Detailed research over the past decade has shown that that the protein stimulator of interferon genes (STING) is a master regulator of type I interferons and as such plays an essential role in activating innate immunity. When the cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) detects double-stranded DNA in the cytosol, from either an infectious pathogen or a damaged nucleus, an immune response is initiated downstream by STING that eventually leads to the activation of T cells. STING’s importance in orchestrating the body’s response to pathogenic, tumor, or self-DNA in the cytoplasm has made it a hot target in immunology research and drug discovery, and several biopharma companies have started programs dedicated to this area spanning infectious and inflammatory diseases as well as cancer.
The potential of STING to enhance antitumor immunity through the induction of a variety of pro-inflammatory cytokines and chemokines, including type I interferons, is a relatively new line of inquiry that is creating considerable excitement, although much of the research on new therapies remains at the early clinical stages.
Aduro Biotech Inc., of Berkeley, Calif., which is focused on developing therapies targeting the immune system cGAS-STING and APRIL (A Proliferation-Inducing Ligand) pathways to treat cancer, autoimmune and inflammatory diseases, in its second quarter financial results reported that they are enrolling patients in a phase II study of ADU-S100 in combination with pembrolizumab in squamous cell carcinoma of the head and neck and are progressing their cGAS-STING antagonist research collaboration with Eli Lilly and Co.
As part of a December 2018 agreement, Lilly gained access to molecules from Aduro that are designed to inhibit the cGAS-STING pathway. The companies are collaborating to advance these molecules, as well as others from Lilly, into clinical development. Aduro received an up-front payment of $12 million and is eligible for development and commercial milestones up to approximately $620 million per product, as well as royalty payments in the single to low-double digits should Lilly successfully commercialize a therapy from the collaboration.
In business development, Aduro is merging with privately held Chinook Therapeutics Inc. and, going forward, Stephen Isaacs, chairman, president and CEO of the company noted, “We ended the second quarter of 2020 with a cash position of $186.1 million, which we believe will enable us to continue our ongoing STING and APRIL programs in the near-term and also meet our net cash requirements at the close of the merger with Chinook.”
Hopkinton, Mass.-based Spring Bank Pharmaceuticals, Inc. also is developing a STING product portfolio with its lead clinical product candidate, SB 11285, an intravenously-administered immunotherapeutic agent for the treatment of selected cancers, as well as STING antagonist compounds for the treatment of a broad range of inflammatory diseases, and a STING agonist ADC program for potential oncology applications. It is collaborating with Roche Holding AG to co-administer SB-11285 with the pharma’s PD-L1 checkpoint inhibitor, atezolizumab (Tecentriq), in patients with advanced solid tumors.
After the company stopped phase II studies of inarigivir soproxil 400 mg to treat chronic hepatitis B virus in December 2019, Martin Driscoll, president and CEO explained that they undertook an extensive review of strategic options that finally led to a proposed combination with F-star Therapeutics Ltd.
The combined company, operating under the name F-star Therapeutics, Inc., will advance an immuno-oncology pipeline of multiple tetravalent bispecific antibody programs, as well as SB-11285, which “the F-star leadership team has committed to continuing the ongoing clinical trial,” Driscoll added.
AbbVie Inc. took a position in the field last year when it acquired Seattle-based Mavupharma Inc., whose lead clinical candidate is MAVU-104, a first-in-class, orally active, small-molecule inhibitor of ENPP1, an enzyme involved in the regulation of the STING pathway. Inhibiting ENPP1 activity with MAVU-104 allows for highly controlled enhancement of STING signaling in tumors without the need for injections, Abbvie explained.
Last year, Novartis AG also gained a foothold in the STING space investing in Boston-based IFM Therapeutics LLC. agreeing to pay IFM shareholders up to $840 million for an exclusive option to acquire a subsidiary they launched to develop new drugs for the treatment of inflammatory and autoimmune diseases, IFM Due Inc.
Lead optimization for the programs – a suite of cGAS (cGMP-AMP synthase) inhibitors and STING (stimulator of interferon genes) antagonists – is underway, with trials of the first STING antagonist expected to begin in 2021.
This wasn’t the first foray into STING R&D for Novartis. However, its collaboration with Aduro’s STING pathway activator ADU-S100 did not generate impressive results and it eventually dropped a phase Ib study of the compound in combination with its own anti-PD-1 monoclonal antibody spartalizumab in advanced, metastatic treatment-refractory solid tumors.
In March, Berlin, Germany-based Bayer entered a research collaboration and license agreement for Curadev Pvt. Ltd.’s STING antagonist program that aims to discover new drug candidates to treat lung, cardiovascular and other inflammatory diseases. The companies will work to optimize and advance these molecules, as well as others generated during the collaboration, into clinical development.
This was the second big pharma deal for Curadev. Last year it licensed its STING agonist (CRD-5500) and associated patents to Takeda Pharmaceutical Co. Ltd.
Editor’s note: Part two of this feature will examine the most recent STING research and clinical pipeline as well as the venture capital now flowing into the field.