Aeglea BioTherapeutics, Inc. (NASDAQ: AGLE), a clinical-stage biotechnology company developing a new generation of human enzyme therapeutics to benefit people with rare metabolic diseases, today announced that it received a Refusal to File (RTF) letter from the U.S. Food and Drug Administration (FDA) regarding the company's Biologics License Application (BLA) for pegzilarginase for the treatment of Arginase 1 Deficiency (ARG1-D).

In the RTF letter the FDA 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 Type A meeting with the FDA to clarify and respond to the items identified in the RTF letter.

"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," said Anthony G. Quinn, M.B., Ch.B., Ph.D., president and chief executive officer of Aeglea. "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."

Dr. Quinn continued, "Without access to any approved therapies for ARG1-D, patients and their families face worsening outcomes and increasing challenges – every day matters to them. We believe pegzilarginase has the potential to help fulfill this unmet medical need. We remain committed to supporting the ARG1-D community and will continue our work to bring this potentially life-changing medicine to patients."

Immedica Pharma AB, Aeglea's commercialization partner for pegzilarginase in Europe and the Middle East, has recently met with the European Medicines Agency (EMA) regarding the Marketing Authorization Application (MAA) for pegzilarginase, which is planned to be submitted in 2022. 

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 novel, 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.

The BLA submission included 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. In the PEACE study, 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.

Pegzilarginase is a novel recombinant human enzyme engineered to degrade the amino acid arginine and has been shown to rapidly and sustainably lower levels of the amino acid arginine in plasma. Aeglea is developing pegzilarginase for the treatment of people with Arginase 1 Deficiency (ARG1-D), a rare debilitating and progressive disease characterized by the accumulation of arginine. ARG1-D presents in early childhood and patients experience spasticity, seizures, developmental delay, intellectual disability and early mortality.

The PEACE Phase 3 clinical trial met its primary endpoint with a 76.7% plasma arginine reduction. Additionally, 90.5% of pegzilarginase treated patients achieved normal plasma arginine levels. The arginine lowering was accompanied by a positive trend in Gross Motor Function Measure Part E, a measure of patient mobility. Aeglea's Phase 1/2 and Phase 2 Open-Label Extension data for pegzilarginase in patients with ARG1-D demonstrated clinical improvements and sustained lowering of plasma arginine. Pegzilarginase has received multiple regulatory designations, including Rare Pediatric Disease, Breakthrough Therapy, Fast Track and Orphan Drug designations from the U.S. Food and Drug Administration as well as Orphan Drug Designation from the European Medicines Agency.

Aeglea BioTherapeutics is a clinical-stage biotechnology company redefining the potential of human enzyme therapeutics to benefit people with rare metabolic diseases with limited treatment options. In December 2021, Aeglea announced positive topline data from its PEACE Phase 3 clinical trial for its lead product candidate, pegzilarginase, in patients with Arginase 1 Deficiency. Pegzilarginase has received both Rare Pediatric Disease and Breakthrough Therapy designations. Aeglea also has an ongoing Phase 1/2 clinical trial of AGLE-177 for the treatment of Homocystinuria. AGLE-177 has been granted Rare Pediatric Disease designation. Aeglea has an active discovery platform focused on engineering small changes in human enzymes to have a big impact on the lives of patients and their families. For more information, please visit http://aeglea.com.

This press release contains "forward-looking" statements within the meaning of the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. Forward-looking statements can be identified by words such as: "anticipate," "intend," "plan," "goal," "seek," "believe," "project," "estimate," "expect," "strategy," "future," "likely," "may," "should," "will" and similar references to future periods. These statements are subject to numerous risks and uncertainties that could cause actual results to differ materially from what we expect. Examples of forward-looking statements include, among others, statements we make regarding our ability to obtain regulatory approval for, and commercialize, pegzilarginase, recognize milestone and royalty payments from our agreement with Immedica, the timing and success of our clinical trials and related data, the timing and expectations for regulatory submissions and approvals, including the resubmission of our BLA for pegzilarginase and the timing of the MAA for pegzilarginase, timing and results of meetings with regulators, the timing of announcements and updates relating to our clinical trials and related data, our ability to enroll patients into our clinical trials, the expected impact of the COVID-19 pandemic on our operations and clinical trials, success in our collaborations, our cash forecasts, the potential addressable markets of our product candidates and the potential therapeutic benefits and economic value of our lead product candidate or other product candidates. Further information on potential risk factors that could affect our business and its financial results are detailed in our most recent Quarterly Report on Form 10-Q for the quarter ended March 31, 2022 filed with the Securities and Exchange Commission (SEC), and other reports as filed with the SEC. We undertake no obligation to publicly update any forward-looking statement, whether written or oral, that may be made from time to time, whether as a result of new information, future developments or otherwise.

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Kelly Boothe, Ph.D.
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