Phase II Study Assessing Safety and Efficacy of APL-2 in Glomerulopathies

A Phase 2 Study to Evaluate the Safety and Biologic Activity of APL- 2 in Patients With IgA Nephropathy, Lupus Nephritis, Primary Membranous Nephropathy, or C3 Glomerulopathy (C3 Glomerulonephritis and Dense Deposit Disease)

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03453619

Enrollment

Registered

2018-03-05

Start date

2018-02-26

Completion date

2023-08-26

Last updated

2025-02-13

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

C3 Glomerulonephritis, Dense Deposit Disease, IgA Nephropathy, Lupus Nephritis, Membranous Nephropathy

Brief summary

This is a Phase II trial assessing the safety and preliminary efficacy of daily APL-2 subcutaneous infusion administered for 16 weeks with a 6 month safety follow up, in patients with glomerulopathies

Interventions

DRUGAPL-2

APL-2 administered as a daily subcutaneous infusion for 48 weeks

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

* Patients of at least 18 years of age at screening (16 years of age for C3G), able to provide written informed consent, and able to understand and comply with all scheduled procedures and other requirements of the study by the opinion of Principal Investigator (PI) * Patients must have a diagnosis of IgAN, LN, Primary MN, or C3G confirmed by renal biopsy and required measurements performed prior to study participation * IgAN: Prior biopsy results for C3 and C4d staining should be made available * LN: Diagnostic biopsy showing proliferative focal, diffuse, or membranous lesions (Class III, IV or V, respectively) by renal biopsy. Subject should have either a biopsy in the last 6 months, or evidence of disease activity (nephritic changes on urinalysis or nephrotic changes) * Primary MN: PLA2R positive titer plus nephrotic range proteinuria (defined as uPCR \>2350 mg/g) * C3G plus one of the following: Low serum C3 level or historical renal biopsy within the last 3 years * Have proteinuria \>750 mg/g (calculated by uPCR on 24 hour urine collection) collected during the first screening visit (Visit 3a). * eGFR≥30mL/min/1.73 m2 calculated by CKD-EPI creatinine equation at screening visit 3a and currently not on dialysis * Must have stable or worsening renal disease, on stable and optimized treatment, in the opinion of the PI, for at least 2 months prior to the first dose of APL-2 (Visit 4); treatments may include, but are not limited to, immunosuppressive agents, anti-hypertensives and/or anti-proteinurics. * Willing to receive vaccinations against Neisseria meningitidis at least 2 weeks prior to dosing on Day 1 with a booster on Day 56 (for both vaccinations) and Pneumococcal and Hib vaccines at least 2 weeks prior to dosing on Day 1.

Exclusion criteria

* Absolute neutrophil count \<1000 cells/mm3 at screening Visits 3a and 3b * ALT or AST \>3.0 x the upper limit of normal at screening Visits 3a and 3b * Previous treatment with APL-2 * History of solid organ transplant * Diagnosis of human immunodeficiency virus (HIV), hepatitis B, or hepatitis C infection, or positive serology at screening Visits 3a and 3b (previous HBV or HCV diagnosis cleared by treatment is allowed) * Renal disease secondary to another condition (e.g. infection, malignancy, monoclonal gammopathy, or a medication) * Presence or suspicion of active bacterial or viral infection or severe recurrent bacterial infections * Participation in any other investigational drug trial or exposure to other investigational agent, device, or procedure within 30 days prior to screening period * Unwillingness to receive or intolerant of SC infusions of study medication or known allergy to ingredients in APL-2.

Design outcomes

Primary

Measure	Time frame	Description
Part A: Change From Baseline in Proteinuria at Week 48	Baseline (Day 1) and Week 48	Change from baseline in proteinuria was assessed based on urinary protein-to-creatinine ratio (uPCR). Baseline was defined as the most recent non-missing measurement prior to or on the first administration of study drug.
Part B: Change From Baseline in Proteinuria at Week 168	Baseline (Part A, Week 48) and Week 168	Change from baseline in proteinuria was assessed based on uPCR. Baseline was defined as the most recent non-missing measurement prior to or on the first administration of study drug during Part B.

Secondary

Measure	Time frame	Description
Parts A and B: Change From Baseline in C3a Concentrations at Week 48 of Part A and Week 168 of Part B	Part A: Baseline (Day 1) and Week 48; Part B: Baseline (Part A, Week 48) and Week 168	Blood samples were collected to measure C3a concentrations. Part A baseline was defined as the most recent non-missing measurement prior to or on the first administration of study drug. Part B baseline was defined as the most recent non-missing measurement prior to or on the first administration of study drug during Part B.
Parts A and B: Change From Baseline in Serum Albumin Levels at Week 48 of Part A and Week 168 of Part B	Part A: Baseline (Day 1) and Week 48; Part B: Baseline (Part A, Week 48) and Week 168	Blood samples were collected to measure serum albumin levels. Part A baseline was defined as the most recent non-missing measurement prior to or on the first administration of study drug. Part B baseline was defined as the most recent non-missing measurement prior to or on the first administration of study drug during Part B.
Parts A and B: Change From Baseline in Serum Complement 3 (C3) Levels at Week 48 of Part A and Week 168 of Part B	Part A: Baseline (Day 1) and Week 48; Part B: Baseline (Part A, Week 48) and Week 168	Blood samples were collected to measure serum C3 levels. Part A baseline was defined as the most recent non-missing measurement prior to or on the first administration of study drug. Part B baseline was defined as the most recent non-missing measurement prior to or on the first administration of study drug during Part B.
Parts A and B: Number of Subjects With Stabilization or Improvement in Estimated Glomerular Filtration Rate (eGFR) From Baseline at Week 48 of Part A and Week 168 of Part B	Part A: Baseline (Day 1) and Week 48; Part B: Baseline (Part A, Week 48) and Week 168	The eGFR stabilization or improvement was defined as an eGFR value that was no more than a 25% decrease relative to baseline. Part A baseline was defined as the most recent non-missing measurement prior to or on the first administration of study drug. Part B baseline was defined as the most recent non-missing measurement prior to or on the first administration of study drug during Part B.
Parts A and B: Number of Subjects With Complete Clinical Remission at Week 48 of Part A and Week 168 of Part B	Part A: Week 48; Part B: Week 168	The complete clinical remission was defined as normalization of proteinuria as defined by \<200 mg/g uPCR.
Parts A and B: Change From Baseline in Alternative Pathway Hemolytic Assay (AH50) Activity at Week 48 of Part A and Week 168 of Part B	Part A: Baseline (Day 1) and Week 48; Part B: Baseline (Part A, Week 48) and Week 168	Blood samples were collected to measure AH50 activity. Part A baseline was defined as the most recent non-missing measurement prior to or on the first administration of study drug. Part B baseline was defined as the most recent non-missing measurement prior to or on the first administration of study drug during Part B.

Countries

United States

Participant flow

Recruitment details

This prospective Phase 2, open-label study was conducted in subjects clinically diagnosed with immunoglobulin A nephropathy (IgAN), lupus nephritis (LN), primary membranous nephropathy (PMN), or C3 glomerulopathy (C3G) between 26 February 2018 and 25 August 2023.

Pre-assignment details

The study consisted of 2 parts: Part A (core study phase; 48 weeks) and Part B (long-term extension phase; until pegcetacoplan was commercially available for the disease under treatment). Subjects were screened within 4 weeks prior to the start of dosing on Day 1. A total of 21 subjects were enrolled in this study.

Participants by arm

Arm	Count
IgAN Subjects Subjects diagnosed with IgAN received pegcetacoplan 360 mg SC infusion once daily up to 48 weeks in Part A and eligible subjects entered Part B to continue to receive pegcetacoplan 360 mg SC infusion until it was commercially available for the disease under treatment. Subjects were able to switch over to twice-weekly dosing with pegcetacoplan 1080 mg, as early as Week 24, but no later than the entrance into Part B.	6
LN Subjects Subjects diagnosed with LN received pegcetacoplan 360 mg SC infusion once daily up to 48 weeks in Part A and eligible subjects entered Part B to continue to receive pegcetacoplan 360 mg SC infusion until it was commercially available for the disease under treatment. Subjects were able to switch over to twice-weekly dosing with pegcetacoplan 1080 mg, as early as Week 24, but no later than the entrance into Part B.	2
PMN Subjects Subjects diagnosed with PMN received pegcetacoplan 360 mg SC infusion once daily up to 48 weeks in Part A and eligible subjects entered Part B to continue to receive pegcetacoplan 360 mg SC infusion until it was commercially available for the disease under treatment. Subjects were able to switch over to twice-weekly dosing with pegcetacoplan 1080 mg, as early as Week 24, but no later than the entrance into Part B.	5
C3G Subjects Subjects diagnosed with C3G received pegcetacoplan 360 mg SC infusion once daily up to 48 weeks in Part A and eligible subjects entered Part B to continue to receive pegcetacoplan 360 mg SC infusion until it was commercially available for the disease under treatment. Subjects were able to switch over to twice-weekly dosing with pegcetacoplan 1080 mg, as early as Week 24, but no later than the entrance into Part B.	8
Total	21

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003
Core Study (Part A)	Other	0	1	0	0
Core Study (Part A)	Physician Decision	0	0	2	0
Core Study (Part A)	Withdrawal by Subject	2	0	2	1
Long-Term Extension (Part B)	Adverse Event	1	0	0	0
Long-Term Extension (Part B)	Lost to Follow-up	1	0	0	1
Long-Term Extension (Part B)	Non-compliance with study drug	0	0	0	1
Long-Term Extension (Part B)	Physician Decision	0	1	0	0

Baseline characteristics

Characteristic	IgAN Subjects	Total	C3G Subjects	PMN Subjects	LN Subjects
Age, Continuous	45.2 years STANDARD_DEVIATION 14.18	40.5 years STANDARD_DEVIATION 18.67	22.5 years STANDARD_DEVIATION 8.65	62.2 years STANDARD_DEVIATION 7.43	44.5 years STANDARD_DEVIATION 10.61
Race/Ethnicity, Customized American Indian or Alaskan Native	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized Asian	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized Black or African American	1 Participants	4 Participants	1 Participants	1 Participants	1 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized Other	1 Participants	3 Participants	1 Participants	0 Participants	1 Participants
Race/Ethnicity, Customized White	4 Participants	14 Participants	6 Participants	4 Participants	0 Participants
Sex: Female, Male Female	1 Participants	7 Participants	5 Participants	1 Participants	0 Participants
Sex: Female, Male Male	5 Participants	14 Participants	3 Participants	4 Participants	2 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk	EG005 affected / at risk	EG006 affected / at risk	EG007 affected / at risk
deaths Total, all-cause mortality	0 / 6	0 / 2	0 / 5	0 / 8	0 / 4	0 / 1	0 / 0	0 / 7
other Total, other adverse events	5 / 6	1 / 2	5 / 5	8 / 8	4 / 4	1 / 1	0 / 0	7 / 7
serious Total, serious adverse events	0 / 6	0 / 2	4 / 5	0 / 8	1 / 4	1 / 1	0 / 0	1 / 7

Outcome results

Primary

Part A: Change From Baseline in Proteinuria at Week 48

Change from baseline in proteinuria was assessed based on urinary protein-to-creatinine ratio (uPCR). Baseline was defined as the most recent non-missing measurement prior to or on the first administration of study drug.

Time frame: Baseline (Day 1) and Week 48

Population: The intent-to-treat (ITT) population included all subjects who received at least 1 dose of pegcetacoplan. Only subjects analyzed at baseline and Week 48 are reported.

Arm	Measure	Value (MEAN)
Part A: IgAN Subjects	Part A: Change From Baseline in Proteinuria at Week 48	-0.1364 ratio
Part A: LN Subjects	Part A: Change From Baseline in Proteinuria at Week 48	0.3560 ratio
Part A: PMN Subjects	Part A: Change From Baseline in Proteinuria at Week 48	0.3430 ratio
Part A: C3G Subjects	Part A: Change From Baseline in Proteinuria at Week 48	-2.0347 ratio

Primary

Part B: Change From Baseline in Proteinuria at Week 168

Change from baseline in proteinuria was assessed based on uPCR. Baseline was defined as the most recent non-missing measurement prior to or on the first administration of study drug during Part B.

Time frame: Baseline (Part A, Week 48) and Week 168

Population: The ITT population included all subjects who received at least 1 dose of pegcetacoplan. Only subjects analyzed at baseline and Week 168 are reported.

Arm	Measure	Value (MEAN)
Part A: IgAN Subjects	Part B: Change From Baseline in Proteinuria at Week 168	-0.3385 ratio
Part A: PMN Subjects	Part B: Change From Baseline in Proteinuria at Week 168	0.9718 ratio

Secondary

Parts A and B: Change From Baseline in Alternative Pathway Hemolytic Assay (AH50) Activity at Week 48 of Part A and Week 168 of Part B

Blood samples were collected to measure AH50 activity. Part A baseline was defined as the most recent non-missing measurement prior to or on the first administration of study drug. Part B baseline was defined as the most recent non-missing measurement prior to or on the first administration of study drug during Part B.

Time frame: Part A: Baseline (Day 1) and Week 48; Part B: Baseline (Part A, Week 48) and Week 168