Seattle Genetics Maps Out a Future With Antibody Drugs That Are “Empowered”

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Some of the best-selling drugs in the pharmaceutical industry are what biotechies call “naked” antibodies. These are engineered Y-shaped proteins that zero in on markers of diseased cells, while sparing healthy ones. They generate an estimated $30 billion in annual sales, from big names like Roche’s trastuzumab (Herceptin) for breast cancer.

But to hear one of the nation’s leading developers of antibody drugs talk today, those treatments aren’t really on the cutting edge anymore.

“It’s unlikely in the future of Seattle Genetics that we’ll put another naked antibody into the clinic,” CEO Clay Siegall says. “The future will be with antibodies that are empowered.”

Seattle Genetics (NASDAQ: SGEN) has come to that conclusion after it has spent more than a decade trying to make antibodies more potent. The company, founded in 1998, has never been able to take a naked antibody drug all the way through to FDA approval, and it has shelved a number of candidates over the years—SGN-10, SGN-15, SGN-30. But Seattle Genetics has generated its most promising data yet from a next-generation “empowered” antibody for Hodgkin’s disease. The technology that makes this possible—linking a regular antibody to a toxin that can give it extra-tumor killing punch—has now been licensed to eight other drug companies. More data emerged this year from competitors Roche and ImmunoGen that suggests they, too, have found a way to link an antibody with a toxin to create a souped-up antibody drug that beats the original. And Seattle Genetics has designs on pushing the envelope further in the future with another next-generation technique for making antibodies more potent.

Clay Siegall

Clay Siegall

Scientists have been dreaming about creating powerful targeted therapies, known as antibody-drug conjugates, for three decades, but the efforts usually failed because the linkers weren’t stable, and the toxins broke off in the bloodstream before they could reach the intended target, causing side effects. Seattle Genetics’ technology is built on the idea that its synthetic linkers remain stable until the antibody reaches the tumor and unleashes its toxic payload.

The lead drug candidate at Seattle Genetics, brentuximab vedotin, opened the eyes of cancer researchers a little more than a year ago with its data. Scientists said that 17 of the 44 patients (38 percent) had their tumors completely disappear or mostly go away after they took the drug. When they looked at patients who got higher doses that are more likely to be tested in late stages, the data look even better. Of the 28 patients who got those doses, about one-third had their tumors completely disappear, while 93 percent had at least some measurable tumor shrinkage. That drug is now in a pivotal clinical trial that could produce results by the end of this year, and may reach the U.S. market by the end of 2011.

While Seattle Genetics still has a couple of naked antibodies moving through clinical trials, Wall Street isn’t counting on them. Last month, Roche pulled the plug on a partnership to develop one of these, dacetuzumab, after it failed in a mid-stage clinical trial of 224 patients with diffuse large B-cell lymphoma. Another naked antibody from Seattle Genetics, SGN-33, is in a mid-stage trial for patients with acute myeloid leukemia. Results from that trial are expected before the end of June.

“Expectations [for SGN-33] are very low given the tough nature of the disease and lack of convincing earlier-stage data,” said JP Morgan analyst Cory Kasimov in a note to clients last month.

Siegall doesn’t want to go quite so far as to declare naked antibodies dead, noting that Seattle Genetics hasn’t decided what to do yet with dacetuzumab, and it doesn’t yet have the data from SGN-33.

“If you are talking about the future, I’d say yes, it’s unlikely that we’ll move another naked antibody into the clinic,” Siegall says.

To that end, Siegall noted he has high hopes for a second antibody-drug conjugate in the clinical pipeline, known as SGN-75. There’s a “high likelihood” the drug will generate clinical trial results in 2010, Siegall says. Plus, Seattle Genetics is looking to introduce a third member of the antibody-drug conjugate class into clinical trials this year.

All told, between Seattle Genetics’ internally developed antibody-drug conjugates and those from its partners, “I would bet that by the end of 2011, there will be close to 10 antibody drug conjugates in clinical trials,” Siegall says.

But Seattle Genetics has more than just antibody-drug conjugates in mind when it talks about making antibodies more potent. The company has also developed another technique, which it calls sugar-engineered antibody technology (SEA).

The basic idea, which the company unveiled back in September, was that Seattle Genetics has found a way to modify naked antibodies with a chemical to block the formation of a certain sugar called fucose that often hangs off the end of a regular antibody. By getting rid of that type of sugar, scientists think they can trigger the immune system to unleash a more powerful assault on the cells that the antibodies bind with, Siegall says.

Since this approach can make antibodies more potent without using a toxin, it’s possible that sugar-engineered antibodies might be better tolerated for long-term usage. That could be useful for diseases in which the antibody needs to be given for a chronic disease, like rheumatoid arthritis, Siegall says.

At least two other companies appear to be further along than Seattle Genetics with this sort of sugar-based approach for empowering antibodies, Siegall says. One is BioWa, a unit of Japan-based Kyowa Hakko Kirin, and the other is GlycArt, now a unit of Roche. The GlycArt technology is being used for a drug candidate called GA-101, an empowered version of Roche and Biogen Idec’s hit rituximab (Rituxan). But Siegall says the Seattle Genetics approach should have an advantage because it only adds one chemical step to the antibody production process, and doesn’t slow things down like the others can.

Like Seattle Genetics’ earlier experience with antibody-drug conjugates, it hopes to use the sugar-engineered antibody approach both for internal programs, and for licensing to other companies, Siegall says. “We are talking to a number of companies about it, and there is interest,” he says.

Since that technology is still relatively new, Siegall tried not to pump up expectations too high about it becoming a moneymaker for the company anytime soon. But it’s a clear indicator that Seattle Genetics is looking at a number of ways to build upon the successes of the plain antibodies from the past.

“These products have been around for a while and they help patients,” Siegall says. “Now we have an opportunity to take antibodies to the next level. The data speaks louder than anything else, and the data are strong.”

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