Alnylam Pharmaceuticals (ALNY) Study update summary

Program overview and scientific rationale

• ALN-6400 is an investigational RNAi therapy targeting liver-expressed plasminogen (PLG) to address rare bleeding disorders, specifically hereditary hemorrhagic telangiectasia (HHT) and von Willebrand disease (VWD).

• RNAi technology enables potent, specific, and reversible gene silencing, allowing for infrequent dosing and improved patient adherence.

• Plasminogen lowering is supported by strong genetic, preclinical, and clinical rationale, aiming to reduce bleeding without increasing thrombotic risk.

• Antifibrinolytics validate the mechanism, and ALN-6400 offers a differentiated, long-acting approach as a universal hemostatic agent.

• The therapeutic hypothesis is that lowering PLG via subcutaneous injection reduces fibrinolysis, providing durable bleeding protection without increasing thrombotic risk.

Disease burden and unmet need

• Over 5 million people globally live with bleeding disorders, with HHT and VWD being the two most common inherited forms, causing significant morbidity, anemia, and reduced quality of life.

• HHT has no approved treatments, with most patients suffering from severe nosebleeds, GI bleeding, iron deficiency, and high rates of hospitalization.

• VWD treatments are burdensome, requiring frequent IV infusions, leading to low prophylactic treatment rates and high rates of heavy menstrual bleeding, nosebleeds, and excessive bleeding after surgery.

• Women with VWD face a disproportionate burden, especially heavy menstrual bleeding.

• Both disorders are linked to significant social stigma, anxiety, and reduced quality of life.

Clinical development and study design

• ALN-6400 progressed from target identification to proof of mechanism in under three years, with Phase 1 dosing in healthy volunteers and ongoing Phase 2 studies in HHT (InsigHHT) and VWD (HM BEACON).

• The Phase 1 study was double-blind, placebo-controlled, and demonstrated deep, sustained antifibrinolytic effects with a single subcutaneous dose, superior to oral tranexamic acid.

• Phase 2 studies are enrolling, with primary objectives of safety and tolerability and secondary objectives of efficacy and pharmacodynamics.

• HHT study targets patients with moderate to severe nosebleeds; VWD study focuses on women with heavy menstrual bleeding.

• Initial Phase 2 results for HHT are expected in the second half of this year (or 2026), with full data to be presented in 2027 and Phase 3 trials anticipated to start in 2027.