Intensive Pegcetacoplan Dosing in the Management of Acute Hemolysis As Part of the 307 Open-Label Extension Study

Background Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, potentially life-threatening disease characterized by complement-mediated hemolysis and thrombosis. Complement C5 inhibitors, i.e., eculizumab (ECU) and ravulizumab, inhibit intravascular (IVH) but can develop extravascular hemolysis (EVH). Pegcetacoplan (PEG) is the first FDA/EMA approved C3 complement inhibitor therapy for adults with PNH (US) and adults with PNH who remain anemic after ≥3 months of C5 inhibitor treatment (EU) that controls both IVH and EVH. PEG led to significantly improved hemoglobin (Hb) levels in early and pivotal late phase studies in patients with PNH who remained anemic with ECU treatment (PHAROAH [NCT02264639]; PEGASUS [NCT03500549]) or were naïve to complement-inhibitor therapy (PALOMINO [NCT03593200]; PADDOCK [NCT02588833]; PRINCE [NCT04085601]). The ongoing PEG 307 open-label extension (OLE) study (NCT03531255) is evaluating the long-term safety and efficacy of PEG in patients with PNH who had completed previous Phase 1-3 PEG trials.

All patients with PNH on complement inhibition are at risk of breakthrough IVH with complement amplifying conditions such as infection, vaccination, or surgery. As expected, some PEG-treated clinical trial patients also experienced episodes of acute hemolysis (AH). We hypothesized that exposure to a higher and sustained PEG dosing regimen may help with immediate management of AH events. Here, we report findings on a subset of patients enrolled in the 307 OLE study examining the effect of acute treatment with intensive subcutaneous (SC) or intravenous (IV) PEG following an AH event.

Methods Patients enrolled in the OLE study, who experienced AH warranting acute intervention, were offered the opportunity to receive intensive PEG SC or IV dosing at the discretion of the investigator. Eligibility criteria for the intensive dosing regimen included lactate dehydrogenase (LDH) >2x the upper limit of normal (ULN) and 1 new or worsening sign or symptom of hemolysis (e.g., decreased Hb, hemoglobinuria, or fatigue).

Patients with AH on a steady-state PEG dose of 1080 mg SC twice weekly received a single dose of 1080 mg IV, or 1080 mg SC every 24 hours for 3 doses (intensive PEG treatment), followed by an increased maintenance regimen of 1080 mg SC every 3 days. For those receiving 1080 mg SC every 3 days or 3 times weekly, intensive PEG treatment was undertaken followed by maintenance doses of 1080 mg SC 3 times weekly.

Levels of Hb and LDH during the event of AH are described. Safety was evaluated by the incidence and severity of adverse events (AEs).

Results In total, 13 of 137 patients who entered the OLE aged 20 to 72 years received intensive PEG treatment: 10 from PEGASUS, 2 from PRINCE, and 1 from PADDOCK (Table 1).

On entry into the OLE study, these 13 patients had a mean LDH level of 249 U/L (5 patients >ULN; 11 patients <1.5x ULN) and a mean Hb level of 12.0 g/dL (range: 8 - 15 g/dL).

Table 1 shows LDH data before and during the intensive PEG treatment. Hb data before and at day 1 are presented. LDH levels from a range of local labs and central lab are presented in Table 1; local lab values were standardized. At day 1, 9 patients had LDH <10x ULN and 4 patients had LDH >10x ULN. From before intensive PEG treatment to day 1, Hb dropped by <2 g/dL in 6 patients and by >2 g/dL in 7 patients. The largest drop in one patient was 4.9 g/dL (from 11.4 g/dL to 6.5 g/dL).

Management of the AH event included intensive PEG SC dosing in 9 patients and a single PEG IV dose in 4 patients. LDH levels decreased between day 1 and day 2 in 8 of 12 evaluable patients (4 of 8 intensive SC and 4 of 4 IV treated patients) and in all 13 patients at day 7-12.

The incidence and severity of AEs was similar to that seen in the overall OLE study. Nine of 13 patients (69%) experienced treatment-emergent AEs; 4 of 13 patients (31%) experienced serious AEs. The majority (76%) of treatment-emergent AEs were mild. No AEs of meningitis or thrombosis occurred. Among the 4 patients who experienced serious AEs, 3 experienced a second event of hemolysis leading to another round of intensive treatment. None of the AEs led to treatment discontinuation.

Conclusions We report novel data from a subset of patients enrolled in the 307 OLE study, which support effective management of AH events with intensive SC or IV dosing regimens of PEG and that LDH levels can be rapidly controlled. Intensive treatment with PEG was safe and well tolerated. The study is ongoing.

Griffin:BioCryst Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria, Other: Conference support; Sobi Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Medscape: Other: educational work sponsored by Apellis with unrestricted grant paid to Medscape. Kelly:Biocryst: Membership on an entity's Board of Directors or advisory committees; Medscape: Other: educational work sponsored by Apellis with unrestricted grant paid to Medscape; Swedish Orphan Biovitrum AB: Membership on an entity's Board of Directors or advisory committees; Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: conference support; Sobi: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Biologix: Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Research Funding; Amgen: Consultancy. Deeren:Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sobi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Goh:Johnson & Johnson: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Medical Pharma: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Antengene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; NS Pharma: Honoraria; Astellas: Honoraria; Abbvie: Honoraria; Roche: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees; MSD: Honoraria; EUSA Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Research Funding. Tse:MSD: Research Funding. Usuki:Astellas: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Ono: Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; MSD: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Apellis Pharmaceuticals: Research Funding; Astellas-Amgen-Biopharma: Research Funding; SynBio: Research Funding; Otsuka: Consultancy, Honoraria, Research Funding; Nippon Shinyaku: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Chugai: Consultancy, Honoraria, Research Funding; SymBio: Consultancy, Research Funding; Celgene: Honoraria, Research Funding; Bristo-Myers Squibb: Honoraria, Research Funding; Janssen: Research Funding; Sumitomo-Dainippon: Research Funding; Eisai: Honoraria, Research Funding; Incyte: Research Funding; Kyowa-Kirin: Consultancy, Honoraria, Research Funding; Mundi: Research Funding; Yakult: Honoraria, Research Funding; Gilead: Research Funding; Pfizer: Honoraria, Research Funding. Wong:Alexion Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Apellis Pharmaceuticals: Research Funding, Speakers Bureau; F. Hoffmann-La Roche AG: Consultancy, Honoraria, Research Funding, Speakers Bureau. Horneff:Swedish Orphan Biovitrum AB: Current Employment. Tan:Swedish Orphan Biovitrum AB: Current Employment. Yeh:Apellis Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Savage:Apellis Pharmaceuticals: Current Employment. Szer:Novartis: Consultancy, Honoraria, Speakers Bureau; Biocryst: Consultancy, Honoraria, Speakers Bureau; Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CSL: Consultancy, Honoraria, Speakers Bureau; Eli-Lilly: Consultancy, Honoraria, Speakers Bureau; Sobi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau.

Pegcetacoplan is an FDA/EMA approved C3 complement-inhibitor therapy for adults with PNH (US) and adults who remain anemic after at least 3 months of C5 inhibitor treatment (EU) that controls both intravascular and extravascular hemolysis. As part of the long-term extension study, we aim to better understand the efficacy and safety of intensive pegcetacoplan dosing for the treatment of acute hemolytic events in patients treated with pegcetacoplan.