Pilot Study to Assess Safety, Preliminary Efficacy and Pharmacokinetics of S.C. Pegcetacoplan (APL-2) in PNH Subjects. (PADDOCK)

A Phase Ib, Open Label, Multiple Ascending Dose, Pilot Study to Assess the Safety, Preliminary Efficacy and Pharmacokinetics of Subcutaneously Administered APL-2 in Subjects With Paroxysmal Nocturnal Hemoglobinuria (PNH)

The objectives of the study are to assess the safety, tolerability, preliminary efficacy and PK of multiple subcutaneous (SC) doses of pegcetacoplan in subjects with paroxysmal nocturnal hemoglobinuria (PNH) who have not received treatment with eculizumab in the past.

An exploratory objective of the study is to assess the pharmacodynamics (PD) of multiple SC doses of pegcetacoplan when administered to PNH patients.

Study Overview

• Status: Completed
• Conditions: Paroxysmal Nocturnal Hemoglobinuria
• Intervention / Treatment: Drug: Pegcetacoplan

Detailed Description

This is a Phase Ib, open-label, multiple ascending dose, pilot study in patients with PNH who have not received eculizumab (Soliris)® in the past. Two cohorts of 3 subjects are planned for evaluation.

Safety will be assessed throughout the study; serial blood and urine samples will be collected for these assessments. Blood samples will be collected for the assessment of pegcetacoplan PK. Additional samples for assessment of PD will also be collected.

The study will consist of four parts;

• Part 1: subjects will receive pegcetacoplan for 28 days.
• Part 2A: subjects may continue to receive pegcetacoplan for a further 56 days if there is evidence of perceived clinical benefit following review of available safety, PK and PD data by the investigator and sponsor
• Part 2B/Part 2C: subjects may continue to receive daily pegcetacoplan treatment for up to 364 days if there is ongoing evidence of clinical benefit following review of the available safety, PK and PD data. After completion of Part 2B, subjects could continue treatment with pegcetacoplan by transitioning to an open-label extension study or Part 2C, if enrollment into the extension study was not yet available. Subjects entering Part 2C continued their pegcetacoplan dose and regimen until enrollment in the open-label extension study was available.
• Part 3: Safety follow up Screening will take place within 30 days prior to the start of dosing on Day 1. If needed (see inclusion criteria), Neisseria menigitides 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) vaccinations will be administered at least 14 days prior to dosing on Day 1.

Subjects will be entered into Part 1 of the study on Day 1 at a time designated by the PI. During Part 1, the first 3 daily SC doses of pegcetacoplan (Day 1 to 3) as well as doses on Day 8, 15 and 22 will be administered at the clinical site. From Day 4 to Day 28 daily doses of pegcetacoplan will be administered off-site by a trained study nurse at the subject's home, workplace, or other location convenient to the subject with the exception of those days where dosing is at the clinical site. Following ongoing review of available safety, PK and PD data by the investigator and sponsor, subjects showing evidence of perceived clinical benefit may progress to Part 2A and then to Part 2B of the study and continue to receive daily doses of pegcetacoplan until Day 84 and then until Day 364.

Cohort 2 will not be initiated until all subjects in Cohort 1 have reached the Day 29 visit and the SMC has reviewed emerging safety and efficacy data and determined that, at the initial dose, pegcetacoplan has an acceptable safety and tolerability profile.

The planned length of participation in the study for each subject in Cohort 2 is approximately 444 days (14.5 months) from Day 30 through completion of the Day 414 Exit visit procedures).

The study is planned to take place over approximately 24 months (from screening of Cohort 1 through completion of Cohort 2).

This time period may change in the event that the study is terminated early, additional cohorts are enrolled, additional time is required to review safety between cohorts, or extended safety and PK sampling is added for a cohort.

• Study Type: Interventional
• Enrollment (Actual): 23
• Phase: Phase 1

Contacts and Locations

Study Locations

• Hong Kong
  • Hong Kong, Hong Kong
    • Queen Mary Hospital
  • Hong Kong, Hong Kong
    • Prince of Wales Hospital
• Malaysia
  • Selangor
    • Ampang, Selangor, Malaysia, 68000
      • Hospital Ampang
• New Zealand
  • Waikato
    • Hamilton, Waikato, New Zealand, 3240
      • Waikato Hospital
• Thailand
  • Bangkok, Thailand, 10700
    • Siriraj Hospital
  • Bangkok, Thailand
    • Phramongkutklao Hospital
  • Bangkok, Thailand, 10400
    • Ramathibodi Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female
• At least 18 years old (inclusive)
• Weigh >55 kg and have a body mass index (BMI) ≤38.0 kg/m2
• Diagnosed with PNH (white blood cell (WBC) clone >10%)
• Lactose dehydrogenase (LD) ≥2 times the upper limit of normal
• Last transfusion within 12 months prior to screening
• Platelet count of >30,000/mm3
• Absolute neutrophil count >cells/500 µL
• 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
• Able to provide documentary evidence of Neisseria meningitidis, Pneumococcal conjugate vaccine (multivalent) or Pneumococcal polysaccharide vaccine 23 (PCV13 or PPSV23) and Haemophilus influenzae Type B (Hib) vaccination within 2 years prior to Day 1 dosing, OR willing to receive vaccinations against Neisseria meningitidis at least two weeks prior to dosing on Day 1 with a booster on Day 57, and PCV13 and Hib vaccines at least two weeks prior to dosing on Day 1.
• Willing and able to give informed consent

Exclusion Criteria:

• Prior eculizumab (Soliris)® treatment
• Active bacterial infection
• Known infection with hepatitis B, hepatitis C or human immunodeficiency virus (HIV)
• 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
• Creatinine clearance (CrCl) <50 mL/min (Cockcroft-Gault formula) at screening
• Breast-feeding women
• History of meningococcal disease

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Cohort 1; 180 mg pegcetacoplan/day	Drug: Pegcetacoplan; Complement (C3) Inhibitor; Other Names: APL-2
EXPERIMENTAL: Cohort 2; 270 mg pegcetacoplan/day	Drug: Pegcetacoplan; Complement (C3) Inhibitor; Other Names: APL-2

What is the study measuring?

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 (AEs) that occurred after dosing on Day 1 and up to 30 days after the last dose of study drug. A treatment-related TEAE is defined as a TEAE with a relationship to study drug of probably, possibly, unlikely, or unrelated. A serious adverse event (SAE) is defined as any AE that resulted in death; was life-threatening; required hospitalization or prolongation of existing hospitalization; resulted in persistent or significant incapacity or substantial disruption of ability to conduct normal life functions; was a congenital anomaly or birth defect. TEAEs were graded according to 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 first dose of study drug (Day 1) up to 30 days after the last dose of study drug, up to approximately 563 days.
Mean Change From Baseline in Lactate Dehydrogenase (LDH) at 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 different parts of the treatment period. LDH results were summarized for Cohort 2 only.	Baseline (Day 1) and Day 365.
Mean Percentage Change From Baseline in LDH at 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 different parts of the treatment period. LDH results were summarized for Cohort 2 only.	Baseline (Day 1) and Day 365.
Mean Change From Baseline in Haptoglobin at 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 different parts of the treatment period. Haptoglobin results were summarized for Cohort 2 only.	Baseline (Day 1) and Day 365.
Mean Percentage Change From Baseline in Haptoglobin at 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 different parts of the treatment period. Haptoglobin results were summarized for Cohort 2 only.	Baseline (Day 1) and Day 365.
Mean Change From Baseline in Hemoglobin at Day 365	Hematology assessments of hemoglobin were made at the last measurement prior to the first dose of pegcetacoplan (baseline) and periodically throughout the different parts of the treatment period. Hemoglobin results were summarized for Cohort 2 only.	Baseline (Day 1) and Day 365.
Mean Percentage Change From Baseline in Hemoglobin at Day 365	Hematology assessments of hemoglobin were made at the last measurement prior to the first dose of pegcetacoplan (baseline) and periodically throughout the different parts of the treatment period. Hemoglobin results were summarized for Cohort 2 only.	Baseline (Day 1) 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 at 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). There are 13 statements with the total score ranging from 0 to 52 and higher scores indicating better quality of life. The FACIT-Fatigue Scale results were summarized for Cohort 2 only.	Baseline (Day 1) and Day 365.
Mean Change From Baseline in Absolute Reticulocyte Count (ARC) at Day 365	Hematology assessments of ARC were made at the last measurement prior to the first dose of pegcetacoplan (baseline) and periodically throughout the different parts of the treatment period. ARC results were summarized for Cohort 2 only.	Baseline (Day 1) and Day 365.
Mean Percentage Change From Baseline in ARC at Day 365	Hematology assessments of ARC were made at the last measurement prior to the first dose of pegcetacoplan (baseline) and periodically throughout the different parts of the treatment period. ARC results were summarized for Cohort 2 only.	Baseline (Day 1) and Day 365.
Mean Change From Baseline in Total Bilirubin at 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 3 parts of the treatment period. Total bilirubin results were summarized for Cohort 2 only.	Baseline (Day 1) and Day 365.
Mean Percentage Change From Baseline in Total Bilirubin at 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 3 parts of the treatment period. Total bilirubin results were summarized for Cohort 2 only.	Baseline (Day 1) and Day 365.
Number of Subjects Receiving Red Blood Cell (RBC) Transfusions	The number of on-study RBC transfusions were monitored throughout the treatment period.	From Day 1 up to Day 533.

Collaborators and Investigators

• Sponsor: Apellis Pharmaceuticals, Inc.

Publications and helpful links

General Publications

• Wong RSM, Pullon HWH, Amine I, Bogdanovic A, Deschatelets P, Francois CG, Ignatova K, Issaragrisil S, Niparuck P, Numbenjapon T, Roman E, Sathar J, Xu R, Al-Adhami M, Tan L, Tse E, Grossi FV. Inhibition of C3 with pegcetacoplan results in normalization of hemolysis markers in paroxysmal nocturnal hemoglobinuria. Ann Hematol. 2022 Sep;101(9):1971-1986. doi: 10.1007/s00277-022-04903-x. Epub 2022 Jul 22.

Study record dates

Study Major Dates

• Study Start (ACTUAL): December 1, 2015
• Primary Completion (ACTUAL): August 26, 2019
• Study Completion (ACTUAL): August 26, 2019

Study Registration Dates

• First Submitted: October 27, 2015
• First Submitted That Met QC Criteria: October 27, 2015
• First Posted (ESTIMATE): October 28, 2015

Study Record Updates

• Last Update Posted (ACTUAL): January 11, 2021
• Last Update Submitted That Met QC Criteria: December 14, 2020
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Keywords: Anemia; PNH; Paroxysmal Nocturnal Hemoglobinuria; Complement inhibitor; Hemoglobinuria; C3 inhibitor; Hemolysis; Hematologic diseases; Extravascular hemolysis (EVH); Intravascular hemolysis (IVH)
• Additional Relevant MeSH Terms: Urologic Diseases; Urological Manifestations; Bone Marrow Diseases; Hematologic Diseases; Urination Disorders; Anemia; Proteinuria; Anemia, Hemolytic; Myelodysplastic Syndromes; Hemoglobinuria; Hemoglobinuria, Paroxysmal
• Other Study ID Numbers: APL2-CP-PNH-204

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No