Hengrui chairman hints CFDA approval of apatinib

Here is a video of Piaoyang Sun, Hengrui chairman, talking about the R&D of apatinib. It hints Hengrui will certainly launch this drug in the second half of the year. So apatinib will be the second domestically developed protein tyrosine kinase (RTK) inhibitor approved by the CFDA. I’d spend some time on this compound.

Apatinib, also known as YN968D1, was first discovered by Advenchen Laboratories that has filed a patent application[1] to protect it. Advenchen is a small company partnering with leading pharmaceutical companies in China (Hengrui, Simcere, Chia-Tai Tianqing, etc) to co-develop RTK inhibitors. Lucitanib (AL3810, E3810, delitinib)[2], Advenchen’s second candidate, has been licensed to Servier and Clovis Oncology.

apatinib

Apatinib is a potent and selective VEGFR-2 inhibitor derived from vatalanib (PTK787), but with a binding affinity 10 times that of vatalanib. Various VEGFR-2 inhibitors such as sorafenib, vandetanib, cediranib, and sunitinib have been developed, however, survival benefits for patients with metastatic gastric cancer (mGC) are poor.

Gastric cancer is the third leading cause of death from cancers (14.3%) in China, although it is not so common in the US and EU. A rational explanation is that East Asians eat more salted and pickled foods. Hengrui first tested apatinib in mGC, with breast cancer and hepatocellular carcinoma behind.

Hengrui released positive phase III data for apatinib in mGC at ASCO2014[3]. Apatinib has been shown to improve progression-free survival (78 days vs 53 days) and overall survival (195 days vs 140 days) in patients with prior failure to second line chemotherapy. Similarly to sunitinib[4] and sorafenib[5], apatinib only reached an objective response rate of 2.84%.

The FDA has approved Eli Lilly’s ramucirumab, an anti-VEGFR mAb which demonstrated a similar progression-free survival (2.1 months vs 1.3 months) and overall survival (5.2 months vs 3.8 months) in advanced gastric cancer. (see FDA label)

Grade 3 or higher adverse events occurring in the ramucirumab arm were bleeding (3.4%), arterial thromboembolic events (1%), and proteinuria (0.4%). However, grade 3/4 hypertension, hand-and-foot syndrome, proteinuria, fatigue, anorexia, elevated aminotransferase were occurred in more than 2% of patients treated with apatinib.

Although ramucirumab seems to be better than apatinib because of less adverse events, Hengrui has no need to worry about Lilly’s competition. Lilly hasn’t submitted an IND for ramucirumab to the CFDA until November 2013. Apatinib will be the only CFDA-approved treatment for advanced gastric cancer after prior chemotherapy for several years.

There’s no doubt that the difference between 195 days and 140 days (p < 0.05) is statistically significant. Is it really significant for patients? For the lucky patients who achieve a partial response, in another word, for only 2.85% of patients, it is indeed. But for most of patients, it’s hard to say.

The health care system in China always doesn’t pay the bills for expensive drugs. Patients may have to pay RMB 15,000+/months for apatinib or ramucirumab. Is it worth to exchange the annual income of a whole family for two months of extra prolonged survival?

Hengrui also released phase II results for apatinib in advanced hepatocellular carcinoma[6]. The median time to progression (mTTP) and the median overall survival (mOS) of the 850 mg group were 4.2 months and 9.7 months respectively. Apatinib was not superior to sorafenib which demonstrated a mTTP of 5.5 months and a mOS of 10.7 months in a phase III study. A pivotal sorafenib-controlled trial may be needed to support the sNDA for hepatocellular carcinoma.

The first domestically developed RTK inhibitor, icotinib, achieved an annual sale of RMB 475 million in 2013. Many analysts forecast the peak annual sales of apatinib will be RMB 1 billion. Considering the limited overall survival of patients with advanced gastric cancer, I think RMB 500 million may be the ceiling.

[1] WO2005000232.

[2] (a) WO2008112408; (b) WO2014113616.

[3] J Clin Oncol 32:5s, 2014 (suppl; abstr 4003).

[4] Invest New Drugs. 2011, 29, 1449-1458.

[5] Invest New Drugs. 2013, 31, 1573-1579.

[6] J Clin Oncol 32:5s, 2014 (suppl; abstr 4019).

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