Activin receptors continue to show efficacy in ß-thalassemia

Attendees at the 20th

Congress of the European

Hematology Association

VIENNA—Two very similar activin receptors, luspatercept and sotatercept, continue to show efficacy in patients with ß-thalassemia, according to research presented at the 20th Congress of the European Hematology Association (EHA).

The “twin compounds” basically differ from each other in the receptor type, but both can increase hemoglobin levels in non-transfusion-dependent (NTD) patients and reduce transfusion burden in transfusion-dependent (TD) patients.

Luspatercept is a recombinant fusion protein containing a modified extracellular domain of the activin receptor type IIB, while sotatercept is an activin receptor type IIA.

Antonio Piga, MD, of Turin University in Italy, presented the most recent results with luspatercept at EHA as abstract S136*. An update on sotatercept was also presented at the meeting.

Acceleron Pharma Inc. and Celgene Corporation are jointly developing both compounds.

The phase 2, multicenter, open-label trial of luspatercept now has results on 39 patients, 35 of whom were in the dose-escalation cohorts and 4 who are in the expansion cohort that is currently underway.

Adult patients age 18 and older received luspatercept subcutaneously every 3 weeks for 3 months. Doses in the dose-escalation cohorts increased from 0.2 mg/kg to 1.25 mg/kg.

Patients in the expansion cohort received a starting dose of 0.8 mg/kg, with an individual dose titration up to 1.25 mg/kg, for an additional 12 months of treatment. Twenty of 30 patients were enrolled in the expansion cohort as of June 8.

For all patients, the median age was 40, 82% had had a splenectomy, and 49% were male. Twenty-five patients were NTD, and 14 were TD.

NTD patients

NTD patients had a median baseline hemoglobin level of 8.4 g/dL and liver iron concentration (LIC) of 5.8 ± 3.8 mg/g dry weight (dw).

Four of 8 patients who received luspatercept at doses ranging from 0.8 mg/kg to 1.25 mg/kg saw an increase in their hemoglobin levels of 1.5 g/dL or more for 2 weeks or longer, and 3 patients (38%) had a mean hemoglobin increase of 1.5 g/dL for 9 weeks or longer.

Patients on the higher doses of luspatercept had larger hemoglobin increases, and, with continued treatment, patients sustained their hemoglobin increases.

Increases in hemoglobin correlated with reductions in LIC.

“There was a trend to lower liver iron concentration,” Dr Piga said, “a trend that seems important.”

Patients achieved reductions in LIC with and without iron chelation therapy.

Eight of 12 patients with a baseline LIC of 5 mg/g dw or greater had decreases of 1 mg or more at month 4. And 10 of 10 patients with a baseline LIC of less than 5 mg/g dw were able to maintain that concentration.

TD patients

At baseline, TD patients required a median of 7.5 red blood cell (RBC) units every 12 weeks and had an LIC of 5.2 ± 5.7 mg/g dw.

Ten of 14 patients were treated for 12 weeks or longer and were evaluable for changes in transfusion burden. And all 10 patients had a 40% or greater reduction in transfusion burden.

Two of 3 patients with an LIC of 7 mg/g dw had decreases of 1 mg/g dw or more at month 4. And all 7 patients with a baseline LIC less than 7 mg/g dw were able to maintain that level.

Leg ulcers

Three patients with long-term, persistent leg ulcers experienced rapid healing with luspatercept treatment.

One NTD patient on the 0.4 mg/kg dose experienced complete healing after 6 weeks, and 1 TD patient on the 1.0 mg/kg dose experienced complete healing after 18 weeks.

Safety

Bone pain (23%), myalgia (18%), headache (15%), and asthenia (10%) were the most common drug-related adverse events. None of the related adverse events were serious.

Two patients had treatment-related, grade 3 adverse events of bone pain (2 events) and asthenia (1 event). Six of 39 patients discontinued treatment early due to an adverse event of headache, ankle pain, back pain, spider nevi, superficial thrombosis, or bone pain.

The US Food and Drug Administration recently granted luspatercept fast track designation for the treatment of patients with TD or NTD β-thalassemia.

Dr Piga said a pivotal phase 3 trial of luspatercept in patients with β -thalassemia and myelodysplastic syndromes is planned.

*Data in the abstract differ from the presentation.

Attendees at the 20th

Congress of the European

Hematology Association

VIENNA—Two very similar activin receptors, luspatercept and sotatercept, continue to show efficacy in patients with ß-thalassemia, according to research presented at the 20th Congress of the European Hematology Association (EHA).

The “twin compounds” basically differ from each other in the receptor type, but both can increase hemoglobin levels in non-transfusion-dependent (NTD) patients and reduce transfusion burden in transfusion-dependent (TD) patients.

Luspatercept is a recombinant fusion protein containing a modified extracellular domain of the activin receptor type IIB, while sotatercept is an activin receptor type IIA.

Antonio Piga, MD, of Turin University in Italy, presented the most recent results with luspatercept at EHA as abstract S136*. An update on sotatercept was also presented at the meeting.

Acceleron Pharma Inc. and Celgene Corporation are jointly developing both compounds.

The phase 2, multicenter, open-label trial of luspatercept now has results on 39 patients, 35 of whom were in the dose-escalation cohorts and 4 who are in the expansion cohort that is currently underway.

Adult patients age 18 and older received luspatercept subcutaneously every 3 weeks for 3 months. Doses in the dose-escalation cohorts increased from 0.2 mg/kg to 1.25 mg/kg.

Patients in the expansion cohort received a starting dose of 0.8 mg/kg, with an individual dose titration up to 1.25 mg/kg, for an additional 12 months of treatment. Twenty of 30 patients were enrolled in the expansion cohort as of June 8.

For all patients, the median age was 40, 82% had had a splenectomy, and 49% were male. Twenty-five patients were NTD, and 14 were TD.

NTD patients

NTD patients had a median baseline hemoglobin level of 8.4 g/dL and liver iron concentration (LIC) of 5.8 ± 3.8 mg/g dry weight (dw).

Four of 8 patients who received luspatercept at doses ranging from 0.8 mg/kg to 1.25 mg/kg saw an increase in their hemoglobin levels of 1.5 g/dL or more for 2 weeks or longer, and 3 patients (38%) had a mean hemoglobin increase of 1.5 g/dL for 9 weeks or longer.

Patients on the higher doses of luspatercept had larger hemoglobin increases, and, with continued treatment, patients sustained their hemoglobin increases.

Increases in hemoglobin correlated with reductions in LIC.

“There was a trend to lower liver iron concentration,” Dr Piga said, “a trend that seems important.”

Patients achieved reductions in LIC with and without iron chelation therapy.

Eight of 12 patients with a baseline LIC of 5 mg/g dw or greater had decreases of 1 mg or more at month 4. And 10 of 10 patients with a baseline LIC of less than 5 mg/g dw were able to maintain that concentration.

TD patients

At baseline, TD patients required a median of 7.5 red blood cell (RBC) units every 12 weeks and had an LIC of 5.2 ± 5.7 mg/g dw.

Ten of 14 patients were treated for 12 weeks or longer and were evaluable for changes in transfusion burden. And all 10 patients had a 40% or greater reduction in transfusion burden.

Two of 3 patients with an LIC of 7 mg/g dw had decreases of 1 mg/g dw or more at month 4. And all 7 patients with a baseline LIC less than 7 mg/g dw were able to maintain that level.

Leg ulcers

Three patients with long-term, persistent leg ulcers experienced rapid healing with luspatercept treatment.

One NTD patient on the 0.4 mg/kg dose experienced complete healing after 6 weeks, and 1 TD patient on the 1.0 mg/kg dose experienced complete healing after 18 weeks.

Safety

Bone pain (23%), myalgia (18%), headache (15%), and asthenia (10%) were the most common drug-related adverse events. None of the related adverse events were serious.

Two patients had treatment-related, grade 3 adverse events of bone pain (2 events) and asthenia (1 event). Six of 39 patients discontinued treatment early due to an adverse event of headache, ankle pain, back pain, spider nevi, superficial thrombosis, or bone pain.

The US Food and Drug Administration recently granted luspatercept fast track designation for the treatment of patients with TD or NTD β-thalassemia.

Dr Piga said a pivotal phase 3 trial of luspatercept in patients with β -thalassemia and myelodysplastic syndromes is planned.

*Data in the abstract differ from the presentation.

Attendees at the 20th

Congress of the European

Hematology Association

VIENNA—Two very similar activin receptors, luspatercept and sotatercept, continue to show efficacy in patients with ß-thalassemia, according to research presented at the 20th Congress of the European Hematology Association (EHA).

The “twin compounds” basically differ from each other in the receptor type, but both can increase hemoglobin levels in non-transfusion-dependent (NTD) patients and reduce transfusion burden in transfusion-dependent (TD) patients.

Luspatercept is a recombinant fusion protein containing a modified extracellular domain of the activin receptor type IIB, while sotatercept is an activin receptor type IIA.

Antonio Piga, MD, of Turin University in Italy, presented the most recent results with luspatercept at EHA as abstract S136*. An update on sotatercept was also presented at the meeting.

Acceleron Pharma Inc. and Celgene Corporation are jointly developing both compounds.

The phase 2, multicenter, open-label trial of luspatercept now has results on 39 patients, 35 of whom were in the dose-escalation cohorts and 4 who are in the expansion cohort that is currently underway.

Adult patients age 18 and older received luspatercept subcutaneously every 3 weeks for 3 months. Doses in the dose-escalation cohorts increased from 0.2 mg/kg to 1.25 mg/kg.

Patients in the expansion cohort received a starting dose of 0.8 mg/kg, with an individual dose titration up to 1.25 mg/kg, for an additional 12 months of treatment. Twenty of 30 patients were enrolled in the expansion cohort as of June 8.

For all patients, the median age was 40, 82% had had a splenectomy, and 49% were male. Twenty-five patients were NTD, and 14 were TD.

NTD patients

NTD patients had a median baseline hemoglobin level of 8.4 g/dL and liver iron concentration (LIC) of 5.8 ± 3.8 mg/g dry weight (dw).

Four of 8 patients who received luspatercept at doses ranging from 0.8 mg/kg to 1.25 mg/kg saw an increase in their hemoglobin levels of 1.5 g/dL or more for 2 weeks or longer, and 3 patients (38%) had a mean hemoglobin increase of 1.5 g/dL for 9 weeks or longer.

Patients on the higher doses of luspatercept had larger hemoglobin increases, and, with continued treatment, patients sustained their hemoglobin increases.

Increases in hemoglobin correlated with reductions in LIC.

“There was a trend to lower liver iron concentration,” Dr Piga said, “a trend that seems important.”

Patients achieved reductions in LIC with and without iron chelation therapy.

Eight of 12 patients with a baseline LIC of 5 mg/g dw or greater had decreases of 1 mg or more at month 4. And 10 of 10 patients with a baseline LIC of less than 5 mg/g dw were able to maintain that concentration.

TD patients

At baseline, TD patients required a median of 7.5 red blood cell (RBC) units every 12 weeks and had an LIC of 5.2 ± 5.7 mg/g dw.

Ten of 14 patients were treated for 12 weeks or longer and were evaluable for changes in transfusion burden. And all 10 patients had a 40% or greater reduction in transfusion burden.

Two of 3 patients with an LIC of 7 mg/g dw had decreases of 1 mg/g dw or more at month 4. And all 7 patients with a baseline LIC less than 7 mg/g dw were able to maintain that level.

Leg ulcers

Three patients with long-term, persistent leg ulcers experienced rapid healing with luspatercept treatment.

One NTD patient on the 0.4 mg/kg dose experienced complete healing after 6 weeks, and 1 TD patient on the 1.0 mg/kg dose experienced complete healing after 18 weeks.

Safety

Bone pain (23%), myalgia (18%), headache (15%), and asthenia (10%) were the most common drug-related adverse events. None of the related adverse events were serious.

Two patients had treatment-related, grade 3 adverse events of bone pain (2 events) and asthenia (1 event). Six of 39 patients discontinued treatment early due to an adverse event of headache, ankle pain, back pain, spider nevi, superficial thrombosis, or bone pain.

The US Food and Drug Administration recently granted luspatercept fast track designation for the treatment of patients with TD or NTD β-thalassemia.

Dr Piga said a pivotal phase 3 trial of luspatercept in patients with β -thalassemia and myelodysplastic syndromes is planned.

*Data in the abstract differ from the presentation.