ALN-6400 / Alnylam - LARVOL DELTA

Hepatic plasminogen lowering with a galnac-conjugated siRNA reduces plasmin generation and fibrinolysis but has no effect on thrombin generation in rats and mice (ASH 2025) - P1/2 | "Introduction: Plasminogen (PLG) is primarily liver-derived and plays a key role in fibrinolysis.Antifibrinolytics, such as tranexamic acid, have been used clinically for decades to prevent bleeding byinhibiting the activation of PLG into plasmin, thereby reducing plasmin generation and fibrinolysis.Lowering hepatic PLG with an N-acetylgalactosamine (GalNAc)-conjugated small interfering RNA(PLG-lowering siRNA) is designed to reduce plasmin generation and fibrinolysis but to leave thrombingeneration unchanged. Hepatic PLG lowering with a GalNAc-conjugated siRNA reduced plasmin generation andplasma and whole blood fibrinolysis in rats, but had no effect on thrombin generation in rats and mice.These results suggest that targeting the fibrinolytic pathway with a liver-directed PLG-lowering siRNA willlikely not be associated with thrombotic risk and may be a safer option compared to alternatives thatincrease thrombin generation. The results support clinical development..."

Preclinical • Cardiovascular • Hematological Disorders • TINCR

ALN-6400-001: A Study to Evaluate ALN-6400 in Healthy Volunteers and Patients With Hereditary Hemorrhagic Telangiectasia (HHT) (clinicaltrials.gov) - P1/2 | N=120 | Recruiting | Sponsor: Alnylam Pharmaceuticals | Trial primary completion date: Aug 2026 ➔ Jan 2028

Trial primary completion date • Hematological Disorders

ALN-6400-001: A Study to Evaluate ALN-6400 in Healthy Volunteers and Patients With Hereditary Hemorrhagic Telangiectasia (HHT) (clinicaltrials.gov) - P1/2 | N=120 | Recruiting | Sponsor: Alnylam Pharmaceuticals | Active, not recruiting ➔ Recruiting

Enrollment open • Hematological Disorders

ALN-6400-001: A Study to Evaluate ALN-6400 in Healthy Volunteers and Patients With Hereditary Hemorrhagic Telangiectasia (HHT) (clinicaltrials.gov) - P1/2 | N=120 | Active, not recruiting | Sponsor: Alnylam Pharmaceuticals | Recruiting ➔ Active, not recruiting | Trial primary completion date: Sep 2025 ➔ Aug 2026

Enrollment closed • Trial primary completion date • Hematological Disorders

ALN-6400-001: A Study to Evaluate ALN-6400 in Healthy Volunteers and Patients With Hereditary Hemorrhagic Telangiectasia (HHT) (clinicaltrials.gov) - P1/2 | N=96 | Recruiting | Sponsor: Alnylam Pharmaceuticals | Phase classification: P1 ➔ P1/2 | N=32 ➔ 96 | Trial completion date: Feb 2026 ➔ Jun 2028

Enrollment change • Phase classification • Trial completion date • Hematological Disorders

HEPATIC PLASMINOGEN LOWERING WITH RNA INTERFERENCE FOR THE TREATMENT OF BLEEDING DISORDERS IS UNLIKELY TO POSE THROMBOTIC RISK BASED ON UK BIOBANK ANALYSES AND MOUSE MODELS OF PROVOKED THROMBOSIS (EHA 2025) - P1 | "Low levels of plasma PLG protein were not associated with thrombosis in UK Biobank analyses, and >99% knockdown of hepatic PLG using a liver-directed siRNA in mouse injury models was not associated with increased thrombus formation. These results suggest that hepatic targeting of PLG with RNAi is unlikely to confer thrombotic risk and support clinical development of ALN-6400, an investigational RNAi therapeutic for the treatment of bleeding disorders (NCT06659640)."

Preclinical • Cardiovascular • Hematological Disorders • Thrombosis • PROS1

Alnylam Announces Preliminary Fourth Quarter and Full Year 2024 Global Net Product Revenues and Provides 2025 Combined Net Product Revenue Guidance and Pipeline Goals (Businesswire) - "Zilebesiran – an investigational RNAi therapeutic in development for the treatment of hypertension, in collaboration with Roche. Alnylam expects to: Report results from the KARDIA-3 Phase 2 study in the second half of 2025.Initiate a Phase 3 cardiovascular outcomes trial in the second half of 2025...ALN-6400 – an investigational RNAi therapeutic in development for the treatment of bleeding disorders. Alnylam expects to: Initiate a Phase 2 study in a bleeding disorder in the second half of 2025. In addition, the Company plans to file Investigational New Drug (IND) applications for four new Alnylam-led programs by the end of 2025."

IND • New P2 trial • New P3 trial • P2 data • Cardiovascular • Hematological Disorders • Hypertension