Pegcetacoplan versus Eculizumab in Paroxysmal Nocturnal Hemoglobinuria

Hillmen, Peter; Szer, Jeff; Weitz, Ilene C.; Röth, Alexander; Höchsmann, Britta; Panse, Jens; Usuki, Kensuke; Griffin, Morag; Kiladjian, Jean Jacques; Castro, Carlos de; Nishimori, Hisakazu; Tan, Lisa; Hamdani, Mohamed; Deschatelets, Pascal; Francois, Cedric; Grossi, F; Ajayi, Temitayo; Risitano, Antonio M.; Tour, Régis Peffault de la

doi:10.1056/nejmoa2029073

Cited by 256 publications

(438 citation statements)

References 25 publications

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“…The recently reported resolution of vaccine-induced thrombotic microangiopathy in two patients following combined treatment with anticoagulants and the C5 inhibitor eculizumab further corroborates our hypothesis that therapeutic complement modulation may offer significant clinical benefits to VITT patients (18). In this regard, C3 inhibitors may exert a broader therapeutic effect than anti-C5 agents by suppressing both terminal pathway activation and thrombogenic pathways operating upstream of C5 (14,19).…”

Section: Potential Treatment Approachesmentioning

confidence: 99%

Is complement the culprit behind COVID-19 vaccine-related adverse reactions?

Mastellos¹,

Skendros²,

Lambris³

2021

Journal of Clinical Investigation

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Section: Potential Treatment Approachesmentioning

confidence: 99%

Is complement the culprit behind COVID-19 vaccine-related adverse reactions?

Mastellos¹,

Skendros²,

Lambris³

2021

Journal of Clinical Investigation

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“…Apellis conducted the PEGASUS study, a phase III randomized, open-label trial assessing the clinical efficacy and safety of pegcetacoplan compared with eculizumab among patients who had previously received eculizumab (NCT03500549). Results at week 16 demonstrated that pegcetacoplan was superior to eculizumab for change in hemoglobin level, and non-inferior for transfusion avoidance and change in absolute reticulocyte count 17 .…”

Section: Introductionmentioning

confidence: 99%

“…In consequence to this, C3 inhibition by pegcetacoplan has a broader effect on subsequent complement cascade inhibition as compared to C5 inhibition by eculizumab and ravulizumab. Broader complement inhibition by pegcetacoplan may mitigate both intravascular hemolysis (which is mediated by the terminal complement protein C5 of the complement cascade and membrane attack complex formation) and extravascular hemolysis (which is mediated by opsonization with C3 fragments and subsequent phagocytosis), and result in improved hematologic benefit in patients with PNH relative to current approved treatments 17 .…”

Section: Introductionmentioning

confidence: 99%

“…While pegcetacoplan has been compared directly to eculizumab in a clinical trial setting in patients previously treated with eculizumab 17 , there are evidence gaps for treatment outcomes with pegcetacoplan compared to other treatment options of patients with PNH. The purpose of this study was to assess the evidence gap that there is no head-to-head comparison of pegcetacoplan and ravulizumab among complement inhibitor-experienced patients who were previously treated with eculizumab (the PEGASUS study was initiated in June 2018; however, ravulizumab was not approved until December 2018).…”

Section: Introductionmentioning

confidence: 99%

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Comparative effectiveness of pegcetacoplan versus ravulizumab in patients with paroxysmal nocturnal hemoglobinuria previously treated with eculizumab: a matching-adjusted indirect comparison

Bhak

Mody-Patel

Baver

et al. 2021

Current Medical Research and Opinion

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Objective: In the absence of a head-to-head study, we assessed the comparative effectiveness of pegcetacoplan, a targeted C3 complement inhibitor, vs. ravulizumab, a C5 complement inhibitor, among patients with paroxysmal nocturnal hemoglobinuria (PNH) previously treated with eculizumab using matching-adjusted indirect comparison methodology. Methods: Individual patient data from the PEGASUS study (NCT03500549) comparing pegcetacoplan and eculizumab enabled adjustment for baseline differences compared with published results from the ALXN1210-PNH-302 study (NCT03056040), comparing ravulizumab and eculizumab. Adjusted differences and 95% confidence intervals (CIs) were computed via weighted Wald tests for comparisons of pegcetacoplan vs. ravulizumab, anchored to the common comparator eculizumab. Results: Sixty-eight patients from PEGASUS (36 pegcetacoplan; 32 eculizumab) and 195 from ALXN1210-PNH-302 (97 ravulizumab; 98 eculizumab) were included. Compared with ravulizumab, treatment with pegcetacoplan was associated with more transfusion avoidance (adjusted difference [95% CI] ¼ þ71.4% [53.5%, 89.3%]), hemoglobin level stabilization (þ75.5% [56.4%, 94.6%]), lactate dehydrogenase (LDH) level normalization (þ64.0% [41.8%, 86.1%]), and fewer blood transfusions (À5.7 units [À7.2, À4.2]). Additionally, patients who received pegcetacoplan experienced clinically meaningful improvements in fatigue (þ8.2 points [3.8, 12.6]), global health status (þ9.6 points [0.1, 19.0]), physical functioning (þ11.5 points [3.6, 19.5]), and fatigue symptoms (À13.3 points [À23.7, À3.0]), compared with ravulizumab. Mean change from baseline in LDH level was not significantly different for pegcetacoplan vs. ravulizumab. Conclusions: Results suggest that among patients previously treated with eculizumab, clinical, hematological, and quality of life endpoints were better for patients who received the C3 complement inhibitor pegcetacoplan vs. patients who received ravulizumab, a C5 complement inhibitor.

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“…Non-natural amino acids are commonly used to increase the binding affinity of peptides. Compstatin, a macrocyclic inhibitor of complement C3 which, in a modified form, was recently approved for paroxysmal nocturnal haemoglobinuria 43 , is one such example; where incorporation of a hydrophobic 1-methyltryptophan results in a 264-fold increase in activity 44 . Similarly, non-proteinogenic residues have been used in the generation of high affinity human leukocyte antigen blockers, which competitively displace the antigenic peptide on major histocompatibility complex receptors to prevent T-cell recognition of the complex 45 .…”

Section: Discussionmentioning

confidence: 99%

The chemical synthesis of knob domain antibody fragments

Macpherson

Birtley

Broadbridge

et al. 2021

Preprint

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Cysteine-rich knob domains found in the ultralong complementarity determining regions of a subset of bovine antibodies, are capable of functioning autonomously as 3-6 kDa peptides. While they can be expressed recombinantly in cellular systems, in this paper we show that knob domains are also readily amenable to chemical synthesis, with a co-crystal structure of a chemically synthesised knob domain in complex with antigen showing structural equivalence to the biological product. For drug discovery, following immunisation of cattle, knob domain peptides can be synthesised directly from antibody sequence data, combining the power and diversity of the bovine immune repertoire with the ability to rapidly incorporate non-biological modifications. We demonstrate that, through rational design with non-natural amino acids, paratope diversity can be massively expanded, in this case improving the efficacy of an allosteric peptide. As a potential route to further improve stability, we also performed head-to-tail cyclisation, exploiting the unusual proximity of the N- and C- termini to synthesise functional, fully cyclic antibody fragments. Lastly, we highlight the stability of knob domains in plasma and, through pharmacokinetic studies, use palmitoylation as a route to extend the plasma half-life of knob domains in vivo. This study presents an antibody-derived medicinal chemistry platform, with protocols for solid-phase synthesis of knob domains; together with characterisation of their molecular structures, in vitro pharmacology and pharmacokinetics.

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Pegcetacoplan versus Eculizumab in Paroxysmal Nocturnal Hemoglobinuria

Cited by 256 publications

References 25 publications

Is complement the culprit behind COVID-19 vaccine-related adverse reactions?

Is complement the culprit behind COVID-19 vaccine-related adverse reactions?

Comparative effectiveness of pegcetacoplan versus ravulizumab in patients with paroxysmal nocturnal hemoglobinuria previously treated with eculizumab: a matching-adjusted indirect comparison

The chemical synthesis of knob domain antibody fragments

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