Emil, Ultragenyx is expecting its first gene therapy approval this year. What is the significance of this for the company and patients alike?
The gene therapy is for Sanfilippo syndrome - a rare lysosomal storage disease where the body can't recycle certain natural compounds due to a missing enzyme. This leads to a buildup of complex sugars in the brain and body, causing tissue damage. It is typically diagnosed in children between two and six years old, and by the age of ten or twelve, they often become bedridden and may pass away as early as the second decade of life. The disease is neurodegenerative and progresses rapidly, making it one of the most challenging conditions to treat. Recent advances in technology, including adeno-associated virus (AAV) gene therapy, offer hope by delivering the missing enzyme directly to the brain, potentially changing the course of the disease if administered early.
Our approach involves using a viral vector to carry the gene for the missing enzyme into the bloodstream, which then crosses the blood-brain barrier and reaches nerve cells.
These cells begin producing the enzyme and correcting the biochemical defect. We have demonstrated that administering the therapy early can prevent further brain damage, allowing children to continue developing, which would not be possible with the usual progression of the disease. This approach marks a significant shift in the treatment of brain diseases by directly addressing the underlying genetic cause, offering a real potential for transforming lives.
How many patients in the U.S. are expected to benefit from it?
The gene therapy is currently under review by the FDA, with a decision expected around mid-year. The condition affects several hundred children in the U.S., with approximately 40 new cases diagnosed each year. While the total number of affected individuals may be in the range of 400 to 500, the impact of this treatment extends far beyond the number of patients. If successful, a one-time gene therapy could drastically improve the quality of life for these children, preventing years of progressive decline and the need for constant care, which is a heavy emotional and financial burden on families.
The ability to prevent such a devastating decline with a single treatment could be life-changing. For families, the emotional toll of seeing their child deteriorate is immense, and economically, the burden of ongoing care for these children is significant. The hope is that this gene therapy will offer a solution to prevent this progression, providing children with a better chance at a normal life.
Would you describe this treatment as a potential cure?
While we are cautious about describing it a full cure at this stage, the treatment could be considered cure-like if it prevents brain disease progression. The issue with using the word "cure" is that it sets expectations too high, as we are still need to determine the long-term effects. The therapy is designed to provide the missing enzyme and prevent the brain damage that defines the disease, which is a significant step forward. However, we still need to monitor how long the effects last and whether the treatment will be permanent or require follow-up care.
Do you see your future focus shifting increasingly toward gene therapies?
Gene therapies have great potential, especially for certain diseases where the underlying genetic cause is well understood. However, we do not plan to focus exclusively on gene therapies. While AAV gene therapies are effective for liver-focused diseases and some brain diseases, they are not suitable for all conditions. For example, we are also working on monoclonal antibody treatments for diseases like X-linked hypophosphatemia, where gene therapy would not be effective. In this case, a monoclonal antibody targets an excess hormone that causes bone weakness, offering a potent solution without requiring gene modification.
We are also working on therapies for other conditions like osteogenesis imperfecta, a bone disease, using monoclonal antibodies to stimulate bone production. Our approach is to choose the most appropriate treatment strategy based on the biology of the disease. While gene therapies offer the advantage of being one-time treatments, chronic therapies are sometimes necessary. Our goal is to bring the first-ever treatments for these diseases to market, and over time, we expect to see advancements in both gene therapies and other therapeutic strategies.
Do you think innovations in rare diseases could help catalyze broader therapeutic advances?
Absolutely. The genetic insights we gain from studying rare diseases are incredibly valuable and can often be applied to more common conditions. These rare diseases serve as natural human experiments, providing a deeper understanding of the biological processes that underlie a wide range of conditions. For instance, our work with galactosialidosis, a rare disease, led to an interesting finding: the protease involved in this condition also affects amyloid buildup, which is central to Alzheimer’s disease. This discovery has the potential to lead to a gene therapy approach for Alzheimer’s, providing a new avenue for treatment.
By studying these rare diseases, we are gaining critical insights that can inform the development of therapies for more widespread diseases. The knowledge we are accumulating, particularly in gene therapy, is already paving the way for treatments that could extend beyond rare conditions, offering new hope for patients with more common diseases like Alzheimer’s. This approach demonstrates how breakthroughs in the treatment of rare diseases can have a far-reaching impact on the broader medical landscape.
Could you share a patient story that illustrates the impact of your therapies?
One powerful example is Crysvita, a treatment for X-linked hypophosphatemia, which helps children who suffer from weak bones due to phosphate loss. These children often experience pain and difficulty with basic activities, such as walking or running, and some even have bowed legs. One patient, a little girl, had a deep passion for gymnastics, but her bone pain was so severe that she would cry after practice. After starting Crysvita, her bones strengthened, and she no longer experienced pain after gymnastics sessions. Her mother even sent us a photo of her performing backflips, something she could not do before.
This transformation is not just physical; it is emotional as well. The ability to live without constant pain and to participate in everyday activities like gymnastics allows these children to experience a more normal childhood. Crysvita has been transformative for many children, and it has been inspiring to see how it changes lives, not only for the kids but also for their families. As the therapy continues to be used worldwide, we hear similar stories from families in different regions, highlighting the profound impact this treatment has had on children’s lives.
