Qilu Pharmaceutical Becomes Third Domestic Company to File ANDA for Lenvatinib Generic

By Cai Cai

On February 25, Qilu Pharmaceutical’s application for market approval of lenvatinib (Acceptance Number: CYHS2000144) was submitted to and accepted by the Center for Drug Evaluation (CDE). Lenvatinib is currently a first-line treatment for advanced hepatocellular carcinoma, with its domestic sales in China predicted to exceed RMB 500 million in 2019. Qilu Pharmaceutical has thus become the third pharmaceutical company, after Chia Tai Tianqing and Nanjing Simcere, to submit a marketing application for a generic version of lenvatinib.

(Source: CDE)

First-line Medications for Advanced Liver Cancer

Lenvatinib (also known as Lenvatinib, English name: Lenvatinib, development code E7080, Chinese brand name: Le Wei Ma) is a multi-target kinase inhibitor developed by Eisai of Japan. It can block a series of regulatory factors within tumor cells, including VEGFR1-3, FGFR1-4, PDGFRα, KIT, and RET, hence it is referred to as the "targeted miracle drug."

It has been approved in multiple countries. It was approved for marketing in China in 2018. The approved indications include thyroid cancer, advanced renal cell carcinoma, and liver cancer. Notably, lenvatinib is currently a first-line treatment for advanced liver cancer.

(Source: NMPA, FDA, EMA, PDMA)

Among them, the most outstanding indication for lenvatinib is liver cancer, especially for Chinese patients with liver cancer.

In the phase III non-inferiority clinical trial of lenvatinib versus sorafenib conducted by Eisai, lenvatinib significantly improved the objective response rate (40.6% vs. 12.4%) and progression-free survival (7.3 vs. 3.6 months) compared with sorafenib. Among Chinese patients, lenvatinib significantly prolonged overall survival (15.0 vs. 10.2 months) and reduced the risk of death by 50%.

Eisai has filed multiple patent applications for lenvatinib in China, most of which have been granted, while some have not yet entered the Chinese market. Core patents, including those covering the compound and crystal forms, expired in 2021 and 2024, respectively.

Chia Tai Tianqing, Nanjing Simcere, and Qilu Pharmaceutical: Three Companies Submitted Marketing Applications

Currently, lenvatinib is approved in China only for the first-line treatment of liver cancer; the application for its second indication, thyroid cancer, was submitted for market approval in December 2019.

From the perspective of the R&D landscape for domestic generic lenvatinib in China, three companies have currently submitted marketing applications: Chia Tai Tianqing, Nanjing Simcere, and Qilu Pharmaceutical.

(Source: CDE)

From a timeline perspective, in June 2019, Chia Tai Tianqing submitted the first marketing application, with the initial indication being thyroid cancer (Acceptance Numbers: CYHS1900381, CYHS1900382), including two strengths: 4 mg and 10 mg. In January 2020, Chia Tai Tianqing submitted another marketing application for the second indication: first-line treatment of liver cancer (Acceptance Number: CYHS2000033). In January and February 2020, Nanjing Simcere and Qilu Pharmaceutical successively submitted marketing applications, both for the first-line treatment of liver cancer (Acceptance Numbers: CYHS2000023, CYHS2000144).

In addition, Jiangsu Ask Pharm’s bioequivalence (BE) study has been completed, and the marketing authorization application is expected to be submitted this year.

Pembrolizumab + Lenvatinib: Favorable Clinical Efficacy of Combination Therapy

Liver cancer is the fourth most common malignancy in China, with approximately 460,000 new cases diagnosed annually. It is also the second leading cause of cancer-related mortality in the country, with a mortality rate of 26 per 100,000 population, surpassed only by lung cancer.

Due to the lack of effective pharmacotherapies, liver cancer has a five-year survival rate of only 10%. For patients with early- to intermediate-stage liver cancer, surgical resection and embolization therapy are recommended. For patients with advanced, metastatic, or unresectable disease who meet specific criteria, targeted drug therapy is recommended. First-line targeted agents for liver cancer include sorafenib and lenvatinib, both of which have been marketed in China. Second-line targeted therapies include regorafenib, cabozantinib, and PD-1 inhibitors; among these, cabozantinib has not yet been launched in China, and domestic PD-1 inhibitors have not yet received approval for the indication of liver cancer.

(Compiled from publicly available information)

As the only first-line targeted therapy for liver cancer competing with sorafenib, lenvatinib has demonstrated superior clinical trial outcomes compared to sorafenib and is currently the most effective small-molecule targeted drug for liver cancer treatment. In combination therapies, pembrolizumab plus lenvatinib has shown the most favorable results to date; in the Phase 1b KEYNOTE-524 trial, the objective response rate (ORR) reached 50%, and progression-free survival (PFS) was extended to 9.7 months, with further data pending publication. Atezolizumab plus bevacizumab has also demonstrated a significant efficacy advantage over sorafenib; in the IMbrave150 trial, the median PFS (mPFS) was 6.8 months versus 4.3 months, respectively, and the overall survival (OS) endpoint for the combination regimen has not yet been reached.

The annual cost of lenvatinib is approximately RMB 400,000, which decreases to RMB 130,000 after patient assistance programs. The drug’s domestic sales are expected to continue growing. Furthermore, given the favorable efficacy of lenvatinib in combination with PD-1 inhibitors for hepatocellular carcinoma, securing the first generic approval for lenvatinib in China would undoubtedly be a advantageous development for any pharmaceutical company.

Original Title: Generic Drugs | The Third in China! Qilu Pharmaceutical's Lenvatinib Generic Drug Application for Market Approval