For the past several years, Peter S. Kim has been obsessed by failure. Now, at last, he is unveiling his plan to combat it.

Since he became president of Merck Research Laboratories in 2003, Kim has had a bird's eye view of the biggest post-marketing debacle in pharmaceutical history—the withdrawal of the pain reliever Vioxx. If what happened with Vioxx wasn't bad enough, leaks have plagued Merck's development pipeline. Some of the first announcements Kim had to make at Merck concerned canceling key programs, including some of the company's brightest hopes—aprepitant for depression and MK-767 for diabetes. Aprepitant just did not work well enough in that indication, while MK-767 caused troubling symptoms in a mouse model.

Merck has thus become the poster child of the industry's chief woes—too few products reaching market and too many unexpected safety problems with those products that do make it. Fixing those problems is Kim's job, and he is not under any delusion about the scope of this challenge. Nor does he seem particularly distressed by it, however. "The pressures are real, and they are here to stay," he said plainly, speaking to the BIO-CEO attendees in New York City on Tuesday, February 14.

Kim went on to share his plan for how the company will emerge from this mess.

Merck has long touted its scientific strength, and despite the setbacks, the company still comes through with truly breakthrough medicines, such as the two vaccines it recently developed—one for cervical cancer (Gardasil) and another for rotavirus (Rotateq). Achieving more such successes and fewer failures, according to Kim, means sticking with a policy of top-notch internal research while retooling the discovery process.

Pharmaceutical companies have been whining for years about the cost of late-stage failure, and enumerable technologies have been offered up as miraculous tools for filtering bad drugs out of the pipeline. But drugs can be bad for a wide variety of reasons, as an internal review has revealed at Merck. It is not only surprise toxicity or poor bioavailability that are killing candidate compounds these days. Most often, the drugs just do not work well enough to be competitive, especially in the more crowded markets.

It is an incredibly complicated problem, with almost every would-be drug requiring its own set of solutions. But the process Kim shared, he says for the first time, is a new model for pushing development candidates forward.

Merck has established a proof-of-concept (POC) process that runs in parallel with the early development stages for any drug.

While the lead compound series is being tested in preclinical and then human studies, simpler, better-understood molecules against the same target are being simultaneously run through a battery of studies aimed at getting a deeper understanding of the related biology. These POC molecules might be monoclonal antibodies, drugs with poor pharmacodynamic properties or that require intravenous delivery, or compounds with a limited patent life: For one reason or another, they are not suitable commercial products, but they are useful for what they can tell the Merck scientists about that target and the implications of interfering with it.  Based on that information, Merck can then decide if the project is worth pursuing, too risky, or just not the right fit for its pipeline.

Scientists at Merck have a different "early development mindset," he said. "We develop disease and target proof-of-concept tools as we are discovering and developing a lead compound."

Kim believes his new strategy is already paying off. He points to Merck's pipeline, which is considerably fuller than it was three years ago. Merck scientists have also shaved months, and sometimes even a couple of years, off of drug development times. But as he said, "The real proof will be seen at Phase III and marketing."

Merck is not the only company taking such an approach. Biomarkers, proof-of-concept, and failing fast have been the watchwords of pharmaceutical discovery over the past few years. But Merck is one of the biggest companies applying such a new process across its entire pipeline.

This greater scientific understanding, Kim said, should not just help the company with internal discovery but with picking the best collaborators and acquisitions going forward because, as Kim added, "You need good science on the inside to make the best deals."

Note: To see a copy of Peter S. Kim's slides posted on the Merck Website, click here.

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