Kurzfassung: Background: ALXN1210 is a humanized monoclonal antibody designed for rapid, complete, sustained inhibition of C5 with less frequent dosing. A previous study in healthy volunteers demonstrated immediate, complete, and sustained C5 inhibition. The terminal half-life of ALXN1210 is approximately 3-4x longer than eculizumab, thus providing continuous suppression of hemolysis with an extended dosing interval. Aims: ALXN1210-PNH-103 is a Phase 1/2, multicenter, open-label, intrapatient dose-escalation study (NCT02598583), evaluating the safety, tolerability, and efficacy of 2 IV maintenance dosing regimens of ALXN1210 in patients (pts) ≥18 y with PNH who were naïve to complement inhibitor therapy. Methods: In this interim analysis, 6 pts in Cohort 1 (C1) received either 400- or 600-mg IV induction doses followed by a 900-mg maintenance dose q4w; 7 pts in Cohort 2 (C2) received 600- and 900-mg induction doses, followed by an 1800-mg maintenance dose q4w for up to 24 wk. The primary efficacy outcome was change in complement-mediated hemolysis as measured by LDH level. Other endpoints included changes in hematologic parameters, blood transfusions, FACIT-Fatigue scores, and pharmacokinetic (PK) parameters. Results: A total of 13 pts consented and enrolled (Table 1). Median duration of exposure was 5.6 mo for C1 and 4.6 mo for C2. Pts had evidence of high hemolytic activity at baseline (BL), with LDH levels approximately 7-fold higher than the upper limit of normal (ULN). LDH levels decreased rapidly by the first evaluable time point (day 8), and improvements were sustained throughout all dosing intervals. Mean percentage reductions from BL in LDH levels were 85.9% in C1 at day 169 (n=6) and 85.2% in C2 at day 141 (n=5), the last available time points; respective LDH mean (SD) values at these time points were 232 (82) and 198 (36) U/L. Mean hemoglobin (Hb) levels were improved or stable in both cohorts. Among 5 pts with red blood cell transfusions in the 12 months prior to treatment (2 in C1, 3 in C2), only 1/2 pts (50%) in C1, became free of transfusions, while 3/3 pts (100%) in C2 were transfusion free. The pt in C1 who required transfusions had LDH levels of 391 and 417 U/L (1.67 and 1.78 x ULN), and Hb levels of 7.7 and 6.9 g/dL (BL Hb of 9.8 g/dL) on days 57 and 141, respectively. This pt consequently received 2 transfusions (2 units each) on these days. No pts in C2 required a transfusion. Mean (SD) FACIT-Fatigue scores increased from BL to day 43 by 28.9% (45.6%) in C1, and by 61.4% (49.9%) in C2 (Table 2). At day 169, FACIT-Fatigue scores were maintained in C1 (28.7% [52.7%] improvement from BL), but improved by 76.2% (70.3%) in C2. It should be noted that the BL FACIT-Fatigue score was lower in C2 than in C1 (10.1 points), indicating more severe fatigue. PK analysis of available data revealed an estimated mean ± SD terminal (beta) half-life of ALXN1210 of 42 ± 6 days. No deaths, serious adverse events (AEs), drug discontinuations, or AEs leading to withdrawals were reported in either cohort. The most common treatment-emergent AE (TEAE) was headache (4 pts). Investigators judged 77% of TEAEs to be unrelated to treatment. All AEs considered at least possibly related to therapy over 4.6 to 5.6 months of median exposure, including atrial flutter, general ache, headache, and worsening of anemia, resolved with ongoing ALXN1210 treatment. Conclusion: In pts with PNH previously-naïve to complement inhibitor therapy, ALXN1210 treatment resulted in rapid, complete, and sustained C5 inhibition. LDH levels were rapidly reduced in all pts. Mean LDH levels were reduced to below the ULN in 4/6 (67%) of pts in C1, and in 6/7 (86%) of pts in C2 at the last evaluable time point. While there was a notable decrease in the need for blood transfusions, 17% (1/6) of pts in C1 (900 mg) experienced a recurrence of hemolysis and required transfusions, while no pts in C2 (1800 mg) had evidence of hemolysis or required a transfusion. FACIT-Fatigue scores improved in both cohorts, but improvement in patients was 2.1-fold greater in the higher dose cohort, consistent with better hemolytic response. These data suggest that the lower dose may be inadequate throughout the monthly dosing interval for complete suppression of hemolysis, which is central to the morbidities of PNH. Supported by a model-derived preliminary mean ± SD terminal elimination half-life of 42 ± 6 days, a Phase 2 study examining longer dosing intervals of up to 12 weeks is ongoing. Disclosures Lee: Alexion Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bachman:Alexion Pharmaceuticals, Inc.: Employment. Aguzzi:Alexion Pharmaceuticals, Inc.: Employment. Jang:Alexion Pharmaceuticals, Inc: Consultancy, Honoraria, Research Funding. Rottinghaus:Alexion Pharmaceuticals, Inc.: Employment. Shafner:Alexion Pharmaceuticals, Inc.: Employment. Szer:Ra Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alnylam: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Kurzfassung: Ravulizumab (ALXN1210), a new complement C5 inhibitor, provides immediate, complete, and sustained C5 inhibition. This phase 3, open-label study assessed the noninferiority of ravulizumab to eculizumab in complement inhibitor–naive adults with paroxysmal nocturnal hemoglobinuria (PNH). Patients with lactate dehydrogenase (LDH) ≥1.5 times the upper limit of normal and at least 1 PNH symptom were randomized 1:1 to receive ravulizumab or eculizumab for 183 days (N = 246). Coprimary efficacy end points were proportion of patients remaining transfusion-free and LDH normalization. Secondary end points were percent change from baseline in LDH, change from baseline in Functional Assessment of Chronic Illness Therapy (FACIT)–Fatigue score, proportion of patients with breakthrough hemolysis, stabilized hemoglobin, and change in serum free C5. Ravulizumab was noninferior to eculizumab for both coprimary and all key secondary end points (Pinf & lt; .0001): transfusion avoidance (73.6% vs 66.1%; difference of 6.8% [95% confidence interval (CI), −4.66, 18.14]), LDH normalization (53.6% vs 49.4%; odds ratio, 1.19 [0.80, 1.77] ), percent reduction in LDH (−76.8% vs −76.0%; difference [95% CI], −0.83% [−5.21, 3.56] ), change in FACIT-Fatigue score (7.07 vs 6.40; difference [95% CI], 0.67 [−1.21, 2.55] ), breakthrough hemolysis (4.0% vs 10.7%; difference [95% CI], −6.7% [−14.21, 0.18] ), and stabilized hemoglobin (68.0% vs 64.5%; difference [95% CI], 2.9 [−8.80, 14.64] ). The safety and tolerability of ravulizumab and eculizumab were similar; no meningococcal infections occurred. In conclusion, ravulizumab given every 8 weeks achieved noninferiority compared with eculizumab given every 2 weeks for all efficacy end points, with a similar safety profile. This trial was registered at www.clinicaltrials.gov as #NCT02946463.

Kurzfassung: Ravulizumab, a new complement component C5 inhibitor administered every 8 weeks, was noninferior to eculizumab administered every 2 weeks in complement-inhibitor–naive patients with paroxysmal nocturnal hemoglobinuria (PNH). This study assessed noninferiority of ravulizumab to eculizumab in clinically stable PNH patients during previous eculizumab therapy. In this phase 3, open-label, multicenter study, 195 PNH patients on labeled-dose (900 mg every 2 weeks) eculizumab for & gt;6 months were randomly assigned 1:1 to switch to ravulizumab (n = 97) or continue eculizumab (n = 98). Primary efficacy end point was percentage change in lactate dehydrogenase (LDH) from baseline to day 183. Key secondary end points included proportion of patients with breakthrough hemolysis, change in Functional Assessment of Chronic Illness Therapy (FACIT)–Fatigue score, transfusion avoidance, and stabilized hemoglobin. In 191 patients completing 183 days of treatment, ravulizumab was noninferior to eculizumab (Pinf & lt; .0006 for all end points), including percentage change in LDH (difference, 9.21% [95% confidence interval (CI), −0.42 to 18.84], P = .058 for superiority), breakthrough hemolysis (difference, 5.1 [95% CI, −8.89 to 18.99] ), change in FACIT-Fatigue score (difference, 1.47 [95% CI, −0.21 to 3.15]), transfusion avoidance (difference, 5.5 [95% CI, −4.27 to 15.68] ), and stabilized hemoglobin (difference, 1.4 [95% CI, −10.41 to 13.31]). The most frequently reported adverse event was headache (26.8%, ravulizumab; 17.3%, eculizumab). No meningococcal infections or discontinuations due to adverse events occurred. Patients with PNH may be safely and effectively switched from labeled-dose eculizumab administered every 2 weeks to ravulizumab administered every 8 weeks. This trial was funded by Alexion Pharmaceuticals, Inc., and is registered at www.clinicaltrials.gov as #NCT03056040.

Kurzfassung: Scholars possess little theoretical understanding of how presidents behave during scandals. Existing presidential scholarship has focused on “offensive” communication, aimed at achieving legislative or policy goals, whereas the authors’ interest is in “defensive” communication. Using a game-theoretic signaling model of the president–media relationship, the authors identify conditions affecting White House stonewalling and media feeding frenzies. The president’s optimal behavior changes depending on circumstances, particularly the level of presidential involvement in the alleged misdeeds. The authors illustrate this with a case study of the Iran-Contra scandals and an empirical analysis of scandals from the Nixon through the Bush administrations.

Kurzfassung: Introduction Ravulizumab, an innovative complement C5 inhibitor given every 8 weeks (q8w), was recently demonstrated in a large phase 3 study of patients (pts) with paroxysmal nocturnal hemoglobinuria (PNH) and naïve to complement inhibitor therapy to be non-inferior to eculizumab given every 2 weeks (q2w) across all endpoints that measured different aspects of PNH disease (transfusion avoidance [TA], lactate dehydrogenase normalization [LDH-N] , percent LDH reduction, breakthrough hemolysis [BTH], Functional Assessment of Chronic Illness Therapy [FACIT] -Fatigue, and hemoglobin stabilization [HGB-S]) (Lee JW et al. EHA Learning Center, Jun 17, 2018; LB2603). PNH pts currently receiving eculizumab may experience treatment burden associated with the q2w dosing regimen. With the development of ravulizumab, PNH pts on prior eculizumab therapy can potentially switch to ravulizumab without interruption of treatment. The primary objective of this study was to assess the noninferiority of ravulizumab compared to eculizumab in adult PNH pts who were clinically stable after having been treated with eculizumab for at least 6 months. Methods In this phase 3, open-label, multicenter study (NCT03056040), adult pts with a documented diagnosis of PNH who were treated with labelled-dose eculizumab for 〉 6 months having LDH levels ≤1.5 times the upper limit of normal at screening were randomly assigned 1:1 to continue eculizumab or switch to ravulizumab. Pts randomized to ravulizumab received weight-based loading [day 1]/maintenance doses [day 15 and q8w thereafter] : ≥40 to 〈 60 kg body weight [2400/3000mg]; ≥60 to 〈 100 kg [2700/3300mg]; ≥100 kg [3000/3600mg] ) through day 183 (primary completion date). Pts randomized to eculizumab received 900mg q2w. All pts must have received vaccination against N. meningitidis. Primary efficacy endpoint was hemolysis, as measured by percentage change in LDH levels from baseline (BL) to day 183. Non-inferiority was declared if the upper bound of the 95% confidence interval (CI) for the difference in change of LDH from BL (ravulizumab-eculizumab) was 〈 15%. Key secondary efficacy endpoints tested in a hierarchal manner were proportion of patients with BTH, change in quality of life assessed by FACIT-Fatigue score, TA (percentage of pts remaining transfusion-free), and proportion of pts with HGB-S from BL to day 183. Change from BL in free C5 level over time was also assessed. Results Of 208 pts screened, 197 pts were randomized (1:1) to ravulizumab or eculizumab, 195 received treatment (ravulizumab, n=97; eculizumab, n=98), and 191 pts completed 183 days of treatment. Pt demographics and baseline clinical characteristics were similar between treatment groups. On average, pts had received prior eculizumab therapy for 5.8 years. All pts received all planned infusions of study medication. Ravulizumab was statistically significantly noninferior to eculizumab for the primary and all key secondary endpoints, with all point estimates favoring ravulizumab: percentage change in LDH levels (difference of -9.21% [95% CI: -18.84, 0.42]), BTH (difference of -5.1 [95% CI -18.89, 8.89] ), change in FACIT-Fatigue score (difference of 1.47 [-0.21, 3.15]), TA (difference of 5.5 [95% CI -4.27, 15.68] ), and HGB-S (difference of 1.4 [-10.41, 13.31]) (Fig A, Fig B). Superiority testing of the primary endpoint (percentage change in LDH) did not reach statistical significance (P=0.0583 vs P 〈 0.05 required). Complete inhibition of serum C5 (mean free C5 serum of 〈 0.5 µg/mL) was observed by the end of the first ravulizumab infusion and was sustained throughout the treatment period (Fig C). The most frequently reported adverse event was headache (26.8% versus 17.3% for ravulizumab and eculizumab, respectively). There were no meningococcal infections or discontinuations due to adverse events. Conclusion Results of this large phase 3 study show that ravulizumab achieved noninferiority compared with eculizumab in pts with PNH on stable eculizumab therapy. Pts can be safely and effectively switched from eculizumab given q2w to ravulizumab given q8w. In pts previously stable on eculizumab, no pts switched to ravulizumab experienced BTH vs 5 pts on eculizumab during the 26-week treatment period. This may be related to optimized ravulizumab dosing compared to eculizumab, resulting in complete and sustained C5 inhibition for all pts. Figure. Figure. Disclosures Kulasekararaj: Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Other: Travel Support . Hill:Apellis: Consultancy, Honoraria; Bioverativ: Consultancy, Honoraria; Regeneron: Consultancy, Honoraria; Akari: Consultancy, Honoraria; Ra Pharma: Consultancy, Honoraria; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria. Rottinghaus:Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Wells:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Alexion Pharmaceuticals, Inc.: Honoraria, Other: Travel Support , Research Funding. Gonzalez-Fernandez:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria. Gaya:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria. Lee:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding. Ojeda Gutierrez:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria. Szer:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Other: Travel Support , Research Funding. Risitano:Pfizer Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amyndas Pharmaceuticals: Consultancy; Alnylam Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ra Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding. Nakao:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria; Kyowa Hakko Kirin Co., Ltd.: Honoraria; Novartis: Honoraria. Bachman:Alexion Pharmaceuticals, Inc.: Equity Ownership, Other: Former employee. Shafner:Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Damokosh:Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Ortiz:Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Röth:Pfizer: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Bioverativ: Consultancy, Honoraria; Amgen: Research Funding. Peffault De Latour:Pfizer Inc.: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Amgen Inc.: Research Funding.

Kurzfassung: Ravulizumab, a novel long‐acting complement component 5 (C5) inhibitor administered every 8 weeks (q8w), was non‐inferior to eculizumab for all efficacy outcomes in two randomised, open‐label, phase 3 trials in C5 inhibitor‐naïve (Study 301) and eculizumab‐experienced (Study 302) adult patients with paroxysmal nocturnal haemoglobinuria (PNH). This pre‐specified analysis characterised ravulizumab pharmacokinetics (PK), pharmacodynamics (PD; free C5 levels), and PD differences between medications (Study 301, n  = 246; Study 302, n  = 195). Ravulizumab PK parameters were determined using non‐compartmental analysis. Serum free C5 was quantified with a Gyros‐based fluorescence assay (ravulizumab) and an electrochemiluminescence ligand‐binding assay (eculizumab). Ravulizumab PK parameters were numerically comparable in both studies; the median time to maximum concentrations ranged from 2·3 to 2·8 and 2·3 to 2·6 h in studies 301 and 302, respectively. Ravulizumab steady‐state serum concentrations were achieved immediately after the first dose and sustained throughout treatment. For ravulizumab, the mean (SD) post hoc terminal elimination half‐life was 49·7 (8·9) days. Serum free C5 concentrations 〈 0·5 µg/ml were achieved after the first ravulizumab dose and sustained throughout treatment in both studies. In a minority of patients, free C5 concentrations 〈 0·5 µg/ml were not consistently achieved with eculizumab in either study. Ravulizumab q8w was more consistent in providing immediate, complete, sustained C5 inhibition than eculizumab every‐2‐weeks in patients with PNH.