Laurence Rahme of Massachuetts General Hospital, who was looking into what Mahadevia says is a “unique target,” a signaling molecule in gram-negative germs that controls most of the machinery these bugs use to make people sick. Rahme has devised a way to make chemical compounds—small molecules—to inhibit that target, theoretically disarming the bacteria and rendering them harmless. Spero was built around that concept.
Mahadevia isn’t disclosing exactly which molecular target Spero interested in, only noting that it’s a transcription factor found in a number of gram-negative bacteria in charge of a variety of functions. That transcription factor, for instance, controls bacteria’s propensity to leak out harmful proteins while fighting the immune system, or lie dormant and survive antibiotic treatment. Blocking it with a drug delivers “a one-two punch” that can impact both of those capabilities, Mahadevia says.
“No one has really to our knowledge doubled down on [those two concepts] like we have,” Mahadevia says. “We’re not developing drugs that actually kill bugs. We’re just shutting them off.”
This is important because when antibiotics kill bacteria, they give those bugs reason to adapt and develop immunity. By using a Spero drug to treat an infection or adding it to a mix of antibiotics, the idea is that patients could manage an infection without triggering resistance, or boost the strength of those other antibiotics, according to Mahadevia.
Of course, Spero has to prove this. So far the startup is going on evidence it’s seen in animal tests and petri dishes showing the effectiveness of its approach and its compounds. It’s a long way away (Mahadevia wouldn’t specify) from the doorstep of its first clinical trial, let alone proving this approach is safe, works in humans, and truly adds another option for treating bacterial infections. And an option from Roche doesn’t necessarily mean a deal will take place—the big drugmaker could just as easily take a look at the preclinical data Spero puts together and walk away.
Mahadevia isn’t saying specifically what its lead program will go after first, but he did add that the company will start off looking at infections where the public data suggest the biggest needs are. It’ll likely look at gram-negative bacteria such as E coli, pseudomonas aeruginosa, and klebsiella, for example, but also look “opportunistically” at gram-positive strains as well, he says. (Gram-negative bacteria have a far less permeable cell membrane than gram-positive bacteria, so they’re tougher to kill with antibiotics).
“We think for a problem that big you should really complement [traditional methods] with novel ways, different ways of doing things,” he says.
Because this could lead to several potential programs, Atlas has set Spero up with an LLC structure. That gives the company the ability to hive off individual programs, flip them, and give the proceeds to shareholders. This is the type of thing Spero could do in the Roche deal—a transaction in which, once Spero puts together its full data package and is ready to file an IND, Roche will get its shot to acquire the program, leaving the rest of Spero independent, and funded.
Mahadevia says Spero is “midway” down that path and that Roche’s R&D funding will cover a “reasonable portion” of the direct cost of getting the lead drug to its first trial (as well as other general ramp-up expenses), though he declined to elaborate further. He also indicated that Spero and Roche might end up working on a few other programs together as well—assuming the data hold up, of course.
The deal “lets us do what we do, it enables us to keep building Spero for additional pipeline targets, and it gives our investors a very nice return on a reasonable timeframe,” Mahadevia says.
