The Other Side of Drug Discovery, Part 2

By Jason Socrates Bardi

In "The Other Side of Drug Discovery, Part 1", TSRI investigator Tamas Bartfai says, "If you make a truly original drug that has a health benefit, people will eventually buy it."

However, drug design is not all wine and roses.


Drug development is the single most regulated human activity. The mandate of the FDA is to protect the public against dangerous drugs, and they do this in a variety of ways, including monitoring approved drugs on the market for unexpected health consequences, reviewing drug applications, and mandating full disclosure in drug labels and advertisements.

Nevertheless, regulation limits the number of drugs that companies can bring on the market, and forces the pharmaceutical companies to make tough choices. Often these choices involve research and development, which sometimes directly affects investigators at universities and institutions like TSRI who partner and collaborate with scientists in industry.

Bringing a drug from the test tube to the prescription bottle costs in excess of $500 million on the average. The amount of this spent on initial research and development may be miniscule by comparison with the clinical trials and the marketing expenses—perhaps only 1.5-5.0 percent of the total.

"The marketing costs, for instance," says Bartfai, "are usually 15 to 20 times the cost of researching the drug."

For the most part, basic research is blind to this sort of decision making because an equal amount of science goes into making a small drugs and big drugs. "With equal ingenuity, you can make a drug that will sell for $100 million or one that will sell for $100 billion by the end of its lifetime," says Bartfai.

But when companies are selecting drug candidates for the proverbial $500 million check, they make sure that the candidates make good economic sense. A new anti-epileptic, for instance, poses formidable economic challenges because of difficulty testing it. "If you cannot figure out how a drug can be tested, you cannot make the drug," says Bartfai.

Consider that there are three types of epilepsy patients: those who are not yet diagnosed and therefore not taking medication; those who are diagnosed and currently taking approved medications; and those who are diagnosed but who are resistant to current medicines.

The best population in which to test a new drug would be newly diagnosed patients, but one would have an uphill battle overcoming doctors' bias towards existing drugs. Why would a doctor put a patient on an experimental drug when there are others that seem to work just fine? One would need an extraordinary amount of data suggesting that the new compound is significantly better.

And anyone who is currently taking an anti-epilepsy drug and doing just fine would not stop to take a new, experimental drug and risk having a seizure. Nor would a doctor recommend an experimental drug to a patient who is responding well to an approved one.

That leaves only the group of people who are resistant to all existing anti-epileptic drugs, who would not be the best test population

"Is a new anti-epilepsy drug a great discovery?" asks Bartfai. "Yes. But does it have great commercial value? No."

"If you want to make a drug that acts on the brain," he adds, "if, then the marketing and clinical development departments will suggest you make a drug for Alzheimer's disease."

Commercial Accessibility

People will only switch to a new drug if the new drug is substantially better—for instance if it is 10 times more powerful, if it can be taken orally rather than injected, or taken once a day as opposed to once every four hours.

In the same vein, there are many drugs that fail because of their side effects, despite the fact that they actually work very well. For instance fat absorption blockers should be a raging success story in the United States, where according to Center for Disease Control and Prevention (CDC) estimates, nearly a third of the adult population is obese. These drugs should allow people to literally have their cake and eat it, but they are one of the failures in the annals of drug design, because they prevent the absorption of fat with the undesirable side effect of causing diarrhea.

However, says Bartfai, if a new drug were to be invented that had the same effect without these side effects, it would be a huge success.

In addition to toxicity, bioavailability, synthesis, and efficacy, a potential drug's commercial accessibility makes a big difference to pharmaceutical companies. Doctors will choose whatever drugs they know to treat the symptoms they see, and if there is not a compelling reason to switch to a new drug, they won't.

"The rule of thumb is that any physician can remember three drugs for any set of symptoms," says Bartfai. "If there are 17 drugs in your category, and you are not in the top three, then forget it." That makes marketing the decisive factor for success of the Pharma companies.

Novel compounds that elicit an existing effect may not be worth the effort of developing into a licensed and approved drug.

"Once you make a human heart beta-receptor and a slightly better one and a slightly better one, there's not much left," says Bartfai. "People buy an effect—they don't buy a new mechanism. No physician or patient is convinced by a new mechanism."

All of this adds up to a drug development landscape that is pock-marked with pitfalls and chasms that can derail a potential drug's success even after it has emerged as a highly successful candidate. Communicating how to navigate this landscape is one of Bartfai's goals for the lectures.

To address this gap in knowledge between the academic and corporate worlds ,"[Bartfai] offered to give these lectures as a primer," says Skaggs Institute Director Julius Rebek.

"Since I came here, I have [had] about five colleagues each week asking me something about drug development," Bartfai says. "People have asked me questions like, 'Why did they stop the development of this drug that we have worked on?'"

He has been asked to look at their business plans or to clear up confusion over a decision by a large company with which they collaborate, for instance, or to help make sense of a new request.

The Sociological Imperative

Another perspective Bartfai hopes to address during the upcoming lectures is how the pharmaceutical industry is highly sensitive to the social context in which it exists.

Drug development follows trends and these trends are informed by the public's actual and perceived wants and needs. In America today, that does not simply mean demands from patients and from doctors tending to their patients' needs, but also pressure from patients' interest groups and health maintenance organizations and other large demographic forces.

We are an aging society. The CDC estimates that by the year 2030, there will be 70 million elderly Americans—more than twice the current number. And the United Nations recently estimated that population of people in the world over the age of 60 will reach two billion within 50 years.

This aging of America and the rest of the world means an increased demand for better compounds to combat those diseases and indications specific to the elderly, and the pharmaceutical companies are a weathervane of this demand.

For instance Alzheimer's disease, which is believed to afflict four million Americans, is now a major area of research. Our aging society has recognized and understood the need to confront the problem of Alzheimer's disease, and today, according to Bartfai, there is no self-respecting pharmaceutical company that does not have 5-15 Alzheimer's programs. Yet this has not always been the case.

"If somebody stood up in 1970 and said, 'I want to make an Alzheimer's drug,' he would not only have not got any support within a drug company, but he would also not have gotten a grant from the NIH [National Institutes of Health]," says Bartfai.

Similarly, other targets of pharmaceutical research are aimed at an aging America.

Osteoporosis drugs are needed to combat the deterioration of bones in the elderly, one of the leading causes of loss of quality of life in later years. Some 44 million Americans—most of whom are women—have already developed osteoporosis or the early signs of bone density loss that lead to it. As our population ages, this number will only increase, and osteoporosis blockers are a major target for pharmaceutical companies. Many companies are also taking aim at other age-related ailments like arthritis, Parkinson's disease, and urinary incontinence.

Besides being an aging society, we are a society that is increasingly aware of mental illness and increasingly more willing to medicate it. Antidepressants already make up one of the largest markets in the United States, amounting for around $15 billion annually. However, there is still a great need for a fast acting antidepressant. Normal antidepressants take two or three weeks to take effect, and as many as a third of patients do not respond to the drugs. This is problematic because the core symptom of serious depression is suicidal tendencies. In 1997, for instance, 30,535 Americans committed suicide, making it the eighth leading cause of death in the United States that year. One of Bartfai's own longstanding goals is to develop a quick-acting compound for the treatment of depression. "We just don't know how to make such a tablet yet," he says.

Some of the other drug targets today are high-profile diseases, like AIDS and various types of cancer. From a global perspective, there is a need for vaccines for tuberculosis and malaria, both major health problems worldwide.

"People would like to have vaccines [against TB and malaria] without a shadow of a doubt," says Bartfai, "Even the rich countries have come to realize that helping to eradicated these diseases would be a formidable form of aid, not only to third world, but also to countries such as Russia with 26 million tuberculosis cases."

Other drug targets are not so obvious to those outside the field, such as drugs to control asthma and other respiratory infections and constrictions, preventative migraine medicine, or a decent (safe, less side-effect prone, but efficacious) acne drug—the market for which, Bartfai insists, should not be underestimated.

"If someone came up with [a decent acne drug], it would sell for billions," says Bartfai.



Upcoming Lectures:

TARGET-BASED DRUG DISCOVERY, on Thursday, May 2. Topics to be discussed include validated drug targets: what they are and for whom, a determination of their value, and comparison of targets for the same clinical indication.

SELECTION OF CLINICAL CANDIDATES: MULTIPLE PRESSURES, on Thursday, May 9. The presentation will focus on the key milestones of preclinical drug development—timing, expenditures, backup strategies, outside validations, and orphan drugs—as these factors play out in big Pharma decision making.

Lectures will be held from 5 to 6:30 PM in the Neurosciences Institute Auditorium, 10640 John Jay Hopkins Drive.


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When companies are selecting drug candidates, they want to make sure that the candidates make good economic sense, according to TSRI investigator Tamas Bartfai.