Boehringer Ingelheim (BI) says the recently-announced extension of its three-year collaboration with University of Dundee to develop new treatments targeting cancer-causing proteins reflects a commitment to open innovation as well as its ongoing focus on developing oncology as a therapeutic area.
The collaboration is designed to combine Boehringer Ingelheim’s pharmaceutical expertise with Dundee professor of chemical structural biology Alessio Ciulli, PhD’s research on proteolysis targeting chimeras (PROTACs), a new class of drug candidates designed against cancer targets deemed as previously-undruggable via traditional medicinal chemistry approaches. The partners began collaborating in 2016, and expanded their partnership last year on PROTACs, which are designed to fight cancer by degrading the entire protein target rather than simply inhibiting it.
On June 10, a team of researchers led by Ciulli published a study in Nature Chemical Biology detailing how a PROTAC shredded the proteins SMARCA2 and SMARCA4 in cancer cells. SMARCA2/4 are subunits of the BAF multi-protein complex, which is involved in regulating gene expression in cells, and is found mutated in approximately 20% of human cancers, including of the lung and ovary—and for which drug discovery approaches had previously proven unsuccessful.
The study, “BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design,” also highlighted the researchers’ use of 3D pictures at atomic resolution to design highly potent and selective drug candidates.
Boehringer Ingelheim has made available through its opnMe open innovation portal the first PROTAC developed through the collaboration, the protein degrader compound MZ-1. Additional PROTAC molecules may eventually be released via opnMe as well.
“BI makes publicly available compounds with high quality, good probes which allow scientists across the world to test their hypothesis,” Ioannis Sapountzis, PhD, corporate senior vice president, business development & licensing with Boehringer Ingelheim, told GEN. “It is really about us helping also the scientific community to advance ideas early on, and of course it is important to engage in these discussions early on, and help to advance the next generation of ideas.”
Sapountzis discussed opnMe and Boehringer Ingelheim’s collaboration with Dundee as part of a broader interview about the company’s approach to drug development and partnering during the recent Biotechnology Innovation Organization (BIO) 2019 International Convention, held in Philadelphia at the Pennsylvania Convention Center.
Three-pillar strategy
Boehringer Ingelheim’s approach to fighting cancer, Sapountzis said, centers on three pillars: T-cell engagers or TCEs; oncolytic viruses and cancer vaccines; and new mechanisms for immune regulatory receptors.
Over the past year, Boehringer Ingleheim has sought to strengthen those pillars through acquisitions. In September 2018, the company exercised its option to buy ViraTherapeutics for €210 million ($237.8 million), in a deal that gave Boehringer full control over a preclinical viral-based cancer immunotherapy the companies have been co-developing for two years.
In March, Boehringer Ingelheim also signaled growing interest in cancer drug development by acquiring Berlin-based ICD Therapeutics for an undisclosed price. And in April, BI agreed to develop new immuno-oncology treatments for an undisclosed number of targets using PureTech Health’s lymphatic targeting technology for immune modulation, launching a collaboration that could generate more than $226 million for Boston-based PureTech.
“Boehringer Ingelheim continues to be committed to both, not only the immune-oncology space, but also the cancer cell directed therapies, and we are there also heavily investing in addressing some of the more challenging targets that have been so far rather elusive to drug discovery efforts,” Sapountzis said.
Boehringer Ingelheim aims to find “smart” combinations of cancer-cell-targeted therapies and immune cell-targeted therapies, including next-generation checkpoint inhibitors and novel approaches to activate the immune system against the tumor to significantly increase response rates and duration.
Over the next 12–24 months, the company plans to advance to clinical phases cancer-cell directed therapies designed to reach four molecular pathways recognized as key drivers of cancer, yet long considered undruggable—KRAS, Wnt, Myc, and p53.
On June 17, Boehringer and OSE Immunotherapeutics announced the dosing of the first patient in a first-in-human Phase I clinical trial (NCT03990233) assessing BI 765063 (formerly OSE-172). The myeloid checkpoint inhibitor is a first-in-class monoclonal antibody antagonist of SIRPα that is being studied in patients with advanced solid tumors, both as monotherapy and in combination with Boehringer Ingelheim’s monoclonal antibody PD-1 antagonist BI 754091, a T-lymphocyte checkpoint inhibitor.
As a result of the first-patient dosing and a clinical trial authorization obtained in March 2019, Boehringer will pay €15 million (about $17 million) in milestone payments to OSE.
“We go where we see unmet medical need, and a way to help patients, and this sometimes really is off the beaten path,” Sapountzis said. “Our unique situation of being a privately-held company allows us to think long-term and through that long-term, really be resilient and committed to bringing these innovations that sometimes take longer to materialize into the clinic and into the market.”
NASH, immunology candidates
Sapountzis also offered updates on Boehringer Ingelheim pipeline progress in therapeutic areas outside of cancer:
In nonalcoholic steatohepatitis (NASH), Boehringer Ingelheim expects to read out data in the second half of this year from a Phase IIa study assessing the oral amine oxidase copper-containing 3 (AOC3) inhibitor BI 1467335. Boehringer acquired the candidate in 2015 for up to €222.5 million (nearly $253 million) from Pharmaxis, which initially developed the drug as PXS-4728A.
“I would say it’s one of our highlights in our NASH pipeline at this point in time,” Sapountzis said. “That is a study that we’re all looking very much forward to reading out in the NASH field.”
Also in NASH, Boehringer Ingelheim exercised an option in January for exclusive rights to a second hepatic disease target from its collaboration with Dicerna Pharmaceuticals. The collaboration, established in October 2017, aims to discover and develop novel RNAi therapeutics for chronic liver diseases, initially focusing on using Dicerna’s GalXC™ technology platform.
“GalXC has a very good value proposition in liver disease. That’s why we went with Dicerna, a leader in the field, to, again, create something bigger together,” Sapountzis said. “It’s a collaboration that we’re very happy with on both sides.”
In immunology, Boehringer Ingelheim is assessing BI 655130, a first-in-class interleukin-36 receptor (IL-36R) inhibitor monoclonal antibody that rapidly cleared symptoms of generalized pustular psoriasis (GPP), a rare and potentially life-threatening form of psoriasis, in results from a Phase I study published in March. Trials are planned to investigate IL-36 receptor inhibition in palmoplantar pustulosis (PPP), ulcerative colitis and Crohn’s disease, with other conditions also being assessed.
In CNS diseases, the company is investigating the PDE9 inhibitor BI 409306 in relapse and first episode prevention in schizophrenia and whether natural language processing can identify patients at risk of developing schizophrenia. Boehringer Ingelheim shifted BI 409306’s development focus to schizophrenia after missing efficacy endpoints in two Phase II trials (NCT 02240693 and NCT 02337907), in patients with cognitive impairment and memory dysfunction in Alzheimer’s.
Also in schizophrenia, Boehringer Ingelheim is partnering with Autifony Therapeutics to develop AUT00206, which generated positive results consistent with modulation of Kv3.1/Kv3.2 ion channels in a Phase Ib “ketamine challenge” study in healthy volunteers whose results were announced April 11. Boehringer Ingelheim acquired an option to purchase Autifony’s Kv3.1/3.2 positive modulator platform in December 2017.
