Aeglea’s Pegzilarginase Hits Primary, but Misses Secondary, Endpoints in Phase 3 Study in Patients with Arginase 1 Deficiency

Aeglea BioTherapeutics reported that its engineered enzyme pegzilarginase met the primary endpoint in the pivotal phase 3 PEACE study in patients with the rare metabolic disease arginase 1 deficiency, with a statistically significant 80 percent reduction in plasma arginine from baseline after 24 weeks of treatment.

Photo: Anthony Quinn, president and CEO of Aeglea

However, the study failed to show statistically significant improvements in the secondary endpoint of improvement in Gross Motor Function Measure Part E (GMFM-E), a key clinical assessment of a patient’s mobility, including the ability to walk, run and jump, even though Aeglea said there was a positive trend in GMFM-E in the treatment group.

Shares of the company slumped 30 percent on the news.

Pegzilarginase is a novel recombinant human enzyme engineered to degrade the amino acid arginine and which 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.

There are currently no FDA-approved treatments that address elevated arginine, the key driver of ARG1-D. Current standard of care includes severe dietary protein restriction and essential amino acid supplementation, which does not effectively or sustainably reduce high arginine levels.

PEACE is the first placebo-controlled clinical trial ever conducted in ARG1-D and pegzilarginase is the first potential therapy to normalize the markedly elevated plasma arginine levels in these patients.

“I have been treating children born with ARG1-D for 20 years and what we are experiencing with pegzilarginase has truly given us a renewed sense of optimism,” said George Diaz, director, Program for Inherited Metabolic Disorders at Mount Sinai Hospital, New York, and PEACE trial principal investigator. “Clinicians recognize the importance of effective arginine control, and I am delighted that the PEACE pivotal trial demonstrated that pegzilarginase lowered plasma arginine to normal levels and showed a positive trend in an important mobility assessment of clinical benefit. I believe that, with early diagnosis and treatment intervention, families have a new reason to hope.”

PEACE is a global, randomized, double-blind, placebo-controlled trial that enrolled 32 patients with ARG1-D aged two years and older. The study was designed to assess the effects of treatment with pegzilarginase versus placebo from baseline through a prespecified 24-week treatment period. The primary endpoint assessed plasma arginine reduction from baseline levels. The key secondary endpoint evaluated mobility using GMFM-E, which consists of 24 tasks involving walking forward/backward, running, jumping and ascending/descending stairs, and the 2-Minute Walk Test (2MWT), a measure of the distance a patient walks in two minutes. Other secondary endpoints included additional outcome assessments, safety and pharmacokinetics.

PEACE demonstrated a highly statistically significant 80 percent reduction in mean plasma arginine in pegzilarginase treated patients, the primary endpoint of the trial. Importantly, normal plasma arginine levels were achieved in 90.5 percent of pegzilarginase treated patients compared to none of the patients in the placebo arm.

The least squares mean GMFM-E score improved by 4.2 units for pegzilarginase treated patients and worsened by 0.4 units in the placebo arm, establishing a positive trend in this mobility assessment. The least squares mean 2MWT distance increased 7.4 meters in pegzilarginase treated patients and 1.9 meters in the placebo arm. Neither of these secondary endpoints achieved statistical significance.

Pegzilarginase was well-tolerated and safety data were consistent with results from previous clinical trials. There were no study discontinuations due to adverse events.

All 31 patients who completed the 24-week double-blind study period continued into the Long-Term Extension (LTE) portion of the PEACE trial. In addition, 13 of the 14 patients in the ongoing phase 1/2 Open Label Extension (OLE) trial have continued pegzilarginase therapy ranging from 2 to 4 years. The previously presented 56-week data from the phase 1/2 OLE trial supports the long-term clinical benefit of pegzilarginase treatment. The company believes that the entirety of data from the pegzilarginase program supports the long-term clinical benefit of pegzilarginase in ARG1-D. Additional data from the pegzilarginase program are expected to be presented at upcoming medical meetings and submitted to peer-reviewed medical journals.

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.

“The dramatic reduction in plasma arginine levels and the positive trend in GMFM-E are very encouraging and represent an important step in our mission to bring a transformative therapy to this underserved patient community,” said Anthony Quinn, president and CEO of Aeglea. “We believe that today’s announcement demonstrates validation of our scientific platform, overall pipeline and potential to address other rare metabolic diseases.”

Based on the results of this trial, Aeglea plans to submit a Biologics License Application to the FDA in the first half of 2022. Additionally, Aeglea will work with Immedica Pharma AB, its commercial partner in Europe and certain countries in the Middle East, to submit marketing authorization applications in those territories.

Author: Rare Daily Staff