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Sotatercept TGF-b ligand trap in β-thalassemia
Clinical response
Extramedullary masses
The effect of sotatercept on extramedullary masses, as measured by magnetic resonance imaging, was reported for four patients with NTDT and one with TDT. The TDT patient experienced a reduction in extramedullary mass volume at 12 months after treatment with sotater- cept 0.75 mg/kg (data not shown); however, due to an unequal distribution of the mass, it was not possible to determine the exact volume of the mass. One NTDT patient experienced reduction in extramedullary mass vol- ume at 12 months after treatment with sotatercept 0.3 mg/kg, with the reduction ranging from 0.4% to 59.3% across three separate extramedullary masses (Online Supplementary Figure S3A), alongside a stable increase in hemoglobin level. Another NTDT patient treated with sotatercept 1.0 mg/kg experienced volume increases of 67% and 55% in two extramedullary masses, at 7 months after treatment (Online Supplementary Figure S3B). This cor- related with an increase in hemoglobin levels (6 g/dL at baseline versus 8 g/dL at 7 months after treatment). Two NTDT patients experienced changes in volumes of extramedullary masses of between −6.3% and +22.5% at 11 months after treatment with sotatercept 1.0 mg/kg (data not shown).
Leg ulcers
Seven NTDT patients had a history of leg ulcers at base- line; the effect of sotatercept on chronic leg ulcers was reported for one NTDT patient. The chronic leg ulcers improved, and the dischromic area was reduced following treatment with sotatercept 0.5 mg/kg for 6 months (Online Supplementary Figure S4).
Red blood cell morphology
Changes to RBC morphology were recorded for all patients during the study. Representative images of the changes observed are provided in Online Supplementary Figure S5. Reductions in hypochromia, anisocytosis, and poikilocytosis, and the proportion of target cells were reported, and were associated with increased hemoglobin levels.
Serum ferritin
Among NTDT patients who responded to sotatercept treatment, mean levels of serum ferritin decreased regard- less of iron chelation therapy status (Online Supplementary Figure S6A,B). In contrast to NTDT patients, all TDT patients received iron chelation therapy. Levels of serum ferritin decreased over time in TDT patients (Online Supplementary Figure S6C).
Safety
Twenty-five of 46 patients (54%) experienced one or more treatment-related adverse events; the most common treatment-related adverse events in all patients were bone pain [26% (n=12)], arthralgia [15% (n=7)], back pain [11% (n=5)], asthenia/fatigue [11% (n=5)], and hypertension [11% (n=5)] (Table 2). Treatment-related adverse events led to discontinuation of sotatercept in eight patients (17%) (Table 2); of these eight patients, seven were not dependent on transfusions and one was transfusion-dependent.
All 46 patients experienced one or more treatment-emer- gent adverse events (Online Supplementary Table S1); six (13%) experienced one or more serious adverse events (Online Supplementary Table S2). Nine patients (20%) expe- rienced one or more grade 3-4 treatment-emergent adverse
Table 2. Incidence of treatment-related adverse events of any grade occurring in sotatercept-treated patients in any dose cohort.
Adverse events, n (%)
Patients with ≥1 treatment-emergent AE* Patients with ≥1 treatment-related AE*
Bone pain Arthralgia
Back pain Asthenia/fatigue Hypertension Pain in extremity
Patients with treatment-emergent
AE leading to discontinuation†
Treatment-emergent AE leading to discontinuation‡
Hypertension
Superficial thrombophlebitis Injection site erythema Pyrexia
Extramedullary hematopoiesis Ventricular extrasystoles Hypersensitivity
Bone pain
Sotatercept dose (data presented prior to intrapatient dose escalation)
Overall (data presented post-intrapatient dose escalation)
(N=46)
46 (100)
25 (54) 12 (26) 7 (15) 5 (11) 5 (11) 5 (11)
0.1 mg/kg (n=8)
8 (100)
2 (25) 2 (25) 0
0
0
0
0
2 (25)
0
1 (13) 0
0
0
0
0
0.3 mg/kg (n=9)
9 (100)
2 (22) 2 (22) 0
0
0
0
0
0
0 0 0 0 0 0 0
0.5 mg/kg (n=8)
8 (100)
4 (50) 2 (25) 1 (13) 1 (13) 1 (13) 1 (13) 1 (13)
1 (13)
0
0
0
0
0
1 (13)
0 1(8) 0
0.75 mg/kg (n=12)
12 (100)
8 (67) 1 (8) 3 (25) 2 (17) 3 (25) 2 (17) 2 (17)
3 (25)
1.0 mg/kg (n=9)
9 (100)
6 (67) 4 (44) 1 (11) 2 (22) 1 (11) 1 (11)
0 3(7)
2 (22)
8 (17)
2 (4) 1 (2) 1 (2) 1 (2) 1 (2) 1 (2) 1 (2) 1 (2)
2 (17) 0
1 (8) 0
0
0
0
0
1 (11) 1 (11)
00
1(13) 0 0 0 0
Adverse events (AE) in each dose cohort are presented prior to intrapatient dose escalation.Total AE are presented after-intrapatient dose escalation.*AE occurring in ≥5% of sotatercept-treated patients. †AE occurring in any sotatercept-treated patient. ‡One patient had both injection site erythema and hypersensitivity as AE leading to treatment dis- continuation.
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