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Rivoceranib, which is being developed by HLB's subsidiary,
Elevar, is a targeted anticancer agent targeting vascular endothelial
growth factor receptor 2 by inhibiting angiogenesis growth of cancer tissues.
Revoceranib is a 'Best-in-class' oral anticancer drug that cures cancer
by inhibiting cancer cell proliferation and normalizing immune cells.

History of Rivoceranib

Rivoceranib

Development
history

2019
  • Elevar, completed global phase III for GC
  • HLB, completed a merger with Elevar
2018
  • Initiated clinical study on combination therapy with immune checkpoint inhibitor (joint development from Hengrui with Opdivo/Keytruda/Camrelizumab)
  • Acquired the rights of Existing Bukwang Pharmaceutical Co., Ltd. from HLB LS
  • Elevar, nitiated clinical study on combination therapy with paclitaxel to enter second line GC treatment market
2017
  • In progress of clinical study with 20 indications in China
  • Elevar initiated global Phase III(12 countries)
  • Designated as orphan drug (US/Europe)
2016
  • (Hengrui) Rivoceranib sales reached approx. 140B KRW
2014
  • (Hengrui) Completed Phase III for GC Obtained CFDA approval
2012
  • (Hengrui) Completed Phase II for breast cancer and non-small cell lung cancer
  • Elevar, inititated US/Korea Multi-country Phase I/IIa
2011
  • Elevar Phase I/IIa IND approval(US FDA)
2010
  • (Hengrui) Completed Phase II for GC
2009
  • (Hengrui) Completed Phase I for solid tumors
  • Elevar, signed contract with Bukwang Pharmaceutical Co., Ltd. For the publication rights in Korea, Europe, and Japan
  • Acquired Apatinib mesylate patent
2007
  • Elevar, Rivoceranib Licensed to Elevar in USA (global copyright)
2005
  • Rivoceranib (Apatinib) Licensed to Jiangsu Hengrui in China
2004
  • Advenchen Laboratories developed Rivoceranib (Apatinib,YN968D1)
  • Obtained substance patent
Selective VEGFR2
Tyrosine kinase inhibitor

Rivoceranib is an oral target anticancer agent that selectively inhibits vascular endothelial growth factor receptor 2 (VEGFR-2), a major factor involved in angiogenesis in tumors.
VEGFR-2 inhibitor is the world's first synthetic drug to be approved for the treatment of gastric cancer.

In addition, we conducted clinical trials on thousands of patients in multiple countries including the US, Europe, Korea, and Japan to confirm their effectiveness in various cancers, including gastric cancer, colon cancer, hematological cancer, non-small cell cancer, esophageal cancer, and thyroid cancer.

Riboceranib has shown significant improvement in combination therapy and maintenance therapy with various drugs such as chemo and immunocancer drugs, and is undergoing various global clinical trials such as indication expansion studies and combination studies.

Mechanism of action
01

Angiogenesis Inhibitory

Inhibiting Angiogenesis

Smaller tumors can live without blood vessels by receiving oxygen by diffusion, but to grow more than 2mm in diameter, oxygen and nutrients must be supplied through the blood. Cancer cells secrete vascular endothelial growth factor (VEGF) for growth. When VEGF binds to receptors on the surface of vascular endothelial cells, it promotes angiogenesis, which supplies oxygen and nutrients. Metastasis can also occur through new blood vessels.

These representative angiogenesis promoters, VEGF, vary in VEGF-A, VEGF-B, VEGF-C, VEGF-D, and PIGF (placentl growth factor). Vascular endothelial cells contain vascular endothelial cell receptors (VEGFR) -1, 2, and 3 that accept vascular endothelial growth factors, and VEGFR-2 is involved in angiogenesis of cancer.

Rivoceranib is a tyrosine kinase inhibitor (TKI) small molecule that selectively inhibits VEGFR-2, which is involved in angiogenesis of cancer, and blocks the receptor signaling system of vascular endothelial cells. It inhibits the proliferation and migration of cells, preventing the formation of new blood vessels.

02

Anticancer Effect + Conquesting Drug Tolerance

Increasing Anticancer Effect &
Overcoming Drug Resistance

Two important processes of cells in our body are proliferation and apoptosis. However, unlike normal cells, cancer cells proliferate and die without control of the process of proliferation and death. According to the paper, Rivoceranib prohibits the proliferation and induces apoptosis of cancer cells.

The most important reason for the failure of chemotherapy is the multidrug resistance (MDR), which causes cancer cells to cross-resistant to several types of anticancer drugs. MDR is the most important cause of excessive production of proteins, such as glycoproteins (P-gp) or multidrug-resistant proteins, in the cell membranes of cancer cells. Anticancer drug resistant cancer cells reduce the efficacy of the anticancer drug by blocking the migration of the anticancer drug into the cancer cell or sending anticancer drug out of cells. It also changes the anticancer agent that enters the cell so that it cannot exert its anticancer effect. Rivoceranib improves drug efficacy by maintaining the concentration of intracellular anticancer drugs by inhibiting the activity of P-glycoprotein, which increases MDR or drug release.

As such, Rivoceranib may not only increase the effectiveness of other anticancer drugs, but also be effective in anticancer drug-resistant tumors, making it the best partner in combination therapy.

03

Active Immunity + Increase Anticancer Drug Effect

Activating Immunity &
Increasing Immunotherapy
Effect

VEGF/VEGFR2 are known to be involved not only in the formation of blood vessels but also in the immunity of the tumor microenvironment. VEGF/VEGFR2 promotes the induction and proliferation of immunosuppressive Regulatory T cells (Tregs) and Myeloid Derived Suppressor Cells (MDSCs), while it inhibits the differentiation and activity of cytotoxic T lympnocytes (CTLs) and dendritic cells (DCs). In particular, the weakening of CTLs is known to be due to increased expression of immune barriers such as PD-1, CTLA-4, Tim-3, and Lag-3 via the VEGFR2 signaling pathway.

Riboceranib lowers the expression of PD-1, Tim-3, and Lag-3, which are immune barriers in CTLs, and stimulates the secretion of immune activators, IFN-r and IL-2, to activate immunity in the tumor microenvironment. This mechanism is expected to produce synergistic effects in combination therapy with immune gateway inhibitors.

Indication
stomach

About Gastric cancer

Gastric Cancer

The stomach, which is the largest digestive organ of our body, is located in the upper part of the abdomen, below the left ribs, and in the upper part of the abdomen.
The stomach is responsible for the storage and digestion of food.

Gastric cancer refers to all cancers of the stomach in principle, but it refers to gastric adenocarcinoma that occurs mainly in the glandular cells of the gastric mucosa. Gastric adenocarcinoma is classified into several types depending on the shape of the cancer cells observed under the microscope. In addition to gastric adenocarcinoma, lymphoma, which rarely develops in lymphoid tissues, gastrointestinal tumors in gastric stromal cells, sarcoma, a malignant tumor derived from non-epithelial cells, and neuroendocrine tumor that secrete hormones may occur.

large intestine

About colorectal cancer

Colorectal Cancer

The large intestine is a long tube-shaped digestive system that begins at the end of the small intestine and reaches the anus, which is about 150cm long. It is usually much shorter than the small intestine, which over 6m, but much wider. Cancer that occurs in this area is colorectal cancer.

The colon is divided into the appendix, the cecum, the colon, the rectum, and the anal canal, and the colon is divided into the ascending colon, the transverse colon, the descending colon, and the S-phase colon, among which malignant tumors of the cecum, colon and rectum are colon cancer. Most of the colorectal cancers are adenocarcinomas (adenocarcinoma), or cancers of the adenocarcinoma of the mucous membranes, and lymphomas, malignant carcinoids, and leiomyosarcomas may be primary.

liver

About liver cancer

Hepatocellular Carcinoma

The liver is the largest organ in our body, located just below the diaphragm and on the inside of the ribs below the right breast when viewed outward.

Liver cancer refers to primary malignant tumors that occur in the liver.
In general, cancer that has spread to the liver from other organs is often called liver cancer, but it is strictly referring to primary cancer.
There are various types of primary liver cancers, such as hepatocellular carcinoma (HCC), cholangiocarcinoma, hepatoblastoma, and hemangiosarcoma. Most of them are hepatocellular carcinoma and cholangiocarcinoma.

large intestine

About adenoid cystic carcinoma

Adenoid Cystic Carcinoma

Adenoid cystic carcinoma (ACC) is a rare cancer that primarily affects salivary glands. It can also occur in the breast, skin, respiratory tract, and reproductive organs.
ACC is a malignant tumor with very high metastasis and a particularly severe onset around the nerves.
It shows slow growth rate, high recurrence rate (more than 40% after initial treatment) and aggressive tendency, low cure rate. In case of recurrence or metastasis after surgery or radiation treatment, chemotherapy is treated.

Chemotherapy is a combination treatment of Doxorubicin, Cisplatin, Cyclophosphamide, etc., but the effect is unclear. There is no standard chemotherapy.

* source: National Information Cancer Center

Pipeline
Indication Mono/Combo Phase 1 Phase 2 Phase 3 NDA
GC (3rd/4th line) Monotherapy
      NDA Expected

Completion of Clinical trial

HCC (1st line) Camrelizumab Combo
     

Patient recruiting

ACC (1st line) Monotherapy
      NDA after phase 2 possible (orphan drug)

Patient recruiting

GC (2nd line) Taxane Combo
     

Patient recruiting

CRC (3rd line) TAS-102 Combo
     

Patient recruiting

Multiple Solid Tumors (Sarcoma) Nivolumab Combo
     

Patient recruiting

clinical trial status
01.
3rd line treatment for Gastric cancer

Global Phase III trials have been completed with Rivoceranib monotherapy for the third line gastric cancer treatment.

02.
1st line treatment for Hepatocellular carcinoma

Global Phase III trials are underway with a combination of Rivoceranib and Camrelizumab (PD-1 antibody therapeutics) from Chinese Hengrui medicine for the first line hepatocellular carcinoma.

03.
1st line treatment for Adenoid cystic carcinoma

Phase II clinical trials are underway in the US and Korea with Rivoceranib monotherapy for the 1st line Adenoid cystic carcinoma.

04.
2nd line treatment for Gastric cancer

Phase I/II clinical trials are underway in Korea for a combination of Rivoceranib and Paclitaxel for the second line gastric cancer

05.
3rd line treatment of Colorectal cancer

Phase II clinical trials are in progress in the US and Korea for the combination of Rivoceranib and Taiho Pharmaceutical's Lonsurf in Japan for the third line colorectal cancer.

06.
Treatment of Solid cancer

Clinical trials are in progress in the US for the combination of Rivoceranib and BMS's immunotherapy 'Opdivo' for sarcoma and various solid cancers.