IVIG Stops Alzheimer's in Its Tracks
By John Gever, Senior Editor, MedPage Today|
Published: July 17, 2012
VANCOUVER -- Three years of treatment with intravenous immunoglobulin (IVIG, GammaGard) prevented further cognitive decline in patients with Alzheimer's disease, according to a small study presented here.
· This study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
· Note that this very small study reports long term stabilization of Alzheimer's disease symptoms with IVIG treatment over a period of 36 months.
As measured by multiple standard instruments -- the Alzheimer's Disease Assessment Scale (ADAS-Cog), the Clinical Global Impression of Change (CGIC) index, the Neuropsychiatric Inventory, and others -- the four patients who received the full 36 months of treatment at 0.4 g/kg every 2 weeks showed no decline in scores, reported Norman Relkin, MD, of Weill Cornell Medical College in New York City.
At a press briefing prior to his formal presentation at the Alzheimer's Association International Conference, Relkin said the treatment was "generally well-tolerated" but did cause some adverse effects. None were unusual and most were relatively mild infusion-related reactions such as rashes.
Some were more serious, though. These included a stroke in one patient, presumably related to the viscosity of IVIG, which is known to increase risk of ischemic events.
A phase III study with 390 patients is already nearing completion, with results expected by mid-2013, he said.
The rationale for IVIG in Alzheimer's disease is that it contains antibodies against beta amyloid proteins and it also modulates immune function to reduce inflammation, Relkin explained.
The current report covered a second open-label extension of an earlier placebo-controlled, double-blind trial that initially lasted 6 months, involving 24 patients with mild to moderate Alzheimer's disease (baseline Mini-Mental State Examination scores of 14 to 26).
As a phase II study, it tested multiple doses and schedules. Besides the four patients assigned to 0.4 g/kg every 2 weeks, four patients each received 0.2 g/kg every 2 weeks, 0.4 g/kg every 4 weeks, and 0.8 g/kg every 4 weeks. Eight patients received placebo.
Results from the randomized phase indicated that, in pooled data for all patients assigned to IVIG, the treatment outperformed placebo in the primary outcome measures of ADAS-Cog and CGIC, as well as in other cognitive assessments.
Participants were allowed to receive an additional year of open-label treatment with IVIG. With continued favorable results -- including inhibition of brain atrophy as well as cognitive protection -- a second 18-month extension was offered, with 21 patients accepting. For this second extension, all patients received 0.4 g/kg every 2 weeks, since that appeared to be the most effective regimen in the previous data.
These included all 16 initially receiving IVIG and five of the placebo group.
The second extension essentially confirmed the earlier findings and showed that the benefits last 3 years, Relkin said.
Patients initially assigned to placebo showed continued decline in cognitive function, but there was "a bend in the curve" when they were switched to IVIG, Relkin said, reflecting a slowing in decline.
Pooled data for the 16 patients in the original IVIG groups showed a significant protective effect relative to the initial placebo group. Mean values for ADAS-Cog and CGIC scores indicated some loss of cognitive ability, but it was relatively small.
But the highlight finding, Relkin said, was that 3-year ADAS-Cog and CGIC scores in the four patients who received 0.4 g/kg every 2 weeks throughout the study were the same as at baseline.
Untreated Alzheimer's disease patients in his clinic nearly always show measurable decline in 3 to 6 months, he said.
"If we have a patient who goes out to 18 or 24 months without changing, usually we begin to doubt that they have Alzheimer's disease. If we have two patients like that in our practice, we begin to doubt our own diagnostic prowess," he said.
"To have four patients... all of whom are effectively unchanged after 3 years, is a remarkable result."
Relkin started his press conference talk with the customary presentation disclaimer that he would be discussing the off-label use of an approved product, but then gave it an unusual emphasis.
He noted that the findings were from very few patients, and therefore very preliminary. "It's a very important point because this agent is in limited supply, and the indications for which it is approved, some of them represent disorders in which patients can only survive by getting this particular product. So we don't want to bankrupt the available supplies."
Primary source: Alzheimer's Association International Conference
Relkin N, et al "Three-year follow-up on the IVIG for Alzheimer's phase II study" AAIC 2012; Abstract P3-381.
A drug already on the market to treat immune disorders may help stabilize patients with Alzheimer's disease for up to three years, according to the results of a tiny study presented at a conference on Tuesday.
All four patients who received the maximum dose of the drug, Gammagard from Baxter International, had no decline in several measures of cognition and daily function for three years, researchers said.
Dr. Norman Relkin of Weill Cornell Medical College, the lead investigator of the study, said the results were "remarkable" because patients with Alzheimer's disease typically worsen within 12 months.
"If we have a patient who goes 18 months without changing we begin to doubt they have Alzheimer's," Dr. Relkin said in a news conference at the Alzheimer's Association International Conference in Vancouver, where the results were presented.
But some experts not involved in the trial said it was premature to conclude that the drug was responsible for the stabilization.
"There will be some patients who at three years don't have a decline" even without an experimental therapy, said Dr. Rachelle S. Doody, director of the Alzheimer's Disease and Memory Disorders Center at Baylor College of Medicine. She said some patients go six or eight years without their condition worsening.
Dr. Samuel Gandy, director of the Center for Cognitive Health at the Mt. Sinai School of Medicine, said the results left him "optimistic to a minor degree, not really gushing."
Whether the results are fluke or not could be known by early next year, when the results of a larger, phase 3, clinical trial are expected.
The results presented Tuesday were from an extension of a 24-patient trial begun some years ago. In the first six months of the study, those who received the drug did better than those who received placebo. After that, patients could continue on the study, with all of them receiving the drug.
Sixteen of the patients completed three years of treatment. The five of those who originally received placebo declined less rapidly once they shifted to the drug. Of the 11 who received the drug for the entire 36 months, those who got the highest dose for the whole time fared the best.
That evidence "really suggests this is a drug effect and not just an accident," said Bill Thies, chief medical and scientific officer of the Alzheimer's Association.
Baxter's shares rose 93 cents, or 1.7 percent, to $55.68.
Gammagard is a brand of intravenous immune globulin, or IVIG. Such products, which are also sold by several other companies, are collections of antibodies from healthy people that are harvested from donated blood plasma. IVIG is used mainly to treat fairly rare immune system deficiencies.
It is not clear why IVIG would work against Alzheimer's. Some evidence suggests that some of the antibodies in IVIG block beta amyloid, a protein thought to be a cause of Alzheimer's. Some evidence points to a general anti-inflammatory effect of IVIG.
Because of the earlier results from the Gammagard study, some patients with Alzheimer's disease are already using IVIG off label. Doctors are allowed to prescribe an approved drug for a non-approved use.
"I have a handful of patients who are doing it," Dr. Gandy said. But he and others said the practice was not widespread, in part because the treatment costs thousands of dollars a month and insurers typically do not reimburse for off-label uses. Treatment requires intravenous infusions every two weeks or so and can cause fever and chills and blood clotting problems.