In 2013, researchers were two years into a revolution that would place the body's immune system at the center of cancer drug development.

A drug called Yervoy, formulated from science that won last year's Nobel Prize, was just beginning to play a role in the treatment of metastatic melanoma. And two experimental compounds in clinical testing were on the cusp of being christened by regulators as Opdivo and Keytruda.

But as the flows of venture funding and pharma research dollars were adjusting to immuno-oncology's advent, Josh Bilenker bet on the genomic revolution of the decade just past.

Inspired by the successes of targeted therapies like Pfizer's Xalkori and then Pharmacyclics' Imbruvica, Bilenker founded Loxo Oncology in 2013 to go after cancer's genetic Achilles' heels.

The drugs Loxo eventually developed — members of a class known as kinase inhibitors — bore out that choice. Vitrakvi, is now approved in the U.S. and licensed by Bayer. Another, known as selpercatinib, drew Eli Lilly to negotiate what became an $8 billion buyout of Loxo in the opening days of 2019.

Measured from the $13 per share at which Loxo launched its public offering to the $235 per share price Lilly paid, Bilenker's company delivered a remarkable 1,700% return in its four-and-a-half year public run.

"Josh and his leadership team kept the focus on validated targets where a best-in-class drug was needed and was feasible," said Ross Levine, a physician scientist at Memorial Sloan Kettering Cancer Center and a former member of Loxo's scientific advisory board, in an email to BioPharma Dive.

Along with other recently acquired cancer companies like Ignyta and Array, Loxo proved out a drug development model that Bilenker likened to baseball's "moneyball" theory.

"Everyone is looking for that home run, $10 billion-a year drug," said Bilenker, a physician who worked in venture capital and at the Food and Drug Administration, in an interview. "The way that unfolds in R&D is it forces you into home run hitting and the strike-out rate increases."

By contrast, many kinase inhibitors are designed to treat small, genetically defined pockets of patients with rare, but vulnerable cancers. Only a few thousand patients a year are estimated to be eligible for Vitrakvi, and the anticipated addressable population for selpercatinib is about 5,000 initially.

"We were the moneyball thesis of target selection," Bilenker said.

The focus on kinase inhibition isn't unique — one recent count by SVB Leerink found 20 deals totaling nearly $100 billion in value over the past decade that centered on kinase inhibitors.

But Loxo's success, and the resulting large pharma interest it drew, helped put targeted cancer therapeutics back on the map, according to ​Athena Countouriotis, CEO of the cancer biotech Turning Point Therapeutics, which was founded in 2013.

"Precision oncology took a little bit of a hit for about five years," said Countouriotis in an interview. "What Josh, Jake [Van Naarden] and that whole team did really set the stage for us in terms of continuing to bring precision oncology back," she added, referring to Loxo's chief operating officer.

If interest in kinase inhibition had waned somewhat by 2013, the drug class is certainly back on drug developers' radar screens. From 2017 through November 2019, the FDA approved 23 kinase inhibitors across a range of cancer types and malignancies, a dramatic swing from the 8 cleared by regulators over the preceding three-year period from 2014 to 2016.

As that track record attests, Loxo wasn't alone. But Bilenker and the team he recruited were particularly effective in achieving what they had set out to accomplish.

In roughly four years, the biotech moved Vitrakvi through Phase 1 testing and to the FDA for a first-of-its-kind approval that cleared the drug for use in tumors of a certain genetic make-up rather than of a particular organ.

And within a two-year span, selpercatinib, the drug that drew Lilly's eye, yielded impressive Phase 2 data that the pharma plans to file for an FDA OK.

A licensing deal with Array in 2013 was a "jump start," Bilenker said, giving Loxo rights to what would become Vitrakvi.

The partnership was also the foundation of a model followed by Bilenker that outsourced some early drug discovery, while internally investing more heavily in target selection and drug profiling.

"He was able to harness the discovery capabilities of Array and combine it with his expertise in drug development in oncology," said David Bonita, a partner at OrbiMed, one of Loxo's venture backers, in an interview. "That was special."

"We allowed Array to continue and persist through what were perceived to be limits but turned out not to be," said Keith Flaherty, a Loxo co-founder and former member of the company's board of directors, in an interview.

"I have to give Josh the credit to develop that intuition and skill-set," Flaherty added. "He had never done that before." (Loxo built out internal discovery capabilities in 2017, opening a laboratory in Boulder, Colorado.)

Bonita, who also served on Loxo's board of directors, noted Bilenker's approach helped Loxo grow quickly and cost-effectively.

"He generated extremely exciting ASCO-quality data on less than 50 full-time employees," said Bonita, referring to the American Society of Clinical Oncology's annual meeting. Loxo headlined ASCO in 2017 with data on Vitrakvi.

"He didn't have to build a massive infrastructure."

To Bonita's point, Loxo accumulated a deficit of $330 million over the six years it existed as an independent company — a sizable sum, to be sure, but one that ranks as modest in a sector accustomed to years, or even decades, of net losses.​

Loxo's track record proved appealing to Lilly and, in a twist on the usual story, the pharma last week put Bilenker, Van Naarden and their Loxo colleague Nisha Nanda in charge of a major revamp of its cancer research.

The trio will lead a new organization that combines Lilly's cancer research laboratories with Loxo's in an effort to replicate the success Loxo found with Vitrakvi more widely across the Lilly portfolio.

"In the past, we were successful one drug at a time," said Bilenker. "We hope to be doing that by multiples moving forward."