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PurposeBirdshot Chorioretinopathy (BSCR) is strongly associated with HLA-A29. This study was designed to elucidate the genetic modifiers of BSCR in HLA-A29 carriers.MethodsWe sequenced the largest BSCR cohort to date, including 286 cases and 108 HLA-A29 positive controls to perform genome wide common and rare variant associations. We further typed the HLA alleles of cases and 45,386 HLA-A29 controls of European ancestry to identify HLA alleles that associate with BSCR risk.ResultsCarrying a second allele that belongs to the HLA-Aw19 broad antigen family (including HLA-A29, A30, A31, and A33) increases the risk for BSCR (OR=4.44, p=2.2e-03). This result was validated by comparing allele frequencies to large HLA-A29-controlled cohorts (n=45,386, OR>2.5, pConclusionsThe genetic factors increasing BSCR risk demonstrate a pattern of increased processing, as well as increased presentation of ERAP2 specific peptides. This suggests a mechanism in which exceeding a peptide presentation threshold activates the immune response in choroids of A29 carriers.

Glaucoma is a leading cause of blindness. Current glaucoma medications work by lowering intraocular pressure (IOP), a risk factor for glaucoma, but most treatments do not directly target the pathological changes leading to increased IOP, which can manifest as medication resistance as disease progresses. To identify physiological modulators of IOP, we performed genome- and exome-wide association analysis in >129,000 individuals with IOP measurements and extended these findings to an analysis of glaucoma risk. We report the identification and functional characterization of rare coding variants (including loss-of-function variants) in ANGPTL7 associated with reduction in IOP and glaucoma protection. We validated the human genetics findings in mice by establishing that Angptl7 knockout mice have lower (~2 mmHg) basal IOP compared to wild-type, with a trend towards lower IOP also in heterozygotes. Conversely, increasing mAngptl7 levels via injection into mouse eyes increases the IOP. We also show that acute gene silencing via siRNA knockdown of Angptl7 in adult mice lowers the IOP (~2-4 mmHg), reproducing the observations in knockout mice. Collectively, our data suggest that ANGPTL7 is important for IOP homeostasis and is amenable to therapeutic modulation to help maintain a healthy IOP that can prevent onset or slow the progression of glaucoma.

Summary Background Dupilumab blocks the shared receptor component for interleukin (IL)‐4 and IL‐13. It is approved in the U.S.A. for patients aged ≥ 12 years with moderate‐to‐severe atopic dermatitis (AD) uncontrolled by topical prescription medicines or who cannot use topical medicines, for patients in Japan whose AD is uncontrolled with existing therapies, for patients with moderate‐to‐severe AD in Europe who are candidates for systemic therapy and for patients aged ≥ 12 years for maintenance treatment of moderate‐to‐severe asthma uncontrolled with their current medicines. AD trials have reported increased incidence of conjunctivitis for dupilumab vs. placebo. Objectives To characterize further the occurrence and risk factors of conjunctivitis in dupilumab clinical trials. Methods We evaluated randomized placebo‐controlled trials of dupilumab in AD (n = 2629), asthma (n = 2876), chronic rhinosinusitis with nasal polyps (CRSwNP) (n = 60) and eosinophilic oesophagitis (EoE) (n = 47). Results In most AD trials, dupilumab‐treated patients had higher conjunctivitis incidence than placebo controls. Higher baseline AD severity and previous history of conjunctivitis were associated with increased conjunctivitis incidence. Conjunctivitis was mostly mild to moderate. Most cases recovered or resolved during the treatment period; two patients permanently discontinued dupilumab due to conjunctivitis or keratitis. Common treatments included ophthalmic corticosteroids, antibiotics, and antihistamines or mast cell stabilizers. Most cases were diagnosed by the investigators. In asthma and CRSwNP trials, the incidence of conjunctivitis was lower for both dupilumab and placebo than in AD trials; dupilumab did not increase the incidence compared with placebo. In the EoE trial, no patients had conjunctivitis. Conclusions Conjunctivitis was more frequent with dupilumab treatment in most AD trials. In dupilumab trials in other type 2 diseases, incidence of conjunctivitis was overall very low, and was similar for dupilumab and placebo. In AD, the incidence of conjunctivitis was associated with AD severity and prior history of conjunctivitis. The aetiology and treatment of conjunctivitis in dupilumab‐treated patients require further study. What's already known about this topic? Ocular disorders, including allergic conjunctivitis, are common in patients with atopic dermatitis (AD).In most dupilumab AD trials, dupilumab‐treated patients had higher conjunctivitis incidence than those receiving placebo.Most cases were mild to moderate and recovered or were recovering during study treatment; study treatment discontinuation due to conjunctivitis was rare.Conjunctivitis incidence was very low and similar for dupilumab and placebo in clinical trials in asthma, chronic rhinosinusitis with nasal polyps and eosinophilic oesophagitis. What does this study add? This analysis confirms and extends the results of the individual clinical trials.Baseline disease‐related factors, including AD severity, prior conjunctivitis history and certain biomarkers (thymus and activation‐regulated chemokine, IgE, eosinophils), were associated with increased incidence of conjunctivitis.Patients who responded well to dupilumab had reduced incidence of conjunctivitis.Further study is needed to elucidate the aetiology and treatment of conjunctivitis in dupilumab‐treated patients with AD., Linked Editorial: https://doi.org/10.1111/bjd.18255. https://doi.org/10.1111/bjd.18276 available online https://www.bjdonline.com/article/

8038 Background: Multiple myeloma (MM) predominantly affects older patients (pts) (median age at diagnosis 69 yrs) in whom comorbidities must be considered to manage the disease appropriately. Some anti-MM therapies can be associated with ocular toxicities and require careful attention when used among pts with pre-existing ocular comorbidities (OC). In 2018, 41% of Medicare enrollees had OC. Despite the potential implication on treatment decisions, information on pre-existing OC (e.g., disorders of lens, glaucoma) in MM pts is limited. This study aims to describe the prevalence of OCs among real-world pts with MM in 2011-2020 in the US. Methods: Adults with newly diagnosed MM (NDMM) with or without treatment, with 1L systemic therapy, and with relapsed/refractory MM (RRMM) who received up to 4 lines of systemic therapies (LOT) for MM were identified in the IQVIA PharMetrics Plus data. The index date was the date of initial MM diagnosis or a LOT initiation date. The prevalence of OC in each group was defined as the presence of any OC ICD 9/10 diagnosis codes in the 12 months prior to the index date. OCs (e.g., disorders of conjunctiva, lens, choroid, retina, glaucoma) were considered a potentially MM-related disease manifestation or MM treatment-related toxicity based on published literature and clinical expert opinion. Results: The median age at initial MM diagnosis was 64 yrs overall (N=49,814), and 63 yrs among treated pts (N=22,963). The median age was 63 yrs at 1L initiation and 64 yrs at 2L, 3L, and 4L initiation. The prevalence of OC at initial MM diagnosis was 39.0% overall and 35.2% among treated pts (Table). The OC prevalence was 35.8% prior to 1L initiation and higher in RRMM pts (42.1%, 44.9%, and 45.7% prior to 2L, 3L, and 4L initiation, respectively). This trend was observed across all OC categories, among MM-related OCs, and across all age groups. The prevalence of OC by MM stage was stable over the years. Conclusions: Approximately 40% of NDMM pts have a pre-existing OC, and the prevalence increases with the number of LOT in RRMM. While some OC may be due to aging, the impact of OC on treatment decisions for MM should be explored. [Table: see text]

Introduction. Pozelimab (REGN3918) and cemdisiran (ALN-CC5) are C5 inhibitors under development for the treatment of paroxysmal nocturnal hemoglobinuria (PNH), myasthenia gravis (MG), and other diseases in which tissue damage is mediated by terminal complement pathway activity. Pozelimab is a fully human monoclonal immunoglobulin G4P (IgG4P) antibody directed against C5, and cemdisiran is a synthetic small interfering RNA (siRNA) targeting C5 mRNA. Both agents can be administered via subcutaneous (SC) injection. Pharmacokinetic (PK)/pharmacodynamic (PD) modeling based on observed data from both pozelimab and cemdisiran healthy volunteer studies (NCT03115996, NCT02352493) suggests that, by combining cemdisiran and pozelimab, the dose of both agents may be significantly reduced and the interval for SC dosing of pozelimab may be significantly increased. Objectives. To provide initial safety and tolerability data for a SC cemdisiran/pozelimab combination approach. Methods. This is an ongoing phase 1, open-label, parallel-dose cohort combination study (NCT04601844) assessing the safety and tolerability of ascending doses of SC pozelimab in combination with SC cemdisiran when administered on the same day or sequentially, on different days, in healthy subjects. Cohort Descriptions. Three parallel ascending-dose cohorts, consisting of six subjects each, were selected based on PK/PD modeling using observed data from both pozelimab and cemdisiran non-combination healthy volunteer studies: Cohort 1: Cemdisiran low dose SC followed by pozelimab low dose SC, administered on different days Cohort 2: Cemdisiran high dose SC followed by pozelimab low dose SC, administered on different days Cohort 3: Cemdisiran high dose SC and pozelimab high dose SC, both administered on the same day Dose regimens were designed to limit the duration of >50% complement inhibition for no longer than 8 weeks, to mitigate risk in the enrolled healthy subjects. An optional additional Cohort 4 was included in the study design and this interim analysis was planned to review safety data to guide the decision regarding whether to enroll this cohort and to inform its dose selection. Interim Analysis: An interim safety analysis was performed with a data cut-off corresponding to study day 127 for Cohort 1, study day 85 for Cohort 2, and study day 71 for Cohort 3. Eighteen healthy volunteer subjects, nine female and nine male, with a mean age of 36 years (standard deviation 9.5 years), were randomized to one of the three cohorts. Demographic and baseline characteristics were comparable for subjects in each cohort. A total of 47 treatment emergent adverse events (TEAEs) were reported, with comparable distribution across cohorts, all mild to moderate in severity with no severe TEAEs. "Nervous system disorders" was the TEAE System Organ Class with the most subjects for all three cohorts, occurring in 12 (66.7%) of the 18 subjects. "Headache" was the most frequent MedDRA Preferred Term for all three cohorts, occurring in 11 (61.1%) of the 18 subjects. All TEAEs were recovered or recovering at the time of data cut-off, and there were no study drug discontinuations or interruptions of treatment due to TEAEs. There were no serious TEAEs or deaths. There were no clinically meaningful findings or treatment-emergent changes reported on the vital signs or laboratory safety tests. Conclusions: The combined SC administration of pozelimab and cemdisiran represents a promising approach to achieve therapeutically significant complement inhibition for extended durations. An interim safety analysis demonstrated that the combined administration was generally safe and well tolerated. Final PK/PD analysis from this healthy volunteer study will allow for assessment of agreement between modeling predictions and observed data, and further inform combination dose regimens for studies in target patient populations. Disclosures van Zyl: Regeneron Pharmaceuticals, Inc.: Current Employment. Weyne: Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Chaudhari: Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Harari: Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Levy: Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Miller: Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Chen: Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Meagher: Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Rodgers: Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Perlee: Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Morton: Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Weinreich: Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Yancopoulos: Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company.

INTRODUCTION Paroxysmal Nocturnal hemoglobuinuria (PNH) is a rare, acquired, life-threatening disorder characterised by intravascular hemolysis and increased risk of thrombosis. Current available treatments represent a significant burden to patients and include anti-complement factor 5 (C5) therapies, eculizumab and ravulizumab, both intravenous infusions, or more recently, twice weekly C3 inhibitor, Pegcetacoplan, a subcutaneous (SC) infusion treatment. Pozelimab (REGN3918), a fully human monoclonal immunoglobulin G4 antibody directed against C5, has been shown to bind with high affinity to wild-type and variant (R885H/C) human C5 and block its activity. In a healthy volunteer study (NCT03115996), SC administration of pozelimab was found to be generally well tolerated while providing complete inhibition of ex vivo-assessed hemolytic activity [Weyne J et al. Blood. 2018;S1:1039]. The data suggested that pozelimab may provide control of intravascular hemolysis in patients with active PNH, and thus could provide an important new alternative for patients supporting progression to a first-in-patient study of pozelimab in patients with active PNH. OBJECTIVE To demonstrate a clinically significant reduction in intravascular hemolysis by once-weekly SC administration of pozelimab over 26 weeks of treatment in patients with active PNH. METHODS This is a phase 2, open-label, single-arm, 26-week treatment study in 24 patients with active symptomatic PNH who are naïve to complement inhibitor therapy, or who have received prior treatment with a complement inhibitor but not within 6 months prior to the start of the study (NCT03946748). The treatment regimen consists of pozelimab as a single IV loading dose of 30 mg/kg followed thereafter by weekly SC 800 mg administrations. The effect of pozelimab on intravascular hemolysis (monitored via LDH levels) and transfusion avoidance, as well as safety, is to be assessed from baseline to week 26 (study day 183; only partial data were available for some patients at the time of abstract submission). Pozelimab pharmacodynamics was assessed utilizing a sheep red blood cell (RBC) complement activity assay (CH50) and rabbit RBC complement activity assay (AH50). RESULTS All 24 patients completed the 26-week treatment period with no study drug discontinuation and have been enrolled into an ongoing open-label extension study (NCT04162470). An interim analysis on the first 17 patients was previously reported. All 17 patients had at least 71 days of treatment, with 10 patients receiving treatment for up to 183 days. All enrolled patients had baseline LDH levels ≥2 x upper limit of normal (ULN). Participants were enrolled in two cohorts: Cohort A for dose confirmation and Cohort B for further evaluation of efficacy and safety. Interim Efficacy Analysis As previously reported, treatment with pozelimab led to a rapid and sustained reduction in LDH through study week 26. All 17 patients achieved LDH reduction to below the clinically significant threshold of LDH ≤1.5 x ULN. All but one patient achieved control of intravascular hemolysis (LDH ≤1.5 x ULN) at week 2, and all but one patient achieved normalization of LDH (LDH ≤1.0 x ULN) at week 4. Importantly, one patient who is a carrier of a C5 variant known to be resistant to blockade by eculizumab/ravulizumab demonstrated rapid and sustained normalization of LDH. Interim Safety As previously reported, no serious adverse events or adverse events leading to treatment discontinuation were reported. Common treatment-emergent adverse events included headache (4 patients; 23.5%) and nausea (2 patients; 11.8%). No breakthrough hemolysis events were observed. CONCLUSIONS Pozelimab administered SC once weekly led to the inhibition of intravascular hemolysis in patients with active PNH and was generally well-tolerated. An update to the previously reported interim analysis will be provided. Upon successful completion of the 26-week treatment period, patients are enrolled into an open-label extension study. Disclosures Weyne: Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Chaudhari: Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Harari: Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Miller: Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Dain: Regeneron Pharmaceuticals, Inc.: Other: Contractor. Meagher: Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Rodgers: Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Perlee: Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Morton: Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Weinreich: Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Yancopoulos: Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Griffin: Alexion, AstraZeneca Rare Disease: Honoraria, Membership on an entity's Board of Directors or advisory committees; BioCryst Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sobi Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Apellis: Other: Educational grant support.

INTRODUCTION: Blockade of complement factor C5 has demonstrated benefit in paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, generalized myasthenia gravis and neuromyelitis optica. We have completed a Phase I study of pozelimab, a fully human anti-C5 IgG4, in healthy volunteers. Pozelimab was well tolerated and resulted in dose-dependent inhibition of hemolytic activity through the classical complement pathway in normal healthy volunteers. Complete inhibition of hemolytic activity was maintained over a 4-week dosing period by a weekly subcutaneous (SC) regimen following an intravenous (IV) loading dose (ASH2018 abstract). OBJECTIVE: To further characterize the impact of pozelimab on the alternative complement pathway activity, we investigated the effect of pozelimab on alternative pathway-mediated hemolysis using an AH50 assay in the completed first-in-human (FIH) study. In addition, we compared the effect of pozelimab in both alternative and classical pathway hemolysis assays with those of in-house eculizumab and in-house ravulizumab in pooled normal human serum (NHS) samples, ex vivo. METHODS: In total, 56 subjects were randomized to 4 sequential ascending IV single dose cohorts plus 2 sequential ascending SC single dose cohorts followed by 1 multiple dose cohort (consisting of an IV loading dose and weekly SC doses). Each cohort consisted of 8 subjects randomized to receive pozelimab or placebo (6 active: 2 placebo). Serum collected at multiple time-points was utilized to assess the effect of pozelimab on alternative pathway activity. For ex vivo spike experiments, pooled NHS was used to compare the hemolytic function of pozelimab, in-house produced eculizumab and in-house produced ravulizumab. Comparator antibodies were synthesized from published sequence. The alternative pathway (AP) and classical pathway (CP) hemolysis assays were performed based on lysis of rabbit red blood cells (RBCs) and sensitized sheep RBCs, respectively. Both assays measure the amount of hemoglobin released from red blood cells at 412 nm. RESULTS: In the FIH study, baseline AH50 was comparable across treatment groups with a mean of 110 U/mL (standard deviation = 19, n = 56). Pozelimab exposure led to dose-dependent inhibition of AH50. In all 4 IV dosing cohorts, peak suppression of hemolysis was observed at end of infusion (EOI). Maximal suppression of hemolysis was approximately −85% change from baseline. This was achieved with the 30 mg/kg IV group and the repeat dose 15 mg/kg IV + 400 mg SC QW group. In the 2 SC cohorts, peak suppression of hemolysis was observed 3-7 days post dosing, which was consistent with observed peak concentrations of pozelimab in serum. In an ex vivo spike study, pozelimab, in-house eculizumab and in-house ravulizumab were spiked into 10, 25 or 48% pooled NHS for AP, and 5, 10 or 25% for CP. The results from AP hemolysis assays showed that, for a given concentration of spiked antibody, the maximal suppression of hemolysis for all the antibodies decreased with increased percentage of serum (Figure). The maximal suppression of hemolysis was consistently higher (32-169%) for pozelimab compared with in-house eculizumab, and lower for in-house ravulizumab compared with pozelimab and in-house eculizumab at all serum percentages tested. The results from CP hemolysis assays showed that, although the maximal suppression of hemolysis was similar for all antibodies tested, in-house ravulizumab was required to be at least a log higher in concentration to achieve a similar effect as the other two anti-C5 antibodies. CONCLUSIONS: Ex vivo studies with pooled NHS demonstrate that pozelimab robustly blocks both CP and AP hemolysis. In-house ravulizumab appeared to be less potent compared with in-house eculizumab in both CP and AP hemolysis assays. The Phase I healthy volunteer study of pozelimab demonstrated dose-dependent and significant inhibition of alternative pathway hemolysis, with the maximal suppression of hemolysis approximately −85% change from baseline. Figure Disclosures Devalaraja-Narashimha: Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Ni:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Huang:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Wang:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Chaudhari:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Prasad:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Harari:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Rankin:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Morton:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Weyne:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. OffLabel Disclosure: The drug is pozelimab and it is a fully human anti-C5 IgG4 being tested a Phase 1 study in healthy volunteers.

Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired, life-threatening blood disease. While PNH is known to be a rare disease, the incidence and prevalence of the condition has been described only in a few small studies. In addition, while the International PNH registry is a rich source of data on real-world PNH patients globally, it is not possible to estimate the incidence and prevalence of PNH directly from the registry. As complement inhibitors are becoming the standard of care for PNH treatment, we also sought to explore how patients are managed following an incident PNH diagnosis. The objective of this study was to estimate the incidence and prevalence of PNH and to describe real-world treatment patterns among patients newly diagnosed with PNH in the United States (US). Methods: We conducted a retrospective cohort study using Truven US MarketScan Commercial/Medicare data (1 Jan 2015 to 30 June 2018), an employer-sponsored insurance claims database including annually approximately 30 million insured patients and their dependents' complete longitudinal records of inpatient services, outpatient services, and prescription drug claims covered under a variety of fee-for-service and capitated health plans. While these data are considered nationally representative of Americans with employer-provided health insurance, data come mainly from large employers. To estimate prevalence, we identified patients with ≥ 1 PNH diagnosis (ICD10: D59.5) among persons continually enrolled in the databases in 2017. To estimate incidence, we required ≥1-year of baseline enrolment and no PNH diagnosis or eculizumab exposure, identified using national drug codes [NDC] or procedure codes for drug administration, during the baseline period. Person-time accrued post-baseline until PNH diagnosis, end of study period, or disenrollment. We stratified incidence and prevalence estimates by age and sex and described patients with incident PNH in terms of demographics, comorbidities, and past-year healthcare resource utilization. Using Kaplan-Meier estimators, we estimated incidence of eculizumab initiation, timing of initiation, treatment duration, and risk of discontinuation/treatment holiday (>42 days between eculizumab exposures [i.e. 14-day exposure period + 28-day grace period between infusions], the equivalent of missing 2 infusions assuming a bi-weekly infusion schedule for eculizumab) following the incident PNH diagnosis. While accounting for censoring, we also investigated patterns of red blood cell (RBC) transfusions, identified using procedure codes, in terms of incidence and timing of first transfusion following an incident PNH diagnosis. Results: The prevalence of PNH varied little between 2016 and 2017, from 12 to 13 per 1,000,000. The incidence rate over the study period was 5.7 per 1,000,000 person-years, representing 257 incident PNH cases. The incidence rate of PNH increased with age and was similar across sex. At diagnosis, mean age was 50.0 years (standard deviation [SD]: 18.6), 3.1% (8/257) were less than 18 years, 52.1% were women, 19.5% had a past-year diagnosis of aplastic anemia, 8.2% had a past-year diagnosis of myelodysplastic syndrome, 14.0% had a past-year RBC transfusion, and 31.5% had been hospitalized in the past-year. Over a mean follow-up time of 385.6 days (SD: 253.2), 10.3% (95% confidence interval [CI]: 6.3-14.1%) of patients initiated eculizumab on average 60.5 days (SD: 55.9) from PNH diagnosis. At 1 year, about one third of patients discontinued eculizumab or had taken a treatment holiday; average treatment duration was 328.2 days (SD:245.4). Cumulative incidence of RBC transfusions at 6 months and 1 year was 14.6% (10.1-18.9%) and 17.4% (12.2-22.3%), respectively. On average, the first RBC transfusion occurred within 63.6 days (SD: 114.4) of an incident PNH diagnosis. Conclusions: In routine clinical practice, only a minority of patients recently diagnosed with PNH are initiated on eculizumab. Among PNH patients treated with eculizumab, less than 70% remain on treatment after 1 year. Findings must be interpreted in the context of limitations including lack of information on clone size, symptom burden, measures of disease activity, or bone marrow failure state which may affect treatment course. Future studies should explore factors affecting eculizumab initiation and persistence on treatment. Disclosures Jalbert: Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Chaudhari:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Zhang:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Weyne:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Shammo:Incyte: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Alexion: Consultancy, Honoraria, Research Funding, Speakers Bureau; Onconova: Research Funding; Apellis: Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Speakers Bureau; Astex Pharma: Research Funding; Novartis: Consultancy, Honoraria; Otsuka: Consultancy, Honoraria; CTI Pharma: Research Funding.

INTRODUCTION: Blockade of complement factor C5 has demonstrated benefit in Paroxysmal Nocturnal Hemoglobinuria (PNH), atypical Hemolytic Uremic Syndrome and Generalized Myasthenia Gravis. We developed a human IgG4P antibody, REGN3918, that binds with high affinity to wild-type and variant (R885H/C) human C5. REGN3918 was well-tolerated in monkey toxicology studies with up to 26 weeks of dosing at up to 100 mg/kg/week. This finding was supportive of conducting this first-in-human study of REGN3918 in healthy volunteers. OBJECTIVE: The primary objective of this ongoing study is to evaluate the safety and tolerability of single ascending intravenous (IV) and subcutaneous (SC) doses and a multiple dose regimen consisting of an IV loading dose plus multiple weekly SC doses of REGN3918 administered in healthy volunteers. The secondary objectives of the study are to assess the pharmacokinetic (PK) and pharmacodynamic (PD) profile of REGN3918. METHODS: 56 subjects were randomized to 4 sequential ascending IV dose cohorts plus 2 sequential ascending SC cohorts followed by 1 multiple dose cohort (consisting of an IV loading dose and weekly SC doses). Each cohort consisted of 8 subjects randomized to receive REGN3918 or placebo (6 active: 2 placebo). An adaptive design was implemented to allow for dose level and dosing interval adjustment utilizing in-study PK and PD measures. The PD profile of REGN3918 was assessed utilizing a sheep red blood cell complement activity assay (CH50 assay) as well as serum concentrations of total C5. REGN3918 was administered as follows:Cohort 1: 1 mg/kg IV, single doseCohort 2a: 3 mg/kg IV, single doseCohort 2b: 300 mg SC, single doseCohort 3a: 10 mg/kg IV, single doseCohort 3b: 600 mg SC, single doseCohort 4: 30 mg/kg IV, single doseCohort 5: Loading dose of 15 mg/kg IV followed by 4 repeat SC doses of 400 mg administered once weekly for four weeks. RESULTS: REGN3918 was found to be well tolerated in single doses of up to 30 mg/kg IV and 600 mg SC. The multiple dose Cohort 5 has completed dosing in all subjects and is currently in safety follow-up. Thus far, there has been one SAE, salpingitis in a subject with an intra-uterine contraceptive device. The SAE occurred in a Cohort 5 subject after completion of dosing and has since resolved. REGN3918 exhibited dose-dependent increases in exposure in serum, with a trend toward prolonged serum concentrations at IV doses ≥10 mg/kg. Following SC administration, concentrations of REGN3918 in serum peaked at 4 to 8 days post dose and bioavailability was estimated as approximately 70%. REGN3918 exposure led to dose-dependent inhibition of CH50. In all 4 IV dosing cohorts, suppression of hemolysis was observed at 15 min post-injection. Complete suppression of hemolysis was achieved with ≥ 3mg/kg dosing. At 30 mg/kg, complete suppression of hemolysis was maintained for >6 weeks, consistent with observed prolonged REGN3918 concentrations following this dose. In the 2 SC cohorts, peak suppression of hemolysis was observed 3-7 days post dosing, again consistent with observed peak concentrations of REGN3918 in serum. In the multiple dose cohort 5, complete suppression of CH50 was observed over the four-week dosing period. CONCLUSIONS: REGN3918 was well tolerated and resulted in dose-dependent inhibition of hemolytic activity in normal healthy volunteers. A single IV infusion of R3918, at 30 mg/kg, blocked hemolytic activity completely for >6 weeks. Complete inhibition of hemolytic activity was maintained over a 4-week dosing period by a weekly SC regimen following an IV loading dose. Disclosures Weyne: Regeneron Pharmaceuticals: Employment, Equity Ownership. Ni:Regeneron Pharmaceuticals: Employment, Equity Ownership. DelGizzi:Regeneron Pharmaceuticals: Employment, Equity Ownership. Godin:Regeneron Pharmaceuticals: Employment. Morton:Regeneron Pharmaceuticals: Employment, Equity Ownership. Prasad:Regeneron Pharmaceuticals: Employment, Equity Ownership. Rankin:Regeneron Pharmaceuticals: Employment, Equity Ownership. Simek-Lemos:Regeneron Pharmaceuticals: Employment, Equity Ownership. Wang:Regeneron Pharmaceuticals: Employment, Equity Ownership. Rippley:Regeneron Pharmaceuticals: Employment, Equity Ownership. Harari:Regeneron Pharmaceuticals, Inc.: Employment.

Histamine receptor activation and degranulation of mast cells are the mechanisms by which the ocular itching, hyperemia, chemosis, eyelid swelling, and tearing of seasonal allergic conjunctivitis are induced. Some of the topical solutions available as anti-allergy therapies are intended to interfere with these mechanisms, and the body of research regarding the capabilities of these therapeutic molecules continues to expand.To review the currently available literature regarding one topical ophthalmic anti-allergy agent, olopatadine (Patanol), and its anti-histaminic and mast cell stabilizing actions, both in pre-clinical and clinical settings.Relevant research of laboratory, animal model, and clinical trial studies performed using olopatadine was reviewed. MEDLINE literature searches were conducted and supplemented by additional reports which furthered relevant discussion or were necessary to verify the information resulting from original searches.Olopatadine demonstrates unique properties both pre-clinically and clinically which differentiate it from other therapeutic molecules in its class of dual action mast cell stabilizer/anti-histamine. Its non-perturbation of cell membranes, human conjunctival mast cell stabilization in vivo and in vitro, and superior efficacy as compared to other topical anti-allergic medications including mast cell stabilizers, anti-histamines, and dual action agents, all contribute to olopatadine's profile.Peer-reviewed literature suggests that olopatadine is clinically superior to the other anti-allergic molecules because of its strong anti-histaminic qualities and its unique ocular mast cell stabilizing properties.