Lindsay Mitchell's scientific contributions

Pegcetacoplan significantly improves outcomes for patients with paroxysmal nocturnal hemoglobinuria (PNH) experiencing extravascular hemolysis (EVH) on eculizumab, leading to approval in 2021/2022 (USA/Europe). We report the first collaborative real‐world evidence on pegcetacoplan use in UK and France. A total of 48 patients were either currently receiving or previously received pegcetacoplan (2019–2023). A total of 12 patients had participated in the PEGASUS clinical trial, continuing treatment after trial completion. Five patients were on combination treatment of C5 inhibition and pegcetacoplan. Mean pegcetacoplan duration was 20.2 months. Indication for pegcetacoplan was EVH on C5 inhibitors (Eculizumab, n = 29, Ravulizumab n = 16, others n = 3) with 35/48 patients requiring blood transfusion within the previous 12 months. Mean hemoglobin and reticulocyte count at pegcetacoplan commencement and after 3 months: 91 g/L and 205 × 10⁹/L and 115.8 g/L and 107 × 10⁹/L, respectively, resulting in mean Hb change of 22.3 g/L. Mean LDH pre‐ and post‐pegcetacoplan was unchanged. Six patients have stopped pegcetacoplan. A total of 32 breakthrough hemolysis (BTH) events occurred in 13/48 patients. A total of 14 events were within clinical trials (reported separately). Six patients experienced 18 acute BTH events outside clinical trials, 7/18 associated with complement activating conditions. Successful clinical management included daily pegcetacoplan subcutaneously for 3 days or single eculizumab doses; these events are manageable with prompt intervention. Pegcetacoplan is effective for patients with PNH experiencing EVH. In this large patient cohort, treatment was well tolerated with improved hemoglobin and reticulocytes and maintained LDH control. Although BTH occurs, this is manageable by acute dose modification, with the majority of patients being maintained on pegcetacoplan.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal hematopoietic disorder which occurs on a background of bone marrow failure (BMF). In PNH, chronic intravascular hemolysis causes an increase in morbidity and mortality, mainly due to thromboses. Over the last 20 years treatment of PNH has focused on the complement protein C5 to prevent intravascular hemolysis using the monoclonal antibody eculizumab and more recently ravulizumab. In the UK, all patients are under review at one of two reference centers. We report on all 509 UK patients with PNH treated with eculizumab and ravulizumab between May 2002 and July 2022. The survival of patients with eculizumab and ravulizumab was significantly lower than age and sex matched controls (p=0.001). Only 4 patients died due to thromboses. The survival of patients with PNH (n=389) when those requiring treatment for BMF (clonal evolution to myelodysplastic syndrome or acute leukemia or had progressive unresponsive aplastic anemia (AA)) were excluded was not significantly different to age and sex matched controls (p=0.12). There were 11 cases of meningococcal sepsis (0.35 events per 100 patient years). Extravascular hemolysis was evident in patients treated, with 26.7% of patients requiring transfusions in the most recent 12 months on therapy. Eculizumab and ravulizumab are safe and effective therapies which reduce mortality and morbidity in PNH but further work is needed to reduce mortality in those with concomitant BMF.

Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by uncontrolled terminal complement activation leading to intravascular hemolysis (IVH), thrombosis, and impairments in quality of life (QoL). The aim of this study was to identify the clinical drivers of improvement in patient-reported outcomes (PROs) in patients with PNH receiving the complement component 5 (C5) inhibitors eculizumab and ravulizumab. This post hoc analysis assessed clinical outcomes and PROs from 246 complement inhibitor-naive patients with PNH enrolled in a phase 3 randomized non-inferiority study that compared the C5 inhibitors ravulizumab and eculizumab (study 301; NCT02946463). The variables of interest were lactate dehydrogenase (LDH) levels, a surrogate measure of IVH, and hemoglobin (Hb) levels. PROs were collected using Functional Assessment of Chronic Illness Therapy—Fatigue (FACIT-F) and European Organisation for Research and Treatment of Cancer, Quality of Life Questionnaire—Core 30 (EORTC QLQ-C30) to assess fatigue and QoL, respectively. Improvements in absolute mean LDH levels were significantly associated with improvements in mean FACIT-F score (p = 0.0024) and EORTC QLQ-C30 global health (GH) score (p < 0.0001) from baseline to day 183. Improvements in scores were achieved despite a non-significant increase in Hb levels. To understand the interaction between LDH and Hb, a regression analysis was performed: LDH response with Hb improvements was a significant predictor of improvement in fatigue. The independent effect of improved Hb did not significantly affect FACIT-F or EORTC QLQ-C30 GH scores. These findings suggest that LDH levels are an important determinant of fatigue and QoL outcomes in patients with PNH. CTR: NCT02946463, October 27, 2016.

Background : Patients with PNH have uncontrolled terminal complement activation that can lead to thrombosis, organ damage, intravascular hemolysis (IVH), and clinical sequelae. It is also associated with debilitating patient-reported outcomes (PROs), such as fatigue, dyspnea, and pain that contribute to a poor quality of life (QoL). Whilst it is known that improvements in clinical outcomes are associated with C5 inhibitor (C5i) therapy in patients with PNH, evidence characterizing the relationship between clinical outcomes and fatigue or QoL are limited. Understanding key clinical drivers of improvements in QoL and fatigue during complement C5i therapy is vital for developing appropriate management strategies. Aims : To assess the relationship between clinical outcomes with fatigue and QoL, as measured by Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Global Health (EORTC QLQ-C30 GH), in patients with PNH receiving C5i therapy. Methods : Post-hoc analyses were performed using data from a 26-week data cut of a randomized phase 3 study (NCT02946463) that assessed ravulizumab and eculizumab in complement inhibitor-naïve patients with PNH and high disease activity (defined as a lactate dehydrogenase [LDH] level ≥ 1.5 × upper limit of normal [ULN; 246 U/L] and ≥ 1 sign or symptom of PNH at screening). The PRO measures (PROMs) used were FACIT-F and EORTC QLQ-C30 GH. Clinical variables included LDH, hemoglobin (Hb), bone marrow disorders, transfusions, and hematological parameters such as reticulocyte, platelet, and neutrophil counts. Multivariable regressions were performed separately for each PROM to assess the effect of clinical variables on PROM score changes from baseline to day 183, controlling for demographic characteristics and baseline PROM scores. Multicollinearity between covariates was tested in each regression model and removed when present. Results : Data for 121 and 125 patients with PNH treated with eculizumab or ravulizumab were included, respectively. Trial data showed that reduced LDH levels at day 183 were associated with improvements in FACIT-F in both treatment groups; however, no equivalent association was observed with Hb levels (Figure 1). In the regression analyses, significant predictors of FACIT-F improvement included reductions in LDH levels from baseline to day 183 (p = 0.0024) and the interaction of both achieving a LDH level ≤ 1.5 × ULN by day 183 and improvements in Hb from baseline (p = 0.0285). Similarly, significant predictors of EORTC QLQ-C30 GH improvement also included reductions in LDH levels from baseline to day 183 (p < 0.0001) and an increase in Hb from baseline to day 183 after receiving a transfusion during the study period (p = 0.02). However, Hb as a main effect, whether as an improvement in Hb levels from baseline to day 183, or Hb values at baseline, were not statistically significant predictors of improvement in either PROM at day 183. Conclusions : In this analysis, key clinical drivers of improvement in PROMs were determined among patients with PNH receiving C5i therapy. When multiple clinical variables were considered, reductions in LDH were one of the strongest predictors of improvements in fatigue and QoL. Increases in Hb levels from baseline were only a significant predictor of improvement in FACIT-F for patients who had attained LDH level ≤ 1.5 × ULN at day 183, highlighting the importance of controlling IVH in patients with PNH. Finally, these results suggest that Hb alone is not a strong predictor of improvements of fatigue and QoL in this disease setting. Figure 1 Figure 1. Disclosures Schrezenmeier: Alexion, AstraZeneca Rare Disease: Honoraria, Other: Travel support, Research Funding; Apellis: Honoraria; Roche: Honoraria; Sanofi: Honoraria; Novartis: Honoraria. Kulasekararaj: F. Hoffmann-La Roche Ltd.: Consultancy, Honoraria, Speakers Bureau; Apellis: Consultancy; Akari: Consultancy, Honoraria, Speakers Bureau; Biocryst: Consultancy, Honoraria, Speakers Bureau; Achilleon: Consultancy, Honoraria, Speakers Bureau; Alexion: Consultancy, Honoraria, Speakers Bureau; Ra Pharma: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Alexion, AstraZeneca Rare Disease Inc.: Consultancy, Honoraria, Other: Travel support. Mitchell: Alexion, AstraZeneca Rare Disease Inc.: Honoraria. Peffault De Latour: Jazz Pharmaceuticals: Honoraria; Amgen: Consultancy, Other, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Alexion, AstraZeneca Rare Disease: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding. Devos: AbbVie: Consultancy; Alexion, AstraZeneca Rare Disease Inc.: Consultancy; Incyte: Consultancy; Novartis: Consultancy; Bristol Myers Squibb - Celegene: Consultancy. Okamoto: Alexion, AstraZeneca Rare Disease Inc.: Honoraria, Research Funding. Wells: Alexion, AstraZeneca Rare Disease Inc.: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Johnston: Broadstreet HEOR: Current Employment. Popoff: Broadstreet HEOR: Current Employment. Cheung: Broadstreet HEOR: Current Employment. Wang: Alexion, AstraZeneca Rare Disease Inc.: Current Employment. Gustovic: Alexion, AstraZeneca Rare Disease: Current Employment. Wang: Alexion, AstraZeneca Rare Disease: Current Employment. Tomazos: Alexion, AstraZeneca Rare Disease: Current Employment. Patel: Alexion, AstraZeneca Rare Disease Inc.: Current Employment. Lee: Alexion, AstraZeneca Rare Disease: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Ravulizumab every 8 weeks showed non‐inferiority to eculizumab every 2 weeks in a 26‐week, phase 3, randomized controlled trial in adults with paroxysmal nocturnal hemoglobinuria (PNH) who were clinically stable on eculizumab (NCT03056040). We report results from the first 26 weeks of the extension period in which patients continued ravulizumab (n = 96) or switched from eculizumab to ravulizumab (n = 95). At week 52, mean (SD) lactate dehydrogenase levels increased 8.8% (29%) with ravulizumab‐ravulizumab and 5.8% (27%) with eculizumab‐ravulizumab from primary evaluation period baseline. During the extension period, four patients (ravulizumab‐ravulizumab, n = 3; eculizumab‐ravulizumab, n = 1) experienced breakthrough hemolysis, but none associated with serum free C5 ≥ 0.5 μg/mL. Mean Functional Assessment of Chronic Illness Therapy (FACIT)‐Fatigue scores remained stable through week 52. During the extension period, proportions of patients avoiding transfusion remained stable (ravulizumab‐ravulizumab, 86.5%; eculizumab‐ravulizumab, 83.2%); 81.2% and 81.1%, respectively, had stabilized hemoglobin. All patients maintained serum free C5 levels < 0.5 μg/mL. Adverse events were generally similar between groups, and rates were lower in the extension period. Adults with PNH on stable eculizumab therapy who received ravulizumab over 52 weeks experienced durable efficacy, with consistent efficacy in patients who received eculizumab during the primary evaluation period and then switched to ravulizumab. Ravulizumab was well tolerated.

Background Ravulizumab, the only long-acting complement C5 inhibitor for adults with paroxysmal nocturnal hemoglobinuria (PNH), demonstrated non-inferiority to eculizumab after 26 weeks of treatment in complement inhibitor-naïve patients during a phase III randomized controlled trial. We present open-label extension results with up to 52 weeks of treatment. Methods Patients assigned to ravulizumab every 8 weeks (q8w) or eculizumab every 2 weeks during the randomized primary evaluation period received ravulizumab q8w during the 26-week extension. Efficacy endpoints were lactate dehydrogenase (LDH) normalization, transfusion avoidance, breakthrough hemolysis (BTH), LDH levels, Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale, and stabilized hemoglobin. Serum free C5 levels and safety were assessed. Outcomes as of the data cut-off (4 September 2018) were summarized using descriptive statistics. Results Overall, 124 patients continued ravulizumab, and 119 switched from eculizumab to ravulizumab. During the extension, 43.5% and 40.3% of patients in the ravulizumab–ravulizumab and eculizumab–ravulizumab arms, respectively, achieved LDH normalization; 76.6% and 67.2% avoided transfusion. BTH decreased in the eculizumab–ravulizumab arm; no events were associated with free C5 ⩾0.5 μg/mL while receiving ravulizumab. Overall, 73.4% and 65.5% of patients in the ravulizumab–ravulizumab and eculizumab–ravulizumab arms, respectively, achieved stabilized hemoglobin. Similar proportions of patients achieved ⩾3-point improvement in FACIT-Fatigue at week 52 (ravulizumab–ravulizumab, 64.5%; eculizumab–ravulizumab, 57.1%). All patients maintained free C5 <0.5 μg/mL during the ravulizumab extension, including those who experienced C5 excursions ⩾0.5 μg/mL while receiving eculizumab during the primary evaluation period. Adverse events were comparable between groups and decreased over time. Conclusion In adult, complement inhibitor–naïve patients with PNH, ravulizumab q8w for up to 52 weeks demonstrated durable efficacy and was well tolerated, with complete and sustained free C5 inhibition and a decreased incidence of BTH with no events associated with loss of free C5 control. Trial registration ClinicalTrials.gov identifier, NCT02946463

A retrospective analysis of presentation clinical, laboratory and immunophenotypic features of 1 081 patients with paroxysmal nocturnal haemoglobinuria (PNH) clones [glycosylphosphatidylinositol (GPI)‐deficient blood cells] identified at our hospital by flow cytometry over the past 25 years was undertaken. Three distinct clusters of patients were identified and significant correlations between presentation disease type and PNH clone sizes were evident. Smaller PNH clones predominate in cytopenic and myelodysplastic subtypes; large PNH clones were associated with haemolytic, thrombotic and haemolytic/thrombotic subtypes. Rare cases with an associated chronic myeloproliferative disorder had either large or small PNH clones. Cytopenia was a frequent finding, highlighting bone marrow failure as the major underlying feature associated with the detection of PNH clones in the peripheral blood. Red cell PNH clones showed significant correlations between the presence of type II (partial GPI deficiency) red cells and thrombotic disease. Haemolytic PNH was associated with type III (complete GPI deficiency) red cell populations of >20%. Those with both haemolytic and thrombotic features had major type II and type III red cell populations. Distinct patterns of presentation age decade were evident for clinical subtypes with a peak incidence of haemolytic PNH in the 30–49 year age group and a biphasic age distribution for the cytopenia group.

INTRODUCTION Ravulizumab, an innovative long-acting C5 complement inhibitor, was recently approved in the United States, Europe, and Japan for the treatment of paroxysmal nocturnal hemoglobinuria (PNH). In the largest phase 3 study (ALXN1210-PNH-302; NCT03056040) in eculizumab-experienced PNH patients (pts), ravulizumab (q8w) was shown to be noninferior to eculizumab (q2w) after 26 wks for all primary and key secondary endpoints. At the end of the 26-wk treatment period, all pts had the option to receive weight-based dosing of ravulizumab in an extension for up to 2 y. We report on the efficacy and safety of ravulizumab through 52 wks of treatment. METHODS This was an extension of the open-label, phase 3, multicenter study described above. Adult PNH pts who were stable on eculizumab for ≥6 mo and with lactate dehydrogenase (LDH) of ≤1.5xULN at screening were randomly assigned 1:1 to switch to ravulizumab or continue receiving eculizumab for 26 wks. After 26 wks, pts in the ravulizumab arm continued ravulizumab maintenance therapy (R-R arm), and pts in the eculizumab arm were switched to ravulizumab (E-R arm). For the 52-wk data, the primary efficacy endpoint was percent change in LDH from baseline (BL), and key secondary endpoints included the proportion of pts with breakthrough hemolysis (BTH), transfusion avoidance, improvement in FACIT-Fatigue total score, and stabilized hemoglobin (HGB-S) levels. Additional endpoints included change in plasma free C5 levels from BL and safety evaluations. RESULTS Of the 192 pts who received ravulizumab during the study, 191 entered the extension period (R-R arm: n=96; E-R arm: n=95). Pts in both groups showed a durable response for percentage change in LDH up to 52 wks, similar to what was observed during the first 26 wks (Figure A). At 52 wks, pts in the R-R arm had an 8.8% increase in LDH from baseline (standard deviation [SD], 29%), while pts in the E-R arm had 5.8% (SD, 27%) change in LDH from baseline. Mean LDH levels in both groups were maintained at 1.0xULN (<246 U/L). The proportion of pts who experienced BTH was low and stable over the 52-wk treatment with ravulizumab (Table). During wks 0-26, no pts in the R-R arm experienced BTH vs 3 during wks 27-52. In the E-R arm, 5 pts experienced BTH during wks 0-26 vs 1 in wks 27-52 after switching to ravulizumab. During wks 27-52, no BTH events were associated with free C5 of ≥0.5 μg/mL (threshold for complete C5 inhibition). The percentage of pts avoiding transfusion remained stable in the extension period (Table). During wks 0-26, 88% of pts in the R-R arm avoided transfusion vs 87% in wks 27-52; in the E-R arm, 83% (0-26 wks) vs 83% (27-52 wks) avoided transfusion. FACIT-Fatigue scores were maintained in both treatment groups through 52 wks. The proportion of pts with HGB-S was 76% in each arm during wks 0-26, and 81% in each arm during wks 27-52. All pts in the R-R arm continued to maintain free C5 of <0.5 μg/mL at all time points through 52 wks (n=96; Figure B). All pts in the ravulizumab treatment group continued to maintain free C5 of <0.5 μg/mL at all time points through 52 wks (n=96). In pts initially randomized to eculizumab, the switch to ravulizumab showed improved free C5 control, and no pts had free C5 of ≥0.5 µg/mL after the switch. During the extension, 79% in the R-R arm experienced a treatment-emergent adverse event (TEAE) vs 75% in the E-R arm. The most frequently reported TEAEs in the R-R arm were upper respiratory tract infection (URTI; 9 pts [9%]), and headache and nasopharyngitis (6 pts [6%] each). The most common TEAEs in the E-R arm were headache (10 pts [10%]), URTI (8 pts [8%]), and nasopharyngitis (7 pts [7%]). Eight pts (8%) in the R-R arm and 5 pts (5%) in the E-R arm experienced serious AEs; none led to discontinuation or death. No new treatment-emergent antidrug antibody-positive responses were reported during wks 27-52. There were no meningococcal infections, deaths, or discontinuations due to AEs. CONCLUSIONS Adult PNH pts receiving stable eculizumab therapy who received ravulizumab over 52 wks experienced durable efficacy; pts who received eculizumab for 26 wks and then switched to ravulizumab had an efficacy response consistent with pts in the R-R arm. All pts who had suboptimal free C5 control receiving eculizumab achieved complete free C5 inhibition after the switch to ravulizumab; no BTH events were associated with free C5 levels of ≥0.5 μg/mL. Ravulizumab continues to be well tolerated through wk 52 with no new safety concerns. Disclosures Kulasekararaj: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Achilleon: Consultancy; Ra Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Akari Therapeutics: Consultancy; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hill:Akari: Honoraria; Alexion: Honoraria; Bioverativ: Honoraria; Apellis: Honoraria; Novartis: Honoraria; Regeneron: Honoraria; Roche: Honoraria; Ra Pharma: Honoraria. Wells:Alexion: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Gonzalez-Fernandez:Alexion: Research Funding, Speakers Bureau. Gaya:Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Honoraria; Novartis: Honoraria. Piatek:Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Dova: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Rigel: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding. Mitchell:Novartis: Honoraria; Alexion: Honoraria. Usuki:Alexion: Honoraria, Speakers Bureau. Brodsky:Achillion: Research Funding; Alexion: Membership on an entity's Board of Directors or advisory committees, Other: Grant funding. Ogawa:Alexion Pharmaceuticals: Employment, Equity Ownership. Ortiz:Alexion: Employment. Röth:Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioverativ: Consultancy, Honoraria; Apellis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Lee:Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Achillion: Research Funding. Peffault de Latour:Alexion: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding.