Tuesday, July 17, 2012

IVIG stops the progression of Alzheimers!!! Or just gives you a stroke?

This just came out in the news today, and I've already received a few calls from some of my patients and their family about it, so I think I should address it.

This study was published as an abstract and presented at a conference (Alzheimer's Association International Conference).
These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
Study abstract title: Relkin N, et al "Three-year follow-up on the IVIG for Alzheimer's phase II study" AAIC 2012; Abstract P3-381.

First, some basics.

The actual constellation of factors which lead to the development of Alzheimer's disease (which, by the way, is just one of a dozen or more causes of the family of neurodegenerative dementias) is hotly debated. BUT, there is a lot of research around the role of a person's immune system, specifically, that people who develop Alzheimer's may be having a problem with their immune system accidentally attacking certain cells or proteins in the brain or causing damaging inflammation in parts of the brain.

As a very broad explanation, we believe that in Alzheimer's Disease, certain proteins in the cells of the brain start misfolding and building up (instead of being dissolved as they should) until they get in the way of normal cellular function... and until the cell eventually dies as a result, slowly adding up over time to affect thinking and behavior. The initial cells to be involved classically affect memory first and later other parts of the brain, sometimes rapidly, and sometimes very slowly.

Current treatment involves trying to keep the cells that are currently living as healthy for as long as possible, or help the chemicals they use to communicate between them (like acetylcholine), stick around longer by stopping the natural enzymes which break this messenger chemical down. The current treatment do NOT really affect the underlying problem/cause and, overall, may add years at best to independent living... but are by no means perfect, and do not add decades to normal living and definitely do not stop the disease.

Most patients with Alzheimer's Disease have notable progression every 3 to 6 months on average.

The treatment they are discussing, IVIG (Intravenous immunoglobulin), is a high-viscosity (thick) infusion (made from donated blood) given in a monitored setting (like a dedicated infusion suite or a hospital) over an hour or so. It is a treatment designed to halt the progression of an autoimmune process (your body attacking some aspect of itself). Because IVIG is thick, it can rarely cause an artery to clot and lead to a heart attack, renal failure, or stroke. Ouch! Normally it causes just a rash as a side effect fortunately. Currently, it costs somebody (insurance or the patient) around $10,000 per treatment (which goes to the pharmaceutical company, not your doctor).

Now, in this study, there is documented cessation of Alzheimer's progression. That is wonderful, and I love that it paves the way for more research in this area. In fact, another study with over 300 patients of somewhat similar design is nearing completion as well.

Over the 3 years that these patients were treated with IVIG, they had NO PROGRESSION OF THEIR ALZHEIMER'S DISEASE.

Wonderful, right?!.... Well, this is an example of how media hype can mislead us.

A closer look:
-Only 4 patients received the full 36 months (3 years) of IVIG treatment every 2 weeks, and only these 4 had complete halting of the disease. One of these 4 had a stroke as a complication.
-There were only 24 total patients enrolled in the treatment (patients with mild-to-moderate dementia). That's not a lot, BUT they all did have reduced progression rates of their decline in thinking compared to those who received sham/fake medication; these latter patients continuing to worse as expected.
-Those that switch from the placebo(sham/fake) treatment to the IVIG treatment, starting doing better as well, in regards to the stabilization of the disease progression.

So, this is very promising, but there were not a lot of patients in the study as a whole, one did have a stroke as a likely treatment complication (which is just as bad as Alzheimer's in my book), they had to get a monitored IV treatment every 2 to 4 weeks, and the cost or copay would be quite high.

I plan to wait on more evidence that it's worth it on all fronts before I set a patient up with this treatment.

If you want to read a more detailed report, see below line:
IVIG Stops Alzheimer's in Its Tracks
Published: July 17, 2012

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.
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."