Therapy Areas: Cardiovascular
Alnylam Touts Positive Interim Results from Ongoing Phase 1 Study of ALN-AGT, an Investigational RNAi Therapeutic for the Treatment of Hypertension
13 November 2020 - - US-based RNAi therapeutics company Alnylam Pharmaceuticals, Inc. (NASDAQ: ALNY) has posted positive interim data from the ongoing Phase 1 study of ALN-AGT, a subcutaneous investigational RNAi therapeutic targeting liver-expressed angiotensinogen for the treatment of hypertension, the company said.

Results were presented in a poster presentation at the American Heart Association Scientific Sessions 2020, taking place virtually from November 13 17, 2020.

Data presented at the AHA Scientific Sessions are from the ongoing Phase 1 study of ALN-AGT with a data cut-off date of September 16, 2020.

The study is a randomized, double-blind, placebo-controlled, single ascending dose study, evaluating the safety, tolerability and preliminary pharmacokinetic and pharmacodynamic activity of ALN-AGT in patients with mild or moderate hypertension, who were either treatment naïve or had discontinued other anti-hypertensive medications.

Patients had a mean age of 52 years (range 35 65) and a mean baseline 24-hour systolic blood pressure and diastolic blood pressure of 139 (standard deviation [SD] +/- 8) millimeters of mercury (mm Hg) and 86 (SD +/- 7) mm Hg, respectively.

Patients were enrolled in ascending dose cohorts of 10 mg, 25 mg, 50 mg, 100 mg or 200 mg ALN-AGT (N=12 per cohort; 2: 1 randomization of ALN-AGT: placebo).

Compared to placebo, patients treated with ALN-AGT experienced dose-dependent reductions in serum AGT -- the sole precursor of all angiotensin peptides, including the potent vasoconstrictor angiotensin II.

In the 200 mg dose cohort, the mean reduction (+/- standard error [SE]) of AGT at 8 weeks was 94.9 +/- 1.6 %. Reductions of more than 90 % persisting through 12 weeks after single doses of 100 or 200 mg were observed, with up to 97.6 % AGT knockdown at 200 mg.

The durability of AGT knockdown supports the potential for once quarterly dosing and possibly even less frequent dosing.

Suboptimal blood pressure control is the most common attributable risk factor for cardiovascular disease and cerebrovascular disease, and a leading cause of chronic kidney disease progression.

In the Phase 1 study, lowering of BP was observed concomitantly with AGT knockdown, with a greater than 10 mm Hg reduction of mean 24-hour SBP observed at Week 8 in cohorts receiving doses of 100 or 200 mg, as measured by ambulatory BP monitoring. At 200 mg, mean BP reductions (+/- SE) at 8 weeks were 11.0 +/- 2.4 mm Hg for systolic and 7.7 +/- 1.1 mm Hg for diastolic BP.

Maximum reductions up to 19.0 mm Hg and 12.3 mm Hg were observed in SBP and DBP, respectively.

ALN-AGT was shown to be generally well tolerated with an acceptable safety profile for continued development.

Most adverse events were mild or moderate in severity and resolved without intervention, with the most common AE consisting of mild and transient injection site reactions in 5 out of 40 patients (12.5%) receiving ALN-AGT.

There were no clinically significant elevations in serum alanine aminotransferase, serum creatinine or serum potassium, and no patient required intervention for hypotension. There were no treatment-related serious AEs, deaths or AEs leading to study withdrawal.

To view the data presented by Alnylam at the AHA Scientific Sessions, visit www.alnylam.com/capella.

The Phase 1 study is a multi-center, randomized, double-blind, placebo-controlled, single dose and active comparator-controlled multiple dose trial designed to evaluate the safety, tolerability, pharmacokinetic, and pharmacodynamic effects of subcutaneously administered ALN-AGT in patients with essential hypertension.

The study will be conducted in four parts: single ascending dose phase in hypertensive patients; SD phase in hypertensive patients with controlled salt intake; MD phase in hypertensive patients who are obese, with once daily oral doses of irbesartan (angiotensin II receptor blocker) used as the active comparator; and open-label SD phase with co-administration of irbesartan in hypertensive patients. Patients will be randomized 2: 1 ALN-AGT to placebo or ALN-AGT to irbesartan.

The planned enrollment for this study, including optional cohorts, is up to 184 patients.
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