Domain-Backed Adynxx Enters the Wide Open World of Pain Drug R&D

Xconomy San Francisco — 

You may not be able to tell by looking at the R&D pipelines of Big Pharma companies, but pain is one of the bigger opportunities in new drug development. There are cheap, decades-old drugs out there everyone knows about. There are not a whole lot of pain drugs in development based on really novel biological ideas. But that’s a void that a San Francisco-based startup called Adynxx is seeking to fill.

Adynxx (pronounced uh-DYE-nix) has kept a low profile since its founding five years ago, but is discussing its work publicly today, announcing it has completed enrollment in its initial clinical trial of 30 healthy volunteers. The company, supported by a Series A venture financing of $18 million from Domain Associates from 2010, is composed of people who worked together on a series of Domain-backed companies that were acquired, including Peninsula Pharmaceuticals, Cerexa, and Calixa Therapeutics.

Despite all the various classes of pain meds that are effective, there’s a massive amount of spending, diminished worker productivity, and despair and suffering from unrelieved pain. The cost to society of all this pain was estimated at $560 billion $635 billion a year, or about $2,000 per person in the U.S., in a recent Institute of Medicine report. The idea at Adynxx is to zero in on one specific kind of pain that affects people immediately after surgery, and which can linger and interfere with rehabilitation. By making a drug that inhibits a transcription factor that acts like a master pain switch for multiple pain signaling pathways, Adynxx is wagering that a single intrathecal (spinal) injection can control post-operative pain and prevent it from flaring back up during rehab.

“We’re developing a transformative way to not just treat pain, but to prevent pain,” says Rick Orr, the company’s CEO. “We want to treat pain as a disease,” not just a symptom of some other ailment.

Given how many surgeries are performed annually—one study in 2008 by researchers at the Harvard School of Public Health put the number at 234 million worldwide each year—there’s potentially a very big pool of customers out there if Adynxx can deliver.

There are already lots of different ways of treating pain with drugs, some stronger than others. Many of the treatments are cheap and widely available. Think of aspirin, non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen, and more powerful opioid-based pain relievers like oxycodone and morphine. Many existing pain drugs come with their own set of baggage—overuse of NSAIDs can cause stomach bleeding, and the COX-2 inhibitors like Merck’s rofecoxib (Vioxx) were linked to risk of heart attacks and strokes. Opioids are addictive, commonly abused, and have other side effects like constipation.

Although the existing drugs leave something to be desired, developing new pain drugs isn’t a straightforward, easy thing. Pain is a subjective experience that varies from person to person—the best clinical measurements of success in pain drug development typically ask people to rate their pain on a scale of 1 to 10. Any drug with potential for mass marketing, to be taken by millions of people, has to be extremely safe. And Big Pharma was stung by the multi-billion dollar legal settlements it had to shell out in the wake of the COX-2 mess.

Adynxx is hoping to sidestep some of these challenges by essentially not trying to be everything to everybody. Its drug is a genetically engineered oligonucleotide called AYX1 which is designed to be injected once into the spinal column in connection with a surgery. The scientific idea, from founder Julien Mamet, is that this compound should inhibit a genetic transcription factor called EGR1, which gets activated to turn on various pain pathways when stimulated with a very specific painful experience—like a surgeon’s scalpel cutting through tissues. By inhibiting this transcription factor, Adynnx is betting that all kinds of pain pathways won’t be activated to send signals to the brain, either on neurological or inflammatory routes.

Mamet, a pharmacologist who previously did postdoctoral work at The Scripps Research Institute and the Genomics Institute of the Novartis Research Foundation in San Diego, says he came up with this idea on his own in 2007 and sought to test the hypothesis at the new company. The technology took shape inside the startup, with no technology license from any institution, he says. There also aren’t any competitors that he says he’s aware of making drugs against the same biological transcription factor.

I had to ask Mamet and Orr if a pain drug that is injected once and turns off pain signals over a significant period might be too effective for its own good. For example, pain signals can be a good thing in that they tell people not to do things like put their hand on a hot stove. Orr says animal studies have shown that Adynxx’s drug doesn’t interfere with that kind of natural pain response, because it acts during a discrete period of time after the surgery, when the pain signals are strong around the surgical site.

Without time to go far into the details on the animal studies, Orr says the results were “dramatic in magnitude.” That was true for both managing acute pain following surgery, and preventing persistent pain later. That kind of product profile has gotten Adynxx thinking about the kind of human clinical trials that the FDA and doctors want to see for any new pain drug. If its results can be duplicated in humans, it should be possible to do some quantifiable and valuable things—like reduce post-surgical opioid use, reduce rehab times, and get people out of the hospital and back to work sooner following surgery. “We are taking a thoughtful, careful, deliberate approach to drug development,” Orr says.

The initial trial won’t do anything to answer those questions, but it should tell Adynxx how safe and tolerable its new drug is this year. Following that, Orr said the company plans to run a more rigorous double-blind, controlled study in which patients will get standard pain medication and the experimental drug, compared with the standard pain medication by itself. That study, expected to enroll about 90-100 patients, is expected to yield results before the end of 2013.

Adynxx, still running lean with a team of seven employees, has enough money to operate through the end of that study, Orr says. The plan is to keep developing the drug in-house, without leaning on a Big Pharma partner, although he says ”there may be interest” at the end of each stage of clinical trials. For now, Adynxx is content with running a couple of clear clinical trials over the next couple years that should give it a good sense of whether it’s onto something new and important for treatment of pain. “Our plan is to build our company for the long-term,” Orr says.