IVIG falls down at GAP study’s finish line

BOSTON – Intravenous immunoglobulin is down, but may not be completely out as a potential treatment for Alzheimer’s disease.

In a disappointing follow-up to last year’s interim data, patients with mild to moderate disease who received intravenous immunoglobulin (IVIG) experienced no significant cognitive or functional benefits relative to the placebo group, Dr. Norman Relkin reported at a press briefing at the Alzheimer’s Association International Conference 2013.

But investigators in the phase III Gammaglobulin Alzheimer’s Partnership (GAP) study saw some positive results in cognition and function in the subgroup of patients with moderate disease and in those who carried the high-risk apolipoprotein E epsilon-4 (APOE epsilon-4) allele. Those hints of benefit are enough to justify keeping IVIG on the table, said Dr. Relkin, the study’s lead investigator.

"It’s too soon to be planning another study," he said. "I think it will be some time before we know how to move forward. But I’m optimistic that there are some signals in these data that are worthy of further study."

GAP randomized 390 patients with mild to moderate Alzheimer’s to placebo or biweekly infusions of 200 or 400 mg/kg IVIG for 18 months. A total of 309 completed the per protocol treatment.

Six-month results, reported at last year’s AAIC meeting, were positive. Those who received IVIG showed significantly slower cognitive decline than did those who got placebo. Patients who received the higher dose experienced virtually no decline from their baseline measurements.

But last May, Baxter, the study sponsor, reported negative results from GAP. After the full 18 months of treatment, there were no significant differences in the rate of cognitive decline between patients in the placebo or active treatment arms.

The results also did not indicate a statistically significant change in functional ability in comparison with placebo.

However, patients with moderate disease and those who were positive for APOE epsilon-4 appeared to reap some benefits from IVIG, said Dr. Relkin, a neurologist at New York–Presbyterian Hospital/Weill Cornell Medical Center, New York.

IVIG treatment in patients with moderate disease showed trends toward benefits relative to placebo on the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-Cog) and the Modified Mini-Mental State Examination (MMSE), with P values of .083 and .067, respectively. Dr. Relkin noted that these subgroup analyses were not powered to detect such differences. APOE epsilon-4 carriers also had numerically better scores on the MMSE than did placebo patients, with a P value of .012.

A breakdown of APOE epsilon-4 patients by drug dosage indicated that those taking 400 mg/kg did better on tests of executive function (Trails B, clock draw, and digit symbol) than did those taking 200 mg/kg. Again, this analysis wasn’t powered to show statistical significance.

GAP also found some biomarker differences in patients treated with IVIG, Dr. Relkin noted. These included:

• A statistically significant, dose-dependent reduction in plasma beta-amyloid 42 levels (but not beta-amyloid 40).

• Statistically significant, dose-dependent increases in anti-oligomer and anti-fibril antibodies in cerebrospinal fluid and plasma.

• A reduction in brain fibrillar amyloid as measured by florbetapir PET scan in those who received the larger IVIG dose.

There was no effect on tau and phosphorylated tau levels in cerebrospinal fluid.

It’s tough to pinpoint just why IVIG didn’t live up to its 6-month promise, Dr. Relkin said. One reason might lie in trial design and patient selection – problems that continue to plague Alzheimer’s treatment studies.

"In these large clinical trials, a certain number of patients deemed to have Alzheimer’s actually don’t have it. A therapy designed to be effective in all disease stages is most likely to show benefit in those with moderate disease and in [APOE epsilon-4] carriers, because those are the ones most likely to be accurately diagnosed."

The positive subgroup findings might also be simply a "statistical fluke," he said.

"This was a pivotal trial and could have been used for drug approval, if the results had been positive. But there is a difference between a negative study and a failed study. A failed study is one that gives you no answer to the question that was asked. A negative study is one that answers that question – and in this case, the answer was ‘no.’ That’s one way in which this trial did succeed. It gave us a clear, unequivocal answer that we can interpret and translate into a clinically meaningful result."

The GAP study was sponsored by Baxter. Dr. Relkin receives study support from Baxter.

msullivan@frontlinemedcom.com

On Twitter @Alz_Gal

BOSTON – Intravenous immunoglobulin is down, but may not be completely out as a potential treatment for Alzheimer’s disease.

In a disappointing follow-up to last year’s interim data, patients with mild to moderate disease who received intravenous immunoglobulin (IVIG) experienced no significant cognitive or functional benefits relative to the placebo group, Dr. Norman Relkin reported at a press briefing at the Alzheimer’s Association International Conference 2013.

But investigators in the phase III Gammaglobulin Alzheimer’s Partnership (GAP) study saw some positive results in cognition and function in the subgroup of patients with moderate disease and in those who carried the high-risk apolipoprotein E epsilon-4 (APOE epsilon-4) allele. Those hints of benefit are enough to justify keeping IVIG on the table, said Dr. Relkin, the study’s lead investigator.

"It’s too soon to be planning another study," he said. "I think it will be some time before we know how to move forward. But I’m optimistic that there are some signals in these data that are worthy of further study."

GAP randomized 390 patients with mild to moderate Alzheimer’s to placebo or biweekly infusions of 200 or 400 mg/kg IVIG for 18 months. A total of 309 completed the per protocol treatment.

Six-month results, reported at last year’s AAIC meeting, were positive. Those who received IVIG showed significantly slower cognitive decline than did those who got placebo. Patients who received the higher dose experienced virtually no decline from their baseline measurements.

But last May, Baxter, the study sponsor, reported negative results from GAP. After the full 18 months of treatment, there were no significant differences in the rate of cognitive decline between patients in the placebo or active treatment arms.

The results also did not indicate a statistically significant change in functional ability in comparison with placebo.

However, patients with moderate disease and those who were positive for APOE epsilon-4 appeared to reap some benefits from IVIG, said Dr. Relkin, a neurologist at New York–Presbyterian Hospital/Weill Cornell Medical Center, New York.

IVIG treatment in patients with moderate disease showed trends toward benefits relative to placebo on the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-Cog) and the Modified Mini-Mental State Examination (MMSE), with P values of .083 and .067, respectively. Dr. Relkin noted that these subgroup analyses were not powered to detect such differences. APOE epsilon-4 carriers also had numerically better scores on the MMSE than did placebo patients, with a P value of .012.

A breakdown of APOE epsilon-4 patients by drug dosage indicated that those taking 400 mg/kg did better on tests of executive function (Trails B, clock draw, and digit symbol) than did those taking 200 mg/kg. Again, this analysis wasn’t powered to show statistical significance.

GAP also found some biomarker differences in patients treated with IVIG, Dr. Relkin noted. These included:

• A statistically significant, dose-dependent reduction in plasma beta-amyloid 42 levels (but not beta-amyloid 40).

• Statistically significant, dose-dependent increases in anti-oligomer and anti-fibril antibodies in cerebrospinal fluid and plasma.

• A reduction in brain fibrillar amyloid as measured by florbetapir PET scan in those who received the larger IVIG dose.

There was no effect on tau and phosphorylated tau levels in cerebrospinal fluid.

It’s tough to pinpoint just why IVIG didn’t live up to its 6-month promise, Dr. Relkin said. One reason might lie in trial design and patient selection – problems that continue to plague Alzheimer’s treatment studies.

"In these large clinical trials, a certain number of patients deemed to have Alzheimer’s actually don’t have it. A therapy designed to be effective in all disease stages is most likely to show benefit in those with moderate disease and in [APOE epsilon-4] carriers, because those are the ones most likely to be accurately diagnosed."

The positive subgroup findings might also be simply a "statistical fluke," he said.

"This was a pivotal trial and could have been used for drug approval, if the results had been positive. But there is a difference between a negative study and a failed study. A failed study is one that gives you no answer to the question that was asked. A negative study is one that answers that question – and in this case, the answer was ‘no.’ That’s one way in which this trial did succeed. It gave us a clear, unequivocal answer that we can interpret and translate into a clinically meaningful result."

The GAP study was sponsored by Baxter. Dr. Relkin receives study support from Baxter.

msullivan@frontlinemedcom.com

On Twitter @Alz_Gal

BOSTON – Intravenous immunoglobulin is down, but may not be completely out as a potential treatment for Alzheimer’s disease.

In a disappointing follow-up to last year’s interim data, patients with mild to moderate disease who received intravenous immunoglobulin (IVIG) experienced no significant cognitive or functional benefits relative to the placebo group, Dr. Norman Relkin reported at a press briefing at the Alzheimer’s Association International Conference 2013.

But investigators in the phase III Gammaglobulin Alzheimer’s Partnership (GAP) study saw some positive results in cognition and function in the subgroup of patients with moderate disease and in those who carried the high-risk apolipoprotein E epsilon-4 (APOE epsilon-4) allele. Those hints of benefit are enough to justify keeping IVIG on the table, said Dr. Relkin, the study’s lead investigator.

"It’s too soon to be planning another study," he said. "I think it will be some time before we know how to move forward. But I’m optimistic that there are some signals in these data that are worthy of further study."

GAP randomized 390 patients with mild to moderate Alzheimer’s to placebo or biweekly infusions of 200 or 400 mg/kg IVIG for 18 months. A total of 309 completed the per protocol treatment.

Six-month results, reported at last year’s AAIC meeting, were positive. Those who received IVIG showed significantly slower cognitive decline than did those who got placebo. Patients who received the higher dose experienced virtually no decline from their baseline measurements.

But last May, Baxter, the study sponsor, reported negative results from GAP. After the full 18 months of treatment, there were no significant differences in the rate of cognitive decline between patients in the placebo or active treatment arms.

The results also did not indicate a statistically significant change in functional ability in comparison with placebo.

However, patients with moderate disease and those who were positive for APOE epsilon-4 appeared to reap some benefits from IVIG, said Dr. Relkin, a neurologist at New York–Presbyterian Hospital/Weill Cornell Medical Center, New York.

IVIG treatment in patients with moderate disease showed trends toward benefits relative to placebo on the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-Cog) and the Modified Mini-Mental State Examination (MMSE), with P values of .083 and .067, respectively. Dr. Relkin noted that these subgroup analyses were not powered to detect such differences. APOE epsilon-4 carriers also had numerically better scores on the MMSE than did placebo patients, with a P value of .012.

A breakdown of APOE epsilon-4 patients by drug dosage indicated that those taking 400 mg/kg did better on tests of executive function (Trails B, clock draw, and digit symbol) than did those taking 200 mg/kg. Again, this analysis wasn’t powered to show statistical significance.

GAP also found some biomarker differences in patients treated with IVIG, Dr. Relkin noted. These included:

• A statistically significant, dose-dependent reduction in plasma beta-amyloid 42 levels (but not beta-amyloid 40).

• Statistically significant, dose-dependent increases in anti-oligomer and anti-fibril antibodies in cerebrospinal fluid and plasma.

• A reduction in brain fibrillar amyloid as measured by florbetapir PET scan in those who received the larger IVIG dose.

There was no effect on tau and phosphorylated tau levels in cerebrospinal fluid.

It’s tough to pinpoint just why IVIG didn’t live up to its 6-month promise, Dr. Relkin said. One reason might lie in trial design and patient selection – problems that continue to plague Alzheimer’s treatment studies.

"In these large clinical trials, a certain number of patients deemed to have Alzheimer’s actually don’t have it. A therapy designed to be effective in all disease stages is most likely to show benefit in those with moderate disease and in [APOE epsilon-4] carriers, because those are the ones most likely to be accurately diagnosed."

The positive subgroup findings might also be simply a "statistical fluke," he said.

"This was a pivotal trial and could have been used for drug approval, if the results had been positive. But there is a difference between a negative study and a failed study. A failed study is one that gives you no answer to the question that was asked. A negative study is one that answers that question – and in this case, the answer was ‘no.’ That’s one way in which this trial did succeed. It gave us a clear, unequivocal answer that we can interpret and translate into a clinically meaningful result."

The GAP study was sponsored by Baxter. Dr. Relkin receives study support from Baxter.

msullivan@frontlinemedcom.com

On Twitter @Alz_Gal