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Second-Generation C5 Inhibitors for Paroxysmal Nocturnal Hemoglobinuria

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Abstract

The C5 targeting monoclonal antibody eculizumab has changed the natural history of paroxysmal nocturnal hemoglobinuria (PNH) in the last 10 years. However, some unmet clinical needs persist, including persistent anemia with some patients requiring transfusions, incomplete C5 inhibition with breakthrough hemolysis (because of pharmacokinetic or pharmacodynamic issues such as infections, as well as conditions increasing complement activity), the underlying bone marrow failure, and the significant burden on patient quality of life (intravenous route of administration and frequency of infusions). Moreover, a subclass of patients carries C5 polymorphisms resistant to eculizumab inhibition. Several second-generation C5 inhibitors are under active study to overcome unmet clinical needs with eculizumab. Current strategies encompass increasing drug half‐life, developing small molecule inhibitors of C5, and exploring new routes of administration (including subcutaneous and oral agents). In this review, we summarize available data on second-generation C5 inhibitors in PNH, including novel monoclonal antibodies, a small interfering RNA, and small molecules.

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  1. Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano e Università degli studi di Milano, Milan, Italy

    Bruno Fattizzo

  2. Department of Haematological Medicine, King’s College Hospital, National Institute of Health Research/Wellcome King’s Clinical Research Facility, London, SE5 9RS, UK

    Austin G. Kulasekararaj

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AK received research support and received compensation for speakers’ bureau from Alexion, Novartis, and Celgene; received compensation for consultancy from Amgen, Ra Pharma and Achillion; received compensation for advisory boards from Akari, Alnylam, Celgene, Amgen, Ra Pharma, Alexion, and Novartis. BF received compensation for consultancy and advisory board from Apellis.

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Fattizzo, B., Kulasekararaj, A.G. Second-Generation C5 Inhibitors for Paroxysmal Nocturnal Hemoglobinuria. BioDrugs 34, 149–158 (2020). https://doi.org/10.1007/s40259-019-00401-1

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