I think when you look at the mlnm pipeline you need to start with ldp-341.
Here's a very interesting article from today's Boston Globe....
Millennium man
Scientist's belief kept study of cancer-fighting drug alive
By Naomi Aoki, Globe Staff, 12/12/2001
CAMBRIDGE - For years, Julian Adams had labored on a drug known as LDP-341. He had watched it rid mice and monkeys of all signs of cancer without the devastating side effects of conventional treatments.
He believed it could be a breakthrough drug, one that mounted an entirely new type of attack on the deadly disease. But convincing the outside world had proved difficult especially as the company he founded changed hands twice in a span of six months. For a time, he feared his could be one of the promising drugs that slipped through the cracks in the system.
Then, in August 2000, came a moment Adams will never forget. In an early-stage clinical test, the drug erased all signs of cancer from a 42-year-old woman who months before was in the advanced stages of multiple myeloma, an often fatal blood-borne form of cancer.
''She would not be alive today'' if not for the drug, Adams said. ''She's been off treatment for 15 months now, and she's still alive. That was a eureka moment.''
It was also the moment that Millennium Pharmaceuticals Inc. decided to make LDP-341 the cornerstone of its oncology program, proving that one man's conviction can keep a drug alive through years of financial and scientific struggle and two mergers.
''Most great drugs have one or two people behind them who are believers,'' said Dr. Michael Kauffman, Millennium's vice president of medicine. ''Julian believes.''
His efforts were rewarded this week when preliminary study results presented at a national cancer meeting showed the drug was effective in fighting an often deadly blood-borne cancer in patients who didn't respond to other treatments.
Adams had been championing the drug since shortly after its inception in 1994. He had created LDP-341 as a research tool to learn more about a little-studied chamber of the cell, called the proteosome, that gets rid of excess or unwanted proteins. Though the role it played in disease was not clear, Adams and a group of other scientists founded a company called ProScript on the theory that a better understanding of its biology could lead to important new drugs.
By creating a chemical compound to block the function of the proteosome, Adams could see what went wrong and understand the role it played in keeping cells healthy. Around the same time, however, a group of Israeli researchers discovered that the proteosome contributed to cell division, suggesting to Adams that ProScript's research might have applications in cancer.
Adams sent LDP-341, then called PS-341, and a host of other compounds to the National Cancer Institute, where they were screened for their potential to fight cancer.
Not only did LDP-341 seem to aggressively attack a variety of cancers in lab tests, but it did so in a way different from any other known drug. By preventing the cell from ridding itself of excess proteins, the drug seemed to trigger cancer cells to self-destruct.
Adams quickly shifted the company's research efforts to developing LDP-341 as a potential treatment for cancer. But skepticism, even among the company's own scientific advisers, was great. The risks in developing a drug unlike any that had come before it were huge. The proteosome is present in every human cell. Blocking it from performing its task might kill cancer cells, but it could also harm healthy cells, causing serious side effects.
The concern was valid, and Adams felt the drug's potential was great enough to warrant further study. He devoted his company's limited resources to studying the drug in lab tests and in animals. He recruited David Livingston, a noted cancer researcher from Dana Farber Cancer Institute, to join the board. NCI researchers, among the few who were excited by the drug's promise, ran additional safety tests.
In October 1998, after years of lab and animal testing, a doctor at MD Anderson Cancer Center in Texas agreed to test the drug in people to evaluate its safety. The first patient was a man with an advanced case of prostate cancer who had exhausted all his treatment options.
''I can tell you it was something of a sleepless night,'' Adams said. ''We had been able to prove to everyone that the drug wouldn't be lethal. But we couldn't accurately predict the side effects.''
The man didn't suffer any serious side effects, however. And as testing continued, Adams became increasingly convinced of the drug's promise. Cancer cells seemed susceptible to the drug's attack. Healthy cells seemed to overcome the action of the drug, quickly bouncing back to normal.
Adams' conviction, NCI's vote of confidence, and the interest of a growing minority of physicians, however, was not enough to attract investors to finance the company or pharmaceutical companies to support the research.
''We were scientific outcasts,'' Adams said. ''We were unsuccessful at raising money. We couldn't afford to run the clinical trials or keep the company going.''
By 1999, time was running out. Wherever Adams turned for support - pharmaceutical companies, investors, even much of the academic research community - he was met with skepticism. With just weeks of cash left, prospects for ProScript Inc. and PS-341 looked dim.
Then LeukoSite Inc., a Cambridge biotechnology company, bought ProScript for $2.4 million, granting the drug a last-minute reprieve. Three months later, however, Adams learned that Millennium was buying LeukoSite for $635 million, again placing in jeopardy the future of the drug, now called LDP-341.
''I was in a state of shock,'' Adams said. ''Living through one merger is quite trying, but living through two in such a short time - LeukoSite had adopted our program, but would Millennium?''
The answer to that question was in greater doubt in the Millennium-LeukoSite merger than it had been in the earlier deal. Millennium had bought LeukoSite for its impressive pipeline of products. But the much-larger company had its sights on two particular drugs, neither of which were LDP-341.
Mergers invariably mean some projects will be shelved. Companies winnow out those with less chance of success or less potential for profit, balancing out the portfolio to assure a steady stream of drugs to market, and allocating resources to priority projects. Even drugs that seem promising in early-stage research can slip through the cracks.
''You hope companies make the right decision, but you never know,'' said Skip Irving, managing director of the strategic consulting firm Health Advances Inc. ''The drugs never go through testing so you never see their potential. The ones that survive usually have a champion, someone who is passionate about the drug. In a large organization, where there is tremendous competition, you need that passion.''
Millennium took a hands-off approach toward LDP-341. They allowed Adams and his team of researchers to continue the early-stage clinical testing of the drug and waited for results to come in.
Meanwhile, Adams forged ahead. He hoped to persuade Millennium to put more muscle behind LDP-341's development.
Then came the successful test in the summer of 2000. After the woman's dramatic recovery, LDP-341 quickly emerged as the cornerstone of Millennium's oncology program. The company pumped resources into the drug to speed and expand its testing, making it Millennium's top-funded program. It is now the most advanced drug in the company's pipeline and is being tested in 30 different clinical trials as a potential treatment for multiple myeloma and other cancers.
On Monday, the company released the preliminary results showing that more than half of the first 54 myeloma patients enrolled in a 200-person study improved on the drug. In another third of patients, the drug stopped the progress of the disease, and in two patients, it sent the cancer into complete remission.
LDP-341 seems to mount a four-pronged attack on myeloma cells: triggering them to commit suicide, preventing them from attaching to the bone marrow, dismantling their defenses against the onslaught of drugs, and starving them of food and blood supplies they need to survive.
Myeloma is one of the more difficult cancers to treat, killing 11,000 people each year in the United States. If the promise of LDP-341 is confirmed in further tests, analysts expect it to reach the market in 2004 and quickly become an important treatment for the disease. If it also proves effective in treating more common solid tumors, such as breast, prostate, or lung cancers, the drug could become a blockbuster.
''A couple of years ago, people thought this drug had a remote possibility of succeeding,'' said Dr. Brian Durie, director of the myeloma study group at Cedars-Sinai Cancer Center in Los Angeles. ''Now people see success as a strong probability.'' |
