This is a first-in-human (FIH), Phase 1/2, 3-part open-label, dose escalation, safety, tolerability, pharmacokinetic (PK), pharmacodynamic (PD), and efficacy study evaluating HMB-002 in participants with VWD. Part A of the study involves a single ascending dose (SAD) regimen design to establish safety, tolerability, PK, and PD effect. In Part B of the study, the safety and tolerability of repeat dosing will be established prior to cohort expansion to explore efficacy. Part C will evaluate the safety, PK, and PD of a single concomitant dose of HMB-002 and factor concentrate with Type 3 VWD or Type 1 VWD with low residual VWF and FVIII who use factor concentrate as prophylaxis.

Key Inclusion Criteria:

1. Weight 50 to 120 kg, inclusive.

2. Documented diagnosis of Congenital VWD, confirmed by laboratory testing consistent with ISTH/ASH) diagnostic guidelines).

3. Vital signs are within normal ranges at Screening.

4. Participants must meet the following baseline organ function, indicated by laboratory criteria as Screening:

   1. Renal: Estimated glomerular filtration rate (eGFR) of ≥45 mL/min/1.73m^2.
   2. Hepatic: Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin ≤1.5 upper limit of normal (ULN) at Screening. For participants with a history of Gilbert's Syndrome, total bilirubin ≤2 × ULN.
   3. Hematology >85 g/L and platelet count >120 x 10^9/L.

   Part A Only:

5. Age: ≥18 and <70 years of age at the time of informed consent.

6. VWD Subtype Eligibility:

   • Cohorts A1 and A2: Participants with Type 1 VWD, only.
   • Cohorts A3 and A4: Participants with Type 1 VWD (including Type 1C) and Type 2A VWD

7. Residual VWF activity of ≤ 50 IU/dL and FVIII activity ≤ 70 IU/dL during screening.

   Part B Only:

8. Age: ≥16 and <70 years of age at the time of informed consent.

9. VWD Subtype Eligibility: Participants with Type 1 VWD (including Type 1C) and Type 2A.

10. Residual VWF activity of ≤50 IU/dL and FVIII activity ≤70 IU/dL during screening.

11. Symptomatic Disease: Participants must be symptomatic, typically reporting bleeding events on a monthly basis.

12. Bleeding History (must meet one of the following):

    1. Prior Observational Study Participation:

       The participant must have participated in the observational study HMB-002-101_SCR (VELORA Discover), have a minimum annualized treated bleeding event (ATBR) of 3; OR

    2. Medical Record-Documented Bleeding History:

    The Investigator confirms that ≥3 treated bleeding events have been documented in the participant's medical record within the preceding 12 months.

    Part C Only:

13. Age: ≥18 and <70 years of age at the time of informed consent.

14. Participants with Type 3 VWD or Type 1 VWD with low residual VWF and FVIII activity levels (VWF activity <5 IU/dL and FVIII activity <10 IU/dL).

15. Receives regular VWF concentrate (at least 1/week) as part of their routine care (usual dose ≤50 IU/kg).

Key Exclusion Criteria:

1. Personal history of venous or arterial thrombosis or thromboembolic disease, except for catheter-associated, superficial venous thrombosis.

2. High risk thrombophilia: Homozygous Factor V Leiden (FVL), compound heterozygous FVL/Prothrombin gene mutation, Antithrombin deficiency with activity <50%. Congenital Protein C and Protein S deficiency with levels <50%.

3. Body mass index (BMI) >35 kg/m^2 (obese, adjusted for ethnicity).

4. Presence of other conditions that substantially increase risk of thrombosis either individually (for participants >65 years of age) or in combination (for participants ≤65 years of age), at the discretion of the Investigator or Medical Monitor.

5. Clinically significant cardiovascular disease.

6. Other known severe bleeding disorder(s) other than VWD.

7. Requirement for concomitant medications that affect hemostasis (including, but not limited to anticoagulation, antiplatelet agents, certain non-steroidal anti-inflammatory drugs) and cannot refrain from use for 14 days prior to the first dose of study drug and throughout the study.

   Exclusion Criteria for Part A and Part B Only

8. Requirement for ongoing hemostatic treatment to prevent bleeding (bleed prophylaxis). Prophylaxis administered intermittently for procedures or surgery to reduce bleeding risk is permitted.