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Acting FDA commissioner issues remarks on ENDS, vaping illnesses
Norman E. Sharpless, MD, acting commissioner of the Food and Drug Administration, has issued remarks that were prepared for a testimony before a U.S. House Energy and Commerce subcommittee on FDA regulation of electronic nicotine delivery systems and investigation of vaping illnesses.
Dr. Sharpless’s statement focuses on two priorities: the continuing investigation into the cause of lung injury associated with the use of vaping products and the FDA’s ongoing efforts to address an epidemic of youth use of electronic nicotine delivery systems (ENDS). In regards to lung injuries associated with vaping, Dr. Sharpless said that the FDA and Centers for Disease Control and Prevention, in conjunction with state partners, have been investigating the outbreak and noted that, while most cases have involved tetrahydrocannabinol, there is as of yet no common cause or product linked to all cases.
The FDA is not currently pursuing any legal action against personal usage of vaping products, but “if we determine that someone is manufacturing or distributing illicit, adulterated vaping products that caused illness and death for personal profit, we would consider that to be a criminal act,” Dr. Sharpless said.
Research from the 2018 and 2019 National Youth Tobacco Surveys has indicated that ENDS usage among youth has risen dramatically in recent years, Dr. Sharpless continued in the statement. The FDA has pursued several courses of action, including the issue of a warning letter to Juul for marketing unauthorized modified-risk tobacco products to children.
However, he noted, youth e-cigarette use continues to rise, which is the reason for the FDA’s intention to finalize a compliance policy related to flavored ENDS, a policy supported by President TRump.
“FDA is not ‘banning’ flavors, as has been described in some news reports. Rather, FDA intends to enforce existing law that limits the marketing of such products,” Dr. Sharpless said. “This policy would not mean that flavored e-cigarettes could never be marketed. If a company can show through an application to FDA that a specific product meets the standard set forth by Congress, then the FDA would authorize that ENDS product for sale.”
Find the full statement on the FDA website.
Norman E. Sharpless, MD, acting commissioner of the Food and Drug Administration, has issued remarks that were prepared for a testimony before a U.S. House Energy and Commerce subcommittee on FDA regulation of electronic nicotine delivery systems and investigation of vaping illnesses.
Dr. Sharpless’s statement focuses on two priorities: the continuing investigation into the cause of lung injury associated with the use of vaping products and the FDA’s ongoing efforts to address an epidemic of youth use of electronic nicotine delivery systems (ENDS). In regards to lung injuries associated with vaping, Dr. Sharpless said that the FDA and Centers for Disease Control and Prevention, in conjunction with state partners, have been investigating the outbreak and noted that, while most cases have involved tetrahydrocannabinol, there is as of yet no common cause or product linked to all cases.
The FDA is not currently pursuing any legal action against personal usage of vaping products, but “if we determine that someone is manufacturing or distributing illicit, adulterated vaping products that caused illness and death for personal profit, we would consider that to be a criminal act,” Dr. Sharpless said.
Research from the 2018 and 2019 National Youth Tobacco Surveys has indicated that ENDS usage among youth has risen dramatically in recent years, Dr. Sharpless continued in the statement. The FDA has pursued several courses of action, including the issue of a warning letter to Juul for marketing unauthorized modified-risk tobacco products to children.
However, he noted, youth e-cigarette use continues to rise, which is the reason for the FDA’s intention to finalize a compliance policy related to flavored ENDS, a policy supported by President TRump.
“FDA is not ‘banning’ flavors, as has been described in some news reports. Rather, FDA intends to enforce existing law that limits the marketing of such products,” Dr. Sharpless said. “This policy would not mean that flavored e-cigarettes could never be marketed. If a company can show through an application to FDA that a specific product meets the standard set forth by Congress, then the FDA would authorize that ENDS product for sale.”
Find the full statement on the FDA website.
Norman E. Sharpless, MD, acting commissioner of the Food and Drug Administration, has issued remarks that were prepared for a testimony before a U.S. House Energy and Commerce subcommittee on FDA regulation of electronic nicotine delivery systems and investigation of vaping illnesses.
Dr. Sharpless’s statement focuses on two priorities: the continuing investigation into the cause of lung injury associated with the use of vaping products and the FDA’s ongoing efforts to address an epidemic of youth use of electronic nicotine delivery systems (ENDS). In regards to lung injuries associated with vaping, Dr. Sharpless said that the FDA and Centers for Disease Control and Prevention, in conjunction with state partners, have been investigating the outbreak and noted that, while most cases have involved tetrahydrocannabinol, there is as of yet no common cause or product linked to all cases.
The FDA is not currently pursuing any legal action against personal usage of vaping products, but “if we determine that someone is manufacturing or distributing illicit, adulterated vaping products that caused illness and death for personal profit, we would consider that to be a criminal act,” Dr. Sharpless said.
Research from the 2018 and 2019 National Youth Tobacco Surveys has indicated that ENDS usage among youth has risen dramatically in recent years, Dr. Sharpless continued in the statement. The FDA has pursued several courses of action, including the issue of a warning letter to Juul for marketing unauthorized modified-risk tobacco products to children.
However, he noted, youth e-cigarette use continues to rise, which is the reason for the FDA’s intention to finalize a compliance policy related to flavored ENDS, a policy supported by President TRump.
“FDA is not ‘banning’ flavors, as has been described in some news reports. Rather, FDA intends to enforce existing law that limits the marketing of such products,” Dr. Sharpless said. “This policy would not mean that flavored e-cigarettes could never be marketed. If a company can show through an application to FDA that a specific product meets the standard set forth by Congress, then the FDA would authorize that ENDS product for sale.”
Find the full statement on the FDA website.
Lung Cancer in the VA at a National Level
Even With No Disease Activity, Recurrence Risk Near 50% When Stopping DMTs for MS
Key clinical point: A small cohort of patients with CIS meeting MS diagnostic criteria stopped DMT after 5 years of no disease activity, and just under half had MS recurrence.
Major finding: Of the cohort of 46 patients, 23 had disease recurrence, with recurrence more likely among younger patients.
Study details: Cohort study of 46 patients with initial clinical episode of MS, meeting Barkhof criteria for MS on magnetic resonance imaging.
Disclosures: The authors reported no conflicts of interest. No external sources of funding were reported.
Citation: Monschein T et al. ECTRIMS 2019. Abstract P654.
Key clinical point: A small cohort of patients with CIS meeting MS diagnostic criteria stopped DMT after 5 years of no disease activity, and just under half had MS recurrence.
Major finding: Of the cohort of 46 patients, 23 had disease recurrence, with recurrence more likely among younger patients.
Study details: Cohort study of 46 patients with initial clinical episode of MS, meeting Barkhof criteria for MS on magnetic resonance imaging.
Disclosures: The authors reported no conflicts of interest. No external sources of funding were reported.
Citation: Monschein T et al. ECTRIMS 2019. Abstract P654.
Key clinical point: A small cohort of patients with CIS meeting MS diagnostic criteria stopped DMT after 5 years of no disease activity, and just under half had MS recurrence.
Major finding: Of the cohort of 46 patients, 23 had disease recurrence, with recurrence more likely among younger patients.
Study details: Cohort study of 46 patients with initial clinical episode of MS, meeting Barkhof criteria for MS on magnetic resonance imaging.
Disclosures: The authors reported no conflicts of interest. No external sources of funding were reported.
Citation: Monschein T et al. ECTRIMS 2019. Abstract P654.
Newer Drugs Provide Superior Disease Activity Control in Pediatric MS
Key clinical point: Newer oral and intravenous drugs for multiple schlerosis provide significantly better disease activity control than the older injectables as initial disease-modifying therapy in children.
Major finding: The number needed to treat with a newer disease-modifying drug rather than an injectable agent to prevent one relapse was 3.7.
Study details: A prospective, multicenter, observational cohort study including 741 pediatric patients with MS followed while on their first-time disease-modifying therapy.
Disclosures: The study was sponsored by the Multiple Sclerosis Society. Dr. Kysko reported having no financial conflicts in regard to the study.
Citation: Krysko KM. ECTRIMS 2019, abstract 249.
Key clinical point: Newer oral and intravenous drugs for multiple schlerosis provide significantly better disease activity control than the older injectables as initial disease-modifying therapy in children.
Major finding: The number needed to treat with a newer disease-modifying drug rather than an injectable agent to prevent one relapse was 3.7.
Study details: A prospective, multicenter, observational cohort study including 741 pediatric patients with MS followed while on their first-time disease-modifying therapy.
Disclosures: The study was sponsored by the Multiple Sclerosis Society. Dr. Kysko reported having no financial conflicts in regard to the study.
Citation: Krysko KM. ECTRIMS 2019, abstract 249.
Key clinical point: Newer oral and intravenous drugs for multiple schlerosis provide significantly better disease activity control than the older injectables as initial disease-modifying therapy in children.
Major finding: The number needed to treat with a newer disease-modifying drug rather than an injectable agent to prevent one relapse was 3.7.
Study details: A prospective, multicenter, observational cohort study including 741 pediatric patients with MS followed while on their first-time disease-modifying therapy.
Disclosures: The study was sponsored by the Multiple Sclerosis Society. Dr. Kysko reported having no financial conflicts in regard to the study.
Citation: Krysko KM. ECTRIMS 2019, abstract 249.
Continuous Treatment Reduces Risk of Confirmed Disability Progression in MS
Key clinical point: Treatment with DMT for more than 10 years reduces the risk of confirmed disability progression in MS.
Major finding: Continuous treatment with DMT reduced the risk of 24-month confirmed disability progression by 35%.
Study details: A retrospective analysis of data for 15,602 patients with relapsing-remitting MS.
Disclosures: Two of the researchers are employees of Biogen International, which supported the research. Several investigators received compensation or funding from various pharmaceutical companies.
Citation: Laffaldano P et al. ECTRIMS 2019. Abstract 94.
Key clinical point: Treatment with DMT for more than 10 years reduces the risk of confirmed disability progression in MS.
Major finding: Continuous treatment with DMT reduced the risk of 24-month confirmed disability progression by 35%.
Study details: A retrospective analysis of data for 15,602 patients with relapsing-remitting MS.
Disclosures: Two of the researchers are employees of Biogen International, which supported the research. Several investigators received compensation or funding from various pharmaceutical companies.
Citation: Laffaldano P et al. ECTRIMS 2019. Abstract 94.
Key clinical point: Treatment with DMT for more than 10 years reduces the risk of confirmed disability progression in MS.
Major finding: Continuous treatment with DMT reduced the risk of 24-month confirmed disability progression by 35%.
Study details: A retrospective analysis of data for 15,602 patients with relapsing-remitting MS.
Disclosures: Two of the researchers are employees of Biogen International, which supported the research. Several investigators received compensation or funding from various pharmaceutical companies.
Citation: Laffaldano P et al. ECTRIMS 2019. Abstract 94.
FDA: Sandoz recalls ranitidine capsules with NDMA
, according to a news release from the agency.
The recall applies to 14 lots in which NDMA, a probable human carcinogen and nitrosamine impurity formed as a byproduct of several industrial and natural processes, has been detected at levels above those set by the FDA, according to a company announcement on Sept. 23 from Sandoz. According to the announcement, which also specifies the affected lots, the company has not received any reports of adverse events related to use of the products in the recall.
According to the FDA release, so far, only the specified lots of ranitidine are known to be contaminated, and patients can continue taking this stomach acid–reducing histamine2 blocker from lots that are not affected by the recall.
“When we identify lapses in the quality of drugs that pose potential risks for patients, the FDA makes all efforts to understand the issue and provide our best recommendation to the public as quickly and accurately as possible,” said acting FDA Commissioner Norman E. Sharpless, MD.
As part of this ongoing investigation, the FDA recently posted a testing protocol for detecting NDMA in ranitidine; the agency hopes regulators and industry will use this protocol to begin their own laboratory testing as well and send samples to the FDA for further testing.
More information about the recall, as well as instructions for patients and health care professionals, can be found in the full news release on the FDA website. The agency also encourages any adverse reactions be reported to its MedWatch program.
, according to a news release from the agency.
The recall applies to 14 lots in which NDMA, a probable human carcinogen and nitrosamine impurity formed as a byproduct of several industrial and natural processes, has been detected at levels above those set by the FDA, according to a company announcement on Sept. 23 from Sandoz. According to the announcement, which also specifies the affected lots, the company has not received any reports of adverse events related to use of the products in the recall.
According to the FDA release, so far, only the specified lots of ranitidine are known to be contaminated, and patients can continue taking this stomach acid–reducing histamine2 blocker from lots that are not affected by the recall.
“When we identify lapses in the quality of drugs that pose potential risks for patients, the FDA makes all efforts to understand the issue and provide our best recommendation to the public as quickly and accurately as possible,” said acting FDA Commissioner Norman E. Sharpless, MD.
As part of this ongoing investigation, the FDA recently posted a testing protocol for detecting NDMA in ranitidine; the agency hopes regulators and industry will use this protocol to begin their own laboratory testing as well and send samples to the FDA for further testing.
More information about the recall, as well as instructions for patients and health care professionals, can be found in the full news release on the FDA website. The agency also encourages any adverse reactions be reported to its MedWatch program.
, according to a news release from the agency.
The recall applies to 14 lots in which NDMA, a probable human carcinogen and nitrosamine impurity formed as a byproduct of several industrial and natural processes, has been detected at levels above those set by the FDA, according to a company announcement on Sept. 23 from Sandoz. According to the announcement, which also specifies the affected lots, the company has not received any reports of adverse events related to use of the products in the recall.
According to the FDA release, so far, only the specified lots of ranitidine are known to be contaminated, and patients can continue taking this stomach acid–reducing histamine2 blocker from lots that are not affected by the recall.
“When we identify lapses in the quality of drugs that pose potential risks for patients, the FDA makes all efforts to understand the issue and provide our best recommendation to the public as quickly and accurately as possible,” said acting FDA Commissioner Norman E. Sharpless, MD.
As part of this ongoing investigation, the FDA recently posted a testing protocol for detecting NDMA in ranitidine; the agency hopes regulators and industry will use this protocol to begin their own laboratory testing as well and send samples to the FDA for further testing.
More information about the recall, as well as instructions for patients and health care professionals, can be found in the full news release on the FDA website. The agency also encourages any adverse reactions be reported to its MedWatch program.
Lumateperone for schizophrenia shows safety, tolerability in long-term study
COPENHAGEN – Lumateperone, a novel investigational drug for schizophrenia with a unique triple mechanism of action, showed impressive safety and tolerability while achieving a continuous decline in schizophrenia symptoms over the course of a year in a long-term, open-label study, Suresh Durgam, MD, said at the annual congress of the European College of Neuropsychopharmacology.
Indeed, patients on lumateperone at the 1-year mark showed significant reductions in LDL cholesterol, total cholesterol, serum prolactin, and body weight, compared with baseline values recorded when participants were on various standard-of-care antipsychotics prior to switching. Other cardiometabolic parameters, including fasting blood glucose, insulin, triglycerides, and HDL cholesterol, showed only negligible change over the course of study, according to Dr. Durgam, a psychiatrist and senior vice president for late-stage clinical development and medical affairs at Intra-Cellular Therapies, the New York–based company developing lumateperone as its lead product.
This favorable cardiometabolic profile contrasts sharply with those of currently available antipsychotic agents, many of which worsen cardiometabolic risk factors. That would seem to be a major advantage for lumateperone and is likely to be a factor in the Food and Drug Administration’s ongoing deliberation over the company’s new drug application. Dr. Durgam said.
Intra-Cellular Therapies’ stock price took a hit in July 2019, when the FDA abruptly canceled an advisory committee meeting scheduled to consider lumateperone. The agency sought additional information on animal toxicology studies. Having received it from the company, the FDA now no longer plans to schedule an advisory committee meeting before issuing its marketing approval decision.
Lumateperone is an oral once-daily drug that doesn’t require titration. Its high degree of tolerability is thought to be attributable to the drug’s mechanism of action, which involves simultaneous modulation of three different neurotransmitter pathways: serotonin, dopamine, and glutamate. The drug is a potent serotonin 5-HT2a antagonist and serotonin reuptake inhibitor, a dopamine D2 presynaptic partial agonist and postsynaptic antagonist, and it also modulates glutamate via activation of the D1 receptor.
Three phase 3, double-blind, placebo-controlled randomized clinical trials of 4-6 weeks duration have been completed in a total of 1,481 patients with acute exacerbation of schizophrenia. Two trials were positive, with lumateperone achieving significantly greater mean reductions in the Positive and Negative Syndrome Scale (PANSS) total score than placebo, while the third was negative, with no significant between-group difference. Of note, the safety profile of lumateperone was indistinguishable from placebo with the sole exception of somnolence, where the 20% incidence was twice that of placebo-treated controls. However, in the open-label program, dosing was switched from morning to evening, with a resultant drop in somnolence to the placebo level, Dr. Durgam said.
The open-label program has two parts. Part 1 was conducted in 302 patients with stable, generally mild schizophrenia symptoms while on risperidone, olanzapine, or various other antipsychotics commonly prescribed in the United States. They were switched to lumateperone at 42 mg once daily for 6 weeks, at which point they demonstrated significant reductions in body weight, serum prolactin, insulin, total cholesterol, and LDL cholesterol. They then were switched back to their former medications, with a resultant worsening of those parameters to prelumateperone levels, providing evidence of a cause-and-effect relationship with cardiometabolic risk factors.
Part 2 of the open-label program is the long-term study, in which 603 patients with stable symptoms on standard-of-care antipsychotics were switched to lumateperone at 42 mg/day, to be followed for 1 year or more. Dr. Durgam presented an interim analysis focused on the first 107 patients to achieve the 1-year treatment milestone. Most were obese at baseline: the group’s mean body mass index was 31.3 kg/m2. They experienced progressive weight loss, with a mean reduction of 1.82 kg on day 175 and 3.16 kg on day 350. About 24% of subjects had a 7% or greater reduction in body weight, while 8% had at least a 7% weight gain. Waist circumference decreased by an average of 5.2 cm from a baseline of 103.2 cm in men and by 1.9 cm in women.
The primary focus of the ongoing long-term study is safety. The most common treatment-emergent adverse events during a full year of therapy were dry mouth, headache, and diarrhea, each occurring in about 7% of patients. Only 0.8% of patients developed extrapyramidal symptoms.
At 150 days of treatment in 340 patients, 30% had achieved a PANSS response, defined as at least a 20% improvement in PANSS total score, compared with baseline. At 300 days in the smaller group who had reached that milestone at the time of the interim analysis, the PANSS response rate had grown to 41%.
Among patients with schizophrenia and comorbid depression as defined by a Calgary Depression Scale for Schizophrenia (CDSS) score of 6 or more at baseline, lumateperone at 42 mg/day improved depressive symptoms, such that 60% of those patients achieved a CDSS response – that is, at least a 50% reduction in the score – by day 75. This finding supports data from earlier short-term studies, and suggests that lumateperone’s multiple mechanisms of action and high tolerability make it a promising candidate for treatment of depression and other symptom domains of schizophrenia that are currently inadequately treated, according to Dr. Durgam.
Dr. Durgam also presented an update on the lumateperone program for bipolar depression, which consists of three phase 3, double-blind, placebo-controlled, 6-week-long clinical trials totaling 1,455 patients. Two have been completed: one positive and the other negative with an unusually high placebo response rate. The ongoing third trial will be the tiebreaker. Safety and tolerability have been as noted in other lumateperone studies.
In the positive trial, the primary efficacy endpoint was change in Montgomery-Åsberg Depression Rating Scale, which improved in lumateperone-treated patients by an average of 16.7 points from a baseline score of just over 30, a significantly better result than the 12.1-point reduction in placebo-treated controls. The treatment benefit was similar in bipolar I and bipolar II patients.
The phase 3 trial* for treatment of agitation in patients with Alzheimer’s disease and other dementias was stopped early for lack of efficacy in an interim analysis. And lumateperone is in ongoing phase 2 trials for sleep disturbances associated with neuropsychiatric disorders. The phase 2 study* in major depressive disorder has been completed.
*This article was updated 9/28/2019.
COPENHAGEN – Lumateperone, a novel investigational drug for schizophrenia with a unique triple mechanism of action, showed impressive safety and tolerability while achieving a continuous decline in schizophrenia symptoms over the course of a year in a long-term, open-label study, Suresh Durgam, MD, said at the annual congress of the European College of Neuropsychopharmacology.
Indeed, patients on lumateperone at the 1-year mark showed significant reductions in LDL cholesterol, total cholesterol, serum prolactin, and body weight, compared with baseline values recorded when participants were on various standard-of-care antipsychotics prior to switching. Other cardiometabolic parameters, including fasting blood glucose, insulin, triglycerides, and HDL cholesterol, showed only negligible change over the course of study, according to Dr. Durgam, a psychiatrist and senior vice president for late-stage clinical development and medical affairs at Intra-Cellular Therapies, the New York–based company developing lumateperone as its lead product.
This favorable cardiometabolic profile contrasts sharply with those of currently available antipsychotic agents, many of which worsen cardiometabolic risk factors. That would seem to be a major advantage for lumateperone and is likely to be a factor in the Food and Drug Administration’s ongoing deliberation over the company’s new drug application. Dr. Durgam said.
Intra-Cellular Therapies’ stock price took a hit in July 2019, when the FDA abruptly canceled an advisory committee meeting scheduled to consider lumateperone. The agency sought additional information on animal toxicology studies. Having received it from the company, the FDA now no longer plans to schedule an advisory committee meeting before issuing its marketing approval decision.
Lumateperone is an oral once-daily drug that doesn’t require titration. Its high degree of tolerability is thought to be attributable to the drug’s mechanism of action, which involves simultaneous modulation of three different neurotransmitter pathways: serotonin, dopamine, and glutamate. The drug is a potent serotonin 5-HT2a antagonist and serotonin reuptake inhibitor, a dopamine D2 presynaptic partial agonist and postsynaptic antagonist, and it also modulates glutamate via activation of the D1 receptor.
Three phase 3, double-blind, placebo-controlled randomized clinical trials of 4-6 weeks duration have been completed in a total of 1,481 patients with acute exacerbation of schizophrenia. Two trials were positive, with lumateperone achieving significantly greater mean reductions in the Positive and Negative Syndrome Scale (PANSS) total score than placebo, while the third was negative, with no significant between-group difference. Of note, the safety profile of lumateperone was indistinguishable from placebo with the sole exception of somnolence, where the 20% incidence was twice that of placebo-treated controls. However, in the open-label program, dosing was switched from morning to evening, with a resultant drop in somnolence to the placebo level, Dr. Durgam said.
The open-label program has two parts. Part 1 was conducted in 302 patients with stable, generally mild schizophrenia symptoms while on risperidone, olanzapine, or various other antipsychotics commonly prescribed in the United States. They were switched to lumateperone at 42 mg once daily for 6 weeks, at which point they demonstrated significant reductions in body weight, serum prolactin, insulin, total cholesterol, and LDL cholesterol. They then were switched back to their former medications, with a resultant worsening of those parameters to prelumateperone levels, providing evidence of a cause-and-effect relationship with cardiometabolic risk factors.
Part 2 of the open-label program is the long-term study, in which 603 patients with stable symptoms on standard-of-care antipsychotics were switched to lumateperone at 42 mg/day, to be followed for 1 year or more. Dr. Durgam presented an interim analysis focused on the first 107 patients to achieve the 1-year treatment milestone. Most were obese at baseline: the group’s mean body mass index was 31.3 kg/m2. They experienced progressive weight loss, with a mean reduction of 1.82 kg on day 175 and 3.16 kg on day 350. About 24% of subjects had a 7% or greater reduction in body weight, while 8% had at least a 7% weight gain. Waist circumference decreased by an average of 5.2 cm from a baseline of 103.2 cm in men and by 1.9 cm in women.
The primary focus of the ongoing long-term study is safety. The most common treatment-emergent adverse events during a full year of therapy were dry mouth, headache, and diarrhea, each occurring in about 7% of patients. Only 0.8% of patients developed extrapyramidal symptoms.
At 150 days of treatment in 340 patients, 30% had achieved a PANSS response, defined as at least a 20% improvement in PANSS total score, compared with baseline. At 300 days in the smaller group who had reached that milestone at the time of the interim analysis, the PANSS response rate had grown to 41%.
Among patients with schizophrenia and comorbid depression as defined by a Calgary Depression Scale for Schizophrenia (CDSS) score of 6 or more at baseline, lumateperone at 42 mg/day improved depressive symptoms, such that 60% of those patients achieved a CDSS response – that is, at least a 50% reduction in the score – by day 75. This finding supports data from earlier short-term studies, and suggests that lumateperone’s multiple mechanisms of action and high tolerability make it a promising candidate for treatment of depression and other symptom domains of schizophrenia that are currently inadequately treated, according to Dr. Durgam.
Dr. Durgam also presented an update on the lumateperone program for bipolar depression, which consists of three phase 3, double-blind, placebo-controlled, 6-week-long clinical trials totaling 1,455 patients. Two have been completed: one positive and the other negative with an unusually high placebo response rate. The ongoing third trial will be the tiebreaker. Safety and tolerability have been as noted in other lumateperone studies.
In the positive trial, the primary efficacy endpoint was change in Montgomery-Åsberg Depression Rating Scale, which improved in lumateperone-treated patients by an average of 16.7 points from a baseline score of just over 30, a significantly better result than the 12.1-point reduction in placebo-treated controls. The treatment benefit was similar in bipolar I and bipolar II patients.
The phase 3 trial* for treatment of agitation in patients with Alzheimer’s disease and other dementias was stopped early for lack of efficacy in an interim analysis. And lumateperone is in ongoing phase 2 trials for sleep disturbances associated with neuropsychiatric disorders. The phase 2 study* in major depressive disorder has been completed.
*This article was updated 9/28/2019.
COPENHAGEN – Lumateperone, a novel investigational drug for schizophrenia with a unique triple mechanism of action, showed impressive safety and tolerability while achieving a continuous decline in schizophrenia symptoms over the course of a year in a long-term, open-label study, Suresh Durgam, MD, said at the annual congress of the European College of Neuropsychopharmacology.
Indeed, patients on lumateperone at the 1-year mark showed significant reductions in LDL cholesterol, total cholesterol, serum prolactin, and body weight, compared with baseline values recorded when participants were on various standard-of-care antipsychotics prior to switching. Other cardiometabolic parameters, including fasting blood glucose, insulin, triglycerides, and HDL cholesterol, showed only negligible change over the course of study, according to Dr. Durgam, a psychiatrist and senior vice president for late-stage clinical development and medical affairs at Intra-Cellular Therapies, the New York–based company developing lumateperone as its lead product.
This favorable cardiometabolic profile contrasts sharply with those of currently available antipsychotic agents, many of which worsen cardiometabolic risk factors. That would seem to be a major advantage for lumateperone and is likely to be a factor in the Food and Drug Administration’s ongoing deliberation over the company’s new drug application. Dr. Durgam said.
Intra-Cellular Therapies’ stock price took a hit in July 2019, when the FDA abruptly canceled an advisory committee meeting scheduled to consider lumateperone. The agency sought additional information on animal toxicology studies. Having received it from the company, the FDA now no longer plans to schedule an advisory committee meeting before issuing its marketing approval decision.
Lumateperone is an oral once-daily drug that doesn’t require titration. Its high degree of tolerability is thought to be attributable to the drug’s mechanism of action, which involves simultaneous modulation of three different neurotransmitter pathways: serotonin, dopamine, and glutamate. The drug is a potent serotonin 5-HT2a antagonist and serotonin reuptake inhibitor, a dopamine D2 presynaptic partial agonist and postsynaptic antagonist, and it also modulates glutamate via activation of the D1 receptor.
Three phase 3, double-blind, placebo-controlled randomized clinical trials of 4-6 weeks duration have been completed in a total of 1,481 patients with acute exacerbation of schizophrenia. Two trials were positive, with lumateperone achieving significantly greater mean reductions in the Positive and Negative Syndrome Scale (PANSS) total score than placebo, while the third was negative, with no significant between-group difference. Of note, the safety profile of lumateperone was indistinguishable from placebo with the sole exception of somnolence, where the 20% incidence was twice that of placebo-treated controls. However, in the open-label program, dosing was switched from morning to evening, with a resultant drop in somnolence to the placebo level, Dr. Durgam said.
The open-label program has two parts. Part 1 was conducted in 302 patients with stable, generally mild schizophrenia symptoms while on risperidone, olanzapine, or various other antipsychotics commonly prescribed in the United States. They were switched to lumateperone at 42 mg once daily for 6 weeks, at which point they demonstrated significant reductions in body weight, serum prolactin, insulin, total cholesterol, and LDL cholesterol. They then were switched back to their former medications, with a resultant worsening of those parameters to prelumateperone levels, providing evidence of a cause-and-effect relationship with cardiometabolic risk factors.
Part 2 of the open-label program is the long-term study, in which 603 patients with stable symptoms on standard-of-care antipsychotics were switched to lumateperone at 42 mg/day, to be followed for 1 year or more. Dr. Durgam presented an interim analysis focused on the first 107 patients to achieve the 1-year treatment milestone. Most were obese at baseline: the group’s mean body mass index was 31.3 kg/m2. They experienced progressive weight loss, with a mean reduction of 1.82 kg on day 175 and 3.16 kg on day 350. About 24% of subjects had a 7% or greater reduction in body weight, while 8% had at least a 7% weight gain. Waist circumference decreased by an average of 5.2 cm from a baseline of 103.2 cm in men and by 1.9 cm in women.
The primary focus of the ongoing long-term study is safety. The most common treatment-emergent adverse events during a full year of therapy were dry mouth, headache, and diarrhea, each occurring in about 7% of patients. Only 0.8% of patients developed extrapyramidal symptoms.
At 150 days of treatment in 340 patients, 30% had achieved a PANSS response, defined as at least a 20% improvement in PANSS total score, compared with baseline. At 300 days in the smaller group who had reached that milestone at the time of the interim analysis, the PANSS response rate had grown to 41%.
Among patients with schizophrenia and comorbid depression as defined by a Calgary Depression Scale for Schizophrenia (CDSS) score of 6 or more at baseline, lumateperone at 42 mg/day improved depressive symptoms, such that 60% of those patients achieved a CDSS response – that is, at least a 50% reduction in the score – by day 75. This finding supports data from earlier short-term studies, and suggests that lumateperone’s multiple mechanisms of action and high tolerability make it a promising candidate for treatment of depression and other symptom domains of schizophrenia that are currently inadequately treated, according to Dr. Durgam.
Dr. Durgam also presented an update on the lumateperone program for bipolar depression, which consists of three phase 3, double-blind, placebo-controlled, 6-week-long clinical trials totaling 1,455 patients. Two have been completed: one positive and the other negative with an unusually high placebo response rate. The ongoing third trial will be the tiebreaker. Safety and tolerability have been as noted in other lumateperone studies.
In the positive trial, the primary efficacy endpoint was change in Montgomery-Åsberg Depression Rating Scale, which improved in lumateperone-treated patients by an average of 16.7 points from a baseline score of just over 30, a significantly better result than the 12.1-point reduction in placebo-treated controls. The treatment benefit was similar in bipolar I and bipolar II patients.
The phase 3 trial* for treatment of agitation in patients with Alzheimer’s disease and other dementias was stopped early for lack of efficacy in an interim analysis. And lumateperone is in ongoing phase 2 trials for sleep disturbances associated with neuropsychiatric disorders. The phase 2 study* in major depressive disorder has been completed.
*This article was updated 9/28/2019.
REPORTING FROM ECNP 2019
FDA approves first live vaccine for smallpox, monkeypox prevention
The Food and Drug Administration has approved Jynneos, a live, nonreplicating vaccine based on the vaccinia virus, for smallpox and monkeypox, becoming the first FDA-approved vaccine for the prevention of monkeypox disease.
FDA approval for Jynneos for smallpox is based on results from a clinical trial that compared Jynneos with ACAM2000, a previously FDA-approved smallpox vaccine, in about 400 healthy adults aged 18-42 years. Adults who received Jynneos had a noninferior immune response to those who received ACAM2000. In addition, safety was assessed in 7,800 people who received at least one vaccine dose, with the most commonly reported side effects including pain, redness, swelling, itching, firmness at the injection site, muscle pain, headache, and fatigue.
The effectiveness of Jynneos to prevent monkeypox – a disease similar to but somewhat milder than smallpox caused by the non–U.S.-native monkeypox virus – was inferred from antibody responses of participants in the smallpox clinical trial and from studies on nonhuman primates that showed protection from the monkeypox virus after being vaccinated with Jynneos.
“Routine [smallpox] vaccination of the American public was stopped in 1972 after the disease was eradicated in the U.S. and, as a result, a large proportion of the U.S., as well as the global population has no immunity,” said Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research. “Although naturally occurring smallpox disease is no longer a global threat, the intentional release of this highly contagious virus could have a devastating effect.”
This vaccine is also part of the Strategic National Stockpile, the nation’s largest supply of potentially lifesaving pharmaceuticals and medical supplies for use in a public health emergency, according to the announcement.
Find the full press release on the FDA website.
The Food and Drug Administration has approved Jynneos, a live, nonreplicating vaccine based on the vaccinia virus, for smallpox and monkeypox, becoming the first FDA-approved vaccine for the prevention of monkeypox disease.
FDA approval for Jynneos for smallpox is based on results from a clinical trial that compared Jynneos with ACAM2000, a previously FDA-approved smallpox vaccine, in about 400 healthy adults aged 18-42 years. Adults who received Jynneos had a noninferior immune response to those who received ACAM2000. In addition, safety was assessed in 7,800 people who received at least one vaccine dose, with the most commonly reported side effects including pain, redness, swelling, itching, firmness at the injection site, muscle pain, headache, and fatigue.
The effectiveness of Jynneos to prevent monkeypox – a disease similar to but somewhat milder than smallpox caused by the non–U.S.-native monkeypox virus – was inferred from antibody responses of participants in the smallpox clinical trial and from studies on nonhuman primates that showed protection from the monkeypox virus after being vaccinated with Jynneos.
“Routine [smallpox] vaccination of the American public was stopped in 1972 after the disease was eradicated in the U.S. and, as a result, a large proportion of the U.S., as well as the global population has no immunity,” said Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research. “Although naturally occurring smallpox disease is no longer a global threat, the intentional release of this highly contagious virus could have a devastating effect.”
This vaccine is also part of the Strategic National Stockpile, the nation’s largest supply of potentially lifesaving pharmaceuticals and medical supplies for use in a public health emergency, according to the announcement.
Find the full press release on the FDA website.
The Food and Drug Administration has approved Jynneos, a live, nonreplicating vaccine based on the vaccinia virus, for smallpox and monkeypox, becoming the first FDA-approved vaccine for the prevention of monkeypox disease.
FDA approval for Jynneos for smallpox is based on results from a clinical trial that compared Jynneos with ACAM2000, a previously FDA-approved smallpox vaccine, in about 400 healthy adults aged 18-42 years. Adults who received Jynneos had a noninferior immune response to those who received ACAM2000. In addition, safety was assessed in 7,800 people who received at least one vaccine dose, with the most commonly reported side effects including pain, redness, swelling, itching, firmness at the injection site, muscle pain, headache, and fatigue.
The effectiveness of Jynneos to prevent monkeypox – a disease similar to but somewhat milder than smallpox caused by the non–U.S.-native monkeypox virus – was inferred from antibody responses of participants in the smallpox clinical trial and from studies on nonhuman primates that showed protection from the monkeypox virus after being vaccinated with Jynneos.
“Routine [smallpox] vaccination of the American public was stopped in 1972 after the disease was eradicated in the U.S. and, as a result, a large proportion of the U.S., as well as the global population has no immunity,” said Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research. “Although naturally occurring smallpox disease is no longer a global threat, the intentional release of this highly contagious virus could have a devastating effect.”
This vaccine is also part of the Strategic National Stockpile, the nation’s largest supply of potentially lifesaving pharmaceuticals and medical supplies for use in a public health emergency, according to the announcement.
Find the full press release on the FDA website.
Effects of hospitalization on readmission rate
Background: There is increasing concern that the patient experience in the hospital may be associated with post-hospital adverse outcomes, including new or recurrent illnesses after discharge or unplanned return to the hospital or readmission.
Study design: Prospective cohort that included 207 patients.
Setting: Two academic hospitals in Toronto.
Synopsis: These patients had been admitted to the internal medicine ward for more than 48 hours and were interviewed at discharge using a standardized questionnaire to assess four domains of the trauma of hospitalization defined as the cumulative effects of patient-reported sleep disturbance, mobility, nutrition, and mood. Among these patients, 64.3% experienced disturbance in more than one domain, and patients who experienced disturbance in three to four domains had a 15.8% greater absolute risk of 30-day readmission or ED visit.
Because this is an observational study, causal inferences were not possible; however, hospitalists should keep in mind the possible association of the patient experience and the link to clinical outcomes.
Bottom line: Trauma of hospitalization is common and may be associated with an increased 30-day risk of readmission or ED visit.
Citation: Rawal J et al. Association of the trauma of hospitalization with 30-day readmission or emergency department visit. JAMA Intern Med. 2019;179(1):38-45.
Dr. Wang is an associate professor of medicine in the division of general and hospital medicine at UT Health San Antonio and a hospitalist at South Texas Veterans Health Care System.
Background: There is increasing concern that the patient experience in the hospital may be associated with post-hospital adverse outcomes, including new or recurrent illnesses after discharge or unplanned return to the hospital or readmission.
Study design: Prospective cohort that included 207 patients.
Setting: Two academic hospitals in Toronto.
Synopsis: These patients had been admitted to the internal medicine ward for more than 48 hours and were interviewed at discharge using a standardized questionnaire to assess four domains of the trauma of hospitalization defined as the cumulative effects of patient-reported sleep disturbance, mobility, nutrition, and mood. Among these patients, 64.3% experienced disturbance in more than one domain, and patients who experienced disturbance in three to four domains had a 15.8% greater absolute risk of 30-day readmission or ED visit.
Because this is an observational study, causal inferences were not possible; however, hospitalists should keep in mind the possible association of the patient experience and the link to clinical outcomes.
Bottom line: Trauma of hospitalization is common and may be associated with an increased 30-day risk of readmission or ED visit.
Citation: Rawal J et al. Association of the trauma of hospitalization with 30-day readmission or emergency department visit. JAMA Intern Med. 2019;179(1):38-45.
Dr. Wang is an associate professor of medicine in the division of general and hospital medicine at UT Health San Antonio and a hospitalist at South Texas Veterans Health Care System.
Background: There is increasing concern that the patient experience in the hospital may be associated with post-hospital adverse outcomes, including new or recurrent illnesses after discharge or unplanned return to the hospital or readmission.
Study design: Prospective cohort that included 207 patients.
Setting: Two academic hospitals in Toronto.
Synopsis: These patients had been admitted to the internal medicine ward for more than 48 hours and were interviewed at discharge using a standardized questionnaire to assess four domains of the trauma of hospitalization defined as the cumulative effects of patient-reported sleep disturbance, mobility, nutrition, and mood. Among these patients, 64.3% experienced disturbance in more than one domain, and patients who experienced disturbance in three to four domains had a 15.8% greater absolute risk of 30-day readmission or ED visit.
Because this is an observational study, causal inferences were not possible; however, hospitalists should keep in mind the possible association of the patient experience and the link to clinical outcomes.
Bottom line: Trauma of hospitalization is common and may be associated with an increased 30-day risk of readmission or ED visit.
Citation: Rawal J et al. Association of the trauma of hospitalization with 30-day readmission or emergency department visit. JAMA Intern Med. 2019;179(1):38-45.
Dr. Wang is an associate professor of medicine in the division of general and hospital medicine at UT Health San Antonio and a hospitalist at South Texas Veterans Health Care System.
RISE analyses highlight further youth vs. adult T2D differences
BARCELONA – Further differences in how adults and adolescents with type 2 diabetes respond to glucose and glucagon have been demonstrated by new data from the Restoring Insulin SEcretion (RISE) studies presented at the annual meeting of the European Association for the Study of Diabetes.
In a comparison of responses to an oral glucose tolerance test (OGTT), youth (n = 85) were more likely than were adults (n = 353) to have a biphasic type of glucose response curve (18.8% vs. 8.2%, respectively), which is considered a more normal response curve. However, that “did not foretell an advantageous outcome to the RISE interventions in the younger age group,” said study investigator Silva Arslanian, MD, of UPMC Children’s Hospital of Pittsburgh.
Fewer youth than adults had an incessant response (10.6% vs. 14.5%, respectively) or monophasic response to an OGTT (70.6% vs. 77.3%), and that was associated with lower beta-cell responses, compared with individuals with monophasic or biphasic glucose curves.
“Irrespective of curve type, insulin sensitivity was lower in youth than in adults,” Dr. Arslanian said. She added that beta-cell responses were greater in youth than in adults, except in youth with the worst incessant-increase curve type. In youth with the incessant-increase glucose curve, there was no evidence of beta-cell hypersecretion, which suggested youth “have more severe beta-cell dysfunction,” compared with adults.
There were also data presented on whether differences in alpha-cell function between youth and adults might be important. Those data showed that although fasting glucagon concentrations did not increase with fasting glucose in youth, they did in adults. It was found that fasting and stimulated glucagon concentrations were lower in youth than in adults, meaning that “alpha-cell function does not explain the beta-cell hyperresponsiveness seen in youth with impaired glucose tolerance or recently diagnosed type 2 diabetes,” reported study investigator Steven Kahn, MD, ChB, of VA Puget Sound Health Care System, University of Washington, Seattle.
“This is a batch of secondary analyses,” Philip Zeitler, MD, PhD, of Children’s Hospital Colorado, Aurora, said in an interview. Dr. Zeitler, who chaired the session at which the new findings were unveiled, noted that the main data from the RISE Pediatric Medication Study (RISE Peds) were published last year (Diabetes Care. 2018;41[8]:1717-25) and results from the RISE Adult Medication Study (RISE Adult) were just presented this year, and explained that the timing difference was because the adult study took longer to complete its target accrual.
Results of these studies showed that, compared with adults, youth were substantially more insulin resistant and had hyperresponsive beta cells. Furthermore, their beta-cell function deteriorated during and after treatment for type 2 diabetes, whereas it improved during treatment and remained stable after stopping treatment in adults (Diabetes. 2019;68:1670-80).
The idea for the RISE trials came about around 6 years ago, with the overall aim of trying to identify approaches that could preserve or improve beta-cell function in younger patients and adults with dysglycemia, Dr. Zeitler explained. When the trials were being planned it was known that young patients with type 2 diabetes often needed much higher doses of insulin, compared with their adult counterparts. So, it “wasn’t entirely unexpected” that they were found to be insulin resistant, particularly, as puberty is an insulin-resistant state, Dr. Zeitler observed.
“What was new, however, was that [the beta-cells of] youth were hyperresponsive and were really making large amounts of insulin.” Increased insulin production might be expected when there is insulin resistance, he added, but the level seen was “more than you would expect.” Over time, that might be toxic to the beta cells, and evidence from the earlier TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) studies suggested that the rate of beta-cell dysfunction was more rapid in youth than in adults.
Giving his perspective, as a pediatrician, on the new OGTT analyses from the RISE studies, Dr. Zeitler said that these data showed that the characteristic beta-cell hyperresponsiveness seen in youth “actually disappears as glycemia worsens.” In youth with the incessant glucose response pattern, “it shows that they cannot tolerate glucose, and their glucose levels just go up and up and up” until the beta cells fail.
This is a critical observation, Dr. Zeitler said, noting that it “sort of had to be the case, because sooner or later you had to lose beta cells ... this is probably the point where aggressive therapy is needed ... it was always a bit of a paradox, if these kids have such an aggressive course, how come they were starting out being so hyperresponsive?”
With regard to alpha-cell function, “these are really fresh data. We haven’t really had a long time to think about it,” said Dr. Zeitler. “What I find interesting is that there isn’t alpha-cell glucagon hypersecretion in youth like there is in adults.” That may be because youth are making so much insulin that they are suppressing glucagon production, but that’s not an entirely satisfying answer,” he said.
“The TODAY study demonstrated that diabetes in kids is aggressive; these RISE data now start to put some physiology around that, why is it more aggressive? Hyperresponsiveness, loss of beta-cell function over time, lack of response to intervention, compared with the adults.”
As for the clinical implications, Dr. Zeitler said that this is further evidence that the default approach to treating younger patients with greater caution than adults is perhaps not the best way to treat type 2 diabetes.
“These data are really showing that there is a very important toxic period that is occurring in these kids early on [and] that probably argues for more, not less, aggressive therapy,” than with adults. “Clearly, something is happening that is putting them at really big risk for rapid progression, and that’s your chance to treat much more aggressively, much earlier.”
The RISE studies are sponsored by the RISE Study Group in collaboration with the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Zeitler disclosed that he had acted as a consultant to Boehringer-Ingelheim, Eli Lilly, Daiichi-Sankyo and Merck, Sharp & Dohme, and had received research support from Janssen. Dr. Arslanian stated that she has nothing to disclose. Dr. Khan did not provide any disclosure information.
SOURCES: Arslanian S. EASD 2019, Oral presentation S34.1; Kahn S. EASD 2019, Oral presentation S34.3
BARCELONA – Further differences in how adults and adolescents with type 2 diabetes respond to glucose and glucagon have been demonstrated by new data from the Restoring Insulin SEcretion (RISE) studies presented at the annual meeting of the European Association for the Study of Diabetes.
In a comparison of responses to an oral glucose tolerance test (OGTT), youth (n = 85) were more likely than were adults (n = 353) to have a biphasic type of glucose response curve (18.8% vs. 8.2%, respectively), which is considered a more normal response curve. However, that “did not foretell an advantageous outcome to the RISE interventions in the younger age group,” said study investigator Silva Arslanian, MD, of UPMC Children’s Hospital of Pittsburgh.
Fewer youth than adults had an incessant response (10.6% vs. 14.5%, respectively) or monophasic response to an OGTT (70.6% vs. 77.3%), and that was associated with lower beta-cell responses, compared with individuals with monophasic or biphasic glucose curves.
“Irrespective of curve type, insulin sensitivity was lower in youth than in adults,” Dr. Arslanian said. She added that beta-cell responses were greater in youth than in adults, except in youth with the worst incessant-increase curve type. In youth with the incessant-increase glucose curve, there was no evidence of beta-cell hypersecretion, which suggested youth “have more severe beta-cell dysfunction,” compared with adults.
There were also data presented on whether differences in alpha-cell function between youth and adults might be important. Those data showed that although fasting glucagon concentrations did not increase with fasting glucose in youth, they did in adults. It was found that fasting and stimulated glucagon concentrations were lower in youth than in adults, meaning that “alpha-cell function does not explain the beta-cell hyperresponsiveness seen in youth with impaired glucose tolerance or recently diagnosed type 2 diabetes,” reported study investigator Steven Kahn, MD, ChB, of VA Puget Sound Health Care System, University of Washington, Seattle.
“This is a batch of secondary analyses,” Philip Zeitler, MD, PhD, of Children’s Hospital Colorado, Aurora, said in an interview. Dr. Zeitler, who chaired the session at which the new findings were unveiled, noted that the main data from the RISE Pediatric Medication Study (RISE Peds) were published last year (Diabetes Care. 2018;41[8]:1717-25) and results from the RISE Adult Medication Study (RISE Adult) were just presented this year, and explained that the timing difference was because the adult study took longer to complete its target accrual.
Results of these studies showed that, compared with adults, youth were substantially more insulin resistant and had hyperresponsive beta cells. Furthermore, their beta-cell function deteriorated during and after treatment for type 2 diabetes, whereas it improved during treatment and remained stable after stopping treatment in adults (Diabetes. 2019;68:1670-80).
The idea for the RISE trials came about around 6 years ago, with the overall aim of trying to identify approaches that could preserve or improve beta-cell function in younger patients and adults with dysglycemia, Dr. Zeitler explained. When the trials were being planned it was known that young patients with type 2 diabetes often needed much higher doses of insulin, compared with their adult counterparts. So, it “wasn’t entirely unexpected” that they were found to be insulin resistant, particularly, as puberty is an insulin-resistant state, Dr. Zeitler observed.
“What was new, however, was that [the beta-cells of] youth were hyperresponsive and were really making large amounts of insulin.” Increased insulin production might be expected when there is insulin resistance, he added, but the level seen was “more than you would expect.” Over time, that might be toxic to the beta cells, and evidence from the earlier TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) studies suggested that the rate of beta-cell dysfunction was more rapid in youth than in adults.
Giving his perspective, as a pediatrician, on the new OGTT analyses from the RISE studies, Dr. Zeitler said that these data showed that the characteristic beta-cell hyperresponsiveness seen in youth “actually disappears as glycemia worsens.” In youth with the incessant glucose response pattern, “it shows that they cannot tolerate glucose, and their glucose levels just go up and up and up” until the beta cells fail.
This is a critical observation, Dr. Zeitler said, noting that it “sort of had to be the case, because sooner or later you had to lose beta cells ... this is probably the point where aggressive therapy is needed ... it was always a bit of a paradox, if these kids have such an aggressive course, how come they were starting out being so hyperresponsive?”
With regard to alpha-cell function, “these are really fresh data. We haven’t really had a long time to think about it,” said Dr. Zeitler. “What I find interesting is that there isn’t alpha-cell glucagon hypersecretion in youth like there is in adults.” That may be because youth are making so much insulin that they are suppressing glucagon production, but that’s not an entirely satisfying answer,” he said.
“The TODAY study demonstrated that diabetes in kids is aggressive; these RISE data now start to put some physiology around that, why is it more aggressive? Hyperresponsiveness, loss of beta-cell function over time, lack of response to intervention, compared with the adults.”
As for the clinical implications, Dr. Zeitler said that this is further evidence that the default approach to treating younger patients with greater caution than adults is perhaps not the best way to treat type 2 diabetes.
“These data are really showing that there is a very important toxic period that is occurring in these kids early on [and] that probably argues for more, not less, aggressive therapy,” than with adults. “Clearly, something is happening that is putting them at really big risk for rapid progression, and that’s your chance to treat much more aggressively, much earlier.”
The RISE studies are sponsored by the RISE Study Group in collaboration with the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Zeitler disclosed that he had acted as a consultant to Boehringer-Ingelheim, Eli Lilly, Daiichi-Sankyo and Merck, Sharp & Dohme, and had received research support from Janssen. Dr. Arslanian stated that she has nothing to disclose. Dr. Khan did not provide any disclosure information.
SOURCES: Arslanian S. EASD 2019, Oral presentation S34.1; Kahn S. EASD 2019, Oral presentation S34.3
BARCELONA – Further differences in how adults and adolescents with type 2 diabetes respond to glucose and glucagon have been demonstrated by new data from the Restoring Insulin SEcretion (RISE) studies presented at the annual meeting of the European Association for the Study of Diabetes.
In a comparison of responses to an oral glucose tolerance test (OGTT), youth (n = 85) were more likely than were adults (n = 353) to have a biphasic type of glucose response curve (18.8% vs. 8.2%, respectively), which is considered a more normal response curve. However, that “did not foretell an advantageous outcome to the RISE interventions in the younger age group,” said study investigator Silva Arslanian, MD, of UPMC Children’s Hospital of Pittsburgh.
Fewer youth than adults had an incessant response (10.6% vs. 14.5%, respectively) or monophasic response to an OGTT (70.6% vs. 77.3%), and that was associated with lower beta-cell responses, compared with individuals with monophasic or biphasic glucose curves.
“Irrespective of curve type, insulin sensitivity was lower in youth than in adults,” Dr. Arslanian said. She added that beta-cell responses were greater in youth than in adults, except in youth with the worst incessant-increase curve type. In youth with the incessant-increase glucose curve, there was no evidence of beta-cell hypersecretion, which suggested youth “have more severe beta-cell dysfunction,” compared with adults.
There were also data presented on whether differences in alpha-cell function between youth and adults might be important. Those data showed that although fasting glucagon concentrations did not increase with fasting glucose in youth, they did in adults. It was found that fasting and stimulated glucagon concentrations were lower in youth than in adults, meaning that “alpha-cell function does not explain the beta-cell hyperresponsiveness seen in youth with impaired glucose tolerance or recently diagnosed type 2 diabetes,” reported study investigator Steven Kahn, MD, ChB, of VA Puget Sound Health Care System, University of Washington, Seattle.
“This is a batch of secondary analyses,” Philip Zeitler, MD, PhD, of Children’s Hospital Colorado, Aurora, said in an interview. Dr. Zeitler, who chaired the session at which the new findings were unveiled, noted that the main data from the RISE Pediatric Medication Study (RISE Peds) were published last year (Diabetes Care. 2018;41[8]:1717-25) and results from the RISE Adult Medication Study (RISE Adult) were just presented this year, and explained that the timing difference was because the adult study took longer to complete its target accrual.
Results of these studies showed that, compared with adults, youth were substantially more insulin resistant and had hyperresponsive beta cells. Furthermore, their beta-cell function deteriorated during and after treatment for type 2 diabetes, whereas it improved during treatment and remained stable after stopping treatment in adults (Diabetes. 2019;68:1670-80).
The idea for the RISE trials came about around 6 years ago, with the overall aim of trying to identify approaches that could preserve or improve beta-cell function in younger patients and adults with dysglycemia, Dr. Zeitler explained. When the trials were being planned it was known that young patients with type 2 diabetes often needed much higher doses of insulin, compared with their adult counterparts. So, it “wasn’t entirely unexpected” that they were found to be insulin resistant, particularly, as puberty is an insulin-resistant state, Dr. Zeitler observed.
“What was new, however, was that [the beta-cells of] youth were hyperresponsive and were really making large amounts of insulin.” Increased insulin production might be expected when there is insulin resistance, he added, but the level seen was “more than you would expect.” Over time, that might be toxic to the beta cells, and evidence from the earlier TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) studies suggested that the rate of beta-cell dysfunction was more rapid in youth than in adults.
Giving his perspective, as a pediatrician, on the new OGTT analyses from the RISE studies, Dr. Zeitler said that these data showed that the characteristic beta-cell hyperresponsiveness seen in youth “actually disappears as glycemia worsens.” In youth with the incessant glucose response pattern, “it shows that they cannot tolerate glucose, and their glucose levels just go up and up and up” until the beta cells fail.
This is a critical observation, Dr. Zeitler said, noting that it “sort of had to be the case, because sooner or later you had to lose beta cells ... this is probably the point where aggressive therapy is needed ... it was always a bit of a paradox, if these kids have such an aggressive course, how come they were starting out being so hyperresponsive?”
With regard to alpha-cell function, “these are really fresh data. We haven’t really had a long time to think about it,” said Dr. Zeitler. “What I find interesting is that there isn’t alpha-cell glucagon hypersecretion in youth like there is in adults.” That may be because youth are making so much insulin that they are suppressing glucagon production, but that’s not an entirely satisfying answer,” he said.
“The TODAY study demonstrated that diabetes in kids is aggressive; these RISE data now start to put some physiology around that, why is it more aggressive? Hyperresponsiveness, loss of beta-cell function over time, lack of response to intervention, compared with the adults.”
As for the clinical implications, Dr. Zeitler said that this is further evidence that the default approach to treating younger patients with greater caution than adults is perhaps not the best way to treat type 2 diabetes.
“These data are really showing that there is a very important toxic period that is occurring in these kids early on [and] that probably argues for more, not less, aggressive therapy,” than with adults. “Clearly, something is happening that is putting them at really big risk for rapid progression, and that’s your chance to treat much more aggressively, much earlier.”
The RISE studies are sponsored by the RISE Study Group in collaboration with the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Zeitler disclosed that he had acted as a consultant to Boehringer-Ingelheim, Eli Lilly, Daiichi-Sankyo and Merck, Sharp & Dohme, and had received research support from Janssen. Dr. Arslanian stated that she has nothing to disclose. Dr. Khan did not provide any disclosure information.
SOURCES: Arslanian S. EASD 2019, Oral presentation S34.1; Kahn S. EASD 2019, Oral presentation S34.3
REPORTING FROM EASD 2019