Publication: November 3, 2020

EDITORIAL

The Twilight Zone: Benefit, Risk & Hope in Clinical Trials for
Fibrodysplasia Ossificans Progressiva (FOP)

From The International Clinical Council on FOP (ICC)

Frederick S. Kaplan¹, Mona Al Mukaddam², Genevieve Baujat³, Amanda Cali⁴, Tae-JoonCho⁵, Carmen L. De Cunto⁶, Patricia Delai⁷, Robert J. Diecidue⁸, Maja DiRocco⁹, Clive Friedman¹⁰, Zvi Grunwald¹¹, Nobuhiko Haga¹², Edward C. Hsiao¹³, Richard Keen¹⁴, Rolf Morhart¹⁵, J.Coen Netelenbos¹⁶, Christiaan Scott¹⁷, Michael A. Zasloff¹⁸, Keqin Zhang¹⁹, Elisabeth M. W. Eekhoff²⁰ and Robert J. Pignolo²¹

¹Departments of Orthopaedic Surgery, Medicine, and The Center for Research in FOP & Related Disorders, The Perelman School of Medicine of The University of Pennsylvania, Philadelphia, PA USA

²Division of Endocrinology, Diabetes and Metabolism, Departments of Medicine and Orthopaedic Surgery, The Perelman School of Medicine of The University of Pennsylvania, Philadelphia, PA, USA

³Centre de Référence Maladies Osseuses Constitutionnelles, Departement de Génétique, Hôpital Necker-Enfants Malades, Institut Imagine, Paris, France

⁴Radiant Hope Foundation and the Ian Cali FOP Research Fund, PENN Medicine, Center for Research in FOP & Related Disorders

⁵Division of Pediatric Orthopaedics, Seoul National University Children's Hospital, Seoul, South Korea

⁶Pediatric Rheumatology Section, Department of Pediatrics, Hospital Italiano de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina

⁷Hospital Israelita Albert Einstein, Instituto de Ensino e Pesquisa, São Paulo-SP, Brazil

⁸Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA

⁹Unit of Rare Diseases, Department of Pediatrics, IRCCS Giannina Gaslini Institute, Genoa, Italy

¹⁰Schulich School of Medicine and Dentistry, Pediatric Oral Health and Dentistry, London, ON, Canada

¹¹Department of Anesthesiology, Thomas Jefferson University, Philadelphia, PA, USA

¹²Department of Rehabilitation Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

¹³Division of Endocrinology and Metabolism, and the Institute for Human Genetics, Department of Medicine, University of California, San Francisco, CA, USA

¹⁴Royal National Orthopaedic Hospital, Stanmore, UK

¹⁵Department of Pediatrics, Klinikum Garmisch-Partenkirchen GmbH, Garmisch- Partenkirchen, Germany

¹⁶Department of Internal Medicine section Endocrinology, Amsterdam Bone Center, Amsterdam University Medical Centers, location VUmc, Amsterdam, the etherlands

¹⁷Paediatric Rheumatology, Red Cross Children's Hospital, University of Cape Town, Cape Town, South Africa

¹⁸Departments of Orthopaedic Surgery and Genetics, The Center for Research in FOP & Related Disorders, The Perelman School of Medicine of The University of Pennsylvania; and MedStar Georgetown Transplant Institute, Georgetown University School of Medicine, Washington, DC, USA

¹⁹Department of Endocrinology, Tongji Hospital, Shanghai Tongji University, Shanghai, China

²⁰Department of Medicine, Mayo Clinic, Rochester, MN, USA

Corresponding Author:

Frederick S. Kaplan, M.D.
Isaac & Rose Nassau Professor of Orthopaedic Molecular Medicine Chief, Division of Orthopaedic Molecular Medicine
Perelman School of Medicine The University of Pennsylvania
c/o Department of Orthopaedic Surgery Penn Musculoskeletal Center - Suite 600 3737 Market Street
Philadelphia, PA 19104
Tel: 215-294-9145
Fax: 215-222-8854
Email: [email protected]

Key Words: fibrodysplasia ossificans progressiva (FOP), heterotopic ossification, ACVR1, BMP pathway signaling, clinical trials

Running Title: Clinical Trials for FOP

Recent developments in clinical trials for fibrodysplasia ossificans progressiva (FOP; MIM # 135100) have left us feeling as if we are in the twilight zone – “that neutral territory somewhere between the real world and fairyland” as the author Nathaniel Hawthorne described [1,2]. On the one hand, we have emerging results from some clinical trials that inspire hope (NCT03312634; NCT03188666) [3, 4]; while on the other hand, the same trials have been paused due to the emergence of serious adverse events or concern for futility [5, 6]. The International Clinical Council on FOP (ICC) has monitored and will continue to monitor these occurrences with vigilance.

This is a critical time to reflect where we have been, where we are now, how we got to where we are now, and where we are going as a community, if indeed we can know. It is not a risk-free journey, and we have been reminded that there are obstacles along the path. But, neither is it a journey devoid of hope; quite the opposite, in fact.

The discovery of the FOP gene heralded the emergence of a new grammar for drug discovery in FOP and the explosion of interest and laser focus of the biopharmaceutical industry on the well-defined and evolutionarily-conserved bone morphogenetic protein (BMP) signaling pathway [7-11]. Like dominoes in descent, the FOP gene discovery enabled the development of genetically correct animal models of FOP – which has been instrumental in testing novel therapeutics for druggable targets [12, 13]. Animal models validated the dysregulated BMP signaling pathway in FOP, the pathophysiology of heterotopic ossification (HO) in FOP, and progenitor cells responsible for HO in FOP

[14-25]. Dramatic basic science discoveries coupled with a comprehensive understanding of the natural history of FOP and methodologies to detect early bone formation further fueled the advent of clinical trials [26-30]. The grammar of investigational drug discovery rapidly became a babble of promising new approaches that were rapidly cast on the stage of human clinical trials – a dazzling place to be for an ultra-rare condition that had existed in the backwaters of medicine for over three centuries and for which no approved treatment and no discernible hope previously existed. But beware of good news. As Shakespeare said, “Roses have thorns and silver fountains mud [31].”

While dramatic advances showed that the FOP gene discovery could enable identification of druggable targets, it also revealed that drug development would likely be constrained by an ancient and highly-conserved signaling pathway that was redundant and iterative thus making therapeutic specificity difficult [10, 11]. While the desired goal of targeting the dysregulated BMP signaling pathway in FOP is clearly the abrogation of HO, the BMP pathway is critically important in the maintenance and repair of nearly every major organ system, thus expanding the risks of collateral side effects of potentially therapeutic drugs [11]. In addition, there are important logistical considerations and constraints of model systems, not the least of which is that FOP mice are laboratory-raised, pathogen-free genetic clones and are not people with FOP, and thus do not inherently manifest either the immunological vitality or genetic variability that underlies both the range of potential benefits and the range of potential risks that human beings will inevitably display [32]. Thus, while translational studies are essential to enlighten the way forward, they in no way guarantee an unobstructed path.

Potential benefits and inherent risks need to be weighed - not just at the outset but continuously throughout a clinical trial. Aspirational outcomes of successful treatments may vary from one clinical trial to another based on the mechanism of action of the investigational drug and the pre-determined, primary outcome of a clinical trial. Possible long-term benefits of patient involvement in a clinical trial may theoretically include but are not limited to decreased flare-ups, decreased HO, preservation of joint mobility, retardation of joint degeneration, liberation of joints ankylosed with HO, pain relief, frequent medical monitoring, increased self- and FOP-awareness, improved quality of life, a pioneer spirit, contribution to a greater good or contribution to future generations.

Individual participation in a clinical trial must be balanced by a thoughtful consideration of potential benefits and risks. Clinical trials are not proven treatments, but rather an opportunity to determine if a potential therapy is effective and safe. Potential risks may vary from one clinical trial to another. These are assessed based on pre-clinical toxicology studies, phase-1 clinical trial results, or knowledge of the mechanisms of action of an investigational drug. However, these assessed risks may not be comprehensive and new risks may be identified when potential therapies are tested in a clinical trial. Common categories of risk include the inconvenience of participating in a clinical trial – especially during a pandemic, the uncertainty of knowing whether one is initially randomized to a placebo group or a treatment group, the occurrence of annoying or harmful side effects both anticipated and unanticipated, potential allergies to a drug, adverse drug reactions, non-response, resistance to possible therapeutic effects, intolerability of a drug, and worsening of FOP despite pre-clinical data that suggest the therapy in question may be helpful.

Every drug has side-effects, but with investigational drug development for FOP, the spectrum of side-effects may not be fully known until the drug is tested in FOP patients, despite extensive pre-clinical toxicology studies. Even approved and re-purposed drugs may have different side-effects in the FOP population than are seen when the same drug is used in other conditions. Potential risks can often be assuaged, but even with safety nets and firewalls in place, certain risks can elude prompt detection. And then, there are the “unknown unknowns” [33] – the unanticipated and unpredictable risks that arise out of nowhere and take everyone by surprise. Often these risks are relatively minor, but sometimes – to the consternation of all – they might be harmful or even fatal.

Our early foray into FOP clinical trials reminds us what we knew from the very beginning - that clinical trials are not proven treatments; they are human experiments, guided by the best available knowledge at the time the trial was designed. They have theoretical benefit and palpable risk that are spelled-out in informed consent. Informed consent is not just a quaint formality; it is a solemn requirement and an ongoing process at every step of the clinical trials journey. Further, patient safety is hard-wired into all clinical trials in the form of an independent Data Safety Monitoring Board (DSMB) comprised of 3-6 experts in various disciplines related to the study drug and trial design that monitors occurrences such as unexpected serious adverse events and can pause or stop a trial in its tracks if it detects an unforeseen problem that may be related to an investigational drug. A DSMB can also stop a clinical trial early if the beneficial effects are so overwhelming to suggest that continuation of the trial would not be necessary or if it was determined that the investigational drug is futile. Thus, the DSMB, the sponsor or regulatory authorities for that matter have the jurisdiction to pause or stop a clinical trial for any reason at any time. And, of course, the trial participant has the absolute right to bail-out at any time, for any reason, or for no expressed reason at all. As one sponsor observed, “There is not an endeavor on the planet that is more highly regulated than clinical trials [34].” Clinical trials are, after all, not proven treatments; not yet at any rate. Some may be. Some may never be. It is worth remembering.

As patients are bombarded by possibilities and choices – by good news and bad – where does that leave them? For the moment – in the twilight zone – somewhere between an old world of symptomatic management and a brave new world of therapeutic possibilities [35-37]. That ultimate gateway is possible only through clinical trials – and patients who embark on that journey are courageous pioneers. Patients and parents must always be aware that there are risks - some known and closely monitored – and some unknown and clearly unexpected – the “unknown unknowns” [33]. So, how should patients proceed? Obviously with caution, but not paralyzed by fear; obviously with hope, but also with respect for the unknown. Novel therapies can emerge only from an FOP community working together. Without clinical trials, there will be no approved treatments and all our efforts will be in vain.

So what is the take-home message? There are two. First, clinical trials are not proven treatments. They have the potential to become treatments if they prove efficacious and safe. They must be both. Each individual (or surrogate) must weigh the potential benefits and risks of enrolling in a clinical trial and decide for themselves if it is right for them - with ongoing informed consent as the guiding light; it is a deeply personal decision. Second, clinical trials are the only path to an approved treatment, and we all have an abiding hope and belief that well-designed and executed clinical trials will be the path that will lead there [30]. We are greatly encouraged that so many pharmaceutical companies are developing novel therapeutics for such a rare and complex disease as FOP - and that they are doing this carefully, responsibly and at great risk to themselves. Side-effects, adverse effects and even unanticipated effects will likely occur. Nobody wants them, but in every case they will be assiduously monitored and immediately investigated by the sponsors and researchers to determine if and how they are related to the investigational drug. And, if and when risks are identified that may be related to the investigational drug, appropriate risk management measures and mitigations will be incorporated into further iterations of the clinical trial to ensure ongoing patient safety. Scientists, doctors, patients, clinical research personnel, pharmaceutical companies and regulatory authorities will continue to work together to make this effort as safe, transparent and successful as possible. This vigilance to safety and transparency on everyone’s part will lead us together through the twilight zone.

In summary, clinical trials are painstaking processes that weigh potential benefits to the patient and society against potential harm to the individual enrolled. Clinical trials are a bold step into the future, along a path like no other - a path that is hopeful, but with obstacles, to be sure. But as someone famously said, “Obstacles along the path are not obstacles – they ARE the path [38].” That is our hope.

Acknowledgments

The authors thank the Center for Research in FOP & Related Disorders at the University of Pennsylvania and The Radiant Hope Foundation for supporting the International Clinical Council for FOP (ICC). FSK received support from the Isaac & Rose Nassau Professorship of Orthopaedic Molecular Medicine at the University of Pennsylvania. RJP received support from the Robert and Arlene Kogod Professorship and the Radiant Hope Foundation. MAM received funding from the Ian Cali FOP Clinical Scholarship.

Author Contributions

The editorial was conceived by FSK and RJP, written by FSK and revised and approved by all of the authors.

Conflict of Interest Statement

GB, CLDC, PD, EMWE, ECH, NH, FSK, RK, MAM, JCN, RJP, MDR and MAZ receive clinical trials research funding from Ipsen/Clementia Pharmaceuticals. RJD and RM are consultants for Ipsen/Clementia Pharmaceuticals.

MAZ is on the data safety monitoring board for Ipsen/Clementia Pharmaceuticals.

EMWE, ECH, RK, FSK, MAM, RJP and MDR receive clinical trials research funding from Regeneron Pharmaceuticals.

RM is a paid consultant for Regeneron Pharmaceuticals.

GB, CLDC, PD, EMWE, NH, ECH, FSK, RK, RM, JCN, RJP, MDR, CS, MAZ and KZ serve as unpaid volunteers on the IFOPA Medical Registry Advisory Board.

EMWE, ECH, RJP and FSK serve as unpaid volunteers on the FOP Biomarker Consortium.

ECH serves as an unpaid volunteer on the Fibrous Dysplasia Foundation Medical Advisory Board.

MDR is a consultant and/or speaker for Sanofi‐Genzyme, Shire, Alexion, Biomarin, Chiesi, Ipsen/Clementia Pharmaceuticals, and Regeneron Pharmaceuticals and receives clinical trial research support from Sanofi-Genzyme, Alexion and Enzyvant.

AC is a trustee of the Radiant Hope Foundation and trustee of the Ian Cali FOP Research Fund ‐ PENN Medicine ‐ Center for Research in FOP & Related Disorders, and is an unpaid volunteer with Ipsen/Clementia Pharmaceuticals Burden of Illness Advisory Group.

PD is an unpaid medical advisor for FOP Brazil. MAM and MAZ are nonpaid consultants for BioCryst.

EMWE is an advisor for AstraZenica and Ipsen Pharmaceuticals. ECH receives clinical trial support from Neurocrine Biosciences, Inc.

RK receives research support from UltraGenyx; is a paid consultant for Ipsen/Clementia Pharmaceuticals, Regeneron Pharmaceuticals, UltraGenyx, Internis, and Alexion; and is a nonpaid member of the Medical Advisory Board for the UK Brittle Bone Society.

All authors are active members of the International Clinical Council (ICC) on FOP.

References

1. Pignolo RJ, Shore EM, Kaplan FS. Fibrodysplasia ossificans progressiva: diagnosis, management, and therapeutic horizons. In Emerging Concepts in Pediatric Bone Disease. Pediatric Endocrinology Reviews. 10(S-2): 437-448, 2013
2. Delbanco A. Night terrors. The New York Review of Books 67(18): 28-30, 2020
3. Monostra M. Palovarotene potential therapeutic option for rare disabling bone disease. Endocrine Today. Sept. 7, 2020
4. Regeneron Press Release: Regeneron announces encouraging Garetosmab phase 2 results in patients with ultra-rare debilitating bone disease. Investor.Regeneron.com. Jan. 9, 2020
5. Bell J. Ipsen pauses studies of drug for rare bone disease. com. Jan 20, 2020
6. Vermes K. Regeneron hits pause on LUMINA-1 trial due to concerns with Garetosmab.com. Nov. 2, 2020
7. Shore EM, Xu M, Feldman GJ, Fenstermacher DA, Cho T-J, Choi IH, Connor JM, Delai P, Glaser DL, Le Merrer M, Morhart R, Rogers JG, Smith R, Triffitt JT, Urtizberea JA, Zasloff M, Brown MA, Kaplan FS. A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nature Genetics 38: 525-527, 2006
8. Kaplan, FS, Xu M, Seemann P, Connor JM, Glaser DL, Carroll L, Delai P, Fastnacht-Urban E, Forman SJ, Gillessen-Kaesbach G, Hoover-Fong J, Köster B, Pauli RM, Reardon W, Zaidi S-A, Zasloff M, Morhart R, Mundlos S, Groppe J, and Shore EM. Classic and atypical fibrodysplasia ossificans progressiva (FOP) phenotypes are caused by mutations in the bone morphogenetic protein (BMP) type I receptor ACVR1. Hum Mutat 30 (3): 379-390, 2008
9. Fishman MC, Porter JA. A new grammar for drug discovery. Nature 437:491- 493, 2005
10. Gomez-Puerto MC, Iyengar PV, García de Vinuesa A, Ten Dijke P, Sanchez- Duffhues G. Bone morphogenetic protein receptor signal transduction in human disease. J Pathol. 2019 Jan;247(1):9-20. doi: 10.1002/path.5170. Epub 2018 Nov 27
11. Wang RN, Green J, Wang Z, Deng Y, Qiao M, Peabody M, Zhang Q, Ye J, Yan Z, Denduluri S, Idowu O, Li M, Shen C, Hu A, Haydon RC, Kang R, Mok J, Lee MJ, Luu HL, Shi LL. Bone Morphogenetic Protein (BMP) signaling in development and human diseases. Genes Dis. 2014 Sep;1(1):87-105. doi: 10.1016/j.gendis.2014.07.005.
12. Chakkalakal SA, Zhang D, Culbert AL, Convente MR, Caron RJ, Wright AC, Maidment AD, Kaplan FS, Shore EM. An Acvr1 Knock-in mouse has fibrodysplasia ossificans progressiva. J Bone Miner Res 27:1746-1756, 2012
13. Chakkalakal S & Shore EM. Heterotopic ossification in mouse models of fibrodysplasia ossificans progressiva. Methods Mol Biol 1891: 247-255, 2019
14. Kaplan FS, Glaser DL, Shore EM, Pignolo RJ, Xu M, Zhang Y, Senitzer D, Forman SJ, Emerson SG. Hematopoietic stem-cell contribution to ectopic skeletogenesis. J Bone Joint Surg Am 89:347-357, 2007
15. Yu PB, Deng DY, Lai CS, Hong CC, Cuny GD, Bouxsein ML, Hong DW, McManus PM, Katagiri T, Sachidanandan C, Kamiya N, Fukuda T, Mishina Y, Peterson RT, Bloch KD. BMP type I receptor inhibition reduces heterotopic [corrected] ossification. Nat Med. 2008 Dec;14(12):1363-9. doi: 10.1038/nm.1888. Epub 2008 Nov
16. Shen Q, Little SC, Xu M, Haupt J, Ast C, Katagiri T, Mundlos S, Seemann P. Kaplan FS, Mullins MC, Shore EM. The fibrodysplasia ossificans progressiva R206H ACVR1 mutation activates BMP-independent chondrogenesis and zebrafish embryo ventralization. J Clin Invest 119(11): 3462-3472, 2009
17. Kaplan FS, Pignolo RJ, Shore EM. The FOP metamorphogene encodes a novel type I receptor that dysregulates BMP signaling. Cytokine Growth Factor Reviews 20:399-407, 2009
18. Shimono K, Tung WE, Macolino C, Chi AH, Didizian JH, Mundy C, Chandraratna RA, Mishina Y, Enomoto-Iwamoto M, Pacifici M, Iwamoto M. Potent inhibition of heterotopic ossification by nuclear retinoic acid receptor-γ agonists. Nat Med. 2011 Apr;17(4):454-60. doi: 10.1038/nm.2334. Epub 2011 Apr
19. Chaikuad A, Alfano I, Kerr G, Sanvitale CE, Boergermann JH, Triffitt JT, von Delft F, Knapp S, Knaus P, Bullock AN. Structure of the bone morphogenetic protein receptor ALK2 and implications for fibrodysplasia ossificans J Biol Chem 287:36990-36998, 2012
20. Culbert AL, Chakkalakal SA, Theosmy EG, Brennan TA, Kaplan FS, Shore Alk2 regulates early chondrogenic fate in fibrodysplasia ossificans progressiva heterotopic endochondral ossification. Stem Cells 32: 1289-1300, 2014
21. Hatsell SJ, Idone V, Wolken DM, Huang L, Kim HJ, Wang L, Wen X, Nannuru KC, Jimenez J, Xie L, Das N, Makhoul G, Chernomorsky R, D'Ambrosio D, Corpina RA, Schoenherr CJ, Feeley K, Yu PB, Yancopoulos GD, Murphy AJ, Economides AN. ACVR1(R206H) receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A. Sci Transl Med 7(303):303ra137, 2015
22. Hino K, Ikeya M, Horigome K, Matsumoto Y, Ebise H, Nishio M, Sekiguchi K, Shibata M, Nagata S, Matsuda S, Toguchida J 2015 Neofunction of ACVR1 in fibrodysplasia ossificans progressiva. PNAS doi/10.1073/pnas.1510540112, 2015
23. Kaplan FS, Pignolo RJ, Shore EM. Granting immunity to FOP and catching heterotopic ossification in the act. Semin Cell Dev Biol 49: 30-36, 2016
24. Wang H, Lindborg C, Lounev V, Kim JH, McCarrick-Walmsley R, Xu M, Mangivani L, Groppe JC, Shore EM, Schipani E, Kaplan FS, Pignolo RJ. Cellular hypoxia promotes heterotopic ossification by amplifying BMP signaling. J Bone Miner Res 31:1652-1665, 2016
25. Lees-Shepard JB, Yamamoto M, Biswas AA, Stoessel SJ, Nicholas SE, Cogswell CA, Devarakonda PM, Schneider MJ Jr, Cummins SM, Legendre NP, Yamamoto S, Kaartinen V, Hunter JW, Goldhamer DJ. Activin-dependent signaling in fibro/adipogenic progenitors causes fibrodysplasia ossificans Nat Commun. 2018 Feb 2;9(1):471. doi: 10.1038/
26. Pignolo RJ, Bedford-Gay C, Liljesthrom M, Durbin-Johnson BP, Shore EM, Rocke DM, Kaplan FS. The natural history of flare-ups in fibrodysplasia ossificans progressiva: a comprehensive global assessment. J Bone Miner Res 31:650-656, 2016
27. Eekhoff EMW, Botman E, Coen Netelenbos J, de Graaf P, Bravenboer N, Micha D, Pals G, de Vries TJ, Schoenmaker T, Hoebink M, Lammertsma AA, Raijmakers PGHM. [18F]NaF PET/CT scan as an early marker of heterotopic ossification in fibrodysplasia ossificans progressiva. Bone. 2018 Apr;109: 143- 146. doi: 10.1016/j.bone.2017.08.012. Epub 2017 Aug
28. Pignolo RJ, Durbin-Johnson BP, Rocke DM, Kaplan FS. Joint -specific risk of impaired function in fibrodysplasia ossificans progressiva (FOP). Bone 109:124- 133, 2018
29. Pignolo R.J., Baujat G, Brown MA, DeCunto C, DiRocco M, Hsiao EC, Keen R, Al Mukaddam M, LeQuan Sang K-H, Wilson A, White B, Grogan DR, Kaplan FS. Natural history of fibrodysplasia ossificans progressiva: cross-sectional analysis of annotated baseline phenotypes. Orphanet J. Rare Diseases. 2019; 14: 98. https://doi.org/10.1186/s13023-019-1068-7
30. Hsaio EC, DiRocco M, Cali A. Zasloff M, Al Mukaddam M, Pignolo R, Grunwald Z, Netelenbos C, Keen R, Baujat G, Brown MA, Cho T-J De Cunto C, Delai P, Haga N, Morhart R, Scott C, Zhang K, Diecidue RJ, Friedman CS, Kaplan FS, Eekhoff EMW. Special considerations for clinical trials in fibrodysplasia ossificans progressiva. Br J Clin Pharmacol 85 (6): 1119-1207, 2019
31. Shakespeare Sonnet XXXV
32. Hamilton SE, Badovinac VP, Beura LK, Pierson M, Jameson SC, Masopust D, Griffith TS. New insights into the immune system using dirty mice. J Immunol 205(1): 3-11, 2020
33. Rumsfeld D.. “There are known knowns.” Wikepedia
34. Desjardins C. Attributed
35. Kaplan FS, Al Mukaddam M, Baujat G, Brown M, Cali A, Cho T-J, Crowe C, DeCunto C, Delai P, Diecidue, R, Di Rocco M, Eekhoff EMW, Friedman C, Grunwald Z, Haga N. Hsiao E, Keen R, Kitterman J, Levy C, Morhart R, Netelenbos C, Scott C, Shore EM, Zasloff M, Zhang K, Pignolo RJ. The medical management of fibrodysplasia ossificans progressiva: current treatment considerations. Proc Intl. Clin. Council FOP 1:1-111, 2019
36. Pignolo RJ & Kaplan FS. Druggable targets, clinical trial design and proposed pharmacological management in fibrodysplasia ossificans progressiva. Expert Opinion Orphan Drugs https://doi.org/10.1080/21678707.2020.1751122
37. Wentworth KL, Masharani U, Hsiao EC. Therapeutic advances for blocking heterotopic ossification in fibrodysplasia ossificans progressiva. Br J Clin Pharmacol. 2019 Jun;85(6):1180-1187. doi: 1111/bcp.13823.
38. Lotter J. com