Boosting Healthy Red Blood Cell Production to Target
Anemia in MDS and β-Thalassemia
A new class of agents developed to enhance the production
of healthy red blood cells (RBCs) provides a much-needed
alternative to current treatment options for patients with
anemia associated with myelodysplastic syndromes (MDS)
and β-thalassemia, according to data presented at the
56th ASH Annual Meeting. These agents, known as activin
receptor fusion proteins, were shown to lower the need for
regular blood transfusions in patients who did not respond
to standard treatments.
Antonio Piga, MD
“Anemia is a persistent burden for many patients
with blood disorders, particularly because many of
these patients cannot tolerate current treatments or
must rely on regular blood transfusions,” said Julie
Panepinto, MD, MSPH, moderator of a press conference at the annual meeting. “We are optimistic
about [these] new strategies to support healthy red
blood cell production without causing additional
complications for these chronically ill patients.”
Sotatercept (ACE-011) in Low-Risk MDS
In a phase 2, open-label, dose-finding study, sotatercept (ACE-011), a
novel and first-in-class activin type IIA receptor fusion protein, resulted
in erythroid hematologic improvement (HI-E) and reduction in need for
transfusions in lower-risk MDS patients who were largely transfusiondependent and ESA-refractory.
Sotatercept, which blocks the activity of the inflammatory cytokines
that inhibit production of immature RBC, was administered via subcutaneous injection once every three weeks at four dose levels.
Of the 53 patients evaluable for efficacy, erythroid hematologic
improvement (HI-E) was observed in 21 patients (40%) overall:
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0 in the 0.1 mg/kg group
4 (67%) in the 0.3 mg/kg group
8 (40%) in the 0.5 mg/kg group
9 (45%) in the 1.0 mg/kg group
Although the duration of transfusion response did appear to be
dose-dependent, he added, larger, randomized studies are necessary to
confirm these results.
ACE-536 in β-Thalassemia
A preliminary phase 2, dose-finding trial ACE-536, a recombinant
fusion protein containing modified activin receptor type IIB and IgG
Fc, showed promising results for patients with β-thalassemia, a blood
disorder characterized by reduced hemoglobin production, and as a
result a need for RBC transfusions that, over the course of year, may lead
to iron overload and organ failure.
While anemic patients with β-thalassemia are unlikely to
respond to ESAs, treatment with ACE-536 reduced the need for
transfusion and decreased serum ferritin levels, according to the
study’s lead author, Antonio G. Piga, MD.
Dr. Piga and colleagues presented data from the first 30 patients
enrolled in this phase 2 trial: seven transfusion-dependent (TD) and 23
non-transfusion-dependent (NTD) patients. Patients received subcutaneous injection of ACE-536 once every three weeks, for up to five doses,
at sequentially increasing dose levels (0.2, 0.4, 0.6, 0.8, or 1 mg/kg).
Seventy-five percent of the 12 patients treated with 0.8-1.0 mg/kg
ACE-536 met the study’s primary endpoint focusing on hemoglobin
level and transfusion needs: three NTD patients experienced a ≥1.5
g/dL hemoglobin increase and all six TD patients experienced a ≥20 percent reduction in transfusion burden. ACE-536 also reduced transfusion
burden by more than 60 percent in all seven TD patients – across all
dosing cohorts.
All five TD patients with iron overload at baseline exhibited 12 to 60
percent reductions in serum ferritin levels – one marker of iron status.
On the safety side, ACE-536 was generally well tolerated, with no
serious adverse events related to the treatment.
“All of the patients had clinically important reductions,” Dr. Piga
reported in a press briefing. “[The findings] are preliminary, but we are
very excited to start a large phase 3 trial to see if these results hold up.” ●
References
Patients also experienced periods of transfusion-independence (≥ 8
weeks), one of the study’s secondary outcomes: 19 of the 44 patients with
high transfusion burden prior to treatment with sotatercept demonstrated a reduced need for transfusions, and five of these patients actually
became transfusion-independent.
Five of the eight patients in the less-transfusion-dependent group
achieved both transfusion independence and increased hemoglobin
levels.
The treatment was generally well tolerated, with 37 percent of patients reporting one or more treatment-related adverse events.
“This drug shows promise as an agent that may reduce the burden
of regular blood transfusions or eliminate this need among anemic,
lower-risk MDS patients,” said Dr. Komrokji. “Importantly, the response
rates are more encouraging in our study than most rates reported with
other investigational agents.”
ASHClinicalNews.org
• Komrokji RS, Garcia-Manero G, Ades L, et al. “An open-label, phase 2, dose-finding
study of sotatercept (ACE-011) in patients with low or intermediate-1 (Int-1)-risk
myelodysplastic syndromes (MDS) or non-proliferative chronic myelomonocytic
leukemia (CMML) and a