Hb Response Research Articles

P1547: ACTIVATE-KIDS: MITAPIVAT IN CHILDREN WITH PYRUVATE KINASE DEFICIENCY WHO ARE NOT REGULARLY TRANSFUSED

Background: Pyruvate kinase (PK) deficiency is a rare, inherited disorder caused by PKLR gene mutations that is associated with chronic hemolytic anemia and lifelong complications. Clinical management includes red blood cell (RBC) transfusions and splenectomy, which only partially improves anemia. No pharmacotherapies are approved for use in children, and therapies targeting the underlying cause of hemolysis are needed. Mitapivat (AG-348), a first-in-class, oral, allosteric activator of the RBC PK enzyme, demonstrated significant and durable improvements in hemoglobin (Hb) and markers of hemolysis, hematopoiesis, and iron metabolism in adults with PK deficiency who were not regularly transfused (ACTIVATE NCT03548220, long-term extension study NCT03853798). Safety and efficacy data support the evaluation of mitapivat in children with PK deficiency who are not regularly transfused. Aims: Report the design of ACTIVATE-Kids (NCT05175105), a phase 3 study, which will evaluate the efficacy and safety of mitapivat in children with PK deficiency who are not regularly transfused. Methods: ACTIVATE-Kids, a global, multicenter, double-blind, placebo-controlled study, will stratify 30 children by age (1 to <6, 6 to <12, and 12 to <18 years); a minimum of 6 patients in each age group will be randomized (2:1) to mitapivat or placebo. The double-blind period comprises an 8-week dose-titration period and a 12-week fixed-dose period. A 5-year open-label period will follow the double-blind period. The study drug will be dosed (1–50 mg twice daily) according to patient age and weight, based on pharmacokinetic modeling data of adults with PK deficiency. Key inclusion criteria: ≥2 PKLR mutant alleles with ≥1 missense mutation, ≤5 RBC transfusions in the past year, Hb concentrations of ≤10 g/dL (12 to <18 years) or ≤9 g/dL (1 to <12 years). Key exclusion criteria: R479H homozygosity, 2 non-missense mutations without a missense mutation in PKLR, or prior stem cell transplantation. The primary endpoint is Hb response, defined as a ≥1.5 g/dL increase in Hb concentration from baseline that is sustained at ≥2 scheduled assessments at Weeks 12, 16, and 20 in the double-blind period. Secondary endpoints will evaluate the effect of mitapivat on Hb, hemolysis, erythropoiesis, iron metabolism and overload, safety, quality of life, and pharmacokinetics. Results: Global site recruitment is in-progress; an update on recruitment and patient enrollment will be provided. Summary/Conclusion: The phase 3 ACTIVATE-Kids study of children with PK deficiency who are not regularly transfused will evaluate treatment with mitapivat, a potential disease-modifying pharmacotherapy.

Open-label, phase 2 study of roxadustat for treatment of anemia in patients receiving chemotherapy for non-myeloid malignancies.

12085 Background: Anemia is prevalent in patients (pts) receiving myelosuppressive chemotherapy (&gt; 60%) and exacerbated by repeated treatment cycles due to cytotoxic agent accumulation. Chemotherapy-induced anemia (CIA) management options are suboptimal. We evaluated the efficacy and safety of roxadustat in pts with anemia receiving myelosuppressive chemotherapy. Methods: This open-label, single-arm, proof-of-concept Phase 2 study included pts with mostly advanced, non-myeloid malignancies and CIA (hemoglobin [Hb] ≤10 g/dL) who had not received red blood cell (RBC) transfusion or erythropoietin-stimulating agents within 4 weeks of enrollment. Patients were treated with oral roxadustat for ≤16 weeks. The primary efficacy endpoint was maximum mean change in Hb within 16 weeks of baseline without RBC transfusion in pts who had received ≥1 dose of roxadustat and who had a baseline and ≥1 post-dose Hb assessment. Hb response and safety data were preliminarily assessed in pts receiving a starting dose of 2.0 mg/kg thrice weekly (TIW) for 4 weeks: doses of 100, 150, and 200 mg were given to pts weighing &lt; 70, 70–100, and &gt; 100 kg, respectively. Following a review of data from these pts, dose was increased to 2.5 mg/kg—150, 200, and 250 mg TIW to pts weighing &lt; 70, 70–100, and &gt; 100 kg, respectively—and adjusted every 4 weeks from Week 5 based on Hb response. Results: Patients were assigned to 2.0 mg/kg (n = 31) and 2.5 mg/kg (n = 61) starting doses, and 89 were assessed for efficacy. The maximum mean Hb change from baseline without RBC transfusion was 2.47±1.51 g/dL and 2.52±1.54 g/dL in the 2.0 mg/kg and 2.5 mg/kg cohorts, respectively. Hb increased by ≥1.5 g/dL in 73% of pts and ≥2.0 g/dL in 61% of pts. Median time to ≥2.0 g/dL Hb increase was 71.0 days. Both cohorts had higher proportions of pts with a Hb increase of ≥1, ≥1.5, or ≥2 g/dL at Week 16 compared with baseline. Median time to ≥1 and ≥2 g/dL Hb increase was shorter in pts who started on 2.5 mg/kg compared with 2.0 mg/kg doses (≥1 g/dL: 30 vs 44; ≥2 g/dL 57 vs 105, respectively). Fewer pts required an RBC transfusion (Week 5 to end of treatment) when starting on 2.5 mg/kg compared with 2.0 mg/kg doses (10.2% vs 20.0%). Subgroup analyses based on major tumor and baseline chemotherapy types demonstrated efficacy of roxadustat at both starting doses. The overall safety profile observed was consistent with the patient population under study. Overall, 92% of pts experienced an adverse event (AE). Most AEs were consistent with the underlying malignancies and chemotherapy regimens used. The incidence of deep vein thrombosis was 15.2% (n = 14) and pulmonary embolism was 9.8% (n = 9). There were 17 deaths (18.5%) during the study; none were attributed to roxadustat, and most were associated with disease progression. Conclusions: Roxadustat increased Hb in CIA regardless of tumor type and chemotherapy regimen. These data support additional clinical study. Clinical trial information: NCT04076943.

MO796: Short-Term Effect of Roxadustat Combined With Erythropoiesis Stimulating Agents (ESAS) Treatment for Anemia in Patients Undergoing Hemodialysis With ESA Resistance

Abstract BACKGROUND AND AIMS Renal anemia is a common complication of chronic kidney disease (CKD) that can decrease the quality of life of patients, especially for patients with maintenance hemodialysis (MHD). The current standard treatment for renal anemia consists of iron plus erythropoiesis-stimulating agents (ESAs). However, high-dose ESA supplementation may cause an increase in blood pressure and induce cardiovascular events and death [1]. Roxadustat (FG-4592) is a new small-molecule oral medication for the treatment of renal anemia that may improve anemia by increasing endogenous erythropoiesis, transferrin receptor expression, and iron absorption [2]. Currently, the use of roxadustat in the treatment of renal anemia is still being explored. Our study aimed to observe the short-term efficacy of roxadustat combined with ESAs on renal anemia in MHD patients with ESA resistance. METHOD This retrospective study included patients with renal anemia using roxadustat for the first time at West China Hospital of Sichuan University from September 2019 to March 2021. Study inclusion criteria: (1) MHD for &amp;gt;3 months (thrice weekly), (2) basal Hb ≤ 100 g/L and (3) ESAs therapy for &amp;gt;2 months, and the first time use of rosadustat for at least 1 month. We excluded those without hemoglobin data and those with a history of blood transfusion within the first month. Patients treated with roxadustat combined with ESAs were as an observation group, and those treated with roxadustat alone were included as a control group. RESULTS A total of 31 MHD patients were included, the baseline data was shown in Table 1. A total of 15 patients were treated with roxadustat combined with ESAs, and 16 patients were treated with roxadustat alone. In the first month, the mean hemoglobin level was significantly increased in the combined group (1.89 ± 1.45 g/dL) but decreased in the alone group (–0.25 ± 1.32 g/dL). According to an analysis of covariance (ANCOVA), after adjusting for basal hemoglobin levels, the combination therapy improved the hemoglobin level better than therapy alone (F = 6.329, P = .018). We defined the Hb response as: hemoglobin change from baseline ≥ 1 g/dL for patients with basal Hb &amp;gt;8.0 g/dL or ≥ 2.0 g/dL for patients with basal Hb ≤8.0 g/dL. Among the 15 patients treated with roxadustat combined with ESAs, 14 patients showed an increase in hemoglobin within the first month and 8 patients get the Hb response, with the Hb response rate of 53.3%. For the 16 patients treated with roxadustat alone, 7 patients showed an increase in hemoglobin, only 2 patients get the Hb response, with the Hb response rate 12.5%. Patients treated with roxadustat combined with ESAs had a higher Hb response rate (P = .023) than those with roxadustat alone within the first month. CONCLUSION Roxadustat combined with ESAs treatment might be more beneficial to improve renal anemia in MHD patients with ESA resistance during the first month of roxadustat therapy replacement.

Intravenous Ferric Carboxymaltose Improves Response to Postoperative Anemia Following Total Knee Arthroplasty: A Prospective Randomized Controlled Trial in Asian Cohort.

Background: Ferric carboxymaltose (FCM) is an intravenous (IV) high-dose iron that is effective in the treatment of iron deficiency anemia. This study was performed to determine whether postoperative FCM infusion is effective at improving hemoglobin (Hb) responders, Hb and iron profiles, and the patient’s quality of life (QOL). Methods: A total of 110 patients with postoperative anemia, defined by a Hb < 10 g/dL within 3 days of unilateral primary TKA, between June 2018 and February 2020 were randomized into either the FCM or Control group. On postoperative day 3, the FCM group (55 patients) received IV FCM while the Control group (55 patients) did not. The Hb responders (Hb increase ≥ 2 g/dL compared to baseline), Hb level, iron profiles (ferritin, total iron-binding capacity (TIBC), transferrin saturation (TSAT)), and EQ-5D scores were compared at weeks 2, 4, and 8. Results: The FCM group demonstrated a significantly greater number of Hb responders (p < 0.001) and a higher Hb level (p = 0.008) at 2 weeks postoperative than did the Control group. The FCM group recovered its preoperative Hb level between 4 and 8 weeks. In contrast, the Control group did not recover its preoperative level until 8 weeks. The FCM infusion group also had higher serum ferritin, iron and TSAT, and lower TIBC levels than those of the Control group between 2 and 8 weeks (all p < 0.001). However, there was no significant difference in the postoperative transfusion rate (p = 0.741) or EQ-5D score between the two groups (all p > 0.05). Discussion: In postoperative anemia following TKA, IV FCM increases the Hb response and improves Hb and iron metabolism variables, however, it does not affect the transfusion rate or QOL.

Safety and efficacy of voxelotor in pediatric patients with sickle cell disease aged 4 to 11 years

Sickle cell disease (SCD) is a devastating, multisystemic disorder that affects millions of people worldwide. The earliest clinical manifestations of SCD can affect infants as young as 6months of age, and pediatric patients are at risk for acute and life-threatening complications. Early intervention with treatments that target the underlying pathophysiological mechanism of SCD, sickle hemoglobin (HbS) polymerization, are expected to slow disease progression and circumvent disease-associated morbidity and mortality. The HOPE-KIDS 1 trial (NCT02850406) is an ongoing four-part, phase 2a, open-label, single- and multiple-dose study to evaluate the pharmacokinetics, efficacy, and safety of voxelotor-a first-in-class HbS polymerization inhibitor-in patients aged 6months to 17years with SCD. Initial findings from a cohort of 45 patients aged 4 to 11years who received voxelotor treatment for up to 48weeks are reported. Hemoglobin (Hb) response, defined as a >1.0g/dl increase from baseline, was achieved at week 24 by 47% (n = 16/34) of patients with Hb measurements at baseline and week 24. At week 24, 35% (n = 12/34) and 21% (n = 7/34) of patients had a >1.5g/dl increase and a >2.0g/dl increase from baseline in Hb concentration, respectively. Concurrent improvements in hemolytic markers were observed. Voxelotor was well tolerated in this young cohort, with no newly emerging safety signals. Based on its mechanism as an HbS polymerization inhibitor, voxelotor improves Hb levels and markers of hemolysis and has the potential to mitigate SCD-related complications; these results support its use in patients aged ≥4years.

Efficacy and Safety of Vadadustat for Anemia in Patients With Chronic Kidney Disease: A Systematic Review and Meta-Analysis.

Background: Vadadustat is a novel drug for treating anemia patients with chronic kidney disease (CKD), but its effect and safety remain uncertain. This study aimed to summarize the evidence for vadadustat in the treatment of CKD patients with anemia. Methods: PubMed, Ovid Medline, Embase, Cochrane CENTRAL, Wanfang Data, China National Knowledge Infrastructure and an international trial register were searched from their inception to June 2021 for randomized controlled trials (RCTs) comparing the efficacy and safety of vadadustat to those of placebo or erythropoiesis-stimulating agents (ESAs) in treating anemia in CKD patients. Data were pooled in a meta-analysis, with results expressed as the mean difference for continuous outcomes and relative risk for categorical outcomes with 95% confidence intervals (95% CIs). The certainty of evidence was rated according to Cochrane methods and the GRADE approach. Results: Ten RCTs comparing vadadustat with placebo (4 RCTs) or darbepoetin alfa (6 RCTs) were included (n = 8,438 participants). Compared with placebo, vadadustat increased the hemoglobin (Hb) response rate (risk ratio 5.27; 95% CI: 2.69 to 10.31; p < 0.001; high certainty of evidence) and Hb level from baseline (∆Hb) (mean difference (MD) 1.28; 95% CI: 0.83 to 1.73; p < 0.001; low certainty of evidence). Compared with placebo or darbepoetin alfa, vadadustat decreased hepcidin (MD -36.62; 95% CI: −54.95 to −18.30; p < 0.001) and ferritin (MD −56.24; 95% CI: −77.37 to −35.11; p < 0.001) levels and increased iron-binding capacity (MD 24.38; 95% CI: 13.69 to 35.07; p < 0.001), with a low to moderate certainty of evidence. Moderate to high certainty evidence suggested that compared with placebo or darbepoetin alfa, vadadustat significantly increased the risk of nausea and diarrhea but did not significantly increase the risk of serious adverse events, especially all-cause mortality, cardiac events and nonfatal stroke. Conclusion: Vadadustat may safely improve Hb levels and promote iron utilization in CKD patients with anemia without increasing the incidence of serious adverse events.

Efficacy and safety of ferric derisomaltose (FDI) compared with iron sucrose (IS) in patients with iron deficiency anemia after bariatric surgery

PurposeIron deficiency is common following bariatric surgery, and treatment with intravenous iron is often required. This post hoc analysis of data from two randomized, open-label, multicenter trials evaluated the efficacy and safety of ferric derisomaltose (FDI; formerly iron isomaltoside 1000) versus iron sucrose (IS) over 4 weeks in adults with iron deficiency anemia (IDA) resulting from prior bariatric surgery.Materials and methodsData were pooled for participants who received FDI or IS in the PROVIDE or FERWON-IDA trials for the treatment of IDA post bariatric surgery. Efficacy outcomes included changes in hemoglobin (Hb) and iron parameters; safety outcomes included the incidence of adverse drug reactions (ADRs), serious or severe hypersensitivity reactions (HSRs), and hypophosphatemia.ResultsThe analysis included 159 patients. Mean (standard deviation) cumulative iron doses were 1199 (± 347) mg for FDI and 937 (± 209) mg for IS. Compared with IS, FDI resulted in a faster and more pronounced Hb response, and a higher proportion of responders (Hb level increase ≥ 2 g/dL from baseline) at all time points. The incidence of ADRs was similar with FDI and IS (15.1% and 18.2%, respectively), with no serious ADRs or serious or severe HSRs reported. The incidence of hypophosphatemia was low and similar in both treatment groups, with no cases of severe hypophosphatemia observed.ConclusionsIn patients with IDA resulting from bariatric surgery, FDI produced a faster and more pronounced Hb response than IS. Both FDI and IS were well tolerated.Graphical abstract

P107: A PHASE 2/3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF MITAPIVAT IN PATIENTS WITH SICKLE CELL DISEASE

Background: The key pathology in sickle cell disease (SCD), a life-threatening, hereditary hemoglobin (Hb) disorder, is red blood cell (RBC) sickling due to polymerization of deoxygenated sickle Hb (HbS), which can be exacerbated by increased levels of the glycolytic metabolite 2,3-diphosphoglycerate (2,3-DPG), and decreased ATP.1–3 Sickled RBCs are rigid, not deformable, and fragile, resulting in vaso-occlusion triggering pain and chronic hemolysis.4–6 SCD treatment options are limited, with an unmet need for safe and effective therapies to improve anemia and reduce pain. Mitapivat is an oral, activator of RBC pyruvate kinase (PKR), a key glycolytic enzyme. PKR activation decreases 2,3-DPG and increases ATP, which may reduce HbS polymerization, RBC sickling, and hemolysis in SCD.3,7–9 Data from the phase (ph) 1 National Institutes of Health multiple ascending dose study of up to 100 mg mitapivat twice daily (BID) in SCD (NCT04000165) showed that mitapivat was safe and tolerable, increased ATP and decreased 2,3-DPG in a dose-dependent manner, and improved anemia and hemolysis.8,10 Aims: To report the study design of RISE UP (NCT05031780, EudraCT: 2021-001674-34), a ph 2/3, double-blind, randomized, placebo-controlled, multicenter study evaluating the efficacy and safety of mitapivat in patients (pts) with SCD. Methods: Eligible: pts aged ≥16 yrs with documented SCD (HbSS, HbSC, HbSβ0/HbSβ+ thalassemia, other SCD variants), 2–10 sickle cell pain crises (SCPCs; acute pain needing medical contact, acute chest syndrome, priapism, hepatic or splenic sequestration) in the prior 12 months, and Hb 5.5–10.5 g/dL. If taking hydroxyurea (HU), the dose must be stable for ≥90 days before starting study drug. Ineligible: pts receiving regularly scheduled blood transfusions, with severe kidney disease or hepatobiliary disorders, currently receiving SCD therapies (excluding HU) or who have received gene therapy, bone marrow or stem cell transplantation. In the double-blind ph 2 part, 69 pts will be randomized (1:1:1) to 50 mg or 100 mg mitapivat, or placebo BID for 12 weeks (wks). The primary objective of ph 2 is to determine the recommended ph 3 mitapivat dose by evaluating anemia and safety vs placebo via the following endpoints: Hb response (≥1.0 g/dL increase in average Hb concentration over Wks 10–12 vs baseline [BL]), and type, severity, and relationship of adverse events and serious AEs. In the double-blind ph 3 part, 198 pts who did not participate in ph 2 will be randomized (2:1) to the selected ph 3 mitapivat dose or placebo BID for 52 wks, stratified by number of SCPCs in the prior yr (<5, ≥5) and HU use. The primary objectives of ph 3 are to determine the effect of mitapivat vs placebo on anemia, measured by Hb response (≥1.0 g/dL increase in average Hb concentration over Wks 24–52 vs BL), and the effect of mitapivat vs placebo on SCPC, measured by annualized rate of SCPCs. Key secondary endpoints include average change from BL in Hb concentration, indirect bilirubin, percent reticulocyte, and Pt-Reported Outcomes Measurement Information System® Fatigue 13a Short Form score over Wks 24–52; and annualized frequency of hospitalizations for SCPC. Pts who complete the double-blind period will be eligible to receive mitapivat in the open-label extension period in each ph. Results: Not yet available. Conclusion: This ph 2/3 study will investigate the efficacy and safety of mitapivat in pts aged ≥16 yrs with SCD. Enrollment is currently ongoing.

S103: TRIAL IN PROGRESS: A PHASE 2, OPEN-LABEL STUDY EVALUATING THE SAFETY AND EFFICACY OF THE PKR ACTIVATOR ETAVOPIVAT (FT-4202) IN PATIENTS WITH THALASSEMIA OR SICKLE CELL DISEASE

Background: Sickle cell disease (SCD) and thalassemia are hemoglobinopathies characterized by lifelong anemia. In SCD, a single β-globin gene mutation results in sickle hemoglobin (HbS) that polymerizes upon deoxygenation, causes RBCs to sickle and leads to various complications. In thalassemia, α- and/or β-globin gene mutation(s) result in reduced or absent adult Hb, ineffective erythropoiesis, and downstream complications. The resultant anemias, exacerbated by impaired RBC health, are associated with lower ATP levels than in healthy RBCs. Supportive care and agents like hydroxyurea are used most in SCD, with some patients (pts) on regular transfusions. Regular or episodic transfusions, with their own set of complications, are the mainstay of treatment for thalassemia. Etavopivat, an investigational, once-daily, selective, erythrocyte pyruvate kinase (PKR) activator increases ATP and decreases 2,3 diphosphoglycerate (2,3-DPG). In a Phase 1 study, etavopivat 300–600 mg once daily in pts with SCD not regularly transfused was well-tolerated, improved hematologic markers, decreased hemolysis, and improved markers of RBC health [1,2]. Etavopivat 200 and 400 mg once daily (dose levels predicted to provide the desired PD response profiles) are being evaluated in a Phase 2/3 study of pts with SCD not on chronic transfusions (The Hibiscus Study, NCT04624659). Aims: Describe the design of a Phase 2, open-label, multicenter study (NCT04987489) evaluating the efficacy and safety of etavopivat in pts with: SCD on chronic transfusions (Cohort A), transfusion-dependent thalassemia (Cohort B), and non–transfusion-dependent thalassemia (Cohort C). Methods: Up to 20 pts (12–65 y) will be enrolled in each of the 3 cohorts described above. Key eligibility criteria are outlined in the Table. Pts will receive etavopivat 400 mg once daily for 48-wks (Figure). Pts will provide written informed consent. Baseline assessments will include medical, disease, transfusion, and medication histories. Transfusions received during the study (every ~3–5 wks) will be recorded and include Hb values before and ≥15 min after transfusion, transfusion dates, number of RBC units, volume of packed RBCs, and hematocrit of the transfused unit (if available). If a pt has an increase in pre-transfusion Hb of ≥1.0 g/dL versus their baseline pre-transfusion Hb, the investigator may delay transfusion 1 wk or reduce the number of RBC units transfused. In pts with SCD, RBC exchange transfusions may also be performed. The primary endpoints are outlined in the Figure. Secondary and exploratory endpoints include the proportion of pts with a reduction in transfusions over 12 wks of ≥33% and ≥50%, respectively, and a reduction in transfusions over 12, 24, and 48 wks (Cohorts A/B); and Hb response at Wks 24 and 48, and changes from baseline in Hb over 12, 24, and 48 wks (Cohort C). The following additional endpoints will be assessed (all cohorts): changes from baseline in quality of life (using the SF-36 and PROMIS); changes from baseline in serum ferritin levels at 12, 24, and 48 wks; liver iron at 48 wks; 2,3-DPG and ATP; PK; and safety. All primary endpoints will be analyzed using a 1-sided test at α=0.025.Summary: Etavopivat is a novel, investigational, once-daily, selective PKR activator with potential to improve RBC health and lifespan. This Phase 2 study will assess the safety of etavopivat and its impact on Hb levels and transfusion burden in pts (12–65 y) with SCD or thalassemia.

P112: ENERGIZE AND ENERGIZE-T: TWO PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDIES OF MITAPIVAT IN ADULTS WITH NON--TRANSFUSION-DEPENDENT OR TRANSFUSION-DEPENDENT ALPHA- OR BETA-THALASSEMIA

Background: Thalassemias are characterized by imbalanced globin-chain production resulting in excess α- or β-globin precipitation, hemolytic anemia, and ineffective erythropoiesis.1,2 ATP levels are reduced in thalassemic red blood cells (RBCs), despite increased energy demands.3,4 Mitapivat is an oral activator of RBC pyruvate kinase (PKR), a glycolytic enzyme that regulates ATP production.5 In a phase 2 study of patients with α- or β-non–transfusion-dependent thalassemia (NTDT), twice-daily (BID) dosing with mitapivat increased hemoglobin (Hb) levels by ≥1.0 g/dL in 80% of patients,6 supporting the broadening of mitapivat’s development in thalassemia. Aims: To report the study designs of ENERGIZE (2021-000211-23) and ENERGIZE-T (2021-000212-34), two phase 3 trials to assess the efficacy and safety of mitapivat in adults with α- or β-NTDT or transfusion-dependent thalassemia (TDT), respectively. Methods: Both studies are phase 3, multicenter, randomized, double-blind, placebo-controlled trials (Figure). In ENERGIZE, approximately 171 eligible adults with NTDT will be randomized (2:1) to receive 100 mg mitapivat BID or placebo for 24 weeks. Upon completion, eligible patients can transition to a 5-year, open-label extension. Key inclusion criteria: documented diagnosis of thalassemia (β-thalassemia ± α-globin mutations, Hb E β-thalassemia, or α-thalassemia [Hb H disease]), Hb concentration ≤10.0 g/dL, and NTDT defined as ≤5 RBC units during the 24-week period before randomization and no RBC transfusion ≤8 weeks prior. The primary endpoint is an Hb response defined as a ≥1.0 g/dL increase in average Hb concentration from Week 12 through 24 compared with baseline. Secondary endpoints include patient-reported outcomes, changes in Hb, markers of hemolysis and erythropoiesis, and safety. In ENERGIZE-T, approximately 240 eligible adults with TDT will be randomized (2:1) to receive 100 mg mitapivat BID or placebo for 48 weeks. Upon completion, eligible patients can transition to a 5-year, open-label extension. Key inclusion criteria: documented diagnosis of thalassemia (same genotypes as detailed for the ENERGIZE study), and TDT defined as 6–20 RBC units transfused and no transfusion-free period ≥6 weeks during the 24 weeks before randomization. The primary endpoint is a transfusion reduction response, defined as a ≥50% reduction in transfused RBC units with a reduction of ≥2 units of transfused RBCs in any consecutive 12-week period through Week 48 compared with baseline. Secondary endpoints include additional measures of transfusion burden, changes in iron markers, and safety. Results: Not yet available. Conclusions: ENERGIZE and ENERGIZE-T are the first pivotal studies to assess a potential treatment across a broad spectrum of patients with thalassemia (ie, patients with TDT and NTDT; α- and β-thalassemias). ENERGIZE and ENERGIZE-T will evaluate the efficacy and safety of mitapivat, a novel, first-in-class oral activator of PKR. Both studies are actively recruiting.

Durability of Hemoglobin Response and Reduction in Transfusion Burden Is Maintained over Time in Patients with Pyruvate Kinase Deficiency Treated with Mitapivat in a Long-Term Extension Study

Durability of Hemoglobin Response and Reduction in Transfusion Burden Is Maintained over Time in Patients with Pyruvate Kinase Deficiency Treated with Mitapivat in a Long-Term Extension Study

Long-Term Efficacy and Safety of the Oral Pyruvate Kinase Activator Mitapivat in Adults with Non-Transfusion-Dependent Alpha- or Beta-Thalassemia

Long-Term Efficacy and Safety of the Oral Pyruvate Kinase Activator Mitapivat in Adults with Non-Transfusion-Dependent Alpha- or Beta-Thalassemia

Post Hoc Analysis of the Effect of Pegcetacoplan Treatment of Patients with Paroxysmal Nocturnal Hemoglobinuria and Baseline Hemoglobin Levels Greater Than 10 Grams per Deciliter

Post Hoc Analysis of the Effect of Pegcetacoplan Treatment of Patients with Paroxysmal Nocturnal Hemoglobinuria and Baseline Hemoglobin Levels Greater Than 10 Grams per Deciliter

A Phase 2/3, Randomized, Double-Blind, Placebo-Controlled Study of Mitapivat in Patients with Sickle Cell Disease

A Phase 2/3, Randomized, Double-Blind, Placebo-Controlled Study of Mitapivat in Patients with Sickle Cell Disease

Trial in Progress: A Phase 2, Open-Label Study Evaluating the Safety and Efficacy of the PKR Activator Etavopivat (FT-4202) in Patients with Thalassemia or Sickle Cell Disease

Trial in Progress: A Phase 2, Open-Label Study Evaluating the Safety and Efficacy of the PKR Activator Etavopivat (FT-4202) in Patients with Thalassemia or Sickle Cell Disease

Overview of Systematic Reviews (SRs) of Erythropoiesis-Stimulating Agents (ESAs) As Standards of Care for Non-Myeloid Cancer Patients with Chemotherapy-Induced-Anemia (CIA)

OBJECTIVES: While chemotherapy is fundamental to the treatment of many cancers, it is associated with adverse events (AEs), including anemia. CIA is linked to many symptoms, including fatigue and cognitive impairment. Most cancer patients receiving chemotherapy experience CIA. ESAs are indicated for treatment of CIA in non-myeloid cancers. Given the extensive data available, we reviewed SRs of the existing evidence on ESAs for treatment of CIA, to assess their relative efficacy and safety.METHODS: A search for published SRs of ESAs for the treatment of CIA in adults with non-myeloid cancers was conducted across seven databases and three online resources, from inception to July 2020. Data were extracted on hemoglobin-related (Hb)-outcomes; mortality; health-related quality of life (HRQoL), iron use, red blood cell (RBC) transfusions, cancer-related outcomes, and serious AEs (SAEs) including thromboembolic events. Risk of bias was assessed by two reviewers using the Assessing the Methodological Quality of Systematic Reviews (AMSTAR) 2 tool.RESULTS: Of 1027 records assessed, 33 records met eligibility criteria; from these, 14 SRs (from 19 publications) were considered core and were extracted. The majority of SRs (n=13) were meta-analyses of randomized, controlled trials. Mortality was evaluated in 9 SRs: 5 reported no difference between ESA vs. control (best supportive care (BSC) and/or placebo and/or no treatment) and 2 reported higher mortality with ESA vs. control (standard care (no iron or oral iron) and/or placebo and/or no treatment). Cancer-related overall survival was not significantly different for ESA vs. control (BSC or placebo) in 2 SRs, or vs. no ESA treatment in 1 SR. Relapse-free, recurrence-free and progression-free survival did not differ between ESA vs. BSC, no treatment, or placebo, according to 1 SR.Two SRs reported a significantly improved change in Hb from baseline for ESA vs. placebo or BSC. Four SRs reported significantly improved hematological response (definitions varied by study) for ESA vs. control (BSC and/or placebo and/or no treatment) (Table). RBC transfusion requirements were reported for 5 treatment comparisons in 12 SRs. For 3 comparisons (ESA vs. control (BSC and/or placebo and/or no treatment); IV iron + ESA vs. standard care; and IV iron + ESA vs. no iron + ESA), there was a consistent statistically significant reduction in transfusion rates with ESA-based treatment. For 2 other comparisons, 1 SR reported no significant difference in transfusion rates with oral iron + ESA vs. no iron + ESA, and 2 SRs found no difference between darbepoetin vs. epoetin. ESA was associated with a requirement for significantly fewer RBC units per patient vs. control (BSC or placebo) in 1 SR.Functional Assessment of Cancer Therapy-Anemia (FACT-An, 6 SRs) and FACT-Fatigue (FACT-F, 7 SRs) were the only HRQoL measures reported. Two SRs reported clinically important improvements in FACT-An with ESA vs. control (BSC and/or placebo); the remaining SRs reported difficulty in interpreting results due to study heterogeneity. Five SRs reported significant improvements in FACT-F with ESA vs. control (BSC and/or placebo and/or no treatment). One SR did not present a meta-analysis, stating that FACT-F results did not differ for ESA vs. placebo groups, and 1 SR reported a significant improvement in FACT-F for IV iron + ESA vs. standard care (no iron or oral iron).Of 2 SRs reporting SAEs, 1 found no difference in incidence for IV iron + ESA vs. standard care (no iron or oral iron) and 1 found significantly greater incidence for ESA vs. no treatment. Of 6 SRs that compared ESA vs. control, 3 reported an increased risk of thromboembolic events with ESAs in the treatment of CIA and 2 reported no significant difference between treatment groups. The remaining SR reported numerically higher incidences of thromboembolic events with ESA vs. control (no statistical comparison).Several outcomes of interest were not reported, including time to first rescue therapy and supplementary iron use. Most SRs did not report on study quality.CONCLUSIONS: In all SRs reporting efficacy, there were improvements in Hb change from baseline, Hb response, and reduction in RBC transfusions for patients with CIA treated with ESAs vs. control. Results were less consistent across SRs for mortality, thromboembolic events, and HRQoL for ESA vs. control. Lack of study quality reporting may affect the strength of these findings. [Display omitted] DisclosuresMorga: Astellas Pharma Europe Ltd.: Current Employment. Atzinger: Astellas Pharma Inc.: Current Employment. Arber: York Health Economics Consortium Ltd: Current Employment. King: York Health Economics Consortium Ltd: Current Employment. Phalguni: York Health Economics Consortium Ltd: Current Employment. Sanderson: York Health Economics Consortium Ltd: Current Employment. Alexandre: Astellas Pharma Europe B.V.: Current Employment.

Changes in Hemoglobin Measures Observed in PNH Patients Treated with Both C5 Inhibitors Ravulizumab and Eculizumab: Real-World Evidence from a US-Based EMR Network

Changes in Hemoglobin Measures Observed in PNH Patients Treated with Both C5 Inhibitors Ravulizumab and Eculizumab: Real-World Evidence from a US-Based EMR Network

Baseline Hepcidin Does Not Predict the Response to Iron Therapy in Pregnant Women with Iron Deficiency

▪Introduction:Hepcidin, the master regulator of iron economy, is decreased during pregnancy to facilitate adequate iron transfer across the placenta. Conversely, iron need increases substantially during pregnancy often leading to iron deficiency and subsequently anemia. The PREG-01 Study compared the efficacy and safety of intravenous (IV) ferric derisomaltose (FDI) vs. oral iron in treating persistent iron deficiency in pregnant women. The study found FDI to be efficacious and well-tolerated in pregnancy and the proportion of non-anaemic patients throughout the course of the study was significantly lower in the FDI group. In this analysis, we investigated the effect of baseline hepcidin on the response to IV and oral iron therapy.Methods:PREG-01 was a single-centre, open-label, randomized controlled trial. Women 14-21 weeks pregnant with persistent iron deficiency (ferritin<30 µg/L despite oral iron treatment) received a single intravenous 1000 mg dose of FDI (n=100) or 100 mg elemental oral iron daily combined with ascorbic acid (n=101). Hemoglobin (Hb), ferritin and transferrin saturation (TSAT%) levels were captured at baseline and monitored throughout the study. The effect of baseline hepcidin on achieving non-anemic status (Hb ≥ 11 g/dL) at all study visits and the effect on change in Hb, ferritin and TSAT% were investigated by estimating odds ratios from a logistic regression model with treatment as factor and interaction between treatment and baseline hepcidin. The odds ratio estimate is for an increment in baseline hepcidin of 1 ng/mL.Results:Mean [standard deviation (SD)] baseline Hb was 11.97 (0.93) g/dL in the FDI group and 11.75 (0.91) g/dL in the oral iron group. Baseline hepcidin was 6.42 ng/mL in the FDI and 5.32 ng/mL in the oral iron group. Baseline hepcidin was not associated with the ability to achieve non-anaemic status either in the FDI (OR 0.98; 95% CI: 0.87-1.09) or the oral iron group (OR 0.96; 95% CI: 0.88-1.05). No statistically significant associations were found between baseline hepcidin and change in Hb, ferritin or TSAT% throughout the study (Figure 1).Conclusions:In a population of pregnant women with iron deficiency, but otherwise healthy, baseline hepcidin was overall low. Although there was a trend for an association between baseline hepcidin and Hb response to oral iron only, baseline hepcidin did not predict the response to iron therapy. [Display omitted] DisclosuresNo relevant conflicts of interest to declare. OffLabel Disclosure:Ferric Derisomaltose is an IV iron preparation indicated for the treatment of iron deficiency anemia in the US.

Title: Efficacy and Safety of Ferric Derisomaltose for Treatment of Anemia in Chronic Kidney Disease Patients: A Systematic Review

BackgroundAnemia in chronic kidney disease (CKD) patients develop primarily due to iron and erythropoietin deficiency, factors contributing to this include uremia induced inhibition of erythropoiesis, shortened red cell survival and nutritional deficiency. Erythropoietin stimulating agents (ESA) used in CKD increases iron demand for the production of new red blood cells (RBCs). Oral iron does not provide a reliable route to meet the demand of the iron required and poses the risk of side effects. The intravenous formulation provides the fastest route, although multiple intravenous formulations are available they require multiple dosing and still carry a risk of an adverse event. Ferric derisomaltose/iron isomaltoside (IIM) is an intravenous formulation of iron recently approved by the Food and drug administration (FDA) for patients intolerant to oral iron and non-dialysis dependent CKD patients. FDI is administered in high dose usually in a single administration. In this systematic review, we evaluated the published literature for the efficacy and safety of ferric derisomaltose in both dialysis-dependent and dialysis independent patients.Material/MethodsA literature search was done using the following databases: PubMed, Cochrane, Embase, Clinical trials.gov, and Web of Science. The search was completed without using any filter and we used the Mesh Terms for “anemia”, “iron deficiency anemia” “chronic kidney disease” and “ferric compounds”. Total of 316 which were further screened and we included 2 trials, and 2 prospective studies. Case reports, preclinical trials, meta-analyses, and review articles were excluded. We followed the PRISMA guidelines for literature search and selection of studies. We only included the trial studies that were completed. We excluded the studies that did not report efficacy and safety.ResultsIn total, amongst the four studies, 1558 CKD patients received ferric derisomaltose in a single dose. Patients in all stages of CKD were studied but most patients were between stages I to stage III CKD, stage IV and V(dialysis-dependent) were studied by Kalra et al (2020). A single dose of 1000 mg/dl of IIM, was administered intravenously. The mean pre-treatment haemoglobin level varied from 9.6g/dl to 10.6 g/dl. The mean serum ferritin ranged from 82.4 µg/L to 161.9 µg/L and the mean transferrin saturation ranged in patients from 15.8% to 18.51%. IIM receiving patients were compared with iron sucrose receiving patients by Bhandari et al, and oral iron by Kalra et al (2015). The remaining two studies compared single IIM with multiple IIM dosages. The results are summarised in the table below.Efficacy: The increase in haemoglobin ranged between 0.9 g/dL to 6.58 g/dL from baseline measured at 8 weeks. At the same time, serum ferritin showed an increase in baseline serum ferritin from 104 µg/L to 277 µg/L and transferrin saturation (TSAT) increased in the range of 5.3%-11.4 %. All markers of iron deficiency showed significant improvement. It achieved a greater Hb response irrespective of ESA treatment in both haemodialysis dependent and non-dependent patients. In the comparison group by Bhandari et al, iron sucrose receiving patients also had similar efficacy as IIM. On the other hand, those receiving oral iron in the study by Kalra et al (2015) had much poorer efficacy as compared to IIMSafety: Severe adverse effect was seen in a total of 10 (0.6%) patients who developed hypersensitivity reaction, acute myocardial infarction and injection site-related adverse effects with hypersensitivity being the most common. 15 (0.9%) patients discontinued the treatment. 21 (1.3%) died, and the death was attributed to end-stage renal disease.ConclusionFerric derisomaltose is an effective parenteral iron therapy to treat iron deficiency when compared to oral iron therapy, however, its efficacy is very similar to other parenteral iron formulations. In terms of safety, being used as a single dose it relatively has lesser adverse events but can seldom lead to discontinuation of the drug. This drug can be recommended for iron therapy especially considering single-dose administration but more studies need to be carried out in comparison to other parenteral formulations to further clarify its efficacy in dialysis-dependent CKD patients. [Display omitted] DisclosuresAnwer: BMS / Celgene: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Janssen pharmaceutical: Honoraria, Research Funding; Allogene Therapeutics: Research Funding.

Efficacy and Safety of Ferric Derisomaltose/Iron Isomaltoside in Patients with Inflammatory Bowel Disease: A Systematic Review

BackgroundAnemia in inflammatory bowel disease (IBD) presents as a common extraintestinal manifestation resulting in many complications. This condition is often missed or underrated, anemia is secondary to blood loss or defective absorption of iron which can result in a combination of iron deficiency anemia (IDA) or anemia of chronic disease (ACD). The management is iron replacement therapy which improves the quality of life in these patients. Due to the constraints in the use of oral iron, parenteral preparations are more used in IBD patients. Commonly used iron sucrose and ferric carboxymaltose are often associated with side effects leading to poor compliance. Our study explores data about ferric derisomaltose also known as iron isomaltoside (IIM), a recently approved IV iron preparation. The FDA approved this drug in 2020 for patients with poor compliance with other iron preparations. We explored the efficacy and safety data of ferric derisomaltose in adult patients with IBD.Material/MethodsA literature search was performed using the following databases: PubMed, Cochrane, Embase, Clinical trials.gov, and Web of Science. The search was completed without using any filter and we used the MeSH Terms for “anemia”, “iron deficiency anemia”, “inflammatory bowel disease”, and “ferric compounds”. A total of 1590 articles were screened, and we finally selected 2 trials and 2 observational studies. We followed the PRISMA guidelines for literature search and selection of studies. Case reports, preclinical trials, meta-analyses, and review articles were excluded. Trial and observational studies related to IBD were included.ResultsIn total, 294 patients with anemia in inflammatory bowel disease received ferric derisomaltose intravenously as a single dose between 500 mg to 2000 mg. All patients were >18 years of age. The mean pre-treatment hemoglobin (Hb) level varied from 10.0 g/dL to 12.3 g/dL. The mean serum ferritin ranged from 19.6 µg/L to 57 µg/L and the mean transferrin saturation (TSAT) ranged from 8.8% to 18.5%. J. Stein et al investigated the effectiveness and safety of IIM in routine practical care of IDA in IBD patients. Dahlerup et al (NCT01599702) compared single dose IIM with multiple dosages of IIM in IBD patients. The remaining two studies investigated the effectiveness and safety of high dose IIM in patients with IBD. Results are summarized in Table 1.Efficacy:The increase in hemoglobin ranged from 0.6 g/dl to 2.9 g/dl from baseline while the increase in serum ferritin ranged between 102 µg /L to 250 µg /L and transferrin saturation increased in the range of 15.0%-23.7% in 10 to 52 weeks post iron isomaltoside (IIM) therapy. All markers of iron deficiency anemia showed significant improvement. In the observational study by J. Stein et al, the hemoglobin increased from a mean of 10.7 g/dl to 13.1 g/dl, serum ferritin increased from 57 µg /L to 146 µg /L, and TSAT from 8.8% to 23.7% at 16 weeks. Dahlerup et al demonstrated a Hb increase of >2 g/dl in 75% of patients at 10 weeks. According to W. Reinisch et al (NCT 01410435), there was a mean increase in serum ferritin from 32 µg /L to 102 µg /L and a decrease in TSAT from the baseline, but this decrease was not statistically significant.Safety:Adverse events were noted in 8 (3.6%) patients. Out of the 8 patients, 4 (<2%) were serious adverse events such as perianal abscess, miliary tuberculosis, nephrolithiasis, and worsening of ulcerative colitis, which may not be related to the study drug. The other 4 (1.8%) had life-threatening events, anaphylaxis being the most common. All four patients recovered. The most common mild adverse events reported were hypersensitivity reaction (HSR) seen in 3 patients. 2 patients discontinued due to mild HSR. There were no reports of death due to side effects of the drug.ConclusionFerric derisomaltose has demonstrated a substantial increment in iron parameters in anemia in patients with IBD. This was measured in terms of hemoglobin response, serum ferritin, and transferrin saturation. Greater Hb response was achieved irrespective of concomitant treatment with steroids and anti-TGF-ß.The adverse events were mild, and patients recovered showing high compliance. Since the average duration of follow-up in our study was 21 weeks, long-term follow-up is limited for this drug, we need further studies to assess the need for maintenance therapy. [Display omitted] DisclosuresAnwer: GlaxoSmithKline: Research Funding; BMS / Celgene: Honoraria, Research Funding; Janssen pharmaceutical: Honoraria, Research Funding; Allogene Therapeutics: Research Funding.