The US Food and Drug Administration has approved Fayuvi, the first treatment for children with Sanfilippo syndrome type A, a rare inherited disease that steadily damages the brain1. The agency announced the decision on September 17, 20261. Until then, doctors could only manage symptoms; no approved therapy aimed at the cause of the disease existed2.
Fayuvi is a gene therapy, given once as a drip into a vein2. It is made by the biotech company Ultragenyx2. Its path to approval took decades and leaned heavily on money raised by families of affected children, including the O’Neill family of Columbia, South Carolina3.
What happened
Children with Sanfilippo syndrome have a faulty gene that leaves them unable to break down heparan sulfate, a sugar-based molecule important for normal cell function3. As it builds up, children lose the ability to speak and walk, have seizures, and usually do not live past their teens, according to the Cure Sanfilippo Foundation3. In type A, the faulty gene is called SGSH, and the buildup in the brain drives severe decline in thinking skills in early childhood4.
Fayuvi (chemical name rebisufligene etisparvovec-hopf) uses a modified, non-infectious virus called AAV9 as a delivery truck to carry a working copy of the SGSH gene into the body’s cells2. The cells can then make sulfamidase, the missing enzyme, which lets heparan sulfate be broken down inside cells and reduces its buildup in the body and brain2.
The National MPS Society, a patient group, said it is the first gene therapy approved for any form of MPS, the wider family of diseases Sanfilippo belongs to5.
The evidence behind the approval
This was an accelerated approval, a faster route the FDA can use when a lab measure is reasonably likely to predict real benefit. Here the measure was a drop in heparan sulfate in the cerebrospinal fluid, the liquid around the brain and spinal cord4. The study’s main goal, as listed on the official trial registry, is that spinal-fluid measure up to the 24-month visit6.
The main study, called Transpher A, was open-label (everyone knew they got the treatment) and single-arm (there was no comparison group inside the study)1. It looked at thinking skills using a standard child development test, the Bayley-III, between 24 and 60 months of age1. In 17 treated children, scores were 23.5 points higher than in 27 untreated children from an earlier “natural history” record of how the disease usually progresses1. A summary from PackGene, a gene therapy manufacturing company, gives the advantage for younger treated children as 23.2 points and describes 27 patients as the efficacy group4; the sources differ on these details.
The FDA said treated children kept or improved their thinking skills, while untreated children from the historical group usually plateaued and then declined in this age window2. According to PackGene’s summary, the median drop in spinal-fluid heparan sulfate was about 64% from the starting level4. Follow-up data stretch to nearly 8 years1.
Side effects and warnings
The most common side effects, seen in more than 5% of patients, were higher liver enzymes, nausea and vomiting, fever, lower appetite, lower white blood cell and platelet counts, and higher amylase, a digestive enzyme2. Warnings include thrombotic microangiopathy, a condition in which small blood clots can damage organs, and, as with other gene therapies of this type, a possible long-term risk that the added genetic material could insert itself into the body’s DNA and lead to tumors2. Children receive steroid medicine starting one day before the infusion and for at least 8 weeks after, and the infusion is given in a medical setting able to handle reactions2.
What it does not show yet
The study had no placebo group. BioPharm International noted that the evidence relies on historical controls rather than children randomly assigned to treatment or comparison at the same time1. That makes it harder to be sure the two groups were alike in every way that matters.
The approval is limited to children whose brain development is still largely preserved1. Ultragenyx chief executive Emil Kakkis said the treatment should work best the younger the child is3.
“The treatment will work best the younger the child is because the more brain is remaining,” says Ultragenyx CEO Emil Kakkis.3
He said the company has treated a few children around 6 months old who have done really well, while children diagnosed at 2, 3 or 4 years old have often already lost a lot of ground3. These are the company’s statements, not published comparisons.
The trial itself is still listed as recruiting, with an estimated 36 participants and main data collection expected to finish in March 20296. No results had been posted to the registry6.
Who is behind it: families, a hospital lab and a company
The science started at Nationwide Children’s Hospital in Columbus, Ohio, where researcher Haiyan Fu had worked on a gene therapy for Sanfilippo in mice since the late 1990s3. Fu thought she would have to quit in 2009 because of funding problems, but families of children with the disease offered money so she could continue3. In all, eight patient foundations, including Ben’s Dream and A Cure for Kirby, kept the work going until it was ready for a first human trial3.
Cara O’Neill, a pediatrician, and her husband Glenn learned in 2013 that their daughter Eliza had Sanfilippo syndrome3. They started the Cure Sanfilippo Foundation, which they still run3. In spring 2014, a video called Saving Eliza, made by filmmaker Benjamin Von Wong, helped the family break GoFundMe’s record at the time, raising $1 million in a few weeks and then $2 million3. That money helped fund the first human trial, which started in May 20163.
Eliza became the first patient to receive the experimental therapy in 2016, at age 6, when she had already lost her ability to speak7. Her speech never returned, but she communicates with picture cards and electronic devices and attends school, according to her family7. She is now almost 177.
The National MPS Society said it began funding and championing early research more than 15 years ago5. It credits Abeona Therapeutics as the pioneer of the treatment; Ultragenyx bought the global rights from Abeona in 20225. Ultragenyx sponsors the current trial6.
The road was not smooth. The society said the therapy went through more than two years of FDA review, including a Complete Response Letter (a formal FDA rejection that lists problems to fix), a full resubmission and further inspections5. Fayuvi had received the FDA’s orphan drug, fast track and breakthrough therapy designations, programs meant to speed up drugs for rare or serious diseases2.
Ultragenyx’s price ties Fayuvi for the second most expensive gene therapy ever, according to drug price research firm 46brooklyn3. Kakkis said the company is committed to making sure every patient is treated regardless of price3.
How it fits the field
FDA official Megha Kaushal said the result shows that a gene therapy given into a vein can reach the brain and spinal cord at useful levels in children2. The National MPS Society said this is the first FDA gene therapy approval built on spinal-fluid heparan sulfate as a marker of disease, an approach it has pushed for more than 15 years5. Fayuvi is Ultragenyx’s second gene therapy to reach the market since August4.
For the researchers and families, the approval came with mixed feelings. Some families who funded Fu’s work lost a child along the way3. “It shouldn’t take this long,” Fu said7.
What to watch next
- Newborn screening. Because timing matters, the National MPS Society says it is now focusing its advocacy on adding Sanfilippo syndrome to newborn screening, so children are found before major brain damage5.
- Longer-term results. The ongoing trial is due to finish its main data collection in 20296, which may show more about how lasting the effects are.
- Access. Whether children across different states and hospitals can actually get the one-time treatment, which Kakkis says the company is committed to3.
- Safety over time. Whether the long-term risks flagged by the FDA, such as tumors, show up in follow-up2.
