Drug may be new option for transfusion-dependent β-thalassemia

Photo from UAB Hospital

SAN DIEGO—Luspatercept can produce “clinically meaningful” results in transfusion-dependent adults with β-thalassemia, according to a speaker at the 2018 ASH Annual Meeting.

In the phase 3 BELIEVE trial, β-thalassemia patients were significantly more likely to experience a reduction in transfusion burden if they were treated with luspatercept rather than placebo.

“Luspatercept showed a statistically significant and clinically meaningful . . . reduction in transfusion burden compared with placebo at any 12- or 24-week [period] along this study,” said Maria Domenica Cappellini, MD, of the University of Milan in Italy.

“At this point, we believe [luspatercept] is a potential new treatment for adult patients with β-thalassemia who are requiring regular blood transfusions.”

Dr. Cappellini presented these results at ASH as abstract 163.

The BELIEVE trial (NCT02604433) enrolled 336 patients from 65 sites in 15 countries. All patients had β-thalassemia or hemoglobin E/β‑thalassemia. They required regular transfusions of six to 20 red blood cell (RBC) units in the 24 weeks prior to randomization, and none had a transfusion-free period lasting 35 days or more.

The patients were randomized 2:1 to receive luspatercept—at a starting dose of 1.0 mg/kg with titration up to 1.25 mg/kg—(n=224) or placebo (n=112) subcutaneously every 3 weeks for at least 48 weeks.

All patients continued to receive RBC transfusions and iron chelation therapy as necessary (so they maintained the same baseline hemoglobin level).

The median age was 30 in both treatment arms (range, 18-66). More than half of patients were female—58.9% in the luspatercept arm and 56.3% in the placebo arm.

A similar percentage of patients in both arms had the β0, β0 genotype—30.4% in the luspatercept arm and 31.3% in the placebo arm.

The median hemoglobin level at baseline was 9.31 g/dL in the luspatercept arm and 9.15 g/dL in the placebo arm. The median RBC transfusion burden was 6.12 units/12 weeks and 6.27 units/12 weeks, respectively.

Other baseline characteristics were similar as well.

Efficacy

“[L]uspatercept showed a statistically significant improvement in the primary endpoint,” Dr. Cappellini noted.

The primary endpoint was at least a 33% reduction in transfusion burden—of at least two RBC units—from week 13 to week 24, as compared to the 12-week baseline period.

This endpoint was achieved by 21.4% (n=48) of patients in the luspatercept arm and 4.5% (n=5) in the placebo arm (odds ratio=5.79; P<0.0001).

“Statistical significance was also demonstrated with luspatercept versus placebo for all the key secondary endpoints,” Dr. Cappellini said.

There were more patients in the luspatercept arm than the placebo arm who achieved at least a 33% reduction in transfusion burden from week 37 to 48—19.6% and 3.6%, respectively (P<0.0001).

Similarly, there were more patients in the luspatercept arm than the placebo arm who achieved at least a 50% reduction in transfusion burden from week 13 to 24—7.6% and 1.8%, respectively (P=0.0303)—and from week 37 to 48—10.3% and 0.9%, respectively (P=0.0017).

During any 12-week interval, 70.5% of luspatercept-treated patients and 29.5% of placebo-treated patients achieved at least a 33% reduction in transfusion burden (P<0.0001), and 40.2% and 6.3%, respectively (P<0.0001), achieved at least a 50% reduction in transfusion burden.

During any 24-week interval, 41.1% of luspatercept-treated patients and 2.7% of placebo-treated patients achieved at least a 33% reduction in transfusion burden (P<0.0001), and 16.5% and 0.9%, respectively (P<0.0001), achieved at least a 50% reduction in transfusion burden.

Safety

Ninety-six percent of patients in the luspatercept arm and 92.7% in the placebo arm had at least one treatment-emergent adverse event (TEAE).

Grade 3 or higher TEAEs occurred in 29.1% of patients in the luspatercept arm and 15.6% of those in the placebo arm. Serious TEAEs occurred in 15.2% and 5.5%, respectively.

One patient in the placebo arm had a TEAE-related death (acute cholecystitis), but there were no treatment-related deaths in the luspatercept arm.

TEAEs leading to treatment discontinuation occurred in 5.4% of luspatercept-treated patients and 0.9% of placebo-treated patients.

TEAEs that occurred more frequently in the luspatercept arm than in the placebo arm (respectively) included bone pain (19.7% and 8.3%), arthralgia (19.3% and 11.9%), and dizziness (11.2% and 4.6%).

Grade 3/4 TEAEs (in the luspatercept and placebo arms, respectively) included anemia (3.1% and 0%), increased liver iron concentration (2.7% and 0.9%), hyperuricemia (2.7% and 0%), hypertension (1.8% and 0%), syncope (1.8% and 0%), back pain (1.3% and 0.9%), bone pain (1.3% and 0%), blood uric acid increase (1.3% and 0%), increased aspartate aminotransferase (1.3% and 0%), increased alanine aminotransferase (0.9% and 2.8%), and thromboembolic events (0.9% and 0%).

Dr. Cappellini noted that thromboembolic events occurred in eight luspatercept-treated patients and one placebo-treated patient. In all cases, the patients had multiple risk factors for thrombosis.

This study was sponsored by Celgene Corporation and Acceleron Pharma. Dr. Cappellini reported relationships with Novartis, Celgene, Sanofi-Genzyme, and Vifor.

Photo from UAB Hospital

SAN DIEGO—Luspatercept can produce “clinically meaningful” results in transfusion-dependent adults with β-thalassemia, according to a speaker at the 2018 ASH Annual Meeting.

In the phase 3 BELIEVE trial, β-thalassemia patients were significantly more likely to experience a reduction in transfusion burden if they were treated with luspatercept rather than placebo.

“Luspatercept showed a statistically significant and clinically meaningful . . . reduction in transfusion burden compared with placebo at any 12- or 24-week [period] along this study,” said Maria Domenica Cappellini, MD, of the University of Milan in Italy.

“At this point, we believe [luspatercept] is a potential new treatment for adult patients with β-thalassemia who are requiring regular blood transfusions.”

Dr. Cappellini presented these results at ASH as abstract 163.

The BELIEVE trial (NCT02604433) enrolled 336 patients from 65 sites in 15 countries. All patients had β-thalassemia or hemoglobin E/β‑thalassemia. They required regular transfusions of six to 20 red blood cell (RBC) units in the 24 weeks prior to randomization, and none had a transfusion-free period lasting 35 days or more.

The patients were randomized 2:1 to receive luspatercept—at a starting dose of 1.0 mg/kg with titration up to 1.25 mg/kg—(n=224) or placebo (n=112) subcutaneously every 3 weeks for at least 48 weeks.

All patients continued to receive RBC transfusions and iron chelation therapy as necessary (so they maintained the same baseline hemoglobin level).

The median age was 30 in both treatment arms (range, 18-66). More than half of patients were female—58.9% in the luspatercept arm and 56.3% in the placebo arm.

A similar percentage of patients in both arms had the β0, β0 genotype—30.4% in the luspatercept arm and 31.3% in the placebo arm.

The median hemoglobin level at baseline was 9.31 g/dL in the luspatercept arm and 9.15 g/dL in the placebo arm. The median RBC transfusion burden was 6.12 units/12 weeks and 6.27 units/12 weeks, respectively.

Other baseline characteristics were similar as well.

Efficacy

“[L]uspatercept showed a statistically significant improvement in the primary endpoint,” Dr. Cappellini noted.

The primary endpoint was at least a 33% reduction in transfusion burden—of at least two RBC units—from week 13 to week 24, as compared to the 12-week baseline period.

This endpoint was achieved by 21.4% (n=48) of patients in the luspatercept arm and 4.5% (n=5) in the placebo arm (odds ratio=5.79; P<0.0001).

“Statistical significance was also demonstrated with luspatercept versus placebo for all the key secondary endpoints,” Dr. Cappellini said.

There were more patients in the luspatercept arm than the placebo arm who achieved at least a 33% reduction in transfusion burden from week 37 to 48—19.6% and 3.6%, respectively (P<0.0001).

Similarly, there were more patients in the luspatercept arm than the placebo arm who achieved at least a 50% reduction in transfusion burden from week 13 to 24—7.6% and 1.8%, respectively (P=0.0303)—and from week 37 to 48—10.3% and 0.9%, respectively (P=0.0017).

During any 12-week interval, 70.5% of luspatercept-treated patients and 29.5% of placebo-treated patients achieved at least a 33% reduction in transfusion burden (P<0.0001), and 40.2% and 6.3%, respectively (P<0.0001), achieved at least a 50% reduction in transfusion burden.

During any 24-week interval, 41.1% of luspatercept-treated patients and 2.7% of placebo-treated patients achieved at least a 33% reduction in transfusion burden (P<0.0001), and 16.5% and 0.9%, respectively (P<0.0001), achieved at least a 50% reduction in transfusion burden.

Safety

Ninety-six percent of patients in the luspatercept arm and 92.7% in the placebo arm had at least one treatment-emergent adverse event (TEAE).

Grade 3 or higher TEAEs occurred in 29.1% of patients in the luspatercept arm and 15.6% of those in the placebo arm. Serious TEAEs occurred in 15.2% and 5.5%, respectively.

One patient in the placebo arm had a TEAE-related death (acute cholecystitis), but there were no treatment-related deaths in the luspatercept arm.

TEAEs leading to treatment discontinuation occurred in 5.4% of luspatercept-treated patients and 0.9% of placebo-treated patients.

TEAEs that occurred more frequently in the luspatercept arm than in the placebo arm (respectively) included bone pain (19.7% and 8.3%), arthralgia (19.3% and 11.9%), and dizziness (11.2% and 4.6%).

Grade 3/4 TEAEs (in the luspatercept and placebo arms, respectively) included anemia (3.1% and 0%), increased liver iron concentration (2.7% and 0.9%), hyperuricemia (2.7% and 0%), hypertension (1.8% and 0%), syncope (1.8% and 0%), back pain (1.3% and 0.9%), bone pain (1.3% and 0%), blood uric acid increase (1.3% and 0%), increased aspartate aminotransferase (1.3% and 0%), increased alanine aminotransferase (0.9% and 2.8%), and thromboembolic events (0.9% and 0%).

Dr. Cappellini noted that thromboembolic events occurred in eight luspatercept-treated patients and one placebo-treated patient. In all cases, the patients had multiple risk factors for thrombosis.

This study was sponsored by Celgene Corporation and Acceleron Pharma. Dr. Cappellini reported relationships with Novartis, Celgene, Sanofi-Genzyme, and Vifor.

Photo from UAB Hospital

SAN DIEGO—Luspatercept can produce “clinically meaningful” results in transfusion-dependent adults with β-thalassemia, according to a speaker at the 2018 ASH Annual Meeting.

In the phase 3 BELIEVE trial, β-thalassemia patients were significantly more likely to experience a reduction in transfusion burden if they were treated with luspatercept rather than placebo.

“Luspatercept showed a statistically significant and clinically meaningful . . . reduction in transfusion burden compared with placebo at any 12- or 24-week [period] along this study,” said Maria Domenica Cappellini, MD, of the University of Milan in Italy.

“At this point, we believe [luspatercept] is a potential new treatment for adult patients with β-thalassemia who are requiring regular blood transfusions.”

Dr. Cappellini presented these results at ASH as abstract 163.

The BELIEVE trial (NCT02604433) enrolled 336 patients from 65 sites in 15 countries. All patients had β-thalassemia or hemoglobin E/β‑thalassemia. They required regular transfusions of six to 20 red blood cell (RBC) units in the 24 weeks prior to randomization, and none had a transfusion-free period lasting 35 days or more.

The patients were randomized 2:1 to receive luspatercept—at a starting dose of 1.0 mg/kg with titration up to 1.25 mg/kg—(n=224) or placebo (n=112) subcutaneously every 3 weeks for at least 48 weeks.

All patients continued to receive RBC transfusions and iron chelation therapy as necessary (so they maintained the same baseline hemoglobin level).

The median age was 30 in both treatment arms (range, 18-66). More than half of patients were female—58.9% in the luspatercept arm and 56.3% in the placebo arm.

A similar percentage of patients in both arms had the β0, β0 genotype—30.4% in the luspatercept arm and 31.3% in the placebo arm.

The median hemoglobin level at baseline was 9.31 g/dL in the luspatercept arm and 9.15 g/dL in the placebo arm. The median RBC transfusion burden was 6.12 units/12 weeks and 6.27 units/12 weeks, respectively.

Other baseline characteristics were similar as well.

Efficacy

“[L]uspatercept showed a statistically significant improvement in the primary endpoint,” Dr. Cappellini noted.

The primary endpoint was at least a 33% reduction in transfusion burden—of at least two RBC units—from week 13 to week 24, as compared to the 12-week baseline period.

This endpoint was achieved by 21.4% (n=48) of patients in the luspatercept arm and 4.5% (n=5) in the placebo arm (odds ratio=5.79; P<0.0001).

“Statistical significance was also demonstrated with luspatercept versus placebo for all the key secondary endpoints,” Dr. Cappellini said.

There were more patients in the luspatercept arm than the placebo arm who achieved at least a 33% reduction in transfusion burden from week 37 to 48—19.6% and 3.6%, respectively (P<0.0001).

Similarly, there were more patients in the luspatercept arm than the placebo arm who achieved at least a 50% reduction in transfusion burden from week 13 to 24—7.6% and 1.8%, respectively (P=0.0303)—and from week 37 to 48—10.3% and 0.9%, respectively (P=0.0017).

During any 12-week interval, 70.5% of luspatercept-treated patients and 29.5% of placebo-treated patients achieved at least a 33% reduction in transfusion burden (P<0.0001), and 40.2% and 6.3%, respectively (P<0.0001), achieved at least a 50% reduction in transfusion burden.

During any 24-week interval, 41.1% of luspatercept-treated patients and 2.7% of placebo-treated patients achieved at least a 33% reduction in transfusion burden (P<0.0001), and 16.5% and 0.9%, respectively (P<0.0001), achieved at least a 50% reduction in transfusion burden.

Safety

Ninety-six percent of patients in the luspatercept arm and 92.7% in the placebo arm had at least one treatment-emergent adverse event (TEAE).

Grade 3 or higher TEAEs occurred in 29.1% of patients in the luspatercept arm and 15.6% of those in the placebo arm. Serious TEAEs occurred in 15.2% and 5.5%, respectively.

One patient in the placebo arm had a TEAE-related death (acute cholecystitis), but there were no treatment-related deaths in the luspatercept arm.

TEAEs leading to treatment discontinuation occurred in 5.4% of luspatercept-treated patients and 0.9% of placebo-treated patients.

TEAEs that occurred more frequently in the luspatercept arm than in the placebo arm (respectively) included bone pain (19.7% and 8.3%), arthralgia (19.3% and 11.9%), and dizziness (11.2% and 4.6%).

Grade 3/4 TEAEs (in the luspatercept and placebo arms, respectively) included anemia (3.1% and 0%), increased liver iron concentration (2.7% and 0.9%), hyperuricemia (2.7% and 0%), hypertension (1.8% and 0%), syncope (1.8% and 0%), back pain (1.3% and 0.9%), bone pain (1.3% and 0%), blood uric acid increase (1.3% and 0%), increased aspartate aminotransferase (1.3% and 0%), increased alanine aminotransferase (0.9% and 2.8%), and thromboembolic events (0.9% and 0%).

Dr. Cappellini noted that thromboembolic events occurred in eight luspatercept-treated patients and one placebo-treated patient. In all cases, the patients had multiple risk factors for thrombosis.

This study was sponsored by Celgene Corporation and Acceleron Pharma. Dr. Cappellini reported relationships with Novartis, Celgene, Sanofi-Genzyme, and Vifor.