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Unblinded data show extent of verubecestat’s failure in mild-moderate Alzheimer’s
BOSTON – The Alzheimer’s research community absorbed yet another downer recently, when Merck scientists revealed the unblinded efficacy and safety data of EPOCH, the company’s failed verubecestat trial: The BACE inhibitor didn’t score in any endpoint, no matter how the data were sliced and diced.
Merck halted the study last February, when an interim analysis determined there was no chance of a positive outcome. No safety data played into the decision, officials said. At the time of discontinuation, Merck had not yet examined the unblinded data, which were released to a packed audience at the Clinical Trials on Alzheimer’s Disease conference in Boston.
Compared with placebo, the nonselective beta-secretase (BACE) inhibitor conferred no cognitive or functional benefit upon patients with mild-moderate Alzheimer’s disease, either in the overall analysis or in any age, disease stage, or genetic subgroup, Michael Egan, MD, said during a panel discussion. And although there was plenty of biomarker evidence that the drug did block beta amyloid production, there was also a plethora of concerning adverse events.
However, the failure of yet another antiamyloid drug doesn’t mean that researchers should abandon amyloid as a therapeutic target, said Dr. Egan, Merck’s associate vice president of clinical neuroscience. Verubecestat is still being investigated in the APECS study of patients with mild cognitive impairment, and a number of antiamyloid antibodies are still going forward in patients whose disease stages run from preclinical to moderate.
“It’s still possible that we may see a clinical benefit in some of these studies, so we have to keep an open mind,” Dr. Egan said.
EPOCH, a pivotal phase 2/3 trial, randomized about 1,200 patients with mild-moderate Alzheimer’s to either placebo or verubecestat 12 mg or 40 mg daily for 18 months. None of the patients had amyloid PET imaging, but in subsets of patients who had the imaging or lumbar puncture for Abeta levels, 90% were amyloid-positive. The primary efficacy outcomes were the change from baseline in the Alzheimer’s Disease Assessment Scale Cognitive Subscale (ADAS-Cog) score and the change from baseline in the Alzheimer’s Disease Cooperative Study–Activities of Daily Living (ADCS-ADL) score.
There were a number of secondary endpoints, including the Clinical Dementia Rating–Sum of Boxes (CDR-sb); total hippocampal volume; cerebrospinal fluid total and phosphorylated tau; changes on the Neuropsychiatric Index and Mini Mental State Exam; and brain amyloid burden.
In a nutshell, Dr. Egan said, there was virtually no efficacy signal on any of the primary or secondary endpoints. On the ADAS-Cog, all patients, regardless of treatment group, lost 7-8 points over the trial. The same was true for the ADCS-ADL, with everyone declining about 8 points over time. On the CDR-sb, all groups declined about 2 points.
“We also looked at a number of subgroups: younger subjects, those with earlier disease, and those who we knew were amyloid-positive, including all of our ApoE4 carriers. We found no evidence of efficacy in any subgroup.”
It is “worth noting,” Dr. Egan said, that in the amyloid PET substudy, there were treatment-related reductions in plaque burden. While those taking placebo showed no changes in brain amyloid, the 12-mg group experienced a mean 2% reduction in amyloid, and the 40-mg group, a 4% reduction. “While this is modest, it does show target engagement,” Dr. Egan said – an important and positive finding in light of the ongoing APECS study.
The study of cerebrospinal fluid showed no effect on either tau protein, but marked, dose-related reductions in Abeta1-40 and soluble amyloid precursor protein – both products of BACE cleavage of the amyloid precursor protein. “We saw a 70% reduction in the 12-mg group and more than an 80% reduction in the 40-mg group, but no change in the placebo group. This is an important finding, demonstrating that the drug got into the brain and turned off production of Abeta. EPOCH is the first phase 3 study of an antiamyloid agent where target engagement of this magnitude has been demonstrated.”
Verubecestat also had its share of adverse events, Dr. Egan said. The most common was rash, which developed in about 10%; 20% of those who developed rash discontinued treatment for that reason. More concerning were falls and injuries; diarrhea and weight loss; and a variety of neuropsychiatric events, including insomnia and sleep disorders, anxiety, depression, and suicidal ideation.*
The drug was also associated with more loss of hippocampal volume, compared with placebo (5.7% vs. 5%), Dr. Egan said in an interview. The etiology isn’t clear; he suggested that it could be related to amyloid plaque removal, resolution of neuroinflammation, or an actual worsening of neurodegeneration. “That is a concerning possibility, although if that were the case we would expect to see worsening cognition, which we did not.”
Falls and injuries occurred in 15% of the placebo group and 20%-23% of the active groups. A detailed analysis didn’t turn up any specific risk factors, though. The episodes of suicidal ideation were passive and more common in the first 6 months of treatment and among patients who had a history of depression or prior suicidal ideation. Four patients discontinued due to that side effect.
Verubecestat is a nonselective inhibitor of both BACE1 and BACE2, and it’s not clear if that wide-ranging inhibition increased the likelihood of adverse events over what might be seen with a more selective compound. “It’s difficult to attribute them to BACE2 over BACE1,” Dr. Egan said. “Any BACE inhibitor could potentially have similar side effects.”
Only time will provide those answers; BACE inhibition is an area of active investigation among several large companies. The newly announced Generation studies will test a selective BACE1 inhibitor called CNP520.
Eli Lilly is recruiting for a phase 2 study of its BACE1 inhibitor, dubbed LY3202626. AstraZeneca is also looking at BACE1 inhibition with its candidate, lanabecestat.
Dr. Egan remains hopeful, though, and said that Merck retains its commitment to bringing an effective Alzheimer’s treatment to market.
“It’s natural to get discouraged with negative trials, and there certainly have been a lot of them. But I think we have to continue to work very hard to try and find something to help patients, and we have more and more knowledge every year about how to do that. I believe BACE inhibition continues to offer the possibility that if we treat earlier that there could be benefit, but for those with dementia, BACE inhibition is just too late.”
Dr. Egan is employed by Merck Sharp & Dohme, which sponsored EPOCH.
This article was updated 11/16/17.
Correction, 11/20/17: An earlier version of this article misstated the percentage of patients who experienced rash.
[email protected]
On Twitter @Alz_Gal
BOSTON – The Alzheimer’s research community absorbed yet another downer recently, when Merck scientists revealed the unblinded efficacy and safety data of EPOCH, the company’s failed verubecestat trial: The BACE inhibitor didn’t score in any endpoint, no matter how the data were sliced and diced.
Merck halted the study last February, when an interim analysis determined there was no chance of a positive outcome. No safety data played into the decision, officials said. At the time of discontinuation, Merck had not yet examined the unblinded data, which were released to a packed audience at the Clinical Trials on Alzheimer’s Disease conference in Boston.
Compared with placebo, the nonselective beta-secretase (BACE) inhibitor conferred no cognitive or functional benefit upon patients with mild-moderate Alzheimer’s disease, either in the overall analysis or in any age, disease stage, or genetic subgroup, Michael Egan, MD, said during a panel discussion. And although there was plenty of biomarker evidence that the drug did block beta amyloid production, there was also a plethora of concerning adverse events.
However, the failure of yet another antiamyloid drug doesn’t mean that researchers should abandon amyloid as a therapeutic target, said Dr. Egan, Merck’s associate vice president of clinical neuroscience. Verubecestat is still being investigated in the APECS study of patients with mild cognitive impairment, and a number of antiamyloid antibodies are still going forward in patients whose disease stages run from preclinical to moderate.
“It’s still possible that we may see a clinical benefit in some of these studies, so we have to keep an open mind,” Dr. Egan said.
EPOCH, a pivotal phase 2/3 trial, randomized about 1,200 patients with mild-moderate Alzheimer’s to either placebo or verubecestat 12 mg or 40 mg daily for 18 months. None of the patients had amyloid PET imaging, but in subsets of patients who had the imaging or lumbar puncture for Abeta levels, 90% were amyloid-positive. The primary efficacy outcomes were the change from baseline in the Alzheimer’s Disease Assessment Scale Cognitive Subscale (ADAS-Cog) score and the change from baseline in the Alzheimer’s Disease Cooperative Study–Activities of Daily Living (ADCS-ADL) score.
There were a number of secondary endpoints, including the Clinical Dementia Rating–Sum of Boxes (CDR-sb); total hippocampal volume; cerebrospinal fluid total and phosphorylated tau; changes on the Neuropsychiatric Index and Mini Mental State Exam; and brain amyloid burden.
In a nutshell, Dr. Egan said, there was virtually no efficacy signal on any of the primary or secondary endpoints. On the ADAS-Cog, all patients, regardless of treatment group, lost 7-8 points over the trial. The same was true for the ADCS-ADL, with everyone declining about 8 points over time. On the CDR-sb, all groups declined about 2 points.
“We also looked at a number of subgroups: younger subjects, those with earlier disease, and those who we knew were amyloid-positive, including all of our ApoE4 carriers. We found no evidence of efficacy in any subgroup.”
It is “worth noting,” Dr. Egan said, that in the amyloid PET substudy, there were treatment-related reductions in plaque burden. While those taking placebo showed no changes in brain amyloid, the 12-mg group experienced a mean 2% reduction in amyloid, and the 40-mg group, a 4% reduction. “While this is modest, it does show target engagement,” Dr. Egan said – an important and positive finding in light of the ongoing APECS study.
The study of cerebrospinal fluid showed no effect on either tau protein, but marked, dose-related reductions in Abeta1-40 and soluble amyloid precursor protein – both products of BACE cleavage of the amyloid precursor protein. “We saw a 70% reduction in the 12-mg group and more than an 80% reduction in the 40-mg group, but no change in the placebo group. This is an important finding, demonstrating that the drug got into the brain and turned off production of Abeta. EPOCH is the first phase 3 study of an antiamyloid agent where target engagement of this magnitude has been demonstrated.”
Verubecestat also had its share of adverse events, Dr. Egan said. The most common was rash, which developed in about 10%; 20% of those who developed rash discontinued treatment for that reason. More concerning were falls and injuries; diarrhea and weight loss; and a variety of neuropsychiatric events, including insomnia and sleep disorders, anxiety, depression, and suicidal ideation.*
The drug was also associated with more loss of hippocampal volume, compared with placebo (5.7% vs. 5%), Dr. Egan said in an interview. The etiology isn’t clear; he suggested that it could be related to amyloid plaque removal, resolution of neuroinflammation, or an actual worsening of neurodegeneration. “That is a concerning possibility, although if that were the case we would expect to see worsening cognition, which we did not.”
Falls and injuries occurred in 15% of the placebo group and 20%-23% of the active groups. A detailed analysis didn’t turn up any specific risk factors, though. The episodes of suicidal ideation were passive and more common in the first 6 months of treatment and among patients who had a history of depression or prior suicidal ideation. Four patients discontinued due to that side effect.
Verubecestat is a nonselective inhibitor of both BACE1 and BACE2, and it’s not clear if that wide-ranging inhibition increased the likelihood of adverse events over what might be seen with a more selective compound. “It’s difficult to attribute them to BACE2 over BACE1,” Dr. Egan said. “Any BACE inhibitor could potentially have similar side effects.”
Only time will provide those answers; BACE inhibition is an area of active investigation among several large companies. The newly announced Generation studies will test a selective BACE1 inhibitor called CNP520.
Eli Lilly is recruiting for a phase 2 study of its BACE1 inhibitor, dubbed LY3202626. AstraZeneca is also looking at BACE1 inhibition with its candidate, lanabecestat.
Dr. Egan remains hopeful, though, and said that Merck retains its commitment to bringing an effective Alzheimer’s treatment to market.
“It’s natural to get discouraged with negative trials, and there certainly have been a lot of them. But I think we have to continue to work very hard to try and find something to help patients, and we have more and more knowledge every year about how to do that. I believe BACE inhibition continues to offer the possibility that if we treat earlier that there could be benefit, but for those with dementia, BACE inhibition is just too late.”
Dr. Egan is employed by Merck Sharp & Dohme, which sponsored EPOCH.
This article was updated 11/16/17.
Correction, 11/20/17: An earlier version of this article misstated the percentage of patients who experienced rash.
[email protected]
On Twitter @Alz_Gal
BOSTON – The Alzheimer’s research community absorbed yet another downer recently, when Merck scientists revealed the unblinded efficacy and safety data of EPOCH, the company’s failed verubecestat trial: The BACE inhibitor didn’t score in any endpoint, no matter how the data were sliced and diced.
Merck halted the study last February, when an interim analysis determined there was no chance of a positive outcome. No safety data played into the decision, officials said. At the time of discontinuation, Merck had not yet examined the unblinded data, which were released to a packed audience at the Clinical Trials on Alzheimer’s Disease conference in Boston.
Compared with placebo, the nonselective beta-secretase (BACE) inhibitor conferred no cognitive or functional benefit upon patients with mild-moderate Alzheimer’s disease, either in the overall analysis or in any age, disease stage, or genetic subgroup, Michael Egan, MD, said during a panel discussion. And although there was plenty of biomarker evidence that the drug did block beta amyloid production, there was also a plethora of concerning adverse events.
However, the failure of yet another antiamyloid drug doesn’t mean that researchers should abandon amyloid as a therapeutic target, said Dr. Egan, Merck’s associate vice president of clinical neuroscience. Verubecestat is still being investigated in the APECS study of patients with mild cognitive impairment, and a number of antiamyloid antibodies are still going forward in patients whose disease stages run from preclinical to moderate.
“It’s still possible that we may see a clinical benefit in some of these studies, so we have to keep an open mind,” Dr. Egan said.
EPOCH, a pivotal phase 2/3 trial, randomized about 1,200 patients with mild-moderate Alzheimer’s to either placebo or verubecestat 12 mg or 40 mg daily for 18 months. None of the patients had amyloid PET imaging, but in subsets of patients who had the imaging or lumbar puncture for Abeta levels, 90% were amyloid-positive. The primary efficacy outcomes were the change from baseline in the Alzheimer’s Disease Assessment Scale Cognitive Subscale (ADAS-Cog) score and the change from baseline in the Alzheimer’s Disease Cooperative Study–Activities of Daily Living (ADCS-ADL) score.
There were a number of secondary endpoints, including the Clinical Dementia Rating–Sum of Boxes (CDR-sb); total hippocampal volume; cerebrospinal fluid total and phosphorylated tau; changes on the Neuropsychiatric Index and Mini Mental State Exam; and brain amyloid burden.
In a nutshell, Dr. Egan said, there was virtually no efficacy signal on any of the primary or secondary endpoints. On the ADAS-Cog, all patients, regardless of treatment group, lost 7-8 points over the trial. The same was true for the ADCS-ADL, with everyone declining about 8 points over time. On the CDR-sb, all groups declined about 2 points.
“We also looked at a number of subgroups: younger subjects, those with earlier disease, and those who we knew were amyloid-positive, including all of our ApoE4 carriers. We found no evidence of efficacy in any subgroup.”
It is “worth noting,” Dr. Egan said, that in the amyloid PET substudy, there were treatment-related reductions in plaque burden. While those taking placebo showed no changes in brain amyloid, the 12-mg group experienced a mean 2% reduction in amyloid, and the 40-mg group, a 4% reduction. “While this is modest, it does show target engagement,” Dr. Egan said – an important and positive finding in light of the ongoing APECS study.
The study of cerebrospinal fluid showed no effect on either tau protein, but marked, dose-related reductions in Abeta1-40 and soluble amyloid precursor protein – both products of BACE cleavage of the amyloid precursor protein. “We saw a 70% reduction in the 12-mg group and more than an 80% reduction in the 40-mg group, but no change in the placebo group. This is an important finding, demonstrating that the drug got into the brain and turned off production of Abeta. EPOCH is the first phase 3 study of an antiamyloid agent where target engagement of this magnitude has been demonstrated.”
Verubecestat also had its share of adverse events, Dr. Egan said. The most common was rash, which developed in about 10%; 20% of those who developed rash discontinued treatment for that reason. More concerning were falls and injuries; diarrhea and weight loss; and a variety of neuropsychiatric events, including insomnia and sleep disorders, anxiety, depression, and suicidal ideation.*
The drug was also associated with more loss of hippocampal volume, compared with placebo (5.7% vs. 5%), Dr. Egan said in an interview. The etiology isn’t clear; he suggested that it could be related to amyloid plaque removal, resolution of neuroinflammation, or an actual worsening of neurodegeneration. “That is a concerning possibility, although if that were the case we would expect to see worsening cognition, which we did not.”
Falls and injuries occurred in 15% of the placebo group and 20%-23% of the active groups. A detailed analysis didn’t turn up any specific risk factors, though. The episodes of suicidal ideation were passive and more common in the first 6 months of treatment and among patients who had a history of depression or prior suicidal ideation. Four patients discontinued due to that side effect.
Verubecestat is a nonselective inhibitor of both BACE1 and BACE2, and it’s not clear if that wide-ranging inhibition increased the likelihood of adverse events over what might be seen with a more selective compound. “It’s difficult to attribute them to BACE2 over BACE1,” Dr. Egan said. “Any BACE inhibitor could potentially have similar side effects.”
Only time will provide those answers; BACE inhibition is an area of active investigation among several large companies. The newly announced Generation studies will test a selective BACE1 inhibitor called CNP520.
Eli Lilly is recruiting for a phase 2 study of its BACE1 inhibitor, dubbed LY3202626. AstraZeneca is also looking at BACE1 inhibition with its candidate, lanabecestat.
Dr. Egan remains hopeful, though, and said that Merck retains its commitment to bringing an effective Alzheimer’s treatment to market.
“It’s natural to get discouraged with negative trials, and there certainly have been a lot of them. But I think we have to continue to work very hard to try and find something to help patients, and we have more and more knowledge every year about how to do that. I believe BACE inhibition continues to offer the possibility that if we treat earlier that there could be benefit, but for those with dementia, BACE inhibition is just too late.”
Dr. Egan is employed by Merck Sharp & Dohme, which sponsored EPOCH.
This article was updated 11/16/17.
Correction, 11/20/17: An earlier version of this article misstated the percentage of patients who experienced rash.
[email protected]
On Twitter @Alz_Gal
AT CTAD
Key clinical point:
Major finding: On the ADAS-Cog score, all patients, regardless of treatment group, lost 7-8 points over the trial. The same was true for the ADCS-ADL score, with everyone declining about 8 points over time. On the CDR-sb, all groups declined about 2 points.
Data source: EPOCH, a pivotal phase 2/3 trial, randomized about 1,200 patients with mild-moderate Alzheimer’s to either placebo or verubecestat 12 mg or 40 mg daily for 18 months.
Disclosures: Dr. Egan is employed by Merck Sharp & Dohme, which sponsored EPOCH.
Amyloid imaging changed management for 80% of patients with uncertain dementia diagnosis
BOSTON – Amyloid imaging with the PET agent florbetaben changed the clinical management of 80% of dementia patients with a complicated or uncertain presentation, Mathieu Ceccaldi, MD, reported at the Clinical Trials on Alzheimer’s Disease conference.
The French real-world study also found that 51% of the patients had a medication change after their amyloid imaging study, said Dr. Ceccaldi, a neurologist at the Timone Hospital in Marseille, France.
“In daily practice, we are sometimes faced with complex presentations and diagnostic uncertainty in patients who have early onset dementia, atypical nonamnestic dementia, unusual behavioral symptoms, or an unexpected rate of progression,” he said. “Amyloid imaging can help resolve those issues.”
The results echo – and even exceed – those returned in an interim analysis of the large U.S.-based Imaging Dementia–Evidence for Amyloid Scanning study. The IDEAS study is examining how amyloid imaging with the PET agent florbetapir may change clinical management of dementia patients. According to data presented at last summer’s Alzheimer’s Association International Conference, knowledge of patients’ brain amyloid status changed clinical management in 68% of cases.
In France, as in the United States, amyloid imaging is not routinely available outside of clinical research programs. French patients normally undergo a lumbar puncture (LP) to obtain amyloid biomarkers. However, if an LP isn’t feasible because of the patient’s clinical condition, it’s attempted and fails, the patient refuses, or the results are unclear, then imaging may be employed.
Dr. Ceccaldi’s study comprised 205 such patients seen in any of 18 memory clinics for dementia of uncertain etiology. The study evaluated how often amyloid PET imaging with florbetaben changed the patient’s diagnosis or management and how often it contributed to improving diagnostic uncertainty.
The patients were a mean of 71 years old, with a mean Mini-Mental State Exam score of 22. An LP had been performed in 42%, but those results were either ambiguous or inconsistent with the patient’s clinical presentation. Other patients (37%) refused the procedure, and the rest had a medical contraindication to LP or had a failed procedure.
The most common diagnosis at baseline was Alzheimer’s dementia (72%), which included typical and atypical sporadic AD, young-onset AD, and rapidly progressing AD. In 16% of the cohort, the diagnosis was non-Alzheimer’s dementia, including frontotemporal dementia, primary progressive aphasia, Lewy body dementia, corticobasal degeneration, semantic dementia, and Parkinson’s disease dementia. The diagnosis was mixed dementia in 8% and nonneurodegenerative dementia in the remainder – a catchall that included vascular dementia, psychiatric disorders, and other forms of dementia.
Imaging determined that 73 patients were amyloid negative and that 132 patients were amyloid positive. These results changed diagnosis in 67% of cases overall, in 58% of amyloid-positive patients, and in 84% of amyloid-negative patients.
In the absence of cerebrospinal fluid data, florbetaben imaging significantly improved diagnostic confidence in 81% of the entire cohort (167 patients). Before imaging, clinicians rated fewer than 5% of their diagnoses as very highly confident; this rose to nearly 100% after imaging. Similarly, before imaging, about 40% of clinicians said they had weak confidence in their initial diagnoses; this dropped to fewer than 5% after imaging.
Of the 67% with a changed diagnosis (137 patients), 76 were amyloid positive, and 61 were amyloid negative. Positive scans reclassified 18 patients as having AD; negative scans removed an AD diagnosis for 38 patients.
AD was the most commonly altered diagnosis, dropping from 72% to 62% of the entire cohort. The proportion of those with non-AD dementia increased from 16% before imaging to 18% after. Mixed dementias decreased from 8% to 5%, and the number diagnosed with nonneurodegenerative dementias increased from 5% to 17%.
In particular, Dr. Ceccaldi noted, the number of patients with potentially treatable nonneurodegenerative dementia rose from 10 to 35. These included revised diagnoses for those with psychiatric disorders (from 3 patients before imaging to 11 patients after), vascular dementias (from 2 to 8 patients), and other treatable causes of dementia (from 5 to 16 patients).
All of these altered diagnoses changed management in 80% of both positive and negative patients. Among these changes were the addition of a new medication (50% of amyloid-positive patients, 18% of amyloid-negative patients), the withdrawal of a medication (15% of amyloid-negative cases), additional testing (5% of amyloid-positive cases, 20% of amyloid-negative cases), and referral to another specialist (5% of amyloid-positive patients, 20% of amyloid-negative patients).
“Our results highlight the significant utility of amyloid PET for patients with complex dementia presentations in the context of the existing work-up,” Dr. Ceccaldi said.
He reported financial relationships with a number of pharmaceutical companies, including Piramal, which developed and manufactures florbetaben.
[email protected]
On Twitter @alz_gal
BOSTON – Amyloid imaging with the PET agent florbetaben changed the clinical management of 80% of dementia patients with a complicated or uncertain presentation, Mathieu Ceccaldi, MD, reported at the Clinical Trials on Alzheimer’s Disease conference.
The French real-world study also found that 51% of the patients had a medication change after their amyloid imaging study, said Dr. Ceccaldi, a neurologist at the Timone Hospital in Marseille, France.
“In daily practice, we are sometimes faced with complex presentations and diagnostic uncertainty in patients who have early onset dementia, atypical nonamnestic dementia, unusual behavioral symptoms, or an unexpected rate of progression,” he said. “Amyloid imaging can help resolve those issues.”
The results echo – and even exceed – those returned in an interim analysis of the large U.S.-based Imaging Dementia–Evidence for Amyloid Scanning study. The IDEAS study is examining how amyloid imaging with the PET agent florbetapir may change clinical management of dementia patients. According to data presented at last summer’s Alzheimer’s Association International Conference, knowledge of patients’ brain amyloid status changed clinical management in 68% of cases.
In France, as in the United States, amyloid imaging is not routinely available outside of clinical research programs. French patients normally undergo a lumbar puncture (LP) to obtain amyloid biomarkers. However, if an LP isn’t feasible because of the patient’s clinical condition, it’s attempted and fails, the patient refuses, or the results are unclear, then imaging may be employed.
Dr. Ceccaldi’s study comprised 205 such patients seen in any of 18 memory clinics for dementia of uncertain etiology. The study evaluated how often amyloid PET imaging with florbetaben changed the patient’s diagnosis or management and how often it contributed to improving diagnostic uncertainty.
The patients were a mean of 71 years old, with a mean Mini-Mental State Exam score of 22. An LP had been performed in 42%, but those results were either ambiguous or inconsistent with the patient’s clinical presentation. Other patients (37%) refused the procedure, and the rest had a medical contraindication to LP or had a failed procedure.
The most common diagnosis at baseline was Alzheimer’s dementia (72%), which included typical and atypical sporadic AD, young-onset AD, and rapidly progressing AD. In 16% of the cohort, the diagnosis was non-Alzheimer’s dementia, including frontotemporal dementia, primary progressive aphasia, Lewy body dementia, corticobasal degeneration, semantic dementia, and Parkinson’s disease dementia. The diagnosis was mixed dementia in 8% and nonneurodegenerative dementia in the remainder – a catchall that included vascular dementia, psychiatric disorders, and other forms of dementia.
Imaging determined that 73 patients were amyloid negative and that 132 patients were amyloid positive. These results changed diagnosis in 67% of cases overall, in 58% of amyloid-positive patients, and in 84% of amyloid-negative patients.
In the absence of cerebrospinal fluid data, florbetaben imaging significantly improved diagnostic confidence in 81% of the entire cohort (167 patients). Before imaging, clinicians rated fewer than 5% of their diagnoses as very highly confident; this rose to nearly 100% after imaging. Similarly, before imaging, about 40% of clinicians said they had weak confidence in their initial diagnoses; this dropped to fewer than 5% after imaging.
Of the 67% with a changed diagnosis (137 patients), 76 were amyloid positive, and 61 were amyloid negative. Positive scans reclassified 18 patients as having AD; negative scans removed an AD diagnosis for 38 patients.
AD was the most commonly altered diagnosis, dropping from 72% to 62% of the entire cohort. The proportion of those with non-AD dementia increased from 16% before imaging to 18% after. Mixed dementias decreased from 8% to 5%, and the number diagnosed with nonneurodegenerative dementias increased from 5% to 17%.
In particular, Dr. Ceccaldi noted, the number of patients with potentially treatable nonneurodegenerative dementia rose from 10 to 35. These included revised diagnoses for those with psychiatric disorders (from 3 patients before imaging to 11 patients after), vascular dementias (from 2 to 8 patients), and other treatable causes of dementia (from 5 to 16 patients).
All of these altered diagnoses changed management in 80% of both positive and negative patients. Among these changes were the addition of a new medication (50% of amyloid-positive patients, 18% of amyloid-negative patients), the withdrawal of a medication (15% of amyloid-negative cases), additional testing (5% of amyloid-positive cases, 20% of amyloid-negative cases), and referral to another specialist (5% of amyloid-positive patients, 20% of amyloid-negative patients).
“Our results highlight the significant utility of amyloid PET for patients with complex dementia presentations in the context of the existing work-up,” Dr. Ceccaldi said.
He reported financial relationships with a number of pharmaceutical companies, including Piramal, which developed and manufactures florbetaben.
[email protected]
On Twitter @alz_gal
BOSTON – Amyloid imaging with the PET agent florbetaben changed the clinical management of 80% of dementia patients with a complicated or uncertain presentation, Mathieu Ceccaldi, MD, reported at the Clinical Trials on Alzheimer’s Disease conference.
The French real-world study also found that 51% of the patients had a medication change after their amyloid imaging study, said Dr. Ceccaldi, a neurologist at the Timone Hospital in Marseille, France.
“In daily practice, we are sometimes faced with complex presentations and diagnostic uncertainty in patients who have early onset dementia, atypical nonamnestic dementia, unusual behavioral symptoms, or an unexpected rate of progression,” he said. “Amyloid imaging can help resolve those issues.”
The results echo – and even exceed – those returned in an interim analysis of the large U.S.-based Imaging Dementia–Evidence for Amyloid Scanning study. The IDEAS study is examining how amyloid imaging with the PET agent florbetapir may change clinical management of dementia patients. According to data presented at last summer’s Alzheimer’s Association International Conference, knowledge of patients’ brain amyloid status changed clinical management in 68% of cases.
In France, as in the United States, amyloid imaging is not routinely available outside of clinical research programs. French patients normally undergo a lumbar puncture (LP) to obtain amyloid biomarkers. However, if an LP isn’t feasible because of the patient’s clinical condition, it’s attempted and fails, the patient refuses, or the results are unclear, then imaging may be employed.
Dr. Ceccaldi’s study comprised 205 such patients seen in any of 18 memory clinics for dementia of uncertain etiology. The study evaluated how often amyloid PET imaging with florbetaben changed the patient’s diagnosis or management and how often it contributed to improving diagnostic uncertainty.
The patients were a mean of 71 years old, with a mean Mini-Mental State Exam score of 22. An LP had been performed in 42%, but those results were either ambiguous or inconsistent with the patient’s clinical presentation. Other patients (37%) refused the procedure, and the rest had a medical contraindication to LP or had a failed procedure.
The most common diagnosis at baseline was Alzheimer’s dementia (72%), which included typical and atypical sporadic AD, young-onset AD, and rapidly progressing AD. In 16% of the cohort, the diagnosis was non-Alzheimer’s dementia, including frontotemporal dementia, primary progressive aphasia, Lewy body dementia, corticobasal degeneration, semantic dementia, and Parkinson’s disease dementia. The diagnosis was mixed dementia in 8% and nonneurodegenerative dementia in the remainder – a catchall that included vascular dementia, psychiatric disorders, and other forms of dementia.
Imaging determined that 73 patients were amyloid negative and that 132 patients were amyloid positive. These results changed diagnosis in 67% of cases overall, in 58% of amyloid-positive patients, and in 84% of amyloid-negative patients.
In the absence of cerebrospinal fluid data, florbetaben imaging significantly improved diagnostic confidence in 81% of the entire cohort (167 patients). Before imaging, clinicians rated fewer than 5% of their diagnoses as very highly confident; this rose to nearly 100% after imaging. Similarly, before imaging, about 40% of clinicians said they had weak confidence in their initial diagnoses; this dropped to fewer than 5% after imaging.
Of the 67% with a changed diagnosis (137 patients), 76 were amyloid positive, and 61 were amyloid negative. Positive scans reclassified 18 patients as having AD; negative scans removed an AD diagnosis for 38 patients.
AD was the most commonly altered diagnosis, dropping from 72% to 62% of the entire cohort. The proportion of those with non-AD dementia increased from 16% before imaging to 18% after. Mixed dementias decreased from 8% to 5%, and the number diagnosed with nonneurodegenerative dementias increased from 5% to 17%.
In particular, Dr. Ceccaldi noted, the number of patients with potentially treatable nonneurodegenerative dementia rose from 10 to 35. These included revised diagnoses for those with psychiatric disorders (from 3 patients before imaging to 11 patients after), vascular dementias (from 2 to 8 patients), and other treatable causes of dementia (from 5 to 16 patients).
All of these altered diagnoses changed management in 80% of both positive and negative patients. Among these changes were the addition of a new medication (50% of amyloid-positive patients, 18% of amyloid-negative patients), the withdrawal of a medication (15% of amyloid-negative cases), additional testing (5% of amyloid-positive cases, 20% of amyloid-negative cases), and referral to another specialist (5% of amyloid-positive patients, 20% of amyloid-negative patients).
“Our results highlight the significant utility of amyloid PET for patients with complex dementia presentations in the context of the existing work-up,” Dr. Ceccaldi said.
He reported financial relationships with a number of pharmaceutical companies, including Piramal, which developed and manufactures florbetaben.
[email protected]
On Twitter @alz_gal
AT CTAD
Key clinical point:
Major finding: A majority of patients (80%) experienced a change in management, including drugs added or withdrawn, or referral to another specialist.
Data source: A naturalistic, clinic-based study comprising 205 patients.
Disclosures: Dr. Ceccaldi reported financial relationships with several pharmaceutical companies, including Piramal, which developed and manufactures florbetaben.
Genotype-guided warfarin dosing reduced adverse events in arthroplasty patients
The difference in the composite endpoint (major bleeding within 30 days, international normalized ratio [INR] of 4 or greater within 30 days, venous thromboembolism within 60 days, or death within 30 days) in the Genetic Informatics Trial of Warfarin to Prevent Deep Vein Thrombosis (GIFT) trial was mainly driven by a significant difference in episodes of elevated INR, reported Brian F. Gage, MD, and his colleagues (JAMA 2017;318[12]:1115-1124. doi: 10.1001/jama.2017.11469).
A total of 1,597 patients completed the trial. Of 808 patients in the genotype-guided group, 10.8% met one of the endpoints. Of 789 in the clinically guided warfarin dosing group, 14.7% met at least 1 of the endpoints. There were no deaths in the study.
“Widespread use of genotype-guided dosing will depend on reimbursement, regulations, and logistics. Although several commercial platforms for warfarin-related genes have been approved by the Food and Drug Administration and the European Medicines Agency, routine genotyping is not yet recommended,” wrote Dr. Gage of Washington University, St. Louis, and his coauthors.
The Centers for Medicare and Medicaid Services used its Coverage with Evidence Development program to fund genotyping in this trial and will review the results to determine future coverage, the researchers added.
In GIFT, patients were randomized to an 11-day regimen of warfarin guided either by a clinical algorithm or by their individual genotype. The team tested for four polymorphisms known to affect warfarin metabolism: VKORC1-1639G>A, CYP2C9*2, CYP2C9*3, and CYP4F2 V433M. The treatment goal was an INR of 1.8-2. After 11 days, physicians could administer warfarin according to their own judgment.
The absolute difference of 3.9% in the composite endpoint was largely driven by a 2.8% absolute difference in the rate of an INR of 4 or greater. The rate difference between the two groups was 0.8% for major bleeding, and 0.7% for VTE.
About 41% of the cohort was considered to be at high risk of bleeding complications, and this group accrued the highest benefit from genotype-based dosing. Among them, the composite endpoint was 11.5% compared with 15.2% in the clinical algorithm group – an absolute difference of 3.76%.
The benefit was consistent among black patients, and those with CYP2C9.
By day 90, one VTE had occurred in each group. An intracranial hemorrhage occurred in one patient in the clinically guided group, 2 months after stopping warfarin.
The clinical benefit of genotype-based dosing influenced 90-day outcomes as well, with the composite endpoint occurring in 11% of the genotype group and 15% of the clinically guided group (absolute difference 3.9%).
Among the 1,588 patients who had their percentage of time in the therapeutic range (PTTR) calculated, genotyping improved PTTR time by 3.4% overall. The effect was especially strong from days 4 to 14, when it improved PTTR by 5.7% relative to clinical guidance.
Three other studies have examined the effect of a genotype-based warfarin dosing regimen, Dr. Gage and his coauthors noted: Two found no benefit, and a third found that such guidance improved INR control. GIFT has several advantages over those trials, which the authors said lend credence to its results.
“Compared with previous studies, this trial was larger, used genotype-guided dosing for a longer duration, and incorporated more genes into the dosing algorithm …The longer period of genotype-guided dosing likely prevented cases of supratherapeutic INR that were common in these trials,” they wrote.
Dr. Gage reported no financial disclosures, but several coauthors reported ties with pharmaceutical and imaging companies.
Warfarin is the most commonly used anticoagulant in the world, and a significant cause of emergency department visits and hospitalizations, especially among older patients. Walking the fine line between dosing too little and too much is not an easy task – especially since warfarin response is influenced by diet, comorbidities, interactions with other medications and – as studies over the last 20 years have confirmed – many genetic variants.
Also, the practicality of genotyping every patient who needs anticoagulation therapy must be questioned. Based on the results of GIFT, 26 patients would need to be genotyped to prevent one event, typically an INR of 4 or greater. Although the cost of genotyping continues to decline, health insurers and publicly funded health systems have not yet been convinced that genotype-guided warfarin prescribing is a cost-effective strategy.
The benefits of genotyping would likely be less in patients with atrial fibrillation, for example, as they run a lower risk of VTE than do arthroplasty patients. The GIFT surgeries were all elective, so there was plenty of time to get back genotyping results before starting warfarin. That is a luxury not afforded to many patients in need of anticoagulation.
It’s possible, however, that the benefits of genotyping might be larger in the real world. GIFT was conducted at academic medical centers and used a clinical dosing algorithm as comparator. As a result, adverse event rates were likely lower in the comparison group than would be expected in other clinical settings with less-intense INR monitoring or empirically based initiation regimens.
Still, GIFT’s results are gaining global attention. Based on prepublication results of the GIFT trial, the Clinical Pharmacogenetics Implementation Consortium (CPIC), an international research network that develops consensus recommendations about the use of pharmacogenomic test results, recently published guidelines about genotype-guided dosing for warfarin. The group now recommends using genotype-guided warfarin dosing based on CYP2C9*2, CYP2C9*3, and VKORC1 variants for adult patients of non-African ancestry. It also recommends that patients with combinations of high-risk variants would benefit from an alternative anticoagulant strategy, because of likely greater risks of poor INR control and bleeding.
A single pharmacogenomic test covering many common variants relevant to multiple prescribing decisions over time is far more likely to be a cost-effective approach; however, there is no evidence for this proposition. Until then, it might be simpler and less expensive to use clinical dosing algorithms to reduce the risks of anticoagulation.
Jon D. Emery, PhD, is the Herman Professor of Primary Care Cancer Research at the University of Melbourne and Western Health, Melbourne. He made these remarks in an accompanying editorial (JAMA 2017;318;110-2 doi: 10.1001/jama.2017.11465 ).
Warfarin is the most commonly used anticoagulant in the world, and a significant cause of emergency department visits and hospitalizations, especially among older patients. Walking the fine line between dosing too little and too much is not an easy task – especially since warfarin response is influenced by diet, comorbidities, interactions with other medications and – as studies over the last 20 years have confirmed – many genetic variants.
Also, the practicality of genotyping every patient who needs anticoagulation therapy must be questioned. Based on the results of GIFT, 26 patients would need to be genotyped to prevent one event, typically an INR of 4 or greater. Although the cost of genotyping continues to decline, health insurers and publicly funded health systems have not yet been convinced that genotype-guided warfarin prescribing is a cost-effective strategy.
The benefits of genotyping would likely be less in patients with atrial fibrillation, for example, as they run a lower risk of VTE than do arthroplasty patients. The GIFT surgeries were all elective, so there was plenty of time to get back genotyping results before starting warfarin. That is a luxury not afforded to many patients in need of anticoagulation.
It’s possible, however, that the benefits of genotyping might be larger in the real world. GIFT was conducted at academic medical centers and used a clinical dosing algorithm as comparator. As a result, adverse event rates were likely lower in the comparison group than would be expected in other clinical settings with less-intense INR monitoring or empirically based initiation regimens.
Still, GIFT’s results are gaining global attention. Based on prepublication results of the GIFT trial, the Clinical Pharmacogenetics Implementation Consortium (CPIC), an international research network that develops consensus recommendations about the use of pharmacogenomic test results, recently published guidelines about genotype-guided dosing for warfarin. The group now recommends using genotype-guided warfarin dosing based on CYP2C9*2, CYP2C9*3, and VKORC1 variants for adult patients of non-African ancestry. It also recommends that patients with combinations of high-risk variants would benefit from an alternative anticoagulant strategy, because of likely greater risks of poor INR control and bleeding.
A single pharmacogenomic test covering many common variants relevant to multiple prescribing decisions over time is far more likely to be a cost-effective approach; however, there is no evidence for this proposition. Until then, it might be simpler and less expensive to use clinical dosing algorithms to reduce the risks of anticoagulation.
Jon D. Emery, PhD, is the Herman Professor of Primary Care Cancer Research at the University of Melbourne and Western Health, Melbourne. He made these remarks in an accompanying editorial (JAMA 2017;318;110-2 doi: 10.1001/jama.2017.11465 ).
Warfarin is the most commonly used anticoagulant in the world, and a significant cause of emergency department visits and hospitalizations, especially among older patients. Walking the fine line between dosing too little and too much is not an easy task – especially since warfarin response is influenced by diet, comorbidities, interactions with other medications and – as studies over the last 20 years have confirmed – many genetic variants.
Also, the practicality of genotyping every patient who needs anticoagulation therapy must be questioned. Based on the results of GIFT, 26 patients would need to be genotyped to prevent one event, typically an INR of 4 or greater. Although the cost of genotyping continues to decline, health insurers and publicly funded health systems have not yet been convinced that genotype-guided warfarin prescribing is a cost-effective strategy.
The benefits of genotyping would likely be less in patients with atrial fibrillation, for example, as they run a lower risk of VTE than do arthroplasty patients. The GIFT surgeries were all elective, so there was plenty of time to get back genotyping results before starting warfarin. That is a luxury not afforded to many patients in need of anticoagulation.
It’s possible, however, that the benefits of genotyping might be larger in the real world. GIFT was conducted at academic medical centers and used a clinical dosing algorithm as comparator. As a result, adverse event rates were likely lower in the comparison group than would be expected in other clinical settings with less-intense INR monitoring or empirically based initiation regimens.
Still, GIFT’s results are gaining global attention. Based on prepublication results of the GIFT trial, the Clinical Pharmacogenetics Implementation Consortium (CPIC), an international research network that develops consensus recommendations about the use of pharmacogenomic test results, recently published guidelines about genotype-guided dosing for warfarin. The group now recommends using genotype-guided warfarin dosing based on CYP2C9*2, CYP2C9*3, and VKORC1 variants for adult patients of non-African ancestry. It also recommends that patients with combinations of high-risk variants would benefit from an alternative anticoagulant strategy, because of likely greater risks of poor INR control and bleeding.
A single pharmacogenomic test covering many common variants relevant to multiple prescribing decisions over time is far more likely to be a cost-effective approach; however, there is no evidence for this proposition. Until then, it might be simpler and less expensive to use clinical dosing algorithms to reduce the risks of anticoagulation.
Jon D. Emery, PhD, is the Herman Professor of Primary Care Cancer Research at the University of Melbourne and Western Health, Melbourne. He made these remarks in an accompanying editorial (JAMA 2017;318;110-2 doi: 10.1001/jama.2017.11465 ).
The difference in the composite endpoint (major bleeding within 30 days, international normalized ratio [INR] of 4 or greater within 30 days, venous thromboembolism within 60 days, or death within 30 days) in the Genetic Informatics Trial of Warfarin to Prevent Deep Vein Thrombosis (GIFT) trial was mainly driven by a significant difference in episodes of elevated INR, reported Brian F. Gage, MD, and his colleagues (JAMA 2017;318[12]:1115-1124. doi: 10.1001/jama.2017.11469).
A total of 1,597 patients completed the trial. Of 808 patients in the genotype-guided group, 10.8% met one of the endpoints. Of 789 in the clinically guided warfarin dosing group, 14.7% met at least 1 of the endpoints. There were no deaths in the study.
“Widespread use of genotype-guided dosing will depend on reimbursement, regulations, and logistics. Although several commercial platforms for warfarin-related genes have been approved by the Food and Drug Administration and the European Medicines Agency, routine genotyping is not yet recommended,” wrote Dr. Gage of Washington University, St. Louis, and his coauthors.
The Centers for Medicare and Medicaid Services used its Coverage with Evidence Development program to fund genotyping in this trial and will review the results to determine future coverage, the researchers added.
In GIFT, patients were randomized to an 11-day regimen of warfarin guided either by a clinical algorithm or by their individual genotype. The team tested for four polymorphisms known to affect warfarin metabolism: VKORC1-1639G>A, CYP2C9*2, CYP2C9*3, and CYP4F2 V433M. The treatment goal was an INR of 1.8-2. After 11 days, physicians could administer warfarin according to their own judgment.
The absolute difference of 3.9% in the composite endpoint was largely driven by a 2.8% absolute difference in the rate of an INR of 4 or greater. The rate difference between the two groups was 0.8% for major bleeding, and 0.7% for VTE.
About 41% of the cohort was considered to be at high risk of bleeding complications, and this group accrued the highest benefit from genotype-based dosing. Among them, the composite endpoint was 11.5% compared with 15.2% in the clinical algorithm group – an absolute difference of 3.76%.
The benefit was consistent among black patients, and those with CYP2C9.
By day 90, one VTE had occurred in each group. An intracranial hemorrhage occurred in one patient in the clinically guided group, 2 months after stopping warfarin.
The clinical benefit of genotype-based dosing influenced 90-day outcomes as well, with the composite endpoint occurring in 11% of the genotype group and 15% of the clinically guided group (absolute difference 3.9%).
Among the 1,588 patients who had their percentage of time in the therapeutic range (PTTR) calculated, genotyping improved PTTR time by 3.4% overall. The effect was especially strong from days 4 to 14, when it improved PTTR by 5.7% relative to clinical guidance.
Three other studies have examined the effect of a genotype-based warfarin dosing regimen, Dr. Gage and his coauthors noted: Two found no benefit, and a third found that such guidance improved INR control. GIFT has several advantages over those trials, which the authors said lend credence to its results.
“Compared with previous studies, this trial was larger, used genotype-guided dosing for a longer duration, and incorporated more genes into the dosing algorithm …The longer period of genotype-guided dosing likely prevented cases of supratherapeutic INR that were common in these trials,” they wrote.
Dr. Gage reported no financial disclosures, but several coauthors reported ties with pharmaceutical and imaging companies.
The difference in the composite endpoint (major bleeding within 30 days, international normalized ratio [INR] of 4 or greater within 30 days, venous thromboembolism within 60 days, or death within 30 days) in the Genetic Informatics Trial of Warfarin to Prevent Deep Vein Thrombosis (GIFT) trial was mainly driven by a significant difference in episodes of elevated INR, reported Brian F. Gage, MD, and his colleagues (JAMA 2017;318[12]:1115-1124. doi: 10.1001/jama.2017.11469).
A total of 1,597 patients completed the trial. Of 808 patients in the genotype-guided group, 10.8% met one of the endpoints. Of 789 in the clinically guided warfarin dosing group, 14.7% met at least 1 of the endpoints. There were no deaths in the study.
“Widespread use of genotype-guided dosing will depend on reimbursement, regulations, and logistics. Although several commercial platforms for warfarin-related genes have been approved by the Food and Drug Administration and the European Medicines Agency, routine genotyping is not yet recommended,” wrote Dr. Gage of Washington University, St. Louis, and his coauthors.
The Centers for Medicare and Medicaid Services used its Coverage with Evidence Development program to fund genotyping in this trial and will review the results to determine future coverage, the researchers added.
In GIFT, patients were randomized to an 11-day regimen of warfarin guided either by a clinical algorithm or by their individual genotype. The team tested for four polymorphisms known to affect warfarin metabolism: VKORC1-1639G>A, CYP2C9*2, CYP2C9*3, and CYP4F2 V433M. The treatment goal was an INR of 1.8-2. After 11 days, physicians could administer warfarin according to their own judgment.
The absolute difference of 3.9% in the composite endpoint was largely driven by a 2.8% absolute difference in the rate of an INR of 4 or greater. The rate difference between the two groups was 0.8% for major bleeding, and 0.7% for VTE.
About 41% of the cohort was considered to be at high risk of bleeding complications, and this group accrued the highest benefit from genotype-based dosing. Among them, the composite endpoint was 11.5% compared with 15.2% in the clinical algorithm group – an absolute difference of 3.76%.
The benefit was consistent among black patients, and those with CYP2C9.
By day 90, one VTE had occurred in each group. An intracranial hemorrhage occurred in one patient in the clinically guided group, 2 months after stopping warfarin.
The clinical benefit of genotype-based dosing influenced 90-day outcomes as well, with the composite endpoint occurring in 11% of the genotype group and 15% of the clinically guided group (absolute difference 3.9%).
Among the 1,588 patients who had their percentage of time in the therapeutic range (PTTR) calculated, genotyping improved PTTR time by 3.4% overall. The effect was especially strong from days 4 to 14, when it improved PTTR by 5.7% relative to clinical guidance.
Three other studies have examined the effect of a genotype-based warfarin dosing regimen, Dr. Gage and his coauthors noted: Two found no benefit, and a third found that such guidance improved INR control. GIFT has several advantages over those trials, which the authors said lend credence to its results.
“Compared with previous studies, this trial was larger, used genotype-guided dosing for a longer duration, and incorporated more genes into the dosing algorithm …The longer period of genotype-guided dosing likely prevented cases of supratherapeutic INR that were common in these trials,” they wrote.
Dr. Gage reported no financial disclosures, but several coauthors reported ties with pharmaceutical and imaging companies.
FROM JAMA
Key clinical point:
Major finding: Genotype-guided dosing reduced adverse events – primarily elevated INRs – by almost 4% compared to clinically based warfarin dosing.
Data source: A randomized trial comprising 1,650 elderly patients undergoing elective knee or hip arthroplasty.
Disclosures: Dr. Gage had no financial disclosures, but several of his coauthors noted relationships with pharmaceutical and imaging companies.
New BACE1 study launches in the shadow of verubecestat’s demise
BOSTON – Undeterred by a failed BACE inhibitor study with worrisome adverse events, an ambitious new clinical trial will investigate a different BACE-inhibiting molecule as an Alzheimer’s preventive in people at high genetic risk of Alzheimer’s disease.
The global Generation 2 trial intends to recruit about 3,300 cognitively normal subjects aged 60-75 years, who have either one or two copies of the apolipoprotein e4 (ApoE4) allele, said Pierre Tariot, MD, who announced the new study during the Clinical Trials on Alzheimer’s Disease 2017 meeting.
The Alzheimer Preventive Initiative and industry partners Novartis and Amgen are sponsoring the trial, which is a sister study to Generation 1. Generation 1, now ongoing, targets cognitively normal ApoE4 subjects only. It is a four-armed trial, comparing placebo to both CNP520 and an active immunotherapy called CAD106. Together, the studies comprise the Generation Program.
Both trials are event-driven, and will run 5-8 years. Generation 2 has a dual primary endpoint – a successful trial will find either a delay in progression to mild cognitive impairment or dementia relative to placebo, or significant differences from baseline in cognitive change as measured by the Alzheimer’s Preclinical Composite Cognitive test, or both.
The study partners are enthusiastic about CNP520, which performed well in its safety and tolerability studies. In an interview, Dr. Tariot called the CNP520 “likely a best-in-class molecule.”
“The only adverse events we saw in the entire safety program were a few cases of itchy skin,” said Dr. Tariot, director of the Banner Alzheimer Institute in Phoenix. “One of the reasons we chose Novartis as a study partner is that this drug of theirs looked remarkably clean – so clean that when we were deciding what doses to look at, the decision related only to what degree of BACE inhibition we wanted, not safety.”
The drug seemed very well-tolerated at every dose tested (1 mg, 10 mg, 25 mg, and 75 mg). Generation 1 employs a 50-mg oral dose per day. Generation 2 will investigate both 50 mg and 15 mg.
Site investigators are solidly behind the choice, said Anton Porsteinsson, MD, a Generation investigator at the University of Rochester (N.Y.) Medical Center, despite the unveiling at CTAD of worrisome adverse events seen in Merck’s failed EPOCH trial.
“I am even more convinced now that BACE inhibitors are drugs that need to be used early and that are probably highly indicated for this population,” he said in an interview. Dr. Porsteinsson wasn’t overly disturbed by data that Merck released during the meeting on its BACE inhibitor, verubecestat. In February, the company pulled the plug on its EPOCH trial investigating verubecestat in patients with mild-moderate AD. An interim analysis determined that there was no chance of success with the molecule.
Despite the general disappointment of yet another rainy-day parade in late-stage AD drug trials, researchers who heard the EPOCH post-mortem during CTAD expressed considerable concern over the unexpected, wide-ranging, and serious adverse events the trial accumulated.
Although there were no cases of Amyloid-Related Imaging Abnormalities (ARIA), a number of adverse events occurred significantly more often in the active groups than the placebo group. These included rash, falls and injuries, insomnia, headache, anxiety, suicidal ideation, diarrhea, dizziness, and weight loss.
At least some of these were hinted at in the bench science that brought verubecestat to late-stage clinical development. BACE is important for proper muscle function, and some BACE-knockout mice displayed a decrease in muscle spindles, receptors that sense changes in the length of muscle fibers. Other peculiarities in the mice have included axon targeting errors, reduced myelination, memory impairment, neurochemical abnormalities, alterations in neurogenesis and astrogenesis, increased age-related neurodegeneration, reduced spine density, retinal pathology, endophenotypes of schizophrenia, and seizures.
But the verubecestat findings aren’t a show-stopper for the more target-specific CNP520, Dr. Porsteinsson said. Verubecestat inhibited both BACE1 and BACE2; CNP520, only BACE1. And Dr. Porsteinsson, like most researchers, believes that preventing the accumulation of neurotoxic AB species will probably be much more effective clinically than trying to dissolve large stubborn brain plaques, which have already wreaked cognitive havoc.
In EPOCH, “even in people with advanced disease and a high load of insoluble plaques; they saw an 80% reduction in the production of AB and a 4% decrease in plaque burden. To me that signals this is not the class to use in moderate patients, or even mild, but in these very early stages where you don’t have full saturation, it might just be perfect,” he said.
“Do the side effects give me pause? Obviously and maybe mostly because we don’t know exactly what the driver was. But what we do is keep a close eye on everyone, maybe do extra safety monitoring, Most importantly, we picked a drug that shows less issues with any of these problems.”
Cognitively normal ApoE4 carriers – especially homozygotes – are an extremely important population to study, both in terms of clinical and scientific need. The gene is the single largest genetic risk factor for Alzheimer’s; those who carry two copies are 60% more likely than the general population to develop Alzheimer’s.
“These people truly need an effective intervention,” said Dr. Porsteinsson. “At the preclinical stage, they don’t truly have a disease yet; they are living their lives unimpaired. But something is percolating, and the results won’t be good. Even early on, there are fairly significant changes going on in the brain: a buildup of amyloid and tau, excess oxidative damage, inflammation. And if you don’t deal with it early on, it’s like trying to cure cancer once it’s metastasized.”
In the larger scientific picture, success in a primary prevention trial would finally put to rest questions about the amyloid cascade hypothesis and explain the long string of anti-amyloid drug trial failures, all of which were targeted at people with more advanced disease.
To enroll the entire cohort, Generation 2 will need to screen about 30,000 people. This sounds like a daunting task, but a new digital platform makes it eminently do-able, Dr. Tariot said. Both Generation studies are enrolling online. The consumer-friendly website offers detailed information about Alzheimer’s disease in general, ApoE4 risk, the studies’ structure, and the investigational medications. Most importantly, Dr. Tariot said, the website has a direct link to GeneMatch. Hosted by Banner Alzheimer Institute, GeneMatch prescreens potential trial participants (U.S. residents aged 55-75 years) by taking baseline demographic information, and mailing out free, simple-to-use cheek swab kits for genetic analysis. The program then stores and sorts the information, matching volunteers with appropriate trials according to location, age, interest, and genetic status. People don’t necessarily learn their ApoE4 status, unless they are recruited into a genetics-driven trial.
Launched 2 years ago, GeneMatch has already accrued more than 280,000 volunteers – a pretty remarkable achievement in itself, Dr. Tariot said. “People are very motivated to help find a cure for Alzheimer’s. Many of them have a family member who has the disease. Others are concerned about themselves, and many people just want to be part of something important.”
Dr. Porsteinsson agreed, relaying a startling interaction he had with a patient, who found out he was not qualified for a Generation study, meaning, of course, that he was ApoE4 negative.
“He told me he was actually kind of disappointed, because he believes so much in this study, and wanted to be part of doing something important for humanity,” Dr. Porsteinsson said. “Of course, I didn’t let him off the hook. I directed him to a bunch of other studies he was qualified for. We need everyone’s help to solve this.”
Both Dr. Tariot and Dr. Porsteinsson have reported financial relationships with numerous pharmaceutical companies.
* This story was updated 11/7/17.
[email protected]
On Twitter @Alz_Gal
BOSTON – Undeterred by a failed BACE inhibitor study with worrisome adverse events, an ambitious new clinical trial will investigate a different BACE-inhibiting molecule as an Alzheimer’s preventive in people at high genetic risk of Alzheimer’s disease.
The global Generation 2 trial intends to recruit about 3,300 cognitively normal subjects aged 60-75 years, who have either one or two copies of the apolipoprotein e4 (ApoE4) allele, said Pierre Tariot, MD, who announced the new study during the Clinical Trials on Alzheimer’s Disease 2017 meeting.
The Alzheimer Preventive Initiative and industry partners Novartis and Amgen are sponsoring the trial, which is a sister study to Generation 1. Generation 1, now ongoing, targets cognitively normal ApoE4 subjects only. It is a four-armed trial, comparing placebo to both CNP520 and an active immunotherapy called CAD106. Together, the studies comprise the Generation Program.
Both trials are event-driven, and will run 5-8 years. Generation 2 has a dual primary endpoint – a successful trial will find either a delay in progression to mild cognitive impairment or dementia relative to placebo, or significant differences from baseline in cognitive change as measured by the Alzheimer’s Preclinical Composite Cognitive test, or both.
The study partners are enthusiastic about CNP520, which performed well in its safety and tolerability studies. In an interview, Dr. Tariot called the CNP520 “likely a best-in-class molecule.”
“The only adverse events we saw in the entire safety program were a few cases of itchy skin,” said Dr. Tariot, director of the Banner Alzheimer Institute in Phoenix. “One of the reasons we chose Novartis as a study partner is that this drug of theirs looked remarkably clean – so clean that when we were deciding what doses to look at, the decision related only to what degree of BACE inhibition we wanted, not safety.”
The drug seemed very well-tolerated at every dose tested (1 mg, 10 mg, 25 mg, and 75 mg). Generation 1 employs a 50-mg oral dose per day. Generation 2 will investigate both 50 mg and 15 mg.
Site investigators are solidly behind the choice, said Anton Porsteinsson, MD, a Generation investigator at the University of Rochester (N.Y.) Medical Center, despite the unveiling at CTAD of worrisome adverse events seen in Merck’s failed EPOCH trial.
“I am even more convinced now that BACE inhibitors are drugs that need to be used early and that are probably highly indicated for this population,” he said in an interview. Dr. Porsteinsson wasn’t overly disturbed by data that Merck released during the meeting on its BACE inhibitor, verubecestat. In February, the company pulled the plug on its EPOCH trial investigating verubecestat in patients with mild-moderate AD. An interim analysis determined that there was no chance of success with the molecule.
Despite the general disappointment of yet another rainy-day parade in late-stage AD drug trials, researchers who heard the EPOCH post-mortem during CTAD expressed considerable concern over the unexpected, wide-ranging, and serious adverse events the trial accumulated.
Although there were no cases of Amyloid-Related Imaging Abnormalities (ARIA), a number of adverse events occurred significantly more often in the active groups than the placebo group. These included rash, falls and injuries, insomnia, headache, anxiety, suicidal ideation, diarrhea, dizziness, and weight loss.
At least some of these were hinted at in the bench science that brought verubecestat to late-stage clinical development. BACE is important for proper muscle function, and some BACE-knockout mice displayed a decrease in muscle spindles, receptors that sense changes in the length of muscle fibers. Other peculiarities in the mice have included axon targeting errors, reduced myelination, memory impairment, neurochemical abnormalities, alterations in neurogenesis and astrogenesis, increased age-related neurodegeneration, reduced spine density, retinal pathology, endophenotypes of schizophrenia, and seizures.
But the verubecestat findings aren’t a show-stopper for the more target-specific CNP520, Dr. Porsteinsson said. Verubecestat inhibited both BACE1 and BACE2; CNP520, only BACE1. And Dr. Porsteinsson, like most researchers, believes that preventing the accumulation of neurotoxic AB species will probably be much more effective clinically than trying to dissolve large stubborn brain plaques, which have already wreaked cognitive havoc.
In EPOCH, “even in people with advanced disease and a high load of insoluble plaques; they saw an 80% reduction in the production of AB and a 4% decrease in plaque burden. To me that signals this is not the class to use in moderate patients, or even mild, but in these very early stages where you don’t have full saturation, it might just be perfect,” he said.
“Do the side effects give me pause? Obviously and maybe mostly because we don’t know exactly what the driver was. But what we do is keep a close eye on everyone, maybe do extra safety monitoring, Most importantly, we picked a drug that shows less issues with any of these problems.”
Cognitively normal ApoE4 carriers – especially homozygotes – are an extremely important population to study, both in terms of clinical and scientific need. The gene is the single largest genetic risk factor for Alzheimer’s; those who carry two copies are 60% more likely than the general population to develop Alzheimer’s.
“These people truly need an effective intervention,” said Dr. Porsteinsson. “At the preclinical stage, they don’t truly have a disease yet; they are living their lives unimpaired. But something is percolating, and the results won’t be good. Even early on, there are fairly significant changes going on in the brain: a buildup of amyloid and tau, excess oxidative damage, inflammation. And if you don’t deal with it early on, it’s like trying to cure cancer once it’s metastasized.”
In the larger scientific picture, success in a primary prevention trial would finally put to rest questions about the amyloid cascade hypothesis and explain the long string of anti-amyloid drug trial failures, all of which were targeted at people with more advanced disease.
To enroll the entire cohort, Generation 2 will need to screen about 30,000 people. This sounds like a daunting task, but a new digital platform makes it eminently do-able, Dr. Tariot said. Both Generation studies are enrolling online. The consumer-friendly website offers detailed information about Alzheimer’s disease in general, ApoE4 risk, the studies’ structure, and the investigational medications. Most importantly, Dr. Tariot said, the website has a direct link to GeneMatch. Hosted by Banner Alzheimer Institute, GeneMatch prescreens potential trial participants (U.S. residents aged 55-75 years) by taking baseline demographic information, and mailing out free, simple-to-use cheek swab kits for genetic analysis. The program then stores and sorts the information, matching volunteers with appropriate trials according to location, age, interest, and genetic status. People don’t necessarily learn their ApoE4 status, unless they are recruited into a genetics-driven trial.
Launched 2 years ago, GeneMatch has already accrued more than 280,000 volunteers – a pretty remarkable achievement in itself, Dr. Tariot said. “People are very motivated to help find a cure for Alzheimer’s. Many of them have a family member who has the disease. Others are concerned about themselves, and many people just want to be part of something important.”
Dr. Porsteinsson agreed, relaying a startling interaction he had with a patient, who found out he was not qualified for a Generation study, meaning, of course, that he was ApoE4 negative.
“He told me he was actually kind of disappointed, because he believes so much in this study, and wanted to be part of doing something important for humanity,” Dr. Porsteinsson said. “Of course, I didn’t let him off the hook. I directed him to a bunch of other studies he was qualified for. We need everyone’s help to solve this.”
Both Dr. Tariot and Dr. Porsteinsson have reported financial relationships with numerous pharmaceutical companies.
* This story was updated 11/7/17.
[email protected]
On Twitter @Alz_Gal
BOSTON – Undeterred by a failed BACE inhibitor study with worrisome adverse events, an ambitious new clinical trial will investigate a different BACE-inhibiting molecule as an Alzheimer’s preventive in people at high genetic risk of Alzheimer’s disease.
The global Generation 2 trial intends to recruit about 3,300 cognitively normal subjects aged 60-75 years, who have either one or two copies of the apolipoprotein e4 (ApoE4) allele, said Pierre Tariot, MD, who announced the new study during the Clinical Trials on Alzheimer’s Disease 2017 meeting.
The Alzheimer Preventive Initiative and industry partners Novartis and Amgen are sponsoring the trial, which is a sister study to Generation 1. Generation 1, now ongoing, targets cognitively normal ApoE4 subjects only. It is a four-armed trial, comparing placebo to both CNP520 and an active immunotherapy called CAD106. Together, the studies comprise the Generation Program.
Both trials are event-driven, and will run 5-8 years. Generation 2 has a dual primary endpoint – a successful trial will find either a delay in progression to mild cognitive impairment or dementia relative to placebo, or significant differences from baseline in cognitive change as measured by the Alzheimer’s Preclinical Composite Cognitive test, or both.
The study partners are enthusiastic about CNP520, which performed well in its safety and tolerability studies. In an interview, Dr. Tariot called the CNP520 “likely a best-in-class molecule.”
“The only adverse events we saw in the entire safety program were a few cases of itchy skin,” said Dr. Tariot, director of the Banner Alzheimer Institute in Phoenix. “One of the reasons we chose Novartis as a study partner is that this drug of theirs looked remarkably clean – so clean that when we were deciding what doses to look at, the decision related only to what degree of BACE inhibition we wanted, not safety.”
The drug seemed very well-tolerated at every dose tested (1 mg, 10 mg, 25 mg, and 75 mg). Generation 1 employs a 50-mg oral dose per day. Generation 2 will investigate both 50 mg and 15 mg.
Site investigators are solidly behind the choice, said Anton Porsteinsson, MD, a Generation investigator at the University of Rochester (N.Y.) Medical Center, despite the unveiling at CTAD of worrisome adverse events seen in Merck’s failed EPOCH trial.
“I am even more convinced now that BACE inhibitors are drugs that need to be used early and that are probably highly indicated for this population,” he said in an interview. Dr. Porsteinsson wasn’t overly disturbed by data that Merck released during the meeting on its BACE inhibitor, verubecestat. In February, the company pulled the plug on its EPOCH trial investigating verubecestat in patients with mild-moderate AD. An interim analysis determined that there was no chance of success with the molecule.
Despite the general disappointment of yet another rainy-day parade in late-stage AD drug trials, researchers who heard the EPOCH post-mortem during CTAD expressed considerable concern over the unexpected, wide-ranging, and serious adverse events the trial accumulated.
Although there were no cases of Amyloid-Related Imaging Abnormalities (ARIA), a number of adverse events occurred significantly more often in the active groups than the placebo group. These included rash, falls and injuries, insomnia, headache, anxiety, suicidal ideation, diarrhea, dizziness, and weight loss.
At least some of these were hinted at in the bench science that brought verubecestat to late-stage clinical development. BACE is important for proper muscle function, and some BACE-knockout mice displayed a decrease in muscle spindles, receptors that sense changes in the length of muscle fibers. Other peculiarities in the mice have included axon targeting errors, reduced myelination, memory impairment, neurochemical abnormalities, alterations in neurogenesis and astrogenesis, increased age-related neurodegeneration, reduced spine density, retinal pathology, endophenotypes of schizophrenia, and seizures.
But the verubecestat findings aren’t a show-stopper for the more target-specific CNP520, Dr. Porsteinsson said. Verubecestat inhibited both BACE1 and BACE2; CNP520, only BACE1. And Dr. Porsteinsson, like most researchers, believes that preventing the accumulation of neurotoxic AB species will probably be much more effective clinically than trying to dissolve large stubborn brain plaques, which have already wreaked cognitive havoc.
In EPOCH, “even in people with advanced disease and a high load of insoluble plaques; they saw an 80% reduction in the production of AB and a 4% decrease in plaque burden. To me that signals this is not the class to use in moderate patients, or even mild, but in these very early stages where you don’t have full saturation, it might just be perfect,” he said.
“Do the side effects give me pause? Obviously and maybe mostly because we don’t know exactly what the driver was. But what we do is keep a close eye on everyone, maybe do extra safety monitoring, Most importantly, we picked a drug that shows less issues with any of these problems.”
Cognitively normal ApoE4 carriers – especially homozygotes – are an extremely important population to study, both in terms of clinical and scientific need. The gene is the single largest genetic risk factor for Alzheimer’s; those who carry two copies are 60% more likely than the general population to develop Alzheimer’s.
“These people truly need an effective intervention,” said Dr. Porsteinsson. “At the preclinical stage, they don’t truly have a disease yet; they are living their lives unimpaired. But something is percolating, and the results won’t be good. Even early on, there are fairly significant changes going on in the brain: a buildup of amyloid and tau, excess oxidative damage, inflammation. And if you don’t deal with it early on, it’s like trying to cure cancer once it’s metastasized.”
In the larger scientific picture, success in a primary prevention trial would finally put to rest questions about the amyloid cascade hypothesis and explain the long string of anti-amyloid drug trial failures, all of which were targeted at people with more advanced disease.
To enroll the entire cohort, Generation 2 will need to screen about 30,000 people. This sounds like a daunting task, but a new digital platform makes it eminently do-able, Dr. Tariot said. Both Generation studies are enrolling online. The consumer-friendly website offers detailed information about Alzheimer’s disease in general, ApoE4 risk, the studies’ structure, and the investigational medications. Most importantly, Dr. Tariot said, the website has a direct link to GeneMatch. Hosted by Banner Alzheimer Institute, GeneMatch prescreens potential trial participants (U.S. residents aged 55-75 years) by taking baseline demographic information, and mailing out free, simple-to-use cheek swab kits for genetic analysis. The program then stores and sorts the information, matching volunteers with appropriate trials according to location, age, interest, and genetic status. People don’t necessarily learn their ApoE4 status, unless they are recruited into a genetics-driven trial.
Launched 2 years ago, GeneMatch has already accrued more than 280,000 volunteers – a pretty remarkable achievement in itself, Dr. Tariot said. “People are very motivated to help find a cure for Alzheimer’s. Many of them have a family member who has the disease. Others are concerned about themselves, and many people just want to be part of something important.”
Dr. Porsteinsson agreed, relaying a startling interaction he had with a patient, who found out he was not qualified for a Generation study, meaning, of course, that he was ApoE4 negative.
“He told me he was actually kind of disappointed, because he believes so much in this study, and wanted to be part of doing something important for humanity,” Dr. Porsteinsson said. “Of course, I didn’t let him off the hook. I directed him to a bunch of other studies he was qualified for. We need everyone’s help to solve this.”
Both Dr. Tariot and Dr. Porsteinsson have reported financial relationships with numerous pharmaceutical companies.
* This story was updated 11/7/17.
[email protected]
On Twitter @Alz_Gal
AT CTAD
Aducanumab continues to rack up positive numbers in phase 1b open-label extension
BOSTON – The antiamyloid antibody aducanumab continued its slide around the bases this week, revealing more positive imaging and cognitive data at 36 months into the phase 1b PRIME trial.
Patients who have been taking the highest dose of aducanumab, 10 mg/kg, for the duration of the study improved the most on two measures of cognition, the Mini Mental State Exam (MMSE) and the Clinical Dementia Rating Scale–sum of boxes (CDR-sb). On the pathology side, at least some of the 10-mg/kg patients dropped below the threshold of PET amyloid positivity by 24 months and stayed at that low level up to 36 months, Samantha Budd Haeberlein, PhD, said at the Clinical Trials on Alzheimer’s Disease conference.
The 36-month data support the continued development of aducanumab, she said. The antibody is now being tested in two phase 3 studies, ENGAGE and EMERGE.
“The aducanumab data reported at CTAD is good news for safety and good news for the signals we need to see in the phase 3 trials,” Maria Carillo, PhD, chief science officer of the Alzheimer’s Association said when asked to comment on the latest data. “These are hopeful signs, but – based on what we’ve learned from past Alzheimer’s studies – we need to wait for the phase 3 trial results.”
Aducanumab is a monoclonal human antibody derived from B cells collected from a cohort of cognitively normal elderly subjects and cognitively impaired elderly subjects who exhibited unusually slow decline, according to Biogen. It binds to fibrillar and oligomeric amyloid aggregates, thus directly reducing amyloid plaque in the brain.
PRIME enrolled 165 patients with prodromal or mild Alzheimer’s disease. Importantly, all of the subjects had brain amyloid proven by PET imaging. PRIME is the first randomized trial of an antiamyloid compound to enroll a purely PET-proven amyloid-positive cohort. These subjects were randomized to placebo or aducanumab at 1, 3, 6, or 10 mg/kg for 1 year. This was followed by a 2-year open-label extension period. Patients who were randomized to placebo or 1 mg/kg were switched to aducanumab 3 mg/kg or to a 3- to 6-mg/kg titration regimen in the long-term extension. Patients randomized to aducanumab at 3, 6 or 10 mg/kg or titration in the placebo-controlled period continued in the same dose group.
Dr. Haeberlein presented only the fixed-dose data; the titration group data will be presented later in the conference.
PRIME’s primary outcomes are safety and tolerability. The cognitive and functional outcomes, not usually assessed in a phase 1b study, are exploratory. This is important to remember, Dr. Haeberlein said. She also stressed that the numbers in each dosing group are quite small. Of the original cohort, 117 entered the extension study and just 50 made it to 166 weeks, at which time 10-16 patients were in each of the dosage cohorts.
At 36 months, the mean change in amyloid plaque level was greatest for the 10-mg/kg group, which, on average, fell below the threshold of amyloid positivity on florbetapir PET scan. The 6-mg/kg group approached the threshold, but did not fall below it. The 1- and 3-mg/kg groups declined similarly to each other, although not as dramatically as the higher-dose group.
Everyone in the trial declined on both cognitive measures, the MMSE and CDR-sb. However, the decline was clearly attenuated in some of the active groups, where the best results were seen in the 10 patients who took 10 mg/kg. The average decline from baseline on the CDR-sb was 2.84 points among those patients. In the other groups, declines from baseline on the CDR-sb were:
- 5.28 points in those who switched from placebo to 3 mg/kg.
- 6.11 points in those who switched from 1 mg/kg to 3 mg/kg.
- 3.86 points in the 3-mg/kg treatment group.
- 4.49 points in the 6-mg/kg treatment group.
Patients taking 10 mg/kg also fared best on the MMSE, declining 4.10 points on average. Declines in the other groups were:
- 7.98 points in those who switched from placebo to 3 mg/kg.
- 6.35 points in those who switched from 1 mg/kg to 3 mg/kg.
- 4.83 points in the 3-mg/kg treatment group.
- 8.97 points in the 6 mg/kg treatment group.
During the presentation, Dr. Haeberlein said these differences were not statistically significant. In an interview, she said, “In this extension trial, we aren’t talking about statistical significance. We are beyond that.”
The incidence of ARIA (Amyloid-Related Imaging Abnormalities), however, did not follow this dose-dependent pattern. All eight cases of ARIA-E (the edematous form) in the long-term extension phase occurred in the placebo group that switched to 1 mg/kg or in the 1-mg/kg group that titrated up to 3 mg/kg. All cases occurred early in the extension phase, with no new cases during the last year, and all but one occurred in APOE4 allele carriers.
Hemorrhagic ARIA was more sporadic, occurring in two placebo switchers, five taking 3 mg/kg, two taking 6 mg/kg, and one patient taking the highest 10 mg/kg dose. Again, these cases occurred early in the trial. All of the ARIA cases, regardless of etiology, were considered mild and resolved spontaneously.
In all of PRIME, 46 patients have experienced ARIA, with 6 experiencing more than one episode.
The most common adverse events in the long-term extension phase were falls, headache, and ARIA. Two patients in the extension phase died – one taking 6 mg/kg and one taking 10 mg/kg. Neither death was related to the study medication.
[email protected]
On Twitter @alz_gal
BOSTON – The antiamyloid antibody aducanumab continued its slide around the bases this week, revealing more positive imaging and cognitive data at 36 months into the phase 1b PRIME trial.
Patients who have been taking the highest dose of aducanumab, 10 mg/kg, for the duration of the study improved the most on two measures of cognition, the Mini Mental State Exam (MMSE) and the Clinical Dementia Rating Scale–sum of boxes (CDR-sb). On the pathology side, at least some of the 10-mg/kg patients dropped below the threshold of PET amyloid positivity by 24 months and stayed at that low level up to 36 months, Samantha Budd Haeberlein, PhD, said at the Clinical Trials on Alzheimer’s Disease conference.
The 36-month data support the continued development of aducanumab, she said. The antibody is now being tested in two phase 3 studies, ENGAGE and EMERGE.
“The aducanumab data reported at CTAD is good news for safety and good news for the signals we need to see in the phase 3 trials,” Maria Carillo, PhD, chief science officer of the Alzheimer’s Association said when asked to comment on the latest data. “These are hopeful signs, but – based on what we’ve learned from past Alzheimer’s studies – we need to wait for the phase 3 trial results.”
Aducanumab is a monoclonal human antibody derived from B cells collected from a cohort of cognitively normal elderly subjects and cognitively impaired elderly subjects who exhibited unusually slow decline, according to Biogen. It binds to fibrillar and oligomeric amyloid aggregates, thus directly reducing amyloid plaque in the brain.
PRIME enrolled 165 patients with prodromal or mild Alzheimer’s disease. Importantly, all of the subjects had brain amyloid proven by PET imaging. PRIME is the first randomized trial of an antiamyloid compound to enroll a purely PET-proven amyloid-positive cohort. These subjects were randomized to placebo or aducanumab at 1, 3, 6, or 10 mg/kg for 1 year. This was followed by a 2-year open-label extension period. Patients who were randomized to placebo or 1 mg/kg were switched to aducanumab 3 mg/kg or to a 3- to 6-mg/kg titration regimen in the long-term extension. Patients randomized to aducanumab at 3, 6 or 10 mg/kg or titration in the placebo-controlled period continued in the same dose group.
Dr. Haeberlein presented only the fixed-dose data; the titration group data will be presented later in the conference.
PRIME’s primary outcomes are safety and tolerability. The cognitive and functional outcomes, not usually assessed in a phase 1b study, are exploratory. This is important to remember, Dr. Haeberlein said. She also stressed that the numbers in each dosing group are quite small. Of the original cohort, 117 entered the extension study and just 50 made it to 166 weeks, at which time 10-16 patients were in each of the dosage cohorts.
At 36 months, the mean change in amyloid plaque level was greatest for the 10-mg/kg group, which, on average, fell below the threshold of amyloid positivity on florbetapir PET scan. The 6-mg/kg group approached the threshold, but did not fall below it. The 1- and 3-mg/kg groups declined similarly to each other, although not as dramatically as the higher-dose group.
Everyone in the trial declined on both cognitive measures, the MMSE and CDR-sb. However, the decline was clearly attenuated in some of the active groups, where the best results were seen in the 10 patients who took 10 mg/kg. The average decline from baseline on the CDR-sb was 2.84 points among those patients. In the other groups, declines from baseline on the CDR-sb were:
- 5.28 points in those who switched from placebo to 3 mg/kg.
- 6.11 points in those who switched from 1 mg/kg to 3 mg/kg.
- 3.86 points in the 3-mg/kg treatment group.
- 4.49 points in the 6-mg/kg treatment group.
Patients taking 10 mg/kg also fared best on the MMSE, declining 4.10 points on average. Declines in the other groups were:
- 7.98 points in those who switched from placebo to 3 mg/kg.
- 6.35 points in those who switched from 1 mg/kg to 3 mg/kg.
- 4.83 points in the 3-mg/kg treatment group.
- 8.97 points in the 6 mg/kg treatment group.
During the presentation, Dr. Haeberlein said these differences were not statistically significant. In an interview, she said, “In this extension trial, we aren’t talking about statistical significance. We are beyond that.”
The incidence of ARIA (Amyloid-Related Imaging Abnormalities), however, did not follow this dose-dependent pattern. All eight cases of ARIA-E (the edematous form) in the long-term extension phase occurred in the placebo group that switched to 1 mg/kg or in the 1-mg/kg group that titrated up to 3 mg/kg. All cases occurred early in the extension phase, with no new cases during the last year, and all but one occurred in APOE4 allele carriers.
Hemorrhagic ARIA was more sporadic, occurring in two placebo switchers, five taking 3 mg/kg, two taking 6 mg/kg, and one patient taking the highest 10 mg/kg dose. Again, these cases occurred early in the trial. All of the ARIA cases, regardless of etiology, were considered mild and resolved spontaneously.
In all of PRIME, 46 patients have experienced ARIA, with 6 experiencing more than one episode.
The most common adverse events in the long-term extension phase were falls, headache, and ARIA. Two patients in the extension phase died – one taking 6 mg/kg and one taking 10 mg/kg. Neither death was related to the study medication.
[email protected]
On Twitter @alz_gal
BOSTON – The antiamyloid antibody aducanumab continued its slide around the bases this week, revealing more positive imaging and cognitive data at 36 months into the phase 1b PRIME trial.
Patients who have been taking the highest dose of aducanumab, 10 mg/kg, for the duration of the study improved the most on two measures of cognition, the Mini Mental State Exam (MMSE) and the Clinical Dementia Rating Scale–sum of boxes (CDR-sb). On the pathology side, at least some of the 10-mg/kg patients dropped below the threshold of PET amyloid positivity by 24 months and stayed at that low level up to 36 months, Samantha Budd Haeberlein, PhD, said at the Clinical Trials on Alzheimer’s Disease conference.
The 36-month data support the continued development of aducanumab, she said. The antibody is now being tested in two phase 3 studies, ENGAGE and EMERGE.
“The aducanumab data reported at CTAD is good news for safety and good news for the signals we need to see in the phase 3 trials,” Maria Carillo, PhD, chief science officer of the Alzheimer’s Association said when asked to comment on the latest data. “These are hopeful signs, but – based on what we’ve learned from past Alzheimer’s studies – we need to wait for the phase 3 trial results.”
Aducanumab is a monoclonal human antibody derived from B cells collected from a cohort of cognitively normal elderly subjects and cognitively impaired elderly subjects who exhibited unusually slow decline, according to Biogen. It binds to fibrillar and oligomeric amyloid aggregates, thus directly reducing amyloid plaque in the brain.
PRIME enrolled 165 patients with prodromal or mild Alzheimer’s disease. Importantly, all of the subjects had brain amyloid proven by PET imaging. PRIME is the first randomized trial of an antiamyloid compound to enroll a purely PET-proven amyloid-positive cohort. These subjects were randomized to placebo or aducanumab at 1, 3, 6, or 10 mg/kg for 1 year. This was followed by a 2-year open-label extension period. Patients who were randomized to placebo or 1 mg/kg were switched to aducanumab 3 mg/kg or to a 3- to 6-mg/kg titration regimen in the long-term extension. Patients randomized to aducanumab at 3, 6 or 10 mg/kg or titration in the placebo-controlled period continued in the same dose group.
Dr. Haeberlein presented only the fixed-dose data; the titration group data will be presented later in the conference.
PRIME’s primary outcomes are safety and tolerability. The cognitive and functional outcomes, not usually assessed in a phase 1b study, are exploratory. This is important to remember, Dr. Haeberlein said. She also stressed that the numbers in each dosing group are quite small. Of the original cohort, 117 entered the extension study and just 50 made it to 166 weeks, at which time 10-16 patients were in each of the dosage cohorts.
At 36 months, the mean change in amyloid plaque level was greatest for the 10-mg/kg group, which, on average, fell below the threshold of amyloid positivity on florbetapir PET scan. The 6-mg/kg group approached the threshold, but did not fall below it. The 1- and 3-mg/kg groups declined similarly to each other, although not as dramatically as the higher-dose group.
Everyone in the trial declined on both cognitive measures, the MMSE and CDR-sb. However, the decline was clearly attenuated in some of the active groups, where the best results were seen in the 10 patients who took 10 mg/kg. The average decline from baseline on the CDR-sb was 2.84 points among those patients. In the other groups, declines from baseline on the CDR-sb were:
- 5.28 points in those who switched from placebo to 3 mg/kg.
- 6.11 points in those who switched from 1 mg/kg to 3 mg/kg.
- 3.86 points in the 3-mg/kg treatment group.
- 4.49 points in the 6-mg/kg treatment group.
Patients taking 10 mg/kg also fared best on the MMSE, declining 4.10 points on average. Declines in the other groups were:
- 7.98 points in those who switched from placebo to 3 mg/kg.
- 6.35 points in those who switched from 1 mg/kg to 3 mg/kg.
- 4.83 points in the 3-mg/kg treatment group.
- 8.97 points in the 6 mg/kg treatment group.
During the presentation, Dr. Haeberlein said these differences were not statistically significant. In an interview, she said, “In this extension trial, we aren’t talking about statistical significance. We are beyond that.”
The incidence of ARIA (Amyloid-Related Imaging Abnormalities), however, did not follow this dose-dependent pattern. All eight cases of ARIA-E (the edematous form) in the long-term extension phase occurred in the placebo group that switched to 1 mg/kg or in the 1-mg/kg group that titrated up to 3 mg/kg. All cases occurred early in the extension phase, with no new cases during the last year, and all but one occurred in APOE4 allele carriers.
Hemorrhagic ARIA was more sporadic, occurring in two placebo switchers, five taking 3 mg/kg, two taking 6 mg/kg, and one patient taking the highest 10 mg/kg dose. Again, these cases occurred early in the trial. All of the ARIA cases, regardless of etiology, were considered mild and resolved spontaneously.
In all of PRIME, 46 patients have experienced ARIA, with 6 experiencing more than one episode.
The most common adverse events in the long-term extension phase were falls, headache, and ARIA. Two patients in the extension phase died – one taking 6 mg/kg and one taking 10 mg/kg. Neither death was related to the study medication.
[email protected]
On Twitter @alz_gal
EXPERT ANALYSIS FROM CTAD
Key clinical point:
Major finding: At 36 months, the mean change in amyloid plaque level was greatest for the 10-mg/kg group, which, on average, fell below the threshold of amyloid positivity on florbetapir PET scan.
Data source: 3-year extension phase data from the phase 1B PRIME trial.
Disclosures: The PRIME trial is sponsored by Biogen. The presenter is an employee of the company.
Analysis of failed Alzheimer’s trials gives two antiamyloid antibodies new momentum
BOSTON – Despite years of frustrating failures, Alzheimer’s researchers keep punching away at beta-amyloid brain plaques, now apparently with a highly focused one-two of “more drug, given sooner.”
Solanezumab and gantenerumab – both of which failed in earlier phase 3 studies – will be pushed forward now at much higher doses, the Alzheimer’s disease research community learned at the opening session of the Clinical Trials on Alzheimer’s Disease conference.
Both drugs are antiamyloid antibodies. In their prior trials, both effectively cleared amyloid plaques, but neither significantly improved cognition in patients with mild-moderate disease. This has been a common theme of every antiamyloid study: Although these drugs stimulate different mechanisms of plaque removal, none has ever significantly improved thinking or memory.
In discussing these failures, the Alzheimer’s research community has collectively wondered whether the doses were high enough. Drug companies have erred on the side of caution in large part because antiamyloid antibodies can cause a syndrome called ARIA (Amyloid-Related Imaging Abnormalities), an inflammatory response of brain edema or microhemorrhages. Concern over this side effect has moderated as researchers accumulate more adverse event data. Most cases are asymptomatic and resolve spontaneously. New open-label extension data from the Scarlet Road and Marguerite Road trials of gantenerumab, plus a new titration model by Roche, have also increased confidence that patients will tolerate the antibody at subcutaneous doses of up to 1,200 mg.
The other fear that plagues researchers is therapeutic timing. It’s increasingly apparent that plaque eradication does not rescue cognition. As heart disease must be attacked before cardiac damage occurs, it seems likely that Alzheimer’s disease must be attacked before amyloid and its attendant protein, tau, wreak havoc in the hippocampus and neocortex.
After reevaluating the high-profile solanezumab and gantenerumab failures, researchers now hope that higher doses delivered much earlier in the disease process might be effective, not at restoring lost cognition, but at preventing cognitive decline in the first place.
“One of the greatest advances in this field over the past 10 years is the recognition that Alzheimer’s disease is a continuum that likely begins well before the stage we recognize as dementia, and even before the stages of mild cognitive impairment [MCI] and prodromal Alzheimer’s,” said Dr. Sperling of Brigham and Women’s Hospital, Boston. “Treating in the presymptomatic phase may be the best opportunity to bend this curve back toward the trajectory of normal aging.”
But amyloid is only part of the Alzheimer’s disease story. Tau is a key player and, some say, the prime antagonist, since it is the main driver of memory and thought decline. Tau is present deep in the brains of most cognitively aging normal people, but something about amyloid deposition spurs its devastating spread into the neocortex. Preventing amyloid accumulation may prevent dementia, not just by keeping amyloid at bay, but by preventing it from igniting the spread of tau.
Dr. Sperling cited unpublished data showing very subtle cognitive decline in cognitively normal patients who have both amyloid and tau in the brain. Although the scores stayed within normal, subjects with both declined over 2 years on specific measures of memory and were more likely to progress to MCI.
“This is very striking to me and made me a little worried about the critical window of intervention,” she said. “What is also striking is that, even though we restricted the eligibility criteria of A4 to those with normal memory and normal cognition, we do see that tau positivity at baseline is associated with lower baseline performance. Again we have this suggestion that amyloid is associated with tau and tau is associated with poor memory even in normal people.”
Although hard to swallow, digesting solanezumab’s failure in the series of EXPEDITION studies has now refined the A4 protocol. “To be honest, I didn’t sleep for months following the release of EXPEDITION 3 data, because I was really concerned about how it should guide us about changes to A4. We think solanezumab has an increased chance of success here [compared with EXPEDITION] because we’re employing it 10-15 years earlier in the disease. But we also want to maximize its chances.”
Thus, she said, investigators and Eli Lilly have now decided to quadruple the dose in A4. Subjects will titrate from 600 mg to 800 mg for 2 months and then go up to 1,600 mg every 4 weeks. A safety cohort of 200 patients will be monitored for any adverse events, with a particular eye out for hemorrhagic or edematous ARIA. “We are also extending the double-blind phase to 240 weeks, which allows everyone to dose-escalate and increases our power to detect small effect sizes,” she said.
Right now, recruitment stands at 1,151; Dr. Sperling expects the full 1,200-subject cohort to be randomized by the end of 2017.
Gantenerumab is also experiencing a rebirth after a deep dive into open-label extension data from both the Scarlet Road and Marguerite Road studies, Dr. Klein said. Patients in these studies were randomized to either 105 or 225 mg of the antibody. While there were no significant cognitive benefits, there were trends toward improvement with the higher dose, as well as dose-dependent plaque clearance. This encouraged researchers to look at higher doses in 52-week open-label extensions of each study.
Dr. Klein presented new imaging data for these studies. Between both, 40 patients were maintained for 6-9 months on the highest doses (900-1,200 mg). Of these, 17 had almost total clearance of their amyloid burden. Their scans, Dr. Klein said, read as traces of amyloid or as amyloid negative. The effect was consistent regardless of the amount of amyloid at baseline.
“These are very encouraging biomarker data,” he said. “We are going into our new phase 3 studies, Graduate I and II, very optimistic.”
Little information is available about these studies. According to a press release, they will target patients with prodromal-mild disease at the higher doses. Emails to Roche and its German partner, MorphoSys, were not returned by press time. But from Dr. Klein’s comments, it seems clear that gantenerumab has not reached the end of its road.
Dr. Sperling disclosed relationships with numerous pharmaceutical companies. Dr. Klein is an employee of Roche.
[email protected]
On Twitter @alz_gal
BOSTON – Despite years of frustrating failures, Alzheimer’s researchers keep punching away at beta-amyloid brain plaques, now apparently with a highly focused one-two of “more drug, given sooner.”
Solanezumab and gantenerumab – both of which failed in earlier phase 3 studies – will be pushed forward now at much higher doses, the Alzheimer’s disease research community learned at the opening session of the Clinical Trials on Alzheimer’s Disease conference.
Both drugs are antiamyloid antibodies. In their prior trials, both effectively cleared amyloid plaques, but neither significantly improved cognition in patients with mild-moderate disease. This has been a common theme of every antiamyloid study: Although these drugs stimulate different mechanisms of plaque removal, none has ever significantly improved thinking or memory.
In discussing these failures, the Alzheimer’s research community has collectively wondered whether the doses were high enough. Drug companies have erred on the side of caution in large part because antiamyloid antibodies can cause a syndrome called ARIA (Amyloid-Related Imaging Abnormalities), an inflammatory response of brain edema or microhemorrhages. Concern over this side effect has moderated as researchers accumulate more adverse event data. Most cases are asymptomatic and resolve spontaneously. New open-label extension data from the Scarlet Road and Marguerite Road trials of gantenerumab, plus a new titration model by Roche, have also increased confidence that patients will tolerate the antibody at subcutaneous doses of up to 1,200 mg.
The other fear that plagues researchers is therapeutic timing. It’s increasingly apparent that plaque eradication does not rescue cognition. As heart disease must be attacked before cardiac damage occurs, it seems likely that Alzheimer’s disease must be attacked before amyloid and its attendant protein, tau, wreak havoc in the hippocampus and neocortex.
After reevaluating the high-profile solanezumab and gantenerumab failures, researchers now hope that higher doses delivered much earlier in the disease process might be effective, not at restoring lost cognition, but at preventing cognitive decline in the first place.
“One of the greatest advances in this field over the past 10 years is the recognition that Alzheimer’s disease is a continuum that likely begins well before the stage we recognize as dementia, and even before the stages of mild cognitive impairment [MCI] and prodromal Alzheimer’s,” said Dr. Sperling of Brigham and Women’s Hospital, Boston. “Treating in the presymptomatic phase may be the best opportunity to bend this curve back toward the trajectory of normal aging.”
But amyloid is only part of the Alzheimer’s disease story. Tau is a key player and, some say, the prime antagonist, since it is the main driver of memory and thought decline. Tau is present deep in the brains of most cognitively aging normal people, but something about amyloid deposition spurs its devastating spread into the neocortex. Preventing amyloid accumulation may prevent dementia, not just by keeping amyloid at bay, but by preventing it from igniting the spread of tau.
Dr. Sperling cited unpublished data showing very subtle cognitive decline in cognitively normal patients who have both amyloid and tau in the brain. Although the scores stayed within normal, subjects with both declined over 2 years on specific measures of memory and were more likely to progress to MCI.
“This is very striking to me and made me a little worried about the critical window of intervention,” she said. “What is also striking is that, even though we restricted the eligibility criteria of A4 to those with normal memory and normal cognition, we do see that tau positivity at baseline is associated with lower baseline performance. Again we have this suggestion that amyloid is associated with tau and tau is associated with poor memory even in normal people.”
Although hard to swallow, digesting solanezumab’s failure in the series of EXPEDITION studies has now refined the A4 protocol. “To be honest, I didn’t sleep for months following the release of EXPEDITION 3 data, because I was really concerned about how it should guide us about changes to A4. We think solanezumab has an increased chance of success here [compared with EXPEDITION] because we’re employing it 10-15 years earlier in the disease. But we also want to maximize its chances.”
Thus, she said, investigators and Eli Lilly have now decided to quadruple the dose in A4. Subjects will titrate from 600 mg to 800 mg for 2 months and then go up to 1,600 mg every 4 weeks. A safety cohort of 200 patients will be monitored for any adverse events, with a particular eye out for hemorrhagic or edematous ARIA. “We are also extending the double-blind phase to 240 weeks, which allows everyone to dose-escalate and increases our power to detect small effect sizes,” she said.
Right now, recruitment stands at 1,151; Dr. Sperling expects the full 1,200-subject cohort to be randomized by the end of 2017.
Gantenerumab is also experiencing a rebirth after a deep dive into open-label extension data from both the Scarlet Road and Marguerite Road studies, Dr. Klein said. Patients in these studies were randomized to either 105 or 225 mg of the antibody. While there were no significant cognitive benefits, there were trends toward improvement with the higher dose, as well as dose-dependent plaque clearance. This encouraged researchers to look at higher doses in 52-week open-label extensions of each study.
Dr. Klein presented new imaging data for these studies. Between both, 40 patients were maintained for 6-9 months on the highest doses (900-1,200 mg). Of these, 17 had almost total clearance of their amyloid burden. Their scans, Dr. Klein said, read as traces of amyloid or as amyloid negative. The effect was consistent regardless of the amount of amyloid at baseline.
“These are very encouraging biomarker data,” he said. “We are going into our new phase 3 studies, Graduate I and II, very optimistic.”
Little information is available about these studies. According to a press release, they will target patients with prodromal-mild disease at the higher doses. Emails to Roche and its German partner, MorphoSys, were not returned by press time. But from Dr. Klein’s comments, it seems clear that gantenerumab has not reached the end of its road.
Dr. Sperling disclosed relationships with numerous pharmaceutical companies. Dr. Klein is an employee of Roche.
[email protected]
On Twitter @alz_gal
BOSTON – Despite years of frustrating failures, Alzheimer’s researchers keep punching away at beta-amyloid brain plaques, now apparently with a highly focused one-two of “more drug, given sooner.”
Solanezumab and gantenerumab – both of which failed in earlier phase 3 studies – will be pushed forward now at much higher doses, the Alzheimer’s disease research community learned at the opening session of the Clinical Trials on Alzheimer’s Disease conference.
Both drugs are antiamyloid antibodies. In their prior trials, both effectively cleared amyloid plaques, but neither significantly improved cognition in patients with mild-moderate disease. This has been a common theme of every antiamyloid study: Although these drugs stimulate different mechanisms of plaque removal, none has ever significantly improved thinking or memory.
In discussing these failures, the Alzheimer’s research community has collectively wondered whether the doses were high enough. Drug companies have erred on the side of caution in large part because antiamyloid antibodies can cause a syndrome called ARIA (Amyloid-Related Imaging Abnormalities), an inflammatory response of brain edema or microhemorrhages. Concern over this side effect has moderated as researchers accumulate more adverse event data. Most cases are asymptomatic and resolve spontaneously. New open-label extension data from the Scarlet Road and Marguerite Road trials of gantenerumab, plus a new titration model by Roche, have also increased confidence that patients will tolerate the antibody at subcutaneous doses of up to 1,200 mg.
The other fear that plagues researchers is therapeutic timing. It’s increasingly apparent that plaque eradication does not rescue cognition. As heart disease must be attacked before cardiac damage occurs, it seems likely that Alzheimer’s disease must be attacked before amyloid and its attendant protein, tau, wreak havoc in the hippocampus and neocortex.
After reevaluating the high-profile solanezumab and gantenerumab failures, researchers now hope that higher doses delivered much earlier in the disease process might be effective, not at restoring lost cognition, but at preventing cognitive decline in the first place.
“One of the greatest advances in this field over the past 10 years is the recognition that Alzheimer’s disease is a continuum that likely begins well before the stage we recognize as dementia, and even before the stages of mild cognitive impairment [MCI] and prodromal Alzheimer’s,” said Dr. Sperling of Brigham and Women’s Hospital, Boston. “Treating in the presymptomatic phase may be the best opportunity to bend this curve back toward the trajectory of normal aging.”
But amyloid is only part of the Alzheimer’s disease story. Tau is a key player and, some say, the prime antagonist, since it is the main driver of memory and thought decline. Tau is present deep in the brains of most cognitively aging normal people, but something about amyloid deposition spurs its devastating spread into the neocortex. Preventing amyloid accumulation may prevent dementia, not just by keeping amyloid at bay, but by preventing it from igniting the spread of tau.
Dr. Sperling cited unpublished data showing very subtle cognitive decline in cognitively normal patients who have both amyloid and tau in the brain. Although the scores stayed within normal, subjects with both declined over 2 years on specific measures of memory and were more likely to progress to MCI.
“This is very striking to me and made me a little worried about the critical window of intervention,” she said. “What is also striking is that, even though we restricted the eligibility criteria of A4 to those with normal memory and normal cognition, we do see that tau positivity at baseline is associated with lower baseline performance. Again we have this suggestion that amyloid is associated with tau and tau is associated with poor memory even in normal people.”
Although hard to swallow, digesting solanezumab’s failure in the series of EXPEDITION studies has now refined the A4 protocol. “To be honest, I didn’t sleep for months following the release of EXPEDITION 3 data, because I was really concerned about how it should guide us about changes to A4. We think solanezumab has an increased chance of success here [compared with EXPEDITION] because we’re employing it 10-15 years earlier in the disease. But we also want to maximize its chances.”
Thus, she said, investigators and Eli Lilly have now decided to quadruple the dose in A4. Subjects will titrate from 600 mg to 800 mg for 2 months and then go up to 1,600 mg every 4 weeks. A safety cohort of 200 patients will be monitored for any adverse events, with a particular eye out for hemorrhagic or edematous ARIA. “We are also extending the double-blind phase to 240 weeks, which allows everyone to dose-escalate and increases our power to detect small effect sizes,” she said.
Right now, recruitment stands at 1,151; Dr. Sperling expects the full 1,200-subject cohort to be randomized by the end of 2017.
Gantenerumab is also experiencing a rebirth after a deep dive into open-label extension data from both the Scarlet Road and Marguerite Road studies, Dr. Klein said. Patients in these studies were randomized to either 105 or 225 mg of the antibody. While there were no significant cognitive benefits, there were trends toward improvement with the higher dose, as well as dose-dependent plaque clearance. This encouraged researchers to look at higher doses in 52-week open-label extensions of each study.
Dr. Klein presented new imaging data for these studies. Between both, 40 patients were maintained for 6-9 months on the highest doses (900-1,200 mg). Of these, 17 had almost total clearance of their amyloid burden. Their scans, Dr. Klein said, read as traces of amyloid or as amyloid negative. The effect was consistent regardless of the amount of amyloid at baseline.
“These are very encouraging biomarker data,” he said. “We are going into our new phase 3 studies, Graduate I and II, very optimistic.”
Little information is available about these studies. According to a press release, they will target patients with prodromal-mild disease at the higher doses. Emails to Roche and its German partner, MorphoSys, were not returned by press time. But from Dr. Klein’s comments, it seems clear that gantenerumab has not reached the end of its road.
Dr. Sperling disclosed relationships with numerous pharmaceutical companies. Dr. Klein is an employee of Roche.
[email protected]
On Twitter @alz_gal
AT CTAD
Some measures to control HAI sound better than they perform
SAN DIEGO – Some almost universally accepted measures against hospital-acquired infections are more costly, annoying, and time consuming than they’re worth, presenters agreed during a panel discussion at the annual clinical congress of the American College of Surgeons.
Intra-abdominal antibiotic irrigation, chlorhexidine bathing, and even postsurgical antibiotic infusions have not consistently been shown to reduce infections. These measures do, however, ratchet up costs and can contribute to antibiotic resistance.
Some of these and other measures to prevent nosocomial infections may indeed reduce the risk, but the gain is small, said Charles H. Cook, MD.
“Chlorhexidine bathing, for example, is touted by many as a panacea for all the infections we’re talking about,” said Dr. Cook, a critical care surgeon at Beth Israel Deaconess Medical Center, New York. “A recent meta-analysis in critical care units did find a reduced relative risk of 0.44 for central line bloodstream infections. But you needed to bathe 360 patients to prevent one infection. It’s what I call a long run for a short slide.”
Therese Duane, MD, FACS, agreed. A surgeon at the John Peter Smith Hospital, Ft. Worth, Tex., Dr. Duane reviewed three different guidelines for the prevention of surgical site infections: the ACS and Surgical Infection Society, the World Health Organization, and the Centers for Disease Control and Prevention. In looking for similarities between the documents, she said she found several well-accepted practices that just aren’t supported by good data.
Presurgical antimicrobial infusions got a strong thumbs-up from all the groups, but only under a very specific circumstance: The medication has to be administered well in advance of surgery for it to be effective.
“Your goal is to get the appropriate concentration into the tissues by the time of incision,” Dr. Duane said. “It takes time to get there – if you give it after the incision, you have bleeding and cellular death, and the antimicrobials cannot get to that incision and do their job. If I’m starting a case and they haven’t been given, I don’t ever start them after the incision, because then you have all of the risks and none of the benefits. In my opinion, we need to move to no further antimicrobials once the incision or case is over because it serves no purpose and is inconsistent with good antibiotic stewardship.”
Adhesive drapes got a resounding “eh” from the guidelines, Dr. Duane said. “You really do not need them. They’re expensive and they’re not improving outcomes, so don’t waste your time or money. We need to think about minimizing what isn’t helpful and maximizing the things that are worthwhile. That’s the way to practice good socially responsible surgery without breaking the bank,” she said.
Antimicrobial sutures got weak recommendations, Dr. Duane said. The evidence supporting their use was not very strong, although she said she feels triclosan-coated sutures are helpful in all kinds of surgery. Preoperative showering with an antiseptic received strong support, with alcohol-containing preps superior to chlorhexidine, which is better than povidone-iodine–containing solutions.
Deep-space irrigation with aqueous iodophor also received a weak recommendation, but Dr. Duane said the evidence does not support the use of antibiotic-containing irrigation in either the abdomen or the incision. “And the guidelines came out strongly against using antimicrobial agents on the incision,” she said. None of the guidelines issued a recommendation for or against antimicrobial dressings.
Protocolized infection-control bundles are a very great help in reducing the incidence of surgical site infections, Dr. Duane added. “They increase attention to detail and decrease the rates of infection.”
Dr. Cook agreed. “Central line bundles are one of the things that work” for line-associated bloodstream infections, he said. Since their large-scale adoption, mortality from these infections has dropped significantly; it was hovering around 28,000 per year in the mid-2000s, he said. “That’s about how many men die from prostate cancer every year.”
Central line infections are very costly too, he added – around $46,000 per event. “That comes to around $2 billion in direct and indirect costs every year.”
A 2006 study demonstrated the efficacy of central line bundles in the fight against these potentially devastating infections.
The bundled intervention comprised hand washing, using full-barrier precautions during the insertion of central venous catheters, cleaning the skin with chlorhexidine, avoiding the femoral site if possible, and removing unnecessary catheters. The median rate of catheter-related bloodstream infections per 1,000 catheter-days decreased from 2.7 at baseline to 0 at 3 months after implementation of the study intervention.
Antibiotic-coated or impregnated catheters do not work as well. A 2016 Cochrane review of 57 studies determined that the devices didn’t improve sepsis, all-cause mortality, or catheter-related local infections.
The jury may still be out on coated dressings or securing devices, however. Another Cochrane review, of 22 studies, found a 40% decrease in central line–associated bloodstream infections with these items. “There was moderate evidence that tip colonization was reduced, but the authors said more research is needed.”
The evidence looks stronger for alcohol-impregnated port protectors, Dr. Cook said. Two studies in particular support their use. In an oncology unit, the rate of these infections dropped from 2.3 to 0.3 per 1,000 catheter days after the port protectors were instituted.
In the second study, infection rates declined from 1.43 to 0.69 per 1,000 line-days after the protectors came on board.
“The advantage was seen mostly in ICUs, so the recommendations are to use them there,” Dr. Cook said.
Neither Dr. Cook nor Dr. Duane had any relevant financial disclosures.
[email protected]
On Twitter @Alz Gal
SAN DIEGO – Some almost universally accepted measures against hospital-acquired infections are more costly, annoying, and time consuming than they’re worth, presenters agreed during a panel discussion at the annual clinical congress of the American College of Surgeons.
Intra-abdominal antibiotic irrigation, chlorhexidine bathing, and even postsurgical antibiotic infusions have not consistently been shown to reduce infections. These measures do, however, ratchet up costs and can contribute to antibiotic resistance.
Some of these and other measures to prevent nosocomial infections may indeed reduce the risk, but the gain is small, said Charles H. Cook, MD.
“Chlorhexidine bathing, for example, is touted by many as a panacea for all the infections we’re talking about,” said Dr. Cook, a critical care surgeon at Beth Israel Deaconess Medical Center, New York. “A recent meta-analysis in critical care units did find a reduced relative risk of 0.44 for central line bloodstream infections. But you needed to bathe 360 patients to prevent one infection. It’s what I call a long run for a short slide.”
Therese Duane, MD, FACS, agreed. A surgeon at the John Peter Smith Hospital, Ft. Worth, Tex., Dr. Duane reviewed three different guidelines for the prevention of surgical site infections: the ACS and Surgical Infection Society, the World Health Organization, and the Centers for Disease Control and Prevention. In looking for similarities between the documents, she said she found several well-accepted practices that just aren’t supported by good data.
Presurgical antimicrobial infusions got a strong thumbs-up from all the groups, but only under a very specific circumstance: The medication has to be administered well in advance of surgery for it to be effective.
“Your goal is to get the appropriate concentration into the tissues by the time of incision,” Dr. Duane said. “It takes time to get there – if you give it after the incision, you have bleeding and cellular death, and the antimicrobials cannot get to that incision and do their job. If I’m starting a case and they haven’t been given, I don’t ever start them after the incision, because then you have all of the risks and none of the benefits. In my opinion, we need to move to no further antimicrobials once the incision or case is over because it serves no purpose and is inconsistent with good antibiotic stewardship.”
Adhesive drapes got a resounding “eh” from the guidelines, Dr. Duane said. “You really do not need them. They’re expensive and they’re not improving outcomes, so don’t waste your time or money. We need to think about minimizing what isn’t helpful and maximizing the things that are worthwhile. That’s the way to practice good socially responsible surgery without breaking the bank,” she said.
Antimicrobial sutures got weak recommendations, Dr. Duane said. The evidence supporting their use was not very strong, although she said she feels triclosan-coated sutures are helpful in all kinds of surgery. Preoperative showering with an antiseptic received strong support, with alcohol-containing preps superior to chlorhexidine, which is better than povidone-iodine–containing solutions.
Deep-space irrigation with aqueous iodophor also received a weak recommendation, but Dr. Duane said the evidence does not support the use of antibiotic-containing irrigation in either the abdomen or the incision. “And the guidelines came out strongly against using antimicrobial agents on the incision,” she said. None of the guidelines issued a recommendation for or against antimicrobial dressings.
Protocolized infection-control bundles are a very great help in reducing the incidence of surgical site infections, Dr. Duane added. “They increase attention to detail and decrease the rates of infection.”
Dr. Cook agreed. “Central line bundles are one of the things that work” for line-associated bloodstream infections, he said. Since their large-scale adoption, mortality from these infections has dropped significantly; it was hovering around 28,000 per year in the mid-2000s, he said. “That’s about how many men die from prostate cancer every year.”
Central line infections are very costly too, he added – around $46,000 per event. “That comes to around $2 billion in direct and indirect costs every year.”
A 2006 study demonstrated the efficacy of central line bundles in the fight against these potentially devastating infections.
The bundled intervention comprised hand washing, using full-barrier precautions during the insertion of central venous catheters, cleaning the skin with chlorhexidine, avoiding the femoral site if possible, and removing unnecessary catheters. The median rate of catheter-related bloodstream infections per 1,000 catheter-days decreased from 2.7 at baseline to 0 at 3 months after implementation of the study intervention.
Antibiotic-coated or impregnated catheters do not work as well. A 2016 Cochrane review of 57 studies determined that the devices didn’t improve sepsis, all-cause mortality, or catheter-related local infections.
The jury may still be out on coated dressings or securing devices, however. Another Cochrane review, of 22 studies, found a 40% decrease in central line–associated bloodstream infections with these items. “There was moderate evidence that tip colonization was reduced, but the authors said more research is needed.”
The evidence looks stronger for alcohol-impregnated port protectors, Dr. Cook said. Two studies in particular support their use. In an oncology unit, the rate of these infections dropped from 2.3 to 0.3 per 1,000 catheter days after the port protectors were instituted.
In the second study, infection rates declined from 1.43 to 0.69 per 1,000 line-days after the protectors came on board.
“The advantage was seen mostly in ICUs, so the recommendations are to use them there,” Dr. Cook said.
Neither Dr. Cook nor Dr. Duane had any relevant financial disclosures.
[email protected]
On Twitter @Alz Gal
SAN DIEGO – Some almost universally accepted measures against hospital-acquired infections are more costly, annoying, and time consuming than they’re worth, presenters agreed during a panel discussion at the annual clinical congress of the American College of Surgeons.
Intra-abdominal antibiotic irrigation, chlorhexidine bathing, and even postsurgical antibiotic infusions have not consistently been shown to reduce infections. These measures do, however, ratchet up costs and can contribute to antibiotic resistance.
Some of these and other measures to prevent nosocomial infections may indeed reduce the risk, but the gain is small, said Charles H. Cook, MD.
“Chlorhexidine bathing, for example, is touted by many as a panacea for all the infections we’re talking about,” said Dr. Cook, a critical care surgeon at Beth Israel Deaconess Medical Center, New York. “A recent meta-analysis in critical care units did find a reduced relative risk of 0.44 for central line bloodstream infections. But you needed to bathe 360 patients to prevent one infection. It’s what I call a long run for a short slide.”
Therese Duane, MD, FACS, agreed. A surgeon at the John Peter Smith Hospital, Ft. Worth, Tex., Dr. Duane reviewed three different guidelines for the prevention of surgical site infections: the ACS and Surgical Infection Society, the World Health Organization, and the Centers for Disease Control and Prevention. In looking for similarities between the documents, she said she found several well-accepted practices that just aren’t supported by good data.
Presurgical antimicrobial infusions got a strong thumbs-up from all the groups, but only under a very specific circumstance: The medication has to be administered well in advance of surgery for it to be effective.
“Your goal is to get the appropriate concentration into the tissues by the time of incision,” Dr. Duane said. “It takes time to get there – if you give it after the incision, you have bleeding and cellular death, and the antimicrobials cannot get to that incision and do their job. If I’m starting a case and they haven’t been given, I don’t ever start them after the incision, because then you have all of the risks and none of the benefits. In my opinion, we need to move to no further antimicrobials once the incision or case is over because it serves no purpose and is inconsistent with good antibiotic stewardship.”
Adhesive drapes got a resounding “eh” from the guidelines, Dr. Duane said. “You really do not need them. They’re expensive and they’re not improving outcomes, so don’t waste your time or money. We need to think about minimizing what isn’t helpful and maximizing the things that are worthwhile. That’s the way to practice good socially responsible surgery without breaking the bank,” she said.
Antimicrobial sutures got weak recommendations, Dr. Duane said. The evidence supporting their use was not very strong, although she said she feels triclosan-coated sutures are helpful in all kinds of surgery. Preoperative showering with an antiseptic received strong support, with alcohol-containing preps superior to chlorhexidine, which is better than povidone-iodine–containing solutions.
Deep-space irrigation with aqueous iodophor also received a weak recommendation, but Dr. Duane said the evidence does not support the use of antibiotic-containing irrigation in either the abdomen or the incision. “And the guidelines came out strongly against using antimicrobial agents on the incision,” she said. None of the guidelines issued a recommendation for or against antimicrobial dressings.
Protocolized infection-control bundles are a very great help in reducing the incidence of surgical site infections, Dr. Duane added. “They increase attention to detail and decrease the rates of infection.”
Dr. Cook agreed. “Central line bundles are one of the things that work” for line-associated bloodstream infections, he said. Since their large-scale adoption, mortality from these infections has dropped significantly; it was hovering around 28,000 per year in the mid-2000s, he said. “That’s about how many men die from prostate cancer every year.”
Central line infections are very costly too, he added – around $46,000 per event. “That comes to around $2 billion in direct and indirect costs every year.”
A 2006 study demonstrated the efficacy of central line bundles in the fight against these potentially devastating infections.
The bundled intervention comprised hand washing, using full-barrier precautions during the insertion of central venous catheters, cleaning the skin with chlorhexidine, avoiding the femoral site if possible, and removing unnecessary catheters. The median rate of catheter-related bloodstream infections per 1,000 catheter-days decreased from 2.7 at baseline to 0 at 3 months after implementation of the study intervention.
Antibiotic-coated or impregnated catheters do not work as well. A 2016 Cochrane review of 57 studies determined that the devices didn’t improve sepsis, all-cause mortality, or catheter-related local infections.
The jury may still be out on coated dressings or securing devices, however. Another Cochrane review, of 22 studies, found a 40% decrease in central line–associated bloodstream infections with these items. “There was moderate evidence that tip colonization was reduced, but the authors said more research is needed.”
The evidence looks stronger for alcohol-impregnated port protectors, Dr. Cook said. Two studies in particular support their use. In an oncology unit, the rate of these infections dropped from 2.3 to 0.3 per 1,000 catheter days after the port protectors were instituted.
In the second study, infection rates declined from 1.43 to 0.69 per 1,000 line-days after the protectors came on board.
“The advantage was seen mostly in ICUs, so the recommendations are to use them there,” Dr. Cook said.
Neither Dr. Cook nor Dr. Duane had any relevant financial disclosures.
[email protected]
On Twitter @Alz Gal
FROM THE ACS CLINICAL CONGRESS
Early evidence shows that surgery can alter gut microbiome
SAN DIEGO – Surgery appears to stimulate abrupt changes in both the skin and gut microbiome, which in some patients may increase the risk of surgical site infections and anastomotic leaks. With that knowledge, researchers are exploring the very first steps toward a presurgical microbiome optimization protocol, Heidi Nelson, MD, FACS, said at the annual clinical congress of the American College of Surgeons.
It’s very early in the journey, said Dr. Nelson, the Fred C. Andersen Professor of Surgery at Mayo Clinic, Rochester. Minn. And it won’t be a straightforward path: The human microbiome appears to be nearly as individually unique as the human fingerprint, so presurgical protocols might have to be individually tailored to each patient.
Dr. Nelson comoderated a session exploring this topic with John Alverdy, MD, FACS, of the University of Chicago. The panel discussed human and animal studies suggesting that the stress of surgery, when combined with subclinical ischemia and any baseline physiologic stress (chronic illness or radiation, for example) can cause some commensals to begin producing collagenase – a change that endangers even surgically sound anastomoses.
“It’s well known that bacteria can change their function in response to host stress,” said Dr. Shogan, a colorectal surgeon at the University of Chicago. “They recognize these factors and change their entire function. In our work, we found that Enterococcus began to express a tissue-destroying phenotype in response to subclinical ischemia related to surgery.”
The pathogenic flip doesn’t occur unless there are a couple of predisposing factors, he theorized. “There have to be multiple stresses involved. These could include smoking, steroids, obesity, and prior exposure to radiation – all things that we commonly see in our colorectal surgery patients. But when the right situation developed, we can see a proliferation of collagen-destroying bacteria that predispose to leaks.”
The skin microbiome is altered as well, with areas around abdominal incisions beginning to express gut flora, which increase the risk of a surgical site infection, said Andrew Yeh, MD, a general surgery resident at the University of Pittsburgh.
He presented data on 28 colorectal surgery patients, detailing perioperative changes in the chest and abdominal skin microbiome. All of the subjects were adults undergoing colon resection who had not been on any antibiotics at least 1 month before surgery. Skin sampling was performed before and after opening, with additional postoperative skin samples taken daily while the patient was in the hospital recovering. Dr. Yeh had DNA/RNA data on 431 samples taken from this group.
“We saw increases in Staphylococcus and Bacteroides on the skin – normally part of the gut microflora – in relative abundance, while Corynebacterium, a normal constituent of the skin microbiome, had decreased.”
These are all very early observations, though, and the surgical community is nowhere near being able to make any specific presurgical recommendations to optimize the microbiome, or postsurgical recommendations to manage it, said Neil Hyman, MD, FACS, professor of surgery at the University of Chicago.
While it does appear that good bacteria “gone bad” are associated with anastomotic leaks, he agreed that the right constellation of factors has to be in place for this to happen, including “the right bacteria [Enterococcus], the right virulence genes [collagenase], the right activating cures [long operation, blood loss], and the wrong microbiome [altered by smoking, chemotherapy, radiation, or other chronic stressors].”
“I think it’s safe to say that developing collagenase-producing bacteria at an anastomosis site is a bad thing, but the individual genetic makeup of every patient makes any one-size-fits-all protocol approach to treatment really problematic,” Dr. Hyman said.
None of the presenters had any financial disclosures.
[email protected]
On Twitter @Alz_Gal
SAN DIEGO – Surgery appears to stimulate abrupt changes in both the skin and gut microbiome, which in some patients may increase the risk of surgical site infections and anastomotic leaks. With that knowledge, researchers are exploring the very first steps toward a presurgical microbiome optimization protocol, Heidi Nelson, MD, FACS, said at the annual clinical congress of the American College of Surgeons.
It’s very early in the journey, said Dr. Nelson, the Fred C. Andersen Professor of Surgery at Mayo Clinic, Rochester. Minn. And it won’t be a straightforward path: The human microbiome appears to be nearly as individually unique as the human fingerprint, so presurgical protocols might have to be individually tailored to each patient.
Dr. Nelson comoderated a session exploring this topic with John Alverdy, MD, FACS, of the University of Chicago. The panel discussed human and animal studies suggesting that the stress of surgery, when combined with subclinical ischemia and any baseline physiologic stress (chronic illness or radiation, for example) can cause some commensals to begin producing collagenase – a change that endangers even surgically sound anastomoses.
“It’s well known that bacteria can change their function in response to host stress,” said Dr. Shogan, a colorectal surgeon at the University of Chicago. “They recognize these factors and change their entire function. In our work, we found that Enterococcus began to express a tissue-destroying phenotype in response to subclinical ischemia related to surgery.”
The pathogenic flip doesn’t occur unless there are a couple of predisposing factors, he theorized. “There have to be multiple stresses involved. These could include smoking, steroids, obesity, and prior exposure to radiation – all things that we commonly see in our colorectal surgery patients. But when the right situation developed, we can see a proliferation of collagen-destroying bacteria that predispose to leaks.”
The skin microbiome is altered as well, with areas around abdominal incisions beginning to express gut flora, which increase the risk of a surgical site infection, said Andrew Yeh, MD, a general surgery resident at the University of Pittsburgh.
He presented data on 28 colorectal surgery patients, detailing perioperative changes in the chest and abdominal skin microbiome. All of the subjects were adults undergoing colon resection who had not been on any antibiotics at least 1 month before surgery. Skin sampling was performed before and after opening, with additional postoperative skin samples taken daily while the patient was in the hospital recovering. Dr. Yeh had DNA/RNA data on 431 samples taken from this group.
“We saw increases in Staphylococcus and Bacteroides on the skin – normally part of the gut microflora – in relative abundance, while Corynebacterium, a normal constituent of the skin microbiome, had decreased.”
These are all very early observations, though, and the surgical community is nowhere near being able to make any specific presurgical recommendations to optimize the microbiome, or postsurgical recommendations to manage it, said Neil Hyman, MD, FACS, professor of surgery at the University of Chicago.
While it does appear that good bacteria “gone bad” are associated with anastomotic leaks, he agreed that the right constellation of factors has to be in place for this to happen, including “the right bacteria [Enterococcus], the right virulence genes [collagenase], the right activating cures [long operation, blood loss], and the wrong microbiome [altered by smoking, chemotherapy, radiation, or other chronic stressors].”
“I think it’s safe to say that developing collagenase-producing bacteria at an anastomosis site is a bad thing, but the individual genetic makeup of every patient makes any one-size-fits-all protocol approach to treatment really problematic,” Dr. Hyman said.
None of the presenters had any financial disclosures.
[email protected]
On Twitter @Alz_Gal
SAN DIEGO – Surgery appears to stimulate abrupt changes in both the skin and gut microbiome, which in some patients may increase the risk of surgical site infections and anastomotic leaks. With that knowledge, researchers are exploring the very first steps toward a presurgical microbiome optimization protocol, Heidi Nelson, MD, FACS, said at the annual clinical congress of the American College of Surgeons.
It’s very early in the journey, said Dr. Nelson, the Fred C. Andersen Professor of Surgery at Mayo Clinic, Rochester. Minn. And it won’t be a straightforward path: The human microbiome appears to be nearly as individually unique as the human fingerprint, so presurgical protocols might have to be individually tailored to each patient.
Dr. Nelson comoderated a session exploring this topic with John Alverdy, MD, FACS, of the University of Chicago. The panel discussed human and animal studies suggesting that the stress of surgery, when combined with subclinical ischemia and any baseline physiologic stress (chronic illness or radiation, for example) can cause some commensals to begin producing collagenase – a change that endangers even surgically sound anastomoses.
“It’s well known that bacteria can change their function in response to host stress,” said Dr. Shogan, a colorectal surgeon at the University of Chicago. “They recognize these factors and change their entire function. In our work, we found that Enterococcus began to express a tissue-destroying phenotype in response to subclinical ischemia related to surgery.”
The pathogenic flip doesn’t occur unless there are a couple of predisposing factors, he theorized. “There have to be multiple stresses involved. These could include smoking, steroids, obesity, and prior exposure to radiation – all things that we commonly see in our colorectal surgery patients. But when the right situation developed, we can see a proliferation of collagen-destroying bacteria that predispose to leaks.”
The skin microbiome is altered as well, with areas around abdominal incisions beginning to express gut flora, which increase the risk of a surgical site infection, said Andrew Yeh, MD, a general surgery resident at the University of Pittsburgh.
He presented data on 28 colorectal surgery patients, detailing perioperative changes in the chest and abdominal skin microbiome. All of the subjects were adults undergoing colon resection who had not been on any antibiotics at least 1 month before surgery. Skin sampling was performed before and after opening, with additional postoperative skin samples taken daily while the patient was in the hospital recovering. Dr. Yeh had DNA/RNA data on 431 samples taken from this group.
“We saw increases in Staphylococcus and Bacteroides on the skin – normally part of the gut microflora – in relative abundance, while Corynebacterium, a normal constituent of the skin microbiome, had decreased.”
These are all very early observations, though, and the surgical community is nowhere near being able to make any specific presurgical recommendations to optimize the microbiome, or postsurgical recommendations to manage it, said Neil Hyman, MD, FACS, professor of surgery at the University of Chicago.
While it does appear that good bacteria “gone bad” are associated with anastomotic leaks, he agreed that the right constellation of factors has to be in place for this to happen, including “the right bacteria [Enterococcus], the right virulence genes [collagenase], the right activating cures [long operation, blood loss], and the wrong microbiome [altered by smoking, chemotherapy, radiation, or other chronic stressors].”
“I think it’s safe to say that developing collagenase-producing bacteria at an anastomosis site is a bad thing, but the individual genetic makeup of every patient makes any one-size-fits-all protocol approach to treatment really problematic,” Dr. Hyman said.
None of the presenters had any financial disclosures.
[email protected]
On Twitter @Alz_Gal
EXPERT ANALYSIS FROM THE ACS CLINICAL CONGRESS
VIDEO: SBO in bariatric patient can mean internal herniation
SAN DIEGO – You get a call from the emergency department at 3 a.m. A 48-year-old woman is presenting with fever, nausea, vomiting, and left upper quadrant pain. And the patient says she had a gastric bypass procedure 3 years ago.
Time to panic? Not necessarily, but things can, and occasionally do, go bad for these patients, even if they have had a long-stable bypass, Jennifer Choi, MD, FACS, said in a video interview at the annual clinical congress of the American College of Surgeons.
“We do have to remember that our bariatric surgery patients can develop all of the same kinds of problems that anyone else can,” said Dr. Choi, a general surgeon at Indiana University, Indianapolis. “Appendicitis, diverticulitis, abdominal wall hernias, and other common things do happen.”
In her book, though, a patient with a gastric bypass who presents with a combination of small-bowel obstruction and pain has an internal herniation until proven otherwise.
“The symptoms can be subtle, and they can either have been building for several weeks or have an acute onset,” Dr. Choi said. These can include nausea, dry heaves, bloating, or nonbilious vomiting. Pain is typically located in the left upper quadrant or mid-back, especially if the hernia is located at one of the two most common spots: Petersen’s defect. This is the point where the biliopancreatic loop tends to slip under the alimentary loop and become trapped. Imaging will show a typical swirling of blood vessels around the herniation, accompanied by dilated small bowel at the point of obstruction.
At the other common herniation point, the site of the jejunojejunostomy, the alimentary loop can slip under the biliopancreatic loop. On imaging, jejunum will be seen in the upper right quadrant.
Both of these can be surgical emergencies, Dr. Choi said. “This needs an operation sooner, rather than later. It needs to be reduced and repaired.”
She typically performs this laparoscopically, but said that some surgeons prefer an open approach, which is a perfectly sound option.
“The key to a successful repair is to start at the ileocecal valve, because it is consistent and fixed, and run the bowel from distal to proximal to reduce the internal hernia. Then close the defect with a permanent suture,” she said.
Chylous ascites is almost always present in these cases because the herniation traumatizes the lymphatic system, Dr. Choi added. “It doesn’t all always have to be removed at the time of surgery, but just be aware that this is definitely something we do see, almost all the time in bariatric patients with these internal hernias.”
Dr. Choi had no financial disclosures.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
[email protected]
On Twitter @alz_gal
SAN DIEGO – You get a call from the emergency department at 3 a.m. A 48-year-old woman is presenting with fever, nausea, vomiting, and left upper quadrant pain. And the patient says she had a gastric bypass procedure 3 years ago.
Time to panic? Not necessarily, but things can, and occasionally do, go bad for these patients, even if they have had a long-stable bypass, Jennifer Choi, MD, FACS, said in a video interview at the annual clinical congress of the American College of Surgeons.
“We do have to remember that our bariatric surgery patients can develop all of the same kinds of problems that anyone else can,” said Dr. Choi, a general surgeon at Indiana University, Indianapolis. “Appendicitis, diverticulitis, abdominal wall hernias, and other common things do happen.”
In her book, though, a patient with a gastric bypass who presents with a combination of small-bowel obstruction and pain has an internal herniation until proven otherwise.
“The symptoms can be subtle, and they can either have been building for several weeks or have an acute onset,” Dr. Choi said. These can include nausea, dry heaves, bloating, or nonbilious vomiting. Pain is typically located in the left upper quadrant or mid-back, especially if the hernia is located at one of the two most common spots: Petersen’s defect. This is the point where the biliopancreatic loop tends to slip under the alimentary loop and become trapped. Imaging will show a typical swirling of blood vessels around the herniation, accompanied by dilated small bowel at the point of obstruction.
At the other common herniation point, the site of the jejunojejunostomy, the alimentary loop can slip under the biliopancreatic loop. On imaging, jejunum will be seen in the upper right quadrant.
Both of these can be surgical emergencies, Dr. Choi said. “This needs an operation sooner, rather than later. It needs to be reduced and repaired.”
She typically performs this laparoscopically, but said that some surgeons prefer an open approach, which is a perfectly sound option.
“The key to a successful repair is to start at the ileocecal valve, because it is consistent and fixed, and run the bowel from distal to proximal to reduce the internal hernia. Then close the defect with a permanent suture,” she said.
Chylous ascites is almost always present in these cases because the herniation traumatizes the lymphatic system, Dr. Choi added. “It doesn’t all always have to be removed at the time of surgery, but just be aware that this is definitely something we do see, almost all the time in bariatric patients with these internal hernias.”
Dr. Choi had no financial disclosures.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
[email protected]
On Twitter @alz_gal
SAN DIEGO – You get a call from the emergency department at 3 a.m. A 48-year-old woman is presenting with fever, nausea, vomiting, and left upper quadrant pain. And the patient says she had a gastric bypass procedure 3 years ago.
Time to panic? Not necessarily, but things can, and occasionally do, go bad for these patients, even if they have had a long-stable bypass, Jennifer Choi, MD, FACS, said in a video interview at the annual clinical congress of the American College of Surgeons.
“We do have to remember that our bariatric surgery patients can develop all of the same kinds of problems that anyone else can,” said Dr. Choi, a general surgeon at Indiana University, Indianapolis. “Appendicitis, diverticulitis, abdominal wall hernias, and other common things do happen.”
In her book, though, a patient with a gastric bypass who presents with a combination of small-bowel obstruction and pain has an internal herniation until proven otherwise.
“The symptoms can be subtle, and they can either have been building for several weeks or have an acute onset,” Dr. Choi said. These can include nausea, dry heaves, bloating, or nonbilious vomiting. Pain is typically located in the left upper quadrant or mid-back, especially if the hernia is located at one of the two most common spots: Petersen’s defect. This is the point where the biliopancreatic loop tends to slip under the alimentary loop and become trapped. Imaging will show a typical swirling of blood vessels around the herniation, accompanied by dilated small bowel at the point of obstruction.
At the other common herniation point, the site of the jejunojejunostomy, the alimentary loop can slip under the biliopancreatic loop. On imaging, jejunum will be seen in the upper right quadrant.
Both of these can be surgical emergencies, Dr. Choi said. “This needs an operation sooner, rather than later. It needs to be reduced and repaired.”
She typically performs this laparoscopically, but said that some surgeons prefer an open approach, which is a perfectly sound option.
“The key to a successful repair is to start at the ileocecal valve, because it is consistent and fixed, and run the bowel from distal to proximal to reduce the internal hernia. Then close the defect with a permanent suture,” she said.
Chylous ascites is almost always present in these cases because the herniation traumatizes the lymphatic system, Dr. Choi added. “It doesn’t all always have to be removed at the time of surgery, but just be aware that this is definitely something we do see, almost all the time in bariatric patients with these internal hernias.”
Dr. Choi had no financial disclosures.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
[email protected]
On Twitter @alz_gal
AT THE ACS Clinical Congress
Psychiatric illness, low IQ often co-occur among male inmates
BERLIN – Among inmates in a Mexican federal prison, psychiatric disorders went hand-in-hand with low or extremely low IQ scores, a study showed.
About 86% of the inmates with a mental illness also had an IQ of 67-69. These men were likely to have multiple psychiatric diagnoses compounded by traumatic brain injury and substance dependence. They also were lowest in the hierarchy of organized crime, Isaac S. Carlos, MD, said at the meeting of the World Psychiatric Association.
Outside prison, this combination of mental illness and low intelligence set these men up for manipulation by more intelligent criminals, who used them most frequently as drug mules or henchmen, Dr. Carlos said. Inside, they were still extremely vulnerable to manipulation and abuse by more intelligent inmates who retain their intellectual dominance in the prison social structure.
Dr. Carlos is an attending psychiatrist in a large, maximum security federal prison that houses thousands of men convicted mostly in organized crime rings associated with drug trafficking. About 45% of the country’s federal inmate population overall has been diagnosed with some kind of mental disorder and requires treatment, but there are few options, he said. In Dr. Carlos’s institution, with one psychiatrist, one criminologist, and 20 psychologists to serve more than 5,000 prisoners, there are few opportunities to do rehabilitative therapy, counseling, or any behavioral interventions. Medication is about the best treatment offered, Dr. Carlos said.
He said he is actively trying to establish an integrative care system there. As part of the project, Dr. Carlos and his colleagues looked at the co-occurrence of psychiatric diagnoses and IQ level.
His group comprised 400 inmates who were sent for psychiatric assessment, which included the Wechsler Abbreviated Scale of Intelligence, Second Edition. Each inmate also received a ranking for his role in organized crime: intellectual (administrative leaders and organizers at the top of the hierarchy), technical (responsible for transportation and transactions), or material (executers of the criminal commands from above).
Of the 400 inmates referred, 300 had at least one ICD-10 mental illness diagnosis. These men were a mean of 30 years old with a mean of 10 years of education. About a third of the group had a triple diagnosis of psychosis, dependence on multiple substances, and dissocial personality disorder (which is comparable to antisocial personality disorder in the DSM-5). These inmates also had the lowest IQ measurements.
Other diagnostic combinations included schizoaffective plus dissocial disorder; substance abuse plus psychosis; dependent personality disorder plus dissocial disorder; traumatic brain injury or posttraumatic stress disorder with psychosis; dependent personality plus dissocial disorder; bipolar disorder plus either dissocial disorder or dependent personality; depression plus borderline personality disorder; depression plus narcissistic disorder; depression plus both personality disorder and dependent personality disorder; adjustment disorder plus dissocial disorder; anxiety plus both dependent and personality disorder, with or without narcissistic disorder; and dependent disorder plus either narcissism or borderline personality disorder.
Only one inmate had a high IQ score. This man had a dual diagnosis of depression and narcissism, and an IQ of 129. He was considered an intellectual offender.
The next highest IQ was 77 – the upper limit of a large group of scores in the 70s. Diagnoses included adjustment disorder plus dissocial disorder; posttraumatic stress disorder plus dissocial disorder; bipolar plus dissocial disorder; and depression plus borderline personality disorder. These men largely fell into the “technical” offender category – the middlemen of organized crime.
At the lower end of the IQ scale were the men categorized as “material” offenders. With IQs ranging from 67 to 69, these men frequently had multiple mental illnesses complicated by brain damage and substance abuse. When psychosis occurred, it was always in conjunction with these lower IQ scores. Low scores were common, Dr. Carlos said: In fact, 45% of the cohort had an IQ of 67; 22%, an IQ of 68; and 19%, an IQ of 69.
“It is necessary to understand the psychiatric comorbidities as well as the IQ in order to get better treatment responses,” Dr. Carlos said. “In some other prisons, this is already understood and a part of therapeutic treatment, but we just don’t have this (in the federal prison system). We have to make the people who run these prisons understand this.”
He had no relevant financial disclosure.
[email protected]
On Twitter @alz_gal
BERLIN – Among inmates in a Mexican federal prison, psychiatric disorders went hand-in-hand with low or extremely low IQ scores, a study showed.
About 86% of the inmates with a mental illness also had an IQ of 67-69. These men were likely to have multiple psychiatric diagnoses compounded by traumatic brain injury and substance dependence. They also were lowest in the hierarchy of organized crime, Isaac S. Carlos, MD, said at the meeting of the World Psychiatric Association.
Outside prison, this combination of mental illness and low intelligence set these men up for manipulation by more intelligent criminals, who used them most frequently as drug mules or henchmen, Dr. Carlos said. Inside, they were still extremely vulnerable to manipulation and abuse by more intelligent inmates who retain their intellectual dominance in the prison social structure.
Dr. Carlos is an attending psychiatrist in a large, maximum security federal prison that houses thousands of men convicted mostly in organized crime rings associated with drug trafficking. About 45% of the country’s federal inmate population overall has been diagnosed with some kind of mental disorder and requires treatment, but there are few options, he said. In Dr. Carlos’s institution, with one psychiatrist, one criminologist, and 20 psychologists to serve more than 5,000 prisoners, there are few opportunities to do rehabilitative therapy, counseling, or any behavioral interventions. Medication is about the best treatment offered, Dr. Carlos said.
He said he is actively trying to establish an integrative care system there. As part of the project, Dr. Carlos and his colleagues looked at the co-occurrence of psychiatric diagnoses and IQ level.
His group comprised 400 inmates who were sent for psychiatric assessment, which included the Wechsler Abbreviated Scale of Intelligence, Second Edition. Each inmate also received a ranking for his role in organized crime: intellectual (administrative leaders and organizers at the top of the hierarchy), technical (responsible for transportation and transactions), or material (executers of the criminal commands from above).
Of the 400 inmates referred, 300 had at least one ICD-10 mental illness diagnosis. These men were a mean of 30 years old with a mean of 10 years of education. About a third of the group had a triple diagnosis of psychosis, dependence on multiple substances, and dissocial personality disorder (which is comparable to antisocial personality disorder in the DSM-5). These inmates also had the lowest IQ measurements.
Other diagnostic combinations included schizoaffective plus dissocial disorder; substance abuse plus psychosis; dependent personality disorder plus dissocial disorder; traumatic brain injury or posttraumatic stress disorder with psychosis; dependent personality plus dissocial disorder; bipolar disorder plus either dissocial disorder or dependent personality; depression plus borderline personality disorder; depression plus narcissistic disorder; depression plus both personality disorder and dependent personality disorder; adjustment disorder plus dissocial disorder; anxiety plus both dependent and personality disorder, with or without narcissistic disorder; and dependent disorder plus either narcissism or borderline personality disorder.
Only one inmate had a high IQ score. This man had a dual diagnosis of depression and narcissism, and an IQ of 129. He was considered an intellectual offender.
The next highest IQ was 77 – the upper limit of a large group of scores in the 70s. Diagnoses included adjustment disorder plus dissocial disorder; posttraumatic stress disorder plus dissocial disorder; bipolar plus dissocial disorder; and depression plus borderline personality disorder. These men largely fell into the “technical” offender category – the middlemen of organized crime.
At the lower end of the IQ scale were the men categorized as “material” offenders. With IQs ranging from 67 to 69, these men frequently had multiple mental illnesses complicated by brain damage and substance abuse. When psychosis occurred, it was always in conjunction with these lower IQ scores. Low scores were common, Dr. Carlos said: In fact, 45% of the cohort had an IQ of 67; 22%, an IQ of 68; and 19%, an IQ of 69.
“It is necessary to understand the psychiatric comorbidities as well as the IQ in order to get better treatment responses,” Dr. Carlos said. “In some other prisons, this is already understood and a part of therapeutic treatment, but we just don’t have this (in the federal prison system). We have to make the people who run these prisons understand this.”
He had no relevant financial disclosure.
[email protected]
On Twitter @alz_gal
BERLIN – Among inmates in a Mexican federal prison, psychiatric disorders went hand-in-hand with low or extremely low IQ scores, a study showed.
About 86% of the inmates with a mental illness also had an IQ of 67-69. These men were likely to have multiple psychiatric diagnoses compounded by traumatic brain injury and substance dependence. They also were lowest in the hierarchy of organized crime, Isaac S. Carlos, MD, said at the meeting of the World Psychiatric Association.
Outside prison, this combination of mental illness and low intelligence set these men up for manipulation by more intelligent criminals, who used them most frequently as drug mules or henchmen, Dr. Carlos said. Inside, they were still extremely vulnerable to manipulation and abuse by more intelligent inmates who retain their intellectual dominance in the prison social structure.
Dr. Carlos is an attending psychiatrist in a large, maximum security federal prison that houses thousands of men convicted mostly in organized crime rings associated with drug trafficking. About 45% of the country’s federal inmate population overall has been diagnosed with some kind of mental disorder and requires treatment, but there are few options, he said. In Dr. Carlos’s institution, with one psychiatrist, one criminologist, and 20 psychologists to serve more than 5,000 prisoners, there are few opportunities to do rehabilitative therapy, counseling, or any behavioral interventions. Medication is about the best treatment offered, Dr. Carlos said.
He said he is actively trying to establish an integrative care system there. As part of the project, Dr. Carlos and his colleagues looked at the co-occurrence of psychiatric diagnoses and IQ level.
His group comprised 400 inmates who were sent for psychiatric assessment, which included the Wechsler Abbreviated Scale of Intelligence, Second Edition. Each inmate also received a ranking for his role in organized crime: intellectual (administrative leaders and organizers at the top of the hierarchy), technical (responsible for transportation and transactions), or material (executers of the criminal commands from above).
Of the 400 inmates referred, 300 had at least one ICD-10 mental illness diagnosis. These men were a mean of 30 years old with a mean of 10 years of education. About a third of the group had a triple diagnosis of psychosis, dependence on multiple substances, and dissocial personality disorder (which is comparable to antisocial personality disorder in the DSM-5). These inmates also had the lowest IQ measurements.
Other diagnostic combinations included schizoaffective plus dissocial disorder; substance abuse plus psychosis; dependent personality disorder plus dissocial disorder; traumatic brain injury or posttraumatic stress disorder with psychosis; dependent personality plus dissocial disorder; bipolar disorder plus either dissocial disorder or dependent personality; depression plus borderline personality disorder; depression plus narcissistic disorder; depression plus both personality disorder and dependent personality disorder; adjustment disorder plus dissocial disorder; anxiety plus both dependent and personality disorder, with or without narcissistic disorder; and dependent disorder plus either narcissism or borderline personality disorder.
Only one inmate had a high IQ score. This man had a dual diagnosis of depression and narcissism, and an IQ of 129. He was considered an intellectual offender.
The next highest IQ was 77 – the upper limit of a large group of scores in the 70s. Diagnoses included adjustment disorder plus dissocial disorder; posttraumatic stress disorder plus dissocial disorder; bipolar plus dissocial disorder; and depression plus borderline personality disorder. These men largely fell into the “technical” offender category – the middlemen of organized crime.
At the lower end of the IQ scale were the men categorized as “material” offenders. With IQs ranging from 67 to 69, these men frequently had multiple mental illnesses complicated by brain damage and substance abuse. When psychosis occurred, it was always in conjunction with these lower IQ scores. Low scores were common, Dr. Carlos said: In fact, 45% of the cohort had an IQ of 67; 22%, an IQ of 68; and 19%, an IQ of 69.
“It is necessary to understand the psychiatric comorbidities as well as the IQ in order to get better treatment responses,” Dr. Carlos said. “In some other prisons, this is already understood and a part of therapeutic treatment, but we just don’t have this (in the federal prison system). We have to make the people who run these prisons understand this.”
He had no relevant financial disclosure.
[email protected]
On Twitter @alz_gal
AT WPA 2017
Key clinical point:
Major finding: Almost 90% of inmates in a Mexican federal prison with a mental disorder also had a low or extremely low IQ.
Data source: A prospective study of 400 men; 300 had at least one ICD-10 mental health diagnosis.
Disclosures: Dr. Carlos had no relevant financial disclosures.