prevent people (those with a specific genetic makeup, Gilman says) from getting to that point.
“[That’s] more exciting to me,” Gilman says. “It’s a remarkable opportunity.”
Gilman also sees potential for PAD inhibitors in lupus and MS. In lupus, the idea would be to stop the body from producing antigenic materials that, like in rheumatoid arthritis, cause the body to attack itself. In MS, Gilman, says, there are a couple of different theories of how PAD enzymes might be implicated in damaging myelin, the material that normally acts like wire insulation on nerve cells. One idea is that, as in the other autoimmune diseases, the enzymes cause the proteins that make up myelin to become antigens, drawing fire from the immune system. But it could also be, Gilman says, that in some patients the enzymes are changing the proteins enough that the myelin begins to break down, even without interference from the immune system.
This all has yet to be proven, of course; Padlock’s most advanced experiments to date have been run in mice. And the biology here isn’t completely understood—including, as Gilman says, why PAD enzymes are doing what they do in the first place. That leaves Padlock with a host of challenges and open questions. Among them: Which of the five-member family of PAD enzymes are implicated in these diseases (Padlock so far is homing in on PAD2 and PAD4)? What type of negative impact, if any, will blocking PAD enzymes have on the body? Gilman notes, for instance, that these enzymes might play a role in switching certain genes on or off—but it’s unclear whether that’s “a bug or a feature.”
“That’s something else we’re going to have to sort out,” he says.
Plus, PAD enzymes have been known for a long time, but for one reason or another, haven’t been extensively pursued as drug targets. Gilman says companies like GlaxoSmithKline and a few others have at least initiated PAD programs, but haven’t carried them forward. In some cases, Gilman says, they got tossed out “with the bathwater” in a strategic review. What are the new insights Padlock is bringing to the table? While Padlock has its own IP from Scripps, Gilman says it’s more that the company has a “pile of know how” from its founders, and collaboration deals it’s putting together with the academic experts in the space—the “PAD people,” Gilman jokes. The implication is that exclusively focusing on PAD enzymes is the company’s competitive advantage.
“Honestly if somebody wanted to come after these enzymes, they could,” Gilman says. “But little companies can do things that big companies can’t. We’re going to be all over these enzymes, so I’m not really afraid of competition—and competition is generally good right? You learn stuff from your competitors.”
The Series A is supposed to give Padlock enough of a runway to identify its first lead molecule, and get it to its first clinical trial. It’s drawn down around half of that cash so far, with the rest tied to certain milestones along the way. Padlock will likely need a lot more cash than that to get where it’s going though. This isn’t another one-drug company like Stromedix, which took a fibrosis drug gathering dust at Biogen, advanced it, and then sold it back. Padlock likely will be a more broad, expensive, time-consuming endeavor. But Gilman says that’s exactly what wanted when he went looking for a new company.
“To be doing this again, and to be rolling around in a brand new biology, it’s the stuff I love,” he says. “This is not a flip. There is a lot of biology that needs to be explored. There’s a lot of chemistry that needs to be done here—it’s clearly a very broad footprint that we need to figure out and it’s going to take awhile, and a lot of capital. [But] we’re in it for the long haul.”
Atlas partner Bruce Booth chairs Padlock’s board, which includes Gilman, J&J’s Marian Nakada, MS Ventures’ Nilesh Kumar, and Index’s David Grainger. Todd Huffman of Scripps is a board observer.
