FDA Approvals, Highlights, and Summaries: Hematology

February 27, 2020

Accrufer (ferric maltol)

Ferric maltol is indicated for adults with iron deficiency anemia. The approval was based on 3 placebo-controlled trials (AEGIS 1 and 2, AEGIS 3). Ferric maltol improved hemoglobin from baseline by 2.18 g/dL in AEGIS 1 and 2 in patients with inflammatory bowel disease (P<.0001). Patients with chronic kidney disease were studied in AEGIS 3, which showed hemoglobin improvement from baseline by 0.52 g/dL (P=.0149).

Inflamm Bowel Dis. 2015 Mar;21(3):579-88

Accrufer prescribing information

Reblozyl (luspatercept)

Luspatercept is an erythroid maturation agent. The drug is a recombinant fusion protein that diminishes Smad2/3 signaling by binding several endogenous transforming growth factor-beta superfamily ligands. In a model of beta-thalassemia, luspatercept decreased abnormally elevated Smad2/3 signaling and improved hematology parameters associated with ineffective erythropoiesis. It is indicated for anemia in adults with beta-thalassemia who require regular red blood cell (RBC) transfusions.

Approval of luspatercept was based on the BELIEVE phase 3 clinical trial that included adults with beta-thalassemia who require regular RBC transfusions (defined as 6-20 RBC units per 24 weeks, with no transfusion-free period >35 days during that period). Patients (n=336) were randomized 2:1 to receive luspatercept (n=224) or placebo (n=112) at a starting dose of 1 mg/kg SC every 21 days for up to 48 weeks. In the patients who received luspatercept, 21.4% achieved a 33% or greater reduction from baseline in RBC transfusion burden (with a reduction of at least 2 units) during weeks 13-24 after randomization, compared with 4.5% (n=5) in the placebo arm (risk difference [95% confidence interval]: 17.0 [10.4, 23.6], P<.0001).

[Cappellini 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. Abstract #163. Presented at the 2018 American Society of Hematology (ASH) Annual Meeting, December 1, 2018; San Diego, CA.]

Givlaari (givosiran)

Givosiran is a small-interfering RNA that causes degradation of aminolevulinate synthase 1 (ALAS1) mRNA in hepatocytes through RNA interference, reducing the elevated levels of liver ALAS1 mRNA. It is approved for adults with acute hepatic porphyrias (AHPs), in which attacks are caused by induction of the enzyme 5-aminolevulinic acid synthase 1 (ALAS1).

Approval of givosiran was based on the ENVISION phase 3 trial (n=94). Givosiran resulted in a 74% mean reduction in annualized composite rate of porphyria attacks in acute intermittent porphyria patients relative to placebo. A corresponding 90% reduction in median annualized attack rate (AAR), with 50% of patients on givosiran who were attack-free compared with 16.3% for placebo was also observed. A 73% reduction in mean AAR was observed in patients with any AHP relative to placebo. Givosiran resulted in a reduction in days of hemin use of 77% compared with placebo. It also led to sustained (~90%) lowering from baseline of ALA and porphobilinogen, the neurotoxic liver heme intermediates that cause attacks and other AHP disease manifestations.

[Balwani M, Gouya L, Rees DC, Stein P, Stölzel U, Aguilera Peiro P, et al. ENVISION, a Phase 3 Study to Evaluate the Efficacy and Safety of Givosiran, an Investigational RNAi Therapeutic Targeting Aminolevulinic Acid Synthase 1, in Acute Hepatic Porphyria Patients. Presented at EASL (European Association for the Study of the Liver) meeting. 13 April 2019, Vienna, Austria.]

Adakveo (crizanlizumab)

Crizanlizumab, a P-selectin inhibitor, was approved by the FDA to reduce frequency of vasoocclusive crisis (VOC) in adults and adolescents aged 16 years or older with sickle cell disease. Binding P-selectin on the surface of activated endothelium and platelet cells blocks interactions between endothelial cells, platelets, red blood cells, and leukocytes. Approval was based on the SUSTAIN clinical trial, which showed crizanlizumab reduced the median annual rate of VOCs leading to healthcare visits by 45.3% compared with placebo (1.63 vs 2.98, P=.010) in patients with or without hydroxyurea.

N Engl J Med. 2017 Feb 2;376(5):429-439

Am J Hematol. 2019 Jan;94(1):55-61

Oxbryta (voxelotor)

Voxelotor is the first drug approved by the FDA for sickle cell disease based solely on data showing an increase in hemoglobin (Hb). It is indicated for treatment of sickle cell disease in adults and adolescents aged 12 years or older. Voxelotor is an HbS polymerization inhibitor that binds to HbS with a 1:1 stoichiometry and exhibits preferential partitioning to red blood cells. By increasing the affinity of Hb for oxygen, voxelotor demonstrates dose-dependent inhibition of HbS polymerization.

Approval of voxelotor was based on results from a clinical trial that enrolled 274 patients with sickle cell disease and treated them with either 1500 mg or 900 mg PO once daily of voxelotor or placebo. Results showed 51% of patients on the higher dose of voxelotor achieved an Hb response, defined as an increase in Hb of at least 1 g/dL after 24 weeks. Just over 6% of the placebo patients had the same Hb response. At week 24, the 1500-mg voxelotor group had significantly greater reductions from baseline in the indirect bilirubin level and percentage of reticulocytes than the placebo group.

N Engl J Med. 2019 Aug 8;381(6):509-519

Cablivi (caplacizumab)

Caplacizumab is a monoclonal antibody fragment that targets the A1-domain of von Willebrand factor (vWF) and inhibits the interaction between vWF and platelets. This inhibition reduces both vWF-mediated platelet adhesion and platelet consumption. Caplacizumab is indicated for acquired thrombotic thrombocytopenic purpura (aTTP) in combination with plasma exchange and immunosuppressive therapy.

Approval was based on results from the phase 3 HERCULES trial (n=145). When caplacizumab was added to plasma exchange and immunosuppression, a significantly shorter time to platelet count response was observed compared with plasma exchange and immunosuppression alone (hazard ratio, 1.55; 95% confidence interval, 1.1-2.2; P = .01). Additionally, a significant reduction of aTTP-related death, recurrence of aTTP, or a major thromboembolic event was reduced with the addition of caplacizumab compared with plasma exchange and immunosuppression alone (12.7% vs 49.3%; P <.0001). There was also a lower recurrence of aTTP in caplacizumab-treated patients (13% vs 38%; P <.001).

N Engl J Med. 2019 Jan 24;380(4):335-346

Additional 2019 Hematology approvals

Wilate (antihemophilic factor vWF complex) gained a new indication for routine prophylaxis or on-demand treatment of bleeding episodes in adults and adolescents with hemophilia A.

Ultomiris (ravulizumab) was approved for atypical hemolytic-uremic syndrome in adults and children aged 1 month or older.

Doptelet (avatrombopag) indication for thrombocytopenia now includes patients with immune thrombocytopenia.


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