PNH
Conditions
Keywords
PNH, Paroxysmal Nocturnal Hemoglobinuria, Complement inhibitor, Anemia, Hemoglobinuria, Hemolysis, Hematologic diseases, Extravascular hemolysis (EVH), Intravascular hemolysis (IVH), C3 inhibitor
Brief summary
This is a Phase IIa, open-label, multiple dose, study in patients with PNH who have not received eculizumab (Soliris ®) in the past. A single cohort of subjects is planned for evaluation.
Interventions
DRUGPegcetacoplan
Complement (C3) Inhibitor
Sponsors
Apellis Pharmaceuticals, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* At least 18 years old (inclusive) * Diagnosed with PNH (white blood cell (WBC) clone \>10%) * Lactose dehydrogenase (LD) ≥2 times the upper limit of normal * Screening Ferritin ≥ normal and Total Iron Binding Capacity (TIBC) \< LLN based on central lab reference ranges. If a subject is receiving iron supplements at screening, the investigator must ensure that his/her dose has been stable for 8 weeks prior to enrolment and must be maintained throughout the study * Last transfusion within 12 months prior to screening * Platelet count of \>30,000/mm3 at the screening visit * Absolute neutrophil count \>500/ mm3 at the screening visit * Women of child-bearing potential (WOCBP) must have a negative pregnancy test at screening and must agree to use protocol defined methods of contraception for the duration of the study * Males must agree to use protocol defined methods of contraception and agree to refrain from donating sperm for the duration of the study * Vaccination against Neisseria meningitides types A, C, W, Y and B, Streptococcus pneumoniae and Haemophilus influenzae Type B (Hib) either within 2 years prior to Day 1 dosing, or within 14 days after starting treatment with pegcetacoplan. Unless documented evidence exists that subjects are non-responders to vaccination as evidenced by titers or display titer levels within acceptable local limits * Willing and able to give informed consent
Exclusion criteria
* Prior eculizumab (Soliris®) treatment * Active bacterial infection * Hereditary complement deficiency * History of bone marrow transplantation * Concurrent severe aplastic anemia (SAA), defined as currently receiving immunosuppressive therapy for SAA including but not limited to cyclosporin A, tacrolimus, mycophenolate mofetil or anti-thymocyte globulin * Participation in any other investigational drug trial or exposure to another investigational agent, device or procedure within 30 days * Evidence of QTcF prolongation defined as \>450 ms for males and \>470 ms for females at screening * Breast-feeding women * History of meningococcal disease
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in Hemoglobin (Hb) Level | Baseline and Day 365 | Hematology assessments of Hb were made at the last measurement prior to the first dose of pegcetacoplan (baseline) and periodically throughout the treatment period. |
| Number of Subjects With Treatment Emergent Adverse Events (TEAEs) Including by Severity | From Day 1 to 30 days after the last dose (approximately 56 weeks) | TEAEs were defined as adverse events (AE) that occurred after dosing on Day 1 and up to 30 days after the last dose of study drug. A treatment-related TEAE was defined as a TEAE with a relationship to study drug of possible, probable, or definite. TEAEs were graded according to the Common Terminology Criteria for Adverse Events (v4.03) based on: Grade 1: Mild, Grade 2: Moderate, Grade 3: Severe, Grade 4: Life-threatening, Grade 5: Death related to AE. |
| Mean Change From Baseline in Lactate Dehydrogenase (LDH) Level | Baseline and Day 365 | Serum chemistry assessments of LDH were made at the last measurement prior to the first dose of pegcetacoplan (baseline) and periodically throughout the treatment period. |
| Mean Change From Baseline in Haptoglobin Level | Baseline and Day 365 | Serum chemistry assessments of haptoglobin were made at the last measurement prior to the first dose of pegcetacoplan (baseline) and periodically throughout the treatment period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in Linear Analog Scale Assessment (LASA) Score for QoL | Baseline and Day 365 | The LASA consists of 3 items, where the respondents were asked to rate their perceived level of functioning. Specific domains included activity level, ability to carry out daily activities, and an item for overall QoL. Their level of functioning was reported on a 0 to 100 scale with 0 indicates As low as could be and 100 indicates As high as could be. The combined score ranged from 0 to 300, with higher scores corresponding to a higher QoL. |
| Mean Serum Concentrations of Pegcetacoplan | Day 365 | Serum concentrations of pegcetacoplan at Day 365 are presented. |
| Mean Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Score | Baseline and Day 365 | The FACIT-Fatigue scale is a 13 item Likert scaled instrument where the subject was presented with 13 statements and asked to indicate their response as it applied to the past 7 days. The 5 possible responses were 'Not at all' (0), 'A little bit (1), 'Somewhat' (2), 'Quite a bit' (3) and 'Very much' (4). With 13 statements the total score had a range of 0 to 52. Higher score corresponds to a higher quality of life (QoL). |
| Mean Maximum Observed Predose Serum Concentration During the Study (Ctrough,Max,Total) | Blood samples were collected predose and at least 2.5 hours post dose on Day 1 and predose on Days 2 up to Day 365. | The Ctrough,max,total of pegcetacoplan was estimated using a non-compartmental approach. |
| Mean Area Under the Serum Concentration Versus Time Curve From Time 0 to the Last Measurable Concentration at the End of the Study (AUCtotal) | Blood samples were collected predose and at least 2.5 hours post dose on Day 1 and predose on Days 2 up to Day 365. | The AUCtotal of pegcetacoplan was estimated using a non-compartmental approach. |
| Mean Change From Baseline in Absolute Reticulocyte Count (ARC) Level | Baseline and Day 365 | Hematology assessments of ARC were made at the last measurement prior to the first dose of pegcetacoplan (baseline) and periodically throughout the treatment period. |
| Mean Change From Baseline in Total Bilirubin Level | Baseline and Day 365 | Serum chemistry assessments of total bilirubin were made at the last measurement prior to the first dose of pegcetacoplan (baseline) and periodically throughout the treatment period. |
| Mean Number of Red Blood Cell (RBC) Transfusions Per Month | From Day 1 to Day 364 | The number of on-study RBC transfusions was monitored throughout the treatment period. |
Countries
Bulgaria, Serbia
Participant flow
Recruitment details
This Phase 2a, open-label, multiple-dose study was conducted in subjects with paroxysmal nocturnal hemoglobinuria (PNH) who had not received treatment with eculizumab (Soliris®) in the past, between 16 August 2018 and 22 October 2019.
Pre-assignment details
Up to 20 subjects were planned to be enrolled; however, the sponsor decided to close recruitment after 4 subjects were enrolled based on the conclusion that sufficient data were collected to meet the study objectives.
Participants by arm
| Arm | Count |
|---|---|
| Pegcetacoplan 270 mg/Day Subjects received SC infusions of pegcetacoplan 270 mg/day up to Day 364. Intrasubject dose escalation up to a dosage of 360 mg/day was permitted if clinically indicated. | 4 |
| Total | 4 |
Baseline characteristics
| Characteristic | Pegcetacoplan 270 mg/Day |
|---|---|
| Age, Continuous | 30.8 years STANDARD_DEVIATION 11.81 |
| Race/Ethnicity, Customized Not Hispanic or Latino | 4 Participants |
| Race/Ethnicity, Customized White | 4 Participants |
| Region of Enrollment Bulgaria | 2 participants |
| Region of Enrollment Serbia | 2 participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 4 |
| other Total, other adverse events | 3 / 4 |
| serious Total, serious adverse events | 1 / 4 |
Outcome results
Primary
Mean Change From Baseline in Haptoglobin Level
Serum chemistry assessments of haptoglobin were made at the last measurement prior to the first dose of pegcetacoplan (baseline) and periodically throughout the treatment period.
Time frame: Baseline and Day 365
Population: The ITT set consisted of all subjects who received at least 1 dose of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pegcetacoplan 270 mg/Day | Mean Change From Baseline in Haptoglobin Level | 0.08 grams/liter | Standard Deviation 0.15 |
Primary
Mean Change From Baseline in Hemoglobin (Hb) Level
Hematology assessments of Hb were made at the last measurement prior to the first dose of pegcetacoplan (baseline) and periodically throughout the treatment period.
Time frame: Baseline and Day 365
Population: The ITT set consisted of all subjects who received at least 1 dose of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pegcetacoplan 270 mg/Day | Mean Change From Baseline in Hemoglobin (Hb) Level | 5.27 grams/deciliter | Standard Deviation 1.875 |
Primary
Mean Change From Baseline in Lactate Dehydrogenase (LDH) Level
Serum chemistry assessments of LDH were made at the last measurement prior to the first dose of pegcetacoplan (baseline) and periodically throughout the treatment period.
Time frame: Baseline and Day 365
Population: The Intent-to-treat (ITT) set consisted of all subjects who received at least 1 dose of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pegcetacoplan 270 mg/Day | Mean Change From Baseline in Lactate Dehydrogenase (LDH) Level | -2322.8 units/liter | Standard Deviation 635.41 |
Primary
Number of Subjects With Treatment Emergent Adverse Events (TEAEs) Including by Severity
TEAEs were defined as adverse events (AE) that occurred after dosing on Day 1 and up to 30 days after the last dose of study drug. A treatment-related TEAE was defined as a TEAE with a relationship to study drug of possible, probable, or definite. TEAEs were graded according to the Common Terminology Criteria for Adverse Events (v4.03) based on: Grade 1: Mild, Grade 2: Moderate, Grade 3: Severe, Grade 4: Life-threatening, Grade 5: Death related to AE.
Time frame: From Day 1 to 30 days after the last dose (approximately 56 weeks)
Population: The safety set consisted of all subjects who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Pegcetacoplan 270 mg/Day | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) Including by Severity | All TEAEs | 3 Participants |
| Pegcetacoplan 270 mg/Day | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) Including by Severity | Treatment-related TEAEs | 2 Participants |
| Pegcetacoplan 270 mg/Day | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) Including by Severity | Serious TEAEs | 1 Participants |
| Pegcetacoplan 270 mg/Day | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) Including by Severity | TEAEs leading to study drug discontinuation | 0 Participants |
| Pegcetacoplan 270 mg/Day | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) Including by Severity | TEAEs with mild intensity | 2 Participants |
| Pegcetacoplan 270 mg/Day | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) Including by Severity | TEAEs with moderate intensity | 0 Participants |
| Pegcetacoplan 270 mg/Day | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) Including by Severity | TEAEs with severe intensity | 1 Participants |
| Pegcetacoplan 270 mg/Day | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) Including by Severity | TEAEs with life threatening intensity | 0 Participants |
| Pegcetacoplan 270 mg/Day | Number of Subjects With Treatment Emergent Adverse Events (TEAEs) Including by Severity | TEAEs leading to death | 0 Participants |
Secondary
Mean Area Under the Serum Concentration Versus Time Curve From Time 0 to the Last Measurable Concentration at the End of the Study (AUCtotal)
The AUCtotal of pegcetacoplan was estimated using a non-compartmental approach.
Time frame: Blood samples were collected predose and at least 2.5 hours post dose on Day 1 and predose on Days 2 up to Day 365.
Population: The PK set consisted of all subjects in the safety set who had at least 1 quantifiable PK sample post dose PK measurement.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pegcetacoplan 270 mg/Day | Mean Area Under the Serum Concentration Versus Time Curve From Time 0 to the Last Measurable Concentration at the End of the Study (AUCtotal) | 5818803.2534 hour*ug/mL | Standard Deviation 975444.77662 |
Secondary
Mean Change From Baseline in Absolute Reticulocyte Count (ARC) Level
Hematology assessments of ARC were made at the last measurement prior to the first dose of pegcetacoplan (baseline) and periodically throughout the treatment period.
Time frame: Baseline and Day 365
Population: The ITT set consisted of all subjects who received at least 1 dose of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pegcetacoplan 270 mg/Day | Mean Change From Baseline in Absolute Reticulocyte Count (ARC) Level | -144.3 ARC/nanoliter | Standard Deviation 98.51 |
Secondary
Mean Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Score
The FACIT-Fatigue scale is a 13 item Likert scaled instrument where the subject was presented with 13 statements and asked to indicate their response as it applied to the past 7 days. The 5 possible responses were 'Not at all' (0), 'A little bit (1), 'Somewhat' (2), 'Quite a bit' (3) and 'Very much' (4). With 13 statements the total score had a range of 0 to 52. Higher score corresponds to a higher quality of life (QoL).
Time frame: Baseline and Day 365
Population: The ITT set consisted of all subjects who received at least 1 dose of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pegcetacoplan 270 mg/Day | Mean Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Score | 6.5 score on a scale | Standard Deviation 5.45 |
Secondary
Mean Change From Baseline in Linear Analog Scale Assessment (LASA) Score for QoL
The LASA consists of 3 items, where the respondents were asked to rate their perceived level of functioning. Specific domains included activity level, ability to carry out daily activities, and an item for overall QoL. Their level of functioning was reported on a 0 to 100 scale with 0 indicates As low as could be and 100 indicates As high as could be. The combined score ranged from 0 to 300, with higher scores corresponding to a higher QoL.
Time frame: Baseline and Day 365
Population: The ITT set consisted of all subjects who received at least 1 dose of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pegcetacoplan 270 mg/Day | Mean Change From Baseline in Linear Analog Scale Assessment (LASA) Score for QoL | 66.5 score on a scale | Standard Deviation 55.75 |
Secondary
Mean Change From Baseline in Total Bilirubin Level
Serum chemistry assessments of total bilirubin were made at the last measurement prior to the first dose of pegcetacoplan (baseline) and periodically throughout the treatment period.
Time frame: Baseline and Day 365
Population: The ITT set consisted of all subjects who received at least 1 dose of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pegcetacoplan 270 mg/Day | Mean Change From Baseline in Total Bilirubin Level | -21.53 micromoles/liter | Standard Deviation 8.358 |
Secondary
Mean Maximum Observed Predose Serum Concentration During the Study (Ctrough,Max,Total)
The Ctrough,max,total of pegcetacoplan was estimated using a non-compartmental approach.
Time frame: Blood samples were collected predose and at least 2.5 hours post dose on Day 1 and predose on Days 2 up to Day 365.
Population: The PK set consisted of all subjects in the safety set who had at least 1 quantifiable PK sample post dose PK measurement.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pegcetacoplan 270 mg/Day | Mean Maximum Observed Predose Serum Concentration During the Study (Ctrough,Max,Total) | 783.5 ug/mL | Standard Deviation 116.25 |
Secondary
Mean Number of Red Blood Cell (RBC) Transfusions Per Month
The number of on-study RBC transfusions was monitored throughout the treatment period.
Time frame: From Day 1 to Day 364
Population: The ITT set consisted of all subjects who received at least 1 dose of study drug.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Pegcetacoplan 270 mg/Day | Mean Number of Red Blood Cell (RBC) Transfusions Per Month | 0 transfusions |
Secondary
Mean Serum Concentrations of Pegcetacoplan
Serum concentrations of pegcetacoplan at Day 365 are presented.
Time frame: Day 365
Population: The Pharmacokinetic (PK) set consisted of all subjects in the safety set who had at least 1 quantifiable PK sample post dose PK measurement.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pegcetacoplan 270 mg/Day | Mean Serum Concentrations of Pegcetacoplan | 622.0 microgram per milliliter (ug/mL) | Standard Deviation 92.13 |