Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematologic disorder characterized by complement-mediated hemolysis. C5 inhibitors (eculizumab/ravulizumab) control intravascular hemolysis but do not prevent residual extravascular hemolysis. The newly approved complement inhibitor, pegcetacoplan, inhibits C3, upstream of C5, and has the potential to improve control of complement-mediated hemolysis. The PADDOCK and PALOMINO clinical trials assessed the safety and efficacy of pegcetacoplan in complement inhibitor-naïve adults (≥ 18 years) diagnosed with PNH. Patients in PADDOCK (phase 1b open-label, pilot trial) received daily subcutaneous pegcetacoplan (cohort 1: 180 mg up to day 28 [n = 3]; cohort 2: 270–360 mg up to day 365 [n = 20]). PALOMINO (phase 2a, open-label trial) used the same dosing protocol as PADDOCK cohort 2 (n = 4). Primary endpoints in both trials were mean change from baseline in hemoglobin, lactate dehydrogenase, haptoglobin, and the number and severity of treatment-emergent adverse events. Mean baseline hemoglobin levels were below the lower limit of normal in both trials (PADDOCK: 8.38 g/dL; PALOMINO: 7.73 g/dL; normal range: 11.90–18.00 g/dL), increased to within normal range by day 85, and were sustained through day 365 (PADDOCK: 12.14 g/dL; PALOMINO: 13.00 g/dL). In PADDOCK, 3 serious adverse events (SAE) led to study drug discontinuation, 1 of which was deemed likely related to pegcetacoplan and 1 SAE, not deemed related to study drug, led to death. No SAE led to discontinuation/death in PALOMINO. Pegcetacoplan was generally well tolerated and improved hematological parameters by controlling hemolysis, while also improving other clinical PNH indicators in both trials. These trials were registered at www.clinicaltrials.gov (NCT02588833 and NCT03593200).

INTRODUCTION Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, clonal hematopoietic stem cell disorder characterized by chronic complement-mediated intravascular and extravascular hemolysis (IVH and EVH), and thrombosis. C5 inhibitors reduce IVH by inhibiting membrane attack complex formation and are the current standard of treatment for PNH. EVH persists in the presence of C5 inhibition. Pegcetacoplan is a C3 inhibitor targeted to control both IVH and EVH. The PADDOCK and PALOMINO studies assessed the safety and preliminary efficacy of pegcetacoplan in complement inhibitor-naïve patients. METHODS PADDOCK was a phase 1b, open-label, pilot study (NCT02588833) with 2 cohorts. Subjects in cohort 1 received pegcetacoplan at a suboptimal dose of 180 mg/day for 28 days; subjects in cohort 2 received pegcetacoplan 270 mg/day for up to 1 year. Subjects could participate in both cohorts. PALOMINO was a phase 2a, open-label, single-cohort study (NCT03593200) in which subjects received pegcetacoplan 270 mg/day for up to 1 year. Both studies enrolled subjects ≥18 years old diagnosed with PNH and no prior treatment with eculizumab. Primary efficacy endpoints in both studies were change from baseline in lactate dehydrogenase (LDH), haptoglobin, and hemoglobin. Secondary efficacy endpoints included change from baseline in reticulocyte count, total bilirubin, and Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score. The number of packed red blood cell transfusions was also recorded. Primary safety endpoints were the incidence and severity of treatment emergent adverse events (TEAEs). RESULTS Three subjects were enrolled in PADDOCK cohort 1 and 20 in cohort 2; 1 subject was enrolled in both cohorts. PALOMINO enrolled 4 subjects. PADDOCK cohort 2 and PALOMINO efficacy data are shown in the Table. At baseline, mean LDH levels were >8× upper limit of normal in both studies. At day 365, mean LDH had decreased to <2× upper limit of normal in PADDOCK and was within the normal range in PALOMINO. At baseline, mean hemoglobin levels were below the lower limit of normal in both studies. At day 365, mean hemoglobin levels had increased to within the normal range in both studies. In PALOMINO, 3 subjects achieved hemoglobin levels above the lower limit of normal at day 365, and 1 subject had a hemoglobin level of 10.14 g/dL. An increase from baseline in mean FACIT-Fatigue scores of 7.1 and 6.5 at day 365 was observed in PADDOCK and PALOMINO, respectively. In PADDOCK and PALOMINO, mean reticulocyte count decreased from 194.9 × 109 cells/L and 238.3 × 109 cells/L at baseline, respectively, to 96.4 × 109 cells/L and 94.0 × 109 cells/L at day 365. Total bilirubin levels also decreased from 42.6 µmol/L and 30.85 µmol/L at baseline to 13.9 µmol/L and 9.33 µmol/L at day 365 in PADDOCK and PALOMINO, respectively. In PADDOCK cohort 2, 18/20 subjects received ≥1 transfusion in the 12 months prior to screening, and 13/20 subjects did not require a transfusion during the study. In PALOMINO, all subjects received ≥1 transfusion in the 12 months prior to screening, and none required a transfusion during the study. Overall, 143 TEAEs were reported in 19/22 subjects (86.4%) in PADDOCK cohorts 1 and 2, of which 35 were either possibly or probably related to pegcetacoplan. Thirteen serious adverse events (SAEs) were reported in PADDOCK. Three SAEs (aplastic anemia, abdominal neoplasm, and hypersensitivity) led to pegcetacoplan discontinuation in 3 subjects. Two of these SAEs (aplastic anemia and abdominal neoplasm) resulted in study discontinuation. The aplastic anemia SAE was fatal and considered not related to pegcetacoplan. In PALOMINO, 60 TEAEs were reported in 3 (75.0%) subjects, of which 52 were possibly treatment-related. One SAE (rib fracture) was reported and was considered not related to pegcetacoplan. In PALOMINO, no TEAEs led to death, pegcetacoplan discontinuation, or study discontinuation. CONCLUSIONS In PADDOCK and PALOMINO, pegcetacoplan improved hematological parameters by controlling both IVH and EVH in patients with PNH. Improvements in clinical parameters were also observed. Pegcetacoplan was shown to have an acceptable safety profile and was generally well tolerated in both studies. PADDOCK and PALOMINO demonstrate the therapeutic potential of pegcetacoplan in the treatment of PNH and support further evaluation in the ongoing phase 3 PRINCE trial (NCT04085601) in complement inhibitor-naïve patients. Disclosures Wong: Alexion: Consultancy, Honoraria, Research Funding, Speakers Bureau; Apellis: Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau. Sathar:Novo Nordisk: Honoraria; Bayer: Honoraria; Roche: Honoraria. Tse:MSD: Research Funding; Janssen: Research Funding. Roman:Alexion: Speakers Bureau; Novartis: Speakers Bureau. Amine:Acibadem City Clinic Tokuda Hospital: Current Employment. Tan:Apellis: Consultancy, Patents & Royalties. Di Casoli:Apellis: Current Employment, Current equity holder in private company. Deschatelets:Apellis: Current Employment, Current equity holder in private company, Patents & Royalties. Francois:Apellis: Current Employment, Current equity holder in private company, Patents & Royalties. Grossi:Apellis: Current Employment, Current equity holder in private company, Patents & Royalties. Bogdanovic:Takeda (regional office in Serbia, only local activities in Serbia): Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer (regional office in Serbia, only local activities in Serbia): Membership on an entity's Board of Directors or advisory committees; Apellis: Other: Investigator fee in clinical trial; Novartis Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. OffLabel Disclosure: Pegcetacoplan is an investigational drug for the treatment of paroxysmal nocturnal hemoglobinuria

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Background:Multiple myeloma (MM) is genetically heterogeneous with varied clinical outcomes, primarily due to the coexistence of diverse numerical and structural cytogenetic abnormalities (CA). The data about prognostic significance of clonal evolution and cumulative effect of multiple high‐risk (HR) CA in complex karyotypes (CK) of MM patience (pts) is controversially.Aims:1) to make cytogenetics profiling of CK in our MM pts with first line bortezomib‐based therapy (BBT); 2) to find relationship between clonal heterogeneity in CK and therapeutic response and OS of our MM pts.MethodsWe examined the cytogenetic features in 78 pts with newly diagnosed MM using conventional cytogenetics and molecular‐genetics (for t(4;14)/MMSET‐IgH) analysis for 5 years (2014‐2018) in SBALHZ–Sofia, Bulgaria. The followed CA were considered as clinically relevant: hyperdiploidy, hypodiploidy, gap 1q, ‐13/13q‐, ‐17/17p‐, t(4;14), t(11;14). OS was calculated using Kaplan‐Meier estimates.Results:The CK was occurred in about 38% (30/78) of our pts: in 77% (23/30) with hyperdiploidy and in 23% (7/30) without it. The features of clonal evolution (2 or more aberrant cell clones) were defined in 57% (17/30) CK and predominantly were connected with hyperdiploidy (15/17). The coexistence of 2 or more adverse prognostic CA was defined in 60% (18/30) CK. The proportion of pts with normal karyotype (NK) who achieved CR and VGPR was two and half times more than in pts with CK (16,7% vs 41,7%). The autologous stem cell transplantation (ASCT) was applied at 26,7% (8/30) pts with CK and 31% (15/48) pts with NK. We have not found a statistically significant difference in the OS of our pts with signs of clonal evolution or multiple HR CA in CK compared to other CK pts. Although the mean OS of pts with HR CA or clonal heterogeneity in CK without ASCT was lower than OS of CK pts treated with ASCT, the difference in OS wasn’t statistically significant (19.0 mths vs 25.2 mths, p = 0.419). Only groups that stratified according to Mayo Stratification of Myeloma (with HR CA, intermediate‐risk CA and standard‐risk CA) had a statistically significant OS difference (p < 0,006).Summary/Conclusion:We have not found cumulative adverse effect of multiple HR CA or signs of clonal evolution in CK on OS of our MM pts.