Luspatercept (ACE-536) Increases Hemoglobin and Reduces Transfusion - - PowerPoint PPT Presentation

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Luspatercept (ACE-536) Increases Hemoglobin and Reduces Transfusion - - PowerPoint PPT Presentation

Dec 25, 2022 1.22k likes •1.52k views

Luspatercept (ACE-536) Increases Hemoglobin and Reduces Transfusion Burden in Patients with Low or Intermediate-1 Risk Myelodysplastic Syndromes (MDS): Preliminary Results from a Phase 2 Study Uwe Platzbecker, MD U Platzbecker 1 , U Germing 2 , A

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SLIDE 1

U Platzbecker1, U Germing2, A Giagounidis3, K Goetze4, P Kiewe5, K Mayer6, O Ottman7, M Radsak8, T Wolff9, D Haase10, M Hankin11, D Wilson11, A Laadem12, M Sherman11 and K Attie11

Study supported by Acceleron and Celgene

D·MDS

Deutsche MDS-Studiengruppe

Uwe Platzbecker, MD

Luspatercept (ACE-536) Increases Hemoglobin and Reduces Transfusion Burden in Patients with Low or Intermediate-1 Risk Myelodysplastic Syndromes (MDS): Preliminary Results from a Phase 2 Study

1Universitätsklinikum Carl Gustav Carus, Dresden; 2Universitätsklinikum Düsseldorf; 3Marien Hospital Düsseldorf; 4Technical University of Munich; 5Onkologischer Schwerpunkt

am Oskar‐Helene‐Heim, Berlin; 6Universitätsklinikum Bonn; 7Klinikum der J.W. Goethe‐Universität Frankfurt;

8University Medical Center ‐ Johannes Gutenberg‐Universität, Mainz; 9OncoResearch Lerchenfeld UG, Hamburg; 10Department of Hematology and Medical Oncology, University Medicine of Göttingen, Germany; 11Acceleron Pharma, Cambridge, MA; 12Celgene Corporation, Summit, NJ, USA

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SLIDE 2

Disclosures for Prof. Platzbecker

  • Honoraria and research funding from Celgene
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SLIDE 3
  • 80–90% of MDS patients become dependent on RBC transfusions
  • Many patients unresponsive/refractory to ESAs
  • Need for novel disease‐specific therapeutics to treat anemia

Limited Therapeutic Options in MDS

Fe-Chelation Fe-Chelation Lenalidomide (del 5q) Lenalidomide (del 5q) ESA ESA

Registered Registered

Intensive CTx/allo Tx Intensive CTx/allo Tx Hypomethylating Agents Hypomethylating Agents Lower-risk Lower-risk Higher-risk Higher-risk

Stratification according to IPSS-(R) Stratification according to IPSS-(R)

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SLIDE 4

Luspatercept in MDS: Background

Erythropoiesis

TGF-β Superfamily Ligands: GDF11, etc. Smad2/3

Suragani R, et al. Nature Med 2014 Zhou L, et al., Blood 2008

Luspatercept

Fusion protein containing modified activin receptor type IIB (ActRIIB) Activin Receptor Domain Human IgG Fc Domain

  • Mechanism is distinct from

erythropoietin

  • Acts on late‐stage

erythropoiesis to increase mature RBCs in the circulation

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SLIDE 5

Effects in MDS Mouse Model

Suragani R et al., Nature Med 2014

Increases Hemoglobin Inhibits Smad2/3 Signaling

###p< 0.001 vs WT+TBS

*p< 0.05 vs MDS+TBS

Studies using RAP‐536, murine analog of luspatercept

Normalizes M:E Ratio in BM

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SLIDE 6

NCT01749514, EudraCT 2012‐002523‐14

  • Primary efficacy endpoints
  • Low Transfusion Burden (LTB, <4U RBC/8 weeks, Hgb <10 g/dL):

Hemoglobin increase of ≥ 1.5 g/dL for ≥ 2 weeks

  • High Transfusion Burden (HTB, ≥4U RBC/8 weeks):

Reduction of ≥4U or ≥50% units transfused over 8 weeks

Luspatercept PACE-MDS Study Overview

  • Phase 2, multicenter, open‐label, dose‐finding study in IPSS low/int‐1 MDS
  • Eligibility criteria: EPO >500 U/L or nonresponsive/refractory to ESA; no prior

azacitidine or decitabine; no current lenalidomide, ESA, G‐CSF

  • 4

BL 3 6 9 12 16 Study Week 24

Luspatercept Treatment Period Screening Period Follow-up Period

  • Luspatercept administered SC every 3 weeks for 3 months
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SLIDE 7

Luspatercept PACE-MDS Study Design

Cohort 7

1.75 mg/kg (N=3)

Cohort 5

1.0 mg/kg (N=3)

Cohort 6

1.33 mg/kg (N=6)

Cohort 1

0.125 mg/kg (N=3)

Cohort 2

0.25 mg/kg (N=3)

Cohort 3

0.5 mg/kg (N=3)

Cohort 4

0.75 mg/kg (N=6)

3 Months Treatment

Expansion Cohort

Individually titrated dose (N=30)

Data available Active

Data from patients who completed treatment are presented; includes 2 patients in Cohort 7

Patients completing base study can enroll into a 12‐month extension study

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SLIDE 8

Baseline Characteristics

All Patients N = 26 Age, yr, median (range) 71 (27‐88) Sex, males (%) 13 (50%) Prior ESA treatment, n (%) 14 (54%) Prior lenalidomide treatment, n (%) 5 (19%) Low Transfusion Burden (LTB) N = 7 (27%) Hemoglobin, g/dL, median (range) 9.1 (8.3‐9.7) Units RBC/8 weeks, median (range) 0 (0‐2) High Transfusion Burden (HTB) N = 19 (73%) Units RBC/8 weeks, median (range) 6 (4‐13)

Data as of 03 Oct 2014

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SLIDE 9

Baseline MDS Characteristics

Classification N = 26 n (%)

WHO Subtype RARS 4 (15%) RCMD‐RS 11 (42%) RCMD 5 (19%) RAEB‐1* 4 (15%) del (5q) 2 (8%) IPSS Low 12 (46%) Int‐1 12 (46%) Int‐2 2 (8%) IPSS‐R Low 15 (58%) Intermediate 8 (31%) High 3 (12%)

Data as of 03 Oct 2014

*Includes 2 patients with ≥15% RS

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SLIDE 10

Pharmacokinetic and Safety Summary

Pharmacokinetics

  • Dose‐dependent increase in Cmax and area under curve (AUC)
  • Mean half‐life (t½) is approximately 14 days, supporting Q3W dosing

Safety

  • No drug‐related serious adverse events (AEs)
  • One possibly related grade 3 AE of blast cell count increase
  • Majority of adverse events were grade 1 or 2

Preferred Term n (%) 0.125 mg/kg (N=3) 0.25 mg/kg (N=3) 0.50 mg/kg (N=3) 0.75 mg/kg (N=6) 1.0 mg/kg (N=3) 1.33 mg/kg (N=6) 1.75 mg/kg (N=2) Overall (N=26) Diarrhea 1 1 1 1 4 (15%) Muscle Spasms 2 1 1 4 (15%) Bone Pain 1 2 3 (12%) Fatigue 3 3 (12%) Myalgia 1 1 1 3 (12%) Nasopharyngitis 1 2 3 (12%)

Adverse Events in ≥ 10% of Patients (Regardless of Causality):

Data as of 03 Oct 2014

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SLIDE 11

Low Transfusion Burden (LTB) Patients

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SLIDE 12

Maximum Hemoglobin Increase in LTB Patients

Data as of 03 Oct 2014

LTB, low transfusion burden Mean (SD) Max. Change in Hemoglobin (g/dL)

0.8 1.0 2.2 3.5 0.0 1.0 2.0 3.0 4.0 0.125 (n=1) 0.25 (n=1) 0.75 (n=3) 1.75 (n=2) Dose Group (mg/kg)

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SLIDE 13

LTB Patients: Hemoglobin Response

Response Criteria 0.125-0.5 mg/kg N=2 n (%) 0.75-1.75 mg/kg N=5 n (%) Hemoglobin increase ≥1.5 g/dL for ≥2 weeks 4 (80%) Hemoglobin increase ≥1.5 g/dL for ≥8 weeks (HI-E) 2 (40%)

  • All 5 patients at the higher dose levels had prior ESA treatment
  • No patients received prior lenalidomide treatment

Data as of 03 Oct 2014

LTB, low transfusion burden

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SLIDE 14

LTB Responder (HI-E): Hemoglobin

Hemoglobin (g/dL) Weeks

  • 0.56 mg/kg (dose reduced by 25%)

Data as of 03 Oct 2014

LTB, low transfusion burden

2

1 2 3 4 5 6 7 8

6 7 8 9 10 11 12 13 ‐8 ‐6 ‐3 BL 3 6 9 12 16 20 24

Units Transfused Hemoglobin Follow‐up Period Dose held for Hb >12 g/dL

  • 0.75 mg/kg (starting dose)

78 year old male RCMD‐RS EPO non‐responder

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SLIDE 15

High Transfusion Burden (HTB) Patients

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SLIDE 16

HTB, high transfusion burden

HTB Patients: Transfusion Response

  • 9/19 (47%) of patients received prior ESA treatment
  • 5/19 (26%) of patients received prior lenalidomide treatment

RBC Transfusion Reduction over 8 Weeks 0.125‐0.5 mg/kg N=7 n (%) 0.75‐1.75 mg/kg N=12 n (%) ≥4 Units or ≥50% 3 (43%) 5 (42%) ≥4 Units (HI‐E) 2 (29%) 5 (42%) Transfusion Independence (TI) 1 (14%) 3 (25%)

Data as of 03 Oct 2014

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SLIDE 17

HTB Responder (HI-E):d RBC Transfusions

Weeks

Data as of 03 Oct 2014

HTB, high transfusion burden

Hemoglobin (g/dL)

Follow‐up Period

2 2

2 4 6 8 10 12

5 6 7 8 9 10 11 ‐3 BL 3 6 9 12 16 20 24

Units Transfused Hemoglobin 0.75 mg/kg (starting dose)

71 year old female RCMD‐RS Failed LEN, EPO

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SLIDE 18

Efficacy Summary: HI-E Response Rate

Patient Subgroup 0.125‐0.5 mg/kg (N=9) n (%) 0.75‐1.75 mg/kg (N=17) n (%) LTB patients (N=7) 0/2 (0%) 2/5 (40%) HTB patients (N=19) 2/7 (29%) 5/12 (42%) All patients (N=26) 2/9 (22%) 7/17 (41%)

HI‐E (IWG): LTB: Hemoglobin increase ≥1.5 g/dL for ≥8 weeks HTB: Reduction of ≥4 units RBCs transfused over 8 weeks

HI‐E, hematologic improvement‐erythroid IWG, International Working Group LTB, low transfusion burden; HTB, high transfusion burden

Data as of 03 Oct 2014

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SLIDE 19

HI-E Response Rate by Ring Sideroblast Morphology, SF3B1 Mutation

Data as of 03 Oct 2014

Baseline Status Response Rate (HI‐E) n (%) All Patients (N=17) 7 (41%) Ring Sideroblasts RS ≥15% (N=13) 7 (54%) RS <15% (N=4) 0 (0%) Response Rate at Higher Dose Levels (0.75‐1.75 mg/kg)

* All 9 patients with SF3B1 mutation present had RS ≥15% ** Includes all 3 patients who became transfusion independent

SF3B1 Mutation SF3B1 Mutation Present (N=9)* 6 (67%)** SF3B1 Mutation Absent (N=8) 1 (13%)

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SLIDE 20

Luspatercept PACE-MDS Study: Conclusions

  • Luspatercept was safe and well tolerated for 3 months of

treatment

  • Erythroid response (HI‐E, IWG) was achieved in 41% of

patients treated at ≥0.75 mg/kg

  • Erythroid response (HI‐E, IWG) was achieved in 67% of

ring sideroblast (+) patients with SF3B1 mutations

  • These data strongly support further evaluation of

luspatercept in patients with lower‐risk MDS

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SLIDE 21

Luspatercept PACE-MDS Study: Acknowledgements

  • German MDS Study Group (DMDS)

– Principal Investigators: U. Platzbecker, U. Germing, A. Giagounidis, K. Goetze,

  • P. Kiewe, K. Mayer, O. Ottman, M. Radsak, T. Wolff

– Sub‐Investigators: K. Sockel, K. Trautmann‐Grill, J. Middeke, C. Müller‐Thomas,

  • F. Crespo, S. Gröpper, G. Bug, F. Lang, L. Wunderle, V. Janzen, J. Alt, J. Beck, G. Heß,
  • T. Kindler, T. Wehler, D. Sasca, A. Kündgen, J. Neukirchen, O. Knigge, A. Kirsch,
  • V. Böhme, A. Mohr, U. Brandl
  • Acceleron: K. Attie, M. Sherman, M. Hankin, D. Wilson, X. Zhang, C. Rovaldi,
  • B. O‘Hare, T. Akers, E. Raptis‐Zarou, T. Sacco
  • Celgene: A. Laadem, S. Ritland
  • Chiltern: C. Lanza, F. VanderSchueren, L. Alexander, G. Hahn
  • Central Labs: CRL, ICON, Genoptix
  • Central Labs (Bone Marrow): A. Giagounidis, D. Haase, H. Kreipe, U. Oelschlägel
  • Sponsored by Acceleron and Celgene

D·MDS

Deutsche MDS-Studiengruppe