AAIC 2013

BOSTON – Long-acting intranasal insulin imparted a significant memory boost to patients with mild cognitive impairment or Alzheimer’s disease who carried a high-risk allele for the disease in a randomized, placebo-controlled trial.

"It’s a very interesting result," principal study investigator Suzanne Craft, Ph.D., of Wake Forest University, Winston-Salem, N.C., said at the Alzheimer’s Association International Conference 2013. "It’s not what we have previously observed with regular insulin, and so far it’s very difficult to find a treatment that benefits these patients."

Intranasal insulin travels quickly up the trigeminal and olfactory nerves and penetrates the blood-brain barrier within 15-30 minutes. Dr. Craft has previously examined the effect of regular insulin delivered intranasally. In those studies, patients had improved cognition and cerebral glucose metabolism. The treatment also modulated levels of biomarkers in cerebrospinal fluid. But because regular insulin’s effect peaks shortly after administration and falls off over 8 hours, she and her colleagues reasoned that long-acting insulin might confer improved cognitive results. "The longer-acting insulins mimic basal insulin, which remains mildly elevated even postprandially," she said.

Michele G. Sullivan/IMNG Medical Media

The trial, dubbed SNIFF-LONG (Study of Nasal Insulin to Fight Forgetfulness), gave 20 or 40 IU of long-acting insulin or placebo to 60 patients (mean age, 72 years) with mild cognitive impairment (MCI) or Alzheimer’s disease. Most (39) had a diagnosis of MCI, and the rest had Alzheimer’s. Patients had a mean Mini-Mental State Examination score of 26. Thirty carried the apolipoprotein E (apo E) epsilon 4 allele, putting them at a very high risk for developing Alzheimer’s.

The patients had an average insulin resistance index of 2.8. At baseline, 14 patients were taking an acetylcholinesterase inhibitor or memantine. The primary endpoints were scores on a test of composite memory; secondary endpoints included scores on pattern separation and visual memory counting tests. There was also a planned subgroup analysis that examined results by apo E epsilon 4 status.

Intranasal insulin and placebo were administered once a day for 3 weeks via a nasal delivery device that has been specially developed for these trials. The group underwent memory testing at baseline and after the treatment period.

Overall, there were no significant improvements on the primary endpoint measuring a composite of scores on verbal memory tests (the Story Recall Test and the Buschke Selective Reminding Test) in patients taking either the 20- or 40-IU dose.

However, in a planned subgroup analysis, patients carrying the apo E epsilon 4 allele performed significantly better than did those without it. Apo E epsilon 4 noncarriers declined about 1 point relative to their baseline score, while carriers improved about 1 point, said Dr. Craft, who conducted the trial when she was professor of psychiatry and behavioral sciences at the University of Washington, Seattle, and director of the Memory Disorders Clinic at the American Lakes division of the VA Puget Sound Health Care System. At Wake Forest, she is a professor of gerontology and geriatric medicine.

"This was a very robust result that characterized the vast majority of patients in each group," she noted.

The results were also examined by the level of insulin resistance. "In those with the highest insulin resistance, the 40-IU dose showed a significant benefit [of about 1 point]; and those without insulin resistance did not, and, in fact, showed memory decline" of about 1 point, she said.

Both patient groups responded well to the 40-IU dose in the secondary endpoints of scores on tests of pattern separation (Benton Visual Retention Rest-Recognition) and visual memory counting (Dot Counting Test). "There were no interactions with [apo E epsilon 4] status or insulin resistance. Instead we saw a nice, robust improvement on both the pattern separation and dot counting tests" for patients taking that dose.

Dr. Craft will soon be recruiting patients for a 1-year study called SNIFF. This will include 240 subjects randomized to 20 IU of insulin (Humilin) inhaled twice daily (total dose, 40 IU) or placebo. At the end of the first 12 months, insulin will be given open-label to all participants for an additional 6 months. Tests of cognition are planned at baseline and at 3, 6, 9, 12, and 15 months. Memory and changes in daily functioning will be assessed at 6, 12, and 18 months.

The study was sponsored by the University of Washington and the National Institute on Aging. Dr. Craft had no financial disclosures.

[email protected]

On Twitter @Alz_Gal

BOSTON – Long-acting intranasal insulin imparted a significant memory boost to patients with mild cognitive impairment or Alzheimer’s disease who carried a high-risk allele for the disease in a randomized, placebo-controlled trial.

"It’s a very interesting result," principal study investigator Suzanne Craft, Ph.D., of Wake Forest University, Winston-Salem, N.C., said at the Alzheimer’s Association International Conference 2013. "It’s not what we have previously observed with regular insulin, and so far it’s very difficult to find a treatment that benefits these patients."

Intranasal insulin travels quickly up the trigeminal and olfactory nerves and penetrates the blood-brain barrier within 15-30 minutes. Dr. Craft has previously examined the effect of regular insulin delivered intranasally. In those studies, patients had improved cognition and cerebral glucose metabolism. The treatment also modulated levels of biomarkers in cerebrospinal fluid. But because regular insulin’s effect peaks shortly after administration and falls off over 8 hours, she and her colleagues reasoned that long-acting insulin might confer improved cognitive results. "The longer-acting insulins mimic basal insulin, which remains mildly elevated even postprandially," she said.

Michele G. Sullivan/IMNG Medical Media

The trial, dubbed SNIFF-LONG (Study of Nasal Insulin to Fight Forgetfulness), gave 20 or 40 IU of long-acting insulin or placebo to 60 patients (mean age, 72 years) with mild cognitive impairment (MCI) or Alzheimer’s disease. Most (39) had a diagnosis of MCI, and the rest had Alzheimer’s. Patients had a mean Mini-Mental State Examination score of 26. Thirty carried the apolipoprotein E (apo E) epsilon 4 allele, putting them at a very high risk for developing Alzheimer’s.

The patients had an average insulin resistance index of 2.8. At baseline, 14 patients were taking an acetylcholinesterase inhibitor or memantine. The primary endpoints were scores on a test of composite memory; secondary endpoints included scores on pattern separation and visual memory counting tests. There was also a planned subgroup analysis that examined results by apo E epsilon 4 status.

Intranasal insulin and placebo were administered once a day for 3 weeks via a nasal delivery device that has been specially developed for these trials. The group underwent memory testing at baseline and after the treatment period.

Overall, there were no significant improvements on the primary endpoint measuring a composite of scores on verbal memory tests (the Story Recall Test and the Buschke Selective Reminding Test) in patients taking either the 20- or 40-IU dose.

However, in a planned subgroup analysis, patients carrying the apo E epsilon 4 allele performed significantly better than did those without it. Apo E epsilon 4 noncarriers declined about 1 point relative to their baseline score, while carriers improved about 1 point, said Dr. Craft, who conducted the trial when she was professor of psychiatry and behavioral sciences at the University of Washington, Seattle, and director of the Memory Disorders Clinic at the American Lakes division of the VA Puget Sound Health Care System. At Wake Forest, she is a professor of gerontology and geriatric medicine.

"This was a very robust result that characterized the vast majority of patients in each group," she noted.

The results were also examined by the level of insulin resistance. "In those with the highest insulin resistance, the 40-IU dose showed a significant benefit [of about 1 point]; and those without insulin resistance did not, and, in fact, showed memory decline" of about 1 point, she said.

Both patient groups responded well to the 40-IU dose in the secondary endpoints of scores on tests of pattern separation (Benton Visual Retention Rest-Recognition) and visual memory counting (Dot Counting Test). "There were no interactions with [apo E epsilon 4] status or insulin resistance. Instead we saw a nice, robust improvement on both the pattern separation and dot counting tests" for patients taking that dose.

Dr. Craft will soon be recruiting patients for a 1-year study called SNIFF. This will include 240 subjects randomized to 20 IU of insulin (Humilin) inhaled twice daily (total dose, 40 IU) or placebo. At the end of the first 12 months, insulin will be given open-label to all participants for an additional 6 months. Tests of cognition are planned at baseline and at 3, 6, 9, 12, and 15 months. Memory and changes in daily functioning will be assessed at 6, 12, and 18 months.

The study was sponsored by the University of Washington and the National Institute on Aging. Dr. Craft had no financial disclosures.

[email protected]

On Twitter @Alz_Gal

BOSTON – Long-acting intranasal insulin imparted a significant memory boost to patients with mild cognitive impairment or Alzheimer’s disease who carried a high-risk allele for the disease in a randomized, placebo-controlled trial.

"It’s a very interesting result," principal study investigator Suzanne Craft, Ph.D., of Wake Forest University, Winston-Salem, N.C., said at the Alzheimer’s Association International Conference 2013. "It’s not what we have previously observed with regular insulin, and so far it’s very difficult to find a treatment that benefits these patients."

Intranasal insulin travels quickly up the trigeminal and olfactory nerves and penetrates the blood-brain barrier within 15-30 minutes. Dr. Craft has previously examined the effect of regular insulin delivered intranasally. In those studies, patients had improved cognition and cerebral glucose metabolism. The treatment also modulated levels of biomarkers in cerebrospinal fluid. But because regular insulin’s effect peaks shortly after administration and falls off over 8 hours, she and her colleagues reasoned that long-acting insulin might confer improved cognitive results. "The longer-acting insulins mimic basal insulin, which remains mildly elevated even postprandially," she said.

Michele G. Sullivan/IMNG Medical Media

The trial, dubbed SNIFF-LONG (Study of Nasal Insulin to Fight Forgetfulness), gave 20 or 40 IU of long-acting insulin or placebo to 60 patients (mean age, 72 years) with mild cognitive impairment (MCI) or Alzheimer’s disease. Most (39) had a diagnosis of MCI, and the rest had Alzheimer’s. Patients had a mean Mini-Mental State Examination score of 26. Thirty carried the apolipoprotein E (apo E) epsilon 4 allele, putting them at a very high risk for developing Alzheimer’s.

The patients had an average insulin resistance index of 2.8. At baseline, 14 patients were taking an acetylcholinesterase inhibitor or memantine. The primary endpoints were scores on a test of composite memory; secondary endpoints included scores on pattern separation and visual memory counting tests. There was also a planned subgroup analysis that examined results by apo E epsilon 4 status.

Intranasal insulin and placebo were administered once a day for 3 weeks via a nasal delivery device that has been specially developed for these trials. The group underwent memory testing at baseline and after the treatment period.

Overall, there were no significant improvements on the primary endpoint measuring a composite of scores on verbal memory tests (the Story Recall Test and the Buschke Selective Reminding Test) in patients taking either the 20- or 40-IU dose.

However, in a planned subgroup analysis, patients carrying the apo E epsilon 4 allele performed significantly better than did those without it. Apo E epsilon 4 noncarriers declined about 1 point relative to their baseline score, while carriers improved about 1 point, said Dr. Craft, who conducted the trial when she was professor of psychiatry and behavioral sciences at the University of Washington, Seattle, and director of the Memory Disorders Clinic at the American Lakes division of the VA Puget Sound Health Care System. At Wake Forest, she is a professor of gerontology and geriatric medicine.

"This was a very robust result that characterized the vast majority of patients in each group," she noted.

The results were also examined by the level of insulin resistance. "In those with the highest insulin resistance, the 40-IU dose showed a significant benefit [of about 1 point]; and those without insulin resistance did not, and, in fact, showed memory decline" of about 1 point, she said.

Both patient groups responded well to the 40-IU dose in the secondary endpoints of scores on tests of pattern separation (Benton Visual Retention Rest-Recognition) and visual memory counting (Dot Counting Test). "There were no interactions with [apo E epsilon 4] status or insulin resistance. Instead we saw a nice, robust improvement on both the pattern separation and dot counting tests" for patients taking that dose.

Dr. Craft will soon be recruiting patients for a 1-year study called SNIFF. This will include 240 subjects randomized to 20 IU of insulin (Humilin) inhaled twice daily (total dose, 40 IU) or placebo. At the end of the first 12 months, insulin will be given open-label to all participants for an additional 6 months. Tests of cognition are planned at baseline and at 3, 6, 9, 12, and 15 months. Memory and changes in daily functioning will be assessed at 6, 12, and 18 months.

The study was sponsored by the University of Washington and the National Institute on Aging. Dr. Craft had no financial disclosures.

[email protected]

On Twitter @Alz_Gal

BOSTON – A drug that blocks the formation of two brain-toxic amyloid beta peptides cleared most of the protein fragments from cerebrospinal fluid in patients with mild to moderate Alzheimer’s disease who took it in a 7-day phase I study.

The CSF load of amyloid beta 40 (Abeta40) dropped by a mean of 90% and that of Abeta42 by a mean of 86%, compared with a placebo group, Dr. Mark S. Forman reported at the Alzheimer’s Association International Conference 2013.

The drug, called MK-8931, is an inhibitor of the beta-secretase 1 enzyme (BACE1), which is also known as beta-site amyloid precursor protein (APP) cleaving enzyme 1. It changes the point at which the APP splits into the Abeta40 and Abeta42 peptide fragments. Researchers hope this alteration might prevent the proteins from forming, and so prevent the buildup of amyloid brain plaques that is a diagnostic hallmark of Alzheimer’s disease.

The placebo-controlled study randomized 30 subjects to three dosage groups (12, 40, and 60 mg) of eight patients each and a placebo group of six patients. The medications were administered once daily for 7 days.

Patients underwent lumbar puncture at baseline to assess CSF levels of Abeta40 and Abeta42. Samples were also drawn hourly for 36 hours after the last dose was administered.

"There was a profound, steady-state reduction in CSF Abeta peptides," Dr. Forman said. The reductions were similar to the results of a prior safety study performed in 40 healthy young adults.

Adverse events reported in two or more subjects in at least one dose group included headache, dizziness, nausea, vomiting, insomnia, and back pain. All adverse events were generally mild to moderate in intensity and transient in duration. No dose-dependent increase in the incidence of adverse events was observed.

The study didn’t examine any cognitive outcomes, Dr. Forman said in an interview. Those will be assessed in the next phase of development of MK-8931 – a phase II/III study called EPOCH, which began recruiting subjects in December 2012. The 78-week trial aims to enroll up to 1,700 patients with mild to moderate Alzheimer’s, randomizing them to the 12-, 40-, and 60-mg doses.

EPOCH’s primary endpoints are changes in the cognitive subscale score of the ADAS-Cog (Alzheimer’s Disease Assessment Scale) and the change from baseline in the score of the ADCS-ADL (Alzheimer’s Disease Cooperative Study – Activities of Daily Living) scale.

So far, manipulating APP to inhibit toxic amyloid production has been difficult. Earlier this year, Eli Lilly pulled the plug on its investigational BACE1 inhibitor, LY2886721, because of abnormal liver enzymes identified during routine monitoring of subjects taking it.

Safety concerns also caused Lilly to yank semagacestat from development in 2010. Semagacestat was also designed to change the APP cleavage point, but it targeted gamma-secretase instead of beta-secretase. Although the drug decreased CSF levels of Abeta42 by up to 65%, patients who took it actually had a significantly greater decline in cognition and function than did the placebo group. They also had a slight increase in skin cancers.

"One thing we are really concerned about is the long-term data from the semagacestat trial, where people actually got worse instead of better," Dr. Forman said. "We don’t know if that’s a reflection of some off-target activity or reducing amyloid in the brain. What will long-term BACE inhibition do? It’s an unknown. But we think the potential upsides outweigh the risks with this compound."

In an interview, Maria Carillo, Ph.D., agreed. "I’m excited that BACE1 is being pursued as an earlier intervention in the amyloid process. It will help prove that the amyloid hypothesis is worth pursing and give us an additional amyloid strategy."

Because Alzheimer’s seems to deliver a number of pathologic hits, effectively treating it will call for a varied armamentarium, said Dr. Carillo, vice president of medical and scientific relations for the Alzheimer’s Association. "At the end of the day, we have to know how to tackle all of them – tau, amyloids, inflammation, and energy pathways."

Merck funded the study of MK-8931. Dr. Forman is the company’s director of clinical research.

[email protected]

On Twitter @Alz_Gal

BOSTON – A drug that blocks the formation of two brain-toxic amyloid beta peptides cleared most of the protein fragments from cerebrospinal fluid in patients with mild to moderate Alzheimer’s disease who took it in a 7-day phase I study.

The CSF load of amyloid beta 40 (Abeta40) dropped by a mean of 90% and that of Abeta42 by a mean of 86%, compared with a placebo group, Dr. Mark S. Forman reported at the Alzheimer’s Association International Conference 2013.

The drug, called MK-8931, is an inhibitor of the beta-secretase 1 enzyme (BACE1), which is also known as beta-site amyloid precursor protein (APP) cleaving enzyme 1. It changes the point at which the APP splits into the Abeta40 and Abeta42 peptide fragments. Researchers hope this alteration might prevent the proteins from forming, and so prevent the buildup of amyloid brain plaques that is a diagnostic hallmark of Alzheimer’s disease.

The placebo-controlled study randomized 30 subjects to three dosage groups (12, 40, and 60 mg) of eight patients each and a placebo group of six patients. The medications were administered once daily for 7 days.

Patients underwent lumbar puncture at baseline to assess CSF levels of Abeta40 and Abeta42. Samples were also drawn hourly for 36 hours after the last dose was administered.

"There was a profound, steady-state reduction in CSF Abeta peptides," Dr. Forman said. The reductions were similar to the results of a prior safety study performed in 40 healthy young adults.

Adverse events reported in two or more subjects in at least one dose group included headache, dizziness, nausea, vomiting, insomnia, and back pain. All adverse events were generally mild to moderate in intensity and transient in duration. No dose-dependent increase in the incidence of adverse events was observed.

The study didn’t examine any cognitive outcomes, Dr. Forman said in an interview. Those will be assessed in the next phase of development of MK-8931 – a phase II/III study called EPOCH, which began recruiting subjects in December 2012. The 78-week trial aims to enroll up to 1,700 patients with mild to moderate Alzheimer’s, randomizing them to the 12-, 40-, and 60-mg doses.

EPOCH’s primary endpoints are changes in the cognitive subscale score of the ADAS-Cog (Alzheimer’s Disease Assessment Scale) and the change from baseline in the score of the ADCS-ADL (Alzheimer’s Disease Cooperative Study – Activities of Daily Living) scale.

So far, manipulating APP to inhibit toxic amyloid production has been difficult. Earlier this year, Eli Lilly pulled the plug on its investigational BACE1 inhibitor, LY2886721, because of abnormal liver enzymes identified during routine monitoring of subjects taking it.

Safety concerns also caused Lilly to yank semagacestat from development in 2010. Semagacestat was also designed to change the APP cleavage point, but it targeted gamma-secretase instead of beta-secretase. Although the drug decreased CSF levels of Abeta42 by up to 65%, patients who took it actually had a significantly greater decline in cognition and function than did the placebo group. They also had a slight increase in skin cancers.

"One thing we are really concerned about is the long-term data from the semagacestat trial, where people actually got worse instead of better," Dr. Forman said. "We don’t know if that’s a reflection of some off-target activity or reducing amyloid in the brain. What will long-term BACE inhibition do? It’s an unknown. But we think the potential upsides outweigh the risks with this compound."

In an interview, Maria Carillo, Ph.D., agreed. "I’m excited that BACE1 is being pursued as an earlier intervention in the amyloid process. It will help prove that the amyloid hypothesis is worth pursing and give us an additional amyloid strategy."

Because Alzheimer’s seems to deliver a number of pathologic hits, effectively treating it will call for a varied armamentarium, said Dr. Carillo, vice president of medical and scientific relations for the Alzheimer’s Association. "At the end of the day, we have to know how to tackle all of them – tau, amyloids, inflammation, and energy pathways."

Merck funded the study of MK-8931. Dr. Forman is the company’s director of clinical research.

[email protected]

On Twitter @Alz_Gal

BOSTON – A drug that blocks the formation of two brain-toxic amyloid beta peptides cleared most of the protein fragments from cerebrospinal fluid in patients with mild to moderate Alzheimer’s disease who took it in a 7-day phase I study.

The CSF load of amyloid beta 40 (Abeta40) dropped by a mean of 90% and that of Abeta42 by a mean of 86%, compared with a placebo group, Dr. Mark S. Forman reported at the Alzheimer’s Association International Conference 2013.

The drug, called MK-8931, is an inhibitor of the beta-secretase 1 enzyme (BACE1), which is also known as beta-site amyloid precursor protein (APP) cleaving enzyme 1. It changes the point at which the APP splits into the Abeta40 and Abeta42 peptide fragments. Researchers hope this alteration might prevent the proteins from forming, and so prevent the buildup of amyloid brain plaques that is a diagnostic hallmark of Alzheimer’s disease.

The placebo-controlled study randomized 30 subjects to three dosage groups (12, 40, and 60 mg) of eight patients each and a placebo group of six patients. The medications were administered once daily for 7 days.

Patients underwent lumbar puncture at baseline to assess CSF levels of Abeta40 and Abeta42. Samples were also drawn hourly for 36 hours after the last dose was administered.

"There was a profound, steady-state reduction in CSF Abeta peptides," Dr. Forman said. The reductions were similar to the results of a prior safety study performed in 40 healthy young adults.

Adverse events reported in two or more subjects in at least one dose group included headache, dizziness, nausea, vomiting, insomnia, and back pain. All adverse events were generally mild to moderate in intensity and transient in duration. No dose-dependent increase in the incidence of adverse events was observed.

The study didn’t examine any cognitive outcomes, Dr. Forman said in an interview. Those will be assessed in the next phase of development of MK-8931 – a phase II/III study called EPOCH, which began recruiting subjects in December 2012. The 78-week trial aims to enroll up to 1,700 patients with mild to moderate Alzheimer’s, randomizing them to the 12-, 40-, and 60-mg doses.

EPOCH’s primary endpoints are changes in the cognitive subscale score of the ADAS-Cog (Alzheimer’s Disease Assessment Scale) and the change from baseline in the score of the ADCS-ADL (Alzheimer’s Disease Cooperative Study – Activities of Daily Living) scale.

So far, manipulating APP to inhibit toxic amyloid production has been difficult. Earlier this year, Eli Lilly pulled the plug on its investigational BACE1 inhibitor, LY2886721, because of abnormal liver enzymes identified during routine monitoring of subjects taking it.

Safety concerns also caused Lilly to yank semagacestat from development in 2010. Semagacestat was also designed to change the APP cleavage point, but it targeted gamma-secretase instead of beta-secretase. Although the drug decreased CSF levels of Abeta42 by up to 65%, patients who took it actually had a significantly greater decline in cognition and function than did the placebo group. They also had a slight increase in skin cancers.

"One thing we are really concerned about is the long-term data from the semagacestat trial, where people actually got worse instead of better," Dr. Forman said. "We don’t know if that’s a reflection of some off-target activity or reducing amyloid in the brain. What will long-term BACE inhibition do? It’s an unknown. But we think the potential upsides outweigh the risks with this compound."

In an interview, Maria Carillo, Ph.D., agreed. "I’m excited that BACE1 is being pursued as an earlier intervention in the amyloid process. It will help prove that the amyloid hypothesis is worth pursing and give us an additional amyloid strategy."

Because Alzheimer’s seems to deliver a number of pathologic hits, effectively treating it will call for a varied armamentarium, said Dr. Carillo, vice president of medical and scientific relations for the Alzheimer’s Association. "At the end of the day, we have to know how to tackle all of them – tau, amyloids, inflammation, and energy pathways."

Merck funded the study of MK-8931. Dr. Forman is the company’s director of clinical research.

[email protected]

On Twitter @Alz_Gal

BOSTON – Patients with mild cognitive impairment had significant improvement in both executive function and verbal memory when they were treated with CHF5074, an experimental gamma-secretase modulator that investigators claim has the potential to partially restore the brain’s innate immune response, investigators reported at Alzheimer’s Association International Conference 2013.

Among 32 patients with mild cognitive impairment (MCI) who reached 64 weeks of follow-up in an open-label extension of a double-blind, placebo-controlled trial, CHF5074 was associated with significant improvement over baseline in the Digital Symbol Substitution Test (P less than .001), Trail-Making Tests A and B (P = .002 and .004, respectively), Immediate Word Recall (P =.001), and Delayed Word Recall (P = .003), said co–principal investigator Dr. Joel Ross of the Memory Enhancement Center of America in Eatontown, N.J.

Carriers of either one or two copies of the apolipoprotein E epsilon-4 (APOE epsilon-4) allele, who are at increased risk for early-onset Alzheimer’s disease (AD), had significantly greater improvements than did noncarriers in both word recall and trail-making tests.

"We think that this medication may be a start, the first step – perhaps a baby step – in preventing the memory loss that of course is the classic hallmark that Dr. Alzheimer described in the early 1900s," Dr. Ross said at a media briefing held several days prior to the presentation of his data.

Microglia, macrophages that serve as the primary active immune response mechanism of the brain, can malfunction in the presence of beta-amyloid (A-beta) protein, releasing inflammatory cytokines such as tumor necrosis factor–alpha (TNF-alpha), which in turn can cause irreversible neural damage.

CHF5074 (1-(3\',4\'-dichloro-2-fluoro[1,1\'-biphenyl]-4-yl)-cyclopropanecarboxylic acid is a small molecule modulator of the gamma-secretase enzymatic complex involved in A-beta formation, which is believed by many to be the hallmark pathologic event of AD.

According to CHF5074’s developer, the compound does not have the anticyclooxygenase (COX) or Notch-interfering properties seen with some gamma-secretase inhibitors (JPET 2007;323:822-30). The drug has been shown to lower cerebrospinal fluid levels of both soluble CD40 ligand and TNF-alpha, which are markers of neuroinflammation.

"That’s the big selling point for gamma-secretase modulators – that they shift the types of A-betas that are produced without affecting COX, without affecting Notch signaling," said Michael Wolfe, Ph.D., professor of neurology at Harvard Medical School and Brigham and Women’s Hospital, both in Boston. Dr. Wolfe, who studies gamma-secretase pathology in dementias, was not involved in the study.

But whether the drug is actually having an effect on microglia is less clear, he said.

"That doesn’t make any sense to me, based on the molecular mechanism," Dr. Wolfe said in an interview.

CHF5074 was evaluated for safety, tolerability, and efficacy in a 14-week trial of 96 patients with MCI who were enrolled in one of three dose regimens (200, 400, or 600 mg daily). Of this group, 74 enrolled in an open-label extension phase, and 32 were available for evaluation after 64 weeks.

An interim analysis of the cognitive tests in this subgroup showed significant improvement over baseline in domains of both verbal recall and executive function, as noted before.

Fourteen patients dropped out of the study at week 40, including 2 patients in the 600-mg/day group because of worsening cognitive function and serum creatinine elevation, and 1 patient in the 400-mg group because of pneumonia.

Gastrointestinal disorders were the most frequent treatment-emergent adverse events, with diarrhea occurring in 16% of patients on the 600-mg dose, 6.3% of those on 400 mg, and 1.4% on 200 mg.

The study was sponsored by Chiesi Pharmaceuticals. Dr. Ross heads the contract research organization that conducted the study. He did not disclose whether he has additional conflicts of interest. Dr. Wolfe reported having nor relevant disclosures.

BOSTON – Patients with mild cognitive impairment had significant improvement in both executive function and verbal memory when they were treated with CHF5074, an experimental gamma-secretase modulator that investigators claim has the potential to partially restore the brain’s innate immune response, investigators reported at Alzheimer’s Association International Conference 2013.

Among 32 patients with mild cognitive impairment (MCI) who reached 64 weeks of follow-up in an open-label extension of a double-blind, placebo-controlled trial, CHF5074 was associated with significant improvement over baseline in the Digital Symbol Substitution Test (P less than .001), Trail-Making Tests A and B (P = .002 and .004, respectively), Immediate Word Recall (P =.001), and Delayed Word Recall (P = .003), said co–principal investigator Dr. Joel Ross of the Memory Enhancement Center of America in Eatontown, N.J.

Carriers of either one or two copies of the apolipoprotein E epsilon-4 (APOE epsilon-4) allele, who are at increased risk for early-onset Alzheimer’s disease (AD), had significantly greater improvements than did noncarriers in both word recall and trail-making tests.

"We think that this medication may be a start, the first step – perhaps a baby step – in preventing the memory loss that of course is the classic hallmark that Dr. Alzheimer described in the early 1900s," Dr. Ross said at a media briefing held several days prior to the presentation of his data.

Microglia, macrophages that serve as the primary active immune response mechanism of the brain, can malfunction in the presence of beta-amyloid (A-beta) protein, releasing inflammatory cytokines such as tumor necrosis factor–alpha (TNF-alpha), which in turn can cause irreversible neural damage.

CHF5074 (1-(3\',4\'-dichloro-2-fluoro[1,1\'-biphenyl]-4-yl)-cyclopropanecarboxylic acid is a small molecule modulator of the gamma-secretase enzymatic complex involved in A-beta formation, which is believed by many to be the hallmark pathologic event of AD.

According to CHF5074’s developer, the compound does not have the anticyclooxygenase (COX) or Notch-interfering properties seen with some gamma-secretase inhibitors (JPET 2007;323:822-30). The drug has been shown to lower cerebrospinal fluid levels of both soluble CD40 ligand and TNF-alpha, which are markers of neuroinflammation.

"That’s the big selling point for gamma-secretase modulators – that they shift the types of A-betas that are produced without affecting COX, without affecting Notch signaling," said Michael Wolfe, Ph.D., professor of neurology at Harvard Medical School and Brigham and Women’s Hospital, both in Boston. Dr. Wolfe, who studies gamma-secretase pathology in dementias, was not involved in the study.

But whether the drug is actually having an effect on microglia is less clear, he said.

"That doesn’t make any sense to me, based on the molecular mechanism," Dr. Wolfe said in an interview.

CHF5074 was evaluated for safety, tolerability, and efficacy in a 14-week trial of 96 patients with MCI who were enrolled in one of three dose regimens (200, 400, or 600 mg daily). Of this group, 74 enrolled in an open-label extension phase, and 32 were available for evaluation after 64 weeks.

An interim analysis of the cognitive tests in this subgroup showed significant improvement over baseline in domains of both verbal recall and executive function, as noted before.

Fourteen patients dropped out of the study at week 40, including 2 patients in the 600-mg/day group because of worsening cognitive function and serum creatinine elevation, and 1 patient in the 400-mg group because of pneumonia.

Gastrointestinal disorders were the most frequent treatment-emergent adverse events, with diarrhea occurring in 16% of patients on the 600-mg dose, 6.3% of those on 400 mg, and 1.4% on 200 mg.

The study was sponsored by Chiesi Pharmaceuticals. Dr. Ross heads the contract research organization that conducted the study. He did not disclose whether he has additional conflicts of interest. Dr. Wolfe reported having nor relevant disclosures.

BOSTON – Patients with mild cognitive impairment had significant improvement in both executive function and verbal memory when they were treated with CHF5074, an experimental gamma-secretase modulator that investigators claim has the potential to partially restore the brain’s innate immune response, investigators reported at Alzheimer’s Association International Conference 2013.

Among 32 patients with mild cognitive impairment (MCI) who reached 64 weeks of follow-up in an open-label extension of a double-blind, placebo-controlled trial, CHF5074 was associated with significant improvement over baseline in the Digital Symbol Substitution Test (P less than .001), Trail-Making Tests A and B (P = .002 and .004, respectively), Immediate Word Recall (P =.001), and Delayed Word Recall (P = .003), said co–principal investigator Dr. Joel Ross of the Memory Enhancement Center of America in Eatontown, N.J.

Carriers of either one or two copies of the apolipoprotein E epsilon-4 (APOE epsilon-4) allele, who are at increased risk for early-onset Alzheimer’s disease (AD), had significantly greater improvements than did noncarriers in both word recall and trail-making tests.

"We think that this medication may be a start, the first step – perhaps a baby step – in preventing the memory loss that of course is the classic hallmark that Dr. Alzheimer described in the early 1900s," Dr. Ross said at a media briefing held several days prior to the presentation of his data.

Microglia, macrophages that serve as the primary active immune response mechanism of the brain, can malfunction in the presence of beta-amyloid (A-beta) protein, releasing inflammatory cytokines such as tumor necrosis factor–alpha (TNF-alpha), which in turn can cause irreversible neural damage.

CHF5074 (1-(3\',4\'-dichloro-2-fluoro[1,1\'-biphenyl]-4-yl)-cyclopropanecarboxylic acid is a small molecule modulator of the gamma-secretase enzymatic complex involved in A-beta formation, which is believed by many to be the hallmark pathologic event of AD.

According to CHF5074’s developer, the compound does not have the anticyclooxygenase (COX) or Notch-interfering properties seen with some gamma-secretase inhibitors (JPET 2007;323:822-30). The drug has been shown to lower cerebrospinal fluid levels of both soluble CD40 ligand and TNF-alpha, which are markers of neuroinflammation.

"That’s the big selling point for gamma-secretase modulators – that they shift the types of A-betas that are produced without affecting COX, without affecting Notch signaling," said Michael Wolfe, Ph.D., professor of neurology at Harvard Medical School and Brigham and Women’s Hospital, both in Boston. Dr. Wolfe, who studies gamma-secretase pathology in dementias, was not involved in the study.

But whether the drug is actually having an effect on microglia is less clear, he said.

"That doesn’t make any sense to me, based on the molecular mechanism," Dr. Wolfe said in an interview.

CHF5074 was evaluated for safety, tolerability, and efficacy in a 14-week trial of 96 patients with MCI who were enrolled in one of three dose regimens (200, 400, or 600 mg daily). Of this group, 74 enrolled in an open-label extension phase, and 32 were available for evaluation after 64 weeks.

An interim analysis of the cognitive tests in this subgroup showed significant improvement over baseline in domains of both verbal recall and executive function, as noted before.

Fourteen patients dropped out of the study at week 40, including 2 patients in the 600-mg/day group because of worsening cognitive function and serum creatinine elevation, and 1 patient in the 400-mg group because of pneumonia.

Gastrointestinal disorders were the most frequent treatment-emergent adverse events, with diarrhea occurring in 16% of patients on the 600-mg dose, 6.3% of those on 400 mg, and 1.4% on 200 mg.

The study was sponsored by Chiesi Pharmaceuticals. Dr. Ross heads the contract research organization that conducted the study. He did not disclose whether he has additional conflicts of interest. Dr. Wolfe reported having nor relevant disclosures.