Safety, Tolerability, PK, PD, and Efficacy of HMB-001 in Participants With Glanzmann Thrombasthenia

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Hemab ApS

Participant type

Patients

Age range

18-64 years

Gender

Male and Female

Therapeutic area

Not possible to specify

Trial duration

3 May 2024 → ongoing

Decision date (initial)

2024-05-17

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Hemab Aps

External identifiers

EU CT number

2023-505995-31-00

WHO UTN

U1111-1293-0166

ClinicalTrials.gov

NCT06211634

ISRCTN

ISRCTN66310879

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Dose response, Safety, Pharmacokinetic, Efficacy, Pharmacogenetic

Part A
• To determine the safety and tolerability of HMB-001
• To establish the dose level(s) and dosing interval(s) of HMB-001 to be investigated in Part B and Part C
Part B and Part C
• To confirm the safety and tolerability profile of HMB-001 following repeat dosing
• To estimate the preliminary prophylactic effect of HMB-001 on bleeding frequency and bleeding severity

Secondary objectives 7

1. 1. Part A • To characterize the systemic PK profile of HMB-001
2. 2. Part A • To characterize immunogenicity of single dosing of HMB-001
3. 3. Part A • To estimate the PD effects of HMB-001
4. 4. Part B and Part C • To further characterize the systemic PK profile of HMB-001
5. 5. Part B and Part C • To estimate the preliminary prophylactic effect of HMB-001 on bleeding frequency and bleeding severity
6. 6. Part B and Part C • To characterize immunogenicity of repeat dosing of HMB-001
7. 7. Part B and Part C • To estimate the effect of HMB-001 on Quality of Life (QOL) scores

Conditions and MedDRA coding

Glanzmann Thrombasthenia

Regulatory references

Scientific advice from competent authorities

Medicines And Healthcare Products Regulatory Agency, Food And Drug Administration

Plan to share IPD

No

IPD plan description

undecided

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 4

1. 1. Part A • Each participant in Part A must meet the following inclusion criteria to be eligible for enrolment in the study: Age 18 to 67 years, inclusive, at the time of signing informed consent. Glanzmann thrombasthenia; documented abnormal, diagnostic platelet aggregometry plus deficiency of the αIIbβ3 (GPIIb/GPIIIa) receptor via flow cytometry; or genetic diagnosis. Has the ability to provide informed consent to participate in the trial, in accordance with the International Council for Harmonisation (ICH) Good Clinical Practice (GCP) Guideline E6 (R2) (2016) and applicable regulations, before completing any trial-related procedures. Has an understanding, ability, and willingness to fully comply with trial procedures and restrictions. Vital signs are within the following ranges at Screening: Resting heart rate ≤ 105 bpm (after at least 5 minutes of resting). Blood pressure (BP): Resting BP (after at least 5 minutes of resting or based on 24 hours monitor demonstrating normotensive BP): Systolic BP: 90 – 140 mmHg. Diastolic BP: 40 – 90 mmHg. Women of child-bearing potential (WOCBP) have a negative serum pregnancy test within 72 hours prior to the first dose of HMB001. WOCBP agree to use highly effective contraceptive methods (excluding estrogen-containing combined oral contraceptive pill; see Section 13.1) 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 HMB001. A woman is considered to be of child-bearing potential unless she: has had a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy; is age > 50 years and has been amenorrhoeic for ≥ 12 months (including no irregular menses or spotting) in the absence of any medication which induces a menopausal state and has documented ovarian failure by follicle-stimulating hormone levels within the institutional laboratory postmenopausal range). Men of child-producing potential agree to use highly effective contraceptive methods (see Section 13.1) and avoid sperm donation for 14 days prior to Day 1, during the study treatment, and for 6 months after the last dose of HMB001. A man is considered to be of child-producing potential unless he has had a bilateral vasectomy with documented aspermia or a bilateral orchiectomy. Participants must meet the following baseline organ function, indicated by laboratory criteria: 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. An aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin ≤ 1.5 x upper limit of normal (ULN) range at Screening. For participants with a history of Gilbert’s Syndrome, total bilirubin ≤ 2 × ULN at Screening. Note: Where a participant exceeds any of the criteria in (b), they may undergo additional safety assessment by a board certified hepatologist, if the findings are subsequently deemed to be non-clinically significant, these results will not prevent the participant’s inclusion. Hemoglobin >85 g/L and platelet count >120 x 10^9/L at Screening.
2. 2. Part B • Each participant in Part B must meet the following inclusion criteria to be eligible for enrolment in the study: Has the ability to provide informed consent to participate in the clinical trial before completing any trial-related procedures, and has an understanding, ability, and willingness to fully comply with clinical trial procedures and restrictions. Age 18 to 67 years, inclusive, at the time of signing informed consent. 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. Patients should experience bleeding symptoms associated with Glanzmann Thrombasthenia defined as approximately two bleeding events per week on average of any severity and any type (including skin bruising) and at least one spontaneous or traumatic bleed that requires a prescribed treatment, medical or surgical procedure for the bleeding event within the last 12 months.
3. 3. Part B • Vital signs are within the following ranges at Screening: Resting heart rate ≤105 bpm (after at least 5 minutes of resting). BP: Resting BP (after at least 5 minutes of resting or based on 24 hours monitor demonstrating normotensive BP): Systolic BP: 90 – 140 mmHg. Diastolic BP: 40 – 90 mmHg. Women of child-bearing potential (WOCBP) have a negative serum pregnancy test within 72 hours prior to the first dose of HMB-001. WOCBP agree to use a highly effective contraceptive method and to avoid egg donation during the study treatment, and for 6 months after the last dose of HMB-001. A woman is considered to be of child-bearing potential unless she: has had a hysterectomy or bilateral oophorectomy; is age >50 years and has been amenorrhoeic for ≥12 months (including no irregular menses or spotting) in the absence of any medication which induces a menopausal state and has documented ovarian failure by follicle-stimulating hormone levels within the institutional laboratory postmenopausal range). Men of child-producing potential agree to use highly effective contraceptive methods and avoid sperm donation during the study treatment, and for 6 months after the last dose of HMB-001. A man is considered to be of child-producing potential unless he has had a bilateral vasectomy with documented aspermia or a bilateral orchiectomy. Participants must meet the following baseline organ function, indicated by laboratory criteria: 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. An AST, ALT, and total bilirubin ≤1.5 x ULN range at Screening. For participants with a history of Gilbert’s Syndrome, total bilirubin ≤2 × ULN at Screening. Note: Where a participant exceeds any of the criteria in (b), they will undergo additional safety assessment by a board certified hepatologist, if the findings are subsequently deemed to be non-clinically significant, these results will not prevent the participant’s inclusion. Hemoglobin >85 g/L and platelet count >120 x 10^9/L at Screening.
4. 4. Part B and Part C Participants included in Part B are eligible for Part C following completion of their Day 85 Visit provided their fulfilled the requirements of Part B, are considered suitable to continue by the Investigator, have not met individual stopping rules, and provide consent. If the participant experiences a toxicity that does not meet individual stopping criteria, symptoms must have resolved to Grade 1 or baseline prior to commencing dosing in Part C.

Exclusion criteria 4

1. 1. Part A • Each participant in Part A must not meet any of the following exclusion criteria to be eligible for enrolment in the study: Severe infection or inflammation at the time of Screening. History of clinically significant hypersensitivity associated with monoclonal antibody therapies. Personal history of venous or arterial thrombosis or thromboembolic disease, with the exception of catheter-associated, superficial vein thrombosis. Known severe congenital or acquired thrombophilia. 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. 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 HMB-001, post-partum within 12 weeks preceding first dose of HMB-001. Women who are using estrogen-containing medication or hormone modulators (within 8 weeks pre-dose to 8 weeks post-dose of HMB-001) including: Women on combined oral contraception with estrogen >3030 μg Women on combined oral contraception with estrogen < 30 μg during the study must not meet any of the following restrictions: Combined oral contraception not established for a minimum of 12 months of continuous use (week off per month for breakthrough bleeding allowed) prior to first dose of HMB-001. Intention to change or interrupt contraceptives use during study. Hormone replacement therapy (excluding transdermal patches). Estrogen receptor modulators (e.g., Tamoxifen). Gonadotropin releasing hormone receptor (GnRH receptor) agonist. Clinically significant cardiovascular disease including, but not limited to: New York Heart Association Class III or IV heart failure, coronary artery disease, uncontrolled arrythmia, moderate to severe valvular heart disease, peripheral vascular disease, and ischemic stroke. Other conditions that substantially increase the risk of cardiovascular events by the discretion of the Investigator including, but not limited to: age, obesity, immobility, moking, cocaine use, and uncontrolled hypertension. Congenital or acquired bleeding disorders other than Glanzmann thrombasthenia. Concurrent disease, treatment, medication, or abnormality in clinical laboratory tests that may pose additional risk in the opinion of the investigator and preclude the participant’s safe participation in and completion of the study. Addiction or other diseases that prevent the participant from appropriately assessing the nature and scope of the clinical study or participating in study procedures by the discretion of the Investigator. Received any live vaccine within 4 weeks of enrollment or is planning to have a live vaccine during the study period. Received investigational medication in another clinical study within 5 half-lives before administration of HMB-001. Female participants who are pregnant (including a positive serum pregnancy test at Screening) or breastfeeding. Participants who initially failed due to temporary non-medically significant issues are eligible for re-screening once the cause has resolved.
2. 2. Part B • Each participant in Part B must not meet any of the following exclusion criteria to be eligible for enrolment in the study: Active severe infection or inflammation at the time of Screening or prior to the first dose of HMB-001. History of clinically significant hypersensitivity associated with monoclonal antibody therapies. Personal history of venous or arterial thrombosis or thromboembolic disease, with the exception of catheter-associated, superfcial vein thrombosis. Has known, documented, high risk congenital thrombophilia. Family history of unprovoked venous thrombosis in first degree relative. Has a positive test for HbsAg, HCV Ab, or 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. 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 HMB-001, post-partum within 12 weeks preceding first dose of HMB-001. Women who are using estrogen-containing medication or hormone modulators from 8 weeks prior to the first dose of HMB-001 until 8 weeks after the last dose of HMB-001 Women on combined oral conraception with estrogen dose > 30 μg Women on combined oral contraception with estrogen < 30 μg during the study must not meet any of the following restrictions: Combined oral contraception not established for a minimum of 12 months of continuous use (week off for breakthrough bleeding allowed)at time of screening Intention to change or interrupt contraceptive use during study: Hormone replacement therapy (excluding transdermal patches) Estrogen receptor modulators (e.g., Tamoxifen) GnRH receptor agonist. Clinically significant cardiovascular disease including, but not limited to: New York Heart Association Class III or IV heart failure, coronary artery disease, uncontrolled arrythmia, moderate to severe valvular heart disease, peripheral vascular disease, and ischemic stroke. Other conditions that substantially increase risk of cardiovascular events by the discretion of the Investigator including, but not limited to: current and previous smoking history, age, obesity, immobility, cocaine use, uncontrolled hypertension and untreated hyperlipidemia. Congenital or acquired bleeding disorders other than Glanzmann thrombasthenia. Concurrent disease, treatment, medication, or abnormality in clinical laboratory tests that may pose additional risk in the opinion of the investigator and preclude the participant’s safe participation in and completion of the study. Addiction or other diseases that prevent the participant from appropriately assessing the nature and scope of the clinical study or participating in study procedures by the discretion of the Investigator. Received any live vaccine within 4 weeks of enrollment or is planning to have a live vaccine during the study period. Received investigational medication in another clinical study within 5 half-lives before administration of HMB-001. Female participants who are pregnant (including a positive serum pregnancy test at Screening or breastfeeding. Participants who initially failed due to temporary non-medically significant issues are eligible for re-screening once the cause has resolved.
3. 3. Part B and Part C • Participants included in Part B are eligible for Part C following completion of their Day 85 Visit provided they fulfilled the requirements of Part B (including acceptable compliance), are considered suitable to continue by the Investigator, have not met individual stopping rules, and provide consent. If the participant experiences a toxicity that does not meet individual stopping criteria, symptoms must have resolved to Grade 1 or baseline prior to commencing dosing in Part C.
4. 4. Part B Co-existing thrombophilic disorder, as determined by the presence of any of the below (or via historical results, where available): • Homozygous for Factor V Leiden gene mutation • Compound heterozygous for Factor V Leiden gene mutation • Prothrombin G20210A mutation • Antithrombin III, Protein C deficiency or Protein S deficiency with activity levels of ≤50% in participants with at least 1 second-degree relative with an unprovoked venous thromboembolism (VTE), or a first-degree relative with a minimally provoked VTE or at Investigator discretion for participants with an unknown family history

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. 1. Part A • Safety as assessed by the incidence of treatment emergent adverse events (AEs) and changes in physical examinations, vital signs, clinical laboratory assessments, and electrocardiogram (ECG) parameters.
2. 2. Part B and Part C • Safety as assessed by the incidence of treatment emergent AEs and changes in physical examinations, vital signs, clinical laboratory assessments, and ECG parameters.
3. 3. Part B and Part C • Preliminary prophylactic effect of HMB-001 as assessed via: − Bleed frequency: annualized treated bleed rate (ATBR) and annualized bleed rate (ABR)

Secondary endpoints 8

1. 1. Part A • Plasma concentrations of HMB-001 • PK parameters including, but not limited to: − Maximum observed plasma concentration (Cmax) − Area under the curve from time zero to last quantifiable concentration (AUClast) − Area under the curve from time zero to extrapolated infinite time (AUCinf) − Time to reach maximum observed plasma concentration (Tmax)
2. 2. Part A • Anti-drug antibody (ADA) formation
3. 3. Part A • PD parameters including, but not limited to: − Maximum, mean increase in FVII from baseline − Maximum, mean decrease from baseline in prothrombin time (PT) − Maximum, mean decrease from baseline in activated partial thromboplastin time (aPTT).
4. 4. Part B and Part C • Plasma concentrations of HMB-001 • PK parameters including, but not limited to: − Cmax − AUClast − AUCinf − Tmax.
5. 5. Part B and Part C • Preliminary prophylactic effect of HMB-001 as assessed by: - Subcategories of ABR, including, but not limited to: o Sponstaneous and impactful − Bleed Severity o Occurrence of severe bleeding events
6. 6. Part B and Part C • Preliminary prophylactic effect of HMB-001 as assessed by: − Requirement for Treatment o Volume of transfusion product use: platelets, fresh frozen plasma, cryoprecipitate o Volume of Factor Concentration use: rFVIIa o Volume of red blood cell (RBC) transfusion − Iron Status o Mean change in hemoglobin from baseline o Mean change in ferritin and total iron from baseline
7. 7. Part B and Part C • ADA formation.
8. 8. Part B and Part C • Changes from baseline in Euro Quality of life 5- Dimensions 5-Level (EQ-5D-5L), Patient-Reported Outcomes Measurement Information System (PROMIS)-29, and Work Productivity and Activity Impairment (WPAI) scores.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Hemab ApS

Sponsor organisation

Hemab ApS

Address

Nordre Fasanvej 215

City

Frederiksberg

Postcode

2000

Country

Denmark

Scientific contact point

Organisation

Hemab ApS

Contact name

Clinical Research

Public contact point

Organisation

Hemab ApS

Contact name

Clinical Research

Third parties 13

Locations

4 EU/EEA countries · 6 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 115 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

12 submissions — initial application plus substantial / non-substantial modifications