Aeglea's engineered enzyme flops outcomes test in rare metabolic disease. Is reducing a key biomarker enough for an approval?
Austin’s Aeglea BioTherapeutics is hoping to blaze a path reducing a key amino acid biomarker for a rare wasting metabolic disease with its engineered enzyme approach. But with a pivotal outcomes readout boding poorly for the drug’s benefit, Aeglea hopes it still has enough data on hand to catch the FDA’s eyes.
Aeglea’s pegzilarginase, a recombinant enzyme designed to degrade the amino acid arginine, hit its primary endpoint reducing arginine levels in the blood over placebo in patients with the rare metabolic disease arginase 1 deficiency (ARG1-D), the Austin-based biotech said Monday.
The 21 patients dosed with pegzilarginase posted an 80% reduction in mean plasma arginine over placebo at six months, good for a statistically significant p=<0.0001. Meanwhile, 90.5% of patients receiving the enzyme reached normal plasma arginine levels compared with no patients in the control arm.
The goal of the Phase III PEACE study was to demonstrate that significantly reducing elevated arginine levels — a therapeutic route with no FDA-approved treatments — would show a correlation with improved outcomes for patients with ARG1-D, which typically presents in early childhood with patients experiencing spasticity, seizures, developmental delay, intellectual disability and early mortality.
But those weren’t the results Aeglea turned up.
On two key secondary endpoints, including improvements in a two-minute walk test and a catch-all mobility test known as GMFM-E, peglizarginase failed to best placebo despite showing what Aeglea called “positive trends” on patient outcomes.
For the two-minute walk test, patients dosed with peglizarginase posted a mean increase in distance walked from baseline of 7.4 meters compared with an increase of 1.9 meters in control patients. That came out to an ugly p=0.5961, far below the bar for statistical significance. On the GMFM-E test, patients dosed with pegzilarginase showed a 4.2-unit increase over baseline compared with a 0.4-unit decline for placebo patients (p=0.1087).
“We are disappointed this isn’t a statistically significant result,” Aeglea Chief Development Officer Eric Bradford said on a call with analysts Monday. “It highlights the challenge of designing a study where there’s no clinical precedent.”
Aeglea said it didn’t flag any new safety concerns in the study and no patients dropping out due to dosing.
Even with no outcomes improvements to show, Aeglea thinks it has enough data in hand to go to the FDA for a ruling. The biotech said it plans to file a BLA in the first of the year and is planning concurrent marketing filings in the “certain countries in Europe and the Middle East” alongside partner Immedica Pharma AB.
Some of that optimism is tied to results from the open-label extension portion of a single-arm Phase I/II study, in which 11 of 14 patients showed improvements across a slate of three mobility tests at 56 weeks. Those results, of course, weren’t powered for significance and weren’t controlled, casting doubt on whether regulators will be convinced.
However, it wouldn’t be the first time the agency has given tacit approval to a surrogate endpoint without the outcomes data to back it up. From Biogen’s Aduhelm to Sarepta’s Exondys 51, the agency has at times handed out accelerated approvals based on a high degree of confidence a given biomarker will eventually lead to significant clinical benefit but without the actual benefits shown in patients.
In this case, Aeglea’s outcomes results are more explicit, likely leading the biotech to pitch a “totality of data” argument to regulators based on incremental improvements and a dearth of therapeutic options — an argument CEO Anthony Quinn highlighted during the team’s call with analysts.
Meanwhile, Aeglea has rolled the PEACE trial patients into a long-term extension portion, where Aeglea hopes to show sustained arginine reduction as well as improvements in clinical outcomes.