Axis Shield : Randomized, Double-Blinded, Active-Controlled (Darbepoetin Alfa), Phase 3 Study of Vadadustat in Chronic Kidney Disease Patients With Anemia on Hemodialysis in Japan

TH-OR024

Randomized, Double-Blinded,Active-Controlled (Darbepoetin Alfa), Phase 3 Study of Vadadustat in Chronic Kidney Disease Patients With Anemia on Hemodialysis in Japan

Masaomi Nangaku1	1The University of Tokyo
Kazuoki Kondo2	School of Medicine,
Tokyo, Japan
Kiichiro Ueta2	2Mitsubishi Tanabe
	Pharma Corporation,
Yoshimasa Kokado2	Tokyo, Japan
Genki Kaneko2	3Gunma University,
	Graduate School of
Hiroki Matsuda2	Medicine, Maebashi,
	Gunma, Japan
Yutaka Kawaguchi2
Yasuhiro Komatsu3

American Society of Nephrology (ASN); Washington, DC, USA; November 5-10, 2019

Disclosures

Funding

• This study was funded by Mitsubishi Tanabe Pharma Corporation.

Potential conflicts of interest

• Masaomi Nangaku has received honoraria, advisory fees, or research funding from Akebia, Alexion, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, GSK, JT, Kyowa Kirin, Mitsubishi Tanabe, Ono, Takeda, and Torii.
• Genki Kaneko, Yutaka Kawaguchi, Yoshimasa Kokado, Kazuoki Kondo, Hiroki Matsuda, and Kiichiro Ueta are employees of Mitsubishi Tanabe Pharma Corporation.
• Yasuhiro Komatsu has received personal fees from Baxter, Chugai, and Kyowa Kirin.

Acknowledgments

• The authors thank the study team and staff for the conduct of this study, their colleagues at Akebia Therapeutics Inc. for editorial input and support with the development of this presentation, and the patient volunteers for participating in the study. The authors would also like to thank Serina Stretton, PhD, CMPP, and Yuriko Kikuchi-Rech, PhD, of ProScribe - Envision Pharma Group for medical writing assistance funded by Mitsubishi Tanabe Pharma Corporation.

2

Introduction

Background

• Vadadustat (VDT) is an investigational oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) under development for the treatment of anemia in patients with CKD
• Phase 2 trials for the treatment of anemia in patients with NDD-CKD and HD-CKD have been conducted1-4
• This study in Japan is the first double-blind,active-controlled phase 3 study (NCT03439137) of VDT for treatment of anemia in patients with HD-CKD for up to 52 weeks

Objectives

• The primary endpoint was to demonstrate noninferiority of VDT in average Hb at weeks 20 and 24 compared with DA for treatment of anemia in patients with HD-CKD who were receiving ESAs
• Here, we present the results for the prespecified primary analysis up to week 24 and recently available data for durability of efficacy and long-term safety up to week 52

DA, darbepoetin alfa; Hb, hemoglobin; HD, hemodialysis-dependent; NDD, nondialysis-dependent; VDT, vadadustat.	3
1. Pergola PE, et al. Kidney Int. 2016;90(5):1115-22; 2. Martin ER, et al. Am J Nephrol. 2017;45:380-88; 3. Haase VH, et al. Nephrol Dial Transplant. 2019;34(1):90-99;

4. Nangaku M, et al. ASN Kidney Week, San Diego, CA, USA; October 23-28, 2018.

Study Design

Multicenter, randomized, double-blinded,active-controlled,double-dummy, phase 3, conducted in Japan

• Target Hb: 10.0-12.0 g/dL
• Main dose adjustment algorithm: adjusted VDT and DA to maintain target Hb
• • Dose increase: Hb <10.0 g/dL; dose reduction: Hb >11.5 g/dL
  • Interval for dose increase: ≥4 weeks for VDT and ≥2 weeks for DA
• Iron supplementation: administered to maintain serum ferritin ≥100 ng/mL or TSAT ≥20%

		Screening	Treatment period	Follow-up
				(up to	period
					(52 weeks)
		6 weeks)		(2 weeks)
					Period I (24 weeks)		Period II (28 weeks)
Randomization ratio)(1:1			VDT
		Starting dose: 300 mg QD
				N = 162	Maintenance dose: 150-600mg QD
				DA
				Starting dose: Determined according to prior ESA dose
				N = 161
				Maintenance dose: 5-180 µg QW, Q2W, or Q4W

Q2W, once every 2 weeks; Q4W, once every 4 weeks; QD, once daily; QW, once every week; TSAT, transferrin saturation.	4

Key Inclusion Criteria

• Age: ≥20 years
• Hemodialysis status: hemodialysis or hemodiafiltration 3 times/week for ≥12 weeks before screening
• ESA use: had used same ESA for ≥8 weeks before screening
• • Epoetin alfa, epoetin beta, or epoetin kappa (≤9000 IU/week)
  • Darbepoetin alfa (≤60 µg/week)
  • Epoetin beta pegol (≤250 µg/4 weeks)
• Baseline Hb level: ≥9.5 to ≤12.0 g/dL
• Iron parameters: serum ferritin ≥100 ng/mL or TSAT ≥20%

5

Statistical Analysis

Primary Endpoint (FAS)

• Noninferiority: VDT was considered noninferior to DA if the 95% CI lower limit for the difference between VDT and DA in the LSMean of the average Hb at weeks 20 and 24 was more than or equal to the predefined noninferiority margin of -0.75 g/dL
• • Difference in LSMean: MMRM with an unstructured covariance matrix within patients

Sample Size

• Planned sample size: 300 enrolled and randomized patients (VDT: 150 patients; DA: 150 patients)
• This sample size was calculated to give 95% power for noninferioity with a two-sided alpha of 0.05 based on the following assumptions: the average Hb at weeks 20 and 24 for DA = 11.0 g/dL, difference in average Hb between VDT and DA = 0, with a noninferiority margin of -0.75 g/dL and standard deviation of 1.73 g/dL

CI, confidence interval; FAS, full analysis set; LS, Least Squares; MMRM, mixed-model repeated measures.	6
FAS: patients with ≥1 study drug dose and ≥1 efficacy measurement after randomization; SAF: safety analysis set; all patients with ≥1 dose of study drug.

Patient Disposition

Randomized (VDT:DA = 1:1)

N = 323

VDT

N = 162

Discontinued, N = 26

• Withdrew consent, n = 10
• AEs, n = 10
• Received rescue therapy, n = 2
• Hyperviscosity syndrome, difficult to control Hb within target range, n = 4

DA

N = 161

Discontinued, N = 9

• Withdrew consent, n = 2
• AEs, n = 4
• Received rescue therapy, n = 1
• Other, investigator discretion, n = 2

Completed treatment period I	Completed treatment period I
N = 136	N = 152

AE, adverse event.	7

Patient Characteristics at Baseline (FAS)

	VDT			DA
Characteristic	N = 162		N = 161
Sex (male), n (%)	104 (64.2)		109 (67.7)
Age (years)	66.0 ± 11.3		64.9 ± 11.7
Body weight (kg) (dry weight)	58.1 ± 11.9		58.8 ± 13.8
BMI (kg/m2)	22.4 ± 3.4		22.4 ± 4.5
Hb (g/dL)	10.73 ±	0.7		10.73 ± 0.7
Duration of dialysis (years)	7.4 ± 6.7		7.6 ± 7.6
Serum ferritin (ng/mL)	144.5 ± 139.6	140.0 ± 95.3
TSAT (%)	28.6 ± 10.6		26.9 ± 9.4
Prior ESA	n (%)	Weekly dose	n (%)	Weekly dose
Epoetin (IU)	49 (30.2)	3704 ± 2118	53 (32.9)	4783 ± 3183
Darbepoetin alfa (µg)	97 (59.9)	17.2 ± 12.2	90 (55.9)	18.7 ± 14.1
Epoetin beta pegol (µg)	16 (9.9)	18.8 ± 12.1	18 (11.2)	22.9 ± 17.4
Comorbidities, n (%)
Hypertension	152 (93.8)		147 (91.3)
Diabetes mellitus	35 (21.6)		49 (30.4)
Dyslipidemia	59 (36.4)		79 (49.1)

Data are mean ± SD unless otherwise noted.

8

Primary Endpoint (FAS)

• VDT demonstrated noninferiority to DA as measured by average Hb at weeks 20 and 24
• • The 95% CIs for both the VDT and DA groups were within the target Hb range of 10.0-12.0 g/dL
  • The 95% CI lower limit of the difference between groups (VDT-DA) was above the predefined noninferiority margin of -0.75 g/dL, confirming the noninferiority of VDT to DA

LSMean of the average Hb at weeks 20 and 24 and the difference

between VDT and DA

		Average Hb, weeks 20 and 24
Treatment group	N	LSMean*	95% CI
VDT	160	10.61	10.45, 10.76
DA	160	10.65	10.50, 10.80
Difference (VDT-DA)		-0.05	-0.26, 0.17

*This MMRM model included treatment group, visits, interaction of treatment group and visits as fixed effects, baseline values as covariate effects, and subject as a random effect (covariance matrix: unstructured).

9

Mean Hb Over Time, 24 Weeks (FAS)

	13
(g/dL)	12
11
Hb	10
Mean													VDT
9												DA
	8												Patients, n:
		162	160	157	155	150	150	147	144	140	138	161	VDT
	7	161	160	159	159	158	157	157	156	154	152	161	DA
		BL	2	4	6	8	10	12	16	20	24	LOCF
									Weeks

Data are mean (95% CI).	10
BL, baseline; LOCF, last observation carried forward.

Mean Hb Over Time, 52 Weeks (FAS)

	13
	12
(g/dL)	11
Hb	10
Mean																				VDT
9																			DA
	8																			Patients, n:
		162	160 157	155 150 150	147	144	140	138	132	131	126	122	118	118	115	161	VDT
	7	161 160 159	159 158 157	157	156	154	152	150	146	142	141	139	133	133	161	DA
		BL	2	4	6	8	10	12	16	20	24	28	32	36	40	44	48	52	LOCF
												Weeks

Data are mean (95% CI).	11
BL, baseline; LOCF, last observation carried forward.

Maintenance Rate of Target Hb Level (FAS)

							Proportion of patients within the target Hb range
		100					VDT										DA
	(%)
																						Above: ≥12.0 g/dL
	patients	80
		60																					Within: ≥10.0 to
																						<12.0 g/dL
	of
	Proportion	40																					Below: <10.0 g/dL
	20
		0	BL	2	4	6	8	10	12	16	20	24	BL	2	4	6	8	10	12	16	20	24
							Weeks									Weeks
	600			Mean daily dose of VDT				40			Mean weekly dose of DA
(mg)VDT	450												30
											(DAμg)
													20
	300												10
	150												0	BL -2	2-4	4-6		6-8	8-10 10 -12	12 -16	16 -20	20 -24
		BL -2	2-4		4-6	6-8	8-10 10 -12	12 -16	16 -20 20 -24
							Weeks												Weeks

Data for average dose are mean (95% CI).	12
BL, baseline.

Mean Hb Over 24 Weeks in VDT-Treated Subgroups Stratified by Prior ESA or Baseline Hb (FAS)

Mean Hb by prior ESA therapy

Mean Hb by baseline Hb

	13			Epoetin		DA		Epoetin beta pegol						13
	12														12
(g/dL)	11													(g/dL)	11
10
Hb													Hb
													10
9
Mean													Mean
8													9
												Patients, n:
	7	49	49	48	47	47	47	46	46	46	46	49	Epoetin		8
		97	95	93	92	87	87	85	84	81	79	96	DA
	6	16	16	16	16	16	16	16	14	13	13	16	EBP		7
	BL	2	4	6	8	10	12	16	20	24	LOCF
									Weeks

Baseline Hb (g/dL):			<10.4		≥10.4 to <11		≥11
											Patients, n:
57	55	53	52	51	50	48	48	47	45	56	<10.4
44	44	43	43	43	43	43	43	42	42	44	≥10.4 to <11
61	61	61	60	56	57	56	53	51	51	61	≥11
BL	2	4	6	8	10	12	16	20	24	LOCF
							Weeks

Data are mean (95% CI).	13
BL, baseline; LOCF, last observation carried forward.

Iron-Related Parameters (FAS)

210				Serum ferritin (ng/mL)	40									TSAT (%)	400		TIBC (μg/dL)
																			35													360
180

320

150											30																				**
																				280
120											25										240
90											20										200
BL	2	4	6	8	10	12	16	20	24	LOCF	BL	2	4	6	8	10	12	16	20	24	LOCF	BL	2	4	6	8	10 12	16	20	24	LOCF
							Weeks										Weeks									Weeks
			Hepcidin (ng/mL)					Serum iron (	μ				Monthly dose of iron, intravenous (mg)
100					100		g/dL)		150
80											90										120
																					**
60										*	80										90
40											70										60										*
																															*
20											60										30
0											50										0	Scr.	BL-2	2-4	4-6	6-8	8-1010-12	12-16	16-20		20-24
BL	2	4	6	8	10	12	16	20	24	LOCF	BL	2	4	6	8	10	12	16	20	24	LOCF
							Weeks										Weeks									Weeks
																VDT			DA

All data are mean (95% CI).	14
Paired t-test compared with BL for all parameters except monthly dose of iron, which is compared with the screening period: *p<0.01; **p<0.001.

BL, baseline; LOCF, last observation carried forward; Scr., screening; TIBC, total iron-binding capacity.

Safety Results, 52 Weeks (SAF)

	Overview, n (%)	VDT (N = 162)	DA (N = 161)
	Subjects with ≥1 AE	154 (95.1)	158 (98.1)
	Adverse drug reaction	18 (11.1)	6	(3.7)
	Serious AEs	41	(25.3)	44	(27.3)
	Serious adverse drug reaction	0	(0.0)	0	(0.0)
	Discontinuation due to AEs	16 (9.9)	14 (8.7)
	Dose reduction or interruption of study drug due to AEs	13 (8.0)	4	(2.5)
	Deaths due to AEs	2	(1.2)	1	(0.6)
	Most common AEs with VDT, n (%)	VDT (N = 162)	DA (N = 161)
	Nasopharyngitis	74	(45.7)	73	(45.3)
	Diarrhea	25	(15.4)	24	(14.9)
	Shunt stenosis	23	(14.2)	26	(16.1)
	AEs of special interest, n (%)	VDT (N = 162)	DA (N = 161)
	Cardiovascular event, cardiac failure	13 (8.0)	15 (9.3)
	Retinal disorder	21 (13.0)	16 (9.9)
	Malignancy	7	(4.3)	9	(5.6)
	Hyperkalemia	1	(0.6)	1	(0.6)
	Pulmonary hypertension	0	(0.0)	0	(0.0)

AE, adverse event.

15

Conclusions

• This study demonstrated noninferiority of VDT to DA
• Mean Hb levels in the VDT group were maintained within the target range throughout the 52-week treatment period. Durability of efficacy was confirmed up to week 52
• VDT significantly decreased hepcidin from baseline to week 24, suggesting an improvement in iron metabolism
• Overall, no new safety concerns were identified
• In this study, no meaningful imbalance between groups was observed in the proportion of patients who reported AEs of special interest; however, the AEs of special interest (cardiovascular event, cardiac failure, retinal disorder, malignancy, hyperkalemia, pulmonary hypertension) need to be further investigated across the HIF-PHI class
• These findings support the usefulness of VDT for treating anemia in Japanese patients with CKD on hemodialysis who convert from ESA therapy

16