8-K

UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

FORM 8-K

CURRENT REPORT

Pursuant to Section 13 or 15(d)

of the Securities Exchange Act of 1934

Date of Report (Date of earliest event reported): December 6, 2021

AEGLEA BIOTHERAPEUTICS, INC.

(Exact name of registrant as specified in its charter)

Delaware	001-37722	46-4312787
(State or other jurisdiction of incorporation)	(Commission File Number)	(IRS Employer Identification No.)

805 Las Cimas Parkway Suite 100 Austin, TX	78746
(Address of principal executive offices)	(Zip Code)

(512) 942-2935

(Registrant’s telephone number, including area code)

N/A

(Former name or former address, if changed since last report)

Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions:

☐	Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425)
☐	Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12)
☐	Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b))
☐	Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c))

Securities registered pursuant to Section 12(b) of the Act:

Title of each class	Trading symbol(s)	Name of each exchange on which registered
Common Stock, $0.0001 Par Value Per Share	AGLE	The Nasdaq Stock Market LLC (Nasdaq Global Market)

Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (§230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§240.12b-2 of this chapter).

Emerging growth company ☒

If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☒

Item 7.01 Regulation FD Disclosure.

On December 6, 2021, Aeglea Biotherapeutics, Inc. (the “Company”) issued a press release announcing updated data from its ongoing Phase 3 PEACE (Pegzilarginase Effect on Arginase 1 Deficiency Clinical Endpoints) trial for patients with Arginase 1 Deficiency. Additionally, the Company held a conference call and webcast with a presentation of the Phase 3 PEACE topline data.

A copy of the press release is attached as Exhibit 99.1 to this Current Report on Form 8-K. A copy of the presentation is attached as Exhibit 99.2 to this Current Report on Form 8-K.

The information furnished in this Item 7.01, including Exhibits 99.1 and 99.2, shall not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934, as amended (the “Exchange Act”), or otherwise subject to the liabilities of that section, nor shall it be deemed incorporated by reference into any other filing under the Exchange Act or the Securities Act of 1933, as amended, except as expressly set forth by specific reference in such a filing.

Item 8.01 Other Events.

On December 6, 2021, the Company announced updated data from its ongoing Phase 3 PEACE trial for patients with Arginase 1 Deficiency. Topline results are summarized as follows:

• PEACE achieved the primary endpoint of the clinical trial and demonstrated a highly statistically significant 80% reduction in mean plasma arginine in pegzilarginase-treated patients (p value <0.0001). Importantly, normal plasma arginine levels (40-115µM) were achieved in 90.5% of pegzilarginase-treated patients compared to none of the patients in the placebo arm (p value <0.0001).

• For the key secondary endpoints, improvements in walking, running and jumping were captured using Gross Motor Function Measure Part E, or GMFM-E, and an increase in walking distance with aids was captured using the 2-Minute Walk Test, or 2MWT. 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 (p value =0.1087; 95% CI [-1.1, 10.2]), 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 (p value =0.5961; 95% CI [-15.6, 26.7]).

• Pegzilarginase was well-tolerated and safety data were consistent with results from the Phase 1/2 and open-label extension clinical trials. There were five patients who experienced treatment related adverse events and four who experienced serious adverse events. No patients discontinued therapy due to adverse events.

Based on these results and the entirety of data from the pegzilarginase program, the Company plans to submit a Biologics License Application, or BLA, to the U.S. Food and Drug Administration, or FDA, in the first half of 2022. If approved, the Company intends to commercialize pegzilarginase in the United States with a small, focused field-based team and key supporting functions. Due to the highly concentrated number of specialists responsible for managing these patients, the Company anticipates an efficient sales force of fewer than 10 representatives.

This current report 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, 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 September 30, 2021 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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Item 9.01 Financial Statements and Exhibits.

(d) Exhibits.

Exhibit Number	Description
99.1	Press release by Aeglea Biotherapeutics, Inc.
99.2	Phase 3 PEACE Topline Presentation.
104	Cover Page Interactive Data File (embedded within the Inline XBRL document)

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SIGNATURE

Pursuant to the requirements of the Securities Exchange Act of 1934, as amended, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.

	AEGLEA BIOTHERAPEUTICS, INC.
Date: December 6, 2021	By:	/s/ Jonathan Alspaugh
		Jonathan Alspaugh
		Chief Financial Officer

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EX-99.1

Exhibit 99.1

 Aeglea BioTherapeutics Announces Achievement of Primary Endpoint in Phase 3 Study of Pegzilarginase in Patients with Arginase 1 Deficiency

80% plasma arginine reduction (primary endpoint; p < 0.0001) accompanied by a positive trend in GMFM-E, a key clinical assessment of patient mobility

90.5% of patients achieved normal plasma arginine levels

Pegzilarginase was well-tolerated; no discontinuations due to adverse events

First potential therapy to address key driver of ARG1-D, a devastating ultra-rare disease

Plan to submit BLA in first half of 2022

Company to host conference call and webcast today at 8:00am EST

AUSTIN, Texas, December 6, 2021 -- Aeglea BioTherapeutics, Inc. (NASDAQ: AGLE), a clinical-stage biotechnology company developing a new generation of human enzyme therapeutics as innovative solutions for rare metabolic diseases, today announced that the pivotal Phase 3 study, PEACE (Pegzilarginase Effect on Arginase 1 Deficiency Clinical Endpoints), met the primary endpoint with a statistically significant reduction in plasma arginine from baseline after 24 weeks of treatment with pegzilarginase (p <0.0001). Importantly, pronounced and sustained plasma arginine reduction was accompanied by a positive trend 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.

PEACE is the first placebo-controlled clinical trial ever conducted in Arginase 1 Deficiency (ARG1-D) and pegzilarginase is the first potential therapy to normalize the markedly elevated plasma arginine levels in these patients. Based on the results of this trial, Aeglea plans to submit a Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA) in the first half of 2022. Additionally, Aeglea will work with Immedica Pharma AB, its commercial partner in certain countries in Europe and the Middle East, to submit marketing authorization applications in those territories.

“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. These children and their families live with a daily burden of not only managing the progressive manifestations of the disease, including mobility limitations, intellectual disability and behavior challenges, but also a burdensome standard of care. A better treatment paradigm for these patients is desperately needed,” said Dr. George Diaz, Director, Program for Inherited Metabolic Disorders at Mount Sinai Hospital, New York, NY 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 also 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.”

ARG1-D is a rare, progressive and debilitating disease characterized by high levels of the amino acid arginine. The disease manifestations include spasticity, developmental delay, intellectual disability and seizures. The functional disability and impact on daily life creates a significant burden for patients and caregivers. 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 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 (n=21) versus placebo (n=11) 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. Topline results are summarized as follows:

• PEACE demonstrated a highly statistically significant 80% reduction in mean plasma arginine in pegzilarginasetreated patients (p<0.0001), the primary endpoint of the trial. Importantly, normal plasma arginine levels (40-115µM) were achieved in 90.5% of pegzilarginasetreated 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 (p=0.1087; 95% CI [-1.1, 10.2]), 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 (p=0.5961; 95% CI [-15.6, 26.7]).

• 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.

“I would like to thank the patients and their caregivers, investigators and staff, and our employees for their contributions to the study. 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 G. Quinn, M.B., Ch.B., Ph.D., president and chief executive officer of Aeglea. “We believe that today’s announcement demonstrates validation of our scientific platform, overall pipeline and potential to address other rare metabolic diseases.”

Conference Call

Investors and the public are invited to listen to a live audio webcast of the conference call, scheduled for December 6, 2021, at 8:00am ET, which may be accessed five minutes prior to the start of the call by dialing 1-877-425-9470 (U.S.) or 1-201-389-0878 (International) Conference ID 13725511 or through the Events & Presentations section of the Company’s website. 

To access live and/or archived Investor Conference webcasts, visit the Events & Presentations section of the Company's website. A replay of Company webcasts is archived on the website for 60 days following presentations.

About the Phase 3 PEACE Study

PEACE is a single, global, randomized, double-blind, placebo-controlled trial that enrolled 32 patients aged 2 years and older with Arginase 1 Deficiency in the United States, Canada and Europe (NCT03921541). PEACE was designed to assess the effects of treatment with pegzilarginase versus placebo over 24 weeks with a primary endpoint of plasma arginine reduction from baseline. Secondary endpoints include clinical outcome assessments focused on several mobility assessments, in addition to safety and pharmacokinetics. Patients were randomized on a two-to-one basis to receive weekly infusions of pegzilarginase, or placebo for the double-blind 24-week treatment period.

About Pegzilarginase in Arginase 1 Deficiency

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.

Aeglea’s Phase 1/2 and Phase 2 Open Label Extension (OLE) data for pegzilarginase in people 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.

About Aeglea BioTherapeutics

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. Aeglea's lead product candidate, pegzilarginase, is in an ongoing Phase 3 pivotal trial in patients with Arginase 1 Deficiency and has received both Rare Pediatric Disease and Breakthrough Therapy designations. Aeglea 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.

Safe Harbor / Forward Looking Statements

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 submission of a BLA 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 financial results are detailed in our Annual Report on Form 10-K for the year ended December 31, 2020 and our most recent Quarterly Report on Form 10-Q for the quarter ended September 30, 2021 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.

Contact Information:

Investors

Kelly Boothe, Ph.D.

Senior Director, Corporate Communications & Investor Relations

512.399.5458

investors@aeglea.com

media@aeglea.com

Media

Mike Beyer

312.961.2502

media@aeglea.com

EX-99.2

Reimagining The Potential Of Human Enzyme Therapeutics PEACE Phase 3 Topline Study Results – December 6, 2021 Exhibit 99.2

Forward Looking Statements ©2021 Aeglea BioTherapeutics. External 2 This presentation and the accompanying oral presentation contain “forward-looking” statements that are based on our management’s beliefs and assumptions and on information currently available to management. Forward-looking statements include all statements other than statements of historical fact contained in this presentation, including information concerning our current and future financial performance, business plans and objectives, current and future clinical and preclinical development activities, timing and success of our ongoing and planned clinical trials and related data, the timing of announcements, updates, results of our clinical trials and related data and our planned BLA submission for our lead product candidate pegzilarginase, our ability to obtain and maintain regulatory approval, the potential therapeutic benefits, safety profile and economic value of pegzilarginase and our other product candidates, potential growth opportunities, financing plans, use and adequacy of financing plans, competitive position, industry environment and potential market opportunities.   Forward-looking statements are subject to known and unknown risks, uncertainties, assumptions and other factors including, but not limited to, those related to the success, cost and timing of our product candidate development activities and ongoing and planned clinical trials; our plans to develop and commercialize targeted therapeutics, including our lead product candidate pegzilarginase and our product candidates for the treatment of homocystinuria and cystinuria; the design, progress of patient enrollment and dosing in our clinical trials; the ability of our product candidates to achieve applicable endpoints in clinical trials; the safety profile of our product candidates in clinical trials; the potential for data from our current and future clinical trials to support a marketing application, as well as the timing of these events; the potential for preclinical studies to be predictive of current or future clinical trials; our ability to obtain funding for our operations, development and commercialization of our product candidates; the impact of the COVID-19 pandemic on our operations and clinical development activities, including on the timing of enrollment of our clinical trials; the timing of and our ability to obtain and maintain regulatory approvals; our ability to obtain regulatory approval for, and commercialize, pegzilarginase, and recognize milestone and royalty payments from our licensing and supply agreement with Immedica; the potential for expedited development and review of pegzilarginase as a result of its Breakthrough Therapy designation; the potential addressable markets of our product candidates; the rate and degree of market acceptance and clinical utility of our product candidates; the size and growth potential of the markets for our product candidates, and our ability to serve those markets; our commercialization, marketing and manufacturing capabilities and strategy; future agreements with third parties in connection with the potential commercialization of our product candidates; our expectations regarding our ability to obtain and maintain intellectual property protection; our dependence on third party manufacturers; our ability to develop our own commercial manufacturing facility; the success of competing therapies that are or may become available; our ability to attract and retain key scientific or management personnel; our ability to identify additional product candidates with significant commercial potential consistent with our commercial objectives; and our estimates regarding expenses, future revenue, capital requirements and needs for additional financing. Moreover, we operate in a very competitive and rapidly changing environment, and new risks may emerge from time to time. It is not possible for our management to predict all risks, nor can we assess the impact of all factors on our business or the extent to which any factor, or combination of factors, may cause actual results to differ materially from those contained in any forward-looking statements we may make. In light of these risks, uncertainties and assumptions, the forward-looking events and circumstances discussed herein may not occur and actual results could differ materially and adversely from those anticipated or implied in the forward-looking statements. Further information on these and other factors that could affect these forward-looking statements is contained in our most recent Quarterly Report on Form 10-Q filed with the U.S. Securities and Exchange Commission (SEC) and other reports filed by the SEC. You should not rely upon forward-looking statements as predictions of future events. Although our management believes that the expectations reflected in our forward-looking statements are reasonable, we cannot guarantee that the future results, levels of activity, performance or events and circumstances described in the forward-looking statements will be achieved or occur. We undertake no obligation to publicly update any forward-looking statements, whether written or oral, that may be made from time to time, whether as a result of new information, future developments or otherwise.

PEACE Phase 3 Study of Pegzilarginase in Patients with ARG1-D ©2021 Aeglea BioTherapeutics. External 3 Thank you to all the patients, families, investigators and study staff who participated in the PEACE study

PEACE Phase 3 Topline Study Results Pegzilarginase in Arginase 1 Deficiency Draft for Internal Discussion Only

©2021 Aeglea BioTherapeutics. External 5 First Potential Therapy to Normalize Plasma Arginine Levels in ARG1-D Lowering Plasma Arginine Accompanied by Improvement in Mobility Pivotal Data Supports Planned BLA Submission in First Half of 2022 Substantial Reduction in Plasma Arginine Impact on Mobility Favorable Safety Profile Primary Endpoint Met 80% reduction in plasma arginine at 24-week analysis (p<0.0001)ǂ  Additional Evidence of Arginine Control 90.5% of patients achieved normal plasma arginine levels (p<0.0001)*  Positive Trend In Mobility Assessment GMFM-E mean score improved by 4.2 units with pegzilarginase and worsened by 0.4 units with placebo Least squares mean difference of 4.6 units (p=0.1087) Well-Tolerated Safety data consistent with results from previous clinical trials No treatment discontinuations due to adverse events GMFM-E = Gross Motor Function Measure Part E which is comprised of 24 individual tasks of walking, running and jumping, each scored from 0 to 3 for a total possible score of 72; ARG1-D = Arginase 1 Deficiency; ǂgeometric mean; *nominal p value

PEACE Phase 3 Study Design ©2021 Aeglea BioTherapeutics. External 6 *Dosing is weekly and, if needed, dose is modified based on plasma arginine levels with maintenance of blinding. ǂThe first 8 weeks of the open-label extension will be blinded. All study participants remain on current disease management for the duration of the trial. Dose adjustments in the double-blind treatment period can be made to optimize plasma arginine control for levels outside the range of 50-150µM. If needed, weekly doses can be increased to 0.15 and 0.2 mg/kg or reduced to 0.05mg/kg ARG1-D = Arginase 1 Deficiency; IV = intravenous; R = randomized. Patients with ARG1-D ≥2 years old Plasma arginine >250 µM (mean) Baseline deficit in clinical response assessments Placebo IV R 2:1 Long Term Extensionǂ Pegzilarginase 0.1 mg/kg* IV 24 weeks Up to 150 weeks n=11 N=32 n=21 N=31

PEACE Baseline Demographics ©2021 Aeglea BioTherapeutics. External 7 Demographic Characteristic Pegzilarginase n=21 Placebo n=11 Overall N=32 Age at Enrollment, y Mean (SD) 9.6 (6.16) 12.9 (6.77) 10.7 (6.47) Range 2-28 5-29 2-29  Age Category, n (%) 2y to less than 6y 5 (23.8) 1 (9.1) 6 (18.8) 6y to less than 12y 8 (38.1) 4 (36.4) 12 (37.5) 12y to less than 18y 7 (33.3) 4 (36.3) 11 (34.4) 18y or older 1 (4.8) 2 (18.2) 3 (9.4) Sex, n (%) Male 12 (57.1) 7 (63.6) 19 (59.4) Female 9 (42.9) 4 (36.4) 13 (40.6) Region, n (%) U.S. 8 (38.1) 6 (54.5) 14 (43.8) Ex-U.S. 13 (61.9) 5 (45.5) 18 (56.3)

PEACE Baseline Clinical Characteristics ©2021 Aeglea BioTherapeutics. External 8 *Based on arithmetic mean Clinical Characteristic Pegzilarginase n=21  Placebo  n=11 Overall  N=32 Plasma Arginine, µM/L Mean* (SD) 365.4 (93.7) 471.7 (79.9) 402.0 (101.8) Median (range) 368.2 (202-572) 483.7 (294-573)  398.2 (202-573) GMFCS level, n (%) 1 9 (42.9) 5 (45.5) 14 (43.8) ≥2 12 (57.1) 6 (54.5) 18 (56.2) GMFM-E Mean (SD) 48.3 (19.9) 46.5 (24.6) 47.7 (21.5) Median (range) 53 (5-71) 56 (0-72) 54 (0-72) 2MWT Mean (SD) 109 (55.7) 99.9 (49.0) 105.8 (52.8) Median (range) 122 (2-202) 102 (0-171) 118 (0-202)

©2021 Aeglea BioTherapeutics. External 9 Highly elevated plasma arginine despite standard of care Mean plasma arginine* Pegzilarginase Baseline: 365.4 µM 24-week: 105.5 µM Placebo Baseline: 471.7 µM 24-week: 448.8 µM Primary Endpoint – 24-Week Analysis 80% reduction in mean plasma arginine with pegzilarginase  (p<0.0001)ǂ  Primary Endpoint Met – Marked and Sustained Reduction in Plasma Arginine Reduction in Plasma Arginine* *Based on arithmetic mean of values from visit and preceding 3 visits, boxes represent middle 50% with error bars depicting 95% confidence interval; ǂStatistical analysis based on geometric mean` Clinical Guideline 0 70 140 280 350 420 490 560 630 700 Pegzilarginase (n=21) Placebo (n=11) Arginine (µM) Baseline 12 Weeks 24 Weeks

90.5% of pegzilarginase treated patients achieved normal plasma arginine levels (p<0.0001)* No meaningful change in plasma arginine levels in placebo arm Treatment with pegzilarginase surpassed current clinical guideline goals of reducing arginine levels below 200 µM ©2021 Aeglea BioTherapeutics. External 10 Normalization of Plasma Arginine Levels in ARG1-D Patients Proportion of Patients Reaching Normal Arginine Levels (40-115 µM) Potential Transformative Therapy for a Patient Population with Previously Unachievable Control of Arginine to Normal Levels * Nominal p value, based on arithmetic mean of values from visit and preceding 3 visits 100% 80% 60% 40% 20% 0% 0% 0% 47.6% 0% 85.7% 0% 90.5% 0% Baseline 6 Weeks 12 Weeks 24 Weeks Pegzilarginase (n=21) Placebo (n=11)

©2021 Aeglea BioTherapeutics. External 11 Gross Motor Function Measure (GMFM) Part E Assesses unaided mobility without bracing or assistive devices 24 tasks involving walking forward/backward, running, jumping and ascending/descending stairs, each scored from 0 to 3 with a total score range of 0-72 PEACE Key Mobility Measurements 2-Minute Walk Test Evaluates aided mobility with any needed bracing or assistive devices over a defined period of time

Positive Trend in GMFM-E in Pegzilarginase Treated Patients ©2021 Aeglea BioTherapeutics. External 12 Mean Change from Baseline in GMFM-E Positive Trend in GMFM-E in Placebo Controlled Study Suggests Potential Improvements in Mobility Mean Change from Baseline (units) Pegzilarginase Placebo 12 Weeks 24 Weeks 12 Weeks 24 Weeks 2.9 4.2 -0.4 -3.2 -5 0 5 Time LS Mean Difference P Value 12 Weeks 6.4 units p=0.0568 24 Weeks 4.6 units p=0.1087

©2021 Aeglea BioTherapeutics. External 13 Mobility Assessment by 2-Minute Walk Test 6MWT – Six Minute Walk Test 2MWT = 2-Minute Walk Test  Mean Change from Baseline in 2MWT 6.8 -7.5 7.3 2.7 -10 0 10 Pegzilarginase Placebo Mean Change from Baseline (m) Pegzilarginase Placebo 12 Weeks 24 Weeks 12 Weeks 24 Weeks Mobility Assessment by 2-Minute Walk Test 6MWT –Six Minute Walk Test 2MWT = 2-Minute Walk TestTime LS Mean Difference P Value 12 Weeks 14.1 meters p=0.2085 24 Weeks 5.5 meters p=0.5961

©2021 Aeglea BioTherapeutics. External 14 PEACE Safety Profile * TEAE: Treatment-Emergent Adverse Event; ǂ SAE: Serious Adverse Event; ♢ Adverse Event of Interest Pegzilarginase was Well-Tolerated with No Discontinuations Due to Adverse Events Patients With: Pegzilarginase n (%) Placebo n (%) Any TEAE * 18 (85.7) 11 (100.0) Drug-related TEAE 5 (23.8) 1 (9.1) TEAE Leading to Discontinuation 0 0 SAE ǂ 4 (19.0) 4 (36.4) Hypersensitivity Reaction ♢ 2 (9.5) 0 Hyperammonemia ♢ 3 (14.3) 4 (36.4)

©2021 Aeglea BioTherapeutics. External 15 First Potential Therapy to Normalize Plasma Arginine Levels in ARG1-D Lowering Plasma Arginine Accompanied by Improvement in Mobility Pivotal Data Supports Planned BLA Submission in First Half of 2022 Substantial Reduction in Plasma Arginine Impact on Mobility Favorable Safety Profile Primary Endpoint Met 80% reduction in plasma arginine at 24-week analysis (p<0.0001)ǂ  Additional Evidence of Arginine Control 90.5% of patients achieved normal plasma arginine levels (p<0.0001)*  Positive Trend In Mobility Assessment GMFM-E mean score improved by 4.2 units with pegzilarginase and worsened by 0.4 units with placebo Least squares mean difference of 4.6 units (p=0.1087) Well-Tolerated Safety data consistent with results from previous clinical trials No treatment discontinuations due to adverse events GMFM-E = Gross Motor Function Measure Part E which is comprised of 24 individual tasks of walking, running and jumping, each scored from 0 to 3 for a total possible score of 72; ARG1-D = Arginase 1 Deficiency; ǂgeometric mean; *nominal p value

Robust Data Package Generated For Pegzilarginase Program ©2021 Aeglea BioTherapeutics. External 16 Clinical Data Manufacturing Regulatory Designations PEACE demonstrated normalization of elevated plasma arginine levels accompanied by a positive trend in mobility assessment Favorable long-term data from Phase 1/2 OLE, consistent with PEACE results Additional PEACE LTE data available to support filing U.S. Rare Pediatric Disease (PRV eligible) Breakthrough Therapy U.S. and EU Orphan Drug Fast Track Robust straightforward biologics manufacturing process Well understood regulatory CMC path Commercial formulation on stability Substantial Derisking of Path to Successful Commercial Launch OLE = open label extension; LTE = long-term extension

©2021 Aeglea BioTherapeutics. External 17 ARG1-D Patient Needs Not Adequately Addressed by Standard of Care Current standard of care: Severe dietary protein restriction Amino acid supplementation Ammonia scavengers Current disease management is inadequate: Limited effectiveness Challenging to maintain Doesn’t address non-dietary sources of arginine Key Areas of Unmet Medical Need in ARG1-D No Treatments or Approved Therapies that Effectively Reduce Arginine Levels

©2021 Aeglea BioTherapeutics. External 18 Attractive Commercial Opportunity for Pegzilarginase in ARG1-D Severe and progressive disease with early mortality Easily diagnosed but often missed due to lack of awareness Standard of care provides poor control of plasma arginine levels No approved therapies to address high arginine levels Significant Unmet Need Estimated Prevalence of >2,500 Patients in Key Global Markets United States >250 patients Western Europe and Middle East1 >900 patients Rest of World >1,350 patients (including 700 in LatAm, 400 in Asia Pacific) 1 Licensing and supply agreement signed with Immedica Pharma AB in March 2021; countries in agreement include European Economic Area, United Kingdom, Switzerland, Andorra, Monaco, San Marino, Vatican City, Turkey, Saudi Arabia, United Arab Emirates, Qatar, Kuwait, Bahrain and Oman.

©2021 Aeglea BioTherapeutics. External 19 Building the Foundation for a Successful Launch and Enduring Commercial Presence Patient Identification Accelerating the diagnosis and identification of patients through ongoing HCP engagement Disease Education and Awareness Driving HCP dialogue about the devastating and progressive nature of ARG1-D Access and Reimbursement Ensuring payer understanding of the significant clinical and economic burden of ARG1-D Organizational Readiness Establishing an internal mindset and infrastructure to meet the needs of the ARG1-D patient community

©2021 Aeglea BioTherapeutics. External 20 Committed to Delivering Innovative Therapies for Patients in Need Countries included in Immedica license and supply agreement – European Economic Area, United Kingdom, Switzerland, Andorra, Monaco, San Marino, Vatican City, Turkey, Saudi Arabia, United Arab Emirates, Qatar, Kuwait, Bahrain and Oman. Significant Patient Need Debilitating and progressive disease with significant burden No effective treatments currently available Estimated worldwide patient prevalence of >2,500 patients in global addressable markets (including >250 in U.S.) Demonstrated Clinical Impact 80% reduction in plasma arginine in pegzilarginase treated patients at 24-week analysis 90.5% of patients achieved normal plasma arginine levels Positive trend in key mobility assessment of clinical benefit Well tolerated; safety data consistent with results from previous clinical trials Advancing Commercial Efforts Patient identification: outpacing relevant benchmarks, driving diagnosis Disease education and awareness: accelerating disease understanding among key specialties Access and reimbursement: articulating disease burden and pegzilarginase value proposition •Organizational readiness: ongoing efforts to prepare for approval and successful launch –U.S.: Building commercial infrastructure –Ex-U.S.: Continued progress in EU/ME with Immedica, ongoing ROW partnership focus

©2021 Aeglea BioTherapeutics. External 21 Aeglea’s Human Enzyme Platform for Rare Metabolic Diseases 1 Ex-U.S. license and supply agreement with Immedica to commercialize pegzilarginase in Europe and certain countries in the Middle East (European Economic Area, United Kingdom, Switzerland, Andorra, Monaco, San Marino, Vatican City, Turkey, Saudi Arabia, United Arab Emirates, Qatar, Kuwait, Bahrain and Oman) 2 ARG1-D case reports ; Diez-Fernandez et al. Mutations and common variants in the human arginase 1 (ARG1) gene: impact on patients, diagnostics and protein structure considerations. Hum Mutat. 2018 Aug;39(8):1029-10502. 3 >30,000 represents estimated prevalence of Classical Homocystinuria in 38 addressable markets based on results of U.S. ICD-10 claims analysis extrapolated to global markets; all figures rounded. Sellos-Moura et al 2020 4 Castro Pereira DJ et al 2015; Leslie and Nazzal Renal Calculi (Cystinuria, Cystine Stones) (2018) Reference; Rozanski et al, Mil Med (2005); Soucie et al, JM Kidney Int (1994); Claes & Jackson, Pediatr Nephrol (2012) 27, 2031; Chillarón, J. et al. Nat. Rev. Nephrol. 2010, 6, 7, 424-34; Biyani, C.S and Cartledge, J.J. EAU-EBU Update Series, 2006, 4, 175-183; Mattoo, A. and Goldfarb D.S. 2008 Sem. Nephrol, 28, 2, 181-191

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805 Las Cimas Parkway Suite 100 Austin, TX 78746 aeglea.com

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Document and Entity Information	Dec. 06, 2021
Cover [Abstract]
Document Type	8-K
Amendment Flag	false
Document Period End Date	Dec. 06, 2021
Entity Registrant Name	AEGLEA BIOTHERAPEUTICS, INC.
Entity Central Index Key	0001636282
Entity Emerging Growth Company	true
Entity Ex Transition Period	true
Entity Incorporation, State or Country Code	DE
Entity File Number	001-37722
Entity Tax Identification Number	46-4312787
Entity Address, Address Line One	805 Las Cimas Parkway
Entity Address, Address Line Two	Suite 100
Entity Address, City or Town	Austin
Entity Address, State or Province	TX
Entity Address, Postal Zip Code	78746
City Area Code	512
Local Phone Number	942-2935
Written Communications	false
Soliciting Material	false
Pre-commencement Tender Offer	false
Pre-commencement Issuer Tender Offer	false
Title of 12(b) Security	Common Stock, $0.0001 Par Value Per Share
Trading Symbol	AGLE
Security Exchange Name	NASDAQ