On the basis of two successful phase III studies in China, Fibrogen Inc. looks headed toward a new drug application submission in the country this year for roxadustat (FG-4592), its oral small molecule to treat anemia in non-dialysis-dependent chronic kidney disease (NDD-CKD) and dialysis-dependent CKD (DD-CKD) patients.

Both phase III studies of the hypoxia-inducible factor, or HIF, prolyl hydroxylase inhibitor met their primary efficacy endpoints vs. control. That finding is especially important in China, where "the market landscape is dramatically different from the U.S." for the treatment of anemia, explained Chris Chung, the company's vice president of China operations. Fibrogen, of San Francisco, operates subsidiaries in Beijing and Shanghai.

Chung called treatment of the indication in the U.S. largely a "safety argument" while in China it's "an efficacy argument." Data, so far, suggest no safety concerns related to roxadustat, but efficacy rules in China because patients either are under-treated or untreated, and Fibrogen's oral drug offers an opportunity to penetrate deep into the market, well beyond patients prescribed epoetin alfa (EPO).

"The EPO market is just a slice of the potential anemia market" in China, Chung told BioWorld Today.

The principal reason for that opportunity is that transfusion – the primary source of red blood cells for medical procedures in patients in the U.S. – is largely not an option for patients in China, observed Tom Neff, Fibrogen's chairman, founder and CEO.

"There's no standard of care, like the U.S., while EPO has been restricted by volume," Neff told BioWorld Today. Consequently, "in China, it may be that a pill replaces blood as a source of red cells."

In the double-blind, placebo-controlled eight-week portion of the 26-week NDD-CKD trial, 151 anemia patients were randomized 2:1 to roxadustat (n=101) or placebo (n=50). Roxadustat met the primary efficacy endpoint of correcting anemia by achieving a statistically significant increase in hemoglobin (Hb) levels compared to placebo over eight weeks. Patients 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 this portion of the trial, 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.

In the study, patients received roxadustat (initial dose of 70 mg or 100 mg, based on body weight) or placebo three times weekly followed by dose titration to Hb levels every four weeks, as needed. After the initial eight-week period, placebo-treated patients crossed over to 18 weeks of roxadustat treatment while the active arm continued on roxadustat for the same period. A subset of roxadustat-treated patients also entered an ongoing open-label extension study to receive roxadustat for up to 52 weeks of continuous exposure.

In the DD-CKD study, 304 patients (271 hemodialysis and 33 peritoneal dialysis patients) previously on a Chinese version of EPO 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 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 non-inferiority but superiority," K. Peony Yu, Fibrogen's chief medical officer, told BioWorld Today. "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."

In the DD-CKD study, patients received roxadustat (initial dose of 100 mg or 120 mg, based on body weight) three times weekly and 100 patients received Kirin EPO, followed by dose titration to Hb levels every four weeks as needed. A subset of roxadustat-treated patients also entered the ongoing open-label extension.

Top-line data from both studies suggested adverse events were consistent with previous trials of roxadustat in the CKD patient population, with no new or unexpected safety signals, according to Fibrogen. The 52-week safety assessment in at least 100 patients is expected to complete by mid-year.

'A POSITIVE TODAY BUT THE BIG EVENTS ARE NEXT YEAR'

Consistency has been a cornerstone of the roxadustat development program across eight phase II studies and the first phase III data, according to Yu.

"This drug works really well, and we do not need iron supplementation in the way that Amgen's EPO does," she said. "We can correct the anemia by raising hemoglobin and keep it at a desired level with a pretty reasonable dose that is well tolerated."

Questions about the safety of Epogen (epoetin alfa) have been a source of consternation for Amgen Inc., of Thousand Oaks, Calif., ever since U.S. drug regulators called for additional trials to establish the optimal hemoglobin target for use of erythropoiesis-stimulating agents. In 2013, the company lost in a Supreme Court ruling over its challenge to the certification of a shareholders class in a securities fraud suit involving statements about the safety of its anemia drugs, Epogen and Aranesp (darbepoetin alfa). Nevertheless, Epogen commanded $1.872 billion in 2015 sales. Amgen is scheduled to report year-end 2016 product sales this week. (See BioWorld Today, Jan. 8, 2010, and Feb. 28, 2013.)

Fibrogen said it plans to report additional findings from the phase III trials of roxadustat once the dataset is complete.

The phase III studies, along with phase I and II studies in the program, were conducted through subsidiary Fibrogen China Medical Technology Development Co. Ltd. That tactic sets up a domestic filing with the CFDA and positions China for the first filing in a global program that includes parallel development in the U.S., Europe and Japan.

"We don't think there's any other program where China is the first-to-file country, which is tremendously exciting for us," Chung said.

Fibrogen, through its subsidiary, plans to seek approval through the CFDA domestic class 1.1 filing for new molecular entities, enabling the company an opportunity to negotiate with the agency on an approval timetable. Provided the roxadustat safety database is complete by mid-year, Fibrogen could submit its new drug application in the second half of the year. The CFDA drug review process typically takes 12 to 15 months, according to Chung.

Another advantage of the oral candidate: Using roxadustat lowers distribution costs by freeing the supply chain of refrigerated storage and the need to maintain sterility.

In a first glance, RBC Capital Markets LLC analyst Michael Yee called the top-line phase III data "an incremental de-risking event" for roxadustat. The findings, he said, support the view "that the oral anemia drug roxadustat is active, efficacious and safe, and thus FGEN remains undervalued for this franchise as well as their fibrosis antibody FG-3019 in [idiopathic pulmonary fibrosis] and pancreatic cancer," Yee wrote.

That said, the larger and more important phase III studies for the U.S. and EU markets, which represent a market opportunity of $2 billion to more than $3 billion, continue to enroll, with read-out likely next year, he added. Too, "chronic safety [specifically cardiovascular risk] is critical in this indication," so safety data beyond one year still is needed, along with more patients to support FDA and EMA requirements.

"So this is a positive today, but the big events are next year," Yee concluded.

Fibrogen is partnered with London-based Astrazeneca plc for the development and commercialization of roxadustat in the U.S., China and other markets. In addition to conducting trials and holding the roxadustat regulatory licenses and permits from the CFDA, Fibrogen China will manage manufacturing and medical affairs in the country while Astrazeneca oversees launch and commercialization activities there. (See BioWorld Today, Aug. 1, 2013.)

In Europe, Japan, the Commonwealth of Independent States, the Middle East and Africa, Fibrogen is partnered on roxadustat with Astellas Pharma Inc., of Tokyo. (See BioWorld Today, Dec. 13, 2012.)

Roxadustat is also entering a phase III trial in the U.S. to treat anemia in patients with myelodysplastic syndrome (MDS). In China, a phase II/III clinical trial application for roxadustat in MDS is under review by the CFDA.

On Monday, Fibrogen's shares (NASDAQ:FGEN) closed at $21.80 for a loss of $1.50, or 6.4 percent.