NEW ORLEANS – Treatment options for patients with type 2 diabetes mellitus have increased markedly post metformin therapy, results from a long-term study suggests. However, the proportion of patients who have maintained a hemoglobin A_1c level of less than 7% has remained steady since 2008.

“It would seem that further research and guidance for personalized treatment pathways is needed to help patients achieve optimal diabetes control,” lead study author Victoria Higgins said at the annual scientific sessions of the American Diabetes Association.

Ms. Higgins, franchise director at Adelphi Real World, Cheshire, United Kingdom, presented data from the Adelphi Real World Diabetes Disease Specific Program, a cross-sectional, observational study of patients with type 2 diabetes in France, Germany, Italy, Spain, the United Kingdom, and the United States. Patients were older than 18 years of age with a confirmed diagnosis of type 2 diabetes and were prescribed at least one antidiabetic drug and/or insulin. Data were collected from the second quarter of 2000 to the second quarter of 2015, gleaned from face-to-face interviews with 3,555 diabetes specialists and 5,109 primary care physicians (PCPs) and completion of physician-reported forms from consultations with patients with type 2 diabetes. Ms. Higgins reported data from 70,657 patients. Of these, 38,489 consulted with a PCP, while 32,168 consulted with a diabetes specialist.

The researchers found that between 2000 and 2015, the number of PCPs who indicated that they would introduce insulin at an HbA_1c level less than 8% fell from 24% to 7%, while among diabetes specialists, it fell from 34% to 7%. In addition, a similar proportion of respondents said they would introduce insulin at an HbA_1c of 9% or higher in 2015 (42% of PCPs and 39% of diabetes specialists), than in 2004 (36% of PCPs and 24% of diabetes specialists). The introduction of new therapies – such as DPP-4, and more recently GLP-1 and SGLT2 agents – affected treatment patterns over the time period studied. “The main treatment is noninsulin only, but among specialists, a higher prevalence of patients are on noninsulin plus insulin, as well as insulin only,” Ms. Higgins said. “Also interesting to see is there are still some type 2 diabetics who are still on diet and exercise only.” (In 2015, the proportion on a diet and exercise only–regimen was 10% of patients who consulted with primary care physicians and 6% of patients who consulted with diabetes specialists.)

Between 2000 and 2015, the mean number of drugs per patient rose from 1.4 to 1.7 among those who consulted with PCPs, while the mean number of drugs per patient rose from 1.6 to 2.1 among those who consulted with diabetes specialists. A metformin-only regimen is used more often by PCPs than by diabetes specialists, moving toward a higher polypharmacy among the specialists.

Ms. Higgins and her colleagues also found that while there were improvements in HbA_1c levels between 2000 and 2008, there has not been any substantial improvement in HbA_1c since that time. In 2008, 48% of patients who consulted with PCPs achieved an HbA_1c level of less than 7%, compared with 39% of those who consulted with diabetes care specialists. In 2015, those percentages were 50% and 36%, respectively.* Ms. Higgins reported having no financial disclosures.

dbrunk@frontlinemedcom.com

*CORRECTION 11/7/16: An earlier version of this article misstated the percentage of patients who consulted with PCPs and achieved an HbA_1c level of less than 7%.

NEW ORLEANS – Treatment options for patients with type 2 diabetes mellitus have increased markedly post metformin therapy, results from a long-term study suggests. However, the proportion of patients who have maintained a hemoglobin A_1c level of less than 7% has remained steady since 2008.

“It would seem that further research and guidance for personalized treatment pathways is needed to help patients achieve optimal diabetes control,” lead study author Victoria Higgins said at the annual scientific sessions of the American Diabetes Association.

Ms. Higgins, franchise director at Adelphi Real World, Cheshire, United Kingdom, presented data from the Adelphi Real World Diabetes Disease Specific Program, a cross-sectional, observational study of patients with type 2 diabetes in France, Germany, Italy, Spain, the United Kingdom, and the United States. Patients were older than 18 years of age with a confirmed diagnosis of type 2 diabetes and were prescribed at least one antidiabetic drug and/or insulin. Data were collected from the second quarter of 2000 to the second quarter of 2015, gleaned from face-to-face interviews with 3,555 diabetes specialists and 5,109 primary care physicians (PCPs) and completion of physician-reported forms from consultations with patients with type 2 diabetes. Ms. Higgins reported data from 70,657 patients. Of these, 38,489 consulted with a PCP, while 32,168 consulted with a diabetes specialist.

The researchers found that between 2000 and 2015, the number of PCPs who indicated that they would introduce insulin at an HbA_1c level less than 8% fell from 24% to 7%, while among diabetes specialists, it fell from 34% to 7%. In addition, a similar proportion of respondents said they would introduce insulin at an HbA_1c of 9% or higher in 2015 (42% of PCPs and 39% of diabetes specialists), than in 2004 (36% of PCPs and 24% of diabetes specialists). The introduction of new therapies – such as DPP-4, and more recently GLP-1 and SGLT2 agents – affected treatment patterns over the time period studied. “The main treatment is noninsulin only, but among specialists, a higher prevalence of patients are on noninsulin plus insulin, as well as insulin only,” Ms. Higgins said. “Also interesting to see is there are still some type 2 diabetics who are still on diet and exercise only.” (In 2015, the proportion on a diet and exercise only–regimen was 10% of patients who consulted with primary care physicians and 6% of patients who consulted with diabetes specialists.)

Between 2000 and 2015, the mean number of drugs per patient rose from 1.4 to 1.7 among those who consulted with PCPs, while the mean number of drugs per patient rose from 1.6 to 2.1 among those who consulted with diabetes specialists. A metformin-only regimen is used more often by PCPs than by diabetes specialists, moving toward a higher polypharmacy among the specialists.

Ms. Higgins and her colleagues also found that while there were improvements in HbA_1c levels between 2000 and 2008, there has not been any substantial improvement in HbA_1c since that time. In 2008, 48% of patients who consulted with PCPs achieved an HbA_1c level of less than 7%, compared with 39% of those who consulted with diabetes care specialists. In 2015, those percentages were 50% and 36%, respectively.* Ms. Higgins reported having no financial disclosures.

dbrunk@frontlinemedcom.com

*CORRECTION 11/7/16: An earlier version of this article misstated the percentage of patients who consulted with PCPs and achieved an HbA_1c level of less than 7%.

NEW ORLEANS – Treatment options for patients with type 2 diabetes mellitus have increased markedly post metformin therapy, results from a long-term study suggests. However, the proportion of patients who have maintained a hemoglobin A_1c level of less than 7% has remained steady since 2008.

“It would seem that further research and guidance for personalized treatment pathways is needed to help patients achieve optimal diabetes control,” lead study author Victoria Higgins said at the annual scientific sessions of the American Diabetes Association.

Ms. Higgins, franchise director at Adelphi Real World, Cheshire, United Kingdom, presented data from the Adelphi Real World Diabetes Disease Specific Program, a cross-sectional, observational study of patients with type 2 diabetes in France, Germany, Italy, Spain, the United Kingdom, and the United States. Patients were older than 18 years of age with a confirmed diagnosis of type 2 diabetes and were prescribed at least one antidiabetic drug and/or insulin. Data were collected from the second quarter of 2000 to the second quarter of 2015, gleaned from face-to-face interviews with 3,555 diabetes specialists and 5,109 primary care physicians (PCPs) and completion of physician-reported forms from consultations with patients with type 2 diabetes. Ms. Higgins reported data from 70,657 patients. Of these, 38,489 consulted with a PCP, while 32,168 consulted with a diabetes specialist.

The researchers found that between 2000 and 2015, the number of PCPs who indicated that they would introduce insulin at an HbA_1c level less than 8% fell from 24% to 7%, while among diabetes specialists, it fell from 34% to 7%. In addition, a similar proportion of respondents said they would introduce insulin at an HbA_1c of 9% or higher in 2015 (42% of PCPs and 39% of diabetes specialists), than in 2004 (36% of PCPs and 24% of diabetes specialists). The introduction of new therapies – such as DPP-4, and more recently GLP-1 and SGLT2 agents – affected treatment patterns over the time period studied. “The main treatment is noninsulin only, but among specialists, a higher prevalence of patients are on noninsulin plus insulin, as well as insulin only,” Ms. Higgins said. “Also interesting to see is there are still some type 2 diabetics who are still on diet and exercise only.” (In 2015, the proportion on a diet and exercise only–regimen was 10% of patients who consulted with primary care physicians and 6% of patients who consulted with diabetes specialists.)

Between 2000 and 2015, the mean number of drugs per patient rose from 1.4 to 1.7 among those who consulted with PCPs, while the mean number of drugs per patient rose from 1.6 to 2.1 among those who consulted with diabetes specialists. A metformin-only regimen is used more often by PCPs than by diabetes specialists, moving toward a higher polypharmacy among the specialists.

Ms. Higgins and her colleagues also found that while there were improvements in HbA_1c levels between 2000 and 2008, there has not been any substantial improvement in HbA_1c since that time. In 2008, 48% of patients who consulted with PCPs achieved an HbA_1c level of less than 7%, compared with 39% of those who consulted with diabetes care specialists. In 2015, those percentages were 50% and 36%, respectively.* Ms. Higgins reported having no financial disclosures.

dbrunk@frontlinemedcom.com

*CORRECTION 11/7/16: An earlier version of this article misstated the percentage of patients who consulted with PCPs and achieved an HbA_1c level of less than 7%.

A recent publication by Chuang et al. carefully characterizes the content of smoke (or plume) created from laser hair removal.¹ At the University of California, Los Angeles, discarded terminal hairs from the trunk and extremities were collected from two adult volunteers. The hair samples were sealed in glass gas chromatography chambers and treated with either an 810-nm diode laser (Lightsheer, Lumenis) or 755-nm alexandrite laser (Gentlelase, Candela). During laser hair removal (LHR) treatment, two 6-L negative-pressure canisters were used to capture 30 seconds of laser plume, and a portable condensation particle counter was used to measure ultrafine particulates (less than 1 mcm). Ultrafine particle concentrations were measured within the treatment room, within the waiting room, and outside the building. The laser plume was then analyzed by gas chromatography–mass spectrometry (GC-MS) at the Boston University department of chemistry.

Analysis with GC-MS identified 377 chemical compounds. Sixty-two of the compounds exhibited strong absorption peaks, of which 13 are known or suspected carcinogens (including benzene, ethylbenzene, benzeneacetonitrile, acetonitrile, quinoline, isoquinoline, sterene, diethyl phthalate, 2-methylpyridine, naphthalene carbonitrile, and propene) and more than 20 are known environmental toxins causing acute toxic effects on exposure (including carbon monoxide, p-xylene, phenol, toluene, benzaldehyde, benzenedicarboxylic acid [phthalic acid], and long-chain and cyclic hydrocarbons).

During LHR, the portable condensation particle counters documented an eightfold increase, compared with the ambient room baseline level of ultrafine particle concentrations (ambient room baseline, 15,300 particles per cubic centimeter [ppc]; LHR with smoke evacuator, 129,376 ppc), even when a smoke evacuator was in close proximity (5.0 cm) to the procedure site. When the smoke evacuator was turned off for 30 seconds, there was a more than 26-fold increase in particulate count, compared with ambient baseline levels (ambient baseline, 15,300 ppc; LHR without smoke evacuator for 30 seconds, 435,888 ppc).

It has long been known that smoke created from electrocautery also may impose a risk on the health care worker. In 2011, Lewin et al. published a comprehensive review of the risk that surgical smoke and laser imposes on the dermatologist.² At this time, most of the laser data was for the plume created by ablative CO₂ lasers. In their review, it was stated that surgical smoke is composed of 95% water and 5% particulate matter (made up of chemicals, blood and tissue particles, viruses, and bacteria). The size of the particulate matter is dictated by the device used, with electrosurgical units creating particles of roughly 0.07 mcm and lasers liberating particles of 0.31 mcm. The size of liberated particles is important as those smaller than 100 mcm in diameter remain airborne, and particles less than 2 mcm are deposited in the bronchioles and alveoli.

Electrocautery plume is composed mostly of hydrocarbons, phenols, nitriles, and fatty acids, but most notably carbon monoxide, acrylonitrile, hydrogen cyanide, and benzene, which may have carcinogenic potential. On the mucosa of the canine tongue, the mutagenic effect of the smoke from 1 g of cauterized tissue with laser and electrocautery was equivalent to those from three or six cigarettes, respectively. Pulmonary changes also may occur. Blood vessel hypertrophy, alveolar congestion, and emphysematous changes were seen in rats after plume created from both electrocautery and Nd:Yag ablation of porcine skin. In that study, pulmonary changes were less severe in rats exposed to surgical smoke collected with single- and double-filtered smoke evacuators than unfiltered smoke.

Infection also poses a risk, with bovine papillomavirus and HPV detected in CO₂ laser plume as early as 1988. In 1995, Gloster and Roenigk at the Mayo Clinic conducted a comparative study using questionnaires sent to members of the American Society for Laser Surgeons and the American Society of Dermatologic Surgery.³ The comparison groups were CO₂ laser surgeons and two large groups of patients in the community with a diagnosis of warts. Analysis revealed that CO₂ laser surgeons had a statistically significant greater risk of acquiring nasopharyngeal warts but were less likely to acquire plantar, genital, and perianal warts than the Mayo Clinic patient group did, demonstrating that laser plume is a likely means by which HPV can be transmitted to the upper airway, suggesting that those using lasers to treat HPV lesions are at greater risk. Staphylococcus, Corynebacterium, and Neisseria also have been detected during laser resurfacing.

Traditional surgical masks are able to capture particles greater than 5 mcm but offer no protection against particulate matter produced by electrosurgical and laser devices liberating byproducts less than 1 mcm. Laser masks or high-filtration masks provide greater protection than do standard surgical masks and are able to filter particles to 1.1 mcm; however, it has been shown that approximately 77% of particulate matter in surgical smoke is 1.1 mcm and smaller. Smoke evacuators consist of a suction unit (vacuum pump), filter, hose, and inlet nozzle. The smoke evacuator should have a capture velocity of approximately 30-45 m/min at the inlet nozzle. As the effectiveness of the smoke evacuator decreases with farther distance away from the procedure site, the current study of laser plume from LHR recommends that the smoke evacuator be placed within 5 cm of plume generation.⁴ In a study of warts treated with CO₂ laser or electrocoagulation, smoke evacuators are 98.6% effective when placed 1 cm from the treatment site, with efficacy decreasing to 50% when moved to 2 cm from the treatment site.

As our specialty likely conducts the highest proportion of laser and electrosurgical procedures of any specialty, current recommendations for electrocautery, laser resurfacing, and LHR should include adequate air filtration and the use of high-filtration masks and smoke evacuators by the health care practitioner.

References

1. JAMA Dermatol. 2016 Jul 6. doi: 10.1001/jamadermatol.2016.2097. [Epub ahead of print]

2. J Am Acad Dermatol. 2011 Sep;65(3):636-41.

3. J Am Acad Dermatol. 1995 Mar;32(3):436-41.

4. J Am Acad Dermatol. 1989 Jul;21(1):41-9.

Dr. Wesley and Dr. Talakoub are co-contributors to this column. Dr. Talakoub is in private practice in McLean, Va. Dr. Wesley practices dermatology in Beverly Hills, Calif. This month’s column is by Dr. Wesley. Write to them at dermnews@frontlinemedcom.com.

A recent publication by Chuang et al. carefully characterizes the content of smoke (or plume) created from laser hair removal.¹ At the University of California, Los Angeles, discarded terminal hairs from the trunk and extremities were collected from two adult volunteers. The hair samples were sealed in glass gas chromatography chambers and treated with either an 810-nm diode laser (Lightsheer, Lumenis) or 755-nm alexandrite laser (Gentlelase, Candela). During laser hair removal (LHR) treatment, two 6-L negative-pressure canisters were used to capture 30 seconds of laser plume, and a portable condensation particle counter was used to measure ultrafine particulates (less than 1 mcm). Ultrafine particle concentrations were measured within the treatment room, within the waiting room, and outside the building. The laser plume was then analyzed by gas chromatography–mass spectrometry (GC-MS) at the Boston University department of chemistry.

Analysis with GC-MS identified 377 chemical compounds. Sixty-two of the compounds exhibited strong absorption peaks, of which 13 are known or suspected carcinogens (including benzene, ethylbenzene, benzeneacetonitrile, acetonitrile, quinoline, isoquinoline, sterene, diethyl phthalate, 2-methylpyridine, naphthalene carbonitrile, and propene) and more than 20 are known environmental toxins causing acute toxic effects on exposure (including carbon monoxide, p-xylene, phenol, toluene, benzaldehyde, benzenedicarboxylic acid [phthalic acid], and long-chain and cyclic hydrocarbons).

During LHR, the portable condensation particle counters documented an eightfold increase, compared with the ambient room baseline level of ultrafine particle concentrations (ambient room baseline, 15,300 particles per cubic centimeter [ppc]; LHR with smoke evacuator, 129,376 ppc), even when a smoke evacuator was in close proximity (5.0 cm) to the procedure site. When the smoke evacuator was turned off for 30 seconds, there was a more than 26-fold increase in particulate count, compared with ambient baseline levels (ambient baseline, 15,300 ppc; LHR without smoke evacuator for 30 seconds, 435,888 ppc).

It has long been known that smoke created from electrocautery also may impose a risk on the health care worker. In 2011, Lewin et al. published a comprehensive review of the risk that surgical smoke and laser imposes on the dermatologist.² At this time, most of the laser data was for the plume created by ablative CO₂ lasers. In their review, it was stated that surgical smoke is composed of 95% water and 5% particulate matter (made up of chemicals, blood and tissue particles, viruses, and bacteria). The size of the particulate matter is dictated by the device used, with electrosurgical units creating particles of roughly 0.07 mcm and lasers liberating particles of 0.31 mcm. The size of liberated particles is important as those smaller than 100 mcm in diameter remain airborne, and particles less than 2 mcm are deposited in the bronchioles and alveoli.

Electrocautery plume is composed mostly of hydrocarbons, phenols, nitriles, and fatty acids, but most notably carbon monoxide, acrylonitrile, hydrogen cyanide, and benzene, which may have carcinogenic potential. On the mucosa of the canine tongue, the mutagenic effect of the smoke from 1 g of cauterized tissue with laser and electrocautery was equivalent to those from three or six cigarettes, respectively. Pulmonary changes also may occur. Blood vessel hypertrophy, alveolar congestion, and emphysematous changes were seen in rats after plume created from both electrocautery and Nd:Yag ablation of porcine skin. In that study, pulmonary changes were less severe in rats exposed to surgical smoke collected with single- and double-filtered smoke evacuators than unfiltered smoke.

Infection also poses a risk, with bovine papillomavirus and HPV detected in CO₂ laser plume as early as 1988. In 1995, Gloster and Roenigk at the Mayo Clinic conducted a comparative study using questionnaires sent to members of the American Society for Laser Surgeons and the American Society of Dermatologic Surgery.³ The comparison groups were CO₂ laser surgeons and two large groups of patients in the community with a diagnosis of warts. Analysis revealed that CO₂ laser surgeons had a statistically significant greater risk of acquiring nasopharyngeal warts but were less likely to acquire plantar, genital, and perianal warts than the Mayo Clinic patient group did, demonstrating that laser plume is a likely means by which HPV can be transmitted to the upper airway, suggesting that those using lasers to treat HPV lesions are at greater risk. Staphylococcus, Corynebacterium, and Neisseria also have been detected during laser resurfacing.

Traditional surgical masks are able to capture particles greater than 5 mcm but offer no protection against particulate matter produced by electrosurgical and laser devices liberating byproducts less than 1 mcm. Laser masks or high-filtration masks provide greater protection than do standard surgical masks and are able to filter particles to 1.1 mcm; however, it has been shown that approximately 77% of particulate matter in surgical smoke is 1.1 mcm and smaller. Smoke evacuators consist of a suction unit (vacuum pump), filter, hose, and inlet nozzle. The smoke evacuator should have a capture velocity of approximately 30-45 m/min at the inlet nozzle. As the effectiveness of the smoke evacuator decreases with farther distance away from the procedure site, the current study of laser plume from LHR recommends that the smoke evacuator be placed within 5 cm of plume generation.⁴ In a study of warts treated with CO₂ laser or electrocoagulation, smoke evacuators are 98.6% effective when placed 1 cm from the treatment site, with efficacy decreasing to 50% when moved to 2 cm from the treatment site.

As our specialty likely conducts the highest proportion of laser and electrosurgical procedures of any specialty, current recommendations for electrocautery, laser resurfacing, and LHR should include adequate air filtration and the use of high-filtration masks and smoke evacuators by the health care practitioner.

References

1. JAMA Dermatol. 2016 Jul 6. doi: 10.1001/jamadermatol.2016.2097. [Epub ahead of print]

2. J Am Acad Dermatol. 2011 Sep;65(3):636-41.

3. J Am Acad Dermatol. 1995 Mar;32(3):436-41.

4. J Am Acad Dermatol. 1989 Jul;21(1):41-9.

Dr. Wesley and Dr. Talakoub are co-contributors to this column. Dr. Talakoub is in private practice in McLean, Va. Dr. Wesley practices dermatology in Beverly Hills, Calif. This month’s column is by Dr. Wesley. Write to them at dermnews@frontlinemedcom.com.

A recent publication by Chuang et al. carefully characterizes the content of smoke (or plume) created from laser hair removal.¹ At the University of California, Los Angeles, discarded terminal hairs from the trunk and extremities were collected from two adult volunteers. The hair samples were sealed in glass gas chromatography chambers and treated with either an 810-nm diode laser (Lightsheer, Lumenis) or 755-nm alexandrite laser (Gentlelase, Candela). During laser hair removal (LHR) treatment, two 6-L negative-pressure canisters were used to capture 30 seconds of laser plume, and a portable condensation particle counter was used to measure ultrafine particulates (less than 1 mcm). Ultrafine particle concentrations were measured within the treatment room, within the waiting room, and outside the building. The laser plume was then analyzed by gas chromatography–mass spectrometry (GC-MS) at the Boston University department of chemistry.

Analysis with GC-MS identified 377 chemical compounds. Sixty-two of the compounds exhibited strong absorption peaks, of which 13 are known or suspected carcinogens (including benzene, ethylbenzene, benzeneacetonitrile, acetonitrile, quinoline, isoquinoline, sterene, diethyl phthalate, 2-methylpyridine, naphthalene carbonitrile, and propene) and more than 20 are known environmental toxins causing acute toxic effects on exposure (including carbon monoxide, p-xylene, phenol, toluene, benzaldehyde, benzenedicarboxylic acid [phthalic acid], and long-chain and cyclic hydrocarbons).

During LHR, the portable condensation particle counters documented an eightfold increase, compared with the ambient room baseline level of ultrafine particle concentrations (ambient room baseline, 15,300 particles per cubic centimeter [ppc]; LHR with smoke evacuator, 129,376 ppc), even when a smoke evacuator was in close proximity (5.0 cm) to the procedure site. When the smoke evacuator was turned off for 30 seconds, there was a more than 26-fold increase in particulate count, compared with ambient baseline levels (ambient baseline, 15,300 ppc; LHR without smoke evacuator for 30 seconds, 435,888 ppc).

It has long been known that smoke created from electrocautery also may impose a risk on the health care worker. In 2011, Lewin et al. published a comprehensive review of the risk that surgical smoke and laser imposes on the dermatologist.² At this time, most of the laser data was for the plume created by ablative CO₂ lasers. In their review, it was stated that surgical smoke is composed of 95% water and 5% particulate matter (made up of chemicals, blood and tissue particles, viruses, and bacteria). The size of the particulate matter is dictated by the device used, with electrosurgical units creating particles of roughly 0.07 mcm and lasers liberating particles of 0.31 mcm. The size of liberated particles is important as those smaller than 100 mcm in diameter remain airborne, and particles less than 2 mcm are deposited in the bronchioles and alveoli.

Electrocautery plume is composed mostly of hydrocarbons, phenols, nitriles, and fatty acids, but most notably carbon monoxide, acrylonitrile, hydrogen cyanide, and benzene, which may have carcinogenic potential. On the mucosa of the canine tongue, the mutagenic effect of the smoke from 1 g of cauterized tissue with laser and electrocautery was equivalent to those from three or six cigarettes, respectively. Pulmonary changes also may occur. Blood vessel hypertrophy, alveolar congestion, and emphysematous changes were seen in rats after plume created from both electrocautery and Nd:Yag ablation of porcine skin. In that study, pulmonary changes were less severe in rats exposed to surgical smoke collected with single- and double-filtered smoke evacuators than unfiltered smoke.

Infection also poses a risk, with bovine papillomavirus and HPV detected in CO₂ laser plume as early as 1988. In 1995, Gloster and Roenigk at the Mayo Clinic conducted a comparative study using questionnaires sent to members of the American Society for Laser Surgeons and the American Society of Dermatologic Surgery.³ The comparison groups were CO₂ laser surgeons and two large groups of patients in the community with a diagnosis of warts. Analysis revealed that CO₂ laser surgeons had a statistically significant greater risk of acquiring nasopharyngeal warts but were less likely to acquire plantar, genital, and perianal warts than the Mayo Clinic patient group did, demonstrating that laser plume is a likely means by which HPV can be transmitted to the upper airway, suggesting that those using lasers to treat HPV lesions are at greater risk. Staphylococcus, Corynebacterium, and Neisseria also have been detected during laser resurfacing.

Traditional surgical masks are able to capture particles greater than 5 mcm but offer no protection against particulate matter produced by electrosurgical and laser devices liberating byproducts less than 1 mcm. Laser masks or high-filtration masks provide greater protection than do standard surgical masks and are able to filter particles to 1.1 mcm; however, it has been shown that approximately 77% of particulate matter in surgical smoke is 1.1 mcm and smaller. Smoke evacuators consist of a suction unit (vacuum pump), filter, hose, and inlet nozzle. The smoke evacuator should have a capture velocity of approximately 30-45 m/min at the inlet nozzle. As the effectiveness of the smoke evacuator decreases with farther distance away from the procedure site, the current study of laser plume from LHR recommends that the smoke evacuator be placed within 5 cm of plume generation.⁴ In a study of warts treated with CO₂ laser or electrocoagulation, smoke evacuators are 98.6% effective when placed 1 cm from the treatment site, with efficacy decreasing to 50% when moved to 2 cm from the treatment site.

As our specialty likely conducts the highest proportion of laser and electrosurgical procedures of any specialty, current recommendations for electrocautery, laser resurfacing, and LHR should include adequate air filtration and the use of high-filtration masks and smoke evacuators by the health care practitioner.

References

1. JAMA Dermatol. 2016 Jul 6. doi: 10.1001/jamadermatol.2016.2097. [Epub ahead of print]

2. J Am Acad Dermatol. 2011 Sep;65(3):636-41.

3. J Am Acad Dermatol. 1995 Mar;32(3):436-41.

4. J Am Acad Dermatol. 1989 Jul;21(1):41-9.

Dr. Wesley and Dr. Talakoub are co-contributors to this column. Dr. Talakoub is in private practice in McLean, Va. Dr. Wesley practices dermatology in Beverly Hills, Calif. This month’s column is by Dr. Wesley. Write to them at dermnews@frontlinemedcom.com.

CHICAGO – The oral multitargeted tyrosine kinase inhibitor cabozantinib confers an overall survival benefit to patients with previously treated renal cell carcinoma, compared with everolimus, according to the final survival analysis of the phase III METEOR trial.

An analysis of the 658 patients enrolled in the study revealed that “treatment with cabozantinib significantly improved overall survival, compared to everolimus. The median overall survival was 21.4 months in the cabozantinib group, compared to 16.5 months in the everolimus group,” Toni Choueiri, M.D., of the Dana-Farber Cancer Institute in Boston reported at the annual meeting of the American Society of Clinical Oncology.

”The hazard ratio of 0.66 does represent a 34% reduction in the rate of deaths,” he said.

An overall survival benefit associated with cabozantinib was consistently observed in all prespecified groups including the groups stratified by Memorial Sloan Kettering Cancer Center (MSKCC) risk criteria, the number and duration of prior vascular endothelial growth factor receptor tyrosine kinase inhibitor therapies, and tumor MET status.

An analysis of the same 658 patients enrolled in the METEOR trial, presented at the Genitourinary Cancers Symposium in early 2016, indicated cabozantinib improved progression-free survival, compared with everolimus (7.4 months vs. 3.9 months, HR, 0.52; P less than .001).

Cabozantinib is the only agent to demonstrate a significant benefit in overall survival, progression-free survival, and overall response rate in a phase III trial in previously treated patients with advanced renal cell carcinoma, according to Dr. Choueiri. “Cabozantinib is an important new treatment option for these patients,” he said.

This study was funded by Exelixis. Dr. Choueiri reported serving in advisory roles and receiving research funding and honoraria from multiple companies.

jcraig@frontlinemedcom.com

On Twitter @jessicolecraig

CHICAGO – The oral multitargeted tyrosine kinase inhibitor cabozantinib confers an overall survival benefit to patients with previously treated renal cell carcinoma, compared with everolimus, according to the final survival analysis of the phase III METEOR trial.

An analysis of the 658 patients enrolled in the study revealed that “treatment with cabozantinib significantly improved overall survival, compared to everolimus. The median overall survival was 21.4 months in the cabozantinib group, compared to 16.5 months in the everolimus group,” Toni Choueiri, M.D., of the Dana-Farber Cancer Institute in Boston reported at the annual meeting of the American Society of Clinical Oncology.

”The hazard ratio of 0.66 does represent a 34% reduction in the rate of deaths,” he said.

An overall survival benefit associated with cabozantinib was consistently observed in all prespecified groups including the groups stratified by Memorial Sloan Kettering Cancer Center (MSKCC) risk criteria, the number and duration of prior vascular endothelial growth factor receptor tyrosine kinase inhibitor therapies, and tumor MET status.

An analysis of the same 658 patients enrolled in the METEOR trial, presented at the Genitourinary Cancers Symposium in early 2016, indicated cabozantinib improved progression-free survival, compared with everolimus (7.4 months vs. 3.9 months, HR, 0.52; P less than .001).

Cabozantinib is the only agent to demonstrate a significant benefit in overall survival, progression-free survival, and overall response rate in a phase III trial in previously treated patients with advanced renal cell carcinoma, according to Dr. Choueiri. “Cabozantinib is an important new treatment option for these patients,” he said.

This study was funded by Exelixis. Dr. Choueiri reported serving in advisory roles and receiving research funding and honoraria from multiple companies.

jcraig@frontlinemedcom.com

On Twitter @jessicolecraig

CHICAGO – The oral multitargeted tyrosine kinase inhibitor cabozantinib confers an overall survival benefit to patients with previously treated renal cell carcinoma, compared with everolimus, according to the final survival analysis of the phase III METEOR trial.

An analysis of the 658 patients enrolled in the study revealed that “treatment with cabozantinib significantly improved overall survival, compared to everolimus. The median overall survival was 21.4 months in the cabozantinib group, compared to 16.5 months in the everolimus group,” Toni Choueiri, M.D., of the Dana-Farber Cancer Institute in Boston reported at the annual meeting of the American Society of Clinical Oncology.

”The hazard ratio of 0.66 does represent a 34% reduction in the rate of deaths,” he said.

An overall survival benefit associated with cabozantinib was consistently observed in all prespecified groups including the groups stratified by Memorial Sloan Kettering Cancer Center (MSKCC) risk criteria, the number and duration of prior vascular endothelial growth factor receptor tyrosine kinase inhibitor therapies, and tumor MET status.

An analysis of the same 658 patients enrolled in the METEOR trial, presented at the Genitourinary Cancers Symposium in early 2016, indicated cabozantinib improved progression-free survival, compared with everolimus (7.4 months vs. 3.9 months, HR, 0.52; P less than .001).

Cabozantinib is the only agent to demonstrate a significant benefit in overall survival, progression-free survival, and overall response rate in a phase III trial in previously treated patients with advanced renal cell carcinoma, according to Dr. Choueiri. “Cabozantinib is an important new treatment option for these patients,” he said.

This study was funded by Exelixis. Dr. Choueiri reported serving in advisory roles and receiving research funding and honoraria from multiple companies.

jcraig@frontlinemedcom.com

On Twitter @jessicolecraig

Anxiety is strongly associated with a higher risk of cognitive impairment, according to a meta-analysis by B. Gulpers and coauthors from Maastricht University Medical Center in the Netherlands.

Investigators performed a literature search up to January 2015 to identify studies on the relationship between anxiety and cognition. Pooled relative risks were calculated to examine anxiety as a possible factor for cognitive impairment, cognitive decline, and dementia in community studies, and for conversion to dementia in patients referred to memory clinics.

Anxiety predicted cognitive impairment (RR = 1.77; 95% confidence interval, 1.38-2.26; z = 4.50; P less than .001) and dementia (RR = 1.57; 95% CI, 1.02-2.42; z = 2.05; P = .040) in the community, especially with increased mean age, the authors reported. Anxiety did not, however, predict conversion to dementia (RR = 1.21; 95% CI, 0.90-1.63; z = 1.28; P = .200).

“Future studies should include mediating mechanism when studying anxiety as a predictor for cognitive decline and/or dementia,” the authors concluded.

Read the full article in the American Journal of Geriatric Psychiatry.

Anxiety is strongly associated with a higher risk of cognitive impairment, according to a meta-analysis by B. Gulpers and coauthors from Maastricht University Medical Center in the Netherlands.

Investigators performed a literature search up to January 2015 to identify studies on the relationship between anxiety and cognition. Pooled relative risks were calculated to examine anxiety as a possible factor for cognitive impairment, cognitive decline, and dementia in community studies, and for conversion to dementia in patients referred to memory clinics.

Anxiety predicted cognitive impairment (RR = 1.77; 95% confidence interval, 1.38-2.26; z = 4.50; P less than .001) and dementia (RR = 1.57; 95% CI, 1.02-2.42; z = 2.05; P = .040) in the community, especially with increased mean age, the authors reported. Anxiety did not, however, predict conversion to dementia (RR = 1.21; 95% CI, 0.90-1.63; z = 1.28; P = .200).

“Future studies should include mediating mechanism when studying anxiety as a predictor for cognitive decline and/or dementia,” the authors concluded.

Read the full article in the American Journal of Geriatric Psychiatry.

Anxiety is strongly associated with a higher risk of cognitive impairment, according to a meta-analysis by B. Gulpers and coauthors from Maastricht University Medical Center in the Netherlands.

Investigators performed a literature search up to January 2015 to identify studies on the relationship between anxiety and cognition. Pooled relative risks were calculated to examine anxiety as a possible factor for cognitive impairment, cognitive decline, and dementia in community studies, and for conversion to dementia in patients referred to memory clinics.

Anxiety predicted cognitive impairment (RR = 1.77; 95% confidence interval, 1.38-2.26; z = 4.50; P less than .001) and dementia (RR = 1.57; 95% CI, 1.02-2.42; z = 2.05; P = .040) in the community, especially with increased mean age, the authors reported. Anxiety did not, however, predict conversion to dementia (RR = 1.21; 95% CI, 0.90-1.63; z = 1.28; P = .200).

“Future studies should include mediating mechanism when studying anxiety as a predictor for cognitive decline and/or dementia,” the authors concluded.

Read the full article in the American Journal of Geriatric Psychiatry.

A Food and Drug Administration advisory committee has unanimously supported approval of the monoclonal antibody brodalumab for the treatment of moderate to severe plaque psoriasis, with the majority recommending risk management options beyond labeling to address concerns about the six completed suicides among patients treated with brodalumab in clinical trials.

Though no members of the FDA’s Dermatologic and Ophthalmic Drugs Advisory Committee disputed the drug’s efficacy for plaque psoriasis, the possibility of a signal for suicidal ideation and behavior (SIB) among the brodalumab group prompted the committee’s chair, Michael Bigby, M.D., to remark, “The big problem is that you have six completed suicides. … I would say it’s a fairly big number for a randomized controlled trial. Patients and clinicians need to be aware of this as a fact.”

Dr. Bigby, professor of dermatology at Harvard Medical School, Boston, headed the 18-member panel, which included dermatologists, psychiatrists, and cardiologists. Fourteen members voted in favor of approval with risk management measures beyond labeling; four members voted for approval with labeling alone.

Brodalumab targets interleukin-17 receptors, inhibiting IL-17 uptake and thus blocking the pathway responsible for the cutaneous and systemic signs and symptoms of psoriasis. The pivotal phase III brodalumab studies, AMAGINE-1, -2, and -3, enrolled a total of 4,373 patients with moderate to severe plaque psoriasis. AMAGINE-1 enrolled 661 patients in a 1:1:1 ratio to a randomized, double-blind placebo-controlled study that included two doses of brodalumab: 210 mg and 140 mg. The placebo-controlled phase of the study ran for 12 weeks, followed by a withdrawal and retreatment phase, and after 52 weeks, by an open label long-term extension phase.

AMAGINE-2 (1,831 patients) and AMAGINE-3 (1,881 patients) were identically designed studies that pitted both doses of brodalumab against an active comparator, ustekinumab (Stelara), as well as placebo, in a 2:2:1:1 ratio. This double-blind phase of the study also lasted 12 weeks. During weeks 12-52, patients on the brodalumab arms continued, with an exploration of wider-dose intervals for the 140-mg dose. Patients also continued with ustekinumab, with a rescue option to transition to brodalumab 210 mg. The placebo group could continue on brodalumab 210 mg as well. These two studies also had an open label long-term extension phase.

At the 12-week mark in AMAGINE-1, 41.9% of patients achieved the coprimary endpoint of 100% reduction in the Psoriasis Area and Severity Index (PASI 100) score, compared with 0.5% of those on placebo (P less than .001). AMAGINE-2 and -3 saw 44.4% and 36.7% of the brodalumab 210-mg arms achieving PASI 100 at the 12-week mark, respectively. These figures were significantly higher than the 21.7% and 18.5% reaching PASI 100 on ustekinumab (P less than .001), as well as significantly higher than the less than 1% of patients in the placebo arm who reached that endpoint.

At the end of 52 weeks, 51% of those on brodalumab 210 mg had completely clear skin, compared with 28.1% of the patients receiving ustekinumab (P less than .001).

The safety analysis for brodalumab showed that the most common adverse events were nasopharyngitis, upper respiratory tract infection, headache, and arthralgia; of these, the last two were considered adverse drug reactions. At 52 weeks, those on brodalumab had a slightly greater risk of having nonserious fungal infections than did those on ustekinumab. Overall, however, there was no difference between the brodalumab and ustekinumab arms at week 52 for treatment-emergent adverse events or for serious adverse events.

A cluster of SIB events occurred in 2013 and 2014 during the clinical trials, and the sponsor consulted the FDA. Additional monitoring for suicidal ideation and depression via the Columbia Suicide Severity Rating Scale (C-SSRS) and the Patient Health Questionnaire (PHQ) were implemented at a point where 84% of trial patients were already in the uncontrolled open label extension stage of the trial; in addition, a retrospective data review searched for suicidal ideation and attempts before the implementation of these two tools.

A total of six brodalumab patients completed suicide in all clinical trials, including those for psoriatic arthritis and RA. Suicides included two during the 12- to 52-week follow-up and four during the long-term follow-up phase. Another 29 patients attempted suicide, had intentional self-injury, or had suicidal ideation during these phases of the study, for a total of 35 SIB events. (SIB includes completed suicide, suicide attempt, suicide behavior, and suicide ideation.)*

The significance of the number of completed suicides was difficult to ascertain, given the increased baseline prevalence of depression and related illnesses among patients with psoriasis. Compared with the general population, individuals with psoriasis have hazard ratios of 1.39, 1.31, and 1.44 for depression, anxiety, and suicidality, according to a cohort study cited by Robert Levin, M.D. , director of the division of pharmacovigilance I at the FDA’s Center for Drug Evaluation and Research (CDER).

In addition, monitoring for suicidal ideation and attempts was stepped up during the course of the clinical trials. Brodalumab’s sponsor, Valeant Pharmaceuticals, noted that the rates of suicidal ideation and attempts increased after implementation of the C-SSRS, while other neuropsychiatric symptoms remained stable or declined during the course of the studies. “This makes us think this is ascertainment bias,” said Valeant consultant Lauren Marangell, M.D., a psychiatrist and president of Brain Health Consultants.

Dr. Marangell also reported that, after stratification for preexisting psychiatric comorbidities and risk factors, “there is no question that the rate of SIB is higher in both arms with patients with baseline risk factors.” The FDA’s data analysis showed an 18-fold increase in the rate of SIB for brodalumab arm participants with a prior history of suicidality.

During its presentation, Valeant also pointed out that patients with histories of drug and alcohol abuse, depression, and suicidality were not specifically excluded from the clinical trials. This differentiates the brodalumab program from other biologic studies, “making the studies more characteristic of the real world,” said R.K. Pillai, Ph.D., Valeant vice president.

Dr. Levin’s analysis, one of several independent analyses conducted by different FDA divisions, found that the data were inconclusive. “We currently can’t conclude whether or not these are drug-related risks,” he said. Considering the critical severity of suicide as an outcome, “we must consider the application and regulatory actions carefully.”

Jean Kim, M.D., medical officer in CDER’s division of psychiatry products (DPP), noted that the number of suicides seen in the brodalumab trials “is higher than typically seen in DPP’s large psychiatric drug trials, which involve populations with higher psychiatric morbidity than patients with psoriasis.”

Patients with psoriasis are also known to have a baseline elevated risk of cardiovascular disease, and no committee member felt the brodalumab data showed any additional signal for major adverse cardiovascular events (MACEs) beyond what would be suspected in this population. “I don’t right now see a safety signal for MACE,” said panelist Michael Blaha, M.D., a cardiologist and director of clinical research at Johns Hopkins Ciccarone Center for Prevention of Heart Disease, Baltimore. He noted, however, that research is ongoing to elucidate the relationship between cytokine levels and MACE. “This question about whether cytokines raise or reduce rates for [cardiovascular] events is an open one.”

One of the dermatologists on the committee, Lynn Drake, M.D., said that her decision making was influenced by the disease burden psoriasis inflicts on the patients she sees in her daily practice. “These patients are ill. People tend to think it’s just skin disease. It is not just skin disease. … I’d hate to see our patients deprived of a drug that might help alleviate their symptoms,” said Dr. Drake.

Though committee members voiced some disagreement about whether a patient registry should be established, and if it should be voluntary, they were in agreement that patients and prescribers both be aware of the potential risks of brodalumab, without making any risk management strategy so burdensome that appropriate patients would be deterred from considering the medication. Psoriasis, Dr. Drake said, “is a devastating disease. We need this in our armamentarium.”

The proposed dosing for brodalumab is 210 mg injected subcutaneously weekly for 3 weeks, followed by 210 mg every 2 weeks thereafter.

The FDA usually follows the recommendations of its advisory committees. The panelists had no relevant financial disclosures.

A Food and Drug Administration advisory committee has unanimously supported approval of the monoclonal antibody brodalumab for the treatment of moderate to severe plaque psoriasis, with the majority recommending risk management options beyond labeling to address concerns about the six completed suicides among patients treated with brodalumab in clinical trials.

Though no members of the FDA’s Dermatologic and Ophthalmic Drugs Advisory Committee disputed the drug’s efficacy for plaque psoriasis, the possibility of a signal for suicidal ideation and behavior (SIB) among the brodalumab group prompted the committee’s chair, Michael Bigby, M.D., to remark, “The big problem is that you have six completed suicides. … I would say it’s a fairly big number for a randomized controlled trial. Patients and clinicians need to be aware of this as a fact.”

Dr. Bigby, professor of dermatology at Harvard Medical School, Boston, headed the 18-member panel, which included dermatologists, psychiatrists, and cardiologists. Fourteen members voted in favor of approval with risk management measures beyond labeling; four members voted for approval with labeling alone.

Brodalumab targets interleukin-17 receptors, inhibiting IL-17 uptake and thus blocking the pathway responsible for the cutaneous and systemic signs and symptoms of psoriasis. The pivotal phase III brodalumab studies, AMAGINE-1, -2, and -3, enrolled a total of 4,373 patients with moderate to severe plaque psoriasis. AMAGINE-1 enrolled 661 patients in a 1:1:1 ratio to a randomized, double-blind placebo-controlled study that included two doses of brodalumab: 210 mg and 140 mg. The placebo-controlled phase of the study ran for 12 weeks, followed by a withdrawal and retreatment phase, and after 52 weeks, by an open label long-term extension phase.

AMAGINE-2 (1,831 patients) and AMAGINE-3 (1,881 patients) were identically designed studies that pitted both doses of brodalumab against an active comparator, ustekinumab (Stelara), as well as placebo, in a 2:2:1:1 ratio. This double-blind phase of the study also lasted 12 weeks. During weeks 12-52, patients on the brodalumab arms continued, with an exploration of wider-dose intervals for the 140-mg dose. Patients also continued with ustekinumab, with a rescue option to transition to brodalumab 210 mg. The placebo group could continue on brodalumab 210 mg as well. These two studies also had an open label long-term extension phase.

At the 12-week mark in AMAGINE-1, 41.9% of patients achieved the coprimary endpoint of 100% reduction in the Psoriasis Area and Severity Index (PASI 100) score, compared with 0.5% of those on placebo (P less than .001). AMAGINE-2 and -3 saw 44.4% and 36.7% of the brodalumab 210-mg arms achieving PASI 100 at the 12-week mark, respectively. These figures were significantly higher than the 21.7% and 18.5% reaching PASI 100 on ustekinumab (P less than .001), as well as significantly higher than the less than 1% of patients in the placebo arm who reached that endpoint.

At the end of 52 weeks, 51% of those on brodalumab 210 mg had completely clear skin, compared with 28.1% of the patients receiving ustekinumab (P less than .001).

The safety analysis for brodalumab showed that the most common adverse events were nasopharyngitis, upper respiratory tract infection, headache, and arthralgia; of these, the last two were considered adverse drug reactions. At 52 weeks, those on brodalumab had a slightly greater risk of having nonserious fungal infections than did those on ustekinumab. Overall, however, there was no difference between the brodalumab and ustekinumab arms at week 52 for treatment-emergent adverse events or for serious adverse events.

A cluster of SIB events occurred in 2013 and 2014 during the clinical trials, and the sponsor consulted the FDA. Additional monitoring for suicidal ideation and depression via the Columbia Suicide Severity Rating Scale (C-SSRS) and the Patient Health Questionnaire (PHQ) were implemented at a point where 84% of trial patients were already in the uncontrolled open label extension stage of the trial; in addition, a retrospective data review searched for suicidal ideation and attempts before the implementation of these two tools.

A total of six brodalumab patients completed suicide in all clinical trials, including those for psoriatic arthritis and RA. Suicides included two during the 12- to 52-week follow-up and four during the long-term follow-up phase. Another 29 patients attempted suicide, had intentional self-injury, or had suicidal ideation during these phases of the study, for a total of 35 SIB events. (SIB includes completed suicide, suicide attempt, suicide behavior, and suicide ideation.)*

The significance of the number of completed suicides was difficult to ascertain, given the increased baseline prevalence of depression and related illnesses among patients with psoriasis. Compared with the general population, individuals with psoriasis have hazard ratios of 1.39, 1.31, and 1.44 for depression, anxiety, and suicidality, according to a cohort study cited by Robert Levin, M.D. , director of the division of pharmacovigilance I at the FDA’s Center for Drug Evaluation and Research (CDER).

In addition, monitoring for suicidal ideation and attempts was stepped up during the course of the clinical trials. Brodalumab’s sponsor, Valeant Pharmaceuticals, noted that the rates of suicidal ideation and attempts increased after implementation of the C-SSRS, while other neuropsychiatric symptoms remained stable or declined during the course of the studies. “This makes us think this is ascertainment bias,” said Valeant consultant Lauren Marangell, M.D., a psychiatrist and president of Brain Health Consultants.

Dr. Marangell also reported that, after stratification for preexisting psychiatric comorbidities and risk factors, “there is no question that the rate of SIB is higher in both arms with patients with baseline risk factors.” The FDA’s data analysis showed an 18-fold increase in the rate of SIB for brodalumab arm participants with a prior history of suicidality.

During its presentation, Valeant also pointed out that patients with histories of drug and alcohol abuse, depression, and suicidality were not specifically excluded from the clinical trials. This differentiates the brodalumab program from other biologic studies, “making the studies more characteristic of the real world,” said R.K. Pillai, Ph.D., Valeant vice president.

Dr. Levin’s analysis, one of several independent analyses conducted by different FDA divisions, found that the data were inconclusive. “We currently can’t conclude whether or not these are drug-related risks,” he said. Considering the critical severity of suicide as an outcome, “we must consider the application and regulatory actions carefully.”

Jean Kim, M.D., medical officer in CDER’s division of psychiatry products (DPP), noted that the number of suicides seen in the brodalumab trials “is higher than typically seen in DPP’s large psychiatric drug trials, which involve populations with higher psychiatric morbidity than patients with psoriasis.”

Patients with psoriasis are also known to have a baseline elevated risk of cardiovascular disease, and no committee member felt the brodalumab data showed any additional signal for major adverse cardiovascular events (MACEs) beyond what would be suspected in this population. “I don’t right now see a safety signal for MACE,” said panelist Michael Blaha, M.D., a cardiologist and director of clinical research at Johns Hopkins Ciccarone Center for Prevention of Heart Disease, Baltimore. He noted, however, that research is ongoing to elucidate the relationship between cytokine levels and MACE. “This question about whether cytokines raise or reduce rates for [cardiovascular] events is an open one.”

One of the dermatologists on the committee, Lynn Drake, M.D., said that her decision making was influenced by the disease burden psoriasis inflicts on the patients she sees in her daily practice. “These patients are ill. People tend to think it’s just skin disease. It is not just skin disease. … I’d hate to see our patients deprived of a drug that might help alleviate their symptoms,” said Dr. Drake.

Though committee members voiced some disagreement about whether a patient registry should be established, and if it should be voluntary, they were in agreement that patients and prescribers both be aware of the potential risks of brodalumab, without making any risk management strategy so burdensome that appropriate patients would be deterred from considering the medication. Psoriasis, Dr. Drake said, “is a devastating disease. We need this in our armamentarium.”

The proposed dosing for brodalumab is 210 mg injected subcutaneously weekly for 3 weeks, followed by 210 mg every 2 weeks thereafter.

The FDA usually follows the recommendations of its advisory committees. The panelists had no relevant financial disclosures.

A Food and Drug Administration advisory committee has unanimously supported approval of the monoclonal antibody brodalumab for the treatment of moderate to severe plaque psoriasis, with the majority recommending risk management options beyond labeling to address concerns about the six completed suicides among patients treated with brodalumab in clinical trials.

Though no members of the FDA’s Dermatologic and Ophthalmic Drugs Advisory Committee disputed the drug’s efficacy for plaque psoriasis, the possibility of a signal for suicidal ideation and behavior (SIB) among the brodalumab group prompted the committee’s chair, Michael Bigby, M.D., to remark, “The big problem is that you have six completed suicides. … I would say it’s a fairly big number for a randomized controlled trial. Patients and clinicians need to be aware of this as a fact.”

Dr. Bigby, professor of dermatology at Harvard Medical School, Boston, headed the 18-member panel, which included dermatologists, psychiatrists, and cardiologists. Fourteen members voted in favor of approval with risk management measures beyond labeling; four members voted for approval with labeling alone.

Brodalumab targets interleukin-17 receptors, inhibiting IL-17 uptake and thus blocking the pathway responsible for the cutaneous and systemic signs and symptoms of psoriasis. The pivotal phase III brodalumab studies, AMAGINE-1, -2, and -3, enrolled a total of 4,373 patients with moderate to severe plaque psoriasis. AMAGINE-1 enrolled 661 patients in a 1:1:1 ratio to a randomized, double-blind placebo-controlled study that included two doses of brodalumab: 210 mg and 140 mg. The placebo-controlled phase of the study ran for 12 weeks, followed by a withdrawal and retreatment phase, and after 52 weeks, by an open label long-term extension phase.

AMAGINE-2 (1,831 patients) and AMAGINE-3 (1,881 patients) were identically designed studies that pitted both doses of brodalumab against an active comparator, ustekinumab (Stelara), as well as placebo, in a 2:2:1:1 ratio. This double-blind phase of the study also lasted 12 weeks. During weeks 12-52, patients on the brodalumab arms continued, with an exploration of wider-dose intervals for the 140-mg dose. Patients also continued with ustekinumab, with a rescue option to transition to brodalumab 210 mg. The placebo group could continue on brodalumab 210 mg as well. These two studies also had an open label long-term extension phase.

At the 12-week mark in AMAGINE-1, 41.9% of patients achieved the coprimary endpoint of 100% reduction in the Psoriasis Area and Severity Index (PASI 100) score, compared with 0.5% of those on placebo (P less than .001). AMAGINE-2 and -3 saw 44.4% and 36.7% of the brodalumab 210-mg arms achieving PASI 100 at the 12-week mark, respectively. These figures were significantly higher than the 21.7% and 18.5% reaching PASI 100 on ustekinumab (P less than .001), as well as significantly higher than the less than 1% of patients in the placebo arm who reached that endpoint.

At the end of 52 weeks, 51% of those on brodalumab 210 mg had completely clear skin, compared with 28.1% of the patients receiving ustekinumab (P less than .001).

The safety analysis for brodalumab showed that the most common adverse events were nasopharyngitis, upper respiratory tract infection, headache, and arthralgia; of these, the last two were considered adverse drug reactions. At 52 weeks, those on brodalumab had a slightly greater risk of having nonserious fungal infections than did those on ustekinumab. Overall, however, there was no difference between the brodalumab and ustekinumab arms at week 52 for treatment-emergent adverse events or for serious adverse events.

A cluster of SIB events occurred in 2013 and 2014 during the clinical trials, and the sponsor consulted the FDA. Additional monitoring for suicidal ideation and depression via the Columbia Suicide Severity Rating Scale (C-SSRS) and the Patient Health Questionnaire (PHQ) were implemented at a point where 84% of trial patients were already in the uncontrolled open label extension stage of the trial; in addition, a retrospective data review searched for suicidal ideation and attempts before the implementation of these two tools.

A total of six brodalumab patients completed suicide in all clinical trials, including those for psoriatic arthritis and RA. Suicides included two during the 12- to 52-week follow-up and four during the long-term follow-up phase. Another 29 patients attempted suicide, had intentional self-injury, or had suicidal ideation during these phases of the study, for a total of 35 SIB events. (SIB includes completed suicide, suicide attempt, suicide behavior, and suicide ideation.)*

The significance of the number of completed suicides was difficult to ascertain, given the increased baseline prevalence of depression and related illnesses among patients with psoriasis. Compared with the general population, individuals with psoriasis have hazard ratios of 1.39, 1.31, and 1.44 for depression, anxiety, and suicidality, according to a cohort study cited by Robert Levin, M.D. , director of the division of pharmacovigilance I at the FDA’s Center for Drug Evaluation and Research (CDER).

In addition, monitoring for suicidal ideation and attempts was stepped up during the course of the clinical trials. Brodalumab’s sponsor, Valeant Pharmaceuticals, noted that the rates of suicidal ideation and attempts increased after implementation of the C-SSRS, while other neuropsychiatric symptoms remained stable or declined during the course of the studies. “This makes us think this is ascertainment bias,” said Valeant consultant Lauren Marangell, M.D., a psychiatrist and president of Brain Health Consultants.

Dr. Marangell also reported that, after stratification for preexisting psychiatric comorbidities and risk factors, “there is no question that the rate of SIB is higher in both arms with patients with baseline risk factors.” The FDA’s data analysis showed an 18-fold increase in the rate of SIB for brodalumab arm participants with a prior history of suicidality.

During its presentation, Valeant also pointed out that patients with histories of drug and alcohol abuse, depression, and suicidality were not specifically excluded from the clinical trials. This differentiates the brodalumab program from other biologic studies, “making the studies more characteristic of the real world,” said R.K. Pillai, Ph.D., Valeant vice president.

Dr. Levin’s analysis, one of several independent analyses conducted by different FDA divisions, found that the data were inconclusive. “We currently can’t conclude whether or not these are drug-related risks,” he said. Considering the critical severity of suicide as an outcome, “we must consider the application and regulatory actions carefully.”

Jean Kim, M.D., medical officer in CDER’s division of psychiatry products (DPP), noted that the number of suicides seen in the brodalumab trials “is higher than typically seen in DPP’s large psychiatric drug trials, which involve populations with higher psychiatric morbidity than patients with psoriasis.”

Patients with psoriasis are also known to have a baseline elevated risk of cardiovascular disease, and no committee member felt the brodalumab data showed any additional signal for major adverse cardiovascular events (MACEs) beyond what would be suspected in this population. “I don’t right now see a safety signal for MACE,” said panelist Michael Blaha, M.D., a cardiologist and director of clinical research at Johns Hopkins Ciccarone Center for Prevention of Heart Disease, Baltimore. He noted, however, that research is ongoing to elucidate the relationship between cytokine levels and MACE. “This question about whether cytokines raise or reduce rates for [cardiovascular] events is an open one.”

One of the dermatologists on the committee, Lynn Drake, M.D., said that her decision making was influenced by the disease burden psoriasis inflicts on the patients she sees in her daily practice. “These patients are ill. People tend to think it’s just skin disease. It is not just skin disease. … I’d hate to see our patients deprived of a drug that might help alleviate their symptoms,” said Dr. Drake.

Though committee members voiced some disagreement about whether a patient registry should be established, and if it should be voluntary, they were in agreement that patients and prescribers both be aware of the potential risks of brodalumab, without making any risk management strategy so burdensome that appropriate patients would be deterred from considering the medication. Psoriasis, Dr. Drake said, “is a devastating disease. We need this in our armamentarium.”

The proposed dosing for brodalumab is 210 mg injected subcutaneously weekly for 3 weeks, followed by 210 mg every 2 weeks thereafter.

The FDA usually follows the recommendations of its advisory committees. The panelists had no relevant financial disclosures.

A Food and Drug Administration advisory committee has unanimously supported approval of the monoclonal antibody brodalumab for the treatment of moderate to severe plaque psoriasis, with the majority recommending risk management options beyond labeling to address concerns about the six completed suicides among patients treated with brodalumab in clinical trials.

Though no members of the FDA’s Dermatologic and Ophthalmic Drugs Advisory Committee disputed the drug’s efficacy for plaque psoriasis, the possibility of a signal for suicidal ideation and behavior (SIB) among the brodalumab group prompted the committee’s chair, Michael Bigby, M.D., to remark, “The big problem is that you have six completed suicides. … I would say it’s a fairly big number for a randomized controlled trial. Patients and clinicians need to be aware of this as a fact.”

Dr. Bigby, professor of dermatology at Harvard Medical School, Boston, headed the 18-member panel, which included dermatologists, psychiatrists, and cardiologists. Fourteen members voted in favor of approval with risk management measures beyond labeling; four members voted for approval with labeling alone.

Brodalumab targets interleukin-17 receptors, inhibiting IL-17 uptake and thus blocking the pathway responsible for the cutaneous and systemic signs and symptoms of psoriasis. The pivotal phase III brodalumab studies, AMAGINE-1, -2, and -3, enrolled a total of 4,373 patients with moderate to severe plaque psoriasis. AMAGINE-1 enrolled 661 patients in a 1:1:1 ratio to a randomized, double-blind placebo-controlled study that included two doses of brodalumab: 210 mg and 140 mg. The placebo-controlled phase of the study ran for 12 weeks, followed by a withdrawal and retreatment phase, and after 52 weeks, by an open label long-term extension phase.

AMAGINE-2 (1,831 patients) and AMAGINE-3 (1,881 patients) were identically designed studies that pitted both doses of brodalumab against an active comparator, ustekinumab (Stelara), as well as placebo, in a 2:2:1:1 ratio. This double-blind phase of the study also lasted 12 weeks. During weeks 12-52, patients on the brodalumab arms continued, with an exploration of wider-dose intervals for the 140-mg dose. Patients also continued with ustekinumab, with a rescue option to transition to brodalumab 210 mg. The placebo group could continue on brodalumab 210 mg as well. These two studies also had an open label long-term extension phase.

At the 12-week mark in AMAGINE-1, 41.9% of patients achieved the coprimary endpoint of 100% reduction in the Psoriasis Area and Severity Index (PASI 100) score, compared with 0.5% of those on placebo (P less than .001). AMAGINE-2 and -3 saw 44.4% and 36.7% of the brodalumab 210-mg arms achieving PASI 100 at the 12-week mark, respectively. These figures were significantly higher than the 21.7% and 18.5% reaching PASI 100 on ustekinumab (P less than .001), as well as significantly higher than the less than 1% of patients in the placebo arm who reached that endpoint.

At the end of 52 weeks, 51% of those on brodalumab 210 mg had completely clear skin, compared with 28.1% of the patients receiving ustekinumab (P less than .001).

The safety analysis for brodalumab showed that the most common adverse events were nasopharyngitis, upper respiratory tract infection, headache, and arthralgia; of these, the last two were considered adverse drug reactions. At 52 weeks, those on brodalumab had a slightly greater risk of having nonserious fungal infections than did those on ustekinumab. Overall, however, there was no difference between the brodalumab and ustekinumab arms at week 52 for treatment-emergent adverse events or for serious adverse events.

A cluster of SIB events occurred in 2013 and 2014 during the clinical trials, and the sponsor consulted the FDA. Additional monitoring for suicidal ideation and depression via the Columbia Suicide Severity Rating Scale (C-SSRS) and the Patient Health Questionnaire (PHQ) were implemented at a point where 84% of trial patients were already in the uncontrolled open label extension stage of the trial; in addition, a retrospective data review searched for suicidal ideation and attempts before the implementation of these two tools.

A total of six brodalumab patients completed suicide in all clinical trials, including those for psoriatic arthritis and RA. Suicides included two during the 12- to 52-week follow-up and four during the long-term follow-up phase. Another 29 patients attempted suicide, had intentional self-injury, or had suicidal ideation during these phases of the study, for a total of 35 SIB events. (SIB includes completed suicide, suicide attempt, suicide behavior, and suicide ideation.)*

The significance of the number of completed suicides was difficult to ascertain, given the increased baseline prevalence of depression and related illnesses among patients with psoriasis. Compared with the general population, individuals with psoriasis have hazard ratios of 1.39, 1.31, and 1.44 for depression, anxiety, and suicidality, according to a cohort study cited by Robert Levin, M.D. , director of the division of pharmacovigilance I at the FDA’s Center for Drug Evaluation and Research (CDER).

In addition, monitoring for suicidal ideation and attempts was stepped up during the course of the clinical trials. Brodalumab’s sponsor, Valeant Pharmaceuticals, noted that the rates of suicidal ideation and attempts increased after implementation of the C-SSRS, while other neuropsychiatric symptoms remained stable or declined during the course of the studies. “This makes us think this is ascertainment bias,” said Valeant consultant Lauren Marangell, M.D., a psychiatrist and president of Brain Health Consultants.

Dr. Marangell also reported that, after stratification for preexisting psychiatric comorbidities and risk factors, “there is no question that the rate of SIB is higher in both arms with patients with baseline risk factors.” The FDA’s data analysis showed an 18-fold increase in the rate of SIB for brodalumab arm participants with a prior history of suicidality.

During its presentation, Valeant also pointed out that patients with histories of drug and alcohol abuse, depression, and suicidality were not specifically excluded from the clinical trials. This differentiates the brodalumab program from other biologic studies, “making the studies more characteristic of the real world,” said R.K. Pillai, Ph.D., Valeant vice president.

Dr. Levin’s analysis, one of several independent analyses conducted by different FDA divisions, found that the data were inconclusive. “We currently can’t conclude whether or not these are drug-related risks,” he said. Considering the critical severity of suicide as an outcome, “we must consider the application and regulatory actions carefully.”

Jean Kim, M.D., medical officer in CDER’s division of psychiatry products (DPP), noted that the number of suicides seen in the brodalumab trials “is higher than typically seen in DPP’s large psychiatric drug trials, which involve populations with higher psychiatric morbidity than patients with psoriasis.”

Patients with psoriasis are also known to have a baseline elevated risk of cardiovascular disease, and no committee member felt the brodalumab data showed any additional signal for major adverse cardiovascular events (MACEs) beyond what would be suspected in this population. “I don’t right now see a safety signal for MACE,” said panelist Michael Blaha, M.D., a cardiologist and director of clinical research at Johns Hopkins Ciccarone Center for Prevention of Heart Disease, Baltimore. He noted, however, that research is ongoing to elucidate the relationship between cytokine levels and MACE. “This question about whether cytokines raise or reduce rates for [cardiovascular] events is an open one.”

One of the dermatologists on the committee, Lynn Drake, M.D., said that her decision making was influenced by the disease burden psoriasis inflicts on the patients she sees in her daily practice. “These patients are ill. People tend to think it’s just skin disease. It is not just skin disease. … I’d hate to see our patients deprived of a drug that might help alleviate their symptoms,” said Dr. Drake.

Though committee members voiced some disagreement about whether a patient registry should be established, and if it should be voluntary, they were in agreement that patients and prescribers both be aware of the potential risks of brodalumab, without making any risk management strategy so burdensome that appropriate patients would be deterred from considering the medication. Psoriasis, Dr. Drake said, “is a devastating disease. We need this in our armamentarium.”

The proposed dosing for brodalumab is 210 mg injected subcutaneously weekly for 3 weeks, followed by 210 mg every 2 weeks thereafter.

The FDA usually follows the recommendations of its advisory committees. The panelists had no relevant financial disclosures.

koakes@frontlinemedcom.com

On Twitter @karioakes

*A previous version of this article misstated the number of patients who experienced SIB events.

A Food and Drug Administration advisory committee has unanimously supported approval of the monoclonal antibody brodalumab for the treatment of moderate to severe plaque psoriasis, with the majority recommending risk management options beyond labeling to address concerns about the six completed suicides among patients treated with brodalumab in clinical trials.

Though no members of the FDA’s Dermatologic and Ophthalmic Drugs Advisory Committee disputed the drug’s efficacy for plaque psoriasis, the possibility of a signal for suicidal ideation and behavior (SIB) among the brodalumab group prompted the committee’s chair, Michael Bigby, M.D., to remark, “The big problem is that you have six completed suicides. … I would say it’s a fairly big number for a randomized controlled trial. Patients and clinicians need to be aware of this as a fact.”

Dr. Bigby, professor of dermatology at Harvard Medical School, Boston, headed the 18-member panel, which included dermatologists, psychiatrists, and cardiologists. Fourteen members voted in favor of approval with risk management measures beyond labeling; four members voted for approval with labeling alone.

Brodalumab targets interleukin-17 receptors, inhibiting IL-17 uptake and thus blocking the pathway responsible for the cutaneous and systemic signs and symptoms of psoriasis. The pivotal phase III brodalumab studies, AMAGINE-1, -2, and -3, enrolled a total of 4,373 patients with moderate to severe plaque psoriasis. AMAGINE-1 enrolled 661 patients in a 1:1:1 ratio to a randomized, double-blind placebo-controlled study that included two doses of brodalumab: 210 mg and 140 mg. The placebo-controlled phase of the study ran for 12 weeks, followed by a withdrawal and retreatment phase, and after 52 weeks, by an open label long-term extension phase.

AMAGINE-2 (1,831 patients) and AMAGINE-3 (1,881 patients) were identically designed studies that pitted both doses of brodalumab against an active comparator, ustekinumab (Stelara), as well as placebo, in a 2:2:1:1 ratio. This double-blind phase of the study also lasted 12 weeks. During weeks 12-52, patients on the brodalumab arms continued, with an exploration of wider-dose intervals for the 140-mg dose. Patients also continued with ustekinumab, with a rescue option to transition to brodalumab 210 mg. The placebo group could continue on brodalumab 210 mg as well. These two studies also had an open label long-term extension phase.

At the 12-week mark in AMAGINE-1, 41.9% of patients achieved the coprimary endpoint of 100% reduction in the Psoriasis Area and Severity Index (PASI 100) score, compared with 0.5% of those on placebo (P less than .001). AMAGINE-2 and -3 saw 44.4% and 36.7% of the brodalumab 210-mg arms achieving PASI 100 at the 12-week mark, respectively. These figures were significantly higher than the 21.7% and 18.5% reaching PASI 100 on ustekinumab (P less than .001), as well as significantly higher than the less than 1% of patients in the placebo arm who reached that endpoint.

At the end of 52 weeks, 51% of those on brodalumab 210 mg had completely clear skin, compared with 28.1% of the patients receiving ustekinumab (P less than .001).

The safety analysis for brodalumab showed that the most common adverse events were nasopharyngitis, upper respiratory tract infection, headache, and arthralgia; of these, the last two were considered adverse drug reactions. At 52 weeks, those on brodalumab had a slightly greater risk of having nonserious fungal infections than did those on ustekinumab. Overall, however, there was no difference between the brodalumab and ustekinumab arms at week 52 for treatment-emergent adverse events or for serious adverse events.

A cluster of SIB events occurred in 2013 and 2014 during the clinical trials, and the sponsor consulted the FDA. Additional monitoring for suicidal ideation and depression via the Columbia Suicide Severity Rating Scale (C-SSRS) and the Patient Health Questionnaire (PHQ) were implemented at a point where 84% of trial patients were already in the uncontrolled open label extension stage of the trial; in addition, a retrospective data review searched for suicidal ideation and attempts before the implementation of these two tools.

A total of six brodalumab patients completed suicide in all clinical trials, including those for psoriatic arthritis and RA. Suicides included two during the 12- to 52-week follow-up and four during the long-term follow-up phase. Another 29 patients attempted suicide, had intentional self-injury, or had suicidal ideation during these phases of the study, for a total of 35 SIB events. (SIB includes completed suicide, suicide attempt, suicide behavior, and suicide ideation.)*

The significance of the number of completed suicides was difficult to ascertain, given the increased baseline prevalence of depression and related illnesses among patients with psoriasis. Compared with the general population, individuals with psoriasis have hazard ratios of 1.39, 1.31, and 1.44 for depression, anxiety, and suicidality, according to a cohort study cited by Robert Levin, M.D. , director of the division of pharmacovigilance I at the FDA’s Center for Drug Evaluation and Research (CDER).

In addition, monitoring for suicidal ideation and attempts was stepped up during the course of the clinical trials. Brodalumab’s sponsor, Valeant Pharmaceuticals, noted that the rates of suicidal ideation and attempts increased after implementation of the C-SSRS, while other neuropsychiatric symptoms remained stable or declined during the course of the studies. “This makes us think this is ascertainment bias,” said Valeant consultant Lauren Marangell, M.D., a psychiatrist and president of Brain Health Consultants.

Dr. Marangell also reported that, after stratification for preexisting psychiatric comorbidities and risk factors, “there is no question that the rate of SIB is higher in both arms with patients with baseline risk factors.” The FDA’s data analysis showed an 18-fold increase in the rate of SIB for brodalumab arm participants with a prior history of suicidality.

During its presentation, Valeant also pointed out that patients with histories of drug and alcohol abuse, depression, and suicidality were not specifically excluded from the clinical trials. This differentiates the brodalumab program from other biologic studies, “making the studies more characteristic of the real world,” said R.K. Pillai, Ph.D., Valeant vice president.

Dr. Levin’s analysis, one of several independent analyses conducted by different FDA divisions, found that the data were inconclusive. “We currently can’t conclude whether or not these are drug-related risks,” he said. Considering the critical severity of suicide as an outcome, “we must consider the application and regulatory actions carefully.”

Jean Kim, M.D., medical officer in CDER’s division of psychiatry products (DPP), noted that the number of suicides seen in the brodalumab trials “is higher than typically seen in DPP’s large psychiatric drug trials, which involve populations with higher psychiatric morbidity than patients with psoriasis.”

Patients with psoriasis are also known to have a baseline elevated risk of cardiovascular disease, and no committee member felt the brodalumab data showed any additional signal for major adverse cardiovascular events (MACEs) beyond what would be suspected in this population. “I don’t right now see a safety signal for MACE,” said panelist Michael Blaha, M.D., a cardiologist and director of clinical research at Johns Hopkins Ciccarone Center for Prevention of Heart Disease, Baltimore. He noted, however, that research is ongoing to elucidate the relationship between cytokine levels and MACE. “This question about whether cytokines raise or reduce rates for [cardiovascular] events is an open one.”

One of the dermatologists on the committee, Lynn Drake, M.D., said that her decision making was influenced by the disease burden psoriasis inflicts on the patients she sees in her daily practice. “These patients are ill. People tend to think it’s just skin disease. It is not just skin disease. … I’d hate to see our patients deprived of a drug that might help alleviate their symptoms,” said Dr. Drake.

Though committee members voiced some disagreement about whether a patient registry should be established, and if it should be voluntary, they were in agreement that patients and prescribers both be aware of the potential risks of brodalumab, without making any risk management strategy so burdensome that appropriate patients would be deterred from considering the medication. Psoriasis, Dr. Drake said, “is a devastating disease. We need this in our armamentarium.”

The proposed dosing for brodalumab is 210 mg injected subcutaneously weekly for 3 weeks, followed by 210 mg every 2 weeks thereafter.

The FDA usually follows the recommendations of its advisory committees. The panelists had no relevant financial disclosures.

koakes@frontlinemedcom.com

On Twitter @karioakes

*A previous version of this article misstated the number of patients who experienced SIB events.

A Food and Drug Administration advisory committee has unanimously supported approval of the monoclonal antibody brodalumab for the treatment of moderate to severe plaque psoriasis, with the majority recommending risk management options beyond labeling to address concerns about the six completed suicides among patients treated with brodalumab in clinical trials.

Though no members of the FDA’s Dermatologic and Ophthalmic Drugs Advisory Committee disputed the drug’s efficacy for plaque psoriasis, the possibility of a signal for suicidal ideation and behavior (SIB) among the brodalumab group prompted the committee’s chair, Michael Bigby, M.D., to remark, “The big problem is that you have six completed suicides. … I would say it’s a fairly big number for a randomized controlled trial. Patients and clinicians need to be aware of this as a fact.”

Dr. Bigby, professor of dermatology at Harvard Medical School, Boston, headed the 18-member panel, which included dermatologists, psychiatrists, and cardiologists. Fourteen members voted in favor of approval with risk management measures beyond labeling; four members voted for approval with labeling alone.

Brodalumab targets interleukin-17 receptors, inhibiting IL-17 uptake and thus blocking the pathway responsible for the cutaneous and systemic signs and symptoms of psoriasis. The pivotal phase III brodalumab studies, AMAGINE-1, -2, and -3, enrolled a total of 4,373 patients with moderate to severe plaque psoriasis. AMAGINE-1 enrolled 661 patients in a 1:1:1 ratio to a randomized, double-blind placebo-controlled study that included two doses of brodalumab: 210 mg and 140 mg. The placebo-controlled phase of the study ran for 12 weeks, followed by a withdrawal and retreatment phase, and after 52 weeks, by an open label long-term extension phase.

AMAGINE-2 (1,831 patients) and AMAGINE-3 (1,881 patients) were identically designed studies that pitted both doses of brodalumab against an active comparator, ustekinumab (Stelara), as well as placebo, in a 2:2:1:1 ratio. This double-blind phase of the study also lasted 12 weeks. During weeks 12-52, patients on the brodalumab arms continued, with an exploration of wider-dose intervals for the 140-mg dose. Patients also continued with ustekinumab, with a rescue option to transition to brodalumab 210 mg. The placebo group could continue on brodalumab 210 mg as well. These two studies also had an open label long-term extension phase.

At the 12-week mark in AMAGINE-1, 41.9% of patients achieved the coprimary endpoint of 100% reduction in the Psoriasis Area and Severity Index (PASI 100) score, compared with 0.5% of those on placebo (P less than .001). AMAGINE-2 and -3 saw 44.4% and 36.7% of the brodalumab 210-mg arms achieving PASI 100 at the 12-week mark, respectively. These figures were significantly higher than the 21.7% and 18.5% reaching PASI 100 on ustekinumab (P less than .001), as well as significantly higher than the less than 1% of patients in the placebo arm who reached that endpoint.

At the end of 52 weeks, 51% of those on brodalumab 210 mg had completely clear skin, compared with 28.1% of the patients receiving ustekinumab (P less than .001).

The safety analysis for brodalumab showed that the most common adverse events were nasopharyngitis, upper respiratory tract infection, headache, and arthralgia; of these, the last two were considered adverse drug reactions. At 52 weeks, those on brodalumab had a slightly greater risk of having nonserious fungal infections than did those on ustekinumab. Overall, however, there was no difference between the brodalumab and ustekinumab arms at week 52 for treatment-emergent adverse events or for serious adverse events.

A cluster of SIB events occurred in 2013 and 2014 during the clinical trials, and the sponsor consulted the FDA. Additional monitoring for suicidal ideation and depression via the Columbia Suicide Severity Rating Scale (C-SSRS) and the Patient Health Questionnaire (PHQ) were implemented at a point where 84% of trial patients were already in the uncontrolled open label extension stage of the trial; in addition, a retrospective data review searched for suicidal ideation and attempts before the implementation of these two tools.

A total of six brodalumab patients completed suicide in all clinical trials, including those for psoriatic arthritis and RA. Suicides included two during the 12- to 52-week follow-up and four during the long-term follow-up phase. Another 29 patients attempted suicide, had intentional self-injury, or had suicidal ideation during these phases of the study, for a total of 35 SIB events. (SIB includes completed suicide, suicide attempt, suicide behavior, and suicide ideation.)*

The significance of the number of completed suicides was difficult to ascertain, given the increased baseline prevalence of depression and related illnesses among patients with psoriasis. Compared with the general population, individuals with psoriasis have hazard ratios of 1.39, 1.31, and 1.44 for depression, anxiety, and suicidality, according to a cohort study cited by Robert Levin, M.D. , director of the division of pharmacovigilance I at the FDA’s Center for Drug Evaluation and Research (CDER).

In addition, monitoring for suicidal ideation and attempts was stepped up during the course of the clinical trials. Brodalumab’s sponsor, Valeant Pharmaceuticals, noted that the rates of suicidal ideation and attempts increased after implementation of the C-SSRS, while other neuropsychiatric symptoms remained stable or declined during the course of the studies. “This makes us think this is ascertainment bias,” said Valeant consultant Lauren Marangell, M.D., a psychiatrist and president of Brain Health Consultants.

Dr. Marangell also reported that, after stratification for preexisting psychiatric comorbidities and risk factors, “there is no question that the rate of SIB is higher in both arms with patients with baseline risk factors.” The FDA’s data analysis showed an 18-fold increase in the rate of SIB for brodalumab arm participants with a prior history of suicidality.

During its presentation, Valeant also pointed out that patients with histories of drug and alcohol abuse, depression, and suicidality were not specifically excluded from the clinical trials. This differentiates the brodalumab program from other biologic studies, “making the studies more characteristic of the real world,” said R.K. Pillai, Ph.D., Valeant vice president.

Dr. Levin’s analysis, one of several independent analyses conducted by different FDA divisions, found that the data were inconclusive. “We currently can’t conclude whether or not these are drug-related risks,” he said. Considering the critical severity of suicide as an outcome, “we must consider the application and regulatory actions carefully.”

Jean Kim, M.D., medical officer in CDER’s division of psychiatry products (DPP), noted that the number of suicides seen in the brodalumab trials “is higher than typically seen in DPP’s large psychiatric drug trials, which involve populations with higher psychiatric morbidity than patients with psoriasis.”

Patients with psoriasis are also known to have a baseline elevated risk of cardiovascular disease, and no committee member felt the brodalumab data showed any additional signal for major adverse cardiovascular events (MACEs) beyond what would be suspected in this population. “I don’t right now see a safety signal for MACE,” said panelist Michael Blaha, M.D., a cardiologist and director of clinical research at Johns Hopkins Ciccarone Center for Prevention of Heart Disease, Baltimore. He noted, however, that research is ongoing to elucidate the relationship between cytokine levels and MACE. “This question about whether cytokines raise or reduce rates for [cardiovascular] events is an open one.”

One of the dermatologists on the committee, Lynn Drake, M.D., said that her decision making was influenced by the disease burden psoriasis inflicts on the patients she sees in her daily practice. “These patients are ill. People tend to think it’s just skin disease. It is not just skin disease. … I’d hate to see our patients deprived of a drug that might help alleviate their symptoms,” said Dr. Drake.

Though committee members voiced some disagreement about whether a patient registry should be established, and if it should be voluntary, they were in agreement that patients and prescribers both be aware of the potential risks of brodalumab, without making any risk management strategy so burdensome that appropriate patients would be deterred from considering the medication. Psoriasis, Dr. Drake said, “is a devastating disease. We need this in our armamentarium.”

The proposed dosing for brodalumab is 210 mg injected subcutaneously weekly for 3 weeks, followed by 210 mg every 2 weeks thereafter.

The FDA usually follows the recommendations of its advisory committees. The panelists had no relevant financial disclosures.

koakes@frontlinemedcom.com

On Twitter @karioakes

*A previous version of this article misstated the number of patients who experienced SIB events.

NEW YORK - Greater access to alcohol is linked with more atrial fibrillation but less myocardial infarction and congestive heart failure, researchers report.

Dr. Gregory M. Marcus, from the Division of Cardiology at the University of California, San Francisco, and colleagues conducted an observational cohort study of differences in health outcomes based on alcohol sales laws by county in Texas.

All patients were residents of Texas, 21 years old or older, and were admitted to hospitals in Texas between 2005 and 2010. More than 1 million patients were included in the analysis.

Of the counties, 47 were wet (no restrictions on the sale of alcohol) and 29 were dry (prohibition of alcohol sales). Seven of them changed from dry to wet during the study period.

The main cardiovascular outcomes were atrial fibrillation, acute myocardial infarction, and congestive heart failure.

After multivariable adjustment, wet county residents had a greater prevalence (odds ratio 1.05, p=0.007) and incidence (HR 1.07, p=0.014) of atrial fibrillation.

Prevalence of myocardial infarction was lower (OR 0.83, p<0.001), as was its incidence (HR 0.91, p=0.019). Prevalence of congestive heart failure was also lower (OR 0.87, p<0.001).

In the seven dry counties that changed their status to wet, the post-conversion interval (from dry to wet county status) was associated with greater odds of hospitalization for atrial fibrillation (OR 1.07, p=0.001) and congestive heart failure (OR 1.07, p<0.001).

The researchers found no difference in acute myocardial infarction (OR 0.99, p=0.746).

"Cardiovascular disease is the most common cause of death worldwide, and alcohol is the most widely consumed drug in the United States," said Dr. Rory Brett Weiner, a cardiologist at Massachusetts General Hospital in Boston.

He said that studying the impact of alcohol intake on incident cardiovascular disease is important for its public health implications.

"Differences in laws affecting access to alcohol are associated with changes in health outcomes, both harmful and protective," said Dr. Marcus, "but the study's findings shouldn't be used to change any specific legislation."

Dr. Weiner agreed. "The study design minimizes confounders commonly seen in prior research that relied on self-report," he said, "but it still doesn't provide conclusive evidence with regard to the use of alcohol and incident cardiovascular disease."

Dr. Weiner said that the study did not contain information on the level of individual alcohol exposure, and therefore, the impact of the 'dose' of alcohol on cardiovascular outcomes could not be ascertained.

"Based on the question at hand -- the impact of alcohol -- it's unlikely that a randomized controlled study will ever be performed," he said, "so analyses like the current one are important."

According to Dr. Marcus, "We still don't understand the mechanisms underlying the relationship between alcohol and cardiovascular disease, and have a long way to go to achieve the sort of personalized medicine needed to figure out how to counsel an individual patient on their particular "prescribed" amount, if any, of alcohol."

The National Institute on Alcohol Abuse and Alcoholism supported this research. Dr. Marcus reported research support from Medtronic and Pfizer and equity interest in InCarda.

SOURCE: http://bit.ly/1tlx1cx

BMJ 2016

NEW YORK - Greater access to alcohol is linked with more atrial fibrillation but less myocardial infarction and congestive heart failure, researchers report.

Dr. Gregory M. Marcus, from the Division of Cardiology at the University of California, San Francisco, and colleagues conducted an observational cohort study of differences in health outcomes based on alcohol sales laws by county in Texas.

All patients were residents of Texas, 21 years old or older, and were admitted to hospitals in Texas between 2005 and 2010. More than 1 million patients were included in the analysis.

Of the counties, 47 were wet (no restrictions on the sale of alcohol) and 29 were dry (prohibition of alcohol sales). Seven of them changed from dry to wet during the study period.

The main cardiovascular outcomes were atrial fibrillation, acute myocardial infarction, and congestive heart failure.

After multivariable adjustment, wet county residents had a greater prevalence (odds ratio 1.05, p=0.007) and incidence (HR 1.07, p=0.014) of atrial fibrillation.

Prevalence of myocardial infarction was lower (OR 0.83, p<0.001), as was its incidence (HR 0.91, p=0.019). Prevalence of congestive heart failure was also lower (OR 0.87, p<0.001).

In the seven dry counties that changed their status to wet, the post-conversion interval (from dry to wet county status) was associated with greater odds of hospitalization for atrial fibrillation (OR 1.07, p=0.001) and congestive heart failure (OR 1.07, p<0.001).

The researchers found no difference in acute myocardial infarction (OR 0.99, p=0.746).

"Cardiovascular disease is the most common cause of death worldwide, and alcohol is the most widely consumed drug in the United States," said Dr. Rory Brett Weiner, a cardiologist at Massachusetts General Hospital in Boston.

He said that studying the impact of alcohol intake on incident cardiovascular disease is important for its public health implications.

"Differences in laws affecting access to alcohol are associated with changes in health outcomes, both harmful and protective," said Dr. Marcus, "but the study's findings shouldn't be used to change any specific legislation."

Dr. Weiner agreed. "The study design minimizes confounders commonly seen in prior research that relied on self-report," he said, "but it still doesn't provide conclusive evidence with regard to the use of alcohol and incident cardiovascular disease."

Dr. Weiner said that the study did not contain information on the level of individual alcohol exposure, and therefore, the impact of the 'dose' of alcohol on cardiovascular outcomes could not be ascertained.

"Based on the question at hand -- the impact of alcohol -- it's unlikely that a randomized controlled study will ever be performed," he said, "so analyses like the current one are important."

According to Dr. Marcus, "We still don't understand the mechanisms underlying the relationship between alcohol and cardiovascular disease, and have a long way to go to achieve the sort of personalized medicine needed to figure out how to counsel an individual patient on their particular "prescribed" amount, if any, of alcohol."

The National Institute on Alcohol Abuse and Alcoholism supported this research. Dr. Marcus reported research support from Medtronic and Pfizer and equity interest in InCarda.

SOURCE: http://bit.ly/1tlx1cx

BMJ 2016

NEW YORK - Greater access to alcohol is linked with more atrial fibrillation but less myocardial infarction and congestive heart failure, researchers report.

Dr. Gregory M. Marcus, from the Division of Cardiology at the University of California, San Francisco, and colleagues conducted an observational cohort study of differences in health outcomes based on alcohol sales laws by county in Texas.

All patients were residents of Texas, 21 years old or older, and were admitted to hospitals in Texas between 2005 and 2010. More than 1 million patients were included in the analysis.

Of the counties, 47 were wet (no restrictions on the sale of alcohol) and 29 were dry (prohibition of alcohol sales). Seven of them changed from dry to wet during the study period.

The main cardiovascular outcomes were atrial fibrillation, acute myocardial infarction, and congestive heart failure.

After multivariable adjustment, wet county residents had a greater prevalence (odds ratio 1.05, p=0.007) and incidence (HR 1.07, p=0.014) of atrial fibrillation.

Prevalence of myocardial infarction was lower (OR 0.83, p<0.001), as was its incidence (HR 0.91, p=0.019). Prevalence of congestive heart failure was also lower (OR 0.87, p<0.001).

In the seven dry counties that changed their status to wet, the post-conversion interval (from dry to wet county status) was associated with greater odds of hospitalization for atrial fibrillation (OR 1.07, p=0.001) and congestive heart failure (OR 1.07, p<0.001).

The researchers found no difference in acute myocardial infarction (OR 0.99, p=0.746).

"Cardiovascular disease is the most common cause of death worldwide, and alcohol is the most widely consumed drug in the United States," said Dr. Rory Brett Weiner, a cardiologist at Massachusetts General Hospital in Boston.

He said that studying the impact of alcohol intake on incident cardiovascular disease is important for its public health implications.

"Differences in laws affecting access to alcohol are associated with changes in health outcomes, both harmful and protective," said Dr. Marcus, "but the study's findings shouldn't be used to change any specific legislation."

Dr. Weiner agreed. "The study design minimizes confounders commonly seen in prior research that relied on self-report," he said, "but it still doesn't provide conclusive evidence with regard to the use of alcohol and incident cardiovascular disease."

Dr. Weiner said that the study did not contain information on the level of individual alcohol exposure, and therefore, the impact of the 'dose' of alcohol on cardiovascular outcomes could not be ascertained.

"Based on the question at hand -- the impact of alcohol -- it's unlikely that a randomized controlled study will ever be performed," he said, "so analyses like the current one are important."

According to Dr. Marcus, "We still don't understand the mechanisms underlying the relationship between alcohol and cardiovascular disease, and have a long way to go to achieve the sort of personalized medicine needed to figure out how to counsel an individual patient on their particular "prescribed" amount, if any, of alcohol."

The National Institute on Alcohol Abuse and Alcoholism supported this research. Dr. Marcus reported research support from Medtronic and Pfizer and equity interest in InCarda.

SOURCE: http://bit.ly/1tlx1cx

BMJ 2016

DURBAN, SOUTH AFRICA – Women who consistently used a monthly vaginal ring containing the antiretroviral drug dapivirine reduced their risk of acquiring HIV infection by 75%-91% in exploratory analyses of the phase III ASPIRE study, Elizabeth R. Brown, ScD, reported at the 21st International AIDS Conference.

ASPIRE (A Study to Prevent Infection with a Ring for Extended use), also known as the Microbicide Trials Network-020 trial, was a multicenter, randomized, double-blind, placebo-controlled, phase III trial of a silicone vaginal ring containing 25 mg of the non-nucleoside reverse transcriptase inhibitor dapivirine. ASPIRE involved 2,629 HIV-uninfected women aged 18-45 years from four Southern African countries with extremely high HIV infection rates: South Africa, Uganda, Malawi, and Zimbabwe. They were prospectively followed monthly for 12-33 months.

As reported at a conference earlier in 2016, seroconversion occurred in 71 women assigned to the dapivirine ring and 97 on a placebo ring during 4,280 person-years of follow-up. The resultant 27% relative risk reduction in an intent-to-treat analysis, while statistically significant, was less than hoped for by investigators.

However, the device only works if it’s used consistently, so the investigators decided to conduct exploratory analyses using an objective measure of adherence: the amount of dapivirine remaining in a ring after a month’s use. This was possible because the rings had been stored for analysis in a central laboratory.

The vaginal ring is self-inserted, then meant to be kept in place continuously for a month before being self-removed and replaced with a fresh ring. Dapivirine is released continuously while the ring is in place, so the less residual dapivirine contained in a used ring, the greater the adherence during that month, explained Dr. Brown, a biostatistician at the University of Washington, Seattle.

A dose-response effect was observed. In the most encouraging of the exploratory time-dependent use analyses, the rate of HIV acquisition was 4.7 cases per 100 person-years with placebo, 4.9/100 person-years in women defined as nonadherent based upon a residual dapivirine level of 23.5 mg or more, 3.1 with low use, 1.9 with moderate use, and 0.4 cases/100 person-years with consistent use as directed, meaning a patient left the device in place continuously for a month as reflected in a residual dapivirine rate below 22 mg.

This translates into a 91% reduction in risk, compared with placebo, in the most consistent users, a 58% relative risk reduction with moderate use, and a 29% reduction with low use, she continued.

The new results were hailed as a major advance in preventing HIV infection.

“We’re meeting here at AIDS 2016 in Durban, capital of the KwaZulu-Natal province of South Africa, which is one of the hardest-hit areas of the world for HIV. Over the course of their lifetime, women in Southern Africa have more than a 50% chance of HIV infection. So a new prevention tool that women can use on their own discretely to protect themselves against HIV would be a game changer,” Jared Baeten, MD, PhD, said in an interview.

Bruce Jancin/Frontline Medical News

“I see this as having an important potential role in the [United States] as well for women who face an increased risk of HIV. It’s extremely valuable for them to have a method of protection that they can control and feel good about and safely use for an extended period of time,” added Dr. Baeten, professor and vice chair of global health, as well as professor of allergy and infectious diseases at the University of Washington, Seattle.

The challenges involved in consistent use of the dapivirine ring are less formidable than are those posed by consistent use of a daily oral medication for preexposure prevention, he noted.

Dr. Baeten was a leader of ASPIRE and is codirector of the HOPE (HIV Open-label Prevention Extension) study, which is now underway. The expectation is that adherence to the dapivirine vaginal ring will be better in HOPE than in ASPIRE because participants can now be counseled that the ring works, it’s safe, and there is no chance of getting a placebo device, he said.

“There is an urgent unmet need to expand long-acting HIV prevention options for women and girls,” Zeda Rosenberg, ScD, founder and chief executive officer of the nonprofit International Partnership for Microbicides (IPM) in Silver Spring, Md., which is the sponsor and developer of the ring.

Toward that end, in the next several months the ASPIRE data will be combined with those from the IPM-sponsored Ring Study, another completed large phase III trial of the dapivirine ring conducted in Africa. The goals will be to try to identify potentially modifiable sociodemographic and behavioral correlates of adherence and to further strengthen the safety and efficacy findings. The plan is to submit the full data package to the Food and Drug Administration and regulat ory agencies in other countries in the spring of 2017.

“Hopefully, the product will receive marketing approval in 2018,” Dr. Rosenberg said.

In addition to sponsoring HOPE, IPM is also sponsoring the ongoing open-label DREAM (Dapivirine Ring Extended Access and Monitoring) study. IPM is also partnering with the Microbicides Trial Network to conduct a separate study of the vaginal ring in adolescents and young women in Africa.

A dapivirine vaginal ring that’s active for 3 months rather than 1 month will begin safety studies later in 2016. The potential advantages of this product are reduced annual cost and fewer clinic visits. Also, a 3-month version of the ring with an added contraceptive has been developed and will begin safety studies in the United States in fall 2016. The possibility that suboptimal adherence can be overcome by a ring containing a higher dose of dapivirine will also be explored, according to Dr. Rosenberg.

Dr. Brown, Dr. Baeten, and Dr. Rosenberg reported having no financial conflicts of interest.

bjancin@frontlinemedcom.com

DURBAN, SOUTH AFRICA – Women who consistently used a monthly vaginal ring containing the antiretroviral drug dapivirine reduced their risk of acquiring HIV infection by 75%-91% in exploratory analyses of the phase III ASPIRE study, Elizabeth R. Brown, ScD, reported at the 21st International AIDS Conference.

ASPIRE (A Study to Prevent Infection with a Ring for Extended use), also known as the Microbicide Trials Network-020 trial, was a multicenter, randomized, double-blind, placebo-controlled, phase III trial of a silicone vaginal ring containing 25 mg of the non-nucleoside reverse transcriptase inhibitor dapivirine. ASPIRE involved 2,629 HIV-uninfected women aged 18-45 years from four Southern African countries with extremely high HIV infection rates: South Africa, Uganda, Malawi, and Zimbabwe. They were prospectively followed monthly for 12-33 months.

As reported at a conference earlier in 2016, seroconversion occurred in 71 women assigned to the dapivirine ring and 97 on a placebo ring during 4,280 person-years of follow-up. The resultant 27% relative risk reduction in an intent-to-treat analysis, while statistically significant, was less than hoped for by investigators.

However, the device only works if it’s used consistently, so the investigators decided to conduct exploratory analyses using an objective measure of adherence: the amount of dapivirine remaining in a ring after a month’s use. This was possible because the rings had been stored for analysis in a central laboratory.

The vaginal ring is self-inserted, then meant to be kept in place continuously for a month before being self-removed and replaced with a fresh ring. Dapivirine is released continuously while the ring is in place, so the less residual dapivirine contained in a used ring, the greater the adherence during that month, explained Dr. Brown, a biostatistician at the University of Washington, Seattle.

A dose-response effect was observed. In the most encouraging of the exploratory time-dependent use analyses, the rate of HIV acquisition was 4.7 cases per 100 person-years with placebo, 4.9/100 person-years in women defined as nonadherent based upon a residual dapivirine level of 23.5 mg or more, 3.1 with low use, 1.9 with moderate use, and 0.4 cases/100 person-years with consistent use as directed, meaning a patient left the device in place continuously for a month as reflected in a residual dapivirine rate below 22 mg.

This translates into a 91% reduction in risk, compared with placebo, in the most consistent users, a 58% relative risk reduction with moderate use, and a 29% reduction with low use, she continued.

The new results were hailed as a major advance in preventing HIV infection.

“We’re meeting here at AIDS 2016 in Durban, capital of the KwaZulu-Natal province of South Africa, which is one of the hardest-hit areas of the world for HIV. Over the course of their lifetime, women in Southern Africa have more than a 50% chance of HIV infection. So a new prevention tool that women can use on their own discretely to protect themselves against HIV would be a game changer,” Jared Baeten, MD, PhD, said in an interview.

Bruce Jancin/Frontline Medical News

“I see this as having an important potential role in the [United States] as well for women who face an increased risk of HIV. It’s extremely valuable for them to have a method of protection that they can control and feel good about and safely use for an extended period of time,” added Dr. Baeten, professor and vice chair of global health, as well as professor of allergy and infectious diseases at the University of Washington, Seattle.

The challenges involved in consistent use of the dapivirine ring are less formidable than are those posed by consistent use of a daily oral medication for preexposure prevention, he noted.

Dr. Baeten was a leader of ASPIRE and is codirector of the HOPE (HIV Open-label Prevention Extension) study, which is now underway. The expectation is that adherence to the dapivirine vaginal ring will be better in HOPE than in ASPIRE because participants can now be counseled that the ring works, it’s safe, and there is no chance of getting a placebo device, he said.

“There is an urgent unmet need to expand long-acting HIV prevention options for women and girls,” Zeda Rosenberg, ScD, founder and chief executive officer of the nonprofit International Partnership for Microbicides (IPM) in Silver Spring, Md., which is the sponsor and developer of the ring.

Toward that end, in the next several months the ASPIRE data will be combined with those from the IPM-sponsored Ring Study, another completed large phase III trial of the dapivirine ring conducted in Africa. The goals will be to try to identify potentially modifiable sociodemographic and behavioral correlates of adherence and to further strengthen the safety and efficacy findings. The plan is to submit the full data package to the Food and Drug Administration and regulat ory agencies in other countries in the spring of 2017.

“Hopefully, the product will receive marketing approval in 2018,” Dr. Rosenberg said.

In addition to sponsoring HOPE, IPM is also sponsoring the ongoing open-label DREAM (Dapivirine Ring Extended Access and Monitoring) study. IPM is also partnering with the Microbicides Trial Network to conduct a separate study of the vaginal ring in adolescents and young women in Africa.

A dapivirine vaginal ring that’s active for 3 months rather than 1 month will begin safety studies later in 2016. The potential advantages of this product are reduced annual cost and fewer clinic visits. Also, a 3-month version of the ring with an added contraceptive has been developed and will begin safety studies in the United States in fall 2016. The possibility that suboptimal adherence can be overcome by a ring containing a higher dose of dapivirine will also be explored, according to Dr. Rosenberg.

Dr. Brown, Dr. Baeten, and Dr. Rosenberg reported having no financial conflicts of interest.

bjancin@frontlinemedcom.com

DURBAN, SOUTH AFRICA – Women who consistently used a monthly vaginal ring containing the antiretroviral drug dapivirine reduced their risk of acquiring HIV infection by 75%-91% in exploratory analyses of the phase III ASPIRE study, Elizabeth R. Brown, ScD, reported at the 21st International AIDS Conference.

ASPIRE (A Study to Prevent Infection with a Ring for Extended use), also known as the Microbicide Trials Network-020 trial, was a multicenter, randomized, double-blind, placebo-controlled, phase III trial of a silicone vaginal ring containing 25 mg of the non-nucleoside reverse transcriptase inhibitor dapivirine. ASPIRE involved 2,629 HIV-uninfected women aged 18-45 years from four Southern African countries with extremely high HIV infection rates: South Africa, Uganda, Malawi, and Zimbabwe. They were prospectively followed monthly for 12-33 months.

As reported at a conference earlier in 2016, seroconversion occurred in 71 women assigned to the dapivirine ring and 97 on a placebo ring during 4,280 person-years of follow-up. The resultant 27% relative risk reduction in an intent-to-treat analysis, while statistically significant, was less than hoped for by investigators.

However, the device only works if it’s used consistently, so the investigators decided to conduct exploratory analyses using an objective measure of adherence: the amount of dapivirine remaining in a ring after a month’s use. This was possible because the rings had been stored for analysis in a central laboratory.

The vaginal ring is self-inserted, then meant to be kept in place continuously for a month before being self-removed and replaced with a fresh ring. Dapivirine is released continuously while the ring is in place, so the less residual dapivirine contained in a used ring, the greater the adherence during that month, explained Dr. Brown, a biostatistician at the University of Washington, Seattle.

A dose-response effect was observed. In the most encouraging of the exploratory time-dependent use analyses, the rate of HIV acquisition was 4.7 cases per 100 person-years with placebo, 4.9/100 person-years in women defined as nonadherent based upon a residual dapivirine level of 23.5 mg or more, 3.1 with low use, 1.9 with moderate use, and 0.4 cases/100 person-years with consistent use as directed, meaning a patient left the device in place continuously for a month as reflected in a residual dapivirine rate below 22 mg.

This translates into a 91% reduction in risk, compared with placebo, in the most consistent users, a 58% relative risk reduction with moderate use, and a 29% reduction with low use, she continued.

The new results were hailed as a major advance in preventing HIV infection.

“We’re meeting here at AIDS 2016 in Durban, capital of the KwaZulu-Natal province of South Africa, which is one of the hardest-hit areas of the world for HIV. Over the course of their lifetime, women in Southern Africa have more than a 50% chance of HIV infection. So a new prevention tool that women can use on their own discretely to protect themselves against HIV would be a game changer,” Jared Baeten, MD, PhD, said in an interview.

Bruce Jancin/Frontline Medical News

“I see this as having an important potential role in the [United States] as well for women who face an increased risk of HIV. It’s extremely valuable for them to have a method of protection that they can control and feel good about and safely use for an extended period of time,” added Dr. Baeten, professor and vice chair of global health, as well as professor of allergy and infectious diseases at the University of Washington, Seattle.

The challenges involved in consistent use of the dapivirine ring are less formidable than are those posed by consistent use of a daily oral medication for preexposure prevention, he noted.

Dr. Baeten was a leader of ASPIRE and is codirector of the HOPE (HIV Open-label Prevention Extension) study, which is now underway. The expectation is that adherence to the dapivirine vaginal ring will be better in HOPE than in ASPIRE because participants can now be counseled that the ring works, it’s safe, and there is no chance of getting a placebo device, he said.

“There is an urgent unmet need to expand long-acting HIV prevention options for women and girls,” Zeda Rosenberg, ScD, founder and chief executive officer of the nonprofit International Partnership for Microbicides (IPM) in Silver Spring, Md., which is the sponsor and developer of the ring.

Toward that end, in the next several months the ASPIRE data will be combined with those from the IPM-sponsored Ring Study, another completed large phase III trial of the dapivirine ring conducted in Africa. The goals will be to try to identify potentially modifiable sociodemographic and behavioral correlates of adherence and to further strengthen the safety and efficacy findings. The plan is to submit the full data package to the Food and Drug Administration and regulat ory agencies in other countries in the spring of 2017.

“Hopefully, the product will receive marketing approval in 2018,” Dr. Rosenberg said.

In addition to sponsoring HOPE, IPM is also sponsoring the ongoing open-label DREAM (Dapivirine Ring Extended Access and Monitoring) study. IPM is also partnering with the Microbicides Trial Network to conduct a separate study of the vaginal ring in adolescents and young women in Africa.

A dapivirine vaginal ring that’s active for 3 months rather than 1 month will begin safety studies later in 2016. The potential advantages of this product are reduced annual cost and fewer clinic visits. Also, a 3-month version of the ring with an added contraceptive has been developed and will begin safety studies in the United States in fall 2016. The possibility that suboptimal adherence can be overcome by a ring containing a higher dose of dapivirine will also be explored, according to Dr. Rosenberg.

Dr. Brown, Dr. Baeten, and Dr. Rosenberg reported having no financial conflicts of interest.

bjancin@frontlinemedcom.com

The cognitive effects of estrogen were no different in women who started taking the hormone within 6 years of menopause, compared with those who began it 10 or more years after menopause, based on data from the double-blind randomized ELITE-Cog trial.

“Some hormone effects on cognition are postulated to vary by age or by timing in relation to the menopause,” wrote Victor W. Henderson, M.D., of Stanford (Calif.) University and his colleagues (Neurology. 2016 Jul 20. doi: 10.1212/WNL.0000000000002980).

©Highwaystarz-Photography/Thinkstock

To test whether the timing of estrogen therapy affected the primary cognitive endpoint of verbal episodic memory, the researchers conducted the ELITE (Early vs. Late Intervention Trial With Estradiol) trial in which they randomized 567 healthy women within 6 years of menopause or 10 or more years post menopause to 1 mg/day of oral 17-beta-estradiol or a placebo. Women with a uterus also received either 45 mg progesterone as a 4% vaginal gel or a matched placebo gel.

The main ELITE trial tested the effect of the timing of estradiol, compared with placebo, on the progression of subclinical atherosclerosis, whereas the ELITE-Cog trial assessed the effects of the timing of estradiol on a composite test of verbal episodic memory.

Overall, composite scores of verbal memory were not significantly different in women randomized to estrogen vs. placebo based on a mean standardized difference of –0.06 (95% confidence interval, –0.22 to 0.09) after an average of 57 months of treatment. The mean standardized difference was similar in the early and late treatment groups. In addition, the mean standardized differences in measures of executive functions (–0.04; 95% CI, –0.21 to 0.14) and global cognition (–0.025; 95% CI, –0.18 to 0.13) were not significantly different between women who started estrogen within 6 years of menopause and those who started estrogen 10 years or more after menopause. Safety profiles were similar between the groups.

“Results of this randomized, double-blind placebo-controlled trial fail to confirm the timing hypothesis for cognitive outcomes in healthy postmenopausal women,” the researchers wrote.

The results don’t generalize to other subgroups including women of reproductive age, those in transition to menopause, or those with premature menopause caused by surgery or chemotherapy, and the study “was not designed to assess short-term cognitive effects of estradiol or effects on risks of mild cognitive impairment or Alzheimer disease,” the researchers noted. However, the findings should be reassuring to healthy, younger postmenopausal women considering estrogen therapy, they said.

The study was supported by a grant from the National Institutes of Health, and the study drugs and placebo were supplied by Teva, Watson, and Abbott Laboratories. Dr. Henderson disclosed research support from the NIH, as well as travel expenses from the NIH, American Academy of Neurology, and International Menopause Society.

The cognitive effects of estrogen were no different in women who started taking the hormone within 6 years of menopause, compared with those who began it 10 or more years after menopause, based on data from the double-blind randomized ELITE-Cog trial.

“Some hormone effects on cognition are postulated to vary by age or by timing in relation to the menopause,” wrote Victor W. Henderson, M.D., of Stanford (Calif.) University and his colleagues (Neurology. 2016 Jul 20. doi: 10.1212/WNL.0000000000002980).

©Highwaystarz-Photography/Thinkstock

To test whether the timing of estrogen therapy affected the primary cognitive endpoint of verbal episodic memory, the researchers conducted the ELITE (Early vs. Late Intervention Trial With Estradiol) trial in which they randomized 567 healthy women within 6 years of menopause or 10 or more years post menopause to 1 mg/day of oral 17-beta-estradiol or a placebo. Women with a uterus also received either 45 mg progesterone as a 4% vaginal gel or a matched placebo gel.

The main ELITE trial tested the effect of the timing of estradiol, compared with placebo, on the progression of subclinical atherosclerosis, whereas the ELITE-Cog trial assessed the effects of the timing of estradiol on a composite test of verbal episodic memory.

Overall, composite scores of verbal memory were not significantly different in women randomized to estrogen vs. placebo based on a mean standardized difference of –0.06 (95% confidence interval, –0.22 to 0.09) after an average of 57 months of treatment. The mean standardized difference was similar in the early and late treatment groups. In addition, the mean standardized differences in measures of executive functions (–0.04; 95% CI, –0.21 to 0.14) and global cognition (–0.025; 95% CI, –0.18 to 0.13) were not significantly different between women who started estrogen within 6 years of menopause and those who started estrogen 10 years or more after menopause. Safety profiles were similar between the groups.

“Results of this randomized, double-blind placebo-controlled trial fail to confirm the timing hypothesis for cognitive outcomes in healthy postmenopausal women,” the researchers wrote.

The results don’t generalize to other subgroups including women of reproductive age, those in transition to menopause, or those with premature menopause caused by surgery or chemotherapy, and the study “was not designed to assess short-term cognitive effects of estradiol or effects on risks of mild cognitive impairment or Alzheimer disease,” the researchers noted. However, the findings should be reassuring to healthy, younger postmenopausal women considering estrogen therapy, they said.

The study was supported by a grant from the National Institutes of Health, and the study drugs and placebo were supplied by Teva, Watson, and Abbott Laboratories. Dr. Henderson disclosed research support from the NIH, as well as travel expenses from the NIH, American Academy of Neurology, and International Menopause Society.

The cognitive effects of estrogen were no different in women who started taking the hormone within 6 years of menopause, compared with those who began it 10 or more years after menopause, based on data from the double-blind randomized ELITE-Cog trial.

“Some hormone effects on cognition are postulated to vary by age or by timing in relation to the menopause,” wrote Victor W. Henderson, M.D., of Stanford (Calif.) University and his colleagues (Neurology. 2016 Jul 20. doi: 10.1212/WNL.0000000000002980).

©Highwaystarz-Photography/Thinkstock

To test whether the timing of estrogen therapy affected the primary cognitive endpoint of verbal episodic memory, the researchers conducted the ELITE (Early vs. Late Intervention Trial With Estradiol) trial in which they randomized 567 healthy women within 6 years of menopause or 10 or more years post menopause to 1 mg/day of oral 17-beta-estradiol or a placebo. Women with a uterus also received either 45 mg progesterone as a 4% vaginal gel or a matched placebo gel.

The main ELITE trial tested the effect of the timing of estradiol, compared with placebo, on the progression of subclinical atherosclerosis, whereas the ELITE-Cog trial assessed the effects of the timing of estradiol on a composite test of verbal episodic memory.

Overall, composite scores of verbal memory were not significantly different in women randomized to estrogen vs. placebo based on a mean standardized difference of –0.06 (95% confidence interval, –0.22 to 0.09) after an average of 57 months of treatment. The mean standardized difference was similar in the early and late treatment groups. In addition, the mean standardized differences in measures of executive functions (–0.04; 95% CI, –0.21 to 0.14) and global cognition (–0.025; 95% CI, –0.18 to 0.13) were not significantly different between women who started estrogen within 6 years of menopause and those who started estrogen 10 years or more after menopause. Safety profiles were similar between the groups.

“Results of this randomized, double-blind placebo-controlled trial fail to confirm the timing hypothesis for cognitive outcomes in healthy postmenopausal women,” the researchers wrote.

The results don’t generalize to other subgroups including women of reproductive age, those in transition to menopause, or those with premature menopause caused by surgery or chemotherapy, and the study “was not designed to assess short-term cognitive effects of estradiol or effects on risks of mild cognitive impairment or Alzheimer disease,” the researchers noted. However, the findings should be reassuring to healthy, younger postmenopausal women considering estrogen therapy, they said.

The study was supported by a grant from the National Institutes of Health, and the study drugs and placebo were supplied by Teva, Watson, and Abbott Laboratories. Dr. Henderson disclosed research support from the NIH, as well as travel expenses from the NIH, American Academy of Neurology, and International Menopause Society.

The Food and Drug Administration is currently accepting public comments on the agency’s proposed plans to implement a law that will restrict compounding of human drug products.

A statement issued by the FDA provides links to two draft guidances that describe how the agency “would implement provisions of federal law that restrict compounding human drug products that are essentially copies of commercially available or approved drug products.” One draft guidance and the legal restrictions referenced therein are relevant to physicians and pharmacists, as well as state-licensed pharmacies or federal facilities that compound drugs, according to the FDA. The other guidance applies to outsourcing facilities.

Although compounded drug products, such as a medication made without a dye for a patient allergic to that dye, or a medication made into liquid form for a patient who cannot swallow a pill, “may benefit certain patients whose medical needs cannot be met by a commercially available or an FDA-approved drug product,” the FDA statement said. “Taking compounded drug products that are essentially copies of a commercially available or approved drug needlessly exposes patients to drug products that FDA has not evaluated for safety, effectiveness, and quality. In addition, the compounded drugs may not have been produced according to appropriate quality standards. Such compounding would also undermine the new drug approval and over-the-counter drug monograph systems in the United States.”

The statement refers to serious adverse events, including infections and deaths that have resulted from “poor-quality” compounded drugs.

Written or electronic comments can be submitted until Oct. 11, and information on submitting comments is available at regulations.gov.

emechcatie@frontlinemedcom.com

The Food and Drug Administration is currently accepting public comments on the agency’s proposed plans to implement a law that will restrict compounding of human drug products.

A statement issued by the FDA provides links to two draft guidances that describe how the agency “would implement provisions of federal law that restrict compounding human drug products that are essentially copies of commercially available or approved drug products.” One draft guidance and the legal restrictions referenced therein are relevant to physicians and pharmacists, as well as state-licensed pharmacies or federal facilities that compound drugs, according to the FDA. The other guidance applies to outsourcing facilities.

Although compounded drug products, such as a medication made without a dye for a patient allergic to that dye, or a medication made into liquid form for a patient who cannot swallow a pill, “may benefit certain patients whose medical needs cannot be met by a commercially available or an FDA-approved drug product,” the FDA statement said. “Taking compounded drug products that are essentially copies of a commercially available or approved drug needlessly exposes patients to drug products that FDA has not evaluated for safety, effectiveness, and quality. In addition, the compounded drugs may not have been produced according to appropriate quality standards. Such compounding would also undermine the new drug approval and over-the-counter drug monograph systems in the United States.”

The statement refers to serious adverse events, including infections and deaths that have resulted from “poor-quality” compounded drugs.

Written or electronic comments can be submitted until Oct. 11, and information on submitting comments is available at regulations.gov.

emechcatie@frontlinemedcom.com

The Food and Drug Administration is currently accepting public comments on the agency’s proposed plans to implement a law that will restrict compounding of human drug products.

A statement issued by the FDA provides links to two draft guidances that describe how the agency “would implement provisions of federal law that restrict compounding human drug products that are essentially copies of commercially available or approved drug products.” One draft guidance and the legal restrictions referenced therein are relevant to physicians and pharmacists, as well as state-licensed pharmacies or federal facilities that compound drugs, according to the FDA. The other guidance applies to outsourcing facilities.

Although compounded drug products, such as a medication made without a dye for a patient allergic to that dye, or a medication made into liquid form for a patient who cannot swallow a pill, “may benefit certain patients whose medical needs cannot be met by a commercially available or an FDA-approved drug product,” the FDA statement said. “Taking compounded drug products that are essentially copies of a commercially available or approved drug needlessly exposes patients to drug products that FDA has not evaluated for safety, effectiveness, and quality. In addition, the compounded drugs may not have been produced according to appropriate quality standards. Such compounding would also undermine the new drug approval and over-the-counter drug monograph systems in the United States.”

The statement refers to serious adverse events, including infections and deaths that have resulted from “poor-quality” compounded drugs.

Written or electronic comments can be submitted until Oct. 11, and information on submitting comments is available at regulations.gov.

emechcatie@frontlinemedcom.com