The FDA’s See-No-Data Approach

A study showed promise in treating a rare disease. The agency wouldn’t even look at the results

By Stephen Cederbaum and Emil Kakkis. 

"We’ve spent most of our medical careers investigating and treating rare genetic conditions, including some afflicting only a few dozen Americans. Recently, scientists developed a treatment for one such condition—arginase 1 deficiency, or ARG1-D, which causes the amino acid arginine to accumulate in the blood, harming the brain and causing seizures, stunted growth and intellectual disability. The Food and Drug Administration has refused to consider the therapy. Its decision ignores the best available data and indicates a lack of understanding of rare-disease research.

Discovering treatments for rare diseases is a daunting task. Recruiting even a few dozen people for a clinical trial requires doctors and drug companies to identify a large share of the patient population. And since the market for such therapies is necessarily small, it’s nearly impossible to attract investment. So when news emerged about

Aeglea BioTherapeutics

’ ARG1-D therapy pegzilarginase, we could hardly believe it. Pegzilarginase is an enzyme engineered to lower the body’s levels of arginine. The randomized placebo-controlled study of pegzilarginase included 32 patients with ARG1-D.

The results speak for themselves. The amount of arginine present in blood plasma declined by 80% for patients on pegzilarginase. After only six months, 90.5% of patients who received pegzilarginase had normal arginine levels, and this was sustained over time. The data also suggested progressive improvements in motor function compared with a placebo. And most patients tolerated the therapy quite well.

These numbers were jaw-dropping. Which is why the FDA’s decision is incomprehensible.

The FDA even refused to look at Aeglea’s data. Instead, the agency demanded that the firm compile additional data suggesting pegzilarginase will produce a clinical benefit in addition to eliminating excess arginine. But for ARG1-D and other rare diseases, measuring clinical outcomes can take years, while measuring biomarkers likely to produce clinical benefits can take weeks.

Biomarkers are precisely why the FDA established its accelerated approval pathway in 1992. Accelerated approval allows developers to submit data measuring “surrogate endpoints” that correlate with clinical outcomes. If any medicine qualifies for accelerated approval, pegzilarginase does. Basic biology and numerous studies indicate that reducing arginine yields clinical improvements.

Evaluating clinical benefits could force sick patients to remain in placebo groups for months. That the FDA would put its rigid rules before the convincing data we already have is unethical. If the FDA doesn’t correct its error soon, patients with ARG1-D will lose their best chance at full, productive lives.

Dr. Cederbaum is a professor emeritus at the University of California, Los Angeles. He has worked as a consultant to Aeglea. Dr. Kakkis, a medical geneticist, is CEO of

Ultragenyx

, a company focused on developing treatments for rare and ultrarare diseases."