Mitsubishi Tanabe Pharma Corp. (MTP) has acquired development and commercialization rights in Japan and other selected Asian markets to Akebia Therapeutics Inc.'s oral therapy for chronic kidney disease (CKD)-related anemia, vadadustat (AKB-6548), in a deal worth up to $350m plus royalties.

The licensing agreement is the first for what is the lead development project of Akebia, whose president and CEO John Butler told an investor briefing that a European partnership is one of the next major near-term goals for the Cambridge, Massachusetts-based firm.

MTP will provide $100m in development costs, $40m of which will be paid up front, and up to $250m in additional development and sales milestones. [See Deal]

Nasdaq-listed Akebia will also be eligible for tiered royalty payments ranging from the low teens to 20% on MTP's sales of the drug in its licensed territories, which include Taiwan, South Korea and other Southeast Asian markets in addition to Japan.

Butler told the briefing that vadadustat "offers a clear strategic fit for their [MTP's] diabetes and kidney franchise", while the economics of the transaction "provide us with significant funding for our Phase III program."

Novel Action

Vadadustat, a small molecule, acts to inhibit hypoxia-inducible factor prolyl hydroxylase to stabilize the transcription factor HIF, which regulates the expression of genes involved in the production of red blood cells in accordance with bodily oxygen levels.

Stabilization of HIF levels helps the mobilization of iron and thereby the production of erythropoietin (EPO), which helps the long-term raising of hemoglobin and red blood cell count.

Vadadustat can be used in both dialysis and non-dialysis patients, with its mode of action providing a more natural physiologic approach to treating renal anemia through modulation of hemoglobin and increased iron mobilization and utilization.

The molecule has already completed Phase II studies and Akebia is planning shortly to initiate an international Phase III program, PRO2TECT, in dialysis-independent anemia patients not receiving or converted from recombinant erythropoiesis stimulating agents (ESAs).

A parallel study in dialysis-dependent CKD patients, INNO2VATE, is also in the works.

Promising Results

Phase IIb results reported earlier this year in non-dialysis-dependent patients with anemia due to chronic renal failure showed that 54.9% of patients receiving vadadustat met the primary endpoint of percent of subjects with mean hemoglobin of ≥11.0g/dL, or an increase of ≥1.2g/dL from baseline, versus 10.3% in the placebo group.

The mean change in hemoglobin at the end of treatment was 0.84g/dL in the vadadustat group versus 0.02g/dL in the placebo group. There were also no drug-related serious events reported or evidence of undesirable vascular response.

MTP said in a statement that safer treatments for CKD anemia remain "a significant unmet need globally," and apparently sees safety as one of vadadustat's main attractions.

Current ESAs - for which Butler noted that the total market in Japan is worth roughly $1bn - had a black box warning added to their safety labeling in the US in 2007, which notes an increased risk of death and serious adverse events in renal failure and cancer patients.

Competitive Benefits

Besides improved safety, the hope is that vadadustat will match the efficacy of injectable ESA agents but with the ease of once-daily oral administration, which in addition allows gradual titration.

The molecule also restores natural diurnal EPO patterns with lower peak levels than seen with injectable ESAs, and allows reduced administration of intravenous or oral iron supplements.

In Japan, where MTP will bring marketing power through its roughly 1,800 sales reps, ESAs are used mainly in dialysis, but the "real growth opportunity" for new agents such as vadadustat will be in the non-dialysis sector, Butler told the investor briefing.

MTP's commercial kidney disease portfolio in Japan already includes Kremezin (oral adsorptive charcoal) for progressive chronic renal failure, and Tanatril (imidapril) for diabetic nephropathy with type 1 diabetes.

It is also developing the SGLT2 inhibitor Canaglu (canagliflozin) for the additional indication of diabetic nephropathy, for which global Phase III trials are underway.

Akebia Strikes $350m+ Asian Vadadustat Alliance

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