Learn more about the FOP Talks given by FOP experts from around the world
On October 13-14, the world’s leading experts in FOP gathered in Sardinia, Italy for the 2017 Drug Development Forum (DDF). The 2017 DDF attracted researchers from 21 different countries to discuss their latest research findings, to solve key issues in FOP drug development, and to strengthen ties among a growing network of collaborating labs across the world. The 2017 DDF was the third meeting of its kind (the DDF was previously held in 2014 and 2016) and has grown with increased interest and participation from the FOP research community. This year’s DDF, which was co-hosted by the IFOPA and FOP Italia, attracted more than 170 researchers, clinicians, biotech and pharmaceutical company representatives, advocates and patients. We were also excited to meet and welcome many new researchers and clinicians from China, India, Russia and South Korea.
Over 30 FOP “talks” were given during the two-day meeting and focused on wide-ranging topics from basic FOP biology to new therapeutic approaches to updates in FOP clinical development. Throughout the DDF, there was plenty of discussion that provided a springboard to advance the collective understanding of FOP, and to generate new hypotheses, questions and avenues of research to pursue. Many at the Forum remarked how much progress has been made since the last DDF in Boston, MA. John B. Shepard, Ph.D., from the University of Connecticut, reflected how “it's amazing to see the field of FOP research advance by leaps and bounds on a yearly basis.” There are now three drugs in clinical development and our understanding of FOP is accelerating.
This year’s DDF featured two panel sessions. During the first panel, Forum attendees heard from seven people living with FOP. The panelists shared their experiences about living with FOP as well as their hopes for future treatments. During the following day, there was a panel of physicians, pharmaceutical representatives and regulatory participants that discussed current and future challenges facing FOP drug development. During the one-hour session, the panel covered a broad range of topics, including clinical trial endpoints and the challenges of trial enrollment, accelerating drug development timelines, and surgical considerations for FOP.
Beyond providing a forum for exchanging the latest findings and ideas, the 2017 DDF was also successful in strengthening old networks and forging new research collaborations. Collaborations formed at prior DDFs were evident as presenters highlighted their cross-laboratory research findings from this past year. Dr. Ben Levi at the University of Michigan noted, “There is no better way to advance science than to bring together patients, scientists and pharmaceutical companies. It’s so great to catch
up with friends who now feel like family.”
FOP presentations were given across five talk sessions, grouped by similar topics. Abbreviated summaries from these talks are highlighted below. Watch for summary slides to be released in the near future.
FOP Talk 1: Clinical Investigation of FOP
It is a remarkable time for the FOP community with three drugs in clinical investigation for the treatment of FOP. This session highlighted the development plans of these three therapies, plus the results of a case report series from Dr. Kaplan on the use of imatinib.
- Dr. Donna Grogan (Clementia Pharmaceuticals) with Dr. Fred Kaplan (University of Pennsylvania) highlighted Clementia’s palovarotene Phase 2 results, as well as their plans to initiate the pivotal Phase 3 trial. The Phase 3 trial will soon begin enrolling 80 people (age > 4) across 18 clinical sites in 14 countries. Trial details are now on clinicaltrials.gov.
- Dr. Xiaobing Qian (Regeneron Pharmaceuticals) announced further details of their Phase 2 trial of REGN2477, an anti-Activin A antibody. The Phase 2 trial will initiate in Q4 2017 in up to 40 individuals with FOP and will investigate the safety, tolerability in adult males and females with FOP and effects of REGN2477 on heterotopic ossification (HO). Trial details are now on clinicaltrials.gov.
- Dr. Junya Toguchida of Kyoto University confirmed the details of a rapamycin trial in Japan, which will enroll 20 individuals with FOP across four Japanese sites. This 52-week trial has already begun enrolling trial participants.
- Dr. Fred Kaplan with the University of Pennsylvania provided the rationale and clinical observations from a seven patient case report on the use of imatinib mesylate in FOP. It was observed that six of the FOP children had a decrease in flare-up
FOP Talk 2: Receptor Targeting in FOP
Although FOP is caused by a single defect in one receptor (ACVR1), four different therapeutic approaches were highlighted in this session as potential ways to silence the underlying disease pathology.
- A new approach to treating FOP was highlighted by Dr. Takenobu Katagiri from Saitama Medical University in Japan. Dr. Katagiri showed early data that anti-ALK2 antibodies can bind the ACVR1 receptor and inhibit (HO) formation. A lead candidate, named “DaVinci,” has been selected.
- Dr. Jay Groppe (Texas A&M University College of Dentistry) presented his innovative work on novel (i.e. new) ways to stop new bone growth by destabilizing the ALK2 receptor. The IFOPA will be funding Dr. Groppe’s research in 2018 through a FOP Competitive Research Grant funded by Joshua's Future of Promises.
- The kinase inhibitor, saracatinib, was highlighted as a potential therapeutic agent by Drs. Alex Bullock (University of Oxford) and Paul Yu (Harvard Medical School and Brigham and Women’s Hospital). Saracatinib was shown in R206H mice to prevent the formation of new HO and to prevent the re-occurrence of HO following surgery. Further clinical work of saracatinib is being considered.*
- Dr. Alex Bullock (University of Oxford) shared insights on how the ALK2 receptor gains function and how an allosteric inhibitor could selectively lock the FOP ACVR1 receptor into an inactive state.*
FOP Talk 3: Building the Foundation for Clinical Advancement
While the current clinical landscape in FOP is encouraging, challenges await future drug developers as they begin planning their development strategies. The topics in this session explored foundational needs for future clinical trials.
- Dr. Bob Pignolo (Mayo Clinic) showed how patient-reported mobility assessments (PRMA) correlates with physician-reported cumulative analogue joint involvement scale (CAJIS) scores. The PRMA, CAJIS, and joint specific survival curves could be used as markers of FOP disease progression for future clinical trials.
- 18F Na PET imaging was highlighted by Dr. Marelise Eekhoff at the VU University Medical Center (VUmc) as a sensitive clinical tool for identifying early disease activity. The PET will be utilized in Regeneron’s Phase 2 REGN2477 trial.
- The need for biomarkers of disease progression has led Dr. Ed Hsiao of University of California, San Francisco (UCSF) to assess levels of inflammatory cytokines and macrophages in FOP. Dr. Hsiao has found abnormal monocyte levels and increased inflammatory markers in FOP.
- Dr. Paul Yu (Harvard Medical School and Brigham and Women’s Hospital) studied the impact of exercise in tendon and joint ossification, as well as the different phenotypes of tissue specific progenitor cells. Voluntary exercise prevents severe HO and delays mild HO in R206H mice.*
- The natural course of disease is being investigated in Clementia’s Natural History Study (NHS). Dr. Ed Hsiao (UCSF) presented data showing the more common medical symptoms in FOP, including hearing loss and restricted chest
expansion. HO volume as measured by whole body CT is sensitive to disease progression over one to two years and could be an appropriate clinical endpoint for an investigational agent.
- There have been limited robust studies looking at the prevalence rates of FOP. Dr. Genevieve Baujat (Necker Hospital) showed a higher prevalence than previously reported -- 1.36 per million people -- in France.
Talk 4: New Therapeutic Approaches in FOP
Researchers are looking for new approaches and compounds that may be efficacious in FOP. This session looked at the latest efforts and discoveries in finding novel therapeutic options for FOP.
- Dr. Yuji Mishina (University of Michigan School of Dentistry) presented the therapeutic approach of inhibiting and reactivating a signaling enzyme called TAK1. Inhibiting TAK1 mitigates HO in a burn-trauma mouse model and reduced
HO volume in a Q207D mouse model. Reactivation of TAK1 impacts cell differentiation and may be advantageous during wound repair.
- Antisense oligonucleotide (AON) therapy has been successfully used in other rare diseases, such as spinal muscular atrophy (SMA). Dr. Toshifumi Yokota (University of Alberta) presented data on AONs that could preferentially target the FOP gene products.*
- Upon screening nearly 1,000 FDA-approved compounds, Dr. Dimitra Micha (VUmc) has identified 27 compounds that inhibit osteogenic mineralization in FOP fibroblasts.*
- Dr. Ben Levi at the University of Michigan highlighted the latest research findings with rapamycin. In a FOP mouse model, rapamycin was shown to prophylactically prevent HO, mitigate muscle fibrosis, and prevent post-surgical HO formation.
Talk 5: Disease Mechanisms with Potential Impact for Future Drug Development
Understanding the underlying disease mechanisms of FOP will help build the scaffolding for future treatments and will optimize existing clinical care. This session featured six presentations from researchers advancing our understanding of FOP biology.
- Dr. Aris Economides (Regeneron) looked at whether one can predict where a lesion will arise, before radiographic evidence. Increased and sustained inflammation (and macrophage infiltration) in FOP mice correlates with HO progression.
- The role of osteoclast involvement in FOP is being investigated at the Academic Center for Dentistry in Amsterdam (ACTA). Ton Schoenmaker showed differences in osteoclast formation between control and FOP fibroblasts.
- Dr. Silvia Brunelli from the University of Milano Bicocca, School of Medicine and Surgery shared data on the role of macrophages in determining the fate of endothelium-derived progenitor cells. Depleting macrophages leads to an
increase in bone volume and density in mouse model.
- The team at the University of Connecticut looked extensively at identifying and characterizing the role of fibro/adipogenic progenitors (FAPs) in FOP pathogenesis. Through bioluminescence and uCT imaging, Dr. John B. Shepard showed the link between Activin A and a sustained growth and survival of FAPs in FOP mice.
- Dr. Laura Silvestri from the San Raffaele Scientific Institute, presented on iron hemostasis regulation and questioned whether momelotnib could be used in treating FOP (as well as other forms of anemia).
- Dr. Dan Perrien from Vanderbilt University shared data showing that macrophages are increased in early lesions and that FOP macrophages may have increased sensitivity toward an anti-inflammatory state.
*Funded through the IFOPA FOP Competitive Research Grant program.