In their search for new ways to treat cancer, biotech firms are learning more about the immune system than ever before. The red hot strategy of activating the immune system to treat cancer is leading some companies to dive into the biology of autoimmune disease.
Yet, the strategy for treating autoimmune disease is, in some cases, the flip side of what it is for cancer immunotherapies: The same drug target that companies are trying to activate to treat cancer could be inhibited to treat autoimmune conditions.
“Many of these targets were well known on the inflammation side before the cancer immunotherapy side,” says Gary Glick, CEO of Boston-based IFM Therapeutics.
Today, Glick’s company is launching a new subsidiary, called IFM Due, to focus on developing inhibitors, or antagonists, of a protein called STING—for stimulator of interferon genes.
At least a dozen companies are currently developing STING activators, or agonists, for cancer immunotherapy. In fact, IFM sold a set of immunotherapy programs that contained STING agonists to Bristol-Myers Squibb for $300 million in 2017. Now IFM is joining a smaller cadre of firms adding STING antagonist programs to their pipelines. The goal is to block overactive STING pathways in autoimmune and inflammatory diseases.
STING is part of the innate immune system, the body’s first line of response to foreign invaders. The protein is like a molecular fire alarm that is triggered by errant DNA signaling the presence of a bacterial or viral infection. Once STING is activated, it causes a cascade of molecular events that leads to inflammation.
Cancer companies want to intentionally trigger STING to spur inflammation in tumors, which may help recruit cancer-killing immune cells and boost the effectiveness of a popular class of immunotherapy drugs called checkpoint inhibitors.
But overactive STING is also linked to several rare genetic diseases. “There are a whole host of diseases where you have DNA appearing where it shouldn’t be,” thus activating STING, says Martin Seidel, IFM’s vice president of R&D.
In some diseases, like STING-associated vasculopathy with onset in infancy (SAVI), a mutation in the protein itself can lead to perpetual STING activation and inflammation. In other diseases, like Aicardi-Goutières syndrome, mutations in DNA-degrading proteins lead to a buildup of DNA inside cells, triggering STING. There are instances where STING is activated by damaged cells releasing their own DNA.
STING is a common link between many immune conditions, Glick explains, and that makes it an attractive drug target. Another related drug target is a protein called cyclic GMP–AMP synthase (cGAS), which makes a molecule that in turn activates STING. Inhibiting cGAS could be a good strategy for these diseases too, he says.
IFM hopes that its experience developing STING activators for cancer will help it with STING inhibitors for immune diseases, but there is no guarantee of success. “STING and cGAS are extremely challenging targets, and people haven’t had very much luck drugging them,” Glick says.
A few other companies have a head start on IFM. Cambridge, Massachusetts-based Nimbus Therapeutics is working with Celgene—which is being acquired by BMS—to develop STING inhibitors for immune diseases. Earlier this year Eli Lilly and Company partnered with Aduro Biotech to develop STING inhibitors. Other small drug companies looking to block STING or cGAS include Curadev, Mavupharma, and Sirenas.
IFM says it expects to begin testing its first STING inhibitor in the clinic in 2020, though the company won’t say which disease it will tackle first. One possible approach, Seidel says, is to first test its compounds in a small group of people with a rare genetic disease related to STING and, if that study is successful, broaden the program to look at diseases that affect larger numbers of people, including Parkinson’s disease and nonalcoholic steatohepatitis (NASH).