The Washington Post published an article, “Her son is dying. She hopes the FDA will let her try to save him.” on Dec. 2, 2023.
The following is a commentary from Cure Sanfilippo Foundation Chief Science Officer & Co-Founder Cara O’Neill, MD, FAAP, regarding access to the U.S. Food & Drug Administration’s (FDA) Accelerated Approval (AA) pathway and drug development for Sanfilippo syndrome.
How many children have to suffer the truly devastating effects of Sanfilippo syndrome while we wait for regulatory certainty?
The Sanfilippo syndrome community’s struggle to navigate the FDA regulatory stance is limiting the ability to move forward and improve lives in this ultra-rare disease. We are not talking about common conditions that can run clinical trials with thousands of patients and drug companies that have billion-dollar budgets that can sustain decades of clinical trials costs and research.
The Accelerated Approval (AA) pathway was designed for diseases just like Sanfilippo syndrome. Diseases that progress over a timeframe, that are not well suited for traditional-lengths clinical trials, that have heterogeneous disease manifestations (as is typical for small-population rare diseases), and that have a biomarker that reflects the disease process.
The crux of this AA pathway is the requirement that the biomarker, if changed by the proposed treatment, is expected to result in a clinical benefit. In Sanfilippo, the clinical benefits of treatments are things like slowing disease progression through maintaining cognitive abilities longer, walking independently longer, eating and drinking by mouth longer, and so on. To date, the FDA and drug developers have focused clinical trials on the first aspect: cognitive ability. A number of clinical trial programs have come and gone in Sanfilippo over the years, all focused on this primary endpoint.
What is known about the neurodevelopment in young children and heparan sulfate? Normal quantity and forms of heparan sulfate are necessary for normal brain development. In the case of Sanfilippo syndrome, too many toxic, partially broken-down heparan sulfate fragments do not allow for typical neural pathways to be formed during those critical early years of development from birth to 3 years old.
The average age of Sanfilippo syndrome diagnosis here in the U.S. is around 4-7 years old. Thus, the majority of the population has missed the critical window for possible treatment to have maximum impact on the cognitive aspect of the disease.
We must be able to identify and enroll children as babies in clinical trials to achieve this. However, without newborn screening, this is not feasible. Additionally, in the U.S., government agencies do not recommend newborn screening unless there is an available treatment for the disease. You see the catch-22 here.
And when you treat a baby who has Sanfilippo, you will need to follow that child until they are 5 years old or older to definitively see the cognitive impact of the treatment. Can drug developers sustain their companies and programs this long? Unfortunately, for most programs in our community’s history, the answer has been no.
Companies shelve the drug, drop investment in Sanfilippo altogether, or go bankrupt and dissolve. As has been the case in six clinical-stage therapies in the last seven years. While Foundations aren’t concerned whether companies make a profit, we do care if they are unable to sustain drug development for our children. Our families pay the ultimate price.
Intervening at a later stage of the disease, after symptoms are evident (when most children are diagnosed), is still extremely meaningful. It could also result in clinically-meaningful improvement or maintaining their of quality of life. Those treatment effects tend to be less dramatic in terms of measuring them on structured scales and take years — and in some disease subtypes decades longer — to determine benefit based on the natural timeline of disease progression.
The question is: How many children have to suffer the truly devastating effects of Sanfilippo syndrome while we wait for regulatory certainty?
Suppose your child had cancer and you knew that, without intervention, they were going to die and suffer greatly in the process. Would anyone question the urgency of moving forward with a potentially-beneficial treatment, even if doctors were not entirely sure it would help? Children with Sanfilippo syndrome should be treated with the same urgency as those with cancer, for which the AA pathway is more-commonly used.
In the few remaining clinical trial programs for Sanfilippo, treatments have had safety profiles and risks that are largely acceptable to those in the trials and the patient community. Further, these therapies have shown promising signs of being able to slow or stop aspects of disease progression, such as improving hearing loss, and stopping the loss of brain tissue. In some of the youngest-treated children, there are signals of more “normal” neurodevelopmental trajectories.
The patient community accepts there is uncertainty around potential benefits and there are risks associated with experimental therapies. Frankly, we welcome uncertainty. Parents report that the opportunity for quality of life, other than the CERTAIN painful future that comes with living and dying with Sanfilippo syndrome, is worth risking what might still be uncertain.
Dr. Peter Marks, Director of the FDA Center for Biologics, which regulates gene therapies, has voiced his understanding for the need for appropriate application of accelerated approval and that its use in Sanfilippo will be necessary to move the needle. In a statement about the Accelerated Approval pathway in rare diseases this November, he noted, “I think we are going to probably have to take some chances on the Accelerated Approval endpoints and then have them translate over the course of years into clinical endpoints of how we feel function or survive over the long term.”
However, the day-to-day decisions on these matters rest with the individual reviewers and teams that meet with sponsors developing treatments for diseases like Sanfilippo. Here, we have not seen the perspective of Dr. Marks realized. Why does there seem to be such a disconnect between leadership and the boots-on-the-ground review teams?
We hope that bringing light to the situation leads to positive change. Change driven by existing science and facilitated by the regulatory flexibility that the FDA has already been given by Congress, intended to meet the needs of children with rare diseases like Sanfilippo syndrome.
Children are being harmed by the lack of access to these treatments that demonstrate change in the relevant biomarker (heparan sulfate). We ask that the Accelerated Approval pathway be applied to appropriate therapies for Sanfilippo syndrome, so that another generation of children will not miss their critical window of treatment opportunity.
The Foundation thanks Jill Wood, Shannon McNeil, and Emil Kakkis for highlighting these challenges and their personal experiences in The Washington Post article discussing this topic.