Angiopoietin-like protein 3 (ANGPTL3) is a protein involved in fat metabolism and blood vessel formation. Variations in the ANGPTL3 gene can lead to familial hypercholesterolemia (HoFH).

On January 31, the clinical trial application for JS401 injection, jointly developed by Runjia Pharmaceuticals and Shanghai Junshi Bioscience and Technology Co., Ltd., received approval from the National Medical Products Administration.【3】

Mechanism

Homozygous Familial 

Hypercholesterolaemia, HoFH

HoFH is a rare and deadly genetic disease. Its main symptoms include extremely high concentrations of low-density lipoprotein cholesterol in the blood and a series of fatal cardiovascular diseases. Previous research has indicated that HoFH is primarily caused by variations in two LDLR genes (MIM 606945). Heterozygotes carrying a single variant do not typically exhibit severe symptoms, and the severity is mostly observed in individuals carrying two variant copies. (Cuchel 2014【2】)

Figure 1: Genetics and genetic heterogeneity of HoFH. 【2】 

JS401 & ANGPTL3

JS401 is a small nucleic acid drug targeting the ANGPTL3 gene. The primary component of this drug is siRNA, which functions to inhibit ANGPTL3 mRNA.

ANGPTL3 primarily produces inhibitors of lipoprotein lipase, and experimental evidence has demonstrated that inhibiting ANGPTL3 can effectively reduce fat density in the body. Therefore, JS401 enhances fat metabolism and suppresses high fat concentrations in patients by increasing the activity of lipoprotein lipase.【3】

Figure 2: ANGPTL3 Involved Signaling Pathways 【4】

Market and Similar Products

Previously, Regeneron Pharmaceuticals’ Evkeeza® has been approved and launched, making it the only drug globally targeting ANGPTL3. Currently, there are no other siRNA drugs of similar kind approved and on the market.【3】

Figure 3: Use of Evkeeza【5】

References

https://new.qq.com/rain/a/20211209A02L1500

【1】https://www.ncbi.nlm.nih.gov/gene/27329

【2】Cuchel M, Bruckert E, Ginsberg HN, Raal FJ, Santos RD, Hegele RA, Kuivenhoven JA, Nordestgaard BG, Descamps OS, Steinhagen-Thiessen E, Tybjærg-Hansen A, Watts GF, Averna M, Boileau C, Borén J, Catapano AL, Defesche JC, Hovingh GK, Humphries SE, Kovanen PT, Masana L, Pajukanta P, Parhofer KG, Ray KK, Stalenhoef AF, Stroes E, Taskinen MR, Wiegman A, Wiklund O, Chapman MJ; European Atherosclerosis Society Consensus Panel on Familial Hypercholesterolaemia. Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. Eur Heart J. 2014 Aug 21;35(32):2146-57. doi: 10.1093/eurheartj/ehu274. Epub 2014 Jul 22. PMID: 25053660; PMCID: PMC4139706.

【3】

Click to access 688180_20230201_HDF8.pdf

【4】Jiang, Shuang, et al. “ANGPTL3: a novel biomarker and promising therapeutic target.” Journal of drug targeting 27.8 (2019): 876-884.

【5】https://www.evkeeza.com/s/

【6】https://new.qq.com/rain/a/20211209A02L1500

 In Transcription

@UCLA

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 文案｜David (Industry)

 排版｜Rita

 校阅｜Jasmine (Industry), Rita