Intravenous immunoglobulin continues to slow the decline in cognitive and other functions seen in Alzheimer’s disease for at least 3 years, suggest data from an extended phase II randomized trial among 21 patients with mild to moderate disease.

Compared with their counterparts who started on a placebo and crossed over to intravenous immunoglobulin (IVIG) in the trial, patients who received the pooled antibody preparation continuously had significantly better scores on measures of cognitive, global, and daily function, and behavior, Dr. Norman Relkin reported at the Alzheimer’s Association International Conference 2012.

Susan London/IMNG Medical Media

Dr. Norman Relkin

Moreover, the subset of patients who received the optimal dose of IVIG for the entire 3-year period had little to no decline in these measures from baseline, suggesting that clinical progression of the disease had been effectively halted.

Adverse effects seen with IVIG were consistent with what was expected, given 30 years of experience with this agent in other diseases – mainly short-lived infusion-related reactions such as rash and fever, although a single patient did experience a stroke. The majority of patients received all planned infusions.

“By the results that we have shown here, we have established that IVIG is potentially a viable therapy for as long as 36 months and perhaps longer,” Dr. Relkin commented in a press briefing. However, he cautioned, the number of patients studied was small, and IVIG is not currently approved to treat Alzheimer’s disease.

“My coinvestigators and I want to really emphasize that this work is investigational, and it’s not intended to promote the off-label use of this particular product to treat Alzheimer’s disease. This is 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,” he explained. “So we don’t want to bankrupt the available supplies by creating false hope or premature use of this product.”

The promising results seen in the extended trial prompted initiation of the phase III Gammaglobulin Alzheimer Partnership (GAP) study, which has been further testing the optimal dose of IVIG against placebo. “The last patient should be through that study by December of this year, and we expect readout [of the results] by the middle of 2013,” he said.

The patients enrolled in the phase II trial had mild to moderate Alzheimer’s disease, with a Mini-Mental State Examination score of 14-26. Those who had experienced myocardial infarction or stroke were generally excluded to reduce the risk of thromboembolic complications.

During the initial 6 months, patients received randomized double-blind treatment with placebo or various doses of IVIG (Gammagard). In a first extension out to 18 months, placebo patients were switched to IVIG and treatment became open-label. In a second extension out to 36 months, all patients were given the dose that had emerged as the optimal one (0.4 g/kg every 2 weeks).

Cognitive function was assessed with the Alzheimer’s Disease Assessment Scale cognitive subscale (ADAS-Cog), global functioning with the Clinical Global Impression of Change (CGIC) scale, daily functioning from Activities of Daily Living (ADL), and behavior from the Neuropsychiatric Inventory (NPI).

Results at 6 months and at 18 months favored IVIG over placebo, according to Dr. Relkin, director of the memory disorders program at Weill Cornell Medical College, New York.

Results for the full 36 months, reported for the first time in a poster session at the meeting, showed that in a comparison of all patients given IVIG continuously in the trial (regardless of dose) with patients who had a delay because they started with placebo, the decline in the four main measures was slower in the former group, with significant differences at nearly all time points.

“Particularly if you look at the global measure and daily function measure, there is a bend in the curve of the group that got placebo, and that bend occurs when they were switched to the optimum dose,” Dr. Relkin noted. “We think that’s important because it shows that even patients who are a little bit further along in the disease state can benefit.”

In what he characterized as “the most striking finding,” analyses restricted to the four patients who received the optimal dose of IVIG continuously showed virtually no decline in the four main measures over 36 months.

“To put this in perspective, when we see patients with Alzheimer’s disease in our clinic untreated, there is usually a measurable decline below baseline within 3-6 months. If we treat them with the currently available agents, they typically drop below their baseline between 6 and 12 months,” he commented. “If we have a patient who goes out to 18 or 24 months without changing, we usually begin to doubt if they have Alzheimer’s disease. If we have two patients like that in our practice, we begin to doubt our own diagnostic prowess. To have four patients, all of whom received the same dose [and] are effectively unchanged after 3 years, is a remarkable result.”

It is still too premature to conclude that IVIG had a disease-modifying effect, according to Dr. Relkin. “However, the shapes of those graphs are exactly what people model when they are predicting what a disease-modifying therapy would look like, which is that there is a divergence of slopes, which means that the curves widen as time goes on. I think we have to wait for the results of the phase III study before we can answer that question,” he concluded.

Dr. Relkin disclosed that he receives research support from Baxter Healthcare, which supported the trial.