FDA’s mixed signals call its commitment to rare diseases into question: Guest Commentary

When even strong biomarker science isn’t accepted and review timelines slip, children lose time — and investors lose confidence

When my son was diagnosed with Hunter syndrome (MPS II) 13 years ago, I was devastated. I had never heard of the disease, and I never dreamed that my son would be anything less than perfectly healthy. I was determined to breastfeed him for two years so that he wouldn’t develop my asthma, which I struggled with as a child. This was my biggest concern. I was so naïve. I didn’t know the whole world of rare diseases existed.

The geneticist told me that Hunter syndrome was a progressive and terminal illness, and to come back to see them when he could no longer walk and needed a wheelchair, a safe bed, and other equipment I would need for him. He would likely die in his early teen years.

Cole just turned 15. I am afraid every morning that this will be the day I go into his room and find him unresponsive. Fifteen has hung over my head since that diagnosis day — the day I screamed, cursed the doctor, and ran until I fell to the ground crying.

I pray every night that Cole is on a different trajectory because of the clinical trial he joined when he was four and a half. That trial lasted more than 10 years, but FDA never approved the drug: TAK-609. In those years, at least 12 boys with Hunter syndrome, all around Cole’s age, died while waiting for a therapy that never came. The only peers of his still alive are the boys who were also in that study.

For those 10 years and every day since, I have lived with an axe hanging over my neck. Will the company decide to pull the drug? Will FDA ask them to stop giving it to our boys? Will the data be enough to show it works? And the obvious question: if cerebrospinal fluid (CSF) heparan sulfate had been accepted as a surrogate endpoint, would TAK-609 have been approved? I believe it would have, and that is infuriating.

Mixed signals on accelerated approval

The rare disease community does not expect shortcuts on safety. But we do need transparency and predictability in regulatory standards — especially when it comes to accelerated approval. The new FDA leadership has stated that it intends to embrace supportive standards for rare diseases. Instead, what we are seeing is a troubling pattern of mixed messages.

RGX121 from Regenxbio: On Monday, FDA extended the review of this BLA after requesting an additional data cut, despite clear biomarker reduction. This delay leaves families wondering whether accelerated approval is truly available.

UX111 from Ultragenyx: For this gene therapy, FDA appears to be prioritizing intermediate clinical outcomes over the surrogate endpoint, potentially setting a precedent that could block the accelerated approval path for future programs.

DNL310 from Denali: This therapy has also demonstrated CSF heparan sulfate reduction and been granted priority review, but there’s no guarantee FDA will accept the surrogate endpoint as approvable.

Contrast this with cancer, where four therapies were recently approved through accelerated approval using well-established biomarkers. In rare diseases like MPS, the science is just as strong, yet the standards seem to shift. That uncertainty makes it nearly impossible for companies to justify the risk of investing in these programs.

The case for CSF heparan sulfate

Experts have studied CSF heparan sulfate in MPS syndromes for decades. The biomarker is consistently linked to neuronopathic MPS progression, and under former CBER Director Peter Marks’ leadership at FDA, it was deemed “reasonably likely” to predict clinical benefit — the statutory standard for accelerated approval. That scientific judgment was reinforced at the Reagan-Udall meeting in February 2024, in peer-reviewed publications, and as recently as June by then-Director of CBER’s Office of Therapeutic Products Nicole Verdun, who was ousted from FDA later that month.

Now, the agency appears to be reopening the debate, questioning whether the surrogate is valid despite 30 years of evidence and consensus among disease experts. This is not a debate over whether the biomarker is mechanistically plausible or tracks with disease, but whether it is validated enough.

Every year of delay means more irreversible brain damage, more lost skills, and more children who will not live to adulthood.

To the rare disease community, FDA’s apparent renewed hesitation to act on this surrogate endpoint is infuriating, as it suggests the new leadership’s decision-making is being guided by factors other than science. Politics seems likely, as accelerated approval has been inappropriately associated with the COVID-19 vaccine.

Even the recent approval of a viral vector-based rare disease therapy from Precigen, which CBER Director Vinay Prasad held up as an example of flexible standards for rare diseases, could be interpreted as a reluctance to issue an accelerated approval. The therapy was being reviewed for accelerated approval, but was instead granted full approval.

A path forward

What parents like me want is simple: clear, consistent, science-based standards. If FDA believes the evidentiary bar for accelerated approval in rare diseases has changed, it must state that publicly and explain why decades of biomarker research no longer qualifies. Without transparency, families lose faith, investors walk away, and companies retreat from rare disease drug development.

When Cole entered the TAK-609 trial in 2014, I knew it wasn’t a cure. By age four, he was already showing signs of brain damage — loss of words, skills and attention. But my goal was to keep him alive long enough for something better to come along. That something better is now within reach, but only if FDA is willing to say: Yes, CSF heparan sulfate is a viable surrogate endpoint. And yes, accelerated approval is available for MPS therapies that meet this standard.

My son no longer speaks. I haven’t heard his sweet voice in six years. His last word was “Mommy.” The only unethical issue here is withholding safe treatments because the rules keep shifting. Families cannot wait another decade for clarity. The science is here. The children are here. The question is whether FDA will act before it’s too late.

Kim Stephens is executive director of the Muenzer MPS Center at the University of North Carolina at Chapel Hill. She’s also board member emeritus at Project Alive, an MPS II research and advocacy organization where she served as president from 2019 to 2023.

Signed commentaries do not necessarily reflect the views of BioCentury.