FDA Issues Refusal to File Letter for Pegzilarginase


The FDA is asking for additional data to support effectiveness of pegzilarginase to treat a rare metabolic disease. If approved, pegzilarginase would be the first treatment for ARG1 deficiency.

The FDA has issued a Refusal to File (RTF) letter for Aeglea BioTherapeutics’ biologics license application (BLA) for pegzilarginase for the treatment of arginase 1 deficiency (ARG1-D).

The FDA has requested additional data to support effectiveness, such as evidence showing that plasma arginine and metabolite reduction predicts clinical benefit in patients with ARG1-D or clinical data demonstrating a treatment effect on clinically meaningful outcomes.

The FDA also requested additional information relating to chemistry manufacturing and controls (CMC). There were no issues related to safety raised in the letter. Aeglea intends to request a meeting with the FDA to clarify and respond to the items identified in the RTF letter.

Anthony G. Quinn, M.B., Ch.B., Ph.D.

Anthony G. Quinn, M.B., Ch.B., Ph.D.

“We believe the requests identified in the RTF letter related to CMC can be readily addressed and we intend to work collaboratively with the FDA to identify a viable path forward to demonstrate that lowering plasma arginine confers clinical benefit,” Anthony G. Quinn, M.B., Ch.B., Ph.D., president and chief executive officer of Aeglea, said in a press release. "While we are disappointed in the outcome of the FDA’s initial review of our BLA, we continue to believe in the potential of pegzilarginase and thank the FDA for their constructive comments and ongoing collaboration.”

Arginase 1 deficiency is a rare, progressive and debilitating disease characterized by high levels of arginine. People living with ARG1-D experience severe spasticity-related mobility limitations, seizures, developmental delay, intellectual disability, and early mortality. There are currently no FDA-approved treatments for this indication. Pegzilarginase is a recombinant human arginase 1 enzyme that in clinical trials has been shown to normalize the elevated levels of the amino acid arginine in patients with ARG1-D.

Related: Aeglea Submits BLA for Pegzilarginase for Rare Metabolic Disease

The BLA was submitted in April 2022 and was based on positive results from Aeglea’s double-blind, placebo-controlled PEACE phase 3 study and its ongoing long-term extension study, as well as a phase 1/2 clinical trial and its open-label extension study. The totality of data demonstrates that pegzilarginase is able to rapidly and sustainably lower arginine levels and is accompanied by improvements in mobility.

The PEACE trial met its primary endpoint with a 76.7% plasma arginine reduction. Additionally, 90.5% of pegzilarginase-treated patients achieved normal plasma arginine levels. Most treatment-emergent adverse events were mild or moderate in severity and there were no discontinuations due to treatment-emergent adverse events.

The FDA has granted pegzilarginase multiple regulatory designations, including rare pediatric disease, breakthrough therapy, fast track and orphan drug designations.

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