On February 21, 2024, the Cure Sanfilippo Foundation, the National MPS Society, and The Ryan Foundation participated in a pre-competitive workshop hosted by the Reagan Udall Foundation in collaboration with the FDA and several drug sponsors. The workshop aimed to discuss the qualification of cerebrospinal fluid-heparan sulfate (CSF-HS) as a primary biomarker supporting accelerated approval in neuropathic MPS disorders. The workshop included presentations from industry leaders, which covered disease pathology, preclinical and clinical data from numerous drug development programs, validated assays used to measure biomarkers, and a panel of rare disease experts discussing the importance of providing accelerated approval in neurodegenerative ultrarare diseases.
“We are asking the FDA for equitable access to the Accelerated Approval pathway. Similar to cancer patients and therapies, which account for nearly all accelerated approvals, children with neuropathic MPS are dying without treatments and suffering immensely in the process. We truly need access now in Sanfilippo syndrome or we are going to lose another generation of our children.”
Cara O’Neill, MD, FAAP, Cure Sanfilippo Foundation
A group of global academic medical experts, 20+ year MPS researchers, highly experienced drug developers, senior leaders from the U.S. Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER), and other specialists recently convened to discuss MPS neuropathic pathophysiology, animal studies, clinical outcomes from decades of studies, and patient-focused drug development, surrogate endpoints, and the accelerated approval pathway. The main focus of the meeting was on MPS subtypes: MPS I, MPS II (Hunter Syndrome), and MPS IIIA, IIIB, IIIC, and IIID (Sanfilippo Syndrome), which all lead to the accumulation of toxic heparan sulfate in the central nervous system, causing progressive brain injury.
“During my quarter century working in the field of MPS research, this workshop was the most unified, consistent, and impactful presentation of the case of CSF heparan sulfate as a surrogate biomarker in neuropathic MPS disorders. I’ve never been prouder to present as a scientist and to represent as an advocate as I was last week at the Reagan-Udall Foundation for the FDA.”
Matthew Ellinwood, DVM, PhD, National MPS Society
In recent years, there have been cases of clinical trials failing to meet the FDA’s criteria due to ultra rare diseases with low prevalence. These diseases are caused by single enzyme defects that lead to the deposition of heparan sulfate in the brain, causing irreversible and progressive brain damage. It has been demonstrated that reducing a primary disease activity biomarker, CSF heparan sulfate, closely correlates with reducing substrate deposition in the brain. Thus, reducing CSF-HS is deemed likely to lead to downstream clinical improvements.
“At least ten companies developing therapies for Sanfilippo syndrome have halted their programs while regulation is struggling to keep up with the science in the field. FDA has the authority, and we now need them to take action in ensuring that transformational science is not being left behind.”
Mark Dant, Volunteer Executive Director, The Ryan Foundation
Bringing together key stakeholders of MPS to share their ideas and research findings in a public forum such as the Reagan-Udall Foundation provides an excellent opportunity to have focused and productive discussions. These discussions can help us find urgently needed solutions and advance therapies that will improve the lives of those affected by neuropathic MPS.
The “Qualifying Biomarkers to Support Rare Disease Regulatory Pathways” workshop was held to discuss the most appropriate regulatory framework for evaluating treatments related to neuropathic MPS diseases. The workshop was attended by clinicians, scientific researchers, drug developers, and patient advocates. They provided confirmatory evidence that characterizes CSF-HS as a primary disease activity biomarker that can drive drug development programs. This path for evidence of effectiveness to support accelerated approval based on reduction of substrate accumulation is outlined in the FDA 2020 Rare Disease Single Enzyme Defect with Substrate Deposition Guidance. The Reagan-Udall Foundation has made the agenda, presentation slides, and recording of this meeting available.
