Presenting author disclosures O.H.: Roche consultancy; BMS - - PowerPoint PPT Presentation

Longitudinal effect of luspatercept treatment on iron

• verload and iron chelation therapy in adult patients

with β-thalassemia in the BELIEVE trial

Olivier Hermine, 1,2 Maria Domenica Cappellini, 3 Ali T . Taher, 4 Thomas D. Coates, 5,6 Vip Viprakasit, 7 Ersi Voskaridou, 8 Ashutosh Lal, 9 Hong Keng Liew, 10 S ilverio Perrotta, 11 Abderrahim Khelif, 12 Antonis Kattamis, 13 Jeevan K. S hetty, 14 George Zhang, 15 Yu (Olivia) Tian, 15 Dimana Miteva, 14 Tatiana Zinger, 14 Derek Tang, 15 Jay T . Backstrom, 16 John B. Porter17

1Imagine Inst it ut e, INS

ERM U1163, Universit y of Paris, Paris, France; 2Depart ment of Hemat ology, Necker Hospit al, Assist ance Publique-Hôpit aux de Paris, Paris, France; 3Fondazione IRCCS Ca’ Granda Policlinico Hospit al, Universit y of Milan, Milan, It aly; 4Depart ment of Int ernal Medicine, American Universit y of Beirut Medical Cent er, Beirut , Lebanon; 5Children's Cent er for Cancer and Blood Diseases, Children's Hospit al Los Angeles, Los Angeles, CA; 6US C Keck S chool of Medicine, Los Angeles, CA; 7S iriraj Hospit al, Mahidol University, Bangkok, Thailand; 8Thalassemia and S ickle Cell Cent er of Laiko General Hospit al, At hens, Greece; 9Universit y of California S an Francisco, Benioff Children’s Hospit al, Oakland, CA; 10Hospit al S ult anah Bahiyah, Alor S et ar, Malaysia; 11Universit à della Campania, Luigi Vanvit elli, Casert a, It aly; 12Farhat Hached Teaching Hospit al, S

• usse Universit y,

Tunisia; 13First Depart ment of Pediatrics, Nat ional and Kapodist rian University of At hens, At hens, Greece; 14Celgene Int ernat ional, a Brist ol-Myers S quibb Company, Boudry, S witzerland; 15Brist ol Myers S quibb, Princet on, NJ; 16Acceleron Pharma, Cambridge, MA; 17Universit y College London, Universit y College London Hospit als, London, UK

Present at ion 1697

Presenting author disclosures

O.H.: Roche – consultancy; BMS – consultancy, research funding; AB S cience – consultancy, current equity holder in publicly-traded company, honoraria, patents, royalties, research funding; Alexion, Novartis - research funding.

2

Introduction

3

• RBC transfusions are the main supportive treatment

for chronic anemia due to β-thalassemia1

–

Transfusion-dependent pat ient s require ICT t o prevent iron overload from RBC t ransfusions and associat ed complicat ions2

• Thus, there is a clinical need to reduce transfusions

and iron burden in patients with anemia due to

β-thalassemia

• Luspatercept, a first-in-class erythroid maturation

agent, is approved by the US Food and Drug Administration for the treatment of anemia in adult

patients with β-thalassemia requiring regular RBC

transfusions3–

6

• This analysis assessed the effect of long-term

luspatercept use on iron loading and ICT use in the phase 3 BELIEVE trial (NCT02604433)7

aβ-thalassemia or Hb E / β-thalassemia (compound β-thalassemia with mutation and/or multiplication of α-globin genes was allowed). bPatients could receive RBC transfusions to maintain their

baseline Hb level and ICT. cThe trial is fully enrolled and patients continue to receive treatment or follow-up. BSC, best supportive care; Hb, hemoglobin; ICT, iron chelation therapy; RBC, red blood cell; s.c., subcutaneously.

• 1. Taher AT, et al. Lancet 2018;391:155–
• 167. 2. Taher AT, Cappellini MD. Blood 2018;132:1781–
• 1791. 3. Suragani RNVS, et al. Blood 2014;123:3864–
• 3872. 4. Attie KM, et al. Am J Hemat ol

2014;89:766–

• 770. 5. Piga A, et al. Blood 2019;133:1279–
• 1289. 6. Reblozyl (luspatercept-aamt) [package insert]. Summit, NJ: Celgene Corporation; April 2020. 7. Cappellini MD, et al.

N Engl J Med 2020;382:1219– 1231.

Patients with β-t halassemiaa ≥ 18 years of age, requiring regular RBC

t ransfusions (defined as: 6– 20 RBC unit s in t he 24 weeks prior t o randomization wit h no > 35-day t ransfusion-free period during t hat t ime) (N = 336) Luspaterceptb 1 mg/ kg s.c. every 21 days + BS C (n = 224) Placebob s.c. every 21 days + BS C

(n = 112)

Open-label (up t o 5 years) Post -t reat ment follow-up (3 years) S t udy unblinding Double-blind period (48 weeks)

Crossover from placebo to luspatercept permitted (n = 92)

Randomized 2:1 Current study statusc

Figure 1. BELIEVE study trial design

Results

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aDefined as the mean of all documented pre-transfusion Hb values during the 24 weeks prior to first dose for each patient. bDefined as started before the start of study treatment and either

ended before the start of the study treatment or continued after study treatment. cAnalyzed using the safety population (luspatercept n = 223, placebo n = 109). dw, dry weight; LIC, liver iron concentration; SD, standard deviation; SF, serum ferritin; T2* MRI, T2-weighted magnetic resonance imaging.

Characteristic Luspatercept (N = 224) Placebo (N = 112) Age, median (range), years 30 (18– 66) 30 (18– 59) Female, n (% ) 132 (58.9) 63 (56.3) Hb (24 weeks), 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 6.1 (3– 14) 6.3 (3– 12) RBC transfusion burden, median (range), units/24 weeks 14 (6– 24) 15 (6– 26) Splenectomy, n (% ) 129 (57.6) 65 (58.0)

SF, mean (SD), μg/L

2,097 (1,757) 1,845 (1,669) LIC, mean (SD), mg/g dw > 3 mg/ g dw, n (% ) 12.0 (14.8) 154 (68.8) 10.1 (11.5) 75 (67.0) Myocardial iron by T2* MRI, mean (SD), ms 33.5 (16.2) 34.8 (10.7) ICT useb,c, n (% ) Deferasirox 139 (62.3) 63 (57.8) Deferiprone 92 (41.3) 40 (36.7) Deferoxamine mesylat e / deferoxamine 83 (37.2) 39 (35.8)

• Table. Patient baseline characteristics

Results (cont.)

5

Data cutoff: July 1, 2019. P values are estimated from Cochran-Mantel-Haenszel test. SF levels ≥ 1,000 μg/L and ≥ 2,500 μg/ L indicate iron overload and increased risk of cardiac-related mortality, respectively.

aPlacebo patients evaluated up to Week 48.

Figure 2. Decrease in SF categories baseline ≥ 1,000 μg/ L to post-baseline < 1,000 μg/ L (A) and baseline ≥ 2,500 μg/ L to post-baseline < 2,500 μg/ L (B)

17.0 (24/ 141) 23.7 (32/ 135) 29.5 (38/ 129) 46.4 (26/ 56) 5.0 (3/ 60) 8.8 (5/ 57)

10 20 30 40 50 60 70 80 90 100

12.3 (8/ 65) 19.0 (12/ 63) 23.7 (14/ 59) 33.3 (7/ 21) 7.7 (2/ 26) 8.3 (2/ 24)

Weeks 1– 24 Weeks 25– 48 Weeks 49– 72 Weeks 73– 96

+39.3% +24.3% +57.6%

Baseline SF ≥ 1,000 μg/L to post-baseline < 1,000 μg/L

Patients (% )

P = 0.023 P = 0.017

Luspat ercept Placeboa

+54.8% +24.6% +40.5%

Baseline SF ≥ 2,500 μg/L to post-baseline < 2,500 μg/L

P = 0.527 P = 0.227

Weeks 1– 24 Weeks 25– 48 Weeks 49– 72 Weeks 73– 96

A B

Results (cont.)

6

Data cutoff: July 1, 2019. P values are estimated from Cochran– Mantel–

Haenszel test. Patients with LIC ≥ 3 mg/g dw are considered to have iron overload. Myocardial iron T2* < 20 ms indicates increased cardiac risk.

aPlacebo patients evaluated up to Week 48.

Figure 3. Decrease in LIC (A) and myocardial iron T2* categories (B)

A B

4.2 (5/ 120) 9.7 (13/ 134) 14.3 (15/ 105) 6.6 (4/ 61) 5.9 (4/ 68)

2 4 6 8 10 12 14 16 Week 24 Week 48 Week 96 Patients (% )

20.0 (6/ 30) 25.0 (6/ 24) 9.1 (1/ 11)

5 10 15 20 25 30 Week 48 Week 96 Patients (% )

LIC Baseline > 3 mg/g dw to post-baseline ≤ 3 mg/g dw Myocardial iron T2*

Baseline ≤ 20 ms to post-baseline > 20 ms

Luspat ercept Placeboa

P = 0.417 P = 0.486 P = 0.357

Results (cont.)

7

• The mean (S

D) daily dose of deferasirox in all luspatercept-treated patients at baseline was 1,332.37 mg (1,087.0)

• During Weeks 85–

96, the mean change (S D) in daily dose of deferasirox from baseline in the luspatercept arm overall (n = 118), responders (n = 32), and non-responders (n = 86) was

−189.8 mg (768.5), −201.1 mg (740.2), and −185.6 mg (783.0), respectively

• The mean change (S

D) in the luspatercept arm

• verall at Week 144 (n = 25) was −810.1 mg

(1,614.8)

Data cutoff: July 1, 2019. Only a small number of patients could be evaluated at the later time points due to poor tracking and ICT adherence.

aIncludes only patients initially randomized to receive luspatercept. bResponders are defined as patients achieving ≥ 33% reduction in transfusion burden during Weeks 13–

24, with a reduction

• f ≥ 2 RBC units, versus baseline.

60 70 80 90 100

Figure 4. Luspatercept-treated patients receiving

≥ 1 ICT over timea

Patients (%

)

Overall Responders Non-responders 219 46 173 92 27 65 133 37 96 142 38 104 148 41 107 186 42 144 169 41 128 161 42 119 217 46 171 207 46 161 200 45 155 195 44 151 28 8 20

Luspat ercept (overall) Luspat ercept respondersb Luspat ercept non-responders

Weeks

S ummary

8

• A significant number of luspatercept-treated patients with baseline SF ≥ 1,000 μg/L shifted to

SF < 1,000 μg/L during the first 48 weeks

• The proportion of patients receiving ≥ 1 ICT gradually declined in both luspatercept responders

and non-responders over time up to Week 144

• Both luspatercept responders and non-responders experienced decreases in mean daily dose of

deferasirox over time

Acknowledgments

• The study was supported by Celgene, a Bristol-Myers S

quibb Company, in collaboration with Acceleron Pharma

• All authors contributed to and approved the presentation; writing and editorial assistance

were provided by Jacqueline Moy, PhD, of Excerpta Medica, funded by Bristol Myers S quibb

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