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M.D. Cappellini et al.
events; hypertension and anemia were the most frequent [4% (n=2)] (Online Supplementary Table S3). The incidences of anemia were not related to treatment with sotatercept and anemia resolved within one treatment cycle.
The most common treatment-emergent adverse events of any grade among the 30 NTDT patients were headache [53% (n=16)], arthralgia [47% (n=14)], cough [40% (n=12)], and asthenia/fatigue [37% (n=11)] (Online Supplementary Table S4).
The most common treatment-emergent adverse events among the 16 TDT patients were bone pain [63% (n=10)], back pain (56% (n=9)], asthenia/fatigue [56% (n=9)]), headache [44% (n=7)], and arthralgia [44% (n=7]) (Online Supplementary Table S4). Most treatment-emergent adverse events were mild and did not lead to treatment discontin- uation (Table 2).
Bone pain was reported equally among the different sotatercept dose cohorts; the mean time to first onset of bone pain was similar between dose cohorts and the dura- tion of bone pain was short (mean 12.0 days).
Asthenia was less frequent at higher dose levels; 13% (3 incidences/23 doses received) versus 5% (4 incidences/81 doses received) for TDT patients and 36% (47 inci- dences/132 doses received) versus 5% (3 incidences/67 doses received) for NTDT patients at 0.1 mg/kg and 1.0 mg/kg, respectively) (data not shown).
Observed differences between baseline and on-treat- ment laboratory values for liver and kidney function, including alanine aminotransferase, aspartate aminotrans- ferase, and serum creatinine levels, were within the ranges expected for this population and were not related to treat- ment (data not shown).
Dose delays for safety reasons were reported in eight patients, all with NTDT.
Discussion
b-thalassemia is characterized by chronic anemia due to ineffective erythropoiesis and peripheral hemolysis. The current treatment for TDT is demanding, requiring regular blood transfusions and lifelong iron chelation therapy. No standardized treatment for NTDT is available, and no
treatment is currently available to improve ineffective ery- thropoiesis. Previous investigational treatments for NTDT have included HbF modulators such as butyrates, azaciti- dine, or hydroxyurea, with or without erythropoietin; however, results with these and other modulators of HbF have been inconsistent.24,25
Sotatercept, a recombinant fusion protein that acts as a ligand trap for TGF-b superfamily ligands, is hypothesized to improve late-stage erythropoiesis by reducing prolifer- ation of early erythroid progenitors and precursors while increasing differentiation and maturation of late-stage RBC precursors.20,21 This drug may therefore present a novel approach to restoring effective erythropoiesis in b- thalassemia.
In this phase II, open-label, dose-finding study, sotater- cept exhibited a good safety profile, and was tolerated by most patients. The most frequent adverse events were bone, articular or back pain, and asthenia/fatigue. Treatment discontinuation due to adverse events was rare, and the incidence of grade 3-4 adverse events was low. Changes in laboratory values for liver and kidney function were not thought to be treatment-related and were in line with fluctuations seen in b-thalassemia patients without treatment. The active dose of sotatercept was ≥0.3 mg/kg for NTDT patients and ≥0.5 mg/kg for TDT patients. Importantly, concomitant administration of hydroxyurea did not appear to interfere with the response to sotater- cept, or with treatment compliance.
The majority (75%) of NTDT patients treated with higher doses (0.75-1.0 mg/kg) of sotatercept achieved sus- tained increases in hemoglobin of ≥1.0 g/dL. Similarly, 66% of TDT patients treated with higher doses of sotater- cept (0.75-1.0 mg/kg) achieved reductions of ≥33% in RBC transfusion requirements. The increase in hemoglo- bin and reduction in RBC transfusion correlated with increased serum exposure to sotatercept (data not shown), although responses were not proportional to sotatercept dose because of interpatient variability in serum drug exposure. The small number of patients in each dose group makes comparisons between sotatercept levels dif- ficult. Studies are ongoing to identify any differences in baseline characteristics between responders and non- responders.
Figure 3. Percentages of transfu- sion-dependent b-thalassemia patients treated with different doses of sotatercept who achieved a reduction in transfusion burden of ≥20%, ≥33%, and ≥50% sus- tained for ≥24 weeks.
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