In February 2024, the Reagan-Udall Foundation for the Food and Drug Administration (FDA) in the USA held a workshop at a crucial moment in time for the Sanfilippo community and the broader neuronopathic MPS community. The workshop led to the acceptance of heparan sulfate (HS) as a biomarker to support drug approvals for Sanfilippo, an outcome that is bringing renewed hope for treatments on the horizon.
The workshop aimed to explore primary disease activity biomarkers in rare genetic diseases using levels HS in cerebrospinal fluid (CSF) as a case study to support accelerated approval of new therapeutics for neuronopathic mucopolysaccharidoses (MPS) disorders.
The consensus views from the workshop have just been published in the scientific journal, Molecular Genetics and Metabolism.
Accelerated Approval is a pathway that the FDA can use to get potentially beneficial treatments to patients with serious conditions faster.
Typically, drugs are approved on the basis that a gold-standard placebo-controlled trial has proven that an experimental therapy makes a difference to patients based on the clinical outcomes (e.g. if neurocognitive development is improved in the long term).
However, in rare diseases, particularly for relatively slow-moving progressive brain disorders, this type of trial is almost impossible to conduct - the trials need to be very long to demonstrate that the clinical course of the disease has been conclusively changed, there are typically not enough patients, and it is arguably unethical to split the patients into groups that will receive treatment or placebo.
Instead, in Accelerated Approvals the FDA can make a judgement based on a ‘surrogate endpoint’. This is a biomarker, such as a laboratory measurement, medical imaging, physical sign or other measure that is thought to predict clinical benefit but is not itself a measure of clinical benefit.
The crucial consideration is that the surrogate endpoint is “reasonably likely to predict clinical benefit”. This type of evidence can be gathered more quickly in shorter trials that do not need to rely on the use of a placebo control group. The treatment can then be made available to patients on the condition that the company continues to collect clinical outcome data for a full approval at a later date.
For Sanfilippo and other neuronopathic MPS disorders, the urgency of this issue was brought into sharp focus by patient organisations, clinicians and others concerned at the prospect of yet another group of potentially beneficial therapies falling over at the final hurdle and leaving another generation of children without a treatment.
At the workshop, an outstanding group of clinical, technical and patient advocacy experts provided convincing, consensus evidence that CSF HS is a surrogate endpoint reasonably likely to predict clinical benefit in neuronopathic MPS disorders. Evidence was presented from animal studies that show that CSF HS levels correlated with brain tissue HS levels and in turn with pathological and clinical outcomes, and from human clinical trials showing that CSF HS predicts clinical outcomes and other markers of lysosomal and neuronal function.
They agreed that CSF HS is a valid biomarker for neuronopathic MPS disorders, and that the FDA accelerated approval pathway for MPS will provide patients access to life-saving therapies.
Following the workshop we are aware of at least one company having had successful meetings with the FDA with agreement that they could use CSF HS levels as the surrogate endpoint to support a drug licensing application for accelerated approval. This shows just how crucial and timely this workshop was.
