EU Panel Backs Luspatercept for Anemia in MDS and Beta Thalassemia

The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) has recommended approval of luspatercept (Reblozyl) for the treatment of anemia in patients with myelodysplastic syndromes (MDS) and beta thalassemia, according to Bristol Myers Squibb and Acceleron Pharma Inc., the codevelopers of the erythroid maturation agent.¹

The recommendation is specifically for adult patients with transfusion-dependent anemia due to very low-, low- and intermediate-risk MDS with ring sideroblasts, who had an unsatisfactory response or are ineligible for erythropoietin-based therapy, as well as for adult patients with transfusion-dependent anemia associated with beta thalassemia.

Data supporting the recommendation came from the phase 3 MEDALIST trial² and the phase 3 BELIEVE trial.³

In the MEDALIST trial, treatment with luspatercept reduced the severity of anemia in patients with very low- to intermediate-risk MDS with ring sideroblasts who require RBC transfusions. Additionally, the benefit with luspatercept extended to patients with refractory disease or those who were unlikely to respond to or were intolerant of ESAs.

The key secondary end point of RBC-TI for ≥12 weeks was met by a higher percentage of patients in the luspatercept group than in the placebo group at 28% versus 8% for weeks 1 through 24, and 33% versus 12% for weeks 1 through 48 (P <.001 for both). In an analysis that applied the International Working Group (IWG) 2018 criteria, 19% of luspatercept-treated patients compared with 4% of patients on placebo had RBC-TI for ≥16 weeks during weeks 1 through 24; these rates were 28% and 7%, respectively, during weeks 1 through 48.

The study met an additional secondary end point, which was hematologic improvement-erythroid (HI-E) for ≥8 weeks, as assessed by IWG 2006 criteria. In weeks 1 through 24, HI-E responses occurred in 53% of patients on luspatercept compared with 12% of those in the placebo group. Fifty-nine percent of patients treated with luspatercept had an HI-E response in weeks 1 through 48 versus 17% of patients on placebo. During the double-blind period, no significant changes in neutrophil or platelet counts were observed.

The double-blind, placebo-controlled, phase 3 MEDALIST trial included 229 patients who were categorized with International Prognostic Scoring System (IPSS)-Revised very low-, low-, or intermediate-risk MDS with ring sideroblasts and required RBC transfusions. Patients were randomized to receive luspatercept at a dose of 1.0 to 1.75 mg/kg (n = 153) or placebo (76) subcutaneously every 3 weeks.

The median age was 71 years (range, 26-95) and 63% of patients were male. SF3B1 mutations were identified in 93% of patients in the luspatercept group and 86% of those on the placebo arm. Ninety-five percent of patients previously received ESAs and 48% had received prior iron chelation treatment. The data cutoff date was May 8, 2018.

Ninety percent (n = 52) of patients in the luspatercept group who had a response had their first response at the starting dose of 1.00 mg/kg, and 7% of patients responded after dose increases at 1.33 mg/kg (n = 2) and 1.75 mg/kg (n = 2).

RBC-TI for ≥8 weeks occurred in 80% of patients on luspatercept who received <4 units per 8 weeks, in 37% of those who received 4 to 6 units per 8 weeks, and in 9% of patients who received ≥6 units per 8 weeks. In the placebo group, these RBC-TI rates were 40%, 4%, and 3%, respectively.

Additionally, the authors noted that the RBC-TI rates with luspatercept at ≥8 weeks during weeks 1 to 24 were similar regardless of number of baseline mutations: 1 (36.4%), 2 (34.9%), 3 (42.4%), and 4 or 5 (33.3%).3

Regarding safety, the most common adverse events (AEs) found in ≥10% of the luspatercept and placebo arms were fatigue (27% vs 13%), diarrhea (22% vs 9%), asthenia (20% vs 12%), nausea (20% vs 8%), dizziness (20% vs 5%), and back pain (19% vs 7%). Grade ≥3 AEs occurred in 42% and 45% of patients on luspatercept and placebo, respectively; the most common were fatigue (5% with luspatercept and 3% with placebo) and injury (5% and 3%, respectively). Thirty-one percent of patients on luspatercept and 30% of those on placebo experienced ≥1 serious AE.

Longer-term analyses from MEDALIST were presented at the 2019 ASH Annual Meeting.⁴ At a data cutoff date of July 1, 2019, results showed that the RBC-TI at ≥8 weeks was 47.7% with luspatercept and 15.8% with placebo (odds ratio [OR], 5.978; 95% CI, 2.840-12.581; P <.0001). At ≥6 units per 8 weeks, the RBC-TI was 21.2% with luspatercept and 6.1% with placebo (OR, 4.17; 95% CI, 0.89-19.60; P = .0547). In those who received 4 to 6 units per 8 weeks, the RBC-TI was 48.8% and 8.7% with luspatercept and placebo, respectively (OR, 10.00; 95% CI, 2.07-48.28; P = .0013). In patients who received <4 units per 8 weeks, the RBC-TI was 84.8% with luspatercept and 40.0% with placebo (OR, 8.36; 95% CI, 2.51-27.83; P = .0002).

Additionally, the longer follow-up showed that of the 73 patients treated with luspatercept achieving RBC-TI ≥8 weeks during the entire treatment period, 69.9% had ≥2 separate response periods, 38.4% of patients had ≥3 separate response periods, and 20.5% had ≥4 separate response periods.

"Patients with myelodysplastic syndromes who experience anemia have limited treatment options, and some have been shown to not respond to available erythropoietin-based therapies," the lead investigator of the MEDALIST study, Uwe Platzbecker, MD, head of Clinic and Policlinic for Hematology and Cell Therapy, Leipzig University Hospital stated in a press release. “If approved, the introduction of a new class of therapy in Reblozyl could provide a promising option to help relieve patients from the burden of regular transfusions to manage their disease.”

The phase 3 BELIEVE study showed that treatment with luspatercept t led to significant reductions in RBC transfusion burden in those with beta-thalassemia—associated anemia. Results specifically showed that 21.4% of patients who received luspatercept-aamt achieved a ≥33% reduction from baseline in RBC transfusion burden, with a reduction of ≥2 units, during weeks 13 to 24 after randomization compared with 4.5% of patients who received placebo (risk difference, 17.0; 95% CI, 10.4-23.6; P <.0001).

In the double-blind, placebo-controlled, multicenter, BELIEVE study, investigators explored the safety and efficacy of luspatercept-aamt in adult patients with beta thalassemia who regularly required RBC transfusions. To be eligible for enrollment, patients had to be aged ≥18 years, had beta thalassemia or hemoglobin (Hb) E/beta thalassemia, and required regular transfusions of 6 to 20 RBC units in the 24 weeks prior to randomization with no transfusion-free period ≥35 days during that time.

A total 336 patients were randomized 2:1 to receive either luspatercept-aamt at a starting dose level of 1.0 mg/kg with titration up to 1.25 mg/kg (n = 224), or placebo (n = 112), subcutaneously every 3 weeks for ≥48 weeks; 332 patients were treated. Those in both arms continued to receive RBC transfusions and iron chelation therapy to maintain the same baseline Hb level.

The primary end point of this trial was a ≥33% reduction in transfusion burden, with a reduction of ≥2 RBC units, during weeks 13 to 24, when compared with a 12-week baseline period. Secondary endpoints included ≥33% reduction in RBC transfusion burden at weeks 37 to 48, ≥50% reduction in transfusion burden at weeks 13 to 24, ≥50% reduction in transfusion burden at weeks 37 to 48, and mean change in transfusion burden at weeks 13 to 24. Moreover, achievement of ≥33% reduction in RBC transfusion burden over any consecutive 12 weeks on study was also evaluated.

The median age was 30 years (range, 18-66) and 58% of patients were female. Additionally, patients received a median of 6 RBC units in the 12 weeks before treatment, and 58% of patients in each arm had undergone splenectomy. B0/B0 genotype was observed in 30.4% and 31.3% of patients in the luspatercept-aamt and placebo arms, respectively.

Additional results showed that 19.6% patients on luspatercept-aamt achieved a ≥33% reduction in RBC transfusion burden at weeks 37 to 48 compared with 3.6% of those receiving placebo (P <.0001). Moreover, 7.6% and 10.3% achieved a ≥50% reduction in RBC transfusion burden at weeks 13 to 24 and 37 to 48, respectively, versus 1.8% and 0.9% of those on placebo (P = .0303 and P = .0017, respectively).

Regarding safety, thromboembolic events occurred in 3.6% of patients on the luspatercept-aamt arm, and hypertension was reported in 10.7% of luspatercept-aamt—treated patients across the clinical development program. Serious AEs occurred in 3.6% of patients receiving luspatercept-aamt, and serious AEs in 1% of patients were cerebrovascular accident and deep vein thrombosis. There was 1 death due to an unconfirmed case of acute myeloid leukemia. The most common AEs were headache (26% with luspatercept-aamt vs 24% with placebo), bone pain (20% vs 8%, respectively), arthralgia (19% vs 12%), fatigue (14% vs 13%), cough (14% vs 11%), abdominal pain (14% vs 12%), diarrhea (12% vs 10%), and dizziness (11% vs 5%) .

Treatment discontinuation due to an AE in grades 1 through 4 occurred in 5.4% of patients who received luspatercept-aamt. The most frequent AEs that required discontinuation in the luspatercept-aamt arm included arthralgia (1%), back pain (1%), bone pain (<1%), and headache (<1%). Furthermore, dose reductions due to an AE occurred in 2.7% of patients who received luspatercept-aamt, the most common were due to hypertension and headache. Dose interruptions due to AEs occurred in 15.2% of those on luspatercept-aamt; the most frequent AEs that led to dose interruptions were upper respiratory tract infection, alanine transaminase increase, and cough.

“Today’s positive CHMP opinion of Reblozyl is an important milestone for adult beta thalassemia patients in the EU who have limited treatment options to address anemia, a serious consequence of the disease,” the lead investigator of the BELIEVE study, Maria Domenica Cappellini, MD, professor of Medicine, University of Milan, Fondazione IRCCS Ca Granda, stated in the press release. “Reblozyl has the potential to significantly decrease the number of red blood cell transfusions patients need.”

References

1. Reblozyl (luspatercept) Receives Positive CHMP Opinion for the Treatment of Adults with Anemia in Beta Thalassemia and Myelodysplastic Syndromes. Published April 30, 2020. https://bit.ly/2xmKj0y. Accessed April 30, 2020.
2. Fenaux P, Platzbecker U, Mufti GJ, et al. Luspatercept in patients with lower-risk myelodysplastic syndromes. N Eng J Med. 2020;382(2):140-151. doi: 10.1056/NEJMoa1908892
3. Cappelini MD, Viprakasit V, Taher A, et al. The BELIEVE Trial: results of a phase 3, randomized, double-blind, placebo-controlled study of luspatercept in adult beta-thalassemia patients who require regular red blood cell (RBC) transfusions. Blood. 2018;132:163. doi: 10.1182/blood-2018-163
4. Fenaux P, Mufti GJ, Buckstein R, et al. Assessment of longer-term efficacy and safety in the phase 3, randomized, double-blind, placebo-controlled medalist trial of luspatercept to treat anemia in patients (pts) with revised International Prognostic Scoring System (IPSS-R) very low-, low-, or intermediate-risk myelodysplastic syndromes (MDS) with ring sideroblasts (RS) who require red blood cell (RBC) transfusions. Blood. 2019;134(suppl_1):841. doi: 10.1182/blood-2019-123064

The findings showed that 38% of patients in the luspatercept group had RBC-transfusion independence (RBC-TI) for ≥8 weeks compared with 13% of those in the placebo group (P <.001), meeting the primary endpoint of the study.