Presented at the 56th Annual Meeting of the American Society of Hematology (ASH); San Francisco, CA, USA; December 6–9, 2014.

BACKGROUND BACKGROUND BACKGROUND• Anemia, a hallmark of myelodysplastic syndromes (MDS), is

challenging to treat, particularly after failure of erythropoiesis-stimulating agents (ESAs)1

• Sotatercept (ACE-011): – Is a novel and � rst-in-class activin type IIA receptor fusion protein2 (Figure 1) that acts on late-stage erythropoiesis to increase the release of mature erythrocytes into circulation3,4

– Inhibits SMAD2/3 signaling3

– Acts via a mechanism distinct from erythropoietin

• Sotatercept stimulated erythropoiesis and signi� cantly increased hemoglobin (Hb) levels in healthy volunteers,5 supporting its clinical development for the treatment of anemia in patients with lower-risk MDS

OB OB OBJECTIVJECTIVJECTIVEEE

• To determine a safe, tolerable, and effective dose of sotatercept in patients with anemia and International Prognostic Scoring System (IPSS)-de� ned Low- or Intermediate (Int)-1-risk MDS or non-proliferative chronic myelomonocytic leukemia (CMML)6

METHODSMETHODSMETHODS

Study Design • This is a phase 2, open-label, dose-� nding study; interim

data are presented• Patients received subcutaneous sotatercept at dose levels

0.1, 0.3, 0.5, or 1.0 mg/kg once every 3 weeks (Figure 2)

CONCLUSIONS CONCLUSIONS CONCLUSIONS

• Sotatercept was well tolerated in lower-risk MDS patients at the dose levels tested

• Sotatercept showed promising evidence of clinical activity in both HTB and LTB lower-risk MDS patients who were anemic and previously treated with ESAs, lenalidomide, hypomethylating agents, and/or other MDS therapies

• In LTB patients, erythroid responses with sustained mean Hb level increases of ≥ 1.5 g/dL were observed in the majority of patients in the absence of RBC transfusions ≥ 56 days

• These data support further exploration of higher sotatercept dose levels; longer-term treatment is ongoing in both HTB and LTB lower-risk MDS patients

References1. Fenaux P, et al. Blood. 2013;121:4280-6.2. Iancu-Rubin C, et al. Exp Hematol. 2013;

41:155-66.3. Carrancio S, et al. Br J Haematol. 2014;

165:870-82.

4. Dussiot M, et al. Nat Med. 2014;20:398-407.5. Sherman ML, et al. J Clin Pharmacol. 2013;

53:1121-30.6. Greenberg P, et al. Blood. 1997;89:2079-88.7. Cheson BD, et al. Blood. 2006;108:419-25.

AcknowledgmentsThis study was supported by Celgene Corporation, Summit, NJ, USA. The authors received editorial assistance and printing support in the preparation of this poster from Excerpta Medica (James O’Reilly, PhD) sponsored by Celgene Corporation. The authors are fully responsible for all content and editorial decisions.

P.F. and A.F.L. contributed equally to this poster as senior coauthors.

DisclosuresR.K.: Celgene Corporation – consultancy, research funding. G.G.-M.: Celgene Corporation – research funding. L.A., O.B.-R.: Celgene Corporation – research funding; Novartis – research funding. A.L.: Celgene Corporation – employment, equity ownership. B.V., J.Z.: Celgene Corporation – employment. T.P.: Celgene Corporation – honoraria. T.B.: US Oncology – research funding. M.A.S.: Celgene Corporation – board of directors or advisory committees; Amgen Corporation – board of directors or advisory committees; Boehringer-Ingelheim Corporation – board of directors or advisory committees. K.M.A.: Acceleron Pharma – employment. M.L.S.: Acceleron Pharma – employment, equity ownership. P.F.: Celgene Corporation – research funding; Janssen – research funding; Novartis – research funding. A.F.L.: Celgene Corporation – consultancy. A.S., J.D., D.P.S.: no con� icts of interest to disclose.

An Open-Label, Phase 2, Dose-Finding Study of Sotatercept (ACE-011) in Patients With Low- or Intermediate (Int)-1-Risk Myelodysplastic Syndromes (MDS) or Non-Proliferative

Chronic Myelomonocytic Leukemia (CMML) and Anemia Requiring Transfusion

P3251

Rami KomrokjiRami KomrokjiRami KomrokjiRami KomrokjiRami KomrokjiRami Komrokji111, Guillermo Garcia-Manero, Guillermo Garcia-Manero, Guillermo Garcia-Manero, Guillermo Garcia-Manero, Guillermo Garcia-Manero, Guillermo Garcia-Manero, Guillermo Garcia-Manero, Guillermo Garcia-Manero, Guillermo Garcia-Manero222, Lionel Ades, Lionel Ades, Lionel Ades333, Abderrahmane Laadem, Abderrahmane Laadem, Abderrahmane Laadem444, Bond Vo, Bond Vo, Bond Vo444, Thomas Prebet, Thomas Prebet, Thomas Prebet555, Aspasia Stamatoullas, Aspasia Stamatoullas, Aspasia Stamatoullas666, Thomas Boyd, Thomas Boyd, Thomas Boyd777, Jacques Delaunay, Jacques Delaunay, Jacques Delaunay888, David P. Steensma, David P. Steensma, David P. Steensma999, Mikkael A. Sekeres, Mikkael A. Sekeres, Mikkael A. Sekeres101010, , , Odile Beyne-RauzyOdile Beyne-RauzyOdile Beyne-Rauzy111111, Jun Zou, Jun Zou, Jun Zou444, Kenneth M. Attie, Kenneth M. Attie, Kenneth M. Attie121212, Matthew L. Sherman, Matthew L. Sherman, Matthew L. Sherman121212, Pierre Fenaux, Pierre Fenaux, Pierre Fenaux131313, Alan F. List, Alan F. List, Alan F. List141414

111Moffi tt Cancer Center, Tampa, FL, USA; Moffi tt Cancer Center, Tampa, FL, USA; Moffi tt Cancer Center, Tampa, FL, USA; Moffi tt Cancer Center, Tampa, FL, USA; Moffi tt Cancer Center, Tampa, FL, USA; Moffi tt Cancer Center, Tampa, FL, USA; 222University of Texas M.D. Anderson Cancer Center, Houston, TX, USA; University of Texas M.D. Anderson Cancer Center, Houston, TX, USA; University of Texas M.D. Anderson Cancer Center, Houston, TX, USA; 333Hôpital Saint-Louis, Paris, France; Hôpital Saint-Louis, Paris, France; Hôpital Saint-Louis, Paris, France; 444Celgene Corporation, Summit, NJ, USA; Celgene Corporation, Summit, NJ, USA; Celgene Corporation, Summit, NJ, USA; 555Institut Paoli Calmettes, Marseille, France; Institut Paoli Calmettes, Marseille, France; Institut Paoli Calmettes, Marseille, France; 666Centre Henri Becquerel, Rouen, France; Centre Henri Becquerel, Rouen, France; Centre Henri Becquerel, Rouen, France; 777North Star Lodge Cancer Center, Yakima, WA, USA; North Star Lodge Cancer Center, Yakima, WA, USA; North Star Lodge Cancer Center, Yakima, WA, USA; North Star Lodge Cancer Center, Yakima, WA, USA; North Star Lodge Cancer Center, Yakima, WA, USA; North Star Lodge Cancer Center, Yakima, WA, USA; 888CHU de Nantes – Hôtel Dieu, Nantes, France; CHU de Nantes – Hôtel Dieu, Nantes, France; CHU de Nantes – Hôtel Dieu, Nantes, France; 999Dana Farber Cancer Institute, Boston, MA, USA; Dana Farber Cancer Institute, Boston, MA, USA; Dana Farber Cancer Institute, Boston, MA, USA; 101010Leukemia Program, Cleveland Clinic, Cleveland, OH, USA; Leukemia Program, Cleveland Clinic, Cleveland, OH, USA; Leukemia Program, Cleveland Clinic, Cleveland, OH, USA; 111111Centre Hospitalier Universitaire Purpan, Pavillion de Médecines, Toulouse, France; Centre Hospitalier Universitaire Purpan, Pavillion de Médecines, Toulouse, France; Centre Hospitalier Universitaire Purpan, Pavillion de Médecines, Toulouse, France;

121212Acceleron Pharma, Cambridge, MA, USA; Acceleron Pharma, Cambridge, MA, USA; Acceleron Pharma, Cambridge, MA, USA; 131313Service d’Hématologie Séniors, Hôpital Saint-Louis, Université Paris 7, Paris, France; Service d’Hématologie Séniors, Hôpital Saint-Louis, Université Paris 7, Paris, France; Service d’Hématologie Séniors, Hôpital Saint-Louis, Université Paris 7, Paris, France; 141414Malignant Hematology, Moffi tt Cancer Center, Tampa, FL, USAMalignant Hematology, Moffi tt Cancer Center, Tampa, FL, USAMalignant Hematology, Moffi tt Cancer Center, Tampa, FL, USA

HTB Patients

• 19 of 45 HTB patients (42%) responded with a reduction in transfusion burden of ≥ 4 RBC units/56 days (Table 2)

– Duration of transfusion response appeared to be dose dependent

• 5 HTB patients (11%) achieved RBC-TI ≥ 56 days (Figure 3) – An example of RBC-TI ≥ 56 days achieved in an individual HTB patient in the sotatercept 1.0 mg/kg dose group is presented in Figure 4

– Duration of RBC-TI ranged from 59 to 345+ days

Changes in Platelet and Neutrophil Levels• Overall, increases in platelet levels of ≥ 30 × 109/L were

observed for 7 of 11 patients with baseline platelet levels < 100 × 109/L

– Baseline platelet counts were missing for 2 patients• Overall, increases in absolute neutrophil count (ANC) of

≥ 0.5 × 109/L were observed in 5 of 5 patients with baseline ANC of < 1.0 × 109/L

• Analysis of ANC and platelet hematologic improvement is ongoing

Safety• Sotatercept was generally well tolerated (Table 3)• 3 patients discontinued due to treatment-emergent adverse

events considered suspected related to sotatercept: 1 patient with grade 2 hemolytic anemia; 1 patient with grade 3 hypertension; and 1 patient with grade 2 muscle weakness in the 0.3, 0.5, and 1.0 mg/kg dose groups, respectively Scan this QR code to receive the PDF fi le of the poster

Sotatercept 0.1 mg/kg SC q3w

Sotatercept 0.3 mg/kg SC q3w

Sotatercept 0.5 mg/kg SC q3w

Sotatercept 2.0 mg/kg SC q3w

Sotatercept 1.0 mg/kg SC q3w

Enroll ≤ 20 evaluable patients per dose level

ResponseContinue

treatment q3w

No responseDiscontinuetreatment

Assesserythroid

hematologicresponseafter 5–8cycles oftreatment

Progressionor therapeutic

failureDiscontinuetreatment

Assess MDS and OS

every 6 months,up to

24 monthsfollowing

�rst treatment

Part 1: Dose finding

Part 2: Recommended dose (as determined by steering committee) in Part 1 carried over into Part 2 with enrollment of 15 additional patients

Figure 2. Study Design

MDS, myelodysplastic syndromes; OS, overall survival; q3w, every 3 weeks; SC, subcutaneous.

Extracelluardomain of ActRIIA

Fc domain of lgG1 antibody

Figure 1. Sotatercept (ACE-011) ActRIIA–Fc Fusion Protein

ActRIIA, activin receptor type IIA; Ig, immunoglobulin.

Key Eligibility Criteria• IPSS-de� ned Low- or Int-1-risk MDS or non-proliferative

CMML (white blood cell count < 13,000/µL)• Anemia (de� ned as Hb level ≤ 9.0 g/dL requiring transfusion

of ≥ 2 units of red blood cells [RBCs] in the 84 days prior to enrollment)

• No response, loss of response, or low chance of response to ESAs (re� ected by serum erythropoietin > 500 mIU/mL)

Study Endpoints• The primary ef� cacy endpoint was rate of erythroid

hematologic improvement (HI-E) as de� ned by modi� ed International Working Group (IWG) 2006 criteria7

• Secondary endpoints included rate of achievement of RBC-transfusion independence (TI) ≥ 56 days and safety

RESULTS RESULTS RESULTS

Baseline Characteristics• As of May 22, 2014, a total of 54 MDS patients were enrolled• Baseline characteristics are presented in Table 1

– 46 of 54 patients (85%) had a RBC transfusion burden of ≥ 4 units/56 days (high transfusion burden; HTB)

– 8 of 54 patients (15%) had a RBC transfusion burden of < 4 units/56 days (low transfusion burden; LTB)

Effi cacy • Of 53 patients evaluable for ef� cacy, HI-E (modi� ed IWG

2006 criteria) was achieved in 24 patients (45%): – 0.1 mg/kg: 0 patients (0%) – 0.3 mg/kg: 4 patients (67%) – 0.5 mg/kg: 8 patients (40%) – 1.0 mg/kg: 12 patients (60%)

• 1 patient in the 0.5 mg/kg dose group was excluded from ef� cacy analysis due to protocol violation

Table 1. Baseline Characteristics

CharacteristicSotatercept dose group

Overall(N = 54)0.1 mg/kg

(n = 7)0.3 mg/kg

(n = 6)0.5 mg/kg (n = 21)

1.0 mg/kg (n = 20)

Age, median (range), years 65 (58–79) 73 (66–86) 69 (56–82) 74 (60–84) 71 (56–86)

Female, n (%) 3 (43) 0 4 (19) 9 (45) 16 (30)

Time since original diagnosis, median (range), years

4 (1–6) 8 (4–10) 6 (<1–31) 3 (<1–20) 4 (<1–31)

RBC transfusion burden, median (range), units/8 weeks

9 (4–10) 8 (6–11) 6 (2–16) 6 (0–14) 6 (0–16)

RBC transfusion status, n (%)HTB (≥ 4 units/56 days) 7 (100) 6 (100) 18 (86) 15 (75) 46 (85)

LTB (< 4 units/56 days) 0 0 3 (14) 5 (25) 8 (15)

IPSS risk, n (%)Low 4 (57) 4 (67) 5 (24) 8 (40) 21 (39)

Int-1 3 (43) 2 (33) 16 (76) 12 (60) 33 (61)

Serum EPO level, n (%)≤ 500 mIU/mL 4 (57) 5 (83) 11 (52) 13 (65) 33 (61)

> 500 mIU/mL 3 (43) 1 (17) 8 (38) 6 (30) 18 (33)

Missing 0 0 2 (10) 1 (5) 3 (6)

Prior use of ESA, n (%) 6 (86) 6 (100) 20 (95) 20 (100) 52 (96)

Prior use of hypomethylating agents, n (%)

6 (86) 6 (100) 13 (62) 6 (30) 31 (57)

Prior use of lenalidomide, n (%) 5 (71) 5 (83) 10 (48) 6 (30) 26 (48)

Prior use of other MDS treatments, n (%)a 6 (86) 5 (83) 8 (38) 7 (35) 26 (48)

aNon-ESA, non-hypomethylating, and non-lenalidomide treatment for MDS.EPO, erythropoietin; ESA, erythropoiesis-stimulating agent; HTB, high transfusion burden; Int, Intermediate; IPSS, International Prognostic Scoring System; LTB, low transfusion burden; MDS, myelodysplastic syndromes; RBC, red blood cell.

0

10

20

30

40

50

60

70

80

90

100

HTB (n = 45)

LTB (n = 8)

Pat

ient

s (%

)

33%

NANA

80%

Sotatercept dose group

0.1 mg/kg 0.3 mg/kg 0.5 mg/kg 1.0 mg/kg

13%12%17%

0%

Figure 3. Proportion of Patients Achieving RBC-TI (HTB) or RBC-TI With Mean Hb Increase ≥ 1.5 g/dL (LTB) Over Any 8-Week Transfusion-Free Period

Hb, hemoglobin; HTB, high transfusion burden; LTB, low transfusion burden; NA, not applicable; RBC-TI, red blood cell transfusion independence.

Table 2. Transfusion Response Among HTB PatientsSotatercept dose group

Overall (N = 45)0.1 mg/kg

(n = 7)0.3 mg/kg

(n = 6)0.5 mg/kg (n = 17)

1.0 mg/kg (n = 15)

Transfusion burden reduction ≥ 4 RBC units/56 days, n (%)

0 4 (67) 7 (41) 8 (53) 19 (42)

Duration of longest response, median (range), days

NA68

(62–144)150

(83–345+)88

(62–154+)106

(62–345+)

RBC-TI ≥ 56 days, n (%) 0 1 (17) 2 (12) 2 (13) 5 (11)HTB, high transfusion burden; NA, not applicable; RBC, red blood cell; RBC-TI, RBC transfusion independence.

Table 3. Treatment-Emergent Adverse Events (TEAEs) Considered Suspected Related to Sotatercept

TEAE, n (%)Sotatercept dose group

Overall (N = 54)0.1 mg/kg

(n = 7)0.3 mg/kg

(n = 6)0.5 mg/kg (n = 21)

1.0 mg/kg (n = 20)

Patients with ≥ 1 TEAE 2 (29) 3 (50) 6 (29) 9 (45) 20 (37)

TEAEs occurring in ≥ 5% of patients

Fatigue/astheniaa 0 0 3 (14) 4 (20) 7 (13)

Headache 0 1 (17) 2 (10) 2 (10) 5 (9)

Decreased appetite 0 0 2 (10) 2 (10) 4 (7)

Nausea 0 0 3 (14) 1 (5) 4 (7)

Dyspnea 0 0 2 (10) 1 (5) 3 (6)

Grade 3–4 TEAEs 0 0 3 (14)b 0 3 (6)aPooled incidence of fatigue and asthenia.b 1 patient had grade 3 pain in both thighs; 1 patient had grade 3 hypertension; 1 patient had transformation to acute leukemia approximately 5.5 months after study treatment discontinuation (baseline WHO subtype: RAEB-1, end-of-treatment WHO subtype: RAEB-2). The investigator could not rule out a contributory role of sotatercept.

RAEB, refractory anemia with excess blasts; WHO, World Health Organization.

–209

0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

–188 –167 –146 –125 –104 –83 –62

Study day

Last dose +21 days

Hb

(g/d

L)

Num

ber of R

BC

transfusion units received

–41 –20 1a 22 43 64 85 106 127

Number of RBC units transfusedHb (central lab)Hb (local lab)b Sotatercept 1.0 mg/kg

Dosing period

Figure 4. Example of RBC-TI ≥ 56 Days Achieved in an Individual HTB Patient in the Sotatercept 1.0 mg/kg Dose Group

a8-week baseline RBC transfusion burden: 6 RBC units. bPre-transfusion Hb reported with pRBC transfusions.EPO, erythropoietin; ESA, erythropoiesis-stimulating agent; Hb, hemoglobin; HTB, high transfusion burden; IPSS, International Prognostic Scoring System; MDS, myelodysplastic syndromes; pRBC, packed RBC; RBC, red blood cell; RBC-TI, RBC transfusion independence; RCMD-RS, refractory cytopenia with multilineage dysplasia and ring sideroblasts; Tx, treatment; WHO, World Health Organization.

Baseline characteristics Original MDS diagnosis: Feb 2010WHO classi� cation: RCMD-RS IPSS risk: Low

Age: 77 yearsEPO level: 116 mIU/mLPrior ESA Tx: Approximately 6 months (max duration)

Other MDS Tx: Lenalidomide approximately 2 years (max duration)

LTB Patients

• Over any 8-week transfusion-free period, 5 of 8 patients (63%) achieved both a mean Hb increase ≥ 1.5 g/dL sustained for ≥ 56 days and RBC-TI ≥ 56 days (Figure 3)

– Maximum mean Hb increases ranged from 1.9 to 4.4 g/dL – Duration of RBC-TI ranged from 76 to 233+ days – Patients with Hb levels > 11.0 g/dL were subject to dose delay as per protocol, which may have impacted duration of Hb increase