What is the evidence level for pegcetacoplan?

The evidence level for pegcetacoplan is classified as high, supported by the PEGASUS phase 3 trial published in NEJM demonstrating superiority over eculizumab in PNH, and the OAKS and DERBY phase 3 trials published in The Lancet demonstrating efficacy in geographic atrophy. Regulatory approvals have been granted by both the FDA and EMA.

Are there clinical trials for pegcetacoplan?

Yes. Key trials include PEGASUS (PNH, 80 patients, NEJM 2021) and OAKS/DERBY (GA, combined enrollment of several hundred patients, Lancet 2023). Extension studies (307 for PNH, GALE for GA) are ongoing. Additional trials for C3 glomerulopathy and IC-MPGN are underway.

What are the research gaps for pegcetacoplan?

Key gaps include long-term visual function outcomes in GA, optimal patient selection for GA treatment, head-to-head comparisons with avacincaptad pegol (Izervay), and comparative effectiveness vs oral complement inhibitors in PNH.

What does the research say about pegcetacoplan?

PEGASUS showed pegcetacoplan was superior to eculizumab for PNH, improving hemoglobin by 3.84 g/dL more than eculizumab (P<0.001) and rendering 85% of patients transfusion-free. OAKS/DERBY showed 19-22% reduction in GA lesion growth at 24 months, establishing pegcetacoplan as the first treatment for this condition.

Pegcetacoplan: Research & Studies

Scientific evidence, clinical trials, and research findings

Evidence Level: high

✓Reviewed byDr. Research Team(MD (composite credential representing medical review team), PhD in Pharmacology)

📅Updated February 18, 2026

Unverified

📌TL;DR

•2 clinical studies cited
•Overall evidence level: high
•5 research gaps identified

Evidence pyramid for Pegcetacoplan research — Overview of evidence quality and study types

Research Studies

Pegcetacoplan versus Eculizumab in Paroxysmal Nocturnal Hemoglobinuria

Hillmen P, Szer J, Weitz I, et al. (2021) • New England Journal of Medicine

PubMed DOI

Phase 3 PEGASUS trial comparing pegcetacoplan SC monotherapy to eculizumab IV in 80 PNH patients with hemoglobin <10.5 g/dL despite eculizumab therapy. After 4-week run-in with both drugs, patients randomized to pegcetacoplan (n=41) or eculizumab (n=39).

Key Findings

Pegcetacoplan superior to eculizumab in hemoglobin improvement (adjusted mean difference 3.84 g/dL; P<0.001)
Transfusion-free: 85% pegcetacoplan vs 15% eculizumab
Pegcetacoplan controlled both intravascular and extravascular hemolysis
Improvements in reticulocyte count and absolute reticulocyte count

Limitations: Open-label after run-in phase; 80 patients; enrolled only patients with suboptimal response to eculizumab; 16-week controlled period

Pegcetacoplan for the treatment of geographic atrophy secondary to age-related macular degeneration (OAKS and DERBY)

Liao DS, Grossi FV, El Mehdi D, et al. (2023) • The Lancet

PubMed DOI

Two phase 3 trials evaluating intravitreal pegcetacoplan monthly (PM) or every other month (PEOM) vs sham in patients with GA secondary to AMD. OAKS enrolled at 110 sites, DERBY at 122 sites worldwide. Primary endpoint was change in GA lesion area at 12 months.

Key Findings

OAKS 24 months: 22% (PM) and 18% (PEOM) reduction in GA lesion growth vs sham
DERBY 24 months: 19% (PM) and 16% (PEOM) reduction in GA lesion growth vs sham
Treatment effects increased over time with greatest benefit at months 18-24 (up to 36% reduction in DERBY monthly group)
No differences in visual function secondary endpoints at 24 months

Limitations: No visual function benefit; DERBY did not meet significance at 12 months; sham comparator (not active); potential for unmasking due to injection procedures

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Research timeline for Pegcetacoplan — Key studies and discoveries over time

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🔍Research Gaps & Future Directions

•Long-term visual function outcomes beyond 36 months in geographic atrophy
•Optimal patient selection criteria for GA treatment initiation
•Head-to-head comparison with avacincaptad pegol (Izervay) for GA
•Comparative effectiveness vs iptacopan or danicopan (oral complement inhibitors) in PNH
•Combination strategies with C5 inhibitors in refractory PNH

Research Overview#

Pegcetacoplan has been evaluated in extensive clinical programs for both paroxysmal nocturnal hemoglobinuria (PNH) and geographic atrophy (GA) secondary to age-related macular degeneration. The PNH program includes the pivotal PEGASUS trial demonstrating superiority over eculizumab, while the ophthalmology program includes the twin OAKS and DERBY trials that established the first approved treatment for GA. Additional indications including C3 glomerulopathy are under investigation.

The evidence level is classified as high based on positive pivotal trials in two indications published in top-tier journals (NEJM and The Lancet), regulatory approvals by the FDA and EMA, and ongoing long-term extension data.

PEGASUS Trial (Phase 3, PNH)#

Hillmen et al., NEJM 2021 (PMID 33730455)#

The PEGASUS trial was a phase 3, randomized, multicenter, active-comparator study comparing pegcetacoplan to eculizumab in adults with PNH.

Study Design:

80 adults with PNH and hemoglobin <10.5 g/dL despite stable eculizumab therapy
4-week run-in: all patients received pegcetacoplan 1,080 mg SC twice weekly plus eculizumab IV
Randomization 1:1: pegcetacoplan monotherapy (n=41) vs eculizumab (n=39) for 16 weeks
Primary endpoint: change in hemoglobin from baseline to week 16

Primary Endpoint Results:

Pegcetacoplan: adjusted mean increase in hemoglobin of 2.37 g/dL
Eculizumab: adjusted mean decrease in hemoglobin of -1.47 g/dL
Adjusted mean difference: 3.84 g/dL (P<0.001), demonstrating noninferiority and superiority

Key Secondary Endpoints:

Transfusion avoidance: 85% pegcetacoplan vs 15% eculizumab
Reticulocyte count normalization with pegcetacoplan
LDH levels controlled in both groups

Why C3 Inhibition Was Superior#

The PEGASUS results highlighted a key limitation of C5 inhibition in PNH. While eculizumab effectively controls intravascular hemolysis (MAC-mediated), it cannot prevent C3b opsonization of PNH red blood cells. These C3b-coated cells are then removed by macrophages in the liver and spleen (extravascular hemolysis), causing persistent anemia. Pegcetacoplan prevents C3b deposition, controlling both hemolytic pathways.

OAKS and DERBY Trials (Phase 3, Geographic Atrophy)#

Liao et al., The Lancet 2023 (PMID 37865470)#

OAKS and DERBY were twin phase 3, randomized, double-masked, sham-controlled trials evaluating intravitreal pegcetacoplan for GA secondary to AMD.

Study Design:

OAKS: 637 patients at 110 sites; DERBY: 621 patients at 122 sites
Three arms: pegcetacoplan monthly (PM), pegcetacoplan every other month (PEOM), or sham
Primary endpoint: change in GA lesion area (square root transformation) at 12 months

OAKS Results:

12 months: PM reduced GA growth by 21% (P=0.0003), PEOM by 16% (P=0.006) vs sham
24 months: PM reduced growth by 22%, PEOM by 18% vs sham

DERBY Results:

12 months: PM reduced GA growth by 12% (not significant), PEOM by 11% (not significant)
24 months: PM reduced growth by 19%, PEOM by 16% vs sham
Greatest benefit observed months 18-24 (up to 36% reduction in monthly group)

Visual Function:

No significant differences in visual function endpoints at 24 months in either trial
This remains a key limitation and area of ongoing study

Safety in OAKS/DERBY#

Endophthalmitis: rare but reported
Signal for increased conversion to neovascular (wet) AMD in pegcetacoplan-treated eyes
No systemic complement inhibition-related safety concerns with intravitreal administration

Evidence Quality Assessment#

Criterion	PNH (PEGASUS)	GA (OAKS/DERBY)
Study design	Phase 3, active-comparator	Phase 3, sham-controlled
Sample size	80	1,258 combined
Primary endpoint	Met (P<0.001)	OAKS met; DERBY not at 12mo
Key outcome	Superiority vs eculizumab	Slowed GA lesion growth
Safety	Acceptable	nAMD conversion signal
Peer-reviewed	NEJM 2021	Lancet 2023
Regulatory	FDA 2021; EMA 2021	FDA 2023; EMA rejected

Key Research Gaps#

Visual function outcomes: Whether slowing GA lesion growth translates to preserved visual function over longer follow-up (36+ months).
Patient selection: Optimal criteria for initiating GA treatment, including lesion size, location, and rate of progression.
Comparative studies: Head-to-head comparison with avacincaptad pegol (Izervay), the other approved GA treatment.
Oral complement inhibitors: Comparative effectiveness vs iptacopan, danicopan, or other oral factor B/D inhibitors in PNH.
Combination strategies: Whether sequential or combination use of C3 and C5 inhibitors provides additional benefit in refractory PNH.

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