Alzheimer's Association International Conference (AAIC)

TORONTO – A highly anticipated phase III trial of an anti-tau drug has posted negative topline results, conferring no cognitive or functional benefits when given in conjunction with standard-of-care Alzheimer’s disease medications.

The drug, LTMX (TauRx, Singapore), also did not slow the progression of brain atrophy on imaging in either of two doses tested, according to a company press release.

Although the study didn’t meet its clinical endpoints in the overall cohort of 891 patients with mild-moderate disease, TauRx promoted it as “promising,” based on a subgroup analysis of the 15% of patients who took the drug as monotherapy.

Among these patients, LMTX was associated with dose-dependent, statistically significant improvements in the Alzheimer’s Disease Assessment Scale measures of cognition (ADAS-cog) and Alzheimer’s Disease Cooperative Study Activities of Daily Living inventory (ADCS-ADL). The drug was also associated with a slowing of brain ventricular expansion, compared with controls, suggesting that it could be preserving brain mass.

Mitchel L. Zoler/Frontline Medical News

Nevertheless, the trial must be read as another negative one, said David S. Knopman, MD, who moderated a press briefing where the data were presented.

“I must say I am disappointed by the results because in my view of clinical trials forged from 30 years of experience, the only thing that really counts is the prespecified primary outcome,” said Dr. Knopman of the Mayo Clinic, Rochester, Minn. “I think the secondary results are interesting, especially imaging findings. But our experience of secondary analyses in this field is that they are fraught with hidden biases. And because this is a small subset of just 15%, it’s very difficult to interpret.”

Details of the study

The 15-month study comprised 891 patients with mild-moderate Alzheimer’s disease. Most of these (85%) were taking standard-of-care symptomatic Alzheimer’s disease medications. Patients were randomized to 75 mg twice daily, 125 mg twice daily, or placebo, which necessarily consisted of a small amount of the medication. LMTX is a derivative of the dye methylene blue and colors urine when excreted. The inactive dose is enough to provide that color so that blinding can be maintained.

Patients were grouped according to whether they took the study drug as add-on therapy (85%) or as monotherapy (15%). However, the results were presented in a somewhat unusual way, with the placebo patients in each therapeutic regimen grouped together. Thus, there was no way to compare the placebo-treated patients who did not receive standard-of-care medications against those who received LMTX monotherapy without standard-of-care medications; instead, the benefits reported in the active monotherapy group were compared with the results seen in placebo patients in both the mono- and add-on groups.

The reason for this was that the numbers in each group were small, said Serge Gauthier, MD, who presented the LMTX data at the Alzheimer’s Association International Conference 2016. Among the monotherapy group, 42 took 75 mg twice daily, 40 took 125 mg twice daily, and 54 took placebo. He suggested that these numbers could be pooled with those in a similar phase III trial of LMTX in about 800 patients with mild disease, which will be completed this fall.

“My proposal would be to combine these groups and then we would really be able to understand what we’re seeing in the control monotherapy versus the study drug monotherapy groups,” said Dr. Gauthier of McGill University, Montreal.

The study was conducted at 115 sites across 16 countries in Europe, North America, and Asia. All of the patients had a clinical diagnosis of Alzheimer’s disease; no one underwent amyloid PET imaging. The patients’ mean age was 70.6 years, and their baseline Mini Mental State Exam score was 18.7.

At the study’s end, patients in the monotherapy group taking 75 mg twice daily had declined 6.3 points less on the ADAS-cog than did the grouped placebo patients, indicating preserved cognition. Those taking 125 mg twice daily declined 5.8 points less than did the grouped placebo patients. On the ADCS-ADL, patients taking 75 mg twice daily scored 6.5 points higher than did the placebo group, indicating better function, and those taking 125 mg twice daily scored 6.9 points higher than did the placebo group.

Lateral ventricular volume expansion on MRI was significantly less than that seen in placebo-treated patients. For those taking 75 mg twice a day, ventricular expansion was reduced by 38%; for those taking 125 mg twice a day, expansion was reduced by 33%. This was accompanied by significant slowing of whole brain atrophy, Dr. Gauthier said, adding that this finding has never been reported in an Alzheimer’s drug trial.

Speculation on lack of effect with standard-of-care medications

Confoundingly, however, LMTX showed no benefit at all in the patients who were taking the usual Alzheimer’s medications. Nor were there similar changes in brain volume.

“We are struggling with this information,” Dr. Gauthier said. “Why this difference in the 15%? They were not older, they did not have milder disease, and there were no obvious differences. The only thing we saw was that they were more likely to have come from Eastern Europe, where access to these drugs is reduced.”

That, however, could play a key role in the findings, Dr. Knopman said in an interview.

“To be honest, I think people who entered the study not on standard of care were in regions where they were not getting any good medical care, and when they became part of this trial they began to get better medical care and experienced a pronounced placebo effect.”

He couldn’t explain how a placebo effect could be related to the MRI findings, although he did say that other medical conditions can be related to changes in brain volume. Quitting alcohol is a big one – alcoholics who stop drinking do experience increases in whole brain volume. And, Dr. Knopman pointed out, alcoholism is rampant in Eastern Europe, where most of these patients lived.

The finding is more problematic because there’s no way to compare the active monotherapy group with the placebo monotherapy group, he said.

“My suspicion is that if they had shown the differences between the monotherapy placebo and the monotherapy active groups, the curves would have looked a lot like what we saw in the add-on therapy groups.”

In an interview, Claude Wischik, MD, PhD, cofounder and executive chair of TauRx and primary investigator on all of the LMTX studies, dismissed Dr. Knopman’s suggestion.

“There’s no geography in the world that can change brain volume,” he said. “You can’t shift the brain simply by wanting it.” And while he fell short of suggesting that LMTX is affecting neurogenesis, he did say that the drug is directly responsible for modifying brain physiology.

Dr. Knopman also pointed out that the lack of baseline amyloid PET imaging almost certainly means that there were patients with other, non-Alzheimer’s dementias in the trial. Baseline amyloid PET imaging is now standard because up to 30% of patients in older antiamyloid studies have now been shown to have not even had the disease. Without baseline amyloid PET imaging to confirm diagnosis, “there’s no telling what they were treating” with LMTX, he said.

The drug’s failure as an add-on therapy is problematic, Dr. Knopman said. The symptomatic Alzheimer’s medications are generally considered to have a very low interaction profile with any other drug. This lack of efficacy, he suggested, is another hint that the benefit in the monotherapy group could be a fluke.

Dr. Wischik said this is not due to pharmacokinetics, but rather to the induction of a cellular clearance pathway called the P-glycoprotein 1 transport pathway.

“The most plausible explanation is this transporter hypothesis. If you’re taking a drug chronically – like an Alzheimer’s medication – this extrusion pathway is turned on. Its net effect is to excrete the drugs from the brain and enhance kidney excretion.” This would accelerate LMTX clearance to the point of inactivity, he said.

When asked if this would be problematic for other drugs taken chronically – statins, for example – Dr. Wischik said the cholinesterase inhibitors were responsible for activating the P-glycoprotein 1 transport pathway. He said there were no other drug interactions observed to inhibit the effect of LMTX.

Dr. Gauthier said research will proceed on LMTX, probably targeting patients with mild Alzheimer’s – or even prodromal disease – who are not yet taking an Alzheimer’s medication. In fact, he suggested that any future it might have would most likely be as part of a staged treatment. LMTX could be given early with the aim of delaying symptom onset, at which time treatment could accelerate to a symptomatic medication, and then, perhaps, to more aggressive measures like an antiamyloid, should one ever come to market.

Dr. Gauthier is on the TauRx advisory board. Dr. Knopman is an investigator on a trial of LMTX in frontotemporal dementia, but has no financial ties with the company.

[email protected]

On Twitter @alz_gal

TORONTO – A highly anticipated phase III trial of an anti-tau drug has posted negative topline results, conferring no cognitive or functional benefits when given in conjunction with standard-of-care Alzheimer’s disease medications.

The drug, LTMX (TauRx, Singapore), also did not slow the progression of brain atrophy on imaging in either of two doses tested, according to a company press release.

Although the study didn’t meet its clinical endpoints in the overall cohort of 891 patients with mild-moderate disease, TauRx promoted it as “promising,” based on a subgroup analysis of the 15% of patients who took the drug as monotherapy.

Among these patients, LMTX was associated with dose-dependent, statistically significant improvements in the Alzheimer’s Disease Assessment Scale measures of cognition (ADAS-cog) and Alzheimer’s Disease Cooperative Study Activities of Daily Living inventory (ADCS-ADL). The drug was also associated with a slowing of brain ventricular expansion, compared with controls, suggesting that it could be preserving brain mass.

Mitchel L. Zoler/Frontline Medical News

Nevertheless, the trial must be read as another negative one, said David S. Knopman, MD, who moderated a press briefing where the data were presented.

“I must say I am disappointed by the results because in my view of clinical trials forged from 30 years of experience, the only thing that really counts is the prespecified primary outcome,” said Dr. Knopman of the Mayo Clinic, Rochester, Minn. “I think the secondary results are interesting, especially imaging findings. But our experience of secondary analyses in this field is that they are fraught with hidden biases. And because this is a small subset of just 15%, it’s very difficult to interpret.”

Details of the study

The 15-month study comprised 891 patients with mild-moderate Alzheimer’s disease. Most of these (85%) were taking standard-of-care symptomatic Alzheimer’s disease medications. Patients were randomized to 75 mg twice daily, 125 mg twice daily, or placebo, which necessarily consisted of a small amount of the medication. LMTX is a derivative of the dye methylene blue and colors urine when excreted. The inactive dose is enough to provide that color so that blinding can be maintained.

Patients were grouped according to whether they took the study drug as add-on therapy (85%) or as monotherapy (15%). However, the results were presented in a somewhat unusual way, with the placebo patients in each therapeutic regimen grouped together. Thus, there was no way to compare the placebo-treated patients who did not receive standard-of-care medications against those who received LMTX monotherapy without standard-of-care medications; instead, the benefits reported in the active monotherapy group were compared with the results seen in placebo patients in both the mono- and add-on groups.

The reason for this was that the numbers in each group were small, said Serge Gauthier, MD, who presented the LMTX data at the Alzheimer’s Association International Conference 2016. Among the monotherapy group, 42 took 75 mg twice daily, 40 took 125 mg twice daily, and 54 took placebo. He suggested that these numbers could be pooled with those in a similar phase III trial of LMTX in about 800 patients with mild disease, which will be completed this fall.

“My proposal would be to combine these groups and then we would really be able to understand what we’re seeing in the control monotherapy versus the study drug monotherapy groups,” said Dr. Gauthier of McGill University, Montreal.

The study was conducted at 115 sites across 16 countries in Europe, North America, and Asia. All of the patients had a clinical diagnosis of Alzheimer’s disease; no one underwent amyloid PET imaging. The patients’ mean age was 70.6 years, and their baseline Mini Mental State Exam score was 18.7.

At the study’s end, patients in the monotherapy group taking 75 mg twice daily had declined 6.3 points less on the ADAS-cog than did the grouped placebo patients, indicating preserved cognition. Those taking 125 mg twice daily declined 5.8 points less than did the grouped placebo patients. On the ADCS-ADL, patients taking 75 mg twice daily scored 6.5 points higher than did the placebo group, indicating better function, and those taking 125 mg twice daily scored 6.9 points higher than did the placebo group.

Lateral ventricular volume expansion on MRI was significantly less than that seen in placebo-treated patients. For those taking 75 mg twice a day, ventricular expansion was reduced by 38%; for those taking 125 mg twice a day, expansion was reduced by 33%. This was accompanied by significant slowing of whole brain atrophy, Dr. Gauthier said, adding that this finding has never been reported in an Alzheimer’s drug trial.

Speculation on lack of effect with standard-of-care medications

Confoundingly, however, LMTX showed no benefit at all in the patients who were taking the usual Alzheimer’s medications. Nor were there similar changes in brain volume.

“We are struggling with this information,” Dr. Gauthier said. “Why this difference in the 15%? They were not older, they did not have milder disease, and there were no obvious differences. The only thing we saw was that they were more likely to have come from Eastern Europe, where access to these drugs is reduced.”

That, however, could play a key role in the findings, Dr. Knopman said in an interview.

“To be honest, I think people who entered the study not on standard of care were in regions where they were not getting any good medical care, and when they became part of this trial they began to get better medical care and experienced a pronounced placebo effect.”

He couldn’t explain how a placebo effect could be related to the MRI findings, although he did say that other medical conditions can be related to changes in brain volume. Quitting alcohol is a big one – alcoholics who stop drinking do experience increases in whole brain volume. And, Dr. Knopman pointed out, alcoholism is rampant in Eastern Europe, where most of these patients lived.

The finding is more problematic because there’s no way to compare the active monotherapy group with the placebo monotherapy group, he said.

“My suspicion is that if they had shown the differences between the monotherapy placebo and the monotherapy active groups, the curves would have looked a lot like what we saw in the add-on therapy groups.”

In an interview, Claude Wischik, MD, PhD, cofounder and executive chair of TauRx and primary investigator on all of the LMTX studies, dismissed Dr. Knopman’s suggestion.

“There’s no geography in the world that can change brain volume,” he said. “You can’t shift the brain simply by wanting it.” And while he fell short of suggesting that LMTX is affecting neurogenesis, he did say that the drug is directly responsible for modifying brain physiology.

Dr. Knopman also pointed out that the lack of baseline amyloid PET imaging almost certainly means that there were patients with other, non-Alzheimer’s dementias in the trial. Baseline amyloid PET imaging is now standard because up to 30% of patients in older antiamyloid studies have now been shown to have not even had the disease. Without baseline amyloid PET imaging to confirm diagnosis, “there’s no telling what they were treating” with LMTX, he said.

The drug’s failure as an add-on therapy is problematic, Dr. Knopman said. The symptomatic Alzheimer’s medications are generally considered to have a very low interaction profile with any other drug. This lack of efficacy, he suggested, is another hint that the benefit in the monotherapy group could be a fluke.

Dr. Wischik said this is not due to pharmacokinetics, but rather to the induction of a cellular clearance pathway called the P-glycoprotein 1 transport pathway.

“The most plausible explanation is this transporter hypothesis. If you’re taking a drug chronically – like an Alzheimer’s medication – this extrusion pathway is turned on. Its net effect is to excrete the drugs from the brain and enhance kidney excretion.” This would accelerate LMTX clearance to the point of inactivity, he said.

When asked if this would be problematic for other drugs taken chronically – statins, for example – Dr. Wischik said the cholinesterase inhibitors were responsible for activating the P-glycoprotein 1 transport pathway. He said there were no other drug interactions observed to inhibit the effect of LMTX.

Dr. Gauthier said research will proceed on LMTX, probably targeting patients with mild Alzheimer’s – or even prodromal disease – who are not yet taking an Alzheimer’s medication. In fact, he suggested that any future it might have would most likely be as part of a staged treatment. LMTX could be given early with the aim of delaying symptom onset, at which time treatment could accelerate to a symptomatic medication, and then, perhaps, to more aggressive measures like an antiamyloid, should one ever come to market.

Dr. Gauthier is on the TauRx advisory board. Dr. Knopman is an investigator on a trial of LMTX in frontotemporal dementia, but has no financial ties with the company.

[email protected]

On Twitter @alz_gal

TORONTO – A highly anticipated phase III trial of an anti-tau drug has posted negative topline results, conferring no cognitive or functional benefits when given in conjunction with standard-of-care Alzheimer’s disease medications.

The drug, LTMX (TauRx, Singapore), also did not slow the progression of brain atrophy on imaging in either of two doses tested, according to a company press release.

Although the study didn’t meet its clinical endpoints in the overall cohort of 891 patients with mild-moderate disease, TauRx promoted it as “promising,” based on a subgroup analysis of the 15% of patients who took the drug as monotherapy.

Among these patients, LMTX was associated with dose-dependent, statistically significant improvements in the Alzheimer’s Disease Assessment Scale measures of cognition (ADAS-cog) and Alzheimer’s Disease Cooperative Study Activities of Daily Living inventory (ADCS-ADL). The drug was also associated with a slowing of brain ventricular expansion, compared with controls, suggesting that it could be preserving brain mass.

Mitchel L. Zoler/Frontline Medical News

Nevertheless, the trial must be read as another negative one, said David S. Knopman, MD, who moderated a press briefing where the data were presented.

“I must say I am disappointed by the results because in my view of clinical trials forged from 30 years of experience, the only thing that really counts is the prespecified primary outcome,” said Dr. Knopman of the Mayo Clinic, Rochester, Minn. “I think the secondary results are interesting, especially imaging findings. But our experience of secondary analyses in this field is that they are fraught with hidden biases. And because this is a small subset of just 15%, it’s very difficult to interpret.”

Details of the study

The 15-month study comprised 891 patients with mild-moderate Alzheimer’s disease. Most of these (85%) were taking standard-of-care symptomatic Alzheimer’s disease medications. Patients were randomized to 75 mg twice daily, 125 mg twice daily, or placebo, which necessarily consisted of a small amount of the medication. LMTX is a derivative of the dye methylene blue and colors urine when excreted. The inactive dose is enough to provide that color so that blinding can be maintained.

Patients were grouped according to whether they took the study drug as add-on therapy (85%) or as monotherapy (15%). However, the results were presented in a somewhat unusual way, with the placebo patients in each therapeutic regimen grouped together. Thus, there was no way to compare the placebo-treated patients who did not receive standard-of-care medications against those who received LMTX monotherapy without standard-of-care medications; instead, the benefits reported in the active monotherapy group were compared with the results seen in placebo patients in both the mono- and add-on groups.

The reason for this was that the numbers in each group were small, said Serge Gauthier, MD, who presented the LMTX data at the Alzheimer’s Association International Conference 2016. Among the monotherapy group, 42 took 75 mg twice daily, 40 took 125 mg twice daily, and 54 took placebo. He suggested that these numbers could be pooled with those in a similar phase III trial of LMTX in about 800 patients with mild disease, which will be completed this fall.

“My proposal would be to combine these groups and then we would really be able to understand what we’re seeing in the control monotherapy versus the study drug monotherapy groups,” said Dr. Gauthier of McGill University, Montreal.

The study was conducted at 115 sites across 16 countries in Europe, North America, and Asia. All of the patients had a clinical diagnosis of Alzheimer’s disease; no one underwent amyloid PET imaging. The patients’ mean age was 70.6 years, and their baseline Mini Mental State Exam score was 18.7.

At the study’s end, patients in the monotherapy group taking 75 mg twice daily had declined 6.3 points less on the ADAS-cog than did the grouped placebo patients, indicating preserved cognition. Those taking 125 mg twice daily declined 5.8 points less than did the grouped placebo patients. On the ADCS-ADL, patients taking 75 mg twice daily scored 6.5 points higher than did the placebo group, indicating better function, and those taking 125 mg twice daily scored 6.9 points higher than did the placebo group.

Lateral ventricular volume expansion on MRI was significantly less than that seen in placebo-treated patients. For those taking 75 mg twice a day, ventricular expansion was reduced by 38%; for those taking 125 mg twice a day, expansion was reduced by 33%. This was accompanied by significant slowing of whole brain atrophy, Dr. Gauthier said, adding that this finding has never been reported in an Alzheimer’s drug trial.

Speculation on lack of effect with standard-of-care medications

Confoundingly, however, LMTX showed no benefit at all in the patients who were taking the usual Alzheimer’s medications. Nor were there similar changes in brain volume.

“We are struggling with this information,” Dr. Gauthier said. “Why this difference in the 15%? They were not older, they did not have milder disease, and there were no obvious differences. The only thing we saw was that they were more likely to have come from Eastern Europe, where access to these drugs is reduced.”

That, however, could play a key role in the findings, Dr. Knopman said in an interview.

“To be honest, I think people who entered the study not on standard of care were in regions where they were not getting any good medical care, and when they became part of this trial they began to get better medical care and experienced a pronounced placebo effect.”

He couldn’t explain how a placebo effect could be related to the MRI findings, although he did say that other medical conditions can be related to changes in brain volume. Quitting alcohol is a big one – alcoholics who stop drinking do experience increases in whole brain volume. And, Dr. Knopman pointed out, alcoholism is rampant in Eastern Europe, where most of these patients lived.

The finding is more problematic because there’s no way to compare the active monotherapy group with the placebo monotherapy group, he said.

“My suspicion is that if they had shown the differences between the monotherapy placebo and the monotherapy active groups, the curves would have looked a lot like what we saw in the add-on therapy groups.”

In an interview, Claude Wischik, MD, PhD, cofounder and executive chair of TauRx and primary investigator on all of the LMTX studies, dismissed Dr. Knopman’s suggestion.

“There’s no geography in the world that can change brain volume,” he said. “You can’t shift the brain simply by wanting it.” And while he fell short of suggesting that LMTX is affecting neurogenesis, he did say that the drug is directly responsible for modifying brain physiology.

Dr. Knopman also pointed out that the lack of baseline amyloid PET imaging almost certainly means that there were patients with other, non-Alzheimer’s dementias in the trial. Baseline amyloid PET imaging is now standard because up to 30% of patients in older antiamyloid studies have now been shown to have not even had the disease. Without baseline amyloid PET imaging to confirm diagnosis, “there’s no telling what they were treating” with LMTX, he said.

The drug’s failure as an add-on therapy is problematic, Dr. Knopman said. The symptomatic Alzheimer’s medications are generally considered to have a very low interaction profile with any other drug. This lack of efficacy, he suggested, is another hint that the benefit in the monotherapy group could be a fluke.

Dr. Wischik said this is not due to pharmacokinetics, but rather to the induction of a cellular clearance pathway called the P-glycoprotein 1 transport pathway.

“The most plausible explanation is this transporter hypothesis. If you’re taking a drug chronically – like an Alzheimer’s medication – this extrusion pathway is turned on. Its net effect is to excrete the drugs from the brain and enhance kidney excretion.” This would accelerate LMTX clearance to the point of inactivity, he said.

When asked if this would be problematic for other drugs taken chronically – statins, for example – Dr. Wischik said the cholinesterase inhibitors were responsible for activating the P-glycoprotein 1 transport pathway. He said there were no other drug interactions observed to inhibit the effect of LMTX.

Dr. Gauthier said research will proceed on LMTX, probably targeting patients with mild Alzheimer’s – or even prodromal disease – who are not yet taking an Alzheimer’s medication. In fact, he suggested that any future it might have would most likely be as part of a staged treatment. LMTX could be given early with the aim of delaying symptom onset, at which time treatment could accelerate to a symptomatic medication, and then, perhaps, to more aggressive measures like an antiamyloid, should one ever come to market.

Dr. Gauthier is on the TauRx advisory board. Dr. Knopman is an investigator on a trial of LMTX in frontotemporal dementia, but has no financial ties with the company.

[email protected]

On Twitter @alz_gal

TORONTO – A highly anticipated phase III trial of an anti-tau drug has posted negative topline results, conferring no cognitive or functional benefits when given in conjunction with standard-of-care Alzheimer’s disease medications.

The drug, LMTX (TauRx, Singapore), also did not slow the progression of brain atrophy on imaging in either of two doses tested, according to a company press release.

Although the study didn’t meet its clinical endpoints in the overall cohort of 891 patients with mild-moderate Alzheimer’s disease, TauRx promoted it as “promising,” based on a subgroup analysis of patients who took the drug as monotherapy. None of these patients were taking any standard-of-care Alzheimer’s medications; the press release did not say how many this group comprised. But it did imply that the group was small enough that the treatment effect was diluted in the pooled primary analysis.

In patients who took the drug as monotherapy, LMTX was associated with dose-dependent, statistically significant improvements in the Alzheimer’s Disease Assessment Scale measures of cognition (ADAS-cog) and Alzheimer’s Disease Cooperative Study Activities of Daily Living inventory (ADCS-ADL). The drug was also associated with a slowing of brain ventricular expansion, compared with controls, suggesting that it could be preserving brain mass.

ADAS-cog scores for patients taking LMTX monotherapy 75 mg twice a day declined 6.3 points less than did controls, indicating preserved cognition. Those taking LMTX monotherapy 125 mg twice a day declined 5.8 points less than did controls. On the ADCS-ADL, patients taking 75 mg twice a day scored 6.5 points higher than controls, indicating better function, and those taking 125 mg twice a day scored 6.9 points higher.

Lateral ventricular volume expansion on MRI was significantly less than that seen in controls. For those taking 75 mg twice a day, ventricular expansion was reduced by 38%, and for those taking 125 mg twice a day, expansion was reduced by 33%.

This indicates a decrease in the rate of brain atrophy, the press release said, and the finding was “confirmed by corresponding increases in the whole-brain volumes in the same patient groups.”

The press release also said that the imaging findings offer physiologic confirmation of the cognitive and functional findings. “This is the first treatment in which a clinical effect has been supported by evidence in delay of progression in brain atrophy shown by MRI scans.”

The missing number of patients who took LMTX monotherapy is key, however, in determining whether the positive effects in that group are real or a chance finding, according to Richard J. Caselli, MD, associate director and clinical core director of the Alzheimer’s Disease Center at the Mayo Clinic, Scottsdale, Ariz.

“Were the monotherapy results a fluke that washed out with bigger numbers or a meaningful effect? That needs to be clarified,” he said when asked to comment on the study. “Smaller ‘N’ trials can have skewed results due to random chances that mean nothing, and that is my fear. It’s unproven at this point but the burden of proof will rest on the investigators to replicate the positive outcome.”

The finding of a positive signal in monotherapy only is puzzling and also demands an explanation, said Michael Wolfe, PhD, a professor of neurology at Harvard University, Boston.

LMTX is a purified form of the dye methylene blue. Its method of action in preventing or dissolving tau tangles is not fully elucidated. A 2013 paper in a German chemistry journal, Angewandte Chemie, suggested that it works through oxidation to maintain the tau protein as a monomer, which prevents aggregation into filaments. There is no reason to think this pathway could intersect or interfere with any of the standard-of-care Alzheimer’s medications.

“There’s nothing obvious that comes to mind regarding interaction,” between the drug classes, Dr. Wolfe said in an interview. “We can’t say anything about this mechanistically. Any explanation here is just hand waving, I think.”

Dean Hartley, PhD, director of science initiatives at the Alzheimer’s Association, commented on the trial in a video interview at the Alzheimer’s Association International Conference 2016.

Neither Dr. Caselli nor Dr. Wolfe had relevant disclosures.

[email protected]

On Twitter @alz_gal

TORONTO – A highly anticipated phase III trial of an anti-tau drug has posted negative topline results, conferring no cognitive or functional benefits when given in conjunction with standard-of-care Alzheimer’s disease medications.

The drug, LMTX (TauRx, Singapore), also did not slow the progression of brain atrophy on imaging in either of two doses tested, according to a company press release.

Although the study didn’t meet its clinical endpoints in the overall cohort of 891 patients with mild-moderate Alzheimer’s disease, TauRx promoted it as “promising,” based on a subgroup analysis of patients who took the drug as monotherapy. None of these patients were taking any standard-of-care Alzheimer’s medications; the press release did not say how many this group comprised. But it did imply that the group was small enough that the treatment effect was diluted in the pooled primary analysis.

In patients who took the drug as monotherapy, LMTX was associated with dose-dependent, statistically significant improvements in the Alzheimer’s Disease Assessment Scale measures of cognition (ADAS-cog) and Alzheimer’s Disease Cooperative Study Activities of Daily Living inventory (ADCS-ADL). The drug was also associated with a slowing of brain ventricular expansion, compared with controls, suggesting that it could be preserving brain mass.

ADAS-cog scores for patients taking LMTX monotherapy 75 mg twice a day declined 6.3 points less than did controls, indicating preserved cognition. Those taking LMTX monotherapy 125 mg twice a day declined 5.8 points less than did controls. On the ADCS-ADL, patients taking 75 mg twice a day scored 6.5 points higher than controls, indicating better function, and those taking 125 mg twice a day scored 6.9 points higher.

Lateral ventricular volume expansion on MRI was significantly less than that seen in controls. For those taking 75 mg twice a day, ventricular expansion was reduced by 38%, and for those taking 125 mg twice a day, expansion was reduced by 33%.

This indicates a decrease in the rate of brain atrophy, the press release said, and the finding was “confirmed by corresponding increases in the whole-brain volumes in the same patient groups.”

The press release also said that the imaging findings offer physiologic confirmation of the cognitive and functional findings. “This is the first treatment in which a clinical effect has been supported by evidence in delay of progression in brain atrophy shown by MRI scans.”

The missing number of patients who took LMTX monotherapy is key, however, in determining whether the positive effects in that group are real or a chance finding, according to Richard J. Caselli, MD, associate director and clinical core director of the Alzheimer’s Disease Center at the Mayo Clinic, Scottsdale, Ariz.

“Were the monotherapy results a fluke that washed out with bigger numbers or a meaningful effect? That needs to be clarified,” he said when asked to comment on the study. “Smaller ‘N’ trials can have skewed results due to random chances that mean nothing, and that is my fear. It’s unproven at this point but the burden of proof will rest on the investigators to replicate the positive outcome.”

The finding of a positive signal in monotherapy only is puzzling and also demands an explanation, said Michael Wolfe, PhD, a professor of neurology at Harvard University, Boston.

LMTX is a purified form of the dye methylene blue. Its method of action in preventing or dissolving tau tangles is not fully elucidated. A 2013 paper in a German chemistry journal, Angewandte Chemie, suggested that it works through oxidation to maintain the tau protein as a monomer, which prevents aggregation into filaments. There is no reason to think this pathway could intersect or interfere with any of the standard-of-care Alzheimer’s medications.

“There’s nothing obvious that comes to mind regarding interaction,” between the drug classes, Dr. Wolfe said in an interview. “We can’t say anything about this mechanistically. Any explanation here is just hand waving, I think.”

Dean Hartley, PhD, director of science initiatives at the Alzheimer’s Association, commented on the trial in a video interview at the Alzheimer’s Association International Conference 2016.

Neither Dr. Caselli nor Dr. Wolfe had relevant disclosures.

[email protected]

On Twitter @alz_gal

TORONTO – A highly anticipated phase III trial of an anti-tau drug has posted negative topline results, conferring no cognitive or functional benefits when given in conjunction with standard-of-care Alzheimer’s disease medications.

The drug, LMTX (TauRx, Singapore), also did not slow the progression of brain atrophy on imaging in either of two doses tested, according to a company press release.

Although the study didn’t meet its clinical endpoints in the overall cohort of 891 patients with mild-moderate Alzheimer’s disease, TauRx promoted it as “promising,” based on a subgroup analysis of patients who took the drug as monotherapy. None of these patients were taking any standard-of-care Alzheimer’s medications; the press release did not say how many this group comprised. But it did imply that the group was small enough that the treatment effect was diluted in the pooled primary analysis.

In patients who took the drug as monotherapy, LMTX was associated with dose-dependent, statistically significant improvements in the Alzheimer’s Disease Assessment Scale measures of cognition (ADAS-cog) and Alzheimer’s Disease Cooperative Study Activities of Daily Living inventory (ADCS-ADL). The drug was also associated with a slowing of brain ventricular expansion, compared with controls, suggesting that it could be preserving brain mass.

ADAS-cog scores for patients taking LMTX monotherapy 75 mg twice a day declined 6.3 points less than did controls, indicating preserved cognition. Those taking LMTX monotherapy 125 mg twice a day declined 5.8 points less than did controls. On the ADCS-ADL, patients taking 75 mg twice a day scored 6.5 points higher than controls, indicating better function, and those taking 125 mg twice a day scored 6.9 points higher.

Lateral ventricular volume expansion on MRI was significantly less than that seen in controls. For those taking 75 mg twice a day, ventricular expansion was reduced by 38%, and for those taking 125 mg twice a day, expansion was reduced by 33%.

This indicates a decrease in the rate of brain atrophy, the press release said, and the finding was “confirmed by corresponding increases in the whole-brain volumes in the same patient groups.”

The press release also said that the imaging findings offer physiologic confirmation of the cognitive and functional findings. “This is the first treatment in which a clinical effect has been supported by evidence in delay of progression in brain atrophy shown by MRI scans.”

The missing number of patients who took LMTX monotherapy is key, however, in determining whether the positive effects in that group are real or a chance finding, according to Richard J. Caselli, MD, associate director and clinical core director of the Alzheimer’s Disease Center at the Mayo Clinic, Scottsdale, Ariz.

“Were the monotherapy results a fluke that washed out with bigger numbers or a meaningful effect? That needs to be clarified,” he said when asked to comment on the study. “Smaller ‘N’ trials can have skewed results due to random chances that mean nothing, and that is my fear. It’s unproven at this point but the burden of proof will rest on the investigators to replicate the positive outcome.”

The finding of a positive signal in monotherapy only is puzzling and also demands an explanation, said Michael Wolfe, PhD, a professor of neurology at Harvard University, Boston.

LMTX is a purified form of the dye methylene blue. Its method of action in preventing or dissolving tau tangles is not fully elucidated. A 2013 paper in a German chemistry journal, Angewandte Chemie, suggested that it works through oxidation to maintain the tau protein as a monomer, which prevents aggregation into filaments. There is no reason to think this pathway could intersect or interfere with any of the standard-of-care Alzheimer’s medications.

“There’s nothing obvious that comes to mind regarding interaction,” between the drug classes, Dr. Wolfe said in an interview. “We can’t say anything about this mechanistically. Any explanation here is just hand waving, I think.”

Dean Hartley, PhD, director of science initiatives at the Alzheimer’s Association, commented on the trial in a video interview at the Alzheimer’s Association International Conference 2016.

Neither Dr. Caselli nor Dr. Wolfe had relevant disclosures.

[email protected]

On Twitter @alz_gal

TORONTO – In 2011, President Barack Obama signed into law the National Alzheimer’s Project Act, with the lofty goal of preventing or effectively treating Alzheimer’s disease by 2025. A year later, a panel of leading researchers translated that goal into harsh reality: Reaching it would cost at least $2 billion each year. That level of funding would put Alzheimer’s research on the same footing as research on cancer, heart disease, and HIV – areas that have experienced rapid and sustained clinical progress.

But securing federal funding support has been a slow go. At the end of 2016, even with historic funding increases, the total allocation still fell short of $1 billion. That’s about to change for the better. The proposed 2017 budget, if approved, will boost the allocation to $1.4 billion.

What will that new money mean to researchers who’ve struggled for years to get grants? And what could it mean to doctors, patients, and families who still face a devastating disease with no cure, no prevention, and no effective treatments? Robert J. Egge, chief public policy officer for the Alzheimer’s Association, breaks it down in this video interview at the Alzheimer’s Association International Conference 2016.

[email protected]

On Twitter @alz_gal

TORONTO – In 2011, President Barack Obama signed into law the National Alzheimer’s Project Act, with the lofty goal of preventing or effectively treating Alzheimer’s disease by 2025. A year later, a panel of leading researchers translated that goal into harsh reality: Reaching it would cost at least $2 billion each year. That level of funding would put Alzheimer’s research on the same footing as research on cancer, heart disease, and HIV – areas that have experienced rapid and sustained clinical progress.

But securing federal funding support has been a slow go. At the end of 2016, even with historic funding increases, the total allocation still fell short of $1 billion. That’s about to change for the better. The proposed 2017 budget, if approved, will boost the allocation to $1.4 billion.

What will that new money mean to researchers who’ve struggled for years to get grants? And what could it mean to doctors, patients, and families who still face a devastating disease with no cure, no prevention, and no effective treatments? Robert J. Egge, chief public policy officer for the Alzheimer’s Association, breaks it down in this video interview at the Alzheimer’s Association International Conference 2016.

[email protected]

On Twitter @alz_gal

TORONTO – In 2011, President Barack Obama signed into law the National Alzheimer’s Project Act, with the lofty goal of preventing or effectively treating Alzheimer’s disease by 2025. A year later, a panel of leading researchers translated that goal into harsh reality: Reaching it would cost at least $2 billion each year. That level of funding would put Alzheimer’s research on the same footing as research on cancer, heart disease, and HIV – areas that have experienced rapid and sustained clinical progress.

But securing federal funding support has been a slow go. At the end of 2016, even with historic funding increases, the total allocation still fell short of $1 billion. That’s about to change for the better. The proposed 2017 budget, if approved, will boost the allocation to $1.4 billion.

What will that new money mean to researchers who’ve struggled for years to get grants? And what could it mean to doctors, patients, and families who still face a devastating disease with no cure, no prevention, and no effective treatments? Robert J. Egge, chief public policy officer for the Alzheimer’s Association, breaks it down in this video interview at the Alzheimer’s Association International Conference 2016.

[email protected]

On Twitter @alz_gal

TORONTO – The annual Medicare wellness visit offers patients and their doctors the chance to review a variety of health concerns, and includes a cognitive health checkup. It’s free for patients and fully reimbursable for physicians. But the visit is far underused, averaging about 14% uptake each year across the United States, according to Pamela Mink, PhD.

Dr. Mink and her colleagues at Minneapolis, Minn.–based Allina Health examined which patients used the visit during 2011-2015 in the Allina Health system. They found annual increases in usage, but by the end of the 5-year period it had been used at least once by only 44% of eligible patients despite some considerable outreach efforts. Those who did were most often white or Asian women who lived in urban areas and were younger than 74 years.

“There’s a real opportunity for tracking and identifying cognitive health issues early here, and it’s being missed,” Dr. Mink said during a press briefing at the Alzheimer’s Association International Conference 2016. “Improving this situation is going to require leadership from health systems, the clinicians administering the visit, and the patients themselves. It’s basic education: Clinicians need to know it’s reimbursable. Patients need to know it’s free, and that it’s a valuable opportunity to address health issues – including any cognitive impairment that may be developing – early.”

Dr. Mink is employed by Allina Health as a senior scientist.

[email protected]

On Twitter @alz_gal

TORONTO – The annual Medicare wellness visit offers patients and their doctors the chance to review a variety of health concerns, and includes a cognitive health checkup. It’s free for patients and fully reimbursable for physicians. But the visit is far underused, averaging about 14% uptake each year across the United States, according to Pamela Mink, PhD.

Dr. Mink and her colleagues at Minneapolis, Minn.–based Allina Health examined which patients used the visit during 2011-2015 in the Allina Health system. They found annual increases in usage, but by the end of the 5-year period it had been used at least once by only 44% of eligible patients despite some considerable outreach efforts. Those who did were most often white or Asian women who lived in urban areas and were younger than 74 years.

“There’s a real opportunity for tracking and identifying cognitive health issues early here, and it’s being missed,” Dr. Mink said during a press briefing at the Alzheimer’s Association International Conference 2016. “Improving this situation is going to require leadership from health systems, the clinicians administering the visit, and the patients themselves. It’s basic education: Clinicians need to know it’s reimbursable. Patients need to know it’s free, and that it’s a valuable opportunity to address health issues – including any cognitive impairment that may be developing – early.”

Dr. Mink is employed by Allina Health as a senior scientist.

[email protected]

On Twitter @alz_gal

TORONTO – The annual Medicare wellness visit offers patients and their doctors the chance to review a variety of health concerns, and includes a cognitive health checkup. It’s free for patients and fully reimbursable for physicians. But the visit is far underused, averaging about 14% uptake each year across the United States, according to Pamela Mink, PhD.

Dr. Mink and her colleagues at Minneapolis, Minn.–based Allina Health examined which patients used the visit during 2011-2015 in the Allina Health system. They found annual increases in usage, but by the end of the 5-year period it had been used at least once by only 44% of eligible patients despite some considerable outreach efforts. Those who did were most often white or Asian women who lived in urban areas and were younger than 74 years.

“There’s a real opportunity for tracking and identifying cognitive health issues early here, and it’s being missed,” Dr. Mink said during a press briefing at the Alzheimer’s Association International Conference 2016. “Improving this situation is going to require leadership from health systems, the clinicians administering the visit, and the patients themselves. It’s basic education: Clinicians need to know it’s reimbursable. Patients need to know it’s free, and that it’s a valuable opportunity to address health issues – including any cognitive impairment that may be developing – early.”

Dr. Mink is employed by Allina Health as a senior scientist.

[email protected]

On Twitter @alz_gal

TORONTO – In 2013, Medicare spent $2.6 billion on potentially avoidable hospitalizations for patients with Alzheimer’s disease and other dementias.

About half of these hospital visits – each of which cost Medicare around $7,000 – were for conditions that could have been effectively managed in primary care settings, Pei-Jung Lin, PhD, said at the Alzheimer’s Association International Conference 2016.

Half of the admissions were for chronic illnesses such as diabetes, hypertension, and asthma that are often poorly controlled as dementia progresses. The other half was for acute illnesses, said Dr. Lin, director of the Center for the Evaluation of Value and Risk in Health at Tufts University, Boston. But these admissions for acute conditions involved problems that could be treated on an outpatient basis if they’d been caught early – urinary tract infections, pneumonias, and dehydration.

“In 2013, 1 in 10 Alzheimer’s disease patients had at least one potentially avoidable hospitalization, and 1 in 7 hospital admissions among these patients (14%) was for a potentially avoidable condition,” she said during a press briefing.

Although the financial finding is striking, it isn’t the whole story, Dr. Lin said. Hospitalizations put patients at increased risk for infections, confusion, and delirium – any of which can initiate a downward clinical spiral that results in more intervention, more stress, and more cost.

“Not only are these incidences expensive, they can be dangerous for our patients. Being in the hospital is stressful for someone with little grasp of reality. Patients can become even more confused and disoriented. They’re at risk for hospital-acquired infections, which increase costs and caregiver stress, and decrease patient quality of life,” she said.

Dr. Lin and her team looked for potentially avoidable hospitalizations filed in 2013 among 2.75 million patients with Alzheimer’s and other dementias. The acute conditions included in the analysis were bacterial pneumonia, urinary tract infection, and dehydration, and chronic conditions were diabetes, cardiovascular diseases, and respiratory conditions.

About half these admissions (188,870; 47%) were for acute conditions, while the rest were for chronic conditions. About half of all the admissions also occurred in patients with late-stage disease, and these were the most expensive ones. Admissions for these late-stage patients accounted for 59% of the expenditures and cost Medicare $1.53 billion in 2013.

Claims data don’t offer the kind of details that allow a case-by-case review of how the admissions could have been prevented. But one message comes through loud and clear, Dr. Lin said.

“Comorbidity management is simply not optimal among many of our patients with Alzheimer’s disease. Many of these admissions, and much of this cost, could have been prevented with better ambulatory care and early, effective treatment.”

Dr. Richard Caselli, professor of neurology at the Mayo Clinic, Scottsdale, Ariz., commented on these issues in a video interview.

Dr. Lin had no financial disclosures.

[email protected]

On Twitter @alz_gal

TORONTO – In 2013, Medicare spent $2.6 billion on potentially avoidable hospitalizations for patients with Alzheimer’s disease and other dementias.

About half of these hospital visits – each of which cost Medicare around $7,000 – were for conditions that could have been effectively managed in primary care settings, Pei-Jung Lin, PhD, said at the Alzheimer’s Association International Conference 2016.

Half of the admissions were for chronic illnesses such as diabetes, hypertension, and asthma that are often poorly controlled as dementia progresses. The other half was for acute illnesses, said Dr. Lin, director of the Center for the Evaluation of Value and Risk in Health at Tufts University, Boston. But these admissions for acute conditions involved problems that could be treated on an outpatient basis if they’d been caught early – urinary tract infections, pneumonias, and dehydration.

“In 2013, 1 in 10 Alzheimer’s disease patients had at least one potentially avoidable hospitalization, and 1 in 7 hospital admissions among these patients (14%) was for a potentially avoidable condition,” she said during a press briefing.

Although the financial finding is striking, it isn’t the whole story, Dr. Lin said. Hospitalizations put patients at increased risk for infections, confusion, and delirium – any of which can initiate a downward clinical spiral that results in more intervention, more stress, and more cost.

“Not only are these incidences expensive, they can be dangerous for our patients. Being in the hospital is stressful for someone with little grasp of reality. Patients can become even more confused and disoriented. They’re at risk for hospital-acquired infections, which increase costs and caregiver stress, and decrease patient quality of life,” she said.

Dr. Lin and her team looked for potentially avoidable hospitalizations filed in 2013 among 2.75 million patients with Alzheimer’s and other dementias. The acute conditions included in the analysis were bacterial pneumonia, urinary tract infection, and dehydration, and chronic conditions were diabetes, cardiovascular diseases, and respiratory conditions.

About half these admissions (188,870; 47%) were for acute conditions, while the rest were for chronic conditions. About half of all the admissions also occurred in patients with late-stage disease, and these were the most expensive ones. Admissions for these late-stage patients accounted for 59% of the expenditures and cost Medicare $1.53 billion in 2013.

Claims data don’t offer the kind of details that allow a case-by-case review of how the admissions could have been prevented. But one message comes through loud and clear, Dr. Lin said.

“Comorbidity management is simply not optimal among many of our patients with Alzheimer’s disease. Many of these admissions, and much of this cost, could have been prevented with better ambulatory care and early, effective treatment.”

Dr. Richard Caselli, professor of neurology at the Mayo Clinic, Scottsdale, Ariz., commented on these issues in a video interview.

Dr. Lin had no financial disclosures.

[email protected]

On Twitter @alz_gal

TORONTO – In 2013, Medicare spent $2.6 billion on potentially avoidable hospitalizations for patients with Alzheimer’s disease and other dementias.

About half of these hospital visits – each of which cost Medicare around $7,000 – were for conditions that could have been effectively managed in primary care settings, Pei-Jung Lin, PhD, said at the Alzheimer’s Association International Conference 2016.

Half of the admissions were for chronic illnesses such as diabetes, hypertension, and asthma that are often poorly controlled as dementia progresses. The other half was for acute illnesses, said Dr. Lin, director of the Center for the Evaluation of Value and Risk in Health at Tufts University, Boston. But these admissions for acute conditions involved problems that could be treated on an outpatient basis if they’d been caught early – urinary tract infections, pneumonias, and dehydration.

“In 2013, 1 in 10 Alzheimer’s disease patients had at least one potentially avoidable hospitalization, and 1 in 7 hospital admissions among these patients (14%) was for a potentially avoidable condition,” she said during a press briefing.

Although the financial finding is striking, it isn’t the whole story, Dr. Lin said. Hospitalizations put patients at increased risk for infections, confusion, and delirium – any of which can initiate a downward clinical spiral that results in more intervention, more stress, and more cost.

“Not only are these incidences expensive, they can be dangerous for our patients. Being in the hospital is stressful for someone with little grasp of reality. Patients can become even more confused and disoriented. They’re at risk for hospital-acquired infections, which increase costs and caregiver stress, and decrease patient quality of life,” she said.

Dr. Lin and her team looked for potentially avoidable hospitalizations filed in 2013 among 2.75 million patients with Alzheimer’s and other dementias. The acute conditions included in the analysis were bacterial pneumonia, urinary tract infection, and dehydration, and chronic conditions were diabetes, cardiovascular diseases, and respiratory conditions.

About half these admissions (188,870; 47%) were for acute conditions, while the rest were for chronic conditions. About half of all the admissions also occurred in patients with late-stage disease, and these were the most expensive ones. Admissions for these late-stage patients accounted for 59% of the expenditures and cost Medicare $1.53 billion in 2013.

Claims data don’t offer the kind of details that allow a case-by-case review of how the admissions could have been prevented. But one message comes through loud and clear, Dr. Lin said.

“Comorbidity management is simply not optimal among many of our patients with Alzheimer’s disease. Many of these admissions, and much of this cost, could have been prevented with better ambulatory care and early, effective treatment.”

Dr. Richard Caselli, professor of neurology at the Mayo Clinic, Scottsdale, Ariz., commented on these issues in a video interview.

Dr. Lin had no financial disclosures.

[email protected]

On Twitter @alz_gal

TORONTO – A rare loss of function in a gene that influences gamma secretase trafficking has been found to reduce the risk of Alzheimer’s by up to 40%, even in people who are homozygous carriers of the apolipoprotein E (apo E) epsilon 4 allele.

The gene – Rab10 – is a member of a family of about 60 genes involved in intracellular protein transport, Keoni Kauwe, PhD, said at the Alzheimer’s Association International Conference 2016. In addition to influencing endocytosis, ciliary transport, phagosome maturation, and insulin transport, Rab10 appears to assist in the transport of gamma secretase to the cell membrane.

By studying a population of elders who appear resistant to developing Alzheimer’s, Dr. Kauwe of Brigham Young University, Provo, Utah, and his associates determined that many of them share a natural inhibition of Rab10 – a unique characteristic that strongly contributes to their resistance to Alzheimer’s, he said. This knocked-down function would decrease the amount of gamma secretase to reach the cell membrane, Dr. Kauwe reasoned. Therefore, the proteolytic pathway that creates amyloid beta (Abeta) should be attenuated, allowing much less amyloid beta to be created and, presumably, be around to initiate the amyloid cascade that sparks Alzheimer’s disease.

His study cohort was drawn from two large data sets of cognitively normal elders, including many who were apo E epsilon 4 homozygotes. About 5% of the sample showed the loss-of-function Rab10 variant, which Dr. Kauwe said conferred a 20%-40% risk reduction for developing Alzheimer’s disease.

To understand the gene’s effects on amyloid beta production, he both overexpressed it and silenced it in cell lines. Overexpression resulted in a significant increase in the Abeta42/Abeta40 ratio (a riskier Alzheimer’s profile), while silencing it resulted in a significant decrease in the Abeta42/Abeta40 ratio (a more favorable profile).

Rab10 could be a therapeutic target, similar to the PCSK9 gene that influences low-density lipoprotein creation, Dr. Kauwe said. Monoclonal antibodies that block PCSK9 have recently been developed after a similar observation that naturally occurring loss of functions in the gene was associated with lower LDL levels.

“We’re going to be looking at the same thing with Rab10,” he said. “We do think that Rab10 inhibition could be a big story. It’s a high-risk venture, certainly, but it could also be high reward.”

Dr. Kauwe discussed his findings in a video interview at the conference.

[email protected]

On Twitter @alz_gal

TORONTO – A rare loss of function in a gene that influences gamma secretase trafficking has been found to reduce the risk of Alzheimer’s by up to 40%, even in people who are homozygous carriers of the apolipoprotein E (apo E) epsilon 4 allele.

The gene – Rab10 – is a member of a family of about 60 genes involved in intracellular protein transport, Keoni Kauwe, PhD, said at the Alzheimer’s Association International Conference 2016. In addition to influencing endocytosis, ciliary transport, phagosome maturation, and insulin transport, Rab10 appears to assist in the transport of gamma secretase to the cell membrane.

By studying a population of elders who appear resistant to developing Alzheimer’s, Dr. Kauwe of Brigham Young University, Provo, Utah, and his associates determined that many of them share a natural inhibition of Rab10 – a unique characteristic that strongly contributes to their resistance to Alzheimer’s, he said. This knocked-down function would decrease the amount of gamma secretase to reach the cell membrane, Dr. Kauwe reasoned. Therefore, the proteolytic pathway that creates amyloid beta (Abeta) should be attenuated, allowing much less amyloid beta to be created and, presumably, be around to initiate the amyloid cascade that sparks Alzheimer’s disease.

His study cohort was drawn from two large data sets of cognitively normal elders, including many who were apo E epsilon 4 homozygotes. About 5% of the sample showed the loss-of-function Rab10 variant, which Dr. Kauwe said conferred a 20%-40% risk reduction for developing Alzheimer’s disease.

To understand the gene’s effects on amyloid beta production, he both overexpressed it and silenced it in cell lines. Overexpression resulted in a significant increase in the Abeta42/Abeta40 ratio (a riskier Alzheimer’s profile), while silencing it resulted in a significant decrease in the Abeta42/Abeta40 ratio (a more favorable profile).

Rab10 could be a therapeutic target, similar to the PCSK9 gene that influences low-density lipoprotein creation, Dr. Kauwe said. Monoclonal antibodies that block PCSK9 have recently been developed after a similar observation that naturally occurring loss of functions in the gene was associated with lower LDL levels.

“We’re going to be looking at the same thing with Rab10,” he said. “We do think that Rab10 inhibition could be a big story. It’s a high-risk venture, certainly, but it could also be high reward.”

Dr. Kauwe discussed his findings in a video interview at the conference.

[email protected]

On Twitter @alz_gal

TORONTO – A rare loss of function in a gene that influences gamma secretase trafficking has been found to reduce the risk of Alzheimer’s by up to 40%, even in people who are homozygous carriers of the apolipoprotein E (apo E) epsilon 4 allele.

The gene – Rab10 – is a member of a family of about 60 genes involved in intracellular protein transport, Keoni Kauwe, PhD, said at the Alzheimer’s Association International Conference 2016. In addition to influencing endocytosis, ciliary transport, phagosome maturation, and insulin transport, Rab10 appears to assist in the transport of gamma secretase to the cell membrane.

By studying a population of elders who appear resistant to developing Alzheimer’s, Dr. Kauwe of Brigham Young University, Provo, Utah, and his associates determined that many of them share a natural inhibition of Rab10 – a unique characteristic that strongly contributes to their resistance to Alzheimer’s, he said. This knocked-down function would decrease the amount of gamma secretase to reach the cell membrane, Dr. Kauwe reasoned. Therefore, the proteolytic pathway that creates amyloid beta (Abeta) should be attenuated, allowing much less amyloid beta to be created and, presumably, be around to initiate the amyloid cascade that sparks Alzheimer’s disease.

His study cohort was drawn from two large data sets of cognitively normal elders, including many who were apo E epsilon 4 homozygotes. About 5% of the sample showed the loss-of-function Rab10 variant, which Dr. Kauwe said conferred a 20%-40% risk reduction for developing Alzheimer’s disease.

To understand the gene’s effects on amyloid beta production, he both overexpressed it and silenced it in cell lines. Overexpression resulted in a significant increase in the Abeta42/Abeta40 ratio (a riskier Alzheimer’s profile), while silencing it resulted in a significant decrease in the Abeta42/Abeta40 ratio (a more favorable profile).

Rab10 could be a therapeutic target, similar to the PCSK9 gene that influences low-density lipoprotein creation, Dr. Kauwe said. Monoclonal antibodies that block PCSK9 have recently been developed after a similar observation that naturally occurring loss of functions in the gene was associated with lower LDL levels.

“We’re going to be looking at the same thing with Rab10,” he said. “We do think that Rab10 inhibition could be a big story. It’s a high-risk venture, certainly, but it could also be high reward.”

Dr. Kauwe discussed his findings in a video interview at the conference.

[email protected]

On Twitter @alz_gal

TORONTO – Hallucinations – especially auditory hallucinations – triple the risk that a risperidone-controlled Alzheimer’s patient with psychoses will relapse if the drug is withdrawn.

“I think the clinical impact we see here is that for patients with hallucinations, and particularly auditory hallucinations, antipsychotic discontinuation should be done very, very cautiously because they do have a very high risk of relapse,” Anjali Patel, DO, said at the Alzheimer’s Association International Conference 2016. “Close monitoring will be necessary and antipsychotic medications promptly reinstated if relapse occurs.”

The findings come from a responder analysis of an open-label study of risperidone (Risperdal) use in Alzheimer’s patients who express neuropsychiatric symptoms. The primary results of the multicenter Antipsychotic Discontinuation in Alzheimer’s Disease (ADAD) trial were published in 2012 (N Engl J Med. 2012;367:1497-507). The 48-week study administered open-label, flexible-dose risperidone for 16 weeks to 180 patients with Alzheimer’s dementia, with agitation and/or aggression. The patients in this study had a mean age of 79 years at baseline. Most (62%) were taking a cholinesterase inhibitor, and many took memantine (35%). Patients commonly used anxiolytics (17%) and antidepressants (24%). The mean Neuropsychiatric Inventory (NPI) score at baseline was 36. Patients were moderately impaired, with a mean Mini Mental State Exam score of 14.

At 16 weeks, patients who had not responded left the study. After 16 weeks of open-label treatment, 110 patients who had responded well continued the dosing schedule for 32 weeks, continued risperidone for 16 weeks and then went on placebo for 16 weeks, or were switched to placebo for 32 weeks. Discontinuation of risperidone was associated with a two- to four-fold increased risk of relapse over 16-32 weeks.

Dr. Patel of Columbia University, New York, presented the preplanned post-hoc analysis that examined the association between the 12 NPI symptom domains and the likelihood of relapse at week 32. In a univariate analysis, only hallucinations posted a significant association with discontinuation of risperidone. Hallucinations of any severity at baseline were present in 43 patients (39%). The relapse rates were similar among patients without baseline hallucinations (35%) and those with mild baseline hallucinations (37%). But 78% of those with severe hallucinations relapsed when risperidone was withdrawn.

Baseline hallucinations remained a strong predictor of relapse in a multivariate model as well, with a risk ratio of 2.96 for relapse among patients who had severe baseline hallucinations, compared with those with mild or no hallucinations. Age, gender, race, and nursing home placement had no significant impact on relapse rate.

Of the 17 patients with any baseline hallucinations who were switched to placebo, 13 (77%) relapsed, compared with 38% of the patients with hallucinations who continued risperidone (risk ratio, 1.98).

The risk for relapse was particularly high when the hallucinations were primarily auditory, Dr. Patel said. “In fact, visual hallucinations were not predictive of relapse.”

Among the 11 patients with severe baseline hallucinations, 10 relapsed when risperidone was withdrawn (91%; RR, 2.88), compared with 57% of patients with severe hallucinations who stayed on the drug (RR, 1.59).

The ADAD trial was funded by the National Institutes of Health and the Department of Veterans Affairs. Dr. Patel had no financial disclosures for the subanalysis.

TORONTO – Hallucinations – especially auditory hallucinations – triple the risk that a risperidone-controlled Alzheimer’s patient with psychoses will relapse if the drug is withdrawn.

“I think the clinical impact we see here is that for patients with hallucinations, and particularly auditory hallucinations, antipsychotic discontinuation should be done very, very cautiously because they do have a very high risk of relapse,” Anjali Patel, DO, said at the Alzheimer’s Association International Conference 2016. “Close monitoring will be necessary and antipsychotic medications promptly reinstated if relapse occurs.”

The findings come from a responder analysis of an open-label study of risperidone (Risperdal) use in Alzheimer’s patients who express neuropsychiatric symptoms. The primary results of the multicenter Antipsychotic Discontinuation in Alzheimer’s Disease (ADAD) trial were published in 2012 (N Engl J Med. 2012;367:1497-507). The 48-week study administered open-label, flexible-dose risperidone for 16 weeks to 180 patients with Alzheimer’s dementia, with agitation and/or aggression. The patients in this study had a mean age of 79 years at baseline. Most (62%) were taking a cholinesterase inhibitor, and many took memantine (35%). Patients commonly used anxiolytics (17%) and antidepressants (24%). The mean Neuropsychiatric Inventory (NPI) score at baseline was 36. Patients were moderately impaired, with a mean Mini Mental State Exam score of 14.

At 16 weeks, patients who had not responded left the study. After 16 weeks of open-label treatment, 110 patients who had responded well continued the dosing schedule for 32 weeks, continued risperidone for 16 weeks and then went on placebo for 16 weeks, or were switched to placebo for 32 weeks. Discontinuation of risperidone was associated with a two- to four-fold increased risk of relapse over 16-32 weeks.

Dr. Patel of Columbia University, New York, presented the preplanned post-hoc analysis that examined the association between the 12 NPI symptom domains and the likelihood of relapse at week 32. In a univariate analysis, only hallucinations posted a significant association with discontinuation of risperidone. Hallucinations of any severity at baseline were present in 43 patients (39%). The relapse rates were similar among patients without baseline hallucinations (35%) and those with mild baseline hallucinations (37%). But 78% of those with severe hallucinations relapsed when risperidone was withdrawn.

Baseline hallucinations remained a strong predictor of relapse in a multivariate model as well, with a risk ratio of 2.96 for relapse among patients who had severe baseline hallucinations, compared with those with mild or no hallucinations. Age, gender, race, and nursing home placement had no significant impact on relapse rate.

Of the 17 patients with any baseline hallucinations who were switched to placebo, 13 (77%) relapsed, compared with 38% of the patients with hallucinations who continued risperidone (risk ratio, 1.98).

The risk for relapse was particularly high when the hallucinations were primarily auditory, Dr. Patel said. “In fact, visual hallucinations were not predictive of relapse.”

Among the 11 patients with severe baseline hallucinations, 10 relapsed when risperidone was withdrawn (91%; RR, 2.88), compared with 57% of patients with severe hallucinations who stayed on the drug (RR, 1.59).

The ADAD trial was funded by the National Institutes of Health and the Department of Veterans Affairs. Dr. Patel had no financial disclosures for the subanalysis.

TORONTO – Hallucinations – especially auditory hallucinations – triple the risk that a risperidone-controlled Alzheimer’s patient with psychoses will relapse if the drug is withdrawn.

“I think the clinical impact we see here is that for patients with hallucinations, and particularly auditory hallucinations, antipsychotic discontinuation should be done very, very cautiously because they do have a very high risk of relapse,” Anjali Patel, DO, said at the Alzheimer’s Association International Conference 2016. “Close monitoring will be necessary and antipsychotic medications promptly reinstated if relapse occurs.”

The findings come from a responder analysis of an open-label study of risperidone (Risperdal) use in Alzheimer’s patients who express neuropsychiatric symptoms. The primary results of the multicenter Antipsychotic Discontinuation in Alzheimer’s Disease (ADAD) trial were published in 2012 (N Engl J Med. 2012;367:1497-507). The 48-week study administered open-label, flexible-dose risperidone for 16 weeks to 180 patients with Alzheimer’s dementia, with agitation and/or aggression. The patients in this study had a mean age of 79 years at baseline. Most (62%) were taking a cholinesterase inhibitor, and many took memantine (35%). Patients commonly used anxiolytics (17%) and antidepressants (24%). The mean Neuropsychiatric Inventory (NPI) score at baseline was 36. Patients were moderately impaired, with a mean Mini Mental State Exam score of 14.

At 16 weeks, patients who had not responded left the study. After 16 weeks of open-label treatment, 110 patients who had responded well continued the dosing schedule for 32 weeks, continued risperidone for 16 weeks and then went on placebo for 16 weeks, or were switched to placebo for 32 weeks. Discontinuation of risperidone was associated with a two- to four-fold increased risk of relapse over 16-32 weeks.

Dr. Patel of Columbia University, New York, presented the preplanned post-hoc analysis that examined the association between the 12 NPI symptom domains and the likelihood of relapse at week 32. In a univariate analysis, only hallucinations posted a significant association with discontinuation of risperidone. Hallucinations of any severity at baseline were present in 43 patients (39%). The relapse rates were similar among patients without baseline hallucinations (35%) and those with mild baseline hallucinations (37%). But 78% of those with severe hallucinations relapsed when risperidone was withdrawn.

Baseline hallucinations remained a strong predictor of relapse in a multivariate model as well, with a risk ratio of 2.96 for relapse among patients who had severe baseline hallucinations, compared with those with mild or no hallucinations. Age, gender, race, and nursing home placement had no significant impact on relapse rate.

Of the 17 patients with any baseline hallucinations who were switched to placebo, 13 (77%) relapsed, compared with 38% of the patients with hallucinations who continued risperidone (risk ratio, 1.98).

The risk for relapse was particularly high when the hallucinations were primarily auditory, Dr. Patel said. “In fact, visual hallucinations were not predictive of relapse.”

Among the 11 patients with severe baseline hallucinations, 10 relapsed when risperidone was withdrawn (91%; RR, 2.88), compared with 57% of patients with severe hallucinations who stayed on the drug (RR, 1.59).

The ADAD trial was funded by the National Institutes of Health and the Department of Veterans Affairs. Dr. Patel had no financial disclosures for the subanalysis.

TORONTO – Hallucinations – especially auditory hallucinations – triple the risk that a risperidone-controlled Alzheimer’s patient with psychoses will relapse if the drug is withdrawn.

“I think the clinical impact we see here is that for patients with hallucinations, and particularly auditory hallucinations, antipsychotic discontinuation should be done very, very cautiously because they do have a very high risk of relapse,” Anjali Patel, DO, said at the Alzheimer’s Association International Conference 2016. “Close monitoring will be necessary and antipsychotic medications promptly reinstated if relapse occurs.”

The findings come from a responder analysis of an open-label study of risperidone (Risperdal) use in Alzheimer’s patients who express neuropsychiatric symptoms. The primary results of the multicenter Antipsychotic Discontinuation in Alzheimer’s Disease (ADAD) trial were published in 2012 (N Engl J Med. 2012;367:1497-507). The 48-week study administered open-label, flexible-dose risperidone for 16 weeks to 180 patients with Alzheimer’s dementia, with agitation and/or aggression. The patients in this study had a mean age of 79 years at baseline. Most (62%) were taking a cholinesterase inhibitor, and many took memantine (35%). Patients commonly used anxiolytics (17%) and antidepressants (24%). The mean Neuropsychiatric Inventory (NPI) score at baseline was 36. Patients were moderately impaired, with a mean Mini Mental State Exam score of 14.

At 16 weeks, patients who had not responded left the study. After 16 weeks of open-label treatment, 110 patients who had responded well continued the dosing schedule for 32 weeks, continued risperidone for 16 weeks and then went on placebo for 16 weeks, or were switched to placebo for 32 weeks. Discontinuation of risperidone was associated with a two- to four-fold increased risk of relapse over 16-32 weeks.

Dr. Patel of Columbia University, New York, presented the preplanned post-hoc analysis that examined the association between the 12 NPI symptom domains and the likelihood of relapse at week 32. In a univariate analysis, only hallucinations posted a significant association with discontinuation of risperidone. Hallucinations of any severity at baseline were present in 43 patients (39%). The relapse rates were similar among patients without baseline hallucinations (35%) and those with mild baseline hallucinations (37%). But 78% of those with severe hallucinations relapsed when risperidone was withdrawn.

Baseline hallucinations remained a strong predictor of relapse in a multivariate model as well, with a risk ratio of 2.96 for relapse among patients who had severe baseline hallucinations, compared with those with mild or no hallucinations. Age, gender, race, and nursing home placement had no significant impact on relapse rate.

Of the 17 patients with any baseline hallucinations who were switched to placebo, 13 (77%) relapsed, compared with 38% of the patients with hallucinations who continued risperidone (risk ratio, 1.98).

The risk for relapse was particularly high when the hallucinations were primarily auditory, Dr. Patel said. “In fact, visual hallucinations were not predictive of relapse.”

Among the 11 patients with severe baseline hallucinations, 10 relapsed when risperidone was withdrawn (91%; RR, 2.88), compared with 57% of patients with severe hallucinations who stayed on the drug (RR, 1.59).

The ADAD trial was funded by the National Institutes of Health and the Department of Veterans Affairs. Dr. Patel had no financial disclosures for the subanalysis.

[email protected]

On Twitter @alz_gal

TORONTO – Hallucinations – especially auditory hallucinations – triple the risk that a risperidone-controlled Alzheimer’s patient with psychoses will relapse if the drug is withdrawn.

“I think the clinical impact we see here is that for patients with hallucinations, and particularly auditory hallucinations, antipsychotic discontinuation should be done very, very cautiously because they do have a very high risk of relapse,” Anjali Patel, DO, said at the Alzheimer’s Association International Conference 2016. “Close monitoring will be necessary and antipsychotic medications promptly reinstated if relapse occurs.”

The findings come from a responder analysis of an open-label study of risperidone (Risperdal) use in Alzheimer’s patients who express neuropsychiatric symptoms. The primary results of the multicenter Antipsychotic Discontinuation in Alzheimer’s Disease (ADAD) trial were published in 2012 (N Engl J Med. 2012;367:1497-507). The 48-week study administered open-label, flexible-dose risperidone for 16 weeks to 180 patients with Alzheimer’s dementia, with agitation and/or aggression. The patients in this study had a mean age of 79 years at baseline. Most (62%) were taking a cholinesterase inhibitor, and many took memantine (35%). Patients commonly used anxiolytics (17%) and antidepressants (24%). The mean Neuropsychiatric Inventory (NPI) score at baseline was 36. Patients were moderately impaired, with a mean Mini Mental State Exam score of 14.

At 16 weeks, patients who had not responded left the study. After 16 weeks of open-label treatment, 110 patients who had responded well continued the dosing schedule for 32 weeks, continued risperidone for 16 weeks and then went on placebo for 16 weeks, or were switched to placebo for 32 weeks. Discontinuation of risperidone was associated with a two- to four-fold increased risk of relapse over 16-32 weeks.

Dr. Patel of Columbia University, New York, presented the preplanned post-hoc analysis that examined the association between the 12 NPI symptom domains and the likelihood of relapse at week 32. In a univariate analysis, only hallucinations posted a significant association with discontinuation of risperidone. Hallucinations of any severity at baseline were present in 43 patients (39%). The relapse rates were similar among patients without baseline hallucinations (35%) and those with mild baseline hallucinations (37%). But 78% of those with severe hallucinations relapsed when risperidone was withdrawn.

Baseline hallucinations remained a strong predictor of relapse in a multivariate model as well, with a risk ratio of 2.96 for relapse among patients who had severe baseline hallucinations, compared with those with mild or no hallucinations. Age, gender, race, and nursing home placement had no significant impact on relapse rate.

Of the 17 patients with any baseline hallucinations who were switched to placebo, 13 (77%) relapsed, compared with 38% of the patients with hallucinations who continued risperidone (risk ratio, 1.98).

The risk for relapse was particularly high when the hallucinations were primarily auditory, Dr. Patel said. “In fact, visual hallucinations were not predictive of relapse.”

Among the 11 patients with severe baseline hallucinations, 10 relapsed when risperidone was withdrawn (91%; RR, 2.88), compared with 57% of patients with severe hallucinations who stayed on the drug (RR, 1.59).

The ADAD trial was funded by the National Institutes of Health and the Department of Veterans Affairs. Dr. Patel had no financial disclosures for the subanalysis.

[email protected]

On Twitter @alz_gal

TORONTO – Hallucinations – especially auditory hallucinations – triple the risk that a risperidone-controlled Alzheimer’s patient with psychoses will relapse if the drug is withdrawn.

“I think the clinical impact we see here is that for patients with hallucinations, and particularly auditory hallucinations, antipsychotic discontinuation should be done very, very cautiously because they do have a very high risk of relapse,” Anjali Patel, DO, said at the Alzheimer’s Association International Conference 2016. “Close monitoring will be necessary and antipsychotic medications promptly reinstated if relapse occurs.”

The findings come from a responder analysis of an open-label study of risperidone (Risperdal) use in Alzheimer’s patients who express neuropsychiatric symptoms. The primary results of the multicenter Antipsychotic Discontinuation in Alzheimer’s Disease (ADAD) trial were published in 2012 (N Engl J Med. 2012;367:1497-507). The 48-week study administered open-label, flexible-dose risperidone for 16 weeks to 180 patients with Alzheimer’s dementia, with agitation and/or aggression. The patients in this study had a mean age of 79 years at baseline. Most (62%) were taking a cholinesterase inhibitor, and many took memantine (35%). Patients commonly used anxiolytics (17%) and antidepressants (24%). The mean Neuropsychiatric Inventory (NPI) score at baseline was 36. Patients were moderately impaired, with a mean Mini Mental State Exam score of 14.

At 16 weeks, patients who had not responded left the study. After 16 weeks of open-label treatment, 110 patients who had responded well continued the dosing schedule for 32 weeks, continued risperidone for 16 weeks and then went on placebo for 16 weeks, or were switched to placebo for 32 weeks. Discontinuation of risperidone was associated with a two- to four-fold increased risk of relapse over 16-32 weeks.

Dr. Patel of Columbia University, New York, presented the preplanned post-hoc analysis that examined the association between the 12 NPI symptom domains and the likelihood of relapse at week 32. In a univariate analysis, only hallucinations posted a significant association with discontinuation of risperidone. Hallucinations of any severity at baseline were present in 43 patients (39%). The relapse rates were similar among patients without baseline hallucinations (35%) and those with mild baseline hallucinations (37%). But 78% of those with severe hallucinations relapsed when risperidone was withdrawn.

Baseline hallucinations remained a strong predictor of relapse in a multivariate model as well, with a risk ratio of 2.96 for relapse among patients who had severe baseline hallucinations, compared with those with mild or no hallucinations. Age, gender, race, and nursing home placement had no significant impact on relapse rate.

Of the 17 patients with any baseline hallucinations who were switched to placebo, 13 (77%) relapsed, compared with 38% of the patients with hallucinations who continued risperidone (risk ratio, 1.98).

The risk for relapse was particularly high when the hallucinations were primarily auditory, Dr. Patel said. “In fact, visual hallucinations were not predictive of relapse.”

Among the 11 patients with severe baseline hallucinations, 10 relapsed when risperidone was withdrawn (91%; RR, 2.88), compared with 57% of patients with severe hallucinations who stayed on the drug (RR, 1.59).

The ADAD trial was funded by the National Institutes of Health and the Department of Veterans Affairs. Dr. Patel had no financial disclosures for the subanalysis.

[email protected]

On Twitter @alz_gal