By Heather McKenzie
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Arginase 1 deficiency, or ARG1-D, is a rare, inherited disorder occurring in approximately 1.1 in 1 million live U.S. births. While born with normal function, by the age of two, patients with the condition have progressive deterioration in their physical ability due to the gradual accumulation of arginine and ammonia in the blood.

The nervous system is particularly sensitive to high levels of ammonia, Stephen Cederbaum, a UCLA professor emeritus who has studied ARG1-D for more than 50 years, told BioSpace. Untreated, children progressively deteriorate, experiencing spasticity and developmental delays. There is currently no disease-modifying treatment for ARG1-D.

So it may have seemed like welcome news for ARG1-D patients and their families when an experimental drug, pegzilarginase, developed by Aeglea BioTherapeutics, was found to rapidly and sustainably lower arginine levels and elicit improvements in mobility. A novel, recombinant human arginase 1 enzyme, pegzilarginase led to a statistically significant 80% reduction in mean plasma arginine—a key biomarker—in the pivotal Phase III PEACE trial; 90.5% of patients treated with the enzyme achieved normal plasma arginine levels compared to none on placebo.

Then, last June, the company received a Refusal to File letter from the FDA in response to its Biologics License Application for pegzilarginase. The FDA requested more data to support its efficacy—particularly evidence showing that plasma arginine and metabolite reduction could predict clinical benefit in patients with ARG1-D. Aeglea has since sold the rights to the drug to its European partner, Immedica Pharma, but a group of experts is appealing to the FDA to give it another shot.

These experts, including Cederbaum, believe the FDA should leverage its accelerated approval pathway, which allows the regulator to exercise flexibility when a treatment proposed for a serious disease or condition demonstrates an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit.

“What we’re appealing [for] is accelerated approval,” said Cederbaum, who served as a one-time consultant to Aeglea and has followed the drug’s saga closely. “Given what we now know, and what has been demonstrated for us . . . when we get some of these patients back on therapy, they’re going to be the living proof that [pegzilarginase] really does help.”

Barriers to Approval

The reason the PEACE trial failed to meet the FDA’s bar for approval, Cederbaum said, is that many of the patients were older and had been diagnosed symptomatically only after severe and irreversible brain damage had occurred. PEACE enrolled 32 patients two years and older.

Cederbaum and his colleagues have collected video evidence showing that participants in Aeglea’s extension trials have deteriorated since going off of pegzilarginase. “In one case, a patient had not gotten particularly better, but when he got off the enzyme, he really just collapsed,” Cederbaum said. While the team feels they have substantial evidence to go back to the FDA, “what we’re now lacking is a supply of enzyme and a company to champion this.”

Cederbaum said he believes the FDA’s skepticism regarding pegzilarginase comes down to the question: has it been proven that increased levels of arginine and ammonia are the cause of ARG1-D and that bringing these levels down to normal is absolutely certain to be beneficial? The answer to that question, he said, is no. But “There is a mechanism now for dealing with this uncertainty, and that is accelerated approval.”

Emil Kakkis

Emil Kakkis, founder, president and CEO of Ultragenyx, a company that develops medicines for patients with rare and ultrarare diseases but has no direct involvement with Aeglea or Immedica, told BioSpace he got involved with the campaign for the drug’s approval because “I felt like arginase, if anything, is a poster child for the failure to use accelerated approval correctly at FDA.”

When asked by BioSpace if the FDA would consider showing flexibility in the case of pegzilarginase, an agency representative declined to comment on this case specifically but said that the FDA “recognizes the importance of facilitating the development of, and access to, safe and effective treatment options for life-threatening and severely debilitating diseases with unmet medical needs, such as arginase 1 deficiency.

“As such, we apply flexibility in these situations to address the particular challenges posed by each disease while upholding our regulatory standards,” the representative said.

While Kakkis said the FDA requested a trial longer than six months, he noted that getting 30 patients into a trial “was already a miracle.” With “a handful of patients” in the U.S. and at a cost of $300,000 to $500,000 per patient per year, it would be impossible to conduct another trial, he said. The only reason Aeglea was able to fund a pivotal trial with 30 patients is that when the company started in 2013, “the stock market was up in the biotech space, and they were able to raise money to work on a disease this rare.” Today, he said, that money doesn’t exist, and there is no way for a company to see a return on its investment.

The other problem with a longer trial, Kakkis said, is “If within six months, you know that the treated group is 90% normalized, it’s kind of unethical to keep the other group on placebo for a long period of time.”

Kakkis recommended that the FDA consider data from the open-label extension (OLE) study of Aeglea’s Phase I/II trial, where 13 patients were treated with pegzilarginase plus standard-of-care for 96 weeks. In an abstract of the study, published this year, the authors concluded that “clinically meaningful improvements in functional mobility” increased with continued pegzilarginase treatment. At the time of Aeglea’s BLA submission, 56-week data from this study was available. The BLA also included data from the ongoing OLE of the PEACE trial.

A Fundamental Problem

Kakkis is the author of Saving Ryan, which documents his race—along with Ryan’s father, Mark Dant—to gain approval for the first-ever treatment for mucopolysaccharidoses (MPS), a group of inherited lysosomal storage disorders.

“From that experience . . . I fundamentally recognized that there is a problem at FDA with dealing with ultra-rare diseases: scientifically knowing what to do with them, interpreting data and just a sort of cynical attitude,” he said.

The MPS treatment, Aldurazyme, was eventually developed by BioMarin and Genzyme and won FDA approval in 2003, “But honestly, it barely made it,” Kakkis said, due to what he called “obstruction of biomarker acceptance” by the regulator.

In 2009, Kakkis founded the EveryLife Foundation to accelerate innovation for rare diseases, which launched a campaign called CureTheProcess. The campaign, Kakkis said, focused on increasing FDA expertise in reviewing rare disease drugs and encouraging the regulator to accept alternative study designs and biomarkers “when the science underpinning them is very strong.”

The FDA representative said the agency “recognizes the unique challenges in rare disease product development and encourages drug developers to consider and discuss with FDA alternative study designs and biomarkers” for the development of these drugs.

Pegzilarginase is currently under review by the European Medicines Agency, and when announcing the sale of the rights to pegzilarginase to Immedica, Aeglea president and CFO Jonathan Alspaugh said the Swedish company would “seek to continue the dialogue with the FDA to discuss a path forward for [the drug] in the United States.”

Kakkis said the regulatory acceptance of biomarkers is critical in ultra-rare diseases. When dealing with a disease marker that represents the underlying disease, he said, “It’s not a random secondary measure. It’s actually the source of the disease.”

Heather McKenzie is a senior editor at BioSpace. You can reach her at Follow her on LinkedIn and X @chicat08.