Marking a key advance for Akebia Therapeutics Inc. in the global race to establish a new class of medicines for chronic kidney disease-associated anemia, the first of its two pivotal phase III programs proved its lead candidate, vadadustat, noninferior to darbepoetin alfa in adults on dialysis. Following a readout of vadadustat's cred in non-dialysis dependent patients, due midyear, the company will file an NDA covering both populations, it said. The encouraging trial readout and a report of strong first-quarter Auryxia (ferric citrate) sales buoyed Akebia's shares (NASDAQ:AKBA), which on May 5 climbed 38% to $11.95.

Vadadustat, one of several oral hypoxia-inducible factor prolyl hydroxylase (HIF-PH) enzyme inhibitors in global development, won't be the first to enter the estimated $3.5 billion global renal anemia market. That honor belongs to Fibrogen Inc.’s Evrenzo (roxadustat), which last year gained initial regulatory approvals in China and Japan for non-dialysis dependent patients. However, both drugs are expected to soar past $1 billion in annual sales if nephrologists adopt their use as an alternative to injectable erythropoiesis-stimulating agents (ESA), especially if they fuel an expansion of treatment rates and duration of therapy.

In INNO2VATE, Akebia sought to test vadadustat vs. the ESA Aranesp (darbepoetin alfa, Amgen Inc.). Vadadustat achieved the primary and key secondary efficacy endpoints in each of the two studies, demonstrating noninferiority as measured by a mean change in hemoglobin (Hb) between baseline and the primary evaluation period (weeks 24 to 36) and secondary evaluation period (weeks 40 to 52).

The HIF-PH inhibitor also achieved the primary safety endpoint of the INNO2VATE program, defined as noninferiority of vadadustat vs. darbepoetin alfa in time to first occurrence of major adverse cardiovascular events. Each analysis was measured against noninferiority margins agreed upon with the FDA and the EMA.

"Multiple large peer-reviewed studies have demonstrated the increased cardiovascular risk associated with the ESA use in both dialysis and non-dialysis patients," Akebia President and CEO John Butler said Tuesday, during a conference call held to discuss the data and Akebia’s first-quarter earnings. "These results were clear and remarkably consistent across all patient populations in dialysis with anemia due to CKD," he said.

The program's positive outcome, lauded by Piper Sandler analyst Christopher Raymond as "a highly derisking event," sets the stage for a readout of the other part of the pivotal program, PRO2TECT in non-dialysis dependent patients, which together with INNO2VATE would back U.S. and European regulatory filings later this year. As of Dec. 31, Akebia had enrolled 7,436 patients in the programs.

INNO2VATE's results arrived just over a year after Akebia first unveiled the readout of two pivotal Japanese studies of vadadustat, which together supported commercial partner Mitsubishi Tanabe Pharma Corp. in filing an NDA seeking Japanese regulatory approval for the drug. With that approval expected later this year, Akebia said Tuesday it is advancing key precommercial activities there.

In addition, the company said it has "reinforced" its intellectual property position for vadadustat, clearing the path for Otsuka Pharmaceutical Co. Ltd. to launch vadadustat in the U.K. and potentially Europe, upon approval. In April, the Patents Court of the U.K. issued a judgment in favor of Akebia and Otsuka, which found that five of Fibrogen's six HIF-related patents were invalid, and a sixth patent would not be infringed by vadadustat’s launch.

If approved, vadadustat will face down not only ESAs from Amgen, Johnson & Johnson and Vifor Pharma Group, but also other HIF-PH inhibitors, like Glaxosmithkline plc's daprodustat.

To give it a leg up, Akebia has an agreement with Vifor Pharma to potentially access a priority review voucher for the vadadustat NDA with the FDA to expedite review. "While there is more work to be done, we believe this path would meaningfully enhance the potential of bringing vadadustat to patients as quickly as possible, subject to regulatory approval," Butler said.

Akebia said Tuesday that it saw its total first-quarter revenue increase 22% to $88.5 million vs. $72.7 million for the first quarter of 2019. Net product revenue was $29.2 million for the quarter, up from $23.1 million in the first quarter of 2019. The company’s cash runway, $115.4 million, is expected to extend well into 2021, it said.

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