CDE official website recently disclosed that the marketing application of the Category 1.2 innovative traditional Chinese medicine "Icaritin" of Shenogen Pharma Group/Kangerfu Pharmaceutical would be included in the priority review as scheduled, and its proposed indication was reported to be unresectable hepatocellular carcinoma (HCC) receiving no previous systemic treatment.

Icaritin is accepted as a Category 1 original natural drug with independent intellectual property rights, with anhydroicaritin as its main component. Anhydroicaritin (Cycloicaritin) is a kind of flavonoid compound that naturally exists in Epimedium brevicornum and is chiefly prepared from icariin by enzymolysis, acidolysis, combined enzymolysis and acidolysis and chemical synthesis.

Icaritin is found to be a multi-target immunomodulatory molecule, which comes into play through IL-6/STAT3, IGF1/STAT3, MAPK/ERK and other signaling pathways. In specific, it controls tumor cell proliferation, lowers cell viability, and induces apoptosis of a high volume of tumor cells. Moreover, it performs immune regulation by inducing the differentiation of immunosuppressive cells and bringing down the level of immunosuppression.

On top of that, it has been revealed in studies that Icaritin can intervene in the formation of IKK kinase complex, and inhibit the migration of NF-kB from the cytoplasm to the nucleus via its application to IKKα and IKKβ in the NF-kB signaling pathway, consequently lowering PD-L1 expression of the immune checkpoint ligand molecule. NF-kB is recognized as a key factor in the most important signal transduction pathway of biological immune responses including apoptosis, anti-inflammation and anti-infection, and its activation and migration are subject to regulation by IKK and other complex molecules These findings render significant molecular biological proof for coming study on the anti-inflammatory and immunomodulatory signaling pathway, anti-tumor mechanism and combination therapy of Icaritin, and allow for more innovative ideas and options for clinical research on the unique immunomodulatory and combination therapy of Icaritin in cancer patients. 

HCC is regarded as a common malignant tumor with high incidence in China. Statistics display 466,000 new cases and 422,000 deaths every year, causing serious threats to people's lives and health. Quite different from Europe and the United States in a variety of ways, HCC in China has a high degree of heterogeneity, the majority of which are highly associated with hepatitis B virus infection. Furthermore, the patients are usually suggested to be in the middle and late stage at the initial diagnosis, resulting in loss of the opportunity for surgery, difficult treatment, poor prognosis and short survival time. Major causes for this include complex conditions of patients, and underlying liver diseases (including hepatitis, cirrhosis, liver dysfunction and related complications) and immune dysfunction.

For the last few years, survival status of partial patients with advanced HCC improved with the help of molecularly targeted drugs, systemic chemotherapeutics and immune checkpoint inhibitors developed and marketed. Nevertheless, existing targeted therapy, systemic chemotherapy and immunotherapy are less available for a considerable part of patients due to their physical fitness, liver function, and later stage, etc. A lack of standard first-line treatment plans and drugs lead to a huge clinical need to be met. 

Icaritin's marketing can't do without the positive results of a prospective, randomized, controlled, double-blind, double-simulation, phase III clinical study of the first-line treatment of patients with advanced HCC compared with Cinobufotalin. Jointly led by renowned oncologists, Academician Sun Yan of the Cancer Hospital of the Chinese Academy of Medical Sciences, and Qin Shukui, Bayi Hospital Affiliated to Nanjing University of Chinese Medicine, the research is designed with a composite biomarker adaptive enrichment, and unfolds in 28 research centers across the country. 

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It was declared by Shenogen Pharma Group in January 2021 that the IDMC judged that the enriched population of advanced patients had arrived at the preset primary study endpoint in the study analysis on December 30, 2020. Icaritin notably enhances the overall survival of patients with hepatitis B virus-related advanced HCC in poor physical condition with high safety. It is remarkable that the results of the study will be presented in 2021 Annual Meeting of ASCO. 

Besides, a multi-center, randomized, open Phase III clinical trial is also on the march over the effectiveness and safety of Icaritin versus Sorafenib in the first-line treatment of patients with PD-L1-positive advanced HCC. 

Beyond Icaritin, a bunch of new drugs or new drug combinations seem to be under development in China for the first-line treatment of HCC, such as Donafenib, CPU-118, Sintilimab combined with bevacizumab biosimilars. 

• Donafenib, an oral multi-target, multi-kinase inhibitor small molecule anti-tumor drug, is developed by Zelgen Biopharmaceuticals with independent intellectual property rights. It has been confirmed in pre-clinical pharmacological studies that Donafenib is possible to inhibit the activity of multiple receptor tyrosine kinases such as VEGFR and PDGFR and various Raf kinases, signaling pathway of downstream Raf/MEK/ERKs, the proliferation of tumor cells and the formation of tumor blood vessels, and achieve the anti-tumor effect of dual inhibition and multi-target blocking. The marketing application of Donafenib for advanced hepatocytes has now been accepted by the CDE and included in the priority review for qualification. This application comes due chiefly to the results of an open, randomized, parallel-controlled, multi-center Phase II/III clinical study (trial code ZGDH3) for the first-line treatment of advanced HCC. Zelgen Biopharmaceuticals announced in January 2021 that the study had met the presupposed primary endpoint and achieved safety results. The mOS of Donafenib group significantly exceeded that of Sorafenib group, which showed statistically significant extension and clinical significance, among the patients with unresectable or metastatic advanced HCC undergoing no systematic treatment. 

• CPU-118, a small molecule innovative drug developed by the team led by Professor Guo Qinglong of China Pharmaceutical University over 10 years, is reported to be an effective active monomer of the traditional Chinese medicine Scutellaria baicalensis Georgi and prepared by chemical total synthesis. As is suggested in preliminary mechanism studies, CPU-118 can induce apoptosis of liver cancer cells by targeting alpha-fetoprotein AFP, and inhibiting the expression of AFP in liver cancer cells and its combination with the tumor suppressor protein PTEN. Approved clinically and domestically in August 2020, CPU-118 is proposed to be used for the treatment of advanced liver cancer. 

• According to Innovent Biologics's announcement in September 2020, its ORIENT-32, a PD-1 monoclonal antibody Sintilimab combined with bevacizumab (a bevacizumab analogue) versus Sorafenib for the first-line treatment of advanced liver cancer clinical trial, has been completed with primary endpoint. This trial is acknowledged to be the world's first randomized, open, multi-center, Phase III study of PD-1 inhibitor combination therapy, for key population with HBV-related liver cancer, which has attained the primary endpoint. The data indicates: mOS of Sintilimab+ bevacizumab group significantly surpassed that of the Sorafenib group (NE vs. 10.4 months, P<0.0001), resulting in a reduced risk of death by 43%; median PFS of Sintilimab+ bevacizumab group presented significant improvements (4.5 vs 2.8 months, P<0.0001), resulting in a reduced risk of progression by 43.5%. Beyond that, results of all relevant subgroups revealed better OS and PFS in Sintilimab + D bevacizumab group than Sorafenib group. The marketing application, of monoclonal antibody Sintilimab combined with bevacizumab for the treatment of hepatocytes, has been admitted by CDE to the priority review procedure (acceptance number: CXSS2100009).