comment Corrected: Author Correction ‘Stealth’ corporate innovation: an emerging threat for therapeutic drug development Therapeutic innovations of potentially great clinical impact should embrace the overarching values of research accountability, data transparency and validation through the scientifc peer-review process. Dimitrios C. Mastellos, Anna M. Blom, E. Sander Connolly, Mohamed R. Daha, Brian V. Geisbrecht, Berhane Ghebrehiwet, Piet Gros, George Hajishengallis, V. Michael Holers, Markus Huber-Lang, Taroh Kinoshita, Tom E. Mollnes, Robert A. Montgomery, B. Paul Morgan, Bo Nilsson, Ruben Pio, Daniel Ricklin, Antonio M. Risitano, Ronald P. Taylor, Alberto Mantovani, John P. A. Ioannidis and John D. Lambris

“It is terrible to become rich and to know publications. Taxpayers and donors should evaluation of its validity and the long-term nothing else.”—Euripides know that their hard-earned contributions consequences of its conclusions. are being invested in work that gets validated The exposure of some types of industrial Academic research and industrial by rigorous peer review and also may research results to rigorous peer review innovation are both integral drivers of eventually help patients. Such opportunities is lagging behind that of their academic the discovery process that eventually can be nourished only by robust scientific counterparts. This insufficient peer culminates in innovative therapies and new evidence and peer-validated technologies validation may be a more prominent issue medicines1. Academic research is conducted in the development of innovative patient for research covering the early stages on university, hospital or research-center treatments2. Naturally, similar requirements of the discovery–to–clinical validation campuses furnished with several degrees for transparency and data integrity should pipeline, which is usually conducted by of freedom but also hampered by funding also apply when such research is partially smaller companies (including start-ups) constraints. Industrial research in large or fully conducted by start-ups, regardless than for larger biopharma companies companies tends to resonate more with the of which investigators are involved (e.g., working further down the pipeline. The rigid organizational blueprint and internal from academic institutions, hospitals and/ lack of peer-reviewed publications from regulatory control that spans the entire or companies). small companies and start-ups has been spectrum of corporate structure. Start-up Rigorous scientific scrutiny at all attributed to many factors, among which the companies (start-ups) are somewhere in the steps of the discovery process is essential protection of corporate intellectual property middle: they may have components of both regardless of whether this innovation is from competition holds a prominent place, academic and industrial origin, but in theory generated in university laboratories or especially for early-stage research3. Most their major advantage is that they can avoid in cubicles at biotechnology (biotech) major pharmaceutical companies engage in both the funding constraints of academia companies. The introduction of therapeutic peer review of their technologies or products and the rigid organizational constraints of innovations of potentially great clinical at critical checkpoints of technology large companies. impact carries even greater responsibility development. However, it is the aspiring Academically led innovation typically for communicating and engaging with the start-ups and small- or medium-sized thrives on competitive funding from public scientific community through clear and biotech enterprises that tend to rely more agencies and charities, and this makes the demonstrably consistent underpinning on media exposure than on actual scientific investment of a comparatively large portion data. Data validation by means of peer- evidence, in an effort to direct investor of such funding on high-risk ideas difficult. reviewed publications should also apply to funding toward their products, as early as Large companies are also increasingly risk- medicinal products discovered and clinically possible4. This evolving and increasingly averse in trying to invest in innovation and developed entirely within industrial accepted practice of shielding scientifically leave much of this early, high-failure-rate venues. The investor-driven funding that important corporate data is at odds with the step to start-ups or academic laboratories. enables start-up and biopharmaceutical standards of research accountability through The reliance of academic research (biopharma) research to advance its pipeline peer evaluation, data transparency, research on public funding mandates a strong of products through clinical development integrity and data openness5. sense of accountability, mainly toward should not create impediments to the Placing such general considerations the contributing taxpayers or charity maintenance of data transparency and into perspective, Cristea and colleagues donors (i.e., the broader public). In turn, open access to research. Industry-based evaluated the lack of peer-reviewed this research accountability should be research should not be communicated evidence from healthcare ‘unicorns’6 — reflected in a high level of data integrity only among company executives, investors, that is, biotech start-ups with promising and transparency, which is achieved mainly stockbrokers or venture capitalists through technologies and market valuations that through several rounds of review by expert vaguely formulated press releases with no exceed the US$1 billion threshold. Many scientists before the described research primary data or independently validated start-ups had secured exceedingly high product (e.g., drug target or candidate) can conclusions. Instead, its underpinning data market valuations despite a lack of peer- reach the public domain in peer-reviewed should be made publicly available to allow reviewed publications to support their

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Market value vs. peer-reviewed research output market valuations that probably reflect 12 2 mounting investor interest in what appears 2009 2007 * to be a rapidly evolving field of not only 1.8 clinical opportunity but also commercial 10 opportunity. But is this interest of the capital 2008 2013 1.6 * market firmly rooted in scientific facts or is Market cap (billions in US$) 1.4 it driven instead by media hype? 8 To gain insight into the extent to 1.2 which complement-dedicated start- 1997 ups with high market valuations have 6 1 1994 engaged in peer-review validation of Publications 1997 0.8 their products, we conducted a literature 2011 4 1998 2007 search for publications co-authored by 0.6 1996 2004 these companies. Scopus (Elsevier) was 1999 selected as our literature search engine, 1994 2004 0.4 2 and our retrievals included original 0.2 research articles, editorials and reviews. The ‘affiliation name’ of the company 2014 2010 0 0 was combined in a search for documents s h a e N s n E x a Ra c s cs s a s ti Akaritic ces one that included the term ‘complement’ in Apellis InflaRx ilen ls Omero S OXXO A Hemer Achillion AmyndaAnnexo N Pharm scien ADIENN the title, abstract and/or keywords and Ophthotec io ChemoCentryxInnate PharmTherapeuTherapeu B Bioscience Zealand Pharma also in extracted metadata (all fields) PharmaceuticalPharmaceuticals Publications Market cap (billions) associated with the document in question. All publications were cross-validated Fig. 1 | Market valuation of complement-related drug–development companies versus research output manually for the true association of their (peer-reviewed publications of company-sponsored research) that validates their complement- content (abstract) to complement research related technology or drug candidate. All market caps were retrieved through Yahoo’s finance search or complement-targeting therapeutics, with engine (https://finance.yahoo.com/) and were converted for uniformity into US currency (right vertical exclusion of use of the term ‘complement’ in axis) on the basis of currency exchange rates as of 30 July 2019. Our analysis included five privately held its grammatical sense. We chose to include companies (not listed on the stock exchange): ADIENNE, Alsonex, Amyndas, Annexon Biosciences and in our analysis 17 companies with clinical- Hemera Biosciences. For reasons of conformity, market values for these companies are shown as US$0 stage complement drug leads disclosed here. ‘Publications’ (left vertical axis) refers to peer-reviewed papers (original research articles, reviews through their official websites, focusing and editorials) retrieved through Elsevier’s Scopus search engine (https://www.elsevier.com/solutions/ on programs whose documentation in the scopus). Conference presentations, conference proceedings or corporate presentations and investor- literature commenced since 2003 and on and/or shareholder-oriented releases have been excluded from this analysis. All the primary data used complement innovators with consistent 9 for this analysis, with details on each company’s publication record and related citations, are provided commitment to this drug space . We in Supplementary Datasets 1 and 2. Numbers above bars indicate the year in which each company was focused only on start-ups; thus, large founded; asterisks indicate companies that are clinically developing different versions of the same C3- global healthcare companies with recently inhibitory peptide compstatin; hashed bar indicates the market cap of InflaRx before the announcement initiated complement drug programs were of the failure of IFX-1 in the phase II trials for hidradenitis suppurativa. not included in this analysis. Our search yielded quite striking results for a group of start-ups and medium-sized enterprises that are either publicly listed on a major market-directed innovations. To further incentives to companies that are developing stock exchange or privately held (Fig. 1) probe the extent of this stealth mode orphan medicinal products, such as The data demonstrate that companies of research and its potential adverse market exclusivity rights and expedited with the highest market valuation tend repercussions in the healthcare industry4, regulatory approval and oversight during to make fewer of their research results we decided to apply their analysis to the clinical development8. Today, complement accessible to the scientific community ‘complement system drug space’ and drug discovery has been thrust into the through peer-reviewed publications. For investigate whether similarly obscure limelight of the healthcare industry, with publicly listed companies with known corporate practices fuel ‘stealth’ innovation more than 20 candidate drugs advancing market valuation, with few exceptions among start-ups active in the clinical through clinical development (i.e., phase (such as Omeros and InflaRx, which both development of complement therapeutics. II and/or phase III) for a wide spectrum have a notable publication record), there We should emphasize that most of the of complement-mediated diseases9–11. A is an inverse relationship between market clinical indications currently targeted in growing number of start-ups have engaged valuation and peer-validated research the complement drug space are designated in the development of complement-targeting output (Fig. 1). This observation should as ‘rare’ or ‘orphan’ diseases7. The small drug candidates, alongside established be considered with some caution given numbers of treatable patients and the pharmaceutical companies that have also the relatively small number of companies projected low financial return of orphan initiated complement drug programs as assessed. However, it not only resonates medicines impose commercial risks, and part of their highly diversified portfolios9. with the main message conveyed by the special policies (such as the US Orphan In exploiting the rekindled interest of perspective article of Cristea et al.6 but Drug Act) have therefore been put in the biopharma industry in targeting this also raises awareness about a ‘stealth’ place to help companies counterbalance innate immune system, several start-ups research culture that may have infiltrated such risks. These policies offer several have managed to acquire exceedingly high the complement-drug-discovery space,

1410 Nature Immunology | VOL 20 | NOVEMBER 2019 | 1409–1413 | www.nature.com/natureimmunology comment disengaging valuation of the for-profit several highly valued public companies development of ALS-205 has gained traction entity from evidence-based scientific have advanced their lead compounds into from the prominent academic publication documentation. late-stage clinical development without record of its equivalent, PMX-2059. It should be noted that InflaRx’s having released into the literature any Our analysis further points to the impressively high market cap of US$1.05 causative and/or mechanistic or preclinical consequences of insufficiently validated billion decreased precipitously under evidence to support the feasibility of their research in a setting that appears to pressure resulting from the negative results clinical program. For example, Omeros be heavily influenced by media hype (released 5 June 2019) from its multi-center has advanced its lead compound, the and disproportionately high investor phase II study evaluating the efficacy of inhibitor OMS721, directed against the expectations. For example, the partnership its lead product, the monoclonal antibody protease MASP2, into two phase III trials, (announced 20 March 2019) of Zealand IFX-1, directed against the complement for immunoglobulin A nephropathy and Pharma, a company with expertise in component C5a, in patients with the atypical hemolytic uremic syndrome, metabolic diseases, with Alexion, the inflammatory skin disorder hidradenitis without any relevant publication supporting leading company in marketed complement suppurativa12. In the wake of this news, proof of concept for these indications9. therapeutics, for the joint development of the company’s stock plummeted, losing On the contrary, all Omeros-affiliated C3-targeted inhibitors15 made the headlines more than 90% of its original value, with publications support the development of of biotech ‘news channels’15. While Zealand the market cap of the company reduced inhibitors of MASP2 as treatment options Pharma has a publication portfolio that to US$75 million in August 2019 (https:// for cerebral, myocardial or gastrointestinal supports its glucagon-like-peptide–related finance.yahoo.com/quote/ifrx?ltr=1) ischemia–reperfusion injury (Supplementary technology, it has yet to publish any paper (Fig. 1). Interestingly, while the company Dataset 1). Apellis Pharmaceuticals, a related to complement-immunomodulatory had published several papers on its main public company that is advancing inhibitors peptides or inhibition of C3 (Fig. 1). product (IFX-1), the decision to advance that target the complement component Finally, the partnership (announced 18 July this candidate to trials for hidradenitis C3 through phase II and phase III trials, 2019) of UK-based Silence Therapeutics, suppurativa in particular was based on weak has already achieved an impressively high a biotech company with expertise in evidence: a single publication (from 2018) market valuation of approximately US$1.8 RNA-interference technology, with with limited translational data, perhaps billion (Fig. 1), the highest among all of the Mallinckrodt Pharmaceuticals, for the insufficient to support full commitment to complement-focused drug-development mutual development of their preclinical clinical trials for hidradenitis suppurativa13. companies, a valuation probably kindled lead compound SLN500 as a C3-targeting The case of InflaRx further indicates that by the release of non–peer-reviewed RNA-interference therapeutic, was widely occasionally a combination of media hype, clinical results of ongoing trials. While publicized in the media16. Despite a potential investor impatience, loosely connected clinically developing its lead drug candidate, return from the partnership of approximately preclinical evidence and lack of sufficient the polyethylene glycol–conjugated, US$2.0 billion in combined milestone peer-reviewed evidence for the targeted compstatin-based C3 inhibitor APL-2, for payments and commercial royalties, Silence indication can drive corporate decisions several indications, Apellis has refrained has yet to produce any peer-evaluated into ‘murky waters’. Of note, the market fall from publishing peer-reviewed articles, line of evidence of how this compound of InflaRx had parallel repercussions on the confining its research output to press can achieve sustainable inhibition of C3 stock price of another complement-related releases, conference posters and corporate in a therapeutically relevant context. The biotech company, ChemoCentryx, which announcements about the status of ongoing rekindled interest of big biopharma in develops an orally available antagonist clinical trials9. Similarly, Ra Pharmaceuticals gene-therapy platforms for the treatment of the complement receptor C5aR1 that has taken its lead compound, zilucoplan of chronic diseases17, along with the prevents activation of the same effector (RA101495), to phase III trials of patients excessively high, multi-billion-dollar buyouts pathway (the pathway targeted by IFX-1) with paroxysmal nocturnal hemoglobinuria, announced for the acquisition of gene- in complement-mediated inflammatory without any published peer-reviewed therapy start-ups by global healthcare leaders disorders. ChemoCentryx’s stock value evidence confirming the drug’s efficacy or (such as Roche’s announced acquisition of dropped sharply by 22% within 2 days (4–6 benchmarking their technology against Spark Therapeutics for US$4.5 billion in June 2019) of the announcement of the the standard of care in this specific clinical February 2019) have evidently garnered a lot InflaRx trial results (https://finance.yahoo. indication14. of momentum for such approaches, as yet com/quote/CCXI/?guccounter=1). It is We further extended our literature-based unsupported by transparent, evidence-based worth mentioning that ChemoCentryx’s analysis to privately held pharmaceutical science or data openness18. candidate drug, Avacopan, is currently companies that are developing complement To gain insight into the overall impact in phase III trials for anti-neutrophil therapeutics. For example, Amyndas, a of the peer-reviewed papers produced by cytoplasmic antibody–associated vasculitis, start-up established in 2013, is advancing complement-based start-ups, we determined and the results are eagerly awaited, given third- and fourth-generation compstatins how many of the papers shown in Fig. 1 these developments9. through phase II trials that have been had received more than 30 citations in The peer-reviewed maturity of a communicated in the scientific literature Scopus as of 6 August 2019. We found that technology (i.e., the pharmacology and/ through nine co-authored publications 14 of a total 48 papers had more than 30 or biological efficacy of a drug candidate) (Fig. 1). Alsonex, a biotech company citations each, covering a time period from is not necessarily reflected in the market that is developing therapeutics for the inception date of each company to the valuation of the respective company. There neurodegenerative diseases, offers another present; this indicates that almost one third is considerable risk of letting investors’ interesting example of how corporate of the research output from these companies decisions and market bias skew the direction innovation can gain leverage from has garnered considerable attention from of clinical research, irrespective of which academically led research results. While its peers (Supplementary Dataset 1 provides a drug candidate the evidence base suggests lead compound (ALS-205) has not been complete record of citations retrieved per might be most efficacious. For example, registered in any publication so far, clinical publication, per company).

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We should caution that the absolute uncertainties are key issues that need to Transplant Institute, New York, NY, USA. 16Systems number of publications is, of course, only a be dealt with in a transparent manner if Immunity Research Institute, School of Medicine, modest marker of the reliability of evidence. these new therapeutics are to be effectively Cardif University, Cardif, UK. 17Division of Clinical Citation impact is also only a modest marker translated into beneficial new treatments Immunology, Uppsala University Hospital, Uppsala, of the extent of validation, let alone an for patients. Despite the registration of a Sweden. 18Program in Solid Tumors, Center for indicator of the future potential of a drug growing number of clinical trials for the Applied Medical Research (CIMA), University under investigation. Despite such clear evaluation of complement-targeting drugs, of Navarra, IDISNA, CIBERONC, Pamplona, limitations, the peer-review system is still peer-reviewed validation of new therapeutic Spain. 19Department of Pharmaceutical Sciences, regarded as the most reliable tool for the concepts, targets and drug candidates University of Basel, Basel, Switzerland. 20Department evaluation of scientific data. Nevertheless, remains problematic, particularly in the of Clinical Medicine and Surgery, Federico II it is important to scrutinize peer-reviewed case of start-ups that have secured large University of Naples, Naples, Italy. 21Department of papers with a critical eye. Additionally, market valuations that capitalize on investor Biochemistry and Molecular Genetics, University the inclination of both authors and editors expectations and increased media attention. of Virginia, Charlottesville, VA, USA. 22Istituto to publish ‘positive’ results, rather than While we acknowledge that corporate Clinico Humanitas, Humanitas University, Milan, ‘negative’ results, has created a bias in the innovation must be protected through Italy. 23Meta-Research Innovation Center at literature with important implications stringent intellectual property policies, we Stanford, and Departments of Medicine, of Health for the field of clinical therapeutics. Peer- contend that healthcare products that affect Research and Policy, of Biomedical Data Science, reviewed papers, even when well cited, patients’ lives, such as complement-targeting and of Statistics, Stanford University, Stanford, CA, may still be suboptimal, flawed or largely drugs, should undergo rigorous peer- USA. 24Department of Pathology & Laboratory irrelevant to the real translational value. An reviewed validation before sizeable resources Medicine, Perelman School of Medicine, University of example illustrating the last is Annexon’s and funds for clinical research and trials Pennsylvania, Philadelphia, PA, USA. technology directed against complement are engaged. ❐ *e-mail: [email protected] component C1q, which despite its sizeable impact in the literature (over 560 citations, Dimitrios C. Mastellos 1, Anna M. Blom 2, Published online: 27 September 2019 according to Scopus) has yet to overcome E. Sander Connolly3, Mohamed R. Daha4, https://doi.org/10.1038/s41590-019-0503-1 substantial translational hurdles for clinical Brian V. Geisbrecht5, Berhane Ghebrehiwet6, 7 8 References evaluation for neurodegenerative diseases. Piet Gros , George Hajishengallis , 1. Chin-Dusting, J., Mizrahi, J., Jennings, G. & Fitzgerald, D. Nat. 9 10 Finally, the credibility and concrete V. Michael Holers , Markus Huber-Lang , Rev. Drug Discov. 4, 891–897 (2005). scientific base of a start-up’s lead technology Taroh Kinoshita 11, Tom E. Mollnes12,13,14, 2. Dahlin, J. L., Inglese, J. & Walters, M. A. Nat. Rev. Drug Discov. 15 16 14, 279–294 (2015). may also be reflected by the record of Robert A. Montgomery , B. Paul Morgan , 3. Grabowski, H. G., DiMasi, J. A. & Long, G. Health Af. (Millwood) 17 18 19 scientific achievements and broader impact Bo Nilsson , Ruben Pio , Daniel Ricklin , 34, 302–310 (2015). of its founders. Retrieving a set of impact Antonio M. Risitano20, Ronald P. Taylor 21, 4. Ioannidis, J. P. A. J. Am. Med. Assoc. 313, 663–664 (2015). Alberto Mantovani 22, John P. A. Ioannidis23 5. Amann, R. I. et al. Science 363, 350–352 (2019). metrics for the co-founders of the 17 6. Cristea, I. A., Cahan, E. M. & Ioannidis, J. P. A. Eur. J. Clin. Invest. 24 companies in Fig. 1, we observed that only 4 and John D. Lambris * 49, e13072 (2019). of these 17 companies were founded on the 1National Center for Scientifc Research ‘Demokritos’, 7. Orphanet. https://www.orpha.net/consor/cgi-bin/Education_ Aghia Paraskevi, Athens, Greece. 2Department of AboutRareDiseases.php?lng=EN. Accessed 4 February 2019. expertise of leading scientists with a sizeable 8. Luzzatto, L. et al. Lancet 392, 791–794 (2018). impact on the literature, as deduced by Translational Medicine, Lund University, Lund, 9. Mastellos, D.C., Ricklin, D. & Lambris, J.D. Nat. Rev. Drug Discov. their h index (which measures productivity Sweden. 3Department of Neurological Surgery, https://doi.org/10.1038/s41573–019-0031-6 (2019). and citation impact of publications: the Columbia University, New York, NY, USA. 4Leiden 10. Ricklin, D., Mastellos, D. C., Reis, E. S. & Lambris, J. D. Nat. Rev. Nephrol. 14, 26–47 (2018). number of publications (h) for which an University Medical Center, Leiden, Netherlands. 11. Yang, K., Deangelis, R. A., Reed, J. E., Ricklin, D. & Lambris, J. D. author has been cited by other authors at 5Department of Biochemistry and Molecular Adv. Exp. Med. Biol. 735, 301–313 (2013). least h times) and total citations (h > 50 Biophysics, Kansas State University, Manhattan, 12. InfaRx. https://www.infarx.de/Home/Investors/Press- 6 Releases/06–2019-InfaRx-Announces–Top-Line-SHINE- and over 20,000 total citations, according KS, USA. Department of Medicine, Division of Phase-IIb-Results-for-IFX-1-in-Hidradenitis-Suppurativa-.html. to Scopus). Although we acknowledge that Rheumatology, Allergy and Immunology, Stony Accessed 31 July 2019. this is not a mandatory condition for the Brook University, New York, NY, USA. 7Department 13. Kanni, T., Zenker, O., Habel, M., Riedemann, N. & Giamarellos- Bourboulis, E. J. Br. J. Dermatol. 179, 413–419 (2018). clinical success of any drug candidate, it of Chemistry, Faculty of Science, Utrecht 14. Morrison, C. Nat. Rev. Drug Discov. 17, 531–533 (2018). 8 does provide an interesting perspective University, Utrecht, Netherlands. Department of 15. Alexion. https://news.alexion.com/press-release/company-news/ on how ‘thought leaders’ in the field shape Microbiology, School of Dental Medicine, University alexion-and-zealand-pharma-announce-collaboration-discover- 9 and-develop-pe. (2019). drug-discovery efforts and become drivers of Pennsylvania, Philadelphia, PA, USA. Division 16. PRNewswire. https://www.prnewswire.com/news-releases/ of corporate innovation. Scientific advisory of Rheumatology, Departments of Medicine and mallinckrodt-and-silence-therapeutics-announce-collaboration- boards are also important for guaranteeing Immunology, University of Colorado School of to-develop-and-commercialize-rnai-therapeutics-for- Medicine, Denver, CO, USA. 10Institute of Clinical complement-mediated-diseases-300887002.html (2019). field expertise. However, information on 17. High, K. A. & Roncarolo, M. G. N. Engl. J. Med. 381, the membership and level of involvement of and Experimental Trauma immunology, University 455–464 (2019). these boards is often lacking6. of Ulm, Ulm, Germany. 11Research Institute 18. Miller, J. Reuters https://www.reuters.com/article/us-spark-m-a- for Microbial Diseases Osaka University and roche-hldg/roche-steps-up-for-gene-therapy-with-4–3-billion- spark-bet-idUSKCN1QE0L6 (2019). Concluding remarks and outlook Laboratory of Immunoglycobiology, Immunology The growing interest in complement Frontier Research Center, Osaka University, Competing interests 12 therapeutics, as exemplified by a burgeoning Osaka, Japan. Department of Immunology, A.M.B. has provided paid consulting services to Zealand pipeline of drug candidates currently in Oslo University Hospital, and University of Oslo, Pharma. B.V.G. collaborates with and has received research early or late-stage clinical development9, Oslo, Norway. 13Research Laboratory, Nordland materials from SomaLogic and Roche Pharma and has also has thrust complement drug discovery Hospital, Bodø, and K.G. Jebsen TREC, University provided paid consulting services for ClearView Health 14 Care Partners and 1776 Health Care. B.G. is the holder of into the spotlight of biopharma research. of Tromsø, Tromsø, Norway. Centre of Molecular a US patent for a monoclonal antibody for the treatment At the same time, corporate data integrity Infammatory Research, NTNU, Trondheim, of angioedema and a patent for monoclonal antibodies to and practices that lead to scientific Norway. 15Department of Surgery, NYU Langone both C1q and C1qRs for the treatment of various types

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of cancer and has consulted for Diaccurate-Pasteur and from Alexion (the manufacturer of Soliris-Eculizumab) Pharmaceuticals, Novartis, Alnylam and Ra Pharma and Orion Pharma but has never received research support and Shire ViroPharma, has served as a paid consultant for lecture fees from Alexion, Novartis, Pfizer and Apellis, from any pharmaceutical company. P.G. has collaborated Alexion, Shire ViroPharma and CSL Behring, has received and served as member of advisory–investigator boards for with and has received research funding and/or research travel honoraria from Alexion and Shire ViroPharma, has Alexion, Roche, Achillion, Novartis, Apellis and Samsung, materials from Genmab and Merus. G.H. is an inventor served on advisory boards for Genentech/Roche, True and as a consultant for Amyndas. R.P.T. has collaborated on patents or patent applications that describe the use North/iPerian, Novartis and Hansa Medical, and received with and received research funding and research of complement inhibitors for therapeutic purposes in consulting fees from OrbidMed, GuidePoint Global, materials from Genmab. J.D.L. is the founder of Amyndas periodontitis, some of which are being developed by Sucampo, Astellas, and Shire and research grants from Pharmaceuticals, which is developing complement Amyndas Pharmaceuticals. V.M.H. is a co-founder of Immune Tolerance Network, ViroPharma, Hansa and inhibitors for therapeutic purposes, is the inventor of Taligen Therapeutics and AdMIRx, receives Taligen-related Alexion. B.P.M. has received research support from GSK patents or patent applications that describe the use of licensing royalties from Alexion, has equity interest in and served as an advisor for GSK, Roche, Alexion and Ra complement inhibitors for therapeutic purposes, some of and consulting income from AdMIRx, and is a recent or Pharma. B.N. is a shareholder and consultant in Tikomed which are being developed by Amyndas Pharmaceuticals, current consultant in non-complement areas to Janssen and iCoat Medical. R.P. is the inventor on patents that is the inventor of the compstatin technology licensed to Research and Development, Amgen, Celgene, BMS and describe the use of complement-related proteins for cancer Apellis Pharmaceuticals (4(1MeW)7W/POT-4/APL-1 Trios. M.H.-L. holds a patent on compositions of matter diagnosis and has received consultant fees from Amadix and PEGylated derivatives such as APL-2/pegcetacoplan), and methods for the diagnosis and treatment of sepsis and research funding from Dompé. D.R. is the inventor and has provided paid consulting services to Achillion, Ra by C5a inhibitory strategies licensed to InflaRx. T.K. on patents or patent applications that describe the use of Pharma, Viropharma, Sanofi, Shire, LipimetiX and Baxter. has received consultant fees and honoraria for lectures complement inhibitors for therapeutic purposes, some of from Alexion. T.E.M. has received consultant fees from which are developed by Amyndas Pharmaceuticals, and Additional information Ra Pharmaceuticals, SVAR Life Science and Alexion has provided paid consulting services to Roche Pharma. Supplementary information is available for this paper at Pharmaceuticals. R.A.M. has received research funding A.M.R. has received research support from Alexion https://doi.org/10.1038/s41590-019-0503-1.

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