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A.M. Risitano et al.
apy in PNH. By disabling the initiating event of comple- ment activation, danicopan prevents generation of C5 convertases, obviating the need for downstream C5 inhi- bition. Additionally, specific targeting of AP can preserve classical and lectin pathway-mediated antimicrobial activ- ity. The landscape of complement inhibition in the treat- ment of PNH will continue to evolve with the availability of proximal inhibitors. In addition to danicopan, other oral agents targeting the AP, such as factor B inhibitors, are under investigation for the treatment of PNH.22,31,32 Proximal complement inhibitors also include subcuta- neously administered agents targeting C3; one of these agents was reported to be effective in a recent phase III trial in patients with PNH.33 All of these approaches look promising for the treatment of PNH and clinical data should tell us very soon what are the viable treatment options in terms of safety and efficacy, and how we can best utilize them in the appropriate patients (i.e., monotherapy vs. add-on treatment). Preclinical data seem to suggest that AP inhibitors may be as effective as termi- nal complement blockade with clinical differences mostly due to the specific pharmacokinetic/pharmacodynamic profile of the individual inhibitor, rather than to its target in the complement cascade.22,31 Indeed targeting the AP, as PNH is a disease due to AP dysregulation (i.e., continuous, spontaneous C3 tick-over, eventually exacerbated at times of additional complement activation), possible applica- tions in other diseases will require an understanding of their pathogenic mechanisms.34
In conclusion, in this study danicopan appeared to be well-tolerated and showed clinically meaningful inhibi- tion of intravascular hemolysis and hemoglobin improve- ment in untreated PNH patients. This is the first evidence that a proximal complement inhibitor, used as monother- apy, can have a clinical impact on PNH by inhibiting intravascular hemolysis and preventing extravascular hemolysis. While second-generation compounds with improved pharmacokinetics and pharmacodynamics are in development, this study paves the way to improved hematologic response and novel standards of care, with an easier mode of administration, for hemolytic PNH patients.
Disclosures
AMR has received research support from Alexion, Novartis, Alnylam and Ra Pharma, lecture fees from Alexion, Novartis, Pfizer and Apellis, served as a member of advisory/investigator boards for Achillion, Alexion, Apellis, Biocryst, Novartis, Roche, and Samsung, and served as a consultant for Amyndas. AGK has served on advisory boards for Alexion, Celgene, Novartis, Ra Pharma, and Regeneron and has received travel grants from Achillion, Celgene, and Ra Pharma. JWL has received grants from Alexion and Achillion, has served as a member of advisory
boards for Alexion and Apellis, has received honoraria from Alexion, and has served as a consultant for AlloVir. JPM has received lecture honoraria from Alexion, Novartis, and Celgene and served as a consultant for Novartis. RN has received lecture fees from Alexion. RB has served on scientific advisory boards for Achillion and Alexion. PB has served as a member of advisory boards for Merck, Janssen, Roche and AbbVie, has served as an associate editor for the Internal Medicine Journal, and received research funding from Roche, Beigene, and Amgen. MH is an employee of Alexion and has equity ownership in the same com- pany. MG was an employee of Achillion, Inc., a subsidiary of Alexion Pharmaceuticals, Inc. and had equity ownership in the same company.
Contributions
MH and MG developed the study protocol, with the contribu- tion of AMR, AGK, RN, RB and PB; AMR, AGK, JWL, and PB recruited and treated patients, and collected the data; AMR, MH and MG analyzed and interpreted the data, and wrote the man- uscript; AGK, JWL, JPM, RN, RB and PB contributed to the manuscript and approved its final version.
Acknowledgments
We thank the patients and investigators, as well as their staff, who participated in this trial: Serena Marotta, Luana Marano and Fabiana Cacace (Naples), Petra Muus and Shreyans Gandhi (London), Federica Barone (Florence), Sung-Soo Park (Seoul), and Paul Hamilton (Auckland).
Funding
The study was sponsored and entirely supported by Achillion Inc., a subsidiary of Alexion Pharmaceuticals, Inc. We thank Heather Robison (an employee of Achillion Inc., a subsidiary of Alexion Pharmaceuticals, Inc.) and Steven Podos, Danny Shin and Julia Catini (Alexion employees and former employees of Achillion Inc., a subsidiary of Alexion Pharmaceuticals, Inc.) for their assistance in writing this manuscript and The Curry Rockefeller Group (funded by Achillion Inc., a subsidiary of Alexion Pharmaceuticals, Inc.) for their editorial assistance.
Data sharing
Alexion will consider requests for disclosure of clinical study participant-level data provided that participant privacy is assured through methods such as data de-identification, pseudo- nymization, or anonymization (as required by applicable law), and if such disclosure was included in the relevant study informed consent form or similar documentation. Qualified academic inves- tigators may request participant-level clinical data and support- ing documents (statistical analysis plan and protocol) pertaining to Alexion-sponsored studies. Further details regarding data availability and instructions for requesting information are avail- able in the Alexion Clinical Trials Disclosure and Transparency Policy at http://alexion.com/research-development.
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