Why are new drugs failing?

Why are new drugs failing?

The FDA’s recent decision to pull Pfizer Cox-2 inhibitor Bextra from the marketplace clearly jolted both Pfizer and the market. Pfizer was initially caught up in the Merck Vioxx dilemma months ago and its stock has declined from $38 per share a year ago to under $25 per share in February. It has recently moved up to the $27 level.
This activity still represents a drop of about 30 percent in the last 12 months.
Though Pfizer still leads the industry with a market valuation of almost $207 billion, this is still a big decline to the tune of more than $80 billion (or more than the total value of Abbott Labs!). Though major Cox-2 product Celebrex is still on the market, this usage will be significantly curtailed due to its potential cardio toxicity and new label warnings.
What about poor Merck?
Merck had been chugging along a year ago with a stock price in the $46 to $47 per-share range compared to its close last Friday of $34.80 per share (and a low in November 2004 of about $25 share). Currently worth about $77 billion, Merck has dropped about 26 percent from a year ago and lost market valuation of about $15 billion.
What’s this all about? Has the FDA been too easy on drug and biotech companies? Does the FDA do a poor job of surveillance once drugs are on the market? The FDA’s action on Bextra was clearly in part due to public criticism of perceived FDA laxness.
The reality is that all drugs have side effects. These side effects are exacerbated in three ways:
• Amount of the drug taken (i.e. more drug equals more potential side effects)
• Food impact (i.e. certain foods can either potentiate or eliminate the effect of drugs)
• The simultaneous use of other drugs at the same time (this is called “drug-drug interaction”)
In reality, the FDA’s action has nothing to do with the above.
While the FDA for some time has been concerned with drug side effects, it is particularly sensitive to cardiovascular side effects (those affecting the heart). It has mandated in the last few years that drug and biotech companies perform additional pre-clinical (animal) and clinical (human) testing of cardiac effects (particularly those known as “QT interval” testing).
What is QT interval testing? The QT interval is a measure of the heartbeat as seen in an electrocardiograph (EKG) readout. It shows the heart’s rhythm and predicts if a drug can potentially alter the rhythm of the heart from its normal pace causing arrhythmias (abnormal heart beat).
Mandated in the last few years by the FDA for all new drugs, this additional testing is necessary as there are very large classes of drugs. A number of them are used to treat diseases of the central nervous system (CNS), cancer and even pain management (the Cox-2 inhibitors), which cause arrhythmias and can lead to heart failure or are cardio toxic.
A biotech company in Boston that has made its central business strategy the reduction of drug side effects is Sepracor (Nasdaq: SEPR).
It took Sepracor many years to establish its unique concept and convince skeptics of the rationale for its business model. Sepracor’s persistence has paid off as it currently is worth about $6 billion and had annual sales close to $400 million last year. This puts the company within the top 20 biotech companies worldwide.
Sepracor works with chiral drugs or racemic mixtures. These are drugs that have dual mirror-image chemical structures (each called enantiomers). Sepracor splits these chiral drugs into two single enantiomers.
The theory is that one enantiomer is usually safer than the other while sharing equal or superior potency. Sepracor then patents the enantioner and theoretically has a better and safer drug than the original. Sepracor’s strategy revolves around picking chiral drugs that have already been marketed by other companies and are already successful.
During its early years, Sepracor would approach the company already marketing the successful chiral drug and offer its services to create a second-generation-approved product with new patent life. This strategy was successful with companies like Schering-Plough and the anti-histamine Clarinex (anti-histamines are also classes of drugs with known cardio toxic effects).
While the Sepracor solution provided a patented and elegant new version of the same drug in concept, the problem was that the side effects didn’t always subside with the enantiomer. Nevertheless, there are an abundance of chiral drugs and Sepracor has a big field in which to play.
The big issue for both Big Pharma and biotech companies is to identify any potential cardio toxicity before a drug starts clinical trials because most of drug development money is spent at this stage.

Getting to the Heart of the Matter in Chicago

Enter stage left a new Chicago-based company called CorDynamics. Its company slogan, which is “getting to the heart of the matter,” aptly describes what this company does for a living. CorDynamics, which is located at the Chicago Technology Park in the Illinois Medical District, was created by enterprising ex-Searle/Pharmacia toxicologists Mike Gralinski (CEO) and Peter Senese (COO).
They brought in yet a third partner from academia named Elaine Tanhehco (chief scientific officer) from Henry Ford Hospital in Detroit. Tanhehco concentrated on cardiovascular pharmacology (where she looked at the pathphysiology and treatment of heart failure) after post-doctoral training in pathology at Brigham and Women’s Hospital in Boston.
CorDynamics is a contract laboratory that specializes in assessing the cardiovascular effects of new drugs. Given the FDA’s concern about this area, it appears that CorDynamics is in the right place at the right time to hit the FDA’s “sweet spot”. The company has already successfully obtained biotech and pharma companies as clients from both coasts and is mining Europe for further business.
CorDynamics uses what’s called the “isolated heart model,” which has a series of benefits for a drug company partner in evaluating its drug candidate. These include:
• A multi-dimensional look at the drug’s cardiovascular effects
• Highly reproducible tests that confirm results
• Doesn’t require a lot of drug (at this stage of experimental development, a company may not have scaled up the drug in large quantities)
• An ability to complete dose-response testing (allowing the company to see the effect of larger amounts of the drug)
• Testing of combinations of drugs to look at the drug-drug interaction
• Running of animal cardio tox tests in a relatively cost-effective manner versus traditional cardio tox studies
The isolated heart model uses a rabbit heart model to determine the effects of new drugs on coronary vasculature and cardiovascular pump function. CorDynamics looks at the left ventricular function, vascular resistance and myocardial contractility.
The company’s initial labs are small – just 1,300 square feet – but as its customer base is rapidly expanding, CorDynamics may soon need to add on additional space and personnel. The cardiovascular problems of the Pfizer and Merck drugs suggest that this may be the tip of the iceberg for the pharmaceutical industry.
By the way, CorDynamics is just one of two toxicology contract companies operating in the Chicago area and composed of ex-Searle/Pharmacia employees. Another group is called Midwest BioResearch. It operates out of the Evanston Research Park at Northwestern University and is led by president Mike Schlosser.
Schlosser had been senior director of safety sciences at Pfizer/Pharmacia/Searle. Before that, he was director of experimental toxicology and pathology at Astra Pharmaceuticals. He also had a similar role at Ciba-Geigy Pharmaceuticals. He is backed up by an experienced toxicology group that all came from Pfizer/Pharmacia/Searle.
The message here for any up-and-coming biotech company (or even Big Pharma) is that it’s more cost effective to thoroughly test your new drug at a pre-clinical stage of development before going into human clinical trials, which are much more expensive and time consuming.
To the degree that you can pick up signs of potential drug toxicity early and “predict” drug behavior in humans, a decision on advancing or “killing” a drug can be made without further expense. All of this is congruent with where the FDA is heading.
Another approach being taken by biotech companies has been to design drug-delivery methods for improving the delivery of drugs that are capable of reducing the cardio toxic side effects of key drugs.
While this approach has been useful particularly for cancer drugs, it seems to have limited impact beyond this class of drugs. NeoPharm in Lake Forest, Ill. has been a leader in this arena using its lipid-based systems. More recently, American Pharmaceutical Partners has been another leader here as it has launched Abbraxane, which is its improved form of the widely used cancer drug Paclitaxel.
Still another approach has been to design new prodrugs of existing drugs. A prodrug is a chemically different but biologically similar form of a drug. While the prodrug converts into the original drug once it is metabolized within the body, it usually avoids a number of the side effects of the original drug. The prodrug can be chemically designed to engineer out certain side effects (such as cardio toxicity).
Barbeau Pharma in Northfield, Ill. has been working for years with prodrugs of already marketed drugs in the U.S. that it has identified in other countries. More recently, the company has moved into designing its own prodrugs that are free of cardio toxicity.
This whole area will become increasingly important with the increased FDA vigilance of drug side effects and in particular cardio toxic side effects. It appears that a number of Midwest-based companies are poised to take advantage of this situation. See you next week!

Michael S. Rosen is the chairman and CEO of Immune Cell Therapy, a new start-up out of the University of Illinois at Chicago developing cancer vaccines. Rosen is also a founder and board member at the Illinois Biotechnology Industry Organization (IBIO). He can be reached at rosenmichaels@aol.com.

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