HONG KONG – China’s Lianyungang-based Jiangsu Hengrui Medicine Co. Ltd. has obtained approval from Korea’s Ministry of Food and Drug Safety (MFDS) to begin a phase III trial for a combination therapy of its PD-1 inhibitor candidate camrelizumab and VEGFR-2 inhibitor rivoceranib.

Jessie Zou, Jiangsu Hengrui’s chief medical officer, told BioWorld that the trial will follow the same format as those that have already been initiated in 13 regions and countries, including the U.S., EU and China since June 2019. The randomized, open-label, international, multi-center, pivotal trial will evaluate the safety and efficacy of the combination therapy vs. sorafenib in advanced or metastatic hepatocellular carcinoma (HCC) patients who have not received previous systematic treatment.

The company aims to kick off the Korean trial sites by October. The study’s co-primary endpoint will be progression-free survival and overall survival. Meanwhile, secondary endpoints will include parameters such as objective response rate, time to progression, safety and immunogenicity parameters.

The current COVID-19 pandemic has impacted not only this study, but the other ongoing studies as well. “We are working with our investigator sites, contract research organization and alliance partner to come up with a series of mitigation plans in order to minimize the impact from the virus,” she said. Multiple measures have been implemented, such as conducting remote source data verification and clinical monitoring, online communication, closely monitoring and managing possible protocol deviations, as well as identifying the key areas that could potentially be impacted by COVID-19 under the relevant regulatory guidelines released recently by the FDA and China’s National Medical Products Administration.

When asked why camrelizumab was combined with rivoceranib, Zou said, “the combination of a PD-1/L1 antibody with a VEGFR inhibitor delivered a significantly synergistic effect on efficacy, as well as safety, when used to treat HCC patients. Our phase II study on patients with advanced or metastatic HCC with a larger sample size proved the efficacy and manageable safety profile of the combination, with the data to be published very soon. The combination will give HCC patients more treatment options, as well as bringing better survival benefits to these patients.” Data from the phase I trials was published in 2018.

Jiangsu Hengrui’s candidate was approved as a third-line treatment in China for recurrent or refractory classical Hodgkin lymphoma indications in June 2019, receiving approval for the HCC indication in March 2020. The company, alongside partner Elevar Therapeutics Inc., a subsidiary of LSK Biopharma, is currently recruiting HCC patients from the U.S., European Union, and other Asian countries/regions. Zou said that the combination is also being tested in other solid tumor indications, such as gastric cancer, lung cancer and biliary tract cancer.

Jiangsu Hengrui signed a license agreement with Korea’s Crystalgenomics Inc. on April 20 to develop, seek regulatory approval for, and commercialize camrelizumab in South Korea, with the Seongnam-based company paying upfront and milestone payments of up to $87.75 million, alongside royalties of 10% to 12%.

The two companies built their relationship in little more than a year via frequent meetups at industry conferences. However, COVID-19 also disrupted agreement negotiations, with the last stage conducted over the phone and via email as in-person meetings were put to a halt with the disruption in overseas travel.

Camrelizumab is one of six approved PD-1 agents available on the Chinese market, with Beigene Ltd.’s tislelizumab receiving the regulator’s approval in December 2019. The first PD-1s to be approved in China were Bristol-Myers Squibb Co.'s Opdivo (nivolumab) for previously treated non-small-cell lung cancer, which was approved in June 2018, and Merck & Co. Inc.'s Keytruda (pembrolizumab) for the unresectable or metastatic melanoma  indication a month later.

China also approved Shanghai Junshi Biosciences Co. Ltd.'s Tuoyi (toripalimab) for metastatic melanoma, Innovent Biologics Inc.'s Tyvyt (sintilimab) for recurrent or refractory classic Hodgkin lymphoma (cHL), and Jiangsu Hengrui Medicine Co. Ltd.’s camrelizumab, also for recurrent or refractory cHL, through December 2018 and June 2019.

Astrazeneca plc’s Imfinzi (durvalumab) became the first PD-L1 inhibitor to enter the Chinese market after it got its nod for the treatment of unresectable, stage III non-small-cell lung cancer in December 2019.

In the midst of fierce domestic competition, companies are looking to differentiate their candidates. Shanghai Junshi Biosciences Co. Ltd. is looking at combining its anti-PD-1 candidate with paclitaxel for injection (albumin-bound), while Innovent Biologics Inc. is investigating combination therapies of its PD-1 candidate Tyvyt with a conjugate of angiopep-2 and paclitaxel.

Meanwhile, the race is on to secure a place on the coveted Chinese national reimbursement drug list, a critical component on the financial front. As of the end of 2019, the only PD-1 antibody on the list was Innovent’s Tyvyt.

In Korea, immune checkpoint inhibitors are also a rapidly growing market, with MSD Korea’s Keytruda, Ono Pharma Co. Ltd.’s Opdivo (nivolumab), Roche’s Tecentriq and BMS Korea’s Yervoy (ipilimumab) some of the candidates making up the market.

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