In this interview with i3 Health, Suzanne Jan de Beur, MD, discusses the recent approval of burosumab-twza (Crysvita®, Ultragenyx Pharmaceutical, Inc.), for patients with tumor-induced osteomalacia (TIO) whose tumors are unable to be localized or resected. Dr. Jan de Beur, lead investigator of one of the phase 2 clinical trials on which the approval was based, explains the challenges involved in diagnosing and treating TIO and discusses the significance of the approval of burosumab-twza for patients with this rare disorder.
What are some of the most challenging aspects of treating patients with TIO?
Suzanne Jan de Beur, MD: There are two main challenging aspects: making the diagnosis and finding the tumor. Many people suffer with symptoms for years before actually being diagnosed with TIO. One of the big barriers is that the symptoms are relatively enigmatic. Patients' symptoms could start with bone pain, unexplained weakness and progressive debility, or fractures. It can really take some time before their doctors start to check the relevant blood work, including the blood phosphorus level.
Because phosphorus is not on the usual chemistry panel, clinicians have to specifically order a phosphorus level and recognize when it is appropriate to do so. Many times, it doesn't get ordered, and it isn't discovered that the patient's symptoms are from low blood phosphorus, or hypophosphatemia, until much later. Without knowing that the phosphorus is low, it is difficult to recognize the seemingly disconnected symptoms and make the diagnosis of TIO. The symptoms become progressive, but it but may be several years before patients start to fracture bones. That is when clinicians tend to start to recognize what is going on and initiate the evaluation that finally leads to the correct diagnosis.
The second challenging aspect is that once the diagnosis is made, finding the tumor can be difficult. These tumors are small and can be located in a variety of areas. Many times, they're tucked away in anatomical locations that aren't amenable to imaging, such as the distal extremities or craniofacial regions. So even once you have the diagnosis, trying to locate the tumor to completely excise it can be challenging.
Can you comment on the significance of the approval of burosumab-twza for patients with TIO?
Dr. Jan de Beur: This approval is really groundbreaking and significant because it is the first therapy that actually targets the pathophysiology of the disorder. The condition is caused by mesenchymal tumors that produce ectopic fibroblast growth factor 23 (FGF23), which prevents the kidney from reabsorbing phosphorus and from making active vitamin D. The kidney becomes a phosphorus sieve, and then the body's ability to make an active Vitamin D, 1,25-hydroxyvitamin D—whose action is to help absorb phosphorus from the gut—is also blunted by the excess FGF23. This not only increases phosphorus excretion but also shuts down the ability to absorb phosphorus from the gut and liberate it from the bone, which are two other mechanisms to get phosphorus into the blood. The increased FGF23 leads to profound hypophosphatemia, which then leads to bone demineralization, fractures, muscle weakness, and the other clinical symptoms seen in TIO.
Burosumab-twza targets the pathophysiologic mechanism, which is excess FGF23. It binds to and neutralizes the FGF23 and therefore restores the phosphorus homeostasis, reversing the symptoms of TIO. With burosumab-twza, we now have a treatment for those patients with TIO in which the tumor can't be localized or for those who are left with unresectable tumors. Previously, treatment with phosphorus and active vitamin D was burdensome and would often result in side effects. Burosumab-twza offers an excellent alternative that restores phosphate homeostasis, heals osteomalacia, and improves functional outcomes in patients with TIO.
How do you see the diagnosis and treatment of TIO evolving in the coming years?
Dr. Jan de Beur: The mainstay of treatment is always going to be localizing and completely excising the tumor, but I think the areas with the most room for advancement are facilitating better and earlier diagnosis of TIO and developing better imaging techniques to locate the tumors. Getting phosphorus back on the chemistry panel would be very useful in shortening time to diagnosis. Of course, now having a new medical therapy that addresses the underlying issue of TIO is really a major advance.
What questions do you commonly encounter from patients with TIO, and how do you counsel them?
Dr. Jan de Beur: Patients are usually just so delighted to finally have a diagnosis, because in many situations they've previously been misdiagnosed while they continue to watch themselves deteriorate. I usually spend a lot of time talking to them about what this diagnosis means, telling them that it's usually a benign tumor that makes too much of a hormone called FGF23 and explaining what FGF23 does in the body. I also talk to them about the next steps: first, we need to find the tumor. If we can't find the tumor, we're going to have to do medical therapy. If we do medical therapy, I explain the different options.
Patients also usually ask how long it will take them to start feeling better. It takes several months for the bones to start to remineralize and for patients to begin regaining their strength, but they do feel much better after initiating treatment. After the bones become mineralized, there are fewer fractures, and patients begin regaining their strength and vitality. In my lectures, I usually use the example of one of my patients who emailed me after he had surgery to remove his tumor. He was a six foot six, huge, strapping man who used to be a correctional officer, and he came to me on a walker. We were able to find his tumor and resect it. Three months later, he wrote to me to say that he was able to walk across the room independently for the first time in seven years. It takes several months, but these patients do get better.
About Dr. Jan de Beur
Suzanne Jan de Beur, MD, is an Associate Professor of Medicine at Johns Hopkins School of Medicine and is the Director of the Bayview Clinical Research Unit of the Johns Hopkins Institute of Clinical and Translational Research. She specializes in skeletal health and the treatment of metabolic bone disease, with particular expertise in calcium disorders, hypercalcemia, hyperparathyroidism, osteoporosis, Paget's disease, rickets, X-linked hypophosphatemia, and TIO. Dr. Jan de Beur's research focuses on bone and mineral metabolism, including hormonal regulators of phosphate homeostasis, FGF23 signaling, and the molecular basis of hypophosphatemic disorders. She has published numerous articles on the mechanisms of bone disorders and the development of novel therapeutics for these conditions.
For More Information
Jan de Beur S, Miller P, Weber T, et al (2019). OR13-1 burosumab improves the biochemical, skeletal, and clinical symptoms of tumor-induced osteomalacia syndrome. J Endocr Soc, 3(suppl_1):OR13-1. DOI:10.1210/js.2019-OR13-1
Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily reflect those of i3 Health.