BEIJING – Five-year-old Jacobio Pharmaceuticals Co. Ltd., of Beijing, has found itself a strong global partner to help advance its two SHP2 inhibitors, JAB-3068 and JAB-3312, both financially and later in the regulatory process. The Chinese startup will work with pharma giant Abbvie Inc., of North Chicago, to develop and commercialize the programs.

Financial terms were not disclosed. What has been made public is that Jacobio will continue to conduct early global clinical trials of JAB-3068 and JAB-3312, then Abbvie will take over global development and commercialization. Once the programs are nearing the registration stage, Jacobio has an option to exclusively develop and commercialize JAB-3068 and JAB-3312 in mainland China, Hong Kong and Macau.

“We are responsible for the early stage clinical trials in China and the U.S., then Abbvie will take over the registration trials,” Stella Xue, Jacobio’s finance director, told BioWorld. She added that the development timeline for the two programs will remain undisclosed for now.

When asked about Abbvie’s payment, Xue explained: “Jacobio will advance the clinical programs before the registration trials, with costs being covered by Abbvie. We won’t need to bear any costs for our R&D work.” 

By adding JAB-3068 and JAB-3312 to its R&D plan, Abbvie will be in a race alongside Novartis AG and Sanofi SA. Novartis is developing a SHP2 inhibitor known as TNO-155, while Sanofi is collaborating with Revolution Medicines Inc. to jointly develop SHP2 inhibitors and is covering all the R&D costs, like Abbvie.

Developed internally, both JAB-3068 and JAB-3312 are core programs of Jacobio, described by CEO Yinxiang Wang as a “novel SHP2 first-in-class therapy” that could be “a new approach for multiple cancer types.” He has said that SHP2 inhibitors have the potential to cure PD-1 non-responders.

JAB-3068 and JAB-3312 are oral small molecules that have cleared the IND process in the U.S. JAB-3068 is now undergoing phase I/IIa trials for treating non-small-cell lung cancer (NSCLC), head and neck cancer, esophageal cancer and other metastatic solid tumors. It has been granted orphan drug designation by the FDA for esophageal cancer. JAB-3312 entered a phase I study in the U.S. in August last year. Jacobio set up a laboratory in Boston in March 2019.

The pact with Abbvie is also the first global partnership for the startup.

When asked how Jacobio attracted the attention of Abbvie, Xue told BioWorld that recent basic medical research shone light on SHP2 inhibition. “KRAS is a hot area of research, and a combination therapy with an SHP2 inhibitor is considered the most promising for now,” she said. “This has generated a stronger interest in SHP2 inhibitors, but there are only a few players in the world that develop them.”

Mohit Trikha, vice president and head of early development oncology and Bay Area site head at Abbvie, echoed Xue’s views. “By targeting a key node in both cancer and immune cell signaling pathways, SHP2 inhibition, both as a monotherapy and potentially in combination with other agents, may rapidly advance new treatment options for cancer patients,” he said.

From lab to clinic

SHP2 is an important protein mediator of cellular signaling through the RAS/MAP kinase pathway. The genetic mutations of many tumors drive abnormal cancer cell growth that relies on SHP2 activity. Meanwhile, SHP2 plays a key role in controlling cytokine production and immune cell response. That means the inhibition of SHP2 possesses dual effects by potentially reducing cancer cell growth while modulating immune responses to generate antitumor activities.

Researchers have found that many KRAS-mutant cancers depend on upstream signaling from RTK and SHP2, which shines light on using SHP2 inhibitors to treat such cancers. They have also identified molecular determinants of tumor response to combined targeting with SHP2 and ERK signaling inhibitors, and said that strategy was effective in triple-negative breast cancer and molecularly defined subsets of RAS and BRAF-mutant tumor models. Earlier in 2018, researchers uncovered the therapeutic potential of combined SHP2 and MEK inhibition to target wild-type KRAS-amplified gastroesophageal cancer.

Based on those findings, drugmakers are actively exploring the potential of combination therapies of SHP2 inhibitors with other agents.

Last year, Novartis unveiled joint efforts with San Diego-based Mirati Therapeutics to evaluate the combination of a KRAS G12C inhibitor and an SHP2 inhibitor in patients with advanced solid tumors that harbor KRAS G12C mutations. Both have begun enrolling patients in second- and third-line NSCLC and colorectal cancer trials.

In March this year, Revolution Medicines also said it provided its SHP2 inhibitor candidate, RMC-4630, to support a phase I/Ib trial that explores the combination of RMC-4630 with an investigational ERK inhibitor in solid tumors harboring RAS mutations with a focus on pancreatic cancer.

RMC-4630 is also being investigated in combination with MEK inhibitor cobimetinib, and it will enter studies in combination with Amgen’s investigational KRASG12C inhibitor, AMG-510, as well as an anti-PD-1 antibody with Sanofi’s support. 

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