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

Glanzmann Thrombasthenia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06211634
• Other study ID #: HMB-001-CL101
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: December 13, 2022
• Est. completion date: February 28, 2026

Study information

• Verified date: January 2024
• Source: Hemab ApS
• Contact: Catherine Rea
• Phone: +44 0808 304 6409
• Email: clinicaltrials[@]hemab.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 57
• Est. completion date: February 28, 2026
• Est. primary completion date: February 28, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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 aIIbß3 (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 aIIbß3 (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.

Related Conditions & MeSH terms

• Glanzmann Thrombasthenia

Intervention

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.

Locations

Country	Name	City	State
Belgium	University Hospital Leuven - Campus Gasthuisberg (Part B/C)	Leuven
France	AP-HP Hopital Bicetre (Part B/C)	Le Kremlin-Bicêtre
France	AP-HP Hopital Necker-Enfants Malades (Part B/C)	Paris
Italy	Azienda Ospedaliero-Universitaria Careggi (Part B/C)	Firenze
Italy	Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano (Part B/C)	Milano
Netherlands	Erasmus MC (Part B/C)	Rotterdam
Netherlands	Universitair Medisch Centrum Utrecht (Part B/C)	Utrecht
United Kingdom	Queen Elizabeth Hospital Birmingham (Part B/C)	Birmingham
United Kingdom	Richmond Pharmacology Ltd (Part A/B/C)	London
United Kingdom	Royal Free London NHS Foundation Trust (Part B/C)	London
United Kingdom	Sheffield Teaching Hospitals NHS Foundation Trust (Part B/C)	Sheffield
United Kingdom	The Royal London Hospital (Part B/C)	Whitechapel
United States	University of California, San Diego (UCSD) (Part B/C)	La Jolla	California
United States	Tulane University Medical Center (Part B/C)	New Orleans	Louisiana
United States	Hemophilia Center of Western Pennsylvania (HCWP) (Part B/C)	Pittsburgh	Pennsylvania
United States	Mayo Clinic - Rochester (Part B/C)	Rochester	Minnesota
United States	Washington Institute for Coagulation (Part B/C)	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Hemab ApS

Countries where clinical trial is conducted

United States,  Belgium,  France,  Italy,  Netherlands,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Part A: Safety as assessed by the incidence of treatment-emergent adverse events (AEs)		From baseline to Day 57
Primary	Part A: Safety as assessed by the changes in physical examinations, vital signs, clinical laboratory assessments, and ECG parameters		From baseline to Day 57
Primary	Part B: Safety as assessed by the incidence of treatment-emergent AEs		From baseline to Day 106/Early Termination (ET)/End of Study (EOS)
Primary	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
Primary	Part B: Preliminary prophylactic effect of HMB-001 as assessed via Bleed frequency: annualized bleed rate (ABR)		From baseline to Day 106/ET/EOS
Primary	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
Primary	Part C: Safety as assessed by the incidence of treatment-emergent AEs		From baseline to Day 339/End of Treatment (EOT)/ET/EOS
Primary	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
Primary	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	Part A: Plasma concentrations of HMB-001		From baseline to Day 57
Secondary	Part A: Pharmacokinetics (PK) parameters: Maximum observed plasma concentration (Cmax)		From baseline to Day 57
Secondary	Part A: PK parameters: Area under the curve from time zero to last quantifiable concentration (AUClast)		From baseline to Day 57
Secondary	Part A: PK parameters: Incremental recovery (IncRec)		From baseline to Day 57
Secondary	Part A: PK parameters: Area under the curve from time zero to extrapolated infinite time (AUCinf)		From baseline to Day 57
Secondary	Part A: PK parameters: Volume of distribution at steady state (Vss)		From baseline to Day 57
Secondary	Part A: PK parameters: Time to reach maximum observed plasma concentration (Tmax)		From baseline to Day 57
Secondary	Part A: Anti-drug antibody (ADA) formation		From baseline to Day 57
Secondary	Part A: Pharmacodynamic parameters: Maximum, mean increase in Coagulation factor VII (FVII) from baseline		From baseline to Day 57
Secondary	Part A: Pharmacodynamic parameters: Maximum, mean decrease from baseline in prothrombin time (PT)		From baseline to Day 57
Secondary	Part A: Pharmacodynamic parameters: Maximum, mean decrease from baseline in activated partial thromboplastin time (aPTT)		From baseline to Day 57
Secondary	Part B: Plasma concentrations of HMB-001		From baseline to Day 106/ET/EOS
Secondary	Part B: PK parameters: Cmax		From baseline to Day 106/ET/EOS
Secondary	Part B: PK parameters: AUClast		From baseline to Day 106/ET/EOS
Secondary	Part B: PK parameters: IncRec		From baseline to Day 106/ET/EOS
Secondary	Part B: PK parameters: AUCinf		From baseline to Day 106/ET/EOS
Secondary	Part B: PK parameters: Vss		From baseline to Day 106/ET/EOS
Secondary	Part B: PK parameters: Tmax		From baseline to Day 106/ET/EOS
Secondary	Part B: Preliminary prophylactic effect of HMB-001 as assessed by Bleeding Events		From baseline to Day 106/ET/EOS
Secondary	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
Secondary	Part B: Preliminary prophylactic effect of HMB-001 as assessed by the volume of transfusion product use		From baseline to Day 106/ET/EOS
Secondary	Part B: Preliminary prophylactic effect of HMB-001 as assessed by the Volume of FVIIa use		From baseline to Day 106/ET/EOS
Secondary	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
Secondary	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
Secondary	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
Secondary	Part B: ADA formation		From baseline to Day 106/ET/EOS
Secondary	Part B: Changes from baseline in Euro Quality of life 5-Dimensions 5-Level (EQ-5D-5L) score		From baseline to Day 57
Secondary	Part B: Changes from baseline in Patient-Reported Outcomes Measurement Information System (PROMIS)-29 score		From baseline to Day 57
Secondary	Part B: Changes from baseline in Work Productivity and Activity Impairment (WPAI) score		From baseline to Day 57
Secondary	Part C: Plasma concentrations of HMB-001		From baseline to Day 339/EOT/ET/EOS
Secondary	Part C: PK parameters: Cmax		From baseline to Day 339/EOT/ET/EOS
Secondary	Part C: PK parameters: AUClast		From baseline to Day 339/EOT/ET/EOS
Secondary	Part C: PK parameters: IncRec		From baseline to Day 339/EOT/ET/EOS
Secondary	Part C: PK parameters: AUCinf		From baseline to Day 339/EOT/ET/EOS
Secondary	Part C: PK parameters: Vss		From baseline to Day 339/EOT/ET/EOS
Secondary	Part C: PK parameters: Tmax		From baseline to Day 339/EOT/ET/EOS
Secondary	Part C: Preliminary prophylactic effect of HMB-001 as assessed by Bleeding Events		From baseline to Day 339/EOT/ET/EOS
Secondary	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
Secondary	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
Secondary	Part C: Preliminary prophylactic effect of HMB-001 as assessed by the Volume of FVIIa use		From baseline to Day 339/EOT/ET/EOS
Secondary	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
Secondary	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
Secondary	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
Secondary	Part C: ADA formation		From baseline to Day 337/EOT
Secondary	Part C: Changes from baseline in Euro Quality of life 5-Dimensions 5-Level (EQ-5D-5L) score		From baseline to Day 337/EOT
Secondary	Part C: Changes from baseline in Patient-Reported Outcomes Measurement Information System (PROMIS)-29 score		From baseline to Day 337/EOT
Secondary	Part C: Changes from baseline in Work Productivity and Activity Impairment (WPAI) score		From baseline to Day 337/EOT