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The Velcade story

Viewed as a model for how to develop cancer drugs efficiently, Millennium’s life-saving Velcade drug

"What if we fail?’’ a colleague asked chemist Julian Adams as they ate lunch in the offices of ProScript Inc. in October 1998.

For four years, Adams and company cofounder Tom Maniatis had been pushing the biotech start-up to develop a promising treatment for cancer then known as PS-341. They had overcome internal dissension as well as doctors’ fears of toxic side effects. But then the venture capitalist who had been paying the bills died suddenly, and Adams, ProScript’s director of research, couldn’t find anyone else willing to put up the tens of millions of dollars needed to test the drug in people.

‘‘They’re taking me out with the furniture,’’ Adams replied. ‘‘If we fail, it will be a noble failure.’’

Ultimately, Adams was turned down by more than 50 potential backers before ProScript was acquired in 1999 by Millennium Pharmaceuticals Inc., which eventually funded studies of PS-341. ‘‘I put so much of my life into this, there was no way I was going to give up,’’ he said recently.

Emblematic success story

Today, PS-341, now known as Velcade, is recognized as a model for how to develop cancer medicines quickly and cheaply, as Adams and other diehard Velcade champions turned four Harvard professors’ idea into a breakthrough treatment for multiple myeloma in half the average time for drug-testing and federal review. Since its approval in 2003, Velcade has helped control the rare but deadly blood cancer in more than 50,000 patients, generating $220 million in sales last year alone.

Along the way, Velcade became an emblematic success story for Boston’s biotech community: a drug that emerged from the city’s vaunted university labs, then was nurtured along by scientist-entrepreneurs into a successful therapy.

But the drug nearly stalled several times as scientists struggled to get financial support for a new approach to fighting disease and disagreed among themselves about what PS-341 should be used for — some wanted to focus on conditions like arthritis. The founders and executives at ProScript — and later Millennium — made smart choices that helped them survive, such as enlisting the aid of National Cancer Institute scientists to refine their drug and working closely with academic laboratories and the Food and Drug Administration to speed the safety review.

The role of luck

Just as important, they refused to quit until good fortune and good news — such as the first patient whose cancer went into remission after taking the drug — gave them fresh momentum. Adams and his collaborators believe that dozens of other promising drugs never make it to patients because biotech companies can’t hang on long enough.

‘‘Most scientists do not realize how the progress of drug development depends so much on nonscientific issues and random events — and luck,’’ said Alfred Goldberg, the Harvard Medical School biologist who, with Maniatis and two others, launched the company that would become ProScript in 1993. More than once, Goldberg said, he feared the 38-employee company’s work was ‘‘headed for obscurity’’ because of events outside the lab.

Geraldine Ferraro, the Democratic vice presidential candidate in 1984, believes she is alive today in part because Velcade’s backers, including the doctors at Dana-Farber Cancer Institute who carried out the human trials, did not give up. Ferraro already had beaten the odds by living with multiple myeloma for six years, but when she started getting intravenous infusions of Velcade in 2004, the disease went into remission. As a result, she was well enough to receive a stem cell transplant, which sometimes triggers long-term remission. She remains well enough today, nine years after diagnosis, to continue a busy public speaking schedule.

‘‘This head cold is more of a problem for me than the cancer,’’ joked Ferraro one day last month during a telephone interview. She said she considers Dr. Kenneth Anderson of Dana-Farber, her oncologist and a prime mover behind the development of Velcade, "my hero."

A company is born

In truth, Goldberg wasn’t even thinking about cancer when he decided to form the company, initially called Myogenics, to take advantage of their seminal research into the way cells dispose of waste. Goldberg and the other cofounders believed that the loss of muscle and strength from diseases such as AIDS and muscular dystrophy happened because cells were dumping too many valuable proteins into the proteasome, the cell’s garbage disposal. If they could slow this process, the researchers figured, they could slow muscle-wasting too.

Within months of his arrival from another pharmaceutical company, Adams concluded that a treatment against muscle-wasting disease ‘‘had a long way to go.’’ The idea was intriguing, but, if a drug stopped cells from getting rid of waste, biologists feared it could cause a toxic reaction. Avram Hershko, an Israeli chemist who would later win a Nobel Prize for his research on cellular waste disposal, suggested that Adams turn his attention to cancer instead. He argued that, by curbing the proteasome’s appetite, PS-341 might prevent the destruction of key proteins that help cells repel cancer. And cancer patients might be willing to endure side effects if the disease extended their lives.

After that, said Adams, ‘‘I fought tooth and nail with my board to go into cancer.’’

ProScript — renamed as the company’s focus turned away from muscle-wasting diseases — didn’t have much money, but it had top-flight scientific connections and, by 1997, outside researchers had demonstrated that PS-341 might work against cancer. Beverly Teicher from the Dana-Farber Cancer Institute showed that the drug shrunk lung cancer tumors in mice, while the National Cancer Institute identified several other potential cancer targets, especially multiple myeloma. The University of North Carolina then funded the first human tests of PS-341, showing that the drug could be effective against cancer and did not cause the kind of toxic reaction some had feared.

A miracle drug

However, ProScript’s money troubles worsened after the death of venture capitalist Wallace Steinberg in 1997. Steinberg, cofounder of HealthCare Ventures, had been willing to take a chance on a new approach to treating cancer, but other financiers were less impressed, and, by June 1999, ProScript was too broke to carry out the large-scale human tests necessary for FDA approval. HealthCare Ventures, which owned all ProScript stock, sold it to another Cambridge firm, LeukoSite, for $2.7 million. Three months after that, Millennium Pharmaceuticals, another Cambridge firm, bought LeukoSite for $635 million, mainly to gain control of LeukoSite’s experimental drugs for inflammation. ProScript’s cancer drug was little more than an afterthought.

But Adams, along with Anderson, a multiple myeloma specialist at Dana-Farber, continued to promote the drug to Millennium, and the University of North Carolina continued preliminary human tests that showed the drug’s potential against several types of cancer. Finally, in August 2000, the first patient with multiple myeloma received PS-341 in North Carolina and the results stunned everyone involved: The 47-year-old woman’s cancer went into complete remission even though she had been given a low dose of the drug intended mainly to evaluate its safety.

‘‘I’ve been in the oncology business for 30 years and that was the first time I have ever seen anything like that,’’ recalled Dr. Joseph Bolen, then the chief of oncology at Millennium. Coupled with positive lab results from the National Cancer Institute, extensive animal testing at ProScript and other human tests at Memorial Sloan Kettering Cancer Center in New York, backers of PS-341 now had enough evidence to push for large-scale human testing.

Getting FDA on board

Armed with the good news, Adams and Anderson had dinner with top Millennium executives at the Blue Room in Cambridge’s Kendall Square where, on the spot, chief executive Mark Levin agreed to fund full clinical trials of the drug. ‘‘I will be forever grateful for that day,’’ recalled Anderson.

Then, the Dana-Farber and Millennium researchers made two crucial moves that dramatically reduced the time required for FDA review of PS-341. First, they worked closely with two multiple myeloma advocacy groups to quickly recruit patients for the experiments. Second, they collaborated with the FDA — which was eager to speed approval of drugs for cancers with high mortality rates such as multiple myeloma — to design experiments requiring a relatively small number of patients. The results were so impressive that the FDA approved the drug on May 13, 2003, even before researchers had finished the third and final phase of human-testing, which involved 700 more patients.

‘‘I want to give the FDA great credit,’’ said Dr. Paul Richardson of Dana-Farber, clinical director for the Velcade trials. ‘‘They have a fabulous cancer team’’ that understood that multiple myeloma patients — who have only a 33 percent five-year survival rate even now — need new medicines. Though only about two-thirds of multiple myeloma patients respond to the drug, Richardson said Velcade nearly doubles the average survival time from 18 months to 30 months for patients who have suffered a relapse.

No longer a death sentence

In the end, the Dana-Farber and Millennium team won approval for Velcade in relapsed multiple myeloma patients just 4Æ years after the first human tests, quicker approval than any other cancer drug except Gleevec and requiring only about half the time biotech companies usually need, according to a 2006 study from the Tufts Center for the Study of Drug Discovery. Researchers are still carrying out about 300 human trials of Velcade, for multiple myeloma as well as other cancers, in hopes of proving that the drug can be used as a first treatment in patients rather than as a back-up after other drugs have failed.

Today, Velcade — at a cost of $24,000 to $36,000 per patient depending on how many infusions are required — accounts for about a third of Millennium’s revenue, and Anderson has repeated his fast-track success on another multiple myeloma drug, Revlimid, which was approved last summer. Richardson said the two drugs, often taken in combination, have helped turn multiple myeloma from ‘‘a great white shark of an illness to more of a chronic disease’’ like diabetes. Patients can still develop resistance to either of the drugs, but the availability of the two drugs reduces the risk that they will become resistant to all multiple myeloma treatments.

That’s good news for patients such as Virginia Najarian, 63, who has been taking Velcade and Revlimid for 2Æ years under the care of Anderson and Richardson; her only major side effect has been an infection that required hospitalization. Velcade ‘‘is my life right now,’’ she said just before leaving for a vacation on Florida’s Sanibel Island. ‘‘If it continues to work, it’s wonderful.’’

Scott Allen can be reached at