Investigational RNA Research Articles

Plozasiran (ARO-APOC3), an investigational RNAI therapeutic, demonstrates profound and durable reductions in APOC-3 and triglycerides (TG) in patients with severe hypertriglyceridemia (SHTG), SHASTA-2 final results

Plozasiran (ARO-APOC3), an investigational RNAI therapeutic, demonstrates profound and durable reductions in APOC-3 and triglycerides (TG) in patients with severe hypertriglyceridemia (SHTG), SHASTA-2 final results

†Plozasiran (ARO-APOC3), an Investigational RNAi, Demonstrates Robust and Durable TG Reductions in Patients with Mixed Dyslipidemia, MUIR Final Results

†Plozasiran (ARO-APOC3), an Investigational RNAi, Demonstrates Robust and Durable TG Reductions in Patients with Mixed Dyslipidemia, MUIR Final Results

†Plozasiran (ARO-APOC3), an Investigational RNAi, Demonstrates Deep and Durable TG Reductions in Patients With SHTG, SHASTA-2 Final Results

†Plozasiran (ARO-APOC3), an Investigational RNAi, Demonstrates Deep and Durable TG Reductions in Patients With SHTG, SHASTA-2 Final Results

Abstract 17120: ARO-ANG3, an Investigational RNAi Therapeutic, Silences the Expression of ANGPTL3 and Decreases Atherogenic Lipoproteins in Patients With Mixed Dyslipidemia: ARCHES-2 Study Results

Background: Angiopoietin-like protein 3 (ANGPTL3) regulates lipoprotein metabolism by inhibiting lipoprotein and endothelial lipases. ANGPTL3 loss-of-function carriers have decreased circulating triglycerides (TGs), LDL-C, and HDL-C, and a lower risk of atherosclerotic cardiovascular disease (ASCVD). ARO-ANG3 is an investigational RNAi therapeutic designed to inhibit hepatic ANGPTL3 expression and reduce atherogenic lipoproteins. Aim: We report end-of-study results (data cutoff 09 December 2022) from ARCHES-2, a Phase 2b double-blind, placebo (pbo)-controlled study (NCT04832971) to evaluate the safety and efficacy of ARO-ANG3 in adults with mixed dyslipidemia (MD). Methods: Patients with fasting TGs 150-499 mg/dL and LDL-C ≥70 mg/dL or non-HDL-C ≥100 mg/dL were randomized to receive 50 mg, 100 mg or 200 mg ARO-ANG3 or pbo by subcutaneous injections on Day 1 and Week 12. Patients were on a stable diet and optimal lipid-lowering therapies. The primary endpoint was the percent change in TGs from baseline at Week 24. Liver fat was assessed at baseline and Week 24 in a subset of patients with hepatic steatosis. Mixed models repeated measures was used for statistical analyses. Results: At Week 24, ARO-ANG3 decreased ANGPTL3 (up to 77%), TGs (up to 56%), remnant cholesterol (up to 56%), and apolipoprotein B (apoB) (up to 20%). Other lipoproteins including LDL-C, non-HDL-C, lipoprotein(a) and HDL-C were also decreased. Liver fat decreased similarly in ARO-ANG3 and pbo groups. TEAEs were consistent with those expected in this patient population and with associated underlying comorbidities. Conclusions: ARCHES-2 data demonstrate ARO-ANG3 efficacy by significantly lowering ANGPTL3 and atherogenic triglyceride-rich lipoproteins (TRLs), LDL and total apoB in patients with MD. The favorable changes in serum lipids and lipoproteins and safety profile support the potential of ARO-ANG3 to treat residual ASCVD risk in patients with elevated TRLs not at LDL-C goal.

ARO-ANG3, an investigational RNAI therapeutic, decreases serum LDL-cholesterol, apolipoprotein B, and angiopoietin-like protein 3 in patients with homozygous familial hypercholesterolaemia

ARO-ANG3, an investigational RNAI therapeutic, decreases serum LDL-cholesterol, apolipoprotein B, and angiopoietin-like protein 3 in patients with homozygous familial hypercholesterolaemia

Abstract 10357: ARO-APOC3, an Investigational RNAi Therapeutic, Shows Similar Efficacy and Safety in Genetically Confirmed FCS and Non-FCS Participants with Severe Hypertriglyceridemia

Background: Familial chylomicronemia syndrome (FCS) is an ultrarare condition caused by biallelic pathogenic DNA variants in lipolysis-associated genes, resulting in severe hypertriglyceridemia (HTG) and associated with high risk of acute pancreatitis with few therapeutic options. In a 16-week Phase 1 study (NCT03783377), subcutaneously administered ARO-APOC3 reduced serum apolipoprotein C3 (APOC3) and TG in healthy volunteers and participants (pts) with HTG and was well tolerated. Purpose: To report on the safety/pharmacodynamic (PD) effects of ARO-APOC3 in both FCS pts with biallelic pathogenic variants and pts with severely elevated TG at screening (>880 mg/dL) but without biallelic pathogenic variants (chylomicronemia (MCM)). Methods: Four genetically confirmed FCS pts received 50 mg ARO-APOC3 and 26 MCM pts received 10, 25, 50, or 100 mg ARO-APOC3 on Days 1 and 29. Since similar PD responses were observed among MCM pts, results were pooled across dose levels. Safety and PD responses were examined. Maximal mean/median changes from baseline for APOC3, TG, non-HDL-C, and HDL-C were reported. Results: Baseline/demographics were comparable between groups, except for mean BMI (22.1 [FCS] and 30.5 [MCM] kg/m 2 ), and mean baseline HDL-C , which were lower in FCS pts (Table 1) (p<0.0001 for both). Mean APOC3 was reduced by 98% and 96% in FCS and MCM pts, respectively. Both groups also showed similar maximum median reductions in TG of 91% and 90%, respectively. Similar to the full study, non-HDL-C was reduced and HDL-C increased with treatment in both groups (Table 1). AEs were similar between groups, suggesting a comparable safety profile. Conclusions: In patients with severe HTG, ARO-APOC3 was safe, and consistently decreased APOC3, TG, and non-HDL-C, and increased HDL-C, regardless of underlying genetic cause of HTG, and may represent a promising RNAi therapeutic for the treatment of severe HTG.

HELIOS-A: 9-month results from the phase 3 study of vutrisiran in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy

Hereditary transthyretin-mediated (hATTR) amyloidosis, also known as ATTRv amyloidosis, is a progressive disease caused by misfolded transthyretin (TTR) that accumulates as amyloid fibrils in multiple tissues and organs. Vutrisiran, an investigational RNAi therapeutic for the treatment of ATTR amyloidosis, targets variant and wild-type TTR.

In silico Modeling of the Impact of Antithrombin Lowering on Thrombin Generation in Rare Bleeding Disorders

Introduction: Rare bleeding disorders (RBDs) arise from deficiencies in various clotting factors, such as factors V, VII, and X, which like hemophilia A or B, are often characterized by an inability to generate sufficient thrombin to prevent bleeds. However, compared to hemophilia, RBDs are less prevalent, more heterogeneous in phenotype, and less understood clinically. Furthermore, RBD patients, subsets of whom can suffer from frequent and severe bleeding episodes, often have limited treatment options. Fitusiran is an investigational RNAi therapeutic targeting antithrombin (AT), a major endogenous inhibitor of thrombin production, and is currently in Phase 3 trials for the treatment of hemophilia A or B, with or without inhibitors. Initial clinical studies with fitusiran have demonstrated that lowering AT resulted in improved thrombin generation and was correlated with reduced bleeding frequency in patients with hemophilia (Pasi et al. New Engl J Med . 2017.). Based on this mechanism of action, pharmacological lowering of AT may potentially have clinical applicability in RBDs. In this light, in silico kinetic models that predict the dynamic behavior of coagulation, including thrombin generation in plasma under a diverse set of experimental conditions, can provide a useful theoretical platform to test whether AT lowering may be effective in RBDs. In this abstract, we demonstrate the use of a computational model to predict the impact of AT lowering on thrombin generation in plasma with various degrees of deficiencies in Factors V, VII, and X.Methods: We implemented the model developed by Nayak et al. (Nayak et al. CPT Pharmacometrics Syst. Pharmacol. 2015.), which describes the coagulation cascade and simulates thrombin generation under various experimental conditions, using Matlab and the Simbiology Toolbox®. For each Factor deficiency (V, VII, X), we tested thrombin generation at factor levels of 0.1, 0.5, 1.0, 2.0, 5.0, and 10.0% of their mean plasma concentrations in normal healthy individuals as well as AT lowering of 0, 40, 60, 80, 90, and 99% of baseline levels. Peak thrombin values from each thrombin curve were computed and compared across experimental conditions. Patient heterogeneity was simulated by monte-carlo sampling of plasma factor concentrations based on known mean and variances reported in literature.Results: Consistent with published results in hemophilia A and B, the model predicted an increase in thrombin generation as AT was lowered in the setting of factor V, VII, and X deficiencies. AT lowering to 20% resulted in increased thrombin generation by 14, 4, and 3-fold for conditions of 1% factor V, VII, and X, respectively.Conclusions: Our results suggest that pharmacological AT lowering may serve as an effective strategy for certain RBDs. DisclosuresSridharan:Alnylam: Employment, Equity Ownership. Liu:Alnylam: Employment, Equity Ownership. Qian:Alnylam: Employment, Equity Ownership. Goel:Alnylam: Employment, Equity Ownership. Huang:Alnylam: Employment, Equity Ownership. Akinc:Alnylam: Employment, Equity Ownership.

Abstract 14387: Dose-Related Reductions in Blood Pressure With a RNA Interference (RNAi) Therapeutic Targeting Angiotensinogen in Hypertensive Patients: Interim Results From a First-In-Human Phase 1 Study of ALN-AGT01

Background: Angiotensinogen (AGT) is the sole precursor of all angiotensin peptides and plays a key role in hypertension pathogenesis. We evaluated the effect of ALN-AGT01, a subcutaneous investigational RNAi therapeutic targeting hepatic AGT synthesis, on blood pressure in hypertensive patients. Methods: As part of a phase 1 program designed to assess the safety and tolerability of ALN-AGT01, we conducted a multicenter study randomizing patients aged 18-65 years with mild to moderate hypertension (mean seated systolic blood pressure [SBP] of >130 and ≤165 mmHg after washout of antihypertensive medication) 2:1 to ascending single doses of ALN-AGT01 or placebo. Change from baseline in BP at 8 weeks was measured by ambulatory BP monitoring (ABPM). We report interim results as of May 14, 2020. Results: Sixty patients (mean age 52 years, 45% female, mean baseline 24h SBP 139 +/- 7 mm Hg) were enrolled in ascending dose cohorts of 10 mg, 25 mg, 50 mg, 100 mg, or 200 mg. Dose-related reductions in serum AGT levels were observed (figure), with reductions >90% in the 100 and 200 mg dose cohorts. AGT remained durably reduced through 12 weeks after single dose administration. Concomitant reductions in BP from baseline were observed with AGT knockdown, with an over 10 mm Hg reduction of mean 24-hour SBP observed at Week 8 after single doses of 100 mg or 200 mg. No symptomatic hypotension, treatment-related serious adverse events, or clinically significant elevations in blood creatinine or potassium were seen. Conclusions: Single dose administration of ALN-AGT01 to hypertensive patients resulted in dose-related reductions in serum AGT and BP over 8 weeks without hypotension or other related serious adverse events. Durable AGT knockdown to 12 weeks supports further evaluation of once quarterly or potentially less frequent dose administration.

Results from the Ongoing Phase 2 Open-Label Extension Study of Lumasiran, an Investigational RNAi Therapeutic, in Patients with Primary Hyperoxaluria Type 1 (PH1)

Results from the Ongoing Phase 2 Open-Label Extension Study of Lumasiran, an Investigational RNAi Therapeutic, in Patients with Primary Hyperoxaluria Type 1 (PH1)

S1169 Twelve-Month Interim Analysis of Efficacy and Safety of Givosiran, an Investigational RNAi Therapeutic for Acute Hepatic Porphyria, in the ENVISION Open Label Extension

INTRODUCTION: Acute hepatic porphyria (AHP) is a family of rare genetic diseases due to enzyme defects in hepatic heme biosynthesis. Induction of 5-aminolevulinic acid synthase 1 (ALAS1), the rate-limiting step in heme biosynthesis, can lead to accumulation of toxic heme intermediates 5-aminolevulinic acid (ALA) and porphobilinogen (PBG), causing neurovisceral attacks and chronic manifestations. Givosiran, an investigational RNAi therapeutic, targets liver ALAS1 to reduce ALA/PBG and ameliorate attacks and clinical manifestations. METHODS: ENVISION (NCT03338816) is an ongoing Phase 3 global, multicenter, randomized, placebo-controlled trial, evaluating the efficacy and safety of subcutaneous monthly doses of 2.5 mg/kg givosiran in AHP patients in a 6-month double-blind (DB) period and an open label extension (OLE) period (up to 30 months). During the OLE, patients received either 2.5 mg/kg or 1.25 mg/kg monthly givosiran. Outcome measures included composite annualized attack rate (AAR) requiring hospitalization, urgent care, or IV-hemin at home, ALA/PBG levels, hemin use, daily worst symptoms, and quality of life (QoL). Analyses were descriptive. RESULTS: As of July 23, 2019, 93 patients entered the OLE: 56 (placebo/givosiran = 29; givosiran/givosiran = 27) received 2.5 mg/kg monthly givosiran, and 37 (placebo/givosiran = 17; givosiran/givosiran = 20) received 1.25 mg/kg. In givosiran patients (both doses), median AAR was 1.1 (range: 0–20.5) through Month 12. In placebo patients who crossed over to givosiran in the OLE, median AAR (DB = 10.65; OLE = 1.81) and proportion of attack-free patients (DB = 17.4%; OLE = 42.2%) were similar to the givosiran group in the DB period (median AAR = 1.04; attack free patients = 48.9%). In addition, sustained lowering of ALA/PBG in the OLE was accompanied by reductions in hemin use, daily worst pain and analgesic use, and improvements in QoL. Among patients on givosiran through Month 12, 62% had ≥1 drug-related adverse event (AE) and 3% had ≥1 drug-related serious AE. There were no new AEs leading to discontinuation and no deaths. No new safety concerns occurred in the OLE. There was a trend toward increased efficacy with the 2.5 mg/kg dose compared to 1.25 mg/kg dose, and safety was acceptable at both doses. CONCLUSION: In an ongoing Phase 3 study, givosiran 2.5 mg/kg monthly demonstrated maintenance or enhancement of clinical efficacy and an acceptable safety profile consistent with that observed in the 6-month DB period.

Knockdown of liver-derived factor XII by GalNAc-siRNA ALN-F12 prevents thrombosis in mice without impacting hemostatic function

BackgroundPlasma coagulation Factor XII (FXII) plays a crucial role in contact activation, ultimately regulating both the kinin-kallikrein system and the intrinsic pathway of coagulation. A growing body of evidence suggests that inhibition of FXII can prevent thrombosis. Given FXII does not appear to modulate hemostasis, targeting FXII is a promising strategy for the prevention of pathological thrombus formation without the hemostatic risks typically associated with anticoagulants. To this end, a subcutaneously administered investigational RNAi therapeutic targeting liver F12 mRNA (ALN-F12) was developed. AimTo investigate the thrombo-protective and hemostatic effects of FXII reduction by ALN-F12 in rodent thrombosis and hemostasis models. MethodsA single dose of ALN-F12 was subcutaneously administered to C57Bl/6 mice. After reaching steady state FXII reduction, the impact on thrombosis (ferric chloride arterial thrombosis and electrolytic injury induced venous thrombosis models) and hemostasis (saphenous vein injury and tail tip transection bleeding models) was evaluated. ResultAdministration of ALN-F12 resulted in dose-dependent reductions of both liver F12 mRNA and plasma FXII protein. In mice, ALN-F12 led to dose-dependent reductions in platelet and fibrin accumulation in the venous electrolytic-injury model and in the time to occlusion in the ferric chloride arterial thrombosis model. At 10 mg/kg ALN-F12, the top dose level evaluated, this resulted in >95% reduction of FXII and ~10 fold reduction in fibrin deposition. Finally, hemostasis models showed that >95% reduction of FXII had no impact on bleeding time or blood loss. ConclusionOur findings support that reduction of plasma Factor XII by ALN-F12 provided thrombo-protective effects with no increased bleeding risk in rodent models of thrombosis and hemostasis.

AS085 - Twelve-month interim analysis of efficacy and safety of givosiran, an investigational RNAi therapeutic for acute hepatic porphyria, in the envision open label extension

AS085 - Twelve-month interim analysis of efficacy and safety of givosiran, an investigational RNAi therapeutic for acute hepatic porphyria, in the envision open label extension

SAT426 - In vitro and in vivo characterization of VIR-2218, an investigational RNAi therapeutic targeting hepatitis B virus

SAT426 - In vitro and in vivo characterization of VIR-2218, an investigational RNAi therapeutic targeting hepatitis B virus

A phase 1/2 open label extension study of givosiran, an investigational RNAi therapeutic, in patients with acute intermittent porphyria

A phase 1/2 open label extension study of givosiran, an investigational RNAi therapeutic, in patients with acute intermittent porphyria

LB002ILLUMINATE-A, A PHASE 3 STUDY OF LUMASIRAN, AN INVESTIGATIONAL RNAI THERAPEUTIC, IN CHILDREN AND ADULTS WITH PRIMARY HYPEROXALURIA TYPE 1 (PH1)

Abstract Background and Aims PH1 is a rare genetic disorder characterized by hepatic oxalate overproduction, leading to recurrent kidney stones, nephrocalcinosis, progressive kidney failure, and multiorgan damage from systemic oxalosis. There are no approved pharmacologic therapies for PH1. Lumasiran is a subcutaneously-administered investigational RNAi therapeutic that targets glycolate oxidase to reduce hepatic oxalate production. We report the first results from the six-month, double-blind period of ILLUMINATE-A, a randomized, placebo-controlled Phase 3 study to evaluate lumasiran in patients with PH1. Method Key inclusion criteria: age≥6 years, 24hr urinary oxalate (UOx)≥0.70 mmol/24hr/1.73m2, confirmed PH1 diagnosis, eGFR≥30 mL/min/1.73m2. Randomization: 2:1; lumasiran (n=26), placebo (n=13). Dosing: 3 mg/kg monthly×3, then quarterly. Primary endpoint: percent change in 24hr UOx excretion from baseline to month (M) 6. Primary comparison: least square (LS) mean treatment difference in percent change from baseline (average of M3-6). Results Lumasiran led to a statistically significant percent reduction in 24hr UOx excretion compared to placebo: the LS mean change from baseline to M6 (average of M3-6) was −65.4% with lumasiran and −11.8% with placebo (LS mean difference: −53.5%; p=1.7 × 10−14). Subgroup analyses of the primary endpoint showed a consistent effect of lumasiran across age, baseline UOx, eGFR, and concomitant pyridoxine use. Lumasiran led to statistically significant improvements in all hierarchically tested secondary endpoints, including: proportion of lumasiran-treated patients that achieved normalization or near-normalization of 24hr UOx at M6 (84% vs 0% of placebo-treated patients, p=8.3 × 10−7), and percent change in plasma oxalate from baseline to M6 (average of months 3-6) (-39.5%, p=2.9 × 10−8). There were no serious or severe adverse events. The most common adverse events related to lumasiran were mild, transient injection site reactions. Conclusion Lumasiran resulted in clinically meaningful, rapid, sustained, and statistically significant reductions in urinary and plasma oxalate levels compared to placebo during the six-month double-blind period. Lumasiran has a favorable safety profile.

Overall Health, Daily Functioning, and Quality of Life in Acute Hepatic Porphyria Patients: ENVISION, a Phase 3 Global, Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial

Objectives: Acute Hepatic Porphyria (AHP) is a family of rare genetic diseases leading to an enzyme deficiency in the heme biosynthesis pathway, causing accumulation of neurotoxic heme intermediates, resulting in neurovisceral attacks and chronic manifestations. Givosiran, an investigational RNAi therapeutic, is being evaluated for its ability to reduce the levels of neurotoxic intermediates thus decreasing attacks and disease manifestations.

SUN-325 SAFETY AND EFFICACY OF LUMASIRAN, AN INVESTIGATIONAL RNA INTERFERENCE (RNAi) THERAPEUTIC, IN ADULT AND PEDIATRIC PATIENTS WITH PRIMARY HYPEROXALURIA TYPE 1

Primary hyperoxaluria type 1 (PH1) is a rare genetic disorder characterized by the hepatic overproduction of oxalate, which forms calcium oxalate crystals in the urinary system. Disease manifestations include recurrent urolithiasis, nephrocalcinosis, progressive renal failure, and multi-organ damage from systemic oxalosis, often resulting in high morbidity and mortality. Lumasiran is a subcutaneously-administered investigational RNAi therapeutic specifically designed to reduce a key substrate thereby decreasing oxalate production. The objective is to the present emerging safety and pharmacodynamic data from the Phase 2 open-label extension (OLE) study of lumasiran. ALN-GO1-001 is a Phase 1/2 randomized, placebo-controlled, single-blind, multicenter trial, evaluating lumasiran in patients with PH1 ≥6 years of age with urinary oxalate (UOx) ≥0.7 mmol/1.73m2/day and eGFR >45 mL/min/1.73m2. The study consists of three dosing regimens: 1 mg/kg monthly for 3 doses, 3 mg/kg monthly for 3 doses, or 3 mg/kg lumasiran every 3 months for 2 doses. Once patients complete follow up in Phase 1/2, eligible patients may enroll in the OLE study for long-term dosing. Endpoints for the OLE study include safety and change in 24-hour UOx from baseline. Patients (N=20; 65% females) in Phase 1/2 had a mean age at enrollment of 14.9 years (range 6-43) and a mean baseline UOx of 1.69 mmol/1.73m2/day (range 0.83–2.97). Previously presented data showed no discontinuations or drug-related serious adverse events (AEs). AEs were reported in 3 (100%) patients during placebo dosing and 19 (95%) patients after lumasiran dosing; the majority of AEs were mild or moderate and deemed unrelated to study drug. Mean maximal reduction in urinary oxalate relative to baseline was 75% after lumasiran dosing; the mean reduction relative to baseline 28 days post last dose of lumasiran was 66%. Among patients receiving lumasiran 3.0 mg/kg monthly or quarterly, 10/12 (83%) achieved urinary oxalate levels within the normal range (<0.46 mmol/1.73m2/day). As of Oct 2018, all patients who have completed follow up in Phase 1/2 have enrolled in the OLE. At the time of data cut off, patients (N=8) have been on the OLE study for 2.7 months (range: 0.03–3.02). Safety data from OLE remains consistent with that observed in the Phase 1/2 study, with no discontinuations or drug related serious adverse events. AEs were reported in 5 (63%) of patients; all AEs were mild or moderate in severity and a majority were unrelated to study drug. The acceptable safety profile and clinically significant reduction in urinary oxalate levels observed in these studies support continued clinical development of lumasiran for patients with PH1. A Phase 3 program to evaluate the efficacy and safety of lumasiran in children and adults with primary hyperoxaluria type 1 is now underway.

P.025 APOLLO, a phase 3 study of patisiran for the treatment of hereditary transthyretin amyloidosis (hATTR): 18-month safety and efficacy in subgroup with cardiac involvement

Background: Hereditary transthyretin-mediated (hATTR) amyloidosis a hereditary, multi-systemic and life-threatening disease resulting in neuropathy and cardiomyopathy. In the APOLLO study, patisiran, an investigational RNAi therapeutic targeting hepatic TTR production resulted in significant improvement in neuropathy and QoL compared to placebo and was generally well tolerated. Methods: APOLLO, a Phase 3 study of patisiran vs. placebo (NCT01960348) prespecified a cardiac subpopulation (n=126 of 225 total) that included patients with baseline left ventricular (LV) wall thickness ≥ 13mm and no medical history of aortic valve disease or hypertension. Cardiac measures included structure and function by electrocardiography, changes in NT-proBNP and 10-MWT gait speed. Results: At 18 months, patisiran treatment resulted in a mean reduction in LV wall thickness of 1 mm (p=0.017) compared to baseline, which was associated with significant improvements relative to placebo in LV end diastolic volume (+8.31 mL, p=0.036), global longitudinal strain (-1.37%, p=0.015) and NT-proBNP (55% reduction, p=7.7 x 10-8) (Figure 1). Gait speed was also improved relative to placebo (+0.35 m/sec, p=7.4 x 10-9). Rate of death or hospitalization was lower with patisiran. mNIS+7 results in the cardiac subpopulation will also be presented. Conclusions: These data suggest patisiran has the potential to halt or reverse cardiac manifestations of hATTR amyloidosis.

Investigational RNAi Therapeutic Targeting C5 Is Efficacious in Pre-clinical Models of Myasthenia Gravis

Complement-mediated damage to the neuromuscular junction (NMJ) is a key mechanism of pathology in myasthenia gravis (MG), and therapeutics inhibiting complement have shown evidence of efficacy in the treatment of MG. In this study, we describe the development of a subcutaneously administered N-acetylgalactosamine (GalNAc)-conjugated small interfering RNA (siRNA) targeting the C5 component of complement that silences C5 expression in the liver (ALN-CC5). Treatment of wild-type rodents with ALN-CC5 resulted in robust and durable suppression of liver C5 expression. Dose-dependent serum C5 suppression was observed in non-human primates, with a lowering of serum C5 of up to 97.5% and the concomitant inhibition of serum complement activity. C5 silencing was efficacious in ameliorating disease symptoms in two standard rat models of MG, demonstrating the key role of circulating C5 in pathology at the NMJ. Improvement in disease activity scores and NMJ pathology was observed at intermediate levels of complement activity inhibition, suggesting that complete ablation of complement activity may not be required for efficacy in MG. The pre-clinical studies of ALN-CC5 and efficacy of C5 silencing in rat models of MG support further clinical development of ALN-CC5 as a potential therapeutic for the treatment of MG and other complement-mediated disorders.