What Is Pegcetacoplan?
Pegcetacoplan is an FDA-approved medication for the treatment of paroxysmal nocturnal hemoglobinuria. It is a type of drug known as a complement C3 inhibitor. The complement system is a part of the body's immune defense, but sometimes it can become overactive and cause damage to healthy cells and tissues. By inhibiting complement C3, pegcetacoplan helps to regulate this immune response and prevent the destruction of red blood cells in conditions like paroxysmal nocturnal hemoglobinuria.
In addition to its approved use, pegcetacoplan is also being investigated in clinical trials for other conditions. For example, it is being studied for its safety and tolerability in patients who have experienced acute ischemic stroke after receiving reperfusion therapy. Acute ischemic stroke is a leading cause of disability worldwide, and researchers are exploring new ways to improve patient outcomes beyond current revascularization treatments.
Uses and Conditions Under Study
Pegcetacoplan is currently being studied in 27 clinical trials with a total enrollment of 3,318 participants. The first trial began in 2014, and the latest is projected to conclude in 2026. These studies are exploring the drug's potential across various conditions, primarily focusing on disorders where an overactive complement system plays a role.
A significant number of trials, totaling 16 studies, are investigating pegcetacoplan for a group of rare kidney diseases. These include Complement 3 Glomerulopathy (C3G), C3 Glomerulonephritis, Membranoproliferative Glomerulonephritis (MPGN), and IC-MPGN. These conditions are characterized by damage to the kidney's filtering units, often due to abnormal activation of the complement system. As a C3 inhibitor, pegcetacoplan aims to reduce this damaging immune activity and protect kidney function.
Another area of active research is Geographic Atrophy, a progressive eye disease that leads to vision loss. Four trials are evaluating pegcetacoplan for this condition. The drug is thought to slow the progression of Geographic Atrophy by targeting complement activation in the retina, which is believed to contribute to the disease's development.
Additionally, pegcetacoplan is being studied for its safety and tolerability in acute ischemic stroke patients following reperfusion, as mentioned previously. This research aims to understand if modulating the complement system can help reduce disability after stroke. Apellis Pharmaceuticals, Inc. is the primary sponsor for 20 of these trials.
Dosing
Pegcetacoplan has been studied in various dosage forms and administration routes depending on the condition being investigated. For its FDA-approved use in paroxysmal nocturnal hemoglobinuria, it is typically administered subcutaneously.
In studies for acute ischemic stroke, participants received three 1,080 mg doses of pegcetacoplan. These doses were delivered within 0-3 hours following endovascular thrombectomy, and then at 24 and 48 hours after the initial dose.
For Geographic Atrophy, pegcetacoplan has been studied as an intravitreal injection, meaning it is injected directly into the eye. Specific regimens included 15 mg/100 μL monthly for up to 36 or 60 months, or 15 mg/100 μL every other month (EOM) for up to 36 months. Some trials also included sham comparator groups for comparison.
Other investigational uses have explored pegcetacoplan administered subcutaneously, often in combination with other therapies like pembrolizumab or bevacizumab, as part of different cohorts (e.g., Cohort 2A-1, Cohort 2B-2). These studies involve various dosing schedules and combinations tailored to the specific research questions.
Side Effects
In clinical trials, patients taking Pegcetacoplan experienced certain side effects more frequently than those on placebo. The most common side effect was fall, with 16.2% of patients on Pegcetacoplan reporting a fall, compared to 11.5% on placebo (from one trial involving 266 patients on Pegcetacoplan).
Other common side effects included:
- Pyrexia (fever): 11.7% of patients on Pegcetacoplan experienced fever, compared to 8.3% on placebo (from two trials involving 154 patients on Pegcetacoplan).
- Vomiting: 9.7% of patients on Pegcetacoplan experienced vomiting, compared to 9.3% on placebo (from one trial involving 124 patients on Pegcetacoplan).
- Nausea: 8.4% of patients on Pegcetacoplan experienced nausea, compared to 4.5% on placebo (from two trials involving 154 patients on Pegcetacoplan).
- Upper respiratory tract infection: 7.8% of patients on Pegcetacoplan experienced this, compared to 4.5% on placebo (from two trials involving 154 patients on Pegcetacoplan).
- Nasopharyngitis (common cold): 7.1% of patients on Pegcetacoplan experienced nasopharyngitis, compared to 5.3% on placebo (from three trials involving 420 patients on Pegcetacoplan).
- Constipation: 6.1% of patients on Pegcetacoplan experienced constipation, compared to 5.5% on placebo (from two trials involving 296 patients on Pegcetacoplan).
- Another instance of upper respiratory tract infection was reported by 5.6% of patients on Pegcetacoplan, compared to 3.1% on placebo (from one trial involving 266 patients on Pegcetacoplan).
Some side effects were reported less frequently in patients taking Pegcetacoplan than in those on placebo. For instance, headache was reported by 8.4% of patients on Pegcetacoplan compared to 13.5% on placebo, and diarrhea was reported by 4.0% of patients on Pegcetacoplan compared to 8.0% on placebo.
Clinical Trial Results
Paroxysmal Nocturnal Hemoglobinuria (PNH)
A pilot study (NCT02588833) evaluated the safety and preliminary effectiveness of subcutaneous Pegcetacoplan in patients with PNH. After 365 days, patients in Cohort 2 showed significant improvements in key markers of the disease:
- Lactate Dehydrogenase (LDH) levels, an indicator of red blood cell destruction, decreased by an average of 2105.2 units per liter (U/L), representing an average reduction of 84.8% from baseline.
- Hemoglobin levels, which are often low in PNH, increased by an average of 3.68 grams per liter (g/L), an average increase of 49.86% from baseline.
- Patients reported an average improvement of 7.1 points on the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Score, indicating reduced fatigue.
In this study, 7 participants in Cohort 2 received red blood cell transfusions, compared to 1 participant in Cohort 1.
Geographic Atrophy (GA)
A study (NCT02503332) investigated Pegcetacoplan therapy in patients with Geographic Atrophy. At 12 months, patients treated with Pegcetacoplan showed a slower increase in GA lesion size compared to sham treatment:
- The least squares mean change from baseline in square root GA lesion size was 0.28 mm for Pegcetacoplan every other month (EOM) and 0.26 mm for Pegcetacoplan monthly, compared to 0.35 mm for sham treatment.
- Similarly, the untransformed GA lesion size increased by 1.69 mm² for Pegcetacoplan EOM and 1.49 mm² for Pegcetacoplan monthly, compared to 2.12 mm² for sham treatment. A smaller increase indicates a slower progression of the disease.
Regarding visual acuity, the least squares mean change from baseline in Best-Corrected Visual Acuity (BCVA) score at Month 12 was a loss of -3.31 ETDRS letter score for Pegcetacoplan monthly, compared to a loss of -4.36 ETDRS letter score for sham. Pegcetacoplan EOM showed a loss of -5.78 ETDRS letter score.
A safety finding in this study was the occurrence of macular neovascularization (MNV) as a treatment-emergent adverse event in the study eye. This occurred in 5 participants receiving Pegcetacoplan EOM, 14 participants receiving Pegcetacoplan monthly, and 1 participant receiving sham treatment.
Wet Age-related Macular Degeneration (Wet AMD)
In a Phase I study (NCT02461771) assessing intravitreal Pegcetacoplan for wet AMD, preliminary data on visual outcomes were observed. The median change from baseline in visual acuity for the study eye was an improvement of 3 letters read correctly in Cohort 2 and 1 letter in Cohort 1, while Cohort 3 experienced a loss of 1 letter. Changes in central retinal thickness varied across cohorts, with Cohort 1 showing median reductions of -29.0, -79.5, and -106 micrometers in different retinal thickness measurements, while Cohorts 2 and 3 showed mixed results including increases and decreases.
Another study (NCT03465709) in neovascular AMD also reported changes in central subfield thickness (CST) over 12 months for 15 mg Pegcetacoplan, with values ranging from a decrease of -10.5 micrometers to an increase of 49.2 micrometers at various time points.
Currently Recruiting Trials
Pegcetacoplan is currently being investigated in several clinical trials for a range of conditions, from various cancers to kidney disease and eye disorders. These studies aim to evaluate its effectiveness and safety, and patients may have the opportunity to participate.
One ongoing Phase 1/2 trial, NCT07214298, sponsored by Roswell Park Cancer Institute, is testing pegcetacoplan in combination with modified FOLFIRINOX for treating metastatic pancreatic ductal adenocarcinoma. This study plans to enroll up to 35 patients to assess the effects of this combination therapy.
For adults at high risk of delayed graft function following kidney allograft transplantation, a Phase 3 study (NCT07020832) is evaluating the efficacy and safety of pegcetacoplan. Sponsored by Apellis Pharmaceuticals, Inc., this trial aims to include 320 participants.
In ophthalmology, a Phase 2 study (NCT07215390) is underway to evaluate multidose APL-3007 in combination with Syfovre/pegcetacoplan (APL-2) for patients with geographic atrophy secondary to age-related macular degeneration. This randomized, placebo-controlled trial, sponsored by Apellis Pharmaceuticals, Inc., is recruiting 240 patients.
An observational study, NCT05776472, is describing the real-world effectiveness of pegcetacoplan in patients with Paroxysmal Nocturnal Hemoglobinuria (PNH). This 36-month, long-term study by Swedish Orphan Biovitrum is following 200 patients.
Pegcetacoplan is also being studied in recurrent ovarian, fallopian tube, or primary peritoneal cancer with malignant effusion. The Phase 2 trial, NCT04919629, sponsored by Roswell Park Cancer Institute, compares pegcetacoplan with pembrolizumab and/or bevacizumab against bevacizumab alone, targeting 60 participants.
Finally, a Phase 2 study (NCT04901936) is investigating the safety and effectiveness of pegcetacoplan in pediatric patients aged 12-17 years with Paroxysmal Nocturnal Hemoglobinuria (PNH). This Apellis Pharmaceuticals, Inc. study plans to enroll 12 adolescents.
Where to Participate
Clinical trials for pegcetacoplan have a broad geographic reach, with studies being conducted across 45 sites in 43 cities and 17 states. This widespread availability helps ensure that many patients can access potential new treatments.
Top participating locations include:
- Buffalo, New York (2 sites)
- Phoenix, Arizona (2 sites)
- Encino, California (1 site)
- Fullerton, California (1 site)
- Huntington Beach, California (1 site)
- Poway, California (1 site)
- Santa Ana, California (1 site)
- Walnut Creek, California (1 site)
- Lakewood, Colorado (1 site)
- Longmont, Colorado (1 site)
Eligibility criteria for these studies generally include participants aged 12 to 60 years, of all genders. Healthy volunteers are typically not included, but children are eligible for specific trials.
Development Timeline
The journey of pegcetacoplan in clinical development began on October 15, 2014, with initial investigations into conditions like IBS-C and hyperphosphatemia. Since then, the development pipeline has significantly expanded, driven primarily by Apellis Pharmaceuticals, Inc., which has sponsored 20 of the 27 total trials.
Over the years, the scope of pegcetacoplan's potential applications has broadened considerably. Early studies expanded to include serious conditions such as Geographic Atrophy, C3 Glomerulopathy, Membranoproliferative Glomerulonephritis, and Paroxysmal Nocturnal Hemoglobinuria (PNH). The development continued to explore new areas, including various forms of ovarian, fallopian tube, and primary peritoneal cancers, as well as metastatic pancreatic ductal adenocarcinoma.
The program has progressed through various phases, with 9 Phase 2 trials and 8 Phase 3 trials indicating significant advancement towards potential approvals. In total, 27 trials have been initiated, enrolling 3,318 participants to date. The latest trial is projected to conclude on March 27, 2026, reflecting ongoing commitment to understanding pegcetacoplan's full therapeutic potential across a diverse range of diseases.