Tiny biotech’s experience raises questions about FDA’s rare disease policies

Grace Science says it has been shut out of plausible mechanism framework, denied flexibility on CMC requirements

The experience of Grace Science, a biotech developing a gene therapy for an ultrarare, fatal condition, shows how gaps between FDA’s commitments to accelerating rare disease drug development and the reality experienced by struggling biotechs impact families facing serious diseases.

According to Grace Science LLC, despite early signs of efficacy for a therapy addressing a well-characterized monogenic disorder, NGLY1 deficiency, FDA told the company it does not qualify for the plausible mechanism framework and must complete a new manufacturing run before seeking approval.

The manufacturing requirement could delay approval by years, which would be a devastating blow to patients and their families and could destroy Grace Science’s economic viability.

The biotech’s experience offers an early test of whether FDA’s push for flexibility in rare disease development will translate into practice for small companies racing against disease progression and limited capital.

The stakes are immediate.

There are no approved therapies for NGLY1 deficiency, a progressive genetic disorder that causes profound developmental impairment and has a median lifespan of about 14.5 years. GS-100 is the only therapy in the clinic, and little else is close behind. A multi-year delay could sentence patients who were not enrolled in the trial to irreversible decline, and some may not survive long enough to be treated.

The delay, according to the company, stems from FDA’s requirement to complete a new full-scale manufacturing run prior to approval to demonstrate it can reproducibly make the therapy at a new facility.

Because the original manufacturing site used for clinical supply was shut down, FDA is requiring the company to validate the process elsewhere before accepting a BLA. Grace Science told BioCentury it asked to defer that work to the postmarketing setting; FDA declined.

Additionally, the company reported that the agency has stated GS-100 does not qualify for the plausible mechanism framework, a pathway intended to support approvals based on mechanistic understanding and limited clinical data when traditional trials are infeasible.

The decisions seem to highlight a gap between FDA’s public messaging and its application in practice.

After the last patient in Grace Science’s trial received GS-100 on March 24, “we asked the FDA if we could submit under the plausible mechanism framework,” co-founder and CEO Matt Wilsey told BioCentury. “They said no, it’s not designed for anything beyond individualized therapies, really N-of-1 therapies.”

Agency leaders, including Commissioner Marty Makary and CDER officials involved in drafting the plausible mechanism guidance, have emphasized that flexibility should extend beyond individualized N-of-1 therapies. Teresa Buracchio, director of CDER’s Office of Neuroscience and co-lead author of the plausible mechanism draft guidance; Tracy Beth Høeg, acting CDER director; and Makary have all publicly stated that the framework is not limited to N-of-1 therapies.

The framework has raised expectations in the rare disease community about the possibility of new regulatory paradigms stimulating the translation of scientific advances into economically viable therapies. 

The manufacturing requirement is the most immediate barrier.

Grace estimates it would take two to three years and about $25 million to complete a new production run and associated process validation, costs that are difficult to justify to investors in the absence of reimbursement for a disease affecting only a few dozen patients in the U.S.

In addition to the plausible mechanism pathway, FDA has emphasized its flexible approach to CMC requirements for cell and gene therapies.

“Regulatory flexibility must be tailored for cell and gene therapies,” Makary said in a January press release announcing the agency’s approach.

The release stated that CBER has leveraged its experience with cell and gene therapy products to “identify and implement regulatory flexibilities allowed under FDA’s regulations that accommodate the unique characteristics of these innovative therapies, while maintaining rigorous quality standards through appropriate control measures.” It added that FDA has a “long history of making concerted efforts to help sponsors meet standards to assure product safety, purity and potency,” but that the “application of flexibilities has not always been fully clear to stakeholders.”

That flexibility does not extend to allowing Grace Science to gain approval based on its initial batch of GS-100.

FDA declined to respond to BioCentury’s questions about whether the plausible mechanism framework is available in practice to sponsors developing therapies for diseases outside the N-of-1 paradigm or to comment on a pending application.

For the company, the timing is critical.

Grace has raised about $70 million to date and expects to run out of funds this summer. Without approval, it cannot access reimbursement or monetize a rare pediatric disease priority review voucher, which could be worth $150 million to $200 million based on recent transactions.

“We are out of money in July,” Wilsey said. The company has enough GS-100 on hand to treat seven more patients, but lacks the financial resources to support their care.

Grace Science’s situation is particularly frustrating to families waiting for help because the company has already cleared many of the scientific hurdles that often stall rare disease programs.

Grace’s story

Grace Wilsey was diagnosed in 2013 with NGLY1 deficiency, a progressive, debilitating disease that causes profound developmental delays. Patients are unable to walk unassisted or to speak. 

At the time, Grace was one of six known patients worldwide. Now there are about 150, and approval of a therapy would almost certainly lead to additional diagnoses.

Matt Wilsey was a technology entrepreneur when his daughter was diagnosed. Matt and his wife Kristen established a foundation to research the condition and then co-founded Grace Science in 2016 with Carolyn Bertozzi, who was awarded a Nobel Prize in 2022. Four other Nobel laureates — Jennifer Doudna, Brian Kobilka, Gary Ruvkun and Shinya Yamanaka — are closely involved with the company.

The extraordinary scientific interest stems from the conviction that tools are available to help children suffering from NGLY1 deficiency, and that an effective therapy could serve as proof of concept for developing treatments for other monogenic disorders.

Wilsey also pointed to the belief that NGLY1’s highly conserved gene pathway plays critical roles in a range of diseases, from oncology to neurodegeneration.

“The hypothesis was that rare diseases unlock common diseases, and if we could figure out that connection, we could start a company,” Wilsey said.

Grace Science developed GS-100, an AAV gene therapy, and has enrolled 10 patients from the 35 known U.S. patients in a trial that has tested four doses. Six patients have been enrolled for more than 52 weeks.

GS-100 has demonstrated consistent signals of benefit, according to the company.

Grace Science reports that patients who previously could not sit, stand, or communicate effectively have gained abilities such as sitting independently, walking with assistance, and interacting more meaningfully with caregivers. Improvements in cognition and motor function have been durable in patients with longer follow-up.

“It’s not like they’re going to go from severely disabled to fully functional,” Wilsey said. “But there is a huge quality-of-life improvement.”

Those gains contrast with the disease’s natural history, which is typically stable at best and often marked by gradual decline, especially in younger patients.

FDA has indicated it would like additional time-on-drug data at the selected commercial dose, including 52-week follow-up, before accepting a BLA, Wilsey said. By early 2027, Grace expects to have that dataset in hand.

The manufacturing requirement, rather than the clinical evidence, is now the gating issue.

Grace’s experience raises broader questions about how FDA is applying flexibility across different types of rare disease programs. While individualized therapies have received accommodations on manufacturing and evidence standards, therapies for ultrarare but multi-patient populations may face more traditional requirements.

Without a viable path forward, Grace is weighing options, including raising $3-$4 million “to keep the lights on,” merging with another company that is developing a gene therapy, or selling the program to a large company that is principally interested in receiving a priority review voucher, Wilsey said.

Another option, he said, is  “moving the asset to China and trying to get the drug approved somewhere outside the United States.”

For patients and families coping with NGLY1 deficiency, time is running out. Each month of delay brings irreversible loss of function, mounting medical crises, and, for some, death.

The consequences will reverberate beyond this disease, influencing whether rare disease families, biotechs, and investors believe FDA can deliver on its promises to dramatically improve rare disease drug development.

This story has been updated to reflect that Grace has raised about $70 million; an earlier version of the story misstated the amount.