One scientist’s seven-year odyssey to commercialize his drug, by trial and (a lot of) error

It wasn’t for social reasons that Dr. Jeff Toretsky became a regular at mixers in suburban Maryland.

The mixers were for the region’s sparse biotech community and Toretsky, a researcher and physician at Georgetown University, was on the prowl for a CEO to help commercialize a molecule his lab discovered.

It’s a story that’s hardly unique in biomedicine: Academic develops a drug, forms a tiny company, carries out human trials, maybe even cashes out when the company gets bought. Boston, New York, and San Francisco are awash with companies that started this way.

But Toretsky found himself in a different situation when trying to commercialize his putative drug for the pediatric cancer Ewing’s sarcoma. Georgetown, at number 120 among institutional recipients of National Institutes of Health funding, isn’t a research powerhouse with a track record of spinning out biotech companies.

And Washington D.C., while an epicenter of so many things, doesn’t have an ecosystem of biotech startups that would provide the resources — the venture capitalists, the networking events, the incubators — to walk a newbie through founding a company.

So Toretsky set out to do it on his own, by trial and error. Seven years and four CEOs later, his drug is now in clinical trials, which should finally provide the answer he’s waited anxiously to know: Would his drug save the lives of his patients with Ewing’s sarcoma?

A rare disease and a small budget

Ewing’s sarcoma is a cancer of the bone and soft tissues surrounding the bone that primarily afflicts young people. It’s exceedingly rare: Only 1 in 1 million Americans will develop it. By comparison, other rare diseases with drugs recently commercialized, such as Duchenne muscular dystrophy and spinal muscular atrophy, occur at rates of around 1 in 100,000 and 1 in 10,000, respectively.

The current treatment for Ewing’s consists of chemotherapy, but for those whose cancer has spread to other parts of the body, or have recurring tumors, chemo doesn’t always work.

In the July 2009 issue of Nature Medicine, Toretsky’s lab published a study on a small molecule that the researchers believed could battle the cancer in a different way.

In Petri dishes and then in mice and rats, the drug appeared to reduce tumor growth by preventing a mutant protein called EWS-FLI1, only present in Ewing’s patients, from interacting with another protein critical for cancer growth.

But EWS-FLI1 had previously been considered “undruggable.” Usually, drug targets are enzymatic, meaning they have well-defined pockets for a drug to fit into, like a key into a lock. EWS-FLI1 was just a protein, and a mutant one. It was floppy and unfolded, with no obvious lock for a key to fit into.

By screening about a thousand small molecules, Toretsky found one that seemed to be binding to it, and inhibiting it. It was untraditional, but he believed it could work. And time and again, experiments in his lab indicated it could.

He was itching to move on to clinical studies. But it would cost around $5 million to get ready for that stage, and that money simply didn’t exist in his lab budget.

The university’s technology transfer office had been trying, setting up meetings with pharmaceutical companies like Johnson & Johnson, GlaxoSmithKline, and Teva to see if any would be interested in funding clinical studies. But what neither he nor his university realized was that these were likely “not the right companies,” said Ethan Perlstein, the founder of biotech startup Perlara. “There’s about a dozen [pharmaceutical] companies that do focus on rare disease development and … they would have a different mindset than pharma at large.”

Toretsky spent the better part of a year pitching companies. Eventually, they all turned him down. While his lab had funding from the National Cancer Institute for research, Toretsky couldn’t get a trial off the ground. And his funding from the NCI’s NExT program for experimental therapeutics was shut down.

And so in late 2009, Toretsky started going to meetings of biotech entrepreneurs in Montgomery County, Md., where he lived. They were essentially mixers, of companies looking for CEOs, and CEOs looking for companies — speed dating for wannabe companies. But they weren’t as flush with candidates in suburban Maryland as in other biotech hotspots.

“Compared to other places like Boston and San Diego, we have a very thin bench as far as biotech startups,” Toretsky said. “So the number of people running around who are moving from one start up to the next, that number is going to be very very small, because we’re not turning over those kinds of companies.”

He formed his first company, an LLC, and hired a CEO who had some experience with biotech. But the relationship went south quickly. “Frankly, I didn’t know what was required of a CEO, I didn’t know what a CEO really did,” Toretsky said. She left the company three months in.

Six months later he hired a new CEO who seemed to have more promise than his first. But as one year passed and then two, his company still hadn’t raised any money, and they weren’t anywhere near manufacturing, let alone a clinical trial. His side project was flailing. “It was incredibly onerous because I didn’t really know what I was doing and the people I was working with also didn’t seem to know what they were doing,” he said.

It was essentially trial and error. He would hire a new CEO, work with the person to garner funding, and if years later, the project stalled, he knew something was wrong. “You end up learning a lot if you’re willing to acknowledge the mistakes and then learn from them,” he said.

Meanwhile, Toretsky was still researching and seeing patients at the hospital. Most of his patients from 2009 who had begged for his drug had died.

“Getting the right people to pay attention is a huge problem,” Toretsky said. “It was my problem.”

The right connection

Contributing to that problem, thinks Dr. George Demetri, director of the Center for Sarcoma and Bone Oncology at Dana-Farber Cancer Institute in Boston, was the rarity of the disease.

“Where do market forces fail in drug development? I think this is a good example of that,” Demetri said.

Some pharmaceutical companies do collaborate with academics on drug development, said Michael Gladstone, a principal at biotech venture capital firm Atlas Venture. But mostly it’s a role he now sees being played by venture capitalists.

“Even with great science and great founders, really talented and driven people working on good things can slip through the cracks,” Gladstone said.

That seemed likely to be the fate of Toretsky’s drug until one day in 2013 when, out of the blue, he got an email from Scott Glenn, a serial entrepreneur who has launched two dozen biotech companies. Glenn was looking to invest in another Ewing’s sarcoma treatment, and had read Toretsky’s papers. After three months of talking, Glenn became the CEO of a new company, called Tokalas Inc., with Toretsky as the inventor and cofounder.

“Scott went to his Rolodex, and he raised 3 million bucks in six weeks,” Toretsky said. “Basically the lights came on.”

Using the money Glenn raised, the company carried out toxicology studies, to make sure the drug wasn’t harmful, and figured out how to formulate and manufacture the medicine. Then it filed its Investigational New Drug application. In January 2016, the IND was approved, meaning the drug was cleared for clinical trials. A few months later, Tokalas was acquired by Oncternal Therapeutics, another biotech working on cancer drugs.

Toretsky’s molecule, dubbed TK216, is now in its first stage of clinical trials. (It’s not the only one: There are several other drugs for Ewing’s sarcoma in clinical trials run by institutions such as the Children’s Oncology Group and SARC.)

It is being tested at low and increasing doses in nine patient volunteers. Right now the outcomes being measured are just safety, not efficacy. Toretsky is hopeful that they’ll be able to publish some initial results by spring 2018, and that they’ll be enough to move the drug to the next stage.

“We still don’t know whether this is going to cure anybody, let’s be humble about that,” he said. “But if I knew that this drug made a difference for even one person, I would be really happy.”