HONG KONG – With a series of advancements in the area of biosimilar development, China's Shanghai Fosun Pharmaceutical Group Co. Ltd. is getting closer to becoming the first domestic company to market a biosimilar product in China. Fosun Pharma said its subsidiary, Shanghai Henlius Biotech Inc., has received a notice from the CFDA that its first marketing application, for a biosimilar rituximab, is officially under review.

According to Fosun Pharma, the pharmaceutical arm of conglomerate Fosun International Ltd., the drug pending approval, a recombinant human/murine chimeric anti-CD20 monoclonal antibody (MAb) injection known as HLX-01, is the first biosimilar developed by Henlius for the treatment of non-Hodgkin's lymphoma (NHL) and rheumatoid arthritis (RA).

The brand drug, Rituxan (Roche Holding AG), is sold in China under the trade name Mabthera for NHL.

In March 2014, HLX-01 received phase I through to phase III trial approval for testing in NHL, marking China's first clinical trial approved for similar biological drug based on the regulatory guidance of biosimilars. In March 2015, HLX-01 entered phase III testing for NHL.

Henlius also submitted an IND application for RA and obtained clinical trial approval in early 2015. Up until September of this year, the company has spent about ¥290 million (US$44 million) on R&D associated with HLX-01.

"As of 30 October 2017, Shanghai Roche Pharmaceuticals Ltd.'s Mabthera is the only rituximab injection being marketed in China, excluding regions of Hong Kong, Macau and Taiwan," said Dorothy Chen from Fosun Pharma's branding and public relations department. "Henlius' competitive advantage is to explore and develop with a focus on provision of high-quality biosimilar with reasonable prices, that is affordable innovation."

There are more than 10 Chinese biopharma companies developing biosimilar versions of rituximab, such as Genor Biopharma Co. Ltd. (phase I), Zhejiang Hisun Pharmaceutical Co. Ltd. (phase I/II), Hualan Biological Engineering Inc. (phase I) and Chia Tai Tianqing Pharmaceutical Group Co. Ltd. (phase I). However, only Fosun Pharma, Innovent Biologics Inc. and Sinocelltech Ltd. have moved their drug development programs to phase III trials. A previous leading developer, Guojian Pharmaceutical Co. Ltd., a member of 3S Group Co. since 2015, withdrew its clinical trial application after the CFDA issued a self-inspection notice cracking down on data falsification in 2015, leaving Fosun Pharma and Innovent (phase III trial started in March 2017) as the top leaders in the area. (See BioWorld Today, Sept. 15, 2016.)

Its work on HLX-01 is not the only progress Fosun Pharma has made in terms of biosimilar development. The company also said that Henlius' biosimilar version of adalimumab – the brand drug is marketed as Humira by Abbvie Inc. – has moved into a phase III study in China. The recombinant TNF-alpha humanized MAb injection, known as HLX-03, is being developed for the RA and psoriasis indications.

HLX-03 was first developed by Henlius in 2009. Its phase I trial in China was initiated in December 2016. According to Fosun Pharma, the company has spent about ¥97 million (US$15 million) on the development of HLX-03 as of September 2017.

"HLX-03 is the third monoclonal antibody developed by Henlius," Chen told BioWorld Asia. "Henlius has submitted the IND application of HLX-03 for the treatment of rheumatoid arthritis in 2013 and received the CFDA approval for clinical trials for the indication in December 2015."

HLX-03 got the green light from the CFDA in April of this year to conduct clinical trials in psoriasis.

"In the eight years since its foundation, Henlius has been a leader in antibody drug development in China, completing the IND submissions of eight product candidates with 13 indications," said Chen.

In addition to the advancement of the two biosimilar drugs, Fosun Pharma said last week it is acquiring, through Henlius, the remaining 69 percent it doesn't already own of Taiwan-San Francisco biotech company Henlix Biotech Co. Ltd. for $98 million. Henlix's focus is on innovative monoclonal antibodies, bifunctional antibodies and antibody-drug conjugates.

"Upon the completion of the transactions contemplated under the share transfer agreements, Henlix will become a wholly owned subsidiary of Shanghai Henlius, which may benefit the group by further promoting its international R&D capability, strengthening the core competitiveness of its pharmaceutical and R&D business and enhancing its leading position in the industry of monoclonal antibody," according to Fosun Pharma in a stock note disclosing the deal.

That deal is in addition to Fosun Pharma's acquisition of a 74 percent stake in India-based Gland Pharma Ltd. for $1.09 billion earlier in the month. The company said in September that it was targeting its acquisition in areas the Chinese government considers appropriate for deals, while CEO Wang Qunbin said in late August that it was not being investigated for its international acquisitions. (See BioWorld, Sept. 20, 2017.)

The clarifications come amid reports that the company was increasingly coming under regulatory scrutiny for its debt-financed acquisitions. The Chinese government has also sought to clamp down on capital outflows amid aggressive overseas acquisition sprees by conglomerates.

As part of its ambitious global expansion plan, the Hong Kong and Shanghai-listed drug company also announced in late October its intention to acquire French drug company Tridem Pharma SAS for €63 million (US$73 million). The acquisition would enable the company to tap into the African market, said Fosun.

"Fosun Pharma always regards innovation as the driving force for its business growth," said Chen. "Besides Henlius as the innovative biologics and biosimilar platform, Fosun Pharma also owns an innovative chemical drug R&D platform, a generic drug platform and a cell therapy platform.

"Looking forward, Henlius will continue to pursue technical innovation and operation excellence in drug discovery and development," she added.

Pexidartinib hits phase III endpoint, shrinks tumors

By Cornelia Zou, Staff Writer

HONG KONG – In a pivotal phase III study, Tokyo-based Daiichi Sankyo Co. Ltd.'s pexidartinib met its primary endpoint of tumor response, measured by size reduction, in patients with symptomatic tenosynovial giant cell tumor (TGCT).

The phase III study (ENLIVEN) aims to evaluate the effectiveness of investigational agent pexidartinib in the treatment of tumor of pigmented villonodular synovitis or giant cell tumor of the tendon sheath, where surgical removal of the tumor is often associated with worsened functional limitation and severe morbidity.

A comprehensive evaluation of the benefit and risk for TGCT based on the totality of the pexidartinib program is now underway.

"The rationale to move forward with the ENLIVEN phase III study was based on results from a single-arm, multicenter extension cohort of a phase I study that assessed the safety and efficacy of pexidartinib at the recommended phase II dose which is 1,000 mg per day," said Jennifer Brennan, global product communications director at Daiichi Sankyo Inc., the U.S. headquarters of Daiichi Sankyo.

In an intention-to-treat analysis of response, 12 out of 23 patients achieved a partial response, for an overall response rate of 52 percent [95 percent CI: 32 percent - 73 percent], and an additional seven patients had stable disease, for a disease control rate of 83 percent [95 percent CI: 67 percent - 98 percent]. Data from the previous clinical studies were published in the July 30, 2015, issue of The New England Journal of Medicine.

"Pexidartinib is a novel, oral small molecule that potently and selectively inhibits CSF-1R," Brennan told BioWorld Asia. "It is hypothesized that inhibition of CSF-1R by pexidartinib could reverse cell accumulation and reduce TGCT size."

ENLIVEN is a global, multicenter, pivotal, two-part phase III study, evaluating pexidartinib in patients with symptomatic TGCT for whom surgical resection would normally do more harm than good.

The first part of ENLIVEN, which is the double-blind phase of the study, enrolled and treated 120 patients to evaluate the efficacy and safety of pexidartinib vs. placebo. The primary endpoint is the percentage of patients achieving a complete or partial response to pexidartinib after 24 weeks of treatment, as assessed with centrally read MRI scans using RECIST 1.1 criteria. Key secondary endpoints include patient-reported outcomes, including measures of pain and physical function, range of motion, tumor volume score and duration of response.

After completing the first part of the study, patients randomized to either pexidartinib or placebo were eligible to take part in the second part of ENLIVEN, a longer-term, open-label study in which patients could receive pexidartinib.

In October 2016, following two reported cases of serious, nonfatal liver toxicity, the data monitoring committee (DMC) of ENLIVEN recommended that no new patients be enrolled and patients receiving placebo should no longer be eligible to receive pexidartinib in the second part of the study. A total of 120 patients who were enrolled and treated prior to the DMC recommendation continued with the study according to the revised protocol. The efficacy and safety endpoints will be assessed throughout the trial.

"Patients who complete part two of the ENLIVEN study without experiencing tumor progression or treatment intolerability will be eligible to continue treatment with pexidartinib as part of longer efficacy and safety follow-up," said Brennan.

The ENLIVEN study started in March 2015 and is set to complete in March 2018. Pexidartinib is also being explored in a range of solid tumors in combination with anti-PD-1 immunotherapy Keytruda (pembrolizumab, Merck & Co. Inc.).

Daiichi Sankyo has two R&D centers focused on oncology, including one in Japan, for immuno-oncology and small molecules; and the other in Berkeley for small molecules. The company's cancer pipeline includes more than 20 small molecules, monoclonal antibodies and antibody-drug conjugates (ADCs). Some of the compounds in development are oral FLT3 inhibitor quizartinib, for newly diagnosed and relapsed or refractory AML with FLT3-ITD mutations, currently in phase III study; and DS-8201, an ADC for HER2-expressing breast and gastric cancers, and other HER2-expressing solid tumors, currently in phase I study.