapy (NSAIDs, DMARDS, glucocorticoids) and had signs of synovitis. The presenter will also discuss the utility of 3-D/4-D musculoskeletal ultrasound, which was used to evaluate some of the knee joints in the patients.

Etanercept for enthesitis-related JIA

Also to be presented are the results of a multicenter German study (abstract L15) evaluating etanercept in 41 patients with the enthesitis-related arthritis form of JIA, which found that etanercept was “highly effective” in these patients. During the first 24 weeks, all patients were treated with etanercept (a weekly dose of 0.8 mg/kg, administered subcutaneously to a maximum of 50 mg), and almost 60% of the patients achieved a Juvenile Arthritis Disease Activity Score meeting remission criteria. Almost all achieved a ACR Pedi 30 response and were randomized to continued treatment or placebo during the subsequent 24-week randomized, double-blind, placebo-controlled withdrawal phase of the study. Most of the patients who continued treatment had no flares during this time, compared with about half of those switched to placebo, and while this difference was significant, discontinuing treatment may be an option to discuss in this group of patients, according to the authors.

Predicting anti-TNF treatment response

A study conducted by investigators in the Netherlands, United Kingdom, and Germany, provides information on how the MRP8/14 serum level may be a useful marker to help identify patients more likely to respond to biologic therapy and those who are less likely to experience disease flares if treatment is discontinued. In the study of 89 patients with JIA (abstract 932), baseline MRP8/14 serum levels were significantly higher among the 71 patients who responded, compared with the 18 nonresponders to tumor necrosis factor (TNF)–blocker therapy (etanercept). Moreover, levels did not change significantly during treatment among nonresponders, but levels significantly decreased among the responders. And in the patients with MRP8/14 levels available at the time they stopped treatment, those with higher levels were at a greater risk of experiencing a flare. Most of the patients in the study had rheumatoid factor–negative polyarthritis (33 patients) or had extended oligoarthritis (24). Others had rheumatoid factor–positive polyarthritis (13), persistent oligoarthritis (5), enthesitis-related arthritis (4), or psoriatic arthritis (10).

Birth outcomes in women with a history of JIA

The results of a Canadian retrospective cohort study that examined administrative data covering the entire population of Quebec indicates that women with a history of JIA should be monitored closely during pregnancy. The study (abstract 1866) compared birth outcomes during January 1983-December 2010 among 1,756 women who had been diagnosed with JIA and about 700 matched controls. Their mean age at delivery was 25 years (range was 16-46 years). With the exception of stillbirths, the rate of adverse birth outcomes was higher among those with a JIA history, which included having a premature baby (relative risk, 1.18), a small-for-gestational-age baby (RR, 1.19), and a baby with a major congenital anomaly (RR, 6.49). Both neural tube defects and congenital heart and circulatory defects were particularly high among the women with JIA, according to the authors, who said that more research is needed to evaluate the possible effects of JIA on pregnancy and the effects of medications in childhood, including the peripubescent period, on birth outcomes.

[email protected]

Some of the bigger studies in juvenile idiopathic arthritis at this year’s annual meeting of the American College of Rheumatology deal with choosing treatment, predicting therapeutic response, and birth outcomes.

These topics include evaluations of treatment strategies in patients who have not been treated with disease-modifying antirheumatic drugs, the safety and effectiveness of intra-articular biologic therapy, predictors of response in patients with nonsystemic juvenile idiopathic arthritis (JIA), and birth outcomes among women with a history of JIA.

Those studies, described below, are just a sampling from the numerous sessions on JIA and other pediatric rheumatic diseases that will be offered at the meeting.

Comparing treatment strategies

Investigators from the Netherlands will be presenting 3-month results of the Best for Kids Study (abstract L2), which is comparing three disease-modifying antirheumatic drug (DMARD) strategies in almost 100 DMARD-naive patients with recent-onset JIA, aged 5-7 years at enrollment, over 2 years. The strategies were sequential DMARD monotherapy, starting with sulfasalazine 50 mg/kg/day or methotrexate 10 mg/m²/week, based on physician’s preference; combination therapy with methotrexate 10 mg/m²/week and 4 weeks of prednisolone bridging 0.5 mg/kg/day, tapered to nothing over 2 weeks; and combination therapy with methotrexate 10 mg/m²/week and etanercept 0.8 mg/kg/week. At 3 months, significantly more of the patients initially treated with a combination of methotrexate and etanercept achieved an ACR Pediatric (Pedi) 50 (52%) and an ACR Pedi 70 (34%), compared with those initially treated with methotrexate (39% and 16%, respectively) or DMARD monotherapy (23% and 10%, respectively). Toxicity was similar in the three treatment arms and no serious adverse events were reported.

Intra-articular knee injections with infliximab

Intra-articular injections of infliximab were safe and effective in treating the knee joints in patients with JIA refractory to standard treatment, according to the results of a small study (abstract L14) that will be presented by investigators at Children’s Hospital Srebrnjak, in Zagreb, Croatia. The study evaluated treatment with intra-articular injections of infliximab at a dose of 50 mg or 25 mg, administered to 22 joints (including 20 knee joints) in 14 patients with monoarticular or oligoarticular JIA who were on standard therapy (NSAIDs, DMARDS, glucocorticoids) and had signs of synovitis. The presenter will also discuss the utility of 3-D/4-D musculoskeletal ultrasound, which was used to evaluate some of the knee joints in the patients.

Etanercept for enthesitis-related JIA

Also to be presented are the results of a multicenter German study (abstract L15) evaluating etanercept in 41 patients with the enthesitis-related arthritis form of JIA, which found that etanercept was “highly effective” in these patients. During the first 24 weeks, all patients were treated with etanercept (a weekly dose of 0.8 mg/kg, administered subcutaneously to a maximum of 50 mg), and almost 60% of the patients achieved a Juvenile Arthritis Disease Activity Score meeting remission criteria. Almost all achieved a ACR Pedi 30 response and were randomized to continued treatment or placebo during the subsequent 24-week randomized, double-blind, placebo-controlled withdrawal phase of the study. Most of the patients who continued treatment had no flares during this time, compared with about half of those switched to placebo, and while this difference was significant, discontinuing treatment may be an option to discuss in this group of patients, according to the authors.

Predicting anti-TNF treatment response

A study conducted by investigators in the Netherlands, United Kingdom, and Germany, provides information on how the MRP8/14 serum level may be a useful marker to help identify patients more likely to respond to biologic therapy and those who are less likely to experience disease flares if treatment is discontinued. In the study of 89 patients with JIA (abstract 932), baseline MRP8/14 serum levels were significantly higher among the 71 patients who responded, compared with the 18 nonresponders to tumor necrosis factor (TNF)–blocker therapy (etanercept). Moreover, levels did not change significantly during treatment among nonresponders, but levels significantly decreased among the responders. And in the patients with MRP8/14 levels available at the time they stopped treatment, those with higher levels were at a greater risk of experiencing a flare. Most of the patients in the study had rheumatoid factor–negative polyarthritis (33 patients) or had extended oligoarthritis (24). Others had rheumatoid factor–positive polyarthritis (13), persistent oligoarthritis (5), enthesitis-related arthritis (4), or psoriatic arthritis (10).

Birth outcomes in women with a history of JIA

The results of a Canadian retrospective cohort study that examined administrative data covering the entire population of Quebec indicates that women with a history of JIA should be monitored closely during pregnancy. The study (abstract 1866) compared birth outcomes during January 1983-December 2010 among 1,756 women who had been diagnosed with JIA and about 700 matched controls. Their mean age at delivery was 25 years (range was 16-46 years). With the exception of stillbirths, the rate of adverse birth outcomes was higher among those with a JIA history, which included having a premature baby (relative risk, 1.18), a small-for-gestational-age baby (RR, 1.19), and a baby with a major congenital anomaly (RR, 6.49). Both neural tube defects and congenital heart and circulatory defects were particularly high among the women with JIA, according to the authors, who said that more research is needed to evaluate the possible effects of JIA on pregnancy and the effects of medications in childhood, including the peripubescent period, on birth outcomes.

[email protected]

Some of the bigger studies in juvenile idiopathic arthritis at this year’s annual meeting of the American College of Rheumatology deal with choosing treatment, predicting therapeutic response, and birth outcomes.

These topics include evaluations of treatment strategies in patients who have not been treated with disease-modifying antirheumatic drugs, the safety and effectiveness of intra-articular biologic therapy, predictors of response in patients with nonsystemic juvenile idiopathic arthritis (JIA), and birth outcomes among women with a history of JIA.

Those studies, described below, are just a sampling from the numerous sessions on JIA and other pediatric rheumatic diseases that will be offered at the meeting.

Comparing treatment strategies

Investigators from the Netherlands will be presenting 3-month results of the Best for Kids Study (abstract L2), which is comparing three disease-modifying antirheumatic drug (DMARD) strategies in almost 100 DMARD-naive patients with recent-onset JIA, aged 5-7 years at enrollment, over 2 years. The strategies were sequential DMARD monotherapy, starting with sulfasalazine 50 mg/kg/day or methotrexate 10 mg/m²/week, based on physician’s preference; combination therapy with methotrexate 10 mg/m²/week and 4 weeks of prednisolone bridging 0.5 mg/kg/day, tapered to nothing over 2 weeks; and combination therapy with methotrexate 10 mg/m²/week and etanercept 0.8 mg/kg/week. At 3 months, significantly more of the patients initially treated with a combination of methotrexate and etanercept achieved an ACR Pediatric (Pedi) 50 (52%) and an ACR Pedi 70 (34%), compared with those initially treated with methotrexate (39% and 16%, respectively) or DMARD monotherapy (23% and 10%, respectively). Toxicity was similar in the three treatment arms and no serious adverse events were reported.

Intra-articular knee injections with infliximab

Intra-articular injections of infliximab were safe and effective in treating the knee joints in patients with JIA refractory to standard treatment, according to the results of a small study (abstract L14) that will be presented by investigators at Children’s Hospital Srebrnjak, in Zagreb, Croatia. The study evaluated treatment with intra-articular injections of infliximab at a dose of 50 mg or 25 mg, administered to 22 joints (including 20 knee joints) in 14 patients with monoarticular or oligoarticular JIA who were on standard therapy (NSAIDs, DMARDS, glucocorticoids) and had signs of synovitis. The presenter will also discuss the utility of 3-D/4-D musculoskeletal ultrasound, which was used to evaluate some of the knee joints in the patients.

Etanercept for enthesitis-related JIA

Also to be presented are the results of a multicenter German study (abstract L15) evaluating etanercept in 41 patients with the enthesitis-related arthritis form of JIA, which found that etanercept was “highly effective” in these patients. During the first 24 weeks, all patients were treated with etanercept (a weekly dose of 0.8 mg/kg, administered subcutaneously to a maximum of 50 mg), and almost 60% of the patients achieved a Juvenile Arthritis Disease Activity Score meeting remission criteria. Almost all achieved a ACR Pedi 30 response and were randomized to continued treatment or placebo during the subsequent 24-week randomized, double-blind, placebo-controlled withdrawal phase of the study. Most of the patients who continued treatment had no flares during this time, compared with about half of those switched to placebo, and while this difference was significant, discontinuing treatment may be an option to discuss in this group of patients, according to the authors.

Predicting anti-TNF treatment response

A study conducted by investigators in the Netherlands, United Kingdom, and Germany, provides information on how the MRP8/14 serum level may be a useful marker to help identify patients more likely to respond to biologic therapy and those who are less likely to experience disease flares if treatment is discontinued. In the study of 89 patients with JIA (abstract 932), baseline MRP8/14 serum levels were significantly higher among the 71 patients who responded, compared with the 18 nonresponders to tumor necrosis factor (TNF)–blocker therapy (etanercept). Moreover, levels did not change significantly during treatment among nonresponders, but levels significantly decreased among the responders. And in the patients with MRP8/14 levels available at the time they stopped treatment, those with higher levels were at a greater risk of experiencing a flare. Most of the patients in the study had rheumatoid factor–negative polyarthritis (33 patients) or had extended oligoarthritis (24). Others had rheumatoid factor–positive polyarthritis (13), persistent oligoarthritis (5), enthesitis-related arthritis (4), or psoriatic arthritis (10).

Birth outcomes in women with a history of JIA

The results of a Canadian retrospective cohort study that examined administrative data covering the entire population of Quebec indicates that women with a history of JIA should be monitored closely during pregnancy. The study (abstract 1866) compared birth outcomes during January 1983-December 2010 among 1,756 women who had been diagnosed with JIA and about 700 matched controls. Their mean age at delivery was 25 years (range was 16-46 years). With the exception of stillbirths, the rate of adverse birth outcomes was higher among those with a JIA history, which included having a premature baby (relative risk, 1.18), a small-for-gestational-age baby (RR, 1.19), and a baby with a major congenital anomaly (RR, 6.49). Both neural tube defects and congenital heart and circulatory defects were particularly high among the women with JIA, according to the authors, who said that more research is needed to evaluate the possible effects of JIA on pregnancy and the effects of medications in childhood, including the peripubescent period, on birth outcomes.

[email protected]

SILVER SPRING, MD. – The majority of a Food and Drug Administration advisory panel agreed that the risk-benefit profile of panobinostat as add-on treatment to bortezomib and dexamethasone did not support approval as a treatment for multiple myeloma at this time, citing issues that included toxicity and marginal progression-free survival results.

At a meeting on Nov. 6, the FDA’s Oncologic Drugs Advisory Committee voted 5-2 that the benefits of panobinostat, combined with the proteasome inhibitor bortezomib (Velcade) and dexamethasone, did not outweigh the risks for treating patients with multiple myeloma who had received at least one prior therapy, the indication proposed by the manufacturer, Novartis Pharmaceuticals. However, those voting against approval agreed that there was evidence that panobinostat had biologic activity against multiple myeloma and had an effect on progression-free survival (PFS), and said they hoped the company would continue to study the drug in patients with the disease.

Like other panelists voting no on the risk-benefit question, Dr. James Liebmann, of the division of hematology-oncology at the University of Massachusetts, Worcester, said the vote was a difficult decision “because I do think that this probably has some activity in this disease and probably can be useful.” But in the study presented by the company, “the toxicity outweighed the marginal benefit in progression-free survival,” he added.

Panobinostat, in a capsule formulation, is a histone deacetylase (DAC) inhibitor. It inhibits class I, II, and IV histone DACs, which “are epigenetic modulators and important cancer targets due to the dysregulation of these enzymes in many types of tumors,” and as an epigenetic regulator, the drug “may help restore cell programming in multiple myeloma,” according to Novartis. If approved, it would be the first drug in this class to be approved for multiple myeloma.

In the pivotal phase III, international PANORAMA-1 study, 768 patients with relapsed or relapsed-refractory multiple myeloma were randomized to treatment with panobinostat or placebo, added to bortezomib and dexamethasone. Treatment was given in two 24-week phases (3-week cycles for the first phase and 6-week cycles for the second phase, with a 2 weeks on, 1 week off schedule), with 20 mg of panobinostat three times a week during both phases, and bortezomib (1.3 mg/m²) administered twice a week during the first phase and once a week during the second phase.

The primary endpoint, median PFS assessed by the investigator, was 12 months in the panobinostat arm, compared with 8.1 months in the placebo arm, a 3.9-month difference (hazard ratio, 0.63) that was statistically significant. When an independent review committee conducted an assessment – a prespecified sensitivity analysis – the median PFS benefit was 1.9 months. Among those on panobinostat, the overall response rate was numerically higher (61% vs. 55%), and there was a trend toward an improvement in overall survival, a secondary endpoint (a difference of about 3 months in the median overall survival).

There were more deaths that were not due to progressive disease among those in the panobinostat arm – 7%, compared with 3.5% in the placebo arm­ – and serious adverse events associated with treatment included pneumonia, diarrhea, thrombocytopenia, sepsis, and fatigue. Treatment had to be interrupted or the dose had to be modified because of an adverse event in 89% of those on panobinostat, compared with 76% of those in the placebo arm. Diarrhea was the most common reason for discontinuation in the panobinostat group: About 25% had grade 3/4 diarrhea, compared with almost 8% of those in the placebo arm. The company had no data showing that quality of life was better among those in the panobinostat arm.

The main issue raised by the FDA was the large amount of missing and censored data, and the effect this had on determining the magnitude of the benefit, weighed against the toxicity, which limited the FDA’s confidence in the results.

“This is a drug that has some activity, but progression-free survival alone, particularly when there are issues of missing data and a high rate of censoring” is a concern, said the panel chair, Dr. Deborah Armstrong, professor of oncology at Johns Hopkins University, Baltimore. She added that she expects that the drug will play a role in the treatment of multiple myeloma, “but potentially in a more narrow population of patients.”

Another panelist, Dr. Tito Fojo, director of the medical oncology fellowship program at the National Cancer Institute, Bethesda, Md., added, “I think this is a drug that likely has activity in this disease and could benefit these patients, but not in this combination.”

Among other concerns raised by panelists were the age of the patients in the study, which was a median of 63 years at enrollment, about 10 years younger than the median age of patients at diagnosis, since toxicity could be worse in older patients, they pointed out.

“While we are disappointed with the committee’s recommendation, we will continue to work with the FDA as it evaluates the application,” Bruno Strigini, Pharm.D., president of Novartis Oncology, said in a statement issued after the vote. The drug is also under review in the European Union and Japan.

The FDA usually follows the recommendations of its advisory panels. The FDA is expected to make the decision this month. No panel members had conflicts of interest to disclose.

Bortezomib was approved as third-line and second-line therapy for multiple myeloma in 2003 and 2005, respectively, and in 2008 it was approved for previously untreated multiple myeloma.

[email protected]

SILVER SPRING, MD. – The majority of a Food and Drug Administration advisory panel agreed that the risk-benefit profile of panobinostat as add-on treatment to bortezomib and dexamethasone did not support approval as a treatment for multiple myeloma at this time, citing issues that included toxicity and marginal progression-free survival results.

At a meeting on Nov. 6, the FDA’s Oncologic Drugs Advisory Committee voted 5-2 that the benefits of panobinostat, combined with the proteasome inhibitor bortezomib (Velcade) and dexamethasone, did not outweigh the risks for treating patients with multiple myeloma who had received at least one prior therapy, the indication proposed by the manufacturer, Novartis Pharmaceuticals. However, those voting against approval agreed that there was evidence that panobinostat had biologic activity against multiple myeloma and had an effect on progression-free survival (PFS), and said they hoped the company would continue to study the drug in patients with the disease.

Like other panelists voting no on the risk-benefit question, Dr. James Liebmann, of the division of hematology-oncology at the University of Massachusetts, Worcester, said the vote was a difficult decision “because I do think that this probably has some activity in this disease and probably can be useful.” But in the study presented by the company, “the toxicity outweighed the marginal benefit in progression-free survival,” he added.

Panobinostat, in a capsule formulation, is a histone deacetylase (DAC) inhibitor. It inhibits class I, II, and IV histone DACs, which “are epigenetic modulators and important cancer targets due to the dysregulation of these enzymes in many types of tumors,” and as an epigenetic regulator, the drug “may help restore cell programming in multiple myeloma,” according to Novartis. If approved, it would be the first drug in this class to be approved for multiple myeloma.

In the pivotal phase III, international PANORAMA-1 study, 768 patients with relapsed or relapsed-refractory multiple myeloma were randomized to treatment with panobinostat or placebo, added to bortezomib and dexamethasone. Treatment was given in two 24-week phases (3-week cycles for the first phase and 6-week cycles for the second phase, with a 2 weeks on, 1 week off schedule), with 20 mg of panobinostat three times a week during both phases, and bortezomib (1.3 mg/m²) administered twice a week during the first phase and once a week during the second phase.

The primary endpoint, median PFS assessed by the investigator, was 12 months in the panobinostat arm, compared with 8.1 months in the placebo arm, a 3.9-month difference (hazard ratio, 0.63) that was statistically significant. When an independent review committee conducted an assessment – a prespecified sensitivity analysis – the median PFS benefit was 1.9 months. Among those on panobinostat, the overall response rate was numerically higher (61% vs. 55%), and there was a trend toward an improvement in overall survival, a secondary endpoint (a difference of about 3 months in the median overall survival).

There were more deaths that were not due to progressive disease among those in the panobinostat arm – 7%, compared with 3.5% in the placebo arm­ – and serious adverse events associated with treatment included pneumonia, diarrhea, thrombocytopenia, sepsis, and fatigue. Treatment had to be interrupted or the dose had to be modified because of an adverse event in 89% of those on panobinostat, compared with 76% of those in the placebo arm. Diarrhea was the most common reason for discontinuation in the panobinostat group: About 25% had grade 3/4 diarrhea, compared with almost 8% of those in the placebo arm. The company had no data showing that quality of life was better among those in the panobinostat arm.

The main issue raised by the FDA was the large amount of missing and censored data, and the effect this had on determining the magnitude of the benefit, weighed against the toxicity, which limited the FDA’s confidence in the results.

“This is a drug that has some activity, but progression-free survival alone, particularly when there are issues of missing data and a high rate of censoring” is a concern, said the panel chair, Dr. Deborah Armstrong, professor of oncology at Johns Hopkins University, Baltimore. She added that she expects that the drug will play a role in the treatment of multiple myeloma, “but potentially in a more narrow population of patients.”

Another panelist, Dr. Tito Fojo, director of the medical oncology fellowship program at the National Cancer Institute, Bethesda, Md., added, “I think this is a drug that likely has activity in this disease and could benefit these patients, but not in this combination.”

Among other concerns raised by panelists were the age of the patients in the study, which was a median of 63 years at enrollment, about 10 years younger than the median age of patients at diagnosis, since toxicity could be worse in older patients, they pointed out.

“While we are disappointed with the committee’s recommendation, we will continue to work with the FDA as it evaluates the application,” Bruno Strigini, Pharm.D., president of Novartis Oncology, said in a statement issued after the vote. The drug is also under review in the European Union and Japan.

The FDA usually follows the recommendations of its advisory panels. The FDA is expected to make the decision this month. No panel members had conflicts of interest to disclose.

Bortezomib was approved as third-line and second-line therapy for multiple myeloma in 2003 and 2005, respectively, and in 2008 it was approved for previously untreated multiple myeloma.

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SILVER SPRING, MD. – The majority of a Food and Drug Administration advisory panel agreed that the risk-benefit profile of panobinostat as add-on treatment to bortezomib and dexamethasone did not support approval as a treatment for multiple myeloma at this time, citing issues that included toxicity and marginal progression-free survival results.

At a meeting on Nov. 6, the FDA’s Oncologic Drugs Advisory Committee voted 5-2 that the benefits of panobinostat, combined with the proteasome inhibitor bortezomib (Velcade) and dexamethasone, did not outweigh the risks for treating patients with multiple myeloma who had received at least one prior therapy, the indication proposed by the manufacturer, Novartis Pharmaceuticals. However, those voting against approval agreed that there was evidence that panobinostat had biologic activity against multiple myeloma and had an effect on progression-free survival (PFS), and said they hoped the company would continue to study the drug in patients with the disease.

Like other panelists voting no on the risk-benefit question, Dr. James Liebmann, of the division of hematology-oncology at the University of Massachusetts, Worcester, said the vote was a difficult decision “because I do think that this probably has some activity in this disease and probably can be useful.” But in the study presented by the company, “the toxicity outweighed the marginal benefit in progression-free survival,” he added.

Panobinostat, in a capsule formulation, is a histone deacetylase (DAC) inhibitor. It inhibits class I, II, and IV histone DACs, which “are epigenetic modulators and important cancer targets due to the dysregulation of these enzymes in many types of tumors,” and as an epigenetic regulator, the drug “may help restore cell programming in multiple myeloma,” according to Novartis. If approved, it would be the first drug in this class to be approved for multiple myeloma.

In the pivotal phase III, international PANORAMA-1 study, 768 patients with relapsed or relapsed-refractory multiple myeloma were randomized to treatment with panobinostat or placebo, added to bortezomib and dexamethasone. Treatment was given in two 24-week phases (3-week cycles for the first phase and 6-week cycles for the second phase, with a 2 weeks on, 1 week off schedule), with 20 mg of panobinostat three times a week during both phases, and bortezomib (1.3 mg/m²) administered twice a week during the first phase and once a week during the second phase.

The primary endpoint, median PFS assessed by the investigator, was 12 months in the panobinostat arm, compared with 8.1 months in the placebo arm, a 3.9-month difference (hazard ratio, 0.63) that was statistically significant. When an independent review committee conducted an assessment – a prespecified sensitivity analysis – the median PFS benefit was 1.9 months. Among those on panobinostat, the overall response rate was numerically higher (61% vs. 55%), and there was a trend toward an improvement in overall survival, a secondary endpoint (a difference of about 3 months in the median overall survival).

There were more deaths that were not due to progressive disease among those in the panobinostat arm – 7%, compared with 3.5% in the placebo arm­ – and serious adverse events associated with treatment included pneumonia, diarrhea, thrombocytopenia, sepsis, and fatigue. Treatment had to be interrupted or the dose had to be modified because of an adverse event in 89% of those on panobinostat, compared with 76% of those in the placebo arm. Diarrhea was the most common reason for discontinuation in the panobinostat group: About 25% had grade 3/4 diarrhea, compared with almost 8% of those in the placebo arm. The company had no data showing that quality of life was better among those in the panobinostat arm.

The main issue raised by the FDA was the large amount of missing and censored data, and the effect this had on determining the magnitude of the benefit, weighed against the toxicity, which limited the FDA’s confidence in the results.

“This is a drug that has some activity, but progression-free survival alone, particularly when there are issues of missing data and a high rate of censoring” is a concern, said the panel chair, Dr. Deborah Armstrong, professor of oncology at Johns Hopkins University, Baltimore. She added that she expects that the drug will play a role in the treatment of multiple myeloma, “but potentially in a more narrow population of patients.”

Another panelist, Dr. Tito Fojo, director of the medical oncology fellowship program at the National Cancer Institute, Bethesda, Md., added, “I think this is a drug that likely has activity in this disease and could benefit these patients, but not in this combination.”

Among other concerns raised by panelists were the age of the patients in the study, which was a median of 63 years at enrollment, about 10 years younger than the median age of patients at diagnosis, since toxicity could be worse in older patients, they pointed out.

“While we are disappointed with the committee’s recommendation, we will continue to work with the FDA as it evaluates the application,” Bruno Strigini, Pharm.D., president of Novartis Oncology, said in a statement issued after the vote. The drug is also under review in the European Union and Japan.

The FDA usually follows the recommendations of its advisory panels. The FDA is expected to make the decision this month. No panel members had conflicts of interest to disclose.

Bortezomib was approved as third-line and second-line therapy for multiple myeloma in 2003 and 2005, respectively, and in 2008 it was approved for previously untreated multiple myeloma.

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A combination oral tablet containing dapagliflozin and extended-release metformin was approved by the Food and Drug Administration for treating adults with type 2 diabetes, the manufacturer, AstraZeneca, announced on Oct. 30.

The dosage strengths approved include 5 mg and 10 mg of dapagliflozin with 500 mg or 1,000 mg of extended-release metformin. The approved indication is as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes when treatment with both dapagliflozin and metformin is appropriate.

This is the first product combing a sodium-glucose cotransporter 2 (SGLT2) inhibitor (dapagliflozin) with a biguanide (metformin) in one tablet administered once a day, the company said in a statement.

Approval was based on four phase III studies evaluating the drugs as combination therapy, but not with the actual combined tablet formulation, the statement said.

The FDA’s approval letter says that as part of its postmarketing requirements, the company should conduct a study evaluating whether pediatric patients with type 2 diabetes or healthy children aged 10-17 years can safely swallow the combination tablets. The letter also describes a randomized, double-blind, placebo-controlled study to evaluate the efficacy, safety, and tolerability of dapagliflozin for the treatment of children and adolescents aged 10-17 years with type 2 diabetes as add-on therapy to metformin or as monotherapy, a required postmarketing study for the approval of dapagliflozin in January 2014.

AstraZeneca is marketing the combined product as Xigduo XR. It is also marketed in Australia under the same trade name. In the European Union, a combination of dapagliflozin and immediate-release metformin is marketed as Xigduo.

[email protected]

A combination oral tablet containing dapagliflozin and extended-release metformin was approved by the Food and Drug Administration for treating adults with type 2 diabetes, the manufacturer, AstraZeneca, announced on Oct. 30.

The dosage strengths approved include 5 mg and 10 mg of dapagliflozin with 500 mg or 1,000 mg of extended-release metformin. The approved indication is as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes when treatment with both dapagliflozin and metformin is appropriate.

This is the first product combing a sodium-glucose cotransporter 2 (SGLT2) inhibitor (dapagliflozin) with a biguanide (metformin) in one tablet administered once a day, the company said in a statement.

Approval was based on four phase III studies evaluating the drugs as combination therapy, but not with the actual combined tablet formulation, the statement said.

The FDA’s approval letter says that as part of its postmarketing requirements, the company should conduct a study evaluating whether pediatric patients with type 2 diabetes or healthy children aged 10-17 years can safely swallow the combination tablets. The letter also describes a randomized, double-blind, placebo-controlled study to evaluate the efficacy, safety, and tolerability of dapagliflozin for the treatment of children and adolescents aged 10-17 years with type 2 diabetes as add-on therapy to metformin or as monotherapy, a required postmarketing study for the approval of dapagliflozin in January 2014.

AstraZeneca is marketing the combined product as Xigduo XR. It is also marketed in Australia under the same trade name. In the European Union, a combination of dapagliflozin and immediate-release metformin is marketed as Xigduo.

[email protected]

A combination oral tablet containing dapagliflozin and extended-release metformin was approved by the Food and Drug Administration for treating adults with type 2 diabetes, the manufacturer, AstraZeneca, announced on Oct. 30.

The dosage strengths approved include 5 mg and 10 mg of dapagliflozin with 500 mg or 1,000 mg of extended-release metformin. The approved indication is as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes when treatment with both dapagliflozin and metformin is appropriate.

This is the first product combing a sodium-glucose cotransporter 2 (SGLT2) inhibitor (dapagliflozin) with a biguanide (metformin) in one tablet administered once a day, the company said in a statement.

Approval was based on four phase III studies evaluating the drugs as combination therapy, but not with the actual combined tablet formulation, the statement said.

The FDA’s approval letter says that as part of its postmarketing requirements, the company should conduct a study evaluating whether pediatric patients with type 2 diabetes or healthy children aged 10-17 years can safely swallow the combination tablets. The letter also describes a randomized, double-blind, placebo-controlled study to evaluate the efficacy, safety, and tolerability of dapagliflozin for the treatment of children and adolescents aged 10-17 years with type 2 diabetes as add-on therapy to metformin or as monotherapy, a required postmarketing study for the approval of dapagliflozin in January 2014.

AstraZeneca is marketing the combined product as Xigduo XR. It is also marketed in Australia under the same trade name. In the European Union, a combination of dapagliflozin and immediate-release metformin is marketed as Xigduo.

[email protected]

SILVER SPRING, MD. – Edoxaban may become the first novel oral anticoagulant drug to be approved by the Food and Drug Administration with an indication for use only in patients with renal impairment.

At a meeting on Oct. 30, the FDA’s Cardiovascular and Renal Drugs Advisory Committee voted 9-1 that edoxaban should be approved for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, the indication proposed by Daiichi Sankyo. But the panel had mixed opinions on whether approval should be limited to patients with mild to moderate renal impairment, or should include patients with normal renal function.

The pivotal trial, ENGAGE-AF TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation), compared high- and low-dose regimens of once-daily edoxaban to warfarin (targeted to an international normalized ratio of 2.0-3.0) in 21,105 patients with nonvalvular AF, at a moderate to high risk of thromboembolic events, followed for a median of almost 3 years. Overall, both doses were noninferior to warfarin in the prevention of stroke or systemic embolism, the primary endpoint. Major bleeding rates, the primary safety endpoint, were significantly lower among those on the two doses, compared with those on warfarin (N. Engl. J. Med. 2013;369:2093-104). The company proposed the high-dose regimen for approval (60 mg, taken once a day; 30 mg a day for those with moderate to severe renal impairment, body weight of 132 pounds or less, and/or concomitant use of a permeability glycoprotein inhibitor, except for amiodarone).

However, in a subgroup analysis of all strokes by baseline renal function, the 60-mg dose was “markedly superior” to warfarin, with a hazard ratio of 0.51 in patients with mild renal impairment (a creatinine clearance of more than 50 and up to 80 mL/min per 1.73 m²⁾; but the 60-mg dose was “almost significantly worse,” with an HR of 1.41 in patients with normal renal function (creatinine clearance of at least 80 mL/min per 1.73 m²), according to the FDA review, which acknowledged issues with subgroup analyses. For ischemic strokes alone, “the advantage of edoxaban in patients with mild renal impairment still seems clear” (HR, 0.62), but the effect of edoxaban “seems even worse” (HR, 1.58) among those with normal renal function. This was the main issue discussed at the meeting.

FDA reviewer recommendations were mixed, and included support for approval of the high-exposure regimen with a 15-mg dose for patients with severe renal impairment, or a higher dose. Edoxaban is 60% renally excreted, so “it is no surprise that better renal function resulted in lower exposures and worse outcomes relative to warfarin,” said Dr. Melanie Blank, a reviewer at the FDA who supported approval of the higher-dose regimen for patients with mild renal impairment only, with a recommendation that the company evaluate a higher dose in a postmarketing clinical study. She concluded that the dose chosen for the ENGAGE-AF study was too low because it was based on a dose-finding study in which the warfarin arm was underdosed.

The panel was divided as to whether the differences by renal function were due to chance or were a real finding, reflecting differences in exposure.

They were also asked what option they would choose, if they supported approval. Half the panelists supported approval of the 60-mg dose for patients with normal or mildly impaired renal function, including one panelist who also supported approval for patients with mild or moderate renal impairment. Several panelists favored the latter option, and one panelist supported approval of a dose higher than 60 mg for patients with normal renal function

“This is a really hard choice,” said Dr. Philip Sager, consulting professor of medicine at Stanford (Calif.) University, and chair of the Scientific Programs Committee at the Cardiac Safety Research Consortium in San Francisco. Based on the totality of the data, “my main concern was the decreased efficacy in the normal renal function group that is more likely than not to be a real finding,” he added. He supported the option of approval only for patients with mild and moderate renal impairment at this time, although with more data on pharmacokinetic dosing and other information, approval of a dose higher than 60 mg for patients with normal renal function “may be an option.”

The panel chair, Dr. A. Michael Lincoff, professor of medicine at the Cleveland Clinic, agreed, although he said he was more comfortable with the idea of “relatively rapidly produced” pharmacokinetic data that would support the higher dose. But if the company did not want to pursue that route, he would support approval for patients with mild and moderate renal impairment, whether or not use in patients with normal renal function would be prohibited or whether there was “clear education that the efficacy appeared to be less than warfarin’s in those patients.”

Dr. Sanjay Kaul, professor of medicine at the University of California, Los Angeles, said that considering currently available options, “I did not find any unique clinical scenario where this drug would offer an advantage that’s not already there ... but physicians like choices.” He supported approval for patients with mild and moderate renal impairment, but added that the company should be given an opportunity to clarify the benefit-risk ratio with regard to a higher dose in patients with normal renal function.

The panelist who voted against approval, Dr. Stuart Rich, professor of medicine at the University of Chicago, said he voted no because the only choice would be to support approval for patients with renal dysfunction, based on the evidence. But he questioned what clinicians would do if a patient’s renal function normalized, which could create problems, and cited the availability of other treatment options.

The FDA, which has never approved a dose higher than the doses studied in clinical trials of a drug, usually follows the recommendations of its advisory panels. Panelists had no conflicts of interest related to the topic of the meeting.

If approved, edoxaban would be the fourth novel oral anticoagulant (NOAC) to be cleared by the FDA, after dabigatran (Pradaxa), rivaroxaban (Xarelto), and apixaban (Eliquis). Edoxaban was approved in Japan for this indication in September, and is under review for this indication in Europe. Daiichi Sankyo plans to market edoxaban as Savaysa in the United States. The drug is also being reviewed for a venous thromboembolism indication (approved in Japan) in the United States and Europe. 

[email protected]

SILVER SPRING, MD. – Edoxaban may become the first novel oral anticoagulant drug to be approved by the Food and Drug Administration with an indication for use only in patients with renal impairment.

At a meeting on Oct. 30, the FDA’s Cardiovascular and Renal Drugs Advisory Committee voted 9-1 that edoxaban should be approved for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, the indication proposed by Daiichi Sankyo. But the panel had mixed opinions on whether approval should be limited to patients with mild to moderate renal impairment, or should include patients with normal renal function.

The pivotal trial, ENGAGE-AF TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation), compared high- and low-dose regimens of once-daily edoxaban to warfarin (targeted to an international normalized ratio of 2.0-3.0) in 21,105 patients with nonvalvular AF, at a moderate to high risk of thromboembolic events, followed for a median of almost 3 years. Overall, both doses were noninferior to warfarin in the prevention of stroke or systemic embolism, the primary endpoint. Major bleeding rates, the primary safety endpoint, were significantly lower among those on the two doses, compared with those on warfarin (N. Engl. J. Med. 2013;369:2093-104). The company proposed the high-dose regimen for approval (60 mg, taken once a day; 30 mg a day for those with moderate to severe renal impairment, body weight of 132 pounds or less, and/or concomitant use of a permeability glycoprotein inhibitor, except for amiodarone).

However, in a subgroup analysis of all strokes by baseline renal function, the 60-mg dose was “markedly superior” to warfarin, with a hazard ratio of 0.51 in patients with mild renal impairment (a creatinine clearance of more than 50 and up to 80 mL/min per 1.73 m²⁾; but the 60-mg dose was “almost significantly worse,” with an HR of 1.41 in patients with normal renal function (creatinine clearance of at least 80 mL/min per 1.73 m²), according to the FDA review, which acknowledged issues with subgroup analyses. For ischemic strokes alone, “the advantage of edoxaban in patients with mild renal impairment still seems clear” (HR, 0.62), but the effect of edoxaban “seems even worse” (HR, 1.58) among those with normal renal function. This was the main issue discussed at the meeting.

FDA reviewer recommendations were mixed, and included support for approval of the high-exposure regimen with a 15-mg dose for patients with severe renal impairment, or a higher dose. Edoxaban is 60% renally excreted, so “it is no surprise that better renal function resulted in lower exposures and worse outcomes relative to warfarin,” said Dr. Melanie Blank, a reviewer at the FDA who supported approval of the higher-dose regimen for patients with mild renal impairment only, with a recommendation that the company evaluate a higher dose in a postmarketing clinical study. She concluded that the dose chosen for the ENGAGE-AF study was too low because it was based on a dose-finding study in which the warfarin arm was underdosed.

The panel was divided as to whether the differences by renal function were due to chance or were a real finding, reflecting differences in exposure.

They were also asked what option they would choose, if they supported approval. Half the panelists supported approval of the 60-mg dose for patients with normal or mildly impaired renal function, including one panelist who also supported approval for patients with mild or moderate renal impairment. Several panelists favored the latter option, and one panelist supported approval of a dose higher than 60 mg for patients with normal renal function

“This is a really hard choice,” said Dr. Philip Sager, consulting professor of medicine at Stanford (Calif.) University, and chair of the Scientific Programs Committee at the Cardiac Safety Research Consortium in San Francisco. Based on the totality of the data, “my main concern was the decreased efficacy in the normal renal function group that is more likely than not to be a real finding,” he added. He supported the option of approval only for patients with mild and moderate renal impairment at this time, although with more data on pharmacokinetic dosing and other information, approval of a dose higher than 60 mg for patients with normal renal function “may be an option.”

The panel chair, Dr. A. Michael Lincoff, professor of medicine at the Cleveland Clinic, agreed, although he said he was more comfortable with the idea of “relatively rapidly produced” pharmacokinetic data that would support the higher dose. But if the company did not want to pursue that route, he would support approval for patients with mild and moderate renal impairment, whether or not use in patients with normal renal function would be prohibited or whether there was “clear education that the efficacy appeared to be less than warfarin’s in those patients.”

Dr. Sanjay Kaul, professor of medicine at the University of California, Los Angeles, said that considering currently available options, “I did not find any unique clinical scenario where this drug would offer an advantage that’s not already there ... but physicians like choices.” He supported approval for patients with mild and moderate renal impairment, but added that the company should be given an opportunity to clarify the benefit-risk ratio with regard to a higher dose in patients with normal renal function.

The panelist who voted against approval, Dr. Stuart Rich, professor of medicine at the University of Chicago, said he voted no because the only choice would be to support approval for patients with renal dysfunction, based on the evidence. But he questioned what clinicians would do if a patient’s renal function normalized, which could create problems, and cited the availability of other treatment options.

The FDA, which has never approved a dose higher than the doses studied in clinical trials of a drug, usually follows the recommendations of its advisory panels. Panelists had no conflicts of interest related to the topic of the meeting.

If approved, edoxaban would be the fourth novel oral anticoagulant (NOAC) to be cleared by the FDA, after dabigatran (Pradaxa), rivaroxaban (Xarelto), and apixaban (Eliquis). Edoxaban was approved in Japan for this indication in September, and is under review for this indication in Europe. Daiichi Sankyo plans to market edoxaban as Savaysa in the United States. The drug is also being reviewed for a venous thromboembolism indication (approved in Japan) in the United States and Europe. 

[email protected]

SILVER SPRING, MD. – Edoxaban may become the first novel oral anticoagulant drug to be approved by the Food and Drug Administration with an indication for use only in patients with renal impairment.

At a meeting on Oct. 30, the FDA’s Cardiovascular and Renal Drugs Advisory Committee voted 9-1 that edoxaban should be approved for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, the indication proposed by Daiichi Sankyo. But the panel had mixed opinions on whether approval should be limited to patients with mild to moderate renal impairment, or should include patients with normal renal function.

The pivotal trial, ENGAGE-AF TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation), compared high- and low-dose regimens of once-daily edoxaban to warfarin (targeted to an international normalized ratio of 2.0-3.0) in 21,105 patients with nonvalvular AF, at a moderate to high risk of thromboembolic events, followed for a median of almost 3 years. Overall, both doses were noninferior to warfarin in the prevention of stroke or systemic embolism, the primary endpoint. Major bleeding rates, the primary safety endpoint, were significantly lower among those on the two doses, compared with those on warfarin (N. Engl. J. Med. 2013;369:2093-104). The company proposed the high-dose regimen for approval (60 mg, taken once a day; 30 mg a day for those with moderate to severe renal impairment, body weight of 132 pounds or less, and/or concomitant use of a permeability glycoprotein inhibitor, except for amiodarone).

However, in a subgroup analysis of all strokes by baseline renal function, the 60-mg dose was “markedly superior” to warfarin, with a hazard ratio of 0.51 in patients with mild renal impairment (a creatinine clearance of more than 50 and up to 80 mL/min per 1.73 m²⁾; but the 60-mg dose was “almost significantly worse,” with an HR of 1.41 in patients with normal renal function (creatinine clearance of at least 80 mL/min per 1.73 m²), according to the FDA review, which acknowledged issues with subgroup analyses. For ischemic strokes alone, “the advantage of edoxaban in patients with mild renal impairment still seems clear” (HR, 0.62), but the effect of edoxaban “seems even worse” (HR, 1.58) among those with normal renal function. This was the main issue discussed at the meeting.

FDA reviewer recommendations were mixed, and included support for approval of the high-exposure regimen with a 15-mg dose for patients with severe renal impairment, or a higher dose. Edoxaban is 60% renally excreted, so “it is no surprise that better renal function resulted in lower exposures and worse outcomes relative to warfarin,” said Dr. Melanie Blank, a reviewer at the FDA who supported approval of the higher-dose regimen for patients with mild renal impairment only, with a recommendation that the company evaluate a higher dose in a postmarketing clinical study. She concluded that the dose chosen for the ENGAGE-AF study was too low because it was based on a dose-finding study in which the warfarin arm was underdosed.

The panel was divided as to whether the differences by renal function were due to chance or were a real finding, reflecting differences in exposure.

They were also asked what option they would choose, if they supported approval. Half the panelists supported approval of the 60-mg dose for patients with normal or mildly impaired renal function, including one panelist who also supported approval for patients with mild or moderate renal impairment. Several panelists favored the latter option, and one panelist supported approval of a dose higher than 60 mg for patients with normal renal function

“This is a really hard choice,” said Dr. Philip Sager, consulting professor of medicine at Stanford (Calif.) University, and chair of the Scientific Programs Committee at the Cardiac Safety Research Consortium in San Francisco. Based on the totality of the data, “my main concern was the decreased efficacy in the normal renal function group that is more likely than not to be a real finding,” he added. He supported the option of approval only for patients with mild and moderate renal impairment at this time, although with more data on pharmacokinetic dosing and other information, approval of a dose higher than 60 mg for patients with normal renal function “may be an option.”

The panel chair, Dr. A. Michael Lincoff, professor of medicine at the Cleveland Clinic, agreed, although he said he was more comfortable with the idea of “relatively rapidly produced” pharmacokinetic data that would support the higher dose. But if the company did not want to pursue that route, he would support approval for patients with mild and moderate renal impairment, whether or not use in patients with normal renal function would be prohibited or whether there was “clear education that the efficacy appeared to be less than warfarin’s in those patients.”

Dr. Sanjay Kaul, professor of medicine at the University of California, Los Angeles, said that considering currently available options, “I did not find any unique clinical scenario where this drug would offer an advantage that’s not already there ... but physicians like choices.” He supported approval for patients with mild and moderate renal impairment, but added that the company should be given an opportunity to clarify the benefit-risk ratio with regard to a higher dose in patients with normal renal function.

The panelist who voted against approval, Dr. Stuart Rich, professor of medicine at the University of Chicago, said he voted no because the only choice would be to support approval for patients with renal dysfunction, based on the evidence. But he questioned what clinicians would do if a patient’s renal function normalized, which could create problems, and cited the availability of other treatment options.

The FDA, which has never approved a dose higher than the doses studied in clinical trials of a drug, usually follows the recommendations of its advisory panels. Panelists had no conflicts of interest related to the topic of the meeting.

If approved, edoxaban would be the fourth novel oral anticoagulant (NOAC) to be cleared by the FDA, after dabigatran (Pradaxa), rivaroxaban (Xarelto), and apixaban (Eliquis). Edoxaban was approved in Japan for this indication in September, and is under review for this indication in Europe. Daiichi Sankyo plans to market edoxaban as Savaysa in the United States. The drug is also being reviewed for a venous thromboembolism indication (approved in Japan) in the United States and Europe. 

[email protected]

New interim guidance that categorizes the risk of people who may have been exposed to Ebola, with recommendations on monitoring and movement restrictions, was announced by the Centers for Disease Control and Prevention Oct. 27.

The document, released the week after enhanced screening of travelers from Liberia, Sierra Leone, and Guinea began at selected U.S. airports, provides guidance to state and local health officials on “managing the movement of individuals being monitored, including travelers from the countries with widespread transmission and others who may have been exposed in the United States,” the statement said.

People traveling from those three countries who have no fever or Ebola symptoms on arrival at airports in six states -- New York, New Jersey, Pennsylvania, Maryland, Virginia, and Georgia -– are subject to active monitoring, where they will be contacted daily for 21 days from the time they left the affected country. Other states will start active monitoring in the following days, according to the statement. If returned travelers develop symptoms, “they can rapidly be assessed and, if they’re found to have Ebola, effectively isolated and treated,” CDC director Dr. Tom Frieden said during a telebriefing announcing the guidance.

The interim guidance outlines four levels of exposure and delineates different public health actions that may be taken for each level. Dr. Frieden acknowledged that it is within the authority of state and local governments to adopt different strategies than those outlined in the guidance.

High-risk: This category includes someone with known exposure to Ebola, such as a needle stick or mucous membrane exposure from the blood or body fluids of a symptomatic patient. For exposed individuals who are asymptomatic, recommendations include direct active monitoring by public health officials, and ensuring, through orders if necessary, no travel on public transportation and no public gatherings. If travel is allowed, it should be by non-commercial conveyances only, coordinated with public health authorities to ensure active monitoring is not interrupted.

“Some risk”: This category would include a person who may have been in the home of someone who was ill with Ebola but who had no direct contact with that person. It also includes health care workers returning from a country where they cared for Ebola patients. Additional precautions, such as daily direct active monitoring, are recommended for this group. The guidance recommends that public health officials “determine on an individualized case-by-case basis whether additional restrictions, such as controlled movement, workplace exclusions, or restrictions on other activities, are appropriate” for this category, the CDC statement said.

“Low but not zero risk”: This group includes people who have traveled in a country affected by the Ebola epidemic but have no known exposure to the virus. It includes health care workers caring for patients with Ebola in the United States. There are “very important differences” from providing care in Africa compared with U.S. hospitals, where the setting is more controlled, Dr. Frieden said. No restrictions on travel, work, or public gathering are recommended for asymptomatic individuals in this group. Direct active monitoring is recommended for U.S.-based health care workers who have cared for symptomatic patients with Ebola, while wearing appropriate protective gear, as well as travelers on an aircraft sitting within 3 feet of a person with Ebola.

“No risk”: This group includes people who have not traveled to an affected country or who have traveled to an affected country more than 21 days previously. Dr. Frieden said that the CDC has received more than 500 inquires from physicians, health departments, and hospitals about patients who were thought to be at risk for Ebola, and in 90% of those cases, the pattern of symptoms or travel history has not been consistent with Ebola.

An average of about 100 people a day enter the United States after having traveled to one of the West African countries affected by Ebola, of which about 5%-6% are returning health care workers, Dr. Frieden said. He emphasized that Ebola is spread only when people are symptomatic and via direct contact with the infected individual or their body fluids. Those caring for Ebola patients are at the greatest risk.

[email protected]

New interim guidance that categorizes the risk of people who may have been exposed to Ebola, with recommendations on monitoring and movement restrictions, was announced by the Centers for Disease Control and Prevention Oct. 27.

The document, released the week after enhanced screening of travelers from Liberia, Sierra Leone, and Guinea began at selected U.S. airports, provides guidance to state and local health officials on “managing the movement of individuals being monitored, including travelers from the countries with widespread transmission and others who may have been exposed in the United States,” the statement said.

People traveling from those three countries who have no fever or Ebola symptoms on arrival at airports in six states -- New York, New Jersey, Pennsylvania, Maryland, Virginia, and Georgia -– are subject to active monitoring, where they will be contacted daily for 21 days from the time they left the affected country. Other states will start active monitoring in the following days, according to the statement. If returned travelers develop symptoms, “they can rapidly be assessed and, if they’re found to have Ebola, effectively isolated and treated,” CDC director Dr. Tom Frieden said during a telebriefing announcing the guidance.

The interim guidance outlines four levels of exposure and delineates different public health actions that may be taken for each level. Dr. Frieden acknowledged that it is within the authority of state and local governments to adopt different strategies than those outlined in the guidance.

High-risk: This category includes someone with known exposure to Ebola, such as a needle stick or mucous membrane exposure from the blood or body fluids of a symptomatic patient. For exposed individuals who are asymptomatic, recommendations include direct active monitoring by public health officials, and ensuring, through orders if necessary, no travel on public transportation and no public gatherings. If travel is allowed, it should be by non-commercial conveyances only, coordinated with public health authorities to ensure active monitoring is not interrupted.

“Some risk”: This category would include a person who may have been in the home of someone who was ill with Ebola but who had no direct contact with that person. It also includes health care workers returning from a country where they cared for Ebola patients. Additional precautions, such as daily direct active monitoring, are recommended for this group. The guidance recommends that public health officials “determine on an individualized case-by-case basis whether additional restrictions, such as controlled movement, workplace exclusions, or restrictions on other activities, are appropriate” for this category, the CDC statement said.

“Low but not zero risk”: This group includes people who have traveled in a country affected by the Ebola epidemic but have no known exposure to the virus. It includes health care workers caring for patients with Ebola in the United States. There are “very important differences” from providing care in Africa compared with U.S. hospitals, where the setting is more controlled, Dr. Frieden said. No restrictions on travel, work, or public gathering are recommended for asymptomatic individuals in this group. Direct active monitoring is recommended for U.S.-based health care workers who have cared for symptomatic patients with Ebola, while wearing appropriate protective gear, as well as travelers on an aircraft sitting within 3 feet of a person with Ebola.

“No risk”: This group includes people who have not traveled to an affected country or who have traveled to an affected country more than 21 days previously. Dr. Frieden said that the CDC has received more than 500 inquires from physicians, health departments, and hospitals about patients who were thought to be at risk for Ebola, and in 90% of those cases, the pattern of symptoms or travel history has not been consistent with Ebola.

An average of about 100 people a day enter the United States after having traveled to one of the West African countries affected by Ebola, of which about 5%-6% are returning health care workers, Dr. Frieden said. He emphasized that Ebola is spread only when people are symptomatic and via direct contact with the infected individual or their body fluids. Those caring for Ebola patients are at the greatest risk.

[email protected]

New interim guidance that categorizes the risk of people who may have been exposed to Ebola, with recommendations on monitoring and movement restrictions, was announced by the Centers for Disease Control and Prevention Oct. 27.

The document, released the week after enhanced screening of travelers from Liberia, Sierra Leone, and Guinea began at selected U.S. airports, provides guidance to state and local health officials on “managing the movement of individuals being monitored, including travelers from the countries with widespread transmission and others who may have been exposed in the United States,” the statement said.

People traveling from those three countries who have no fever or Ebola symptoms on arrival at airports in six states -- New York, New Jersey, Pennsylvania, Maryland, Virginia, and Georgia -– are subject to active monitoring, where they will be contacted daily for 21 days from the time they left the affected country. Other states will start active monitoring in the following days, according to the statement. If returned travelers develop symptoms, “they can rapidly be assessed and, if they’re found to have Ebola, effectively isolated and treated,” CDC director Dr. Tom Frieden said during a telebriefing announcing the guidance.

The interim guidance outlines four levels of exposure and delineates different public health actions that may be taken for each level. Dr. Frieden acknowledged that it is within the authority of state and local governments to adopt different strategies than those outlined in the guidance.

High-risk: This category includes someone with known exposure to Ebola, such as a needle stick or mucous membrane exposure from the blood or body fluids of a symptomatic patient. For exposed individuals who are asymptomatic, recommendations include direct active monitoring by public health officials, and ensuring, through orders if necessary, no travel on public transportation and no public gatherings. If travel is allowed, it should be by non-commercial conveyances only, coordinated with public health authorities to ensure active monitoring is not interrupted.

“Some risk”: This category would include a person who may have been in the home of someone who was ill with Ebola but who had no direct contact with that person. It also includes health care workers returning from a country where they cared for Ebola patients. Additional precautions, such as daily direct active monitoring, are recommended for this group. The guidance recommends that public health officials “determine on an individualized case-by-case basis whether additional restrictions, such as controlled movement, workplace exclusions, or restrictions on other activities, are appropriate” for this category, the CDC statement said.

“Low but not zero risk”: This group includes people who have traveled in a country affected by the Ebola epidemic but have no known exposure to the virus. It includes health care workers caring for patients with Ebola in the United States. There are “very important differences” from providing care in Africa compared with U.S. hospitals, where the setting is more controlled, Dr. Frieden said. No restrictions on travel, work, or public gathering are recommended for asymptomatic individuals in this group. Direct active monitoring is recommended for U.S.-based health care workers who have cared for symptomatic patients with Ebola, while wearing appropriate protective gear, as well as travelers on an aircraft sitting within 3 feet of a person with Ebola.

“No risk”: This group includes people who have not traveled to an affected country or who have traveled to an affected country more than 21 days previously. Dr. Frieden said that the CDC has received more than 500 inquires from physicians, health departments, and hospitals about patients who were thought to be at risk for Ebola, and in 90% of those cases, the pattern of symptoms or travel history has not been consistent with Ebola.

An average of about 100 people a day enter the United States after having traveled to one of the West African countries affected by Ebola, of which about 5%-6% are returning health care workers, Dr. Frieden said. He emphasized that Ebola is spread only when people are symptomatic and via direct contact with the infected individual or their body fluids. Those caring for Ebola patients are at the greatest risk.

[email protected]

SILVER SPRING, MD. – The boxed warning about the risk of serious neuropsychiatric effects associated with the smoking cessation drug varenicline should remain on the drug’s label, and the need for this warning can be reevaluated when the results of a postmarketing safety study become available next year, according to the majority of a Food and Drug Administration advisory panel.

On Oct. 16, at a joint meeting of the FDA’s Psychopharmacologic Drugs and the Drug Safety and Risk Management Advisory committees, 11 of the 18 panelists voted to retain the boxed warning about neuropsychiatric symptoms and suicidality, agreeing that a decision about whether to retain the warning should not be made until the results of the study are available.

Pfizer, which manufactures varenicline, a nicotinic receptor partial agonist in a tablet formulation, as Chantix, is conducting the prospective, randomized, double-blind study comparing neuropsychiatric events in 8,000 smokers, with and without a psychiatric history, treated with varenicline, nicotine replacement therapy, bupropion, or placebo. Although the results are expected in 2015, the company maintained that the boxed warning is no longer justified and can be put in the warnings and precautions section, based on analyses of observational studies and randomized clinical trials. The company submitted those analyses to the FDA earlier this year.

The boxed warning in the drug’s prescribing information states that the serious events reported in patients taking the drug include but “are not limited to” depression, suicidal ideation, suicide attempts, and completed suicides; and that some cases “may have been complicated by the symptoms of nicotine withdrawal in patients who stopped smoking.” The reason the boxed warning is used for this drug is that there is a “serious adverse reaction that can be prevented or reduced in frequency or severity,” the FDA said.

Because the precedent for removing a boxed warning from a drug label is limited and the FDA’s view that the decision should consider the final results of the postmarketing trial, the agency convened the joint meeting to review the analyses submitted by the company. Overall, the panelists were not convinced by the analyses. They cited various weaknesses in the observational studies and the meta-analysis, including questions about whether the correct outcomes were being captured.

Six panelists voted to modify (but not weaken) the language in the boxed warning, and most recommended that the last few lines about the health benefits of quitting smoking be removed and argued that the wording had a promotional tone and did not belong in a boxed warning. Several panelists recommended adding sleep disruption and disorders, and recognized adverse events of the drugs to the boxed warning.

Among those who voted to retain the boxed warning, Dr. Jeanmarie Perrone, director of the medical toxicology division in the emergency medicine department at the University of Pennsylvania, Philadelphia, said there was biologic plausibility for these events. Her biggest concern, she said, was that removing the boxed warning might be interpreted as “an endorsement of safety and that has not been demonstrated.” In the emergency department, she said, she sees many patients who have been prescribed varenicline “by a myriad of clinicians,” and the presence of a boxed warning helps keep this safety issue in mind.

Dr. Rajiv N. Rimal, professor and chair of the department of prevention and community health, George Washington University, Washington, who voted to retain the warning with modified wording, said: “I heard enough compelling evidence to suggest that even some of the more rare events were severe enough” that revisiting the labeling change would be necessary once the other data became available.

Varenicline, approved by the FDA in 2006 as an aid to smoking-cessation treatment, provides a “low level” of dopamine release as people try to quit smoking, according to Pfizer. The boxed warning was added to the label in July 2009, based on the FDA’s review of spontaneous adverse event reports, conducted after an alert about suicidality reports associated with the drug from European regulators about 1 year after FDA approval. About the same time, there was a widely publicized case of a Texas musician who was taking varenicline and was shot and killed by a neighbor while exhibiting uncharacteristic aggressive behavior in the fall of 2007.

The reports provided by the company at that time included 102 suicide-related cases, and 525 reports of aggressive/irrational behavior. A review of the reports in the FDA’s adverse events database included many cases with “hallmarks of drug relatedness,” patients reporting unusual symptoms with “similar distinctive language,” and positive dechallenges and rechallenges, said Dr. Celia Winchell, the medical team leader of addiction products in the FDA’s division of anesthesia, analgesia, and addiction products. Not all cases involved suicidality, depression, or aggression. Postmarketing reports have provided a “rich narrative with detail” about patient experiences, including descriptions that are relatively easy to describe or classify, such as suicide and aggression, while others “defy coding,” such as one person who reported feeling “like a zombie,” she told the panel.

“Based on a review of the cases, there appears to be a syndrome of debilitating symptoms that interfere with people’s ability to function in their daily lives that is associated with the use of Chantix,” Dr. Winchell said.

The company agreed that the spontaneous reports in late 2007 raised concerns about whether the drug was associated with an increase in serious neuropsychiatric events. But since 2009, this issue has been evaluated in controlled studies, which “consistently show no evidence of an increased risk,” Dr. Christopher Wohlberg, the head of Pfizer’s safety surveillance and risk management group, told the panel.

These include a meta-analysis of adverse events in 18 controlled studies of about 5,000 patients treated with varenicline and about 3,500 on placebo, which found no significant difference in the rate of neuropsychiatric events (with the exception of sleep disorders and disturbance) among those on the drug vs. those on placebo; and a meta-analysis of 5 placebo-controlled studies that used the Columbia-Suicide Severity Rating Scale to evaluate suicidal ideation and behavior, which also found no significant differences between the two groups.

In addition, four observational studies that included patients with psychiatric illnesses showed that the rates of serious neuropsychiatric events in patients treated with varenicline were not significantly different from those treated with nicotine replacement therapy or bupropion for smoking cessation. In individual studies of patients with psychiatric illnesses (schizophrenia, schizoaffective disorder, or major depressive disorder), no evidence was found of an increased risk among those treated with varenicline, compared with those on placebo, according to the company.

But the FDA reviewers raised issues with the meta-analysis of the 18 studies and the observational data. The observational data have limitations and “preclude” a conclusion that there is no association of varenicline and an increased risk of neuropsychiatric events, said Natasha Chen, Ph.D., an epidemiologist in the FDA’s office of surveillance and epidemiology. The ongoing postmarketing safety trial “is likely to offer better insights into varenicline’s neuropsychiatric risks,” she added.

The one panelist who voted to remove the warning, Dr. Andrew J. Saxon, said while there “may be some serious adverse or neuropsychiatric effects, the data, while not perfect,” do not show a signal in his view. He added that in his experience working daily with patients who are trying to quit smoking, “patients are afraid to take this medication because of the boxed warning, and it does deter use.” Moreover, in the Veterans Affairs system, there are restrictions on prescribing the drug because of the boxed warning, including a limitation on prescriptions to a 28-day supply, with no refills. Such restrictions increase hassles for patients and prescribers, and often result in patients stopping treatment after 4 weeks.

“If I’m doing a good job as a physician, I’m going to monitor the patient,” said Dr. Saxon, director of the addiction psychiatry residency program, University of Washington, Seattle.

The FDA usually follows the recommendations of its advisory panels, which are not binding. Members of these two panels had no conflicts to disclose. Occasionally, panelists with a conflict are given a waiver, but not at this meeting.

In a statement issued by Pfizer after the meeting, Dr. Steven Romano, senior vice president and head of the medicines development group for Pfizer, said the “completion of our currently ongoing safety study will represent one more step forward in the process of accurately characterizing the neuropsychiatric safety of this important medication.”

The varenicline label is available at http://labeling.pfizer.com/ShowLabeling.aspx?id=557. Serious adverse events associated with this drug should be reported to the FDA’s MedWatch program at http://www.fda.gov/Safety/MedWatch/default.htm.

SILVER SPRING, MD. – The boxed warning about the risk of serious neuropsychiatric effects associated with the smoking cessation drug varenicline should remain on the drug’s label, and the need for this warning can be reevaluated when the results of a postmarketing safety study become available next year, according to the majority of a Food and Drug Administration advisory panel.

On Oct. 16, at a joint meeting of the FDA’s Psychopharmacologic Drugs and the Drug Safety and Risk Management Advisory committees, 11 of the 18 panelists voted to retain the boxed warning about neuropsychiatric symptoms and suicidality, agreeing that a decision about whether to retain the warning should not be made until the results of the study are available.

Pfizer, which manufactures varenicline, a nicotinic receptor partial agonist in a tablet formulation, as Chantix, is conducting the prospective, randomized, double-blind study comparing neuropsychiatric events in 8,000 smokers, with and without a psychiatric history, treated with varenicline, nicotine replacement therapy, bupropion, or placebo. Although the results are expected in 2015, the company maintained that the boxed warning is no longer justified and can be put in the warnings and precautions section, based on analyses of observational studies and randomized clinical trials. The company submitted those analyses to the FDA earlier this year.

The boxed warning in the drug’s prescribing information states that the serious events reported in patients taking the drug include but “are not limited to” depression, suicidal ideation, suicide attempts, and completed suicides; and that some cases “may have been complicated by the symptoms of nicotine withdrawal in patients who stopped smoking.” The reason the boxed warning is used for this drug is that there is a “serious adverse reaction that can be prevented or reduced in frequency or severity,” the FDA said.

Because the precedent for removing a boxed warning from a drug label is limited and the FDA’s view that the decision should consider the final results of the postmarketing trial, the agency convened the joint meeting to review the analyses submitted by the company. Overall, the panelists were not convinced by the analyses. They cited various weaknesses in the observational studies and the meta-analysis, including questions about whether the correct outcomes were being captured.

Six panelists voted to modify (but not weaken) the language in the boxed warning, and most recommended that the last few lines about the health benefits of quitting smoking be removed and argued that the wording had a promotional tone and did not belong in a boxed warning. Several panelists recommended adding sleep disruption and disorders, and recognized adverse events of the drugs to the boxed warning.

Among those who voted to retain the boxed warning, Dr. Jeanmarie Perrone, director of the medical toxicology division in the emergency medicine department at the University of Pennsylvania, Philadelphia, said there was biologic plausibility for these events. Her biggest concern, she said, was that removing the boxed warning might be interpreted as “an endorsement of safety and that has not been demonstrated.” In the emergency department, she said, she sees many patients who have been prescribed varenicline “by a myriad of clinicians,” and the presence of a boxed warning helps keep this safety issue in mind.

Dr. Rajiv N. Rimal, professor and chair of the department of prevention and community health, George Washington University, Washington, who voted to retain the warning with modified wording, said: “I heard enough compelling evidence to suggest that even some of the more rare events were severe enough” that revisiting the labeling change would be necessary once the other data became available.

Varenicline, approved by the FDA in 2006 as an aid to smoking-cessation treatment, provides a “low level” of dopamine release as people try to quit smoking, according to Pfizer. The boxed warning was added to the label in July 2009, based on the FDA’s review of spontaneous adverse event reports, conducted after an alert about suicidality reports associated with the drug from European regulators about 1 year after FDA approval. About the same time, there was a widely publicized case of a Texas musician who was taking varenicline and was shot and killed by a neighbor while exhibiting uncharacteristic aggressive behavior in the fall of 2007.

The reports provided by the company at that time included 102 suicide-related cases, and 525 reports of aggressive/irrational behavior. A review of the reports in the FDA’s adverse events database included many cases with “hallmarks of drug relatedness,” patients reporting unusual symptoms with “similar distinctive language,” and positive dechallenges and rechallenges, said Dr. Celia Winchell, the medical team leader of addiction products in the FDA’s division of anesthesia, analgesia, and addiction products. Not all cases involved suicidality, depression, or aggression. Postmarketing reports have provided a “rich narrative with detail” about patient experiences, including descriptions that are relatively easy to describe or classify, such as suicide and aggression, while others “defy coding,” such as one person who reported feeling “like a zombie,” she told the panel.

“Based on a review of the cases, there appears to be a syndrome of debilitating symptoms that interfere with people’s ability to function in their daily lives that is associated with the use of Chantix,” Dr. Winchell said.

The company agreed that the spontaneous reports in late 2007 raised concerns about whether the drug was associated with an increase in serious neuropsychiatric events. But since 2009, this issue has been evaluated in controlled studies, which “consistently show no evidence of an increased risk,” Dr. Christopher Wohlberg, the head of Pfizer’s safety surveillance and risk management group, told the panel.

These include a meta-analysis of adverse events in 18 controlled studies of about 5,000 patients treated with varenicline and about 3,500 on placebo, which found no significant difference in the rate of neuropsychiatric events (with the exception of sleep disorders and disturbance) among those on the drug vs. those on placebo; and a meta-analysis of 5 placebo-controlled studies that used the Columbia-Suicide Severity Rating Scale to evaluate suicidal ideation and behavior, which also found no significant differences between the two groups.

In addition, four observational studies that included patients with psychiatric illnesses showed that the rates of serious neuropsychiatric events in patients treated with varenicline were not significantly different from those treated with nicotine replacement therapy or bupropion for smoking cessation. In individual studies of patients with psychiatric illnesses (schizophrenia, schizoaffective disorder, or major depressive disorder), no evidence was found of an increased risk among those treated with varenicline, compared with those on placebo, according to the company.

But the FDA reviewers raised issues with the meta-analysis of the 18 studies and the observational data. The observational data have limitations and “preclude” a conclusion that there is no association of varenicline and an increased risk of neuropsychiatric events, said Natasha Chen, Ph.D., an epidemiologist in the FDA’s office of surveillance and epidemiology. The ongoing postmarketing safety trial “is likely to offer better insights into varenicline’s neuropsychiatric risks,” she added.

The one panelist who voted to remove the warning, Dr. Andrew J. Saxon, said while there “may be some serious adverse or neuropsychiatric effects, the data, while not perfect,” do not show a signal in his view. He added that in his experience working daily with patients who are trying to quit smoking, “patients are afraid to take this medication because of the boxed warning, and it does deter use.” Moreover, in the Veterans Affairs system, there are restrictions on prescribing the drug because of the boxed warning, including a limitation on prescriptions to a 28-day supply, with no refills. Such restrictions increase hassles for patients and prescribers, and often result in patients stopping treatment after 4 weeks.

“If I’m doing a good job as a physician, I’m going to monitor the patient,” said Dr. Saxon, director of the addiction psychiatry residency program, University of Washington, Seattle.

The FDA usually follows the recommendations of its advisory panels, which are not binding. Members of these two panels had no conflicts to disclose. Occasionally, panelists with a conflict are given a waiver, but not at this meeting.

In a statement issued by Pfizer after the meeting, Dr. Steven Romano, senior vice president and head of the medicines development group for Pfizer, said the “completion of our currently ongoing safety study will represent one more step forward in the process of accurately characterizing the neuropsychiatric safety of this important medication.”

The varenicline label is available at http://labeling.pfizer.com/ShowLabeling.aspx?id=557. Serious adverse events associated with this drug should be reported to the FDA’s MedWatch program at http://www.fda.gov/Safety/MedWatch/default.htm.

SILVER SPRING, MD. – The boxed warning about the risk of serious neuropsychiatric effects associated with the smoking cessation drug varenicline should remain on the drug’s label, and the need for this warning can be reevaluated when the results of a postmarketing safety study become available next year, according to the majority of a Food and Drug Administration advisory panel.

On Oct. 16, at a joint meeting of the FDA’s Psychopharmacologic Drugs and the Drug Safety and Risk Management Advisory committees, 11 of the 18 panelists voted to retain the boxed warning about neuropsychiatric symptoms and suicidality, agreeing that a decision about whether to retain the warning should not be made until the results of the study are available.

Pfizer, which manufactures varenicline, a nicotinic receptor partial agonist in a tablet formulation, as Chantix, is conducting the prospective, randomized, double-blind study comparing neuropsychiatric events in 8,000 smokers, with and without a psychiatric history, treated with varenicline, nicotine replacement therapy, bupropion, or placebo. Although the results are expected in 2015, the company maintained that the boxed warning is no longer justified and can be put in the warnings and precautions section, based on analyses of observational studies and randomized clinical trials. The company submitted those analyses to the FDA earlier this year.

The boxed warning in the drug’s prescribing information states that the serious events reported in patients taking the drug include but “are not limited to” depression, suicidal ideation, suicide attempts, and completed suicides; and that some cases “may have been complicated by the symptoms of nicotine withdrawal in patients who stopped smoking.” The reason the boxed warning is used for this drug is that there is a “serious adverse reaction that can be prevented or reduced in frequency or severity,” the FDA said.

Because the precedent for removing a boxed warning from a drug label is limited and the FDA’s view that the decision should consider the final results of the postmarketing trial, the agency convened the joint meeting to review the analyses submitted by the company. Overall, the panelists were not convinced by the analyses. They cited various weaknesses in the observational studies and the meta-analysis, including questions about whether the correct outcomes were being captured.

Six panelists voted to modify (but not weaken) the language in the boxed warning, and most recommended that the last few lines about the health benefits of quitting smoking be removed and argued that the wording had a promotional tone and did not belong in a boxed warning. Several panelists recommended adding sleep disruption and disorders, and recognized adverse events of the drugs to the boxed warning.

Among those who voted to retain the boxed warning, Dr. Jeanmarie Perrone, director of the medical toxicology division in the emergency medicine department at the University of Pennsylvania, Philadelphia, said there was biologic plausibility for these events. Her biggest concern, she said, was that removing the boxed warning might be interpreted as “an endorsement of safety and that has not been demonstrated.” In the emergency department, she said, she sees many patients who have been prescribed varenicline “by a myriad of clinicians,” and the presence of a boxed warning helps keep this safety issue in mind.

Dr. Rajiv N. Rimal, professor and chair of the department of prevention and community health, George Washington University, Washington, who voted to retain the warning with modified wording, said: “I heard enough compelling evidence to suggest that even some of the more rare events were severe enough” that revisiting the labeling change would be necessary once the other data became available.

Varenicline, approved by the FDA in 2006 as an aid to smoking-cessation treatment, provides a “low level” of dopamine release as people try to quit smoking, according to Pfizer. The boxed warning was added to the label in July 2009, based on the FDA’s review of spontaneous adverse event reports, conducted after an alert about suicidality reports associated with the drug from European regulators about 1 year after FDA approval. About the same time, there was a widely publicized case of a Texas musician who was taking varenicline and was shot and killed by a neighbor while exhibiting uncharacteristic aggressive behavior in the fall of 2007.

The reports provided by the company at that time included 102 suicide-related cases, and 525 reports of aggressive/irrational behavior. A review of the reports in the FDA’s adverse events database included many cases with “hallmarks of drug relatedness,” patients reporting unusual symptoms with “similar distinctive language,” and positive dechallenges and rechallenges, said Dr. Celia Winchell, the medical team leader of addiction products in the FDA’s division of anesthesia, analgesia, and addiction products. Not all cases involved suicidality, depression, or aggression. Postmarketing reports have provided a “rich narrative with detail” about patient experiences, including descriptions that are relatively easy to describe or classify, such as suicide and aggression, while others “defy coding,” such as one person who reported feeling “like a zombie,” she told the panel.

“Based on a review of the cases, there appears to be a syndrome of debilitating symptoms that interfere with people’s ability to function in their daily lives that is associated with the use of Chantix,” Dr. Winchell said.

The company agreed that the spontaneous reports in late 2007 raised concerns about whether the drug was associated with an increase in serious neuropsychiatric events. But since 2009, this issue has been evaluated in controlled studies, which “consistently show no evidence of an increased risk,” Dr. Christopher Wohlberg, the head of Pfizer’s safety surveillance and risk management group, told the panel.

These include a meta-analysis of adverse events in 18 controlled studies of about 5,000 patients treated with varenicline and about 3,500 on placebo, which found no significant difference in the rate of neuropsychiatric events (with the exception of sleep disorders and disturbance) among those on the drug vs. those on placebo; and a meta-analysis of 5 placebo-controlled studies that used the Columbia-Suicide Severity Rating Scale to evaluate suicidal ideation and behavior, which also found no significant differences between the two groups.

In addition, four observational studies that included patients with psychiatric illnesses showed that the rates of serious neuropsychiatric events in patients treated with varenicline were not significantly different from those treated with nicotine replacement therapy or bupropion for smoking cessation. In individual studies of patients with psychiatric illnesses (schizophrenia, schizoaffective disorder, or major depressive disorder), no evidence was found of an increased risk among those treated with varenicline, compared with those on placebo, according to the company.

But the FDA reviewers raised issues with the meta-analysis of the 18 studies and the observational data. The observational data have limitations and “preclude” a conclusion that there is no association of varenicline and an increased risk of neuropsychiatric events, said Natasha Chen, Ph.D., an epidemiologist in the FDA’s office of surveillance and epidemiology. The ongoing postmarketing safety trial “is likely to offer better insights into varenicline’s neuropsychiatric risks,” she added.

The one panelist who voted to remove the warning, Dr. Andrew J. Saxon, said while there “may be some serious adverse or neuropsychiatric effects, the data, while not perfect,” do not show a signal in his view. He added that in his experience working daily with patients who are trying to quit smoking, “patients are afraid to take this medication because of the boxed warning, and it does deter use.” Moreover, in the Veterans Affairs system, there are restrictions on prescribing the drug because of the boxed warning, including a limitation on prescriptions to a 28-day supply, with no refills. Such restrictions increase hassles for patients and prescribers, and often result in patients stopping treatment after 4 weeks.

“If I’m doing a good job as a physician, I’m going to monitor the patient,” said Dr. Saxon, director of the addiction psychiatry residency program, University of Washington, Seattle.

The FDA usually follows the recommendations of its advisory panels, which are not binding. Members of these two panels had no conflicts to disclose. Occasionally, panelists with a conflict are given a waiver, but not at this meeting.

In a statement issued by Pfizer after the meeting, Dr. Steven Romano, senior vice president and head of the medicines development group for Pfizer, said the “completion of our currently ongoing safety study will represent one more step forward in the process of accurately characterizing the neuropsychiatric safety of this important medication.”

The varenicline label is available at http://labeling.pfizer.com/ShowLabeling.aspx?id=557. Serious adverse events associated with this drug should be reported to the FDA’s MedWatch program at http://www.fda.gov/Safety/MedWatch/default.htm.

SILVER SPRING, MD. – The human monoclonal antibody secukinumab is expected to be the first biologic that targets interleukin-17A to be approved by the agency for treating psoriasis, with a Food and Drug Administration advisory panel’s unanimous support for the approval.

At a meeting on Oct. 20, the FDA’s Dermatologic and Ophthalmic Drugs Advisory committee voted 7-0 to recommend approval of secukinumab for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy, the indication proposed by Novartis Pharmaceuticals. Secukinumab “selectively binds and neutralizes” IL-17A, a proinflammatory cytokine “that is involved in normal inflammatory and immune responses and plays a key role in the pathogenesis of plaque psoriasis,” according to the company.

If approved, secukinumab would be the first IL-17A blocker available and would be available in a lyophilized formulation for reconstitution, and in a liquid formulation in a refilled syringe or autoinjector pen. The 300-mg dose was determined to be the best dose to achieve clear or almost clear skin, with a favorable safety profile that was comparable to that of the 150-mg dose, which was also studied in phase II and III studies, according to Novartis. The company has proposed a dose of 300 mg, administered with a subcutaneous injection, at 0, 1, 2, 3, and 4 weeks, followed by 300 mg once a month.

The panel agreed that the 300-mg dose was effective with an acceptable risk-benefit profile, but agreed that it would be useful to have the 150-mg dose, which was also effective in trials, be available as well. The panel also recommended that the 450-mg dose, which was not formally studied, be evaluated further in postmarketing studies, because it could be useful in nonresponders and for heavier patients weighing 90 kg (about 198 pounds) or more, because of evidence that the 300-mg dose was less effective in heavier patients.

Secukinumab has been studied in 10 phase II and III studies of almost 4,000 patients with psoriasis. In the two main phase III studies, the 150-mg and 300-mg doses were compared with placebo (and to a formulation of etanercept not available in the United States in one study); the primary endpoints were the Psoriasis Area and Severity Index (PASI) 75, a 75% improvement of psoriasis from baseline, and an Investigator Global Assessment (IGA) score of 0 or 1 (clear or almost clear skin).

In one study of 738 patients, PASI 75 scores at 12 weeks were achieved by almost 82% and almost 72% of those on the 300-mg and 150-mg doses respectively, vs. 4.5% of those on placebo. In the second study, PASI 75 scores at 12 weeks were achieved by 77% and 67% of those on the 300-mg and 150-mg doses respectively, vs. almost 5% of those on placebo. About 63%-65% of those on the 300-mg dose and about 51% of those on the 150-mg dose had an IGA of 0/1 at 12 weeks, vs. about 2.4%-2.8% of those on placebo. Differences in the responses were sustained at week 52, according to Novartis.

Concentration of the drug decreases as body weight increases, and in studies, weight had a significant effect on efficacy results. The proportion of patients who achieved the PASI 75 and IGA 0/1 endpoints was higher among those weighing under 90 kg than those weighing 90 kg or more at both the 150-mg and 300-mg doses tested.

Pooled data of phase III trial data were used to evaluate safety over 12 and 52 weeks. Serious infections, malignancies and serious cardiovascular events were low; there were no reports of reactivation of latent tuberculosis. No deaths were reported related to treatment. During the first 12 weeks of treatment, there was a higher rate of nonserious upper respiratory infections among the treated patients, and superficial Candida infections were more common among those on the 300-mg dose (1.2%) than among those on the 150-mg dose (0.4%) and placebo (0.3%). The FDA’s analysis of safety concluded that infection rates “tend to increase” as the concentration of secukinumab increases, but that most adverse events associated with greater exposure in patients weighing less than 90 kg were mild to moderate.

The panel agreed with the company’s plan to follow long-term safety in a postmarketing registry of patients with moderate to severe psoriasis, in at least 2,000 patients treated with secukinumab, 2,500 treated with other biologics, and 500 treated with other systemic medications. One panelist also recommended that long-term safety be evaluated in studies using large administrative databases for outcomes including malignancies and autoimmune events.

The FDA is expected to decide on approval by early 2015, according to Novartis, which plans to market secukinumab as Cosentyx if approved. The FDA usually follows the recommendations of its advisory panels. Members of these two panels had no conflicts to disclose; occasionally, panelists with a conflict are given a waiver, but not at this meeting. Secukinumab is not yet approved elsewhere, and is also under review in Europe. Phase III studies in patients with psoriatic arthritis are underway.

SILVER SPRING, MD. – The human monoclonal antibody secukinumab is expected to be the first biologic that targets interleukin-17A to be approved by the agency for treating psoriasis, with a Food and Drug Administration advisory panel’s unanimous support for the approval.

At a meeting on Oct. 20, the FDA’s Dermatologic and Ophthalmic Drugs Advisory committee voted 7-0 to recommend approval of secukinumab for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy, the indication proposed by Novartis Pharmaceuticals. Secukinumab “selectively binds and neutralizes” IL-17A, a proinflammatory cytokine “that is involved in normal inflammatory and immune responses and plays a key role in the pathogenesis of plaque psoriasis,” according to the company.

If approved, secukinumab would be the first IL-17A blocker available and would be available in a lyophilized formulation for reconstitution, and in a liquid formulation in a refilled syringe or autoinjector pen. The 300-mg dose was determined to be the best dose to achieve clear or almost clear skin, with a favorable safety profile that was comparable to that of the 150-mg dose, which was also studied in phase II and III studies, according to Novartis. The company has proposed a dose of 300 mg, administered with a subcutaneous injection, at 0, 1, 2, 3, and 4 weeks, followed by 300 mg once a month.

The panel agreed that the 300-mg dose was effective with an acceptable risk-benefit profile, but agreed that it would be useful to have the 150-mg dose, which was also effective in trials, be available as well. The panel also recommended that the 450-mg dose, which was not formally studied, be evaluated further in postmarketing studies, because it could be useful in nonresponders and for heavier patients weighing 90 kg (about 198 pounds) or more, because of evidence that the 300-mg dose was less effective in heavier patients.

Secukinumab has been studied in 10 phase II and III studies of almost 4,000 patients with psoriasis. In the two main phase III studies, the 150-mg and 300-mg doses were compared with placebo (and to a formulation of etanercept not available in the United States in one study); the primary endpoints were the Psoriasis Area and Severity Index (PASI) 75, a 75% improvement of psoriasis from baseline, and an Investigator Global Assessment (IGA) score of 0 or 1 (clear or almost clear skin).

In one study of 738 patients, PASI 75 scores at 12 weeks were achieved by almost 82% and almost 72% of those on the 300-mg and 150-mg doses respectively, vs. 4.5% of those on placebo. In the second study, PASI 75 scores at 12 weeks were achieved by 77% and 67% of those on the 300-mg and 150-mg doses respectively, vs. almost 5% of those on placebo. About 63%-65% of those on the 300-mg dose and about 51% of those on the 150-mg dose had an IGA of 0/1 at 12 weeks, vs. about 2.4%-2.8% of those on placebo. Differences in the responses were sustained at week 52, according to Novartis.

Concentration of the drug decreases as body weight increases, and in studies, weight had a significant effect on efficacy results. The proportion of patients who achieved the PASI 75 and IGA 0/1 endpoints was higher among those weighing under 90 kg than those weighing 90 kg or more at both the 150-mg and 300-mg doses tested.

Pooled data of phase III trial data were used to evaluate safety over 12 and 52 weeks. Serious infections, malignancies and serious cardiovascular events were low; there were no reports of reactivation of latent tuberculosis. No deaths were reported related to treatment. During the first 12 weeks of treatment, there was a higher rate of nonserious upper respiratory infections among the treated patients, and superficial Candida infections were more common among those on the 300-mg dose (1.2%) than among those on the 150-mg dose (0.4%) and placebo (0.3%). The FDA’s analysis of safety concluded that infection rates “tend to increase” as the concentration of secukinumab increases, but that most adverse events associated with greater exposure in patients weighing less than 90 kg were mild to moderate.

The panel agreed with the company’s plan to follow long-term safety in a postmarketing registry of patients with moderate to severe psoriasis, in at least 2,000 patients treated with secukinumab, 2,500 treated with other biologics, and 500 treated with other systemic medications. One panelist also recommended that long-term safety be evaluated in studies using large administrative databases for outcomes including malignancies and autoimmune events.

The FDA is expected to decide on approval by early 2015, according to Novartis, which plans to market secukinumab as Cosentyx if approved. The FDA usually follows the recommendations of its advisory panels. Members of these two panels had no conflicts to disclose; occasionally, panelists with a conflict are given a waiver, but not at this meeting. Secukinumab is not yet approved elsewhere, and is also under review in Europe. Phase III studies in patients with psoriatic arthritis are underway.

SILVER SPRING, MD. – The human monoclonal antibody secukinumab is expected to be the first biologic that targets interleukin-17A to be approved by the agency for treating psoriasis, with a Food and Drug Administration advisory panel’s unanimous support for the approval.

At a meeting on Oct. 20, the FDA’s Dermatologic and Ophthalmic Drugs Advisory committee voted 7-0 to recommend approval of secukinumab for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy, the indication proposed by Novartis Pharmaceuticals. Secukinumab “selectively binds and neutralizes” IL-17A, a proinflammatory cytokine “that is involved in normal inflammatory and immune responses and plays a key role in the pathogenesis of plaque psoriasis,” according to the company.

If approved, secukinumab would be the first IL-17A blocker available and would be available in a lyophilized formulation for reconstitution, and in a liquid formulation in a refilled syringe or autoinjector pen. The 300-mg dose was determined to be the best dose to achieve clear or almost clear skin, with a favorable safety profile that was comparable to that of the 150-mg dose, which was also studied in phase II and III studies, according to Novartis. The company has proposed a dose of 300 mg, administered with a subcutaneous injection, at 0, 1, 2, 3, and 4 weeks, followed by 300 mg once a month.

The panel agreed that the 300-mg dose was effective with an acceptable risk-benefit profile, but agreed that it would be useful to have the 150-mg dose, which was also effective in trials, be available as well. The panel also recommended that the 450-mg dose, which was not formally studied, be evaluated further in postmarketing studies, because it could be useful in nonresponders and for heavier patients weighing 90 kg (about 198 pounds) or more, because of evidence that the 300-mg dose was less effective in heavier patients.

Secukinumab has been studied in 10 phase II and III studies of almost 4,000 patients with psoriasis. In the two main phase III studies, the 150-mg and 300-mg doses were compared with placebo (and to a formulation of etanercept not available in the United States in one study); the primary endpoints were the Psoriasis Area and Severity Index (PASI) 75, a 75% improvement of psoriasis from baseline, and an Investigator Global Assessment (IGA) score of 0 or 1 (clear or almost clear skin).

In one study of 738 patients, PASI 75 scores at 12 weeks were achieved by almost 82% and almost 72% of those on the 300-mg and 150-mg doses respectively, vs. 4.5% of those on placebo. In the second study, PASI 75 scores at 12 weeks were achieved by 77% and 67% of those on the 300-mg and 150-mg doses respectively, vs. almost 5% of those on placebo. About 63%-65% of those on the 300-mg dose and about 51% of those on the 150-mg dose had an IGA of 0/1 at 12 weeks, vs. about 2.4%-2.8% of those on placebo. Differences in the responses were sustained at week 52, according to Novartis.

Concentration of the drug decreases as body weight increases, and in studies, weight had a significant effect on efficacy results. The proportion of patients who achieved the PASI 75 and IGA 0/1 endpoints was higher among those weighing under 90 kg than those weighing 90 kg or more at both the 150-mg and 300-mg doses tested.

Pooled data of phase III trial data were used to evaluate safety over 12 and 52 weeks. Serious infections, malignancies and serious cardiovascular events were low; there were no reports of reactivation of latent tuberculosis. No deaths were reported related to treatment. During the first 12 weeks of treatment, there was a higher rate of nonserious upper respiratory infections among the treated patients, and superficial Candida infections were more common among those on the 300-mg dose (1.2%) than among those on the 150-mg dose (0.4%) and placebo (0.3%). The FDA’s analysis of safety concluded that infection rates “tend to increase” as the concentration of secukinumab increases, but that most adverse events associated with greater exposure in patients weighing less than 90 kg were mild to moderate.

The panel agreed with the company’s plan to follow long-term safety in a postmarketing registry of patients with moderate to severe psoriasis, in at least 2,000 patients treated with secukinumab, 2,500 treated with other biologics, and 500 treated with other systemic medications. One panelist also recommended that long-term safety be evaluated in studies using large administrative databases for outcomes including malignancies and autoimmune events.

The FDA is expected to decide on approval by early 2015, according to Novartis, which plans to market secukinumab as Cosentyx if approved. The FDA usually follows the recommendations of its advisory panels. Members of these two panels had no conflicts to disclose; occasionally, panelists with a conflict are given a waiver, but not at this meeting. Secukinumab is not yet approved elsewhere, and is also under review in Europe. Phase III studies in patients with psoriatic arthritis are underway.

SILVER SPRING, MD. – The human monoclonal antibody secukinumab is expected to be the first biologic that targets interleukin-17A to be approved by the agency for treating psoriasis, with a Food and Drug Administration advisory panel’s unanimous support for the approval.

At a meeting on Oct. 20, the FDA’s Dermatologic and Ophthalmic Drugs Advisory committee voted 7-0 to recommend approval of secukinumab for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy, the indication proposed by Novartis Pharmaceuticals. Secukinumab “selectively binds and neutralizes” IL-17A, a proinflammatory cytokine “that is involved in normal inflammatory and immune responses and plays a key role in the pathogenesis of plaque psoriasis,” according to the company.

If approved, secukinumab would be the first IL-17A blocker available and would be available in a lyophilized formulation for reconstitution, and in a liquid formulation in a refilled syringe or autoinjector pen. The 300-mg dose was determined to be the best dose to achieve clear or almost clear skin, with a favorable safety profile that was comparable to that of the 150-mg dose, which was also studied in phase II and III studies, according to Novartis. The company has proposed a dose of 300 mg, administered with a subcutaneous injection, at 0, 1, 2, 3, and 4 weeks, followed by 300 mg once a month.

The panel agreed that the 300-mg dose was effective with an acceptable risk-benefit profile, but agreed that it would be useful to have the 150-mg dose, which was also effective in trials, be available as well. The panel also recommended that the 450-mg dose, which was not formally studied, be evaluated further in postmarketing studies, because it could be useful in nonresponders and for heavier patients weighing 90 kg (about 198 pounds) or more, because of evidence that the 300-mg dose was less effective in heavier patients.

Secukinumab has been studied in 10 phase II and III studies of almost 4,000 patients with psoriasis. In the two main phase III studies, the 150-mg and 300-mg doses were compared with placebo (and to a formulation of etanercept not available in the United States in one study); the primary endpoints were the Psoriasis Area and Severity Index (PASI) 75, a 75% improvement of psoriasis from baseline, and an Investigator Global Assessment (IGA) score of 0 or 1 (clear or almost clear skin).

In one study of 738 patients, PASI 75 scores at 12 weeks were achieved by almost 82% and almost 72% of those on the 300-mg and 150-mg doses respectively, vs. 4.5% of those on placebo. In the second study, PASI 75 scores at 12 weeks were achieved by 77% and 67% of those on the 300-mg and 150-mg doses respectively, vs. almost 5% of those on placebo. About 63%-65% of those on the 300-mg dose and about 51% of those on the 150-mg dose had an IGA of 0/1 at 12 weeks, vs. about 2.4%-2.8% of those on placebo. Differences in the responses were sustained at week 52, according to Novartis.

Concentration of the drug decreases as body weight increases, and in studies, weight had a significant effect on efficacy results. The proportion of patients who achieved the PASI 75 and IGA 0/1 endpoints was higher among those weighing under 90 kg than those weighing 90 kg or more at both the 150-mg and 300-mg doses tested.

Pooled data of phase III trial data were used to evaluate safety over 12 and 52 weeks. Serious infections, malignancies and serious cardiovascular events were low; there were no reports of reactivation of latent tuberculosis. No deaths were reported related to treatment. During the first 12 weeks of treatment, there was a higher rate of nonserious upper respiratory infections among the treated patients, and superficial Candida infections were more common among those on the 300-mg dose (1.2%) than among those on the 150-mg dose (0.4%) and placebo (0.3%). The FDA’s analysis of safety concluded that infection rates “tend to increase” as the concentration of secukinumab increases, but that most adverse events associated with greater exposure in patients weighing less than 90 kg were mild to moderate.

The panel agreed with the company’s plan to follow long-term safety in a postmarketing registry of patients with moderate to severe psoriasis, in at least 2,000 patients treated with secukinumab, 2,500 treated with other biologics, and 500 treated with other systemic medications. One panelist also recommended that long-term safety be evaluated in studies using large administrative databases for outcomes including malignancies and autoimmune events.

The FDA is expected to decide on approval by early 2015, according to Novartis, which plans to market secukinumab as Cosentyx if approved. The FDA usually follows the recommendations of its advisory panels. Members of these two panels had no conflicts to disclose; occasionally, panelists with a conflict are given a waiver, but not at this meeting. Secukinumab is not yet approved elsewhere, and is also under review in Europe. Phase III studies in patients with psoriatic arthritis are underway.

[email protected]

SILVER SPRING, MD. – The human monoclonal antibody secukinumab is expected to be the first biologic that targets interleukin-17A to be approved by the agency for treating psoriasis, with a Food and Drug Administration advisory panel’s unanimous support for the approval.

At a meeting on Oct. 20, the FDA’s Dermatologic and Ophthalmic Drugs Advisory committee voted 7-0 to recommend approval of secukinumab for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy, the indication proposed by Novartis Pharmaceuticals. Secukinumab “selectively binds and neutralizes” IL-17A, a proinflammatory cytokine “that is involved in normal inflammatory and immune responses and plays a key role in the pathogenesis of plaque psoriasis,” according to the company.

If approved, secukinumab would be the first IL-17A blocker available and would be available in a lyophilized formulation for reconstitution, and in a liquid formulation in a refilled syringe or autoinjector pen. The 300-mg dose was determined to be the best dose to achieve clear or almost clear skin, with a favorable safety profile that was comparable to that of the 150-mg dose, which was also studied in phase II and III studies, according to Novartis. The company has proposed a dose of 300 mg, administered with a subcutaneous injection, at 0, 1, 2, 3, and 4 weeks, followed by 300 mg once a month.

The panel agreed that the 300-mg dose was effective with an acceptable risk-benefit profile, but agreed that it would be useful to have the 150-mg dose, which was also effective in trials, be available as well. The panel also recommended that the 450-mg dose, which was not formally studied, be evaluated further in postmarketing studies, because it could be useful in nonresponders and for heavier patients weighing 90 kg (about 198 pounds) or more, because of evidence that the 300-mg dose was less effective in heavier patients.

Secukinumab has been studied in 10 phase II and III studies of almost 4,000 patients with psoriasis. In the two main phase III studies, the 150-mg and 300-mg doses were compared with placebo (and to a formulation of etanercept not available in the United States in one study); the primary endpoints were the Psoriasis Area and Severity Index (PASI) 75, a 75% improvement of psoriasis from baseline, and an Investigator Global Assessment (IGA) score of 0 or 1 (clear or almost clear skin).

In one study of 738 patients, PASI 75 scores at 12 weeks were achieved by almost 82% and almost 72% of those on the 300-mg and 150-mg doses respectively, vs. 4.5% of those on placebo. In the second study, PASI 75 scores at 12 weeks were achieved by 77% and 67% of those on the 300-mg and 150-mg doses respectively, vs. almost 5% of those on placebo. About 63%-65% of those on the 300-mg dose and about 51% of those on the 150-mg dose had an IGA of 0/1 at 12 weeks, vs. about 2.4%-2.8% of those on placebo. Differences in the responses were sustained at week 52, according to Novartis.

Concentration of the drug decreases as body weight increases, and in studies, weight had a significant effect on efficacy results. The proportion of patients who achieved the PASI 75 and IGA 0/1 endpoints was higher among those weighing under 90 kg than those weighing 90 kg or more at both the 150-mg and 300-mg doses tested.

Pooled data of phase III trial data were used to evaluate safety over 12 and 52 weeks. Serious infections, malignancies and serious cardiovascular events were low; there were no reports of reactivation of latent tuberculosis. No deaths were reported related to treatment. During the first 12 weeks of treatment, there was a higher rate of nonserious upper respiratory infections among the treated patients, and superficial Candida infections were more common among those on the 300-mg dose (1.2%) than among those on the 150-mg dose (0.4%) and placebo (0.3%). The FDA’s analysis of safety concluded that infection rates “tend to increase” as the concentration of secukinumab increases, but that most adverse events associated with greater exposure in patients weighing less than 90 kg were mild to moderate.

The panel agreed with the company’s plan to follow long-term safety in a postmarketing registry of patients with moderate to severe psoriasis, in at least 2,000 patients treated with secukinumab, 2,500 treated with other biologics, and 500 treated with other systemic medications. One panelist also recommended that long-term safety be evaluated in studies using large administrative databases for outcomes including malignancies and autoimmune events.

The FDA is expected to decide on approval by early 2015, according to Novartis, which plans to market secukinumab as Cosentyx if approved. The FDA usually follows the recommendations of its advisory panels. Members of these two panels had no conflicts to disclose; occasionally, panelists with a conflict are given a waiver, but not at this meeting. Secukinumab is not yet approved elsewhere, and is also under review in Europe. Phase III studies in patients with psoriatic arthritis are underway.

[email protected]

SILVER SPRING, MD. – The human monoclonal antibody secukinumab is expected to be the first biologic that targets interleukin-17A to be approved by the agency for treating psoriasis, with a Food and Drug Administration advisory panel’s unanimous support for the approval.

At a meeting on Oct. 20, the FDA’s Dermatologic and Ophthalmic Drugs Advisory committee voted 7-0 to recommend approval of secukinumab for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy, the indication proposed by Novartis Pharmaceuticals. Secukinumab “selectively binds and neutralizes” IL-17A, a proinflammatory cytokine “that is involved in normal inflammatory and immune responses and plays a key role in the pathogenesis of plaque psoriasis,” according to the company.

If approved, secukinumab would be the first IL-17A blocker available and would be available in a lyophilized formulation for reconstitution, and in a liquid formulation in a refilled syringe or autoinjector pen. The 300-mg dose was determined to be the best dose to achieve clear or almost clear skin, with a favorable safety profile that was comparable to that of the 150-mg dose, which was also studied in phase II and III studies, according to Novartis. The company has proposed a dose of 300 mg, administered with a subcutaneous injection, at 0, 1, 2, 3, and 4 weeks, followed by 300 mg once a month.

The panel agreed that the 300-mg dose was effective with an acceptable risk-benefit profile, but agreed that it would be useful to have the 150-mg dose, which was also effective in trials, be available as well. The panel also recommended that the 450-mg dose, which was not formally studied, be evaluated further in postmarketing studies, because it could be useful in nonresponders and for heavier patients weighing 90 kg (about 198 pounds) or more, because of evidence that the 300-mg dose was less effective in heavier patients.

Secukinumab has been studied in 10 phase II and III studies of almost 4,000 patients with psoriasis. In the two main phase III studies, the 150-mg and 300-mg doses were compared with placebo (and to a formulation of etanercept not available in the United States in one study); the primary endpoints were the Psoriasis Area and Severity Index (PASI) 75, a 75% improvement of psoriasis from baseline, and an Investigator Global Assessment (IGA) score of 0 or 1 (clear or almost clear skin).

In one study of 738 patients, PASI 75 scores at 12 weeks were achieved by almost 82% and almost 72% of those on the 300-mg and 150-mg doses respectively, vs. 4.5% of those on placebo. In the second study, PASI 75 scores at 12 weeks were achieved by 77% and 67% of those on the 300-mg and 150-mg doses respectively, vs. almost 5% of those on placebo. About 63%-65% of those on the 300-mg dose and about 51% of those on the 150-mg dose had an IGA of 0/1 at 12 weeks, vs. about 2.4%-2.8% of those on placebo. Differences in the responses were sustained at week 52, according to Novartis.

Concentration of the drug decreases as body weight increases, and in studies, weight had a significant effect on efficacy results. The proportion of patients who achieved the PASI 75 and IGA 0/1 endpoints was higher among those weighing under 90 kg than those weighing 90 kg or more at both the 150-mg and 300-mg doses tested.

Pooled data of phase III trial data were used to evaluate safety over 12 and 52 weeks. Serious infections, malignancies and serious cardiovascular events were low; there were no reports of reactivation of latent tuberculosis. No deaths were reported related to treatment. During the first 12 weeks of treatment, there was a higher rate of nonserious upper respiratory infections among the treated patients, and superficial Candida infections were more common among those on the 300-mg dose (1.2%) than among those on the 150-mg dose (0.4%) and placebo (0.3%). The FDA’s analysis of safety concluded that infection rates “tend to increase” as the concentration of secukinumab increases, but that most adverse events associated with greater exposure in patients weighing less than 90 kg were mild to moderate.

The panel agreed with the company’s plan to follow long-term safety in a postmarketing registry of patients with moderate to severe psoriasis, in at least 2,000 patients treated with secukinumab, 2,500 treated with other biologics, and 500 treated with other systemic medications. One panelist also recommended that long-term safety be evaluated in studies using large administrative databases for outcomes including malignancies and autoimmune events.

The FDA is expected to decide on approval by early 2015, according to Novartis, which plans to market secukinumab as Cosentyx if approved. The FDA usually follows the recommendations of its advisory panels. Members of these two panels had no conflicts to disclose; occasionally, panelists with a conflict are given a waiver, but not at this meeting. Secukinumab is not yet approved elsewhere, and is also under review in Europe. Phase III studies in patients with psoriatic arthritis are underway.

[email protected]