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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).

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.

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

Iron deficiency anemia (IDA) is common in many chronic diseases, and intravenous (IV) iron offers a rapid and efficient iron correction. This trial compared the efficacy and safety of iron isomaltoside (also known as ferric derisomaltose) and iron sucrose in patients with IDA who were intolerant of, or unresponsive to, oral iron. The trial was an open‐label, comparative, multi‐center trial. Five hundred and eleven patients with IDA from different causes were randomized 2:1 to iron isomaltoside or iron sucrose and followed for 5 weeks. The cumulative dose of iron isomaltoside was based on body weight and hemoglobin (Hb), administered as either a 1000 mg infusion over more than 15 minutes or 500 mg injection over 2 minutes. The cumulative dose of iron sucrose was calculated according to Ganzoni and administered as repeated 200 mg infusions over 30 minutes. The mean cumulative dose of iron isomaltoside was 1640.2 (standard deviation (SD): 357.6) mg and of iron sucrose 1127.9 (SD: 343.3) mg. The primary endpoint was the proportion of patients with a Hb increase ≥2 g/dL from baseline at any time between weeks 1‐5. Both non‐inferiority and superiority were confirmed for the primary endpoint, and a shorter time to Hb increase ≥2 g/dL was observed with iron isomaltoside. For all biochemical efficacy parameters, faster and/or greater improvements were found with iron isomaltoside. Both treatments were well tolerated; 0.6% experienced a serious adverse drug reaction. Iron isomaltoside was more effective than iron sucrose in achieving a rapid improvement in Hb. Furthermore, iron isomaltoside has an advantage over iron sucrose in allowing higher cumulative dosing in fewer administrations. Both treatments were well tolerated in a broad population with IDA.

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.

396 Background: RX-3117 is an oral small-molecule antimetabolite, cyclopentyl pyrimidyl nucleoside that is activated by uridine cytidine kinase 2. RX-3117 has shown efficacy in xenograft models of gemcitabine resistant pancreatic, bladder and colorectal cancer. Data from stage 2 of the Phase 1b/2a clinical study of RX3117 as a single agent in subjects with metastatic pancreatic cancer is described below. Methods: Stage 2 of the Phase 1b/2a study (NCT02030067) is designed to evaluate safety, tolerability and efficacy following treatment with 700 mg administered orally once-daily for 5 consecutive days with 2 days off per week for 3 weeks with 1 week off in each 4 week cycle. Eligible subjects (aged ≥ 18 years) had relapsed/refractory metastatic pancreatic cancer. The primary endpoint is a ≥ 20% rate of progression free survival (PFS) benefit (i.e., proportion of subjects with stable disease for at least 4 months) and/or a 10% of evaluable subjects with a partial response rate or better. Results: As of Sep 2017, 44 subjects have been enrolled (22 females, 22 males). The median age was 68 years, ECOG performance statuses were 0 (13 subjects) and 1 (31 subjects) and 6 subjects had received 4 or more prior therapies. One subject had an unconfirmed partial response and 21 subjects met the primary endpoint of stable disease with a duration of 30-224 days. The most frequent adverse events were mild to moderate anemia (19%), mild to moderate fatigue (15%), mild to moderate diarrhea (11%), and severe anemia (9%). Conclusions: This ongoing trial shows an early efficacy signal where RX-3117 is active against advanced pancreatic cancer. The study continues to enroll subjects with advanced pancreatic cancer into stage 2. A phase 2 study with nab-paclitaxel in first-line patients with advanced pancreatic cancer has been started. Clinical trial information: NCT02030067.