More Failed Studies of Antibody Treatment for Alzheimer’s Disease.

I was unaware that the  result from Lilly was not the only recent major failure of a clinical trial of antibodies to the amyloid plaques in the brains of Alzheimer’s patients.  It seems that many other big and little-name drug companies have been trying the same approach with their dozen or so different antibodies. Each is trying to make it to market first where the biggest money lies.  (Consumers should beware when the commercial pressures are this great.)

Last month, Pfizer and its partners announced a similar failure of several studies which showed no clinical improvement when their particular antibody, bapineuzumab, was administered to several thousand patients over 18 months.

It seems to me that this is a lot of effort for what was at best a theoretical possibility of effectiveness.  The brains of patients with Alzheimer’s syndrome contain microscopic clumps (plaques) made of a sort of featureless “junk” containing a protein called beta-amyloid. It has never been shown that the plaques are the cause of the loss of brain function or whether they are just another result or marker of the disease.    It is oh so easy to jump to conclusions in medicine.

Humans and other mammals make countless different protein antibodies to infectious agents and damaged tissue that protect and maintain the body. Each family of antibody is specific to its corresponding target antigen in the classic sense of a key and lock.  Once the antibody attaches to its antigen, the combination activates the inflammatory process and signals the body that a “bad” actor is present. The body’s cleanup and disposal systems attempt to neutralize and remove the target antigen.  Much of the time this works to our advantage and we are protected from an offending bacteria or virus.  (This is why immunization against disease is effective.)  However, the antibody-induced inflammatory process is not always on target: autoimmune disease can result when we make antibodies against ourselves.  Sometimes the inflammation overdoes it and normal tissues are damaged.  This is what happened in some of the early attempts to induce antibody against beta-amyloid in the brains of people with Alzheimer’s disease.  When patients were immunized against their own amyloid, they had swelling and bleeding of the brain that did not simply go away. This was worse than the disease for which the treatment was offered. (Not an unusual occurrence even in modern medicine!)

Instead of immunizing people against their own brain tissue, this series of clinical trials used intravenous man-made antibodies to beta-amyloid. (In related trials, pooled antibodies from normal people are given in the hopes to open up this gigantic market.  No disease can be called incurable until normal immunoglobulin has been tried!)  The hope is that the antibodies will attach to the Alzheimer plaques, that the plaques will go away, and that brain function will improve.  However, functional improvement has not occurred, and because no brain biopsies have been done, it cannot be said that the brains did not suffer collateral structural damage from antibody-induced inflammation.  The party line that seems to be coming from the the drug companies is that just because the drugs do not work in patients with mild to moderate disease, perhaps they will work in patients who are asymptomatic!  Any of you normally-functioning people out there ready to sign up for such a study?

No one wants a successful treatment for Alzheimer’s syndrome more than I do– believe me.  This current conundrum stems in part from a change in paradigm for clinical research.  When I started in medicine, the first order of business was to try to understand the cause of disease and the mechanisms involved.  Nowadays, in the rush to find a blockbuster for your company or university, understanding the cause of the disease seems to take a lower priority.  Getting to market in my opinion, even for a short time, seems to be all.

The studies referenced above and similar ones must have been fantastically expensive to conduct.  In my mind, using the money to learn more about the underlying disease, or even providing more practical solutions to families who suffer as a unit from this disease would have been a better use.  What I predict is that the companies will lobby the FDA to approve even more modest  goals and to try to find some way to sell their expensive drugs to recover their development costs.  Desperate families will line up in support.  The families, but not the companies have my sympathy.  I only ask of my fellow Alzheimer sufferers that they consider the principles I have offered elsewhere.  It is always possible to make a bad situation worse.

Peter Hasselbacher, MD
President, KHPI
Emeritus Professor of Medicine, UofL
Sept 2, 2012

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