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Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease characterized by complement-mediated hemolysis. Pegcetacoplan is the first C3-targeted therapy approved for adults with PNH (United States), adults with PNH with inadequate response or intolerance to a C5 inhibitor (Australia), and adults with anemia despite C5-targeted therapy for ≥3 months (European Union). PRINCE was a phase 3, randomized, multicenter, open-label, controlled study to evaluate the efficacy and safety of pegcetacoplan vs control (supportive care only; eg, blood transfusions, corticosteroids, and supplements) in complement inhibitor–naive patients with PNH. Eligible adults receiving supportive care only for PNH were randomly assigned and stratified based on their number of transfusions (1-g/dL decrease in hemoglobin levels without transfusions) from baseline through week 26 and lactate dehydrogenase (LDH) change at week 26. Overall, 53 patients received pegcetacoplan (n = 35) or control (n = 18). Pegcetacoplan was superior to control for hemoglobin stabilization (pegcetacoplan, 85.7%; control, 0; difference, 73.1%; 95% confidence interval [CI], 57.2-89.0; P < .0001) and change from baseline in LDH (least square mean change: pegcetacoplan, −1870.5 U/L; control, −400.1 U/L; difference, −1470.4 U/L; 95% CI, −2113.4 to −827.3; P < .0001). Pegcetacoplan was well tolerated. No pegcetacoplan-related adverse events were serious, and no new safety signals were observed. Pegcetacoplan rapidly and significantly stabilized hemoglobin and reduced LDH in complement inhibitor–naive patients and had a favorable safety profile. This trial was registered at www.clinicaltrials.gov as NCT04085601.

Background: In the PEGASUS trial, the complement C3 inhibitor, pegcetacoplan, showed superiority to eculizumab in improving haematological outcomes in adult patients with paroxysmal nocturnal haemoglobinuria and suboptimal response to eculizumab at 16 weeks. The aim of the open-label period was to evaluate the long-term efficacy and safety of pegcetacoplan through to 48 weeks. Methods: PEGASUS was a phase 3, randomised, open-label, active-comparator controlled trial conducted in 44 centres in Australia, Belgium, Canada, France, Germany, Japan, Russia, South Korea, Spain, the UK, and the USA. Eligible participants were aged 18 years or older, had paroxysmal nocturnal haemoglobinuria, and had a haemoglobin concentration of less than 10·50 g/dL after 3 months or longer of stable eculizumab treatment. After a 4-week run-in with eculizumab plus pegcetacoplan, patients were randomly assigned (1:1) by interactive response technology to pegcetacoplan (1080 mg subcutaneously twice weekly) or eculizumab (according to their regimen at enrolment) for 16 weeks and could continue to the open-label period (32 weeks of pegcetacoplan monotherapy [pegcetacoplan-to-pegcetacoplan] or 28 weeks of pegcetacoplan monotherapy [eculizumab-to-pegcetacoplan]). Randomisation was stratified by platelet count and number of previous blood transfusions. The primary endpoint was change from baseline in haemoglobin at week 16, which has previously been reported. The outcomes of the open-label period (week 16 to week 48) are reported here. At 48 weeks, efficacy (including mean haemoglobin concentration and quality of life measured on the Functional Assessment of Chronic Illness Therapy [FACIT]-Fatigue scale) was assessed in the intention-to-treat population and safety was assessed per protocol. This trial was registered with ClinicalTrials.gov, NCT03500549, and has been completed. Findings: Between June 14, 2018, and Nov 14, 2019, 80 patients were randomly assigned to receive treatment with pegcetacoplan (41 patients) or eculizumab (39 patients). Most participants were women (49 [61%]) and 31 (39%) were men; 12 (15%) were Asian, two (3%) were Black, 49 (61%) were White, and 17 (21%) were another race or did not report their race. The open-label period had 77 participants (38 pegcetacoplan-to-pegcetacoplan, 39 eculizumab-to-pegcetacoplan). Patients in the pegcetacoplan-to-pegcetacoplan group maintained high mean haemoglobin concentrations between 16 weeks (11·54 g/dL [SD 1·96]) and 48 weeks (11·30 g/dL [1·77]; p=0·14). Patients in the eculizumab-to-pegcetacoplan group had significantly greater mean haemoglobin concentrations at 48 weeks (11·57 g/dL [2·21]) versus 16 weeks (8·58 g/dL [0·96]; p

Objective Geographic atrophy (GA), a late stage of age-related macular degeneration, is a major cause of irreversible blindness. Even while central visual acuity remains relatively well preserved, GA often causes considerable compromise of visual function and quality of life. No treatment currently exists. We evaluated the safety and efficacy of pegcetacoplan (APL-2), a complement C3 inhibitor, for the treatment of GA. Design Prospective, multicenter, randomized, sham-controlled phase 2 study. Subjects 246 subjects with GA. Methods Subjects with GA were randomly assigned in a 2:2:1:1 ratio to receive intravitreal injections of 15 mg pegcetacoplan monthly or every-other-month (EOM) or sham intravitreal injections monthly or EOM, for 12 months with follow-up at months 15 and 18. Area and growth of GA were measured using fundus autofluorescence imaging. Main outcome measures The primary efficacy endpoint was mean change in square root GA lesion area from baseline to month 12. Secondary outcome measures included mean change from baseline in GA lesion area without the square root transformation, distance of GA lesion from the fovea (foveal encroachment), best corrected visual acuity (BCVA), low luminance BCVA (LL-BCVA), and low luminance visual acuity deficit (LL-VD). The primary safety endpoint was the number and severity of treatment emergent adverse events. Results In subjects receiving pegcetacoplan monthly or EOM, the GA growth rate was reduced by 29% (95% CI, 9 to 49; p=0·008) and 20% (95% CI, 0 to 40; p=0.067) compared with sham. Post-hoc analysis showed that the effect was greater in the second 6 months of treatment, with observed reductions of 45% (p=0.0004) and 33% (p=0.009) for pegcetacoplan monthly and EOM, respectively. Two cases of culture-positive endophthalmitis and one case of culture negative endophthalmitis occurred in the pegcetacoplan monthly group. New onset investigator-determined exudative AMD was reported more frequently in pegcetacoplan-treated eyes (18/86 eyes, or 20.9%, and 7/79 eyes, or 8.9%, in monthly and EOM groups, respectively) than in sham-treated eyes (1/81 eyes, or 1.2%). Conclusion Local inhibition of C3 with pegcetacoplan resulted in statistically significant reductions in the growth of GA compared with sham. Phase 3 study will further define the efficacy and safety profile.

Background Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired disease characterized by chronic complement-mediated hemolysis. C5 inhibition controls intravascular hemolysis in untreated PNH but cannot address extravascular hemolysis. Pegcetacoplan, a pegylated peptide targeting proximal complement protein C3, potentially inhibits both intravascular and extravascular hemolysis. Methods We conducted a phase 3 open-label, controlled trial to assess the efficacy and safety of pegcetacoplan as compared with eculizumab in adults with PNH and hemoglobin levels lower than 10.5 g per deciliter despite eculizumab therapy. After a 4-week run-in phase in which all patients received pegcetacoplan plus eculizumab, we randomly assigned patients to subcutaneous pegcetacoplan monotherapy (41 patients) or intravenous eculizumab (39 patients). The primary end point was the mean change in hemoglobin level from baseline to week 16. Additional clinical and hematologic markers of hemolysis and safety were assessed. Results Pegcetacoplan was superior to eculizumab with respect to the change in hemoglobin level from baseline to week 16, with an adjusted (least squares) mean difference of 3.84 g per deciliter (P Conclusions Pegcetacoplan was superior to eculizumab in improving hemoglobin and clinical and hematologic outcomes in patients with PNH by providing broad hemolysis control, including control of intravascular and extravascular hemolysis. (Funded by Apellis Pharmaceuticals; PEGASUS ClinicalTrials.gov, NCT03500549. opens in new tab.)

Context: Pegcetacoplan (PEG) is a C3 complement inhibitor recently approved by the FDA for the treatment of paroxysmal nocturnal hemoglobinuria (PNH). PEG was superior to eculizumab (ECU; C5-inhibitor) in improving hemoglobin levels at week 16 during the phase 3 PEGASUS trial (NCT03500549) in patients with suboptimal response to prior ECU treatment. Objective: We report on efficacy and safety of PEG and results from a post hoc time-aligned analysis based on start of PEG dosing. Design: Eighty PNH patients (≥18 years, hemoglobin levels Results: PEG-to-PEG patients achieved sustained improvements in hemoglobin levels at week 16 through the OLP (week 48 mean hemoglobin level: 11.3 g/dL; CFB: 2.5 g/dL). ECU-to-PEG patients displayed improved hemoglobin levels during the OLP (week 48 mean hemoglobin level: 11.6 g/dL; CFB: 2.9 g/dL). Timepoint alignment demonstrated no significant difference (p=0.64) between improvements in hemoglobin levels at 28 and 48 weeks among PEG-to-PEG and ECU-to-PEG groups, respectively. Thirty percent of patients reported a serious AE, 6% possibly PEG-related. Common AEs for PEG-treated patients were injection site reactions (36%), hemolysis (24%), and diarrhea (21%). Twelve patients (15%) discontinued PEG due to AEs: 3 in RCP, 8 in OLP, 1 during follow-up, including one death due to COVID-19, unrelated to PEG. Conclusions: PEG-treated patients experienced sustained improvements in hemoglobin levels at week 48, and the safety profile of PEG was consistent with previously reported data. The treatment effect of PEG on hemoglobin levels over time was similar between PEG-to-PEG and ECU-to-PEG groups. Thus, PEG represents a new effective therapeutic option for PNH patients.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired, life‐threatening hematologic disease characterized by chronic complement‐mediated hemolysis and thrombosis. Despite treatment with eculizumab, a C5 inhibitor, 72% of individuals remain anemic. Pegcetacoplan (APL‐2), a PEGylated C3 inhibitor, has the potential to provide more complete hemolysis control in patients with PNH. This open‐label, phase Ib study was designed to assess the safety, tolerability, and pharmacokinetics of pegcetacoplan in subjects with PNH who remained anemic during treatment with eculizumab. Pharmacodynamic endpoints were also assessed as an exploratory objective of this study. Data are presented for six subjects in cohort 4 who received treatment for up to 2 years. In total, 427 treatment‐emergent adverse events (TEAEs) were reported, 68 of which were possibly related to the study drug. Eight serious TEAEs occurred in two subjects; three of these events were considered possibly related to the study drug. Pegcetacoplan pharmacokinetic concentrations accumulated with repeated dosing, and steady state was reached at approximately 6‐8 weeks. Lactate dehydrogenase levels were well controlled by eculizumab at baseline. Pegcetacoplan increased hemoglobin levels and decreased both reticulocyte count and total bilirubin in all six subjects. Improvements were observed in Functional Assessment of Chronic Illness Therapy Fatigue scores. Two subjects discontinued for reasons unrelated to pegcetacoplan. All four subjects who completed the study transitioned to pegcetacoplan monotherapy following eculizumab discontinuation and avoided transfusions. In this small study, pegcetacoplan therapy was generally well‐tolerated, and resulted in an improved hematological response by achieving broad hemolysis control, enabling eculizumab discontinuation.

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and life-threatening disease characterized by hemolysis and thrombosis. Many patients with PNH use C5-inhibitors (i.e., eculizumab/ravulizumab) to control their symptoms. Although C5-inhibition prevents intravascular hemolysis (IVH), it fails to prevent extravascular hemolysis (EVH). Because of persistent EVH, up to 72% of eculizumab-treated patients remain anemic, and up to 36% require at least one transfusion per year. Pegcetacoplan (PEG), a C3-inhibitor recently approved by the US FDA to treat adults with PNH, controls IVH and prevents EVH. Studies of PEG treatment in patients with PNH that remained anemic despite eculizumab treatment demonstrated that PEG was superior to eculizumab in achieving improvements in hemoglobin (Hb) levels (Hillmen P, et al., N Engl J Med, 2021 384 (11):1028-1037). Additionally, two early phase open-label trials demonstrated the efficacy of PEG in complement-inhibitor naïve patients with PNH (Wong RS, et al., Blood, 2020 136 [Supplement 1]). Aims: To present results from the Phase 3 PRINCE study (NCT04085601), a multicenter, randomized, open-label, controlled study evaluating the efficacy and safety of PEG compared to standard of care (SOC; excluding complement-inhibitors) in complement-inhibitor naïve patients with PNH. Methods: Fifty-three adult (≥18 years old), complement-inhibitor naïve (no complement-inhibitor treatment [i.e., eculizumab/ravulizumab] within 3 months prior to screening) patients with PNH and Hb levels below the lower limits of normal (males: ≤13.6 g/dL; females: ≤12.0 g/dL), and lactate dehydrogenase (LDH) levels ≥1.5 times the upper limit of normal (1.5x ULN; ≥339 U/L) were enrolled. Patients were randomized 2:1 to receive PEG (1080 mg subcutaneously twice weekly [n=35]) or SOC (excluding complement-inhibitors eculizumab/ravulizumab [n=18]) through Week 26. Patients on SOC had the option to switch to the PEG group if their Hb decreased by ≥2 g/dL from baseline. Co-primary endpoints were Hb stabilization (avoidance of a >1 g/dL decrease in Hb levels in the absence of transfusions) and change from baseline (CFB) in LDH level from baseline to Week 26. Secondary endpoints included CFB in Hb levels, transfusion avoidance (defined as the proportion of subjects who did not require a transfusion through Week 26), and the incidence of adverse events (AEs). Statistical analyses were performed using the Cochran-Mantel-Haenszel test and ANCOVA model. Results: PEG was superior to SOC in both co-primary endpoints. Hb stabilization was achieved by 85.7% (n=30) of PEG-treated patients and 0.0% of SOC patients through Week 26 (p Conclusions: Patients with PNH that were naïve to complement-inhibitor treatment demonstrated meaningful hematological and clinical improvements following 26 weeks of PEG treatment. The safety profile of PEG was similar to previous study results and represent a favorable risk-benefit profile. These results provide evidence for the safety and efficacy of PEG treatment in complement-inhibitor naïve patients with PNH. Figure 1 Figure 1. Disclosures Wong: Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Apellis Pharmaceuticals: Research Funding, Speakers Bureau; Alexion: Consultancy, Honoraria, Research Funding, Speakers Bureau. Al-Adhami: Apellis Pharmaceuticals: Current Employment. Ajayi: Apellis Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Alvarenga: Apellis Pharmaceuticals: Consultancy. Deschatelets: Apellis Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Francois: Apellis Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Grossi: Apellis Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company.

Background: The complement cascade is part of innate immunity and is involved in multiple inflammatory processes and implicated in several diseases. Pegcetacoplan (PEG) is a pegylated, cyclic peptide that binds to complement protein C3 and is a broad inhibitor of the complement cascade. Subcutaneous (SC) dosing of PEG has demonstrated efficacy in the treatment of chronic conditions, such as paroxysmal nocturnal hemoglobinuria (PNH) and was recently approved by the FDA for the treatment of PNH in adults. Intravenous (IV) PEG administration may allow for more rapid and robust reduction of uncontrolled complement activation, especially in an acute setting, such as an acute hemolytic episode in PNH. Aims: To determine the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of IV PEG in acetate-buffered saline treatment in a Phase 1 single ascending dose study (ACTRN12616000700437) in healthy subjects. Methods: On Day 1, four cohorts with PEG doses (200mg, 600mg, 1500mg, 2300mg) received a single bolus of PEG IV (or matching placebo) administered over 30min. Blood samples for PK analyses of PEG concentration and PD analyses of alternative complement pathway hemolytic activity (AH50), total complement hemolytic activity (CH50), C3 and C3a levels were collected at 15, 30, and 60min, 4, 8, 12, and 24hrs, and Days 3, 4, 5, 6, 7, 8, 15, 22, 29, and 43. Subjects were monitored during a safety period from Day 2 to 8 by physical examination, ECG, hematology, serum chemistry, monitoring for injection site reaction and treatment emergent adverse events (TEAEs). Follow-up safety assessments were performed on Days 15, 22, 29, and 43. Results: Twenty subjects were enrolled and allocated 4:1 to PEG or placebo per cohort (PEG-200mg, n=4; PEG-600mg, n=4; PEG-1500mg, n=4; PEG-2300mg, n=4; pooled placebo, n=4). Following a single IV dose, peak concentration (C max) of PEG was observed at 1hr post-dose (infusion start) for most cohorts (mean serum concentration: PEG-200mg, 61μg/mL; PEG-600mg, 193μg/mL; PEG-2300mg, 708μg/mL) except PEG-1500mg (occurred at 4hrs, 542μg/mL). PEG concentration at the end of infusion was similar to the observed C max. PEG concentration declined in a mono-exponential manner, with a terminal elimination half-life ranging from 200 to 285 hrs (Figure). Total body clearance of PEG after IV administration was similar across cohorts. Early, immediate decreases in mean AH50 values were detected within 1hr in all PEG cohorts, with 1500 and 2300mg doses decreasing AH50 to undetectable levels (Figure). Decreases in mean AH50 values were maintained for at least 12, 72, 144 and 168hrs after single doses of 200, 600, 1500 and 2300mg PEG, respectively. All PEG groups had an initial rapid decrease within 1hr in mean C3a levels, with all dose groups having trough mean C3a levels within 24hrs of dosing. Dose related decreases in mean C3a were not observed, all doses recorded a max mean decrease of 47% to 57%. No changes seen with placebo for C3a. C3 and CH50 results will be forthcoming. Of the twenty subjects included in the study, 11 (55.0%) experienced a treatment-related adverse event (TEAE). The most common TEAEs in the PEG group were headache, (n=6, 37.5%); upper respiratory infections attributed to seasonal viral infection (n=2, 12.5%); diarrhea (n=2, 12.5%). No serious adverse events, deaths, or severe TEAEs occurred. One subject (5.0%) in the PEG-2300mg cohort experienced a moderate TEAE (infusion-related reaction, dizziness, clamminess, nausea) that led to study discontinuation. Conclusions: These results suggest that administration of IV PEG in a sodium acetate solution has a favorable safety profile and effectively increases PEG serum concentrations while decreasing complement activity within the first hour post-dose in healthy subjects. Although the safety and efficacy of SC PEG treatment has been demonstrated in patients with PNH, IV PEG administration could serve as a useful therapeutic option for patients with a need for rapid control of complement activity. While this formulation is different than the commercially available PEG (EMPAVELI), which is administered SC and is suspended in sorbitol, the results suggest that IV PEG is well tolerated and provides the grounds for future investigations of IV PEG administration. Figure 1 Figure 1. Disclosures Grossi: Apellis Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Yeh: Apellis Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Xu: Apellis Pharmaceuticals: Current Employment. Deschatelets: Apellis Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. OffLabel Disclosure: Pegcetacoplan, a subcutaneously administered C3-inhibitor that was recently approved by the US FDA for the treatment of PNH, controls IVH and prevents EVH. While subcutaneous pegcetacoplan is safe and effective, the aim of this study was to determine the safety, pharmacokinetics, and pharmacodynamics of IV pegcetacoplan in acetate-buffered saline treatment, different from current FDA approved formulation.

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 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

BACKGROUND In paroxysmal nocturnal hemoglobinuria (PNH), intravascular hemolysis (IVH) is mediated by the membrane attack complex, while extravascular hemolysis (EVH) is facilitated by C3 opsonization. Although eculizumab (ECU), a C5 inhibitor, inhibits IVH, ~70% of patients remain anemic and 36% require ≥1 transfusion per year due to C3-mediated EVH. Pegcetacoplan (APL-2), a C3 inhibitor, has the potential to control both IVH and EVH in PNH. AIMS PEGASUS, a phase 3, randomized, open-label, controlled trial (NCT03500549), assessed the efficacy and safety of pegcetacoplan compared to ECU in patients with PNH. METHODS Eighty patients aged ≥18 years with a confirmed diagnosis of PNH, hemoglobin levels 1.0 × ULN, platelets >50 × 109/L and neutrophils >0.5 × 109/L were included. All patients provided written informed consent and completed a run-in period of 4 weeks with pegcetacoplan plus ECU before 1:1 randomization to monotherapy with pegcetacoplan (41 patients, 1080 mg subcutaneously twice a week) or ECU (39 patients, continuing current dosing regimen). The primary endpoint was change in hemoglobin level from baseline (start of run-in period) to week 16. Key secondary and secondary endpoints were hemoglobin normalization (defined as hemoglobin level greater than or equal to lower limit of normal range) in the absence of transfusions, transfusion avoidance, absolute reticulocyte counts, lactate dehydrogenase (LDH), Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score, and adverse events (AEs). Hierarchical significance testing for secondary efficacy endpoints was gated on the success of the primary efficacy endpoint. Post hoc analyses included hemoglobin stabilization (defined as avoidance of a >1 g/dL decrease from baseline) in the absence of transfusions. RESULTS Pegcetacoplan demonstrated superiority to ECU in change in hemoglobin level at week 16, with an adjusted treatment difference of 3.84 g/dL (p CONCLUSIONS In this phase 3 trial in patients with PNH, pegcetacoplan demonstrated superiority to ECU in hemoglobin level, and improved clinical outcomes at week 16 with transfusion avoidance in most patients. The safety profile of pegcetacoplan was comparable to that of ECU. The efficacy of pegcetacoplan validates the prevention of extravascular as well as intravascular hemolysis in PNH, leading to a potential new therapeutic option. Disclosures Hillmen: Acerta: Other: Financial or material support; AbbVie: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; Roche: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; Gilead: Other: Financial or material support, Research Funding; Alexion: Consultancy, Research Funding, Speakers Bureau; Apellis: Consultancy, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Speakers Bureau; Pharmacyclics: Other: Financial or material support, Research Funding; Janssen: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau. Szer:Prevail Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Apellis: Consultancy; Takeda: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Weitz:Apellis: Consultancy, Honoraria; Alexion: Consultancy, Honoraria, Speakers Bureau. Röth:Biocryst: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Apellis: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Research Funding. Hoechsmann:Alexion: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Apellis: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Panse:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Apellis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Speakers Bureau; Alexion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Membership on an entity's Board of Directors or advisory committees; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees; Grunenthal: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai: Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Blueprint Medicines: Consultancy, Membership on an entity's Board of Directors or advisory committees. Usuki:Apellis: Research Funding; Chugai: Research Funding; Novartis: Research Funding, Speakers Bureau; Alexion: Research Funding, Speakers Bureau. Griffin:Biocryst: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals: Honoraria, Other: Conference Support. Kiladjian:Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. de Castro:Biocryst: Honoraria, Other: Data monitoring committee; Novartis: Honoraria, Other: Steering committee; Alexion: Honoraria, Research Funding; Apellis: Consultancy, Honoraria, Research Funding. Tan:Apellis: Consultancy, Patents & Royalties. Hamdani:Apellis: Current Employment, Current equity holder in publicly-traded 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. Risitano:Jazz: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; 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; Apellis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Achillion: Membership on an entity's Board of Directors or advisory committees; Pfizer: Speakers Bureau; 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. Peffault De Latour:Apellis: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Pfizer: 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; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. OffLabel Disclosure: Pegcetacoplan is an investigational drug for the treatment of paroxysmal nocturnal hemoglobinuria.

Context Anemia persists in up to 72% of patients with paroxysmal nocturnal hemoglobinuria (PNH) despite the inhibition of C5 with eculizumab. Pegcetacoplan, a C3 inhibitor, has the potential to control both intravascular (IVH) and extravascular hemolysis (EVH). Objective The phase 3, randomized, open-label, controlled PEGASUS trial ( NCT03500549 ) assessed efficacy and safety of pegcetacoplan compared to eculizumab in patients with PNH. Patients, Interventions, Main Outcome Measures Patients aged ≥18 years with PNH and hemoglobin Results Pegcetacoplan demonstrated superiority to eculizumab in change in hemoglobin at week 16, with an adjusted treatment difference of 3.84 g/dL (p Conclusions In this phase 3 trial in patients with PNH and suboptimal response to eculizumab, pegcetacoplan demonstrated superiority to eculizumab in change in hemoglobin level at week 16 with improved clinical outcomes including transfusion avoidance in most patients. The safety profile of pegcetacoplan was comparable to eculizumab.

Background: Autoimmune hemolytic anemia (AIHA) is a rare autoimmune disease characterized by hemolysis mediated by autoantibodies directed against red blood cells (RBC). AIHA is classified as either warm (60-70%), or cold agglutinin disease (CAD, 20-25%), depending upon the temperature at which the autoantibodies show maximum binding. Warm AIHA is mediated by warm reactive autoantibodies, which are usually of the immunoglobulin G class (IgG). Almost 90% of CAD is medicated by monoclonal antibodies of IgM class. The diagnosis of wAIHA or CAD is based on the presence of hemolytic anemia, signs of hemolysis, and a positive direct antiglobulin test (DAT) for IgG or IgM, and/or complement C3. Complement plays an important role in warm antibody AIHA. When erythrocytes are heavily coated with immunoglobulin, the amount of antigen-antibody complex can be sufficient for binding complement protein complex C1, thereby activating the classical complement pathway. CAD is almost entirely a complement-dependent disorder. Cold antibodies (IgM) temporarily bind to the RBC membrane, activate complement, and deposit complement factor C3 on the cell surface. These C3-coated RBCs are cleared slowly by the macrophages of the liver through extravascular hemolysis. Less frequently, the complete complement cascade is activated on the cell surface, resulting in the insertion of membrane attack complex C5b to C9 and intravascular hemolysis. Therefore, treatment with inhibitors of complement cascade may halt or at least attenuate acute complement mediated hemolysis in AIHA patients and improve recovery of RBC destruction. Aims: This Phase 2, open-label study is being conducted in the US and Italy to assess the safety, tolerability, efficacy, and PK of multiple subcutaneous (SC) doses of APL-2 administered daily in subjects with wAIHA or CAD. Methods: Patients with primary AIHA are eligible. Patients are required to have hemoglobin (Hb) levels Results: 2 subjects with CAD (Subject 1: 270 mg/d; Subject 2: 360 mg/d) have been treated for at least 8 weeks and up to 12 weeks; 2 subjects with wAIHA (Subject 3: 270 mg/d; Subject 4: 360 mg/d) have been treated for at least 4 weeks. Subject 1 screened with Hb (NR 13.5 g/dL-17.5g/dL) of 10.0 g/dL and reported an increase to 13.0 g/dL at Week 12, with reticulocyte (NR 30-100 10^9/L) reduction from 99.6 10^9/L at Week 2 to 56.34 10^9/L at Week 8 (screening/baseline values not available). Subject 2 had baseline Hb of 7.9 g/dL and reported an increase to 13.6 g/dL at Week 8, with reticulocyte reduction from 154.34 10^9/L at baseline to 67 10^9/L at Week 8. Subject 3 had baseline Hb of 8.0 g/dL and reported an increase to 11.2 g/dL at Week 4, with reticulocyte reduction from 223.44 10^9/L at baseline to 27.12 10^9/L at Week 4. Subject 4 did not show signs of haematological improvement by Week 4, and the principal investigator decided to discontinue the subject at Day 42. Subject 1 had LDH levels within the normal range (100-200 I/U) at screening and remained normal through the study. Subjects 2 reported a baseline LDH of 339 I/U with a reduction to within NR to 107 I/U at Week 8. Subject 3 reported a baseline LDH of 235 I/U, which was also reduced to within NR at Week 4 to 123 I/U. Subject 1 had consistent indirect bilirubin (NR 0.2-0.7 mg/dL) through the study with a baseline value of 1.5 mg/dL and a Week 12 value of 1.4 mg/dL. Subject 2 had a reduction in indirect bilirubin with a baseline value of 1.3 mg/dL and a Week 8 value of 0.5 mg/dL.To date, APL-2 has generally been well-tolerated. No significant infections have been observed. Summary/Conclusions: Interim results demonstrate that systemic inhibition of C3 with APL-2 has demonstrated positive trends in haematological parameters in patients with wAIHA and CAD as early as Week 4. To date, APL-2 has been safe and well tolerated. The study is ongoing and will enroll up to 12 subjects with wAIHA and 12 subjects with CAD. Disclosures Grossi: Apellis Pharmaceuticals: Employment, Equity Ownership. Gertz:spectrum: Consultancy, Honoraria; Medscape: Consultancy; Amgen: Consultancy; Physicians Education Resource: Consultancy; Apellis: Consultancy; Teva: Consultancy; Alnylam: Honoraria; Prothena: Honoraria; janssen: Consultancy; Ionis: Honoraria; Research to Practice: Consultancy; celgene: Consultancy; Abbvie: Consultancy; annexon: Consultancy. Deschatelets:Apellis Pharmaceuticals: Employment, Equity Ownership. Hamdani:Apellis Pharmaceuticals: Employment, Equity Ownership. Stout:Apellis Pharmaceuticals: Employment, Equity Ownership. Francois:Apellis Pharmaceuticals: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Background: PNH is characterized by a degree of bone marrow failure and hemolysis resulting in debilitating hemolytic anemia and an increased risk of thrombosis. Uncontrolled complement activation leads to intravascular hemolysis mediated by the membrane attack complex and extravascular hemolysis mediated by accumulation of C3 fragments, such as C3b, at the cell surface. The only approved treatment for PNH is Soliris®, a C5 inhibitor which targets intravascular hemolysis however, a significant number of patients treated with Soliris® continue to experience ongoing anemia and its associated symptoms. Due to the key role of C3 in the complement cascade, upstream of C5, APL-2, a cyclic peptide inhibitor of C3, acts to prevent both intravascular and extravascular hemolysis. To our knowledge these data represent the first time that PNH patients have experienced significant increases in haemoglobin (Hb) combined with normalisation of lactate dehydrogenase (LDH), absolute reticulocyte count (ARC) and total bilirubin. Aims: This Phase Ib open-label, dose-escalation study being conducted in New Zealand, Thailand, Malaysia and Hong Kong was designed to assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of multiple doses of APL-2, administered by daily subcutaneous injection (SC), in patients with PNH. Methods: To be eligible for entry, PNH patients are required to have Hb levels < 105 g/L (normal range [NR] 119-180), LDH levels >2 times upper limit of normal (x ULN) at screening and have received ≥ 1 blood transfusion in the prior 12 months. The study will recruit 3 subjects into Cohort 1 and up to 20 subjects in Cohort 2 receiving 180 mg/d or 270 mg/d of APL-2, respectively. Efficacy is assessed by change from baseline in Hb, LDH, ARC, total bilirubin and transfusion requirements. Change from baseline in FACIT fatigue score is also reported. Results: As of 24 July 2018, Cohort 1 has been fully recruited and 17 subjects have been dosed in Cohort 2. Of the 17 subjects dosed in Cohort 2, 15 have been treated with APL-2 for >28 days and 9 have been treated for >84 days. Data is summarized for 14 (and 10) subjects in Cohort 2 who have received 270 mg/d of APL-2 for at least 28 (and 84) days; not included in the summary are 2 subjects who have not yet reached Day 28 and one subject who had underlying metastatic ovarian cancer with a chronic low gastrointestinal bleed, unknown at time of screening, resulting in artificially low Hb and high LDH levels determined to be unrelated to PNH. Baseline Hb was 84 g/L (range 55-110) which increased to 110 (74-135) and 116 (71-145) g/L at Days 29 and 85 respectively, representing a mean increase in Hb of 29 g/L and 33 g/L. At Day 29, Hb levels had increased in 100% of subjects with 57% achieving levels within the normal range. Hb increases were maintained in the 10 subjects with Day 85 data available. In the 12 months prior to APL-2 dosing, subjects received a total of 67 transfusions (average 4.8 per year per patient; range 0 to 15). Except for 2 subjects, each of whom received a single transfusion within the first two weeks of treatment i.e. before APL-2 had reached steady state concentration, no transfusions have been reported for any patient during the APL-2 treatment period. Mean baseline LDH of 2459 I/U (9.8x ULN) was reduced to 197 I/U (0.8x ULN) by Day 29. Mean baseline ARC and total bilirubin were reduced from 193 to 89 10^9/L (NR 30-100 10^9/L) and 39 umol/L to 10 umol/L (NR 3-15 umol/L), respectively. Of the 14 subjects, 13 (92%) had LDH and bilirubin within the normal range, and 11 (79%) had ARC in the normal range at Day 29. The Figure shows mean +/- SE for all available data for the 14 subjects through to Week 12. To date, APL-2 has been well-tolerated. No significant infections or thromboembolic events have been observed. One subject was withdrawn from the study due to progression of aplastic anemia related to underlying PNH. In clinical trials in PNH patients more than 5000 SC doses of APL-2 ≥ 270 mg/day have been administered, representing a cumulative systemic exposure of >700 patient weeks of APL-2 treatment. Summary/Conclusions: We demonstrate that systemic inhibition of C3 with APL-2, controls both intravascular and extravascular hemolysis in patients with PNH as shown by significant reductions in LDH, total bilirubin and ARC. Broad control of hemolysis leads to significant and sustained increases in Hb in the absence of transfusions. APL-2 was safe and well tolerated. Disclosures Wong: Alexion: Honoraria. Deschatelets:Apellis Pharmaceuticals: Employment, Equity Ownership. Francois:Apellis Pharmaceuticals: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Hamdani:Apellis Pharmaceuticals: Employment, Equity Ownership. Johnson:Apellis Pharmaceuticals: Consultancy, Equity Ownership. Tan:Apellis Pharmacueticals: Consultancy. Tse:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; MSD: Research Funding; Roche Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees. Grossi:Apellis Pharmaceuticals: Employment, Equity Ownership.

The surgical techniques necessary to transplant a human face are well established, and the early success of human hand transplants suggests that the immunological hurdles of transplanting human facial tissues have largely been overcome. Therefore, it is the ethical barriers that pose the greatest challenge to performing facial transplantation. At the center of the ethical debate is the question, "Do the risks posed by the life-long immunosuppression that a recipient would have to take justify the benefits of receiving a face transplant?" In this study, the authors answer this question by assessing the degree of risk individuals would be willing to accept to receive a face transplant.To quantitatively assess risks versus benefits in facial transplantation, the authors developed the Louisville Instrument for Transplantation, or LIFT, which contains 237 standardized questions. Respondents in three study populations (healthy individuals, n = 150; organ transplant recipients, n = 42; and individuals with facial disfigurement, n = 34) were questioned about the extent to which they would trade off specific numbers of life-years, or sustain other costs, in exchange for receiving seven different transplant procedures.The authors found that the three populations would accept differing degrees of risk for the seven transplant procedures. Organ transplant recipients were the most risk-tolerant group, while facially disfigured individuals were the least risk tolerant. All groups questioned would accept the highest degree of risk to receive a face transplant compared with the six other procedures.This study presents an empirical basis for assessing risk versus benefit in facial transplantation. In doing so, it provides a more solid foundation upon which to introduce this exciting new reconstructive modality into the clinical arena.

BACKGROUND The role of lymph nodes (LNs) in adaptive immune responses has been the subject of extensive research. In previous studies, the surgical removal of lymph nodes from rat hind limbs prevented the development of lethal graft-versus-host disease (GVHD) after allogeneic hind limb transplantation to chimeric recipient rats. The purpose of this study was to establish the role of the cellular fraction versus the microenvironment of LNs in the development of GVHD in this model. METHODS A rat model for vascularized LN transplantation was developed and graft-versus-host responses were compared after: 1) naive ACI LN cells were infused into Wistar-Furth (WF) rats as chimeric recipients (e.g. [ACI-->WF]); 2) vascularized WF lymph nodes were transplanted to syngeneic WF recipients; 3) nonvascularized ACI lymph nodes were transplanted to [ACI-->WF] chimeric recipients; 4) vascularized ACI lymph nodes were transplanted to [ACI-->WF] chimeric recipients. RESULTS Transplantation of vascularized ACI lymph nodes to [ACI-->WF] chimeric recipient rats resulted in severe and sometimes lethal GVHD. In contrast, neither the infusion of purified ACI LN cells nor the transplantation of nonvascularized LNs led to GVHD in chimeric recipients. CONCLUSIONS When introducing allogeneic cells into chimeric recipients, concomitant transplantation of the vascularized LN microenvironment makes a manifest difference between induction and absence of GVHD. This illustrates the important role of the LN microenvironment in adaptive immune responses.

Purpose Twenty-four hands have been transplanted in 18 individuals and clinicians continue to debate whether the risks justify the benefits in these procedures. To assess quantitatively the risks versus benefits in hand transplantation we used a validated instrument (Louisville Instrument for Transplantation) to measure the degree of risk individuals are willing to accept to receive different types of transplantation procedures. Methods The Louisville Instrument for Transplantation contains 237 standardized questions that incorporate modified standard gamble and time trade-off outcome measures and questions that assess body image perception, depression, self-esteem, optimism, socially desirable responding, and demographics. Respondents were questioned on the extent to which they would trade off specific numbers of life-years or sustain other costs in exchange for receiving 7 different transplantation procedures. For this study we questioned 227 individuals in 4 study populations with differing life experiences: healthy individuals, organ transplant recipients, upper-extremity amputee patients, and lower-extremity amputee patients. Results All populations questioned perceived risk similarly despite their differing life experiences and would accept differing degrees of risk for the different transplantation procedures. Organ transplant recipients were the most risk-tolerant group whereas upper-extremity amputee patients were the most risk adverse, even when considering a single hand transplant. All groups that were questioned would accept a higher degree of risk to receive a double versus a single hand transplant. Conclusions By questioning individuals who have experienced directly the risks of immunosuppression and those who could benefit from hand transplantation, this study presents an empiric basis for assessing risk versus benefit in this procedure.

Main Response Topics • Introduction • Open display and public evaluation • Publicity versus patient privacy • Facial tissue donation • Validity of Louisville Instrument for Risk Acceptance • Patients' understanding of risk • Face versus hand transplantation • Rejection rates/risks • Patient compliance • Exit strategy • Functional recovery • Societietal implications • Psychological implications • Conclusion: Uncertainty likely to persist

Transplantation continues to push the frontiers of medicine into domains that summon forth troublesome ethical questions. Looming on the frontier today is human facial transplantation. We develop criteria that, we maintain, must be satisfied in order to ethically undertake this as-yet-untried transplant procedure. We draw on the criteria advanced by Dr. Francis Moore in the late 1980s for introducing innovative procedures in transplant surgery. In addition to these we also insist that human face transplantation must meet all the ethical requirements usually applied to health care research. We summarize the achievements of transplant surgery to date, focusing in particular on the safety and efficacy of immunosuppressive medications. We also emphasize the importance of risk/benefit assessments that take into account the physical, aesthetic, psychological, and social dimensions of facial disfiguration, reconstruction, and transplantation. Finally, we maintain that the time has come to move facial transplantation research into the clinical phase.

Composite tissue allotransplantation (CTA) has recently emerged as a new therapeutic modality to reconstruct major tissue defects of the face, larynx, and extremities. However, because the risk-versus-benefit ratio for CTA procedures has not yet been defined, the decision as to whether or not to perform these new reconstructive techniques is based on subjective opinions rather than objective data. To address this problem, the authors developed a reliable and valid instrument to objectively assess the relative risk that individuals are willing to accept in order to receive the benefits of various CTA procedures.

Background Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, potentially life-threatening disease characterized by complement-mediated hemolytic anemia. PNH arises from a somatic mutation resulting in impairment of an anchor protein responsible for the expression of numerous proteins at the cell surface of the red blood cells, including CD55 and CD59, two complement inhibitory proteins. The subsequent uncontrolled activation of the complement system leads to both intravascular hemolysis triggered by the membrane attack complex (MAC) and extravascular hemolysis, or cell opsonization, mediated by C3b accumulation at the cell surface. Eculizumab, an anti-C5 antibody, is available as a treatment for PNH, however some patients continue to be transfusion-dependent as a result of on-going activation of C3, upstream of C5. Due to the key position of C3 in the complement cascade, APL-2, a cyclic peptide inhibitor of C3, may prevent both intravascular and extravascular hemolysis and could therefore be potential treatment for PNH and beneficial for patients still requiring transfusions despite standard of care treatment. Aims These initial phase I studies were designed to assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single and multiple doses of APL-2 administered by subcutaneous injection (SC) in healthy adult volunteers. Methods Both studies were conducted at a single center (Australia) and were double-blind, placebo-controlled designs. Subjects were monitored for up to 43 days following single dosing and 84 days following multiple dosing. Safety was assessed by intensive clinical monitoring. Serial blood sampling was performed for the determination of APL-2 concentrations in serum. Blood samples were also obtained to determine relevant markers of complement activity (C3, CH50 and AP50). Additional relevant PD markers (intact C3, iC3b, C3a, C4a and C5a) were measured in latter Cohorts. Prior to multiple dosing subjects received Neisseria meningitides, Streptococcus pneumoniae, and Haemophilus influenzae Type B (Hib) vaccinations. Results In total 51 subjects were enrolled into the two studies. Twenty-four subjects received APL-2 as a single dose (ranging from 45 to 1,440mg) and 7 subjects received placebo. Sixteen subjects received repeated daily doses of APL-2 for 28 consecutive days (ranging from 30 to 270 mg/day) and 4 subjects received placebo. There were no serious adverse events (SAE's), treatment emergent adverse events (TEAEs) leading to study drug discontinuation, or severe adverse events reported. There were no clinically relevant changes in vital signs, ECG findings or safety laboratory tests. Following single and multiple doses APL-2 exposure increased linearly with increasing dose up to the highest doses tested and APL-2 serum concentrations were close to steady-state after 28 days of daily dosing. A reduction in AP50 was seen following a single dose of 1440mg APL-2 and following multiple daily doses of 180 and 270 mg. Conclusion The studies concluded that pharmacological doses of APL-2 were safe and well tolerated and that APL-2's PK/PD profile supports daily SC administration. In addition, daily APL-2 doses of 180mg and 270mg significantly reduced hemolytic activity as early as eight days after the start of dosing, and this inhibition was maintained through the dosing period. PK data from these studies has been used to develop a PK/PD model which has been used to aid dose selection in the subsequent studies in PNH patients. Disclosures Grossi: Apellis Pharmaceuticals Inc: Employment, Equity Ownership. Bedwell:Apellis Pharmaceuticals Inc: Consultancy. Deschatelets:Apellis Pharmaceuticals Inc: Employment, Equity Ownership. Edis:Apellis Pharmaceuticals Inc: Employment, Equity Ownership. Francois:Revon Systems Inc: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Liberate Medical Inc: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Apellis Pharmaceuticals Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Johnson:Apellis Pharmaceuticals Inc: Consultancy. Richardson:Apellis Pharmaceuticals Inc: Consultancy. Tan:Apellis Pharmaceuticals Inc: Consultancy. Vega:Apellis Pharmaceuticals Inc: Employment, Equity Ownership.

Background: The immunosuppressant FK506 has been reported to increase the rate of peripheral nerve regeneration in nerve crush injury and nerve allograft models. The purpose of this study was to determine whether low doses of FK506 and mycophenolate mofetil had a neuroregenerative effect in revascularized peripheral nerve allografts in a rat hind limb transplantation model. Methods: Wistar Furth rat recipients received limbs from syngeneic Wistar Furth donors (group 1, n = 4) or from allogeneic August X Copenhagen Irish rat donors (group 2, n = 6). Wistar Furth recipients received limbs from August X Copenhagen Irish donors and were treated with FK506/mycophenolate mofetil for 5 months (group 3, n = 7). At the end of the follow-up period, histomorphometric analysis of sciatic and tibial nerves from transplanted and intact hind limbs was conducted. Sciatic and tibial nerves were examined at the level of coaptation and near the neuromuscular junction, respectively. Results: Transplanted limbs in groups 1 and 3 completed the study without rejection, while the limbs in group 2 were rejected within a few days. Sciatic and tibial nerve analysis in groups 1 and 3 limbs showed myelinated axons of various diameters but in significantly fewer numbers than in nontransplanted contralateral nerves. The number and size of myelinated axons of transplanted nerves at corresponding levels were not significantly different between syngeneic and allogeneic (FK506/mycophenolate mofetil–treated) transplants. Conclusions: The authors conclude that long-term neuroregeneration of revascularized peripheral nerves using low-dose FK506/mycophenolate mofetil was similar to that of syngeneic transplants. The occurrence of acute rejection episodes with low-dose FK506/mycophenolate mofetil did not appear to benefit nor impair neuroregeneration.

Age related macular degeneration (AMD) is the leading cause of irreversible vision loss and blindness. It is a complex disease whose molecular basis of pathogenesis is poorly understood. Many studi...

Background: The time course of the late phase of ischemic preconditioning (IPC) was determined in latissimus dorsi muscle (LDM) flaps using viability and function as the endpoints. Materials and Methods: LDM flaps from Sprague-Dawley rats were allocated into 6 groups. LDMs were preconditioned with 2 30-minute periods of ischemia separated by 10 minutes of reperfusion and subjected to a 4-hour ischemic insult after 24, 48, 72, and 96 hours from IPC. LDMs were evaluated for percent necrosis and muscle contractile function and compared with controls. Results: The late phase of IPC provides significant protection against necrosis up to 72 hours. Conversely, when the end point used was muscle contractile function, the protection only lasted 48 hours. Conclusion: The time course of late-phase protection in skeletal muscle is 2-3 days. Late phase IPC appears to protect muscle flaps during the most critical time period following elevation.

METHODS: Microvascular EC were exposed to up to 8 hours of either SS at 14 dynes/cm2, or CS at 60 cycles per minute 24% maximal strain. Lysates were studied for the expression and activity of PKC-z through immunoblotting analysis and by performing activity assays in which lysates were immunoprecipitated, labeled with the isotope gamma-32P, and then analyzed using liquid scintillation spectroscopy.

INTRODUCTION: In the US it is estimated that more than 1.2 million partial or complete limb amputations per year cannot be saved because of excessive ischemia time. The purpose of this study was to determine whether perfusion with a novel fusogenic lipid vesicle (FLV) that delivers magnesium adenosine triphosphate (Mg-ATP) directly into cells could maintain amputated limbs viable after prolonged warm ischemia.