The challenges of discovering a new medicine

It’s hard to imagine a task more difficult than searching for a new medicine: it’s been likened to searching for a particular grain of sand on a mile-long stretch of beach. Behind every new medicine that makes it into a patient’s hand, lies the story of a research team with extraordinary abilities, knowledge and technologies that guided the searching and sifting of the sand grain’s molecular structure.

Their story begins with a novel idea, continues with hard work over a decade and lives on through the millions of lives that are extended and the scientific discoveries that are gained.

Our grain of sand is the molecule celecoxib, or Celebrex®, a medicine for osteoarthritis, rheumatoid arthritis and pain. We posited that there were two COX (cyclooxygenase) enzymes; COX-1 involved in normal housekeeping functions and COX-2 involved in inflammation. After years of work by our research team, involving the chemical synthesis of thousands of candidates and extensive testing through a battery of biological assays, we were successful in selectively blocking the COX-2 enzyme and identifying a safe and effective candidate.

Clinical trials of Celebrex began in 1995. Three years later we submitted an application to the U.S. Food and Drug Administration (FDA) and received an accelerated review. Celebrex was approved in 1998 for osteoarthritis and rheumatoid arthritis and today new uses for the medicine continue to be uncovered, including its efficacy in helping to stop the growth of precancerous polyps or adenomas that can become colon cancer.

Not every researcher is fortunate to make it to this point. The time spent trying to find one successful compound and move it through development, testing, trials, FDA approval and to patients is measured in years. It takes an average of 10 to 14 years to move a compound from an idea in a scientist’s mind to a marketed medicine available to patients. The time involved means the typical short-term emotional incentives for going to work each day do not apply for research scientists. It takes a persistently optimistic person to thrive in this business. A focus on the potential impact that their efforts will have on patients is essential. In some cases, the researchers themselves live with a disease.

The expense is enormous, too — it takes as much as $1 billion to bring a single drug to market, which translates to millions of dollars a week to fund hundreds of early-stage, preclinical discovery projects; the majority of those efforts will not pass. With data as a guide and patients’ safety the utmost concern, researchers jump from hurdle to hurdle. Ideas for new medicines are born in discovery where biologists, well versed in how a particular disease affects the body, identify a specific biological target, usually a gene or protein that plays a role in the onset or progression of a disease.

Then, teams of chemists synthesize thousands of compounds that show promise in affecting the target. For every approved drug, 5,000 to 10,000 compounds synthesized and evaluated don’t make the cut. Hopefully, out of that extensive evaluation come a number of “lead compounds,” molecules that have all of the desired properties. Traditionally, most of these lead compounds are small molecule drugs which are then developed as pill-in-a-bottle medicines or biological drugs developed from larger, more complex protein-based molecules that are injected rather than swallowed to treat the disease. Either way, getting to this point is one of the many small victories along the way.

Now, the molecule is a lead drug candidate, and it moves into the clinic where all eyes are watching to see how it performs in people. These carefully conducted trials begin in Phase 1 with dose-ranging assessments in 10 to 20 healthy human volunteers. New teams of scientists utilize the data gained to determine the molecule’s metabolism and safety. This information allows them to move to Phase 2, where they try to prove the original laboratory hypothesis in some 40 to 60 patients: Does the drug candidate hit the target? If so, what does it do next?

Once the concept is proven in small groups, the study moves to Phase 3 clinical trials and thousands of patients who fit the target profile are studied. This final phase, if the teams’ drug makes it this far, can take many years and involve many patients. All the while, the original discovery team waits and watches to learn about the compound’s effectiveness, potential side effects and how long it lasts in the body.

If the compound does not clear Phase 3 trials, scientists use the knowledge they have gained to either terminate the program or identify candidates with even better properties. If the compound is successful, a New Drug Application is filed with the FDA that includes an enormous amount of data from both preclinical and clinical studies. After careful review, involving discussions with panels of experts and requests for additional information, the FDA decides whether the new medicine will benefit patients. When, and if, the drug receives government approval, there is great joy and jubilation among the scientists who labored so long and hard for this ultimate victory.

The struggle to create a new medicine is indeed long and arduous. But what can be more rewarding to a scientist than to overcome these many challenges

and see their work translated into a medicine that alleviates suffering or prolongs life?