Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Antianaemic preparations, other antianaemic preparations, ATC code: B03XA06.

Mechanism of action
Luspatercept, an erythroid maturation agent, is a recombinant fusion protein that binds selected transforming growth factor-β (TGF-β) superfamily ligands. By binding to specific endogenous ligands (e.g. GDF-11, activin B) luspatercept inhibits Smad2/3 signalling, resulting in erythroid maturation through expansion and differentiation of late-stage erythroid precursors (normoblasts) in the bone marrow, thereby restoring effective erythropoiesis. Smad2/3 signalling is abnormally high in disease models characterised by ineffective erythropoiesis, i.e. MDS and β-thalassaemia, and in the bone marrow of MDS patients.

Somatic mutations in MDS patients
Luspatercept demonstrated clinical benefit and favourability over epoetin alfa across multiple genomic mutations that are frequently observed in lower-risk MDS with the exception of CBL gene mutations.

Clinical efficacy and safety

Myelodysplastic syndromes
The efficacy and safety of luspatercept were evaluated in a Phase 3 multicentre, randomised, open- label, active controlled study COMMANDS (ACE-536-MDS-002) comparing luspatercept versus epoetin alfa in patients with anaemia due to International Prognostic Scoring System-Revised (IPSS-R) very low-, low- or intermediate-risk MDS or with myelodysplastic/ myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN RS-T) in ESA naïve patients (with endogenous sEPO levels of < 500 U/L) who require red blood cell transfusions. For eligibility, patients were required to have had 2 to 6 RBC units/8 weeks confirmed for a minimum of 8 weeks immediately preceding randomization. Patients with deletion 5q (del5q) MDS were excluded from the study.

Patients were treated for at least 24 weeks, unless the patient experienced unacceptable toxicities, withdrew the consent or met any other treatment discontinuation criteria. The treatment was continued beyond week 24 in case of clinical benefit (defined as a transfusion reduction of ≥ 2 pRBC units/8 weeks compared with baseline) and absence of disease progression. Based on the outcome of these assessments, patients either were discontinued from treatment and entered into the Post-Treatment Follow-up Period or continued open-label treatment (with luspatercept or epoetin alfa) as long as the above criteria continued to be met or until the patient experienced unacceptable toxicities, withdrew consent, or met any other discontinuation criteria.

A total of 363 patients were randomized to receive subcutaneously luspatercept (N = 182) or epoetin alfa (N = 181) at 1.0 mg/kg every 3 weeks or at 450 U/kg every week, respectively. Randomization was stratified by RBC transfusion burden, RS status, and endogenous serum erythropoietin (sEPO) level at baseline. Two dose level increases were allowed for luspatercept (to 1.33 mg/kg and to 1.75 mg/kg). Doses were held and subsequently reduced for adverse reactions, reduced if the haemoglobin increased by ≥ 2 g/dL from the prior cycle, and held if the pre-dose haemoglobin was ≥ 12 g/dL. All patients received best supportive care, which included RBC transfusions, use of antibiotic, antiviral and antifungal therapy, and nutritional support as needed. BSC for this study excluded the use of ESAs outside of the study treatment. The key baseline disease characteristics in MDS patients in ACE-536- MDS-002 are shown in Table 8.

Table 8: Baseline demographics and disease characteristics of MDS patients in ACE-536-MDS- 002
Luspatercept            Epoetin alfa
(N = 182)               (N = 181)
Demographics
Agea (years)
Median (min, max)                                                    74 (46, 93)            74 (31, 91) Age categories, n (%)
≤64 years                                                             27 (14.8)              25 (13.8) 65-74 years                                                           68 (37.4)              66 (36.5) ≥75                                                                   87 (47.8)              90 (49.7) Sex, n (%)
Male                                                                 109 (59.9)              92 (50.8) Female                                                               73 (40.1)               89 (49.2) Race, n (%)
Asian                                                                19 (10.4)               25 (13.8) Black                                                                  2 (1.1)                   0 White                                                                146 (80.2)              143 (79) Not collected or reported                                             15 (8.2)               13 (7.2) Disease Characteristics
Hb (g/dL), n (%)b
Median (min, max)                                                  7.80 (4.7, 9.2)       7.80 (4.5, 10.2) Time since original MDS diagnosis (months)c
Median                                                                   7.97                   5.13 Serum EPO (U/L) categories, n (%)d
≤200                                                                 145 (79.7)             144 (79.6) >200                                                                 37 (20.3)              37 (20.4) Median serum EPO                                                      77.245                 85.370 Serum ferritin (µg/L)                                                 623.00                 650.00 Median (min, max)                                                  (12.4, 3170.0)         (39.4, 6960.5) Baseline transfusion burden / 8 weekse (pRBC units),
n (%)
<4 units                                                             118 (64.8)             111 (61.3) ≥4 units                                                             64 (35.2)              70 (38.7) 
MDS Classification WHO 2016 at baseline, n (%)
MDS-SLD                                                                1 (0.5)                4 (2.2) MDS-MLD                                                              50 (27.5)              47 (26.0) MDS-RS-SLD                                                             2 (1.1)                6 (3.3) MDS-RS-MLD                                                           127 (69.8)             118 (65.2) MDS/MPN-RS-T                                                           2 (1.1)                5 (2.8) Missing                                                                   0                   1 (0.6) IPSS-R classification risk category, n (%)
Very low                                                              16 (8.8)               17 (9.4) Low                                                                  130 (71.4)             133 (73.5) Intermediate                                                         34 (18.7)              29 (16.0) Other / missing                                                        2 (1.1)                2 (1.1) Ring sideroblast status (per WHO criteria), n (%)
RS+                                                                  133 (73.1)             130 (71.8) RS-                                                                  49 (26.9)              50 (27.6) Missing                                                                  0                    1 (0.6) SF3B1 mutation status, n (%)
Mutated                                                              114 (62.6)             101 (55.8) Non-mutated                                                          65 (35.7)              72 (39.8) Missing                                                                3 (1.6)                8 (4.4) Hb = haemoglobin; IPSSR = International Prognostic Scoring System-Revised; MDS-SLD = MDS with single lineage dysplasia; MDS-MLD = MDS with multilineage dysplasia; MDS-RS-SLD = MDS with ring sideroblasts with single lineage dysplasia; MDS-RS-MLD = MDS with ring sideroblasts with multilineage dysplasia; MDS/MPN-RS-T = myelodysplastic/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis; RS+ = with ring sideroblasts; RS-= without ring sideroblasts; SF3B1 = Splicing Factor 3B Subunit 1A MDS mutation a
Age was calculated based on the informed consent signing date.
b After applying the 14/3-day rule (only Hb values that are measured at least 14 days after a transfusion may be used unless  there is another transfusion within 3 days after the Hb assessment. If a transfusion within 3 days after the Hb assessment occurs, that Hb value will be used despite being < 14 days after the previous transfusion), the baseline Hb value (efficacy) is defined as the lowest Hb value from the central, or local laboratory, or pre-transfusion Hb from transfusion records that is within the 35 days prior to the first dose of study drug, if it was available.
c
The number of months from the date of original diagnosis to the date of informed consent.
d Baseline EPO was defined as the highest EPO value within the 35 days preceding the first dose of study drug.
e Collected over 8 weeks prior to randomisation.


The efficacy results are summarised below.

Table 9: Efficacy results in MDS patients in ACE-536-MDS-002
Endpoint                                              Luspatercept                                  Epoetin alfa (N = 182)                                     (N = 181)
Primary endpoint
• RBC-TI for 12 weeks with associated concurrent mean Hb increase of ≥ 1.5 g/dL (Weeks 1-24)
Number of responders (response rate %)                                      110 (60.4)               63 (34.8) (95% CI)                                                                   (52.9, 67.6)             (27.9, 42.2) a
Common Risk Difference (95% CI)                                                     25.4 (15.8, 35.0) p-value                                                                                  < 0.0001 a
Odds Ratio (95% CI)                                                                   3.1 (2.0, 4.8) Secondary endpoints
• HI-E per IWG ≥8 weeks (Weeks 1-24)b
Number of responders (response rate %)                                      135 (74.2)               96 (53.0) (95% CI)                                                                   (67.2, 80.4)             (45.5, 60.5) Common Risk Difference (95% CI)a                                                    21.5 (12.2, 30.7) p-value                                                                                  < 0.0001 a
Odds Ratio (95% CI)                                                                   2.8 (1.8, 4.5) • RBC-TI for 24 weeks (Weeks 1-24)
Number of responders (response rate %)                                      87 (47.8)                56 (30.9) (95% CI)                                                                   (40.4, 55.3)             (24.3, 38.2) Common Risk Difference (95% CI)a                                                     16.3 (7.1, 25.4) p-value                                                                                   0.0003 a
Odds Ratio (95% CI)                                                                   2.3 (1.4, 3.7) • RBC-TI for ≥24 weeks (Weeks 1-48)                                            163                      167 Number of responders (response rate %)                                      99 (60.7)                66 (39.5) (95% CI)                                                                  (52.8, 68.3)             (32.1, 47.4) a
Common Risk Difference (95% CI)                                                     20.7 (10.8, 30.6) p-value                                                                                p < 0.0001c Odds Ratio (95% CI)a                                                                  2.6 (1.6, 4.3) Hb = haemoglobin; RBC = red blood transfusion a
Based on CMH test stratified by baseline RBC transfusion burden (< 4, ≥ 4 pRBC units), RS status (RS+, RS-) and sEPO level (≤ 200, > 200 U/L). 1-sided p-value is presented.
b HI-E = haematological improvement – erythroid. The proportion of patients meeting the HI-E criteria as per International 
Working Group (IWG) 2006 criteria sustained over a consecutive 56-day period during the indicated treatment period. For 
patients with baseline RBC transfusion burden of ≥ 4 units/8 weeks, HI-E was defined as a reduction in RBC transfusion of at least 4 units/8 weeks. For patients with baseline RBC transfusion burden of < 4 units/8 weeks, HI-E was defined as a mean increase in Hb of ≥ 1.5 g/dL for 8 weeks in the absence of RBC transfusions.
c
Nominal p-value

The treatment effect of luspatercept on RBC-TI ≥ 12 weeks and Hb increase of ≥ 1.5 g/dL was higher than epoetin alfa across all clinically relevant baseline demographic and most disease characteristic subgroups, except in patients without ring sideroblasts, where the treatment effect of luspatercept was comparable to epoetin alfa.

• Myelodysplastic syndromes in ESA-refractory or -intolerant patients The efficacy and safety of luspatercept were evaluated in a Phase 3 multicentre, randomised, double-blind, placebo-controlled study MEDALIST (ACE-536-MDS-001) in adult patients with anaemia requiring RBC transfusions (≥ 2 units/8 weeks) due to IPSS-R very low-, low- or intermediate-risk MDS who have ring sideroblasts (≥ 15%). Patients with del5q MDS or without ring sideroblasts (RS-) were not included in the study. Patients were required to have either received prior treatment with an ESA with inadequate response, to be ineligible for ESAs (determined to be unlikely to respond to ESA treatment with serum erythropoietin (EPO) > 200 U/L), or intolerant to ESA treatment.

Patients in both arms were treated for 24 weeks, then continued treatment if they had demonstrated clinical benefit and absence of disease progression. The study was unblinded for analyses when all patients had at least received 48 weeks of treatment or discontinued treatment.

A total of 229 patients were randomised to receive luspatercept 1.0 mg/kg (N = 153) or placebo (N = 76) subcutaneously every 3 weeks. A total of 128 (83.7%) and 68 (89.5%) patients receiving luspatercept and placebo respectively completed 24 weeks of treatment. A total of 78 (51%) and 12 (15.8%) patients receiving luspatercept and placebo respectively completed 48 weeks of treatment.
Dose titration up to 1.75 mg/kg was allowed. Dose could be delayed or reduced depending upon Hb level. All patients were eligible to receive best supportive care (BSC), which included RBC transfusions, iron-chelating agents, use of antibiotic, antiviral and antifungal therapy, and nutritional support, as needed. The key baseline disease characteristics in patients with MDS in study ACE-536- MDS-001 are shown in Table 10.

Table 10: Baseline demographics and disease characteristics of MDS patients with < 5% marrow blasts in study ACE-536-MDS-001
Luspatercept        Placebo
(N = 153)         (N = 76)
Demographics
Agea (years)
Median (min, max)                                         71 (40, 95)      72 (26, 91) Age categories, n (%)
≤ 64 years                                                 29 (19.0)        16 (21.1) 65-74 years                                                72 (47.1)        29 (38.2) ≥ 75                                                       52 (34.0)        31 (40.8) Sex, n (%)
Male                                                       94 (61.4)        50 (65.8) Female                                                     59 (38.6)        26 (34.2) Race, n (%)
Black                                                       1 (0.7)          0 (0.0) White                                                     107 (69.9)        51 (67.1) Not collected or reported                                  44 (28.8)        24 (31.6) Other                                                       1 (0.7)          1 (1.3) 


Luspatercept               Placebo
(N = 153)                 (N = 76)
Disease characteristics
Serum EPO (U/L) categories b, n (%)
< 200                                                                         88 (57.5)               50 (65.8) 200 to 500                                                                    43 (28.1)               15 (19.7)
> 500                                                                         21 (13.7)               11 (14.5) Missing                                                                        1 (0.7)                    0 Serum ferritin (µg/L)
Median (min, max)                                                              1089.2                  1122.1 (64, 5968)              (165, 5849)
IPSS-R classification risk category, n (%)
Very low                                                                     18 (11.8)                 6 (7.9) Low                                                                          109 (71.2)               57 (75.0) Intermediate                                                                 25 (16.3)                13 (17.1) Other                                                                          1 (0.7)                    0 Baseline RBC transfusion burden/ 8 weeksc, n (%)
≥ 6 units                                                                     66 (43.1)               33 (43.4) ≥ 6 and < 8 units                                                           35 (22.9)               15 (20.2) ≥ 8 and < 12 units                                                          24 (15.7)               17 (22.4) ≥ 12 units                                                                   7 (4.6)                 1 (1.3) < 6 units                                                                     87 (56.9)               43 (56.6) ≥ 4 and < 6 units                                                           41 (26.8)               23 (30.3) < 4 units                                                                   46 (30.1)               20 (26.3) Hbd (g/dL)
Median (min, max)                                                            7.6 (6, 10)              7.6 (5, 9) SF3B1, n (%)
Mutated                                                                      149 (92.2)               65 (85.5) Unmutated                                                                     12 (7.8)                10 (13.2) Missing                                                                          0                     1 (1.3) EPO = erythropoietin; Hb = haemoglobin; IPSS-R = International Prognostic Scoring System-Revised a Age was calculated based on the informed consent signing date.
b Baseline EPO was defined as the highest EPO value within 35 days of the first dose of study drug.
c
Collected over 16 weeks prior to randomisation.
d
Baseline Hb was defined as the last value measured on or before the date of the first dose of investigational product (IP).
After applying the 14/3-day rule, baseline Hb was defined as the lowest Hb value that was within 35 days on or prior to the first dose of IP.

The efficacy results are summarised below.

Table 11: Efficacy results in patients with MDS in study ACE-536-MDS-001 Endpoint                                                   Luspatercept          Placebo (N = 153)           (N = 76)
Primary endpoint
• RBC-TI ≥ 8 weeks (Weeks 1-24)
Number of responders (response rate %)                    58 (37.9)           10 (13.2) • Common risk difference on response rate (95% CI)              24.56 (14.48, 34.64) Odds ratio (95% CI)a                                          5.065 (2.278, 11.259) p-valuea                                                            < 0.0001 Secondary endpoints
• RBC-TI ≥ 12 weeks (Weeks 1-24)
Number of responders (response rate %)                    43 (28.1)            6 (7.9) • Common risk difference on response rate (95% CI)              20.00 (10.92, 29.08) Odds ratio (95% CI)a                                          5.071 (2.002, 12.844) p-valuea                                                              0.0002 

Endpoint                                                                       Luspatercept               Placebo (N = 153)                 (N = 76)
• RBC-TI ≥ 12 weeks (Weeks 1-48)
Number of responders (response rate %)b                                        51 (33.3)           9 (11.8) • Common risk difference on response rate (95% CI)                                   21.37 (11.23, 31.51) Odds ratio (95% CI)a                                                               4.045 (1.827, 8.956) p-valuea                                                                                  0.0003 Transfusion event frequencyc
• Weeks 1-24
Interval transfusion rate (95% CI)                                         6.26 (5.56, 7.05) 9.20 (7.98, 10.60) Relative risk vs. placebo                                                           0.68 (0.58, 0.80) • Weeks 25-48
Interval transfusion rate (95% CI)                                        6.27 (5.47, 7.19) 8.72 (7.40, 10.28) Relative risk vs. placebo                                                           0.72 (0.60, 0.86) RBC Transfusion unitsc
• Weeks 1-24
Baseline transfusion burden < 6 units/8 weeks
LS Mean (SE)                                                                 7.2 (0.58)           12.8 (0.82) 95% CI for LS mean                                                            6.0, 8.3             11.1, 14.4 LS mean difference (SE) (luspatercept vs. placebo)                                     -5.6 (1.01) 95% CI for LS mean difference                                                           -7.6, -3.6 Baseline transfusion burden ≥ 6 units/8 weeks
LS Mean (SE)                                                                 18.9 (0.93)          23.7 (1.32) 95% CI for LS mean                                                           17.1, 20.8            21.1, 26.4 LS mean difference (SE) (luspatercept vs. placebo)                                     -4.8 (1.62) 95% CI for LS mean difference                                                           -8.0, -1.6 • Weeks 25-48
Baseline transfusion burden < 6 units/8 weeks
LS Mean (SE)                                                                 7.5 (0.57)           11.8 (0.82) 95% CI for LS mean                                                            6.3, 8.6             10.1, 13.4 LS mean difference (SE) (luspatercept vs. placebo)                                     -4.3 (1.00) 95% CI for LS mean difference                                                           -6.3, -2.3 Baseline transfusion burden ≥ 6 units/8 weeks
LS Mean (SE)                                                                 19.6 (1.13)          22.9 (1.60) 95% CI for LS mean                                                           17.4, 21.9            19.7, 26.0 LS mean difference (SE) (luspatercept vs. placebo)                                     -3.3 (1.96) 95% CI for LS mean difference                                                            -7.1, 0.6 RBC-TI: RBC Transfusion Independent; CI: confidence interval; CMH = Cochran-Mantel-Haenszel a CMH test stratified for average baseline transfusion burden (≥ 6 units vs. < 6 units per 8 weeks), and baseline IPSS-R score 
(very low or low vs. intermediate).
b After the Week 25 disease assessment visit, patients who were no longer deriving benefit discontinued therapy; few placebo  patients contributed data for evaluation at the later timepoint compared with luspatercept (N = 12 vs. N = 78 respectively).
c
Post-hoc analysis using baseline imputation.

A treatment effect in favour of luspatercept over placebo was observed in most subgroups analysed using transfusion independence ≥ 12 weeks (during week 1 to week 24), including patients with high baseline endogenous EPO level (200-500 U/L) (23.3% vs. 0%, explorative analysis).

Only limited data are available for the group with transfusion burden of ≥ 8 units/8 weeks. Safety and efficacy have not been established in patients with a transfusion burden of > 12 units/8 weeks.



Exploratory findings

Table 12: Exploratory efficacy results in patients with MDS in study ACE-536-MDS-001 Endpoint                                                       Luspatercept           Placebo (N = 153)           (N = 76) mHI-Ea
• Weeks 1-24
Number of responders (response rate %)                         81 (52.9)           9 (11.8) (95% CI)                                                    (44.72, 61.05)      (5.56, 21.29) RBC transfusion reduction of 4 units/8 weeks, n (%)        52/107 (48.6)        8/56 (14.3) Mean Hb increase of ≥ 1.5 g/dL for 8 weeks, n (%)           29/46 (63.0)         1/20 (5.0) • Weeks 1-48
Number of responders (response rate %)                        90 (58.8)          13 (17.1) (95% CI)                                                   (50.59, 66.71)      (9.43, 27.47) RBC transfusion reduction of 4 units/8 weeks, n (%)        58/107 (54.2)       12/56 (21.4) Mean Hb increase of ≥ 1.5 g/dL for 8 weeks, n (%)           32/46 (69.6)         1/20 (5.0) Mean change from baseline in mean serum ferritin with imputation by baseline (ITT population)
Mean change from baseline in mean serum ferritin averaged over Weeks 9 through 24 (μg/L)b
LS Mean (SE)                                                     9.9 (47.09)       190.0 (60.30) 95% CI for LS Mean                                              -82.9, 102.7        71.2, 308.8 Treatment comparison (luspatercept vs. placebo)c
LS mean difference (SE)                                              -180.1 (65.81) 95% CI for LS mean difference                                         -309.8, -50.4 Hb = haemoglobin a mHI-E = modified haematological improvement – erythroid. The proportion of patients meeting the HI-E criteria as per 
International Working Group (IWG) 2006 criteria sustained over a consecutive 56-day period during the indicated treatment period. For patients with baseline RBC transfusion burden of ≥ 4 units/8 weeks, mHI-E was defined as a reduction in RBC transfusion of at least 4 units/8 weeks. For patients with baseline RBC transfusion burden of < 4 units/8 weeks, mHI-E was defined as a mean increase in Hb of ≥ 1.5 g/dL for 8 weeks in the absence of RBC transfusions.
b If a patient did not have a serum ferritin value within the designated postbaseline interval, the serum ferritin is  imputed from the baseline value.
c
Analysis of covariance was used to compare the treatment difference between groups (including nominal p-value), with the change in serum ferritin as the dependent variable, treatment group (2 levels) as a factor, and baseline serum ferritin value as covariates, stratified by average baseline RBC transfusion requirement (≥ 6 units vs. < 6 units of RBC per 8 weeks), and baseline IPSS-R (very low or low vs. intermediate).

The median duration of the longest RBC Transfusion Independent (RBC-TI) period among responders in the luspatercept treatment arm was 30.6 weeks.

A total of 62.1% (36/58) of the luspatercept responders who achieved RBC-TI ≥ 8 weeks from Weeks 1-24 had 2 or more episodes of RBC-TI at the time of analysis.

• Transfusion-dependent β-thalassaemia
The efficacy and safety of luspatercept were evaluated in a Phase 3 multicentre, randomised, double-blind, placebo-controlled study BELIEVE (ACE-536-B-THAL-001) in adult patients with transfusion-dependent β-thalassaemia–associated anaemia who require RBC transfusions (6-20 RBC units/24 weeks) with no transfusion-free period > 35 days during that period.

Patients in both the luspatercept and placebo arms were treated for at least 48 and up to 96 weeks.
After unblinding, placebo patients were able to cross-over to luspatercept.

A total of 336 adult patients were randomised to receive luspatercept 1.0 mg/kg (N = 224) or placebo (N = 112) subcutaneously every 3 weeks. Dose titration to 1.25 mg/kg was allowed. Dose could be delayed or reduced depending upon Hb level. All patients were eligible to receive BSC, which included RBC transfusions, iron-chelating agents, use of antibiotic, antiviral and antifungal therapy, and nutritional support, as needed. The study excluded patients with Hb S/β-thalassaemia or alpha (α)-thalassaemia or who had major organ damage (liver disease, heart disease, lung disease, renal insufficiency). Patients with recent DVT or stroke or recent use of ESA, immunosuppressant or hydroxyurea therapy were also excluded. The key baseline disease characteristics in patients with β-thalassaemia in study ACE-536-B-THAL-001 are shown in Table 13.

Table 13: Baseline demographics and disease characteristics of patients with transfusion-dependent β-thalassaemia in study ACE-536-B-THAL-001
Luspatercept         Placebo
(N = 224)        (N = 112)
Demographics
Age (years)
Median (min, max)                                         30.0 (18, 66)    30.0 (18, 59) Age categories, n (%)
≤ 32                                                       129 (57.6)        63 (56.3) > 32 to ≤ 50                                                78 (34.8)        44 (39.3) > 50                                                         17 (7.6)          5 (4.5) Sex, n (%)
Male                                                        92 (41.1)        49 (43.8) Female                                                     132 (58.9)        63 (56.3) Race, n (%)
Asian                                                       81 (36.2)        36 (32.1) Black                                                        1 (0.4)              0 White                                                      122 (54.5)        60 (53.6) Not collected or reported                                    5 (2.2)           5 (4.5) Other                                                        15 (6.7)         11 (9.8) Disease characteristics
Pretransfusion Hb thresholda, 12 week run-in (g/dL)
Median (min, max)                                        9.30 (4.6, 11.4) 9.14 (6.2, 11.5) Baseline transfusion burden 12 weeks
Median (min, max)
(units/12 weeks) (Week -12 to Day 1)                     6.12 (3.0, 14.0) 6.27 (3.0, 12.0) β-thalassaemia gene mutation grouping, n (%)
β0/β0                                                       68 (30.4)        35 (31.3) Non-β0/β0                                                  155 (69.2)        77 (68.8) Missingb                                                     1 (0.4)              0 a The12-week pretransfusion threshold was defined as the mean of all documented pretransfusions Hb values for a patient during the 12 weeks prior to Cycle 1 Day 1.
b
“Missing” category includes patients in the population who had no result for the parameter listed.

The study was unblinded for analyses when all patients had at least received 48 weeks of treatment or discontinued treatment.

The efficacy results are summarised below.

Table 14: Efficacy results in patients with transfusion-dependent β-thalassaemia in study ACE-536-B-THAL-001
Endpoint                                                    Luspatercept         Placebo (N = 224)               (N = 112)
Primary endpoint
≥ 33% reduction from baseline in RBC transfusion burden with a reduction of at least 2 units for
12 consecutive weeks compared to the 12-week interval prior to treatment
Weeks 13-24                                                                   47 (21.0)            5 (4.5) Difference in proportions (95% CI)a                                              16.5 (10.0, 23.1) p-valueb                                                                             < 0.0001 Endpoint                                                                       Luspatercept                 Placebo (N = 224)                (N = 112)
Secondary endpoints
Weeks 37-48                                                                       44 (19.6)             4 (3.6) Difference in proportions (95% CI)a                                                  16.1 (9.8, 22.3) p-valueb                                                                                 < 0.0001 ≥ 50% reduction from baseline in RBC transfusion burden with a reduction of at least 2 units for
12 consecutive weeks compared to the 12-week interval prior to treatment
Weeks 13-24                                                                       16 (7.1)              2 (1.8) Difference in proportions (95% CI)a                                                   5.4 (1.2, 9.5) p-valueb                                                                                  0.0402 Weeks 37-48                                                                       23 (10.3)             1 (0.9) Difference in proportions (95% CI)a                                                   9.4 (5.0, 13.7) p-valueb                                                                                  0.0017 CI: confidence interval.
a Difference in proportions (luspatercept + BSC – placebo + BSC) and 95% CIs estimated from the unconditional exact test.
b P-value from the Cochran Mantel-Haenszel test stratified by the geographical region.


Exploratory findings

Table 15: Exploratory efficacy results in patients with transfusion-dependent β-thalassaemia in study ACE-536-B-THAL-001
Endpoint                                                    Luspatercept        Placebo (N = 224)                (N = 112)
≥ 33% reduction from baseline in RBC transfusion burden with a reduction of at least 2 units for 12 consecutive weeks compared to the 12-week interval prior to treatment
Any consecutive 12 weeks*                                   173 (77.2)             39 (34.8) Difference in proportions (95% CI)a                             42.4 (31.5, 52.5) Any consecutive 24 weeks*                                   116 (51.8)              3 (2.7) Difference in proportions (95% CI)a                             49.1 (41.3, 56.2) ≥ 50% reduction from baseline in RBC transfusion burden with a reduction of at least 2 units for 12 consecutive weeks compared to the 12-week interval prior to treatment
Any consecutive 12 weeks*                                   112 (50.0)              9 (8.0) Difference in proportions (95% CI)a                             42.0 (32.7, 49.9) Any consecutive 24 weeks*                                    53 (23.7)              1 (0.9) Difference in proportions (95% CI)a                             22.8 (16.5, 29.1) Least square (LS) mean change from baseline in transfusion burden (RBC units/48 weeks) Weeks 1 to Week 48
LS mean                                                     -4.69                 +1.17 LS mean of difference (luspatercept-placebo)                           -5.86 (95% CI)b                                                         (-7.04, -4.68) Weeks 49 to Week 96
LS mean                                                     -5.43                 +1.80 LS mean of difference (luspatercept-placebo)                           -7.23 (95% CI)b                                                        (-13.84, -0.62) ANCOVA = analysis of covariance; CI: confidence interval.
a
Difference in proportions (luspatercept + BSC – placebo + BSC) and 95% CIs estimated from the unconditional exact test.
b
Estimates are based on ANCOVA model with geographical regions and baseline transfusion burden as covariates.
*Placebo patients are assessed up to prior to crossing over to luspatercept. For the rolling analyses at any consecutive 12 / 24 weeks, luspatercept treatment arm does not include placebo patients who crossed over to luspatercept.

A reduction in mean serum ferritin levels was observed from baseline in the luspatercept arm compared to an increase in the placebo arm at Week 48 (-235.56 μg/L vs. +107.03 μg/L which resulted in a least square mean treatment difference of -342.59 µg/L (95% CI: -498.30, -186.87).


A total of 85% (147/173) of luspatercept responders who achieved at least a 33% reduction in transfusion burden during any consecutive 12-week interval achieved 2 or more episodes of response at the time of analysis.

Non-transfusion-dependent β-thalassaemia
The efficacy and safety of luspatercept were evaluated in a Phase 2 multicentre, randomised, double-blind, placebo-controlled study BEYOND (ACE-536-B-THAL-002) in adult patients with non-transfusion-dependent β-thalassaemia-associated anaemia (Hb concentration ≤ 10 g/dL).

A total of 145 adult patients receiving RBC transfusions (0-5 RBC units in the 24-week period prior to randomization), with a baseline Hb level ≤ 10.0 g/dL (defined as average of at least 2 Hb measurements ≥ 1 week apart within 4 weeks prior to randomization) were randomized to receive luspatercept (N = 96) or placebo (N = 49) subcutaneously every 3 weeks. Patients were stratified at randomization based on their baseline Hb level and their non-transfusion-dependent β-thalassaemia (NTDT) patient-reported outcome (PRO; NTDT-PRO) Tiredness/Weakness (T/W) weekly domain score. Dose titration to 1.25 mg/kg was allowed. Dose could be delayed or reduced depending upon Hb level. Overall, 53% of luspatercept patients (N = 51) and 92% of patients on placebo (N = 45) had their dose increased to 1.25 mg/kg within the 48-week treatment period. Among patients receiving luspatercept, 96% were exposed for 6 months or longer and 86% were exposed for 12 months or longer. A total of 89 (92.7%) patients receiving luspatercept and 35 (71.4%) patients receiving placebo completed 48 weeks of treatment.


All patients were eligible to receive BSC, which included RBC transfusions, iron-chelating agents, use of antibiotic, antiviral, and antifungal therapy, and nutritional support, as needed. Concurrent treatment for anaemia with blood transfusions was allowed, at the discretion of the physician, for low haemoglobin levels, symptoms associated with anaemia (e.g. haemodynamic or pulmonary compromise requiring treatment) or comorbidities. The study excluded patients with Hb S/β-thalassaemia or alpha (α)-thalassaemia or who had major organ damage (liver disease, heart disease, lung disease, renal insufficiency), active hepatitis C or B, or HIV. Patients with recent DVT or stroke or recent use of ESA, immunosuppressant or hydroxyurea therapy, or on chronic anticoagulant or uncontrolled hypertension were also excluded. Only a limited number of patients with comorbidities associated with underlying anaemia such as pulmonary hypertension, liver and kidney disease and diabetes were included in the study.
The key baseline disease characteristics in the Intention-To-Treat (ITT) population with non-transfusion-dependent β-thalassaemia in study ACE-536-B-THAL-002 are shown in Table 16.

Table 16: Baseline demographics and disease characteristics of patients with non-transfusion- dependent β-thalassaemia in study ACE-536-B-THAL-002
ITT population
Luspatercept                             Placebo
(N=96)                                 (N=49)
Demographics
Age (years)
Median (min, max)                     39.5 (18, 71)                          41 (19, 66) Sex, n (%)
Male                                    40 (41.7)                             23 (46.9) Female                                  56 (58.3)                             26 (53.1) Race, n (%)
Asian                                   31 (32.3)                             13 (26.5) White                                   59 (61.5)                             28 (57.1) Other                                    6 (6.3)                              8 (16.3) 


ITT population
Luspatercept                                    Placebo
(N=96)                                        (N=49)
Disease characteristics
β-thalassaemia diagnosis, n (%)
β-thalassaemia                                63 (65.6)                                    34 (69.4) HbE/β-thalassaemia                            28 (29.2)                                    11 (22.4) β-thalassaemia                                 5 (5.2)                                      4 (8.2) combined with
α-thalassaemia
Baseline Hb levela
(g/dL)
Median (min, max)                          8.2 (5.3, 10.1)                              8.1 (5.7, 10.1) Patients with mean baseline Hb levela category (g/dL), n (%)
< 8.5                                         55 (57.3)                                    29 (59.2) Baseline NTDT-PRO
T/W domain scoreb, n
(%)
Median (min, max)                            4.3 (0, 9.5)                               4.1 (0.4, 9.5) Baseline NTDT-PRO
T/W domain scoreb category, n (%)
≥3                                            66 (68.8)                                    35 (71.4) Baseline transfusion burden
(units/24 weeks)
Median (min, max)                               0 (0, 4)                                    0 (0, 4) Splenectomy, n (%)
Yes                                           34 (35.4)                                    26 (53.1) MRI LIC (mg/g dw)c, n
Median (min, max)
95                                           47
3.9 (0.8, 39.9)                              4.1 (0.7, 28.7)
MRI spleen volume
(cm3), n
Median (min, max)                                60                                          22 879.9                                       1077.0
(276.1, 2419.0)                             (276.5, 2243.0)
Baseline use of ICT, n                        28 (29.2)                                   16 (32.7) (%)
Baseline serum ferritin
(μg/L)d
Median (min, max)                              456.5                                        360.0 (30.0, 3528.0)                               (40.0, 2265.0)
Hb = haemoglobin; HbE = haemoglobin E; ICT = Iron Chelation Therapy; LIC = liver iron concentration; max = maximum; min = minimum; MRI = magnetic resonance imaging; NTDT-PRO T/W = non-transfusion-dependent β- thalassaemia patient-reported outcome tiredness and weakness domain score; a
Mean of at least 2 Hb values by the central laboratory during the 28-day screening period.
b
Baseline defined as the average of non-missing NTDT-PRO T/W domain score over 7 days before Dose 1 Day 1.
c The value of LIC was either the value collected from the electronic Case Report Form (eCRF) or the value derived from 
T2*, R2*, or R2 parameter depending on which techniques and software were used for MRI LIC acquisition.
d
Baseline mean serum ferritin was calculated during the 24 weeks on or prior to Dose 1 Day 1. Baseline ICT was calculated during the 24 weeks on or prior to Dose 1 Day 1.

The efficacy results are summarised below.
Table 17: Efficacy results in patients with non-transfusion-dependent β-thalassaemia in study ACE-536-B-THAL-002
ITT population
Endpoint                              Luspatercept                       Placebo (N = 96)                        (N = 49)
Primary endpoint
Increase from baseline ≥1.0 g/dL in mean Hb over continuous 12-week interval (in absence of transfusions)
• Weeks 13-24
Response ratea, n
[(%) (95% CI)]b                           74                              0.0 [(77.1) (67.4, 85.0)]             [(0.0) (0.0, 7.3)] p-valuec                                                  < 0.0001
CI = confidence interval; Hb = haemoglobin a
Defined as number of patients with ≥ 1.0 g/dL Hb increase in the absence of RBC transfusion compared to baseline (i.e. the average of ≥2 Hb measurements at ≥ 1 week apart within 4 weeks before Dose 1 Day 1).
b The 95% CI for response rate (%) was estimated from the Clopper-Pearson exact test.
c The odds ratio (luspatercept vs. placebo) with 95% CI and p-value were estimated from the CMH test stratified by baseline 
Hb category (<8.5 vs. ≥ 8.5 g/dL) and baseline NTDT-PRO T/W domain score category (≥ 3 vs. < 3) defined at randomization as covariates.
Note: Patients with missing Hb at Weeks 13-24 were classified as non-responders in the analysis.

A total of 77.1% of luspatercept treated patients achieved an increase from baseline ≥ 1.0 g/dL in mean Hb over continuous 12-week interval (in absence of transfusions) (Weeks 13-24). This effect was maintained in the 57.3% of patients who reached Week 144 of treatment.

Pharmacokinetic Properties

5.2    Pharmacokinetic properties

Absorption
In healthy volunteers and patients, luspatercept is slowly absorbed following subcutaneous administration, with the Cmax in serum often observed approximately 7 days post-dose across all dose levels. Population pharmacokinetic (PK) analysis suggests that the absorption of luspatercept into the circulation is linear over the range of studied doses, and the absorption is not significantly affected by the subcutaneous injection location (upper arm, thigh or abdomen). Interindividual variability in AUC was approximately 37% in both β-thalassaemia and MDS patients.

Distribution
At the recommended doses, the geometric mean apparent volume of distribution was 9.56 L for MDS patients and 7.26 L for β-thalassaemia patients. The small volume of distribution indicates that luspatercept is confined primarily in extracellular fluids, consistent with its large molecular mass.

Biotransformation
Luspatercept is expected to be catabolised into amino acids by general protein degradation process.

Elimination
Luspatercept is not expected to be excreted into urine due to its large molecular mass that is above the glomerular filtration size exclusion threshold. At the recommended doses, the geometric mean apparent total clearance was 0.47 L/day for MDS patients and 0.44 L/day for β-thalassaemia. The geometric mean half-lives in serum were approximately 14.1 days for MDS patients and 11 days for β-thalassaemia patients.

Linearity/non-linearity
The increase of luspatercept Cmax and AUC in serum is approximately proportional to increases in dose from 0.125 to 1.75 mg/kg. Luspatercept clearance was independent of dose or time.

When administered every three weeks, luspatercept serum concentration reaches the steady state after 3 doses, with an accumulation ratio of approximately 1.5.
Hb response
In patients who received < 4 units of RBC transfusion within 8 weeks prior to the study, Hb increased within 7 days of treatment initiation and the increase correlated with the time to reach luspatercept Cmax. The greatest mean Hb increase was observed after the first dose, with additional smaller increases observed after subsequent doses. Hb levels returned to baseline value approximately 6 to 8 weeks from the last dose (0.6 to 1.75 mg/kg). Increasing luspatercept serum exposure (AUC) was associated with a greater Hb increase in patients with ESA refractory or -intolerant MDS or β-thalassaemia.

In non-transfusion-dependent β-thalassaemia patients who had a baseline transfusion burden of 0 to 5 units within 24 weeks, increasing luspatercept serum exposure (time-averaged AUC) was associated with a greater probability of achieving a Hb increase (≥ 1 g/dL or ≥ 1.5 g/dL) and a longer duration of such Hb increases. The luspatercept serum concentration achieving 50% of the maximum stimulatory effect on Hb production was estimated to be 7.6 μg/mL.

Special populations

Elderly
Population PK analysis for luspatercept included patients with ages ranging from 27 to 95 and 18 to 71 years old, for MDS and β-thalassaemia patients, respectively, with a median age of 72.5 years for MDS patients and of 33 years for β-thalassaemia patients. No clinically significant difference in AUC or clearance was found across age groups in MDS patients (≤ 64, 65-74, and ≥ 75 years) or in β-thalassaemia patients (18 to 71 years).

Hepatic impairment
Population PK analysis for luspatercept included patients with normal hepatic function (BIL, ALT, and AST ≤ ULN; N = 62 for β-thalassaemia patients and N = 311 for MDS patients), mild hepatic impairment (BIL > 1 – 1.5 x ULN, and ALT or AST > ULN; N = 89 for β-thalassaemia patients and N = 126 for MDS patients), moderate hepatic impairment (BIL > 1.5 – 3 x ULN, any ALT or AST; N = 157 for β-thalassaemia patients and N = 32 for MDS patients), or severe hepatic impairment (BIL > 3 x ULN, any ALT or AST; N = 73 for β-thalassaemia patients and N = 1 for MDS patients) as defined by the National Cancer Institute criteria of hepatic dysfunction. Effects of hepatic function categories, elevated liver enzymes (ALT or AST, up to 3 x ULN) and elevated total BIL (4 – 246 mol/L) on luspatercept clearance were not observed. No clinically significant difference in mean steady state Cmax and AUC was found across hepatic function groups. PK data are insufficient for patients with liver enzymes (ALT or AST) ≥ 3 x ULN. No PK data are available for patients with liver cirrhosis (Child-Pugh Classes A, B and C) as no dedicated study was performed.

Renal impairment
Population PK analysis for luspatercept included patients with normal renal function (individual eGFR ≥ 90 mL/min N = 302 for β-thalassaemia patients and N = 169 for MDS patients), mild renal impairment (individual eGFR 60 to 89 mL/min; N = 74 for β-thalassaemia patients and N = 204 for MDS patients), or moderate renal impairment (individual eGFR 30 to 59 mL/min; N = 4 for β-thalassaemia patients and N = 88 for MDS patients) as defined by Modification of Diet in Renal Disease (MDRD) formula. Luspatercept steady-state serum exposure (AUC) was 24% to 41% higher in patients with mild to moderate renal impairment than in patients with normal renal function. PK data are insufficient for patients with severe renal impairment (individual eGFR < 30 mL/min) or end- stage kidney disease.

Other intrinsic factors
The following population characteristics have no clinically significant effect on luspatercept AUC or clearance: sex and race (Asian vs. White).

The following baseline disease characteristics had no clinically significant effect on luspatercept clearance: serum erythropoietin level (2.4 – 1680 U/L for β-thalassaemia patients and 7.80 – 2920 U/L for MDS patients), RBC transfusion burden (0 – 43.4 units/24 weeks), MDS ring sideroblasts, β-thalassaemia genotype (β0/β0 vs. non-β0/β0) and splenectomy.

The volume of distribution and clearance of luspatercept increased with increase of body weight (33 – 124 kg), supporting the body weight-based dosing regimen.