Small-molecule factor D inhibitors targeting the alternative complement pathway

Maibaum, Jürgen; Liao, Sha-Mei; Vulpetti, Anna; Ostermann, Nils; Randl, Stefan; Rüdisser, Simon; Lorthiois, Edwige; Erbel, P.; Kinzel, Bernd; Kolb, Fabrice A.; Barbieri, Samuel; Wagner, Julia A.; Durand, Corinne; Fettis, Kamal; Dussauge, Solene; Hughes, Nicola; Delgado, Omar; Hommel, Ulrich; Gould, Ty; Sweeney, A. Mac; Gerhartz, Bernd; Cumin, Frédéric; Flohr, Stefanie; Schubart, Anna; Jaffee, Bruce; Harrison, Richard A.; Risitano, Antonio M.; Eder, Jörg; Anderson, Karen

doi:10.1038/nchembio.2208

Cited by 64 publications

(143 citation statements)

References 48 publications

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“…FD has emerged as an attractive target owing to its comparatively low plasma concentration, high specificity and bottleneck role in convertase assembly. Novartis has developed small-molecule FD inhibitors inspired by kallikrein blockers that bind to the catalytic site of FD, are orally bioavailable and appear to distribute into ocular tissue, with potential implications for AMD therapy 122,123 . Similarly, Achillion has introduced small FD inhibitors, one of which, ACH-4471, has been assessed in preclinical PNH and aHUS models 124 and is currently being evaluated in phase II clinical trials in an orally administered form 125 .…”

Section: Complement-targeting Therapeuticsmentioning

confidence: 99%

The renaissance of complement therapeutics

et al. 2017

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The increasing number of clinical conditions that involve a pathological contribution from the complement system — many of which affect the kidneys — has spurred a regained interest in therapeutic options to modulate this host defence pathway. Molecular insight, technological advances, and the first decade of clinical experience with the complement-specific drug eculizumab, have contributed to a growing confidence in therapeutic complement inhibition. More than 20 candidate drugs that target various stages of the complement cascade are currently being evaluated in clinical trials, and additional agents are in preclinical development. Such diversity is clearly needed in view of the complex and distinct involvement of complement in a wide range of clinical conditions, including rare kidney disorders, transplant rejection and haemodialysis-induced inflammation. The existing drugs cannot be applied to all complement-driven diseases, and each indication has to be assessed individually. Alongside considerations concerning optimal points of intervention and economic factors, patient stratification will become essential to identify the best complement-specific therapy for each individual patient. This Review provides an overview of the therapeutic concepts, targets and candidate drugs, summarizes insights from clinical trials, and reflects on existing challenges for the development of complement therapeutics for kidney diseases and beyond.

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Section: Complement-targeting Therapeuticsmentioning

confidence: 99%

The renaissance of complement therapeutics

et al. 2017

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“…A second group of inhibitors intercept the complement cascade upstream C5; they include broad inhibitors of C3 and agents which specifically target complement activating pathways—classical (CCP), alternative (CAP), and mannose/lectine (CMP) ones (Figure ; Table ) . For PNH, candidate inhibitors target the CAP, inhibiting C3 convertase C3bBb, or one of CAP key early components, ie, factor D (FD), factor B (FB), and properdin. These upstream inhibitors include mAb, small compounds, as well as engineered proteins based on endogenous regulators of complement activation .…”

Section: Novel Strategies Of Complement Inhibitionmentioning

confidence: 99%

“…ACH‐4471 is one of the anti‐FD small molecules developed by Achillion with in vitro efficacy in PNH . In a phase I study in healthy volunteers investigating single, oral, ascending doses of ACH‐4471 no major safety issue was raised; doses of 200–600 mg resulted in peak plasma level within a few (1–2) hours, with terminal half‐life of about 9 hours .…”

Section: Novel Strategies Of Complement Inhibitionmentioning

confidence: 99%

Toward complement inhibition 2.0: Next generation anticomplement agents for paroxysmal nocturnal hemoglobinuria

Risitano

Marotta

2018

American J Hematol

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Therapeutic complement inhibition by eculizumab has revolutionized the treatment of paroxysmal nocturnal hemoglobinuria (PNH) with a major impact on its natural history. Nevertheless, emerging unmet clinical needs may benefit from the development of novel complement inhibitors. Novel strategies of complement inhibition exploit different agents targeting C5, as well as compound intercepting the complement cascade at the level of its key component C3, or even upstream at the level of components involved in complement alternative pathway initiation. Many of these agents are already in their clinical development; preliminary data together with a deep understanding of PNH biology may help to anticipate their possible clinical effect. Novel anti-C5 agents include monoclonal antibodies (even long-lasting) as well as other small molecules bioavailable by subcutaneous administration; an anti-C5 small interfering RNA has been developed too. All these anti-C5 agents seem to recapitulate safety and efficacy of current eculizumab treatment; their main improvement pertains to better patient's convenience due to longer dosing interval and/or possible subcutaneous self-administration. The possibility of achieving a deeper C5 inhibition has been shown as well, but its actual clinical meaning remains to be elucidated. Upstream complement inhibitors include the anti-C3 small peptide compstatin (and its derivatives), and small inhibitors of complement factor D or complement factor B. This class of compounds anticipates a possible efficacy in prevention of C3-mediated extravascular hemolysis, in addition to inhibition of intravascular hemolysis, eventually leading to improved hematological responses. The availability of all these compounds will result soon in a substantial improvement of PNH management.

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“…in cases of aberrant CFHR binding to deposited C3b). The recent disclosure of new AP-inhibiting compounds that specifically target factor D, a key protease that contributes to the formation of active AP C3 convertases, provides a range of diversified approaches for tackling dysregulated C3 turnover in C3G and other AP-driven clinical disorders [45]. …”

Section: C3 Glomerulopathy: Bridging the Gap Between Pathophysiolomentioning

confidence: 99%

Complement C3-Targeted Therapy: Replacing Long-Held Assertions with Evidence-Based Discovery

Mastellos

Reis

Ricklin

et al. 2017

Trends in Immunology

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Complement dysregulation underlies several inflammatory disorders, and terminal complement inhibition has thus far afforded significant clinical gains. Nonetheless, emerging pathologies, fueled by complement imbalance and therapy-skewing genetic variance, underscore the need for more comprehensive, disease-tailored interventions. Modulation at the level of C3, a multifaceted orchestrator of the complement cascade, opens up prospects for broader therapeutic efficacy by targeting multiple pathogenic pathways modulated by C3-triggered proinflammatory crosstalk. Notably, C3 intervention is emerging as a viable therapeutic strategy for renal disorders with predominantly complement-driven etiology, such as C3 glomerulopathy (C3G). Using C3G as a paradigm, we argue that concerns about the feasibility of long-term C3 intervention need to be placed into perspective and weighed against actual therapeutic outcomes in prospective clinical trials.

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Small-molecule factor D inhibitors targeting the alternative complement pathway

Cited by 64 publications

References 48 publications

The renaissance of complement therapeutics

The renaissance of complement therapeutics

Toward complement inhibition 2.0: Next generation anticomplement agents for paroxysmal nocturnal hemoglobinuria

Complement C3-Targeted Therapy: Replacing Long-Held Assertions with Evidence-Based Discovery

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