CTAD

BARCELONA – A failed phase III clinical trial for the investigational antiamyloid antibody gantenerumab in patients with Alzheimer’s disease may have had better results with a higher dose aimed at a more targeted population, new post hoc analyses of the trial’s data suggest.

The subanalyses of the now-defunct SCARLET ROAD study indicate that patients who had a more rapid progression of disease and took gantenerumab 225 mg received some cognitive benefit, especially in those who had the highest plasma concentrations.

Agnieszka Letowska/Thinkstock

Biomarker results also shifted toward the positive, according to data presented at the Clinical Trials in Alzheimer’s Disease conference. Amyloid PET imaging showed significantly greater plaque reduction in the brains of those with the highest gantenerumab exposure. Cerebrospinal fluid tests found that the antibody significantly decreased the level of phosphorylated tau. This, said Dr. Tania Nikolcheva, is the first evidence that attacking amyloid brain plaques can have a downstream effect on tau, which is now considered to be the major player in Alzheimer’s cognitive decline.

“We demonstrated that gantenerumab shows a consistent effect on the intended target as well as on downstream biomarkers,” said Dr. Nikolcheva of Hoffman-LaRoche, which is developing the drug. “These seem to be exposure- and dose-dependent, which supports following this trial with tests of higher dosages.”

In December 2014, Roche’s SCARLET ROAD study was halted after a 2-year interim analysis found that neither the 105 mg nor 225 mg dose conferred a significant cognitive benefit relative to placebo. But the antibody’s story is still unfolding: The drug is still being investigated in another Roche-sponsored trial of patients with mild disease called MARGUERITE ROAD.

Gantenerumab’s most highly anticipated test, however, will be in the Dominantly Inherited Alzheimer Network Trial(DIAN-TU). This study is comparing gantenerumab to another antiamyloid antibody, solanezumab, and to placebo. A crucial investigation with the potential of proving the amyloid cascade hypothesis, DIAN-TU is enrolling people who are cognitively normal at baseline but are virtually guaranteed to develop early-onset Alzheimer’s because they carry a mutation in the presenilin or amyloid precursor protein gene. The hope is that the drugs will prevent or at least delay the onset of cognitive symptoms by preventing or slowing amyloid plaque formation.

Roche didn’t release any clinical or biomarker data when it ended SCARLET ROAD a year ago. During the Alzheimer’s Association International Conference (AAIC) in July, the company disclosed that there were no significant differences after 2 years of treatment between placebo and either drug dose in the primary cognitive endpoint, the Clinical Dementia Rating–sum of boxes (CDR-sb), or in any secondary endpoints: the Alzheimer’s Disease Assessment Scale–cognitive subscale 13 (ADAS-cog13), the Mini-Mental State Examination (MMSE), and the Functional Activities Questionnaire (FAQ).

Rate of disease progression proved important

However, there were signs that the 225-mg dose of gantenerumab was at least somewhat effective in the subgroup of patients who seemed destined to have more rapidly progressing disease, Roche’s Dr. Robert Lasser said at AAIC. The benefit was obscured in the overall analysis, he said, because patient progression rates varied so highly – about a third progressed rapidly, a third slowly, and a third didn’t progress at all over the 2-year period examined in the interim analysis.

While the dropout rates were similar in the three treatment arms, data presented at CTAD showed that patients in the placebo group who dropped out were progressing four times faster on the MMSE and three times faster on the ADAS-cog13 than did those who remained in the study. Dropping out probably reflected their desire to abandon a noneffective therapy and seek symptomatic treatment, which was not allowed in the study protocol, said Dr. Juergen Dukart of Roche.

Conversely, patients with rapidly progressing disease in the active groups may have responded well to the treatment, making them more likely to stay in the trial. The disproportionate retention combined with variable progression could have masked the real treatment effect, he said.

Drug exposure in rapidly progressing disease

The trial-ending interim analysis of 315 subjects didn’t include data on the 190 who had dropped out by 2 years. But outcomes presented at CTAD did include data on those subjects, and significant treatment differences appeared, especially in light of drug exposure levels. Of the fast progressers, those with higher plasma gantenerumab concentrations had less clinical decline than did those with lower drug exposure or those taking placebo, said Dr. Sylvie Retout of Roche. Among fast progressers, the ADAS-cog13 increased (indicating worsening) by 6 points in the placebo group; by 5 points in the low-exposure group; by 4 points in the medium-exposure group; and by 2 points in the high-exposure group. Similar exposure trends among fast progressers were seen on MMSE scores, but not on CDR-sb scores.

The story was different among patients who progressed slowly, Dr. Retout said. “Among slow progressers, no exposure-response relationship could be observed, indicating that the slow disease progression over the 2-year treatment period was probably limiting the detection of a drug effect,” she said.

Finding the right trial population

The problem of progression variability, dropout rates, and potentially skewed clinical outcomes is a tough nut for Alzheimer’s drug trials, Dr. Lasser said at the CTAD conference.

“This is likely to continue to surprise us if we still have this 25%-30% in our trials who don’t decline over the course of treatment. There really aren’t any big differences at baseline that stand out so that you could create the inclusion criteria to minimize this population of patients.”

Amyloid imaging, which does at least allow recruitment of a pure Alzheimer’s cohort, was not widely available when the SCARLET ROAD cohort was recruited. And although amyloid imaging is a great tool for predicting conversion to dementia from mild cognitive impairment, it’s not terribly useful as a tool for predicting progression.

Factoring baseline cerebrospinal fluid tau levels into the equation didn’t improve prediction, Dr. Lasser noted. Apolipoprotein E (APOE) allele status was similarly unhelpful.

“We didn’t find very much difference among the allele groups; there was no consistent pattern, and the between-group differences were small. So we’re beginning to hypothesize that while APOE is an excellent risk marker before cognitive decline develops, once it does start, allele status may not be as crucial in determining the patient’s eventual outcome.”

The only hints of progression speed at baseline were in the two functional measures of CDR-sb and FAQ. Fast progressers showed significantly more impairment on both of these at baseline than did slow progressers.

“Progression seems to be more likely in those who have functional decline already present as part of their prodromal presentation,” Dr. Lasser said. “At baseline, the most meaningful difference was not the MMSE, but the CDR-sb. This indicates that functional impairment may be a critical factor to look at when you’re enrolling subjects.”

msullivan@frontlinemedcom.com

On Twitter @Alz_Gal

BARCELONA – A failed phase III clinical trial for the investigational antiamyloid antibody gantenerumab in patients with Alzheimer’s disease may have had better results with a higher dose aimed at a more targeted population, new post hoc analyses of the trial’s data suggest.

The subanalyses of the now-defunct SCARLET ROAD study indicate that patients who had a more rapid progression of disease and took gantenerumab 225 mg received some cognitive benefit, especially in those who had the highest plasma concentrations.

Agnieszka Letowska/Thinkstock

Biomarker results also shifted toward the positive, according to data presented at the Clinical Trials in Alzheimer’s Disease conference. Amyloid PET imaging showed significantly greater plaque reduction in the brains of those with the highest gantenerumab exposure. Cerebrospinal fluid tests found that the antibody significantly decreased the level of phosphorylated tau. This, said Dr. Tania Nikolcheva, is the first evidence that attacking amyloid brain plaques can have a downstream effect on tau, which is now considered to be the major player in Alzheimer’s cognitive decline.

“We demonstrated that gantenerumab shows a consistent effect on the intended target as well as on downstream biomarkers,” said Dr. Nikolcheva of Hoffman-LaRoche, which is developing the drug. “These seem to be exposure- and dose-dependent, which supports following this trial with tests of higher dosages.”

In December 2014, Roche’s SCARLET ROAD study was halted after a 2-year interim analysis found that neither the 105 mg nor 225 mg dose conferred a significant cognitive benefit relative to placebo. But the antibody’s story is still unfolding: The drug is still being investigated in another Roche-sponsored trial of patients with mild disease called MARGUERITE ROAD.

Gantenerumab’s most highly anticipated test, however, will be in the Dominantly Inherited Alzheimer Network Trial(DIAN-TU). This study is comparing gantenerumab to another antiamyloid antibody, solanezumab, and to placebo. A crucial investigation with the potential of proving the amyloid cascade hypothesis, DIAN-TU is enrolling people who are cognitively normal at baseline but are virtually guaranteed to develop early-onset Alzheimer’s because they carry a mutation in the presenilin or amyloid precursor protein gene. The hope is that the drugs will prevent or at least delay the onset of cognitive symptoms by preventing or slowing amyloid plaque formation.

Roche didn’t release any clinical or biomarker data when it ended SCARLET ROAD a year ago. During the Alzheimer’s Association International Conference (AAIC) in July, the company disclosed that there were no significant differences after 2 years of treatment between placebo and either drug dose in the primary cognitive endpoint, the Clinical Dementia Rating–sum of boxes (CDR-sb), or in any secondary endpoints: the Alzheimer’s Disease Assessment Scale–cognitive subscale 13 (ADAS-cog13), the Mini-Mental State Examination (MMSE), and the Functional Activities Questionnaire (FAQ).

Rate of disease progression proved important

However, there were signs that the 225-mg dose of gantenerumab was at least somewhat effective in the subgroup of patients who seemed destined to have more rapidly progressing disease, Roche’s Dr. Robert Lasser said at AAIC. The benefit was obscured in the overall analysis, he said, because patient progression rates varied so highly – about a third progressed rapidly, a third slowly, and a third didn’t progress at all over the 2-year period examined in the interim analysis.

While the dropout rates were similar in the three treatment arms, data presented at CTAD showed that patients in the placebo group who dropped out were progressing four times faster on the MMSE and three times faster on the ADAS-cog13 than did those who remained in the study. Dropping out probably reflected their desire to abandon a noneffective therapy and seek symptomatic treatment, which was not allowed in the study protocol, said Dr. Juergen Dukart of Roche.

Conversely, patients with rapidly progressing disease in the active groups may have responded well to the treatment, making them more likely to stay in the trial. The disproportionate retention combined with variable progression could have masked the real treatment effect, he said.

Drug exposure in rapidly progressing disease

The trial-ending interim analysis of 315 subjects didn’t include data on the 190 who had dropped out by 2 years. But outcomes presented at CTAD did include data on those subjects, and significant treatment differences appeared, especially in light of drug exposure levels. Of the fast progressers, those with higher plasma gantenerumab concentrations had less clinical decline than did those with lower drug exposure or those taking placebo, said Dr. Sylvie Retout of Roche. Among fast progressers, the ADAS-cog13 increased (indicating worsening) by 6 points in the placebo group; by 5 points in the low-exposure group; by 4 points in the medium-exposure group; and by 2 points in the high-exposure group. Similar exposure trends among fast progressers were seen on MMSE scores, but not on CDR-sb scores.

The story was different among patients who progressed slowly, Dr. Retout said. “Among slow progressers, no exposure-response relationship could be observed, indicating that the slow disease progression over the 2-year treatment period was probably limiting the detection of a drug effect,” she said.

Finding the right trial population

The problem of progression variability, dropout rates, and potentially skewed clinical outcomes is a tough nut for Alzheimer’s drug trials, Dr. Lasser said at the CTAD conference.

“This is likely to continue to surprise us if we still have this 25%-30% in our trials who don’t decline over the course of treatment. There really aren’t any big differences at baseline that stand out so that you could create the inclusion criteria to minimize this population of patients.”

Amyloid imaging, which does at least allow recruitment of a pure Alzheimer’s cohort, was not widely available when the SCARLET ROAD cohort was recruited. And although amyloid imaging is a great tool for predicting conversion to dementia from mild cognitive impairment, it’s not terribly useful as a tool for predicting progression.

Factoring baseline cerebrospinal fluid tau levels into the equation didn’t improve prediction, Dr. Lasser noted. Apolipoprotein E (APOE) allele status was similarly unhelpful.

“We didn’t find very much difference among the allele groups; there was no consistent pattern, and the between-group differences were small. So we’re beginning to hypothesize that while APOE is an excellent risk marker before cognitive decline develops, once it does start, allele status may not be as crucial in determining the patient’s eventual outcome.”

The only hints of progression speed at baseline were in the two functional measures of CDR-sb and FAQ. Fast progressers showed significantly more impairment on both of these at baseline than did slow progressers.

“Progression seems to be more likely in those who have functional decline already present as part of their prodromal presentation,” Dr. Lasser said. “At baseline, the most meaningful difference was not the MMSE, but the CDR-sb. This indicates that functional impairment may be a critical factor to look at when you’re enrolling subjects.”

msullivan@frontlinemedcom.com

On Twitter @Alz_Gal

BARCELONA – A failed phase III clinical trial for the investigational antiamyloid antibody gantenerumab in patients with Alzheimer’s disease may have had better results with a higher dose aimed at a more targeted population, new post hoc analyses of the trial’s data suggest.

The subanalyses of the now-defunct SCARLET ROAD study indicate that patients who had a more rapid progression of disease and took gantenerumab 225 mg received some cognitive benefit, especially in those who had the highest plasma concentrations.

Agnieszka Letowska/Thinkstock

Biomarker results also shifted toward the positive, according to data presented at the Clinical Trials in Alzheimer’s Disease conference. Amyloid PET imaging showed significantly greater plaque reduction in the brains of those with the highest gantenerumab exposure. Cerebrospinal fluid tests found that the antibody significantly decreased the level of phosphorylated tau. This, said Dr. Tania Nikolcheva, is the first evidence that attacking amyloid brain plaques can have a downstream effect on tau, which is now considered to be the major player in Alzheimer’s cognitive decline.

“We demonstrated that gantenerumab shows a consistent effect on the intended target as well as on downstream biomarkers,” said Dr. Nikolcheva of Hoffman-LaRoche, which is developing the drug. “These seem to be exposure- and dose-dependent, which supports following this trial with tests of higher dosages.”

In December 2014, Roche’s SCARLET ROAD study was halted after a 2-year interim analysis found that neither the 105 mg nor 225 mg dose conferred a significant cognitive benefit relative to placebo. But the antibody’s story is still unfolding: The drug is still being investigated in another Roche-sponsored trial of patients with mild disease called MARGUERITE ROAD.

Gantenerumab’s most highly anticipated test, however, will be in the Dominantly Inherited Alzheimer Network Trial(DIAN-TU). This study is comparing gantenerumab to another antiamyloid antibody, solanezumab, and to placebo. A crucial investigation with the potential of proving the amyloid cascade hypothesis, DIAN-TU is enrolling people who are cognitively normal at baseline but are virtually guaranteed to develop early-onset Alzheimer’s because they carry a mutation in the presenilin or amyloid precursor protein gene. The hope is that the drugs will prevent or at least delay the onset of cognitive symptoms by preventing or slowing amyloid plaque formation.

Roche didn’t release any clinical or biomarker data when it ended SCARLET ROAD a year ago. During the Alzheimer’s Association International Conference (AAIC) in July, the company disclosed that there were no significant differences after 2 years of treatment between placebo and either drug dose in the primary cognitive endpoint, the Clinical Dementia Rating–sum of boxes (CDR-sb), or in any secondary endpoints: the Alzheimer’s Disease Assessment Scale–cognitive subscale 13 (ADAS-cog13), the Mini-Mental State Examination (MMSE), and the Functional Activities Questionnaire (FAQ).

Rate of disease progression proved important

However, there were signs that the 225-mg dose of gantenerumab was at least somewhat effective in the subgroup of patients who seemed destined to have more rapidly progressing disease, Roche’s Dr. Robert Lasser said at AAIC. The benefit was obscured in the overall analysis, he said, because patient progression rates varied so highly – about a third progressed rapidly, a third slowly, and a third didn’t progress at all over the 2-year period examined in the interim analysis.

While the dropout rates were similar in the three treatment arms, data presented at CTAD showed that patients in the placebo group who dropped out were progressing four times faster on the MMSE and three times faster on the ADAS-cog13 than did those who remained in the study. Dropping out probably reflected their desire to abandon a noneffective therapy and seek symptomatic treatment, which was not allowed in the study protocol, said Dr. Juergen Dukart of Roche.

Conversely, patients with rapidly progressing disease in the active groups may have responded well to the treatment, making them more likely to stay in the trial. The disproportionate retention combined with variable progression could have masked the real treatment effect, he said.

Drug exposure in rapidly progressing disease

The trial-ending interim analysis of 315 subjects didn’t include data on the 190 who had dropped out by 2 years. But outcomes presented at CTAD did include data on those subjects, and significant treatment differences appeared, especially in light of drug exposure levels. Of the fast progressers, those with higher plasma gantenerumab concentrations had less clinical decline than did those with lower drug exposure or those taking placebo, said Dr. Sylvie Retout of Roche. Among fast progressers, the ADAS-cog13 increased (indicating worsening) by 6 points in the placebo group; by 5 points in the low-exposure group; by 4 points in the medium-exposure group; and by 2 points in the high-exposure group. Similar exposure trends among fast progressers were seen on MMSE scores, but not on CDR-sb scores.

The story was different among patients who progressed slowly, Dr. Retout said. “Among slow progressers, no exposure-response relationship could be observed, indicating that the slow disease progression over the 2-year treatment period was probably limiting the detection of a drug effect,” she said.

Finding the right trial population

The problem of progression variability, dropout rates, and potentially skewed clinical outcomes is a tough nut for Alzheimer’s drug trials, Dr. Lasser said at the CTAD conference.

“This is likely to continue to surprise us if we still have this 25%-30% in our trials who don’t decline over the course of treatment. There really aren’t any big differences at baseline that stand out so that you could create the inclusion criteria to minimize this population of patients.”

Amyloid imaging, which does at least allow recruitment of a pure Alzheimer’s cohort, was not widely available when the SCARLET ROAD cohort was recruited. And although amyloid imaging is a great tool for predicting conversion to dementia from mild cognitive impairment, it’s not terribly useful as a tool for predicting progression.

Factoring baseline cerebrospinal fluid tau levels into the equation didn’t improve prediction, Dr. Lasser noted. Apolipoprotein E (APOE) allele status was similarly unhelpful.

“We didn’t find very much difference among the allele groups; there was no consistent pattern, and the between-group differences were small. So we’re beginning to hypothesize that while APOE is an excellent risk marker before cognitive decline develops, once it does start, allele status may not be as crucial in determining the patient’s eventual outcome.”

The only hints of progression speed at baseline were in the two functional measures of CDR-sb and FAQ. Fast progressers showed significantly more impairment on both of these at baseline than did slow progressers.

“Progression seems to be more likely in those who have functional decline already present as part of their prodromal presentation,” Dr. Lasser said. “At baseline, the most meaningful difference was not the MMSE, but the CDR-sb. This indicates that functional impairment may be a critical factor to look at when you’re enrolling subjects.”

msullivan@frontlinemedcom.com

On Twitter @Alz_Gal

BARCELONA – An investigational anti-tau vaccine has passed its first big clinical milestone with a successful phase I trial of 30 patients with mild to moderate Alzheimer’s disease.

©luiscar/Thinkstockphotos.com

The vaccine, AADvac-1, was safe and induced a robust immune response in the study. Patients who received the vaccine generally showed stable cognition over 6 months, although their trajectories were variable and the follow-up was short, Dr. Matej Ondrus said at the Clinical Trials in Alzheimer’s Disease conference.

The results in all three areas examined – safety, immunogenicity, and cognition – were good enough to propel AADvac-1 into aphase II study, scheduled for launch in early 2016, said Dr. Ondrus, medical director of Axon Neuroscience, the vaccine’s developer.

Dr. Ondrus refrained from overemphasizing the importance of such early cognitive findings. “We must stress that the variability was high and that this trial was not powered to show cognition. However, we did observe that cognition remained stable,” he said.

AADvac-1 is an active vaccine that targets neurofibrillary tau tangles. According to the company, it induces antibodies against a pathological conformation in the microtubule binding domain of diseased tau protein. An emerging body of evidence suggests that tau aggregation, rather than amyloid plaque formation, is directly linked to cognitive decline in Alzheimer’s. Only one other anti-tau vaccine, (ACI-35), is being investigated.

Patients in the phase I trial were randomized at four Austrian sites to either placebo (n = 6) or to the active vaccine (n = 24), in six monthly infusions. After 3 months of treatment, patients in the placebo arm crossed over to the active vaccine. Two patients dropped out, leaving 28 to finish the study. Of these, 25 have entered the 18-month follow-up study.

At baseline, patients were a mean age of 68 years and had a mean score of 20 on the Mini-Mental State Exam. Most (19) were taking an acetylcholinesterase inhibitor, including 11 in conjunction with memantine. One was on memantine monotherapy.

Infusion reactions were common, occurring in 43% of patients; 98% of these were mild.

There were five serious adverse events, all of them different. Two patients dropped out because of a serious adverse event, but only one – a viral infection followed by epileptic seizure – was judged as possibly related to the active vaccine.

There were three abnormal findings on brain imaging, Dr. Ondrus said. Two of these were expected brain changes for the study population and not reported as adverse events. The third finding was of two new microbleeds in a patient who had already experienced microbleeds at baseline. These were mild and not accompanied by any clinical symptoms, but nonetheless, were reported as an adverse event.

There were no differences seen on electrocardiogram and no physical manifestations of cardiovascular effects, he added.

AADvac-1 induced a robust immune response in 29 patients, which was seen after the second infusion and continued to mount thereafter. One patient reached maximum titer after two infusions; the rest reached it after six infusions. The average geometric mean titer after infusion six was 1:52,000.

The main cognitive endpoint was the Alzheimer’s Disease Assessment Scale–Cognitive Subscale. Dr. Ondrus showed data indicating that the vaccine was associated with a stabilizing of cognition, although the company did not conduct a statistical analysis of the data. He also noted that the company is looking for associations between cognitive results and individual antibody titer levels.

Only four patients contributed cerebrospinal fluid at baseline and study’s end, he added. Those samples are currently being analyzed.

msullivan@frontlinemedcom.com

On Twitter @alz_gal

BARCELONA – An investigational anti-tau vaccine has passed its first big clinical milestone with a successful phase I trial of 30 patients with mild to moderate Alzheimer’s disease.

©luiscar/Thinkstockphotos.com

The vaccine, AADvac-1, was safe and induced a robust immune response in the study. Patients who received the vaccine generally showed stable cognition over 6 months, although their trajectories were variable and the follow-up was short, Dr. Matej Ondrus said at the Clinical Trials in Alzheimer’s Disease conference.

The results in all three areas examined – safety, immunogenicity, and cognition – were good enough to propel AADvac-1 into aphase II study, scheduled for launch in early 2016, said Dr. Ondrus, medical director of Axon Neuroscience, the vaccine’s developer.

Dr. Ondrus refrained from overemphasizing the importance of such early cognitive findings. “We must stress that the variability was high and that this trial was not powered to show cognition. However, we did observe that cognition remained stable,” he said.

AADvac-1 is an active vaccine that targets neurofibrillary tau tangles. According to the company, it induces antibodies against a pathological conformation in the microtubule binding domain of diseased tau protein. An emerging body of evidence suggests that tau aggregation, rather than amyloid plaque formation, is directly linked to cognitive decline in Alzheimer’s. Only one other anti-tau vaccine, (ACI-35), is being investigated.

Patients in the phase I trial were randomized at four Austrian sites to either placebo (n = 6) or to the active vaccine (n = 24), in six monthly infusions. After 3 months of treatment, patients in the placebo arm crossed over to the active vaccine. Two patients dropped out, leaving 28 to finish the study. Of these, 25 have entered the 18-month follow-up study.

At baseline, patients were a mean age of 68 years and had a mean score of 20 on the Mini-Mental State Exam. Most (19) were taking an acetylcholinesterase inhibitor, including 11 in conjunction with memantine. One was on memantine monotherapy.

Infusion reactions were common, occurring in 43% of patients; 98% of these were mild.

There were five serious adverse events, all of them different. Two patients dropped out because of a serious adverse event, but only one – a viral infection followed by epileptic seizure – was judged as possibly related to the active vaccine.

There were three abnormal findings on brain imaging, Dr. Ondrus said. Two of these were expected brain changes for the study population and not reported as adverse events. The third finding was of two new microbleeds in a patient who had already experienced microbleeds at baseline. These were mild and not accompanied by any clinical symptoms, but nonetheless, were reported as an adverse event.

There were no differences seen on electrocardiogram and no physical manifestations of cardiovascular effects, he added.

AADvac-1 induced a robust immune response in 29 patients, which was seen after the second infusion and continued to mount thereafter. One patient reached maximum titer after two infusions; the rest reached it after six infusions. The average geometric mean titer after infusion six was 1:52,000.

The main cognitive endpoint was the Alzheimer’s Disease Assessment Scale–Cognitive Subscale. Dr. Ondrus showed data indicating that the vaccine was associated with a stabilizing of cognition, although the company did not conduct a statistical analysis of the data. He also noted that the company is looking for associations between cognitive results and individual antibody titer levels.

Only four patients contributed cerebrospinal fluid at baseline and study’s end, he added. Those samples are currently being analyzed.

msullivan@frontlinemedcom.com

On Twitter @alz_gal

BARCELONA – An investigational anti-tau vaccine has passed its first big clinical milestone with a successful phase I trial of 30 patients with mild to moderate Alzheimer’s disease.

©luiscar/Thinkstockphotos.com

The vaccine, AADvac-1, was safe and induced a robust immune response in the study. Patients who received the vaccine generally showed stable cognition over 6 months, although their trajectories were variable and the follow-up was short, Dr. Matej Ondrus said at the Clinical Trials in Alzheimer’s Disease conference.

The results in all three areas examined – safety, immunogenicity, and cognition – were good enough to propel AADvac-1 into aphase II study, scheduled for launch in early 2016, said Dr. Ondrus, medical director of Axon Neuroscience, the vaccine’s developer.

Dr. Ondrus refrained from overemphasizing the importance of such early cognitive findings. “We must stress that the variability was high and that this trial was not powered to show cognition. However, we did observe that cognition remained stable,” he said.

AADvac-1 is an active vaccine that targets neurofibrillary tau tangles. According to the company, it induces antibodies against a pathological conformation in the microtubule binding domain of diseased tau protein. An emerging body of evidence suggests that tau aggregation, rather than amyloid plaque formation, is directly linked to cognitive decline in Alzheimer’s. Only one other anti-tau vaccine, (ACI-35), is being investigated.

Patients in the phase I trial were randomized at four Austrian sites to either placebo (n = 6) or to the active vaccine (n = 24), in six monthly infusions. After 3 months of treatment, patients in the placebo arm crossed over to the active vaccine. Two patients dropped out, leaving 28 to finish the study. Of these, 25 have entered the 18-month follow-up study.

At baseline, patients were a mean age of 68 years and had a mean score of 20 on the Mini-Mental State Exam. Most (19) were taking an acetylcholinesterase inhibitor, including 11 in conjunction with memantine. One was on memantine monotherapy.

Infusion reactions were common, occurring in 43% of patients; 98% of these were mild.

There were five serious adverse events, all of them different. Two patients dropped out because of a serious adverse event, but only one – a viral infection followed by epileptic seizure – was judged as possibly related to the active vaccine.

There were three abnormal findings on brain imaging, Dr. Ondrus said. Two of these were expected brain changes for the study population and not reported as adverse events. The third finding was of two new microbleeds in a patient who had already experienced microbleeds at baseline. These were mild and not accompanied by any clinical symptoms, but nonetheless, were reported as an adverse event.

There were no differences seen on electrocardiogram and no physical manifestations of cardiovascular effects, he added.

AADvac-1 induced a robust immune response in 29 patients, which was seen after the second infusion and continued to mount thereafter. One patient reached maximum titer after two infusions; the rest reached it after six infusions. The average geometric mean titer after infusion six was 1:52,000.

The main cognitive endpoint was the Alzheimer’s Disease Assessment Scale–Cognitive Subscale. Dr. Ondrus showed data indicating that the vaccine was associated with a stabilizing of cognition, although the company did not conduct a statistical analysis of the data. He also noted that the company is looking for associations between cognitive results and individual antibody titer levels.

Only four patients contributed cerebrospinal fluid at baseline and study’s end, he added. Those samples are currently being analyzed.

msullivan@frontlinemedcom.com

On Twitter @alz_gal

BARCELONA – A new look at aducanumab’s phase I study data has reinforced the developer’s confidence that its newly launched phase III trials are targeting the right group: patients with very early Alzheimer’s disease.

A subgroup analysis of patients in the phase IPRIME study with the mildest disease showed that the antibody effectively cleared amyloid plaques and that three of the four doses tested effected at least some cognitive improvement at 54 weeks, Dr. Vissia Viglietta said at the Clinical Trials on Alzheimer’s Disease conference.

©Tashatuvango/Thinkstock

The parsed cognitive data look slightly better in this very mild group than they did in the overall analysis, especially those associated with the 6-mg/kg dose, which failed to confer significant benefit in either of the study’s two cognitive measures, the Mini–Mental State Exam (MMSE) and Clinical Dementia Rating scale-sum of boxes (CDR-SB). In the subgroup analysis, however, the 6-mg/kg dose significantly slowed decline as measured by the CDR-SB. It still had no significant effect on the MMSE, compared with placebo.

The subanalysis should be viewed with the same caution as the overall PRIME data, said Dr. Viglietta, director of medical research at Biogen, which is developing the drug. The phase I study was designed to prove safety, not efficacy. The numbers in each dosing group were small, and the numbers in the subanalysis were even smaller.

“The confidence intervals were also quite large, and it was obviously not powered to detect clinical endpoints,” which were investigated in an exploratory analysis that was not prespecified, Dr. Viglietta said. But the numbers provide some assurance that the phase III trials – dubbed EMERGE and ENGAGE – are targeting the right population. “We hope to be able to confirm both the safety and efficacy we saw in PRIME’s early Alzheimer’s population.”

The subanalysis comprised 92 of the original 166-patient cohort. They had a mean age of 72 years. About 70% had prodromal disease, and the rest had mild disease. Importantly, all patients in the PRIME study had confirmed amyloid pathology as measured by PET amyloid imaging, making it the first antiamyloid drug trial comprising only amyloid-positive patients. The phase III studies will also employ baseline PET amyloid imaging in patient selection.

By 26 weeks, aducanumab at the 3-, 6-, and 10-mg/kg doses was associated with significant clearance of amyloid plaque; the effect was sustained at 54 weeks. The 1-mg/kg dose had no significant effect on plaque. Amyloid was removed throughout the entire brain, with no one region driving the change, Dr. Viglietta noted.

All doses except 1 mg/kg significantly slowed decline on the CDR-SB. On the MMSE, the 3-mg/kg and 10-mg/kg doses conferred significant benefit. The 1-mg/kg and 6-mg/kg doses did not.

As in the overall PRIME analysis, amyloid-related imaging abnormalities (ARIA) were the most common adverse event. ARIA can be classified as hemorrhagic (ARIA-H) or edematous (ARIA-E); all of the 15 cases were ARIA-E. None of these were symptomatic; all were revealed during routine imaging studies. The incidence was dose dependent: There were no cases in the 1-mg/kg group, but it occurred in 11% of the 3-mg/kg group, 29% of the 6-mg/kg group, and 44% of the 10-mg/kg group.

ARIA-E was also more prevalent and seemed to be more serious among patients who carried the apolipoprotein E epsilon-4 (APOE4) allele. Twelve of the 15 cases occurred in APOE4 carriers. Eight patients with ARIA-E discontinued treatment (seven in the 10-mg/kg group and one in the 6-mg/kg group). Of these, six were APOE4 positive. The rest of the patients continued treatment either at the same or a reduced dose.

“ARIA-E was monitorable and manageable, and the majority of patients did not have a recurrence when they continued their treatment,” Dr. Viglietta said.

The two identical phase III trials, EMERGE and ENGAGE, are beginning to get underway. In September, Biogen announced that the first patient had been recruited. In all, the studies aim to enroll 2,700 patients with early Alzheimer’s. They will be conducted in more than 20 countries, according to the company website.

In addition to a positive PET amyloid imaging study for either trial, participants must have a CDR global score of 0.5, an MMSE score of 24-30; and a Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) score of 85 or lower.

Each study will randomize patients to placebo or two active doses, depending on APOE4 status. APOE4 carriers will be randomized to either 3- or 6-mg/kg doses and noncarriers to either 6- or 10-mg/kg doses. The 3.5-year studies will have an active randomization phase of 18 months, followed by a 24-month extension study.

The primary endpoint is change from baseline on the CDR-SB. Secondary endpoints are change on the MMSE, the Alzheimer’s Disease Assessment Study cognitive scale (ADAS-cog), and the Alzheimer’s Disease Cooperative Study activities of daily living and mild cognitive impairment scales (ADCS ADL, MCI). A subset of patients will undergo additional PET amyloid imaging as a tertiary endpoint.

Biogen is actively seeking patients for these studies. A recruitment website walks patients through some questions to identify those who might initially qualify.

msullivan@frontlinemedcom.com

BARCELONA – A new look at aducanumab’s phase I study data has reinforced the developer’s confidence that its newly launched phase III trials are targeting the right group: patients with very early Alzheimer’s disease.

A subgroup analysis of patients in the phase IPRIME study with the mildest disease showed that the antibody effectively cleared amyloid plaques and that three of the four doses tested effected at least some cognitive improvement at 54 weeks, Dr. Vissia Viglietta said at the Clinical Trials on Alzheimer’s Disease conference.

©Tashatuvango/Thinkstock

The parsed cognitive data look slightly better in this very mild group than they did in the overall analysis, especially those associated with the 6-mg/kg dose, which failed to confer significant benefit in either of the study’s two cognitive measures, the Mini–Mental State Exam (MMSE) and Clinical Dementia Rating scale-sum of boxes (CDR-SB). In the subgroup analysis, however, the 6-mg/kg dose significantly slowed decline as measured by the CDR-SB. It still had no significant effect on the MMSE, compared with placebo.

The subanalysis should be viewed with the same caution as the overall PRIME data, said Dr. Viglietta, director of medical research at Biogen, which is developing the drug. The phase I study was designed to prove safety, not efficacy. The numbers in each dosing group were small, and the numbers in the subanalysis were even smaller.

“The confidence intervals were also quite large, and it was obviously not powered to detect clinical endpoints,” which were investigated in an exploratory analysis that was not prespecified, Dr. Viglietta said. But the numbers provide some assurance that the phase III trials – dubbed EMERGE and ENGAGE – are targeting the right population. “We hope to be able to confirm both the safety and efficacy we saw in PRIME’s early Alzheimer’s population.”

The subanalysis comprised 92 of the original 166-patient cohort. They had a mean age of 72 years. About 70% had prodromal disease, and the rest had mild disease. Importantly, all patients in the PRIME study had confirmed amyloid pathology as measured by PET amyloid imaging, making it the first antiamyloid drug trial comprising only amyloid-positive patients. The phase III studies will also employ baseline PET amyloid imaging in patient selection.

By 26 weeks, aducanumab at the 3-, 6-, and 10-mg/kg doses was associated with significant clearance of amyloid plaque; the effect was sustained at 54 weeks. The 1-mg/kg dose had no significant effect on plaque. Amyloid was removed throughout the entire brain, with no one region driving the change, Dr. Viglietta noted.

All doses except 1 mg/kg significantly slowed decline on the CDR-SB. On the MMSE, the 3-mg/kg and 10-mg/kg doses conferred significant benefit. The 1-mg/kg and 6-mg/kg doses did not.

As in the overall PRIME analysis, amyloid-related imaging abnormalities (ARIA) were the most common adverse event. ARIA can be classified as hemorrhagic (ARIA-H) or edematous (ARIA-E); all of the 15 cases were ARIA-E. None of these were symptomatic; all were revealed during routine imaging studies. The incidence was dose dependent: There were no cases in the 1-mg/kg group, but it occurred in 11% of the 3-mg/kg group, 29% of the 6-mg/kg group, and 44% of the 10-mg/kg group.

ARIA-E was also more prevalent and seemed to be more serious among patients who carried the apolipoprotein E epsilon-4 (APOE4) allele. Twelve of the 15 cases occurred in APOE4 carriers. Eight patients with ARIA-E discontinued treatment (seven in the 10-mg/kg group and one in the 6-mg/kg group). Of these, six were APOE4 positive. The rest of the patients continued treatment either at the same or a reduced dose.

“ARIA-E was monitorable and manageable, and the majority of patients did not have a recurrence when they continued their treatment,” Dr. Viglietta said.

The two identical phase III trials, EMERGE and ENGAGE, are beginning to get underway. In September, Biogen announced that the first patient had been recruited. In all, the studies aim to enroll 2,700 patients with early Alzheimer’s. They will be conducted in more than 20 countries, according to the company website.

In addition to a positive PET amyloid imaging study for either trial, participants must have a CDR global score of 0.5, an MMSE score of 24-30; and a Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) score of 85 or lower.

Each study will randomize patients to placebo or two active doses, depending on APOE4 status. APOE4 carriers will be randomized to either 3- or 6-mg/kg doses and noncarriers to either 6- or 10-mg/kg doses. The 3.5-year studies will have an active randomization phase of 18 months, followed by a 24-month extension study.

The primary endpoint is change from baseline on the CDR-SB. Secondary endpoints are change on the MMSE, the Alzheimer’s Disease Assessment Study cognitive scale (ADAS-cog), and the Alzheimer’s Disease Cooperative Study activities of daily living and mild cognitive impairment scales (ADCS ADL, MCI). A subset of patients will undergo additional PET amyloid imaging as a tertiary endpoint.

Biogen is actively seeking patients for these studies. A recruitment website walks patients through some questions to identify those who might initially qualify.

msullivan@frontlinemedcom.com

BARCELONA – A new look at aducanumab’s phase I study data has reinforced the developer’s confidence that its newly launched phase III trials are targeting the right group: patients with very early Alzheimer’s disease.

A subgroup analysis of patients in the phase IPRIME study with the mildest disease showed that the antibody effectively cleared amyloid plaques and that three of the four doses tested effected at least some cognitive improvement at 54 weeks, Dr. Vissia Viglietta said at the Clinical Trials on Alzheimer’s Disease conference.

©Tashatuvango/Thinkstock

The parsed cognitive data look slightly better in this very mild group than they did in the overall analysis, especially those associated with the 6-mg/kg dose, which failed to confer significant benefit in either of the study’s two cognitive measures, the Mini–Mental State Exam (MMSE) and Clinical Dementia Rating scale-sum of boxes (CDR-SB). In the subgroup analysis, however, the 6-mg/kg dose significantly slowed decline as measured by the CDR-SB. It still had no significant effect on the MMSE, compared with placebo.

The subanalysis should be viewed with the same caution as the overall PRIME data, said Dr. Viglietta, director of medical research at Biogen, which is developing the drug. The phase I study was designed to prove safety, not efficacy. The numbers in each dosing group were small, and the numbers in the subanalysis were even smaller.

“The confidence intervals were also quite large, and it was obviously not powered to detect clinical endpoints,” which were investigated in an exploratory analysis that was not prespecified, Dr. Viglietta said. But the numbers provide some assurance that the phase III trials – dubbed EMERGE and ENGAGE – are targeting the right population. “We hope to be able to confirm both the safety and efficacy we saw in PRIME’s early Alzheimer’s population.”

The subanalysis comprised 92 of the original 166-patient cohort. They had a mean age of 72 years. About 70% had prodromal disease, and the rest had mild disease. Importantly, all patients in the PRIME study had confirmed amyloid pathology as measured by PET amyloid imaging, making it the first antiamyloid drug trial comprising only amyloid-positive patients. The phase III studies will also employ baseline PET amyloid imaging in patient selection.

By 26 weeks, aducanumab at the 3-, 6-, and 10-mg/kg doses was associated with significant clearance of amyloid plaque; the effect was sustained at 54 weeks. The 1-mg/kg dose had no significant effect on plaque. Amyloid was removed throughout the entire brain, with no one region driving the change, Dr. Viglietta noted.

All doses except 1 mg/kg significantly slowed decline on the CDR-SB. On the MMSE, the 3-mg/kg and 10-mg/kg doses conferred significant benefit. The 1-mg/kg and 6-mg/kg doses did not.

As in the overall PRIME analysis, amyloid-related imaging abnormalities (ARIA) were the most common adverse event. ARIA can be classified as hemorrhagic (ARIA-H) or edematous (ARIA-E); all of the 15 cases were ARIA-E. None of these were symptomatic; all were revealed during routine imaging studies. The incidence was dose dependent: There were no cases in the 1-mg/kg group, but it occurred in 11% of the 3-mg/kg group, 29% of the 6-mg/kg group, and 44% of the 10-mg/kg group.

ARIA-E was also more prevalent and seemed to be more serious among patients who carried the apolipoprotein E epsilon-4 (APOE4) allele. Twelve of the 15 cases occurred in APOE4 carriers. Eight patients with ARIA-E discontinued treatment (seven in the 10-mg/kg group and one in the 6-mg/kg group). Of these, six were APOE4 positive. The rest of the patients continued treatment either at the same or a reduced dose.

“ARIA-E was monitorable and manageable, and the majority of patients did not have a recurrence when they continued their treatment,” Dr. Viglietta said.

The two identical phase III trials, EMERGE and ENGAGE, are beginning to get underway. In September, Biogen announced that the first patient had been recruited. In all, the studies aim to enroll 2,700 patients with early Alzheimer’s. They will be conducted in more than 20 countries, according to the company website.

In addition to a positive PET amyloid imaging study for either trial, participants must have a CDR global score of 0.5, an MMSE score of 24-30; and a Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) score of 85 or lower.

Each study will randomize patients to placebo or two active doses, depending on APOE4 status. APOE4 carriers will be randomized to either 3- or 6-mg/kg doses and noncarriers to either 6- or 10-mg/kg doses. The 3.5-year studies will have an active randomization phase of 18 months, followed by a 24-month extension study.

The primary endpoint is change from baseline on the CDR-SB. Secondary endpoints are change on the MMSE, the Alzheimer’s Disease Assessment Study cognitive scale (ADAS-cog), and the Alzheimer’s Disease Cooperative Study activities of daily living and mild cognitive impairment scales (ADCS ADL, MCI). A subset of patients will undergo additional PET amyloid imaging as a tertiary endpoint.

Biogen is actively seeking patients for these studies. A recruitment website walks patients through some questions to identify those who might initially qualify.

msullivan@frontlinemedcom.com

BARCELONA – A novel small molecule that may help clear misfolded proteins imparted some significant cognitive benefits to Alzheimer’s patients after 5 weeks, even with a mid-study washout period in which patients stopped taking the drug, according to the results of a small, open-label, uncontrolled, phase IIa crossover trial.

The investigational drug, called Anavex 2-73, also was associated with significant improvements in the P300 electroencephalogram wave, a measure of nerve conduction associated with cognitive processing, Dr. Stephen Macfarlane said at the Clinical Trials on Alzheimer’s disease conference.

©roberthyrons/thinkstockphotos.com

The study was small – just 32 patients with mild to moderate Alzheimer’s disease – and not powered for cognitive endpoints, said Dr. Macfarlane, director of Aged Psychiatry for Alfred Health, Victoria, Australia. Nevertheless, its clinical findings add an intriguing cachet to the study’s successful pharmacokinetic data, he said.

The results were encouraging enough for the manufacturer, Anavex Life Sciences to lengthen its preplanned 26-week extension trial to 52 weeks and move ahead with phase III planning, Dr. Macfarlane said.

Anavex 2-73 is an agonist of the sigma-1 receptor but also activates the muscarinic receptor. The sigma-1 receptoris found on neurons and glia in many areas of the central nervous system. It modulates a number of processes implicated in neurodegenerative diseases, including glutamate and calcium activity, reaction to oxidative stress, and mitochondrial function. There is also some evidence that sigma-1 receptor activation can induce neuronal regrowth and functional recovery after stroke. The sigma-1 receptor 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.

In preclinical testing, Anavex 2-73 showed an additional cognitive property, Dr. Macfarlane said. “It seems to have a cognitive-enhancing effect, not only on transgenic mice, but on wild-type mice as well. When the [Alzheimer’s model] mice were fed it, they did significantly better on the water maze test. But when wild-type mice consumed it, they did better as well. This does suggest that it can enhance cognition.”

The study that Dr. Macfarlane presented at the conference randomized patients to either oral or intravenous treatment for 12 days, followed by a 12-day washout period, then crossed to the opposite administration for 12 days. At the end of 5 weeks, all patients were invited to continue with oral treatment out to 52 weeks. All of the 30 patients who finished the 5-week study elected to participate.

Patients were a mean of 71 years old. The median Mini-Mental State Examination (MMSE) score was 20.5. Most (78%) were taking a stable dose of acetylcholinesterase inhibitor.

The primary endpoints were safety, tolerability, and pharmacokinetics. The exploratory cognitive measures included electroencephalogram/event-related potential, MMSE, and the Cogstate battery. Function was assessed with the Alzheimer’s Disease Cooperative Study activities of daily living scale (ADCS-ADL) in patients who had completed at least 12 weeks of the follow-up study.

There were no safety concerns, Dr. Macfarlane said. While 94% 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; it was not considered related to the study drug.

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 incidents were considered mild or moderate.

At the end of 5 weeks, the drug was associated with a median MMSE score increase of 1.5 points. While this change was not statistically significant, improvements on five of the six Cogstate battery measures were significant, with the biggest boost seen in the one-back test of working memory.

Dr. Macfarlane compared the magnitude of improvement to that which has been seen in a large Australian prospective cohort study, AIBL (Australian Imaging, Biomarkers & Lifestyle Flagship Study of Ageing). The Anavex 2-73 cohort made significant gains relative to the AIBL cohort taking acetylcholinesterase inhibitors at the same time period.

“Our group improved by 1.5 standard deviations across 5 weeks [compared with AIBL subjects], which included that 12-day period with no exposure to the study drug,” Dr. Macfarlane said. “This was quite an unexpected finding but potentially an important one.”

Anavex 2-73 was also associated with significant changes on EEG measures of event-related potential, particularly the P300 wave, which measures decision-making speed. The drug closed 80% of the gap between patients and historical controls in P300 amplitude. It also closed 85% of the gap in task accuracy and 66% of that in reaction time. Finally, patients taking Anavex 2-73 exceeded control performance on false-alarm reactions by 4%.

Patients who have completed 12 weeks of treatment in the 52-week extension trial experienced a mean improvement of 3.2 points on the ADCS-ADL measure. The difference, while not statistically significant, is encouraging at this point in treatment, Dr. Macfarlane said.

Dr. Macfarlane has no financial interest in Anavex 2-73, and has no financial disclosures.

msullivan@frontlinemedcom.com

BARCELONA – A novel small molecule that may help clear misfolded proteins imparted some significant cognitive benefits to Alzheimer’s patients after 5 weeks, even with a mid-study washout period in which patients stopped taking the drug, according to the results of a small, open-label, uncontrolled, phase IIa crossover trial.

The investigational drug, called Anavex 2-73, also was associated with significant improvements in the P300 electroencephalogram wave, a measure of nerve conduction associated with cognitive processing, Dr. Stephen Macfarlane said at the Clinical Trials on Alzheimer’s disease conference.

©roberthyrons/thinkstockphotos.com

The study was small – just 32 patients with mild to moderate Alzheimer’s disease – and not powered for cognitive endpoints, said Dr. Macfarlane, director of Aged Psychiatry for Alfred Health, Victoria, Australia. Nevertheless, its clinical findings add an intriguing cachet to the study’s successful pharmacokinetic data, he said.

The results were encouraging enough for the manufacturer, Anavex Life Sciences to lengthen its preplanned 26-week extension trial to 52 weeks and move ahead with phase III planning, Dr. Macfarlane said.

Anavex 2-73 is an agonist of the sigma-1 receptor but also activates the muscarinic receptor. The sigma-1 receptoris found on neurons and glia in many areas of the central nervous system. It modulates a number of processes implicated in neurodegenerative diseases, including glutamate and calcium activity, reaction to oxidative stress, and mitochondrial function. There is also some evidence that sigma-1 receptor activation can induce neuronal regrowth and functional recovery after stroke. The sigma-1 receptor 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.

In preclinical testing, Anavex 2-73 showed an additional cognitive property, Dr. Macfarlane said. “It seems to have a cognitive-enhancing effect, not only on transgenic mice, but on wild-type mice as well. When the [Alzheimer’s model] mice were fed it, they did significantly better on the water maze test. But when wild-type mice consumed it, they did better as well. This does suggest that it can enhance cognition.”

The study that Dr. Macfarlane presented at the conference randomized patients to either oral or intravenous treatment for 12 days, followed by a 12-day washout period, then crossed to the opposite administration for 12 days. At the end of 5 weeks, all patients were invited to continue with oral treatment out to 52 weeks. All of the 30 patients who finished the 5-week study elected to participate.

Patients were a mean of 71 years old. The median Mini-Mental State Examination (MMSE) score was 20.5. Most (78%) were taking a stable dose of acetylcholinesterase inhibitor.

The primary endpoints were safety, tolerability, and pharmacokinetics. The exploratory cognitive measures included electroencephalogram/event-related potential, MMSE, and the Cogstate battery. Function was assessed with the Alzheimer’s Disease Cooperative Study activities of daily living scale (ADCS-ADL) in patients who had completed at least 12 weeks of the follow-up study.

There were no safety concerns, Dr. Macfarlane said. While 94% 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; it was not considered related to the study drug.

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 incidents were considered mild or moderate.

At the end of 5 weeks, the drug was associated with a median MMSE score increase of 1.5 points. While this change was not statistically significant, improvements on five of the six Cogstate battery measures were significant, with the biggest boost seen in the one-back test of working memory.

Dr. Macfarlane compared the magnitude of improvement to that which has been seen in a large Australian prospective cohort study, AIBL (Australian Imaging, Biomarkers & Lifestyle Flagship Study of Ageing). The Anavex 2-73 cohort made significant gains relative to the AIBL cohort taking acetylcholinesterase inhibitors at the same time period.

“Our group improved by 1.5 standard deviations across 5 weeks [compared with AIBL subjects], which included that 12-day period with no exposure to the study drug,” Dr. Macfarlane said. “This was quite an unexpected finding but potentially an important one.”

Anavex 2-73 was also associated with significant changes on EEG measures of event-related potential, particularly the P300 wave, which measures decision-making speed. The drug closed 80% of the gap between patients and historical controls in P300 amplitude. It also closed 85% of the gap in task accuracy and 66% of that in reaction time. Finally, patients taking Anavex 2-73 exceeded control performance on false-alarm reactions by 4%.

Patients who have completed 12 weeks of treatment in the 52-week extension trial experienced a mean improvement of 3.2 points on the ADCS-ADL measure. The difference, while not statistically significant, is encouraging at this point in treatment, Dr. Macfarlane said.

Dr. Macfarlane has no financial interest in Anavex 2-73, and has no financial disclosures.

msullivan@frontlinemedcom.com

BARCELONA – A novel small molecule that may help clear misfolded proteins imparted some significant cognitive benefits to Alzheimer’s patients after 5 weeks, even with a mid-study washout period in which patients stopped taking the drug, according to the results of a small, open-label, uncontrolled, phase IIa crossover trial.

The investigational drug, called Anavex 2-73, also was associated with significant improvements in the P300 electroencephalogram wave, a measure of nerve conduction associated with cognitive processing, Dr. Stephen Macfarlane said at the Clinical Trials on Alzheimer’s disease conference.

©roberthyrons/thinkstockphotos.com

The study was small – just 32 patients with mild to moderate Alzheimer’s disease – and not powered for cognitive endpoints, said Dr. Macfarlane, director of Aged Psychiatry for Alfred Health, Victoria, Australia. Nevertheless, its clinical findings add an intriguing cachet to the study’s successful pharmacokinetic data, he said.

The results were encouraging enough for the manufacturer, Anavex Life Sciences to lengthen its preplanned 26-week extension trial to 52 weeks and move ahead with phase III planning, Dr. Macfarlane said.

Anavex 2-73 is an agonist of the sigma-1 receptor but also activates the muscarinic receptor. The sigma-1 receptoris found on neurons and glia in many areas of the central nervous system. It modulates a number of processes implicated in neurodegenerative diseases, including glutamate and calcium activity, reaction to oxidative stress, and mitochondrial function. There is also some evidence that sigma-1 receptor activation can induce neuronal regrowth and functional recovery after stroke. The sigma-1 receptor 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.

In preclinical testing, Anavex 2-73 showed an additional cognitive property, Dr. Macfarlane said. “It seems to have a cognitive-enhancing effect, not only on transgenic mice, but on wild-type mice as well. When the [Alzheimer’s model] mice were fed it, they did significantly better on the water maze test. But when wild-type mice consumed it, they did better as well. This does suggest that it can enhance cognition.”

The study that Dr. Macfarlane presented at the conference randomized patients to either oral or intravenous treatment for 12 days, followed by a 12-day washout period, then crossed to the opposite administration for 12 days. At the end of 5 weeks, all patients were invited to continue with oral treatment out to 52 weeks. All of the 30 patients who finished the 5-week study elected to participate.

Patients were a mean of 71 years old. The median Mini-Mental State Examination (MMSE) score was 20.5. Most (78%) were taking a stable dose of acetylcholinesterase inhibitor.

The primary endpoints were safety, tolerability, and pharmacokinetics. The exploratory cognitive measures included electroencephalogram/event-related potential, MMSE, and the Cogstate battery. Function was assessed with the Alzheimer’s Disease Cooperative Study activities of daily living scale (ADCS-ADL) in patients who had completed at least 12 weeks of the follow-up study.

There were no safety concerns, Dr. Macfarlane said. While 94% 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; it was not considered related to the study drug.

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 incidents were considered mild or moderate.

At the end of 5 weeks, the drug was associated with a median MMSE score increase of 1.5 points. While this change was not statistically significant, improvements on five of the six Cogstate battery measures were significant, with the biggest boost seen in the one-back test of working memory.

Dr. Macfarlane compared the magnitude of improvement to that which has been seen in a large Australian prospective cohort study, AIBL (Australian Imaging, Biomarkers & Lifestyle Flagship Study of Ageing). The Anavex 2-73 cohort made significant gains relative to the AIBL cohort taking acetylcholinesterase inhibitors at the same time period.

“Our group improved by 1.5 standard deviations across 5 weeks [compared with AIBL subjects], which included that 12-day period with no exposure to the study drug,” Dr. Macfarlane said. “This was quite an unexpected finding but potentially an important one.”

Anavex 2-73 was also associated with significant changes on EEG measures of event-related potential, particularly the P300 wave, which measures decision-making speed. The drug closed 80% of the gap between patients and historical controls in P300 amplitude. It also closed 85% of the gap in task accuracy and 66% of that in reaction time. Finally, patients taking Anavex 2-73 exceeded control performance on false-alarm reactions by 4%.

Patients who have completed 12 weeks of treatment in the 52-week extension trial experienced a mean improvement of 3.2 points on the ADCS-ADL measure. The difference, while not statistically significant, is encouraging at this point in treatment, Dr. Macfarlane said.

Dr. Macfarlane has no financial interest in Anavex 2-73, and has no financial disclosures.

msullivan@frontlinemedcom.com

BARCELONA – RVT-101, a novel small molecule that increases acetylcholine release, is poised for what its developers say could be its pivotal trial for U.S. approval.

The MINDSET study will examine the effect of the 5-HT₆ receptor antagonist RVT-101, which will be given in conjunction with donepezil.

As an acetylcholine booster, RVT-101 would not be a disease-modifying therapy. And like other symptomatic drugs, it would not alter the trajectory of Alzheimer’s disease.

Launched last month, MINDSET will be conducted in North America, South America, Europe, and Asia. The study investigators want to enroll least 1,000 patients with mild to moderate Alzheimer’s disease who are on stable doses of donepezil, Dr. Lawrence Friedhoff said at the Clinical Trials on Alzheimer’s Disease conference.

Axovant Sciences’ RVT-101, formerly developed as SB742457 by GlaxoSmithKline, has been investigated in 13 studies of both monotherapy and adjunctive therapy in more than 2,000 patients with Alzheimer’s, said Dr. Friedhoff, chief development officer at Axovant Sciences. As monotherapy, it was ineffective, conferring no significant benefits on either cognition or function.

The earlier study upon which MINDSET is modeled was a modestly successful phase IIb dose-ranging trial that comprised 684 patients. At 48 weeks, the combination of 35 mg SB742457 (RVT-101) and donepezil conferred about a 2-point benefit on the Alzheimer’s Disease Assessment Scale–Cognitive (ADAS-cog) and the Alzheimer’s Disease Cooperative Study–Activities of Daily Living (ADCS-ADL) over donepezil alone. Neither the 35-mg dose nor the 15-mg dose, which was also tested, conferred any benefit on the Clinical Dementia Rating Scale–Sum of Boxes (CDR-SB) test.

“Regulators have told us that if our results are similar, then this study will be suitable for submission for approval,” Dr. Friedhoff said. “We have a reasonably high level of confidence that it will also be effective in this trial.”

The 24-week MINDSET will randomize patients to their donepezil dosage plus either placebo or 35 mg RVT-101 daily. Coprimary endpoints are the ADAS-cog and the ADCS-ADL. The CDR-SB is not an endpoint in MINDSET, which Dr. Friedhoff noted was designed to maximize the chance of success. A 12-month open-label extension study focusing on long-term safety will follow the randomized trial.

GSK ceased development of RVT-101 in 2010 without public explanation. However, a recent review of several of the GSK studies suggests that it simply didn’t meet the studies’ success criteria.

Axovant was formed in 2014 to give RVT-101 a new shot as an add-on treatment. The combination makes sense, Dr. Friedhoff said.

“It increases acetylcholine in the brain. We already know this is an effective way to treat Alzheimer’s, because our acetylcholinesterase inhibitors achieve this in a different way, by inhibiting the breakdown of acetylcholine,” Dr. Friedhoff explained. “It makes sense that they should work well together. It doesn’t help much to increase the release if it’s broken down quickly.”

RVT-101 has an attractive safety profile, Dr. Friedhoff said. It had a low rate of gastrointestinal side effects (nausea 2%, diarrhea 5%) and was associated with very few falls in prior studies (about 3%). That probably is because the 5-HT₆ receptor is located only in the central nervous system; there is no peripheral binding, so cholinergic toxicities to other systems are limited, he noted.

That relatively benign side effect profile is probably reflected in the study’s large completer rate, Dr. Friedhoff said. The placebo and 35-mg dose had virtually identical completer rates of 88% and 89%, respectively. The dropout rates were low and similar in both groups.

Axovant also aims to investigate RVT-101 in patients with Lewy body dementia, Dr. Friedhoff added. The company expects to launch a phase IIb clinical study early next year.

Axovant Sciences is sponsoring the MINDSET study. Dr. Friedhoff is an employee of the company.

msullivan@frontlinemedcom.com

On Twitter @Alz_Gal

BARCELONA – RVT-101, a novel small molecule that increases acetylcholine release, is poised for what its developers say could be its pivotal trial for U.S. approval.

The MINDSET study will examine the effect of the 5-HT₆ receptor antagonist RVT-101, which will be given in conjunction with donepezil.

As an acetylcholine booster, RVT-101 would not be a disease-modifying therapy. And like other symptomatic drugs, it would not alter the trajectory of Alzheimer’s disease.

Launched last month, MINDSET will be conducted in North America, South America, Europe, and Asia. The study investigators want to enroll least 1,000 patients with mild to moderate Alzheimer’s disease who are on stable doses of donepezil, Dr. Lawrence Friedhoff said at the Clinical Trials on Alzheimer’s Disease conference.

Axovant Sciences’ RVT-101, formerly developed as SB742457 by GlaxoSmithKline, has been investigated in 13 studies of both monotherapy and adjunctive therapy in more than 2,000 patients with Alzheimer’s, said Dr. Friedhoff, chief development officer at Axovant Sciences. As monotherapy, it was ineffective, conferring no significant benefits on either cognition or function.

The earlier study upon which MINDSET is modeled was a modestly successful phase IIb dose-ranging trial that comprised 684 patients. At 48 weeks, the combination of 35 mg SB742457 (RVT-101) and donepezil conferred about a 2-point benefit on the Alzheimer’s Disease Assessment Scale–Cognitive (ADAS-cog) and the Alzheimer’s Disease Cooperative Study–Activities of Daily Living (ADCS-ADL) over donepezil alone. Neither the 35-mg dose nor the 15-mg dose, which was also tested, conferred any benefit on the Clinical Dementia Rating Scale–Sum of Boxes (CDR-SB) test.

“Regulators have told us that if our results are similar, then this study will be suitable for submission for approval,” Dr. Friedhoff said. “We have a reasonably high level of confidence that it will also be effective in this trial.”

The 24-week MINDSET will randomize patients to their donepezil dosage plus either placebo or 35 mg RVT-101 daily. Coprimary endpoints are the ADAS-cog and the ADCS-ADL. The CDR-SB is not an endpoint in MINDSET, which Dr. Friedhoff noted was designed to maximize the chance of success. A 12-month open-label extension study focusing on long-term safety will follow the randomized trial.

GSK ceased development of RVT-101 in 2010 without public explanation. However, a recent review of several of the GSK studies suggests that it simply didn’t meet the studies’ success criteria.

Axovant was formed in 2014 to give RVT-101 a new shot as an add-on treatment. The combination makes sense, Dr. Friedhoff said.

“It increases acetylcholine in the brain. We already know this is an effective way to treat Alzheimer’s, because our acetylcholinesterase inhibitors achieve this in a different way, by inhibiting the breakdown of acetylcholine,” Dr. Friedhoff explained. “It makes sense that they should work well together. It doesn’t help much to increase the release if it’s broken down quickly.”

RVT-101 has an attractive safety profile, Dr. Friedhoff said. It had a low rate of gastrointestinal side effects (nausea 2%, diarrhea 5%) and was associated with very few falls in prior studies (about 3%). That probably is because the 5-HT₆ receptor is located only in the central nervous system; there is no peripheral binding, so cholinergic toxicities to other systems are limited, he noted.

That relatively benign side effect profile is probably reflected in the study’s large completer rate, Dr. Friedhoff said. The placebo and 35-mg dose had virtually identical completer rates of 88% and 89%, respectively. The dropout rates were low and similar in both groups.

Axovant also aims to investigate RVT-101 in patients with Lewy body dementia, Dr. Friedhoff added. The company expects to launch a phase IIb clinical study early next year.

Axovant Sciences is sponsoring the MINDSET study. Dr. Friedhoff is an employee of the company.

msullivan@frontlinemedcom.com

On Twitter @Alz_Gal

BARCELONA – RVT-101, a novel small molecule that increases acetylcholine release, is poised for what its developers say could be its pivotal trial for U.S. approval.

The MINDSET study will examine the effect of the 5-HT₆ receptor antagonist RVT-101, which will be given in conjunction with donepezil.

As an acetylcholine booster, RVT-101 would not be a disease-modifying therapy. And like other symptomatic drugs, it would not alter the trajectory of Alzheimer’s disease.

Launched last month, MINDSET will be conducted in North America, South America, Europe, and Asia. The study investigators want to enroll least 1,000 patients with mild to moderate Alzheimer’s disease who are on stable doses of donepezil, Dr. Lawrence Friedhoff said at the Clinical Trials on Alzheimer’s Disease conference.

Axovant Sciences’ RVT-101, formerly developed as SB742457 by GlaxoSmithKline, has been investigated in 13 studies of both monotherapy and adjunctive therapy in more than 2,000 patients with Alzheimer’s, said Dr. Friedhoff, chief development officer at Axovant Sciences. As monotherapy, it was ineffective, conferring no significant benefits on either cognition or function.

The earlier study upon which MINDSET is modeled was a modestly successful phase IIb dose-ranging trial that comprised 684 patients. At 48 weeks, the combination of 35 mg SB742457 (RVT-101) and donepezil conferred about a 2-point benefit on the Alzheimer’s Disease Assessment Scale–Cognitive (ADAS-cog) and the Alzheimer’s Disease Cooperative Study–Activities of Daily Living (ADCS-ADL) over donepezil alone. Neither the 35-mg dose nor the 15-mg dose, which was also tested, conferred any benefit on the Clinical Dementia Rating Scale–Sum of Boxes (CDR-SB) test.

“Regulators have told us that if our results are similar, then this study will be suitable for submission for approval,” Dr. Friedhoff said. “We have a reasonably high level of confidence that it will also be effective in this trial.”

The 24-week MINDSET will randomize patients to their donepezil dosage plus either placebo or 35 mg RVT-101 daily. Coprimary endpoints are the ADAS-cog and the ADCS-ADL. The CDR-SB is not an endpoint in MINDSET, which Dr. Friedhoff noted was designed to maximize the chance of success. A 12-month open-label extension study focusing on long-term safety will follow the randomized trial.

GSK ceased development of RVT-101 in 2010 without public explanation. However, a recent review of several of the GSK studies suggests that it simply didn’t meet the studies’ success criteria.

Axovant was formed in 2014 to give RVT-101 a new shot as an add-on treatment. The combination makes sense, Dr. Friedhoff said.

“It increases acetylcholine in the brain. We already know this is an effective way to treat Alzheimer’s, because our acetylcholinesterase inhibitors achieve this in a different way, by inhibiting the breakdown of acetylcholine,” Dr. Friedhoff explained. “It makes sense that they should work well together. It doesn’t help much to increase the release if it’s broken down quickly.”

RVT-101 has an attractive safety profile, Dr. Friedhoff said. It had a low rate of gastrointestinal side effects (nausea 2%, diarrhea 5%) and was associated with very few falls in prior studies (about 3%). That probably is because the 5-HT₆ receptor is located only in the central nervous system; there is no peripheral binding, so cholinergic toxicities to other systems are limited, he noted.

That relatively benign side effect profile is probably reflected in the study’s large completer rate, Dr. Friedhoff said. The placebo and 35-mg dose had virtually identical completer rates of 88% and 89%, respectively. The dropout rates were low and similar in both groups.

Axovant also aims to investigate RVT-101 in patients with Lewy body dementia, Dr. Friedhoff added. The company expects to launch a phase IIb clinical study early next year.

Axovant Sciences is sponsoring the MINDSET study. Dr. Friedhoff is an employee of the company.

msullivan@frontlinemedcom.com

On Twitter @Alz_Gal

BARCELONA – A combination of cognitive and physical training plus omega-3 fatty acid supplements boosted cognitive performance significantly in a group of people with subjective memory complaints.

Among those with more serious memory issues, the combination worked even better, preventing any decline at all over the 3-year study period, Dr. Bruno Vellas said at the Clinical Trials on Alzheimer’s Disease conference.

The program was also especially effective in subjects who were homozygous for the high-risk e4 allele of the apolipoprotein E gene, said Dr. Vellas, chief of the Alzheimer’s Disease Clinical and Research Center at the University Hospital Center in Toulouse, France.

The findings must be confirmed in larger studies, he said, but they strengthen the growing body of evidence supporting nonpharmacologic Alzheimer’s prevention tactics.

©Clayton Hansen/iStockphoto

“This confirms the data from FINGER. In FINGER we had some improvement, but here we are able to show that we can prevent decline, which is maybe even more important, especially for high-risk patients,” Dr. Vellas said.

The Multidomain Alzheimer Preventive Trial (MAPT) comprised 1,680 people who had reported subjective memory complaints to their primary care physician. It examined the effect of a comprehensive cognitive, nutrition, and physical training program, with or without omega-3 fatty acid supplementation. In addition to the cognitive outcome, MAPT used functional PET imaging to examine brain glucose metabolism at baseline and 6 and 12 months, and amyloid plaque burden at 12-18 months.

Cognitive training focused on reasoning and memory training. Its main objective was to teach participants how to use adaptive strategies in solving everyday problems – for example, using mnemonics to remember a grocery list.

The physical training component involved at least 150 minutes of moderate exercise each week; walking 30 minutes/day was the most frequently recommended. Participants also received an individually designed at-home exercise plan that was reviewed and updated every 6 months.

Nutritional counseling was based on the French National Nutrition and Health Program. Eight key guidelines on healthy diet were discussed.

These interventions were all offered in small groups, during 12 2-hour sessions in the first 2 months. There were brief individual interviews every 6 months, and intensive booster sessions after 1 year and 2 years.

Each supplement capsule contained a specially compounded combination of 400 mg docosahexaenoic acid (DHA) and 112.5 mg eicosapentaenoic acid (EPA). It was taken twice a day.

The trial consisted of four arms: omega-3 supplements (DHA) alone; placebo capsules alone; training without DHA supplements; and both training and DHA

The mean age of the study participants was 75 years. While the mean Mini Mental State Exam score was 28, indicating no cognitive impairment, some subjects did dip down into the mild cognitive impairment range. About 40% had a Clinical Dementia Rating sum of boxes (CDR) score of 0.5 (very mild Alzheimer’s); the rest had a 0 score. No one had frank dementia. About 23% were positive for APOE e4.

Compliance with the program was very good, Dr. Vellas said: a mean of 71% for the training programs and 84% for the supplements over the 3 years.

In both the intent-to-treat and per-protocol analyses, the training program and the combination of training and DHA were significantly more effective than either DHA or placebo.

Those taking DHA alone or placebo declined similarly from baseline. Those in the training program (with or without DHA) experienced a significant uptick in cognitive score during the first year. During the second year that gain fell, but it still remained significantly above baseline in both groups.

Dr. Vellas also examined the composite cognitive endpoint in the subgroup with a 0.5 score on the CDR scale. Those taking placebo or DHA-only experienced no improvement and fell significantly below baseline by the end of the study. Those who were in the training program only experienced a boost in scores in the first 6 months, which rapidly fell off. By 2 years, the scores were significantly below baseline, although not as depressed as those in the placebo and DHA-only groups.

The best outcome occurred in the training program plus DHA group. Their test scores remained completely stable over the entire period, suggesting that the combination intervention prevented cognitive decline.

It conferred the biggest benefit on those who were APOE e4-positive. Their scores rose significantly by 12 months and, although they did begin to decline, they remained significantly improved through the study’s end. The training program alone also improved the cognitive score by 12 months, but that dipped back to baseline by the end of the study. Those taking placebo or DHA alone experienced significant score declines.

Amyloid imaging was not performed at baseline, but was done 12-18 months into the study. At that point, the combination intervention group had the lowest percentage of amyloid-positive subjects (22%). The rate of amyloid positivity was 34% in the training program alone; 46% in the DHA group alone; and 51% in the placebo group.

It’s not possible to determine whether the intervention altered the trajectory of amyloid deposition, Dr. Vellas said; that will be explored in a different study.

PET imaging showed striking between-group differences in glucose metabolism. Those in the training-alone group experienced a transient metabolic increase in the right and left temporal regions, which, compared with placebo, was significant at 6 months but not at 12 months.

In the DHA-only group, there was no difference at 6 months, compared with placebo. At 12 months, there was significantly more activity in the left supplementary motor area.

The combination group showed significant increases in metabolism in a number of regions, including the right hemisphere cluster (insula/putamen/amygdala/superior and middle temporal region); the left middle temporal pole fusiform gyrus and anterior temporal region; the right middle and inferior frontal region; and the right rolandic opercula.

The European Commission funded the study. Dr. Vellas had no financial disclosures.

BARCELONA – A combination of cognitive and physical training plus omega-3 fatty acid supplements boosted cognitive performance significantly in a group of people with subjective memory complaints.

Among those with more serious memory issues, the combination worked even better, preventing any decline at all over the 3-year study period, Dr. Bruno Vellas said at the Clinical Trials on Alzheimer’s Disease conference.

The program was also especially effective in subjects who were homozygous for the high-risk e4 allele of the apolipoprotein E gene, said Dr. Vellas, chief of the Alzheimer’s Disease Clinical and Research Center at the University Hospital Center in Toulouse, France.

The findings must be confirmed in larger studies, he said, but they strengthen the growing body of evidence supporting nonpharmacologic Alzheimer’s prevention tactics.

©Clayton Hansen/iStockphoto

“This confirms the data from FINGER. In FINGER we had some improvement, but here we are able to show that we can prevent decline, which is maybe even more important, especially for high-risk patients,” Dr. Vellas said.

The Multidomain Alzheimer Preventive Trial (MAPT) comprised 1,680 people who had reported subjective memory complaints to their primary care physician. It examined the effect of a comprehensive cognitive, nutrition, and physical training program, with or without omega-3 fatty acid supplementation. In addition to the cognitive outcome, MAPT used functional PET imaging to examine brain glucose metabolism at baseline and 6 and 12 months, and amyloid plaque burden at 12-18 months.

Cognitive training focused on reasoning and memory training. Its main objective was to teach participants how to use adaptive strategies in solving everyday problems – for example, using mnemonics to remember a grocery list.

The physical training component involved at least 150 minutes of moderate exercise each week; walking 30 minutes/day was the most frequently recommended. Participants also received an individually designed at-home exercise plan that was reviewed and updated every 6 months.

Nutritional counseling was based on the French National Nutrition and Health Program. Eight key guidelines on healthy diet were discussed.

These interventions were all offered in small groups, during 12 2-hour sessions in the first 2 months. There were brief individual interviews every 6 months, and intensive booster sessions after 1 year and 2 years.

Each supplement capsule contained a specially compounded combination of 400 mg docosahexaenoic acid (DHA) and 112.5 mg eicosapentaenoic acid (EPA). It was taken twice a day.

The trial consisted of four arms: omega-3 supplements (DHA) alone; placebo capsules alone; training without DHA supplements; and both training and DHA

The mean age of the study participants was 75 years. While the mean Mini Mental State Exam score was 28, indicating no cognitive impairment, some subjects did dip down into the mild cognitive impairment range. About 40% had a Clinical Dementia Rating sum of boxes (CDR) score of 0.5 (very mild Alzheimer’s); the rest had a 0 score. No one had frank dementia. About 23% were positive for APOE e4.

Compliance with the program was very good, Dr. Vellas said: a mean of 71% for the training programs and 84% for the supplements over the 3 years.

In both the intent-to-treat and per-protocol analyses, the training program and the combination of training and DHA were significantly more effective than either DHA or placebo.

Those taking DHA alone or placebo declined similarly from baseline. Those in the training program (with or without DHA) experienced a significant uptick in cognitive score during the first year. During the second year that gain fell, but it still remained significantly above baseline in both groups.

Dr. Vellas also examined the composite cognitive endpoint in the subgroup with a 0.5 score on the CDR scale. Those taking placebo or DHA-only experienced no improvement and fell significantly below baseline by the end of the study. Those who were in the training program only experienced a boost in scores in the first 6 months, which rapidly fell off. By 2 years, the scores were significantly below baseline, although not as depressed as those in the placebo and DHA-only groups.

The best outcome occurred in the training program plus DHA group. Their test scores remained completely stable over the entire period, suggesting that the combination intervention prevented cognitive decline.

It conferred the biggest benefit on those who were APOE e4-positive. Their scores rose significantly by 12 months and, although they did begin to decline, they remained significantly improved through the study’s end. The training program alone also improved the cognitive score by 12 months, but that dipped back to baseline by the end of the study. Those taking placebo or DHA alone experienced significant score declines.

Amyloid imaging was not performed at baseline, but was done 12-18 months into the study. At that point, the combination intervention group had the lowest percentage of amyloid-positive subjects (22%). The rate of amyloid positivity was 34% in the training program alone; 46% in the DHA group alone; and 51% in the placebo group.

It’s not possible to determine whether the intervention altered the trajectory of amyloid deposition, Dr. Vellas said; that will be explored in a different study.

PET imaging showed striking between-group differences in glucose metabolism. Those in the training-alone group experienced a transient metabolic increase in the right and left temporal regions, which, compared with placebo, was significant at 6 months but not at 12 months.

In the DHA-only group, there was no difference at 6 months, compared with placebo. At 12 months, there was significantly more activity in the left supplementary motor area.

The combination group showed significant increases in metabolism in a number of regions, including the right hemisphere cluster (insula/putamen/amygdala/superior and middle temporal region); the left middle temporal pole fusiform gyrus and anterior temporal region; the right middle and inferior frontal region; and the right rolandic opercula.

The European Commission funded the study. Dr. Vellas had no financial disclosures.

BARCELONA – A combination of cognitive and physical training plus omega-3 fatty acid supplements boosted cognitive performance significantly in a group of people with subjective memory complaints.

Among those with more serious memory issues, the combination worked even better, preventing any decline at all over the 3-year study period, Dr. Bruno Vellas said at the Clinical Trials on Alzheimer’s Disease conference.

The program was also especially effective in subjects who were homozygous for the high-risk e4 allele of the apolipoprotein E gene, said Dr. Vellas, chief of the Alzheimer’s Disease Clinical and Research Center at the University Hospital Center in Toulouse, France.

The findings must be confirmed in larger studies, he said, but they strengthen the growing body of evidence supporting nonpharmacologic Alzheimer’s prevention tactics.

©Clayton Hansen/iStockphoto

“This confirms the data from FINGER. In FINGER we had some improvement, but here we are able to show that we can prevent decline, which is maybe even more important, especially for high-risk patients,” Dr. Vellas said.

The Multidomain Alzheimer Preventive Trial (MAPT) comprised 1,680 people who had reported subjective memory complaints to their primary care physician. It examined the effect of a comprehensive cognitive, nutrition, and physical training program, with or without omega-3 fatty acid supplementation. In addition to the cognitive outcome, MAPT used functional PET imaging to examine brain glucose metabolism at baseline and 6 and 12 months, and amyloid plaque burden at 12-18 months.

Cognitive training focused on reasoning and memory training. Its main objective was to teach participants how to use adaptive strategies in solving everyday problems – for example, using mnemonics to remember a grocery list.

The physical training component involved at least 150 minutes of moderate exercise each week; walking 30 minutes/day was the most frequently recommended. Participants also received an individually designed at-home exercise plan that was reviewed and updated every 6 months.

Nutritional counseling was based on the French National Nutrition and Health Program. Eight key guidelines on healthy diet were discussed.

These interventions were all offered in small groups, during 12 2-hour sessions in the first 2 months. There were brief individual interviews every 6 months, and intensive booster sessions after 1 year and 2 years.

Each supplement capsule contained a specially compounded combination of 400 mg docosahexaenoic acid (DHA) and 112.5 mg eicosapentaenoic acid (EPA). It was taken twice a day.

The trial consisted of four arms: omega-3 supplements (DHA) alone; placebo capsules alone; training without DHA supplements; and both training and DHA

The mean age of the study participants was 75 years. While the mean Mini Mental State Exam score was 28, indicating no cognitive impairment, some subjects did dip down into the mild cognitive impairment range. About 40% had a Clinical Dementia Rating sum of boxes (CDR) score of 0.5 (very mild Alzheimer’s); the rest had a 0 score. No one had frank dementia. About 23% were positive for APOE e4.

Compliance with the program was very good, Dr. Vellas said: a mean of 71% for the training programs and 84% for the supplements over the 3 years.

In both the intent-to-treat and per-protocol analyses, the training program and the combination of training and DHA were significantly more effective than either DHA or placebo.

Those taking DHA alone or placebo declined similarly from baseline. Those in the training program (with or without DHA) experienced a significant uptick in cognitive score during the first year. During the second year that gain fell, but it still remained significantly above baseline in both groups.

Dr. Vellas also examined the composite cognitive endpoint in the subgroup with a 0.5 score on the CDR scale. Those taking placebo or DHA-only experienced no improvement and fell significantly below baseline by the end of the study. Those who were in the training program only experienced a boost in scores in the first 6 months, which rapidly fell off. By 2 years, the scores were significantly below baseline, although not as depressed as those in the placebo and DHA-only groups.

The best outcome occurred in the training program plus DHA group. Their test scores remained completely stable over the entire period, suggesting that the combination intervention prevented cognitive decline.

It conferred the biggest benefit on those who were APOE e4-positive. Their scores rose significantly by 12 months and, although they did begin to decline, they remained significantly improved through the study’s end. The training program alone also improved the cognitive score by 12 months, but that dipped back to baseline by the end of the study. Those taking placebo or DHA alone experienced significant score declines.

Amyloid imaging was not performed at baseline, but was done 12-18 months into the study. At that point, the combination intervention group had the lowest percentage of amyloid-positive subjects (22%). The rate of amyloid positivity was 34% in the training program alone; 46% in the DHA group alone; and 51% in the placebo group.

It’s not possible to determine whether the intervention altered the trajectory of amyloid deposition, Dr. Vellas said; that will be explored in a different study.

PET imaging showed striking between-group differences in glucose metabolism. Those in the training-alone group experienced a transient metabolic increase in the right and left temporal regions, which, compared with placebo, was significant at 6 months but not at 12 months.

In the DHA-only group, there was no difference at 6 months, compared with placebo. At 12 months, there was significantly more activity in the left supplementary motor area.

The combination group showed significant increases in metabolism in a number of regions, including the right hemisphere cluster (insula/putamen/amygdala/superior and middle temporal region); the left middle temporal pole fusiform gyrus and anterior temporal region; the right middle and inferior frontal region; and the right rolandic opercula.

The European Commission funded the study. Dr. Vellas had no financial disclosures.

BARCELONA – New, unpublished data from the FINGER multimodal lifestyle intervention study indicates that targeting nutrition, exercise, and metabolic and cardiovascular risk factors boosted overall cognitive performance, memory, and executive function to the greatest extent in elderly people at risk of cognitive decline who carried the apolipoprotein E–epsilon 4 allele.

“The findings were especially clear in changes on the comprehensive neuropsychological test battery,” which was the study’s primary endpoint, Dr. Miia Kivipelto of the Karolinska Institute, Stockholm, said at the Clinical Trials on Alzheimer’s Disease conference. “This is a very effective intervention that we can recommend, especially for people with this genetic risk factor.”

Keith Brofsky/Thinkstock.com

The randomized, controlled FINGER (Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability) trial was a proof-of-concept study designed to show how a multimodal lifestyle intervention might not only slow or prevent cognitive decline, but help improve cognition among patients who are already experiencing decline. It enrolled 1,260 participants aged 60-77 years who were cognitively normal at baseline but at risk for decline based on their CAIDE (Cardiovascular Risk Factors, Aging, and Incidence of Dementia) risk score.

The cohort was randomized to a control program of 2 years of regular health counseling with their physician, or to the intervention, which consisted of:

• Dietary counseling with recommendations to consume increased amounts of fruit, vegetables, whole grains, lean protein, and healthy fats.

• Progressive aerobic exercise and weight training, conducted by physical therapists, several times each week.

• Cognitive training several times a week with a computer program that targeted executive processes, working memory, episodic memory, and mental speed.

• Managing metabolic and cardiovascular risk factors, including blood pressure, weight, and body mass index. This was addressed in group sessions and with visits to participants’ own physicians.

The subjects had a mean age of 69 years at baseline. About 70% reported physical activity at least twice a week. About half reported eating fish at least twice a week, and 60% reported a daily intake of vegetables. Most (65%) had hypertension and hypercholesterolemia (70%). Another 13% had diabetes, and 5% had a prior heart attack.

The primary endpoint was change on an extended version of the neuropsychological test battery, which was conducted at baseline and at months 12 and 24. Secondary endpoints were changes on the individual components of executive function, memory, and processing speed.

By the end of the study, subjects in the intervention group experienced a significant, 25% greater improvement on the overall score than did those in the control group. Improvements on the secondary measures were significant for the intervention group as well: 150% better than the control group in processing speed, 83% better in executive functioning, and 40% better in short-term memory.

The risk of cognitive decline increased by 30% in the control group by the study’s end, whereas subjects in the intervention group experienced no increased risk. The Lancet published the study’s main results earlier this year (Lancet. 2015;385[9984]:2255-63).

The new data that Dr. Kivipelto described showed that people with at least one apolipoprotein E (APOE)–epsilon 4 allele reaped a significantly greater benefit than did those without the high-risk allele. In the intervention group, carriers had an estimated mean change z-score on the overall neuropsychological test battery that was significantly higher than in noncarriers (0.17 vs. 0.10, respectively; P = .045), whereas the difference between carriers and noncarriers in the control group was not statistically significant (0.22 vs. 0.19; P = .28). Carriers in the intervention group also tended to benefit more than did noncarriers in the individual domains.

Dr. Kivipelto explored how the program might be working on a molecular level. In an analysis of 756 subjects, including 244 APOE–epsilon 4 carriers, she found attenuated telomere shortening in carriers in the intervention group, but not in carriers assigned to the control group or any of the noncarriers. This attenuation was also more pronounced in younger subjects, Dr. Kivipelto added.

She also presented some preliminary data on how the intervention improved function and quality of life. “There was some decline after 2 years in the control group, but the intervention group remained stable,” Dr. Kivipelto said. “There was also significant improvement in general health, mental function, and social function in the intervention group.”

General daily function was good for the entire cohort at baseline, but by the end of the study, significant differences had emerged, she said. “We were surprised to see that after 2 years, the control group actually had a 50% increased risk for at least one new difficulty with activities of daily living, and for those with no difficulties at baseline, the increased risk was even stronger, 76%.”

The program was not associated with any serious adverse events, or any adverse event at all other than musculoskeletal soreness from exercise activities. It also appeared to be practical and made a lasting impact, which was a gratifying finding, Dr. Kivipelto said. At the end of the study, intervention group participants had decreased their body mass index by about 0.8 kg/m^{2, which was} significantly more than for control group subjects. Most reported that they were still eating fish and exercising at least twice a week and eating vegetables every day.

“FINGER is the first long-term trial to show that a multidomain intervention like this one can maintain and improve cognitive decline,” she said. “It important that we’ve also seen the program is feasible, has no obvious side effects, and that it’s not limited to cognitive domains. It also has a positive impact on function and quality of life.”

Dr. Kivipelto had no financial disclosures. The study was supported by grants from the Academy of Finland’s Responding to Public Health Challenges Research Programme, La Carita Foundation, the Alzheimer’s Association, the Alzheimer’s Research and Prevention Foundation, the Juho Vainio Foundation, Novo Nordisk Foundation, the Finnish Social Insurance Institution, the Finnish Ministry of Education and Culture Research, Salama Bint Hamdan Al Nahyan Foundation, the Axa Research Fund, and various University Hospitals in Finland.

*This story was updated on 11/6/2015.

msullivan@frontlinemedcom.com

BARCELONA – New, unpublished data from the FINGER multimodal lifestyle intervention study indicates that targeting nutrition, exercise, and metabolic and cardiovascular risk factors boosted overall cognitive performance, memory, and executive function to the greatest extent in elderly people at risk of cognitive decline who carried the apolipoprotein E–epsilon 4 allele.

“The findings were especially clear in changes on the comprehensive neuropsychological test battery,” which was the study’s primary endpoint, Dr. Miia Kivipelto of the Karolinska Institute, Stockholm, said at the Clinical Trials on Alzheimer’s Disease conference. “This is a very effective intervention that we can recommend, especially for people with this genetic risk factor.”

Keith Brofsky/Thinkstock.com

The randomized, controlled FINGER (Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability) trial was a proof-of-concept study designed to show how a multimodal lifestyle intervention might not only slow or prevent cognitive decline, but help improve cognition among patients who are already experiencing decline. It enrolled 1,260 participants aged 60-77 years who were cognitively normal at baseline but at risk for decline based on their CAIDE (Cardiovascular Risk Factors, Aging, and Incidence of Dementia) risk score.

The cohort was randomized to a control program of 2 years of regular health counseling with their physician, or to the intervention, which consisted of:

• Dietary counseling with recommendations to consume increased amounts of fruit, vegetables, whole grains, lean protein, and healthy fats.

• Progressive aerobic exercise and weight training, conducted by physical therapists, several times each week.

• Cognitive training several times a week with a computer program that targeted executive processes, working memory, episodic memory, and mental speed.

• Managing metabolic and cardiovascular risk factors, including blood pressure, weight, and body mass index. This was addressed in group sessions and with visits to participants’ own physicians.

The subjects had a mean age of 69 years at baseline. About 70% reported physical activity at least twice a week. About half reported eating fish at least twice a week, and 60% reported a daily intake of vegetables. Most (65%) had hypertension and hypercholesterolemia (70%). Another 13% had diabetes, and 5% had a prior heart attack.

The primary endpoint was change on an extended version of the neuropsychological test battery, which was conducted at baseline and at months 12 and 24. Secondary endpoints were changes on the individual components of executive function, memory, and processing speed.

By the end of the study, subjects in the intervention group experienced a significant, 25% greater improvement on the overall score than did those in the control group. Improvements on the secondary measures were significant for the intervention group as well: 150% better than the control group in processing speed, 83% better in executive functioning, and 40% better in short-term memory.

The risk of cognitive decline increased by 30% in the control group by the study’s end, whereas subjects in the intervention group experienced no increased risk. The Lancet published the study’s main results earlier this year (Lancet. 2015;385[9984]:2255-63).

The new data that Dr. Kivipelto described showed that people with at least one apolipoprotein E (APOE)–epsilon 4 allele reaped a significantly greater benefit than did those without the high-risk allele. In the intervention group, carriers had an estimated mean change z-score on the overall neuropsychological test battery that was significantly higher than in noncarriers (0.17 vs. 0.10, respectively; P = .045), whereas the difference between carriers and noncarriers in the control group was not statistically significant (0.22 vs. 0.19; P = .28). Carriers in the intervention group also tended to benefit more than did noncarriers in the individual domains.

Dr. Kivipelto explored how the program might be working on a molecular level. In an analysis of 756 subjects, including 244 APOE–epsilon 4 carriers, she found attenuated telomere shortening in carriers in the intervention group, but not in carriers assigned to the control group or any of the noncarriers. This attenuation was also more pronounced in younger subjects, Dr. Kivipelto added.

She also presented some preliminary data on how the intervention improved function and quality of life. “There was some decline after 2 years in the control group, but the intervention group remained stable,” Dr. Kivipelto said. “There was also significant improvement in general health, mental function, and social function in the intervention group.”

General daily function was good for the entire cohort at baseline, but by the end of the study, significant differences had emerged, she said. “We were surprised to see that after 2 years, the control group actually had a 50% increased risk for at least one new difficulty with activities of daily living, and for those with no difficulties at baseline, the increased risk was even stronger, 76%.”

The program was not associated with any serious adverse events, or any adverse event at all other than musculoskeletal soreness from exercise activities. It also appeared to be practical and made a lasting impact, which was a gratifying finding, Dr. Kivipelto said. At the end of the study, intervention group participants had decreased their body mass index by about 0.8 kg/m^{2, which was} significantly more than for control group subjects. Most reported that they were still eating fish and exercising at least twice a week and eating vegetables every day.

“FINGER is the first long-term trial to show that a multidomain intervention like this one can maintain and improve cognitive decline,” she said. “It important that we’ve also seen the program is feasible, has no obvious side effects, and that it’s not limited to cognitive domains. It also has a positive impact on function and quality of life.”

Dr. Kivipelto had no financial disclosures. The study was supported by grants from the Academy of Finland’s Responding to Public Health Challenges Research Programme, La Carita Foundation, the Alzheimer’s Association, the Alzheimer’s Research and Prevention Foundation, the Juho Vainio Foundation, Novo Nordisk Foundation, the Finnish Social Insurance Institution, the Finnish Ministry of Education and Culture Research, Salama Bint Hamdan Al Nahyan Foundation, the Axa Research Fund, and various University Hospitals in Finland.

*This story was updated on 11/6/2015.

msullivan@frontlinemedcom.com

BARCELONA – New, unpublished data from the FINGER multimodal lifestyle intervention study indicates that targeting nutrition, exercise, and metabolic and cardiovascular risk factors boosted overall cognitive performance, memory, and executive function to the greatest extent in elderly people at risk of cognitive decline who carried the apolipoprotein E–epsilon 4 allele.

“The findings were especially clear in changes on the comprehensive neuropsychological test battery,” which was the study’s primary endpoint, Dr. Miia Kivipelto of the Karolinska Institute, Stockholm, said at the Clinical Trials on Alzheimer’s Disease conference. “This is a very effective intervention that we can recommend, especially for people with this genetic risk factor.”

Keith Brofsky/Thinkstock.com

The randomized, controlled FINGER (Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability) trial was a proof-of-concept study designed to show how a multimodal lifestyle intervention might not only slow or prevent cognitive decline, but help improve cognition among patients who are already experiencing decline. It enrolled 1,260 participants aged 60-77 years who were cognitively normal at baseline but at risk for decline based on their CAIDE (Cardiovascular Risk Factors, Aging, and Incidence of Dementia) risk score.

The cohort was randomized to a control program of 2 years of regular health counseling with their physician, or to the intervention, which consisted of:

• Dietary counseling with recommendations to consume increased amounts of fruit, vegetables, whole grains, lean protein, and healthy fats.

• Progressive aerobic exercise and weight training, conducted by physical therapists, several times each week.

• Cognitive training several times a week with a computer program that targeted executive processes, working memory, episodic memory, and mental speed.

• Managing metabolic and cardiovascular risk factors, including blood pressure, weight, and body mass index. This was addressed in group sessions and with visits to participants’ own physicians.

The subjects had a mean age of 69 years at baseline. About 70% reported physical activity at least twice a week. About half reported eating fish at least twice a week, and 60% reported a daily intake of vegetables. Most (65%) had hypertension and hypercholesterolemia (70%). Another 13% had diabetes, and 5% had a prior heart attack.

The primary endpoint was change on an extended version of the neuropsychological test battery, which was conducted at baseline and at months 12 and 24. Secondary endpoints were changes on the individual components of executive function, memory, and processing speed.

By the end of the study, subjects in the intervention group experienced a significant, 25% greater improvement on the overall score than did those in the control group. Improvements on the secondary measures were significant for the intervention group as well: 150% better than the control group in processing speed, 83% better in executive functioning, and 40% better in short-term memory.

The risk of cognitive decline increased by 30% in the control group by the study’s end, whereas subjects in the intervention group experienced no increased risk. The Lancet published the study’s main results earlier this year (Lancet. 2015;385[9984]:2255-63).

The new data that Dr. Kivipelto described showed that people with at least one apolipoprotein E (APOE)–epsilon 4 allele reaped a significantly greater benefit than did those without the high-risk allele. In the intervention group, carriers had an estimated mean change z-score on the overall neuropsychological test battery that was significantly higher than in noncarriers (0.17 vs. 0.10, respectively; P = .045), whereas the difference between carriers and noncarriers in the control group was not statistically significant (0.22 vs. 0.19; P = .28). Carriers in the intervention group also tended to benefit more than did noncarriers in the individual domains.

Dr. Kivipelto explored how the program might be working on a molecular level. In an analysis of 756 subjects, including 244 APOE–epsilon 4 carriers, she found attenuated telomere shortening in carriers in the intervention group, but not in carriers assigned to the control group or any of the noncarriers. This attenuation was also more pronounced in younger subjects, Dr. Kivipelto added.

She also presented some preliminary data on how the intervention improved function and quality of life. “There was some decline after 2 years in the control group, but the intervention group remained stable,” Dr. Kivipelto said. “There was also significant improvement in general health, mental function, and social function in the intervention group.”

General daily function was good for the entire cohort at baseline, but by the end of the study, significant differences had emerged, she said. “We were surprised to see that after 2 years, the control group actually had a 50% increased risk for at least one new difficulty with activities of daily living, and for those with no difficulties at baseline, the increased risk was even stronger, 76%.”

The program was not associated with any serious adverse events, or any adverse event at all other than musculoskeletal soreness from exercise activities. It also appeared to be practical and made a lasting impact, which was a gratifying finding, Dr. Kivipelto said. At the end of the study, intervention group participants had decreased their body mass index by about 0.8 kg/m^{2, which was} significantly more than for control group subjects. Most reported that they were still eating fish and exercising at least twice a week and eating vegetables every day.

“FINGER is the first long-term trial to show that a multidomain intervention like this one can maintain and improve cognitive decline,” she said. “It important that we’ve also seen the program is feasible, has no obvious side effects, and that it’s not limited to cognitive domains. It also has a positive impact on function and quality of life.”

Dr. Kivipelto had no financial disclosures. The study was supported by grants from the Academy of Finland’s Responding to Public Health Challenges Research Programme, La Carita Foundation, the Alzheimer’s Association, the Alzheimer’s Research and Prevention Foundation, the Juho Vainio Foundation, Novo Nordisk Foundation, the Finnish Social Insurance Institution, the Finnish Ministry of Education and Culture Research, Salama Bint Hamdan Al Nahyan Foundation, the Axa Research Fund, and various University Hospitals in Finland.

*This story was updated on 11/6/2015.

msullivan@frontlinemedcom.com