In a second first in the same week for China, roxadustat (previously FG-4592), developed by Fibrogen Inc. and partnered in the country with Astrazeneca plc, became the first drug advanced by a global biopharma to receive its initial nod from the National Medical Products Administration (NMPA, formerly the CFDA) before applications were submitted to the FDA and EMA. The oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) was approved to treat anemia caused by chronic kidney disease (CKD) in patients who are dialysis dependent (DD) and use either hemodialysis or peritoneal dialysis.

The nod went to Fibrogen (China) Medical Technology Development Co. Ltd., the Beijing-based subsidiary of San Francisco-based Fibrogen.

A day earlier last week, Shanghai Junshi Biosciences Co. Ltd. won the PD-1 race in China, where JS-001 (toripalimab) became the first China-developed anti-PD-1 monoclonal antibody product approved by the NMPA. That news came ahead of next Monday's debut of the company's shares on the Hong Kong Stock Exchange (HKEX). (See BioWorld, Dec. 12, 2018.)

Fibrogen was "extraordinarily proud" to advance roxadustat to the end zone as the first oral HIF-PHI in China, said Chris Chung, senior vice president of China operations and managing director of Fibrogen China, calling the win "a huge landmark" for the world's second largest pharmaceutical market.

Fibrogen China conducted the open-label, active-control phase III trial that enrolled 304 participants (271 hemodialysis and 33 peritoneal dialysis patients) previously on a Chinese version of EPO who were randomized to and treated with roxadustat (n=204) or a higher grade of EPO (n=100), known as Kirin EPO, for 26 weeks. The primary endpoint was hemoglobin (Hb) change from baseline to the Hb level averaged during the final five weeks of the 26-week treatment period.

Roxadustat met the primary endpoint of non-inferiority in comparison to Kirin EPO, and more. On superiority testing of the primary endpoint, the mean Hb increase observed in the roxadustat arm was higher than in the Kirin EPO arm, at 0.75g/dL vs. 0.46g/dL (p=0.037) in the per protocol set analysis.

"We not only showed noninferiority but superiority," K. Peony Yu, Fibrogen's chief medical officer, told BioWorld Asia when the data were reported last year. "I have not seen any clinical trials where another drug beat premium EPO. This is very, very important for Chinese dialysis patients, who tend to be challenged in reaching target hemoglobin." (See BioWorld Today, Jan. 31, 2017.)

Fibrogen China also completed a 26-week phase III trial of roxadustat in 151 non-dialysis-dependent (NDD) CKD patients in China. During the double-blind, eight-week portion of the trial, which randomized participants 2:1 to roxadustat or placebo, roxadustat met the primary efficacy endpoint of correcting anemia by achieving a statistically significant increase in Hb levels compared to placebo. Individuals treated with roxadustat achieved a mean Hb increase of 1.9g/dL from baseline (8.9g/dL) over the treatment period compared with a mean change in Hb of -0.4g/dL (from 8.9g/dL baseline) in the placebo arm (p<0.00001). In addition, 84.2 percent of patients in the roxadustat arm also achieved Hb response (an increase ≥1g/dL from baseline) compared to 0.0 percent (p<0.00001) in the placebo arm, meeting a secondary endpoint.

Fibrogen said it expects the NMPA to add treatment of NDD patients to the label once the agency completes regulatory inspections of the trial sites. The company also has roxadustat in phase II/III development in China to treat anemia associated with myelodysplastic syndromes and plans to add studies in at least two more indications next year, according to Chung.

The company and partner Astrazeneca, of Cambridge, U.K., plan to launch the product in the second half of 2019. Chinese regulations require that domestic pharmas cannot begin manufacturing commercial product prior to approval, Chung pointed out. Although lead time pushes the first commercial batch into the second half of next year, the company's manufacturing infrastructure is in place and certified by Chinese regulators, she said.

An upside is that Fibrogen "very much believes" that, by launch date, the NDD indication will be included in roxadustat's label, expanding the market opportunity. The dialysis market in China has exploded since Fibrogen began the agent's development program in 2009, from 100,000 to some 500,000 patients. "We hope that we can get all of the new dialysis patients and convert some of the existing patients," Chung told BioWorld Asia.

The potential NDD market is even larger, "but we need to build that market because right now there's no established standard of care," she pointed out. "However, given that this is an oral drug with a very good safety and tolerability profile, we think roxadustat is particularly well suited to the non-dialysis population so we're very optimistic about our prospects there."

'Compelling value proposition'

Fibrogen China, which sponsored the development and registration of roxadustat through a domestic class 1 innovative drug filing, will manage manufacturing, medical affairs, continued development and regulatory affairs. Astrazeneca will manage commercialization activities through a partnership forged in 2013 that provided Fibrogen with $350 million up front and another $450 million in potential milestone payments. (See BioWorld Today, Aug. 1, 2013.)

Fibrogen and Astrazeneca will work together in pricing roxadustat for the Chinese market.

"We're trying to balance a couple things here," Chung said. On the one hand, the first-in-class drug has a "compelling value proposition" with a product profile that should help drive attractive reimbursement, she pointed out. "At the same time, we need to take into consideration that this is going to be a government-reimbursed drug and there's a single payer for it."

In addition to those tradeoffs, Fibrogen is cognizant of potential future pricing opportunities in markets like Europe, Japan and the U.S. The company also is partnered with Astrazeneca to develop and commercialize roxadustat in the U.S. and other markets in the Americas, Australia, New Zealand and Southeast Asia. In Europe, Japan, the Commonwealth of Independent States, the Middle East and South Africa, Fibrogen is partnered on roxadustat with Astellas Pharma Inc., of Tokyo. (See BioWorld Today, Dec. 13, 2012.)

Fibrogen shares (NASDAQ:FGEN) gained 51 cents, or 1.3 percent, to close at $39.50 Dec. 18, but analysts were much more enthused. Leerink Partners LLC's Geoffrey Porges called the NMPA nod "the first of many milestones" for Fibrogen, which he presciently named a day earlier "our top mid-cap biotech stock for 2019 based on our analysis of a highly favorable risk/reward for the upcoming phase III roxadustat trials and an attractive catalyst pathway as the company nears initial regulatory approvals and commercialization in China and Japan."

The China approval, though largely expected, served to confirm the view of the NMPA, traditionally cautious in evaluating new drug applications, toward roxadustat's safety and efficacy. Timing was especially auspicious, with top-line data from the U.S. and EU phase III programs due to report any day, Porges pointed out.

"The major catalyst for roxadustat, and Fibrogen's stock, continues to be the binary MACE cardiovascular safety analysis expected in March/April 2019," he wrote in a flash note, projecting "substantial upside" from that analysis and other upcoming catalysts.

Porges also calculated that Fibrogen likely was due a milestone payment from Astrazeneca in the neighborhood of $50 million on the DD-CKD approval in China. "We estimate Fibrogen has ~$900 million in global regulatory milestones outstanding, the majority of which should be realized over the next 12-18 months," he noted.

Porges forecast 2019 sales of roxadustat in China as about $9 million but said the total could reach $1 billion by 2025. The consensus five-year global forecast puts the drug at about $1.7 billion by 2023, according to Cortellis Competitive Intelligence.

Jefferies Group LLC analyst Michael Yee also predicted upside for Fibrogen from the approval.

"We see FGEN stock trading up towards our $75 PT over the 6-12 months, as phase III top-line efficacy data is expected in the coming weeks (with some potential positive comments on top-line broad safety) followed by key MACE safety data by March/April 2019," he wrote in a research note. "These two events should have the stock up closer to our target of $75 and a range towards our upside scenario of $100-150," depending on details from the MACE analysis.

"To be clear, the key is for FGEN to show 1) non-inferiority on safety and efficacy for dialysis and 2) superiority to a placebo on efficacy in non-dialysis and at least noninferior on safety," Yee added, with the "home run" scenario predicated on superiority on MACE in both populations.

Combo prospects could follow first Junshi PD-1 approval

Junshi took a share of the spotlight with NMPA marketing approval of its core asset after awarding toripalimab priority review. The approval came in 284 days; Junshi filed an NDA with the NMPA on March 8 as the first applicant in the PD-1 space.

While the trade name in English is yet to be determined, the NMPA said the product will be marketed under the Chinese name Tuo Yi as second-line treatment of metastatic melanoma.

"Clinical trial results of this product show that in treating patients with unresectable or metastatic melanoma who have failed previous systemic therapies, it reaches an objective response rate of 17.3 percent, disease control rate of 57.5 percent and one-year survival rate of 69.3 percent," the NMPA said.

The drug watchdog granted conditional approval based on efficacy data from the phase II study in individuals with advanced melanoma that was conducted in China and safety data from seven clinical trials.

"We anticipate to carry out commercial manufacturing of JS-001 at our Wujiang production base and conduct marketing and sales of JS-001 leveraging our commercialization team," the company said in its prospectus, adding that such work will begin shortly after obtaining the green light.

A spokesperson for Junshi said the company would provide additional details about the launch next week, following the IPO. Last week, investors started subscribing to Junshi's IPO shares, which were priced between HK$19.38 (US$2.48) and HK$20.38.

Before the clearance of JS-001, the only PD-1 inhibitors approved in China were foreign bred, including Bristol-Myers Squibb Co.'s Opdivo (nivolumab) for previously treated non-small-cell lung cancer and Merck & Co. Inc.'s Keytruda (pembrolizumab) for unresectable or metastatic melanoma, approved in June and July, respectively.

While both Keytruda and JS-001 treat the same indication, it is not yet known how Junshi will price its PD-1 inhibitor to compete. The U.S. firm's blockbuster retails at ¥17,918 (US$2,598) per 100-mg/4-mL vial in China, half its price in the U.S.

Junshi said it believes JS-001 has great market potential and will contribute significantly to its financial performance. In addition to use as a monotherapy, the anti-PD-1 agent is expected to serve as an important combination therapy candidate for follow-up immunotherapeutic products.

In the first quarter of 2019, Junshi plans to initiate a phase III study of the drug for nasopharyngeal carcinoma, gastric carcinoma and non-small-cell lung carcinoma.

This year, the FDA also approved the IND JS-001, which moved into a phase I study in the U.S. in March.

With the home country's approval under its belt, the Chinese firm is aiming further afield and plans to launch a global large-scale pivotal clinical trial in the second half of 2019 to obtain more overseas approvals.

In China, other competitors in the PD-1 space include Jiangsu Hengrui Medicine Co. Ltd.'s SHR-1210 (camrelizumab), Innovent Biologics Inc.'s IBI-308 (sintilimab) and Beigene Ltd.'s BGBA-317 (tislelizumab).

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