March 14, 2006 | NEW YORK — Peter Kim, president of Merck Research Laboratories (MRL), says that small changes in the drug discovery and development process can yield significant benefits in bringing new drugs to market. At his keynote speech at the Biotechnology Industry Organization (BIO) CEO Conference in New York last month, entitled “Creating New Hope Through Research,” Kim discussed Merck’s strategies to fill its pipelines and get more drugs approved. “[It’s a] very exciting time in terms of what we can bring to patients,” said Kim.
MERCK MOVES: "We are
using biomarkers and taking
prudent execution risks,"
says Peter Kim.
Kim’s speech was a welcome opportunity to escape the problems posed by the Vioxx debacle and instead focus on Merck’s vision. But Kim did acknowledge the plethora of financial and regulatory issues that complicate bringing new drugs to market. “The pressure on this industry is very real and severe and increasingly we need to figure out how to respond to the pressure,” Kim said. “Discovery and development of new drugs and vaccines is incredibly hard and the probability of success is very low. It adds to the challenge we all have.”
In practical terms Kim believes pharmaceutical companies must focus on improving productivity, especially in the first two phases of clinical trials. All pharmaceutical companies face similar challenges — increased spending on R&D, declining success rates, and increased price sensitivity and pressure from various groups on pricing. There has been what Kim calls a “democratization of the drug discovery process,” whereby virtually all drug companies use the same technology approaches, thus eradicating any inherent advantages over one another.
Against that backdrop, Kim argued that relatively small gains or advantages in drug discovery and development have the potential to produce significant benefits. “You want to increase the probability of success,” said Kim. “This is a low probability business, so if you make even a small change, it can have a [high impact].”
Swimming in the Deep End
Five years ago, Edward M. Scolnick hired Kim, an academic structural biologist with no drug industry experience, to join MRL as executive vice president, R&D. Kim was Scolnick’s heir apparent as MRL president — a post he assumed in January 2003. But less than two years later, Kim had to call then Merck CEO Raymond Gilmartin with news that a clinical trial committee had recommended halting a study of Vioxx. Merck voluntarily withdrew the COX-2 inhibitor a week later, and the aftershocks are still being felt today as Merck battles an estimated 10,000 lawsuits.
Before joining MRL, Kim spent a dozen years at the Whitehead Institute, researching the mechanism of protein folding and the structure of viral proteins, especially those of HIV. His studies helped to develop new drug candidates for treating AIDS.
Today Kim and Merck also face the pending patent expiration on its statin blockbuster Zocor, and reorganization stemming from 7,000 job cuts last year, which will save roughly $5 billion.
To select better drug targets, Kim is touting new technologies such as RNA interference (RNAi), which Merck is using to avoid off-target activity. Last year, Merck ran more than 1 million RNAi arrays through its labs — a fivefold increase from the previous year. Additionally, Kim noted that the company is collaborating with partners in knocking down genes in animals. Other areas of interest include molecular profiling to identify gene signatures for efficacy, toxicity, and side effects. And there is an increased effort to identify biomarkers. But here Merck is using an interesting approach.
Kim said the question Merck asked itself was, “How do you use the external world to discover biomarkers?” In the case of its work in atherosclerosis, Merck is collaborating with FoxHollow Technologies. Under the collaboration, Merck obtains pre-dose and end-of-dosing-period plaque samples to use to develop biomarkers.
Looking to new technologies to help select and identify potential new drug candidates is just part of Merck’s effort to speed a drug through Phase I and II trials. Merck is using biomarkers and other information to help decide which drugs to concentrate on. One strategy involves gathering useful information from drug candidates that have poor pharmacokinetic (PK) properties. For example, a candidate that has to be dosed many times a day might not be commercially viable. But testing it for other ADME mechanisms before conducting human tests might help identify characteristics to look for in another drug candidate with better PK properties. “We are using biomarkers and taking prudent execution risks to shorten the cycle time,” said Kim.
He noted there have been several examples where the technique is yielding measurable results. For instance, Sitagliptin for type 2 diabetes (known as MK-0431) and an integrase inhibitor (MK-0518) for HIV treatments took, respectively, 2.1 and 1.8 years to go through Phases I and II. (The norm is 3.5 years, according to CMR International.)
Merck is also relying on more partnerships to acquire best-of-breed technology. “Alliances are essential to our strategy,” said Kim. Last year, the company had more than 5,000 initial interactions with potential partners. Those initial approaches were whittled down to more than 600 exchanges under confidentiality agreements. By year’s end, Merck had signed 44 deals.
Another area that Kim stressed is the role of manufacturing. Once a new drug is approved, manufacturing takes over. “You have a drug ready to go, but you have to hand off between two organizations [R&D and manufacturing],” said Kim.
Merck has established a group that takes charge of the process, with the goal of shortening the cycle time to get the drug out the door. Kim believes any time saved here is essential. “Everything has a patent life, near the end of the patent you wish you had [done everything in manufacturing] a couple of months faster.” The combined efforts to improve the R&D process in small but significant ways seems to be paying off. Last year, Merck had 23 molecules entering humans for the first time — a number that is trending upwards.