Yiviva announced positive results from its Phase 2b study evaluating YIV-906 in combination with sorafenib for advanced hepatocellular carcinoma (HCC) patients with chronic hepatitis B. The multi-regional, randomized, double-blind, placebo-controlled trial demonstrated significant improvements in both efficacy and tolerability compared to sorafenib monotherapy.
Clinical Trial Results
The CALM study (NCT04000737) enrolled 62 treatment-naïve patients with advanced HBV-positive HCC across multiple regions including the United States, Mainland China, Hong Kong, and Taiwan. Patients were randomized 2:1 to receive either YIV-906 plus sorafenib or placebo plus sorafenib.
Results presented by Dr. Ghassan Abou-Alfa at Memorial Sloan Kettering Cancer Center showed substantial improvements across key efficacy endpoints. Median overall survival reached 14.3 months in the combination arm versus 7.5 months with sorafenib alone. Median progression-free survival improved to 4.1 months compared to 3.5 months in the intention-to-treat analysis, while median time to tumor progression extended to 5.59 months versus 2.33 months.
"These results demonstrate the obligation to further study YIV-906's potential to benefit hepatocellular carcinoma patients with hepatitis B who have limited treatment options," said co-principal investigator Prof. Dr. Ghassan Abou-Alfa. "YIV-906 could broaden the therapeutic index and improve efficacy, safety and tolerability, and merits further clinical exploration with other studies and standards-of-care as a potential new treatment modality and paradigm."
Safety and Tolerability Profile
The study revealed improved tolerability in patients receiving YIV-906, with participants demonstrating greater duration of treatment exposure and continuation. Patients were able to remain on treatment longer compared to those receiving sorafenib monotherapy, suggesting reduced treatment-limiting toxicities.
Mechanism of Action
YIV-906 functions as a novel multi-targeted modality developed using a systems biology approach. The drug acts as an immunomodulator in the tumor microenvironment, reprogramming and priming the TME through STING, IFNγ, IFNβ, and P-IRF3 pathways. It enhances innate immunity by polarizing and increasing M1-like macrophage infiltration while promoting apoptosis.
The compound also enhances adaptive immunity by promoting T-cell activation through NFAT promotion and SHP1/SHP2 inhibition, modulating immune checkpoints including PD1/PDL1, and reducing immune tolerance by suppressing IDO. Additionally, YIV-906 increases safety by cytoprotecting the gastrointestinal tract through reduced GI inflammation via NF-κB, COX2, iNOS, and IL-6 pathways, promoting damaged tissue repair through the Wnt pathway, and reducing pain through NK1 modulation.
Broader Clinical Development
More than 250 gastrointestinal cancer patients across liver, pancreatic, colorectal, and rectal cancers have been treated in YIV-906 clinical studies, demonstrating proof-of-concept efficacy and safety. The drug has been studied in nine clinical trials in solid tumors, with data showing potential to improve overall survival and/or progression-free survival while reducing non-hematological toxicities including diarrhea, nausea, vomiting, fatigue, and hand-foot syndrome.
Regulatory Status
YIV-906, formerly known as PHY906 or KD018, is a patented, orally administered investigational drug being developed under the FDA's botanical drug regulatory pathway. The compound was inspired by an 1800-year-old traditional medicine and has received two FDA Orphan Drug Designations for the treatment of hepatocellular carcinoma and pancreatic cancers.
The study was conducted from January 2020 to November 2024 and was sponsored by Yiviva with grant support from the Henry Bronson Endowment of Yale University, National Foundation for Cancer Research, Asian Fund for Cancer Research, and China 13-5 National Major Scientific and Technological Special Project for Significant New Drug Development.
