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Brexanolone injection quickly improves postpartum depression
BARCELONA – Brexanolone injection provided rapid and durable improvement in postpartum depression in an integrated analysis of three pivotal randomized trials collectively known as the Hummingbird trials, Christine Clemson, PhD, reported at the annual congress of the European College of Neuropsychopharmacology.
This was accomplished with a favorable safety experience. The most common treatment-emergent adverse events – dizziness and sleepiness – were roughly twice as common as with placebo in the 247-patient Hummingbird safety analysis.
On Dec. 19, 2018, the agency is expected to respond to SAGE Therapeutics’s application for marketing approval of intravenous brexanolone given as a continuous 60-hour infusion at 90 mcg/kg per hour, according to Dr. Clemson, senior medical director at Cambridge, Mass.–based SAGE Therapeutics, which is developing the therapy.
Brexanolone is a proprietary IV formulation of allopregnanolone, a metabolite of progesterone. The drug’s mechanism of action involves modulation of the neurotransmitter gamma-aminobutyric acid (GABA). The drug binds to both synaptic and extra-synaptic GABA A receptors, thereby increasing receptor functionality.
The decision to target GABA as a novel therapeutic strategy in PPD was based upon translational studies demonstrating that GABA is the chief neuroinhibitory mechanism in the brain, and its actions are mediated mainly by GABA A receptors. Brexanolone’s efficacy is consistent with a theory that the pathogenesis of PPD involves triggers such as inflammation, hormonal fluctuations, or chronic stress, which in some women cause GABA hypofunction, both at the receptors and in terms of tissue GABA levels. This, in turn, leads to an overactive HPA axis and dysregulated neural networks, with resultant PPD, Dr. Clemson explained.
The three Hummingbird clinical trials were double blind, randomized, and placebo controlled. Two were restricted to women with severe PPD. The third and largest focused on moderately affected patients as defined by a baseline Hamilton Depression Scale for Depression (HAM-D) score of 20-25.
The efficacy analysis included 207 patients who received brexanolone at 90 mcg/kg per hour or placebo for 60 hours in an inpatient setting and were followed for 30 days. The primary endpoint was the change in HAM-D total score from baseline to 60 hours. The mean 17-point reduction in the active treatment arm was significantly better than the 12.8-point decrease with placebo. The between-group difference was significant within the first 24 hours and remained so at all time points out to the study’s end at day 30. There was no individual item on the HAM-D in which the drug performed worse than placebo, and there were many in which brexanolone performed significantly better, including depressed mood, anxiety, insomnia, and feelings of guilt.
In terms of the rigorous secondary endpoint of HAM-D remission as defined by a total score of 7 or less, the brexanolone injection significantly outperformed placebo at every time point except for day 30.
There was a 2% rate of serious adverse events in both study arms. These included suicidal ideation, an intentional overdose attempt post discharge, altered state of consciousness, and syncope.
A vastly more convenient once-daily oral formulation of brexanolone is now in phase 3 clinical trials for PPD and major depressive disorder, and in phase 2 for insomnia and bipolar depression.
Elsewhere at the ECNP congress, other investigators from Sage Therapeutics presented for the first time the outcomes of an 89-patient, randomized, double-blind, multicenter, placebo-controlled, phase 2 clinical trial of SAGE-217 for treatment of major depressive disorder.
Participants received a nightly 30-mg dose of the drug or placebo for 2 weeks, with a primary study endpoint being the change in HAM-D total score from baseline to day 15. Patients on the oral GABA A receptor positive modulator averaged a 17.4-point improvement, significantly better than the 10.3-point spread in placebo-treated controls. A statistically significant between-group difference was noted on days 2 through 28. HAM-D remission at day 15 was documented in 64% of the oral brexanolone group, compared with 26% of controls.
Those improvements in depression were accompanied by significant gains in numerous domains of health-related quality of life as assessed via the 36-Item Short Form Health Survey. Indeed, day 15 health-related quality of life scores in the oral brexanolone group approached normative values for the general population.
The studies were funded by SAGE Therapeutics.
BARCELONA – Brexanolone injection provided rapid and durable improvement in postpartum depression in an integrated analysis of three pivotal randomized trials collectively known as the Hummingbird trials, Christine Clemson, PhD, reported at the annual congress of the European College of Neuropsychopharmacology.
This was accomplished with a favorable safety experience. The most common treatment-emergent adverse events – dizziness and sleepiness – were roughly twice as common as with placebo in the 247-patient Hummingbird safety analysis.
On Dec. 19, 2018, the agency is expected to respond to SAGE Therapeutics’s application for marketing approval of intravenous brexanolone given as a continuous 60-hour infusion at 90 mcg/kg per hour, according to Dr. Clemson, senior medical director at Cambridge, Mass.–based SAGE Therapeutics, which is developing the therapy.
Brexanolone is a proprietary IV formulation of allopregnanolone, a metabolite of progesterone. The drug’s mechanism of action involves modulation of the neurotransmitter gamma-aminobutyric acid (GABA). The drug binds to both synaptic and extra-synaptic GABA A receptors, thereby increasing receptor functionality.
The decision to target GABA as a novel therapeutic strategy in PPD was based upon translational studies demonstrating that GABA is the chief neuroinhibitory mechanism in the brain, and its actions are mediated mainly by GABA A receptors. Brexanolone’s efficacy is consistent with a theory that the pathogenesis of PPD involves triggers such as inflammation, hormonal fluctuations, or chronic stress, which in some women cause GABA hypofunction, both at the receptors and in terms of tissue GABA levels. This, in turn, leads to an overactive HPA axis and dysregulated neural networks, with resultant PPD, Dr. Clemson explained.
The three Hummingbird clinical trials were double blind, randomized, and placebo controlled. Two were restricted to women with severe PPD. The third and largest focused on moderately affected patients as defined by a baseline Hamilton Depression Scale for Depression (HAM-D) score of 20-25.
The efficacy analysis included 207 patients who received brexanolone at 90 mcg/kg per hour or placebo for 60 hours in an inpatient setting and were followed for 30 days. The primary endpoint was the change in HAM-D total score from baseline to 60 hours. The mean 17-point reduction in the active treatment arm was significantly better than the 12.8-point decrease with placebo. The between-group difference was significant within the first 24 hours and remained so at all time points out to the study’s end at day 30. There was no individual item on the HAM-D in which the drug performed worse than placebo, and there were many in which brexanolone performed significantly better, including depressed mood, anxiety, insomnia, and feelings of guilt.
In terms of the rigorous secondary endpoint of HAM-D remission as defined by a total score of 7 or less, the brexanolone injection significantly outperformed placebo at every time point except for day 30.
There was a 2% rate of serious adverse events in both study arms. These included suicidal ideation, an intentional overdose attempt post discharge, altered state of consciousness, and syncope.
A vastly more convenient once-daily oral formulation of brexanolone is now in phase 3 clinical trials for PPD and major depressive disorder, and in phase 2 for insomnia and bipolar depression.
Elsewhere at the ECNP congress, other investigators from Sage Therapeutics presented for the first time the outcomes of an 89-patient, randomized, double-blind, multicenter, placebo-controlled, phase 2 clinical trial of SAGE-217 for treatment of major depressive disorder.
Participants received a nightly 30-mg dose of the drug or placebo for 2 weeks, with a primary study endpoint being the change in HAM-D total score from baseline to day 15. Patients on the oral GABA A receptor positive modulator averaged a 17.4-point improvement, significantly better than the 10.3-point spread in placebo-treated controls. A statistically significant between-group difference was noted on days 2 through 28. HAM-D remission at day 15 was documented in 64% of the oral brexanolone group, compared with 26% of controls.
Those improvements in depression were accompanied by significant gains in numerous domains of health-related quality of life as assessed via the 36-Item Short Form Health Survey. Indeed, day 15 health-related quality of life scores in the oral brexanolone group approached normative values for the general population.
The studies were funded by SAGE Therapeutics.
BARCELONA – Brexanolone injection provided rapid and durable improvement in postpartum depression in an integrated analysis of three pivotal randomized trials collectively known as the Hummingbird trials, Christine Clemson, PhD, reported at the annual congress of the European College of Neuropsychopharmacology.
This was accomplished with a favorable safety experience. The most common treatment-emergent adverse events – dizziness and sleepiness – were roughly twice as common as with placebo in the 247-patient Hummingbird safety analysis.
On Dec. 19, 2018, the agency is expected to respond to SAGE Therapeutics’s application for marketing approval of intravenous brexanolone given as a continuous 60-hour infusion at 90 mcg/kg per hour, according to Dr. Clemson, senior medical director at Cambridge, Mass.–based SAGE Therapeutics, which is developing the therapy.
Brexanolone is a proprietary IV formulation of allopregnanolone, a metabolite of progesterone. The drug’s mechanism of action involves modulation of the neurotransmitter gamma-aminobutyric acid (GABA). The drug binds to both synaptic and extra-synaptic GABA A receptors, thereby increasing receptor functionality.
The decision to target GABA as a novel therapeutic strategy in PPD was based upon translational studies demonstrating that GABA is the chief neuroinhibitory mechanism in the brain, and its actions are mediated mainly by GABA A receptors. Brexanolone’s efficacy is consistent with a theory that the pathogenesis of PPD involves triggers such as inflammation, hormonal fluctuations, or chronic stress, which in some women cause GABA hypofunction, both at the receptors and in terms of tissue GABA levels. This, in turn, leads to an overactive HPA axis and dysregulated neural networks, with resultant PPD, Dr. Clemson explained.
The three Hummingbird clinical trials were double blind, randomized, and placebo controlled. Two were restricted to women with severe PPD. The third and largest focused on moderately affected patients as defined by a baseline Hamilton Depression Scale for Depression (HAM-D) score of 20-25.
The efficacy analysis included 207 patients who received brexanolone at 90 mcg/kg per hour or placebo for 60 hours in an inpatient setting and were followed for 30 days. The primary endpoint was the change in HAM-D total score from baseline to 60 hours. The mean 17-point reduction in the active treatment arm was significantly better than the 12.8-point decrease with placebo. The between-group difference was significant within the first 24 hours and remained so at all time points out to the study’s end at day 30. There was no individual item on the HAM-D in which the drug performed worse than placebo, and there were many in which brexanolone performed significantly better, including depressed mood, anxiety, insomnia, and feelings of guilt.
In terms of the rigorous secondary endpoint of HAM-D remission as defined by a total score of 7 or less, the brexanolone injection significantly outperformed placebo at every time point except for day 30.
There was a 2% rate of serious adverse events in both study arms. These included suicidal ideation, an intentional overdose attempt post discharge, altered state of consciousness, and syncope.
A vastly more convenient once-daily oral formulation of brexanolone is now in phase 3 clinical trials for PPD and major depressive disorder, and in phase 2 for insomnia and bipolar depression.
Elsewhere at the ECNP congress, other investigators from Sage Therapeutics presented for the first time the outcomes of an 89-patient, randomized, double-blind, multicenter, placebo-controlled, phase 2 clinical trial of SAGE-217 for treatment of major depressive disorder.
Participants received a nightly 30-mg dose of the drug or placebo for 2 weeks, with a primary study endpoint being the change in HAM-D total score from baseline to day 15. Patients on the oral GABA A receptor positive modulator averaged a 17.4-point improvement, significantly better than the 10.3-point spread in placebo-treated controls. A statistically significant between-group difference was noted on days 2 through 28. HAM-D remission at day 15 was documented in 64% of the oral brexanolone group, compared with 26% of controls.
Those improvements in depression were accompanied by significant gains in numerous domains of health-related quality of life as assessed via the 36-Item Short Form Health Survey. Indeed, day 15 health-related quality of life scores in the oral brexanolone group approached normative values for the general population.
The studies were funded by SAGE Therapeutics.
REPORTING FROM THE ECNP CONGRESS
Key clinical point: A novel investigational GABA modulator is turning heads for treatment of postpartum depression.
Major finding: At 60 hours, mean HAM-D total scores had dropped by 17 points with brexanolone, versus 12.8 with placebo.
Study details: A prespecified integrated safety and efficacy analysis incorporating three pivotal clinical trials.
Disclosures: The studies were funded by SAGE Therapeutics and presented by a company executive.
Lithium/cancer link debunked
BARCELONA – A large Swedish national registry study has found no hint of increased cancer risk in bipolar patients on long-term lithium therapy.
“This is a very important null result. There is no increased risk for cancer for bipolar patients on lithium. It’s a bad rumor. It’s important to tell patients we’re very confident this is true. We studied every single type of cancer. We would have seen something here if there was something to see,” Lina Martinsson, MD, PhD, said at the annual congress of the European College of Neuropsychopharmacology.
Using comprehensive registry data on nearly 2.6 million Swedes aged 50-84 years with 4 years of follow-up, including 2,393 patients with bipolar disorder on long-term lithium and 3,049 patients not on lithium, the overall cancer incidence rate was 5.9% in the group on lithium and 6.0% in those not taking the drug. Those rates were not different from the general Swedish population, reported Dr. Martinsson, a senior psychiatrist at the Karolinska Institute in Stockholm.
Such patients had a 72% greater risk of lung cancer and other cancers of the respiratory system than the general population, a 47% increased risk of GI cancers, and a 150% greater risk of endocrine organ cancers.
“The increase in respiratory and digestive organ cancers might depend upon bipolar patients’ tendency for smoking and other types of hard living. We can’t explain the increase in endocrine cancers,” she said.
In contrast, the rates of these types of cancer were no different from the general population in bipolar patients taking lithium, hinting at a possible protective effect of the drug, although this remains speculative, the psychiatrist added.
The question of whether lithium is associated with increased cancer risk has been controversial. In particular, several groups have reported a possible increased risk of renal cancer on the basis of what Dr. Martinsson considers weak evidence. She felt a responsibility to undertake this definitive Swedish national study examining the issue because the cancer speculation arose following her earlier study demonstrating that bipolar patients on lithium had much longer telomeres than those not on the drug, and that the ones who responded well to lithium had longer telomeres than those who did not (Transl Psychiatry. 2013 May 21. doi: 10.1038/tp.2013.37).
“If longer telomere length gives longer life to the wrong cells, it might enhance the risk of cancer,” she noted.
But this theoretical concern did not hold up under close Swedish scrutiny. “Warnings for cancer in patients with long-term lithium treatment are unnecessary and ought to be omitted from the current policies,” Dr. Martinsson said.
She reported no financial conflicts regarding her study, which was funded by the Swedish Research Council.
BARCELONA – A large Swedish national registry study has found no hint of increased cancer risk in bipolar patients on long-term lithium therapy.
“This is a very important null result. There is no increased risk for cancer for bipolar patients on lithium. It’s a bad rumor. It’s important to tell patients we’re very confident this is true. We studied every single type of cancer. We would have seen something here if there was something to see,” Lina Martinsson, MD, PhD, said at the annual congress of the European College of Neuropsychopharmacology.
Using comprehensive registry data on nearly 2.6 million Swedes aged 50-84 years with 4 years of follow-up, including 2,393 patients with bipolar disorder on long-term lithium and 3,049 patients not on lithium, the overall cancer incidence rate was 5.9% in the group on lithium and 6.0% in those not taking the drug. Those rates were not different from the general Swedish population, reported Dr. Martinsson, a senior psychiatrist at the Karolinska Institute in Stockholm.
Such patients had a 72% greater risk of lung cancer and other cancers of the respiratory system than the general population, a 47% increased risk of GI cancers, and a 150% greater risk of endocrine organ cancers.
“The increase in respiratory and digestive organ cancers might depend upon bipolar patients’ tendency for smoking and other types of hard living. We can’t explain the increase in endocrine cancers,” she said.
In contrast, the rates of these types of cancer were no different from the general population in bipolar patients taking lithium, hinting at a possible protective effect of the drug, although this remains speculative, the psychiatrist added.
The question of whether lithium is associated with increased cancer risk has been controversial. In particular, several groups have reported a possible increased risk of renal cancer on the basis of what Dr. Martinsson considers weak evidence. She felt a responsibility to undertake this definitive Swedish national study examining the issue because the cancer speculation arose following her earlier study demonstrating that bipolar patients on lithium had much longer telomeres than those not on the drug, and that the ones who responded well to lithium had longer telomeres than those who did not (Transl Psychiatry. 2013 May 21. doi: 10.1038/tp.2013.37).
“If longer telomere length gives longer life to the wrong cells, it might enhance the risk of cancer,” she noted.
But this theoretical concern did not hold up under close Swedish scrutiny. “Warnings for cancer in patients with long-term lithium treatment are unnecessary and ought to be omitted from the current policies,” Dr. Martinsson said.
She reported no financial conflicts regarding her study, which was funded by the Swedish Research Council.
BARCELONA – A large Swedish national registry study has found no hint of increased cancer risk in bipolar patients on long-term lithium therapy.
“This is a very important null result. There is no increased risk for cancer for bipolar patients on lithium. It’s a bad rumor. It’s important to tell patients we’re very confident this is true. We studied every single type of cancer. We would have seen something here if there was something to see,” Lina Martinsson, MD, PhD, said at the annual congress of the European College of Neuropsychopharmacology.
Using comprehensive registry data on nearly 2.6 million Swedes aged 50-84 years with 4 years of follow-up, including 2,393 patients with bipolar disorder on long-term lithium and 3,049 patients not on lithium, the overall cancer incidence rate was 5.9% in the group on lithium and 6.0% in those not taking the drug. Those rates were not different from the general Swedish population, reported Dr. Martinsson, a senior psychiatrist at the Karolinska Institute in Stockholm.
Such patients had a 72% greater risk of lung cancer and other cancers of the respiratory system than the general population, a 47% increased risk of GI cancers, and a 150% greater risk of endocrine organ cancers.
“The increase in respiratory and digestive organ cancers might depend upon bipolar patients’ tendency for smoking and other types of hard living. We can’t explain the increase in endocrine cancers,” she said.
In contrast, the rates of these types of cancer were no different from the general population in bipolar patients taking lithium, hinting at a possible protective effect of the drug, although this remains speculative, the psychiatrist added.
The question of whether lithium is associated with increased cancer risk has been controversial. In particular, several groups have reported a possible increased risk of renal cancer on the basis of what Dr. Martinsson considers weak evidence. She felt a responsibility to undertake this definitive Swedish national study examining the issue because the cancer speculation arose following her earlier study demonstrating that bipolar patients on lithium had much longer telomeres than those not on the drug, and that the ones who responded well to lithium had longer telomeres than those who did not (Transl Psychiatry. 2013 May 21. doi: 10.1038/tp.2013.37).
“If longer telomere length gives longer life to the wrong cells, it might enhance the risk of cancer,” she noted.
But this theoretical concern did not hold up under close Swedish scrutiny. “Warnings for cancer in patients with long-term lithium treatment are unnecessary and ought to be omitted from the current policies,” Dr. Martinsson said.
She reported no financial conflicts regarding her study, which was funded by the Swedish Research Council.
REPORTING FROM THE ECNP CONGRESS
Key clinical point: Long-term lithium therapy does not increase cancer risk.
Major finding: The overall incidence of cancer during 4 years of follow-up was 5.9% in bipolar patients on long-term lithium and 6.0% in those who were not.
Study details: This Swedish national registry study compared cancer incidence rates in more than 5,400 patients with bipolar disorder and nearly 2.6 million controls.
Disclosures: The presenter reported no financial conflicts regarding the study, which was supported by the Swedish Research Council.
Promising novel antidepressant cruising in pipeline
BARCELONA – An investigational antidepressant known for now simply as MIN-117 shows the potential – at least, in phase 2 development – of offering significant advantages over currently available antidepressants in patients with major depressive disorder, Michael Davidson, MD, said at the annual congress of the European College of Neuropsychopharmacology. 
“This is a compound with a very, very rich pharmacology – so rich that we don’t know exactly which of the pharmacologic effects are really making the difference. This rich pharmacology is related to pathways that may confer to MIN-117 a unique positioning in the field of antidepressants and address unmet medical needs not well covered by existing therapies. For example, faster onset of action, complete restoration of euthymia, and beneficial effects on cognition and sexual functioning,” according to Michael Davidson, MD, chief medical officer at Minerva Neurosciences, which is developing the drug..
In the completed phase 2 study, the drug also displayed a strong anxiolytic effect and no prolongation of REM sleep latency in polysomnographic testing.
“So it may be that this is the first antidepressant which does not affect sleep architecture,” observed Dr. Davidson, professor of psychiatry at the Sackler School of Medicine in Tel Aviv.
Preclinical studies established that MIN-117 has high affinity for the 5HT serotonin transporter, serotonin 1A and 2A receptors, the dopamine transporter, and the alpha-1A and -1B adrenergic receptors. In animal models of depression, the drug results in sustained release of dopamine and serotonin. In human studies, the drug has a long half-life of roughly 60 hours.
“One possibility is that MIN-117 will be administered not once a day, but once or twice a week. It may be that here we have an antidepressant that doesn’t have to be administered every day,” the psychiatrist said.
In the completed phase 2 study, however, the drug was given once daily in what he described as a “classic design” for an antidepressant clinical trial: a 4-week washout period, then 6 weeks of double-blind treatment with MIN-117 at 2.5 or 0.5 mg/day, paroxetine at 20 mg/day, or placebo, then a 2-week posttreatment follow-up phase.
In describing the results of the study of 84 patients with major depressive disorder, Dr. Davidson painted a picture of MIN-117’s safety and efficacy with broad strokes because the trial wasn’t powered to demonstrate statistically significant differences. But the treatment effect sizes for the novel drug were impressive. A much more complete picture of the safety and efficacy of MIN-117 will be provided by an ongoing 324-patient phase 2b multicenter U.S. and European trial of the drug given at 2.5 or 5 mg/day or placebo.
The primary endpoint in the completed trial was change from baseline to 6 weeks in mean Montgomery-Åsberg Rating Depression Scale (MADRS) score. From a baseline score of about 33, MADRS scores improved by 9 points with placebo, 11 with MIN-117 at 0.5 mg, and by 12 points with 2.5 mg of the drug. MIN-117 was superior to placebo in this regard from the time of the earliest assessment, at 2 weeks.
One-quarter of patients on MIN-117 at 2.5 mg/day achieved remission, prospectively defined as a MADRS score below 12. Remission was 2.1-fold more likely in this group than with placebo at week 4 and 3.1-fold more likely at 6 weeks. The remission rate with MIN-117 also was better than with paroxetine.
“So , and that we’ll be able to produce full remission of the depressive symptoms,” Dr. Davidson said.
MIN-117 also showed a solid anxiolytic effect, with mean scores on the Hamilton Anxiety Rating Scale – a secondary endpoint – improving by 10 points in both the 0.5- and 2.5-mg groups from a baseline of 26 points. As a result of this impressive showing, the large ongoing phase 2b study is recruiting patients with an ongoing episode of major depressive disorder and prominent secondary anxiety.
Both doses of MIN-117 were well tolerated. Scores on the Arizona Sexual Experiences Scale showed that the drug did not result in any impairment of sexual function. Nor was MIN-117 associated with evidence of cognitive impairment; in fact, scores on the Digit-Symbol Substitution Test and Digit Span Backwards tool were better than in the placebo arm.
The study was sponsored by Minerva Neurosciences and presented by the company’s chief medical officer.
BARCELONA – An investigational antidepressant known for now simply as MIN-117 shows the potential – at least, in phase 2 development – of offering significant advantages over currently available antidepressants in patients with major depressive disorder, Michael Davidson, MD, said at the annual congress of the European College of Neuropsychopharmacology.
“This is a compound with a very, very rich pharmacology – so rich that we don’t know exactly which of the pharmacologic effects are really making the difference. This rich pharmacology is related to pathways that may confer to MIN-117 a unique positioning in the field of antidepressants and address unmet medical needs not well covered by existing therapies. For example, faster onset of action, complete restoration of euthymia, and beneficial effects on cognition and sexual functioning,” according to Michael Davidson, MD, chief medical officer at Minerva Neurosciences, which is developing the drug..
In the completed phase 2 study, the drug also displayed a strong anxiolytic effect and no prolongation of REM sleep latency in polysomnographic testing.
“So it may be that this is the first antidepressant which does not affect sleep architecture,” observed Dr. Davidson, professor of psychiatry at the Sackler School of Medicine in Tel Aviv.
Preclinical studies established that MIN-117 has high affinity for the 5HT serotonin transporter, serotonin 1A and 2A receptors, the dopamine transporter, and the alpha-1A and -1B adrenergic receptors. In animal models of depression, the drug results in sustained release of dopamine and serotonin. In human studies, the drug has a long half-life of roughly 60 hours.
“One possibility is that MIN-117 will be administered not once a day, but once or twice a week. It may be that here we have an antidepressant that doesn’t have to be administered every day,” the psychiatrist said.
In the completed phase 2 study, however, the drug was given once daily in what he described as a “classic design” for an antidepressant clinical trial: a 4-week washout period, then 6 weeks of double-blind treatment with MIN-117 at 2.5 or 0.5 mg/day, paroxetine at 20 mg/day, or placebo, then a 2-week posttreatment follow-up phase.
In describing the results of the study of 84 patients with major depressive disorder, Dr. Davidson painted a picture of MIN-117’s safety and efficacy with broad strokes because the trial wasn’t powered to demonstrate statistically significant differences. But the treatment effect sizes for the novel drug were impressive. A much more complete picture of the safety and efficacy of MIN-117 will be provided by an ongoing 324-patient phase 2b multicenter U.S. and European trial of the drug given at 2.5 or 5 mg/day or placebo.
The primary endpoint in the completed trial was change from baseline to 6 weeks in mean Montgomery-Åsberg Rating Depression Scale (MADRS) score. From a baseline score of about 33, MADRS scores improved by 9 points with placebo, 11 with MIN-117 at 0.5 mg, and by 12 points with 2.5 mg of the drug. MIN-117 was superior to placebo in this regard from the time of the earliest assessment, at 2 weeks.
One-quarter of patients on MIN-117 at 2.5 mg/day achieved remission, prospectively defined as a MADRS score below 12. Remission was 2.1-fold more likely in this group than with placebo at week 4 and 3.1-fold more likely at 6 weeks. The remission rate with MIN-117 also was better than with paroxetine.
“So , and that we’ll be able to produce full remission of the depressive symptoms,” Dr. Davidson said.
MIN-117 also showed a solid anxiolytic effect, with mean scores on the Hamilton Anxiety Rating Scale – a secondary endpoint – improving by 10 points in both the 0.5- and 2.5-mg groups from a baseline of 26 points. As a result of this impressive showing, the large ongoing phase 2b study is recruiting patients with an ongoing episode of major depressive disorder and prominent secondary anxiety.
Both doses of MIN-117 were well tolerated. Scores on the Arizona Sexual Experiences Scale showed that the drug did not result in any impairment of sexual function. Nor was MIN-117 associated with evidence of cognitive impairment; in fact, scores on the Digit-Symbol Substitution Test and Digit Span Backwards tool were better than in the placebo arm.
The study was sponsored by Minerva Neurosciences and presented by the company’s chief medical officer.
BARCELONA – An investigational antidepressant known for now simply as MIN-117 shows the potential – at least, in phase 2 development – of offering significant advantages over currently available antidepressants in patients with major depressive disorder, Michael Davidson, MD, said at the annual congress of the European College of Neuropsychopharmacology.
“This is a compound with a very, very rich pharmacology – so rich that we don’t know exactly which of the pharmacologic effects are really making the difference. This rich pharmacology is related to pathways that may confer to MIN-117 a unique positioning in the field of antidepressants and address unmet medical needs not well covered by existing therapies. For example, faster onset of action, complete restoration of euthymia, and beneficial effects on cognition and sexual functioning,” according to Michael Davidson, MD, chief medical officer at Minerva Neurosciences, which is developing the drug..
In the completed phase 2 study, the drug also displayed a strong anxiolytic effect and no prolongation of REM sleep latency in polysomnographic testing.
“So it may be that this is the first antidepressant which does not affect sleep architecture,” observed Dr. Davidson, professor of psychiatry at the Sackler School of Medicine in Tel Aviv.
Preclinical studies established that MIN-117 has high affinity for the 5HT serotonin transporter, serotonin 1A and 2A receptors, the dopamine transporter, and the alpha-1A and -1B adrenergic receptors. In animal models of depression, the drug results in sustained release of dopamine and serotonin. In human studies, the drug has a long half-life of roughly 60 hours.
“One possibility is that MIN-117 will be administered not once a day, but once or twice a week. It may be that here we have an antidepressant that doesn’t have to be administered every day,” the psychiatrist said.
In the completed phase 2 study, however, the drug was given once daily in what he described as a “classic design” for an antidepressant clinical trial: a 4-week washout period, then 6 weeks of double-blind treatment with MIN-117 at 2.5 or 0.5 mg/day, paroxetine at 20 mg/day, or placebo, then a 2-week posttreatment follow-up phase.
In describing the results of the study of 84 patients with major depressive disorder, Dr. Davidson painted a picture of MIN-117’s safety and efficacy with broad strokes because the trial wasn’t powered to demonstrate statistically significant differences. But the treatment effect sizes for the novel drug were impressive. A much more complete picture of the safety and efficacy of MIN-117 will be provided by an ongoing 324-patient phase 2b multicenter U.S. and European trial of the drug given at 2.5 or 5 mg/day or placebo.
The primary endpoint in the completed trial was change from baseline to 6 weeks in mean Montgomery-Åsberg Rating Depression Scale (MADRS) score. From a baseline score of about 33, MADRS scores improved by 9 points with placebo, 11 with MIN-117 at 0.5 mg, and by 12 points with 2.5 mg of the drug. MIN-117 was superior to placebo in this regard from the time of the earliest assessment, at 2 weeks.
One-quarter of patients on MIN-117 at 2.5 mg/day achieved remission, prospectively defined as a MADRS score below 12. Remission was 2.1-fold more likely in this group than with placebo at week 4 and 3.1-fold more likely at 6 weeks. The remission rate with MIN-117 also was better than with paroxetine.
“So , and that we’ll be able to produce full remission of the depressive symptoms,” Dr. Davidson said.
MIN-117 also showed a solid anxiolytic effect, with mean scores on the Hamilton Anxiety Rating Scale – a secondary endpoint – improving by 10 points in both the 0.5- and 2.5-mg groups from a baseline of 26 points. As a result of this impressive showing, the large ongoing phase 2b study is recruiting patients with an ongoing episode of major depressive disorder and prominent secondary anxiety.
Both doses of MIN-117 were well tolerated. Scores on the Arizona Sexual Experiences Scale showed that the drug did not result in any impairment of sexual function. Nor was MIN-117 associated with evidence of cognitive impairment; in fact, scores on the Digit-Symbol Substitution Test and Digit Span Backwards tool were better than in the placebo arm.
The study was sponsored by Minerva Neurosciences and presented by the company’s chief medical officer.
REPORTING FROM THE ECNP CONGRESS
Key clinical point: An investigational antidepressant might address important unmet needs in the treatment of major depression.
Major finding: Patients with major depressive disorder were 3.1-fold more likely to be in remission after 6 weeks on MIN-117 at 2.5 mg/day than with placebo.
Study details: This prospective, double-blind, randomized, double-blind, placebo- and active-controlled study included 84 patients with major depressive disorder.
Disclosures: The study was sponsored by Minerva Neurosciences and presented by the company’s chief medical officer.
Home telemonitoring for heart failure cuts mortality
MUNICH – A comprehensive home telemonitoring program paid off big for selected patients with heart failure in a large, German nationwide masked randomization trial.
First, TIM-HF2 didn’t rely on passive monitoring of the patients’ daily electronically submitted home data. Instead, the data went straight to a central telemonitoring center staffed 24/7 by physicians and nurses with heart failure expertise. There, the information was immediately analyzed using proprietary telemedical analytic software known as the Fontane system. The software employs individually tailored, self-adapting algorithms in order to alert staff when trouble is brewing.
But the telemonitoring intervention doesn’t merely detect early clinical deterioration. It’s also a vehicle for ongoing patient education, outpatient adjustment of drugs, management of major comorbid conditions, and hospital admissions as needed. The patient’s local primary care physician was also plugged into the remote monitoring system and kept abreast of the patient’s condition.
Second, TIM-HF2 focused on a carefully selected subgroup of heart failure patients whom prior studies suggested were particularly likely to benefit from home telemedical management. All participants were NYHA class II or III with a left ventricular ejection fraction of 45% or less, a hospitalization for heart failure within 12 months prior to randomization, and free of moderate or severe depression as evidenced by a baseline Patient Health Questionnaire-9 score of 9 or less, explained Dr. Koehler, head of the center for cardiovascular telemedicine at Charite University in Berlin.
Why exclude patients with depression?
“In this concept, with wholistic remote patient management, we need an active patient who is able to measure every day, who is able to communicate with the telemedical center, and who is able to communicate in this network created between the telemedical center and local caregivers. If someone is really depressed, unable to act, lying in bed saying it makes no sense to take drugs or do anything, then we cannot help. That is for us, I think, the most important thing. We’ve seen it now in two trials,” according to the cardiologist.
The all-cause mortality rate was 7.86 per 100 person-years in the home-telemonitoring group versus 11.34 in usual-care controls. Patients in the active intervention arm lost a mean of 17.8 days per year because of unplanned cardiovascular hospital admissions, compared with 24.2 days per year in controls.
Importantly, outcomes were equally good in the remote patient-management group regardless of whether patients were among the 40% of participants living in urban Germany or the 60% in rural areas. Thus, the telemonitoring intervention eliminated the geographic disparity in health care outcomes which is a prominent issue in Germany, as well as the United States.
A formal cost-benefit analysis of the TIM-HF2 results is in the works, Dr. Koehler said.
Simultaneous with his presentation in Munich, the TIM-HF2 study was published online in the Lancet.
In an accompanying editorial, two prominent heart failure experts – John F.G. Cleland, MD, of the University of Glasgow and Robin A. Clark, MD, of Flinders University in Adelaide – hailed TIM-HF2 as a major advance and indicated in sharp terms that it’s time for guideline writers to sit up and take notice.
“Despite much clinical skepticism and feeble support from most guidelines, in our view the growing weight of evidence suggests that home telemonitoring does reduce mortality for patients with heart failure, and this effect might be substantial. These and other trials also show that the emphasis placed on hospital admission for heart failure might be misplaced, at least from a patient’s perspective, because the proportion of days lost due to hospital admission is small, compared with those lost to death,” the physicians wrote in the editorial.
They also noted that, even though the between-group difference in the number of days during which patients were hospitalized for cardiovascular causes was relatively small, it’s clear that home telemonitoring triggered some potentially life-saving hospitalizations. “Home telemonitoring puts the patient back in the center of health care, ensuring that they know what the health professional is trying to achieve and that they agree with those aims. Ultimately, patients and their families are a large and relatively untapped health care resource,” they wrote.
The TIM-HF 2 trial was funded by the German Federal Ministry of Education and Research. Dr. Koehler reported receiving speaking and/or consultant fees from Novartis, Abbott, and Medtronic.
bjancin@mdedge.com
SOURCE: Koehler F et al. ESC Congress 2018. Lancet. 2018 Sep 22;392(10152):1047-57.
MUNICH – A comprehensive home telemonitoring program paid off big for selected patients with heart failure in a large, German nationwide masked randomization trial.
First, TIM-HF2 didn’t rely on passive monitoring of the patients’ daily electronically submitted home data. Instead, the data went straight to a central telemonitoring center staffed 24/7 by physicians and nurses with heart failure expertise. There, the information was immediately analyzed using proprietary telemedical analytic software known as the Fontane system. The software employs individually tailored, self-adapting algorithms in order to alert staff when trouble is brewing.
But the telemonitoring intervention doesn’t merely detect early clinical deterioration. It’s also a vehicle for ongoing patient education, outpatient adjustment of drugs, management of major comorbid conditions, and hospital admissions as needed. The patient’s local primary care physician was also plugged into the remote monitoring system and kept abreast of the patient’s condition.
Second, TIM-HF2 focused on a carefully selected subgroup of heart failure patients whom prior studies suggested were particularly likely to benefit from home telemedical management. All participants were NYHA class II or III with a left ventricular ejection fraction of 45% or less, a hospitalization for heart failure within 12 months prior to randomization, and free of moderate or severe depression as evidenced by a baseline Patient Health Questionnaire-9 score of 9 or less, explained Dr. Koehler, head of the center for cardiovascular telemedicine at Charite University in Berlin.
Why exclude patients with depression?
“In this concept, with wholistic remote patient management, we need an active patient who is able to measure every day, who is able to communicate with the telemedical center, and who is able to communicate in this network created between the telemedical center and local caregivers. If someone is really depressed, unable to act, lying in bed saying it makes no sense to take drugs or do anything, then we cannot help. That is for us, I think, the most important thing. We’ve seen it now in two trials,” according to the cardiologist.
The all-cause mortality rate was 7.86 per 100 person-years in the home-telemonitoring group versus 11.34 in usual-care controls. Patients in the active intervention arm lost a mean of 17.8 days per year because of unplanned cardiovascular hospital admissions, compared with 24.2 days per year in controls.
Importantly, outcomes were equally good in the remote patient-management group regardless of whether patients were among the 40% of participants living in urban Germany or the 60% in rural areas. Thus, the telemonitoring intervention eliminated the geographic disparity in health care outcomes which is a prominent issue in Germany, as well as the United States.
A formal cost-benefit analysis of the TIM-HF2 results is in the works, Dr. Koehler said.
Simultaneous with his presentation in Munich, the TIM-HF2 study was published online in the Lancet.
In an accompanying editorial, two prominent heart failure experts – John F.G. Cleland, MD, of the University of Glasgow and Robin A. Clark, MD, of Flinders University in Adelaide – hailed TIM-HF2 as a major advance and indicated in sharp terms that it’s time for guideline writers to sit up and take notice.
“Despite much clinical skepticism and feeble support from most guidelines, in our view the growing weight of evidence suggests that home telemonitoring does reduce mortality for patients with heart failure, and this effect might be substantial. These and other trials also show that the emphasis placed on hospital admission for heart failure might be misplaced, at least from a patient’s perspective, because the proportion of days lost due to hospital admission is small, compared with those lost to death,” the physicians wrote in the editorial.
They also noted that, even though the between-group difference in the number of days during which patients were hospitalized for cardiovascular causes was relatively small, it’s clear that home telemonitoring triggered some potentially life-saving hospitalizations. “Home telemonitoring puts the patient back in the center of health care, ensuring that they know what the health professional is trying to achieve and that they agree with those aims. Ultimately, patients and their families are a large and relatively untapped health care resource,” they wrote.
The TIM-HF 2 trial was funded by the German Federal Ministry of Education and Research. Dr. Koehler reported receiving speaking and/or consultant fees from Novartis, Abbott, and Medtronic.
bjancin@mdedge.com
SOURCE: Koehler F et al. ESC Congress 2018. Lancet. 2018 Sep 22;392(10152):1047-57.
MUNICH – A comprehensive home telemonitoring program paid off big for selected patients with heart failure in a large, German nationwide masked randomization trial.
First, TIM-HF2 didn’t rely on passive monitoring of the patients’ daily electronically submitted home data. Instead, the data went straight to a central telemonitoring center staffed 24/7 by physicians and nurses with heart failure expertise. There, the information was immediately analyzed using proprietary telemedical analytic software known as the Fontane system. The software employs individually tailored, self-adapting algorithms in order to alert staff when trouble is brewing.
But the telemonitoring intervention doesn’t merely detect early clinical deterioration. It’s also a vehicle for ongoing patient education, outpatient adjustment of drugs, management of major comorbid conditions, and hospital admissions as needed. The patient’s local primary care physician was also plugged into the remote monitoring system and kept abreast of the patient’s condition.
Second, TIM-HF2 focused on a carefully selected subgroup of heart failure patients whom prior studies suggested were particularly likely to benefit from home telemedical management. All participants were NYHA class II or III with a left ventricular ejection fraction of 45% or less, a hospitalization for heart failure within 12 months prior to randomization, and free of moderate or severe depression as evidenced by a baseline Patient Health Questionnaire-9 score of 9 or less, explained Dr. Koehler, head of the center for cardiovascular telemedicine at Charite University in Berlin.
Why exclude patients with depression?
“In this concept, with wholistic remote patient management, we need an active patient who is able to measure every day, who is able to communicate with the telemedical center, and who is able to communicate in this network created between the telemedical center and local caregivers. If someone is really depressed, unable to act, lying in bed saying it makes no sense to take drugs or do anything, then we cannot help. That is for us, I think, the most important thing. We’ve seen it now in two trials,” according to the cardiologist.
The all-cause mortality rate was 7.86 per 100 person-years in the home-telemonitoring group versus 11.34 in usual-care controls. Patients in the active intervention arm lost a mean of 17.8 days per year because of unplanned cardiovascular hospital admissions, compared with 24.2 days per year in controls.
Importantly, outcomes were equally good in the remote patient-management group regardless of whether patients were among the 40% of participants living in urban Germany or the 60% in rural areas. Thus, the telemonitoring intervention eliminated the geographic disparity in health care outcomes which is a prominent issue in Germany, as well as the United States.
A formal cost-benefit analysis of the TIM-HF2 results is in the works, Dr. Koehler said.
Simultaneous with his presentation in Munich, the TIM-HF2 study was published online in the Lancet.
In an accompanying editorial, two prominent heart failure experts – John F.G. Cleland, MD, of the University of Glasgow and Robin A. Clark, MD, of Flinders University in Adelaide – hailed TIM-HF2 as a major advance and indicated in sharp terms that it’s time for guideline writers to sit up and take notice.
“Despite much clinical skepticism and feeble support from most guidelines, in our view the growing weight of evidence suggests that home telemonitoring does reduce mortality for patients with heart failure, and this effect might be substantial. These and other trials also show that the emphasis placed on hospital admission for heart failure might be misplaced, at least from a patient’s perspective, because the proportion of days lost due to hospital admission is small, compared with those lost to death,” the physicians wrote in the editorial.
They also noted that, even though the between-group difference in the number of days during which patients were hospitalized for cardiovascular causes was relatively small, it’s clear that home telemonitoring triggered some potentially life-saving hospitalizations. “Home telemonitoring puts the patient back in the center of health care, ensuring that they know what the health professional is trying to achieve and that they agree with those aims. Ultimately, patients and their families are a large and relatively untapped health care resource,” they wrote.
The TIM-HF 2 trial was funded by the German Federal Ministry of Education and Research. Dr. Koehler reported receiving speaking and/or consultant fees from Novartis, Abbott, and Medtronic.
bjancin@mdedge.com
SOURCE: Koehler F et al. ESC Congress 2018. Lancet. 2018 Sep 22;392(10152):1047-57.
REPORTING FROM THE ESC CONGRESS 2018
Key clinical point: Comprehensive home-telemonitoring program for heart failure saves lives.
Major finding: All-cause mortality was reduced by 30% at 1 year with a comprehensive home-telemonitoring program.
Study details: This prospective, masked randomization study included 1,538 German heart failure patients.
Disclosures: The TIM-HF2 trial was funded by the German Federal Ministry of Education and Research.
Source: Koehler F. ESC Congress 2018. Lancet. 2018 Sep 22;392(10152):1047-57.
PCI bests medical therapy for FFR grey zone stable angina
PARIS – Patients with stable angina and a fractional flow reserve (FFR) value in the grey zone of 0.75-0.81 experienced a significant reduction in myocardial ischemia and substantially greater quality of life improvement if they were randomized to percutaneous coronary intervention (PCI) plus optimal medical therapy than to optimal medical therapy alone in the Scottish Grey-zone FFR Study.
The Grey-zone FFR Study was a single-center, prospective, unblinded, randomized trial that included 100 patients with stable angina, single-vessel disease, and a fractional flow reserve in the grey zone of 0.75-0.81. While broad consensus exists that an FFR below 0.75 constitutes evidence of a hemodynamically significant coronary lesion warranting revascularization and an FFR greater than 0.80 indicates a lesion isn’t functionally significant and therefore PCI can safely be deferred, there has been uncertainty on what to do about lesions in the grey zone, which are frequently encountered in the cardiac catheterization laboratory.
“In my clinical practice, I tend to go ahead with PCI for patients in the grey zone if I felt it was clinically feasible and safe to do so, particularly if I was worried about their lesion morphology,” Barry Hennigan, MD, said in response to questions after presenting the results at the annual meeting of the European Association of Percutaneous Cardiovascular Interventions. “If it’s a proximal LAD [left anterior descending artery] lesion and it’s a grey zone patient, particularly if it’s a lesion morphology that you’re not comfortable with, I think you need to be very careful before you defer a case.”
The twin purposes of the Scottish study were to define the prevalence of major ischemia by stress MRI and invasive flow assessment via a pressure wire in grey zone patients – something which hadn’t been done before – and to determine if PCI deferral in such patients is appropriate in terms of symptom control. The primary outcome was change in angina severity at 3 months follow-up using the Seattle Angina Questionnaire (SAQ).
Scores on two of the five domains of the SAQ – anginal frequency and quality of life – were significantly improved in the PCI group. Anginal frequency scores improved by a mean of 20.58 points in the PCI plus optimal medical therapy (OMT) group, compared with a 9.39-point improvement with OMT alone. Quality of life scores improved by 24.04 points in the PCI group versus 9.39 points in controls, said Dr. Hennigan, an interventional cardiologist at the University of Glasgow and Golden Jubilee National Hospital. Scores in the other three SAQ domains – physical limitations, anginal stability, and treatment satisfaction – didn’t differ significantly between the two study arms, although consistently greater improvements were seen in the PCI group.
Baseline stress perfusion MRI as assessed by two blinded observers demonstrated that 17.4% of patients with stable angina and a grey zone FFR had major ischemia, while any ischemia – major or minor – was present in 24.4%. Follow-up scans at 3 months showed a roughly 50% reduction in the prevalence of ischemia in the PCI group, with 7.3% of treated patients still having major ischemia and 12.2% having any ischemia.
Also, 28% of participants had evidence of ischemia at baseline based upon their coronary flow reserve measurements and 8% had a hyperemic stenosis resistance measurement indicative of ischemia. So the FFR grey zone encompasses a range of cardiovascular risks.
In the PCI plus OMT group, 89% of patients (eight of nine) with baseline ischemia on stress MRI had a greater than 10-point improvement in quality of life scores on the SAQ at follow-up in contrast to 53% of patients without ischemia, which made for a statistically significant difference. An improvement of that magnitude is generally considered clinically meaningful. In contrast, in the OMT-only group, 9 of 14 patients with baseline ischemia (64.2%) had a greater than 10-point quality of life improvement, which wasn’t significantly different from the 45.5% improvement rate in patients with no ischemia.
The lessons? Grey zone patients who benefit most from prompt revascularization are those with demonstrable ischemia. In addition, roughly half of grey zone patients with stable angina will improve their quality of life scores by more than 10 points with OMT alone regardless of the presence of myocardial ischemia or not.
Dr. Hennigan was repeatedly asked how he reconciles the results of the grey zone study with those of the much-discussed ORBITA trial, the first and only randomized trial of real versus sham PCI in patients with stable angina. ORBITA didn’t find a significant quality of life advantage for real PCI over sham PCI.
“It is quite possible that a lot of the effect that we saw in our PCI group was placebo related,” he conceded. “However, we do have objective evidence that we reduced ischemia on MRI. Also, 29% of ORBITA patients had an FFR above 0.8, whereas nearly all our patients were below that threshold. So we perhaps had more prevalent ischemia than the ORBITA cohort.”
Also informative is a comparison of SAQ scores at follow-up in the sham PCI ORBITA control group versus the grey zone Scottish PCI group, Dr. Hennigan continued. The Scottish PCI group had a mean 20.6-point improvement in anginal frequency scores while on an average of 1.3 antianginal medications, compared with a 9.6-point improvement in ORBITA patients on 2.9 drugs. The grey zone group who got PCI plus OMT also had a mean 16.1-point improvement in the SAQ physical limitations domain, versus a 5.0-point improvement in the ORBITA controls.
The Grey-zone FFR Study was supported by the British Heart Foundation. Dr. Hennigan reported having no financial conflicts of interest.
PARIS – Patients with stable angina and a fractional flow reserve (FFR) value in the grey zone of 0.75-0.81 experienced a significant reduction in myocardial ischemia and substantially greater quality of life improvement if they were randomized to percutaneous coronary intervention (PCI) plus optimal medical therapy than to optimal medical therapy alone in the Scottish Grey-zone FFR Study.
The Grey-zone FFR Study was a single-center, prospective, unblinded, randomized trial that included 100 patients with stable angina, single-vessel disease, and a fractional flow reserve in the grey zone of 0.75-0.81. While broad consensus exists that an FFR below 0.75 constitutes evidence of a hemodynamically significant coronary lesion warranting revascularization and an FFR greater than 0.80 indicates a lesion isn’t functionally significant and therefore PCI can safely be deferred, there has been uncertainty on what to do about lesions in the grey zone, which are frequently encountered in the cardiac catheterization laboratory.
“In my clinical practice, I tend to go ahead with PCI for patients in the grey zone if I felt it was clinically feasible and safe to do so, particularly if I was worried about their lesion morphology,” Barry Hennigan, MD, said in response to questions after presenting the results at the annual meeting of the European Association of Percutaneous Cardiovascular Interventions. “If it’s a proximal LAD [left anterior descending artery] lesion and it’s a grey zone patient, particularly if it’s a lesion morphology that you’re not comfortable with, I think you need to be very careful before you defer a case.”
The twin purposes of the Scottish study were to define the prevalence of major ischemia by stress MRI and invasive flow assessment via a pressure wire in grey zone patients – something which hadn’t been done before – and to determine if PCI deferral in such patients is appropriate in terms of symptom control. The primary outcome was change in angina severity at 3 months follow-up using the Seattle Angina Questionnaire (SAQ).
Scores on two of the five domains of the SAQ – anginal frequency and quality of life – were significantly improved in the PCI group. Anginal frequency scores improved by a mean of 20.58 points in the PCI plus optimal medical therapy (OMT) group, compared with a 9.39-point improvement with OMT alone. Quality of life scores improved by 24.04 points in the PCI group versus 9.39 points in controls, said Dr. Hennigan, an interventional cardiologist at the University of Glasgow and Golden Jubilee National Hospital. Scores in the other three SAQ domains – physical limitations, anginal stability, and treatment satisfaction – didn’t differ significantly between the two study arms, although consistently greater improvements were seen in the PCI group.
Baseline stress perfusion MRI as assessed by two blinded observers demonstrated that 17.4% of patients with stable angina and a grey zone FFR had major ischemia, while any ischemia – major or minor – was present in 24.4%. Follow-up scans at 3 months showed a roughly 50% reduction in the prevalence of ischemia in the PCI group, with 7.3% of treated patients still having major ischemia and 12.2% having any ischemia.
Also, 28% of participants had evidence of ischemia at baseline based upon their coronary flow reserve measurements and 8% had a hyperemic stenosis resistance measurement indicative of ischemia. So the FFR grey zone encompasses a range of cardiovascular risks.
In the PCI plus OMT group, 89% of patients (eight of nine) with baseline ischemia on stress MRI had a greater than 10-point improvement in quality of life scores on the SAQ at follow-up in contrast to 53% of patients without ischemia, which made for a statistically significant difference. An improvement of that magnitude is generally considered clinically meaningful. In contrast, in the OMT-only group, 9 of 14 patients with baseline ischemia (64.2%) had a greater than 10-point quality of life improvement, which wasn’t significantly different from the 45.5% improvement rate in patients with no ischemia.
The lessons? Grey zone patients who benefit most from prompt revascularization are those with demonstrable ischemia. In addition, roughly half of grey zone patients with stable angina will improve their quality of life scores by more than 10 points with OMT alone regardless of the presence of myocardial ischemia or not.
Dr. Hennigan was repeatedly asked how he reconciles the results of the grey zone study with those of the much-discussed ORBITA trial, the first and only randomized trial of real versus sham PCI in patients with stable angina. ORBITA didn’t find a significant quality of life advantage for real PCI over sham PCI.
“It is quite possible that a lot of the effect that we saw in our PCI group was placebo related,” he conceded. “However, we do have objective evidence that we reduced ischemia on MRI. Also, 29% of ORBITA patients had an FFR above 0.8, whereas nearly all our patients were below that threshold. So we perhaps had more prevalent ischemia than the ORBITA cohort.”
Also informative is a comparison of SAQ scores at follow-up in the sham PCI ORBITA control group versus the grey zone Scottish PCI group, Dr. Hennigan continued. The Scottish PCI group had a mean 20.6-point improvement in anginal frequency scores while on an average of 1.3 antianginal medications, compared with a 9.6-point improvement in ORBITA patients on 2.9 drugs. The grey zone group who got PCI plus OMT also had a mean 16.1-point improvement in the SAQ physical limitations domain, versus a 5.0-point improvement in the ORBITA controls.
The Grey-zone FFR Study was supported by the British Heart Foundation. Dr. Hennigan reported having no financial conflicts of interest.
PARIS – Patients with stable angina and a fractional flow reserve (FFR) value in the grey zone of 0.75-0.81 experienced a significant reduction in myocardial ischemia and substantially greater quality of life improvement if they were randomized to percutaneous coronary intervention (PCI) plus optimal medical therapy than to optimal medical therapy alone in the Scottish Grey-zone FFR Study.
The Grey-zone FFR Study was a single-center, prospective, unblinded, randomized trial that included 100 patients with stable angina, single-vessel disease, and a fractional flow reserve in the grey zone of 0.75-0.81. While broad consensus exists that an FFR below 0.75 constitutes evidence of a hemodynamically significant coronary lesion warranting revascularization and an FFR greater than 0.80 indicates a lesion isn’t functionally significant and therefore PCI can safely be deferred, there has been uncertainty on what to do about lesions in the grey zone, which are frequently encountered in the cardiac catheterization laboratory.
“In my clinical practice, I tend to go ahead with PCI for patients in the grey zone if I felt it was clinically feasible and safe to do so, particularly if I was worried about their lesion morphology,” Barry Hennigan, MD, said in response to questions after presenting the results at the annual meeting of the European Association of Percutaneous Cardiovascular Interventions. “If it’s a proximal LAD [left anterior descending artery] lesion and it’s a grey zone patient, particularly if it’s a lesion morphology that you’re not comfortable with, I think you need to be very careful before you defer a case.”
The twin purposes of the Scottish study were to define the prevalence of major ischemia by stress MRI and invasive flow assessment via a pressure wire in grey zone patients – something which hadn’t been done before – and to determine if PCI deferral in such patients is appropriate in terms of symptom control. The primary outcome was change in angina severity at 3 months follow-up using the Seattle Angina Questionnaire (SAQ).
Scores on two of the five domains of the SAQ – anginal frequency and quality of life – were significantly improved in the PCI group. Anginal frequency scores improved by a mean of 20.58 points in the PCI plus optimal medical therapy (OMT) group, compared with a 9.39-point improvement with OMT alone. Quality of life scores improved by 24.04 points in the PCI group versus 9.39 points in controls, said Dr. Hennigan, an interventional cardiologist at the University of Glasgow and Golden Jubilee National Hospital. Scores in the other three SAQ domains – physical limitations, anginal stability, and treatment satisfaction – didn’t differ significantly between the two study arms, although consistently greater improvements were seen in the PCI group.
Baseline stress perfusion MRI as assessed by two blinded observers demonstrated that 17.4% of patients with stable angina and a grey zone FFR had major ischemia, while any ischemia – major or minor – was present in 24.4%. Follow-up scans at 3 months showed a roughly 50% reduction in the prevalence of ischemia in the PCI group, with 7.3% of treated patients still having major ischemia and 12.2% having any ischemia.
Also, 28% of participants had evidence of ischemia at baseline based upon their coronary flow reserve measurements and 8% had a hyperemic stenosis resistance measurement indicative of ischemia. So the FFR grey zone encompasses a range of cardiovascular risks.
In the PCI plus OMT group, 89% of patients (eight of nine) with baseline ischemia on stress MRI had a greater than 10-point improvement in quality of life scores on the SAQ at follow-up in contrast to 53% of patients without ischemia, which made for a statistically significant difference. An improvement of that magnitude is generally considered clinically meaningful. In contrast, in the OMT-only group, 9 of 14 patients with baseline ischemia (64.2%) had a greater than 10-point quality of life improvement, which wasn’t significantly different from the 45.5% improvement rate in patients with no ischemia.
The lessons? Grey zone patients who benefit most from prompt revascularization are those with demonstrable ischemia. In addition, roughly half of grey zone patients with stable angina will improve their quality of life scores by more than 10 points with OMT alone regardless of the presence of myocardial ischemia or not.
Dr. Hennigan was repeatedly asked how he reconciles the results of the grey zone study with those of the much-discussed ORBITA trial, the first and only randomized trial of real versus sham PCI in patients with stable angina. ORBITA didn’t find a significant quality of life advantage for real PCI over sham PCI.
“It is quite possible that a lot of the effect that we saw in our PCI group was placebo related,” he conceded. “However, we do have objective evidence that we reduced ischemia on MRI. Also, 29% of ORBITA patients had an FFR above 0.8, whereas nearly all our patients were below that threshold. So we perhaps had more prevalent ischemia than the ORBITA cohort.”
Also informative is a comparison of SAQ scores at follow-up in the sham PCI ORBITA control group versus the grey zone Scottish PCI group, Dr. Hennigan continued. The Scottish PCI group had a mean 20.6-point improvement in anginal frequency scores while on an average of 1.3 antianginal medications, compared with a 9.6-point improvement in ORBITA patients on 2.9 drugs. The grey zone group who got PCI plus OMT also had a mean 16.1-point improvement in the SAQ physical limitations domain, versus a 5.0-point improvement in the ORBITA controls.
The Grey-zone FFR Study was supported by the British Heart Foundation. Dr. Hennigan reported having no financial conflicts of interest.
REPORTING FROM EUROPCR 2018
Key clinical point:
Major finding: Patients with stable angina and a fractional flow reserve in the grey zone of 0.75-0.81 experienced a 50% reduction in objectively defined myocardial ischemia if they received percutaneous coronary intervention plus medical therapy, compared with medical therapy alone.
Study details: This single-center, prospective, open-label trial randomized 100 stable angina patients with a grey zone fractional flow reserve of 0.75-0.81 to percutaneous coronary intervention plus optimal medical therapy or optimal medical therapy alone.
Disclosures: The study was supported by the British Heart Foundation. The presenter reported having no financial conflicts.
A new era arrives in alopecia areata therapy
PARIS – Each of two oral Janus kinase inhibitors individually showed impressive efficacy and acceptable safety and tolerability for treatment of chronic moderate to severe alopecia areata in a phase 2 study that promises to alter the therapeutic landscape in this challenging disease, Rodney Sinclair, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.
“My personal view is that these results represent a paradigm shift in the treatment of alopecia areata. Perhaps a line in the sand. On the one side, clinical observation, case reports, and small case series, but no reliably effective treatment. And on the other side of the line, investigational new drugs specifically targeting the pathogenesis, tested in prospective, multicenter, double-blind, placebo-controlled studies – and perhaps the first instance of evidence-based medicine arriving for alopecia areata. And I think that our patients with alopecia areata now have reason to be optimistic,” the dermatologist said.
“No reliably effective therapies now exist for alopecia areata, especially for patients with chronic extensive disease. There is an unmet need for a reliably effective therapy with a benefit-to-risk ratio that is appropriate for long-term use,” he added.
The phase 2 multicenter, placebo-controlled, double-blind study randomized 142 patients with chronic alopecia of at least 6 months duration and 50% or greater hair loss at baseline to an , or placebo for 24 weeks. The first 4 weeks of the double-blind trial involved induction dosing of the JAK3 inhibitor at 200 mg per day and the TYK2/JAK 1 inhibitor at 60 mg per day. Thereafter, participants switched to maintenance dosing at 50 mg and 30 mg per day, respectively.
Participants had a median 2.3 years of disease duration; 62 patients had alopecia totalis, and 42 had alopecia universalis.
The primary efficacy endpoint was the mean change from baseline to week 24 in the Severity of Alopecia Tool (SALT) score, a well-validated metric widely utilized in hair loss studies. The mean baseline score was 88.1. At week 24, the score had dropped by a mean of 33.6% in the JAK 3 inhibitor group, 49.5% in the TYK2/JAK1 inhibitor group, and zero in placebo-treated controls.
A key secondary endpoint known as the SALT 30, reflecting at least 30% improvement in SALT score, was achieved in 47.9% of patients on the oral JAK 3 inhibitor, 59.6% of those on the TYK2/JAK1 inhibitor, and by no one in the control group. The utter unresponsiveness of placebo-treated controls confirms the investigators’ success in recruiting a study population with truly chronic alopecia areata, Dr. Sinclair noted.
Of note, 25% of patients on the JAK 3 inhibitor and 31.9% on the TYK2/JAK1 inhibitor achieved a SALT 90 response, and 12.5% and 12.8% reached SALT 100.
Significant improvement on the Eyelash Assessment and Eyebrow Assessment Scales occurred in 45.2% and 36.2% of the JAK 3 inhibitor group and in 60.7% and 51.7% of the TYK2/JAK 1 inhibitor group.
The study is ongoing. It’s Dr. Sinclair’s anecdotal impression that further improvement is occurring in the active treatment arms with continued therapy after 24 weeks, but that remains to be seen.
Adverse events were similar in nature and frequency in all three study arms with one notable exception: two cases of rhabdomyolysis in the TYK2/JAK 1 inhibitor group.Session chair DeDee Murrell, MD, homed in on that piece of information, pressing for further details.
“Are you concerned? Were there predictors?” asked Dr. Murrell, professor of dermatology at the University of New South Wales in Sydney.
The two affected patients had muscle pain and elevated creatinine kinase levels. “They didn’t feel particularly unwell but were withdrawn as a precaution, after which the condition quickly resolved,” Dr. Sinclair said.
The investigators were unable to identify any risk factors for rhabdomyolysis in the study population, he added.
Dr. Sinclair reported receiving research grants from and serving as a consultant to Pfizer, which sponsored the phase 2 study, as well as more than a dozen other pharmaceutical companies.
PARIS – Each of two oral Janus kinase inhibitors individually showed impressive efficacy and acceptable safety and tolerability for treatment of chronic moderate to severe alopecia areata in a phase 2 study that promises to alter the therapeutic landscape in this challenging disease, Rodney Sinclair, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.
“My personal view is that these results represent a paradigm shift in the treatment of alopecia areata. Perhaps a line in the sand. On the one side, clinical observation, case reports, and small case series, but no reliably effective treatment. And on the other side of the line, investigational new drugs specifically targeting the pathogenesis, tested in prospective, multicenter, double-blind, placebo-controlled studies – and perhaps the first instance of evidence-based medicine arriving for alopecia areata. And I think that our patients with alopecia areata now have reason to be optimistic,” the dermatologist said.
“No reliably effective therapies now exist for alopecia areata, especially for patients with chronic extensive disease. There is an unmet need for a reliably effective therapy with a benefit-to-risk ratio that is appropriate for long-term use,” he added.
The phase 2 multicenter, placebo-controlled, double-blind study randomized 142 patients with chronic alopecia of at least 6 months duration and 50% or greater hair loss at baseline to an , or placebo for 24 weeks. The first 4 weeks of the double-blind trial involved induction dosing of the JAK3 inhibitor at 200 mg per day and the TYK2/JAK 1 inhibitor at 60 mg per day. Thereafter, participants switched to maintenance dosing at 50 mg and 30 mg per day, respectively.
Participants had a median 2.3 years of disease duration; 62 patients had alopecia totalis, and 42 had alopecia universalis.
The primary efficacy endpoint was the mean change from baseline to week 24 in the Severity of Alopecia Tool (SALT) score, a well-validated metric widely utilized in hair loss studies. The mean baseline score was 88.1. At week 24, the score had dropped by a mean of 33.6% in the JAK 3 inhibitor group, 49.5% in the TYK2/JAK1 inhibitor group, and zero in placebo-treated controls.
A key secondary endpoint known as the SALT 30, reflecting at least 30% improvement in SALT score, was achieved in 47.9% of patients on the oral JAK 3 inhibitor, 59.6% of those on the TYK2/JAK1 inhibitor, and by no one in the control group. The utter unresponsiveness of placebo-treated controls confirms the investigators’ success in recruiting a study population with truly chronic alopecia areata, Dr. Sinclair noted.
Of note, 25% of patients on the JAK 3 inhibitor and 31.9% on the TYK2/JAK1 inhibitor achieved a SALT 90 response, and 12.5% and 12.8% reached SALT 100.
Significant improvement on the Eyelash Assessment and Eyebrow Assessment Scales occurred in 45.2% and 36.2% of the JAK 3 inhibitor group and in 60.7% and 51.7% of the TYK2/JAK 1 inhibitor group.
The study is ongoing. It’s Dr. Sinclair’s anecdotal impression that further improvement is occurring in the active treatment arms with continued therapy after 24 weeks, but that remains to be seen.
Adverse events were similar in nature and frequency in all three study arms with one notable exception: two cases of rhabdomyolysis in the TYK2/JAK 1 inhibitor group.Session chair DeDee Murrell, MD, homed in on that piece of information, pressing for further details.
“Are you concerned? Were there predictors?” asked Dr. Murrell, professor of dermatology at the University of New South Wales in Sydney.
The two affected patients had muscle pain and elevated creatinine kinase levels. “They didn’t feel particularly unwell but were withdrawn as a precaution, after which the condition quickly resolved,” Dr. Sinclair said.
The investigators were unable to identify any risk factors for rhabdomyolysis in the study population, he added.
Dr. Sinclair reported receiving research grants from and serving as a consultant to Pfizer, which sponsored the phase 2 study, as well as more than a dozen other pharmaceutical companies.
PARIS – Each of two oral Janus kinase inhibitors individually showed impressive efficacy and acceptable safety and tolerability for treatment of chronic moderate to severe alopecia areata in a phase 2 study that promises to alter the therapeutic landscape in this challenging disease, Rodney Sinclair, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.
“My personal view is that these results represent a paradigm shift in the treatment of alopecia areata. Perhaps a line in the sand. On the one side, clinical observation, case reports, and small case series, but no reliably effective treatment. And on the other side of the line, investigational new drugs specifically targeting the pathogenesis, tested in prospective, multicenter, double-blind, placebo-controlled studies – and perhaps the first instance of evidence-based medicine arriving for alopecia areata. And I think that our patients with alopecia areata now have reason to be optimistic,” the dermatologist said.
“No reliably effective therapies now exist for alopecia areata, especially for patients with chronic extensive disease. There is an unmet need for a reliably effective therapy with a benefit-to-risk ratio that is appropriate for long-term use,” he added.
The phase 2 multicenter, placebo-controlled, double-blind study randomized 142 patients with chronic alopecia of at least 6 months duration and 50% or greater hair loss at baseline to an , or placebo for 24 weeks. The first 4 weeks of the double-blind trial involved induction dosing of the JAK3 inhibitor at 200 mg per day and the TYK2/JAK 1 inhibitor at 60 mg per day. Thereafter, participants switched to maintenance dosing at 50 mg and 30 mg per day, respectively.
Participants had a median 2.3 years of disease duration; 62 patients had alopecia totalis, and 42 had alopecia universalis.
The primary efficacy endpoint was the mean change from baseline to week 24 in the Severity of Alopecia Tool (SALT) score, a well-validated metric widely utilized in hair loss studies. The mean baseline score was 88.1. At week 24, the score had dropped by a mean of 33.6% in the JAK 3 inhibitor group, 49.5% in the TYK2/JAK1 inhibitor group, and zero in placebo-treated controls.
A key secondary endpoint known as the SALT 30, reflecting at least 30% improvement in SALT score, was achieved in 47.9% of patients on the oral JAK 3 inhibitor, 59.6% of those on the TYK2/JAK1 inhibitor, and by no one in the control group. The utter unresponsiveness of placebo-treated controls confirms the investigators’ success in recruiting a study population with truly chronic alopecia areata, Dr. Sinclair noted.
Of note, 25% of patients on the JAK 3 inhibitor and 31.9% on the TYK2/JAK1 inhibitor achieved a SALT 90 response, and 12.5% and 12.8% reached SALT 100.
Significant improvement on the Eyelash Assessment and Eyebrow Assessment Scales occurred in 45.2% and 36.2% of the JAK 3 inhibitor group and in 60.7% and 51.7% of the TYK2/JAK 1 inhibitor group.
The study is ongoing. It’s Dr. Sinclair’s anecdotal impression that further improvement is occurring in the active treatment arms with continued therapy after 24 weeks, but that remains to be seen.
Adverse events were similar in nature and frequency in all three study arms with one notable exception: two cases of rhabdomyolysis in the TYK2/JAK 1 inhibitor group.Session chair DeDee Murrell, MD, homed in on that piece of information, pressing for further details.
“Are you concerned? Were there predictors?” asked Dr. Murrell, professor of dermatology at the University of New South Wales in Sydney.
The two affected patients had muscle pain and elevated creatinine kinase levels. “They didn’t feel particularly unwell but were withdrawn as a precaution, after which the condition quickly resolved,” Dr. Sinclair said.
The investigators were unable to identify any risk factors for rhabdomyolysis in the study population, he added.
Dr. Sinclair reported receiving research grants from and serving as a consultant to Pfizer, which sponsored the phase 2 study, as well as more than a dozen other pharmaceutical companies.
REPORTING FROM THE EADV CONGRESS
Key clinical point: Targeted therapy with Janus kinase inhibitors shows great promise in chronic alopecia areata.
Major finding: Mean placebo-subtracted improvement in Severity of Alopecia Tool scores was 50% after 24 weeks of treatment with an oral TYK2/JAK 1 inhibitor.
Study details: This was a prospective, multicenter, double-blind, placebo-controlled, 24-week phase 2 study of 142 patients with chronic moderate to severe alopecia areata.
Disclosures: The presenter reported receiving research grants from and serving as a consultant to Pfizer, which sponsored the phase 2 study, as well as to more than a dozen other pharmaceutical companies.
Dupilumab positive in phase 3 study for treating adolescent atopic dermatitis
PARIS – Dupilumab scorched its way through a landmark pivotal phase 3 clinical trial in adolescents with moderate to severe atopic dermatitis (AD), achieving unprecedented clinically meaningful improvements in signs and symptoms of the disease along with important quality of life benefits, Eric L. Simpson, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.
Indeed, akin to that previously shown in adults with moderate to severe AD in phase 3 trials that earned the biologic U.S. and European regulatory approval in the adult population, noted Dr. Simpson, professor of dermatology at Oregon Health & Science University, Portland.
This positive phase 3 study represents a major development in pediatric dermatology because of the pressing unmet need for better treatments for teens with moderate to severe AD whose disease can’t be controlled with topical therapies. The adolescent years are, after all, a critical period in growth and development, and a debilitating, uncontrolled disease can reshape that experience in unwelcome ways.
“Atopic dermatitis profoundly affects quality of life in adolescents and their family: The itching affects mood and sleep, these patients commonly have anxiety and depression, and the chronic and relapsing nature of the disease adversely affects the family,” the dermatologist observed.
Currently, no systemic agent is approved for pediatric patients with AD because evidence demonstrating a favorable benefit-to-risk profile has been lacking. The dupilumab study was the first-ever phase 3 trial of a biologic in such a population.
The phase 3 adolescent trial was a 16-week, randomized, double-blind, multicenter, placebo-controlled study of 251 patients aged 12-17 years with moderate to severe AD, which could not be adequately controlled with topical therapies. Participants averaged 14 years of age, with a 12-year history of AD. “These patients had the disease basically their whole life,” Dr. Simpson noted.
They were more severely affected than participants in the adult clinical trials, with mean Eczema Area And Severity Index (EASI) scores in the mid-30s and an average 56% involved body surface area. The adolescent AD patients had a heavy burden of comorbid allergic type 2 immune comorbidity: Fully 92% of them had documented asthma, food allergy, allergic rhinitis, and/or some other form of allergic comorbidity. The majority of the teens were categorized as having severe AD, whereas most participants in the adult phase 3 trials of dupilumab had moderate disease. That distinction becomes relevant in comparing the trial results.
Participants were randomized to once-monthly subcutaneous injections of dupilumab at 300 mg, following a 600-mg loading dose, or to an injection of 200 mg or 300 mg every 2 weeks with an initial dose of 400 mg or 600 mg based upon a body weight cutoff of 60 kg, or to biweekly placebo injections.
The coprimary endpoints were the proportion of patients who achieved an EASI 75 response at week 16 and achievement of an Investigator’s Global Assessment (IGA) score of 0 or 1, meaning clear or almost clear, on a 5-point scale at week 16.
This trial introduced an important new design feature that physicians can expect to see more of in the future: regulatory agencies now want to see the effects of monotherapy in pivotal studies in AD. Previously, participants in AD studies of systemic agents could also utilize topical steroids as needed. No longer. In the adolescent dupilumab study, resort to rescue topical steroids led to exclusion from inclusion in the primary outcome results. Not surprisingly, this lack of access to rescue medication resulted in a 60% dropout rate by 16 weeks in placebo-treated controls, a 30% dropout rate in teens on dupilumab every 4 weeks, and a 20% dropout rate with biweekly dupilumab.
The EASI 75 rate at week 16 was 8.2% with placebo, 38.1% with monthly dupilumab, and 41.5% with biweekly dosing. The other coprimary endpoint – an IGA of 0 or 1 at 16 weeks – was achieved in 2.4% of controls, 17.9% with dupilumab at 300 mg every 4 weeks, and 41.5% with biweekly dosing.
Turning to secondary endpoints, Dr. Simpson reported that baseline peak pruritus Numeric Rating Scale scores dropped by 19% with placebo at 16 weeks, compared with reductions of 45.5% and 47.9% with monthly and biweekly dupilumab, respectively.
An EASI 50 response,while not as impressive as an EASI 75, is nonetheless considered clinically meaningful improvement. It was attained in 12.9% on placebo and 54.8% and 61% on monthly and biweekly dupilumab.
From a mean baseline score of 13.6 on the Children’s Dermatology Life Quality Index, scores improved over the course of 16 weeks by a mean of 5.1 points with placebo, 8.5 points with monthly dupilumab, and 8.8 points with biweekly biologic therapy. The same pattern was noted with regard to the Patient-Oriented Eczema Measure or POEM.
Adverse events mirrored those documented in the pivotal trials in adults: increased rates of mild to moderate conjunctivitis: 4.7% with placebo, 10.8% with monthly dupilumab, and 9.8% with biweekly dupilumab, along with single-digit rates of injection-site reactions. As in adult AD patients, however, these side effects were counterbalanced by significantly reduced rates of skin infections in the adolescent group: 20% during 16 weeks with placebo, and 13.3% and 11% with monthly and biweekly biologic therapy, respectively.
Study participants had a mean baseline score of 12.5 on the Hospital Anxiety and Depression Scale, which is categorized as clinically significant psychiatric disease. The impact of dupilumab therapy on those scores will be the topic of a future presentation, Dr. Simpson said.
Across the board, specific outcomes were consistently numerically better in patients who received dupilumab biweekly than monthly, albeit not statistically significantly so. Dr. Simpson thinks he knows why: Lab studies showed that the mean serum concentration of functional dupilumab in patients who got the biologic biweekly was nearly twice that for the group with monthly dosing.
At first glance, the IGA “clear” or “almost clear” response rates seen with dupilumab in the adolescent study appeared to be less robust than in the adult pivotal phase 3 trials, such as the SOLO 1 and SOLO 2 trials (N Engl J Med. 2016 Dec 15;375[24]:2335-48), also led by Dr. Simpson.
“I think that’s because of the greater severity of that baseline adolescent population,” he commented. “It made for a much lower placebo response rate. But when you correct for the placebo-subtracted difference, the rates are actually pretty similar, and a lot of the other endpoints are the same or even better than in SOLO.”
After his presentation, Dr. Simpson commented, “This is huge. This is the study we’ve been waiting for.”
Elsewhere at the EADV congress, Emma Guttman-Yassky, MD, PhD, deemed the pivotal phase 3 trial in adolescent AD patients one of the meeting’s highlights. And it’s a harbinger of more good things to come, because the investigational drug pipeline for AD is full of promising candidates addressing the disease from a variety of novel directions. The long therapeutic drought in AD appears to have finally ended, observed Dr. Guttman-Yassky, professor and vice-chair of the department of dermatology at Icahn School of Medicine at Mount Sinai, New York.
That’s welcome news because AD is the most common inflammatory skin disease, both in adults, where the latest data puts the prevalence at 7%-10%, and in children, where the global rate is 15%-25%.
And while at the EADV congress only the 16-week data were reported in the new adolescent study, there is reason to be optimistic that the benefits will remain durable over time. Dr. Guttman-Yassky cited the published 52-week data from the large phase 3 CHRONOS trial in adults with moderate to severe AD. In that trial, in which patients could use concomitant topical steroids, the EASI 75 rates at week 16 were 69% in patients on dupilumab at 300 mg every 2 weeks, 64% with 300 mg weekly, and 23% with placebo. Reassuringly, at 52 weeks the EASI 75 response rates were essentially unchanged: 65%, 64%, and 22% (Lancet. 2017 Jun 10;389[10086]:2287-303).
“This is what we are seeking: not just treatment that is able to quickly modify disease, but we want the treatment to be sustained, and of course we want it to be safe for our patients because we know we cannot use cyclosporine for a long time,” Dr. Guttman-Yassky said.
Dr. Simpson reported serving as a consultant to and recipient of research grants from Sanofi and Regeneron, which sponsored the adolescent study, as well as more than a dozen other pharmaceutical companies. Dr. Guttman-Yassky reported serving as an advisor and consultant, and has received grants/research funding from Regeneron, and multiple other companies.
PARIS – Dupilumab scorched its way through a landmark pivotal phase 3 clinical trial in adolescents with moderate to severe atopic dermatitis (AD), achieving unprecedented clinically meaningful improvements in signs and symptoms of the disease along with important quality of life benefits, Eric L. Simpson, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.
Indeed, akin to that previously shown in adults with moderate to severe AD in phase 3 trials that earned the biologic U.S. and European regulatory approval in the adult population, noted Dr. Simpson, professor of dermatology at Oregon Health & Science University, Portland.
This positive phase 3 study represents a major development in pediatric dermatology because of the pressing unmet need for better treatments for teens with moderate to severe AD whose disease can’t be controlled with topical therapies. The adolescent years are, after all, a critical period in growth and development, and a debilitating, uncontrolled disease can reshape that experience in unwelcome ways.
“Atopic dermatitis profoundly affects quality of life in adolescents and their family: The itching affects mood and sleep, these patients commonly have anxiety and depression, and the chronic and relapsing nature of the disease adversely affects the family,” the dermatologist observed.
Currently, no systemic agent is approved for pediatric patients with AD because evidence demonstrating a favorable benefit-to-risk profile has been lacking. The dupilumab study was the first-ever phase 3 trial of a biologic in such a population.
The phase 3 adolescent trial was a 16-week, randomized, double-blind, multicenter, placebo-controlled study of 251 patients aged 12-17 years with moderate to severe AD, which could not be adequately controlled with topical therapies. Participants averaged 14 years of age, with a 12-year history of AD. “These patients had the disease basically their whole life,” Dr. Simpson noted.
They were more severely affected than participants in the adult clinical trials, with mean Eczema Area And Severity Index (EASI) scores in the mid-30s and an average 56% involved body surface area. The adolescent AD patients had a heavy burden of comorbid allergic type 2 immune comorbidity: Fully 92% of them had documented asthma, food allergy, allergic rhinitis, and/or some other form of allergic comorbidity. The majority of the teens were categorized as having severe AD, whereas most participants in the adult phase 3 trials of dupilumab had moderate disease. That distinction becomes relevant in comparing the trial results.
Participants were randomized to once-monthly subcutaneous injections of dupilumab at 300 mg, following a 600-mg loading dose, or to an injection of 200 mg or 300 mg every 2 weeks with an initial dose of 400 mg or 600 mg based upon a body weight cutoff of 60 kg, or to biweekly placebo injections.
The coprimary endpoints were the proportion of patients who achieved an EASI 75 response at week 16 and achievement of an Investigator’s Global Assessment (IGA) score of 0 or 1, meaning clear or almost clear, on a 5-point scale at week 16.
This trial introduced an important new design feature that physicians can expect to see more of in the future: regulatory agencies now want to see the effects of monotherapy in pivotal studies in AD. Previously, participants in AD studies of systemic agents could also utilize topical steroids as needed. No longer. In the adolescent dupilumab study, resort to rescue topical steroids led to exclusion from inclusion in the primary outcome results. Not surprisingly, this lack of access to rescue medication resulted in a 60% dropout rate by 16 weeks in placebo-treated controls, a 30% dropout rate in teens on dupilumab every 4 weeks, and a 20% dropout rate with biweekly dupilumab.
The EASI 75 rate at week 16 was 8.2% with placebo, 38.1% with monthly dupilumab, and 41.5% with biweekly dosing. The other coprimary endpoint – an IGA of 0 or 1 at 16 weeks – was achieved in 2.4% of controls, 17.9% with dupilumab at 300 mg every 4 weeks, and 41.5% with biweekly dosing.
Turning to secondary endpoints, Dr. Simpson reported that baseline peak pruritus Numeric Rating Scale scores dropped by 19% with placebo at 16 weeks, compared with reductions of 45.5% and 47.9% with monthly and biweekly dupilumab, respectively.
An EASI 50 response,while not as impressive as an EASI 75, is nonetheless considered clinically meaningful improvement. It was attained in 12.9% on placebo and 54.8% and 61% on monthly and biweekly dupilumab.
From a mean baseline score of 13.6 on the Children’s Dermatology Life Quality Index, scores improved over the course of 16 weeks by a mean of 5.1 points with placebo, 8.5 points with monthly dupilumab, and 8.8 points with biweekly biologic therapy. The same pattern was noted with regard to the Patient-Oriented Eczema Measure or POEM.
Adverse events mirrored those documented in the pivotal trials in adults: increased rates of mild to moderate conjunctivitis: 4.7% with placebo, 10.8% with monthly dupilumab, and 9.8% with biweekly dupilumab, along with single-digit rates of injection-site reactions. As in adult AD patients, however, these side effects were counterbalanced by significantly reduced rates of skin infections in the adolescent group: 20% during 16 weeks with placebo, and 13.3% and 11% with monthly and biweekly biologic therapy, respectively.
Study participants had a mean baseline score of 12.5 on the Hospital Anxiety and Depression Scale, which is categorized as clinically significant psychiatric disease. The impact of dupilumab therapy on those scores will be the topic of a future presentation, Dr. Simpson said.
Across the board, specific outcomes were consistently numerically better in patients who received dupilumab biweekly than monthly, albeit not statistically significantly so. Dr. Simpson thinks he knows why: Lab studies showed that the mean serum concentration of functional dupilumab in patients who got the biologic biweekly was nearly twice that for the group with monthly dosing.
At first glance, the IGA “clear” or “almost clear” response rates seen with dupilumab in the adolescent study appeared to be less robust than in the adult pivotal phase 3 trials, such as the SOLO 1 and SOLO 2 trials (N Engl J Med. 2016 Dec 15;375[24]:2335-48), also led by Dr. Simpson.
“I think that’s because of the greater severity of that baseline adolescent population,” he commented. “It made for a much lower placebo response rate. But when you correct for the placebo-subtracted difference, the rates are actually pretty similar, and a lot of the other endpoints are the same or even better than in SOLO.”
After his presentation, Dr. Simpson commented, “This is huge. This is the study we’ve been waiting for.”
Elsewhere at the EADV congress, Emma Guttman-Yassky, MD, PhD, deemed the pivotal phase 3 trial in adolescent AD patients one of the meeting’s highlights. And it’s a harbinger of more good things to come, because the investigational drug pipeline for AD is full of promising candidates addressing the disease from a variety of novel directions. The long therapeutic drought in AD appears to have finally ended, observed Dr. Guttman-Yassky, professor and vice-chair of the department of dermatology at Icahn School of Medicine at Mount Sinai, New York.
That’s welcome news because AD is the most common inflammatory skin disease, both in adults, where the latest data puts the prevalence at 7%-10%, and in children, where the global rate is 15%-25%.
And while at the EADV congress only the 16-week data were reported in the new adolescent study, there is reason to be optimistic that the benefits will remain durable over time. Dr. Guttman-Yassky cited the published 52-week data from the large phase 3 CHRONOS trial in adults with moderate to severe AD. In that trial, in which patients could use concomitant topical steroids, the EASI 75 rates at week 16 were 69% in patients on dupilumab at 300 mg every 2 weeks, 64% with 300 mg weekly, and 23% with placebo. Reassuringly, at 52 weeks the EASI 75 response rates were essentially unchanged: 65%, 64%, and 22% (Lancet. 2017 Jun 10;389[10086]:2287-303).
“This is what we are seeking: not just treatment that is able to quickly modify disease, but we want the treatment to be sustained, and of course we want it to be safe for our patients because we know we cannot use cyclosporine for a long time,” Dr. Guttman-Yassky said.
Dr. Simpson reported serving as a consultant to and recipient of research grants from Sanofi and Regeneron, which sponsored the adolescent study, as well as more than a dozen other pharmaceutical companies. Dr. Guttman-Yassky reported serving as an advisor and consultant, and has received grants/research funding from Regeneron, and multiple other companies.
PARIS – Dupilumab scorched its way through a landmark pivotal phase 3 clinical trial in adolescents with moderate to severe atopic dermatitis (AD), achieving unprecedented clinically meaningful improvements in signs and symptoms of the disease along with important quality of life benefits, Eric L. Simpson, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.
Indeed, akin to that previously shown in adults with moderate to severe AD in phase 3 trials that earned the biologic U.S. and European regulatory approval in the adult population, noted Dr. Simpson, professor of dermatology at Oregon Health & Science University, Portland.
This positive phase 3 study represents a major development in pediatric dermatology because of the pressing unmet need for better treatments for teens with moderate to severe AD whose disease can’t be controlled with topical therapies. The adolescent years are, after all, a critical period in growth and development, and a debilitating, uncontrolled disease can reshape that experience in unwelcome ways.
“Atopic dermatitis profoundly affects quality of life in adolescents and their family: The itching affects mood and sleep, these patients commonly have anxiety and depression, and the chronic and relapsing nature of the disease adversely affects the family,” the dermatologist observed.
Currently, no systemic agent is approved for pediatric patients with AD because evidence demonstrating a favorable benefit-to-risk profile has been lacking. The dupilumab study was the first-ever phase 3 trial of a biologic in such a population.
The phase 3 adolescent trial was a 16-week, randomized, double-blind, multicenter, placebo-controlled study of 251 patients aged 12-17 years with moderate to severe AD, which could not be adequately controlled with topical therapies. Participants averaged 14 years of age, with a 12-year history of AD. “These patients had the disease basically their whole life,” Dr. Simpson noted.
They were more severely affected than participants in the adult clinical trials, with mean Eczema Area And Severity Index (EASI) scores in the mid-30s and an average 56% involved body surface area. The adolescent AD patients had a heavy burden of comorbid allergic type 2 immune comorbidity: Fully 92% of them had documented asthma, food allergy, allergic rhinitis, and/or some other form of allergic comorbidity. The majority of the teens were categorized as having severe AD, whereas most participants in the adult phase 3 trials of dupilumab had moderate disease. That distinction becomes relevant in comparing the trial results.
Participants were randomized to once-monthly subcutaneous injections of dupilumab at 300 mg, following a 600-mg loading dose, or to an injection of 200 mg or 300 mg every 2 weeks with an initial dose of 400 mg or 600 mg based upon a body weight cutoff of 60 kg, or to biweekly placebo injections.
The coprimary endpoints were the proportion of patients who achieved an EASI 75 response at week 16 and achievement of an Investigator’s Global Assessment (IGA) score of 0 or 1, meaning clear or almost clear, on a 5-point scale at week 16.
This trial introduced an important new design feature that physicians can expect to see more of in the future: regulatory agencies now want to see the effects of monotherapy in pivotal studies in AD. Previously, participants in AD studies of systemic agents could also utilize topical steroids as needed. No longer. In the adolescent dupilumab study, resort to rescue topical steroids led to exclusion from inclusion in the primary outcome results. Not surprisingly, this lack of access to rescue medication resulted in a 60% dropout rate by 16 weeks in placebo-treated controls, a 30% dropout rate in teens on dupilumab every 4 weeks, and a 20% dropout rate with biweekly dupilumab.
The EASI 75 rate at week 16 was 8.2% with placebo, 38.1% with monthly dupilumab, and 41.5% with biweekly dosing. The other coprimary endpoint – an IGA of 0 or 1 at 16 weeks – was achieved in 2.4% of controls, 17.9% with dupilumab at 300 mg every 4 weeks, and 41.5% with biweekly dosing.
Turning to secondary endpoints, Dr. Simpson reported that baseline peak pruritus Numeric Rating Scale scores dropped by 19% with placebo at 16 weeks, compared with reductions of 45.5% and 47.9% with monthly and biweekly dupilumab, respectively.
An EASI 50 response,while not as impressive as an EASI 75, is nonetheless considered clinically meaningful improvement. It was attained in 12.9% on placebo and 54.8% and 61% on monthly and biweekly dupilumab.
From a mean baseline score of 13.6 on the Children’s Dermatology Life Quality Index, scores improved over the course of 16 weeks by a mean of 5.1 points with placebo, 8.5 points with monthly dupilumab, and 8.8 points with biweekly biologic therapy. The same pattern was noted with regard to the Patient-Oriented Eczema Measure or POEM.
Adverse events mirrored those documented in the pivotal trials in adults: increased rates of mild to moderate conjunctivitis: 4.7% with placebo, 10.8% with monthly dupilumab, and 9.8% with biweekly dupilumab, along with single-digit rates of injection-site reactions. As in adult AD patients, however, these side effects were counterbalanced by significantly reduced rates of skin infections in the adolescent group: 20% during 16 weeks with placebo, and 13.3% and 11% with monthly and biweekly biologic therapy, respectively.
Study participants had a mean baseline score of 12.5 on the Hospital Anxiety and Depression Scale, which is categorized as clinically significant psychiatric disease. The impact of dupilumab therapy on those scores will be the topic of a future presentation, Dr. Simpson said.
Across the board, specific outcomes were consistently numerically better in patients who received dupilumab biweekly than monthly, albeit not statistically significantly so. Dr. Simpson thinks he knows why: Lab studies showed that the mean serum concentration of functional dupilumab in patients who got the biologic biweekly was nearly twice that for the group with monthly dosing.
At first glance, the IGA “clear” or “almost clear” response rates seen with dupilumab in the adolescent study appeared to be less robust than in the adult pivotal phase 3 trials, such as the SOLO 1 and SOLO 2 trials (N Engl J Med. 2016 Dec 15;375[24]:2335-48), also led by Dr. Simpson.
“I think that’s because of the greater severity of that baseline adolescent population,” he commented. “It made for a much lower placebo response rate. But when you correct for the placebo-subtracted difference, the rates are actually pretty similar, and a lot of the other endpoints are the same or even better than in SOLO.”
After his presentation, Dr. Simpson commented, “This is huge. This is the study we’ve been waiting for.”
Elsewhere at the EADV congress, Emma Guttman-Yassky, MD, PhD, deemed the pivotal phase 3 trial in adolescent AD patients one of the meeting’s highlights. And it’s a harbinger of more good things to come, because the investigational drug pipeline for AD is full of promising candidates addressing the disease from a variety of novel directions. The long therapeutic drought in AD appears to have finally ended, observed Dr. Guttman-Yassky, professor and vice-chair of the department of dermatology at Icahn School of Medicine at Mount Sinai, New York.
That’s welcome news because AD is the most common inflammatory skin disease, both in adults, where the latest data puts the prevalence at 7%-10%, and in children, where the global rate is 15%-25%.
And while at the EADV congress only the 16-week data were reported in the new adolescent study, there is reason to be optimistic that the benefits will remain durable over time. Dr. Guttman-Yassky cited the published 52-week data from the large phase 3 CHRONOS trial in adults with moderate to severe AD. In that trial, in which patients could use concomitant topical steroids, the EASI 75 rates at week 16 were 69% in patients on dupilumab at 300 mg every 2 weeks, 64% with 300 mg weekly, and 23% with placebo. Reassuringly, at 52 weeks the EASI 75 response rates were essentially unchanged: 65%, 64%, and 22% (Lancet. 2017 Jun 10;389[10086]:2287-303).
“This is what we are seeking: not just treatment that is able to quickly modify disease, but we want the treatment to be sustained, and of course we want it to be safe for our patients because we know we cannot use cyclosporine for a long time,” Dr. Guttman-Yassky said.
Dr. Simpson reported serving as a consultant to and recipient of research grants from Sanofi and Regeneron, which sponsored the adolescent study, as well as more than a dozen other pharmaceutical companies. Dr. Guttman-Yassky reported serving as an advisor and consultant, and has received grants/research funding from Regeneron, and multiple other companies.
REPORTING FROM THE EADV CONGRESS
Key clinical point: Dupilumab gets solid green-light evidence for use in teens with atopic dermatitis (AD).
Major finding: Dupilumab was as safe and effective in adolescents with moderate to severe AD as previously established in adult patients.
Study details: This prospective, randomized, double-blind, placebo-controlled, 16-week pivotal phase 3 trial included 251 adolescents with moderate to severe AD.
Disclosures: The presenter reported serving as a consultant to and recipient of research grants from Sanofi and Regeneron, which sponsored the adolescent study, as well as more than a dozen other pharmaceutical companies.
Topical cyclosporine safely tamed atopic dermatitis in 4-week study
PARIS – A first-of-its-kind Ana M. Giménez-Arnau, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.
The 5% cyclosporine topical spray, known as Cyclatop, showed significantly better results across the board than its vehicle, even during the first week of treatment in the 4-week, multicenter, Spanish, double-blind, randomized trial, which included 44 patients with mild or moderate atopic dermatitis (AD), according to Dr. Giménez-Arnau, a dermatologist at Hospital del Mar and the Autonomous University of Barcelona.
“Besides the clinical efficacy, the study also demonstrated that, when cyclosporine was detectable in the blood, the highest blood level was at least 200-fold less than after systemic administration of cyclosporine at therapeutic doses,” she noted.
The motivation to develop a topical formulation of cyclosporine stemmed from the need to find substitutes for topical corticosteroids, especially in the pediatric population, where steroid phobia is rampant among parents. And while systemic cyclosporine is approved by European regulators for treatment of difficult cases of AD and is widely utilized off label for this purpose in the United States, the fact is that it is an immunosuppressant that paints with a broad brush and is best utilized for a matter of weeks as induction therapy.
But developing a topical formulation of cyclosporine suitable for long-term use posed many challenges. Lack of stability in cream and ointment formulations was a recurring issue. “Cyclosporine is a very big molecule, which is not easy to work with topically,” she explained. “The challenge was to find a stable formulation with good skin penetration, but without systemic absorption.”
Indeed, researchers at Barcelona-based Spherium Biomed evaluated more than 100 prototype compounds in animal models before settling on a proprietary oil emulsion formulation of 5% cyclosporine delivered via a spray without propellant gas.
Key study findings
The 44 study participants had a mean baseline of 8.3% body surface area involvement. As a condition of participation, they needed to have similar lesional areas bilaterally. They treated involved areas on one side of the body twice daily with Cyclatop, while they sprayed those on the opposite side with its vehicle.
From a mean baseline Eczema Area and Severity Index (EASI) score of 5.5, EASI scores improved by an average of 3.2 points after 28 days of cyclosporine spray, compared with 1.7 points with vehicle. Atopic Dermatitis Area and Severity Index (ADSI) scores improved from a mean baseline of 6.5 by 3.6 points with topical cyclosporine versus 2.4 points with vehicle.
At week 3, an EASI 75 response – that is, at least a 75% reduction from baseline EASI scores – was achieved at 44.4% of actively treated sites, compared with 25.9% of control sites. ADSI 75 rates at 3 weeks were 33.3% and 11.1%, respectively. An Investigator’s Global Assessment of clear or almost clear was reached at week 4 at 61.5% of active treatment sites, compared with 42.3% of vehicle-treated sites.
Itching responded dramatically to topical cyclosporine. From a mean baseline score of 3.3 on a standard 10-point pruritus visual analog scale, cyclosporine spray–treated areas showed a mean 1.2-point decrease at week 4, compared with a 0.4-point reduction at vehicle-treated areas. About 50% of the reduction in pruritus scores was achieved within the first week of active treatment. Moreover, among patients with moderate as opposed to mild itching scores at baseline, who had a mean pruritus score of 5.6, topical cyclosporine spray resulted in a mean 3.3-point reduction at week 4, Dr. Giménez-Arnau continued.
No safety signals emerged in this initial study. Side effects associated with the cyclosporine spray were the same as with its vehicle, and in exit interviews, more than 85% of patients indicated they were satisfied with the comfort and practicality of topical cyclosporine.
Session chair DeDee Murrell, MD, professor of dermatology at the University of New South Wales, Sydney, noted that the study was restricted to patients with less than 10% body surface area of involvement.
“Are you concerned that if you use this product over widespread areas, as is quite common in eczema, that you might get positive blood levels?” she asked.
“We don’t know. We should check that,” Dr. Giménez-Arnau replied. She added that more studies need to be done before cyclosporine spray is ready for the market. These studies will need to address the optimal dosing schedule and duration, the spectrum of disease severity where the topical spray works best, and other key issues.
Cyclatop is being developed by Spherium Biomed, which sponsored the study. Dr. Giménez-Arnau reported receiving research grants from and/or serving as a consultant to roughly half a dozen pharmaceutical companies.
PARIS – A first-of-its-kind Ana M. Giménez-Arnau, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.
The 5% cyclosporine topical spray, known as Cyclatop, showed significantly better results across the board than its vehicle, even during the first week of treatment in the 4-week, multicenter, Spanish, double-blind, randomized trial, which included 44 patients with mild or moderate atopic dermatitis (AD), according to Dr. Giménez-Arnau, a dermatologist at Hospital del Mar and the Autonomous University of Barcelona.
“Besides the clinical efficacy, the study also demonstrated that, when cyclosporine was detectable in the blood, the highest blood level was at least 200-fold less than after systemic administration of cyclosporine at therapeutic doses,” she noted.
The motivation to develop a topical formulation of cyclosporine stemmed from the need to find substitutes for topical corticosteroids, especially in the pediatric population, where steroid phobia is rampant among parents. And while systemic cyclosporine is approved by European regulators for treatment of difficult cases of AD and is widely utilized off label for this purpose in the United States, the fact is that it is an immunosuppressant that paints with a broad brush and is best utilized for a matter of weeks as induction therapy.
But developing a topical formulation of cyclosporine suitable for long-term use posed many challenges. Lack of stability in cream and ointment formulations was a recurring issue. “Cyclosporine is a very big molecule, which is not easy to work with topically,” she explained. “The challenge was to find a stable formulation with good skin penetration, but without systemic absorption.”
Indeed, researchers at Barcelona-based Spherium Biomed evaluated more than 100 prototype compounds in animal models before settling on a proprietary oil emulsion formulation of 5% cyclosporine delivered via a spray without propellant gas.
Key study findings
The 44 study participants had a mean baseline of 8.3% body surface area involvement. As a condition of participation, they needed to have similar lesional areas bilaterally. They treated involved areas on one side of the body twice daily with Cyclatop, while they sprayed those on the opposite side with its vehicle.
From a mean baseline Eczema Area and Severity Index (EASI) score of 5.5, EASI scores improved by an average of 3.2 points after 28 days of cyclosporine spray, compared with 1.7 points with vehicle. Atopic Dermatitis Area and Severity Index (ADSI) scores improved from a mean baseline of 6.5 by 3.6 points with topical cyclosporine versus 2.4 points with vehicle.
At week 3, an EASI 75 response – that is, at least a 75% reduction from baseline EASI scores – was achieved at 44.4% of actively treated sites, compared with 25.9% of control sites. ADSI 75 rates at 3 weeks were 33.3% and 11.1%, respectively. An Investigator’s Global Assessment of clear or almost clear was reached at week 4 at 61.5% of active treatment sites, compared with 42.3% of vehicle-treated sites.
Itching responded dramatically to topical cyclosporine. From a mean baseline score of 3.3 on a standard 10-point pruritus visual analog scale, cyclosporine spray–treated areas showed a mean 1.2-point decrease at week 4, compared with a 0.4-point reduction at vehicle-treated areas. About 50% of the reduction in pruritus scores was achieved within the first week of active treatment. Moreover, among patients with moderate as opposed to mild itching scores at baseline, who had a mean pruritus score of 5.6, topical cyclosporine spray resulted in a mean 3.3-point reduction at week 4, Dr. Giménez-Arnau continued.
No safety signals emerged in this initial study. Side effects associated with the cyclosporine spray were the same as with its vehicle, and in exit interviews, more than 85% of patients indicated they were satisfied with the comfort and practicality of topical cyclosporine.
Session chair DeDee Murrell, MD, professor of dermatology at the University of New South Wales, Sydney, noted that the study was restricted to patients with less than 10% body surface area of involvement.
“Are you concerned that if you use this product over widespread areas, as is quite common in eczema, that you might get positive blood levels?” she asked.
“We don’t know. We should check that,” Dr. Giménez-Arnau replied. She added that more studies need to be done before cyclosporine spray is ready for the market. These studies will need to address the optimal dosing schedule and duration, the spectrum of disease severity where the topical spray works best, and other key issues.
Cyclatop is being developed by Spherium Biomed, which sponsored the study. Dr. Giménez-Arnau reported receiving research grants from and/or serving as a consultant to roughly half a dozen pharmaceutical companies.
PARIS – A first-of-its-kind Ana M. Giménez-Arnau, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.
The 5% cyclosporine topical spray, known as Cyclatop, showed significantly better results across the board than its vehicle, even during the first week of treatment in the 4-week, multicenter, Spanish, double-blind, randomized trial, which included 44 patients with mild or moderate atopic dermatitis (AD), according to Dr. Giménez-Arnau, a dermatologist at Hospital del Mar and the Autonomous University of Barcelona.
“Besides the clinical efficacy, the study also demonstrated that, when cyclosporine was detectable in the blood, the highest blood level was at least 200-fold less than after systemic administration of cyclosporine at therapeutic doses,” she noted.
The motivation to develop a topical formulation of cyclosporine stemmed from the need to find substitutes for topical corticosteroids, especially in the pediatric population, where steroid phobia is rampant among parents. And while systemic cyclosporine is approved by European regulators for treatment of difficult cases of AD and is widely utilized off label for this purpose in the United States, the fact is that it is an immunosuppressant that paints with a broad brush and is best utilized for a matter of weeks as induction therapy.
But developing a topical formulation of cyclosporine suitable for long-term use posed many challenges. Lack of stability in cream and ointment formulations was a recurring issue. “Cyclosporine is a very big molecule, which is not easy to work with topically,” she explained. “The challenge was to find a stable formulation with good skin penetration, but without systemic absorption.”
Indeed, researchers at Barcelona-based Spherium Biomed evaluated more than 100 prototype compounds in animal models before settling on a proprietary oil emulsion formulation of 5% cyclosporine delivered via a spray without propellant gas.
Key study findings
The 44 study participants had a mean baseline of 8.3% body surface area involvement. As a condition of participation, they needed to have similar lesional areas bilaterally. They treated involved areas on one side of the body twice daily with Cyclatop, while they sprayed those on the opposite side with its vehicle.
From a mean baseline Eczema Area and Severity Index (EASI) score of 5.5, EASI scores improved by an average of 3.2 points after 28 days of cyclosporine spray, compared with 1.7 points with vehicle. Atopic Dermatitis Area and Severity Index (ADSI) scores improved from a mean baseline of 6.5 by 3.6 points with topical cyclosporine versus 2.4 points with vehicle.
At week 3, an EASI 75 response – that is, at least a 75% reduction from baseline EASI scores – was achieved at 44.4% of actively treated sites, compared with 25.9% of control sites. ADSI 75 rates at 3 weeks were 33.3% and 11.1%, respectively. An Investigator’s Global Assessment of clear or almost clear was reached at week 4 at 61.5% of active treatment sites, compared with 42.3% of vehicle-treated sites.
Itching responded dramatically to topical cyclosporine. From a mean baseline score of 3.3 on a standard 10-point pruritus visual analog scale, cyclosporine spray–treated areas showed a mean 1.2-point decrease at week 4, compared with a 0.4-point reduction at vehicle-treated areas. About 50% of the reduction in pruritus scores was achieved within the first week of active treatment. Moreover, among patients with moderate as opposed to mild itching scores at baseline, who had a mean pruritus score of 5.6, topical cyclosporine spray resulted in a mean 3.3-point reduction at week 4, Dr. Giménez-Arnau continued.
No safety signals emerged in this initial study. Side effects associated with the cyclosporine spray were the same as with its vehicle, and in exit interviews, more than 85% of patients indicated they were satisfied with the comfort and practicality of topical cyclosporine.
Session chair DeDee Murrell, MD, professor of dermatology at the University of New South Wales, Sydney, noted that the study was restricted to patients with less than 10% body surface area of involvement.
“Are you concerned that if you use this product over widespread areas, as is quite common in eczema, that you might get positive blood levels?” she asked.
“We don’t know. We should check that,” Dr. Giménez-Arnau replied. She added that more studies need to be done before cyclosporine spray is ready for the market. These studies will need to address the optimal dosing schedule and duration, the spectrum of disease severity where the topical spray works best, and other key issues.
Cyclatop is being developed by Spherium Biomed, which sponsored the study. Dr. Giménez-Arnau reported receiving research grants from and/or serving as a consultant to roughly half a dozen pharmaceutical companies.
REPORTING FROM THE EADV CONGRESS
Key clinical point: Cyclosporine 5% topical spray shows promise for atopic dermatitis.
Major finding: About 62% of patients with mild to moderate atopic dermatitis were clear or almost clear after 4 weeks of twice-daily cyclosporine 5% topical spray.
Study details: This prospective, multicenter, double-blind, vehicle-controlled study included 44 children and adults with mild or moderate atopic dermatitis.
Disclosures: The study was sponsored by Spherium Biomed. The presenter reported receiving research grants from and/or serving as a consultant to that and roughly half a dozen other pharmaceutical companies.
Pediatric data on novel axillary hyperhidrosis treatment reported
PARIS – Two compelling reasons exist to take excessive sweating in children and adolescents more seriously, Lawrence J. Green, MD, asserted at the annual congress of the European Academy of Dermatology and Venereology.
One is that this is a surprisingly common and embarrassing medical condition that can have a profound adverse developmental impact in young people at a time when they are engaged in forming their self-image.
The other reason to get serious about addressing primary axillary hyperhidrosis in pediatric patients is the recent approval of glycopyrronium tosylate as a topical therapy, Dr. Green, a dermatologist at George Washington University, Washington. The treatment, glycopyrronium pads (Qbrexza), was approved by the Food and Drug Administration for the topical treatment of primary axillary hyperhidrosis in patients aged 9 years and older in June 2018, and will be available in October 2018.
He presented new data from a 44-week, open-label extension of two pivotal 4-week, phase 3, randomized, double-blind, placebo-controlled trials known as ATMOS-1 and ATMOS-2. The new post hoc analysis from the extension study, known as the ARIDO study, provides reassurance that the product remains both safe and durably effective with longterm use.
Dr. Green’s analysis focused on the 44 pediatric participants aged 9-16 years. That’s because even though primary axillary hyperhidrosis affects people of all ages, with an estimated 4.8% prevalence in the U.S. population – 5.3 million people – it is more common in children and adolescents than adults. And it hits them particularly hard.
“Hyperhidrosis is largely underdiagnosed and undertreated, particularly among pediatric patients,” he said. “The impact on quality of life is comparable to or greater than acne, psoriasis, or eczema.”
The glycopyrronium pad is self-applied as a once-daily wipe. Glycopyrronium is an anticholinergic agent, which blocks sweat production by inhibiting the receptors that activate sweat glands.
Dr. Green noted several key findings from the 44-week ARIDO analysis, presented for the first time at the EADV congress.
The median absolute decrease in sweat production in pediatric patients at 44 weeks as measured gravimetrically was 50.3 mg per 5 minutes from a baseline of 150 mg per 5 minutes, comparable with the mean 75 mg reduction from a baseline of 175 mg in the 507-patient older cohort. However, Dr. Green advised not to make too much of this endpoint, as sweat production is notoriously difficult to measure accurately. In addition, an individual’s sweat rate can vary widely depending upon a multitude of factors, including ambient temperature and even what a patient is thinking about. The FDA recognizes this and therefore elevated several validated patient-reported outcomes to the status of coprimary endpoints in the clinical trials.
A positive result on one such patient-reported outcome, the Hyperhidrosis Severity Scale, was achieved in 57% of pediatric patients and 64% of adults at week 44 of open-label therapy. This required at least a 2-grade improvement from baseline, when roughly 60% of youths had a score of 3 and the remainder scored 4 on the 1-4 point scale.
From a mean baseline score of 9.2 on the Children’s Dermatology Life Quality Index, the pediatric group averaged a mean 6.2-point improvement at week 44, while adults experienced a mean 8.7-point improvement on the Dermatology Life Quality Index from a baseline of 11.25.
There was no diminution in treatment efficacy through 44 weeks, Dr. Green noted. Treatment-emergent adverse events consisted largely of transient mild to moderate anticholinergic effects, which seldom led to study discontinuation.
Dilated pupils and blurred vision were more common in children than adults (7.9% and 10.5% vs. 5.1% and 6.4%, respectively). “Why that is I can only speculate. Kids do tend to touch their eyes more often than adults. Pretty much everything else was the same. The adverse events can be worked around by educating people to use the pads appropriately. We saw the anticholinergic side effects more often in the first 4 weeks of the double-blind trials than in the longterm extension because once patients learned how to use the pad and not touch themselves afterwards, the adverse events came down,” he said.
The studies were sponsored by Dermira. Dr. Green has received research funding from and been a consultant to the company.
PARIS – Two compelling reasons exist to take excessive sweating in children and adolescents more seriously, Lawrence J. Green, MD, asserted at the annual congress of the European Academy of Dermatology and Venereology.
One is that this is a surprisingly common and embarrassing medical condition that can have a profound adverse developmental impact in young people at a time when they are engaged in forming their self-image.
The other reason to get serious about addressing primary axillary hyperhidrosis in pediatric patients is the recent approval of glycopyrronium tosylate as a topical therapy, Dr. Green, a dermatologist at George Washington University, Washington. The treatment, glycopyrronium pads (Qbrexza), was approved by the Food and Drug Administration for the topical treatment of primary axillary hyperhidrosis in patients aged 9 years and older in June 2018, and will be available in October 2018.
He presented new data from a 44-week, open-label extension of two pivotal 4-week, phase 3, randomized, double-blind, placebo-controlled trials known as ATMOS-1 and ATMOS-2. The new post hoc analysis from the extension study, known as the ARIDO study, provides reassurance that the product remains both safe and durably effective with longterm use.
Dr. Green’s analysis focused on the 44 pediatric participants aged 9-16 years. That’s because even though primary axillary hyperhidrosis affects people of all ages, with an estimated 4.8% prevalence in the U.S. population – 5.3 million people – it is more common in children and adolescents than adults. And it hits them particularly hard.
“Hyperhidrosis is largely underdiagnosed and undertreated, particularly among pediatric patients,” he said. “The impact on quality of life is comparable to or greater than acne, psoriasis, or eczema.”
The glycopyrronium pad is self-applied as a once-daily wipe. Glycopyrronium is an anticholinergic agent, which blocks sweat production by inhibiting the receptors that activate sweat glands.
Dr. Green noted several key findings from the 44-week ARIDO analysis, presented for the first time at the EADV congress.
The median absolute decrease in sweat production in pediatric patients at 44 weeks as measured gravimetrically was 50.3 mg per 5 minutes from a baseline of 150 mg per 5 minutes, comparable with the mean 75 mg reduction from a baseline of 175 mg in the 507-patient older cohort. However, Dr. Green advised not to make too much of this endpoint, as sweat production is notoriously difficult to measure accurately. In addition, an individual’s sweat rate can vary widely depending upon a multitude of factors, including ambient temperature and even what a patient is thinking about. The FDA recognizes this and therefore elevated several validated patient-reported outcomes to the status of coprimary endpoints in the clinical trials.
A positive result on one such patient-reported outcome, the Hyperhidrosis Severity Scale, was achieved in 57% of pediatric patients and 64% of adults at week 44 of open-label therapy. This required at least a 2-grade improvement from baseline, when roughly 60% of youths had a score of 3 and the remainder scored 4 on the 1-4 point scale.
From a mean baseline score of 9.2 on the Children’s Dermatology Life Quality Index, the pediatric group averaged a mean 6.2-point improvement at week 44, while adults experienced a mean 8.7-point improvement on the Dermatology Life Quality Index from a baseline of 11.25.
There was no diminution in treatment efficacy through 44 weeks, Dr. Green noted. Treatment-emergent adverse events consisted largely of transient mild to moderate anticholinergic effects, which seldom led to study discontinuation.
Dilated pupils and blurred vision were more common in children than adults (7.9% and 10.5% vs. 5.1% and 6.4%, respectively). “Why that is I can only speculate. Kids do tend to touch their eyes more often than adults. Pretty much everything else was the same. The adverse events can be worked around by educating people to use the pads appropriately. We saw the anticholinergic side effects more often in the first 4 weeks of the double-blind trials than in the longterm extension because once patients learned how to use the pad and not touch themselves afterwards, the adverse events came down,” he said.
The studies were sponsored by Dermira. Dr. Green has received research funding from and been a consultant to the company.
PARIS – Two compelling reasons exist to take excessive sweating in children and adolescents more seriously, Lawrence J. Green, MD, asserted at the annual congress of the European Academy of Dermatology and Venereology.
One is that this is a surprisingly common and embarrassing medical condition that can have a profound adverse developmental impact in young people at a time when they are engaged in forming their self-image.
The other reason to get serious about addressing primary axillary hyperhidrosis in pediatric patients is the recent approval of glycopyrronium tosylate as a topical therapy, Dr. Green, a dermatologist at George Washington University, Washington. The treatment, glycopyrronium pads (Qbrexza), was approved by the Food and Drug Administration for the topical treatment of primary axillary hyperhidrosis in patients aged 9 years and older in June 2018, and will be available in October 2018.
He presented new data from a 44-week, open-label extension of two pivotal 4-week, phase 3, randomized, double-blind, placebo-controlled trials known as ATMOS-1 and ATMOS-2. The new post hoc analysis from the extension study, known as the ARIDO study, provides reassurance that the product remains both safe and durably effective with longterm use.
Dr. Green’s analysis focused on the 44 pediatric participants aged 9-16 years. That’s because even though primary axillary hyperhidrosis affects people of all ages, with an estimated 4.8% prevalence in the U.S. population – 5.3 million people – it is more common in children and adolescents than adults. And it hits them particularly hard.
“Hyperhidrosis is largely underdiagnosed and undertreated, particularly among pediatric patients,” he said. “The impact on quality of life is comparable to or greater than acne, psoriasis, or eczema.”
The glycopyrronium pad is self-applied as a once-daily wipe. Glycopyrronium is an anticholinergic agent, which blocks sweat production by inhibiting the receptors that activate sweat glands.
Dr. Green noted several key findings from the 44-week ARIDO analysis, presented for the first time at the EADV congress.
The median absolute decrease in sweat production in pediatric patients at 44 weeks as measured gravimetrically was 50.3 mg per 5 minutes from a baseline of 150 mg per 5 minutes, comparable with the mean 75 mg reduction from a baseline of 175 mg in the 507-patient older cohort. However, Dr. Green advised not to make too much of this endpoint, as sweat production is notoriously difficult to measure accurately. In addition, an individual’s sweat rate can vary widely depending upon a multitude of factors, including ambient temperature and even what a patient is thinking about. The FDA recognizes this and therefore elevated several validated patient-reported outcomes to the status of coprimary endpoints in the clinical trials.
A positive result on one such patient-reported outcome, the Hyperhidrosis Severity Scale, was achieved in 57% of pediatric patients and 64% of adults at week 44 of open-label therapy. This required at least a 2-grade improvement from baseline, when roughly 60% of youths had a score of 3 and the remainder scored 4 on the 1-4 point scale.
From a mean baseline score of 9.2 on the Children’s Dermatology Life Quality Index, the pediatric group averaged a mean 6.2-point improvement at week 44, while adults experienced a mean 8.7-point improvement on the Dermatology Life Quality Index from a baseline of 11.25.
There was no diminution in treatment efficacy through 44 weeks, Dr. Green noted. Treatment-emergent adverse events consisted largely of transient mild to moderate anticholinergic effects, which seldom led to study discontinuation.
Dilated pupils and blurred vision were more common in children than adults (7.9% and 10.5% vs. 5.1% and 6.4%, respectively). “Why that is I can only speculate. Kids do tend to touch their eyes more often than adults. Pretty much everything else was the same. The adverse events can be worked around by educating people to use the pads appropriately. We saw the anticholinergic side effects more often in the first 4 weeks of the double-blind trials than in the longterm extension because once patients learned how to use the pad and not touch themselves afterwards, the adverse events came down,” he said.
The studies were sponsored by Dermira. Dr. Green has received research funding from and been a consultant to the company.
REPORTING FROM THE EADV CONGRESS
Key clinical point: Glycopyrronium tosylate pads address a common and undertreated medical condition in children: primary axillary hyperhidrosis.
Major finding: Mean scores on the Children’s Dermatology Life Quality Index improved by an average of 6.2 points from a baseline of 9.2 in children aged 9-16 years with primary axillary hyperhidrosis treated with once-daily glycopyrronium tosylate pads during an open-label, 44-week study.
Study details: This was a post hoc analysis of 44 patients aged 9-16 years and 507 patients aged 17 years and older who participated in a 44-week, open-label extension study of once-daily glycopyrronium tosylate pads for treatment of primary axillary hyperhidrosis.
Disclosures: The study was sponsored by Dermira. The presenter has received research funding from and been a consultant to the company.
Rivaroxaban bonus: Early unmasking of occult GI cancers
MUNICH – The increased risk of major GI bleeding documented with dual-antiplatelet therapy using rivaroxaban and aspirin when compared with aspirin alone for vascular protection in the previously reported massive COMPASS trial may turn out to be a blessing in disguise.
“Among COMPASS patients with vascular disease receiving long-term antithrombotic therapy, more than 1 in 5 new diagnoses of cancer are preceded by bleeding. GI and GU bleeding are powerful and relatively specific predictors of new GI and GU cancer diagnoses, respectively, and more than 75% of these cancers diagnosed after bleeding are diagnosed within 6 months of the bleed,” John W. Eikelboom, MD, reported at the annual congress of the European Society of Cardiology.
These findings strongly suggest that rivaroxaban (Xarelto), a direct-acting oral anticoagulant (DOAC), may be unmasking occult GI and GU cancers earlier than the malignancies would otherwise have declared themselves.
“Although overall cancer rates were similar in the three treatment groups [rivaroxaban at 2.5 mg twice daily plus aspirin at 100 mg/day, rivaroxaban monotherapy at 5 mg twice daily, or aspirin alone at 100 mg/day], the early increase in GI bleeding with rivaroxaban-based therapy resulted in earlier diagnosis of GI cancer in these patients. By reducing major cardiovascular events and mortality, the combination of rivaroxaban and aspirin already produces a clear net benefit, and by unmasking GI cancers at an earlier stage, the combination could potentially lead to the added benefit of improved GI cancer outcomes,” commented Dr. Eikelboom, a hematologist at McMaster University in Hamilton, Ont., and lead investigator of the previously published COMPASS trial (N Engl J Med. 2017 Oct 5;377[14]:1319-30).
This possibility that unmasking of occult GI cancer might result in improved survival deserves to be a high research priority in light of the enormous death toll caused by colorectal cancer. Planned longer-term follow-up of the COMPASS participants should be helpful in this regard, he added.
This new COMPASS finding effectively makes a silk purse out of a sow’s ear. When the primary outcomes of COMPASS were announced, many physicians reasoned that if the other commercially available DOACs also outperform warfarin but don’t pose a significantly increased threat of serious bleeding events, why not preferentially turn to them rather than rivaroxaban in patients with high HAS-BLED scores? But now rivaroxaban’s increased GI bleeding risk has begun to look like a potentially important advantage.
As previously reported, COMPASS participants on rivaroxaban plus aspirin had a 3.1% major bleeding rate as defined according to modified International Society on Thrombosis and Hemostasis criteria, for a statistically significant 70% increase in risk, compared with the 1.9% rate in patients on aspirin alone. Rivaroxaban monotherapy also was associated with increased bleeding risk. Of note, most of the excess in bleeding involved GI bleeding, and it was front-loaded during the first year of the trial. Also, reassuringly, there was no increased incidence of intracranial or fatal bleeding in patients on rivaroxaban.
A total of 1,082 patients were diagnosed with a new cancer during 23 months of follow-up. Nearly a quarter (23%) of the new GI cancers and 45% of the new GU cancers were diagnosed after bleeding from those sites.
The incidence of GI cancer diagnosed after GI bleeding was 7.8%, whereas patients with no prior GI bleeding had a mere 0.9% rate of newly diagnosed GI cancer during the study period. Thus, roughly 1 out of every 12 cases of GI bleeding was associated with diagnosis of a new GI cancer, and GI bleeding was associated with a 13-fold increased risk of subsequent GI cancer diagnosis. Put another way, the number of cases of GI bleeding occurring in patients on rivaroxaban that needed to be investigated in order to find one new GI cancer was 12.
Similarly, 13% of COMPASS participants who developed GU bleeding were subsequently diagnosed with a new GU cancer, compared with just 0.3% of subjects without GU bleeding. That translates into an 83.4-fold increased risk of GU cancer in patients with GU bleeding.
In contrast, the incidence of non-GI cancer following a GI bleed was 1.5%, while the rate was 1.0% in patients with no prior GI bleeding.
“That relationship was much weaker, with an odds ratio of 1.77, indicating that the relationship between GI bleeding and GI cancer is not only very strong but it’s rather specific,” according to Dr. Eikelboom.
Of GI cancers associated with a prior major GI bleed, 77% were diagnosed within 6 months following the bleed, as were nearly 89% of GU cancers. Another 9%-10% were diagnosed 6-12 months after the bleeding event.
“The implication for clinical practice is certainly that in patients who have GI or GU bleeding while receiving antithrombotic therapy, we should conduct a vigorous search for underlying cancer in the same organ system,” he concluded.
Discussant Lars C. Wallentin, MD, concurred. He called it a wake-up call for cardiologists to broaden their horizons and recognize that their elderly patients with vascular disease also are at substantial competing risk for major noncardiovascular diseases – and that his colleagues may have an important role to play in earlier cancer diagnoses.
He and his coinvestigators in the RE-LY (Randomized Evaluation of Long-Term Anticoagulant Therapy) study made a similar point in their investigation of 18,113 patients with atrial fibrillation on oral anticoagulation for stroke protection. In that randomized trial of dabigatran (Pradaxa) versus warfarin, roughly 1 in 12 major GI bleeding events was found to be related to an occult colorectal or gastric cancer (Clin Gastroenterol Hepatol. 2017 May;15[5]:682-90).
“The data are very consistent. The message to cardiologists is that no bleeding should be disregarded in patients on oral anticoagulation,” declared Dr. Wallentin, professor of cardiology at Uppsala (Sweden) University.
COMPASS was sponsored by Bayer. Dr. Eikelboom reported receiving research grants from that company and more than half a dozen others.
MUNICH – The increased risk of major GI bleeding documented with dual-antiplatelet therapy using rivaroxaban and aspirin when compared with aspirin alone for vascular protection in the previously reported massive COMPASS trial may turn out to be a blessing in disguise.
“Among COMPASS patients with vascular disease receiving long-term antithrombotic therapy, more than 1 in 5 new diagnoses of cancer are preceded by bleeding. GI and GU bleeding are powerful and relatively specific predictors of new GI and GU cancer diagnoses, respectively, and more than 75% of these cancers diagnosed after bleeding are diagnosed within 6 months of the bleed,” John W. Eikelboom, MD, reported at the annual congress of the European Society of Cardiology.
These findings strongly suggest that rivaroxaban (Xarelto), a direct-acting oral anticoagulant (DOAC), may be unmasking occult GI and GU cancers earlier than the malignancies would otherwise have declared themselves.
“Although overall cancer rates were similar in the three treatment groups [rivaroxaban at 2.5 mg twice daily plus aspirin at 100 mg/day, rivaroxaban monotherapy at 5 mg twice daily, or aspirin alone at 100 mg/day], the early increase in GI bleeding with rivaroxaban-based therapy resulted in earlier diagnosis of GI cancer in these patients. By reducing major cardiovascular events and mortality, the combination of rivaroxaban and aspirin already produces a clear net benefit, and by unmasking GI cancers at an earlier stage, the combination could potentially lead to the added benefit of improved GI cancer outcomes,” commented Dr. Eikelboom, a hematologist at McMaster University in Hamilton, Ont., and lead investigator of the previously published COMPASS trial (N Engl J Med. 2017 Oct 5;377[14]:1319-30).
This possibility that unmasking of occult GI cancer might result in improved survival deserves to be a high research priority in light of the enormous death toll caused by colorectal cancer. Planned longer-term follow-up of the COMPASS participants should be helpful in this regard, he added.
This new COMPASS finding effectively makes a silk purse out of a sow’s ear. When the primary outcomes of COMPASS were announced, many physicians reasoned that if the other commercially available DOACs also outperform warfarin but don’t pose a significantly increased threat of serious bleeding events, why not preferentially turn to them rather than rivaroxaban in patients with high HAS-BLED scores? But now rivaroxaban’s increased GI bleeding risk has begun to look like a potentially important advantage.
As previously reported, COMPASS participants on rivaroxaban plus aspirin had a 3.1% major bleeding rate as defined according to modified International Society on Thrombosis and Hemostasis criteria, for a statistically significant 70% increase in risk, compared with the 1.9% rate in patients on aspirin alone. Rivaroxaban monotherapy also was associated with increased bleeding risk. Of note, most of the excess in bleeding involved GI bleeding, and it was front-loaded during the first year of the trial. Also, reassuringly, there was no increased incidence of intracranial or fatal bleeding in patients on rivaroxaban.
A total of 1,082 patients were diagnosed with a new cancer during 23 months of follow-up. Nearly a quarter (23%) of the new GI cancers and 45% of the new GU cancers were diagnosed after bleeding from those sites.
The incidence of GI cancer diagnosed after GI bleeding was 7.8%, whereas patients with no prior GI bleeding had a mere 0.9% rate of newly diagnosed GI cancer during the study period. Thus, roughly 1 out of every 12 cases of GI bleeding was associated with diagnosis of a new GI cancer, and GI bleeding was associated with a 13-fold increased risk of subsequent GI cancer diagnosis. Put another way, the number of cases of GI bleeding occurring in patients on rivaroxaban that needed to be investigated in order to find one new GI cancer was 12.
Similarly, 13% of COMPASS participants who developed GU bleeding were subsequently diagnosed with a new GU cancer, compared with just 0.3% of subjects without GU bleeding. That translates into an 83.4-fold increased risk of GU cancer in patients with GU bleeding.
In contrast, the incidence of non-GI cancer following a GI bleed was 1.5%, while the rate was 1.0% in patients with no prior GI bleeding.
“That relationship was much weaker, with an odds ratio of 1.77, indicating that the relationship between GI bleeding and GI cancer is not only very strong but it’s rather specific,” according to Dr. Eikelboom.
Of GI cancers associated with a prior major GI bleed, 77% were diagnosed within 6 months following the bleed, as were nearly 89% of GU cancers. Another 9%-10% were diagnosed 6-12 months after the bleeding event.
“The implication for clinical practice is certainly that in patients who have GI or GU bleeding while receiving antithrombotic therapy, we should conduct a vigorous search for underlying cancer in the same organ system,” he concluded.
Discussant Lars C. Wallentin, MD, concurred. He called it a wake-up call for cardiologists to broaden their horizons and recognize that their elderly patients with vascular disease also are at substantial competing risk for major noncardiovascular diseases – and that his colleagues may have an important role to play in earlier cancer diagnoses.
He and his coinvestigators in the RE-LY (Randomized Evaluation of Long-Term Anticoagulant Therapy) study made a similar point in their investigation of 18,113 patients with atrial fibrillation on oral anticoagulation for stroke protection. In that randomized trial of dabigatran (Pradaxa) versus warfarin, roughly 1 in 12 major GI bleeding events was found to be related to an occult colorectal or gastric cancer (Clin Gastroenterol Hepatol. 2017 May;15[5]:682-90).
“The data are very consistent. The message to cardiologists is that no bleeding should be disregarded in patients on oral anticoagulation,” declared Dr. Wallentin, professor of cardiology at Uppsala (Sweden) University.
COMPASS was sponsored by Bayer. Dr. Eikelboom reported receiving research grants from that company and more than half a dozen others.
MUNICH – The increased risk of major GI bleeding documented with dual-antiplatelet therapy using rivaroxaban and aspirin when compared with aspirin alone for vascular protection in the previously reported massive COMPASS trial may turn out to be a blessing in disguise.
“Among COMPASS patients with vascular disease receiving long-term antithrombotic therapy, more than 1 in 5 new diagnoses of cancer are preceded by bleeding. GI and GU bleeding are powerful and relatively specific predictors of new GI and GU cancer diagnoses, respectively, and more than 75% of these cancers diagnosed after bleeding are diagnosed within 6 months of the bleed,” John W. Eikelboom, MD, reported at the annual congress of the European Society of Cardiology.
These findings strongly suggest that rivaroxaban (Xarelto), a direct-acting oral anticoagulant (DOAC), may be unmasking occult GI and GU cancers earlier than the malignancies would otherwise have declared themselves.
“Although overall cancer rates were similar in the three treatment groups [rivaroxaban at 2.5 mg twice daily plus aspirin at 100 mg/day, rivaroxaban monotherapy at 5 mg twice daily, or aspirin alone at 100 mg/day], the early increase in GI bleeding with rivaroxaban-based therapy resulted in earlier diagnosis of GI cancer in these patients. By reducing major cardiovascular events and mortality, the combination of rivaroxaban and aspirin already produces a clear net benefit, and by unmasking GI cancers at an earlier stage, the combination could potentially lead to the added benefit of improved GI cancer outcomes,” commented Dr. Eikelboom, a hematologist at McMaster University in Hamilton, Ont., and lead investigator of the previously published COMPASS trial (N Engl J Med. 2017 Oct 5;377[14]:1319-30).
This possibility that unmasking of occult GI cancer might result in improved survival deserves to be a high research priority in light of the enormous death toll caused by colorectal cancer. Planned longer-term follow-up of the COMPASS participants should be helpful in this regard, he added.
This new COMPASS finding effectively makes a silk purse out of a sow’s ear. When the primary outcomes of COMPASS were announced, many physicians reasoned that if the other commercially available DOACs also outperform warfarin but don’t pose a significantly increased threat of serious bleeding events, why not preferentially turn to them rather than rivaroxaban in patients with high HAS-BLED scores? But now rivaroxaban’s increased GI bleeding risk has begun to look like a potentially important advantage.
As previously reported, COMPASS participants on rivaroxaban plus aspirin had a 3.1% major bleeding rate as defined according to modified International Society on Thrombosis and Hemostasis criteria, for a statistically significant 70% increase in risk, compared with the 1.9% rate in patients on aspirin alone. Rivaroxaban monotherapy also was associated with increased bleeding risk. Of note, most of the excess in bleeding involved GI bleeding, and it was front-loaded during the first year of the trial. Also, reassuringly, there was no increased incidence of intracranial or fatal bleeding in patients on rivaroxaban.
A total of 1,082 patients were diagnosed with a new cancer during 23 months of follow-up. Nearly a quarter (23%) of the new GI cancers and 45% of the new GU cancers were diagnosed after bleeding from those sites.
The incidence of GI cancer diagnosed after GI bleeding was 7.8%, whereas patients with no prior GI bleeding had a mere 0.9% rate of newly diagnosed GI cancer during the study period. Thus, roughly 1 out of every 12 cases of GI bleeding was associated with diagnosis of a new GI cancer, and GI bleeding was associated with a 13-fold increased risk of subsequent GI cancer diagnosis. Put another way, the number of cases of GI bleeding occurring in patients on rivaroxaban that needed to be investigated in order to find one new GI cancer was 12.
Similarly, 13% of COMPASS participants who developed GU bleeding were subsequently diagnosed with a new GU cancer, compared with just 0.3% of subjects without GU bleeding. That translates into an 83.4-fold increased risk of GU cancer in patients with GU bleeding.
In contrast, the incidence of non-GI cancer following a GI bleed was 1.5%, while the rate was 1.0% in patients with no prior GI bleeding.
“That relationship was much weaker, with an odds ratio of 1.77, indicating that the relationship between GI bleeding and GI cancer is not only very strong but it’s rather specific,” according to Dr. Eikelboom.
Of GI cancers associated with a prior major GI bleed, 77% were diagnosed within 6 months following the bleed, as were nearly 89% of GU cancers. Another 9%-10% were diagnosed 6-12 months after the bleeding event.
“The implication for clinical practice is certainly that in patients who have GI or GU bleeding while receiving antithrombotic therapy, we should conduct a vigorous search for underlying cancer in the same organ system,” he concluded.
Discussant Lars C. Wallentin, MD, concurred. He called it a wake-up call for cardiologists to broaden their horizons and recognize that their elderly patients with vascular disease also are at substantial competing risk for major noncardiovascular diseases – and that his colleagues may have an important role to play in earlier cancer diagnoses.
He and his coinvestigators in the RE-LY (Randomized Evaluation of Long-Term Anticoagulant Therapy) study made a similar point in their investigation of 18,113 patients with atrial fibrillation on oral anticoagulation for stroke protection. In that randomized trial of dabigatran (Pradaxa) versus warfarin, roughly 1 in 12 major GI bleeding events was found to be related to an occult colorectal or gastric cancer (Clin Gastroenterol Hepatol. 2017 May;15[5]:682-90).
“The data are very consistent. The message to cardiologists is that no bleeding should be disregarded in patients on oral anticoagulation,” declared Dr. Wallentin, professor of cardiology at Uppsala (Sweden) University.
COMPASS was sponsored by Bayer. Dr. Eikelboom reported receiving research grants from that company and more than half a dozen others.
REPORTING FROM THE ESC CONGRESS 2018
Key clinical point:
Major finding: Among patients on rivaroxaban, 1 in 12 GI bleeding events was associated with an occult GI cancer.
Study details: This was a secondary analysis looking at cancers in COMPASS, a randomized trial of more than 27,000 patients on rivaroxaban and/or aspirin for vascular prevention.
Disclosures: The presenter reported receiving research grants from Bayer, which sponsored the COMPASS trial.