Hemophilia A
Conditions
Keywords
Haemophilia A, Cell therapy, Gene therapy
Brief summary
SIG-001-121 is a first-in-human (FIH), phase 1/2, multi-centre, open-label, dose escalation study to assess the safety, tolerability, and preliminary efficacy of SIG-001 in adults with severe or moderately severe haemophilia A without inhibitors. Up to three dose cohorts (3 patients each) are planned. Cohort expansions (up to 3 additional patients) may be triggered to collect additional information about safety and efficacy.
Interventions
COMBINATION_PRODUCTSIG-001
Laparoscopic administration of SIG-001 spheres, an encapsulated allogeneic cell therapy genetically modified with a non-viral vector to produce BDD-hFVIII.
Sponsors
Sigilon Therapeutics, Inc.
Eli Lilly and Company
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Males aged 18 years or older * Diagnosis of Haemophilia A defined as ≤2% FVIII activity * Greater than 150 exposure days to treatment with FVIII products * Use of reliable barrier contraception if applicable * Normal levels of von Willebrand factor (VWF) antigen * Able and willing to provide informed consent * Willing to withdraw from FVIII prophylaxis during specified periods in the study
Exclusion criteria
* Body mass index (BMI) ≥35 * Current FVIII inhibitors (\>0.6 Nijmegen Bethesda Units/mL) or prior Immune Tolerance Induction (ITI) * History of allergic reaction or anaphylaxis to recombinant FVIII products or SIG-001 components * Evidence of any bleeding disorder in addition to haemophilia A * Abnormal laboratory values as defined in the protocol * Active infection with Hepatitis B or Hepatitis C virus or currently managed with antiviral medications for Hepatitis B or C * Uncontrolled HIV infection * Active alcoholism or drug addiction during the 12 months before the screening visit * Active malignancy or history of malignancy in the 5 years prior to study entry * Participation in another investigational medicine or device study * Prior administration of a gene therapy product * Significant underlying disease or comorbidities that are a contraindication for general anaesthesia or laparoscopic procedure
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Baseline Up to 115 Weeks | Number of Participants with at least one TEAEs are reported. A summary of other nonserious adverse events (AEs), and all serious adverse events (SAE's), regardless of causality, is located in the Reported Adverse Events section. |
| Number of Participants With Serious Treatment Emergent Adverse Events (TEAEs) | Baseline Up to 115 Weeks | Number of Participants with at least one serious TEAEs are reported. A summary of other nonserious AEs, and all SAE's, regardless of causality, is located in the Reported Adverse Events section. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Inhibitor Titer Values Assessed by Nijmegen Bethesda Assay | Baseline Up to 115 Weeks | Development of FVIII inhibitors is measured using the Nijmegen Bethesda inhibitor assay. The assay measures inhibitors to BDD-FVIII and also other forms of FVIII in the plasma, although rFVIII-BDD was used as a calibrator. |
| Change From Baseline in FVIII Activity Levels Assessed by One-stage and Chromogenic Assays | Baseline Up to 115 Weeks | The change from baseline in FVIII activity, as measured by one-stage and chromogenic assays) is summarized. |
| Number of Bleeding Events [Annualized Bleeding Rate (ABR)] for All Bleeds Following SIG-001 Administration | Time Frame: Pre-infusion (bleeding events in 12 months prior to sphere placement), 1 year, 2 year and 3-year post-infusion (post sphere placement) from SIG-001 administration annualized up to 115 Weeks. | The annualized number of bleeds per participant (annualized bleeding rate) is calculated as the number of bleeding events divided by length of time on study product follow-up, in years. The duration of assessment for this outcome measure was two years and three months, and Year 3 includes only the three-month part of this study period. |
| Total Number of Replacement FVIII Therapies | Baseline Up to 115 weeks | Number of doses after prophylaxis discontinued is reported. |
Countries
United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 Participants received a single dose of 50 mL SIG-001 spheres \[an encapsulated allogeneic cell therapy genetically modified with a non-viral vector to produce B-Domain Deleted Human Factor VIII (BDD-hFVIII) producing Spheres\] administered laparoscopically into the peritoneal cavity. | 1 |
| Cohort 2 Participants received a single dose of 78.5 mL SIG-001 spheres \[an encapsulated allogeneic cell therapy genetically modified with a non-viral vector to produce BDD-hFVIII producing Spheres\] administered laparoscopically into the peritoneal cavity. | 1 |
| Cohort 3 Participants received a single dose of 133 mL SIG-001 spheres \[an encapsulated allogeneic cell therapy genetically modified with a non-viral vector to produce BDD-hFVIII producing Spheres\] administered laparoscopically into the peritoneal cavity. | 1 |
| Total | 3 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Study Terminated | 1 | 1 | 1 |
Baseline characteristics
| Characteristic | Cohort 1 | Cohort 2 | Cohort 3 | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 1 Participants | 1 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | 1 Participants | 1 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 1 Participants | 1 Participants | 3 Participants |
| Region of Enrollment United Kingdom | 1 participants | 1 participants | 0 participants | 2 participants |
| Region of Enrollment United States | 0 participants | 0 participants | 1 participants | 1 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 1 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 1 | 0 / 1 | 0 / 1 |
| other Total, other adverse events | 1 / 1 | 1 / 1 | 1 / 1 |
| serious Total, serious adverse events | 0 / 1 | 0 / 1 | 1 / 1 |
Outcome results
Primary
Number of Participants With Serious Treatment Emergent Adverse Events (TEAEs)
Number of Participants with at least one serious TEAEs are reported. A summary of other nonserious AEs, and all SAE's, regardless of causality, is located in the Reported Adverse Events section.
Time frame: Baseline Up to 115 Weeks
Population: All participants who received at least one dose of study drug and have at least one postdose safety assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 | Number of Participants With Serious Treatment Emergent Adverse Events (TEAEs) | 0 participants |
| Cohort 2 | Number of Participants With Serious Treatment Emergent Adverse Events (TEAEs) | 0 participants |
| Cohort 3 | Number of Participants With Serious Treatment Emergent Adverse Events (TEAEs) | 1 participants |
Primary
Number of Participants With Treatment Emergent Adverse Events (TEAEs)
Number of Participants with at least one TEAEs are reported. A summary of other nonserious adverse events (AEs), and all serious adverse events (SAE's), regardless of causality, is located in the Reported Adverse Events section.
Time frame: Baseline Up to 115 Weeks
Population: All participants who received at least one dose of study drug and have at least one postdose safety assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 1 Participants |
| Cohort 2 | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 1 Participants |
| Cohort 3 | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 1 Participants |
Secondary
Change From Baseline in FVIII Activity Levels Assessed by One-stage and Chromogenic Assays
The change from baseline in FVIII activity, as measured by one-stage and chromogenic assays) is summarized.
Time frame: Baseline Up to 115 Weeks
Population: All participants who received at least one dose of study drug and had at least one postbaseline efficacy assessment.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Cohort 1 | Change From Baseline in FVIII Activity Levels Assessed by One-stage and Chromogenic Assays | Chromogenic Assay | 13.03 International Unit/deciliter (IU/dL) |
| Cohort 1 | Change From Baseline in FVIII Activity Levels Assessed by One-stage and Chromogenic Assays | One-stage | 15.46 International Unit/deciliter (IU/dL) |
| Cohort 2 | Change From Baseline in FVIII Activity Levels Assessed by One-stage and Chromogenic Assays | Chromogenic Assay | 223.78 International Unit/deciliter (IU/dL) |
| Cohort 2 | Change From Baseline in FVIII Activity Levels Assessed by One-stage and Chromogenic Assays | One-stage | 118.28 International Unit/deciliter (IU/dL) |
| Cohort 3 | Change From Baseline in FVIII Activity Levels Assessed by One-stage and Chromogenic Assays | Chromogenic Assay | -122.71 International Unit/deciliter (IU/dL) |
| Cohort 3 | Change From Baseline in FVIII Activity Levels Assessed by One-stage and Chromogenic Assays | One-stage | 189.63 International Unit/deciliter (IU/dL) |
Secondary
Number of Bleeding Events [Annualized Bleeding Rate (ABR)] for All Bleeds Following SIG-001 Administration
The annualized number of bleeds per participant (annualized bleeding rate) is calculated as the number of bleeding events divided by length of time on study product follow-up, in years. The duration of assessment for this outcome measure was two years and three months, and Year 3 includes only the three-month part of this study period.
Time frame: Time Frame: Pre-infusion (bleeding events in 12 months prior to sphere placement), 1 year, 2 year and 3-year post-infusion (post sphere placement) from SIG-001 administration annualized up to 115 Weeks.
Population: All participants who received at least one dose of study drug and had at least one postbaseline efficacy assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 | Number of Bleeding Events [Annualized Bleeding Rate (ABR)] for All Bleeds Following SIG-001 Administration | Pre-infusion | 4 Bleeding events per year |
| Cohort 1 | Number of Bleeding Events [Annualized Bleeding Rate (ABR)] for All Bleeds Following SIG-001 Administration | Year 1 | 7 Bleeding events per year |
| Cohort 1 | Number of Bleeding Events [Annualized Bleeding Rate (ABR)] for All Bleeds Following SIG-001 Administration | Year 2 | 5 Bleeding events per year |
| Cohort 1 | Number of Bleeding Events [Annualized Bleeding Rate (ABR)] for All Bleeds Following SIG-001 Administration | Year 3 | 0 Bleeding events per year |
| Cohort 2 | Number of Bleeding Events [Annualized Bleeding Rate (ABR)] for All Bleeds Following SIG-001 Administration | Year 3 | 0 Bleeding events per year |
| Cohort 2 | Number of Bleeding Events [Annualized Bleeding Rate (ABR)] for All Bleeds Following SIG-001 Administration | Pre-infusion | 0 Bleeding events per year |
| Cohort 2 | Number of Bleeding Events [Annualized Bleeding Rate (ABR)] for All Bleeds Following SIG-001 Administration | Year 2 | 0 Bleeding events per year |
| Cohort 2 | Number of Bleeding Events [Annualized Bleeding Rate (ABR)] for All Bleeds Following SIG-001 Administration | Year 1 | 1 Bleeding events per year |
| Cohort 3 | Number of Bleeding Events [Annualized Bleeding Rate (ABR)] for All Bleeds Following SIG-001 Administration | Year 3 | NA Bleeding events per year |
| Cohort 3 | Number of Bleeding Events [Annualized Bleeding Rate (ABR)] for All Bleeds Following SIG-001 Administration | Year 1 | 10 Bleeding events per year |
| Cohort 3 | Number of Bleeding Events [Annualized Bleeding Rate (ABR)] for All Bleeds Following SIG-001 Administration | Year 2 | 0 Bleeding events per year |
| Cohort 3 | Number of Bleeding Events [Annualized Bleeding Rate (ABR)] for All Bleeds Following SIG-001 Administration | Pre-infusion | 4 Bleeding events per year |
Secondary
Number of Participants With Inhibitor Titer Values Assessed by Nijmegen Bethesda Assay
Development of FVIII inhibitors is measured using the Nijmegen Bethesda inhibitor assay. The assay measures inhibitors to BDD-FVIII and also other forms of FVIII in the plasma, although rFVIII-BDD was used as a calibrator.
Time frame: Baseline Up to 115 Weeks
Population: All participants who received at least one dose of study drug and had at least one postbaseline efficacy assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 | Number of Participants With Inhibitor Titer Values Assessed by Nijmegen Bethesda Assay | 0 participants |
| Cohort 2 | Number of Participants With Inhibitor Titer Values Assessed by Nijmegen Bethesda Assay | 0 participants |
| Cohort 3 | Number of Participants With Inhibitor Titer Values Assessed by Nijmegen Bethesda Assay | 1 participants |
Secondary
Total Number of Replacement FVIII Therapies
Number of doses after prophylaxis discontinued is reported.
Time frame: Baseline Up to 115 weeks
Population: All participants who received at least one dose of study drug and had at least one postbaseline efficacy assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 | Total Number of Replacement FVIII Therapies | 401 Number of doses |
| Cohort 2 | Total Number of Replacement FVIII Therapies | 327 Number of doses |
| Cohort 3 | Total Number of Replacement FVIII Therapies | 1558 Number of doses |