scholarly journals Comparative Effectiveness of Pegcetacoplan Versus Ravulizumab in Patients with Paroxysmal Nocturnal Hemoglobinuria Previously Treated with Eculizumab: A Matching-Adjusted Indirect Comparison

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 37-38
Author(s):  
Rachel Y Bhak ◽  
Nikita Mody-Patel ◽  
Scott B. Baver ◽  
Colin Kunzweiler ◽  
Christopher Yee ◽  
...  
Keyword(s):  
Comparative Effectiveness ◽  
Research Funding ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Indirect Comparison ◽  
Publicly Traded ◽  
Phase 3 ◽  
Fatigue Score ◽  
Study Results ◽  
Adjusted Indirect Comparison ◽  
Previously Treated

INTRODUCTION Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematological disease characterized by complement-mediated hemolysis, resulting in anemia, thrombosis, and bone marrow failure. Currently available treatment options for PNH include the C5 inhibitors eculizumab and ravulizumab, which target intravascular hemolysis through terminal complement inhibition. Pegcetacoplan is a targeted C3 inhibitor being developed to control both intravascular and extravascular hemolysis, to improve hematologic and clinical outcomes. There is no head-to-head study of pegcetacoplan vs ravulizumab in patients with PNH. We assessed the comparative effectiveness of pegcetacoplan to ravulizumab through comparison of phase 3 study results, using matching-adjusted indirect comparison (MAIC) methodology, anchoring on the common comparator arm in the studies, eculizumab. We also acknowledge inherent limitations to MAIC (eg, lack of generalizability beyond the analyzed population). METHODS Individual patient data from PEGASUS, an ongoing, randomized, phase 3 study comparing pegcetacoplan and eculizumab among patients with PNH previously treated with eculizumab, were used to adjust for baseline differences compared to aggregate, published results from the randomized 302 study (Kulasekararaj AG, et al. Blood. 2019;133(6):540-549), which compared ravulizumab and eculizumab among patients with PNH with previous eculizumab. Both studies had similar eligibility criteria. However, PEGASUS also required hemoglobin <10.5 g/dL and absolute reticulocyte count >1.0× the upper limit of normal; these criteria were not applicable in the 302 study. To adjust for cross-study differences in baseline characteristics, propensity score weighting was used to balance demographic and clinical characteristics. Outcomes assessed included transfusion avoidance, total number of units of packed red blood cells (PRBCs) transfused, hemoglobin stabilization, and change in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score. Outcomes were assessed from PEGASUS at week 16 and from the 302 study at week 26. Unadjusted mean and least-squares mean change in FACIT-Fatigue score were compared for PEGASUS and the 302 study, respectively. Weighted Wald tests and 95% confidence intervals (CIs) were computed for comparisons of categorical and continuous outcomes (ie, chi-square and z tests, respectively). RESULTS Sixty-eight patients from PEGASUS (36 pegcetacoplan; 32 eculizumab) and 195 from the 302 study (97 ravulizumab; 98 eculizumab) were included. Among pegcetacoplan and ravulizumab patients, mean age was 46.4 years, 48.5% were female, and 51.5% were white. Overall, 51.5% received ≥4 transfusions in the 12 months before screening in PEGASUS. The adjusted difference in proportion of transfusion avoidance was 71.4% (95% CI, 53.5-89.3%; P < 0.0001) for pegcetacoplan vs ravulizumab, indicating that pegcetacoplan is associated with 71.4% more transfusion avoidance than ravulizumab. The difference in mean number of units of PRBCs transfused during follow-up was -5.7 units (95% CI, -7.2 to -4.2; P < 0.0001) for pegcetacoplan vs ravulizumab, indicating that pegcetacoplan is associated with 5.7 fewer units of PRBCs transfused during treatment than ravulizumab. The adjusted difference in proportion of hemoglobin stabilization was 75.5% (95% CI, 56.4-94.6%; P < 0.0001), suggesting that pegcetacoplan is associated with 75.5% more patients who achieved hemoglobin stabilization than ravulizumab. The adjusted difference in mean change from baseline in FACIT-Fatigue score was 8.8 points (95% CI, 4.2-13.3; P < 0.0001), suggesting that pegcetacoplan is associated with an improvement ~3 times greater than the clinically meaningful improvement of 3 points than ravulizumab. See the Figure for additional details. CONCLUSIONS MAIC methodology allowed the examination of the comparative effectiveness of pegcetacoplan vs ravulizumab in the absence of a head-to-head trial. Results suggest an improvement in transfusion avoidance, hemoglobin stabilization, and fatigue and a reduction in the total number of units of PRBCs transfused for patients who received pegcetacoplan, a C3 inhibitor, in PEGASUS, vs patients who received ravulizumab, a C5 inhibitor, in the 302 study. As PEGASUS progresses, week 26 data will be used to refresh these analyses. Disclosures Bhak: Apellis: Research Funding. Mody-Patel:Apellis: Current Employment, Current equity holder in publicly-traded company. Baver:Apellis: Current Employment, Current equity holder in publicly-traded company. Kunzweiler:Apellis: Research Funding. Yee:Apellis: Research Funding. Sundaresan:Apellis: Research Funding. Swartz:Apellis: Research Funding. Duh:Pharmacyclics: Research Funding; Takeda Oncology: Research Funding; GlaxoSmithKline: Research Funding; AstraZeneca: Research Funding; Blueprint Medicine: Research Funding; Novartis: Research Funding; Shire: Research Funding; Apellis: Research Funding; Merck: Research Funding. Krishnan:Apellis: Current Employment, Current equity holder in publicly-traded company. Sarda:Apellis: Current Employment, Current equity holder in publicly-traded company. OffLabel Disclosure: Pegcetacoplan is an investigational drug for the treatment of paroxysmal nocturnal hemoglobinuria

scholarly journals Categorized Hematologic Response to Pegcetacoplan Versus Eculizumab in Patients with Paroxysmal Nocturnal Hemoglobinuria: Post Hoc Analysis of Data from a Phase 3 Randomized Trial (PEGASUS)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 44-45
Author(s):  
Antonio Risitano ◽  
Ilene C. Weitz ◽  
Carlos M. de Castro ◽  
Jean-Jacques Kiladjian ◽  
Morag Griffin ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Response To Treatment ◽  
Publicly Traded ◽  
Phase 3 ◽  
Advisory Committees ◽  
Post Hoc Analysis ◽  
Hematologic Response ◽  
Post Hoc

INTRODUCTION Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, clonal, nonmalignant hematologic disease characterized by complement-mediated red blood cell hemolysis. The current standard of care for patients with PNH is C5 inhibition. Anemia persists in up to ~70% of patients receiving eculizumab and is attributed to persistent intravascular hemolysis (IVH) and mostly to C3-mediated extravascular hemolysis (EVH). Pegcetacoplan is a pegylated pentadecapeptide C3 inhibitor targeting proximal complement to control both IVH and EVH. PEGASUS is a phase 3, open-label, active-comparator controlled study of efficacy and safety of pegcetacoplan versus eculizumab. This post hoc analysis of data from PEGASUS categorized the clinical response to pegcetacoplan or ECU in patients with PNH and hemoglobin <10.5 g/dL (despite stable ECU for ≥3 months). METHODS Hematologic response to treatment was categorized (per Risitano AM, et al. Front Immunol. 2019;10:1157) as complete, major, good, partial, minor, or no response, using number of packed red blood cell transfusions required, hemoglobin level, lactate dehydrogenase (LDH) level, and absolute reticulocyte count (ARC). Complete response: no transfusions required, stable hemoglobin in the normal range, and no evidence of hemolysis (ie, LDH ≤1.5× upper limit of normal, ARC ≤150,000/µL). Major response: no transfusion, normal hemoglobin, but with evidence of hemolysis (LDH >1.5× upper limit of normal and/or ARC >150,000/µL). Good response: no transfusion, but with chronic mild anemia or evidence of hemolysis. Partial response: chronic moderate anemia and/or occasional transfusions (<3 units/6 months). Minor response: regular transfusions required (3-6 units/6 months). No response: regular and frequent transfusions required (>6 units/6 months). Nine patients (6 from the pegcetacoplan arm and 3 from the eculizumab arm) did not readily fit within the existing criteria due to the availability of data at week 16. Although these 9 patients were manually categorized identically by the lead and senior author in a blinded, independent manner, they were not included among these data. RESULTS The intention-to-treat population was comprised of 41 patients randomized to pegcetacoplan and 39 patients randomized to eculizumab. Four patients in the pegcetacoplan arm and 1 patient in the eculizumab arm were not evaluable for analysis due to incomplete data at week 16. Altogether, 61.0% of patients (25/41) in the pegcetacoplan arm have achieved at least a good hematological response, in contrast to 5.1% (2/39) of the eculizumab arm. At week 16, the distribution of response categories was as follows (Figure): in the pegcetacoplan arm and eculizumab arm, respectively, complete responses were 36.6% and 0%, good responses were 24.4% and 5.1%, partial responses were 12.2% and 33.3%, minor responses were 2.4% and 23.1%, and no responses were 0% and 28.2%. The addition of the 9 manually categorized patients did not significantly alter the proportions reported here. Among the factors that may contribute to heterogeneity of hematologic response to treatment are impaired bone marrow function, residual IVH, and residual C3-mediated EVH. Bone marrow failure was ruled out, and no difference in LDH was observed, suggesting that the major factor accounting for the difference between the 2 arms was the prevention of C3-mediated EVH (as confirmed by reduction of C3-opsonization of PNH red blood cells). CONCLUSION In PEGASUS, treatment with pegcetacoplan resulted in a greater proportion of patients with better hematological responses compared to eculizumab. These results further support the concept that proximal complement inhibition, by preventing EVH in addition to controlling IVH, leads to clinical and hematological improvement in the treatment of PNH. Disclosures Risitano: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alnylam: Research Funding; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Samsung: Membership on an entity's Board of Directors or advisory committees; Amyndas: Consultancy; RA pharma: Research Funding; Biocryst: Membership on an entity's Board of Directors or advisory committees; Achillion: Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Pfizer: Speakers Bureau; Apellis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Weitz:Alexion: Consultancy, Honoraria, Speakers Bureau; Apellis: Consultancy, Honoraria. de Castro:Novartis: Honoraria, Other: Steering committee; Alexion: Honoraria, Research Funding; Biocryst: Honoraria, Other: Data monitoring committee; Apellis: Consultancy, Honoraria, Research Funding. Kiladjian:AbbVie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees. Griffin:Biocryst: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals: Honoraria, Other: Conference Support. Hamdani:Apellis: Current Employment, Current equity holder in publicly-traded company. Ajayi:Apellis Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Baver:Apellis: Current Employment, Current equity holder in publicly-traded company. Peffault De Latour:Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Research Funding. OffLabel Disclosure: Pegcetacoplan is an investigational drug for the treatment of paroxysmal nocturnal hemoglobinuria.

scholarly journals Matching Adjusted Indirect Comparison (MAIC) of Oral Azacitidine (Oral-AZA) Versus Injectable AZA in Patients (pts) with Acute Myeloid Leukemia (AML) in First Remission after Intensive Induction Chemotherapy

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3015-3015
Author(s):  
Clara Chen ◽  
Gerwin A. Huls ◽  
Heather Cameron ◽  
Beatrice Suero ◽  
Alberto Vasconcelos ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Indirect Comparison ◽  
Sensitivity Analyses ◽  
Publicly Traded ◽  
Phase 3 ◽  
Eligibility Criteria ◽  
Free Survival ◽  
First Remission ◽  
Adjusted Indirect Comparison ◽  
Rbc Transfusion

Abstract INTRODUCTION: Oral-AZA was approved in the United States in September 2020 for continued treatment (Tx) of adult patients (pts) with AML in first remission after intensive chemotherapy (IC). The phase 3 QUAZAR AML-001 trial showed that Oral-AZA significantly improved overall and relapse-free survival (OS/RFS) vs placebo (PBO) and was generally well-tolerated (Wei, NEJM 2020). In the phase 3 HOVON97 trial, subcutaneous (SC) AZA maintenance Tx significantly improved disease-free survival vs observation, but did not show an OS benefit (Huls, Blood 2019). Although Oral-AZA and SC AZA contain the same active drug, they are not bioequivalent. Oral administration allows extended exposure to lower drug concentrations, which could increase the number of diseased progenitor cells exposed to AZA and maximize therapeutic effects (eg, drug incorporation into RNA leading to apoptosis), and may improve tolerability by decreasing AZA-related exacerbations of existing cytopenias. In the absence of head-to-head trials, a matching adjusted indirect comparison (MAIC), which adjusts for potential Tx effect modifiers, was previously conducted to evaluate the relative OS benefit with Oral-AZA vs SC AZA (Chen, EHA 2021). This MAIC was performed to determine the relative safety profile and health care resource utilization (HCRU) with Oral-AZA vs SC AZA maintenance therapy in pts with AML in first remission after IC. METHODS: Anchored MAIC analyses of serious Tx-emergent adverse events (SAEs) and HCRU were performed using individual pt data (IPD) from QUAZAR AML-001 to match to baseline (BL) summary statistics from HOVON97. IPD from QUAZAR AML-001 were removed when a pt did not meet HOVON97 eligibility criteria. Remaining QUAZAR AML-001 pt data were weighted using a method-of-moments propensity score model. Matched and adjusted variables were BL age, platelet count, neutrophil count, ECOG performance score, cytogenetic risk, and response status. Analysis endpoints were times to first SAE, hospitalization, and platelet or red blood cell (RBC) transfusion. In HOVON97, pts could receive SC AZA for up to 12 cycles; therefore, QUAZAR AML-001 outcomes were limited to the first 12 cycles of Tx. Hospitalizations for SC AZA administration only in HOVON97 were excluded from analyses. Endpoints are adjusted for pt-years of drug exposure and compared between studies by calculating relative risks (RR). Exposure to SC AZA in HOVON97 was imputed based on the number of pts entering each Tx cycle, and relies on the assumption that events/censoring happened at the end of the cycle and led to Tx discontinuation. Sensitivity analyses of model robustness relaxed these assumptions, comparing only the difference in cumulative hazard vs PBO/observation using a cloglog link binomial model. RESULTS: IPD for 398/469 pts (85%) in the QUAZAR AML-001 safety population (Oral-AZA n=203, PBO n=195) met the eligibility criteria of the HOVON97 population and were adjusted to the comparator. For all endpoints, rate ratios for Oral-AZA vs PBO were less than those for SC AZA vs observation (Table). MAIC-weighted safety comparisons showed the risk of SAEs was reduced by 65% for patients treated with Oral-AZA vs SC AZA (RR 0.35 [95% CI: 0.18-0.68]). Similarly, the risks of hospitalization requirements, platelet transfusion, and RBC transfusion were reduced with Oral-AZA vs SC AZA by 59% (RR 0.41 [95% CI: 0.24-0.71), 54% (RR 0.46 [0.23-0.93]), and 47% (RR 0.53 [0.28-1.00]), respectively. All findings were robust to the sensitivity analyses relaxing assumptions of imputed Tx exposure in HOVON97, which showed pts treated with Oral-AZA are 70% less likely to experience SAEs than pts treated with SC AZA (hazard ratio: 0.30 [95% CI: 0.09-1.02]), and hazard reductions for hospitalization and transfusions ranged from -51% to -58% (Table). CONCLUSIONS : These data suggest that in controlled clinical trials with pts in first remission after IC, Oral-AZA maintenance therapy not only significantly improves OS, but also provides a better safety profile and requires less HCRU than SC AZA maintenance therapy. Interpretation of results should be limited to the differences in the rate to first SAE while on Tx, as stronger generalizations are limited by competing risks and informative censoring. Figure 1 Figure 1. Disclosures Chen: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Huls: Universaity Medical Center Groningen: Current Employment. Cameron: Bristol Myers Squibb: Consultancy. Suero: Bristol Myers Squibb: Consultancy. Vasconcelos: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Gaugler: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Beach: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company.

scholarly journals Impact of Modified Thalidomide Dosing in Bortezomib/Thalidomide/Dexamethasone for Patients with Newly Diagnosed Multiple Myeloma Who Are Transplant-Eligible: A Matching-Adjusted Indirect Comparison

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4739-4739
Author(s):  
Pieter Sonneveld ◽  
Maria-Victoria Mateos ◽  
Adrián Alegre ◽  
Thierry Facon ◽  
Cyrille Hulin ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Board Of Directors ◽  
Research Funding ◽  
Indirect Comparison ◽  
Employment Equity ◽  
Advisory Committees ◽  
Post Transplant ◽  
Post Induction ◽  
Adjusted Indirect Comparison ◽  
Equity Ownership

Introduction: For patients with newly diagnosed multiple myeloma (NDMM) who are transplant-eligible, bortezomib/thalidomide/dexamethasone (VTd) is a standard of care (SoC) for induction and consolidation therapy. Clinical practice has evolved to use a modified VTd dose (VTd-mod; 100 mg thalidomide daily), which is reflected in recent treatment guidelines. As VTd-mod has become a real-world SoC, a matching-adjusted indirect comparison (MAIC) of the VTd-mod dose from recent clinical trials versus the dose included in the label (VTd-label; ramp up to 200 mg thalidomide daily) was performed to understand the effect on efficacy of modified VTd dosing for patients with NDMM who are transplant-eligible. Methods: For each outcome (overall survival [OS], progression-free survival [PFS], overall response rates [ORR] post-induction and post-transplant, and rate of peripheral neuropathy), a naïve comparison and a MAIC were performed. Data for VTd-label were obtained from the phase 3 PETHEMA/GEM study (Rosiñol L, et al. Blood. 2012;120[8]:1589-1596). Data for VTd-mod were pooled from the phase 3 CASSIOPEIA study (Moreau P, et al. Lancet. 2019;394[10192]:29-38) and the phase 2 NCT00531453 study (Ludwig H, et al. J Clin Oncol. 2013;31[2]:247-255). Patient-level data for PETHEMA/GEM and CASSIOPEIA were used to generate outcomes of interest and were validated against their respective clinical study reports; aggregate data for NCT00531453 were extracted from the primary publication. Matched baseline characteristics were age, sex, ECOG performance status, myeloma type, International Staging System (ISS) stage, baseline creatinine clearance, hemoglobin level, and platelet count. Results: Patients received VTd-mod (n = 591) or VTd-label (n = 130). After matching, baseline characteristics were similar across groups. For OS, the naïve comparison and the MAIC showed that VTd-mod was non-inferior to VTd-label (MAIC HR, 0.640 [95% CI: 0.363-1.129], P = 0.121; Figure 1A). VTd-mod significantly improved PFS versus VTd-label in the naïve comparison and MAIC (MAIC HR, 0.672 [95% CI: 0.467-0.966], P = 0.031; Figure 1B). Post-induction ORR was non-inferior for VTd-mod versus VTd-label (MAIC odds ratio, 1.781 [95% CI: 1.004-3.16], P = 0.065). Post-transplant, VTd-mod demonstrated superior ORR in both the naïve comparison and MAIC (MAIC odds ratio, 2.661 [95% CI: 1.579-4.484], P = 0.001). For rates of grade 3 or 4 peripheral neuropathy, the naïve comparison and MAIC both demonstrated that VTd-mod was non-inferior to VTd-label (MAIC rate difference, 2.4 [⁻1.7-6.49], P = 0.409). Conclusions: As naïve, indirect comparisons are prone to bias due to patient heterogeneity between studies, a MAIC can provide useful insights for clinicians and reimbursement decision-makers regarding the relative efficacy and safety of different treatments. In this MAIC, non-inferiority of VTd-mod versus VTd-label was demonstrated for OS, post-induction ORR, and peripheral neuropathy. This analysis also showed that VTd-mod significantly improved PFS and ORR post-transplant compared with VTd-label for patients with NDMM who are transplant-eligible. A limitation of this analysis is that unreported or unobserved confounding factors could not be adjusted for. Disclosures Sonneveld: Takeda: Honoraria, Research Funding; SkylineDx: Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Honoraria; Amgen: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding. Mateos:Janssen, Celgene, Takeda, Amgen, Adaptive: Honoraria; AbbVie Inc, Amgen Inc, Celgene Corporation, Genentech, GlaxoSmithKline, Janssen Biotech Inc, Mundipharma EDO, PharmaMar, Roche Laboratories Inc, Takeda Oncology: Other: Advisory Committee; Janssen, Celgene, Takeda, Amgen, GSK, Abbvie, EDO, Pharmar: Membership on an entity's Board of Directors or advisory committees; Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Takeda Oncology.: Speakers Bureau; Amgen Inc, Janssen Biotech Inc: Other: Data and Monitoring Committee. Alegre:Celgene, Amgen, Janssen, Takeda: Membership on an entity's Board of Directors or advisory committees. Facon:Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hulin:celgene: Consultancy, Honoraria; Janssen, AbbVie, Celgene, Amgen: Honoraria. Hashim:Ingress-Health: Employment. Vincken:Janssen: Employment, Equity Ownership. Kampfenkel:Janssen: Employment, Equity Ownership. Cote:Janssen: Employment, Equity Ownership. Moreau:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria.

scholarly journals Efficacy and Safety of Ravulizumab in Older Patients Aged >65 Years with Paroxysmal Nocturnal Hemoglobinuria in the 301 and 302 Phase 3 Extension Studies

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 42-43
Author(s):  
Regis Peffault De Latour ◽  
Jeffrey Szer ◽  
Austin Kulasekararaj ◽  
Jin Seok Kim ◽  
Caroline I. Piatek ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Older Patients ◽  
Research Funding ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Complement Inhibitor ◽  
Efficacy And Safety ◽  
Phase 3 ◽  
Advisory Committees ◽  
Treatment Naïve ◽  
Secondary Endpoints

Background: In the two largest phase 3 studies in patients with paroxysmal nocturnal hemoglobinuria (PNH), ravulizumab given every 8 weeks was noninferior to eculizumab given every 2 weeks across all efficacy endpoints. Data on efficacy and safety of ravulizumab in patients aged >65 years with PNH are limited. Aims: To compare the efficacy and safety of ravulizumab in patients with PNH aged >65 years with those aged ≤65 years. Methods: The population included patients from two phase 3 studies that assessed ravulizumab vs eculizumab in complement-inhibitor-naïve (301; NCT02946463) and -experienced (302; NCT03056040) adults with PNH. In study 301, patients were aged ≥18 years with a confirmed PNH diagnosis by flow cytometry and had a lactate dehydrogenase (LDH) level ≥1.5x upper limit of normal (ULN; 246U/L). In study 302, patients were aged ≥18 years with a confirmed PNH diagnosis by flow cytometry, were clinically stable on eculizumab having received ≥6 months of treatment and had a LDH level ≤1.5x ULN. Patients were randomized to either ravulizumab or eculizumab for 26 weeks after which all received ravulizumab up to 52 weeks. This prespecified analysis stratified patients by age: ≤65 or >65 years. Primary endpoints included percentage change in LDH from baseline to weeks 26 and 52, percentage of patients achieving LDH-normalization (LDH-N; LDH levels: ≤1x ULN) at weeks 26 and 52 and transfusion avoidance (TA) from baseline to weeks 26 and 52. Breakthrough hemolysis (BTH), hemoglobin (Hgb) stabilization and FACIT-fatigue score were secondary endpoints. Treatment emergent adverse events (TEAEs) were assessed as an indicator of safety. Results: A total of 58 patients aged >65 years and 383 patients aged ≤65 years were included. Disposition and medical history were similar among subgroups at baseline (Table 1). Results for primary and secondary endpoints for the two subgroups were comparable across studies and efficacy was maintained through 52 weeks. A higher proportion of treatment-experienced patients (>65 years) achieved all endpoints vs -naïve patients (Table 2). The percentage change in LDH levels from baseline to 26 and 52 weeks was similar between subgroups in study 301 (-66.5 to -80.0%) whereas in study 302, LDH levels remained stable in all subgroups up to 52 weeks (-3.7 to 22%). The percentage of patients achieving LDH-N in both studies at 26 and 52 weeks differed; 43.8-63.9% of patients aged ≤65 years achieved LDH-N compared with 21.4-77.8% of patients aged >65 years. A higher proportion of older treatment-experienced patients (57.1‒77.8%) achieved LDH-N compared with older treatment-naive patients (21.4‒50.0%) at 26 and 52 weeks. In patients aged ≤65 years in both studies, 63.7‒89.4% achieved TA. In the >65 years subgroup, 14.3‒50.0% of treatment-naive patients achieved TA whereas in study 302, 54.5‒72.7% of patients achieved TA. The number of BTH events was low, with no events reported in older patients to date. Hgb stabilization was consistent in the ≤65 year subgroup between the studies; a higher proportion of older patients in study 302 (45.5‒71.4%) achieved stabilized Hgb compared with older patients in study 301 (14.3‒35.3%). A clinically significant 3-point change was seen in FACIT-fatigue scores (indicating improvements in fatigue), with higher scores observed for ravulizumab in both subgroups (Figure 1). One patient discontinued the extension of study 301 due to lung cancer onset during the 26-week period and died following discontinuation. Headache was the most frequent TEAE. The incidence of TEAEs reported during ravulizumab treatment up to 52 weeks did not increase vs the 26-week period, with few events (Table 3) and no difference between subgroups. Conclusions: We present clinical outcomes in the largest cohort of patients with PNH (>65 years) on ravulizumab in a clinical trial setting to date. Ravulizumab was associated with similar efficacy and safety in both age subgroups and showed consistent and durable efficacy through 52 weeks of treatment. A higher proportion of patients in study 302 achieved all efficacy endpoints than in study 301, which can be due to patients' prior complement inhibitor experience. This observation was more evident in older patients. There were no BTH events in the older patients to date, and the number of infections in both subgroups was low. Ravulizumab was well tolerated in older patients with no additional safety concerns compared to younger patients. Disclosures Peffault De Latour: Apellis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Szer:Pfizer: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Apellis: Consultancy; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Prevail Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Speakers Bureau. Kulasekararaj:Alexion Pharmaceuticals Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kim:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Piatek:Alexion Pharmaceuticals: Consultancy, Research Funding. Kulagin:Alexion Pharmaceuticals Inc.: Consultancy, Research Funding. Hill:Alexion Pharmaceuticals Inc.: Current Employment. Wang:Alexion Pharmaceuticals Inc.: Current Employment. Yu:Alexion Pharmaceuticals Inc.: Current Employment. Ogawa:Alexion Pharmaceuticals Inc.: Current Employment. Schrezenmeier:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Lee:Alexion Pharmaceuticals Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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