Phase 2 Randomized Double‑Blind Study of Subcutaneous ALN‑6400 in Women with Von Willebrand Disease and Heavy Menstrual Bleeding

Primary objective: to assess the safety and tolerability of multiple subcutaneous doses of ALN‑6400 in female patients with von Willebrand disease and heavy menstrual bleeding, thereby defining the adverse‑event profile and acceptability of the investigational therapy. Secondary objectives: – pharmacodynamics: to characterize the pharmacodynamic effects of repeated ALN‑6400 dosing; – efficacy: to evaluate the therapeutic efficacy of ALN‑6400 in reducing menstrual blood loss and improving disease‑related outcomes.

Sixteen female participants were enrolled; age eligibility required 18–45 years, with a reduced upper limit of 34 years for subjects using low‑dose combined oral contraceptives. All subjects had a documented diagnosis of Von Willebrand Disease (any type, with or without inhibitors) and a history of heavy menstrual bleeding, defined by two screening cycles with a pictorial blood assessment chart score greater than 100. Eligible individuals demonstrated regular menstrual cycles (21–35 days) over the preceding six months and maintained a stable standard‑of‑care regimen for bleeding, with required discontinuation of tranexamic acid before study start and of factor‑containing products before day 15. Participants receiving combined oral contraceptives were required to have a body‑mass index below 30 kg/m². Selection was based on these predefined inclusion criteria and on the ability to comply with daily menstrual bleed diary entries and study procedures. The cohort represents a vulnerable population of patients with a rare bleeding disorder and associated heavy menstrual bleeding.

The study is a Phase 2, randomized, double‑blind, placebo‑controlled trial evaluating multiple subcutaneous doses of ALN‑6400 (50 mg solution for injection) in female participants with Von Willebrand Disease and heavy menstrual bleeding. After an initial screening visit to confirm eligibility, participants enter a double‑blind treatment period during which study drug or matching placebo is administered according to the predefined dosing schedule. Safety and tolerability are monitored through adverse‑event reporting, vital signs, electrocardiograms, and clinical laboratory tests at each scheduled follow‑up visit, while efficacy endpoints include changes in plasma activity levels, menstrual blood loss measured by the pictorial blood assessment chart, and patient‑reported outcome scores. The protocol mandates a final end‑of‑study visit to perform comprehensive assessments and to collect remaining study data. The overall trial timeline extends from the anticipated recruitment start in May 2026 to study completion in June 2027, encompassing the screening, treatment, follow‑up, and end‑of‑study phases for each enrolled subject.

The investigational product, designated ALN-6400, consists of a complex RNA construct (RNA, (UM‑SP‑(2′‑DEOXY‑2′‑FLUORO)A‑SP‑GM‑AM‑AM‑(2′‑DEOXY‑2′‑FLUORO)A‑CM‑UM‑CM‑AM‑UM‑AM‑GM‑(2′‑DEOXY‑2′‑FLUORO)C‑GM‑(2′‑DEOXY‑2′‑FLUORO)A‑UM‑UM‑GM‑CM‑AM‑SP‑CM‑SP‑AM) complexed with a second RNA sequence, formulated as a solution for injection. Each dose contains 50 mg of the RNA complex and is administered by subcutaneous injection. Dosing follows the protocol‑specified schedule of multiple administrations, with each administration delivered as a single 50 mg injection. Compliance with the dosing regimen is monitored by study staff through documentation of each injection event and verification of dose preparation and administration procedures.

Efficacy will be assessed by measuring the change from baseline in PLG plasma activity levels and plasma protein concentrations, the reduction in menstrual blood loss as quantified by the Pictorial Blood Assessment Chart (PBAC), and patient‑reported outcomes including PRO scores, PGI‑C, and PGI‑S. Laboratory analyses will be performed on blood samples collected at predefined visits. The PBAC will be completed by participants for each menstrual cycle. PRO instruments will be administered using validated questionnaires. Changes from baseline will be calculated for each parameter to determine treatment effect.

Comparative analyses will be conducted between the ALN‑6400 and placebo groups. Descriptive statistics and inferential tests will be applied to the change‑from‑baseline values for each endpoint, with significance thresholds defined in the statistical analysis plan.