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FDA approves pembrolizumab for relapsed/refractory PMBCL
The immune checkpoint inhibitor in adult and pediatric patients.
The Food and Drug Administration based the accelerated approval on results from 53 patients with relapsed or refractory primary mediastinal large B-cell lymphoma in the KEYNOTE-170 trial. In the phase 2 trial, patients received 200 mg of pembrolizumab intravenously for 3 weeks until unacceptable toxicity or documented disease progression occurred. This continued for up to 24 months in patients who did not display progression. The overall response rate to pembrolizumab was 45% (95% CI, 32-60), which included both complete (11%) and partial (34%) responses. The median duration of response was not met within the follow-up period (median, 9.7 months) and the median time to first objective response was 2.8 months.
The recommended dose for pembrolizumab in adults is 200 mg every 3 weeks. It is recommended that pediatric patients receive 2 mg/kg every 3 weeks, with a maximum dose of 200 mg.
The most common adverse reactions to pembrolizumab were musculoskeletal pain, upper respiratory tract infection, pyrexia, fatigue, cough, dyspnea, diarrhea, nausea, arrhythmia, and headache. In total, a quarter of patients with adverse reactions required systemic treatment with a corticosteroid and 26% of patients had serious adverse reactions.
Pembrolizumab was approved via the FDA’s accelerated approval process, which allows for earlier approval of drugs that treat serious medical conditions and fulfill an unmet medical need. The drug was approved based on tumor response rate and durability of response, the FDA noted.
The immune checkpoint inhibitor in adult and pediatric patients.
The Food and Drug Administration based the accelerated approval on results from 53 patients with relapsed or refractory primary mediastinal large B-cell lymphoma in the KEYNOTE-170 trial. In the phase 2 trial, patients received 200 mg of pembrolizumab intravenously for 3 weeks until unacceptable toxicity or documented disease progression occurred. This continued for up to 24 months in patients who did not display progression. The overall response rate to pembrolizumab was 45% (95% CI, 32-60), which included both complete (11%) and partial (34%) responses. The median duration of response was not met within the follow-up period (median, 9.7 months) and the median time to first objective response was 2.8 months.
The recommended dose for pembrolizumab in adults is 200 mg every 3 weeks. It is recommended that pediatric patients receive 2 mg/kg every 3 weeks, with a maximum dose of 200 mg.
The most common adverse reactions to pembrolizumab were musculoskeletal pain, upper respiratory tract infection, pyrexia, fatigue, cough, dyspnea, diarrhea, nausea, arrhythmia, and headache. In total, a quarter of patients with adverse reactions required systemic treatment with a corticosteroid and 26% of patients had serious adverse reactions.
Pembrolizumab was approved via the FDA’s accelerated approval process, which allows for earlier approval of drugs that treat serious medical conditions and fulfill an unmet medical need. The drug was approved based on tumor response rate and durability of response, the FDA noted.
The immune checkpoint inhibitor in adult and pediatric patients.
The Food and Drug Administration based the accelerated approval on results from 53 patients with relapsed or refractory primary mediastinal large B-cell lymphoma in the KEYNOTE-170 trial. In the phase 2 trial, patients received 200 mg of pembrolizumab intravenously for 3 weeks until unacceptable toxicity or documented disease progression occurred. This continued for up to 24 months in patients who did not display progression. The overall response rate to pembrolizumab was 45% (95% CI, 32-60), which included both complete (11%) and partial (34%) responses. The median duration of response was not met within the follow-up period (median, 9.7 months) and the median time to first objective response was 2.8 months.
The recommended dose for pembrolizumab in adults is 200 mg every 3 weeks. It is recommended that pediatric patients receive 2 mg/kg every 3 weeks, with a maximum dose of 200 mg.
The most common adverse reactions to pembrolizumab were musculoskeletal pain, upper respiratory tract infection, pyrexia, fatigue, cough, dyspnea, diarrhea, nausea, arrhythmia, and headache. In total, a quarter of patients with adverse reactions required systemic treatment with a corticosteroid and 26% of patients had serious adverse reactions.
Pembrolizumab was approved via the FDA’s accelerated approval process, which allows for earlier approval of drugs that treat serious medical conditions and fulfill an unmet medical need. The drug was approved based on tumor response rate and durability of response, the FDA noted.
Web portal does not reduce phone encounters or office visits for IBD patients
WASHINGTON – Inflammatory bowel disease patients may love web-based portals that allow them to interact with their doctors and records, but it does not seem to reduce their trips to the doctor.
“There was actually no decrease in office visits or phone encounters with patients that are utilizing MyChart [a web-based patient portal],” said Alexander Hristov, MD, a resident at the University of Wisconsin–Madison, in a video interview at the annual Digestive Disease Week®. “So in fact, the patients that had MyChart use were also the patients that were calling in more frequently and visiting the clinic more frequently, which is interesting because we did not see that there was an offset for emergency room visits or hospitalizations.”
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Out of the 616 total patients with either Crohn’s disease (355 patients) or ulcerative colitis (261 patients) analyzed in the study, 28% used MyChart. MyChart users also had higher number of prednisone prescriptions, compared with nonusers (51.9% vs. 40.8%, P = .01). There was no difference between MyChart users and nonusers for emergency room visits (P = .11) or hospitalizations (P = .16).
Interestingly, most messages sent via MyChart were for administrative reasons (54%), with both symptoms (28%) and education (18%) lagging behind.
Even though patients seem to like the portal, there is no billable time set aside for physicians to add the data for patients to access or respond to patient comments and requests through the portal. Unless MyChart can be shown to improve outcomes in some way, it is only an added burden for physicians.
Dr. Hristov mentioned that further work should be done to understand how web-based portals like MyChart can help both doctors and patients utilize this technology.
“We want to see the actual, measurable clinical outcomes of MyChart use,” he said. “So we want to set up a protocol where we can actually have measurable statistics looking at disease activity, inflammatory markers, and is there an impact that we are having on the patients disease course.”
Dr. Hristov had no financial disclosures to report.
SOURCE: Hristov A et al. Gastroenterology. 2018 May. doi: 0.1016/S0016-5085(18)32737-9.
WASHINGTON – Inflammatory bowel disease patients may love web-based portals that allow them to interact with their doctors and records, but it does not seem to reduce their trips to the doctor.
“There was actually no decrease in office visits or phone encounters with patients that are utilizing MyChart [a web-based patient portal],” said Alexander Hristov, MD, a resident at the University of Wisconsin–Madison, in a video interview at the annual Digestive Disease Week®. “So in fact, the patients that had MyChart use were also the patients that were calling in more frequently and visiting the clinic more frequently, which is interesting because we did not see that there was an offset for emergency room visits or hospitalizations.”
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Out of the 616 total patients with either Crohn’s disease (355 patients) or ulcerative colitis (261 patients) analyzed in the study, 28% used MyChart. MyChart users also had higher number of prednisone prescriptions, compared with nonusers (51.9% vs. 40.8%, P = .01). There was no difference between MyChart users and nonusers for emergency room visits (P = .11) or hospitalizations (P = .16).
Interestingly, most messages sent via MyChart were for administrative reasons (54%), with both symptoms (28%) and education (18%) lagging behind.
Even though patients seem to like the portal, there is no billable time set aside for physicians to add the data for patients to access or respond to patient comments and requests through the portal. Unless MyChart can be shown to improve outcomes in some way, it is only an added burden for physicians.
Dr. Hristov mentioned that further work should be done to understand how web-based portals like MyChart can help both doctors and patients utilize this technology.
“We want to see the actual, measurable clinical outcomes of MyChart use,” he said. “So we want to set up a protocol where we can actually have measurable statistics looking at disease activity, inflammatory markers, and is there an impact that we are having on the patients disease course.”
Dr. Hristov had no financial disclosures to report.
SOURCE: Hristov A et al. Gastroenterology. 2018 May. doi: 0.1016/S0016-5085(18)32737-9.
WASHINGTON – Inflammatory bowel disease patients may love web-based portals that allow them to interact with their doctors and records, but it does not seem to reduce their trips to the doctor.
“There was actually no decrease in office visits or phone encounters with patients that are utilizing MyChart [a web-based patient portal],” said Alexander Hristov, MD, a resident at the University of Wisconsin–Madison, in a video interview at the annual Digestive Disease Week®. “So in fact, the patients that had MyChart use were also the patients that were calling in more frequently and visiting the clinic more frequently, which is interesting because we did not see that there was an offset for emergency room visits or hospitalizations.”
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Out of the 616 total patients with either Crohn’s disease (355 patients) or ulcerative colitis (261 patients) analyzed in the study, 28% used MyChart. MyChart users also had higher number of prednisone prescriptions, compared with nonusers (51.9% vs. 40.8%, P = .01). There was no difference between MyChart users and nonusers for emergency room visits (P = .11) or hospitalizations (P = .16).
Interestingly, most messages sent via MyChart were for administrative reasons (54%), with both symptoms (28%) and education (18%) lagging behind.
Even though patients seem to like the portal, there is no billable time set aside for physicians to add the data for patients to access or respond to patient comments and requests through the portal. Unless MyChart can be shown to improve outcomes in some way, it is only an added burden for physicians.
Dr. Hristov mentioned that further work should be done to understand how web-based portals like MyChart can help both doctors and patients utilize this technology.
“We want to see the actual, measurable clinical outcomes of MyChart use,” he said. “So we want to set up a protocol where we can actually have measurable statistics looking at disease activity, inflammatory markers, and is there an impact that we are having on the patients disease course.”
Dr. Hristov had no financial disclosures to report.
SOURCE: Hristov A et al. Gastroenterology. 2018 May. doi: 0.1016/S0016-5085(18)32737-9.
REPORTING FROM DDW 2018
Key clinical point: Inflammatory bowel disease patients had more office visits and phone calls with physicians, and had worse outcomes.
Major finding: MyChart patients averaged 7.2 office visits and 19.2 phone encounters, compared with 5.6 office visits and 13.7 phone encounters in nonusers.
Study details: A review of patient electronic health records from Jan. 1, 2012, to December 31, 2015.
Disclosures: Dr. Hristov had no relevant financial disclosures to report.
Source: Hristov A et al Gastroenterology. 2018 May. doi: 10.1016/S0016-5085(18)32737-9.
Multiple therapies for NAFLD and NASH are now in phase 3 clinical trials
WASHINGTON – Several potential treatments for nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) currently in phase 3 trials show promise in treating these complex disorders.
“When we talk emerging treatments in NASH, focusing on phase 3s [trials], there are really four drugs,” said Stephen Harrison, MD, the medical director of Pinnacle Clinical Research at the annual Digestive Disease Week®. “There’s elafibranor, obeticholic acid (OCA), selonsertib, and cenicriviroc. Each of these have there own phase 3.”
The phase 3 trials for these drugs have different primary endpoints, an important factor to consider, according to Dr. Harrison.
OCA is one of the promising drugs to treat NASH. It is already approved by the Food and Drug Administration to treat primary biliary cholangitis. In FLINT (The Farnesoid X Receptor Ligand Obeticholic Acid in NASH Treatment Trial), a phase 2 study, OCA showed promise in treating NASH. In this double-blind, randomized, controlled trial, 141 patients received 25 mg of OCA daily for 72 weeks while another 142 received placebo. By the end of the study, 45% of 110 patients in the OCA group had improved their liver histology, compared with only 21% of patients receiving placebo.
Currently, the REGENERATE trial is evaluating the effects of obeticholic acid on histologic improvement and liver related outcomes in NASH patients. Patients have been randomized to receive either 10 mg of OCA, 25 mg of OCA, or placebo. As of yet, no results have been posted.
Much as he did for trials involving OCA, Dr. Harrison also detailed the results of a phase 2b elafibranor study that led to a registration trial that is currently underway. In Golden 505 (Phase IIb Study to Evaluate the Efficacy and Safety of GFT505 Versus Placebo in Patients With Non-Alcoholic Steatohepatitis), patients were randomized to receive either GFT505 80 mg, GFT505 120 mg, or placebo. The aim of the study was to identify the percentage of responders with disappearance of steatohepatitis without worsening of fibrosis. Unfortunately, there was no difference between placebo and the treatment groups for this outcome, although a post hoc analysis did reveal that NASH resolved in a higher proportion of the 120-mg elafibranor group, compared with the placebo group (19% vs. 12%, respectively). This also translated into a reduction of 0.65 in liver fibrosis stages in responders, compared with a 0.10 increase in nonresponders (P less than .001).
Now, elafibranor is being further examined in RESOLVE-IT (Phase 3 Study to Evaluate the Efficacy and Safety of Elafibranor Versus Placebo in Patients With Nonalcoholic Steatohepatitis), but no results have been posted at press time.
Cenicriviroc has followed a similar path, with a phase 2b leading to a phase 3 study.
CENTAUR (Efficacy and Safety Study of Cenicriviroc for the Treatment of NASH in Adult Subjects With Liver Fibrosis) looked at histologic improvement in NAFLD over the course of 2 years. Patients were randomized into either the cenicriviroc 150-mg group (group A) or two placebo groups (groups B and C) for the first year of the study. In the second year of the study patients in placebo group B started to receive 150 mg cenicriviroc and group C remained as the placebo until the end of year 2. NAFLD activity scores were similar between placebo and cenicriviroc. But, fibrosis outcomes were met at a much higher rate in the cenicriviroc group, compared with those seen with placebo (20% vs. 10%, respectively; P = 0.02).
Based on these findings, AURORA (Phase 3 Study for the Efficacy and Safety of Cenicriviroc for the Treatment of Liver Fibrosis in Adults With NASH) is now evaluating the safety and efficacy of cenicriviroc in the treatment of liver fibrosis in adults with NASH.
Finally, there is selonsertib, an ASK1 inhibitor. A phase 2 trial showed that it had the potential to induce stage reduction in fibrosis at an 18-mg dose.
Now there are two phase 3 studies, STELLAR 3 and STELLAR 4, evaluating the effects of selonsertib in adults with NASH and NASH with compensated cirrhosis.
Dr. Harrison recognizes that, because of the complexity of NASH and other fatty liver diseases, trials testing therapies for these conditions face unique challenges in the approval process.
“In fatty liver disease it’s been recognized that, to do those types of studies, it’s going to take a long time to get FDA approval,” he said. “So there’s a way to get conditional approval; it’s called the Subpart H pathway, and the FDA has accepted a couple reasonable, likely surrogates. One is resolution of NASH without worsening of fibrosis, and you need to know what that definition is: resolution of NASH.” He explained this means eliminating inflammation and ballooning rather than worrying about fat on the liver biopsy.With these four drugs in the development pipeline, Dr. Harrison sees them becoming available sometime next year.
“Looking at the data, the earliest that we are looking at therapy getting into the clinic is mid-2019,” Dr. Harrison said.
Dr. Harrison has received research grants from Genfit, Intercept, and Gilead among others. He consults for Medpace, Innovate Biopharmaceuticals, and other companies. He is also on the speakers bureau for Alexion Pharmaceuticals and AbbVie.
SOURCE: Harrison S. DDW 2018, Presentation 2230.
WASHINGTON – Several potential treatments for nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) currently in phase 3 trials show promise in treating these complex disorders.
“When we talk emerging treatments in NASH, focusing on phase 3s [trials], there are really four drugs,” said Stephen Harrison, MD, the medical director of Pinnacle Clinical Research at the annual Digestive Disease Week®. “There’s elafibranor, obeticholic acid (OCA), selonsertib, and cenicriviroc. Each of these have there own phase 3.”
The phase 3 trials for these drugs have different primary endpoints, an important factor to consider, according to Dr. Harrison.
OCA is one of the promising drugs to treat NASH. It is already approved by the Food and Drug Administration to treat primary biliary cholangitis. In FLINT (The Farnesoid X Receptor Ligand Obeticholic Acid in NASH Treatment Trial), a phase 2 study, OCA showed promise in treating NASH. In this double-blind, randomized, controlled trial, 141 patients received 25 mg of OCA daily for 72 weeks while another 142 received placebo. By the end of the study, 45% of 110 patients in the OCA group had improved their liver histology, compared with only 21% of patients receiving placebo.
Currently, the REGENERATE trial is evaluating the effects of obeticholic acid on histologic improvement and liver related outcomes in NASH patients. Patients have been randomized to receive either 10 mg of OCA, 25 mg of OCA, or placebo. As of yet, no results have been posted.
Much as he did for trials involving OCA, Dr. Harrison also detailed the results of a phase 2b elafibranor study that led to a registration trial that is currently underway. In Golden 505 (Phase IIb Study to Evaluate the Efficacy and Safety of GFT505 Versus Placebo in Patients With Non-Alcoholic Steatohepatitis), patients were randomized to receive either GFT505 80 mg, GFT505 120 mg, or placebo. The aim of the study was to identify the percentage of responders with disappearance of steatohepatitis without worsening of fibrosis. Unfortunately, there was no difference between placebo and the treatment groups for this outcome, although a post hoc analysis did reveal that NASH resolved in a higher proportion of the 120-mg elafibranor group, compared with the placebo group (19% vs. 12%, respectively). This also translated into a reduction of 0.65 in liver fibrosis stages in responders, compared with a 0.10 increase in nonresponders (P less than .001).
Now, elafibranor is being further examined in RESOLVE-IT (Phase 3 Study to Evaluate the Efficacy and Safety of Elafibranor Versus Placebo in Patients With Nonalcoholic Steatohepatitis), but no results have been posted at press time.
Cenicriviroc has followed a similar path, with a phase 2b leading to a phase 3 study.
CENTAUR (Efficacy and Safety Study of Cenicriviroc for the Treatment of NASH in Adult Subjects With Liver Fibrosis) looked at histologic improvement in NAFLD over the course of 2 years. Patients were randomized into either the cenicriviroc 150-mg group (group A) or two placebo groups (groups B and C) for the first year of the study. In the second year of the study patients in placebo group B started to receive 150 mg cenicriviroc and group C remained as the placebo until the end of year 2. NAFLD activity scores were similar between placebo and cenicriviroc. But, fibrosis outcomes were met at a much higher rate in the cenicriviroc group, compared with those seen with placebo (20% vs. 10%, respectively; P = 0.02).
Based on these findings, AURORA (Phase 3 Study for the Efficacy and Safety of Cenicriviroc for the Treatment of Liver Fibrosis in Adults With NASH) is now evaluating the safety and efficacy of cenicriviroc in the treatment of liver fibrosis in adults with NASH.
Finally, there is selonsertib, an ASK1 inhibitor. A phase 2 trial showed that it had the potential to induce stage reduction in fibrosis at an 18-mg dose.
Now there are two phase 3 studies, STELLAR 3 and STELLAR 4, evaluating the effects of selonsertib in adults with NASH and NASH with compensated cirrhosis.
Dr. Harrison recognizes that, because of the complexity of NASH and other fatty liver diseases, trials testing therapies for these conditions face unique challenges in the approval process.
“In fatty liver disease it’s been recognized that, to do those types of studies, it’s going to take a long time to get FDA approval,” he said. “So there’s a way to get conditional approval; it’s called the Subpart H pathway, and the FDA has accepted a couple reasonable, likely surrogates. One is resolution of NASH without worsening of fibrosis, and you need to know what that definition is: resolution of NASH.” He explained this means eliminating inflammation and ballooning rather than worrying about fat on the liver biopsy.With these four drugs in the development pipeline, Dr. Harrison sees them becoming available sometime next year.
“Looking at the data, the earliest that we are looking at therapy getting into the clinic is mid-2019,” Dr. Harrison said.
Dr. Harrison has received research grants from Genfit, Intercept, and Gilead among others. He consults for Medpace, Innovate Biopharmaceuticals, and other companies. He is also on the speakers bureau for Alexion Pharmaceuticals and AbbVie.
SOURCE: Harrison S. DDW 2018, Presentation 2230.
WASHINGTON – Several potential treatments for nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) currently in phase 3 trials show promise in treating these complex disorders.
“When we talk emerging treatments in NASH, focusing on phase 3s [trials], there are really four drugs,” said Stephen Harrison, MD, the medical director of Pinnacle Clinical Research at the annual Digestive Disease Week®. “There’s elafibranor, obeticholic acid (OCA), selonsertib, and cenicriviroc. Each of these have there own phase 3.”
The phase 3 trials for these drugs have different primary endpoints, an important factor to consider, according to Dr. Harrison.
OCA is one of the promising drugs to treat NASH. It is already approved by the Food and Drug Administration to treat primary biliary cholangitis. In FLINT (The Farnesoid X Receptor Ligand Obeticholic Acid in NASH Treatment Trial), a phase 2 study, OCA showed promise in treating NASH. In this double-blind, randomized, controlled trial, 141 patients received 25 mg of OCA daily for 72 weeks while another 142 received placebo. By the end of the study, 45% of 110 patients in the OCA group had improved their liver histology, compared with only 21% of patients receiving placebo.
Currently, the REGENERATE trial is evaluating the effects of obeticholic acid on histologic improvement and liver related outcomes in NASH patients. Patients have been randomized to receive either 10 mg of OCA, 25 mg of OCA, or placebo. As of yet, no results have been posted.
Much as he did for trials involving OCA, Dr. Harrison also detailed the results of a phase 2b elafibranor study that led to a registration trial that is currently underway. In Golden 505 (Phase IIb Study to Evaluate the Efficacy and Safety of GFT505 Versus Placebo in Patients With Non-Alcoholic Steatohepatitis), patients were randomized to receive either GFT505 80 mg, GFT505 120 mg, or placebo. The aim of the study was to identify the percentage of responders with disappearance of steatohepatitis without worsening of fibrosis. Unfortunately, there was no difference between placebo and the treatment groups for this outcome, although a post hoc analysis did reveal that NASH resolved in a higher proportion of the 120-mg elafibranor group, compared with the placebo group (19% vs. 12%, respectively). This also translated into a reduction of 0.65 in liver fibrosis stages in responders, compared with a 0.10 increase in nonresponders (P less than .001).
Now, elafibranor is being further examined in RESOLVE-IT (Phase 3 Study to Evaluate the Efficacy and Safety of Elafibranor Versus Placebo in Patients With Nonalcoholic Steatohepatitis), but no results have been posted at press time.
Cenicriviroc has followed a similar path, with a phase 2b leading to a phase 3 study.
CENTAUR (Efficacy and Safety Study of Cenicriviroc for the Treatment of NASH in Adult Subjects With Liver Fibrosis) looked at histologic improvement in NAFLD over the course of 2 years. Patients were randomized into either the cenicriviroc 150-mg group (group A) or two placebo groups (groups B and C) for the first year of the study. In the second year of the study patients in placebo group B started to receive 150 mg cenicriviroc and group C remained as the placebo until the end of year 2. NAFLD activity scores were similar between placebo and cenicriviroc. But, fibrosis outcomes were met at a much higher rate in the cenicriviroc group, compared with those seen with placebo (20% vs. 10%, respectively; P = 0.02).
Based on these findings, AURORA (Phase 3 Study for the Efficacy and Safety of Cenicriviroc for the Treatment of Liver Fibrosis in Adults With NASH) is now evaluating the safety and efficacy of cenicriviroc in the treatment of liver fibrosis in adults with NASH.
Finally, there is selonsertib, an ASK1 inhibitor. A phase 2 trial showed that it had the potential to induce stage reduction in fibrosis at an 18-mg dose.
Now there are two phase 3 studies, STELLAR 3 and STELLAR 4, evaluating the effects of selonsertib in adults with NASH and NASH with compensated cirrhosis.
Dr. Harrison recognizes that, because of the complexity of NASH and other fatty liver diseases, trials testing therapies for these conditions face unique challenges in the approval process.
“In fatty liver disease it’s been recognized that, to do those types of studies, it’s going to take a long time to get FDA approval,” he said. “So there’s a way to get conditional approval; it’s called the Subpart H pathway, and the FDA has accepted a couple reasonable, likely surrogates. One is resolution of NASH without worsening of fibrosis, and you need to know what that definition is: resolution of NASH.” He explained this means eliminating inflammation and ballooning rather than worrying about fat on the liver biopsy.With these four drugs in the development pipeline, Dr. Harrison sees them becoming available sometime next year.
“Looking at the data, the earliest that we are looking at therapy getting into the clinic is mid-2019,” Dr. Harrison said.
Dr. Harrison has received research grants from Genfit, Intercept, and Gilead among others. He consults for Medpace, Innovate Biopharmaceuticals, and other companies. He is also on the speakers bureau for Alexion Pharmaceuticals and AbbVie.
SOURCE: Harrison S. DDW 2018, Presentation 2230.
REPORTING FROM DDW 2018
Barrett’s segment length, low-grade dysplasia tied to increased risk of neoplastic progression
WASHINGTON – , investigators here reported, but risk of esophageal progression from Barrett’s esophagus to adenocarcinoma remains low.
Tracking neoplastic progression is of prime importance in patients with Barrett’s esophagus (BE) because it can lead to the formation of esophageal adenocarcinoma (EAD), Esther Klaver of the Academic Medical Center of the University of Amsterdam noted at the annual Digestive Disease Week. By the time many patients present with symptoms, they are at an incurable stage of the disease and have 5-year survival rates below 20%. Endoscopic surveillance of patients with BE can detect neoplastic progression and EAD when it is still curable.
Ms. Klaver and her colleagues attempted to conduct the “perfect study” by observing patients with BE to identify endoscopic and clinical factors associated with increased risk of neoplastic progression. They did this by establishing a surveillance program to track disease progression that enrolled 987 patients from 2003 to 2017 at six community-based hospitals. The patients who enrolled had been diagnosed with BE and identified via a Dutch pathology registry or were newly diagnosed BE patients. Those with any history of EAD or high-grade dysplasia (HGD) were not included.
Ms. Klaver and her colleagues found that after a 7-year follow-up period the annual risk of progression to HGD or EAD was 0.79% per patient year, with 68 of the 987 patients progressing. Of the patients who progressed, 27 progressed to HGD (40%), and 41 progressed to EAD (60%). An overwhelming majority of patients received endoscopic management (59 patients, 87%), while some patients required surgery (9, 13%). Only 32 (3%) patients in the entire study population were lost to follow-up.
Low-grade dysplasia at baseline was the factor with the highest risk for esophageal progression, with a hazard ratio (HR) of 2.33 (95% CI, 1.27-4.29). Longer BE length (HR 1.07, 95% CI 1.04-1.10) and age at baseline (HR 1.17, 95% CI 1.12-1.24) were less associated with risk of HGD or EAD, but still significant.
Ms. Klaver pointed out that this study is unique in its design. The long-term follow-up and the focus on strict adherence to guidelines and optimal surveillance set this study apart from many BE studies.
“We tried to perform the perfect, optimal, prospective Barrett’s surveillance study in a large cohort with almost 1,000 patients with a median follow-up of almost 8 years.” Ms. Klaver said. “We have done this in a community, nonacademic setting, with the average Barrett’s patient. We have showed you that even with perfect surveillance that progression risk is low, with only 68 of almost 1,000 patients showing progression.”
The study was managed by tertiary referral centers that had two research nurses who attended surveillance endoscopies to ensure that guidelines were followed. Additionally, all endoscopies were performed by a dedicated endoscopist. As part of the endoscopy visit, patients filled out questionnaires containing demographic and clinical data. Researchers also retrospectively collected any prior surveillance data for patients who had previously been under histologic and endoscopic surveillance.
Ms. Klaver and her colleagues had no financial conflicts of interest to report.
SOURCE: Klaver E. et al. Gastroenterology. 154 (6). Abstract 10. doi: 10.1016/S0016-5085(18)30500-6.
WASHINGTON – , investigators here reported, but risk of esophageal progression from Barrett’s esophagus to adenocarcinoma remains low.
Tracking neoplastic progression is of prime importance in patients with Barrett’s esophagus (BE) because it can lead to the formation of esophageal adenocarcinoma (EAD), Esther Klaver of the Academic Medical Center of the University of Amsterdam noted at the annual Digestive Disease Week. By the time many patients present with symptoms, they are at an incurable stage of the disease and have 5-year survival rates below 20%. Endoscopic surveillance of patients with BE can detect neoplastic progression and EAD when it is still curable.
Ms. Klaver and her colleagues attempted to conduct the “perfect study” by observing patients with BE to identify endoscopic and clinical factors associated with increased risk of neoplastic progression. They did this by establishing a surveillance program to track disease progression that enrolled 987 patients from 2003 to 2017 at six community-based hospitals. The patients who enrolled had been diagnosed with BE and identified via a Dutch pathology registry or were newly diagnosed BE patients. Those with any history of EAD or high-grade dysplasia (HGD) were not included.
Ms. Klaver and her colleagues found that after a 7-year follow-up period the annual risk of progression to HGD or EAD was 0.79% per patient year, with 68 of the 987 patients progressing. Of the patients who progressed, 27 progressed to HGD (40%), and 41 progressed to EAD (60%). An overwhelming majority of patients received endoscopic management (59 patients, 87%), while some patients required surgery (9, 13%). Only 32 (3%) patients in the entire study population were lost to follow-up.
Low-grade dysplasia at baseline was the factor with the highest risk for esophageal progression, with a hazard ratio (HR) of 2.33 (95% CI, 1.27-4.29). Longer BE length (HR 1.07, 95% CI 1.04-1.10) and age at baseline (HR 1.17, 95% CI 1.12-1.24) were less associated with risk of HGD or EAD, but still significant.
Ms. Klaver pointed out that this study is unique in its design. The long-term follow-up and the focus on strict adherence to guidelines and optimal surveillance set this study apart from many BE studies.
“We tried to perform the perfect, optimal, prospective Barrett’s surveillance study in a large cohort with almost 1,000 patients with a median follow-up of almost 8 years.” Ms. Klaver said. “We have done this in a community, nonacademic setting, with the average Barrett’s patient. We have showed you that even with perfect surveillance that progression risk is low, with only 68 of almost 1,000 patients showing progression.”
The study was managed by tertiary referral centers that had two research nurses who attended surveillance endoscopies to ensure that guidelines were followed. Additionally, all endoscopies were performed by a dedicated endoscopist. As part of the endoscopy visit, patients filled out questionnaires containing demographic and clinical data. Researchers also retrospectively collected any prior surveillance data for patients who had previously been under histologic and endoscopic surveillance.
Ms. Klaver and her colleagues had no financial conflicts of interest to report.
SOURCE: Klaver E. et al. Gastroenterology. 154 (6). Abstract 10. doi: 10.1016/S0016-5085(18)30500-6.
WASHINGTON – , investigators here reported, but risk of esophageal progression from Barrett’s esophagus to adenocarcinoma remains low.
Tracking neoplastic progression is of prime importance in patients with Barrett’s esophagus (BE) because it can lead to the formation of esophageal adenocarcinoma (EAD), Esther Klaver of the Academic Medical Center of the University of Amsterdam noted at the annual Digestive Disease Week. By the time many patients present with symptoms, they are at an incurable stage of the disease and have 5-year survival rates below 20%. Endoscopic surveillance of patients with BE can detect neoplastic progression and EAD when it is still curable.
Ms. Klaver and her colleagues attempted to conduct the “perfect study” by observing patients with BE to identify endoscopic and clinical factors associated with increased risk of neoplastic progression. They did this by establishing a surveillance program to track disease progression that enrolled 987 patients from 2003 to 2017 at six community-based hospitals. The patients who enrolled had been diagnosed with BE and identified via a Dutch pathology registry or were newly diagnosed BE patients. Those with any history of EAD or high-grade dysplasia (HGD) were not included.
Ms. Klaver and her colleagues found that after a 7-year follow-up period the annual risk of progression to HGD or EAD was 0.79% per patient year, with 68 of the 987 patients progressing. Of the patients who progressed, 27 progressed to HGD (40%), and 41 progressed to EAD (60%). An overwhelming majority of patients received endoscopic management (59 patients, 87%), while some patients required surgery (9, 13%). Only 32 (3%) patients in the entire study population were lost to follow-up.
Low-grade dysplasia at baseline was the factor with the highest risk for esophageal progression, with a hazard ratio (HR) of 2.33 (95% CI, 1.27-4.29). Longer BE length (HR 1.07, 95% CI 1.04-1.10) and age at baseline (HR 1.17, 95% CI 1.12-1.24) were less associated with risk of HGD or EAD, but still significant.
Ms. Klaver pointed out that this study is unique in its design. The long-term follow-up and the focus on strict adherence to guidelines and optimal surveillance set this study apart from many BE studies.
“We tried to perform the perfect, optimal, prospective Barrett’s surveillance study in a large cohort with almost 1,000 patients with a median follow-up of almost 8 years.” Ms. Klaver said. “We have done this in a community, nonacademic setting, with the average Barrett’s patient. We have showed you that even with perfect surveillance that progression risk is low, with only 68 of almost 1,000 patients showing progression.”
The study was managed by tertiary referral centers that had two research nurses who attended surveillance endoscopies to ensure that guidelines were followed. Additionally, all endoscopies were performed by a dedicated endoscopist. As part of the endoscopy visit, patients filled out questionnaires containing demographic and clinical data. Researchers also retrospectively collected any prior surveillance data for patients who had previously been under histologic and endoscopic surveillance.
Ms. Klaver and her colleagues had no financial conflicts of interest to report.
SOURCE: Klaver E. et al. Gastroenterology. 154 (6). Abstract 10. doi: 10.1016/S0016-5085(18)30500-6.
REPORTING FROM DDW 2018
Key clinical point: Barrett’s segment length and low-grade dysplasia are associated with neoplastic progression.
Major finding: Low-grade dysplasia at baseline is associated with an increased risk of high-grade dysplasia or esophageal adenocarcinoma, hazard ratio of 2.38 (1.30 - 4.36).
Study details: This study was a prospective, multi-center cohort study involving 986 patients receiving treatment in six Dutch community-based hospitals from 2003 to 2017.
Disclosures: The study author did not report any financial disclosures.
Source: Klaver E et al. Gastroenterology. 154 (6). Abstract 10. doi: 10.1016/S0016-5085(18)30500-6.
FDA approves Olumiant for treatment of rheumatoid arthritis
, an orally administered Janus kinase (JAK) inhibitor, to treat adults with moderate to severe rheumatoid arthritis (RA) who have responded inadequately or poorly to methotrexate, its manufacturer, Eli Lilly, announced June 1. The regulators voted against approval of the 4-mg dose because of concerns about the safety profile.
Olumiant is accompanied by a boxed warning about the risk of serious infections, malignancies, and thrombosis. Patients taking Olumiant also have experienced tuberculosis and opportunistic viral, fungal, and bacterial infections. These infections have led to hospitalization or death.
As part of the approval, Lilly and the original developer of baricitinib, Incyte, have agreed to conduct further randomized and controlled clinical trials to evaluate the long-term safety of Olumiant.
Lilly said in its announcement that it expects to launch Olumiant in the United States by the end of the second quarter of 2018 at a targeted price that is 60% less than “the leading TNF inhibitor.” Additionally, Lilly will offer patient support in the form of a patient support program called Olumiant Together. More information for the program can be obtained by calling 844-OLUMIANT.
, an orally administered Janus kinase (JAK) inhibitor, to treat adults with moderate to severe rheumatoid arthritis (RA) who have responded inadequately or poorly to methotrexate, its manufacturer, Eli Lilly, announced June 1. The regulators voted against approval of the 4-mg dose because of concerns about the safety profile.
Olumiant is accompanied by a boxed warning about the risk of serious infections, malignancies, and thrombosis. Patients taking Olumiant also have experienced tuberculosis and opportunistic viral, fungal, and bacterial infections. These infections have led to hospitalization or death.
As part of the approval, Lilly and the original developer of baricitinib, Incyte, have agreed to conduct further randomized and controlled clinical trials to evaluate the long-term safety of Olumiant.
Lilly said in its announcement that it expects to launch Olumiant in the United States by the end of the second quarter of 2018 at a targeted price that is 60% less than “the leading TNF inhibitor.” Additionally, Lilly will offer patient support in the form of a patient support program called Olumiant Together. More information for the program can be obtained by calling 844-OLUMIANT.
, an orally administered Janus kinase (JAK) inhibitor, to treat adults with moderate to severe rheumatoid arthritis (RA) who have responded inadequately or poorly to methotrexate, its manufacturer, Eli Lilly, announced June 1. The regulators voted against approval of the 4-mg dose because of concerns about the safety profile.
Olumiant is accompanied by a boxed warning about the risk of serious infections, malignancies, and thrombosis. Patients taking Olumiant also have experienced tuberculosis and opportunistic viral, fungal, and bacterial infections. These infections have led to hospitalization or death.
As part of the approval, Lilly and the original developer of baricitinib, Incyte, have agreed to conduct further randomized and controlled clinical trials to evaluate the long-term safety of Olumiant.
Lilly said in its announcement that it expects to launch Olumiant in the United States by the end of the second quarter of 2018 at a targeted price that is 60% less than “the leading TNF inhibitor.” Additionally, Lilly will offer patient support in the form of a patient support program called Olumiant Together. More information for the program can be obtained by calling 844-OLUMIANT.
Liver transplantation is on the rise for patients with severe alcoholic hepatitis
More transplant centers are offering liver transplantation as a viable therapeutic option for patients with severe alcoholic hepatitis who do not respond to steroid treatment.
“Alcoholic hepatitis is a disease caused by drinking alcohol. Excessive alcohol consumption causes fat to build up in your liver cells, as well as inflammation and scarring of the liver,” stated Saroja Bangaru, MD, chief resident at the University of Texas, Dallas. “Severe alcoholic hepatitis has an extremely high mortality and steroids are really the mainstay of therapy. Some alcoholic hepatitis patients do not respond to steroids and a significant percentage of them will die within 3 months. For these patients, liver transplantation is a therapeutic option.”
Dr. Bangaru and her colleagues conducted a survey that gathered data from 45 transplant centers in the United States and found that an increasing number have changed this practice and now offer liver transplantation to patients with severe alcoholic hepatitis.
The survey revealed that 51.1% of the 45 clinics offered liver transplantation to patients who had not yet been sober for 6 months, and 47.8% of transplant centers reported performing at least one liver transplant for severe alcoholic hepatitis. Just over a third (34.8%) of these centers had conducted three to five liver transplants, while only 8.9% of clinics performed at least six transplants. It is of note that most clinics have transplanted livers in fewer than five patients with severe alcoholic hepatitis, Dr. Bangaru said at the annual Digestive Disease Week®.
Patients experienced positive outcomes from these transplants, with almost 75% of surveyed clinics reporting 1-year survival rates of more than 90%, and 15% reporting 1-year survival rates of 80%-90%.
A factor that may have contributed to such positive outcomes was good patient selection based on liver transplant criteria for severe alcoholic hepatitis. More than 85% of center directors believed that liver transplant candidates should have a strong social support system, absence of severe psychiatric disorders, and a completed psychosocial evaluation, among other criteria.
Dr. Bangaru pointed out that the change in treating patients who have not abstained from alcohol is a break from traditional medical practice. “Historically, transplant centers would not consider a liver transplantation as an option unless a patient had abstained from drinking alcohol for 6 months. This rule was due to a concern that the patient would return to drinking after transplant as well as a perceived high risk that patients who continued drinking would miss medical appointments, fail to take their immunosuppressants and medications, and that this would lead to eventual graft failure.”
Another compounding issue was that patients were not counseled on their alcohol consumption habits, leading to further issues with transplantation. “Not infrequently, patients receive a diagnosis of severe alcoholic hepatitis during their initial visit and no one had previously told them to stop drinking. Since their presentation was preceded by active alcohol consumption, they would essentially be rendered ineligible for a transplant at that time,” she said.
Despite the history surrounding liver transplants in patients with severe alcoholic hepatitis, Dr. Bangaru hopes the shift in practice will improve the lives of more patients. “Because this practice of transplantation is being increasingly accepted and demonstrating positive outcomes, the hope is that more patients will be evaluated for transplantation and that transplant centers will improve their posttransplant support to ensure patients have great success after transplantation.”
Digestive Disease Week® is jointly sponsored by the American Association for the Study of Liver Diseases (AASLD), the American Gastroenterological Association (AGA) Institute, the American Society for Gastrointestinal Endoscopy (ASGE), and the Society for Surgery of the Alimentary Tract (SSAT).
More transplant centers are offering liver transplantation as a viable therapeutic option for patients with severe alcoholic hepatitis who do not respond to steroid treatment.
“Alcoholic hepatitis is a disease caused by drinking alcohol. Excessive alcohol consumption causes fat to build up in your liver cells, as well as inflammation and scarring of the liver,” stated Saroja Bangaru, MD, chief resident at the University of Texas, Dallas. “Severe alcoholic hepatitis has an extremely high mortality and steroids are really the mainstay of therapy. Some alcoholic hepatitis patients do not respond to steroids and a significant percentage of them will die within 3 months. For these patients, liver transplantation is a therapeutic option.”
Dr. Bangaru and her colleagues conducted a survey that gathered data from 45 transplant centers in the United States and found that an increasing number have changed this practice and now offer liver transplantation to patients with severe alcoholic hepatitis.
The survey revealed that 51.1% of the 45 clinics offered liver transplantation to patients who had not yet been sober for 6 months, and 47.8% of transplant centers reported performing at least one liver transplant for severe alcoholic hepatitis. Just over a third (34.8%) of these centers had conducted three to five liver transplants, while only 8.9% of clinics performed at least six transplants. It is of note that most clinics have transplanted livers in fewer than five patients with severe alcoholic hepatitis, Dr. Bangaru said at the annual Digestive Disease Week®.
Patients experienced positive outcomes from these transplants, with almost 75% of surveyed clinics reporting 1-year survival rates of more than 90%, and 15% reporting 1-year survival rates of 80%-90%.
A factor that may have contributed to such positive outcomes was good patient selection based on liver transplant criteria for severe alcoholic hepatitis. More than 85% of center directors believed that liver transplant candidates should have a strong social support system, absence of severe psychiatric disorders, and a completed psychosocial evaluation, among other criteria.
Dr. Bangaru pointed out that the change in treating patients who have not abstained from alcohol is a break from traditional medical practice. “Historically, transplant centers would not consider a liver transplantation as an option unless a patient had abstained from drinking alcohol for 6 months. This rule was due to a concern that the patient would return to drinking after transplant as well as a perceived high risk that patients who continued drinking would miss medical appointments, fail to take their immunosuppressants and medications, and that this would lead to eventual graft failure.”
Another compounding issue was that patients were not counseled on their alcohol consumption habits, leading to further issues with transplantation. “Not infrequently, patients receive a diagnosis of severe alcoholic hepatitis during their initial visit and no one had previously told them to stop drinking. Since their presentation was preceded by active alcohol consumption, they would essentially be rendered ineligible for a transplant at that time,” she said.
Despite the history surrounding liver transplants in patients with severe alcoholic hepatitis, Dr. Bangaru hopes the shift in practice will improve the lives of more patients. “Because this practice of transplantation is being increasingly accepted and demonstrating positive outcomes, the hope is that more patients will be evaluated for transplantation and that transplant centers will improve their posttransplant support to ensure patients have great success after transplantation.”
Digestive Disease Week® is jointly sponsored by the American Association for the Study of Liver Diseases (AASLD), the American Gastroenterological Association (AGA) Institute, the American Society for Gastrointestinal Endoscopy (ASGE), and the Society for Surgery of the Alimentary Tract (SSAT).
More transplant centers are offering liver transplantation as a viable therapeutic option for patients with severe alcoholic hepatitis who do not respond to steroid treatment.
“Alcoholic hepatitis is a disease caused by drinking alcohol. Excessive alcohol consumption causes fat to build up in your liver cells, as well as inflammation and scarring of the liver,” stated Saroja Bangaru, MD, chief resident at the University of Texas, Dallas. “Severe alcoholic hepatitis has an extremely high mortality and steroids are really the mainstay of therapy. Some alcoholic hepatitis patients do not respond to steroids and a significant percentage of them will die within 3 months. For these patients, liver transplantation is a therapeutic option.”
Dr. Bangaru and her colleagues conducted a survey that gathered data from 45 transplant centers in the United States and found that an increasing number have changed this practice and now offer liver transplantation to patients with severe alcoholic hepatitis.
The survey revealed that 51.1% of the 45 clinics offered liver transplantation to patients who had not yet been sober for 6 months, and 47.8% of transplant centers reported performing at least one liver transplant for severe alcoholic hepatitis. Just over a third (34.8%) of these centers had conducted three to five liver transplants, while only 8.9% of clinics performed at least six transplants. It is of note that most clinics have transplanted livers in fewer than five patients with severe alcoholic hepatitis, Dr. Bangaru said at the annual Digestive Disease Week®.
Patients experienced positive outcomes from these transplants, with almost 75% of surveyed clinics reporting 1-year survival rates of more than 90%, and 15% reporting 1-year survival rates of 80%-90%.
A factor that may have contributed to such positive outcomes was good patient selection based on liver transplant criteria for severe alcoholic hepatitis. More than 85% of center directors believed that liver transplant candidates should have a strong social support system, absence of severe psychiatric disorders, and a completed psychosocial evaluation, among other criteria.
Dr. Bangaru pointed out that the change in treating patients who have not abstained from alcohol is a break from traditional medical practice. “Historically, transplant centers would not consider a liver transplantation as an option unless a patient had abstained from drinking alcohol for 6 months. This rule was due to a concern that the patient would return to drinking after transplant as well as a perceived high risk that patients who continued drinking would miss medical appointments, fail to take their immunosuppressants and medications, and that this would lead to eventual graft failure.”
Another compounding issue was that patients were not counseled on their alcohol consumption habits, leading to further issues with transplantation. “Not infrequently, patients receive a diagnosis of severe alcoholic hepatitis during their initial visit and no one had previously told them to stop drinking. Since their presentation was preceded by active alcohol consumption, they would essentially be rendered ineligible for a transplant at that time,” she said.
Despite the history surrounding liver transplants in patients with severe alcoholic hepatitis, Dr. Bangaru hopes the shift in practice will improve the lives of more patients. “Because this practice of transplantation is being increasingly accepted and demonstrating positive outcomes, the hope is that more patients will be evaluated for transplantation and that transplant centers will improve their posttransplant support to ensure patients have great success after transplantation.”
Digestive Disease Week® is jointly sponsored by the American Association for the Study of Liver Diseases (AASLD), the American Gastroenterological Association (AGA) Institute, the American Society for Gastrointestinal Endoscopy (ASGE), and the Society for Surgery of the Alimentary Tract (SSAT).
REPORTING FROM DDW
A methylene blue dye pill sheds light on hard-to-see polyps
A methylene blue dye pill increases the adenoma detection rate in patients undergoing colonoscopy screenings.
“An oral, delayed-release, methylene blue tablet taken during the standard bowel preparation for colonoscopy has the potential to increase the adenoma detection rate and could assist in the early detection and prevention of colorectal cancer,” according to Michael B. Wallace, MD, professor of medicine and director of digestive disease research at the Mayo Clinic in Jacksonville, Fla.
“The number of polyps that providers find during a screening colonoscopy and remove is referred to as the adenoma detection rate. This is the most widely accepted national benchmark on quality for screening colonoscopy,” Dr. Wallace said in a media briefing in advance of the annual Digestive Disease Week®.
Dr. Wallace pointed out that missed adenomas tend to go on and develop into cancer.
“The ones that are most frequently missed are typically called ‘flat’ or ‘subtle’ polyps, making them very difficult to identify,” he said. “If they cannot be identified, they cannot be removed.”
The study involved more than 1,200 patients scheduled for colonoscopies at 20 centers around the world. Patients were randomly assigned to receive a full dose of the methylene blue dye, a half dose, or placebo. Patients receiving a half dose were not included in the statistical analysis, but served the purpose of not allowing doctors to know which patients were in the study group. Dr. Wallace noted that the nature of this study made it impossible to perform a truly double-blind study because the blue dye is visible during colonoscopy.
For the patients who took the full dose of methylene blue, the adenoma detection rate increased by nearly 9%, compared with the placebo group, with detection rates of 56.29% and 47.81%, respectively.
“While 9% may not actually seem like a large number, it is actually very clinically significant,” Dr. Wallace said. For every 1% increase in the absolute adenoma detection rate, there was a corresponding 3% decline in the incidence of colorectal cancer and a 5% decline in colorectal cancer deaths.
While the results of this study are overwhelmingly positive, Dr. Wallace pointed out that utilizing blue dye to increase adenoma detection rate is not a new concept, with a number of clinical trials showing its benefit.
Apart from improving adenoma detection rates, the tablet formulation of methylene blue dye no longer requires on-site mixing by providers. This was a limiting factor because the dye itself is difficult to mix and hard to obtain for many health care centers around the world. The mixed solution was also not as effective because it was sprayed during colonoscopies. Dr. Wallace asserted that spraying through the colonoscope could be imprecise, time consuming, and localized. For these reasons, this technique was never widely adopted. The primary advantage of the tablet formulation is that it releases the dye in the colon at or near the time of the colonoscopy.
Dr. Wallace emphasized that there is no substitute for good colonoscopy practice and that methylene blue is just another tool to help improve the practice.
“The oral, delayed-release methylene blue provides gastroenterologists with a new and supplemental method to improve their adenoma detection rate on top of what is otherwise a high-quality examination.
A methylene blue dye pill increases the adenoma detection rate in patients undergoing colonoscopy screenings.
“An oral, delayed-release, methylene blue tablet taken during the standard bowel preparation for colonoscopy has the potential to increase the adenoma detection rate and could assist in the early detection and prevention of colorectal cancer,” according to Michael B. Wallace, MD, professor of medicine and director of digestive disease research at the Mayo Clinic in Jacksonville, Fla.
“The number of polyps that providers find during a screening colonoscopy and remove is referred to as the adenoma detection rate. This is the most widely accepted national benchmark on quality for screening colonoscopy,” Dr. Wallace said in a media briefing in advance of the annual Digestive Disease Week®.
Dr. Wallace pointed out that missed adenomas tend to go on and develop into cancer.
“The ones that are most frequently missed are typically called ‘flat’ or ‘subtle’ polyps, making them very difficult to identify,” he said. “If they cannot be identified, they cannot be removed.”
The study involved more than 1,200 patients scheduled for colonoscopies at 20 centers around the world. Patients were randomly assigned to receive a full dose of the methylene blue dye, a half dose, or placebo. Patients receiving a half dose were not included in the statistical analysis, but served the purpose of not allowing doctors to know which patients were in the study group. Dr. Wallace noted that the nature of this study made it impossible to perform a truly double-blind study because the blue dye is visible during colonoscopy.
For the patients who took the full dose of methylene blue, the adenoma detection rate increased by nearly 9%, compared with the placebo group, with detection rates of 56.29% and 47.81%, respectively.
“While 9% may not actually seem like a large number, it is actually very clinically significant,” Dr. Wallace said. For every 1% increase in the absolute adenoma detection rate, there was a corresponding 3% decline in the incidence of colorectal cancer and a 5% decline in colorectal cancer deaths.
While the results of this study are overwhelmingly positive, Dr. Wallace pointed out that utilizing blue dye to increase adenoma detection rate is not a new concept, with a number of clinical trials showing its benefit.
Apart from improving adenoma detection rates, the tablet formulation of methylene blue dye no longer requires on-site mixing by providers. This was a limiting factor because the dye itself is difficult to mix and hard to obtain for many health care centers around the world. The mixed solution was also not as effective because it was sprayed during colonoscopies. Dr. Wallace asserted that spraying through the colonoscope could be imprecise, time consuming, and localized. For these reasons, this technique was never widely adopted. The primary advantage of the tablet formulation is that it releases the dye in the colon at or near the time of the colonoscopy.
Dr. Wallace emphasized that there is no substitute for good colonoscopy practice and that methylene blue is just another tool to help improve the practice.
“The oral, delayed-release methylene blue provides gastroenterologists with a new and supplemental method to improve their adenoma detection rate on top of what is otherwise a high-quality examination.
A methylene blue dye pill increases the adenoma detection rate in patients undergoing colonoscopy screenings.
“An oral, delayed-release, methylene blue tablet taken during the standard bowel preparation for colonoscopy has the potential to increase the adenoma detection rate and could assist in the early detection and prevention of colorectal cancer,” according to Michael B. Wallace, MD, professor of medicine and director of digestive disease research at the Mayo Clinic in Jacksonville, Fla.
“The number of polyps that providers find during a screening colonoscopy and remove is referred to as the adenoma detection rate. This is the most widely accepted national benchmark on quality for screening colonoscopy,” Dr. Wallace said in a media briefing in advance of the annual Digestive Disease Week®.
Dr. Wallace pointed out that missed adenomas tend to go on and develop into cancer.
“The ones that are most frequently missed are typically called ‘flat’ or ‘subtle’ polyps, making them very difficult to identify,” he said. “If they cannot be identified, they cannot be removed.”
The study involved more than 1,200 patients scheduled for colonoscopies at 20 centers around the world. Patients were randomly assigned to receive a full dose of the methylene blue dye, a half dose, or placebo. Patients receiving a half dose were not included in the statistical analysis, but served the purpose of not allowing doctors to know which patients were in the study group. Dr. Wallace noted that the nature of this study made it impossible to perform a truly double-blind study because the blue dye is visible during colonoscopy.
For the patients who took the full dose of methylene blue, the adenoma detection rate increased by nearly 9%, compared with the placebo group, with detection rates of 56.29% and 47.81%, respectively.
“While 9% may not actually seem like a large number, it is actually very clinically significant,” Dr. Wallace said. For every 1% increase in the absolute adenoma detection rate, there was a corresponding 3% decline in the incidence of colorectal cancer and a 5% decline in colorectal cancer deaths.
While the results of this study are overwhelmingly positive, Dr. Wallace pointed out that utilizing blue dye to increase adenoma detection rate is not a new concept, with a number of clinical trials showing its benefit.
Apart from improving adenoma detection rates, the tablet formulation of methylene blue dye no longer requires on-site mixing by providers. This was a limiting factor because the dye itself is difficult to mix and hard to obtain for many health care centers around the world. The mixed solution was also not as effective because it was sprayed during colonoscopies. Dr. Wallace asserted that spraying through the colonoscope could be imprecise, time consuming, and localized. For these reasons, this technique was never widely adopted. The primary advantage of the tablet formulation is that it releases the dye in the colon at or near the time of the colonoscopy.
Dr. Wallace emphasized that there is no substitute for good colonoscopy practice and that methylene blue is just another tool to help improve the practice.
“The oral, delayed-release methylene blue provides gastroenterologists with a new and supplemental method to improve their adenoma detection rate on top of what is otherwise a high-quality examination.
New ‘immune checkpoint’ vaccine shows promise in treating colorectal cancer
A novel vaccine may provide a breakthrough treatment option in colorectal and other cancers.
“We [researchers] at the Peter MacCallum Cancer Centre in Melbourne, Australia, have developed a new, DNA-based vaccine, which we call TetMYB, for the treatment of MYB-overexpressing cancers such as colorectal, adenoid cystic carcinoma, and breast cancer, to name a few,” Toan Pham, MD, of the Peter MacCallum Cancer Centre, said in a media briefing in advance of the annual Digestive Disease Week® conference.
The immunotherapy approach described by Dr. Pham involves combining the TetMYB vaccine, which boosts the immune system, and an antibody, BGB-A317, that helps enhance the effectiveness of the vaccine.
“The research we are presenting at DDW involves testing this approach in mouse models, which we had previously published. In our studies, tumors in the mice responded very well to the treatment and cancer was cured in about half of them,” stated Dr. Pham.
The study is really composed of two smaller studies that looked at colonic adenoma, induced using tamoxifen-enriched feed, in a total of 22 mice. The mice were split into two study groups: 15 in a prophylactic study and 7 in a therapeutic pilot study.
In the prophylactic study, eight treatment mice received three TetMYB vaccinations at weeks 7, 9, and 11. Tamoxifen was given to the treatment and control mice at week 13.
The seven mice in the therapeutic pilot study were given tamoxifen at week 9 and subsequently monitored via colonoscopy weekly. Once the presence of adenoma was identified, mice received six doses of TetMYB and four doses of anti-PD1 antibody.
In both the prophylactic and therapeutic study, the mice survival rates were higher than expected. In the prophylactic study, the treatment groups’ median survival time was 356 days, nearly double the control group (183 days). More impressively, all mice in the therapeutic group were alive at 235 days.
“The mice were only expected to live for a couple of days or weeks. But, about 50% of them, they lived for more than 2 years,” said Dr. Pham. “Additionally, when the cured mice from the original study were later rechallenged with the same treatment, it was immediately rejected, thus proving there is an immune memory induced by the vaccine.”
With the positive results of the mouse trial, Dr. Pham spoke to the ongoing human clinical trial and the future of this vaccine.
“Currently, we are conducting a first-in-human phase 1 clinical trial,” stated Dr. Pham. “The next phase of evolution for our vaccine, which I will also be presenting at DDW, is testing our vaccine as an anti-adenoma vaccine.” Adenomas account for nearly 80% of bowel cancers, according to Dr. Pham.
Should the safety data from the phase 1 trial prove the vaccine to be safe, a follow-up clinical trial looking at high-risk populations would be the next step.
A novel vaccine may provide a breakthrough treatment option in colorectal and other cancers.
“We [researchers] at the Peter MacCallum Cancer Centre in Melbourne, Australia, have developed a new, DNA-based vaccine, which we call TetMYB, for the treatment of MYB-overexpressing cancers such as colorectal, adenoid cystic carcinoma, and breast cancer, to name a few,” Toan Pham, MD, of the Peter MacCallum Cancer Centre, said in a media briefing in advance of the annual Digestive Disease Week® conference.
The immunotherapy approach described by Dr. Pham involves combining the TetMYB vaccine, which boosts the immune system, and an antibody, BGB-A317, that helps enhance the effectiveness of the vaccine.
“The research we are presenting at DDW involves testing this approach in mouse models, which we had previously published. In our studies, tumors in the mice responded very well to the treatment and cancer was cured in about half of them,” stated Dr. Pham.
The study is really composed of two smaller studies that looked at colonic adenoma, induced using tamoxifen-enriched feed, in a total of 22 mice. The mice were split into two study groups: 15 in a prophylactic study and 7 in a therapeutic pilot study.
In the prophylactic study, eight treatment mice received three TetMYB vaccinations at weeks 7, 9, and 11. Tamoxifen was given to the treatment and control mice at week 13.
The seven mice in the therapeutic pilot study were given tamoxifen at week 9 and subsequently monitored via colonoscopy weekly. Once the presence of adenoma was identified, mice received six doses of TetMYB and four doses of anti-PD1 antibody.
In both the prophylactic and therapeutic study, the mice survival rates were higher than expected. In the prophylactic study, the treatment groups’ median survival time was 356 days, nearly double the control group (183 days). More impressively, all mice in the therapeutic group were alive at 235 days.
“The mice were only expected to live for a couple of days or weeks. But, about 50% of them, they lived for more than 2 years,” said Dr. Pham. “Additionally, when the cured mice from the original study were later rechallenged with the same treatment, it was immediately rejected, thus proving there is an immune memory induced by the vaccine.”
With the positive results of the mouse trial, Dr. Pham spoke to the ongoing human clinical trial and the future of this vaccine.
“Currently, we are conducting a first-in-human phase 1 clinical trial,” stated Dr. Pham. “The next phase of evolution for our vaccine, which I will also be presenting at DDW, is testing our vaccine as an anti-adenoma vaccine.” Adenomas account for nearly 80% of bowel cancers, according to Dr. Pham.
Should the safety data from the phase 1 trial prove the vaccine to be safe, a follow-up clinical trial looking at high-risk populations would be the next step.
A novel vaccine may provide a breakthrough treatment option in colorectal and other cancers.
“We [researchers] at the Peter MacCallum Cancer Centre in Melbourne, Australia, have developed a new, DNA-based vaccine, which we call TetMYB, for the treatment of MYB-overexpressing cancers such as colorectal, adenoid cystic carcinoma, and breast cancer, to name a few,” Toan Pham, MD, of the Peter MacCallum Cancer Centre, said in a media briefing in advance of the annual Digestive Disease Week® conference.
The immunotherapy approach described by Dr. Pham involves combining the TetMYB vaccine, which boosts the immune system, and an antibody, BGB-A317, that helps enhance the effectiveness of the vaccine.
“The research we are presenting at DDW involves testing this approach in mouse models, which we had previously published. In our studies, tumors in the mice responded very well to the treatment and cancer was cured in about half of them,” stated Dr. Pham.
The study is really composed of two smaller studies that looked at colonic adenoma, induced using tamoxifen-enriched feed, in a total of 22 mice. The mice were split into two study groups: 15 in a prophylactic study and 7 in a therapeutic pilot study.
In the prophylactic study, eight treatment mice received three TetMYB vaccinations at weeks 7, 9, and 11. Tamoxifen was given to the treatment and control mice at week 13.
The seven mice in the therapeutic pilot study were given tamoxifen at week 9 and subsequently monitored via colonoscopy weekly. Once the presence of adenoma was identified, mice received six doses of TetMYB and four doses of anti-PD1 antibody.
In both the prophylactic and therapeutic study, the mice survival rates were higher than expected. In the prophylactic study, the treatment groups’ median survival time was 356 days, nearly double the control group (183 days). More impressively, all mice in the therapeutic group were alive at 235 days.
“The mice were only expected to live for a couple of days or weeks. But, about 50% of them, they lived for more than 2 years,” said Dr. Pham. “Additionally, when the cured mice from the original study were later rechallenged with the same treatment, it was immediately rejected, thus proving there is an immune memory induced by the vaccine.”
With the positive results of the mouse trial, Dr. Pham spoke to the ongoing human clinical trial and the future of this vaccine.
“Currently, we are conducting a first-in-human phase 1 clinical trial,” stated Dr. Pham. “The next phase of evolution for our vaccine, which I will also be presenting at DDW, is testing our vaccine as an anti-adenoma vaccine.” Adenomas account for nearly 80% of bowel cancers, according to Dr. Pham.
Should the safety data from the phase 1 trial prove the vaccine to be safe, a follow-up clinical trial looking at high-risk populations would be the next step.
REPORTING FROM DDW
Experimental drug may help those living with celiac disease
“Contamination with gluten happens during food processing, food packaging, cooking, and [because of] inadequate labeling,” Francisco Leon, MD, a consultant for Amgen and former CEO of Celimmune, said in a media briefing in advance of the annual Digestive Disease Week® (DDW). “Gluten is [also] present in unsuspected places like lipstick, toothpaste, even medicines. It is virtually impossible for celiac patients to completely avoid gluten.”
The new drug, AMG 714, works by blocking interleukin 15, a known intestinal inflammatory mediator, and lowers inflammation, resulting in fewer symptoms for patients.
In a 12-week study, patients received either 150- or 300-mg doses of subcutaneous AMG 714, or placebo. All doses of AMG 714 were administered six times over the course of the study. From weeks 2 to 12, patients were challenged with a daily dose of 2.5 grams of gluten, which is considered a high dose.
The results showed that AMG 714 significantly reduced Celiac Disease Patient Reported Outcomes at the 300-mg dose (P = .02) compared with placebo. Similarly, AMG 714 decreased Celiac Disease Gastrointestinal Symptom Rating Scale scores at the 150-mg (P = .17) and 300-mg (P = .07) doses, compared with placebo.
Dr. Leon noted that there was another subset of patients who did not receive the gluten challenge because they were shown to have intestinal atrophy – marked by the presence of flat mucosa – because of contamination in their gluten-free diets. This was measured by way of a novel stool and urine detection test. This information will be presented at DDW.
AMG 714 also improved gluten-triggered diarrhea and physician assessments, according to Dr. Leon. In fact, using the Bristol Stool Form Scale, patients who received both the 150-mg (P = .01) and 300-mg (P = .0002) doses had substantially lower rates of diarrhea, compared with placebo.
These positive results were not isolated to the Bristol Stool Form Scale scores, but extended to the Physician Global Assessment as well.
“The proportion of subjects whom physicians evaluated as clinically active at week 12 was 0 in the high dose of AMG 714 while it was 33% in the placebo group,” stated Dr. Leon.
While AMG 714 has shown promise in alleviating celiac disease symptoms for patients inadvertently exposed to gluten, it is not intended to treat exposure to high amounts of gluten.
“It is important to note that AMG 714 is intended to protect against modest contamination [with] gluten and not against the effects of regularly eaten large amounts of gluten, like bread or pasta,” Dr. Leon cautioned. “But we know that people with celiac disease are inadvertently exposed to gluten. So it is our hope that AMG 714 will allow these patients to experience fewer gluten-triggered events.”
The information presented by Dr. Leon was only a taste of what will be presented at DDW®.
“At DDW, we will show you a reduction in inflammation, and we will also show you the safety profile. There were no serious adverse events.
“We are hopeful that this will become one of the tools to combat celiac disease.”
“Contamination with gluten happens during food processing, food packaging, cooking, and [because of] inadequate labeling,” Francisco Leon, MD, a consultant for Amgen and former CEO of Celimmune, said in a media briefing in advance of the annual Digestive Disease Week® (DDW). “Gluten is [also] present in unsuspected places like lipstick, toothpaste, even medicines. It is virtually impossible for celiac patients to completely avoid gluten.”
The new drug, AMG 714, works by blocking interleukin 15, a known intestinal inflammatory mediator, and lowers inflammation, resulting in fewer symptoms for patients.
In a 12-week study, patients received either 150- or 300-mg doses of subcutaneous AMG 714, or placebo. All doses of AMG 714 were administered six times over the course of the study. From weeks 2 to 12, patients were challenged with a daily dose of 2.5 grams of gluten, which is considered a high dose.
The results showed that AMG 714 significantly reduced Celiac Disease Patient Reported Outcomes at the 300-mg dose (P = .02) compared with placebo. Similarly, AMG 714 decreased Celiac Disease Gastrointestinal Symptom Rating Scale scores at the 150-mg (P = .17) and 300-mg (P = .07) doses, compared with placebo.
Dr. Leon noted that there was another subset of patients who did not receive the gluten challenge because they were shown to have intestinal atrophy – marked by the presence of flat mucosa – because of contamination in their gluten-free diets. This was measured by way of a novel stool and urine detection test. This information will be presented at DDW.
AMG 714 also improved gluten-triggered diarrhea and physician assessments, according to Dr. Leon. In fact, using the Bristol Stool Form Scale, patients who received both the 150-mg (P = .01) and 300-mg (P = .0002) doses had substantially lower rates of diarrhea, compared with placebo.
These positive results were not isolated to the Bristol Stool Form Scale scores, but extended to the Physician Global Assessment as well.
“The proportion of subjects whom physicians evaluated as clinically active at week 12 was 0 in the high dose of AMG 714 while it was 33% in the placebo group,” stated Dr. Leon.
While AMG 714 has shown promise in alleviating celiac disease symptoms for patients inadvertently exposed to gluten, it is not intended to treat exposure to high amounts of gluten.
“It is important to note that AMG 714 is intended to protect against modest contamination [with] gluten and not against the effects of regularly eaten large amounts of gluten, like bread or pasta,” Dr. Leon cautioned. “But we know that people with celiac disease are inadvertently exposed to gluten. So it is our hope that AMG 714 will allow these patients to experience fewer gluten-triggered events.”
The information presented by Dr. Leon was only a taste of what will be presented at DDW®.
“At DDW, we will show you a reduction in inflammation, and we will also show you the safety profile. There were no serious adverse events.
“We are hopeful that this will become one of the tools to combat celiac disease.”
“Contamination with gluten happens during food processing, food packaging, cooking, and [because of] inadequate labeling,” Francisco Leon, MD, a consultant for Amgen and former CEO of Celimmune, said in a media briefing in advance of the annual Digestive Disease Week® (DDW). “Gluten is [also] present in unsuspected places like lipstick, toothpaste, even medicines. It is virtually impossible for celiac patients to completely avoid gluten.”
The new drug, AMG 714, works by blocking interleukin 15, a known intestinal inflammatory mediator, and lowers inflammation, resulting in fewer symptoms for patients.
In a 12-week study, patients received either 150- or 300-mg doses of subcutaneous AMG 714, or placebo. All doses of AMG 714 were administered six times over the course of the study. From weeks 2 to 12, patients were challenged with a daily dose of 2.5 grams of gluten, which is considered a high dose.
The results showed that AMG 714 significantly reduced Celiac Disease Patient Reported Outcomes at the 300-mg dose (P = .02) compared with placebo. Similarly, AMG 714 decreased Celiac Disease Gastrointestinal Symptom Rating Scale scores at the 150-mg (P = .17) and 300-mg (P = .07) doses, compared with placebo.
Dr. Leon noted that there was another subset of patients who did not receive the gluten challenge because they were shown to have intestinal atrophy – marked by the presence of flat mucosa – because of contamination in their gluten-free diets. This was measured by way of a novel stool and urine detection test. This information will be presented at DDW.
AMG 714 also improved gluten-triggered diarrhea and physician assessments, according to Dr. Leon. In fact, using the Bristol Stool Form Scale, patients who received both the 150-mg (P = .01) and 300-mg (P = .0002) doses had substantially lower rates of diarrhea, compared with placebo.
These positive results were not isolated to the Bristol Stool Form Scale scores, but extended to the Physician Global Assessment as well.
“The proportion of subjects whom physicians evaluated as clinically active at week 12 was 0 in the high dose of AMG 714 while it was 33% in the placebo group,” stated Dr. Leon.
While AMG 714 has shown promise in alleviating celiac disease symptoms for patients inadvertently exposed to gluten, it is not intended to treat exposure to high amounts of gluten.
“It is important to note that AMG 714 is intended to protect against modest contamination [with] gluten and not against the effects of regularly eaten large amounts of gluten, like bread or pasta,” Dr. Leon cautioned. “But we know that people with celiac disease are inadvertently exposed to gluten. So it is our hope that AMG 714 will allow these patients to experience fewer gluten-triggered events.”
The information presented by Dr. Leon was only a taste of what will be presented at DDW®.
“At DDW, we will show you a reduction in inflammation, and we will also show you the safety profile. There were no serious adverse events.
“We are hopeful that this will become one of the tools to combat celiac disease.”
REPORTING FROM DDW 2018
FDA advisory panelists reject Buvaya for acute pain
HYATTSVILLE, MD. – Two Food and Drug Administration advisory panels voted May 22 to reject buprenorphine sublingual spray for the treatment of moderate to severe postoperative pain.
At a joint meeting, advisers of the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee voted 18 to 1 not to recommend the spray for approval. The proposed trade name for the spray is Buvaya.
“I think that if this were a standard schedule II opioid with the efficacy profile of this drug, we probably would not be here,”stated Steven Meisel, PharmD, system director of medication safety at Fairview Health Services, Minneapolis. “We would not be here, because the efficacy [is] so weak compared to what is already out there. It just does not work for acute postoperative pain.”
According to INSYS Therapeutics, developer of the buprenorphine sublingual spray, opioid painkillers remain one of the best treatment options in managing moderate to severe pain despite the risk of addiction. The sublingual spray formulation also has a lower abuse potential, according to the company. This was corroborated in a briefing document of currently marketed buprenorphine products by the FDA.
Buprenorphine, an opioid partial agonist-antagonist, is a long-acting Schedule III opioid. The sublingual spray was developed as part of the Buprenorphine Sublingual Spray clinical development program, consisting of 10 studies including 7 phase 1 studies, a phase 2 open label study, and two phase 3 efficacy studies. The company’s application was based on the results of those two efficacy studies. Both phase 3 studies had similar designs, randomizing patients to receive varying doses of the sublingual spray. They also shared the primary endpoint of assessing postoperative pain using the Numeric Rating Scale (NRS) Summed Pain and Intensity Difference 48 hours (SPID-48) after surgery. The similarities continued with secondary endpoints, with both phase 3 studies looking at NRS-SPID scores at 4, 8, and 24 hours after surgery, NRS pain intensity difference (NRS PID) and score at each time point, and total pain relief (TOTPAR) at 4, 8, 24, and 48 hours after surgery. The only difference between the studies were the doses of sublingual buprenorphine administered to patients.
One of the phase 3 trials was discontinued when several patients because of sedation events at higher doses, but that trial still was used to guide the dose selection for the pivotal phase 3 study. In that study, 40 patients postoperative bunionectomy patients were randomized to receive placebo, 0.5 mg, or 1.0 mg of sublingual buprenorphine (SBS) three times daily (t.i.d.) or 1.0 mg of SBS twice a day (b.i.d.). The study demonstrated that all doses were superior to placebo in reducing pain based on reductions in NRS SPID-48 scores. In fact, the mean NRS SPID-48 scores were 260%, 216%, and 236% higher for the 0.5-mg t.i.d., 1.0-mg b.i.d., and 1.0-mg t.i.d. doses, respectively, compared with placebo, indicating a decrease in pain. The study also found that sublingual buprenorphine doses of greater than 0.5 mg were not more effective in treating postoperative pain.
The pivotal phase 3 efficacy study randomized 322 patients after bunionectomy into one of four treatment groups: placebo, 0.5 mg t.i.d., 0.25 mg t.i.d., or 0.125 mg t.i.d. Sublingual buprenorphine was much more effective in reducing pain and SPID-48 scores, compared with placebo. Patients taking placebo had SPID-48 scores of 93.40, compared with 135.84, 125.75, and 182.81 for the 0.125-mg, 0.25-mg, and 0.5-mg SBS groups, respectively.
The most common adverse events were nausea, vomiting, and hypoxia. Specifically, in the pivotal study, nausea was reported at all three doses of 0.125 mg, 0.25 mg, and 0.50 mg in 43.9%, 58.8%, and 83.3% of patients.
Anne-Michelle Ruha, MD, of the University of Arizona, Phoenix, cited the risk of hypoxia as her biggest concern. “There’s so many factors that we can’t predict, like undiagnosed sleep apnea,” she said. “We just don’t know when the respiratory depression worsens, so I’m uncomfortable with the high rate of hypoxia.”
Although not directly related to this application, INSYS had been the subject of an investigation by the federal government in regard to an illegal marketing scheme that provided incentives for doctors to prescribe Subsys, a powerful and highly addictive synthetic opioid. Documents recently have been unsealed in federal court that prompted the federal government to investigate INSYS. The company has addressed the previous allegations of wrongdoing and states that INSYS has become a “... new and better company in many important respects across the organization,” according to a statement.The FDA usually follows the recommendations of its advisory panels, but they are not binding.
HYATTSVILLE, MD. – Two Food and Drug Administration advisory panels voted May 22 to reject buprenorphine sublingual spray for the treatment of moderate to severe postoperative pain.
At a joint meeting, advisers of the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee voted 18 to 1 not to recommend the spray for approval. The proposed trade name for the spray is Buvaya.
“I think that if this were a standard schedule II opioid with the efficacy profile of this drug, we probably would not be here,”stated Steven Meisel, PharmD, system director of medication safety at Fairview Health Services, Minneapolis. “We would not be here, because the efficacy [is] so weak compared to what is already out there. It just does not work for acute postoperative pain.”
According to INSYS Therapeutics, developer of the buprenorphine sublingual spray, opioid painkillers remain one of the best treatment options in managing moderate to severe pain despite the risk of addiction. The sublingual spray formulation also has a lower abuse potential, according to the company. This was corroborated in a briefing document of currently marketed buprenorphine products by the FDA.
Buprenorphine, an opioid partial agonist-antagonist, is a long-acting Schedule III opioid. The sublingual spray was developed as part of the Buprenorphine Sublingual Spray clinical development program, consisting of 10 studies including 7 phase 1 studies, a phase 2 open label study, and two phase 3 efficacy studies. The company’s application was based on the results of those two efficacy studies. Both phase 3 studies had similar designs, randomizing patients to receive varying doses of the sublingual spray. They also shared the primary endpoint of assessing postoperative pain using the Numeric Rating Scale (NRS) Summed Pain and Intensity Difference 48 hours (SPID-48) after surgery. The similarities continued with secondary endpoints, with both phase 3 studies looking at NRS-SPID scores at 4, 8, and 24 hours after surgery, NRS pain intensity difference (NRS PID) and score at each time point, and total pain relief (TOTPAR) at 4, 8, 24, and 48 hours after surgery. The only difference between the studies were the doses of sublingual buprenorphine administered to patients.
One of the phase 3 trials was discontinued when several patients because of sedation events at higher doses, but that trial still was used to guide the dose selection for the pivotal phase 3 study. In that study, 40 patients postoperative bunionectomy patients were randomized to receive placebo, 0.5 mg, or 1.0 mg of sublingual buprenorphine (SBS) three times daily (t.i.d.) or 1.0 mg of SBS twice a day (b.i.d.). The study demonstrated that all doses were superior to placebo in reducing pain based on reductions in NRS SPID-48 scores. In fact, the mean NRS SPID-48 scores were 260%, 216%, and 236% higher for the 0.5-mg t.i.d., 1.0-mg b.i.d., and 1.0-mg t.i.d. doses, respectively, compared with placebo, indicating a decrease in pain. The study also found that sublingual buprenorphine doses of greater than 0.5 mg were not more effective in treating postoperative pain.
The pivotal phase 3 efficacy study randomized 322 patients after bunionectomy into one of four treatment groups: placebo, 0.5 mg t.i.d., 0.25 mg t.i.d., or 0.125 mg t.i.d. Sublingual buprenorphine was much more effective in reducing pain and SPID-48 scores, compared with placebo. Patients taking placebo had SPID-48 scores of 93.40, compared with 135.84, 125.75, and 182.81 for the 0.125-mg, 0.25-mg, and 0.5-mg SBS groups, respectively.
The most common adverse events were nausea, vomiting, and hypoxia. Specifically, in the pivotal study, nausea was reported at all three doses of 0.125 mg, 0.25 mg, and 0.50 mg in 43.9%, 58.8%, and 83.3% of patients.
Anne-Michelle Ruha, MD, of the University of Arizona, Phoenix, cited the risk of hypoxia as her biggest concern. “There’s so many factors that we can’t predict, like undiagnosed sleep apnea,” she said. “We just don’t know when the respiratory depression worsens, so I’m uncomfortable with the high rate of hypoxia.”
Although not directly related to this application, INSYS had been the subject of an investigation by the federal government in regard to an illegal marketing scheme that provided incentives for doctors to prescribe Subsys, a powerful and highly addictive synthetic opioid. Documents recently have been unsealed in federal court that prompted the federal government to investigate INSYS. The company has addressed the previous allegations of wrongdoing and states that INSYS has become a “... new and better company in many important respects across the organization,” according to a statement.The FDA usually follows the recommendations of its advisory panels, but they are not binding.
HYATTSVILLE, MD. – Two Food and Drug Administration advisory panels voted May 22 to reject buprenorphine sublingual spray for the treatment of moderate to severe postoperative pain.
At a joint meeting, advisers of the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee voted 18 to 1 not to recommend the spray for approval. The proposed trade name for the spray is Buvaya.
“I think that if this were a standard schedule II opioid with the efficacy profile of this drug, we probably would not be here,”stated Steven Meisel, PharmD, system director of medication safety at Fairview Health Services, Minneapolis. “We would not be here, because the efficacy [is] so weak compared to what is already out there. It just does not work for acute postoperative pain.”
According to INSYS Therapeutics, developer of the buprenorphine sublingual spray, opioid painkillers remain one of the best treatment options in managing moderate to severe pain despite the risk of addiction. The sublingual spray formulation also has a lower abuse potential, according to the company. This was corroborated in a briefing document of currently marketed buprenorphine products by the FDA.
Buprenorphine, an opioid partial agonist-antagonist, is a long-acting Schedule III opioid. The sublingual spray was developed as part of the Buprenorphine Sublingual Spray clinical development program, consisting of 10 studies including 7 phase 1 studies, a phase 2 open label study, and two phase 3 efficacy studies. The company’s application was based on the results of those two efficacy studies. Both phase 3 studies had similar designs, randomizing patients to receive varying doses of the sublingual spray. They also shared the primary endpoint of assessing postoperative pain using the Numeric Rating Scale (NRS) Summed Pain and Intensity Difference 48 hours (SPID-48) after surgery. The similarities continued with secondary endpoints, with both phase 3 studies looking at NRS-SPID scores at 4, 8, and 24 hours after surgery, NRS pain intensity difference (NRS PID) and score at each time point, and total pain relief (TOTPAR) at 4, 8, 24, and 48 hours after surgery. The only difference between the studies were the doses of sublingual buprenorphine administered to patients.
One of the phase 3 trials was discontinued when several patients because of sedation events at higher doses, but that trial still was used to guide the dose selection for the pivotal phase 3 study. In that study, 40 patients postoperative bunionectomy patients were randomized to receive placebo, 0.5 mg, or 1.0 mg of sublingual buprenorphine (SBS) three times daily (t.i.d.) or 1.0 mg of SBS twice a day (b.i.d.). The study demonstrated that all doses were superior to placebo in reducing pain based on reductions in NRS SPID-48 scores. In fact, the mean NRS SPID-48 scores were 260%, 216%, and 236% higher for the 0.5-mg t.i.d., 1.0-mg b.i.d., and 1.0-mg t.i.d. doses, respectively, compared with placebo, indicating a decrease in pain. The study also found that sublingual buprenorphine doses of greater than 0.5 mg were not more effective in treating postoperative pain.
The pivotal phase 3 efficacy study randomized 322 patients after bunionectomy into one of four treatment groups: placebo, 0.5 mg t.i.d., 0.25 mg t.i.d., or 0.125 mg t.i.d. Sublingual buprenorphine was much more effective in reducing pain and SPID-48 scores, compared with placebo. Patients taking placebo had SPID-48 scores of 93.40, compared with 135.84, 125.75, and 182.81 for the 0.125-mg, 0.25-mg, and 0.5-mg SBS groups, respectively.
The most common adverse events were nausea, vomiting, and hypoxia. Specifically, in the pivotal study, nausea was reported at all three doses of 0.125 mg, 0.25 mg, and 0.50 mg in 43.9%, 58.8%, and 83.3% of patients.
Anne-Michelle Ruha, MD, of the University of Arizona, Phoenix, cited the risk of hypoxia as her biggest concern. “There’s so many factors that we can’t predict, like undiagnosed sleep apnea,” she said. “We just don’t know when the respiratory depression worsens, so I’m uncomfortable with the high rate of hypoxia.”
Although not directly related to this application, INSYS had been the subject of an investigation by the federal government in regard to an illegal marketing scheme that provided incentives for doctors to prescribe Subsys, a powerful and highly addictive synthetic opioid. Documents recently have been unsealed in federal court that prompted the federal government to investigate INSYS. The company has addressed the previous allegations of wrongdoing and states that INSYS has become a “... new and better company in many important respects across the organization,” according to a statement.The FDA usually follows the recommendations of its advisory panels, but they are not binding.