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something pretty unusual in development, Sliwkowski says. Most basic scientists at an early stage of research wouldn’t bother to think about things like enlisting the help of toxicologists, the people who help assess whether a drug is being properly absorbed and metabolized in the body or whether it’s going to be too toxic. People with that skill are often busy working on drugs in later stages of development. But many drugs that look good in a petri dish stumble later in animals or people when they prove to be too toxic. In this case, Scheller made sure Sliwkowski and his colleagues got important early help from their peers in toxicology.
So Sliwkowski felt he had the resources he needed to help screen out the duds early on, and improve the odds of success.
Even with all that support, the worst was yet to come. By 2002, Genentech had taken its lead antibody-drug conjugate into its first clinical trial. At the time, it used what is known as a disulfide linker. This was thought to have the nifty ability to remain stable in the blood, but selectively release its toxic cargo once confronted by certain enzymes in cancer cells. It looked great on the whiteboard, and it showed a clear affect on cancer cells in the lab. But when this candidate with the disulfide linker entered animal testing, it flopped. “We really tripped up on safety,” Sliwkowski says. [[Correction: 1:25 pm, 6/16/10: An earlier version said the drug and disulfide linker failed in a clinical trial.]]
Though the researchers had poured three years and a lot of resources into the first conjugate, it was time to start over. Genentech started to run its usual battery of tests, altering one variable at a time to see how it changed the results, in cancer cells and healthy cells in the lab.
Fast forward three more years, to Valentine’s Day, 2005. Sliwkowski says that’s the day senior management gave the green light for the R&D teams to do the last experiments they needed to seek FDA clearance to begin a new round of clinical trials. This time, they used a “thioether” linker from ImmunoGen. The big difference with this new linker, scientists learned, was that it instead of releasing the cell-killing agent, it formed a covalent bond between the antibody and the toxin that couldn’t be broken.
Using that new linker meant that the whole antibody-drug package could get internalized into the cell, trafficked to the place where it encountered certain enzymes, and then be degraded, the same way enzymes in your stomach break down the steak you ate for dinner. Through this degradation process, a huge antibody is ultimately broken down into amino acid building blocks, still clinging to the potent toxin, which can then do its anti-tumor thing.
By April 2006, the scientists had raced through their preparations to get what was now T-DM1 ready to enter its very first clinical trial. One year later, Genentech’s senior brass started raving about how the company was seeing anti-tumor activity from T-DM1 in this original study of 18 patients, even in some cases at the tiniest doses that were just intended to assess safety, not effectiveness. When I was a reporter at Bloomberg, Ian Krop, a researcher at the Dana-Farber Cancer Institute, told me, “We’re about as excited about this one as we can get this early in the game.” More details emerged a couple months later at the biggest annual cancer meeting of the year, the American Society of Clinical Oncology.
The scientists were still a little nervous, and a little scared of what might happen, given how they’d been rudely surprised by the failure of the earlier souped-up version of Herceptin, Sliwkowski says. He says it was a sobering moment, to realize that actual patients were gutsy enough to take an experimental drug like this, with so many potential risks that could have emerged.
But those days are now past, Sliwkowski says. Even though scientists expect most of their creations to fail, they now expect T-DM1 to succeed.
“This thing works, and it works pretty well. We expect as we move it up the ladder into earlier and earlier breast cancer, it’s going to work even better,” Sliwkowski says.
That’s not to say this program is risk-free. Genentech is planning to seek FDA approval this year based on a relatively thin body of evidence, from a clinical trial that didn’t have a control group. It’s possible the FDA could convene an expert advisory committee to debate whether to wait for data from more rigorous clinical trials.
T-DM1 also takes twice as long to manufacture as a regular version of Herceptin, and is more complicated to piece together from various contract manufacturers around the world, says spokeswoman Krysta Pellegrino. If the drug is approved for sale, and lives up to its billing in early-stage breast cancer, then Genentech will need to invest more in commercial-scale manufacturing.
And what about those 50 other antibody-drug conjugates at earlier stages of R&D? Will they benefit from the lessons learned through the T-DM1 experience, and truly usher in a new paradigm for cancer treatment? Genentech can’t say that for sure. Each target is different, and so is the way the cell internalizes the antibody-drug conjugate, Sliwkowski says. All the usual questions about the right target, right antibody, right linker, and right number and positioning for the toxins all still apply.
Still, this is a technology that could become a reusable “platform,” for the discovery of multiple products, not just a one-hit wonder or a “me-too” incremental advance. Before I left the Genentech South San Francisco campus last week, I had to ask Sliwkowski how much confidence he has in the 50 other drug candidates, and whether they will represent a new wave of cancer treatment.
“I certainly hope so,” Sliwkowski says. “But you’ll have to hold onto that pipeline chart and come back and see us in 10 years.”
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