A Phase IIa Study to Assess the Safety, Efficacy, and Pharmacokinetics of Subcutaneously Administered Pegcetacoplan (APL-2) in Subjects With PNH

Study Overview
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Brief Summary
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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.

Official Title
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Phase IIa, Open Label, Multiple Dose Study to Assess the Safety, Efficacy and Pharmacokinetics of Subcutaneously Administered APL-2 in Subjects With Paroxysmal Nocturnal Hemoglobinuria (PNH).

Conditions
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PNH

Intervention / Treatment
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* Drug: Pegcetacoplan


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental: Cohort 1<br>270 mg/day (up to 360 mg/day from Day 29) from Day 1 to Day 364* | Drug: Pegcetacoplan<br>* Complement (C3) Inhibitor<br>* Other names: APL-2;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | From Day 1 to 30 days after the last dose (approximately 56 weeks) | 
| 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. | Baseline and Day 365 | 
| 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. | Baseline and Day 365 | 
| 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. | Baseline and Day 365 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | Baseline and Day 365 | 
| 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. | Baseline and Day 365 | 
| 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. | Baseline and Day 365 | 
| Mean Number of Red Blood Cell (RBC) Transfusions Per Month | The number of on-study RBC transfusions was monitored throughout the treatment period. | From Day 1 to Day 364 | 
| 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. | Baseline and Day 365 | 
| Mean Serum Concentrations of Pegcetacoplan | Serum concentrations of pegcetacoplan at Day 365 are presented. | Day 365 | 
| 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. | 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. | 
| 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. | 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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PNH, Paroxysmal Nocturnal Hemoglobinuria, Complement inhibitor, Anemia, Hemoglobinuria, Hemolysis, Hematologic diseases, Extravascular hemolysis (EVH), Intravascular hemolysis (IVH), C3 inhibitor