Pemphigus, Pemphigus Foliaceus, Pemphigus Vulgaris
Conditions
Brief summary
This was a multicenter, open-label safety study to determine the dose regimen of SYNT001 (ALXN1830) administered intravenously in participants with pemphigus (vulgaris or foliaceus).
Detailed description
This study planned to evaluate 2 cohorts: up to 8 participants to receive 5 weekly intravenous (IV) doses of ALXN1830 at 10 milligram/kilogram (mg/kg) (Cohort 1) and up to 12 participants to receive 3 x 30 mg/kg weekly doses of ALXN1830 IV (loading) followed by 5 x 10 mg/kg doses of ALXN1830 IV every other week or 10 weekly doses of ALXN1830 IV (maintenance) (Cohort 2). This study was terminated after the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy were characterized in participants with pemphigus at a single dose level (10 mg/kg) in Cohort 1, before any participants were enrolled in Cohort 2. The study consisted of 3 periods: Screening, Treatment, and Follow-Up.
Interventions
DRUGALXN1830
Administered via IV infusion.
Sponsors
Alexion Pharmaceuticals, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Participants must have meet the following criteria to be included: * Were willing and able to read, understand and sign an informed consent form * Documented diagnosis of pemphigus vulgaris or foliaceus * Were required to use medically acceptable contraception
Exclusion criteria
Participants meeting any of the following criteria were excluded: * Were unable or unwilling to comply with the protocol * Active non-hematologic malignancy or history of non-hematologic malignancy in the 3 years prior to screening (exclusive of non-melanoma skin cancer and cervical cancer in situ) * Positive for human immunodeficiency virus (HIV) or hepatitis C antibody * Positive for hepatitis B surface antigen * IV immunoglobulin treatment within 30 days of screening * Any exposure to an investigational drug or device within the 30 days prior to screening * Plasmapheresis or immunoadsorption within 30 days of screening * Participant had any current medical condition that, in the opinion of the Investigator, may have compromised their safety or compliance, preclude successful conduct of the study, or interfere with interpretation of the results
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Count Of Participants Reporting Treatment-emergent Adverse Events (TEAEs) | Day 1 (after first dose) through Day 112 | A TEAE was defined as any adverse event (AE) that starts on or after the first dose of study drug or occurs prior to the first dose and worsens in severity on or after the first dose of study drug, during the Treatment Period and Follow-up Period. A TEAE was considered serious (Grade 3) if, in the view of either the investigator or sponsor, it resulted in any of the following outcomes: death, life-threatening adverse drug event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, congenital anomaly/birth defect, or an event that may have jeopardized the participant and may have required medical or surgical intervention to prevent one of the previously listed outcomes. A summary of serious and all other non-serious adverse events, regardless of causality, is located in the Reported Adverse Events module. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Percent Reduction Of Mean Total Immunoglobulin G (IgG) Levels From Baseline | Baseline through Day 112 | Pharmacodynamic samples were collected for analysis throughout the study. The maximum percent reduction of mean serum total IgG levels from Baseline observed during the study is presented. |
| Maximum Percent Reduction In Mean Pemphigus Disease Area Index (PDAI) Total Activity Score From Baseline | Baseline through Day 112 | Pemphigus severity and disease activity was measured using the PDAI in regions where a validated questionnaire was available. The PDAI was administered during Treatment Period and Follow-up Period. PDAI total activity was comprised of scores for the skin, mucous membrane, and scalp subscales. The investigator determined a PDAI score as 0 to 250 points for total activity score (0 to 120 for skin, 0 to 10 for scalp, and 0 to 120 for mucosa). A higher score indicated higher impact on skin disease. The maximum percent reduction in PDAI total activity score from Baseline observed during the study is presented. |
| Maximum Percent Reduction Of Mean Circulating Immune Complexes (CIC) Levels From Baseline | Baseline through Day 112 | Pharmacodynamic samples were collected for analysis throughout the study. The maximum percent reduction of mean CIC levels from Baseline observed during the study is presented. |
| Maximum Percent Reduction Of Mean Anti-Desmoglein (Dsg) 1 And 3 Antibodies From Baseline | Baseline through Day 112 | Pharmacodynamic samples were collected for analysis throughout the study. The maximum percent reduction of mean anti-Dsg 1 and 3 antibodies from Baseline observed during the study is presented. |
Countries
United States
Participant flow
Pre-assignment details
This study was terminated after the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy were characterized at a single dose level (10 milligram/kilogram \[mg/kg\]) in Cohort 1, before any participants were enrolled in Cohort 2. This results disclosure is for Cohort 1 only.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: ALXN1830 Participants received 5 doses of ALXN1830 10 mg/kg administered weekly. | 8 |
| Total | 8 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Need for Medication not Permitted | 1 |
| Overall Study | Physician Decision | 3 |
Baseline characteristics
| Characteristic | Cohort 1: ALXN1830 |
|---|---|
| Age at Diagnosis of Pemphigus | 41.3 years STANDARD_DEVIATION 18.9 |
| Age, Continuous | 51.4 years STANDARD_DEVIATION 16.43 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 5 Participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 3 Participants |
| Type of Pemphigus Foliaceus | 1 Participants |
| Type of Pemphigus Vulgaris | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 8 |
| other Total, other adverse events | 7 / 8 |
| serious Total, serious adverse events | 1 / 8 |
Outcome results
Primary
Count Of Participants Reporting Treatment-emergent Adverse Events (TEAEs)
A TEAE was defined as any adverse event (AE) that starts on or after the first dose of study drug or occurs prior to the first dose and worsens in severity on or after the first dose of study drug, during the Treatment Period and Follow-up Period. A TEAE was considered serious (Grade 3) if, in the view of either the investigator or sponsor, it resulted in any of the following outcomes: death, life-threatening adverse drug event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, congenital anomaly/birth defect, or an event that may have jeopardized the participant and may have required medical or surgical intervention to prevent one of the previously listed outcomes. A summary of serious and all other non-serious adverse events, regardless of causality, is located in the Reported Adverse Events module.
Time frame: Day 1 (after first dose) through Day 112
Population: All participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1: ALXN1830 | Count Of Participants Reporting Treatment-emergent Adverse Events (TEAEs) | TEAEs | 7 Participants |
| Cohort 1: ALXN1830 | Count Of Participants Reporting Treatment-emergent Adverse Events (TEAEs) | Serious TEAEs | 1 Participants |
| Cohort 1: ALXN1830 | Count Of Participants Reporting Treatment-emergent Adverse Events (TEAEs) | Discontinuations due to TEAEs | 0 Participants |
| Cohort 1: ALXN1830 | Count Of Participants Reporting Treatment-emergent Adverse Events (TEAEs) | Deaths | 0 Participants |
Secondary
Maximum Percent Reduction In Mean Pemphigus Disease Area Index (PDAI) Total Activity Score From Baseline
Pemphigus severity and disease activity was measured using the PDAI in regions where a validated questionnaire was available. The PDAI was administered during Treatment Period and Follow-up Period. PDAI total activity was comprised of scores for the skin, mucous membrane, and scalp subscales. The investigator determined a PDAI score as 0 to 250 points for total activity score (0 to 120 for skin, 0 to 10 for scalp, and 0 to 120 for mucosa). A higher score indicated higher impact on skin disease. The maximum percent reduction in PDAI total activity score from Baseline observed during the study is presented.
Time frame: Baseline through Day 112
Population: All participants who received at least 1 dose of study drug and had postdose pharmacodynamic data available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: ALXN1830 | Maximum Percent Reduction In Mean Pemphigus Disease Area Index (PDAI) Total Activity Score From Baseline | 45.7 percentage of reduction |
Secondary
Maximum Percent Reduction Of Mean Anti-Desmoglein (Dsg) 1 And 3 Antibodies From Baseline
Pharmacodynamic samples were collected for analysis throughout the study. The maximum percent reduction of mean anti-Dsg 1 and 3 antibodies from Baseline observed during the study is presented.
Time frame: Baseline through Day 112
Population: All participants who received at least 1 dose of study drug and had postdose pharmacodynamic data available.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1: ALXN1830 | Maximum Percent Reduction Of Mean Anti-Desmoglein (Dsg) 1 And 3 Antibodies From Baseline | anti-Dsg 1 | 8.9 percentage of reduction |
| Cohort 1: ALXN1830 | Maximum Percent Reduction Of Mean Anti-Desmoglein (Dsg) 1 And 3 Antibodies From Baseline | anti-Dsg 3 | 20.4 percentage of reduction |
Secondary
Maximum Percent Reduction Of Mean Circulating Immune Complexes (CIC) Levels From Baseline
Pharmacodynamic samples were collected for analysis throughout the study. The maximum percent reduction of mean CIC levels from Baseline observed during the study is presented.
Time frame: Baseline through Day 112
Population: All participants who received at least 1 dose of study drug and had postdose pharmacodynamic data available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: ALXN1830 | Maximum Percent Reduction Of Mean Circulating Immune Complexes (CIC) Levels From Baseline | 51.4 percentage of reduction |
Secondary
Maximum Percent Reduction Of Mean Total Immunoglobulin G (IgG) Levels From Baseline
Pharmacodynamic samples were collected for analysis throughout the study. The maximum percent reduction of mean serum total IgG levels from Baseline observed during the study is presented.
Time frame: Baseline through Day 112
Population: All participants who received at least 1 dose of study drug and had postdose pharmacodynamic data available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: ALXN1830 | Maximum Percent Reduction Of Mean Total Immunoglobulin G (IgG) Levels From Baseline | 57.3 percentage of reduction |