Issued: February 23, 2026
EDITORIAL
The Twilight Zone: Between Disappointment and Hope in Clinical Trials for FOP
From The International Clinical Council on FOP (ICC)
Frederick S. Kaplan1, Mona Al Mukaddam2, Javier Bachiller3, Genevieve Baujat4, Staffan K. Berglund5, Amanda Cali6, Angela M. Cheung7, Tae-Joon Cho8, Carmen L. De Cunto9, Patricia Delai10, Robert J. Diecidue11, Elisabeth M. W. Eekhoff12, Lisa Friedlander13, Clive Friedman14, Zvi Grunwald15, Nobuhiko Haga16, Alberto Hidalgo-Bravo17, Edward C. Hsiao18, Richard Keen19, Jung Min Ko20, Vrisha Madhuri21, Rolf Morhart22, J. Coen Netelenbos23, Johannes Roth24, Christiaan Scott25, Raphaella Stander26, Clemens Stockklausner27, Xiaobing Yu28, Michael A. Zasloff29, Keqin Zhang30, and Robert J. Pignolo31
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, and The Center for Research in FOP & Related Disorders, The Perelman School of Medicine of The University of Pennsylvania. Philadelphia, PA, USA
3Department of Rheumatology, Hospital Universitario Ramón y Cajal. Universidad de Alcalá. Madrid, Spain
4Centre de Référence Maladies Osseuses Constitutionnelles, Departement de Génétique, Hôpital Necker-Enfants Malades, Institut Imagine. Paris, France
5Department of Clinical Sciences, Pediatrics, Umeå University. Umeå, Sweden
6Radiant Hope Foundation. Mountain Lakes, NJ, USA
7Divisions of General Internal Medicine and Endocrinology and Metabolism, Department of Medicine, and Joint Department of Medical Imaging, University Health Network; Centre of Excellence in Skeletal Health Assessment, University of Toronto. Toronto, Ontario, Canada
8Division of Pediatric Orthopaedics, Seoul National University Children's Hospital. Seoul, South Korea
9Pediatric Rheumatology Section, Department of Pediatrics, Hospital Italiano de Buenos Aires. Buenos Aires, Argentina 3
10Hospital Israelita Albert Einstein, Instituto de Ensino e Pesquisa. São Paulo-SP, Brazil
11Sidney Kimmel Medical College, Thomas Jefferson University. Philadelphia, PA, USA
12Department of Internal Medicine Section Endocrinology, Amsterdam Bone Center, Amsterdam University Medical Centers, Location VUmc. Amsterdam, the Netherlands
13Department Reference Center for Rare Diseases – Craniofacial Malformations and Clefts, Department of Maxillofacial Surgery, Necker–Enfants Malades Hospital, Imagine Institute. Paris, France
14Schulich School of Medicine and Dentistry, Pediatric Oral Health and Dentistry. London, Ontario, Canada
15Department of Anesthesiology, Thomas Jefferson University. Philadelphia, PA, USA
16Department of Rehabilitation Medicine, National Rehabilitation Center for Persons with Disabilities, 4-1 Namiki, Tokorozawa City. Saitama, Japan
17Department of Genomic Medicine, Instituto Nacional de Rehabilitación. Mexico City, Mexico
18Division of Endocrinology and Metabolism, and the Institute for Human Genetics, Departments of Medicine and Orthopaedics, University of California. San Francisco, CA, USA
19Royal National Orthopaedic Hospital. Stanmore, UK
20Division of Clinical Genetics, Department of Pediatrics, Seoul National University Children's Hospital. Seoul, South Korea 4
21Department of Paediatric Orthopaedics, Amara Stem Cell and Molecular Research Centre. Amara Hospital. Tirupati, India
22Department of Pediatrics, Klinikum Garmisch-Partenkirchen. Garmisch-Partenkirchen, Germany
23Department of Internal Medicine Section Endocrinology, Amsterdam Bone Center, Amsterdam University Medical Centers. Amsterdam, the Netherlands
24Center for Rare Diseases and Pediatric Rheumatology, Children’s Hospital of Central Switzerland and Cantonal Hospital of Lucerne. Lucerne, Switzerland
25Department of Pediatrics, Division of Dermatology and Rheumatology, University of Ottawa. Ottawa, Ontario, Canada
26University of Cape Town, Clinical Research Centre. Cape Town, South Africa
27Department of Pediatrics, Klinikum Garmisch-Partenkirchen. Garmisch-Partenkirchen, Germany
28Department of Anesthesia and Perioperative Care, Division of Pain Medicine, Center for Pain Medicine. University of California, San Francisco, USA
29Georgetown University School of Medicine. Washington, DC, USA
30Department of Endocrinology, Tongji Hospital, Shanghai Tongji University. Shanghai, China
31Department of Medicine, Mayo Clinic. Rochester, MN, USA
Corresponding Author:
Frederick S. Kaplan, MD
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, clinical trials
Running Title: Clinical Trials for FOP
Developments in clinical trials for fibrodysplasia ossificans progressiva (FOP) have left us feeling as if we are in the twilight zone – “that middle ground between light and shadow” as the screenwriter Rod Serling described [1, 2]. On the one hand, we have emerging results from some clinical trials that inspire hope; while on the other hand, disappointment prevails as some clinical trials have been stopped due to futility or the emergence of serious adverse events [3-7].
This is a critical time to reflect, revisit, and remind us where we have been, where we are now, and where we are going as a community. It is not a risk-free journey. 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 of the pharmaceutical industry on the bone morphogenetic protein (BMP) pathway [8-10]. The FOP gene discovery enabled the development of animal models of FOP – which have been instrumental in testing novel and repurposed drugs. Animal models validated the FOP gene discovery, the pathway of heterotopic ossification (HO) in FOP, and the cells responsible for HO in FOP. Dramatic basic science discoveries coupled with a comprehensive understanding of the natural history of FOP further fueled the advent of clinical trials - a dazzling place to be for an ultra-rare condition like FOP that had existed in the backwaters of medicine for over three centuries and for which no approved treatment and no discernible hope previously existed [11].
While the FOP gene discovery enabled identification of druggable targets, it also revealed that drug development was constrained by the fact that the FOP gene is critically important for the maintenance and repair of nearly every major organ system, thereby expanding the risks of side effects from potentially therapeutic drugs [11].
In addition, there are important considerations and constraints of animal models, 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 manifest either the immunological vitality or genetic variability of human beings. Thus, while studies in FOP mice do not guarantee an unobstructed path in clinical trials, they are essential to enlighten the way forward.
Potential benefits and risks need to be assessed continuously throughout a clinical trial. Possible long-term benefits of involvement in a clinical trial may include decreased flare-ups, decreased HO, preservation of joint mobility, slowing 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, and contribution to future generations.
Common categories of risk include the inconvenience of participating in a clinical trial, 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. All of these can occur despite pre-clinical data that suggest the therapy in question may be helpful.
As in any condition, the spectrum of side-effects induced by an investigational drug may not be fully known until the drug is tested in FOP patients, despite extensive pre-clinical 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 reduced, but even with safety nets and firewalls in place, certain risks can elude prompt detection. And then, there are the “unknown unknowns” - the unanticipated and unpredictable risks that arise out of nowhere and take everyone by surprise [12]. Often these risks are relatively minor, but sometimes – to the consternation of all – they might be harmful or even fatal.
Clinical trials are not proven treatments, but rather an opportunity to determine if a potential therapy is safe and effective. Potential benefits and risks vary from one clinical trial to another. This balance is determined based on pre-clinical studies, phase-1 clinical trial results, and knowledge of how the drug to be tested works. However, these possible benefits and risks may not be comprehensive and new benefits and risks may be identified when a drug is tested in a clinical trial. 9
The stubborn fact is that nearly 75% of all investigational drugs fail at the phase-2 clinical trial stage [13]. There are many reasons why a drug may not reach efficacy in a clinical trial: the primary endpoints may not reflect the main activity of the drug in humans, there may be discrepancies between the animal models used to validate the drug and the variability and complexity of the human disease, the endpoint may not be the correct assessment, or there may be inadequate sample size. Also, despite using the best predictions possible, translating dosing from animal studies to humans is difficult. There may be insufficient dose of the study drug to adequately neutralize the target, there may be a narrow therapeutic window between potential efficacy and toxicity of the study drug thus limiting the doses that can be tested safely, there may be substantial variation between individuals in the metabolism of the study drug, or differences in threshold effects of the drug that are necessary to neutralize the intended target at various stages of the disease. Studies may also have insufficient recruitment, differences in the characteristics between the placebo group and the treatment group that cloud the results, dropout from the trial, poor adherence to the drug, unaccounted protocol deviations during the trial, or statistical issues with the analysis of the data. And, it is possible that the investigational drug simply does not work in humans. Some issues may be anticipated and addressable during the planning stages of a trial; others may not be.
Despite these caveats, patient safety is hard-wired into all interventional clinical trials in the form of an independent Data Safety Monitoring Board (DSMB) comprised of three to five experts in various disciplines related to the study drug and trial design. The DSMB 10 monitors occurrences such as unexpected serious adverse events and can pause or stop a trial if they detect 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 as to suggest that continuation of the trial would not be necessary or if it was determined that the investigational drug is futile. The DSMB, the sponsor, or regulatory authorities have the authority to pause or stop a clinical trial for any reason at any time. And, importantly, the trial participants have 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 [14].” Clinical trials are, after all, not proven treatments. But, if positive results are found, some investigational drugs may become treatments. There is hope.
An important point to consider in assessing one’s own outcome compared to others in a clinical trial is that FOP progression has a highly variable and unpredictable course, and flare-ups and new HO can occur intermittently and often without a clear trigger. Some people with FOP may remain relatively stable for long periods, while others experience more frequent or more active flare-ups and HO. Thus, what appears to be an improvement during a clinical trial may reflect a naturally quieter phase of FOP rather than a true treatment effect, while continued flare-ups may still occur despite therapy in those with more active disease. This natural variability makes it scientifically challenging to determine whether differences observed between patients are due to the drug itself or to the underlying course of the condition. For this reason, sponsors and regulators look for consistent and reproducible benefit across groups, rather than improvement in isolated individuals. Trials may be stopped if pre-defined efficacy endpoints such as meaningful reductions in new HO are not met, even when some individuals experience improvement. If a study drug fails to meet efficacy, there are likely to be individuals in a clinical trial who are distraught over the discontinuation of the drug. From their perspective the drug was working since, during treatment, their FOP was quieted into apparent remission. Regardless, the drug cannot be approved if it does not meet pre-defined efficacy standards and thus the sponsor has no incentive to expend further resources on it. As to whether the study drug was actually working in a subset of patients - or whether their disease fluctuated in synchrony with the treatment, we may only speculate.
Even when a clinical trial has been successfully completed, a drug has been approved, and individuals start using the drug in the real world, unanticipated issues may surface. This is especially true in rare conditions where relatively small numbers of patients are studied prior to approval. 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, efficacy, and transparency on everyone’s part even after a drug has been approved will lead us together through the twilight zone.
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. Futility, side-effects, adverse effects and even unanticipated effects may unfortunately occur. Nobody wants them, but in every case they will be monitored and investigated by the sponsors and researchers. 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.
Each individual (or surrogate) must weigh the potential benefits and risks of participating 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. Clinical trials are the only path to an approved, safe, and scientifically validated treatment. We all have an abiding hope and belief that well-designed and executed clinical trials will be the path that will lead us there. Our foray into FOP clinical trials reminds us what we knew from the very beginning - that clinical trials are not proven treatments; they are human investigations, guided by the best available knowledge at the time the trial was designed [15].
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 [16]. That ultimate gateway is possible only through clinical trials – and patients who embark on that journey are courageous pioneers. 13
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 effective and safe. They must be both. Second, novel therapies can emerge only from a FOP community working together and understanding that clinical trials are absolutely necessary to find safe and effective therapies.
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 [17].” That is our hope. 14
Acknowledgements
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).
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
Updated conflict of interest statements for all authors can be found on the International Clinical Council on FOP (ICC) website (www.iccfop.org)
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