On February 10, the official website of CDE announced the Vinacra tablets included in the priority review. According to the provisions of the Opinions of the General Administration on Encouraging the Implementation of Priority Review and Approval of Drug Innovation, Food and Drug Administration [2017] No. 126, Vinacra applied for drug registration for the prevention and treatment of the following diseases with obvious clinical advantages (4. Rare disease; 5. Malignant tumors;) and apply for the registration of drugs urgently needed in clinical practice and in short supply in the market.

 

VENCLEXTA (Venetoclax) is a BCL-2 inhibitor, which has been proven to be effective against many types of malignant lymphatic tumors, including recurrent/incurable CLL deletion 17p, with a total response rate of about 80%. Venetolax is an oral B-cell lymphoma factor-2 (Bcl-2) inhibitor jointly developed by Abervi/Roch. It was first approved by the FDA on 4/11/2016 and is the first drug for Bcl-2 approved by the FDA.

 

Target

 

Bcl-2:0.01 nM (Ki)

 

Bcl-xL:48 nM (Ki)

 

Bcl-W: 245 nM (Ki)

 

In vitro research Venetoclax (ABT-199) effectively kills FL5.12-BCL-2 cells (EC50 = 4nM), Venetoclax (ABT-199) shows weaker activity on FL5.12-BCL-XL cells (E C50 = 261nM). ABT-199 also shows selectivity in cellular mammalian double hybridization analysis, in which it destroys the BCL-2-BIM complex (EC50 = 3 nM), but has a much worse effect on BCL-XL-BCL-XS (EC50 = 2.2μM) or MCL.-1 -NOXA complex [1].

 

In-body research After a single oral 12.5mg/kg body weight in a heterogeneous graft from RS4; 11 cells (ALL), Venetolax (ABT-199) caused the maximum tumor growth suppression (TGImax) of 47% (P <0.001) and Tumor growth retardation (TGD) is 26% (P <0.05) [1]. The tumor established with Venetoclax (ABT-199) 100mg/kg (T-ALL cell line LOUCY's mouse heterogeneic transplantation model) tumor resulted in a significant reduction in the leukemia load in 4 days (P = 0.0048) [2].

 

In vitro activity: ABT-199 has low sensitivity to Bcl-xL, Mcl-1 and Bcl-w, and Ki is 48 nM, >444 nM and 245 nM respectively. ABT-199 effectively inhibits FL5.12-Bcl-2 cells, RS4; 11 cells, EC50 is 4 nM and 8 nM respectively, which has low activity on FL5.12-Bcl-xL cells, and EC50 is 261 nM. ABT-199 induces RS4; 11 cell rapid apoptosis, cytochrome c release, caspase activation, phosphatidylserine externalization, and sub-G0/G1 DNA accumulation. Quantitative immune imprints show that the sensitivity of ABT-199 to NHL, DLBCL, MCL, AML and ALL cell lines is strongly related to the expression of Bcl-2. ABT-199 also induces CLL apoptosis, with an average EC50 of 3.0 nM.

 

In vivo activity: ABT-199 (100 mg/kg) treated with RS4; 11 transplant tumors, the maximum tumor growth inhibition rate is 95%, and the tumor growth delay is 152%. ABT-199 treated alone or in combination with SDX-105 and other drugs to treat DoHH2 and Granta-519 transplant tumors, it also inhibits tumor growth.

 

Up to now, Vinacra's drugs are as follows:

 

The original research drug

 

China's Aberway/Roch-Venetoclax-venetolax

 

American version of Veneclyxta (venetoclax)

 

Taiwan version of Venclyxta (venetoclax)

 

European Turkish version - Veneclyxta (venetoclax)

 

European Russian version - Veneclyxta (venetoclax)

 

Eurozone French version-Venclyxta(venetoclax)Venetoc

 

Eurozone Italian version-Venclyxta(venetoclax)Venetoc

 

Generic drugs

 

Lao version-ASEAN Pharmaceuticals-Ventok-Venetoclax

 

Bengal Yaopin International-Venetoclax-DIL-Venetoclax-Venex-100

 

Strong generic drugs

 

Lucius Pharmaceuticals of India-LUCIUS-Venetoclax-LuciVenet

 

At present, the price of original research drugs in the United States is the highest, reaching 100,000 yuan/box. The median average price of original research drugs in Europe is 50% of the United States, while generic drugs are as low as 1/10 of the market price in the United States.

 

At present, the approved indications of venetolax are:

 

1) Second-line treatment of chronic lymphocytic leukemia with abnormal chromosome 17p deletion;

 

2) Treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma in combination with rituximab second line;

 

3) The first-line treatment of azacytide/dexitabine/glycocytide is not suitable for standard induction treatment of acute granulocytic leukemia.

 

Domestic enterprises developing Bcl-2 inhibitors include Yasheng Pharmaceutical (APG-1252, APG-2575) and Baiji Shenzhou (BGB-11417)

 

Data reference:

 

1. Huayuan.com https://www.chemsrc.com/cas/1257044-40-8_224294.html

 

2. Medical Rubik's Cube

 

3. CDE official website