By Alissa Poh

November 5, 2008 | When the Human Genome Project first took off, the genomics space teemed with life science entrepreneurs, all raring to create startups. It was no different for those who started Tranzyme Pharma. 

“Our original idea was to create cell lines that behaved more like human cells, for drug discovery,” says Vipin Garg, Tranzyme’s scientist-turned-CEO. “Whereas most genes are delivered in cis, we had the technology to do so in trans, which explains our company’s name.” Many post-genomics companies died a slow but sure death, however, when the model on which they were based failed to produce exciting blockbuster drugs, as promised. Tranzyme’s story, on the other hand, is one of embracing evolution – a key ingredient when it comes to keeping a small biotech on its feet. 

The evolution

“We went back to the roots of pharmaceutical drug discovery, figuring that it was necessary for us to possess some sort of proprietary technology in that regard, whether it was chemistry or recombinant DNA,” Garg says. Hence the decision to buy a Canadian biotech with chemistry-based technology in 2003, “the most significant thing we did, and why we’re still here today.” Tranzyme’s R&D facility is now situated just outside of Montreal – of roughly 40 employees in total, 25 are working in Canada – while the company maintains business development, clinical and corporate headquarters in North Carolina’s Research Triangle Park. 

Tranzyme’s technology, called Macrocyclic Template Chemistry (MATCH), exploits macrocycles, a distinct and typically complex class of molecules from nature, with cyclosporin being the best-known example. MATCH has enabled the company to create simplified versions of these complicated compounds, while retaining their properties. “Cyclized molecules have functional groups sticking out in every direction; they can fit into complex pockets and modulate receptor activity,” Garg explains. “Since we start off in solid phase, we can make hundreds of these compounds at a time, with different flavors, and test them rapidly – once we know which ones work, it’s easy to further refine them by scaling production up in liquid phase.” Tranzyme’s MATCH compounds tend to possess favorable receptor binding characteristics; biomolecule issues such as poor metabolic stability are also taken off the table, since these are purely synthetic products. 

The company has devoted the last five years to finding novel small-molecule drugs targeting receptors that regulate GI motility, appetite and metabolism. Post-operative ileus (POI), where the GI tract temporarily shuts down in response to surgical trauma, is one of the most common causes of delayed hospital discharge – for instance, three million colon cancer patients in the US undergo resection surgeries each year, and at least one third experience significant POI. Yet there are precious few GI prokinetic agents available – Reglan (metoclopramide), the only drug out there for GI motility, is often ineffective, with CNS side effects as an added risk. Entereg (from GSK and Adolor), was FDA-approved last August despite not being particularly effective and with black-box warnings to boot, because surgeons were mindful of the huge need in this area. Novartis’ Zelnorm was removed last year due to cardiovascular risks. And J&J’s Propulsid, a billion-dollar drug in 1999, was pulled the following year, also for toxicity reasons. 

The mantra, when it comes to GI drug history, has been one of modulating symptoms through the brain, Garg says. “Serotonin and dopamine receptors are the two major classes scientists have gone after, telling the brain to shut off the sensation of nausea, for instance. But that doesn’t do anything for the underlying problem, which is in the GI tract.” So at Tranzyme, researchers have chosen instead to focus on the ghrelin receptor. Ghrelin, otherwise known as the “hunger hormone,” is responsible for gastric accommodation. “Our stomach, typically, is like a football without much air in it, but it opens up to accommodate food as we experience hunger pangs, and ghrelin is responsible for this,” Garg explains. 

The pipeline

Currently, Tranzyme has two drugs in the clinic, both potent ghrelin agonists. The idea, Garg says, is to promote the body’s own ability to improve gastric motility. Intravenous TZP-101 is being prepared for Phase III trials; oral TZP-102 is almost to the Phase II stage. TZP-101 will be used to treat acute POI, and has also received Fast Track Designation from the FDA for acute gastroparesis, or paralysis of the GI tract, a major complication of diabetes. As well, Garg adds, it could potentially be used for GERD (gastroesophageal reflux disease) – approximately 30 percent of patients in this category don’t get enough relief from treatment with proton pump inhibitors, and there is “very clear consensus within the medical community that if there was a prokinetic agent over and above PPIs, it would help resolve GERD.” Functional dyspepsia, which affects millions of people yet lacks specific cause or treatment, is another indication for this drug. TZP-102, on the other hand, will hopefully meet the needs of those with chronic gastroparesis, which requires long-term oral medication. 

“With TZP-101, we can pretty much time GI tract recovery close to the rest of a patient’s recovery – approximately three days, as opposed to the statistics right now, where it takes anywhere from four to six days before patients can be discharged from the hospital,” Garg says. He also believes Tranzyme’s drug candidates will succeed where the likes of Progenics’ opioid antagonists have failed in Phase III. “It’s true that the constipation seen in POI is opioid-driven,” he says, “but POI is a lot more than just constipation; there’s a whole inflammatory cascade triggered as soon as you cut into the gut, and that has nothing to do with opioids.” 

Tranzyme’s pipeline also includes two other candidates in preclinical development. TZP-201 is a motilin antagonist – motilin being the hormone that controls the contraction of migrating motor complexes (MMCs) throughout the GI tract, thus mediating digestive system motility. High motilin levels can provoke diarrhea, and Garg sees potential in TZP-201 for this indication – not only diarrhea associated with infection or irritable bowel syndrome, but also chemotherapy-induced runs. The fourth drug, TZP-301, is what Garg calls “the flip side of ghrelin,” in other words, an antagonist of this hormone to treat obesity and metabolic syndrome. “We’re just getting proof-of-principle animal data for our anti-obesity drug, and we hope to file an IND for our motilin antagonist next year,” he says. 

The future

Considering that the company is eyeing a potentially multi-billion-dollar opportunity in the GI space, it’s perhaps not surprising that, according to Garg, discussions are under way with approximately half a dozen mid-size to large pharma companies for “some sort of game-changing transaction,” over the next three to six months.

“It’d be tough to find another company out there with two drugs in these phases, achieved with less than $50 million,” Garg remarks. “We’ve been very capital-efficient. Phase III assets are few and far between; every pharma needs them. On top of that, TZP-101 at least will likely reach the market by 2011 – if you look at the timeline, that’s just about when pharma will hit the patent cliff.”

Garg, whose job portfolio includes Arco and Sepracor (where he was involved in developing Lunesta), has learned some tricks of the sales trade along the way, “as a scientist placed in situations where my ability to convince others of my idea had significant premium on it.” He certainly isn’t fretting about Tranzyme’s future, whether this “game-changing transaction” turns out to be a corporate partnership, something along the lines of an M&A, or Tranzyme raising more money to venture into Phase III trials independently. Stay tuned.