Orbimed Advisors portfolio firm Smartzyme Biopharma Inc. joined forces with Hemoshear Therapeutics Inc. to come up with protein-based drugs for rare metabolic diseases, spinning off the former's protein-engineering platform into a new enterprise called Carnot Biosciences.

Charlottesville, Va.-based Hemoshear "brings in a lot of expertise in in vitro organ modeling, specifically liver," Mark Leavitt, Carnot's chief scientific officer, told BioWorld. "That's really important for the kind of enzymes we're going to be working on." Carnot provides "the protein engineering and mutagenesis part of the equation – modifying enzymes or proteins to get the characteristics we want in vivo," he said.

After the spin-off, Smartzyme, of Ness Ziona, Israel, will focus on advancing its core asset, a glucose-sensing enzyme designed to make continuous glucose monitors significantly more affordable and easier to manufacture for use by people living with type 1 and insulin-requiring type 2 diabetes.

Hemoshear's drug discovery platform, REVEAL-TX, enables the creation of biologically relevant human disease models to uncover underlying mechanisms of disease and translate the discoveries into drug candidates, the companies said. Under the terms of the agreement, Carnot will use its know-how in directed enzyme evolution to alter specific human enzymes identified by Hemoshear to treat certain undisclosed inborn errors of metabolism, including enzyme deficiencies and mutations. The targeted defects do not allow the body's systems to properly turn food into energy, causing a wide range of symptoms, many potentially lethal.

Christopher Shepard, general manager and CEO of Smartzyme, will serve as Carnot's interim general manager and CEO. Leavitt, formerly with Synageva Biopharma Corp., of Lexington, Mass., and Alexion Pharmaceuticals Inc., of Boston, will collaborate with a team of former Synageva/Alexion colleagues who bring expertise in clinical development, regulatory affairs and market access.

"We have some candidate proteins that we're interested in working on, and we're looking for more," Leavitt said. "There's a lot that goes into that decision, including the commercial side, the prevalence, incidence, severity of disease, the ability to hit that target." The firms are "moving from first-generation enzyme replacement therapy [ERT] to second generation," he said, likening the evolution to that with insulin, first made from tissues. "You can see that [progress] probably first in the hemophilia area, you're getting second and third-generation modified molecules," and the advance is happening with established targets as well as new ones, he said. "In general, the clinical development for these kinds of targets is pretty fast. I think that's one of the advantages in this field, provided you can find patients. You're looking for obvious clinical benefit, and that would happen pretty quickly."

The safety of ERTs "has been remarkably good," he noted. "There's always the issue of immunogenesis, but that goes along with the territory of giving a protein to someone who doesn't have the natural protein."

Asked about timelines for entering the clinic, he said it's "a little early for [estimating] that. What we want to do is get to the first inflection point, and for us that's having a protein that we show benefit in a good model. Right now we're just going to focus on this project and show what we can do." He said the firms have "adequate money to get to the next inflection point. We want to be frugal with the capital and make sure everything we do is aimed toward getting to that point as quickly and efficiently as possible."

After 20 minutes at JPM

Brian Wamhoff, Hemoshear's co-founder and head of innovation, told BioWorld the approach deployed "is not new at all, but I think it's going to start making its way into mainstream biotech. It's been around in basic science and academia, [the notion of] engineering enzymes that metabolize one substrate to metabolize another substrate more efficiently – hijacking an enzyme that normally metabolizes 'A' at, say, 90 percent and 'B' at 10 percent, and flipping that enzyme so that now it metabolizes 'B' at 90 percent, and 'A' at 10 percent, and you want to get rid of 'B,' essentially. There are a lot of examples out there in the literature. The key is identifying these enzymes in a disease scenario."

Wamhoff said that, "for a lot of these diseases, traditional ERTs won't work. You take the wild-type enzyme, you inject it into the patient, it goes to the liver and fixes the defect," but other processes interfere. "At this point, we're not at liberty to disclose the diseases Carnot is working on in the collaboration or the diseases we're working on with Carnot. I think you'll see that early to mid-next year. We're still in the process of locking down intellectual property and making sure it's bulletproof," he said.

Hemoshear has "identified several targets that we felt could be modified to do something else and alleviate toxins in patients. Some of these targets were identified well over three years ago, and we didn't have the current biotech relationship to really go after them. This [deal] came out of last year's J.P. Morgan Healthcare Conference meeting. Chris Shepard and I met. It was a very last-minute meeting, where Smartzyme investors had encouraged Chris to meet with Hemoshear, based on some things that Smartzyme wanted to do, which has now become Carnot. At Hemoshear, we weren't quite aware what the meeting was for. But as soon as Chris Shepard began discussing what Carnot wanted to do with Hemoshear, which was use our disease platform to validate their directed evolution protein therapies, I realized that we had identified several targets as well that we could use their platform for, to create the proteins to validate in our technology. It took almost a year to bring the deal together. The meeting was maybe 20 minutes long," but the mutual advantages quickly became apparent, he said.

As for the origin of Carnot's name: Shepard completed his post-graduate training in statistical physics, and has an affinity for that area of study. Sadi Carnot was a French engineer and physicist who is regarded as the father of thermodynamics. The engineer was convinced that steam engines of his day, widely used in industrial processes, were inadequate and inefficient. He published a book, Reflections on the Motive Power of Fire, in 1824. The founders of Carnot, like the company's namesake, say they believe current use of ERTs is inadequate, and the unmet need vast.