Learn more about FOP Talks given by experts from around the world
The International Fibrodysplasia Ossificans Progressiva Association (IFOPA) held its fourth Drug Development Forum (DDF) on November 13-14, 2019 in Orlando, Florida. The 2019 DDF attracted participants from 19 different countries around the world. The IFOPA hosts this symposium to bring FOP experts together to discuss the latest research, solve drug development challenges and to strengthen the growing network of research collaborations across the globe. This year’s DDF brought together approximately 160 researchers, clinicians, biotech and pharmaceutical company representatives, regulators, advocates and people living with FOP. We were also excited to meet with and welcome many new academic and industry researchers as well as new FOP clinicians to the Forum.
The 2019 DDF keynote speaker was Dr. Emil Kakkis, President and CEO of the pharmaceutical company Ultragenyx and President of the nonprofit EveryLife Foundation for Rare Diseases. Dr. Kakkis highlighted his experience developing 10 treatments for rare diseases. During this talk, several pragmatic development recommendations for FOP were discussed, including the integration of imaging and biomarkers into development plans as well as blinded-start study designs.
Dr. Jacqueline Karp, FDA Division of Bone, Reproductive and Urologic Products, participated in the 2019 DDF and addressed some of the key regulatory challenges in developing rare diseases treatments. Dr. Karp also participated in a moderated panel session.
There were two panel session at this year’s DDF. During the first panel session, eight people living with or impacted by FOP shared their personal stories. During the moderated session, topics around clinical trial participation and expectations for future treatments were discussed. During the second day of the Forum, there was a panel session that included pharmaceutical and regulatory representatives. During the session, the panel covered a broad range of development topics, including clinical trial endpoints, the challenges of trial enrollment with multiple clinical trials, and accelerating drug development timelines for FOP.
Following the conclusion of the DDF, the IFOPA hosted a scientific poster reception for attendees of both the Drug Development Forum and the FOP Family Gathering. It was a wonderful opportunity for FOP families to interact with researchers and hear firsthand how the FOP research field is advancing.
With six drugs in clinical trials for FOP, this was an exciting time to hold this year’s DDF. During the two-day meeting, 35 FOP presentations were given, with a focus on a wide-range of research and development topics. Throughout the DDF, there was plenty of discussion during the moderated Q&A sessions that sparked new ideas and also challenged our current understanding of FOP. It was remarkable to see how much progress has occurred since our last DDF meeting in 2017.
FOP presentations were given across six “talk” sessions, grouped by similar topics. Abbreviated summaries from these talks are highlighted below.
FOP Talks 1: Advances in Clinical Investigation of FOP
This session of the DDF highlighted the latest advances in clinical research for FOP.
- Dr. Timothy LaBranche from Blueprint Medicines discussed the progress of BLU-782, which is a selective ALK2 inhibitor being developed for FOP. Preclinical data was presented showing the effect of BLU-782 on heterotopic ossification (HO) formation and early edema in R206H mice. The BLU-782 program completed a Phase 1 trial in healthy volunteers and the investigational drug was shown to be well tolerated. Get BLU-782 Trial details.
- The natural course of FOP is being investigated in a Natural History Study (NHS) conducted by Clementia, an Ipsen company. Dr. Rose Marino presented 1-year outcomes data from the NHS and highlighted correlations between flares and HO formation. The data showed a significant percentage of reported flare-ups, which were not followed by HO. Additionally, during the same 12-month period, there were a percentage of patients who developed new HO that was not preceded by a flare. Notable changes on physical function questionnaires (e.g. CAJIS) were not observed during this period. Get MOVE Trial details.
- Dr. Alex Bullock, University of Oxford, presented the study rationale and plans for the clinical trial, STOPFOP (“Saracatinib trial TO Prevent FOP”). STOPFOP will assess the safety and efficacy of the repurposed drug, saracatinib, in the treatment of FOP. At the last DDF meeting, preclinical data was presented that showed how the investigational drug acts as a potent inhibitor of the ALK2 receptor and highlighted data in physiologically-relevant FOP mouse models. The trial will be conducted at three sites in Europe (The Netherlands, United Kingdom and Germany) and is expected to enroll patients in 2020.
- A FOP patient recently underwent surgery at the Amsterdam University Medical Center (VUmc). Dr. Marelise Eekhoff described the medical necessity for this case report and shared a video which documented the preparation and successful outcomes from the surgery. The video documented interviews with the patient and the surgeon prior to and following the surgery.
FOP Talks 2: Clinical Concepts for Trial 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 clinical concepts for future trials.
- FDA representative, Dr. Jacqueline Karp, discussed the regulatory challenges in rare disease drug development and FDA considerations. Some of the common challenges unique to rare diseases include a limited characterization of the natural history, a lack of established clinical trial endpoints, use of adequate control groups and a limited number of trial subjects. Dr. Karp provided suggestions on how to mitigate some of these challenges in FOP.
- Dr. Robert Pignolo, Mayo Clinic, shared biomarker data collected from 44 FOP patients. Using multiplex analyses of plasma-soluble analytes, Dr. Pignolo highlighted one biomarker which was shown to be elevated in FOP compared to age and sex-matched controls. This protein has a role in the regulation of bone metabolism and has been associated with osteogenesis. A second biomarker, which gets activated during inflammation, was shown to be significantly correlated with flare-up activity.
- An update on the Global Burden of FOP survey was provided by Dr. Ali Majdi from Ipsen. The survey is being conducted to assess the impact of FOP on the quality of life of patients and their caregivers, on healthcare utilization, as well as the impact on educational and employment opportunities. The global online survey will be announced to the FOP community in 2020.
- 18F-NaF PET/CT imaging was highlighted by Dr. Marelise Eekhoff at the Amsterdam University Medical Center (VUmc) as a promising modality to identify asymptomatic, chronically progressive HO lesions. Dr. Eekhoff presented case reports of patients, which showed the correlation between early metabolic activity measured on PET and the resulting HO formation measured by CT. The 18F-NaF PET/CT has the potential to serve as a biomarker of disease progression in FOP clinical trials.
- Dr. Esmée Botman from the Amsterdam University Medical Center (VUmc) presented baseline 18F-NaF PET/CT imaging data from 44 FOP patients enrolled in Regeneron’s LUMINA-1 Phase 2 clinical trial. Lesions were observed in 44/44 (100%) subjects, suggesting that metabolically-active HO may occur independently from clinically diagnosed flare-ups. Ultimately, longitudinal clinical data is needed to better understand the correlation between 18F-NaF PET/CT signals and HO progression on CT. Get LUMINA-1 Trial details.
FOP Talks 3: Receptor Targeting in FOP
Several different therapeutic approaches were highlighted in this session as potential ways to silence FOP.
- Dr. Daniel Perrien from Emory University tackled the question of whether an ALK2 kinase inhibitor (VU002) could reduce HO if treatment initiation was delayed. Results from this research in R206H mice showed that the window to initiate treatment with ALK2-selective inhibitory compounds may extend only into the early stages of mineralization. Dr. Perrien’s data suggests that continued expansion of HO after delayed treatment in FOP mice may be independent of ALK2 signaling.
- A computational platform has been developed by Dr. Kumar Ashtekar at Yale University for designing dual inhibitors that can simultaneously engage their targets and increase protein-protein interactions. Employing this strategy, the dual inhibitor approach depicts a proof-of-concept for designing mutant selective inhibitors for ALK2.
- Dr. Alex Bullock, University of Oxford, described an open science model to organize public and philanthropic-funded research to develop novel treatments for rare disorders. Dr. Bullock reviewed drug screening results, the application of novel cell assays, as well as drug potency for different ALK2 mutations.
- The research team at Navrogen has developed a novel approach to treating FOP by developing an antibody that targets the FOP receptor and an immune component believed to contribute to the underlying cause of FOP flare-ups. Dr. Nicholas Nicolaides presented the rationale for this bispecific approach and highlighted preclinical efficacy data in FOP mice models.
- Keros Therapeutics is developing KER-047 as an orally delivered treatment for people with FOP. KER-047 is a potent and selective ALK2 kinase inhibitor and has demonstrated efficacy in multiple animal models of heterotopic ossification, including the R206H mouse model. Dr. Jas Seehra from Keros discussed the Phase 1 clinical trial which was initiated in healthy volunteers to evaluate the safety and tolerability of KER-047. Completion of this study will enable the initiation of a safety and efficacy study in patients in 2020.
FOP Talks 4: New Therapeutic Approaches in FOP
This session of FOP presentations looked at the latest efforts and discoveries in finding novel therapeutic options for FOP.
- TGF-beta Activating Kinase1 (TAK1) is a MAP3K that is activated by BMP receptors and is involved in SMAD-independent signaling pathways. Dr Yuji Mishina at the University of Michigan found that phosphorylated TAK1 is highly present at the sites of trauma-induced HO; genetic ablation of Tak1 significantly mitigates trauma-induced HO. In R206H mouse models, intraperitoneal injection (IP) administration of a TAK1 inhibitor significantly reduces HO formation.
- Antisense oligonucleotide (AON) therapy has been successfully used in other rare diseases, such as spinal muscular atrophy (SMA). Dr. Toshifumi Yokota, University of Alberta, showed that gapmer antisense oligonucleotides could efficiently knock down disease-causing mutant transcripts of ALK2/ACVR1 in-vitro. Administered gapmer antisense oligonucleotides were also shown to reduce the size of HO in FOP mice.
- Dr. Takenobu Katagiri from Saitama Medical University identified a single amino acid residue in the extracellular domain of ALK2 that is essential for the binding and inhibition by DaVinci, an anti-ALK2 antibody. DaVinci blocked BMP signaling in vitro and inhibited HO in wild-type mice. However, DaVinci enhanced HO in FOP mice, which expressed the R206H mutation. Dr. Katagiri found that human and mouse R206H ALK2 show different responses to DaVinci due to a single amino acid difference in the kinase domain.
- Dr. Masahiro Iwamoto at the University of Maryland assessed potency and efficacy benefits of reformulating palovarotene in nanoparticles (NPs). Dr. Iwamoto showed that the biological activity of drug loaded nanoparticles is fully retained and that palovarotene is released over eight days. One-time injections were shown to suppress HO in FOP mouse models.
- Segmental progeroid syndromes, which are observed in some genetic diseases, recapitulate aspects of physiological aging. Dr. Bob Pignolo, Mayo Clinic, highlighted similar progeroid features in FOP and hypothesized that the accumulation of senescent cells in soft tissues may alter stem cells’ myogenic fate. Work is ongoing at Mayo to look for senolytic agents for therapeutic intervention in FOP.
- Dr. Haitao Wang at the Mayo Clinic showed an accumulation of senescent cells in early lesion formation in a FOP mouse model. Dr. Wang is screening bioflavonoids to clear senescent cells and inhibit ectopic bone formation in FOP. The combination of two identified bioflavonoids together were shown to significantly inhibit BMP signaling and the formation of HO in two FOP mouse models.
FOP Talks 5: New Directions for FOP
Understanding the underlying disease mechanisms of FOP will help enable the development of future treatments and will optimize existing clinical care. This session featured six presentations from researchers advancing our understanding of FOP.
- Although the vast majority of FOP cases are caused by a R206H mutation in the GS domain of ACVR1, FOP-causing mutations can occur throughout the kinase domain. Dr. John Lees-Shepard from Regeneron Pharmaceuticals showed mice with the ACVR1 R258G mutation presented a more severe skeletal phenotype than mice with the ACVR1 R206H mutation. This is consistent with findings in human FOP.
- Dr. Eileen Shore, University of Pennsylvania, presented data on microenvironment changes in FOP. Specifically, Dr. Shore showed that the ACVR1 R206H alters the physical properties of the FOP tissue, including increased tissue stiffness and altered matrix composition. Increased BMP signaling also results in altered responses to mechanical stimuli.
- Zebrafish embryonic dorso-ventral patterning has been an important tool to measure BMP pathway activity. In this model, Dr. Mary Mullins at the University of Pennsylvania showed that ACVR1 R206H does not require ligand binding to over-activate BMP signaling. Further, it was shown that the receptor is hyper-responsive in the presence of BMP ligand, suggesting that the ACVR1 R206H receptor has both ligand-independent and dependent hyperactivities.
- Dr. Aris Economides, Regeneron Pharmaceuticals, engineered a series of variants of ACVR1 R206H that retain responsiveness to BMPs but cannot be activated by Activin A. Through this model, Dr. Economides identified regions of Activin A that are vital for the formation of the non-signaling ACVR1-Activin A-Type II receptor complex, while also documenting the key signaling regions on ACVR1.
- Dr. Sarah Hatsell from Regeneron Pharmaceuticals investigated the role of Activin A in trauma-induced HO. While traumatic HO has similar phenotypic characteristics to HO found in FOP, Dr. Hatsell found that Activin A does not elicit SMAD 1/5/8 signaling in trauma-induced HO mice, and furthermore, Activin A antibody treatment does not alter HO formation in the same model.
- Dr. Xiaobing Yu, University of California, San Francisco, has been investigating the incidence as well as the associated cellular mechanisms of neuropathic pain in patients with FOP. Quantitative sensory testing (QST) on a cohort of FOP patients showed heat and mechanical pain hypersensitivity. Further, nociceptive sensory neurons derived from FOP iPSC lines showed increased baseline neuronal excitability compared to controls.
FOP Talks 6: Emerging Investigator Talks
The Emerging Investigator section was added to this year’s DDF in order to recognize the next generation of FOP researchers.
- Little is known about the macrophages populations involved in heterotopic ossification. Dr. Amanda Huber at the University of Michigan characterized cell populations during HO formation in a trauma-induced model. An in-depth analysis identified several changes in macrophage phenotype. Further, Dr. Huber investigated the effects of TGFb1 deletion and CD47 activating peptide in decreasing HO.
- Lorraine Apuzzo, University of Connecticut, presented whether there was a correlation between sex and HO formation in a FOP mouse model. A retrospective study showed greater HO in female mice. Preliminary data indicate that there are no significant differences in the number or density of FAP stem cells between uninjured male and female mice.
- Dr. Kelly Wentworth, University of California, San Francisco, investigated whether people living with more “mild” FOP symptoms may harbor genetic modifications that act as modifiers of BMP signaling and confer a protective effect. Dr. Wentworth performed whole exome sequencing on a cohort of FOP patients and identified a gene that may play a role in amplifying SMAD 1/5/8 signaling.
- Haichun Pan, University of Michigan, presented work to identify a BMP Type 1 receptor kinase inhibitor. RK783 was selected as an efficient suppressor of heterotopic bone formation. Oral administration of 30 mg/kg of RK783 for 14 days inhibited BMP signaling in FAP cells and significantly decreased HO formation in the R206H mouse model.