Opsona, And Pharma Backers, Await Day of Reckoning for Kidney Drug

Xconomy National — 

Few biotech startups out of Dublin have gotten the type of industry backing that Opsona Therapeutics has. The company’s investor list reads like a who’s who of international pharma venture arms—among them Novartis, Amgen, and Roche—and investors close and abroad. It’s raised more than 60 million euros in venture cash to date.

The lure: Opsona offered a promising new way to control the immune system by targeting certain receptors on immune system cells. But promise and deep pockets only get a biotech so far. At some point, some real substantial clinical data is needed to keep the spigot from running dry. For Opsona, that critical day is coming.

Opsona is in the midst of testing its lead—and only—drug candidate, OPN-305, in a mid-stage clinical trial. It’s an antibody drug designed, initially, for patients that have just gotten kidney transplants. The idea is that OPN-305 would help reduce the risk of delayed graft function (DGF)—a common complication of transplants, when there’s a “delay” before the new organ starts working. During such delays, which may last several days, kidney transplant patients must be put on a dialysis machine. Some patients experience outright kidney failure.

Success in the trial, which is expected to wrap up towards the end of next year, could turn Opsona into acquisition fodder for one of its Big Pharma/Big Biotech backers—many of whom have been supporting the Irish biotech for close to a decade. Failure would bring a much tougher road, like trying to salvage the drug for another condition.

“That’s the real moment for the company, when we find out [the results of the trial],” says Opsona co-founder and chief scientific officer Luke O’Neill (pictured above), the chair of Trinity College Dublin’s biochemistry department.

Of course, in the competitive world of biotech even a successful clinical trial doesn’t necessarily mean commercial success. Other deep-pocketed companies are going after the same indication. Cheshire, CT-based Alexion Pharmaceuticals (NASDAQ: ALXN) is testing its blockbuster drug eculizumab, which already approved for rare blood diseases. San Francisco, CA-based Quark Pharmaceuticals is developing an RNA-based drug for the condition as well, though the drug failed a mid-stage trial in June.

But O’Neill believes Opsana has got a leg up on the competition, because of how it’s going after DGF. Opsana’s antibody targets a specific so-called “toll-like receptor” on immune cells called TLR2. These receptors are implicated in inflammation and infection-fighting. And O’Neill says they’re the key driver for the inflammation and injury in a newly transplanted kidney.

“Very early in the cascade these receptors get triggered,” O’Neill says. “So you’re getting in at the ground level, if you like, and stopping all the cascade of events that might happen next.”

O’Neill has been on a roughly 10-year quest to demonstrate the value of targeting the toll-like receptors. Opsona started up in 2004, budding out of the work O’Neill and two other immunologists at Trinity—Kingston Mills and Dermot Kelleher—were doing in inflammation.

It hasn’t been easy, historically, for startup biotechs in Dublin to get the necessary funding to leap from academic research to developing real products—crossing the so-called valley of death. There just wasn’t a critical mass of local venture firms and government support. But in the late 90s and early 2000s, initiatives like Enterprise Ireland (a government agency supporting Irish startups) and Science Foundation Ireland (a non-profit national foundation funding scientific and engineering research) sprouted up to help local startups. Opsona was one of the beneficiaries, landing an initial $20,000 from Enterprise Ireland.

That sum, of course, is a pittance in biotech, where it takes exorbitant amounts of cash to even get a drug into clinical trials, let alone all the way through development. And as O’Neill notes, the Dublin VC community was “sparse, to say the least, at the time.”

But Opsona had two things working in its favor: First, after setting up his lab at Trinity in the early 90s to study the molecular basis of inflammatory diseases, O’Neil worked hard to build relationships with industry. He did contract research and other collaborative work for Big Pharma and established relationships with people involved with biotech companies, like South San Francisco, CA-based Genentech. So after Enterprise Ireland got Opsona started, Seroba BioVentures (now Seroba Kernel) and Genentech joined in and helped back a 6.6 million euro Series A round in February 2005.

“I knew those guys [at Genentech], because I worked with them and collaborated before with them,” O’Neill says. “I was very plugged in internationally, [and] you’ve got to be.”

Second, Opsona was going after a hot target in biotech research—the toll-like receptors. TLRs are important components of what’s known as the innate immune system—the body’s first line of defense, which recognizes foreign invaders attacking the body at entry points just under the skin, or in the lining of the gut. (The adaptive immune system, by comparison, makes antibodies that can remember and develop the ability to destroy certain pathogens.)

Research into TLRs has shown they play a key role in diseases involving overactive immune responses. Most of the mega drugs approved for rheumatoid arthritis or other inflammatory diseases—such as adalimumab (Humira) or etanercept (Enbrel)—work by using an antibody to target and block a molecule called tumor necrosis factor (TNF), which is involved in the inflammatory response that leads to the symptoms associated in those diseases. O’Neill says that TNF, however, is being “driven by” TLRs. So Opsona’s hypothesis has been, “if we block them [the TLRs], we’ll block down everything—we’ll shut down the whole massive inflammatory attack,” O’Neill says.

The hypothesis’ promise caught the attention of investors. Since the Series A round in 2005, a number of other corporate venture entities have jumped in: Amgen, Baxter International, Roche Venture Fund, and Novartis Venture Fund. Other venture groups that provided funds include Fountain Healthcare Partners, BB Biotech Ventures, Inventages Venture Capital, and Sunstone. It all added up to more than 60 million euros ($75 million).

Of course, it’s still a risky investment. Opsona is by no means the only company looking into TLRs. Seattle-based VentiRx, for instance, has been developing a drug that stimulates a specific TLR, TLR8, to boost the immune system’s response to cancer. It cut a big option-to-buy deal with Summit, NJ-based Celgene (NASDAQ: CELG) in 2012. Swiss biotech Novimmune is developing an antibody drug that blocks TLR4. Berkeley, CA-based Dynavax Technologies is developing drugs blocking TLR 7, 8, and 9. No one’s made it to the finish line yet: A TLR4-targeting drug Eisai was developing for sepsis failed a Phase 3 test last year.

“In general there’s been no human documentation to date that blocking a toll-like receptor reduces disease in humans. [But] the lack of efficacy of the TLR4 drug was due to the trial, and not necessarily the concept,” says Charles Dinarello, an immunology professor at the University of Colorado School of Medicine, who has published papers on toll-like receptors, and isn’t involved with Opsona. “Sepsis is a graveyard for very good drugs.”

Even so, Opsona’s first two projects didn’t pan out either. Its first idea was to engineer a certain anti-inflammatory bacterial factor, but O’Neill says the company just couldn’t make the drug. Second came projects focused on different TLRs, which Opsona used to cut a partnership deal with Wyeth and help fund the company. But Pfizer bought Wyeth in 2009 and purchased the IP around those programs. The only thing left standing for Opsona was its TLR2 work. Opsona is the only company targeting TLR2 (“we own all the IP around it,” O’Neill says).

Dinarello says there’s good reason Opsona was able to draw investments from that research: “All these TLR2 pathways have many indications. Probably a list of about 20 things. I think an antibody for TLR2 will have clinical use—I would definitely say it has a pretty good chance of doing well.”

Now, 10 years in, Opsona is about to find out whether that work will lead to something of real value. The specific goal: to show that administering OPN-305 after a kidney transplant will reduce the likelihood that a patient will still be on dialysis after 7 days—without increasing the risk of infection from a suppressed immune system. If it can? “That’s a very valuable drug,” O’Neill says. “There’s 2,000 patients waiting for transplants in each hospital around Europe. And our product would be part of the standard of care.”

Success would also enable Opsona to explore other uses for OPN-305. O’Neill says the company already has encouraging preclinical data in cancer (in combination with chemotherapy), and what’s known as “NSTEMI,” an acronym for a certain type of heart attack.

“Some of these guys have been with us since 2004, so they want to know, when are we gonna cash in our chips here?” O’Neill says. “It’s all about that graph at the end [of the study].”

Photo courtesy of Flickr user Discover Science & Engineering via Creative Commons