MEDALIST Trial Background and Rationale

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August Holt
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The MEDALIST Tril: Results of Phse 3, Rndomized, Double-Blind, Plcebo-Controlled Study of to Tret Ptients With Very Low-, Low-, or Intermedite-Risk Myelodysplstic Syndromes (MDS) Associted Anemi With

1 The MEDALIST Tril: Results of Phse 3, Rndomized, Double-Blind, Plcebo-Controlled Study of to Tret Ptients With Very Low-, Low-, or Intermedite-Risk Myelodysplstic Syndromes (MDS) Associted Anemi With Ring Sideroblsts (RS) Who Require Red Blood Cell (RBC) Trnsfusions Pierre Fenux, Uwe Pltzbecker, Ghulm J. Mufti, Guillermo Grci-Mnero, Ren Buckstein, Vleri Sntini, Mrí Díez-Cmpelo, Crlo Finelli, Mrio Czzol, Osmn Ilhn, Mikkel A. Sekeres, José F. Flntes, Betriz Arrizblg, Flvi Slvi, Vlentin Gii, Presh Vys, Dvid Bowen, Dominik Selleslg, Amy E. DeZern, Joseph G. Jurcic, Ulrich Germing, Kthrin S. Götze, Bruno Quesnel, Odile Beyne-Ruzy, Thoms Cluzeu, Mri Teres Voso, Dominiek Mzure, Edo Velleng, Peter L. Greenberg, Ev Hellström-Lindberg, Amer M. Zeidn, Abderrhmne Ldem, Aziz Benzohr, Jennie Zhng, Anit Rmpersd, Peter G. Linde, Mtthew L. Shermn, Rmi S. Komrokji, Aln F. List

2 Bckground nd Rtionle Ptients with lower-risk (LR) trnsfusion-dependent MDS hve poorer prognosis, with greter risk of progression to AML nd inferior overll survivl compred with ptients with trnsfusion-independent MDS RBC trnsfusion-dependent LR, non-del(5q) MDS ptients hve trnsient response to ESAs, with n ttendnt risk of iron overlod nd secondry orgn complictions Few tretment options exist for the lrge number of ptients with LR MDS who re either refrctory to or become unresponsive to ESAs 1 IPSS-R-defined criteri. AML, cute myeloid leukemi; ESA, erythropoiesis-stimulting gent; IPSS-R, revised Interntionl Prognostic Scoring System; MDS, myelodysplstic syndromes; RBC, red blood cell. 1. Fenux P, nd Adès L. Blood. 2013;121:

3 is n investigtionl first-in-clss erythroid mturtion gent tht neutrlizes select TGF-β superfmily lignds to inhibit berrnt Smd2/3 signling nd enhnce lte-stge erythropoiesis in MDS models 1 In phse 2 study in LR, non-del(5q) MDS, lusptercept yielded high frequency of trnsfusion reduction or RBC-TI in ptients with MDS-RS vs other subtypes 2 ActRIIB / IgG1 Fc recombinnt fusion protein Modified extrcellulr domin of ActRIIB Humn IgG1 Fc domin TGF-β superfmily lignd Cytoplsm Nucleus Erythroid mturtion ActRIIB, humn ctivin receptor type IIB; IgG1 Fc, immunoglobulin G1 frgment crystllizble; RBC-TI, red blood cell trnsfusion independence; RS, ring sideroblsts; TGF-β, trnsforming growth fctor bet. ActRIIB P Smd2/3 Complex 1. Surgni RN, et l. Nt Med. 2014;20: ; 2. Pltzbecker U, et. A. Lncet Oncol. 2017; 18:1338.

Study Design A Rndomized, Double-Blind, Plcebo-Controlled, Phse 3 Study Ptient Popultion MDS-RS (WHO): 15% RS or 5% with SF3B1 muttion < 5% blsts in bone mrrow No del(5q) MDS IPSS-R Very Low-, Low-,

4 Study Design A Rndomized, Double-Blind, Plcebo-Controlled, Phse 3 Study Ptient Popultion MDS-RS (WHO): 15% RS or 5% with SF3B1 muttion < 5% blsts in bone mrrow No del(5q) MDS IPSS-R Very Low-, Low-, or Intermedite-risk Prior ESA response Refrctory, intolernt ESA nive: EPO > 200 U/L Averge RBC trnsfusion burden 2 units/8 weeks No prior tretment with disese-modifying gents (e.g. imids, HMAs) Rndomize 2:1 1.0 mg/kg (s.c.) every 21 dys n = 153 Dose titrted up to mximum of 1.75 mg/kg Plcebo (s.c.) every 21 dys n = 76 Disese & Response Assessment week 24 & every 6 months Tretment discontinued for lck of clinicl benefit or disese progression per IWG criteri; no crossover llowed Subjects followed 3 yers post finl dose for AML progression, subsequent MDS tretment nd overll survivl Dt cutoff: My 8, 2018 Includes lst subject rndomized + 48 weeks. EPO, erythropoietin; HMA, hypomethylting gent; imid, immunomodultory drug; IWG, Interntionl Working Group; s.c., subcutneously; SF3B1, splicing fctor 3b subunit 1; WHO, World Helth Orgniztion.

5 Study Design (cont.) Ptients were rndomized between Mrch 2016 nd June 2017 t 65 sites in Belgium, Cnd, Frnce, Germny, Itly, the Netherlnds, Spin, Sweden, Turkey, UK, nd USA

6 Study Endpoints Primry endpoint: Red blood cell trnsfusion independence 8 weeks (weeks 1 24) Key secondry endpoint: Red blood cell trnsfusion independence 12 weeks (weeks 1 24 nd weeks 1 48) Additionl secondry endpoints: HI-E (IWG 2006 criteri 1 ) for ny consecutive 56-dy period Reduction in red blood cell trnsfusion burden 4 RBC units/8 weeks or Men Hb increse of 1.5 g/dl/8 weeks b Durtion of response Hb chnge from bseline In ptients with bseline RBC trnsfusion burden 4 units/8 weeks. b In ptients with bseline RBC trnsfusion burden < 4 units/8 weeks. Hb, hemoglobin; HI-E, hemtologicl improvement erythroid. 1. Cheson BD, et l. Blood. 2006;108:

7 Demogrphics nd Bseline Disese Chrcteristics Chrcteristic (n = 153) Plcebo (n = 76) Age, medin (rnge), yers 71 (40 95) 72 (26 91) Mle, n (%) 94 (61.4) 50 (65.8) Time since originl MDS dignosis, medin (rnge), months 44.0 (3 421) 36.1 (4 193) WHO clssifiction RCMD-RS, n (%) 145 (94.8) 74 (97.4) RBC trnsfusion burden, medin (rnge), units/8 weeks 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-trnsfusion Hb, medin (rnge), g/dl 7.6 (6 10) 7.6 (5 9) IPSS-R risk ctegory b Very Low, Low, n (%) 127 (83.0) 63 (82.9) Intermedite, n (%) 25 (16.3) 13 (17.1) SF3B1 muttion, 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) In the 16 weeks prior to rndomiztion. b 1 (0.7%) ptient in the lusptercept rm ws clssified s IPSS-R High-risk. c Dt were missing for 1 ptient. RCMD-RS, refrctory cytopeni with multilinege dysplsi with RS.

8 Tretment Exposure Prmeter (n = 153) Plcebo (n = 76) Tretment durtion, medin (rnge), weeks 49 (6 114) 24 (7 89) Completed 24 weeks of tretment (primry phse), n (%) 128 (83.7) 68 (89.5) Completed 48 weeks of tretment, n (%) 78 (51.0) 12 (15.8) Number of doses received, medin (rnge) 16 (2 37) 8 (3 30) Mximum dose escltion, n (%) 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) Ptients remining on tretment, n (%) 70 (45.8) 6 (7.9) Ptients discontinued from tretment, n (%) 83 (54.2) 70 (92.1) Lck of benefit 51 (33.3) 50 (65.8) Ptient withdrwl 14 (9.2) 10 (13.2) AE 10 (6.5) 4 (5.3) Disese progression 3 (2.0) 2 (2.6) Other 5 (3.3) 4 (5.3) Dose my be titrted up to mximum of 1.75 mg/kg. AE, dverse event.

9 Primry Endpoint: Red Blood Cell Trnsfusion Independence 8 Weeks RBC-TI 8 weeks (n = 153) Plcebo (n = 76) Weeks 1 24, n (%) 58 (37.9) 10 (13.2) 95% CI P vlue < Cochrn Mntel Henszel test strtified for verge bseline RBC trnsfusion requirement ( 6 units vs < 6 units of RBCs/8 weeks) nd bseline IPSS-R score (Very Low or Low vs Intermedite). CI, confidence intervl.

10 Primry Endpoint: Subgroup Anlysis, n (%) Plcebo, n (%) OR (95% CI) P Vlue Overll 58/153 (37.9) 10/76 (13.2) 5.06 ( ) < Averge bseline RBC trnsfusion requirement 6 units/8 weeks 6/66 (9.1) 1/33 (3.0) 3.20 ( ) < 6 units/8 weeks 52/87 (59.8) 9/43 (20.9) 5.61 ( ) < to < 6 units/8 weeks 15/41 (36.6) 1/23 (4.3) 12.7 ( ) < 4 units/8 weeks 37/46 (80.4) 8/20 (40.0) 6.17 ( ) Bseline serum EPO (U/L) < /51 (45.1) 7/31 (22.6) 2.82 ( ) to < /37 (37.8) 2/19 (10.5) 5.17 ( ) /43 (39.5) 1/15 (6.7) 9.15 ( ) Age group 64 yers 17/29 (58.6) 3/16 (18.8) 6.14 ( ) yers 23/72 (31.9) 4/29 (13.8) 2.93 ( ) yers 18/52 (34.6) 3/31 (9.7) 4.94 ( ) Gender Mle 32/94 (34.0) 4/50 (8.0) 5.94 ( ) Femle 26/59 (44.1) 6/26 (23.1) 2.63 ( ) Time since initil dignosis t bseline 2 yers 14/40 (35.0) 3/19 (15.8) 2.87 ( ) > 2 5 yers 30/62 (48.4) 4/34 (11.8) 7.03 ( ) > 5 yers 14/51 (27.5) 3/23 (13.0) 2.52 ( ) Bseline IPSS-R risk Very Low or Low 48/127 (37.8) 9/63 (14.3) 3.65 ( ) Intermedite 10/25 (40.0) 1/13 (7.7) 8.00 ( ) Bseline pltelet count < /L 2/8 (25.0) 1/6 (16.7) 1.67 ( ) /L 42/128 (32.8) 8/61 (13.1) 3.24 ( ) > /L 14/17 (82.4) 1/9 (11.1) 37.3 ( ) OR, odds rtio ,500 Fvors plcebo Fvors lusptercept

11 Key Secondry Endpoint: Red Blood Cell Trnsfusion Independence 12 Weeks RBC-TI 12 Weeks (n = 153) Plcebo (n = 76) Weeks 1 24, n (%) 43 (28.1) 6 (7.9) 95% CI P vlue Weeks 1 48, n (%) 51 (33.3) 9 (11.8) 95% CI P vlue Cochrn Mntel Henszel test strtified for verge bseline RBC trnsfusion requirement ( 6 units vs < 6 units of RBCs/8 weeks) nd bseline IPSS-R score (Very Low or Low vs Intermedite).

12 Probbility of Mintining RBC-TI MEDALIST Tril Durtion of RBC-TI Response in Primry Endpoint Responders Medin durtion (weeks) (95% CI): 30.6 ( ) vs 13.6 ( ) Durtion of RBC-TI (week) Plcebo Censored Number of ptients Plcebo During indicted tretment period. Ptients who mintined RBC-TI t the time of nlysis re censored.

13 Secondry Endpoint: Erythroid Response (HI-E) (n = 153) Plcebo (n = 76) Achieved HI-E (weeks 1 24), n (%) 81 (52.9) 9 (11.8) Reduction of 4 RBC units/8 weeks (bseline trnsfusion burden 4 units/8 weeks) 52/107 (48.6) 8/56 (14.3) Hb increse of 1.5 g/dl (bseline trnsfusion burden < 4 units/8 weeks) 29/46 (63.0) 1/20 (5.0) 95% CI P vlue b < Achieved HI-E (weeks 1 48), n (%) 90 (58.8) 13 (17.1) Reduction of 4 RBC units/8 weeks (bseline RBC trnsfusion burden 4 units/8 weeks) 58/107 (54.2) 12/56 (21.4) Hb increse of 1.5 g/dl (bseline RBC trnsfusion burden < 4 units/8 weeks) 32/46 (69.6) 1/20 (5.0) 95% CI P vlue b < Defined s the proportion of ptients meeting the HI-E criteri per IWG 2006 criteri (Cheson et l. 2006) sustined over consecutive 56-dy period during the indicted tretment period. b compred with plcebo, Cochrn Mntel Henszel test.

14 Hb Men Chnge (± SE) From Bseline (g/dl) MEDALIST Tril Chnge in Hemoglobin Concentrtion 3 Responder receiving lusptercept Non-responder receiving lusptercept Plcebo /5/2018 Bseline 1 211/26/ /17/ /7/ /28/ /18/ /11/ /1/ /22/ Anlysis Week Visit Medin pek hemoglobin increse in lusptercept responders: 2.55 g/dl (1 4.1 g/dl) Number of ptients Responder Non-responder Plcebo LS men difference (95% CI) for lusptercept responders versus plcebo: 1.08 (0.84, 1.31), P < Only ptients with RBC-TI 8 weeks during weeks 1 24 re included. Hb mesurement ws excluded within 14 dys fter RBC trnsfusion unless within 3 dys prior to nother RBC trnsfusion. Men nd SE were not clculted if the number of ptients ws < 8 in the lusptercept non-responder group or < 4 in the plcebo group. SE, stndrd error.

15 Sfety Summry (n = 153) Plcebo (n = 76) Ptients with 1 TEAE, n (%) 150 (98.0) 70 (92.1) Ptients with 1 serious TEAE 48 (31.4) 23 (30.3) Ptients with 1 Grde 3 or 4 TEAE 65 (42.5) 34 (44.7) Ptients with TEAEs leding to deth 5 (3.3) 4 (5.3) Ptients with 1 TEAE cusing discontinution, n (%) 13 (8.5) 6 (7.9) TEAEs were blnced between the rms b Progression to AML occurred in 4 ptients (3/153 [2.0%] in the lusptercept rm; 1/76 [1.3%] in the plcebo rm) In lusptercept rm: sepsis (n = 2), multiple orgn dysfunction syndrome, renl filure, nd hemorrhgic shock; in plcebo rm: sepsis, urosepsis, generl physicl helth deteriortion, nd respirtory filure. b The most common grde 3 or 4 TEAEs reported in lusptercept-treted ptients were nemi (6.5% of ptients), fll (4.6%), nd ftigue (4.6%). TEAE, tretment-emergent dverse event.

16 TEAEs 10% Incidence in Either Arm Plcebo n (%) (n = 153) (n = 76) Ftigue 41 (26.8) 10 (13.2) Dirrhe 34 (22.2) 7 (9.2) Astheni 31 (20.3) 9 (11.8) Nuse 31 (20.3) 6 (7.9) Dizziness 30 (19.6) 4 (5.3) Bck pin 29 (19.0) 5 (6.6) Cough 27 (17.6) 10 (13.2) Edem peripherl 25 (16.3) 13 (17.1) Hedche 24 (15.7) 5 (6.6) Dyspne 23 (15.0) 5 (6.6) Bronchitis 17 (11.1) 1 (1.3) Constiption 17 (11.1) 7 (9.2) Urinry trct infection 17 (11.1) 4 (5.3) Fll 15 (9.8) 9 (11.8) TEAEs 10% incidence in either rm by preferred term

17 Conclusions In lower-risk, RS-positive MDS, tretment with lusptercept resulted in significntly higher percentge of ptients who chieved RBC-TI, mjor RBC trnsfusion reduction, or hemoglobin increse, compred with plcebo Erythroid responses were durble, with pproximtely 40% of ptients chieving RBC-TI sustined t 12 months of tretment ws generlly well tolerted in this ptient popultion is potentil new therpy for the tretment of ptients with lower-risk, RS-positive MDS with RBC trnsfusion-dependent nemi

18 Acknowledgements We thnk ll the ptients, fmilies, nd investigtors who prticipted in the study This study ws sponsored by Celgene Corportion, Summit, NJ, USA nd Acceleron Phrm, Cmbridge, MA, USA The uthors received editoril ssistnce from Excerpt Medic (Mirim de Boeck, Emily Poulin, PhD), supported by Celgene Corportion nd Acceleron Phrm The uthors re fully responsible for ll content nd editoril decisions for this presenttion

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