A Phase I Study to Assess the Safety of Pegcetacoplan (APL-2) as an Add-On to Standard of Care in Subjects With PNH

Study Overview
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Brief Summary
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This study will be the initial exploration of pegcetacoplan in patients with PNH. The assessments of the safety, tolerability, PK, and PD following administration of single and multiples doses of pegcetacoplan will guide decisions to further develop the drug.

Official Title
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An Open Label, Single and Multiple Ascending Dose Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of APL-2 as an Add-On to Standard of Care in Subjects With Paroxysmal Nocturnal Hemoglobinuria (PNH).

Conditions
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Paroxysmal Nocturnal Hemoglobinuria (PNH)

Intervention / Treatment
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* Drug: Pegcetacoplan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or Female At least 18 years of age Weigh >55 kg Diagnosed with PNH On treatment with eculizumab (Soliris®) for at least 3 months Hb < 10 g/dL at screening OR have received at least one transfusion within 12 months prior to screening Platelet count of >30,000/mm3 Absolute neutrophil count > 500/mm3 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 (see below) Males with female partners of child bearing potential must agree to use protocol defined methods of contraception (see below) and agree to refrain from donating sperm for the duration of the study Willing and able to give informed consent Exclusion Criteria: Active bacterial infection Known infection with hepatitis B, C or HIV Hereditary complement deficiency History of bone marrow transplantation Participation in any other investigational drug trial or exposure to other 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 Creatinine clearance (CrCl) < 50 mL/min (Cockcroft-Gault formula) at screening Breast-feeding women History of meningococcal disease No vaccination against N. meningitidis types A, C, W, Y and B (administered as two separate vaccinations), Pneumococcal conjugate vaccine or Pneumococcal polysaccharide vaccine 23 (PCV13 or PPSV23, respectively) and Haemophilus influenzae Type B (Hib) vaccination within 2 years prior to Day 1 (Visit 2) dosing.

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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>First Dose 25mg, Repeated Dose 5 mg/day | Drug: Pegcetacoplan<br>* Complement (C3) Inhibitor<br>* Other names: APL-2;|
| Experimental: Cohort 2<br>First Dose 50 mg, Repeated Dose 30 mg/day | Drug: Pegcetacoplan<br>* Complement (C3) Inhibitor<br>* Other names: APL-2;|
| Experimental: Cohort 3<br>Repeated Dose 180 mg/day | Drug: Pegcetacoplan<br>* Complement (C3) Inhibitor<br>* Other names: APL-2;|
| Experimental: Cohort 4<br>Repeated Dose 270 mg/day | 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, During Single-dose Phase | TEAEs were defined as AEs that developed or worsened after first dose of study drug (Day 1), and up to 30 days after last dose of study drug. The Investigator assessed AEs for severity and relatedness to study drug. AEs were graded according to the Common Terminology Criteria for Adverse Events (CTCAE, v4.03) based on: Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening; Grade 5: Death related to AE. | From single dose of study drug (Day 1) up to 30 days | 
| Number of Subjects With TEAEs, Including by Severity, During Multiple-dose Phase | TEAEs were defined as AEs that developed or worsened after first dose of study drug (Day 1), and up to 30 days after last dose of study drug. The Investigator assessed AEs for severity and relatedness to study drug. AEs were graded according to CTCAE, v4.03 based on: Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening; Grade 5: Death related to AE. | From first dose of study drug up to 30 days after last dose of study drug (Cohorts 1-3: up to 58 days; Cohort 4: up to 759 days). | 
| Area Under the Curve (AUC) From Time 0 to the Last Measurable Concentration (AUC0-t) Over the Multiple Dosing Phase for Cohort 4 | Assessment of AUC0-t of pegcetacoplan over the multiple dosing phase, estimated using a non-compartmental approach and calculated by the linear-log trapezoidal method. Pegcetacoplan pharmacokinetic (PK) parameters were summarized for Cohort 4 only. | Blood samples for PK assessment were collected pre-dose and 4 hours post dose on Day 1 and pre-dose (trough) on Day 2 and up to Day 785. | 
| Maximum Pre-dose Serum Concentration (Ctrough,Max) Over the Multiple Dosing Phase for Cohort 4 | Assessment of Ctrough,max of pegcetacoplan over the multiple dosing phase, estimated using a non-compartmental approach. Pegcetacoplan PK parameters were summarized for Cohort 4 only. Ctrough,max was calculated for both 270 mg/day and 360 mg/day where subjects received both doses. Note: 1 subject in Cohort 4 who was receiving 360 mg/day was granted Sponsor and institutional review board approval to increase the dose further to the equivalent of 440 mg/day and Ctrough,max is also reported for this dose. | Blood samples for PK assessment were collected pre-dose and 4 hours post dose on Day 1 and pre-dose (trough) on Day 2 and up to Day 785. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Paroxysmal Nocturnal Hemoglobinuria, Complement inhibitor, Anemia, Hemoglobinuria, hematologic diseases, extravascular hemolysis (EVH), intravascular hemolysis (IVH), C3 inhibitor, PNH