Developing Sanfilippo, MPS disorder biomarkers aired in workshop

Role of heparan sulfate in MPS disorders emphasized at Reagan-Udall event

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by Mary Chapman |

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Developing biomarkers may help support accelerated federal approval for treatments in Sanfilippo syndrome and related diseases.

That was the subject of an in-person and virtual workshop last month by the Reagan-Udall Foundation for the Food and Drug Administration that discussed primary disease activity biomarkers and focused on the role of heparan sulfate in neuronopathic mucopolysaccharidoses (MPS). The workshop, titled “Qualifying Biomarkers to Support Rare Disease Regulatory Pathways,” featured presentations by the U.S. Food and Drug Administration (FDA), patient advocates, scientists, and industry representatives.

Discussions centered around disease processes, clinical and preclinical data from treatment development programs, and validated assays used to assess biomarkers, which can assist with diagnosing disease and often help assess the probability of a clinical event, disorder recurrence, or disease progression.

A panel of rare disease experts raised the “urgent” need for the FDA to provide access to the accelerated approval pathway in ultra-rare neurodegenerative diseases. The federal program is an expedited treatment development track with approvals based on surrogate endpoints such as biomarkers.

“We are asking the FDA for equitable access to the accelerated approval pathway,” Cara O’Neill, MD, Cure Sanfilippo Foundation co-founder and chief science officer, said in a press release. “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.”

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Promoting heparan sulfate as MPS biomarker

Qualifying cerebrospinal fluid-heparan sulfate (CSF-HS) as a primary biomarker in MPS disorders such as Sanfilippo, or MPS type III, a genetic disease that results in a form of childhood dementia was a focus of the discussion, with emphasis given to Sanfilippo types IIIA, IIIB, IIIC, and IIID, along with MPS I and MPS II (Hunter syndrome).

Sanfilippo is caused by mutations in genes that code for enzymes that break down heparan sulfate. Due to the mutations, a functional enzyme can’t be produced and the complex sugar molecule accumulates to toxic levels in cells. This causes systemwide damage, particularly to the brain.

Heparan sulfate in the CSF, the liquid that surrounds the brain and the spinal cord, has been correlated with reduced brain substrate deposition, which is “reasonably likely” to translate to clinical outcomes, according to the press release. Several participants offered scientific data that characterizes CSF-HS as a primary biomarker that could drive treatment development programs.

Meanwhile, over the past several years, several clinical studies have ended due to a failure to meet FDA criteria.

“At least 10 companies developing therapies for Sanfilippo syndrome have halted their programs while regulation is struggling to keep up with the science in the field,” said Mark Dant, volunteer executive director at The Ryan Foundation. “FDA has the authority and we now need them to take action in ensuring that transformational science is not left behind.”

The need to advance treatments for those affected by neuropathic MPS was emphasized.

“During my quarter-century working in the field of MPS research, this workshop was the most unified, consistent, and impactful case of CSF heparan sulfate as a surrogate biomarker in neuropathic MPS disorders,” said Matthew Ellinwood, PhD, chief scientific officer at the National MPS Society. “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.”

The event was sponsored by Denali Therapeutics, Orchard Therapeutics, Regenxbio, and Ultragenyx. The Reagan-Udall Foundation seeks to advance the mission of the FDA to modernize product development, accelerate innovation, and enhance product safety.