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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.

This is a randomized, double‐blind, single‐dose, parallel group phase 1 study to assess pharmacokinetic similarity, safety, and tolerability of BS‐503a, a proposed bevacizumab biosimilar. A total of 114 male healthy subjects were randomized (1:1) to receive a single 3 mg/kg intravenous dose of either BS‐503a or bevacizumab (Avastin®). Pharmacokinetic (PK) blood samples were collected up to Day 78, and serum drug concentrations were measured using a validated enzyme‐linked immunosorbent assay. Pharmacokinetic similarity was evaluated using area under the serum concentration‐time curve from zero to infinity (AUC inf) as a primary PK parameter, and maximum serum concentration (C max) and area under the serum concentration‐time curve from zero to the last measurable time (AUC last) as secondary PK parameters. The 90% confidence intervals (CIs) of geometric mean ratio of AUC inf ranged 0.980–1.105, which met the predefined criteria of 0.80–1.25. The 90% CIs of geometric mean ratios for C max and AUC last were 1.009–1.125 and 0.982–1.096, respectively, falling into the same criteria. At least one drug‐related treatment emergent adverse event occurred in 18 and 21 subjects treated with BS‐503a and bevacizumab, respectively. The most common adverse events were headache, epistaxis, and rhinorrhea. Most adverse events were mild or moderate; however, one drug‐related serious adverse event of duodenal ulcer perforation was reported by a subject 47 days after treatment of BS‐503a. In conclusion, BS‐503a was demonstrated to have highly similar PK to bevacizumab and adverse events observed were consistent with those observed for bevacizumab.

AICA-riboside (5-amino-4-imidazole carboxamide ribonucleoside) is a novel adenosine-regulating agent that is currently being investigated for the treatment of ischemic heart disease. In a placebo-controlled, double-blind study in healthy men, we evaluated the safety and kinetics of the drug after oral and IV administration of 10, 25, 50, and 100 mg/kg doses. At each dose level, four subjects received active drug and two subjects received placebo with a 1-week wash-out period between the IV and oral doses. The drug was well tolerated at all dose levels with only mild and transient side effects reported in some instances by the subjects who received placebo and those patients who received the drug. The post-infusion plasma concentrations of AICA-riboside declined rapidly in a biphasic fashion, and the terminal elimination phase had a harmonic mean t1/2 beta of 1.4 hours. Total plasma clearance (CL), mean residence time (MRTIV), and volume of distribution at steady-state (VSS) were 2.5 L/hr/kg, 0.7 hr, and 1.6 L/kg, respectively. The drug was not protein bound, and there was rapid uptake and phosphorylation in RBCs to its 5'-monophosphate nucleotide. Renal clearance (CLR) was 0.2 L/hr/kg with only 8% of the IV dose excreted in the urine as intact AICA-riboside. Although there was a trend towards a decrease in CL with increasing dose, there were no significant differences (P greater than .05) in the mean estimates of t1/2 beta, CL, CLR, MRTIV and VSS associated with dose. The drug was poorly bioavailable (less than 5%) when administered orally in solution.