FDA delays mean more deaths: Ultrarare diseases need a fit-for-purpose pathway 

The agency must act with urgency and not be trapped by standards that can only be met in large indications

Process is slowing down progress. Science has evolved, and promising treatments are no longer the barrier to children with severe diseases living healthier, longer lives. Frequently, the barrier is an archaic regulatory process that was built for large populations and fails to act with the urgency that ultrarare disease patients need.

As physicians who focus on very rare disorders, we have watched children respond well to new investigational treatments, their disease progression slowed or halted, only to have those treatments taken away because the biotechnology company runs out of money due to a lengthy approval process and the challenges of clinical trials for ultrarare disorders.

Standard placebo-controlled clinical trials are not realistic for ultrarare disorders that affect the brain, where the age of onset and rate of impairment are highly variable. This heterogeneity adds years to the time it takes to measure a statistically significant clinical difference. Meanwhile, the patients in the control group suffer irreversible brain damage.

Long, drawn-out trials are not economically sustainable when the market size is small. Companies have gone bankrupt while promising treatments are left in limbo and inaccessible to dying patients. 

In our area of specialization, mucopolysaccharidoses (MPS), children are missing an enzyme that removes waste from the body. This waste accumulates in cells, causing progressive damage in the body’s systems and organs, ultimately leading to premature death. In severe forms of MPS II and MPS III, we see significant cognitive involvement — brain damage. Caregivers watch their children lose the ability to speak, eat and walk. These are skills that cannot be regained. Once the damage is done, they are gone forever.

We have tremendous hope for the future of treatments for these devastating diseases. For example, in an intravenous AAV gene therapy clinical trial for Sanfilippo A syndrome (MPS IIIA), the results we have seen are nothing short of miraculous. Consider this report about a boy with Sanfilippo A who is 4.5 years old and was treated at 5.5 months of age:

“He is markedly different from his older sibling, who also has Sanfilippo A. At the same age he is now, his sister was having 5-15 loose bowel movements per day, never slept more than 4 hours at a time, and was up screaming through the night. She had significant delays and behavioral disturbances.

“He is potty training (his bowel movements are normal), speaks in full sentences, sleeps so easily in his bed all night, and can brush his own teeth. He knows colors, counts, and loves the math cartoon on TV. He is bilingual in American Sign Language and English.”

His mom says she forgets he even has Sanfilippo. That’s how well he’s doing.

Although this is a single story, the published data from the trial, which tested UX111 from Ultragenyx Pharmaceutical Inc., are compelling and robust.

• In the pivotal Phase I/II/III Transpher A trial, 22 children received the high dose of UX111 (3×10¹³  vg/kg). At ~34 months post-treatment, cerebrospinal fluid levels of heparan sulfate, a key biomarker indicating restored enzyme activity, were reduced by a median of 65-66% (p<0.0001).

• Among 17 children in the modified intent-to-treat cohort, Bayley-III cognitive scores improved by 16 points, corresponding to a 22.7-point treatment effect versus natural history declines (p< 0.0001); receptive/expressive communication and fine motor domains also showed statistically significant gains.

• All age and disease-severity subgroups demonstrated stabilization or slowed loss of vital functions such as ambulation, speech and self-feeding.

This is why we must demand urgency in decisions about treatments for ultrarare disorders.

Ultragenyx received a complete response letter (CRL) last month due to a CMC issue it believes is readily addressable. In cases like this, FDA should meet with the company before issuing a CRL that could reset the approval clock, potentially extending the timeline by a year or more.

Time is not on the patient’s side. The natural history of these disorders is very clear — without intervention, children with early brain involvement will die prematurely, usually in their mid-teens. In our 70 years of combined practice, we have never seen otherwise.

The clinical trial process must change for ultrarare diseases. We cannot expect a model designed for large populations to succeed in diseases with fewer than 500 patients, most of whom already have profound impairment. Nor can a system that takes 8-10 years to approve a drug meet the needs of patients with progressive, brain-damaging disorders.

We are not advocating for the approval of unsafe or untested treatments. No one in the rare disease community wants that. Long-term, placebo-controlled clinical trials are simply not ethical for slowly progressive brain disorders, where no two children are alike. The process can be streamlined to deliver treatments to patients faster using the FDA accelerated approval pathway.

For MPS disorders with brain involvement, FDA has said reduction in cerebrospinal fluid heparan sulfate can be used as a predictor of clinical outcome, making it appropriate as a surrogate endpoint for accelerated approval. If the agency honors this commitment, it will be a step in the right direction.

After an accelerated approval, likely based on an open-label Phase I/II trial showing safety and heparan sulfate reduction, children would then be able to receive life-saving treatments while the company continues confirmatory studies to prove clinical benefit.

As physicians and researchers, we have consistently relied on FDA and biotech companies as our partners. There is no conflict of interest among the three of us. We are all working for the patients, in their best interests, finding ways to deliver treatments to them with urgency and care.

If the science is solid, our next step together is to ensure that the treatment reaches its intended goal and helps save lives. Let’s not let the process slow down progress. Our children deserve better.

Joseph Muenzer is a professor of pediatrics at the University of North Carolina at Chapel Hill and directs the UNC MPS Research and Treatment Center. Paul Harmatz is a professor of pediatrics at the University of California San Francisco, and a physician at the Pediatric Clinical Research Program for MPS and related disorders at UCSF Benioff Children’s Hospital Oakland. Both have run clinical trials of MPS therapies, although neither of their institutions are listed as sites in the Ultragenyx study.

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