Novartis Aims To Leap-Frog Into Next Immuno-Oncology Wave With Aduro

Novartis hopes its multi-year deal with Aduro Biotech to develop molecules to unlock dormant immune cells by targeting and activating a central signaling pathway called STING will allow it to make up for lost time and catch “the next wave” in immuno-oncology.

Novartis AG is ramping up its immuno-oncology strategy and betting that the next big thing will be ways to alter the nature of the tumor microenvironment.

The Swiss group on March 30 said it was setting up a new immuno-oncology research group and has signed a multi-year alliance with Aduro Biotech Inc., worth up to $750 million, to develop cancer immunotherapies based on the California biotech’s STING (STimulator of INterferon Genes) technology, a next-generation approach to harness the body’s immune system to fight cancer. [See Deal]

Novartis also announced the launch of a new immuno-oncology research group, headquartered in Cambridge, Mass., and led by Glenn Dranoff, who joins from the Dana-Farber Cancer Institute.

The Switzerland-based company was not in the first wave of big pharma players entering the immuno-oncology space, but it hopes its own internal STING program and the collaboration with Aduro will let it eventually gain a leading role. Novartis’ current CAR-T cell programs – and Aduro’s STING platform using cyclic dinucleotides that target and activate the STING receptor – will be key vehicles for reaching this objective, says Mark Fishman, president of Novartis Institutes for BioMedical Research (NIBR).

“While we are enthusiastically embracing the inhibition of checkpoint inhibitors as part of cancer therapy, we feel the next wave will be different. The next wave of immune therapy will be to enhance the response of the immune system to cancers and make the immune system recognize the cancers as being ‘foreign,’” he said in an interview.

STING Explained

Cyclic dinucleotides (CDNs) target and activate the STING receptor. Studies show that once activated, the STING receptor initiates an immune response through three different signaling pathways: pro-inflammatory cytokines that alert the immune system; interferons that trigger varying innate immune responses; and chemokines that activate tumor-cell targeting immune cells.

Naturally occurring CDNs are synthesized by bacteria or produced by mammalian cells in response to viral infection. Aduro says it has engineered more potent CDNs that activate all known human STING variants, and have stronger binding capability and more stability compared to natural CDNs. As a result, in preclinical models, Aduro’s CDNs induce more effective and durable tumor antigen-specific immune responses.

NIBR President Fishman said activation of the STING pathway within dendritic cells present in the tumor microenvironment has the potential to transform the cells into important and effective messengers that recruit, activate and induce the proliferation of tumor-specific immune cells, or T cells. Dendritic cells process antigen material and present it on the cell surface to the T cells of the immune system, acting as messengers between the innate and the adaptive immune systems.

“What STING does in animal studies is that it enhances the response of dendritic cells, and so when STING agonists, CDNs, get injected into a tumor, the tumor gets effectively rejected. But much more exciting is the fact that other tumors in that animal, although not having themselves been injected, also disappear. And if you attempt to go back in afterwards and add a tumor of the same type to that animal, it won’t take. So it’s as though you have immunized the animal to that tumor – and you’ve done it without actually having to know what it is about the tumor that’s foreign,” Fishman said.

In preclinical mouse-tumor models, direct injection of Aduro’s lead CDN, called ADU-S100, induced tumor shrinkage and generated immune responses that may provide long-lasting systemic antigen-specific T cell immunity to stop further growth of untreated tumor metastases, a response known as an abscopal effect.

Novartis is keen to progress ADU-S100, which so far has been tested in melanoma, colon and breast cancers.

“We have a fair amount of confidence about ADU-S100. There are backups and there are also other components of the pathway that we’re working on internally and which we’ll now work collaboratively with Aduro Biotech, but they are at earlier stages,” Fishman said.

Terms of their pact entail Novartis paying Aduro $225 million up front, comprising $200 million cash and $25 million for a 2.7% equity stake in Aduro. The biotech may also receive up to $500 million in development milestones and another $25 million investment. The partners will jointly conduct R&D, with Aduro leading commercialization and booking sales in the U.S. and Novartis doing the same elsewhere in the world. The duo will share profits in the U.S., Japan and major European countries; in all other markets, Aduro is eligible for a mid-teens royalty.

Aduro Deal With Novartis Is Synergistic

Aduro’s management says Novartis thereby has put its money where its mouth is and thus displayed commitment to taking a leading role in immuno-oncology (IO) – despite coming a bit late to the IO party.

“That may be the perception, but of course they have a checkpoint inhibitor program, several of those compounds underway, they are one of the leaders in CAR-T cells with Carl Jung at the University of Pennsylvania, and now going through the STING receptor, I think that in a way that puts them out ahead of some of the competition through this particular mechanism,” Steve Isaacs, president and CEO of Aduro, said in an interview.

He said the alliance was quite unique – and synergistic. Aduro was set to take ‘S100 into clinical development later this year, Isaacs noted, but Novartis now will determine the path forward for that compound. The two companies currently are determining how work under the collaboration will be apportioned.

“It will be a co-development program, so we’re looking right now at the best way to divide those activities,” the exec explained. “But we’re very strong in chemistry … so we’ll continue on that front. And then, we’re very strong in STING biology, [such as] being able to look at the interaction of different molecules that stimulate STING down to the level of doing crystal structures and seeing how the ‘hand fits in the glove.’”

“One of the reasons we partnered with Novartis, beyond the resources they can provide in terms of cash, is the capabilities,” Isaacs said. “They’re very good in formulation, they’re very good in preclinical activities and they’re very good in clinical trials.”

Analysts also seem to like the deal, although the terms Novartis has agreed to look expensive. Citibank in a same-day reaction note wrote that the latest news shows “Novartis’s IO strategy is becoming more visible, namely to target the circa. Fifty percent of patients with non-immunogenic tumors that are unlikely to respond to checkpoint agents … While Novartis has not participated in the first wave of IO players, we believe that Novartis's oncology expertise will ultimately make it an important IO player.”

New IO Team To Drive On Three Key Fronts

Fishman said the new IO research unit will give crucial momentum to its efforts. “Glenn Dranoff will be helping to integrate and propel our entire program forward using all our various assets. This will be a standalone, autonomous group. Glenn will be taking over the supervision of the internalized assets that we have now from CoStim as well as from Aduro and also the University of Pennsylvania alliance around CAR-T (Also see "A New Industry-Academic Model: Novartis And Penn Make A Splash In Cancer Immunotherapy" - In Vivo, 26 Nov, 2012.) [See Deal]).

Fishman said the newly established IO team will drive the discovery and early clinical efforts in cancer immunotherapy in three main categories: “First, they will search for ways to prime or educate the immune system, so that it can recognize a threat. STING will be part of this category,” he said.

Secondly, they will attempt to unleash immune cells that already have been primed. “This is called immunomodulation and is where our CoStim Pharmaceuticals Inc. acquisition fits in,” as Novartis is using that vehicle to investigate checkpoint inhibitors [See Deal].

“And thirdly, the team will find ways to make the tumor microenvironment more hospitable to immune cells, which must infiltrate the diseased tissue to be effective. To some degree, STING is part of that as well, but there are a couple of other preclinical approaches in that direction, but it’s early and we’re not ready to divulge that yet.”