[Updated and corrected 9:35 am PT] Anyone who invested in Sunnyvale, CA-based Pharmacyclics (NASDAQ: PCYC) or Bedford, MA-based Avila Therapeutics the past couple years must love to see the words “covalent” and “drug” in the same sentence.
While most people probably haven’t thought much about covalent bonds since high school chemistry, those two companies have helped popularize the phrase in biotech, after making a fortune for investors through drugs that form covalent bonds with molecular targets. Their success has also helped clear a path for a new entrant in the field called Principia Biopharma. This company, a UCSF spinoff, has dreams of going even further than the other two companies, and defying much of the conventional wisdom in Big Pharma, which long pooh-poohed the idea of making covalent-binding drugs.
Principia, a South San Francisco-based company with 20 employees, has kept a pretty low profile since it raised $36 million in a Series A venture financing in February 2011. The company, which spun out of Jack Taunton’s lab at UCSF, received that big vote of confidence from New Leaf Venture Partners, OrbiMed Advisors, Morgenthaler Ventures, GlaxoSmithKline’s SR One venture group, and Mission Bay Capital. This week, it announced that it has made enough progress to rake in the second of three $12 million installments of that venture financing, and that it has attracted Jens Oliver Funk, a former senior vice president at Merck Serono, to be its new chief scientist.
The traditional knock on covalent drugs is that they form an irreversible bond with the target. That might sound like a good way to inhibit a biological process you want to shut down, but it’s not quite so simple. After a drug binds to its target, it eventually gets chewed up and disposed of by ordinary metabolic processes. But in the case of a covalent bond, the metabolism usually leaves a chewed-up protein stuck to a fragment of a drug. That combination can alert the immune system to the presence of a foreign invader, which can be bad news. In the case of covalent-binding drugs like aspirin or penicillin, some patients will get allergic reactions. In the case of Warner Lambert’s diabetes compound troglitazone (Rezulin), the immune reactions were so serious that at least 63 patients died. The drug was yanked off the market in 2000, Pfizer (which acquired Warner-Lambert) paid more than $750 million in legal settlements with patients, and the whole episode scared away most Big Pharma companies from working on covalent binders for years, says Principia CEO Martin Babler. [Corrected to say to Rezulin was marketed by Warner Lambert, not Wyeth.]
“These drugs haven’t been pursued much, because like in the case of Rezulin, people were afraid you’d make a drug that would go all the way to Phase III or the market, and then you’d find out you have a dangerous drug,” Babler says.
Pharmacyclics (NASDAQ: PCYC) and Avila shrugged off some of the skepticism long before it was cool. Those companies worked over the past few years on advancing chemistry techniques for making small-molecule drugs that form irreversible covalent bonds, particularly against a molecular target called Bruton’s tyrosine kinase (Btk) that had eluded industry chemists using traditional techniques. Pharmacyclics came up with ibrutinib, a covalent-binding compound that has shown it hits this target and has a positive impact against B-cell lymphomas. Avila Therapeutics also showed it could make a potent compound against the elusive Btk target, which enticed Celgene (NASDAQ: CELG) to buy the company for $350 million upfront earlier this year.
Those companies, Babler says, have had success with irreversible covalent binders, which can be fine for the treatment of cancer. That’s because 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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