GAP: IVIG Negative in Alzheimer's, But Some Hints of Benefit

Susan Jeffrey

July 17, 2013

BOSTON, Massachusetts — Final results of a pivotal phase 3 trial confirm that overall, there was no significant effect of treatment with intravenous immunoglobulin (IVIG; Gammagard, Baxter International Inc) on the co-primary endpoints of reducing cognitive decline and preserving functional abilities in patients with mild to moderate Alzheimer's disease (AD).

Topline results of the Gammaglobulin Alzheimer's Partnership (GAP), conducted by Baxter in collaboration with the Alzheimer's Disease Cooperative Study (ADCS), a clinical trial consortium supported by the National Institute on Aging, were released in May 2013 and reported by Medscape Medical News at that time.

"We find that the IVIG phase 3 study does not support clinical efficacy of IVIG for the treatment of mild to moderate Alzheimer's disease at the doses tested," Norman Relkin, MD, PhD, a neurologist from the Weill Cornell Medical College, New York, New York, and GAP principal investigator, concluded, although treatment was safe and well tolerated.

However, the data hint there may be subpopulations, specifically patients with moderate AD and those carrying the apolipoprotein E ε4 risk allele, that may yet benefit from treatment and warrant further study, he noted.

The results were presented here at the Alzheimer's Association International Conference (AAIC) 2013.

GAP Study

Dr. Norman Relkin

The GAP trial was a double-blind, placebo-controlled multicenter trial that randomly assigned 390 patients meeting criteria for probable AD from 45 centers in the United States and Canada to receive 400 mg/kg or 200 mg/kg intravenous infusions of IVIG or a low-dose albumin placebo dilution every 2 weeks. Patients received 36 infusions over 18 months in addition to other approved medications for AD.

Randomization was balanced for baseline Modified Mini-Mental State (3MS) Examination scores and APOE genotype, the researchers report. Co-primary endpoints were the rate of cognitive decline, measured by using the Alzheimer's Disease Assessment Scale–Cognitive Subscale (ADAS-Cog) vs placebo, or change in functional ability vs placebo measured by using the Alzheimer's Disease Cooperative Study–Activities of Daily Living (ADCS-ADL) scale.

All patients underwent serial plasma collection, as well as MRI, but subsets of patients underwent collection of cerebrospinal fluid and positron emission tomography (PET) using fluorodeoxyglucose and florbetapir (AV-45).

After 18 months, there was no significant difference in the rate of cognitive decline or in changes in functional ability on the 2 primary outcome measures, Dr. Relkin said, confirming the topline results released in May. The curves for the various groups overlapped within confidence intervals, he noted, "meaning that there's no statistical difference between them on these measures. This is clearly negative."

Table. GAP Study: Co-Primary Endpoints

Endpoint IVIG 400 mg/kg IVIG 200 mg/kg Placebo
ADAS-Cog 7.4 8.9 8.4
ADCS-ADL –11.4 –12.4 –11.4

 

The study was not powered to show statistical significance among the subgroups, but in prespecified intention-to-treat subgroup analyses, patients in the 400 mg/kg group who were APOE ε4 carriers vs noncarriers, and those with moderate (3MS scores of 16 to 20) vs mild disease severity appeared to have numerically superior results. "The difference between mild and moderate disease does not appear to be a robust one, but there may be an effect related to APOE ε4," he said.

Treatment was well tolerated, and no new safety signals were identified in this patient population, Dr. Relkin noted. Adverse events seen more frequently with IVIG treatment included rash, chills, arthralgia, vomiting, epistaxis, and eczema. There was no apparent increase in the risk for amyloid-related imaging abnormalities on MRI related to treatment.

New data were also presented on the effect of treatment on several biomarkers. First, the investigators were able to show that IVIG treatment increased IgG in plasma, but also in cerebrospinal fluid, showing penetration into the central nervous system, he said. "This was not known prior to this study."

Further, IVIG treatment reduced blood levels of amyloid-β 42, the more pathologically relevant form of amyloid, "and did so dramatically," in a dose-dependent fashion, Dr. Relkin noted. Finally, florbetapir PET amyloid imaging showed a reduction in fibrillar amyloid, the type deposited in amyloid plaques, although the study was not powered to confirm this effect.

"These reductions that we saw in brain amyloid are of some interest because we would want to know from the standpoint of doing future studies how we can follow the effects of treatment, and this might be a viable way," he said.

Dr. Relkin emphasized that the trial was not a "failed" but a "negative" trial. "A failed study is one that gives you no answer, and to that extent, I'm very happy that this study did succeed in giving us a clear and unequivocal answer that we can interpret and translate into a clinically meaningful result," he said.

Analysis of phase 2 results, including extension results presented last summer at this meeting and reported by Medscape Medical News at that time, suggested long-term treatment had a stabilizing effect in patients with AD over time, for some up to 8 years. Asked about those patients, Dr. Relkin noted that many of those patients are still stable. "I'm not going to tell you that they haven't progressed, but the degree to which they have progressed is much slower than expectation," he said.

Only 16 patients were exposed to IVIG in the first trial, but most of them, looking back now, fell into those subgroups of moderate disease or APOE ε4 carriers who appeared to have better results in the phase 3 trial. "So I think it was the luck of the draw," he added, and underlines the importance of larger trials.

Off-Label Use

Still, the promising phase 2 results combined with the fact that IVIG is already approved by the US Food and Drug Administration (FDA) for use in other autoimmune and neurological conditions has meant that some patients with AD are being treated with IVIG off-label.

"Given that there are responders out there, I think it would be a disservice to them to say they have to stop because the clinical trial did not have a positive result," Dr. Relkin said in an interview. "By the same token, the clinical trial doesn't support starting it now, even with some of the positive results, but those will have to be verified in a prospective way before a clinical recommendation can be made."

 
… given that it's in limited supply, it's wrong to propagate the idea that it should be used off-label. Dr. Norman Relkin
 

He added that this is a drug that is "lifesaving in many other diseases, and given that it's in limited supply, it's wrong to propagate the idea that it should be used off-label."

After the topline results were released in May, Baxter discontinued a second ongoing phase 3 trial of IVIG in patients with mild to moderate disease that was enrolling in Europe and the United States, and will decide by the end of 2013 whether they plan to continue the program, Dr. Relkin told Medscape Medical News. Another phase 2 trial of IVIG in patients with mild cognitive impairment, using the same dose of IVIG but with a shorter interval of treatment, is still ongoing.

Commenting on the GAP findings here, Mary Sano, PhD, professor of psychiatry, director of the Alzheimer's Disease Research Center at Mount Sinai School of Medicine, Bronx, New York, and also a member of the executive committee for the GAP trial, said these results, despite being negative, make a significant contribution.

"It's demonstrated our ability to answer important questions about practice today," Dr. Sano said. "We have a drug that is actually in the armamentarium of physicians and studies like this are designed to determine if we can repurpose them and use them in these new and creative ways. It's important to realize that we've actually done the hard work here of assessing it and determining whether or not it has value."

Given a drug like this, that may have a limited supply or that is expensive or difficult to deliver, she added, "it's really of public health importance to be sure we know the answer about repurposing, does it really work?"

Clues to Mechanism

In separate presentations also featured during the press conference, researchers reported data that provide some clues to a theoretical mechanism of benefit from IVIG in the setting of AD.

In 1 study, researchers led by Scott Counts, PhD, from Rush University Medical Center, Chicago, Illinois, looked at whether IVIG alters expression of tau neurofibrillary tangle-like deposits within hippocampal CA1 neurons, which are vulnerable in AD, in the 3 x Tg mouse model of AD.

They found that mice treated with IVIG had a small but significant 15% decrease in hippocampal cells bearing tangles compared with saline-treated mice. Treatment also resulted in a 40% to 50% increase in plasma levels of several modulators of neuronal cytoskeletal plasticity.

"Our preliminary data suggest that IVIG may reduce Alzheimer's-like tangle pathology and increase neuroprotective gene expression," Dr. Counts concluded in a statement from the Alzheimer's Association. "Irrespective of the disappointing results of the phase 3 trial, what we think is within the context of our mouse model, the IVIG still has some translational impact for allowing us to understand how these tangles are formed, and how they might be prevented in the disease."

In a second study, Debomoy Lahiri, PhD, from Indiana University School of Medicine, Indianapolis, report that in primary human fetal brain neuron cultures, pretreatment with IVIG significantly protected against the damaging effects of exposure to reactive oxygen species, and in fact, showed "rescue" of cells, promoting and protecting dying neurons.

"Our results suggest IVIG treatments may make neurons less vulnerable to damage from reactive oxygen species," Dr. Lahiri said. "Since preventing brain cell loss in Alzheimer's is an important goal of therapy, our results suggest that IVIG may be beneficial for preserving and protecting neurons against oxidative damage."

The GAP study was conducted by Baxter in collaboration with the Alzheimer's Disease Cooperative Study (ADCS), a clinical trial consortium supported by the National Institute on Aging. Dr. Counts' study was funded by Baxter.

Alzheimer's Association International Conference (AAIC) 2013. Abstracts 03-06-04, P2-031, P4-257. Presented July 16, 15, and 17, 2013, respectively.

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