Interim Analysis of ACE-011-REN-001: The First 28-Day Dose...

Interim Analysis of ACE-011-REN-001: The First 28-Day Dose Cycle of Low and Medium Starting Doses of Sotatercept Compared to Placebo for Correction of Anemia in Hemodialysis Subjects

Mohamed El-Shahawy1; James Cotton2; Jeffrey Kaupke3; Thomas D. Wooldridge4; Hem N. Singh5; William T. Smith51Academic Medical Research Institute, Los Angeles, CA, USA; 2Tyler Nephrology Associates PC, Tyler, TX, USA; 3Nephrology Specialist Medical Group, Orange, CA, USA; 4Nephrology & Hypertension Associates LTD, Tupelo, MS, USA; 5Celgene Corporation, Warren, NJ, USA

INTRODUCTION• The anemia seen in patients with end-stage kidney disease (ESKD) is largely due to decreased biosynthesis of erythropoietin from the kidneys.1-3

• A number of erythropoiesis-stimulating agents (ESAs) have demonstrated efficacy in increasing hemoglobin (Hb) levels in patients with ESKD,4,5 but pose significant safety risks, including persistent hypertension, serious cardiovascular events, and increased risk of death.4,5

• Multiple observational studies have linked low Hb levels to poor cardiovascular outcomes.6 However, recent clinical studies have demonstrated that ESAs are unable to modify this risk when targeting a normal Hb level.5,7-9

• Sotatercept (ACE-011) is an ActRIIA-IgG1 fusion protein trap that binds with high affinity to activin A and other members of the TGFb superfamily and acts on late-stage erythropoiesis to increase the production of mature erythrocytes into the circulation.10-12

• This 2-part, phase IIA, randomized, placebo-controlled trial is the first to evaluate the pharmacokinetics (PK), safety, tolerability, and Hb effect of sotatercept in ESKD subjects with renal anemia receiving hemodialysis.

• In part 1, after a single subcutaneous dose (0.1 mg/kg) of sotatercept13:

– PK parameters were similar to a phase I study in healthy postmenopausal women, with a long half-life (21 days).

– Sotatercept was not dialyzable.

– There was no evidence of a pharmacodynamic effect on Hb concentrations at the single, 0.1 mg/kg dose.

– Sotatercept was well tolerated with no observed changes in blood pressure (BP), and no consistent changes in safety laboratory or electrocardiographic parameters.

• Part 2 is an ongoing, randomized, single-blind, placebo-controlled, sequential dose-escalation study in subjects with ESKD on hemodialysis evaluating the PK, safety, tolerability, and Hb effects of sotatercept for the correction of ESKD-related anemia.

• We report the preliminary, interim analysis of the sotatercept 0.3 mg/kg (low dose) and 0.5 mg/kg (medium dose) treatment groups.

• Pending acceptable interim analysis results, additional patients may be randomized in a staggered parallel fashion to sotatercept 0.7 mg/kg once every 28 days (high dose) and sotatercept 0.7 mg/kg once every 14 days for 28 days followed by 0.4 mg/kg every 14 days for the remainder of the treatment period (Figure 1).

METHODSKey Inclusion Criteria• Adults receiving at least 3 hours of high-flux hemodialysis at each session for at least 12 weeks before screening and no planned changes to the hemodialysis regimen

during the study period

• Adequate Hb response (Hb ≥10 to ≤12 g/dL predialysis mean of 3 consecutive Hb concentrations) to stable doses of ESA (epoetin alfa, darbepoetin) for at least 6 weeks before and during screening, excluding dose holds for high Hb (maximum dose: epoetin alfa ≤500 IU/kg/week; darbepoetin ≤95 μg/week)

• ESKD-related anemia: Hb ≥8 to ≤10 g/dL predialysis after ESA washout

• Adequate iron status (transferrin saturation ≥20%)

• Kt/V ≥1.2 or urea reduction ratio ≥65%

• Parathyroid hormone concentration ≤1,000 pg/mL; phosphorous ≤7 mg/dL; and total albumin-corrected calcium ≥8.0 to ≤10.5 mg/dL

Key Exclusion Criteria• Anemia due to non-renal causes

• ESKD due to malignancy or history of malignancy (excluding excised and cured non-melanoma skin cancer and cervical carcinoma in situ)

• Systemic hematologic disease

• Peritoneal dialysis or compromised venous access

• Uncontrolled diabetes mellitus (HbA1C >9%), hypertension (home systolic BP [SBP] >160 mm Hg, home diastolic BP [DBP] >90 mm Hg), or heart failure (New York Heart Association class ≥3)

• Alanine transaminase and/or aspartate transaminase values >2× the upper limit of normal; C-reactive protein >50 mg/L

• Red blood cell transfusion <8 weeks before screening

• Anticipated or scheduled living donor renal transplant

Study Design• This was a randomized, single-blind, placebo-controlled, sequential dose-escalation study in subjects with ESKD on hemodialysis (Figure 1).

• Eligible subjects were randomized to 2 arms (sotatercept or placebo in a 3:1 ratio) in 4 sequential dose groups (sotatercept 0.3 mg/kg, 0.5 mg/kg, 0.7 mg/kg, or 0.7 mg/kg loading dose followed by 0.4 mg/kg).

– This interim analysis informed the data monitoring committee’s decision to open enrollment for the high-dose group (sotatercept 0.7 mg/kg).

– At the time of abstract submission:

§ Enrollment in the sotatercept 0.3 mg/kg and 0.5 mg/kg dose groups was completed.

§ Enrollment in the sotatercept 0.7 mg/kg dose group was ongoing.

• Sotatercept doses could have been delayed, reduced, or discontinued based on the subject’s absolute predialysis Hb level or change in Hb level observed after dosing, or discontinued based on change in home BP measurements.

– Delayed: Hb ≥11 to <13 g/dL on Dose Cycle Day 36 (0.3, 0.5, and 0.7 mg/kg dose groups) or Dose Cycle Day 19 (0.7/0.4 mg/kg dose group)

– Reduced: If a dose was delayed, OR if Hb <11 g/dL AND rate of rise of >2 g/dL (0.3, 0.5, and 0.7 mg/kg dose groups) or >1 g/dL (0.7/0.4 mg/kg dose group)

– Discontinued:

§ Persistent hypertension recorded by home BP monitor mean of 4 days of home SBP >160 mm Hg AND increase in SBP from baseline of >20 mm Hg, or mean increase from baseline DBP of >10 mm Hg

§ Hb ≥13 g/dL at any time after randomization

§ Hb ≥12 to <13 g/dL for 2 consecutive weeks at any time after randomization

• Rescue treatment was recommended for subjects with Hb <9 g/dL after the first dose cycle, and those required to discontinue sotatercept could receive ESA treatment or red blood cell transfusion.

• All randomized subjects, including those who were rescued or discontinued early, continued to follow the visit schedule and home BP monitoring throughout the 200-day treatment phase and 112-day follow-up phase.

• The current report describes interim analysis of the sotatercept 0.3 mg/kg and 0.5 mg/kg dose groups for the purpose of determining safety of proceeding to the next dose group.

Figure 1. Study Design

Follow-up phase for 112 days for PK

and safety

Screening andESA washout

(Day –90 to Day –1)

Sotatercept 0.3 mg/kgSC (n ~9) q28d,up to 8 doses

Placebo (n ~3)q28d, up to 8 doses







Sotatercept 0.7 mg/kgSC (n ~9) q28d,

up to 8 doses




Sotatercept 0.7 mg/kg SC q14d(2 doses), then 0.4 mg/kg SC q14d

up to 13 doses (n ~9)


Note: All randomized subjects will continue treatment with sotatercept 0.3, 0.5, or 0.7 mg/kg or placebo for up to 8 doses* unless rescued or discontinued early. *At 0.7/0.4 mg/kg, all randomized subjects will continue treatment for up to 15 doses unless rescued or discontinued early.28 days after the 6th subject is dosed with sotatercept in each dose group (0.3, 0.5, and 0.7 mg/kg), an interim analysis will occur to evaluate PK and safety before opening the next dose group.

Table 3. Sotatercept PK in ESKD Subjects on Hemodialysis (Dose 1, Cycle 1)

Sotatercept

Parameter0.3 mg/kg

n=90.5 mg/kg

n=6

tmax, mean (min–max), day 12 (2–14) 7 (2–14)

Cmax, mean (SD), μg/mL 2.4 (0.96) 3.5 (0.73)

AUC28d, mean (SD), day•μg/mL 50.5 (17.4) 73.2 (11.5)

t1/2,z, mean (SD), day 22.3 (3.0)* 24.5 (8.9)*†

CL/F, mean (SD), mL/day/kg 3.65 (1.60)* 3.83 (1.19)*†

Vz/F, mean (SD), mL/kg 117 (54)* 124 (27.9)*†

AUC28d=area under the concentration-vs.-time curve up to 28 days; CL/F=oral clearance; Vz/F=apparent volume of distribution.*Estimated according to a 1-compartment model.†The 28-day data may not be sufficient for accurate estimation in some subjects.

Figure 2. Sotatercept Serum Concentration Over Time

Seru

m S

otat

erce

pt (µ

g/m

L)

5

4

3

2

1

0

Days After the First Dose

0 7 14 21 28

Sotatercept 0.3 mg/kg


Safety• An overview of AEs is provided in Table 4.

• A decrease in serum calcium levels during follow-up in subjects who had received sotatercept 0.3 mg/kg was noted, without AEs of hypocalcemia.

• There were no other observed trends in laboratory, electrocardiogram, or vital sign parameters, including study visit and intra-dialytic BP, in either dose group of sotatercept during long-term follow-up.

• No anti-drug antibodies, injection site reactions, or hypersensitivity reactions were observed.

Table 4. Overview of AEs (Safety Population, N=20)

Placebo Sotatercept

n=50.3 mg/kg

n=90.5 mg/kg

n=6

Subjects, n (%)

Cumulative days on study 864 2046 634

Any AE 3 (60.0) 8 (88.8) 3 (50.0)

≥1 severe AE 2 (40.0) 2 (22.2) 2 (33.3)

≥1 serious AE 2 (40.0) 2 (22.2) 1 (16.7)

Death 1 (20.0) 0 (0.0) 0 (0.0)

AEs in ≥2 subjects in a treatment group, n (%)

Fatigue 1 (20.0) 2 (22.2) 0 (0.0)

Pain 0 (0.0) 2 (22.2) 0 (0.0)

Constipation 1 (20.0) 2 (22.2) 0 (0.0)

Hypertension 0 (0.0) 3 (33.3)* 0 (0.0)

*A total of 3 subjects randomized to sotatercept 0.3 mg/kg reported 4 AEs of hypertension; 3 of the 4 events occurred after rescue with erythropoietin.

EfficacyTarget Hb Increase (≥1 g/dL), and Target Hb Range (10–12 g/dL) During the First 28 Days

• Baseline Hb levels were 9.7 g/dL in subjects receiving placebo, 9.3 g/dL in subjects receiving sotatercept 0.3 mg/kg, and 8.9 g/dL in subjects receiving sotatercept 0.5 mg/kg.

• Hb increase ≥1.0 g/dL was achieved by 20% (placebo), 37.5% (sotatercept 0.3 mg/kg), and 40% (sotatercept 0.5 mg/kg) of subjects (Figure 3).

• The desired Hb range (10–12 g/dL) was achieved in 60% (placebo), 25% (sotatercept 0.3 mg/kg), and 60% (sotatercept 0.5 mg/kg) during the first dose cycle.

• Mean peak Hb increase in the first 28-day dose cycle was 0.1 g/dL in subjects receiving placebo, 0.5 g/dL in subjects receiving sotatercept 0.3 mg/kg, and 0.8 g/dL in subjects receiving sotatercept 0.5 mg/kg (Figure 4).

• Rescue therapy was required (Hb <9 g/dL) in 2 of 5 subjects after administration of placebo and 1 of 8 subjects after administration of sotatercept 0.3 mg/kg, while none required rescue after sotatercept 0.5 mg/kg (Figure 3).

Figure 3. Hb Increase During the First 28-Day Dose Cycle (Per-Protocol Population)*

0

30

20

10

40

60

50

70

80

90

100

Subj

ects

(%)

Placebo(n=5)

40

40

20

Sotatercept 0.3 mg/kg(n=8)

13

50

37


(n=5)

60

40

0.1-0.9 g/dL

Required Rescue (Hb <9 g/dL)

≥1.0 g/dL

*Two subjects with a major protocol violation were excluded from efficacy analyses.

PK Assessment• Blood samples for analysis of sotatercept PK were collected at each study visit and on each sotatercept or placebo dosing day. Additional samples were obtained after

dose 1 at 4 hours post-dose on Day 1 and at 48 hours post-dose on Day 3.

• A validated, competitive enzyme-linked immunosorbent assay using anti‐human ActRIIA antibodies (R&D Systems, Minneapolis, MN) was used to measure the sotatercept serum concentration.

Hb Assessments• Blood samples for Hb assessment were obtained at all scheduled study visits, including before dosing.

Home BP Monitoring• Because of the burden of hypertension in the hemodialysis population, and the inherent variability in hemodialysis-related BP measurement, home BP monitoring was

used to provide a BP profile more reflective of the subject’s steady state.

• Subjects obtained their BP at home 2×/day (3 measurements each upon waking and at bedtime) for 4 consecutive days within 7 days of a scheduled dosing day. Each subject was trained to use a sponsor-provided BP monitor.

• At least 3 waking and 3 bedtime values downloaded from the device by study personnel were used to calculate mean BP values before screening, randomization, and re-dosing.

• Home BP monitoring continued for subjects requiring rescue.

Safety Assessments• Safety assessments included collection of adverse events (AEs), hematology testing, and vital signs at each visit and physical examination and 12-lead

electrocardiogram at selected scheduled time points.

– Safety assessments were done in the event of early termination/withdrawal.

• Proportions of subjects with Hb >12 g/dL at any time and rise in Hb >2 g/dL over 4 weeks were also determined.

• At each interim analysis, blood samples were analyzed for the presence of anti-sotatercept antibodies.

Statistical Analysis• Sotatercept multidose PK was examined among all subjects who received at least 1 dose of study medication and who had evaluable PK data.

• Sotatercept efficacy was evaluated in the full analysis set (FAS), which comprised all randomized subjects who received at least 1 dose of study medication and had at least 1 post-dose follow-up visit, and a baseline value (for analyses that require baseline comparison). Subjects assigned to placebo in both dose groups were combined to form a single placebo group for analysis purposes.

• Efficacy end points included:

– Proportion of subjects achieving target Hb increase (≥1 g/dL increase from baseline).

– Proportion of subjects achieving target Hb concentration >10 g/dL to <12 g/dL.

– Proportion of subjects requiring rescue therapy.

– Change from baseline Hb during the first 28-day dosing cycle, including peak Hb response.

• Proportional and continuous end points were summarized descriptively.

• The final mean home BP value was calculated by first determining the mean of 3 waking and 3 bedtime sets of BP measures. Next, the mean waking and mean bedtime values from a single day were both used to calculate the day mean. Finally, the mean of the day means was calculated, and this comprised the final mean home BP.

• Home BP measures and safety measures were summarized descriptively.

RESULTSSubjects• A total of 21 subjects were randomized and received study medication. One subject was randomized to sotatercept 0.5 mg/kg and received 1 dose of study medication;

however, this subject did not have the first follow-up visit at the time of the interim database cutoff point and was not included in either the safety or efficacy population. A total of 20 subjects comprise the FAS and safety population:

– 5 who received placebo.

– 9 who received sotatercept 0.3 mg/kg.


• Interim subject disposition is illustrated in Table 1.

• Baseline subject demographics and disease characteristics were generally similar across treatment groups (Table 2).

• Major protocol violations were noted for 2 subjects randomized to sotatercept. One subject (0.3 mg/kg) received erythropoietin prior to randomization and through the first dose cycle, and was discontinued from the study; 1 subject (0.5 mg/kg) had an incomplete baseline home BP evaluation, which showed a non-qualifying elevation in BP prior to randomization, and was discontinued from study medication early. These subjects were excluded from efficacy analyses, as a per-protocol analysis defined in the protocol. Included in the efficacy analysis population were:




Table 1. Subject Disposition (FAS, N=20)

GroupOngoing on Study Drug

D/C Study Drug (Being Followed)

Completers on Study Drug (≥200 Days)

Completers After D/C Study Drug Early Termination Total Rescued

D/C Study Drug Due to Stopping Rule

Placebo, n=5 0 2 1 1 1 3 0

Sotatercept 0.3 mg/kg, n=9 0 0 2 5 2 7 0


D/C=discontinued.

Table 2. Demographic Characteristics of Subjects (FAS, N=20)

Placebo Sotatercept

n=50.3 mg/kg

n=90.5 mg/kg

n=6

Age, mean, years 58.4 59.9 60.7

Female, n (%) 1 (20.0) 6 (66.7) 1 (16.7)

Race, n (%)

White 1 (20.0) 3 (33.3) 4 (66.7)

Black 3 (60.0) 6 (66.7) 2 (33.3)

Asian 1 (20.0) 0 (0.0) 0 (0.0)

Ethnicity

Hispanic 0 (0.0) 2 (22.2) 4 (66.7)

Non-Hispanic 5 (100.0) 7 (77.8) 2 (33.3)

Weight, postdialysis mean, kg 75.8 79.4 81.0

Body mass index, mean, kg/m2 25.4 27.8 27.3

Sotatercept PK• Preliminary, interim PK data, based on analysis of all subjects randomized to sotatercept 0.3 mg/kg and the first 6 subjects randomized to sotatercept 0.5 mg/kg, are

presented in Table 3.

• Sotatercept exhibited dose-dependent increases in the serum drug exposure (Cmax and AUC), with a mean elimination half-life (t1/2,z) of 22 to 25 days.

• Sotatercept mean concentration-vs.-time profiles for the 0.3 mg/kg and 0.5 mg/kg dose groups are shown in Figure 2.

Figure 4. Mean Peak Hemoglobin Increase During the First 28-Day Dose Cycle (Per-Protocol Population)*

Sotatercept 0.3 mg/kg (n=8)


Placebo (n=5)

0.1

0.5

0.8

0

0.3

0.2

0.1

0.4

0.5

0.6

0.7

0.8

0.9

Hb (g

/dL)

Cha

nge

From

Bas

elin

e

Mean Peak Hemoglobin Response


Change From Baseline in Hb Concentration• Mean Hb concentration in subjects who received sotatercept 0.3 mg/kg and 0.5 mg/kg exhibited a greater increase from baseline in the first 15 days post-dose

(vs. placebo); however, the increases were not sustained through the entire dose cycle.

• Hb levels throughout multiple dose cycles among subjects who did not require rescue were generally highest among subjects receiving sotatercept 0.5 mg/kg (Figure 5).

Figure 5. Hb Change From Baseline During Long-term Sotatercept Treatment Censored for Rescue

−3

−2

−1

0

1

2

3

4

50 100 150 200 250


Hem

oglo

bin

(g/d

L)

Sotatercept 0.3 mg/kg (n=8)Sotatercept 0.5 mg/kg (n=5)

Placebo (n=5)

Home BP Measurements• Home BP measures in the first dose cycle revealed that all 3 groups had increases in group mean SBP, with the largest change in subjects receiving sotatercept

0.3 mg/kg, while the largest change in DBP was in subjects receiving placebo. All the group mean changes were <10 mm Hg (Figure 6A and B).

– Findings were similar when analyzed for both the per-protocol population (Figure 6A) and FAS (Figure 6B).

• With long-term treatment, home BP measures showed no consistent change from baseline among subjects in any of the treatment groups (Figure 7).

Figure 6. Change From Baseline in Home BP at the End of Dose Cycle 1 in the (A) Per-Protocol Population* and (B) FAS



Placebo (n=3)



Placebo (n=4)

Chan

ge F

rom

Bas

elin

e BP

(mm

Hg)

0.0

2.0

6.0

3.3 3.3

–0.3 –1.0

0.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

SBP DBP

A

B

Chan

ge F

rom

Bas

elin

e BP

(mm

Hg)

2.3

7.5

3.0 2.5

7.6

0.4

0.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

8.0

SBP DBP

*Data exclude subjects with protocol violations and are censored for those who required rescue in the first dose cycle.

Figure 7. Change From Baseline Home BP Measurements (FAS) of (A) SBP and (B) DBP During Long-term Sotatercept Treatment, Censored for Rescue

A SBP

B DBP

–20

–15

–10

–5

0

5

10

15

20

25

50 100 150 200 250


Placebo (n=4)

Hom

e DB

P (m

m H

g)

–50

–40

–30

–20

–10

0

10

20

30

40

50 100 150 200 250


Placebo (n=4)

Hom

e SB

P (m

m H

g)

CONCLUSIONS• Sotatercept exhibited linear PK characteristics, and a long half-life of 22 to 25 days.

• Sotatercept was well tolerated, with AEs similar to those observed with placebo and no trends toward increased BP.

• Exposure to sotatercept was not associated with the development of anti-drug antibodies, injection site reactions, or hypersensitivity reactions.

• In the first 28 days of treatment, the proportion of subjects achieving the target Hb increase of ≥1 g/dL was greater in the treatment groups than in the placebo group, and the proportion requiring rescue therapy in the first 28 days was dose-related, with no subjects in the sotatercept 0.5 mg/kg group requiring rescue.

• In this initial 28-day analysis, in which the placebo and sotatercept 0.3 mg/kg groups had higher baseline Hb, no differences between groups achieving the target Hb range (10-12 g/dL) were observed. Dose escalation continues per protocol.

• Mean peak Hb response in the first 28 days was dose-related, with the sotatercept 0.5 mg/kg dose having the highest mean peak Hb response.

• Hb improvements were generally sustained for multiple dosing cycles in the sotatercept 0.5 mg/kg dose group.

• This preliminary interim analysis indicates adequate Hb responses and safety of sotatercept at 0.3 and 0.5 mg/kg and provides evidence to continue the evaluation of sotatercept at 0.7 mg/kg in patients with ESKD on hemodialysis.

REFERENCES1. Babitt JL, Lin HY. Mechanisms of anemia in CKD. J Am Soc Nephrol. 2012;23:1631-1634.

2. Jacobson LO, Goldwasser E, Fried W, et al. Role of the kidney in erythropoiesis. Nature. 1957;179:633-634.

3. McGonigle RJ, Wallin JD, Shadduck RK, et al. Erythropoietin deficiency and inhibition of erythropoiesis in renal insufficiency. Kidney Int. 1984;25:437-444.

4. Eschbach JW, Egrie JC, Downing MR, et al. Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. Results of a combined phase I and II clinical trial. N Engl J Med. 1987;316:73-78.

5. Singh AK, Szczech L, Tang KL, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006;355: 2085-2098.

6. Fishbane S. Anemia and cardiovascular risk in the patient with kidney disease. Heart Fail Clin. 2008;4:401-410.

7. Besarab A, Bolton WK, Browne JK, et al. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med. 1998;339:584-590.

8. Drueke TB, Locatelli F, Clyne N, et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med. 2006;355:2071-2084.

9. Pfeffer MA, Burdmann EA, Chen CY, et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med. 2009;361:2019-2032.

10. Pearsall RS, Canalis E, Cornwall-Brady M, et al. A soluble activin type IIA receptor induces bone formation and improves skeletal integrity. Proc Natl Acad Sci U S A. 2008;105:7082-7087.

11. Iancu-Rubin C, Mosoyan G, Wang J, et al. Stromal cell-mediated inhibition of erythropoiesis can be attenuated by sotatercept (ACE-011), an activin receptor type II ligand trap. Exp Hematol. 2013;41:155-166.

12. Sherman ML, Borgstein NG, Mook L, et al. Multiple-dose, safety, pharmacokinetic, and pharmacodynamic study of sotatercept (ActRIIA-IgG1), a novel erythropoietic agent, in healthy postmenopausal women. J Clin Pharmacol. 2013;53:1121-1130.

13. Wooldridge T, Kaplan M, Alcorn H Jr, et al. The pharmacokinetics and safety of a single-dose of sotatercept (ACE-011) in subjects on hemodialysis and the effects of its murine analog (RAP-011) on anemia and in preventing bone loss in C57BL/6 mice with 5/6 nephrectomy [oral presentation]. Presented at: American Society of Nephrology Kidney Week 2012; October 30-November 4, 2012; San Diego, CA.

This study was sponsored by Celgene Corporation.

Presented at: the National Kidney Foundation (NKF) 2014 Spring Clinical Meeting; April 22–26, 2014; Las Vegas, NV.Scan this QR code to receive

the PDF of the poster

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an

ActR

IIA-Ig

G1 fu

sion

pro

tein

trap

that

bin

ds w

ith h

igh

affin

ity to

act

ivin

A a

nd o

ther

mem

bers

of t

he T

GFb

supe

rfam

ily a

nd a

cts

on la

te-s

tage

er

ythr

opoi

esis

to in

crea

se th

e pr

oduc

tion

of m

atur

e er

ythr

ocyt

es in

to th

e ci

rcul

atio

n.10

-12

• Th

is 2

-par

t, ph

ase

IIA, r

ando

miz

ed, p

lace

bo-c

ontro

lled

trial

is th

e fir

st to

eva

luat

e th

e ph

arm

acok

inet

ics

(PK)

, saf

ety,

tole

rabi

lity,

and

Hb e

ffect

of s

otat

erce

pt in

ESK

D su

bjec

ts w

ith re

nal a

nem

ia re

ceiv

ing

hem

odia

lysi

s.

• In

par

t 1, a

fter a

sin

gle

subc

utan

eous

dos

e (0

.1 m

g/kg

) of s

otat

erce

pt13

:

–PK

par

amet

ers

wer

e si

mila

r to

a ph

ase

I stu

dy in

hea

lthy

post

men

opau

sal w

omen

, with

a lo

ng h

alf-

life

(21

days

).

–So

tate

rcep

t was

not

dia

lyza

ble.

–Th

ere

was

no

evid

ence

of a

pha

rmac

odyn

amic

effe

ct o

n Hb

con

cent

ratio

ns a

t the

sin

gle,

0.1

mg/

kg d

ose.

–So

tate

rcep

t was

wel

l tol

erat

ed w

ith n

o ob

serv

ed c

hang

es in

blo

od p

ress

ure

(BP)

, and

no

cons

iste

nt c

hang

es in

saf

ety

labo

rato

ry o

r ele

ctro

card

iogr

aphi

c pa

ram

eter

s.

• Pa

rt 2

is a

n on

goin

g, ra

ndom

ized

, sin

gle-

blin

d, p

lace

bo-c

ontro

lled,

seq

uent

ial d

ose-

esca

latio

n st

udy

in s

ubje

cts

with

ESK

D on

hem

odia

lysi

s ev

alua

ting

the

PK, s

afet

y, to

lera

bilit

y, an

d Hb

effe

cts

of s

otat

erce

pt fo

r the

cor

rect

ion

of E

SKD-

rela

ted

anem

ia.

• W

e re

port

the

prel

imin

ary,

inte

rim a

naly

sis

of th

e so

tate

rcep

t 0.3

mg/

kg (l

ow d

ose)

and

0.5

mg/

kg (m

ediu

m d

ose)

trea

tmen

t gro

ups.

• Pe

ndin

g ac

cept

able

inte

rim a

naly

sis

resu

lts, a

dditi

onal

pat

ient

s m

ay b

e ra

ndom

ized

in a

sta

gger

ed p

aral

lel f

ashi

on to

sot

ater

cept

0.7

mg/

kg o

nce

ever

y 28

day

s (h

igh

dose

) and

sot

ater

cept

0.7

mg/

kg o

nce

ever

y 14

day

s fo

r 28

days

follo

wed

by

0.4

mg/

kg e

very

14

days

for t

he re

mai

nder

of t

he tr

eatm

ent p

erio

d (F

igur

e 1)

.

MET

HODS

Key

Incl

usio

n Cr

iteria

• Ad

ults

rece

ivin

g at

leas

t 3 h

ours

of h

igh-

flux

hem

odia

lysi

s at

eac

h se

ssio

n fo

r at l

east

12

wee

ks b

efor

e sc

reen

ing

and

no p

lann

ed c

hang

es to

the

hem

odia

lysi

s re

gim

en

durin

g th

e st

udy

perio

d

• Ad

equa

te H

b re

spon

se (H

b ≥1

0 to

≤12

g/d

L pr

edia

lysi

s m

ean

of 3

con

secu

tive

Hb c

once

ntra

tions

) to

stab

le d

oses

of E

SA (e

poet

in a

lfa, d

arbe

poet

in) f

or a

t lea

st 6

wee

ks

befo

re a

nd d

urin

g sc

reen

ing,

exc

ludi

ng d

ose

hold

s fo

r hig

h Hb

(max

imum

dos

e: e

poet

in a

lfa ≤

500

IU/k

g/w

eek;

dar

bepo

etin

≤95

μg/

wee

k)

• ES

KD-r

elat

ed a

nem

ia: H

b ≥8

to ≤

10 g

/dL

pred

ialy

sis

afte

r ESA

was

hout

• Ad

equa

te ir

on s

tatu

s (tr

ansf

errin

sat

urat

ion

≥20%

)

• Kt

/V ≥

1.2

or u

rea

redu

ctio

n ra

tio ≥

65%

• Pa

rath

yroi

d ho

rmon

e co

ncen

tratio

n ≤1

,000

pg/

mL;

pho

spho

rous

≤7

mg/

dL; a

nd to

tal a

lbum

in-c

orre

cted

cal

cium

≥8.

0 to

≤10

.5 m

g/dL

Key

Excl

usio

n Cr

iteria

• An

emia

due

to n

on-r

enal

cau

ses

• ES

KD d

ue to

mal

igna

ncy

or h

isto

ry o

f mal

igna

ncy

(exc

ludi

ng e

xcis

ed a

nd c

ured

non

-mel

anom

a sk

in c

ance

r and

cer

vica

l car

cino

ma

in s

itu)

• Sy

stem

ic h

emat

olog

ic d

isea

se

• Pe

riton

eal d

ialy

sis

or c

ompr

omis

ed v

enou

s ac

cess

• Un

cont

rolle

d di

abet

es m

ellit

us (H

bA1C

>9%

), hy

perte

nsio

n (h

ome

syst

olic

BP

[SBP

] >16

0 m

m H

g, h

ome

dias

tolic

BP

[DBP

] >90

mm

Hg)

, or h

eart

failu

re (N

ew Y

ork

Hear

t As

soci

atio

n cl

ass

≥3)

• Al

anin

e tra

nsam

inas

e an

d/or

asp

arta

te tr

ansa

min

ase

valu

es >

2× th

e up

per l

imit

of n

orm

al; C

-rea

ctiv

e pr

otei

n >

50 m

g/L

• Re

d bl

ood

cell

trans

fusi

on <

8 w

eeks

bef

ore

scre

enin

g

• An

ticip

ated

or s

ched

uled

livi

ng d

onor

rena

l tra

nspl

ant

Stud

y De

sign

• Th

is w

as a

rand

omiz

ed, s

ingl

e-bl

ind,

pla

cebo

-con

trolle

d, s

eque

ntia

l dos

e-es

cala

tion

stud

y in

sub

ject

s w

ith E

SKD

on h

emod

ialy

sis

(Fig

ure

1).

• El

igib

le s

ubje

cts

wer

e ra

ndom

ized

to 2

arm

s (s

otat

erce

pt o

r pla

cebo

in a

3:1

ratio

) in

4 se

quen

tial d

ose

grou

ps (s

otat

erce

pt 0

.3 m

g/kg

, 0.5

mg/

kg, 0

.7 m

g/kg

, or

0.7

mg/

kg lo

adin

g do

se fo

llow

ed b

y 0.

4 m

g/kg

).

–Th

is in

terim

ana

lysi

s in

form

ed th

e da

ta m

onito

ring

com

mitt

ee’s

dec

isio

n to

ope

n en

rollm

ent f

or th

e hi

gh-d

ose

grou

p (s

otat

erce

pt 0

.7 m

g/kg

).

–At

the

time

of a

bstra

ct s

ubm

issi

on:

§En

rollm

ent i

n th

e so

tate

rcep

t 0.3

mg/

kg a

nd 0

.5 m

g/kg

dos

e gr

oups

was

com

plet

ed.

§En

rollm

ent i

n th

e so

tate

rcep

t 0.7

mg/

kg d

ose

grou

p w

as o

ngoi

ng.

• So

tate

rcep

t dos

es c

ould

hav

e be

en d

elay

ed, r

educ

ed, o

r dis

cont

inue

d ba

sed

on th

e su

bjec

t’s a

bsol

ute

pred

ialy

sis

Hb le

vel o

r cha

nge

in H

b le

vel o

bser

ved

afte

r dos

ing,

or

dis

cont

inue

d ba

sed

on c

hang

e in

hom

e BP

mea

sure

men

ts.

–De

laye

d: H

b ≥1

1 to

<13

g/d

L on

Dos

e Cy

cle

Day

36 (0

.3, 0

.5, a

nd 0

.7 m

g/kg

dos

e gr

oups

) or D

ose

Cycl

e Da

y 19

(0.7

/0.4

mg/

kg d

ose

grou

p)

–Re

duce

d: If

a d

ose

was

del

ayed

, OR

if Hb

<11

g/d

L AN

D ra

te o

f ris

e of

>2

g/dL

(0.3

, 0.5

, and

0.7

mg/

kg d

ose

grou

ps) o

r >1

g/dL

(0.7

/0.4

mg/

kg d

ose

grou

p)

–Di

scon

tinue

d:

§Pe

rsis

tent

hyp

erte

nsio

n re

cord

ed b

y ho

me

BP m

onito

r mea

n of

4 d

ays

of h

ome

SBP

>16

0 m

m H

g AN

D in

crea

se in

SBP

from

bas

elin

e of

>20

mm

Hg,

or m

ean

incr

ease

from

bas

elin

e DB

P of

>10

mm

Hg

§Hb

≥13

g/d

L at

any

tim

e af

ter r

ando

miz

atio

n

§Hb

≥12

to <

13 g

/dL

for 2

con

secu

tive

wee

ks a

t any

tim

e af

ter r

ando

miz

atio

n

• Re

scue

trea

tmen

t was

reco

mm

ende

d fo

r sub

ject

s w

ith H

b <

9 g/

dL a

fter t

he fi

rst d

ose

cycl

e, a

nd th

ose

requ

ired

to d

isco

ntin

ue s

otat

erce

pt c

ould

rece

ive

ESA

treat

men

t or

red

bloo

d ce

ll tra

nsfu

sion

.

• Al

l ran

dom

ized

sub

ject

s, in

clud

ing

thos

e w

ho w

ere

resc

ued

or d

isco

ntin

ued

early

, con

tinue

d to

follo

w th

e vi

sit s

ched

ule

and

hom

e BP

mon

itorin

g th

roug

hout

the

200-

day

treat

men

t pha

se a

nd 1

12-d

ay fo

llow

-up

phas

e.

• Th

e cu

rren

t rep

ort d

escr

ibes

inte

rim a

naly

sis

of th

e so

tate

rcep

t 0.3

mg/

kg a

nd 0

.5 m

g/kg

dos

e gr

oups

for t

he p

urpo

se o

f det

erm

inin

g sa

fety

of p

roce

edin

g to

the

next

do

se g

roup

.

Figu

re 1

. Stu

dy D

esig

n

Follo

w-u

p ph

ase

for

112

days

for P

K a

nd s

afet

y

Scre

enin

g an

dES

A w

asho

ut(D

ay –

90 to

Day

–1)

Sota

terc

ept 0

.3 m

g/kg

SC (n

~9)

q28

d,up

to 8

dos

es

Plac

ebo

(n ~

3)q2

8d, u

p to

8 d

oses

Scre

enin

g an

dES

A w

asho

ut(D

ay –

90 to

Day

–1)

Sota

terc

ept 0

.5 m

g/kg

SC (n

~9)

q28

d,up

to 8

dos

es

Plac

ebo

(n ~

3)q2

8d, u

p to

8 d

oses

Scre

enin

g an

dES

A w

asho

ut(D

ay –

90 to

Day

–1)

Sota

terc

ept 0

.7 m

g/kg

SC (n

~9)

q28

d,

up to

8 d

oses

Plac

ebo

(n ~

3)q2

8d, u

p to

8 d

oses

Scre

enin

g an

dES

A w

asho

ut(D

ay –

90 to

Day

–1)

Sota

terc

ept 0

.7 m

g/kg

SC

q14d

(2 d

oses

), th

en 0

.4 m

g/kg

SC

q14d

up to

13

dose

s (n

~9)

Plac

ebo

(n ~

3)q1

4d, u

p to

15

dose

s

Note

: All

rand

omiz

ed s

ubje

cts

will

con

tinue

trea

tmen

t with

sot

ater

cept

0.3

, 0.5

, or 0

.7 m

g/kg

or p

lace

bo fo

r up

to 8

dos

es*

unle

ss re

scue

d or

dis

cont

inue

d ea

rly.

*At 0

.7/0

.4 m

g/kg

, all

rand

omiz

ed s

ubje

cts

will

con

tinue

trea

tmen

t for

up

to 1

5 do

ses

unle

ss re

scue

d or

dis

cont

inue

d ea

rly.

28 d

ays

afte

r the

6th

sub

ject

is d

osed

with

sot

ater

cept

in e

ach

dose

gro

up (0

.3, 0

.5, a

nd 0

.7 m

g/kg

), an

inte

rim a

naly

sis

will

occ

ur to

eva

luat

e PK

and

saf

ety

befo

re o

peni

ng th

e ne

xt d

ose

grou

p.

Tabl

e 3.

Sot

ater

cept

PK

in E

SKD

Subj

ects

on

Hem

odia

lysi

s (D

ose

1, C

ycle

1)

Sota

terc

ept

Para

met

er0.

3 m

g/kg

n=9

0.5

mg/

kg

n=6

t max

, mea

n (m

in–m

ax),

day

12 (2

–14)

7 (2

–14)

C max

, mea

n (S

D), μ

g/m

L2.

4 (0

.96)

3.5

(0.7

3)

AUC 28

d, m

ean

(SD)

, day

•μg/

mL

50.5

(17.

4)73

.2 (1

1.5)

t 1/2,

z, m

ean

(SD)

, day

22.3

(3.0

)*24

.5 (8

.9)*

†

CL/F

, mea

n (S

D), m

L/da

y/kg

3.65

(1.6

0)*

3.83

(1.1

9)*†

V z/F, m

ean

(SD)

, mL/

kg11

7 (5

4)*

124

(27.

9)*†

AUC 28

d=ar

ea u

nder

the

conc

entra

tion-

vs.-

time

curv

e up

to 2

8 da

ys; C

L/F=

oral

cle

aran

ce; V

z/F=

appa

rent

vol

ume

of d

istri

butio

n.*E

stim

ated

acc

ordi

ng to

a 1

-com

partm

ent m

odel

.† T

he 2

8-da

y da

ta m

ay n

ot b

e su

ffici

ent f

or a

ccur

ate

estim

atio

n in

som

e su

bjec

ts.

Figu

re 2

. Sot

ater

cept

Ser

um C

once

ntra

tion

Over

Tim

e

Serum Sotatercept (µg/mL)

5 4 3 2 1 0

Days

Afte

r the

Firs

t Dos

e

07

1421

28

Sota

terc

ept 0

.3 m

g/kg

Sota

terc

ept 0

.5 m

g/kg

Safe

ty•

An o

verv

iew

of A

Es is

pro

vide

d in

Tab

le 4

.

• A

decr

ease

in s

erum

cal

cium

leve

ls d

urin

g fo

llow

-up

in s

ubje

cts

who

had

rece

ived

sot

ater

cept

0.3

mg/

kg w

as n

oted

, with

out A

Es o

f hyp

ocal

cem

ia.

• Th

ere

wer

e no

oth

er o

bser

ved

trend

s in

labo

rato

ry, e

lect

roca

rdio

gram

, or v

ital s

ign

para

met

ers,

incl

udin

g st

udy

visi

t and

intra

-dia

lytic

BP,

in e

ither

dos

e gr

oup

of

sota

terc

ept d

urin

g lo

ng-t

erm

follo

w-u

p.

• No

ant

i-dru

g an

tibod

ies,

inje

ctio

n si

te re

actio

ns, o

r hyp

erse

nsiti

vity

reac

tions

wer

e ob

serv

ed.

Tabl

e 4.

Ove

rvie

w o

f AEs

(Saf

ety

Popu

latio

n, N

=20

)

Plac

ebo

Sota

terc

ept

n=5

0.3

mg/

kg

n=9

0.5

mg/

kg

n=6

Subj

ects

, n (%

)

Cum

ulat

ive

days

on

stud

y86

420

4663

4

Any

AE3

(60.

0)8

(88.

8)3

(50.

0)

≥1 s

ever

e AE

2 (4

0.0)

2 (2

2.2)

2 (3

3.3)

≥1 s

erio

us A

E2

(40.

0)2

(22.

2)1

(16.

7)

Deat

h1

(20.

0)0

(0.0

)0

(0.0

)

AEs

in ≥

2 su

bjec

ts in

a tr

eatm

ent g

roup

, n (%

)

Fatig

ue1

(20.

0)2

(22.

2)0

(0.0

)

Pain

0 (0

.0)

2 (2

2.2)

0 (0

.0)

Cons

tipat

ion

1 (2

0.0)

2 (2

2.2)

0 (0

.0)

Hype

rtens

ion

0 (0

.0)

3 (3

3.3)

*0

(0.0

)

*A to

tal o

f 3 s

ubje

cts

rand

omiz

ed to

sot

ater

cept

0.3

mg/

kg re

porte

d 4

AEs

of h

yper

tens

ion;

3 o

f the

4 e

vent

s oc

curr

ed a

fter r

escu

e w

ith e

ryth

ropo

ietin

.

Effic

acy

Targ

et H

b In

crea

se (≥

1 g/

dL),

and

Targ

et H

b Ra

nge

(10–

12 g

/dL)

Dur

ing

the

Firs

t 28

Days

• Ba

selin

e Hb

leve

ls w

ere

9.7

g/dL

in s

ubje

cts

rece

ivin

g pl

aceb

o, 9

.3 g

/dL

in s

ubje

cts

rece

ivin

g so

tate

rcep

t 0.3

mg/

kg, a

nd 8

.9 g

/dL

in s

ubje

cts

rece

ivin

g so

tate

rcep

t 0.

5 m

g/kg

.

• Hb

incr

ease

≥1.

0 g/

dL w

as a

chie

ved

by 2

0% (p

lace

bo),

37.5

% (s

otat

erce

pt 0

.3 m

g/kg

), an

d 40

% (s

otat

erce

pt 0

.5 m

g/kg

) of s

ubje

cts

(Fig

ure

3).

• Th

e de

sire

d Hb

rang

e (1

0–12

g/d

L) w

as a

chie

ved

in 6

0% (p

lace

bo),

25%

(sot

ater

cept

0.3

mg/

kg),

and

60%

(sot

ater

cept

0.5

mg/

kg) d

urin

g th

e fir

st d

ose

cycl

e.

• M

ean

peak

Hb

incr

ease

in th

e fir

st 2

8-da

y do

se c

ycle

was

0.1

g/d

L in

sub

ject

s re

ceiv

ing

plac

ebo,

0.5

g/d

L in

sub

ject

s re

ceiv

ing

sota

terc

ept 0

.3 m

g/kg

, and

0.8

g/d

L

in s

ubje

cts

rece

ivin

g so

tate

rcep

t 0.5

mg/

kg (F

igur

e 4)

.

• Re

scue

ther

apy

was

requ

ired

(Hb

<9

g/dL

) in

2 of

5 s

ubje

cts

afte

r adm

inis

tratio

n of

pla

cebo

and

1 o

f 8 s

ubje

cts

afte

r adm

inis

tratio

n of

sot

ater

cept

0.3

mg/

kg, w

hile

no

ne re

quire

d re

scue

afte

r sot

ater

cept

0.5

mg/

kg (F

igur

e 3)

.

Figu

re 3

. Hb

Incr

ease

Dur

ing

the

Firs

t 28-

Day

Dose

Cyc

le (P

er-P

roto

col P

opul

atio

n)*

030 20 104060 50708090100

Subjects (%)

Plac

ebo

(n=

5)

404020

Sota

terc

ept 0

.3 m

g/kg

(n=

8)

135037

So

tate

rcep

t 0.5

mg/

kg(n

=5)

6040

0.1-

0.9

g/dL

Requ

ired

Resc

ue (H

b <

9 g/

dL)

≥1.0

g/d

L

*Tw

o su

bjec

ts w

ith a

maj

or p

roto

col v

iola

tion

wer

e ex

clud

ed fr

om e

ffica

cy a

naly

ses.

PK A

sses

smen

t•

Bloo

d sa

mpl

es fo

r ana

lysi

s of

sot

ater

cept

PK

wer

e co

llect

ed a

t eac

h st

udy

visi

t and

on

each

sot

ater

cept

or p

lace

bo d

osin

g da

y. Ad

ditio

nal s

ampl

es w

ere

obta

ined

afte

r do

se 1

at 4

hou

rs p

ost-

dose

on

Day

1 an

d at

48

hour

s po

st-d

ose

on D

ay 3

.

• A

valid

ated

, com

petit

ive

enzy

me-

linke

d im

mun

osor

bent

ass

ay u

sing

ant

i‐hum

an A

ctRI

IA a

ntib

odie

s (R

&D S

yste

ms,

Min

neap

olis

, MN)

was

use

d to

mea

sure

the

sota

terc

ept s

erum

con

cent

ratio

n.

Hb A

sses

smen

ts•

Bloo

d sa

mpl

es fo

r Hb

asse

ssm

ent w

ere

obta

ined

at a

ll sc

hedu

led

stud

y vi

sits

, inc

ludi

ng b

efor

e do

sing

.

Hom

e BP

Mon

itorin

g•

Beca

use

of th

e bu

rden

of h

yper

tens

ion

in th

e he

mod

ialy

sis

popu

latio

n, a

nd th

e in

here

nt v

aria

bilit

y in

hem

odia

lysi

s-re

late

d BP

mea

sure

men

t, ho

me

BP m

onito

ring

was

us

ed to

pro

vide

a B

P pr

ofile

mor

e re

flect

ive

of th

e su

bjec

t’s s

tead

y st

ate.

• Su

bjec

ts o

btai

ned

thei

r BP

at h

ome

2×/d

ay (3

mea

sure

men

ts e

ach

upon

wak

ing

and

at b

edtim

e) fo

r 4 c

onse

cutiv

e da

ys w

ithin

7 d

ays

of a

sch

edul

ed d

osin

g da

y.

Each

sub

ject

was

trai

ned

to u

se a

spo

nsor

-pro

vide

d BP

mon

itor.

• At

leas

t 3 w

akin

g an

d 3

bedt

ime

valu

es d

ownl

oade

d fro

m th

e de

vice

by

stud

y pe

rson

nel w

ere

used

to c

alcu

late

mea

n BP

val

ues

befo

re s

cree

ning

, ran

dom

izat

ion,

an

d re

-dos

ing.

• Ho

me

BP m

onito

ring

cont

inue

d fo

r sub

ject

s re

quiri

ng re

scue

.

Safe

ty A

sses

smen

ts•

Safe

ty a

sses

smen

ts in

clud

ed c

olle

ctio

n of

adv

erse

eve

nts

(AEs

), he

mat

olog

y te

stin

g, a

nd v

ital s

igns

at e

ach

visi

t and

phy

sica

l exa

min

atio

n an

d 12

-lead

el

ectro

card

iogr

am a

t sel

ecte

d sc

hedu

led

time

poin

ts.

–Sa

fety

ass

essm

ents

wer

e do

ne in

the

even

t of e

arly

term

inat

ion/

with

draw

al.

• Pr

opor

tions

of s

ubje

cts

with

Hb

>12

g/d

L at

any

tim

e an

d ris

e in

Hb

>2

g/dL

ove

r 4 w

eeks

wer

e al

so d

eter

min

ed.

• At

eac

h in

terim

ana

lysi

s, b

lood

sam

ples

wer

e an

alyz

ed fo

r the

pre

senc

e of

ant

i-sot

ater

cept

ant

ibod

ies.

Stat

istic

al A

naly

sis

• So

tate

rcep

t mul

tidos

e PK

was

exa

min

ed a

mon

g al

l sub

ject

s w

ho re

ceiv

ed a

t lea

st 1

dos

e of

stu

dy m

edic

atio

n an

d w

ho h

ad e

valu

able

PK

data

.

• So

tate

rcep

t effi

cacy

was

eva

luat

ed in

the

full

anal

ysis

set

(FAS

), w

hich

com

pris

ed a

ll ra

ndom

ized

sub

ject

s w

ho re

ceiv

ed a

t lea

st 1

dos

e of

stu

dy m

edic

atio

n an

d ha

d at

le

ast 1

pos

t-do

se fo

llow

-up

visi

t, an

d a

base

line

valu

e (fo

r ana

lyse

s th

at re

quire

bas

elin

e co

mpa

rison

). Su

bjec

ts a

ssig

ned

to p

lace

bo in

bot

h do

se g

roup

s w

ere

com

bine

d to

form

a s

ingl

e pl

aceb

o gr

oup

for a

naly

sis

purp

oses

.

• Ef

ficac

y en

d po

ints

incl

uded

:

–Pr

opor

tion

of s

ubje

cts

achi

evin

g ta

rget

Hb

incr

ease

(≥1

g/dL

incr

ease

from

bas

elin

e).

–Pr

opor

tion

of s

ubje

cts

achi

evin

g ta

rget

Hb

conc

entra

tion

>10

g/d

L to

<12

g/d

L.

–Pr

opor

tion

of s

ubje

cts

requ

iring

resc

ue th

erap

y.

–Ch

ange

from

bas

elin

e Hb

dur

ing

the

first

28-

day

dosi

ng c

ycle

, inc

ludi

ng p

eak

Hb re

spon

se.

• Pr

opor

tiona

l and

con

tinuo

us e

nd p

oint

s w

ere

sum

mar

ized

des

crip

tivel

y.

• Th

e fin

al m

ean

hom

e BP

val

ue w

as c

alcu

late

d by

firs

t det

erm

inin

g th

e m

ean

of 3

wak

ing

and

3 be

dtim

e se

ts o

f BP

mea

sure

s. N

ext,

the

mea

n w

akin

g an

d m

ean

bedt

ime

valu

es fr

om a

sin

gle

day

wer

e bo

th u

sed

to c

alcu

late

the

day

mea

n. F

inal

ly, th

e m

ean

of th

e da

y m

eans

was

cal

cula

ted,

and

this

com

pris

ed th

e fin

al m

ean

hom

e BP

.

• Ho

me

BP m

easu

res

and

safe

ty m

easu

res

wer

e su

mm

ariz

ed d

escr

iptiv

ely. RE

SULT

SSu

bjec

ts•

A to

tal o

f 21

subj

ects

wer

e ra

ndom

ized

and

rece

ived

stu

dy m

edic

atio

n. O

ne s

ubje

ct w

as ra

ndom

ized

to s

otat

erce

pt 0

.5 m

g/kg

and

rece

ived

1 d

ose

of s

tudy

med

icat

ion;

ho

wev

er, t

his

subj

ect d

id n

ot h

ave

the

first

follo

w-u

p vi

sit a

t the

tim

e of

the

inte

rim d

atab

ase

cuto

ff po

int a

nd w

as n

ot in

clud

ed in

eith

er th

e sa

fety

or e

ffica

cy p

opul

atio

n.

A to

tal o

f 20

subj

ects

com

pris

e th

e FA

S an

d sa

fety

pop

ulat

ion:

–5

who

rece

ived

pla

cebo

.

–9

who

rece

ived

sot

ater

cept

0.3

mg/

kg.

–6

who

rece

ived

sot

ater

cept

0.5

mg/

kg.

• In

terim

sub

ject

dis

posi

tion

is il

lust

rate

d in

Tab

le 1

.

• Ba

selin

e su

bjec

t dem

ogra

phic

s an

d di

seas

e ch

arac

teris

tics

wer

e ge

nera

lly s

imila

r acr

oss

treat

men

t gro

ups

(Tab

le 2

).

• M

ajor

pro

toco

l vio

latio

ns w

ere

note

d fo

r 2 s

ubje

cts

rand

omiz

ed to

sot

ater

cept

. One

sub

ject

(0.3

mg/

kg) r

ecei

ved

eryt

hrop

oiet

in p

rior t

o ra

ndom

izat

ion

and

thro

ugh

the

first

dos

e cy

cle,

and

was

dis

cont

inue

d fro

m th

e st

udy;

1 s

ubje

ct (0

.5 m

g/kg

) had

an

inco

mpl

ete

base

line

hom

e BP

eva

luat

ion,

whi

ch s

how

ed a

non

-qua

lifyi

ng e

leva

tion

in B

P pr

ior t

o ra

ndom

izat

ion,

and

was

dis

cont

inue

d fro

m s

tudy

med

icat

ion

early

. The

se s

ubje

cts

wer

e ex

clud

ed fr

om e

ffica

cy a

naly

ses,

as

a pe

r-pr

otoc

ol a

naly

sis

defin

ed

in th

e pr

otoc

ol. I

nclu

ded

in th

e ef

ficac

y an

alys

is p

opul

atio

n w

ere:

–5

who

rece

ived

pla

cebo

.

–8

who

rece

ived

sot

ater

cept

0.3

mg/

kg.

–5

who

rece

ived

sot

ater

cept

0.5

mg/

kg.

Tabl

e 1.

Sub

ject

Dis

posi

tion

(FAS

, N=

20)

Grou

pOn

goin

g on

St

udy

Drug

D/C

Stud

y Dr

ug

(Bei

ng F

ollo

wed

)Co

mpl

eter

s on

Stu

dy D

rug

(≥20

0 Da

ys)

Com

plet

ers

Afte

r D/C

St

udy

Drug

Early

Ter

min

atio

nTo

tal R

escu

edD/

C St

udy

Drug

Du

e to

Sto

ppin

g Ru

le

Plac

ebo,

n=

50

21

11

30

Sota

terc

ept 0

.3 m

g/kg

, n=

90

02

52

70

Sota

terc

ept 0

.5 m

g/kg

, n=

63

20

01

21

D/C=

disc

ontin

ued.

Tabl

e 2.

Dem

ogra

phic

Cha

ract

eris

tics

of S

ubje

cts

(FAS

, N=

20)

Plac

ebo

Sota

terc

ept

n=5

0.3

mg/

kg

n=9

0.5

mg/

kg

n=6

Age,

mea

n, y

ears

58.4

59.9

60.7

Fem

ale,

n (%

)1

(20.

0)6

(66.

7)1

(16.

7)

Race

, n (%

)

Whi

te1

(20.

0)3

(33.

3)4

(66.

7)

Blac

k3

(60.

0)6

(66.

7)2

(33.

3)

Asia

n1

(20.

0)0

(0.0

)0

(0.0

)

Ethn

icity

Hisp

anic

0 (0

.0)

2 (2

2.2)

4 (6

6.7)

Non-

Hisp

anic

5 (1

00.0

)7

(77.

8)2

(33.

3)

Wei

ght,

post

dial

ysis

mea

n, k

g75

.879

.481

.0

Body

mas

s in

dex,

mea

n, k

g/m

225

.427

.827

.3

Sota

terc

ept P

K•

Prel

imin

ary,

inte

rim P

K da

ta, b

ased

on

anal

ysis

of a

ll su

bjec

ts ra

ndom

ized

to s

otat

erce

pt 0

.3 m

g/kg

and

the

first

6 s

ubje

cts

rand

omiz

ed to

sot

ater

cept

0.5

mg/

kg, a

re

pres

ente

d in

Tab

le 3

.

• So

tate

rcep

t exh

ibite

d do

se-d

epen

dent

incr

ease

s in

the

seru

m d

rug

expo

sure

(Cm

ax a

nd A

UC),

with

a m

ean

elim

inat

ion

half-

life

(t 1/2,

z) of

22

to 2

5 da

ys.

• So

tate

rcep

t mea

n co

ncen

tratio

n-vs

.-tim

e pr

ofile

s fo

r the

0.3

mg/

kg a

nd 0

.5 m

g/kg

dos

e gr

oups

are

sho

wn

in F

igur

e 2.

Figu

re 4

. Mea

n Pe

ak H

emog

lobi

n In

crea

se D

urin

g th

e Fi

rst 2

8-Da

y Do

se C

ycle

(Per

-Pro

toco

l Pop

ulat

ion)

*

Sota

terc

ept 0

.3 m

g/kg

(n=

8)

Sota

terc

ept 0

.5 m

g/kg

(n=

5)

Plac

ebo

(n=

5)

0.1

0.5

0.8

0

0.3

0.2

0.1

0.4

0.5

0.6

0.7

0.8

0.9

Hb (g/dL) Change From Baseline

Mea

n Pe

ak H

emog

lobi

n Re

spon

se

*Tw

o su

bjec

ts w

ith a

maj

or p

roto

col v

iola

tion

wer

e ex

clud

ed fr

om e

ffica

cy a

naly

ses.

Chan

ge F

rom

Bas

elin

e in

Hb

Conc

entra

tion

• M

ean

Hb c

once

ntra

tion

in s

ubje

cts

who

rece

ived

sot

ater

cept

0.3

mg/

kg a

nd 0

.5 m

g/kg

exh

ibite

d a

grea

ter i

ncre

ase

from

bas

elin

e in

the

first

15

days

pos

t-do

se

(vs.

pla

cebo

); ho

wev

er, t

he in

crea

ses

wer

e no

t sus

tain

ed th

roug

h th

e en

tire

dose

cyc

le.

• Hb

leve

ls th

roug

hout

mul

tiple

dos

e cy

cles

am

ong

subj

ects

who

did

not

requ

ire re

scue

wer

e ge

nera

lly h

ighe

st a

mon

g su

bjec

ts re

ceiv

ing

sota

terc

ept 0

.5 m

g/kg

(F

igur

e 5)

.

Figu

re 5

. Hb

Chan

ge F

rom

Bas

elin

e Du

ring

Long

-ter

m S

otat

erce

pt T

reat

men

t Cen

sore

d fo

r Res

cue

−3

−2

−101234

5010

015

020

025

0

Days

Afte

r the

Firs

t Dos

e

Hemoglobin (g/dL)

Sota

terc

ept 0

.3 m

g/kg

(n=

8)So

tate

rcep

t 0.5

mg/

kg (n

=5)

Plac

ebo

(n=

5)

Hom

e BP

Mea

sure

men

ts•

Hom

e BP

mea

sure

s in

the

first

dos

e cy

cle

reve

aled

that

all

3 gr

oups

had

incr

ease

s in

gro

up m

ean

SBP,

with

the

larg

est c

hang

e in

sub

ject

s re

ceiv

ing

sota

terc

ept

0.3

mg/

kg, w

hile

the

larg

est c

hang

e in

DBP

was

in s

ubje

cts

rece

ivin

g pl

aceb

o. A

ll th

e gr

oup

mea

n ch

ange

s w

ere

<10

mm

Hg

(Fig

ure

6A a

nd B

).

–Fi

ndin

gs w

ere

sim

ilar w

hen

anal

yzed

for b

oth

the

per-

prot

ocol

pop

ulat

ion

(Fig

ure

6A) a

nd F

AS (F

igur

e 6B

).

• W

ith lo

ng-t

erm

trea

tmen

t, ho

me

BP m

easu

res

show

ed n

o co

nsis

tent

cha

nge

from

bas

elin

e am

ong

subj

ects

in a

ny o

f the

trea

tmen

t gro

ups

(Fig

ure

7).

Figu

re 6

. Cha

nge

From

Bas

elin

e in

Hom

e BP

at t

he E

nd o

f Dos

e Cy

cle

1 in

the

(A) P

er-P

roto

col P

opul

atio

n*

and

(B) F

AS

Sota

terc

ept 0

.3 m

g/kg

(n=

7)

Sota

terc

ept 0

.5 m

g/kg

(n=

4)

Plac

ebo

(n=

3)

Sota

terc

ept 0

.3 m

g/kg

(n=

9)

Sota

terc

ept 0

.5 m

g/kg

(n=

5)

Plac

ebo

(n=

4)

Change From Baseline BP (mm Hg)

0.0

2.0

6.0

3.3

3.3

–0.3

–1

.0

0.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

SBP

DBP

A B

Change From Baseline BP (mm Hg)

2.3

7.5

3.0

2.5

7.6

0.4

0.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

8.0

SBP

DBP

*Dat

a ex

clud

e su

bjec

ts w

ith p

roto

col v

iola

tions

and

are

cen

sore

d fo

r tho

se w

ho re

quire

d re

scue

in th

e fir

st d

ose

cycl

e.

Figu

re 7

. Cha

nge

From

Bas

elin

e Ho

me

BP M

easu

rem

ents

(FAS

) of (

A) S

BP a

nd (B

) DBP

Dur

ing

Long

-ter

m

Sota

terc

ept T

reat

men

t, Ce

nsor

ed fo

r Res

cue

ASB

P

BDB

P

–20

–15

–10–50510152025

5010

015

020

025

0

Sota

terc

ept 0

.3 m

g/kg

(n=

9)So

tate

rcep

t 0.5

mg/

kg (n

=5)

Plac

ebo

(n=

4)

Home DBP (mm Hg)

–50

–40

–30

–20

–10010203040

5010

015

020

025

0

Sota

terc

ept 0

.3 m

g/kg

(n=

9)So

tate

rcep

t 0.5

mg/

kg (n

=5)

Plac

ebo

(n=

4)

Home SBP (mm Hg)

CONC

LUSI

ONS

• So

tate

rcep

t exh

ibite

d lin

ear P

K ch

arac

teris

tics,

and

a lo

ng h

alf-

life

of 2

2 to

25

days

.

• So

tate

rcep

t was

wel

l tol

erat

ed, w

ith A

Es s

imila

r to

thos

e ob

serv

ed w

ith p

lace

bo a

nd n

o tre

nds

tow

ard

incr

ease

d BP

.

• Ex

posu

re to

sot

ater

cept

was

not

ass

ocia

ted

with

the

deve

lopm

ent o

f ant

i-dru

g an

tibod

ies,

inje

ctio

n si

te re

actio

ns, o

r hyp

erse

nsiti

vity

reac

tions

.

• In

the

first

28

days

of t

reat

men

t, th

e pr

opor

tion

of s

ubje

cts

achi

evin

g th

e ta

rget

Hb

incr

ease

of ≥

1 g/

dL w

as g

reat

er in

the

treat

men

t gro

ups

than

in th

e pl

aceb

o gr

oup,

and

the

prop

ortio

n re

quiri

ng re

scue

ther

apy

in th

e fir

st 2

8 da

ys w

as d

ose-

rela

ted,

with

no

subj

ects

in th

e so

tate

rcep

t 0.5

mg/

kg g

roup

requ

iring

resc

ue.

• In

this

initi

al 2

8-da

y an

alys

is, i

n w

hich

the

plac

ebo

and

sota

terc

ept 0

.3 m

g/kg

gro

ups

had

high

er b

asel

ine

Hb, n

o di

ffere

nces

bet

wee

n gr

oups

ach

ievi

ng th

e ta

rget

Hb

rang

e (1

0-12

g/d

L) w

ere

obse

rved

. Dos

e es

cala

tion

cont

inue

s pe

r pro

toco

l.

• M

ean

peak

Hb

resp

onse

in th

e fir

st 2

8 da

ys w

as d

ose-

rela

ted,

with

the

sota

terc

ept 0

.5 m

g/kg

dos

e ha

ving

the

high

est m

ean

peak

Hb

resp

onse

.

• Hb

impr

ovem

ents

wer

e ge

nera

lly s

usta

ined

for m

ultip

le d

osin

g cy

cles

in th

e so

tate

rcep

t 0.5

mg/

kg d

ose

grou

p.

• Th

is p

relim

inar

y in

terim

ana

lysi

s in

dica

tes

adeq

uate

Hb

resp

onse

s an

d sa

fety

of s

otat

erce

pt a

t 0.3

and

0.5

mg/

kg a

nd p

rovi

des

evid

ence

to c

ontin

ue th

e ev

alua

tion

of s

otat

erce

pt a

t 0.7

mg/

kg in

pat

ient

s w

ith E

SKD

on h

emod

ialy

sis.

REFE

RENC

ES1.

Ba

bitt

JL, L

in H

Y. M

echa

nism

s of

ane

mia

in C

KD. J

Am

Soc

Nep

hrol

. 201

2;23

:163

1-16

34.

2.

Jaco

bson

LO,

Gol

dwas

ser E

, Frie

d W

, et a

l. Ro

le o

f the

kid

ney

in e

ryth

ropo

iesi

s. N

atur

e. 1

957;

179:

633-

634.

3.

McG

onig

le R

J, W

allin

JD,

Sha

dduc

k RK

, et a

l. Er

ythr

opoi

etin

defi

cien

cy a

nd in

hibi

tion

of e

ryth

ropo

iesi

s in

rena

l ins

uffic

ienc

y. Ki

dney

Int.

1984

;25:

437-

444.

4.

Esch

bach

JW

, Egr

ie J

C, D

owni

ng M

R, e

t al.

Corr

ectio

n of

the

anem

ia o

f end

-sta

ge re

nal d

isea

se w

ith re

com

bina

nt h

uman

ery

thro

poie

tin. R

esul

ts o

f a c

ombi

ned

phas

e I

and

II cl

inic

al tr

ial.

N En

gl J

Med

. 198

7;31

6:73

-78.

5.

Sing

h AK

, Szc

zech

L, T

ang

KL, e

t al.

Corr

ectio

n of

ane

mia

with

epo

etin

alfa

in c

hron

ic k

idne

y di

seas

e. N

Eng

l J M

ed. 2

006;

355:

208

5-20

98.

6.

Fish

bane

S. A

nem

ia a

nd c

ardi

ovas

cula

r ris

k in

the

patie

nt w

ith k

idne

y di

seas

e. H

eart

Fail

Clin

. 200

8;4:

401-

410.

7.

Besa

rab

A, B

olto

n W

K, B

row

ne J

K, e

t al.

The

effe

cts

of n

orm

al a

s co

mpa

red

with

low

hem

atoc

rit v

alue

s in

pat

ient

s w

ith c

ardi

ac d

isea

se w

ho a

re re

ceiv

ing

hem

odia

lysi

s an

d ep

oetin

. N E

ngl J

Med

. 199

8;33

9:58

4-59

0.

8.

Drue

ke T

B, L

ocat

elli

F, Cl

yne

N, e

t al.

Norm

aliz

atio

n of

hem

oglo

bin

leve

l in

patie

nts

with

chr

onic

kid

ney

dise

ase

and

anem

ia. N

Eng

l J M

ed. 2

006;

355:

2071

-208

4.

9.

Pfef

fer M

A, B

urdm

ann

EA, C

hen

CY, e

t al.

A tri

al o

f dar

bepo

etin

alfa

in ty

pe 2

dia

bete

s an

d ch

roni

c ki

dney

dis

ease

. N E

ngl J

Med

. 200

9;36

1:20

19-2

032.

10. P

ears

all R

S, C

anal

is E

, Cor

nwal

l-Bra

dy M

, et a

l. A

solu

ble

activ

in ty

pe II

A re

cept

or in

duce

s bo

ne fo

rmat

ion

and

impr

oves

ske

leta

l int

egrit

y. Pr

oc N

atl A

cad

Sci U

S A

. 20

08;1

05:7

082-

7087

.

11. I

ancu

-Rub

in C

, Mos

oyan

G, W

ang

J, e

t al.

Stro

mal

cel

l-med

iate

d in

hibi

tion

of e

ryth

ropo

iesi

s ca

n be

atte

nuat

ed b

y so

tate

rcep

t (AC

E-01

1), a

n ac

tivin

rece

ptor

type

II

ligan

d tra

p. E

xp H

emat

ol. 2

013;

41:1

55-1

66.

12. S

herm

an M

L, B

orgs

tein

NG,

Moo

k L,

et a

l. M

ultip

le-d

ose,

saf

ety,

phar

mac

okin

etic

, and

pha

rmac

odyn

amic

stu

dy o

f sot

ater

cept

(Act

RIIA

-IgG1

), a

nove

l ery

thro

poie

tic

agen

t, in

hea

lthy

post

men

opau

sal w

omen

. J C

lin P

harm

acol

. 201

3;53

:112

1-11

30.

13. W

oold

ridge

T, K

apla

n M

, Alc

orn

H Jr

, et a

l. Th

e ph

arm

acok

inet

ics

and

safe

ty o

f a s

ingl

e-do

se o

f sot

ater

cept

(ACE

-011

) in

subj

ects

on

hem

odia

lysi

s an

d th

e ef

fect

s of

its

mur

ine

anal

og (R

AP-0

11) o

n an

emia

and

in p

reve

ntin

g bo

ne lo

ss in

C57

BL/6

mic

e w

ith 5

/6 n

ephr

ecto

my

[ora

l pre

sent

atio

n]. P

rese

nted

at:

Amer

ican

Soc

iety

of

Neph

rolo

gy K

idne

y W

eek

2012

; Oct

ober

30-

Nove

mbe

r 4, 2

012;

San

Die

go, C

A.

This

stu

dy w

as s

pons

ored

by

Celg

ene

Corp

orat

ion.

Pres

ente

d at

: the

Nat

iona

l Kid

ney

Foun

datio

n (N

KF) 2

014

Sprin

g Cl

inic

al M

eetin

g; A

pril

22–2

6, 2

014;

Las

Veg

as, N

V.Sc

an th

is Q

R co

de to

rece

ive

the

PDF

of th

e po

ster








































– Discontinued:









and safety












up to 8 doses









Sotatercept

Parameter0.3 mg/kg

n=90.5 mg/kg

n=6


Cmax, mean (SD), μg/mL 2.4 (0.96) 3.5 (0.73)


t1/2,z, mean (SD), day 22.3 (3.0)* 24.5 (8.9)*†


Vz/F, mean (SD), mL/kg 117 (54)* 124 (27.9)*†



Seru

m S

otat

erce

pt (µ

g/m

L)

5

4

3

2

1

0


0 7 14 21 28








Placebo Sotatercept

n=50.3 mg/kg

n=90.5 mg/kg

n=6

Subjects, n (%)


Any AE 3 (60.0) 8 (88.8) 3 (50.0)

≥1 severe AE 2 (40.0) 2 (22.2) 2 (33.3)

≥1 serious AE 2 (40.0) 2 (22.2) 1 (16.7)

Death 1 (20.0) 0 (0.0) 0 (0.0)


Fatigue 1 (20.0) 2 (22.2) 0 (0.0)

Pain 0 (0.0) 2 (22.2) 0 (0.0)

Constipation 1 (20.0) 2 (22.2) 0 (0.0)

Hypertension 0 (0.0) 3 (33.3)* 0 (0.0)









0

30

20

10

40

60

50

70

80

90

100

Subj

ects

(%)

Placebo(n=5)

40

40

20


13

50

37


(n=5)

60

40

0.1-0.9 g/dL


≥1.0 g/dL











































Placebo, n=5 0 2 1 1 1 3 0



D/C=discontinued.


Placebo Sotatercept

n=50.3 mg/kg

n=90.5 mg/kg

n=6

Age, mean, years 58.4 59.9 60.7

Female, n (%) 1 (20.0) 6 (66.7) 1 (16.7)

Race, n (%)

White 1 (20.0) 3 (33.3) 4 (66.7)

Black 3 (60.0) 6 (66.7) 2 (33.3)

Asian 1 (20.0) 0 (0.0) 0 (0.0)

Ethnicity

Hispanic 0 (0.0) 2 (22.2) 4 (66.7)

Non-Hispanic 5 (100.0) 7 (77.8) 2 (33.3)










Placebo (n=5)

0.1

0.5

0.8

0

0.3

0.2

0.1

0.4

0.5

0.6

0.7

0.8

0.9

Hb (g

/dL)

Cha

nge

From

Bas

elin

e







−3

−2

−1

0

1

2

3

4

50 100 150 200 250


Hem

oglo

bin

(g/d

L)


Placebo (n=5)








Placebo (n=3)



Placebo (n=4)

Chan

ge F

rom

Bas

elin

e BP

(mm

Hg)

0.0

2.0

6.0

3.3 3.3

–0.3 –1.0

0.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

SBP DBP

A

B

Chan

ge F

rom

Bas

elin

e BP

(mm

Hg)

2.3

7.5

3.0 2.5

7.6

0.4

0.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

8.0

SBP DBP



A SBP

B DBP

–20

–15

–10

–5

0

5

10

15

20

25

50 100 150 200 250


Placebo (n=4)

Hom

e DB

P (m

m H

g)

–50

–40

–30

–20

–10

0

10

20

30

40

50 100 150 200 250


Placebo (n=4)

Hom

e SB

P (m

m H

g)
































































– Discontinued:









and safety












up to 8 doses









Sotatercept

Parameter0.3 mg/kg

n=90.5 mg/kg

n=6


Cmax, mean (SD), μg/mL 2.4 (0.96) 3.5 (0.73)


t1/2,z, mean (SD), day 22.3 (3.0)* 24.5 (8.9)*†


Vz/F, mean (SD), mL/kg 117 (54)* 124 (27.9)*†



Seru

m S

otat

erce

pt (µ

g/m

L)

5

4

3

2

1

0


0 7 14 21 28








Placebo Sotatercept

n=50.3 mg/kg

n=90.5 mg/kg

n=6

Subjects, n (%)


Any AE 3 (60.0) 8 (88.8) 3 (50.0)

≥1 severe AE 2 (40.0) 2 (22.2) 2 (33.3)

≥1 serious AE 2 (40.0) 2 (22.2) 1 (16.7)

Death 1 (20.0) 0 (0.0) 0 (0.0)


Fatigue 1 (20.0) 2 (22.2) 0 (0.0)

Pain 0 (0.0) 2 (22.2) 0 (0.0)

Constipation 1 (20.0) 2 (22.2) 0 (0.0)

Hypertension 0 (0.0) 3 (33.3)* 0 (0.0)









0

30

20

10

40

60

50

70

80

90

100

Subj

ects

(%)

Placebo(n=5)

40

40

20


13

50

37


(n=5)

60

40

0.1-0.9 g/dL


≥1.0 g/dL











































Placebo, n=5 0 2 1 1 1 3 0



D/C=discontinued.


Placebo Sotatercept

n=50.3 mg/kg

n=90.5 mg/kg

n=6

Age, mean, years 58.4 59.9 60.7

Female, n (%) 1 (20.0) 6 (66.7) 1 (16.7)

Race, n (%)

White 1 (20.0) 3 (33.3) 4 (66.7)

Black 3 (60.0) 6 (66.7) 2 (33.3)

Asian 1 (20.0) 0 (0.0) 0 (0.0)

Ethnicity

Hispanic 0 (0.0) 2 (22.2) 4 (66.7)

Non-Hispanic 5 (100.0) 7 (77.8) 2 (33.3)










Placebo (n=5)

0.1

0.5

0.8

0

0.3

0.2

0.1

0.4

0.5

0.6

0.7

0.8

0.9

Hb (g

/dL)

Cha

nge

From

Bas

elin

eMean Peak Hemoglobin Response






−3

−2

−1

0

1

2

3

4

50 100 150 200 250


Hem

oglo

bin

(g/d

L)


Placebo (n=5)








Placebo (n=3)



Placebo (n=4)

Chan

ge F

rom

Bas

elin

e BP

(mm

Hg)

0.0

2.0

6.0

3.3 3.3

–0.3 –1.0

0.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

SBP DBP

A

B

Chan

ge F

rom

Bas

elin

e BP

(mm

Hg)

2.3

7.5

3.0 2.5

7.6

0.4

0.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

8.0

SBP DBP



A SBP

B DBP

–20

–15

–10

–5

0

5

10

15

20

25

50 100 150 200 250


Placebo (n=4)

Hom

e DB

P (m

m H

g)

–50

–40

–30

–20

–10

0

10

20

30

40

50 100 150 200 250


Placebo (n=4)

Hom

e SB

P (m

m H

g)
































































– Discontinued:









and safety












up to 8 doses









Sotatercept

Parameter0.3 mg/kg

n=90.5 mg/kg

n=6


Cmax, mean (SD), μg/mL 2.4 (0.96) 3.5 (0.73)


t1/2,z, mean (SD), day 22.3 (3.0)* 24.5 (8.9)*†


Vz/F, mean (SD), mL/kg 117 (54)* 124 (27.9)*†



Seru

m S

otat

erce

pt (µ

g/m

L)

5

4

3

2

1

0


0 7 14 21 28








Placebo Sotatercept

n=50.3 mg/kg

n=90.5 mg/kg

n=6

Subjects, n (%)


Any AE 3 (60.0) 8 (88.8) 3 (50.0)

≥1 severe AE 2 (40.0) 2 (22.2) 2 (33.3)

≥1 serious AE 2 (40.0) 2 (22.2) 1 (16.7)

Death 1 (20.0) 0 (0.0) 0 (0.0)


Fatigue 1 (20.0) 2 (22.2) 0 (0.0)

Pain 0 (0.0) 2 (22.2) 0 (0.0)

Constipation 1 (20.0) 2 (22.2) 0 (0.0)

Hypertension 0 (0.0) 3 (33.3)* 0 (0.0)









0

30

20

10

40

60

50

70

80

90

100

Subj

ects

(%)

Placebo(n=5)

40

40

20


13

50

37


(n=5)

60

40

0.1-0.9 g/dL


≥1.0 g/dL











































Placebo, n=5 0 2 1 1 1 3 0



D/C=discontinued.


Placebo Sotatercept

n=50.3 mg/kg

n=90.5 mg/kg

n=6

Age, mean, years 58.4 59.9 60.7

Female, n (%) 1 (20.0) 6 (66.7) 1 (16.7)

Race, n (%)

White 1 (20.0) 3 (33.3) 4 (66.7)

Black 3 (60.0) 6 (66.7) 2 (33.3)

Asian 1 (20.0) 0 (0.0) 0 (0.0)

Ethnicity

Hispanic 0 (0.0) 2 (22.2) 4 (66.7)

Non-Hispanic 5 (100.0) 7 (77.8) 2 (33.3)










Placebo (n=5)

0.1

0.5

0.8

0

0.3

0.2

0.1

0.4

0.5

0.6

0.7

0.8

0.9

Hb (g

/dL)

Cha

nge

From

Bas

elin

e







−3

−2

−1

0

1

2

3

4

50 100 150 200 250


Hem

oglo

bin

(g/d

L)


Placebo (n=5)








Placebo (n=3)



Placebo (n=4)

Chan

ge F

rom

Bas

elin

e BP

(mm

Hg)

0.0

2.0

6.0

3.3 3.3

–0.3 –1.0

0.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

SBP DBP

A

B

Chan

ge F

rom

Bas

elin

e BP

(mm

Hg)

2.3

7.5

3.0 2.5

7.6

0.4

0.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

8.0

SBP DBP



A SBP

B DBP

–20

–15

–10

–5

0

5

10

15

20

25

50 100 150 200 250


Placebo (n=4)

Hom

e DB

P (m

m H

g)

–50

–40

–30

–20

–10

0

10

20

30

40

50 100 150 200 250


Placebo (n=4)

Hom

e SB

P (m

m H

g)

























Interim Analysis of ACE-011-REN-001: The First 28-Day Dose...

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Transcript of Interim Analysis of ACE-011-REN-001: The First 28-Day Dose...