UCSF Spinout Principia Biopharma Thinking Big and Covalent

Xconomy San Francisco — 

[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.]

Martin Babler, CEO of Principia Biopharma

“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 … Next Page »

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2 responses to “UCSF Spinout Principia Biopharma Thinking Big and Covalent”

  1. pd alum says:

    Interesting articfle on Principia, but some incorrect history on Rezulin. Troglitazone was discovered at Daiichi Sankyo and developed and marketed by Parke-Davis, a division of Warner-Lambert Co. in the US. It was withdrawn from the market near the time Pfizer acquired (ahem, merged) Warner-Lambert. Wyeth had nothing to do with Rezulin, except that Pfizer settled most of the lawsuits about the time it acquired Wyeth.

  2. PD alum: thanks for the bit of history. I’ve corrected the story.