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late-stage lymphomas are such serious diseases that patients and doctors are willing to accept some side effects for anything that works. That’s less true for chronic conditions like autoimmune disease or diabetes, in which significant side effects aren’t as acceptable. And those are the areas Principia is aiming for. It is seeking to make drugs that hit targets and form strong covalent bonds that are also reversible.
The chemistry, at least in concept, is fairly simple. Principia’s team is working on small-molecule drugs that can be given orally and are chemically linked to a potent “warhead.” Principia’s drugs are being designed to be easily distributed through the body, and they can be engineered to have a long or short bonding time with the target, Babler says. When the protein target and drug come into contact with the usual metabolic enzymes, the protein and drug let go of each other, meaning there shouldn’t be a degraded protein clinging to a fragment of drug that sets off alarm bells for the immune system. These drugs—at least in concept—should act as potent, long-lasting, specific binders against a target, and they shouldn’t cause serious allergic reactions.
Babler, a former vice president of sales and marketing at Genentech and CEO of Talima Therapeutics, says his biggest challenge at Principia is figuring out which drug development programs to focus on first, and which ought to be de-prioritized. Since Principia pulled in its Series A financing in February 2011, it has shown that its technology can be applied to a variety of molecular targets, and that it can design drugs that bind for a short time or a long time against the target, depending on what’s desired, Babler says.
Principia also has moved a lead compound forward against the Btk target (made fashionable by the other companies above) into preclinical toxicology testing. Principia doesn’t intend to compete against Pharmacyclics or Avila in the cancer world, but Babler said his company’s drug is being designed to go after autoimmune diseases that require a compound with minimal side effects. So far, the company has found that the drug can be given orally in animals, and that it “works beautifully.” The goal is to move that program into clinical trials in 2013, he says.
“When you think about what the industry tries to do, you are trying to give very little drug with a long duration of effect,” Babler says. “That’s the ideal world we want to live in. But the industry for 40 years didn’t go there, because the only way to go there was to have irreversible covalent inhibitors, or slow-off reversible inhibitors. Those are really hard to make.”
Peter Thompson, a venture partner with OrbiMed Advisors—one of Principia’s investors—says this is “definitely a project to watch.” He served as interim CEO before Babler was recruited to run the show.
“Principia’s unique proprietary chemistry platform allows for the rapid development of highly specific drugs that demonstrate prolonged target inhibition without requiring proportionate systemic exposure and without the potential safety issues,” of traditional irreversible covalent drugs, Thompson says.
Former Avila CEO Katrine Bosley says she’s glad to see other companies moving into this area of chemistry, especially since there was so much skepticism when Avila started in 2006. “We hoped that by tackling head-on the concerns that people had about covalent drugs we could open up the ability to address therapeutic targets that weren’t well addressed by more traditional medicinal chemistry,” Bosley says. “And it worked. By pioneering the space we were able to open it up broadly for ourselves and (inevitably) for others—that’s really exciting.”
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