LUSPATERCEPT INCREASES HEMOGLOBIN AND DECREASES TRANSFUSION BURDEN IN ADULTS WITH Β-THALASSEMIA
Author(s): ,
Antonio Piga
Affiliations:
Turin University,Turin,Italy
,
Immacolata Tartaglione
Affiliations:
Second University of Naples,Naples,Italy
,
Rita Gamberini
Affiliations:
Arcispedale S. Anna, Cona,Ferrara,Italy
,
Ersi Voskaridou
Affiliations:
Laiko General Hospital,Athens,Greece
,
Angela Melpignano
Affiliations:
Ospedale 'A. Perrino',Brindisi,Italy
,
Paolo Ricchi
Affiliations:
AORN 'A. Cardarelli“,Naples,Italy
,
Vincenzo Caruso
Affiliations:
ARNAS Garibaldi,Catania,Italy
,
Antonello Pietrangelo
Affiliations:
CEMEF, Medicina 2,Modena,Italy
,
Xiaosha Zhang
Affiliations:
Acceleron Pharma Inc,Cambridge,United States
,
Dawn Wilson
Affiliations:
Acceleron Pharma Inc,Cambridge,United States
,
Ashley Leneus
Affiliations:
Acceleron Pharma Inc,Cambridge,United States
,
Abderrahmane Laadem
Affiliations:
Celgene Corporation,Summit,United States
,
Matthew L. Sherman
Affiliations:
Acceleron Pharma Inc,Cambridge,United States
,
Kenneth M. Attie
Affiliations:
Acceleron Pharma Inc,Cambridge,United States
Peter G. Linde
Affiliations:
Acceleron Pharma Inc,Cambridge,United States
(Abstract release date: May 18, 2017) EHA Learning Center. Piga A. Jun 23, 2017; 181416
Dr. Antonio Piga
Dr. Antonio  Piga

Access to EHA Members only content is an EHA membership benefit. Click here to join EHA or renew your membership here.


Abstract
Discussion Forum (0)
Rate & Comment (0)

Abstract: S129

Type: Oral Presentation

Presentation during EHA22: On Friday, June 23, 2017 from 11:45 - 12:00

Location: Room N105

Background
Luspatercept (ACE-536), a fusion protein containing a modified activin receptor type IIB, is being developed for the treatment of β-thalassemia. Luspatercept binds to select TGF-β superfamily ligands (such as GDF11) reducing aberrant Smad2/3 signaling and promoting late-stage erythroid differentiation and increased hemoglobin (Hgb). Luspatercept corrected the effects of ineffective erythropoiesis in a mouse model of thalassemia (Suragani R, Blood, 2014) and increased Hgb and was well tolerated in a phase 1 study in healthy volunteers (Attie K, Am J Hematol, 2014).

Aims
This ongoing, phase 2, multicenter, open-label study followed by a long-term extension (ext) study evaluates the effects of luspatercept in patients (pts) with either transfusion-dependent (TD) or non-transfusion dependent (NTD) β-thalassemia with key endpoints of erythroid response (including Hgb increase) and pt-reported quality-of-life (QoL) in NTD patients, and reductions in RBC transfusion burden in TD patients.

Methods
Inclusion criteria: age ≥18 yr and either TD (≥4 RBC U/8 weeks prior to first dose, confirmed over 6 months) or NTD (<4 RBC U/8 weeks prior to first dose with baseline Hgb <10 g/dL). Pts were treated every 3 weeks subcutaneously for up to 5 doses; 6 cohorts were treated at dose levels from 0.2-1.25 mg/kg. Pts in the expansion cohort and those who rolled over to the ext study were treated at ≥0.8 mg/kg with titration up to 1.25 mg/kg (base completed NCT01749540; ext ongoing NCT02268409).

Results
As of 02Sept2016, a total of 64 pts enrolled in the base study (31 TD, 33 NTD) and, of those, 51 enrolled in the ext study (24 TD, 27 NTD). Median (range) age (yr) was 38.5 (20-62); 67% had prior splenectomy. For TD pts, at baseline, median (range) transfusion burden was 8 U/12 weeks (4-18 U); mean (SD) liver iron concentration (LIC, mg/g dw) was 5.0 (5.3). For NTD pts, at baseline, median (range) Hgb (g/dL) 8.5 (6.5-9.8); mean (SD) LIC (mg/g dw) was 5.4 (3.8).

In base and ext, respectively, 22/31 (71%) and 20/24 (83%) TD pts achieved ≥33% and 17/31 (55%) and 17/24 (71%) achieved ≥50% reduction in transfusion burden over any 12-week period compared to baseline. Median duration of ≥33% reduction was 6.3 months (treatment ongoing).  
In base and ext, respectively, in NTD pts treated with ≥0.6 mg/kg, 13/21 (62%) and 21/27 (78%) achieved ≥1.0 g/dL and 7/21 (33%) and 14/27 (52%) achieved ≥1.5 g/dL increases in mean Hgb over any 12-week period compared to baseline. Median duration of Hgb increase ≥1.0 g/dL over 12 weeks in responders was 13.5 months (treatment ongoing). Increases in mean Hgb over a 12-week period correlated with improvement in a pt-reported QoL questionnaire, FACIT-F. 
Luspatercept was generally well tolerated, with no related serious adverse events and few grade 3 related AEs: bone pain (n=3), asthenia (n=2), and headache (n=1). The most frequent related AEs (≥10%) were bone pain, myalgia, headache, musculoskeletal pain, arthralgia, and injection site pain. 

Conclusion
Long-term luspatercept treatment in pts with β-thalassemia was generally safe and well tolerated. Efficacy was clinically relevant in both TD pts (decreased transfusion burden) and NTD pts (increased Hgb levels, improved QoL). A Phase 3, double-blind, placebo-controlled study of luspatercept in regularly transfused adults with β-thalassemia is ongoing (NCT02604433).

Session topic: 26. Thalassemias

Keyword(s): Thalassemia, TGF-, Erythropoieisis, Clinical Trial

Code of conduct/disclaimer available in General Terms & Conditions