A Study Assessing HMB-002 in Participants With Von Willebrand Disease

Official title

A Phase 1/2 Study to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of HMB-002 in Participants With Von Willebrand Disease (Velora Pioneer)

Overview

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.

Interventions

• Drug HMB-002 (Part A)
  HMB-002 will be administered subcutaneously. Part A will utilize sentinel dosing. The planned duration of study participants in Part A is approximately 12 weeks.
• Drug HMB-002 (Part B)
  HMB-002 will be administered subcutaneously. Part B dosing intervals will be determined following evaluation of Part A results. The planned duration of study participants in Part B will be approximately 21 weeks.
• Drug HMB-002 with Concomitant Factor Concentrate (Part C) (Not Applicable in US)
  HMB-002 will be administered as a single dose with a concomitant single dose of factor concentrate. The planned duration of study participants in Part C will be approximately 17 weeks.

Primary outcome measures

• Incidence of Treatment emergent adverse events (TEAE) [Time frame: up to Day 113]

Secondary outcome measures (9)

• Pharmacokinetic Parameter: Maximum observed plasma concentration (Cmax) [Time frame: Day 1 to Day 113]
• Pharmacokinetic Parameter: Area under the curve from time zero to last quantifiable concentration (AUClast) [Time frame: Day 1 to Day 113]
• Pharmacokinetic Parameter: Area under the curve from time zero to extrapolated infinite time (AUCinf) [Time frame: Day 1 to Day 113]
• Pharmacokinetic Parameter: Time to reach maximum observed plasma concentration (Tmax) [Time frame: Day 1 to Day 113]
• Pharmacodynamics Parameters: Assessment of VWF antigen (VWF:Ag) [Time frame: Day 1 to Day 113]
• Pharmacodynamics Parameters: Assessment of VWF activity [Time frame: Day 1 to Day 113]
• Pharmacodynamics Parameters: Assessment of FVIII activity [Time frame: Day 1 to Day 113]
• Annualized Bleeding Rate Assessments [Time frame: Day 1 to Day 113]
• Pharmacokinetic Parameter: Terminal elimination half-life (t1/2) [Time frame: Day 1 to Day 113]

Eligibility criteria

Inclusion criteria

• Weight 50 to 120 kg, inclusive.
• Documented diagnosis of Congenital VWD, confirmed by laboratory testing consistent with ISTH/ASH) diagnostic guidelines).
• Vital signs are within normal ranges at Screening.
• Participants must meet the following baseline organ function, indicated by laboratory criteria as Screening:

• Renal: Estimated glomerular filtration rate (eGFR) of ≥45 mL/min/1.73m\^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.
• Hematology >85 g/L and platelet count >120 x 10\^9/L.

Part A Only:

• Age: ≥18 and <70 years of age at the time of informed consent.
• 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
• Residual VWF activity of ≤ 50 IU/dL and FVIII activity ≤ 70 IU/dL during screening.

Part B Only:

• Age: ≥16 and <70 years of age at the time of informed consent.
• VWD Subtype Eligibility: Participants with Type 1 VWD (including Type 1C) and Type 2A.
• Residual VWF activity of ≤50 IU/dL and FVIII activity ≤70 IU/dL during screening.
• Symptomatic Disease: Participants must be symptomatic, typically reporting bleeding events on a monthly basis.
• Bleeding History (must meet one of the following):

• 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

• 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:

• Age: ≥18 and <70 years of age at the time of informed consent.
• 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).
• Receives regular VWF concentrate (at least 1/week) as part of their routine care (usual dose ≤50 IU/kg).

Exclusion criteria

• Personal history of venous or arterial thrombosis or thromboembolic disease, except for catheter-associated, superficial venous thrombosis.
• 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%.
• Body mass index (BMI) >35 kg/m\^2 (obese, adjusted for ethnicity).
• 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.
• Clinically significant cardiovascular disease.
• Other known severe bleeding disorder(s) other than VWD.
• 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

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 13 centers

• Phoenix Children's Hospital — Phoenix
• Arkansas Children's Hospital — Little Rock
• Children's Hospital of Los Angeles — Los Angeles
• University of Miami Hospital and Clinics, Sylvester Comprehensive Cancer Center — Miami
• Emory Children's Center — Atlanta
• Innovative Hematology, Inc./Indiana Hemophilia and Thrombosis Center — Indianapolis
• Tulane University School of Medicine — New Orleans
• University of Michigan Hospitals, Department of Hemophilia and Coagulation Disorders — Ann Arbor
• … and 5 more centers

United Kingdom · 9 centers

• Basingstoke and North Hampshire Hospital — Basingstoke
• St George's Hospital — Tooting
• Royal London Hospital — Whitechapel
• University Hospitals Birmingham NHS Foundation Trust — Birmingham
• University Hospital of Wales — Cardiff
• St James's University Hospital, Leeds Haemophilia Centre — Leeds
• Royal Liverpool and Broadgreen University Hospitals NHS TRUST, The Roald Dahl Haemostasis — Liverpool
• Richmond Pharmacology — London
• … and 1 more center

Australia · 3 centers

• Fiona Stanley Hospital — Murdoch
• Royal Prince Alfred Hospital — Camperdown
• The Alfred Hospital — Melbourne

Identifiers

NCT: NCT06754852 · HMB-002-102

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗