Document


 
 
 
 
 

UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C.  20549
 
___________________________
 
FORM 8-K
 
CURRENT REPORT
Pursuant to Section 13 or 15(d) of the Securities Exchange Act of 1934
 
Date of Report (Date of earliest event reported):  December 1, 2018
 
___________________________
 
ACCELERON PHARMA INC.
(Exact name of Registrant as specified in its charter)
 

Delaware
(State or other jurisdiction
of incorporation)
 
001-36065
(Commission
File Number)
 
27-0072226
(I.R.S. Employer
Identification Number)
 
 
 
 
 
128 Sidney Street
Cambridge, MA
 (Address of principal
executive offices)
 
 
 
02139
(Zip Code)
 
Registrant’s telephone number, including area code:  (617) 649-9200
 
Not Applicable
(Former name or former address, if changed since last report)
 
Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions:
o            Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425)
o            Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12)
o            Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b))
o            Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c))
Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (§230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§240.12b-2 of this chapter).
Emerging growth company            o
If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act.            o
 
 
 
 
 




Item 7.01     Regulation FD Disclosure.

On December 1, 2018, Acceleron Pharma Inc. ("Acceleron") and Celgene Corporation ("Celgene") announced results from the pivotal, phase 3 trial (BELIEVE) evaluating the safety and efficacy of luspatercept for the treatment of adults with beta-thalassemia-associated anemia who require regular red blood cell (RBC) transfusions. The data were presented by Maria Domenica Cappellini, M.D. in an oral session of the 60th American Society of Hematology (ASH) Annual Meeting and Exposition in San Diego, CA. A copy of the presentation is attached as Exhibit 99.1 to this Current Report on Form 8-K.

On December 2, 2018, Acceleron and Celgene announced results from the pivotal, phase 3 MEDALIST trial evaluating the efficacy and safety of investigational luspatercept to treat patients with ring sideroblast (RS+) myelodysplastic syndromes (MDS)-associated anemia who require red blood cell transfusions and who had failed, were intolerant to, or ineligible for erythropoietin therapy. Results were presented by Alan F. List, M.D. of the Moffitt Cancer Center during the Plenary Scientific Session at the 60th ASH Annual Meeting and Exposition in San Diego, CA. A copy of the presentation is attached as Exhibit 99.2 to this Current Report on Form 8-K.

On December 3, 2018, Acceleron will host a previously announced conference call and live audio webcast to review the MEDALIST and BELIEVE phase 3 trial presentations of luspatercept that were presented at the 60th ASH Annual Meeting and Exposition in San Diego, CA.

A copy of this slide presentation to be presented during the conference call and webcast on December 3, 2018 is attached as Exhibit 99.3 to this Current Report on Form 8-K.

The information contained in Item 7.01 of this Current Report on Form 8-K and Exhibits 99.1, 99.2, and 99.3 attached hereto are being furnished and shall not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934, as amended (the “Exchange Act”) or for any other purpose, and shall not be deemed incorporated by reference in any filing under the Securities Act of 1933, as amended, or the Exchange Act, regardless of any general incorporation language in any such filing, except as expressly set forth by specific reference in such a filing.

Item 8.01     Other Events.

BELIEVE Data

BELIEVE met the primary endpoint of erythroid response, defined as a ≥33% reduction in RBC transfusion burden (with a reduction of ≥ 2 units of RBC) during weeks 13-24 compared to the baseline 12-week interval prior to randomization. The study also included secondary endpoints that evaluated the impact of treatment on RBC transfusion burden. Mean change in transfusion burden from baseline to weeks 13-24 (luspatercept vs. placebo) was -1.35 RBC units.

RBC Transfusion Burden Reduction of ≥ 33% Response Rates1\ 
Response Time Interval
Luspatercept
Placebo
P-value
Weeks 13-24
21.4% (48/224)
4.5% (5/112)
< 0.0001
Weeks 37-48
19.6% (44/224)
3.6% (4/112)
< 0.0001
Any 12 weeks during the entire treatment period
70.5% (158/224)
29.5% (33/112)
< 0.0001
Any 24 weeks during the entire treatment period
41.1% (92/224)
2.7% (3/112)
< 0.0001

RBC Transfusion Burden Reduction of ≥ 50% Response Rates1
Response Time Interval
Luspatercept
Placebo
P-value
Weeks 13-24
7.6% (17/224)
1.8% (2/112)
0.0303
Weeks 37-48
10.3% (23/224)
0.9% (1/112)
0.0017
Any 12 weeks during the entire treatment period
40.2% (90/224)
6.3% (7/112)
< 0.0001
Any 24 weeks during the entire treatment period
16.5% (37/224)
0.9% (1/112)
< 0.0001
1RBC transfusion burden reduction response rates are calculated versus baseline (i.e., the 12 weeks prior to randomization)

BELIEVE Safety Summary (Safety Population)


2



Grade 3 or higher treatment-emergent adverse events (TEAEs) were reported in 29.1% (65/223) of patients receiving luspatercept and 15.6% (17/109) of patients receiving placebo. Serious adverse events were reported in 15.2% (34/223) of patients receiving luspatercept and 5.5% (6/109) of patients receiving placebo. A TEAE of acute cholecystitis resulted in death in one placebo-treated patient (0.9%). No luspatercept-treated patients died due to TEAEs.

Grade 3 or 4 TEAEs in at least 1% of patients in either arm

 
Luspatercept
N= 223
Placebo
N= 109
Anemia
3.1%
0.0%
Increased liver iron concentration
2.7%
0.9%
Hyperuricemia
2.7%
0.0%
Hypertension
1.8%
0.0%
Syncope
1.8%
0.0%
Back pain
1.3%
0.9%
Bone pain
1.3%
0.0%
Blood uric acid increased
1.3%
0.0%
Increased aspartate aminotransferase
1.3%
0.0%
Increase alanine aminotransferase
0.9%
2.8%
Thromboembolic events*
0.9%
0.0%
*All grades of thromboembolic events, including DVT, PE, portal vein thrombosis, ischemic stroke, thrombophlebitis, and superficial phlebitis were reported in 8 of 223 (3.6%) luspatercept-treated versus 1 of 109 (0.9%) placebo-treated patients

MEDALIST Data

MEDALIST met the primary endpoint of red blood cell transfusion independence (RBC-TI) for 8 or more weeks during the first 24 weeks of the study. Treatment with luspatercept resulted in a statistically significantly greater proportion of patients achieving RBC-TI ≥ 8 weeks compared to placebo. The study also found in secondary endpoints that treatment with luspatercept resulted in a statistically significant higher percentage of patients achieving RBC-TI of 12 or more weeks in the first 24 or 48 weeks of the study, as well as hematologic improvement-erythroid (HI-E) of 8 or more weeks.

Endpoints
Luspatercept
Placebo
P-Value
RBC-TI ≥8 weeks (weeks 1-24)
37.9% (58/153)
13.2% (10/76)
< 0.0001
RBC-TI ≥12 weeks (weeks 1-24)
28.1% (43/153)
7.9% (6/76)
0.0002
RBC-TI ≥12 weeks (weeks 1-48)
33.3% (51/153)
11.8% (9/76)
0.0003
HI-E ≥ 8 weeks (IWG 2006, weeks 1-24)
52.9% (81/153)
11.8% (9/76)
< 0.0001

MEDALIST Safety Summary

Treatment-emergent adverse events (TEAEs) of Grade 3 or 4 were reported in 42.5% (65/153) of patients receiving luspatercept and 44.7% (34/76) of patients receiving placebo. Progression to acute myeloid leukemia (AML) occurred in four patients, three patients (2.0%) receiving luspatercept and one patient (1.3%) receiving placebo. Five patients receiving luspatercept (3.3%) and four patients receiving placebo (5.3%) experienced one or more TEAE that resulted in death.

Most common TEAEs of any Grade in Greater than 10% of Patients in Either Arm

3



 
Luspatercept
N=153
Placebo
N=76
Fatigue
26.8%
13.2%
Diarrhea
22.2%
9.2%
Asthenia
20.3%
11.8%
Nausea
20.3%
7.9%
Dizziness
19.6%
5.3%
Back pain
19.0%
6.6%
Luspatercept is not approved in any region for any indication. The companies are planning regulatory application submissions of luspatercept in the United States and Europe in the first half of 2019.


About BELIEVE

BELIEVE is a phase 3, randomized, double blind, placebo-controlled multicenter study comparing luspatercept + best supportive care (BSC) versus placebo + BSC in adult beta-thalassemia patients who require regular RBC transfusions. The median age of the patients was 30 years in both treatment arms. 336 patients were randomized 2:1 to receive either luspatercept 1.0 mg/kg + BSC (224 patients) or placebo + BSC (112 patients) every 3 weeks for up to 48 weeks. Patients in the luspatercept + BSC arm were able to be titrated up to 1.25 mg/kg of luspatercept every 3 weeks. BSC was defined as RBC transfusions and iron chelation therapy to maintain each patient’s baseline hemoglobin level. Crossover to the luspatercept treatment group was allowed after unblinding and assessment by an independent Data Safety Monitoring committee; patients receiving luspatercept + BSC will be followed for up to 3 years. The study was conducted at 65 sites in 15 countries.

About MEDALIST

MEDALIST is a phase 3, randomized, double blind, placebo-controlled, multi-center study evaluating the safety and efficacy of luspatercept in patients with very low-, low-, or intermediate-risk non-del(5q) myelodysplastic syndromes (MDS). All patients were RBC transfusion dependent and were either refractory or intolerant to prior erythropoiesis-stimulating agent (ESA) therapy, or were ESA naïve with endogenous serum erythropoietin ≥ 200 U/L, and had no prior treatment with disease modifying agents. The median age of the patients enrolled in the trial was 71 years in the luspatercept treatment group and 72 years in the placebo group. Median transfusion burden in both treatment arms was 5 RBC units/8 weeks. 229 patients were randomized to receive either luspatercept 1.0 mg/kg (153 patients) or placebo (76 patients) via subcutaneous injection once every 21 days. The study was conducted at 65 sites in 11 countries.

About Luspatercept
Luspatercept is a first-in-class erythroid maturation agent (EMA) that is believed to regulate late-stage red blood cell maturation. Acceleron and Celgene are jointly developing luspatercept as part of a global collaboration. Phase 3 clinical trials continue to evaluate the safety and efficacy of luspatercept in patients with MDS (the MEDALIST trial) and in patients with beta-thalassemia (the BELIEVE trial). A COMMANDS phase 3 trial in first-line, lower-risk, MDS patients, the BEYOND phase 2 trial in non-transfusion-dependent beta-thalassemia, and a phase 2 trial in myelofibrosis are ongoing. For more information, please visit www.clinicaltrials.gov.

Item 9.01    Financial Statements and Exhibits.
 
(d)    Exhibits.
        
Exhibit Number
 
Description of Exhibit
99.1
 
99.2
 
99.3
 


4



SIGNATURES
 
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
 

 
ACCELERON PHARMA INC.
 
 
 
 
 
By:
/s/ John D. Quisel, J.D., Ph.D.
 
 
John D. Quisel, J.D., Ph.D.
 
 
Executive Vice President and Chief Business Officer
 
 
 
Date: December 3, 2018
 
 


5
xlrn20181203ex991
Exhibit 99.1 The BELIEVE Trial: Results of a Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Luspatercept in Adult Beta-Thalassemia Patients Who Require Regular Red Blood Cell (RBC) Transfusions Maria Domenica Cappellini, Vip Viprakasit, Ali Taher, Pencho Georgiev, Kevin H.M. Kuo, Thomas Coates, Ersi Voskaridou, Hong Keng Liew, Idit Pazgal-Kobrowski, Gianluca Forni, Silverio Perrotta, Abderrahim Khelif, Ashutosh Lal, Antonis Kattamis, Efthymia Vlachaki, Raffaella Origa, Yesim Aydınok, Mohamed Bejaoui, P. Joy Ho, Lee Ping Chew, Ping Chong Bee, Soo Min Lim, Meng-Yao Lu, Adisak Tantiworawit, Penka Ganeva, Liana Gercheva, Farrukh Shah, Ellis J. Neufeld, Abderrahmane Laadem, Jeevan K. Shetty, Jun Zou, Dimana Miteva, Tatiana Zinger, Peter G. Linde, Matthew L. Sherman, Olivier Hermine, John Porter, Antonio Piga Presented at the 60th Annual Meeting of the American Society of Hematology (ASH); December 1–4, 2018; San Diego, CA, USA.


 
BELIEVE Trial BACKGROUND • β-thalassemia is a hereditary hemoglobinopathy due to a globin chain synthesis production defect, leading to ineffective erythropoiesis and anemia1–3 • Currently the standard of care for management of β-thalassemia is life-long red blood cell transfusions and iron chelation • In spite of iron chelation therapy, many patients experience multiple morbidities due to iron toxicity, including increased mortality • Therefore, there is a need for new treatment options for patients with β-thalassemia to reduce the dependence on transfusions and the associated morbidities4 1. Higgs DR, et al. Lancet. 2012;379:373-383. 2. Camaschella C, Nai A. Br J Haematol. 2016;172:512-523. 3. Taher AT, et al. Lancet. 2018;391:155-167. The BELIEVE Trial studied adult patients. 4. Taher AT, et al. Blood. 2018;132:1781-1791.


 
BELIEVE Trial LUSPATERCEPT • Luspatercept is an investigational first-in-class erythroid maturation agent that neutralizes select TGF-β superfamily ligands to inhibit aberrant Smad2/3 signaling and enhance late-stage erythropoiesis1,2 Luspatercept ActRIIB / IgG1 Fc recombinant fusion protein Modified TGF-β extracellular superfamily ligand ActRIIB domain of P ActRIIB Cytoplasm Smad2/3 Complex Nucleus Human IgG1 Fc domain Erythroid maturation ActRIIB, human activin receptor type IIB; IgG1 Fc, immunoglobulin G1 fragment crystallizable; TGF-β, transforming growth factor beta. 1. Attie KM, et al. Am J Hematol. 2014;89:766-770. The BELIEVE Trial studied adult patients. 2. Suragani RN, et al. Nat Med. 2014;20:408-414.


 
BELIEVE Trial A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PHASE 3 STUDY β-thalassemiaa patients Current study ≥ 18 years, statusc requiring regular Luspaterceptb RBC transfusions 1 mg/kg s.c. every 21 days + BSC (defined as: (n = 224) 6–20 RBC units in the Open- Post- 24 weeks prior to 2:1 May be titrated up to 1.25 mg/kg label treatment randomization with no b Study (up to 5 follow-up Randomized Placebo ≥ 35-day transfusion- unblinding years) (3 years) free period during that s.c. every 21 days + BSC time) (n = 112) (N = 336) 12-week period 12-week period Double-blind period Crossover permitted historical screening / run-in (48 weeks) transfusions transfusions a β-thalassemia or hemoglobin E / β-thalassemia (β-thalassemia with mutation and / or multiplication of α-globin was allowed. b RBC transfusions and iron chelation therapy to maintain each patient’s baseline hemoglobin level. c The trial is fully enrolled and patients continue to receive treatment or follow-up. BSC, best supportive care; RBC, red blood cell; s.c., subcutaneously. The BELIEVE Trial studied adult patients.


 
BELIEVE Trial STUDY DESIGN • Patients were randomized between July 2016 and June 2017 at 65 sites in 15 countries UNITED KINGDOM CANADA FRANCE ITALY BULGARIA UNITED STATES GREECE ISRAEL TAIWAN TUNISIA THAILAND TURKEY LEBANON MALAYSIA AUSTRALIA BELIEVE Trial studied adult patients.


 
BELIEVE Trial STUDY ENDPOINTS Primary endpoint: • ≥ 33% reduction from baseline in RBC transfusion burden (with a reduction of ≥ 2 RBC units) during weeks 13–24 Key secondary endpoints: • ≥ 33% reduction from baseline in RBC transfusion burden during weeks 37–48 • ≥ 50% reduction from baseline in RBC transfusion burden during weeks 13–24 • ≥ 50% reduction from baseline in RBC transfusion burden during weeks 37–48 • Mean change from baseline in RBC transfusion burden during weeks 13–24 Additional endpoint: • ≥ 33% or ≥ 50% reduction from baseline in RBC transfusion burden during any 12 weeks or 24 weeks on study The BELIEVE Trial studied adult patients.


 
BELIEVE Trial DEMOGRAPHICS AND BASELINE DISEASE CHARACTERISTICS Luspatercept Placebo Characteristic (n = 224) (n = 112) Age, median (range), years 30 (18–66) 30 (18–59) Female, n (%) 132 (58.9) 63 (56.3) β0/β0 n (%) 68 (30.4) 35 (31.3) Hemoglobin (24 week),a median (range), g/dL 9.31 (4.5–11.4) 9.15 (5.8–11.7) RBC transfusion burden, median (range), units/12 weeks 6.12 (3–14) 6.27 (3–12) RBC transfusion burden, median (range), units/24 weeks 14 (6–24) 15 (6–26) Splenectomy, n (%) 129 (57.6) 65 (58.0) Serum ferritin, median (range), μg/L 1,447 (88–6,400) 1,304 (136–6,400) LIC, median (range), mg/g dry weight 6.14 (0.8–125.0) 5.05 (0.2–53.2) > 7 mg/g dry weight, n (%) 103 (46.0) 45 (40.2) Myocardial iron by T2*, median (Q1–Q3), ms 34.7 (27.4–40.3) 36.3 (29.0–42.0) a Defined as the mean of all documented pre-transfusion hemoglobin values during the 24 weeks prior to first dose for each patient. LIC, liver iron concentration. The BELIEVE Trial studied adult patients.


 
BELIEVE Trial PRIMARY ENDPOINT MET: RATE OF ERYTHROID RESPONSE A significantly greater proportion of luspatercept-treated patients achieved a ≥ 33% reduction from baseline in transfusion burden during weeks 13 to 24 Luspatercept 30 Placebo P < 0.0001 (OR 5.79, 95% CI 2.24–14.97) 25 20 15 21.4% (n = 48) 10 Patients Achieving ≥ 33% 33% ≥ Achieving Patients 5 Transfusion Burden Reduction (%) Reduction Burden Transfusion 4.5% (n = 5) 0 Luspatercept Placebo (n = 224) (n = 112) CI, confidence interval; OR, odds ratio. The BELIEVE Trial studied adult patients.


 
BELIEVE Trial PRIMARY ENDPOINT: SUBGROUP ANALYSIS FAVORS LUSPATERCEPT Luspatercept Placebo Sub-groups OR (95% CI) P value n/N (%) n/N (%) Overall 48/224 (21.4) 5/112 (4.5) 5.79 (2.24, 14.97) < 0.0001 Region: North America & Europe 23/100 (23.0) 1/51(2.0) 14.94 (1.95, 114.12) 0.0009 Region: Middle East & North Africa 11/52 (21.2) 2/26 (7.7) 3.22 (0.66, 15.77) 0.1351 Region: Asia–Pacific 14/72 (19.4) 2/35 (5.7) 3.98 (0.85, 18.62) 0.0629 Age: ≤ 32 years 22/129 (17.1) 4/63 (6.3) 3.00 (0.98, 9.20) 0.0476 Age: > 32 years 26/95 (27.4) 1/49 (2.0) 17.50 (2.27, 134.98) 0.0004 Splenectomy: Yes 31/129 (24.0) 2/65 (3.1) 9.72 (2.22, 42.53) 0.0003 Splenectomy: No 17/95 (17.9) 3/47 (6.4) 2.94 (0.81, 10.69) 0.0918 Sex: Female 35/132 (26.5) 4/63 (6.3) 5.33 (1.80, 15.80) 0.0011 Sex: Male 13/92 (14.1) 1/49 (2.0) 8.05 (1.01, 64.16) 0.0218 β-thalassemia Gene: β0/β0 9/68 (13.2) 2/35 (5.7) 2.54 (0.48, 13.51) 0.2708 β-thalassemia Gene: Non-β0/β0 39/155 (25.2) 3/77 (3.9) 8.35 (2.47, 28.23) < 0.0001 Baseline Transfusion Burden: ≤ 6 units/12 weeks 27/112 (24.1) 3/56 (5.4) 5.61 (1.60, 19.65) 0.0033 Baseline Transfusion Burden: > 6 units/12 weeks 21/112 (18.8) 2/56 (3.6) 6.16 (1.38, 27.44) 0.0082 Baseline Hemoglobin: < 9 g/dL 22/87 (25.3) 4/51 (7.8) 3.78 (1.25, 11.42) 0.0128 Baseline Hemoglobin: ≥ 9 g/dL 26/137 (19.0) 1/61 (1.6) 14.17 (1.85, 108.79) 0.0012 Baseline Liver Iron: ≤ 3 mg/g dry weight 12/70 (17.1) 1/37 (2.7) 7.18 (0.88, 58.63) 0.0335 Baseline Liver Iron: > 3 to ≤ 7 mg/g dry weight 13/51 (25.5) 0/30 (0) Infinity 0.0053 Baseline Liver Iron: > 7 to ≤ 15 mg/g dry weight 10/38 (26.3) 1/19 (5.3) 5.41 (0.67, 43.34) 0.0741 Baseline Liver Iron: > 15 mg/g dry weight 13/65 (20.0) 3/26 (11.5) 1.79 (0.47, 6.78) 0.3831 0.1 1 10 100 Favors placebo Favors luspatercept The BELIEVE Trial studied adult patients.


 
BELIEVE Trial ALL KEY SECONDARY ENDPOINTS MET: RATES OF ERYTHROID RESPONSE A significantly greater proportion of luspatercept-treated patients achieved clinically meaningful reductions in transfusion burden of ≥ 33% and ≥ 50% 30 Luspatercept P < 0.0001a 25 Placebo 20 P = 0.0017c 15 P = 0.0303b 10 19.6 Burden Reduction (%) Reduction Burden 5 10.3 7.6 1.8 Patients Achieving Transfusion Achieving Patients 3.6 0.9 0 ≥ 33% ≥ 50% ≥ 50% (from week 37 to 48) (from week 13 to 24) (from week 37 to 48) • The least squares mean change in transfusion burden from baseline to weeks 13–24 (luspatercept versus placebo) was −1.35 RBC units/12 weeks (95% CI −1.77 to −0.93; P < 0.0001) a OR 6.44, 95% CI 2.27–18.26. b OR 4.55, 95% CI 1.03–20.11. c OR 11.92, 95% CI 1.65–86.29. The BELIEVE Trial studied adult patients.


 
BELIEVE Trial REDUCTION IN TRANSFUSION BURDEN DURING ANY 12- AND 24-WEEK INTERVAL During any 12- or 24-week interval, a significantly greater proportion of luspatercept-treated patients achieved clinically meaningful reductions in transfusion burden of ≥ 33% and ≥ 50% Any 12-week interval Any 24-week interval 100 100 Luspatercept P < 0.0001a Placebo 80 80 60 60 P < 0.0001b P < 0.0001c 40 40 P < 0.0001d 70.5 Burden Reduction (%) Reduction Burden 20 40.2 (%) Reduction Burden 20 41.1 16.5 29.5 6.3 Patients Achieving Transfusion Achieving Patients Patients Achieving Transfusion Transfusion Achieving Patients 2.7 0.9 0 0 ≥ 33% ≥ 50% ≥ 33% ≥ 50% a OR 5.69, 95% CI 3.46–9.35. b OR 9.95, 95% CI 4.44–22.33. c OR 25.02, 95% CI 7.76–80.71. d OR 20.37, 95% CI 2.86–144.94. The BELIEVE Trial studied adult patients.


 
BELIEVE Trial ADDITIONAL ENDPOINTS: IRON PARAMETERS Luspatercept Placebo LS Mean of 95% CI P Value (n = 224) (n = 112) Difference Mean change from baseline at week 48 Serum ferritin, μg/L (SD) −245 (780) 105 (521) −340 −502, −177 < 0.0001 LIC, mg/g dry weight (SD) 0.10 (5.760) 0.08 (5.229) 0.11 −1.16, 1.38 0.8685 Myocardial iron by T2*, ms (SD) −1.83 (15.084) 0.02 (6.843) −2.39 −4.67, −0.12 0.0391 SD, standard deviation. The BELIEVE Trial studied adult patients.


 
BELIEVE Trial SAFETY SUMMARY Luspatercept Placebo Treatment-Emergent Adverse Events, n (%) (n = 223a) (n = 109a) Patients with at least 1 TEAE (any grade) 214 (96.0) 101 (92.7) Patients with at least 1 grade TEAE (grade ≥ 3)b 65 (29.1) 17 (15.6) Patients with at least 1 serious TEAEc 34 (15.2) 6 (5.5) Patients with at least 1 TEAE resulting in the following: Deathd 01 (0.9) Study drug discontinuation 12 (5.4) 1 (0.9) a Safety population. b No one organ class or system was predominant.c Anemia was the only serious TEAE occurring in > 1% of patients in either arm (luspatercept, n = 3 [1.4%]; placebo, n = 0 [0%]). d TEAE of acute cholecystitis resulted in death in 1 of 109 (0.9%) placebo patients; no luspatercept-treated patients died due to TEAEs. TEAE, treatment-emergent adverse event. The BELIEVE Trial studied adult patients.


 
BELIEVE Trial TEAEs BY FREQUENCY ≥ 10% IN EITHER ARM (ALL GRADES) Luspatercept Placebo n (%) (n = 223a) (n = 109a) Back pain 61 (27.4) 32 (29.4) Upper respiratory tract infection 59 (26.5) 36 (33.0) Headache 58 (26.0) 26 (23.9) Bone pain 44 (19.7) 9 (8.3) Arthralgia 43 (19.3) 13 (11.9) Pyrexia 36 (16.1) 23 (21.1) Cough 32 (14.3) 12 (11.0) Fatigue 30 (13.5) 14 (12.8) Oropharyngeal pain 28 (12.6) 12 (11.0) Diarrhea 27 (12.1) 11 (10.1) Dizziness 25 (11.2) 5 (4.6) Asthenia 22 (9.9) 11 (10.1) Myalgia 22 (9.9) 11 (10.1) Pharyngitis 20 (9.0) 13 (11.9) a Safety population. The BELIEVE Trial studied adult patients.


 
BELIEVE Trial GRADE 3–4 TEAEs BY FREQUENCY ≥ 1% IN EITHER ARM Luspatercept Placebo n (%) (n = 223a) (n = 109a) Anemia 7 (3.1) 0 Increased LIC 6 (2.7) 1 (0.9) Hyperuricemia 6 (2.7) 0 Hypertension 4 (1.8) 0 Syncope 4 (1.8) 0 Back pain 3 (1.3) 1 (0.9) Bone pain 3 (1.3) 0 Blood uric acid increased 3 (1.3) 0 Increased AST 3 (1.3) 0 Increased ALT 2 (0.9) 3 (2.8) Thromboembolic eventsb 2 (0.9) 0 • In total, thromboembolic events (all grades) were reported in 8/223 (3.6%) luspatercept-treated patients (deep venous thrombosis, pulmonary embolism, portal vein thrombosis, ischemic stroke, thrombophlebitis, superficial phlebitis) and 1/109 (0.9%) placebo-treated patients (phlebitis). In all cases, patients had multiple risk factors for thromboembolic events a Safety population. b Thromboembolic events included as a TEAE of interest; other events occurring in < 1% of patients are not shown. ALT, alanine aminotransferase; AST, aspartate aminotransferase. The BELIEVE Trial studied adult patients.


 
BELIEVE Trial CONCLUSIONS • Luspatercept showed a statistically significant improvement in the primary endpoint of ≥ 33% reduction in transfusion burden compared with placebo • Statistical significance was also demonstrated with luspatercept versus placebo for all key secondary endpoints, including ≥ 33% and ≥ 50% reductions in transfusion burden • Luspatercept showed a statistically significant and clinically meaningful reduction in transfusion burden compared with placebo during any 12 or 24 weeks in the study period • Luspatercept was generally well tolerated in this patient population • Luspatercept is a potential new treatment for adult patients with β-thalassemia who require regular RBC transfusions The BELIEVE Trial studied adult patients.


 
BELIEVE Trial ACKNOWLEDGEMENTS • We thank all the patients, their families, and the investigators who participated in the study • This study was sponsored by Celgene Corporation, Summit, NJ, USA and Acceleron Pharma, Cambridge, MA, USA • The authors received editorial assistance from Excerpta Medica (Daria I. Grisanzio, PharmD), supported by Celgene Corporation and Acceleron Pharma


 
xlrn20181203ex992
Exhibit 99.2 The MEDALIST Trial: Results of a Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Luspatercept to Treat Patients With Very Low-, Low-, or Intermediate-Risk Myelodysplastic Syndromes (MDS) Associated Anemia With Ring Sideroblasts (RS) Who Require Red Blood Cell (RBC) Transfusions Pierre Fenaux, Uwe Platzbecker, Ghulam J. Mufti, Guillermo Garcia-Manero, Rena Buckstein, Valeria Santini, María Díez-Campelo, Carlo Finelli, Mario Cazzola, Osman Ilhan, Mikkael A. Sekeres, José F. Falantes, Beatriz Arrizabalaga, Flavia Salvi, Valentina Giai, Paresh Vyas, David Bowen, Dominik Selleslag, Amy E. DeZern, Joseph G. Jurcic, Ulrich Germing, Katharina S. Götze, Bruno Quesnel, Odile Beyne-Rauzy, Thomas Cluzeau, Maria Teresa Voso, Dominiek Mazure, Edo Vellenga, Peter L. Greenberg, Eva Hellström-Lindberg, Amer M. Zeidan, Abderrahmane Laadem, Aziz Benzohra, Jennie Zhang, Anita Rampersad, Peter G. Linde, Matthew L. Sherman, Rami S. Komrokji, Alan F. List


 
MEDALIST Trial Background and Rationale • Patients with lower-risk (LR)a transfusion-dependent MDS have a poorer prognosis, with greater risk of progression to AML and inferior overall survival compared with patients with transfusion-independent MDS • RBC transfusion-dependent LR, non-del(5q) MDS patients have a transient response to ESAs, with an attendant risk of iron overload and secondary organ complications • Few treatment options exist for the large number of patients with LR MDS who are either refractory to or become unresponsive to ESAs1 a IPSS-R-defined criteria. AML, acute myeloid leukemia; ESA, erythropoiesis-stimulating agent; IPSS-R, revised International Prognostic Scoring System; MDS, myelodysplastic syndromes; RBC, red blood cell. 1. Fenaux P, and Adès L. Blood. 2013;121:4280-4286.


 
MEDALIST Trial Luspatercept • Luspatercept is an investigational first-in-class erythroid maturation agent that neutralizes select TGF-β superfamily ligands to inhibit aberrant Smad2/3 signaling and enhance late-stage erythropoiesis in MDS models1 • In a phase 2 study in LR, non-del(5q) MDS, luspatercept yielded a high frequency of transfusion reduction or RBC-TI in patients with MDS-RS vs other subtypes2 Luspatercept ActRIIB / IgG1 Fc recombinant TGF-β fusion protein superfamily ActRIIB Modified ligand extracellular Cytoplasm P domain of Smad2/3 ActRIIB Nucleus Complex Human IgG1 Fc domain Erythroid maturation ActRIIB, human activin receptor type IIB; IgG1 Fc, immunoglobulin G1 fragment crystallizable; RBC-TI, red blood cell transfusion independence; 1. Suragani RN, et al. Nat Med. 2014;20:408-414; RS, ring sideroblasts; TGF-β, transforming growth factor beta. 2. Platzbecker U, et. A. Lancet Oncol. 2017; 18:1338.


 
MEDALIST Trial Study Design – A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study Patient Population Luspatercept 1.0 mg/kg (s.c.) every 21 days • MDS-RS (WHO): ≥ 15% RS or ≥ 5% with SF3B1 n = 153 mutation Randomize Dose titrated up to a maximum of 1.75 mg/kg • < 5% blasts in bone marrow 2:1 • No del(5q) MDS Placebo (s.c.) every 21 days • IPSS-R Very Low-, Low-, or Intermediate-risk n = 76 • Prior ESA response – Refractory, intolerant Disease & Response Assessment week 24 & every 6 months Treatment discontinued for lack of clinical benefit or disease – ESA naive: EPO > 200 U/L progression per IWG criteria; no crossover allowed • Average RBC transfusion burden ≥ 2 units/8 weeks • No prior treatment with disease-modifying Subjects followed ≥ 3 years postp final dose for AML agents (e.g. iMIDs, HMAs) progression, subsequent MDS treatment and overall survival Data cutoff: May 8, 2018 Includes last subject randomized + 48 weeks. EPO, erythropoietin; HMA, hypomethylating agent; iMID, immunomodulatory drug; IWG, International Working Group; s.c., subcutaneously; SF3B1, splicing factor 3b subunit 1; WHO, World Health Organization.


 
MEDALIST Trial Study Design (cont.) • Patients were randomized between March 2016 and June 2017 at 65 sites in Belgium, Canada, France, Germany, Italy, the Netherlands, Spain, Sweden, Turkey, UK, and USA


 
MEDALIST Trial Study Endpoints Primary endpoint: • Red blood cell transfusion independence ≥ 8 weeks (weeks 1–24) Key secondary endpoint: • Red blood cell transfusion independence ≥ 12 weeks (weeks 1–24 and weeks 1–48) Additional secondary endpoints: • HI-E (IWG 2006 criteria1) for any consecutive 56-day period – Reduction in red blood cell transfusion burden ≥ 4 RBC units/8 weeksa or – Mean Hb increase of ≥ 1.5 g/dL/8 weeksb • Duration of response • Hb change from baseline a In patients with baseline RBC transfusion burden ≥ 4 units/8 weeks. b In patients with baseline RBC transfusion burden < 4 units/8 weeks. Hb, hemoglobin; HI-E, hematological improvement–erythroid. 1. Cheson BD, et al. Blood. 2006;108:419-425.


 
MEDALIST Trial Demographics and Baseline Disease Characteristics Luspatercept Placebo Characteristic (n = 153) (n = 76) Age, median (range), years 71 (40–95) 72 (26–91) Male, n (%) 94 (61.4) 50 (65.8) Time since original MDS diagnosis, median (range), months 44.0 (3–421) 36.1 (4–193) WHO classification RCMD-RS, n (%) 145 (94.8) 74 (97.4) RBC transfusion burden, median (range), units/8 weeksa 5 (1–15) 5 (2–20) ≥ 6 units/8 weeks, n (%) 66 (43.1) 33 (43.4) < 6 units/8 weeks, n (%) 87 (56.9) 43 (56.6) Pre-transfusion Hb, median (range), g/dL 7.6 (6–10) 7.6 (5–9) IPSS-R risk categoryb Very Low, Low, n (%) 127 (83.0) 63 (82.9) Intermediate, n (%) 25 (16.3) 13 (17.1) SF3B1 mutation, n (%) 141 (92.2) 65 (85.5)c Serum EPO < 200 U/L, n (%) 88 (57.5)c 50 (65.8) ≥ 200 U/L, n (%) 64 (41.8)c 26 (34.2) a In the 16 weeks prior to randomization. b 1 (0.7%) patient in the luspatercept arm was classified as IPSS-R High-risk. c Data were missing for 1 patient. RCMD-RS, refractory cytopenia with multilineage dysplasia with RS.


 
MEDALIST Trial Treatment Exposure Luspatercept Placebo Parameter (n = 153) (n = 76) Treatment duration, median (range), weeks 49 (6–114) 24 (7–89) Completed ≥ 24 weeks of treatment (primary phase), n (%) 128 (83.7) 68 (89.5) Completed ≥ 48 weeks of treatment, n (%) 78 (51.0) 12 (15.8) Number of doses received, median (range) 16 (2–37) 8 (3–30) Maximum dose escalation, n (%)a 1.0 mg/kg 35 (22.9) 5 (6.6) 1.33 mg/kg 28 (18.3) 8 (10.5) 1.75 mg/kg 90 (58.8) 63 (82.9) Patients remaining on treatment, n (%) 70 (45.8) 6 (7.9) Patients discontinued from treatment, n (%) 83 (54.2) 70 (92.1) Lack of benefit 51 (33.3) 50 (65.8) Patient withdrawal 14 (9.2) 10 (13.2) AE 10 (6.5) 4 (5.3) Disease progression 3 (2.0) 2 (2.6) Other 5 (3.3) 4 (5.3) a Dose may be titrated up to a maximum of 1.75 mg/kg. AE, adverse event.


 
MEDALIST Trial Primary Endpoint: Red Blood Cell Transfusion Independence ≥ 8 Weeks Luspatercept Placebo RBC-TI ≥ 8 weeks (n = 153) (n = 76) Weeks 1–24, n (%) 58 (37.9) 10 (13.2) 95% CI 30.2–46.1 6.5–22.9 P valuea < 0.0001 a Cochran–Mantel–Haenszel test stratified for average baseline RBC transfusion requirement (≥ 6 units vs < 6 units of RBCs/8 weeks) and baseline IPSS-R score (Very Low or Low vs Intermediate). CI, confidence interval.


 
MEDALIST Trial Primary Endpoint: Subgroup Analysis Luspatercept, n (%) Placebo, n (%) OR (95% CI) P Value Overall 58/153 (37.9) 10/76 (13.2) 5.06 (2.28–11.3) < 0.0001 Average baseline RBC transfusion requirement ≥ 6 units/8 weeks 6/66 (9.1) 1/33 (3.0) 3.20 (0.37–27.7) 0.2699 < 6 units/8 weeks 52/87 (59.8) 9/43 (20.9) 5.61 (2.40–13.1) < 0.0001 4 to < 6 units/8 weeks 15/41 (36.6) 1/23 (4.3) 12.7 (1.55–104) 0.0046 < 4 units/8 weeks 37/46 (80.4) 8/20 (40.0) 6.17 (1.95–19.5) 0.0013 Baseline serum EPO (U/L) < 100 23/51 (45.1) 7/31 (22.6) 2.82 (1.03–7.71) 0.0413 100 to < 200 14/37 (37.8) 2/19 (10.5) 5.17 (1.04–25.9) 0.0338 200–500 17/43 (39.5) 1/15 (6.7) 9.15 (1.10–76.2) 0.0188 Age group ≤ 64 years 17/29 (58.6) 3/16 (18.8) 6.14 (1.43–26.3) 0.0108 65–74 years 23/72 (31.9) 4/29 (13.8) 2.93 (0.91–9.41) 0.0635 ≥ 75 years 18/52 (34.6) 3/31 (9.7) 4.94 (1.32–18.5) 0.0120 Gender Male 32/94 (34.0) 4/50 (8.0) 5.94 (1.96–18.0) 0.0006 Female 26/59 (44.1) 6/26 (23.1) 2.63 (0.92–7.48) 0.0673 Time since initial diagnosis at baseline ≤ 2 years 14/40 (35.0) 3/19 (15.8) 2.87 (0.71–11.6) 0.1312 > 2–5 years 30/62 (48.4) 4/34 (11.8) 7.03 (2.21–22.3) 0.0004 > 5 years 14/51 (27.5) 3/23 (13.0) 2.52 (0.65–9.83) 0.1756 Baseline IPSS-R risk Very Low or Low 48/127 (37.8) 9/63 (14.3) 3.65 (1.65–8.05) 0.0009 Intermediate 10/25 (40.0) 1/13 (7.7) 8.00 (0.89–71.6) 0.0398 Baseline platelet count < 100 u 109/L 2/8 (25.0) 1/6 (16.7) 1.67 (0.11–24.3) 0.7171 100–400 u 109/L 42/128 (32.8) 8/61 (13.1) 3.24 (1.41–7.42) 0.0042 > 400 u 109/L 14/17 (82.4) 1/9 (11.1) 37.3 (3.31–422) 0.0006 0 0.1 0.25 0.5 2 10 20 100 1,500 OR, odds ratio. Favors placebo Favors luspatercept


 
MEDALIST Trial Key Secondary Endpoint: Red Blood Cell Transfusion Independence ≥ 12 Weeks Luspatercept Placebo RBC-TI ≥ 12 Weeks (n = 153) (n = 76) Weeks 1–24, n (%) 43 (28.1) 6 (7.9) 95% CI 21.14–35.93 2.95–16.40 P valuea 0.0002 Weeks 1–48, n (%) 51 (33.3) 9 (11.8) 95% CI 25.93–41.40 5.56–21.29 P valuea 0.0003 a Cochran–Mantel–Haenszel test stratified for average baseline RBC transfusion requirement (≥ 6 units vs < 6 units of RBCs/8 weeks) and baseline IPSS-R score (Very Low or Low vs Intermediate).


 
MEDALIST Trial Duration of RBC-TI Response in Primary Endpoint Responders 1.0 Median duration (weeks) (95% CI): 30.6 (20.6–40.6) vs 13.6 (9.1–54.9) 0.9 Luspatercept 0.8 Placebo 0.7 Censored 0.6 0.5 RBC-TI 0.4 0.3 0.2 0.1 Probability Probability of Maintaining 0 0 10 20 30 40 50 60 70 80 90 100 110 120 Duration of RBC-TIa (week) Number of patients Luspatercept 58 49 37 29 22 18 10 6 3 2 1 1 0 Placebo 10932220 a During indicated treatment period. Patients who maintained RBC-TI at the time of analysis are censored.


 
MEDALIST Trial Secondary Endpoint: Erythroid Response (HI-E) Luspatercept Placebo (n = 153) (n = 76) Achieved HI-Ea (weeks 1–24), n (%) 81 (52.9) 9 (11.8) Reduction of ≥ 4 RBC units/8 weeks (baseline transfusion burden ≥ 4 units/8 weeks) 52/107 (48.6) 8/56 (14.3) Hb increase of ≥ 1.5 g/dL (baseline transfusion burden < 4 units/8 weeks) 29/46 (63.0) 1/20 (5.0) 95% CI 44.72–61.05 5.56–21.29 P valueb <0.0001 Achieved HI-Ea (weeks 1–48), n (%) 90 (58.8) 13 (17.1) Reduction of ≥ 4 RBC units/8 weeks (baseline RBC transfusion burden ≥ 4 units/8 weeks) 58/107 (54.2) 12/56 (21.4) Hb increase of ≥ 1.5 g/dL (baseline RBC transfusion burden < 4 units/8 weeks) 32/46 (69.6) 1/20 (5.0) 95% CI 50.59–66.71 9.43–27.47 P valueb <0.0001 a Defined as the proportion of patients meeting the HI-E criteria per IWG 2006 criteria (Cheson et al. 2006) sustained over a consecutive 56-day period during the indicated treatment period. b Luspatercept compared with placebo, Cochran–Mantel–Haenszel test.


 
MEDALIST Trial Change3 in Hemoglobin Concentration Responder receiving luspatercept Non-responder receiving luspatercept Placebo 2 1 SE) FromBaseline (g/dL) ± 0 -1 11/5/2018Baseline 1 211/26/20183 12/17/20186 1/7/2019912 1/28/201913 2/18/201915 3/11/2019 18 4/1/2019 21 4/22/201924 Hb MeanChange( Analysis Week Visit • Median peak hemoglobin increase in luspatercept responders: 2.55 g/dL (1–4.1 g/dL) Number of patients Respondera 24 36 55 53 52 50 42 47 50 42 45 153 Non-responder 33 51 61 52 60 53 34 45 56 48 35 Placebo 76 32 36 41 47 44 52 29 44 47 44 32 a LS mean difference (95% CI) for luspatercept responders versus placebo: 1.08 (0.84, 1.31), P < 0.0001. Only patients with RBC-TI ≥ 8 weeks during weeks 1–24 are included. Hb measurement was excluded within 14 days after a RBC transfusion unless within 3 days prior to another RBC transfusion. Mean and SE were not calculated if the number of patients was < 8 in the luspatercept non-responder group or < 4 in the placebo group. SE, standard error.


 
MEDALIST Trial Safety Summary Luspatercept Placebo (n = 153) (n = 76) Patients with ≥ 1 TEAE, n (%) 150 (98.0) 70 (92.1) Patients with ≥ 1 serious TEAE 48 (31.4) 23 (30.3) Patients with ≥ 1 Grade 3 or 4 TEAE 65 (42.5) 34 (44.7) Patients with TEAEs leading to deatha 5 (3.3) 4 (5.3) Patients with ≥ 1 TEAE causing discontinuation, n (%) 13 (8.5) 6 (7.9) • TEAEs were balanced between the armsb • Progression to AML occurred in 4 patients (3/153 [2.0%] in the luspatercept arm; 1/76 [1.3%] in the placebo arm) a In luspatercept arm: sepsis (n = 2), multiple organ dysfunction syndrome, renal failure, and hemorrhagic shock; in placebo arm: sepsis, urosepsis, general physical health deterioration, and respiratory failure. b The most common grade 3 or 4 TEAEs reported in luspatercept-treated patients were anemia (6.5% of patients), fall (4.6%), and fatigue (4.6%). TEAE, treatment-emergent adverse event.


 
MEDALIST Trial TEAEs ≥ 10% Incidence in Either Arm Luspatercept Placebo n (%) (n = 153) (n = 76) Fatigue 41 (26.8) 10 (13.2) Diarrhea 34 (22.2) 7 (9.2) Asthenia 31 (20.3) 9 (11.8) Nausea 31 (20.3) 6 (7.9) Dizziness 30 (19.6) 4 (5.3) Back pain 29 (19.0) 5 (6.6) Cough 27 (17.6) 10 (13.2) Edema peripheral 25 (16.3) 13 (17.1) Headache 24 (15.7) 5 (6.6) Dyspnea 23 (15.0) 5 (6.6) Bronchitis 17 (11.1) 1 (1.3) Constipation 17 (11.1) 7 (9.2) Urinary tract infection 17 (11.1) 4 (5.3) Fall 15 (9.8) 9 (11.8) TEAEs ≥ 10% incidence in either arm by preferred term


 
MEDALIST Trial Conclusions • In lower-risk, RS-positive MDS, treatment with luspatercept resulted in a significantly higher percentage of patients who achieved RBC-TI, major RBC transfusion reduction, or hemoglobin increase, compared with placebo • Erythroid responses were durable, with approximately 40% of patients achieving RBC-TI sustained at 12 months of treatment • Luspatercept was generally well tolerated in this patient population • Luspatercept is a potential new therapy for the treatment of patients with lower-risk, RS-positive MDS with RBC transfusion-dependent anemia


 
Acknowledgements • We thank all the patients, families, and investigators who participated in the study • This study was sponsored by Celgene Corporation, Summit, NJ, USA and Acceleron Pharma, Cambridge, MA, USA • The authors received editorial assistance from Excerpta Medica (Miriam de Boeck, Emily Poulin, PhD), supported by Celgene Corporation and Acceleron Pharma • The authors are fully responsible for all content and editorial decisions for this presentation


 
xlrn20181203ex993
Exhibit 99.3 ASH 2018 MEDALIST & BELIEVE Phase 3 Trial Presentation Highlights December 3, 2018


 
ASH 2018 Call Agenda Introduction Welcome/Agenda – Todd James, IRC Luspatercept and ASH 2018 Overview – Habib Dable MEDALIST Phase 3 Trial Results Phase 3 Results Alan F. List, M.D. – Moffitt Cancer Center BELIEVE Phase 3 Trial Results Maria Domenica Cappellini, M.D. – University of Milan Summary/Closing Luspatercept and ASH 2018 Summary - Habib Dable Q&A 2


 
Acceleron Forward-Looking Statements THIS PRESENTATION CONTAINS FORWARD-LOOKING STATEMENTS ABOUT THE COMPANY’S STRATEGY, FUTURE PLANS and prospects, including statements regarding the development of the Company's compounds, the timeline for clinical development and regulatory approval of the Company’s compounds and the expected timing for reporting of data from ongoing clinical trials. The words “anticipate,” “believe,” “could,” “estimate,” “expect,” “goal,” “intend,” “may,” “plan,” “potential,” “project,” “should,” “target,” “will,” “would,” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. ACTUAL RESULTS COULD DIFFER MATERIALLY FROM THOSE INCLUDED IN THE FORWARD-LOOKING STATEMENTS DUE to various factors, risks and uncertainties, including, but not limited to, that preclinical testing of the Company's compounds and data from clinical trials may not be predictive of the results or success of ongoing or later clinical trials, that the results of any clinical trial may not be predictive of the results or success of other clinical trials of the same product candidate, that the development of the Company's compounds will take longer and/or cost more than planned, that the Company, or its collaboration partner, Celgene, will be unable to successfully complete the clinical development of the Company’s compounds, that the Company, or Celgene, may be delayed in initiating, enrolling or completing any clinical trials, and that the Company's compounds will not receive regulatory approval or become commercially successful products. These and other risks and uncertainties are identified under the heading "Risk Factors" included in the Company's most recent Annual Report on Form 10-K, and other filings that the Company has made and may make with the SEC in the future. THE FORWARD-LOOKING STATEMENTS CONTAINED IN THIS PRESENTATION ARE BASED ON MANAGEMENT’S CURRENT views, plans, estimates, assumptions and projections with respect to future events, and the Company does not undertake and specifically disclaims any obligation to update any forward-looking statements. 3


 
Habib Dable Chief Executive Officer


 
Building a Platform Treatment for Anemia with Luspatercept Phase 1 Phase 2 Phase 3 Hematology Luspatercept MEDALIST Phase 3 Trial Myelodysplastic Syndromes (MDS) COMMANDS Phase 3 Trial BELIEVE Phase 3 Trial Beta-Thalassemia BEYOND Phase 2 Trial MF Phase 2 Myelofibrosis (MF) Phase 2 Base/Extension MDS/Beta-Thalassemia Additional indications being evaluated and prioritized for future clinical trials 5


 
MEDALIST and BELIEVE Phase 3 Trial Presentations ƒ Session: Plenary Scientific Session ƒ Session: Thalassemia Globin Gene Regulation: Clinical ƒ Date: Sunday, December 2nd ƒ Date: Saturday, December 1st 6


 
Alan F. List, M.D. President and CEO of Moffitt Cancer Center, Senior member in the Department of Malignant Hematology and the Experimental Therapeutics Program; Professor of Internal Medicine and Oncology at the University of South Florida Morsani College of Medicine 7


 
The MEDALIST Trial: Results of a Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Luspatercept to Treat Patients With Very Low-, Low-, or Intermediate-Risk Myelodysplastic Syndromes (MDS) Associated Anemia With Ring Sideroblasts (RS) Who Require Red Blood Cell (RBC) Transfusions Pierre Fenaux, Uwe Platzbecker, Ghulam J. Mufti, Guillermo Garcia-Manero, Rena Buckstein, Valeria Santini, María Díez-Campelo, Carlo Finelli, Mario Cazzola, Osman Ilhan, Mikkael A. Sekeres, José F. Falantes, Beatriz Arrizabalaga, Flavia Salvi, Valentina Giai, Paresh Vyas, David Bowen, Dominik Selleslag, Amy E. DeZern, Joseph G. Jurcic, Ulrich Germing, Katharina S. Götze, Bruno Quesnel, Odile Beyne-Rauzy, Thomas Cluzeau, Maria Teresa Voso, Dominiek Mazure, Edo Vellenga, Peter L. Greenberg, Eva Hellström-Lindberg, Amer M. Zeidan, Abderrahmane Laadem, Aziz Benzohra, Jennie Zhang, Anita Rampersad, Peter G. Linde, Matthew L. Sherman, Rami S. Komrokji, Alan F. List


 
MEDALIST Trial Background and Rationale • Patients with lower-risk (LR)a transfusion-dependent MDS have a poorer prognosis, with greater risk of progression to AML and inferior overall survival compared with patients with transfusion-independent MDS • RBC transfusion-dependent LR, non-del(5q) MDS patients have a transient response to ESAs, with an attendant risk of iron overload and secondary organ complications • Few treatment options exist for the large number of patients with LR MDS who are either refractory to or become unresponsive to ESAs1 a IPSS-R-defined criteria. AML, acute myeloid leukemia; ESA, erythropoiesis-stimulating agent; IPSS-R, revised International Prognostic Scoring System; MDS, myelodysplastic syndromes; RBC, red blood cell. 1. Fenaux P, and Adès L. Blood. 2013;121:4280-4286.


 
MEDALIST Trial Luspatercept • Luspatercept is a first-in-class erythroid maturation agent that neutralizes select TGF-β superfamily ligands to inhibit aberrant Smad2/3 signaling and enhance late-stage erythropoiesis in MDS models1 • In a phase 2 study in LR, non-del(5q) MDS, luspatercept yielded a high frequency of transfusion reduction or RBC-TI in patients with MDS-RS vs other subtypes2 Luspatercept ActRIIB / IgG1 Fc recombinant TGF-β fusion protein superfamily ActRIIB Modified ligand extracellular Cytoplasm P domain of Smad2/3 ActRIIB Nucleus Complex Human IgG1 Fc domain Erythroid maturation ActRIIB, human activin receptor type IIB; IgG1 Fc, immunoglobulin G1 fragment crystallizable; RBC-TI, red blood cell transfusion independence; 1. Suragani RN, et al. Nat Med. 2014;20:408-414; RS, ring sideroblasts; TGF-β, transforming growth factor beta. 2. Platzbecker U, et. A. Lancet Oncol. 2017; 18:1338.


 
MEDALIST Trial Study Design – A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study Patient Population Luspatercept 1.0 mg/kg (s.c.) every 21 days • MDS-RS (WHO): ≥ 15% RS or ≥ 5% with SF3B1 n = 153 mutation Randomize Dose titrated up to a maximum of 1.75 mg/kg • < 5% blasts in bone marrow 2:1 • No del(5q) MDS Placebo (s.c.) every 21 days • IPSS-R Very Low-, Low-, or Intermediate-risk n = 76 • Prior ESA response – Refractory, intolerant Disease & Response Assessment week 24 & every 6 months Treatment discontinued for lack of clinical benefit or disease – ESA naive: EPO > 200 U/L progression per IWG criteria; no crossover allowed • Average RBC transfusion burden ≥ 2 units/8 weeks • No prior treatment with disease-modifying Subjects followed ≥ 3 years postp final dose for AML agents (e.g. iMIDs, HMAs) progression, subsequent MDS treatment and overall survival Data cutoff: May 8, 2018 Includes last subject randomized + 48 weeks. EPO, erythropoietin; HMA, hypomethylating agent; iMID, immunomodulatory drug; IWG, International Working Group; s.c., subcutaneously; SF3B1, splicing factor 3b subunit 1; WHO, World Health Organization.


 
MEDALIST Trial Study Endpoints Primary endpoint: • Red blood cell transfusion independence ≥ 8 weeks (weeks 1–24) Key secondary endpoints: • Red blood cell transfusion independence ≥ 12 weeks (weeks 1–24) • Red blood cell transfusion independence ≥ 12 weeks (weeks 1–48) Additional secondary endpoints: • HI-E (IWG 2006 criteria1) for any consecutive 56-day period – Reduction in red blood cell transfusion burden ≥ 4 RBC units/8 weeksa or – Mean Hb increase of ≥ 1.5 g/dL/8 weeksb • Duration of response • Hb change from baseline a In patients with baseline RBC transfusion burden ≥ 4 units/8 weeks. b In patients with baseline RBC transfusion burden < 4 units/8 weeks. Hb, hemoglobin; HI-E, hematological improvement–erythroid. 1. Cheson BD, et al. Blood. 2006;108:419-425.


 
MEDALIST Trial Demographics and Baseline Disease Characteristics Luspatercept Placebo Characteristic (n = 153) (n = 76) Age, median (range), years 71 (40–95) 72 (26–91) Male, n (%) 94 (61.4) 50 (65.8) Time since original MDS diagnosis, median (range), months 44.0 (3–421) 36.1 (4–193) WHO classification RCMD-RS, n (%) 145 (94.8) 74 (97.4) RBC transfusion burden, median (range), units/8 weeksa 5 (1–15) 5 (2–20) ≥ 6 units/8 weeks, n (%) 66 (43.1) 33 (43.4) < 6 units/8 weeks, n (%) 87 (56.9) 43 (56.6) Pre-transfusion Hb, median (range), g/dL 7.6 (6–10) 7.6 (5–9) IPSS-R risk categoryb Very Low, Low, n (%) 127 (83.0) 63 (82.9) Intermediate, n (%) 25 (16.3) 13 (17.1) SF3B1 mutation, n (%) 141 (92.2) 65 (85.5)c Serum EPO < 200 U/L, n (%) 88 (57.5)c 50 (65.8) ≥ 200 U/L, n (%) 64 (41.8)c 26 (34.2) a In the 16 weeks prior to randomization. b 1 (0.7%) patient in the luspatercept arm was classified as IPSS-R High-risk. c Data were missing for 1 patient. RCMD-RS, refractory cytopenia with multilineage dysplasia with RS.


 
MEDALIST Trial Primary Endpoint: Red Blood Cell Transfusion Independence ≥ 8 Weeks Luspatercept Placebo RBC-TI ≥ 8 weeks (n = 153) (n = 76) Weeks 1–24, n (%) 58 (37.9) 10 (13.2) 95% CI 30.2–46.1 6.5–22.9 P valuea < 0.0001 a Cochran–Mantel–Haenszel test stratified for average baseline RBC transfusion requirement (≥ 6 units vs < 6 units of RBCs/8 weeks) and baseline IPSS-R score (Very Low or Low vs Intermediate). CI, confidence interval.


 
MEDALIST Trial Primary Endpoint: Subgroup Analysis Luspatercept, n (%) Placebo, n (%) OR (95% CI) P Value Overall 58/153 (37.9) 10/76 (13.2) 5.06 (2.28–11.3) < 0.0001 Average baseline RBC transfusion requirement ≥ 6 units/8 weeks 6/66 (9.1) 1/33 (3.0) 3.20 (0.37–27.7) 0.2699 < 6 units/8 weeks 52/87 (59.8) 9/43 (20.9) 5.61 (2.40–13.1) < 0.0001 4 to < 6 units/8 weeks 15/41 (36.6) 1/23 (4.3) 12.7 (1.55–104) 0.0046 < 4 units/8 weeks 37/46 (80.4) 8/20 (40.0) 6.17 (1.95–19.5) 0.0013 Baseline serum EPO (U/L) < 100 23/51 (45.1) 7/31 (22.6) 2.82 (1.03–7.71) 0.0413 100 to < 200 14/37 (37.8) 2/19 (10.5) 5.17 (1.04–25.9) 0.0338 200–500 17/43 (39.5) 1/15 (6.7) 9.15 (1.10–76.2) 0.0188 Age group ≤ 64 years 17/29 (58.6) 3/16 (18.8) 6.14 (1.43–26.3) 0.0108 65–74 years 23/72 (31.9) 4/29 (13.8) 2.93 (0.91–9.41) 0.0635 ≥ 75 years 18/52 (34.6) 3/31 (9.7) 4.94 (1.32–18.5) 0.0120 Gender Male 32/94 (34.0) 4/50 (8.0) 5.94 (1.96–18.0) 0.0006 Female 26/59 (44.1) 6/26 (23.1) 2.63 (0.92–7.48) 0.0673 Time since initial diagnosis at baseline ≤ 2 years 14/40 (35.0) 3/19 (15.8) 2.87 (0.71–11.6) 0.1312 > 2–5 years 30/62 (48.4) 4/34 (11.8) 7.03 (2.21–22.3) 0.0004 > 5 years 14/51 (27.5) 3/23 (13.0) 2.52 (0.65–9.83) 0.1756 Baseline IPSS-R risk Very Low or Low 48/127 (37.8) 9/63 (14.3) 3.65 (1.65–8.05) 0.0009 Intermediate 10/25 (40.0) 1/13 (7.7) 8.00 (0.89–71.6) 0.0398 Baseline platelet count < 100 u 109/L 2/8 (25.0) 1/6 (16.7) 1.67 (0.11–24.3) 0.7171 100–400 u 109/L 42/128 (32.8) 8/61 (13.1) 3.24 (1.41–7.42) 0.0042 > 400 u 109/L 14/17 (82.4) 1/9 (11.1) 37.3 (3.31–422) 0.0006 0 0.1 0.25 0.5 2 10 20 100 1,500 OR, odds ratio. Favors placebo Favors luspatercept


 
MEDALIST Trial Duration of RBC-TI Response in Primary Endpoint Responders 1.0 Median duration (weeks) (95% CI): 30.6 (20.6–40.6) vs 13.6 (9.1–54.9) 0.9 Luspatercept 0.8 Placebo 0.7 Censored 0.6 0.5 RBC-TI 0.4 0.3 0.2 0.1 Probability Probability of Maintaining 0 0 10 20 30 40 50 60 70 80 90 100 110 120 Duration of RBC-TIa (week) Number of patients Luspatercept 58 49 37 29 22 18 10 6 3 2 1 1 0 Placebo 10932220 a During indicated treatment period. Patients who maintained RBC-TI at the time of analysis are censored.


 
MEDALIST Trial Secondary Endpoint: Erythroid Response (HI-E) Luspatercept Placebo (n = 153) (n = 76) Achieved HI-Ea (weeks 1–24), n (%) 81 (52.9) 9 (11.8) Reduction of ≥ 4 RBC units/8 weeks (baseline transfusion burden ≥ 4 units/8 weeks) 52/107 (48.6) 8/56 (14.3) Hb increase of ≥ 1.5 g/dL (baseline transfusion burden < 4 units/8 weeks) 29/46 (63.0) 1/20 (5.0) 95% CI 44.72–61.05 5.56–21.29 P valueb <0.0001 Achieved HI-Ea (weeks 1–48), n (%) 90 (58.8) 13 (17.1) Reduction of ≥ 4 RBC units/8 weeks (baseline RBC transfusion burden ≥ 4 units/8 weeks) 58/107 (54.2) 12/56 (21.4) Hb increase of ≥ 1.5 g/dL (baseline RBC transfusion burden < 4 units/8 weeks) 32/46 (69.6) 1/20 (5.0) 95% CI 50.59–66.71 9.43–27.47 P valueb <0.0001 a Defined as the proportion of patients meeting the HI-E criteria per IWG 2006 criteria (Cheson et al. 2006) sustained over a consecutive 56-day period during the indicated treatment period. b Luspatercept compared with placebo, Cochran–Mantel–Haenszel test.


 
MEDALIST Trial Change3 in Hemoglobin Concentration Responder receiving luspatercept Non-responder receiving luspatercept Placebo 2 1 SE) FromBaseline (g/dL) ± 0 P <0.0001 -1 11/5/2018Baseline 1 211/26/20183 12/17/20186 1/7/2019912 1/28/201913 2/18/201915 3/11/2019 18 4/1/2019 21 4/22/201924 Hb MeanChange( Analysis Week Visit • Median peak hemoglobin increase in luspatercept responders: 2.55 g/dL (1–4.1 g/dL) Number of patients Respondera 24 36 55 53 52 50 42 47 50 42 45 153 Non-responder 33 51 61 52 60 53 34 45 56 48 35 Placebo 76 32 36 41 47 44 52 29 44 47 44 32 a LS mean difference (95% CI) for luspatercept responders versus placebo: 1.08 (0.84, 1.31), P < 0.0001. Only patients with RBC-TI ≥ 8 weeks during weeks 1–24 are included. Hb measurement was excluded within 14 days after a RBC transfusion unless within 3 days prior to another RBC transfusion. Mean and SE were not calculated if the number of patients was < 8 in the luspatercept non-responder group or < 4 in the placebo group. SE, standard error.


 
MEDALIST Trial Safety Summary Luspatercept Placebo (n = 153) (n = 76) Patients with ≥ 1 TEAE, n (%) 150 (98.0) 70 (92.1) Patients with ≥ 1 serious TEAE 48 (31.4) 23 (30.3) Patients with ≥ 1 Grade 3 or 4 TEAE 65 (42.5) 34 (44.7) Patients with TEAEs leading to deatha 5 (3.3) 4 (5.3) Patients with ≥ 1 TEAE causing discontinuation, n (%) 13 (8.5) 6 (7.9) • Progression to AML occurred in 4 patients (3/153 [2.0%] in the luspatercept arm; 1/76 [1.3%] in the placebo arm) a In luspatercept arm: sepsis (n = 2), multiple organ dysfunction syndrome, renal failure, and hemorrhagic shock; in placebo arm: sepsis, urosepsis, general physical health deterioration, and respiratory failure. TEAE, treatment-emergent adverse event.


 
MEDALIST Trial Conclusions • In lower-risk, RS-positive MDS, treatment with luspatercept resulted in a significantly higher percentage of patients who achieved RBC-TI, major RBC transfusion reduction, or hemoglobin increase, compared with placebo • Erythroid responses are durable, with approximately 40% of patients achieving RBC-TI sustained at 12 months of treatment • Luspatercept was well tolerated in this patient population • Luspatercept is a potential new therapy for the treatment of patients with lower-risk, RS-positive MDS with RBC transfusion-dependent anemia


 
Maria Domenica Cappellini, M.D. Chief of the Internal Medicine Unit, Professor of Internal Medicine, University of Milan; Chief of the Rare Disease Centre at the Policlinico Hospital IRCCS Foundation Ca’ Granda, Milan, Italy 21


 
The BELIEVE Trial: Results of a Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Luspatercept in Adult Beta-Thalassemia Patients Who Require Regular Red Blood Cell (RBC) Transfusions Maria Domenica Cappellini, Vip Viprakasit, Ali Taher, Pencho Georgiev, Kevin H.M. Kuo, Thomas Coates, Ersi Voskaridou, Hong Keng Liew, Idit Pazgal-Kobrowski, Gianluca Forni, Silverio Perrotta, Abderrahim Khelif, Ashutosh Lal, Antonis Kattamis, Efthymia Vlachaki, Raffaella Origa, Yesim Aydınok, Mohamed Bejaoui, P. Joy Ho, Lee Ping Chew, Ping Chong Bee, Soo Min Lim, Meng-Yao Lu, Adisak Tantiworawit, Penka Ganeva, Liana Gercheva, Farrukh Shah, Ellis J. Neufeld, Abderrahmane Laadem, Jeevan K. Shetty, Jun Zou, Dimana Miteva, Tatiana Zinger, Peter G. Linde, Matthew L. Sherman, Olivier Hermine, John Porter, Antonio Piga Presented at the 60th Annual Meeting of the American Society of Hematology (ASH); December 1–4, 2018; San Diego, CA, USA.


 
BELIEVE Trial BACKGROUND • β-thalassemia is a hereditary hemoglobinopathy due to a globin chain synthesis production defect, leading to ineffective erythropoiesis and anemia1–3 • Currently the standard of care for management of β-thalassemia is life-long red blood cell transfusions and iron chelation • In spite of iron chelation therapy, many patients experience multiple morbidities due to iron toxicity, including increased mortality • Therefore, there is a need for new treatment options for patients with β-thalassemia to reduce the dependence on transfusions and the associated morbidities4 1. Higgs DR, et al. Lancet. 2012;379:373-383. 2. Camaschella C, Nai A. Br J Haematol. 2016;172:512-523. 3. Taher AT, et al. Lancet. 2018;391:155-167. The BELIEVE Trial studied adult patients. 4. Taher AT, et al. Blood. 2018;132:1781-1791.


 
BELIEVE Trial A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PHASE 3 STUDY β-thalassemiaa patients Current study ≥ 18 years, statusc requiring regular Luspaterceptb RBC transfusions 1 mg/kg s.c. every 21 days + BSC (defined as: (n = 224) 6–20 RBC units in the Open- Post- 24 weeks prior to 2:1 May be titrated up to 1.25 mg/kg label treatment randomization with no b Study (up to 5 follow-up Randomized Placebo ≥ 35-day transfusion- unblinding years) (3 years) free period during that s.c. every 21 days + BSC time) (n = 112) (N = 336) 12-week period 12-week period Double-blind period Crossover permitted historical screening / run-in (48 weeks) transfusions transfusions a β-thalassemia or hemoglobin E / β-thalassemia (β-thalassemia with mutation and / or multiplication of α-globin was allowed. b RBC transfusions and iron chelation therapy to maintain each patient’s baseline hemoglobin level. c The trial is fully enrolled and patients continue to receive treatment or follow-up. BSC, best supportive care; RBC, red blood cell; s.c., subcutaneously. The BELIEVE Trial studied adult patients.


 
BELIEVE Trial PRIMARY ENDPOINT MET: RATE OF ERYTHROID RESPONSE A significantly greater proportion of luspatercept-treated patients achieved a ≥ 33% reduction from baseline in transfusion burden during weeks 13 to 24 Luspatercept 30 Placebo P < 0.0001 (OR 5.79, 95% CI 2.24–14.97) 25 20 15 21.4% (n = 48) 10 Patients Achieving ≥ 33% 33% ≥ Achieving Patients 5 Transfusion Burden Reduction (%) Reduction Burden Transfusion 4.5% (n = 5) 0 Luspatercept Placebo (n = 224) (n = 112) CI, confidence interval; OR, odds ratio. The BELIEVE Trial studied adult patients.


 
BELIEVE Trial PRIMARY ENDPOINT: SUBGROUP ANALYSIS FAVORS LUSPATERCEPT Luspatercept Placebo Sub-groups OR (95% CI) P value n/N (%) n/N (%) Overall 48/224 (21.4) 5/112 (4.5) 5.79 (2.24, 14.97) < 0.0001 Region: North America & Europe 23/100 (23.0) 1/51(2.0) 14.94 (1.95, 114.12) 0.0009 Region: Middle East & North Africa 11/52 (21.2) 2/26 (7.7) 3.22 (0.66, 15.77) 0.1351 Region: Asia–Pacific 14/72 (19.4) 2/35 (5.7) 3.98 (0.85, 18.62) 0.0629 Age: ≤ 32 years 22/129 (17.1) 4/63 (6.3) 3.00 (0.98, 9.20) 0.0476 Age: > 32 years 26/95 (27.4) 1/49 (2.0) 17.50 (2.27, 134.98) 0.0004 Splenectomy: Yes 31/129 (24.0) 2/65 (3.1) 9.72 (2.22, 42.53) 0.0003 Splenectomy: No 17/95 (17.9) 3/47 (6.4) 2.94 (0.81, 10.69) 0.0918 Sex: Female 35/132 (26.5) 4/63 (6.3) 5.33 (1.80, 15.80) 0.0011 Sex: Male 13/92 (14.1) 1/49 (2.0) 8.05 (1.01, 64.16) 0.0218 β-thalassemia Gene: β0/β0 9/68 (13.2) 2/35 (5.7) 2.54 (0.48, 13.51) 0.2708 β-thalassemia Gene: Non-β0/β0 39/155 (25.2) 3/77 (3.9) 8.35 (2.47, 28.23) < 0.0001 Baseline Transfusion Burden: ≤ 6 units/12 weeks 27/112 (24.1) 3/56 (5.4) 5.61 (1.60, 19.65) 0.0033 Baseline Transfusion Burden: > 6 units/12 weeks 21/112 (18.8) 2/56 (3.6) 6.16 (1.38, 27.44) 0.0082 Baseline Hemoglobin: < 9 g/dL 22/87 (25.3) 4/51 (7.8) 3.78 (1.25, 11.42) 0.0128 Baseline Hemoglobin: ≥ 9 g/dL 26/137 (19.0) 1/61 (1.6) 14.17 (1.85, 108.79) 0.0012 Baseline Liver Iron: ≤ 3 mg/g dry weight 12/70 (17.1) 1/37 (2.7) 7.18 (0.88, 58.63) 0.0335 Baseline Liver Iron: > 3 to ≤ 7 mg/g dry weight 13/51 (25.5) 0/30 (0) Infinity 0.0053 Baseline Liver Iron: > 7 to ≤ 15 mg/g dry weight 10/38 (26.3) 1/19 (5.3) 5.41 (0.67, 43.34) 0.0741 Baseline Liver Iron: > 15 mg/g dry weight 13/65 (20.0) 3/26 (11.5) 1.79 (0.47, 6.78) 0.3831 0.1 1 10 100 Favors placebo Favors luspatercept The BELIEVE Trial studied adult patients.


 
BELIEVE Trial ALL KEY SECONDARY ENDPOINTS MET: RATES OF ERYTHROID RESPONSE A significantly greater proportion of luspatercept-treated patients achieved clinically meaningful reductions in transfusion burden of ≥ 33% and ≥ 50% 30 Luspatercept P < 0.0001a 25 Placebo 20 P = 0.0017c 15 P = 0.0303b 10 19.6 Burden Reduction (%) Reduction Burden 5 10.3 7.6 1.8 Patients Achieving Transfusion Achieving Patients 3.6 0.9 0 ≥ 33% ≥ 50% ≥ 50% (from week 37 to 48) (from week 13 to 24) (from week 37 to 48) • The least squares mean change in transfusion burden from baseline to weeks 13–24 (luspatercept versus placebo) was −1.35 RBC units/12 weeks (95% CI −1.77 to −0.93; P < 0.0001) a OR 6.44, 95% CI 2.27–18.26. b OR 4.55, 95% CI 1.03–20.11. c OR 11.92, 95% CI 1.65–86.29. The BELIEVE Trial studied adult patients.


 
BELIEVE Trial REDUCTION IN TRANSFUSION BURDEN DURING ANY 12- AND 24-WEEK INTERVAL During any 12- or 24-week interval, a significantly greater proportion of luspatercept-treated patients achieved clinically meaningful reductions in transfusion burden of ≥ 33% and ≥ 50% Any 12-week interval Any 24-week interval 100 100 Luspatercept P < 0.0001a Placebo 80 80 60 60 P < 0.0001b P < 0.0001c 40 40 P < 0.0001d 70.5 Burden Reduction (%) Reduction Burden 20 40.2 (%) Reduction Burden 20 41.1 16.5 29.5 6.3 Patients Achieving Transfusion Achieving Patients Patients Achieving Transfusion Transfusion Achieving Patients 2.7 0.9 0 0 ≥ 33% ≥ 50% ≥ 33% ≥ 50% a OR 5.69, 95% CI 3.46–9.35. b OR 9.95, 95% CI 4.44–22.33. c OR 25.02, 95% CI 7.76–80.71. d OR 20.37, 95% CI 2.86–144.94. The BELIEVE Trial studied adult patients.


 
BELIEVE Trial ADDITIONAL ENDPOINTS: IRON PARAMETERS Luspatercept Placebo LS Mean of 95% CI P Value (n = 224) (n = 112) Difference Mean change from baseline at week 48 Serum ferritin, μg/L (SD) −245 (780) 105 (521) −340 −502, −177 < 0.0001 LIC, mg/g dry weight (SD) 0.10 (5.760) 0.08 (5.229) 0.11 −1.16, 1.38 0.8685 Myocardial iron by T2*, ms (SD) −1.83 (15.084) 0.02 (6.843) −2.39 −4.67, −0.12 0.0391 SD, standard deviation. The BELIEVE Trial studied adult patients.


 
BELIEVE Trial SAFETY SUMMARY Luspatercept Placebo Treatment-Emergent Adverse Events, n (%) (n = 223a) (n = 109a) Patients with at least 1 TEAE (any grade) 214 (96.0) 101 (92.7) Patients with at least 1 grade TEAE (grade ≥ 3)b 65 (29.1) 17 (15.6) Patients with at least 1 serious TEAEc 34 (15.2) 6 (5.5) Patients with at least 1 TEAE resulting in the following: Deathd 01 (0.9) Study drug discontinuation 12 (5.4) 1 (0.9) a Safety population. b No one organ class or system was predominant.c Anemia was the only serious TEAE occurring in > 1% of patients in either arm (luspatercept, n = 3 [1.4%]; placebo, n = 0 [0%]). d TEAE of acute cholecystitis resulted in death in 1 of 109 (0.9%) placebo patients; no luspatercept-treated patients died due to TEAEs. TEAE, treatment-emergent adverse event. The BELIEVE Trial studied adult patients.


 
BELIEVE Trial TEAEs BY FREQUENCY ≥ 10% IN EITHER ARM (ALL GRADES) Luspatercept Placebo n (%) (n = 223a) (n = 109a) Back pain 61 (27.4) 32 (29.4) Upper respiratory tract infection 59 (26.5) 36 (33.0) Headache 58 (26.0) 26 (23.9) Bone pain 44 (19.7) 9 (8.3) Arthralgia 43 (19.3) 13 (11.9) Pyrexia 36 (16.1) 23 (21.1) Cough 32 (14.3) 12 (11.0) Fatigue 30 (13.5) 14 (12.8) Oropharyngeal pain 28 (12.6) 12 (11.0) Diarrhea 27 (12.1) 11 (10.1) Dizziness 25 (11.2) 5 (4.6) Asthenia 22 (9.9) 11 (10.1) Myalgia 22 (9.9) 11 (10.1) Pharyngitis 20 (9.0) 13 (11.9) a Safety population. The BELIEVE Trial studied adult patients.


 
BELIEVE Trial GRADE 3–4 TEAEs BY FREQUENCY ≥ 1% IN EITHER ARM Luspatercept Placebo n (%) (n = 223a) (n = 109a) Anemia 7 (3.1) 0 Increased LIC 6 (2.7) 1 (0.9) Hyperuricemia 6 (2.7) 0 Hypertension 4 (1.8) 0 Syncope 4 (1.8) 0 Back pain 3 (1.3) 1 (0.9) Bone pain 3 (1.3) 0 Blood uric acid increased 3 (1.3) 0 Increased AST 3 (1.3) 0 Increased ALT 2 (0.9) 3 (2.8) Thromboembolic eventsb 2 (0.9) 0 • In total, thromboembolic events (all grades) were reported in 8/223 (3.6%) luspatercept-treated patients (deep venous thrombosis, pulmonary embolism, portal vein thrombosis, ischemic stroke, thrombophlebitis, superficial phlebitis) and 1/109 (0.9%) placebo-treated patients (phlebitis). In all cases, patients had multiple risk factors for thromboembolic events a Safety population. b Thromboembolic events included as a TEAE of interest; other events occurring in < 1% of patients are not shown. ALT, alanine aminotransferase; AST, aspartate aminotransferase. The BELIEVE Trial studied adult patients.


 
BELIEVE Trial CONCLUSIONS • Luspatercept showed a statistically significant improvement in the primary endpoint of ≥ 33% reduction in transfusion burden compared with placebo • Statistical significance was also demonstrated with luspatercept versus placebo for all key secondary endpoints, including ≥ 33% and ≥ 50% reductions in transfusion burden • Luspatercept showed a statistically significant and clinically meaningful reduction in transfusion burden compared with placebo during any 12 or 24 weeks in the study period • Luspatercept was generally well tolerated in this patient population • Luspatercept is a potential new treatment for adult patients with β-thalassemia who require regular RBC transfusions The BELIEVE Trial studied adult patients.


 
Habib Dable Chief Executive Officer


 
ASH 2018 Takeaways Low-to-Intermediate Risk MDS, RS+ β-Thalassemia, Transfusion-Dependent ƒ Unmet Medical Need: High disease burden with no approved agents for anemia ƒ Positive Results: Luspatercept met all primary and key secondary endpoints ƒ Duration and Safety: Durable responses with an appropriate safety profile 35


 
Additional Luspatercept Trials Underway Phase 3 Lower-Risk MDS, First-line ƒ Enrolling up to 350 patients Phase 2 Phase 2 β-Thalassemia, Non-Transfusion- Monotherapy / Combination Therapy Dependent ƒ Enrolling up to 150 patients ƒ Enrolling up to 70 patients 36


 
A Potential Platform Treatment for Chronic Anemias Potential US/EU Addressable Patient Population: >120K Second-line MDS (RS+) Beta-Thalassemia (TD) >40K PATIENTS >20K PATIENTS Myelofibrosis First-line MDS Beta-Thalassemia (NTD) >25K PATIENTS >20K PATIENTS >15K PATIENTS Additional anemia indications being evaluated and prioritized for future clinical trials 37


 
Collaborating for Over 10 Years in Hematology Worldwide Royalty Program Costs Low- to mid-20% 100% Celgene funded Milestones Co-Promote $185M outstanding North America 38


 
Upcoming Luspatercept Corporate Priorities HEMATOLOGY ƒ Luspatercept – Regulatory application submissions in US and EU in 1H 2019 – MEDALIST and BELIEVE Phase 3 trial results publication in 2019 – Myelofibrosis Phase 2 trial preliminary topline results in 2H 2019 – BEYOND Phase 2 trial preliminary topline results in 2020 – COMMANDS Phase 3 trial patient enrollment – Actively evaluating additional diseases associated with anemia for future clinical development 39


 
ASH 2018: Q&A Session Habib Dable Chief Executive Officer Alan F. List, M.D. Moffitt Cancer Center Nica Cappellini, M.D. University of Milan Robert Zeldin, M.D. Chief Medical Officer John Quisel, Ph.D., J.D. Chief Business Officer Sujay Kango Chief Commercial Officer Todd James, IRC VP, Investor Relations and Corp. Comm. 40


 
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