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By Malorye A. Branca

February 10, 2003 | Millennium Pharmaceuticals Inc. is doing a lot of pushing these days. It’s trying to push its new cancer drug Velcade to market a year earlier than expected. Conversely, it has  pushed profitability out to 2006 instead of 2004 as originally projected. And, it has announced groundbreaking pharmacogenomic trial results, reaffirming its push in that pioneering field.

That last push may be the biggest surprise. To date, no company has created a single drug based on genomics, let alone one that is pharmacogenomic -- or genetically “personalized”.  That fact isn’t deterring Millennium.

In the recent Phase II trial of Velcade, Millennium didn’t just look at the drug’s effect on patients with multiple myeloma -- a rare, and usually fatal, blood cancer. More than half the 202 patients in the study also provided bone marrow specifically for genetic screening. Those patients’ entire genomes were scanned to see if a particular set of  turned-on genes can differentiate patients the drug helps from those it does not.

These results are groundbreaking, according to Geoffrey Ginsburg, vice president of molecular medicine at Millennium. “This was the first study integrated into a Phase II trial expressly to find RNA markers predictive of [drug] responsiveness,” he says. “Companies typically just look at metabolizing enzymes that flag non-responders  (patients that can’t metabolize or process the drug properly).” Those kinds of studies don’t provide nearly the detail of a genome-wide study.

Velcade is designed specifically to inhibit proteasomes, which are enzyme complexes in all cells responsible for breaking down a variety of proteins, including many that regulate the cell cycle. Laboratory studies have suggested that by inhibiting proteasomes, Velcade disrupts turnover of regulatory proteins in cancer cells and ultimately induces apoptosis, or programmed cell death (see The Promise of Proteasome Inhibitors).

Millennium isn’t just looking at markers for its own drugs. It recently teamed up with M.D. Anderson Cancer Center researchers to find drug-response markers in breast cancer patients. The collaborators found a set of five genes that seem to identify women who are most likely to be helped by a common treatment that uses multiple drugs. The next step will be to validate those markers in follow-up clinical trials. That would be another milestone, since no such markers have yet been validated this way.

A new three-year deal with the Cleveland Clinic extends a longstanding relationship, and could generate more genetic markers. The researchers will gather data from thousands of heart patients. This project is also about finding markers of drug response. If those markers are found, Millennium says it will use them to design better clinical trials and , the company hopes,new heart drugs.

All this reinforces the company’s original goal. “Millenium is committed to being a leader in personalized medicine,” Ginsburg says. “We think this will help solve some of the productivity issues facing the industry.”

But it’s not yet clear how pharmacogenomics will do that, and it makes financial analysts nervous.

“Pharmacogenomics holds very promising long-term potential, but in the near term it will require a substantial investment,” says S.G. Cowen’s Yaron Werber. “So far they [Millennium] have found interesting expressed genes correlated with tumors and pathways. The onus is to find out what those do.”

Ideally, the Velcade-response markers will hold up, and help the company get more approvals, for more drugs. According to Ginsburg, that’s a possibility. “The Velcade results are among the first that could be delivered to market,” he says.

The company recently lost several senior executives, and laid off about 5 percent of its workforce. Some analysts wondered if the executives left because they didn’t agree with the decision to speed Velcade to market. But the company says all the staffing changes are just a part of its evolution from startup to drug company. CEO Mark Levin also said last month that expenditures associated with the early launch of Velcade are responsible for pushing out profitability.

Uncertainty and probably more bumps in the road lie ahead. But with its track record of innovation, some drugs already on or near the market, and $1.3 billion in hand, Millennium is in a reasonable position to hold on to its dream, at least for a few more years.

 


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