Akebia's study of its investigational anemia treatment for CKD patients not on dialysis shows positive results

In this Phase 2b trial, treatment with AKB-6548 controlled hemoglobin (HGB) levels in a sustained manner and in the clinically relevant range, according to Akebia Therapeutics Inc. Akebia presented of results from its Phase 2b trial of AKB-6548 in non-dialysis patients with anemia related to chronic kidney disease at the International Society of Nephrology’s biennial World Congress of Nephrology (WCN), 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, MD, 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.”

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
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.

Percent of HGB Measurements Taken From Week 8 to 20

Within Specified Ranges

HGB Measurements

Between:

AKB-6548

Group

Placebo

Group

10.0 and 12.0 g/dL

73%

43%

10.0 and 13.0 g/dL

80%

43%

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.

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,” 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