User login
Light Therapy May Treat Excessive Daytime Sleepiness in Parkinson’s Disease
Light therapy may reduce excessive daytime sleepiness and improve sleep quality in patients with Parkinson’s disease, according to trial results published in the April issue of JAMA Neurology. The treatment modality is well tolerated, widely available, and “relatively easy to prescribe and incorporate into a clinical practice,” said Aleksandar Videnovic, MD, a neurologist at Massachusetts General Hospital in Boston, and colleagues. 
Impaired sleep and alertness are common nonmotor manifestations of Parkinson’s disease with limited treatment options. Patients’ sleep disturbances have been attributed to Parkinson’s disease symptoms, adverse medication effects, and neurodegeneration of central sleep regulatory areas. Altered circadian rhythms also may play a role. Supplemental exposure to bright light improves sleep quality and daytime vigilance in healthy older people and patients with dementia, but the treatment modality has not been studied systematically in patients with Parkinson’s disease, the researchers said.
One-Hour Treatment Intervals
To determine the safety and efficacy of light therapy on excessive daytime sleepiness associated with Parkinson’s disease, Dr. Videnovic and colleagues conducted a randomized, placebo-controlled trial.
They enrolled 31 patients with Parkinson’s disease and excessive daytime sleepiness (ie, an Epworth Sleepiness Scale score of 12 or greater). Patients were receiving stable dopaminergic therapy and did not have cognitive impairment or a primary sleep disorder. Investigators randomized participants 1:1 to receive bright light therapy (10,000 lux) or a control condition of dim-red light therapy (less than 300 lux). After a two-week baseline phase, participants received light therapy in one-hour intervals twice daily—in the morning (between 9 am and 11 am) and in the afternoon (between 5 pm and 7 pm)—for 14 days. The primary outcome measure was change in Epworth Sleepiness Scale score from baseline. During the study, each patient wore an actigraphy monitor and completed a daily sleep log and various other assessments.
During treatment, a light box was placed 86.4 cm away from the patient. Participants were instructed to sit quietly and not nap. They could listen to music or audiobooks.
The 31 patients (18 females) had an average age of about 63 (range, 32 to 77) and an average disease duration of about six years. Among patients who received bright light therapy, mean Epworth Sleepiness Scale score significantly improved from 15.81 at baseline to 11.19 post intervention. The improvement was significantly greater than that for patients in the control group, who had a mean Epworth Sleepiness Scale score of 15.47 at baseline and 13.67 post intervention.
Improvements in sleep quality, latency, and fragmentation were significantly greater in the bright light therapy group than in the control group. In both treatment arms, light therapy was associated with increased daily physical activity, as assessed by actigraphy, and reduced disease severity, as assessed by the Unified Parkinson’s Disease Rating Scale. Light therapy was not associated with significant changes in depression, anxiety, or quality of life.
In the active treatment group, one patient reported headache, and another patient reported sleepiness. One participant in the control group reported itchy eyes. The adverse events resolved spontaneously, and adherence to the study protocol was excellent, the researchers said.
Although improvement in the control arm may have been due to the placebo effect, it is also possible that “anchoring the light therapy to a strict twice-daily regimen provided means for structuring daily activities, which itself may be an interesting possible mechanism underlying the beneficial effects of … light therapy,” Dr. Videnovic and colleagues said. Future studies should address the optimal treatment parameters for light therapy in Parkinson’s disease, they added.
Whether light therapy produces direct alerting effects, influences the circadian system, or works through another mechanism is not clear. A limitation of the study was that light levels were not measured throughout the day, so patients in the control group could have received more light from other sources overall, compared with patients in the active treatment group, the investigators noted.
Chronobiologic Interventions
The study shows that chronobiologic interventions “can be used therapeutically in patients with Parkinson’s disease” and “introduce
—Jake Remaly
Suggested Reading
Högl B. Circadian rhythms and chronotherapeutics-Underappreciated approach to improving sleep and wakefulness in Parkinson disease. JAMA Neurol. 2017;74(4):387-388.
Videnovic A, Klerman EB, Wang W, et al. Timed light therapy for sleep and daytime sleepiness associated with Parkinson disease: A randomized clinical trial. JAMA Neurol. 2017;74(4):411-418.
Light therapy may reduce excessive daytime sleepiness and improve sleep quality in patients with Parkinson’s disease, according to trial results published in the April issue of JAMA Neurology. The treatment modality is well tolerated, widely available, and “relatively easy to prescribe and incorporate into a clinical practice,” said Aleksandar Videnovic, MD, a neurologist at Massachusetts General Hospital in Boston, and colleagues.
Impaired sleep and alertness are common nonmotor manifestations of Parkinson’s disease with limited treatment options. Patients’ sleep disturbances have been attributed to Parkinson’s disease symptoms, adverse medication effects, and neurodegeneration of central sleep regulatory areas. Altered circadian rhythms also may play a role. Supplemental exposure to bright light improves sleep quality and daytime vigilance in healthy older people and patients with dementia, but the treatment modality has not been studied systematically in patients with Parkinson’s disease, the researchers said.
One-Hour Treatment Intervals
To determine the safety and efficacy of light therapy on excessive daytime sleepiness associated with Parkinson’s disease, Dr. Videnovic and colleagues conducted a randomized, placebo-controlled trial.
They enrolled 31 patients with Parkinson’s disease and excessive daytime sleepiness (ie, an Epworth Sleepiness Scale score of 12 or greater). Patients were receiving stable dopaminergic therapy and did not have cognitive impairment or a primary sleep disorder. Investigators randomized participants 1:1 to receive bright light therapy (10,000 lux) or a control condition of dim-red light therapy (less than 300 lux). After a two-week baseline phase, participants received light therapy in one-hour intervals twice daily—in the morning (between 9 am and 11 am) and in the afternoon (between 5 pm and 7 pm)—for 14 days. The primary outcome measure was change in Epworth Sleepiness Scale score from baseline. During the study, each patient wore an actigraphy monitor and completed a daily sleep log and various other assessments.
During treatment, a light box was placed 86.4 cm away from the patient. Participants were instructed to sit quietly and not nap. They could listen to music or audiobooks.
The 31 patients (18 females) had an average age of about 63 (range, 32 to 77) and an average disease duration of about six years. Among patients who received bright light therapy, mean Epworth Sleepiness Scale score significantly improved from 15.81 at baseline to 11.19 post intervention. The improvement was significantly greater than that for patients in the control group, who had a mean Epworth Sleepiness Scale score of 15.47 at baseline and 13.67 post intervention.
Improvements in sleep quality, latency, and fragmentation were significantly greater in the bright light therapy group than in the control group. In both treatment arms, light therapy was associated with increased daily physical activity, as assessed by actigraphy, and reduced disease severity, as assessed by the Unified Parkinson’s Disease Rating Scale. Light therapy was not associated with significant changes in depression, anxiety, or quality of life.
In the active treatment group, one patient reported headache, and another patient reported sleepiness. One participant in the control group reported itchy eyes. The adverse events resolved spontaneously, and adherence to the study protocol was excellent, the researchers said.
Although improvement in the control arm may have been due to the placebo effect, it is also possible that “anchoring the light therapy to a strict twice-daily regimen provided means for structuring daily activities, which itself may be an interesting possible mechanism underlying the beneficial effects of … light therapy,” Dr. Videnovic and colleagues said. Future studies should address the optimal treatment parameters for light therapy in Parkinson’s disease, they added.
Whether light therapy produces direct alerting effects, influences the circadian system, or works through another mechanism is not clear. A limitation of the study was that light levels were not measured throughout the day, so patients in the control group could have received more light from other sources overall, compared with patients in the active treatment group, the investigators noted.
Chronobiologic Interventions
The study shows that chronobiologic interventions “can be used therapeutically in patients with Parkinson’s disease” and “introduce
—Jake Remaly
Suggested Reading
Högl B. Circadian rhythms and chronotherapeutics-Underappreciated approach to improving sleep and wakefulness in Parkinson disease. JAMA Neurol. 2017;74(4):387-388.
Videnovic A, Klerman EB, Wang W, et al. Timed light therapy for sleep and daytime sleepiness associated with Parkinson disease: A randomized clinical trial. JAMA Neurol. 2017;74(4):411-418.
Light therapy may reduce excessive daytime sleepiness and improve sleep quality in patients with Parkinson’s disease, according to trial results published in the April issue of JAMA Neurology. The treatment modality is well tolerated, widely available, and “relatively easy to prescribe and incorporate into a clinical practice,” said Aleksandar Videnovic, MD, a neurologist at Massachusetts General Hospital in Boston, and colleagues.
Impaired sleep and alertness are common nonmotor manifestations of Parkinson’s disease with limited treatment options. Patients’ sleep disturbances have been attributed to Parkinson’s disease symptoms, adverse medication effects, and neurodegeneration of central sleep regulatory areas. Altered circadian rhythms also may play a role. Supplemental exposure to bright light improves sleep quality and daytime vigilance in healthy older people and patients with dementia, but the treatment modality has not been studied systematically in patients with Parkinson’s disease, the researchers said.
One-Hour Treatment Intervals
To determine the safety and efficacy of light therapy on excessive daytime sleepiness associated with Parkinson’s disease, Dr. Videnovic and colleagues conducted a randomized, placebo-controlled trial.
They enrolled 31 patients with Parkinson’s disease and excessive daytime sleepiness (ie, an Epworth Sleepiness Scale score of 12 or greater). Patients were receiving stable dopaminergic therapy and did not have cognitive impairment or a primary sleep disorder. Investigators randomized participants 1:1 to receive bright light therapy (10,000 lux) or a control condition of dim-red light therapy (less than 300 lux). After a two-week baseline phase, participants received light therapy in one-hour intervals twice daily—in the morning (between 9 am and 11 am) and in the afternoon (between 5 pm and 7 pm)—for 14 days. The primary outcome measure was change in Epworth Sleepiness Scale score from baseline. During the study, each patient wore an actigraphy monitor and completed a daily sleep log and various other assessments.
During treatment, a light box was placed 86.4 cm away from the patient. Participants were instructed to sit quietly and not nap. They could listen to music or audiobooks.
The 31 patients (18 females) had an average age of about 63 (range, 32 to 77) and an average disease duration of about six years. Among patients who received bright light therapy, mean Epworth Sleepiness Scale score significantly improved from 15.81 at baseline to 11.19 post intervention. The improvement was significantly greater than that for patients in the control group, who had a mean Epworth Sleepiness Scale score of 15.47 at baseline and 13.67 post intervention.
Improvements in sleep quality, latency, and fragmentation were significantly greater in the bright light therapy group than in the control group. In both treatment arms, light therapy was associated with increased daily physical activity, as assessed by actigraphy, and reduced disease severity, as assessed by the Unified Parkinson’s Disease Rating Scale. Light therapy was not associated with significant changes in depression, anxiety, or quality of life.
In the active treatment group, one patient reported headache, and another patient reported sleepiness. One participant in the control group reported itchy eyes. The adverse events resolved spontaneously, and adherence to the study protocol was excellent, the researchers said.
Although improvement in the control arm may have been due to the placebo effect, it is also possible that “anchoring the light therapy to a strict twice-daily regimen provided means for structuring daily activities, which itself may be an interesting possible mechanism underlying the beneficial effects of … light therapy,” Dr. Videnovic and colleagues said. Future studies should address the optimal treatment parameters for light therapy in Parkinson’s disease, they added.
Whether light therapy produces direct alerting effects, influences the circadian system, or works through another mechanism is not clear. A limitation of the study was that light levels were not measured throughout the day, so patients in the control group could have received more light from other sources overall, compared with patients in the active treatment group, the investigators noted.
Chronobiologic Interventions
The study shows that chronobiologic interventions “can be used therapeutically in patients with Parkinson’s disease” and “introduce
—Jake Remaly
Suggested Reading
Högl B. Circadian rhythms and chronotherapeutics-Underappreciated approach to improving sleep and wakefulness in Parkinson disease. JAMA Neurol. 2017;74(4):387-388.
Videnovic A, Klerman EB, Wang W, et al. Timed light therapy for sleep and daytime sleepiness associated with Parkinson disease: A randomized clinical trial. JAMA Neurol. 2017;74(4):411-418.
More treatments becoming available for tardive dyskinesia
MIAMI – The pathophysiology of tardive dyskinesia remains a mystery, but patients with this involuntary movement disorder have new hope – thanks to recent approval of the first agent indicated for the condition and the anticipated approval of a second.
“These drugs actually work and are safe,” Ira D. Glick, MD, professor emeritus of psychiatry and behavioral sciences at Stanford (Calif.) University, said during a panel addressing the disorder at a meeting of the American Society of Clinical Psychopharmacology, formerly the New Clinical Drug Evaluation Unit meeting. 
The vesicular monoamine transport type 2 inhibitor valbenazine (Ingrezza, Neurocrine Biosciences) was approved earlier this year by the Food and Drug Administration, and a second VMAT2 inhibitor, deutetrabenazine (Teva), is scheduled for an FDA Prescription Drug User Fee Act review later this summer.
Those two novel agents downregulate the delivery of dopamine released by monoamine-containing presynaptic vesicles, thus decreasing the stimulation of the D2 receptors, and lessening the frequency and severity of involuntary movements associated with tardive dyskinesia (TD). The difference between them is that valbenazine converts to metabolites with no off-target affinities; deutetrabenazine modifies the pharmacokinetic pathway, slowing the rate of metabolization of the agent.
A phase 2, 6‐week dose‐titration study of valbenazine in 102 subjects with moderate to severe TD showed that the drug significantly reduced TD severity according to the Abnormal Involuntary Movement Scale (AIMS) when dosed at 25 mg and 75 mg, compared with placebo (P = .0005), and to the Clinical Global Impression of Change–Tardive Dyskinesia (P less than .0001) (Mov Disord. 2015 Oct;30[2]:1681-7).
Efficacy data from a pivotal 6-week, phase 3, double-blind, fixed-dosage, placebo-controlled, intention-to-treat study of 234 participants with moderate to severe antipsychotic-induced TD also showed favorable changes in AIMS scores in both the 80-mg and 40-mg groups, compared with placebo (P less than .05 for the valbenazine 40-mg group and P less than .001 for the 80-mg group) (Am J Psychiatry. 2017 May 1;174[5]:476-84). Both doses were efficacious and showed superiority over placebo with the 80-mg dose having a large effect size of 0.90. According to 52-week follow-up maintenance data presented by Dr. Glick, TD symptoms in the 80-mg group remitted until week 48, when patients were removed from their regimens.
“Here is what happens when you take patients off the drug: They relapse to where they were,” Dr. Glick said, noting that by week 52, the cohort essentially had returned to baseline AIMS scores. Somnolence is the main side effect, according to the drug’s package insert.
Clinical data for deutetrabenazine summarized by Dr. Glick indicated that in a 12-week trial in 117 people with moderate to severe TD, 24-mg and 36-mg doses of the drug separated “nicely” from placebo, had a robust efficacy profile in patients with worse symptoms, compared with placebo, a number needed to treat of 6, mild side effects, and no associated adverse events. Dr. Glick said phase 3 clinical trial data indicate that somnolence is once again the main side effect, that the drug was not associated with depression or suicidal ideation, and had low rates of psychiatric adverse events.
Although the exact pathophysiology of TD is unknown, according to panelist Leslie L. Citrome, MD, MPH, traditionally it was thought to be an associated adverse event of antidopaminergic use, particularly with first-generation antipsychotics. However, since TD also occurs with second-generation antipsychotics, and because symptoms frequently persist after antipsychotic use is discontinued, Dr. Citrome said the role of neurodegeneration, which can be exacerbated by oxidative stress and genetic vulnerability, also is implicated in the development of TD. The relationship between TD and decreased levels of brain-derived neurotropic factor, which contributes to the health of neurons, also is nascent in the literature, said Dr. Citrome, clinical professor of psychiatry and behavioral sciences at New York Medical College in Valhalla.
Until valbenazine’s approval, the most common treatment for TD was the orphan drug oral tetrabenazine, a reversible VMAT2 inhibitor that succeeded reserpine for TD treatment when it was discovered not to affect VMAT1, which occurs primarily in the peripheral nervous system. Reserpine irreversibly affects both VMAT1 and VMAT2. Tetrabenazine in the United States is indicated only for chorea in Huntington’s disease, making it highly expensive, according to Dr. Citrome, who also cited the drug’s short half-life and boxed warning for depression and suicidality as drawbacks.
“Its adverse events are problematic, and we don’t really have terrific evidence for its efficacy in TD,” he said.
However, of all the available TD treatments with any associated clinical data, including clonazepam, ginkgo biloba, branch chain amino acids, and amantadine, tetrabenazine’s wide acceptance made it the most “logical” starting point for a more effective treatment of TD, said Dr. Citrome.
The most well tolerated approach remains unclear, Dr. Citrome said. No head-to-head trials of valbenazine vs. deutetrabenazine have as yet been completed, and there are no prospective data. However, said Dr. Glick: “Think of your patients. They have schizophrenia, bipolar disease, terrible diseases. Then they get TD on top of that. How they suffer. Then you give them something that actually works.”
Dr. Glick disclosed that he has many industry ties, including with deutetrabenazine’s study sponsor Teva, as well as with Otsuka, and Takeda. Dr. Citrome disclosed that among his many pharmaceutical industry ties is Neurocrine Biosciences, manufacturer of valbenazine.
[email protected]
On Twitter @whitneymcknight
MIAMI – The pathophysiology of tardive dyskinesia remains a mystery, but patients with this involuntary movement disorder have new hope – thanks to recent approval of the first agent indicated for the condition and the anticipated approval of a second.
“These drugs actually work and are safe,” Ira D. Glick, MD, professor emeritus of psychiatry and behavioral sciences at Stanford (Calif.) University, said during a panel addressing the disorder at a meeting of the American Society of Clinical Psychopharmacology, formerly the New Clinical Drug Evaluation Unit meeting.
The vesicular monoamine transport type 2 inhibitor valbenazine (Ingrezza, Neurocrine Biosciences) was approved earlier this year by the Food and Drug Administration, and a second VMAT2 inhibitor, deutetrabenazine (Teva), is scheduled for an FDA Prescription Drug User Fee Act review later this summer.
Those two novel agents downregulate the delivery of dopamine released by monoamine-containing presynaptic vesicles, thus decreasing the stimulation of the D2 receptors, and lessening the frequency and severity of involuntary movements associated with tardive dyskinesia (TD). The difference between them is that valbenazine converts to metabolites with no off-target affinities; deutetrabenazine modifies the pharmacokinetic pathway, slowing the rate of metabolization of the agent.
A phase 2, 6‐week dose‐titration study of valbenazine in 102 subjects with moderate to severe TD showed that the drug significantly reduced TD severity according to the Abnormal Involuntary Movement Scale (AIMS) when dosed at 25 mg and 75 mg, compared with placebo (P = .0005), and to the Clinical Global Impression of Change–Tardive Dyskinesia (P less than .0001) (Mov Disord. 2015 Oct;30[2]:1681-7).
Efficacy data from a pivotal 6-week, phase 3, double-blind, fixed-dosage, placebo-controlled, intention-to-treat study of 234 participants with moderate to severe antipsychotic-induced TD also showed favorable changes in AIMS scores in both the 80-mg and 40-mg groups, compared with placebo (P less than .05 for the valbenazine 40-mg group and P less than .001 for the 80-mg group) (Am J Psychiatry. 2017 May 1;174[5]:476-84). Both doses were efficacious and showed superiority over placebo with the 80-mg dose having a large effect size of 0.90. According to 52-week follow-up maintenance data presented by Dr. Glick, TD symptoms in the 80-mg group remitted until week 48, when patients were removed from their regimens.
“Here is what happens when you take patients off the drug: They relapse to where they were,” Dr. Glick said, noting that by week 52, the cohort essentially had returned to baseline AIMS scores. Somnolence is the main side effect, according to the drug’s package insert.
Clinical data for deutetrabenazine summarized by Dr. Glick indicated that in a 12-week trial in 117 people with moderate to severe TD, 24-mg and 36-mg doses of the drug separated “nicely” from placebo, had a robust efficacy profile in patients with worse symptoms, compared with placebo, a number needed to treat of 6, mild side effects, and no associated adverse events. Dr. Glick said phase 3 clinical trial data indicate that somnolence is once again the main side effect, that the drug was not associated with depression or suicidal ideation, and had low rates of psychiatric adverse events.
Although the exact pathophysiology of TD is unknown, according to panelist Leslie L. Citrome, MD, MPH, traditionally it was thought to be an associated adverse event of antidopaminergic use, particularly with first-generation antipsychotics. However, since TD also occurs with second-generation antipsychotics, and because symptoms frequently persist after antipsychotic use is discontinued, Dr. Citrome said the role of neurodegeneration, which can be exacerbated by oxidative stress and genetic vulnerability, also is implicated in the development of TD. The relationship between TD and decreased levels of brain-derived neurotropic factor, which contributes to the health of neurons, also is nascent in the literature, said Dr. Citrome, clinical professor of psychiatry and behavioral sciences at New York Medical College in Valhalla.
Until valbenazine’s approval, the most common treatment for TD was the orphan drug oral tetrabenazine, a reversible VMAT2 inhibitor that succeeded reserpine for TD treatment when it was discovered not to affect VMAT1, which occurs primarily in the peripheral nervous system. Reserpine irreversibly affects both VMAT1 and VMAT2. Tetrabenazine in the United States is indicated only for chorea in Huntington’s disease, making it highly expensive, according to Dr. Citrome, who also cited the drug’s short half-life and boxed warning for depression and suicidality as drawbacks.
“Its adverse events are problematic, and we don’t really have terrific evidence for its efficacy in TD,” he said.
However, of all the available TD treatments with any associated clinical data, including clonazepam, ginkgo biloba, branch chain amino acids, and amantadine, tetrabenazine’s wide acceptance made it the most “logical” starting point for a more effective treatment of TD, said Dr. Citrome.
The most well tolerated approach remains unclear, Dr. Citrome said. No head-to-head trials of valbenazine vs. deutetrabenazine have as yet been completed, and there are no prospective data. However, said Dr. Glick: “Think of your patients. They have schizophrenia, bipolar disease, terrible diseases. Then they get TD on top of that. How they suffer. Then you give them something that actually works.”
Dr. Glick disclosed that he has many industry ties, including with deutetrabenazine’s study sponsor Teva, as well as with Otsuka, and Takeda. Dr. Citrome disclosed that among his many pharmaceutical industry ties is Neurocrine Biosciences, manufacturer of valbenazine.
[email protected]
On Twitter @whitneymcknight
MIAMI – The pathophysiology of tardive dyskinesia remains a mystery, but patients with this involuntary movement disorder have new hope – thanks to recent approval of the first agent indicated for the condition and the anticipated approval of a second.
“These drugs actually work and are safe,” Ira D. Glick, MD, professor emeritus of psychiatry and behavioral sciences at Stanford (Calif.) University, said during a panel addressing the disorder at a meeting of the American Society of Clinical Psychopharmacology, formerly the New Clinical Drug Evaluation Unit meeting.
The vesicular monoamine transport type 2 inhibitor valbenazine (Ingrezza, Neurocrine Biosciences) was approved earlier this year by the Food and Drug Administration, and a second VMAT2 inhibitor, deutetrabenazine (Teva), is scheduled for an FDA Prescription Drug User Fee Act review later this summer.
Those two novel agents downregulate the delivery of dopamine released by monoamine-containing presynaptic vesicles, thus decreasing the stimulation of the D2 receptors, and lessening the frequency and severity of involuntary movements associated with tardive dyskinesia (TD). The difference between them is that valbenazine converts to metabolites with no off-target affinities; deutetrabenazine modifies the pharmacokinetic pathway, slowing the rate of metabolization of the agent.
A phase 2, 6‐week dose‐titration study of valbenazine in 102 subjects with moderate to severe TD showed that the drug significantly reduced TD severity according to the Abnormal Involuntary Movement Scale (AIMS) when dosed at 25 mg and 75 mg, compared with placebo (P = .0005), and to the Clinical Global Impression of Change–Tardive Dyskinesia (P less than .0001) (Mov Disord. 2015 Oct;30[2]:1681-7).
Efficacy data from a pivotal 6-week, phase 3, double-blind, fixed-dosage, placebo-controlled, intention-to-treat study of 234 participants with moderate to severe antipsychotic-induced TD also showed favorable changes in AIMS scores in both the 80-mg and 40-mg groups, compared with placebo (P less than .05 for the valbenazine 40-mg group and P less than .001 for the 80-mg group) (Am J Psychiatry. 2017 May 1;174[5]:476-84). Both doses were efficacious and showed superiority over placebo with the 80-mg dose having a large effect size of 0.90. According to 52-week follow-up maintenance data presented by Dr. Glick, TD symptoms in the 80-mg group remitted until week 48, when patients were removed from their regimens.
“Here is what happens when you take patients off the drug: They relapse to where they were,” Dr. Glick said, noting that by week 52, the cohort essentially had returned to baseline AIMS scores. Somnolence is the main side effect, according to the drug’s package insert.
Clinical data for deutetrabenazine summarized by Dr. Glick indicated that in a 12-week trial in 117 people with moderate to severe TD, 24-mg and 36-mg doses of the drug separated “nicely” from placebo, had a robust efficacy profile in patients with worse symptoms, compared with placebo, a number needed to treat of 6, mild side effects, and no associated adverse events. Dr. Glick said phase 3 clinical trial data indicate that somnolence is once again the main side effect, that the drug was not associated with depression or suicidal ideation, and had low rates of psychiatric adverse events.
Although the exact pathophysiology of TD is unknown, according to panelist Leslie L. Citrome, MD, MPH, traditionally it was thought to be an associated adverse event of antidopaminergic use, particularly with first-generation antipsychotics. However, since TD also occurs with second-generation antipsychotics, and because symptoms frequently persist after antipsychotic use is discontinued, Dr. Citrome said the role of neurodegeneration, which can be exacerbated by oxidative stress and genetic vulnerability, also is implicated in the development of TD. The relationship between TD and decreased levels of brain-derived neurotropic factor, which contributes to the health of neurons, also is nascent in the literature, said Dr. Citrome, clinical professor of psychiatry and behavioral sciences at New York Medical College in Valhalla.
Until valbenazine’s approval, the most common treatment for TD was the orphan drug oral tetrabenazine, a reversible VMAT2 inhibitor that succeeded reserpine for TD treatment when it was discovered not to affect VMAT1, which occurs primarily in the peripheral nervous system. Reserpine irreversibly affects both VMAT1 and VMAT2. Tetrabenazine in the United States is indicated only for chorea in Huntington’s disease, making it highly expensive, according to Dr. Citrome, who also cited the drug’s short half-life and boxed warning for depression and suicidality as drawbacks.
“Its adverse events are problematic, and we don’t really have terrific evidence for its efficacy in TD,” he said.
However, of all the available TD treatments with any associated clinical data, including clonazepam, ginkgo biloba, branch chain amino acids, and amantadine, tetrabenazine’s wide acceptance made it the most “logical” starting point for a more effective treatment of TD, said Dr. Citrome.
The most well tolerated approach remains unclear, Dr. Citrome said. No head-to-head trials of valbenazine vs. deutetrabenazine have as yet been completed, and there are no prospective data. However, said Dr. Glick: “Think of your patients. They have schizophrenia, bipolar disease, terrible diseases. Then they get TD on top of that. How they suffer. Then you give them something that actually works.”
Dr. Glick disclosed that he has many industry ties, including with deutetrabenazine’s study sponsor Teva, as well as with Otsuka, and Takeda. Dr. Citrome disclosed that among his many pharmaceutical industry ties is Neurocrine Biosciences, manufacturer of valbenazine.
[email protected]
On Twitter @whitneymcknight
EXPERT ANALYSIS FROM The ASCP ANNUAL MEETING
Do you talk about marijuana with your patients?
Do you talk about marijuana with your patients?
In medical school, I had a roommate. He was a smart law school graduate, good looking, outgoing, had lots of friends, was funny, and he was a great cook.
I should tell you another thing about my friend: He was a heavy, daily user of marijuana.
I believe that most of us, at a certain point of our lives, have met someone like my friend. The combination of a high-stress lifestyle, high self-expectations, and lack of appropriate skills to tackle life’s obstacles when encountered with failure frequently leads to addiction or a behavioral problem. In most cases, that will cause a pathological relationship with an outside substance or stimuli (Internet overuse/shopping too much/overeating or drinking, and so on).
Living a life filled with severe trauma and pain, especially at a developmental stage, often leads to an addiction. We frequently see people escape to the sweet narcotic-induced sleep via opioid abuse. On the other hand, for people who did not suffer trauma and are highly functional, marijuana offers a means of emotional detachment from pain, in its different form, and existential depression. That is the main benefit my patients who live with marijuana addiction get.
My friend serves as a rather stereotypical – and some may say – subjective, simplistic example of what is becoming more and more common in our society. I’m willing to bet that a good number of clinicians who read this have a similar example in mind.
With its intoxication state perceived as benign and the limited medicinal advantages, marijuana rapidly is gaining more and more legitimacy in the eyes of the general public (Addict Behav. 2008 Mar;33:397-411), (Monitoring the Future: National Results on Drug Use: 1975-2016). The risk of addiction is perceived as negligible and often nonexistent.
Almost no one knows about the potential risk of addiction (around 9%) (Drug Alcohol Depend. 2011;115:120-30). No one knows about about tolerance and withdrawal states – or about the real risk of psychosis (N Engl J Med. 2014 Jun 5;370:2219-27) or about the possible risk of schizophrenia in vulnerable populations (Schizophr Res. 2016 Mar;171:[1-3]:62-7). No one talks about the fact that it’s often used with tobacco. (How many times have you been told during history taking that a patient doesn’t smoke tobacco, only to find that in drug history he smokes 3-5 joints with tobacco daily?)
[polldaddy:9796432]
Throughout my journey in the psychiatric world (studying and working on three different continents) another typical marijuana user is the patient living with chronic mental illness. My Israeli mentor often complained about not having a single “clean” patient with schizophrenia anymore. I now see the same phenomena in Philadelphia and was also exposed to the same reality in Europe during medical school.
As physicians, and especially as psychiatrists, I believe we are obligated to educate our patients by telling them about the risks in their behaviors. Educating patients about marijuana in today’s atmosphere can be a very important preventive measure, and awareness is an important step toward change.
The current generation of psychiatrists is dealing with an opioid epidemic. Let’s educate ourselves and our patients so this current epidemic won’t be followed by another, severe cannabis epidemic.
Dr. Shilo is a second-year PGY in the department of psychiatry at Einstein Medical Center, Philadelphia.
Do you talk about marijuana with your patients?
In medical school, I had a roommate. He was a smart law school graduate, good looking, outgoing, had lots of friends, was funny, and he was a great cook.
I should tell you another thing about my friend: He was a heavy, daily user of marijuana.
I believe that most of us, at a certain point of our lives, have met someone like my friend. The combination of a high-stress lifestyle, high self-expectations, and lack of appropriate skills to tackle life’s obstacles when encountered with failure frequently leads to addiction or a behavioral problem. In most cases, that will cause a pathological relationship with an outside substance or stimuli (Internet overuse/shopping too much/overeating or drinking, and so on).
Living a life filled with severe trauma and pain, especially at a developmental stage, often leads to an addiction. We frequently see people escape to the sweet narcotic-induced sleep via opioid abuse. On the other hand, for people who did not suffer trauma and are highly functional, marijuana offers a means of emotional detachment from pain, in its different form, and existential depression. That is the main benefit my patients who live with marijuana addiction get.
My friend serves as a rather stereotypical – and some may say – subjective, simplistic example of what is becoming more and more common in our society. I’m willing to bet that a good number of clinicians who read this have a similar example in mind.
With its intoxication state perceived as benign and the limited medicinal advantages, marijuana rapidly is gaining more and more legitimacy in the eyes of the general public (Addict Behav. 2008 Mar;33:397-411), (Monitoring the Future: National Results on Drug Use: 1975-2016). The risk of addiction is perceived as negligible and often nonexistent.
Almost no one knows about the potential risk of addiction (around 9%) (Drug Alcohol Depend. 2011;115:120-30). No one knows about about tolerance and withdrawal states – or about the real risk of psychosis (N Engl J Med. 2014 Jun 5;370:2219-27) or about the possible risk of schizophrenia in vulnerable populations (Schizophr Res. 2016 Mar;171:[1-3]:62-7). No one talks about the fact that it’s often used with tobacco. (How many times have you been told during history taking that a patient doesn’t smoke tobacco, only to find that in drug history he smokes 3-5 joints with tobacco daily?)
[polldaddy:9796432]
Throughout my journey in the psychiatric world (studying and working on three different continents) another typical marijuana user is the patient living with chronic mental illness. My Israeli mentor often complained about not having a single “clean” patient with schizophrenia anymore. I now see the same phenomena in Philadelphia and was also exposed to the same reality in Europe during medical school.
As physicians, and especially as psychiatrists, I believe we are obligated to educate our patients by telling them about the risks in their behaviors. Educating patients about marijuana in today’s atmosphere can be a very important preventive measure, and awareness is an important step toward change.
The current generation of psychiatrists is dealing with an opioid epidemic. Let’s educate ourselves and our patients so this current epidemic won’t be followed by another, severe cannabis epidemic.
Dr. Shilo is a second-year PGY in the department of psychiatry at Einstein Medical Center, Philadelphia.
Do you talk about marijuana with your patients?
In medical school, I had a roommate. He was a smart law school graduate, good looking, outgoing, had lots of friends, was funny, and he was a great cook.
I should tell you another thing about my friend: He was a heavy, daily user of marijuana.
I believe that most of us, at a certain point of our lives, have met someone like my friend. The combination of a high-stress lifestyle, high self-expectations, and lack of appropriate skills to tackle life’s obstacles when encountered with failure frequently leads to addiction or a behavioral problem. In most cases, that will cause a pathological relationship with an outside substance or stimuli (Internet overuse/shopping too much/overeating or drinking, and so on).
Living a life filled with severe trauma and pain, especially at a developmental stage, often leads to an addiction. We frequently see people escape to the sweet narcotic-induced sleep via opioid abuse. On the other hand, for people who did not suffer trauma and are highly functional, marijuana offers a means of emotional detachment from pain, in its different form, and existential depression. That is the main benefit my patients who live with marijuana addiction get.
My friend serves as a rather stereotypical – and some may say – subjective, simplistic example of what is becoming more and more common in our society. I’m willing to bet that a good number of clinicians who read this have a similar example in mind.
With its intoxication state perceived as benign and the limited medicinal advantages, marijuana rapidly is gaining more and more legitimacy in the eyes of the general public (Addict Behav. 2008 Mar;33:397-411), (Monitoring the Future: National Results on Drug Use: 1975-2016). The risk of addiction is perceived as negligible and often nonexistent.
Almost no one knows about the potential risk of addiction (around 9%) (Drug Alcohol Depend. 2011;115:120-30). No one knows about about tolerance and withdrawal states – or about the real risk of psychosis (N Engl J Med. 2014 Jun 5;370:2219-27) or about the possible risk of schizophrenia in vulnerable populations (Schizophr Res. 2016 Mar;171:[1-3]:62-7). No one talks about the fact that it’s often used with tobacco. (How many times have you been told during history taking that a patient doesn’t smoke tobacco, only to find that in drug history he smokes 3-5 joints with tobacco daily?)
[polldaddy:9796432]
Throughout my journey in the psychiatric world (studying and working on three different continents) another typical marijuana user is the patient living with chronic mental illness. My Israeli mentor often complained about not having a single “clean” patient with schizophrenia anymore. I now see the same phenomena in Philadelphia and was also exposed to the same reality in Europe during medical school.
As physicians, and especially as psychiatrists, I believe we are obligated to educate our patients by telling them about the risks in their behaviors. Educating patients about marijuana in today’s atmosphere can be a very important preventive measure, and awareness is an important step toward change.
The current generation of psychiatrists is dealing with an opioid epidemic. Let’s educate ourselves and our patients so this current epidemic won’t be followed by another, severe cannabis epidemic.
Dr. Shilo is a second-year PGY in the department of psychiatry at Einstein Medical Center, Philadelphia.
Student Hospitalist Scholars: The importance of communication
Editor’s Note: The Society of Hospital Medicine’s (SHM’s) Physician in Training Committee launched a scholarship program in 2015 for medical students to help transform healthcare and revolutionize patient care. The program has been expanded for the 2017-18 year, offering two options for students to receive funding and engage in scholarly work during their 1st, 2nd, and 3rd years of medical school. As a part of the program, recipients are required to write about their experience on a biweekly basis.
Quality improvement in clinical practice has recently become very important to me. What use is clinical knowledge if it cannot be appropriately used to benefit patients in a clinical setting?
Throughout my 1st year at medical school, my interest in communication continued to grow. In one of my classes, Essentials of Clinical Reasoning, we were taught to continually consider how to effectively translate our thought processes and potential diagnoses to our patients. To begin crafting effective HPIs, we created complete, whole histories from visit to visit.
At this time, I discovered the subfield of research concerning strategies surrounding handoffs as transition of care changes, with patients often suffering due to breakdowns in communication.
With my interest in handoffs, and with direction from the Society of Hospital Medicine, I reached out to Dr. Vineet Arora, a leading academic hospitalist at the University of Chicago with a highly impressive history of research concerning quality of care toward hospitalized adults. Under the supervision of Dr. Arora and Dr. Juan Rojas, a pulmonary critical care fellow, I will help investigate whether receiving floor physicians and intensive care unit physicians possess similar shared mental models in regards to the most pertinent point of care – when patients are transferred out of the ICU.
We seek to identify if there are any associations present between readmission from the general floor, the providers’ rated likelihood of the patient returning to the ICU, and whether floor and ICU physicians are on the same page concerning condition management while on the floor.
I believe the experience I gain at the University of Chicago Medical Center will be invaluable to my future as a physician. I am very excited to get to know the various clinicians at UChicago, to gain clinical experience by observing the management of the general ward, and to identify how effective physicians communicate.
Above all, I hope to use any knowledge I gain this summer to become an efficient, knowledgeable, and compassionate physician capable of providing the highest quality of care to my future patients.
Anton Garazha is a medical student at Chicago Medical School at Rosalind Franklin University in North Chicago, Ill. He received his B.S. in Biology from Loyola University in Chicago in 2015 and his Master of Biomedical Science from Rosalind Franklin University in 2016. Anton is very interested in community outreach and quality improvement, and in his spare time tutors students in science-based subjects.
Editor’s Note: The Society of Hospital Medicine’s (SHM’s) Physician in Training Committee launched a scholarship program in 2015 for medical students to help transform healthcare and revolutionize patient care. The program has been expanded for the 2017-18 year, offering two options for students to receive funding and engage in scholarly work during their 1st, 2nd, and 3rd years of medical school. As a part of the program, recipients are required to write about their experience on a biweekly basis.
Quality improvement in clinical practice has recently become very important to me. What use is clinical knowledge if it cannot be appropriately used to benefit patients in a clinical setting?
Throughout my 1st year at medical school, my interest in communication continued to grow. In one of my classes, Essentials of Clinical Reasoning, we were taught to continually consider how to effectively translate our thought processes and potential diagnoses to our patients. To begin crafting effective HPIs, we created complete, whole histories from visit to visit.
At this time, I discovered the subfield of research concerning strategies surrounding handoffs as transition of care changes, with patients often suffering due to breakdowns in communication.
With my interest in handoffs, and with direction from the Society of Hospital Medicine, I reached out to Dr. Vineet Arora, a leading academic hospitalist at the University of Chicago with a highly impressive history of research concerning quality of care toward hospitalized adults. Under the supervision of Dr. Arora and Dr. Juan Rojas, a pulmonary critical care fellow, I will help investigate whether receiving floor physicians and intensive care unit physicians possess similar shared mental models in regards to the most pertinent point of care – when patients are transferred out of the ICU.
We seek to identify if there are any associations present between readmission from the general floor, the providers’ rated likelihood of the patient returning to the ICU, and whether floor and ICU physicians are on the same page concerning condition management while on the floor.
I believe the experience I gain at the University of Chicago Medical Center will be invaluable to my future as a physician. I am very excited to get to know the various clinicians at UChicago, to gain clinical experience by observing the management of the general ward, and to identify how effective physicians communicate.
Above all, I hope to use any knowledge I gain this summer to become an efficient, knowledgeable, and compassionate physician capable of providing the highest quality of care to my future patients.
Anton Garazha is a medical student at Chicago Medical School at Rosalind Franklin University in North Chicago, Ill. He received his B.S. in Biology from Loyola University in Chicago in 2015 and his Master of Biomedical Science from Rosalind Franklin University in 2016. Anton is very interested in community outreach and quality improvement, and in his spare time tutors students in science-based subjects.
Editor’s Note: The Society of Hospital Medicine’s (SHM’s) Physician in Training Committee launched a scholarship program in 2015 for medical students to help transform healthcare and revolutionize patient care. The program has been expanded for the 2017-18 year, offering two options for students to receive funding and engage in scholarly work during their 1st, 2nd, and 3rd years of medical school. As a part of the program, recipients are required to write about their experience on a biweekly basis.
Quality improvement in clinical practice has recently become very important to me. What use is clinical knowledge if it cannot be appropriately used to benefit patients in a clinical setting?
Throughout my 1st year at medical school, my interest in communication continued to grow. In one of my classes, Essentials of Clinical Reasoning, we were taught to continually consider how to effectively translate our thought processes and potential diagnoses to our patients. To begin crafting effective HPIs, we created complete, whole histories from visit to visit.
At this time, I discovered the subfield of research concerning strategies surrounding handoffs as transition of care changes, with patients often suffering due to breakdowns in communication.
With my interest in handoffs, and with direction from the Society of Hospital Medicine, I reached out to Dr. Vineet Arora, a leading academic hospitalist at the University of Chicago with a highly impressive history of research concerning quality of care toward hospitalized adults. Under the supervision of Dr. Arora and Dr. Juan Rojas, a pulmonary critical care fellow, I will help investigate whether receiving floor physicians and intensive care unit physicians possess similar shared mental models in regards to the most pertinent point of care – when patients are transferred out of the ICU.
We seek to identify if there are any associations present between readmission from the general floor, the providers’ rated likelihood of the patient returning to the ICU, and whether floor and ICU physicians are on the same page concerning condition management while on the floor.
I believe the experience I gain at the University of Chicago Medical Center will be invaluable to my future as a physician. I am very excited to get to know the various clinicians at UChicago, to gain clinical experience by observing the management of the general ward, and to identify how effective physicians communicate.
Above all, I hope to use any knowledge I gain this summer to become an efficient, knowledgeable, and compassionate physician capable of providing the highest quality of care to my future patients.
Anton Garazha is a medical student at Chicago Medical School at Rosalind Franklin University in North Chicago, Ill. He received his B.S. in Biology from Loyola University in Chicago in 2015 and his Master of Biomedical Science from Rosalind Franklin University in 2016. Anton is very interested in community outreach and quality improvement, and in his spare time tutors students in science-based subjects.
Secondary Cancers After Prostate Cancer: What’s the Risk?
Men with prostate cancer (PCa) have a higher risk of secondary primary cancers (SPM) in the thyroid compared with that of men without PCa, say researchers from the National Defense Medical Center in Taipei and China Medical University in Taichung, both in Taiwan. Their study of 30,964 men also found a trend toward higher risk of SPM in the urinary bladder and rectum/anus.
Related: First Cancer Treatment Based on Biomarkers Is Approved
However, the study, which covered years 2000-2010, also showed a trend toward lower risk of developing overall SPM among PCa survivors, compared with men who did not have PCa. The risks of lung and liver cancer, for instance, were significantly lower. The risk of thyroid cancer was higher in patients diagnosed when aged < 64 years, but the overall number of cases was small, particularly in that group.
When the researchers analyzed the data according to treatment, they found that patients with PCa who had radiation therapy had a higher risk of overall SPM, hematologic malignancies, esophageal cancer, liver cancer, lung cancer, and urinary bladder cancer, compared with those who did not have radiation therapy. The risk of hematologic malignancies and urinary bladder cancer were significantly lower in patients with PCa treated with androgen deprivation therapy than in those who were not.
Related: Treatment and Management of Patients With Prostate Cancer
Patients who had undergone prostatectomy had a significantly lower risk of overall SPM, hematologic malignancies, liver cancer, and urinary bladder cancer; however, they had a significantly higher risk of thyroid cancer.
The researchers say, given the increases in incidence and life expectancy of patients with PCa, there is growing interest in predicting the risk of SPM. Knowing the risk factors, they note, highlights the need for continued cancer surveillance among PCa survivors.
Source:
Fan CY, Huang WY, Lin CS, et al. PLoS One. 2017:12(4):e0175217.
doi: 10.1371/journal.pone.0175217.
Men with prostate cancer (PCa) have a higher risk of secondary primary cancers (SPM) in the thyroid compared with that of men without PCa, say researchers from the National Defense Medical Center in Taipei and China Medical University in Taichung, both in Taiwan. Their study of 30,964 men also found a trend toward higher risk of SPM in the urinary bladder and rectum/anus.
Related: First Cancer Treatment Based on Biomarkers Is Approved
However, the study, which covered years 2000-2010, also showed a trend toward lower risk of developing overall SPM among PCa survivors, compared with men who did not have PCa. The risks of lung and liver cancer, for instance, were significantly lower. The risk of thyroid cancer was higher in patients diagnosed when aged < 64 years, but the overall number of cases was small, particularly in that group.
When the researchers analyzed the data according to treatment, they found that patients with PCa who had radiation therapy had a higher risk of overall SPM, hematologic malignancies, esophageal cancer, liver cancer, lung cancer, and urinary bladder cancer, compared with those who did not have radiation therapy. The risk of hematologic malignancies and urinary bladder cancer were significantly lower in patients with PCa treated with androgen deprivation therapy than in those who were not.
Related: Treatment and Management of Patients With Prostate Cancer
Patients who had undergone prostatectomy had a significantly lower risk of overall SPM, hematologic malignancies, liver cancer, and urinary bladder cancer; however, they had a significantly higher risk of thyroid cancer.
The researchers say, given the increases in incidence and life expectancy of patients with PCa, there is growing interest in predicting the risk of SPM. Knowing the risk factors, they note, highlights the need for continued cancer surveillance among PCa survivors.
Source:
Fan CY, Huang WY, Lin CS, et al. PLoS One. 2017:12(4):e0175217.
doi: 10.1371/journal.pone.0175217.
Men with prostate cancer (PCa) have a higher risk of secondary primary cancers (SPM) in the thyroid compared with that of men without PCa, say researchers from the National Defense Medical Center in Taipei and China Medical University in Taichung, both in Taiwan. Their study of 30,964 men also found a trend toward higher risk of SPM in the urinary bladder and rectum/anus.
Related: First Cancer Treatment Based on Biomarkers Is Approved
However, the study, which covered years 2000-2010, also showed a trend toward lower risk of developing overall SPM among PCa survivors, compared with men who did not have PCa. The risks of lung and liver cancer, for instance, were significantly lower. The risk of thyroid cancer was higher in patients diagnosed when aged < 64 years, but the overall number of cases was small, particularly in that group.
When the researchers analyzed the data according to treatment, they found that patients with PCa who had radiation therapy had a higher risk of overall SPM, hematologic malignancies, esophageal cancer, liver cancer, lung cancer, and urinary bladder cancer, compared with those who did not have radiation therapy. The risk of hematologic malignancies and urinary bladder cancer were significantly lower in patients with PCa treated with androgen deprivation therapy than in those who were not.
Related: Treatment and Management of Patients With Prostate Cancer
Patients who had undergone prostatectomy had a significantly lower risk of overall SPM, hematologic malignancies, liver cancer, and urinary bladder cancer; however, they had a significantly higher risk of thyroid cancer.
The researchers say, given the increases in incidence and life expectancy of patients with PCa, there is growing interest in predicting the risk of SPM. Knowing the risk factors, they note, highlights the need for continued cancer surveillance among PCa survivors.
Source:
Fan CY, Huang WY, Lin CS, et al. PLoS One. 2017:12(4):e0175217.
doi: 10.1371/journal.pone.0175217.
Link Between Intestinal Fungi and Alcoholic Liver Disease Grows Stronger
Alcoholic liver disease (ALD) has been associated with bacterial overgrowth in the intestines, as well as a shift in the types of bacteria found there. But until now, according to the National Institute on Alcohol Abuse and Alcoholism, little was actually known about the role of intestinal fungi in ALD. A University of California-San Diego and J. Craig Venter Institute in Rockville, Maryland study offers more evidence to support the connection.
In the study, the researchers found that fungi flourished in the intestines of mice with chronic alcohol exposure, and that fungal overgrowth exacerbated alcohol-induced liver disease. Treatment with amphotericin B reduced levels of liver injury and fat accumulation.
In small preliminary studies with humans, the researchers also linked intestinal fungi to ALD. People with alcohol use disorder and various stages of liver disease tended to have an overgrowth of a specific fungal species, as well as less fungal diversity, compared with healthy control subjects. Moreover, the more prevalent the fungal overgrowth in people with ALD, the higher the risk of death.
The researchers say that if further study confirms that fungi are involved in the worsening of ALD, it may be possible to slow disease progression by adjusting the balance of fungal species in the intestine.
Alcoholic liver disease (ALD) has been associated with bacterial overgrowth in the intestines, as well as a shift in the types of bacteria found there. But until now, according to the National Institute on Alcohol Abuse and Alcoholism, little was actually known about the role of intestinal fungi in ALD. A University of California-San Diego and J. Craig Venter Institute in Rockville, Maryland study offers more evidence to support the connection.
In the study, the researchers found that fungi flourished in the intestines of mice with chronic alcohol exposure, and that fungal overgrowth exacerbated alcohol-induced liver disease. Treatment with amphotericin B reduced levels of liver injury and fat accumulation.
In small preliminary studies with humans, the researchers also linked intestinal fungi to ALD. People with alcohol use disorder and various stages of liver disease tended to have an overgrowth of a specific fungal species, as well as less fungal diversity, compared with healthy control subjects. Moreover, the more prevalent the fungal overgrowth in people with ALD, the higher the risk of death.
The researchers say that if further study confirms that fungi are involved in the worsening of ALD, it may be possible to slow disease progression by adjusting the balance of fungal species in the intestine.
Alcoholic liver disease (ALD) has been associated with bacterial overgrowth in the intestines, as well as a shift in the types of bacteria found there. But until now, according to the National Institute on Alcohol Abuse and Alcoholism, little was actually known about the role of intestinal fungi in ALD. A University of California-San Diego and J. Craig Venter Institute in Rockville, Maryland study offers more evidence to support the connection.
In the study, the researchers found that fungi flourished in the intestines of mice with chronic alcohol exposure, and that fungal overgrowth exacerbated alcohol-induced liver disease. Treatment with amphotericin B reduced levels of liver injury and fat accumulation.
In small preliminary studies with humans, the researchers also linked intestinal fungi to ALD. People with alcohol use disorder and various stages of liver disease tended to have an overgrowth of a specific fungal species, as well as less fungal diversity, compared with healthy control subjects. Moreover, the more prevalent the fungal overgrowth in people with ALD, the higher the risk of death.
The researchers say that if further study confirms that fungi are involved in the worsening of ALD, it may be possible to slow disease progression by adjusting the balance of fungal species in the intestine.
Health Canada approves new use for brentuximab vedotin
Health Canada has issued a non-conditional marketing authorization for brentuximab vedotin (Adcetris).
This means the drug is now approved for use as consolidation after autologous stem cell transplant (ASCT) in patients with Hodgkin lymphoma (HL) who have an increased risk of relapse or progression.
Brentuximab vedotin previously received approval with conditions in Canada to treat HL patients who relapse after ASCT or HL patients who are not ASCT candidates and relapse after at least 2 multi-agent chemotherapy regimens.
Brentuximab vedotin also has conditional approval in Canada to treat patients with systemic anaplastic large-cell lymphoma who relapse after at least 1 multi-agent chemotherapy regimen.
Brentuximab vedotin is an antibody-drug conjugate consisting of an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E.
Brentuximab vedotin has marketing authorization in 67 countries for the treatment of relapsed or refractory HL and systemic anaplastic large-cell lymphoma.
Seattle Genetics and Takeda are jointly developing brentuximab vedotin. Seattle Genetics has US and Canadian commercialization rights, and Takeda has rights to commercialize the drug in the rest of the world.
AETHERA trial
Health Canada’s decision to extend the marketing authorization of brentuximab vedotin is based on results from the phase 3 AETHERA trial.
The trial was designed to compare brentuximab vedotin to placebo, both administered for up to 16 cycles (approximately 1 year) every 3 weeks following ASCT. Results from the trial were published in The Lancet in March 2015.
The study enrolled 329 HL patients at risk of relapse or progression—165 on the brentuximab vedotin arm and 164 on the placebo arm.
Patients were eligible for enrollment if they had a history of primary refractory HL, relapsed within a year of receiving frontline chemotherapy, and/or had disease outside of the lymph nodes at the time of pre-ASCT relapse.
Brentuximab vedotin conferred a significant increase in progression-free survival over placebo, with a hazard ratio of 0.57 (P=0.001). The median progression-free survival was 43 months for patients who received brentuximab vedotin and 24 months for those who received placebo.
The most common adverse events (≥20%), of any grade and regardless of causality, in the brentuximab vedotin arm were neutropenia (78%), peripheral sensory neuropathy (56%), thrombocytopenia (41%), anemia (27%), upper respiratory tract infection (26%), fatigue (24%), peripheral motor neuropathy (23%), nausea (22%), cough (21%), and diarrhea (20%).
The most common adverse events (≥20%), of any grade and regardless of causality, in the placebo arm were neutropenia (34%), upper respiratory tract infection (23%), and thrombocytopenia (20%).
In all, 67% of patients on the brentuximab vedotin arm experienced peripheral neuropathy. Of those patients, 85% had resolution (59%) or partial improvement (26%) in symptoms at the time of their last evaluation, with a median time to improvement of 23 weeks (range, 0.1-138). 
Health Canada has issued a non-conditional marketing authorization for brentuximab vedotin (Adcetris).
This means the drug is now approved for use as consolidation after autologous stem cell transplant (ASCT) in patients with Hodgkin lymphoma (HL) who have an increased risk of relapse or progression.
Brentuximab vedotin previously received approval with conditions in Canada to treat HL patients who relapse after ASCT or HL patients who are not ASCT candidates and relapse after at least 2 multi-agent chemotherapy regimens.
Brentuximab vedotin also has conditional approval in Canada to treat patients with systemic anaplastic large-cell lymphoma who relapse after at least 1 multi-agent chemotherapy regimen.
Brentuximab vedotin is an antibody-drug conjugate consisting of an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E.
Brentuximab vedotin has marketing authorization in 67 countries for the treatment of relapsed or refractory HL and systemic anaplastic large-cell lymphoma.
Seattle Genetics and Takeda are jointly developing brentuximab vedotin. Seattle Genetics has US and Canadian commercialization rights, and Takeda has rights to commercialize the drug in the rest of the world.
AETHERA trial
Health Canada’s decision to extend the marketing authorization of brentuximab vedotin is based on results from the phase 3 AETHERA trial.
The trial was designed to compare brentuximab vedotin to placebo, both administered for up to 16 cycles (approximately 1 year) every 3 weeks following ASCT. Results from the trial were published in The Lancet in March 2015.
The study enrolled 329 HL patients at risk of relapse or progression—165 on the brentuximab vedotin arm and 164 on the placebo arm.
Patients were eligible for enrollment if they had a history of primary refractory HL, relapsed within a year of receiving frontline chemotherapy, and/or had disease outside of the lymph nodes at the time of pre-ASCT relapse.
Brentuximab vedotin conferred a significant increase in progression-free survival over placebo, with a hazard ratio of 0.57 (P=0.001). The median progression-free survival was 43 months for patients who received brentuximab vedotin and 24 months for those who received placebo.
The most common adverse events (≥20%), of any grade and regardless of causality, in the brentuximab vedotin arm were neutropenia (78%), peripheral sensory neuropathy (56%), thrombocytopenia (41%), anemia (27%), upper respiratory tract infection (26%), fatigue (24%), peripheral motor neuropathy (23%), nausea (22%), cough (21%), and diarrhea (20%).
The most common adverse events (≥20%), of any grade and regardless of causality, in the placebo arm were neutropenia (34%), upper respiratory tract infection (23%), and thrombocytopenia (20%).
In all, 67% of patients on the brentuximab vedotin arm experienced peripheral neuropathy. Of those patients, 85% had resolution (59%) or partial improvement (26%) in symptoms at the time of their last evaluation, with a median time to improvement of 23 weeks (range, 0.1-138).
Health Canada has issued a non-conditional marketing authorization for brentuximab vedotin (Adcetris).
This means the drug is now approved for use as consolidation after autologous stem cell transplant (ASCT) in patients with Hodgkin lymphoma (HL) who have an increased risk of relapse or progression.
Brentuximab vedotin previously received approval with conditions in Canada to treat HL patients who relapse after ASCT or HL patients who are not ASCT candidates and relapse after at least 2 multi-agent chemotherapy regimens.
Brentuximab vedotin also has conditional approval in Canada to treat patients with systemic anaplastic large-cell lymphoma who relapse after at least 1 multi-agent chemotherapy regimen.
Brentuximab vedotin is an antibody-drug conjugate consisting of an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E.
Brentuximab vedotin has marketing authorization in 67 countries for the treatment of relapsed or refractory HL and systemic anaplastic large-cell lymphoma.
Seattle Genetics and Takeda are jointly developing brentuximab vedotin. Seattle Genetics has US and Canadian commercialization rights, and Takeda has rights to commercialize the drug in the rest of the world.
AETHERA trial
Health Canada’s decision to extend the marketing authorization of brentuximab vedotin is based on results from the phase 3 AETHERA trial.
The trial was designed to compare brentuximab vedotin to placebo, both administered for up to 16 cycles (approximately 1 year) every 3 weeks following ASCT. Results from the trial were published in The Lancet in March 2015.
The study enrolled 329 HL patients at risk of relapse or progression—165 on the brentuximab vedotin arm and 164 on the placebo arm.
Patients were eligible for enrollment if they had a history of primary refractory HL, relapsed within a year of receiving frontline chemotherapy, and/or had disease outside of the lymph nodes at the time of pre-ASCT relapse.
Brentuximab vedotin conferred a significant increase in progression-free survival over placebo, with a hazard ratio of 0.57 (P=0.001). The median progression-free survival was 43 months for patients who received brentuximab vedotin and 24 months for those who received placebo.
The most common adverse events (≥20%), of any grade and regardless of causality, in the brentuximab vedotin arm were neutropenia (78%), peripheral sensory neuropathy (56%), thrombocytopenia (41%), anemia (27%), upper respiratory tract infection (26%), fatigue (24%), peripheral motor neuropathy (23%), nausea (22%), cough (21%), and diarrhea (20%).
The most common adverse events (≥20%), of any grade and regardless of causality, in the placebo arm were neutropenia (34%), upper respiratory tract infection (23%), and thrombocytopenia (20%).
In all, 67% of patients on the brentuximab vedotin arm experienced peripheral neuropathy. Of those patients, 85% had resolution (59%) or partial improvement (26%) in symptoms at the time of their last evaluation, with a median time to improvement of 23 weeks (range, 0.1-138).
Survey reveals change in public perception of clinical trials
More Americans are viewing clinical trials in a positive light, according to a survey commissioned by Research!America and the Association of Clinical Research Organizations (ACRO).
The results of the survey, which included 1000 participants and was conducted this month, reveal a shift in public attitudes about clinical trials since a similar survey was commissioned in 2013.
Thirty-seven percent of respondents involved in the current survey said they would “very likely” enroll in a clinical trial if their doctor recommended it. This represents an 11% increase from 2013.
Eighty-four percent of current survey respondents said they are willing to share personal health information, assuming that appropriate privacy protections are in place, so researchers can better understand diseases and develop new ways to prevent, treat, and cure them. This is a 10% increase from 2013.
When asked how much they admire people who volunteer for clinical trials, 46% of current respondents said “a great deal,” which is a 9% increase from 2013.
“More and more Americans appear to recognize the value of clinical trials—a very positive sign—but stubborn barriers to participation remain in place,” said Mary Woolley, president and CEO of Research!America.
“Development of incentives to drive more discussions between patients and healthcare professionals about the importance of participating in trials could encourage both ill and healthy individuals to view this as a routine health behavior.”
“We are pleased to have joined with Research!America in commissioning this important survey and gratified that the public’s knowledge of and attitudes toward clinical trials have moved in positive directions since 2013,” said Doug Peddicord, executive director of ACRO.
“The option to participate in a clinical trial, when appropriate, should be a routine part of the healthcare encounter, and ACRO will continue to work with Research!America and others to spread that message to doctors and patients alike.”
Survey results
The survey of 1000 US adults was conducted by Zogby Analytics for Research!America and ACRO in July 2017. The margin of error is +/- 3.1 percentage points.
Ninety percent of survey respondents said clinical trials are important to advancing science, and 87% said trials are important to improving the nation’s health. Seventy-five percent said taking part in clinical trials is as valuable to the US healthcare system as giving blood.
Eighty-six percent of respondents said healthcare professionals should discuss clinical trials with patients diagnosed with a disease as part of their standard care.
And 44% of respondents said clinical trial participation should be a routine health behavior, whether a person is healthy or ill, similar to getting an annual checkup with a healthcare provider.
Men (48%) were significantly more likely than women (39%) to say trial participation should be routine. A larger percentage of 18- to 29-year-olds (53%) and 30- to 49-year olds (48%) were in favor of routine trial participation, compared to people ages 50 to 64 (38%) and those 65 and older (34%).
Eighty percent of respondents said they had heard of a clinical trial, and 18% said they or someone in their family had participated in one.
Seventy-four percent of respondents said they would participate in a clinical trial if asked by someone they trust.
However, respondents were split on whether it’s important for everyone to take part in a clinical trial if asked. Forty-four percent said it is important, 45% disagreed, and 12% were not sure.
More than half of respondents (55%) said people don’t participate in clinical trials because of lack of awareness and information, 43% said it’s because trials are viewed as “too risky,” 41% said it’s due to a lack of information about the process, 38% said it’s due to a lack of trust, and 34% said it’s due to the risk of adverse health effects.
Nearly two-thirds of respondents (64%) said a doctor or healthcare provider is a reliable source for clinical trial information.
Respondents said doctors and other healthcare providers (44%), followed by the government (23%), have the greatest responsibility in educating the public about clinical trials. However, 74% said no healthcare professional has ever talked to them about medical research.
Seventy-two percent of respondents said they would be likely to use technology such as apps and monitoring devices to share their personal health data for clinical research.
Eighty-eight percent said clinical trial participants should have access to trial results. And 47% said they would like having clinical trial information/data/results delivered through their phone.
More Americans are viewing clinical trials in a positive light, according to a survey commissioned by Research!America and the Association of Clinical Research Organizations (ACRO).
The results of the survey, which included 1000 participants and was conducted this month, reveal a shift in public attitudes about clinical trials since a similar survey was commissioned in 2013.
Thirty-seven percent of respondents involved in the current survey said they would “very likely” enroll in a clinical trial if their doctor recommended it. This represents an 11% increase from 2013.
Eighty-four percent of current survey respondents said they are willing to share personal health information, assuming that appropriate privacy protections are in place, so researchers can better understand diseases and develop new ways to prevent, treat, and cure them. This is a 10% increase from 2013.
When asked how much they admire people who volunteer for clinical trials, 46% of current respondents said “a great deal,” which is a 9% increase from 2013.
“More and more Americans appear to recognize the value of clinical trials—a very positive sign—but stubborn barriers to participation remain in place,” said Mary Woolley, president and CEO of Research!America.
“Development of incentives to drive more discussions between patients and healthcare professionals about the importance of participating in trials could encourage both ill and healthy individuals to view this as a routine health behavior.”
“We are pleased to have joined with Research!America in commissioning this important survey and gratified that the public’s knowledge of and attitudes toward clinical trials have moved in positive directions since 2013,” said Doug Peddicord, executive director of ACRO.
“The option to participate in a clinical trial, when appropriate, should be a routine part of the healthcare encounter, and ACRO will continue to work with Research!America and others to spread that message to doctors and patients alike.”
Survey results
The survey of 1000 US adults was conducted by Zogby Analytics for Research!America and ACRO in July 2017. The margin of error is +/- 3.1 percentage points.
Ninety percent of survey respondents said clinical trials are important to advancing science, and 87% said trials are important to improving the nation’s health. Seventy-five percent said taking part in clinical trials is as valuable to the US healthcare system as giving blood.
Eighty-six percent of respondents said healthcare professionals should discuss clinical trials with patients diagnosed with a disease as part of their standard care.
And 44% of respondents said clinical trial participation should be a routine health behavior, whether a person is healthy or ill, similar to getting an annual checkup with a healthcare provider.
Men (48%) were significantly more likely than women (39%) to say trial participation should be routine. A larger percentage of 18- to 29-year-olds (53%) and 30- to 49-year olds (48%) were in favor of routine trial participation, compared to people ages 50 to 64 (38%) and those 65 and older (34%).
Eighty percent of respondents said they had heard of a clinical trial, and 18% said they or someone in their family had participated in one.
Seventy-four percent of respondents said they would participate in a clinical trial if asked by someone they trust.
However, respondents were split on whether it’s important for everyone to take part in a clinical trial if asked. Forty-four percent said it is important, 45% disagreed, and 12% were not sure.
More than half of respondents (55%) said people don’t participate in clinical trials because of lack of awareness and information, 43% said it’s because trials are viewed as “too risky,” 41% said it’s due to a lack of information about the process, 38% said it’s due to a lack of trust, and 34% said it’s due to the risk of adverse health effects.
Nearly two-thirds of respondents (64%) said a doctor or healthcare provider is a reliable source for clinical trial information.
Respondents said doctors and other healthcare providers (44%), followed by the government (23%), have the greatest responsibility in educating the public about clinical trials. However, 74% said no healthcare professional has ever talked to them about medical research.
Seventy-two percent of respondents said they would be likely to use technology such as apps and monitoring devices to share their personal health data for clinical research.
Eighty-eight percent said clinical trial participants should have access to trial results. And 47% said they would like having clinical trial information/data/results delivered through their phone.
More Americans are viewing clinical trials in a positive light, according to a survey commissioned by Research!America and the Association of Clinical Research Organizations (ACRO).
The results of the survey, which included 1000 participants and was conducted this month, reveal a shift in public attitudes about clinical trials since a similar survey was commissioned in 2013.
Thirty-seven percent of respondents involved in the current survey said they would “very likely” enroll in a clinical trial if their doctor recommended it. This represents an 11% increase from 2013.
Eighty-four percent of current survey respondents said they are willing to share personal health information, assuming that appropriate privacy protections are in place, so researchers can better understand diseases and develop new ways to prevent, treat, and cure them. This is a 10% increase from 2013.
When asked how much they admire people who volunteer for clinical trials, 46% of current respondents said “a great deal,” which is a 9% increase from 2013.
“More and more Americans appear to recognize the value of clinical trials—a very positive sign—but stubborn barriers to participation remain in place,” said Mary Woolley, president and CEO of Research!America.
“Development of incentives to drive more discussions between patients and healthcare professionals about the importance of participating in trials could encourage both ill and healthy individuals to view this as a routine health behavior.”
“We are pleased to have joined with Research!America in commissioning this important survey and gratified that the public’s knowledge of and attitudes toward clinical trials have moved in positive directions since 2013,” said Doug Peddicord, executive director of ACRO.
“The option to participate in a clinical trial, when appropriate, should be a routine part of the healthcare encounter, and ACRO will continue to work with Research!America and others to spread that message to doctors and patients alike.”
Survey results
The survey of 1000 US adults was conducted by Zogby Analytics for Research!America and ACRO in July 2017. The margin of error is +/- 3.1 percentage points.
Ninety percent of survey respondents said clinical trials are important to advancing science, and 87% said trials are important to improving the nation’s health. Seventy-five percent said taking part in clinical trials is as valuable to the US healthcare system as giving blood.
Eighty-six percent of respondents said healthcare professionals should discuss clinical trials with patients diagnosed with a disease as part of their standard care.
And 44% of respondents said clinical trial participation should be a routine health behavior, whether a person is healthy or ill, similar to getting an annual checkup with a healthcare provider.
Men (48%) were significantly more likely than women (39%) to say trial participation should be routine. A larger percentage of 18- to 29-year-olds (53%) and 30- to 49-year olds (48%) were in favor of routine trial participation, compared to people ages 50 to 64 (38%) and those 65 and older (34%).
Eighty percent of respondents said they had heard of a clinical trial, and 18% said they or someone in their family had participated in one.
Seventy-four percent of respondents said they would participate in a clinical trial if asked by someone they trust.
However, respondents were split on whether it’s important for everyone to take part in a clinical trial if asked. Forty-four percent said it is important, 45% disagreed, and 12% were not sure.
More than half of respondents (55%) said people don’t participate in clinical trials because of lack of awareness and information, 43% said it’s because trials are viewed as “too risky,” 41% said it’s due to a lack of information about the process, 38% said it’s due to a lack of trust, and 34% said it’s due to the risk of adverse health effects.
Nearly two-thirds of respondents (64%) said a doctor or healthcare provider is a reliable source for clinical trial information.
Respondents said doctors and other healthcare providers (44%), followed by the government (23%), have the greatest responsibility in educating the public about clinical trials. However, 74% said no healthcare professional has ever talked to them about medical research.
Seventy-two percent of respondents said they would be likely to use technology such as apps and monitoring devices to share their personal health data for clinical research.
Eighty-eight percent said clinical trial participants should have access to trial results. And 47% said they would like having clinical trial information/data/results delivered through their phone.
Predicting response to treatment in AML, MDS
Researchers say they have determined which patients will respond to treatment with SY-1425, a retinoic acid receptor alpha (RARα) agonist.
The team discovered a subset of patients with acute myeloid leukemia (AML) who had a super-enhancer associated with the RARA gene, which is predictive of response to SY-1425.
The researchers also identified a subset of patients with myelodysplastic syndromes (MDS) who had high expression of the RARA gene.
And experiments showed that RARA-high MDS had a similar response to SY-1425 as that seen in AML driven by the RARA super-enhancer.
Ravindra Majeti MD, PhD, of Stanford University School of Medicine in California, and colleagues reported these findings in Cancer Discovery. Employees of Syros Pharmaceuticals, the company developing SY-1425, were also involved in this research.
In collaboration with the Majeti lab, Syros used its gene control platform to analyze 66 AML patients’ tumor samples. In this way, the researchers identified 6 distinct patient subsets based on super-enhancer profiles, including 1 enriched for a super-enhancer associated with the RARA gene.
The team found that super-enhancer profiles were strongly associated with survival outcomes, often independent of known genetic mutations in AML.
The RARA super-enhancer was associated with high expression of the RARA gene, which codes for a transcription factor targeted by SY-1425.
The RARA super-enhancer was predictive of response to SY-1425. In AML cells with high RARA expression, SY-1425 reduced proliferation and promoted differentiation.
Moreover, SY-1425 decreased tumor burden and prolonged survival in patient-derived xenograft models of AML with high RARA expression. However, there was no effect on AML cells or models with low RARA expression.
The researchers said SY-1425 induced profound transcriptional changes promoting cell differentiation in AML cells with high RARA expression, but the drug produced little to no transcriptional changes in AML cells with low RARA expression.
DHRS3 was the most strongly and rapidly induced gene in response to treatment with SY-1425. This led to the identification of DHRS3 induction as an early indicator of whether SY-1425 is affecting the targeted biology in defined subsets of AML and MDS patients. It is therefore used as a pharmacodynamic marker in the ongoing phase 2 trial of SY-1425.
In this trial, researchers are assessing the safety and efficacy of SY-1425 as a single agent in 4 AML and MDS patient populations, as well as testing SY-1425 in combination with azacitidine in newly diagnosed AML patients who are not suitable candidates for standard chemotherapy.
Researchers say they have determined which patients will respond to treatment with SY-1425, a retinoic acid receptor alpha (RARα) agonist.
The team discovered a subset of patients with acute myeloid leukemia (AML) who had a super-enhancer associated with the RARA gene, which is predictive of response to SY-1425.
The researchers also identified a subset of patients with myelodysplastic syndromes (MDS) who had high expression of the RARA gene.
And experiments showed that RARA-high MDS had a similar response to SY-1425 as that seen in AML driven by the RARA super-enhancer.
Ravindra Majeti MD, PhD, of Stanford University School of Medicine in California, and colleagues reported these findings in Cancer Discovery. Employees of Syros Pharmaceuticals, the company developing SY-1425, were also involved in this research.
In collaboration with the Majeti lab, Syros used its gene control platform to analyze 66 AML patients’ tumor samples. In this way, the researchers identified 6 distinct patient subsets based on super-enhancer profiles, including 1 enriched for a super-enhancer associated with the RARA gene.
The team found that super-enhancer profiles were strongly associated with survival outcomes, often independent of known genetic mutations in AML.
The RARA super-enhancer was associated with high expression of the RARA gene, which codes for a transcription factor targeted by SY-1425.
The RARA super-enhancer was predictive of response to SY-1425. In AML cells with high RARA expression, SY-1425 reduced proliferation and promoted differentiation.
Moreover, SY-1425 decreased tumor burden and prolonged survival in patient-derived xenograft models of AML with high RARA expression. However, there was no effect on AML cells or models with low RARA expression.
The researchers said SY-1425 induced profound transcriptional changes promoting cell differentiation in AML cells with high RARA expression, but the drug produced little to no transcriptional changes in AML cells with low RARA expression.
DHRS3 was the most strongly and rapidly induced gene in response to treatment with SY-1425. This led to the identification of DHRS3 induction as an early indicator of whether SY-1425 is affecting the targeted biology in defined subsets of AML and MDS patients. It is therefore used as a pharmacodynamic marker in the ongoing phase 2 trial of SY-1425.
In this trial, researchers are assessing the safety and efficacy of SY-1425 as a single agent in 4 AML and MDS patient populations, as well as testing SY-1425 in combination with azacitidine in newly diagnosed AML patients who are not suitable candidates for standard chemotherapy.
Researchers say they have determined which patients will respond to treatment with SY-1425, a retinoic acid receptor alpha (RARα) agonist.
The team discovered a subset of patients with acute myeloid leukemia (AML) who had a super-enhancer associated with the RARA gene, which is predictive of response to SY-1425.
The researchers also identified a subset of patients with myelodysplastic syndromes (MDS) who had high expression of the RARA gene.
And experiments showed that RARA-high MDS had a similar response to SY-1425 as that seen in AML driven by the RARA super-enhancer.
Ravindra Majeti MD, PhD, of Stanford University School of Medicine in California, and colleagues reported these findings in Cancer Discovery. Employees of Syros Pharmaceuticals, the company developing SY-1425, were also involved in this research.
In collaboration with the Majeti lab, Syros used its gene control platform to analyze 66 AML patients’ tumor samples. In this way, the researchers identified 6 distinct patient subsets based on super-enhancer profiles, including 1 enriched for a super-enhancer associated with the RARA gene.
The team found that super-enhancer profiles were strongly associated with survival outcomes, often independent of known genetic mutations in AML.
The RARA super-enhancer was associated with high expression of the RARA gene, which codes for a transcription factor targeted by SY-1425.
The RARA super-enhancer was predictive of response to SY-1425. In AML cells with high RARA expression, SY-1425 reduced proliferation and promoted differentiation.
Moreover, SY-1425 decreased tumor burden and prolonged survival in patient-derived xenograft models of AML with high RARA expression. However, there was no effect on AML cells or models with low RARA expression.
The researchers said SY-1425 induced profound transcriptional changes promoting cell differentiation in AML cells with high RARA expression, but the drug produced little to no transcriptional changes in AML cells with low RARA expression.
DHRS3 was the most strongly and rapidly induced gene in response to treatment with SY-1425. This led to the identification of DHRS3 induction as an early indicator of whether SY-1425 is affecting the targeted biology in defined subsets of AML and MDS patients. It is therefore used as a pharmacodynamic marker in the ongoing phase 2 trial of SY-1425.
In this trial, researchers are assessing the safety and efficacy of SY-1425 as a single agent in 4 AML and MDS patient populations, as well as testing SY-1425 in combination with azacitidine in newly diagnosed AML patients who are not suitable candidates for standard chemotherapy.
PEARL score for COPD exacerbations
TITLE: PEARL score predicts COPD readmissions
CLINICAL QUESTION: Which prognostic score is best at predicting 90-day readmission and mortality for patients admitted with an acute exacerbation of chronic obstructive pulmonary disease (AECOPD)?
STUDY DESIGN: Prospective study with three separate cohorts: derivation, internal validation, and external validation.
SETTING: Six hospitals in the United Kingdom.
SYNOPSIS: 2,417 patients were included and 936 were readmitted or died within 90 days of index admission. Patients with expected survival for less than 1 year for reasons other than COPD were excluded. The indices retained in the final PEARL score were: Previous admissions for AECOPD of 2 or more (2 points), extended medical research council (MRC) dyspnea score of 4, 5a or 5b (1, 2, or 3 points), age of 80 or older (1 point), clinical diagnoses of right-sided heart failure (1 point) and/or left-sided heart failure on echocardiogram (1 point). Higher scores were associated with a shorter time to death or readmission. The performance of PEARL was superior to all alternative scoring systems. The major limitation to this study is that it did not differentiate between respiratory and other causes of readmission.
BOTTOM LINE: The PEARL score can be calculated for patients hospitalized for AECOPD to predict their 90-day readmission rate and/or mortality risk.
CITATION: Echevarria C, Steer J, Heslop-Marshall K, Stenton SC, Hickey PM, Hughes R, et al. The PEARL score predicts 90-day readmission or death after hospitalization for acute exacerbation of COPD. Thorax. 2017; doi: 10.1136/thoraxjnl-2016-209298.
Dr. Ayoubieh is assistant professor in the division of hospital medicine at the University of New Mexico.
TITLE: PEARL score predicts COPD readmissions
CLINICAL QUESTION: Which prognostic score is best at predicting 90-day readmission and mortality for patients admitted with an acute exacerbation of chronic obstructive pulmonary disease (AECOPD)?
STUDY DESIGN: Prospective study with three separate cohorts: derivation, internal validation, and external validation.
SETTING: Six hospitals in the United Kingdom.
SYNOPSIS: 2,417 patients were included and 936 were readmitted or died within 90 days of index admission. Patients with expected survival for less than 1 year for reasons other than COPD were excluded. The indices retained in the final PEARL score were: Previous admissions for AECOPD of 2 or more (2 points), extended medical research council (MRC) dyspnea score of 4, 5a or 5b (1, 2, or 3 points), age of 80 or older (1 point), clinical diagnoses of right-sided heart failure (1 point) and/or left-sided heart failure on echocardiogram (1 point). Higher scores were associated with a shorter time to death or readmission. The performance of PEARL was superior to all alternative scoring systems. The major limitation to this study is that it did not differentiate between respiratory and other causes of readmission.
BOTTOM LINE: The PEARL score can be calculated for patients hospitalized for AECOPD to predict their 90-day readmission rate and/or mortality risk.
CITATION: Echevarria C, Steer J, Heslop-Marshall K, Stenton SC, Hickey PM, Hughes R, et al. The PEARL score predicts 90-day readmission or death after hospitalization for acute exacerbation of COPD. Thorax. 2017; doi: 10.1136/thoraxjnl-2016-209298.
Dr. Ayoubieh is assistant professor in the division of hospital medicine at the University of New Mexico.
TITLE: PEARL score predicts COPD readmissions
CLINICAL QUESTION: Which prognostic score is best at predicting 90-day readmission and mortality for patients admitted with an acute exacerbation of chronic obstructive pulmonary disease (AECOPD)?
STUDY DESIGN: Prospective study with three separate cohorts: derivation, internal validation, and external validation.
SETTING: Six hospitals in the United Kingdom.
SYNOPSIS: 2,417 patients were included and 936 were readmitted or died within 90 days of index admission. Patients with expected survival for less than 1 year for reasons other than COPD were excluded. The indices retained in the final PEARL score were: Previous admissions for AECOPD of 2 or more (2 points), extended medical research council (MRC) dyspnea score of 4, 5a or 5b (1, 2, or 3 points), age of 80 or older (1 point), clinical diagnoses of right-sided heart failure (1 point) and/or left-sided heart failure on echocardiogram (1 point). Higher scores were associated with a shorter time to death or readmission. The performance of PEARL was superior to all alternative scoring systems. The major limitation to this study is that it did not differentiate between respiratory and other causes of readmission.
BOTTOM LINE: The PEARL score can be calculated for patients hospitalized for AECOPD to predict their 90-day readmission rate and/or mortality risk.
CITATION: Echevarria C, Steer J, Heslop-Marshall K, Stenton SC, Hickey PM, Hughes R, et al. The PEARL score predicts 90-day readmission or death after hospitalization for acute exacerbation of COPD. Thorax. 2017; doi: 10.1136/thoraxjnl-2016-209298.
Dr. Ayoubieh is assistant professor in the division of hospital medicine at the University of New Mexico.