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Type 2 diabetes remitted with low-calorie diet
Type 2 diabetes mellitus remitted without medication in 46% of subjects who followed a strict, calorie-controlled diet for 1 year, judging from the findings of an open-label, cluster-randomized trial.
Remission rates closely tracked weight loss, Michael E.J. Lean, MD, reported in the Dec. 5 online issue of the Lancet. Among those who lost 15 kg or more, 86% also normalized their hemoglobin A1c levels. Lesser weight losses were successful too, with diabetes remitting in 57% of those who lost 10-15 kg and 34% of those who lost 5-10 kg, reported Dr. Lean, who is chair of human nutrition at the University of Glasgow.
Weight loss conferred other benefits as well. Quality of life improved significantly, triglycerides declined, and about half of the subjects were able to discontinue both their antidiabetic and antihypertension prescriptions.
DiRECT (the Diabetes Remission Clinical Trial) didn’t include a strict exercise component – something that sets it apart from most dietary interventions, Dr. Lean noted in a press statement. Instead, the study’s “Counterweight-plus” diet intervention focused on very strict calorie control. Counterweight is a proprietary, subscription-based weight-loss program that costs about $570 for 1 year.
The paper offered few details about the intervention, which was supervised by a nurse and/or dietitian. For the first 3-5 months, patients consumed only Counterweight-branded soups and shakes, amounting to about 850 calories per day. After that, solid foods were reintroduced over 2-8 weeks. There was ongoing support for weight-loss maintenance, including cognitive-behavioral therapy, combined with strategies to increase physical activity. Activity strategies were confined to encouraging subjects to walk up to 15,000 steps per day in the second and third phase, but the investigators had little hope that this would actually occur.
“It was recognized that this target was unlikely to be achieved by many, and objectively measured physical activity showed no increase in physical activity in either group between baseline and 12 months, which underlines the difficulty this population has in maintaining increased activity,” they noted.
DiRECT enrolled 298 adults with type 2 diabetes recruited from 49 primary care practices across Scotland and England. They were about 54 years old, with a mean diabetes duration of about 3 years. Subjects were assigned to either the Counterweight-plus weight management program or best practice care under current guidelines. At baseline, subjects’ mean body mass index was 35 mg/m2. Their mean HbA1c was about 7.6%; about 75% were taking at least one antidiabetic medication, and 30% taking two or more. Hypertension was present in more than half.
In the active group, investigators withdrew all antidiabetic and antihypertensive medications when the diet commenced. Antihypertensives were restarted only if subjects experienced an increase in systolic blood pressure. Patients in the control group stayed on their medications.
At 12 months, the mean weight loss was significantly greater in the intervention group than the control group (10 kg vs. 1 kg). Weight loss of at least 15 kg occurred in 24% of the intervention group and none of the control group. It was most pronounced in the total diet replacement phase, falling by a mean of 14.5 kg; participants regained weigh during the food reintroduction phase (mean, 1 kg) and again during the maintenance phase (mean, 1.9 kg). Four subjects in the intervention group who experienced diabetes remission needed a “short rescue plan” on the total diet replacement phase because of weight regain within 60 days of the study’s end. The authors didn’t say how much weight these patients regained.
By the end of the study period, diabetes had remitted in 46% of the intervention group and 4% of the control group (odds ratio, 19.7) and was positively associated with the amount of weight loss.
At 12 months, 74% of the intervention group and 18% of the control group were off antidiabetic medications. HbA1c was significantly better in the intervention group (mean 6.4% vs. 7.2%). Antihypertensive drugs also were less common among the intervention group (32% vs. 61%) at 12 months. Despite the reduction in medication, there were no significant changes in blood pressure from baseline.
Nine serious adverse events occurred among seven intervention subjects. Two (biliary colic and abdominal pain) occurred in the same subject and were considered related to the diet, but they did not withdraw promptly.
Counterweight sponsored the trial, and several of the coinvestigators are stockholders and were company employees during the study. Dr. Lean reported financial remuneration from Counterweight.
SOURCE: Lean M et al. Lancet 2017 Dec 5; doi: 10.1016/ S0140-6736(17)33102-1.
The results of the DiRECT are “impressive and strongly support the view that type 2 diabetes is tightly associated with excessive fat mass in the body,” Matti Uusitupa, MD, wrote in an accompanying editorial.
Emerging data point at weight loss as the most effective treatment for type 2 diabetes, Dr. Uusitupa wrote. It confers a variety of benefits: improved insulin sensitivity in muscles and liver, decreased organ fat, and improved insulin secretion. Some studies suggest that fat loss also helps preserve beta cells in the pancreas.
Nevertheless, the study raises some questions. Without long-term data, it’s tough to know whether DiRECT should be a watershed moment in type 2 diabetes treatment, shifting efforts more toward weight loss and less toward medications.
“In view of the results of the DiRECT trial, a nonpharmacologic approach should be revived. In clinical practice, antidiabetic drugs seldom result in normalization of glucose metabolism if patients’ lifestyles remain unchanged. Mechanisms of action of some drugs for type 2 diabetes might not be in line with current knowledge of pathophysiology of disease, whereas intensive weight management along with physical activity and healthy diet is targeted therapy for type 2 diabetes.”
The best time to start a weight-loss war on type 2 diabetes is probably at the time of diagnosis, Dr. Uusitupa suggested, because patients are most highly motivated at that point.
“However, disease prevention should be maintained as the primary goal that requires both individual-level and population-based strategies.”
Dr. Uusitupa is an emeritus professor at the University of Eastern Finland, Kuopio.
The results of the DiRECT are “impressive and strongly support the view that type 2 diabetes is tightly associated with excessive fat mass in the body,” Matti Uusitupa, MD, wrote in an accompanying editorial.
Emerging data point at weight loss as the most effective treatment for type 2 diabetes, Dr. Uusitupa wrote. It confers a variety of benefits: improved insulin sensitivity in muscles and liver, decreased organ fat, and improved insulin secretion. Some studies suggest that fat loss also helps preserve beta cells in the pancreas.
Nevertheless, the study raises some questions. Without long-term data, it’s tough to know whether DiRECT should be a watershed moment in type 2 diabetes treatment, shifting efforts more toward weight loss and less toward medications.
“In view of the results of the DiRECT trial, a nonpharmacologic approach should be revived. In clinical practice, antidiabetic drugs seldom result in normalization of glucose metabolism if patients’ lifestyles remain unchanged. Mechanisms of action of some drugs for type 2 diabetes might not be in line with current knowledge of pathophysiology of disease, whereas intensive weight management along with physical activity and healthy diet is targeted therapy for type 2 diabetes.”
The best time to start a weight-loss war on type 2 diabetes is probably at the time of diagnosis, Dr. Uusitupa suggested, because patients are most highly motivated at that point.
“However, disease prevention should be maintained as the primary goal that requires both individual-level and population-based strategies.”
Dr. Uusitupa is an emeritus professor at the University of Eastern Finland, Kuopio.
The results of the DiRECT are “impressive and strongly support the view that type 2 diabetes is tightly associated with excessive fat mass in the body,” Matti Uusitupa, MD, wrote in an accompanying editorial.
Emerging data point at weight loss as the most effective treatment for type 2 diabetes, Dr. Uusitupa wrote. It confers a variety of benefits: improved insulin sensitivity in muscles and liver, decreased organ fat, and improved insulin secretion. Some studies suggest that fat loss also helps preserve beta cells in the pancreas.
Nevertheless, the study raises some questions. Without long-term data, it’s tough to know whether DiRECT should be a watershed moment in type 2 diabetes treatment, shifting efforts more toward weight loss and less toward medications.
“In view of the results of the DiRECT trial, a nonpharmacologic approach should be revived. In clinical practice, antidiabetic drugs seldom result in normalization of glucose metabolism if patients’ lifestyles remain unchanged. Mechanisms of action of some drugs for type 2 diabetes might not be in line with current knowledge of pathophysiology of disease, whereas intensive weight management along with physical activity and healthy diet is targeted therapy for type 2 diabetes.”
The best time to start a weight-loss war on type 2 diabetes is probably at the time of diagnosis, Dr. Uusitupa suggested, because patients are most highly motivated at that point.
“However, disease prevention should be maintained as the primary goal that requires both individual-level and population-based strategies.”
Dr. Uusitupa is an emeritus professor at the University of Eastern Finland, Kuopio.
Type 2 diabetes mellitus remitted without medication in 46% of subjects who followed a strict, calorie-controlled diet for 1 year, judging from the findings of an open-label, cluster-randomized trial.
Remission rates closely tracked weight loss, Michael E.J. Lean, MD, reported in the Dec. 5 online issue of the Lancet. Among those who lost 15 kg or more, 86% also normalized their hemoglobin A1c levels. Lesser weight losses were successful too, with diabetes remitting in 57% of those who lost 10-15 kg and 34% of those who lost 5-10 kg, reported Dr. Lean, who is chair of human nutrition at the University of Glasgow.
Weight loss conferred other benefits as well. Quality of life improved significantly, triglycerides declined, and about half of the subjects were able to discontinue both their antidiabetic and antihypertension prescriptions.
DiRECT (the Diabetes Remission Clinical Trial) didn’t include a strict exercise component – something that sets it apart from most dietary interventions, Dr. Lean noted in a press statement. Instead, the study’s “Counterweight-plus” diet intervention focused on very strict calorie control. Counterweight is a proprietary, subscription-based weight-loss program that costs about $570 for 1 year.
The paper offered few details about the intervention, which was supervised by a nurse and/or dietitian. For the first 3-5 months, patients consumed only Counterweight-branded soups and shakes, amounting to about 850 calories per day. After that, solid foods were reintroduced over 2-8 weeks. There was ongoing support for weight-loss maintenance, including cognitive-behavioral therapy, combined with strategies to increase physical activity. Activity strategies were confined to encouraging subjects to walk up to 15,000 steps per day in the second and third phase, but the investigators had little hope that this would actually occur.
“It was recognized that this target was unlikely to be achieved by many, and objectively measured physical activity showed no increase in physical activity in either group between baseline and 12 months, which underlines the difficulty this population has in maintaining increased activity,” they noted.
DiRECT enrolled 298 adults with type 2 diabetes recruited from 49 primary care practices across Scotland and England. They were about 54 years old, with a mean diabetes duration of about 3 years. Subjects were assigned to either the Counterweight-plus weight management program or best practice care under current guidelines. At baseline, subjects’ mean body mass index was 35 mg/m2. Their mean HbA1c was about 7.6%; about 75% were taking at least one antidiabetic medication, and 30% taking two or more. Hypertension was present in more than half.
In the active group, investigators withdrew all antidiabetic and antihypertensive medications when the diet commenced. Antihypertensives were restarted only if subjects experienced an increase in systolic blood pressure. Patients in the control group stayed on their medications.
At 12 months, the mean weight loss was significantly greater in the intervention group than the control group (10 kg vs. 1 kg). Weight loss of at least 15 kg occurred in 24% of the intervention group and none of the control group. It was most pronounced in the total diet replacement phase, falling by a mean of 14.5 kg; participants regained weigh during the food reintroduction phase (mean, 1 kg) and again during the maintenance phase (mean, 1.9 kg). Four subjects in the intervention group who experienced diabetes remission needed a “short rescue plan” on the total diet replacement phase because of weight regain within 60 days of the study’s end. The authors didn’t say how much weight these patients regained.
By the end of the study period, diabetes had remitted in 46% of the intervention group and 4% of the control group (odds ratio, 19.7) and was positively associated with the amount of weight loss.
At 12 months, 74% of the intervention group and 18% of the control group were off antidiabetic medications. HbA1c was significantly better in the intervention group (mean 6.4% vs. 7.2%). Antihypertensive drugs also were less common among the intervention group (32% vs. 61%) at 12 months. Despite the reduction in medication, there were no significant changes in blood pressure from baseline.
Nine serious adverse events occurred among seven intervention subjects. Two (biliary colic and abdominal pain) occurred in the same subject and were considered related to the diet, but they did not withdraw promptly.
Counterweight sponsored the trial, and several of the coinvestigators are stockholders and were company employees during the study. Dr. Lean reported financial remuneration from Counterweight.
SOURCE: Lean M et al. Lancet 2017 Dec 5; doi: 10.1016/ S0140-6736(17)33102-1.
Type 2 diabetes mellitus remitted without medication in 46% of subjects who followed a strict, calorie-controlled diet for 1 year, judging from the findings of an open-label, cluster-randomized trial.
Remission rates closely tracked weight loss, Michael E.J. Lean, MD, reported in the Dec. 5 online issue of the Lancet. Among those who lost 15 kg or more, 86% also normalized their hemoglobin A1c levels. Lesser weight losses were successful too, with diabetes remitting in 57% of those who lost 10-15 kg and 34% of those who lost 5-10 kg, reported Dr. Lean, who is chair of human nutrition at the University of Glasgow.
Weight loss conferred other benefits as well. Quality of life improved significantly, triglycerides declined, and about half of the subjects were able to discontinue both their antidiabetic and antihypertension prescriptions.
DiRECT (the Diabetes Remission Clinical Trial) didn’t include a strict exercise component – something that sets it apart from most dietary interventions, Dr. Lean noted in a press statement. Instead, the study’s “Counterweight-plus” diet intervention focused on very strict calorie control. Counterweight is a proprietary, subscription-based weight-loss program that costs about $570 for 1 year.
The paper offered few details about the intervention, which was supervised by a nurse and/or dietitian. For the first 3-5 months, patients consumed only Counterweight-branded soups and shakes, amounting to about 850 calories per day. After that, solid foods were reintroduced over 2-8 weeks. There was ongoing support for weight-loss maintenance, including cognitive-behavioral therapy, combined with strategies to increase physical activity. Activity strategies were confined to encouraging subjects to walk up to 15,000 steps per day in the second and third phase, but the investigators had little hope that this would actually occur.
“It was recognized that this target was unlikely to be achieved by many, and objectively measured physical activity showed no increase in physical activity in either group between baseline and 12 months, which underlines the difficulty this population has in maintaining increased activity,” they noted.
DiRECT enrolled 298 adults with type 2 diabetes recruited from 49 primary care practices across Scotland and England. They were about 54 years old, with a mean diabetes duration of about 3 years. Subjects were assigned to either the Counterweight-plus weight management program or best practice care under current guidelines. At baseline, subjects’ mean body mass index was 35 mg/m2. Their mean HbA1c was about 7.6%; about 75% were taking at least one antidiabetic medication, and 30% taking two or more. Hypertension was present in more than half.
In the active group, investigators withdrew all antidiabetic and antihypertensive medications when the diet commenced. Antihypertensives were restarted only if subjects experienced an increase in systolic blood pressure. Patients in the control group stayed on their medications.
At 12 months, the mean weight loss was significantly greater in the intervention group than the control group (10 kg vs. 1 kg). Weight loss of at least 15 kg occurred in 24% of the intervention group and none of the control group. It was most pronounced in the total diet replacement phase, falling by a mean of 14.5 kg; participants regained weigh during the food reintroduction phase (mean, 1 kg) and again during the maintenance phase (mean, 1.9 kg). Four subjects in the intervention group who experienced diabetes remission needed a “short rescue plan” on the total diet replacement phase because of weight regain within 60 days of the study’s end. The authors didn’t say how much weight these patients regained.
By the end of the study period, diabetes had remitted in 46% of the intervention group and 4% of the control group (odds ratio, 19.7) and was positively associated with the amount of weight loss.
At 12 months, 74% of the intervention group and 18% of the control group were off antidiabetic medications. HbA1c was significantly better in the intervention group (mean 6.4% vs. 7.2%). Antihypertensive drugs also were less common among the intervention group (32% vs. 61%) at 12 months. Despite the reduction in medication, there were no significant changes in blood pressure from baseline.
Nine serious adverse events occurred among seven intervention subjects. Two (biliary colic and abdominal pain) occurred in the same subject and were considered related to the diet, but they did not withdraw promptly.
Counterweight sponsored the trial, and several of the coinvestigators are stockholders and were company employees during the study. Dr. Lean reported financial remuneration from Counterweight.
SOURCE: Lean M et al. Lancet 2017 Dec 5; doi: 10.1016/ S0140-6736(17)33102-1.
FROM LANCET
Key clinical point: Diet alone may be enough to cause remission of type 2 diabetes.
Major finding: Type 2 diabetes remitted without medication in 46% of subjects who followed a strict, calorie-controlled diet for 1 year, according to results from a randomized, controlled trial.
Study details: The randomized study comprised 298 subjects.
Disclosures: Counterweight sponsored the trial, and several of the coinvestigators are stockholders and were company employees during the study. Dr. Lean reported financial remuneration from Counterweight.
Source: Lean M et al. Lancet. 2017. doi: 10.1016/ S0140-6736(17)33102-1.
High-intensity treadmill workouts preserved motor function in early-stage Parkinson’s
Six months of high-intensity treadmill walking largely preserved motor function in patients with recently diagnosed Parkinson’s disease, a phase 2 study has determined.
Patients randomized to the high-intensity exercise arm stayed very close to their baseline motor scores on the Unified Parkinson’s Disease Rating Scale (UPDRS), while the scores of those randomized to a wait list increased a mean of 3 points over 24 weeks. The scores of patients randomized to an intermediate-intensity treadmill workout increased 2 points over the study, which was not significantly different than the increase seen in the control group, Margaret Schenkman, PhD, and her colleagues wrote Dec. 11 in JAMA Neurology.
“A larger efficacy trial is warranted to determine whether exercising at 80%-85% maximum heart rate produces meaningful clinical benefits in de novo Parkinson disease,” wrote Dr. Schenkman and her colleagues. “Meanwhile, clinicians may safely prescribe exercise at this intensity level for this population.”
The Study in Parkinson Disease of Exercise (SPARX) randomized 128 patients with newly diagnosed Parkinson’s to 30-minute treadmill workouts, four times weekly, at either 80%-85% or 60%-65% maximum heart rate. They were compared against a control group of wait-listed patients.
Subjects were a mean of 64 years old and had been diagnosed for about 3-4 months before enrolling. Their mean total UPDRS score was 23.
Both active arms hit the gym a mean of 3 days/week and were able to exercise at their target heart rates, confirming the feasibility of treadmill workouts for this patient population.
The mean change in UPDRS motor score in the high-intensity group was an increase of 0.3 at 24 weeks, compared with an increase of 3.2 in the usual care group – a statistically significant difference. The mean change in the moderate-intensity group was an increase of 2.0, a nonsignificant difference.
Adverse events consisted largely of falls and musculoskeletal pain. There were 6 falls in the high-intensity group, 5 in the moderate-intensity group, and 11 in the control group. Of these falls, one in the high-intensity and one in the moderate-intensity group were considered serious.
SPARX was largely funded by a grant from the National Institute of Neurological Disorders and Stroke. None of the investigators reported having any financial conflicts.
SOURCE: Schenkman M et al. JAMA Neurol. 2017 Dec 11. doi: 10.1001/jamaneurol.2017.3517
Six months of high-intensity treadmill walking largely preserved motor function in patients with recently diagnosed Parkinson’s disease, a phase 2 study has determined.
Patients randomized to the high-intensity exercise arm stayed very close to their baseline motor scores on the Unified Parkinson’s Disease Rating Scale (UPDRS), while the scores of those randomized to a wait list increased a mean of 3 points over 24 weeks. The scores of patients randomized to an intermediate-intensity treadmill workout increased 2 points over the study, which was not significantly different than the increase seen in the control group, Margaret Schenkman, PhD, and her colleagues wrote Dec. 11 in JAMA Neurology.
“A larger efficacy trial is warranted to determine whether exercising at 80%-85% maximum heart rate produces meaningful clinical benefits in de novo Parkinson disease,” wrote Dr. Schenkman and her colleagues. “Meanwhile, clinicians may safely prescribe exercise at this intensity level for this population.”
The Study in Parkinson Disease of Exercise (SPARX) randomized 128 patients with newly diagnosed Parkinson’s to 30-minute treadmill workouts, four times weekly, at either 80%-85% or 60%-65% maximum heart rate. They were compared against a control group of wait-listed patients.
Subjects were a mean of 64 years old and had been diagnosed for about 3-4 months before enrolling. Their mean total UPDRS score was 23.
Both active arms hit the gym a mean of 3 days/week and were able to exercise at their target heart rates, confirming the feasibility of treadmill workouts for this patient population.
The mean change in UPDRS motor score in the high-intensity group was an increase of 0.3 at 24 weeks, compared with an increase of 3.2 in the usual care group – a statistically significant difference. The mean change in the moderate-intensity group was an increase of 2.0, a nonsignificant difference.
Adverse events consisted largely of falls and musculoskeletal pain. There were 6 falls in the high-intensity group, 5 in the moderate-intensity group, and 11 in the control group. Of these falls, one in the high-intensity and one in the moderate-intensity group were considered serious.
SPARX was largely funded by a grant from the National Institute of Neurological Disorders and Stroke. None of the investigators reported having any financial conflicts.
SOURCE: Schenkman M et al. JAMA Neurol. 2017 Dec 11. doi: 10.1001/jamaneurol.2017.3517
Six months of high-intensity treadmill walking largely preserved motor function in patients with recently diagnosed Parkinson’s disease, a phase 2 study has determined.
Patients randomized to the high-intensity exercise arm stayed very close to their baseline motor scores on the Unified Parkinson’s Disease Rating Scale (UPDRS), while the scores of those randomized to a wait list increased a mean of 3 points over 24 weeks. The scores of patients randomized to an intermediate-intensity treadmill workout increased 2 points over the study, which was not significantly different than the increase seen in the control group, Margaret Schenkman, PhD, and her colleagues wrote Dec. 11 in JAMA Neurology.
“A larger efficacy trial is warranted to determine whether exercising at 80%-85% maximum heart rate produces meaningful clinical benefits in de novo Parkinson disease,” wrote Dr. Schenkman and her colleagues. “Meanwhile, clinicians may safely prescribe exercise at this intensity level for this population.”
The Study in Parkinson Disease of Exercise (SPARX) randomized 128 patients with newly diagnosed Parkinson’s to 30-minute treadmill workouts, four times weekly, at either 80%-85% or 60%-65% maximum heart rate. They were compared against a control group of wait-listed patients.
Subjects were a mean of 64 years old and had been diagnosed for about 3-4 months before enrolling. Their mean total UPDRS score was 23.
Both active arms hit the gym a mean of 3 days/week and were able to exercise at their target heart rates, confirming the feasibility of treadmill workouts for this patient population.
The mean change in UPDRS motor score in the high-intensity group was an increase of 0.3 at 24 weeks, compared with an increase of 3.2 in the usual care group – a statistically significant difference. The mean change in the moderate-intensity group was an increase of 2.0, a nonsignificant difference.
Adverse events consisted largely of falls and musculoskeletal pain. There were 6 falls in the high-intensity group, 5 in the moderate-intensity group, and 11 in the control group. Of these falls, one in the high-intensity and one in the moderate-intensity group were considered serious.
SPARX was largely funded by a grant from the National Institute of Neurological Disorders and Stroke. None of the investigators reported having any financial conflicts.
SOURCE: Schenkman M et al. JAMA Neurol. 2017 Dec 11. doi: 10.1001/jamaneurol.2017.3517
FROM JAMA NEUROLOGY
Key clinical point:
Major finding: The high-intensity exercisers had a mean increase of 0.3 points on the UPDRS motor scale, compared with a 3.2-point increase in the control group.
Study details: The study randomized 128 patients to high-intensity or moderate-intensity treadmill exercise or to a wait list.
Disclosures: SPARX was largely funded by a grant from the National Institute of Neurological Disorders and Stroke. None of the investigators reported having any financial conflicts.
Source: Schenkman M et al. JAMA Neurol. 2017 Dec 11. doi: 10.1001/jamaneurol.2017.3517
Shaping practice: Z1071 continues to redefine axillary management
SAN DIEGO – A 2013 breast cancer trial is changing the way lymph nodes are managed in women with node-positive disease who have an axillary pathologic complete response to neoadjuvant chemotherapy.
Emerging additional data support the initial theory of the American College of Surgeons Oncology Group (ACOSOG) Z1071 trial, said Judy C. Boughey, MD, FACS, at the American College of Surgeons Clinical Congress: Performing sentinel lymph node surgery after chemotherapy is an acceptable alternative for some women. This change in practice could bestow a profound long-term benefit on the approximately 40% of patients, who have an axillary pathologic complete response after neoadjuvant chemotherapy (NAC) – patients who otherwise might undergo an unnecessary axillary node exploration, which can lead to higher risk of lymphedema, said Dr. Boughey, head of surgical research at the Mayo Clinic, Rochester, Minn.
“About 20% of patients who are treated with chemotherapy for their breast cancer receive the chemotherapy prior to surgery. Of those who do receive neoadjuvant chemotherapy, probably half could benefit from this approach,” she said. “Lymphedema after axillary dissection is one of the situations patients are most concerned about. This approach is a great one when patients have a good chemotherapy response, and we want to reliably reassure ourselves that there’s no disease left in the axilla without automatically removing all the nodes. Of course, if there is any remaining disease in any of the lymph nodes, the current standard is still to remove all the nodes. This approach, however, optimizes management for patients who have the best response to chemotherapy.”
Neoadjuvant therapy success
Prechemotherapy nodal exploration was routine a decade or so ago and is what many surgeons were most comfortable with, Dr. Boughey said. “We know the false-negative rate, and chemotherapy doesn’t interfere with axillary staging. However, it means patients have to go through two surgeries, and, although the chemotherapy does not interfere with the procedure, if any of the sentinel nodes are positive and an axillary dissection is performed at the same setting, then systemic therapy will be delayed. However, most importantly, when the sentinel node is removed prior to chemotherapy, we lose the ability to assess axillary response to chemotherapy – which correlates with survival.”
The biggest drawback of axillary dissection is its potential for lifelong morbidity from lymphedema. “Women know about this. They worry about this, and they want to avoid it if at all possible,” Dr. Boughey said.
More effective, targeted chemotherapeutic agents have resulted in higher rates of eradication of disease with neoadjuvant treatment. So this leads to the question: Why not reassess nodes after treatment, when these drugs have had a chance to work? Doing so reduces the one-size-fits-all prescription of axillary dissection and, thus, the number of women with lasting adverse events.
Some early data supported this theory
In 2009, researchers at the MD Anderson Center reported that sentinel node surgery after chemotherapy in patients with node-negative breast cancer resulted in fewer positive sentinel nodes and decreased unnecessary axillary dissections. Node identification rates were about 98% whether the surgery came before or after treatment. The false-negative rate hovered around 5%. And there were significantly fewer axillary dissections with posttreatment surgery: 20% vs. 36% in women with T2 disease and 30% vs. 51% in those with T3 disease. Importantly, holding off on the surgery didn’t lead to higher local-regional failure rates or survival among the 3,746 women treated during 1994-2007.
The American College of Surgeons Oncology Group Z1071 trial was designed to explore this question in patients with node-positive breast cancer. The Z1071 trial enrolled 756 women who had clinical T0-T4, N1-N2, M0 breast cancer and received neoadjuvant chemotherapy. Patients underwent both sentinel lymph node surgery and axillary lymph node dissection following chemotherapy. The primary endpoint was the false-negative rate of sentinel lymph node surgery after chemotherapy in women who presented with cN1 disease and had at least two sentinel nodes resected; a rate of 10% lower was considered acceptable and would justify the approach.
Of the entire cohort, 40% had a complete pathologic nodal response rate. The sentinel node identification rate was nearly 93%. The false-negative rate among 525 women with two or more positive sentinel nodes, however, was 12.6% – short of the 10% rate investigators needed to deem the study a success, Dr. Boughey said.
But there were some positive findings in subgroup analyses. Among women who had nodes identified with a dual tracer (both dye and radioactive clipping), the false-negative rate dipped to 10.8%. It was just 9% in those who had more than two sentinel nodes identified.
A recent subanalysis of the Z1071 trial further refined these data. It looked at 170 of the patients with cN1 disease (32%) who had had a clip placed in the positive lymph node at the time of percutaneous biopsy and compared false-negative rates among them with rates in the 355 patients who were not clipped.
“When we looked at them, if the clipped node came out during the sentinel node surgery, then the false-negative rate dropped down to about 7%,” Dr. Boughey said. The comparator group pointed out the value of using a clip. The false-negative rate was 13% in patients who didn’t have a clip placed and 19% in the patients whose clip wasn’t retrieved until axillary dissection.
The results of Z1071 and its subanalyses have popularized nodal clipping, Dr. Boughey said. “When we ran Z1071, clipping wasn’t commonly being performed, but there has been a huge uptake in it now.”
Confirmatory data
Other recent studies confirm the feasibility of this approach in women who have clinically negative nodes after NAC.
In 2013, the German study SENTINA (sentinel-lymph-node biopsy in patients with breast cancer before and after neoadjuvant chemotherapy) explored the false-negative rate in women who had sentinel node biopsy before or after neoadjuvant chemotherapy. Overall, it found an unacceptably high false-negative rate of 14% in women with node positive disease who converted to clinically negative nodal status. However, when the analysis was limited to those cases with at least two sentinel nodes, the false-negative rate was less than 10%, once more suggesting a potential role for sentinel node surgery after neoadjuvant chemotherapy.
In 2015, the Sentinel Node Biopsy Following Neoadjuvant Chemotherapy (SN FNAC) study highlighted the potential effect of sentinel node surgery after NAC. The prospective study showed not only that the strategy was safe, with a false-negative rate around 8%, but also that it could have eliminated complete axillary dissection in about 30% of the cohort.
The study enrolled 153 women with biopsy-proven node-positive breast cancer (T0-3, N1-2) who underwent both sentinel node surgery and complete nodal dissection. Immunohistochemistry of the retrieved sentinel nodes was mandatory, and the presence of any tumor cells in the sentinel node rendered it positive.
The sentinel node retrieval rate was 88%, and the false-negative rate, 8.4%. The study also employed dual tracers of isotope and blue dye in a majority of patients; this was associated with a threefold decrease in the false-negative rate in those patients, dropping it to around 5%. “By using sentinel node biopsy after NAC, axillary node dissection could potentially be avoided in at least 30% of patients who present with node-positive breast cancer,” the study’s team concluded.
Long-term consequences?
It’s increasingly clear that for carefully selected patients, with robust NAC response, a postchemotherapy assessment can accurately assess nodal disease – especially if dual tracers are employed, several sentinel nodes examined, and the biopsy-proven positive node is resected. What isn’t clear yet is the long-term effect of this strategy, Dr. Boughey said.
“Five years ago, when Z1071 was first being reported, I would discuss it in terms of the controversy, and give the pros and cons,” she said. “But now that we have more information about this strategy under our belts, I feel much more confident. However, we still do not have information on patients with node-positive disease who have been treated with sentinel node only after neoadjuvant chemotherapy and followed for 5 or 10 years. That’s the piece we just can’t have, without time.”
Dr. Boughey had no relevant financial disclosures.
SOURCE: Boughey JC. Session PS108.
SAN DIEGO – A 2013 breast cancer trial is changing the way lymph nodes are managed in women with node-positive disease who have an axillary pathologic complete response to neoadjuvant chemotherapy.
Emerging additional data support the initial theory of the American College of Surgeons Oncology Group (ACOSOG) Z1071 trial, said Judy C. Boughey, MD, FACS, at the American College of Surgeons Clinical Congress: Performing sentinel lymph node surgery after chemotherapy is an acceptable alternative for some women. This change in practice could bestow a profound long-term benefit on the approximately 40% of patients, who have an axillary pathologic complete response after neoadjuvant chemotherapy (NAC) – patients who otherwise might undergo an unnecessary axillary node exploration, which can lead to higher risk of lymphedema, said Dr. Boughey, head of surgical research at the Mayo Clinic, Rochester, Minn.
“About 20% of patients who are treated with chemotherapy for their breast cancer receive the chemotherapy prior to surgery. Of those who do receive neoadjuvant chemotherapy, probably half could benefit from this approach,” she said. “Lymphedema after axillary dissection is one of the situations patients are most concerned about. This approach is a great one when patients have a good chemotherapy response, and we want to reliably reassure ourselves that there’s no disease left in the axilla without automatically removing all the nodes. Of course, if there is any remaining disease in any of the lymph nodes, the current standard is still to remove all the nodes. This approach, however, optimizes management for patients who have the best response to chemotherapy.”
Neoadjuvant therapy success
Prechemotherapy nodal exploration was routine a decade or so ago and is what many surgeons were most comfortable with, Dr. Boughey said. “We know the false-negative rate, and chemotherapy doesn’t interfere with axillary staging. However, it means patients have to go through two surgeries, and, although the chemotherapy does not interfere with the procedure, if any of the sentinel nodes are positive and an axillary dissection is performed at the same setting, then systemic therapy will be delayed. However, most importantly, when the sentinel node is removed prior to chemotherapy, we lose the ability to assess axillary response to chemotherapy – which correlates with survival.”
The biggest drawback of axillary dissection is its potential for lifelong morbidity from lymphedema. “Women know about this. They worry about this, and they want to avoid it if at all possible,” Dr. Boughey said.
More effective, targeted chemotherapeutic agents have resulted in higher rates of eradication of disease with neoadjuvant treatment. So this leads to the question: Why not reassess nodes after treatment, when these drugs have had a chance to work? Doing so reduces the one-size-fits-all prescription of axillary dissection and, thus, the number of women with lasting adverse events.
Some early data supported this theory
In 2009, researchers at the MD Anderson Center reported that sentinel node surgery after chemotherapy in patients with node-negative breast cancer resulted in fewer positive sentinel nodes and decreased unnecessary axillary dissections. Node identification rates were about 98% whether the surgery came before or after treatment. The false-negative rate hovered around 5%. And there were significantly fewer axillary dissections with posttreatment surgery: 20% vs. 36% in women with T2 disease and 30% vs. 51% in those with T3 disease. Importantly, holding off on the surgery didn’t lead to higher local-regional failure rates or survival among the 3,746 women treated during 1994-2007.
The American College of Surgeons Oncology Group Z1071 trial was designed to explore this question in patients with node-positive breast cancer. The Z1071 trial enrolled 756 women who had clinical T0-T4, N1-N2, M0 breast cancer and received neoadjuvant chemotherapy. Patients underwent both sentinel lymph node surgery and axillary lymph node dissection following chemotherapy. The primary endpoint was the false-negative rate of sentinel lymph node surgery after chemotherapy in women who presented with cN1 disease and had at least two sentinel nodes resected; a rate of 10% lower was considered acceptable and would justify the approach.
Of the entire cohort, 40% had a complete pathologic nodal response rate. The sentinel node identification rate was nearly 93%. The false-negative rate among 525 women with two or more positive sentinel nodes, however, was 12.6% – short of the 10% rate investigators needed to deem the study a success, Dr. Boughey said.
But there were some positive findings in subgroup analyses. Among women who had nodes identified with a dual tracer (both dye and radioactive clipping), the false-negative rate dipped to 10.8%. It was just 9% in those who had more than two sentinel nodes identified.
A recent subanalysis of the Z1071 trial further refined these data. It looked at 170 of the patients with cN1 disease (32%) who had had a clip placed in the positive lymph node at the time of percutaneous biopsy and compared false-negative rates among them with rates in the 355 patients who were not clipped.
“When we looked at them, if the clipped node came out during the sentinel node surgery, then the false-negative rate dropped down to about 7%,” Dr. Boughey said. The comparator group pointed out the value of using a clip. The false-negative rate was 13% in patients who didn’t have a clip placed and 19% in the patients whose clip wasn’t retrieved until axillary dissection.
The results of Z1071 and its subanalyses have popularized nodal clipping, Dr. Boughey said. “When we ran Z1071, clipping wasn’t commonly being performed, but there has been a huge uptake in it now.”
Confirmatory data
Other recent studies confirm the feasibility of this approach in women who have clinically negative nodes after NAC.
In 2013, the German study SENTINA (sentinel-lymph-node biopsy in patients with breast cancer before and after neoadjuvant chemotherapy) explored the false-negative rate in women who had sentinel node biopsy before or after neoadjuvant chemotherapy. Overall, it found an unacceptably high false-negative rate of 14% in women with node positive disease who converted to clinically negative nodal status. However, when the analysis was limited to those cases with at least two sentinel nodes, the false-negative rate was less than 10%, once more suggesting a potential role for sentinel node surgery after neoadjuvant chemotherapy.
In 2015, the Sentinel Node Biopsy Following Neoadjuvant Chemotherapy (SN FNAC) study highlighted the potential effect of sentinel node surgery after NAC. The prospective study showed not only that the strategy was safe, with a false-negative rate around 8%, but also that it could have eliminated complete axillary dissection in about 30% of the cohort.
The study enrolled 153 women with biopsy-proven node-positive breast cancer (T0-3, N1-2) who underwent both sentinel node surgery and complete nodal dissection. Immunohistochemistry of the retrieved sentinel nodes was mandatory, and the presence of any tumor cells in the sentinel node rendered it positive.
The sentinel node retrieval rate was 88%, and the false-negative rate, 8.4%. The study also employed dual tracers of isotope and blue dye in a majority of patients; this was associated with a threefold decrease in the false-negative rate in those patients, dropping it to around 5%. “By using sentinel node biopsy after NAC, axillary node dissection could potentially be avoided in at least 30% of patients who present with node-positive breast cancer,” the study’s team concluded.
Long-term consequences?
It’s increasingly clear that for carefully selected patients, with robust NAC response, a postchemotherapy assessment can accurately assess nodal disease – especially if dual tracers are employed, several sentinel nodes examined, and the biopsy-proven positive node is resected. What isn’t clear yet is the long-term effect of this strategy, Dr. Boughey said.
“Five years ago, when Z1071 was first being reported, I would discuss it in terms of the controversy, and give the pros and cons,” she said. “But now that we have more information about this strategy under our belts, I feel much more confident. However, we still do not have information on patients with node-positive disease who have been treated with sentinel node only after neoadjuvant chemotherapy and followed for 5 or 10 years. That’s the piece we just can’t have, without time.”
Dr. Boughey had no relevant financial disclosures.
SOURCE: Boughey JC. Session PS108.
SAN DIEGO – A 2013 breast cancer trial is changing the way lymph nodes are managed in women with node-positive disease who have an axillary pathologic complete response to neoadjuvant chemotherapy.
Emerging additional data support the initial theory of the American College of Surgeons Oncology Group (ACOSOG) Z1071 trial, said Judy C. Boughey, MD, FACS, at the American College of Surgeons Clinical Congress: Performing sentinel lymph node surgery after chemotherapy is an acceptable alternative for some women. This change in practice could bestow a profound long-term benefit on the approximately 40% of patients, who have an axillary pathologic complete response after neoadjuvant chemotherapy (NAC) – patients who otherwise might undergo an unnecessary axillary node exploration, which can lead to higher risk of lymphedema, said Dr. Boughey, head of surgical research at the Mayo Clinic, Rochester, Minn.
“About 20% of patients who are treated with chemotherapy for their breast cancer receive the chemotherapy prior to surgery. Of those who do receive neoadjuvant chemotherapy, probably half could benefit from this approach,” she said. “Lymphedema after axillary dissection is one of the situations patients are most concerned about. This approach is a great one when patients have a good chemotherapy response, and we want to reliably reassure ourselves that there’s no disease left in the axilla without automatically removing all the nodes. Of course, if there is any remaining disease in any of the lymph nodes, the current standard is still to remove all the nodes. This approach, however, optimizes management for patients who have the best response to chemotherapy.”
Neoadjuvant therapy success
Prechemotherapy nodal exploration was routine a decade or so ago and is what many surgeons were most comfortable with, Dr. Boughey said. “We know the false-negative rate, and chemotherapy doesn’t interfere with axillary staging. However, it means patients have to go through two surgeries, and, although the chemotherapy does not interfere with the procedure, if any of the sentinel nodes are positive and an axillary dissection is performed at the same setting, then systemic therapy will be delayed. However, most importantly, when the sentinel node is removed prior to chemotherapy, we lose the ability to assess axillary response to chemotherapy – which correlates with survival.”
The biggest drawback of axillary dissection is its potential for lifelong morbidity from lymphedema. “Women know about this. They worry about this, and they want to avoid it if at all possible,” Dr. Boughey said.
More effective, targeted chemotherapeutic agents have resulted in higher rates of eradication of disease with neoadjuvant treatment. So this leads to the question: Why not reassess nodes after treatment, when these drugs have had a chance to work? Doing so reduces the one-size-fits-all prescription of axillary dissection and, thus, the number of women with lasting adverse events.
Some early data supported this theory
In 2009, researchers at the MD Anderson Center reported that sentinel node surgery after chemotherapy in patients with node-negative breast cancer resulted in fewer positive sentinel nodes and decreased unnecessary axillary dissections. Node identification rates were about 98% whether the surgery came before or after treatment. The false-negative rate hovered around 5%. And there were significantly fewer axillary dissections with posttreatment surgery: 20% vs. 36% in women with T2 disease and 30% vs. 51% in those with T3 disease. Importantly, holding off on the surgery didn’t lead to higher local-regional failure rates or survival among the 3,746 women treated during 1994-2007.
The American College of Surgeons Oncology Group Z1071 trial was designed to explore this question in patients with node-positive breast cancer. The Z1071 trial enrolled 756 women who had clinical T0-T4, N1-N2, M0 breast cancer and received neoadjuvant chemotherapy. Patients underwent both sentinel lymph node surgery and axillary lymph node dissection following chemotherapy. The primary endpoint was the false-negative rate of sentinel lymph node surgery after chemotherapy in women who presented with cN1 disease and had at least two sentinel nodes resected; a rate of 10% lower was considered acceptable and would justify the approach.
Of the entire cohort, 40% had a complete pathologic nodal response rate. The sentinel node identification rate was nearly 93%. The false-negative rate among 525 women with two or more positive sentinel nodes, however, was 12.6% – short of the 10% rate investigators needed to deem the study a success, Dr. Boughey said.
But there were some positive findings in subgroup analyses. Among women who had nodes identified with a dual tracer (both dye and radioactive clipping), the false-negative rate dipped to 10.8%. It was just 9% in those who had more than two sentinel nodes identified.
A recent subanalysis of the Z1071 trial further refined these data. It looked at 170 of the patients with cN1 disease (32%) who had had a clip placed in the positive lymph node at the time of percutaneous biopsy and compared false-negative rates among them with rates in the 355 patients who were not clipped.
“When we looked at them, if the clipped node came out during the sentinel node surgery, then the false-negative rate dropped down to about 7%,” Dr. Boughey said. The comparator group pointed out the value of using a clip. The false-negative rate was 13% in patients who didn’t have a clip placed and 19% in the patients whose clip wasn’t retrieved until axillary dissection.
The results of Z1071 and its subanalyses have popularized nodal clipping, Dr. Boughey said. “When we ran Z1071, clipping wasn’t commonly being performed, but there has been a huge uptake in it now.”
Confirmatory data
Other recent studies confirm the feasibility of this approach in women who have clinically negative nodes after NAC.
In 2013, the German study SENTINA (sentinel-lymph-node biopsy in patients with breast cancer before and after neoadjuvant chemotherapy) explored the false-negative rate in women who had sentinel node biopsy before or after neoadjuvant chemotherapy. Overall, it found an unacceptably high false-negative rate of 14% in women with node positive disease who converted to clinically negative nodal status. However, when the analysis was limited to those cases with at least two sentinel nodes, the false-negative rate was less than 10%, once more suggesting a potential role for sentinel node surgery after neoadjuvant chemotherapy.
In 2015, the Sentinel Node Biopsy Following Neoadjuvant Chemotherapy (SN FNAC) study highlighted the potential effect of sentinel node surgery after NAC. The prospective study showed not only that the strategy was safe, with a false-negative rate around 8%, but also that it could have eliminated complete axillary dissection in about 30% of the cohort.
The study enrolled 153 women with biopsy-proven node-positive breast cancer (T0-3, N1-2) who underwent both sentinel node surgery and complete nodal dissection. Immunohistochemistry of the retrieved sentinel nodes was mandatory, and the presence of any tumor cells in the sentinel node rendered it positive.
The sentinel node retrieval rate was 88%, and the false-negative rate, 8.4%. The study also employed dual tracers of isotope and blue dye in a majority of patients; this was associated with a threefold decrease in the false-negative rate in those patients, dropping it to around 5%. “By using sentinel node biopsy after NAC, axillary node dissection could potentially be avoided in at least 30% of patients who present with node-positive breast cancer,” the study’s team concluded.
Long-term consequences?
It’s increasingly clear that for carefully selected patients, with robust NAC response, a postchemotherapy assessment can accurately assess nodal disease – especially if dual tracers are employed, several sentinel nodes examined, and the biopsy-proven positive node is resected. What isn’t clear yet is the long-term effect of this strategy, Dr. Boughey said.
“Five years ago, when Z1071 was first being reported, I would discuss it in terms of the controversy, and give the pros and cons,” she said. “But now that we have more information about this strategy under our belts, I feel much more confident. However, we still do not have information on patients with node-positive disease who have been treated with sentinel node only after neoadjuvant chemotherapy and followed for 5 or 10 years. That’s the piece we just can’t have, without time.”
Dr. Boughey had no relevant financial disclosures.
SOURCE: Boughey JC. Session PS108.
EXPERT ANALYSIS FROM THE ACS CLINICAL CONGRESS
Flare of nonradiographic axial SpA occurs often after adalimumab withdrawal for remission
Patients with nonradiographic axial spondyloarthritis (nr-axSpA) who enter remission on adalimumab are likely to relapse if the medication is withdrawn – and many won’t attain remission again, even if the drug is restarted.
However, the findings of the ABILITY-3 trial do offer an intriguing potential, Robert Landewé, MD, PhD, said at the annual meeting of the American College of Rheumatology. About 30% of the study group did maintain remission after adalimumab (Humira) withdrawal, suggesting that at least a portion of these patients can stay in good clinical shape off TNF inhibition.
ABILITY-3 is the successor to ABILITY-1, the 2012 placebo-controlled study that established adalimumab as an effective treatment for nr-axSpA. Adalimumab is approved in the United States for the treatment of ankylosing spondylitis (radiographic axSpA), but not for nr-axSpA.
ABILITY-3 assessed the impact of withdrawing adalimumab from nr-axSpA patients who had attained remission on the medication. It enrolled 673 adults with active disease at baseline and an inadequate response to at least two nonsteroidal anti-inflammatory drugs.
The study commenced with open-label adalimumab at 40 mg every other week for 28 weeks. At that point, the 305 patients who had attained disease remission were randomized to either continued adalimumab at the same dose and schedule or to placebo. Randomized treatment continued for 40 more weeks. Any patient who experienced a flare resumed the drug as rescue therapy. The investigators calculated the number of patients with a disease flare at week 68 as the primary endpoint. The study also examined a number of secondary endpoints, including response measures, time to flare, functional status, quality of life, and remission.
At baseline, patients were a mean of 35 years old, with a mean disease duration of about 7 years. Most (88%) were HLA-B27 positive, and about 60% had elevated C-reactive protein levels.
At 68 weeks, patients who discontinued adalimumab were 77% more likely to have experienced a disease flare than were those who stayed on the drug (83% vs. 57% or 70% vs. 47% with nonresponder imputation; relative risk, 1.77). A time-to-flare analysis found a significant 67% reduction in the risk of flare among those continuing to take adalimumab.
While those who experienced a disease flare were allowed to resume adalimumab, it appeared to be far less effective at that point. After 12 weeks of rescue therapy, only 57% had regained remission, leaving 43% with persistent active disease.
Nearly all of the secondary endpoints were in favor of continuing therapy, Dr. Landewé said, including the Ankylosing Spondyloarthritis Disease Activity Score-inactive disease (ASDAS-ID), ASDAS-major improvement, ASDAS-clinically important improvement; the Assessment in Spondyloarthritis International Society (ASAS) 20% and 40% rates; the ASAS 5/6 and ASAS-partial response rates; the Bath Ankylosing Spondylitis Disease Activity Index 50; and the Bath Ankylosing Spondylitis Functional Index. Only health-related quality of life as measured by the Health Assessment Questionnaire for the Spondyloarthropathies did not significantly improve to a greater extent among those staying on adalimumab.
There were no new or concerning safety signals, Dr. Landewé said. In the placebo-controlled period, there were 10 serious adverse events in the placebo group and 1 – a case of ureterolithiasis – in the adalimumab group. There was one malignancy, which occurred in the placebo group. No patient died during the study.
“These results support the continuation of adalimumab therapy after achieving a sustained remission,” Dr. Landewé said. “But it will be an important research goal to identify predictors for the population in whom treatment may be safely discontinued.”
AbbVie sponsored the study. Dr. Landewé reported relationships with numerous pharmaceutical companies, including AbbVie.
Patients with nonradiographic axial spondyloarthritis (nr-axSpA) who enter remission on adalimumab are likely to relapse if the medication is withdrawn – and many won’t attain remission again, even if the drug is restarted.
However, the findings of the ABILITY-3 trial do offer an intriguing potential, Robert Landewé, MD, PhD, said at the annual meeting of the American College of Rheumatology. About 30% of the study group did maintain remission after adalimumab (Humira) withdrawal, suggesting that at least a portion of these patients can stay in good clinical shape off TNF inhibition.
ABILITY-3 is the successor to ABILITY-1, the 2012 placebo-controlled study that established adalimumab as an effective treatment for nr-axSpA. Adalimumab is approved in the United States for the treatment of ankylosing spondylitis (radiographic axSpA), but not for nr-axSpA.
ABILITY-3 assessed the impact of withdrawing adalimumab from nr-axSpA patients who had attained remission on the medication. It enrolled 673 adults with active disease at baseline and an inadequate response to at least two nonsteroidal anti-inflammatory drugs.
The study commenced with open-label adalimumab at 40 mg every other week for 28 weeks. At that point, the 305 patients who had attained disease remission were randomized to either continued adalimumab at the same dose and schedule or to placebo. Randomized treatment continued for 40 more weeks. Any patient who experienced a flare resumed the drug as rescue therapy. The investigators calculated the number of patients with a disease flare at week 68 as the primary endpoint. The study also examined a number of secondary endpoints, including response measures, time to flare, functional status, quality of life, and remission.
At baseline, patients were a mean of 35 years old, with a mean disease duration of about 7 years. Most (88%) were HLA-B27 positive, and about 60% had elevated C-reactive protein levels.
At 68 weeks, patients who discontinued adalimumab were 77% more likely to have experienced a disease flare than were those who stayed on the drug (83% vs. 57% or 70% vs. 47% with nonresponder imputation; relative risk, 1.77). A time-to-flare analysis found a significant 67% reduction in the risk of flare among those continuing to take adalimumab.
While those who experienced a disease flare were allowed to resume adalimumab, it appeared to be far less effective at that point. After 12 weeks of rescue therapy, only 57% had regained remission, leaving 43% with persistent active disease.
Nearly all of the secondary endpoints were in favor of continuing therapy, Dr. Landewé said, including the Ankylosing Spondyloarthritis Disease Activity Score-inactive disease (ASDAS-ID), ASDAS-major improvement, ASDAS-clinically important improvement; the Assessment in Spondyloarthritis International Society (ASAS) 20% and 40% rates; the ASAS 5/6 and ASAS-partial response rates; the Bath Ankylosing Spondylitis Disease Activity Index 50; and the Bath Ankylosing Spondylitis Functional Index. Only health-related quality of life as measured by the Health Assessment Questionnaire for the Spondyloarthropathies did not significantly improve to a greater extent among those staying on adalimumab.
There were no new or concerning safety signals, Dr. Landewé said. In the placebo-controlled period, there were 10 serious adverse events in the placebo group and 1 – a case of ureterolithiasis – in the adalimumab group. There was one malignancy, which occurred in the placebo group. No patient died during the study.
“These results support the continuation of adalimumab therapy after achieving a sustained remission,” Dr. Landewé said. “But it will be an important research goal to identify predictors for the population in whom treatment may be safely discontinued.”
AbbVie sponsored the study. Dr. Landewé reported relationships with numerous pharmaceutical companies, including AbbVie.
Patients with nonradiographic axial spondyloarthritis (nr-axSpA) who enter remission on adalimumab are likely to relapse if the medication is withdrawn – and many won’t attain remission again, even if the drug is restarted.
However, the findings of the ABILITY-3 trial do offer an intriguing potential, Robert Landewé, MD, PhD, said at the annual meeting of the American College of Rheumatology. About 30% of the study group did maintain remission after adalimumab (Humira) withdrawal, suggesting that at least a portion of these patients can stay in good clinical shape off TNF inhibition.
ABILITY-3 is the successor to ABILITY-1, the 2012 placebo-controlled study that established adalimumab as an effective treatment for nr-axSpA. Adalimumab is approved in the United States for the treatment of ankylosing spondylitis (radiographic axSpA), but not for nr-axSpA.
ABILITY-3 assessed the impact of withdrawing adalimumab from nr-axSpA patients who had attained remission on the medication. It enrolled 673 adults with active disease at baseline and an inadequate response to at least two nonsteroidal anti-inflammatory drugs.
The study commenced with open-label adalimumab at 40 mg every other week for 28 weeks. At that point, the 305 patients who had attained disease remission were randomized to either continued adalimumab at the same dose and schedule or to placebo. Randomized treatment continued for 40 more weeks. Any patient who experienced a flare resumed the drug as rescue therapy. The investigators calculated the number of patients with a disease flare at week 68 as the primary endpoint. The study also examined a number of secondary endpoints, including response measures, time to flare, functional status, quality of life, and remission.
At baseline, patients were a mean of 35 years old, with a mean disease duration of about 7 years. Most (88%) were HLA-B27 positive, and about 60% had elevated C-reactive protein levels.
At 68 weeks, patients who discontinued adalimumab were 77% more likely to have experienced a disease flare than were those who stayed on the drug (83% vs. 57% or 70% vs. 47% with nonresponder imputation; relative risk, 1.77). A time-to-flare analysis found a significant 67% reduction in the risk of flare among those continuing to take adalimumab.
While those who experienced a disease flare were allowed to resume adalimumab, it appeared to be far less effective at that point. After 12 weeks of rescue therapy, only 57% had regained remission, leaving 43% with persistent active disease.
Nearly all of the secondary endpoints were in favor of continuing therapy, Dr. Landewé said, including the Ankylosing Spondyloarthritis Disease Activity Score-inactive disease (ASDAS-ID), ASDAS-major improvement, ASDAS-clinically important improvement; the Assessment in Spondyloarthritis International Society (ASAS) 20% and 40% rates; the ASAS 5/6 and ASAS-partial response rates; the Bath Ankylosing Spondylitis Disease Activity Index 50; and the Bath Ankylosing Spondylitis Functional Index. Only health-related quality of life as measured by the Health Assessment Questionnaire for the Spondyloarthropathies did not significantly improve to a greater extent among those staying on adalimumab.
There were no new or concerning safety signals, Dr. Landewé said. In the placebo-controlled period, there were 10 serious adverse events in the placebo group and 1 – a case of ureterolithiasis – in the adalimumab group. There was one malignancy, which occurred in the placebo group. No patient died during the study.
“These results support the continuation of adalimumab therapy after achieving a sustained remission,” Dr. Landewé said. “But it will be an important research goal to identify predictors for the population in whom treatment may be safely discontinued.”
AbbVie sponsored the study. Dr. Landewé reported relationships with numerous pharmaceutical companies, including AbbVie.
REPORTING FROM ACR 2017
Key clinical point:
Major finding: Withdrawing adalimumab increased the risk of flare by 77%.
Study details: The study randomized 305 patients in remission to placebo or 40 mg adalimumab every other week.
Disclosures: AbbVie sponsored the study. The presenter reported relationships with numerous pharmaceutical companies, including AbbVie.
Source: Landewé R et al. ACR 2017 Abstract 1787
Retinal changes may reflect brain changes in preclinical Alzheimer’s
BOSTON – Changes in the retina seem to mirror changes that begin to reshape the brain in preclinical Alzheimer’s disease.
Manifested as a reduction in volume in the retinal nerve fiber layer, these changes appear to track the aggregation of beta amyloid brain plaques well before cognitive problems arise – and can be easily measured with a piece of equipment already in many optometry offices, Peter J. Snyder, PhD, said at the Clinical Trials in Alzheimer’s Disease conference.
“If we are lucky enough to live past age 45, then it’s a given that we’re all going to develop some presbyopia. So we all have to go to the optometrist sometime, and that may become a point of entry for broad screening and to track changes over time, to keep an eye on at-risk patients, and to refer those with retinal changes that fit the preclinical AD profile to specialty care for more comprehensive diagnostic evaluations.”
The retina begins to form in the third week of embryologic life, arising from the neural tube cells that also form the brain and spinal cord. It makes sense then that very early neuronal changes in Alzheimer’s disease could be occurring in the retina as well, said Dr. Snyder, professor of neurology and surgery (ophthalmology) at Rhode Island Hospital and Brown University, Providence.
“The retina is really a protrusion of the brain, and it is part and parcel of the central nervous system. In terms of the neuronal structure, the retina develops in layers with very specific cell types that are neurochemically and physiologically the same as the nervous tissue in the brain. That’s why it is, potentially, literally a window that could let us see what’s happening in the brain in early Alzheimer’s disease.”
Other researchers have explored amyloid in the lens and retina as a possible early Alzheimer’s identification tool. But Dr. Snyder’s study is the first to demonstrate a longitudinal association between neuronal changes in the eye and amyloid burden in the brain among clinically normal subjects.
For 27 months, he followed 56 people who had normal cognition but were beginning to experience subjective memory complaints. All subjects had at least one parent with Alzheimer’s disease. Everyone underwent an amyloid PET scan at baseline. Of the cohort, 15 had PET imaging evidence of abnormal beta-amyloid protein aggregation in the neocortex. This group was deemed to have preclinical Alzheimer’s disease, while the remainder served as a control group.
Dr. Snyder imaged each subject’s retinas twice – once at baseline and once at 27 months, when everyone underwent a second amyloid PET scan as well. He examined the retina with spectral domain optical coherence tomography, a relatively new method of imaging the retina.
These scanners are becoming increasingly more common in optometry practices, Dr. Snyder said. “Graduate optometrists tell me they would not want to be in a practice without one.” The scanners are typically used to detect retinal and ocular changes associated with diabetes, macular degeneration, glaucoma and multiple sclerosis.
Dr. Snyder used the scanner to examine the optic nerve head and macula at both baseline and 27 months in his cohort. He was looking for volumetric changes in several of the retinal layers: the peripapillary retinal nerve fiber layer (pRNFL), macular RNFL (mRNFL), ganglion cell layer (GCL), inner plexiform layer (IPL), outer nuclear layer (ONL), outer plexiform layer (OPL), and inner nuclear layer (INL). He also computed changes in total retinal volume.
Even at baseline, he found a significant difference between the groups. Among the amyloid-positive subjects, the inner plexiform layer was slightly larger in volume. “This seems a bit counterintuitive, but I think it suggests that there may be some inflammatory processes going on in this early stage and that we are catching that inflammation.”
Dr. Snyder noted that this finding has recently been replicated by an independent research group in Perth, Australia – with a much larger sample of participants – and will be reported at international conferences this coming year.
At 27 months, both the total retinal volume and the macular retinal nerve fiber layer volume were significantly lower in the preclinical AD group than in the control group. There was also a volume reduction in the peripapillary retinal nerve fiber layer, although the between-group difference was not statistically significant.
In a multivariate linear regression model that controlled for age and total amyloid burden, the mean volume change in the macular retinal nerve fiber layer accounted for about 10% of the variation in PET binding to brain amyloid by 27 months. Volume reductions in all the other layers appeared to be associated only with age, representing normal age-related changes in the eye.
Dr. Snyder said this volume loss in the retinal nerve fiber layer probably represents early demyelination and/or degeneration of the axons coursing from the cell bodies in the ganglion cell layer, which project to the optic nerve head.
“This finding in the retina appears analogous, and possibly directly related to, a similar loss of white matter that is readily observable in the early stages of Alzheimer’s disease. At the same time, patients are beginning to experience both cholinergic changes in the basal forebrain and the abnormal aggregation of fibrillar beta-amyloid plaques. I don’t know to what extent these changes are mechanistically dependent on each other, but they appear to also be happening, in the earliest stages of the disease course, in the retina.”
There is a lot of work left to be done before retinal scanning could be employed as a risk-assessment tool, however. With every new biomarker – and especially with imaging – the ability to measure change occurs far in advance of an understanding of what those changes mean, and how to judge them accurately.
“Every time we have a major advance in imaging, the technical engineering breakthroughs precede our detailed understanding of what we’re looking at and what to measure. This is where we are right now with retinal imaging. Biologically, it makes sense to be looking at this as a marker of risk in those who are clinically healthy, and maybe later as a marker of disease progression. But there is a lot of work to be done here yet.”
Dr. Snyder’s project was funded in part by a research award from Pfizer, with PET imaging supported in part by a grant from Avid Radiopharmaceuticals. He has no financial ties to the company, or other financial interest related to the study.
[email protected]
On Twitter @Alz_Gal
BOSTON – Changes in the retina seem to mirror changes that begin to reshape the brain in preclinical Alzheimer’s disease.
Manifested as a reduction in volume in the retinal nerve fiber layer, these changes appear to track the aggregation of beta amyloid brain plaques well before cognitive problems arise – and can be easily measured with a piece of equipment already in many optometry offices, Peter J. Snyder, PhD, said at the Clinical Trials in Alzheimer’s Disease conference.
“If we are lucky enough to live past age 45, then it’s a given that we’re all going to develop some presbyopia. So we all have to go to the optometrist sometime, and that may become a point of entry for broad screening and to track changes over time, to keep an eye on at-risk patients, and to refer those with retinal changes that fit the preclinical AD profile to specialty care for more comprehensive diagnostic evaluations.”
The retina begins to form in the third week of embryologic life, arising from the neural tube cells that also form the brain and spinal cord. It makes sense then that very early neuronal changes in Alzheimer’s disease could be occurring in the retina as well, said Dr. Snyder, professor of neurology and surgery (ophthalmology) at Rhode Island Hospital and Brown University, Providence.
“The retina is really a protrusion of the brain, and it is part and parcel of the central nervous system. In terms of the neuronal structure, the retina develops in layers with very specific cell types that are neurochemically and physiologically the same as the nervous tissue in the brain. That’s why it is, potentially, literally a window that could let us see what’s happening in the brain in early Alzheimer’s disease.”
Other researchers have explored amyloid in the lens and retina as a possible early Alzheimer’s identification tool. But Dr. Snyder’s study is the first to demonstrate a longitudinal association between neuronal changes in the eye and amyloid burden in the brain among clinically normal subjects.
For 27 months, he followed 56 people who had normal cognition but were beginning to experience subjective memory complaints. All subjects had at least one parent with Alzheimer’s disease. Everyone underwent an amyloid PET scan at baseline. Of the cohort, 15 had PET imaging evidence of abnormal beta-amyloid protein aggregation in the neocortex. This group was deemed to have preclinical Alzheimer’s disease, while the remainder served as a control group.
Dr. Snyder imaged each subject’s retinas twice – once at baseline and once at 27 months, when everyone underwent a second amyloid PET scan as well. He examined the retina with spectral domain optical coherence tomography, a relatively new method of imaging the retina.
These scanners are becoming increasingly more common in optometry practices, Dr. Snyder said. “Graduate optometrists tell me they would not want to be in a practice without one.” The scanners are typically used to detect retinal and ocular changes associated with diabetes, macular degeneration, glaucoma and multiple sclerosis.
Dr. Snyder used the scanner to examine the optic nerve head and macula at both baseline and 27 months in his cohort. He was looking for volumetric changes in several of the retinal layers: the peripapillary retinal nerve fiber layer (pRNFL), macular RNFL (mRNFL), ganglion cell layer (GCL), inner plexiform layer (IPL), outer nuclear layer (ONL), outer plexiform layer (OPL), and inner nuclear layer (INL). He also computed changes in total retinal volume.
Even at baseline, he found a significant difference between the groups. Among the amyloid-positive subjects, the inner plexiform layer was slightly larger in volume. “This seems a bit counterintuitive, but I think it suggests that there may be some inflammatory processes going on in this early stage and that we are catching that inflammation.”
Dr. Snyder noted that this finding has recently been replicated by an independent research group in Perth, Australia – with a much larger sample of participants – and will be reported at international conferences this coming year.
At 27 months, both the total retinal volume and the macular retinal nerve fiber layer volume were significantly lower in the preclinical AD group than in the control group. There was also a volume reduction in the peripapillary retinal nerve fiber layer, although the between-group difference was not statistically significant.
In a multivariate linear regression model that controlled for age and total amyloid burden, the mean volume change in the macular retinal nerve fiber layer accounted for about 10% of the variation in PET binding to brain amyloid by 27 months. Volume reductions in all the other layers appeared to be associated only with age, representing normal age-related changes in the eye.
Dr. Snyder said this volume loss in the retinal nerve fiber layer probably represents early demyelination and/or degeneration of the axons coursing from the cell bodies in the ganglion cell layer, which project to the optic nerve head.
“This finding in the retina appears analogous, and possibly directly related to, a similar loss of white matter that is readily observable in the early stages of Alzheimer’s disease. At the same time, patients are beginning to experience both cholinergic changes in the basal forebrain and the abnormal aggregation of fibrillar beta-amyloid plaques. I don’t know to what extent these changes are mechanistically dependent on each other, but they appear to also be happening, in the earliest stages of the disease course, in the retina.”
There is a lot of work left to be done before retinal scanning could be employed as a risk-assessment tool, however. With every new biomarker – and especially with imaging – the ability to measure change occurs far in advance of an understanding of what those changes mean, and how to judge them accurately.
“Every time we have a major advance in imaging, the technical engineering breakthroughs precede our detailed understanding of what we’re looking at and what to measure. This is where we are right now with retinal imaging. Biologically, it makes sense to be looking at this as a marker of risk in those who are clinically healthy, and maybe later as a marker of disease progression. But there is a lot of work to be done here yet.”
Dr. Snyder’s project was funded in part by a research award from Pfizer, with PET imaging supported in part by a grant from Avid Radiopharmaceuticals. He has no financial ties to the company, or other financial interest related to the study.
[email protected]
On Twitter @Alz_Gal
BOSTON – Changes in the retina seem to mirror changes that begin to reshape the brain in preclinical Alzheimer’s disease.
Manifested as a reduction in volume in the retinal nerve fiber layer, these changes appear to track the aggregation of beta amyloid brain plaques well before cognitive problems arise – and can be easily measured with a piece of equipment already in many optometry offices, Peter J. Snyder, PhD, said at the Clinical Trials in Alzheimer’s Disease conference.
“If we are lucky enough to live past age 45, then it’s a given that we’re all going to develop some presbyopia. So we all have to go to the optometrist sometime, and that may become a point of entry for broad screening and to track changes over time, to keep an eye on at-risk patients, and to refer those with retinal changes that fit the preclinical AD profile to specialty care for more comprehensive diagnostic evaluations.”
The retina begins to form in the third week of embryologic life, arising from the neural tube cells that also form the brain and spinal cord. It makes sense then that very early neuronal changes in Alzheimer’s disease could be occurring in the retina as well, said Dr. Snyder, professor of neurology and surgery (ophthalmology) at Rhode Island Hospital and Brown University, Providence.
“The retina is really a protrusion of the brain, and it is part and parcel of the central nervous system. In terms of the neuronal structure, the retina develops in layers with very specific cell types that are neurochemically and physiologically the same as the nervous tissue in the brain. That’s why it is, potentially, literally a window that could let us see what’s happening in the brain in early Alzheimer’s disease.”
Other researchers have explored amyloid in the lens and retina as a possible early Alzheimer’s identification tool. But Dr. Snyder’s study is the first to demonstrate a longitudinal association between neuronal changes in the eye and amyloid burden in the brain among clinically normal subjects.
For 27 months, he followed 56 people who had normal cognition but were beginning to experience subjective memory complaints. All subjects had at least one parent with Alzheimer’s disease. Everyone underwent an amyloid PET scan at baseline. Of the cohort, 15 had PET imaging evidence of abnormal beta-amyloid protein aggregation in the neocortex. This group was deemed to have preclinical Alzheimer’s disease, while the remainder served as a control group.
Dr. Snyder imaged each subject’s retinas twice – once at baseline and once at 27 months, when everyone underwent a second amyloid PET scan as well. He examined the retina with spectral domain optical coherence tomography, a relatively new method of imaging the retina.
These scanners are becoming increasingly more common in optometry practices, Dr. Snyder said. “Graduate optometrists tell me they would not want to be in a practice without one.” The scanners are typically used to detect retinal and ocular changes associated with diabetes, macular degeneration, glaucoma and multiple sclerosis.
Dr. Snyder used the scanner to examine the optic nerve head and macula at both baseline and 27 months in his cohort. He was looking for volumetric changes in several of the retinal layers: the peripapillary retinal nerve fiber layer (pRNFL), macular RNFL (mRNFL), ganglion cell layer (GCL), inner plexiform layer (IPL), outer nuclear layer (ONL), outer plexiform layer (OPL), and inner nuclear layer (INL). He also computed changes in total retinal volume.
Even at baseline, he found a significant difference between the groups. Among the amyloid-positive subjects, the inner plexiform layer was slightly larger in volume. “This seems a bit counterintuitive, but I think it suggests that there may be some inflammatory processes going on in this early stage and that we are catching that inflammation.”
Dr. Snyder noted that this finding has recently been replicated by an independent research group in Perth, Australia – with a much larger sample of participants – and will be reported at international conferences this coming year.
At 27 months, both the total retinal volume and the macular retinal nerve fiber layer volume were significantly lower in the preclinical AD group than in the control group. There was also a volume reduction in the peripapillary retinal nerve fiber layer, although the between-group difference was not statistically significant.
In a multivariate linear regression model that controlled for age and total amyloid burden, the mean volume change in the macular retinal nerve fiber layer accounted for about 10% of the variation in PET binding to brain amyloid by 27 months. Volume reductions in all the other layers appeared to be associated only with age, representing normal age-related changes in the eye.
Dr. Snyder said this volume loss in the retinal nerve fiber layer probably represents early demyelination and/or degeneration of the axons coursing from the cell bodies in the ganglion cell layer, which project to the optic nerve head.
“This finding in the retina appears analogous, and possibly directly related to, a similar loss of white matter that is readily observable in the early stages of Alzheimer’s disease. At the same time, patients are beginning to experience both cholinergic changes in the basal forebrain and the abnormal aggregation of fibrillar beta-amyloid plaques. I don’t know to what extent these changes are mechanistically dependent on each other, but they appear to also be happening, in the earliest stages of the disease course, in the retina.”
There is a lot of work left to be done before retinal scanning could be employed as a risk-assessment tool, however. With every new biomarker – and especially with imaging – the ability to measure change occurs far in advance of an understanding of what those changes mean, and how to judge them accurately.
“Every time we have a major advance in imaging, the technical engineering breakthroughs precede our detailed understanding of what we’re looking at and what to measure. This is where we are right now with retinal imaging. Biologically, it makes sense to be looking at this as a marker of risk in those who are clinically healthy, and maybe later as a marker of disease progression. But there is a lot of work to be done here yet.”
Dr. Snyder’s project was funded in part by a research award from Pfizer, with PET imaging supported in part by a grant from Avid Radiopharmaceuticals. He has no financial ties to the company, or other financial interest related to the study.
[email protected]
On Twitter @Alz_Gal
AT CTAD
Key clinical point: Retinal scans might eventually be an easy, noninvasive, and inexpensive way to tag people who may be at elevated risk for Alzheimer’s disease.
Major finding: At 27 months, both the total retinal volume and the macular retinal nerve fiber layer volume were significantly lower in 15 patients in the preclinical AD group than in the 41 patients in the control group.
Data source: A follow-up study of 56 people who had at least one parent with Alzheimer’s disease and were beginning to experience subjective memory complaints.
Disclosures: Dr. Snyder’s project was funded in part by a research award from Pfizer, with PET imaging supported in part by a grant from Avid Radiopharmaceuticals. He has no financial ties to the company, or other financial interest related to the study.
Walking has beneficial cognitive effects in amyloid-positive older adults
BOSTON – Walking appears to moderate cognitive decline in people with elevated brain amyloid, a 4-year observational study has determined.
Among a group of cognitively normal older adults with beta-amyloid brain plaques, those who walked the most experienced significantly less decline in memory and thinking than those who didn’t walk much, Dylan Kirn reported at the Clinical Trials on Alzheimer’s Disease conference. Walking didn’t affect any of the hallmark biomarkers of Alzheimer’s disease, such as brain glucose utilization, amyloid accumulation, or hippocampal volume, but it was associated with significantly better cognitive scores on a composite measure of memory over time.
“We should be careful in interpreting these data, because this is an observational cohort and we can’t make claims regarding causality or the mechanism by which physical activity may be influencing cognitive decline,” said Mr. Kirn of the Athinoula A. Martinos Center for Biomedical Imaging at Massachusetts General Hospital, Boston. “But I find these results interesting and novel, and I think they support further investigation.”
The walking study comprised 255 subjects with a mean age of 73 years. They were highly educated, with a mean of 16 years’ schooling. About 24% were amyloid-positive by PET imaging. All were cognitively normal, with a Clinical Dementia Rating scale score of 0. Activity was established at baseline with a pedometer, which was worn for 7 consecutive days; only those who walked at least 100 steps per day were included in the analysis.
In addition to amyloid PET imaging, subjects also underwent a 18F-fluorodeoxyglucose (FDG) PET scan to assess brain glucose utilization, and MRI to measure hippocampal volume changes and assess white matter hyperintensities (WMHs). Changes in all of these biomarkers can herald the onset of Alzheimer’s.
The primary outcome was the relationship between physical activity as measured by number of walking steps per day and changes on the Preclinical Alzheimer’s Cognitive Composite (PACC) test. This relatively new cognitive scale is an increasingly popular item in clinical trials. The PACC is a composite of the Digit Symbol Substitution Test score from the Wechsler Adult Intelligence Scale–Revised, the Mini Mental State Exam, the Total Recall score from the Free and Cued Selective Reminding Test, and the Delayed Recall score on the Logical Memory IIa sub-test from the Wechsler Memory Scale. It correlates well with amyloid accumulation in the brain, Mr. Kirn said.
The cohort was followed for up to 6 years (median of 4), and PACC scores were calculated annually. The investigators looked at the relationship between walking at baseline and PACC decline over the study period in two multivariate models: One controlling for age, sex, and years of education, and the second for those variables plus the biomarkers of cortical WMHs, bilateral hippocampal volume (HV), and FDG-PET in brain regions typically affected by Alzheimer’s.
Physical activity was divided into tertiles by the average number of steps per day over the 7-day measuring period: Mean (5,616 steps), one standard deviation above mean (high; 8,482 steps), and one standard deviation below mean (low, 2,751 steps). Amyloid-positive patients were further divided into those with high brain amyloid load and those with low amyloid brain load.
There were no significant relationships between any of the biomarkers and any level of physical activity in either of the analyses, Mr. Kirn said. However, when looking at the time-linked changes in the PACC, significant differences did emerge. Subjects who walked at least the mean number of steps per day were much more likely to maintain a stable cognitive score, while those who walked the fewest steps declined about a quarter of a point on the PACC. The difference in decline between the high activity and low activity subjects was statistically significant, even when the investigators controlled for amyloid burden and the other hallmark Alzheimer’s biomarkers.
The level of physical activity at baseline was a particularly strong predictor of cognitive health among amyloid-positive subjects. Those in the high-activity group maintained a steady score on the PACC. Those in the mean activity group declined slightly, and those in the low activity group showed a sharp decline, losing almost a full point on the PACC by the end of follow-up.
In the amyloid-negative group, there was no association between cognition and activity. All the groups improved their PACC scores over the study period, probably reflecting a practice effect, Mr. Kirn said.
Finally, he split the amyloid-positive group into subjects with low and high brain amyloid levels. “We observed that physical activity was significantly predictive of cognitive decline in high-amyloid participants, but not in low-amyloid participants,” he said. “Individuals with high amyloid and low physical activity at baseline had the steepest decline in cognition over time. But in those with high amyloid and high physical activity at baseline, we didn’t see a tremendous amount of decline.”
The study suggests that pedometers may have a place in stratifying patients for clinical trials, or assessing cognitive risk in elderly subjects. “Most studies that have looked at physical activity and dementia use a self-reported activity level, so the results have been varied,” Mr. Kirn said. “These findings support consideration of objectively measured physical activity in clinical research, and perhaps in stratification for risk of cognitive decline.”
He had no financial disclosures.
[email protected]
On Twitter @Alz_Gal
BOSTON – Walking appears to moderate cognitive decline in people with elevated brain amyloid, a 4-year observational study has determined.
Among a group of cognitively normal older adults with beta-amyloid brain plaques, those who walked the most experienced significantly less decline in memory and thinking than those who didn’t walk much, Dylan Kirn reported at the Clinical Trials on Alzheimer’s Disease conference. Walking didn’t affect any of the hallmark biomarkers of Alzheimer’s disease, such as brain glucose utilization, amyloid accumulation, or hippocampal volume, but it was associated with significantly better cognitive scores on a composite measure of memory over time.
“We should be careful in interpreting these data, because this is an observational cohort and we can’t make claims regarding causality or the mechanism by which physical activity may be influencing cognitive decline,” said Mr. Kirn of the Athinoula A. Martinos Center for Biomedical Imaging at Massachusetts General Hospital, Boston. “But I find these results interesting and novel, and I think they support further investigation.”
The walking study comprised 255 subjects with a mean age of 73 years. They were highly educated, with a mean of 16 years’ schooling. About 24% were amyloid-positive by PET imaging. All were cognitively normal, with a Clinical Dementia Rating scale score of 0. Activity was established at baseline with a pedometer, which was worn for 7 consecutive days; only those who walked at least 100 steps per day were included in the analysis.
In addition to amyloid PET imaging, subjects also underwent a 18F-fluorodeoxyglucose (FDG) PET scan to assess brain glucose utilization, and MRI to measure hippocampal volume changes and assess white matter hyperintensities (WMHs). Changes in all of these biomarkers can herald the onset of Alzheimer’s.
The primary outcome was the relationship between physical activity as measured by number of walking steps per day and changes on the Preclinical Alzheimer’s Cognitive Composite (PACC) test. This relatively new cognitive scale is an increasingly popular item in clinical trials. The PACC is a composite of the Digit Symbol Substitution Test score from the Wechsler Adult Intelligence Scale–Revised, the Mini Mental State Exam, the Total Recall score from the Free and Cued Selective Reminding Test, and the Delayed Recall score on the Logical Memory IIa sub-test from the Wechsler Memory Scale. It correlates well with amyloid accumulation in the brain, Mr. Kirn said.
The cohort was followed for up to 6 years (median of 4), and PACC scores were calculated annually. The investigators looked at the relationship between walking at baseline and PACC decline over the study period in two multivariate models: One controlling for age, sex, and years of education, and the second for those variables plus the biomarkers of cortical WMHs, bilateral hippocampal volume (HV), and FDG-PET in brain regions typically affected by Alzheimer’s.
Physical activity was divided into tertiles by the average number of steps per day over the 7-day measuring period: Mean (5,616 steps), one standard deviation above mean (high; 8,482 steps), and one standard deviation below mean (low, 2,751 steps). Amyloid-positive patients were further divided into those with high brain amyloid load and those with low amyloid brain load.
There were no significant relationships between any of the biomarkers and any level of physical activity in either of the analyses, Mr. Kirn said. However, when looking at the time-linked changes in the PACC, significant differences did emerge. Subjects who walked at least the mean number of steps per day were much more likely to maintain a stable cognitive score, while those who walked the fewest steps declined about a quarter of a point on the PACC. The difference in decline between the high activity and low activity subjects was statistically significant, even when the investigators controlled for amyloid burden and the other hallmark Alzheimer’s biomarkers.
The level of physical activity at baseline was a particularly strong predictor of cognitive health among amyloid-positive subjects. Those in the high-activity group maintained a steady score on the PACC. Those in the mean activity group declined slightly, and those in the low activity group showed a sharp decline, losing almost a full point on the PACC by the end of follow-up.
In the amyloid-negative group, there was no association between cognition and activity. All the groups improved their PACC scores over the study period, probably reflecting a practice effect, Mr. Kirn said.
Finally, he split the amyloid-positive group into subjects with low and high brain amyloid levels. “We observed that physical activity was significantly predictive of cognitive decline in high-amyloid participants, but not in low-amyloid participants,” he said. “Individuals with high amyloid and low physical activity at baseline had the steepest decline in cognition over time. But in those with high amyloid and high physical activity at baseline, we didn’t see a tremendous amount of decline.”
The study suggests that pedometers may have a place in stratifying patients for clinical trials, or assessing cognitive risk in elderly subjects. “Most studies that have looked at physical activity and dementia use a self-reported activity level, so the results have been varied,” Mr. Kirn said. “These findings support consideration of objectively measured physical activity in clinical research, and perhaps in stratification for risk of cognitive decline.”
He had no financial disclosures.
[email protected]
On Twitter @Alz_Gal
BOSTON – Walking appears to moderate cognitive decline in people with elevated brain amyloid, a 4-year observational study has determined.
Among a group of cognitively normal older adults with beta-amyloid brain plaques, those who walked the most experienced significantly less decline in memory and thinking than those who didn’t walk much, Dylan Kirn reported at the Clinical Trials on Alzheimer’s Disease conference. Walking didn’t affect any of the hallmark biomarkers of Alzheimer’s disease, such as brain glucose utilization, amyloid accumulation, or hippocampal volume, but it was associated with significantly better cognitive scores on a composite measure of memory over time.
“We should be careful in interpreting these data, because this is an observational cohort and we can’t make claims regarding causality or the mechanism by which physical activity may be influencing cognitive decline,” said Mr. Kirn of the Athinoula A. Martinos Center for Biomedical Imaging at Massachusetts General Hospital, Boston. “But I find these results interesting and novel, and I think they support further investigation.”
The walking study comprised 255 subjects with a mean age of 73 years. They were highly educated, with a mean of 16 years’ schooling. About 24% were amyloid-positive by PET imaging. All were cognitively normal, with a Clinical Dementia Rating scale score of 0. Activity was established at baseline with a pedometer, which was worn for 7 consecutive days; only those who walked at least 100 steps per day were included in the analysis.
In addition to amyloid PET imaging, subjects also underwent a 18F-fluorodeoxyglucose (FDG) PET scan to assess brain glucose utilization, and MRI to measure hippocampal volume changes and assess white matter hyperintensities (WMHs). Changes in all of these biomarkers can herald the onset of Alzheimer’s.
The primary outcome was the relationship between physical activity as measured by number of walking steps per day and changes on the Preclinical Alzheimer’s Cognitive Composite (PACC) test. This relatively new cognitive scale is an increasingly popular item in clinical trials. The PACC is a composite of the Digit Symbol Substitution Test score from the Wechsler Adult Intelligence Scale–Revised, the Mini Mental State Exam, the Total Recall score from the Free and Cued Selective Reminding Test, and the Delayed Recall score on the Logical Memory IIa sub-test from the Wechsler Memory Scale. It correlates well with amyloid accumulation in the brain, Mr. Kirn said.
The cohort was followed for up to 6 years (median of 4), and PACC scores were calculated annually. The investigators looked at the relationship between walking at baseline and PACC decline over the study period in two multivariate models: One controlling for age, sex, and years of education, and the second for those variables plus the biomarkers of cortical WMHs, bilateral hippocampal volume (HV), and FDG-PET in brain regions typically affected by Alzheimer’s.
Physical activity was divided into tertiles by the average number of steps per day over the 7-day measuring period: Mean (5,616 steps), one standard deviation above mean (high; 8,482 steps), and one standard deviation below mean (low, 2,751 steps). Amyloid-positive patients were further divided into those with high brain amyloid load and those with low amyloid brain load.
There were no significant relationships between any of the biomarkers and any level of physical activity in either of the analyses, Mr. Kirn said. However, when looking at the time-linked changes in the PACC, significant differences did emerge. Subjects who walked at least the mean number of steps per day were much more likely to maintain a stable cognitive score, while those who walked the fewest steps declined about a quarter of a point on the PACC. The difference in decline between the high activity and low activity subjects was statistically significant, even when the investigators controlled for amyloid burden and the other hallmark Alzheimer’s biomarkers.
The level of physical activity at baseline was a particularly strong predictor of cognitive health among amyloid-positive subjects. Those in the high-activity group maintained a steady score on the PACC. Those in the mean activity group declined slightly, and those in the low activity group showed a sharp decline, losing almost a full point on the PACC by the end of follow-up.
In the amyloid-negative group, there was no association between cognition and activity. All the groups improved their PACC scores over the study period, probably reflecting a practice effect, Mr. Kirn said.
Finally, he split the amyloid-positive group into subjects with low and high brain amyloid levels. “We observed that physical activity was significantly predictive of cognitive decline in high-amyloid participants, but not in low-amyloid participants,” he said. “Individuals with high amyloid and low physical activity at baseline had the steepest decline in cognition over time. But in those with high amyloid and high physical activity at baseline, we didn’t see a tremendous amount of decline.”
The study suggests that pedometers may have a place in stratifying patients for clinical trials, or assessing cognitive risk in elderly subjects. “Most studies that have looked at physical activity and dementia use a self-reported activity level, so the results have been varied,” Mr. Kirn said. “These findings support consideration of objectively measured physical activity in clinical research, and perhaps in stratification for risk of cognitive decline.”
He had no financial disclosures.
[email protected]
On Twitter @Alz_Gal
AT CTAD
Key clinical point:
Major finding: Subjects with high amyloid burden who walked the least declined by almost 1 point on the PACC score; high-amyloid subjects who walked the most stayed at their baseline score.
Data source: A prospective, observational study comprising 255 elderly subjects with normal cognition.
Disclosures: The presenter had no financial disclosures.
Intepirdine flops in phase 3 study of mild to moderate Alzheimer’s patients
BOSTON – An investigational Alzheimer’s drug intended to potentiate acetylcholine release didn’t pass muster in a global phase 3 study, despite a successful phase 2 trial.
Intepirdine on a background of stable-dose donepezil failed to confer any cognitive or functional benefit in patients with mild to moderate Alzheimer’s disease, Ilise Lombardo, PhD, said at the Clinical Trials on Alzheimer’s Disease conference.
Intepirdine blocks the 5-hydroxytryptamine receptor 6 and increases the release of acetylcholine, according to Dr. Lombardo. By giving it on a stable background of an acetylcholinesterase inhibitor, researchers hoped to improve cognition by increasing acetylcholine signaling between neurons. In a modestly successful phase 2b study reported out last summer, intepirdine did confer some cognitive and functional benefits.
The study was scheduled to be presented at the Alzheimer’s Association International Conference, but was pulled at the last minute when Axovant announced its initial public offering of stock shortly before the July meeting. However, Dr. Lombardo did review study 866 at CTAD. It randomized 269 patients with mild to moderate AD to placebo or intepirdine at 15 mg or 35 mg/day for 24 weeks. By 12 weeks, patients taking the 35-mg dose had declined 1.6 points less than those on placebo on the Alzheimer’s Disease Assessment Scale–cognitive subscale (ADAS-cog) and 1.94 points on the Alzheimer’s Disease Cooperative Study–Activities of Daily Living (ADCS-ADL). Both differences were statistically significant. The drug moved into a phase 3 study, dubbed MINDSET, at 35 mg.
MINDSET enrolled 1, 315 patients with mild to moderate Alzheimer’s disease and randomized them to placebo or 35 mg intepirdine for 24 weeks. All patients were on stable background donepezil. Again, the coprimary endpoints were the ADAS-cog and the ADCS-ADL at the end of the study. There were three secondary endpoints: the Clinician Interview-Based Impression of Change plus caregiver interview (CIBIC+), the Dependence Scale, and the Neuropsychiatric Inventory.
Patients were a mean of 70 years old with a mean Mini-Mental State Exam (MMSE) score of 18.5. The mean ADAS-cog score was 24 and the mean ADCS-ADL score, 58.
On the ADAS-cog, both groups exhibited a positive placebo response in the first 6 weeks, followed by a mean decline of 0.36 points. There was no statistically significant between-group difference. The story was much the same on the ADCS-ADL measure. Both groups had a brief placebo response, followed by a mean decline of 1.06 points. Again, the intepirdine and placebo groups declined similarly. There were no significant differences on either measure when the groups were broken down into patients with mild and moderate disease.
The CIBIC+ score was the only positive response among the secondary endpoints. Compared with those taking placebo, those taking intepirdine were more likely to be rated as minimally improved or unchanged.
The drug was safe however, with virtually no between-group difference in the occurrence of or the type of serious adverse events (about 6% in each group). Five patents died during the study; none of the deaths were related to the study drug.
Although Axovant no longer lists intepirdine as a potential Alzheimer’s treatment, investigation continues in a phase 3 placebo-controlled study in patients with Lewy body dementia. HEADWAY is testing a 70-mg dose, Dr. Lombardo said.
“Enrollment is finished and we are looking forward to results,” in early 2018. Answering a question about why the company went with 35 mg instead of 70 mg in MINDSET, she said that Axovant wanted to recreate the success of study 866.
“Since we had statistical significance even at 12 weeks with 35 mg, that’s what we went with,” she said. However, reviewing the adverse events told investigators that “we were not even near the maximum tolerated dose” at 35 mg. “Certainly we are now faced with the question of whether there will be a better response with 70 mg, and we are looking forward to answering that question with HEADWAY.”
Dr. Lombardo is senior vice president for clinical research at Axovant Sciences.
[email protected]
On Twitter @alz_gal
BOSTON – An investigational Alzheimer’s drug intended to potentiate acetylcholine release didn’t pass muster in a global phase 3 study, despite a successful phase 2 trial.
Intepirdine on a background of stable-dose donepezil failed to confer any cognitive or functional benefit in patients with mild to moderate Alzheimer’s disease, Ilise Lombardo, PhD, said at the Clinical Trials on Alzheimer’s Disease conference.
Intepirdine blocks the 5-hydroxytryptamine receptor 6 and increases the release of acetylcholine, according to Dr. Lombardo. By giving it on a stable background of an acetylcholinesterase inhibitor, researchers hoped to improve cognition by increasing acetylcholine signaling between neurons. In a modestly successful phase 2b study reported out last summer, intepirdine did confer some cognitive and functional benefits.
The study was scheduled to be presented at the Alzheimer’s Association International Conference, but was pulled at the last minute when Axovant announced its initial public offering of stock shortly before the July meeting. However, Dr. Lombardo did review study 866 at CTAD. It randomized 269 patients with mild to moderate AD to placebo or intepirdine at 15 mg or 35 mg/day for 24 weeks. By 12 weeks, patients taking the 35-mg dose had declined 1.6 points less than those on placebo on the Alzheimer’s Disease Assessment Scale–cognitive subscale (ADAS-cog) and 1.94 points on the Alzheimer’s Disease Cooperative Study–Activities of Daily Living (ADCS-ADL). Both differences were statistically significant. The drug moved into a phase 3 study, dubbed MINDSET, at 35 mg.
MINDSET enrolled 1, 315 patients with mild to moderate Alzheimer’s disease and randomized them to placebo or 35 mg intepirdine for 24 weeks. All patients were on stable background donepezil. Again, the coprimary endpoints were the ADAS-cog and the ADCS-ADL at the end of the study. There were three secondary endpoints: the Clinician Interview-Based Impression of Change plus caregiver interview (CIBIC+), the Dependence Scale, and the Neuropsychiatric Inventory.
Patients were a mean of 70 years old with a mean Mini-Mental State Exam (MMSE) score of 18.5. The mean ADAS-cog score was 24 and the mean ADCS-ADL score, 58.
On the ADAS-cog, both groups exhibited a positive placebo response in the first 6 weeks, followed by a mean decline of 0.36 points. There was no statistically significant between-group difference. The story was much the same on the ADCS-ADL measure. Both groups had a brief placebo response, followed by a mean decline of 1.06 points. Again, the intepirdine and placebo groups declined similarly. There were no significant differences on either measure when the groups were broken down into patients with mild and moderate disease.
The CIBIC+ score was the only positive response among the secondary endpoints. Compared with those taking placebo, those taking intepirdine were more likely to be rated as minimally improved or unchanged.
The drug was safe however, with virtually no between-group difference in the occurrence of or the type of serious adverse events (about 6% in each group). Five patents died during the study; none of the deaths were related to the study drug.
Although Axovant no longer lists intepirdine as a potential Alzheimer’s treatment, investigation continues in a phase 3 placebo-controlled study in patients with Lewy body dementia. HEADWAY is testing a 70-mg dose, Dr. Lombardo said.
“Enrollment is finished and we are looking forward to results,” in early 2018. Answering a question about why the company went with 35 mg instead of 70 mg in MINDSET, she said that Axovant wanted to recreate the success of study 866.
“Since we had statistical significance even at 12 weeks with 35 mg, that’s what we went with,” she said. However, reviewing the adverse events told investigators that “we were not even near the maximum tolerated dose” at 35 mg. “Certainly we are now faced with the question of whether there will be a better response with 70 mg, and we are looking forward to answering that question with HEADWAY.”
Dr. Lombardo is senior vice president for clinical research at Axovant Sciences.
[email protected]
On Twitter @alz_gal
BOSTON – An investigational Alzheimer’s drug intended to potentiate acetylcholine release didn’t pass muster in a global phase 3 study, despite a successful phase 2 trial.
Intepirdine on a background of stable-dose donepezil failed to confer any cognitive or functional benefit in patients with mild to moderate Alzheimer’s disease, Ilise Lombardo, PhD, said at the Clinical Trials on Alzheimer’s Disease conference.
Intepirdine blocks the 5-hydroxytryptamine receptor 6 and increases the release of acetylcholine, according to Dr. Lombardo. By giving it on a stable background of an acetylcholinesterase inhibitor, researchers hoped to improve cognition by increasing acetylcholine signaling between neurons. In a modestly successful phase 2b study reported out last summer, intepirdine did confer some cognitive and functional benefits.
The study was scheduled to be presented at the Alzheimer’s Association International Conference, but was pulled at the last minute when Axovant announced its initial public offering of stock shortly before the July meeting. However, Dr. Lombardo did review study 866 at CTAD. It randomized 269 patients with mild to moderate AD to placebo or intepirdine at 15 mg or 35 mg/day for 24 weeks. By 12 weeks, patients taking the 35-mg dose had declined 1.6 points less than those on placebo on the Alzheimer’s Disease Assessment Scale–cognitive subscale (ADAS-cog) and 1.94 points on the Alzheimer’s Disease Cooperative Study–Activities of Daily Living (ADCS-ADL). Both differences were statistically significant. The drug moved into a phase 3 study, dubbed MINDSET, at 35 mg.
MINDSET enrolled 1, 315 patients with mild to moderate Alzheimer’s disease and randomized them to placebo or 35 mg intepirdine for 24 weeks. All patients were on stable background donepezil. Again, the coprimary endpoints were the ADAS-cog and the ADCS-ADL at the end of the study. There were three secondary endpoints: the Clinician Interview-Based Impression of Change plus caregiver interview (CIBIC+), the Dependence Scale, and the Neuropsychiatric Inventory.
Patients were a mean of 70 years old with a mean Mini-Mental State Exam (MMSE) score of 18.5. The mean ADAS-cog score was 24 and the mean ADCS-ADL score, 58.
On the ADAS-cog, both groups exhibited a positive placebo response in the first 6 weeks, followed by a mean decline of 0.36 points. There was no statistically significant between-group difference. The story was much the same on the ADCS-ADL measure. Both groups had a brief placebo response, followed by a mean decline of 1.06 points. Again, the intepirdine and placebo groups declined similarly. There were no significant differences on either measure when the groups were broken down into patients with mild and moderate disease.
The CIBIC+ score was the only positive response among the secondary endpoints. Compared with those taking placebo, those taking intepirdine were more likely to be rated as minimally improved or unchanged.
The drug was safe however, with virtually no between-group difference in the occurrence of or the type of serious adverse events (about 6% in each group). Five patents died during the study; none of the deaths were related to the study drug.
Although Axovant no longer lists intepirdine as a potential Alzheimer’s treatment, investigation continues in a phase 3 placebo-controlled study in patients with Lewy body dementia. HEADWAY is testing a 70-mg dose, Dr. Lombardo said.
“Enrollment is finished and we are looking forward to results,” in early 2018. Answering a question about why the company went with 35 mg instead of 70 mg in MINDSET, she said that Axovant wanted to recreate the success of study 866.
“Since we had statistical significance even at 12 weeks with 35 mg, that’s what we went with,” she said. However, reviewing the adverse events told investigators that “we were not even near the maximum tolerated dose” at 35 mg. “Certainly we are now faced with the question of whether there will be a better response with 70 mg, and we are looking forward to answering that question with HEADWAY.”
Dr. Lombardo is senior vice president for clinical research at Axovant Sciences.
[email protected]
On Twitter @alz_gal
AT CTAD
Key clinical point:
Major finding: On the ADAS-cog at 24 weeks, there was a mean decline of 0.36 points; on the ADCS-ADL, the mean decline was 1.06 points. There were no between-group differences, either overall or in the mild to moderate groups separately.
Data source: The placebo-controlled study randomized 1,315 patients to placebo or 35 mg daily intepirdine.
Disclosures: Dr. Lombardo is senior vice president for clinical research at Axovant Sciences, which is developing the drug.
Development of a sigma 1 receptor agonist for Alzheimer’s proceeds based on 2-year phase 2 data
BOSTON – A reputedly neuroprotective compound will advance along its developmental pathway after developers said it exerted a blood level–dependent relationship with both cognitive and functional measures in patients with mild to moderate Alzheimer’s.
Most of the 26 patients left in the ongoing phase 2a extension study of ANAVEX 2-73 declined cognitively and functionally by varying degrees over 1 year. But a few, most of whom had high drug plasma levels, did experience cognitive and functional changes for the better. Some maintained stability, and some improved on both measures over 109 weeks, according to Christopher U. Missling, PhD, president and chief executive officer of Anavex.
“Improvement of cognition or function was a rare occurrence, but our analysis showed that patients who had a plasma concentration of 4-12 ng/mL had the best chance of experiencing this,” Dr. Missling said in an interview.
Mohammad Afshar, MD, PhD, presented these data at the Clinical Trials in Alzheimer’s Disease conference. He is the head of Ariana Pharmaceuticals, a firm hired to perform an independent analysis of the Anavex data. Concentrating on the pharmacodynamics data, he said ANAVEX 2-73 exhibits a clear drug concentration–clinical response relationship, which supports taking the drug into a phase 2/3 study.
“When focusing on the best responders at week 57, they continued to perform well. Patients with a score of greater than 20 on the Mini-Mental State Exam at baseline tended to respond better, as well as those with the highest plasma concentration,” he said.
The concentration-response picture is not completely clear, however. While five patients with high levels did improve on the MMSE at 57 weeks, one patient with a low plasma level also improved, and four patients with high levels declined. Functional results appeared more clearly related to drug levels: All of the high-level patients except one improved, as did about half of those with moderate plasma levels. Everyone with a low level declined.
During a later interview, Dr. Missling reviewed the data with an eye toward understatement. The study’s primary endpoints are safety and tolerability, as well as dosing and pharmacokinetics, he noted – cognitive and functional endpoints are exploratory measures. The study never had a control arm, other than several historical cohorts that served as reference points for decline in typically managed Alzheimer’s patients. And of course, he said, the numbers are very, very small.
And yet, the results are a source of “cautious optimism,” Dr. Missling said.
“While we think this is remarkable – because no drug has yet shown this long a response in non-decline among Alzheimer’s patients – we want to be very cautious. We are only looking at six patients here. We can’t overinterpret this.”
Dr. Missling and his colleagues are trying to find commonalities in these patients’ characteristics and clinical responses, hoping to enroll a phase 2/3 cohort of similar profile – whatever that may be. “We’re looking at the patients who improved to try and identify characteristics and be sure to enroll people who match them, to try and maximize our chance of success in phase 2/3,” which he said should be announced by the end of this year.
Just as important, he said, is to scrutinize the outliers – patients whose high and low plasma levels didn’t line up with the group’s overall response curve. “We’re looking at them in depth,” Dr. Missling said, adding that every patient in the study will undergo a full genomic profile, along with both an RNA and gut microbiota profile.
ANAVEX 2-73 is a sigma 1 receptor agonist. A chaperone protein, sigma 1 is activated in response to acute and chronic cellular stressors, several of which are important in neurodegeneration. The sigma 1 receptor is found on neurons and glia in many areas of the central nervous system. It modulates numerous processes implicated in neurodegenerative diseases, including glutamate and calcium activity, reaction to oxidative stress, and mitochondrial function. There is some evidence that sigma 1 receptor activation can induce neuronal regrowth and functional recovery after stroke. Sigma 1 also appears to play a role in helping cells clear misfolded proteins – a pathway that makes it an attractive drug target in Alzheimer’s disease, as well as other neurodegenerative diseases with aberrant proteins, such as Parkinson’s and Huntington’s diseases.
“Sigma 1 is never used except in times of trouble,” Dr. Missling said. “It’s only needed if we have a serious dysfunction in cells. By giving an agonist, we are increasing the expression of this protein, so it’s a bit like immune stimulation in oncology. We’re using the body’s own mechanism,” to fight neurodegeneration.
ANAVEX 2-73’s phase 2 development started with a 5-week crossover trial of 32 patients; they were a mean of 71 years old, with a mean MMSE of 21. The initial phase was followed by a 52-week, open-label trial of 10, 20, 30, and 50 mg/day orally, titrating each patient to the maximum tolerated dose.
Dr. Afshar presented 57-week data for the 26 patients who were still in the trial at that point and 109-week data for the six patients who had the best response at 57 weeks. Patients in both analyses were grouped by plasma level, not by their dosage level, although Dr. Missling said higher dosage generally correlated with higher plasma levels.
At 57 weeks, six patients had improved on the MMSE: four with high plasma levels and two with low plasma levels – patients identified as “outliers.” One patient with a high level remained stable. The rest of the cohort declined: seven with low levels, eight with moderate levels, and four with high levels, who were also identified as outliers. Also at 57 weeks, 24 patients had full data on the functional measure, the Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL). Nine patients had improved: five with high plasma levels, three with moderate levels, and one with a low level, identified as an outlier. One patient, with a moderate level, remained stable. The remaining 14 patients declined: nine with moderate levels, four with low levels, and one with a high level, dubbed an outlier.
Dr. Afshar reported more detailed data on the six best-performing patients. These included the two patients with low plasma levels who were characterized in the 57-week MMSE data as outliers. Their mean baseline MMSE went from 23.2 to 25.7 at 57 weeks; their mean functional score on the ADCS-ADL scale rose from 72 to 73.7.
He then showed each of these patients’ 109-week changes. Each was identified with a unique number in both the 57- and 109-week datasets. Numbers here are estimates drawn from the company’s data slides, which are publicly available on the Anavex website.
The ADCS-ADL is a caregiver-rated questionnaire of 23 items, with possible scores over a range of 0-78, where 78 implies full functioning with no impairment. On the 30-point MMSE scale, a score greater of 24 or higher indicates a normal cognition.
• 101009 (low plasma level)
MMSE: 20-29 ADCS-ADL: 73-71
• 101011 (low plasma level)
MMSE: 20-21 ADCS-ADL: 72-70
•101013 (high plasma level)
MMSE: 22-18 ADCS-ADL: 73-57
• 101014 (high plasma level)
MMSE: 20-25 ADCS-ADL: 75-74
• 102006 (high plasma level)
MMSE: 25-28 ADCS-ADL: 74-78
• 102010 (high plasma level)
MMSE: 25-28 ADCS-ADL: 64-68
Dr. Missling said ANAVEX 2-73 still appears safe and well tolerated. In the initial study phase, 98% of the subjects did have an adverse event; only one was considered serious. This was a case of delirium that developed in a patient who had several risk factors for the disorder, including a prior episode, and was not considered related to the study drug. Three patients withdrew because of an adverse event in the first 57 weeks; no one has withdrawn because of a side effect since then.
Dizziness was the most common adverse event (20 incidents in 15 patients), followed by headache (16 in 10 patients). Most (94%) occurred in the first week of treatment. All were mild or moderate. Headache and dizziness are considered signs that patients are approaching their maximum tolerated dose, Dr. Missling said.
The company’s task now is to find a standard minimum dose that is strong enough to get patients to at least 4 ng/mL plasma level, without inducing these side effects. The extension study will close out in November 2018. Anavex hopes to begin the drug’s next phase of development before then, with a phase 2/3 study of about 200 patients.
“We’re trying to gather as much data as possible so we can do this properly,” Dr. Missling said. “You can make the case that some developers have rushed into these studies after interpreting early results the wrong way. They said the glass was half-full when it was really half-empty. For us, it’s very important not to do that. We won’t go ahead with this until we are completely comfortable with what we see.”
[email protected]
On Twitter @alz_gal
BOSTON – A reputedly neuroprotective compound will advance along its developmental pathway after developers said it exerted a blood level–dependent relationship with both cognitive and functional measures in patients with mild to moderate Alzheimer’s.
Most of the 26 patients left in the ongoing phase 2a extension study of ANAVEX 2-73 declined cognitively and functionally by varying degrees over 1 year. But a few, most of whom had high drug plasma levels, did experience cognitive and functional changes for the better. Some maintained stability, and some improved on both measures over 109 weeks, according to Christopher U. Missling, PhD, president and chief executive officer of Anavex.
“Improvement of cognition or function was a rare occurrence, but our analysis showed that patients who had a plasma concentration of 4-12 ng/mL had the best chance of experiencing this,” Dr. Missling said in an interview.
Mohammad Afshar, MD, PhD, presented these data at the Clinical Trials in Alzheimer’s Disease conference. He is the head of Ariana Pharmaceuticals, a firm hired to perform an independent analysis of the Anavex data. Concentrating on the pharmacodynamics data, he said ANAVEX 2-73 exhibits a clear drug concentration–clinical response relationship, which supports taking the drug into a phase 2/3 study.
“When focusing on the best responders at week 57, they continued to perform well. Patients with a score of greater than 20 on the Mini-Mental State Exam at baseline tended to respond better, as well as those with the highest plasma concentration,” he said.
The concentration-response picture is not completely clear, however. While five patients with high levels did improve on the MMSE at 57 weeks, one patient with a low plasma level also improved, and four patients with high levels declined. Functional results appeared more clearly related to drug levels: All of the high-level patients except one improved, as did about half of those with moderate plasma levels. Everyone with a low level declined.
During a later interview, Dr. Missling reviewed the data with an eye toward understatement. The study’s primary endpoints are safety and tolerability, as well as dosing and pharmacokinetics, he noted – cognitive and functional endpoints are exploratory measures. The study never had a control arm, other than several historical cohorts that served as reference points for decline in typically managed Alzheimer’s patients. And of course, he said, the numbers are very, very small.
And yet, the results are a source of “cautious optimism,” Dr. Missling said.
“While we think this is remarkable – because no drug has yet shown this long a response in non-decline among Alzheimer’s patients – we want to be very cautious. We are only looking at six patients here. We can’t overinterpret this.”
Dr. Missling and his colleagues are trying to find commonalities in these patients’ characteristics and clinical responses, hoping to enroll a phase 2/3 cohort of similar profile – whatever that may be. “We’re looking at the patients who improved to try and identify characteristics and be sure to enroll people who match them, to try and maximize our chance of success in phase 2/3,” which he said should be announced by the end of this year.
Just as important, he said, is to scrutinize the outliers – patients whose high and low plasma levels didn’t line up with the group’s overall response curve. “We’re looking at them in depth,” Dr. Missling said, adding that every patient in the study will undergo a full genomic profile, along with both an RNA and gut microbiota profile.
ANAVEX 2-73 is a sigma 1 receptor agonist. A chaperone protein, sigma 1 is activated in response to acute and chronic cellular stressors, several of which are important in neurodegeneration. The sigma 1 receptor is found on neurons and glia in many areas of the central nervous system. It modulates numerous processes implicated in neurodegenerative diseases, including glutamate and calcium activity, reaction to oxidative stress, and mitochondrial function. There is some evidence that sigma 1 receptor activation can induce neuronal regrowth and functional recovery after stroke. Sigma 1 also appears to play a role in helping cells clear misfolded proteins – a pathway that makes it an attractive drug target in Alzheimer’s disease, as well as other neurodegenerative diseases with aberrant proteins, such as Parkinson’s and Huntington’s diseases.
“Sigma 1 is never used except in times of trouble,” Dr. Missling said. “It’s only needed if we have a serious dysfunction in cells. By giving an agonist, we are increasing the expression of this protein, so it’s a bit like immune stimulation in oncology. We’re using the body’s own mechanism,” to fight neurodegeneration.
ANAVEX 2-73’s phase 2 development started with a 5-week crossover trial of 32 patients; they were a mean of 71 years old, with a mean MMSE of 21. The initial phase was followed by a 52-week, open-label trial of 10, 20, 30, and 50 mg/day orally, titrating each patient to the maximum tolerated dose.
Dr. Afshar presented 57-week data for the 26 patients who were still in the trial at that point and 109-week data for the six patients who had the best response at 57 weeks. Patients in both analyses were grouped by plasma level, not by their dosage level, although Dr. Missling said higher dosage generally correlated with higher plasma levels.
At 57 weeks, six patients had improved on the MMSE: four with high plasma levels and two with low plasma levels – patients identified as “outliers.” One patient with a high level remained stable. The rest of the cohort declined: seven with low levels, eight with moderate levels, and four with high levels, who were also identified as outliers. Also at 57 weeks, 24 patients had full data on the functional measure, the Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL). Nine patients had improved: five with high plasma levels, three with moderate levels, and one with a low level, identified as an outlier. One patient, with a moderate level, remained stable. The remaining 14 patients declined: nine with moderate levels, four with low levels, and one with a high level, dubbed an outlier.
Dr. Afshar reported more detailed data on the six best-performing patients. These included the two patients with low plasma levels who were characterized in the 57-week MMSE data as outliers. Their mean baseline MMSE went from 23.2 to 25.7 at 57 weeks; their mean functional score on the ADCS-ADL scale rose from 72 to 73.7.
He then showed each of these patients’ 109-week changes. Each was identified with a unique number in both the 57- and 109-week datasets. Numbers here are estimates drawn from the company’s data slides, which are publicly available on the Anavex website.
The ADCS-ADL is a caregiver-rated questionnaire of 23 items, with possible scores over a range of 0-78, where 78 implies full functioning with no impairment. On the 30-point MMSE scale, a score greater of 24 or higher indicates a normal cognition.
• 101009 (low plasma level)
MMSE: 20-29 ADCS-ADL: 73-71
• 101011 (low plasma level)
MMSE: 20-21 ADCS-ADL: 72-70
•101013 (high plasma level)
MMSE: 22-18 ADCS-ADL: 73-57
• 101014 (high plasma level)
MMSE: 20-25 ADCS-ADL: 75-74
• 102006 (high plasma level)
MMSE: 25-28 ADCS-ADL: 74-78
• 102010 (high plasma level)
MMSE: 25-28 ADCS-ADL: 64-68
Dr. Missling said ANAVEX 2-73 still appears safe and well tolerated. In the initial study phase, 98% of the subjects did have an adverse event; only one was considered serious. This was a case of delirium that developed in a patient who had several risk factors for the disorder, including a prior episode, and was not considered related to the study drug. Three patients withdrew because of an adverse event in the first 57 weeks; no one has withdrawn because of a side effect since then.
Dizziness was the most common adverse event (20 incidents in 15 patients), followed by headache (16 in 10 patients). Most (94%) occurred in the first week of treatment. All were mild or moderate. Headache and dizziness are considered signs that patients are approaching their maximum tolerated dose, Dr. Missling said.
The company’s task now is to find a standard minimum dose that is strong enough to get patients to at least 4 ng/mL plasma level, without inducing these side effects. The extension study will close out in November 2018. Anavex hopes to begin the drug’s next phase of development before then, with a phase 2/3 study of about 200 patients.
“We’re trying to gather as much data as possible so we can do this properly,” Dr. Missling said. “You can make the case that some developers have rushed into these studies after interpreting early results the wrong way. They said the glass was half-full when it was really half-empty. For us, it’s very important not to do that. We won’t go ahead with this until we are completely comfortable with what we see.”
[email protected]
On Twitter @alz_gal
BOSTON – A reputedly neuroprotective compound will advance along its developmental pathway after developers said it exerted a blood level–dependent relationship with both cognitive and functional measures in patients with mild to moderate Alzheimer’s.
Most of the 26 patients left in the ongoing phase 2a extension study of ANAVEX 2-73 declined cognitively and functionally by varying degrees over 1 year. But a few, most of whom had high drug plasma levels, did experience cognitive and functional changes for the better. Some maintained stability, and some improved on both measures over 109 weeks, according to Christopher U. Missling, PhD, president and chief executive officer of Anavex.
“Improvement of cognition or function was a rare occurrence, but our analysis showed that patients who had a plasma concentration of 4-12 ng/mL had the best chance of experiencing this,” Dr. Missling said in an interview.
Mohammad Afshar, MD, PhD, presented these data at the Clinical Trials in Alzheimer’s Disease conference. He is the head of Ariana Pharmaceuticals, a firm hired to perform an independent analysis of the Anavex data. Concentrating on the pharmacodynamics data, he said ANAVEX 2-73 exhibits a clear drug concentration–clinical response relationship, which supports taking the drug into a phase 2/3 study.
“When focusing on the best responders at week 57, they continued to perform well. Patients with a score of greater than 20 on the Mini-Mental State Exam at baseline tended to respond better, as well as those with the highest plasma concentration,” he said.
The concentration-response picture is not completely clear, however. While five patients with high levels did improve on the MMSE at 57 weeks, one patient with a low plasma level also improved, and four patients with high levels declined. Functional results appeared more clearly related to drug levels: All of the high-level patients except one improved, as did about half of those with moderate plasma levels. Everyone with a low level declined.
During a later interview, Dr. Missling reviewed the data with an eye toward understatement. The study’s primary endpoints are safety and tolerability, as well as dosing and pharmacokinetics, he noted – cognitive and functional endpoints are exploratory measures. The study never had a control arm, other than several historical cohorts that served as reference points for decline in typically managed Alzheimer’s patients. And of course, he said, the numbers are very, very small.
And yet, the results are a source of “cautious optimism,” Dr. Missling said.
“While we think this is remarkable – because no drug has yet shown this long a response in non-decline among Alzheimer’s patients – we want to be very cautious. We are only looking at six patients here. We can’t overinterpret this.”
Dr. Missling and his colleagues are trying to find commonalities in these patients’ characteristics and clinical responses, hoping to enroll a phase 2/3 cohort of similar profile – whatever that may be. “We’re looking at the patients who improved to try and identify characteristics and be sure to enroll people who match them, to try and maximize our chance of success in phase 2/3,” which he said should be announced by the end of this year.
Just as important, he said, is to scrutinize the outliers – patients whose high and low plasma levels didn’t line up with the group’s overall response curve. “We’re looking at them in depth,” Dr. Missling said, adding that every patient in the study will undergo a full genomic profile, along with both an RNA and gut microbiota profile.
ANAVEX 2-73 is a sigma 1 receptor agonist. A chaperone protein, sigma 1 is activated in response to acute and chronic cellular stressors, several of which are important in neurodegeneration. The sigma 1 receptor is found on neurons and glia in many areas of the central nervous system. It modulates numerous processes implicated in neurodegenerative diseases, including glutamate and calcium activity, reaction to oxidative stress, and mitochondrial function. There is some evidence that sigma 1 receptor activation can induce neuronal regrowth and functional recovery after stroke. Sigma 1 also appears to play a role in helping cells clear misfolded proteins – a pathway that makes it an attractive drug target in Alzheimer’s disease, as well as other neurodegenerative diseases with aberrant proteins, such as Parkinson’s and Huntington’s diseases.
“Sigma 1 is never used except in times of trouble,” Dr. Missling said. “It’s only needed if we have a serious dysfunction in cells. By giving an agonist, we are increasing the expression of this protein, so it’s a bit like immune stimulation in oncology. We’re using the body’s own mechanism,” to fight neurodegeneration.
ANAVEX 2-73’s phase 2 development started with a 5-week crossover trial of 32 patients; they were a mean of 71 years old, with a mean MMSE of 21. The initial phase was followed by a 52-week, open-label trial of 10, 20, 30, and 50 mg/day orally, titrating each patient to the maximum tolerated dose.
Dr. Afshar presented 57-week data for the 26 patients who were still in the trial at that point and 109-week data for the six patients who had the best response at 57 weeks. Patients in both analyses were grouped by plasma level, not by their dosage level, although Dr. Missling said higher dosage generally correlated with higher plasma levels.
At 57 weeks, six patients had improved on the MMSE: four with high plasma levels and two with low plasma levels – patients identified as “outliers.” One patient with a high level remained stable. The rest of the cohort declined: seven with low levels, eight with moderate levels, and four with high levels, who were also identified as outliers. Also at 57 weeks, 24 patients had full data on the functional measure, the Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL). Nine patients had improved: five with high plasma levels, three with moderate levels, and one with a low level, identified as an outlier. One patient, with a moderate level, remained stable. The remaining 14 patients declined: nine with moderate levels, four with low levels, and one with a high level, dubbed an outlier.
Dr. Afshar reported more detailed data on the six best-performing patients. These included the two patients with low plasma levels who were characterized in the 57-week MMSE data as outliers. Their mean baseline MMSE went from 23.2 to 25.7 at 57 weeks; their mean functional score on the ADCS-ADL scale rose from 72 to 73.7.
He then showed each of these patients’ 109-week changes. Each was identified with a unique number in both the 57- and 109-week datasets. Numbers here are estimates drawn from the company’s data slides, which are publicly available on the Anavex website.
The ADCS-ADL is a caregiver-rated questionnaire of 23 items, with possible scores over a range of 0-78, where 78 implies full functioning with no impairment. On the 30-point MMSE scale, a score greater of 24 or higher indicates a normal cognition.
• 101009 (low plasma level)
MMSE: 20-29 ADCS-ADL: 73-71
• 101011 (low plasma level)
MMSE: 20-21 ADCS-ADL: 72-70
•101013 (high plasma level)
MMSE: 22-18 ADCS-ADL: 73-57
• 101014 (high plasma level)
MMSE: 20-25 ADCS-ADL: 75-74
• 102006 (high plasma level)
MMSE: 25-28 ADCS-ADL: 74-78
• 102010 (high plasma level)
MMSE: 25-28 ADCS-ADL: 64-68
Dr. Missling said ANAVEX 2-73 still appears safe and well tolerated. In the initial study phase, 98% of the subjects did have an adverse event; only one was considered serious. This was a case of delirium that developed in a patient who had several risk factors for the disorder, including a prior episode, and was not considered related to the study drug. Three patients withdrew because of an adverse event in the first 57 weeks; no one has withdrawn because of a side effect since then.
Dizziness was the most common adverse event (20 incidents in 15 patients), followed by headache (16 in 10 patients). Most (94%) occurred in the first week of treatment. All were mild or moderate. Headache and dizziness are considered signs that patients are approaching their maximum tolerated dose, Dr. Missling said.
The company’s task now is to find a standard minimum dose that is strong enough to get patients to at least 4 ng/mL plasma level, without inducing these side effects. The extension study will close out in November 2018. Anavex hopes to begin the drug’s next phase of development before then, with a phase 2/3 study of about 200 patients.
“We’re trying to gather as much data as possible so we can do this properly,” Dr. Missling said. “You can make the case that some developers have rushed into these studies after interpreting early results the wrong way. They said the glass was half-full when it was really half-empty. For us, it’s very important not to do that. We won’t go ahead with this until we are completely comfortable with what we see.”
[email protected]
On Twitter @alz_gal
AT CTAD
Key clinical point:
Major finding: Among the six best responders, the mean baseline MMSE went from 23.2 to 25.7; the mean functional score on the Alzheimer’s Disease Cooperative Study-activities of daily living scale rose from 72 to 73.7.
Data source: The phase 2a study is following 26 patients.
Disclosures: Dr. Christopher Missling is the chief executive officer of Anavex, which is developing 2-73. Dr. Mohammed Afshar is the CEO of Ariana Pharmaceuticals, which was hired to perform an independent data analysis of the study.
Long-term cholinesterase inhibition may slow cognitive decline – and more
BOSTON – Long-term use of cholinesterase inhibitors appears to confer a number of benefits, including protection from heart attack, stroke, diabetes-related mortality, and – according to a large new observational study – an annual 30% slowing of the cognitive decline associated with Alzheimer’s disease.
Long-term follow-up of thousands of patients in the Swedish Dementia Registry (SveDem) finds consistent, dose-dependent benefits associated with the drugs, Maria Eriksdotter, MD, said at the Clinical Trials on Alzheimer’s Disease conference. Most recently, her 3-year analysis of 29,000 patients showed that each year, those taking the drugs lost almost a point less on the Mini Mental State Exam (MMSE) than did nontreated patients.
“These drugs do reduce mortality and cardiovascular events, and improve cognitive decline,” she said in an interview. “It can be a difficult discussion to have with families, because yes, the patient is still declining, although more slowly. But combined with these other benefits that we are showing, I would say there is no reason not to get patients on a cholinesterase inhibitor as soon as possible. You want to get those benefits online as early as possible.”
The findings also strongly argue for cholinesterase inhibition to stay part of the standard treatment picture, even after disease-modifying medications do come on board.
“One could say you gain 30% of the decline back, and that 30% is something we could start from when we eventually begin talking about these therapies,” Dr. Eriksdotter said.
SveDem, launched in 2007, is a national project to improve the quality of diagnostics, treatment, and care of Swedish patients with dementia disorders. Patients newly diagnosed with a dementia disorder are registered and followed up yearly. Currently, it contains information on close to 70,000 patients.
The cognition study comprised almost 29,000 of those (CTAD abstract OC15). Dr. Eriksdotter and her colleagues categorized them as using or not using cholinesterase inhibitors (ChEI), and then examined the 3-year curves of cognitive decline, adjusting for age, sex, and a propensity score of whether or not they got a ChEI at baseline. The primary endpoint was MMSE decline by 3 years
At baseline, patients were a median of 80 years old. Alzheimer’s dementia was the most common diagnosis (63%), and 63% were taking a ChEI. Prescribing increased during each year of follow-up; by year 3, 91% were taking a ChEI. The median baseline MMSE was 22; this declined over time, to a median of 18. Patients taking the drugs were significantly younger than those not taking them (79 vs. 83 years), and less cognitively impaired (MMSE of 22 vs. 20). Most patients taking them had a diagnosis of Alzheimer’s dementia (70%), while others had a mix of vascular, frontotemporal, and Parkinson’s disease dementia.
Patients in both groups declined cognitively over the 3-year period, but the curves of decline were significantly different. The median MMSE decline regardless of treatment was 2.89 points. But in the fully adjusted model, those taking the drugs declined by about 0.85-point less each year than did those not taking them. This translated into an annual 30% reduction in cognitive decline, compared with untreated patients, Dr. Eriksdotter said.
She briefly discussed additional SveDem data supporting the drugs’ benefits in cardiovascular disorders and diabetes.
In 2013, she and her colleagues examined the link between ChEIs and heart attack in more than 7,000 SveDem registrants over a period of up to 5 years (Eur Heart J. 2013 Sep;34[33]:2585-91). After adjustment for confounding factors, the team found that ChEIs conferred a 34% risk reduction for a composite endpoint of myocardial infarction or death, compared with nonusers. The differences in the individual endpoints were also significant: a 36% lower risk of heart attack and 38% lower risk of death. She also found a dose-dependent response, with patients taking the highest recommended doses having the lowest risk of heart attack (hazard ratio, 0.35) and death (HR, 0.54).
Data from a similar study on stroke risk have been submitted for publication, Dr. Eriksdotter noted. This observational study comprised 22,300 patients followed for up to 5 years. Those who had ever taken a ChEI had a 33% decreased risk of ischemic stroke and 38% decreased risk of all-cause mortality. While the benefit was seen with the use of donepezil, rivastigmine, and galantamine, it was most pronounced with galantamine (30% decreased stroke risk, 32% decreased mortality risk). The study further determined that only patients taking high-dose ChEIs experienced the significant stroke benefit (HR, 0.59). The decreased risk of death was significant for all doses, but showed a dose-dependent benefit (low: HR, 0.85; medium: HR, 0.73; high: HR, 0.57).
Finally, Dr. Eriksdotter discussed a study in preparation comprising about 7,000 Alzheimer’s disease patients who also had diabetes. Of these, about 1,600 were taking a ChEI. In a fully adjusted model, the drugs were associated with a 16% decreased risk of death – exactly the same mortality benefit conferred by metformin. As an interesting side note, insulin use in this population was associated with a significant 15% increase in the risk of death, after full adjustment for confounding factors. None of the other antidiabetes medications (thiazolidinediones, dipeptidyl peptidase-4 inhibitors, or any newer drugs) showed any significant mortality benefit.
The protective mechanisms at work in these studies aren’t fully elucidated, Dr. Eriksdotter said. “But we do know that cholinesterase inhibitors exert an anti-inflammatory effect, and inflammation is definitely part of the cardiovascular disease and diabetes pictures. They also tend to slow heart rate, which has been found to have survival benefit in animal models.”
She had no financial disclosures.
[email protected]
On Twitter @Alz_Gal
The cholinesterase inhibitors are widely used for patients with Alzheimer’s disease, and to some extent other forms of cognitive impairment (rightly or wrongly). Their observed symptomatic benefits are modest and families frequently question whether the drugs are having any beneficial effect. So the idea that they may have long-term benefits is an extremely encouraging thought.
We do not have all the information that may be available at this time, and all or many of these issues undoubtedly occurred to the investigators who may have controlled for them, or been able to at least partially control for them, so that for now, I want to believe and am hoping the investigators are able to justify that belief with further data.
Richard J. Caselli, MD, is professor of neurology and medical director for service at the Mayo Clinic, Scottsdale, Ariz., and is associate director and clinical core director of the Arizona Alzheimer’s Disease Center. He has no relevant disclosures.
The cholinesterase inhibitors are widely used for patients with Alzheimer’s disease, and to some extent other forms of cognitive impairment (rightly or wrongly). Their observed symptomatic benefits are modest and families frequently question whether the drugs are having any beneficial effect. So the idea that they may have long-term benefits is an extremely encouraging thought.
We do not have all the information that may be available at this time, and all or many of these issues undoubtedly occurred to the investigators who may have controlled for them, or been able to at least partially control for them, so that for now, I want to believe and am hoping the investigators are able to justify that belief with further data.
Richard J. Caselli, MD, is professor of neurology and medical director for service at the Mayo Clinic, Scottsdale, Ariz., and is associate director and clinical core director of the Arizona Alzheimer’s Disease Center. He has no relevant disclosures.
The cholinesterase inhibitors are widely used for patients with Alzheimer’s disease, and to some extent other forms of cognitive impairment (rightly or wrongly). Their observed symptomatic benefits are modest and families frequently question whether the drugs are having any beneficial effect. So the idea that they may have long-term benefits is an extremely encouraging thought.
We do not have all the information that may be available at this time, and all or many of these issues undoubtedly occurred to the investigators who may have controlled for them, or been able to at least partially control for them, so that for now, I want to believe and am hoping the investigators are able to justify that belief with further data.
Richard J. Caselli, MD, is professor of neurology and medical director for service at the Mayo Clinic, Scottsdale, Ariz., and is associate director and clinical core director of the Arizona Alzheimer’s Disease Center. He has no relevant disclosures.
BOSTON – Long-term use of cholinesterase inhibitors appears to confer a number of benefits, including protection from heart attack, stroke, diabetes-related mortality, and – according to a large new observational study – an annual 30% slowing of the cognitive decline associated with Alzheimer’s disease.
Long-term follow-up of thousands of patients in the Swedish Dementia Registry (SveDem) finds consistent, dose-dependent benefits associated with the drugs, Maria Eriksdotter, MD, said at the Clinical Trials on Alzheimer’s Disease conference. Most recently, her 3-year analysis of 29,000 patients showed that each year, those taking the drugs lost almost a point less on the Mini Mental State Exam (MMSE) than did nontreated patients.
“These drugs do reduce mortality and cardiovascular events, and improve cognitive decline,” she said in an interview. “It can be a difficult discussion to have with families, because yes, the patient is still declining, although more slowly. But combined with these other benefits that we are showing, I would say there is no reason not to get patients on a cholinesterase inhibitor as soon as possible. You want to get those benefits online as early as possible.”
The findings also strongly argue for cholinesterase inhibition to stay part of the standard treatment picture, even after disease-modifying medications do come on board.
“One could say you gain 30% of the decline back, and that 30% is something we could start from when we eventually begin talking about these therapies,” Dr. Eriksdotter said.
SveDem, launched in 2007, is a national project to improve the quality of diagnostics, treatment, and care of Swedish patients with dementia disorders. Patients newly diagnosed with a dementia disorder are registered and followed up yearly. Currently, it contains information on close to 70,000 patients.
The cognition study comprised almost 29,000 of those (CTAD abstract OC15). Dr. Eriksdotter and her colleagues categorized them as using or not using cholinesterase inhibitors (ChEI), and then examined the 3-year curves of cognitive decline, adjusting for age, sex, and a propensity score of whether or not they got a ChEI at baseline. The primary endpoint was MMSE decline by 3 years
At baseline, patients were a median of 80 years old. Alzheimer’s dementia was the most common diagnosis (63%), and 63% were taking a ChEI. Prescribing increased during each year of follow-up; by year 3, 91% were taking a ChEI. The median baseline MMSE was 22; this declined over time, to a median of 18. Patients taking the drugs were significantly younger than those not taking them (79 vs. 83 years), and less cognitively impaired (MMSE of 22 vs. 20). Most patients taking them had a diagnosis of Alzheimer’s dementia (70%), while others had a mix of vascular, frontotemporal, and Parkinson’s disease dementia.
Patients in both groups declined cognitively over the 3-year period, but the curves of decline were significantly different. The median MMSE decline regardless of treatment was 2.89 points. But in the fully adjusted model, those taking the drugs declined by about 0.85-point less each year than did those not taking them. This translated into an annual 30% reduction in cognitive decline, compared with untreated patients, Dr. Eriksdotter said.
She briefly discussed additional SveDem data supporting the drugs’ benefits in cardiovascular disorders and diabetes.
In 2013, she and her colleagues examined the link between ChEIs and heart attack in more than 7,000 SveDem registrants over a period of up to 5 years (Eur Heart J. 2013 Sep;34[33]:2585-91). After adjustment for confounding factors, the team found that ChEIs conferred a 34% risk reduction for a composite endpoint of myocardial infarction or death, compared with nonusers. The differences in the individual endpoints were also significant: a 36% lower risk of heart attack and 38% lower risk of death. She also found a dose-dependent response, with patients taking the highest recommended doses having the lowest risk of heart attack (hazard ratio, 0.35) and death (HR, 0.54).
Data from a similar study on stroke risk have been submitted for publication, Dr. Eriksdotter noted. This observational study comprised 22,300 patients followed for up to 5 years. Those who had ever taken a ChEI had a 33% decreased risk of ischemic stroke and 38% decreased risk of all-cause mortality. While the benefit was seen with the use of donepezil, rivastigmine, and galantamine, it was most pronounced with galantamine (30% decreased stroke risk, 32% decreased mortality risk). The study further determined that only patients taking high-dose ChEIs experienced the significant stroke benefit (HR, 0.59). The decreased risk of death was significant for all doses, but showed a dose-dependent benefit (low: HR, 0.85; medium: HR, 0.73; high: HR, 0.57).
Finally, Dr. Eriksdotter discussed a study in preparation comprising about 7,000 Alzheimer’s disease patients who also had diabetes. Of these, about 1,600 were taking a ChEI. In a fully adjusted model, the drugs were associated with a 16% decreased risk of death – exactly the same mortality benefit conferred by metformin. As an interesting side note, insulin use in this population was associated with a significant 15% increase in the risk of death, after full adjustment for confounding factors. None of the other antidiabetes medications (thiazolidinediones, dipeptidyl peptidase-4 inhibitors, or any newer drugs) showed any significant mortality benefit.
The protective mechanisms at work in these studies aren’t fully elucidated, Dr. Eriksdotter said. “But we do know that cholinesterase inhibitors exert an anti-inflammatory effect, and inflammation is definitely part of the cardiovascular disease and diabetes pictures. They also tend to slow heart rate, which has been found to have survival benefit in animal models.”
She had no financial disclosures.
[email protected]
On Twitter @Alz_Gal
BOSTON – Long-term use of cholinesterase inhibitors appears to confer a number of benefits, including protection from heart attack, stroke, diabetes-related mortality, and – according to a large new observational study – an annual 30% slowing of the cognitive decline associated with Alzheimer’s disease.
Long-term follow-up of thousands of patients in the Swedish Dementia Registry (SveDem) finds consistent, dose-dependent benefits associated with the drugs, Maria Eriksdotter, MD, said at the Clinical Trials on Alzheimer’s Disease conference. Most recently, her 3-year analysis of 29,000 patients showed that each year, those taking the drugs lost almost a point less on the Mini Mental State Exam (MMSE) than did nontreated patients.
“These drugs do reduce mortality and cardiovascular events, and improve cognitive decline,” she said in an interview. “It can be a difficult discussion to have with families, because yes, the patient is still declining, although more slowly. But combined with these other benefits that we are showing, I would say there is no reason not to get patients on a cholinesterase inhibitor as soon as possible. You want to get those benefits online as early as possible.”
The findings also strongly argue for cholinesterase inhibition to stay part of the standard treatment picture, even after disease-modifying medications do come on board.
“One could say you gain 30% of the decline back, and that 30% is something we could start from when we eventually begin talking about these therapies,” Dr. Eriksdotter said.
SveDem, launched in 2007, is a national project to improve the quality of diagnostics, treatment, and care of Swedish patients with dementia disorders. Patients newly diagnosed with a dementia disorder are registered and followed up yearly. Currently, it contains information on close to 70,000 patients.
The cognition study comprised almost 29,000 of those (CTAD abstract OC15). Dr. Eriksdotter and her colleagues categorized them as using or not using cholinesterase inhibitors (ChEI), and then examined the 3-year curves of cognitive decline, adjusting for age, sex, and a propensity score of whether or not they got a ChEI at baseline. The primary endpoint was MMSE decline by 3 years
At baseline, patients were a median of 80 years old. Alzheimer’s dementia was the most common diagnosis (63%), and 63% were taking a ChEI. Prescribing increased during each year of follow-up; by year 3, 91% were taking a ChEI. The median baseline MMSE was 22; this declined over time, to a median of 18. Patients taking the drugs were significantly younger than those not taking them (79 vs. 83 years), and less cognitively impaired (MMSE of 22 vs. 20). Most patients taking them had a diagnosis of Alzheimer’s dementia (70%), while others had a mix of vascular, frontotemporal, and Parkinson’s disease dementia.
Patients in both groups declined cognitively over the 3-year period, but the curves of decline were significantly different. The median MMSE decline regardless of treatment was 2.89 points. But in the fully adjusted model, those taking the drugs declined by about 0.85-point less each year than did those not taking them. This translated into an annual 30% reduction in cognitive decline, compared with untreated patients, Dr. Eriksdotter said.
She briefly discussed additional SveDem data supporting the drugs’ benefits in cardiovascular disorders and diabetes.
In 2013, she and her colleagues examined the link between ChEIs and heart attack in more than 7,000 SveDem registrants over a period of up to 5 years (Eur Heart J. 2013 Sep;34[33]:2585-91). After adjustment for confounding factors, the team found that ChEIs conferred a 34% risk reduction for a composite endpoint of myocardial infarction or death, compared with nonusers. The differences in the individual endpoints were also significant: a 36% lower risk of heart attack and 38% lower risk of death. She also found a dose-dependent response, with patients taking the highest recommended doses having the lowest risk of heart attack (hazard ratio, 0.35) and death (HR, 0.54).
Data from a similar study on stroke risk have been submitted for publication, Dr. Eriksdotter noted. This observational study comprised 22,300 patients followed for up to 5 years. Those who had ever taken a ChEI had a 33% decreased risk of ischemic stroke and 38% decreased risk of all-cause mortality. While the benefit was seen with the use of donepezil, rivastigmine, and galantamine, it was most pronounced with galantamine (30% decreased stroke risk, 32% decreased mortality risk). The study further determined that only patients taking high-dose ChEIs experienced the significant stroke benefit (HR, 0.59). The decreased risk of death was significant for all doses, but showed a dose-dependent benefit (low: HR, 0.85; medium: HR, 0.73; high: HR, 0.57).
Finally, Dr. Eriksdotter discussed a study in preparation comprising about 7,000 Alzheimer’s disease patients who also had diabetes. Of these, about 1,600 were taking a ChEI. In a fully adjusted model, the drugs were associated with a 16% decreased risk of death – exactly the same mortality benefit conferred by metformin. As an interesting side note, insulin use in this population was associated with a significant 15% increase in the risk of death, after full adjustment for confounding factors. None of the other antidiabetes medications (thiazolidinediones, dipeptidyl peptidase-4 inhibitors, or any newer drugs) showed any significant mortality benefit.
The protective mechanisms at work in these studies aren’t fully elucidated, Dr. Eriksdotter said. “But we do know that cholinesterase inhibitors exert an anti-inflammatory effect, and inflammation is definitely part of the cardiovascular disease and diabetes pictures. They also tend to slow heart rate, which has been found to have survival benefit in animal models.”
She had no financial disclosures.
[email protected]
On Twitter @Alz_Gal
AT CTAD
Key clinical point:
Major finding: Patients taking the drugs lost almost 1 point less on the Mini Mental State Exam each year than did those who didn’t take them.
Data source: The 3-year observational study comprised almost 29,000 patients in the Swedish Dementia Registry.
Disclosures: Dr. Eriksdotter had no financial disclosures.
Pimavanserin found modestly effective in phase 2 Alzheimer’s psychosis study
BOSTON – Pimavanserin, an atypical antipsychotic approved for use in psychosis associated with Parkinson’s disease, was modestly effective in treating psychosis associated with Alzheimer’s dementia in a phase 2 study.
The study of 181 patients showed that pimavanserin (Nuplazid) was associated with a statistically significant 3.76-point improvement on the Neuropsychiatric Inventory–Nursing Home Version (NPI-NH) psychosis score, Clive Ballard, MD, reported at the Clinical Trials on Alzheimer’s Disease conference. But although pimavanserin was significantly more effective than placebo at 6 weeks, it lost its statistical edge by the trial’s end at 12 weeks, largely because the placebo group improved over the study period.
A key finding was that pimavanserin was more effective in a subset of patients with severe symptoms, reducing those by more than 4 points on the NPI scale, said Dr. Ballard, codirector of the Biomedical Research Unit for Dementia in the Institute for Psychiatry at King’s College London. “A 4-point change is the difference from having moderate symptoms daily to having them weekly. I think this is the most clinically relevant finding.”
The drug seemed to largely spare cognition, which is another notch in its clinical belt, said Richard J. Caselli, MD, professor of neurology at the Mayo Clinic, Scottsdale, Ariz.
“The relative preservation of cognition as seen in an absence of adverse cognitive effects is encouraging, and something pimavanserin may have over its antipsychotic rivals,” Dr. Caselli said in an interview. “The improved scores on the NPI seem modest as does the relative percentage of responders, defined as at least 30% improved NPI-NH score. But at least it is a positive result. One concern is that the company advises it may take 4-6 weeks to see an improvement, which is not the kind of timeline one has with acutely and severely agitated patients. So I suspect antipsychotic drugs, which work more quickly, are likely not going away.”
The 12-week, phase 2 study randomized 181 patients with advanced Alzheimer’s dementia to placebo or 40 mg pimavanserin. They were a mean of 86 years old. The mean baseline NPI-NH psychosis score was 9.8 and the mean Mini–Mental State Exam score was 10.
By 6 weeks, the psychosis score had improved significantly more in the pimavanserin group than in the placebo group (–3.76 vs. –1.93 points; P = .0451). The drug was more effective among patients with severe psychosis at baseline, defined as an NPI-NH psychosis score of at least 12. Among this group, the score improved by 4.43 points. The results were slightly, but not significantly, better in patients who had responded to prior antipsychotic medications and among those who were also taking a selective serotonin reuptake inhibitor. A responder analysis also favored treatment, with 90% of those taking pimavanserin experiencing at least a 30% improvement on the NPI-NH psychosis score, compared with 43% of those taking placebo.
At 12 weeks, however, the overall between-group difference was no longer statistically significant, because the placebo group continued to improve over the treatment period.
Safety and tolerability were important considerations in such an elderly and cognitively compromised group, Dr. Ballard noted. In this respect, pimavanserin performed relatively well. There were more serious adverse events in the treated group (16.7% vs. 11%). These included respiratory infections (5 vs. 2) and urinary tract infection (2 vs. 0). Falls and fractures were similar in both groups. There was one fall in the active group, with one laceration, one hip fracture, and one femoral neck fracture. In the placebo group, there was one fall, one upper limb fracture, one wrist fracture, and one vertebral fracture. Among treated patients, there was also one heart attack and one case of renal failure. Four patients in each group died during the study.
Psychiatric events were more common in the pimavanserin group, most notably agitation (21% vs. 14%). Other psychiatric adverse events included aggression (10% vs. 4%), anxiety (5.6% vs. 2.2%), and dementia-related behavioral symptoms (5.6% vs. 2%). The drug had no effect on Mini–Mental State Exam score.
Pimavanserin was associated with a mean change of 9.4 ms in the heart rate-corrected QT interval, and was more likely to induce a weight loss of 7% or more.
Dr. Ballard had no financial disclosures with regard to pimavanserin or Acadia Pharmaceuticals, which sponsored the trial.
[email protected]
On Twitter @Alz_Gal
BOSTON – Pimavanserin, an atypical antipsychotic approved for use in psychosis associated with Parkinson’s disease, was modestly effective in treating psychosis associated with Alzheimer’s dementia in a phase 2 study.
The study of 181 patients showed that pimavanserin (Nuplazid) was associated with a statistically significant 3.76-point improvement on the Neuropsychiatric Inventory–Nursing Home Version (NPI-NH) psychosis score, Clive Ballard, MD, reported at the Clinical Trials on Alzheimer’s Disease conference. But although pimavanserin was significantly more effective than placebo at 6 weeks, it lost its statistical edge by the trial’s end at 12 weeks, largely because the placebo group improved over the study period.
A key finding was that pimavanserin was more effective in a subset of patients with severe symptoms, reducing those by more than 4 points on the NPI scale, said Dr. Ballard, codirector of the Biomedical Research Unit for Dementia in the Institute for Psychiatry at King’s College London. “A 4-point change is the difference from having moderate symptoms daily to having them weekly. I think this is the most clinically relevant finding.”
The drug seemed to largely spare cognition, which is another notch in its clinical belt, said Richard J. Caselli, MD, professor of neurology at the Mayo Clinic, Scottsdale, Ariz.
“The relative preservation of cognition as seen in an absence of adverse cognitive effects is encouraging, and something pimavanserin may have over its antipsychotic rivals,” Dr. Caselli said in an interview. “The improved scores on the NPI seem modest as does the relative percentage of responders, defined as at least 30% improved NPI-NH score. But at least it is a positive result. One concern is that the company advises it may take 4-6 weeks to see an improvement, which is not the kind of timeline one has with acutely and severely agitated patients. So I suspect antipsychotic drugs, which work more quickly, are likely not going away.”
The 12-week, phase 2 study randomized 181 patients with advanced Alzheimer’s dementia to placebo or 40 mg pimavanserin. They were a mean of 86 years old. The mean baseline NPI-NH psychosis score was 9.8 and the mean Mini–Mental State Exam score was 10.
By 6 weeks, the psychosis score had improved significantly more in the pimavanserin group than in the placebo group (–3.76 vs. –1.93 points; P = .0451). The drug was more effective among patients with severe psychosis at baseline, defined as an NPI-NH psychosis score of at least 12. Among this group, the score improved by 4.43 points. The results were slightly, but not significantly, better in patients who had responded to prior antipsychotic medications and among those who were also taking a selective serotonin reuptake inhibitor. A responder analysis also favored treatment, with 90% of those taking pimavanserin experiencing at least a 30% improvement on the NPI-NH psychosis score, compared with 43% of those taking placebo.
At 12 weeks, however, the overall between-group difference was no longer statistically significant, because the placebo group continued to improve over the treatment period.
Safety and tolerability were important considerations in such an elderly and cognitively compromised group, Dr. Ballard noted. In this respect, pimavanserin performed relatively well. There were more serious adverse events in the treated group (16.7% vs. 11%). These included respiratory infections (5 vs. 2) and urinary tract infection (2 vs. 0). Falls and fractures were similar in both groups. There was one fall in the active group, with one laceration, one hip fracture, and one femoral neck fracture. In the placebo group, there was one fall, one upper limb fracture, one wrist fracture, and one vertebral fracture. Among treated patients, there was also one heart attack and one case of renal failure. Four patients in each group died during the study.
Psychiatric events were more common in the pimavanserin group, most notably agitation (21% vs. 14%). Other psychiatric adverse events included aggression (10% vs. 4%), anxiety (5.6% vs. 2.2%), and dementia-related behavioral symptoms (5.6% vs. 2%). The drug had no effect on Mini–Mental State Exam score.
Pimavanserin was associated with a mean change of 9.4 ms in the heart rate-corrected QT interval, and was more likely to induce a weight loss of 7% or more.
Dr. Ballard had no financial disclosures with regard to pimavanserin or Acadia Pharmaceuticals, which sponsored the trial.
[email protected]
On Twitter @Alz_Gal
BOSTON – Pimavanserin, an atypical antipsychotic approved for use in psychosis associated with Parkinson’s disease, was modestly effective in treating psychosis associated with Alzheimer’s dementia in a phase 2 study.
The study of 181 patients showed that pimavanserin (Nuplazid) was associated with a statistically significant 3.76-point improvement on the Neuropsychiatric Inventory–Nursing Home Version (NPI-NH) psychosis score, Clive Ballard, MD, reported at the Clinical Trials on Alzheimer’s Disease conference. But although pimavanserin was significantly more effective than placebo at 6 weeks, it lost its statistical edge by the trial’s end at 12 weeks, largely because the placebo group improved over the study period.
A key finding was that pimavanserin was more effective in a subset of patients with severe symptoms, reducing those by more than 4 points on the NPI scale, said Dr. Ballard, codirector of the Biomedical Research Unit for Dementia in the Institute for Psychiatry at King’s College London. “A 4-point change is the difference from having moderate symptoms daily to having them weekly. I think this is the most clinically relevant finding.”
The drug seemed to largely spare cognition, which is another notch in its clinical belt, said Richard J. Caselli, MD, professor of neurology at the Mayo Clinic, Scottsdale, Ariz.
“The relative preservation of cognition as seen in an absence of adverse cognitive effects is encouraging, and something pimavanserin may have over its antipsychotic rivals,” Dr. Caselli said in an interview. “The improved scores on the NPI seem modest as does the relative percentage of responders, defined as at least 30% improved NPI-NH score. But at least it is a positive result. One concern is that the company advises it may take 4-6 weeks to see an improvement, which is not the kind of timeline one has with acutely and severely agitated patients. So I suspect antipsychotic drugs, which work more quickly, are likely not going away.”
The 12-week, phase 2 study randomized 181 patients with advanced Alzheimer’s dementia to placebo or 40 mg pimavanserin. They were a mean of 86 years old. The mean baseline NPI-NH psychosis score was 9.8 and the mean Mini–Mental State Exam score was 10.
By 6 weeks, the psychosis score had improved significantly more in the pimavanserin group than in the placebo group (–3.76 vs. –1.93 points; P = .0451). The drug was more effective among patients with severe psychosis at baseline, defined as an NPI-NH psychosis score of at least 12. Among this group, the score improved by 4.43 points. The results were slightly, but not significantly, better in patients who had responded to prior antipsychotic medications and among those who were also taking a selective serotonin reuptake inhibitor. A responder analysis also favored treatment, with 90% of those taking pimavanserin experiencing at least a 30% improvement on the NPI-NH psychosis score, compared with 43% of those taking placebo.
At 12 weeks, however, the overall between-group difference was no longer statistically significant, because the placebo group continued to improve over the treatment period.
Safety and tolerability were important considerations in such an elderly and cognitively compromised group, Dr. Ballard noted. In this respect, pimavanserin performed relatively well. There were more serious adverse events in the treated group (16.7% vs. 11%). These included respiratory infections (5 vs. 2) and urinary tract infection (2 vs. 0). Falls and fractures were similar in both groups. There was one fall in the active group, with one laceration, one hip fracture, and one femoral neck fracture. In the placebo group, there was one fall, one upper limb fracture, one wrist fracture, and one vertebral fracture. Among treated patients, there was also one heart attack and one case of renal failure. Four patients in each group died during the study.
Psychiatric events were more common in the pimavanserin group, most notably agitation (21% vs. 14%). Other psychiatric adverse events included aggression (10% vs. 4%), anxiety (5.6% vs. 2.2%), and dementia-related behavioral symptoms (5.6% vs. 2%). The drug had no effect on Mini–Mental State Exam score.
Pimavanserin was associated with a mean change of 9.4 ms in the heart rate-corrected QT interval, and was more likely to induce a weight loss of 7% or more.
Dr. Ballard had no financial disclosures with regard to pimavanserin or Acadia Pharmaceuticals, which sponsored the trial.
[email protected]
On Twitter @Alz_Gal
AT CTAD
Key clinical point:
Major finding: The psychosis score at 6 weeks improved significantly more in patients taking pimavanserin than in those taking placebo (–3.76 vs. –1.93 points; P = .0451).
Data source: The randomized, placebo-controlled study enrolled 181 patients.
Disclosures: Acadia Pharmaceuticals makes pimavanserin and sponsored the trial. Dr. Ballard has no financial relationship with the company.