Breakthrough in AD with vaccine placebo?

[J11]

The results announced for the AFFiRiS phase II trial are claiming that the placebo arm had
impressive results.

They are now calling this placebo AD04.

[Julie G]

Weird, huh? The placebo had better effects then the actual vaccine being tested...Hard to get any detailed info

http://www.fiercebiotech.com/story/biot ... 2014-06-04

[J11]

Weird, though perhaps there is something behind this. The placebo was not a straight sugar pill: it was an immunomodulator. The effect they announced is large. The company is claiming that this is the first
drug ever to demonstrate clinical and biomarker effects consistent with disease modification. 47% of treated patients
benefited for at least 18 months.

It is hard to understand why regulators would allow a trial to be conducted without having an established, true
placebo.

However, the big question is:

What is the immunomodulator?

[SusanJ]

Well, it probably was considered a placebo because it was exactly the same solution, just without the AD02 active ingredient. And they obviously thought AD02 needed some kind of adjuvant to get the appropriate immune response they were after. So, it depends on what part of the immune system they were trying to tickle into activity.

Wonder if there is a clinical trials database for Austria. Might hold a clue, but I don't have time to dig at the moment.

[SpunkyPup]

placebo usually have around 20% effectiveness and some drugs have a low threshold just above to be accepted as it might help many in a large population.

gotta love the way medical science works its way more statistical modelling than biochemical process really proves we still at the primitive stage of a mess of confusing to understand trials but this one is a whopper. but it was not April fools in the announcement!

[SusanJ]

Spunk, so true. Someday researchers will look back on our current "primitive mess" and shake their heads...let's hope someone is innovative and actually comes up with a methodology based on other foundations like genetics and biochemical processes.

When I studied pharmacy (and was a research assistant) in the mid-70's it always frustrated me that research studies were done mostly on men (except for women's drugs like Premarin), and dosing recommendations set accordingly. So maybe they've inched forward slightly. Although it seems we still have a ways to go if CBS deemed the issue newsworthy enough in 2014 to do a show on it. http://www.cbsnews.com/news/sex-matters ... erently-2/

Sigh.

[J11]

The reported p value was 0.0016 and there was a dose effect. I am not sure whether they have demonstrated a dose effect with placebos.

A 2011 patent application for Affiris for an Alzheimer vaccine lists a "pharmaceutically acceptable, carrier, preferably KLH (Keyhole Limpet Hemocyanin)" as a possibility for the immunomodulator. The patent also mentions aluminum hydroxide as a possible adjuvant.

KLH is a widely used substance and is derived from the sera of the marine mollusk Giant Keyhole Limpet. KLH is apparently blue in color (possibly because it contains copper). If KLH is in fact bluish in color, then this could explain why it was thought necessary to use KLH in the placebo formulation.

It will be interesting to see how the regulatory process moves forward if KLH is, in fact, what is now named AD04.
Will Alzheimer patients wait years for treatment with KLH, when it has been used safely for decades in other indications and is now produced on an industrial scale?

[Julie G]

More about KLH:
http://en.wikipedia.org/wiki/Keyhole_limpet_hemocyanin

Keyhole limpet hemocyanin (KLH) is used extensively as a carrier protein in the production of antibodies for research, biotechnology and therapeutic applications. Haptens are substances with a low molecular weight such as peptides, small proteins and drug molecules that are generally not immunogenic and require the aid of a carrier protein to stimulate a response from the immune system in the form of antibody production.[3] KLH is the most widely employed carrier protein for this purpose. KLH is an effective carrier protein for several reasons. Its large size and numerous epitopes generate a substantial immune response, and abundance of lysine residues for coupling haptens allows a high hapten:carrier protein ratio, increasing the likelihood of generating hapten-specific antibodies. In addition, because KLH is derived from the limpet, a gastropod, it is phylogenetically distant from mammalian proteins, thus reducing false positives in immunologically-based research techniques in mammalian model organisms.

KLH can also be a challenging molecule to work with because of its propensity to aggregate and precipitate. Aggregates remain immunogenic, but limit the ability to conjugate haptens, and are difficult to manipulate in the laboratory. A high-quality KLH preparation with clear opalescent blue color is the best indicator of KLH solubility.

[J11]

biosyn manufactures KLH on an industrial scale.

http://biosyncorp.com/start/

This is their documentation for their KLH products.
http://biosyncorp.com/fileadmin/biosync ... acmune.pdf

How could this be patented for Alzheimer's disease treatment?

[SusanJ]

Good find, J11. And KLH does contain copper. Used as adjuvant in cancer vaccines. Now lets just hope they don't get overharvested (see wiki article), or maybe someone needs to invest in figuring out how to raise them.

http://en.wikipedia.org/wiki/Keyhole_limpet_hemocyanin