Gilead Sciences is paying tiny Tango Therapeutics $50 million to tap into the startup’s cancer drug program, adding to what has been so far an expensive, but not yet lucrative, foray into cancer immunotherapy for Gilead.
Cambridge, MA-based Tango is still in the early phases of looking for cancer drugs by exploiting a well-known tumor vulnerability, known as synthetic lethality, in a very modern way: gene editing. Gilead could potentially combine Tango’s drugs with an established kind of immunotherapy called checkpoint inhibitors, said Tango CEO and president Barbara Weber.
It is unclear if Foster City, CA-based Gilead (NASDAQ: [[ticker:GILD]]) plans to develop its own checkpoint inhibitor, license one—seven have already been approved—or go in a different direction altogether. Gilead representatives did not respond to requests for comment.
The Tango deal will not provide drugs to combine with Gilead’s live T-cell therapies known as CAR-T—upon which the bigger company has already made a massive bet. “That’s not part of this collaboration,” said Weber.
Gilead spent $11 billion in 2017 to acquire Kite Pharma, a developer of CAR-T therapies. Kite’s first CAR-T, axicabtagene ciloleucel (Yescarta), is now approved for lymphoma patients who have tried other therapies without benefiting from them. The frenzy around CAR-T has not yet been matched by outsized sales for Gilead. Approved in late 2017, Yescarta notched $108 million in sales through the first six months of 2018. The other approved CAR-T, Kymriah from Novartis, has tallied even less.
The U.S. government has yet to decide how Medicare will pay for the two treatments, a problem that FDA Commissioner Scott Gottlieb said was worrisome. “We need to figure [this] out for all of these therapies where there’s, you know, potentially curative therapy, but a big upfront cost,” Gottlieb told STAT last week.
Results have been disappointing for another Gilead acquisition designed to augment its oncology pipeline. In 2011, Gilead acquired Calistoga Pharmaceuticals for $375 million to bring in idelalisib, then an experimental treatment for blood cancers. Approved as Zydelig, the drug was blocked for use in larger populations of first-time patients after several deaths in clinical trials.
Now Gilead, which generates more than $25 billion in annual sales mainly from antiviral drugs, is turning to a tiny startup to add to its young cancer franchise.
Tango is basing its work on an old concept. Synthetic lethality—synthetic in this case meaning “a synthesis of two elements,” not “artificial”—comes from fruit fly studies a century ago. Researchers noted that two flies each carrying a separate mutation lived unharmed, but their offspring that inherited both mutations did not survive. Scientists wondered whether cancer cells with one mutation that allows them to thrive could also be killed by disabling another gene within the same cells. Tango is trying to identify the lethal gene pairings.
Many cancer cells thrive because they carry mutations to genes that normally suppress tumor growth. The normal versions of these genes slow down cell division, or fix DNA errors, or force cells to self-destruct.
It can be hard to kill those cancer cells without killing a lot of non-cancerous cells, too, however. To find drugs with fewer side effects, Tango is looking for the second gene that, when knocked out, brings the tumor cell down with it. To look faster, it is using CRISPR-Cas9 gene editing tools to add mutations to cancer cells that already have mutations in their tumor suppression genes. Because Tango can screen thousands of combinations and, it hopes, pinpoint which secondary mutations make the best targets, Weber argues that the drugs that emerge could make more precise attacks.
If synthetic lethality is a kind of one-two punch, the trick in fighting cancer is landing the right second punch. The only precedent is a type of drug called PARP inhibitors, such as Clovis Pharma’s rucapirib (Rubraca). PARP inhibitors knock out an enzyme, poly (ADP-ribose) polymerase, that cancer cells use to bounce back from treatment. In cells that are also missing the tumor suppressor genes BRCA1 and BRCA2, the PARP knockout takes down the entire cell. But not all the time, warns Tango CEO Weber: “It’s all context dependent,” she says, noting that PARP inhibitors have worked better to date in BRCA1 or BRCA2-mutated ovarian cancer than in breast cancer.
PARP inhibitors can stop working, too. Writing in Science in 2017, Christopher Lord of the Institute of Cancer Research in London and Alan Ashworth of the University of California, San Francisco, noted, “As with other targeted therapies, resistance to PARP [inhibition] arises in advanced disease.” In the 1990s, Ashworth helped make the connection between BRCA mutations and PARP inhibition, sparking the use of synthetic lethality to fight cancer. He is a Tango cofounder.
(Tango was in the news in September when an investigation found that another cofounder, Memorial Sloan Kettering chief medical officer Jose Baselga, failed to disclose many of his industry ties. Baselga quickly resigned from the cancer center.)
Tango’s deal allows Gilead the rights to as many as five cancer targets that Tango discovers, and additional payments down the road could climb as high as $1.7 billion—highly speculative payments that are often referred to as “biobucks.”
