dm+d

Unassigned

New Medicines

ReblozylBeta-thalassaemia - treatment of anaemia in regularly transfused adults

Information

Reblozyl
New molecular entity
Celgene
Acceleron

Development and Regulatory status

Licensed but not launched
Licensed but not launched
Launched
Yes
Yes
Jun 20Approved in EU for treatment of transfusion-dependent anaemia associated with myelodysplastic syndromes (MDS) or beta thalassaemia [19].
Apr 20Recommended for EU approval by CHMP - the full indication is "treatment of adult patients with transfusion-dependent anaemia due to very low, low and intermediate-risk myelodysplastic syndromes (MDS) with ring sideroblasts, who had an unsatisfactory response to or are ineligible for erythropoietin-based therapy and for the treatment of adult patients with transfusion-dependent anaemia associated with beta-thalassaemia" [17].
Nov 19Launched US [18].
Nov 19Approved in US for treatment of anemia in adult patients with beta thalassemia who require regular red blood cell transfusions. [15]
Jun 19FDA priority review has an an action date of 4.12.19 [14].
Apr 19Biological license application (BLA) filed for luspatercept for treatment of adults with with beta-thalassemia-associated anemia who require RBC transfusions. Filing was based on data from the BELIEVE study [12].
Apr 19Celgene has submitted an application to the European Medicines Agency [13].
Dec 18The companies announced plans for regulatory application submissions in the USA and Europe in H1 2019 [11].
Jul 16Now in PIII development [6].
May 15FDA grant luspatercept fast track designation for treating beta-thalassaemia [4].
Feb 15Plans to finalise PIII development plans with the regulatory authorities in 2015 [3].
Aug 14Orphan Drug status granted in EU [9].
Mar 13Granted orphan drug status in the US for the treatment of beta-thalassaemia [1].

Category

ACE-536 is a modified type II activin receptor fusion protein that acts as a ligand trap for members in the TGF-β superfamily involved in erythropoiesis. ACE-536 regulates late-stage erythrocyte precursor cell differentiation and maturation [1]
1.5% (80-90 million people) of the world population are carriers of β thalassaemia and 5% are carriers of α thalassaemia. β thalassaemia is prevalent in areas around the Mediterranean, in the Middle East, in Central, South, and Southeast Asia, and in Southern China [3].
Beta-thalassaemia - treatment of anaemia in regularly transfused adults
Subcutaneous injection

Further information

Yes

Trial or other data

Mar 20PIII BELIEVE trial is published; in adults with transfusion-dependent β-thalassemia (n=336), a larger proportion of patients who received luspatercept plus best supportive care had a reduction in their transfusion burden (of ≥33% and by ≥2 units at weeks 13-24 vs baseline; 21.4% vs. 4.5% with placebo, P<0.001) [16].
Dec 18Results of the PIII BELIEVE Trial (n=336) announced at the American Society of Hematology (ASH) Annual Meeting 2018. The trial assessed the ability of luspatercept to reduce the need for adults with anemia related to beta thalassemia to undergo red blood cell transfusions. BELIEVE met the primary endpoint of erythroid response, defined as a ≥33% reduction in RBC transfusion burden (with a reduction of ≥ 2 units of RBC) during weeks 13–24 compared to the baseline 12-week interval prior to randomization. Around 20% of pts who received luspatercept every 3 weeks experienced a 33% reduction in transfusion burden during weeks 13 - 24 vs. ~5% of those on placebo which resulted in the trial meeting its primary endpoint (p< 0.0001). Serious adverse events (anaemia, increased liver iron concentration and hyperuricaemia were the most common) were reported in 15% of those on luspatercept and 5.5% in those on placebo. A TEAE of acute cholecystitis resulted in death in one placebo-treated patient (0.9%). No luspatercept-treated patients died due to TEAEs.[11]
Jul 18Acceleron and Celgene announce that the BELIEVE study has met its primary and major secondary endpoints. Further details will be published at a medical meeting during 2018, and the companies plan regulatory submissions during the first half of 2019 [10].
May 16PIII BELIEVE (NCT02604433) study begins. Primary outcome is proportion of subjects with haematological improvement from Week 13 to Week 24 compared to 12-week prior to randomization. Collection of primary outcome data should complete Sep 18 [7].
Oct 15PIII BELIEVE study planned to begin by the end of the year; double-blind, randomized, placebo-controlled study of luspatercept in 300 regularly transfused beta-thalassemia patients. The primary endpoint is the proportion of patients with = 33% reduction in transfusion burden from weeks 13 to 24 compared to the 12 weeks preceding treatment. [5]
Jan 13NCT01749540 is a PII open-label, ascending dose study to evaluate the effects of ACE-536 in 50 patients with beta-thalassemia intermedia. ACE-536 will be administered subcutaneously every 3 weeks for up to 5 cycles. The primary outcome is erythroid response, defined as a Hb increase of ≥ 1.5 g/dl from baseline for ≥ 14 days (in the absence of transfusion) assessed at ~ 24 weeks from patient screening. The study started Jan 13 and is due to complete Nov 14 [2].

Evidence based evaluations

ReblozylMyelodysplastic syndromes (MDS) in patients previously treated with ESAs

Information

Reblozyl
New molecular entity
Celgene
Acceleron

Development and Regulatory status

Licensed but not launched
Licensed but not launched
Launched
Yes
Yes
Jun 20Approved in EU for treatment of transfusion-dependent anaemia associated with myelodysplastic syndromes (MDS) or beta thalassaemia [16].
Apr 20Recommended for EU approval by CHMP - the full indication is "treatment of adult patients with transfusion-dependent anaemia due to very low, low and intermediate-risk myelodysplastic syndromes (MDS) with ring sideroblasts, who had an unsatisfactory response to or are ineligible for erythropoietin-based therapy and for the treatment of adult patients with transfusion-dependent anaemia associated with beta-thalassaemia" [15].
Apr 20The FDA has approved luspatercept-aamt for the treatment of anemia failing an erythropoiesis stimulating agent and requiring 2 or more red blood cell (RBC) units over 8 weeks in adult patients with very low- to intermediate-risk myelodysplastic syndromes with ring sideroblasts or with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis [14].
Jun 19Licence application accepted in the US with a target action date of Apr 2020. The Marketing Authorization Application in the EU has also been successfully validated and the review is now underway [12].
Apr 19MAA submitted to EMA for treatment of adult patients with very low to intermediate-risk myelodysplastic syndromes (MDS)-associated anemia who have ring sideroblasts, require red blood cell (RBC) transfusions and have received or are not eligible for erythropoiesis-stimulating agents [11].
Apr 19Biological license application (BLA) filed for luspatercept for treatment of adults with very low to intermediate risk MDS-associated anemia who have ring sideroblasts and require RBC transfusions - filing was based on data from MEDALAST study [10].
Jul 18Companies plan to file regulatory applications in the US and Europe in the first half of 2019 [8].
Jul 16Now in PIII development [5].
Feb 15Celgene aims to finalise PIII development plans with the regulatory authorities in 2015 [3].
Aug 14Orphan Drug status granted in EU [7].
Mar 13Granted orphan drug status in the US for the treatment of myelodysplastic syndromes [1].

Category

ACE-536 is a modified type II activin receptor fusion protein that acts as a ligand trap for members in the TGF-β superfamily involved in erythropoiesis. ACE-536 regulates late-stage erythrocyte precursor cell differentiation and maturation. [1].
Annual incidence of MDS is estimated at 4 per 100,000, but many cases remain undiagnosed.
Myelodysplastic syndromes (MDS) in patients previously treated with ESAs
Subcutaneous injection

Further information

Yes

Trial or other data

Jan 20PIII MEDALIST (NCT02631070; n=153) is published; it found luspatercept reduced severity of anaemia in patients who had had disease refractory to/unlikely to respond to erythropoiesis-stimulating agents, with transfusion independence for ≥8 weeks reported in 38% patients as compared to 13% in placebo group (p<0.001) [13].
Dec 18Full data from PIII MEDALIST trial announced. As well as meeting its primary endpoint, the study also found that luspatercept treatment resulted in a significantly higher percentage of pts achieving RBC-TI of >12 weeks in the first 24 or 48 weeks as well as hematologic improvement-erythroid (HI-E) of >8 weeks. Treatment-emergent adverse events (TEAEs) of Grade 3 or 4 were reported in 42.5% (65/153) of pts receiving luspatercept vs. 44.7% on placebo. Progression to AML occurred in 4 pts, 3 (2.0%) on luspatercept and 1 (1.3%) on placebo. Five pts on luspatercept (3.3%) and 4 on placebo (5.3%) experienced >1 TEAE that resulted in death [9].
Jul 18Luspatercept meets primary endpoint in PIII MEDALIST trial. In patients with MDS, luspatercept achieved a statistically significant improvement in red blood cell transfusion independence of ≥8 consecutive weeks of treatment vs. placebo [8].
Feb 16PIII MEDALIST (NCT02631070) study starts. Collection of primary outcome data should complete June 2019 [6].
Oct 15PIII MEDALIST study planned to begin by the end of the year; double-blind, randomized, placebo-controlled study of luspatercept in 210 very low to intermediate risk MDS patients (the “MEDALIST” study). The primary endpoint is the proportion of patients that become red blood cell transfusion independent (= 8 weeks) during the first 24 weeks of the study [4].
Feb 15Luspatercept is a soluble, modified type II activin receptor fusion protein that promotes red blood cell formation by acting as a ligand trap for members of the TGF-beta superfamily involved in late stages of erythropoiesis. Luspatercept promotes late-stage erythrocyte precursor cell differentiation, in contrast to EPO which acts during the early, proliferative stages of erythropoiesis [3]
Mar 13NCT01749514 is a PII, open label, ascending dose study of ACE-536 for the treatment of anaemia in 60 patients with low or intermediate-1 risk myelodysplastic syndromes. ACE-536 will be administered subcutaneously every 3 weeks for up to 5 cycles The primary outcome is a modified erythroid response (MHI-eassessed at ~ 28 weeks from patient screening. The study started Jan 13 and is due to complete Nov 14 [2].

Evidence based evaluations

ReblozylThalassaemia beta - treatment of anaemia in non-transfusion-dependent adults

Information

Reblozyl
Licence extension / variation
Celgene
Acceleron

Development and Regulatory status

Phase II Clinical Trials
Pre-registration (Filed)
Filing withdrawn
Jun 22 BMS announces it has withdrawn sBLA for the the treatment of anemia in adults with non-transfusion dependent (NTD) beta thalassemia. They could not appropriately address the FDA´s questions about the benefit-risk profile n this patient population based on the current dataset from the Phase 2 BEYOND trial. While BMS will not pursue this indication in the US they will continue to evaluate luspatercept in a broad clinical development programme [8]
Dec 21FDA has accepted for priority review the sBLA for the treatment of anemia in adults with non-transfusion dependent (NTD) beta thalassemia. The FDA has set a Prescription Drug User Fee Act (PDUFA) goal date of March 27, 2022. In addition, the EMA has validated the Type II variation for Reblozyl in NTD beta thalassemia [6]
Feb 20Has orphan drug status in EU [3].

Category

ACE-536 is a modified type II activin receptor fusion protein that acts as a ligand trap for members in the TGF-β superfamily involved in erythropoiesis. ACE-536 regulates late-stage erythrocyte precursor cell differentiation and maturation [1]
1.5% (80-90 million people) of the world population are carriers of β thalassaemia and 5% are carriers of α thalassaemia. β thalassaemia is prevalent in areas around the Mediterranean, in the Middle East, in Central, South, and Southeast Asia, and in Southern China [3].
Thalassaemia beta - treatment of anaemia in non-transfusion-dependent adults
Subcutaneous

Further information

Yes

Trial or other data

Jun 21Company announces data from PII BEYOND study showed 77.7% of pts treated with luspatercept achieved a hemoglobin increase vs 0% of pts with placebo. For a key secondary endpoint, the study found during weeks 13-24, 52.1% of pts with luspatercept achieved a mean hemoglobin increase of ≥1.5 g/dL compared to baseline vs 0 pts with placebo. Also, 89.6% of pts with luspatercept remained transfusion free at weeks 1-24 vs 67.3% of pts with placebo. [5]
Apr 20PII BEYOND study is now due to complete collection of primary outcome data in Sep 20 [4].
Nov 19PII BEYOND study is no longer recruiting [2].
Feb 18PII BEYOND study to determine the efficacy and safety of luspatercept (ACE-536) versus placebo in adults with non-transfusion dependent beta (β)-thalassemia starts (NCT03342404).The study is divided into the Screening Period, Double-blind Treatment Period (DBTP) and Post-Treatment Follow-up Period (PTFP). It is planned to randomise 145 adults at a 2:1 ratio of luspatercept versus placebo in the US, Greece, Lebanon, Thailand, Italy and UK. Primary outcome is proportion of subjects who have an increase from baseline ≥1.0 g/dl in mean of haemoglobin values over a continuous 12-week interval Week 13 to Week 24 in the absence of transfusions; collection of these data is due to complete Nov 20 [2].

ReblozylMyelodysplastic syndromes (MDS) in ESA-naive patients

Information

Reblozyl
Licence extension / variation
Celgene
Acceleron

Development and Regulatory status

Phase III Clinical Trials
Phase III Clinical Trials
Phase III Clinical Trials
Yes
Yes

Category

ACE-536 is a modified type II activin receptor fusion protein that acts as a ligand trap for members in the TGF-β superfamily involved in erythropoiesis. ACE-536 regulates late-stage erythrocyte precursor cell differentiation and maturation [1].
Annual incidence of MDS is estimated at 4 per 100,000, but many cases remain undiagnosed.
Myelodysplastic syndromes (MDS) in ESA-naive patients
Subcutaneous injection

Further information

Yes