The pharmaceutical business tends to split into a couple of camps: Either molecules ought to be small, or large. But some interesting work these days is happening in the middle, where Cambridge, MA-based Ensemble Therapeutics has been carving out its niche.
Ensemble has been toiling away since 2004, based on work in David Liu’s lab at Harvard University, to synthesize a class of mid-sized molecules known as macrocycles. The idea is to try to combine the best of both worlds with small and large molecules. The mid-sized drugs are supposed to have a big advantage of traditional small-molecule drugs-their ability to be made into oral pills-along with the precision targeting capability of large-molecule biotech drugs, like antibodies or other engineered proteins. Ideally, the mid-sized drug candidates should be lean and mean enough to hit biological targets inside cells that bulkier protein drugs can’t reach.
There have been plenty of skeptics. Macrocycles are complex molecules found in nature. Scientists know they can sometimes be made into useful pharmaceuticals, including antibiotics like erythromycin, but no one has developed a fast, cheap, industrialized way to synthesize new macrocycle drugs to fill up a library, like with small molecules. It’s only been in the last year, Ensemble CEO Mike Taylor says, that the company has really hit its groove, developing a method that had created a vast library of about 3 million new macrocycles (soon to be an estimated 4.2 million) with potential to run through screening campaigns against some of biology’s hard-to-reach targets.
All of Ensemble’s molecules are still in their infancy, and need to run the usual gauntlet of tests in animal models before the company even thinks seriously about advancing them into clinical trials. But Ensemble has gotten much positive feedback from its two partners, Pfizer and Bristol-Myers Squibb, and is now in position to add a third or, maybe, fourth partner, Taylor says.
“There were a lot of biases against macrocycles when we started, based on historic challenges,” Taylor says. “We had a checklist to work on, to convince people that yes, we could make lots of them, and yes, we can make discrete molecules, and yes, we can make them with drug-like properties, and yes, we can get them into cells. There were about 12 things we had to tick off, which we have essentially done.”
Ensemble recently reported that it had been granted a couple of key patents on its technology. This patented method has put little Ensemble, with a little more than 30 employees, in a position to do what Big Pharma companies do—run industrialized campaigns to see if certain new drugs can hit a target, and can elicit the desired biological activity.
“We’ve become very productive, we can screen millions of macrocycles against dozens of targets in a short period of time. It’s extremely efficient and fast,” Taylor says.
Taylor has his Ph.D in medicinal chemistry and prior experience as a senior vice president of R&D at Pfizer, so he knows how this is easy to say and hard to do. He’s been joined in this effort by Nick Terrett, Ensemble’s chief scientist, another Pfizer veteran, and a co-inventor of the hit erectile dysfunction drug, sildenafil (Viagra).
Taylor and Terrett know from experience that Big Pharma companies have huge libraries of small molecule compounds of their own. For Ensemble to really have something new and valuable, it has to bring new molecular structures to the table, with ability to hit new targets. And it needs to be done cheaply, because R&D costs have been rising, without extra productivity to show for it. Big Pharma, as those who follow the headlines know, has been under a lot of pressure to get more bang out of its research bucks.
“Big pharma had so many compounds in its collections, it was getting too expensive to screen,” Terrett says. Taylor adds that it could sometimes cost $3 million to $4 million to screen an entire library of small molecules against a biological target of interest, just looking for hits, before even starting the long and expensive work of animal and human testing. Ensemble’s synthetic macrocycles are now made for just 9 cents each, Terrett says.
Of course, nobody knows whether those 9 cent molecules will ever go on to become FDA approved products worth hundreds of millions, or even billions. Ensemble did, in the last year, change its name from Ensemble Discovery to Ensemble Therapeutics, so that’s a pretty clear indicator of what it wants to grow up and become. Ensemble currently has 15 protein targets at various stages of test development, screening, and validation of “hits.” It will soon take the next steps by picking one or two lead drug candidates, Taylor says.
“Over the next year or so, that’s where the progress of the company will be most dramatic,” Taylor says.
Ensemble is still playing a lot of its cards quite close to the vest, partly because of agreements it has made with partners. On my recent visit to Ensemble’s offices, Taylor did say that the company received a milestone payment from its partner Bristol-Myers for developing a macrocycle molecule that was able to bind with two targets at the nexus of a protein-protein interaction. Another program is seeking to hit an interaction between a protein known as a cytokine and a cytokine receptor, Taylor says.
He didn’t name the targets, and the company hasn’t published any description to peers of what it has done with macrocycles against these specific targets. That could change over time, Taylor says. “We plan to publish and disclose our work on those targets so that people can understand the power of what we can accomplish,” Taylor says.
Ensemble isn’t the only company with its eye on macrocycles. Research Triangle Park, NC-based Tranzyme Pharma (NASDAQ: TZYM) has built its own library of macrocycle compounds, which it described in its recent IPO filings to investors. Ensemble believes that it has a much bigger library of macrocycles with more diversity of structures, Taylor says. None of the Big Pharma companies, and no other biotech company, has a library like Ensemble’s in their toolkit, he says.
Pharma has already shown a fair bit of interest in breaking out of the rut of small vs. large molecules, by ponying up for partnerships to develop RNA interference drugs, or peptide therapies as alternatives to the standard fare. That same kind of desire—to find new compounds that can hit currently inaccessible biological targets—is working in Ensemble’s favor. “There’s a lot of interest in Big Pharma in what we’re doing,” Taylor says.
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