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

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

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.

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.

PNH, Paroxysmal Nocturnal Hemoglobinuria, Complement inhibitor, Anemia, Hemoglobinuria, Hemolysis, Hematologic diseases, Extravascular hemolysis (EVH), Intravascular hemolysis (IVH), C3 inhibitor

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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.