A Phase 1/2 Study to Investigate Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of HMB-001 in Glanzmann Thrombasthenia

A Phase 1/2, First-in-Human, Single and Multiple Ascending Dose Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of HMB-001 in Participants With Glanzmann Thrombasthenia

The goal of this clinical trial is to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of HMB-001 in Participants with Glanzmann Thrombasthenia.

The main questions it aims to answer are:

• Parts A, B, and C: To determine the safety and tolerability of HMB-001
• Part A: To establish the dose level(s) and dosing interval(s) of HMB-001 to be investigated in Parts B and C
• Parts B and C: To estimate the ability of HMB-001 to prevent the number and severity of bleeds

Part A will assess differing singular doses of HMB-001 in small groups of participants. The dose administered to a newly enrolled participant (or groups of participants) may only increase if analysis of data from previous dosing shows it is safe to do so. The planned duration of participation in Part A is approximately 6 months, which consists of a Screening Period, an optional Run-in Observation Period, and a follow-up period of 8 weeks.

Part B is similar to Part A as it involves testing different dose levels of HMB-001 in small groups of participants. However, in Part B, HMB-001 is given multiple times over a 3-month period, either weekly, every 2 weeks, or every 4 weeks. Part B consists of a Screening Period, a Run-in Observation Period, a 3-month Treatment Period, and a Safety Follow-up following the last dose of HMB-001.

Part C is open to participants from Part B and consists of approximately a 9-month Treatment Period and a Safety Follow-up following the last dose of HMB-001.

Study Overview

• Status: Recruiting
• Conditions: Glanzmann Thrombasthenia
• Intervention / Treatment: Drug: HMB-001

• Study Type: Interventional
• Enrollment (Estimated): 57
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Catherine Rea; Phone Number: +44 0808 304 6409; Email: clinicaltrials@hemab.com

Study Locations

• Belgium
  • Leuven, Belgium
    • Not yet recruiting
    • University Hospital Leuven - Campus Gasthuisberg (Part B/C)
• France
  • Le Kremlin-Bicêtre, France
    • Not yet recruiting
    • AP-HP Hopital Bicetre (Part B/C)
  • Paris, France
    • Not yet recruiting
    • AP-HP Hopital Necker-Enfants Malades (Part B/C)
• Italy
  • Firenze, Italy
    • Not yet recruiting
    • Azienda Ospedaliero-Universitaria Careggi (Part B/C)
  • Milano, Italy
    • Not yet recruiting
    • Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano (Part B/C)
• Netherlands
  • Rotterdam, Netherlands
    • Not yet recruiting
    • Erasmus MC (Part B/C)
  • Utrecht, Netherlands
    • Not yet recruiting
    • Universitair Medisch Centrum Utrecht (Part B/C)
• United Kingdom
  • Birmingham, United Kingdom
    • Not yet recruiting
    • Queen Elizabeth Hospital Birmingham (Part B/C)
  • London, United Kingdom
    • Recruiting
    • Richmond Pharmacology Ltd (Part A/B/C)
  • London, United Kingdom
    • Not yet recruiting
    • Royal Free London NHS Foundation Trust (Part B/C)
  • Sheffield, United Kingdom
    • Not yet recruiting
    • Sheffield Teaching Hospitals NHS Foundation Trust (Part B/C)
  • Whitechapel, United Kingdom
    • Not yet recruiting
    • The Royal London Hospital (Part B/C)
• United States
  • California
    • La Jolla, California, United States, 92093
      • Not yet recruiting
      • University of California, San Diego (UCSD) (Part B/C)
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Not yet recruiting
      • Tulane University Medical Center (Part B/C)
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Not yet recruiting
      • Mayo Clinic - Rochester (Part B/C)
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Not yet recruiting
      • Hemophilia Center of Western Pennsylvania (HCWP) (Part B/C)
  • Washington
    • Seattle, Washington, United States, 98101
      • Not yet recruiting
      • Washington Institute for Coagulation (Part B/C)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Part A Inclusion Criteria:

1. Age 18 to 65 years, at the time of signing informed consent.
2. Glanzmann thrombasthenia; documented abnormal, diagnostic platelet aggregometry plus deficiency of the αIIbβ3 (GPIIb/GPIIIa) receptor via flow cytometry; or genetic diagnosis.
3. Has not received a COVID-19 vaccine dose in the last 28 days. Has not received any live vaccine within 4 weeks of enrollment and is not planning to have a live vaccine during the study period.
4. Agrees not to receive COVID-19 vaccination throughout the dosing period and for 4 weeks after the final dose.
5. Has the ability to provide informed consent.
6. Has an understanding, ability, and willingness to fully comply with trial procedures and restrictions.

7. Vital signs are within the following ranges at Screening:

   1. Supine heart rate ≤ 105 bpm (after at least 5 minutes of supine rest).
   2. Blood pressure (BP): Supine BP (after at least 5 minutes of supine rest or based on 24 hours monitor demonstrating normotensive BP): i. Systolic blood pressure: 90 - 140 mmHg. ii. Diastolic blood pressure: 40 - 90 mmHg.
8. Women of child-bearing potential have a negative serum pregnancy test within 72 hours prior to the first dose of study drug.
9. Women of child-bearing potential agree to use highly effective contraceptive methods (excluding estrogen-containing combined oral contraceptive pill) as per exclusion criteria and avoid egg donation for 14 days prior to Day 1, during the study treatment, and for 6 months after the last dose of study drug.
10. Men of child-producing potential agree to use highly effective contraceptive methods and avoid sperm donation for 14 days prior to Day 1, during the study treatment, and for 6 months after the last dose of study drug.

11. Participants must meet the following baseline organ function, indicated by laboratory criteria:

    1. Evidence of no greater than mild to moderate reduction in renal function (stage 3a kidney disease), measured by an estimated glomerular filtration rate (eGFR) of ≥45 ml/min/1.73m2 at Screening
    2. An aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin ≤ 1.5 upper limit of normal (ULN) range at Screening. For participants with a history of Gilbert's Syndrome, total bilirubin ≤ 2 × ULN at Screening
    3. Hemoglobin >85 g/L and platelet count >150 x 10^9/L at Screening.

Part B Inclusion Criteria:

1. Has the ability to provide informed consent, and has an understanding, ability, and willingness to fully comply with clinical trial procedures and restrictions.
2. Age 18 to 65 years.
3. Glanzmann thrombasthenia; Genetic diagnosis is required. Abnormal, diagnostic platelet aggregometry plus deficiency of the αIIbβ3 (GPIIb/GPIIIa) receptor via flow cytometry should be recorded if available.
4. Patients should experience bleeding symptoms associated with Glanzmann Thrombasthenia defined as approximately two bleeding events per week of any severity and any type and at least one spontaneous or traumatic bleed that requires a prescribed treatment, medical or surgical procedure within the last 12 months.
5. Has not received a COVID-19 vaccine dose in the last 28 days. Has not received any live vaccine within 4 weeks of enrollment and is not planning to have a live vaccine during the study period.

6. Vital signs are within the following ranges at Screening:

   1. Supine heart rate ≤105 bpm (after at least 5 minutes of supine rest)
   2. BP: Supine BP (after at least 5 minutes of supine rest or based on 24 hours monitor demonstrating normotensive BP): i. Systolic blood pressure: 90 - 140 mmHg; ii. Diastolic blood pressure: 40 - 90 mmHg.
7. Women of child-bearing potential have a negative serum pregnancy test within 72 hours prior to the first dose of study drug.
8. Women of child-bearing potential agree to use a highly effective contraceptive method and to avoid egg donation for 14 days prior to Day 1, during the study treatment, and for 6 months after the last dose of study drug. If utilizing an oral contraceptive, women must be on a stable dose of a non-estrogen-containing formulation for at least 8 weeks prior to the start of the Run-in Observation Period and for 8 weeks after the last dose of study drug.
9. Men of child-producing potential agree to use highly effective contraceptive methods and avoid sperm donation for 14 days prior to Day 1, during the study treatment, and for 6 months after the last dose of study drug.

10. Participants must meet the following baseline organ function, indicated by laboratory criteria:

    1. Evidence of no greater than mild to moderate reduction in renal function (stage 3a kidney disease), measured by an eGFR of ≥45 ml/min/1.73m2 at Screening.
    2. An AST, ALT, and total bilirubin ≤1.5 ULN range at Screening. For participants with a history of Gilbert's Syndrome, total bilirubin ≤2 × ULN at Screening.
    3. Hemoglobin >85 g/L and platelet count >120 x 10^9/L at Screening.

Part A Exclusion Criteria

1. Severe infection or inflammation at the time of Screening.
2. History of clinically significant hypersensitivity associated with monoclonal antibody therapies.
3. Personal history of venous or arterial thrombosis or thromboembolic disease, with the exception of catheter-associated, mild thrombophlebitis events.
4. Known severe congenital or acquired thrombophilia.
5. Has a positive test for Hepatitis B surface antigen (HbsAg), Hepatitis C antibody (HCV Ab), or human immunodeficiency virus antibody (HIV Ab) at Screening with RNA level above the lower limit of detection. Participants with a positive test for HCV Ab may be included if they have a negative RNA test, consistent with cleared infection. Participants with an HIV RNA level lower than the limit of detection may be included.
6. Is positive for COVID-19 based on lateral flow or Polymerase chain reaction (PCR) within 48 hours prior to the first dose or had a known COVID-19 infection confirmed by lateral flow or PCR within 6 weeks prior to the first dose of study drug.
7. Other conditions that substantially increase risk of thrombosis by the discretion of the investigator including, but not limited to: significant family history, body mass index (BMI) >30 kg/m2 (moderately obese, adjusted for ethnicity), reduced mobility, active malignancy, major surgery within 6 weeks preceding first dose of study drug, post-partum within 12 weeks preceding first dose of study drug.
8. Women who are using estrogen-containing medication or hormone modulators (within 8 weeks pre-dose to 8 weeks post-dose of study drug).
9. Clinically significant cardiovascular disease.
10. Other conditions that substantially increase the risk of cardiovascular events by the discretion of the Investigator including, but not limited to: smoking, cocaine use, and uncontrolled hypertension.
11. Congenital or acquired bleeding disorders other than Glanzmann thrombasthenia.
12. Concurrent disease, treatment, medication, or abnormality in clinical laboratory tests that may pose additional risk.
13. Addiction or other diseases that prevent the participant from appropriately assessing the nature and scope of the clinical study or participating in study procedures.
14. Received investigational medication in another clinical study within 5 half-lives before administration of study drug.
15. Female participants who are pregnant or breastfeeding.

Part B Exclusion Criteria

1. Active severe infection or inflammation at the time of Screening or prior to the first dose of study drug.
2. History of clinically significant hypersensitivity associated with monoclonal antibody therapies.
3. Personal history of venous or arterial thrombosis or thromboembolic disease, with the exception of catheter-associated, mild thrombophlebitis events.
4. Has known, documented, high risk congenital thrombophilia.
5. Family history of unprovoked venous thrombosis in first degree relative.
6. Has a positive test for Hepatitis B surface antigen (HbsAg), Hepatitis C antibody (HCV Ab), or human immunodeficiency virus antibody (HIV Ab) at Screening with RNA level above the lower limit of detection. Participants with a positive test for HCV Ab may be included if they have a negative RNA test, consistent with cleared infection. Participants with an HIV RNA level lower than the limit of detection may be included.
7. Other conditions that substantially increase risk of thrombosis by the discretion of the investigator including, but not limited to: BMI >30 kg/m2 (moderately obese, adjusted for ethnicity), reduced mobility, active malignancy major surgery within 6 weeks preceding first dose of study drug, post-partum within 12 weeks preceding first dose of study drug.
8. Women who are using estrogen-containing medication or hormone modulators from 8 weeks prior to the first dose of study drug until 8 weeks after the last dose of study drug (see separate inclusion criterion for non-estrogen containing contraception requirement).
9. Clinically significant cardiovascular disease.
10. Other conditions that substantially increase risk of cardiovascular events by the discretion of the Investigator including, but not limited to: smoking tobacco products, cocaine use, uncontrolled hypertension and untreated hyperlipidemia.
11. Congenital or acquired bleeding disorders other than Glanzmann thrombasthenia.
12. Concurrent disease, treatment, medication, or abnormality in clinical laboratory tests that may pose additional risk.
13. Addiction or other diseases that prevent the participant from appropriately assessing the nature and scope of the clinical study or participating in study procedures.
14. Received investigational medication in another clinical study within 5 half-lives before administration of study drug.
15. Female participants who are breastfeeding.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Single or Multiple ascending dose of HMB-001; Open-label, single or multiple ascending dose of HMB-001	Drug: HMB-001; HMB-001 is a bispecific antibody being developed as a prophylactic treatment option to prevent and reduce bleeding events in patients with Glanzmann thrombasthenia.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Part A: Safety as assessed by the incidence of treatment-emergent adverse events (AEs)	From baseline to Day 57
Part A: Safety as assessed by the changes in physical examinations, vital signs, clinical laboratory assessments, and ECG parameters	From baseline to Day 57
Part B: Safety as assessed by the incidence of treatment-emergent AEs	From baseline to Day 106/Early Termination (ET)/End of Study (EOS)
Part B: Safety as assessed by the changes in physical examinations, vital signs, clinical laboratory assessments, and ECG parameters	From baseline to Day 106/ET/EOS
Part B: Preliminary prophylactic effect of HMB-001 as assessed via Bleed frequency: annualized bleed rate (ABR)	From baseline to Day 106/ET/EOS
Part B: Preliminary prophylactic effect of HMB-001 as assessed via Bleed frequency: annual treated bleed rate (ATBR)	From baseline to Day 106/ET/EOS
Part C: Safety as assessed by the incidence of treatment-emergent AEs	From baseline to Day 339/End of Treatment (EOT)/ET/EOS
Part C: Safety as assessed by the changes in physical examinations, vital signs, clinical laboratory assessments, and ECG parameters	From baseline to Day 339/EOT/ET/EOS
Part C: Preliminary prophylactic effect of HMB-001 as assessed via Bleed frequency: annual treated bleed rate (ATBR)	From baseline to Day 339/EOT/ET/EOS

Secondary Outcome Measures

Outcome Measure	Time Frame
Part A: Plasma concentrations of HMB-001	From baseline to Day 57
Part A: Pharmacokinetics (PK) parameters: Maximum observed plasma concentration (Cmax)	From baseline to Day 57
Part A: PK parameters: Area under the curve from time zero to last quantifiable concentration (AUClast)	From baseline to Day 57
Part A: PK parameters: Incremental recovery (IncRec)	From baseline to Day 57
Part A: PK parameters: Area under the curve from time zero to extrapolated infinite time (AUCinf)	From baseline to Day 57
Part A: PK parameters: Volume of distribution at steady state (Vss)	From baseline to Day 57
Part A: PK parameters: Time to reach maximum observed plasma concentration (Tmax)	From baseline to Day 57
Part A: Anti-drug antibody (ADA) formation	From baseline to Day 57
Part A: Pharmacodynamic parameters: Maximum, mean increase in Coagulation factor VII (FVII) from baseline	From baseline to Day 57
Part A: Pharmacodynamic parameters: Maximum, mean decrease from baseline in prothrombin time (PT)	From baseline to Day 57
Part A: Pharmacodynamic parameters: Maximum, mean decrease from baseline in activated partial thromboplastin time (aPTT)	From baseline to Day 57
Part B: Plasma concentrations of HMB-001	From baseline to Day 106/ET/EOS
Part B: PK parameters: Cmax	From baseline to Day 106/ET/EOS
Part B: PK parameters: AUClast	From baseline to Day 106/ET/EOS
Part B: PK parameters: IncRec	From baseline to Day 106/ET/EOS
Part B: PK parameters: AUCinf	From baseline to Day 106/ET/EOS
Part B: PK parameters: Vss	From baseline to Day 106/ET/EOS
Part B: PK parameters: Tmax	From baseline to Day 106/ET/EOS
Part B: Preliminary prophylactic effect of HMB-001 as assessed by Bleeding Events	From baseline to Day 106/ET/EOS
Part B: Preliminary prophylactic effect of HMB-001 as assessed by Bleed Severity (occurrence of severe bleeding events)	From baseline to Day 106/ET/EOS
Part B: Preliminary prophylactic effect of HMB-001 as assessed by the volume of transfusion product use	From baseline to Day 106/ET/EOS
Part B: Preliminary prophylactic effect of HMB-001 as assessed by the Volume of FVIIa use	From baseline to Day 106/ET/EOS
Part B: Preliminary prophylactic effect of HMB-001 as assessed by the Volume of red blood cell (RBC) transfusion	From baseline to Day 106/ET/EOS
Part B: Preliminary prophylactic effect of HMB-001 as assessed by the Iron Status: Mean change in hemoglobin from baseline	From baseline to Day 106/ET/EOS
Part B: Preliminary prophylactic effect of HMB-001 as assessed by the Iron Status: Mean change in ferritin and total iron from baseline	From baseline to Day 106/ET/EOS
Part B: ADA formation	From baseline to Day 106/ET/EOS
Part B: Changes from baseline in Euro Quality of life 5-Dimensions 5-Level (EQ-5D-5L) score	From baseline to Day 57
Part B: Changes from baseline in Patient-Reported Outcomes Measurement Information System (PROMIS)-29 score	From baseline to Day 57
Part B: Changes from baseline in Work Productivity and Activity Impairment (WPAI) score	From baseline to Day 57
Part C: Plasma concentrations of HMB-001	From baseline to Day 339/EOT/ET/EOS
Part C: PK parameters: Cmax	From baseline to Day 339/EOT/ET/EOS
Part C: PK parameters: AUClast	From baseline to Day 339/EOT/ET/EOS
Part C: PK parameters: IncRec	From baseline to Day 339/EOT/ET/EOS
Part C: PK parameters: AUCinf	From baseline to Day 339/EOT/ET/EOS
Part C: PK parameters: Vss	From baseline to Day 339/EOT/ET/EOS
Part C: PK parameters: Tmax	From baseline to Day 339/EOT/ET/EOS
Part C: Preliminary prophylactic effect of HMB-001 as assessed by Bleeding Events	From baseline to Day 339/EOT/ET/EOS
Part C: Preliminary prophylactic effect of HMB-001 as assessed by Bleed Severity (occurrence of severe bleeding events)	From baseline to Day 339/EOT/ET/EOS
Part C: Preliminary prophylactic effect of HMB-001 as assessed by the volume of transfusion product use	From baseline to Day 339/EOT/ET/EOS
Part C: Preliminary prophylactic effect of HMB-001 as assessed by the Volume of FVIIa use	From baseline to Day 339/EOT/ET/EOS
Part C: Preliminary prophylactic effect of HMB-001 as assessed by the Volume of red blood cell (RBC) transfusion	From baseline to Day 339/EOT/ET/EOS
Part C: Preliminary prophylactic effect of HMB-001 as assessed by the Iron Status: Mean change in hemoglobin from baseline	From baseline to Day 339/EOT/ET/EOS
Part C: Preliminary prophylactic effect of HMB-001 as assessed by the Iron Status: Mean change in ferritin and total iron from baseline	From baseline to Day 339/EOT/ET/EOS
Part C: ADA formation	From baseline to Day 337/EOT
Part C: Changes from baseline in Euro Quality of life 5-Dimensions 5-Level (EQ-5D-5L) score	From baseline to Day 337/EOT
Part C: Changes from baseline in Patient-Reported Outcomes Measurement Information System (PROMIS)-29 score	From baseline to Day 337/EOT
Part C: Changes from baseline in Work Productivity and Activity Impairment (WPAI) score	From baseline to Day 337/EOT

Collaborators and Investigators

• Sponsor: Hemab ApS

Study record dates

Study Major Dates

• Study Start (Actual): December 13, 2022
• Primary Completion (Estimated): February 28, 2026
• Study Completion (Estimated): February 28, 2026

Study Registration Dates

• First Submitted: January 9, 2024
• First Submitted That Met QC Criteria: January 9, 2024
• First Posted (Actual): January 18, 2024

Study Record Updates

• Last Update Posted (Actual): January 18, 2024
• Last Update Submitted That Met QC Criteria: January 9, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hematologic Diseases; Blood Coagulation Disorders, Inherited; Hemorrhagic Disorders; Genetic Diseases, Inborn; Blood Coagulation Disorders; Blood Platelet Disorders; Thrombasthenia
• Other Study ID Numbers: HMB-001-CL101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No