HONG KONG – Jiangsu Hengrui Medicine Co. Ltd. said the China National Drug Administration (CNDA) granted a conditional approval to its self-developed compound pyrotinib for treating HER2-positive breast cancer. The approval was based on clinical data from phase II studies, demonstrating China's effort in marketing domestic innovative drugs faster.

Administered orally, pyrotinib is a small-molecule irreversible pan-ErbB receptor tyrosine kinase inhibitor that targets epidermal growth factor receptor as well as HER2 and HER4 receptors. Deemed as best in class, it took only 10 months from NDA to approval, making pyrotinib the first of its kind marketed by a domestic company.

"Based on clinical data and performance, pyrotinib is the best-in-class drug," Lianshan Zhang, president of global research and development at Hengrui, told BioWorld Asia.

"The findings from the phase II study were promising. Compared to Tykerb (lapatinib, Novartis), progression-free survival (PFS) was prolonged to nearly one year [when using pyrotinib plus capecitabine]," explained Zhang.

Lapatinib in combination with capecitabine is one of the standard treatments for patients with HER2-positive breast cancer, and pyrotinib was proven to be more efficacious.

In the head-to-head comparative phase II study, researchers compared pyrotinib plus capecitabine to lapatinib plus capecitabine in 128 patients with HER2-positive metastatic breast cancer previously treated with taxanes, anthracyclines and/or trastuzumab.

The median PFS was 18.1 months when using pyrotinib plus capecitabine, compared to seven months with lapatinib plus capecitabine. Objective response rate (ORR) was 78.5 percent in the pyrotinib arm and 57.1 percent in the lapatinib arm.

The researchers noted that pyrotinib plus capecitabine yield statistically significant better PFS and ORR than lapatinib plus capecitabine in their paper. Data from the phase II study was presented at San Antonio Breast Cancer Symposium in December 2017.

"In China, the current treatments targeting HER2-positive breast cancer are trastuzumab and lapatinib only. The marketing of pyrotinib will give doctors and patients an alternative to the current options," said Zhang.

He added that the development of pyrotinib spanned over almost 10 years. The research and development cost for the drug has mounted up to ¥556 million (US$81 million).

In addition to Tykerb, Gilotrif (afatinib, Boehringer Ingelheim GmbH) is available for the same treatment. In 2015, the two drugs generated annual global sales of US$188.5 million and US$230.6 million, respectively.

System reform yields speedy approval

Zhang called the fast approval a landmark.

"It took just one year to obtain the conditional approval based on the data from phase II clinical studies, after pyrotinib was granted the priority review last year," said Zhang.

He noted the CNDA's role in this speedy approval of pyrotinib.

"The fast approval for pyrotinib is closely related to the reform of the CNDA," said Zhang. "Without the reform, the issue of drug accessibility in China would not have been addressed."

Last December, CNDA's Center for Drug Evaluation (CDE) said conditional approval could be granted to innovative drugs that address severe life-threatening diseases without any existing effective cures.

One condition is that the early and mid-stage study data indicate the innovative drugs' efficacy and can predict their clinical values, but a confirmatory clinical study must be completed after the conditional approval is issued in this case.

Last year, the CDE approved 394 drugs for marketing, and 53 of them were given the priority review, accounting for 13.5 percent of the total marketed drugs.

Ongoing clinical success

Though agents such as trastuzumab and lapatinib were available to treat HER2-positive breast cancer, Hengrui execs believe a better option is needed since those drugs can lead to cardiac or gastrointestinal adverse effects, which may hamper continuous administration.

Pyrotinib has been showing promising qualities over the course of the clinical development.

The phase I study, which enrolled 38 patients from August 2013 to August 2015, showed that "continuous once-per-day pyrotinib was well tolerated and demonstrated promising antitumor activity in HER2-positive patients with metastatic breast cancer", the researchers wrote in the paper.

Researchers also noted that all pyrotinib-related diarrhea events were effectively controlled by use of antidiarrheal agents, and only one patient experienced dose interruption for one day because of diarrhea.

In May 2017, the results of the phase I study of pyrotinib were published in the Journal of Clinical Oncology. Three months later, the CDE put pyrotinib under its fast track review program based on the data from the phase II trial.

Data from preclinical trials also suggested that the compound can irreversibly inhibit multiple ErbB receptors and effectively inhibit the proliferation of HER2-overexpressing cells both in vivo and in vitro.

Coupled with the promising results from the phase II study, it is no surprise the CDE granted Hengrui the greenlight to market pyrotinib.

But Hengrui still must carry out the clinical work for pyrotinib.

"There are two phase III clinical trials ongoing to examine the safety and efficacy of pyrotinib. This is our promise to the CDE for this conditional approval," said Zhang.

"The studies aim to further investigate the therapeutic utilities of pyrotinib for other HER-mutant solid tumors, especially HER2-mutant non-small-cell lung cancer," he added.

The phase III studies are double-blind, randomized, multi-centered ones for patients with HER2-positive breast cancer. The compound is also being tested for other indications including gastric cancer.

Hengrui received the approval to kick-start the phase III clinical work in July 2016, and the trial is expected to be completed by December 2019.

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