Akebia Announces Presentation of Results from its Phase 2b Study of AKB-6548 in Non-Dialysis Patients with Anemia Related to Chronic Kidney Disease at the International Society of Nephrology’s World Congress of Nephrology

Akebia Therapeutics, Inc. (NASDAQ:AKBA), a biopharmaceutical company focused on delivering innovative therapies to patients with kidney disease through the biology of hypoxia-inducible factor (HIF), today announced the presentation of results from its Phase 2b trial of AKB-6548 in non-dialysis patients with anemia related to chronic kidney disease (CKD) at the International Society of Nephrology’s biennial World Congress of Nephrology (WCN), which is being held in Cape Town, South Africa from March 13-17, 2015. In this Phase 2b trial, treatment with AKB-6548 controlled hemoglobin (HGB) levels in a sustained manner and in the clinically relevant range, producing a coordinated physiologic response to resolve anemia, while avoiding excessive fluctuations in HGB levels which have been associated with increased cardiovascular risks.

“Clinical experience with anemia in the last decade shows us that the goal of treatment is not just to elevate hemoglobin levels, but to control them in a sustained manner,” stated Bruce S. Spinowitz, M.D., an investigator in the Phase 2b study and Vice-Chairman, Department of Medicine and Associate Director, Renal Division, New York Hospital Queens and Clinical Professor of Medicine, Weill Medical College of Cornell University. “In this study, after an initial dose titration period, 73% of all hemoglobin measurements for treated patients were within a clinically-relevant range of 10 to 12 g/dL. In addition, treatment with AKB-6548 resulted in the physiological restoration of iron mobilization, which is often disrupted in patients with anemia, underscoring the ability of AKB-6548 to produce a coordinated biological response to resolve anemia. If borne out in larger outcome studies, this treatment effect could become the standard by which all next generation therapies are measured. I look forward to further testing this promising compound in Phase 3 trials.”

Dr. Spinowitz described the Phase 2b data in a poster presentation titled, “A Phase 2b Study of AKB-6548, a Novel Hypoxia-Inducible Factor Prolyl-Hydroxylase Inhibitor for the Treatment of Anemia in Patients with Chronic Kidney Disease Not on Dialysis (ND-CKD)”. Dr. Spinowitz also reviewed the overall clinical development program for AKB-6548 in a symposium presentation titled “AKB-6548 Clinical Development Program Overview and Topline Results From the Phase 2b Study in CKD”.

Results in Detail

The placebo-controlled, 20-week Phase 2b study enrolled 210 patients with CKD stages 3, 4 and 5 who were randomized 2:1 to receive once-daily AKB-6548 (N=138) or placebo (N=72). Patients were assigned to one of three study groups based on recombinant erythropoiesis stimulating agent (rESA) treatment exposure: rESA treatment naïve, rESA previously treated, or rESA actively treated. The initial 450mg dose of AKB-6548 was adjusted in accordance with the patient's hemoglobin response and using a dose titration algorithm designed to minimize HGB excursions of greater than 13.0 g/dL.

The primary endpoint was defined as achieving or maintaining a mean HGB ≥ 11.0 g/dL or increasing HGB by ≥ 1.2 g/dL above the pre-treatment value as measured by the mean HGB value at weeks 19 and 20. For the “rESA actively treated” group, the treatment goal was to maintain baseline HGB levels throughout the study period; therefore, the study protocol set the uppermost threshold for the primary endpoint at approximately 60% percent of patients treated with AKB-6548 versus 20% in the placebo arm. As previously reported, the results showed that 54.9% of patients who received AKB-6548 met the primary endpoint versus 10.3% in the placebo arm (p < 0.0001). Furthermore, and consistent with the approach to dosing, only six patients (4.4%) treated with AKB-6548 experienced a HGB excursion above 13.0 g/dL.

The AKB-6548 dosing algorithm effectively maintained HGB levels within a clinically relevant range, as noted in the table below.

Consistent with prior studies, treatment with AKB-6548 resulted in an increase in reticulocyte (immature red blood cell) counts and enhanced iron mobilization throughout the study period, suggesting that AKB-6548 produces a coordinated physiologic response which leads to a gradual and sustained increase in HGB levels and the resolution of anemia. In addition, among patients treated with AKB-6548, there were no changes in mean baseline levels of vascular endothelial growth factor (VEGF) levels, a marker typically associated with HIF-1α response. This is consistent with AKB-6548’s preferential targeting of HIF-2α, the main regulator of EPO production and iron mobilization in vivo.1

AKB-6548 was generally well tolerated in the Phase 2b trial. Treatment emergent adverse events (TEAEs) were well balanced between the active and placebo groups (74.6% and 73.6%, respectively). There was a higher incidence of serious adverse events (SAEs) reported in the active arm versus the placebo arm (23.9% and 15.3%, respectively), driven primarily by variability in the investigators’ classification of renal SAEs. Dialysis initiations, an objective measure for the severity of renal events, were balanced between the two groups, with 8.0% in the active arm and 9.7% in the placebo arm. In addition, renal or dialysis-related TEAEs were well balanced between the two groups, with 9.4% in the active arm and 9.7% in the placebo arm. The three deaths in patients receiving AKB-6548 in the study were within the expected range for this patient population based on previous large outcome studies (TREAT and CHOIR). Further, in patients treated with AKB-6548, there were no changes from baseline in mean cystatin C or serum creatinine, two biomarkers associated with worsening renal disease.

“The totality of this data speaks to the best-in-class potential for AKB-6548 in anemia related to CKD, and reinforces our confidence in this once-daily, oral therapy as we move into Phase 3 studies to support approval in the U.S. and Europe,” stated John P. Butler, President and Chief Executive Officer of Akebia. “In this study, treatment with AKB-6548 resulted in a coordinated physiologic response that led to a predictable and controlled hemoglobin response that was sustained throughout the study. In addition, we confirmed that AKB-6548 doesn’t alter VEGF levels, consistent with a preferential HIF-2α response. We look forward to launching the Phase 3 program later this year.”

Conference Call and Slide Presentation

Akebia will host a conference call with an accompanying slide presentation available via webcast.

About AKB-6548

AKB-6548 is a once-daily, oral therapy currently in development for the treatment of anemia related to CKD. AKB-6548 is designed to stabilize HIF, a transcription factor that regulates the expression of genes involved with red blood cell (RBC) production in response to changes in oxygen levels, by inhibiting the hypoxia-inducible factor prolyl hydroxylase (HIF-PH) enzyme. AKB-6548 exploits the same mechanism of action used by the body to naturally adapt to lower oxygen availability associated with a moderate increase in altitude. At higher altitudes, the body responds to lower oxygen availability with increased production of HIF, which coordinates the interdependent processes of iron mobilization and erythropoietin (EPO) production to increase RBC production and, ultimately, improve oxygen delivery.

As a HIF stabilizer with best-in-class potential, AKB-6548 raises hemoglobin levels predictably and sustainably, with a dosing regimen that allows for a gradual and controlled titration. AKB-6548 has been shown to improve iron mobilization, potentially eliminating the need for intravenous iron administration and reducing the overall need for iron supplementation.

About Anemia Related to CKD

Approximately 30 million people in the United States have CKD, with an estimated 1.8 million of these patients suffering from anemia. Anemia results from the body's inability to coordinate RBC production in response to lower oxygen levels due to the progressive loss of kidney function, which occurs in patients with CKD. Left untreated, anemia significantly accelerates patients' overall deterioration of health with increased morbidity and mortality. Renal anemia is currently treated with injectable recombinant erythropoiesis-stimulating agents, or rESAs, which are associated with inconsistent hemoglobin responses and well-documented safety risks.

About Akebia Therapeutics

Akebia Therapeutics, Inc. is a biopharmaceutical company headquartered in Cambridge, Massachusetts, focused on delivering innovative therapies to patients with kidney disease through HIF biology. Akebia's lead product candidate, AKB-6548, is a once-daily, oral therapy, which has completed a Phase 2b study for the treatment of anemia related to CKD in non-dialysis patients and is also being tested in a Phase 2 study for the treatment of anemia in patients undergoing dialysis. For more information on Akebia, please visit www.akebia.com.

Forward-Looking Statements

This press release includes forward-looking statements. Such forward-looking statements include those about Akebia's strategy, future plans and prospects, including statements regarding the potential indications and benefits of AKB-6548, the commencement of Phase 3 clinical studies of AKB-6548 in non-dialysis patients with renal-anemia, the development plan for AKB-6548, and the potential of AKB-6548 to be a "best-in-class" product. The words "anticipate," "appear," "believe," "estimate," "expect," "intend," "may," "plan," "predict," "project," "target," "potential," "will," "would," "could," "should," "continue," and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Each forward-looking statement is subject to risks and uncertainties that could cause actual results to differ materially from those expressed or implied in such statement, including the risk that existing preclinical and clinical data may not be predictive of the results of ongoing or later clinical trials; the ability of Akebia to successfully complete the clinical development of AKB-6548; the funding required to develop Akebia's product candidates and operate the company, and the actual expenses associated therewith; the timing and content of decisions made by the FDA and other regulatory authorities; the actual time it takes to prepare for and initiate Phase 3 clinical studies, the success of competitors in developing product candidates for diseases for which Akebia is currently developing its product candidates; and Akebia's ability to obtain, maintain and enforce patent and other intellectual property protection for AKB-6548. Other risks and uncertainties include those identified under the heading "Risk Factors" in Akebia's Annual Report on Form 10-K for the year ended December 31, 2014, and other filings that Akebia may make with the Securities and Exchange Commission in the future. Akebia does not undertake, and specifically disclaims, any obligation to update any forward-looking statements contained in this press release.

1 Blood Reviews 27 (2013) 41–53, http://dx.doi.org/10.1016/j.blre.2012.12.003