Investigational RNA Interference Research Articles

Subgroup results from KARDIA-2: impact of demographic and baseline disease characteristics on zilebesiran response in patients with hypertension uncontrolled by a standard oral antihypertensive

Abstract Background Zilebesiran is an investigational RNA interference therapeutic targeting hepatic angiotensinogen synthesis. In KARDIA-1, a single subcutaneous (SC) dose of zilebesiran monotherapy significantly reduced 24-hr mean ambulatory and office systolic blood pressure (SBP) from baseline to Months 3 and 6 versus placebo. The Phase 2 KARDIA-2 study assessed efficacy and safety of zilebesiran with a standard oral antihypertensive in patients with uncontrolled hypertension. Purpose Uncontrolled hypertension is a leading cause of cardiovascular morbidity and mortality, and medication non-adherence affects blood pressure control. Developing effective, long-lasting treatments is crucial for patients with hypertension uncontrolled by standard therapy. Methods KARDIA-2 enrolled adults with mild-to-moderate hypertension who were untreated or receiving stable therapy with ≤2 antihypertensives. Patients discontinued prior antihypertensive medication and were randomized 10:7:4 to open-label, once-daily oral treatment with 40 mg olmesartan, 5 mg amlodipine, or 2.5 mg indapamide. After ≥4 weeks on protocol-specified medication, patients with a 24-hr mean ambulatory SBP of 130–160 mmHg were randomized 1:1 in a double-blind manner to a single SC dose of zilebesiran 600 mg or placebo as add-on therapy. The primary endpoint was change from baseline to Month 3 in 24-hr mean ambulatory SBP versus placebo for each group. Efficacy and safety were also assessed in pre-specified subgroups: age (<65; ≥65 years), sex, race (Black; other), baseline 24-hr mean ambulatory SBP (<145; ≥145 mmHg), and baseline estimated glomerular filtration rate (≥60; <60 mL/min/1.73m2). Results The primary analysis included 667 patients (median age [range] 59 [27–75] years; 57% male, 28% Black). At Month 3, least-squares mean differences (LSMD) (95% confidence interval [CI]) between zilebesiran and placebo for the olmesartan, amlodipine, and indapamide groups were −4.0 (−7.6, −0.3), −9.7 (−12.9, −6.6), and −12.1 (−16.5, −7.6) mmHg, respectively, for 24-hr mean ambulatory SBP (all p<0.05). LSMD (95% CI) in office SBP for the same groups were −7.0 (−10.4, −3.6), −10.2 (−13.5, −6.9), and −18.5 (−22.8, −14.2) mmHg, respectively, (all p<0.001). SBP reductions were consistent across subgroups, except for a trend towards an attenuated response observed in Black patients (Figs 1, 2). More patients receiving zilebesiran (49–58%) than placebo (39–48%) experienced ≥1 adverse event through Month 6, with low rates of hyperkalaemia, hypotension, or acute kidney injury reported across all groups. Conclusion In KARDIA-2, a single dose of zilebesiran significantly reduced SBP versus placebo at Month 3 on top of a standard oral antihypertensive, with encouraging safety data. SBP reduction was consistent across most subgroups. Treatment with zilebesiran combined with standard antihypertensives may be effective for a broad population of patients with hypertension uncontrolled on monotherapy.

Fazirsiran for Adults With Alpha-1 Antitrypsin Deficiency Liver Disease: A Phase 2 Placebo Controlled Trial (SEQUOIA)

Homozygous ZZ alpha-1 antitrypsin (AAT) deficiency produces mutant AAT (Z-AAT) proteins in hepatocytes, leading to progressive liver fibrosis. We evaluated the safety and efficacy of an investigational RNA interference therapeutic, fazirsiran, that degrades Z-AAT messenger RNA, reducing deleterious protein synthesis. This ongoing, phase 2 study randomized 40 patients to subcutaneous placebo or fazirsiran 25, 100, or 200 mg. The primary endpoint was percent change in serum Z-AAT concentration from baseline to week 16. Patients with fibrosis on baseline liver biopsy received treatment on day 1, at week 4, and then every 12 weeks and had a second liver biopsy at or after weeks 48, 72, or 96. Patients without fibrosis received 2 doses on day 1 and at week4. At week 16, least-squares mean percent declines in serum Z-AAT concentration were-61%,-83%, and-94% with fazirsiran 25, 100, and 200 mg, respectively, vs placebo (all P < .0001). Efficacy was sustained through week 52. At postdose liver biopsy, fazirsiran reduced median liver Z-AAT concentration by 93% compared with an increase of 26% with placebo. All fazirsiran-treated patients had histologic reduction from baseline in hepatic globule burden. Portal inflammation improved in 5 of 12 and 0 of 8 patients with a baseline score of >0 in the fazirsiran and placebo groups, respectively. Histologic meta-analysis of histologic data in viral hepatitis score improved by >1 point in 7 of 14 and 3 of 8 patients with fibrosis of >F0 at baseline in the fazirsiran and placebo groups, respectively. No adverse events led to discontinuation, and pulmonary function tests remained stable. Fazirsiran reduced serum and liver concentrations of Z-AAT in a dose-dependent manner and reduced hepatic globule burden. (ClinicalTrials.gov, Number NCT03945292).

859-P: ALN-KHK, an Investigational RNA Interference Therapeutic, Successfully Targets Hepatic Ketohexokinase in a Single Ascending Dose Study of Overweight to Obese Adults

859-P: ALN-KHK, an Investigational RNA Interference Therapeutic, Successfully Targets Hepatic Ketohexokinase in a Single Ascending Dose Study of Overweight to Obese Adults

RNA Interference With Zilebesiran for Mild to Moderate Hypertension

Angiotensinogen is the most upstream precursor of the renin-angiotensin-aldosterone system, a key pathway in blood pressure (BP) regulation. Zilebesiran, an investigational RNA interference therapeutic, targets hepatic angiotensinogen synthesis. To evaluate antihypertensive efficacy and safety of different zilebesiran dosing regimens. This phase 2, randomized, double-blind, dose-ranging study of zilebesiran vs placebo was performed at 78 sites across 4 countries. Screening initiation occurred in July 2021 and the last patient visit of the 6-month study occurred in June 2023. Adults with mild to moderate hypertension, defined as daytime mean ambulatory systolic BP (SBP) of 135 to 160 mm Hg following antihypertensive washout, were randomized. Randomization to 1 of 4 subcutaneous zilebesiran regimens (150, 300, or 600 mg once every 6 months or 300 mg once every 3 months) or placebo (once every 3 months) for 6 months. The primary end point was between-group difference in least-squares mean (LSM) change from baseline to month 3 in 24-hour mean ambulatory SBP. Of 394 randomized patients, 377 (302 receiving zilebesiran and 75 receiving placebo) comprised the full analysis set (93 Black patients [24.7%]; 167 [44.3%] women; mean [SD] age, 57 [11] years). At 3 months, 24-hour mean ambulatory SBP changes from baseline were -7.3 mm Hg (95% CI, -10.3 to -4.4) with zilebesiran, 150 mg, once every 6 months; -10.0 mm Hg (95% CI, -12.0 to -7.9) with zilebesiran, 300 mg, once every 3 months or every 6 months; -8.9 mm Hg (95% CI, -11.9 to -6.0) with zilebesiran, 600 mg, once every 6 months; and 6.8 mm Hg (95% CI, 3.6-9.9) with placebo. LSM differences vs placebo in change from baseline to month 3 were -14.1 mm Hg (95% CI, -19.2 to -9.0; P < .001) with zilebesiran, 150 mg, once every 6 months; -16.7 mm Hg (95% CI, -21.2 to -12.3; P < .001) with zilebesiran, 300 mg, once every 3 months or every 6 months; and -15.7 mm Hg (95% CI, -20.8 to -10.6; P < .001) with zilebesiran, 600 mg, once every 6 months. Over 6 months, 60.9% of patients receiving zilebesiran had adverse events vs 50.7% patients receiving placebo and 3.6% had serious adverse events vs 6.7% receiving placebo. Nonserious drug-related adverse events occurred in 16.9% of zilebesiran-treated patients (principally injection site reactions and mild hyperkalemia) and 8.0% of placebo-treated patients. In adults with mild to moderate hypertension, treatment with zilebesiran across a range of doses at 3-month or 6-month intervals significantly reduced 24-hour mean ambulatory SBP at month 3. ClinicalTrials.gov Identifier: NCT04936035.

Abstract 116: Safety And Tolerability Of Zilebesiran, An RNA Interference Therapeutic Targeting Hepatic Angiotensinogen Synthesis, In Obese Patients With Hypertension

Introduction: Single subcutaneous (SC) doses of zilebesiran, an investigational RNA interference therapeutic targeting hepatic angiotensinogen (AGT) synthesis, have been shown to reduce serum AGT levels and blood pressure (BP) in patients with mild-moderate hypertension based on results from phase 1 studies. Limited data are available on the safety, pharmacodynamics, and efficacy of multiple dosing or administration of zilebesiran in patients with Class II/III obesity. Methods: Patients with hypertension (mean seated office systolic BP (SBP) of &gt;130 and ≤165 mmHg after washout of antihypertensive medication) and Class II/III obesity (BMI &gt;35 kg/m 2 and ≤50 kg/m 2 ) without diabetes were randomized 2:1 to zilebesiran or irbesartan in a double-blind, double-dummy design. Patients received either sequential doses of zilebesiran 800 mg SC (Day 1 and 85) and daily oral placebo, or sequential SC doses of saline (Day 1 and 85) and daily 150mg oral irbesartan. Key endpoints included safety, change in AGT level from baseline to week 24 (using an enzyme-linked immunosorbent assay), and change in BP from baseline to week 24 (by 24-h ambulatory BP monitoring). Results: Twelve patients were enrolled (zilebesiran, N=8; irbesartan, N=4; median (range) age 56 (46-64) years, 67% female, mean ± SD BMI 40 ± 4 kg/m 2 , baseline 24-h mean ± SD [systolic/diastolic] BP 144 ± 10 / 88 ± 9 mmHg). At least one adverse event (AE) was reported in 6 zilebesiran patients and 4 irbesartan patients, most of which were mild or moderate; one serious AE occurred with zilebesiran and was considered unrelated. There were no episodes of hypotension requiring intervention in either arm. AGT levels did not change with irbesartan but were reduced with zilebesiran by 99% from week 4 to week 24. Change in SBP from baseline to week 24 was -27 ± 8 mmHg with zilebesiran versus -19 ± 6 mmHg with irbesartan. Conclusions: In this Phase 1 study of obese patients with hypertension, administration of two sequential doses of zilebesiran was associated with durable reductions in serum AGT levels and sustained reductions in BP persisting to 24 weeks. Zilebesiran was also generally well tolerated in this patient population. These data suggest that pharmacodynamics, efficacy, and safety of zilebesiran may not be influenced by BMI.

Safety, Pharmacokinetics, and Exposure-Response Modeling of Nedosiran in Participants With Severe Chronic Kidney Disease.

Nedosiran is an investigational RNA-interference therapeutic in development for primary hyperoxaluria (PH). Because nedosiran undergoes renal clearance, we assessed its pharmacokinetic profile in non-PH participants with normal kidney function and Stages 4/5 chronic kidney disease (CKD), the latter with/without dialysis. Nedosiran exposure-response modeling in patients with PH Subtype 1 (PH1) with different renal function level was performed to recommend a nedosiran dose for this subpatient population. In this open-label, single-dose, Phase 1 study, 24 participants with estimated glomerular filtration rate <30mL/min/1.73m2 (CKD Stages 4/5; on hemodialysis [Groups 1a, 1b] and not on hemodialysis [Group 2]) and 10participants with normal kidney function (estimated glomerular filtration rate ≥90mL/min/1.73m2 ; Group 3) received a single dose of subcutaneous nedosiran sodium 170mg. Group 1a received nedosiran 8hours before beginning hemodialysis, Group 1b received nedosiran 2hours after completing hemodialysis; Group 2 was not on hemodialysis. Nedosiran population pharmacokinetic-pharmacodynamic analyses were conducted using pooled data from this study and 4 others. Nedosiran pharmacokinetic exposure in non-PH participants with CKD Stages 4/5 was approximately 2-fold higher versus participants with normal kidney function. Hemodialysis timing relative to nedosiran administration had no clinically significant impact on pharmacokinetics (Group 1a vs 1b). Nedosiran was well tolerated. Modeling indicated that in patients with PH1 with CKD Stages 4/5, lower nedosiran doses provide similar exposure and potential reduction in 24-hour urinary oxalate to standard nedosiran doses in patients with PH1 with normal kidney function or CKD Stages 2/3. Nedosiran dosage reductions are recommended in patients with PH1 with CKD Stages 4/5; further adjustments are unnecessary if dialysis is started.

Zilebesiran, an RNA Interference Therapeutic Agent for Hypertension

BackgroundAngiotensinogen is the sole precursor of angiotensin peptides and has a key role in the pathogenesis of hypertension. Zilebesiran, an investigational RNA interference therapeutic agent with a prolonged duration of action, inhibits hepatic angiotensinogen synthesis.MethodsIn this phase 1 study, patients with hypertension were randomly assigned in a 2:1 ratio to receive either a single ascending subcutaneous dose of zilebesiran (10, 25, 50, 100, 200, 400, or 800 mg) or placebo and were followed for 24 weeks (Part A). Part B assessed the effect of the 800-mg dose of zilebesiran on blood pressure under low- or high-salt diet conditions, and Part E the effect of that dose when coadministered with irbesartan. End points included safety, pharmacokinetic and pharmacodynamic characteristics, and the change from baseline in systolic and diastolic blood pressure, as measured by 24-hour ambulatory blood-pressure monitoring.ResultsOf 107 patients enrolled, 5 had mild, transient injection-site reactions. There were no reports of hypotension, hyperkalemia, or worsening of renal function resulting in medical intervention. In Part A, patients receiving zilebesiran had decreases in serum angiotensinogen levels that were correlated with the administered dose (r=−0.56 at week 8; 95% confidence interval, −0.69 to −0.39). Single doses of zilebesiran (≥200 mg) were associated with decreases in systolic blood pressure (>10 mm Hg) and diastolic blood pressure (>5 mm Hg) by week 8; these changes were consistent throughout the diurnal cycle and were sustained at 24 weeks. Results from Parts B and E were consistent with attenuation of the effect on blood pressure by a high-salt diet and with an augmented effect through coadministration with irbesartan, respectively.ConclusionsDose-dependent decreases in serum angiotensinogen levels and 24-hour ambulatory blood pressure were sustained for up to 24 weeks after a single subcutaneous dose of zilebesiran of 200 mg or more; mild injection-site reactions were observed. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov number, NCT03934307; EudraCT number, 2019-000129-39.)

Evaluation of RNAi therapeutics VIR-2218 and ALN-HBV for chronic hepatitis B: Results from randomized clinical trials

Current therapy for chronic hepatitis B virus (cHBV) infection involves lifelong treatment. New treatments that enable HBV functional cure would represent a clinically meaningful advance. ALN-HBV and VIR-2218 are investigational RNA interference therapeutics that targetall major HBV transcripts. We report on: i) the safety of single doses of VIR-2218 (modified from ALN-HBV by enhanced stabilization chemistry plus technology to reduce off-target, seed-mediated binding while maintaining on-target antiviral activity) and ALN-HBV in humanized mice; ii) a cross-study comparison of the safety of single doses of VIR-2218 and ALN-HBV in healthy human volunteers (n= 24 and n= 49, respectively); and iii) the antiviral activity of two doses of 20, 50, 100, 200mg of VIR-2218 (total n= 24) vs. placebo (n= 8), given 4 weeks apart, in participants with cHBV infection. In humanized mice, alanine aminotransferase (ALT) levels were markedly lower following administration of VIR-2218 compared with ALN-HBV. In healthy volunteers, post-treatment ALT elevations occurred in 28% of participants receiving ALN-HBV compared with none in those receiving VIR-2218. In participants with cHBV infection, VIR-2218 was associated with dose-dependent reductions in hepatitis B surface antigen (HBsAg). The greatest mean reduction of HBsAg at Week 20 in participants receiving 200mg was 1.65 log IU/ml. The HBsAg reduction was maintained at 0.87 log IU/ml at Week 48. No participants had serum HBsAg loss or hepatitis B surface antibody seroconversion. VIR-2218 demonstrated an encouraging hepatic safety profile in preclinical and clinical studies as well as dose-dependent HBsAg reductions in patients with cHBV infection. These data support future studies with VIR-2218 as part of combination regimens with a goal of HBV functional cure. ClinicalTrials.gov identifiers: NCT02826018 and NCT03672188. A significant unmet need exists for therapies for chronic HBV (cHBV) infection that achieve functional cure. We report clinical and non-clinical data on two investigational small-interfering RNAs that target HBx, ALN-HBV and VIR-2218, demonstrating that incorporation of enhanced stabilization chemistry plus technology in VIR-2218 reduces its propensity to cause ALT elevations relative to its parent compound, ALN-HBV. We also show that VIR-2218 reduces hepatitis B surface antigen levels in a dose-dependent manner in participants with cHBV infection. These studies support the continued development of VIR-2218 as part of therapeutic regimens for cHBV infection, with the goal of a functional cure, and are important for HBV researchers and physicians.

Lumasiran for primary hyperoxaluria type 1: What we have learned?

Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive genetic disorder caused by mutations in the AGXT gene. The hepatic peroxisomal enzyme alanine glyoxylate aminotransferase (AGT) defects encoded by the AGXT gene increase oxalate production, resulting in nephrocalcinosis, nephrolithiasis, chronic kidney disease, and kidney failure. Traditional pharmacological treatments for PH1 are limited. At present, the treatment direction of PH1 is mainly targeted therapy which refer to a method that targeting the liver to block the pathway of the production of oxalate. Lumasiran (OxlumoTM, developed by Alnylam Pharmaceuticals), an investigational RNA interference (RNAi) therapeutic agent, is the first drug approved for the treatment of PH1, which was officially approved by the US Food and Drug Administration and the European Union in November 2020. It is also the only drug that has been shown to decrease harmful oxalate. Currently, there are 5 keys completed and ongoing clinical trials of lumasiran in PH1. Through the three phase III trials that completed the primary analysis period, lumasiran has been shown to be effective in reducing oxalate levels in urine and plasma in different age groups, such as children, adults, and patients with advanced kidney disease, including those on hemodialysis. In addition to clinical trials, cases of lumasiran treatment for PH1 have been reported in small infants, twin infants, and children diagnosed with PH1 after kidney transplantation. These reports confirm the effectiveness and safety of lumasiran. All adverse events were of mild to moderate severity, with the most common being mild, transient injection-site reactions. No deaths or severe adverse events were reported. This article reviews PH1 and lumasiran which is the only approved therapeutic drug, and provide new options and hope for the treatment of PH1.

PHYOX2: a pivotal randomized study of nedosiran in primary hyperoxaluria type 1 or 2

Nedosiran is an investigational RNA interference agent designed to inhibit expression of hepatic lactate dehydrogenase, the enzyme thought responsible for the terminal step of oxalate synthesis. Oxalate overproduction is the hallmark of all genetic subtypes of primary hyperoxaluria (PH). In this double-blind, placebo-controlled study, we randomly assigned (2:1) 35 participants with PH1 (n= 29) or PH2 (n= 6) with eGFR≥30 mL/min/1.73 m2 to subcutaneous nedosiran or placebo once monthly for 6 months. The area under the curve (AUC) of percent reduction from baseline in 24-hour urinary oxalate (Uox) excretion (primary endpoint), between day 90-180, was significantly greater with nedosiran vs placebo (least squares mean [SE],+3507 [788] vs-1664 [1190], respectively; difference, 5172; 95% CI 2929-7414; P< 0.001). A greater proportion of participants receiving nedosiran vs placebo achieved normal or near-normal (<0.60 mmol/24 hours;<1.3× ULN) Uox excretion on≥2 consecutive visits starting at day 90 (50% vs 0; P= 0.002); this effect was mirrored in the nedosiran-treated PH1 subgroup (64.7% vs 0; P< 0.001). The PH1 subgroup maintained a sustained Uox reduction while on nedosiran, whereas no consistent effect was seen in the PH2 subgroup. Nedosiran-treated participants with PH1 also showed a significant reduction in plasma oxalate versus placebo (P= 0.017). Nedosiran was generally safe and well tolerated. In the nedosiran arm, the incidence of injection-site reactions was 9% (all mild and self-limiting). In conclusion, participants with PH1 receiving nedosiran had clinically meaningful reductions in Uox, the mediator of kidney damage in PH.

Abstract 11276: Safety and Tolerability of ALN-AGT, an RNA Interference Therapeutic Targeting Hepatic Angiotensinogen Synthesis, in Hypertensive Patients During Sodium Depletion or Irbesartan Coadministration

Introduction: We have recently reported that ALN-AGT, a subcutaneous (SC) investigational RNA interference therapeutic targeting hepatic angiotensinogen (AGT) synthesis, reduced BP and was generally well tolerated in a single ascending dose study of hypertensive patients. To further assess its safety profile, additional studies have been initiated to test the effects of peak ALN-AGT pharmacology during salt depletion or irbesartan add-on treatment. Methods: As part of a Phase 1 program, hypertensive patients (mean seated SBP of &gt;130 and ≤165 mm Hg after washout of antihypertensive medication) were given a single dose of ALN-AGT 800 mg SC that has been shown to reduce serum AGT by ≥95%. At Day 43 (corresponding to expected peak serum AGT reduction), these ALN-AGT-treated patients were admitted to receive interventions of a 7-day sodium restricted diet (10 mmol sodium day) or a 14-day add-on treatment regimen with the angiotensin receptor blocker irbesartan 300 mg by oral administration daily. Results: In the salt depletion cohort, 12 patients (mean age 56 years, 75% male, 25% black, mean baseline 24-h SBP 141+/- 8 mm Hg) have been dosed 2:1 with ALN-AGT or placebo SC in advance of the sodium restricted diet. In the irbesartan add-on cohort, 10 patients (mean age 55 years, 30% male, 30% black, mean baseline 24-h SBP 147 +/- 8 mm Hg) have received ALN-AGT in advance of irbesartan add-on. The study has completed patient enrollment and interventions with no patient discontinuations due to AEs. The data analysis is ongoing at the time of abstract submission. Conclusions: This ongoing study will provide insight into ALN-AGT tolerability during potential augmented pharmacology, using salt restriction to test ALN-AGT’s effects during reduced extracellular fluid volume and irbesartan coadministration to assess the effects of ALN-AGT’s liver-specific AGT silencing during angiotensin II receptor blockade. Data on tolerability, laboratory safety monitoring, serum AGT reduction, RAAS-related biomarkers, and blood pressure will be presented.

Abstract 10974: Durable Reductions in Circulating Angiotensinogen and Blood Pressure Six Months After Single Doses of ALN-AGT, an RNA Interference Therapeutic Targeting Hepatic Angiotensinogen Synthesis, in Hypertensive Patients

Introduction: ALN-AGT, a subcutaneous (SC) investigational RNA interference therapeutic targeting hepatic angiotensinogen (AGT) synthesis, is being evaluated as a novel treatment for hypertension in a multicenter, randomized, placebo-controlled single ascending dose study. Here we present new data on the long-term pharmacodynamic and antihypertensive effects of ALN-AGT six months after single-dose administration. Methods: As part of a Phase 1 program to assess the safety and tolerability of ALN-AGT, hypertensive patients (mean seated systolic blood pressure [SBP] of &gt;130 and ≤165 mmHg after a washout of antihypertensive medications) were randomized 2:1 to ascending single doses of ALN-AGT (10-800 mg) or placebo. Change from baseline BP was measured by ambulatory BP monitoring (ABPM) at Week 8, Week 12, and Month 6. Interim results as of May 28, 2021 are reported. Results: 84 hypertensive patients (mean age 53 years, 61% male, 26% black, mean (SD) baseline 24-h SBP 140 (9) mm Hg) were enrolled in ascending single dose cohorts of ALN-AGT up to 800 mg SC. Dose-dependent and durable reductions in serum AGT levels were observed, with single doses ≥100 mg achieving serum AGT reductions &gt;90% and 24-h SBP reductions &gt;10 mm Hg (17 mm Hg in the 800 mg cohort) through Week 12. The 24-hour ABPM profile of ALN-AGT-treated patients showed sustained reductions of daytime BP with equally marked nighttime BP reduction. Notably, new data from follow-up visits show that all patients who received a single dose of 800 mg maintained serum AGT reductions &gt;90% from Week 3 to Month 6, with a mean (SD) 24-h SBP reduction of 22 (15) mm Hg at Month 6 (5 of 8 patients without add-on antihypertensive treatment). There were no treatment-related serious adverse events or clinically significant elevations in blood creatinine or potassium. No patient required intervention for hypotension. Conclusions: Single dose administration of ALN-AGT to hypertensive patients was generally well tolerated and resulted in profound reductions in serum AGT and BP through Month 6. The durable reduction of serum AGT &gt;90% with sustained 24-hour BP reduction over a period of 6 months after single dose SC administration of ALN-AGT 800 mg supports further evaluation of both quarterly and biannual dose administration.

Perioperative Management in Patients with Hemophilia Receiving Fitusiran, an Investigational RNAi Therapeutic Targeting Antithrombin for the Treatment of Hemophilia

Introduction: Hemophilia is a bleeding disorder characterized by ineffective clot formation due to insufficient thrombin generation. Fitusiran is a subcutaneously (SC) administered investigational RNA interference (RNAi) therapeutic targeting antithrombin (AT) as a means to improve thrombin generation (TG) and promote hemostasis in patients with hemophilia A or B with and without inhibitors. Previously reported data have shown that monthly administration of fitusiran led to dose dependent AT lowering, improved thrombin generation and decreased bleeding frequency. (Pasi et al. Blood . 2016.; Pasi et al. New Engl J Med . 2017.) Data from an open-label extension study demonstrated an encouraging safety and tolerability profile, including when used in combination with factor or bypassing agents to treat breakthrough bleeds. (Pasi et al. Res Pract Thromb Haemost . 2017.) The management of operative procedures while on novel, non-factor therapies for hemophilia, such as fitusiran, is of clinical interest. The purpose of this abstract is to describe details as reported by study investigators on the perioperative hemostatic management during dental/surgical procedures in patients with hemophilia receiving fitusiran in a clinical trial.Methods: The fitusiran Phase 1 study (NCT02035605) followed by the Phase 2 open-label extension (OLE) study (NCT02554773) included patients with hemophilia A or B with and without inhibitors. After the Phase 1 dose-escalation study, patients eligible to continue dosing in the Phase 2 OLE received monthly, fixed SC doses of fitusiran, 50 mg or 80 mg. Data on perioperative hemostatic treatment and hemostatic response were collected for patients undergoing dental/surgical procedures while AT was lowered on study.Results: Four patients, ages 22-36, with severe hemophilia A (2 with inhibitors) underwent 5 surgical procedures: endoscopic cholecystectomy and septoplasty; thoracotomy/partial lung segmentectomy; molar teeth extraction; premolar tooth extraction. Prior to the procedures, the AT level for each of these patients was <20% (range: 10.7 - 19%) relative to baseline. At the Investigators' discretion, perioperative hemostatic treatments (FVIII, rFVIIa, and/or aPCC) were administered for 4 of the 5 procedures. The duration of hemostatic treatment coverage varied depending on the type of procedure: 15 hours post-procedure (premolar tooth extraction), 7 days post-procedures (endoscopic cholecystectomy and septoplasty), and 13 days post-procedure (thoracotomy/partial lung segmentectomy). No thromboprophylaxis was used in any procedure. All procedures were rated by the respective investigator as resulting in minimal blood loss or blood loss similar to a patient without hemophilia. Further details on the perioperative treatment regimens and hemostatic responses will be presented.Conclusion: Successful perioperative hemostatic management of patients in the context of AT lowering with fitusiran has been observed; the number of dental/surgical procedures is limited and additional data are needed to further define appropriate perioperative hemostatic management plans. DisclosuresNegrier:Baxter: Research Funding; Inspiration: Research Funding; LFB: Honoraria, Speakers Bureau; Octapharma: Honoraria, Research Funding, Speakers Bureau; CSL Behring: Honoraria, Research Funding, Speakers Bureau; Baxalta: Honoraria, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau; Alnylam: Research Funding; Bayer: Honoraria, Research Funding, Speakers Bureau; Novo Nordisk: Honoraria, Research Funding, Speakers Bureau; Biogen/SOBI: Honoraria, Research Funding, Speakers Bureau. Ragni:Alnylam: Consultancy, Honoraria, Research Funding; Biomarin: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; MOGAM: Consultancy, Honoraria; Sangamo: Research Funding; Genentech/Roche: Research Funding; Bioverativ: Consultancy, Honoraria, Research Funding; NovoNordisk: Honoraria; SPARK: Research Funding; Shire: Consultancy, Honoraria, Research Funding. Georgiev:Alnylam: Consultancy. Van Nguyen:Alnylam: Employment, Equity Ownership. Madigan:Alnylam: Employment, Equity Ownership. Pasi:Bayer HealthCare; Biotest; Novo Nordisk; Pfizer Inc.; Roche: Speakers Bureau; Alnylam Pharmaceuticals, Inc; Biogen Idec Inc.; BioMarin Pharmaceutical Inc.; Octapharmal; Roche; Shire; SOBI: Consultancy; Pfizer, SOBI, Octapharma, Shire, Bayer, Alnylam, Biomarin, Biotest: Honoraria; Alnylam Pharmaceuticals; BioMarin Pharmaceutical Inc.; SOBI: Membership on an entity's Board of Directors or advisory committees; Roche, NovoNordisk, Pfizer: Other: paid instructor; BioMarin Pharmaceutical Inc.; Octapharma, Alnylam Pharmaceuticals, Bioverativ: Research Funding.

Lumasiran, an RNAi Therapeutic for Primary Hyperoxaluria Type 1

BackgroundPrimary hyperoxaluria type 1 (PH1) is a rare genetic disease caused by hepatic overproduction of oxalate that leads to kidney stones, nephrocalcinosis, kidney failure, and systemic oxalosis. Lumasiran, an investigational RNA interference (RNAi) therapeutic agent, reduces hepatic oxalate production by targeting glycolate oxidase.MethodsIn this double-blind, phase 3 trial, we randomly assigned (in a 2:1 ratio) patients with PH1 who were 6 years of age or older to receive subcutaneous lumasiran or placebo for 6 months (with doses given at baseline and at months 1, 2, 3, and 6). The primary end point was the percent change in 24-hour urinary oxalate excretion from baseline to month 6 (mean percent change across months 3 through 6). Secondary end points included the percent change in the plasma oxalate level from baseline to month 6 (mean percent change across months 3 through 6) and the percentage of patients with 24-hour urinary oxalate excretion no higher than 1.5 times the upper limit of the normal range at month 6.ResultsA total of 39 patients underwent randomization; 26 were assigned to the lumasiran group and 13 to the placebo group. The least-squares mean difference in the change in 24-hour urinary oxalate excretion (lumasiran minus placebo) was −53.5 percentage points (P<0.001), with a reduction in the lumasiran group of 65.4% and an effect seen as early as month 1. The between-group differences for all hierarchically tested secondary end points were significant. The difference in the percent change in the plasma oxalate level (lumasiran minus placebo) was −39.5 percentage points (P<0.001). In the lumasiran group, 84% of patients had 24-hour urinary oxalate excretion no higher than 1.5 times the upper limit of the normal range at month 6, as compared with 0% in the placebo group (P<0.001). Mild, transient injection-site reactions were reported in 38% of lumasiran-treated patients.ConclusionsLumasiran reduced urinary oxalate excretion, the cause of progressive kidney failure in PH1. The majority of patients who received lumasiran had normal or near-normal levels after 6 months of treatment. (Funded by Alnylam Pharmaceuticals; ILLUMINATE-A ClinicalTrials.gov number, NCT03681184.)

SAFETY, PHARMACODYNAMICS, AND BLOOD PRESSURE EFFECTS OF ALN-AGT, AN RNA INTERFERENCE THERAPEUTIC TARGETING ANGIOTENSINOGEN, IN A RANDOMIZED SINGLE ASCENDING DOSE STUDY OF HYPERTENSIVE ADULTS

Objective: Angiotensinogen (AGT) is the sole precursor of all angiotensin peptides and plays a key role in hypertension pathogenesis. We evaluated the effect of ALN-AGT, a subcutaneous investigational RNA interference (RNAi) therapeutic targeting hepatic AGT synthesis, on blood pressure in hypertensive patients. Design and Method: As part of a phase 1 program designed to assess the safety and tolerability of ALN-AGT, we conducted a multicenter study randomizing patients aged 18–65 years with mild to moderate hypertension (mean seated systolic blood pressure [SBP] of &gt; 130 and ?165 mmHg after washout of antihypertensive medication) 2:1 to ascending single doses of ALN-AGT or placebo. Change from baseline in BP at 8 weeks was measured by ambulatory BP monitoring (ABPM). We report interim results as of Oct 27, 2020. Design and method: Eighty-four patients (mean age 53 years, 39% female, mean baseline 24 h SBP 139.7 +/- 8.9 mm Hg) were enrolled in ascending dose cohorts of 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 400 mg or 800 mg. Dose-related reductions in serum AGT levels were observed (figure), with mean reductions of &gt; 90% at doses ?100 mg. AGT remained durably reduced through 12 weeks after single dose administration (data pending for 800 mg cohort). Concomitant reductions in BP from baseline were observed with AGT knockdown, with mean reductions in 24-hour SBP of &gt; 10 mm Hg observed at Week 8 after single doses of 100 mg or higher. No treatment-related serious adverse events or clinically significant elevations in blood creatinine or potassium were seen. No patient required intervention for low blood pressure. Results: Single dose administration of ALN-AGT to hypertensive patients was generally well tolerated and resulted in dose-related reductions in serum AGT and BP over 8 weeks. Durable AGT knockdown to 12 weeks supports further evaluation of once quarterly or potentially less frequent dose administration.

Abstract 12594: Pharmacodynamic Effect of ARO-APOC3, an Investigational Hepatocyte-targeted RNA Interference Therapeutic Targeting Apolipoprotein C3, in Patients With Hypertriglyceridemia and Multifactorial Chylomicronemia

Background: Hypertriglyceridemia (HTG) increases the risk of acute pancreatitis and atherosclerosis. In a Phase 1 study (NCT03783377), single subcutaneous doses of investigational RNA interference (RNAi) therapeutic ARO-APOC3 (10, 25, 50, and 100 mg; N=24) demonstrated deep and prolonged reductions in apolipoprotein C3 (APOC3) and triglycerides (TG) and increases in HDL-C in healthy volunteers with good tolerability, compared with placebo (N=16). Purpose: We report initial results of the effects of ARO-APOC3 in patients with HTG (fasting TG ≥ 300 mg/dL) or multifactorial chylomicronemia (MCM; fasting TG ≥ 880 mg/dL). Methods: Up to 40 subjects with HTG and 20 subjects with MCM will receive ARO-APOC3 or placebo on days 1 and 29. Pharmacodynamic responses include serum APOC3, TG, and other lipid parameters reported up to week 4 prior to the 2 nd dose. Results: At the data cutoff (16 March 2020), the first 4 enrolled patients with HTG and 6 enrolled patients with MCM were administered ARO-APOC3 50 mg. ARO-APOC3 substantially reduced mean (range) APOC3 levels by 96% (88-99%) in both patient groups at Week 4 (Table). ARO-APOC3 substantially reduced mean (range) TG by 78% (67-87%) in HTG patients and by 92% (90-95%) in MCM patients at Week 4. Three of 4 HTG patients and 3 of 6 MCM patients had TG levels below 150 mg/dL. All MCM patients had TG ≤ 500 mg/dL. To date, ARO-APOC3 has been generally well tolerated with no reports of treatment-related serious or severe adverse events. Two of the 6 unblinded MCM patients experienced a transient ALT elevation to &gt;3X ULN that returned to approximate pre-dose baseline by Day 113. Conclusions: Preliminary results indicate that a single dose of ARO-APOC3 reduces APOC3 levels by &gt;90% and TG by ~80% 4 weeks after treatment in patients with HTG and MCM. The magnitude of treatment effect was similar in both populations and ARO-APOC3 had a favorable safety profile. Using RNAi to silence expression of APOC3 appears promising for treating patients with HTG and MCM.

Abstract 15751: Pharmacodynamic Effect of ARO-ANG3, an Investigational RNA Interference Targeting Hepatic Angiopoietin-like Protein 3, in Patients With Hypercholesterolemia

Background: Angiopoietin-like protein 3 (ANGPTL3) regulates triglyceride (TG) and lipoprotein (LP) metabolism by inhibiting liver and endothelial LP lipases and reduces plasma LDL-C. In Phase 1 Study AROANG1001 (NCT03747224), single and multiple doses of RNA interference therapeutic ARO-ANG3 (100, 200, or 300 mg; n=36) in healthy volunteers substantially reduced ANGPTL3, LDL-C, and other LPs (AHA 2019) compared with placebo (n=16). Purpose: We report preliminary results following repeat doses (days 1 and 29) of ARO-ANG3 in patients with heterozygous familial hypercholesterolemia (FH) with elevated LDL-C despite statin therapy and average LDL-C of 130 mg/dL. An additional group (non-FH patients) had LDL-C &gt; 70 mg/dL despite statin therapy. Methods: Seventeen FH patients received open-label, subcutaneous, ARO-ANG3 100 mg (n=6), 200 mg (n=6), or 300 mg (n=5). Nine non-FH, high risk patients with elevated LDL-C not at goal received either 200 mg ARO-ANG3 (n=6) or placebo (n=3) using a randomized double-blind design. Pharmacodynamic markers included serum ANGPTL3, LDL-C, TG, and others. Results: Results are reported as of 04 May 2020. In FH patients, ARO-ANG3 significantly reduced mean ANGPTL3 levels between 62-92% at week 16 in a dose-dependent manner (Table). LDL-C (23-37%) and TG (25-43%) were consistently reduced at all doses (Table). The mean percent reductions in non-FH patients for ANGPTL3 (85%), LDL-C (28%), and TG (29%) were comparable to those in FH patients, despite their initially lower LDL-C at baseline. As of 15 May 2020, there were no drug-related serious or severe adverse events (AEs) or discontinuations and most AEs were mild. The most common AEs reported in subjects receiving ARO-ANG3 were respiratory tract infection (30% of subjects) and injection site AEs (13% of subjects). Conclusions: In FH and non-FH patients, repeat doses of ARO-ANG3 significantly reduced ANGPTL3, LDL-C, and TG, with favorable safety.

Long-Term Durability, Safety and Efficacy of Fitusiran Prophylaxis in People with Hemophilia a or B, with or without Inhibitors - Results from the Phase II Study

Long-Term Durability, Safety and Efficacy of Fitusiran Prophylaxis in People with Hemophilia a or B, with or without Inhibitors - Results from the Phase II Study

Fitusiran Treatment Impacts on Health-Related Quality of Life in Subjects with Hemophilia A and B with Inhibitors Assessed with the Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QoL)

Background: Fitusiran, an investigational RNA interference treatment for people with hemophilia A or B (PwH), with or without inhibitors, has shown dose-dependent lowering of antithrombin, increase in thrombin generation, and decrease in bleeding frequency in clinical trials. The novel mechanism of action and long pharmacodynamic effect enables once-monthly subcutaneous administration. This sustained hemostatic protection and less burdensome administration may improve patient-reported outcomes (PRO). Objective: To evaluate changes in PRO in terms of patient-relevant improvements in health-related quality of life (HRQoL) in PwH with inhibitors (PwHI) on prophylactic fitusiran treatment. Methods: Fitusiran was evaluated in a phase 1 dose-escalation study (NCT02035605) followed by a phase 2 open-label extension (OLE) study (NCT02554773) with monthly subcutaneous fixed doses of 50 mg or 80 mg. HRQoL was assessed using the Haem-A-QoL and the EuroQol 5 Dimensions (EQ-5D) questionnaires at baseline and at end of study in a cohort of 17 PwHI (Hemophilia A, n=15; Hemophilia B, n=2) from the phase 1 study. Results: Subjects previously treated on-demand or prophylactically had a mean (standard deviation [SD]) age of 34.6 (10.3) years and a mean (SD) number of bleeding episodes in the 6 months before baseline of 16.6 (10.7). Mean (SD) changes from baseline to end of study (day 84 or later) in Haem-A-QoL total (-9.2 [11.2]) and physical health (−12.3 [15.1]) domain scores suggest clinically meaningful improvement (lower scores indicate better HRQoL). Numeric reduction (i.e., improvement) in all other domains appeared to be dose-dependent (greater improvement in the 80 mg group) (Table 1). Changes in EQ-5D utility and EQ-VAS scores were not clinically meaningful. Further analyses in PwH with and without inhibitors from the phase 2 OLE will be presented. Conclusions: Fitusiran prophylaxis may improve HRQoL - particularly the Haem-A-QoL 'Physical health' domain (painful swelling, joint pain, pain with movement, difficulty walking, and time to get ready) as shown in a cohort of 17 PwHI . Additional analyses from ongoing OLE and phase 3 studies are planned to quantify the patient-relevant changes with fitusiran treatment in all hemophilia patients over time. Disclosures Von Mackensen: Sanofi, Bayer, Sobi, Chugai, Kedrion, Spark: Consultancy; Biotest, Sobi, CSL Behring: Honoraria; Novo Nordisk, Sobi: Research Funding. Chowdary:BioMarin: Honoraria; Bayer, CSL Behring, Freeline, Novo Nordisk, Pfizer and Sobi: Research Funding; Chugai, CSL Behring, Novo Nordisk, Pfizer, Roche, Sobi: Speakers Bureau; Bayer, Chugai, CSL Behring, Freeline, Novo Nordisk, Pfizer, Roche, Sanofi, Shire (Baxalta), Sobi, Spark: Membership on an entity's Board of Directors or advisory committees. Mangles:Roche, Takeda, Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sobi, Octapharma, Novo Nordisk, Shire and Roche/Chugai: Other: travel funding. Yu:Sanofi: Other: was an employee and stockholder of Sanofi, at the time of study; Albireo Pharmaceuticals, Inc: Current Employment. Mei:Sanofi: Current Employment, Current equity holder in publicly-traded company. Andersson:Sanofi: Current Employment, Current equity holder in publicly-traded company. Dasmahapatra:Sanofi: Current Employment, Current equity holder in publicly-traded company.

Longitudinal Assessment of Thrombin Generation in Patients with Hemophilia Receiving Fitusiran Prophylaxis: Phase II Study Results

Longitudinal Assessment of Thrombin Generation in Patients with Hemophilia Receiving Fitusiran Prophylaxis: Phase II Study Results