Monday, March 30, 2015
Tiny Aduro Biotech Inc. hopes to put the STING on cancer with a potential $750 million deal between the Berkeley company and drug giant Novartis AG.
The deal centers on experimental synthetic small molecules, developed by Aduro, that could be the latest weapon in the hot field of cancer immunotherapy. The molecules bind to a receptor for a protein known as STING, which researchers believe plays a critical role in helping the immune system recognize and marshal its tumor-fighting forces against cancer.
What's more, by activating STING, Aduro leaders believe their experimental drug can knock out not only the main tumor but also similar tumors that have spread to other parts of the body with a single injection.
It is the latest big news from Aduro, which earlier this month said it would seek $86 million in an initial public offering. The 55-employee company has raised more than $143 million in all and reached deals with Johnson & Johnson around its "cancer vaccine" technology.
Aduro's own pancreatic cancer therapy is in a mid-stage clinical trial.
In this latest collaboration, Novartis (NYSE: NVS) will pay $200 million upfront and take an initial 2.7 percent equity stake in Aduro for $25 million, the companies said late Sunday night. Novartis committed to another $25 million investment and Aduro could receive another $500 million for hitting development undisclosed milestones.
Aduro, which Chairman, President and CEO Stephen Isaacs said had been talking to "all the major players" in cancer immunotherapy, worked with Novartis for about nine months.
"We had choices, but we decided to go with Novartis," he said, noting the co-development and co-promotion parts of the deal and the Swiss company's scientific know-how.
Aduro, whose scientific team is led by Chief Scientific Officer Tom Dubensky Jr., plans to grow to at least 80 employees this year.
Novartis and Aduro haven't yet decided when to move into human clinical trials with the deal's centerpiece drug, called ADU-S100, but the companies would share profits, if the drug ultimately is approved by the Food and Drug Administration and sold.
At the deal's core are synthetic small molecule modulators — known as cyclic dinucleotide, or CDN, that are modified chemically to fit into the STING receptor and set off a cascade of events.
STING stands for the "stimulator of interferon genes" complex, which researchers believe detects damaged or misplaced DNA.
When Aduro's synthetic CDN docks with the STING receptor. That stimulates the production of interferon, which, in turn, activates infection-recognizing dendritic cells turned off by tumors.
When turned on again, the dendritic cells can show the immune system evidence that something amiss in the body — like a giving a tracking dog a scent. The immune system's advance guard, white blood cells known as lymphocytes, then are released to determine what kind of attack to mount against the tumor, and the battle begins.
"The magic really is in the molecule itself," Isaacs said.
Such STING-focused drugs could be the next wave in the fast-developing field of immuno-oncology. The growing list of cancer immunotherapy drugs includes so-called checkpoint inhibitors, which stop tumors from secreting proteins, such as PD1, that keep lymphocytes at bay. Another is CAR (chimeric antigen receptor)-T therapy, which involves removing and genetically enhancing a type of infection-fighting cells, called T cells, then returning those to the body.
Novartis, one of the top three drug companies worldwide in terms of sales, is involved with both kinds of work. In spite of manufacturing well-known drugs such as Ritalin and Lamisil, it is perhaps best known in the Bay Area for its 2006 acquisition of Chiron Corp.
"With deep sequencing of tumors, we recognize that all tumors make unusual, abnormal proteins. There's genetic instability," said Dr. Mark Fishman, president of the Novartis Institutes for BioMedical Research in Cambridge, Mass. "And if that's true that they're making 'neoantigens,' they should be recognized as foreign."
A key question, though, is how to enhance the immune system's recognition of the "foreign-ness of these tumors," Fishman said.
STING, he said, is an important way to boost the immune response by freeing dendritic cells to educate the immune system to new-found antigens.
But Aduro's experimental drug is even more exciting to the leaders of the two companies for another reason: It not only halted tumors into which it was injected — albeit in mice — but it also stopped genetically similar tumors in the lungs.
"There's very high hopes that what we see in the mice will be repeated in humans," Isaacs said.
Researchers also hope that by injecting ADU-S100 directly into a tumor, dendritic cells would upload their information to the immune system faster, allowing for a quicker immune response than seen historically in other cancer immunotherapy approaches.
"One could imagine a fairly rapid response," Isaacs said. "It certainly was in mice."
Novartis and Aduro are considering combining ADU-S100 and radiotherapy in their first clinical trial.
An unrelated University of Chicago research team last year reported that targeted high doses of radiation therapy could amp up the STING pathway.
Aduro and Novartis, which has run its own STING programs, haven't determined when the ADU-S100 study would begin.
Aduro has manufactured the drug and completed preclinical toxicology work, Isaacs said, indicating that a trial could begin as early as the end of this year.
STING eventually may offer a route for curing cancer, Fishman said, but it is early in a drug-development process that some experts say can burn a decade and more than $1 billion.
"Targeted therapies to date are powerful, and some turn cancer into a chronic disease, but we will need the immune system for a long-term, persistent effect," Fishman said. "We'll have to wait and see."
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