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Fibrogen Anemia Therapy Gets $350M from Astrazeneca

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By Randy Osborne
Staff Writer

Pipeline-scanty Astrazeneca plc wagered big on Fibrogen Inc.'s late-stage FG-4592, the oral prolyl hydroxylase inhibitor for anemia, forking over $350 million up front and another potential $450 million in milestone payments.

In the U.S., the firms are putting together an expanded Phase III development program with the compound, which targets patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD). Phase III trials will begin in China, too, where a regulatory filing could come as early as 2015. Regulators in the U.S. will be asked to approve the drug in 2017, if all goes well.

"We'll take a six-study program and turn it into perhaps 10 studies," said Thomas Neff, chairman, founder and CEO of Fibrogen. More trials will begin near the end of this year or the start of next year, depending on how quickly regulators agree. "We'll be submitting the entire package for review to the FDA shortly. The Astrazeneca deal brings enough cash to fully develop and commercialize the compound in both territories, Neff said.

Astrazeneca, of London, will handle the U.S. commercialization, with Fibrogen taking care of some promotional activities in the ESRD segment in this market. In China, Fibrogen will oversee clinical trials, regulatory matters, manufacturing and medical affairs, while Astrazeneca takes care of promotional activities and commercial distribution.

Fibrogen, of San Francisco, could reap more from the deal down the road, if sales-related goals are met. Tiered royalties in the low 20 percent range are part of the arrangement, too. Excluded from the agreement are Japan and Europe, which are already part of Fibrogen's pact with Tokyo-based Astellas Pharma Inc., which has been conducting trials in Europe and the former Soviet Union as Fibrogen proceeded with its work in the U.S. and Asia.

Last December, the start of Phase III trials triggered a $50 million payment for Fibrogen from Astellas, the two having sealed their agreement – which brought $300 million up front for Fibrogen, plus potential milestone payments totaling as much as $465 million – in 2006. Astellas also bought $50 million in Fibrogen stock as part of that deal. (See BioWorld Today, Dec. 13, 2012, and May 1, 2006.)

Separately, as the new Astrazeneca deal was disclosed, Astellas started a Phase II study in Japan with FG-4592 in CKD patients on dialysis, prompting a $12.5 million payment to Fibrogen. Another Japanese Phase II study in nondialysis patients is expected to start late this year.

The Astellas/Fibrogen program envisioned 3,500 to 4,000 patients altogether. "Now, we'll be talking about 50 percent to 100 percent more than that," Neff said.

Prolyl hydroxylase, which FG-4592 blocks, is an enzymatic mediator of the degradation of hypoxia-inducible factor (HIF), needed by the body to make erythropoietin. It's a new approach to the disease, in a market dominated by erythropoietin-stimulating agents (ESAs), and the would-be competition is cranking up. ESAs, typically given intravenously with dialysis, in recent years have been discovered to carry a greater risk of cardiovascular events and tumors. This meant black-box warnings, reimbursement restrictions and labeling changes for the class. (See BioWorld Insight, Dec. 19, 2011 .)

The opportunities are large but different in the U.S. and China, Neff said.

"The FDA has put very severe restrictions on the use of ESAs in 2011, independent of any new clinical trial data," he said, adding that it's "pretty difficult to use those products anymore" in pre-dialysis patients, since only a few patients qualify.

"Historically speaking, the use of ESAs has been restricted pretty much to nephrology, after referral, in anticipation of dialysis," Neff said. "Pre-dialysis was simply a few months of getting ESA therapy while you're getting fistula or other shunts set up for dialysis. The utilization of [ESA] therapies upstream, for instance in endocrinology – which is where the diabetics are, or in cardiology where hypertensive patients are, and where the flows into nephrology from – weren't feasible. It was Part B Medicare billing because the physicians had to buy and bill. But the surveys consistently show a very large number of patients who are anemic in those settings for many years before there is a decision made that the end of life will be kidney failure rather than other complications."

Astrazeneca brings the capacity to detail those upstream arenas.

Akebia, GSK Also Players, but . . .

In dialysis, "when patients show up [for treatment], they typically have hemoglobins in the single digits, and they need to be pushed up rapidly," Neff said. "By all accounts, the ESAs are overused extensively in the first four or five months of therapy, and this is the period in which there are very serious safety side effects" of the kind that FG-4592 has not shown.

China has the same rate of CKD, but five times as many people. "They now have the ability to reimburse and provide therapy on a scale comparable to the U.S. for about half the population," Neff said. The country "didn't start investing seriously in dialysis until this most recent decade," and currently has very low capacity, with many seriously anemic patients who cannot get treatment. FG-4592 could offer a "low-priced therapy that addresses a problem that is going to be persistent for another two decades as they build out their dialysis system," he said.

"In nondialysis, by comparison with the West, there's really no penetration of ESAs," Neff said, and a very low number of patients are treated annually – less than 10,000, or about 2 percent of the population. "That's 2.7 million who have serious anemia as a consequence of CKD," he said. "In China, [the potential market advantage is] a combination of oral [delivery] and the fact that what we invented, the HIF system of erythropoiesis, is very disruptive technology. It replaces a lot of things in current use in the U.S., and in China, we have the ability to declare that disruption, if you like."

Fibrogen began negotiating with China seven years ago, and promised an affordable therapy, Neff told BioWorld Today. "When you're talking about a therapy that might be priced at $1 ,000 per patient per year, or $1,500 per year, we can make that an attractive business," he added.

Akebia Therapeutics Inc., of Cincinnati, last month dosed the first patient in the Phase IIb trial of oral AKB-6548, with the same mechanism of action as FG-4592, for CKD anemia. In June, it raised $41 million in a Series C financing, which the company said would support the Phase IIb trial and preparations for Phase III work. London-based Glaxosmithkline plc (GSK) has a player in the space, as well. Known as NCT01587898, it has completed Phase II trials. (See BioWorld Today, June 5, 2013.)

"All of those people developed programs after they met with us, one way or the other," Neff said. "In some ways, we might have gained some advantage [by way of the Astrazeneca deal], compared to people who need financing. But [GSK] has these capabilities so I don't think it changes the competitive difference there. It was what it was, and it is what it is; we're just in a more certain position. We believe that we have more knowledge of the area when we select our lead compound, and our lead compound has a better profile than either of those companies. And we believe that based on data, but we have to prove it."

Amgen Hanging On

Alnylam Pharmaceuticals Inc., of Cambridge, Mass., is investigating the mechanism. At the American Society of Hematology meeting in 2011 , the company, along with collaborators at the Dana-Farber Cancer Institute, offered data in a presentation titled, "Liver-specific Delivery of siRNA Targeting EGLN Prolyl Hydroxylases Activates Hepatic [Erythropoietin] Production and Stimulates Erythropoiesis."

Even antisense is involved. In June, Burnaby, British Columbia-based Xenon Pharmaceuticals Inc. exercised its option with Carlsbad, Calif.-based Isis Pharmaceuticals Inc. to an exclusive worldwide license to XEN701, discovered in a collaboration between the pair. Isis collected a $2 million payment from Xenon for the option to XEN701, designed to inhibit the production of hepcidin, a target Xenon identified utilizing its extreme genetics platform for the treatment of anemia of chronic disorders (ACD). Xenon plans to develop it for patients with CKD who are intolerant or poor responders to EPO.

Iron therapy has made news lately in anemia, too, as Rockwell Medical Inc. last month offered top-line data to offer the Phase III study known as CRUISE-1, testing SFP, an iron-delivery compound for CKD patients on dialysis. Shares of the company jumped about 15 percent on word that SFP, delivered to hemodialysis patients via dialysate during their procedures as a way replacing the 5 mg to 7 mg of iron that are lost, met its primary endpoint, reaching a statistically significant mean change in hemoglobin from baseline to end of treatment. (See BioWorld Today, July 12, 2013.)

Thousand Oaks, Calif.-based Amgen seems to be holding its own with ESAs. This week, the company reported second-quarter earnings that beat estimates, although Epogen (epoetin alfa) and Aranesp (darbepoetin alfa) sales declined a little, adding up to $502 million and $524 million, respectively. Still, quarter-over-quarter sales of Epogen rose 15 percent, helped by Medicaid rebate adjustments by the February recall of competing ESA Omontys (peginesatide), from Affymax Inc. and Takeda Pharmaceutical Co. Ltd., after reports of serious hypersensitivity reactions. (See BioWorld Today, Feb. 26, 2013.)

Neff said that, as the pioneer in the space, Fibrogen has an advantage, "but the challenges still remain, which are to do good trials and get good results."