Gettysburg Medical News
The Clinical News
by P.E. Hoffsten, MD
13 June 2007 

ANIMAL STUDIES – WHY?

            When a new drug is brought to the market, extensive studies have already been done in test tubes and then in animals before studies in humans have been begun.  The question is often asked as to why animal studies are done when application to humans may not be valid or useful not to mention the “cruelty to animals’ issue”.  The story below describes an animal study recently completed in the investigation of a new drug called aliskiren (Tekturna).  It is an excellent example of why animal studies are important. 

            Last week’s column was devoted to a blood pressure maintaining system of hormones called the RAS system.  One component of this system is called renin and its action is the pivotal step in activating the RAS system.  For more than 40 years, scientists have recognized that if this step can be effectively blocked safely, a very useful blood pressure medication will become available. 

            Over the past 40 years, the renin protein has been studied and its chemical structure determined using a scientific tool called x-ray crystallography.  The active site on the renin molecule was mapped.  Then on the drawing board, a chemical was devised that would specifically block this active site on the renin molecule.  After several failures, a chemical molecule was found called aliskiren.  It was found that in test tubes this newly devised molecule would block renin activation. 

            Now question #1is:  “Will aliskiren lower blood pressure in an animal?”  In order to answer this question, there needed to be an animal model of high blood pressure to see if the aliskiren would work.  Starting with experiments in humans is not felt save so an animal model is needed. Unfortunately, rat renin is not the same as human renin and aliskiren really had little effect on rat renin.  So the genetic scientists did a most amazing thing.  They transplanted the human renin gene into a rat; but then came the second problem.  The human renin in the rat would not activate the rat’s RAS system.  This was because the protein called angiotensinogen that renin activates was different in rats as compared to people.  Thus scientists had to do the second trick of transplanting the human angiotensinogen gene into a rat.  This was achieved also.  Next, came the very clever trick of cross breeding the rat with the human renin gene with the rats that had the human angiotensinogen gene.  When this was done, we finally had a rat that had both human renin and human angiotensinogen in the same rat.  This rat with the two human genes became severely hypertensive and died of a stroke by eight weeks of age.  Normally a rat lives to three years of age. 

            So the stage was set.  Scientists now had a rat model that had both human renin and human angiotensinogen.  This rat developed severe hypertension and died of strokes by eight weeks of age. 

            Then question #2 is:  “Will aliskerin prevent the high blood pressure that occurs in this rat model with human renin and human angiotensinogen?”  The answer was yes.  When aliskiren was administered to this animal model of human hypertension, the high blood pressure was prevented.  But, that is still not enough to say the drug should be tried in humans.  The drug first had to be certified as safe.  That was shown in the rat model.

            Now the most important question #3 is:  “If the high blood pressure is prevented in this animal model, will the rat live normally and avoid the problem of strokes and heart disease?”  The answer to this question was an emphatic “yes”.  Once the blood pressure elevation was prevented, this animal model of high blood pressure did not develop strokes, did not develop heart disease, and did not develop kidney disease.  The natural history of this animal model without aliskiren was the development of very high blood pressure, strokes, heart strains and kidney failure.  All of these were prevented with the drug aliskiren in this animal model.  Note this research could be carried out and completed in the course of a single year once the animal model and the drug were available.  Such experiments would take at least 5 years to carry out in humans and the safety of the drug would not be certified prior to starting the experiment.  Thus to carry out these experiments in humans would be both risky and very time consuming.  In an animal model that could all be done very quickly and without the risk to human life. 

            Now question #4 is:  “Will aliskiren prevent hypertension, heart disease, stroke, and kidney disease in humans? “  The drug has now been released on the market to treat hypertension.  Studies have been carried out in humans demonstrating that the drug is safe with very few side effects and effective to prevent hypertension.  But the more important question long term, is will it prevent heart attacks, strokes, and kidney disease in humans.  To determine that in humans is going to cost at least 3-5 years of studies that are in progress at this time.  At this point, the drug can only be certified to be an effective anti-hypertensive drug.   Whether it will prevent end organ disease is in process but the studies in animals are very promising.

            So now question #5 is:  “Why do our new drugs cost so much?”  Satisfying the demand of the American public for medications that are both safe and effective is the primary charge of the FDA.  For a drug to be filed with the FDA, it costs an estimated $450 million dollars before pill #1 is ever sold.  An example of how risky this type of endeavor can be is a recent Pfizer Pharmaceutical Company’s application for a new drug to treat high blood cholesterols.  When experiments were done in humans before release on the market, this drug was found to have a higher mortality in the treated group than in the group not treated.  Pfizer Pharmaceutical Company is estimated to have lost a billion dollars in this effort and they will never sell pill #1 of this drug.  Yes, our drugs do cost a large amount and the safety and effectiveness is the paramount demand of the American public and that doesn’t come cheap.  After that $450 billion dollar investment in making the new drug applications come the post marketing phase certifying drug safety after it is released to the public.  Drug companies have to monitor their medication for safety and side effects after it is released to thousands or even millions of people in the general public.  Continued review is the mandate of the FDA and costs millions of dollars more.  Even then recall of Baycol and Vioxx are examples of drugs that went down the drain in the post marketing surveillance period with massive losses to the drug company that developed these medications. The Avandia mess is still in flux.  Progress does not come cheaply.