luspatercept (ace-536) increases hemoglobin and decreases...

Luspatercept (ACE-536) Increases Hemoglobin and Decreases Transfusion Burden and Liver Iron Concentration in Adults with Beta-Thalassemia: Preliminary Results from a Phase 2 Study

Antonio G. Piga, MD1, Silverio Perrotta, MD2, Angela Melpignano, MD3, Caterina Borgna-Pignatti, MD4, M. Rita Gamberini, MD4, Ersi Voskaridou, MD5, Vincenzo Caruso, MD6, Aldo Filosa, MD7, Yesim Aydinok, MD8, Antonello Pietrangelo, MD9 Xiaosha Zhang10, Ashley Bellevue10, Dawn M. Wilson10, Abderrahmane Laadem, MD11, Matthew L. Sherman, MD10 and Kenneth M. Attie, MD10

1A.O.U. San Luigi Gonzaga, Orbassano, Turin, 2A.O.U. Second University of Naples, 3Ospedale "A. Perrino", Brindisi, 4Arcispedale S.Anna, Cona, Ferrara, Italy; 5Laiko General Hospital, Athens, Greece; 6ARNAS Garibaldi, Catania, 7AORN "A. Cardarelli“, Naples, Italy; 8Ege University Children's Hospital, Bornova-Izmir, Turkey; 9CEMEF, Medicina 2, Modena, Italy; 10Acceleron Pharma, Cambridge, MA, USA; 11Celgene Corporation, Summit, NJ, USA.

β-Thalassemia

β-thalassemia is an inherited anemia due to defective synthesis of β-globin

– Excess unpaired α-globin chains lead to ineffective erythropoiesis

Ineffective erythropoiesis is characterized by expanded RBC proliferation and elevated GDF11 and other TGF-β superfamily ligands and Smad 2/3 signaling

Rund D, Rachmilewitz E, NEJM 2005

Erythroid Precursors in Bone Marrow

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β-Thalassemia

β-thalassemia is an inherited anemia due to defective synthesis of β-globin

– Excess unpaired α-globin chains lead to ineffective erythropoiesis

Ineffective erythropoiesis is characterized by expanded RBC proliferation and elevated GDF11 and other TGF-β superfamily ligands and Smad 2/3 signaling

Retic Baso E BFU-E CFU-E Pro E RBC Poly E Ortho E

Increased GDF signaling inhibits RBC maturation

Increased EPO levels drive proliferation

2

Ineffective Erythropoiesis Drives β-Thalassemia Complications

No approved drug therapy for anemia due to β-thalassemia

Ineffective Erythropoiesis

Anemia/Hemolysis

Splenomegaly, EMH Masses, Bone Deformities,

Osteoporosis

Pulmonary Hypertension, Thrombotic events,

Leg Ulcers

Iron Overload

Endocrinopathies, Liver disease, Heart Disease

RBC Transfusions

Iron chelation

Modified ECD of ActRIIB receptor

Fc domain of human IgG1 antibody

Luspatercept is an experimental drug that is a recombinant fusion protein containing a modified extracellular domain (ECD) of the activin receptor type IIB (ActRIIB)

Binds to GDF11 and other ligands, inhibits Smad 2/3 signaling, and promotes late-stage erythroid differentiation1

Increased hemoglobin levels in a Phase 1 healthy volunteer study2

1Suragani R et al., Nature Med 2014 2Attie, K et al.. Am J Hematol 2014 3

RAP-536 (Murine Luspatercept) Reduces Ineffective Erythropoiesis and Disease Burden in Mouse Model of β-thalassemia

Ineffective Erythropoiesis

Anemia/Hemolysis

Splenomegaly, EMH Masses, Bone Deformities,

Osteoporosis

Pulmonary Hypertension, Thrombotic events,

Leg Ulcers

Iron Overload

Endocrinopathies, Liver disease, Heart Disease

Luspatercept

Spleen Bone Liver Iron

Suragani R et al., Blood, 2014

RBC Transfusions

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Luspatercept β-Thalassemia Phase 2 Study - Overview

A phase 2, multicenter, open-label, dose escalation study in adults with β-thalassemia

Primary efficacy objectives:

• Non-transfusion dependent (NTD): Hemoglobin increase ≥ 1.5 g/dL

• Transfusion dependent (TD): Transfusion burden decrease over 12 wk

Secondary objectives:

• Safety

• Liver iron concentration (by MRI)

• Health-related Quality of Life (SF-36, FACT-An, NTD-PRO)

• Biomarkers of erythropoiesis

NTD: Non-transfusion dependent patients (< 4 Units/8 wk, Hb <10 g/dL)

TD: Transfusion dependent patients (≥ 4 Units/8 wk) 5

Luspatercept β-Thalassemia Phase 2 Study - Overview

Base study (n=64): Up to 5 doses SC q 3 weeks for 3 months

• Dose escalation phase (n=35): 0.2, 0.4, 0.6, 0.8, 1.0, 1.25 mg/kg

• Expansion cohort (n=29): starting dose 0.8, titration up to 1.25 mg/kg

• 59 patients were efficacy evaluable (5 patients ongoing with <12 weeks treatment)

Base Study (n=64) 3 Months

Follow-Up 2 Months

NCT01749540

Extension Study (n=51) 24 Months (ongoing)

NCT02268409

Data as of 25 Sept 2015 6

Extension study (n=51): additional 24 months of treatment

Baseline Characteristics

Evaluable Patients N=59

Age, yr, median (range) 37 (20-61)

Sex, male, n (%) 29 (49%)

Splenectomy, n (%) 41 (70%)

Non-Transfusion Dependent (NTD) N=31 (53%)

Hemoglobin, g/dL, median (range) 8.4 (6.5-9.6)

LIC, mg/g dw, mean ± SD 5.6 ± 3.8

Transfusion Dependent (TD) N=28 (47%)

RBC Units/12 weeks, median (range) 8 (4-18)

LIC, mg/g dw, mean ± SD 4.5 ± 4.6

LIC: liver iron concentration (by MRI); dw: = dry weight

Data as of 25 Sept 2015



EFFICACY: Hemoglobin in NTD Patients with 3 Months Treatment Dose-Dependent Increase

Mean hemoglobin increased steadily during 3 months of luspatercept treatment and returned to baseline in the absence of treatment during (n=24)

Data as of 25 Sept 2015 NTD: Non-transfusion dependent patients (< 4 Units/8 wk, Hb <10 g/dL) 8

PLANNED DOSES:

3

2

1

0

-1

0 1 2 3 4 5 6 Months

Me

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SE)

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g/d

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PROGRAM: W:\Production\ACL\A536\04_06_All\program\tfl\f_01c4_bchg_hgb_se_04_ntd_ppt2_njs.sas, Date: 04DEC2015 14:42

PostBaseline=Mean Change from baseline in Hgb values excluding Hgb values <14 days following a transfusion

Baseline=Mean of 2 or more pretreatment Hgb values between (-28<= day <=1), excluding Hgb values <14 days following a transfusion

Patient calculated study days which are +/- 3 days of a scheduled study day are windowed to that study day

# of subjects = Number of Observations at T ime point in dose group

Note: Interrupted patients use 04 data only

Figure 1.C4 Hemoglobin Mean Change From Baseline(Low Transfusion Burden)

Preliminary Data as of Sep 25, 2015

Acceleron Pharma - Protocol: A536-04

17 17 17 17 17 17 17 17 17 16 16 17 15 12 17 12 12 5

7 7 7 7 7 7 7 6 6 6 6 5 6 5 4 4 3 1

Low:

High:

# of subjects:

0 1 2 3 4 5 6

Months

-1.0

-0.5

0.0

0.5

1.0

1.5

2.0

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3.0

Hgb

Cha

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from

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e (g

/dL

)

High Dose Group (N=7)Low Dose Group (N=17)

0 1 2 3 4 5 6

Months

-1.0

-0.5

0.0

0.5

1.0

1.5

2.0

2.5

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Hgb

Cha

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/dL

)

High Dose Group (N=7)Low Dose Group (N=17)0.2-0.6 mg/kg (N=17) 0.8-1.25 mg/kg (N=7)

Follow-up Period

Increase in mean hemoglobin over a 12-week period in NTD patients treated in the long-term extension study (n=17)

• 65% (11/17) increased Hb ≥ 1.0 g/dL • 47% (8/17) increased Hb ≥ 1.5 g/dL

Data as of 25 Sept 2015 NTD: Non-transfusion dependent patients (< 4 Units/8 wk, Hb <10 g/dL)

3

2

1

0

-1

0 1 2 3 4 5 6 Months

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EFFICACY: Hemoglobin in NTD Patients with > 3 Mo Treatment Sustained Improvement

Me

an (

SE)

Ch

ange

in H

em

ogl

ob

in (

g/d

L)

PROGRAM: W:\Production\ACL\A536\04_06_All\program\tfl\f_01c4_bchg_hgb_se_06_ntd_ppt5_njs.sas, Date: 04DEC2015 14:48

PostBaseline=Mean Change from baseline in Hgb values excluding Hgb values <14 days following a transfusion

Baseline=Mean of 2 or more pretreatment Hgb values between (-28<= day <=1), excluding Hgb values <14 days following a transfusion

Patient calculated study days which are +/- 3 days of a scheduled study day are windowed to that study day

# of subjects = Number of Observations at T ime point in dose group

Note: Direct rollover patients use both 04/06 data and Interrupted patients use 06 data only

Figure 1.C4 Hemoglobin Mean Change From Baseline(Non-Transfusion Dependent)

Preliminary Data as of Sep 25, 2015

Acceleron Pharma - Protocol: A536-06

17 17 8 16 8 8 16 14 7 14 9 8 15 15 8 15 13 11 *

# of subjects:

0 1 2 3 4 5 6

Months

-1.0

-0.5

0.0

0.5

1.0

1.5

2.0

2.5

3.0

Hgb

Cha

nge

from

Bas

elin

e (g

/dL

)

0.8-1.25 mg/kg (N=17)

EFFICACY: Reduction in Transfusion Burden, LIC in TD Patients

Transfusion reduction from 12 weeks pre-treatment to a 12-week period on treatment: • 79% (22/28) had ≥ 20% reduction (study primary endpoint) • 75% (21/28) had ≥ 33% reduction; 57% (16/28) had ≥ 50% reduction

Data as of 25 Sept 2015 * 5 subjects discontinued before completing 12 weeks

10

-100

-90

-80

-70

-60

-50

-40

-30

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-10

018 14 12 12 8 7 7 8 8 8 9 7 5 8 8 6 6 7 8 8 4 6 6

% C

han

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RB

C U

nit

s /1

2 W

ee

ks

1° Endpoint

Mean: -56% (n=23*)

Baseline Units / 12 Wks:

>20 Units/ 24 Wk

Liver Iron Concentration (LIC): All TD patients received iron chelation therapy • 50% (4/8) with baseline LIC ≥ 5 mg/g dw had decrease in LIC ≥ 2 mg/g dw • 100% (14/14) with baseline LIC < 5 mg/g dw maintained LIC < 5

Change in Liver Iron Concentration (MRI) at Wk 16 in NTD Patients


< 5 mg/g dw ≥ 5 mg/kg dw

Baseline LIC:

LIC

Ch

ange

at

We

ek

16

(m

g/g

dw

)

-5

-4

-3

-2

-1

0

1

2

3

1.7 1.0 2.4 1.9 3.6 3.3 1.3 3.6 0.9 4.9 1.0 2.1 4.3 4.1 7.9 5.4 8.0 8.9 11.1 5.4 8.5 8.6 8.5 5.2 7.0 13.6 11.1 15.1

No Iron Chelation Therapy Iron Chelation Therapy

36% (5/14) with baseline LIC ≥ 5 mg/g dw had decrease in LIC ≥ 2 mg/g dw

100% (14/14) patients with baseline LIC < 5 mg/g dw maintained LIC < 5

EFFICACY: Quality of Life (SF-36,FACT-An) in NTD Patients Improvement Correlated with Increase in Hemoglobin

Hemoglobin change from baseline (g/dL)

Ch

ange

in F

AC

T-A

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ne

mia

Sco

re

Data as of 25 Sept 2015 NTD: Non-transfusion dependent patients (< 4 Units/8 wk, Hb <10 g/dL) 12

SF-36 (Short Form 36-item health survey)

– Patient-Reported Outcome (PRO) survey of health status

– Physical Component Summary (PCS) sub-score increase correlated with hemoglobin increase at Week 12 and Week 24 (p<0.05)

FACT-An (Functional Assessment of Cancer Therapy – Anemia)

– PRO assesses fatigue and anemia-related symptoms

– Anemia subscale (20 items) increase correlated with hemoglobin increase:

EFFICACY: Leg Ulcers Persistent Healing

3 patients with long-term, persistent leg ulcers experienced rapid healing with luspatercept treatment

– 2 additional patients have had partial response

Sustained healing in a patient treated over 2 years

Pre-Treatment After 6 Weeks After 2 Years


SAFETY: Summary

No related serious adverse events

Related grade 3 adverse events included: headache (n=1), bone pain (n=3), asthenia (n=2), myalgia (n=1)

6/59 (10%) patients discontinued early associated with an AE: bone pain (n=2), arthralgia, asthenia, cerebrovascular accident, headache (n=1 each)

Preferred Term NTD N=31

TD N=28

Overall N=59

Bone pain 8 (26%) 13 (46%) 21 (36%) Myalgia 3 (10%) 8 (29%) 11 (19%) Headache 5 (16%) 6 (21%) 11 (19%) Arthralgia 3 10%) 7 (25%) 10 (17%) Musculoskeletal pain 4 (13%) 4 (14%) 8 (14%) Asthenia 1 (3%) 5 (18%) 6 (10%) Injection site pain 1 (3%) 3 (11%) 4 (7%) Back pain 1 (3%) 2 (7%) 3 (5%) Pain in Jaw 1 (3%) 2 (7%) 3 (5%)

Related Adverse Events (all grades) in ≥ 5% Patients, n (%)

Data as of 25 Sept 2015



Luspatercept β-Thalassemia Phase 2 Study: Conclusions

Favorable safety profile with no related serious adverse events

Sustained hemoglobin increases in NTD patients and reduced transfusion burden in TD patients were observed in the majority of patients in the higher dose groups

Reductions in liver iron concentration (LIC), improvement in Quality of Life scores, and rapid healing of leg ulcers were also observed

These results support Phase 3 studies of luspatercept in patients with β-thalassemia (BELIEVE)

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The BELIEVE Study Phase 3 Study of Luspatercept in β-thalassemia

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Patient Population / Study Design

Key Inclusion Criteria

Primary Efficacy Endpoint

Randomized, double-blind, placebo-controlled study in adult β-thalassemia patients (including HbE/β-thal)

300 patients, randomized 2:1; luspatercept 1 mg/kg SC every 3 weeks, titration up to 1.25 mg/kg possible

Patients who receive 6-20 units of RBCs over past 24 weeks and no transfusion-free period ≥ 35 days (regularly transfused patients)

No ESA or hydroxyurea

Sponsored by Celgene NCT02604433

Proportion of patients with ≥ 33% reduction in transfusion burden from weeks 13-24 compared to the 12 weeks preceding treatment

Luspatercept β-Thalassemia Phase 2 Study: Acknowledgments

Investigators: A Piga, A Melpignano, S Perrotta, C Borgna-Pignatti, MR Gamberini, V Caruso, E Voskaridou, A Filosa, A Pietrangelo

Sub-investigators: I Alasia, M Limone, E Longoni, F Della Rocca, U Pugliese, I Tartaglione, L Manfredini, A Quarta, G Abbate, S Anastasi, R Lisi, M Casale, P Cinque, S Costantini, M Marsella, P Ricchi, A Spasiano

Acceleron: K Attie, M Sherman, D Wilson, A Bellevue, C Rovaldi, B O‘Hare, T Akers, X Zhang, J Desiderio, S Ertel, T Sacco

Celgene: A Laadem, S Ritland, J Zou, N Chen

Chiltern: C Lanza, F Van der Schueren, M Belfiore

Central Labs: CRL, ICON, ILS

Independent Safety Reviewer: E Neufeld

Sponsored by Acceleron Pharma and Celgene

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luspatercept (ace-536) increases hemoglobin and decreases...

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