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RNAi therapeutics for treatment of hypertension: sustained reductions in serum angiotensinogen at 12 weeks and reduced blood pressure with single dose of ALN-AGT

Interim results from the ongoing phase 1 study of ALN-AGT, a subcutaneous investigational RNAi therapeutic targeting liver-expressed angiotensinogen ( AGT ) for the treatment of hypertension, were announced.

ALN-AGT treatment was associated with dose-dependent knockdown of AGT and reductions in blood pressure with a durability that supports the potential for a once quarterly or biannual dosing regimen, and was found to be generally safe and well tolerated.

Eighty-four patients with hypertension were randomized in this double-blind, placebo-controlled, single ascending dose ( SAD ) study evaluating the safety, tolerability and preliminary pharmacokinetic and pharmacodynamic activity of ALN-AGT.
Patients, who were either treatment naïve or had discontinued other anti-hypertensive medications prior to study entry, were enrolled in ascending dose cohorts of 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 400 mg or 800 mg ALN-AGT.

Patients treated with single doses of ALN-AGT at 100 mg or higher experienced durable reductions in serum AGT of more than 90% through 12 weeks.
In the 800 mg dose cohort, all patients experienced reductions in serum AGT of 96-98% at week 12.
Concomitant reductions in blood pressure were observed with AGT knockdown, with clinically meaningful mean reductions in 24-hour systolic blood pressure ( SBP ) of more than 10 mm Hg observed at week 8 after single doses of 100 mg or higher.
At 800 mg, mean reductions in 24-hour SBP of 17 mm Hg were observed at week 8 ( compared to a mean increase of 1 mm Hg in the placebo group ) and sustained through week 12.
All data are as of a February 25, 2021 cut-off date.

Suboptimal blood pressure control remains the most common attributable risk factor for cardiovascular disease and cerebrovascular disease, and a leading cause of chronic kidney disease progression.
These durable pharmacologic effects of ALN-AGT may support tonic control of blood pressure with once quarterly and potentially biannual dosing.
Less frequent dosing than available with current treatment options may help achieve improved medication adherence, an important part of maintaining blood pressure control.

ALN-AGT was shown to be generally well tolerated with an acceptable safety profile that supports advancement into phase 2 studies.
Most adverse events were mild or moderate in severity and resolved without intervention, with the most common adverse effects consisting of mild and transient injection site reactions in 5 out of 56 patients ( 8.9% ) receiving ALN-AGT.
There were no clinically significant elevations in serum alanine aminotransferase ( ALT ), serum creatinine or serum potassium, and no patient required intervention for hypotension.
There were no treatment-related serious adverse effects, deaths or adverse efects leading to study withdrawal.

ALN-AGT is an investigational, subcutaneously administered RNAi therapeutic targeting angiotensinogen.
AGT is the most upstream precursor in the renin-angiotensin-aldosterone system ( RAAS ), a cascade which has a demonstrated role in blood pressure regulation and whose inhibition has well-established anti-hypertensive effects.
ALN-AGT inhibits the synthesis of AGT in the liver, potentially leading to durable reductions in AGT protein and ultimately, in the vasoconstrictor angiotensin (Ang ) II.

Hypertension is a complex multifactorial disease clinically defined by most major guidelines as a systolic blood pressure ( SBP ) of above 140 mm Hg or a diastolic blood pressure ( DBP ) greater than 90 mm Hg, though AHA/ACC guidelines have a lower threshold of a SBP above 130 mm Hg or a DBP greater than 80 mm Hg. ( Xagena )

Source: Alnylam Pharmaceuticals, 2021